Concise enantioselective synthesis of ent-malbrancheamide B

Full text of DOI:10.1021/ja900688y

Published on Web 03/10/2009
Concise Enantioselective Synthesis of ent-Malbrancheamide B
Frederic Frebault,† Nigel S. Simpkins,†,* and Ashley Fenwick‡
School of Chemistry, The UniVersity of Birmingham, Edgbaston, Birmingham B15 2TT, U.K., and Pfizer Central
Research (Animal Health), Ramsgate Road, Sandwich CT13 9NJ, U.K.
Received January 28, 2009; E-mail: n.simpkins@bham.ac.uk
Scheme 1. Retrosynthetic Analysis of Malbrancheamide B
There is a growing family of fungi-derived alkaloids whose
members feature a bicyclo[2.2.2]diazaoctane core as part of a more
complex polycyclic structure.1 Important examples include brevi-
anamide B (1), paraherquamide A (2), stephacidin A (3), and the
most recently added members of the group, the malbrancheamides
4 and 5 (Figure 1).2
These compounds combine synthetically challenging structures,
intriguing biosynthetic origins, and, in many cases, potent biological
activities. The malbrancheamides, recently isolated from the fungus
Malbranchea aurantiaca, are unique in having a chlorinated indole
nucleus, and compound 4 was shown to be a new calmodulin (CaM)
inhibitor.2a,3
generated by union of a suitably protected prenylated proline
amide 9 (P ) protecting group) and the indole-3-pyruvic acid
derivative 10. As several other groups have done, we initially
chose to explore our synthesis in the unnatural series, because
of the relative cheapness of L-proline.
Potentially suitable proline amide derivatives conforming to the
generic structure 9 were readily available using the Seebach “self-
reproduction of chirality” approach.7 After exploring a number of
alternatives, we settled on the use of the O-benzylhydroxamic acid
derivative 13, which is easily prepared from the “Seebach acetal”
11 via prenylated derivative 12 (Scheme 2).8
Scheme 2. Synthesis of Hydroxamic Acid Derivative 13a
Figure 1. Structures of natural products containing bicyclo[2.2.2]-
diazaoctane.
The synthesis and biosynthesis of these compounds have been
probed for many years, most notably by the Williams group,
which has established a biomimetic IMDA strategy as a concise
access to several members of this family of natural products,
including malbrancheamides 4 and 5.4 However, because of the
prochiral nature of the key intermediate in this sequence, the
products are necessarily racemic.5 Herein, we describe a new
and general enantioselective approach to this type of compound,
which we illustrate with a concise synthesis of ent-malbranchea-
mide B (5).
Our chosen penultimate synthesis intermediate was 5-oxamal-
brancheamide B (6), which had been previously synthesized by
Williams4a and shown to be reduced to 5 by the action of DIBAL-H
(Scheme 1). This compound would be formed by double cyclization
of hydroxydiketopiperazine (hydroxy-DKP) compound 8 via the
unusual R-amido N-acyliminium species 7.
a Reagents and conditions: (a) LDA, THF, -78 °C, prenyl bromide, 76%;
(b) BnONH2, n-BuLi, THF, -78 °C, 75%.
Attempts at direct coupling of such proline amides with
pyruvic acid 10 were presumably thwarted by the intervention
of the enol form of the keto acid, which completely undermined
the usual amide-forming protocols.9 To avoid this problem, we
employed the tactic of coupling an enol ether derivative
corresponding to 10.
Readily prepared aldehyde 14 was condensed with ester 15 to
give aldol adduct 16 as a 4:1 mixture of diastereomers (Scheme
3). This compound underwent ready elimination via mesylation and
base treatment to give an unsaturated ester, which was then
hydrolyzed to give acid 17 (3:1 Z/E).
Model studies indicated that such a cyclization should
predominantly give the stereochemistry at C-12a required for
the malbrancheamides.6 The key intermediate 8 would be
With the troublesome R-keto acid function of the indole pyruvic
acid system suitably protected, the required coupling with proline
† University of Birmingham.
‡ Pfizer Central Research.
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4214 J. AM. CHEM. SOC. 2009, 131, 4214–4215
10.1021/ja900688y CCC: $40.75
2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Amide Coupling and DKP Formationa
Scheme 4. Completion of the Malbrancheamide B Synthesisa
a Reagents and conditions: (a) TMSOTf, CH2Cl2, 0 °C to RT, 64%, 4:1
dr; (b) SmI2, LiCl, THF, RT, 70%; (c) DIBAL-H, toluene, RT, 63% (74%4a).
Acknowledgment. We acknowledge Pfizer, Sandwich, U.K.,
and the Universities of Nottingham and Birmingham for support
of F.F. through a studentship. We also thank Dr. Richard Webster
(Pfizer) for his support of this work.
Supporting Information Available: Complete experimental details
and characterization data. This material is available free of charge via
the Internet at http://pubs.acs.org.
a Reagents and conditions: (a) LHMDS, THF, -78 °C, 97%; (b) MsCl,
CH2Cl2, Et3N, then DBU, 91%; (c) LiOH, THF(aq), 58% (+14% N-H
derivative + 12% rec SM); (d) HATU, i-PrNEt2, MeCN, 74%; (e) i-PrOH,
CBr4, 50 °C, 52%.
References
(1) (a) For a review, see: Williams, R. M.; Cox, R. J. Acc. Chem. Res. 2003,
36, 127. (b) For leading references, see: Ding, Y.; Gruschow, S.; Greshock,
T. J.; Finefield, J. M.; Sherman, D. H.; Williams, R. M. J. Nat. Prod. 2008,
71, 1574.
amide 13 proceeded smoothly to give the anticipated OSEM ether
product 18 as a mixture of Z and E isomers. Unexpectedly, SEM
ether 18 resisted all attempts at deprotection using TBAF, TBAT,
or HF-py.10 After screening alternative acidic conditions, we
eventually established that conversion of 18 into the key DKP 19
was possible, albeit in moderate yield, by use of CBr4 in warm
i-PrOH.11
With our key precursor DKP 19 in hand, we were delighted to
observe that treatment of this compound with TMSOTf in CH2Cl2
resulted in smooth cyclization accompanied by loss of the indole
NBoc group (Scheme 4). The desired polycyclic DKP 20 was
obtained in 64% yield as a separable 4:1 mixture favoring the
desired C12a epimer.12 The major product arises from a preferred
conformation of the intermediate 7 in which the prenyl group is
oriented away from the OBn group on nitrogen.
Conversion of 20 into ent-malbrancheamide B (5) was then
accomplished by reductive cleavage of the N-OBn linkage using
SmI2 in the presence of excess LiCl13 followed by reduction
according to the published Williams protocol. Our synthetic ent-
malbrancheamide B (5) displayed spectroscopic properties fully in
accord with those published previously.14
The efficiency of our total synthesis of ent-malbrancheamide B
is, at present, compromised by several steps having modest yields,
especially the SEM removal leading to 19, but the route is very
concise, requiring only 10 steps from commercial 6-chloroindole.
Further streamlining of the route and its application to other natural
products in this family are underway.
(2) (a) Mart´ınez-Luis, S.; Rodr´ıguez, R.; Acevedo, L.; Gonza´lez, M. C.; Lira-
Rocha, A.; Mata, R. Tetrahedron 2006, 62, 1817. (b) Figueroa, M.; Del
Carmen Gonza´lez, M.; Mata, R. Nat. Prod. Res. 2008, 22, 709.
(3) Miller, K. A.; Figueroa, M.; Valente, M. W. N.; Greshock, T. J.; Mata, R.;
Williams, R. M. Bioorg. Med. Chem. Lett. 2008, 18, 6479.
(4) (a) Miller, K. A.; Welch, T. R.; Greshock, T. J.; Ding, Y.; Sherman, D. H.;
Williams, R. M. J. Org. Chem. 2008, 73, 3116. Also see: (b) Ding, Y.;
Greshock, T. J.; Miller, K. A.; Sherman, D. H.; Williams, R. M. Org. Lett.
2008, 10, 4863. (c) Valente, M. W. N.; Williams, R. M. Heterocycles 2006,
70, 249.
(5) This assumes that no bystander asymmetric centers are present; see ref 1
for examples.
(6) Pichowicz, M.; Simpkins, N. S.; Blake, A. J.; Wilson, C. Tetrahedron 2008,
64, 3713.
(7) Seebach, D.; Boes, M.; Naef, R.; Schweizer, W. B. J. Am. Chem. Soc.
1983, 105, 5390.
(8) A number of alternatives, including N-PMB, N-DMB, and N-allyl were
prepared but either proved incompatible with subsequent steps or could
not be removed efficiently later on.
(9) Non-benzylic types of pyruvic acids can be coupled effectively. See:
Siwicka, A.; Wojtasiewicz, K.; Rosiek, B.; Leniewski, A.; Maurin, J. K.;
Czarnocki, Z. Tetrahedron: Asymmetry 2005, 16, 975.
(10) More usual ethers, including OMe and OPMB types, were tried first, but
this system appears to be unexpectedly stable toward acidic reagents,
presumably because of the push-pull nature of the extended conjugated
indole carboxamide. Forcing conditions resulted in destruction of the starting
materials with no constructive cyclization.
(11) Chen, M.-Y.; Lee, A. S.-Y. J. Org. Chem. 2002, 67, 1384.
(12) This type of cyclization is completely diastereoselective if the ring nitrogen
bears a PMB group, but this is not easily removed later (see ref 1).
(13) Fuchs, J. R.; Mitchell, M. L.; Shabangi, M.; Flowers, R. A., III. Tetrahedron
Lett. 1997, 38, 8157.
(14) We thank Professor R. M. Williams (Colorado State University) and
Professor R. Mata (Instituto de Biologı´a, Universidad Nacional Auto´noma
de Me´xico) for their assistance in clarifying the identity of our synthetic
sample.
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