Total synthesis of bengazole A

Article abstract of DOI:10.1021/ol9024138

(Figure presented) The divergent and enantioselective total synthesis of the powerful antifungal marine natural product bengazole A has been achieved.

Full text of DOI:10.1021/ol9024138

ORGANIC
LETTERS
2010
Vol. 12, No. 2
236-238
Total Synthesis of Bengazole A
Srivari Chandrasekhar* and Ambadi Sudhakar
Organic DiVision-I, Indian Institute of Chemical Technology, Hyderabad, India 500 007
sriVaric@iict.res.in
Received November 3, 2009
ABSTRACT
The divergent and enantioselective total synthesis of the powerful antifungal marine natural product bengazole A has been achieved.
Bengazole A (1) is a (bis)oxazole sugar hybrid isolated
by Crews et al. from the marine sponge Jaspidae fiji-
sponge.1 It exhibited antihelminthic activity against Nip-
postrongylus braziliensis1 and also showed powerful
antifungal properties against Candida albicans (MIC 7 µg/
mL) comparable to those of amphotericin B.2 This
intriguing biological profile coupled with our own interest
in synthesizing natural products of marine origin3 pro-
voked us to devise an approach amenable for both its
synthetic simplicity and its easy access to analogues. The
key steps that we hoped to use were a Sharpless asym-
metric dihydroxylation,4 a catalyst-controlled syn-reduc-
tion,5 and intramolecular oxazole assembly.
However, they ended up with an inseparable mixture (1:1)
of bengazole A and its C10-epimer. Later, in 2006 Ley and
co-workers7 achieved a stereocontrolled total synthesis of 1
in 3.4% overall yield. Apart from these two total syntheses
there are a few reports directed toward the synthesis of
bengazole A.8 Herein, we report a new enantioselective total
synthesis of bengazole A.
Bengazole A (1), on logical disconnection, provided two
fragments: the bisoxazole unit 2 and myristoyl chloride 3.
The bisoxazole unit 2 was further disengaged to the oxazole
acid 4 and the amino polyol 5 (Scheme 1).
The oxazole acid 4 was synthesized from the known
triisopropyl silyl formyl oxazole 89 following the path shown
in Scheme 2. Compound 8 underwent a smooth Wittig
Although bengazole A (1) was isolated in 1988, the first
synthesis was reported in 1999 by Molinski and co-workers.6
+
olefination (PPh3 CH3I-) to provide vinyl oxazole 9, and
this was followed by a Sharpless asymmetric dihydroxylation
to yield 10 in 60% ee;10 the unwanted isomer was separated
at a later stage by column chromatography (Scheme 5).
Compound 10 was treated with p-TsOH followed by selec-
(1) Adamczeski, M.; Quin˜oa´, E.; Crews, P. J. Am. Chem. Soc. 1988,
110, 1598.
(2) (a) Molinski, T. F. J. Nat. Prod. 1993, 56, 1. (b) Antonio, J.;
Molinski, T. F. J. Nat. Prod. 1993, 56, 54.
(3) (a) Bugni, T. S.; Richards, B.; Bhoite, L.; Cimbora, D.; Harper,
M. K.; Ireland, C. M. J. Nat. Prod. 2008, 71, 1095. (b) Newman, D. J.;
Cragg, G. M. J. Nat. Prod. 2007, 70, 461. (c) Butler, M. S. J. Nat. Prod.
2004, 61, 2141. (d) Cragg, G. M.; Grothaus, P. G.; Newman, D. J. Chem.
ReV. 2009, 109, 3012. (e) Chandrasekhar, S.; Rambabu, C.; Reddy, A. S.
Org. Lett. 2008, 10, 4355. (f) Chandrasekhar, S.; Yaragorla, S. R.;
Sreelakshmi, L. Tetrahedron Lett. 2007, 48, 7339.
(7) (a) Bull, J. A.; Balskus, E. P.; Horan, R. A. J.; Langner, M.; Ley,
S. V. Angew. Chem., Int. Ed. 2006, 45, 6714. (b) Bull, J. A.; Balskus, E. P.;
Horan, R. A. J.; Langner, M.; Ley, S. V. Chem.sEur. J. 2007, 13, 5515.
(8) (a) Shafer, C. M.; Molinski, T. F. Tetrahedron Lett. 1998, 39, 2903.
(b) Chittari, P.; Hamada, Y.; Shioiri, T. Heterocycles 2000, 59, 465. (c)
Chittari, P.; Hamada, Y.; Shioiri, T. Synlett 1998, 1022.
(9) Miller, R. A.; Smith, R. M.; Marcune, B. J. Org. Chem. 2005, 70,
9074.
(4) Kolb, H. C.; Nieuwenhze, M. S. V.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483.
(5) Chen, K. M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro, M. J.
Tetrahedron Lett. 1987, 28, 155.
(10) HPLC method: Chiral pak IC 250 mm × 4.6 mm, 5 µ (column),
10% IPA in hexanes (mobile phase), flow rate 1 mL/min. tR: 8.12 and 12.65
min.
(6) (a) Mulder, R. J.; Shafer, C. M.; Molinski, T. F. J. Org. Chem. 1999,
64, 4995.
10.1021/ol9024138  2010 American Chemical Society
Published on Web 12/17/2009

Scheme 1
.
Retrosynthetic Analysis of Bengazole A (1)
Scheme 3. Synthesis of Aminopolyol 5
tive protection of the primary hydroxyl group as a TES ether
11, which was further transformed to desired oxazole acid 4
via intermediates 12 and 13.7
Scheme 2. Synthesis of Oxazole Acid 4
3-hydroxy group were trans to each other in 21a, which
implied that the configuration of the newly generated
stereocenter in 14 (major) was indeed the required one.
Chelation-controlled reduction of the keto group in 14 with
Et2BOMe and NaBH4 at low temperature afforded the syn-
diol 15 (98:2 de).5,15 To confirm stereochemistry of the
required product, 15 was protected as acetonide, and the
stereochemistry of major product was confirmed by Rych-
novsky’s acetonide method16 (Scheme 4). Diol 15 was
Scheme 4. Confirmation of Stereocenters
The amino polyol 5 was prepared starting from serinol
611 through aldolization and dihydroxylation (Scheme 3).
Thus 6 on Swern oxidation11,12 followed by aldolization
with 3-pentene-2-one 7 in the presence of LiHMDS at -78
°C furnished the aminol 14 (96:4 de).13 To investigate the
stereochemical integrity of the major product, 14 was
subjected to Pd(OH)2 catalyzed hydrogenation14 in the
presence of Boc2O to furnish Boc-protected pyrrolidines 21a
and 21b (Scheme 4). By 300 MHz NOE analysis in CDCl3
it was found that the O-protected silyl group and the
Org. Lett., Vol. 12, No. 2, 2010
237

protected as di-MOM ether 16 in 87% yield (MOMCl,
i-Pr2NEt). Oxidative osmylation of 16 provided the syn-diol
17a as a major diastereomer (4:1); the latter was separated
from the unwanted diastereomer by column chromatography.
The stereochemical outcome of the dihydroxylation was
confirmed by NMR studies in addition to reports from the
literature that Sharpless asymmetric dihydroxylation of 16
using AD mix-ꢀ4 provided exclusively the required diol 17
(matched pair).17 The protection of the two hydroxyl groups
as MOM ethers was a rather trivial one (i-Pr2NEt, MOMCl,
CH2Cl2, 87% yield) to obtain 18. Selective desilylation of
18 (n-Bu4NF, 0 °C) provided the desired fragment 5 in 95%
yield (Scheme 3).
Scheme 5. Total Synthesis of Bengazole A
With substantial quantities of the key synthons 4 and 5
in hand, we completed the total synthesis of bengazole
A. Thus, compound 5 was subjected to hydrogenolysis to
liberate the free amine, which was immediately reacted
with 4 under EDCI-HOBT conditions to produce 19a.18
A smooth oxidative intramolecular cyclization19 of 19a
was accomplished in two steps to give bisoxazolyl
methanol derivative 2 in moderate yield. Desilylation
liberated the free C-10 hydroxy group, and esterification
with myristoyl chloride 3 generated the fully protected
bengazole A, 20, which on exposure to TiCl420 in CH2Cl2
yielded the final compound bengazole A (Scheme 5). This
compound is identical in all respects to the reported natural
product including NMR, optical rotation, and HRMS. The
synthesis, thus constitutes the shortest reported to date
for this powerful antifungal agent.
(11) La¨ıb, T.; Chastanet, J.; Zhu, J. J. Org. Chem. 1998, 63, 1709.
(12) Omura, K.; Swern, D. Tetrahedron Lett. 1996, 37, 1651.
(13) HPLC method: YMC cyano 250 mm × 4.6 mm, 5 µ (column),
5% H2O in ACN (mobile phase), flow rate 1 mL/min. tR: 5.8 and 8.8
min.
(14) Pan, Q.; Zou, B.; Wang, Y.; Ma, D. Org. Lett. 2004, 6, 1009.
(15) HPLC method: YMC cyano 250 mm × 4.6 mm, 5 µ (column),
30% H2O in ACN (mobile phase), flow rate 1 mL/min. tR: 6.6 and 8.4
min.
(16) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I. Acc. Chem.
Res. 1998, 31, 9.
Acknowledgment. A.S. thanks CSIR, New Delhi for the
award of research fellowship, and S.C. thanks DST for
financial assistance.
(17)
AD mix-ꢀ
16.
17a (exclusive product)
tBuOH-H2O (1:1); CH2SO2NH2
Supporting Information Available: Spectroscopic, ana-
lytical data, and experimental details. This material is
available free of charge via the Internet at http://pubs.acs.org.
(18) The unwanted isomer 19b was separated by column chromatog-
raphy.
(19) (a) Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604. (b) Wipf,
P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558. (c) Panek, J. S.; Beresis,
R. T. J. Org. Chem. 1996, 61, 6496.
(20) Kiyooka, S. Tetrahedron: Asymmetry 2003, 14, 2897.
OL9024138
238
Org. Lett., Vol. 12, No. 2, 2010