A chemoenzymatic total synthesis of ent-bengamide E

Article abstract of DOI:10.1021/jo0159486

The cis-1,2-dihydrocatechol 3, which can be obtained in enantiomerically pure form by microbial dihydroxylation of bromobenzene, has been converted into the enantiomer, ent-1, of the cyclolysine-based marine natural product bengamide E (1).

Full text of DOI:10.1021/jo0159486

6768
J . Org. Chem. 2001, 66, 6768-6774
A Ch em oen zym a tic Tota l Syn th esis of en t-Ben ga m id e E
Martin G. Banwell* and Kenneth J . McRae
Research School of Chemistry, Institute of Advanced Studies, The Australian National University,
Canberra, ACT 0200, Australia
mgb@rsc.anu.edu.au
Received J uly 18, 2001
The cis-1,2-dihydrocatechol 3, which can be obtained in enantiomerically pure form by microbial
dihydroxylation of bromobenzene, has been converted into the enantiomer, ent-1, of the cyclolysine-
based marine natural product bengamide E (1).
In tr od u ction
at N-15. The carboxylic acid residue, which is common
to all of the bengamides, is probably the most syntheti-
cally challenging substructure associated with those
compounds and has been synthesized by a number of
methods starting from cyclitol, glucose, R-D-glucohep-
tonic-γ-lactone, tartaric acid, and glyceraldehyde-type
chirons.2 We now wish to report a concise and chemoen-
zymatic total synthesis of ent-bengamide E (ent-1) wherein
the relevant acid fragment 2 has been prepared, in
suitably protected form, from the cis-1,2-dihydrocatechol
3, a compound available in large quantity and enantio-
merically pure form by microbial oxidation of bromoben-
zene.3 Since the enantiomer of diol 3 is also available,4
the work described herein constitutes a formal total
synthesis of bengamide E itself. Furthermore, since
appropriate derivatives of acid 2, and by implication ent-
2, are readily available by the means described herein,
both enantiomeric forms of all the bengamides should
now be accessible for further biological study.
The bengamides, which constitute one of the most
prominent classes of natural product isolated from sponges
of the genus J apus (family J aspidae), display a useful
range of biological activities including often striking
differential cytotoxicity patterns as well as antihelmin-
thic properties.1 Furthermore, a very recent reevaluation
of the bengamides, carried out by Crews and his col-
laborators at the Novartis Institute for Biochemical
Research (NJ ),1h has revealed that some are exceptionally
potent, in vitro, against the MDA-MB-435 human breast
carcinoma cell line and several of them (bengamides B,
E, and Z)2 exhibit significant anti-proliferative effects
against xenografts of this same cell line in nude mice.
These workers have also suggested that the cytotoxicity
of the bengamides may be due to inhibition of a novel
target. As such, and because of their highly restricted
supply from natural sources, these compounds would
appear to represent very worthy targets for synthesis.
Bengamide E (1) is a representative member of the
class, and this amide is comprised of a 10-carbon car-
boxylic acid and an R-amino-ꢀ-caprolactam residue. The
remaining bengamides vary in the nature of the latter
residue with some of the more active members carrying
acylated hydroxyl groups at C-13 and/or a methyl group
(1) (a) Quinoa, E.; Adamczeski, M.; Crews, P.; Bakus, G. J . J . Org.
Chem. 1986, 51, 4494. (b) Adamczeski, M.; Quinoa, E.; Crews, P. J .
Am. Chem. Soc. 1989, 111, 647. (c) Adamczeski, M.; Quinoa, E.; Crews,
P. J . Org. Chem. 1990, 55, 240. (d) Rudi, A.; Kashman, Y.; Benayahu,
Y.; Schleyer, M. J . Nat. Prod. 1994, 57, 829. (e) D’Auria, M. V.;
Giannini, C.; Minale, L.; Zampella, A.; Debitus, C.; Frostin, M. J . Nat.
Prod. 1997, 60, 814. (f) Fernandez, R.; Dherbomez, M.; Letourneux,
Y.; Nabil, M.; Verbist, J . F.; Biard, J . F. J . Nat. Prod. 1999, 62, 678.
(g) Groweiss, A.; Newcomer, J . J .; O’Keefe, B. R.; Blackman, A.; Boyd,
M. R. J . Nat. Prod. 1999, 62, 1691. (h) Thale, Z.; Kinder, F. R.; Bair,
K. W.; Bontempo, J .; Czuchta, A. M.; Versace, R. W.; Phillips, P. E.;
Sanders, M. L.; Wattanasin, S.; Crews, P. J . Org. Chem. 2001, 66, 1733.
(2) (a) Chida, N.; Tobe, T.; Ogawa, S. Tetrahedron Lett. 1991, 32,
1063. (b) Gurjar, M. K.; Srinivas, N. R. Tetrahedron Lett. 1991, 32,
3409. (c) Broka, C. A.; Ehrler, J . Tetrahedron Lett. 1991, 32, 5907. (d)
Kishimoto, H.; Ohrui, H.; Meguro, H. J . Org. Chem. 1992, 57, 5042.
(e) Chida, N.; Tobe, T.; Okada, S.; Ogawa, S. J . Chem. Soc., Chem.
Commun. 1992, 1064. (f) Marshall, J . A.; Luke, G. P. J . Org. Chem.
1993, 58, 6229. (g) Mukai, C.; Kataoka, O.; Hanaoka, M. Tetrahedron
Lett. 1994, 35, 6899. (h) Chida, N.; Tobe, T.; Murai, K.; Yamazaki, K.;
Ogawa, S. Heterocycles 1994, 38, 2383. (i) Mukai, C.; Kataoka, O.;
Hanaoka, M. J . Org. Chem. 1995, 60, 5910. (j) Mukai, C.; Moharram,
S. M.; Kataoka, O.; Hanaoka, M. J . Chem. Soc., Perkin Trans. 1 1995,
2849. (k) Mukai, C.; Hanaoka, M. Synlett 1996, 11. (l) Chida, N.;
Ogawa, S. Chem. Commun. 1997, 807. (m) Kinder, F. R., J r.; Watta-
nasin, S.; Versace, R. W.; Bair, K. W.; Bontempo, J .; Green, M. A.; Lu,
Y. J .; Marepalli, H. R.; Phillips, P. E.; Roche, D.; Tran, L. D.; Wang,
R.; Waykole, L.; Xu, D. D.; Zabludoff, S. J . Org. Chem. 2001, 66, 2118.
Discu ssion
The early stages of our synthetic approach to the tris-
TBS-ether of carboxylic acid 2 involved formation of
bromoconduritol 7 by the route shown in Scheme 1. Thus,
epoxidation of the well-known5 and readily available
acetonide derivative, 4, of diol 3 with m-chloroperbenzoic
acid afforded the previously reported5,6 epoxide 5 (95%)
in a fully regio- and diastereoselective manner. Treat-
(3) For a very useful review on the preparation and utilization of
this and related cis-1,2-dihydrocatechols, see: Hudlicky, T.; Gonzales,
D.; Gibson, D. T. Aldrichim. Acta 1999, 32, 35.
(4) Hudlicky, T.; Claeboe, C. D.; Brammer, L. E., J r.; Koroniak, L.;
Butora, G.; Ghiviriga, I. J . Org. Chem. 1999, 64, 4909.
(5) Hudlicky, T.; Abboud, K. A.; Bolonick, J .; Maurya, R.; Stanton,
M. L.; Thorpe, A. J . Chem. Commun. 1996, 1717.
10.1021/jo0159486 CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/13/2001

Chemoenzymatic Total Synthesis of ent-Bengamide E
J . Org. Chem., Vol. 66, No. 20, 2001 6769
Sch em e 1a
a
Reagents and conditions: (i) Me2C(OMe)2 (neat), p-TsOH (catalyst), 18 °C, 1 h; (ii) m-CPBA (1.0 molar equiv), CH2Cl2, 0-18 °C, 15
h; (iii) HCl (catalyst), THF-H2O (2:1), 18 °C, 24 h; (iv) AcOH-THF-H2O (2:1:1), 60 °C, 15 h; (v) TBSCl (4.0 molar equiv), imidazole (8.0
molar equiv), DMF, 50 °C, 24 h; (vi) MeOTf (6.0 molar equiv), 2,6-di-tert-butyl-4-methylpyridine (7.0 molar equiv), CH2Cl2, 90 °C, 4 h;
(vii) TBSOTf (4.0 molar equiv), 2,6-lutidine (10.0 molar equiv), CH2Cl2, -40 °C, 3.5 h; (viii) Ag2O (9.0 molar equiv), MeI (neat), 110 °C,
24 h.
ment of the last compound with 1% HCl in 2:1 (v/v) THF-
water resulted in smooth and completely regioselective
epoxide ring opening6 so as to deliver trans-diol 6 (92%),7
which was immediately subjected to acetonide hydrolysis
using aqueous acetic acid. In this manner, the bromo
derivative 7 of (-)-conduritol F was obtained as a
crystalline solid in 90% yield. We reasoned that it should
be possible to effect selective silylation of the C-3, C-4
and C-5 hydroxyl groups within conduritol 7 because
their C-6 counterpart is sterically shielded by the flank-
ing bromine and cis-related C-5 hydroxyl group.
This selective protection would afford a tris-silyl ether
that could be O-methylated (at C-6) and thereby allowing
for regiocontrolled introduction of the C-2 (bengamide
numbering) methoxy group as required in target 2. In
the event, treatment of tetra-ol 7 with tert-butyldimeth-
ylsilyl chloride (TBSCl) and imidazole in DMF at 50 °C
for 24 h resulted in the formation of the undesired tris-
silyl ether derivative 8 (70%), the structure of which
follows from extensive NMR spectroscopic analysis8 of the
derived O-methyl ether 9 (87%) which is readily prepared
using methyl triflate. In contrast, when tetra-ol 7 was
reacted with TBSOTf and 2,6-lutidine in DCM at -40
°C for 3.5 h then the required tris-ether 10 (70%) was
obtained as the major product of reaction. O-Methylation
of compound 10 under Irvine-Purdie conditions9 then
afforded the required ether 11 (95%).10 The reaction
sequence (Scheme 1) leading from diol 3 to ether 11,
which embodies C-1 to C-6 of target ent-1, is a rather
efficient process that allows for the generation of sub-
stantial quantities of the latter compound.
The completion of the synthesis of ent-bengamide E
(ent-1) is outlined in Scheme 2 and involves initial
treatment of a methanolic solution of bromoalkene 11
with ozone followed by a reductive workup using dimeth-
yl sulfide. The resulting aldehyde ester 12 was im-
mediately subjected to a J ulia olefination reaction11 using
the anion derived from 2-[(2-methylpropyl)sulfonyl]ben-
zothiazole,12 and in this manner, alkene 13 (62% ex
bromoalkene 11) contaminated with less than 2% of the
corresponding Z-isomer was obtained. LiOH-promoted
(10) It is assumed that compound 8 is the thermodynamic product
of tris-silylation of tetra-ol 7 while isomer 10 is the kinetic product of
the same process.
(11) Baudin, J . B.; Hareau, G.; J ulia, S. A.; Lorne, R.; Ruel, O. Bull.
Soc. Chim. Fr. 1993, 130, 856.
(12) Gayral, P.; Bourdais, J .; Lorre, A.; Abenhaim, D.; Dusset, F.;
Pommies, M.; Fouret, G. Eur. J . Med. Chem.-Chim. Ther. 1978, 13,
171 (Chem. Abstr. 1978, 89, 109204). For the purposes of the present
work this sulfone was made by the following two-step sequence:
(6) Banwell, M. G.; Haddad, N.; Hudlicky, T.; Nugent, T. C.; Mackay,
M. F.; Richards, S. L. J . Chem. Soc., Perkin Trans. 1 1997, 1779.
(7) Banwell, M. G.; De Savi, C.; Hockless, D. C. R.; Pallich, S.;
Watson, K. G. Synlett 1999, 885.
(8) In particular, a series of 1D nOe, HMBC and HMQC experiments
was carried out to establish the structures of compounds 9 and 11.
(9) Purdie, T.; Irvine, J . C. J . Chem. Soc. 1903, 83, 1021.

6770 J . Org. Chem., Vol. 66, No. 20, 2001
Banwell and McRae
Sch em e 2a
a
Reagents and conditions: (i) ozone (excess), pyridine (20.0 molar equiv), MeOH-CH2Cl2 (1:1), -78 °C, 0.33 h then DMS (excess), 18
°C, 12 h; (ii) Compound 12 (1.0 molar equiv), 2-[(2-methylpropyl)sulfonyl]benzothiazole (1.3 molar equiv), LiHMDS (1.1 molar equiv of a
1 M solution in THF), DME, -78 to +18 °C, 1.5 h; (iii) LiOH (4.0 molar equiv), THF-MeOH (4:1), reflux, 4 h; (iv) HOBt (1.2 molar equiv),
EDCI (1.2 molar equiv), compound 14 (1.0 molar equiv), DMF, 18 °C, 0.33 h then compound 15 (1.5 molar equiv), DMF, 0-18 °C, 16 h;
(v) TBAF (6.5 molar equiv of a 1 M solution in THF), THF, 18 °C, 1.5 h.
Gemini 300 or Varian Mercury 300 spectrometer operating at
300 MHz for proton and 75.4 MHz for carbon nuclei. Chemical
shifts were recorded as δ values in parts per million (ppm).
Spectra were acquired in deuteriochloroform (CDCl3) at 20 °C
unless otherwise stated. For 1H NMR spectra recorded in
CDCl3, the peak due to residual CHCl3 (δ 7.26) was used as
saponification of this material gave, after acidic workup,
the corresponding acid 14 (63% at 53% conversion). The
derived NMR spectral data matched those reported for
its well-characterized enantiomer, which represents a
late-stage intermediate in Broka’s synthesis2c of benga-
mide E.
1
the internal reference. H NMR data are recorded as follows:
Coupling of acid 14 with readily available D-(+)-R-
amino-ꢀ-caprolactam (15)13 was achieved using HOBt-
EDCI14 and the amide 16 thereby obtained in 72% yield.
Treatment of this amide with TBAF in THF resulted in
smooth and complete desilylation and formation of ent-
bengamide E (ent-1), which was obtained in 86% yield.
chemical shift (δ) [multiplicity, coupling constant(s) J ) (Hz),
relative integral, assignment (where possible)] where multi-
plicity is defined as follows: s ) singlet; d ) doublet; t )
triplet; q ) quartet; quintet; septet; m ) multiplet or combina-
tions of the above. The central peak (δ 77.0) of the CDCl3 triplet
was used as the reference for proton-decoupled 13C NMR
spectra. For 13C NMR spectra the data are given as: chemical
shift (δ) (protonicity), where protonicity is defined as follows:
1
The H and 13C NMR data derived from compound ent-1
matched those reported1b for the natural product while
the specific rotation {[R]D -32 (c 0.2, MeOH)} was of the
opposite sign but of essentially the same magnitude as
observed1b for bengamide E.
ent-Bengamide E was tested in a monolayer cell
proliferation assay using A549 nonsmall cell lung cancer
cells, HCT116 colon cancer cells, and primary human
umbilical vein endothelial cells.1h For all three cell types,
there was no growth inhibition observed at concentra-
tions up to 50 µM. For comparison purposes, the IC50
values for bengamide E in this format are 1.9, 0.6, and
0.3 µM, respectively.
C ) quaternary; CH ) methine; CH2 ) methylene; CH3
methyl; C or CH2 ) quaternary or methylene; CH or CH3
)
)
methine or methyl. The assignments of signals observed in
various NMR spectra were often assisted by conducting
attached proton test (APT), homonuclear (1H/1H) correlation
spectroscopy (COSY), nuclear Overhauser effect (NOE), and/
or heteronuclear (1H/13C) correlation spectroscopy (HETCOR)
experiments.
Infrared spectra (νmax) were recorded on either a Perkin-
Elmer 1800 Fourier transform infrared spectrophotometer or
a Perkin-Elmer Spectrum One instrument. Samples were
analyzed as KBr disks (for solids) or as thin films on KBr
plates (for liquids/oils).
Optical rotations were measured with a Perkin-Elmer 241
polarimeter at the sodium D line (589 nm) using the spectro-
scopic grade solvents specified at 20 °C and at the concentra-
tions (c) (g/100 mL) indicated. The measurements were carried
out in a cell with a path length of 1 dm. Specific rotations
([R]20D) were calculated using the equation [R]D ) (100R)/(c1)
Exp er im en ta l Section
Gen er a l P r oced u r es. Unless otherwise specified, proton
(1H) and carbon (13C) NMR spectra were recorded on a Varian
(13) Boyle, W. J ., J r.; Sifniades, S.; Van Peppen, J . F. J . Org. Chem.
1979, 44, 4841. For the purposes of the present work this R-amino-
caprolactam was made by the following three-step sequence. The
starting material was purchased from Auspep (Melbourne, Australia;
www.auspep.com.au).
and are given in 10-1 deg‚cm2‚g-1
Melting points were recorded on
.
a
Reichert hot-stage
apparatus and are uncorrected except where otherwise stated.
Elemental analyses were performed by the Australian
National University Microanalytical Services Unit based in
the Research School of Chemistry, The Australian National
University, Canberra, Australia.
Analytical thin-layer chromatography (TLC) was conducted
on aluminum-backed 0.2 mm thick silica gel 60 F254 plates
(Merck) and the chromatograms were visualized under a 254
nm UV lamp and/or by treatment with an anisaldehyde-
sulfuric acid-ethanol (3 mL: 4.5 mL: 200 mL) dip or, occasion-
ally, with a phosphomolybdic acid-ceric sulfate-sulfuric acid-
water (37.5 g: 7.5 g: 37.5 mL: 720 mL) dip, followed by heating.
The retention factor (Rf) quoted is rounded to the nearest 0.1.
Flash chromatography was conducted according to the method
(14) Fields, G. B.; Noble, R. L. Int. J . Pept. Protein Res. 1990, 35,
161.

Chemoenzymatic Total Synthesis of ent-Bengamide E
J . Org. Chem., Vol. 66, No. 20, 2001 6771
of Still and co-workers (Still, W. C. et al. J . Org. Chem. 1978,
43, 2923) using silica gel 60 (mesh size 0.040-0.063 mm) as
the stationary phase and the analytical reagent (AR) grade
solvents indicated.
Many starting materials and reagents were available from
the Aldrich Chemical Co. or EGA-Chemie and were used as
supplied or simply distilled. Drying agents and other inorganic
salts were purchased from AJ AX or BDH Chemicals. Reactions
employing air- and/or moisture-sensitive reagents and inter-
mediates were carried out under an atmosphere of dry, oxygen-
free nitrogen in flame-dried apparatus.
(1S,2S,5S,6R)-3-Br om o-2,5,6-tr is-[(1,1-d im eth yleth yl)-
d im eth ylsiloxy)-3-cycloh exen -1-ol (8). tert-Butyldimethyl-
silyl chloride (984 mg, 6.51 mmol) was added to a magnetically
stirred solution of compound 7 (366 mg, 1.63 mmol) and
imidazole (886 mg, 13.04 mmol) in anhydrous DMF (3.5 mL)
maintained at room temperature under an atmosphere of
nitrogen. After 24 h at 50 °C, the reaction mixture was diluted
with water (20 mL) and extracted with diethyl ether (3 × 50
mL). The combined organic phases were washed with HCl
(1 × 50 mL of a 5% v/v aqueous solution), water (1 × 50 mL),
and brine (1 × 50 mL) before being dried (MgSO4), filtered,
and concentrated under reduced pressure to afford a pale
yellow oil. Subjection of this material to flash chromatography
(silica, 10 f 50% v/v toluene-petrol elution) provided, after
concentration of the appropriate fractions (Rf 0.2 in 2% v/v
ethyl acetate-petrol), compound 8 (648 mg, 70%) as a clear,
Room temperature is assumed to be ca. 18 °C.
Tetrahydrofuran and diethyl ether were dried using sodium
metal and then distilled, as required, from sodium benzophe-
none ketyl. Methanol was distilled from magnesium methox-
ide. Dichloromethane (CH2Cl2) was distilled from calcium
hydride. Ethylene glycol dimethyl ether (DME) was refluxed
over calcium hydride then distilled, as required, from sodium
benzophenone ketyl. N,N-dimethylformamide (DMF) was heated
at reflux over calcium hydride for 16 h then distilled and stored
over 3 Å molecular sieves.
Organic solutions obtained from workup of reaction mix-
tures were dried with magnesium sulfate (MgSO4). Petrol
refers to petroleum spirits boiling in the range 40-60 °C unless
otherwise specified. Organic solutions were concentrated under
reduced pressure on a rotary evaporator with the water bath
generally not exceeding 40 °C.
(3a S,4R,5S,7a S)-7-Br om o-3a ,4,5,7a -t et r a h yd r o-2,2-d i-
m eth yl-1,3-ben zod ioxole-4,5-d iol (6). HCl (1.5 mL of a
1% v/v solution of concd HCl in THF) was added to a mag-
netically stirred solution of epoxide 5 (7.80 g, 31.5 mmol) in
THF-water (90 mL of a 2:1 v/v mixture). The resulting
solution was stirred at 18 °C for 24 h then concentrated under
reduced pressure. The residue thus obtained was partitioned
between ethyl acetate (200 mL) and NaCl (200 mL of a 50%
w/v aqueous solution). The separated aqueous phase was
extracted with ethyl acetate (3 × 200 mL) and the combined
organic phases were then dried (MgSO4), filtered, and concen-
trated under reduced pressure to afford a white solid. Recrys-
tallization (dichloromethane-hexane) of this material gave the
title compound 6 (7.80 g, 92%) as fine white needles: mp 146-
147 °C (lit.7 mp 147 °C); [R]D -1.5 (c 1.3, CHCl3); 1H NMR
(300 MHz) δ 6.26 (d, J ) 2.7 Hz, 1H), 4.68 (d, J ) 6.1 Hz, 1H),
4.20 (dd, J ) 7.6 and 6.1 Hz, 1H), 4.09 (m, 1H), 3.77 (td, J )
7.6 and 3.2 Hz, 1H), 2.73 (d, J ) 6.1 Hz, 1H), 2.71 (d, J ) 3.4
Hz, 1H), 1.54 (s, 3H), 1.42 (s, 3H); 13C NMR (75 MHz) δ 134.5
(CH), 119.2 (C), 111.1 (C), 77.5 (CH), 77.1 (CH), 73.3 (CH),
70.9 (CH), 28.0 (CH3), 25.9 (CH3); IR νmax 3501, 3363, 2984,
1645, 1257, 1082, 1050, 871 cm-1; MS (70 eV) m/z 251 and
249 [(M - H3C•)+, 96 and 100], 110 (63), 101 (58); HRMS calcd
for C9H1379BrO4 (M - H3C•)+ 248.9762, found 248.9764. Anal.
Calcd for C9H13BrO4: C, 40.78; H, 4.94; Br, 30.14. Found: C,
40.80; H, 4.71; Br, 30.18.
1
colorless oil: [R]D +10 (c 1.9, CHCl3); H NMR (300 MHz) δ
6.04 (m, 1H), 4.42 (d, J ) 4.1 Hz, 1H), 3.95 (m, 2H), 3.74 (m,
1H), 2.91 (br d, J ) 7.1 Hz, 1H), 0.95 (s, 9H), 0.89(3) (s, 9H),
0.89 (s, 9H), 0.21 (s, 3H), 0.15 (s, 3H), 0.11 (s, 3H), 0.10 (s,
9H); 13C NMR (75 MHz) δ 130.7 (CH), 127.1 (C), 72.9 (CH),
72.6 (2 × CH, overlapping), 72.1 (CH), 25.9 (CH3), 25.8(5)
(CH3), 25.7(8) (CH3), 18.5 (C), 18.1 (C), 18.0 (C), -4.2(7) (CH3),
-4.3(7) (CH3), -4.4(5) (CH3), -4.5 (CH3), -4.6 (2 × CH3
overlapping); IR νmax 3582, 2930, 2858, 1641, 1472, 1362, 1254,
1100, 837, 778 cm-1; MS (70 eV) m/z 553 and 551 [(M - H3C•)+,
<1 and <1], 511 and 509 {[M - (CH3)3C•]+, 5 and 4}, 73 (100);
HRMS calcd for C24H5179BrO4Si3 [M-(CH3)3C•]+ 509.1574, found
509.1583. Anal. Calcd for C24H51BrO4Si3: C, 50.77; H, 9.05;
Br, 14.07. Found: C, 50.70; H, 9.10; Br, 14.07.
(3S,4R,5S,6S)-1-Br om o-3,4,6-tr is-[(1,1-d im eth yleth yl)-
d im eth ylsiloxy)-5-m eth oxycycloh exen e (9). A solution of
compound 8 (84 mg, 0.15 mmol) in dichloromethane (0.5 mL)
was treated with 2,6-di-tert-butyl-4-methylpyridine (210 mg,
1.05 mmol) and methyl trifluoromethanesulfonate (101 µL,
0.90 mmol) and heated to 90 °C in a sealed tube. After 4 h,
the reaction mixture was to cooled to 18 °C, poured into water
(5 mL), and extracted with ethyl acetate (3 × 10 mL). The
combined organic phases were washed with HCl (1 × 10 mL
of a 5% v/v aqueous solution), water (1 × 10 mL), and brine
(1 × 10 mL) before being dried (MgSO4), filtered, and concen-
trated under reduced pressure to afford a pale yellow oil.
Subjection of this material to flash chromatography (silica,
10f25% v/v toluene-petrol elution) provided, after concentra-
tion of the appropriate fractions (Rf 0.6 in 25% v/v toluene-
petrol), compound 9 (76 mg, 87%) as a clear, colorless oil: [R]D
-20 (c 0.9, CHCl3); 1H NMR (300 MHz) δ 5.92 (d, J ) 2.8 Hz,
1H), 4.36 (d, J ) 3.3 Hz, 1H), 4.00 (dd, J ) 6.5, 2.8 Hz, 1H),
3.91 (dd, J ) 9.5, 6.5 Hz, 1H), 3.35 (s, 3H), 3.00 (dd, J ) 9.5,
3.3 Hz, 1H), 0.92 (s, 9H), 0.90 (s, 18H), 0.13 (s, 3H), 0.10 (s,
6H), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (75 MHz) δ 133.8 (CH),
123.5 (C), 82.1 (CH), 75.5 (CH), 72.3 (CH), 72.2 (CH), 57.9
(CH3), 26.2 (CH3), 26.1 (CH3), 25.9 (CH3), 18.4 (C), 18.2 (C),
18.1(8) (C), -3.7 (CH3), -3.8 (CH3), -4.0 (CH3), -4.2 (CH3),
-4.4 (2 × CH3 overlapping); IR νmax 2954, 1646, 1472, 1463,
1361, 1253, 1114, 956, 836, 778 cm-1; MS (70 eV) m/z 567 and
565 [(M - H3C•)+, <1 and <1], 525 and 523 {[M - (CH3)3C•]+,
28 and 25}, 73 (100); HRMS calcd for C25H5379BrO4Si3 (M -
H3C•)+ 565.2200, found 565.2202.
(1S,2R,3S,4S)-5-Br om o-5-cycloh exen e-1,2,3,4-tetr ol (7).
A solution of compound 6 (1.00 g, 3.77 mmol) in AcOH-THF-
water (25 mL of a 2:1:1 v/v/v mixture) was stirred at 60 °C for
15 h, and then the cooled reaction mixture was concentrated
under reduced pressure to give a white solid (this material
could be used, without further purification, in the next step
of the reaction sequence). Recrystallization (MeOH-diethyl
ether) of this material provided an analytically pure sample
of compound 7 (763 mg, 90%) as a white powder: mp 164-
(1S,4S,5R,6S)-2-Br om o-4,5,6-tr is-[(1,1-d im eth yleth yl)-
d im eth ylsiloxy)-2-cycloh exen -1-ol (10). tert-Butyldimeth-
ylsilyl trifluoromethanesulfonate (8.16 mL, 35.2 mmol) was
added to a magnetically stirred solution of compound 7 (2.0 g,
8.9 mmol) and 2,6-lutidine (10.2 mL, 88.0 mmol) in anhydrous
dichloromethane (88 mL) maintained at -40 °C under an
atmosphere of nitrogen. After 3.5 h, the reaction mixture was
poured into HCl (50 mL of a 5% v/v aqueous solution) and then
extracted with diethyl ether (3 × 200 mL). The combined
organic phases were washed with water (1 × 300 mL) and
brine (1 × 300 mL) before being dried (MgSO4), filtered, and
concentrated under reduced pressure to afford a pale yellow
oil. Subjection of this material to flash chromatography (silica,
25% v/v toluene-petrol elution) afforded, after concentration
of the appropriate fractions (Rf 0.2 in 2% v/v ethyl acetate-
petrol), compound 10 (3.50 g, 70%) as crystalline masses: mp
1
166 °C; [R]D -44 (c 1.1, MeOH); H NMR (300 MHz, CD3OD)
δ 6.05 (d, J ) 2.6 Hz, 1H), 4.21 (d, J ) 4.2 Hz, 1H), 3.89 (dd,
J ) 7.4, 2.6 Hz, 1H), 3.60 (dd, J ) 10.5, 7.4 Hz, 1H), 3.50 (dd,
J ) 10.5, 4.2 Hz, 1H) (resonances due to OHs not observed);
13C NMR (75 MHz, CD3OD) δ 135.2 (CH), 124.4 (C), 74.7 (CH),
74.1 (CH), 73.0 (CH), 72.4 (CH); IR νmax 3350, 2914, 1640, 1412,
1262, 1103, 1066 cm-1; MS (70 eV) m/z 208 and 206 [(M -
H2O)•+, 1 and 1], 190 and 188 [(M - 2H2O)•+, 2 and 2], 179
and 177 (12 and 13), 166 and 164 [(C4H5O2Br)•+, 94 and 100];
HRMS calcd for C6H979BrO4 (M-H2O)•+ 205.9579, found
205.9581. Anal. Calcd for C6H9BrO4: C, 32.02; H, 4.03; Br,
35.51. Found: C, 32.20; H, 4.14; Br, 35.43.

6772 J . Org. Chem., Vol. 66, No. 20, 2001
Banwell and McRae
60-62 °C; [R]D +35 (c 1.6, CHCl3); 1H NMR (300 MHz) δ 6.03
(dm, J ) 4.2 Hz, 1H), 4.22 (dm, J ) 9.8 Hz, 1H), 3.96 (m, 1H),
3.94-3.86 (complex m, 2H), 2.47 (d, J ) 9.8 Hz, 1H), 0.92 (s,
9H), 0.90 (s, 9H), 0.88 (s, 9H), 0.14 (s, 3H), 0.13 (s, 3H), 0.09
(m, 9H), 0.08 (s, 3H); 13C NMR (75 MHz) δ 131.0 (CH), 126.2
(C), 73.3 (CH), 73.1 (CH), 72.0 (CH), 69.0 (CH), 26.1 (CH3),
26.0 (CH3), 25.8 (CH3), 18.3(3) (C), 18.2(5) (C), 17.9 (C), -3.8
(CH3), -4.3 (CH3), -4.4 (CH3), -4.5 (2 × CH3 overlapping),
-4.9 (CH3); IR νmax 3564, 2930, 1644, 1472, 1255, 1086, 836
cm-1; MS (70 eV) m/z 553 and 551 [(M-H3C•)+, <1 and <1],
511 and 509 {[M - (CH3)3C•]+, 10 and 8}, 288 (40), 73 (100);
HRMS calcd for C24H5179BrO4Si3: (M - H2O)•+ 548.2173, found
548.2176. Anal. Calcd for C24H51BrO4Si3: C, 50.77; H, 9.05;
Br, 14.07. Found: C, 50.65; H, 8.92; Br, 14.27.
2-[(2-Meth ylp r op yl)su lfon yl]ben zoth ia zole. A magneti-
cally stirred solution of 2-mercaptobenzothiazole (5.00 g, 29.9
mmol) in THF-DMF (80 mL of a 3:1 v/v mixture) and
maintained at 0 °C under an atmosphere of nitrogen was
treated, portionwise, with sodium hydride (1.55 g of a 60%
dispersion in mineral oil, 38.9 mmol). After 0.5 h, the reaction
mixture was treated, dropwise, with 1-bromo-2-methylpropane
(6.5 mL, 59.8 mmol), and the resulting mixture was allowed
to warm to room temperature over 0.5 h before being heated
to 50 °C. After 1 h at this temperature, the reaction mixture
was cooled and then poured into water (200 mL) and extracted
with diethyl ether (3 × 200 mL). The combined organic phases
were washed with NaOH (1 × 200 mL of a 1 M aqueous
solution), water (2 × 200 mL), and brine (1 × 200 mL) before
being dried (MgSO4), filtered, and concentrated under reduced
pressure to afford a pale yellow oil. Subjection of this material
to flash chromatography (silica, 10% v/v ethyl acetate-petrol
elution) provided, after concentration of the appropriate frac-
tions (Rf 0.5), 2-[(2-methylpropyl)sulfanyl]benzothiazole (5.1
g, 77%) as a pale yellow oil.
(3S,4R,5S,6S)-1-Br om o-3,4,5-tr is-[(1,1-d im eth yleth yl)-
d im eth ylsiloxy)-6-m eth oxycycloh exen e (11). A solution of
compound 10 (300 mg, 0.53 mmol) in iodomethane (4 mL) was
treated with Ag2O (367 mg, 1.58 mmol) and heated to 110 °C
in a sealed tube. After 8 h, the reaction mixture was allowed
to cool to 18 °C and then treated with extra Ag2O (367 mg,
1.58 mmol). The reaction mixture was again heated at 110 °C
for 8 h. This procedure was repeated for a third time, and 8 h
after the final addition of Ag2O the reaction mixture was cooled
to 18 °C and the solid material removed by filtration. The
filtrate thus obtained was concentrated under reduced pres-
sure to afford a pale yellow oil that was subjected to flash
chromatography (silica, 2% v/v ethyl acetate-petrol elution).
Concentration of the appropriate fractions (Rf 0.4) then
provided compound 11 (292 mg, 95%) as a clear, colorless oil:
A magnetically stirred solution of 2-[(2-methylpropyl)sul-
fanyl]benzothiazole (3.00 g, 13.4 mmol), prepared as described
above, in dichloromethane (200 mL) maintained at 0 °C was
treated, portionwise, with m-chloroperbenzoic acid [8.20 g (80%
technical grade), 33.6 mmol]. After 14 h at 18 °C, the reaction
mixture was treated with sodium sulfite (100 mL of a 15%
w/v aqueous solution) and stirred vigorously for 15 min. The
resulting solution was extracted with diethyl ether (3 × 200
mL) and the combined organic phases were washed with
NaHCO3 (1 × 200 mL of a saturated aqueous solution), water
(1 × 200 mL), and brine (1 × 200 mL) before being dried
(MgSO4), filtered, and concentrated under reduced pressure
to afford a pale yellow oil. Subjection of this material to flash
chromatography (silica, 10% v/v ethyl acetate-petrol elution)
provided, after concentration of the appropriate fractions (Rf
0.2), the title compound (2.94 g, 86%) as a clear, colorless oil
that crystallized upon standing. Recrystallization (diethyl
ether-hexane) of a portion of this material afforded an
analytically pure sample of 2-[(2-methylpropyl)sulfonyl]ben-
zothiazole as white crystals: mp 42-43 °C; 1H NMR (300 MHz)
δ 8.22 (m, 1H), 8.02 (m, 1H), 7.62 (m, 2H), 3.44 (d, J ) 6.7 Hz,
2H), 2.43 (nonatet, J ) 6.7 Hz, 1H), 1.13 (d, J ) 6.7 Hz, 6H);
13C NMR (75 MHz) δ 166.5 (C), 152.5 (C), 136.5 (C), 127.9 (CH),
127.5 (CH), 125.2 (CH), 122.3 (CH), 61.9 (CH2), 24.0 (CH), 22.5
1
[R]D +16 (c 1.3, CHCl3); H NMR (300 MHz) δ 5.97 (m, 1H),
3.92 (m, 1H), 3.86 (m, 2H), 3.81 (m, 1H), 3.52 (s, 3H), 0.89(3)
(s, 18H), 0.88(7) (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H),
0.08 (s, 3H), 0.07 (s, 6H); 13C NMR (75 MHz) δ 131.4 (CH),
123.5 (C), 79.6 (CH), 74.4 (CH), 74.2 (CH), 70.7 (CH), 59.5
(CH3), 26.1 (CH3), 26.0 (CH3), 18.4 (C), 18.3 (C), 18.0 (C), -4.2
(2 × CH3 overlapping), -4.3 (CH3), -4.3(9) (CH3), -4.4(3)
(CH3), -4.5 (CH3) (one signal obscured or overlapping); IR νmax
2930, 1642, 1472, 1463, 1254, 1152, 1116, 1087, 836 cm-1; MS
(70 eV) m/z 567 and 565 [(M - H3C•)+, <1 and <1], 525 and
523 {[M - (CH3)3C•]+, 28 and 25}, 288 (42), 73 (100); HRMS
calcd for C25H5381BrO4Si3 (M - H3C•)+ 567.2180, found 567.2186.
Met h yl 2-O-Met h yl-3,4,5-t r is-O-[(1,1-d im et h ylet h yl)-
d im eth ylsilyl]-L-gu lor on a te (12). A magnetically stirred
solution of compound 11 (115 mg, 0.20 mmol) in MeOH (2 mL)
containing dichloromethane (2 mL) and pyridine (320 µL, 3.95
mmol) was cooled to -78 °C and treated with a stream of ozone
(ca. 40% ozone in oxygen). When the green/blue color of ozone
persisted and TLC analysis indicated that no starting material
remained (ca. 0.33 h), the reaction mixture was purged with
nitrogen (20 min), treated with dimethyl sulfide (1 mL), and
allowed to warm to 18 °C. After 12 h, the reaction mixture
was concentrated under reduced pressure, and the residue
thus obtained was treated with water (10 mL) and extracted
with diethyl ether (3 × 10 mL). The combined organic phases
were washed with HCl (1 × 10 mL of a 5% v/v aqueous
solution), water (2 × 10 mL), and brine (1 × 10 mL) before
being dried (MgSO4), filtered, and concentrated under reduced
pressure to afford compound 12 (107 mg, 95%) as a light yellow
oil: [R]D +2 (c 1.3, CHCl3); 1H NMR (300 MHz) δ 9.70 (s, 1H),
4.38 (br d, J ) 6.1 Hz, 1H), 4.26 (d, J ) 3.7 Hz, 1H), 4.02 (dd,
J ) 4.4, 3.7 Hz, 1H), 3.92 (dd, J ) 6.1, 4.4 Hz, 1H), 3.73 (s,
3H), 3.32 (s, 3H), 0.92 (s, 9H), 0.90 (s, 9H), 0.84 (s, 9H), 0.11
(CH3); IR νmax 2964, 1554, 1470, 1322, 1148, 855, 762, 628 cm-1
;
MS (70 eV) m/z 255 (M•+, 8), 240 [(M - H3C•)+, 2], 198 (10),
135 (100); HRMS calcd for C11H13NO232S2 (M - H3C•)+ 240.0153,
found 240.0156. Anal. Calcd for C11H13NO2S2: C, 51.74; H,
5.13; N, 5.49. Found: C, 51.62; H, 5.23; N, 5.50.
Meth yl (6E)-6,7,8,9-Tetr adeoxy-3,4,5-tr is-O-[(1,1-dim eth -
yleth yl)d im eth ylsilyl]-8-m eth yl-2-O-m eth yl-L-gu lon on -6-
en on oa te (13). A magnetically stirred solution of aldehyde
12 (658 mg, 1.16 mmol) and 2-[(2-methylpropyl)sulfonyl]-
benzothiazole (385 mg, 1.51 mmol) in DME (22 mL) main-
tained under an atmosphere of nitrogen was cooled to -78 °C
and then treated with LiHMDS (1.28 of a 1 M solution in THF,
1.28 mmol). After being warmed to 18 °C over 1.5 h, the
reaction mixture was treated with HCl (10 mL of a 5% v/v
aqueous solution) and extracted with diethyl ether (3 × 50
mL). The combined organic phases were washed with NaOH
(50 mL of a 1 M aqueous solution) and brine (1 × 50 mL) before
being dried (MgSO4), filtered, and concentrated under reduced
pressure to afford a light yellow oil. Subjection of this material
to flash chromatography (silica, 2% v/v ethyl acetate-petrol
elution) provided, after concentration of the appropriate frac-
tions (Rf 0.4), compound 13 (434 mg, 62% ex bromoalkene 11)
(s, 3H), 0.08 (s, 6H), 0.07 (s, 3H), 0.06 (s, 3H), 0.04 (s, 3H); 13
C
NMR (75 MHz) δ 201.7 (CH), 170.7 (C), 82.3 (CH), 78.0 (CH),
74.9 (CH), 74.3 (CH), 58.1 (CH3), 51.6 (CH3), 25.9 (CH3), 25.8
(CH3), 18.3 (C), 18.1 (C), 18.0 (C), -4.4 (4 × CH3 overlapping),
-4.6 (2 × CH3 overlapping) (one signal obscured or overlap-
ping); IR νmax 2930, 1755, 1737, 1472, 1463, 1255, 1197, 1114
cm-1; MS (70 eV) m/z 549 [(M - H3C•)+, <1], 533 [(M -
CH3O•)+, 1], 507 {[M - (CH3)3C•]+, 7}, 73 (100); HRMS calcd
for C26H56O7Si3: [M - (CH3)3C•]+ 507.2630, found 507.2647.
Anal. Calcd for C26H56O7Si3: C, 55.27; H, 9.99. Found: C,
55.35; H, 9.87.
1
as a clear, colorless oil: [R]D -6 (c 1.4, CHCl3); H NMR (300
MHz) δ 5.57 (m, 2H), 4.52 (br s, 1H), 4.35 (br s, 1H) 3.93 (br
s, 2H), 3.71 (s, 3H), 3.31 (s, 3H), 2.32 (m, 1H), 1.01 (d, J ) 6.6
Hz, 3H), 0.99 (d, J ) 6.6 Hz, 3H), 0.92 (s, 9H), 0.90 (s, 9H),
0.86 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H), 0.06 (s, 3H), 0.05 (s,
3H), 0.04 (s, 3H), 0.02 (s, 3H); 13C NMR (75 MHz) δ 171.1,
138.6, 126.8, 82.8, 74.8, 74.1, 73.8, 57.8, 51.2, 30.9, 26.2, 26.1,
26.0, 22.3, 22.2, 18.2(4), 18.1(9), -3.6, -3.9, -4.4(8), -4.5(0),
-4.6 (two signals overlapping); IR νmax 2954, 1760, 1733, 1472,
In general, this somewhat unstable material was im-
mediately subjected to the next step of the reaction sequence.

Chemoenzymatic Total Synthesis of ent-Bengamide E
J . Org. Chem., Vol. 66, No. 20, 2001 6773
1463, 1254, 1110, 837 cm-1; MS (70 eV) m/z 589 [(M - H3C•)+,
3], 547 {[M - (CH3)3C•]+, 32}, 359 (90), 213 (71), 73 (100);
HRMS calcd for C30H64O6Si3 (M - H3C•)+ 589.3776, found
589.3773.
41.9 (CH2), 31.9 (CH2), 28.7 (CH2), 27.9 (CH2); IR νmax 3395,
3300, 2928, 1710, 1669, 1477, 1449, 1364, 1249, 1211, 1049,
738 cm-1; MS (70 eV) m/z 350 (M•+, 1), 178 (100); HRMS calcd
for C21H22N2O3 M•+ 350.1630, found 350.1627.
(6E)-6,7,8,9-Tetr a d eoxy-3,4,5-tr is-O-[(1,1-d im eth yleth -
yl)d im eth ylsilyl]-8-m eth yl-2-O-m eth yl-L-gu lon on -6-en on -
ic a cid (14). A magnetically stirred solution of ester 13 (100
mg, 0.17 mmol) in THF (4 mL) containing MeOH (1 mL) was
treated with LiOH (680 µL of a 1 M aqueous solution, 0.68
mmol). After 4 h at reflux, the cooled reaction mixture was
treated with HCl (10 mL of a 5% v/v aqueous solution) and
then extracted with diethyl ether (3 × 10 mL). The combined
organic phases were washed with brine (1 × 20 mL) before
being dried (MgSO4), filtered, and concentrated under reduced
pressure to afford a light yellow oil. Subjection of this material
to flash chromatography (silica, 20% v/v ethyl acetate-petrol
elution) then provided two fractions, A and B.
(6E)-6,7,8,9-Tetr a d eoxy-3,4,5-tr is-O-[(1,1-d im eth yleth -
yl)d im eth ylsilyl]-N-[(3R)-h exa h yd r o-2-oxo-1H-a zep in -3-
yl]-8-m eth yl-2-O-m eth yl-L-gu lon on -6-en on a m id e (16). A
magnetically stirred solution of the Fmoc-D-(+)-R-amino-ꢀ-
caprolactam (22 mg, 0.06 mmol) in THF (1 mL) maintained
at 18 °C under a nitrogen atmosphere was treated with
piperidine (1 mL). After 3 h, the reaction mixture was
concentrated under reduced pressure to afford D-(+)-R-amino-
ꢀ-caprolactam (15)14 as a pale yellow solid that was used,
without purification, in the next step of the reaction sequence.
A magnetically stirred solution of compound 14 (25 mg, 0.04
mmol) in DMF (1 mL) maintained at room temperature under
an atmosphere of nitrogen was treated with 1-hydroxybenzo-
triazole (HOBt) hydrate (7.0 mg, 0.05 mmol) and 1-(3-dimeth-
ylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (9.8
mg, 0.05 mmol). After 0.33 h, the reaction mixture was cooled
to 0 °C and treated, dropwise and via cannula, with a solution
of D-(+)-R-amino-ꢀ-caprolactam (22 mg) in DMF (1 mL). After
16 h at room temperature, the reaction mixture was diluted
with HCl (2 mL of a 5% v/v aqueous solution) and extracted
with diethyl ether (3 × 5 mL). The combined organic phases
were washed with water (1 × 5 mL) and brine (1 × 5 mL)
before being dried (MgSO4), filtered, and concentrated under
reduced pressure to afford a light yellow oil. Subjection of this
material to flash chromatography (silica, 1:98:1 v/v/v MeOH-
chloroform-NEt3 elution) provided, after concentration of the
appropriate fractions (Rf 0.5), compound 16 (21 mg, 72%) as a
clear, colorless oil: [R]D -41 (c 0.6, CHCl3); 1H NMR (300 MHz)
δ 7.85 (d, J ) 5.7 Hz, 1H), 6.05 (m, 1H), 5.61 (m, 2H), 4.47 (m,
1H), 4.26-4.17 (complex m, 3H), 4.01 (dd, J ) 7.5, 1.5 Hz,
1H), 3.35 (s, 3H), 3.28-3.20 (complex m, 2H), 2.32 (m, 1H),
2.13 (m, 1H), 1.96-1.76 (complex m, 4H), 1.53-1.28 (complex
m, 2H), 1.01 (d, J ) 6.6 Hz, 3H), 0.99 (d, J ) 6.9 Hz, 3H), 0.90
(s, 18H), 0.84 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H), 0.06 (s, 6H),
0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (75 MHz) δ 175.3 (C), 169.1
(C), 138.4 (CH), 126.0 (CH), 84.1 (CH), 75.2 (CH), 72.7 (CH),
72.6 (CH), 57.9 (CH3), 51.6 (CH), 42.0 (CH2), 31.5 (CH2), 30.9
(CH), 29.0 (CH2), 27.9 (CH2), 26.3 (CH3), 26.2 (CH3), 26.0 (CH3),
22.4 (CH3), 22.3 (CH3), 18.3 (C), 18.2(6) (C), 18.2(2) (C), -3.6
(CH3), -3.7 (CH3), -4.0 (CH3), -4.4 (CH3), -4.5 (CH3), -4.6
(CH3); IR νmax 3394, 3233, 2929, 2862, 1666, 1471, 1361, 1254,
1099, 836, 671 cm-1; MS (70 eV) m/z 685 [(M - H3C•)+, 5], 643
{[M - (CH3)3C•]+, 92}, 487 (80), 455 (56), 355 (58), 213 (62),
155 (72), 73 (100); HRMS calcd for C35H72N2O6Si3 (M - H3C•)+
685.4464, found 685.4459.
Concentration of fraction A (Rf 0.5) afforded acid 14 (33 mg,
63% at 53% conversion) as a clear, colorless oil: [R]D +5 (c
1
0.8, CHCl3); H NMR (300 MHz) δ 10.03 (br s, 1H), 5.65 (m,
2H), 4.46 (m, 1H), 4.32 (d, J ) 1.7 Hz, 1H), 3.98 (dd, J ) 7.5,
1.7 Hz, 1H), 3.81 (dd, J ) 7.5, 3.0 Hz, 1 H), 3.38 (s, 3H), 2.33
(m, 1H), 1.02 (d, J ) 6.9 Hz, 3H), 1.00 (d, J ) 6.6 Hz, 3H),
0.93 (s, 9H), 0.90 (s, 9H), 0.88 (s, 9H), 0.13 (s, 3H), 0.11 (s,
3H), 0.09 (s, 3H), 0.08 (s, 2 × CH3 overlapping, 6H), 0.06 (s,
3H); 13C NMR (75 MHz) δ 170.2 (C), 140.0 (CH), 125.8 (CH),
82.2 (CH), 75.0 (CH), 73.9 (CH), 73.5 (CH), 58.0 (CH3), 30.9
(CH), 26.1 (CH3), 26.0 (CH3), 22.1 (2 × CH3), 18.4 (C), 18.1(9)
(C), 18.1(7) (C), -3.7 (CH3), -3.8 (CH3), -3.9 (CH3), -4.6 (3 ×
CH3 overlapping) (one signal obscured); IR νmax 2955, 1720,
1463, 1362, 1254, 1110, 938, 836, 776, 671 cm-1; MS (70 eV)
m/z 533 {[M - (CH3)3C•]+, 2}, 213 (69), 201 (58), 73 (100);
HRMS calcd for C29H62O6Si3: [M - (CH3)3C•]+ 533.3150, found
533.3155.
Concentration of fraction B (Rf 0.4) afforded ester 13 (47
mg, 47% recovery) which proved identical with an authentic
sample.
9H-Flu or en -9-ylm eth yl (R)-h exah ydr o-2-oxo-1H-azepin -
3-ylca r ba m a te. A magnetically stirred solution of Fmoc-D-
Lys(Boc)-OH (700 mg, 1.49 mmol) in dichloromethane (15 mL)
maintained at 0 °C under an atmosphere of nitrogen was
treated with TFA (15 mL), in a dropwise manner and over a
period of 5 min. After 0.5 h, the reaction mixture was diluted
with toluene (20 mL) and then concentrated under reduced
pressure to afford a light yellow solid. This material was
dissolved in water (10 mL), cooled to -78 °C, and then freeze-
dried for 12 h to afford Fmoc-D-Lys-OH‚TFA (719 mg, 100%)
as a white flocculent solid. This material was used, without
purification, in the next step of the reaction sequence. Thus,
a
magnetically stirred solution of the above-mentioned
(6E)-6,7,8,9-Tet r a d eoxy-N-[(3R)-h exa h yd r o-2-oxo-1H -
azepin -3-yl]-8-m eth yl-2-O-m eth yl-L-gu lon on -6-en on am ide
(en t-1). A magnetically stirred solution of compound 16 (15.0
mg, 0.02 mmol) in THF (1 mL), maintained at 18 °C under a
nitrogen atmosphere, was treated with TBAF (130 µL of a 1
M solution in THF, 0.13 mmol). After 1.5 h, the reaction
mixture was treated with HCl (1 mL of a 5% v/v aqueous
solution) and then extracted with ethyl acetate (5 × 2 mL).
The combined organic phases were washed with brine (1 × 3
mL), dried (MgSO4), filtered, and concentrated under reduced
pressure to afford a light yellow oil. Subjection of this material
to flash chromatography (silica, 5% v/v MeOH-chloroform
elution) provided, after concentration of the appropriate frac-
tions (Rf 0.1), ent-bengamide E (ent-1) (6.5 mg, 86%) as a clear,
colorless and viscous oil: [R]D -32 (c, 0.2 CHCl3); 1H NMR (300
MHz) δ 7.98 (d, J ) 6.3 Hz, 1H), 6.22 (m, 1H), 5.81 (ddd, J )
15.3, 6.3, 0.6 Hz, 1H), 5.48 (ddd, J ) 15.3, 7.2, 1.2 Hz, 1H),
4.54 (dd, J ) 9.0, 6.0 Hz, 1H), 4.37 (br s, 1H), 4.22 (br t, J )
6.6 Hz, 1H), 3.82-3.77 (complex m, 1H), 3.60 (m, 1H), 3.53 (s,
3H), 3.48-3.20 (complex m, 5H), 2.31 (m, 1H), 2.06 (m, 1H),
2.12-1.36 (complex m, 5H), 1.00 (d, J ) 6.9 Hz, 3H), 0.98 (d,
J ) 6.9 Hz, 3H); 13C NMR (125 MHz) δ 174.7 (C), 172.1 (C),
141.8 (CH), 125.4 (CH), 80.9 (CH), 74.3 (CH), 72.8 (CH), 72.4
(CH), 59.9 (CH3), 52.0 (CH), 42.1 (CH2), 31.0 (CH2), 30.8 (CH),
28.8 (CH2), 27.9 (CH2), 22.2 (CH3), 22.1 (CH3); IR νmax 3355,
2930, 1651, 1110, 973, 911, 731 cm-1; MS (70 eV) m/z 359
TFA.salt (719 mg, 1.49 mmol) in dichloromethane (57 mL)
containing DMF (14 mL) and maintained at 18 °C under an
atmosphere of nitrogen was treated with Hu¨nig’s base (287
µL, 1.1 mmol). After 10 min, the resulting white suspension
was cooled to 0 °C and treated with 1-hydroxybenzotriazole
(HOBt) hydrate (243.6 mg, 1.79 mmol) and 1-(3-dimethyl-
aminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (343.8
mg, 1.79 mmol). After 16 h at 18 °C, the reaction mixture was
diluted with tartaric acid (20 mL of a 1 M aqueous solution)
then extracted with ethyl acetate (3 × 30 mL). The combined
organic phases were washed with NaHCO3 (1 × 50 mL of a
saturated aqueous solution), water (1 × 50 mL), and brine
(1 × 50 mL) before being dried (MgSO4), filtered, and concen-
trated under reduced pressure to afford a light yellow oil.
Subjection of this material to flash chromatography (silica,
1:98:1 v/v/v MeOH-chloroform-NEt3 elution) provided, after
concentration of the appropriate fractions (Rf 0.5), Fmoc-D-(+)-
R-amino-ꢀ-caprolactam (460 mg, 88%) as a white powder: mp
1
115-117 °C; H NMR (300 MHz) δ 7.77 (d, J ) 7.5 Hz, 2H),
7.64 (d, J ) 7.5 Hz, 2H), 7.42 (t, J ) 7.5 Hz, 2H), 7.34 (t, J )
7.5 Hz, 2H), 6.90 (m, 1H), 6.31 (br d, J ) 6.0 Hz, 1H), 4.38 (m,
3H), 4.25 (m, 1H), 3.26 (m, 2H), 2.12 (br d, J ) 12.6 Hz, 1H),
2.04 (m, 1H), 1.85-1.37 (complex m, 4H); 13C NMR (75 MHz)
δ 175.5 (C), 155.4 (C), 143.8 (C), 141.1 (C), 127.5 (CH), 126.9
(CH), 125.1 (CH), 119.8 (CH), 66.8 (CH2), 53.5 (CH), 47.1 (CH),

6774 J . Org. Chem., Vol. 66, No. 20, 2001
Banwell and McRae
[(M + H)+, 12], 57 (100); HRMS calcd for C17H30N2O6 359.2182,
found 359.2171.
caprolactam (15). We are indebted to Drs. Penny Phil-
lips and Fred Kinder (Novartis Institute, NJ ) for the
testing of ent-bengamide E.
Ack n ow led gm en t. We thank the Australian Gov-
ernment for provision of an APA to K.J .M. and the
Institute of Advanced Studies for generous financial
support. Dr. Chris Chandler of Auspep is thanked for
his advice concerning the synthesis of D-(+)-R-amino-ꢀ-
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for ent-bengamide E. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O0159486