Total synthesis and determination of the absolute configuration of guadinomines B and C2

Article abstract of DOI:10.1002/chem.200801024

This article describes the determination of the absolute configurations of the guadinomines, which are novel cyclic guanidyl natural products that are inhibitors of the type III secretion system (TTSS) of bacteria. Any compound that interrupts the TTSS of bacteria is potentially an ideal anti-infectious drug. The reliable asymmetric synthesis of guadinomines has revealed their absolute configurations, which could not have been defined without this synthetic approach. Our report not only describes the asymmetric total synthesis of the title compounds, but also demonstrates the novel concise synthesis of tri-substituted piperazinone cores as optically pure forms. The novel feature of our method is an intramolecular S_N2 cyclization that uses PPh ₃ and I₂ to construct the unique 5membered cyclic guanidine substructure.

Full text of DOI:10.1002/chem.200801024

DOI: 10.1002/chem.200801024
Total Synthesis and Determination of the Absolute Configuration of
A
Guadinomines B and C2
Tomoyasu Hirose, Toshiaki Sunazuka,* Satoshi Tsuchiya, Toshiaki Tanaka,
[a]
¯
Yasuhiro Kojima, Ryuma Mori, Masato Iwatsuki, and Satoshi Omura*
Abstract: This article describes the de-
termination of the absolute configura-
tions of the guadinomines, which are
novel cyclic guanidyl natural products
that are inhibitors of the type III secre-
tion system (TTSS) of bacteria. Any
compound that interrupts the TTSS of
bacteria is potentially an ideal anti-in-
fectious drug. The reliable asymmetric
synthesis of guadinomines has revealed
their absolute configurations, which
could not have been defined without
this synthetic approach. Our report not
only describes the asymmetric total
synthesis of the title compounds, but
also demonstrates the novel concise
synthesis of tri-substituted piperazi-
none cores as optically pure forms. The
novel feature of our method is an intra-
molecular SN2 cyclization that uses
PPh3 and I2 to construct the unique 5-
membered cyclic guanidine substruc-
ture.
Keywords: configuration determi-
nation
· guadinomines · natural
products · total synthesis · type III
secretion system
Introduction
Original structural analysis was mainly carried out by
NMR spectroscopic methods to elucidate the novel cyclic
guanidine natural products.[3] However, the relative and ab-
solute configurations of guadinomines 1 to 5 remained unde-
termined, except for the peptide moiety. It is difficult to de-
termine exact configurations, even with highly advanced
spectroscopic methods, especially for linear portions that in-
clude consecutive stereocenters for 1,2-diamine or piperazi-
none and polyol. Moreover, work was hampered by insuffi-
cient quantities of the natural products. These difficulties
encouraged establishment of the configurations of guadino-
mines by chemical synthesis. Our previous research demon-
strated the asymmetric preparation of 6, which allowed the
determination of the configuration of two stereocenters.[8]
The stereo information of 6 suggested that the configuration
of C7 (or C2’) and C4’ (or C4’’) in 1 to 5 should be related
to C5 and C4’ in 6, respectively. Nevertheless, other configu-
rations of 1 to 5 remained unclear. Herein, we report the
total assignment of the configuration of 2 (B) and 4 (C2),
through the first asymmetric total synthesis of these natural
products.
Extracts from culture broths of Streptomyces sp. K01-0509
have been recognized for their ability to inhibit the type III
secretion system (TTSS) of bacteria.[1] The property has
been traced to the novel guadinomines A to D (1–5), and
three of them, 1, 2, and 5, have been identified as being se-
lective inhibitors of the TTSS.[1–3] In the process of isolation,
a new compound, guadinomic acid (K01–0509 B) 6, was de-
tected, which occurred as a biosynthetic intermediate.[1,3]
The TTSS is expressed by many Gram-negative pathogens,
including enteropathogenic Escherichia coli (EPEC),[4] en-
terohemoragic E. coli (EHEC), Pseudomonas aeruginosa,
Salmonella spp., and Shigella spp.[5] where it helps deliver
effector proteins into the host cell during the infection pro-
cess.[6] Consequently, guadinomines may prove to be novel
anti-infectious drugs.[7]
[a] Dr. T. Hirose, Prof. Dr. T. Sunazuka, Dr. S. Tsuchiya, T. Tanaka,
¯
Y. Kojima, R. Mori, M. Iwatsuki, Prof. Dr. S. Omura
Kitasato Institute for Life Science
Kitasato University, 5-9-1 Shirokane
Minato-ku, Tokyo, 108-8641 (Japan)
Fax : (+81)3-5791-6340
Results and Discussion
E-mail: sunazuka@lisci.kitasato-u.ac.jp
omuras@insti.kitasato-u.ac.jp
In our synthetic strategy, we made an intuitive assumption
that the prediction of the relative and absolute configuration
for C5 and C6 with C3 in 4 would be more conclusively ac-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801024.
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Chem. Eur. J. 2008, 14, 8220 – 8238

FULL PAPER
constructed in a similar fashion
to
7 from trans-epoxide 15,
which can also be generated
from 14.[12]
Synthesis of the 5,6-trans-piper-
azinone 7: The route to
(3S,5R,6S)-5,6-trans-3,6-syn-pi-
perazinone 7 (Scheme 2) com-
menced with (R)-oxazolidinone
((R)-16), which was subjected
to the Evans aldol reaction[13]
with valeraldehyde, followed by
hydrolytic removal of the auxil-
iary, which afforded a-chloro-b-
hydroxy acid 18 as a single en-
antiomer. Condensation with
the known peptide section
(NH2-l-Ala-l-Val-OtBu) 19 and
subsequent epoxide formation
complished by comparison with
simple piperazinone com-
pounds.[9] Moreover, evidence
for the syn-relationship between
C3 and C6 in 4 was conclusive
because of the observation of an
NOE between H-5’ and CH3-3
by detailed analysis of its
1H NMR spectra.[10] Therefore,
our first aim was to elucidate
the relative and absolute config-
uration of the piperazinone
moiety of 4 by comparing 4 with
simple piperazinone model com-
pounds, which contain the pep-
tide moiety (7, 8; Scheme 1).
Retrosynthetic analysis of piper-
azinone core: Our retrosynthet-
ic analysis of piperazinone
model compounds, as shown in
Scheme 1, involved installing
the stereogenic centers from op-
tically active reagents in a relia-
ble fashion. To avoid any doubt
about the configurations, opti-
cally active 2-bromopropionic
acid (10) and syn-chlorohydrin
(14) were selected as chiral
Scheme 1. Retrosynthetic analysis of model compounds 7 and 8.
sources. We envisaged that it
would be efficient to construct
each stereocenter by SN2 cyclization for C3 and regioselec-
tive azidolysis of aziridine[11] for the C5 and C6 positions.
The optically active aziridine could be prepared from 1,2-hy-
droxylamine (12), derived from 14 by epoxide chemistry.[12]
Additionally, the C3, C6-epi model compound 8 could be
under mild basic conditions afforded cis-epoxide 20 as a
single form. Azidolysis of 20 followed by reduction of the
azide gave 1,2-hydroxylamine, which led to cis-Ns-aziridine
21 (Ns=2-nitrobenzenesulfonyl) as a single form upon the
formation of an Ns-aziridine via ring closure of the N,O-bis-
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T. Sunazuka, S. Omura et al.
sure[16] via azidolysis of the ep-
oxide. Azidolysis of 24 gave us
a mixture of a and b azido
products, leading to the same
chiral product 25. The Ns group
was introduced to activate aziri-
dine followed by azidolysis of
the resulting Ns-aziridine to the
inseparable regioisomers of azi-
doamine, which upon elimina-
tion of the Ns group, yielded
separable isomers 26 and 27
with moderate selectivity (26/
27=3.7:1). Azido 26 was con-
densed with (S)-2-bromopro-
pionic acid ((S)-10), which
upon intramolecular SN2 cycli-
zation through Staudinger ami-
nation, yielded the desired pi-
perazinone core 28. tert-Butoxy-
carbonyl (Boc) protection of
28, followed by hydrolysis, and
condensation with peptide 19,
finally led to the target model
piperazinone 8[15] by total de-
protection.
Scheme 2. Reagents and conditions: a) valeraldehyde, nBu2BOTf, iPr2NEt, CH2Cl2, À78 to 08C, 1 h, 72%
(dr>20:1); b) LiOH, H2O2, THF/H2O (5/1), 08C, 25 min; c) bromotrispyrrolidinophosphonium hexafluoro-
phosphate (PyBrop), iPr2NEt, H2N-l-Ala-l-Val-OtBu 19, CH2Cl2, 08C to RT, 1 h, 82% (2 steps); d) K2CO3,
H2O, DMF, RT, 2.5 h, 100%; e) NaN3, NH4Cl, MeOH/H2O (20:1), 708C, 56 h, 91% (predominantly the b-N3
isomer); f) 10%Pd/C, H2, EtOAc, RT, 9 h; g) p-nitrobenzenesulfonyl chloride (NsCl) (3 equiv), Et3N
(3 equiv), 4-(dimethylamino)pyridine (0.05 equiv), CH2Cl2, RT, 12 h, 91% (2 steps); h) NaN3, DMF, 08C to
RT, 2.5 h, 91%; i) PPh3, H2O, THF, 458C, 20 h, 85%; j) (R)-10, 1-hydroxybenzotriazole (HOBt), N’-(3-dime-
thylaminopropyl)-N-ethylcarbodiimide (EDCI), 08C, 1 h, 91%; k) iPr2NEt, MeCN, 608C, 19 h, then PhSH,
608C, 21 h, 100%; l) TFA/H2O (3:1), RT, 3 h, 100%.
Ns intermediate.[14] Regioselective azidolysis of 21 gave only
the b-azide, which upon reduction by Staudinger amination
followed by condensation with (R)-2-bromopropionic acid
1
((R)-10) and intramolecular SN2 cyclization, ended with for-
mation of the piperadinone ring. This reaction proceeded
without any epimerization and subsequent elimination of
the Ns group gave piperadinone compound 23 as a single
isomer. Final deprotection of the t-butyl group yielded the
desired model compound 7.[15]
Comparison of H NMR spectra of natural 3 and the model
compounds: The respective NMR spectra of the synthetic
piperazinone compounds were compared to naturally occur-
ring 3 and 4. Clearly, the coupling constants between Ha’
and Hb’ of 8 (J=4.5 Hz in 1% trifluoroacetic acid (TFA)/
Synthesis of the 5,6-cis-pipera-
zinone 8: The route to
(3R,5R,6R)-5,6-cis-3,6-syn-pi-
perazinone (8, Scheme 3) com-
menced from 17 in similar reac-
tion sequence to the prepara-
tion of 7. The requisite epoxy
geometry was installed through
a modified Azerad protocol[12]
under harsh basic conditions in
EtOH, involving in situ ester
preparation and isomerization
at the a position of the ester
followed by ring closure due to
the fast cyclization rate of the
anti isomer. This gave the de-
sired trans-epoxy ester 24 as a
Scheme 3. Reagents and conditions: a) NaH, EtOH, 08C, 20 min, 98% (as a mixture of trans/cis-epoxide; pre-
dominantly the trans isomer; 5.4:1); b) NaN3, NH4Cl, 1,4-dioxane/H2O (1:1), 608C, 40 h, 55%; c) PPh3, dehy-
drated MeCN, 808C, 89% as only the trans-isomer; d) NsCl, Et3N, 4-(dimethylamino)pyridine (0.1 equiv),
CH2Cl2, RT, 20 h; e) NaN3, DMF, 08C to RT, 0.5 h; f) PhSH, iPr2NEt, MeCN, RT, 2.5 h, 53% for 26, 14% for
27 (3 steps); g) (S)-10, (benzotriazol-1-yloxy)trispyrrolidinophosphonium hexafluorophosphate (PyBOP),
iPr2NEt, RT, 80 min, 94%; h) PPh3, Et3N, MeCN, RT, 1 h; then H2O, 60 8C, 1.5 h, 73%; i) Boc2O, EtOAc,
808C, 20 min, 73%; j) LiOH, MeOH/THF/H2O (2:2:1), RT, 85 min; k) PyBOP, iPr2NEt, H2N-l-Ala-l-Val-
major isomer (5.4:1). The selec-
tivity was critical for our plan-
ned formation of the C5,C6 cis-
piperazinone. Subsequent cis-
aziridine formation was accom-
plished by Staudinger ring clo- OtBu 19, CH2Cl2, RT, 1 h, 67% (2 steps); l) TFA/H2O (3/1), RT, 2.5 h, 98%.
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Total Synthesis of Guadinomines B and C2
FULL PAPER
D2O) confirmed the structures of guadinomine Cs (3 and 4;
both 4.2 Hz for J values; Schemes 2 and 3). Therefore, it
was convincing that the cis-conformation of the 5,6 position
of piperazinone is an essential part of natural 3 and 4. To in-
dicate the absolute configuration of the piperazinone moiety
of 4, NH-d-Ala-d-Val-OH derivative 31 (Figure 1), which
can be likened to the (3S,5S,6S)-analogue containing the l-
peptide, ent-31, used to compare 4 with 31, was concisely
tionship between H-5 and H-2’ should be the most affected
signals in the diastereomers (8 and 31). The 13C NMR spec-
troscopy data are also in good agreement with the natural
structures.[17] From these observations described and prior
work on guadinomine E (6), the absolute configuration of
guadinomine C2 (4) was envisaged and narrowed down to
two stereoisomers, as shown in Scheme 4, from the 26 possi-
ble stereoisomers (six stereocenters exist). However, the ab-
solute configuration for C3’ remained undetermined. To
verify the absolute structure of 4, and to facilitate the dis-
covery of novel analogues with advantageous pharmaceuti-
cal profiles, we executed the first asymmetric total synthesis
of both key stereoisomers of 4.
Retrosynthetic analysis of 4: Our targets were both C3’-epi-
mers of 4 (Scheme 4), which can be crafted from syn- (33)
and anti-diol (34) derivatives through a sequence that in-
volves the introduction of a piperazinone core, by applying
the protocol described in Scheme 3, and the construction of
a cyclic guanidine possessing a carbamoyl function, as estab-
lished in our earlier preparation of 6.[8]
Preparation of anti-diol 33: The route to (3’R)-4 began with
the preparation of protected anti-diol 33 (Scheme 5). Chiral
alcohol 35, prepared from (R)-benzylglycidol with vinylmag-
nesium bromide by Boininꢁs protocol,[18] was subjected to
hydroboration and oxidation with protection chemistry to
give aldehyde 36. A construction of the anti-diol unit, the
diastereoselective vinylation of 36, proceeded with a diaste-
reomeric ratio (dr) of 5:1, but the resulting isomers could
not be separated. After removal of the bis-TBS (TBS=tert-
butyldimethylsilyl) groups, protection of the diol with a
cyclic acetal and the primary alcohol with a benzyl group
gave 38 as a single diastereomer after chromatographic sep-
aration.[19,20] Sequential hydroboration and oxidation with
protection techniques gave the desired anti-diol product
anti-33.
1
Figure 1. Comparison between H NMR spectra of 4, 8, and 31.
prepared from piperazinone
ester 29 in the same manner.
As can be seen in Figure 1,
the correlation between H-5
(d=4.49 ppm (d, J=4.5 Hz))
and H-2’ (d=4.40 ppm (q, J=
7.2 Hz)) of 31 in the 1H NMR
spectra recorded in 1% TFA/
D2O show better agreement
with natural 4 (d=4.50 ppm (d,
J=4.2 Hz)
for
H-5;
d=
4.44 ppm (q, J=7.2 Hz) for H-
2’’’) than 8 (d=4.53 ppm (d, J=
4.5 Hz) for H-5; d=4.35 ppm
(q, J=7.2 Hz) for H-2’). H-2’ in
the peptide moiety for this
NMR spectrum observation is
situated closest to the piperazi-
none core. Therefore, the rela- Scheme 4. Proposed structure and retrosynthetic analysis of 4.
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T. Sunazuka, S. Omura et al.
with the construction of the pi-
perazinone and cyclic guanidine
moieties (Scheme 7). Introduc-
tion of the piperazinone moiety
with designated stereo configu-
rations from anti-33 was adapt-
ed to our procedure (indicated
in Scheme 3). Although the diol
unit has additional functions
compared with the model piper-
azinone compound all reaction
sequences progressed quite
smoothly[26] to form piperazi-
none aldehyde 44 in a pure
form.[20] We subsequently ap-
plied Yamadaꢁs conditions for
the asymmetric nitro aldol reac-
tion,[27] which have been exam-
ined under various conditions
Scheme 5. Reagents and conditions: a) BH3·Me2S, THF, 08C to RT, 2 h; then aqueous H2O2, 4n aqueous
NaOH, RT, 2 h, 87%; b) TBSCl, imidazole, DMF, RT, 2 h, 95%; c) H2, Pd(OH)2/C, EtOAc, RT, 20 min, 96%;
d) (COCl)2, DMSO, Et3N, CH2Cl2, 08C, 15 min; e) CH2=CHMgBr, Et2O, À788C, 35 min, 84% (2 steps) (dr=
5:1); f) 4n HCl in dioxane, RT, 20 min, 94%; g) 2,2-dimethoxypropane, TsOH·H2O (TsOH=p-toluenesulfonic
acid), acetone, RT, 15 min, 92%; h) BnBr, tetrabutylammonium iodide (TBAI), NaH, THF, 708C, 6.5 h, 85%
(dr>20:1); i) BH3·Me2S, THF, 08C to RT, 2 h; then NaBO3, 4n aqueous NaOH, 508C, 1.5 h, 69%; j) tert-bu-
tyldiphenylsilyl chloride (TBDPSCl), imidazole, DMF, RT, 40 min; k) H2, Pd(OH)2, EtOAc, RT, 2.5 h, 78% (2
steps); l) (COCl)2, DMSO, Et3N, CH2Cl2, 08C, 20 min.
Preparation of syn-diol unit 34: Synthesis of syn-diol 34
(Scheme 6) began with the introduction of a stereocenter at
the a position of aldehyde 39[21] by an a-aminooxylation de-
with simpler substrates, as discussed in our previous paper.[8]
Thus 44 was treated with the (R,R)-salen–cobalt catalyst 45
under modified conditions to eventually give 46 with high
stereoselectivity (90% de). In-
troduction of a guanidyl group
was achieved through reduction
of the nitro group followed by
guanylation with 47[28] to give
48. We have previously investi-
gated the SN2 cyclization proce-
dure for cyclic guanidine by
mesylation of the alcohol fol-
lowed by ring closure under
basic conditions.[8] Applying
Scheme 6. Reagents and conditions: a) d-proline, nitrosobenzene, CHCl3, 08C, 105 min; then NaBH4, EtOH,
08C, 0.5 h; b) H2, 10% Pd/C, EtOAc, RT, 4 h, 40% (2 steps), >98% ee; c) PMB(OMe)2 (PMB=p-methoxy-
this two-step procedure with 48,
however, resulted in low repro-
ducibility for production of 50
due to mesylation on the other
amide moiety, a yield of 82%
could only be obtained once.
This problem was overcome by
using SN2 cyclization conditions
AHCTREUNG
benzyl), pyridinium p-toluenesulfonate (PPTS), CH2Cl2, 08C, 100 min, 92%; d) DIBAL-H, CH2Cl2, À788C,
1 h, 93%; e) (COCl)2, DMSO, Et3N, CH2Cl2, 08C, 15 min; f) 1-ethylthio-1-trimethylsilyloxyethene, TiCl3-
(OiPr), CH2Cl2, À788C, 2 h, 64% (>99% de); g) LiBH4, THF, À108C, 2 h, 88%; h) TBDPSCl, Et3N, 4-(dime-
thylamino)pyridine, CH2Cl2, RT, 3.5 d; i) Pd(OH)2/C, H2, RT, 2 h, 90% (2 steps); j) 2,2-dimethoxypropane,
TsOH·H2O, acetone, RT, 5 min, 97%; k) (COCl)2, DMSO, Et3N, CH2Cl2, 08C, 15 min.
veloped by McMillan et al.[22] The resulting aminooxylated
aldehyde was reduced to alcohol 40 with excellent enantio-
selectivity (99% enantiomeric excess (ee)).[23] Cleavage of
via a phosphonium intermediate, which is generated from I2
and PPh3. The SN2 cyclization proceeded very smoothly
under mild conditions without any side reactions, such as io-
dination of the hydroxy group. This reaction has not only
great advantages regarding simplicity for purification, but
also better efficiency than the standard Mitsunobu-type re-
action in the case of the 5-membered cyclic guanidine for-
mation. The final sequence for the formation of the carba-
moyl and total deprotection proceeded as expected, and
(3’R)-guadinomine C2 ((3’R)-4) was obtained. Access to the
isomer, (3’S)-4, was also obtained by applying an identical
reaction sequence as that used for the preparation of (3’R)-4
from syn-34. The spectral characteristics of (3’R)-4 showed a
clear match with the data from naturally occurring 4. Thus,
we established that guadinomine C2 has the configuration
3S,5S,6S,2’S,3’R,4’’R with the l-peptide moiety.
À
the N O bond by hydrogenation, followed by protection of
the secondary alcohol, and oxidation, gave aldehyde 41. The
chiral aldehyde was then transformed in a Ti-chelation-con-
trolled Mukaiyama aldol reaction, using the trimethylsilyl
(TMS) enolate of thioethylacetate in the presence of TiCl3-
(O-iPr), to give syn-aldol 42 with exceptional diastereoselec-
tivity (>99% diastereomeric excess (de)).[20,24,25] Subsequent
reduction of the thioester unit in the stepwise sequence of
protection, deprotection, and oxidation of the hydroxy
group, yielded the desired aldehyde of syn-34.
Total synthesis of 4: With both diol units in hand, we turned
our attention to completing the synthesis of guadinomine C2
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Total Synthesis of Guadinomines B and C2
FULL PAPER
Scheme 7. Reagents and conditions: a) (S)-16, nBu2BOTf, Et3N, CH2Cl2, À78 to 08C, 65% (2 steps); b) NaH, EtOH, 08C, 20 min, 88% (as a mixture of
the trans/cis-epoxide; predominantly the trans isomer; 5.8:1); c) NaN3, NH4Cl, EtOH/H2O (20:1), 608C, 38 h, 56%; d) PPh3, dehydrated MeCN, 808C,
21 h, 76% as only the trans-aziridine isomer; e) NsCl, 4-(dimethylamino)pyridine, Et3N, CH2Cl2, 08C to RT, 4 h; f) NaN3, DMF, RT, 1 h, 93% (2 steps)
(>20:1=a/b-N3); g) PhSH, DIPEA, MeCN, RT, 6 h, 65%; h) (R)-10, PyBOP, iPr2NEt, CH2Cl2, RT, 1 h, 95%; i) PPh3, Et3N, MeCN, 1 h; then H2O, 60 8C,
7 h; j) Boc2O, EtOAc, 808C, 1 h, 68% (2 steps); k) LiOH, THF/MeOH/H2O (2:2:1), RT, 1 h; l) H2N-l-Ala-l-Val-OtBu 19, PyBOP, HOBt, iPr2NEt,
CH2Cl2, RT, 4 h, 70% (2 steps); m) tetrabutylammonium fluoride (TBAF), THF, RT, 3 h, 79%; n) SO3·pyridine, DMSO, Et3N, CH2Cl2, 08C to RT, 1 h;
o) (R,R)-45, MeNO2, iPr2NEt, CH2Cl2, À408C, 46 h, 53% (2 steps), 90% de; p) HCO2NH4, 10% Pd/C, MeOH, RT, 2 h; q) 47, iPr2NEt, MeCN, RT, 1 h,
57% (2 steps); r) I2, PPh3, imidazole, CH2Cl2, 08C to RT, 2 h, 88%; s) Ms2O ( Ms=methanesulfonyl), pyridine, 4-(dimethylamino)pyridine, CH2Cl2, 08C,
0.5 h; t) iPr2NEt, MeCN, 658C, 4 h, ꢀ82%; u) p-methoxyphenylisocyanate, PhH, RT, 10 min; v) ceric ammonium nitrate (CAN), MeCN/H2O (1/1), 08C,
2.5 h; w) TFA/H2O (3/1), RT, 5 h 60% (3 steps); for the reaction sequence from syn-34 to (3’S)-4, see the Supporting Information.
Total synthesis of guadinomine B: We next approached the
total synthesis of guadinomine B (2), which differs only in
the diamine part from 4 (diamine is converted to piperazi-
none in 4). Therefore, to access 2, 1, 2-azidoamine 43 was
converted to 1,2-bis(Boc-amine) 51, which subsequently un-
derwent the same reaction sequence as that for the synthesis
of 4 to give 2 (Scheme 8). Synthetic 2 was identical to natu-
rally occurring 2 in all respects. Hence, we established that
guadinomine B has the configuration 2S,3S,6R,7S,4’R with
the l-peptide moiety.
Inhibitory activity of TTSS for natural and synthetic guadi-
nomine B and C2: By using the synthetic guadinomines B
and C2 thus obtained, a TTSS assay with TTSS-expressing
EPEC was conducted. TTSS
activity was measured as the
hemolytic activity caused by
TTSS of EPEC in a 96-well
microplate, as reported previ-
ously.[1]
TTSS-expressing
EPEC and erythrocytes were
mixed and placed in contact,
and the hemolytic activity was
measured
spectrometrically.
Namely, the noninfectious
strain EPEC DCesT, which
was defective of the chaperon
protein of the translocated in-
timin receptor (Tir), was used
in this assay. As shown in
Figure 2, the inhibitory activity
Scheme 8. Reagents and conditions: a) H2, 10% Pd/C, EtOAc, RT, 1 h; b) Boc2O, EtOAc, 608C, 45 min, 91%
(2 steps); c) LiOH, THF/MeOH/H2O (2:2:1), RT, 0.5 h; d) H2N-l-Ala-l-Val-OtBu 19, PyBOP, HOBt,
iPr2NEt, CH2Cl2, RT, 3 h, 89% (2 steps); for the reaction sequence from 51 to 2, see the Supporting Informa-
tion.
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rotations were measured by using JASCO DIP-370 polarimeter. Melting
points were measured on a Yanagimoto Micro Apparatus.
(4R,2’R,3’S)-4-Benzyl-(2’-chloro-3’-hydroxyheptanoyl)-2-oxazolizinone
(17): DIPEA (2.62 mL, 18.0 mmol), and nBu2BOTf (1.0m in CH2Cl2,
14.0 mL, 14.0 mmol) were added to a solution of chloroacetyloxazolidi-
none (R)-16 (2.4 g, 10.0 mmol) in CH2Cl2 (104 mL) at À788C. After stir-
ring for 1 h at RT, the reaction mixture was cooled to À788C. Then, va-
leraldehyde (2.69 mL, 14.0 mmol) was added to the reaction solution.
After stirring for 5 min, the solution was warmed to 08C and stirred for
1 h. Phosphate buffer (pH 7.2; 6 mL) and 30% aqueous H2O2/MeOH
(1:2) (20 mL) were added to the reaction solution at 08C, then the mix-
ture was stirred for 1 h. The organic layer was separated and water layer
was extracted with CHCl3 (40 mL”3). The combined organic extracts
were washed with a saturated aqueous solution of NH4Cl (20 mL) and
brine (20 mL), then dried over Na2SO4, filtered, and the solvent was
evaporated under reduced pressure. Purification by flash chromatography
on silica gel (hexane/EtOAc 4:1) gave 17 as a colorless oil (1.93 g, 72%).
Rf =0.58 (silica gel, hexane/EtOAc 1:1); [a]2D7 =À46.4 (c=1.93, CHCl3);
1H NMR (270 MHz, CDCl3): d=7.37–7.21 (m, 5H; 4-CH2Ph), 5.68 (d,
J=3.0 Hz, 1H; 2’-H), 4.72 (dddd, J=2.3, 3.3, 5.6, 9.6 Hz, 1H; 4-H), 4.28
(dd, J=5.6, 9.2 Hz, 1H; 5-H2), 4.23 (dd, J=2.3, 9.2 Hz, 1H; 5-H2), 4.10
(m, 1H; 3’-H), 3.32 (dd, J=3.3, 13.5 Hz, 1H; 4-CH2Ph), 2.83 (dd, J=9.6,
13.5 Hz, 1H; 4-CH2Ph), 2.70 (d, J=5.5 Hz, 1H; 3’-OH), 1.72–1.54 (com-
plex m, 2H; 4’-H2), 1.52–1.31 (complex m, 2H; 6’-H2), 1.43–1.31 (com-
plex m, 2H; 5’-H2), 0.92 ppm (t, J=6.6 Hz, 3H; 7’-H3); 13C NMR
(67.5 MHz, CDCl3): d=169.3, 153.6, 135.2, 130.2 (2C), 130.1 (2C), 128.2,
71.7, 66.9, 60.4, 55.8, 37.3, 33.8, 27.6, 22.5, 13.9 ppm; IR (NaCl) n˜ =3523
(br, OH), 1780 (C=O, ester), 1711 (C=O, imide), 1389, 1365, 1209,
1113, 1057, 1001, 750, 698 cmÀ1; HRMS (FAB, NBA matrix): m/z calcd
for C17H23NO4Cl: 340.1316 [M+H]; found: 340.1309 [M+H]+.
Figure 2. Inhibitory activity of TTSS-induced hemolysis for synthetic and
natural guadinomine B and C2: natural guadinomine B (d), synthetic
guadinomine B (g), natural guadinomine C2 (b), and synthetic gua-
dinomine C2 (c).
of synthetic 2 was almost the same as that of natural 2 (Ac-
tually, natural 2 was slightly less active than synthetic 2 due
to its impurity). On the other hand, natural and synthetic
guadinomine C2, ( 3’R)-4, showed no activity at 100 mgmLÀ1
in this assay. The basic structure of guadinomines with the
piperazinone moiety on 1,2-diamine lost activity. Thus, the
activity of synthetic and natural guadinomines B and C2
were essentially identical.
(2’’R,3’’S)-tert-Butyl-[N’-(2’’-chloro-3’’-hydroxyheptanoyl)-l-alanyl]-l-va-
linate (52): 30% aqueous H2O2 (1.55 mL, 13.7 mmol) and 1n aqueous
LiOH (5.27 mL, 5.27 mmol) were added to a solution of 17 (896 mg,
2.64 mmol) in THF/H2O (5:1) (26.4 mL) at 08C. After stirring for 25 min
Conclusion
In summary, the first asymmetric total synthesis of guadino-
mines B (2) and C2 (4) has been achieved. The longest
linear sequence proceeded in 32 steps for 2 and 33 steps for
4. This synthetic process not only provides viable routes to
these guadinomines, as well as to potential analogues there-
of, but also establishes the absolute configurations of natural
2 and 4.
at the same temperature,
a saturated aqueous solution of Na2SO3
(5.0 mL) and CHCl3 (50 mL) were added to the reaction mixture. The or-
ganic layer was separated, and 1n aqueous HCl (10 mL) was added to
the aqueous layer, which was then extracted with CHCl3 (50 mL”3). The
combined organic extracts were washed with brine (20 mL), dried over
Na2SO4, filtered, and evaporated under reduced pressure. Crude product
18 was used in the next reaction without further purification. The residue
was dissolved in CH2Cl2 (24.2 mL) and then tert-butyl l-alanyl-l-valinate
19 (886 mg, 3.63 mmol), DIPEA (829 mL, 4.84 mmol), PyBrop (1.69 g,
3.63 mmol) were added. After stirring for 10 min at 08C under argon, the
reaction mixture was warmed up to RT, and stirred for 1 h. The reaction
was quenched with a saturated aqueous solution of NH4Cl (10 mL). The
organic layer was separated and the aqueous layer was extracted with
CHCl3 (20 mL”2). The combined organic extracts were washed with
brine (20 mL), dried over Na2SO4, filtered, and evaporated under re-
duced pressure. Purification by flash chromatography on silica gel
(hexane/EtOAc=3:1) gave 52 as a colorless oil (876 mg, 82% in 2 steps).
Rf =0.35 (silica gel, hexane/EtOAc=1:1); [a]2D6 =+10.2 (c=1.30, CHCl3);
1H NMR (270 MHz, CDCl3): d=6.97 (d, J=6.9 Hz, 1H; 2’-NH), 6.76 (d,
J=8.9 Hz, 1H; 2-NH), 4.45 (dq, J=6.9, 6.9 Hz, 1H; 2’-H), 4.44 (dd, J=
4.5, 8.9 Hz, 1H; 2-H), 4.36 (d, J=1.7 Hz, 1H; 2’’-H), 4.21 (m, 1H; 3’’-H),
4.11 (d, J=6.3 Hz, 1H; 3’’-OH), 2.09 (dqq, J=4.5, 7.3, 7.6 Hz, 1H; 3-H),
1.74–1.66 (m, 1H; 4’’-H2), 1.61–1.52 (m, 1H; 4’’-H2), 1.47 (d, J=6.9 Hz,
Experimental Section
General remarks: Dry THF, toluene, ethyl ether, and CH2Cl2 were pur-
chased from Kanto Chemical. Precoated silica gel plates with a fluores-
cent indicator (Merck 60 F254) were used for analytical and preparative
thin layer chromatography. Flash column chromatography was carried
out with Kanto Chemical silica gel (Kanto Chemical, silica gel 60N,
spherical neutral, 0.040–0.050 mm, Cat.-No. 37563–84). 1H NMR spectra
were recorded at 270, 300, or 400 MHz and 13C NMR spectra were re-
corded at 67.5, 75, or 100 MHz on JEOL JNM-EX270 (270 MHz), Varian
VXR-300 (300 MHz), Varian XL-400 (400 MHz), or Varian UNITY-400
(400 MHz) spectrometers. The chemical shifts are expressed in ppm
downfield from the internal solvent peaks for CHCl3 (7.26 ppm,
1H NMR), CH3OH (3.31, 4.84 ppm, 1H NMR), H2O (4.76 ppm,
1H NMR), CDCl3 (77.0 ppm, 13C NMR), CD3OD (49.0 ppm, 13C NMR),
or D2O (the end of both fields; 0, 200 ppm, 13C NMR) and J values are
given in hertz. The coupling patterns are denoted s (singlet), d (doublet),
dd (double doublet), ddd (double double doublet), t (triplet), dt (double
triplet), q (quartet), m (multiplet), or br (broad). All infrared spectra
were measured on a Horiba FT-210 spectrometer. High- and low-resolu-
tion mass spectra were measured on a JEOL JMS-DX300 and JEOL
JMS-AX505 HA spectrometer. Liquid chromatographic preparation was
conducted on a Jasco PU-980 with Senshu Pak-PEGASIL ODS. Optical
3H; 3’-H3), 1.45 (s, 9H; 1-OC(CH3)3), 1.41–1.31 (complex m, 4H; 5’’-H2,
R
6’’-H2), 0.91 (t, J=6.6 Hz, 3H; 7’’-H3), 0.90 (d, J=7.6 Hz, 3H; 3-CH3),
0.87 ppm (d, J=7.3 Hz, 3H; 3-CH3); 13C NMR (67.5 MHz, CDCl3): d=
171.7, 171.5, 168.7, 82.3, 71.6, 64.5, 57.5, 49.9, 33.5, 31.4, 27.8 (3C), 27.5,
22.2, 18.7, 17.8, 17.5, 13.8 ppm; IR (KBr) n˜ =3313 (br, -NH), 3072 (br,
-OH), 1732 (C=O, ester), 1651 (C=O, amide), 1520, 1456, 1369, 1313,
1223, 1155 cmÀ1
;
HRMS (FAB, NBA matrix): m/z calcd for
C19H36N2O5Cl: 407.2313 [M+H]: found: 407.2312 [M+H]+.
(2’’S,3’’S)-(À)-tert-Butyl-[N’-(2’’,3’’-epoxyheptanoyl)-l-alanyl]-l-valinate
(20): H2O (47.0 mL, 2.61 mmol) and milled K2CO3 (144 mg, 1.04 mmol)
were added to a solution of chlorohydrin 52 (212 mg, 522 mmol) in DMF
8226
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 8220 – 8238

Total Synthesis of Guadinomines B and C2
FULL PAPER
(2.60 mL) at RT. After stirring for 2.5 h, the reaction mixture was diluted
with EtOAc (10 mL) and H2O (2.0 mL) was added. The organic layer
was separated, and the aqueous layer was extracted with EtOAc
(10 mL”2). The combined organic extracts were washed with H2O
(10 mL”5) and brine (20 mL), dried over Na2SO4, filtered, and evaporat-
ed under reduced pressure. Purification by flash chromatography on
silica gel (hexane/EtOAc=4:1) gave 20 (193 mg, 100%) as a colorless
oil. Rf =0.41 (silica gel, hexane/EtOAc=1:1); [a]2D6 =À30.6 (c=1.10,
(d, J=7.3, 3H; 3’-H3), 1.31–1.20 (complex m, 2H; 6’’-H2), 0.87 (d, J=
6.9 Hz, 3H; 3-(CH3)2), 0.86 (d, J=6.9 Hz, 3H; 3-(CH3)2), 0.81 ppm (t, J=
6.9 Hz, 3H; 7’’-H3); 13C NMR (67.5 MHz, CDCl3): d=171.1, 170.5, 164.2,
148.6, 135.0, 132.3, 131.3, 130.9, 124.6, 81.9, 57.4, 48.8, 48.2, 44.5, 31.1,
28.8, 27.9 (3C), 26.7, 21.8, 18.7, 17.8, 17.4, 13.6 ppm; IR (KBr): n˜ =3317
(br, -NH), 1728 (C=O, ester), 1687 (C=O, amide), 1658 (C=O, amide),
1547 (NO2), 1367 (NO2), 1344 (N-SO2), 1167 (N-SO2), 960, 852, 781, 739,
602 cmÀ1; HRMS (FAB, NBA matrix): m/z calcd for C25H38N4O8SNa:
577.2308 [M+Na]; found: 577.2310 [M+Na]+.
1
CHCl3); H NMR (270 MHz, CDCl3): d=6.73 (d, J=7.3 Hz, 1H; 2’-NH),
6.42 (d, J=8.9 Hz, 1H; 2-NH), 4.53 (dq, J=6.9, 7.3 Hz, 1H; 2’-H), 4.41
(dd, J=4.6, 8.9 Hz, 1H; 2-H), 3.45 (d, J=4.6 Hz, 1H; 2’’-H), 3.17 (m,
1H; 3’’-H), 2.09 (dqq, J=4.6, 6.6, 6.6 Hz, 1H; 3-H), 1.57–1.32 (complex
m, 2H; 4’’-H2), 1.57–1.32 (complex m, 4H; 5’’-H2, 6’’-H2), 1.47 (s, 9H; 1-
(2’’R,3’’S)-(À)-tert-Butyl-{N’-[3’’-azido-2’’-(o-nitrobenzenesulfonamido)-
heptanoyl]-l-alanyl}-l-valinate (54): NaN3 (33.4 mg, 428 mmol) was added
to a solution of 21 (142 mg, 257 mmol) in DMF (2.57 mL) under Ar at
08C. After stirring for 30 min, the reaction solution was warmed to RT
and stirred for 2 h. The mixture was diluted with EtOAc (5.0 mL), H2O
(5.0 mL) was added, and the organic layer was separated. The aqueous
layer was extracted with EtOAc (10 mL). The combined organic extracts
were washed with H2O (10.0 mL”3) and brine (10 mL), dried over
Na2SO4, filtered, and evaporated under reduced pressure. Purification by
flash chromatography on silica gel (hexane/EtOAc=3:1) gave 54 as a
white solid (140 mg, 91%). Rf =0.47 (silica gel, hexane/EtOAc=1:1);
m.p. 153–1578C; [a]2D7 =À31.2 (c=1.70, CHCl3); 1H NMR (270 MHz,
CDCl3): d=8.11 (m, 1H; N’’-S(O2)-Ph-NO2), 7.91 (m, 1H; N’’-S(O2)-Ph-
NO2), 7.75 (complex m, 2H; N’’-S(O2)-Ph-NO2), 7.04 (d, J=7.3 Hz, 1H;
2’-NH), 6.37 (d, J=8.3 Hz, 1H; 2-NH), 4.38 (dd, J=4.3, 8.3 Hz, 1H; 2-
H), 4.38 (dq, J=6.9, 7.3 Hz, 1H; 2’-H), 4.13 (ddd, J=2.6, 6.0, 7.6 Hz, 1H;
3’’-H), 4.04 (d, J=2.6 Hz, 1H; 2’’-H), 2.14 (dqq, J=4.3, 6.9, 7.3 Hz, 1H;
3-H), 1.69–1.56 (complex m, 2H; 4’’-H2), 1.48–1.32 (complex m, 2H; 5’’-
OC(CH3)3), 1.39 (d, J=6.9 Hz, 3H; 3’-H3), 0.93, 0.90 (d, J=6.6 Hz, each
N
3H; 3-(CH3)2), 0.90 ppm (t, J=6.9 Hz, 3H; 7’’-H3); 13C NMR (67.5 MHz,
CDCl3): d=171.3, 170.6, 167.3, 82.0, 58.4, 57.6, 54.9, 48.4, 31.2, 28.0, 28.0
(3C), 27.2, 22.3, 18.9, 18.5, 17.5, 13.8 ppm; IR (KBr): n˜ =3317 (br, -NH),
1734 (C=O, ester), 1684 (C=O, amide), 1655 (C=O, amide), 1541,
1522, 1458, 1369, 1157 cmÀ1; HRMS (FAB, NBA matrix): m/z calcd for
C19H35N2O5: 371.2546 [M+H]; found: 371.2545 [M+H]+.
(2’’S,3’’R)-(À)-tert-Butyl-[N’-(3’’-azido-2’’-hydroxyheptanoyl)-l-alanyl]-l-
valinate (53): NaN3 (67.6 mg, 1.04 mmol) and NH4Cl (55.6 mg,
1.04 mmol) were added to a solution of 20 (193 mg, 520 mmol) in MeOH/
H2O (20:1) (5.20 mL) at RT and the reaction mixture was warmed to
708C. After stirring for 56 h, the reaction mixture was cooled to RT, di-
luted with CHCl3 (15 mL), and H2O (2.0 mL) was added. The organic
layer was separated, and the aqueous layer was extracted with CHCl3
(10 mL”3). The combined organic extracts were washed with brine
(20 mL), dried over Na2SO4, filtered, and evaporated under reduced pres-
sure. Purification by flash chromatography on silica gel (hexane/EtOAc=
2:1) gave 53 as colorless needles (197 mg, 91%). Rf =0.39 (silica gel,
hexane/EtOAc=1:1); m.p. 189.5–191.08C; [a]2D9 =À46.1 (c=0.80,
H2), 1.46 (s, 9H; 1-OC(CH3)3), 1.32–1.10 (complex m, 2H; 6’’-H2), 1.24
A
(d, J=6.9 Hz, 3H; 3’-H3), 0.89 (d, J=6.9 Hz, 3H; 3-(CH3)2), 0.88 (d, J=
6.9 Hz, 3H; 3-(CH3)2), 0.82 ppm (t, J=7.3 Hz, 3H; 7’’-H3); 13C NMR
(67.5 MHz, CDCl3): d=171.1, 170.5, 168.1, 147.7, 133.9, 133.5, 132.9,
130.7, 125.3, 81.9, 63.4, 59.7, 57.5, 49.1, 31.1, 30.7, 27.9 (3C), 27.9, 22.2,
18.6, 18.0, 17.4, 13.6 ppm; IR (KBr): n˜ =3373 (br, -NH), 3315 (br, -NH),
2108 (N=N+ =NÀ), 1728 (C=O, ester), 1649 (C=O, amide), 1543
1
CHCl3); H NMR (270 MHz, CDCl3): d=7.23 (d, J=7.3 Hz, 1H; 2’-NH),
6.48 (d, J=8.6 Hz, 1H; 2-NH), 4.53 (dq, J=6.9, 7.3 Hz, 1H; 2’-H), 4.39
(dd, J=4.6, 8.6 Hz, 1H; 2-H), 4.11 (dd, J=2.6, 6.6 Hz, 1H; 2’’-H), 3.79
(ddd, J=2.6, 6.6, 8.6 Hz, 1H; 3’’-H), 3.66 (d, J=6.6 Hz, 1H; 2’’-OH), 2.16
(dqq, J=4.5, 6.6, 6.6 Hz, 1H; 3-H), 1.74–1.58 (complex m, 2H; 4’’-H2),
(NO2), 1454, 1362 (N-SO2), 1163 (N-SO2), 847, 789, 741, 588 cmÀ1
;
HRMS (FAB, NBA matrix): m/z calcd for C25H39N7O8SNa: 620.2479
[M+Na]; found: 620.2503 [M+Na]+.
1.51–1.33 (complex m, 4H; 5’’-H2, 6’’-H2), 1.47 (s, 9H; 1-OC(CH3)3), 1.46
U
(2’’R,3’’S)-(+)-tert-Butyl-{N’-[3’’-amino-2’’-(o-nitrobenzenesulfonamido)-
heptanoyl]-l-alanyl}-l-valinate (22): H2O (30.4 mL, 1.69 mmol) and PPh3
(66.5 mg, 0.253 mmol) were added to a solution of 54 (101 mg, 169 mmol)
in THF (1.70 mL) at RT. After stirring for 20 h at 458C, the reaction so-
lution was cooled to RT. Then the solution was evaporated under re-
duced pressure to remove the solvent. Purification by flash chromatogra-
phy on silica gel (CHCl3/MeOH=50:1) gave 22 as a yellow powder
(82.5 mg, 85%). Rf =0.31 (silica gel, CHCl3/MeOH=10:1); [a]2D9 =+1.66
(c=0.84, MeOH); 1H NMR (270 MHz, CD3OD): d=7.94 (m, 1H; N’’-
S(O2)-Ph-NO2), 7.70–7.58 (complex m, 3H; N’’-S(O2)-Ph-NO2), 4.12 (q,
J=7.3 Hz, 1H; 2’-H), 4.05 (d, J=5.9 Hz, 1H; 2-H), 3.85 (d, J=3.3 Hz,
1H; 2’’-H), 3.15 (dt, J=3.3, 6.9 Hz, 1H; 3’’-H), 2.01 (m, 1H; J=6.9 Hz,
3-H), 1.64–1.42 (m, 1H; 4’’-H2), 1.39–1.12 (complex m, 5H; 4’’-H2, 5’’-H2,
(d, J=6.9, 3H; 3’-H3), 0.94 (t, J=6.9 Hz, 3H; 7’’-H3), 0.92 (d, J=6.6 Hz,
3H; 3-(CH3)2), 0.90 ppm (d, J=6.6 Hz, 3H; 3-(CH3)2); 13C NMR
(67.5 MHz, CDCl3): d=173.2, 171.8, 170.4, 81.9, 73.4, 63.3, 57.8, 48.6,
31.1, 29.9, 28.3, 27.9 (3C), 22.4, 18.8, 18.5, 17.6, 13.9 ppm; IR (KBr): n˜ =
3369 (br, -NH), 3297 (br, -NH), 3103 (br, -OH), 2108 (N=N+ =NÀ),
1734 (C=O, ester), 1647 (C=O, amide), 1547, 1458, 1371, 1261, 1159,
1144 cmÀ1
; HRMS (FAB, NBA matrix): m/z calcd for C19H36N5O5:
414.2716 [M+H]; found: 414.2712 [M+H]+.
(2’’R,3’’R)-(+)-tert-Butyl-{N’-[2’’,3’’-(N’’-o-nitrobenzenesulfonylimino)-
heptanoyl]-l-alanyl}-l-valinate (21): 10% Pd on carbon (25.8 mg,
24.2 mmol) was added to a solution of 53 (100 mg, 242 mmol) in EtOAc
(2.42 mL) under H2 at RT. After stirring for 8.5 h, the reaction solution
was filtered through a Celite pad to remove the catalyst, and the pad was
washed with EtOAc. The filtrate solution was evaporated to remove the
solvent, the residue was dissolved in CH2Cl2 (4.84 mL), and then 2-nitro-
benzenesulfonyl chloride (161 mg, 726 mmol), TEA (100 mL, 726 mmol),
and DMAP (1.5 mg, 12.1 mmol) were added to the solution. After stirring
for 11.5 h under argon at RT, the reaction solution was quenched with a
saturated aqueous solution of NH4Cl (3.0 mL), the organic layer was sep-
arated and the aqueous layer was extracted with CHCl3 (10 mL”2). The
combined organic extracts were washed with brine (5.0 mL), dried over
Na2SO4, filtered, and evaporated under reduced pressure. Purification by
flash chromatography on silica gel (hexane/EtOAc=2:1) gave 21 as a
yellow oil (121 mg, 91% in 2 steps). Rf =0.46 (silica gel, hexane/EtOAc=
1:1); [a]2D5 =+3.9 (c=0.87, CHCl3); 1H NMR (270 MHz, CDCl3): d=
8.19–8.15 (m, 1H; N’’-S(O2)-Ph-NO2), 7.85–7.76 (m, 3H; N’’-S(O2)-Ph-
NO2), 6.92 (d, J=7.6 Hz, 1H; 2’-NH), 6.38 (d, J=8.9 Hz, 1H; 2-NH),
4.44 (dq, J=7.3, 7.6 Hz, 1H; 2’-H), 4.36 (dd, J=4.3, 8.9 Hz, 1H; 2-H),
3.65 (d, J=7.6 Hz, 1H; 2’’-H), 3.24 (ddd, J=5.9, 7.6, 7.6 Hz, 1H; 3’’-H),
2.12 (dqq, J=4.3, 6.9, 6.9 Hz, 1H; 3-H), 1.60–1.50 (complex m, 2H; 4’’-
6’’-H2), 1.37 (s, 9H; 1-OC(CH3)3), 1.12 (d, J=7.3 Hz, 3H; 3’-H3), 0.86 (d,
A
J=6.9 Hz, 6H; 3-(CH3)2), 0.79 ppm (t, J=6.9 Hz, 3H; 7’’-H3); 13C NMR
(67.5 MHz, CD3OD): d=175.0, 173.9, 172.1, 149.2, 137.0, 133.9, 133.2,
131.2, 125.3, 82.8, 61.5, 60.1, 55.6, 50.3, 32.5, 31.7, 28.8, 28.3 (3C), 23.5,
19.5, 18.5, 18.1, 14.2 ppm; IR (KBr): n˜ =3375 (-NH), 3321 (-NH), 1730
(C=O, ester), 1655 (C=O, amide), 1541 (NO2), 1456, 1369 (N-SO2),
1165 (N-SO2), 850, 787, 737, 658 cmÀ1; HRMS (FAB, NBA matrix): m/z
calcd for C25H41N5O8SNa: 594.2574 [M+Na]; found: 594.2568 [M+Na]+.
(2’’R,3’’S,2’’’R)-(À)-tert-Butyl-{N’-[3’’-(2’’’-bromopropanamido)-2’’-(o-ni-
trobenzenesulfonamido)heptanoyl]-l-alanyl}-l-valinate (55): Compound
(R)-10 (19.0 mL, 211 mmol), HOBt (32.4 mg, 239 mmol), and EDCI
(40.5 mg, 211 mmol) were added to a solution of 22 (80.5 mg, 141 mmol)
in CH2Cl2 (1.40 mL) under argon at 08C. After stirring for 1 h, H2O
(1.0 mL) was added to the reaction and the organic layer was separated.
The aqueous layer was extracted with CHCl3 (10 mL”3). The combined
organic extracts were washed with H2O (5.0 mL) and brine (5.0 mL),
dried over Na2SO4, filtered, and evaporated under reduced pressure. Pu-
rification by flash chromatography on silica gel (CHCl3/MeOH=100:1)
H2), 1.45–1.35 (complex m, 2H; 5’’-H2), 1.45 (s, 9H; 1-OC(CH3)3), 1.39
A
Chem. Eur. J. 2008, 14, 8220 – 8238
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8227

¯
T. Sunazuka, S. Omura et al.
gave 55 as a yellow powder (90.5 mg, 91%). Rf =0.49 (silica gel, CHCl3/
MeOH=10:1); [a]2D6 =À21.0 (c=0.47, CHCl3); 1H NMR (270 MHz,
CDCl3): d=8.12 (m, 1H; N’’-S(O2)-Ph-NO2), 7.85 (m, 1H; N’’-S(O2)-Ph-
NO2), 7.77–7.64 (complex m, 2H; N’’-S(O2)-Ph-NO2), 7.15 (d, J=6.9 Hz,
1H; 2’-NH), 7.00 (d, J=8.2 Hz, 1H; 3’’-NH), 6.38 (d, J=8.6 Hz, 1H; 2-
NH), 4.37 (q, J=7.3 Hz, 1H; 2’-H), 4.36 (q, J=6.9 Hz, 1H; 2’’’-H), 4.34
(dd, J=4.6, 8.6 Hz, 1H; 2-H), 4.21 (d, J=4.3 Hz, 1H; 2’’-H), 4.05 (ddd,
J=4.3, 8.2, 8.9 Hz, 1H; 3’’-H), 2.11 (dq, J=4.6, 6.9 Hz, 1H; 3-H), 1.95–
1.60 (complex m, 2H; 4’’-H2), 1.80 (d, J=8.2 Hz, 3H; 3’’’-H3), 1.45 (s,
(FAB, NBA matrix): m/z calcd for C18H33N4O5: 385.2451 [M+H]; found:
385.2436 [M+H]+.
A
oil, 446 mg, 11.1 mmol) was added to a solution of 17 (3.30 g, 10.1 mmol)
in EtOH (50.5 mL) at 08C. After stirring for 20 min, a saturated aqueous
solution of NH4Cl (30 mL) and CH2Cl2 (100 mL) was added to the reac-
tion mixture. The organic layer was separated, and the aqueous layer was
extracted with CH2Cl2 (100 mL”2), dried over Na2SO4, filtered, and
evaporated under reduced pressure. Purification by flash chromatography
on silica gel (hexane/EtOAc=5:1) gave a mixture of trans-epoxide 24
and cis-epoxide (5.4:1) as a colorless oil (1.70 g, 98%). Rf =0.56 (silica
gel, hexane/EtOAc=2:1); [a]D27 =À18.3 (c=1.00, CHCl3), as a mixture;
1H NMR (270 MHz, CDCl3), major isomer 24 is reported d=4.23 (dq,
J=3.3, 7.3 Hz, 2H; 1-OCH2CH3), 3.20 (d, J=2.0 Hz, 1H; 2-H), 3.15
(ddd, J=2.0, 5.0, 5.9 Hz, 1H; 3-H), 1.70–1.54 (complex m, 2H; 4-H2),
1.49–1.35 (complex m, 2H; 5-H2, 6-H2), 1.30 (t, J=7.3 Hz, 3H; 1-
OCH2CH3), 0.92 ppm (t, J=6.9 Hz, 3H; 7-H3); 13C NMR (67.5 MHz,
CDCl3), major isomer 24 is reported d=169.3, 61.4, 58.4, 53.0, 31.1, 27.7,
22.3, 14.0, 13.8 ppm; IR (NaCl): n˜ =1753 (C=O, ester), 1446, 1284 (C-O,
epoxide), 1196, 1036, 906 cmÀ1; MS (FAB, EI): could not be observed.
9H; 1-OC(CH3)3), 1.30–1.13 (complex m, 4H; 5’’-H2, 6’’-H2), 1.23 (d, J=
R
7.3 Hz, 3H; 3’-H3), 0.87 (d, J=6.9 Hz, 3H; 3-(CH3)2), 0.86 (d, J=6.9 Hz,
3H; 3-(CH3)2), 0.77 ppm (t, J=6.6 Hz, 3H; 7’’-H3); 13C NMR (67.5 MHz,
CDCl3): d=171.5, 170.8, 170.5, 169.2, 147.6, 133.7, 133.7, 133.0, 131.2,
124.9, 82.0, 61.2, 57.6, 52.4, 49.1, 43.9, 31.0, 29.8, 28.0, 28.0 (3C), 22.2,
22.1, 18.8, 18.7, 17.7, 13.8 ppm; IR (KBr): n˜ =3315 (-NH), 1730 (C=O,
ester), 1662 (C=O, amide), 1541 (NO2), 1454, 1363 (N-SO2), 1163 (N-
SO2), 785, 739, 586 cmÀ1; HRMS (FAB, NBA matrix): m/z calcd for
C28H45N5O9SBr: 706.2121 [M+H]; found: 706.2135 [M+H]+.
(3S,5R,6S)-(À)-6-Butyl-5-(O1-tert-butyl-l-valinyl-l-alanyl)carbonyl-3-
methyl-2-piperazinone (23): DIPEA (37.0 mL, 428 mmol) was added to a
solution of 55 (75.0 mg, 106 mmol) in MeCN (2.12 mL) under argon at
RT. After stirring for 19 h at 608C, the reaction solution was cooled to
RT. Then thiophenol (16.3 mL, 159 mmol) and DIPEA (27.7 mL,
159 mmol) were added and the solution was stirred for 21 h at RT. The so-
lution was then evaporated under reduced pressure to remove the sol-
vent. Purification by flash chromatography on silica gel (CHCl3/MeOH=
60:1) gave 23 as a colorless oil (40.4 mg, 100%). Rf =0.27 (silica gel,
CHCl3/MeOH=10:1); [a]2D9 =À40.5 (c=0.86, CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.89 (d, J=8.0 Hz, 1H; 2’-NH), 6.97 (d, J=
8.8 Hz, 1H; 2’’-NH), 6.45 (d, J=2.5 Hz, 1H; 1-H), 4.59 (dq, J=6.8,
8.0 Hz, 1H; 2’-H), 4.38 (dd, J=4.6, 8.8 Hz, 1H; 2’’-H), 3.87 (dddd, J=
2.5, 4.8, 5.0, 8.3 Hz, 1H; 6-H), 3.41 (q, J=7.0 Hz, 1H; 3-H), 3.36 (d, J=
4.8 Hz, 1H; 5-H), 2.11 (dqq, J=4.6, 7.8, 7.8 Hz, 1H; 3’’-H), 1.73–1.64 (m,
1H; 6-CH2CH2CH2CH3), 1.61–1.52 (m, 1H; 6-CH2CH2CH2CH3), 1.44 (s,
A mixture of (2S,3S)-ethyl-2-azido-3-hydroxyheptanate and (2R,3R)-
ethyl-3-azido-2-hydroxyheptanate (56): NH4Cl (792 mg, 14.8 mmol) and
NaN3 (963 mg, 14.8 mmol) were added to a solution of 24 and cis-epoxide
mixture (1.70 g, 9.87 mmol) in 1,4-dioxane/H2O (1:1) (66.0 mL) at RT
and warmed to 608C. After stirring for 40 h, the reaction mixture was
cooled to RT, diluted with CHCl3 (100 mL), and the organic layer was
washed with brine (20 mL), dried over Na2SO4, filtered, and evaporated
under reduced pressure. Purification by flash chromatography on silica
gel (hexane/EtOAc=5:1) gave a mixture of 56 as a colorless oil (478 mg,
55%). Rf =0.39 (hexane/EtOAc=3:1); 1H NMR (270 MHz, CDCl3): as a
mixture of four compounds d=4.36–4.10 (complex m, 2H; 1-OCH2CH3),
3.97–3.88 (complex m, 1H; 2-H), 3.58–3.45 (complex m, 1H; 3-H), 3.07
(brs, 1H; -OH), 1.90–1.65 (complex m, 1H; 4-H2), 1.56–1.23 (complex m,
5H; 4-H2, 5-H2, 6-H2), 1.37–1.27 (complex m, 3H; 1-OCH2CH3), 0.98–
0.86 ppm (complex m, 3H; 7-H3); 13C NMR (67.5 MHz, CDCl3): two
major isomers were indicated. d=171.9 and 168.8, 73.3 and 71.7, 66.1 and
64.2, 61.9 and 61.7, 32.4 and 29.3, 28.2 and 27.3, 22.2 and 22.0, 13.8, 13.6
and 13.5 ppm; IR (NaCl) n˜ =3483 (br, -OH), 2109 (-N=N+ =NÀ), 1739
(-C=O, ester), 1468, 1371, 1265, 1203, 1130, 1095, 1026, 862 cmÀ1; HRMS
(FAB, NBA matrix): m/z: calcd for C9H17N3O3Na: 238.1168 [M+Na];
found: 238.1161 [M+Na]+.
9H; 1’’-OC(CH3)3), 1.41–1.25 (complex m, 4H; 6-CH2CH2CH2CH3), 1.37
N
(d, J=7.0 Hz, 3H; 3-CH3), 1.34 (d, J=6.8 Hz, 3H; 3’-H3), 0.88 (d, J=
7.8 Hz, 3H; 3’’-(CH3)2), 0.88 (t, J=7.0 Hz, 3H; 6-CH2CH2CH2CH3),
0.86 ppm (d, J=7.8 Hz, 3H; 3’’-(CH3)2); 13C NMR (75.0 MHz, CDCl3):
d=172.8 (C-2), 171.9 (C-1’), 170.9 (C-1’’), 170.3 (5-CO-), 81.9 (1’’-OCH-
ACHTREUNG
AHCTREUNG
CH2CH2CH2CH3), 22.4 (1C, 6-CH2CH2CH2CH3), 18.8 (1C, 3’’-(CH3)2),
18.5 (C-3’), 17.8 (1C, 3-CH3), 17.6 (1C, 3’’-(CH3)2), 13.9 ppm (1C, 6-
CH2CH2CH2CH3); IR (KBr) n˜ =3662, 3288 (-NH), 1730 (C=O, ester),
1655 (C=O, amide), 1545, 1466, 1379, 1155, 935, 841, 627 cmÀ1; HRMS
(FAB, NBA matrix): m/z calcd for C22H40N4O5Na: 463.2896 [M+Na];
found: 463.2896 [M+Na]+.
A
added to a solution of 56 (943 mg, 4.38 mmol) in MeCN (21.9 mL) under
argon at RT. After stirring for 30 min, the reaction solution was warmed
to 808C and stirred for 1.5 h. Then the solution was cooled to RT and
evaporated under reduced pressure to remove the solvent. Purification
by flash chromatography on silica gel (hexane/EtOAc=5:1) gave 25
(667.6 mg, 89%) and cis-aziridine 57 (75 mg, 10%) as colorless oils. 25:
Rf =0.46 (silica gel, hexane/EtOAc=3:1); [a]2D5 =+73.8 (c=0.50, CHCl3);
1H NMR (270 MHz, CDCl3): d=4.22 (dq, J=3.2, 7.3 Hz, 2H; 1-
OCH2CH3), 2.26 (d, J=2.3 Hz, 1H; 2-H), 2.21 (m, 1H; 3-H), 1.44–1.32
(complex m, 6H; 4-H2, 5-H2, 6-H2), 1.29 (t, J=7.3 Hz, 3H; 1-OCH2CH3),
0.90 ppm (t, J=7.3 Hz, 3H; 7-H3); 13C NMR (67.5 MHz, CDCl3): d=
172.4, 61.0, 39.2, 35.0, 32.1, 29.0, 22.1, 13.9, 13.6 ppm; IR (NaCl): n˜ =3288
(br, -NH), 1728 (C=O, ester), 1468, 1431, 1373, 1342, 1209, 1036,
845 cmÀ1; HRMS (FAB, NBA matrix): m/z calcd for C9H18NO2 172.1338
[M+H]; found: 172.1336 [M+H]+. 57: Rf =0.25 (silica gel, hexane/
EtOAc=3:1); [a]2D3 =À47.6 (c=1.41, CHCl3); 1H NMR (270 MHz,
CDCl3): d=4.22 (q, J=7.3 Hz, 2H; 1-OCH2CH3), 2.63 (brd, J=5.9 Hz,
1H; 2-H), 2.21 (brm, 1H; 3-H), 1.24–1.67 (complex m, 6H; 4-H2, 5-H2,
6-H2), 1.30 (t, J=7.3 Hz, 3H; 1-OCH2CH3), 0.89 ppm (t, J=6.6 Hz, 3H;
7-H3); 13C NMR (67.5 MHz, CDCl3): d=170.8, 61.1, 38.7, 34.5, 29.8, 27.4,
22.2, 14.1, 13.8 ppm; IR (NaCl): n˜ =3267 (br, NH), 1727 (C=O), 1466,
1408, 1383, 1198, 1034, 827 cmÀ1; HRMS (FAB, NBA matrix): m/z calcd
for C9H18NO2: 172.1338 [M+H]; found: 172.1336 [M+H]+.
(3S,5R,6S)-(À)-6-Butyl-3-methyl-5-(l-valinyl-l-alanyl)carbonyl-2-pipera-
zinone (7): After dissolving 23 (45.8 mg, 104 mmol) in a solution of TFA/
H2O (3:1) (2.08 mL), the reaction solution was stirred for 3 h at RT. The
solution was diluted with H2O (3.0 mL), and evaporated under reduced
pressure to remove the solvent. Purification by flash chromatography on
silica gel (CHCl3/MeOH=10:1) gave 7 as a white powder (40.4 mg,
100%). Rf =0.12 (silica gel, CHCl3/MeOH=10:1); [a]2D4 =À35.2 (c=1.50,
MeOH); 1H NMR (400 MHz, 1% TFA in D2O): d=4.35 (q, J=7.0 Hz,
1H; 2’-H), 4.17 (q, J=7.2 Hz, 1H; 3-H), 4.16 (d, J=6.0 Hz, 1H; 2’’-H),
4.02 (d, J=9.0 Hz, 1H; 5-H), 3.81 (ddd, J=4.5, 6.5, 9.0 Hz, 1H; 6-H),
2.09 (dq, J=6.0, 6.9 Hz, 1H; 3’’-H), 1.65–1.58 (m, 1H; 6-
CH2CH2CH2CH3), 1.56–1.49 (m, 1H; 6-CH2CH2CH2CH3), 1.51 (d, J=
7.0 Hz, 3H; 3-CH3), 1.33 (d, J=7.0 Hz, 3H; 3’-H3), 1.28–1.17 (complex
m, 4H; 6-CH2CH2CH2CH3), 0.86 (d, J=6.9 Hz, 3H; 3’’-(CH3)2), 0.85 (d,
J=6.9 Hz, 3H; 3’’-(CH3)2), 0.84 ppm (t, J=7.0 Hz, 3H; 6-
CH2CH2CH2CH3); 13C NMR (100 MHz, 1% TFA in D2O), reference 0–
200 ppm. d=177.7 (C-1’’), 177.2 (C-1’), 171.4 (C-2), 168.5 (5-CO-), 61.2
(C-2’’), 56.8 (C-5), 54.3 (C-3), 53.7 (C-6), 52.5 (C-2’), 33.4 (1C, 6-
CH2CH2CH2CH3), 32.4 (C-3’’), 28.1 (1C, 6-CH2CH2CH2CH3), 24.2 (1C,
6-CH2CH2CH2CH3), 20.9 (1C, 3’’-(CH3)2), 19.9 (1C, 3’’-(CH3)2), 19.3 (C-
3’), 17.2 (1C, 3-CH3), 15.6 ppm (1C, 6-CH2CH2CH2CH3); IR (KBr): n˜ =
3435 (br, -NH), 1672 (C=O, amide), 1566, 1196, 1142, 723 cmÀ1; HRMS
AHCTREUNG
AHCTREUNG
8228
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 8220 – 8238

Total Synthesis of Guadinomines B and C2
FULL PAPER
were added to a solution of 25 (666 mg, 3.89 mmol) in CH2Cl2 (38.9 mL)
at RT under argon. After stirring for 20 h, the reaction was quenched
with a saturated aqueous solution of NH4Cl (10 mL), the organic layer
was separated and aqueous layer was extracted with CHCl3 (30 mL”3).
The combined organic extracts were dried over Na2SO4, filtered, and
evaporated under reduced pressure. The residue was roughly purified
with silica gel (hexane/EtOAc=5:1) to provide the residue of Ns-aziri-
dine. The residue was dissolved in DMF (38.9 mL), and then NaN3
(506 mg, 7.78 mmol) was added to the solution at 08C under argon, and
then the reaction mixture was warmed to RT. After stirring for 30 min,
the solution was diluted with EtOAc (40 mL), H2O (20 mL) was added,
and the organic layer was separated. The organic extracts were washed
with brine (10.0 mL”3), dried over Na2SO4, filtered, and evaporated
under reduced pressure to provide a mixture of azido-Ns-amine. The
azido-Ns-amine residue was dissolved in MeCN (38.9 mL), and then thio-
phenol (999 mL, 9.73 mmol), and DIPEA (1.69 mL, 9.73 mmol) were
added to the solution at RT under argon. After stirring for 2.5 h, a satu-
rated aqueous solution of NaHCO3 (10 mL) was added to the reaction
mixture. Then the mixture was extracted with CHCl3 (30 mL”3). The or-
ganic extracts were dried over Na2SO4, filtered, and evaporated under re-
duced pressure. Purification by flash chromatography on silica gel
rification by flash chromatography on silica gel (CHCl3) gave 28 as a col-
orless oil (65.0 mg, 73%). Rf =0.37 (CHCl3/MeOH=10:1); [a]3D0 =+92.9
(c=0.50, CHCl3); H NMR (400 MHz, 1% TFA in D2O): d=4.22 (q, J=
1
7.0 Hz, 2H; 5-CO-O-CH2CH3), 4.03 (d, J=4.2 Hz, 1H; 5-H), 3.72 (ddd,
J=3.5, 4.2, 10.3 Hz, 1H; 6-H), 3.53 (q, J=6.9 Hz, 1H; 3-H), 1.56 (m,
1H; 6-CH2CH2CH2CH3), 1.36 (m, 1H; 6-CH2CH2CH2CH3), 1.31 (d, J=
6.9 Hz, 3H; 3-CH3), 1.31–1.21 (complex m, 4H; 6-CH2CH2CH2CH3), 1.25
(t, J=7.0 Hz, 3H; 5-CO-O-CH2CH3), 0.83 ppm (t, J=7.0 Hz, 3H; 6-
CH2CH2CH2CH3); 13C NMR (100 MHz, D2O with TFA): d=175.1 (C-2),
171.5 (1C, 5-CO-O-CH2CH3), 62.7 (1C, 5-CO-O-CH2CH3), 57.6 (C-5),
52.7 (C-3), 52.6 (C-6), 30.9 (1C, 6-CH2CH2CH2CH3), 27.3 (1C, 6-
CH2CH2CH2CH3), 21.9 (1C, 6-CH2CH2CH2CH3), 16.9 (1C, 3-CH3), 13.4
(1C, 5-CO-O-CH2CH3), 13.2 ppm (1C, 6-CH2CH2CH2CH3); IR (NaCl):
n˜ =3330 (br, -NH), 3207 (br, -NH), 1739 (C=O, ester), 1668 (C=O,
amide), 1468, 1371, 1329, 1217, 1176, 1041, 1020, 856, 771, 719 cmÀ1
;
HRMS (FAB, NBA matrix): m/z calcd for C12H23N2O3: 243.1709 [M+H];
found: 243.1707 [M+H]+.
(3R,5R,6R)-(+)-4-tert-Butoxycarbonyl-6-butyl-5-ethoxycarbonyl-3-
methyl-2-piperazinone
(29):
Di-tert-butyl
dicarbonate
(385 mg,
1.76 mmol) was added to a solution of 28 (85.3 mg, 352 mmol) in EtOAc
(3.50 mL) at RT under argon. After stirring for 20 min at 808C, the reac-
tion solution was cooled to RT. Then brine (2.0 mL) was added to the re-
action mixture, the organic layer was then separated, and the aqueous
layer was extracted with CHCl3 (10 mL”2). The combined organic ex-
tracts were dried over Na2SO4, filtered, and evaporated under reduced
pressure. Purification by flash chromatography on silica gel (hexane/
EtOAc=2:1) gave 29 as a yellow powder (88.5 mg, 73%). Rf =0.35
(hexane/EtOAc=1:1); [a]3D0 =+13.7 (c=1.00, CHCl3); 1H NMR
(270 MHz, CDCl3): as two rotamers. d=5.73 (brs, 1H; 1-H), 5.04 (brd,
J=3.3 Hz, 2/3H; 5-H), 4.78 (brs, 1/3H; 5-H), 4.42 (q, J=6.6 Hz, 1H; 3-
H), 4.20 (q, J=7.3 Hz, 4/3H; 5-CO-O-CH2CH3), 4.19 (q, J=7.3 Hz, 2/
3H; 5-CO-O-CH2CH3), 3.66 (m, 1H; 6-H), 1.75–1.49 (complex m, 2H; 6-
CH2CH2CH2CH3), 1.59 (brd, J=6.6 Hz, 3H; 3-CH3), 1.49 (s, 9H; 4-CO-
(hexane/EtOAc=1:1) gave 26 (385 mg, 53% in
3 steps) and 27
(101.7 mg, 14% in steps) as colorless oils. 26; Rf =0.24 (hexane/
3
EtOAc=2:1); [a]2D4 =+60.3 (c=0.50, CHCl3); 1H NMR (270 MHz,
CDCl3): d=4.25 (dq, J=1.3, 7.3 Hz, 2H; 1-OCH2CH3), 3.86 (d, J=
5.3 Hz, 1H; 2-H), 3.08 (ddd, J=1.6, 5.3, 8.9 Hz, 1H; 3-H), 1.54–1.42
(complex m, 2H; 4-H2), 1.37–1.23 (complex m, 4H; 5-H2, 6-H2), 1.30 (t,
J=7.3 Hz, 3H; 1-OCH2CH3), 0.88 ppm (t, J=7.0 Hz, 3H; 7-H3);
13C NMR (67.5 MHz, CDCl3): d=169.0, 67.9, 61.7, 53.1, 33.0, 28.1, 22.5,
14.1, 13.9 ppm; IR (NaCl): n˜ =2108 (N=N+ =NÀ), 1739 (C=O, ester),
1466, 1265, 1194, 1028, 854 cmÀ1; HRMS (FAB, NBA matrix): m/z calcd
for C9H19N4O2 215.1508 [M+H]; found: 215.1508 [M+H]+. 27; Rf =0.35
(hexane/EtOAc=2:1); [a]D30À23.5 (c=1.00, CHCl3); 1H NMR (270 MHz,
CDCl3): d=4.23 (dq, J=3.3, 6.9 Hz, 2H; 1-OCH2CH3), 3.61 (d, J=
4.6 Hz, 1H; 2-H), 3.52 (ddd, J=4.6, 7.6, 8.9 Hz, 1H; 3-H), 1.80–1.50
(complex m, 2H; 4-H2), 1.51–1.25 (complex m, 4H; 5-H2, 6-H2), 1.30 (t,
J=6.9 Hz, 3H; 1-OCH2CH3), 0.92 ppm (t, J=6.9 Hz, 3H; 7-H3);
13C NMR (67.5 MHz, CDCl3): d=171.2, 64.0, 61.8, 57.4, 29.8, 28.3, 22.3,
OC(CH3)3), 1.46–1.36 (complex m, 4H; 6-CH2CH2CH2CH3), 1.28 (t, J=
N
7.3 Hz, 3H; 5-CO-O-CH2CH3), 0.92 ppm (t, J=6.6 Hz, 3H; 6-
CH2CH2CH2CH3); 13C NMR (67.5 MHz, CDCl3): d=171.1, 168.8, 154.0,
81.3, 61.0, 54.0, 52.4, 31.4, 28.2 (3C), 27.5, 22.3, 18.2, 14.0, 13.7 ppm; IR
(NaCl): n˜ =3203 (br, -NH), 3087 (br, -NH), 1747 (C=O, ester), 1695
(C=O, urethane), 1682 (C=O, amide), 1456, 1369, 1327, 1257, 1186,
1169, 1130, 1028, 935, 816, 769 cmÀ1; HRMS (FAB, NBA matrix): m/z
calcd for C17H31N2O5: 343.2233 [M+H]; found: 343.2232 [M+H]+.
14.1, 13.8 ppm; IR (NaCl): n˜ =3302
(br, -NH), 2106 (N=N+ =NÀ), 1739
G
(C=O, ester), 1514, 1468, 1369, 1257, 1234, 1028, 861 cmÀ1; HRMS
(FAB, NBA matrix): m/z calcd for C9H19N4O2: 215.1508 [M+H]; found:
215.1515 [M+H]+.
(3R,5R,6R)-(+)-4-tert-Butoxycarbonyl-6-butyl-5-(O1-tert-butyl-l-valinyl-
l-analyl)-carbonyl-3-methyl-2-piperazinone (30): Lithium hydroxide
(10.5 mg, 438 mmol) was added to a solution of 29 (15.0 mg, 43.8 mmol) in
MeOH/THF/H2O (2:2:1) (880 mL) at RT. After stirring for 85 min, a sa-
turated aqueous solution of NH4Cl (1.0 mL) was added to the reaction
mixture, which was then extracted with CHCl3 (5.0 mL”3). The com-
bined organic extracts were dried over Na2SO4, filtered, and evaporated
under reduced pressure. The crude product was used in the next reaction
without further purification. The residue was dissolved in CH2Cl2
(880 mL) and then 19 (12.8 mg, 52.6 mmol), DIPEA (11.2 mL, 65.7 mmol),
and PyBOP (27.4 mg, 52.6 mmol) were added at RT under Ar. After stir-
ring for 1 h, the reaction solution was quenched with a saturated aqueous
solution of NH4Cl (1.0 mL), the organic layer was separated, and the
aqueous layer was extracted with CHCl3 (10 mL”2). The combined or-
ganic extracts were dried over Na2SO4, filtered, and evaporated under re-
duced pressure. Purification by flash chromatography on silica gel
(CHCl3/MeOH=50:1) gave 30 as a colorless oil (15.9 mg, 67% in 2
steps). Rf =0.47 (silica gel, CHCl3/MeOH=10:1); [a]2D4 =+29.1 (c=1.00,
(2R,3R,2’S)-(+)-Ethyl-2-azido-3-(2’-bromopropanamido)heptanate (58):
Compound (S)-10 (85.7 mL, 953 mmol), PyBOP (496 mg, 953 mmol), and
DIPEA (204 mL, 1.19 mmol) were added to a solution of 26 (88.7 mg, 476
mmol) in CH2Cl2 (4.80 mL) at RT under argon. After stirring for 80 min,
a saturated aqueous solution of NH4Cl (3.0 mL) was added to the reac-
tion solution. The organic layer was separated, then the aqueous layer
was extracted with CH2Cl2 (10 mL”3). The combined organic extracts
were dried over Na2SO4, filtered, and evaporated under reduced pres-
sure. Purification by flash chromatography on silica gel (hexane/EtOAc=
5:1) gave 58 as a yellow powder (156 mg, 94%). Rf =0.44 (hexane/
EtOAc=3:1); [a]3D0 =+61.3 (c=1.00, CHCl3); 1H NMR (270 MHz,
CDCl3): d=6.51 (d, J=8.3 Hz, 1H; 3-NH-CO-), 4.42 (q, J=7.3 Hz, 1H;
2’-H), 4.37 (m, 1H; 3-H), 4.30 (dq, J=1.0, 6.9 Hz, 2H; 1-OCH2CH3), 4.24
(d, J=4.0 Hz, 1H; 2-H), 1.90 (d, J=6.9 Hz, 3H; 3’-H3), 1.56–1.43 (com-
plex m, 2H; 4-H2), 1.37–1.20 (complex m, 4H; 5-H2, 6-H2), 1.34 (t, J=
7.3 Hz, 3H; 1-OCH2CH3), 0.88 ppm (3H; t, J=6.9, 7-H3); 13C NMR
(67.5 MHz, CDCl3): d=169.3, 168.2, 64.4, 62.2, 50.8, 44.7, 29.6, 27.8, 22.9,
22.1, 14.1, 13.7 ppm; IR (NaCl): n˜ =3300 (br, -NH), 2112 (N=N+ =NÀ),
1743 (C=O, ester), 1658 (C=O, amide), 1541, 1446, 1373, 1269, 1246,
1
CHCl3); H NMR (270 MHz, CDCl3): d=6.96 (d, J=7.3 Hz, 1H; 2’-NH),
6.50 (d, J=8.9 Hz, 1H; 2’’-NH), 6.14 (s, 1H; 1-H), 4.69 (d, J=3.6 Hz,
1H; 5-H), 4.48 (q, J=7.3 Hz, 1H; 3-H), 4.46–4.38 (m, 1H; 2’-H), 4.41
(dd, J=4.6, 8.9 Hz, 1H; 2’’-H), 3.62 (ddd, J=3.6, 6.9, 6.9 Hz, 1H; 6-H),
2.13 (dqq, J=4.6, 6.6, 6.6 Hz, 1H; 3’’-H), 1.82–1.65 (complex m, 2H; 6-
CH2CH2CH2CH3), 1.50–1.24 (complex m, 4H; 6-CH2CH2CH2CH3), 1.50
1196, 1026 cmÀ1
;
HRMS (FAB, NBA matrix): m/z calcd for
C12H22N4O3Br: 349.0875 [M+H]; found: 349.0890 [M+H]+.
(3R,5R,6R)-(+)-6-Butyl-5-ethoxycarbonyl-3-methyl-2-piperazinone (28):
PPh3 (308 mg, 1.17 mmol) and TEA (164 mL, 1.17 mmol) were added to a
solution of 58 (129 mg, 369 mmol) in MeCN (7.37 mL) under argon at RT.
After stirring for 1 h, H2O (730 mL) was added to the reaction solution, it
was warmed to 608C, and stirred for 1.5 h. Then the solution was cooled
to RT and evaporated under reduced pressure to remove the solvent. Pu-
(s, 9H; 4-CO-OC
N
N
6.9 Hz, 3H; 3-CH3), 1.36 (d, J=6.9 Hz, 3H; 3’-H3), 0.90 (t, J=7.0 Hz,
3H; 6-CH2CH2CH2CH3), 0.87, 0.84 ppm (d, J=6.6 Hz, each 3H; 3’’-
(CH3)2); 13C NMR (67.5 MHz, CDCl3): d=171.4, 170.8, 170.2, 168.1,
Chem. Eur. J. 2008, 14, 8220 – 8238
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8229

¯
T. Sunazuka, S. Omura et al.
154.4, 82.0, 81.9, 57.3, 53.5, 53.2, 52.4, 48.6, 31.2, 31.1, 28.3, 28.0, 27.9,
22.4, 18.9, 17.4, 18.6, 18.1, 13.8 ppm; IR (NaCl): n˜ =3315 (br, -NH), 1734
(C=O, ester), 1672 (C=O, amide, urethane), 1535, 1458, 1369, 1331,
1255, 1165, 1132, 1018, 849, 756 cmÀ1; HRMS (FAB, NBA matrix): m/z
calcd for C27H48N4O7Na: 563.3421 [M+Na]; found: 563.3420 [M+Na]+.
1C, 3’’-(CH3)2), 19.2 (C-3’), 16.5 (1C, 3-CH3), 15.6 ppm (1C, 6-
CH2CH2CH2CH3); IR (KBr): n˜ =3431 (br, -NH), 3286 (br, -NH), 1668
(C=O, amide), 1552, 1431, 1385, 1203, 1144, 800, 723 cmÀ1; HRMS
(FAB, NBA matrix): m/z calcd for C18H33N4O5: 385.2451 [M+H]; found:
385.2442 [M+H]+.
(R)-(À)-1-Benzyloxy-2,5-pentanediol (60): BH3·Me2S complex (5.16 mL,
48.8 mmol) was slowly added to a solution of 35 (4.70 g, 24.4 mmol) in
THF (122 mL) at 08C under argon. After stirring for 80 min, the reaction
mixture was quenched with 4.0n aqueous NaOH (65 mL) and 30% aque-
ous H2O2 (65 mL) at 08C, then the mixture was warmed up to RT, and
stirred for 2 h. The resulting mixture was extracted with EtOAc
(200 mL”3), the combined organic layers were washed with brine
(100 mL), dried over Na2SO4, filtered, and concentrated under reduced
pressure. Flash chromatography on silica gel (CHCl3/MeOH=100:1)
gave 60 as a colorless oil (4.50 g, 87%). Rf =0.20 (silica gel, CHCl3/
MeOH=10:1); [a]2D0 =À2.84 (c=1.00, CHCl3); 1H NMR (270 MHz,
CDCl3): d=7.40–7.26 (complex m, 5H; 1-O-CH2-Ph), 4.56 (s, 2H; 1-O-
CH2-Ph), 3.87 (ddd, J=1.1, 3.3, 7.9 Hz, 1H; 2-H), 3.51 (dd, J=3.3,
9.2 Hz, 1H; 1-H2), 3.66 (dt, J=3.9, 5.9 Hz, 2H; 5-H2), 3.36 (dd, J=7.9,
9.2 Hz, 1H; 1-H2), 2.06 (brs, 2H; 2-OH, 5-OH), 1.77–1.64 (complex m,
2H; 3-H2), 1.62–1.43 ppm (complex m, 2H; 4-H2); 13C NMR (67.5 MHz,
CDCl3): d=138.7, 129.2 (2C), 128.6 (2C), 128.5, 74.9, 73.7, 70.7, 63.0,
30.3, 29.1 ppm; IR (NaCl): n˜ =3365 (OH), 1454, 1093, 1059, 739,
698 cmÀ1; HRMS (FAB, NBA matrix): m/z calcd for C12H19O3:211.1334
[M+H]; found: 211.1342 [M+H]+.
(3R,5R,6R)-(+)-6-Butyl-5-(l-valinyl-l-alanyl)carbonyl-3-methyl-2-piper-
azinone (8): After dissolving 30 (15.9 mg, 29.4 mmol) in a solution of
TFA/H2O (3:1) (980 mL), the reaction solution was stirred for 2.5 h at
RT. The solution was diluted with H2O (1.0 mL) and evaporated under
reduced pressure. Purification by flash chromatography on silica gel
(CHCl3/MeOH=10:1) gave 8 as a white powder (14.4 mg, 98%). Rf =
0.14 (silica gel, CHCl3/MeOH=10:1); m.p. 129–1318C; [a]2D3 =+19.8 (c=
1.00, MeOH); 1H NMR (400 MHz, 1%TFA in D2O): d=4.53 (d, J=
4.5 Hz, 1H; 5-H), 4.35 (q, J=7.2 Hz, 1H; 2’-H), 4.16 (d, J=6.0 Hz, 1H;
2’’-H), 4.10 (q, J=7.0 Hz, 1H; 3-H), 3.93 (ddd, J=3.2, 4.2, 10.5 Hz, 1H;
6-H), 2.10 (dq, J=6.0, 6.6 Hz, 1H; 3’’-H), 1.52 (m, 1H; 6-
CH2CH2CH2CH3), 1.50 (d, J=7.0 Hz, 3H; 3-CH3), 1.45–1.35 (complex m,
3H; 6-CH2CH2CH2CH3), 1.32 (d, J=7.2 Hz, 3H; 3’-H3), 1.30–1.17 (com-
plex m, 2H; 6-CH2CH2CH2CH3), 0.88 (d, J=6.6 Hz, 6H; 3’’-(CH3)2),
0.78 ppm (t, J=6.6 Hz, 3H; 6-CH2CH2CH2CH3); 13C NMR (100 MHz,
1%TFA in D2O), reference 0–200 ppm, d=177.7 (C-1’’), 177.3 (C-1’),
170.7 (C-2), 167.7 (5-CO-NH-), 61.2 (C-2’’), 59.7 (C-5), 54.8 (C-3), 53.0
(C-6), 52.3 (C-2’), 33.0 (1C, 6-CH2CH2CH2CH3), 32.4 (C-3’’), 29.5 (1C, 6-
CH2CH2CH2CH3), 24.0 (1C, 6-CH2CH2CH2CH3), 20.9, 20.0 (each 1C, 3’’-
(CH3)2), 19.3 (C-3’), 16.4 (1C, 3-CH3), 15.5 ppm (1C, 6-
CH2CH2CH2CH3); IR (KBr): n˜ =3410 (C=O, -NH), 3278 (C=O, -NH),
1670 (C=O, amide), 1547, 1431, 1394, 1201, 1142, 723 cmÀ1; HRMS
(FAB, NBA matrix): m/z calcd for C18H33N4O5: 385.2451 [M+H]; found:
385.2459 [M+H]+.
(3R,5R,6R)-(À)-4-tert-Butoxycarbonyl-6-butyl-5-(O1-tert-butyl-d-valin-
yl-d-alanyl)-carbonyl-3-methyl-2-piperazinone (59): According to the
procedure of the compound 30, compound 59 (86.0 mg, 74% in 2 steps)
was obtained from 29 as a colorless oil (73.5 mg, 215 mmol). Rf =0.47
(silica gel, CHCl3/MeOH=10:1); [a]2D2 =+69.4 (c=1.00, CHCl3);
1H NMR (270 MHz, CDCl3): d=6.88 (d, J=6.6 Hz, 1H; 2’-NH), 6.68 (d,
J=7.9 Hz, 1H; 2’’-NH), 6.08 (brs, 1H; 1-H), 4.66 (brs, 1H; 5-H), 4.49–
4.39 (complex m, 2H; 3-H, 2’-H), 4.41 (dd, J=4.3, 7.9 Hz, 1H; 2’’-H),
3.61 (dt, J=4.3, 7.3 Hz, 1H; 6-H), 2.15 (dq, J=4.3, 6.9 Hz, 1H; 3’’-H),
1.81–1.69 (complex m, 2H; 6-CH2CH2CH2CH3), 1.50–1.22 (complex m,
(R)-(+)-1-Benzyloxy-2,5-di-(tert-butyldimethylsiloxy)-pentane (61): Imi-
dazole (6.66 g, 113 mmol) and TBSCl (11.1 g, 73.3 mmol) were added to
a solution of 60 (5.14 g, 24.4 mmol) in DMF (48.9 mL) at RT under
argon. After stirring for 2 h at RT, the reaction solution was diluted with
hexane/EtOAc (2/1) (800 mL), and the solution was washed with H2O
(600 mL”6), dried over Na2SO4, filtered, and evaporated under reduced
pressure. Purification by flash chromatography on silica gel (hexane/
EtOAc=15:1) gave 61 as a colorless oil (9.16 g, 95%). Rf =0.76 (silica
gel, hexane/EtOAc=2:1); [a]2D6 =+9.40 (c=1.00, CHCl3); 1H NMR
(270 MHz, CDCl3): d=7.36–7.23 (complex m, 5H; 1-O-CH2-Ph), 4.52 (s,
2H; 1-O-CH2-Ph), 3.84 (m, 1H; 2-H), 3.63–3.57 (complex m, 2H; 5-H2),
3.41 (dd, J=5.6, 9.6 Hz, 1H; 1-H2), 3.36 (dd, J=5.3, 9.6 Hz, 1H; 1-H2),
1.65–1.40 (complex m, 4H; 3-H2, 4-H2), 0.89 (s, 9H; 2-OSi
(CH3)3), 0.87 (s, 9H; 5-OSi[CH3]2C(CH3)3), 0.05 (s, 3H; 2-OSi
(CH3)3), 0.04 (s, 6H; 5-OSi[CH3]2C(CH3)3), 0.04 ppm (s, 3H; 2-OSi-
[CH3]2C
(CH3)3); 13C NMR (67.5 MHz, CDCl3): d=138.4, 128.2 (2C),
ACHTREUNG
A
G
A
ACHTREUNG
A
N
ACHTREUNG
4H; 6-CH2CH2CH2CH3), 1.50 (s, 9H; 4-CO-OC
A
A
ACHTREUNG
plex m, 3H; 3-CH3), 1.45 (s, 9H; 1’’-OC(CH3)3), 1.31 (d, J=6.9 Hz, 3H;
AHCTREUNG
127.5 (2C), 127.4, 74.7, 73.2, 71.3, 63.3, 31.0, 28.6, 26.0 (3C), 25.9 (3C),
3’-H3), 0.89 (d, J=6.9 Hz, 3H; 6-CH2CH2CH2CH3), 0.89 ppm (d, J=
6.9 Hz, 3H; 3’’-(CH3)2); 13C NMR (67.5 MHz, CDCl3): d=171.6 (C-2),
170.8 (C-1’), 170.0 (C-1’’), 168.3 (1C, 5-CO-NH-), 154.7 (1C, 4-CO-OC-
18.3 (2C), À4.38, À4.78, À5.28 ppm (2C); IR (NaCl) n˜ =1471,1255, 1099,
1051, 835, 775 cmÀ1
; HRMS (FAB, NBA matrix): m/z calcd for
C24H47O3Si2: 439.3064 [M+H]; found: 439.3063 [M+H]+.
(R)-(À)-2,5-Di-(tert-butyldimethylsiloxy)pentanol (62):
A
G
A
20
wt%
AHCTREUNG
Pd(OH)2/C (791 mg, 1.12 mmol) was added to a solution of 61 (5.10 g,
11.2 mmol) in EtOH (112.6 mL) at RT. After stirring for 20 min under
H2, the reaction solution was filtered through a Celite pad to remove the
Pd(OH)2 catalyst, then the pad was washed with EtOAc. The filtrate was
washed with a saturated aqueous solution of NaHCO3 (50 mL), dried
over Na2SO4, filtered, and evaporated to remove the solvent. Purification
by flash chromatography on silica gel (hexane/EtOAc=7:1) gave 62 as a
colorless oil (3.77 g, 96%). Rf =0.43 (silica gel, hexane/EtOAc=4:1);
[a]2D6 =À13.3 (c=2.00, CHCl3,); 1H NMR (270 MHz, CDCl3): d=3.75 (m,
1H; 2-H), 3.62–3.50 (complex m, 2H; 5-H2), 3.53 (dd, J=5.0, 11.2 Hz,
1H; 1-H2), 3.44 (dd, J=5.6, 11.2 Hz, 1H; 1-H2), 1.60–1.42 (complex m,
AHCTREUNG
18.9, 17.4 (each 1C, 3’’-(CH3)2), 18.0 (1C, 3-CH3), 18.0 (C-3’), 13.8 ppm
(1C, 6-CH2CH2CH2CH3); IR (KBr) n˜ =3300 (br, -NH), 1728 (C=O,
ester), 1689 (C=O, amide), 1531, 1456, 1371, 1331, 1159, 1132, 1070, 849,
756 cmÀ1; HRMS (FAB, NBA+NaI matrix): m/z calcd for C27H49N4O7:
541.3601 [M+Na]; found: 541.33597 [M+H]+.
(3R,5R,6R)-(+)-6-Butyl-5-(d-valinyl-d-alanyl)carbonyl-3-methyl-2-piper-
azinone (31): According to the procedure for 8, compound 31 (43.0 mg,
93%) was obtained from 59 as a TFA salt (50.1 mg, 45.0 mmol). Rf =0.14
(silica gel, CHCl3/MeOH=10:1); [a]2D3 =+70.9 (c=1.00, MeOH);
1H NMR (400 MHz, 1%TFA in D2O): d=4.49 (d, J=4.5 Hz, 1H; 5-H),
4.40 (q, J=7.2 Hz, 1H; 2’-H), 4.14 (d, J=5.8 Hz, 1H; 2’’-H), 4.09 (q, J=
7.2 Hz, 1H; 3-H), 3.89 (ddd, J=3.9, 4.5, 11.2 Hz, 1H; 6-H), 2.09 (dq, J=
5.8, 7.0 Hz, 1H; 3’’-H), 1.52–1.33 (complex m, 2H; 6-CH2CH2CH2CH3),
1.49 (d, J=7.2 Hz, 3H; 3-CH3), 1.33–1.10 (complex m, 4H; 6-
CH2CH2CH2CH3), 1.30 (d, J=7.2 Hz, 3H; 3’-H3), 0.86 (d, J=7.0 Hz, 6H;
3’’-(CH3)2), 0.76 ppm (t, J=7.0 Hz, 3H; 6-CH2CH2CH2CH3); 13C NMR
(100 MHz, 1%TFA in D2O), reference 0–200 ppm d=177.6 (C-1’’), 176.7
(C-1’), 170.6 (C-2), 167.5 (5-CO-NH-), 61.0 (C-2’’), 59.7 (C-5), 54.8 (C-3),
53.3 (C-6), 52.0 (C-2’), 32.9 (1C, 6-CH2CH2CH2CH3), 32.5 (C-3’’), 29.6
(1C, 6-CH2CH2CH2CH3), 24.2 (1C, 6-CH2CH2CH2CH3), 21.0, 19.9 (each
4H; 3-H2, 4-H2), 0.89 (s, 9H; 2-OSi
[CH3]2C(CH3)3), 0.07 (s, 6H; 5-OSi[CH3]2C
OSi[CH3]2C
(CH3)3); 13C NMR (67.5 MHz, CDCl3): d=72.7, 66.2, 63.1,
30.3, 28.5, 25.9 (3C), 25.8 (3C), 18.3, 18.0, À4.5, À4.6, À5.4 ppm (2C); IR
(NaCl): n˜ =3435 (-OH), 1473, 1464, 1255, 1099, 1049, 837, 775 cmÀ1
A
N
A
G
A
ACHTREUNG
A
ACHTREUNG
;
HRMS (FAB, NBA matrix): m/z calcd for C17H41O3Si2: 349.2594 [M+H];
found: 349.2583 [M+H]+.
A
chloride (4.75 mL, 43.6 mmol) was slowly added to a solution of DMSO
(7.73 mL, 109 mmol) in CH2Cl2 (160 mL) at À788C under argon. The so-
lution was stirred for 30 min, then 62 (7.60 g, 21.8 mmol) in CH2Cl2
8230
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 8220 – 8238

Total Synthesis of Guadinomines B and C2
FULL PAPER
(48.0 mL) was added dropwise at À788C. After stirring for 30 min, TEA
(18.2 mL, 131 mmol) was added to the solution at À788C, then it was
warmed to 08C. The mixture was stirred for 15 min, and quenched with a
saturated aqueous solution of NH4Cl (60 mL). Then the two layers were
separated and the aqueous layer was extracted with hexane/EtOAc (3:1)
(60 mL”2). The combined organic extracts were washed with a saturated
aqueous solution of NH4Cl (60 mL), a saturated aqueous solution of
NaHCO3 (60 mL), H2O (60 mL), and brine (60 mL), dried over Na2SO4,
filtered, and evaporated under reduced pressure to give 36, which was
used in the next reaction without further purification. A 1.0m solution of
vinylmagnesium bromide in THF (65.4 mL, 65.4 mmol) was added to a
solution of 36 (ꢀ21.8 mmol) in Et2O (218 mL) at À788C under argon.
After stirring for 35 min, the reaction mixture was poured through a
funnel into a stirred solution of saturated aqueous NaHCO3/hexane (1:1)
(200 mL), then the two layers mixture were separated, the organic layer
was washed with a saturated aqueous solution of NH4Cl (60 mL), a satu-
rated aqueous solution of NaHCO3 (60 mL), H2O (60 mL), and brine
(60 mL), dried over Na2SO4, filtered, and evaporated under reduced pres-
sure. Flash chromatography on silica gel (hexane/EtOAc=10:1) afforded
37 and the C3-epimer of 37 (5:1) as an inseparable mixture (6.84 g, 84%
926, 872 cmÀ1; HRMS (FAB, NBA matrix): m/z calcd for C10H19O3:
187.1334 [M+H]; found: 187.1337 [M+H]+.
A
4R)-(+)-7-Benzyloxy-3,4-O-isopropylidenehept-1-ene (C3-epi 38): 55%
NaH (1.20 g, 27.4 mmol) was added to a solution of the diastereomixture
(ca. 6:1) of 64 (3.40 g, 18.3 mmol) in THF (183 mL) at 08C under argon.
Then the mixture was warmed to 608C and stirred for 30 min and cooled
to RT. Then TBAI (8.80 g, 23.7 mmol) and BnBr (2.82 mL, 23.7 mmol)
were added to the mixture, and the resulting reaction mixture was heated
to 708C under stirring. After stirring for 6.5 h, the reaction mixture was
cooled to 08C and quenched with a saturated aqueous solution of NH4Cl,
then the two layers mixture was separated, the aqueous layer was extract-
ed with EtOAc (200 mL”4). The organic layers were washed with H2O
(80 mL) and brine (80 mL), dried over Na2SO4, filtered, and evaporated
under reduced pressure. Flash chromatography on silica gel (hexane/
EtOAc=20:1) afforded 38 (4.30 g, 85%; dr=>20:1) and C3-epi 38
(348 mg, 7%) as colorless oils. Major product 38: Rf =0.42 (silica gel,
hexane/EtOAc=4:1); [a]2D7 =+1.78 (c=1.00, CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.38–7.25 (complex m, 5H; 7-O-CH2-Ph), 5.82
(ddd, J=7.8, 10.2, 18.0 Hz, 1H; 2-H), 5.30 (ddd, J=1.0, 1.3, 18.0 Hz, 1H;
1-H2), 5.23 (ddd, J=1.0, 1.7, 10.2 Hz, 1H; 1-H2), 4.50 (s, 2H; 7-O-
CH2Ph), 4.49 (dd, J=7.8, 8.0 Hz, 1H; 3-H), 4.14 (ddd, J=6.0, 6.2, 8.0 Hz,
1H; 4-H), 3.57–3.44 (complex m, 2H; 7-H2), 1.80 (m, 1H; 6-H2), 1.66 (m,
1H; 6-H2), 1.60–1.48 (complex m, 2H; 5-H2),1.48 (s, 3H; 3, 4-O-iPr),
1.36 ppm (s, 3H; 3, 4-O-iPr); 13C NMR (67.5 MHz, CDCl3): d=137.9,
133.8, 127.7 (2C), 127.0 (2C), 126.8, 117.6, 107.5, 79.2, 77.4, 72.1, 69.3,
27.6, 26.5, 25.8, 25.0 ppm; IR (NaCl): n˜ =1454, 1369, 1248, 1215, 1099,
1045, 926, 737, 698 cmÀ1; HRMS (FAB, NBA matrix): m/z calcd for
C17H25O3: 277.1804 [M+H]; found: 277.1811 [M+H]+. Minor product
C3-epi 38: Rf =0.45 (silica gel, hexane/EtOAc=4:1); [a]2D6 =+0.52 (c=
1.00, CHCl3); 1H NMR (270 MHz, CDCl3): d=7.37–7.22 (complex m,
5H; 7-O-CH2-Ph), 5.80 (ddd, J=7.3, 10.2, 17.2 Hz, 1H; 2-H), 5.36 (ddd,
J=1.3, 1.3, 17.2 Hz, 1H; 1-H2), 5.24 (ddd, J=1.3, 1.6, 10.2 Hz, 1H; 1-H2),
4.50 (s, 2H; 7-O-CH2Ph), 4.00 (dd, J=7.3, 8.3 Hz, 1H; 3-H), 3.69 (ddd,
J=4.0, 7.6, 8.3 Hz, 1H; 4-H), 3.56–3.44 (complex m, 2H; 7-H2), 1.88–1.53
(complex m, 4H; 5-H2, 6-H2), 1.41 (s, 3H; 3, 4-O-iPr), 1.40 ppm (s, 3H;
3, 4-O-iPr); 13C NMR (67.5 MHz, CDCl3): d=138.5, 135.4, 128.3, 128.3,
127.6 (2C), 127.5, 118.9, 108.5, 82.7, 80.4, 72.8, 70.0, 28.4, 27.3, 26.9,
26.2 ppm; IR (NaCl): n˜ =1454, 1369, 1242, 1217, 1097, 1053, 928, 885,737,
698 cmÀ1; HRMS (FAB, NBA matrix): m/z calcd for C17H25O3: 277.1804
[M+H]; found: 277.1796 [M+H]+.
for
2
steps). Rf =0.53 (silica gel, hexane/EtOAc=4:1); 1H NMR
(270 MHz, CDCl3), major isomer is indicated. d=5.85 (ddd, J=6.3, 10.6,
16.8 Hz, 1H; 2-H), 5.30 (ddd, J=1.7, 1.7, 16.8 Hz, 1H; 1-H2), 5.19 (ddd,
J=1.7, 1.7, 10.6 Hz, 1H; 1-H2), 4.11 (m, 1H; 3-H), 3.72 (m, 1H; 4-H),
3.65–3.55 (complex m, 2H; 7-H2), 1.73–1.41 (complex m, 4H; 5-H2, 6-
H2), 0.91 (s, 6H; 4-OSi
(CH3)3), 0.89 (s, 9H; 7-OSi
(CH3)3), 0.09 (s, 3H; 4-OSi
[CH3]2C
(CH3)3); 13C NMR (67.5 MHz, CDCl3), major isomer is indicated.
A
N
ACHTREUNG
A
G
A
ACHTREUNG
A
N
ACHTREUNG
A
ACHTREUNG
d=136.6, 116.4, 75.8, 75.2, 63.2, 28.8, 28.1, 26.0 (3C), 25.9 (3C), 18.3,
18.1, À4.4 (2C), À5.3 ppm (2C); IR (NaCl): n˜ =3467 (OH), 1471, 1464,
1255, 1099, 837, 775 cmÀ1; HRMS (FAB, NBA+NaI matrix): m/z calcd
for C19H42O3Si2Na: 397.2570 [M+Na]; found: 397.2582 [M+Na]+.
A
in a 4n solution of HCl in dioxane (36.8 mL) and stirred for 20 min at
RT. Then the reaction mixture was concentrated under reduced pressure.
Flash chromatography on silica gel (CHCl3/MeOH=20:1) gave 63 as an
inseparable mixture of diastereomers (1.61 g, 94%). Rf =0.13 (silica gel,
CHCl3/MeOH=8:1); 1H NMR (270 MHz, CDCl3), major isomer is re-
ported d=5.93 (ddd, J=6.6, 10.6, 17.2 Hz, 1H; 2-H), 5.35 (ddd, J=1.3,
1.3, 17.2 Hz, 1H; 1-H2), 5.28 (ddd, J=1.3, 1.3, 10.6 Hz, 1H; 1-H2), 4.12
(ddd, J=1.3, 4.0, 6.6 Hz, 1H; 3-H), 3.79–3.61 (complex m, 3H; 4-H, 7-
H2), 1.96 (brs, 3H; 3-OH, 4-OH, 7-OH), 1.80–1.69 (complex m, 2H; 5-
H2), 1.65 (m, 1H; 7-H2), 1.47 ppm (m, 1H; 7-H2); 13C NMR (67.5 MHz,
CD3OD), major isomer is reported. d=139.0, 116.6, 77.3, 75.3, 63.0,
30.0 ppm (2C); IR (NaCl): n˜ =3367 (-OH), 1644, 1429, 1053, 997,
926 cmÀ1; HRMS (FAB, thioglycerol+glycerol matrix): m/z calcd for
C7H15O3: 147.1021 [M+H]; found: 147.1017 [M+H]+.
A
plex (656 mL, 6.77 mmol) was slowly added to a solution of 38 (1.70 g,
6.15 mmol) in THF (61.5 mL) at 08C under argon. After stirring for
30 min, the reaction mixture was warmed to RT and stirred for a further
2 h. The reaction was quenched with H2O (65 mL), NaBO3·4H2O (3.12 g,
20.3 mmol) and NaOH (271 mg, 6.77 mmol), then the mixture was
warmed to 508C with stirring for 90 min. The resulting two layers were
separated, and the aqueous layer was extracted with EtOAc (200 mL”2),
the combined organic layers were washed with H2O (100 mL) and brine
(100 mL), dried over Na2SO4, filtered, and concentrated under reduced
pressure. Flash chromatography on silica gel (CHCl3/MeOH=100:1) af-
forded 65 as a colorless oil (1.25 g, 69%). Rf =0.41 (silica gel, CHCl3/
MeOH=10:1); [a]2D7 =À17.8 (c=1.00, CHCl3); 1H NMR (270 MHz,
CDCl3): d=7.38–7.26 (complex m, 5H; 7-O-CH2Ph), 4.50 (s, 2H; 7-O-
CH2Ph), 4.25 (ddd, J=3.0, 5.9, 10.6 Hz, 1H; 3-H), 4.10 (dt, J=5.9, 7.9,
1H; 4-H), 3.82 (dt, J=3.3, 5.6 Hz, 2H; 7-H2), 3.59–3.44 (complex m, 2H;
1-H2), 1.91–1.70 (complex m, 4H; 2-H2, 5-H2), 1.70–1.50 (complex m,
2H; 6-H2), 1.45 (s, 3H; 3, 4-O-iPr), 1.33 ppm (s, 3H; 3, 4-O-iPr);
13C NMR (67.5 MHz, CDCl3): d=138.3, 128.2 (2C), 127.5 (2C), 127.4,
107.7, 77.5, 76.5, 72.7, 69.7, 60.6, 31.9, 28.3, 26.3, 26.3, 25.7 ppm; IR
A
pane (1.70 mL, 13.8 mmol) and TsOH·H2O (131 mg, 690 mmol) were
added to a solution of 63 (1.01 g, 6.90 mmol) in acetone (68.9 mL) at RT.
After stirring for 15 min, the reaction mixture was quenched with H2O
(4 mL) to remove the acetal on the primary alcohol. The mixture was
then diluted with brine (20 mL) and CHCl3 (100 mL), the resulting two
layers were separated. The aqueous layer was extracted with CHCl3
(100 mL”2), the combined organic layers were dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. Flash chromatography
on silica gel (hexane/EtOAc=6:1) afforded 64 (1.18 g, 92%) as a diaster-
eomixture (drꢀ6:1). Rf =0.12 (silica gel, hexane/EtOAc=4:1) for the
major isomer and 0.15 (silica gel, hexane/EtOAc=4:1) for the minor
isomer, 1H NMR (270 MHz, CDCl3), major isomer is reported d=5.81
(ddd, J=7.6, 10.2, 17.2 Hz, 1H; 2-H), 5.30 (ddd, J=1.0, 1.0, 17.2 Hz, 1H;
1-H2), 5.24 (ddd, J=1.0, 1.0, 10.2 Hz, 1H; 1-H2), 4.52 (dd, J=6.6, 7.6 Hz,
1H; 3-H), 4.16 (dt, J=6.6, 7.3 Hz, 1H; 4-H), 3.67 (t, J=5.9 Hz, 2H; 7-
H2), 1.80–1.58 (complex m, 4H; 5-H2, 6-H2), 1.49 (s, 3H; 3, 4-O-iPr),
1.37 ppm (s, 3H; 3, 4-O-iPr); 13C NMR (67.5 MHz, CDCl3), major isomer
is reported d=133.7, 117.7, 107.6, 79.2, 77.5, 61.6, 28.9, 27.5, 26.5,
25.0 ppm; IR (NaCl): n˜ =3438 (OH), 1379, 1371, 1246, 1217, 1047, 1016,
(NaCl): n˜ =3429 (-OH), 1367, 1246, 1217, 1093, 1057, 739, 698 cmÀ1
;
HRMS (FAB, NBA matrix): m/z calcd for C17H27O4: 295.1909 [M+H];
found: 295.1919 [M+H]+.
A
(66): Imidazole (429 mg, 6.32 mmol) and TBDPSCl (1.29 mL, 5.05 mmol)
were added to a solution of 65 (1.24 g, 4.21 mmol) in DMF (8.4 mL) at
RT under argon. After stirring for 40 min at RT, the reaction was
Chem. Eur. J. 2008, 14, 8220 – 8238
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8231

¯
T. Sunazuka, S. Omura et al.
quenched with H2O (10 mL) and extracted with EtOAc (20 mL”3). The
combined extracts were washed with 1n aqueous HCl (20 mL), a saturat-
ed aqueous solution of NaHCO3 (50 mL”2), H2O (50 mL), and brine
(50 mL), dried over Na2SO4, filtered, and evaporated under reduced pres-
sure to afford the crude product, which was used in the next reaction
without further purification. 20 wt% Pd(OH)2/C (296 mg, 421 mmol) was
added to a solution of crude product in EtOAc (42.1 mL) at RT. After
stirring for 2.5 h under H2, the reaction solution was filtered through a
Celite pad to remove the Pd(OH)2 catalyst, then the pad was washed
with EtOAc. The filtrate was concentrated, and purified by flash chroma-
tography on silica gel (hexane/EtOAc=4:1) to give 66 as a colorless oil
(1.45 g, 78% for 2 steps). Rf =0.22 (hexane/EtOAc=2:1); [a]2D3 =À7.80
(c=1.00, CHCl3); 1H NMR (270 MHz, CDCl3): d=7.80–7.63 (complex
(S)-(À)-5-tert-Butyldimethylsiloxy-1,2-pentanediol (68): Nitrosobenzene
(13.1 g, 122 mmol) was added to
a solution of d-proline (2.81 g,
24.4 mmol) in CHCl3 (250 mL). A solution of 39 (31.8 g, 147 mmol) in
CHCl3 (44.0 mL) was added dropwise to the reaction mixture over
10 min at 08C under argon, and stirred for 105 min. Then a solution of
NaBH4 (10.9 g, 294 mmol) in EtOH (118 mL) was added to the reaction
solution. After stirring for 30 min at 08C, a saturated aqueous solution of
NaHCO3 (100 mL) was poured into the reaction solution. The organic
layer was separated, washed with brine (100 mL), dried over Na2SO4, fil-
tered, and evaporated under reduced pressure. The crude product of 40
was dissolved in EtOAc (735 mL) and 10% wt Pd/C (15.6 g, 14.7 mmol)
was added. After stirring for 4 h under H2, the reaction solution was fil-
tered through a Celite pad to remove the Pd catalyst, then the pad was
washed with EtOAc. The filtrate solution was evaporated to remove the
solvent. Purification by flash chromatography on silica gel (hexane/
EtOAc=1:1) gave 68 as a colorless oil (13.7 g, 40% for 2 steps). Rf =0.10
m, 4H; 7-OSi(Ph)2C
A
ACHTREUNG
10.6 Hz, 1H; 4-H), 3.81 (t, J=6.3 Hz, 2H; 1-H2), 3.67 (dt, J=1.7, 6.0 Hz,
2H; 7-H2), 1.79–1.60 (complex m, 4H; 2-H2, 6-H2), 1.59–1.44 (complex
m, 2H; 3-H2), 1.39 (s, 3H; 4,5-O-iPr), 1.33 (s, 3H; 4,5-O-iPr), 1.05 ppm
1
(silica gel, hexane/EtOAc=1:1); [a]2D7 =À4.29 (c=1.00, CHCl3); H NMR
(270 MHz, CDCl3): d=3.76–3.58 (complex m, 4H; 1-H2, 2-H, 5-H2), 3.45
(dd, J=7.3, 9.9 Hz, 1H; 1-H2), 1.76–1.56 (complex m, 3H; 3-H2, 4-H2),
(s, 9H; 7-OSi(Ph)2C
(CH3)3); 13C NMR (67.5 MHz, CDCl3): d=135.4
A
1.48 (m, 1H; 4-H2), 0.89 (s, 9H; 5-OSi
N
N
(4C), 133.7, 133.6, 129.5, 127.7, 127.5 (4C), 107.4, 77.8, 74.6, 62.5, 60.9,
32.6, 29.6, 28.4, 26.8 (3C), 25.8, 20.9, 19.1 ppm; IR (NaCl): n˜ =3404 (-
OH), 1375, 1219, 1099, 1018, 743, 700, 611 cmÀ1; HRMS (FAB, NBA
matrix): m/z calcd for C26H39O4Si 443.2618 [M+H]; found: 443.2617
[M+H]+.
5-OSi[CH3]2C
N
N
31.0, 29.1, 25.9 (3C), 18.3, À5.4 ppm (2C); IR (NaCl): n˜ =3363 cmÀ1
(OH); HRMS (FAB, NBA matrix): m/z calcd for C11H27O3Si: 235.1729
[M+H]; found: 235.1732 [M+H]+.
A
(4S,2’S,3’R,6’R,7’S)-(+)-3-[9’-(tert-Butyldiphenylsilyloxy)-2’-chloro-3’-hy-
1,3-dioxolane (69): p-Anisaldehyde dimethylacetal (3.92 mL, 23.0 mmol)
and PPTS (386 mg, 1.53 mmol) were added to a solution of 68 (3.60 g,
15.3 mmol) in CH2Cl2 (153 mL) at 08C. After stirring for 100 min, the re-
droxy-6’,7’-O-isopropylidenenonanoyl]-4-benzyloxazolidinone
(67):
Oxalyl chloride (1.07 mL, 12.3 mmol) was slowly added to a solution of
DMSO (1.74 mL, 24.5 mmol) in CH2Cl2 (50.0 mL) at À788C under Ar.
The solution was stirred for 20 min, then 66 (2.70 g, 6.12 mmol) in
CH2Cl2 (11.2 mL) was added dropwise at À788C. After stirring for
30 min at À788C, TEA (4.27 mL, 30.6 mmol) was added to the solution,
and then it was warmed to 08C. The mixture was stirred for 10 min, and
quenched with a saturated aqueous solution of NH4Cl (20 mL). Then the
two layers were separated, and the aqueous layer was extracted with
hexane/EtOAc (1/1) (40 mL”2). The combined organic extracts were
washed with H2O (60 mL), saturated aqueous NH4Cl (60 mL), saturated
aqueous NaHCO3 (60 mL), and brine (60 mL), dried over Na2SO4, fil-
tered, and evaporated under reduced pressure to give anti-33, which was
used in the next reaction without further purification. Et3N (2.13 mL,
15.3 mmol) was added to a solution of (S)-16 (3.11 g, 12.3 mmol) in
CH2Cl2 (75.5 mL) at À788C, followed by nBu2BOTf (1.0m in CH2Cl2,
12.6 mL, 12.6 mmol). The solution was stirred for 1 h at À788C and for
1 h at RT. After the solution was cooled to À788C, crude anti-33 in
CH2Cl2 (12.1 mL) was added. After stirring for 10 min at À788C, the re-
action mixture was warmed to 08C, stirred for 80 min, and then quenched
with phosphate buffer (Ph 7.2, 20 mL), 30% aqueous H2O2/MeOH (1:2;
10 mL), and stirred for a further 1 h at RT. The resulting mixture was ex-
tracted with CHCl3 (80 mL”3) and the combined extracts were washed
with brine (100 mL), dried over Na2SO4, filtered, and concentrated. Flash
chromatography (hexane/EtOAc=2:1) gave 67 as a colorless oil (2.77 g,
65% for 2 steps). Rf =0.35 (silica gel, hexane/EtOAc=2:1); [a]2D8 =+24.5
(c=1.00, CHCl3); 1H NMR (270 MHz, CDCl3): d=7.70–7.63 (complex
action mixture was quenched with
a saturated aqueous solution of
NaHCO3 (70 mL), and the resulting two layers were separated. The
aqueous layer was extracted with CHCl3 (100 mL”), the combined or-
ganic layers were washed with H2O (50 mL) and brine (50 mL), dried
over Na2SO4, filtered, and concentrated under reduced pressure. The
crude product was diluted with EtOH (40 mL) and treated with NaBH4
(1.5 g, 39.7 mmol) under stirring for 10 min. H2O (100 mL) was added to
the resulting mixture, and it was extracted with CHCl3 (120 mL”3). The
combined organic layers were dried over Na2SO4, filtered, and concen-
trated under reduced pressure. Flash chromatography on NH-silica(NH,
100ꢀ200 mm; purchased from Fuji Silysia; hexane/EtOAc=200:1) afford-
ed 69 as a colorless oil (5.00 g, 92%). Rf =0.64 (silica gel, hexane/
EtOAc=1:1); 1H NMR (270 MHz, CDCl3), as a mixture of two diaste-
reomers d=7.41 (t, J=6.6 Hz, 4/5H; 2-O-Ph-CH3), 7.40 (t, J=5.0 Hz, 6/
5H; 2-O-Ph-CH3), 6.90 (d, J=8.3 Hz, 2H; 2-O-Ph-CH3), 5.87 (s, 2/5H;
2-H), 5.76 (s, 3/5H; 2-H), 4.36–4.15 (m, 7/5H; 5-H2), 4.09 (t, J=6.9 Hz, 3/
5H; 5-H2), 3.81 (s, 3H; 2-CH-Ph-OCH3), 3.75–3.54 (complex m, 1H; 4-
H), 3.75–3.54 (complex m, 2H; 1’-H2), 1.85–1.53 (complex m, 2H; 2’-H2),
1.85–1.53 (complex m, 2H; 3’-H2), 0.90 (s, 9H; 1’-OSi
N
N
0.05 ppm (s, 6H; 1’-OSi[CH3]2C
A
ACHTREUNG
a mixture of two diastereomers d=161.0, 131.0 (3/5C), 130.0 (2/5C),
128.0, 127.8, 113.7 (2C), 104.0 (3/5C), 102.9 (2/5C), 76.3, 70.8 (3/5C),
70.0 (2/5C), 62.8, 55.2, 30.0 (3/5C), 29.8 (2/5C), 29.0, 25.9 (3C), 18.3,
À5.3 ppm (2C); HRMS (FAB, NBA matrix): m/z calcd for C19H33O4Si:
353.2148 [M+H]; found: 351.1995 [M+H]+.
m, 4H; 9’-O-Si(Ph)2C
A
(S)-(+)-5-(tert-Butyldimethylsiloxy)-2-(p-methoxybenzyloxy)-1-pentanol
(70): DIBAL-H solution (0.94m in hexane, 45.3 mL, 42.5 mmol) was
added dropwise over 20 min to a solution of 69 (5.00 g, 14.1 mmol) in
CH2Cl2 (141 mL) at À788C under argon. After stirring for 1 h, the solu-
tion was quenched by the addition of a saturated aqueous solution of Ro-
chelleꢁs salt (100 mL) and stirred for 1 h at RT. The organic layer was
then separated, and the aqueous layer was extracted with CHCl3
(150 mL”3). The combined organic extracts were washed with a saturat-
ed aqueous solution of Rochelleꢁs salt (75 mL”3), dried over Na2SO4, fil-
tered, and evaporated under reduced pressure. Purification by flash chro-
matography on silica gel (hexane/EtOAc=5:1) gave 70 as colorless oil
(4.69 g, 93%; >99% ee). Rf =0.15 (silica gel, hexane/EtOAc=1:1);
[a]2D7 =+16.0 (c=1.00, CHCl3); 1H NMR (270 MHz, CDCl3): d=7.27 (d,
J=8.6 Hz, 2H; 2-O-CH2-Ph-OCH3), 6.88 (d, J=8.6 Hz, 2H; 2-O-CH2-
Ph-OCH3), 4.56 (d, J=11.2 Hz, 1H; 2-O-CH2-Ph-OCH3), 4.46 (d, J=
11.2 Hz, 1H; 2-O-CH2-Ph-OCH3), 3.80 (s, 3H; 2-O-CH2-Ph-OCH3), 3.61
O-Si(Ph)2C(CH3)3), 7.26–7.21 (complex m, 2H; 4-CH2Ph), 5.68 (d, J=
ACHTREUNG
3.3 Hz, 1H; 2’-H), 4.72 (dddd, J=3.3, 3.6, 6.9, 9.6 Hz, 1H; 4-H), 4.32
(ddd, J=3.3, 5.9, 7.2 Hz, 1H; 3’-H), 4.26 (d, J=6.9 Hz, 1H; 4-CH2Ph),
4.26 (d, J=3.6 Hz, 1H; 4-CH2Ph), 4.15 (m, 1H; 6’-H), 4.07 (m, 1H; 7’-
H), 3.81 (t, J=6.9 Hz, 2H; 9’-H2), 3.33 (dd, J=3.3, 13.5 Hz, 1H; 5-H2),
2.83 (dd, J=9.6, 13.5 Hz, 1H; 5-H2), 1.89–1.57 (complex m, 6H; 4’-H2, 5’-
H2, 8’-H2), 1.38 (s, 3H; 6’, 7’-O-iPr), 1.32 (s, 3H; 6’, 7’-O-iPr), 1.05 ppm
(s, 9H; 9-O-Si(Ph)2C
(CH3)3); 13C NMR (67.5 MHz, CDCl3): d=167.8,
A
152.5, 135.5 (2C), 135.3 (2C), 134.5, 133.6, 133.5, 129.4 (2C), 129.2 (2C),
128.8 (2C), 127.6, 127.4 (2C), 127.2, 107.4, 77.2, 74.3, 71.0, 66.3, 60.7,
59.8, 55.2, 36.9, 32.4, 30.6, 28.3, 26.8, 26.7 (3C), 26.0, 25.8, 18.9 ppm; IR
(NaCl): n˜ =3558 (-OH), 3431 (-NH), 1782 (C=O, imide), 1711 (C=O,
amide), 1389, 1213, 1111, 1084, 760, 742, 702 cmÀ1; HRMS (FAB, NBA+
NaI matrix): m/z calcd for C38H49NO7SiClNa: 716.2796 [M+Na]; found:
716.2786 [M+Na]+.
8232
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 8220 – 8238

Total Synthesis of Guadinomines B and C2
FULL PAPER
(t, J=5.9 Hz, 2H; 5-H), 3.73–3.48 (complex m, 3H; 1-H2, 2-H), 1.70–1.51
25.9 (3C), 18.3, À5.3 ppm (2C); IR (NaCl): n˜ =3425 cmÀ1 (OH); HRMS
(FAB, NBA matrix): m/z calcd for C21H39O5Si: 399.2567 [M+H]; found:
399.2561 [M+H]+.
(complex m, 4H; 3-H2, 4-H2), 0.89 (s, 9H; 5-OSi
N
N
0.05 ppm (s, 6H; 5-OSi[CH3]2C
A
ACHTREUNG
d=159.3, 130.5, 129.4 (2C), 113.9 (2C), 79.2, 71.1, 64.2, 63.0, 55.3, 28.5,
27.0, 26.0 (3C), 18.3, À5.3 ppm (2C); IR (NaCl): n˜ =3437 cmÀ1 (-OH);
HRMS (FAB, NBA matrix): m/z calcd for C19H35O4Si: 355.2305 [M+H];
found: 355.2312 [M+H]+.
A
(93.9 mg, 768 mmol), TEA (1.61 mL, 11.5 mmol) and TBDPSCl (2.36 mL,
9.22 mmol) were added to a solution of 71 (3.06 g, 7.68 mmol) in CH2Cl2
(76.8 mL) at 08C under argon. After stirring for 3 h, the mixture was
warmed to RT and stirred for a further 3.5 d. The reaction was quenched
with a saturated aqueous solution of NH4Cl (30 mL) and extracted with
CHCl3 (80 mL”3). The combined extracts were washed with brine
(80 mL), dried over Na2SO4, filtered, and evaporated under reduced pres-
sure to afford crude product, which was used in the next reaction without
further purification. 20 wt% Pd(OH)2/C (539 mg, 768 mmol) was added
to a solution of crude product in EtOAc (76.8 mL) at RT. After stirring
for 2 h under H2, the reaction solution was filtered through a Celite pad
to remove the Pd(OH)2 catalyst, then the pad was washed with EtOAc.
The filtrate was concentrated, and purification by flash chromatography
on silica gel (CHCl3/MeOH=10:1) gave 72 as a colorless oil (2.80 g,
90% for 2 steps). Rf =0.70 (silica gel, hexane/EtOAc=2:1); [a]2D6 =À1.22
A
benzyloxy)thioheptanate (42): Oxalyl chloride (0.956 mL, 10.9 mmol) was
slowly added over 5 min to a solution of DMSO (1.55 mL, 21.9 mmol) in
CH2Cl2 (50.0 mL) at À788C under argon. The solution was stirred over
15 min, then 70 (1.94 g, 5.48 mmol) in CH2Cl2 (4.8 mL) was added drop-
wise at À788C. After stirring for 30 min at À788C, TEA (3.82 mL,
27.4 mmol) was added to the solution, and then it was warmed to 08C.
The mixture was stirred for 15 min, and quenched with H2O (20 mL).
Then the two layers were separated, and the aqueous layer was extracted
with hexane/EtOAc (1/1; 100 mL). The combined organic extracts were
washed with H2O (30 mL”2), saturated aqueous NH4Cl (30 mL), saturat-
ed aqueous NaHCO3 (30 mL), and brine (10 mL”2), dried over Na2SO4,
filtered, and evaporated under reduced pressure to give crude aldehyde
41, which was used in the next reaction without further purification.
TiCl4 (1.0m in CH2Cl2; 4.52 mL, 4.52 mmol) was added to a solution of
(c=1.00, CHCl3); H NMR (270 MHz, CDCl3) d=7.70–7.62 (complex m,
4H; 7-OSi(Ph)2C
AHCTREUNG
Ti
for 30 min, the mixture, as a solution of TiCl3
À788C. Crude aldehyde 41 in CH2Cl2 (40 mL) was added by using a can-
nula to a solution of TiCl3
(O-iPr) in CH2Cl2 at À788C, and the resulting
ACHTREUNG
3.76 (m, 1H; 5-H), 3.73–3.60 (complex m, 2H; 7-H2), 3.50 (m, 1H; 4-H),
1.89–1.47 (complex m, 2H; 6-H2), 1.89–1.47 (complex m, 4H; 3-H2, 2-
AHCTREUNG
H2), 1.04 ppm (s, 9H; 7-OSi(Ph)2C
(CH3)3); 13C NMR (67.5 MHz, CDCl3):
A
AHCTREUNG
d=135.4 (4C), 132.9 (2C), 129.8 (2C), 127.7 (4C), 74.3, 73.5, 62.6, 60.4,
35.1, 30.4, 29.1, 26.7 ppm (3C); IR (NaCl) n˜ =3425 cmÀ1 (-OH), 1513
(Ar-C); HRMS (FAB, NBA PEG 200+400+NaI matrix): m/z calcd for
C23H34O4SiNa: 425.2124 [M+Na]; found: 425.2126 [M+Na]+.
mixture was stirred for 10 min. 1-Ethylthio-1-trimethylsilyloxyethene
(1.95 mL, 9.90 mmol) was then added to the mixture. After stirring for
2 h, the cooled mixture was added to a saturated aqueous solution of
NaHCO3 (60 mL)by using a cannula with stirring at RT over 30 min. The
resulting mixture was extracted with CHCl3 (80 mL) and the extracts was
washed with a saturated aqueous solution of NaHCO3 (60 mL) and brine
(60 mL), dried over Na2SO4, filtered, and concentrated. Flash chromatog-
raphy (hexane/EtOAc=5:1) gave 42 as a colorless oil (1.61 g, 64% for 2
steps; >99% ee). Rf =0.5 (silica gel, hexane/EtOAc=2:1); [a]2D5 =+1.93
(c=1.00, CHCl3); 1H NMR (270 MHz, CDCl3): d=7.27–7.20 (complex
m, 2H; 4-OCH2-Ph-OCH3), 6.91–6.85 (complex m, 2H; 4-OCH2-Ph-
OCH3), 4.57 (d, J=10.9 Hz, 1H; 4-OCH2-Ph-OCH3), 4.45 (d, J=10.9 Hz,
1H; 4-OCH2-Ph-OCH3), 4.12 (ddd, J=2.3, 6.3, 10.6 Hz, 1H; 3-H), 3.81
(s, 3H; 4-OCH2-Ph-OCH3), 3.61 (t, J=5.6 Hz, 2H; 7-H2), 3.37 (dd, J=
4.6, 8.9 Hz, 1H; 4-H), 2.90 (q, J=7.6 Hz, 2H; 1-SCH2CH3), 2.74 (appar-
ent d, J=7.0 Hz, 2H; 2-H2), 1.76–1.54 (complex m, 2H; 5-H2), 1.76–1.54
(complex m, 2H; 6-H2), 1.25 (t, J=7.3 Hz, 3H; 1-SCH2CH3), 0.90 (s, 9H;
A
(73): 2,2-Dimethoxypropane (1.60 mL, 13.0 mmol) and TsOH·H2O
(124 mg, 651 mmol) were added to a solution of 72 (2.62 g, 6.51 mmol) in
acetone (65.1 mL) at RT. After stirring for 5 min, the reaction mixture
was quenched with a saturated aqueous solution of NaHCO3 (20 mL).
The resulting two layers were separated, and the aqueous layer was ex-
tracted with CHCl3 (60 mL”3), the combined organic layers were dried
over Na2SO4, filtered, and concentrated under reduced pressure. Flash
chromatography on silica gel (hexane/EtOAc=2:1) afforded 73 as a col-
orless oil (2.80 g, 97%). Rf =0.30 (silica gel, hexane/EtOAc=3:1); [a]D25
=
1
À19.1 (c=1.00, CHCl3); H NMR (270 MHz, CDCl3): d=7.69–7.64 (com-
plex m, 4H; 7-OSi(Ph)2C
A
OSi(Ph)2C(CH3)3), 3.83 (m, 1H; 5-H), 3.88–3.78 (complex m, 2H; 1-H2),
AHCTREUNG
3.71–3.61 (complex m, 2H; 7-H2), 3.66 (m, 1H; 4-H), 1.87–1.64 (complex
7-OSi
A
N
G
N
m, 6H; 2-H2, 3-H2, 6-H2), 1.38 (s, 3H; 3,4-OiPr), 1.36 (s, 3H; 3,4-OiPr),
(67.5 MHz, CDCl3): d=198.5, 159.3, 130.2, 129.5 (2C), 113.8 (2C), 80.1,
71.8, 69.4, 63.0, 55.2, 47.4, 28.6, 26.0, 25.9 (3C), 23.4, 14.5, 18.3, À5.3 ppm
(2C); IR (NaCl): n˜ =3425 cmÀ1 (-OH), 1685 (C=O, ester); HRMS (FAB,
NBA matrix): m/z calcd for C23H40O5SSiNa: 479.2263 [M+Na]; found:
479.2245 [M+Na]+.
1.05 ppm (s, 9H; 1-OSi(Ph)2C
(CH3)3); 13C NMR (67.5 MHz, CDCl3): d=
C
135.5 (4C), 133.6 (2C), 129.6 (2C), 127.6 (4C), 108.1, 80.8, 77.6, 62.6,
60.6, 35.5, 29.5, 29.2, 27.2, 27.1, 26.8 (3C), 19.1 ppm; IR (NaCl): n˜ =
3425 cmÀ1 (OH); HRMS (FAB, NBA matrix): m/z calcd for C26H39O4Si:
443.2618 [M+H]; found: 443.2626 [M+H]+.
A
(4S,2’S,3’R,6’S,7’S)-(À)-3-[9’-(tert-Butyldiphenylsilyloxy)-2’-chloro-3’-hy-
droxy-6’,7’-O-isopropylidenenonanoyl]-4-benzyloxazolidinone (74): Ac-
cording to the procedure for 67, compound 74 (2.69 g, 62% for 2 steps)
was obtained from 73 (2.69 g, 6.08 mmol). Rf =0.39 (silica gel, hexane/
EtOAc=2:1); [a]2D5 =À6.0 (c=1.26, CHCl3); 1H NMR (400 MHz,
loxy)heptanol (71): The solution of 42 (4.06 g, 8.90 mmol) in THF
(44.5 mL) was treated with LiBH4 (0.969 g, 44.5 mmol) under stirring for
2 h at À108C. A saturated aqueous solution of NaHCO3 (20 mL), then
H2O (20 mL), and EtOAc (200 mL) were added to the resulting mixture.
The two layers mixture was separated, and the aqueous layer was extract-
ed with EtOAc (200 mL”4). The combined organic layers were washed
with H2O (80 mL) and brine (80 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure. Flash chromatography on silica gel
(hexane/EtOAc=1:1) afforded 71 as a colorless oil (3.11 g, 88%). Rf =
0.10 (silica gel, hexane/EtOAc=2:1); [a]2D5 =+12.4 (c=1.00, CHCl3);
1H NMR (270 MHz, CDCl3): d=7.28–7.20 (complex m, 2H; 4-O-CH2-
Ph-OCH3), 7.00–6.83 (complex m, 2H; 4-O-CH2-Ph-OCH3), 4.43 (d, 1H;
J=10.9 Hz, 4-O-CH2-Ph-OCH3), 4.42 (d, J=10.9 Hz, 1H; 4-O-CH2-Ph-
OCH3), 3.89–3.74 (complex m, 3H; 1-H2, 3-H), 3.81 (s, 3H; 4-O-CH2-Ph-
OCH3), 3.62 (t, J=5.6 Hz, 2H; 7-H2), 3.34 (apparent dd, J=4.9, 5.9 Hz,
1H; 4-H), 1.75–1.68 (complex m, 2H; 2-H2), 1.63–1.52 (complex m, 4H;
CDCl3): d=7.70–7.66 (complex m, 4H; 9’-O-Si(Ph)2C(CH3)3), 7.43–7.29
G
(complex m, 3H; 4-CH2Ph), 7.43–7.29 (complex m, 6H; 9’-O-Si(Ph)2C-
(CH3)3), 7.26–7.21 (complex m, 2H; 4-CH2Ph), 5.70 (d, J=3.2 Hz, 1H;
AHCTREUNG
2’-H), 4.73 (dddd, J=3.2, 3.5, 7.0, 9.1 Hz, 1H; 4-H), 4.27 (dd, J=7.0,
9.0 Hz, 1H; 4-CH2Ph), 4.23 (dd, J=3.5, 9.0 Hz, 1H; 4-CH2Ph), 4.17 (ddd,
J=3.2, 5.0, 8.7 Hz, 1H; 3’-H), 3.86 (ddd, J=5.0, 8.5, 9.0 Hz, 1H; 7’-H),
3.84 (t, J=6.0 Hz, 2H; 9’-H2), 3.68 (ddd, J=2.7, 8.5, 8.5 Hz, 1H; 6’-H),
3.35 (dd, J=3.2, 13.5 Hz, 1H; 5-H2), 2.84 (dd, J=9.1, 13.5 Hz, 1H; 5-H2),
1.88 (m, 1H; 8’-H2), 1.87 (m, 1H; 5’-H2), 1.86–1.78 (complex m, 2H; 4’-
H2), 1.75 (m, 1H; 8’-H2), 1.58 (m, 1H; 5’-H2), 1.39 (s, 3H; 6’, 7’-O-iPr),
1.36 (s, 3H; 6’, 7’-O-iPr), 1.06 ppm (s, 9H; 9-O-Si(Ph)2C
13C NMR (75.0 MHz, CDCl3): d=168.2 (C-1’), 152.6 (C-2), 135.5 (2C, 9’-
O-Si(Ph)2C(CH3)3), 135.5 (2C, 9’-O-Si(Ph)2C(CH3)3), 134.6 (1C, 4-
CH2Ph), 133.8 (1C, 9’-O-Si(Ph)2C(CH3)3), 133.7 (1C, 9’-O-Si(Ph)2C-
A
5-H2, 6-H2), 0.90 (s, 9H; 7-OSi
[CH3]2C
(CH3)3); 13C NMR (67.5 MHz, CDCl3): d=159.3, 130.2, 129.5
(2C), 113.9 (2C), 81.1, 72.7, 71.9, 63.0, 61.3, 55.2, 34.7 (C-2), 28.0, 26.1,
A
G
A
N
A
ACHTREUNG
AHCTREUNG
Chem. Eur. J. 2008, 14, 8220 – 8238
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8233

¯
T. Sunazuka, S. Omura et al.
A
G
1.33 (complex m, 2H; 4-H2), 1.37 (s, 3H; 6,7-O-iPr), 1.31 (s, 3H; 6,7-O-
iPr), 1.31 (t, J=7.3 Hz, 3H; 1-OCH2CH3), 1.05 ppm (s, 9H; 9-O-
ACHTREUNG
Si(Ph)2C
(CH3)3); 13C NMR (67.5 MHz, CDCl3): d=172.4, 135.4 (4C),
A
G
133.6, 133.5, 129.4 (2C), 127.5 (2C), 127.5 (2C), 107.4, 77.5, 74.4, 61.3,
60.8, 39.2, 35.2, 32.5, 29.6, 28.4, 27.5, 26.7 (3C), 25.8, 19.0, 14.0 ppm; IR
(NaCl): n˜ =3286 (NH), 1741 (C=O, ester), 1462, 1429, 1369, 1217, 1111,
1088, 823, 702, 688, 613 cmÀ1; HRMS (FAB, NBA matrix): m/z calcd for
C30H44NO5Si: 526.2989 [M+H]; found: 526.2993 [M+H]+. cis-77: Rf =
0.23 (silica gel, hexane/EtOAc=1:1); [a]2D6 =+14.6 (c=1.00, CHCl3);
1H NMR (270 MHz, CDCl3): d=7.75–7.62 (complex m, 4H; 9-O-
108.1 (1C, 6’,7’-O-iPr), 80.6 (C-6’), 77.5 (C-7’), 71.3 (C-3’), 66.5 (C-5),
60.6 (C-9’), 59.8 (C-2), 55.4 (C-4), 37.2 (1C, 4-CH2Ph), 35.5 (C-8), 30.6
(C-4’), 28.3 (C-5’), 27.3 (1C, 6’,7’-O-iPr), 27.2 (1C, 6’,7’-O-iPr), 26.8 (3C,
9’-O-Si(Ph)2C
N
N
n˜ =3444 (-OH), 1782 (C=O, imide), 1711 cmÀ1 (C=O, amide); HRMS
(FAB, NBA matrix): m/z calcd for C38H49NO7SiCl: 694.2967 [M+H];
found: 694.2987 [M+H]+.
Si(Ph)2C
N
A
(2S,3R,6R,7S)-Ethyl-9-(tert-butyldiphenylsilyloxy)-2,3-epoxy-6,7-O-iso-
propylidenenonanate (major) and (2R,3R,6R,7S)-ethyl-9-(tert-butyldi-
phenylsilyloxy)-2,3-epoxy-6,7-O-isopropylidenenonanate (minor) (75):
NaH (60 wt% in mineral oil, 176 mg, 4.39 mmol) was added to a solution
of chlorohydrin 74 (2.77 g, 3.99 mmol) in EtOH (20.0 mL) at 08C. After
stirring for 20 min, a saturated aqueous solution of NH4Cl (15 mL) and
CHCl3 (80 mL) were added to the reaction mixture. The organic layer
was separated, and the aqueous layer was extracted with CHCl3 (40 mL”
2), dried over Na2SO4, filtered, and evaporated under reduced pressure.
Purification by flash chromatography on silica gel (hexane/EtOAc=10:1)
gave a mixture of trans- and cis-75 (5.8:1) as a colorless oil (1.85 g, 88%).
Rf =0.58 (silica gel, hexane/EtOAc=2:1); [a]2D5 =+11.2 (c=1.00, CHCl3)
as mixture of trans and cis (5.8:1); 1H NMR (270 MHz, CDCl3), major
(m, 1H; 7-H), 4.21 (dq, J=2.3, 6.9 Hz, 2H; 1-OCH2CH3), 4.05 (dd, J=
5.9, 12.9 Hz, 1H; 6-H), 3.81 (t, J=6.3 Hz, 2H; 9-H2), 2.65 (brd, J=
5.6 Hz, 1H; 2-H), 2.28–2.18 (brm, 1H; 3-H), 1.82–1.45 (complex m, 6H;
4-H2, 5-H2, 8-H2), 1.36 (s, 3H; 6,7-O-iPr), 1.31 (s, 3H; 6,7-O-iPr), 1.29 (t,
J=6.9 Hz, 2H; 1-OCH2CH3), 1.05 ppm (s, 9H; 9-O-Si(Ph)2C(CH3)3); IR
N
(NaCl): n˜ =3446 (-NH), 1728 (C=O, ester), 1653, 1462, 1423, 1379, 1248,
1217, 1198, 1111, 1086, 1032, 823, 741, 704 cmÀ1; HRMS (FAB, NBA+
NaI matrix): m/z calcd for C30H44NO5Si: 548.2808 [M+Na]; found:
548.2784 [M+Na]+.
(2S,3S,6R,7S)-(À)-Ethyl-2-azido-9-(tert-butyldiphenylsilyloxy)-3-(p-ni-
trobenzensulfonylimino)-6,7-O-isopropylidenenonanate
TEA
(312 mg,
(327 mL,
2.35 mmol),
4-nitrobenzenesulfonyl
1.41 mmol), and DMAP (28.7 mg, 235 mmol) were added to a solution of
trans-77 (247 mg, 470 mmol) in CH2Cl2 (9.40 mL) under argon at 08C, and
then warmed to RT. After stirring for 4 h at RT, the reaction solution
was quenched with a saturated aqueous solution of NH4Cl (7.0 mL), the
organic layer was separated and the aqueous layer was extracted with
CHCl3 (10 mL”3). The combined organic extracts were washed with a
saturated aqueous solution of NaHCO3 (10 mL), a saturated aqueous so-
lution of NH4Cl (10 mL”2), H2O (10 mL), and brine (10 mL), dried over
Na2SO4, filtered, and evaporated under reduced pressure. The residue
was roughly purified with silica gel (hexane/EtOAc=2:1) to provide the
residue of Ns-aziridine. The residue was dissolved in DMF (4.70 mL),
and then NaN3 (61.2 mg, 0.940 mmol) was added to the solution at 08C
under argon, and then the reaction mixture was warmed to RT. After stir-
ring for 1 h, the solution was diluted with hexane/EtOAc (2:1; 20 mL).
The mixture was washed with H2O (10 mL”6), dried over Na2SO4, fil-
tered, and evaporated under reduced pressure to provide a crude mix-
ture. Flash chromatography on silica gel (hexane/EtOAc=6:1) gave 78
as a colorless oil (331 mg, 93% for 2 steps; >20:1=a-/b-N3). Rf =0.62
isomer is indicated. d=7.70–7.63 (complex m, 4H; 9-O-Si(Ph)2C
G
7.47–7.33 (complex m, 6H; 9-O-Si(Ph)2C(CH3)3), 4.32–4.11 (complex m,
AHCTREUNG
2H; 1-OCH2CH3), 4.27 (m, 1H; 7-H), 4.07 (ddd, J=3.6, 5.3, 9.2 Hz, 1H;
6-H), 3.81 (t, J=6.6 Hz, 2H; 9-H2), 3.23 (d, 1.7 Hz, 1H; 2-H), 3.21 (m,
1H; 3-H), 1.92–1.42 (complex m, 6H; 4-H2, 5-H2, 8-H2), 1.37 (s, 3H; 6,7-
O-iPr), 1.32 (s, 3H; 6,7-O-iPr), 1.30 (t, J=7.3 Hz, 3H; 1-OCH2CH3),
1.5 ppm (s, 9H; 9-O-Si(Ph)2C
(CH3)3); 13C NMR (67.5 MHz, CDCl3),
A
major isomer is indicated. d=168.8, 135.3 (2C), 135.2 (2C), 133.4, 133.3,
129.3 (2C), 127.4 (2C), 127.4 (2C), 107.3, 76.5, 74.3, 61.1, 60.7, 57.5, 52.7,
32.3, 28.2, 27.8, 26.6 (3C), 25.8, 25.6, 18.9, 13.8 ppm; IR (NaCl): n˜ =1751
(C=O, ester), 1736, 1429, 1369, 1248, 1196, 1111, 1086, 1030, 823, 741,
702, 615 cmÀ1
; HRMS (FAB, NBA+NaI matrix): m/z calcd for
C30H42O6SiNa: 549.2648 [M+Na]; found: 549.2659 [M+Na]+.
(2R,3R,6R,7S)-Ethyl-2-azido-9-(tert-butyldiphenylsilyloxy)-3-hydroxy-
6,7-O-isopropylidenenonanate (major) and (2S,3S,6R,7S)-ethyl-3-azido-
9-(tert-butyldiphenylsilyloxy)-2-hydroxy-6,7-O-isopropylidenenonanate
(minor) (76): NH4Cl (282 mg, 5.27 mmol) and NaN3 (343 mg, 5.27 mmol)
were added to a solution of mixture of 75 (1.85 g, 3.52 mmol) in EtOH/
H2O (20:1) (35.2 mL) at RT and the reaction mixture was warmed to
608C. After stirring for 38 h, the reaction mixture was cooled to RT and
diluted with EtOAc (200 mL). The resulting single layer was washed with
H2O (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and evapo-
rated under reduced pressure. Purification by flash chromatography on
silica gel (hexane/EtOAc=8:1) gave a 3:1 mixture of 76 as a inseparable
mixture (1.08 g, 56%). Rf =0.59 (silica gel, hexane/EtOAc=2:1); IR
(NaCl) n˜ =3458 (-OH), 2110 (-N=N+ =NÀ), 1739 (C=O, ester), 1473,
1429, 1369, 1248, 1219, 1111, 1088, 1026, 823, 740, 704, 613 cmÀ1; HRMS
(FAB, NBA matrix): m/z calcd for C30H44N3O6Si: 570.2999 [M+H];
found: 570.2999 [M+H]+.
1
(silica gel, hexane/EtOAc=1:1); [a]2D7 =À24.1 (c=1.00, CHCl3); H NMR
(270 MHz, CDCl3): d=8.34 (ddd, J=2.2, 2.2, 8.6 Hz, 2H; N’’-S(O2)-Ph-
NO2), 8.08 (ddd, J=2.2, 2.2, 8.6 Hz, 2H; N’’-S(O2)-Ph-NO2), 7.70–7.62
(complex m, 4H; 9-O-Si(Ph)2C
A
Si(Ph)2C(CH3)3), 5.44 (d, J=9.5 Hz, 1H; 3-NH), 4.26 (m, 1H; 7-H), 4.24
AHCTREUNG
(q, J=7.0 Hz, 2H; 1-OCH2CH3), 4.14 (d, J=4.3 Hz, 1H; 2-H), 3.87 (ddd,
J=5.7, 9.7, 15.1 Hz, 1H; 6-H), 3.78 (m, 1H; 3-H), 3.76 (t, J=8.6 Hz, 2H;
9-H2), 1.72–1.38 (complex m, 6H; 4-H2, 5-H2, 8-H2), 1.34 (s, 3H; 6,7-O-
iPr), 1.30 (s, 3H; 6,7-O-iPr), 1.30 (t, J=7.0 Hz, 3H; 1-OCH2CH3),
1.05 ppm (s, 9H; 9-O-Si(Ph)2C
(CH3)3); 13C NMR (67.5 MHz, CDCl3): d=
A
167.7, 149.8, 146.6, 135.4 (4C), 133.6, 133.4, 129.5 (2C), 128.1 (2C), 127.6
(4C), 124.2 (2C), 107.5, 74.1, 65.3, 62.3, 60.6, 60.2, 55.3, 36.5, 28.1, 27.4,
26.7 (3C), 26.5, 25.6, 19.1, 14.0 ppm; IR (NaCl) n˜ =3292 (-NH), 2114 (-
N=N+ =NÀ), 1741 (C=O, ester), 1533 (NO2), 1427, 1350 (SO2), 1217,
1167 (N-SO2), 1111, 1092, 854, 737, 704, 687 cmÀ1; HRMS (FAB, NBA+
NaI matrix): m/z calcd for C36H47N5O9SiSNa: 776.2761 [M+Na]; found:
776.2771 [M+Na]+.
(2R,3S,6R,7S)-(À)-Ethyl-9-(tert-butyldiphenylsilyloxy)-2,3-imino-6,7-O-
isopropylidenenonanate (major) and (2S,3S,6R,7S)-(+)-ethyl-9-(tert-bu-
tyldiphenylsilyloxy)-2,3-imino-6,7-O-isopropylidenenonanate
(77): PPh3 (1.03 g, 3.93 mmol) was added to a solution of the mixture of
76 (1.72 g, 3.02 mmol) in MeCN (30.2 mL) under Ar at RT. After stirring
for 30 min, the reaction solution was warmed to 808C and stirred for
21 h. Then the solution was cooled to RT and evaporated under reduced
pressure. Purification by flash chromatography on silica gel (hexane/
EtOAc=8:1) gave trans-77 (1.21 g, 76%; single isomer) and cis-77
(157 mg, 13%; single isomer) as colorless oils. trans-77: Rf =0.39 (silica
gel, hexane/EtOAc=1:1); [a]2D6 =À35.0 (c=1.00, CHCl3); 1H NMR
(2S,3S,6R,7S)-(À)-Ethyl-3-amino-2-azido-9-(tert-butyldiphenylsiloxy)-
6,7-O-isopropylidenenonanate (43): Compound 78 (331 mg, 439 mmol)
was dissolved in MeCN (4.39 mL), and then thiophenol (226 mL,
2.20 mmol) and DIPEA (382 mL, 2.20 mmol) were added to the solution
at RT under Ar. After stirring for 6 h, the reaction was quenched with a
saturated aqueous solution of NaHCO3 (10 mL). Then the mixture was
extracted with CHCl3 (20 mL”3). The organic extracts were dried over
Na2SO4, filtered, and evaporated under reduced pressure. Purification by
flash chromatography on silica gel (hexane/EtOAc=2:1) gave 43 as a
colorless oil (161 mg, 65%). Rf =0.24 (silica gel, hexane/EtOAc=1:1);
[a]2D5 =À22.4 (c=1.00, CHCl3); 1H NMR (270 MHz, CD2Cl2): d=7.70–
(270 MHz, CDCl3): d=7.70–7.62 (complex m, 4H; 9-O-Si(Ph)2C
7.46–7.33 (complex m, 6H; 9-O-Si(Ph)2C(CH3)3), 4.25 (dq, J=6.3,
AHCTREUNG
12.5 Hz, 2H; 1-OCH2CH3), 4.18 (m, 1H; 7-H), 4.03 (ddd, J=5.6, 5.6,
8.3 Hz, 1H; 6-H), 3.81 (t, J=6.3 Hz, 2H; 9-H2), 2.34 (d, J=2.3 Hz, 1H;
2-H), 2.28 (brm, 1H; 3-H), 1.82–1.65 (complex m, 4H; 5-H2, 8-H2), 1.60–
8234
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 8220 – 8238

Total Synthesis of Guadinomines B and C2
FULL PAPER
7.62 (complex m, 4H; 9-O-Si(Ph)2C
A
(67.5 MHz, CDCl3): d=171.0, 168.6, 154.0, 135.5 (2C), 135.4 (2C), 133.7,
133.5, 129.5, 129.5, 127.5 (2C), 127.5 (2C), 107.6, 81.3, 77.1, 74.3, 61.1,
60.8, 54.1, 54.0, 52.3, 32.5, 28.6, 28.3, 28.2 (3C), 26.7 (3C), 26.5, 25.7, 19.1,
18.2, 14.0 ppm; IR (NaCl): n˜ =3205 (-NH), 1745 (C=O, ester), 1699 (C=
O, urethane), 1676 (C=O, amide), 1473, 1429, 1369, 1329, 1186, 1171,
1111, 1092, 1028, 823, 742, 669 cmÀ1; HRMS (FAB, NBA matrix): m/z
calcd for C38H57N2O8Si: 697.3884 [M+H]; found: 697.3909 [M+H]+.
9-O-Si(Ph)2C(CH3)3), 4.26 (m, 1H; 7-H), 4.25 (dq, J=1.0, 6.9 Hz, 2H; 1-
ACHTREUNG
OCH2CH3), 4.02 (ddd, J=3.3, 5.9, 9.3 Hz, 1H; 6-H), 3.87 (d, J=5.3 Hz,
1H; 2-H), 3.82 (d, J=5.6 Hz, 1H; 9-H2), 3.79 (d, J=5.6 Hz, 1H; 9-H2),
3.12 (ddd, J=4.0, 5.3, 8.9 Hz, 1H; 3-H), 1.78–1.32 (complex m, 6H; 4-H2,
5-H2, 6-H2), 1.34 (s, 3H; 6,7-O-iPr), 1.29 (s, 3H; 6,7-O-iPr), 1.30 (t, J=
7.3 Hz, 3H; 1-OCH2CH3), 1.04 ppm (s, 9H; 9-O-Si(Ph)2C(CH3)3);
13C NMR (67.5 MHz, CDCl3): d=168.8, 135.4 (3C), 135.4, 133.6, 133.6,
129.5, 129.4, 127.5 (4C), 107.4, 77.9, 74.5, 67.7, 61.7, 60.9, 53.2, 32.5, 30.2,
28.4, 26.7 (3C), 26.7, 25.8, 19.1, 14.1 ppm; IR (NaCl): n˜ =3394 (-NH),
2108 (-N=N+ =NÀ), 1739 (C=O, ester), 1379, 1367, 1246, 1217, 1194,
1169, 1111, 1088, 1028, 823, 741, 702, 615 cmÀ1; HRMS (FAB, NBA
matrix): m/z calcd for C30H45N4O5Si: 569.3159 [M+H]; found: 569.3149
[M+H]+.
(3S,5S,6S,3’’’S,4’’’R)-(À)-4-(tert-Butoxycarbonyl)-6-[1’’’-(tert-butyldiphe-
nylsiloxy)-3’’’,4’’’-O-isopropylidenehexane-6’’’-yl]- 5-(O1-tert-butyl-l-valin-
yl-l-alanyl)carbonyl-3-metyl-2-piperazinone (82): Lithium hydroxide
(49.9 mg, 2.08 mmol) was added to a solution of 81 (145 mg, 208 mmol) in
MeOH/THF/H2O (2:2:1; 4.16 mL) was added at RT. After stirring for
60 min, a saturated aqueous solution of NH4Cl (6.0 mL) was added to the
reaction mixture and then it was extracted with CHCl3 (10 mL”3). The
combined organic extracts were washed with brine (10 mL), dried over
Na2SO4, filtered, and evaporated under reduced pressure to give the
crude product, which was used in the next reaction without further purifi-
cation. The residue was dissolved in CH2Cl2 (2.08 mL) and then 19
(102 mg, 416 mmol), DIPEA (72.5 mL, 416 mmol), HOBt (28.1 mg,
208 mmol), and PyBOP (163 mg, 312 mmol) were added at 08C under Ar.
After stirring for 1 h at 08C, the reaction mixture was warmed to RT, and
stirred for further 4 h. Then, the reaction solution was quenched with a
saturated aqueous solution of NH4Cl (4.0 mL), the organic layer was sep-
arated and the aqueous layer was extracted with CHCl3 (10 mL”3). The
combined organic extracts were washed with a saturated aqueous solu-
(2S,3S,6R,7S,2’R)-(À)-Ethyl-2-azido-3-(2’-bromopropanamido)-9-(tert-
butyldiphenylsilyloxy)-6,7-O-isopropylidenenonanate (79): Compound
(R)-10 (50.5 mL, 562 mmol), PyBOP (292 mg, 562 mmol), and DIPEA
(120 mL, 0.703 mmol) were added to a solution of 43 (160 mg, 281 mmol)
in CH2Cl2 (9.37 mL) at RT under argon. After stirring for 60 min, a satu-
rated aqueous solution of NH4Cl (3.0 mL) was added to the reaction mix-
ture. Then, the organic layer was separated, and the aqueous layer was
extracted with CH2Cl2 (7.0 mL”3). The combined organic extracts were
washed with a saturated aqueous solution of NaHCO3 (20 mL), dried
over Na2SO4, filtered, and evaporated under reduced pressure. Purifica-
tion by flash chromatography on silica gel (hexane/EtOAc=15:1) gave
79 as a colorless oil (188 mg, 95%). Rf =0.52 (silica gel, hexane/EtOAc=
1:1); [a]2D3 =À21.1 (c=1.00, CHCl3); 1H NMR (270 MHz, CDCl3): d=
tion of NH4Cl (10 mL),
a saturated aqueous solution of NaHCO3
(10 mL), and brine (10 mL), dried over Na2SO4, filtered, and evaporated
under reduced pressure. Purification by flash chromatography on silica
gel (hexane/EtOAc=3:1) gave 82 as a colorless oil (131 mg, 70% for 2
steps). Rf =0.25 (silica gel, hexane/EtOAc=1:2); [a]2D6 =À31.0 (c=1.00,
CHCl3); 1H NMR (270 MHz, CDCl3) d=7.72–6.84 (complex m, 4H; 1’’’-
7.70–7.61 (complex m, 4H; 9-O-Si(Ph)2C
A
6H; 9-O-Si(Ph)2C(CH3)3), 6.56 (d, J=8.6 Hz,1H; 3-NH), 4.37 (m, 1H; 3-
ACHTREUNG
H), 4.32 (q, J=7.3 Hz, 1H; 2’-H), 4.29 (q, J=6.9 Hz, 2H; 1-OCH2CH3),
4.27 (m, 1H; 7-H), 4.26 (d, J=4.3 Hz, 1H; 2-H), 3.99 (dd, J=5.6,
12.5 Hz, 1H; 6-H), 3.80 (t, J=5.9 Hz, 2H; 9-H2), 1.85 (d, J=7.3 Hz, 3H;
3’-H3), 1.84 (m, 1H; 8-H2), 1.77–1.62 (complex m, 3H; 5-H2, 8-H2,), 1.61–
1.28 (complex m, 2H; 4-H2), 1.37 (s, 3H; 6,7-O-iPr), 1.31 (s, 3H; 6,7-O-
iPr), 1.33 (t, J=6.9 Hz, 3H; 1-OCH2CH3), 1.05 ppm (s, 9H; 9-O-
O-Si(Ph)2C
N
N
6.92 (brd, J=6.3 Hz, 1H; 2’-NH), 6.53 (brd, J=8.6 Hz, 1H; 2’’-NH), 6.36
(brs, 1H; 1-H), 4.67 (brs, 1H; 5-H), 4.53–4.35 (complex m, 3H; 3-H, 2’-
H, 2’’-H), 4.30 (dd, J=6.6, 12.9 Hz, 1H; 3’’’-H), 3.99 (dd, J=6.3, 12.9 Hz,
1H; 4’’’-H), 3.80 (t, J=5.9 Hz, 2H; 1’’’-H2), 3.60 (dd, J=6.3, 12.6 Hz, 1H;
6-H), 2.17 (m, 1H; 3’’-H), 1.93–1.82 (complex m, 2H; 6’’’-H2, 2’’’-H2),
1.72–1.62 (complex m, 2H; 6’’’-H2, 2’’’-H2), 1.55–1.45 (complex m, 2H;
Si(Ph)2C
(CH3)3); 13C NMR (67.5 MHz, CDCl3): d=169.4, 168.1, 135.4
A
(2C), 135.4 (2C), 133.7, 133.5, 129.5 (2C), 127.6 (4C), 107.5, 77.4, 74.5,
64.1, 62.2, 60.9, 51.1, 44.4, 32.3, 30.8, 28.3 (2C), 26.8 (3C), 25.8, 22.6, 19.1,
14.1 ppm; IR (NaCl): n˜ =3296 (-NH), 2112 (-N=N+ =NÀ), 1741 (C=O,
ester), 1658 (C=O, amide), 1379, 1369, 1248, 1217, 1111, 1086, 1026, 823,
5’’’-H2), 1.52 (s, 9H; 4-CO-OC
1.46 (s, 9H; 1’’-OC(CH3)3), 1.36 (s, 3H; 3’’’,4’’’-O-iPr), 1.30 (s, 3H; 3’’’,4’’’-
O-iPr), 1.33 (d, J=6.9 Hz, 3H; 3’-H3), 1.04 (s, 9H; 1’’’-O-Si(Ph)2C-
(CH3)3), 0.90 (d, J=6.6 Hz, 3H; 3’’-(CH3)2), 0.88 ppm (d, J=6.9 Hz, 3H;
(CH3)3), 1.46 (d, J=7.2 Hz, 3H; 3-CH3),
AHCTREUNG
740, 702 cmÀ1
;
HRMS (FAB, NBA matrix): m/z calcd for
C33H48N4O6BrSi: 703.2527 [M+H]; found: 703.2532 [M+H]+.
ACHTREUNG
3’’-(CH3)2); 13C NMR (67.5 MHz, CDCl3): d=171.5, 170.8, 170.0, 168.1,
154.6, 135.5 (2C), 135.4 (2C), 133.7, 133.6, 129.5, 129.5, 127.5, (2C), 127.5
(2C), 107.6, 81.9, 81.8, 76.9, 74.3, 60.9, 57.4, 53.5, 53.2, 52.1, 48.4, 32.6,
31.1, 28.4, 28.2 (3C), 28.1, 28.0 (6C), 26.8 (2C), 25.7, 19.1, 18.9, 18.1,
18.0, 17.5 ppm; IR (NaCl) n˜ =3317 (-NH), 1732 (C=O, ester), 1672 (C=
O, urethane), 1656 (C=O, amide), 1539, 1369, 1155, 1111, 1086, 756,
(3S,5S,6S,3’S,4’R)-(+)-4-(tert-Butoxycarbonyl)-6-[1’-(tert-butyldiphenyl-
siloxy)-3’,4’-O-isopropylidenehexane-6’-yl]-5-ethyloxycarbonyl-3-metyl-2-
piperazinone (81): PPh3 (197 mg, 1.02 mmol) and TEA (143 mL,
1.02 mmol) were added to a solution of 79 (239 mg, 339 mmol) in MeCN
(3.39 mL) under argon at RT. After stirring for 1 h, H2O (730 mL) was
added to the reaction mixture. The resulting mixture was warmed to
608C and stirred for 7 h. Then the solution was cooled to RT and evapo-
rated under reduced pressure. The crude product was roughly purified by
flash chromatography on silica gel (CHCl3/MeOH=120:1) to provide pi-
perazinone 80. Di-tert-butyl dicarbonate (519 mg, 2.37 mmol) was added
to a solution of crude 80 in EtOAc (3.39 mL) at RT under argon. After
stirring for 60 min at 808C, the reaction solution was cooled to RT. Then
the reaction mixture was diluted with CHCl3 (20 mL), the mixture was
washed with brine (10 mL), dried over Na2SO4, filtered, and evaporated
under reduced pressure. Purification by flash chromatography on silica
gel (hexane/EtOAc=10:1) gave 81 as a colorless oil (160 mg, 68% for 2
steps). Rf =0.29 (silica gel, hexane/EtOAc=1:1); [a]2D6 =+2.77 (c=0.50,
CHCl3); 1H NMR (270 MHz, CDCl3), as two rotamers. d=7.70–7.62
704 cmÀ1
;
HRMS (FAB, NBA+NaI matrix): m/z calcd for
C48H74N4O10SiNa: 917.5072 [M+Na]; found: 917.5096 [M+Na]+.
(3S,5S,6S,3’’’S,4’’’R)-(À)-4-(tert-Butoxycarbonyl)-5-(O1-tert-butyl-l-valin-
yl-l-alanyl)carbonyl-6-[1’’’-hydroxy-3’’’,4’’’-O-isopropylidenehexane-6’’’-
yl]-3-metyl-2-piperazinone (83): Compound 82 (129 mg, 145 mmol) was
dissolved in THF (1.45 mL) and TBAF (1.0m THF solution, 362 mL,
362 mmol) was added at RT. After stirring for 3 h, a saturated aqueous so-
lution of NH4Cl (5.0 mL) and CHCl3 (5.0 mL) were added, then the two
layers were separated, and the aqueous phase was extracted with CHCl3
(10 mL”3). The combined organic layers were washed with brine
(20 mL), dried over Na2SO4, filtered, and evaporated under reduced pres-
sure. Purification by flash chromatography on silica gel (CH3Cl/MeOH=
10:1) gave 83 as a colorless oil (75 mg, 79%). Rf =0.30 (silica gel, CHCl3/
MeOH=10:1); [a]2D1 =À47.5 (c=2.00, CHCl3); 1H NMR (270 MHz,
CDCl3): d=7.04 (brs, 1H; 2’-NH), 6.95 (brs, 1H; 1-H), 6.82 (brd, J=
7.0 Hz, 1H; 2’’-NH), 4.72 (brs, 1H; 5-H), 4.63–4.43 (complex m, 2H; 3-
H, 2’-H), 4.30 (dd, J=4.6, 8.9 Hz, 1H; 2’’-H), 4.24 (ddd, J=4.9, 5.3,
10.2 Hz, 1H; 3’’’-H), 4.05 (ddd, J=3.0, 5.3, 9.6 Hz, 1H; 4’’’-H), 3.89–3.71
(complex m, 2H; 1’’’-H), 3.68 (dd, J=6.6, 10.9 Hz, 1H; 6-H), 2.88 (brs,
1H; 1’’’-OH), 2.15 (m, 1H; 3’’-H), 1.94–1.78 (complex m, 2H; 6’’’-H2),
1.81–1.60 (complex m, 3H; 2’’’-H2, 5’’’-H2), 1.51 (m, 1H; 5’’’-H2), 1.51 (s,
(complex m, 4H; 1’-O-Si(Ph)2C
A
Si(Ph)2C(CH3)3), 5.92 (brs, 1H; 1-H), 5.02 (brs, 5/6H; 5-H), 4.75 (brs, 1/
ACHTREUNG
6H; 5-H), 4.52–4.36 (brm, 1H; 3-H), 3.80 (dd, J=6.3, 12.9 Hz, 1H; 3’-
H), 4.19 (q, J=7.3 Hz, 2H; 1-OCH2CH3), 4.02 (brm, 1H; 4’-H), 3.81 (t,
J=5.9 Hz, 2H; 1’-H2), 3.64 (brm, 1H; 6-H), 1.98–1.85 (brm, 1H; 2’-H2),
1.69 (dd, J=6.6, 13.2 Hz, 1H; 2’-H2), 1.70–1.38 (complex m, 4H; 5’-H2,
6’-H2), 1.59 (d, J=6.9 Hz, 3H; 3-CH3), 1.50 (s, 9H; 4-CO-OC
1.38 (s, 3H; 3’,4’-O-iPr), 1.33 (s, 3H; 3’,4’-O-iPr), 1.28 (t, J=7.3 Hz, 3H;
1-OCH2CH3), 1.05 ppm (s, 9H; 1’-O-Si(Ph)2C
(CH3)3); 13C NMR
A
AHCTREUNG
Chem. Eur. J. 2008, 14, 8220 – 8238
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8235

¯
T. Sunazuka, S. Omura et al.
9H; 1’’-OC
A
G
57% for 2 steps). Rf =0.32 (silica gel, CHCl3/MeOH=10:1); [a]2D2 =À25.6
(c=1.00, CHCl3) 1H NMR (300 MHz, CD2Cl2): d=11.48 (s, 1H; 1’-NH-
3H; 3-CH3), 1.32 (s, 6H; 3’’’,4’’’-O-iPr), 1.30 (d, J=7.0 Hz, 3H; 3’-H3),
0.90 (d, J=6.9 Hz, 3H; 3’’-(CH3)2), 0.70 ppm (d, J=6.9 Hz, 3H; 3’’-
(CH3)2); 13C NMR (67.5 MHz, CDCl3): d=171.8, 170.8, 170.4, 168.3,
154.6, 107.8, 83.9, 82.3, 81.9, 76.3, 60.4, 57.4, 53.4, 52.0, 49.9, 48.3, 32.3,
31.2, 28.3 (2C), 28.2 (3C), 28.0 (3C), 26.7, 25.7, 18.9, 18.3, 17.9, 17.5 ppm;
IR (NaCl): n˜ =3327 (NH), 1732 (C=O, ester), 1686 (C=O, urethane),
C
C
C
N
A
ACHTREUNG
ACHTREUNG
8.0 Hz, 1H; 2’’-NH), 6.57 (brs, 1H; 2’’’-NH), 5.02–4.86 (brs, 1H; 5-H),
4.71 (brs, 1H; 2’’-H), 4.60–4.46 (brm, 1H; 3-H), 4.40 (m, 1H; 2’’’-H),
4.31 (m, 1H; 2’-H), 4.05 (ddd, J=3.0, 5.8, 9.2 Hz, 1H; 4’-H), 3.88 (m,
1H; 5’-H), 3.66 (m, 1H; 6-H), 3.61 (ddd, J=2.5, 6.0, 13.8 Hz, 1H; 1’-H2),
3.34 (ddd, J=5.0, 7.2, 13.8 Hz, 1H; 1’-H2), 2.15 (m, 1H; 3’’’-H), 1.72–1.48
1666 (C=O, amide), 1539, 1456, 1369, 1315, 1219, 1157, 850, 789 cmÀ1
HRMS (FAB, NBA+NaI matrix): m/z calcd for C32H56N4O10Na:
679.3894 [M+Na]; found: 679.3920 [M+Na]+.
(complex m, 4H; 3’-H2, 7’-H2, 7’-H2), 1.51 (s, 9H; 1’-NH-C
(CH3)3][NCO-OC(CH3)3]), 1.45 (s, 18H; 1’-NH-C[NHCO-OC
[NCO-OC(CH3)3], 4-CO-OC(CH3)3), 1.42 (d, J=7.0 Hz, 3H; 3-CH3),
1.40 (s, 9H; 1’’’-OC(CH3)3), 1.31 (s, 6H; 4’,5’-O-iPr), 1.28 (d, J=7.0 Hz,
ACHTREUNG
(3S,5S,6S,2’S,4’S,5’R)-(À)-4-(tert-Butoxycarbonyl)-5-(O1-tert-butyl-l-va-
linyl-l-alanyl)carbonyl-6-[2’-hydroxy-4’,5’-O-isopropylidene-1’-nitrohex-
ane-7’-yl]-3-methyl-2-piperazinone (46): DMSO (73.0 mL, 1.03 mmol),
TEA (72.3 mL, 515 mmol), and SO3·Py (41.0 mg, 2.57 mmol) were added
to a solution of 83 (67.7 mg, 103 mmol) in CH2Cl2 (2.58 mL) at 08C under
argon. After stirring for 5 min, then the reaction mixture was warmed to
RT and stirred for further 1 h. Then the reaction was quenched with a sa-
turated aqueous solution of NH4Cl (5 mL), diluted with EtOAc (10 mL),
and the two layers were separated. The aqueous layer was extracted with
EtOAc (10 mL”3). The combined organic extracts were washed with a
saturated aqueous solution of NH4Cl (20 mL”2), H2O (20 mL), and
brine (20 mL), dried over Na2SO4, filtered, and evaporated under re-
duced pressure to give crude aldehyde 44, which was used in the next re-
action without further purification. Compound (R,R)-45 (31.0 mg,
52 mmol) and MeNO2 (167 mL, 3.09 mmol) were added to a solution of 44
in CH2Cl2 (2.58 mL) at room temperature. Then the solution was cooled
to À408C and DIPEA (44.9 mL, 257 mmol) was added. After stirring for
46 h, the reaction was quenched with a saturated aqueous solution of
NH4Cl (3.0 mL), then the aqueous layer was extracted with CHCl3
(10 mL”3). The combined organic extracts were washed with brine
(20 mL), dried over Na2SO4, filtered, and evaporated under reduced pres-
sure. Purification by flash chromatography on silica gel (CHCl3/MeOH=
20:1) gave 46 as a colorless oil (38.9 mg, 53% for 2 steps; 90% de). The
de was determined by HPLC (CHIRALCEL OD 4.6f”250 mm, hexane/
A
G
U
G
ACHTREUNG
A
N
ACHTREUNG
AHCTREUNG
3H; 3’’-H3), 0.92 (d, J=7.0 Hz, 3H; 3’’’-(CH3)2), 0.89 ppm (d, J=7.0 Hz,
3H; 3’’’-(CH3)2); 13C NMR (67.5 MHz, CD2Cl2): d=171.7, 170.9, 170.0,
168.4, 163.0, 157.3, 154.4, 153.0, 107.9, 83.3, 81.9, 81.8, 81.6, 79.1, 77.0,
74.7, 69.1, 57.7, 52.8, 52.2, 48.5, 47.8, 35.0, 31.3, 29.7, 28.3, 28.1 (3C), 28.0
(3C), 27.8 (3C), 27.8 (3C), 26.9, 25.6, 18.9, 18.2, 18.0, 17.5 ppm; IR
(NaCl): n˜ =3329 (-NH), 3298 (-OH), 1726 (C=N, guanidyl), 1726 (C=O,
ester), 1664 (C=O, urethane), 1654 (C=O, amide), 1620, 1568, 1369,
1327, 1157, 1142, 1055, 877, 849, 810 cmÀ1; HRMS (FAB, NBA matrix):
m/z calcd for C44H78N7O14: 928.5607 [M+H]; found: 928.5644 [M+H]+.
(3S,5S,6S,2’S,3’R,4’’R)-(À)-6-{1’-[N,3’’-Di-(tert-butoxycarbonyl)-2’’-
imino-imidazolidin-4’’-yl]-2’,3’-O-isopropylidenehexan-5’-yl}-4-(tert-but-
A
perazinone (50): Pyridine (4.90 mL, 60.3 mmol), methanesulfonic anhy-
dride (34.0 mg, 0.197 mmol), and DMAP (one crystal) were added to a
solution of 48 (5.6 mg, 6.03 mmol) in CH2Cl2 (0.603 mL) at 08C under
argon. After stirring for 30 min, the reaction mixture was quenched with
a saturated aqueous solution of NH4Cl (2.0 mL). Then the mixture was
extracted with CHCl3 (5 mL”3). The combined organic extracts were
washed with a saturated aqueous solution of NH4Cl (5.0 mL), a saturated
aqueous solution of NaHCO3 (5.0 mL), and brine (5.0 mL), dried over
Na2SO4, filtered, and evaporated under reduced pressure to give the
crude product, which was used in the next reaction without further purifi-
cation. The crude mesylate was dissolved in MeCN (603 mL), DIPEA
(2.60 mL) was added, and the mixture was heated to 658C and stirred for
4 h. The reaction mixture was then cooled to RT and concentrated to
afford the crude material, which was purified by preparative TCL
(CHCl3/MeOH=10:1) to give 50 as a colorless amorphous solid (4.5 mg,
82% for 2 steps).
2-propanol=99:1, 0.9 mLminÀ1
CHCl3/MeOH=10:1); [a]2D2 =À52.0 (c=1.00, CHCl3); 1H NMR
(270 MHz, CD2Cl2): d=6.83 (brs, 1H; 2’’’-NH), 6.70 (brs, 1H; 2’’-NH),
6.60 (brs, 1H; 1-H), 4.58 (brs, 1H; 5-H), 4.52–4.33 (complex m, 2H; 3-H,
2’-H), 4.46 (d, J=9.3 Hz, 1H; 1’-H2), 4.33 (d, J=9.3 Hz, 1H; 1’-H2), 4.25
(dd, J=4.3, 7.9 Hz, 1H; 2’’’-H), 4.19 (dd, J=5.9, 13.5 Hz, 1H; 4’-H), 3.96
(m, 1H; 5’-H), 3.96 (m, 1H; 6-H), 2.04 (m, 1H; 3’’’-H), 1.79–1.60 (com-
plex m, 2H; 3’-H2, 7’-H2), 1.59–1.36 (complex m, 4H; 3’-H2, 6’-H2, 7’-H2),
Alternative method: PPh3 (14.8 mg, 56.4 mmol), imidazole (4.82 mg,
70.5 mmol), and I2 (6.3 mg, 49.4 mmol) were added to a solution of 48
(13.1 mg, 14.1 mmol) in CH2Cl2 (0.282 mL) 08C. After stirring for 60 min
at 08C, the reaction mixture was warmed to RT and stirred for further
2 h. Then the reaction mixture was diluted with CHCl3 (5.0 mL). The
1.38 (s, 9H; 1’’’-OC
6.8 Hz, 3H; 3-CH3), 1.19 (s, 3H; 4’,5’-O-iPr), 1.15 (d, J=6.8 Hz, 3H; 3’’-
H3), 1.14 (s, 3H; 4’,5’-O-iPr), 0.78 (d, J=6.9 Hz, 3H; 3’’’-(CH3)2),
0.74 ppm (d, J=6.9 Hz, 3H; 3’’’-(CH3)2); 13C NMR (67.5 MHz, CD2Cl2):
d=171.9, 171.0, 170.7, 168.4, 154.7, 108.1, 82.1, 81.9, 81.4, 77.6, 77.0, 74.2,
67.2, 57.7, 52.8, 52.3, 48.2, 34.5, 31.3, 29.7, 28.2, 28.1 (3C), 27.9, 27.8 (3C),
27.1, 18.9, 18.7, 18.1, 17.4 ppm; IR (NaCl): n˜ =3327 (-OH, -NH), 1728
(C=O, ester), 1687 (C=O, urethane), 1665 (C=O, amide), 1554 (NO2),
1520, 1381, 1369, 1315, 1219, 1157, 1074, 877, 847, 756 cmÀ1; HRMS
(FAB, NBA+NaI matrix): m/z calcd for C33H57N5O12Na: 738.3901
[M+Na]; found: 738.3908 [M+Na]+.
(3S,5S,6S,2’S,4’S,5’R)-(À)-4-(tert-Butoxycarbonyl)-5-(O1-tert-butyl-l-va-
linyl-l-alanyl)carbonyl-6-{1’-[N,N-di-(tert-butoxycarbonyl)guanidino]-2’-
hydroxy-4’,5’-O-isopropylidenehexane-7’-yl}-3-methyl-2-piperazinone
(48): 10% Pd/C (54.4 mg, 51.1 mmol) and ammonium formate (34.3 mg,
544 mmol) were added to a solution of 46 (38.9 mg, 54.4 mmol) in MeOH
(1.09 mL) under Ar at RT. After stirring for 2 h, the reaction mixture
was filtered through a Celite pad, and the pad was washed with MeOH.
The solvent was removed and the residue was dissolved in CHCl3
(30 mL), washed with a saturated aqueous solution of NaHCO3 (10 mL),
dried over Na2SO4, filtered, and evaporated under reduced pressure to
afford crude amine, which was used in the next reaction without further
purification. The crude amine was dissolved in CH3CN (1.09 mL) and
then added 47 (25.3 mg, 81.6 mmol) and iPrNEt (14.2 mL, 81.6 mmol) were
added at RT. After stirring for 60 min, the solution was evaporated under
reduced pressure. Purification by flash chromatography on silica gel
(CHCl3/MeOH=100:1) gave 48 as a colorless amorphous solid (28.9 g,
mixture was washed with
a saturated aqueous solution of NH4Cl
(3.0 mL) and brine (3.0 mL), dried over Na2SO4, filtered, and evaporated
under reduced pressure. Purification by flash column chromatography
(CHCl3/MeOH=90:1) gave 50 as an amorphous solid (11.3 mg, 88%).
Rf =0.32 (silica gel, CHCl3/MeOH=10:1); [a]2D0 =À27.4 (c=0.75,
CHCl3); 1H NMR (300 MHz, CD2Cl2): d=6.90 (brd, J=7.3 Hz, 1H; 2’’’-
NH), 6.54 (brd, J=8.6 Hz, 1H; 2’’’’-NH), 6.20 (brs, 1H; 1-H), 4.69 (brs,
1H; 5-H), 4.43 (dq, J=6.8, 7.3 Hz, 1H; 2’’’-H), 4.42 (q, J=6.8 Hz, 1H; 3-
H), 4.38 (m, 1H; 4’’-H), 4.35 (dd, J=4.2, 8.6 Hz, 1H; 2’’’’-H), 4.15–4.03
(complex m, 2H; 2’-H, 3’-H), 3.74 (dd, J=8.5, 10.5 Hz, 1H; 5’’-H2), 3.66
(ddd, J=4.5, 5.5, 8.2 Hz, 1H; 6-H), 3.50 (dd, J=3.5, 10.5 Hz, 1H; 5’’-H2),
2.15 (dqq, J=6.5, 6.5, 8.6 Hz, 1H; 3’’’’-H), 1.86 (m, 1H; 1’-H2), 1.95–1.85
(complex m, 2H; 5’-H2), 1.72–1.48 (complex m, 3H; 1’-H2, 4’-H2), 1.52 (s,
9H; 2’’-N-CO-O-C
1’’’’-O-C(CH3)3), 1.42 (d, J=7.3 Hz, 3H; 3-CH3), 1.42 (s, 9H; 4-CO-O-C-
(CH3)3), 1.41 (s, 3H; 2’,3’-O-iPr), 1.30 (d, J=7.3 Hz, 3H; 3’’’-H3), 1.29 (s,
A
G
AHCTREUNG
AHCTREUNG
3H; 2’,3’-O-iPr), 0.92 (d, J=6.5 Hz, 3H; 3’’’’-(CH3)2), 0.90 ppm (d, J=
6.5 Hz, 3H; 3’’’’-(CH3)2); 13C NMR (75.0 MHz, CD2Cl2): d=171.5 (C-1’’’),
170.8 (C-1’’’’), 169.8 (C-2), 168.5 (1C, 5-CO-NH-), 155.7 (C-2’’), 154.9
(1C, 4-CO-O-C
CO-O-C(CH3)3), 108.5 (1C, 2’,3’-O-iPr), 83.0 (1C, 2’’-N-CO-O-C
82.0 (1C, 1’’’’-O-C(CH3)3), 82.0 (1C, 3’’-CO-O-C(CH3)3), 82.0 (1C, 4-CO-
O-C(CH3)3), 77.0 (C-3’), 73.6 (C-2’), 57.8 (C-2’’’’), 54.3 (C-4’’), 54.2 (C-
A
ACHTREUNG
A
ACHTREUNG
A
ACHTREUNG
AHCTREUNG
8236
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 8220 – 8238

Total Synthesis of Guadinomines B and C2
FULL PAPER
5’’), 53.4 (C-6), 53.2 (C-5), 52.3 (C-3), 48.8 (C-2’’’), 33.5 (C-1’), 31.4 (C-
3’’’’), 29.9, 27.1 (each 1C, 2’,3’-O-iPr), 28.4 (C-5’), 28.3 (C-4’), 28.1 (3C,
10:1) gave 84 as a colorless oil (185 mg, 91% in 2 steps). Rf =0.55 (silica
gel, hexane/EtOAc=2:1); [a]2D7 =+1.29 (c=0.75, CHCl3); 1H NMR
(270 MHz, CD2Cl2): d=7.70–7.61 (complex m, 4H; 9-O-Si(Ph)2C
A
2’’-N-CO-O-C
G
G
7.47–7.34 (complex m, 6H; 9-O-Si(Ph)2C(CH3)3), 5.37 (m, 1H; 2-NH),
AHCTREUNG
C
A
ACHTREUNG
4.77 (brd, J=7.9 Hz, 1H; 3-NH), 4.44–4.27 (brm, 1H; 2-H), 4.27 (m,
1H; 7-H), 4.20 (q, J=6.9 Hz, 2H; 1-OCH2CH3), 3.99–3.88 (brm, 1H; 3-
H), 3.98 (dd, J=5.9, 12.5 Hz, 1H; 6-H), 3.80 (t, J=5.6 Hz, 2H; 9-H2),
1.82–1.61 (complex m, 3H; 4-H2, 8-H2), 1.59–1.32 (complex m, 3H; 5-H2,
17.9 (1C, 3-CH3), 17.6 ppm (1C, 3’’’’-(CH3)2); IR (NaCl): n˜ =3319 (-OH;
-NH), 1761 (C=N, guanidyl), 1732 (C=O, carboxylic acid), 1668 (C=O,
amide), 1608 (C=O, amide), 1531, 1379, 1369, 1317, 1254, 1146, 999, 849,
769 cmÀ1
; HRMS (FAB, NBA matrix): m/z calcd for C44H76N7O13:
910.5501 [M+H]; found: 910.5538 [M+H]+.
8-H2), 1.44 (s, 9H; 3-CO-OC
(s, 3H; 6,7-O-iPr), 1.29 (s, 3H; 6,7-O-iPr), 1.26 (t, J=6.9 Hz, 3H; 1-
OCH2CH3), 1.04 ppm (s, 9H; 9-O-Si(Ph)2C
(CH3)3); 13C NMR (67.5 MHz,
A
G
(3S,5S,6S,2’S,3’R,4’’R)-(À)-5-(l-Valinyl-l-alanyl)carbonyl-6-[2’,3’-dihy-
droxy-1’-(1’’-carbamoyl-2’’-iminoimidazolidinyl)heptan-5’-yl]-3-methyl-2-
AHCTREUNG
CD2Cl2): d=170.9, 155.8, 155.5, 135.6 (2C), 135.6 (2C), 134.0, 133.9,
129.7 (2C), 127.7 (4C), 107.8, 79.9, 79.5, 77.8, 74.6, 74.4, 61.6, 61.2, 60.3,
57.2, 32.7, 28.5, 28.2 (3C), 28.1 (3C), 27.0, 26.7 (3C), 25.8, 20.9, 19.1,
14.1 ppm; IR (NaCl): n˜ =3365 (-NH), 1741 (C=O, ester), 1707 (C=O,
urethane), 1512, 1367, 1248, 1219, 1169, 1111, 1086, 1022, 868, 823, 756,
704 cmÀ1; HRMS (FAB, NBA matrix): m/z calcd for C40H62N2O9SiNa:
765.4122 [M+Na]; found: 765.4144 [M+Na]+.
(2S,3S,6R,7S,)-(À)-(O1-tert-Butyl-l-valinyl-l-alanyl)-2,3-bis(tert-butoxy-
carbonylamino)-9-(tert-butyldiphenylsiloxy)-6,7-O-isopropylidenenona-
nate (51): Lithium hydroxide monohydrate (105 mg, 2.50 mmol) was
added to a solution of 84 (185 mg, 250 mmol) in MeOH/THF/H2O ( 2:2:1;
4.99 mL) at RT. After stirring for 30 min, a saturated aqueous solution of
NH4Cl (5.0 mL) was added to the reaction mixture and then it was ex-
tracted with CHCl3 (10 mL”3). The combined organic extracts were
washed with brine (10 mL), dried over Na2SO4, filtered, and evaporated
under reduced pressure to give the crude product, which was used in the
next reaction without further purification. The residue was dissolved in
CH2Cl2 (4.99 mL) and then 19 (91.4 mg, 374 mmol), ADIPEA (69.4 mL,
399 mmol), and PyBOP (208 mg, 399 mmol) were added at RT under Ar.
After stirring for 3 h, the reaction was then quenched with a saturated
aqueous solution of NH4Cl (5.0 mL). The organic layer was separated
and aqueous layer was extracted with CHCl3 (10 mL”2). The combined
piperazinone ((3’R)-4): p-Methoxyphenyl isocyanate (2.21 mL, 16.9 mmol)
was added to a solution of 50 (13.1 mg, 14.1 mmol) in PhH (0.470 mL) at
RT under argon. After stirring for 10 min, the reaction mixture was
quenched with a saturated aqueous solution of NH4Cl (1.0 mL). Then the
mixture was extracted with CHCl3 (5.0 mL”3). The combined organic
extracts were dried over Na2SO4, filtered, and evaporated under reduced
pressure to give the crude product, which was used in the next reaction
without further purification. Cerium(IV) ammonium nitrate (15.8 mg,
28.2 mmol) was added to a solution of the crude material in CH3CN/H2O
(1:1; 470 mL) at 08C. After stirring for 2.5 h, the reaction mixture was di-
luted with CHCl3 (6.0 mL) and a saturated aqueous solution of NaHCO3
(3.0 mL). The mixture was extracted with CHCl3 (10 mL”3), the com-
bined organic extracts were dried over Na2SO4, filtered, and evaporated
under reduced pressure to give the crude product, which was used in the
next reaction without further purification. The crude material was dis-
solved in TFA/H2O (3:1) (470 mL) and the reaction mixture was stirred
for 5 h at RT. The reaction mixture was then concentrated and purified
by preparative HPLC (Develosil C30 UG-5, 20f”250 mm, 15% MeOH
in H2O/with 0.1% TFA, 8.0 mLminÀ1, UV at 210 nm) to give (3’R)-4 as a
colorless oil (7.3 mg, 60% for 3 steps). tR =9.71 min (Analytical HPLC,
Develosil C30 UG-5, 4.6 f”250 mm, 0.1% TFA/15% MeOH/H2O,
1.0 mLminÀ1, 210 nm); [a]D27 =À25.7, ꢀÀ13.8 (c=0.10, MeOH), [a]2D0
=
organic extracts were washed with
a saturated aqueous solution of
À10.7 (c=0.10, 1% TFA in MeOH) (natural: [a]2D6 =À7.8 (c=0.10,
MeOH)}; 1H NMR (400 MHz, D2O with TFA): d=4.52 (d, J=4.5 Hz,
1H; 5-H), 4.44 (q, J=7.2 Hz, 1H; 2’’’-H), 4.25 (dddd, J=5.8, 5.8, 6.0,
8.4 Hz, 1H; 4’’-H), 4.21 (dd, J=8.4, 8.4 Hz, 1H; 5’’-H2), 4.10 (q, J=
7.2 Hz, 1H; 3-H), 4.08 (d, J=6.0 Hz, 1H; 2’’’’-H), 3.99 (ddd, J=2.5, 4.5,
11.2 Hz, 1H; 6-H), 3.78 (dd, J=5.8, 8.4 Hz, 1H; 5’’-H2), 3.61 (ddd, J=
2.1, 5.8, 10.0 Hz, 1H; 2’-H), 3.48 (ddd, J=3.0, 5.8, 10.0 Hz, 3’-H), 2.12
(dsep, J=6.0, 6.8 Hz, 1H; 3’’’’-H), 1.92 (ddd, J=2.1, 6.0, 14.0 Hz, 1H; 1’-
H2), 1.75 (ddd, J=5.8, 10.0, 14.0 Hz, 1H; 1’-H2), 1.74 (m, 1H; 4’-H2), 1.70
(m, 1H; 5’-H2), 1.59 (m, 1H; 5’-H2), 1.58 (q, J=7.2 Hz, 3H; 3-CH3), 1.43
(m, 1H; 4’-H2), 1.38 (d, J=7.2 Hz, 3H; 3’’’-H3), 0.92 ppm (d, J=6.8 Hz,
6H; 3’’’’-(CH3)2); 13C NMR (100 MHz, D2O with TFA), reference (0 and
200 ppm): d=177.8 (C-1’’’’), 177.1 (C-1’’’), 170.8 (C-2), 167.5 (1C, 5-CO-
NH), 159.0 (C-2’’), 158.4 (1C, 1’’-CO-NH2), 76.7 (C-3’), 74.2 (C-2’), 61.4
(C-2’’’’), 59.7 (C-5), 54.8 (C-3), 54.0 (C-4’’), 53.4 (C-6), 53.1 (C-5’’), 52.1
(C-2’’’), 38.7 (C-1’), 32.3 (C-3’’’’), 30.4 (C-5’), 30.1 (C-4’), 20.9 (1C, 3’’’’-
(CH3)2), 20.1 (1C, 3’’’’-(CH3)2), 19.2 (C-3’’’), 16.5 ppm (1C, 3-CH3); IR
(KBr): n˜ =3427 (-OH), 3217 (-NH), 1730 (C=O, carboxylic acid), 1672
(C=O, amide), 1562, 1427, 1201, 1138, 841, 800, 723 cmÀ1; HRMS (FAB,
NBA matrix): m/z calcd for C23H41N8O8: 557.3047 [M+H]; found:
557.3036 [M+H]+; see the Supporting Information for the NMR spectra.
NaHCO3 (10 mL), dried over Na2SO4, filtered, and evaporated under re-
duced pressure. Purification by flash chromatography on silica gel
(hexane/EtOAc=4:1) gave 51 as a colorless solid (210 mg, 89% for 2
steps). Rf =0.61 (silica gel, hexane/EtOAc=1:1); m.p. 133–1378C
(CHCl3); [a]2D6 =À22.3 (c=1.00, CHCl3; 1H NMR (270 MHz, CDCl3 d=
7.70–7.63 (complex m, 4H; 9-O-Si(Ph)2C
6H; 9-O-Si(Ph)2C
ACHTREUNG
AHCTREUNG
1H; 2’’-NH), 5.70 (brd, J=5.9 Hz, 1H; 2-NH), 5.39 (brd, J=7.9 Hz, 1H;
3-NH), 4.40 (dd, J=4.6, 8.9 Hz, 1H; 2’’-H), 4.37 (m, 1H; 2’-H), 4.27 (m,
1H; 2-H), 4.25 (apparent t, J=5.9 Hz, 1H; 7-H), 3.97 (dd, J=5.6,
12.9 Hz, 1H; 6-H), 3.86–3.77 (brm, 1H; 3-H), 3.80 (t, J=6.3 Hz, 2H; 9-
H2), 2.15 (m, 1H; 3’’-H), 1.82 (m, 1H; 8-H2), 1.71–1.58 (complex m, 3H;
5-H2, 8-H2), 1.52–1.40 (complex m, 2H; 4-H2), 1.46 (s, 9H; 3-CO-OC-
A
G
A
AHCTREUNG
0.88 ppm (d, J=6.9 Hz, 3H; 3’’-(CH3)2); 13C NMR (67.5 MHz, CDCl3):
d=171.5, 170.8, 170.4, 156.4, 155.7, 135.4 (2C), 135.3 (2C), 133.6, 133.5,
129.4, 129.4, 127.5 (2C), 127.4 (2C), 107.4, 81.7, 80.0, 79.4, 77.6, 74.2,
60.8, 60.2, 57.3, 53.6, 49.2, 32.6, 31.2, 29.3, 28.4, 28.4 (3C), 28.2 (3C), 27.9
(3C), 26.9, 26.7 (3C), 25.7, 19.0, 18.8, 17.7, 17.5 ppm; IR (NaCl): n˜ =3329
(-NH), 1720 (C=O,ester), 1691 (C=O, urethane), 1643 (C=O, amide),
Compound (3’S)-4: See the Supporting Information for details.
1523, 1454, 1392, 1367, 1248, 1221, 1169, 1113, 1088, 872, 823, 702 cmÀ1
;
(2S,3S,6R,7S)-(+)-Ethyl-2,3-bis(tert-butoxycarbonylamino)-9-(tert-butyl-
diphenylsiloxy)-6,7-O-isopropylidenenonanate (84): 10% Pd/C (146 mg,
137 mmol) was added to a solution of 43 (156 mg, 274 mmol) in EtOAc
(5.48 mL) under H2 at RT. After stirring for 1 h, the reaction solution
was filtered through a Celite pad to remove the catalyst, and the pad was
washed with EtOAc. The solvent was removed to give crude diamine
compound, which was used in the next reaction without further purifica-
tion. The crude diamine was dissolved in EtOAc (5.48 mL), and then
Boc2O (598 mg, 2.74 mmol) was added, and the mixture was heated to
608C with stirring. After 45 min, the reaction solution was cooled to RT
and diluted with EtOAc (50 mL). The mixture was washed with brine
(10 mL), dried over Na2SO4, filtered, and evaporated under reduced pres-
sure. Purification by flash chromatography on silica gel (hexane/EtOAc=
HRMS (FAB, NBA matrix): m/z calcd for C50H81N4O11Si: 941.5671
[M+H]; found: 941.5662 [M+H]+.
(2S,3S,6R,7S,4’R)-(À)-(l-Valinyl-l-alanyl)-2,3-diamino-8-(1’-carbamoyl-
2’-iminoimidazolidin-4’-yl)-6,7-dihydroxy-octanate (2): tR =16.8 min (An-
alytical HPLC, Develosil C30 UG-5, 4.6 f”250 mm, 0.1% TFA/10%
MeOH/H2O, 1.0 mLminÀ1, 210 nm); [a]2D8 =+8.5 (c=0.10, 1% TFA in
MeOH), {natural: [a]2D7 =+13.7 (c=0.10, 1% TFA in MeOH)}; 1H NMR
(400 MHz, 1% TFA in D2O): d=4.41 (q, J=7.3 Hz, 1H; 2’’-H), 4.26 (d,
J=3.5 Hz, 1H; 2-H), 4.19 (dddd, J=5.9, 6.0, 6.0, 8.9 Hz, 1H; 4’-H), 4.16
(dd, J=8.9, 14.5 Hz, 1H; 5’-H2), 4.12 (d, J=5.9 Hz, 1H; 2’’’-H), 3.78
(ddd, J=3.5, 5.2, 8.6 Hz, 1H; 3-H), 3.72 (dd, J=6.0, 14.5 Hz, 1H; 5’-H2),
3.56 (ddd, J=2.2, 6.0, 10.0 Hz, 1H; 7-H), 3.46 (ddd, J=2.0, 5.5, 9.5 Hz,
Chem. Eur. J. 2008, 14, 8220 – 8238
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8237

¯
T. Sunazuka, S. Omura et al.
1H; 6-H), 2.11 (dsep, J=5.9, 6.9 Hz, 1H; 3’’’-H), 1.98 (dddd, J=4.5, 5.2,
10.0, 14.5 Hz, 1H; 4-H2), 1.87 (ddd, J=2.2, 5.9, 14.0 Hz, 1H; 8-H2), 1.76
(ddt, J=5.0, 8.6, 14.5 Hz, 1H; 4-H2), 1.72 (dddd, J=2.0, 5.0, 10.0,
14.5 Hz, 1H; 5-H2), 1.71 (ddd, J=6.0, 10.2, 14.0 Hz, 1H; 8-H2), 1.44 (ddt,
J=4.5, 9.5, 14.5 Hz, 1H; 5-H2), 1.35 (d, J=7.3 Hz, 3’’-H3), 0.89 ppm (d,
J=6.9 Hz, 6H; 3’’’-(CH3)2); 13C NMR (100 MHz, 1% TFA in D2O): d=
177.7 (C-1’’’), 177.3 (C-1’’), 167.9 (C-1), 159.0 (C-2’), 158.4 (1C, 1’-CO-
NH2), 76.2 (C-6), 74.3 (C-7), 61.5 (C-2’’’), 56.2 (C-2), 54.7 (C-3), 54.0 (C-
4’), 53.1 (C-5’), 52.5 (C-2’’), 38.8 (C-8), 32.3 (C-3’’’), 29.8 (C-5), 28.5 (C-4),
20.9 (1C, 3’’’-(CH3)2), 20.0 (1C, 3’’’-(CH3)2), 19.3 ppm (C-3’’); IR (KBr):
n˜ =3365 (-OH, -NH), 1734 (C=N, guanidyl), 1732 (C=O, carboxylic
acid), 1672 (C=O, amide), 1608 (C=O, amide), 1531, 1379, 1369, 1317,
1254, 1146, 999, 849, 769 cmÀ1; HRMS (FAB, NBA matrix): m/z calcd for
C20H39N8O7: 503.2942 [M+H]; found: 503.2944 [M+H]+; see the Sup-
porting Information for detailed procedures, data (for intermediates) and
NMR spectra for synthetic 2.
989–995; b) A. Viso, R. F. de la Pradilla, A. Flores, A. Garcꢂa, M.
Tortosa, M. L. Lꢃpez-Rodrꢂguez, J. Org. Chem. 2006, 71, 1142–
1148.
[10] NOE data are described in the Supporting Information (Figure S1).
[11] a) H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem. 2001, 113,
2056–2075; Angew. Chem. Int. Ed. 2001, 40, 2004–2021; b) Y. Luo,
M. A. Blaskovich, G. A. Lajoie, J. Org. Chem. 1999, 6, 1587–1588;
c) H. Han, J. Yoon, K. D. Janda, J. Org. Chem. 1998, 63, 2045–2048.
[12] O. Cabon, D. Buisson, M. Larcheveque, R. Azerad, Tetrahedron:
Asymmetry 1995, 6, 2211–2218.
[13] a) A. Abdel-Magid, L. N. Pridegen, D. S. Eggleston, I. Lantos, J.
Am. Chem. Soc. 1986, 108, 4595–4602; b) D. A. Evans, J. Bartroli,
T. L. Shih, J. Am. Chem. Soc. 1981, 103, 2127–2129.
[14] J. Farras, X. Ginesta, P. W. Sutton, J. Taltavull, F. Egelar, P. Romea,
F. Urpi, J. Vilarrasa, Tetrahedron 2001, 57, 7665–7674.
[15] The configurational integrity of both piperazinones was evaluated
by detailed 1H NMR spectroscopy; see the Supporting Information.
(Figures S2 and S3)
[16] a) C. Xiong, W. Wang, V. J. Hruby, J. Org. Chem. 2002, 67, 3514–
3517; b) Y. G. Gololobov, I. N. Zhmurova, L. F. Kasukhin, Tetrahe-
dron 1981, 37, 437–472.
Acknowledgements
[17] See Figure S4 in the Supporting Information.
[18] C. Bonini, L. Chiummiento, M. Pullez, G. Solladiꢄ, F. J. Colobert, J.
Org. Chem. 2004, 69, 5015–5022.
This work was supported by the Grant for the 21st Century COE Pro-
gram, Ministry of Education Culture, Sports, Science and Technology
(18790022). We also thank A. Nakagawa, C. Sakabe, N. Sato, and Y. Ka-
wauchi (all Kitasato University) for various instrumental analyses.
[19] The stereochemistry of the anti-diol unit was checked by NOE ob-
servation of compound 38; see the Supporting Information. (Fig-
ure S5)
1
[20] No other diastereomers were detected by H NMR spectroscopy.
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(Scheme S2)
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Received: May 28, 2008
Published online: July 24, 2008
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