Biomimetic synthesis of (-)-Xestospongin A, (+)-Xestospongin C, (+)- Araguspongine B and the correction of their absolute configurations [22]

Full text of DOI:10.1021/ja980765v

J. Am. Chem. Soc. 1998, 120, 8559-8560
8559
derived from bis-hydroxypyridinium dimer 2. The occurrence
of macrocyclic and polymeric 3-alkylpyridinium compounds
among marine sponges6 supports this proposal. In fact the
hypothesis suggesting bis-3-alkyldihydropyridine dimers as bio-
synthetic precursors for marine alkaloids has been previously
proposed by Baldwin.7 The proposed dimeric biosynthetic
intermediate 2 could be prepared from monomer 8 which is the
cornerstone and the initial target of our synthesis.
Biomimetic Synthesis of (-)-Xestospongin A,
(+)-Xestospongin C, (+)-Araguspongine B and the
Correction of Their Absolute Configurations
Jack E. Baldwin,* Artem Melman, Victor Lee,
Catherine R. Firkin, and Roger C. Whitehead
The Dyson Perrins Laboratory, UniVersity of Oxford
Thus Weiler alkylation of ethyl acetoacetate with 1-bromo-4-
chlorobutane8,9 gave ethyl 8-chloro-3-oxooctanoate (3, 78%).
Noyori hydrogenation of 3 with [Ru(II)-S-BINAP]10 provided
hydroxy ester 4 (96% yield, ee 96% as determined by 19F NMR
analysis of its Mosher ester11). Reduction of 4 by lithium
borohydride afforded diol 5 (84%) which was converted into its
acetonide derivative 6 (94%) by pyridinium tosylate/2,2-
dimethoxypropane/acetone. Reaction of 6 with sodium iodide
in refluxing acetone gave iodide 7 (98%). Treatment of 7 with
lithiated 3-picoline,12 generated from 3-picoline and LDA,
provided pyridine 8 (72%). Diol 9 was obtained (94%) by
removal of acetonide with dilute hydrochloric acid in ethanol.
Selective tosylation of 9 afforded monotosylate 10 (88%). Slow
addition of a solution of 10 in butan-2-one to a refluxing solution
of sodium iodide in the same solvent gave a mixture of products,
containing dimer 2. Reduction of this mixture with lithium
borohydride gave the tetrahydropyridine dimer 11 (34%) after
chromatographic separation. The 1H NMR of 11 revealed a small
amount of its ∆-4,5 double bond isomer (ca. 5%) was present.
Reaction of 11 with diethyl azodicarboxylate (DEAD)13 gave
dehydro-bis-oxaquinolizidine 12 (53%), presumably via an imi-
nium ion intermediate. X-ray diffraction studies revealed the
trans-ring junctions in crystalline 12.14 Hydrogenation of 12 with
Raney nickel in methanol surprisingly delivered Araguspongine
B (13)2,15,16 as the major product (77%) and a small amount of
Xestospongin C (14)1 (7%). Hydrogenation of 12 with rhodium
on alumina in methanol followed by refluxing the reaction mixture
with a small amount of alumina16 gave Xestospongin A (1, 23%),
Xestospongin C (14, 17%), and Araguspongine B (13, 9.5%) after
HPLC separation (Scheme 1).
South Parks Road, Oxford, OX1 3QY, U.K.
ReceiVed March 9, 1998
(+)-Xestospongin A (1) is one of the four bis-oxaquinolizidine
alkaloids first isolated from the Australian sponge Xestospongia
exigua by Nakagawa et al.1 in 1984. Subsequently in 1989,
Kitagawa et al.2 reported the isolation of nine bis-oxaquinolizidine
alkaloids (Araguspongines A-J) from a marine sponge Xesto-
spongia sp. found in the Okinawa region. Interestingly, it was
found that Araguspongine D is a 3:7 mixture of (+)- and (-)-
Xestospongin A. In all previous publications,2-5 the absolute
configuration of (+)-Xestospongin A is depicted as (2S,9S,-
9aR,2′S,9′S,9a′R). Throughout this paper we shall refer to
Kitagawa’s proposed structure of (+)-Xestospongin A as 1.
The intriguing structure of (+)-Xestospongin A and its
vasodilatory properties have encouraged a number of studies
directed toward its synthesis.3 To date only one total synthesis
of (+)-Xestospongin A and its enantiomer has been reported.4,5
Herein we disclose the synthesis of 1 and other related alkaloids
based on a biosynthetic hypothesis along with the surprising
results which lead to the correction of their absolute configura-
tions. Biosynthetically, 1 and other related alkaloids [including
Araguspongine B (13)2,15,16 and Xestospongin C (14)1] can be
The identities of the synthetic 13, 1, and 14 were established
by comparison with the published 1H and 13C NMR data2,5,16 and
confirmed by doping experiments with the authentic samples.
Surprisingly 13, which was described by Kitagawa2 and Koba-
yashi16 as (-)-Araguspongine B, possessed a specific rotation
value of [R]23D +10.7. Interestingly, the observed specific rotation
value of our synthetic 1 is [R]23 -9.5 {lit. value5 of (+)-
D
23
Xestospongin A [R]RT +8.9} and that of synthetic 14 is [R]D
D
+1.6 {lit. value5 of (-)-Xestospongin C [R]D -1.2}, i.e., the
RT
(1) Nakagawa, M.; Endo, M.; Tanaka, N.; Lee, G.-P. Tetrahedron Lett.
1984, 25, 3227-3230.
(2) Kobayashi, M.; Kawazoe, K.; Kitagawa, I. Chem. Pharm. Bull. 1989,
37, 1676-1678.
specific rotations of both 1 and 14 are opposite to their expected
values. These results differ significantly from those of Hoye4,5
and Kitagawa.2,17 We are certain about the stereochemistries of
13, 1, and 14 because their precursors 9 and 10 were also
(3) (a) Hoye, T. R.; North, J. T. Tetrahedron Lett. 1990, 31, 4281-4284.
(b) Ahn, K. H.; Lee, S. J. Tetrahedron Lett. 1992, 33, 507-510. (c) Bo¨rjesson,
L.; Welch, C. J. Tetrahedron 1992, 48, 6325-6334. (d) Bentley, N.; Singh,
G.; Howarth, O. W. Tetrahedron 1993, 49, 4315-4320. (e) Bo¨rjesson, L.;
Cso¨regh, I.; Welch, C. J. J. Org. Chem. 1995, 60, 2989-2999.
(4) Hoye, T. R.; North, J. T.; Yao, L. J. J. Am. Chem. Soc. 1994, 116,
2617-2618.
(13) Smissman, E. E.; Makriyannis, A. J. Org. Chem. 1973, 38, 1652-
1657.
(14) Crystal structure data for 12: C28H46O2N2, monoclinic, P21, a ) 8.62-
(1) Å, b ) 9.88(1) Å, c ) 15.31(1) Å, â ) 96.33(1)°, Z ) 2, R ) 0.0311,
GOF ) 1.0308.
(5) Hoye, T. R.; Ye, Z.; Yao, L. J.; North, J. T. J. Am. Chem. Soc. 1996,
118, 12074-12081.
(15) (a) Hoye, T. R.; North, J. T.; Yao, L. J.; J. Org. Chem. 1994, 59,
6904-6910. (b) Hoye, T. R.; North, J. T.; Yao, L. J. J. Org. Chem. 1995, 60,
4958.
(6) For example, see: Sepcic, K.; Guella, G.; Mancini, I.; Pietra, F.; Dalla
Serra, M.; Menestrina, G.; Tubbs, K.; Macek, P.; Turk, T. J. Nat. Prod. 1997,
60, 991-996 and references therein.
(16) Kobayashi, M.; Miyamoto, Y.; Aoki, S.; Murakami, N.; Kitagawa, I.;
In, Y.; Ishida, T. Heterocycles 1998, 47, 195-203.
(17) The absolute stereochemistry of (-)-Araguspongine D [enantiomer
of (+)-Xestospongin A] was assigned by chemical correlation with a C2
symmetrical diol obtained from the degradation of (-)-Araguspongine J.
However, the complication arising from the desymmetrization of the diol was
not addressed, see ref 2 for details.
(18) Firkin, C. R. D. Phil. Thesis, University of Oxford, 1997.
(19) The authors concluded that the absolute configurations of Aragu-
spongine F, G, H, and J were similar to that of (-)-Araguspongine D, see ref
2 for details.
(7) Baldwin, J. E.; Whitehead, R. C. Tetrahedron Lett. 1992, 33, 2059-
2062.
(8) Huckin, S. N.; Weiler, L. J. Am. Chem. Soc. 1974, 96, 1082-1087.
(9) Lambert, P. H.; Vaultier, M.; Carrie´, R. J. Org. Chem. 1985, 50, 5352-
5356.
(10) (a) Kitamura, M.; Tokunaga, M.; Ohkuma, T.; Noyori, R. Tetrahedron
Lett. 1991, 32, 4163-4166. (b) Kitamura, M.; Tokunaga, M.; Ohkuma, T.;
Noyori, R. Org. Synth. 1993, 71, 1-13.
(11) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512-519.
(12) Kaiser, E. M.; Petty, J. D. Synthesis 1975, 705-706.
S0002-7863(98)00765-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/11/1998

8560 J. Am. Chem. Soc., Vol. 120, No. 33, 1998
Communications to the Editor
Scheme 1a
Chart 1. Revised Structures of (+)-Xestospongin A,
(-)-Xestospongin C, and (-)-Araguspongine B
imply that the absolute stereochemistries of other Araguspongine
alkaloids (Araguspongines F, G, H, and J)2,19 may need to be
reexamined and, finally, it is likely that the intermediate 12 is an
as yet undiscovered sponge alkaloid.
n
a Key: (a) i. NaH, THF; ii. BuLi; iii. Br(CH2)4Cl, 78%; (b) Ru(II)-
Acknowledgment. We are indebted to Prof. Motomasa Kobayashi,
Faculty of Pharmaceutical Sciences, Osaka University, for supplying us
a preprint of his publication and gifts of Araguspongine B and Aragu-
spongine E (Xestospongin C). We thank Professor Thomas Hoye,
Department of Chemistry, University of Minnesota, for a sample of
Xestospongin A. We are grateful to Mr. Mike Leech, Chemical Crystal-
lography Laboratory, University of Oxford, for X-ray diffraction studies
and to Dr. Tim Claridge and Mrs. Elizabeth McGuiness for NMR studies.
We also thank The British Council for a fellowship (to A.M.) and the
EPSRC for a studentship (to C.R.F.).
S-BINAP, H2, EtOH, 96%; (c) LiBH4, Et2O, 84%; (d) PPTS, 2,2-
dimethoxypropane, acetone, 94%; (e) NaI, acetone, reflux, 98%; (f)
3-picoline, LDA, THF, 72%; (g) HCl(aq), EtOH, 94%; (h) TsCl, Et3N,
i
CH2Cl2, 88%; (i) NaI, butan-2-one, reflux; (j) LiBH4, MeOH, PrOH,
34%, over 2 steps; (k) DEAD, CH2Cl2, 53%; (l) Raney Ni, H2, MeOH,
77% for 13 and 7% for 14; (m) Rh on alumina, MeOH, H2, then add
alumina, reflux and HPLC, 23% for 1, 17% for 14, 9.5% for 13.
previously prepared from (S)-aspartic acid.18 It is beyond doubt
that synthetic 13, 1, and 14 are (+)-Araguspongine B, (-)-
Xestospongin A, and (+)-Xestospongin C, respectively.
In conclusion we have demonstrated the validity of our
proposed biosynthetic theory. In addition our results unambigu-
ously establish the correct absolute configurations of (+)-
Xestospongin A as (2R,9R,9aS,2′R,9′R,9a′S), of (-)-Xestospongin
C as (2R,9S,9aS,2′R,9′R,9a′S), and of (-)-Araguspongine B as
(2R,9S,9aS,2′R,9′S,9a′S) (Chart 1). Furthermore, our results also
Supporting Information Available: Detailed experimental proce-
dures for the preparation of all new compounds, X-ray structural
information on 12, and the schematic summary of the alternative synthesis
of 9 and 10 from (S)-aspartic acid (15 pages, print/PDF). An X-ray
crystallographic file, in CIF format, is available via the Web only. See
any current masthead page for ordering information and Web access
instructions.
JA980765V