Asymmetric synthesis of the cytotoxic marine natural product (+)-awajanomycin and its C-11 epimer

Article abstract of DOI:10.1021/jo100744c

Full details of the convergent synthetic approach to awajanomycin, and the first total syntheses of the marine natural product (+)-awajanomycin (1) and its C-11 epimer 38 by an improved 13-step approach, are described. The key elements of the synthetic strategy resided in the use of (R)-18 as the chiral building block to construct the γ-lactone-δ-lactam core 3 and cross-olefin metathesis as the key reaction to couple the latter with the allylic alcohol segment (R- or S-4). The efficient construction of the core 3 was realized by taking advantage of the inherent multiple reactivities of the chiral building block (R)-18. A highly diastereoselective one-pot transformation of 6 to 26 was achieved in a one stone four birds manner. On the other hand, enantioselective synthesis of both enantiomers of the segment 4 has been undertaken by an alternative and more efficient two-step procedure. Both awajanomycin (1) and 11-epi-awajanomycin 38 have been synthesized with overall yields of 3.8% and 3.6%, respectively. Quantum chemical calculations were undertaken to reveal the low reactivity of compound 27 toward methoxycarbonylation and to get an insight into the favored conformations of the intermediates 25-27. In addition, the geometry of the side product 39 arising from the homocoupling of the allylic alcohol moiety 4 was revised as E, and an unusual cyclopropanation reaction was discovered.

Full text of DOI:10.1021/jo100744c

pubs.acs.org/joc
Asymmetric Synthesis of the Cytotoxic Marine Natural Product
(þ)-Awajanomycin and Its C-11 Epimer
Rui Fu,† Jian-Liang Ye,*,† Xi-Jie Dai,† Yuan-Ping Ruan,† and Pei-Qiang Huang*,†,‡
†Department of Chemistry and Key Laboratory for Chemical Biology of Fujian Province, College
of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, P. R. China, and
‡State Key Laboratory of Bioorganic and Natural Products Chemistry, 354 Fenglin Lu, Shanghai 200032,
P. R. China
pqhuang@xmu.edu.cn
Received April 16, 2010
Full details of the convergent synthetic approach to awajanomycin, and the first total syntheses of the
marine natural product (þ)-awajanomycin (1) and its C-11 epimer 38 by an improved 13-step
approach, are described. The key elements of the synthetic strategy resided in the use of (R)-18 as
the chiral building block to construct the γ-lactone-δ-lactam core 3 and cross-olefin metathesis as the
key reaction to couple the latter with the allylic alcohol segment (R- or S-4). The efficient construction
of the core 3 was realized by taking advantage of the inherent multiple reactivities of the chiral building
block(R)-18. A highly diastereoselectiveone-pottransformation of6 to26was achieved ina “one stone
four birds” manner. On the other hand, enantioselective synthesis of both enantiomers of the segment 4
has been undertaken by an alternative and more efficient two-step procedure. Both awajanomycin (1)
and 11-epi-awajanomycin 38 have been synthesized with overall yields of 3.8% and 3.6%, respectively.
Quantum chemical calculations were undertaken to reveal the low reactivity of compound 27 toward
methoxycarbonylation and to get an insight into the favored conformations of the intermediates
25-27. In addition, the geometry of the side product 39 arising from the homocoupling of the allylic
alcohol moiety 4 was revised as E, and an unusual cyclopropanation reaction was discovered.
Introduction
important sources of chemically interesting and biologically
active secondary metabolites for the development of new
pharmaceutical agents.3 In 2006, Jang and co-workers re-
ported the isolation of (þ)-awajanomycin (1, Figure 1) from
the marine-derived fungus Acremonium sp. AWA16-1, col-
lected from sea mud off Awajishima island in Japan.4
Awajanomycin (1) exhibited cytotoxic activity against the
One of the contemporary trends in drug discovery from
natural sources is the investigation of natural products from
the marine environment.1-3 Marine microorganisms,2 in par-
ticular, marine-derived fungi have recently gained attention as
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4230 J. Org. Chem. 2010, 75, 4230–4243
Published on Web 05/27/2010
DOI: 10.1021/jo100744c
r
2010 American Chemical Society

Fu et al.
JOCArticle
SCHEME 1
FIGURE 1. Structure of (þ)-awajanomycin.
FIGURE 2. Multiple reactivities of the building block 2 displayed
by synthon A.
A549 cells with an IC50 value of 27.5 μg/mL. The structure,
including the relative stereochemistry of (þ)-awajanomycin
(1), was elucidated by spectroscopic analysis and chemical
methods, while the stereochemistry at C-11 and the absolute
configuration of the natural product have not been deter-
mined in the original report.
the stereochemistry at C-11 as well as the absolute configura-
tion of the natural product as 3R,5R,6S,8S,11S.6 Here, the full
account of the strategy is described, and the first total syntheses
of the natural (þ)-awajanomycin (1) and its 11-epimer 38 by an
improved approach are reported.
Awajanomycin (1) possesses a characteristic γ-lactone-δ-
lactam core with a fully substituted 2-piperidinone ring bearing
four chiral centers including a quaternary carbon. The intri-
guing structural features, unknown absolute stereochemistry,
and significant cytotoxicity exhibited by awajanomycin make
it an attractive and challenging synthetic target.5,6 In 2009, a
racemic synthesis of the core ring system was reported.5a Soon
after this report, we accomplished the first total synthesis of the
unnatural enantiomer of awajanomycin (ent-1) and established
Results and Discussion
In recent years, we have been engaged in the development of
protected (R)- and (S)-glutarimides 2 (Figure 2) as versatile
building blocks7,8 for the asymmetric synthesis of substituted
3-piperidinol-containing alkaloids and pharmaceutically rele-
vant molecules. Taking advantage of the multiple reactivities
possessed by these building blocks shown by synthon A, meth-
ods have been established for alkylation and/or functionaliza-
tion at any of the six positions of the 3-piperidinol nucleus.7 On
the basis of this methodology, we have demonstrated that the
building block 2 can serve as an effective template for the
asymmetric construction of awajanomycin bicyclic core in the
recent total synthesis of (-)-awajanomycin (ent-1).
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Our retrosynthetic analysis of 1 and its diastereomer is
displayed in Scheme 1. The basic strategy was to connect
the γ-lactone-δ-lactam core 3 with the lipid side chain 4 by
cross-olefin metathesis.9 For the construction of γ-lactone-
δ-lactam moiety 3 and its enantiomer, a chiral relay tactic
was envisioned. It was based on the hydroxyl group direc-
ted cis-diastereoselective vinylation of either R,β-epoxy
ester/amide 510 or R,β-unsaturated amide 6,11 both of
which were accessible from the corresponding enantiomer
of the building block 2e. Thus, from the existing chiral
center in the building block 2e, three other chiral centers
could be established in stereocontrolled manners. In this
study, more efficient methods, other than the asymmetric
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J. Org. Chem. Vol. 75, No. 12, 2010 4231

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SCHEME 2
SCHEME 4
SCHEME 3
the benzylation13a and opposed to the nonhydroxylated
δ-lactam systems.13b-f
Formation of the diastereomer 8 could be explained on the
basis of the predominant conformer B, where the two
substituents OTBS and Me were both in favorable equatorial
orientations (Scheme 3). Then, a stereoelectronic controlled
addition14 led to C, which underwent a fast conformational
equilibrium to give 8.15 The conformation of 8 was deduced
from the small coupling constants between the protons at
C-5 and C-6 (3J5,6 = 2.7 Hz) as well as the large coupling
constants between the protons at C-3 and C-4 (3J3,4 = 11.6,
7.5 Hz). The preferential axial orientation of protected
hydroxyl groups in saturated δ-lactams has been reported.15
The carbon-carbon double bond was introduced16 by
successive treatment of compound 8 with NaH and PhSeBr
at 0 °C, followed by oxidation of the resultant crude R-phenyl
selenide with a 30% aqueous hydrogen peroxide in CH2Cl2
and in situ elimination of the resultant selenoxide, which
produced compound 10 in 87% yield (Scheme 4). Epoxida-
tion of 10 was performed with tert-butyl hydroperoxide
(TBHP) in the presence of DBN17 at rt for 1 h giving
stereospecifically the epoxide 11 in 93% yield. The stereo-
chemistry of the epoxide was determined by the observed
correlation between H-4 and SiCH3 in the NOESY spec-
trum, and the stereochemical outcome of the reaction might
be attributed to the steric effect of the OTBS group. To
carry out a hydroxyl group-directed regio- and diastereo-
selective epoxide ring-opening reaction,10 O-desilylation
was first undertaken. Treatment of a THF solution of 11
with tetrabutylammonium fluoride at 0 °C provided the
desired epoxy alcohol 5 in 91% yield, along with 3% of the
catalytic transfer hydrogenation of the corresponding pro-
pargyl alcohol12 used in our previous synthesis of ent-
awajanomycin,6 were exploited for the synthesis of the
chiral nonracemic allylic alcohol moiety 4.
For the synthesis of segment ent-3, we first investigated
route A (cf. Scheme 1). As outlined in Scheme 2, deprotona-
tion of the known N-Boc-amide 76 with LiHMDS at -78 °C
followed by trapping the resultant enolate with benzyl
chloroformate produced smoothly the desired product 8 as
a single diastereomer in 80% yield, along with 13% of the
O-benzyloxycarbonylation product 9, which showed a char-
acteristic downfield signal of the olefinic proton at δH 4.78
(t, J = 3.7 Hz). The stereochemistry at the newly formed
stereocenter in 8 was established by NOESY experiments,
which implicated that the stereochemical outcome of the
reaction was the same with what we previously observed in
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SCHEME 5
FIGURE 3. Some cis-3,4-epoxy-2-piperidone alkaloids.
Payne rearrangement18 product 12. It is noteworthy that
the partial conversion of the epoxide 5 to 12 was also
observed by standing a pure sample of 5 in a refrigerator.
We next investigated the key vinylative ring-opening of
epoxide 5 in the hope of obtaining the vinylated product 13.
A literature search revealed that addition of carbon nucleo-
philes to epoxyesters could take place chemoselectively at
either ester19a,d or epoxide19a-c moiety, and CuI or CuBr
3
SMe2-mediated additions of Grignard reagents led to ep-
oxide ring-opening products.19a-c For 2,3-epoxypropano-
ates and their homologues in particular, the regiospecific
ring-opening at the β-position can be achieved by various
organometallic compounds.10g,19f,19g However, all attempts
(Piper methysticum).22c In addition, epoxy piperidines have
been shown to possess cytotoxicity.23
to perform a CuI or CuBr SMe2-mediated addition of
3
Thus, this approach was abandoned, and we turned to
investigate route B (cf. Scheme 1). In view of the synthesis of
natural enantiomer (þ)-awajanomycin, (R)-N-allyl-3-hydroxy-
glutarimide 18 was prepared from D-glutamic acid by following
the procedure described for its enantiomer.7e,f O-Silylation
(TBSCl, DMAP, imidazole, CH2Cl2, rt, overnight) gave the
building block (R)-2e in 93% yield (Scheme 5). Treatment of
(R)-2e with MeMgI in CH2Cl2 at -20 °C produced the C2 and
C6 adducts in 90:10 ratio. Without separation, the crude add-
ucts (a regio- and diastereomeric mixture) were subjected to
vinylmagnesium bromide to 5 were unsuccessful. No desired
product was isolated, instead, products arising from the
addition of the vinyl group to the ester group and the
N-Boc group were observed. The failure to achieve the
chemo- and regio-selective β-vinylation was attributed to
the severe steric hindrance of the ring system 5 (vide infra).
In spite of the unsuccessful attempts to serve as an ad-
vanced intermediate for the synthesis of (þ)-awajanomycin,
the enantioselective construction of highly functionalized
cis-3,4-epoxy-2-piperidone motif 5 is of value in organic
synthesis. Such a skeleton is found in some bioactive natural
products; however its enantioselective synthesis has been
rarely reported.20 For example, the mother nucleus cis-3,4-
epoxy-2-piperidone (14, tedanalactam) (Figure 3), isolated
from sponge Tedania ignis21a and leaves of Piper crassiner-
vium (Piperaceae),21b displays promising fungicidal activity.
Its N-acyl derivative, piplaroxide 15, is an ant-repellant
alkaloid isolated from Piper tuberculatum,22a 3,4-epoxy-
8,9-dihydropiplartine 16 was isolated from the leaves22b
and twigs of Piper verrucosum, and 3,4-epoxy-5-piper-
methystine 17 was isolated from roots of the kava shrub
BF3 OEt2-mediated Et3SiH reduction (-78 °C to rt, 5.5 h),
3
giving lactam 19 and its diastereomer 20 in an 88:12 ratio with a
combined yield of 78%. The high regio- and diastereoselectivities
observed for the stepwise reductive methylation of glutarimide
derivative 2e were in contrast with the similar reactions of the
N-benzyl, O-TBS protected malimide, where low regio- and
diastereoselectivities (C2/C6 addition = 64:36; dr = 82:18) were
obtained.24 Treatment of the major diastereomer 19 with 5 mol %
of RhCl3 hydrate in refluxing n-propanol25 for 2.5 h cleaved the
N-allyl group to give lactam 21 in 71% yield. During the formation
of the N-Boc-activated lactam 22, a remarkable solvent effect26 was
observed. Among the tested solvents (THF, NMP, MeCN, Py,
CH2Cl2), acetonitrile turned out to be the best [(Boc)2O, DMAP
(cat.), MeCN], which afforded 22 in 94% yield. The introduction
of a double bond into compound 22 was achieved in 83% yield by
phenylselenylation followed by oxidative elimination. Desilylation
of compound 23 under standard conditions (TBAF, THF, 0 °C,
1 h) produced the requisite amide (5R,6S)-6 in 90% yield.
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Chem. 2007, 72, 35–42.
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related example, see: (b) Luo, J.-M.; Dai, C.-F.; Lin, S.-Y.; Huang, P.-Q.
Chem. Asian J. 2009, 4, 328–335.
(26) Burk, M. J.; Allen, J. G. J. Org. Chem. 1997, 62, 7054–7057.
J. Org. Chem. Vol. 75, No. 12, 2010 4233

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SCHEME 6
SCHEME 7
TABLE 1. Conditions Tried for the One-Pot Conversion of 6 into 26
TABLE 2. Conditions Tried for the Conversion of Compound 27 into
Compound 25
entry
conditions
yield (%)
1
2
3
4
DMAP, NEt3, CNCO2CH3, THF
NaH, CNCO2CH3, THF
NaH, CNCO2CH3, THF, HMPA
NaH (2.2 equiv), ClCO2CH3 (2.1 equiv),
THF, HMPA (5 equiv)
NR
NR
NR
29 (62)
entry
1
conditions
yield (%)
28 (73)
CH2dCHMgBr (2.5 equiv), ZnCl2 (2.5 equiv),
CNCO2CH3 (3 equiv), HMPA (5 equiv), THF
CH2dCHMgBr (2.5 equiv), ZnMe2 (2.5 equiv),
CNCO2CH3 (3 equiv), HMPA (5 equiv), THF
CH2dCHMgBr (5 equiv), AlEt2Cl (5 equiv),
CNCO2CH3 (5 equiv), HMPA (5 equiv), CH2Cl2
CH2dCHMgBr (2.5 equiv), CNCO2CH3
(3 equiv), DMPU (5 equiv), THF
2
3
4
5
26 (36) þ 28 (34)
26 (36)
After extensive investigations, including use of organozinc
reagents generated from ZnCl228 or ZnMe2,29 or organoalu-
minum reagent generated from AlEt2Cl30 (cf. Table 1), we
found that use of vinylmagnesium bromide as the vinylation
reagent and HMPA as a cosolvent gave the best result
(Table 1, entry 5). Thus, compound (5R,6S)-6 was succes-
sively treated with 2.5 equiv of vinylmagnesium bromide and
3.0 equiv of the Mander’s reagent (CNCO2Me) in a mixed
THF-HMPA (HMPA: 6 = 5:1 molar ratio) solvent system
at -78 °C, then the reaction was warmed to rt and stirred for
2 h. Using this method, C,O-bis-methoxycarbonylated com-
pounds 25 and 26 were obtained in 49% yield and in 11: 89
diastereomeric ratio (determined by 1H NMR) in favor of the
3,4-trans-diastereomer 26, alongside with compound 27 in
9% yield (Scheme 7). The structures of diastereomer 26 and
its 3,4-cis-diastereomer 25 were ascertained by comparing
with their corresponding enantiomers,6 and the structure of
compound 27 was determined on the basis of analytical and
spectroscopic methods including NOESY experiment.
We next tried to transform compound 27 into 25. How-
ever, all attempts to perform O-methoxycarbonylation of the
hydroxyl group with the Mander’s reagent in the presence of
either triethylamine or NaH failed (Table 2, entries, 1-3).
The starting 27 remained intact. When methyl chloroformate
26 (34) þ 27 (19)
26 (49) þ 27 (9)
CH2dCHMgBr (2.5 equiv), CNCO2CH3
(3 equiv), HMPA (5 equiv), THF
produced the desired 4,5-cis-adduct 24 as a single diastereomer
in 68% yield (Scheme 6). The stereochemistry at C-4 of 24 was
established on the basis of the observed correlations between
H-4 and H-5 as well as H-4 and CH3 in the NOESY spectrum.
To our surprise, successive treatment of compound 24 with
2.2 equiv of LHMDS and 2.3 equiv of Mander’s reagent (CN-
CO2Me)27 gave the concomitantly C,O-bis-methoxycarbony-
lated compound 25 and its diastereomer 26 in 33% com-
bined yield with a ratio of 87:13 (determined by 1H NMR).
The 3,4-cis-stereochemistry for diastereomer 25 was as-
signed on the basis of the observed correlation between
H-3 and H-5 in the NOESY spectrum, while no such a
correlation was observed for its diastereomer 26. Forma-
tion of C,O-bis-methoxycarbonylated compound 25 as the
major product is somewhat surprising because the Man-
der’s reagent is known to be a chemoselective C-methox-
ycarbonylation reagent. Although unexpected, it was dis-
covered that compound 25 would be a useful substrate for
the subsequent hydroxylation. However, efforts to improve
the yields on both steps failed, which prompted us to per-
form a one-pot transformation of 6 to 25.
(28) (a) Dunkerton, L.; Euske, J. M.; Serino, A. J. Carbohydr. Res. 1987,
171, 89–107. (b) Shintani, R.; Yamagami, T.; Hayashi, T. Org. Lett. 2006, 8,
4799–4801.
(29) Yamaguchi, J.; Toyoshima, M.; Shoji, M.; Kakeya, H.; Osada, H.;
Hayashi, Y. Angew. Chem., Int. Ed. 2006, 45, 789–793.
(30) Rodeschini, V.; Boiteau, J. G.; Weghe, P. V. D.; Tarnus, C.;
Eustache, J. J. Org. Chem. 2004, 69, 357–373.
(27) Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425–5428.
4234 J. Org. Chem. Vol. 75, No. 12, 2010

Fu et al.
JOCArticle
FIGURE 4. B3LYP/6-31G*-optimized geometries and relative energies of three conformers of 27 together with 2D NOESY correlations: no
intramolecular hydrogen bond formed (27-conformers A, C) and intramolecular hydrogen bond formed (27-conformer B). Distances of O-H
bonds are given in angstroms.
SCHEME 8
was used as a methoxycarbonylation reagent, compound
2931 was obtained in 62% yield.
The failure to convert compound 27 into compound 25
led us to study the structure of this compound in detail. To
this end, quantum chemical calculations at B3LYP/6-31G*
level were undertaken, and three stable conformers of 27,
conformers A-C, were located, which all adopt a boat
conformation. As observed from Figure 4, the formation of
an intramolecular H-bond was indicated by a short distance
˚
(1.932 A) between H (5-OH) and O (3-CO) in 27-conformer
B, which was more stable than the no H-bonding 27-
conformer A by 2.92 kcal/mol, although in the latter case
both C3 and C5 substituents disposed the equatorial orien-
tation. In contrast, another non-H-bonding 27-conformer
C, whose C3 and C5 substituents also adopt axial orienta-
tion as those of 27-conformer B, was less stable than 27-
1
conformer A by 4.24 kcal/mol. In addition, the H NMR
experiments also provided evidence that a strong intramo-
lecular H-bond existed: the resonance peak of H-3 (δ 4.00)
readily exchanged with D2O in DMSO-d6, while that of the
hydroxyl group at C-5 (δ 7.07) exchanged very slowly. A
complete exchange was observed only after standing in a
refrigerator for nine days. Consequently, the hydroxyl
group was fairly inert to any acylation. The DEPT 90
experiments, which selectively acquired methine carbon
resonance, also indicated that H-3 (δ 4.00) exchanged
readily with D2O in DMSO-d6. The methine C-3 peak was
recorded at 52.6 ppm in DMSO- d6 in DEPT 90 spectrum,
while the peak was not shown when D2O was added. It was
suggested that H-3 exchanged with D2O and the methine
C-3 was converted to a quaternary carbon, which cannot be
recorded in a DEPT 90 spectrum.
In contrast with the high acidity of the H-3 of diastereomer
27, the H-3 of diastereomer 26 was much less acidic: after
standing in a refrigerator for 4 days, only 55.5% of the
resonance peak of H-3 (δ 3.58) was exchanged with D2O in
DMSO-d6.
At this stage, we have a clearer image about the mechanism
of the reaction (Scheme 8). First, the conjugate addition of
vinylmagnesium bromide was followed by the capture of the
resultant enolate intermediate with the Mander’s reagent,
leading to the formations of enolate E, and alcolates F and
G, with the conformer F as the predominant intermediate.
Further reaction of alcolates F with Mander’s reagent pro-
duced the desired 26, while for alcoholate G, due to the high
acidity of the H-3, a proton exchange occurred spontaneously
(31) We were unable to purify this compound, which prohibited its full
characterization.
J. Org. Chem. Vol. 75, No. 12, 2010 4235

Fu et al.
JOCArticle
FIGURE 5. B3LYP/6-31G*-optimized conformers and relative energies of 25 and 26 together with 2D NOESY correlations.
SCHEME 9
FIGURE 6. 2D HMBC and NOESY correlations of 30.
to give enolate H, which was stabilized by the H-bonding.
Under the control of both A1,2-interaction and stereoelectro-
nic effect, protonation of the intermediated H then gave
FIGURE 7. B3LYP/6-31G*-optimized geometries and relative en-
ergies of 30 (with R configuration at C-3) and 300 (with S config-
uration at C-3).
diastereomer 27 as a sole diastereomer. In the case of stepwise
vinylation-methoxycarbonylation (cf. Scheme 6), it was pos-
sible that methoxycarbonylation first occurred to give lithium
enolate I, which reacted, via a conformation similar to that
displayed in Scheme 3 (conformer A), with a second Mander’s
reagent to give 25 as the major diastereomer. However, for
what reason was lithium enolate I formed as the primary
intermediate in the stepwise manner (Scheme 6) while magne-
sium alcoholate F formed predominantly in the tandem
reaction (Scheme 7) remained unclear.
4.16 kcal/mol; thus, 26 is the thermodynamically more stable
product. Unexpectedly, in an attempt to convert epimer 25
into 26 by treatment of 25 with DBN in THF at 0 °C for 5 h,
the expected epimer 26 was not observed; instead, the start-
ing 25 was recovered (Scheme 9). More interestingly, treat-
ment of epimer 26 with DBN in THF at 0 °C for 6 h led to
bicyclic product 30 in 77% yields.
To get an insight into the conformations of the diastere-
omers 25 and 26, we also undertook quantum chemical
calculations at B3LYP/6-31G* level. As shown in Figure 5,
diastereomer 25 prefers a boat conformation with axial H-3,
H-5, H-6, and equatorial H-4, which is in agreement with the
coupling constant between H-3 and H-4 (J3,4 = 11.2 Hz) and
H-5 and H-6 (J5,6 = 9.2 Hz), while diastereomer 26 prefer-
entially adopts a chair conformation with equatorial H-5,
H-6, and axial H-3, H-4, which is in agreement with coupling
constant between H-3 and H-4 (J3,4 = 12.1 Hz), H-5 and H-6
(J5,6 = 2.5 Hz). Diastereomer 26 is more stable than 25 by
The structure of compound 30 was determined by 1H-1H
COSY combined with HSQC, HMBC, and DEPT-135
techniques. The C3-C5 bond formation was confirmed
by the connectivities around the quaternary carbon, i.e.,
C-3/H-6, C-2/H-5 and C-7/H-5, which was established by a
HMBC experiment (Figure 6). The NOEs detected between
H-4/H-5 and H-5/CH3 suggested R configuration at C-5.
However, the relative stereochemistry at C-3 could not be
established by NOESY experiments. To tackle this pro-
blem, quantum chemical calculations were undertaken
once again.
4236 J. Org. Chem. Vol. 75, No. 12, 2010

Fu et al.
JOCArticle
TABLE 3. Asymmetric Addition of Alkynylzinc Reagents to Octanal
entry
alkyne (equiv)
ZnMe2 (equiv)
BINOL (equiv)
Ti(OPri)4 (equiv)
solvent
time (h)
yield (%)
% ee (config)
1
2
3
4
5
6
4
4
4
4
6
6
4
4
4
4
R (0.4)
S (0.4)
R (1.0)
R (1.0)
R (1.0)
R (1.0)
1.0
1.0
2.5
2.5
2.5
2.5
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CH2Cl2
CH2Cl2
5.5
30
26
26
26
18, 0 °C
36
76
70
93
92
87
86.7 (S)
84.5 (R)
83.5 (S)
77.5 (S)
83.2 (S)
78.4 (S)
6
ZnEt2, 6
n-octanal (1.0 molar equiv)
SCHEME 10
SCHEME 11
SCHEME 12
As the computational results showed (Figure 7), 30 (with
R-configuration at C-3) is more stable than 300 (with S-config-
uration at C-3) by 68.01 kcal/mol, and in 30, the H5-C5-C6-
H6 dihedral angle is 97.00, which is in agreement with the
observed coupling constant (3J5,6 ≈ 0 Hz).
Although the yield of compound 26 was only 49%, taking
into account that two C-C bonds and a C-O bond were
formed in one-pot, and two adjacent chiral centers were
established in a highly cis-diastereoselective way, this trans-
formation is both efficient and highly diastereoselective in
establishing the C-4 stereogenic center.
As we have demonstrated in the synthesis of (-)-
awajanomycin,6 both diastereomers of compound 26 might
be used in the subsequent synthesis of the core structure 3.
Successive treatment of the diastereomeric mixture of com-
pound 26 with sodium hydride and the Davis’ oxaziridine32
in THF at 0 °C afforded compound 31 as a single diaster-
eomer in 64% yield (Scheme 10). Cleavage of the N-Boc
group by treatment of compound 31 with trifluoroacetic
acid in CH2Cl2 at 0 °C for 30 min smoothly gave lactam 32
in 88% yields. Finally, stirring a methanolic solution of 32 in
the presence of 1.2 equiv of K2CO3, as described for its
enantiomer6 afforded the segment 3 in 58% yield. Using only
0.12 molar equiv of K2CO3, the yield was significantly im-
proved to 81%. Thus, starting from glutarimide derivative (R)-
18, segment 3 was synthesized in 10 steps with an overall yield
of 8.1%, which is a significant improvement when compared to
the synthesis of ent-3 (4.9%).6
We next focused on the synthesis of the chiral lipid side
chain 4. In our previous synthesis, five steps were required for
either enantiomer of 4,6 herein we set to explore a more
efficientmethod. We first studiedthe enantioselectiveaddition
of monoprotected ethyne to n-octanal.33 The method of Pu
and co-workers was tried.34 As can be seen from Table 3, only
moderate enantioselectivities (78%-87% ee) were obtained.
(33) For a recent review on the enantioselective addition of alkyne
nucleophiles to carbonyl groups, see: Trost, B. M.; Weiss, A. H. Adv. Synth.
Catal. 2009, 351, 963–983.
(34) (a) Gao, G.; Xie, R.-G.; Pu, L. Proce. Natl. Acad. Sci. U.S.A. 2004,
101, 5417–5420. (b) Gao, G.; Moore, D.; Xie, R.-G.; Pu, L. Org. Lett. 2002, 4,
4143–4146. (c) Pu, L. Tetrahedron 2003, 59, 9873–9886.
(32) (a) Dounay, A. B.; Forsyth, C. J. Org. Lett. 1999, 1, 451–453. (b)
White, J. D.; Carter, R. G.; Sundermann, K. F. J. Org. Chem. 1999, 64, 684–
685. (c) White, J. D.; Shin, H.; Kim, T. S.; Cutshall, N. S. J. Am. Chem. Soc.
1997, 119, 2404–2419. (d) Evans, D. A.; Morrissey, M. M.; Dorow, R. L.
J. Am. Chem. Soc. 1985, 107, 4346–4348.
J. Org. Chem. Vol. 75, No. 12, 2010 4237

Fu et al.
JOCArticle
SCHEME 13
Other catalytic systems35,36 were also tried and were shown to
be not reactive enough.
The stage was set for the key cross-olefin metathesis
reaction. In the presence of 20 mol % of Grubbs’ second-
generation catalyst,41 the coupling of segment 3 with seg-
ment (R)-4 in CH2Cl2 at 34 °C for 6 h proceeded smoothly to
give 11-epi-awajanomycin (38) in 58% yield (based on 3),
along with the homocoupling product (8R,11R)-39 in 20%
yield (based on R-4) (Scheme 13).
We next tried another approach. Vinyl ketone 35 was
then prepared from Weinreb amide37 34 by reaction with
vinylmagnesium bromide. The enantioselective reduction by
Corey’s method [(R)-CBS-Me, BH3 Me2S or BH3 NEt2Ph,
3
3
-78 to þ20 °C],38 however, gave the corresponding allylic
alcohol in only 69-82% ee and 70-88% yields (Scheme 11).
Finally, the protocol developed by Yadav and co-workers39
was attempted. To this end, commercially available E-allylic
alcohol 36 was subjected to the Sharpless asymmetric
epoxidation40 to give the 2,3-epoxy alcohol (2S,3S)-37 in
94% yield (Scheme 12). Titanium(III) [(C5H5)2TiCl]-in-
duced regioselective deoxygenation of 37 led smoothly to
the formation of (S)-dec-1-en-3-ol 4 in 85% yield. The
enantiomeric excess of (S)-4 was determined to be >99%
by chiral HPLC analysis of its O-benzyloyl derivative.
Using (-)-DIPT in the Sharpless asymmetric epoxidation,
and following the same procedure as that described for
(2S,3S)-37, (R)-4 was obtained in 84% yield and >99% ee.
In that way, from commercially available E-allylic alcohol
36, (S)-4 and (R)-4 were synthesized in just two steps,
respectively, with high overall yields (79.4% and 76.4%)
and excellent enantioselctivities (>99% ee).
Similarly, the cross-coupling of segment 3 with segment
(S)-4 catalyzed by the same catalyst afforded (þ)-awajano-
mycin (1) in 59% yield, along with the homocoupling
product (8S,11S)-39 in 24% yield. It should be mentioned
that the reaction in toluene at 70 °C gave poorer yields (22%
1
of 1 and 17% of 39). The H and 13C NMR spectroscopic
data of the two synthetic products (1 and its C-11 epimer 38)
are in accordance with those of the natural product, which
prohibited the identification of the natural product from two
synthetic products. By comparing the optical rotation data
of the two synthetic diastereomers with that of the natural
product [synthetic 1: [R]20D þ70.9 (c 0.6, CH3OH) [lit. [R]20
D
þ78 (c 0.1, CH3OH)] for natural product;4 [R]20 -70.5
D
(c 0.21, CH3OH) for its synthetic enantiomer;6 38: [R]20
D
þ47.5 (c 0.52, CH3OH)], compound 1 was determined as the
natural product (þ)-awajanomycin (1). Through the total
synthesis of the natural (þ)-1 and its C-11 epimer 38, we
further confirmed the absolute configuration of the natural
(þ)-awajanomycin as 3R,5R,6S,8S,11S.
€
(35) (a) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc.
2000, 122, 1806–1807. (b) Frantz, D. E.; Fassler, R.; Tomooka, C. S.;
It should be noted that, in our previous communication,6
the stereochemistry of the homocoupling products (8R,11R)-
39 and (8S,11S)-39 was assigned as Z on the basis of the
estimated small coupling constants of the proton at C-9 of
the homocoupling products (J = 3.8, 1.9 Hz). Considering
that the cross-metathesis of 3 and 4 led to E-olefins such as 38
and 1, the Z-geometry previously assigned for the homo-
coupling products came into question. It should be recognized
€
Carreira, E. M. Acc. Chem. Res. 2000, 33, 373–381.
(36) Jiang, B.; Chen, Z.-L.; Xiong, W.-N. Chem. Commun. 2002, 1524–
1525.
(37) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815–3818.
(38) (a) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986–
2012. (b) Matsuo, J.-I.; Kozai, T.; Nishikawa, O.; Hattori, Y.; Ishibashi, H.
J. Org. Chem. 2008, 73, 6902–6904. (c) Stone, G. B. Tetrahedron: Asymmetry
1994, 5, 465–472.
(39) (a) Yadav, J. S.; Shekharam, T.; Gadgil, V. R. J. Chem. Soc., Chem.
Commun. 1990, 843–844. (b) Yadav, J. S.; Madabhushi, Y.; Prasad, A. R.
Tetrahedron 1998, 54, 7551–7562. For a related method, see: (c) Sarandeses,
ꢂ
L. A.; Mourino, A.; Luche, J.-L. J. Chem. Soc., Chem. Commun. 1991, 818–
820. (d) Fujii, N.; Habashita, H.; Akaji, M.; Nakai, K.; Ibuka, T.; Fujiwara,
M.; Tamamura, H.; Yamamoto, Y. J. Chem. Soc., Perkin. Trans. 1 1996,
865–866. For recent applications of this method, see: (e) Evans, P. A.;
Murthy, V. S. J. Org. Chem. 1998, 63, 6768–6769. (f) Aggarwal, V. K.;
Davies, P. W.; Schmidt, A. T. Chem. Commun. 2004, 1232–1233.
(40) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765–5780.
(41) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953–956. (b) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H.
J. Am. Chem. Soc. 2003, 125, 11360–11370.
4238 J. Org. Chem. Vol. 75, No. 12, 2010

Fu et al.
JOCArticle
that diol 39 is a C2-symmetric chiral molecule, the protons at
C-9 and C-10 are equivalent, and do not have a coupling
constant (it was confirmed by decoupling the proton at C-8).
Therefore, it was not possibletodetermine the geometry ofthe
C-C double bond according to the coupling constant. To
tackle this problem, diol 39 was monoacetylated (Ac2O, NEt3,
DMAP, CH2Cl2) to give compound 40. From the vicinal
coupling constant of the protons at C-9 and C-10 of com-
pound 40 (J9,10 = 15.6 Hz), the stereochemistry of olefin 40
was determined as E. Thus, diols (8R,11R)-39 and (8S,11S)-39
each possessed a E-geometry. The Z-geometry previously
assigned for the homocoupling products6 should be revised
as E, and the observed coupling constants J = 3.8, 1.9 Hz
1H), 2.37 (ddd, J = 13.6, 11.6, 2.7 Hz, 1H), 3.83 (dd, J = 11.6,
7.5 Hz, 1H), 3.93 (dt, J = 3.6, 2.7 Hz, 1H), 4.20 (qdd, J = 6.8,
2.7, 2.0 Hz, 1H), 5.16 (d, J = 12.4 Hz, 1H), 5.26 (d, J = 12.4 Hz,
1H), 7.30-7.42 (m, 5H); 13C NMR (100 MHz, CDCl3) δ -5.1,
-4.9, 17.9, 19.4, 25.6, 27.9, 29.1, 47.5, 58.5, 67.1, 67.8, 83.0,
128.1, 128.2, 128.5, 135.6, 152.8, 167.0, 170.4; MS (ESI, m/z) 500
(M þ Naþ, 100). Anal. Calcd for C25H39NO6Si: C, 62.86; H,
8.23; N, 2.93. Found: C, 62.71; H, 8.43; N, 2.83.
tert-Butyl (5S,6R)-2-(benzyloxycarbonyloxy)-5-(tert-butyldi-
methylsilyloxy)-6-methyl-4,5-dihydropyridine-1(2H)-carboxylate
(9): pale yellow oil; [R]20D -65.4 (c 1.2, CHCl3); IR (film) νmax
2949, 2930, 2852, 1704, 1680, 1369, 1330, 1299, 1229 cm-1; 1H
NMR (400 MHz, CDCl3) δ 0.07 (s, 3H), 0.08 (s, 3H), 0.89 (s,
9H), 1.07 (d, J = 7.0 Hz, 3H), 1.42 (s, 9H), 2.10 (dd, J = 18.4,
3.7 Hz, 1H), 2.30 (ddd, J = 18.4, 4.3, 3.7 Hz, 1H), 3.79 (dd, J =
4.3, 3.2 Hz, 1H), 4.42 (qd, J = 7.0, 3.2 Hz, 1H), 4.78 (t, J =
3.7 Hz, 1H), 5.19 (d, J = 12.2 Hz, 1H), 5.24 (d, J = 12.2 Hz, 1H),
7.32-7.44 (m, 5H); 13C NMR (100 MHz, CDCl3) δ -5.0, 14.1,
18.0, 25.7, 28.0, 28.3, 55.1, 67.9, 69.7, 80.8, 96.6, 128.2, 128.4
(2C), 134.8, 138.5, 152.4, 152.9; MS (ESI, m/z) 500 (M þ Naþ,
100). Anal. Calcd for C25H39NO6Si: C, 62.86; H, 8.23; N, 2.93.
Found: C, 62.76; H, 8.18; N, 2.83.
3
4
should be reassigned to J8,9 and J9,11 respectively. This is
also proven by the observed absorption at 970 cm-1 in the IR
spectrum of 39, which is an indication of an E-olefin (990-
960 cm-1 for E-olefins; 725-675 cm-1 for Z-olefins).
Conclusion
We have reported the first total synthesis of the natural
product (þ)-awajanomycin (1) and its diastereomer (þ)-
11-epi-awajanomycin (38). Starting from the building block
18 and E-allylic alcohol 36, the diastereodivergent syntheses
of 1 and 11-epi-awajanomycin 38 have been achieved both in
13 steps with overall yields of 3.8% and 3.6%, respectively.
The low reactivity of compound 27 toward methoxycarbo-
nylation agents has been attributed to the presence of a
strong intramolecular H-bond on the basis of both quantum
chemical calculations and D2O exchange experiments. That
also used to reveal the favored conformations of the inter-
mediates 25 ∼ 27, which were helpful to understand the
mechanism and stereochemical outcome of the tandem
reaction (6 f 26). Through this work, the absolute config-
uration of the natural product was further confirmed, and
the geometry of the homocoupling products (8R,11R)-39
and (8S,11S)-39 have been revised as E. Comparing with the
route developed for the unnatural (-)-awajanomycin (-)-1,6
the improved synthetic route presented herein was three
steps shorter, and the overall yield was improved from
1.9% to 3.8%.
3-Benzyl 1-tert-Butyl (5S,6R)-5-(tert-butyldimethylsilyloxy)-
6-methyl-2-oxo-5,6-dihydropyridine-1,3(2H)-dicarboxylate (10).
To a suspension of NaH (91.2 mg, 60% in mineral oil, 2.28
mmol) in THF (7 mL) at 0 °C was added dropwise a solution of 8
(726 mg, 1.52 mmol) in THF (4 mL). After the mixture was
stirred for 30 min at 0 °C, a solution of phenylselenyl bromide
(424 mg, 1.82 mmol) in THF (4 mL) was added. The reaction
was stirred for 1 h at this temperature before being quenched
with saturated aqueous ammonium chloride solution (3 mL).
The mixture was extracted with EtOAc (6 mL ꢀ 3), washed with
brine, dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The residue was diluted with CH2Cl2
(8 mL), and 30% aqueous H2O2 solution was added dropwise
until the reaction was complete by TLC monitoring. The mixture
was quenched with saturated aqueous NaHCO3 solution at 0 °C,
extracted with CH2Cl2 (6 mL ꢀ 3), washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. Theresidue was purifiedbycolumn chromatography on
silica gel (eluent: EtOAc/PE 1:10) to give compound 10 (631 mg,
87%) as a white solid: mp 122-124 °C (PE/EtOAc); [R]20
D
þ148.7 (c 0.94, CHCl3); IR (film) νmax 2953, 2930, 2852, 1723,
1704, 1692, 1291, 1268 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.10
(s, 3H), 0.12 (s, 3H), 0.88 (s, 9H), 1.24 (d, J = 7.0 Hz, 3H), 1.56 (s,
9H), 4.11 (dd, J = 6.0, 1.8 Hz, 1H), 4.51 (qt, J = 7.0, 1.8 Hz, 1H),
5.29(d, J = 12.5 Hz, 1H), 5.32 (d, J = 12.5 Hz, 1H), 7.13 (dd, J =
6.0, 1.8 Hz, 1H), 7.32-7.46 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ -4.9, -4.4, 18.0, 18.1, 25.5, 28.0, 57.1, 66.0, 67.2,
83.3, 128.2 (2C), 128.5, 131.0, 135.5, 142.5, 152.4, 158.6, 163.9;
MS (ESI, m/z) 498 (M þ Naþ, 100). Anal. Calcd for C25H37NO6-
Si: C, 63.13; H, 7.84; N, 2.94. Found: C, 63.59; H, 8.04; N, 2.95.
3-Benzyl 1-tert-Butyl (3S,4S,5R,6R)-5-(tert-butyldimethyl-
silyloxy)-6-methyl-3,4-epoxy-2-oxopiperidine-1,3-dicarboxylate
(11). DBN (0.2 mL, 1.64 mmol) was added to a stirring solution
of tert-butyl hydroperoxide (TBHP, 0.5 mL, 5.5 M solution in
nonane, 2.74 mmol) in CH2Cl2 (7.7 mL). After the mixture was
stirred at room temperature for 20 min, a solution of 10 (651 mg,
1.37mmol) inCH2Cl2 (6 mL) was addedat0 °C. The reaction was
stirred for 2 h at 0 °C before being quenched with saturated
aqueous ammonium chloride solution. The mixture was ex-
tracted with CH2Cl2 (7 mL ꢀ 3), washed with brine, dried over
anhydrous Na2SO4, filtered, and evaporated. The residue was
purified by column chromatography on silica gel (eluent: EtOAc/
PE 1:10) to give compound 11 (629 mg, 94%) as a white solid: mp
112-113 °C (PE/EtOAc); [R]20D þ27.3 (c 0.94, CHCl3); IR (film)
Experimental Section
3-Benzyl 1-tert-Butyl (3S,5S,6R)-5-(tert-butyldimethylsilyloxy)-
6-methyl-2-oxopiperidine-1,3-dicarboxylate (8). To a solution
of hexamethyldisilazane (HMDS, 0.26 mL, 1.24 mmol) in THF
(3.9 mL) at -78 °C was added n-butyllithium (0.47 mL, 2.5 M in
hexane, 1.18 mmol). After the mixture was stirred for 20 min at
-78 °C, a solution of 7 (203 mg, 0.59 mmol) in THF (2 mL) was
added dropwise. The mixture was stirred at -78 °C for 1 h, and
benzyl chloroformate (0.1 mL, 0.65 mmol) was added dropwise.
The reaction was stirred for 1 h at this temperature before being
quenched with saturated aqueous ammonium chloride solution
(1 mL). The mixture was extracted with EtOAc (3 mL ꢀ 3),
washed with brine, dried over anhydrous Na2SO4, filtered, and
evaporated. The residue was purified by column chromatography
on silica gel eluting with EtOAc/PE (1:10) to give compound 8
(226 mg, yield 80%) and 9 (37 mg, yield 13%).
Compound 8: white solid; mp 101-102 °C (EtOAc/PE);
[R]20 -8.0 (c 0.97, CHCl3); IR (film) νmax 2949, 2934, 2848,
D
1735, 1715, 1696, 1291, 1241, 1143 cm-1; 1H NMR (400 MHz,
CDCl3) δ 0.067 (s, 3H), 0.071 (s, 3H), 0.86 (s, 9H), 1.26 (d, J =
6.8 Hz, 3H), 1.50 (s, 9H), 2.05 (dddd, J = 13.6, 7.5, 3.6, 2.0 Hz,
1
νmax 2961, 2934, 2856, 1758, 1723, 1272, 1256, 1132 cm-1; H
NMR (400 MHz, CDCl3) δ 0.06 (s, 3H), 0.09 (s, 3H), 0.83 (s, 9H),
J. Org. Chem. Vol. 75, No. 12, 2010 4239

Fu et al.
JOCArticle
1.30 (d, J = 7.1 Hz, 3H), 1.52 (s, 9H), 3.61 (dd, J = 3.1, 2.0 Hz,
1H), 4.22 (dd, J = 3.1, 2.0 Hz, 1H), 4.29 (qt, J = 7.1, 2.0 Hz, 1H),
5.22 (d, J = 12.4 Hz, 1H), 5.37 (d, J = 12.4 Hz, 1H), 7.27-7.39
(m, 5H); 13C NMR (100 MHz, CDCl3) δ -5.0, -4.9, 17.8, 18.7,
25.4, 25.7, 27.8, 57.5, 57.7, 60.4, 67.6, 83.9, 128.1, 128.3, 128.4,
134.9, 151.9, 163.8, 164.4; MS (ESI, m/z) 514 (M þ Naþ, 100).
Anal. Calcd for C25H37NO7Si: C, 61.07; H, 7.59; N, 2.85. Found:
C, 60.91; H, 7.97; N, 2.80.
mixture was stirred at -20 °C for 3 h. A saturated aqueous
solution of NH4Cl (15 mL) was added, and the aqueous layer
was extracted with CH2Cl2 (25 mL ꢀ 3). The combined organic
layers were washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The N,O-
acetal was used in the next step without further purification.
To a cooled solution (-78 °C) of the above residue (N,O-acetal)
in CH2Cl2 (42 mL) were successively added dropwise Et3SiH
3-Benzyl 1-tert-Butyl (3S,4S,5R,6R)-5-Hydroxy-6-methyl-
3,4-epoxy-2-oxopiperidine-1,3-dicarboxylate (5). A 1 M solution
of tetrabutylammonium fluoride (TBAF) in THF (0.75 mL, 0.75
mmol) was added to a solution of 11 (184 mg, 0.375 mmol) in
THF (1.3 mL) at 0 °C. The reaction mixture was stirred for 1 h
and then quenched with saturated aqueous NH4Cl (2 mL). The
mixture was extracted with EtOAc (3 mL ꢀ 3), washed with
brine, dried over anhydrous Na2SO4, filtered, and evaporated.
The residue was purified by column chromatography on silica
gel (eluent: EtOAc/PE 1:1) to give compounds 5 (129 mg, 91%)
as a colorless oil and a small amount compounds 12 (5 mg, 3%)
as a white solid.
(16.6 mL, 105 mmol) and BF3 OEt2 (3.9 mL, 31.5 mmol). The
3
mixture was stirred at -78 °C for 3 h and then allowed to warm for
∼2.5 h. The reaction was quenched with a saturated aqueous
NaHCO3 (10 mL) and extracted with CH2Cl2 (15 mL ꢀ 3). The
combined organic layers were washed with brine, dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel
(eluent: EtOAc/PE 2:3) to give compound 19 (2045 mg, 69%) and
its diastereomer 20 (267 mg, 9%) (diastereomeric ratio = 88:12).
19 (major diastereomer): colorless oil; [R]20 -81.8 (c 1.0,
D
CHCl3); IR (film) νmax 2953, 2930, 2852, 1638, 1470, 1256 cm-1
;
1H NMR (400 MHz, CDCl3) δ 0.07 (s, 6H), 0.88 (s, 9H), 1.17
(d, J = 6.8 Hz, 3H), 1.69-1.78 (m, 1H), 2.00 (dddd, J = 18.6,
11.9, 6.6, 2.1 Hz, 1H), 2.32 (ddd, J = 17.8, 6.6, 2.1 Hz, 1H), 2.62
(ddd, J = 17.8, 11.9, 7.1 Hz, 1H), 3.32-3.40 (m, 2H), 3.83 (dt,
J = 4.4, 2.1 Hz, 1H), 4.64 (ddt, J = 15.6, 4.3, 2.8 Hz, 1H), 5.10
(ddt, J = 10.3, 2.8, 1.6 Hz, 1H), 5.22 (ddt, J = 17.2, 2.8, 1.6 Hz,
1H), 5.72 (dddd, J = 17.2, 10.3, 6.8, 4.3 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ -5.0, -4.9, 17.9, 18.5, 24.3, 25.6, 26.8, 46.9,
58.5, 69.0, 116.5, 133.1, 169.0; MS (ESI, m/z) 306 (M þ Naþ,
100). Anal. Calcd for C15H29NO2Si: C, 63.55; H, 10.31; N, 4.94.
Found: C, 63.21; H, 10.12; N, 5.13.
Compound 5: [R]20D þ3.1 (c 1.0, CHCl3); IR (film) νmax 3471,
2976, 2934, 1758, 1276, 1252, 1155, 1132 cm-1;1H NMR (400 MHz,
CDCl3) δ1.30 (d, J = 7.1 Hz, 3H), 1.51 (s, 9H), 3.49 (d, J = 5.9 Hz,
1H, OH, D2O exchangeable), 3.76 (dd, J = 2.9, 1.8 Hz, 1H),
4.23-4.28 (m, 1H), 4.35 (qt, J = 7.1, 1.8 Hz, 1H), 5.26 (s, 2H),
7.28-7.39 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 19.1, 27.8,
57.6 (2C), 60.1, 66.7, 67.9, 84.3, 128.2, 128.4, 128.5, 134.7,
151.8, 163.9, 164.6; MS (ESI, m/z) 400 (M þ Naþ, 100). Anal.
Calcd for C19H23NO7: C, 60.47; H, 6.14; N, 3.71. Found: C,
60.21; H, 6.50; N, 3.60.
3-Benzyl 1-tert-butyl (3S,4R,5R,6R)-3-hydroxy-6-methyl-4,5-
epoxy-2-oxopiperidine-1,3-dicarboxylate (12): white solid; mp
105-106 °C (EtOAc/PE); [R]20D -63.9 (c 1.1, CHCl3); IR (film)
(5R,6R)-1-Allyl-5-(tert-butyldimethylsilyloxy)-6-methylpiper-
idin-2-one (20). 20 (minor diastereomer): colorless oil; [R]20
D
þ54 (c 1.2, CHCl3); IR (film) νmax 2949, 2926, 2852, 1642, 1470,
1252, 1093 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.05 (s, 3H),
0.06 (s, 3H), 0.88 (s, 9H), 1.18 (d, J = 6.6 Hz, 3H), 1.78 (dddd,
J = 17.1, 7.8, 4.4, 3.9 Hz, 1H), 1.88-1.99 (m, 1H), 2.40 (ddd,
J = 18.2, 9.4, 7.8 Hz, 1H), 2.53 (ddd, J = 18.2, 7.4, 3.9 Hz, 1H),
3.35-3.43 (m, 1H), 3.45-3.52 (m, 1H), 3.98 (dt, J = 10.6,
4.4 Hz, 1H), 4.48 (ddt, J = 15.4, 4.6, 1.7 Hz, 1H), 5.11-5.14 (m,
1H), 5.15-5.17 (m, 1H), 5.76 (dddd, J = 18.1, 9.3, 6.9, 4.6 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ -5.0, -4.7, 13.7, 18.0, 25.4,
25.7, 29.0, 47.4, 55.8, 68.2, 116.8, 133.4, 168.8; MS (ESI, m/z)
306 (M þ Naþ, 100). Anal. Calcd for C15H29NO2Si: C, 63.55; H,
10.31; N, 4.94. Found: C, 63.30; H, 10.12; N, 5.11.
ν
max 3432, 2976, 2934, 1723, 1272, 1241, 1140 cm-1; 1H NMR
(400 MHz, CDCl3) δ 1.48 (d, J = 6.8 Hz, 1H), 1.51 (s, 9H), 3.38
(dd, J = 4.1, 2.4 Hz, 1H), 3.41 (dd, J = 4.1, 1.2 Hz, 1H), 4.24
(s, 1H, OH, D2O exchangeable), 4.79 (qdd, J = 6.8, 2.4, 1.2 Hz,
1H), 5.31 (d, J = 12.4 Hz, 1H), 5.44 (d, J = 12.4 Hz, 1H), 7.28-
7.41 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 17.4, 27.9, 49.9, 52.1,
52.9, 68.7, 77.5, 84.1, 127.8, 128.4, 128.6, 134.7, 151.6, 165.6, 170.3;
MS (ESI, m/z) 400 (M þ Naþ, 100). Anal. Calcd for C19H23NO7:
C, 60.47; H, 6.14; N, 3.71. Found: C, 60.40; H, 6.38; N, 3.60.
(R)-1-Allyl-3-(tert-butyldimethylsilyloxy)piperidine-2,6-dione
(2e). To a solution of (R)-N-allyl-3-hydroxyglutarimide 18
(2.929 g, 17.3 mmol) prepared from D-glutamic acid by the
procedure described for its enantiomer7e in CH2Cl2 (87 mL) were
added successively imidazole (2.353 g, 34.6 mmol), 4-(N,N-di-
methylamino)pyridine (DMAP) (422 mg, 3.5 mmol), and tert-
butyldimethylsilyl chloride (3.114 g, 20.8 mmol) at room tempera-
ture under N2. After being stirredat rt overnight, the reaction was
quenched with saturated aqueous NH4Cl. The mixture was
extracted with CH2Cl2 (20 mL ꢀ 3), washed with brine, dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography on
silica gel (eluent: EtOAc/PE 1:12) to give compound 2e (4.550 g,
(5R,6S)-5-(tert-Butyldimethylsilyloxy)-6-methylpiperidin-2-one
(21). Toa solutionofcompound19 (2.264 g, 8.0 mmol) inn-PrOH
(16 mL) was added RhCl3 xH2O (107 mg, 0.4 mmol). The
3
solution was heated to reflux for 2.5 h. After being cooled to
room temperature, the reaction mixture was concentrated under
reduced pressure and purified by column chromatography on
silica gel (eluent: EtOAc/PE 1:1) to give compound 21 (1.383 g,
71%) as a white solid: mp 101-103 °C (PE/EtOAc); [R]20D -25.3
(c 0.97, CHCl3); IR (film) νmax 3198, 3089, 2949, 2929, 2852, 1669,
1459, 1404, 1322, 1252 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.07
(s, 6H), 0.88 (s, 9H), 1.14 (d, J = 6.4 Hz, 3H), 1.67-1.78 (m, 1H),
1.83-1.91 (m, 1H), 2.26 (ddd, J = 17.8, 8.8, 6.4 Hz, 1H), 2.45 (dt,
J = 17.8, 6.1 Hz, 1H), 3.27 (m, 1H), 3.51 (ddd, J = 9.0, 6.4,
3.1 Hz, 1H), 7.05 (br s, 1H, NH, D2O exchangeable); 13C NMR
(100 MHz, CDCl3) δ -5.0, -4.5, 17.8, 20.2, 25.6, 27.8, 28.3, 54.8,
70.6, 171.8; MS (ESI, m/z) 266 (M þ Naþ, 100). Anal. Calcd for
C12H25NO2Si: C, 59.21; H, 10.35; N, 5.75. Found: C, 59.03; H,
10.28; N, 5.74.
93%) as a colorless oil: [R]20 þ31.9 (c 1.2, CHCl3); IR (KBr)
D
1
νmax 2953, 2926, 2856, 1731, 1684, 1334, 1167 cm-1; H NMR
(400 MHz, CDCl3) δ 0.11 (s, 6H), 0.87 (s, 9H), 1.90-2.10 (m,
2H), 2.57 (ddd, J = 17.7, 7.0, 5.8 Hz, 1H), 2.84-2.94 (m, 1H),
4.26-4.33 (m, 3H), 5.05-5.15 (m, 2H), 5.68-5.80 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ -5.5, -4.8, 18.1, 25.5, 26.5, 28.9,
41.6, 69.1, 117.1, 131.8, 171.3, 171.8; MS (ESI, m/z) 306 (M þ
Naþ, 100). Anal. Calcd for C14H25NO3Si: C, 59.32; H, 8.89; N,
4.94. Found: C, 59.23; H, 8.98; N, 5.06.
(5R,6S)-1-Allyl-5-(tert-butyldimethylsilyloxy)-6-methylpiper-
idin-2-one (19). To a cooled solution (-20 °C) of compound 2e
(2.963 g, 10.5 mmol) in CH2Cl2 (70 mL) was added dropwise a
2.0 M solution of CH3MgI in Et2O (15.7 mL, 31.4 mmol). The
tert-Butyl (5R,6S)-5-(tert-Butyldimethylsilyloxy)-6-methyl-1-
oxopiperidine-1-carboxylate (22). To a solution of 21 (2.624 g,
10.8 mmol) in MeCN (54 mL) were added di-tert-butyl dicar-
bonate (3.2 mL, 14.0 mmol) and 4-(dimethylamino)pyridine
(527 mg, 4.3 mmol). The mixture was stirred at room tempera-
ture for 48 h. After concentration, the residue was diluted with
4240 J. Org. Chem. Vol. 75, No. 12, 2010

Fu et al.
JOCArticle
EtOAc (25 mL) and H2O (15 mL). The resultant solution was
extracted with EtOAc (15 mL ꢀ 3). The organic phases were
washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel (eluent: EtOAc/PE 1:8)
to give compound 22 (2.553 g, 94% based on recovered starting
material 21, 700 mg, 26.7%) as a white solid: mp 71-72 °C (PE/
EtOAc); [R]20D þ2.5 (c 0.93, CHCl3); IR (film) νmax 2953, 2930,
2848, 1766, 1711 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.09 (s,
6H), 0.88 (s, 9H), 1.16 (d, J = 6.8 Hz, 3H), 1.52 (s, 9H), 1.68-
1.77 (m, 1H), 1.97 (dddd, J = 13.8, 11.3, 7.1, 2.6 Hz, 1H), 2.34
(ddd, J = 17.6, 7.1, 2.4 Hz, 1H), 2.68 (ddd, J = 17.6, 11.3,
7.8 Hz, 1H), 3.83 (dt, J = 3.4, 2.6 Hz, 1H), 4.14 (qdd, J = 6.8,
3.4, 1.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ -5.1, -5.0,
17.8, 19.3, 24.6, 25.5, 27.8, 29.4, 58.3, 68.2, 82.3, 152.7, 170.8;
MS (ESI, m/z) 366 (M þ Naþ, 100). Anal. Calcd for C17H33NO4-
Si: C, 59.44; H, 9.68; N, 4.08. Found: C, 59.42; H, 9.51; N, 4.03.
tert-Butyl (5R,6S)-5-(tert-Butyldimethylsilyloxy)-6-methyl-2-
oxo-5,6-dihydropyridine-1(2H)-carboxylate (23). To a solution
of hexamethyldisilazane (HMDS, 2.1 mL, 9.85 mmol) in THF
(26 mL) at -78 °C was added n-butyllithium (3.8 mL, 2.5 M in
hexane, 9.5 mmol). After the mixture was stirred at -78 °C
for 20 min, a solution of amide 22 (1.300 g, 3.8 mmol) in THF
(6 mL) and HMPA (3.3 mL) was added dropwise. The mixture
was stirred at -78 °C for 1 h, and phenylselenyl bromide (1.003 g,
4.3 mmol) in THF (6 mL) was added. The mixture was stirred for
1 h at -78 °C before being quenched with a saturated aqueous
ammonium chloride solution (5 mL). The mixture was extracted
with EtOAc (10 mL ꢀ 3). The combined organic phases were
washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. After dilution with CH2Cl2
(12 mL), a 30% aqueous H2O2 solution (1 mL) was added drop-
wise. The mixture was quenched with saturated aqueous NaH-
CO3 solution (2 mL) at 0 °C. The resultant mixture was extracted
with CH2Cl2 (6 mL ꢀ 3). The combined organic phases were
washed with brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by column
chromatography on silica gel (eluent: EtOAc/PE 1:8) to give
compound 23 (1.072 g, 83%) as a white solid: mp 65-67 °C (PE/
EtOAc); [R]20D -182 (c 1.0, CHCl3); IR (film) νmax 2949, 2922,
2856, 1770, 1712, 1291, 1244 cm-1; 1H NMR (400 MHz, CDCl3)
δ 0.08 (s, 3H), 0.09 (s, 3H), 0.86 (s, 9H), 1.17 (d, J = 7.0 Hz, 3H),
1.53 (s, 9H), 3.96 (dd, J = 5.7, 1.6 Hz, 1H), 4.42 (qt, J = 7.0,
1.6 Hz, 1H), 5.97 (d, J = 9.7 Hz, 1H), 6.51 (ddd, J = 9.7, 5.7,
1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ -4.9, -4.5, 17.9,
18.2, 25.5, 27.9, 57.3, 66.4, 82.6, 127.2, 139.0, 152.1, 162.2; MS
(ESI, m/z) 364 (M þ Naþ, 100). Anal. Calcd for C17H31NO4Si: C,
59.79; H, 9.15; N, 4.10. Found: C, 59.80; H, 8.19; N, 4.05.
tert-Butyl (4S,5R,6S)-5-Hydroxy-6-methyl-2-oxo-4-vinylpi-
peridine-1-carboxylate (24). To a round-bottomed flask contain-
ing a THF solution (6.7 mL) of (5R,6S)-6 (110 mg, 0.49 mmol)
was added, at -78 °C, a 1.0 M solution of vinylmagnesium
bromide (1.5 mL, 1.5 mmol) in THF. The mixture was stirred at
-78 °C for 1.5 h and allowed to warm to room temperature for
2 h. The mixture was quenched with a saturated NH4Cl solution(2
mL) and extracted with EtOAc (4 mL ꢀ 3). The combined organic
phases were washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel (eluent:
EtOAc/PE 1:3) to give compound 24 (84.6 mg, 68%) as a colorless
oil: [R]20D þ21.8 (c 1.6, CHCl3); IR (film) νmax 3332, 2979, 2921,
2848, 1753, 1708, 1250, 1156 cm-1; 1H NMR (400 MHz, CDCl3)
δ 1.27 (d, J = 6.8 Hz, 1H), 1.50 (s, 9H), 2.24 (d, J = 3.4 Hz, 1H,
OH, D2O exchangeable), 2.45 (dd, J = 17.0, 6.0 Hz, 1H), 2.68
(dd, J = 17.0, 12.0 Hz, 1H), 2.77-2.85 (m, 1H), 3.81-3.85 (m,
1H), 4.31 (qd, J = 6.8, 2.6 Hz, 1H), 5.16 (dt, J = 17.2, 1.3 Hz,
1H), 5.22 (dt, J = 10.6, 1.1 Hz, 1H), 5.83 (ddd, J = 17.2, 10.6,
6.0 Hz, 1H); 13C NMR(100 MHz, CDCl3) δ 19.3, 27.9, 33.7, 37.0,
57.6, 70.5, 83.0, 117.1, 137.1, 152.7, 170.2; MS (ESI, m/z) 278
(M þ Naþ, 100); HRMS calcd for C13H21NNaO4 [M þ Naþ]
278.1368, found 278.1366.
1-tert-Butyl 3-Methyl (3S,4R,5R,6S)-5-(Methoxycarboxy)-6-
methyl-2-oxo-4-vinylpiperidine-1,3-dicarboxylate (25). To a solu-
tion of hexamethyldisilazane (HMDS, 40 μL, 0.21 mmol) in THF
(0.5 mL) at -78 °C was added n-butyllithium (80 μL, 2.5 M in
hexane, 0.2 mmol). After the mxiture was stirred at -78 °C for 20
min, a solutionof amide 24(22.4mg, 0.09 mmol) inTHF(0.4 mL)
and HMPA (80 μL) was added dropwise. After the mixture
was stirred at -78 °C for 33 min, methyl cyanoformate (20 μL,
0.21 mmol) was added dropwise at -78 °C. The reaction tem-
perature was allowed to rise to room temperature for 2 h. The
mixture was quenched with a saturated NaHCO3 solution (1 mL)
and extracted with EtOAc (1 mL ꢀ 3). The combined organic
phases were washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The residue
was purified by column chromatography (eluent: EtOAc/PE 1:4)
to give compound 25 and its diastereomer 26 (10.6 mg, combined
yield: 33%) in 87:13 ratio as determined by 1H NMR.
A sample of pure major diastereomeric (25) was obtained by
column chromatography. Major diastereomer (25): colorless oil;
[R]20 þ26.5 (c 0.53, CHCl3); IR (film) νmax 2982, 2957, 1784,
D
1741, 1699, 1439 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.46 (d,
J = 6.8 Hz, 3H), 1.50 (s, 9H), 3.33-3.43 (m, 1H), 3.48 (d, J =
11.2 Hz, 1H), 3.76 (s, 3H), 3.79 (s, 3H), 4.47 (dq, J = 9.2, 6.8 Hz,
1H), 4.73 (t, J = 9.2 Hz, 1H), 5.07-5.20 (m, 2H), 5.66 (ddd, J =
17.0, 10.2, 8.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 16.4, 28.0,
48.5, 53.0, 53.4, 53.7, 56.0, 82.9, 83.7, 118.9, 133.8, 151.8, 154.6,
167.0, 169.8; MS (ESI, m/z) 394 (M þ Naþ, 100); HRMS calcd
for C17H25NNaO8 [M þ Naþ] 394.1478, found 394.1487.
1-tert-Butyl 3-Methyl (3R,4R,5R,6S)-5-(Methoxycarboxy)-6-
tert-Butyl (5R,6S)-5-Hydroxy-6-methyl-2-oxo-5,6-dihydro-
pyridine-1(2H)-carboxylate (6). To a solution of compound 23
(1.346 g, 3.95 mmol) in THF (13.2 mL) was added a 1 M solution
of tetrabutylammonium fluoride (TBAF) in THF (7.9 mL, 7.9
mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. After being
quenched with saturated aqueous NH4Cl (5 mL), the mixture was
extracted with EtOAc (10 mL ꢀ 3). The combined organic phases
were washed with brine, dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel(eluent: EtOAc/PE 1:1) to
give compound (5R,6S)-6 (809 mg, 90%) as a white solid: mp
97.5-98.1 °C (PE/EtOAc); [R]20D -168 (c 1.2, CHCl3); IR (film)
methyl-2-oxo-4-vinylpiperidine-1,3-dicarboxylate (26). To
a
round-bottomed flask containing a THF solution (3 mL) of
(5R,6S)-6 (100 mg, 0.44 mmol) was added, at -78 °C, a 1.0 M
solution of vinylmagnesium bromide (1.1 mL, 1.1 mmol) in
THF. The mixture was stirred at -78 °C for 1 h and allowed to
warm to room temperature. After the mixture was stirred at
room temperature for 2 h, methyl cyanoformate (0.1 mL, 1.3
mmol) in THF (1.4 mL) and HMPA (0.38 mL) was added
dropwise at -78 °C. The reaction temperature was allowed to
warm to room temperature over 2 h. The mixture was quenched
with a saturated NaHCO3 solution (2 mL) and extracted with
EtOAc (2 mL ꢀ 3). The combined organic phases were washed
with brine, dried over anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure. The residue was purified by
column chromatography (eluent: EtOAc/PE 1:4) to give com-
pound 26 and its diastereomer 25 (80.8 mg, combined yield:
ν
max 3405, 2976, 1762, 1742, 1396, 1373, 1287, 1248, 1155 cm-1; 1H
NMR (400 MHz, CDCl3) δ l.21 (d, J = 6.9 Hz, 3H), 1.53 (s, 9H),
3.17 (d, J = 7.0 Hz, 1H, OH, D2O exchangeable), 4.01 (dd, J =
5.8, 1.4 Hz, 1H), 4.48 (qt, J = 6.9, 1.4 Hz, 1H), 6.01 (d, J = 9.7 Hz,
1H), 6.70 (ddd, J = 9.7, 5.8, 1.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 18.3, 28.0, 57.4, 65.9, 83.3, 127.6, 139.3, 152.1, 162.2; MS
(ESI, m/z) 250 (M þ Naþ, 100). Anal. Calcd for C11H17NO4: C,
58.14; H, 7.54; N, 6.16. Found: C, 57.80; H, 8.04; N, 5.96.
J. Org. Chem. Vol. 75, No. 12, 2010 4241

Fu et al.
JOCArticle
1
49%) in an 89:11 ratio (determined by H NMR), along with
compound 27 (12.8 mg, 9%).
mixture was stirred for 1 h at 0 °C before being quenched by
addition of a saturated aqueous ammonium chloride solution.
The mixturewas extracted with EtOAc (5 mL ꢀ 3). Thecombined
organic phases were washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography (eluent: EtOAc/
PE 1:2) to give compound 31 (316 mg, 64%) as a white solid: mp
A sample of pure major diastereomeric 26 was obtained by
column chromatography. Major diastereomer (26): white solid;
mp 78-80 °C (PE/EtOAc); [R]20D þ78 (c 0.91, CHCl3); IR (film)
ν
max 2984, 2957, 1754, 1712, 1642, 1447 cm-1;1H NMR (400 MHz,
CDCl3) δ 1.41 (d, J = 6.8 Hz, 3H), 1.50 (s, 9H), 3.27-3.34 (m,
1H), 3.69 (d, J = 12.1 Hz, 1H), 3.75 (s, 3H), 3.80 (s, 3H), 4.44 (qd,
J = 6.8, 2.5 Hz, 1H), 4.89 (t, J = 2.5 Hz, 1H), 5.17-5.25 (m, 2H),
5.71 (ddd, J = 17.6, 10.3, 7.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 19.4, 27.9, 40.1, 52.3, 52.6, 55.1, 55.2, 75.7, 83.9, 119.2,
133.5, 152.3, 154.9, 166.0, 169.3; MS (ESI, m/z) 394 (M þ Naþ,
100); HRMS calcd for C17H25NNaO8 [M þ Naþ] 394.1478,
found 394.1480.
79-80 °C (PE/EtOAc); [R]20 þ129.7 (c 1.2, CHCl3); IR (film)
D
1
νmax 3447, 2980, 1754, 1719, 1447, 1373, 1264, 1151 cm-1; H
NMR (400 MHz, CDCl3) δ 1.41 (d, J = 6.8 Hz, 3H), 1.53 (s, 9H),
3.07 (dd, J = 8.2, 2.7 Hz, 1H), 3.77 (s, 3H), 3.80 (s, 3H), 4.26 (s,
1H, OH, D2O exchangeable), 4.49 (qd, J = 6.8, 2.7 Hz, 1H),
4.90 (t, J = 2.7 Hz, 1H), 5.27-5.33 (m, 2H), 6.00 (ddd, J = 18.2,
10.0, 8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 19.4, 27.9, 47.3,
53.0, 55.2, 55.5, 75.9 (2C), 84.0, 120.2, 130.9, 151.8, 154.9, 169.7,
170.1; MS (ESI, m/z) 410 (M þ Naþ, 100); HRMS calcd for
C17H25NNaO9 [M þ Naþ] 410.1427, found 410.1428.
1-tert-Butyl 3-methyl (3S,4R,5R,6S)-5-hydroxy-6-methyl-2-
oxo-4-vinylpiperidine-1,3-dicarboxylate (27): white solid; mp
140-141 °C (PE/EtOAc); [R]20 -19.5 (c 0.97, CHCl3); IR
D
(film) νmax 3377, 2976, 2926, 1786, 1727, 1677, 1517, 1159 cm-1
;
Methyl (3R,4S,5R,6S)-3-Hydroxy-5-(methoxycarboxy)-6-
methyl-2-oxo-4-vinylpiperidine-3-carboxylate (32). To a stirring
solution of compound 31 (457.4 mg, 1.18 mmol) in anhydrous
CH2Cl2 (16.9 mL) was added dropwise trifluoroacetic acid (2.0 mL)
at 0 °C. After being stirred for 30 min at 0 °C, the mixture was
concentrated under reduced pressure. The residue was purified by
flash column chromatograph (eluent: EtOAc/PE 6:1) to afford
compound 32 (296 mg, 88%) as a white solid: mp 178-180 °C (PE/
EtOAc); [R]20D -41.8 (c 1.2, CH3OH); IR (film) νmax 3354, 1754,
1743, 1677, 1642, 1264 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.35
(d,J= 6.6 Hz, 3H), 3.02 (dd, J= 9.8, 4.0 Hz, 1H), 3.76 (s, 3H), 3.78
(s, 3H), 3.73-3.85 (m, 1H), 4.49 (s, 1H, OH, D2O exchangeable),
4.90 (dd, J = 5.9, 4.0 Hz, 1H), 5.22 (dd, J = 16.9, 1.2 Hz, 1H), 5.29
(dd, J = 9.8, 1.2 Hz, 1H), 5.94 (dt, J = 16.9, 9.8 Hz, 1H), 6.72 (br s,
1H, -CONH, D2O exchangeable); 13CNMR(100MHz, CDCl3) δ
20.3, 49.2, 50.3, 52.8, 55.1, 75.9 (2C), 120.8, 130.2, 154.8, 169.2,
170.4; MS (ESI, m/z) 310 (M þ Naþ, 100); HRMS calcd for
C12H17NNaO7 [M þ Naþ] 310.0903, found 310.0898.
1H NMR (500 MHz, CDCl3) δ 1.22 (d, J = 6.9 Hz, 3H), 1.41 (s,
9H), 3.31-3.41 (m, 1H), 3.51 (d, J = 11.3 Hz, 1H), 3.80 (s, 3H),
3.88-4.00 (m, 1H), 4.29 (dd, J = 9.3, 2.4 Hz, 1H), 4.70 (br s, 1H,
OH), 5.23 (d, J = 10.3 Hz, 1H), 5.28 (d, J = 17.2 Hz, 1H), 5.74
(ddd, J = 17.2, 10.3, 7.9 Hz, 1H); 13C NMR (125 MHz, CDCl3)
δ 14.4, 28.3, 46.7, 47.1, 53.0, 53.1, 79.8, 84.5, 120.0, 133.0, 154.9,
1
167.1, 170.0; H NMR (400 MHz, DMSO-d6) δ 1.08 (d, J =
6.8 Hz, 3H), 1.35 (s, 9H), 3.23-3.30 (m, 1H), 3.65-3.80 (m, 1H),
3.70 (s, 3H), 4.01 (d, J = 11.5 Hz, H-3, readily exchanged with
D2O in DMSO-d6), 4.23 (dd, J = 9.4, 5.5 Hz, 1H), 5.11 (d, J =
10.2 Hz, 1H), 5.18 (d, J = 17.2 Hz, 1H), 5.81 (ddd, J = 17.2,
10.2, 8.4 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H, OH, slowly ex-
changed with D2O in DMSO-d6); 13C NMR (100 MHz, DMSO-
d6) δ 16.0, 28.3, 47.4, 47.5, 52.7 (2C), 77.9, 83.8, 118.4, 134.7,
154.9, 167.8, 170.6; MS (ESI, m/z) 336 (M þ Naþ, 100); HRMS
calcd for C15H23NNaO6 [M þ Naþ] 336.1423, found 336.1432.
tert-Butyl (5R,6S)-5-(methoxycarboxy)-6-methyl-2-oxo-5,6-
dihydropyridine-1(2H)-carboxylate (28). white solid; mp 84.2-
85.4 °C (EtOAc/PE); [R]20D -230 (c 0.9, CHCl3); IR (film) νmax
2979, 2933, 1750, 1717, 1296, 1263, 1247, 1156 cm-1; 1H NMR
(400 MHz, CDCl3) δ 1.29 (d, J = 7.0 Hz, 1H), 1.52 (s, 9H), 3.80
(s, 3H), 4.63 (qt, J = 7.0, 1.6 Hz, 1H), 4.93 (dd, J = 5.8, 1.6 Hz,
1H), 6.17 (dd, J = 9.7 Hz, 1H), 6.68 (ddd, J = 9.7, 5.8, 1.6 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 18.4, 28.0, 54.0, 55.1, 70.2,
83.4, 130.8, 133.9, 151.9, 154.8, 161.1; MS (ESI, m/z) 308 (M þ
Naþ, 100). Anal. Calcd for C13H19NO6: C, 54.73; H, 6.71; N,
4.91. Found: C, 54.95; H, 6.37; N, 4.78.
(1R,4S,5R,8S)-1-Hydroxy-4-methyl-8-vinyl-6-oxa-3-azabicyclo-
[3.2.1]octane-2,7-dione (3). To a solution of compound 31 (234 mg,
0.82 mmol) in CH3OH (8.2 mL) was added K2CO3 (13.6 mg, 0.098
mmol) at room temperature. After being stirred at rt overnight,
the mixture was concentrated under reduced pressure. The residue
was purified by flash column chromatograph (eluent: CH2Cl2/
CH3OH = 20:1) to afford compound 3 (130 mg, 81%) as a white
solid: mp 164-165 °C (CH2Cl2/CH3OH); [R]20 þ56.0 (c 1.3,
D
CH3OH); IR (film) νmax 3291, 2918, 1789, 1677 cm-1; 1H NMR
(400 MHz, DMSO-d6) δ 1.21 (d, J = 6.8 Hz, 3H), 3.33 (d, J =
5.1 Hz, 1H), 3.70 (qt, J = 6.8, 1.7 Hz, 1H), 4.73 (t, J = 1.7 Hz, 1H),
5.29 (dt, J = 10.6, 1.2 Hz, 1H), 5.37 (dt, J = 17.4, 1.2 Hz, 1H),
5.78 (ddd, J = 17.4, 10.6, 6.7 Hz, 1H), 6.07 (s, 1H, -OH, D2O
1-tert-Butyl 3-Methyl (3R,4S,5R,6S)-6-Methyl-2-oxo-4-vinyl-
1-azabicyclo[3.1.0]hexane-1,3-dicarboxylate (30). To a solution of
compound 26 (45 mg, 0.12 mmol) in THF (2.4 mL) was added
DBN (0.03 mL, 0.24 mmol) at 0 °C. After being stirred for 6 h at
0 °C, the reaction mixture was concentrated under reduced
pressure. The residue was purified by flash chromatograph on
silica gel (eluent: EtOAc/PE 1:4) to give compound 30 (27.7 mg,
77%) as a colorless oil: [R]20D -34.4 (c 1.0, CHCl3); IR (film) νmax
2973, 2927, 1784, 1753, 1720, 1299, 1254, 1159 cm-1; 1H NMR
(400 MHz, CDCl3) δ 1.44 (d, J = 6.3 Hz, 3H), 1.50 (s, 9H), 2.25
(d, J = 8.3 Hz, 1H), 2.79-2.85 (m, 1H), 3.80 (s, 3H), 4.04 (q, J =
exchangeable), 8.25 (br s, 1H, -CONH, D2O exchangeable); 13
C
NMR (100 MHz, DMSO-d6) δ 18.1, 44.8, 51.6, 77.0, 78.9, 119.1,
131.3, 165.8, 172.4; MS (ESI, m/z) 220 (M þ Naþ, 100); HRMS
calcd for C9H11NNaO4 [M þ Naþ] 220.0586, found 220.0582.
(2S,3S)-2,3-Epoxydecan-1-ol (37). To a stirring and cooled
˚
(-25 °C) suspension of activated powered 4 A molecular sieves
(950 mg) in anhydrous CH2Cl2 (19 mL) were added successively,
and under a nitrogen atmosphere, (þ)-DIPT (263 mg, 1.12
mmol) in anhydrous CH2Cl2 (2 mL) and Ti(OPr-i)4 (0.27 mL,
0.9 mmol) in anhydrous CH2Cl2 (2 mL). After the mixture was
stirred for 15 min, allylic alcohol 36 (700 mg, 4.49 mmol) in
anhydrous CH2Cl2 (3.3 mL) was added and the stirring con-
tinued for 30 min. To the resultant mixture was added slowly
TBHP (1.0 mL, 5.5 M solution in nonane, 5.5 mmol). After
being stirred at the same temperature for 5 h, the reaction was
quenched with an aqueous solution (7.6 mL) containing FeSO4
(2.415 g) and citric acid (760 mg). The mixture was stirred for
15 min. The organic layer was separated, and the aqueous layer
was extracted with CH2Cl2 (10 mL ꢀ 3). The combined organic
extracts were washed with brine, dried over anhydrous Na2SO4,
1
6.3 Hz, 1H), 5.28-5.35 (m, 1H), 5.43-5.48 (m, 2H); H NMR
(100 MHz, CDCl3) δ 21.2, 28.0, 33.8(2C), 38.5, 50.6, 52.8, 83.3,
122.4, 127.5, 149.5, 165.3, 168.3; MS (ESI, m/z) 318 (M þ Naþ,
100); HRMS calcd for C15H21NNaO5 [M þ Naþ] 318.1317,
found 318.1305.
1-tert-Butyl 3-Methyl (3R,4S,5R,6S)-3-Hydroxy-5-(methoxy-
carboxy)-6-methyl-2-oxo-4-vinylpiperidine-1,3-dicarboxylate (31).
To a suspension of NaH (66.6 mg, 60% in mineral oil, 1.66 mmol)
in THF (6 mL) at 0 °C was added dropwise a solution of 26
(475 mg, 1.28 mmol) in THF (4 mL). After the mixture was stirred
for 30 min at 0 °C, a precooled (0 °C) THF (2.8 mL) solution of
Davis’ oxaziridine (468 mg, 1.79 mmol) was added dropwise. The
4242 J. Org. Chem. Vol. 75, No. 12, 2010

Fu et al.
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1
filtered, and concentrated under reduced pressure. The residue
was purified by flash column chromatograph on silica gel
(EtOAc/PE = 1:5) to give compound 37 (725 mg, 94%) as a
white solid: mp 51.2-51.3 °C (EtOAc/PE); [R]20D -34.8 (c 1.1,
CHCl3) [lit.40 [R]20D -36.5 (c 2.8, CHCl3)]; IR (film) νmax 3421,
νmax 3331, 2957, 2922, 2852, 1474, 1013, 970 cm-1; H NMR
(400 MHz, CDCl3) δ 0.9 (t, J = 6.9 Hz, 6H), 1.22-1.43 (m, 20H),
1.45-1.62 (m, 4H), 1.81 (br s, 2H, OH, D2O exchangeable),
4.08-4.14 (m, 2H), 5.68 (dd, J = 3.8, 1.9 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 14.1, 22.6, 25.4, 29.2, 29.5, 31.8, 37.3, 72.5,
133.9; MS (ESI, m/z) 307 (M þ Naþ, 100). Anal. Calcd for
C18H36O2: C, 76.00; H, 12.76. Found: C, 76.23; H, 12.48.
(þ)-11-epi-Awajanomycin (38). To a stirring solution of com-
pound 3 (32.2 mg, 0.163 mmol) and (R)-4 (127.5 mg, 0.82 mmol)
in CH2Cl2 (1.6 mL) was added Grubbs’ second-generation
catalyst (27.3 mg, 0.032 mmol). After being stirred at 34 °C
for 6 h, the mixture was concentrated under reduced pressure.
The residue was purified by column flash chromatography
(eluent: EtOAc/PE 5:1) on silica gel to give (þ)-11-epi-awaja-
nomycin (38) (30.8 mg, 58%) and homocoupling product
(8R,11R)-39 (23.4 mg, 20%).
3119, 2951, 2918, 2848, 876, 760 cm-1; H NMR (400 MHz,
1
CDCl3) δ 0.88 (t, J = 6.8 Hz, 3H), 1.20-1.40 (m, 8H), 1.40-1.50
(m, 2H), 1.50-1.65 (m, 2H), 1.68 (dd, J = 7.3, 5.6 Hz, 1H, OH,
D2O exchangeable), 2.90-2.98 (m, 2H), 3.63 (ddd, J = 12.5, 7.3,
4.3 Hz, 1H), 3.91 (ddd, J = 12.5, 5.5, 2.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 14.1, 22.6, 25.9, 29.2, 29.3, 31.5, 31.7, 56.0,
58.4, 61.7; MS (ESI, m/z) 195 (M þ Naþ, 100).
(S)-Dec-1-en-3-ol (S-4). Toa redsolutionof Cp2TiCl2 (797 mg,
3.2 mmol) in anhydrous THF (11.5 mL) were added zinc chloride
(1.3 mL, 1.0 M in Et2O, 1.3 mmol) and zinc powder (208 mg,
3.2 mmol). The mixture was stirred for 1 h at room tempera-
ture while the solution turned green. To the resultant mixture
was added epoxide 37 (110 mg, 0.64 mmol) in anhydrous THF
(1.3 mL), and the resultant mixture was stirred for 30 min. The
reaction was quenched with aqueous HCl (1.0 M, 2.4 mL), and
the mixture was extracted with Et2O (10 mL ꢀ 3). The organic
layers were successively washed with water, 10% aqueous
NaHCO3, water, and brine, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The residue
was purified by flash column chromatography on silica gel
(Et2O/PE (30-60 °C) = 1:6) to give compound (S)-4 (84.3 mg,
(þ)-11-epi-Awajanomycin (38): colorless gum; [R]20 þ47.5
D
(c 0.52, CH3OH); IR (film) νmax 3320, 2922, 2847, 1794, 1677,
1246, 1151, 979 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 0.86
(t, J = 6.8 Hz, 3H), 1.21 (d, J = 6.8 Hz, 3H), 1.23-1.31 (m,
10H), 1.33-1.41 (m, 2H), 3.29 (d, J = 6.8 Hz, 1H), 3.68 (q, J =
6.7 Hz, 1H), 3.92 (m, 1H), 4.62 (s, 1H), 4.72 (d, J = 4.9 Hz, 1H,
11-OH, D2O exchangeable), 5.52 (dd, J = 15.7, 6.8 Hz, 1H),
5.75 (dd, J = 15.6, 5.5 Hz, 1H), 5.96 (s, 1H, 3-OH, D2O
exchangeable), 8.23 (br s, 1H, NH, D2O exchangeable); 13C
NMR (100 MHz, DMSO-d6) δ 13.9, 18.1, 22.0, 24.9, 28.6, 29.0,
31.2, 37.2, 43.7, 51.6, 70.2, 77.1, 79.6, 121.1, 138.4, 165.9, 172.5;
MS (ESI, m/z) 348 (M þ Naþ, 100); HRMS calcd for C17H27-
NNaO5 [M þ Naþ] 348.1787, found 348.1785.
85%) as a colorless liquid: [R]20D þ8.2 (c 1.2, CHCl3) [lit.42 [R]25
D
þ13.0 (neat)]; IR (film) νmax 3339, 2954, 2924, 2854, 1595, 991,
918 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.86 (t, J = 6.9 Hz,
3H), 1.18-1.41 (m, 10H), 1.42-60 (m, 2H), 1.95 (s, 1H, OH,
D2O exchangeable), 4.06 (m, 1H), 5.06 (dt, J = 10.4, 1.4 Hz,
1H), 5.18 (dt, J = 17.2, 1.4 Hz, 1H), 5.83 (ddd, J = 17.2, 10.4,
6.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 14.0, 22.6, 25.3,
29.2, 29.5, 31.8, 37.0, 73.2, 114.4, 141.3; MS (ESI, m/z) 179
(M þ Naþ, 100).
(8R,11R,E)-Octadec-9-ene-8,11-diol ((8R,11R)-39): [R]20D -7.7
(c 1.0, CHCl3).
(8S,11S,E)-11-Hydroxyoctadec-9-en-8-yl Acetate (40). To a
stirring solution of compound (8S,11S)-39 (34 mg, 0.12 mmol)
and DMAP (7.3 mg, 0.06 mmol) in CH2Cl2 (1.2 mL) were added
successively Ac2O (12 μL, 0.126 mmol) and Et3N (20 μL, 0.144
mmol). After being stirred overnight at rt, the reaction was
quenched with a saturated aqueous solution of NH4Cl. The
organic layer was separated, and the aqueous layer was extrac-
ted with CH2Cl2 (2 mL ꢀ 3). The combined organic extracts
were washed with brine, dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel (EtOAc/
PE = 1: 9) to give compound 40 (27.3 mg, 70%) as a colorless
oil: [R]20D -22.2 (c 0.7, CHCl3); IR (film) νmax 3448, 2954, 2924,
(R)-Dec-1-en-3-ol (R-4): [R]20D -8.2 (c 1.6, CHCl3) [lit.6 [R]25
D
-8.2 (c 1.1, CHCl3)]; [R]20 -9.4 (c 1.4, CH2Cl2) [lit.43 [R]23
D
D
-9.8 (c 0.30, CH2Cl2)].
(þ)-Awajanomycin (1). To a stirring solution of compound 3
(27.4 mg, 0.139 mmol) and (S)-4 (108.5 mg, 0.695 mmol) in
CH2Cl2 (1.4 mL) was added Grubbs’ second-generation catalyst
(23.6 mg, 0.028 mmol). After being stirred at 34 °C for 6 h, the
mixture was concentrated under reduced pressure. The residue
was purified by column flash chromatography (eluent: EtOAc/
PE 5:1) on silica gel to give (þ)-awajanomycin (1) (26.7 mg,
59%) and homocoupling product (8S,11S)-39 (23.5 mg, 24%).
2851, 1738, 1369, 1238, 1016, 970 cm-1; H NMR (400 MHz,
1
CDCl3) δ 0.87 (t, J = 6.9 Hz, 6H), 1.15-1.40 (m, 20H),
1.40-1.70 (m, 5H, 2 ꢀ CH2, OH, D2O exchangeable), 2.05 (s,
3H), 4.08 (q, J = 6.4 Hz, 1H), 5.22 (q, J = 6.5 Hz, 1H), 5.58 (dd,
J = 15.6, 6.4 Hz, 1H), 5.69 (dd, J = 15.6, 6.5 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 14.0 (2C), 21.3, 22.6, 25.1, 25.3, 29.2 (2C),
29.3, 29.5, 29.7, 31.7, 31.8, 34.4, 37.1, 72.3, 74.2, 128.9, 135.7,
170.4; MS (ESI, m/z) 349 (M þ Naþ, 100); HRMS calcd for
C20H38NaO3 [M þ Naþ] 349.2719, found 349.2711.
(þ)-Awajanomycin (1): colorless gum; [R]20 þ70.9 (c 0.6,
D
CH3OH); [R]20D þ70.0 (c 0.45, CH3OH) [lit.4 [R]25D þ78 (c 0.1,
CH3OH)]; IR (film) νmax 3320, 2922, 2847, 1794, 1677, 1246,
1151, 979 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 0.86 (t, J =
6.8 Hz, 3H), 1.21 (d, J = 6.8 Hz, 3H), 1.23-1.31 (m, 10H),
1.33-1.41 (m, 2H), 3.29 (d, J = 7.2 Hz, 1H), 3.68 (q, J = 6.7 Hz,
1H), 3.92 (m, 1H), 4.62 (s, 1H), 4.72 (d, J = 4.9 Hz, 1H, 11-OH,
D2O exchangeable), 5.50 (dd, J = 15.6, 7.1 Hz, 1H), 5.76 (dd,
J = 15.6, 5.6 Hz, 1H), 5.96 (s, 1H, 3-OH, D2O exchangeable),
8.23 (br s, 1H, NH, D2O exchangeable); 13C NMR (100 MHz,
DMSO-d6) δ 13.9, 18.1, 22.0, 24.8, 28.6, 29.0, 31.2, 37.2, 43.9;
51.6, 70.2, 77.0, 79.7, 121.2, 138.8, 165.9, 172.5; MS (ESI, m/z)
348 (M þ Naþ, 100); HRMS calcd for C17H27NNaO5 [M þ
Naþ] 348.1787, found 348.1785.
Acknowledgment. We are grateful to the NSF of China
(20832005, 20602028) and the National Basic Research Pro-
gram (973 Program) of China (Grant No. 2010CB833200) for
financial support.
Supporting Information Available: 1H and 13C NMR spec-
tra of new compounds; NOESY of some compounds, HMBC of
compound 30, and chiral HPLC chromatograms of the O-benzyloyl
derivative of 4. This material is available free of charge via the
Internet at http://pubs.acs.org.
(8S,11S,E)-Octadec-9-ene-8,11-diol ((8S,11S)-39): white solid;
mp 46-48 °C (PE/EtOAc); [R]20D þ7.8 (c 1.0, CHCl3); IR (film)
(42) Rinaldi, P. L.; Levy, G. C. J. Org. Chem. 1980, 45, 4348–4351.
(43) Menz, H.; Kirsch, S. F. Org. Lett. 2009, 11, 5634–5637.
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