Stereoselective synthesis of dihydropyrone-containing marine natural products. Total synthesis and structural elucidation of (-)-membrenone-C.

Article abstract of DOI:10.1021/ol006835w

[figure: see text] Three diastereomers of membrenone-C were separately prepared using a common two directional chain extending synthetic strategy. This has established the absolute and relative configuration of the natural product to be as shown in the fo

Full text of DOI:10.1021/ol006835w

ORGANIC
LETTERS
2001
Vol. 3, No. 1
123-126
Stereoselective Synthesis of
Dihydropyrone-Containing Marine
Natural Products. Total Synthesis and
Structural Elucidation of
(−)-Membrenone-C
Michael V. Perkins* and Rebecca A. Sampson
School of Chemistry, Physics and Earth Sciences, The Flinders UniVersity of
South Australia, G.P.O. Box 2100, S.A. 5001, Australia
mike.perkins@flinders.edu.au
Received November 7, 2000
ABSTRACT
Three diastereomers of membrenone-C were separately prepared using a common two directional chain extending synthetic strategy. This
has established the absolute and relative configuration of the natural product to be as shown in the foregoing graphic. Key steps in the
synthesis of all the isomers are a stereoselective aldol coupling and reduction giving the C −C stereocenters, a two direction chain extending
7
9
double titanium aldol coupling, and the trifluoroacetic acid promoted double cyclization/dehydration giving the two dihydropyrone rings.
Membrenone-A, membrenone-B, and membrenone-C are
three γ-dihydropyrone containing polypropionates, isolated
from the skin of a Mediterranean mollusc by Ciavatta and
co-workers.1 In that paper the structures were assigned by
extensive NMR analysis, but the relative and absolute
configuration at C8, C9, and C10 was not assigned.
1H NMR spectroscopic analysis reported in the original
publication1 (H6-H7, J ) 13.7 Hz) suggested a pseudo trans
for membrenone-C (1-4) were possible (each a pair of
diaxial relationship (i.e., trans diequatorial alkyl substituents)
enantiomers).
for one γ-dihydropyrone ring in membrenone-C. The other
We recently reported a short, enantiocontrolled synthesis
dihydropyrone ring exhibited a small coupling (J9-10 ) 2.6
of isomer 4 of membrenone-C, exploiting a novel two
Hz) suggesting a cis orientation of the substituents at C9 and
C10. Thus, since the relative configuration from one dihy-
dropyrone ring to the other is uncertain, and the configuration
of the C8 methyl is unknown, four diastereomeric structures
(2) Perkins, M. V.; Sampson, R. A. Tetrahedron Lett. 1998, 39, 8367.
(3) (a) Paterson, I. Pure Appl. Chem. 1992, 64, 1821-30. (b) Paterson,
I.; Perkins, M. V. Tetrahedron Lett. 1992, 33, 801. (c) Paterson, I.; Channon,
J. A. Tetrahedron Lett. 1992, 33, 797. (d) Paterson, I.; Perkins, M. V.
Tetrahedron 1996, 52, 1811. (e) Paterson, I.; Norcross, R. D.; Ward, R.
A.; Romea, P.; Lister, M. A. J. Am. Chem. Soc. 1994, 116, 11287. (f)
Paterson, I.; Cumming, J. G.; Ward, R. A.; Lamboley, S. Tetrahedron 1995,
51, 9393. (g) Paterson, I.; Schlapbach, A. Synlett 1995, 498.
(1) Ciavatta, M. L.; Trivellone, E.; Villani, G.; Cimino, G. Tetrahedron
Lett. 1993, 34, 6791.
10.1021/ol006835w CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/16/2000

directional chain extending double titanium aldol coupling.2
We now report extension of this method to the synthesis of
the three possible remaining diastereoisomers of mem-
brenone-C (1-3), which establishes the relative and absolute
configuration of the natural product to be the enantiomer of
isomer 3.
Scheme 2
Scheme 1 outlines our general strategy for the synthesis
of isomers 1-3 of membrenone-C via 5 and 6, based on a
Scheme 1
obtained by precomplexation of (R)-9 with TiCl4 at -78 °C
for 30 min followed by addition of diisopropylethlyamine,
to chiral aldehyde (R)-10 at -90 °C gave the syn-syn aldol
isomer 11 with >95% ds. This selectivity is significantly
higher than that reported5 for the reaction of the Ti(IV)
enolate of (R)-9 with the achiral aldehyde methacrolein.
Reduction to the syn 1,3-diol 12 was achieved in a modifica-
tion of the procedure of Narasaka6 where the alcohol was
added to a (cC6H11)2BCl/Et3N mixture at -23 °C to form a
borinate complex, which was reduced with LiBH4 in 88%
yield and >95% ds. Protection of the diol as the di-tert-
butylsilylene7 gave the key intermediate 13. Thus the C5-
C11 segment 13 was obtained in 44.3% yield in three steps
from (R)-9 and (R)-10 with >90% ds, forming three new
stereocenters and resulting in a total of five contiguous
stereocenters.
The remainder of the synthesis is shown in Scheme 3.
double aldol-type disconnection of the C4-C5 and C11-C12
bonds. The sequence of five contiguous stereogenic centers
in 7 and 8, linking C6 and C10, were amenable to the general
protocol developed by Paterson3 for the synthesis of such
stereopentads.
Scheme 3
The synthesis of the required stereopentad for ent-3 is
shown in Scheme 2. Addition of the titanium enolate,4
(4) (a) Evans, D. A.; Clark, J. S.; Metternich, R.; Novak, V. J.; Sheppard,
G. S. J. Am. Chem. Soc. 1990, 112, 866. (b) Evans, D. A.; Urp´ı, F.; Somers,
T. C.; Clark, J. S.; Bilodeau, M. T. J. Am. Chem. Soc. 1990, 112, 8215. (c)
Evans, D. A.; Riegler, D. L.; Bilodeau, M. T.; Urpi, F. J. Am. Chem. Soc.
1991, 113, 1047.
(5) Paterson, I.; Tillyer, R. D. Tetrahedron Lett. 1992, 33, 4233.
(6) (a) Narasaka, K.; Pai, F.-C. Tetrahedron 1984, 40, 2233. (b) Paterson,
I.; Donghi, M.; Gerlach, K. Angew. Chem., Int. Ed. 2000, 39, 3315.
(7) (a) Trost, B. M.; Caldwell, C. G. Tetrahedron Lett. 1981, 22, 4999.
(b) Corey, E. J.; Hopkins, P. B. Tetrahedron Lett. 1982, 23, 4871. (c) Trost,
B. M.; Caldwell, C. G.; Murayama, E.; Heissler, D. J. Org. Chem. 1983,
48, 3252.
124
Org. Lett., Vol. 3, No. 1, 2001

Debenzylation (catalytic hydrogenolysis) of 13 and oxidation
(PCC) gave the dialdehyde 14. The two directional chain
extending double aldol was achieved by treating 14 with the
Ti(IV)4 enolate 15 of diethyl ketone. This gave predominantly
one isomer (>90% ds) 16 in 90% yield. This high selectivity
shows significant substrate control for this isomer of the
dialdehyde, which is not apparent in the reaction of any of
the other isomeric dialdehydes with the highly reactive
titanium enolates. The configuration of the four stereocenters
produced in the formation of 16 is tentatively assigned as
shown; however, they are not present in the final product
and are removed in the subsequent steps. Double Swern
oxidation of 16 gave a quantitative yield of the tetraone as
a mixture of C4 and C12 epimers (enol forms were also
evident from NMR studies). The protecting group was
removed by treatment with HF-pyridine, buffered with excess
pyridine, giving a mixture of diols and hemiacetals. Rapid
acid catalyzed cyclization/dehydration was achieved by
treatment with trfluoroacetic acid, giving a single product
ent-3 as a crystalline solid (mp 98-100 °C) after purifica-
tion.8
of these spectra confirms the relative configuration of the
natural product to be that shown for ent-3.9 The optical
rotation obtained for the synthetic material [R2D0] ) -28.2
(c 0.46, CHCl3) was somewhat lower than that reported for
the natural product [R20] ) -58.09 (c 0.1, CHCl3); how-
D
ever, the same signs of rotation confirms the assigned
absolute configuration of the natural product.10 Thus the total
synthesis of (-)-membrenone-C was achieved in eight steps
from (R)-9 and (R)-10 in an overall yield of 10.7%.
While we are confident the assigned configuration of the
natural product is correct, we have also synthesized the
remaining two possible isomers 1 and 2. The synthesis of
the isomer 1 is shown in Scheme 4.
Scheme 4
1
The H and 13C NMR reported1 for the natural product
and that obtained for ent-3 are shown in Table 1. Comparison
1
Table 1. Comparison of the H and 13C NMR Data for
Synthetic Isomer ent-3 and That Previously Reported1 for
(-)-Membrenone-C
(-)-membrenone-Ca
isomer ent-3b
3
3
C
δ
13Cc δ 1H, m, J (Hz)c
δ
13Cc
δ 1H, m, J (Hz)c
1
10.9 1.06, t, 7.6
25.16 2.35, m
172.5
108.4
194.51
39.93 2.51, dq, 13.7, 6.9
81.74 3.90, dd, 13.7, 2.1 80.93 3.89, dd, 13.8, 2.1
34.68 2.20, m
83.05 4.25, dd, 10, 2.6
10.92 1.06, t, 7.5
25.43d 2.36-2.22, m
172.48
108.65
194.57
Addition of methacrolein to the E-enol dicylohexylborinate
of ketone (S)-9 followed by in situ reduction of the
intermediate boron aldolate gave diol 17, which contains the
C7-C9 stereocenters required for isomer 1, with a diaste-
reoselectivity greater than 95%. Protection as the di-tert-
butylsilylene7 gave 18, which was selectively hydroborated
with BH3‚SMe2 (>95% ds)3b-d to give the key intermediate
19. This compound was converted to isomer 1 of mem-
brenone-C by the same debenzylation, double aldol, oxida-
tion, and deprotection/cyclization/dehydration sequence used
above.
2
3
4
5
6
7
8
9
39.91 2.51, dq, 13.8, 7.2
34.67 2.20, dqd, 10.2, 6.6, 2.1
81.69 4.24, dd, 10.2, 3.0
40.43 2.40, m
197.11
107.70
173.73
25.45d 2.46-2.32, m
10.82 1.17, t, 7.5
9.10 1.73, s
9.79 1.01, d, 7.2
9.26 1.19, d, 6.6
9.33 1.08, d, 7.2
9.11 1.70, s
10 40.25 2.40, m
11 197.41
12 107.48
13 173.81
14 25.16 2.40, m
15 10.8 1.17, t, 7.6
16
17
18
19
20
(8) The natural product was reported (ref 1) as an oil, presumably as a
result of the small amount isolated (3 mg).
9.11 1.74, s
1
(9) All of the signals in the H NMR spectrum match in chemical shift
9.77 1.02, d, 7.3
9.11 1.19, d, 6.8
9.33 1.09, d, 6.9
9.11 1.71, s
and coupling constants. All of the signals in the 13C NMR spectrum match
except for the signal reported (ref 1) at δ ) 81.74 ppm, which was found
to occur at δ ) 80.93 ppm, and the signal at δ ) 83.05 ppm, which was
found to occur at δ ) 81.69 ppm. We cannot explain this discrepancy, but
the identity of all of the other signal confirms the stereochemical assignment.
(10) Synthetic membrenone-B, having the same absolute configuration
a Chemical shifts and coupling constants as reported in ref 1 (Bruker
as ent-3, was found to have an optical rotation of [R2D0] ) -44 (c 0.68,
500 AMX). b Varian Unity Inova 600 MHz NMR Spectrometer. Assigments
assisted by H-13C HMBC, HSQC, and H-1H COSY. c Chemical shifts
in ppm referenced to CHCl3 at 7.26 ppm and to CDCl3 at 77.0 ppm.
d Tentative assignment and may be interchanged.
1
1
CHCl3) (Perkins, M. V.; Sampson, R. A. unpublished results) compared to
the reported (ref 1) [R20] ) -24.77 (c 0.2 CHCl3).
D
(11) Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J.
Am. Chem. Soc. 1990, 112, 7001.
Org. Lett., Vol. 3, No. 1, 2001
125

10 to give the syn-syn aldol product 20 in 70% yield and
>95% ds. Selective anti reduction11 gave 21 in 88% yield,
which was protected as the di-tert-butylsilylene7 to give the
key intermediate 22. The debenzylation, aldol, oxidation, and
deprotection/cyclization/dehydration sequence was again
employed giving isomer 2 of membrenone-C.
Scheme 5
1
Comparison of the H and 13C NMR reported1 for the
natural product and that obtained for isomers 1, 2, and 42
shows significant differences both in the 1H NMR chemical
shifts and coupling constants and in the 13C NMR chemical
shifts, further confirming the stereochemical assignment of
(-)-membrenone-C as that depicted in ent-3.
Acknowledgment. We thank the Australian Research
Council (Large ARC grant A00000585 to M.V.P.) and
Flinders University (Flinders University establishment grant
to M.V.P.) for support.
Supporting Information Available: Copies of NMR
spectra, experimental procedures and data for key com-
pounds. This material is available via the Internet at
http://pubs.acs.org
The synthesis of the isomer 2 is shown in Scheme 5. In
this case the Ti(IV)4 enolate of (S)-9 was treated with (R)-
OL006835W
126
Org. Lett., Vol. 3, No. 1, 2001