General synthesis route to benanomicin-pradimicin antibiotics

Article abstract of DOI:10.1002/chem.200700863

A general approach to the regio- and stereoselective total synthesis of the benanomicin-pradimicin antibiotics (BpAs) is described. Construction of the aglycon has been achieved by 1)the diastereoselective ring-opening of a biaryl lactone by using (R)-val

Full text of DOI:10.1002/chem.200700863

FULL PAPER
DOI: 10.1002/chem.200700863
General Synthesis Route to Benanomicin-Pradimicin Antibiotics
Minoru Tamiya,[a] Ken Ohmori,[a] Mitsuru Kitamura,[a, b] Hirohisa Kato,[a]
Tadamasa Arai,[a] Mami Oorui,[a] and Keisuke Suzuki*[a]
Dedicated to the memory of Professor Tsuguo Mizuochi
Abstract: A general approach to the
regio- and stereoselective total synthe-
sis of the benanomicin-pradimicin anti-
biotics (BpAs) is described. Construc-
tion of the aglycon has been achieved
by 1) the diastereoselective ring-open-
ing of a biaryl lactone by using (R)-va-
linol as a chiral nucleophile and 2) the
stereocontrolled semi-pinacol cycliza-
tion of the aldehyde acetal by using
SmI2 in the presence of BF3·OEt2 and a
proton source to afford the ABCD tet-
racyclic monoprotected diol. This strat-
egy enabled us to control the two ste-
reogenic sites in the B ring (C-5 and C-
6) and the regioselective introduction
of the carbohydrate moiety. The
ABCD tetracycle could serve as an
ideal platform for the divergent access
to various BpAs. The amino acid (d-
alanine) was introduced onto the
ABCD tetracycle. Glycosylation was
promoted by the combination of
Cp2HfCl2 and AgOTf (1:2 ratio). Con-
struction of the E ring followed by de-
protection completed the first total
synthesis of benanomicin A (2a), bena-
nomicin B (2b), and pradimicin A
(1a). The route is flexible enough to
allow the synthesis of other congeners
differing in their amino acid and carbo-
hydrate moieties.
Keywords: antibiotics · benanomi-
cin · natural products · pradimicin ·
total synthesis
Introduction
Because of these intriguing biological properties as well
as their structural novelty, the synthetic community,[3] which
includes our group,[4–7] has focused considerable attention on
the BpAs. This paper will detail our efforts towards the syn-
thesis of BpAs with particular emphasis on the new strat-
The benanomicin-pradimicin antibiotics (BpAs) were isolat-
ed from the culture of the Actinomyces species in 1988 by
two independent groups.[1] To date, more than 20 congeners
have been identified (Figure 1) that share a unique struc-
ture, which consists of a benzo[a]naphthacene core with dif-
ferent amino acid and disaccharide moieties. Their potent
antifungal and anti-HIV activities are attributed to Ca2+
-
mediated specific binding to the mannose-rich oligosacchar-
ides presented on fungi or virus surfaces, and therefore, they
are called “lectin-mimics”.[2]
[a]Dr. M. Tamiya, Dr. K. Ohmori, Dr. M. Kitamura, Dr. H. Kato,
T. Arai, M. Oorui, Prof. Dr. K. Suzuki
Department of Chemistry, Tokyo Institute of Technology
SORST-JST, 2-12-1 O-okayama, Meguro-ku
Tokyo 152-8551 (Japan)
Fax : (+81)3-5734-2788
E-mail: ksuzuki@chem.titech.ac.jp
[b]Dr. M. Kitamura
Current Address: Department of Applied Chemistry
Kyushu Institute of Technology
1-1 Sensui, Tobata-ku, Kitakyushu, Fukuoka 804-8550 (Japan)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Figure 1. Structures of the benanomicin-pradimicin antibiotics.
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egies and tactics developed during the course of this syn-
thetic study.
In planning the total synthesis of the BpAs, three prob-
lems were considered: 1) The construction of the densely
functionalized pentacyclic chromophore, 2) the control of
the diol stereochemistry in the B ring, and 3) the regioselec-
tive introduction of the sugar moiety.
Scheme 2. Pinacol cyclization strategy.
To our delight, initial attempts to solve the diastereocon-
trol problem immediately gave positive results.[5] Reaction
Results and Discussion
[9]
of biaryl dialdehyde 3[8] with SmI2 cleanly afforded trans-
Strategic considerations
diol 4[10] as the sole product [Eq. (1)]. Consistently high
yields and trans selectivity were attained in the intramolecu-
lar pinacol coupling reaction of various biaryl dialdehydes
by using various reducing agents (cf. Sm, V, Ti).[5] In particu-
lar, SmI2 gave excellent trans selectivity.
Pseudo-symmetry problem: The major challenge in this
whole synthetic venture was the regio- and stereochemical
control of the vicinal diol at C-5 and C-6 with pseudo-sym-
metry. To highlight the essence of the problem, Scheme 1
shows a hypothetical route based on the asymmetric epoxi-
dation of benzo[a]naphthacene core A (Step 1) followed by
hydrolytic epoxide cleavage (Step 2). Even if Step 1 oc-
curred with high enantiofacial selectivity, Step 2 must occur
regioselectively to obtain the enantiopure diol. This would
not be straightforward because the two ends of the epoxide
have similar reactivities, both are benzylic and there is little
difference in the sterics in the vicinity of the epoxide
moiety. In addition, even if this pseudo-Cs-symmetry prob-
lem were somehow managed, one must confront the
pseudo-C2 symmetry of the resulting diol, which would raise
the problem of regioselective installation of the carbohy-
drate moiety (Step 3) that would once again not be a trivial
issue.
The clue to enantiocontrol was obtained when pinacol
cyclization was applied to chiral, nonracemic biaryl dialde-
hyde 5. For example, reaction of (M)-5 with SmI2 gave a
quantitative yield of the trans-diol (S,S)-6 [Eq. (2)]. Thus,
the axial stereochemistry in 5 was completely transmitted
into the stereogenicities of trans-diol 6.[11]
Stereochemical clues from model studies: With these issues
in mind, we became interested in another possible route to
the stereogenic diol motif, that is, the pinacol cyclization of
a biaryl dialdehyde (Scheme 2). The problems of diastereo-
and enantiocontrol need to be addressed for this particular
approach to be valid.
Scheme 1. Hypothetical route to BpAs based on a three-step protocol.
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Synthesis of Benanomicin-Pradimicin Antibiotics
FULL PAPER
Additional information: During the structure determination
of diol 6, we discovered an interesting fact concerning its
axial stereochemistry. Diacetate 7, which was derived from
diol 6, has a low barrier (ca. 15 kcalmolꢀ1) for conforma-
tional flipping, as estimated by variable-temperature NMR
spectroscopy [Eq. (3)].[5] The ratio of 7diequatorial and 7diaxial at
ꢀ408C was about 1:1.
This observation was in line with the pioneering work of
Mislow and Harvey who reported that the flipping barrier
of tethered biaryl B (DG° =24.1 kcalmolꢀ1) is much lower
than that of the nontethered counterpart C (DH° =50.8 kcal
molꢀ1, calculated; Figure 2).[12a] In general, a two-atom
bridge renders the biaryl configurationally labile, allowing
the interconversion of B and ent-B, in sharp contrast to the
behavior of nontethered biaryl C.
Figure 3. Three-step strategy for the construction of the tetrol substruc-
ture.
Although the axial stereochemistry, set inertly during the
formation of F from E, becomes labile again in G, the ste-
reochemical interplay between the stereochemistry of the
diol and the biaryl axis results in the preservation of stereo-
chemical information.[10a,12]
Retrosynthetic analysis: Scheme 3 shows our retrosynthetic
analysis of the BpAs, which starts with the fragmentation of
the target into three moieties, a sugar, an amino acid, and
aglycon I. By assuming that the B ring would be constructed
by the pinacol cyclization reaction, the enantiopure biaryl
dialdehyde II was set as the precursor, which could in princi-
ple be available by the asymmetric ring-opening reaction of
lactone III pioneered by Bringmann and co-workers.[14] To
cope with the sterically encumbered biaryl bond formation
between the anthracene and the A ring segment, we envi-
Figure 2. Properties of biaryl compounds.
Such properties of tethered biaryls (configurationally
labile) and tetra-ortho-substituted biaryls (configurationally
inert) inspired us to envision a three-step strategy for a ste-
reocontrolled access to the key tetrol structure H embedded
in the target molecules (Figure 3): 1) Biaryl lactone E, even
if it is sterically encumbered, would be available by taking
ꢀ
sioned an intramolecular biaryl C C bond formation (cf.
Figure 3).[13] Ester IV could be further dissected into anthra-
cene VI and the orsellinic acid derivative V. Anthracene VI
would be constructed by the Diels–Alder reaction of naph-
thoquinone VIII with diene VII.[15]
ꢀ
advantage of intramolecular C C bond formation in the
ester precursor D (Step 1),[13] 2) chiral biaryl dialdehyde F
would be obtained by the Bringmann-type asymmetric
cleavage of the configurationally labile lactone E[14] by em-
ploying a chiral, nonracemic reagent (Step 2), and 3) dihy-
drophenanthrenetetrol G could be constructed by stereospe-
cific pinacol cyclization of enantioenriched biaryl dialdehyde
F (Step 3).
First-generation total synthesis
Initial approach to the aglycon: Based on these analyses, A-
ring segment 14 was synthesized from the known orsellinic
acid derivative 8 (Scheme 4).[16] Phenol 8 was converted into
triflate 9 by selective triflation of the phenol para to a me-
thoxycarbonyl group followed by protection of the remain-
ing phenol as a methoxymethyl (MOM) ether. Carbonyla-
This strategy takes advantage of the stereochemical labili-
ty of lactone E to drive the enantioselective ring-opening
completely to a single enantiomer of F, which subsequently
undergoes stereospecific pinacol coupling to trans-diol G.
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K. Suzuki et al.
Scheme 3. Retrosynthetic analysis.
Scheme 5. Preparation of the CD-ring segment (unless otherwise noted,
the reactions were performed at ambient temperatures). Reagents and
conditions: a) 19, LiCl, DBU, CH3CN, 20 h, 77% (E/Z=20:1);
b) CF3CO2H, H2O, 3.5 h, 90%; c) NaOAc, Ac2O, 1408C, 30 min, 99%;
Scheme 4. Preparation of the A-ring segment (unless otherwise noted,
the reactions were performed at ambient temperatures). Reagents and
conditions: a) PhNTf2, K2CO3, acetone, 24 h, 70%; b) MOMCl, iPr2NEt,
d) Ce
N
G
diazabicyclo
AHCTREUNG
CH2Cl2, 5.5 h, quant; c) Pd
A
3 h, quant; d) LiBH4, THF, 24 h, 98%; e) MOMCl, iPr2NEt, CH2Cl2, 3 h,
88%; f) CF3CO2H, CH2Cl2, 08C, 3 h, 99%; g) BnMe3N+ICl2ꢀ, NaHCO3,
MeOH, CH2Cl2, 08C, 10 h, 83%. Tf=trifluoromethanesulfonyl, DPPF=
diphenylphosphinoferrocene.
action of 15 with phosphonate 19[19] gave the corresponding
unsaturated ester, the tert-butyl ester of which was selective-
ly hydrolyzed under acidic conditions to give unsaturated
acid 17.[20] Treatment of 17 with acetic anhydride in the pres-
ence of sodium acetate afforded naphthalene 18a,[20,21]
which corresponds to the CD-ring system.
To annulate the E ring, naphthalene 18a was oxidized to
the corresponding naphthoquinone 20a in preparation for a
Diels–Alder reaction with siloxydiene 21 (Table 1).[15] Be-
cause the regioselectivity of the Diels–Alder reaction of 1,4-
naphthoquinones is highly sensitive to the substitution pat-
tern, we tested four related quinones 20a–d with different
protecting groups (R) for comparison purposes.
tion of triflate 9 in the presence of phenol afforded phenyl
ester 10.[17] Selective reduction of the phenyl ester in 10 was
cleanly achieved with LiBH4 without affecting the methyl
ester moiety to give alcohol 11, which was protected as bis-
MOM ether 12. Acid treatment of 12 gave selective removal
of the MOM protecting group of the phenol to give 13 and
ꢀ
its iodination by using BnMe3N+ICl2 gave iodophenol
14.[18]
Synthesis of the CDE-ring segment started with commer-
cially available aldehyde 15 (Scheme 5). Wittig–Horner re-
The reactions were conducted by adding diene 21 to a so-
lution of quinone 20a–d in THF at 08C. After stirring for
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Synthesis of Benanomicin-Pradimicin Antibiotics
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Table 1. Diels–Alder reactions of quinone 20a–d.
Entry
Substrate
R
Hydrolysis
22:22’:23
Yield[b] [%]
conditions[a]
1
2
3
4
5
20a
20b
20c
20d
20b
Ac
MOM
Me
H
MOM
SiO2
SiO2
SiO2
SiO2
2:0:1
4:3:1
34:1:0
0:0:1
1:0:0
34
40
59
49
84
nBu4NF
[a]In THF at 0 8C, 7 h. [b]Combined yield of 22, 22’, and 23.
Scheme 6. Preparation of biaryl lactone 28 (unless otherwise noted, the
reactions were performed at ambient temperatures). Reagents and condi-
tions: a) Cs2CO3, BnBr, DMF, 7.5 h, 89%; b) Na2S2O4, cat. nBu4NBr,
THF, 30 min; c) Me2SO4, 50% aq. KOH, 1 h, 98% (2 steps); d) 5m aq.
KOH, EtOH, reflux, 1.5 h, 91%; e) 2,4,6-trichlorobenzoyl chloride, Et3N,
toluene, 3 h, then 14, DMAP, 0.5 h, 94%; f) CF3CO2H, CH2Cl2, 2 h, 87%;
7 h at room temperature, acidic silica gel was added to hy-
drolyze the silyl acetal. The resulting ketone underwent tau-
tomerization and spontaneous air-oxidation to afford a
varied mixture of desired anthraquinone 22, undesired
methyl ether 22’, and undesired regioisomer 23 (entries 1–
3). When 20d was used as the substrate, only undesired re-
gioisomer 23 was obtained (entry 4).[22]
g) Pd
N
N
Bn=benzyl, TMS=trimethylsilyl, DMAP=4-dimethylaminopyridine,
DMA=N,N-dimethylacetamide.
For ease later in the synthesis (for deprotection of the R
group in 22 in the palladium-mediated cyclization reaction,
cf. Scheme 6) and to optimize the regioselectivity of the
Diels–Alder reaction, we decided to employ MOM ether
20b as the substrate for the synthesis. The remaining prob-
lems in this context were the low yield and the presence of
another mode of acetal cleavage that produces methyl ether
22’. TLC analysis suggested that the cycloaddition step pro-
ceeded without a problem and it seemed that the low yield
stemmed from the workup conditions: 1) The hydrolysis of
the silyl acetal, 2) the tautomerization step to the hydroqui-
none, and 3) the oxidation step.
the resulting ester was treated with CF3CO2H to detach the
MOM group to give ester 27 in high yield. Because ester 27
turned out to be rather labile, easily undergoing color
change upon exposure to air and/or light, it was immediately
subjected to the palladium-mediated cyclization reaction.[13]
After careful optimization, we were able to obtain lactone
28 in a yield of 64% by using Pd(OCOCF3)2. Unfortunately,
A
handling of this advanced intermediate 28 was even more
difficult, particularly in terms of its air-sensitivity, and there-
fore, we decided to abandon this synthetic route.
Extensive optimization studies revealed a protocol that
would achieve smooth conversion to desired anthraquinone
22 with complete regioselectivity (entry 5). Thus, upon treat-
ment of the crude cycloadduct with nBu4NF under air in
THF, the color changed from yellow to purple, and after
several minutes, the color returned to light yellow, which
gave the anthraquinone 22 in a yield of 84%.
Anthraquinone 22, thus obtained, was converted into an-
thracene 26 because the quinone moiety would be incompat-
ible with the reductive conditions of the pinacol cyclization
reaction (Scheme 6). After protection of the phenol in 22,
the resulting benzyl ether 24 was subjected to reductive di-
methylation to afford anthracene 25, which was hydrolyzed
to give carboxylic acid 26.
Successful pathway to aglycon: Recognizing the instability of
anthracene derivatives, we decided to postpone the con-
struction of the E ring until a later stage of the synthesis
(Scheme 7). To secure the regioselectivity of the Diels–
Alder reaction with siloxydiene 21, we planned to introduce
a chlorine atom (X=Cl) into the CD-ring precursor VIII’
en route to the ABCD-ring segment IX.
Chloronaphthalene 32, the CD-ring intermediate,[4a] was
synthesized from the known compound 29[25] (Scheme 8).
Regioselective hydroxymethylation of 29 under Casiraghi
conditions,[26] followed by methylation of the phenol, and
MnO2 oxidation of the benzylic alcohol afforded benzalde-
hyde 30. The same sequence of reactions, which was already
described for the conversion of 15 into 18 (see Scheme 5),
was applied to aldehyde 30 to give naphthalene 31 in an
overall yield of 76%. Hydrolysis of ester 31 gave carboxylic
acid 32 in a yield of 87%.
With A-ring segment 14 and CDE-ring segment 26 in
hand, their combination was attempted. After esterification
of 14 and 26 by using 2,4,6-trichlorobenzoyl chloride,[23,24]
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K. Suzuki et al.
prone to hydrolysis during purification by silica gel column
chromatography. Lactone 34, which was once obtained in a
small amount, was stable as a crystalline material. In spite
of various attempts to improve the workup procedure, we
were unable to find a suitable protocol for the high-yielding
formation of 34. At this juncture, we opted to reduce the
crude product of 34 with NaBH4 to obtain alcohol 35 in a
yield of 86%. Thus, at this stage, the opportunity for the
planned asymmetric lactone-opening was lost and we decid-
ed to resort to optical resolution as an alternative means of
obtaining the requisite biaryl enantiomer.
Scheme 10 shows the optical resolution protocol. After
detachment of the MOM group in 35, the benzyl alcohol
Scheme 7. Naphthalene route.
Scheme 8. Preparation of the CD-ring segment (unless otherwise noted,
the reactions were performed at ambient temperatures). Reagents and
conditions: a) (HCHO)n, Me2AlCl, CH2Cl2, 5 h, 93%; b) Me2SO4, K2CO3,
acetone, reflux, 13 h, 91%; c) MnO2, CH2Cl2, 408C, 17 h, 90%; d) NaH,
19, THF, 08C!RT, 1 h; e) CF3CO2H, H2O, 40 min; f) NaOAc, Ac2O,
reflux, 1 h, 76% (3 steps); g) 3m aq. NaOH, THF, EtOH, 708C, 1 h,
87%.
Scheme 10. Optical resolution protocol. Reagents and conditions: a) 6m
aq. HCl, DME, 3 h, 508C, 93%; b) TBSCl, imidazole, DMF, RT, 25 min,
84%; c) (1S,4R)-(ꢀ)-camphanoyl chloride, DMAP, pyridine, RT, 20 h;
separation by silica gel column chromatography (see text), 38%. DME=
1,2-dimethoxyethane, TBS=tert-butyldimethylsilyl.
Joining the A-ring segment 14 and the CD-ring segment
32 was achieved by using a water-soluble carbodiimide
(EDCI: 1-(3-dimethyaminopropyl)-3-ethylcarbodiimide hy-
drochloride) to give ester 33, which was ready for biaryl
bond formation (Scheme 9). After considerable optimiza-
tion, the palladium-catalyzed cyclization of ester 33 proceed-
ed smoothly in the presence of sodium pivalate to give tetra-
cycle 34.[13] However, the product 34 turned out to be highly
moieties in the resulting tetrol were protected by TBS
groups to give bis-phenol 36, which was treated with (ꢀ)-
(1S,4R)-camphanoyl chloride. Esterification occurred selec-
tively at the phenol ortho to the methoxycarbonyl in the A
ring to give a diastereomeric mixture of monoesters 37a and
37b. Column chromatography (SiO2, hexane/EtOAc=7:3)
allowed separation of these diastereomers, which gave the
more polar isomer 37a (Rf =0.34, hexane/EtOAc=7:3;
38%) and the less polar isomer 37b (Rf =0.42, hexane/
EtOAc=7:3; 40%), respectively. Isomer 37a possessed the
requisite M configuration.[27]
The requisite diastereomer 37a was then converted in two
steps into enantiopure tetrol (M)-38 (Scheme 11). After pro-
tection of the phenols in (M)-38 as methyl ethers, the re-
maining benzyl alcohols were oxidized to afford enantiomer-
ically pure biaryl dialdehyde (M)-39.[28] Upon treatment of
(M)-39 with SmI2 (08C, THF, 10 min), the pinacol cycliza-
tion reaction proceeded smoothly to afford trans-diol 40 as a
single product in quantitative yield with high stereoselectiv-
ity (>99% enantiomeric excess (ee)), as shown by HPLC
analysis.[29] The circular dichroism (CD) measurement re-
vealed an absolute configuration of 5S,6S for trans-diol
Scheme 9. Preparation of triol 35. Reagents and conditions: a) EDCI,
DMAP, CH2Cl2, RT, 3 h, 78%; b) Pd
A
1108C, 1.5 h; c) NaBH4, THF, MeOH, ꢀ408C, 3 h, 86% (2 steps).
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Synthesis of Benanomicin-Pradimicin Antibiotics
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Scheme 11. Synthesis of benanomicinone methyl ester (unless otherwise noted, the reactions were performed at ambient temperatures). Reagents and
conditions: a) HF, CH3CN, 08C!RT, 45 min, 97%; b) K2CO3, MeOH, 19 h, quant; c) MeI, K2CO3, acetone, 408C, 11 h, 91%; d) MnO2, CH2Cl2, 26 h,
79%; e) SmI2, THF, 08C, 10 min, quant; f) Ac2O, pyridine, DMAP, 20 min, 98%; g) Ce
N
N
THF, 08C!RT, 2 h; i) SiO2, 12 h; j) K2CO3, THF, CH2Cl2, 2.5 h, 90% (3 steps); k) BCl3, CH2Cl2, ꢀ108C, 30 min, 99%; l) 2m aq. NaOH, 708C, 2.5 h;
m) d-alanine methyl ester·HCl, BOP, Et3N, DMF, 1.5 h, 80% (2 steps).
40.[10] Pleasingly, the axial stereochemistry in 39 was com-
pletely transmitted into the stereogenicities of trans-diol 40.
For elaborating tetracycle 40 into the pentacyclic full
carbon skeleton, the two hydroxy groups were protected as
presumably owing to the presence of the quinone moiety,
the handling of 45 was especially difficult.
Condensation of acid 45 with d-alanine methyl ester was
effected by using benzotriazol-1-yloxytris(dimethylamino)-
phosphonium hexafluorophosphate (BOP) in DMF, which
gave benanomicinone methyl ester (46) in a yield of 80%
from 45, which was identical to an authentic specimen.[30]
diacetate 41. Reaction of 41 with Ce
N
N
effected the selective oxidation of the D ring to afford a
quantitative yield of chloroquinone 42, which was then sub-
jected to the Diels–Alder reaction with siloxydiene 21 to an-
nulate the E ring.[15]
Glycosylation study—towards the formation of benanomicin
B: With aglycon 46 in hand, the stage was set for the final
installation of the carbohydrate moiety. Considering the po-
tential problems expected from the presence of the quinone
functionality (e.g., deactivation of the Lewis acid used for
the glycosylation,[31] poor solubility), we chose to reduce the
oxidation level of the aglycon moiety (Scheme 12). Accord-
ing to the procedure of Oki and co-workers, conversion of
anthraquinone 46 into the corresponding anthraquinone di-
acetate 48 was carried out.[2g] After protection of the 1,2-
diol in 46 as an acetonide, the resulting product was subject-
ed to reductive acetylation (acetic anhydride, zinc powder,
pyridine) to afford anthracene 47, in which all of the phe-
nols as well as two hydroquinone phenoxides, reductively
generated in situ, were fully acetylated. Again, careful han-
dling was required to cope with the sensitive nature of the
anthracene derivative to light and oxygen after the quinone
functionality of 46 had been reduced. Careful removal of
the acetonide and purification afforded pentacycle 48 in a
yield of 68% (three steps), which was ready for glycosylation.
We were pleased to find that the following optimized pro-
tocol enabled the formation of pentacycle 43 in high yield.
This method for E-ring annulation turned out to be highly
reliable and was repeatedly employed in the later syntheses
(cf. Scheme 17, Scheme 19, and Scheme 20).
A solution of siloxydiene 21 in THF was added to a solu-
tion of 42 in THF at 08C and stirring was continued until
the consumption of the starting material was complete
(TLC assay, 2 h). The resulting silyl acetal was selectively
hydrolyzed by treatment with acidic silica gel. Elimination
of HCl was achieved with K2CO3 to give naphthacenequi-
none 43 in a yield of 90% from 42. Note that the chloro
group played two roles: 1) To direct the regioselective cyclo-
addition and 2) to facilitate the aromatization.
Having pentacycle 43 in hand, selective removal of the
methyl ethers proximal to the carbonyl groups was readily
achieved with BCl3 to give ester 44, which was saponified to
give carboxylic acid 45. Compounds 44–46 were scarcely
soluble in solvents other than water, DMF, and/or DMSO,
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K. Suzuki et al.
1
as a red solid. As the H NMR spectrum proved highly de-
pendent on the pH, the concentration, and the temperature,
identification of 2b was not an easy issue. However, its iden-
tification was finally achieved by the measurement of a
1H NMR spectrum of a sample that contained a mixture of
synthetic and authentic 2b at a low pH (ca. 3.5).[35]
Second-generation total synthesis
Improved strategies for the regio- and stereocontrolled total
synthesis of BpAs: In the total synthesis described above,
two issues remained unsolved (Figure 4): 1) The axially
Figure 4. The two remaining tasks for the fully-controlled total synthesis.
Scheme 12. Glycosylation study and synthesis of benanomicin B (unless
otherwise noted, the reactions were performed at ambient temperatures).
Reagents and conditions: a) CH2=C(OCH3)CH3, TsOH·H2O, DMF, 18 h;
A
chiral biaryl dialdehyde (M)-39 was only obtained by tedi-
ous optical resolution, which inevitably produced the useless
enantiomer (P)-39 and 2) the sugar moiety was introduced
with poor regioselectivity, originating from the approximate
C2-symmetric structure. Seeking a fully controlled total syn-
thesis, we next addressed these two problems.[4b]
b) Ac2O, Zn, pyridine, 10 h, 73% (2 steps); c) TsOH·H2O, CH3CN, H2O,
2 h, 93%; d) fluoride 51, Cp2HfCl2/AgClO4 (1:2), MS4A, CH2Cl2, ꢀ128C,
25 min, 44% (49/50=3:2); e) H2, Pd/C, 1m aq. HCl, MeOH, 6 h; f) 1m
aq. NaOH, MeOH, 2 h, then 2m aq. HCl, 68% (2 steps). Ts=p-toluene-
sulfonyl.
Control of axial stereochemistry: Our original plan to tackle
the first problem, that is, the control of axial stereochemis-
try, involved using the Bringmann-type asymmetric ring-
opening of the biaryl lactone.[14] This strategy was, however,
hampered by the difficulty in preparing the related lactone
34 as a result of its high lability to hydrolysis during silica
gel chromatography (cf. Scheme 9). Thus, the prerequisite
was the preparation of the lactone itself, which had seemed
hopeless in the early phase of our investigation.
Fortunately, however, the following protocol enabled us
to achieve this goal (Scheme 13). After Yamaguchi esterifi-
cation of carboxylic acid 52 with the A-ring segment 53
(TIPS was used as the protecting group of the benzyl alco-
hol (TIPS: triisopropylsilyl)), the MOM protecting group of
the resulting ester was removed by CF3CO2H to afford the
ester 54, which was subjected to the palladium-catalyzed
cyclization reaction. Again, lactone product 55 was highly
labile to hydrolysis during purification by silica gel chroma-
tography. However, addition of water to the reaction mix-
ture at 08C effected the precipitation of lactone 55 as fine
needles that were collected by filtration. The overall yield
from 52 was 59% in three steps.[34]
Benanomicin B (2b) was selected as the initial target. In
accordance with the results of model studies on the glycosi-
dation of glycosyl fluoride 51, Cp2HfCl2 and AgClO4 (1:2
ratio) were used in combination as promoters.[32,33] A sus-
pension of Cp2HfCl2 and AgClO4 in the presence of molecu-
lar sieves (MS4A) in CH2Cl2 was stirred at room tempera-
ture for 10 min and chilled to ꢀ788C. A CH2Cl2 solution of
glycosyl fluoride 51 and diol 48 was added to this mixture.
Reaction at ꢀ128C for 25 min afforded two regioisomeric b-
glycosides 49 and 50 in yields of 26 and 18%, respectively
(Scheme 12). Extensive NMR studies, which included
HMBC and HMQC analyses, showed that 49 was the neces-
sary regioisomer for the total synthesis.[34] Although unfortu-
nate, the poor regioselectivity at this stage was not surpris-
ing if one took into consideration the approximate C2 sym-
metry of the diol.
In any event, the final stage of the total synthesis was ex-
amined. After reduction of the azide in 49 by hydrogenolysis
in the presence of aqueous HCl, treatment with 1m aqueous
NaOH accomplished the detachment of all of the acyl
groups and hydrolysis of the methyl ester. The reaction mix-
ture was acidified with 2m aqueous HCl (pH 3.5) to afford
the final product, benanomicin B hydrochloride (2b·HCl),
Prior to asymmetric ring-opening, we observed the dy-
namic behavior of lactone 55 by using variable-temperature
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Synthesis of Benanomicin-Pradimicin Antibiotics
FULL PAPER
With the requisite lactone 55 in hand, asymmetric ring-
opening was examined (Table 2). For the enantioselective
Table 2. Enantioselective biaryl lactone ring-opening.
Entry Reductant Chiral modifier
Yield ee
Recovery
–
[%]
[%] [%]
1
BH3·SMe2
B
A
10
pyrrolidine-2-methanol
N,N-dibenzoylcysteine
N,N-dibenzoylcysteine
diethyl l-tartrate
diethyl l-tartrate
l-valine
Scheme 13. Preparation of biaryl lactone 55. Reagents and conditions:
a) 2,4,6-Trichlorobenzoyl chloride, Et3N, DMAP, toluene, RT, 20 min,
2
3
4
5
6
LiBH4
NaBH4
LiBH4
NaBH4
NaBH4
17
57
–
–
5
–
0
2
42
–
–
40
–
99%; b) CF3CO2H, CH2Cl2, RT, 3.5 h, 99%; c) Pd(OAc)2, PPh3, tBu-
A
[a]
CO2Na, DMA, 1108C, 20 min, 60%.
40
8[b]
[a]No reaction. [b]Amide 57a was obtained in a yield of 54% with a
1H NMR analysis of lactone 55 (Figure 5). At ꢀ158C, a sin-
glet was observed at 4.95 ppm, which could be assigned to
the benzyl protons. Upon cooling, the peak broadened and
finally started to split at ꢀ758C (coalescence temperature)
and two peaks appeared upon further cooling (ꢀ958C).
The estimated barrier for the conformational interchange
was DG° =9.8 kcalmolꢀ1, which indicated an extremely
facile interconversion between enantiomers (P)-55 and (M)-
55.
90:10 diastereomeric ratio.
ring-opening of 55, we first applied borane reduction cata-
lyzed by a chiral oxazaborolidine which, unfortunately, gave
poor
enantioselectivity
(entry 1). The enantioselectivi-
ties were also disappointing in
reactions carried out with
LiBH4 or NaBH4 in the pres-
ence of various stoichiometric
chiral modifiers, such as N,N-
dibenzoylcysteine
(entries 2
and 3)[36] and diethyl l-tartrate
(entries 4 and 5).[37] However,
an unexpected but important
pointer was obtained when l-
valine
was
employed
the
(entry 6).[38]
Although
result from the reaction itself
was again poor (8% yield, 2%
ee), the formation of a sizable
amount of a polar by-product
was noted which was identified
as amide 57a, that is, the direct
addition product of l-valine.
Importantly, amide 57a was
highly enriched in one of the
diastereomers (90:10 diastereo-
meric ratio).
This finding encouraged us
to pursue the diastereoselec-
tive ring-opening of 55 by
1
Figure 5. Variable-temperature H NMR spectra of 55.
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K. Suzuki et al.
using various stoichiometric chiral nucleophiles (Table 3).
Of course, the first choice was l-valine in the absence of
NaBH4. However, no reaction occurred, presumably as a
result of the insolubility of the amino acid in less polar or-
Indeed, such an N,O acyl rearrangement happens without
mutation of the axial stereochemistry. Upon retreatment
with valinol, isolated ester 58 (d.r. 3:2) was converted into
amide 57c in a yield of 86% (d.r. 3:2).[39] Thus, albeit a
minor path, the competing O-
Table 3. Diastereoselective biaryl lactone ring-opening.
addition process, which gave
ester 58, serves as an indirect
supplier of amide 57c, al-
though with a lower diastereo-
meric ratio.
To eliminate this stereode-
teriorating O-addition path-
way, the O-methylated valinol
Entry
R
R’
Ratio[a]
Temperature[b]
[8C]
Time
[h]
Product
Yield
[%]
derivative was used. However,
a very slow and nonselective
ring-opening was observed,
after one month amide 57d
was obtained in a yield of
82% with a 1:1 diastereomeric
ratio (entry 5). Thus, the hy-
droxy group in the amino alco-
hol is essential for the smooth
progress of the reaction and
for high diastereoselection.
Fortunately, optimization ex-
periments showed that the re-
action temperature was deci-
sive. The reaction at 08C for
43 h gave the best result to
afford a yield of 90% of amide
57c in a diastereomeric ratio
of 91:9 (entry 6). The O-addi-
tion pathway seemed to be less
pronounced under these condi-
tions.
[c]
1
2
3
4
5
6
7
8
9
CO2H
CO2Et
iPr
iPr
iPr
iPr
iPr
iPr
tBu
Bn
Me
Me
–
RT
RT
RT
RT
0
0
0
0
0
–
–
–
70:30
90:10
86:14
50:50
91:9
85:15
86:14
76:24
45:55
120
1.8
11
720
43
37
56
15
48
57b
57c
57c
57d
57c
57e
57 f
57g
57h
51
72[d]
88
82
90
92
79
79
79
CH2OH
CH2OH
CH2OMe
CH2OH
CH2OH
CH2OH
CH2OH
CH(Ph)OH[e]
10
0
[a]The ratio was determined by 1H NMR analysis. [b]RT =room temperature. [c]No reaction. [d]Ester 58
was obtained in a yield of 14% (3:2 d.r.). [e]( ꢀ)-Norephedrine was employed.
Hoping for further enhance-
ganic solvents such as CH2Cl2 (entry 1). When l-valine ethyl
ester was used as a “soluble nucleophile”, a slow reaction
proceeded, which gave the ring-opened product in a yield of
51%, albeit with poor stereoselectivity (entry 2).
ment of the diastereoselectivity, other amino alcohols, such
as tert-leucinol, phenylalaninol, alaninol, and norephedrine,
were also examined, but their use only resulted in lower se-
lectivities (entries 7–10).
A breakthrough came with the use of an amino alcohol;
treatment of lactone 55 with (S)-valinol at room tempera-
ture for 1.8 h gave amide 57c in a yield of 72% in a diaste-
reomeric ratio (d.r.) of 90:10 (entry 3). Although the result
was adequate, the material balance was low. TLC inspection
(TLC A, Table 3) showed three new polar spots (Rf =0.38,
0.25, and <0.1, hexane/EtOAc=1:1), the first two spots cor-
respond to the minor/major diastereomers of amide 57c and
the most polar product corresponds to a small amount
(14%) of the O-addition product 58 formed with a low dia-
stereomeric ratio (3:2).
In contrast, when the reaction was prolonged (11 h), ester
58 disappeared (see TLC B, Table 3) and only amide 57c
was obtained in an improved yield (88%) with a slightly
lower diastereomeric ratio (84:16, entry 4). We ascribed this
phenomenon to the in situ conversion of ester 58 into amide
57c.
In summary, (S)-valinol turned out to be the best chiral
nucleophile for this diastereoselective biaryl lactone ring-
opening process. The structure of the major isomer of 57c
was unambiguously established by single-crystal X-ray anal-
ysis. After separation of the diastereomers of 57c by column
chromatography (silica gel, hexane/EtOAc=1:2), the major
isomer of 57c gave single crystals suitable for X-ray analysis
(Figure 6).[40] The biaryl axis was revealed to have the P con-
figuration, which was the wrong stereochemistry for our syn-
thetic purposes (cf. Scheme 11).
Thus, (R)-valinol was proven to be the right enantiomer
for establishing the requisite M configuration in the biaryl
intermediate in the total synthesis (see Scheme 15).
Discrimination of the 1,2-diol moiety: To address the pivotal
issue of diol discrimination at the B ring, we planned a
semi-pinacol cyclization (Scheme 14). The hope was that
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Synthesis of Benanomicin-Pradimicin Antibiotics
FULL PAPER
Table 4. Attempts at the semi-pinacol cyclization reaction.
Entry Acid
Additive Yield Entry Acid Additive Yield
[%]
[%]
[a]
[b]
1
2
3
4
5
BF3·OEt2
BF3·OEt2
BF3·OEt2 MeOH
TMSOTf
TMSOTf
–
H2O
–
6
7
8
9
TiCl4
TiCl4
TfOH
TfOH
–
H2O
–
–
Figure 6. X-ray structure of the major isomer of 57c. Hydrogen atoms
have been omitted for clarity.
85
95
32[d]
–
[b]
–
H2O
–
H2O
29[e]
71[c]
[a]The yield of 60 fluctuated, varying between 0 and 70%, and sizable
amounts of by-products were produced. [b]Many unidentified by-prod-
ucts were produced. [c]Acetal 61 was obtained in a yield of 21%. [d]Di-
aldehyde 64 was obtained in a yield of 60%. [e]Acetal 61 was obtained
in a yield of 41%.
Scheme 14. Semi-pinacol cyclization strategy.
mono-masked diol XII would be accessible from the acetal
aldehyde XI by activation with an acid (e.g., Lewis acid)
and a net two-electron reduction. If the strategy proved to
be viable then the product would be ideally suited to regio-
selective installation of the sugar moiety.[6] Of course, we ex-
pected that a careful choice of the reaction conditions would
be necessary because the timing between the generation of
the oxocarbenium intermediate (XI!XIII) and net two-
electron reduction (XIII!XII) would be critical.
source. In all cases (entries 4–9), compound 60 was only
formed when H2O was added to the reaction (entries 5, 7,
and 9), otherwise a complex mixture was produced (en-
tries 4, 6, and 8). When TMSOTf was employed with H2O,
compound 60 was formed in a yield of 71% along with
acetal 61 (entry 5). In the case of a combination of TiCl4
and H2O, the yield of 60 decreased to 32% and was accom-
panied by the formation of dialdehyde 64 (entry 7). TfOH
was also used as a Brønsted acid in the presence of H2O.
The yield of 60 was 29% with 61 was also formed in a yield
of 41% (entry 9).
With this scenario in mind, we began extensive modeling
studies[6] by using acetal aldehyde 59 as the substrate
(Table 4). The first attempt proceeded smoothly by treat-
ment of (ꢁ)-59 with SmI2 in the presence of BF3·OEt2.[41]
[9]
Thus, SmI2 in THF (0.1m) was added to a solution of (ꢁ)-59
and BF3·OEt2 in degassed THF at ꢀ788C. Stirring at 08C
for 30 min afforded cyclized product 60 in a yield of 70% in
a fully trans-selective manner. However, this key reaction
turned out to be capricious because all of the subsequent at-
tempts suffered from poor reproducibility; the yields fluctu-
ated widely in the range of 0 to 70% with concomitant for-
mation of varying amounts of by-products (e.g., cyclic acetal
61, aldehyde 62, alcohol 63, and/or dialdehyde 64), even
with slight changes in the reaction parameters (entry 1).
After numerous unfruitful experiments, we finally found
that the presence of a suitable proton source was the key to
securing reproducibility. In the presence of H2O, the reac-
tion occurred cleanly to give semi-pinacol 60 in a yield of
85% (entry 2) and methanol proved to be even more effec-
tive (entry 3).
In summary, BF3·OEt2 turned out to be the best acid for
the semi-pinacol cyclization reaction.
To gain a further insight into this transformation, the reac-
tion was monitored by time-resolved IR spectroscopy
(Figure 7). Thus, in a solution of 59 in THF at ꢀ788C, ab-
sorptions were observed that are characteristic of the C=O
stretching of the methoxycarbonyl (1732 cmꢀ1) and formyl
groups (1698 cmꢀ1). Amazingly, these signals persisted at
ꢀ788C even after the addition of BF3·OEt2, MeOH, and
SmI2 (Time A).
However, when the reaction temperature was raised to
08C (Time B), the absorption at 1698 cmꢀ1 disappeared with
the emergence of a strong absorption at 1572 cmꢀ1 which
could be assigned to the stretching vibration of a ketyl radi-
ꢀ
[42]
C
cal ( C-O ) species.
This observation suggested that the one-electron reduc-
tion of the formyl group to form the ketyl radical species is
the initial step, though the precise mechanism still remains
uncertain.
As the need for a proton source for the facile formation
of 60 is clearly evident from entries 2 and 3, other acids
were also examined in the absence/presence of a proton
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K. Suzuki et al.
R,M configurations was isolated as yellow crystals (1.9 g) by
silica gel column chromatography and recrystallization.
After the selective benzylation of the two phenolic hy-
droxy groups in the amide (R,M)-57c, the hydroxy amide
moiety in the resulting bis-benzyl ether 65 was cyclized
(PPh3, I2, imidazole), which gave oxazoline 66 in quantita-
tive yield. After N-methylation of 66, the activated C=N
bond underwent facile reduction with l-Selectride, and the
resulting N,O-acetal was hydrolyzed by exposure to silica
gel to give aldehyde 67 in a yield of 96%.[43] Conversion of
67 into the corresponding dibenzyl acetal,[44] followed by de-
tachment of the silyl protection, and MnO2 oxidation afford-
ed the enantiopure acetal aldehyde (M)-59, which was ready
for the key cyclization reaction.[45]
Figure 7. Time-resolved IR monitoring (React-IR) of the semi-pinacol re-
action of 59.
SmI2 (2.5 equiv) was added to a solution of (M)-59 in the
presence of BF3·OEt2 (3.0 equiv) and MeOH (1.0 equiv) in
THF at ꢀ788C. The temperature was immediately raised to
08C and the stirring was continued for 30 min to give (S,S)-
60 in a yield of 95%. Importantly, this semi-pinacol cycliza-
tion reaction also allowed the specific transmission of the
axial stereochemistry, as shown by HPLC analyses on a
chiral stationary phase (Figure 8).[46]
Preparation of enantiopure tetracycle (S,S)-60: After estab-
lishing these two stereoselective processes, that is, the lac-
tone ring-opening of biaryl lactone with valinol and the
semi-pinacol cyclization of acetal aldehyde 59, we applied
these to the preparative-scale synthesis of chiral, nonracemic
60 (Scheme 15). We were pleased to find that asymmetric
ring-opening was viable for the gram-scale reaction, and lac-
tone 55 (2.0 g), upon treatment with (R)-valinol (08C, 43 h),
afforded a combined yield of 90% of amide 57c with a dia-
stereoselectivity of 91:9. The desired diastereomer 57c with
Figure 8. HPLC analyses of the semi-pinacol cyclization reaction. HPLC
conditions: for (M)-59 and rac-59, Chiralpak AD-H (0.46”25 cm)
column, 258C, UV detection at 254 nm, flow rate: 1.0 mLminꢀ1, eluent:
hexane/iPrOH 9:1; for (S,S)-60 and rac-60: Chiralpak AD-H (0.46”
25 cm) column, 258C, UV detection at 300 nm, flow rate: 1.0 mLminꢀ1
,
eluent: hexane/EtOH 9:1.
Divergent approach to BpAs: Enantiopure tetracycle (S,S)-
60, thus obtained, could serve as an ideal platform for the
divergent access to various natural/unnatural congeners of
BpAs. Figure 9 represents the three branching points for the
divergency: 1) introduction of the amino acid moiety, 2) gly-
cosylation with a disaccharide derivative, and 3) construc-
tion of the E ring by Diels–Alder reaction with a diene. To
demonstrate such divergency, we report herein the total syn-
Scheme 15. Preparation of tetracycle (S,S)-60 (unless otherwise noted,
the reactions were performed at ambient temperatures). Reagents and
conditions: a) (R)-Valinol, CH2Cl2, 08C, 43 h, 90% (M/P=91:9);
b) BnBr, Cs2CO3, DMF, 08C, 1 h, 97%; c) PPh3, I2, imidazole, CH2Cl2,
20 min, quant; d) MeOTf, 2,6-di-tert-butylpyridine, CH2Cl2, 1 h; e) l-Se-
lectride, 08C, 20 min; f) SiO2, 17 h, 96% (3 steps); g) BnOTMS, cat.
TMSOTf, toluene, ꢀ78!ꢀ158C, 4 h, quant; h) nBu4NF, THF, 1 h, 08C,
quant; i) MnO2, CH2Cl2, 15 h, 99%; j) BF3·OEt2, SmI2, MeOH, THF,
ꢀ78!08C, 30 min, 95%. l-Selectride=lithium tri-sec-butylborohydride.
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Synthesis of Benanomicin-Pradimicin Antibiotics
FULL PAPER
amide 68 in excellent yield whose structure was unambigu-
ously established by single-crystal X-ray analysis
(Figure 10).[47]
Figure 10. X-ray structure of amide 68. Hydrogen atoms have been omit-
ted for clarity.
Figure 9. Divergent access to various BpAs.
Amide 68 served as a key intermediate for the divergent
synthesis of the three natural products 2b, 1a, and 2a, pre-
pared by installing three different disaccharides followed by
E-ring annulation.
thesis of three natural BpAs, that is, benanomicin B (2b),
pradimicin A (1a), and benanomicin A (2a). These three
BpAs share d-alanine as the amino acid, but differ in their
disaccharide moieties. Among the possibilities in assembling
these three modules, we chose to form the amide bond first,
then perform the glycosylation reaction, and finally the syn-
thesis was completed by E-ring annulation. This choice has
the advantage of reserving the generation of the quinone
functionality until the latest stage because we knew that qui-
nones might pose problems associated with chemical trans-
formations and poor solubility (cf. Scheme 11).
Scheme 16 shows the installation of the amino acid, the
methyl ester of d-alanine. Tetracycle (S,S)-60 was hydro-
lyzed under basic conditions to afford the corresponding car-
boxylic acid. This saponification reaction proceeded only
under harsh basic conditions that nonetheless did not cause
aromatization. The resulting carboxylic acid was condensed
with the methyl ester of d-alanine by using BOP to give the
Benanomicin B (2b): The first target was benanomicin B
(2b), which has a primary amine in the sugar moiety. Glyco-
syl fluoride 51 was used as the glycosyl donor (cf.
Scheme 12) because it has an azide that can be converted
into the corresponding primary amine at the appropriate
time (Scheme 17).
The glycosylation process was initially attempted by using
a combination of Cp2HfCl2 and AgClO4 (1:2 ratio). Al-
though this procedure had previously given the best
result,[33] it only induced the decomposition of 68 at the re-
action temperature of ꢀ368C.[48] After careful reinvestiga-
tion of the protocol (Ag salt, molarity, and temperature),
optimal conditions were found: Treatment of fluoride 51
and alcohol 68 with a 1:2 ratio of Cp2HfCl2 and AgOTf (in-
stead of AgClO4) in the presence of MS4A at ꢀ368C for
11 h gave b-glycoside 69 in a yield of 72% along with its a
anomer in a yield of 9%. After separation, b anomer 69 was
oxidized with CAN and the resulting unstable chloroqui-
none was immediately subjected to a Diels–Alder reaction
with siloxydiene 21.[15] The previously described protocol
(see Scheme 11, 42!43) worked well to afford pentacycle
70 in a fully regiocontrolled manner (74% overall yield in
three steps).
The next stage was the removal of the protecting groups
in 70, which was rather difficult as a result of the high polar-
ity and the poor solubility of the partially deprotected inter-
mediates in organic solvents. Careful optimization showed
that the removal of the four acyl protecting groups and
saponification of the methyl ester was possible by treatment
Scheme 16. Installation of the amino acid moiety into (S,S)-60. Reagents
and conditions: a) 5m aq. KOH, EtOH, sealed tube, 1008C, 3 h; b) BOP,
Et3N, d-alanine methyl ester·HCl, DMF, RT, 1 h, 84% (2 steps).
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9803

K. Suzuki et al.
tion to afford benanomicin B hydrochloride (2b·HCl),
which was identical to an authentic specimen (m.p. 213–
2158C, [a]2D2 =+360 (c=0.0501 in H2O); lit.:[1a] m.p.>2208C,
[a]3D0 =+353 (c=0.05 in H2O)).
Pradimicin A (1a): The second target was pradimicin A
(1a), the most abundant congener of the pradimicins. This
compound possesses an N-monomethylamino group instead
of the primary amino group in 2b. Because the direct con-
version of a primary amine into the corresponding monoal-
kylamine is often hampered by bis-alkylation,[51] indirect
routes are often employed, such as temporary protection, al-
kylation, and deprotection.
However, we have developed a method for the selective
conversion of an azide into the corresponding N-monome-
thylamino group without forming the bis-methylation prod-
uct [Eq. (4)].[7] Trimethylphosphine reacts with an azide to
form the corresponding iminophosphorane,[52] which under-
goes aza-Wittig reaction with (HCHO)n to form the corre-
sponding imine. In situ reduction of this imine with NaBH4
affords the requisite N-monomethylamine.
Scheme 17. Synthesis of benanomicin B (unless otherwise noted, the re-
actions were performed at ambient temperatures). Reagents and condi-
tions: a) Fluoride 51, Cp2HfCl2/AgOTf (1:2), MS4A, CH2Cl2, ꢀ368C,
11 h, 9% for the a anomer, 72% for the b anomer; b) CAN, H2O,
CH3CN, 20 min; c) diene 21, THF, 20 min, then SiO2, 8 h; d) K2CO3,
CH2Cl2, THF, 408C, 3 h, 74% (3 steps); e) 2m aq. NaOH, MeOH, 8.5 h;
f) H2, Pd/C, 1m aq. HCl, MeOH, DMF, 2 h, then 2m aq. HCl, 53% (2
steps), for purification see text.
By adapting this synthetic protocol, the azide-containing
intermediates used for the synthesis of 2b could be utilized
for the synthesis of 1a. In terms of the timing of the trans-
ꢀ
ꢀ
with 2m aqueous NaOH (room temperature, 8.5 h), which
gave compound 71. Although the acyl protecting groups
were removed fairly rapidly (2.5 h), hydrolysis of the methyl
ester required a longer time (8.5 h).
formation ( N3! NHMe), there were three optional stages
(Scheme 18),[53] stage 1: advanced intermediate 70; stage 2:
tetracyclic glycoside 69; stage 3: glycosyl donor 51.
We examined these three possibilities and stage 2 turned
out to be the best choice, as described below. stage 1 proved
to be inappropriate because the attempted conversion of 70
only produced an intractable mixture of multiple products,
presumably owing to side reactions at the quinone function-
ality.
On the other hand, stage 3 revealed a different problem.
Azide sugar 51 was successfully converted into monomethyl-
amine 74 and subsequently to trifluoroacetylated glycosyl
fluoride 75. However, glycosidation of 75 with acceptor 68
gave exclusively the undesired a-glycoside 76 owing to the
remote participation of the trifluoroacetamido group.[54]
Fortunately, stage 2 was a viable one: Glycoside 69 in
CH2Cl2 was successively treated with Me3P, (HCHO)n, and
NaBH4 to give monomethylamine 73 in a yield of 75% (see
Scheme 18), which was successfully converted into the
target 1a (see below).
The final stage of the synthesis required the removal of
the three benzyl protecting groups and conversion of the
azide into the primary amine, which could be achieved
under catalytic hydrogenation conditions. This stage was
again troublesome owing to the poor solubility of the parti-
ally deprotected intermediates and also to catalyst deactiva-
tion by the resulting amino group. After considerable
screening of the reaction conditions, an appropriate choice
of solvent and additives allowed us to achieve the total syn-
thesis: Treatment of 71 with 5% Pd/C in MeOH and DMF
(3:1)[49] in the presence of dilute aqueous HCl[50] effected
the desired conversion. During the filtration of the catalyst
in air through Hyfro Super-Cel, the color of the filtrate
changed from orange to purple, which suggested the trans-
formation of the in situ formed hydroquinone back to the
quinone.
The filtrate was purified by successive column chromatog-
raphy on Cosmosil (C18, CH3CN/H2O=3:7, phosphate
buffer pH 3) and then on Sephadex LH-20 (DMF) to afford
benanomicin B as a DMF solvate that was dissolved in
MeOH and the pH adjusted to 3.5 by the addition of 2m
aqueous HCl. After removal of the solvent, the residue was
dissolved in a small amount of DMSO to which CHCl3 was
added. The resulting red precipitate was collected by filtra-
Scheme 19 illustrates the final stages en route to target
1a. The amino group in 73 was masked with a trifluoroace-
tyl group to give b-76 in a yield of 90%. After oxidation of
b-76 with CAN, construction of the E ring was achieved by
the standard protocol (see Scheme 11) to give pentacycle 77
in a yield of 75% (three steps). After hydrogenolysis of 77
to detach the three benzyl groups, final removal of the five
acyl groups (including a trifluoroacetyl group) and hydroly-
9804
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Chem. Eur. J. 2007, 13, 9791 – 9823

Synthesis of Benanomicin-Pradimicin Antibiotics
FULL PAPER
DMF solvate that was dissolved in MeOH and the pH was
adjusted to 3.5 by the addition of 2m aqueous HCl. The rep-
recipitation protocol described above (see above) gave a red
powder of pradimicin A hydrochloride (1a·HCl) in a yield
of 61%[56] which was identical to an authentic sample (m.p.
194–1978C, [a]2D6 =+280 (c=0.0100 in 1.00m aq. HCl);
lit.:[1d] m.p. 193–1958C, [a]3D0 =+287 (c=0.01 in 1.0m aq.
HCl)).
Benanomicin A (2a): The last target was benanomicin A
(2a), which has a neutral sugar (Scheme 20). Fluoride 80
Scheme 18. Three optional stages for the conversion of azide into the N-
monomethylamine derivative (unless otherwise noted, the reactions were
performed at ambient temperatures). Reagents and conditions: a) Me3P,
1.5 h, (HCHO)n, CH2Cl2, 15.5 h, NaB(CN)H3, MeOH, 08C, 10 min, 60%
(contaminated with unidentified by-products); b) Me3P, 1.5 h, (HCHO)n,
CH2Cl2, 11 h, NaBH4, MeOH, 08C, 10 min, 75%; c) Me3P, 1.5 h,
(HCHO)n, CH2Cl2, 13 h, NaBH4, MeOH, 08C, 10 min, 78%;
d) (CF3CO)2O, pyridine, CH2Cl2, 08C, 30 min, 91%; e) amide 68,
Cp2HfCl2/AgOTf (1:2), MS4A, CH2Cl2, ꢀ258C, 11 h, 93%.
Scheme 20. Synthesis of benanomicin A (unless otherwise noted, the re-
actions were performed at ambient temperatures). Reagents and condi-
tions: a) 80, Cp2HfCl2/AgOTf (1:2), MS4A, CH2Cl2, ꢀ308C, 17 h, 7% for
the a anomer and 74% for the b anomer; b) CAN, H2O, CH3CN, 20 min;
c) diene 21, THF, 30 min then SiO2, 14 h; d) K2CO3, CH2Cl2, THF, 408C,
2 h, 66% (3 steps); e) H2, Pd/C, MeOH, DMF, 50 min; f) 0.5m aq.
NaOH, 15 h, then 1m aq. HCl, 68% (2 steps).
was used as the glycosyl donor.[57] The glycosidation reaction
was initially attempted under exactly the same conditions as
those used for the synthesis of 69. Unexpectedly, however,
the reactivity of this neutral glycosyl fluoride 80 was lower
than that of the azide-containing glycosyl donor 51, and
therefore, no reaction occurred at ꢀ368C. Fortunately, a
subtle difference in the reaction temperature proved deci-
sive and the reaction proceeded smoothly at ꢀ308C. Fluo-
ride 80 and alcohol 68 were treated with Cp2HfCl2 and
AgOTf (1:2 ratio) in the presence of MS4A in CH2Cl2 at
ꢀ788C and stirred at ꢀ308C for 17 h to give b-glycoside 78
(74%) along with its a anomer (7%). After isolation and
oxidation of b-78 by CAN, the resulting unstable chloroqui-
none was immediately subjected to the previously described
E-ring annulation protocol (see Scheme 11) to give pentacy-
cle 79 in a fully regiocontrolled manner (66% yield over
three steps). After hydrogenolysis of 79 in a mixed solvent
Scheme 19. Synthesis of pradimicin A (unless otherwise noted, the reac-
tions were performed at ambient temperatures). Reagents and condi-
tions: a) (CF3CO)2O, pyridine, CH2Cl2, 20 min, 08C, 90%; b) CAN, H2O,
CH3CN, 20 min; c) diene 21, THF, 20 min then SiO2, 14 h; d) K2CO3,
CH2Cl2, THF, 2 h, 408C, 75% (3 steps); e) H2, Pd/C, MeOH, DMF,
30 min; f) 0.5m aq. NaOH, 24 h, then 2m aq. HCl, 61% (2 steps), for pu-
rification, see text.
sis of the methyl ester were achieved by treatment with
0.5m aqueous NaOH without MeOH (cf. Scheme 17).[55]
After acidification with 2m aqueous HCl (pH 3.5), the fil-
trate was purified by successive column chromatography on
Cosmosil (C18, CH3CN/H2O=3:7, phosphate buffer pH 3)
and Sephadex LH-20 (DMF) to afford pradimicin A as a
Chem. Eur. J. 2007, 13, 9791 – 9823
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9805

K. Suzuki et al.
(MeOH/DMF=3:1) for 50 min,[49] removal of the five acyl
groups and hydrolysis of the methyl ester were achieved by
treatment with 0.5m aqueous NaOH for 15 h. After acidifi-
cation with 2m aqueous HCl (pH 3.5), the residue was puri-
fied by successive column chromatography on Diaion HP-20
(H2O/MeOH=1:0 to 0:1, gradient elution) and Sephadex
LH-20 (DMF). After removal of the DMF, the residue was
dissolved in a small amount of DMSO to which CHCl3 was
added. The resulting precipitates were collected by filtration
to afford benanomicin A (2a) as a red powder (68% yield).
The synthetic sample showed spectroscopic properties iden-
tical to those of the natural product (m.p. 242–2448C
(decomp); lit.:[1b] m.p.>2208C).
First-generation total synthesis
Methyl 2-hydroxy-6-methyl-4-(trifluoromethylsulfonyloxy)benzoate:
K2CO3 (4.55 g, 24.7 mmol) and PhNTf2 (5.88 g, 16.5 mmol) were added to
a solution of 8 (3.00 g, 16.5 mmol) in acetone (30 mL) at 08C. After stir-
ring for 24 h at room temperature, the reaction mixture was filtered
through a Celite pad (washed with methanol). The filtrate was concen-
trated in vacuo, the mixture was diluted with H2O, and extracted with
EtOAc (”3). The combined organic extracts were washed with brine,
dried (Mg2SO4), and concentrated in vacuo. Flash column chromatogra-
phy (silica gel, hexane/EtOAc=95:5 to 80:20, gradient elution) gave the
undesired regioisomer methyl 4-hydroxy-2-methyl-6-(trifluoromethylsul-
fonyloxy)benzoate as a white crystalline solid (1.09 g, 21%) and some-
what impure methyl 2-hydroxy-6-methyl-4-(trifluoromethylsulfonyloxy)-
benzoate contaminated with PhNHTf, which was further purified by
washing with saturated aqueous K2CO3, followed by extraction with
EtOAc to afford a pure form of methyl 2-hydroxy-6-methyl-4-(trifluoro-
methylsulfonyloxy)benzoate as a white amorphous solid (3.63 g, 70%).
M.p. 52–538C (Et2O); 1H NMR (400 MHz, CDCl3): d=2.58 (s, 3H), 3.99
(s, 3H), 6.65 (d, J=2.6 Hz, 1H), 6.78 (d, J=2.6 Hz, 1H), 11.6 ppm (s,
1H; OH); 13C NMR (100 Hz, CDCl3): d=24.2, 52.6, 108.4, 115.4, 118.6
(q, 1JC,F =317 Hz), 128.6, 114.5, 152.4, 164.4, 171.2 ppm; IR (film): n˜ =
3090, 3050, 2990, 2970, 1660, 1610, 1590, 1510, 1460, 1440, 1410, 1380,
1350, 1310, 1270, 1240, 1220, 1200, 1140, 1130, 1060, 1040, 970, 950, 880,
850, 810, 770 cmꢀ1; elemental analysis calcd (%) for C10H9F3O6S: C 38.22,
H 2.89, S 10.20; found: C 38.03, H 2.90, S 10.11. Methyl 4-hydroxy-2-
methyl-6-(trifluoromethylsulfonyloxy)benzoate: M.p. 88–898C (hexane
and Et2O); 1H NMR (400 MHz, CDCl3): d=2.41 (s, 3H), 3.93 (s, 3H),
5.77 (s, 1H; OH), 6.65 (d, J=2.4 Hz, 1H), 6.71 ppm (d, J=2.4 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=20.7, 52.7, 107.1, 117.6, 118.2, 118.4 (q,
1JC,F =318 Hz), 141.9, 148.1, 158.2, 166.2 ppm; IR (KBr): n˜ =3380, 2950,
1700, 1610, 1570, 1490, 1450, 1410, 1300, 1240, 1210, 1120, 1100, 1040,
970, 940, 850, 810, 780, 760, 700, 680 cmꢀ1; elemental analysis calcd (%)
for C10H9F3O6S (314.24): C 38.22, H 2.89, S 10.20; found: C 38.25, H 3.02,
S 10.05.
Conclusion
A general synthetic route to benanomicin-pradimicin antibi-
otics has been developed that is based on three significant
findings: 1) Diastereoselective biaryl lactone ring-opening,
2) correlation of the biaryl educt configuration to pinacol
product stereochemistry, and 3) semi-pinacol cyclization for
the discrimination of the diol moiety in the B ring. By using
this synthetic strategy, it should be possible to synthesize
various natural/unnatural BpA congeners.
Experimental Section
Methyl
2-methoxymethoxy-6-methyl-4-(trifluoromethylsulfonyloxy)ben-
solution of MOMCl
General methods: All experiments involving air- and moisture-sensitive
compounds were conducted under an atmosphere of dry argon. Dichloro-
methane was successively distilled from P2O5 and CaH2 and stored over
4 Š molecular sieves. For TLC analyses, Merck precoated plates (silica
gel 60 F254, Art 5715, 0.25 mm) were used. For flash column chromatogra-
phy, silica gel 60N (Spherical, neutral, 23–210 mm) from Kanto Chemicals
was used. Preparative TLC (PTLC) was performed on Merck silica gel
60 PF254 (Art 7747). Melting point (m.p.) determinations were performed
zoate (9): iPr2NEt (33 mL, 0.191 mol) and
a
(11.6 mL, 0.152 mol) in CH2Cl2 (80 mL) were added over 1 h to a solu-
tion of methyl 2-hydroxy-6-methyl-4-(trifluoromethylsulfonyloxy)ben-
zoate (40.0 g, 0.127 mol) in CH2Cl2 (100 mL) at 08C. After the reaction
mixture had been stirred for 5.5 h at RT, the reaction was stopped by
adding pH 7 phosphate buffer and then the mixture was extracted with
CH2Cl2 (”3). The combined organic extracts were washed with 2m aq.
HCl, saturated aqueous NaHCO3, and brine, dried (Na2SO4), and concen-
trated in vacuo. After adding Et2O and hexane to the residue, the precip-
itate was collected by filtration to afford 9 (1st crop: 25.1 g, 55%; 2nd
crop: 10.7 g, 23%) as a white solid. The filtrate was concentrated in
vacuo and the residue was purified by flash column chromatography
(silica gel, hexane/EtOAc=86:14) to afford 9 (9.83 g, 22%, total yield:
quant) as a white solid. M.p. 41–428C (hexane and Et2O); 1H NMR
(400 MHz, CDCl3): d=2.33 (s, 3H), 3.47 (s, 3H), 3.93 (s, 3H), 5.18 (s,
1
by using a Yanako MP-S3 or MP-500 instrument and are uncorrected; H
and 13C NMR spectra were recorded by using a JEOL JNM EX-270
(270 MHz), a JNM AL-400 (400 MHz), a JNM lambda-400 (400 MHz),
or a Bruker DRX-500 (500 MHz) spectrometer in the solvent indicated;
chemical shifts (d) are given in ppm relative to tetramethylsilane and
coupling constants (J) are reported in Hz. Multiplicities are described by
the following abbreviations s=singlet, d=doublet, t=triplet, q=quartet,
sept=septet, m=multiplet, br=broad. Infrared (IR) spectra were re-
corded by using a Jasco IR-Report-100 or a Perkin–Elmer Spectrum 100
spectrometer. Attenuated total reflectance Fourier-transform infrared
(ATR-FTIR) spectra were recorded by using a Perkin–Elmer 1600 FTIR
spectrometer. In situ IR spectra were recorded by using a REMSPEC
mid-IR fiber-Optic probe with an MCT detector. Ten scans were ac-
quired per spectrum at a resolution of 4 cmꢀ1 by using the Time Base
software package (Perkin–Elmer). Optical rotations ([a]D) were mea-
sured by using a Jasco DIP-1000 polarimeter. UV spectra were recorded
by using a Hitachi 300 spectrometer. CD spectra were recorded by using
a Jasco J500C spectropolarimeter. High-performance liquid chromatogra-
phy (HPLC) analyses were performed by using a Jasco 880PU instrument
with UV detection at 254 or 300 nm. Low-resolution mass spectra
(LRMS) were obtained with a Shimadzu Kratos Kompact MALDI IIS
spectrometer. High-resolution mass spectra (HRMS) were obtained with
a JEOL JMS-700 spectrometer. Elementary analyses were performed on
a Perkin–Elmer series II 2004 instrument. X-ray crystallographic data
were recorded with a Rigaku RAXIS-RAPID diffractometer at the
Tokyo Institute of Technology X-ray Laboratory.
2H), 6.79 (d, J=2.0 Hz, 1H), 6.95 ppm (d, J=2.0 Hz, 1H); 13C NMR
(100 Hz, CDCl3): d=19.4, 52.4, 56.3, 94.9, 106.1, 115.9, 118.9 (q, JC,F
319 Hz), 124.8, 138.7, 150.0, 155.1, 167.2ppm; IR (neat): n˜ =3460, 3100,
2960, 2830, 2080, 1970, 1730, 1590, 1480, 1430, 1280, 1210, 1140, 1050,
1000, 970, 930, 860, 840, 760 cmꢀ1; elemental analysis calcd (%) for
C12H13O7F3S: C 40.23, H 3.66, S 8.95; found: C 40.16, H 3.73, S 8.90.
1
=
1-Methyl 4-phenyl 2-methoxymethoxy-6-methylterephthalate (10): A mix-
ture of 9 (2.37 g, 6.62 mmol), Pd(OAc)2 (75.6 mg, 0.337 mmol), 1,1’-bis(di-
A
phenylphosphino)ferrocene (181 mg, 0.326 mmol), Et3N (2.11 g,
20.9 mmol), and PhOH (3.04 g, 32.3 mmol) in DMF (13 mL) was bubbled
with CO gas for 10 min. The reaction mixture was stirred for 1.5 h at
608C and then for 1.5 h at 808C. After cooling to RT, the reaction mix-
ture was diluted with water and extracted with Et2O (”3). The combined
organic extracts were washed with brine, dried (Na2SO4), and concentrat-
ed in vacuo. The residue was purified by flash column chromatography
(silica gel, hexane/EtOAc=84:16) to afford 10 as a white solid (2.18 g,
quant). M.p. 71.5–72.08C (hexane and EtOAc); 1H NMR (400 MHz,
CDCl3): d=2.37 (s, 3H), 3.49 (s, 3H), 3.95 (s, 3H), 5.25 (s, 2H), 7.27 (t,
9806
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Chem. Eur. J. 2007, 13, 9791 – 9823

Synthesis of Benanomicin-Pradimicin Antibiotics
FULL PAPER
J=7.8 Hz, 1H), 7.27 (d, J=7.8 Hz, 2H), 7.43 (t, J=7.8 Hz, 2H), 7.72 (s,
1H), 7.77 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=19.2, 52.4, 56.4,
94.7, 113.5, 121.7, 125.3, 126.0, 129.5, 129.6, 131.2, 136.9, 150.8, 153.9,
164.5, 167.8 ppm; IR (KBr): n˜ =2950, 2830, 1730, 1590, 1490, 1430, 1400,
1320, 1300, 1270, 1200, 1160, 1120, 1100, 1080, 1050, 1000, 940, 930, 840,
790, 760, 730 cmꢀ1; elemental analysis calcd (%) for C18H18O6: C 65.45, H
5.49; found: C 65.41, H 5.57.
122.6, 141.5, 147.1, 160.9, 171.8 ppm; IR (KBr): n˜ =2960, 2890, 1660,
1600, 1540, 1450, 1390, 1370, 1350, 1290, 1250, 1200, 1150, 1110, 1060,
1000, 960, 940, 910, 860, 810, 770, 710 cmꢀ1; elemental analysis calcd (%)
for C12H15O5I: C 39.36, H 4.13; found: C 39.47, H 4.34.
4-tert-Butyl 1-ethyl 2-(2,5-dimethoxybenzylidene)succinate (16): Phospho-
nate 19 (4.90 g, 14.5 mmol) in CH3CN (15 mL), DBU (2.20 g, 1.44 mmol),
and 2,5-dimethoxybenzaldehyde (2.00 g, 12.0 mmol) were added to a sus-
pension of LiCl (0.827 g, 19.6 mmol) in CH3CN (90 mL) at RT and the
reaction mixture was stirred for 44 h. The reaction was stopped by
adding water and the mixture was extracted with EtOAc (”3). The com-
bined organic extracts were washed with brine, dried (Na2SO4), and con-
centrated in vacuo. The residue was purified by flash column chromatog-
raphy (silica gel, hexane/Et2O/CHCl3 =14:3:3) to afford the E (3.12 g,
73%) and Z isomers (156 mg, 3.7%) of 16 as yellow oils.
16 (E isomer): 1H NMR (400 MHz, CDCl3): d=1.32 (t, J=7.1 Hz, 3H),
1.42 (s, 9H), 3.39 (s, 2H), 3.73 (s, 3H), 3.77 (s, 3H), 4.25 (q, J=7.1 Hz,
2H), 6.81 (d, J=9.0 Hz, 1H), 6.85 (dd, J=2.7, 9.0 Hz, 1H), 6.89 (d, J=
2.7 Hz, 1H), 7.91 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=14.2,
27.9, 35.3, 55.6, 55.9, 60.8, 80.7, 111.6, 114.8, 115.5, 124.7, 126.9, 137.4,
151.7, 153.1, 167.3, 170.5ppm; IR (neat): n˜ =2730, 2725, 1720, 1710, 1640,
1580, 1500, 1460 cmꢀ1; elemental analysis calcd (%) for C19H26O6: C
65.13, H 7.48; found: C 65.43, H 7.50.
Methyl
4-hydroxymethyl-2-methoxymethoxy-6-methylbenzoate
(11):
LiBH4 (1.62 g, 74.5 mmol) was added to
a
solution of 10 (24.6 g,
74.5 mmol) in THF (260 mL) at 08C. The reaction temperature was al-
lowed to rise to RT and the mixture was stirred for 24 h. The reaction
was stopped by adding AcOH and the mixture was extracted with
EtOAc (”3). The combined organic extracts were washed with brine,
dried (Na2SO4), and concentrated in vacuo. The residue was purified by
flash column chromatography (silica gel, hexane/EtOAc=1:1) to afford
11 as a colorless oil (17.5 g, 98%). 1H NMR (400 MHz, CDCl3): d=2.28
(s, 3H), 2.31 (t, J=6.0 Hz, 1H; OH), 3.45 (s, 3H), 3.91 (s, 3H), 4.61 (d,
J=6.0 Hz, 2H), 5.16 (s, 2H), 6.83 (s, 1H), 6.96 ppm (s, 1H); 13C NMR
(100 MHz, CDCl3): d=19.3, 52.2, 56.2, 64.7, 94.6, 110.4, 121.7, 123.8,
136.8, 143.7, 154.1, 168.7 ppm; IR (film): n˜ =3430, 2950, 2830, 1740, 1720,
1610, 1580, 1440, 1400, 1360, 1280, 1210, 1190, 1150, 1090, 1050, 1000,
930, 850, 820, 780, 750 cmꢀ1; elemental analysis calcd (%) for C12H16O5:
C 59.99, H 6.71; found: C 59.87, H 6.94.
16 (Z isomer): 1H NMR (400 MHz, CDCl3): d=1.08 (t, J=7.1 Hz, 3H),
1.44 (s, 9H), 3.38 (s, 2H), 3.73 (s, 3H), 3.75 (s, 3H), 4.09 (q, J=7.1 Hz,
2H), 6.74–6.81 (m, 3H), 6.86 ppm (s, 1H); 13C NMR (100 MHz, CDCl3):
d=13.7, 28.0, 42.0, 55.7, 56.0, 60.4, 81.0, 111.4, 114.4, 115.6, 125.8, 128.0,
134.5, 151.2, 152.9, 167.7, 170.0ppm; IR (neat): n˜ =2730, 2725, 1720,
1490, 1220 1160 cmꢀ1; elemental analysis calcd (%) for C19H26O6: C
65.13, H 7.48; found: C 65.43, H 7.74.
Methyl 2-methoxymethoxy-4-(methoxymethoxy)methyl-6-methylbenzoate
(12): iPr2NEt (17.0 mL, 97.2 mmol) and MOMCl (7.2 mL, 95 mmol) were
added to a solution of 11 (7.82 g, 32.5 mmol) in CH2Cl2 (65 mL) at 08C.
The reaction mixture was allowed to warm to RT and stirred for 3 h. The
reaction was stopped by adding water and the mixture was extracted
with EtOAc (”3). The combined organic extracts were washed with 2m
aq. HCl, saturated aqueous NaHCO3, and brine, dried (Na2SO4), and
concentrated in vacuo. The residue was purified by flash column chroma-
tography (silica gel, hexane/EtOAc=8:2) to afford 12 as a colorless oil
3-(2,5-dimethoxybenzylidene)succinic acid monoethyl ester (17): Tri-
fluoroacetic acid (5.2 mL) was added to a solution of (E)-16 (2.99 g,
8.55 mmol) in water (0.58 mL). After stirring for 3.5 h, volatile materials
were removed by azeotropic distillation with toluene (”3). The resulting
solid was filtered to afford 17 as a white powder (2.13 g, 85%). The fil-
trate was purified by flash column chromatography (silica gel, hexane/
EtOAc=1:1 then MeOH/CHCl3 =1:9) to afford 17 as a white solid
(0.14 g, 5%; total yield: 90%). 1H NMR (270 MHz, CDCl3): d=1.35 (t,
J=7.1 Hz, 3H), 3.51 (s, 2H), 3.77 (s, 3H), 3.80 (s, 3H), 4.31 (q, J=
7.1 Hz, 2H), 6.82–6.82 (m, 3H), 7.99 (s, 1H), 10.6 ppm (s, 1H).
1
(8.11 g, 88%). H NMR (400 MHz, CDCl3): d=2.29 (s, 3H), 3.41 (s, 3H),
3.47 (s, 3H), 3.91 (s, 3H), 4.54 (s, 2H), 4.69 (s, 2H), 5.18 (s, 2H), 6.86
(brs, 1H), 6.98 ppm (brs, 1H); 13C NMR (100 MHz, CDCl3): d=19.3,
52.1, 55.4, 56.2, 68.7, 94.7, 95.7, 111.4, 122.7, 124.1, 136.7, 140.5, 154.1,
168.6ppm; IR (neat): n˜ =3620, 2950, 2830, 2070, 1970, 1900, 1730, 1620,
1580, 1560, 1440, 1400, 1370, 1320, 1270, 1210, 1190, 1150, 1090, 1050,
1010, 950, 920, 850, 820 cmꢀ1; elemental analysis calcd (%) for C14H20O6:
C 59.14, H 7.09; found: C 58.92, H 7.26.
Ethyl 4-acetoxy-5,8-dimethoxy-2-naphthoate (18a): NaOAc (0.800 g,
9.75 mmol) was added to a solution of 17 (2.10 g, 7.13 mmol) in acetic an-
hydride (11.5 mL) at RT and the reaction mixture was stirred for 30 min
at 1408C. After cooling to RT, the resulting precipitate was collected by
filtration to afford 18a as a white powder (1.99 g, 88%). The filtrate was
concentrated in vacuo. The residue was azeotroped with toluene (”2) to
remove volatile materials and recrystallized (hexane/EtOAc) to afford
18a (0.162 g, 7%). The mother liquor was extracted with EtOAc (”3)
and the combined organic extracts were washed with brine, dried
(Na2SO4), and concentrated in vacuo. The residue was purified by flash
column chromatography (silica gel, hexane/EtOAc=7:3) to afford 18a as
a white solid (0.0937 g, 11%; total yield: 99%). 1H NMR (270 MHz,
CDCl3): d=1.43 (t, J=7.1 Hz, 3H), 2.38 (s, 3H), 3.89 (s, 3H), 3.97 (s,
3H), 4.42 (q, J=7.1 Hz, 2H), 6.77 (d, J=8.6 Hz, 1H), 6.87 (d, J=8.6 Hz,
1H), 7.69 (d, J=1.7 Hz, 1H), 8.90 ppm (d, J=1.7 Hz, 1H).
Methyl 2-hydroxy-4-(methoxymethoxy)methyl-6-methylbenzoate (13): Tri-
fluoroacetic acid (1.2 mL, 16 mmol) was added to a solution of 12 (1.45 g,
5.09 mmol) in CH2Cl2 (25 mL) at 08C. After stirring for 3 h, the reaction
was stopped by adding water and the mixture was extracted with EtOAc
(”3). The combined organic extracts were washed with saturated aque-
ous NaHCO3, water, and brine, dried (Na2SO4), and concentrated in
vacuo. The residue was purified by flash column chromatography (silica
gel, hexane/EtOAc=9:1) to afford phenol 13 as a colorless oil (1.22 g,
1
99%). H NMR (400 MHz, CDCl3): d=2.54 (s, 3H), 3.41 (s, 3H), 3.95 (s,
3H), 4.52 (s, 2H), 4.71 (s, 2H), 6.70 (s, 1H), 6.84 (s, 1H), 11.33 ppm (s,
1H; OH); 13C NMR (100 MHz, CDCl3): d=24.1, 52.1, 55.5, 68.2, 95.9,
111.3, 114.1, 121.7, 141.5, 144.8, 163.1, 172.1ppm; IR (neat): n˜ =2950,
2890, 1730, 1660, 1620, 1570, 1440, 1420, 1380, 1360, 1320, 1260, 1210,
1150, 1100, 1050, 1010, 990, 940, 920, 850, 810, 750 cmꢀ1; elemental analy-
sis calcd (%) for C12H16O5: C 59.99, H 6.71; found: C 59.97, H 6.79.
Ethyl 4-hydroxy-5,8-dimethoxy-2-naphthoate (18d): K2CO3 (56.8 g,
0.411 mol) was added to a solution of 18a (26.3 g, 0.0826 mol) in EtOH
(410 mL) at RT. After stirring for 1 h at 708C, the reaction was extracted
with EtOAc (”3) and the combined organic extracts were washed with
brine, dried (Na2SO4), and concentrated in vacuo. The residue was puri-
fied by recrystallization (hexane/EtOAc) to afford 18d as a white powder
(20.1 g, 89%). The mother liquor was concentrated in vacuo and the resi-
due was purified by flash column chromatography (silica gel, hexane/
EtOAc=65:35) to afford 18d as a white powder (2.03 g, 9%; total yield:
98%). M.p. 120.0–120.28C (hexane and EtOAc); 1H NMR (400 MHz,
CDCl3): d=1.43 (t, J=7.2 Hz, 3H), 3.97 (s, 3H), 4.03 (s, 3H), 4.41 (q, J=
7.2 Hz, 2H), 6.69 (d, J=8.4 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 7.49 (d, J=
1.2 Hz, 1H), 8.46 (d, J=1.2 Hz, 1H), 9.49 ppm (s, 1H; OH); 13C NMR
(100 MHz, CDCl3): d=14.4, 55.7, 56.3, 61.0, 103.5, 105.7, 110.5, 115.7,
Methyl
2-hydroxy-3-iodo-4-(methoxymethoxy)methyl-6-methylbenzoate
ꢀ
(14): NaHCO3 (5.23 g, 62.7 mmol) and BnMe3N+ICl2 (10.8 mL,
30.9 mmol) were added to a solution of 13 (7.48 g, 31.1 mmol) in CH2Cl2/
MeOH (5:2, 310 mL) at 08C. The reaction mixture was stirred for 10 h at
08C. The reaction was stopped by adding 10% aqueous Na2S2O3 and the
mixture was extracted with CH2Cl2 (”3). The combined organic extracts
were washed with 10% aqueous Na2S2O3 and brine, dried (Na2SO4), and
concentrated in vacuo. The residue was purified by recrystallization from
EtOH to afford 14 as a white solid (1st crop: 8.00 g, 70%; 2nd crop:
0.75 g, 6.5%; 3rd crop: 0.75 g, 6.5%; total yield: 83%). M.p. 67.5–68.08C
(EtOH); 1H NMR (400 MHz, CDCl3): d=2.54 (s, 3H), 3.45 (s, 3H), 3.99
(s, 3H), 4.59 (s, 2H), 4.79 (s, 2H), 6.94 (s, 1H), 12.36 ppm (s, 1H; OH);
13C NMR (100 MHz, CDCl3): d=23.9, 52.6, 55.7, 73.4, 85.6, 96.4, 111.3,
Chem. Eur. J. 2007, 13, 9791 – 9823
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9807

K. Suzuki et al.
117.5, 127.4, 128.8, 149.5, 150.9, 154.4, 166.5 ppm; IR (KBr): n˜ =3370,
1710, 1620, 1520, 1450, 1390, 1290, 1250, 1230, 1110, 1050, 1030, 810,
770 cmꢀ1; elemental analysis calcd (%) for C15H16O5 : C 65.21, H 5.84;
found: C 65.33, H 5.90.
J=7.6 Hz, 1H), 7.38 (s, 1H), 7.43 (t, J=7.6 Hz, 2H), 7.61 (d, J=7.6 Hz,
2H), 8.07 (s, 1H), 8.61 ppm (s, 1H); 13C NMR (125 MHz, CDCl3): d=
14.3, 55.8, 56.7, 61.8, 71.0, 95.3, 103.7, 105.7, 115.8, 120.9, 121.8, 124.3,
126.8, 127.9, 128.7, 136.00, 136.01, 137.6, 139.0, 157.1, 161.0, 164.8, 165.0,
179.9, 182.3 ppm; IR (KBr): n˜ =2460, 1710, 1670, 1650, 1600, 1560, 1460,
1390, 1310, 1240, 1150, 1110, 1030, 970, 930, 760 cmꢀ1; elemental analysis
calcd (%) for C27H24O8: C 68.06, H 5.08; found: C 67.96, H 5.31.
Ethyl 5,8-dimethoxy-4-methoxymethoxy-2-naphthoate (18b): Compound
18d (20.9 g, 0.0766 mmol) and MOMCl (9.33 g, 0.116 mol) were added to
a suspension of NaH (60% dispersion in mineral oil, washed with hexane
(4.02 g, 0.100 mol)) in DMF (240 mL) at 08C. After stirring for 20 min,
the reaction was stopped by adding water and the mixture was extracted
with Et2O (”3). The combined organic extracts were washed with brine,
dried (MgSO4), and concentrated in vacuo. After adding Et2O and
hexane to the residue, the precipitate was collected by filtration to afford
Ethyl
8-benzyloxy-6,9,10-trimethoxy-4-(methoxymethoxy)anthracene-2-
carboxylate (25): A solution of Na2S2O4 (5.14 g, 29.4 mmoL) in degassed
water (112 mL) was added to a suspension of anthraquinone 24 (1.40 g,
2.94 mmol) and nBu4NBr (237 mg, 0.735 mmol) in degassed THF
(50 mL). After stirring for 30 min at RT, 50% aqueous KOH (9 mL) was
added to the mixture, which was stirred for 30 min. After adding Me2SO4
(0.735 mL, 7.35 mmoL) and stirring for 1 h, the reaction was stopped by
adding water and N,N-dimethyl-1,3-propanediamine (2 mL) at 08C and
the organic layer was extracted with CH2Cl2 (”3). The combined organic
extracts were washed with brine, dried (Na2SO4), and concentrated in
vacuo. The residue was purified by flash column chromatography (silica
gel, hexane/EtOAc=75:25) to afford 25 as a yellow amorphous solid
(1.46 g, 98%). M.p. 144.5–145.48C (hexane and EtOAc); 1H NMR
(400 MHz, CDCl3): d=1.44 (t, J=7.2 Hz, 3H), 3.66 (s, 3H), 3.87 (s, 3H),
3.98 (s, 3H), 4.00 (s, 3H), 4.44 (q, J=7.2 Hz, 2H), 5.24 (s, 2H), 5.43 (s,
2H), 6.63 (d, J=1.6 Hz, 1H), 7.26 (d, J=1.6 Hz, 1H), 7.37 (t, J=7.5 Hz,
1H), 7.45 (t, J=7.5 Hz, 2H), 7.57 (d, J=1.4 Hz, 1H), 7.62 (d, J=7.5 Hz,
2H), 8.81 ppm (d, J=1.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=14.9,
55.8, 57.1, 61.4, 62.9, 64.6, 71.7, 92.5, 96.6, 101.4, 109.3, 116.6, 120.8, 122.0,
126.2, 126.3, 128.1, 128.5, 129.0, 131.4, 137.0, 146.7, 151.8, 153.1, 157.2,
158.9, 167.1 ppm; IR (KBr): n˜ =2940, 1700, 1620, 1540, 1410, 1360, 1310,
1260, 1220, 1150, 1110, 1060, 990, 830, 770, 750, 700 cmꢀ1; elemental anal-
ysis calcd (%) for C29H30O8: C 68.76, H 5.77; found: C 68.46, H 5.98.
18b as
a white solid (23.8 g, 99%). M.p. 78.7–79.28C (hexane and
1
EtOAc); H NMR (400 MHz, CDCl3): d=1.44 (t, J=7.2 Hz, 3H), 3.62 (s,
3H), 3.92 (s, 3H), 3.98 (s, 3H), 4.43 (q, J=7.2 Hz, 2H), 5.41 (s, 2H), 6.78
(d, J=8.4 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 7.66 (d, J=1.6 Hz, 1H),
8.70 ppm (d, J=1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=14.5, 55.8,
56.6, 57.3, 61.1, 96.7, 104.6, 109.5, 112.8, 119.4, 121.4, 127.5, 127.9, 150.2,
150.4, 153.6, 166.4 ppm; IR (KBr): n˜ =2980, 1710, 1600, 1520, 1470, 1380,
1280, 1150, 1090, 1040, 920, 800, 760, 730, 720, 660 cmꢀ1; elemental analy-
sis calcd (%) for C17H20O6: C 63.74, H 6.29; found: C 63.53, H 6.45.
Ethyl 8-methoxymethoxy-1,4-naphthoquinone-6-carboxylate (20b): A so-
lution of CAN (20.1 g, 36.6 mmol) in water (63 mL) was added to a solu-
tion of 18b (5.80 g, 18.3 mmol) in CH3CN (183 mL) at 08C. After stirring
for 10 min, the reaction was stopped by adding water, the precipitate was
collected by filtration, and washed with Et2O. After adding water and
stirring for 10 min, precipitate was collected by filtration to afford 20b
(4.36 g, 83%) as a yellow solid. The filtrate was extracted with EtOAc (”
3). The combined organic extracts were washed with brine, dried
(MgSO4), and concentrated in vacuo. The precipitate was collected by fil-
tration and washed with Et2O to afford 20b as a yellow solid (0.683 g,
13%; total yield: 96%). M.p. 107–1088C (hexane and EtOAc); 1H NMR
(400 MHz, CDCl3): d=1.44 (t, J=7.2 Hz, 3H), 3.56 (s, 3H), 4.45 (q, J=
7.2 Hz, 2H), 5.42 (s, 2H), 6.92 (d, J=10.4 Hz, 1H), 6.90 (d, J=10.4 Hz,
1H), 8.16 (d, J=1.6 Hz, 1H), 8.41 ppm (d, J=1.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d=14.3, 56.8, 62.0, 95.1, 122.4, 123.0, 134.0, 135.9,
137.0, 140.7, 157.0, 164.5, 183.5, 184.1 ppm; IR (KBr): n˜ =3680 3630,
1720, 1660, 1610, 1600, 1560, 1550, 1430, 1370, 1340, 1320, 1270, 1210,
1170, 1110, 1090, 1000, 920, 880, 850, 770 cmꢀ1; elemental analysis calcd
(%) for C15H14O6 : C 62.06, H 4.86; found: C 61.84, H 4.95.
8-Benzyloxy-6,9,10-trimethoxy-4-(methoxymethoxy)anthracene-2-carbox-
ylic acid (26): A 5m aq. KOH solution (133 mL) was added to a suspen-
sion of anthracene 25 (1.30 g, 2.57 mmoL) in EtOH (186 mL) and stirred
for 1.5 h under reflux conditions. After cooling to RT, the reaction mix-
ture was diluted with water and washed with Et2O (”3). The aqueous
layer was acidified with 2m aq. HCl and extracted with EtOAc (”3). The
combined organic extracts were washed with brine, dried (Na2SO4), and
concentrated in vacuo. The precipitate was collected by filtration and
washed with Et2O to afford 26 as a yellow powder (1.12 g, 91%). M.p.
198–1998C (hexane and EtOAc); 1H NMR (400 MHz, CDCl3): d=3.66
(s, 3H), 3.88 (s, 3H), 3.99 (s, 3H), 4.00 (s, 3H), 5.26 (s, 2H), 5.44 (s, 2H),
6.64 (d, J=1.7 Hz, 1H), 7.27 (d, J=1.7 Hz, 1H), 7.38 (t, J=7.3 Hz, 1H),
7.45 (t, J=7.3 Hz, 2H), 7.58 (s, 1H), 7.63 (d, J=7.3 Hz, 2H), 8.93 (s,
1H) ppm; IR (KBr): n˜ =2370, 2340, 1680, 1640, 1560, 1460, 1420, 1360,
1330, 1250, 1160, 1060, 1030, 1000, 830 cmꢀ1; elemental analysis calcd
(%) for C27H26O8: C 67.77, H 5.48; found: C 68.07, H 5.30. This title com-
pound was carried on to the subsequent experiment without further char-
acterization.
Ethyl 8-hydroxy-6-methoxy-4-methoxymethoxy-9,10-anthraquinone-2-car-
boxylate (22b): Diene 21 (3.47 g, 10.5 mmol) was added to a solution of
20b (2.50 g, 8.73 mmol) in THF (87 mL) at 08C. After stirring the reac-
tion mixture for 7 h at ꢀ788C, nBu4NF (1.0m in THF, 13 mL, 13 mmol)
was added and the mixture bubbled with O2 for 5 min at RT. The mixture
was poured into water (150 mL) and stirred for 15 min. The resulting pre-
cipitate was collected by filtration to afford 22b as a yellow solid (2.11 g,
84%). M.p. 195.0–195.48C (hexane and EtOAc); 1H NMR (400 MHz,
CDCl3): d=1.45 (t, J=7.2 Hz, 3H), 3.59 (s, 3H), 3.94 (s, 3H), 4.46 (q, J=
7.2 Hz, 2H), 5.45 (s, 2H), 6.69 (d, J=2.4 Hz, 1H), 7.32 (d, J=2.4 Hz,
1H), 8.16 (d, J=1.5 Hz, 1H), 8.62 (d, J=1.5 Hz, 1H), 12.71 ppm (s, 1H;
OH); 13C NMR (100 MHz, CDCl3): d=14.3, 56.0, 56.9, 62.1, 95.2, 106.0,
107.7, 110.2, 121.3, 122.5, 124.8, 136.0, 136.1, 136.4, 158.0, 164.7, 165.1,
166.7, 181.2, 185.5 ppm; IR (KBr): n˜ =2380, 2360, 1730, 1680, 1650, 1630,
1590, 1560, 1430, 1400, 1300, 1260, 1150, 1010, 960, 930, 820 cmꢀ1; ele-
mental analysis calcd (%) for C20H18O8: C 62.17, H 4.70; found: C 62.11,
H 4.78.
2-Iodo-6-methoxycarbonyl-3-(methoxymethoxy)methyl-5-methylphenyl 8-
benzyloxy-6,9,10-trimethoxy-4-(methoxymethoxy)anthracene-2-carboxyl-
ate: Et3N (140 mg, 1.38 mmol) and 2,4,6-trichlorobenzoyl chloride
(459 mg, 1.88 mmol) were added to a solution of carboxylic acid 26
(600 mg, 1.25 mmol) in toluene (10 mL) at RT. After stirring for 3 h at
RT, iodophenol 14 (689 mg, 1.88 mmol) and DMAP (460 mg, 3.77 mmol)
was added to the reaction mixture and then stirred for 30 min. The reac-
tion was stopped by adding water and the mixture was extracted with
CH2Cl2 (”3). The combined organic extracts were washed with brine,
dried (Na2SO4), and concentrated in vacuo. The residue was purified by
flash column chromatography (silica gel, hexane/EtOAc=70:30) to
afford the title compound as a yellow amorphous solid (974 mg, 94%).
1H NMR (500 MHz, CDCl3): d=2.45 (s, 3H), 3.45 (s, 3H), 3.67 (s, 3H),
3.71 (s, 3H), 3.90 (s, 3H), 4.00 (s, 3H), 4.03 (s, 3H), 4.64 (s, 2H), 4.80 (s,
2H), 5.26 (s, 2H), 5.46 (s, 2H), 6.65 (d, J=2.2 Hz, 1H), 7.28 (d, J=
2.2 Hz, 1H), 7.32 (s, 1H), 7.37 (t, J=7.4 Hz, 1H), 7.45 (t, J=7.4 Hz, 2H),
7.62 (d, J=7.4 Hz, 1H), 7.64 (d, J=1.4 Hz, 1H), 9.05 ppm (d, J=1.4 Hz,
1H); 13C NMR (125 MHz, CDCl3): d=20.0, 52.3, 55.4, 55.7, 56.8, 62.6,
64.3, 71.3, 73.0, 91.9, 92.1, 96.2, 96.3, 101.0, 108.7, 116.3, 120.6, 123.4,
124.1, 125.7, 126.6, 127.3, 127.6, 127.8, 128.1, 128.6, 131.5, 136.4, 138.5,
Ethyl
8-benzyloxy-6-methoxy-4-methoxymethoxy-9,10-anthraquinone-2-
carboxylate (24): Cs2CO3 (4.29 g, 13.2 mmol) and BnBr (1.44 mL,
11.6 mmol) were added to a solution of anthraquinone 22b (2.02 g,
5.27 mmol) in DMF (150 mL) at 08C. After stirring for 7.5 h at RT, the
reaction was stopped by adding water and the mixture was extracted
with CH2Cl2 (”3). The combined organic extracts were washed with
brine, dried (Na2SO4), and concentrated in vacuo. The precipitate was
collected by filtration and washed with Et2O to afford 24 as a yellow
powder (2.23 g, 89%). M.p. 179–1808C (hexane and EtOAc); 1H NMR
(500 MHz, CDCl3): d=1.43 (t, J=7.0 Hz, 3H), 3.59 (s, 3H), 3.92 (s, 3H),
4.43 (q, J=7.0 Hz, 2H), 5.27 (s, 2H), 5.43 (s, 2H), 6.78 (s, 1H), 7.33 (t,
9808
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 9791 – 9823

Synthesis of Benanomicin-Pradimicin Antibiotics
FULL PAPER
144.0, 146.4, 149.3, 151.8, 152.9, 156.9, 163.8, 166.0 ppm; IR (KBr): n˜ =
2930, 1740, 1690, 1650, 1620, 1560, 1540, 1450, 1410, 1360, 1260, 1210,
1170, 1060, 980 cmꢀ1; elemental analysis calcd (%) for C39H39O12I: C
56.67, H 4.63; found: C 56.46, H 4.63.
droxymethyl-4-methoxyphenol (18.6 g, 98.6 mmol) in acetone (400 mL)
at RT. The reaction mixture was heated at reflux for 13 h. After cooling
to 08C, Et3N (150 mL) was added and the stirring was continued for 1 h.
The resulting suspension was filtered through a Celite pad (washed with
EtOAc) and the volatile materials were removed in vacuo. The resulting
mixture was diluted with EtOAc and water, and the mixture was extract-
ed with EtOAc (”3). The combined organic extracts were washed with
brine, dried (Na2SO4), and concentrated in vacuo. Recrystallization from
benzene afforded 3-chloro-2,5-(dimethoxyphenyl)methanol as colorless
needles (1st crop: 11.0 g, 55%; 2nd crop: 4.57 g, 23%). The filtrate was
concentrated in vacuo and the residue was purified by flash column chro-
matography (silica gel, hexane/EtOAc=7:3) to afford 3-chloro-2,5-dime-
thoxyphenylmethanol as a white solid (2.50 g, 13%; total yield: 91%).
M.p. 54–558C (benzene); 1H NMR (400 MHz, CDCl3): d=2.25 (t, J=
3.9 Hz, 1H; OH), 3.77 (s, 3H), 3.83 (s, 3H), 4.69 (d, J=3.9 Hz, 2H), 6.84
(d, J=2.9 Hz, 1H), 6.85 ppm (d, J=2.9 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d=55.7, 61.1, 61.2, 112.8, 114.7, 127.9, 136.2, 147.4, 156.0ppm;
IR (neat): n˜ =3420, 2940, 2840, 1600, 1570, 1480, 1430, 1360, 1310, 1270,
1230, 1180, 1120, 1050, 1000, 950, 860, 760 cmꢀ1; elemental analysis calcd
(%) for C9H11O3Cl: C 53.35, H 5.47; found: C 53.46, H 5.49.
2-Iodo-6-methoxycarbonyl-3-(methoxymethoxy)methyl-5-methylphenyl 8-
benzyloxy-4-hydroxy-6,9,10-trimethoxyanthracene-2-carboxylate (27): Tri-
fluoroacetic acid (133 mg, 1.17 mmol) was added to a degassed solution
of
2-iodo-6-(methoxycarbonyl)-3-(methoxymethoxy)methyl-5-methyl-
phenyl 8-(benzyloxy)-6,9,10-trimethoxy-4-(methoxymethoxy)anthracene-
2-carboxylate (320 mg, 0.387 mmol) in CH2Cl2 (6 mL) at 08C. After stir-
ring for 2 h at RT, the reaction was stopped by adding saturated aqueous
NaHCO3 and water, and then the mixture was extracted with CH2Cl2 (”
3). The combined organic extracts were washed with brine, dried
(Na2SO4), and concentrated in vacuo. The residue was purified by flash
column chromatography (silica gel, benzene/EtOAc=9:1) to afford 27 as
a yellow solid (264 mg, 87%). M.p. 187–1888C (hexane and EtOAc);
1H NMR (500 MHz, CDCl3): d=2.44 (s, 3H), 3.45 (s, 3H), 3.70 (s, 3H),
3.90 (s, 3H), 4.01 (s, 3H), 4.10 (s, 3H), 4.63 (s, 2H), 4.80 (s, 2H), 5.26 (s,
2H), 6.63 (d, J=2.2 Hz, 1H), 7.01 (d, J=2.2 Hz, 1H), 7.32 (s, 1H), 7.38
(t, J=7.3 Hz, 1H), 7.45 (dd, J=7.3, 7.6 Hz, 2H), 7.53 (d, J=1.5 Hz, 1H),
7.62 (d, J=7.6 Hz, 2H), 8.85 (d, J=1.5 Hz, 1H), 9.81 ppm (s, 1H; OH);
13C NMR (125 MHz, CDCl3): d=20.0, 52.4, 55.5, 55.7, 63.2, 64.3, 71.4,
73.1, 90.7, 91.9, 96.3, 100.9, 107.8, 116.4, 118.6, 120.2, 125.3, 125.6, 126.6,
127.7, 127.8, 128.2, 128.7, 128.9, 136.2, 138.6, 144.0, 145.4, 149.4, 152.8,
153.1, 157.3, 159.1, 163.9, 166.1 ppm; IR (KBr): n˜ =3320, 2950, 1740,
1650, 1620, 1560, 1540, 1450, 1410, 1370, 1260, 1190, 1060, 960, 820, 740,
700 cmꢀ1; elemental analysis calcd (%) for C37H35O11I: C 56.79, H 4.51;
found: C 56.76, H 4.56.
3-Chloro-2,5-dimethoxybenzaldehyde (30): MnO2 (33.4 g, 384 mmol) was
added to a solution of 3-chloro-2,5-(dimethoxyphenyl)methanol (15.5 g,
76.5 mmol) in CH2Cl2 (260 mL) at RT and the reaction mixture was
warmed to 408C and stirred. After about every 1 h, MnO2 (ca. 5 g) was
added seven times and then the suspension was stirred further 10 h. The
reaction mixture was filtered through a Celite pad (washed with EtOAc)
and concentrated in vacuo. Recrystallization from benzene afforded alde-
hyde 30 as colorless needles (1st crop: 7.92 g, 52%; 2nd crop: 1.27 g, 8%;
3rd crop: 2.85 g. 19%). The filtrate was concentrated in vacuo and the
residue was purified by flash column chromatography (silica gel, hexane/
EtOAc=9:1) to afford 30 as a white solid (1.72 g, 11%; total yield:
90%). M.p. 69–708C (benzene); 1H NMR (400 MHz, CDCl3): d=3.82 (s,
3H), 3.95 (s, 3H), 7.21 (d, J=3.0 Hz, 1H), 7.23 (d, J=3.0 Hz, 1H),
10.25 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=56.0, 63.5, 109.4,
123.6, 129.4, 130.6, 153.4, 156.1, 188.9 ppm; IR (KBr): n˜ =3080, 3020,
2970, 2940, 2870, 2840, 2750, 1690, 1610, 1470, 1420, 1390, 1330, 1260,
1230, 1210, 1110, 1050, 990, 870, 850, 770 cmꢀ1; elemental analysis calcd
(%) for C9H9O3Cl: C 53.88, H 4.52; found: C 53.72, H 4.65.
Methyl 9-benzyloxy-14-hydroxy-8,11,13-trimethoxy-1-(methoxymethoxy)-
methyl-3-methyl-6-oxo-6H-anthra
PPh3 (41.4 mg, 0.158 mmol) and 27 (99.8 mg, 0.128 mmol) were added to
a suspension of Pd(OCOCF3)2 (99.8 mg, 0.128 mmol), sodium pivalate
(44.6 mg, 0.359 mmol), and (t-Bu)3 (35 mL, 0.15 mmol) in DMA
A
(28):
ACHTREUNG
P
ACHTREUNG
(12.8 mL). After stirring at 1108C for 25 min, the reaction mixture was
cooled to 08C. The reaction was stopped by adding water and saturated
aqueous NaHCO3. The mixture was extracted with EtOAc (”3) and the
combined organic extracts were washed with brine, dried (Na2SO4), and
concentrated in vacuo. The residue was azeotropically distiled with ben-
zene (100 mL) and purified by flash column chromatography (silica gel,
benzene/EtOAc=9:1) to afford 28 as a red amorphous solid (53.6 mg,
Ethyl 4-acetoxy-7-chloro-5,8-dimethoxy-2-naphthoate (31): tert-Butyl 3-
ethoxycarbonyl-3-diethoxyphosphorylpropionate (19) (1.80 g, 5.32 mmol)
in THF (10 mL) was added to a suspension of NaH (60% dispersion in
mineral oil, washed with hexane (209 mg, 5.22 mmol)) in THF (10 mL) at
08C and the reaction mixture was stirred for 2 h. A solution of 30
(955 mg, 4.76 mmol) in THF (10 mL) was added at 08C. The reaction
mixture was warmed to RT and the stirring was continued for 1 h. The re-
action was stopped by adding water and the mixture was extracted with
EtOAc (”3). The combined organic extracts were washed with water and
brine, dried (Na2SO4), and concentrated in vacuo. The resulting mixture
was dissolved in trifluoroacetic acid/water (9:1, 34 mL) and the reaction
mixture was stirred for 40 min at RT. After adding toluene, azeotropic
evaporation was performed three times. NaOAc (3.45 g, 42.0 mmol) and
Ac2O (47.0 mL, 499 mmol) were added to this crude material at RT. The
reaction mixture was heated at reflux for 1 h. After cooling to RT, the re-
action was stopped by adding water and then the mixture was extracted
with EtOAc (”3). The combined organic extracts were washed with satu-
rated aqueous NaHCO3 and brine, dried (Na2SO4), and concentrated in
vacuo. The residue was purified by flash column chromatography (silica
gel, hexane/EtOAc=77:23) to afford 31 as a pale yellow solid (1.24 g,
76%). M.p. 104–1058C (hexane and EtOAc); 1H NMR (400 MHz,
CDCl3): d=1.43 (t, J=7.3 Hz, 3H), 2.38 (s, 3H), 3.92 (s, 3H), 3.99 (s,
3H), 6.88 (s, 1H), 4.44 (q, J=7.3 Hz, 2H), 7.68 (d, J=1.7 Hz, 1H),
8.71 ppm (d, J=1.7 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=14.3, 20.8,
56.6, 61.5, 61.8, 109.9, 119.5, 120.8, 123.0, 124.2, 129.3, 131.0, 146.5, 147.0,
151.6, 165.5, 170.7 ppm; IR (KBr): n˜ =3411, 2984, 2942, 2846, 1770, 1760,
1715, 1593, 1478, 1459, 1424, 1387, 1366, 1333, 1271, 1232, 1214, 1160,
1130, 1117, 1029, 939, 914, 872, 840, 814 cmꢀ1; elemental analysis calcd
(%) for C17H17O3Cl: C 57.88, H 4.86; found: C 57.66, H 4.98.
1
64%). H NMR (400 MHz, CDCl3): d=2.38 (s, 3H), 3.22 (s, 3H), 3.84 (s,
3H), 3.93 (s, 3H), 3.95 (s, 3H), 4.05 (s, 3H), 4.53 (s, 2H), 4.78 (s, 2H),
5.19 (s, 2H), 6.57 (d, J=1.7 Hz, 1H), 6.94 (d, J=1.7 Hz, 1H), 7.33 (t, J=
7.3 Hz, 1H), 7.38(s, 1H), 7.40 (t, J=7.3 Hz, 2H), 7.55 (d, J=7.3 Hz, 2H),
R
8.84 (s, 1H), 10.73 ppm (s, 1H; OH).
2-Chloro-6-hydroxymethyl-4-methoxyphenol: Me2AlCl (1.0m toluene so-
lution, 24.4 mL, 0.263 mol) and (HCHO)n (8.67 g, 0.263 mol) were added
to a solution of 2-chloro-4-methoxyphenol (29) (27.7 g, 0.175 mol) in
CH2Cl2 (500 mL) at 08C. After the addition was complete, the ice bath
was removed and the reaction mixture was stirred for 5 h. The reaction
was stopped by adding 2m aq. HCl at 08C and the mixture was extracted
with EtOAc (”3). The combined organic extracts were washed with
brine, dried (Na2SO4), and concentrated in vacuo. After adding Et2O and
hexane to the residue, the precipitate was collected by filtration to afford
2-chloro-6-hydroxymethyl-4-methoxyphenol as a white crystalline solid
(25.9 g, 89%). The filtrate was concentrated in vacuo and the residue was
purified by flash column chromatography (silica gel, hexane/EtOAc=
6:4) to afford 2-chloro-6-hydroxymethyl-4-methoxyphenol as
a white
solid (4.94 g, 4%; total yield: 93%). M.p. 70–728C (hexane and EtOAc);
1H NMR (400 MHz, CDCl3): d=2.51 (t, J=5.3 Hz, 1H; OH), 3.75 (s,
3H), 4.73 (d, J=5.3 Hz, 2H), 6.26 (brs, 1H; OH), 6.70 (d, J=3.0 Hz,
1H), 6.82 ppm (d, J=3.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=55.9,
62.7, 113.2, 113.6, 120.4, 128.0, 144.1, 153.1ppm; IR (neat): n˜ =3510,
3250, 2930, 2840, 1590, 1480, 1450, 1430, 1380, 1350, 1320, 1290, 1240,
1190, 1170, 1130, 1050, 1040, 980, 930, 860, 830, 790 cmꢀ1; elemental anal-
ysis calcd (%) for C8H9O3Cl: C 50.94, H 4.81; found: C 50.77, H 4.95.
3-Chloro-2,5-dimethoxybenzyl alcohol: K2CO3 (68.1 g, 492 mmol) and
Me2SO4 (15.0 mL, 158 mmol) were added to a solution of 2-chloro-6-hy-
Chem. Eur. J. 2007, 13, 9791 – 9823
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9809

K. Suzuki et al.
7-Chloro-4-hydroxy-5,8-dimethoxy-2-naphthoic acid (32):
A
3m aq.
56.6, 61.3, 64.1, 67.4, 96.2, 105.9, 111.9, 113.1, 114.0, 117.2, 121.3, 122.8,
123.3, 131.3, 141.2, 141.4, 143.7, 146.6, 151.3, 152.5, 159.9, 172.4 ppm; IR
(KBr): n˜ =3390, 2940, 1660, 1620, 1600, 1450, 1380, 1360, 1290, 1260,
1200, 1150, 1110, 1050, 1010, 970, 950, 820 cmꢀ1; elemental analysis calcd
(%) for C25H27O9Cl: C 59.23, H 5.37; found: C 59.14, H 5.50.
NaOH solution of (23.0 mL) was added to a suspension of 31 (2.60 g,
7.35 mmol) in THF/EtOH (1:1) (30 mL) and the reaction mixture was
heated at 708C for 1 h. After cooling to RT, the aqueous layer was
washed with Et2O (”2). The aqueous phase was acidified with 2m aq.
HCl. The precipitates were collected by filtration to afford 32 as a white
powder (1.81 g, 87%). M.p.>2508C; 1H NMR (400 MHz, [D6]DMSO):
d=3.86 (s, 3H), 3.99 (s, 3H), 7.06 (s, 1H), 7.27 (d, J=1.4 Hz, 1H), 8.06
(d, J=1.4 Hz, 1H), 9.65 (s, 1H; OH), 13.0–13.4 ppm (br, 1H); 13C NMR
(100 MHz, [D6]DMSO): d=56.9, 61.2, 107.7, 110.3, 114.3, 116.5, 123.0,
130.2, 130.7, 145.7, 152.9, 155.1, 167.0 ppm; IR (KBr): n˜ =3380, 2940,
2640, 1680, 1630, 1600, 1510, 1470, 1430, 1380, 1340, 1310, 1280, 1240,
1210, 1120, 1090, 1020, 940, 820, 800, 770 cmꢀ1; elemental analysis calcd
(%) for C13H11O5Cl: C 55.24, H 3.92; found: C 55.24, H 4.15.
Methyl (ꢁ)-3-(6-chloro-1-hydroxy-3-hydroxymethyl-5,8-dimethoxynaph-
thalen-2-yl)-2-hydroxy-4-hydroxymethyl-6-methylbenzoate (38): A 6m aq.
HCl solution (7 mL) was added to
a
solution of (ꢁ)-35 (516 mg,
1.02 mmol) in DME (10 mL) at RT and the reaction mixture was heated
at 508C for 3 h. After the mixture had cooled to RT, water was added
and the mixture was extracted with EtOAc (”3). The combined organic
extracts were washed with water and brine, dried (Na2SO4), and concen-
trated in vacuo. The residue was purified by flash column chromatogra-
phy (silica gel, hexane/EtOAc=45:55) to afford (ꢁ)-38 as a white solid
(440 mg, 93%). M.p. 117–1208C (hexane and EtOAc); 1H NMR
(500 MHz, CDCl3): d=2.64 (s, 3H), 2.35–2.70 (br, 2H; OH), 3.98 (s,
3H), 3.99 (s, 3H), 4.01 (s, 3H), 4.32 (s, 2H), 4.45 (d, J=12.0 Hz, 1H),
4.50 (d, J=12.0 Hz, 1H), 6.76 (s, 1H), 7.04 (s, 1H), 7.79 (s, 1H), 9.54 (s,
1H; OH), 11.76 ppm (s, 1H; OH); 13C NMR (125 MHz, CDCl3): d=24.2,
52.3, 56.6, 61.3, 63.4, 64.2, 106.2, 111.9, 113.4, 114.1, 117.5, 121.0, 123.0,
123.8, 131.1, 140.8, 141.7, 146.3, 146.7, 151.3, 152.4, 160.6, 172.4 ppm; IR
(neat): n˜ =3390, 2940, 1650, 1620, 1600, 1450, 1390, 1360, 1300, 1260,
1200, 1130, 1110, 1070, 1040, 1000, 980, 820, 750 cmꢀ1; elemental analysis
calcd (%) for C23H23O8Cl: C 59.68, H 5.01; found: C 59.76, H 5.31.
2-Iodo-6-methoxycarbonyl-3-(methoxymethoxy)methyl-5-methylphenyl 7-
chloro-4-hydroxy-5,8-dimethoxy-2-naphthoate (33): 1-Ethyl-3-[3-(dime-
thylamino)propyl]carbodiimide
hydrochloride
(EDCI)
(196 mg,
0.981 mmol) and DMAP (125 mg, 1.02 mmol) were added to a mixed sus-
pension of acid 32 (252 mg, 0.892 mmol) and phenol 14 (651 mg,
1.78 mmol) in CH2Cl2 (9 mL) at RT. After stirring for 3 h, the reaction
was stopped by adding water. The mixture was extracted with EtOAc (”
3) and the combined organic extracts were washed with brine, dried
(Na2SO4), and concentrated in vacuo. The residue was purified by flash
column chromatography (silica gel, hexane/EtOAc=7:3) to afford 33 as
a yellow solid (438 mg, 78%). M.p. 174.5–175.28C (hexane and EtOAc);
1H NMR (400 MHz, CDCl3): d=2.45 (s, 3H), 3.45 (s, 3H), 3.70 (s, 3H),
4.00 (s, 3H), 4.09 (s, 3H), 4.63 (s, 2H), 4.81 (s, 2H), 6.88 (s, 1H), 7.33 (s,
1H), 7.63 (s, 1H), 8.50 (s, 1H), 9.32 ppm (s, 1H; OH); 13C NMR
(100 MHz, CDCl3): d=20.1, 52.4, 55.7, 56.8, 61.7, 73.0, 91.7, 96.2, 108.2,
111.1, 116.8, 117.1, 123.6, 126.4, 128.0, 129.0, 130.9, 138.7, 144.2, 147.5,
149.2, 152.4, 155.4, 163.6, 165.9 ppm; IR (KBr): n˜ =3390, 2950, 2890,
2850, 1740, 1600, 1520, 1450, 1390, 1340, 1280, 1200, 1180, 1150, 1120,
1070, 1060, 1040, 990, 950, 920, 880, 800, 750 cmꢀ1; elemental analysis
calcd (%) for C25H24O9Cl: C 47.60, H 3.83; found: C 47.62, H 4.03. Start-
ing material 14 was also recovered (359 mg, 55%).
Methyl (ꢁ)-4-(tert-butyldimethylsiloxy)methyl-3-[3-(tert-butyldimethylsi-
loxy)methyl-6-chloro-1-hydroxy-5,8-dimethoxynaphthalen-2-yl]-2-hy-
droxy-6-methylbenzoate (36): Imidazole (211 mg, 3.10 mmol) and tert-bu-
tylchlorodimethylsilane (355 mg, 2.36 mmol) were added to a solution of
(ꢁ)-38 (358 mg, 0.774 mmol) in DMF (5 mL) at RT. After stirring for
25 min, the reaction was stopped by adding water and the mixture was
extracted with Et2O (”3). The combined organic extracts were washed
with water and brine, dried (Na2SO4), and concentrated in vacuo. The
residue was purified by flash column chromatography (silica gel, hexane/
EtOAc=85:15) to afford (ꢁ)-36 as a white solid (451 mg, 84%). M.p.
162.5–163.48C (hexane and EtOAc); 1H NMR (500 MHz, CDCl3): d=
ꢀ0.05 (s, 3H), ꢀ0.04 (s, 3H), 0.01 (s, 3H), 0.03 (s, 3H), 0.88 (s, 9H), 0.95
(s, 9H), 2.64 (s, 3H), 3.97 (s, 3H), 3.98 (s, 3H), 3.99 (s, 3H), 4.27 (d, J=
15.0 Hz, 1H), 4.40 (d, J=16.0 Hz, 1H), 4.49 (d, J=15.0 Hz, 1H), 4.59 (d,
J=16.0 Hz, 1H), 6.71 (s, 1H), 7.11 (s, 1H), 7.90 (s, 1H), 9.36 (s, 1H;
OH), 11.55 ppm (s, 1H; OH); 13C NMR (125 MHz, CDCl3): d=ꢀ5.49,
ꢀ5.43, ꢀ5.40, ꢀ5.38, 18.3 (2C), 24.5, 25.9, 52.1, 56.5, 61.1, 62.5, 62.9,
105.3, 110.0, 110.9, 113.5, 115.5, 118.7, 120.9, 122.4, 130.9, 140.9, 141.8,
146.5, 147.1, 150.8, 152.7, 159.6, 172.5ppm; IR (neat): n˜ =3400, 2960,
2860, 1740, 1660, 1610, 1500, 1460, 1390, 1360, 1290, 1260, 1200, 1120,
1060, 1020, 1010, 990, 960, 950, 840, 780 cmꢀ1; elemental analysis calcd
(%) for C35H51O8ClSi2: C 60.80, H 7.43; found: C 60.57, H 7.62.
Methyl (ꢁ)-3-(6-chloro-1-hydroxy-3-hydroxymethyl-5,8-dimethoxynaph-
thalen-2-yl)-2-hydroxy-4-(methoxymethoxy)methyl-6-methylbenzoate (35):
A suspension of ester 33 (307 mg, 0.486 mmol), Pd(OAc)2 (33.3 mg,
E
0.148 mmol, 30 mol%), PPh3 (81.1 mg, 0.309 mmol), and sodium pivalate
(187 mg, 1.50 mmol) in DMA (33 mL) was heated at 1108C for 1.5 h.
After cooling to RT, the resulting dark brown suspension was filtered
through a Celite pad (washed with EtOAc). The filtrate was washed with
water and brine, dried (Na2SO4), and concentrated in vacuo. NaBH4
(29.2 mg, 0.772 mmol) was added to a solution of this crude material,
which included 34, in THF/MeOH (20:1) (17 mL) at ꢀ408C. After stir-
ring for 3 h, the reaction was stopped by adding five drops of AcOH at
that temperature. After warming to RT, water was added and the mixture
was extracted with EtOAc (”3). The combined organic extracts were
washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and
concentrated in vacuo. The residue was purified by flash column chroma-
tography (silica gel, benzene/EtOAc=85:15) to afford (ꢁ)-35 as a yellow
solid (211 mg, 86%).
Camphanoyl esters 37a and 37b: (1S)-(ꢀ)-Camphanic chloride (235 mg,
1.08 mmol) and DMAP (18.0 mg, 0.147 mmol) were added to a solution
of (ꢁ)-36 (497 mg, 0.719 mmol) in pyridine (3.6 mL) at RT and the reac-
tion mixture was stirred for 20 h. The reaction was stopped by adding
water and the mixture was extracted with EtOAc (”3). The combined or-
ganic extracts were washed with 2m aq. HCl (”2), saturated aqueous
NaHCO3, and brine, dried (Na2SO4), and concentrated in vacuo. The res-
idue was purified by column chromatography (hexane/EtOAc=8:2) to
afford the less polar ester 37b as a white solid (250 mg, 40%) and a
more polar mixture that included 37a. The mixture was further purified
by column chromatography (benzene/EtOAc=6:4) to afford the more
polar ester 37a (237 mg, 38%).
1
34: M.p. 218.5–219.38C (hexane and Et2O); H NMR (400 MHz, CDCl3):
d=2.44 (s, 3H), 3.31 (s, 3H), 3.98 (s, 3H), 4.03 (s, 3H), 4.15 (s, 3H), 4.58
(s, 2H), 4.72 (s, 2H), 6.94 (s, 1H), 7.43 (s, 1H), 8.57 (s, 1H), 10.16 ppm (s,
1H; OH); 13C NMR (100 MHz, CDCl3): d=19.6, 52.7, 55.5, 57.1, 61.8,
68.9, 96.2, 109.0, 113.7, 114.3, 116.4, 116.7, 121.2, 123.5, 124.3, 126.0,
129.9, 136.6, 138.9, 146.8, 147.6, 151.4, 152.2, 160.4, 167.0 ppm; IR (KBr):
n˜ =3310, 2950, 1740, 1720, 1610, 1600, 1460, 1440, 1390, 1360, 1330, 1260,
1200, 1150, 1090, 1050, 1040, 1010, 950, 920, 840, 810, 760, 710 cmꢀ1; ele-
mental analysis calcd (%) for C25H23O9Cl: C 59.71, H 4.61; found: C
59.65, H 4.57.
(ꢁ)-35: M.p. 142.5–143.38C (hexane and EtOAc); 1H NMR (400 MHz,
CDCl3): d=2.64 (s, 3H), 2.72 (t, J=6.3 Hz, 1H; OH), 3.13 (s, 3H), 3.979
(s, 3H), 3.981 (s, 3H), 4.00 (s, 3H), 4.27 (d, J=12.2 Hz, 1H), 4.34 (d, J=
12.2 Hz, 1H), 4.42 (d, J=6.6 Hz, 1H), 4.46 (d, J=6.3 Hz, 2H), 4.53 (d,
J=6.6 Hz, 1H), 6.74 (s, 1H), 7.03 (s, 1H), 7.80 (s, 1H), 9.45 (s, 1H; OH),
11.77 ppm (s, 1H; OH); 13C NMR (100 MHz, CDCl3): d=24.3, 52.4, 55.3,
37a: Rf =0.34 (hexane/EtOAc=7:3); m.p. 97.0–98.08C (hexane and
EtOAc); [a]2D2 =ꢀ60.3 (c=0.975 in CHCl3); 1H NMR (400 MHz, CDCl3):
d=ꢀ0.07 (brs, 6H), 0.03 (s, 3H), 0.05 (s, 3H), 0.40 (s, 3H), 0.64 (s, 3H),
0.86 (s, 9H), 0.93 (s, 3H), 0.96 (s, 9H), 1.40–1.72 (m, 3H), 1.90–2.02 (m,
1H), 2.51 (s, 3H), 3.85 (s, 3H), 3.92 (s, 3H), 4.01 (s, 3H), 4.33 (d, J=
14.2 Hz, 1H), 4.35 (d, J=15.4 Hz, 1H), 4.44 (d, J=14.2 Hz, 1H), 4.57 (d,
J=15.4 Hz, 1H), 6.73 (s, 1H), 7.48 (s, 1H), 7.87 (s, 1H), 9.30 ppm (s, 1H;
OH); 13C NMR (100 MHz, CDCl3): d=ꢀ5.53, ꢀ5.47, ꢀ5.45, ꢀ5.3, 9.5,
15.6, 15.9, 18.2, 18.3, 20.8, 25.9 (2C), 28.7, 30.6, 52.3, 53.7, 54.7, 56.7, 61.0,
62.3, 62.5, 90.8, 105.5, 110.2, 113.3, 114.1, 123.0, 124.4, 125.2, 127.2, 130.9,
9810
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 9791 – 9823

Synthesis of Benanomicin-Pradimicin Antibiotics
FULL PAPER
138.0, 141.9, 144.1, 145.7, 146.3, 151.6, 152.5, 165.0, 166.8, 177.8ppm; IR
(neat): n˜ =3380, 2950, 2860, 1790, 1730, 1620, 1600, 1500, 1460, 1390,
1360, 1320, 1260, 1210, 1170, 1120, 1060, 1020, 990, 950, 840 cmꢀ1; ele-
mental analysis calcd (%) for C45H63O11ClSi2: C 62.01, H 7.29; found: C
61.77, H 7.55.
1100, 1050, 960, 920, 890, 800, 750 cmꢀ1; elemental analysis calcd (%) for
C25H27O8Cl: C 61.16, H 5.54; found: C 61.25, H 5.61.
MnO2 (62.0 mg, 0.713 mmol) was added to a solution of the dimethyl
ether derivative of (M)-38 (71.3 mg, 0.145 mmol) in CH2Cl2 (3 mL) at RT
and the reaction mixture was stirred for 26 h. The reaction was moni-
tored by TLC and MnO2 (62.0 mg, 0.713 mmol) was added about every
4 h. When the reaction was completed, the mixture was filtered through
a Celite pad and concentrated in vacuo. The residue was purified by
PTLC (benzene/EtOAc=6:4) to afford dialdehyde 39 as a yellow oil
(55.4 mg, 79%). [a]2D7 =+16.7 (c=1.08 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=2.46 (s, 3H), 3.36 (s, 3H), 3.46 (s, 3H), 3.95 (s, 3H), 3.97 (s,
3H), 4.06 (s, 3H), 6.99 (s, 1H), 7.71 (s, 1H), 8.59 (s, 1H), 9.74 (s, 1H),
9.88 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=19.4, 52.6, 56.8, 61.4,
61.5, 61.9, 110.8, 122.0, 122.2 (2C), 123.4, 125.0, 125.5, 128.0, 131.4, 133.4,
133.6, 135.9, 137.5, 146.9, 152.8, 155.2, 167.7, 190.8, 190.9 ppm; IR (neat):
n˜ =3380, 3020, 2940, 2840, 2750, 2000, 1740, 1700, 1600, 1570, 1460, 1390,
1360, 1340, 1280, 1240, 1210, 1190, 1140, 1100, 1080, 1050, 1000, 970, 930,
810, 750 cmꢀ1; elemental analysis calcd (%) for C25H23O8Cl: C 61.67, H
4.76; found: C 61.77, H 5.02.
37b: Rf =0.42 (hexane/EtOAc=7:3); [a]2D4 =+58.2 (c=1.00 in CHCl3);
1H NMR (400 MHz, CDCl3): d=ꢀ0.07 (s, 3H), ꢀ0.06 (s, 3H), 0.04 (s,
3H), 0.06 (s, 3H), 0.24 (s, 3H), 0.61 (s, 3H), 0.86 (s, 9H), 0.92 (s, 3H),
0.96 (s, 9H), 1.45–1.56 (m, 1H), 1.63–1.76 (m, 2H), 1.96–2.05 (m, 1H),
2.51 (s, 3H), 3.85 (s, 3H), 3.93 (s, 3H), 4.00 (s, 3H), 4.33 (d, J=14.4 Hz,
1H), 4.35 (d, J=15.1 Hz, 1H), 4.45 (d, J=14.4 Hz, 1H), 4.57 (d, J=
15.1 Hz, 1H), 6.71 (s, 1H), 7.48 (s, 1H), 7.87 (s, 1H), 9.29 ppm (s, 1H;
OH); 13C NMR (100 MHz, CDCl3): d=ꢀ5.44, ꢀ5.40, ꢀ5.37, ꢀ5.2, 9.6,
15.4, 16.0, 18.28, 18.34, 20.8, 25.7, 25.9, 28.7, 30.8, 52.2, 53.6, 54.7, 56.7,
61.0, 62.3, 62.4, 90.6, 105.4, 110.0, 113.2, 113.9, 122.9, 124.4, 124.9, 127.0,
130.8, 138.0, 141.7, 143.9, 145.8, 146.0, 151.6, 152.5, 165.0, 166.6,
177.7 ppm; IR (neat): n˜ =3380, 3020, 2960, 2930, 2860, 1790, 1730, 1620,
1600, 1500, 1460, 1390, 1360, 1320, 1260, 1210, 1100, 1060, 1030, 990, 950,
840, 760 cmꢀ1; elemental analysis calcd (%) for C45H63O11ClSi2: C 62.01,
H 7.29; found: C 61.73, H 7.39.
The enantiomeric purity of 39 was assessed by HPLC analysis (DAICEL
CHIRALCEL OD-H (0.46 cm f”25 cm), hexane/iPrOH=9:1, flow
rate=0.7 mLminꢀ1, tR =18.3 min for the M isomer, 26.4 min for the P
isomer).
Tetrol (M)-38: Two drops of 40% aqueous HF were added to a solution
of 37a (237 mg, 0.272 mmol) in CH3CN (3 mL) at 08C. The reaction mix-
ture was gradually warmed to RT and stirred for 45 min. The reaction
was stopped by adding water and the mixture was extracted with EtOAc
(”3). The combined organic extracts were washed with saturated aque-
ous NaHCO3 and brine, dried (Na2SO4), and concentrated in vacuo. The
residue was purified by flash column chromatography (silica gel, hexane/
EtOAc=35:65) to afford the triol derivative of 37a as a white solid
(170 mg, 97%). M.p. 242–2438C; [a]2D6 =ꢀ108 (c=1.07 in CHCl3);
1H NMR (400 Hz, CDCl3): d=0.26 (s, 3H), 0.67 (s, 3H), 0.92 (s, 3H),
1.42–1.78 (m, 3H), 1.95–2.08 (m, 1H), 2.48 (s, 3H), 2.70–3.15 (br, 2H;
OH), 3.86 (s, 3H), 3.92 (s, 3H), 4.01 (s, 3H), 4.29 (d, J=12.5 Hz, 1H),
4.34 (d, J=12.5 Hz, 1H), 4.42 (d, J=12.5 Hz, 1H), 4.49 (d, J=12.5 Hz,
1H), 6.76 (s, 1H), 7.44 (s, 1H), 7.55 (s, 1H), 9.47 ppm (s, 1H; OH);
13C NMR (100 MHz, CDCl3): d=9.5, 15.4, 16.0, 20.4, 28.7, 30.8, 52.4,
53.7, 54.7, 56.8, 61.3, 62.8, 63.1, 90.6, 106.2, 113.2, 113.7, 115.8, 123.4,
126.1, 126.4, 129.7, 131.1, 138.4, 141.1, 143.8, 145.8, 146.4, 152.1, 152.3,
165.2, 166.6, 177.6ppm; IR (neat): n˜ =3380, 2960, 2880, 1770, 1730, 1620,
1600, 1510, 1460, 1390, 1360, 1320, 1260, 1210, 1170, 1130, 1100, 1060,
1040, 990, 940, 870, 810, 800 cmꢀ1; elemental analysis calcd (%) for
C33H35O11Cl: C 61.63, H 5.49; found: C 61.35, H 5.69.
Diol 40: SmI2 (0.1m THF solution, 3.5 mL, 0.35 mmol) was added to a
solution of (M)-39 (68.5 mg, 0141 mmol) in THF (3.0 mL) at 08C. After
stirring for 10 min at 08C, the reaction was stopped by adding water and
the mixture was extracted with EtOAc (”3). The combined organic ex-
tracts were successively washed with 2m aq. HCl, water, and brine, dried
(Na2SO4), and concentrated in vacuo. The residue was purified by PTLC
(benzene/EtOAc=50:50) to afford 40 as a yellow solid (68.9 mg, quant).
M.p. 225–2268C (decomp); [a]2D6 =ꢀ282 (c=1.08 in CHCl3), [a]2D7 =ꢀ215
(c=1.11 in MeOH); 1H NMR (400 MHz, CDCl3): d=2.37 (s, 3H), 3.11–
3.36 (br, 2H; OH), 3.39 (s, 3H), 3.42 (s, 3H), 3.92 (s, 3H), 3.94 (s, 3H),
3.97 (s, 3H), 4.36–4.56 (br, 2H), 6.79 (s, 1H), 7.30 (brs, 1H), 8.06 ppm (s,
1H); 13C NMR (100 MHz, CDCl3): d=19.4, 52.3, 56.5, 61.3, 61.5, 62.3,
73.8, 74.0, 107.4, 111.6, 119.2, 119.4, 120.0, 120.3, 123.8, 128.4, 131.3,
136.5, 137.7, 140.7, 145.3, 153.6, 154.8, 155.1, 169.1ppm; IR (neat): n˜ =
3453, 3009, 2936, 2837, 1728, 1619, 1589, 1574, 1454, 1421, 1343, 1285,
1216, 1120, 1096, 1044, 1002, 969, 926, 892, 816, 798, 755 cmꢀ1; UV
(MeOH): lmax =357 (e=8500), 339 (7800), 323 (9500), 309 (10000), 278
(34000), 270 (34000), 229 nm (34000 mꢀ1 cmꢀ1); CD (MeOH): lext =354
(De=ꢀ2.8), 321 (ꢀ8.0), 278 (+14), 246 (ꢀ32), 224.5 nm (+35 mꢀ1 cmꢀ1);
elemental analysis calcd (%) for C25H25O8Cl: C 61.42, H 5.15; found: C
61.25, H 5.35.
K2CO3 (367 mg, 2.66 mmol) was added to a solution of the triol deriva-
tive of 37a (170 mg, 0.264 mmol) in MeOH (3 mL). After stirring for
19 h at RT, the reaction was stopped by adding 2m aq. HCl and the mix-
ture was extracted with EtOAc (”3). The combined organic extracts
were washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4),
and concentrated in vacuo. The residue was purified by flash column
chromatography (silica gel, hexane/EtOAc=4:6) to afford tetrol (M)-38
as a white solid (122 mg, quant). [a]2D8 =ꢀ52.7 (c=1.07 in CHCl3); m.p.
117–1198C (hexane and EtOAc).
The enantiomeric purity of 40 was assessed by HPLC analysis (DAICEL
CHIRALCEL OD-H (0.46 cm f”25 cm), hexane/iPrOH=9:1, flow
rate=1.0 mLminꢀ1, tR =10.9 min for the R,R isomer, 15.0 min for the S,S
isomer).
Diacetate 41: Ac2O (0.050 mL, 0.53 mmol) and a catalytic amount of
DMAP were added to a solution of 40 (63.5 mg, 0.131 mmol) in pyridine
(2.6 mL) at RT. After stirring for 20 min, the reaction was stopped by
adding water and the mixture was extracted with EtOAc (”2). The com-
bined organic extracts were successively washed with 1m aq. HCl, water,
saturated aqueous NaHCO3, and brine, dried (Na2SO4), and concentrated
in vacuo. The residue was purified by PTLC (benzene/EtOAc=85:15) to
afford 41 as a white amorphous solid (72.9 mg, 98%). M.p. 98–1008C;
[a]2D6 =+106 (c=1.15 in CHCl3); 1H NMR (400 MHz, CDCl3 at 300 K):
d=1.70–2.45 (br, 6H), 2.37 (s, 3H), 3.43 (s, 3H), 3.46 (s, 3H), 3.94 (s,
3H), 3.98 (brs, 6H), 5.58–6.20 (br, 2H), 6.84 (brs, 1H), 7.05–7.30 (br,
Dialdehyde (M)-39: K2CO3 (235 mg, 1.70 mmol) and MeI (0.11 mL,
1.77 mmol) were added to a solution of (M)-38 (78.6 mg, 0.170 mmol) in
acetone (3.4 mL) at RT. The reaction mixture was warmed to 408C and
stirred for 11 h. The reaction was stopped by adding water and the mix-
ture was extracted with EtOAc (”3). The combined organic extracts
were washed with 2m aq. HCl, saturated aqueous NaHCO3, and brine,
dried (Na2SO4), and concentrated in vacuo. The residue was purified by
PTLC (benzene/EtOAc=1:1) to afford the dimethyl ether derivative of
(M)-38 as a white solid (75.8 mg, 91%). M.p. 171.5–172.38C; [a]2D7 =ꢀ106
(c=1.10 in CHCl3); 1H NMR (400 MHz, CDCl3): d=2.38 (s, 3H), 3.01
(brs, 1H; OH), 3.23 (brs, 1H; OH), 3.44 (s, 3H), 3.53 (s, 3H), 3.92 (s,
3H), 3.95 (s, 3H), 3.99 (s, 3H), 4.23 (brs, 2H), 4.37 (d, J=12.4 Hz, 1H),
4.45 (d, J=12.4 Hz, 1H), 6.81 (s, 1H), 7.22 (s, 1H), 8.04 ppm (s, 1H);
13C NMR (100 MHz, CDCl3): d=19.4, 52.3, 56.6, 61.4 (2C), 61.8, 63.2,
63.7, 107.7, 118.5, 119.4, 123.5, 126.2, 126.6, 127.0, 127.5, 131.8, 137.1,
139.9, 142.5, 145.6, 152.7, 153.8, 154.5, 168.7ppm; IR (neat): n˜ =3390,
3010, 2940, 2840, 1730, 1590, 1570, 1460, 1390, 1340, 1290, 1200, 1140,
1
1H), 7.55–8.15 ppm (br, 1H); H NMR (400 MHz, [D6]DMSO, at 333 K):
d=1.80–2.20 (br, 6H), 2.28 (s, 3H), 3.321 (s, 3H), 3.324 (s, 3H), 3.88 (s,
3H), 3.90 (s, 3H), 3.96 (s, 3H), 5.91 (d, J=7.1 Hz, 1H), 6.00 (d, J=
7.1 Hz, 1H), 7.02 (s, 1H), 7.06–7.14 (br, 1H), 7.60–7.92 ppm (br, 1H);
13C NMR (100 MHz, CDCl3): d=18.3, 20.2, 20.3, 51.8, 56.8, 60.4, 60.9,
61.2, 70.1, 70.3, 108.5, 119.5, 120.4, 123.1, 129.0, 130.0, 132.3, 135.3, 135.4,
144.7, 153.1, 155.0, 155.1, 167.5, 169.3 ppm (signals for four sp2 carbon
atoms were not detected presumably owing to peak-broadening ascribed
to the slow conformational interconversion, diaxialQdiequatorial); IR
Chem. Eur. J. 2007, 13, 9791 – 9823
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9811

K. Suzuki et al.
(neat): n˜ =3010, 2940, 2840, 1760, 1730, 1620, 1580, 1460, 1370, 1340,
1290, 1220, 1140, 1100, 1030, 970, 940, 920, 900, 890, 850, 810, 760 cmꢀ1
elemental analysis calcd (%) for C29H29O10Cl: C 60.79, H 5.10; found: C
60.69, H 5.38.
70.8, 107.5, 108.5, 110.7, 116.2, 116.8, 118.2 (br), 121.0 (br), 127.3, 132.5,
134.5, 136.8, 140.9, 142.4, 156.0, 158.2, 165.8, 166.6, 169.7, 169.8, 170.2,
185.0, 188.7 ppm (signals for four sp2 carbon atoms were not detected
presumably owing to the peak-broadening ascribed to the slow conforma-
tional interconversion, diaxialQdiequatorial); IR (KBr): n˜ =2950, 1760,
1660, 1610, 1490, 1450, 1420, 1370, 1350, 1290, 1260, 1230, 1180, 1160,
1120, 1080, 1030, 970, 920, 810, 750 cmꢀ1; elemental analysis calcd (%)
for C30H24O12: C 62.50, H 4.20; found: C 62.80, H 4.47.
;
Quinone 42: A solution of CAN (299 mg, 0.545 mmol) in water (2 mL)
was added to a solution of 41 (126 mg, 0.220 mmol) in CH3CN (3 mL) at
08C. After stirring for 10 min at 08C, the reaction was stopped by adding
water and the mixture was extracted with EtOAc (”3). The combined or-
ganic extracts were washed with brine, dried (Na2SO4), and concentrated
in vacuo. The residue was purified by flash column chromatography
(silica gel, hexane/EtOAc=4:6) to afford 42 as a yellow solid (120 mg,
quant). M.p. 187–1888C; [a]2D5 =+98.9 (c=1.04 in CHCl3); 1H NMR
(400 MHz, [D6]DMSO, 333 K): d=1.92–2.26 (br, 6H), 2.30 (s, 3H), 3.39
(s, 3H), 3.49 (s, 3H), 3.89 (s, 3H), 5.94 (d, J=7.3 Hz, 1H), 6.00 (d, J=
7.3 Hz, 1H), 7.06–7.20 (br, 1H), 7.36 (s, 1H), 7.77–7.94 pppm (br, 1H);
13C NMR (100 MHz, [D6]DMSO): d=18.5, 20.17, 20.22, 52.0, 60.9, 61.5,
69.6 (br, 2C), 78.9, 119.0 (br), 120.7, 123.6 (br), 128.8, 131.2, 132.2, 135.2
(br), 137.4, 137.5, 138.8 (br), 142.4, 155.2, 157.9, 167.1, 169.3 (2C), 177.0,
180.7ppm; IR (neat): n˜ =3470, 3020, 2930, 2850, 1740, 1680, 1660, 1610,
1580, 1460, 1370, 1300, 1260, 1230, 1140, 1080, 1040, 980, 940, 900, 860,
750 cmꢀ1; elemental analysis calcd (%) for C27H23O10Cl: C 59.73, H 4.27;
found: C 59.49, H 4.48.
Benanomicinone methyl ester (46): A suspension of 44 (9.9 mg, 17 mmol)
in 2m aq. NaOH (5 mL) was heated at 708C for 2.5 h. After cooling to
RT, the reaction mixture was acidified with 2m aq. HCl. The precipitates
were collected by filtration to afford crude material of carboxylic acid 45
as a deep-red powder (8.5 mg). d-Ala-OMe·HCl (12.4 mg, 88.8 mmol),
BOP (112 mg, 25.3 mmol), and Et3N (17 mL, 120 mmol) were added to a
solution of crude 45 (8.5 mg) in DMF (0.4 mL) at RT. After stirring for
1.5 h, the reaction was stopped by adding 2m aq. HCl and the reaction
mixture was diluted with EtOAc. After separating the two layers, the or-
ganic layer was washed with 2m aq. HCl and brine, dried (Na2SO4), and
concentrated in vacuo. After adding Et2O to the residue, the precipitate
was collected by filtration to afford 46 as a red powder (6.1 mg, 63%).
The filtrate was concentrated in vacuo and the residue was purified by
column chromatography (CHCl3/MeOH=93:7) to afford 46 (2.8 mg,
17%; total yield: 80%).
Anthraquinone 43: A solution of siloxydiene 21 (94.5 mg, 0.467 mmol) in
THF (2 mL) was added to a solution of 42 (120 mg, 0.220 mmol) in THF
(3 mL) at 08C. Immediately, the ice bath was removed and the reaction
mixture was stirred for 2 h at RT. Acidic SiO2 (pH 6) (8 g) was added to
the reaction mixture and the solvent removed in vacuo. After standing
for 12 h, the SiO2 was placed on a Celite pad, washed with EtOAc, and
then the filtrate was concentrated in vacuo. K2CO3 (348 mg, 2.52 mmol)
was added to the solution of this crude material in THF/CH2Cl2 (1:3)
(10 mL) at RT. After stirring for 1.5 h, K2CO3 (324 mg, 2.34 mmol) was
added to the reaction mixture and stirred for a further 1 h. The reaction
was stopped by adding 1m aq. HCl and the mixture was extracted with
CH2Cl2 (”3). The combined organic extracts were washed with water
and brine, dried (Na2SO4), and concentrated in vacuo. After adding Et2O
to the residue, the precipitate was collected by filtration to afford qui-
none 43 as a yellow powder (101 mg, 76%). The filtrate was concentrated
in vacuo and the residue was purified by PTLC (CHCl3/MeOH=95:5) to
afford 43 as a yellow solid (18.8 mg, 14%; total yield: 90%). M.p.>
2208C; [a]2D6 =+76.8 (c=0.800 in CHCl3); 1H NMR (400 MHz, CDCl3):
d=1.70–2.37 (br, 6H), 2.38 (s, 3H), 3.51 (s, 3H), 3.64 (s, 3H), 3.95 (s,
3H), 3.96 (s, 3H), 5.90–6.16 (br, 2H), 6.68 (d, J=2.5 Hz, 1H), 6.80–7.30
(br, 1H), 7.34 (d, J=2.5 Hz, 1H), 7.80–8.40 (br, 1H), 12.71 ppm (s, 1H;
OH); 13C NMR (100 MHz, CDCl3, 323 K): d=19.4, 20.8, 29.7, 52.4, 56.1,
61.8, 62.2, 70.7 (br), 106.1, 107.6, 110.6, 126.3 (br), 129.8 (br), 131.7 (br),
135.0, 135.6 (br), 136.8, 138.3, 139.9 (br), 156.3, 159.5, 165.1, 166.8, 168.2,
169.8, 181.1, 185.7 ppm (signals for four sp2 carbon atoms were not de-
tected presumably owing to peak-broadening ascribed to the slow confor-
mational interconversion, diaxialQdiequatorial); IR (KBr): n˜ =3450,
3020, 2950, 1740, 1680, 1630, 1610, 1590, 1440, 1370, 1310, 1260, 1230,
1160, 1120, 1070, 1040, 970, 750 cmꢀ1; elemental analysis calcd (%) for
C32H28O12: C 63.57, H 4.67; found: C 63.37, H 4.86.
45: M.p.>2308C; 1H NMR (400 MHz, [D6]DMSO, 313 K): d=2.48 (s,
3H), 3.94 (s, 3H), 4.25 (d, J=10.5 Hz, 1H), 4.32 (d, J=10.5 Hz, 1H),
6.90 (d, J=2.3 Hz, 1H), 7.08 (s, 1H), 7.27 (d, J=2.3 Hz, 1H), 8.08 (s,
1H), 12.86 ppm (s, 1H; OH); 13C NMR (100 MHz, [D6]DMSO, 313 K):
d=21.7, 56.3, 71.6, 72.2, 106.6, 107.4, 110.1, 114.3, 115.1, 115.4, 117.8,
118.1, 125.7, 131.4, 134.6, 139.7, 143.6, 149.4, 155.7, 157.7, 164.6, 165.9,
171.4, 185.3, 187.0 ppm; IR (KBr): n˜ =3396, 2930, 2850, 1715, 1605, 1488,
1446, 1386, 1296, 1255, 1188, 1162, 1119, 1083, 1064, 1033, 983, 967,
822 cmꢀ1
.
46: M.p.>2308C; 1H NMR (400 MHz, [D6]DMSO, 313 K): d=1.32 (d,
J=7.3 Hz, 3H), 2.32 (s, 3H), 3.67 (s, 3H), 3.91 (s, 3H), 4.23 (d, J=
10.0 Hz, 1H), 4.25 (d, J=10.0 Hz, 1H), 4.46 (qd, J=6.7, 7.3 Hz, 1H),
5.95 (brs, 1H; OH), 6.15 (brs, 1H; OH), 6.86 (d, J=2.4 Hz, 1H), 7.07 (s,
1H), 7.19 (d, J=2.4 Hz, 1H), 8.08 (s, 1H), 8.46 (brs, 1H), 8.68 (d, J=
6.7 Hz, 1H; NH), 12.81 (s, 1H; OH), 13.84 ppm (brs, 1H; OH);
13C NMR (100 MHz, [D6]DMSO, 313 K): d=16.7, 19.0, 47.8, 51.7, 56.4,
71.4, 72.3, 106.8, 107.6, 110.0, 113.7, 115.3, 115.6, 117.5, 125.8, 127.1,
131.2, 134.2, 137.4, 141.0, 149.9, 150.8, 156.6, 164.8, 165.9, 173.0, 185.1,
187.4 ppm (signals for four sp2 carbon atoms were not detected presuma-
bly owing to peak-broadening ascribed to the slow conformational inter-
conversion, diaxialQdiequatorial); IR (neat): n˜ =3490, 3250, 1740, 1640,
1600, 1450, 1430, 1400, 1380, 1340, 1290, 1240, 1210, 1160, 1140, 1110,
1080, 1070, 1030, 1000, 980, 960, 920, 900, 880, 840, 810, 800, 790 cmꢀ1; el-
emental analysis calcd (%) for C29H25NO11: C 61.81, H 4.47, N 2.49;
found: C 61.51, H 4.71, N 2.29.
Benzo[a]naphthacene 48: 2-Methoxypropene (264 mg, 3.65 mmol) and
TsOH·H2O (21.5 mg, 0.113 mmol) were added to
a solution of 46
(205 mg, 0.364 mmol) in DMF (3 mL) at RT. After stirring 18 h at RT,
the reaction was stopped by adding water and the mixture was extracted
with EtOAc (”3). The combined organic extracts were washed with
water (”3) and brine, dried (Na2SO4), and concentrated in vacuo. Ac2O
(0.8 mL) and zinc powder (40 mg, 0.764 mmol) were added to the solu-
tion of this crude material in pyridine (6 mL) at RT. After stirring for
10 h at this temperature, the reaction was stopped by adding MeOH and
the mixture was extracted with EtOAc (”3). The combined organic ex-
tracts were successively washed with 2m aq. HCl (”3), water (”1), satu-
rated aqueous NaHCO3 (”1), and brine (”2), dried (Na2SO4), and con-
centrated in vacuo. The residue was purified by PTLC (benzene/ace-
tone=75:25) to afford pentacycle 47 as a yellow solid (218 mg, 73%, two
steps) contaminated with a trace amount of impurity (<1%, 1H NMR)
arising from the air sensitivity of this compound. This material was em-
ployed in the next experiment without further purification. 1H NMR
(400 MHz, CDCl3): d=1.46 (d, J=7.1 Hz, 3H), 1.60 (s, 3H), 1.63 (s, 3H),
2.17 (s, 3H), 2.28 (s, 3H), 2.44 (s, 3H), 2.46 (s, 3H), 2.57 (s, 3H), 2.60 (s,
3H), 3.78 (s, 3H), 3.93 (s, 3H), 4.54 (d, J=10.7 Hz, 1H), 4.60 (d, J=
Phenol 44: BCl3 (1.0m in hexane, 0.50 mL, 0.50 mmol) was added to a so-
lution of 43 (31.9 mg, 52.8 mmol) in CH2Cl2 (2 mL) at ꢀ108C. The reac-
tion mixture was stirred for 30 min and then the reaction was stopped by
adding saturated aqueous NaHCO3. After adding 1m aq. HCl, the mix-
ture was extracted with CH2Cl2 (”3). The combined organic extracts
were washed with brine, dried (Na2SO4), and concentrated in vacuo.
After adding Et2O to the residue, the precipitate was collected by filtra-
tion to afford quinone 44 as an orange powder (28.1 mg, 92%). The fil-
trate was concentrated in vacuo and the residue was purified by PTLC
(CHCl3/MeOH=97:3) to afford 44 as a red powder (2.0 mg, 7%; total
yield: 99%). M.p.>2208C; [a]3D1 =+127 (c=0.500 in CHCl3); 1H NMR
(400 MHz, CDCl3, 323 K): d=2.08 (s, 3H), 2.13 (s, 3H), 2.48 (s, 3H),
3.94 (s, 3H), 3.99 (s, 3H), 5.99 (d, J=7.8 Hz, 1H), 6.05 (d, J=7.8 Hz,
1H), 6.72 (d, J=2.5 Hz, 1H), 6.85 (s, 1H), 7.40 (d, J=2.5 Hz, 1H), 7.90
(s, 1H), 10.18 (brs, 1H; OH), 12.78 (s, 1H; OH), 14.27 ppm (brs, 1H;
OH); 13C NMR (100 MHz, CDCl3, 323 K): d=20.8, 21.7, 52.3, 56.2, 70.6,
9812
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 9791 – 9823

Synthesis of Benanomicin-Pradimicin Antibiotics
FULL PAPER
10.7 Hz, 1H), 4.79 (qd, J=7.1, 7.8 Hz, 1H), 6.25 (d, J=7.8 Hz, 1H; NH),
6.93 (d, J=2.4 Hz, 1H), 7.09 (d, J=2.4 Hz, 1H), 7.29 (s, 1H), 7.86 ppm
(s, 1H); 13C NMR (100 MHz, CDCl3): d=18.3, 19.1, 20.7, 21.06, 21.14,
21.2, 27.28, 27.31, 48.0, 52.6, 55.5, 79.2, 79.7, 96.8, 112.5, 115.4, 116.0,
116.7, 120.8, 122.3, 124.6, 127.8, 131.0, 133.3, 138.1, 138.5, 138.7, 139.3,
141.3, 143.8, 146.2, 150.7, 157.5, 166.1, 168.3, 168.7, 169.0, 169.2, 169.8,
172.6 ppm.
2H), 4.64 (d, J=7.4 Hz, 1H), 4.77 (qd, J=7.2, 7.5 Hz, 1H), 4.86 (d, J=
8.1 Hz, 1H), 4.93 (dd, J=7.4, 9.2 Hz, 1H), 4.95 (ddd, J=6.7, 9.2, 10.0 Hz,
1H), 5.06 (dd, J=9.2, 9.2 Hz, 1H), 5.70 (brs, 1H), 6.22 (d, J=7.5 Hz,
1H; NH), 6.92 (s, 1H), 7.03 (s, 1H), 7.38 (s, 1H), 7.53 (dd, J=7.4, 7.8 Hz,
2H), 7.65 (t, J=7.4 Hz, 1H), 8.09 (d, J=7.8 Hz, 2H), 8.22 ppm (brs,
1H); 13C NMR (125 MHz, CDCl3): d=17.2, 18.3 (2C), 19.2, 19.7, 20.0,
20.6, 20.7, 20.8, 21.0, 21.1, 21.2, 48.0, 52.5, 55.4, 62.6, 65.9, 69.0, 69.5, 71.1,
71.2, 71.7, 72.4, 72.8, 80.4, 96.6, 102.4, 103.0, 115.8, 116.7, 117.1, 119.9,
120.6, 121.6, 123.9, 124.6, 127.8, 129.0, 129.6, 131.0, 133.4, 133.9, 137.6,
137.9, 139.9, 140.0, 140.5, 143.2, 146.5, 157.4, 164.6, 166.1, 168.1, 168.9
(br), 169.0, 169.2, 169.7, 169.8, 170.0, 170.2, 172.7 ppm (signals for four
sp2 carbon atoms were not detected presumably owing to peak-broaden-
ing ascribed to the slow conformational interconversion, diaxialQdiequa-
torial); IR (ATR): n˜ =3528, 3376, 2941, 2109, 1741, 1667, 1638, 1513,
1432, 1361, 1247, 1184, 1113, 1025, 876, 712 cmꢀ1; elemental analysis
calcd (%) for C63H64N4O27: C 57.80, H 4.93, N 4.28; found: C 58.01, H
5.17, N 4.01.
TsOH·H2O (36.5 mg, 0.192 mmol) was added to
a solution of 47
(63.6 mg, 0.0780 mmol) in CH3CN/H2O (4:1) (3 mL) at RT. After stirring
for 2 h at RT, the reaction was stopped by adding water, the mixture was
extracted with EtOAc (”2), and washed with saturated aqueous
NaHCO3 and water. The combined organic extracts were washed with
brine, dried (Na2SO4), and concentrated in vacuo. The residue was puri-
fied by PTLC (benzene/acetone=1:1) to afford 48 as a yellow solid
(56.5 mg, 93%). M.p. 190–1918C (hexane and EtOAc); 1H NMR
(400 MHz, [D6]acetone): d=1.46 (d, J=7.2 Hz, 3H), 2.21 (s, 3H), 2.31 (s,
3H), 2.44 (s, 3H), 2.46 (s, 3H), 2.61 (s, 3H), 2.71 (s, 3H), 3.76 (s, 3H),
3.99 (s, 3H), 4.36 (dd, J=4.8, 10.8 Hz, 1H), 4.44 (ddd, J=0.8 4.4,
10.8 Hz, 1H), 4.68 (qd, J=7.2, 7.2 Hz, 1H), 5.13(brs, 1H; OH), 5.26 (d,
J=4.8 Hz, 1H; OH), 7.05 (d, J=0.8 Hz, 1H), 7.27 (s, 1H), 7.55 (s, 1H),
7.62 (d, J=7.2 Hz, 1H; NH), 8.25 ppm (s, 1H); 13C NMR (100 MHz,
[D6]acetone): d=17.6, 19.3, 20.7, 21.0, 21.16, 21.21, 21.3, 48.9, 52.3, 56.1,
73.6, 74.2, 97.2, 115.2, 116.5, 117.4, 120.9, 121.6, 123.9, 124.3, 125.3, 128.5,
132.2, 138.2, 138.4, 138.8, 140.2, 141.2, 142.5, 144.5, 147.7, 158.5, 166.8,
168.9, 169.1, 169.8, 169.9, 170.1, 173.5 ppm; IR (ATR): n˜ =3490, 3340,
2940, 2860, 1760, 1640, 1530, 1450, 1430, 1420, 1360, 1240, 1180, 1120,
1020, 880 cmꢀ1; elemental analysis calcd (%) for C39H37NO16: C 60.39, H
4.81, N 1.81; found: C 60.61, H 5.01, N 1.72.
Benanomicin B hydrochloride (2b·HCl): A 2m aq. HCl solution (100 mL)
and 5% Pd/C (30 mg) were added to
a solution of 49 (37.0 mg,
0.0283 mmol) in MeOH (5.0 mL). After stirring under H2 (1 atm) at RT
for 6 h, the reaction mixture was filtered though a Celite pad (washed
with MeOH) and the filtrate was concentrated in vacuo. A 1m aq. NaOH
solution (5 mL) was added to a solution of this crude material (36.0 mg)
in MeOH (5.0 mL). After stirring for 2 h, the reaction was stopped by
adding 2m aq. HCl (ca. 3.0 mL) and the mixture concentrated in vacuo
(azeotropic evaporation ”5). The residue was purified by Sephadex LH-
20 (DMF) to afford a dimethyformamide solvate of benanomicin B
which was dissolved in MeOH and then 2m aq. HCl was added until
pH 3.5. After removal of the volatile material in vacuo, the residue was
dissolved in DMSO (0.05 mL) and CHCl3 (ca. 6.0 mL) was added. The
precipitate was collected by filtration to afford benanomicin B hydro-
chloride (16.7 mg, 68%67% given in legend to Scheme 12.) as a red
amorphous powder. M.p. 213–2158C (decomp) (lit.:[1b] >2208C
(decomp)); [a]2D2 =+353 (c=0.0501 in H2O) (lit.:[1b] +360 (c=0.05,
H2O)); 1H NMR (500 MHz, [D6]DMSO, 313 K): d=1.18 (d, J=6.5 Hz,
3H), 1.34 (d, J=7.3 Hz, 3H), 2.33 (s, 3H), 3.07 (dd, J=10.7, 10.9 Hz,
1H), 3.16–3.18 (m, 3H), 3.29–3.34 (m, 1H), 3.39–3.44 (m, 1H), 3.60 (br,
1H), 3.72 (dd, J=5.3, 11.3 Hz, 1H), 3.83 (brq, J=6.5, 1H), 3.91–3.94 (m,
1H), 3.95 (s, 3H), 4.42 (dq, J=7.1, 7.3 Hz, 1H), 4.53–4.56 (m, 2H), 4.58–
4.65 (m, 1H), 4.74 (d, J=7.6 Hz, 1H), 6.94 (d, J=2.4 Hz, 1H), 7.23 (brs,
1H), 7.31 (d, J=2.4 Hz, 1H), 8.06 (s, 1H), 8.43 (d, J=7.1 Hz, 1H),
12.8 ppm (s, 1H); 13C NMR (125 MHz, [D6]DMSO, 313 K): d=16.3, 16.9,
19.1, 47.6, 54.2, 56.4, 65.7, 66.9, 69.4, 69.7, 73.3, 75.9, 77.4, 80.9, 104.0,
104.5, 106.9, 107.6, 110.1, 113.7, 115.6, 125.7, 127.5, 131.3, 134.3, 137.3,
137.8, 147.9, 151.0, 156.9, 164.7, 166.0, 166.8, 173.9, 185.0, 187.5 ppm; IR
b-Glycosides 49 and 50: MS4A (300 mg) was placed in a two-necked
round-bottomed flask and flame dried. The promoter was prepared in
situ by stirring
a mixture of Cp2HfCl2 (31.5 mg, 0.0830 mmol) and
AgClO4 (32.0 mg, 0.154 mmol) in CH2Cl2 (1.0 mL) for 10 min at RT. A
solution of 48 (20.3 mg, 0.0261 mmol) and glycosyl fluoride 51 (28.3 mg,
0.0530 mmol) in CH2Cl2 (3.0 mL) was added to this suspension at ꢀ788C.
The reaction mixture was warmed to ꢀ128C, stirred for 25 min, and the
reaction was stopped by adding saturated aqueous NaHCO3. The mixture
was filtered through a Celite pad and extracted with EtOAc (”3). The
combined organic extracts were washed with brine, dried (Na2SO4), and
concentrated in vacuo. The residue was purified by PTLC (acetone/ben-
zene=3:7) to afford b-glycoside 49 as a yellow amorphous solid (9.1 mg,
27%) and its regioisomeric b-glycoside 50 also as a yellow amorphous
solid (5.1 mg, 17%).
49: M.p. 198.2–199.18C; [a]2D5 =ꢀ75.2 (c=0.874 in CHCl3); 1H NMR
(500 MHz, CDCl3): d=1.34 (d, J=6.3 Hz, 3H), 1.44 (d, J=7.2 Hz, 3H),
1.62 (s, 3H), 1.97 (s, 3H), 2.01 (s, 3H), 2.11 (s, 3H), 2.26 (s, 3H), 2.42 (s,
6H), 2.49 (s, 3H), 2.57 (s, 3H), 3.33 (dd, J=9.3, 11.6 Hz, 1H), 3.66–3.72
(m, 1H), 3.78 (s, 3H), 3.89 (dd, J=0.8, 3.6 Hz, 1H), 3.92 (s, 3H), 4.08
(dd, J=3.6, 10.0 Hz, 1H), 4.14 (dd, J=5.2, 11.6 Hz, 1H), 4.49 (brd,
11.2 Hz, 1H), 4.66 (d, J=7.2 Hz, 1H), 4.77 (qd, J=7.2, 7.7 Hz, 1H),
4.9016 (dd, J=7.2, 9.2 Hz, 1H), 4.9025 (d, J=8.2 Hz, 1H), 4.94 (ddd, J=
5.2, 9.1, 9.3 Hz, 1H), 5.05 (dd, J=9.1, 9.2 Hz, 1H), 5.68 (dd, J=8.2,
10.0 Hz, 1H), 6.16 (d, J=7.7 Hz, 1H; NH), 6.91 (d, J=2.3 Hz, 1H), 7.05
(s, 1H), 7.50–7.67 (m, 4H), 7.98 (s, 1H), 8.08–8.13 ppm (m, 2H);
13C NMR (125 MHz, CDCl3): d=17.2, 18.2, 19.3, 19.9, 20.6, 20.7 (2C),
20.98, 21.03, 21.1, 21.2, 48.0, 52.5, 55.5, 62.4, 65.6, 68.9, 69.7, 71.0, 71.3,
71.6, 72.8, 80.3, 81.7, 96.7, 102.2, 102.3, 114.8, 115.9, 116.5, 119.9, 120.3,
121.9, 124.5, 125.6, 127.8, 128.9, 129.2, 129.7, 131.1, 133.8, 134.6, 137.8,
138.1, 139.2, 139.5, 140.4, 143.1, 146.3, 157.5, 164.7, 166.2, 168.5, 168.6–
169.3 (3C), 169.1, 169.6, 169.8, 170.2, 172.6; IR (ATR): n˜ =3488, 3369,
2941, 2111, 1742, 1667, 1638, 1520, 1450, 1433, 1361, 1247, 1175, 1116,
1025, 876, 713 cmꢀ1; elemental analysis calcd (%) for C63H64N4O27: C
57.80, H 4.93, N 4.28; found: C 57.60, H 5.21, N 4.05.
(KBr): n˜ =3360, 1730, 1610, 1300, 1160, 1080, 1040 cmꢀ1
; LRMS
(MALDI-TOF, DHBA matrix): m/z: calcd for C39H42O18N2Na ([M+Na]+):
849.2; found: 849.2; HRMS (FAB): m/z: calcd for C39H43O18N2 ([M+H]+):
827.2511; found: 827.2506.
Second-generation synthesis
Methyl
2-methoxymethoxy-6-methyl-4-[(triisopropylsiloxy)methyl]ben-
zoate: Imidazole (17.3 g, 0.254 mol) and triisopropylsilyl chloride
(28.2 mL, 0.133 mol) were added to a solution of 11 (30.5 g, 0.127 mol) in
DMF (130 mL) at 08C. After stirring for 2 h at RT, the reaction was stop-
ped by adding water and the mixture was extracted with EtOAc (”3).
The combined organic extracts were washed with brine, dried (Na2SO4),
and concentrated in vacuo. The residue was purified by flash column
chromatography (silica gel, hexane/EtOAc=4:1 to 3:1, gradient elution)
to afford methyl 2-methoxymethoxy-6-methyl-4-[(triisopropylsiloxy)me-
thyl]benzoate as
a
colorless oil (50.5 g, quant). 1H NMR (400 MHz,
CDCl3): d=1.05–1.25 (m, 21H), 2.29 (s, 3H), 3.46 (s, 3H), 3.90 (s, 3H),
4.79 (s, 2H), 5.16 (s, 2H), 6.83 (s, 1H), 7.04 ppm (s, 1H); 13C NMR
(100 MHz, CDCl3): d=12.1, 18.1, 19.5, 52.1, 56.0, 64.5, 94.7, 109.6, 120.4,
123.0, 136.2, 144.4, 154.1, 168.6ppm; IR (neat): n˜ =3000, 2890, 2870,
1730, 1610, 1590, 1460, 1440, 1270, 1160, 1110, 1090, 1050, 1000, 930, 880,
810 cmꢀ1; elemental analysis calcd (%) for C21H36O5Si: C 63.60, H 9.15;
found: C 63.50, H 9.08.
50: M.p. 191.5–192.58C; [a]2D6 =ꢀ192 (c=0.705 in CHCl3); 1H NMR
(500 MHz, CDCl3): d=1.32 (brs, 3H), 1.45 (d, J=7.2 Hz, 3H), 1.66 (s,
3H), 1.97 (s, 3H), 2.01 (s, 3H), 2.16 (s, 3H), 2.20 (s, 3H), 2.39 (s, 3H),
2.49 (s, 3H), 2.56 (s, 3H), 2.77 (s, 3H), 3.32 (dd, J=10.0, 11.2 Hz, 1H),
3.68 (brs, 1H), 3.77 (s, 3H), 3.91 (s, 3H), 3.94 (d, J=3.6 Hz, 1H), 4.10
(dd, J=3.6, 10.0 Hz, 1H), 4.13 (dd, J=6.7, 11.2 Hz, 1H), 4.41–4.52 (m,
Chem. Eur. J. 2007, 13, 9791 – 9823
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9813

K. Suzuki et al.
Methyl 2-hydroxy-6-methyl-4-[(triisopropylsiloxy)methyl]benzoate: Tri-
fluoroacetic acid (8.8 mL, 0.12 mol) was added to a solution of methyl 2-
methoxymethoxy-6-methyl-4-[(triisopropylsiloxy)methyl]benzoate
(30.4 g, 76.5 mmol) in CH2Cl2 (300 mL) at 08C. After stirring for 3.5 h at
08C and then for 2.5 h at RT, the reaction was stopped by adding saturat-
ed aqueous NaHCO3 and the mixture was extracted with EtOAc (”3).
The combined organic extracts were washed with brine, dried (Na2SO4),
and concentrated in vacuo. After adding Et2O and hexane to the residue,
the precipitate was collected by filtration to afford methyl 2-hydroxy-6-
methyl-4-[(triisopropylsiloxy)methyl]benzoate (1st crop: 22.8 g, 85%; 2nd
crop: 1.50 g, 5.5%) as a white solid. The filtrate was concentrated in
vacuo and the residue was purified by flash column chromatography
(silica gel, hexane/EtOAc=95:5) to afford methyl 2-hydroxy-6-methyl-4-
[(triisopropylsiloxy)methyl]benzoate as a white solid (1.40 g, 5.2%; total
yield: 96%). M.p. 56.5–57.28C (hexane and Et2O); 1H NMR (400 MHz,
CDCl3): d=1.06–1.27 (m, 21H), 2.53 (s, 3H), 3.95 (s, 3H), 4.76 (s, 2H),
6.67 (s, 1H), 6.87 (s, 1H), 11.37 ppm (s, 1H; OH); 13C NMR (100 MHz,
CDCl3): d=12.1, 18.1, 24.3, 52.0, 64.3, 110.5, 112.2, 119.9, 141.0, 148.6,
163.0, 172.1; IR (ATR): n˜ =2950, 2890, 2860, 1660, 1630, 1580, 1450,
1420, 1370, 1320, 1280, 1220, 1160, 1110, 1060, 1010, 990, 950, 880, 850,
800 cmꢀ1; elemental analysis calcd (%) for C19H32O4Si: C 64.73, H 9.15;
found: C 64.93, H 9.39.
Ethyl 7-chloro-5,8-dimethoxy-4-methoxymethoxy-2-naphthoate: 7-Chloro-
4-hydroxy-5,8-dimethoxy-2-naphthoate (25.7 g, 82.8 mmol) and MOMCl
(9.43 mL, 0.124 mmol) were added to a suspension of NaH (55% disper-
sion in mineral oil, washed with hexane (4.69 g, 0.108 mol)) in DMF
(830 mL) at 08C. After stirring for 1 h, the reaction was stopped by
adding water and the resulting mixture was extracted with Et2O (”3).
The combined organic extracts were washed with brine, dried (MgSO4),
and concentrated in vacuo. After adding Et2O and hexane to the residue,
the precipitate was collected by filtration to afford the title compound as
a white powder (1st crop: 14.8 g, 51%; 2nd crop: 8.94 g, 30%; 3rd crop:
4.39 g, 15%; 4th crop: 1.17 g, 4%; total yield: quant). M.p. 119.7–120.08C
1
(hexane and EtOAc); H NMR (400 MHz, CDCl3): d=1.44 (t, J=8.1 Hz,
3H), 3.60 (s, 3H), 3.95 (s, 3H), 3.98 (s, 3H), 4.44 (q, J=8.1 Hz, 2H), 5.31
(s, 2H), 6.88 (s, 1H), 7.62 (d, J=1.6 Hz, 1H), 8.49 ppm (d, J=1.6 Hz,
1H); 13C NMR (100 MHz, CDCl3): d=14.4, 56.6, 56.7, 61.3, 61.6, 96.4,
109.6, 112.0, 118.8, 120.1, 123.9, 129.3, 131.3, 146.3, 153.4, 154.5,
166.2 ppm; IR (KBr): n˜ =3120, 3070, 2980, 2830, 1730, 1590, 1510, 1460,
1390, 1330, 1270, 1230, 1180, 1150, 1140, 1050, 1030, 930, 820, 770 cmꢀ1
;
elemental analysis calcd (%) for C17H19O6Cl: C 57.55, H 5.40; found: C
57.35, H 5.55.
7-Chloro-5,8-dimethoxy-4-methoxymethoxy-2-naphthoic acid (52): A 6m
aq. NaOH solution (330 mL) was added to a suspension of ethyl 7-
chloro-5,8-dimethoxy-4-methoxymethoxy-2-naphthoate
(35.0 g,
Methyl 2-hydroxy-3-iodo-6-methyl-4-[(triisopropylsiloxy)methyl]benzoate
98.5 mmol) in THF (450 mL) and EtOH (180 mL) and the reaction mix-
ture was heated at 708C for 1 h. After cooling to RT, the reaction mix-
ture was diluted with water and then the aqueous layer was washed with
Et2O (”3). The aqueous phase was acidified with 6m aq. HCl. The crys-
talline precipitates were collected by filtration and dried to afford 52 as a
white powder (32.1 g, quant). M.p. 192–1938C (Et2O and EtOAc);
1H NMR (400 MHz, [D6]DMSO): d=3.32 (s, 3H), 3.87 (s, 3H), 3.99 (s,
3H), 5.29 (s, 2H), 7.08 (s, 1H), 7.53 (d, J=1.5 Hz, 1H), 8.28 (d, J=
1.5 Hz, 1H), 13.3 ppm (brs, 1H); 13C NMR (100 MHz, [D6]DMSO): d=
56.0, 56.7, 61.3, 95.7, 109.3, 111.1, 117.3, 119.1, 123.4, 129.8, 130.5, 145.2,
153.4, 154.6, 166.8 ppm; IR (ATR): n˜ =2960, 2930, 2910, 2840, 1640, 2540,
1700, 1590, 1510, 1460, 1440, 1370, 1330, 1280, 1230, 1160, 1130, 1090,
1030, 990, 970, 920, 910, 890, 800, 770, 710 cmꢀ1; elemental analysis calcd
(%) for C15H15O6Cl: C 55.14, H 4.63; found: C 54.91, H 4.86.
ꢀ
(53): NaHCO3 (2.39 g, 28.4 mmol), BnMe3N+ICl2 (4.99 g, 14.3 mmol),
and MeOH (35 mL) were added to a solution of methyl 2-hydroxy-6-
methyl-4-[(triisopropylsiloxy)methyl]benzoate (5.00 g, 14.2 mmol) in
CH2Cl2 (90 mL). After stirring for 4 h at RT, the reaction was stopped by
adding aqueous Na2S2O3 and the mixture was extracted with EtOAc (”
3). The combined organic extracts were washed with brine, dried
(Na2SO4), and concentrated in vacuo. The residue was passed through a
silica gel column (hexane/EtOAc=95:5) to afford somewhat impure 53
with trace amounts of by-products. The mixture was further purified by
washing with MeOH to give a pure form of 53 as a white amorphous
solid (5.77 g, 85%). The filtrate was concentrated in vacuo and the resi-
due was further purified by flash column chromatography (silica gel,
hexane/benzene=1:1) to afford an additional product of 53 as a white
amorphous solid (0.650 g, 9.6%; total yield: 95%). M.p. 33.9–34.18C
(hexane); 1H NMR (400 MHz, CDCl3): d=1.06–1.24 (m, 21H), 2.53 (s,
3H), 3.96 (s, 3H), 4.68 (s, 2H), 7.05 (s, 1H), 12.3 (s, 1H); 13C NMR
(100 MHz, CDCl3): d=12.0, 18.1, 24.2, 52.5, 70.0, 83.4, 110.8, 121.6, 141.2,
149.9, 160.4, 171.8 ppm; IR (KBr): n˜ =2940, 2890, 2870, 1660, 1600, 1540,
1470, 1450, 1390, 1360, 1340, 1280, 1240, 1200, 1180, 1120, 1060, 980, 950,
880, 820 cmꢀ1; elemental analysis calcd (%) for C19H31IO4Si: C 47.70, H
6.53; found: C 47.70, H 6.56.
2-Iodo-6-methoxycarbonyl-5-methyl-3-[(triisopropylsiloxy)methyl]phenyl
7-chloro-5,8-dimethoxy-4-methoxymethoxy-2-naphthoate: Et3N (8.45 mL,
60.6 mmol) and 2,4,6-trichlorobenzoyl chloride (9.47 mL, 60.6 mmol)
were added to a solution of carboxylic acid 52 (18.0 g, 55.1 mmol) in tolu-
ene (540 mL) at RT. After stirring for 3 h at RT, iodophenol 53 (27.7 g,
57.9 mmol) and DMAP (10.2 g, 82.7 mmol) were added to the reaction
mixture which was then stirred for 20 min. The reaction was stopped by
adding water and the mixture was extracted with EtOAc (”3). The com-
bined organic extracts were washed with brine, dried (Na2SO4), and con-
centrated in vacuo. After adding Et2O and hexane to the residue, the pre-
cipitate was collected by filtration to afford the title compound as a
yellow solid (40.1 g, 95%). The filtrate was concentrated in vacuo and
the residue was purified by flash column chromatography (silica gel,
hexane/EtOAc=9:1 to 7:3, gradient elution) to afford further 2-iodo-6-
methoxycarbonyl-5-methyl-3-(triisopropylsiloxymethyl)phenyl 7-chloro-
5,8-dimethoxy-4-methoxymethoxy-2-naphthoate as a yellow solid (1.67 g,
4%; total yield: 99%). M.p. 156–1578C (hexane and Et2O); 1H NMR
(400 MHz, CDCl3): d=1.08–1.28 (m, 21H), 2.47 (s, 3H), 3.62 (s, 3H),
3.70 (s, 3H), 3.97 (s, 3H), 4.00 (s, 3H), 4.75 (s, 2H), 5.34 (s, 2H), 6.93 (s,
1H), 7.46 (s, 1H), 7.75 (s, 1H), 8.72 (s, 1H); 13C NMR (100 MHz,
CDCl3): d=12.1, 18.1, 20.4, 52.3, 56.7, 56.8, 61.7, 69.7, 89.6, 96.4, 110.2,
112.0, 120.0, 120.5, 124.2, 125.6, 126.9, 127.7, 131.3, 138.5, 146.3, 146.8,
148.5, 153.4, 154.8, 163.4, 166.0 ppm; IR (KBr): n˜ =2940, 2890, 2860,
1730, 1590, 1460, 1370, 1340, 1260, 1190, 1150, 1120, 1080, 1020, 980, 920,
880, 820, 800, 750 cmꢀ1; elemental analysis calcd (%) for C34H44ClO9Si: C
51.88, H 5.63; found: C 52.08, H 5.64.
Ethyl 7-chloro-4-hydroxy-5,8-dimethoxy-2-naphthoate: K2CO3 (33.9 g,
0.245 mol) was added to a solution of 31 (28.8 g, 81.7 mmol) in EtOH
(350 mL) at RT. The reaction mixture was warmed to 608C and heated
at this temperature with stirring for 1.5 h. After cooling to 08C, the reac-
tion mixture was diluted with water and then the reaction was stopped
by adding 6m aq. HCl. The mixture was filtered through a Celite pad
(washed with EtOAc) and extracted with EtOAc (”3). The combined or-
ganic extracts were washed with brine, dried (Na2SO4), and concentrated
in vacuo. After adding Et2O and hexane to the residue, the precipitate
was collected by filtration to afford the title compound as a white crystal-
line solid (22.2 g, 88%). The filtrate was concentrated in vacuo and the
residue was purified by flash column chromatography (silica gel, hexane/
EtOAc=7:3) to afford further ethyl 7-chloro-4-hydroxy-5,8-dimethoxy-2-
naphthoate as a white crystalline solid (2.84 g, 11%; total yield: 99%).
M.p. 130–1318C (hexane and EtOAc); 1H NMR (400 MHz, CDCl3): d=
1.43 (t, J=7.1 Hz, 3H), 3.97 (s, 3H), 4.06 (s, 3H), 4.43 (q, J=7.1 Hz,
2H), 6.82 (s, 1H), 7.49 (d, J=1.7 Hz, 1H), 8.29 (d, J=1.7 Hz, 1H),
9.22 ppm (s, 1H; OH); 13C NMR (100 MHz, CDCl3): d=14.3, 56.7, 61.3,
61.5, 107.6, 110.9, 115.5, 116.6, 123.2, 130.6, 130.8, 147.4, 152.3, 155.0,
166.3 ppm; IR (KBr): n˜ =3560, 3100, 3030, 2990, 2950, 2900, 2850, 1720,
1600, 1520, 1460, 1390, 1340, 1310, 1270, 1230, 1210, 1160, 1120, 1090,
1030, 1020, 970, 940, 870, 840, 810, 770 cmꢀ1; elemental analysis calcd
(%) for C15H15O5Cl: C 57.98, H 4.87; found: C 58.0, H 5.03.
2-Iodo-6-methoxycarbonyl-5-methyl-3-[(triisopropylsiloxy)methyl]phenyl
7-chloro-4-hydroxy-5,8-dimethoxy-2-naphthoate (54): Trifluoroacetic acid
(9.4 mL, 0.122 mol) was added to a solution of 2-iodo-6-methoxycarbon-
yl-5-methyl-3-[(triisopropylsiloxy)methyl]phenyl 7-chloro-5,8-dimethoxy-
4-methoxymethoxy-2-naphthoate (32.0 g, 40.7 mmol) in CH2Cl2 (410 mL)
9814
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 9791 – 9823

Synthesis of Benanomicin-Pradimicin Antibiotics
FULL PAPER
1
at 08C. After stirring for 3.5 h at RT, the reaction was stopped by adding
saturated aqueous NaHCO3 and water, and then the mixture was extract-
ed with EtOAc (”3). The combined organic extracts were washed with
brine, dried (Na2SO4), and concentrated in vacuo. After adding Et2O and
hexane to the residue, the precipitate was collected by filtration to afford
phenol 54 as a white crystalline (21.2 g; 70%). The filtrate was concen-
trated in vacuo, and the residue was purified by flash column chromatog-
raphy (silica gel, hexane/EtOAc=4:1) to afford crude material that in-
cluded 54. Addition of Et2O and hexane allowed the formation of a pre-
cipitate that was collected by filtration to afford 54 as a white solid (1st
crop; 4.39 g, 15%; 2nd crop; 4.32 g, 14%; total yield: 99%). M.p. 139.5–
140.08C (hexane and Et2O); 1H NMR (400 MHz, CDCl3): d=1.09–1.30
(m, 21H), 2.46 (s, 3H), 3.70 (s, 3H), 4.00 (s, 3H), 4.08 (s, 3H), 4.75 (s,
2H), 6.87 (s, 1H), 7.45 (s, 1H), 7.63 (s, 1H), 8.50 (s, 1H), 9.30 ppm (s,
1H; OH); 13C NMR (100 MHz, CDCl3): d=12.1, 18.1, 20.4, 52.3, 56.8,
61.6, 69.7, 89.6, 108.1, 111.0, 116.7, 117.0, 123.5, 125.6, 126.9, 129.0, 130.8,
138.5, 146.8, 147.3, 148.6, 152.2, 155.2, 163.5, 166.0 ppm; IR (KBr): n˜ =
3394, 2943, 2866, 1736, 1603, 1514, 1448, 1387, 1340, 1265, 1205, 1151,
1119, 1078, 1026, 978, 951, 922, 883, 845, 820, 798, 756 cmꢀ1; elemental
analysis calcd (%) for C32H40ClO8Si: C 51.72, H 5.43; found: C 51.44, H
5.31.
(R,P)-57c: [a]2D7 =ꢀ26.8 (c=1.09 in CHCl3); H NMR (400 MHz, CDCl3):
d=0.80 (d, J=6.8 Hz, 3H), 0.85 (d, J=6.8 Hz, 3H), 0.92–1.08 (m, 21H),
1.54–1.62 (m, 1H), 1.92 (brs, 1H; OH), 2.64 (s, 3H), 3.12–3.29 (m, 2H),
3.68–3.73 (m, 1H), 3.97 (s, 3H), 3.99 (s, 3H), 4.01 (s, 3H), 4.42 (d, J=
15.2 Hz, 1H), 4.55 (d, J=15.2 Hz, 1H), 6.35 (d, J=8.8 Hz, 1H; NH), 6.80
(s, 1H), 7.23 (s, 1H), 7.95 (s, 1H), 9.56 (s, 1H; OH), 11.83 ppm (s, 1H;
OH); 13C NMR (100 MHz, CDCl3): d=11.9, 17.9, 18.2, 19.3, 24.4, 28.7,
52.3, 56.7, 57.6, 61.4, 62.8, 63.8, 106.8, 110.8, 113.0, 114.3, 114.7, 119.5,
121.4, 123.2, 130.6, 138.1, 141.3, 146.8, 147.7, 151.6, 152.2, 159.1, 169.1,
172.4ppm; IR (neat): n˜ =3380, 2960, 2940, 2870, 1660, 1610, 1600, 1520,
1450, 1410, 1360, 1290, 1260, 1200, 1130, 1100, 1040, 990, 950, 880, 810,
750 cmꢀ1; elemental analysis calcd (%) for C37H52ClNO9Si: C 61.86, H
7.30, N 1.95; found: C 61.58, H 7.20, N 1.67; HRMS (FAB): m/z: calcd
for C37H53O9NClSi ([M+H]+): 718.3179; found: 718.3184.
Benzyl ether (R,M)-65: BnBr (0.59 mL, 4.93 mmol) and Cs2CO3 (2.66 g,
8.15 mmol) were added to a solution of (R,M)-57c (1.48 g, 2.06 mmol) in
DMF (15 mL) at 08C. After stirring for 1 h, the reaction was stopped by
adding water and N,N-dimethylpropanediamine (0.5 mL), and the mix-
ture was extracted with Et2O (”3). The combined organic extracts were
washed with brine, dried (Na2SO4), and concentrated in vacuo. The resi-
due was purified by flash column chromatography (silica gel, hexane/
EtOAc=65:35) to afford (R,M)-65 as a yellow oil (1.79 g, 97%). [a]D27
=
Biaryl lactone 55: A suspension of ester 54 (1.50 g, 2.02 mmol), Pd(OAc)2
A
ꢀ80.7 (c=0.976 in CHCl3); 1H NMR (400 MHz, CDCl3): d=0.69 (d, J=
6.8 Hz, 3H), 0.73 (d, J=6.8 Hz, 3H), 0.88–1.05 (m, 21H), 1.64–1.70 (m,
1H), 2.41 (s, 3H), 2.62 (brs, 1H; OH), 3.40–3.50 (m, 2H), 3.59–3.63 (m,
1H), 3.75 (s, 3H), 3.76 (s, 3H), 4.00 (s, 3H), 4.59–4.77 (m, 6H), 6.23 (d,
J=6.8 Hz, 1H; NH), 6.85 (s, 1H), 6.96–7.00 (m, 4H), 7.10–7.11 (m, 3H),
7.25–7.26 (m, 3H), 7.32 (s, 1H), 8.47 ppm (s, 1H); 13C NMR (100 MHz,
CDCl3): d=11.9, 17.87, 17.93, 18.8, 19.0, 19.6, 28.9, 52.3, 56.4, 58.5, 61.7,
63.7, 63.8, 75.8, 75.9, 109.0, 119.8, 120.9, 123.9, 124.0, 125.1, 126.2, 127.2,
127.3, 127.4, 127.5, 127.8, 128.0, 131.2, 136.6, 136.9, 137.1, 137.5, 143.0,
146.1, 152.5, 152.7, 153.6, 168.2, 168.3ppm; IR (neat): n˜ =3420, 2940,
2870, 1730, 1660, 1600, 1570, 1520, 1460, 1340, 1280, 1060, 1040, 740,
700 cmꢀ1; elemental analysis calcd (%) for C51H64ClNO9Si: C 68.17, H
7.18, N 1.56; found: C 68.17, H 7.33, N 1.36; HRMS (FAB): m/z: calcd
for C51H65O9NClSi ([M+H]+): 898.4117; found: 898.4126.
(136 mg, 0.604 mmol), PPh3 (317 mg, 1.21 mmol), and sodium pivalate
(751 mg, 6.05 mmol) in DMA (100 mL) was heated at 1108C for 20 min.
After cooling the mixture to 08C, the reaction was stopped by adding
water. The crystalline precipitates were collected by filtration and
washed with Et2O. The resulting powder was dissolved in CH2Cl2 and fil-
tered through a Celite pad. The filtrate was concentrated in vacuo to
afford 55 as yellow solid (747 mg, 60%). M.p. 233.5–234.28C (CH2Cl2
and hexane); 1H NMR (500 MHz, CDCl3): d=0.91–1.08 (m, 21H), 2.45
(s, 3H), 4.01 (s, 3H), 4.02 (s, 3H), 4.14 (s, 3H), 4.93 (s, 2H), 6.96 (s, 1H),
7.51 (s, 1H), 8.61 (s, 1H), 10.2 ppm (s, 1H); 13C NMR (125 MHz, CDCl3):
d=11.9, 17.9, 19.6, 52.6, 57.1, 61.9, 65.1, 109.1, 113.0, 114.8, 116.3, 116.8,
120.9, 123.6, 124.1, 125.6, 129.9, 136.5, 142.2, 146.8, 147.8, 151.4, 152.1,
160.5, 167.2 ppm; IR (KBr): n˜ =3310, 2960, 2860, 1750, 1610, 1460, 1390,
1330, 1260, 1210, 1150, 1090, 1060, 1040, 950, 880, 830, 810 cmꢀ1; elemen-
tal analysis calcd (%) for C32H39ClO8Si: C 62.48, H 6.39; found: C 62.21,
H 6.26; HRMS (FAB): m/z: calcd for C32H40O8ClSi ([M+H]+): 615.2181;
found: 615.2199.
Oxazoline (R,M)-66: I2 (1.17 g, 4.62 mmol) was added to a solution of
(R,M)-65 (2.06 g, 2.30 mmol), imidazole (390 mg, 5.73 mmol), and PPh3
(1.53 g, 5.83 mmol) in CH2Cl2 (80 mL). After stirring for 20 min, the reac-
tion was stopped by adding saturated aqueous Na2S2O3 and the mixture
was extracted with EtOAc (”3). The combined organic extracts were
washed with brine, dried (Na2SO4), and concentrated in vacuo. The resi-
due was purified by flash column chromatography (silica gel, hexane/
Et2O/CHCl3 =70:15:15) to afford oxazoline (R,M)-66 as a yellow oil
(2.02 g, quant). [a]2D8 =ꢀ58.6 (c=1.06 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=0.76 (d, J=6.8 Hz, 3H), 0.76 (d, J=6.8 Hz, 3H), 0.93–1.05
(m, 21H), 1.52–1.56 (m, 1H), 2.39 (s, 3H), 3.72 (s, 3H), 3.76 (s, 3H),
3.80–3.87 (m, 2H), 3.99 (s, 3H), 4.18–4.25 (m, 1H), 4.54 (d, 14.4 Hz, 1H),
4.58 (d, 14.4 Hz, 1H), 4.59 (d, J=11.2 Hz, 1H), 4.63 (d, J=10.0 Hz, 1H)
4.69 (d, J=11.2 Hz, 1H), 4.73 (d, J=10.0 Hz, 1H), 6.83–6.85 (m, 3H),
6.96–7.05 (m, 5H), 7.17–7.24 (m, 3H), 7.34 (s, 1H), 8.44 ppm (s, 1H);
13C NMR (100 MHz, CDCl3): d=12.0, 18.0, 18.6, 18.9, 19.8, 33.3, 51.9,
56.6, 61.3, 63.1, 70.2, 73.5, 75.6, 75.9, 109.1, 120.0, 121.4, 122.6, 123.5,
126.0, 126.3, 126.7, 127.0, 127.1, 127.2, 127.7, 127.9, 128.0, 128.5, 130.7,
135.5, 137.6, 137.7, 143.8, 145.9, 152.7, 153.3, 153.6, 161.8, 169.1 ppm; IR
(neat): n˜ =2940, 2870, 1730, 1660, 1600, 1570, 1450, 1400, 1370, 1340,
1280, 1230, 1140, 1100, 1060, 1040, 950, 880, 810, 750, 700 cmꢀ1; elemental
analysis calcd (%) for C51H62ClNO8Si: C 69.56, H 7.10, N 1.59; found: C
69.66, H 7.37, N 1.53; HRMS (FAB): m/z: calcd for C51H63O8NClSi
([M+H]+): 880.4011; found: 880.4003.
Amide alcohol 57c: (R)-Valinol (0.875 g, 8.48 mmol) was added to a solu-
tion of 55 (2.01 g, 3.27 mmol) in CH2Cl2 (20 mL) at 08C. After stirring
for 43 h at 08C, the reaction was stopped by adding water and the mix-
ture was extracted with EtOAc (”3). The combined organic extracts
were washed with brine, dried (Na2SO4), and concentrated in vacuo. The
residue was purified by flash column chromatography (silica gel, hexane/
EtOAc=4:6) to afford a diastereomeric mixture of 57c as a yellow solid
(2.11 g, 90%, R,M:R,P=10:1). Recrystallization from hexane/EtOAc
gave pure (R,M)-57c (1.85 g, 79%) as a yellow powder. The filtrate was
concentrated in vacuo and the residue was further purified by PTLC
(hexane/EtOAc=4:6) to afford (R,M)-57c (0.0622 g, 2.6%, total yield:
82%) as a yellow powder and (R,P)-57c (0.187 g, 8%) as a yellow amor-
phous solid.
(R,M)-57c: M.p. 184–1858C (hexane and EtOAc); [a]2D5 =+58.0 (c=
0.994 in CHCl3); 1H NMR (400 MHz, CDCl3): d=0.63 (d, J=6.8 Hz,
3H), 0.67 (d, J=6.8 Hz, 3H), 0.78–1.12 (m, 21H), 1.59 (dsept, J=6.8,
6.8 Hz, 1H), 2.47 (t, J=5.6 Hz, 1H; OH), 2.62 (s, 3H), 3.50–3.55 (m,
2H), 3.61–3.72 (m, 1H), 3.96 (s, 3H), 3.99 (s, 3H), 4.01 (s, 3H), 4.44 (d,
J=14.4 Hz, 1H), 4.58 (d, J=14.4 Hz, 1H), 6.35 (d, J=8.0 Hz, 1H; NH),
6.79 (s, 1H), 7.18 (s, 1H), 7.99 (s, 1H), 9.55 (s, 1H; OH), 11.76 ppm (s,
1H; OH); 13C NMR (100 MHz, CDCl3): d=12.0, 18.0, 18.4, 18.9, 24.4,
28.9, 52.3, 56.7, 57.9, 61.5, 63.1, 64.1, 106.9, 111.1, 113.6, 114.5, 114.8,
119.7, 121.5, 123.2, 130.6, 138.0, 141.3, 146.9, 147.3, 151.5, 152.2, 159.4,
169.2, 172.2 ppm; IR (KBr): n˜ =3360, 2940, 2890, 2870, 1660, 1620, 1600,
1520, 1460, 1400, 1360, 1290, 1270, 1200, 1180, 1130, 1110, 1040, 1000,
950, 880, 810 cmꢀ1; elemental analysis calcd (%) for C37H52ClNO9Si: C
61.86, H 7.30, N 1.95; found: C 62.14, H 7.45, N 1.86; HRMS (FAB):
m/z: calcd for C37H53O9NClSi ([M+H]+): 718.3179; found: 718.3164.
Aldehyde (M)-67: 2,6-Di-tert-butylpyridine (325 mL, 1.48 mmol) and
MeOTf (160 mL, 1.46 mmol) were added to
a solution of (R,M)-66
(434 mg, 0.493 mmol) in CH2Cl2 (4.5 mL) at RT. The reaction mixture
was stirred for 1 h at RT before l-Selectride (1.0m in THF, 1.97 mL,
1.97 mmol) was added at 08C and the mixture was then stirred for an ad-
ditional 20 min at 08C. The reaction was stopped by adding water and
the mixture was extracted with EtOAc (”3). The combined organic ex-
tracts were washed with brine, dried (Na2SO4), and concentrated in
Chem. Eur. J. 2007, 13, 9791 – 9823
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9815

K. Suzuki et al.
vacuo. Acidic silica gel (5 g, pH 6, Kanto Chemical) was added to the res-
idue and organic solvents were removed by evaporation. After kept
standing for 17 h, the SiO2 was placed on a glass filter and washed with
EtOAc, and then the filtrate was concentrated in vacuo. The residue was
purified by flash column chromatography (silica gel, hexane/EtOAc=
7:3) to afford aldehyde (M)-67 as a yellow powder (379 mg, 96%). M.p.
144–1458C (hexane and EtOAc); [a]2D9 =ꢀ92.2 (c=1.07 in CHCl3);
1H NMR (400 MHz, CDCl3): d=0.76–1.01 (m, 21H), 2.46 (s, 3H), 3.79 (s,
3H), 3.81 (s, 3H), 4.03 (s, 3H), 4.40 (d, J=13.2 Hz, 1H), 4.57 (d, J=
10.8 Hz, 1H), 4.62 (d, J=13.2 Hz, 1H), 4.65 (d, J=10.8 Hz, 1H), 4.72 (s,
2H), 6.81–6.85 (m, 2H), 6.95 (s, 1H), 7.01–7.12 (m, 6H), 7.26–7.30 (m,
2H), 7.38 (s, 1H), 8.57 (s, 1H), 9.82 ppm (s, 1H); 13C NMR (100 MHz,
CDCl3): d=11.9, 17.9, 19.8, 52.2, 56.6, 61.9, 63.5, 75.8, 76.2, 110.5, 119.4,
123.0, 123.2, 124.1, 124.8, 127.1, 127.2, 127.4, 127.48, 127.51, 127.8, 127.9,
128.1, 130.9, 133.5, 136.7, 137.2, 137.3, 143.3, 147.0, 152.7, 153.7, 153.9,
168.5, 191.4 ppm; IR (KBr): n˜ =2950, 2940, 2860, 1730, 1700, 1600, 1570,
1460, 1400, 1360, 1340, 1280, 1210, 1100, 1060, 990, 970, 940, 910, 880,
810, 740, 700 cmꢀ1; elemental analysis calcd (%) for C46H53ClO8Si: C
69.28, H 6.70; found: C 69.09, H 6.95; HRMS (FAB): m/z: calcd for
C46H54O8ClSi ([M+H]+): 797.3277; found: 797.3257.
pad and the filtrate was concentrated in vacuo to afford analytically pure
(M)-59 (4.11 g, 99%) as a white amorphous solid. [a]3D0 =ꢀ59.1 (c=1.07
in CHCl3); 1H NMR (400 MHz, CDCl3): d=2.38 (s, 3H), 3.71 (s, 3H),
3.85 (s, 3H), 3.98 (s, 3H) 4.27 (d, J=11.6 Hz, 1H), 4.35 (d, 11.6 Hz, 1H),
4.41 (s, 2H), 4.54 (d, J=10.4 Hz, 1H), 4.60 (d, J=10.4 Hz, 1H), 4.68 (d,
J=10.4 Hz, 1H), 4.76 (d, J=10.4 Hz, 1H), 5.49 (s, 1H), 6.76 (d, J=
7.6 Hz, 2H), 6.83 (s, 1H), 6.91–6.95 (m, 2H), 6.95–6.99 (m, 2H), 7.04 (t,
J=7.6 Hz, 2H), 7.09–7.13 (m, 1H), 7.16–7.32 (m, 11H), 7.48 (s, 1H), 8.45
(s, 1H), 9.66 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=9.4, 52.4,
56.3, 61.5, 68.1, 69.1, 75.6, 76.2, 99.0, 108.3, 116.5, 119.9, 124.0, 124.1,
124.5, 126.9, 127.3, 127.4, 127.5, 127.69, 127.72, 127.9, 127.96, 128.05,
128.1, 128.2, 130.6, 131.5, 133.6, 133.8, 136.0, 136.4, 136.6, 136.7, 137.3,
137.35, 137.42, 145.9, 152.6, 153.40, 153.45, 167.7, 191.0 ppm; IR (KBr):
n˜ =3030, 3000, 2950, 2930, 2870, 2840, 1730, 1700, 1590, 1570, 1500, 1450,
1340, 1280, 1220, 1100, 1040, 910, 850, 810, 740, 700 cmꢀ1; elemental anal-
ysis calcd (%) for C51H45ClO9: C 73.15, H 5.42; found: C 73.44, H 5.62;
HRMS (FAB): m/z: calcd for C51H46O9Cl ([M+H]+): m/z: 837.2831;
found: 837.2803.
The enantiomeric purity of (M)-59 was assessed by HPLC analysis
(DAICEL CHIRALPAK AD-H (0.46 cm f”25 cm), hexane/iPrOH=
9:1, flow rate=1.0 mLminꢀ1, tR =5.4 min for the M isomer, 8.0 min for
the P isomer).
Acetal aldehyde (M)-59: Benzyloxytrimethylsilane (3.5 mL, 18 mmol)
was added to a solution of (M)-67 (2.13 g, 2.67 mmol) in toluene (21 mL)
at RT. TMSOTf (5.7 mg, 0.026 mmol) was added to the reaction mixture
at ꢀ788C and stirred for 4 h at ꢀ158C. The reaction was stopped by
adding Et3N (0.1 mL) and saturated aqueous NaHCO3, and the mixture
was extracted with EtOAc (”3). The combined organic extracts were
washed with brine, dried (Na2SO4), and concentrated in vacuo. The resi-
due was purified by flash column chromatography (silica gel, hexane/
EtOAc=95:5 to 80:20, gradient elution) to afford the acetal derivative of
(M)-67 as a white amorphous solid (2.66 g, quant). [a]2D9 =ꢀ64.2 (c=1.22
in CHCl3); 1H NMR (400 MHz, CDCl3): d=0.89–1.02 (m, 21H), 2.43 (s,
3H), 3.70 (s, 3H), 3.80 (s, 3H), 3.96 (s, 3H), 4.24 (d, J=11.6 Hz, 1H),
4.30–4.42 (m, 4H), 4.57 (d, J=10.4 Hz, 1H), 4.67–4.74 (m, 3H), 4.79 (d,
J=10.4 Hz, 1H), 5.52 (s, 1H), 6.75 (d, J=7.2 Hz, 2H), 6.82 (s, 1H), 7.09
(m, 7H), 7.20–7.26 (m, 11H), 7.39 (s, 1H), 8.42 ppm (s, 1H); 13C NMR
(100 MHz, CDCl3): d=12.0, 18.0, 20.0, 52.0, 56.6, 61.5, 62.8, 68.6, 68.7,
75.5, 75.6, 99.4, 108.4, 116.3, 120.4, 123.2, 123.7, 124.3, 126.4, 126.7, 127.1,
127.2, 127.26, 127.29, 127.4, 127.5, 127.78, 127.80, 127.85, 127.87, 128.1
(2C), 131.2, 136.3, 137.2, 137.3, 137.7, 137.8, 137.9, 144.2, 146.0, 152.7,
152.79, 152.80, 168.8ppm; IR (neat): n˜ =3430, 2940, 1730, 1650, 1600,
1570, 1500, 1450, 1410, 1340, 1280, 1220, 1190, 1120, 1060, 1000, 910, 880,
810, 740, 700 cmꢀ1; elemental analysis calcd (%) for C60H67ClO9Si: C
72.37, H 6.78; found: C 72.20, H 6.83.
Tetracycle (S,S)-60: BF3·OEt2 (21.5 mL, 0.174 mmol) and a solution of
MeOH (0.57m in THF, 100 mL, 0.057 mmol) were added to a solution of
(M)-59 (48.4 mg, 0.0578 mmol) in THF (3.0 mL) at ꢀ788C. Samarium
diiodide (0.1m in THF, 1.5 mL, 0.15 mmol) was added to the mixture at
ꢀ788C and the reaction temperature was immediately raised to 08C.
After stirring for 30 min at 08C, the reaction was stopped by adding 5%
aqueous K2CO3 and the mixture was extracted with EtOAc (”3). The
combined organic extracts were washed with brine, dried (Na2SO4), and
concentrated in vacuo. The residue was purified by PTLC (hexane/
EtOAc=7:3 and benzene/EtOAc=8:2) to afford tetracycle (S,S)-60 as a
white amorphous solid (40.2 mg, 95%).
Experimental procedure for the preparative-scale synthesis of (S,S)-60:
BF3·OEt2 (88 mL, 0.72 mmol) and MeOH (19 mL, 0.0567 mmol) was
added to a solution of (M)-59 (200 mg, 0.239 mmol) in THF (12 mL) at
ꢀ788C. Samarium diiodide (0.1m in THF, 1.5 mL, 0.15 mmol) was added
to the reaction mixture at ꢀ788C and the reaction temperature was im-
mediately raised to ꢀ308C. The reaction temperature was then gradually
raised from ꢀ308C to ꢀ158C over 30 min. The reaction was stopped by
adding 5% aqueous K2CO3 and the mixture was extracted with EtOAc
(”3). The combined organic extracts were washed with brine, dried
(Na2SO4), and concentrated in vacuo. The residue was purified by PTLC
(benzene/EtOAc=9:1) to afford tetracycle (S,S)-60 as a white amor-
phous solid (155 mg, 89%). Compound (S,S)-60 was formed as a mixture
of two conformers: diaxial/diequatorial=1:3.5). [a]2D9 =ꢀ30.8 (c=0.866 in
nBu4NF (1.0m in THF, 1.28 mL, 1.28 mmol) was added to a solution of
the acetal (1.07 g, 1.01 mmol) in THF (10 mL) at 08C. After stirring for
1 h at 08C, the reaction was stopped by adding water and the mixture
was extracted with EtOAc (”3). The combined organic extracts were
washed with brine, dried (Na2SO4), and concentrated in vacuo. The resi-
due was purified by flash column chromatography (silica gel, hexane/
EtOAc=7:3) to afford the acetal alcohol derivative of (M)-67 as a white
amorphous solid (0.898 g, quant). [a]3D0 =ꢀ111 (c=0.924 in CHCl3);
1H NMR (400 MHz, CDCl3): d=2.42 (s, 3H), 2.45 (t, J=6.6, OH), 3.77
(s, 3H), 3.82 (s, 3H), 3.97 (s, 3H), 4.15 (d, J=11.2 Hz, 1H), 4.15–4.26 (m,
2H), 4.34 (d, J=11.2 Hz, 1H), 4.11 (s, 2H), 4.50 (d, J=10.0 Hz, 1H),
4.63 (d, J=10.0 Hz, 1H), 4.72 (d, J=10.0 Hz, 1H), 4.76 (d, J=10.0 Hz,
1H), 5.59 (s, 1H), 6.77 (d, J=7.6 Hz, 2H), 6.85 (s, 1H), 6.97–7.29 (m,
19H), 8.44 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=19.6, 52.2, 56.4,
61.5, 63.5, 68.3, 69.4, 75.7, 75.8, 99.4, 108.3, 116.5, 120.1, 123.6, 125.9,
126.8, 126.9, 127.48, 127.50, 127.57, 127.59 (2C), 127.63, 127.7, 127.8,
128.0, 128.1, 128.16, 128.20, 128.3, 131.2, 136.7, 136.8 (2C), 137.2, 137.4,
137.6, 143.5, 145.9, 152.57, 152.59, 152.7, 168.5 ppm; IR (neat): n˜ =3500,
3090, 3060, 3030, 3010, 2950, 2930, 2870, 1730, 1600, 1590, 1570, 1500,
1450, 1440, 1400, 1370, 1340, 1280, 1220, 1200, 1140, 1100, 1050, 1030,
1
CHCl3); H NMR (500 MHz, CDCl3, the minor conformer is indicated by
an asterisk): d=0.42* (d, J=6.5 Hz, OH), 2.36* (s, 3H), 2.38 (s, 3H),
2.88 (d, J=1.8 Hz, 1H; OH), 3.84* (s, 3H) 3.90 (s, 3H), 3.94 (s, 3H), 3.95
(s, 3H), 3.98 (dd, J=1.8, 10.6 Hz, 1H), 4.00* (s, 3H), 4.01* (s, 3H), 4.05
(d, J=10.6 Hz, 1H), 4.36 (d, J=11.4 Hz, 1H), 4.41* (d, J=12.4 Hz, 1H),
4.476* (d, J=12.1 Hz, 1H), 4.480* (s, 2H), 4.52* (d, J=3.3 Hz, 1H),
4.55* (dd, J=3.3, 6.5 Hz, 1H), 4.59 (d, J=12.1 Hz, 1H), 4.68 (d, J=
11.2 Hz, 1H), 4.81 (d, J=11.2 Hz, 1H), 4.89 (d, J=11.4 Hz, 1H), 5.00 (d,
J=11.2 Hz, 1H), 5.11* (d, J=12.1 Hz, 1H), 6.75–6.79* (m, 2H), 6.81–
6.85 (m, 3H), 6.87* (s, 1H), 6.89* (s, 1H), 6.93* (t, J=7.6 Hz, 2H), 6.96–
7.16 (m, 8H), 6.96–7.16* (m, 9H), 7.20–7.27* (m, 2H), 7.24 (s, 1H), 7.36–
7.41 (m, 1H), 7.43–7.47 (m, 2H), 7.54–7.58 (m, 2H), 7.72* (s, 1H),
7.92 ppm (s, J=1.4 Hz, 1H); 13C NMR (125 MHz, CDCl3, the minor con-
former is indicated by an asterisk): d=19.2*, 19.5, 52.1*, 52.2, 56.4, 56.5*,
61.2, 61.4*, 69.9*, 70.8*, 72.3, 74.9, 76.4, 76.7*, 77.1*, 77.2, 78.0*, 82.4,
107.3, 108.1*, 111.6, 119.5, 120.0, 120.2*, 120.5*, 120.9, 122.5*, 122.6,
122.8*, 123.5, 123.8*, 126.5*, 127.4, 127.48, 127.515, 127.517*, 127.598*,
127.60, 127.7, 127.9, 128.2, 128.36, 128.38, 128.6*, 128.81, 128.83, 129.2,
130.5*, 131.0*, 131.4, 132.5*, 136.09, 136.10*, 136.5, 136.8, 137.0*, 137.4*,
137.6, 137.9*, 138.8*, 139.8, 145.5, 145.6*, 152.2, 153.0, 153.1*, 153.2*,
153.4, 154.9, 168.6*, 169.0ppm; IR (neat): n˜ =3480, 2950, 2870, 1730,
910, 810, 750, 740, 700 cmꢀ1
; elemental analysis calcd (%) for
C51H47ClO9: C 72.98, H 5.64; found: C 72.92, H 5.85.
MnO2 (8.67 g, 99.6 mmol) was added to a solution of the acetal alcohol
derivative of (M)-67 (4.18 g, 4.98 mmol) in CH2Cl2 (100 mL). After stir-
ring for 15 h at RT, the reaction mixture was filtered through a Celite
1590, 1570, 1450, 1340, 1280, 1220, 1130, 1100, 1050, 810, 750, 700 cmꢀ1
;
9816
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 9791 – 9823

Synthesis of Benanomicin-Pradimicin Antibiotics
FULL PAPER
elemental analysis calcd (%) for C44H39ClO8: C 72.27, H 5.38; found: C
72.27, H 5.50; HRMS (FAB): m/z: calcd for C44H40O8Cl ([M+H]+):
731.2411; found: 731.2377.
3H), 1.35 (d, J=7.3 Hz, 3H), 1.362 (d, J=6.6 Hz, 3H), 1.37 (s, 3H), 1.38
(d, J=6.6 Hz, 3H), 1.57 (s, 3H), 1.89 (s, 3H), 1.96 (s, 3H), 1.99 (s, 3H),
2.02 (s, 3H), 2.34 (s, 3H), 2.45 (s, 3H), 3.24 (dd, J=9.1, 11.7 Hz, 1H),
3.35 (dd, J=9.2, 11.6, 1H), 3.62 (dq, J=1.3, 6.6 Hz, 1H), 3.65 (s, 3H),
3.70–3.74 (m, 1H), 3.72 (s, 3H), 3.79 (s, 3H), 3.80 (dd, J=1.3, 3.7 Hz,
1H), 3.84 (s, 3H), 3.85 (s, 3H), 3.88 (dd, J=1.1, 3.8 Hz, 1H), 3.89 (s,
3H), 3.92 (dd, J=3.7, 9.9 Hz, 1H), 3.99 (d, J=11.3 Hz, 1H), 4.04 (dd, J=
1.4, 10.8 Hz, 1H), 4.071 (dd, J=5.0, 11.7 Hz, 1H), 4.072 (dd, J=3.8,
10.1 Hz, 1H), 4.16 (dd, J=5.1, 11.6 Hz, 1H), 4.25 (d, J=11.3 Hz, 1H),
4.38 (s, 2H), 4.39 (d, J=12.1 Hz, 1H), 4.46 (d, J=12.3 Hz, 1H), 4.451 (d,
J=7.1 Hz, 1H), 4.46–4.50 (m, 3H), 4.53 (d, J=8.0 Hz, 1H), 4.55 (d, J=
10.8 Hz, 1H), 4.58 (dq, J=7.2, 7.3 Hz, 1H), 4.63 (d, J=11.6 Hz, 1H),
4.65 (d, J=3.2 Hz, 1H), 4,655 (qd, J=7.2, 7.9 Hz, 1H), 4.660 (d, J=
7.3 Hz, 1H), 4.71 (d, J=12.3 Hz, 1H), 4.73 (dd, J=7.3, 8.9 Hz, 1H), 4.85
(ddd, J=5.1, 8.9, 9.1 Hz, 1H), 4.87–4.92 (m, 3H), 4.93 (ddd, J=5.0, 8.9,
9.2 Hz, 1H), 5.02 (d, J=3.2 Hz, 1H), 5.03 (dd, J=8.9, 8.9 Hz, 1H), 5.15
(dd, J=8.0, 10.1 Hz, 1H), 5.16 (d, J=7.9 Hz, 1H), 5.54 (d, J=7.9 Hz,
1H; NH), 5.69 (dd, J=7.9, 9.9 Hz, 1H), 6.23 (d, J=7.2 Hz, 1H; NH),
6.65 (s, 1H), 6.76 (s, 1H), 6.80–6.89 (m, 3H), 6.92–6.99 (m, 4H), 7.03–
7.16 (m, 5H), 7.17–7.37 (m, 23H), 7.39–7.44 (m, 4H), 7.46 (s, 1H), 7.48–
7.54 (m, 1H), 7.81 (d, J=1.4 Hz, 1H), 7.95–7.99 ppm (m, 1H); 13C NMR
(125 MHz, CDCl3, without distinction of the two conformers): d=17.29,
17.30, 17.4, 18.1, 19.0, 19.6, 19.8, 19.9, 20.5, 20.60, 20.65, 20.69, 47.9, 48.4,
52.2, 56.47, 56.52, 61.1 (2C), 62.3, 62.4, 65.5, 65.8, 68.9, 69.0, 69.2, 69.4,
69.9, 70.6, 70.8, 70.9, 71.3, 71.5, 71.6, 74.0, 74.3, 74.4, 75.9, 76.50, 76.53,
77.1, 77.2 (overlapped by a signal of CDCl3), 77.4, 79.8, 80.4, 81.5, 97.8,
100.8, 102.1, 102.4, 107.3, 107.9, 112.3, 118.9, 119.6, 120.9, 122.5, 122.8,
123.1, 123.23, 123.25, 127.1, 127.2, 127.3, 127.47, 127.52, 127.54, 127.59,
127.63, 127.67, 127.73, 127.8, 127.9, 128.0, 128.1, 128.3, 128.4, 128.5, 128.6,
128.7, 129.7 (2C), 130.3, 131.2, 132.7, 133.0, 133.3, 136.5, 136.6, 136.9,
137.2, 137.3, 137.5, 137.89, 138.0, 138.2, 138.8, 145.1, 145.5, 152.3, 152.7,
153.3, 153.4, 154.3, 154.4, 163.8, 164.7, 167.4, 168.9, 169.1, 169.70, 169.73,
170.05, 170.14, 172.9, 173.1 ppm; IR (KBr): n˜ =2100, 1760, 1750, 1660,
1590, 1510, 1450, 1370, 1340, 1270, 1220, 1060, 750, 710, 700 cmꢀ1; ele-
mental analysis calcd (%) for C71H71ClN4O20: C 63.84, H 5.36, N 4.19;
found: C 63.56, H 5.32, N 3.91.
The enantiomeric purity of (S,S)-60 was analyzed by HPLC analysis
(DAICEL CHIRALPAK AD-H (0.46 cm f”25 cm), hexane/EtOH=8:2,
flow rate=1.0 mLminꢀ1, tR =6.6 min for the S,S isomer, 9.3 min for the
R,R isomer; Figure 1).
Amide 68: A 5m aq. KOH solution (10 mL) was added to a solution of
(S,S)-60 (199 mg, 0.272 mmol) in EtOH (18 mL). The mixture was sealed
in a thick-walled glass tube and heated at 1008C. After stirring for 3 h at
1008C, the mixture was diluted with Et2O and the phases were separated.
The organic layer was extracted with water (”2). The combined water
layers were acidified with 2m aq. HCl and extracted with EtOAc (”3).
The combined organic extracts were washed with brine, dried (Na2SO4),
and concentrated in vacuo. The residue was dissolved in DMF (6 mL),
and BOP (172 mg, 0.388 mmol), d-Ala-OMe·HCl (185 mg, 1.33 mmol),
and Et3N (250 mL, 1.79 mmol) were added to the resulting solution. After
stirring for 1 h at RT, the reaction was stopped by adding 2m aq. HCl
and then the mixture was extracted with EtOAc (”3). The combined or-
ganic extracts were washed with brine, dried (Na2SO4), and concentrated
in vacuo. The residue was purified by flash column chromatography
(silica gel, hexane/EtOAc=1:1) to afford amide 68 as a white solid
(184 mg, 84%). Mixture of two conformers: diaxial/diequatorial=1:4.5;
m.p. 163.6–164.38C (hexane and Et2O); [a]2D9 =ꢀ25.3 (c=0.872 in
1
CHCl3); H NMR (500 MHz, CDCl3, the minor conformer is indicated by
an asterisk): d=0.99* (d, J=6.2 Hz, 1H; OH), 1.23* (d, J=7.2 Hz, 3H),
1.39 (d, J=7.2 Hz, 3H), 2.42* (s, 3H), 2.44 (s, 3H), 2.94 (d, J=2.3 Hz,
1H; OH), 3.67 (s, 3H), 3.73* (s, 3H), 3.94 (s, 3H), 3.95 (s, 3H), 3.96* (s,
3H), 3.97 (dd, J=1.4, 11.4 Hz, 1H; 6-H), 4.00* (s, 3H), 4.24 (d, J=
11.4 Hz, 1H), 4.25 (d, J=11.4 Hz, 1H; C-5), 4.37* (d, J=11.6 Hz, 1H),
4.43* (d, J=12.3 Hz, 1H), 4.45* (d, J=11.0 Hz, 1H), 4.51* (d, J=
12.3 Hz, 1H), 4.54* (d, J=11.0 Hz, 1H), 4.578 (d, J=11.5 Hz, 1H),
4.585* (d, J=4.3 Hz, 1H; 6-H), 4.66* (dq, J=7.3, 7.3 Hz, 1H), 4.67 (dq,
J=7.1, 7.1 Hz, 1H), 4.70* (d, J=4.3 Hz, 1H; 5-H),4.76 (d, J=11.5 Hz,
1H), 4.82 (d, J=11.2 Hz, 1H), 4.91 (d, J=11.4 Hz, 1H), 5.01 (d, J=
11.2 Hz, 1H), 6.06* (d, J=7.2 Hz, 1H; NH), 6.35 (d, J=7.2 Hz, NH),
6.82 (s, 1H), 6.87* (s, 1H), 6.92–6.99 (m, 5H), 7.02–7.19 (m, 6H), 7.23–
7.30 (m, 1H), 7.37–7.41* (m, 2H), 7.44–7.48 (m, 2H), 7,57–7.59 (m, 2H),
7.93 ppm (d, J=1.4 Hz, 1H); 13C NMR (125 MHz, CDCl3, the minor con-
former is indicated by an asterisk): d=17.8*, 18.1, 19.2*, 19.8, 48.2*, 48.4,
52.25, 52.31*, 56.5, 61.2, 61.4*, 69.9*, 71.1*, 72.4, 74.9, 76.1*, 76.6, 76.8*
(overlapped by a signal of CDCl3), 77.2, 78.0*, 82.4, 107.3, 108.1*, 111.7,
119.5, 120.2*, 120.6*, 120.7, 121.0, 122.1*, 122.6, 122.9*, 123.5, 123.8*,
126.9*, 127.39*, 127.43, 127.47, 127.50*, 127.6, 127.7*, 127.8*, 127.88,
127.89*, 128.1*, 128.18, 128.22, 128.37, 128.40*, 128.7, 128.8, 136.3, 136.8,
137.3, 137.5*, 137.6, 137.7*, 137.9*, 138.1, 138.9*, 139.6, 145.47, 145.54*,
152.5, 152.9, 153.2*, 153.3, 153.5*, 154.7*, 167.2*, 167.4, 173.1,
173.2*ppm; IR (neat): n˜ =3420, 3060, 3030, 3000, 2940, 2870, 2840, 2360,
1740, 1660, 1650, 1590, 1570, 1500, 1450, 1340, 1210, 1150, 1130, 1110,
1050, 750, 700 cmꢀ1; elemental analysis calcd (%) for C47H44ClNO9: C
70.36, H 5.53, N 1.75; found: C 70.11, H 5.44, N 1.70; HRMS (FAB):
m/z: calcd for C47H45O9NCl ([M+H]+): 802.2782; found: 802.2809.
a-69 (mixture of two conformers: diaxial/diequatorial=75:25): M.p. 95–
978C; [a]2D8 =+111 (c=0.960 in CHCl3); 1H NMR (500 MHz, CDCl3, the
minor conformer is indicated by an asterisk): d=0.84* (d, J=6.4 Hz,
3H), 1.05 (d, J=7.2 Hz, 3H), 1.23 (s, 3H), 1.36* (d, J=7.2 Hz, 3H), 1.38
(d, J=6.4 Hz, 3H), 1.48* (s, 3H), 1.62* (s, 3H), 1.89 (s, 3H), 1.98* (s,
3H), 2.01 (s, 3H), 2.07* (s, 3H), 2.29 (s, 3H), 3.24 (dd, J=9.2, 11.8 Hz,
1H), 3.52* (dd, J=9.0, 11.8 Hz, 1H), 3.57–3.59 (m, 1H), 3.60 (d, J=
11.3 Hz, 1H), 3.63* (s, 3H), 3.67 (s, 3H), 3.69 (s, 3H), 3.85 (d, J=
11.3 Hz, 1H), 3.87 (dd, J=1.3, 3.6 Hz, 1H), 3.91–3.96 (m, 1H), 3.96* (s,
3H), 3.99* (s, 3H), 4.05 (dd, J=5.2, 11.8 Hz, 1H), 4.06 (s, 3H), 4.09 (dd,
J=3.6, 10.2 Hz, 1H), 4.21* (dd, J=1.3, 11.0 Hz, 1H), 4.21* (d, J=
11.0 Hz, 1H), 4.257 (dd, J=5.0, 11.8 Hz, 1H), 4.258* (d, J=11.5 Hz,
1H), 4.35 (d, J=11.1 Hz, 1H), 4.43* (d, J=11.4 Hz, 1H), 4.45 (d, J=
12.4 Hz, 1H), 4.45–4.49* (m, 1H), 4.46 (d, J=11.1 Hz, 1H), 4.48 (d, J=
7.3 Hz, 1H), 4.52 (d, J=12.4 Hz, 1H), 4.55–4.60* (m, 1H), 4.58 (qd, J=
7.2, 7.9 Hz, 1H), 4.59* (dq, J=7.0, 7.9 Hz, 1H), 4.71* (d, J=11.4 Hz,
1H), 4.73 (dd, J=7.3, 9.1 Hz, 1H), 4.75 (d, J=3.3 Hz, 1H), 4.76 (d, J=
3.3 Hz, 1H), 4.84* (d, J=10.6 Hz, 1H), 4.85 (ddd, J=5.2, 9.2, 9.2 Hz,
1H), 4.88* (d, J=11.5 Hz, 1H), 4.89–4.94* (m, 2H), 4.90–4.95 (m, 1H),
4.99* (ddd, J=5.0, 8.6, 9.0 Hz, 1H), 5.03* (d, J=10.6 Hz, 1H), 5.07 (d,
J=4.0 Hz, 1H), 5.14* (dd, J=8.6, 9.0 Hz, 1H), 5.18* (d, J=3.6 Hz, 1H),
5.19 (dd, J=4.0, 10.1 Hz, 1H), 5.53 (d, J=7.9 Hz, 1H; NH), 5.56* (dd,
J=3.6, 10.5 Hz, 1H), 6.34* (d, J=7.0 Hz, 1H; NH), 6.64* (s, 1H), 6.68 (s,
1H), 6.82–6.86 (m, 1H), 6.89–7.05 (m, 4H), 7.07–7.13 (m, 4H), 7.15–7.36
(m, 10H), 7.39–7.66 (m, 2H), 7.81 (s, 1H), 8.01* (d, J=1.3 Hz, 1H),
8.19–8.23 ppm* (m, 2H); 13C NMR (125 MHz, CDCl3, without distinction
of the two conformers): d=16.5, 17.3, 17.4, 18.1, 18.7, 19.0, 19.5, 19.8,
20.55, 20.64, 20.68, 20.75, 47.9, 48.5, 52.2, 52.3, 56.2, 56.5, 61.2, 61.5, 62.3,
62.4, 64.75, 64.85, 66.1, 66.6, 68.95, 69.02, 69.1, 70.0, 70.1, 71.0, 71.1, 71.5,
71.6, 74.6, 75.0, 75.8, 75.9, 76.2, 76.5, 77.21, 77.16 (overlapped by a signal
of CDCl3), 77.5, 77.68, 80.0, 93.4, 96.1, 100.9, 101.0, 102.1, 102.3, 107.3,
107.9, 112.1, 119.3, 119.5, 119.8, 120.8, 122.0, 122.3, 122.7, 122.9, 123.6,
126.8, 127.1, 127.2, 127.4, 127.6, 127.68, 127.73, 127.76, 127.80, 127.82,
Glycoside 69: MS4A (320 mg) was placed in a two-necked round-bot-
tomed flask and flame dried. The promoter was prepared in situ by stir-
ring a mixture of Cp2HfCl2 (62.8 mg, 0.165 mmol) and AgOTf (84.2 mg,
0.328 mmol) in CH2Cl2 (0.8 mL) for 10 min at RT. A solution of 68
(122 mg, 0.152 mmol) and 51 (100 mg, 0.181 mmol) in CH2Cl2 (2.8 mL)
were added to this suspension at ꢀ788C. After stirring for 11 h at ꢀ368C,
the reaction was stopped by adding saturated aqueous NaHCO3. The
mixture was filtered through a Celite pad and extracted with EtOAc (”
3). The combined organic extracts were washed with brine, dried
(Na2SO4), and concentrated in vacuo. The residue was purified by PTLC
(hexane/Et2O/CH3CN=3:4.5:1.5) to afford b-glycoside 69 as a white
amorphous solid (145 mg, 72%) and a-glycoside 69 also as a white amor-
phous solid (18.4 mg, 9%).
b-69 (a mixture of two conformers: diaxial/diequatorial=50:50): M.p.
114–1168C; [a]2D2 =+20.0 (c=0.880 in CHCl3); 1H NMR (500 MHz,
CDCl3, without distinction of the two conformers): d=1.07 (d, J=7.2 Hz,
Chem. Eur. J. 2007, 13, 9791 – 9823
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9817

K. Suzuki et al.
128.0, 128.1, 128.3, 128.5, 128.6, 128.7, 128.9, 128.99, 129.01, 129.2, 129.3,
130.1, 130.3, 130.5, 131.4, 132.9, 133.0, 133.9, 133.98, 134.0, 136.8, 137.0,
137.1, 137.77, 137.82, 137.84, 137.9, 138.7, 145.3, 145.5, 152.3, 153.0, 153.4,
153.8, 154.6, 164.7, 165.7, 167.2, 167.3, 168.9, 169.0, 169.75, 169.83, 170.0,
170.1, 172.8, 173.0 ppm; IR (KBr): n˜ =3060, 3030, 2940, 2110, 1760, 1660,
1590, 1500, 1450, 1370, 1340, 1270, 1250, 1220, 1160, 1110, 1070, 1050,
950, 900, 880, 820, 750, 740, 710, 700 cmꢀ1; elemental analysis calcd (%)
for C71H71ClN4O20: C 63.84, H 5.36, N 4.19; found: C 63.59, H 5.49, N
3.94.
Benanomicin
B
hydrochloride (2b·HCl):
A
2m aq. NaOH solution
(0.25 mL) was added to a solution of 70 (59.3 mg, 0.0434 mmol) in
MeOH (5.0 mL). After stirring for 8.5 h, the reaction was stopped by
adding 2m aq. HCl (0.55 mL) and the mixture was concentrated in vacuo
(azeotropic evaporation ”5). The residue was purified by reversed-phase
silica gel column chromatography (Cosmosil: MeOH/H2O=9:1) and Se-
phadex (LH-20: MeOH) to afford the crude product of 71. A 1m aq.
HCl solution (100 mL) and 5% Pd/C (82.3 mg) were added to a solution
of this crude material (46.5 mg) in MeOH (4.5 mL) and DMF (1.5 mL).
After stirring under H2 (1 atm) at RT for 2 h, the reaction mixture was
filtered through a Hyflo Super-Cel pad (washed with DMF) and concen-
trated in vacuo. The residue was purified by reversed-phase silica gel
column chromatography (Cosmosil: CH3CN/H2O=3:7, pH 3) to give red
precipitates, which were further purified by Sephadex LH-20 (DMF)
(twice) to afford benanomicin B dimethylformamide solvate which was
dissolved in MeOH and then 2m aq. HCl was added to adjust the pH
value to 3.5. After removal of the solvent in vacuo, the residue was dis-
solved in DMSO (0.1 mL), and CHCl3 (6.0 mL) was added. The precipi-
tates were collected by filtration to afford benanomicin B hydrochloride
(2b·HCl) as a red amorphous powder (19.7 mg, 53%). M.p. 213–2158C
(decomp) (lit.:[1b] >2208C (decomp)); [a]D22 =+353 (c=0.0501, H2O)
(lit.:[1b] +360 (c=0.05, H2O)); 1H NMR (500 MHz, [D6]DMSO, 313 K):
d=1.18 (d, J=6.5 Hz, 3H), 1.34 (d, J=7.3 Hz, 3H), 2.33 (s, 3H), 3.07
(dd, J=10.7, 10.9 Hz, 1H), 3.16–3.18 (m, 3H), 3.29–3.34 (m, 1H), 3.39–
3.44 (m, 1H), 3.60 (br, 1H), 3.72 (dd, J=5.3, 11.3 Hz, 1H), 3.83 (brq, J=
6.5, 1H), 3.91–3.94 (m, 1H), 3.95 (s, 3H), 4.42 (dq, J=7.1, 7.3 Hz, 1H),
4.53–4.56 (m, 2H), 4.58–4.65 (m, 1H), 4.74 (d, J=7.6 Hz, 1H), 6.94 (d,
J=2.4 Hz, 1H), 7.23 (brs, 1H), 7.31 (d, J=2.4 Hz, 1H), 8.06 (s, 1H), 8.43
(d, J=7.1 Hz, 1H), 12.8 ppm (s, 1H); 13C NMR (125 MHz, [D6]DMSO,
313 K): d=16.3, 16.9, 19.1, 47.6, 54.2, 56.4, 65.7, 66.9, 69.4, 69.7, 73.3,
75.9, 77.4, 80.9, 104.0, 104.5, 106.9, 107.6, 110.1, 113.7, 115.6, 125.7, 127.5,
131.3, 134.3, 137.3, 137.8, 147.9, 151.0, 156.9, 164.7, 166.0, 166.8, 173.9,
185.0, 187.5 ppm; IR (KBr): n˜ =3360, 1730, 1610, 1300, 1160, 1080,
Quinone 70:
A solution of CAN (158 mg, 0.288 mmol) in water
(0.32 mL) was added to a solution of glycoside 69 (165 mg, 0.123 mmol)
in CH3CN (0.9 mL) at RT. After stirring for 20 min, water (15 mL) was
added to the reaction and a precipitate was formed which was collected
by filtration as a red powder (154 mg). The powder was directly added to
a solution of diene 21 (250 mg, 0.123 mmol) in THF (2.5 mL) at RT. Mix-
ture allowed to stand for 20 min, acidic silica gel (pH 6, Kanto chemical)
was added, and the organic solvent was removed in vacuo. After standing
for 8 h, the silica gel was placed on a glass filter and washed with EtOAc.
Then the filtrate was concentrated in vacuo. K2CO3 (176 mg) was added
to the solution of this crude material (227 mg) in THF/CH2Cl2 (1:3,
8 mL) at RT. The mixture was heated at 408C for 3 h, and the reaction
was stopped by adding 2m aq. HCl and then the mixture was extracted
with CH2Cl2 (”3). The combined organic extracts were washed with
brine, dried (Na2SO4), and concentrated in vacuo. The residue was puri-
fied by PTLC (hexane/Et2O/CH3CN=2:3:1) and HPLC (Cica-reagent,
Myghtysil Si60, 250–20 (5 mm), hexane/EtOAc=1:2, 3.5 mLminꢀ1) to
afford quinone 70 as a yellow solid (124 mg, 74%). Mixture of two con-
formers: diaxial/diequatorial=78:22; m.p. 126.0–126.88C (hexane and
EtOAc); [a]2D0 =+111 (c=1.17 in CHCl3); 1H NMR (500 MHz, CDCl3,
the minor conformer is indicated by an asterisk): d=1.08 (d, J=7.2 Hz,
3H), 1.26 (s, 3H), 1.35* (d, J=6.3 Hz, 3H), 1.37* (d, J=7.2 Hz, 3H),
1.45 (d, J=6.3 Hz, 3H), 1.87 (s, 3H), 1.96* (s, 3H), 1.98 (s, 3H), 2.02* (s,
3H), 2.04* (s, 3H), 2.36 (s, 3H), 2.48* (s, 3H), 3.26 (dd, J=8.9, 11.8 Hz,
1H), 3.36* (dd, J=9.3, 11.6 Hz, 1H), 3.63* (s, 3H), 3.69–3.73 (m, 1H),
3.70–3.74* (m, 1H), 3.75 (s, 3H), 3.85 (dd, J=1.4, 3.9 Hz, 1H), 3.89*
(brd, J=4.1 Hz, 1H), 3.91* (dd, J=1.1, 11.0 Hz, 1H), 3.946* (s, 3H),
3.947 (dd, J=3.9, 9.9 Hz, 1H), 4.00 (s, 3H), 4.06* (dd, J=4.1, 9.9 Hz,
1H), 4.08 (dd, J=5.2, 11.8 Hz, 1H), 4.12 (d, J=11.0 Hz, 1H), 4.17* (dd,
J=5.2, 11.6 Hz, 1H), 4.30* (d, J=11.2 Hz, 1H), 4.32 (d, J=11.5 Hz, 1H),
4.41 (d, J=12.1 Hz, 1H), 4.42* (d, J=11.6 Hz, 1H), 4.441 (d, J=12.1 Hz,
1H), 4.442 (d, J=11.5 Hz, 1H), 4.47* (d, J=11.4 Hz, 1H), 4.48 (d, J=
7.3 Hz, 1H), 4.51 (d, J=7.8 Hz, 1H), 4.52* (d, J=11.0 Hz, 1H), 4.55 (qd,
J=7.2, 7.9 Hz, 1H), 4.57 (d, J=3.0 Hz, 1H), 4.64* (qd, J=7.2, 7.2 Hz,
1H), 4.65* (d, J=7.3 Hz, 1H), 4.69* (d, J=11.4 Hz, 1H), 4.71 (dd, J=
7.3, 8.7 Hz, 1H), 4.77* (d, J=11.6 Hz, 1H), 4.85 (ddd, J=5.2, 8.9, 9.8 Hz,
1H), 4.90 (dd, J=8.7, 8.9 Hz, 1H), 4.91* (dd, J=7.3, 9.0 Hz, 1H), 4.91–
4.95* (m, 1H), 4.96 (d, J=3.0 Hz, 1H), 5.03* (dd, 1H; J=9.0, 9.0 Hz,
1H), 5.12* (d, J=8.0 Hz, 1H), 5.14 (d, J=11.0 Hz, 1H), 5.15 (dd, J=7.8,
9.9 Hz, 1H), 5.18* (d, J=11.2 Hz, 1H), 5.37 (d, J=7.9 Hz, 1H; NH),
5.69* (dd, J=8.0, 9.9 Hz, 1H), 6.24* (d, J=7.2 Hz, 1H; NH), 6.69–6.80
(m, 3H), 6.95–7.14 (m, 11H), 7.19–7.40 (m, 7H), 7.51–7.59 (m, 2H), 7.60
(s, 1H), 7.95* (s, 1H), 7.97* (s, 1H), 8.08* (d, J=1.1 Hz, 1H), 12.7 (s,
1H; OH), 12.9 ppm* (s, 1H; OH); 13C NMR (125 MHz, CDCl3, without
distinction of the two conformers): d=17.25, 17.3, 17.35, 18.0, 19.0, 19.5,
19.9, 20.1, 20.5, 20.60, 20.64, 20.7, 47.8, 48.4, 52.2, 52.3, 56.0, 56.1, 62.4,
62.5, 65.4, 65.7, 68.9, 69.0, 69.4, 69.5, 70.6, 70.8, 70.9, 71.1, 71.2, 71.5, 71.6,
73.2, 74.1, 74.6, 76.7, 76.8 (overlapped by a signal of CDCl3), 77.1, 77.3
(2C, overlapped by a signal of CDCl3), 79.8, 80.3, 80.5, 98.1, 100.6, 102.2,
102.4, 105.8, 106.0, 107.0, 107.3, 110.4, 110.8, 118.2, 120.3, 121.5, 123.1,
123.2, 125.1, 126.1, 127.3, 127.55, 127.58, 127.64, 127.66, 127.8, 127.9,
128.1, 128.26, 128.31, 128.4, 128.49, 128.50, 128.6, 128.67, 128.68, 128.8,
129.0, 129.6, 129.7, 130.2, 132.4, 132.9, 133.1, 133.3, 133.4, 134.4, 135.3,
136.1, 136.3, 136.5, 136.6, 136.7, 137.27, 137.31, 137.4, 137.8, 138.2, 139.1,
139.9, 140.1, 144.1, 152.9, 154.8, 156.5, 158.5, 163.5, 164.6, 164.7, 164.9,
166.51, 166.54, 166.99, 167.02, 168.8, 169.1, 169.70, 169.75, 170.0, 170.1,
172.8, 172.9, 180.5, 181.0, 185.5, 186.0 ppm; IR (KBr): n˜ =2960, 2920,
2850, 2110, 1740, 1670, 1630, 1600, 1580, 1450, 1380, 1310, 1260, 1220,
1040 cmꢀ1
; LRMS (MALDI-TOF, DHBA matrix): m/z: calcd for
C39H42O18N2Na ([M+Na]+): 849.2; found: 849.2; HRMS (FAB): m/z:
calcd for C39H43O18N2 ([M+H]+): 827.2511; found: 827.2506.
N-Monomethylamine 73: A solution of Me3P in toluene (0.91m, 50 mL,
0.048 mmol) was added to a solution of 69 (53.5 mg, 0.0401 mmol) in
CH2Cl2 (0.67 mL) at 08C. After stirring for 1.5 h at RT, (HCHO)n
(6.50 mg, 0.201 mmol) was added. The reaction mixture was stirred for
11 h at RT before treatment with MeOH (0.50 mL) and NaBH4 (10.6 mg,
0.281 mmol) at 08C. After stirring for 10 min, the reaction was stopped
by adding AcOH and the mixture was extracted with EtOAc (”3). The
combined organic extracts were washed with saturated aqueous NaHCO3
and brine, dried (Na2SO4), and concentrated in vacuo. The residue was
purified by PTLC (hexane/Et2O/CH3CN/MeOH=22:55:17:6) to afford
N-monomethylamine 73 (39.9 mg, 75%) as a white amorphous solid.
Mixture of two conformers: diaxial/diequatorial=57:43); m.p. 95–978C;
[a]3D0 =+42.6 (c=1.14 in CHCl3); 1H NMR (500 MHz, CDCl3, the minor
conformer is indicated by an asterisk): d=1.06 (d, J=7.3 Hz, 3H), 1.338*
(d, J=6.0 Hz, 3H), 1.342 (s, 3H), 1.36* (d, J=7.3 Hz, 1H), 1.37 (d, J=
6.0 Hz, 3H), 1.57* (s, 3H), 1.88 (s, 3H), 1.96* (s, 3H), 1.99 (s, 3H), 2.04*
(s, 3H), 2.35 (s, 3H), 2.44* (s, 3H), 2.51 (s, 3H), 2.65* (s, 3H), 2.75 (brd,
J=4.3 Hz, 1H), 2.86* (brd, J=4.3 Hz, 1H), 3.24 (dd, J=8.7, 11.8 Hz,
1H), 3.36* (dd, J=8.9, 11.6 Hz, 1H), 3.54–3.60 (m, 1H), 3.65* (s, 3H),
3.67–3.72* (m, 1H), 3.72 (s, 3H), 3.76 (s, 3H), 3.79* (s, 3H), 3.83 (s, 3H),
3.85 (s, 3H), 3.91* (s, 3H), 3.94 (d, J=11.3 Hz, 1H), 3.95* (dd, J=4.3,
10.0 Hz, 1H), 4.00* (dd, J=1.3, 10.6 Hz, 1H), 4.06* (dd, J=5.0, 11.6 Hz,
1H), 4.15* (dd, J=5.1, 11.8 Hz, 1H), 4.25 (d, J=11.4 Hz, 1H), 4.38 (s,
2H), 4.39* (d, J=7.0 Hz, 1H), 4.41* (s, 2H), 4.43 (d, J=11.6 Hz, 1H),
4.46* (d, J=11.3 Hz, 1H), 4.47* (d, J=12.0 Hz, 1H), 4.49 (d, J=7.8 Hz,
1H), 4.56* (d, J=10.6 Hz, 1H), 4.57 (dq, J=6.8, 7.3 Hz, 1H), 4.62 (d, J=
7.1 Hz, 1H), 4.63* (d, J=11.3 Hz, 1H), 4.66* (dq, J=7.2, 7.3 Hz, 1H),
4.67 (d, J=3.1 Hz, 1H), 4.71 (dd, J=7.1, 8.7 Hz, 1H), 4.72* (d, J=
12.0 Hz, 1H), 4.84 (ddd, J=5.1, 8.7, 8.7 Hz, 1H), 4.87 (dd, J=8.7, 8.7 Hz,
1H), 4.88* (dd, J=7.0, 8.9 Hz, 1H), 4.90 (d, J=11.4 Hz, 1H), 4.93* (ddd,
J=5.0, 8.9, 8.9 Hz, 1H), 5.00* (dd, J=8.9, 8.9 Hz, 1H), 5.04 (dd, J=7.8,
10.3 Hz, 1H), 5.07 (d, J=3.1 Hz, 1H), 5.16* (d, J=7.6 Hz, 1H), 5.54 (d,
J=6.8 Hz, 1H; NH), 5.59* (dd, J=7.6, 10.0 Hz, 1H), 6.24* (d, J=7.2 Hz,
1100, 1070, 1030, 800, 710 cmꢀ1
C74H70N4O22: C 65.00, H 5.16, N 4.10; found: C 65.00, H 5.29, N 4.08.
; elemental analysis calcd (%) for
9818
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 9791 – 9823

Synthesis of Benanomicin-Pradimicin Antibiotics
FULL PAPER
1H; NH), 6.65 (s, 1H), 6.77* (s, 1H), 6.78–6.83 (m, 1H), 6.83–6.87* (m,
1H), 6.90–6.93 (m, 2H), 6.94–6.97* (m, 2H), 7.05–7.37 (m, 16H), 7.34–
7.42 (m, 2H), 7.47 (s, 1H), 7.42–7.52* (m, 1H), 7.80* (d, J=1.3 Hz, 1H),
7.93–7.97 ppm* (m, 2H); 13C NMR (125 MHz, CDCl3, without distinction
of the two conformers): d=17.2, 17.4 (2C), 18.1, 19.0, 19.7, 19.8, 19.9,
20.55, 20.61, 20.69, 20.73, 38.1, 38.2, 47.9, 48.4, 52.19, 52.22, 56.4, 56.5,
61.08, 61.10, 62.1, 62.2, 63.9, 64.0, 69.0, 69.1, 69.9, 70.6, 70.8, 71.2, 71.5,
71.6, 71.8, 72.1, 73.7, 74.2, 74.3, 75.9, 76.5, 76.6, 77.3 (overlapped by
CDCl3), 80.6, 81.2, 81.6, 97.9, 101.0, 101.8, 102.1, 107.2, 107.8, 112.3,
118.9, 119.5, 120.8, 121.0, 122.5, 122.7, 122.8, 123.1, 123.20, 123.22, 127.05,
127.06, 127.2, 127.3, 127.50, 127.51, 127.56, 127.63, 127.66, 127.3, 127.8,
127.89, 127.94, 128.0, 128.1, 128.3, 128.4, 128.49, 128.52, 128.7, 128.9,
129.6, 129.8, 130.16, 130.23, 131.2, 132.2, 132.6, 133.1, 133.2, 136.6, 136.8,
137.17, 137.22, 137.7, 137.89, 137.93, 138.2, 138.8, 139.0, 145.1, 145.4,
152.2, 152.6, 153.2, 153.3, 154.2, 154.3, 163.9, 165.0, 167.5, 169.2, 169.4,
169.8, 169.9, 169.96, 170.04, 172.9, 173.1 ppm; IR (KBr): n˜ =3640, 3410,
2940, 2870, 1750, 1660, 1590, 1590, 1500, 1450, 1370, 1340, 1270, 1220,
1110, 1050, 910, 820, 750, 700 cmꢀ1; elemental analysis calcd (%) for
C72H75ClN2O20: C 65.32, H 5.71, N 2.12; found: C 65.05, H 5.97, N 1.96.
900, 820, 750, 700 cmꢀ1
C74H74ClF3N2O21: C 62.60, H 5.25, N 1.97; found: C 62.33, H 5.28, N 1.87.
;
elemental analysis calcd (%) for
Anthraquinone 77: A solution of CAN (77.8 mg, 0.142 mmol) in water
(0.18 mL) was added to a solution of b-76 (96.0 mg, 0.0676 mmol) in
CH3CN (0.53 mL) at 08C. After stirring for 20 min at RT, the reaction
was stopped by adding water. The precipitates were collected by filtra-
tion to afford the chloroquinone (71.3 mg) as a red powder. The filtrate
was extracted with EtOAc (”3) and the combined organic extracts were
washed with brine, dried (Na2SO4), and concentrated in vacuo. A solu-
tion of diene 21 (150 mg, 0.744 mmol) in THF (1.4 mL) was added to the
combined crude material (99.6 mg) at RT and stirred for 20 min. Acidic
silica gel (pH 6, Kanto chemical) was added and the organic solvent was
removed in vacuo. After standing for 14 h, the silica gel was placed on a
glass filter (washed with CHCl3/MeOH=9:1) and then the filtrate was
concentrated in vacuo. K2CO3 (251 mg) was added to the solution of this
crude material in THF/CH2Cl2 (1:3, 6.8 mL) at RT. After stirring for 3 h
at 408C, the reaction was stopped by adding 2m aq. HCl and then the
mixture was extracted with CH2Cl2 (”3). The combined organic extracts
were washed with brine, dried (Na2SO4), and concentrated in vacuo. The
residue was purified by PTLC (hexane/Et2O/CH3CN=2:3:1) to afford
anthraquinone 77 as a yellow solid (73.9 mg, 75%). Mixture of two con-
formers: diaxial/diequatorial=75:25; m.p. 123–1268C (Et2O and
hexane); [a]3D0 =+110 (c=1.10 in CHCl3); 1H NMR (500 MHz, CDCl3,
the minor conformer is indicated by an asterisk): d=1.12 (d, J=7.3 Hz,
3H), 1.25* (d, J=6.4 Hz, 3H), 1.35 (d, J=6.4 Hz, 3H), 1.366* (d, J=
7.2 Hz, 3H), 1.371 (s, 3H), 1.64* (s, 3H), 1.85 (s, 3H), 1.95* (s, 3H), 1.96
(s, 3H), 2.00* (s, 3H), 2.38 (s, 3H), 2.47* (s, 3H), 3.22 (dd, J=8.0,
12.2 Hz, 1H), 3.27 (s, 3H), 3.32* (dd, J=8.1, 12.2 Hz, 1H), 3.56* (s, 3H),
3.69* (s, 3H), 3.75 (s, 3H), 3.88–3.93* (m, 1H), 3.92–3.96 (m, 1H), 3.938
(dd, J=5.0, 12.1 Hz, 1H), 3.946* (dd, J=0.6, 12.4 Hz, 1H), 3.949* (s,
3H), 4.00 (s, 3H), 4.03* (dd, J=4.9, 12.2 Hz, 1H), 4.09 (dd, J=7.1,
10.3 Hz, 1H), 4.20 (d, J=11.1 Hz, 1H), 4.24* (dd, J=7.2, 10.3 Hz, 1H),
4.29* (d, J=11.2 Hz, 1H), 4.34 (d, J=11.5 Hz, 1H), 4.38 (d, J=6.8 Hz,
1H), 4.42 (d, J=12.1 Hz, 1H), 4.43* (d, J=11.7 Hz, 1H), 4.46 (d, J=
12.1 Hz, 1H), 4.465 (d, J=11.5 Hz, 1H), 4.471* (d, J=12.1 Hz, 1H),
4.54* (d, J=12.4 Hz, 1H), 4.55 (d, J=7.9 Hz, 1H), 4.57 (d, J=3.3 Hz,
1H), 4.54–4.59 (m, 1H), 4.61 (dd, J=6.8, 8.8 Hz, 1H), 4.61–4.67* (m,
1H), 4.69* (d, J=12.1 Hz, 1H), 4.76–4.81 (m, 1H), 4.78–4.82* (m, 3H),
4.82 (dd, J=8.8, 8.8 Hz, 1H), 4.89* (ddd, J=4.9, 8.1, 8.2 Hz, 1H), 4.95
(d, J=3.3 Hz, 1H), 4.96* (dd, J=8.2, 9.2 Hz, 1H), 5.04 (dd, J=3.2,
7.1 Hz, 1H), 5.11 (d, J=11.1 Hz, 1H), 5.10–5.14* (m, 1H), 5.17* (d, J=
11.2 Hz, 1H), 5.21* (d, J=7.9 Hz, 1H) 5.30* (dd, J=7.9, 10.3 Hz, 1H),
5.52* (d, J=7.9 Hz, 1H; NH), 5.87 (dd, J=7.9, 10.3 Hz, 1H), 6.29 (d, J=
7.2 Hz, 1H; NH), 6.70* (d, J=2.5 Hz, 1H), 6.72 (d, J=2.5 Hz, 1H), 6.72–
6.81 (m, 1H), 6.98–7.18 (m, 10H), 7.20–7.25 (m, 2H), 7.25–7.40 (m, 7H),
7.53–7.62 (m, 1H), 7.62 (s, 1H), 7.96–7.98 (m, 1H), 8.08* (d, J=0.6 Hz,
1H), 12.6 (s, 1H; OH), 12.8 ppm (s, 1H; OH); 13C NMR (125 MHz,
CDCl3, without distinction of the two conformers): d=16.0, 16.1, 17.5,
18.0, 19.2, 19.7, 20.0, 20.4, 20.5, 20.57, 20.63, 20.7, 29.7, 34.2, 47.9, 48.4,
52.26, 52.31, 56.06, 56.11, 56.2, 56.6, 62.2, 62.4, 68.9, 69.1, 70.2, 70.4, 71.0,
71.1, 71.16, 71.17, 71.2, 71.4, 71.5, 72.3, 73.4, 74.0, 74.6, 76.4, 76.8, 76.9
(2C), 77.2, 77.3, 80.4, 98.7, 101.3, 101.9, 102.1, 105.8, 106.0, 107.1, 107.4,
110.4, 110.7, 116.6 (q, 1JC,F =286 Hz), 118.3, 120.5, 121.7, 122.5, 123.2,
125.2, 126.2, 127.3, 127.4, 127.5, 127.6, 127.68, 127.72, 127.9, 128.05,
128.12, 128.2, 128.3, 128.4, 128.45, 128.48, 128.56, 128.64, 128.8, 129.0,
129.1, 129.7, 130.3, 132.6, 132.8, 133.1, 133.5, 133.7, 134.6, 135.1, 136.0,
136.3, 136.4, 136.5, 136.8, 137.1, 137.2, 138.0, 138.1, 139.2, 139.8, 140.0,
144.0, 153.1, 154.9, 156.5, 158.4, 158.8 (q, 2JC,F =35 Hz), 163.7, 164.6,
164.9, 166.6, 166.9, 168.9, 169.1, 169.55, 169.59, 169.9, 170.0, 172.86,
172.90, 180.5, 181.1 ppm; IR (KBr): n˜ =3410, 2960, 1750, 1700, 1670,
1630, 1610, 1580, 1540, 1500, 1450, 1380, 1320, 1260, 1220, 1150, 1070,
1030, 900 870, 800, 740, 700 cmꢀ1; elemental analysis calcd (%) for
C77H73F3N2O23: C 63.72, H 5.07, N 1.93; found: C 64.00, H 5.21, N 1.76.
Trifluoroacetoamide b-76: Pyridine (0.1 mL, 1.25 mmol) and trifluoroace-
tic anhydride (0.01 mL, 0.625 mmol) were added to a solution of 73
(82.7 mg, 0.0625 mmol) in CH2Cl2 (0.8 mL) at 08C. After stirring for
20 min, the reaction was stopped by adding saturated aqueous NaHCO3
and then the mixture was extracted with EtOAc (”3). The combined or-
ganic extracts were washed with 2m aq. HCl and brine, dried (Na2SO4),
and concentrated in vacuo. The residue was purified by PTLC (hexane/
EtOAc=4:6) to afford trifluoroacetoamide b-76 as
a white solid
(79.9 mg, 90%). Mixture of two conformers: diaxial/diequatorial=
57:43); m.p. 110–1138C (Et2O and hexane); [a]3D0 =+32.2 (c=1.13 in
1
CHCl3); H NMR (500 MHz, CDCl3, the minor conformer is indicated by
an asterisk): d=1.09 (d, J=7.2 Hz, 3H), 1.25* (d, J=6.4 Hz, 3H), 1.27
(d, J=6.4 Hz, 3H), 1.35* (d, J=7.2 Hz, 3H), 1.45 (s, 3H), 1.65* (s, 3H),
1.88 (s, 3H), 1.95* (s, 3H), 1.96 (s, 3H), 2.00* (s, 3H), 2.36 (s, 3H), 2.43*
(s, 3H), 3.19 (dd, J=7.9, 12.0 Hz, 1H), 3.25 (s, 2H), 3.32* (dd, J=8.1,
12.0 Hz, 1H), 3.57* (s, 3H), 3.66* (s, 3H), 3.71 (s, 3H), 3.78* (s, 3H),
3.80–3.84 (m, 1H), 3.82 (s, 3H), 3.85 (s, 3H), 3.90* (s, 3H), 3.93 (dd, J=
5.0, 12.0 Hz, 1H), 3.93–3.98* (m, 1H), 4.03* (dd, J=5.3, 12.0 Hz, 1H),
4.04 (dd, J=7.3, 10.3 Hz, 1H), 4.05* (dd, J=1.5, 10.7 Hz, 1H), 4.06 (d,
J=11.3 Hz, 1H), 4.24 (d, J=11.4 Hz, 1H), 4.26* (dd, J=7.2, 10.3 Hz,
1H), 4.35 (d, J=6.9 Hz, 1H), 4.403* (d, J=12.4 Hz, 1H), 4.405 (s, 2H),
4.457* (d, J=10.8 Hz, 1H), 4.460* (d, J=12.3 Hz, 1H), 4.47 (d, J=
11.3 Hz, 1H), 4.48* (d, J=12.4 Hz, 1H), 4.57* (d, J=10.7 Hz, 1H), 4.561
(d, J=8.0 Hz, 1H), 4.562* (d, J=6.8 Hz, 1H), 4.60 (qd, J=7.2, 7.8 Hz,
1H), 4.63 (dd, J=6.9, 8.8 Hz, 1H), 4.64* (d, J=10.8 Hz, 1H), 4.65 (d, J=
3.1 Hz, 1H), 4.67* (qd, J=7.2, 7.3 Hz, 1H), 4.69* (d, J=12.3 Hz, 1H),
4.79 (ddd, J=5.0, 7.9, 8.5 Hz, 1H), 4.80* (dd, J=6.8, 8.4 Hz, 1H), 4.83
(dd, J=8.5, 8.8 Hz, 1H), 4.87 (d, J=11.4 Hz, 1H), 4.89* (ddd, J=5.3, 8.1,
8.4 Hz, 1H), 4.96* (dd, J=8.4, 8.4 Hz, 1H), 4.99 (dd, J=3.1, 7.3 Hz, 1H),
5.01 (d, J=3.1 Hz, 1H), 5.11* (dd, J=7.2, 10.3 Hz, 1H), 5.24* (d, J=
8.0 Hz, 1H), 5.29 (dd, J=8.0, 10.3 Hz, 1H), 5.67 (d, J=7.8 Hz, 1H; NH),
5.88* (dd, J=8.0, 10.3 Hz, 1H), 6.29* (d, J=7.3 Hz, 1H; NH), 6.64 (s,
1H), 6.77* (s, 1H), 6.81–6.85 (m, 2H), 6.86–6.90* (m, 1H), 6.91–6.95*
(m, 2H), 6.98–7.02* (m, 2H), 7.05–7.18 (m, 7H), 7.18–7.40 (m, 10H),
7.41–7.46 (m, 2H), 7.48 (s, 1H), 7.51–7.56 (m, 1H), 7.81 (d, J=1.6 Hz,
1H), 7.95–7.99 ppm (m, 2H); 13C NMR (125 MHz, CDCl3, without dis-
tinction of the two conformers): d=16.0 (2C), 17.5, 18.1, 19.1, 19.8, 20.0,
20.1, 20.5, 20.57, 20.64, 20.7, 34.23, 34.24, 47.9, 48.3, 52.2, 56.2, 56.4, 56.5,
56.6, 61.1, 62.2, 62.4, 68.9, 69.1, 70.3, 70.4, 70.8, 71.0, 71.3, 71.4, 71.5, 72.4,
74.31, 74.34, 74.5, 76.0, 76.4, 76.5, 76.6, 77.1, 77.2, 77.6, 81.4, 98.6, 100.8,
101.4, 101.8, 102.1, 107.4, 108.0, 112.4, 116.7 (q, 1JC,F =286 Hz), 116.8 (q,
1JC,F =286 Hz), 119.0, 119.6, 120.8, 121.1, 122.8, 122.9, 123.4, 123.5, 127.1,
127.2, 127.4, 127.5, 127.6, 127.7, 127.8, 127.9, 128.01, 128.03, 128.2, 128.4,
128.5, 128.7, 128.8, 129.3, 129.7, 130.30, 130.32, 131.2, 132.5, 132.8, 133.0,
Pradimicin A hydrochloride (1a·HCl): 5% Pd/C (27.8 mg) was added to
a solution of 77 (21.0 mg, 0.0145 mmol) in MeOH (1.6 mL) and DMF
(0.5 mL). After stirring under H2 (1 atm) at RT for 30 min, the reaction
mixture was filtered though a Hyflo Super-Cel pad (washed with CHCl3/
MeOH=9:1) and concentrated in vacuo. The residue was purified by
PTLC (CHCl3/MeOH=9:1) to afford the corresponding tetrol (13.5 mg)
133.6, 136.3, 136.7, 136.8, 137.3, 137.4, 137.8, 137.8, 138.0, 138.7, 138.8,
2
145.2, 145.5, 152.4, 153.0, 153.2, 153.3, 154.35, 154.39, 158.76 (q, JC,F
=
35 Hz), 158.83 (q, 2JC,F =35 Hz), 164.0, 164.9, 167.30, 167.33, 168.9, 169.1,
169.56, 169.59, 169.9, 170.0, 172.9, 173.1 ppm; IR (KBr): n˜ =3410, 2940,
1750, 1700, 1660, 1580, 1510, 1460, 1370, 1340, 1250, 1220, 1150, 1070,
Chem. Eur. J. 2007, 13, 9791 – 9823
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9819

K. Suzuki et al.
as a red amorphous solid. A 5m aq. NaOH solution (0.07 mL) was added
to the solution of this crude material in H2O (0.71 mL) at 08C. After stir-
ring for 24 h at RT, the reaction was stopped by adding 2m aq. HCl
(pH 3.5) and the mixture concentrated in vacuo. The residue was purified
by reversed-phase silica gel column chromatography (Cosmosil: CH3CN/
H2O=3:7, pH 3) to give red precipitates that were further purified by Se-
phadex LH-20 (DMF) to afford pradimicin A (1a) dimethylformamide
solvate, which was dissolved in MeOH and then 2m aq. HCl was added
until a pH value of 3.5 was obtained. After removal of the solvent in
vacuo, the residue was dissolved in DMSO (25 mL) and CHCl3 was
added. The precipitates were collected by filtration to afford 1a·HCl as a
red amorphous powder (4.3 mg, 61%). M.p. 194–1978C (decomp) (lit.[1d]
193–1958C (decomp)); [a]2D6 =+280 (c=0.100 in 0.1m aq. HCl) (authen-
tic: +287 (c=0.100 in 0.1m aq. HCl)); 1H NMR (500 MHz, [D6]DMSO,
313 K): d=1.25 (d, J=6.2 Hz, 3H), 1.35 (d, J=7.0 Hz, 3H), 2.29 (s, 3H),
2.61 (s, 3H), 3.74 (dd, J=5.3, 11.2 Hz, 1H), 3.84 (q, J=6.2 Hz, 1H), 4.39
(q, J=7.0 Hz, 1H), 4.44 (d, J=7.3 Hz, 1H), 4.46 (d, J=10.3 Hz, 1H),
4.49 (d, J=10.3 Hz, 1H), 4.73 (d, J=7.7 Hz, 1H), 6.71 (d, J=2.4 Hz,
1H), 6.85 (s, 1H), 7.11 (d, J=2.4 Hz, 1H), 7.69 (s, 1H), 8.78 ppm (d, J=
7.0 Hz, 1H); 13C NMR (125 MHz, [D6]DMSO, 313 K): d=16.6, 17.5, 19.7,
36.8, 48.2, 57.0, 63.8, 66.4, 68.0, 70.0, 70.6, 74.1, 76.5, 79.7, 81.5, 104.6,
105.3, 107.5, 108.2, 110.7, 114.4, 116.2, 126.4, 128.2, 131.9, 134.9, 137.9,
138.3, 148.5, 151.7, 157.5, 165.3, 166.6, 167.4, 174.5, 185.6, 188.1 ppm; IR
(KBr): n˜ =3380, 2980, 2880, 1720, 1610, 1450, 1390, 1330, 1300, 1260,
1200, 1160, 1060, 970, 910, 880, 790, 750, 660, 650 cmꢀ1; LRMS (MALDI-
TOF, DHBA matrix): m/z: calcd for C40H44O18N2Na ([M+Na]+): 863.2;
found: 863.1; HRMS (FAB): m/z: calcd for C40H45O18N2 ([M+H]+):
841.2667; found: 841.2679.
16.42, 17.5, 18.1, 19.0, 19.6, 19.8, 20.0, 20.2, 20.4, 20.7, 20.8, 47.9, 48.4,
52.2, 56.4, 56.5, 61.08, 61.10, 61.4, 61.5, 68.7, 68.8, 69.5, 69.7, 69.9 (2C),
70.1, 70.18, 70.22, 71.4, 72.2, 72.8, 73.2, 74.37, 74.43, 75.4, 76.0, 76.47,
76.50, 77.0 (overlapped by a signal of CDCl3), 77.1, 77.3, 77.6, 78.0, 81.3,
98.1, 100.9, 101.0, 101.4, 107.3, 107.9, 112.5, 119.1, 119.6, 120.9, 121.1,
122.4, 122.97, 123.04, 123.29, 123.31, 127.0, 127.1, 127.25, 127.31, 127.4,
127.55, 127.64, 127.65, 127.72, 127.81, 127.82, 127.9, 127.98, 128.00, 128.1,
128.3, 128.40, 128.44, 128.5, 128.57, 128.62, 128.7, 128.8, 129.5, 129.6,
129.7, 129.8, 130.07, 130.13, 130.3, 131.2, 132.4, 132.7, 133.0, 133.2, 133.3,
133.4, 136.5, 136.8, 136.9, 137.3, 137.4, 137.7, 137.87, 137.91, 138.2, 138.8,
139.1, 145.2, 145.5, 152.4, 152.8, 153.26, 153.33, 154.3, 154.4, 164.0, 164.9,
166.15, 166.24, 167.39, 167.41, 168.5, 168.7, 169.6, 169.69, 169.72, 169.8,
172.9, 173.1 ppm; IR (KBr): n˜ =2940, 1730, 1660, 1590, 1570, 1560, 1510,
1460, 1370, 1340, 1270, 1220, 1160, 1110, 1100, 1070, 1030, 910, 810, 740,
710 cmꢀ1; elemental analysis calcd (%) for C78H76ClNO22: C 66.21, H
5.41, N 0.99; found: C 65.99, H 5.43, N 0.78.
a-78 (a mixture of two conformers: diaxial/diequatorial=82:18): M.p.
105–1078C (Et2O and hexane); [a]2D3 =+143 (c=0.990 in CHCl3);
1H NMR (500 MHz, CDCl3, the minor conformer is indicated by an aster-
isk): d=0.78* (d, J=6.6 Hz, 3H), 1.06 (d, J=7.2 Hz, 3H), 1.25 (s, 3H),
1.26 (d, J=6.6 Hz, 3H), 1.36* (d, J=7.2 Hz, 3H), 1.55* (s, 3H), 1.657 (s,
3H), 1.662* (s, 3H), 1.69* (s, 3H), 1.99 (s, 3H), 2.07* (s, 3H), 2.31 (s,
3H), 3.33 (dd, J=6.2, 12.5 Hz, 1H), 3.62* (dd, J=5.7, 12.8 Hz, 1H),
3.63* (s, 3H), 3.68 (s, 3H), 3.697 (s, 3H), 3.698 (d, J=11.2 Hz, 1H), 3.93
(d, J=11.2 Hz, 1H), 3.95* (s, 3H), 4.00* (s, 3H), 4.05 (dd, J=4.1,
12.5 Hz, 1H), 4.068 (s, 3H), 4.070 (brq, J=6.6 Hz, 1H), 4.17* (dd, J=
0.9, 11.2 Hz, 1H), 4.19 (dd, J=3.5, 10.3 Hz, 1H), 4.27* (d, J=11.3 Hz,
1H), 4.28* (dd, J=4.5, 12.8 Hz, 1H), 4.30* (d, J=11.2 Hz, 1H), 4.40 (d,
J=11.0 Hz, 1H), 4.46* (d, J=11.4 Hz, 1H), 4.48 (d, J=12.3 Hz, 1H),
4.493 (d, J=11.0 Hz, 1H), 4.50 (dd, J=5.5, 7.5 Hz, 1H), 4.54 (d, J=
5.5 Hz, 1H), 4.55 (d, J=12.3 Hz, 1H), 4.55 (d, J=12.3 Hz, 1H), 4.57–
4.63* (m, 2H), 4.60 (qd, J=7.2, 7.9 Hz, 1H), 4.69–4.74* (m, 3H), 4.70–
4.75 (m, 1H), 4.78 (dd, J=7.5, 7.5 Hz, 1H), 4.82 (s, 2H), 4.83–4.87* (m,
H), 4.90* (d, J=11.1 Hz, 1H), 4.93* (d, J=11.3 Hz, 1H), 4.96* (dd, J=
6.7, 6.7 Hz, 1H), 5.01* (d, J=4.9 Hz, 1H), 5.05* (d, J=11.1 Hz, 1H),
5.22 (d, J=4.0 Hz, 1H), 5.33* (dd, J=1.0, 3.0 Hz, 1H), 5.34 (dd, J=4.0,
10.3 Hz, 1H), 5.36* (d, J=3.6 Hz, 1H), 5.54 (dd, J=1.0, 4.6 Hz, 1H),
5.58 (d, J=7.9 Hz, 1H), 5.74* (dd, J=3.6, 10.7 Hz, 1H), 6.34* (d, J=
7.1 Hz, 1H), 6.68 (s, 1H), 6.74* (s, 1H), 6.83* (s, 1H), 6.87–7.00 (m, 3H),
7.02–7.08 (m, 1H), 7.09–7.14 (m, 2H), 7.16–7.36 (m, 8H), 7.42–7.65 (m,
5H), 7.84 (s, 1H), 8.04* (d, J=1.0 Hz, 1H), 8.04–8.15 (m, 2H), 8.20–
8.23 ppm* (m, 2H); 13C NMR (125 MHz, CDCl3, without distinction of
the two conformers): d=15.6, 16.4, 17.5, 18.1, 18.8, 19.1, 19.6, 20.0, 20.25,
20.32, 20.8, 20.9, 47.9, 48.5, 52.20, 52.24, 56.2, 56.5, 61.1, 61.2, 61.3, 61.4,
65.7, 65.8, 68.6, 68.8, 69.4, 69.5, 69.7, 70.09 (2C), 70.14, 71.0, 73.3, 73.46,
73.49, 73.9, 75.0, 75.2, 75.8, 75.9, 76.3, 76.7, 77.2, 77.3 (overlapped by a
signal of CDCl3), 80.1, 93.4, 96.1, 100.9, 101.0, 107.3, 107.9, 112.1, 119.4,
119.6, 119.9, 120.7, 122.0, 122.3, 122.8, 122.9, 123.6, 123.7, 126.8, 127.0,
127.2, 127.4, 127.6, 127.7, 127.8, 127.9, 128.0, 128.1, 128.2, 128.4, 128.46,
128.47, 128.52, 128.6, 128.8, 128.9, 129.0, 129.16, 129.24, 129.6, 129.77,
129.80, 130.0, 130.09, 130.13, 130.4, 130.5, 131.4, 132.9, 133.0, 133.18,
133.23, 133.3, 133.9, 134.0, 134.3, 137.1, 137.2, 137.3, 137.79, 137.80,
137.82, 137.83, 138.7, 138.9, 145.4, 145.5, 152.3, 153.0 (2C), 153.4, 153.8,
154.7, 165.0, 166.0, 166.11, 166.14, 167.2, 167.3, 168.5, 168.6, 169.692,
169.694, 169.73, 169.8, 172.8, 173.0ppm; IR (neat): n˜ =3400, 2930, 1760,
1740, 1720, 1660, 1600, 1580, 1570, 1550, 1500, 1450, 1360, 1340, 1260,
1240, 1220, 1160, 1100, 1070, 1050, 900, 810, 720, 710 cmꢀ1; elemental
analysis calcd (%) for C78H76ClNO22: C 66.21, H 5.41, N 0.99; found: C
65.97, H 5.18, N 0.69.
Glycoside 78: MS4A (537 mg) was placed in a two-necked round-bot-
tomed flask and flame dried. The promoter was prepared in situ by stir-
ring a mixture of Cp2HfCl2 (104 mg, 0.274 mmol) and AgOTf (141 mg,
0.548 mmol) in CH2Cl2 (1.9 mL) for 10 min at RT. A solution of 68
(200 mg, 0.249 mmol) and 80 (189 mg, 0.299 mmol) in CH2Cl2 (4.0 mL)
was added to this suspension at ꢀ788C. After stirring for 17 h at ꢀ308C,
the reaction was stopped by adding saturated aqueous NaHCO3. The
mixture was filtered through a Celite pad and extracted with EtOAc (”
3). The combined organic extracts were washed with brine, dried
(Na2SO4), and concentrated in vacuo. The residue was purified by PTLC
(hexane/Et2O/CH3CN=2:3:1) to afford b-glycoside 78 as a white amor-
phous (261 mg, 74%), along with some mixed fractions including a-glyco-
side 78. Further purification by PTLC (hexane/EtOAc=1:1) gave pure
a-glycoside 78 (26.2 mg, 7.4%) as a white amorphous solid.
b-78 (a mixture of two conformers: diaxial/diequatorial=54:46): M.p.
118–1198C (Et2O and hexane); [a]2D4 =+54.0 (c=1.00 in CHCl3);
1H NMR (500 MHz, CDCl3, the minor conformer is indicated by an aster-
isk): d=1.10 (d, J=7.2 Hz, 3H), 1.25?* (d, J=6.4 Hz, 3H), 1.29 (d, J=
6.4 Hz, 3H), 1.340 (s, 3H), 1.341* (d, J=7.2 Hz, 3H), 1.51* (s, 3H), 1.65
(s, 3H), 1.76* (s, 3H), 1.97 (s, 3H), 2.02* (s, 3H), 2.35 (s, 3H), 2.47* (s,
3H), 3.31* (dd, J=6.5, 12.4 Hz, 1H), 3.44* (dd, J=6.3, 12.4 Hz, 3H),
3.65* (s, 3H), 3.71 (s, 3H), 3.78–3.84 (m, 1H), 3.81* (s, 3H), 3.82 (s, 3H),
3.89* (s, 3H), 3.92* (dq, J=1.0, 6.4 Hz, 1H), 3.98 (dd, J=3.7, 10.3 Hz,
1H), 4.03 (dd, J=4.3, 12.4 Hz, 1H), 4.10* (dd, J=1.6, 10.7 Hz, 1H), 4.13
(d, J=11.3 Hz, 1H), 4.16* (dd, J=3.6, 10.1 Hz, 1H), 4.17* (dd, J=4.4,
10.2 Hz, 1H), 4.25* (d, J=11.3 Hz, 1H), 4.41 (s, 2H), 4.42* (d, J=
11.9 Hz, 1H), 4.47 (d, J=11.8 Hz, 1H), 4.49* (d, J=11.9 Hz, 1H), 4.50
(d, J=11.3 Hz, 1H), 4.5098 (dd, J=7.4, 7.9 Hz, 1H), 4.510* (d, J=
12.4 Hz, 1H), 4.60 (qd, J=7.2, 8.4 Hz, 1H), 4.64* (d, J=10.7 Hz, 1H),
4.650 (d, J=11.8 Hz, 1H), 4.652* (qd, J=7.2, 7.2 Hz, 1H), 4.67–4.70* (m,
1H), 4.68* (d, J=7.9 Hz, 1H), 4.69 (d, J=7.9 Hz, 1H), 4.70–4.73 (m,
1H), 4.71 (d, J=3.3 Hz, 1H), 4.71–4.74* (m, 1H), 4.75* (d, J=12.4 Hz,
1H), 4.76 (dd, J=7.1, 7.4 Hz, 1H), 4.81–4.84* (m, 1H), 4.87* (d, J=
11.3 Hz, 1H), 4.90* (dd, J=7.2, 7.6 Hz, 1H), 5.08 (d, J=3.3 Hz, 1H),
5.29* (dd, J=7.9, 10.2 Hz, 1H), 5.30 (d, J=7.9 Hz, 1H), 5.51 (dd, J=1.1,
3.7 Hz, 1H), 5.62* (dd, J=1.0, 4.4 Hz, 1H), 5.63 (d, J=8.4 Hz, 1H), 5.87
(dd, J=7.9, 10.2 Hz, 1H), 6.27* (d, J=7.2 Hz, 1H), 6.65 (s, 1H), 6.77* (s,
1H), 6.82–6.91 (m, 4H), 6.94–7.03 (m, 6H), 7.05–7.46 (m, 12H), 7.48–
7.58 (m, 3H), 7.63–7.67* (m, 1H), 7.86* (d, J=1.6 Hz, 1H), 7.97–8.01*
(m, 1H), 8.01–8.05 (m, 1H), 8.21–8.25 ppm* (m, 2H); 13C NMR
(125 MHz, CDCl3, without distinction of the two conformers): d=16.38,
Anthraquinone 79: A solution of CAN (85.9 mg, 0.157 mmol) in water
(0.19 mL) was added to a solution of 78 (106 mg, 0.0746 mmol) in
CH3CN (0.57 mL) at 08C. After stirring for 20 min at RT, a further solu-
tion of CAN (22.5 mg, 0.0411 mmol) in water (0.05 mL) was added and
the reaction mixture was stirred for a further 10 min. The reaction was
stopped by adding water and then the precipitates were collected by fil-
tration to afford the chloroquinone as a red powder (79.7 mg). The fil-
trate was extracted with EtOAc (”3) and the combined organic extracts
were washed with brine, dried (Na2SO4), and concentrated in vacuo. A
solution of diene 21 (166 mg, 0.821 mmol) in THF (1.5 mL) was added to
9820
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 9791 – 9823