employ reagents impractical for use on larger scale, or suffer
one or more low yielding steps that significantly reduce the
overall yield, limiting throughput and increasing cost.2a,5
Since all of the bengamides share a common polyol acid,
we sought to develop a single short sequence to access the
major structural subtypes of the bengamides differing only
in the nature of the lactam coupling partner.
enantioselective alkylation of the known imine 8 with
iodoepoxide 9 and subsequent ring closure. An alternative,
efficient sequence to the required caprolactams beginning
with hydroxylysine was recently disclosed.2a
Scheme 2
Scheme 1
Our route to benzyl-protected thioester 10 was initiated
by acylation of the lithium salt of lactam 11 (R ) Li) with
benzyloxyacetyl chloride, affording the chiral imide 12.6
Generation of the Z boron enolate by treatment of 12 with
Et2BOTf6,7 and condensation with commercial E enal 68 at
-50 °C afforded the expected syn aldol adduct 13 in >24:1
dr, which was immediately protected as TBS ether 14 in 80%
overall yield from 12 (Scheme 2). The auxiliary was removed
with EtSLi to give an intermediate ethyl thioester (95%) and
11 (R ) H) (93%). The resulting thioester was reduced at
-78 °C with DIBAL-H to give the sensitive aldehyde 15 in
91% yield. A variant of the chelation-controlled Gennari-
Mukaiyama aldol reaction of 15 with phenylthioketene acetal
16 in the presence of SnCl4 then afforded the required 2,3-
anti, 3,4-syn aldol adduct 10 (73% of 10) with 11.5:1 dr.9,10
The diastereoselectivity obtained with 16 was superior to
that of the related tert-butylthioketene acetal.9
As have all previous efforts, our construction of the
bengamide skeleton relies on the coupling of two general
subunits 4 and 5. Remarkably, what we perceived as the most
direct route to the polyol side chain 4, via sequential syn
and anti asymmetric aldol reactions beginning with the
commercially available E enal 6, had not been described,2b,5
although an anti aldol construction had been utilized by
Mukai on related protected alkyne analogues.5c,d An efficient
sequence to amino caprolactam 5 was envisioned via
(2) (a) Kinder, F. R.; 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. (b) Kinder, F. R., Jr.; Versace, R. W.; Bair,
K. W.; Bontempo, J. M.; Cesarz, D.; Chen, S.; Crews, P.; Czuchta, A. M.;
Jagoe, C. T.; Mou, Y.; Nemzek, R.; Phillips, P. E.; Tran, L. D.; Wang, R.;
Weltchek, S.; Zabludoff, S. J. Med. Chem. 2001, 44, 3692-3699. (c)
Phillips, P. E.; Bair, K. W.; Bontempo, J.; Crews, P.; Czuchta, A. M.;
Kinder, F. R.; Vattay, A.; Versace, R. W.; Wang, B.; Wang, J.; Wood, A.;
Zabludoff, S. Proc. Am. Assoc. Cancer Res. 2000, 41, 59.
(3) Phillips, P. E.; Allegrini, P.; Bair, K. W.; Bontempo, J.; Czuchta, A.
M.; Kinder, F. R.; Mu¨ller, D.; Schindler, P.; Stolz, B.; Towbin, H.; van
Oostrum, J.; Vattay, A.; Versace, R. W.; Voshol, H.; Wood, A. W.;
Zabludoff, S. Proc. Am. Assoc. Cancer Res. 2001, 42, 182.
The relative and absolute stereochemistry of 10 was readily
confirmed by conversion to (+)-bengamide E (3) (Scheme
3). Heating a mixture of commercial (-)-R-amino-ꢀ-capro-
lactam 17 and thioester 10 at reflux in dioxane effected
coupling affording amide 18 (98%). Deblocking of protected
bengamide E derivative 18 was effected by sequential Na/
(4) Dumez, H.; Giaccone, G.; Yap, A.; Barbier, N.; Pfister, C.; Cohen,
P.; Reese, S. F.; Van Oosterom, A. T.; Pinedo, H. M. Proc. Am. Assoc.
Cancer Res. 2001, 42, 227.
(6) Boeckman, R. K., Jr.; Connell, B. T. J. Am. Chem. Soc. 1995, 117,
12368-12369.
(5) (a) Liu, W.; Szewczyk, J. M.; Waykole, L.; Repic, O.; Blacklock, T.
J. Tetrahedron Lett. 2002, 43, 1373-1375. (b) Banwell, M. G.; McRae, K.
J. J. Org. Chem. 2001, 66, 6768-6774. (c) Mukai, C.; Moharram, S. M.;
Kataoka, O.; Hanaoka, M. J. Chem. Soc., Perkin Trans. 1 1995, 2849-
2854. (d) Mukai, C.; Kataoka, O.; Hanaoka, M. J. Org. Chem. 1995, 60,
5910-5918. (e) Chida, N.; Tobe, T.; Murai, K.; Yamazaki, K.; Ogawa, S.
Heterocycles 1994, 38, 2383-2388. (f) Marshall, J. A.; Luke, G. P. J. Org.
Chem. 1993, 58, 6229-6234. (g) Chida, N.; Tobe, T.; Okada, S.; Ogawa,
S. J. Chem. Soc., Chem. Commun. 1992, 1064-1066. (h) Kishimoto, H.;
Ohrui, H.; Meguro, H. J. Org. Chem. 1992, 57, 5042-5044. (i) Broka, C.
A.; Ehrler, J. Tetrahedron Lett. 1991, 32, 5907-5910. (j) Chida, N.; Tobe,
T.; Ogawa, S. Tetrahedron Lett. 1991, 32, 1063-1066.
(7) (a) Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 83-91. (b) Evans,
D. A.; Vogel, E.; Nelson, J. V. J. Am. Chem. Soc. 1979, 101, 6120-6123.
(8) Larger quantities of 6 were prepared by isomerization of the adduct
of isobutyraldehyde and acetylene to 6 (81%): (a) Chodkiewicz, W. Ann.
Chim. (Paris) [13] 1957, 2, 819-69. (b) Chabardes, P. Tetrahedron Lett.
1988, 29, 6253-6256.
(9) Gennari, C.; Grazia Beretta, M.; Bernardi, A.; Moro, G.; Scolastico,
C.; Todeschini, R. Tetrahedron 1986, 42, 893-909.
(10) Phenylthioketene acetal 16 was prepared as a variable but highly
E-enriched E/Z mixture by treatment of the phenyl thioester of methoxy-
acetic acid with TMSOTf.9 The diastereoselectivity of the subsequent aldol
condensation did not depend on the E/Z ratio of 16.
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Org. Lett., Vol. 4, No. 12, 2002