Total synthesis of bengamide E

Article abstract of DOI:10.1016/S0040-4039(02)00022-9

A total synthesis of bengamide E is reported. The synthesis includes the utilization of D-tartrate as the chiral building block, construction of the E-olefin by the Julia protocol, an anti-aldol reaction to generate C-2 and C-3 stereocenters, and coupling of the thioester with caprolactam hydrochloride using sodium 2-ethylhexanoate.

Full text of DOI:10.1016/S0040-4039(02)00022-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1373–1375
Total synthesis of bengamide E
Wenming Liu,* Joanna M. Szewczyk, Liladhar Waykole, Oljan Repicˇ and Thomas J. Blacklock
Process R&D, Chemical and Analytical Development, Novartis Institute for Biomedical Research, One Health Plaza,
East Hanover, NJ 07936, USA
Received 29 November 2001; accepted 12 December 2001
Abstract—A total synthesis of bengamide E is reported. The synthesis includes the utilization of
D-tartrate as the chiral building
block, construction of the E-olefin by the Julia protocol, an anti-aldol reaction to generate C-2 and C-3 stereocenters, and
coupling of the thioester with caprolactam hydrochloride using sodium 2-ethylhexanoate. © 2002 Elsevier Science Ltd. All rights
reserved.
Bengamides (1a–1f) are a family of compounds isolated
from a Choristida sponge from the Fiji Islands.1 Their
structures differ only in the lactam moiety, while a
polyhydroxylated C10 side chain is the common feature
(Fig. 1). They have shown significant cytotoxicity,
anthelminthic and antitumor activities.1,2 Since the dis-
covery of the bengamides, tremendous efforts from
different laboratories have resulted in several total syn-
theses of these biologically important molecules.3
Recently a chemoenzymatic total synthesis of ent-
bengamide E has been reported.4 Herein we report a
short total synthesis of bengamide E utilizing inexpen-
sive D-tartrate as the building block to construct the
polyhydroxylated C10 side chain, followed by coupling
with caprolactam hydrochloride in the presence of
sodium 2-ethylhexanoate.
The synthesis started with diisopropyl
resembles the C-4 and C-5 stereocenters in the side
chain (Scheme 1).5 Thus,
-tartrate 2 was dibenzylated
D-tartrate, which
D
using sodium hydride and benzyl bromide in the pres-
ence of a catalytic amount of tetrabutylammonium
iodide in 60% yield. Treatment of diester 3 with lithium
aluminum hydride gave rise to diol 4 in 86% yield after
Figure 1.
Keywords: bengamide E; Julia olefination; anti-aldol; sodium 2-ethylhexanoate.
* Corresponding author. E-mail: wenming.liu@pharma.novartis.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00022-9

1374
W. Liu et al. / Tetrahedron Letters 43 (2002) 1373–1375
OBn
O
OBn
O
OH
b
a
OH
O
O
HO
O
O
OBn
4
OBn O
OH
O
2
3
c
OBn
H
OBn
d
OTIPS
OTIPS
HO
O
OBn
OBn
5
6
Scheme 1. (a) NaH, BnBr, nBu4NI (cat.), THF, rt, 60%; (b) LAH, THF, rt, 86%; (c) NaH, TIPSCl, nBu4NI (cat.), THF, 92%;
(d) ClCOCOCl, DMSO, CH2Cl2, −78°C, then Et3N“rt.
chromatography. The diol 4 was monosilylated to 5
using 1.1 equiv. of sodium hydride and 1.1 equiv. of
triisopropylsilyl chloride in the presence of a catalytic
amount of tetrabutylammonium iodide (92%). Swern
oxidation of alcohol 5 generated aldehyde 6, which was
subsequently subjected to the Julia olefination without
further purification.
With aldehyde 10 in hand, we were set to explore the
crucial aldol reaction with S-phenyl methoxythioac-
etate to construct the C-2 and C-3 anti-stereocenters in
the side chain. However, extensive efforts using various
reaction conditions (nBu2BOTf/iPr2NEt, SnCl4, etc.)
were futile. None of those conditions produced signifi-
cant amount of the desired anti-aldol product (2R,3R).
Later, the conditions reported by Annunziata et al.8
were studied. When the standard conditions (TiCl4,
Et3N) were applied, a pair of anti-aldol products was
obtained. The desired adduct was the minor isomer
(ꢀ1:4). However, equal amounts of the two isomers
were generated when some modifications were made to
the reported reaction conditions. Thus, S-phenyl
thioacetate (2 equiv.) was treated with titanium tetra-
chloride (2 equiv.) and N,N-dimethylethylamine (2
equiv.) in dichloromethane at −78°C, and the resulting
dark-red enolate solution was added to the aldehyde
premixed with lithium iodide (4 equiv.) at −78°C. After
1 h, most of the aldehyde 10 was consumed and reac-
tion was quenched. 1H NMR of the crude mixture
showed the presence of the two anti-aldol products. No
2-Benzothiazolyl-sulfone 76 was treated with lithium
bis(trimethylsilyl)amide in THF at −78°C, and to this
lithiated sulfone was added freshly prepared aldehyde 6
(Scheme 2). The reaction mixture was stirred at −78°C
for another hour, then gradually warmed up to room
temperature. After the reaction was completed, aqueous
workup was conducted. 1H NMR of the mixture
revealed that the stereoselectivity of the olefination
reaction predominantly favored the E-olefin (E:Z=
>20:1) as described in the literature.7 Purification of the
mixture over silica gel gave 8 in 92% yield from 5.
Removal of the silyl group in 8 was accomplished using
tetrabutylammonium fluoride in THF at 0°C in 83%
yield after chromatography. Alcohol 9 was easily con-
verted to its corresponding aldehyde 10 that was used
for the subsequent aldol reaction without further
purification.
1
syn-aldol product was observed by H NMR. The ratio
of the two isomers was 1:1. All of our attempts to
OBn
R
OBn
b
S
N
a
OTIPS
S
O
O
OBn
OBn
7
9 R= CH2OH
10 R= CHO
8
c
d (see text)
OBn OMe
O
OBn OMe
H
N
f
e
SPh
NH
1e
OBn OH
O
OBn OH
O
12
11
Scheme 2. (a) LHMDS, THF, 6, −78°C to rt, 92% from 5; (b) TBAF, THF, 0°C, 83%; (c) ClCOCOCl, DMSO, CH2Cl2, −78°C,
then Et3N“rt; (d) S-phenyl methoxythioacetate, TiCl4, EtNMe2, LiI, CH2Cl2, −78°C, 71% from 9; (e) -(−)-a-amino-o-caprolac-
tam hydrochloride, sodium 2-ethylhexanoate, THF, 87%; (f) Na/NH3, (CH3OCH2CH2)2NH, THF, −78°C, 87%.
L

W. Liu et al. / Tetrahedron Letters 43 (2002) 1373–1375
1375
improve upon this selectivity were unsuccessful. Those
efforts included the utilization of other Lewis acids
(MgBr2, LiCl, Et2BOMe, Ti(OiPr)4, SnCl4) to complex
with the aldehyde 10 in order to distinguish the two
benzyl ether groups, and different ratios of TiCl4 and
the base. The two isomers can be separated carefully by
silica gel chromatography and were obtained in 71%
combined yield from alcohol 9. It nevertheless set the
stage for coupling of 11 with the caprolactam moiety to
construct the bengamide E molecule.
5044; (d) Marshall, J. A.; Luke, G. P. J. Org. Chem.
1993, 58, 6229–6234; (e) Chida, N.; Tobe, T.; Murai, K.;
Yamazaki, K.; Ogawa, S. Heterocycles 1994, 38, 2383–
2388; (f) Mukai, C.; Kataoka, O.; Hanaoka, M. J. Org.
Chem. 1995, 60, 5910–5918; (g) Mukai, C.; Moharram, S.
M.; Kataoka, O.; Hanaoka, M. J. Chem. Soc., Perkin
Trans. 1 1995, 2849–2854; (h) Clark, T. J.; Boeckman, R.
K., Jr. Book of Abstracts, 219th National Meeting of the
American Chemical Society, San Francisco, CA, March
26–31, 2000, Abstr. ORGN-58; (i) Kinder, F. R., Jr.;
Wattanasin, S.; Versace, R. W.; Bair, K. W.; Bontempo,
J.; Green, M. A.; Lu, Y. J.; Marepalli, H. R.; Philips, P.
E.; Roche, D.; Tran, L. D.; Wang, R.; Waykole, L.; Xu,
D. D.; Zabludoff, S. J. Org. Chem. 2001, 66, 2118–2122.
4. Banwell, M. G.; McRae, K. J. J. Org. Chem. 2001, 66,
6768–6774.
5. For a review on tartaric acid and tartrates in the synthe-
sis of bioactive molecules, see: Ghosh, A. K.; Koltun, E.
S.; Bilcer, G. Synthesis 2001, 1281–1301.
6. Sulfone 7 was prepared in two steps from 2-mercaptoben-
zothiazole and isobutyl bromide in 88% yield: (i) NaH,
N-methyl-2-pyrrolidinone, rt; (ii) Oxone®, THF/water,
reflux.
Treatment of 11 with
L
-(−)-a-amino-o-caprolactam
hydrochloride in the presence of sodium 2-ethylhex-
anoate (2 equiv.) in THF produced amide 12 smoothly
in 87% yield after chromatographic purification.9 It is
noteworthy that the hydrochloride salt of the caprolac-
tam was used, and that the reaction was carried out at
room temperature. These conditions are close to neutral
and compatible with a variety of acid/base sensitive
substrates,10 therefore it provides a very mild alterna-
tive for preparing amides from thioesters. The mecha-
nism of this coupling reaction of a thioester and a
lactam is not clear, but presumably involves the con-
certed actions of sodium 2-ethylhexanoate and its con-
jugated acid.11 Reductive removal (Na/NH3) of benzyl
groups in 12 in the presence of bis(2-methoxyethyl)-
amine12 afforded bengamide E, [h]2D4 +33.6 (c 1.0,
MeOH), lit.1b [h]2D0 +36.9 (c 0.043, MeOH), in 87% yield
7. (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O.
Tetrahedron Lett. 1991, 32, 1175–1178; (b) Blakemore, P.
R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998,
26–28; (c) Julia, M.; Badet, B. Bull. Chem. Soc. Fr. 1975,
1363–1366.
1
after purification over silica gel (EtOH/EtOAc). The H
8. Annunziata, R.; Cinquini, M.; Cozzi, F.; Borgia, A. L. J.
Org. Chem. 1992, 57, 6339–6342.
and 13C NMR spectra were in excellent accordance
with those reported for natural bengamide E.1b
9. 12: [h]2D4 −8.3 (c 1.0, MeOH); 1H NMR (CDCl3, 300
MHz) l 7.84 (d, 1H, J=6.2 Hz), 7.18–7.43 (m, 10H), 6.63
(m, 1H), 5.76 (dd, 1H, J=15.6, 6.4 Hz), 5.37 (dd, 1H,
J=15.5, 8.4 Hz), 4.95 (d, 1H, J=10.9 Hz), 4.62 (dd, 2H,
J=11.3, 6.6 Hz), 4.47 (m, 1H), 4.38 (d, 1H, J=11.9 Hz),
4.13 (t, 1H, J=7.8 Hz), 3.80 (s, 2H), 3.73 (d, 1H, J=6.8
Hz), 3.52 (m, 1H), 3.31 (s, 3H), 2.96 (m, 2H), 2.35 (m,
1H), 2.07 (m, 1H), 1.95 (m, 1H), 1.75 (m, 2H), 1.45 (m,
1H), 1.27 (m, 1H), 1.01 (dd, 6H, J=6.7, 4.8 Hz); 13C
NMR (75 MHz, CDCl3) l 175.9, 171.0, 144.0, 139.1,
139.0, 128.8, 128.7, 128.3, 128.1, 127.8, 123.9, 82.6, 81.6,
80.7, 75.5, 72.2, 70.5, 58.7, 52.4, 42.1, 31.5, 31.3, 29.0,
28.3, 22.7.; MS m/z 561 (M+Na)+, 431; HRMS m/z calcd
for C31H43N2O6 (M+H)+ 539.3121; found 539.3117.
10. Liu, W.; Xu, D. D.; Repic, O.; Blacklock, T. J. Tetra-
hedron Lett. 2001, 42, 2439–2441.
In summary, we have achieved a total synthesis of
bengamide E. The side chain was constructed from
D
-tartrate as the chiral building block, with E-olefina-
tion by the Julia protocol and an anti-aldol reaction.
Coupling of the side chain with the caprolactam moiety
was accomplished using sodium 2-ethylhexanoate.
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