Synthesis of (±)-vibralactone

Article abstract of DOI:10.1021/ol800118c

(Chemical Equation Presented) Reductive alkylation of methyl 2-methoxybenzoate with prenyl bromide and hydrolysis afforded methyl 6-oxo-1-prenyl-2-cyclohexenecarboxylate. Reduction of the ketone, hydrolysis, iodolactonization, ozonolysis, and intramolecular aldol reaction provided a spiro lactone cyclopentenal. Retro-iodolactonization with activated Zn, formation of the β-lactone, and reduction of the aldehyde completed an efficient first synthesis of (±)-vibralactone. No protecting groups were used except for the novel use of an iodolactone to protect both the prenyl double bond and carboxylic acid.

Full text of DOI:10.1021/ol800118c

ORGANIC
LETTERS
2008
Vol. 10, No. 7
1401-1404
Synthesis of (±)-Vibralactone
Quan Zhou and Barry B. Snider*
Department of Chemistry MS 015, Brandeis UniVersity,
Waltham, Massachusetts 02454-9110
snider@brandeis.edu
Received January 17, 2008
ABSTRACT
Reductive alkylation of methyl 2-methoxybenzoate with prenyl bromide and hydrolysis afforded methyl 6-oxo-1-prenyl-2-cyclohexenecarboxylate.
Reduction of the ketone, hydrolysis, iodolactonization, ozonolysis, and intramolecular aldol reaction provided a spiro lactone cyclopentenal.
Retro-iodolactonization with activated Zn, formation of the
)-vibralactone. No protecting groups were used except for the novel use of an iodolactone to protect both the prenyl double bond and
carboxylic acid.
â-lactone, and reduction of the aldehyde completed an efficient first synthesis of
(
±
Liu and co-workers recently reported the isolation of the
unusual fused â-lactone vibralactone (1) from cultures of
the Basidiomycete Boreostereum Vibrans (see Scheme 1).1
The structure was assigned by detailed spectroscopic analysis,
and the absolute stereochemistry was assigned by compu-
tational methods. Vibralactone inhibits pancreatic lipase with
an IC50 of 0.4 µg/mL. The pancreatic lipase inhibitor
percyquinnin, which was originally assigned as a regioisomer
of 1,2 has the same planar structure as vibralactone (1).1
Pancreatic lipase inhibitors are clinically used for the
treatment of obesity, and improved drugs are needed.3 This
prompted us to undertake the synthesis of vibralactone (1),
a new lead structure that should be readily amenable to
analogue synthesis.
The instability of the â-lactone ring and the functional
group density makes the synthesis of vibralactone a chal-
lenging problem despite its small size. We envisioned that
the â-lactone ring of vibralactone (1) could be prepared from
cis hydroxy acid 2 by activation of the acid group followed
by â-lactonization with retention of stereochemistry.4 Al-
ternatively, vibralactone should be accessible from trans
hydroxy acid 3 by conversion of the alcohol to a good leaving
group and â-lactonization by an SN2 reaction with inversion.
This less common approach to â-lactone formation has
recently been improved by Wu and Sun.5 The cyclopentenal
moiety of 2 and 3 should be readily available by oxidative
cleavage of the cyclohexene double bond of 5 and 6,
respectively, followed by an intramolecular aldol reaction.
Unfortunately, the cyclohexene double bond cannot be
oxidatively cleaved in the presence of the more nucleophilic
side chain double bond. This necessitated the protection of
the side chain double bond of 5 or 6, which might be
accomplished by formation of iodolactone 7.6 However,
iodolactonization could occur at either double bond of 5 or
6. Even if iodolactonization occurs selectively as expected
and required at the more nucleophilic side chain double bond,
stereoisomeric mixtures of γ- and δ-lactones could be formed
that would complicate product analysis. Furthermore, it was
by no means certain that oxidative cleavage of the double
(4) For reviews on â-lactones, see: (a) Pommier, A.; Pons, J.-M.
Synthesis 1993, 441-459. (b) Pommier, A.; Pons J.-M. Synthesis 1995,
729-744. (c) Lowe, C.; Vederas, J. C. Org. Prep. Proced. Int. 1995, 27,
305-346. (d) Yang, H. W.; Romo, D. Tetrahedron 1999, 55, 6403-6434.
(e) Wang, Y.; Tennyson, R. L.; Romo, D. Heterocycles 2004, 64, 605-
658.
(5) (a) Wu, Y.; Sun, Y.-P. Chem. Commun. 2005, 1906-1908. (b) Sun,
Y.-P.; Wu, Y. Synlett 2005, 1477-1479. (c) Wu, Y.; Sun, Y.-P. J. Org.
Chem. 2006, 71, 5748-5751.
(6) For a review, see: Dowle, M. D.; Davies, D. I. Chem. Soc. ReV.
1979, 8, 171-197.
(1) Liu, D.-Z.; Wang, F.; Liao, T.-G.; Tang, J.-G.; Steglich, W.; Zhu,
H.-J.; Liu, J.-K. Org. Lett. 2006, 8, 5749-5752.
(2) Hoppmann, C.; Kurz, M.; Mu¨ller, G.; Toti, L. Eur. Pat. Appl. 2001,
1142886; Chem. Abstr. 2001, 287595.
(3) Birari, R. H.; Bhutani, K. K. Drug Disc. Today 2007, 12, 879-889
and references cited therein.
10.1021/ol800118c CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/01/2008

Scheme 1. Retrosynthesis of (()-Vibralactone (1)
Scheme 2. Synthesis of Model â-Lactone 14
bond and intramolecular aldol reaction to give cyclopentenal
4 could be accomplished in the presence of a reactive tertiary
iodide. Retro-iodolactonization by zinc reduction of 4 would
regenerate 2 or 3 with both the side chain double bond and
the free acid needed for lactonization.
Alcohols 5 and 6 should be accessible by the diastereo-
selective reduction of ketone 9, which surprisingly proved
to be the most challenging step in the synthesis. Ketone 9
can be easily prepared by reductive alkylation7 of methyl
2-methoxybenzoate (8) with prenyl bromide followed by
acidic hydrolysis of the methyl enol ether.
Reduction of 8 with K in liquid NH3 at -78 °C, addition
of LiI and prenyl bromide, and slow warming to 25 °C
afforded the alkylated cyclohexadiene 10 in 77% yield (see
Scheme 2).7 Hydrolysis of the enol ether with methanolic
HCl gave ketone 9 in 84% yield. Reduction of 9 with NaBH4
in MeOH cleanly provided a 2:1 mixture of trans hydroxy
ester 6 and cis hydroxy ester 5.8,9 Magnus reported similar
ratios of products from the NaBH4 reduction of a related
keto amide and also found that Zn(BH4)2 gave the trans
hydroxy amide with >99:1 selectivity.10 Reduction of 9 with
Zn(BH4)2 in ether11 afforded trans hydroxy ester 6 in 69%
yield. Reduction with CaCl2 and NaBH4, which selectively
provides trans hydroxy esters from 1-alkyl-2-oxocyclohex-
anone carboxylates,12 gave a 7.5:1 mixture of 6 and 5, from
which 6 was isolated in 69% yield.
We chose to carry out a model study exploring lactone
formation with inversion by hydroxy group activation using
the now readily available trans hydroxy ester 6. Hydrolysis
of the methyl ester with KOH in MeOH at 60 °C provided
the required trans hydroxy acid. In their studies with acyclic
â-hydroxy acids, Wu and Sun needed to activate the alcohol
without activating the carboyxlic acid because lactonization
by acid activation will give the other stereoisomer.5 Trans
hydroxy acid 11 would form a highly strained trans-fused
â-lactone by reaction of the alcohol with an activated acyl
group. Therefore there is no need to selectively activate the
alcohol. Treatment of 11 with MsCl and Et3N in CH2Cl2
(7) (a) Hook, J. M.; Mander, L. N.; Woolias, M. Tetrahedron Lett. 1982,
23, 1095-1098. (b) Schultz, A. G.; Dittami, J. P.; Lavieri, F. P.; Salowey,
C.; Sundararaman, P.; Szymula, M. B. J. Org. Chem. 1984, 49, 4429-
4440.
(8) The stereochemistry of alcohols 5 and 6 was established by an IR
study in dilute (0.1 M) CCl4 solution and a 1D NOESY experiment. Trans
hydroxy ester 6 showed two equally intense peaks at 1734 cm-1 (free
carbonyl) and 1711 cm-1 (hydrogen bonded carbonyl), whereas cis hydroxy
ester 5 showed one medium peak at 1734 cm-1 (free carbonyl) and a very
strong peak at 1716 cm-1 (hydrogen bonded carbonyl).9 In a 1D NOESY
experiment, irradiation of the CHOH hydrogen at δ 4.14 in 6 showed NOEs
to the hydroxy hydrogen at δ 2.77 and the ring hydrogens at δ 1.88-1.76.
Irradiation of the CHOH hydrogen at δ 3.79 in 5 showed NOEs to the
hydroxy hydrogen at δ 3.28 and the allylic side chain methylene group at
δ 2.52-2.40 establishing that the hydrogen is cis to the prenyl side chain.
(9) Castells, J.; Palau, J. J. Chem. Soc. 1964, 4938-4941.
(10) Magnus, P.; Tavares, F.; Westwood, N.; Tetrahedron Lett. 1997,
38, 1341-1344.
(11) Nakata, T.; Tani, Y.; Hatozaki, M.; Oishi, T. Chem. Pharm. Bull.
1984, 32, 1411-1415.
(12) Fraga, C. A. M.; Teixeira, L. H. P.; Menezes, C. M. de S.;
Sant’Anna, C. M. R.; Ramos, M. da C. K. V.; de Aquino Neto, F. R.;
Barreiro, E. J. Tetrahedron 2004, 60, 2745-2755.
1402
Org. Lett., Vol. 10, No. 7, 2008

afforded the mesylate mixed anhydride 12. Hydrolysis of
the more reactive mixed anhydride with NaHCO3 in aqueous
THF gave mesylate carboxylate 15, which underwent an
intramolecular SN2 reaction with inversion (red arrow) to
provide the desired lactone 14 in 33% overall yield from
hydroxy ester 6. Unfortunately, Grob fragmentation with loss
of CO2 (blue arrows) to give triene 13 in 46% overall yield
from 6 was the major reaction. An even greater percentage
of 13 was obtained using DBU or solid K2CO3 as bases in
THF. This fragmentation reaction was previously noted by
Wu and Sun, but has not been widely observed in â-lactone
synthesis.5 This fragmentation process is quite distinct from
the well-known decarboxylation of â-lactones that occurs
on heating;13 lactone 14 is stable under the reaction condi-
tions. These results suggested that trans hydroxy ester 6 and
trans hydroxy acid 3 are not ideal precursors for vibralactone
(1) synthesis.
Scheme 3. Synthesis of (()-Vibralactone (1)
On the other hand, lactone formation from cis hydroxy
ester 5, the minor product from the NaBH4 reduction,
proceeded cleanly and in high yield. Hydrolysis of the methyl
ester with KOH in MeOH at 60 °C afforded the hydroxy
acid, which was treated with TsCl in pyridine to form the
mixed anhydride, which cyclized to give lactone 14 in 83%
yield (see eq 1).
We therefore turned our attention to methods to selectively
prepare the cis hydroxy ester 5. As expected, Mitsunobu
reaction with the hindered secondary alcohol 6 failed, even
using procedures optimized for hindered alcohols.14 Fraga
reported that reduction of ethyl 1-allyl-2-oxocyclohexanon-
ecarboxylate with (n-Bu)4NBH4 in MeOH gave an 8.2:1
mixture favoring the cis hydroxy ester.12 Eventually, we
found that reduction of 9 with Me4NBH4 in 1:1 THF/MeOH
at 25 °C afforded a 3:2 mixture of 5 and 6 from which pure
5 was isolated in 42% yield along with a 1:2 mixture of 5
and 6 in 40% yield (see Scheme 3). This mixture can easily
be recycled by oxidation with Dess-Martin periodinane to
give ketone 9 in 94% yield.
Hydrolysis of the methyl ester of 5 with KOH in MeOH
at 60 °C provided the hydroxy acid, which was treated with
NaHCO3, I2 and KI in aqueous THF to give the desired
iodolactones 16 (63%) and 17 (32%). These iodolactones
were separated to aid in characterization of intermediates
but can be carried through as a mixture because the sequence
converges at cis hydroxy acid 2. Both isomers are γ-lactones
with carbonyl absorptions at 1752 and 1749 cm-1, respec-
tively. The methyl groups absorb between δ 1.92-2.00 as
expected for CMe2I. X-ray crystal structure determination
of the minor isomer 17 established the stereochemistry of
the lactone ring and confirmed our stereochemical assignment
of the hydroxy group.8 Ozonolysis at -78 °C followed by
reduction of the ozonide with Ph3P afforded a dialdehyde,
which was immediately subjected to Corey’s protocol
(Bn2NH‚TFA in benzene)15 to effect the intramolecular aldol
reaction. This sequence converted cyclohexenes 16 and 17
to cyclopentenals 18 and 19 in 80 and 90% yields, respec-
tively.
Completion of the synthesis required reduction of the
aldehyde to the alcohol, retro-iodolactonization to regenerate
the unsaturated acid, and â-lactone formation. Reduction of
18 or 19 with NaBH4 gave a complex mixture, probably as
a result of the instability of the tertiary iodide. Fortunately,
retro-iodolactonization of 18 and 19 under mild conditions
(13) Mulzer, J.; Pointner, A.; Chucholowski, A.; Bru¨ntrup, G. J. Chem.
Soc., Chem. Commun. 1979, 52-54.
(14) (a) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017-
3020. (b) Sa¨ıah, M.; Bessodes, M.; Antonakis, K. Tetrahedron Lett. 1992,
33, 4317-4320.
(15) Corey, E. J.; Danheiser, R. L.; Chandrasekaran, S.; Siret, P.; Keck,
G. E.; Gras, J.-L. J. Am. Chem. Soc. 1978, 100, 8031-8034.
Org. Lett., Vol. 10, No. 7, 2008
1403

with activated Zn16 in 4:1 THF/HOAc at 0 °C for 15 min
regenerated prenyl acid 2 without pinacol coupling of the
aldehyde.17 We chose to prepare the â-lactone prior to
reduction of the aldehyde because this would not require the
use of a protecting group for the primary alcohol. Treatment
of 2 with TsCl in pyridine for 12 h at 0-4 °C afforded mixed
anhydride 20, which cyclized to give â-lactone 21 in 50%
overall yield from 18 and 53% overall yield from 19.
Unfortunately, reduction of the aldehyde of 21 with NaBH4
in MeOH also hydrolyzed the â-lactone to the hydroxy
methyl ester. This problem was easily solved using a
procedure developed by Corey and Schreiber for reductions
of ketones in the presence of the â-lactone of omuralide.18
Reduction of aldehyde 21 with NaBH4 in 100:1 DME/H2O
for 40 min at 0 to 25 °C gave (()-vibralactone (1) in 78%
yield with spectral data identical to those reported.1
prenyl bromide that proceeds in 9% (higher if recycled 6 is
included) overall yield. No protecting groups are used except
for the novel use of an iodolactone to protect both the prenyl
double bond and carboxylic acid. This synthesis is readily
amenable to analogue preparation, and we are currently
adapting it to the preparation of optically pure vibralactone
using the diastereoselective reductive alkylation of chiral
benzamides.19
Acknowledgment. We are grateful to the National
Institutes of Health (GM-50151) for support of this work.
We thank the National Science Foundation for the partial
support of this work through grant CHE-0521047 for the
purchase of an X-ray diffractometer. We thank Prof. Bruce
M. Foxman, Brandeis University, for assistance with the
X-ray structure determination.
In conclusion, we have developed a 10-step synthesis of
(()-vibralactone (1) from methyl 2-methoxy benzoate and
Supporting Information Available: Complete experi-
mental procedures, copies of 1H and 13C NMR spectral data,
and X-ray crystallographic data for 17. This material is
available free of charge via the Internet at http://pubs.acs.org.
(16) Hannick, S. M.; Kishi, Y. J. Org. Chem. 1983, 48, 3833-3835.
(17) Hara, A.; Sekiya, M. Chem. Pharm. Bull. 1972, 20, 309-312.
(18) (a) Fenteany, G.; Standaert, R. F.; Lane, W. S.; Choi, S.; Corey, E.
J.; Schreiber, S. L. Science 1995, 268, 726-731. (b) Macherla, V. R.;
Mitchell, S. S.; Manam, R. R.; Reed, K. A.; Chao, T.-H.; Nicholson, B.;
Deyanat-Yazdi, G.; Mai, B.; Jensen, P. R.; Fenical, W. F.; Neuteboom, S.
T. C.; Lam, K. S.; Palladino, M. A.; Potts, B. C. M. J. Med. Chem. 2005,
48, 3684-3687.
OL800118C
(19) Schultz, A. G. Acc. Chem. Res. 1990, 23, 207-213.
1404
Org. Lett., Vol. 10, No. 7, 2008