Total synthesis and absolute configuration of malyngamide W

Article abstract of DOI:10.1039/c0ob01118e

A concise enantioselective synthesis of malyngamide W (1) and its 2′-epimer was described. The strategy was based on three key steps: (1) ozonolysis of compound 11 which was derived from (R)-(-)-carvone 8, followed by copper-iron-catalyzed rearrangement to give the key cyclohex-2-enone intermediate 5, (2) Nozaki-Hiyama-Kishi coupling reaction between aldehyde 4 and iodide 14 to afford alcohol 3, and (3) asymmetric (R)-CBS reduction of the ketone functionality in compound 21 to establish the C-2′ chiral center in the target compound 1. The absolute configuration of malyngamide W (1) was thus confirmed via the synthesis of 1 and 2′-epi-1.

Full text of DOI:10.1039/c0ob01118e

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PAPER
Total synthesis and absolute configuration of malyngamide W†
Xian-Liang Qi, Jun-Tao Zhang, Jian-Peng Feng and Xiao-Ping Cao*
Received 6th December 2010, Accepted 25th February 2011
DOI: 10.1039/c0ob01118e
A concise enantioselective synthesis of malyngamide W (1) and its 2¢-epimer was described. The
strategy was based on three key steps: (1) ozonolysis of compound 11 which was derived from
(R)-(-)-carvone 8, followed by copper-iron-catalyzed rearrangement to give the key cyclohex-2-enone
intermediate 5, (2) Nozaki–Hiyama–Kishi coupling reaction between aldehyde 4 and iodide 14 to
afford alcohol 3, and (3) asymmetric (R)-CBS reduction of the ketone functionality in compound 21 to
establish the C-2¢ chiral center in the target compound 1. The absolute configuration of malyngamide
W (1) was thus confirmed via the synthesis of 1 and 2¢-epi-1.
the confirmation of the absolute configuration of its stereogenic
centers and more extensive biological evaluation.
Introduction
The malyngamides are a class of complex lipopeptides, which
are both broadly represented and highly varied within various
strains of the marine cyanobacterium Lyngbya majuscula. Up
to now, 30 variants of this structure type were known from
collections made around the world, including malyngamides
A–X, serinol-derived malyngamides, toxic-type malyngamides
(hermitamides A and B), and isomalyngamides.1 Most of the
malyngamides consist of an optically active (4E,7S) 12- or 14-
carbon methoxylated monounsaturated fatty acid moiety in the
form of an amide. The amino end is usually appended to a
heavily oxygenated six-membered ring or heterocycle and/or with
a vinylic chloride function.1 Malyngamide W, together with U
and V, were isolated from a shallow water L. majuscula Harvey
ex Gomont (Oscillatoriaceae) by Gerwick’s group in 2003.2 The
absolute stereochemistry of the 2¢-position on the amine portion
of malyngamide W was not determined due to a lack of material.
At the same time, the scarcity of 1 in natural sources had hampered
the biological evaluation of this fascinating molecule. Thus far, the
synthetic studies on malyngamides are centered on the synthesis
of the acid part3 and only a few on total synthesis have appeared.
Isobe disclosed the synthesis of malyngamide X in 2007.4a The
other total syntheses of malyngamides such as malyngamides M,
O, P, Q, R, U and several serinol-derived malyngamides were
mainly completed by our group,4b–e however, there are no reports
on the synthesis of malyngamide W (1). Hence, we were interested
in the synthesis of malyngamide W (1) to provide materials for
Malyngamide W (1) has a polyoxygenated cyclohexane ring
similar to its congeners H, I, J, L, N, U, and V (Fig. 1).2,5 We envi-
sioned that a previously reported a,b-unsaturated cyclohexanone
56 was a key intermediate towards the synthesis of this series of
compounds. Up to now, only one method had been reported for
the synthesis of 5 by Sato. The compound was prepared in 34%
overall yield in 9 steps starting from an optically active (R)-ethyl-3-
hydroxy-4-chlorobutyrate.6 To improve the synthetic efficiency, we
herein wish to report a much more concise and efficient synthetic
route to this compound by modifying Schreiber’s method.7 This
State Key Laboratory of Applied Organic Chemistry and College of Chem-
istry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, P.
R. China. E-mail: caoxplzu@163.com; Fax: 86 931 8912582
† Electronic supplementary information (ESI) available: Experimental
procedures for 9, 10, 15, 17, 20, 2¢-epi-19, 22, and 2¢-epi-20; NMR spectra
for all synthetic compounds. CCDC reference numbers 784532. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c0ob01118e
Fig. 1 Structure of malyngamides H, I, J, L, N, U, V, and W, potentially
accessible from intermediate 5.
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new methodology should also allow the rapid synthesis of the
other structurally related malyngamides.
The chiral fatty acid 2, (4E,7S)-7-methoxydodec-4-enoic acid, had
been synthesized earlier by us in six steps via a Johnson–Claisen
rearrangement starting from hexanal in 43% overall yield.4c For the
key intermediate 3, it could be readily obtained by a stereoselective
Nozaki–Hiyama–Kishi reaction9e between an aldehyde 4 and a
chiral a,b-unsaturated cyclohexanone 5. In turn, the aldehyde
4 could be generated from monoethanolamine (6) and phthalic
anhydride (7), and the enone 5 could be synthesized from the
commercially available (R)-(-)-carvone (8).
In a search for convenient methods for the construction of the
C(2¢)–C(1¢¢) bond of malyngamide W (1) and 2¢-epi-1, we became
aware of a few methods that may be of use in this project such as
the Baylis–Hillman reaction,8 Nozaki–Hiyama–Kishi reaction,9
Weinreb ketone synthesis,10 and rely on the addition of allyl
or vinyl lithium reagents to an aldehyde or ketone. After much
experimentation, we found that only the Nozaki–Hiyama–Kishi
reaction offered a successful entry to construct the C(2¢)–C(1¢¢)
bond efficiently. Herein we report a concise synthesis of 1 and
2¢-epi-1 via Nozaki–Hiyama–Kishi reaction as a key reaction
capable of providing a high enough quantity of the product for
further biological investigations, as well as clarifying its absolute
configuration. This newly developed procedure is more succinct
and practical, and should offer a convenient entry to other
structurally related malyngamides.
The preparation of the key intermediate 5 was started from
(R)-(-)-carvone 8 (Scheme 2). Thus, base-catalyzed stereoselective
epoxidation of 8 using hydrogen peroxide in methanol at -20 ◦C
provided the a,b-epoxy ketone 9 in 98% yield.11 Reductive ring
opening of the epoxide 9 by N-acetyl-L-cysteine and a catalytic
amount of diphenyl diselenide in methanol led to the syn-3a-
hydroxyl ketone 10 in 65% yield.12 This was followed by protection
of the hydroxy group using tert-butyldimethylsilyl chloride (TB-
SCl) and imidazole in N,N-dimethylformamide (DMF) to provide
its TBS-ether 11 in 93% yield. Ozonolysis of 11 in methanol–
dichloromethane (2 : 1) at -78 ◦C and subsequent treatment
with copper(II) acetate monohydrate/iron sulfate heptahydrate
Results and Discussion
The structure of malyngamide W (1) consists of a chiral 12-
carbon fatty acid portion containing a 4E double bond and a 7S
chiral center, connecting to a highly oxygenated a,b-unsaturated
cyclohexane moiety. The retrosynthetic analysis for 1 and 2¢-epi-
1 is shown in Scheme 1. As the absolute stereochemistry of 2¢-
methoxyl carbon center in malyngamide W was not confirmed in
the literature,2 it seemed well advised to synthesize both the two 2¢-
position diastereoisomers. The diastereomer could be synthesized
directly by amidation of acid 2 and an unmasked amine derived
from phathalimide 3, while the other diasteroisomer 1 could be
prepared by stereoselective epimerization of the 2¢-carbon center.
◦
at -20 C to furnish the enone 5 in 85% yield.7 Therefore the
preparation of the optically pure enone 5 was accomplished in 4
steps and 50% overall yield from (R)-(-)-carvone (8).
Scheme 2 Preparation of 5 and 14.
With the enone 5 in hand, we began the synthesis of
the intermediate 14. Iodination of 5 in the presence of 4-
dimethylaminopyridine (DMAP) in dichloromethane gave an a-
iodo-a,b-unsaturated cyclohexone 12 in 84% yield.13 Subsequent
Scheme 1 Retrosynthetic analysis of malyngamide W (1) and 2¢-epi-1.
3818 | Org. Biomol. Chem., 2011, 9, 3817–3824
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reduction of enone 12 under Luche’s conditions (sodium borohy-
drite and cerium(III) chloride heptahydrate) generated stereoselec-
tively the enol 13 in nearly quantitative yield.14 The stereochem-
istry of 13 was unambiguously established to be 1R,5R,6S by X-ray
crystallographic analysis (Fig. 2). Finally, the hydroxyl group in
compound 13 was protected as its benzyl ether by alkylation with
benzyl bromide (BnBr) in the presence of sodium hydride and a
catalytic amount of tetrabutylammonium iodide [(n-Bu)4NI] to
give the key iodide 14 in 94% yield.15
1). Initially, we sought to couple aldehyde 4 with a,b-unsaturated
cyclohexanone 5 under Baylis–Hillman conditions in the presence
of 1.2 equiv. of titanium tetrachloride (TiCl4) in dichloromethane
at 0 ◦C.8b This protocol failed to give the desired products despite
many attempts. We then resorted to reacting the a-iodo enone
12 with aldehyde 4 under the Nozaki–Hiyama–Kishi conditions
[chromium(II) chloride (CrCl2) and nickel(II) chloride (NiCl2)], but
again no desirable product could be obtained.9d However, when the
Nozaki–Hiyama–Kishi conditions was applied to the iodinated
benzyl ether 14 and aldehyde 4 in the presence of 6 equiv. of CrCl2
and 0.06 equiv. of NiCl2 in dry dimethyl sulfoxide (DMSO),9e
the desired adduct 3 was obtained in 40% yield, together with a
substantial amount (50%) of the deiodinated compound. When
the reaction was run in DMF, the coupling product 3 as a single
isomer was obtained in slightly high yield (53%) along with a
smaller amount (40%) of the deiodinated compound. Our next
challenge was how to confirm the stereochemistry of C(2) in 3.
After some aborted efforts to obtain crystals for X-ray diffraction
analysis and the failure of employing the Mosher’s method to
define the stereochemistry of 3 (see ESI†),18 the unambiguous
stereochemistry assignment of compound 3 was confirmed by
NOE experiment of its derivative 16 (see Scheme 4 and ESI†).
Hence, selective irradiations of H-4 of 16 resulted in signal
enhancements of H-1¢a, H-1¢b, and H-5, H-8a resulted in signal
enhancements of H-2, H-7, and H-8, and H-1¢a resulted in signal
enhancements of H-2, H-8a, H-4, and H-1¢b. Therefore the new
chiral center at C-2 in compound 3 has an S configuration.
Fig. 2 ORTEP diagram of 13.
Synthesis of aldehyde fragment
4
began with mo-
noethanolamine 6. The amino group was first protected by
treatment with phthalic anhydride 7 at 145 ◦C in the absence
of solvent to give compound 15 in 89% yield.16 Subsequent
oxidation of 15 with o-iodoxybenzoic acid (IBX) in ethyl acetate
under refluxing temperature provided the aldehyde 4 in 99% yield
(Scheme 3).17
Scheme 4 Determination of absolute configuration of 3.
Scheme 3 Preparation of aldehyde 4.
With the chiral fatty acid 2 and amine 3 in hand, we focused
our efforts on the formation of the skeleton of malyngamide W
(1) by an amidation reaction (Scheme 5). Thus, deprotection of
compound 3 with hydrazine hydrate (NH2NH2·H2O) in ethanol
In order to construct the C(2)–C(1¢) bond framework of 3 for the
formation of the amine portion in malyngamides W (1) and 2¢-epi-
1, several methods and reaction conditions were explored (Table
Table 1 Optimization for the coupling reaction of 4 with 5, 12, and 14
entry
substrates
R1, R2
conditions
% yield
product
1
2
3
5
12
14
R1 = H
R1 = I
TiCl4, CH2Cl2, 0 ◦C for 10 min and then stirred for another 12 h at room temperature.
CrCl2, NiCl2 (1%), DMSO.a
no reaction
no reaction
40%
R1 = I
CrCl2, NiCl2 (1%), DMSO.a
3
3
R2 = Bn
R1 = I
4
14
CrCl2, NiCl2 (1%), DMF.a
53%
R2 = Bn
a 6 equiv. of CrCl2 and 0.06 equiv. of NiCl2 dissolved in dry DMSO or DMF vortexed for about 10 min, then aldehyde 4 and iodide 12 or 14 were added
to the mixture respectively, the reaction stirred for 36 h at 28 ◦C.
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Scheme 5 Synthesis of 2¢-epi-1.
Scheme 6 Synthesis of malyngamide W (1).
◦
at 60 C,19 followed by amidation of the resulting crude amine
with the chiral fatty acid 2 in the presence of dicyclohexyl-
carbodiimide (DCC), 1-hydroxybenzotriazole (HOBt), and 4-
methylmorpholine (NMM) in dichloromethane, afforded the
amide 17 in 80% yield over two steps.4b However, O-methylation
of compound 17 with calcium sulfate (CaSO4) and silver oxide
(Ag2O) in neat methyl iodide (MeI) at 40 ◦C gave compound
19 in a very poor yield (24%), and a mixture was obtained
if the reaction was warmed to reflux. On the other hand, O-
methylation of 3 with MeI in the presence of CaSO4 and Ag2O
under refluxing temperature gave amide 18 in 46% yield (89%
yield, BORSM).4c,20 Subsequent removal of the phthalimide group
in compound 18 with NH2NH2·H2O in ethanol at 60 ◦C, followed
by amidation with the acid 2 in the presence of DCC, HOBt,
and NMM afforded the target amide 19 in 78% yield for two
steps. Then removal of the Bn protecting group in amide 19 and
concomitant oxidation of the hydroxyl group in the presence of
4 equiv. of dichlorodicyano benzoquinone (DDQ) in a cosolvent
of dicloromethane–water (9 : 1) produced the amide 20 in 75%
yield.4b,21 Finally, removal of the TBS moiety by trifluoroacetic
acid (TFA) in wet dichloromethane afforded the desired product
in 85% yield. However, both the 1H and 13C NMR data of
synthetic product disagreed with the reported data for the isolated
malyngamide W. As the absolute configuration of compound 2¢-
epi-1 had been unambiguously confirmed by the crystal structure
of compound 13 and the NOE experiments of compound 16,
the structure of malyngamide W should be 1, with the absolute
configuration at the C-2¢ being opposite to that of 2¢-epi-1 (i.e., R
instead of S). Hence, our next goal was to prepare the 2¢R-epimer.
In order to secure the desired absolute configuration at 2¢,
a redox strategy was performed. The synthesis of 1 started
from compound 17 (Scheme 6). Thus, oxidation of 17 with
Dess–Martin periodinane (DMP) in dichloromethane afforded
amide 21 in 80% yield.22 After several unsuccessful trials, the
Corey–Bakshi–Shibata oxazaborolidine (CBS catalyst) mediated
reduction23 was used to reduce the a,b-unsaturated ketone 21
to give the diastereomeric amides 2¢-epi-17 and 17 (20 : 1) in 85%
yield. Subsequent O-methylation of the hydroxyl group in 2¢-epi-17
in neat MeI by treatment with CaSO4 and Ag2O at 40 ◦C afforded
the amide 2¢-epi-19 in 70% yield. It was interesting to note that
when amide 2¢-epi-19 was treated with DDQ, only the alcohol 22
was obtained despite using a large excess of DDQ (8 equiv). This
result could be due to a large difference in steric hindrance around
the vicinity of the epimeric alcohol functionality in compounds 19
and 2¢-epi-19.24 In the end, oxidation of compound 22 could be
realized with DMP to afford amide 2¢-epi-20 in nearly quantitative
yield. Finally, removal of the TBS moiety in 2¢-epi-20 by TFA
gave malyngamide W (1) in 69% yield. The NMR data of 1 were
identical to the data reported for the isolated malyngamide W.
The specific rotation of 1 was found to be [a]2D0 -19 (c 0.06 in
CHCl3), which was consistent with the reported value of [a]2D0 -15
(c 0.06 in CHCl3). To conclude, we have completed the synthesis
of malyngamide W (1) and 2¢-epi-1 in 4.1% and 3.6% yield,
respectively. In addition, we clarified the absolute configuration
of malyngamide W (1), which can now be assigned as 7S, 2¢R,
3¢¢R, and 4¢¢R.
Conclusions
In summary, we reported the first enantioselective synthesis of
malyngamide W (1) and its 2¢-epimer. The absolute configuration
of the C-2¢ position on the amine portion of malyngamide W
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was also confirmed. The stereochemistry of the amine part was
secured by a stereoselective Nozaki–Hiyama–Kishi reaction and
an asymmetric (R)-CBS reduction. The key intermediate 5 was
prepared from relatively inexpensive (R)-(-)-carvone in 4 steps
with 50% overall yield. This new synthetic protocol not only offers
a concise entry to malyngamide W, but also to other structurally
related malyngamides. Further synthesis work is currently under
progress and will be presented in due course.
was stirred at -20 ◦C for 7 h and then warmed up to ambient
temperature. The stirring was continued for an additional 3 h, then
water (20 mL) was added and extracted with dichloromethane (60
mL ¥ 6). The combined organic layer was washed with saturated
sodium bicarbonate solution, brine, and then dried over MgSO4,
filtered, and concentrated in vacuo. Flash chromatography of the
residue over silica gel (petroleum ether–EtOAc, 50 : 1) afforded
a,b-unsaturated cyclohexenone 5 (2.17 g, 85%) as a colorless
oil. [a]2D0 -41 (c 1.0 in CHCl3); IR (KBr, nmax/cm-1: 3038, 2932,
2858, 1684, 1254, 1109, 777; dH (400 MHz; CDCl3; Me4Si) 0.02
(s, 6H, 2 ¥ CH3), 0.82 (s, 9H, 3 ¥ CH3), 1.10 (d, J 6.8, 3H, CH3),
2.38–2.55 (m, 3H, 4-H and 6-H), 4.19 (dd, J 4.0 4.8, 1H, 5-H),
5.98 (d, J 10.0, 1H, 2-H), 6.71–6.75 (m, 1H, 3-H); dC (100 MHz;
CDCl3; Me4Si) -5.0 (CH3), -4.8 (CH3), 10.6 (CH3), 17.9 (C), 25.6
(CH3), 33.6 (CH2, 4-C), 48.3 (CH, 6-C), 71.0 (CH, 5-C), 129.2
(CH, 2-C), 144.9 (CH, 3-C), 201.5 (CO); HRMS (ESI) m/z calcd
for C13H25O2Si [M + H]+ 241.1618, found 241.1615.
Experimental
General
All reactions that required anhydrous conditions were carried
by standard procedures under argon atmosphere. Commercially
available reagents were used as received. The solvents were dried by
distillation over the appropriate drying reagents. Petroleum ether
◦
used had a bp range of 60–90 C. Reactions were monitored by
(5R,6R)-5-tert-Butyldimethylsilyloxy-2-iodo-6-methylcyclohex-
2-enone (12). To a solution of a,b-unsaturated cyclohexenone
5 (2.05 g, 8.53 mmol) and DMAP (2.10 g, 17.1 mmol) in
dichloromethane (20 mL), a solution of I2 (2.59 g, 10.24 mmol)
in dichloromethane (120 mL) was added dropwise over 20 min at
room temperature. After stirring for 10 h at the same temperature,
the reaction mixture was quenched by the addition of water
and extracted with dichloromethane. The organic layer was
washed with 1 M hydrochloric acid aqueous solution, water,
10% sodium thiosulfate aqueous solution, water and brine. Then
dried over MgSO4, filtered, and concentrated in vacuo. Flash
chromatography of the residue over silica gel (petroleum ether–
EtOAc, 100 : 1) afforded ketone 12 (2.62 g, 84%) as a yellow oil:
[a]D20 +2 (c 1.0 in CHCl3); IR (KBr, nmax/cm-1: 2953, 2857, 2708,
1692, 1252, 839; dH (400 MHz; CDCl3; Me4Si) 0.02 (s, 6H, 2 ¥
CH3), 0.83 (s, 9H, 3 ¥ CH3), 1.17 (d, J 6.8, 3H, CH3), 2.45–2.52
(m, 1H, 4b-H), 2.59–2.66 (m, 1H, 4a-H), 2.73–2.77 (m, 1H, 6-H),
4.23 (dt, J 3.6, 4, 1H, 5-H), 7.51 (t, J 4.4, 1H, H-3); dC (100 MHz;
CDCl3; Me4Si) -5.0 (CH3), -4.8 (CH3), 11.5 (CH3), 17.9 (C), 25.6
(3 ¥ CH3), 37.7 (CH2, 4-C), 48.1 (CH, 6-C), 70.9 (CH, 5-C), 103.0
(C, 2-C), 153.3 (CH, 3-C), 194.1 (CO); HRMS (ESI) m/z calcd
for C13H24IO2Si [M + H]+ 367.0585, found 367.0579.
TLC on silica gel plates. Column chromatography was generally
performed through silica gel (200–300 mesh). IR spectra were
reported in wave numbers (cm-1). 1H and 13C NMR, DEPT
1
135, H–1H COSY and NOE experiments were recorded on an
400 MHz or 600 MHz spectrometer. Chemical shifts (d) were
reported in ppm relative to TMS (dH 0.00) for the 1H NMR and
to chloroform (dC 77.0) for the 13C NMR measurements. High
resolution mass spectra (HRMS) and mass spectra (MS) were
obtained on the mass spectrometer.
(2R,3R,5R)-3-tert-Butyldimethylsilyloxy-2-methyl-5-(1-methyl-
ethenyl)-cyclohexanone (11). To a stirred solution of ketone 10
(2.00 g, 11.89 mmol) in dry N,N-dimethylformamide (2.5 mL),
imidazole (2.43 g, 35.67 mmol) and TBSCl (3.60 g, 23.78 mmol)
was added at 0 ◦C and the stirring was continued at room
temperature for 24 h. Then the solution was poured into water
(10 mL) and extracted with petroleum ether (20 mL ¥ 4). The
organic layer was dried over MgSO4, filtered, and concentrated
in vacuo. Flash chromatography of the residue over silica gel
(petroleum ether–EtOAc, 100 : 1) afforded ketone 11 (3.12 g, 93%)
as a colorless oil: [a]2D0 -22 (c 1.0 in CHCl3); IR (KBr, nmax/cm-1:
2932, 2858, 1718, 1254, 1069, 835; dH (400 MHz; CDCl3; Me4Si)
0.05 (s, 6H, 2 ¥ CH3), 0.87 (s, 9H, 3 ¥ CH3), 1.06 (d, J 6.8, 3H,
CH3), 1.70–1.80 (m, 4H, 4b-H and CH3), 1.99–2.05 (m, 1H, 6b-H),
2.25 (dt, J 13.2, 13.6, 1H, 4a-H), 2.45–2.49 (m, 2H, 2-H and 6a-
H), 2.84–2.92 (m, 1H, 5-H), 4.26 (br, 1H, 3-H), 4.72 (d, J 11, 1H,
2¢b-H), 4.80 (d, J 11, 1H, 2¢a-H); dC (100 MHz; CDCl3; Me4Si)
-5.0 (CH3), -4.5 (CH3), 11.4 (CH3), 18.1 (C), 20.6 (CH3), 25.7 (3 ¥
CH3), 38.7 (CH2), 39.9 (CH, 2-C), 46.5 (CH2), 49.9 (CH, 5-C),
74.2 (CH, 3-C), 109.7 (CH2, 2¢-C), 147.5 (C, 1¢-C), 210.7 (CO);
HRMS (ESI) m/z calcd for C16H31O2Si [M + H]+ 283.2088, found
283.2083.
(1R,5R,6S)-5-tert-Butyldimethylsilyloxy-2-iodo-6-methylcy-
clohex-2-enol (13). To a stirred solution of 12 (2.10 g, 5.73 mmol)
in methanol and dichloromethane (60 mL, MeOH–CH2Cl2 2 : 1),
cerium(III) chloride heptahydrate (2.35 g, 6.30 mmol) was added,
followed by several portions of sodium borohydride (0.25 g, 96%,
6.30 mmol) at 0 ◦C. After stirring for 30 min, the reaction was
quenched by saturated ammonium chloride solution. The aqueous
phase was extracted with dichloromethane (40 mL ¥ 3). The
organic layer was washed with brine, dried over MgSO4, filtered,
and concentrated in vacuo. Flash chromatography of the residue
over silica gel (petroleum ether–EtOAc, 100 : 1) afforded alcohol
13 (2.09 g, 99%) as a white solid: mp 58–60 ◦C; [a]D20 -10 (c 2.0 in
CHCl3); IR (KBr, nmax/cm-1: 3497, 2931, 2875, 1420, 1256, 1005,
949; dH (400 MHz; CDCl3; Me4Si) 0.05 (s, 3H, CH3), 0.07 (s, 3H,
CH3), 0.86 (s, 9H, 3 ¥ CH3), 1.17 (d, J 7.2, 3H, CH3), 1.95–2.01
(m, 1H, 6-H), 2.20–2.34 (m, 2H, H-4), 3.28 (d, J 11.2, 1H), 3.86–
3.90 (m, 1H, 5-H), 4.03 (br, 1H, 1-H), 6.26 (dd, J 1.6, 3.0, 1H,
3-H); dC (100 MHz; CDCl3; Me4Si) -5.1 (CH3), -4.8 (CH3), 14.7
(CH3), 17.7 (C), 25.6 (CH3), 25.7 (CH3), 38.1 (CH2, 4-C), 38.6 (CH,
(5R,6R)-5-tert-Butyldimethylsilyloxy-6-methyl-2-cyclohexenone
(5)7. To a stirred solution of 11 (3.00 g, 10.60 mmol) in methanol
and dichlormethane (60 mL, MeOH–CH2Cl2, 2 : 1), the mixture
was bubbled with ozone at -78 ◦C. After consumption of 11
(monitored by TLC), argon was purged and the reaction mixture
was allowed to warm up to -20 ◦C and copper(II) acetate
monohydrate (4.23 g, 21.19 mmol) was then added. After stirring
for 20 min at the same temperature, ferrous sulfate heptahydrate
(3.53 g, 12.70 mmol) was added in small portions. The suspension
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6-C), 70.1 (CH, 5-C), 76.8 (CH, 1-C), 102.9 (C, 2-C), 133.6 (CH,
3-C); HRMS (ESI) m/z calcd for C13H26IO2Si [M + H]+ 369.0741,
found 369.0744; Crystal data for 13: C13H25IO2Si, M = 368.32,
at this temperature for 36 h. The reaction mixture was diluted
with ether and poured into water, then the aqueous phase was
extracted with ether (40 mL ¥ 4). The organic layer was washed
with brine, dried over MgSO4, filtered, and concentrated in vacuo.
Flash chromatography of the residue over silica gel (petroleum
ether–EtOAc, 6 : 1) afforded 3 (1.33 g, 53%) as a colorless oil: [a]D20
-15 (c 1.0 in CHCl3); IR (KBr, nmax/cm-1: 3412, 3004, 2920, 1714,
1362, 1222, 1092, 902, 748; dH (400 MHz; CDCl3; Me4Si) 0.04 (s,
3H, CH3), 0.06 (s, 3H, CH3), 0.90 (s, 9H, 3 ¥ CH3), 0.95 (d, J
6.8, 3H, CH3), 1.97–2.14 (m, 2H, 3¢-H), 2.44–2.48 (m, 1H, 5¢-H),
3.75–3.81 (m, 1H, 4¢-H), 3.82–3.87 (m, 1H, 1b-H), 3.91 (d, J 11.2,
1H, 6¢-H), 3.93–3.98 (m, 1H, 1a-H), 4.31–4.37 (m, 1H, 2-H), 4.66
(br, 1H, OH), 4.68 (d, J 10.8, 1H, ArCH), 4.75 (d, J 10.8, 1H,
ArCH), 5.61 (dt, J 2.4, 2.8, 1H, 2¢-H), 7.32–7.36 (m, 1H, ArH),
7.39–7.42 (m, 2H, 2 ¥ ArH), 7.52 (d, J 7.2, 2H, 2 ¥ ArH), 7.71–
7.73 (m, 2H, 2 ¥ ArH), 7.84–7.86 (m, 2H, 2 ¥ ArH); dC (100 MHz;
CDCl3; Me4Si) -4.9 (CH3), -4.7 (CH3), 5.4 (CH3), 17.9 (C), 25.7
(3 ¥ CH3), 30.8 (CH2, 3¢-C), 36.5 (CH, 5¢-C), 42.8 (CH2, 1-C), 68.2
(CH, 4¢-C), 70.3 (CH2), 74.4 (CH, 2-C), 78.4 (CH, 6¢-C), 123.1 (2 ¥
ArCH), 126.8 (CH, 2¢-C), 128.0 (CH), 128.5 (2 ¥ ArCH), 128.6
(2 ¥ ArCH), 132.0 (2 ¥ ArC), 133.8 (2 ¥ ArCH), 134.6 (C, 1¢-C),
137.1 (ArC), 168.3 (2 ¥ CO); HRMS (ESI) m/z C30H39NO5SiNa
[M + Na]+ 544.2490, found 544.2492.
orthorhombic, a = 11.5224(12), b = 11.6757(14), c = 12.5624(15)
3
˚
˚
A, U = 1690.0(3) A , T = 296(2) K, space group P212121, Z = 4,
Dx = 1.448 g cm-3, Mo-Ka radiation, 10387 reflections measured,
3682 unique (Rint = 0.0416), final R indices [I > 2s(I)]: R1 = 0.0295,
wR2 = 0.0669, R indices (all data): R1 = 0.0368, wR2 = 0.0702.
[(1R,5R,6S)-5-Benzyloxy-4-iodo-6-methylcyclohex-3-enyloxy]-
tert- butyldimethylsilane (14). To a suspension of sodium hydride
(0.28 g, 6.52 mmol) in dry THF (50 mL), a solution of alcohol 13
(2.00 g, 5.43 mmol) in dry THF (10 mL) was added at 0 ◦C under
an argon atmosphere. After being stirred for 30 min at the same
temperature, benzyl bromide (0.77 mL, 6.52 mmol) and tetra-n-
butylammunium iodide (18 mg, 0.05 mmol) were added to the
mixture. After being stirred for 12 h at room temperature, the
reaction mixture was diluted with ether and poured into water,
then the aqueous phase was extracted with ether (40 mL ¥ 4). The
organic layer was washed with brine, dried over MgSO4, filtered,
and concentrated in vacuo. Flash chromatography of the residue
over silica gel (petroleum ether–EtOAc, 150 : 1) afforded iodide
14 (2.34 g, 94%) as a colorless oil: [a]2D0 -10 (c 1.0 in CHCl3); IR
(KBr, nmax/cm-1: 3040, 2929, 2856, 1254, 1116, 833; dH (400 MHz;
CDCl3; Me4Si) 0.070 (s, 3H, CH3), 0.074 (s, 3H, CH3), 0.92 (s, 9H,
3 ¥ CH3), 0.99 (d, J 7.2, 3H, CH3), 2.05–2.11 (m, 1H, 2b-H), 2.12–
2.22 (m, 1H, 2a-H), 2.28–2.36 (m, 1H, 6-H), 3.94–4.00 (m, 1H,
1-H), 4.01–4.03 (m, 1H, 5-H), 4.67 (dd, J 11.6, 15.6, 2H, ArCH2),
6.37–6.40 (m, 1H, 3-H), 7.31–7.41 (m, 3H, 3 ¥ ArH), 7.51 (d, J
6.8, 2H, 2 ¥ ArH); dC NMR (CDCl3, 100 MHz) -4.9 (CH3), -4.7
(CH3), 5.8 (CH3), 18.0 (C), 25.7 (3 ¥ CH3), 34.5 (CH2, 2-C), 39.1
(CH, 6-C), 68.2 (CH, 1-C), 71.6 (CH2), 79.7 (CH, 5-C), 102.5 (C,
4-C), 127.6 (ArCH), 128.0 (2 ¥ ArCH), 128.3 (2 ¥ ArCH), 136.5
(CH, 3-C), 137.9 (ArC); HRMS (ESI) m/z calcd for C20H32IO2Si
[M + H]+ 459.1211, found 459.1216.
1-{[(2S,4R,7R,8S,8aR)-7-tert-Butyldimethylsilyloxy-8-methyl-
2-phenyl-6,7,8,8a-tetrahydro-4H-benzo[d]1,3 dioxin-4-yl]-methyl}-
isoindoline-1,3-dione (16). To a stirred solution of 3 (63 mg,
0.12 mmol) in dichloromethane (1.8 mL) and water (0.2 mL),
DDQ (217 mg, 0.96 mmol) was added and the mixture was stirred
for a further 12 h. Then the reaction mixture was concentrated
in vacuo. Flash chromatography of the residue over silica gel
(petroleum ether–EtOAc, 8 : 1) afforded amide 16 (18 mg, 29%) as
a colorless oil: [a]D20 +3 (c 1.0 in CHCl3); IR (KBr, nmax/cm-1: 2949,
2929, 1715, 1396, 1095, 1032, 864, 716; dH (400 MHz; CDCl3;
Me4Si) 0.080 (s, 3H, CH3), 0.084 (s, 3H, CH3), 0.91 (s, 9H, 3 ¥
CH3), 1.04 (d, J 6.8, 3H, CH3), 2.08–2.23 (m, 2H, 6-H), 2.41–2.45
(m, 1H, 8-H), 3.69 (dd, J 2.2, 5.2, 1H, 1¢b-H), 3.90–3.95 (m, 1H,
7-H), 4.46–4.53 (m, 1H, 1¢a-H), 4.77–4.80 (m, 1H, 4-H), 4.83 (br,
1H, 8a-H), 5.58 (br, 1H, 5-H), 6.18 (s, 1H, 2-H), 7.31–7.34 (m,
3H, 3 ¥ ArH), 7.49–7.51 (m, 2H, 2 ¥ ArH), 7.70–7.73 (m, 2H, 2 ¥
ArH), 7.83–7.85 (m, 2H, 2 ¥ ArH); dC (100 MHz; CDCl3; Me4Si)
-4.8 (CH3), -4.7 (CH3), 5.9 (CH3), 18.1 (C), 25.8 (3 ¥ CH3), 31.1
(CH2, 6-C), 38.5 (CH, 8-C), 39.1 (CH2, 1¢-C), 68.3 (CH, 7-C),
74.0 (CH, 4-C), 74.3 (CH, 8a-C), 94.7 (CH, 2-C), 123.1 (CH,
5-C), 123.3 (2 ¥ ArCH), 126.5 (2 ¥ ArCH), 128.2 (2 ¥ ArCH),
128.8 (CH), 128.6 (ArC), 132.1 (2 ¥ ArC), 134.0 (2 ¥ ArCH),
138.3 (C, 4a-C), 168.2 (2 ¥ CO); HRMS (ESI-TOF) m/z calcd
for C30H37NO5SiNa [M + Na]+ 542.2333, found 542.2354.
2-(1,3-Dioxoisoindolin-2-yl)acetaldehyde (4). To a solution of
amide alcohol 15 (3.00 g, 15.69 mmol) in dry ethyl acetate (60 mL),
IBX (8.79 g, 31.38 mmol) was added. The resulti◦ng suspension
was immersed in an oil bath which was set to 78 C and stirred
vigorously under an argon atmosphere for 10 h. The reaction was
cooled to room temperature and filtered through a medium glass
frit. The filter cake was washed with ethyl acetate (150 mL). The
filtrate was concentrated in vacuo which afforded aldehyde 4 (2.94
g, 99%) as a white solid: mp 114–115 ◦C; IR (KBr, nmax/cm-1: 3059,
2933, 1708, 1610, 1014, 872, 714; dH (400 MHz; CDCl3; Me4Si)
4.55 (s, 2H, 2-H), 7.74–7.76 (m, 2H, 2 ¥ ArH), 7.85–7.88 (m, 2H,
2 ¥ ArH), 9.65 (s, 1H, 1-H); dC (100 MHz; CDCl3; Me4Si) 47.3
(CH2, 2-C), 123.6 (2 ¥ CH), 131.9 (C), 134.3 (2 ¥ CH), 167.5 (CO),
193.5 (CO, 1-C); HRMS (ESI) m/z calcd for C10H11N2O3 [M +
NH4]+ 207.0764, found 207.0768.
2-{(2S)-[(4R,5S,6R)-6-Benzyloxy-4-tert-butyldimethylsilyoxy-
5-methyl-1-cylohexenyl]-2-methoxyethyl}-isoindoline-1,3-dione
(18). To a stirred solution of alcohol 3 (486 mg, 0.93 mmol)
in MeI (10.0 mL), dry calcium sulfate (1.64 g, 12.09 mmol) was
added, followed by silver oxide (1.08 g, 4.65 mmol) in one portion.
N-2S-{[(4R,5S,6R)-6-Benzyloxy-4-tert-butyldimethylsilyoxy)-
5-methyl-1-cyclohexenyl]-2-hydroxyethyl}-isoindolin-1,3-dione (3).
To a mixture of 1% anhydrous nickelous chloride (w/w 4 mg,
0.03 mmol) of chromium chloride (3.54 g, 28.80 mmol) in N,N-
dimethylformamide (2 mL) at 28 ◦C, a mixture of the vinyl iodide
14 (2.2 g, 4.80 mmol) and aldehyde 4 (2.72 g, 14.38 mmol)
in N,N-dimethylformamide (20 mL) was added. The reaction
mixture was deep green in color and was stirred continuously
◦
The reaction mixture was stirred for 24 h at 55 C, then filtered
through celite. The filter cake was washed with EtOAc (20 mL ¥ 4),
dried over MgSO4 and the filtrate was concentrated in vacuo. Flash
chromatography of the residue over silica gel (petroleum ether–
EtOAc, 7 : 1) afforded amide 18 (230 mg, 46%) as a colorless oil:
[a]D20 +40 (c 0.8 in CHCl3); IR (KBr, nmax/cm-1: 2930, 1717, 1394,
3822 | Org. Biomol. Chem., 2011, 9, 3817–3824
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1106, 838, 718; dH (400 MHz; CDCl3; Me4Si) 0.02 (d, J 10.8, 6H,
2 ¥ CH3), 0.77 (d, J 6.8, 3H, CH3), 0.89 (s, 9H, 3 ¥ CH3), 2.12–2.16
(m, 2H, 3¢-H), 2.26–2.30 (m, 1H, 5¢-H), 3.12 (s, 3H, OCH3), 3.76–
3.82 (m, 1H, 1b-H), 3.83–3.85 (m, 1H, 4¢-H), 3.92–3.97 (m, 1H,
1a-H), 4.07 (br, 1H, 6¢-H), 4.21 (t, J 6.8, 1H, 2-H), 4.44 (d, J 11.6,
1H, ArCH), 4.53 (d, J 11.6, 1H, ArCH), 5.87 (t, J 2.4, 1H, 2¢-H),
7.29–7.38 (m, 3H, 3 ¥ ArH), 7.44 (d, J 7.2, 2H, 2 ¥ ArH), 7.67–
7.69 (m, 2H, 2 ¥ ArH), 7.79–7.81 (m, 2H, 2 ¥ ArH); dC (100 MHz;
CDCl3; Me4Si) -4.8 (CH3), -4.6 (CH3), 5.5 (CH3), 18.0 (C), 25.8
(3 ¥ CH3), 30.8 (CH2, 3¢-C), 37.0 (CH, 5¢-C), 42.8 (CH2, 2-C), 56.4
(OCH3), 68.9 (CH, 4¢-C), 70.4 (CH2), 76.5 (CH, 2-C), 77.8 (CH,
6¢-C), 123.0 (2 ¥ CH), 124.0 (CH, 2¢-C), 127.6 (ArCH), 128.3 (2 ¥
ArCH), 128.4 (2 ¥ ArCH), 132.4 (2 ¥ C), 133.5 (2 ¥ CH), 135.6
(C, 1¢-C), 138.2 (C), 168.4 (2 ¥ CO); HRMS (ESI) m/z calcd for
C31H45N2O5Si [M + NH4]+ 553.3092, found 553.3087.
with saturated ammonium chloride solution, dried over MgSO4,
filtered, and concentrated in vacuo. Flash chromatography of the
residue over silica gel (petroleum ether–EtOAc, 1 : 1) afforded
amide 2¢-epi-1 (9 mg, 85%) as a colorless oil: [a]2D0 -52 (c 0.5
in CHCl3); IR (KBr, nmax/cm-1: 3411, 2928, 1711, 1363, 1219,
1142, 974; dH (400 MHz; CDCl3; Me4Si) 0.89 (dt, J 6.4, 7.2, 3H,
CH3 and 12-H), 1.28–1.30 (m, 9H, 9-H, 10-H, 11-H and CH3),
1.41–1.45 (m, 2H, 8-H), 2.18–2.31 (m, 6H, 2-H, 3-H, and 6-H),
2.59–2.75 (m, 4H, 3¢¢-H, 5¢¢-H, and OH), 3.14–3.25 (m, 2H, 1¢b-H
and 7-H), 3.27 (s, 3H, OCH3), 3.32 (s, 3H, OCH3), 3.74–3.80 (m,
1H, 1¢a-H), 4.14 (br, 1H, 4¢¢-H), 4.28 (br, 1H, 2¢-H), 5.44–5.47
(m, 2H, 4-H and 5-H), 5.90 (br, 1H, NH), 6.66 (br, 1H, 6¢¢-H);
dC (100 MHz; CDCl3; Me4Si) 11.6 (CH3), 14.4 (CH3, 12-C),
23.0 (CH2, 11-C), 25.4 (CH2, 9-C), 28.8 (CH2, 3-C), 32.4 (CH2,
10-C), 33.6 (CH2, 8-C), 34.9 (CH2, 5¢¢-C), 36.7 (CH2, 6-C), 36.9
(CH2, 2-C), 43.0 (CH2, 1¢-C), 48.4 (CH, 3¢¢-C), 56.8 (OCH3), 57.4
(OCH3), 71.9 (CH, 4¢¢-C), 76.4 (CH, 2¢-C), 81.1 (CH, 7-C), 128.0
(CH, 5-C), 131.1 (CH, 4-C), 136.1 (C, 1¢¢-C), 140.3 (CH, 6¢¢-C),
174.8 (CO, 1-C), 199.7 (CO, 2¢¢-C); HRMS (ESI) m/z calcd for
C23H40NO5 [M + H]+ 410.2901, found 410.2905.
(4E,7S)-N -{(2S)-[(4R,5S,6R)-6-Benzyloxyl-4-tert-butyldi-
methylsilyoxy-5-methyl-1-cyclohexenyl]-2-methoxyethyl}-7-metho-
xydodec-4-enamide (19). To a stirred solution of compound 18
(182 mg, 0.34 mmol) in ethanol (4 mL), hydrazine monohydrate
(0.99 mL, 2.04 mmol) was added and the resulting mixture was
stirred for 2 h at 60 ◦C. The precipitate formed was filtered off
and the filtrate was evaporated to give crude amine, which was
immediately used in the next step without further purification.
To the crude amine, a solution of acid 2 (84 mg, 0.37 mmol) in
dichloromethane (10 mL), DCC (85 mg, 0.41 mmol), HOBt (46
mg, 0.34 mmol) and NMM (34 mg, 0.34 mmol) were added at
(4E,7S)-N -{[(4R,5S,6R)-6-Benzyloxy-4-tert-butyldimethyl-
silyoxy-5-methyl-1-cyclohexenyl]-2-oxoethyl}-7-methoxydodec-4-
enamide (21). To a stirred solution of amide 17 (150 mg,
0.25 mmol) in dichloromethane (8 mL), Dess–Martin periodinane
(127 mg, 0.30 mmol) was added at room temperature. The reaction
mixture was stirred for 1 h at this temperature and was then
concentrated in vacuo. Flash chromatography of the residue over
silica gel (petroleum ether–EtOAc, 3 : 1) afforded amide 21 (120
mg, 80%) as colorless oil: [a]2D0 +8 (c 1.0 in CHCl3); IR (KBr,
0
◦C. After being stirred for 30 min at the same temperature,
the reaction was warmed to room temperature and stirred for
8 h. Then the reaction mixture was concentrated in vacuo and
flash chromatography of the residue over silica gel (petroleum
ether–EtOAc, 2 : 1) afforded amide 19 as a colorless oil. (163 mg,
78%): [a]2D0 +20 (c 0.2 in CHCl3); IR (KBr, nmax/cm-1: 2985, 2938,
1742, 1374, 1242, 1047, 937; dH (400 MHz; CDCl3; Me4Si) 0.05
(s, 3H, CH3), 0.06 (s, 3H, CH3), 0.87 (m, 6H, 2 ¥ CH3), 0.90 (s,
9H, 3 ¥ CH3), 1.26–1.43 (m, 8H, 8-H, 9-H, 10-H, and 11-H),
2.00–2.38 (m, 8H, 2-H, 3¢¢-H, 3-H, and 6-H), 2.39–2.42 (m, 1H,
5¢¢-H), 3.12–3.15 (m, 1H, 7-H), 3.20 (s, 3H, OCH3), 3.26–3.31
(m, 1H, 1¢a-H), 3.32 (s, 3H, OCH3), 3.48–3.52 (m, 1H, 1¢b-H),
3.81–3.84 (m, 1H, 2¢-H), 3.85–3.89 (m, 1H, 4¢¢-H), 4.17 (br, 1H,
6¢¢-H), 4.41 (d, J 11.6, 1H, ArCH), 4.68 (d, J 11.6, 1H, ArCH),
5.39–5.42 (m, 2H, 4-H and 5-H), 5.71 (t, J 2.4, 2¢¢-H), 6.09 (br,
1H, NH), 7.29–7.36 (m, 5H, 5 ¥ ArH); dC (100 MHz; CDCl3;
Me4Si) -4.8 (CH3), -4.6 (CH3), 5.7 (CH3), 14.0 (CH3, 12-C), 18.0
(C), 22.6 (CH2, 11-C), 24.9 (CH2, 9-C), 25.7 (3 ¥ CH3), 28.7 (CH2,
3-C), 30.7 (CH2, 10-C), 32.0 (CH2, 8-C), 33.3 (CH2, 3¢¢-C), 36.3
(CH2), 36.4 (CH2, 2-C), 37.0 (CH, 5¢¢-C), 44.1 (CH2, 1¢-C), 56.2
(OCH3), 56.5 (OCH3), 68.7 (CH, 4¢¢-C), 70.6 (CH2), 77.8 (CH,
2¢-C), 78.7 (CH, 6¢¢-C), 80.8 (CH, 7-C), 123.4 (CH, 2¢¢-C), 127.1
(CH, 5-C), 127.8 (CH), 127.9 (2 ¥ CH), 128.5 (2 ¥ CH), 131.0
(CH, 4-C), 135.5 (C, 1¢¢-C), 137.9 (C), 172.1 (CO); HRMS (ESI)
m/z calcd for C36H62NO5Si [M + H+] 616.4392, found 616.4380.
n
max/cm-1: 2930, 2860, 1653, 1459, 1254, 1095, 838, 77; dH (400
MHz; CDCl3; Me4Si) 0.05 (s, 6H, 2 ¥ CH3), 0.88 (br, 12H, 4 ¥
CH3), 0.96 (d, J 6.8, 3H, CH3), 1.27–1.43 (m, 8H, 8-H, 9-H, 10-H,
and 11-H), 2.18–2.36 (m, 9H, 2-H, 3-H, 6-H, and 3¢¢-H, 5¢¢-H),
3.13–3.15 (m, 1H, 7-H), 3.31 (s, 3H, OCH3), 3.81–3.85 (m, 1H, 4¢¢-
H), 4.11–4.17 (m, 1H, 1¢b-H), 4.49–4.54 (m, 2H, 1¢a-H and 2¢¢-H),
4.57 (d, J 11.0, 1H, ArCH), 4.64 (d, J 11.0, 1H, ArCH), 5.47–5.48
(m, 2H, 4-H and 5-H), 6.40 (br, 1H, NH), 6.60 (br, 1H, 6¢¢-H), 7.26–
7.37 (m, 5H, ArH); dC (100 MHz; CDCl3; Me4Si) -4.9 (CH3), -4.8
(CH3), 6.6 (CH3), 14.0 (CH3, 12-C), 17.9 (C), 22.7 (CH2, 11-C),
24.8 (CH2, 9-C), 25.7 (3 ¥ CH3), 28.5 (CH2, 3-C), 31.4 (CH2, 10-C),
31.9 (CH2, 8-C), 33.2 (CH2, 6-C), 36.16 (CH2), 36.24 (CH2), 37.0
(CH, 3¢¢-C), 46.9 (CH2, 1¢-C), 56.4 (OCH3), 67.9 (CH, 4¢¢-C), 71.6
(CH2), 75.1 (CH, 6¢¢-C), 80.6 (CH, 7-C), 127.5 (CH, 5-C), 127.6
(ArCH), 128.1 (2 ¥ ArCH), 128.3 (2 ¥ ArCH), 130.6 (CH, 4-C),
136.5 (CH, 2¢¢-C), 137.8 (C), 138.2 (C), 172.3 (CO), 196.2 (CO);
HRMS (ESI) m/z calcd for C35H61N2O5Si [M + NH4]+ 617.4344,
found 617.4333.
(4E,7S)-N -{(2R)-[(4R,5S,6R)-6-Benzyloxy-4-tert-butyldime-
thylsilyloxy-5-methyl-1-cyclohexenyl]-2-hydroxyethyl}-7-metho-
xydodec-4-enamide (2¢-epi-17). To a stirred solution of (R)-CBS
oxazaborolidine catalyst (47 mg, 0.17 mmol) in THF (6 mL),
BH3·(CH3)2S (2 M in THF, 0.17 mL) was added at 0 ◦C. The
reaction was stirred for 15 min and a solution of amide 21 (100
mg, 0.17 mmol) in THF was then added. The reaction mixture was
stirred at 0 ◦C for 30 min and then at room temperature for 3 h.
It was then re-cooled to 0 ◦C, another equivalent of BH3·(CH3)2S
(2 M in THF, 0.17 mL) was added and the reaction stirred for
an additional 2 h. The reaction was quenched with methanol and
(4E,7S)-N-{(2S)-[(3R,4R)-4-Hydroxy-3-methyl-2-oxocyclohex-
1-enyl]-2-methoxyethyl}-7-methoxydodec-4-enamide
(2¢-epi-1).
To a stirred solution of 20 (15 mg, 0.03 mmol) in dichloromethane
◦
(7.5 mL), TFA (0.6 mL) and water (0.15 mL) was added at 0 C
and the stirring was continued at this temperature for 20 h. Then
the reaction mixture was poured into brine (8 mL) and extracted
with dichloromethane (10 mL ¥ 6). The organic layer was washed
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residue partitioned between dichloromethane (10 mL) and water
(5 mL). The organic layer was dried over MgSO4, filtered and
concentrated in vacuo. Flash chromatography of the residue over
silica gel (petroleum ether–EtOAc, 1 : 1) afforded amide 2¢-epi-17
(85 mg, 85%) as a colorless oil: [a]2D0 -22 (c 0.5 in CHCl3); IR
(KBr, nmax/cm-1: 3375, 2928, 1561, 1383, 1068, 837, 636; dH (400
MHz; CDCl3; Me4Si) 0.05 (s, 3H, CH3), 0.06 (s, 3H, CH3), 0.90
(s, 9H, 3 ¥ CH3), 0.87–0.92 (m, 3H, CH3), 1.24–1.45 (m, 8H, 8-
H, 9-H, 10-H, and 11-H), 2.09–2.12 (m, 2H, 3-H), 2.17–2.23 (m,
4H, 2-H and 6-H), 2.30–2.34 (m, 2H, 3¢¢-H), 2.41–2.42 (m, 1H,
5¢¢-H), 3.14–3.16 (m, 1H, 7-H), 3.22–3.28 (m, 1H, 1¢b-H), 3.31 (s,
3H, OCH3), 3.50–3.55 (m, 1H, 1¢a-H), 3.82–3.84 (m, 1H, 4¢¢-H),
4.28 (d, J 2.0, 1H, 2¢-H), 4.34 (d, J 6.8, 1H, 6¢¢-H), 4.41(d, J 11.0,
1H, ArCH2), 4.68 (d, J 11.0, 1H, ArCH2), 5.46–5.48 (m, 2H, 4-H
and 5-H), 5.62 (br, 1H, NH), 5.94–5.97 (m, 1H, 2¢¢-H), 7.31–7.37
(m, 5H, 5 ¥ ArH); dC (100 MHz; CDCl3; Me4Si) -4.8 (CH3), -4.6
(CH3), 5.5 (CH3), 14.1 (CH3, 12-C), 18.1 (C), 22.7 (CH2, 11-C),
25.0 (CH2, 9-C), 25.8 (3 ¥ CH3), 28.8 (CH2, 3-C), 30.7 (CH2, 3¢¢-
C), 32.0 (CH2, 10-C), 33.3 (CH2, 8-C), 36.3 (CH2, 6-C), 36.5 (CH2,
2-C), 36.8 (CH, 5¢¢-C), 44.1 (CH2, 1¢-C), 56.4 (OCH3), 68.5 (CH,
7-C), 70.4 (CH2), 70.9 (CH, 4¢¢-C), 78.6 (CH, 2¢-C), 80.7 (CH, 6¢¢-
C), 121.8 (CH, 2¢¢-C), 127.5 (CH, 5-C), 127.9 (ArCH), 128.0 (2 ¥
ArCH), 128.6 (2 ¥ ArCH), 130.8 (CH, 4-C), 136.5 (C, 1¢¢-C), 137.8
(ArC), 172.9 (CO, 1-C); HRMS (ESI) m/z calcd for C35H60NO5Si
[M + H]+ 602.4235, found 602.4237.
Notes and references
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(4E,7S)-N -{(2R)-[(3R,4R)-4-Hydroxy-3-methyl-2-oxocyclo-
hex-1-enyl]-2-methoxyethyl}-7-methoxydodec-4-enamide
(1).
According to the preceding procedure for 2¢-epi-1, amide 2¢-epi-20
(15 mg, 0.03 mmol), TFA (0.6 mL) and water (0.15 mL), afforded
1 (8 mg, 69%) as a colorless oil: [a]2D0 -19 (c 0.06 in CHCl3); IR
(KBr, nmax/cm-1: 3411, 2828, 1677, 1142, 1093, 974; dH (400 MHz;
CDCl3; Me4Si) 0.89 (t, J 6.8, 3H, 12-H), 1.21 (d, J 7.2, 3H, CH3),
1.26–1.32 (m, 6H, 9-H, 10-H, and 11-H), 1.34–1.46 (m, 2H, 8-H),
2.18–2.31 (m, 6H, 2-H, 3-H, and 6-H), 2.64–2.72 (m, 3H, 3¢¢-H
and 5¢¢-H), 3.14–3.17 (m, 1H, 7-H), 3.28 (s, 3H, OCH3), 3.33 (s,
3H, OCH3), 3.40 (t, J 5.2, 2H, 1¢-H), 4.26–4.32 (m, 2H, 2¢-H and
4¢¢-H), 5.46–5.49 (m, 2H, 4-H and 5-H), 5.80 (br, 1H, NH), 6.67
(t, J 7.2, 1H, 6¢¢-H); dC (100 MHz; CDCl3; Me4Si) 11.1 (CH3),
14.5 (CH3, 12-C), 23.0 (CH2, 11-C), 25.4 (CH2, 9-C), 29.1 (CH2,
3-C), 32.4 (CH2, 10-C), 33.70 (CH2, 8-C), 33.78 (CH2, 5¢¢-C),
36.8 (CH2, 6-C), 36.9 (CH2, 2-C), 43.0 (CH2, 1¢-C), 48.0 (CH,
3¢¢-C), 56.9 (OCH3), 57.4 (OCH3), 71.6 (CH, 4¢¢-C), 77.0 (CH,
2¢-C), 81.1 (CH, 7-C), 127.9 (CH, 5-C), 131.2 (CH, 4-C), 136.3
(C, 1¢¢-C), 140.4 (CH, 6¢¢-C), 172.8 (CO, 1-C), 200.0 (CO, 2¢¢-C);
HRMS (ESI) m/z calcd for/C23H40NO5 [M + H]+ 410.2901,
found 410.2908.
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Acknowledgements
The authors are grateful to the National Basic Research Program
of China (973 Program, Grant No. 2010CB833203) and the
National Natural Science Foundation of China (Grant Nos.
20872055 and 20972060) for continuing financial support, the
specialized Research Fund for the Doctoral Program of Higher
Education (Grant No. 20090211110007), and 111 Project for
the continuing financial support. We also gratefully acknowledge
Professor Hak–Fun Chow, The Chinese University of Hong Kong,
for his helpful guidance in preparing the manuscript.
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3824 | Org. Biomol. Chem., 2011, 9, 3817–3824
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