Enantioselective total syntheses of ircinal A and related manzamine alkaloids [6]

Full text of DOI:10.1021/ja9829259

866
J. Am. Chem. Soc. 1999, 121, 866-867
Scheme 1
Enantioselective Total Syntheses of Ircinal A and
Related Manzamine Alkaloids
Stephen F. Martin,* John M. Humphrey, Amjad Ali, and
Michael C. Hillier
Department of Chemistry and Biochemistry
The UniVersity of Texas, Austin, TX 78712
ReceiVed August 14, 1998
The manzamines constitute a growing family of structurally
complex indole alkaloids that have been isolated from marine
sponges of the genera Haliclona and Pellina, which are found
off the coast of Okinawa.1 Manzamine A (1), which exhibits
potent antitumor activity in a number of assays,2 was the first
member of this group of alkaloids to be isolated. Subsequent to
this exciting discovery, a number of related alkaloids including
ircinal A (2), which was first converted into 1 by Kobayashi,3
have been isolated. A novel biosynthetic pathway to the man-
zamine alkaloids has been proposed.4 The combination of the
complex and unusual structure of manzamine A and its promising
biological activity has inspired numerous synthetic investigations,5
one of which recently culminated in its synthesis.6 Herein we
report a concise enantioselective synthesis of ircinal A (2), and
hence a formal synthesis of manzamine A (1), according to the
overall plan outlined in Scheme 1. The key intermediate 5 is first
assembled by coupling an unsaturated amino ester subunit with
a chiral dienophilic subunit (disconnection a). A novel domino
Stille/Diels-Alder reaction is then marshaled to create the ABC
tricyclic core 3 in a single operation from 5 via the triene 6, which
is generated in situ. Two sequential ring-closing metathesis (RCM)
reactions are exploited to elaborate the requisite 13- and eight-
membered rings leading to ircinal A (2).
In early investigations, we had established the underlying
viability of several key aspects of our strategy for the synthesis
of ircinal A (2).7 In particular, we had demonstrated that an
intramolecular [4 + 2] cycloaddition of a dienic vinylogous imide
related to 6 provided a facile entry to the ABC tricyclic core and
that an RCM reaction of an R,ω-diene could be implemented to
form the eight-membered E ring. However, the tetracyclic ABCE
subunit thus prepared was not ideally endowed for transformation
to 2, and a modification of the approach was conceived that would
provide a concise route to intermediates more readily amenable
for conversion to ircinal A.
Scheme 2
nitrogen that is suitable for eventual construction of the 13-
membered ring. Thus, the amino alcohol 7 was converted into
the protected amino aldehyde 8 in three steps (69% overall yield)
by a sequence that featured the acid-catalyzed conjugate addition
of a carbamate to acrolein.8 Wittig olefination of 8 gave 9 in 91%
yield together with small quantities (7%) of the E-isomer (Scheme
2). Removal of the nitrogen protecting group led to the tosylate
salt 10 (85%) as a stable crystalline solid.9
The chiral dienophilic precursor 12 was prepared in >95% yield
by a one-pot procedure involving the carboxylation and reduction
of the known imide 11,7a which was available in two steps (89%)
from commercially available (5S)-5-(hydroxymethyl)-2-pyrroli-
dinone (Scheme 3). Although the carboxylic acid derived from
12 could be prepared, it was unstable and suffered facile
decarboxylation, whereas the salt 12 could be stored without
noticeable decomposition. Sequential reaction of 12 with oxalyl
chloride (2.5 equiv) and then the free base of 10 in the presence
of triethylamine afforded 13 (79% overall yield), thereby setting
the stage for the critical domino Stille/Diels-Alder reaction. In
the event, reaction of 13 with vinyl tributylstannane in the
presence of Pd(0) afforded the triene 14 that spontaneously
cyclized via an intramolecular Diels-Alder reaction to give solely
15 in 68% overall yield. In this novel sequence, the single
stereocenter in 13 defines the absolute and relative stereochemistry
at the remaining centers in the ABC ring subunit of 2. Oxidation
of the allylic methylene group in 15 proved somewhat troublesome
and was best achieved by a modified Salmond protocol [CrO3
(20 equiv), 3,5-dimethylpyrazole (30 equiv), CH2Cl2, rt, 48 h]
that gave 16 in 63% yield (80% based upon recovered 15).10,11
The synthesis commenced with the preparation of the diene
precursor 10, which bears a functionalized alkyl substituent on
(1) For reviews, see: (a) Tsuda, M.; Kobayashi, J. Heterocycles 1997, 46,
765. (b) Matzanke, N.; Gregg, R.; Weinreb, S. Org. Prep. Proc. Intl. 1998,
30, 1. (c) Magnier, E.; Langlois, Y. Tetrahedron 1998, 54, 6201.
(2) (a) Sakai, R.; Higa, T.; Jefford, C. W.; Bernardinelli, G. J. Am. Chem.
Soc. 1986, 108, 6404. (b) Nakamura, H.; Deng, S.; Kobayashi, J.; Ohizumi,
Y.; Tomotake, Y.; Matsuzaki, T.; Hirata, Y. Tetrahedron Lett. 1987, 28, 621.
(3) Kondo, K; Shigemori, H.; Kikuchi, Y.; Ishibashi, M.; Sasaki, T.;
Kobayashi, J. Org. Chem. 1992, 57, 2480.
(4) (a) Baldwin, J. E.; Whitehead, R. C. Tetrahedron Lett. 1992, 33, 2059.
(b) Baldwin, J. E.; Claridge, T. D. W.; Culshaw, A. J.; Heupel, F. A.; Lee,
V.; Spring, D. R.; Whitehead, R. C.; Boughtflower, R. J.; Mutton, I. M.; Upton,
R. J. Angew. Chem., Int. Ed. 1998, 37, 2661.
(5) For selected recent studies, see: (a) Kamenecka, T.; Overman, L.
Tetrahedron 1994, 35, 4279. (b) Pandit, U.; Borer, B.; Bieraugel, H. S. Pure
Appl. Chem. 1996, 68, 659. (c) Torisawa, Y.; Hosaka, T.; Tanabe, K.; Suzuki,
N.; Motohashi, Y.; Hino, T.; Nakagawa, M. Tetrahedron 1996, 52, 10597.
(d) Magnier, E.; Langlois, Y. Tetrahedron Lett. 1998, 39, 837. (e) Baldwin,
J.; Bischoff, L.; Claridge, T.; Heupel, F.; Spring, D.; Whitehead, R.
Tetrahedron 1997, 53, 2271. (f) Brands, K.; DiMichele, L. Tetrahedron Lett.
1998, 39, 1677. (g) Li, S.; Kosemura, S.; Yamamura, S. Tetrahedron 1998,
54, 6661. (h) Li, S.; Yamamura, S. Tetrahedron 1998, 54, 8691.
(6) Winkler, J. D.; Axten, J. M. J. Am. Chem. Soc. 1998, 120, 6425.
(7) (a) Martin, S. F.; Liao, Y.; Wong, Y.; Rein, T. Tetrahedron Lett. 1994,
35, 691. (b) Martin, S. F.; Chen, H. J.; Courtney, A. K.; Liao, Y.; Pa¨tzel, M.;
Ramser, M. N.; Wagman, A. S. Tetrahedron 1996, 52, 7251.
(8) All new compounds were purified (>95%) by distillation, recrystalli-
zation, or preparative HPLC and were characterized by 1H and 13C NMR, IR,
and HRMS.
(9) Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 55, 870.
(10) Salmond, W. G.; Barta, M. A.; Havens, J. L. J. Org. Chem. 1978, 43,
2057.
10.1021/ja9829259 CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/15/1999

Communications to the Editor
J. Am. Chem. Soc., Vol. 121, No. 4, 1999 867
Scheme 3
Scheme 4
In the next phase of the synthesis, the tricyclic subunit 16 was
elaborated to set the stage for forming the 13- and eight-membered
rings by sequential RCM reactions,5b,7,12 and the sequence
commenced with the parallel refunctionalization of the two
protected primary alcohols (Scheme 4). Thus, deprotection of the
two hydroxyl groups in 16 (84%) followed by Swern oxidation13
of the intermediate alcohols furnished a dialdehyde (89%) that
underwent a double Wittig reaction under salt-free conditions14
to give 17 (63%). Global reduction of the carbonyl groups in 17
followed by oxidation of the two allylic alcohols thus produced
with Dess-Martin periodinane15 gave 18 in 53% overall yield.
Selective protection of the aldehyde function of 18 as a dimethyl
acetal (84%) followed by the stereoselective 1,2-addition of
4-butenyllithium16 to the R,â-unsaturated ketone array (Et2O/
pentane, -78 °C f -20 °C; 65%) gave 19 in which the tertiary
alcohol group is internally protected as a cyclic carbamate. When
the diene 19 was exposed to the Grubbs ruthenium catalyst 20
(0.005 M in CH2Cl2, 0.13 equiv 20, reflux, 3 h),17 a facile RCM
reaction ensued to furnish a mixture of geometric isomers (Z/E
) ca. 8:1) from which 21 was isolated in 67% yield. In contrast
to a previous observation in the literature, protonation of the
tertiary amine in 19 prior to the RCM was not necessary.18
Hydrolytic removal of the cyclic carbamate from 21 and N-
acylation gave 22 (75% overall yield), which was characterized
by X-ray crystallography. Although the 13-membered ring in 21
was readily formed by a RCM, the cyclization of the R,ω-diene
array of 22 to generate the eight-membered E ring via a RCM
was surprisingly problematic.7 Under the best conditions identified
thus far, we found that cyclization of 22 with the ruthenium
catalyst 20 (0.004 M in C6H6, 1.1 equiv 20, reflux, 30 min)
followed by an aqueous acid workup to hydrolyze the dimethyl
acetal moiety gave 23 in 26% yield.
Reduction of 23 with DIBAL-H gave ircinol A (63%),19 which
was oxidized to ircinal A (2) (89%). The synthetic ircinal A gave
a
1H NMR spectrum that was identical with that of natural
material, a 13C NMR spectrum that matched the published data,3
and a specific rotation that corresponded to previous reports
{[R]D ) +48° (c ) 0.07, CHCl3); lit.3 +48° (c ) 2.9, CHCl3);
lit.6 +46° (c ) 0.23, CHCl3)}. We did not have an authentic
sample of ircinal A; therefore, to further validate the identity of
synthetic 2, a small quantity was converted into 1, following the
published protocol of Kobayashi.3 The material thus obtained was
identical (TLC, HPLC, 1H NMR, HRMS) with a sample of natural
manzamine A.
Thus, we have completed the enantioselective syntheses of
ircinal A (2) and the related manzamine alkaloids ircinol A and
manzamine A (1). The synthesis of 2 required a total of 24
operations from commercially available starting materials, and
the longest linear sequence was 21 steps. This concise synthesis
of ircinal A highlights a novel strategy for assembling the tricyclic
ABC ring core by a domino Stille/Diels-Alder reaction, and it
also demonstrates the power and versatility of RCM reactions
for constructing 13- and eight-membered heterocyclic rings in
highly functionalized settings.
Acknowledgment. We thank the National Institutes of Health and
The Robert A. Welch Foundation for their generous support of this
research. We thank Professor C. W. Jefford (University of Geneva) and
J. Kobayashi (Hokkaido University) for generous samples of manzamine
(11) Use of equimolar ratios of chromium trioxide and dimethylpyrazole
gave imide side products. See: Blay, G.; Cardona, L.; Garcia, B.; Garcia, C.
L.; Pedro, J. R. Tetrahedron Lett. 1997, 38, 8257.
(12) For reviews, see: (a) Grubbs, R.; Miller, S.; Fu, G. Acc. Chem. Res.
1995, 28, 446. (b) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl.
1997, 36, 2036. (c) Armstrong, S. J. Chem. Soc., Perkin Trans. 1 1998, 371.
(d) Grubbs, R.; Chang, S. Tetrahedron 1998, 54, 4413.
(13) Tidwell, T. T. Synthesis 1990, 857.
(14) Sreekumar, C.; Darst, K. P.; Still, W. C. J. Org. Chem. 1980, 45,
4260.
(15) (a) Dess, D. B.; Martin, J. C. J. Org.Chem. 1983, 48, 4155. (b) Meyer,
S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549.
(16) Negishi, E., Swanson, D. R.; Rousset, C. J. J. Org.Chem. 1990, 55,
5406.
(17) Schwab, P.; Grubbs, R.; Ziller, J. J. Am. Chem. Soc. 1996, 118, 100.
(18) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993,
115, 9856.
1
A and Professor Kobayashi for a H NMR spectrum of ircinal A.
Supporting Information Available: Complete characterization (1H
and 13C NMR and IR spectra and mass spectral data) for all new
1
compounds, H NMR spectra of synthetic and natural 2, experimental
procedures for preparing 15, 19, 21-23, and 2, and X-ray data for 22
(PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
JA9829259
(19) Tsuda, M.; Kawasaki, N.; Kobayashi, J. Tetrahedron 1994, 50, 7957.