Total synthesis of (-)-(6S,7S,8S,9R,10S,2'S)-membrenone-A and (-)-(6S,7S,8S,9R,10S)- membrenone-B and structural assignment of membrenone-C.

Article abstract of DOI:10.1021/ol025674o

[reaction: see text] (-)-(6S,7S,8S,9R,10S,2'S)-Membrenone-A and (-)-(6S,7S,8S,9R,10S)-membrenone-B were prepared in 11 steps (3% and 2.4% overall yield, respectively). Key steps included a tin(II)-mediated aldol followed by a syn selective reduction, givi

Full text of DOI:10.1021/ol025674o

ORGANIC
LETTERS
2002
Vol. 4, No. 10
1655-1658
Total Synthesis of
(−)-(6S,7S,8S,9R,10S,2′S)-Membrenone-A
and (−)-(6S,7S,8S,9R,10S)-
Membrenone-B and Structural
Assignment of Membrenone-C
Rebecca A. Sampson and Michael V. Perkins*
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 February 5, 2002
ABSTRACT
(−)-(6S,7S,8S,9R,10S,2′S)-Membrenone-A and (−)-(6S,7S,8S,9R,10S)-membrenone-B were prepared in 11 steps (3% and 2.4% overall yield,
respectively). Key steps included a tin(II)-mediated aldol followed by a syn selective reduction, giving the C7−C9 stereocenters, a second
chain extending aldol coupling, and a p-TsOH-promoted cyclization/dehydration giving the common γ-dihydropyrone precursor. We have thus
established that synthetic (−)-(6S,7S,8S,9R,10S,2′S)-membrenone-A, (−)-(6S,7S,8S,9R,10S)-membrenone-B, and (−)-(6S,7S,8S,9R,10S)-mem-
brenone-C are the enantiomers of the natural products.
Membrenone-A, membrenone-B, and membrenone-C are
three structurally related γ-dihydropyrone-containing poly-
propionates, 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.
on the sign of the reported1 optical rotation, which we now
believe is incorrect.
Assuming a common biosynthesis, membrenone-A and -B
are proposed to have the same absolute configuration as
structurally related membrenone-C.
We recently reported a short, enantiocontrolled synthesis
of (-)-(6S,7S,8S,9R,10S)-membrenone-C 1, exploiting a
novel two directional chain extending double titanium aldol
coupling.2 In that paper we correctly assigned the relative
configuration of membrenone-C but incorrectly assigned (-)-
(6S,7S,8S,9R,10S)-membrenone-C 1 as the absolute config-
uration of the natural product. This assignment2 was based
We now report the first total synthesis of (-)-(6S,7S,
8S,9R,10S,2′S)-membrenone-A 2 and (-)-(6S,7S,8S,9R,10S)-
membrenone-B 3 and revise the assignment2 of the structure
(1) Ciavatta, M. L.; Trivellone, E.; Villani, G.; Cimino, G. Tetrahedron
Lett. 1993, 34, 6791.
(2) Perkins, M. V.; Sampson, R. A. Org. Lett. 2001, 3, 123.
10.1021/ol025674o CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/19/2002

of (-)-(6S,7S,8S,9R,10S)-membrenone-C 1 to be the enan-
tiomer of the natural product.
Scheme 2
Scheme 1 outlines our general strategy for the synthe-
sis of (-)-(6S,7S,8S,9R,10S,2′S)-membrenone-A and (-)-
Scheme 1
ether in the presence of the benzyl ether protecting group
was achieved using DDQ7 to give the known primary alcohol
13.3g The C5-C11 segment 13 was obtained in 23.2% yield
in four steps from (R)-9 and (R)-10.
The chain extending aldol and debenzylation is shown in
Scheme 3. Oxidation (PCC) of 13 gave the aldehyde 7, which
(6S,7S,8S,9R,10S)-membrenone-B based on the common
γ-dihydropyrone intermediate 4, where acylation using the
appropriate acid equivalent would give access to either (-)-
(6S,7S,8S,9R,10S,2′S)-membrenone-A 2 or (-)-(6S,7S,8S,
9R,10S)-membrenone-B 3. The γ-dihydropyrone 4 was
envisaged to result from the deprotection and subsequent
cyclization of trione 5. The construction of the trione was
based on a disconnection between the C11-C12 bond via a
Grignard addition to aldehyde 6 followed by oxidation of
the resulting secondary alcohol. Formation of 6 is by an aldol
disconnection of the C4-C5 bond leaving aldehyde 7.
Aldehyde 7 is available from the differentially protected diol
8. The sequence of five contiguous stereogenic centers, C6
to C10 in 8, was amenable to the general protocol developed
by Paterson3 for the synthesis of such stereopentads.
Scheme 3
The synthesis of the required stereopentad for 4 is shown
in Scheme 2. The tin enolate4 was prepared by precomplex-
ation of Sn(OTf)2 and Et3N at -50 °C for 10 min followed
by the addition of ketone (R)-9 at -60 to -70 °C and stirring
for 2 h. Subsequent addition of the chiral aldehyde (R)-10
at -78 °C gave the syn-syn aldol product 11 with >95%
ds. Reduction to the syn 1,3-diol 8 (containing five contigu-
ous stereocenters) was achieved in 80% ds using DIBAL.5
Protection of the diol as the di-tert-butylsilylene6 gave a
mixture of 12 and the primary alcohol 13 resulting from
partial hydrolysis of the PMB-ether. Removal of the PMB-
(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.
(4) Paterson, I.; Tillyer, R. D. Tetrahedron Lett. 1992, 33, 4233.
(5) Kiyooka, S.; Kuroda, H.; Shimasaki, Y. Tetrahedron Lett. 1986, 27,
3009.
was used immediately in the subsequent aldol employing
the Ti(IV)8 enolate 14 of diethyl ketone. This reaction gave
predominantly one isomer (>95% ds) 15 in 89% yield. This
(6) (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.
1656
Org. Lett., Vol. 4, No. 10, 2002

high selectivity shows significant substrate control for the
aldehyde 7. Although the new C4-C5 stereocenters produced
in the formation of 15 are not present in the final product,
the configuration of these two stereocenters was determined
by treatment with HF-pyridine and subsequent cyclization
to give the thermodynamically favorable hemiacetal 16.
Evidence for the structure of hemiacetal 16 was provided
by NMR analysis. A NOE correlation between H5 and H7
confirmed the stereochemistry, thus revealing unexpected
Felkin selectivity of aldehyde 7 to give the 6,5-syn-5,4-syn-
aldol adduct 15. The terminal benzyl ether was removed from
15 by catalytic hydrogenolysis to give the diol 17 for
continuation of the synthesis.
Because of low yields from the PCC oxidation of 17 and
the subsequent chemoselective addition of EtMgBr (23.5%
over two steps), an alternative pathway was attempted. Swern
oxidation of 17 gave an assumed quantitative yield of the
aldehyde-dione 6 as a 1:1 C4 epimeric mixutre. A chemo-
selective Grignard addition to the aldehydic carbonyl group
of 6 in the presence of the C3 and C5 ketones gave a 3:2
mixture of epimeric alcohols 20 (83% yield over two steps)
with >95% ds for the new C11 stereocenter. The high
diastereoselectivity for this reaction is again testament to the
intrinsic π-facial selectivity of the aldehyde 6. It appears the
addition of excess Grignard reagent to the aldehyde 6 in the
presence of a â-diketone moiety results in proton abstraction
to give a resonance stabilized anion. This protects the
â-diketone from addition of the organometallic reagent at
room temperature, allowing complete addition of EtMgBr
to the aldehyde. Finally, oxidation of both 19 and 20 under
Swern conditions gave the protected trione 5 as a 3:2 mixture
of C5 epimers.
In the initial synthesis of (-)-(6S,7S,8S,9R,10S)-mem-
brenone-B 3, selective oxidation of the primary C11 alcohol
of diol 17 (while preserving the secondary C5 alcohol) was
achieved employing PCC to give the unstable aldehyde 18
in modest yield (Scheme 4). The immediate chemoselective
The synthesis of(-)-(6S,7S,8S,9R,10S)-membrenone-B 3
is shown in Scheme 5. Removal of the di-tert-butylsilylene
Scheme 4
Scheme 5
protecting group from 5 by treatment with HF-pyridine,
buffered with excess pyridine, gave a complex mixture of
compounds. However, acid catalysis (p-TsOH) assisted the
cyclization/dehydration, giving a 1:1 mixture of two products,
21 and 4. Thus formation of the γ-dihydropyrone ring was
less efficient than we previously found in the two directional
example,2 as the neighboring â-hydroxyketone moiety was
sensitive to the acidic conditions necessary for this conver-
sion.
addition of EtMgBr9 to the C11 aldehydic carbonyl group in
18 was attempted at -100 °C to minimize the addition of
the Grignard reagent to the C3 ketone. Quenching at -50
°C with MeOH/NH4Cl produced a single alcohol product
19 in >95% ds; however, the configuration of the C11
stereocenter remains uncertain. Controlling the temperature
of this addition reaction was critical, and substantial amounts
of a double addition product were observed when the mixture
was allowed to warm to above -50 °C before quenching.
However, the two products 21 and 4 were separable, and
acylation of the hydroxyl group of dihydropyrone 4 with
propionyl chloride in the presence of pyridine gave a
crystalline solid (76% yield, mp 63-65 °C) after purification.
The 1H and 13C NMR spectra were identical to that reported1
for membrenone-B, confirming the relative configuration of
the natural product to be that shown in 3. Thus the total
synthesis of (-)-(6S,7S,8S,9R,10S)-membrenone-B 3 was
achieved in 2.4% yield over 11 steps.
(7) (a) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885. (b) Horita, H.; Yoshioka, T.; Tanaka, T.; Oikawa, Y. Tetrahedron
1986, 42, 3021.
(8) (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.; Urp´ı, F. J. Am. Chem. Soc.
1991, 113, 1047.
Scheme 6 outlines the preparation of (-)-(6S,7S,8S,9R,
10S,2′S)-membrenone-A. Acylation of 4 using a modified
(9) Paterson, I.; Perkins, M. V. Tetrahedron 1996, 52, 1811.
Org. Lett., Vol. 4, No. 10, 2002
1657

CHCl3) and CD curve: [θ]300 +6613 (max), [θ]267 -15438
(max). Notably the optical rotation and CD curve are of the
same sign as that observed for synthetic (-)-(6S,7S,8S,9R,
10S,2′S)-membrenone-A 2 with the same configuration of
the C6-C10 stereopentad. The reported rotation1 for the
natural membrenone-B was [R]2D0 ) -24.77° (c 0.2, CHCl3),
but this is not consistent (being of the opposite sign to natural
membrenone-A) with the nearly identical CD curves11
reported for membrenone-A and -B. Thus it appears that the
sign of the rotation for membrenone-B was misreported,1,12
and natural membrenone-B should have a positive rotation,
the same sign as that reported for membrenone-A. Similarly
it appears that the sign of rotation for membrenone-C was
reported incorrectly1 (assuming all three natural products
have the same absolute configuration). Thus we now believe
our previous assignment2,13 of the absolute configuration of
natural membrenone-C (based on the reported1 negative
rotation) was incorrect. The absolute and relative configu-
ration of the natural membrenones is summarized below.
Scheme 6
Yonemitsu-Yamaguchi esterification procedure10 with (S)-
(+)-2-methylbutyric acid gave a product (92%) whose H
1
and 13C NMR data were identical to that reported for (-)-
(6S,7S,8S,9R,10S,2′S)-membrenone-A (3% over 11 steps).
The acylation of 4 was also performed using racemic
2-methylbutyric acid to give an inseparable 1:1 mixture of
2 and 22. NMR analysis of the mixture showed 2 and 22
were similar; however, a distinct chemical shift difference
in the 1H NMR was observed for the 5′ methyl group doublet
for the C2′ epimers. The 5′ methyl for 22 (C2′ ) R
configuration) occurred at δ ) 1.142 ppm, and the 5′ methyl
for 2 (C2′ ) S configuration) occurred at δ ) 1.132 ppm in
direct agreement with that reported for the natural product.1
Thus it can be concluded that the relative configuration of
natural membrenone-A is that shown in 2. In the original
isolation the authors determined the absolute configuration
of the acyl residue of (+)-membrenone-A to be of the
R-configuration. However, we have just shown acylation of
4 using (S)-(+)-2-methylbutyric acid gives a product with
1H and 13C NMR data identical to those reported1 for the
natural membrenone-A. The optical rotation obtained for the
synthetic material was [R]2D0 ) -23.7° (c 0.51, CHCl3),
which is of the same magnitude as the natural product
([R]2D0 ) +24.72° (c 0.05, CHCl3)),1 but of the opposite
sign. Furthermore the CD curve: [θ]300 +5661 (max), [θ]260
-10654 (max) of the synthetic material is opposite in sign
to that reported1 for the natural product. These three pieces
of information show that 2 is the enantiomer of the natural
product, (+)-membrenone-A.
Acknowledgment. We thank the Australian Research
Council (Large ARC grant A00000585 to M.V.P.) for
support. Thanks also to Mr. Paul Gugger (Research School
of Chemistry, Australian National University) for performing
the CD spectral analysis.
Supporting Information Available: Copies of NMR
spectra, experimental procedures, and data for key com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL025674O
(11) Membrenone-A and -B were reported (ref 1) to have opposite signs
of rotation but had almost identical CD curves. Reported values were
membrenone-A [R]2D0 ) +24.72° (c 0.05, CHCl3), CD curve [θ]300 -2278
(max), [θ]270 +6126 (max); membrenone-B [R]2D0 ) -24.77° (c 0.2,
CHCl3), CD curve [θ]302 -2354 (max), [θ]269 +6230 (max); membrenone-C
[R]2D0 ) -58.09° (c 0.1, CHCl3), CD curve [θ]318 -166 (max), [θ]270
+2023 (max).
We now consider synthetic (-)-(6S,7S,8S,9R,10S)-mem-
brenone-B 3 with optical rotation [R]2D0 ) -44.4° (c 0.68
(12) Authentic samples of the membrenones were not available for direct
comparison of the [R]2D0 and CD curve.
(10) (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989. (b) Hikotam, M.; Sakurai, Y.; Horita,
K.; Yonemitsu, O. Tetrahedron 1990, 31, 6367.
(13) Synthetic (-)-ent-membrenone-C was observed to have [R]D20
)
-28.2 (c 0.46, CHCl3) and CD curve [θ]322 +5550 (max), [θ]263 -16232
(max).
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Org. Lett., Vol. 4, No. 10, 2002