Studies toward the syntheses of pluramycin natural products. the first total synthesis of isokidamycin

Article abstract of DOI:10.1016/j.tet.2011.05.117

We report the first total synthesis of the complex C-aryl glycoside isokidamycin, the epimer of the naturally-occurring pluramycin antibiotic kidamycin. The synthesis features a highly efficient Diels-Alder reaction between a substituted naphthyne and a glycosylated furan to form the anthracene core bearing a pendent angolosamine C-glycoside. The regiochemical outcome of the Diels-Alder reaction was controlled by employing a disposable silicon tether to link the reactive naphthyne and the glycosyl furan, rendering the cycloaddition intramolecular. The benzopyranone moiety of the aromatic nucleus was appended by cyclization of a functionalized vinylogous amide onto an advanced anthrol intermediate. The vancosamine amino glycoside was introduced by an O→C-glycoside rearrangement that produced the β-anomer. Subsequent refunctionalizations then led to isokidamycin.

Full text of DOI:10.1016/j.tet.2011.05.117

Tetrahedron 67 (2011) 6524e6538
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Studies toward the syntheses of pluramycin natural products. The first total
synthesis of isokidamycin
*
B. Michael O’Keefe, Douglas M. Mans, David E. Kaelin, Jr., Stephen F. Martin
Department of Chemistry and Biochemistry, The University of Texas at Austin, 1 University Station A5300 Austin, TX 78712-0165, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 April 2011
Received in revised form 28 May 2011
Accepted 28 May 2011
Available online 2 June 2011
We report the first total synthesis of the complex C-aryl glycoside isokidamycin, the epimer of the
naturally-occurring pluramycin antibiotic kidamycin. The synthesis features a highly efficient DielseAlder
reaction between a substituted naphthyne and a glycosylated furan to form the anthracene core bearing
a pendent angolosamine C-glycoside. The regiochemical outcome of the DielseAlder reaction was con-
trolled by employing a disposable silicon tether to link the reactive naphthyne and the glycosyl furan,
rendering the cycloaddition intramolecular. The benzopyranone moiety of the aromatic nucleus was
appended by cyclization of a functionalized vinylogous amide onto an advanced anthrol intermediate.
The vancosamine amino glycoside was introduced by an O/C-glycoside rearrangement that produced
Keywords:
Aryne
DielseAlder
Glycosyl furans
C-Aryl glycosides
Pluramycins
the
b
-anomer. Subsequent refunctionalizations then led to isokidamycin.
Ó 2011 Elsevier Ltd. All rights reserved.
Carbonylative cross-coupling
Natural products
Total synthesis
1. Introduction
conformation similar to that observed in the X-ray structure of
a trimethylammonium derivative of kidamycin.5a The assumption
that the underivatized natural product also adopted this confor-
mation in solution was shown, however, likely to be incorrect when
the analysis of an underivatized sample of hedamycin (3) revealed
that the F-ring sugar existed in a chair-conformation, with the
The pluramycin family of natural products are an important
group of complex C-aryl glycoside antibiotics that possess the tet-
racyclic 4H-anthra[1,2-b]pyran-4,7,12-trione moiety AeD as an
aromatic core (Fig. 1).1 The D-ring is adorned with two deoxyamin-
osugars that are appended by C-aryl glycosidic linkages. The E-ring
sugar is angolosamine, a carbohydrate that is also found in the
antibiotic angolamycin.2 The F-ring sugar is the N,N-dimethyl de-
rivative of vancosamine, which is the sugar found in the glyco-
peptide antibiotic vancomycin.3
Me
Me
1: R =
Me
R
Kidamycin
Kidamycin (1), which was isolated as a secondary metabolite
from Streptomyces phaeoverticillatus, is the member of the plur-
amycin class that has been most extensively studied.4 Its structure
was unequivocally determined by NMR and X-ray analysis.4b,5
These investigations revealed that the conformation of the E-ring
sugar exists in a typical chair-conformation, with all of the sub-
stituents in an equatorial orientation. However, the conformation
of the F-ring sugar has been the source of some confusion. Fur-
ukawa initially proposed that the F-ring of 1 resided in a boat
HO
Me
O
OH
O
O
H
A
F
Me
O
O
NMe2
D
C
B
Me
Me
H
O
2: R =
O
Pluramycin A
E
Me
NMe2
Me
OH
O
Me
O
3: R =
Hedamycin
* Corresponding author. Tel.: þ1 512 471 3915; fax: þ1 512 471 4180; e-mail
address: sfmartin@mail.utexas.edu (S.F. Martin).
Fig. 1. The pluramycin family of natural products.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.117

B.M. O’Keefe et al. / Tetrahedron 67 (2011) 6524e6538
6525
bulky aryl substituent in an axial position.6 In order to relieve the
2. Results and discussion
strain associated with this orientation, the chair conformer was
slightly flattened.
2.1. Development of the synthetic approach
In addition to its interesting structure, kidamycin (1) has an
intriguing biological profile. It is active against gram positive
bacteria, and it exhibits anticancer activity against Ehrlich ascites
carcinoma, leukemia L1210, sarcoma-180, NF-sarcoma, and
Yoshida sarcoma.7 Hurley and co-workers, who have extensively
studied the mode of action of the pluramycin natural products,8
found that the pluramycins intercalate into the DNA helix by
positioning the carbohydrate residues in both the major and
minor grooves of the helix. The complex is stabilized by
hydrogen-bonds between the protonated dimethylamino groups
of the sugar moieties and the DNA strand. The side-chain epoxide
of pluramycin A then alkylates N7 of a guanine residue leading to
the formation of a cationic lesion in the DNA that can lead to
single strand cleavage in the presence of a base. Kidamycin has
been shown to be cardiotoxic and possesses an LD50 of 18 mg/kg
in mice;7a however, it also significantly prolongs the life of mice
bearing Ehrlich ascites tumors at single doses (ip) as low as one-
sixteenth of the LD50. Kidamycin is the only member of the
pluramycin family to have been derivatized in an attempt to in-
crease the therapeutic index.9
Members of the pluramycin family of natural products exhibit
striking chemical lability. They are heat-sensitive, and readily
undergo decomposition when heated above 60 ꢀC.10 They are
unstable toward UV or even daylight in solution.11 Only one
major degradation reaction has been reported for kidamycin.4b
Kidamycin undergoes epimerization at the anomeric center of
the vancosamine-derived sugar upon heating under reflux in
chloroform in the presence anhydrous p-TsOH to give iso-
kidamycin (4) in which the aromatic nucleus occupies the more
stable equatorial orientation (Eq. 1). Because these are the only
conditions reported, it is unclear how easily kidamycin might be
epimerized under milder acidic conditions. The potential of
kidamycin (1) to serve as an anticancer agent, coupled with its
challenging structure have led to a number of synthetic in-
vestigations, but no member of the pluramycin family has been
synthesized via these approaches.12,13
The major elements of our plan for completing the synthesis
of kidamycin (1) are outlined in retrosynthetic format in Scheme 1.
The end-game relied on the stereoselective introduction
of the vancosaminyl moiety onto the intermediate 5 by the
O/C-glycoside rearrangement pioneered by Suzuki,17 which
should deliver the requisite a-anomer if the reaction were con-
ducted under kinetically-controlled conditions. We reasoned that
the incorporation of this residue late in the synthesis would
minimize the opportunity for deleterious epimerization of the
anomeric center. The benzopyranone ring in 5 would be formed by
cyclization of an acetylenic ketone that would be introduced onto
the tricyclic core 6 by a cross-coupling reaction.18 The anthrol
moiety in 6 would emanate from complete removal of the silicon
tether in 7 and ring opening of the oxabicycle. The key in-
termediate 7 would be produced by an intramolecular DielseAlder
cycloaddition of the glycosyl furan ring in 8 with a naphthyne
generated in situ from the dibromonaphthalene subunit in 8. As-
sembly of 8 would then entail alkylation of 10 with 9, a furyl
glycoside that would be prepared using methods previously de-
veloped in our group.14,15
We have long been interested in developing new entries to
oxygenated natural products, and we have disclosed a unified
strategy for the synthesis of the four major classes of C-aryl gly-
cosides.14 The approach features the ring opening of cycloadducts
obtained from the DielseAlder reactions of substituted arynes with
glycosyl furans. The power and utility of this approach has been
demonstrated by the successful syntheses of a number of C-aryl
glycoside natural products.15 However, despite these successes, we
had not applied this general method to the synthesis of any bis-C-
aryl glycoside antibiotics, such as those of the complex pluramycin
family. Accordingly, we embarked on the challenge of preparing
kidamycin (1), an endeavor that ultimately resulted in a total syn-
thesis of isokidamycin (4).16 We now wish to disclose the details of
this successful campaign.
Scheme 1.
2.2. Synthesis of glycosyl furan and naphthalene precursors
The synthesis of the glycosyl furan 9 commenced with acety-
lation of
-rhamnal (11)19 to furnish diacetate 12 in excellent yield
D
(Scheme 2). Hydration of 12, followed by treatment of the in-
termediate lactol with hydrazoic acid provided 13 in near quanti-
tative yield as a mixture of four diastereomers that were not
separated.20 O-Acetylation of the anomeric hydroxyl group fur-
nished 14 (95% yield), which underwent facile FriedeleCrafts
ꢀ
alkylation with furan in the presence of BF3$OEt2 and 4 A MS to
afford furyl glycoside 15 in 78% yield, at which point the desired b-

6526
B.M. O’Keefe et al. / Tetrahedron 67 (2011) 6524e6538
anomer was isolated, as a mixture (72:28) of diastereomers at C3.
The relative configuration at the anomeric position of 15 was
assigned based upon the observed coupling constants of 11.9 and
2.0 Hz for the anomeric proton; the ratio of C3 epimers was de-
termined through 1H NMR spectroscopy by integration of the
equatorial methyl substituent at C5.
The next stage of the synthesis required preparation of the
dibromonaphthalene 30 that would then be coupled with 22. The
synthesis of 30 commenced with the naphthoquinone 25, which
was obtained by the DielseAlder reaction of benzoquinone (23)
with the diene 1822 according to a known procedure (Scheme 4).23
O-Benzylation of 25 to provide 26 was most efficiently achieved
using the combination of Ag2O and benzyl bromide; lower yields
were obtained when various bases and benzyl bromide or chloride
were employed. Furthermore, attempted O-benzylation of 25 un-
der acidic conditions utilizing benzyltrichloroacetimidate was in-
effective. Dibromination of 26 was accomplished in a two-step
procedure. The first bromination was effected by exposing naph-
thoquinone 26 to 1 equiv of molecular bromine followed by
dehydrobromination with NEt3 to deliver bromonaphthoquinone
27 in 97% yield. The second bromination to give 28 was more
problematic as significant quantities of the debenzylated product
29 were observed under standard bromination protocols. We pos-
tulated that this side reaction was promoted by the HBr that was
formed during the reaction. Indeed, when 27 was allowed to react
with Br2 in the presence of K2CO3 to sequester the liberated HBr, 28
was isolated in 65% yield; however, lesser quantities of the
debenzylated naphthoquinone 29 were still obtained. After some
experimentation, we discovered that reproducibly high yields of
dibromonaphthoquinone 28 could be obtained by treating 27 with
1 equiv of pyridinium bromide perbromide (PyHBr3) in CH2Cl2.
Reduction of 28 with sodium dithionite and subsequent mono-
methylation of the sterically less encumbered hydroxyl group using
1 equiv of methyl Meerwein’s salt (Me3OBF4) then delivered
dibromonaphthol 30 in 90% yield over the two steps. When 2 equiv
of Me3OBF4 were used, the dimethyl ether 31 could be isolated in
about 50% (unoptimized) yield.
Scheme 2.
Although it was possible to separate the C3 epimers of 15, it was
more convenient to carry the mixture forward, because separation
of the derived alcohols 16 was more facile. In the event, treatment
of 15 with K2CO3 in MeOH, followed by separation of the di-
astereomers delivered the azido alcohol 16, in 60% yield. The
structure of 16 was established by X-ray analysis.21 O-Benzylation
of 16 gave 17 in nearly quantitative yield. Reduction of the azide and
protection of the intermediate amine as its tert-butyl carbamate
(Boc) afforded 18 in 95% yield over two steps. N-Alkylation of car-
bamate 18 with MeI provided the furyl glycoside 19 in 95% yield.
With quantities of furyl glycoside 19 in hand, we turned to its
transformation into the silyl ethanol derivative 22 (Scheme 3).
Metalation of 19 with s-BuLi gave a furyllithium intermediate that
was allowed to react with chlorodimethylvinylsilane (20) to afford
vinyl silane 21 in 82% yield. Although the deprotonation step was
faster at 0 ꢀC, the isolated yield of 21 was only 63%, and numerous
unidentifiable side-products were formed. Hydroboration of 21
with 9-BBN, followed by oxidation then delivered alcohol 22 in 84%
yield.
Me
Me
Scheme 4.
Si
O
O
H
i. s-BuLi, THF
H
Me
O
Me
O
–78 → –50 o
C
2.3. DielseAlder reactions to form the anthrone subunit
Me Me
BnO
BnO
, –78 o
C
ii.
Si
Our original synthetic plan called for an intramolecular
DielseAlder reaction of a glycosyl furan with a substituted naph-
thyne to assemble a precursor of the anthrone subunit of kidamycin
(see Scheme 1, 8/7). This strategy was based upon our reasoned
hypothesis that the regiochemistry of an intermolecular cycload-
dition reaction would not be high. It occurred to us that this ra-
tionale, compelling as it was based upon our prior experience,
should be tested by experiment. Toward this objective, equal molar
solutions of 31 and n-BuLi were added dropwise to a solution of
furan 19 at ꢁ25 ꢀC to deliver a mixture of the four possible cyclo-
adducts in good overall yield (Scheme 5). Based upon integration of
Cl
NMeBoc
NMeBoc
20
82%
O
21
19
Me
Si
Me
O
OH
H
i. 9-BBN, THF
ii. H2O2, NaOH
Me
BnO
84%
NMeBoc
22
Scheme 3.

B.M. O’Keefe et al. / Tetrahedron 67 (2011) 6524e6538
6527
the oxabicyclic bridgehead protons of 32 and 33 in the 1H NMR
spectrum of the crude reaction mixture, the ratio of regioisomers
32 and 33 was 1.6:1. The desired regioisomers 32 could be isolated
in 35% yield after careful column chromatography.
chemical operations in the intramolecular route is only two more
than the intermolecular pathway, as the latter required an addi-
tional step to prepare 31.
2.4. Synthesis of the tetracyclic core of kidamycin
With the oxabicycle 32 in hand, we turned our focus to opening
of the oxabicyclic ring and installing the benzopyranone A-ring.
After an extensive screen of Brønsted and Lewis acidic conditions,
we found that exposure of 32 to TMSOTf, in the presence of 2,6-di-
tert-butylpyridine induced the requisite ring opening with con-
comitant loss of the tert-butyl carbamate protecting group to afford
amino anthrol 36 in 85% yield (Scheme 7). Reductive N-methylation
of the secondary amino group on the sugar residue under standard
conditions gave tertiary amine 37 in near quantitative yield.
OMe OBn
OH OMe OBn
TIPSOTf
2,6-lutidine
TMSOTf,
Di-t-BuPyr
O
CH2Cl2
0 oC → rt;
then TBAF
CH2Cl2
80%
Me
Me
H
O
H
O
OMe
OMe
Scheme 5.
85%
Me
NMeBoc
Me
NRMe
OBn
The question to be resolved at this juncture was whether an
intramolecular DielseAlder reaction might be more efficient. In the
event, coupling the alcohol 22 with the dibromonaphthol 30 under
Mitsunobu conditions furnished 34 in 92% yield (Scheme 6). Opti-
mizing the conditions for inducing the intramolecular cycloaddi-
tion of the naphthyne derived from 34 required extensive
optimization of the reaction temperature, time, and alkyllithium
reagent, and it was necessary to rigorously dry 34 prior to the re-
action. We eventually found that treatment of 34 with n-BuLi in
THF at ꢁ25 ꢀC for 15 min, followed by slow warming to ambient
temperature delivered the oxabicycle 35 in 92% yield. Complete
removal of the silicon-derived tether using fluoride anion, followed
by methylation of the intermediate naphthol in a one-pot protocol
delivered oxabicycle 32 in 85% yield. The inherent advantages as-
sociated with the intramolecular cycloaddition approach are thus
evident. In particular, the overall yield of the intramolecular route
to 32 (Scheme 6) is 50% based upon the more valuable starting
material 19, whereas the intermolecular approach (Scheme 5)
provided 32 in a 35% overall yield from 19. The total number of
OBn
32
36: R = H
NaBH(OAc)3
formalin, DCE
95%
37: R = Me
TIPSO
OMe OR
TIPSO
OMe OH
R1
NIS or NBS,
CH2Cl2, toluene
Me
Me
–78 oC → rt
H
O
H
O
OMe
OMe
Me
NMe2
Me
NMe2
OBn
OBn
40: R1 = I (80%)
H2, Pd(OH)2,
pyr, MeOH,
EtOAc
38: R = Bn
39: R = H
41: R1 = Br (77%)
90%
TIPSO
OMe OMOM
R1
NaH, THF;
then MOMCl
Me
THF
H
O
OMe
Me
NMe2
OBn
42: R1 = I (77%)
43: R1 = Br (89%)
Scheme 7.
In anticipation of installing the benzopyranone ring, several
functional group manipulations were now required. In the event,
silylation of anthrol 37, followed by selective hydrogenolysis of the
anthrolic benzyl ether gave 39. Because a functional handle was
needed to introduce the pyranone ring, 39 was converted into the
corresponding iodide 40 and bromide 41 by ortho-selective iodin-
ation or bromination, respectively. Protection of these anthrols as
their MOM-ethers then provided 42 and 43.
We first explored methods to convert the iodide 42 into the
ketone 45 using carbonylative cross-coupling protocols that were
developed in our laboratories specifically for the synthesis of
sterically hindered ortho-disubstituted aryl alkynyl ketones.24
Unfortunately, when 42 was treated with the boronate ester 44
and CO in the presence of PEPPSIeIPr25 under our optimized con-
ditions, we were unable to obtain any of the desired 45 (Scheme 8);
only unreacted starting material was recovered. Similar attempts
using the alkynyl zinc reagent 46 were also unsuccessful. This
disappointing setback notwithstanding, we turned to other possi-
bilities, even though these would not benefit from the same level of
step economy.
Scheme 6.

6528
B.M. O’Keefe et al. / Tetrahedron 67 (2011) 6524e6538
TIPSO
OMe OMOM O
cyclization completely dominated in complete preference to the de-
PEPPSI-IPr (10 mol %)
Cs2CO3, CO (60 psi)
sired 6-endo-digonal cyclization mode. The cyclizations of phenolic
ynones to give benzofuranones was known,26 and in some cases may
be avoided by first converting the ynone to a vinylogous amide.18b
Accordingly, 52 was converted into vinylogous amide 54 in virtually
quantitative yield. When a solution of 54 in aqueous acetonitrile
containing LiBF4 was heated briefly with microwave irradiation, the
6-endo-digonal ring closure occurred to give benzopyranone 55,
which was treated directly with fluoride ion to remove the TIPS
protecting group and furnish 56 in 50% overall yield from 54.
42
Me
Me
Me
(i-PrO)2B
H
O
Me
OMe
Me
44
dioxane, 100 o
C
Me
NMe2
OBn
45
Me
BrZn
Me
Scheme 8.
46
In one such effort, we attempted to install the enyne side-chain
by generating the dianion from bromide 41 and trapping it with the
aldehyde 49, which was prepared by CoreyeFuchs homologation of
tiglic aldehyde (47) and trapping of the resultant alkynyl anion with
DMF (Scheme 9). Despite numerous efforts, we were able to obtain
50 in at best an 18% yield.
Scheme 9.
In light of these results, we reasoned that the protected bromide
43 might be a better substrate for introducing the enyne side-chain.
In the event, treatment of 43 with a slight excess of t-BuLi in THF,
followed by addition of aldehyde 49 gave 51 in 75% yield (Scheme
10); about 14% of dehalogenated anthracene was obtained that
could be recycled. Oxidation of 51 with BaMnO4 gave 52 in 96%
yield; other oxidants, such as IBX, DesseMartin periodinane, TPAP,
and MnO2 furnished lower yields of 52.
Scheme 11.
2.5. Introduction of vancosaminyl residue by O/C-glycoside
rearrangement
In order to introduce a vancosaminyl residue on the D-ring (1), it
was first necessary to prepare a suitably protected vancosamine
donor. In consideration of the prevailing protecting group strategy
for the anthrapyran core, we concluded that the vancosamine de-
rivative 60 would likely meet our needs. Although there are
a number of routes to vancosamine derivatives of the general type
60,27 the expediency of using vancomycin as a starting material was
attractive. Accordingly, vancomycin hydrochloride (57) was sub-
jected to Cbz-protection followed by acidic methanolysis to deliver
58 in good yield (Scheme 12).28 Hydrolysis of the methyl acetal and
acetylation of the resultant lactol delivered vancosamine donor 60
TIPSO
OMe OMOM OH
tert-BuLi; then
49
BaMnO4
43
Me
THF, –78 o
75%
C
benzene
96%
Me
H
O
Me
OMe
Me
NMe2
OBn
51
TIPSO
OMe OMOM O
as a mixture (10:1) of a- and b-anomers, respectively.
Me
Me
1) Cbz-O-Succ.
Dioxane, H2O
2) HCl, MeOH
H
O
Me
HOAc, H2O
OMe
Me
HO
O
OMe
100 o
71%
C
Vancomycin•HCl
57
89%
Me
NMe2
Me
NHCbz
OBn
58
52
Ac2O, Pyr.
Me
HO
O
OH
Me
O
OAc
Scheme 10.
DMAP, CH2Cl2
85%
AcO
The stage was now set for forming the pyranone ring on 52 by
removal of the MOM-ether protecting group, and cyclization of the
unmasked anthrol onto the alkynyl ketone.13cee,26 Although treating
52 with a variety of Brønsted acids led largely to recovered starting
material under most of the conditions examined, we discovered that
heating 52 in aqueous acetonitrile containing LiBF4 gave the benzo-
furanone 53 in 80% yield (Scheme 11); the undesired 5-exo-digonal
Me
NHCbz
Me
NHCbz
59
60
Scheme 12.
We were now poised to install the vancosamine glycoside using
an O/C-glycoside rearrangement as pioneered by Suzuki.17 To-
ward this end, the anthrol 56 was first treated with 1.5 equiv of

B.M. O’Keefe et al. / Tetrahedron 67 (2011) 6524e6538
6529
vancosamine donor 60 in the presence of 4 equiv of Sc(OTf)3, but no
C-aryl glycoside was isolated from the mixture. Although the
anthrol 56 could be recovered, the vancosamine donor could not.
Increasing the amount of 60 to 4 equiv and using 8 equiv of Sc(OTf)3
led to the formation of a bis-C-aryl glycoside in 80% yield (Scheme
13). This initially exciting result was tempered by the realization
that the O/C-glycoside rearrangement had given 61, which is the
undesired b-anomer of the vancosaminyl glycoside. This stereo-
chemical assignment was made based on analysis of the 1D and 2D
1H NMR spectra. The coupling constants of the vancosamine
anomeric proton (J¼11.7, 2.4 Hz, DMSO-d6, 100 ꢀC), as well as its
chemical shift (5.32 ppm)5b,12b confirmed that the vancosamine
glycoside was in its
b-configuration. Furthermore, an NOE in-
teraction was not observed between the anomeric proton and the
methyl substituent at C5 on the vancosamine residue.
Me
Me
Me
OH OMe
Me
OH OMe
Me
AcO
Me
Fig. 2. Conformational analysis of oxonium ion 62.
O
O
O
H
O
60, Sc(OTf)3
O
NHCbz
Me
the pyran ring. If the carbamate is in an axial orientation as in 62A
and 62C, these interactions are relieved. Although axial attack on
either 62A or 62C will give the undesired b-anomer, a destabilizing
Drierite, DCE
–30→0 °C, 60 h
80%
Me
Me
H
O
H
O
OMe
NMe2
56
OMe
1,3-diaxial interaction between the carbamate and the methyl
group on the pyran ring in 62A suggests that attack may occur on
the twist boat conformation 62C. This analysis suggests an alter-
native protecting group strategy might bias the formation of the
Me
NMe2
OBn
OBn
61
Scheme 13.
desired a
-C-aryl glycoside.12b,31
In an attempt to retard any equilibration of the
a-anomer that
was presumably formed as the kinetic product in the reaction of 56
2.6. Total synthesis of isokidamycin: the end game
with 60 to the undesired b-anomer, the reaction temperature was
maintained at ꢁ30 ꢀC; however, under these conditions no C-gly-
Although the O/C-glycoside rearrangement did not deliver the
desired a-anomer of the vancosamine C-aryl glycoside, it was ap-
cosylation of 56 was observed. We then explored other conditions
that we reasoned might not enable deleterious a/b-equilibration.
parent that 61 would be a viable intermediate in a total synthesis of
isokidamycin (4). We envisioned that conversion of 61 into 4 could
be realized following cleavage of the acetate protecting group,
hydrogenolysis of the benzyl and Cbz protecting groups, reductive
methylation of the primary amine, and oxidation of the central
anthracene ring. Though ultimately successful, this superficially
straightforward undertaking was littered with numerous pitfalls.
We initiated our efforts with removal of the acetate protecting
group of 61 using catalytic amounts of K2CO3 in MeOH. However,
these and related attempts to saponify this ester did not provide the
expected secondary alcohol; rather the cyclic carbamate 63 was
invariably isolated (Scheme 14). Attempts to hydrolyze the
Suzuki had reported that the Cp2HfCl2/AgClO4 promoter was a much
more reactive promoter than Sc(OTf)3 for inducing C-glycosylations
via the O/C-glycoside rearrangement.17c,29 When 56 and 60 were
allowed to react in the presence of this dual promoter system, no
glycosylated56 was isolated. Wealso examined the utilityof SnCl4 as
a promoter in accord with the findings of McDonald, who prepared
a vancosamine-derived
tions, 61 was again produced, albeit in only 28% yield.
The obtention of the undesired -bis-C-aryl glycoside 61 was
somewhat surprising and merits brief analysis. It is possible that the
desired -anomer of the vancosamine glycoside was formed, but
a
-C-aryl glycoside.12b Under these condi-
b,b
a
rapidly underwent epimerization under the reaction conditions. Be-
cause we never observed any product other than 61 in the reaction
mixture by TLC, this explanation is not completely satisfying. Alter-
natively, our initial predictions of the preferred transition state ge-
ometry of the vancosaminyl donor cation could be flawed. The
putative intermediate oxonium ion 62 can adopt several different
conformations in solution; representative conformers include
62Ae62D (Fig. 2). Axial attack onconformers62B and 62D would give
Me
Me
Me
Me
Me
Me
AcO
Me
O
O
OH OMe O
O
OH OMe O
O
K2CO3
H
H
N
H
O
O
Me
NHCbz
Me
MeOH
65%
Me
Me
H
O
H
O
OMe
OMe
the desired
a-anomeric C-aryl glycoside, whereas axial attack on 62A
Me
OH
NMe2
OBn
NMe2
OBn
and 62C would afford the undesired
b-anomeric C-aryl glycoside.
We originally predicted that the N-carbamyl group would reside
in an equatorial orientation as in either 62B or 62D, thereby leading
to the a-anomer; however, a retrospective analysis of various fac-
61
63
Me
O
O
OH OMe OH
OMe
O
O
H
tors leads to a different conclusion. Namely, the geminal sub-
stitution of the methyl and N-carbamate groups requires that the
axis of the C-methyl bond be approximately orthogonal to the plane
of the carbamate array to minimize unfavorable interactions similar
to those found in 1-methyl-1-phenylcyclohexane.30 Placement of
the carbamate moiety in an equatorial position as shown in 62B
and 62D should thus be disfavored due to resulting gauche in-
teractions with the adjacent acetoxy substituent and CeH bond on
N
H
Me
Me
Me
Me
H
O
Me
NMe2
OBn
64
Scheme 14.

6530
B.M. O’Keefe et al. / Tetrahedron 67 (2011) 6524e6538
carbamate under more forcing conditions led to cleavage of the
pyranone ring and formation of 64. Treating 61 with methanol
under mildly acidic conditions simply returned starting material.
In order to obviate the formation of cyclic carbamates upon
removing the acetate group, we elected to remove the Cbz and
benzyl protecting groups from the vancosamine and angolosamine
subunits in 61 first. Although there was ample precedent for the
hydrogenolysis of benzyl-derived protecting groups in the presence
of olefins,32 we were unable to selectively remove these groups
from 61 without concomitant reduction of the alkenyl side-chain
and/or formation of an amide in the vancosamine ring via O/N-
acetyl migration.
The aforegoing reactions provided us some critical insights for
planning the sequential removal of the various protecting groups.
Armed with this information, we then examined conditions for the
Lewis acid-promoted removal of the O-benzyl and N-Cbz groups.
During these experiments, we found that the presence of the free
phenol group on the D-ring of 61 rendered it unstable to many
Lewis acids. However, after acetylation of this hydroxy group, the
resulting acetate 65 could be treated with BBr3 at low temperatures
to cleave the angolosaminyl benzyl protecting group (Scheme 15).
The crude alcohol thus obtained was treated with TMSI to effect
cleavage of the N-Cbz protecting group. Key to the success of this
reaction was the discovery that quenching the reaction with pH¼7
phosphate buffer prevented migration of the vancosaminyl acetate
onto the newly formed primary amine. Because of its propensity to
suffer O/N-acetyl migration, the crude amine was immediately
dimethylated by reductive amination to afford 66, which was used
without purification.
Removal of the vancosaminyl and phenolic acetate protecting
groups from 66 proved unexpectedly difficult, as saponification of
the former acetate group was slow. Prolonged exposure of 66 to
base led to cleavage of the benzopyranone subunit. We eventually
discovered that short treatment of 66 with K2CO3 in MeOH cleaved
the phenolic acetate; stirring the crude monoacetate in MeOH for 3
days33 led to transesterification of the remaining acetate group,
delivering the penultimate intermediate 67 in 46% overall yield
from 65.
All that remained to complete the synthesis of isokidamycin (4)
was the oxidative demethylation of the C-ring of 67 to form the
anthraquinone. Although reaction of 67 with ceric ammonium ni-
trate (CAN) furnished quantities of isokidamycin (4), the use of
cerium (IV) sulfate proved to be superior, delivering 4 in 51% yield.
The synthetic sample of isokidamycin thus obtained exhibited
physical properties and 1H and 13C NMR data identical with those of
an authentic sample and those reported in the literature.1,6b
3. Conclusion
In summary, we have completed the first total synthesis of
isokidamycin (4) and thus the synthesis of a bis-C-aryl glycoside
from the pluramycin family of natural products. The synthesis
highlights our unified strategy for the synthesis of C-aryl glycosides
using silicon tethers as disposable linkers in intramolecular ary-
neefuran cycloadditions to combine a benzene annelation with the
installation of a C-aryl glycoside. Although the use of an O/C-
glycoside rearrangement to install the vancosamine glycoside did
not give the requisite stereochemistry for synthesis of kidamycin
(1), modification of the protecting group strategy of the vancos-
amine donor may lead to a solution to this problem.
4. Experimental
4.1. General
Tetrahydrofuran and diethyl ether were dried by filtration
through two columns of activated, neutral alumina according to the
procedure described by Grubbs.34 Methanol, acetonitrile, and
dimethylformamide were dried by filtration through two columns
of activated molecular sieves, and toluene was dried by filtration
through one column of activated, neutral alumina followed by one
column of Q5 reactant. Benzene was distilled from sodium and
benzophenone. Methylene chloride, diisopropylamine, triethyl-
amine, and diisopropylethylamine were distilled from calcium
hydride immediately prior to use. Pyridine was distilled from po-
tassium hydroxide (KOH) and calcium hydride and stored over
KOH. BaMnO4, the quality of which was supplier dependent, was
purchased from Aldrich and was ground with a mortar and pestle
immediately before use. All solvents were determined to have less
than 50 ppm H2O by Karl Fischer coulometric moisture analysis. All
reactions involving air or moisture sensitive reagents or in-
termediates were performed under an inert atmosphere of nitro-
gen or argon in glassware that was flame-dried. Volatile solvents
€
were removed under reduced pressure using a Buchi rotary evap-
orator (20 mmHg, 25 ꢀC). Thin layer chromatography was per-
formed on pre-coated plates of silica gel with a 0.25 mm thickness
containing 60F-254 indicator (Merck) unless otherwise noted. Pu-
rification by column chromatography was performed using forced
flow (flash chromatography) of the indicated solvent system on
Scheme 15.

B.M. O’Keefe et al. / Tetrahedron 67 (2011) 6524e6538
6531
230e400 mesh silica gel (E. Merck reagent silica gel 60) unless
otherwise noted.
d 152.8, 142.5, 137.5, 128.5, 128.3, 128.1, 110.2, 107.2, 83.4, 76.2, 75.3,
70.8, 63.6, 35.0, 18.4; IR (neat) 2878, 2097, 1080, 742 cmꢁ1; mass
spectrum (CI) m/z 314.1507 [C17H20N3O3 (Mþ1) requires 314.1505],
227 (base), 271, 286, 314.
Infrared (IR) spectra were obtained either neat on sodium
chloride or as solutions in the solvent indicated. Proton nuclear
magnetic resonance (1H NMR) spectra were obtained as solutions
in the indicated solvent at the indicated field strength. Chemical
shifts are reported in parts per million (ppm) and are referenced to
the indicated deuterated solvent. Coupling constants (J) are repor-
ted in hertz and the splitting abbreviations used are: s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; comp, overlapping
multiplets of magnetically non-equivalent protons; br, broad; app,
apparent. Carbon nuclear magnetic resonance (13C NMR) spectra
were obtained at the indicated field strength using the solvent in-
dicated as the internal reference. Reaction temperatures refer to the
temperature of the cooling bath.
4.2.3. tert-Butyl-(1R,3R,4S,5R)-4-benzyloxy-1-(furan-10-yl)-tetrahy-
dro-5-methyl-2H-pyran-3-ylcarbamate
(18). LiAlH4
(1.55 g,
40.7 mmol) was added to a suspension of 17 (11.6 g, 37.0 mmol) in
Et2O (185 mL) at 0 ꢀC in a 1 L round bottom flask. Caution: volu-
minous amounts of gas are evolved. The slurry was stirred at 0 ꢀC
until gas evolution subsided, whereupon the cooling bath was re-
moved and the solution stirred at room temperature for 1.5 h. The
solution was recooled to 0 ꢀC, and H2O (1.55 mL), 15% NaOH(aq)
(1.55 mL), then H2O (4.65 mL) were added sequentially, dropwise.
The slurry was filtered through a pad of Celite, eluting with EtOAc.
The combined filtrate and washings were dried (MgSO4), filtered,
and concentrated under reduced pressure. Boc2O (12.1 g,
55.5 mmol) was then added in one portion to a solution of the
crude amine in CH2Cl2 (74 mL) at room temperature and stirring
was continued for 18 h, whereupon the solvent was removed under
reduced pressure. The residue was purified by flash column chro-
matography, eluting with hexanes/EtOAc (19:1/4:1) to afford
13.6 g (95%) of 18 as a white solid: mp¼86e87 ꢀC; 1H NMR
4.2. Experimental procedures
4.2.1. (1R,3R,4S,5R)-3-Azido-1-(furan-10-yl)-tetrahydro-5-methyl-
2H-pyran-4-ol (16). Boron trifluoride diethyl etherate (BF3$OEt2)
(18.6 g, 16.6 mL, 131 mmol) was added to a stirred solution of 14
(30.7 g, 119 mmol) and freshly distilled (KOH) furan (43.4 mL,
597 mmol) in MeCN (595 mL) at room temperature. Stirring was
continued for 30 min, whereupon saturated NaHCO3 (150 mL) and
H2O (150 mL) were added. The layers were separated, and the
aqueous layer was extracted with EtOAc (3ꢂ300 mL). The combined
organic layers were washed with brine (1000 mL), dried (MgSO4),
filtered, and concentrated under reduced pressure. The residue was
purified by flash column chromatography, eluting with hexanes/
EtOAc (9:1) to give 22.5 g (71%) of the furyl glycoside as a mixture of
epimers at C3 (dr¼72:28). This mixture was dissolved in MeOH
(170 mL) containing anhydrous K2CO3 (0.59 g, 4.2 mmol), and the
resultant mixture was stirred at room temperature for 20 h. The
solvent was removed under reduced pressure, at which point the
desired epimeric azide was isolated by flash column chromatogra-
phy, eluting with hexanes/EtOAc (9:1) to afford 11.4 g (60%) of al-
cohol 16 as a white solid: mp¼85e86 ꢀC; 1H NMR (500 MHz, CDCl3)
(500 MHz, DMSO-d6,100 ꢀC)
d
7.52 (dd, J¼1.8, 0.8 Hz,1H), 7.34e7.25
(comp, 5H), 6.64 (s, 1H), 6.37 (dd, J¼3.3, 1.8 Hz, 1H), 6.29 (d,
J¼3.3 Hz, 1H), 4.70 (d, J¼11.3 Hz, 1H), 4.60 (d, J¼11.3 Hz, 1H), 4.52
(dd, J¼11.7, 2.1 Hz, 1H), 3.74 (dtd, J¼11.9, 9.3, 4.8 Hz, 1H), 3.48 (dq,
J¼9.2, 6.1 Hz, 1H), 3.13 (app t, J¼9.5 Hz, 1H), 2.00 (ddd, J¼13.0, 4.8,
2.3 Hz,1H), 1.88 (m, 1H), 1.40 (s, 9H), 1.21 (d, J¼6.2 Hz, 3H); 13C NMR
(125 MHz, DMSO-d6, 100 ꢀC)
d 154.6, 153.5, 141.5, 138.4, 127.5, 127.0,
126.7, 109.6, 105.9, 81.9, 77.3, 75.1, 72.8, 70.1, 52.1, 35.9, 27.8, 18.0; IR
(neat) 3345, 1683, 1594, 1159, 1099 cmꢁ1; mass spectrum (CI) m/z
388.2126 [C22H30NO5 (Mþ1) requires 388.2124], 169 (base), 388.
4.2.4. tert-Butyl-(1R,3R,4S,5R)-4-benzyloxy-1-(furan-10-yl)-tetrahy-
dro-5-methyl-2H-pyran-2-ylmethylcarbamate (19). NaH (1.50 g,
36.4 mmol) was added in one portion to a solution of 18 (12.8 g,
33.1 mmol) and MeI (2.50 mL, 39.8 mmol) in DMF (166 mL) at room
temperature. The resultant slurry was stirred for 1 h and then
cooled to 0 ꢀC, whereupon saturated NH4Cl (60 mL), H2O (60 mL),
and Et2O (100 mL) were sequentially added. The layers were sep-
arated, and the aqueous layer was extracted with Et2O (3ꢂ100 mL).
The combined organics were washed with H2O (4ꢂ400 mL), brine
(400 mL), dried (MgSO4), filtered, and concentrated under reduced
pressure. The crude residue was purified by flash column chro-
matography, eluting with hexanes/EtOAc (9:1) to afford 12.6 g
(95%) of 19 as a clear oil, which slowly solidified to a white solid
upon standing: mp¼70e73 ꢀC; 1H NMR (500 MHz, DMSO-d6,
d
7.37 (dd, J¼1.8, 0.9 Hz, 1H), 6.32 (dd, J¼3.2, 1.8 Hz, 1H), 6.29 (dt,
J¼3.2, 0.7 Hz,1H), 4.53 (dd, J¼11.8, 1.0 Hz,1H), 3.53 (ddd, J¼12.0, 9.3,
4.8 Hz, 1H), 3.46 (dq, J¼9.0, 6.2 Hz, 1H), 3.21 (td, J¼9.2, 3.7 Hz, 1H),
2.28 (ddd, J¼12.8, 4.9, 1.8 Hz, 1H), 2.22 (d, J¼3.8 Hz, 1H), 2.02 (dt,
J¼13.1, 12.0 Hz, 1H), 1.34 (d, J¼6.2 Hz, 3H); 13C NMR (125 MHz,
CDCl3) d 152.7, 142.6, 110.2, 107.3, 76.3, 75.6, 70.8, 64.0, 34.2, 18.0; IR
(neat) 3433 (br), 2877, 2102, 1255, 1071 cmꢁ1; mass spectrum (CI)
m/z 224.1039 [C10H14N3O3 (Mþ1) requires 224.1035], 137 (base),
224.
4.2.2. (1R,3R,4S,5R)-3-Azido-4-benzyloxy-1-(furan-10-yl)-tetrahy-
dro-5-methyl-2H-pyran (17). NaH (1.95 g, 48.7 mmol) was added in
one portion to a stirred solution of 16 (9.05 g, 40.6 mmol) and
benzyl bromide (5.79 mL, 48.7 mmol) in DMF (200 mL) at 0 ꢀC.
After gas evolution had subsided, the cooling bath was removed
and stirring was continued for 2 h. The mixture was recooled to
0 ꢀC, whereupon saturated NH4Cl (100 mL) and H2O (100 mL) were
added. The layers separated, and the aqueous layer was extracted
with EtOAc (3ꢂ100 mL). The combined organics were washed with
H2O (3ꢂ400 mL), brine (4100 mL), dried (MgSO4), filtered, and
concentrated under reduced pressure. The residue was purified by
flash column chromatography, eluting with hexanes/EtOAc (9:1) to
afford 12.6 g (99%) of 17 as a white solid: mp¼85e88 ꢀC; 1H NMR
100 ꢀC)
d
7.53 (s, 1H), 7.34e7.25 (comp, 5H), 6.38 (dd, J¼3.1, 1.8 Hz,
1H), 6.34 (d, J¼3.3 Hz, 1H), 4.60e4.53 (comp, 3H), 4.19e4.06 (br,
1H), 3.53 (dq, J¼8.9, 6.1 Hz, 1H), 3.41 (app t, J¼9.3 Hz, 1H), 2.80 (s,
3H), 2.17 (app q, J¼12.4 Hz, 1H), 1.87 (comp, 1H), 1.41 (s, 9H), 1.27 (d,
J¼6.1 Hz, 3H); 13C NMR (125 MHz, DMSO-d6, 100 ꢀC)
d 154.4, 153.4,
141.6, 138.2, 127.5, 126.9, 126.8, 109.6, 106.1, 78.9, 78.3, 75.4, 72.0,
70.4, 57.5, 32.6, 30.1, 27.7, 18.1; IR (neat) 2974, 2359, 1691, 1365,
1155 cmꢁ1; mass spectrum (CI) m/z 402.2276 [C23H32NO5 (Mþ1)
requires 402.2280], 302, 346 (base), 402.
4.2.5. tert-Butyl-(1R,3R,4S,5R)-4-benzyloxytetrahydro-5-methyl-1-
(40-(dimethylvinylsilyl)furan-10-yl)-2H-pyran-3-ylmethylcarbamate
(21). s-BuLi (28.5 mL, 36.5 mmol, 1.28 M solution in cyclohexane)
was added dropwise to a stirred solution of 19 (12.22 g, 3.4 mmol)
in THF (152 mL) at ꢁ78 ꢀC. The yellow solution was stirred at ꢁ78 ꢀC
for 2 h, then at ꢁ50 ꢀC for 30 min. The solution was recooled to
ꢁ78 ꢀC, whereupon chlorodimethylvinylsilane (6.3 mL, 45.6 mmol)
was added slowly dropwise. The cooling bath was kept in place and
(500 MHz, CDCl3)
d 7.39e7.34 (comp, 5H), 7.32e7.28 (comp, 1H),
6.32 (dd, J¼3.2,1.8 Hz,1H), 6.28 (d, J¼3.2 Hz,1H), 4.88 (d, J¼10.6 Hz,
1H), 4.65 (d, J¼10.6 Hz, 1H), 4.49 (dd, J¼11.8, 2.0 Hz, 1H), 3.65 (ddd,
J¼12.1, 9.2, 4.9 Hz, 1H), 3.51 (dq, J¼9.2, 6.2 Hz, 1H), 3.08 (app t,
J¼9.3 Hz, 1H), 2.26 (ddd, J¼13.1, 4.9, 2.0 Hz, 1H), 1.98 (dt, J¼13.1,
12.1 Hz, 1H), 1.35 (d, J¼6.2 Hz, 3H); 13C NMR (125 MHz, CDCl3)

6532
B.M. O’Keefe et al. / Tetrahedron 67 (2011) 6524e6538
allowed to warm to room temperature. A saturated solution of
NaHCO3 (100 mL) was added, and the mixture was diluted with
EtOAc (100 mL). The layers were separated, and the organic layer
was washed with brine (100 mL), dried (MgSO4), filtered, and
concentrated under reduced pressure. The crude residue was pu-
rified by flash column chromatography, eluting with hexanes/Et2O
(9:1) to afford 12.05 g (82%) of 21 as a clear oil: 1H NMR (500 MHz,
additional 15 min. The cooling bath was then removed and the
solution was warmed to room temperature, whereupon saturated
Na2S2O3 (700 mL) was added. The layers were separated, and the
organic layer was washed with H2O (700 mL), brine (700 mL), dried
(MgSO4), filtered, and concentrated under reduced pressure. The
crude residue was recrystallized from EtOH to afford 50.9 g (97%) of
27 as an orange solid: mp¼108e109 ꢀC; 1H NMR (400 MHz, CDCl3)
DMSO-d6, 100 ꢀC)
d
7.33e7.25 (comp, 5H), 6.66 (d, J¼3.1 Hz, 1H),
d
7.60 (s, 1H), 7.56 (comp, 2H), 7.43e7.39 (comp, 2H), 7.34e7.32
(comp, 2H), 7.14 (s, 1H), 5.24 (s, 2H), 2.43 (s, 3H); 13C NMR
(100 MHz, CDCl3) 180.9, 178.4, 158.9, 146.5, 142.3, 136.5, 135.8,
6.33 (d, J¼3.3 Hz, 1H), 6.24 (dd, J¼20.3, 14.7 Hz, 1H), 6.04 (dd,
J¼14.7, 3.7 Hz, 1H), 5.78 (dd, J¼20.3, 3.7 Hz, 1H), 4.61e4.54 (comp,
3H), 4.18e4.02 (br, 1H), 3.53 (dq, J¼8.8, 6.2 Hz, 1H), 3.43 (app t,
J¼9.6 Hz, 1H), 2.81 (s, 3H), 2.16 (app q, J¼12.2 Hz, 1H), 1.88 (ddd,
J¼12.9, 4.2, 2.0 Hz, 1H), 1.42 (s, 9H), 1.27 (d, J¼6.1 Hz, 3H), 0.31 (s,
d
132.7, 128.6, 127.9, 126.5, 121.7, 120.3, 117.4, 70.7, 22.2; IR (neat)
3064, 1651, 1599, 1252 cmꢁ1; mass spectrum (CI) m/z 357.0125
[C18H14BrO3 (Mþ1) requires 357.0126], 357, 358, 359, 360.
6H); 13C NMR (125 MHz, DMSO-d6, 100 ꢀC)
d 158.2, 156.6, 154.4,
138.2, 136.1, 132.8, 127.5, 126.9, 126.8, 120.9, 106.1, 79.0, 78.3, 75.4,
72.1, 70.6, 68.7, 32.8, 27.7, 18.1, ꢁ3.9; IR (neat) 2973, 1693, 1152,
1109 cmꢁ1; mass spectrum (ESI) m/z 486.26703 [C27H40NO5Si
(Mþ1) requires 486.2679], 524, 508, 486.
4.2.9. 5-Benzyloxy-2,3-dibromo-7-methylnaphthalene-1,4-dione
(28). Pyridinium bromide perbromide (42.7 g, 134 mmol) was
added to a solution of 27 (43.4 g,122 mmol) in CH2Cl2 (1.2 L) at 0 ꢀC.
Stirring was continued for 50 min, at which point TLC analysis
showed that starting material was consumed. Saturated Na2S2O3
(1 L) was added, the cooling bath was removed, and the mixture
was warmed to room temperature. The layers were separated, and
the aqueous layer was extracted with CH2Cl2 (700 mL). The com-
bined organic layers were washed with H2O (1 L), brine (1 L), dried
(MgSO4), filtered, and concentrated. The crude residue was filtered
through a short pad of silica gel, eluting with CH2Cl2 to afford 47.9 g
(90%) of 28 as an orange solid: mp¼161e163 ꢀC (orange needles
4.2.6. tert-Butyl-(1R,3R,4S,5R)-4-benzyloxytetrahydro-1-(40-((80-hy-
droxyethyl)dimethylsilyl)-furan-10-yl)-5-methyl-2H-pyran-3-
ylmethylcarbamate (22). 9-BBN (0.94 g, 7.67 mmol) was added to
a stirred solution of 21 (1.24 g, 2.56 mmol) in THF (28 mL) at room
temperature. The solution was stirred for 6 h and then cooled to
0
ꢀC, whereupon 3 M NaOH (2.56 mL) and 30% H2O2 (0.74 mL,
7.67 mmol) were added sequentially. The solution was stirred at
room temperature for 1 h, and H2O (10 mL) was added. The layers
were separated, and the aqueous portion was extracted with Et2O
(3ꢂ15 mL). The combined organic layers were washed with brine
(30 mL), dried (MgSO4), filtered, and concentrated under reduced
pressure. The residue was purified by flash column chromatogra-
phy, eluting with hexanes/EtOAc (4:1) to afford 1.08 g (84%) of al-
cohol 22 as a clear oil: 1H NMR (500 MHz, DMSO-d6, 100 ꢀC)
from EtOH); 1H NMR (500 MHz, CDCl3)
d
7.63 (comp,1H), 7.57e7.55
(comp, 2H), 7.42e7.39 (comp, 2H), 7.31 (tt, J¼7.3, 1.3 Hz, 1H), 7.15 (s,
1H), 5.26 (s, 2H), 2.45 (s, 3H); 13C NMR (125 MHz, CDCl3)
176.5,
173.5,159.7,147.1,145.2,139.5,135.7,132.8, 128.8, 126.8,122.1, 120.3,
116.6, 71.1, 22.3; IR (neat) 2360, 1673, 1599, 1571, 1326, 1233 cmꢁ1
d
;
mass spectrum (CI) m/z 434.9233 [C18H13Br2O3 (Mþ1) requires
434.9231], 100.96 (base), 434, 435, 436, 437.
d
7.34e7.25 (comp, 5H), 6.64 (d, J¼3.3 Hz,1H), 6.31 (d, J¼3.1 Hz,1H),
4.60e4.53 (comp, 3H), 4.20e4.02 (br, 2H), 3.59e3.50 (comp, 2H),
3.42 (app t, J¼9.2 Hz, 1H), 2.80 (s, 3H), 2.16 (app q, J¼11.6 Hz, 1H),
1.87 (comp, 1H), 1.42 (s, 9H), 1.27 (d, J¼6.1 Hz, 3H), 1.05 (comp, 2H),
4.2.10. 8-Benzyloxy-2,3-dibromo-4-methoxy-6-methylnaphthalen-
1-ol (30). A biphasic mixture of 28 (26.0 g, 59.9 mmol) in CH2Cl2
(600 mL) and Et2O (600 mL) and Na2S2O4 (156 g, 899 mmol) in H2O
(1200 mL) was vigorously stirred for 2 h with mechanical stirring.
The layers were separated, and the organic layer was washed with
H2O (500 mL), dried (MgSO4), filtered, and concentrated under
reduced pressure to furnish a light yellow solid. Molecular sieves
0.24 (s, 6H); 13C NMR (125 MHz, DMSO-d6, 100 ꢀC)
d 157.9, 157.8,
154.4, 138.2, 127.5, 126.9, 126.8, 120.3, 106.1, 79.0, 78.3, 75.4, 72.1,
70.7, 56.8, 56.7, 32.8, 27.7,19.6,18.1, ꢁ3.4; IR (neat) 3453, 2974,1692,
1366, 1108 cmꢁ1; mass spectrum (CI) m/z 504.2785 [C27H41NO6Si
(Mþ1) requires 504.2781], 170 (base), 487, 503.
ꢀ
(4 A, 2.80 g) and Me3OBF3 (9.00 g, 60.8 mmol) were added to the
crude hydroquinone in the glove box. The flask was removed from
the glove box and put under an atmosphere of dry nitrogen and the
mixture was then dissolved in dry CH2Cl2 (600 mL) and cooled to
4.2.7. 5-Benzyloxy-7-methylnaphthalene-1,4-dione
(26). Ag2O
(135 g, 585 mmol) was added to a solution of 25 (27.5 g, 146 mmol)
and benzyl bromide (52.0 mL, 438 mmol) in CHCl3 (730 mL) at
room temperature. The mixture was vigorously stirred (mechanical
stirring) for 72 h in the dark. The mixture was then filtered through
a pad of Celite, eluting with CH2Cl2. The combined filtrate and
washings were concentrated under reduced pressure, and the
crude residue was purified by flash column chromatography, elut-
ing with hexanes/EtOAc (9:1) to afford 37.0 g (91%) of 26 as a yellow
0
ꢀC. Proton sponge (13.8 g, 64.4 mmol) was then added in one
portion to the stirred solution. The resultant mixture was stirred at
0 ꢀC for 1 h, whereupon the ice bath was removed and the solution
stirred at room temperature for 14 h. H2O (500 mL) was added, and
the aqueous layer was extracted with CH2Cl2 (3ꢂ200 mL). The
combined organics were washed with 1 M HCl(aq) (500 mL), brine
(500 mL), dried (MgSO4), filtered, and concentrated under reduced
pressure. The crude residue was purified by flash column chro-
matography, eluting with hexanes/EtOAc (9:1 to 2:1), to afford
24.4 g (90%) of 30 as an orange solid: mp¼154e156 ꢀC; 1H NMR
solid: mp¼90e93 ꢀC; 1H NMR (400 MHz, CDCl3)
d 7.59e7.57 (comp,
2H), 7.53 (s, 1H), 7.42e7.31 (comp, 3H), 7.12 (s, 1H), 6.82 (s, 2H), 5.25
(s, 2H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 185.5, 183.9, 158.7,
146.3, 141.0, 136.1, 136.0, 133.8, 128.6, 128.5, 127.9, 126.9, 126.6,
120.3, 120.0, 118.0, 70.8, 22.3; IR (neat) 3500, 3064, 2920, 1658,
1599 cmꢁ1; mass spectrum (CI) m/z 279.1018 [C18H15O3 (Mþ1) re-
quires 279.1021], 297, 279, 183, 165.
(500 MHz, CDCl3) d 10.04 (s, 1H), 7.47e7.40 (comp, 6H), 6.81 (dd,
J¼1.0 Hz, 1H), 5.23 (s, 2H), 3.88 (s, 3H), 2.48 (s, 3H); 13C NMR
(500 MHz, CDCl3)
d 154.6, 148.7, 146.1, 137.5, 134.5, 129.7, 129.2,
128.4, 118.2, 115.4, 113.0, 109.0, 105.8, 72.1, 61.2, 22.3; IR (neat) 3324,
2933, 2360, 1599, 1393, 1048 cmꢁ1; mass spectrum (CI) m/z
449.9466 [C19H16Br2O3 requires 449.9469], 372, 452 (base).
4.2.8. 5-Benzyloxy-2-bromo-7-methylnaphthalene-1,4-dione
(27). Bromine (7.65 mL, 149 mmol) in CHCl3 (74 mL) was added
dropwise to a solution of 26 (41.0 g, 147 mmol) in CHCl3 (735 mL) at
4.2.11. 5-Benzyloxy-2,3-dibromo-1,4-dimethoxy-7-methylnap-
hthalene (31). A biphasic mixture of 28 (1.0 g, 2.30 mmol) in Et2O
(58 mL) and CH2Cl2 (58 mL) and Na2S2O4 (6.02 g, 34.6 mmol) in
H2O (115 mL) was shaken vigorously in a separatory funnel for
0
ꢀC. Stirring was continued for 1 h, whereupon the solution was
sparged with dry nitrogen for 15 min. NEt3 (22.1 mL, 159 mmol)
was then added dropwise and stirring was continued at 0 ꢀC for an

B.M. O’Keefe et al. / Tetrahedron 67 (2011) 6524e6538
6533
15 min. The layers were separated, and the organic layer was
(comp, 3H), 0.22e0.16 (comp, 3H); IR (neat) 2930, 2361, 1691, 1366,
1154 cmꢁ1; mass spectrum (CI) m/z 778.3776 [C46H56NO8Si (Mþ1)
requires 778.3775], 346 (base), 402, 777.
washed with brine (100 mL), dried (MgSO4), filtered, and concen-
ꢀ
trated. MS (4 A, 0.10 g) and Me3OBF4 (0.71 g, 4.83 mmol) were
added to the crude hydroquinone, and the solids were dissolved in
CH2Cl2 (58 mL). The mixture was cooled to 0 ꢀC, whereupon proton
sponge (1.04 g, 4.83 mmol) was added in one portion. The solution
was stirred for 30 min, whereupon the cooling bath was removed.
Stirring was continued for 1 h, and H2O (50 mL) was then added.
The layers were separated, and the aqueous layer was extracted
with CH2Cl2 (3ꢂ50 mL). The combined organics were washed with
1 M HCl (2ꢂ150 mL), H2O (150 mL), brine (150 mL), dried (MgSO4),
filtered, and concentrated under reduced pressure. The crude res-
idue was purified via flash column chromatography, eluting with
hexanes/EtOAc (9:1) to afford 0.519 g (48%) of 31 as an off white
4.2.14. Oxabicycle 32. Method A. A solution of TBAF$3H2O (5.11 g,
16.2 mmol) and 35 (2.1 g, 2.70 mmol) in DMF (27 mL) was placed
into a 70 ꢀC oil bath and heated with stirring for 1.5 h. The solution
was cooled to 0 ꢀC, and MeI (1.68 mL, 27.0 mmol) and NaH (0.54 g,
13.5 mmol) were sequentially added. The cooling bath was re-
moved, and the slurry was stirred at room temperature for 20 min.
The slurry was then poured into a mixture of EtOAc (100 mL) and
saturated NH4Cl (25 mL), and the layers were separated. The
aqueous layer was extracted with EtOAc (3ꢂ20 mL), and the com-
bined organic layers were washed with H2O (4ꢂ200 mL), brine
(200 mL), dried (MgSO4), filtered, and concentrated under reduced
pressure. The crude residue was purified by flash column chro-
matography, eluting with hexanes/EtOAc (17:3/3:1), to afford
1.62 g (85%) of 32 as a pale orange oil, and as a mixture of di-
solid: mp¼103 ꢀC; 1H NMR (400 MHz, CDCl3)
d
7.56 (d, J¼7.4 Hz,
2H), 7.50 (s, 1H), 7.42 (t, J¼7.2 Hz, 2H), 7.36 (t, J¼7.2 Hz, 1H), 6.87 (s,
1H), 5.17 (s, 2H), 3.94 (s, 3H), 3.72 (s, 3H), 2.50 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 154.7, 151.1, 150.0, 137.8, 136.5, 130.6, 128.4 (2C),
127.9, 127.5 (2C), 119.0, 116.9 (2C), 114.4, 111.1, 71.4, 61.7, 61.0, 22.2;
IR (neat) 2932, 1620, 1552, 1342 cmꢁ1; mass spectrum (CI) m/z
463.9618 [C20H18Br2O3 requires 463.9623], 469, 468, 467, 466, 465,
464, 389, 388, 387, 386.
astereomers: 1H NMR (400 MHz, CDCl3)
d 7.56e7.25 (comp, 9H),
6.98e6.92 (comp, 2H), 6.84e6.79 (comp, 1H), 5.99 (s, 1H), 5.14 (s,
2H), 4.80e4.50 (comp, 4H), 3.90e3.80 (comp, 3H), 3.75e3.60
(comp, 4H), 2.90e2.72 (comp, 2H), 2.70e2.55 (comp, 2H), 2.45 (s,
3H), 2.05e1.85 (comp, 2H), 1.62e1.55 (comp, 2H), 1.50e1.32 (comp,
12H); IR (neat) 2928, 1691, 1454, 1366 cmꢁ1; mass spectrum (CI)
m/z 707.3458 [C43H49NO8 requires 707.3458], 577, 608, 652, 707
(base).
Method B. A solution of 31 (0.096 g, 0.239 mmol) in THF (0.3 mL,
0.8 M) and a solution of n-BuLi (0.098 mL, 0.8 M) were added si-
multaneously via syringe pump to a solution of 19 (0.096 g,
0.239 mmol) in THF (2.4 mL) over 10 min at ꢁ30 ꢀC over 10 min.
Stirring was continued for 5 min, whereupon saturated NaHCO3
(3 mL) and EtOAc (5 mL) were added. The layers were separated,
and the aqueous layer was extracted with EtOAc (3ꢂ5 mL). The
combined organic layers were washed with H2O (15 mL), brine
(15 mL), dried (MgSO4), filtered, and concentrated under reduced
pressure. The crude residue was purified by flash column chro-
matography, eluting with hexanes/EtOAc (99:1/4:1) to afford
0.060 g (35%) of 32 and 0.037 g (22%) of 33 as orange oils.
4.2.12. tert-Butyl-(1R,3R,4S,5R)-1-(40-(80-(500-benzyloxy-200,300-di-
bromo-100-methoxy-700-methylnaphthalen-400-yloxy)ethyldimethy-
lsilyl)furan-10-yl)-4-benzyloxytetrahydro-5-methyl-2H-pyran-3-
ylmethylcarbamate (34). DIAD (4.65 g, 4.53 mL, 23.0 mmol) was
added dropwise to a stirred solution of 30 (7.96 g, 17.7 mmol), 22
(9.08 g, 18.0 mmol), and PPh3 (6.03 g, 23.0 mmol) in toluene
(450 mL) at room temperature. The solution was stirred for 40 min,
and the solvent was removed under reduced pressure. The residue
was purified by flash column chromatography, eluting with hex-
anes/EtOAc (6:1) to afford 15.27 g (92%) of 34 as an orange glass: 1H
NMR (500 MHz, DMSO-d6, 100 ꢀC)
d
7.51 (d, J¼7.2 Hz, 2H), 7.46 (s,
1H), 7.41e7.25 (comp, 8H), 7.08 (s, 1H), 6.57 (d, J¼3.2 Hz, 1H), 6.29
(d, J¼3.1 Hz, 1H), 5.20 (s, 2H), 4.59e4.51 (comp, 3H), 4.09 (br, 1H),
3.92 (app t, J¼6.8 Hz, 2H), 3.88 (s, 3H), 3.50 (dq, J¼8.8, 5.8 Hz, 1H),
3.37 (app t, J¼6.8 Hz, 2H), 2.75 (s, 3H), 2.45 (s, 3H), 2.12 (app q,
J¼13.1 Hz, 1H), 1.83 (comp, 1H), 1.40 (s, 9H), 1.23 (d, J¼6.1 Hz, 3H),
1.11 (app t, J¼8.2 Hz, 2H), 0.14 (s, 6H); 13C NMR (125 MHz, DMSO-d6,
4.2.15. (E)-4-Methylhex-4-en-2-ynal (49). A solution of PPh3
(10.9 g, 41.6 mmol) in CH2Cl2 (26 mL) was transferred via cannula
to a solution of freshly sublimed CBr4 (6.87 g, 20.7 mmol) in CH2Cl2
(26 mL) at ꢁ20 ꢀC. Stirring was continued for 20 min, then the
solution was cooled to ꢁ78 ꢀC. Tiglic aldehyde (1.0 mL, 10.4 mmol)
was added dropwise. Stirring was continued for 10 min, where-
upon the cooling bath was removed and the mixture was allowed
to warm to room temperature. The mixture was poured into pen-
tane (700 mL) and the resulting mixture was filtered through a pad
a Celite, eluting with pentane. The combined filtrate and washings
were concentrated under reduced pressure to w10% of the original
volume, and the precipitated solids were removed by vacuum
100 ꢀC)
d 157.9, 156.9, 154.4, 154.3, 149.5, 149.3, 138.2, 137.6, 136.2,
129.8, 127.8, 127.7, 127.5, 127.4, 126.9, 126.8, 120.6, 118.6, 115.8, 113.5,
111.5, 110.2, 109.8, 106.1, 81.3, 78.3, 75.4, 72.1, 71.0, 70.8, 70.6, 60.5,
32.7, 27.7, 21.1, 18.1, 16.3, ꢁ3.80, ꢁ3.83; IR (neat) 2930, 1693, 1551,
1337, 1152 cmꢁ1; mass spectrum (CI) m/z 936.2146 [C46H56Br2NO8Si
(Mþ1) requires 936.2142], 911, 938 (base), 941.
4.2.13. Cycloadduct 35. Compound 34 (4.56 g, 4.88 mmol) was
dried by azeotropic distillation from toluene (3ꢂ100 mL) and then
by heating at 120 ꢀC under high vacuum for 2 h. n-BuLi (2.04 mL,
5.12 mmol, 2.51 M solution in hexanes) was then added dropwise
to a stirred solution of 34 in THF (120 mL) at ꢁ25 ꢀC. Stirring was
continued for 15 min, whereupon saturated NH4Cl (50 mL), H2O
(50 mL), and EtOAc (100 mL) were added. The cooling bath was
removed, and the solution was allowed to warm to room temper-
ature. The layers were separated, and the aqueous layer was
extracted with EtOAc (3ꢂ50 mL). The combined organic layers
were washed with brine (200 mL), dried (MgSO4), filtered, and
concentrated under reduced pressure. The crude residue was pu-
rified by flash column chromatography, eluting with toluene/EtOAc
(96:4/92:8) to afford 3.80 g (92%) of cycloadduct 35 as a mixture
filtration through
a plug of Celite washing with additional
pentane. The filtrate was again concentrated to w10% of the
original volume and was purified by passage through a plug of
silica gel, eluting with pentane to give 1.95 g (79%) of
(E)-1,1-dibromo-3-methylpenta-1,3-diene (48) as a colorless oil
that was identical in all respects to the reported compound.35
n-BuLi (7.1 mL, 19.4 mmol, 2.74 M solution in hexanes) was
added dropwise to a solution of a portion of the previously prepared
vinyl dibromide (2.20 g, 9.25 mmol) in Et2O (46 mL) at ꢁ78 ꢀC.
Stirring was continued for 1 h at ꢁ78 ꢀC, and then at 0 ꢀC for 1 h. The
solution was recooled to ꢁ78 ꢀC, whereupon DMF (0.86 mL,
11.1 mmol) was added dropwise. Stirring was continued for 5 min,
whereupon the cooling bath was removed and the solution was
warmed to room temperature. The reaction mixture was diluted
with saturated NH4Cl (5 mL), then Et2O (20 mL). The layers were
of diastereomers: 1H NMR (400 MHz, CDCl3)
d 7.56e7.25 (comp,
11H), 6.98e6.90 (comp, 1H), 6.78 (s, 1H), 5.18e5.08 (comp, 2H),
4.68e4.55 (comp, 3H), 4.42e4.35 (comp, 1H), 3.95e3.86 (comp,
2H), 3.80 (s, 3H), 2.90e2.60 (br, 4H), 2.44 (s, 3H), 2.00e1.84 (comp,
2H), 1.50e1.38 (comp, 14H), 0.96e0.88 (comp, 2H), 0.48e0.44

6534
B.M. O’Keefe et al. / Tetrahedron 67 (2011) 6524e6538
separated, and the aqueous layer was extracted with Et2O
(2ꢂ10 mL). The combined organics were washed with H2O
(2ꢂ20 mL), brine (20 mL), dried (Na2SO4), filtered, and concentrated
under reduced pressure while keeping the vacuum w300 mmHg or
higher. The crude material was purified by flash column chroma-
tography, eluting with pentane/Et2O (95:5). The eluant was then
3H), 1.42e1.31 (comp, 1H); 13C NMR (100 MHz, CDCl3)
d 154.7, 153.8,
149.5,148.5,139.0,136.7,135.8,128.6, 128.5,128.3,128.1, 127.5, 125.4,
124.2, 117.0, 115.6, 114.2, 108.7, 108.1, 80.4, 76.9, 76.2, 74.3, 71.4, 67.2,
64.84, 64.83, 62.7, 40.9, 32.6, 22.5, 19.3; IR (neat) 2931, 1633, 1452,
1356 cmꢁ1; mass spectrum (CI) m/z 622.3170 [C39H44NO6 (Mþ1)
requires 622.3169], 623, 622, 621, 249, 222.
ꢀ
concentrated to a volume of ca. 6 mL. MS (4 A) were added (2 spatula
tips) and the mixture was stirred under N2 for 2 h. The solution was
then filtered into a dry flask using a syringe fitted with a 0.45 mm
4.2.18. (1R,3R,4S,5R)-4-Benzyloxy-1-(60-benzyloxy-50,100-dimethoxy-
8 0- m e t hyl - 4 0- t r i i s o p r o p yl o x ya n t h ra c e n - 1 0- yl ) - N , N , 5 -
trimethyltetrahydro-2H-pyran-3-amine (38). TIPSOTf (0.84 mL,
3.11 mmol) was added dropwise to a solution of anthrol 37 (1.76 g,
2.83 mmol) and 2,6-lutidine (0.43 mL, 3.68 mmol) in CH2Cl2
(14 mL) at 0 ꢀC. The cooling bath was removed, and stirring was
continued for 21 h, whereupon CH2Cl2 (10 mL) and saturated
NaHCO3 (20 mL) were added. The layers were separated, and the
aqueous layer was extracted with CH2Cl2 (3ꢂ10 mL). The combined
organics were washed with H2O (40 mL), brine (40 mL), dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
crude residue was purified by flash column chromatography, elut-
ing with hexanes/EtOAc/NEt3 (90:9:1) to afford 1.73 g (80%) of 38 as
nitrocellulose filter tip and the resultant solution was used imme-
diately as aldehyde 49 was quite unstable. The eluant could also be
concentrated to deliver 0.449 g (45%) of the unstable aldehyde 49 as
a yellow oil:36 1H NMR (400 MHz, C6D6)
d
8.93 (s, 1H), 5.89 (qq,
J¼7.2, 1.4 Hz, 1H), 1.39 (dq, J¼2.7, 1.4 Hz, 3H), 1.16 (dq, J¼7.2, 1.0 Hz,
3H); 13C NMR (100 MHz, C6D6)
d 175.8, 141.0, 116.9, 97.4, 86.7, 15.6,
14.2; IR (neat) 3412, 2925, 2854, 2182, 1662 cmꢁ1; mass spectrum
(CI) m/z 109.0651 [C7H9O (Mþ1) requires 109.0653].
4.2.16. 8-Benzyloxy-4-((10R,30R,40S,50R)-40-benzyloxytetrahydro-50-
methyl-30-methylamino-2H-pyran-10-yl)-9,10-dimethoxy-6-
methylanthracen-1-ol (36). TMSOTf (4.64 g, 3.78 mL, 20.9 mmol)
was added dropwise to a stirred solution of 32 (2.96 g, 4.18 mmol)
and di-t-BuPy (4.77 g, 5.6 mL, 25.1 mmol) in CH2Cl2 (42 mL) at 0 ꢀC.
Stirring was continued at 0 ꢀC for 5 min, whereupon the cooling
bath was removed and stirring was continued for an additional
1.75 h. The solution was recooled to 0 ꢀC, TBAF (5.5 g, 20.9 mmol)
was added, and stirring was continued for 10 min. Saturated
NaHCO3 (50 mL) was added, and the solution was allowed to warm
to room temperature. The layers were separated, and the aqueous
layer was extracted with CH2Cl2 (3ꢂ30 mL). The combined organic
layers were washed with H2O (100 mL), brine (100 mL), dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
crude reside was purified by flash column chromatography, eluting
with hexanes/EtOAc/NEt3 (70:25:5/60:35:5) to afford 2.16 g (85%)
a yellow oil: 1H NMR (600 MHz, C6D6)
d
8.20 (d, J¼7.5 Hz, 1H), 7.80
(s, 1H), 7.64 (d, J¼7.0 Hz, 2H), 7.47 (d, J¼7.6 Hz, 2H), 7.36 (t, J¼7.5 Hz,
2H), 7.24e7.21 (comp, 3H), 7.14e7.12 (comp, 1H), 6.97 (d, J¼7.5 Hz,
1H), 6.48 (s, 1H), 5.66 (d, J¼10.1 Hz, 1H), 5.15 (d, J¼11.2 Hz, 1H),
4.98e4.82 (br s, 2H), 4.67 (d, J¼11.2 Hz, 1H), 3.99 (dq, J¼8.3, 6.0 Hz,
1H), 3.74 (s, 3H), 3.54 (s, 3H), 3.26e3.20 (comp, 2H), 2.54 (d,
J¼11.8 Hz, 1H), 2.29 (s, 3H), 2.15 (s, 6H), 1.71 (d, J¼6.0 Hz, 3H),
1.47e1.35 (comp, 4H), 1.21e1.18 (br s, 18H); 13C NMR (150 MHz,
C6D6)
d 156.6, 152.84, 147.8, 140.3, 138.2, 135.8, 131.2, 129.4, 128.5,
128.4, 128.3, 128.1, 127.9, 127.7, 127.4, 127.3, 125.7, 124.5, 121.8, 118.3,
114.5, 113.1, 109.3, 80.7, 77.5, 77.4, 74.5, 71.3, 68.2, 63.8, 62.4, 40.7,
32.9, 22.4, 19.8, 18.4, 13.7; IR (neat) 2941, 2865, 1568, 1356 cmꢁ1
;
mass spectrum (CI) m/z 778.44974 [C48H63NO6Si (Mþ1) requires
778.4495], 780, 779, 778.
of 36 as a yellow oil: 1H NMR (500 MHz, CDCl3)
d 10.61 (s, 1H), 7.72
(d, J¼7.9 Hz, 1H), 7.63 (s, 1H), 7.57e7.59 (comp, 2H), 7.45e7.24
(comp, 8H), 6.80 (d, J¼8.1 Hz, 1H), 6.73 (s, 1H), 5.64 (d, J¼10.3 Hz,
1H), 5.24 (s, 2H), 4.79 (d, J¼11.0 Hz, 1H), 4.72 (d, J¼11.0 Hz, 1H), 3.84
(s, 3H), 3.82 (s, 3H), 3.77 (dq, J¼9.2, 6.1 Hz,1H), 3.18 (app t, J¼9.0 Hz,
1H), 2.97e2.92 (comp, 1H), 2.52 (s, 3H), 2.39e2.46 (comp, 1H), 2.36
(s, 3H), 1.48 (d, J¼6.2 Hz, 1H), 1.45e1.35 (comp, 1H); 13C NMR
4.2.19. 50-((1R,3R,4S,5R)-4-Benzyloxy-3-dimethylamino-5-
methyltetrahydro-2H-pyran-1-yl)-90,100-dimethoxy-30-methyl-80-
triisopropylsilyloxyanthracen-10-ol (39). A mixture of 38 (1.73 g,
2.22 mmol) and pyridine (0.09 mL, 1.11 mmol) in MeOH (44 mL)
and EtOAc (4.0 mL) was sonicated for 60 min until all solids had
dissolved. Pd(OH)2 (0.31 g, 0.44 mmol; 20% on carbon) was added
in one portion, and the mixture was vigorously stirred under an
atmosphere of H2 (balloon pressure) for 2 h. The resultant mixture
was filtered through a pad of Celite, eluting with EtOAc. The yellow
solution was concentrated under reduced pressure, and the crude
residue was purified by flash column chromatography, eluting with
hexanes/EtOAc/NEt3 (90:9:1) to deliver 1.37 g (90%) of 39 as a yel-
(125 MHz, CDCl3)
d 154.7, 154.0, 149.6, 148.5, 138.3, 136.7, 135.8,
128.7, 128.6, 128.5, 128.1, 127.94, 127.90, 127.5, 127.4, 126.1, 124.4,
117.1, 115.6, 114.2, 108.8, 108.2, 85.4, 76.5, 75.7, 75.1, 71.4, 64.9, 62.7,
62.2, 39.0, 33.2, 22.6, 19.2; IR (neat) 3275, 2931, 2279, 1633, 1447,
1356 cmꢁ1; mass spectrum (CI) m/z 608.3009 [C38H42NO6 (Mþ1)
requires 608.3012], 608, 302, 208, 125, 113.
low oil: 1H NMR (600 MHz, DMSO-d6)
d 10.14 (s, 1H), 7.60 (d,
4.2.17. 8-Benzyloxy-4-((10R,30R,40S,50R)-40-benzyloxytetrahydro-30-
dimethylamino-50-methyl-2H-pyran-10-yl)-9,10-dimethoxy-6-
methylanthracen-1-ol (37). NaBH(OAc)3 (1.34 g, 6.32 mmol) was
added in one portion to a solution of 36 (1.28 g, 2.11 mmol) and 37%
aqueous formaldehyde (0.47 mL, 6.32 mmol) in DCE (42 mL) at room
temperature. Stirring was continued for 5 min, whereupon saturated
NaHCO3 (40 mL) and CH2Cl2 (40 mL) were sequentially added. The
biphasic solution was stirred vigorously for 10 min. The layers were
separated, and the organic layer was washed with saturated NaHCO3
(2 mL), H2O (2 mL), brine (2 mL), dried (Na2SO4), filtered, and con-
centrated under reduced pressure to afford 1.25 g (95%) of 37 as an
orange oil that needed no further purification: 1H NMR (400 MHz,
J¼7.9 Hz, 1H), 7.43 (s, 1H), 7.38e7.33 (comp, 4H), 7.27 (tt, J¼6.9,
1.8 Hz, 1H), 6.79 (d, J¼7.9 Hz, 1H), 6.65 (d, J¼1.5 Hz, 1H), 5.38 (d,
J¼8.1 Hz, 1H), 4.91 (d, J¼11.3 Hz, 1H), 4.64 (d, J¼11.3 Hz, 1H), 3.84 (s,
3H), 3.81 (s, 3H), 3.62 (dq, J¼8.7, 6.1 Hz, 1H), 3.18 (app t, J¼9.3 Hz,
1H), 2.97e2.93 (comp, 1H), 2.44 (s, 3H), 2.25 (s, 6H), 2.22e2.14
(comp, 1H), 1.37 (septet, J¼7.6 Hz, 3H), 1.33 (d, J¼6.1 Hz, 3H),
1.25e1.15 (comp, 1H), 1.14e1.00 (br s, 18H); 13C NMR (150 MHz,
DMSO-d6)
d 153.8, 150.4, 149.6, 147.6, 139.2, 137.2, 130.3, 128.1,
127.48, 127.37, 127.2, 124.2, 124.0, 118.3, 114.8, 112.1, 111.5, 110.5,
79.6, 76.0, 75.7, 73.0, 66.4, 64.4, 62.8, 40.4, 32.0, 21.9, 19.0, 17.78,
17.75, 17.74, 12.5; IR (neat) 3309, 2941, 2865, 1640, 1449, 1362,
1031 cmꢁ1; mass spectrum (CI) m/z 687.3950 [C41H57NO6Si (Mþ0)
requires 687.3955], 688, 532, 222.
CDCl3)
d
10.62 (s, 1H), 7.72 (d, J¼8.0 Hz, 1H), 7.65e7.64 (comp, 1H),
7.60e7.58 (comp, 2H), 7.47e7.26 (comp, 8H), 6.80 (d, J¼8.0 Hz, 1H),
6.75 (d, J¼1.0 Hz, 1H), 5.52 (d, J¼10.3 Hz, 1H), 5.24 (s, 2H), 5.03 (d,
J¼10.7 Hz, 1H), 4.68 (d, J¼10.7 Hz, 1H), 3.833 (s, 3H), 3.828 (s, 3H),
3.69e3.76 (comp, 1H), 3.21 (app t, J¼9.4 Hz, 1H), 3.09e3.03 (comp,
1H), 2.53 (s, 3H), 2.36 (s, 6H), 2.24e2.28 (comp,1H),1.46 (d, J¼6.1 Hz,
4.2.20. 50-((1R,3R,4S,5R)-4-Benzyloxy-3-dimethylamino-5-
methyltetrahydro-2H-pyran-1-yl)-20-bromo-90,100-dimethoxy-30-
methyl-80-triisopropylsilyloxyanthracen-10-ol (41). A solution of
freshly recrystallized and rigorously dried NBS (0.083 g,

B.M. O’Keefe et al. / Tetrahedron 67 (2011) 6524e6538
6535
0.467 mmol) in CH2Cl2 (12 mL) was added dropwise to a solution of
39 (0.318 g, 0.463 mmol) in CH2Cl2 (12 mL) ꢁ78 ꢀC. The cooling
bath was left in place, and the mixture was allowed to slowly warm
to room temperature for 4 h, whereupon saturated NaHCO3 (20 mL)
was added. The layers were separated, and the aqueous layer was
extracted with Et2O (3ꢂ10 mL). The combined organics were
washed with H2O (40 mL), brine (40 mL), dried (Na2SO4), filtered,
and concentrated under reduced pressure. The crude residue was
purified by flash column chromatography, eluting with hexanes/
EtOAc/NEt3 (90:9:1) to afford 0.272 g (77%) of 41 as an orange foam;
purified by flash column chromatography, eluting with hexanes/
EtOAc/NEt3 (90:9:1) to afford 0.581 g (75%) of 51 as a mixture of C10
epimers; 1H NMR (400 MHz, C6D6)
d 8.16 (s,1H), 8.01 (s,1H), 7.46 (d,
J¼7.2 Hz, 2H), 7.22 (t, J¼7.6 Hz, 2H), 7.14e7.11 (comp,1H), 7.00e6.92
(comp, 2H), 6.00e5.88 (comp, 1H), 5.62e5.61 (comp, 1H), 5.22 (d,
J¼6.1 Hz, 1H), 5.13 (d, J¼11.2 Hz, 1H), 4.65 (d, J¼11.2 Hz, 1H),
4.00e3.92 (comp, 1H), 3.80e3.65 (comp, 3H), 3.47e3.40 (comp,
4H), 3.30e3.21 (comp, 4H), 3.15e3.00 (comp, 2H), 2.98e2.82
(comp, 2H), 2.53 (d, J¼12.5 Hz, 1H), 2.20e2.10 (br s, 6H), 1.69e1.67
(comp, 6H), 1.43e1.30 (comp, 8H), 1.25e1.05 (br s, 18H); 13C NMR
1H NMR (500 MHz, DMSO-d6)
d
11.04 (s, 1H), 7.65 (d, J¼8.1 Hz, 1H),
(100 MHz, C6D6) d 152.4, 151.1, 148.3, 140.1, 136.8, 135.1, 132.2, 131.2,
7.64 (s, 1H), 7.38e7.33 (comp, 4H), 7.29e7.26 (comp, 1H), 6.84 (d,
J¼8.1 Hz, 1H), 5.45e5.30 (br, 1H), 4.91 (d, J¼11.3 Hz, 1H), 4.65 (d,
J¼11.3 Hz, 1H), 3.89 (s, 3H), 3.83 (s, 3H), 3.63 (dq, J¼8.7, 6.2 Hz, 1H),
3.19 (app t, J¼9.2 Hz,1H), 3.00e2.91 (comp,1H), 2.54 (s, 3H), 2.26 (s,
6H), 2.24e2.15 (br, 1H), 1.44e1.26 (comp, 6H), 1.28e1.18 (br, 1H),
128.1, 128.4, 127.5, 125.5, 124.4, 122.0, 118.9, 113.2, 101.6, 80.6, 77.4,
77.3, 74.4, 68.0, 63.4, 62.5, 59.0, 57.4, 45.7, 40.7, 32.6, 30.2, 21.4, 19.7,
18.3, 13.8, 10.7; IR (neat) 3416, 2932, 2866, 2350, 1602, 1451, 1358,
1026 cmꢁ1; mass spectrum (ESI) m/z 840.48652 [C50H70NO8Si
(Mþ1) requires 840.4865], 842, 841, 840.
1.12e0.91 (comp, 18H); 13C NMR (125 MHz, DMSO-d6)
d 150.3,
150.1,148.3,148.1,139.0, 136.4,130.3,128.1,127.5,127.3,125.2, 124.6,
118.8, 114.5, 113.2, 106.5, 79.3, 76.0, 75.4, 74.2, 72.9, 66.3, 64.7, 63.3,
40.3, 32.0, 23.8, 18.9, 17.8, 12.5; IR (neat) 3249, 2941, 2866, 1628,
4.2.23. (E)-100-(50-((2R,4R,5S,6R)-5-Benzyloxy-4-dimethylamino-6-
methyltetrahydro-2H-pyran-2-yl)-90,100-dimethoxy-10-methoxy-
methoxy-30-methyl-80-(triisopropylsilyloxy)anthracen-20-yl)-400-
methylhex-400-en-200-yn-100-one (52). Freshly ground BaMnO4
(2.55 g, 9.96 mmol) was added in one portion to a solution of 51
(0.418 g, 0.498 mmol) in benzene (10 mL) at room temperature.
Vigorous stirring was continued for 3.5 h, whereupon the mixture
was filtered through a pad of Celite, eluting with CH2Cl3. The filtrate
was concentrated to provide 0.401 g (96%) of 52 as an orange oil
1447, 1103 cmꢁ1
;
mass spectrum (ESI) m/z 766.31331
[C41H56BrNO6Si (Mþ1) requires 766.3124], 770, 769, 768, 767, 766.
4.2.21. (2R,3S,4R,6R)-3-Benzyloxy-6-(60-bromo-90,100-dimethoxy-50-
methoxymethoxy-70-methyl-40-triisopropylsilyloxyanthracen-10-yl)-
N,N,2-trimethyltetrahydro-2H-pyran-4-amine (43). NaH (0.21 g,
0.53 mmol; 60% dispersion in mineral oil) was added in one portion
to a solution of 41 (0.272 g, 0.355 mmol) and MOMCl (0.058 mL,
0.533 mmol) in THF (3.6 mL) at 0 ꢀC. After gas evolution has sub-
sided, the cooling bath was removed, and stirring was continued for
25 min. The mixture was recooled to 0 ꢀC, whereupon saturated
NH4Cl (8 mL), Et2O (20 mL) and H2O (10 mL) were sequentially
added. The layers were separated, and the aqueous layer was
extracted with Et2O (3ꢂ10 mL). The combined organics were
washed with H2O (40 mL), brine (40 mL), dried (Na2SO4), filtered,
and concentrated under reduced pressure. The crude residue was
purified by flash column chromatography, eluting with hexanes/
EtOAc/NEt3 (90:9:1) to afford 0.258 g (89%) of 43 as a yellow oil: 1H
that needed no further purification: 1H NMR (600 MHz, C6D6)
d 8.19
(d, J¼7.8 Hz, 1H), 7.87 (s, 1H), 7.47 (d, J¼7.0 Hz, 2H), 7.23 (t, J¼7.5 Hz,
2H), 7.14e7.12 (comp, 1H), 6.94 (d, J¼8.0 Hz, 1H), 6.01 (dq, J¼7.2,
1.6 Hz, 1H), 5.60 (d, J¼9.2 Hz, 1H), 5.45e5.48 (br, 2H), 5.16 (d,
J¼11.2 Hz, 1H), 4.67 (d, J¼11.2 Hz, 1H), 3.99e3.94 (br, 1H), 3.82 (s,
3H), 3.61 (s, 3H), 3.43 (s, 3H), 3.26e3.20 (comp, 2H), 2.53 (d,
J¼13.6 Hz, 1H), 2.50 (s, 3H), 2.18 (s, 6H), 1.70 (d, J¼6.0 Hz, 3H), 1.52
(s, 3H), 1.39e1.34 (br, 4H), 1.21 (d, J¼7.2 Hz, 3H), 1.19e1.15 (br, 18H);
13C NMR (150 MHz, C6D6)
d 181.0, 152.6, 151.8, 151.7, 148.5, 140.2,
139.8, 134.3, 133.0,131.3, 128.8, 126.2, 125.0, 122.3, 119.7, 117.7, 113.5,
102.0, 95.3, 88.6, 80.6, 77.5, 77.3, 74.5, 68.1, 63.8, 62.5, 57.9, 40.8,
32.8, 30.2, 20.3, 19.8, 18.3, 15.9, 14.2, 13.7; IR (neat) 2932, 2866,
2183, 1650, 1451, 1360 cmꢁ1; mass spectrum (ESI) 838.47087
[C50H68NO8Si (Mþ1) requires 838.47190].
NMR (600 MHz, C6D6)
d
8.18 (d, J¼7.5 Hz, 1H), 7.91 (s, 1H), 7.47 (d,
J¼7.6 Hz, 2H), 7.23 (app t, J¼7.5 Hz, 2H), 7.14e7.10 (comp, 1H), 6.94
(d, J¼7.5 Hz, 1H), 5.60 (d, J¼10.2 Hz, 1H), 5.49e5.32 (br, 2H), 5.15 (d,
J¼11.2 Hz, 1H), 4.67 (d, J¼11.2 Hz, 1H), 4.05e3.94 (comp, 1H), 3.75
(s, 3H), 3.68e3.62 (br s, 3H), 3.43 (s, 3H), 3.23e3.19 (comp, 2H), 2.50
(d, J¼12.0 Hz, 1H), 2.42 (s, 3H), 2.16 (s, 6H), 1.70 (d, J¼6.0 Hz, 3H),
1.41e1.32 (comp, 4H), 1.21e1.08 (comp, 18H); 13C NMR (150 MHz,
4.2.24. (Z)-70-((2R,4R,5S,6R)-5-Benzyloxy-4-dimethylamino-6-
methyltetrahydro-2H-pyran-2-yl)-60,110-dimethoxy-40-methyl-20-
((E)-200-methylbut-20-enylidene)-100-triisopropylsilyloxyanthra[1,2,b]
furan-300(2H)one (53). A freshly made solution of LiBF4 (0.21 mL,
1.0 M in MeCN) was added to a solution of 52 (0.017 g, 0.021 mmol)
in MeCN (1.0 mL) at room temperature. The resultant solution was
heated to 75 ꢀC for 2 h, whereupon H2O (0.05 mL) was added.
Stirring was continued for 30 min, and the solution was then cooled
to room temperature. Saturated NaHCO3 (2.0 mL) and Et2O (2.0 mL)
were added. The layers were separated, and the aqueous layer was
extracted with Et2O (3ꢂ1 mL). The combined organics were washed
with H2O (2.0 mL), brine (2.0 mL), dried (Na2SO4), filtered, and
concentrated under reduced pressure. The crude residue was pu-
rified by flash column chromatography, eluting with hexanes/
EtOAc/NEt3 (90:9:1) to afford 0.013 g (80%) of 53 as a red oil: 1H
DMSO-d6)
d 152.6, 150.2, 148.5, 140.2, 136.5, 131.3, 125.6, 124.7,
122.4, 119.9, 119.3, 113.5, 101.2, 80.6, 77.5, 77.2, 75.8, 74.5, 74.1, 68.1,
67.5, 65.9, 63.6, 62.5, 58.3, 40.8, 32.8, 24.6, 19.8, 18.3, 13.7; IR (neat)
2942, 2866, 1607, 1451, 1033 cmꢁ1; mass spectrum (CI) m/z
810.33952 [C43H60BrNO7Si (Mþ1) requires 810.3395], 814, 813, 811,
809, 649, 647, 593, 592, 590.
4.2.22. (E)-10-(500-((2R,4R,5S,6R)-5-Benzyloxy-4-dimethylamino-6-
methyltetrahydro-2H-pyran-2-yl)-900,1000-dimethoxy-100-methoxy-
methoxy-300-methyl-800-triisopropylsilyloxyanthracen-200-yl)-40-meth-
ylhex-40-en-20-yn-10-ol (51). t-BuLi (1.21 mL, 1.6 M solution in
pentane) was added at a fast, dropwise rate to a solution of 43
(0.75 g, 0.925 mmol) in THF (9.3 mL) at ꢁ78 ꢀC. Stirring was con-
tinued for 10 s, whereupon a solution of 49 (0.50 g, 4.63 mmol) in
THF (6 mL) was quickly added. Stirring was continued for 2 min,
whereupon the cooling bath was removed, and the solution was
warmed to room temperature. H2O (10 mL) and Et2O (10 mL) were
then added. The layers were separated, and the aqueous layer was
extracted with Et2O (3ꢂ10 mL). The combined organics were
washed with H2O (30 mL), brine (30 mL), dried (Na2SO4), filtered,
and concentrated under reduced pressure. The crude residue was
NMR (600 MHz, C6D6)
d
8.25 (d, J¼8.0 Hz,1H), 7.58 (d, J¼1.3 Hz,1H),
7.49 (d, J¼7.5 Hz, 2H), 7.24 (t, J¼7.4 Hz, 2H), 7.14e7.12 (comp, 1H),
6.98 (d, J¼8.0 Hz, 1H), 6.78 (s, 1H), 5.88 (qq, J¼7.2, 1.3 Hz, 1H), 5.60
(d, J¼9.8 Hz, 1H), 5.17 (d, J¼11.1 Hz, 1H), 4.67 (d, J¼11.1 Hz, 1H),
4.05e3.92 (comp, 1H), 3.78 (s, 3H), 3.44 (s, 3H), 3.26e3.20 (comp,
2H), 2.54e2.46 (comp, 1H), 2.28 (s, 3H), 2.17 (s, 6H), 1.69 (d,
J¼6.0 Hz, 3H), 1.51 (d, J¼7.6 Hz, 3H), 1.41e1.29 (comp, 7H),
1.24e1.04 (br s, 18H); 13C NMR (150 MHz, C6D6)
d 184.0, 167.7, 153.2,
153.0,148.5,147.8,146.0,140.1,137.6,133.5,132.4,129.7,128.5,127.6,
126.3, 121.7, 117.7, 116.81, 116.77, 114.2, 113.5, 80.5, 77.6, 77.1, 74.5,

6536
B.M. O’Keefe et al. / Tetrahedron 67 (2011) 6524e6538
68.0, 64.4, 62.7, 40.8, 33.1, 19.7, 18.3, 14.5, 14.4, 13.6; IR (neat) 2941,
2846, 1687, 1602, 1367, 1071 cmꢁ1; mass spectrum (low res ESI) m/z
794.22 [C48H63NO7Si (Mþ1) requires 794.10].
4.2.27. Benzyl (2S,3S,4S)-3-hydroxy-6-methoxy-2,4-dimethy-
ltetrahydro-2H-pyran-4-ylcarbamate(58). NaHCO3 (1.0 g, 12.0 mmol)
was added to a solution of vancomycin$HCl (57) (5.94 g, 4.0 mmol) in
dioxane (33 mL) and H2O (33 mL) at room temperature. Stirring was
continued for 5 min, whereupon CbzeO-Succinimide (3.99 g,
16.0 mmol) was added in one portion. Stirring was continued for 3 h.
The resulting solution was poured into acetone (400 mL) and was
sonicated for 30 min. The solids were collected in a medium porosity
fritted funnel. The collected solids were azeotroped from toluene
(3ꢂ200 mL) and placed under vacuum overnight. The resulting
crude Cbzevancomycin was dissolved in MeOH (133 mL), where-
upon a solution of concentrated HCl (2.67 mL, 32.0 mmol) in dioxane
(5.4 mL) was added dropwise at room temperature. White pre-
cipitate formed after ca. 1 min. Stirring was continued for 3 h,
whereupon NaHCO3 (2.72 g, 32.3 mmol) was added. Stirring was
continued for 20 min, whereupon the mixture was concentrated to
ca. 10% of its original volume. Acetone (400 mL) was added and the
resultant mixture was sonicated for 30 min. The solids were col-
lected in a medium porosity fritted funnel and the filtrate was
concentrated under reduced pressure. The crude material thus
obtained was absorbed onto silica gel and purified by flash column
chromatography, eluting with hexanes/EtOAc (3:2) to afford 1.10 g
4.2.25. (200E,400E)-100-(((2R,4R,5S,6R)-5-Benzyloxy-4-dimethylamino-
6-methyltetrahydro-2H-pyran-2-yl)-90,100-dimethoxy-10-methoxy-
methoxy-30-methyl-80-(triisopropylsilyloxy)anthracen-20-yl)-300-di-
ethylamino-400-methylhexa-200,400-dien-100-one (54). Freshly distilled
Et2NH (0.92 mL, 8.86 mmol) was added to a solution of 52 (0.372 g,
0.443 mmol) in EtOH (4.4 mL) at room temperature. Stirring was
continued for 3 h, whereupon the solution was concentrated under
reduced pressure. The crude residue was dissolved in Et2O (50 mL)
and the resultant solution was washed with H2O (50 mL), brine
(50 mL), dried (Na2SO4), filtered, and concentrated under reduced
pressure to provide 0.396 g (99%) of 54 as a yellow oil, which re-
quired no further purification: 1H NMR (600 MHz, C6D6)
d 8.17 (d,
J¼7.9 Hz, 1H), 7.98 (s, 1H), 7.47 (d, J¼6.9 Hz, 2H), 7.22 (t, J¼7.4 Hz,
2H), 7.13e7.10 (comp, 1H), 6.96 (d, J¼7.9 Hz, 1H), 5.64 (d, J¼10.1 Hz,
1H), 5.55 (s, 1H), 5.50e5.44 (br, 3H), 5.16 (d, J¼11.2 Hz, 1H), 4.67 (d,
J¼11.2 Hz, 1H), 3.98 (dq, J¼8.0, 5.9 Hz, 1H), 3.93 (s, 3H), 3.67 (s, 3H),
3.50 (s, 3H), 3.26e3.19 (comp, 2H), 2.90e2.64 (br, 4H), 2.60 (s, 3H),
2.58e2.52 (br, 1H), 2.16 (s, 6H), 2.40e1.92 (br, 3H), 1.70 (d, J¼6.1 Hz,
3H), 1.64e1.51 (br, 3H), 1.42e1.30 (comp, 4H), 1.25e1.10 (br comp,
(89%) of 58 as an inseparable mixture of
(400 MHz, CDCl3) 7.37e7.27 (comp, 5H), 5.45e5.43 (comp, 1H),
a/b
anomers (3:2): 1H NMR
18H), 0.83e0.70 (br, 6H); 13C NMR (150 MHz, C6D6)
d
188.7, 163.7,
d
159.9, 152.5,151.3,151.2,148.3,148.1,140.3,139.2,134.8,133.4,131.3,
128.7, 128.5, 127.6, 127.4, 125.2, 124.1, 122.0, 119.0, 113.2, 101.8, 97.1,
80.6, 77.5, 77.4, 74.4, 68.1, 63.8, 62.6, 57.9, 43.5, 40.8, 32.8, 22.8, 20.6,
19.8, 18.3, 16.5, 15.1, 13.8, 13.6; IR (neat) 2935, 1513, 1358,
1036 cmꢁ1; mass spectrum (ESI) 911.56002 m/z [C54H79N2O8Si
(Mþ1) requires 911.55881].
5.12e5.02 (comp, 2H), 4.71e4.39 (comp, 1H), 4.12e3.80 (comp, 1H),
3.47 (s, 1H), 3.24e3.36 (comp, 3H), 2.36e2.04 (comp, 2H), 1.87e1.77
(comp, 1H), 1.62e1.51 (comp, 3H), 1.35e1.22 (comp, 3H); 13C NMR
(100 MHz, CDCl3)
73.0, 72.5, 68.8, 66.2, 62.9, 60.2, 56.4, 55.0, 54.9, 53.6, 37.4, 35.2, 23.2,
21.6, 20.8, 17.2, 17.1; IR (neat) 3411 (br), 2937, 1714, 1502, 1222 cmꢁ1
d 155.0, 136.5, 128.5, 128.0, 103.8, 100.2, 98.1, 88.7,
;
mass spectrum (CI) m/z 310.1654 [C16H24NO5 (Mþ1) requires
4.2.26. 80-((2R,4R,5S,6R)-5-Benzyloxy-4-dimethylamino-6-
methyltetrahydro-2H-pyran-2-yl)-10-((E)-but-200-en-200-yl)-110-hy-
droxy-70,120-dimethoxy-50-methyl-4H-naphtho[2,3-h]chromen-40-
one (56). A solution of 54 (0.182 g, 0.200 mmol) and LiBF4 (4.0 mL,
1.0 M solution in 5% aq MeCN) was heated at 82 ꢀC in the micro-
wave (with simultaneous cooling; w12 W) for 15 min. The reaction
was cooled, and the mixture was partitioned between Et2O (2 mL)
and saturated NaHCO3 (2 mL). The layers were separated, and the
organic layer was washed with H2O (2 mL), brine (2 mL), dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
crude residue was purified by flash column chromatography, elut-
ing with hexanes/EtOAc/NEt3 (80:19:1/60:39:1) to afford 0.061 g,
38% of the TIPS protected anthrol as a yellow oil, along with 0.017 g,
14% of 56 as an orange oil.
310.1658] 310, 279, 278.
4.2.28. Benzyl (2S,3S,4S)-3,6-dihydroxy-2,4-dimethyltetrahydro-2H-
pyran-4-ylcarbamate (59). A solution of 58 (0.707 g, 2.29 mmol) in
H2O (2.3 mL) and HOAc (9.15 mL) was heated to 100 ꢀC for 1 h,
whereupon the solvent was removed under reduced pressure. The
crude residue was purified by flash column chromatography, eluting
with hexanes/EtOAc (1:1/1:4) to afford 0.486 g (71%) of 59 as an
inseparable mixture (ca. 2:1) of
a/b
anomers: 1H NMR
(400 MHz, CDCl3) 7.38e7.29 (comp, 5H), 5.66e5.46 (comp, 1H),
d
5.32e4.76 (comp, 4H), 3.76e3.36 (comp, 1H), 3.40e3.19 (comp, 1H),
2.80e1.94 (comp, 2H), 1.82e1.52 (comp, 2H), 1.48e1.36 (comp, 2H),
1.26e1.19 (comp, 3H); 13C NMR (100 MHz, CDCl3)
d 155.2, 136.3,
136.0, 128.4, 128.0, 97.7, 96.9, 93.1, 91.3, 72.9, 72.0, 69.1, 66.7, 66.2,
65.9, 63.2, 62.7, 59.6, 55.0, 53.5, 47.7, 46.9, 38.7, 35.2, 23.4, 22.1, 21.5,
21.0, 20.3, 17.23, 17.17; IR (neat) 3406 (br), 2939, 1705, 1503, 1276,
1068 cmꢁ1; mass spectrum (CI) m/z 296.1501 [C15H22NO5 (Mþ1)
requires 296.1498] 296, 279, 278.
A 1.0 M solution of TBAF$3H2O in THF (0.17 mL, 0.17 mmol) was
added dropwise to a stirred solution of the TIPS protected anthrol
(0.09 g, 0.114 mmol) in THF (11 mL) at 0 ꢀC. Stirring was continued
for 5 min, whereupon saturated NaHCO3 (5 mL), Et2O (20 mL), and
H2O (5 mL) were sequentially added. The layers were separated,
and the organic layer was washed with H2O (20 mL), brine (20 mL),
dried (Na2SO4), filtered, and concentrated under reduced pressure.
The crude residue was purified by flash column chromatography,
eluting with hexanes/EtOAc/NEt3 (80:18:2) to afford 0.065 g (90%)
4.2.29. (4S,5S,6S)-4-Benzyloxycarbonylamino-4,6-dimethyltet-
rahydro-2H-pyran-2,5-diyl acetate (60). Ac2O (0.62 mL 6.59 mmol)
was added dropwise to a solution of 59 (0.486 g, 1.65 mmol), pyr-
idine (0.80 mL, 9.9 mmol), and DMAP (0.02 g, 0.17 mmol) in CH2Cl2
(17 mL) at room temperature. Stirring was continued for 24 h,
whereupon the solvent was removed under reduced pressure. The
crude residue was dissolved in Et2O (20 mL), and the resultant
solution was washed with saturated CuSO4 (2ꢂ20 mL), H2O
(20 mL), brine (20 mL), dried (Na2SO4), filtered, and concentrated
under reduced pressure. The crude residue was purified by flash
column chromatography, eluting with hexanes/EtOAc (5:1/1:1) to
of 56 as an orange oil: 1H NMR (600 MHz, C6D6)
d 10.64e10.54 (br,
1H), 8.27 (d, J¼8.0 Hz, 1H), 7.82 (s, 1H), 7.49 (d, J¼8.0 Hz, 2H),
7.29e7.23 (comp, 3H), 6.78 (q, J¼7.3 Hz, 1H), 6.45 (s, 1H), 5.61 (d,
J¼9.5 Hz, 1H), 5.16 (d, J¼11.2 Hz, 1H), 4.68 (d, J¼11.2 Hz, 1H),
3.97e3.93 (comp, 1H), 3.46 (s, 3H), 3.30 (s, 3H), 3.22e3.20 (comp,
2H), 3.18 (s, 3H), 2.48e2.40 (br, 1H), 2.20 (s, 6H), 1.66 (d, J¼6.1 Hz,
3H), 1.50 (s, 3H), 1.45 (d, J¼7.2 Hz, 3H); 13C NMR (150 MHz, C6D6)
d
179.2, 162.4, 155.2, 154.7, 150.6, 149.1, 140.1, 135.7, 129.7, 120.6,
afford 0.531 g (85%) of 60 as a mixture (9:1) of
NMR (400 MHz, CDCl3)
a/b
anomers: 1H
7.38e7.29 (comp, 5H), 5.87 (dd, J¼10.2,
120.2, 118.5, 114.1, 110.7, 110.3, 80.5, 77.6, 76.9, 74.5, 68.1, 65.9, 63.9,
62.6, 40.8, 33.3, 32.8, 30.2, 24.2, 19.7, 15.5, 14.1, 11.9; IR (neat) 3314,
2926, 1643, 1443, 1371, 1114 cmꢁ1; mass spectrum (ESI) 638.31123
[C39H44NO7 (Mþ1) requires 638.3114].
d
2.4 Hz, 1H), 5.14e4.82 (comp, 4H), 4.15e4.96 (comp, 1H), 2.18e2.05
(comp, 8H), 1.64 (s, 3H) 1.22e1.15 (comp, 3H); 13C NMR (125 MHz,
DMSO-d6, 100 ꢀC)
d 170.9, 168.9, 168.0, 153.7, 136.7, 127.7, 127.1, 90.4,

B.M. O’Keefe et al. / Tetrahedron 67 (2011) 6524e6538
6537
71.2, 68.4, 64.4, 53.4, 36.0, 21.3, 20.2, 20.1, 19.8, 16.6; IR (neat) 3358,
2987, 1746, 1526, 1245, 1045 cmꢁ1; mass spectrum (CI) m/z
378.1555 [C19H24NO7 (MꢁH) requires 378.1553] 667, 438, 414,
378, 293.
1H), 3.03 (ddd, J¼12.0, 9.8, 3.9 Hz, 1H), 2.91 (s, 3H), 2.44 (s, 3H),
2.35e2.31 (comp, 7H), 2.27 (ddd, J¼12.6, 4.0, 1.5 Hz, 1H), 2.16e2.10
(comp,1H), 2.08 (s, 3H),1.98 (d, J¼7.1 Hz, 3H),1.72 (s, 3H), 1.45e1.42
(comp, 1H), 1.38 (d, J¼6.0 Hz, 3H), 1.10 (d, J¼6.3 Hz, 3H); 13C NMR
(150 MHz, DMSO-d6, 100 ꢀC)
d 179.4, 169.9, 168.4, 162.4, 155.8,
4.2.30. (200S,300S,400S,600S)-600-(80((2R,4R,5S,6R)-5-Benzyloxy-4-
dimethylamino-6-methyltetrahydro-2H-pyran-2-yl)-10-((E)-but-2000-
en-2000-yl)-110-hydroxy-70,120-dimethoxy-50-methyl-40-oxo-4H-naph-
tho[2,3-h]chromen-100-yl)-400-benzyloxycarbonylamino-200,400-dime-
thyltetrahydro-2H-pyran-300-yl acetate (61). A solution of 56
(0.073 g, 0.115 mmol) and 60 (0.174 g, 0.460 mmol) in DCE (1.5 mL)
was transferred dropwise, via cannula, to a stirred suspension of
Sc(OTf)3 (0.453 g, 0.920 mmol) and powdered Drierite (0.453 g) in
DCE (2.3 mL) at ꢁ30 ꢀC. The cooling bath was left in place, and the
reaction mixture was allowed to reach 0 ꢀC over 30 min. Stirring
was continued at 0 ꢀC for 67 h, whereupon saturated NaHCO3
(3 mL) and EtOAc (5 mL) were added. Stirring was continued for
5 min, whereupon the mixture was filtered through a pad of Celite,
eluting with EtOAc. The filtrate was washed with H2O (20 mL),
brine (20 mL), dried (Na2SO4), filtered, and concentrated under
reduced pressure. The crude residue was purified by two flash
column chromatographic separations, eluting the first with CH2Cl2/
MeOH (99:1/95:5), and the second with hexanes/EtOAc/NEt3
(80:19:1/50:49:1) to afford 0.088 g (80%) of 61 as an orange oil,
along with 0.014 g (19%) of recovered 56 [61 exists as a mixture of
rotomers, which decompose upon extended heating at 100 ꢀC in
154.6, 150.8, 148.4, 142.1, 140.1, 137.4, 137.1, 136.2, 131.4, 129.6, 126.0,
124.2, 121.0, 120.8, 120.0, 119.8, 116.9, 110.5, 80.3, 77.5, 77.2, 74.5,
72.8, 71.4, 70.5, 68.2, 66.3, 63.1, 62.8, 54.1, 40.8, 39.8, 32.3, 30.2, 24.2,
21.2, 20.3, 20.1, 19.6, 18.2, 14.1, 11.7; IR (neat) 2933, 1747, 1642, 1440,
1200, 1081 cmꢁ1; mass spectrum (CI) 999.4637 m/z [C58H67N2O13
(Mþ1) requires 999.4643].
4.2.32. 10-((E)-But-2000-en-2000-yl)-100-((200S,300S,400S,600S)-400-dimethyl-
amino-500-hydroxy-400,600-dimethyltetrahydro-2H-pyran-600-yl)-80-
((2R,4R,5S,6R)-4-dimethylamino-5-hydroxy-6-methyltetrahydro-2H-
pyran-2-yl)-110-hydroxy-70,120-dimethoxy-50-methyl-4H-naphtho
[2,3-h]chromen-40-one (67). A solution of BBr3 (0.65 mL, 0.326
mmol, 0.5 M in CH2Cl2) was added dropwise to a stirred solution of
65 (0.054 g, 0.054 mmol) in CH2Cl2 (2.7 mL) at ꢁ90 ꢀC. Stirring was
continued for 5 min, whereupon MeOH (1.5 mL) and saturated
NaHCO3 (1.5 mL) were added. The cooling bath was removed, and
the mixture was vigorously stirred while warming to room tem-
perature. The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (3ꢂ1 mL). The combined organic layers were
washed with H2O (5 mL), brine (5 mL), dried (Na2SO4), filtered, and
concentrated under reduced pressure. The crude residue was puri-
fied by flash column chromatography, eluting with hexanes/EtOAc/
NEt3 (50:49:1)/hexanes/EtOAc/MeOH/NEt3 (50:45:4:1) to afford
a mixture of alcohols (ca. 1:1 by HPLC).
A portion of the above mixture of alcohols (0.021 g, 0.024 mmol)
was dissolved in CH2Cl2 (0.5 mL) containing di-t-BuPy (0.019 g,
0.022 mL, 0.096 mmol) at 0 ꢀC, and TMSI (0.027 mL, 0.191 mmol)
was added with stirring. The solution was stirred for 45 min,
whereupon MeOH (0.5 mL) and pH¼7 phosphate buffer (0.5 mL)
were added. The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (2ꢂ1 mL). The combined organic layers were
diluted with MeOH (5 mL), dried (Na2SO4), filtered, and concen-
trated under reduced pressure to a volume of ca. 1.2 mL (it is im-
portant to keep the crude product in MeOH throughout the workup
and not to concentrate the solution to dryness in order to avoid
O/N-acetyl migration.) This solution was used immediately in the
next reaction.
DMSO-d6]: 1H NMR (600 MHz, DMSO-d6, 100 ꢀC)
d 8.06 (s, 1H), 7.80
(s, 1H), 7.40e7.26 (comp, 10H), 7.13 (dq, J¼7.1, 1.3 Hz, 1H), 6.44 (s,
1H), 5.50 (d, J¼10.0 Hz, 1H), 5.32 (dd, J¼11.7, 2.4 Hz, 1H), 5.13e5.09
(comp, 1H), 5.04 (d, J¼12.6 Hz, 1H), 4.93 (d, J¼11.5 Hz, 1H), 4.90 (d,
J¼12.6 Hz, 1H), 4.70 (d, J¼11.5 Hz, 1H), 4.08 (qd, J¼6.2, 1.1 Hz, 1H),
3.92 (s, 3H), 3.88 (s, 3H), 3.68 (dq, J¼8.7, 6.2 Hz, 1H), 3.20 (t,
J¼9.2 Hz, 1H), 3.00 (td, J¼9.2, 4.0 Hz, 1H), 2.90 (s, 3H), 2.33 (s, 6H),
2.16 (dd, J¼13.8, 4.0 Hz, 1H), 2.08 (s, 3H), 2.06e2.02 (comp, 4H),
1.99e1.96 (comp, 4H), 1.82 (d, J¼12.5 Hz, 1H), 1.73 (s, 3H), 1.36 (d,
J¼6.02 Hz, 3H), 1.12 (d, J¼6.3 Hz, 3H); 13C NMR (150 MHz, C6D6)
d
179.2, 170.5, 170.1, 162.3, 155.1, 154.7, 150.5, 149.3, 149.0, 140.1,
137.5, 135.7,129.7, 129.2, 125.9, 125.8, 122.7,120.6, 120.2, 118.1,114.2,
110.6, 92.8, 91.7, 80.4, 77.6, 76.9, 74.4, 73.6, 72.5, 71.4, 70.0, 68.1,
66.3, 63.8, 63.1, 54.7, 53.3, 40.9, 39.2, 36.3, 34.3, 32.8, 24.2, 21.7, 20.3,
19.5, 18.2, 14.2, 11.9; IR (neat) 3287, 2974, 1746, 1643, 1231 cmꢁ1
;
mass spectrum (ESI) 957.45320 m/z [C56H64N2O12 (Mþ1) requires
957.4538].
A solution of 37% aqueous formalin (0.011 mL, 0.144 mmol) and
NaCNBH3 (0.009 g, 0.144 mmol) were added to the above meth-
anolic solution, and the pH was then adjusted to pH¼4e5 with
HOAc. The solution was stirred at room temperature for 15 min,
whereupon saturated NaHCO3 (1 mL) and CH2Cl2 (1 mL) were
added. The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (3ꢂ1 mL). The combined organic layers were
washed with H2O (5 mL), brine (5 mL), dried (Na2SO4), filtered, and
concentrated under reduced pressure. The residue was dissolved in
MeOH (1.2 mL), K2CO3 (0.033 g, 0.240 mmol) was added, and the
mixture was stirred at room temperature for 1.5 h. Saturated NH4Cl
(1.5 mL) and CHCl3 (2 mL) were added and the layers separated, and
the aqueous layer was extracted with CHCl3 (4ꢂ2 mL). The com-
bined organic layers were washed with brine (10 mL), dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
residue was dissolved in dry MeOH (1.2 mL), and the solution was
stirred for 3 days. The solvent was removed under reduced pres-
sure, and the residue was purified by flash column chromatogra-
phy, eluting with toluene/NEt3 (4:1) to obtain 0.010 g (46% over five
steps) of 67 as a yellow solid: mp¼150 ꢀC (decomp.); 1H NMR
4.2.31. 100-((200S,300S,400S,600S)-300-Acetoxy-400-benzyloxycarbony-
lamino-200,400-dimethyltetrahydro-2H-pyran-600-yl)-80-((2R,4R,5S,6R)-
5-benzyloxy-4-dimethylamino-6-methyltetrahydro-2H-pyran-2-yl)-
10-((E)-but-2000-3n-2000-yl)-70,120-dimethoxy-50-methyl-40-oxo-4H-
naphtho[2,3-h]chromen-110-yl
0.412 mmol) was added dropwise to a solution of 61 (0.079 g,
0.082 mmol), pyridine (66 L, 0.820 mmol), and DMAP (0.005 g,
acetate
(65). Ac2O
(39 mL,
m
0.041 mmol) in CH2Cl2 (1.64 mL) at room temperature. Stirring was
continued for 30 min, whereupon the solution was concentrated
and redissolved in Et2O (5 mL). The ethereal solution was washed
with H2O (3ꢂ5 mL), brine (5 mL), dried (Na2SO4), filtered, and
concentrated under reduced pressure. The resultant crude material
was purified by flash column chromatography, eluting with hex-
anes/EtOAc/NEt3 (75:23:2/50:48:2) to afford 0.081 g (99%) of 65
as a yellow solid that existed as a mixture of rotomers that de-
compose upon extended heating at 100 ꢀC in DMSO-d6:
mp¼125e126 ꢀC; 1H NMR (600 MHz, DMSO-d6, 100 ꢀC)
d 8.13 (s,
1H), 7.81 (s, 1H), 7.40e7.26 (comp, 10H), 7.12 (dq, J¼7.1, 1.3 Hz, 1H),
6.63 (s, 1H), 6.45 (s, 1H), 5.54 (d, J¼10.1 Hz, 1H), 5.12 (s, 1H),
5.11e5.06 (comp, 1H), 5.04 (d, J¼12.6 Hz, 1H), 4.93 (d, J¼11.5 Hz,
1H), 4.90 (d, J¼12.6 Hz, 1H), 4.70 (d, J¼11.5 Hz, 1H), 4.09 (qd, J¼6.3,
1.1 Hz, 1H), 3.91 (s, 3H), 3.77e3.69 (comp, 4H), 3.21 (app t, J¼9.3 Hz,
(400 MHz, CDCl3)
d 10.84e10.60 (br, 1H), 8.13 (s, 1H), 7.79 (s, 1H),
7.15 (q, J¼6.8 Hz, 1H), 6.46 (s, 1H), 5.56 (d, J¼10.3 Hz, 1H), 5.15e4.92
(br, 1H), 4.00e3.80 (comp, 7H), 3.68e3.62 (comp, 1H), 3.32e3.25
(comp, 2H), 2.98 (s, 3H), 2.80e2.72 (comp, 1H), 2.30 (s, 6H), 2.23 (s,

6538
B.M. O’Keefe et al. / Tetrahedron 67 (2011) 6524e6538
7. (a) Kanda, N.; Kono, M.; Asano, K. J. Antibiot. 1972, 25, 553; (b) Maeda, K.;
Takeuchi, T.; Nitta, K.; Yagishita, K.; Utahara, R.; Osato, T.; Ueda, M.; Kondo, S.;
Okami, Y.; Umezawa, H. J. Antibiot., Ser. A 1956, 9, 75.
8. (a) Hansen, M. R.; Hurley, L. H. Acc. Chem. Res. 1996, 29, 249; (b) Hansen, M. R.;
Hurley, L. H. J. Am. Chem. Soc. 1995, 117, 2421; (c) Sun, D.; Hansen, M. R.; Hurley,
L. H. J. Am. Chem. Soc. 1995, 117, 2430; (d) Sun, D.; Hansen, M. R.; Clement, J. J.;
Hurley, L. H. Biochemistry 1993, 32, 8068.
9. (a) Kanda, N. J. Antibiot. 1972, 25, 557; (b) Umezawa, I.; Komiyama, K.; Take-
shima, H.; Hata, T.; Kono, M.; Kanda, N. J. Antibiot. 1973, 26, 669.
10. Gonda, S. K.; Byrne, K. M.; Herber, P. K.; Tondeur, Y.; Liberato, D.; Hilton, B. D. J.
Antibiot. 1984, 37, 1344.
6H), 2.03 (s, 3H), 1.98 (d, J¼6.8 Hz, 3H), 1.50e1.44 (comp, 6H), 1.20
(s, 3H); 13C NMR (150 MHz, CDCl3)
180.1, 162.8, 155.2, 148.6, 134.8,
d
130.4, 128.1, 127.1, 126.1, 125.6, 122.6, 120.1, 120.0, 117.8, 113.7, 110.3,
78.4, 77.9, 73.3, 72.2, 71.8, 70.4, 68.2, 64.5, 59.0, 58.6, 52.1, 40.4, 37.5,
36.6, 30.3, 29.7, 23.9, 18.8, 17.2, 14.7, 12.4, 11.0, 8.4; IR (neat); 3281,
2934, 1640, 1440, 1082 cmꢁ1; mass spectrum (CI) m/z 719.3895
[C41H55N2O9 (Mþ1) requires 719.3908].
4.2.33. Isokidamycin (4). A solution of Ce(SO4)2 (0.013 mL,
0.064 mmol, 0.5 M in H2O) was added dropwise to a stirred solution
of 67 (0.023 g, 0.032 mmol) in MeCN (0.058 mL) and H2O (0.006 mL)
at 0 ꢀC. Stirring was continued for 10 min, whereupon the mixture
was partitioned between saturated NaHCO3 (1 mL) and CHCl3
(1 mL). The layers were separated, and the aqueous layer was
extracted with CHCl3 (3ꢂ1 mL). The combined organic layers were
washed with H2O (4 mL), brine (4 mL), dried (Na2SO4), filtered, and
concentrated under reduced pressure. The crude residue was puri-
fied by flash column chromatography, eluting with CHCl3/hexanes/
NEt3 (3:2:1) to afford 0.011 g (51%) of isokidamycin (4) as a red solid:
11. Fredenhagen, A.; Sequin, U. J. Antibiot. 1985, 38, 236.
12. (a) Fei, Z.; McDonald, F. E. Org. Lett. 2005, 7, 3617; (b) Fei, Z.; McDonald, F. E. Org.
Lett. 2007, 9, 3547.
13. (a) Hauser, F. M.; Rhee, R. P. J. Am. Chem. Soc. 1979, 101, 1628; (b) Hauser, F. M.;
Rhee, R. P. J. Org. Chem. 1980, 45, 3061; (c) Tietze, L. F.; Singidi, R. R.; Gericke, K.
M. Org. Lett. 2006, 8, 5873; (d) Tietze, L. F.; Gericke, K. M.; Singidi, R. R. Angew.
Chem., Int. Ed. 2006, 45, 6990; (e) Tietze, L. F.; Gericke, K. M.; Singidi, R. R.;
Scuberth, I. Org. Biomol. Chem. 2007, 5, 1191; (f) Krohn, K.; Tran-Thien, H. T.;
Vitz, J.; Vidal, A. Eur. J. Org. Chem. 2007, 1905; (g) Krohn, K.; Tran-Thien, H. T.;
Ahmed, I. Eur. J. Org. Chem. 2011, 2223.
14. (a) Kaelin, D. E., Jr.; Lopez, O. D.; Martin, S. F. J. Am. Chem. Soc. 2001, 123, 6937;
(b) Martin, S. F. Pure Appl. Chem. 2003, 75, 63; (c) Kaelin, D. E., Jr.; Sparks, S. M.;
Plake, H. R.; Martin, S. F. J. Am. Chem. Soc. 2003, 125, 12994.
15. (a) Apsel, B.; Bender, J. A.; Escobar, M.; Kaelin, D. E., Jr.; Lopez, O. D.; Martin, S. F.
Tetrahedron Lett. 2003, 44, 1075; (b) Chen, C.-L.; Martin, S. F. J. Am. Chem. Soc.
2006, 128, 13696; (c) Sparks, S.; Chen, C.; Martin, S. Tetrahedron 2007, 63, 8619;
(d) Procko, K. J.; Li, H.; Martin, S. F. Org. Lett. 2010, 12, 5632.
16. O’Keefe, B. M.; Mans, D. M.; Kaelin, D. E., Jr.; Martin, S. F. J. Am. Chem. Soc. 2010,
132, 15528.
17. For leading references to O/C-glycoside rearrangements, see: (a) Matsumoto,
T.; Katsuki, M.; Suzuki, K. Tetrahedron Lett. 1988, 29, 6935; (b) Matsumoto, T.;
Katsuki, M.; Jona, H.; Suzuki, K. J. Am. Chem. Soc. 1991, 113, 6982; (c) Ben, A.;
Yamauchi, T.; Matsumoto, T.; Suzuki, K. Synlett 2004, 225.
18. (a) Kobayashi, T.; Tanaka, M. J. Chem. Soc., Chem. Commun. 1981, 333; (b) Torii, S.;
Okumoto, H.; Xu, L. H.; Sadakane, M.; Shostakovsky, M. V.; Ponomaryov, A. B.;
Kalinin, V. N. Tetrahedron 1993, 49, 6773.
19. Pihko, A. J.; Nicolaou, K. C.; Koskinen, A. M. P. Tetrahedron: Asymmetry 2001, 12,
937.
20. Brimble, M. A.; Davey, R. M.; McLeod, M. D.; Murphy, M. Aust. J. Chem. 2003, 56,
787.
21. CCDC 826963 contains the crystallographic data for compound 16. These data
can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
mp¼199e200 ꢀC (decomp.); 1H NMR (600 MHz, CDCl3)
d 13.94 (s,
1H), 8.39 (s, 1H), 7.94 (s, 1H), 7.45 (q, J¼6.2 Hz, 1H), 6.36 (s, 1H), 5.29
(dd, J¼8.7, 6.0 Hz, 1H), 4.89 (d, J¼10.4 Hz, 1H), 3.81 (q, J¼5.6 Hz, 1H),
3.48 (dq, J¼8.7, 6.0 Hz, 1H), 3.32 (t, J¼9.5 Hz,1H), 3.28 (s, 1H), 2.99 (s,
3H), 2.87e2.82 (m, 1H), 2.38 (s, 6H), 2.30e2.24 (comp, 2H), 2.21 (s,
6H), 2.05e2.01 (comp, 2H), 2.00 (d, J¼7.2 Hz, 3H), 1.99 (s, 3H), 1.48
(d, J¼6.5 Hz, 3H), 1.37 (d, J¼6.1 Hz, 3H), 1.18 (s, 3H); 13C NMR
(150 MHz, CDCl3) d 188.1, 183.5, 179.7, 164.1, 158.8, 155.9, 149.7, 137.3,
134.1, 132.6, 127.4, 126.4, 126.0, 125.5, 119.1, 115.6, 108.9, 77.6, 75.5,
72.4, 71.3, 71.2, 70.3, 67.7, 40.5, 36.9, 36.7, 28.4, 24.1, 18.6, 18.0, 15.0,
12.2; IR (neat) 3390, 2928, 1643, 1085 cmꢁ1; mass spectrum (ESI) m/
z 345.17513 [C39H50N2O9 (Mþ2)/2 requires 345.17527].
Acknowledgements
22. Savard, J.; Brassard, P. Tetrahedron 1984, 40, 3455.
We thank the National Institutes of Health (GM31077) and the
Robert A. Welch Foundation (F-652) for generous support of this
research. We are grateful to Eli Lilly and Abbott Laboratories for
generous gifts of vancomycin$HCl. We also thank Professor U.
23. Bringmann, G.; Gotz, R.; Keller, P. A.; Walter, R.; Boyd, M. R.; Lang, F.; Garcia, A.;
Walsh, J. J.; Tellitu, I.; Bhaskar, V.; Kelly, T. R. J. Org. Chem. 1998, 63, 1090.
24. (a) O’Keefe, B. M.; Simmons, N.; Martin, S. F. Org. Lett. 2008, 10, 5301; (b)
O’Keefe, B. M.; Simmons, N.; Martin, S. F. Tetrahedron 2011, 67, 4344.
25. Organ, M. G.; Avola, S.; Dubovyk, I.; Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.;
Valente, C. Chem.dEur. J. 2006, 12, 4749.
26. Nakatani, K.; Okamoto, A.; Saito, I. Tetrahedron 1996, 52, 9427.
27. For example: (a) Doi, T.; Shibata, K.; Kinbara, A.; Takahashi, T. Chem. Lett. 2007,
36, 1372; (b) Nicolaou, K. C.; Mitchell, H. J.; van Delft, F. L.; Rubsam, F.; Ro-
driguez, R. M. Angew. Chem., Int. Ed. 1998, 37, 1871; (c) Parker, K. A.; Chang, W. S.
Org. Lett. 2003, 5, 3891.
ꢁ
Sequin (University of Basel, Switzerland) for providing authentic
samples of 1 and 4 for comparison. We also thank Y. Ichikawa
(Kyoto University) for assisting in the preparation of some starting
materials.
28. Thompson, C.; Ge, M.; Kahne, D. J. Am. Chem. Soc. 1999, 121, 1237.
29. Matsumoto, T.; Hosoya, T.; Suzuki, K. Tetrahedron Lett. 1990, 31, 4629.
30. Eliel, E. L.; Manoharan, M. J. Org. Chem. 1981, 46, 1959.
31. Hosoya, T.; Ohashi, Y.; Matsumoto, T.; Suzuki, K. Tetrahedron Lett. 1996, 37, 663.
32. For example: (a) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
Tetrahedron 1986, 42, 3021; (b) Harried, S. S.; Yang, G.; Strawn, M. A.; Myles, D.
C. J. Org. Chem. 1997, 62, 6098; (c) Oikawa, Y.; Tanaka, T.; Horita, K.; Yonemitsu,
O. Tetrahedron Lett. 1984, 25, 5397.
References and notes
ꢁ
1. Sequin, U. The antibiotics of the pluramycin group (4H-anthra[1,2-b]pyran an-
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tibiot. 1993, 46, 692.
Antibiot. Annu. 1955, 56, 606.
34. Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.
Organometallics 1996, 15, 1518.
4. (a) Kanda, N. J. Antibiot. 1971, 24, 599; (b) Furukawa, M.; Hayakawa, I.; Ohta, G.;
Iitaka, Y. Tetrahedron 1975, 31, 2989.
35. Bertrand, M.; Monti, H. Tetrahedron Lett. 1968, 9, 1069.
5. (a) Furukawa, M.; Itai, A.; Iitaka, Y. Tetrahedron Lett. 1972, 13, 1065;
(b) Furukawa, M.; Iitaka, Y. Tetrahedron Lett. 1974, 15, 3287.
6. (a) Zehnder, M.; Sequin, U.; Nadig, H. Helv. Chim. Acta 1979, 62, 2525;
(b) Sequin, U.; Furukawa, M. Tetrahedron 1978, 34, 3623.
36. Complete removal of the solvent (Et2O) frequently resulted in extensive de-
composition of the unstable aldehyde 49, therefore some residual Et2O is ob-
served in the 1H and 13C NMR spectra.