Synthesis of (±)- and (-)-vibralactone and vibralactone C

Article abstract of DOI:10.1021/jo8015743

(Chemical Equation Presented) Mander reductive alkylation of methyl 2-methoxybenzoate with prenyl bromide and hydrolysis of the enol ether afforded methyl 6-oxo-1-prenyl-2-cyclohexenecarboxylate. This was converted in five steps (reduction of the ketone, saponification, iodolactonization, ozonolysis, and intramolecular aldol reaction) to a spiro lactone cyclopentenal. An efficient first synthesis of (±)-vibralactone was completed by retro- iodolactonization with activated Zn, formation of the β-lactone (vibralactone C), and reduction of the aldehyde. Except for the novel use of an iodolactone to protect both the prenyl double bond and carboxylic acid, no protecting groups were used. A similar sequence starting with asymmetric reductive alkylation of the (2S)-2-methoxymethoxymethylpyrrolidine amide of 2-methoxybenzoic acid with prenyl bromide afforded (-)-vibralactone confirming the absolute stereochemical assignment that was based on computational methods.

Full text of DOI:10.1021/jo8015743

Synthesis of (()- and (-)-Vibralactone and Vibralactone C†
Quan Zhou and Barry B. Snider*
Department of Chemistry MS 015, Brandeis UniVersity, Waltham, Massachusetts 02454-9110
snider@brandeis.edu
ReceiVed July 16, 2008
Mander reductive alkylation of methyl 2-methoxybenzoate with prenyl bromide and hydrolysis of the
enol ether afforded methyl 6-oxo-1-prenyl-2-cyclohexenecarboxylate. This was converted in five steps
(reduction of the ketone, saponification, iodolactonization, ozonolysis, and intramolecular aldol reaction)
to a spiro lactone cyclopentenal. An efficient first synthesis of (()-vibralactone was completed by retro-
iodolactonization with activated Zn, formation of the ꢀ-lactone (vibralactone C), and reduction of the
aldehyde. Except for the novel use of an iodolactone to protect both the prenyl double bond and carboxylic
acid, no protecting groups were used. A similar sequence starting with asymmetric reductive alkylation
of the (2S)-2-methoxymethoxymethylpyrrolidine amide of 2-methoxybenzoic acid with prenyl bromide
afforded (-)-vibralactone confirming the absolute stereochemical assignment that was based on
computational methods.
Introduction
The unusual fused ꢀ-lactone vibralactone (1) was recently
isolated from cultures of the Basidiomycete Boreostereum
Vibrans by Liu and co-workers (see Figure 1).1 The structure
was assigned by detailed spectroscopic analysis, and the absolute
stereochemistry was assigned by the B3LYP/aug-cc-pVDA//
B3LYP/6-31G* computational method. Percyquinnin was orig-
inally assigned as a regioisomer of 12 but has since been shown
to have the same planar structure as vibralactone (1).1 Vibra-
lactone inhibits pancreatic lipase with an IC50 of 0.4 µg/mL,
and percyquinnin inhibits lipase with an IC50 of 2 µg/mL.2
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 modification of
either the prenyl side chain or the allylic alcohol. More recently,
Liu reported the isolation of four minor congeners of vibralac-
FIGURE 1. Structures of vibralactone (1), vibralactone B (4), vibra-
lactone C (2), and 1,5-secovibralactone (5).
tone, vibralactone B (4), vibralactone C (2), vibralactone acetate
(3), and 1,5-secovibralactone (5).4
The synthesis of vibralactone is a much more challenging
problem than its small size would suggest because of the
instability of the ꢀ-lactone ring and the presence of both an
allylic alcohol and a side-chain double bond.5 There are two
obvious approaches to form the ꢀ-lactone ring of vibralactone
(1). The standard method of ꢀ-lactone formation would involve
activation of the acid moiety of cis-hydroxy acid 6 followed
by displacement with the alkoxide to form the ꢀ-lactone with
retention of stereochemistry at the alcohol carbon (see Scheme
† We dedicate this paper to Prof. E. J. Corey on the occasion of his 80th
birthday.
(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.
(4) Jiang, M.-Y.; Wang, F.; Yang, X.-L.; Fang, L.-Z.; Dong, Z.-J.; Zhu, H.-
J.; Liu, J.-K. Chem. Pharm. Bull. 2008, 56, 1286–1288.
(5) For a preliminary report on a portion of this work see: Zhou, Q.; Snider,
B. B. Org. Lett. 2008, 10, 1401–1404.
(3) Birari, R. H.; Bhutani, K. K Drug DiscoV. Today 2007, 12, 879–889,
and references cited therein.
10.1021/jo8015743 CCC: $40.75
Published on Web 09/19/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8049–8056 8049

Zhou and Snider
SCHEME 2. Synthesis of Model ꢀ-Lactone 18
SCHEME 1. Retrosynthesis of (()-Vibralactone (1)
1).6 Alternatively, the alcohol of trans-hydroxy acid 7 could
be converted to a good leaving group; ꢀ-lactone formation by
an SN2 reaction with the carboxylate as nucleophile would
produce the same ꢀ-lactone with inversion at the alcohol carbon.
This rarely used approach to ꢀ-lactones has recently been
improved by Wu and Sun.7
7 with both the side-chain double bond and the free acid needed
for lactone formation.
Diastereoselective reduction of ketone 13 will provide alco-
hols 9 and 10. Surprisingly, this proved to be the most
challenging step in the synthesis. Mander reductive alkylation9
of methyl 2-methoxybenzoate (12) with prenyl bromide followed
by acidic hydrolysis of the methyl enol ether will provide ready
access to ketone 13.
Oxidative cleavage of the cyclohexene double bond of 9 and
10 followed by an intramolecular aldol reaction should provide
the cyclopentenal moieties of 6 and 7, respectively. Unfortu-
nately, the side-chain double bond is more electron rich and
will have to be protected before the cyclohexene double bond
can be oxidatively cleaved. Iodolactonization8 of the side-chain
double bond of 9 or 10 to give 11 would provide a suitable
substrate for conversion to cyclopentenal 8. However, both 9
and 10 have two double bonds that could undergo iodolacton-
ization. Even if iodolactonization occurs selectively as expected
and required at the more electron-rich side-chain double bond,
stereoisomeric mixtures of γ- and δ-lactones that will complicate
product analysis will be formed. Most importantly, it was not
clear whether oxidative cleavage of the double bond and
intramolecular aldol reaction to give cyclopentenal 8 could be
accomplished in the presence of a reactive tertiary iodide. Retro-
iodolactonization of 8 by zinc would form hydroxy acids 6 or
Results and Discussion
Formation of and ꢀ-Lactone Formation from Hydroxy
Esters 9 and 10. Reduction of methyl 2-methoxybenzoate (12)
with K in liquid NH3 at -78 °C, addition of 1,3-pentadiene to
consume excess K, LiI to make the lithium dienolate, and prenyl
bromide followed by slow warming to 25 °C afforded the
alkylated cyclohexadiene 14 in 77% yield (see Scheme 2).9
Methyl 3-(3-methyl-2-butenyl)-6-methoxy-1,5-cycloexadiene-
carboxylate, resulting from γ-alkylation of the dienolate, was
formed as a minor byproduct but was easily removed by
chromatography. The enol ether of 14 was hydrolyzed with
methanolic HCl to give ketone 13 in 84% yield. Reduction of
ketone 13 with NaBH4 in MeOH formed a 2:1 mixture of trans-
hydroxy ester 10 and cis-hydroxy ester 9 in high yield. The
stereochemistry of alcohols 9 and 10 was established by analysis
of IR spectra obtained in dilute (0.1 M) CCl4 solution and 1D
NOESY NMR spectra. There were two equally intense peaks
(6) For reviews on ꢀ-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.
(7) (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.
(9) (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) For a review, see: Dowle, M. D.; Davies, D. I. Chem. Soc. ReV. 1979, 8,
171–197.
8050 J. Org. Chem. Vol. 73, No. 20, 2008

Synthesis of (()- and (-)-Vibralactone
at 1734 cm-1 (free carbonyl) and 1711 cm-1 (hydrogen-bonded
carbonyl) in the IR spectrum of trans-hydroxy ester 10, whereas
there was a medium peak at 1734 cm-1 (free carbonyl) and a
very strong peak at 1716 cm-1 (hydrogen-bonded carbonyl) in
cis-hydroxy ester 9.10 Irradiation of the CHOH hydrogen of 10
at δ 4.14 in a 1D NOESY experiment 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 of 9 at δ 3.79
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.
hydroxy acid with TsCl in pyridine as described by Adam15
formed the hydroxy mixed anhydride, which cyclized providing
lactone 18 in 83% yield (see eq 1).
Synthesis of (()-Vibralactone (1). We now needed to
develop a stereoselective route to cis-hydroxy ester 9. As
expected, Mitsunobu reaction with the hindered secondary
alcohol 10 failed, even using procedures optimized for hindered
alcohols.16 We were encouraged by Fraga’s report that reduction
of ethyl 1-allyl-2-oxocyclohexanecarboxylate with (n-Bu)4NBH4
in MeOH gave an 8.2:1 mixture favoring the cis-hydroxy ester.13
Unfortunately, similar reductions of 10 are not nearly as
selective; apparently, the presence of the double bond in the
ring has a significant effect on the reduction stereochemistry.
We explored the reduction of 10 with (n-Bu)4NBH4 and
Me4NBH4 in a variety of solvents. The best result was obtained
by reduction of 13 with Me4NBH4 in 1:1 THF/MeOH at 25 °C
to afford a 3:2 mixture of 9 and 10 from which pure 9 was
isolated in 42% yield (see Scheme 3). We also isolated a less
polar 1:2 mixture of 9 and 10 in 40% yield that can be easily
recycled to give ketone 13 in 94% yield by oxidation with
Dess-Martin periodinane.
The desired iodolactones 20 (63%) and 21 (32%) were
prepared by hydrolysis of the methyl ester of 9 with KOH in
MeOH at 60 °C to provide the hydroxy acid, which was treated
with NaHCO3, I2, and KI in aqueous THF. 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 6. The carbonyl absorptions at
1752 and 1749 cm-1, respectively, establish that both isomers
are γ-lactones. The methyl groups absorb between δ 1.92-2.0
as expected for CMe2I groups. X-ray crystal structure determi-
nation of the minor isomer 21 established the stereochemistry
of the lactone ring and confirmed our stereochemical assignment
of the hydroxy group (for details, see the Supporting Informa-
tion). Ozonolysis at -78 °C followed by reduction of the
ozonide with Ph3P afforded an unstable dialdehyde, which was
immediately subjected to Corey’s protocol (Bn2NH·TFA in
benzene)17 to effect the intramolecular aldol reaction. This two-
step sequence formed cyclopentenals 22 and 23 in 80% and
90% yields, respectively, from cyclohexenes 20 and 21.
Completion of the synthesis required reduction of the
aldehyde to the alcohol, retro-iodolactonization to regenerate
the unsaturated acid, and ꢀ-lactone formation. Reduction of 22
or 23 with NaBH4 gave a complex mixture, probably as a result
of the instability of the tertiary iodide. Fortunately, retro-
iodolactonization of 22 and 23 under mild conditions with
activated Zn18 in 4:1 THF/HOAc at 0 °C for 15 min regenerated
Magnus reported that similar ratios of products were produced
in the NaBH4 reduction of a related keto amide and also showed
that Zn(BH4)2 gave the trans-hydroxy amide with >99:1
selectivity.11 Reduction of 13 with Zn(BH4)2 in ether12 afforded
trans-hydroxy ester 10 in 69% yield. Reduction with CaCl2 and
NaBH4, which selectively provides trans-hydroxy esters from
1-alkyl-2-oxocyclohexanone carboxylates,13 gave a 7.5:1 mix-
ture of 10 and 9, from which 10 was isolated in 69% yield.
Lactone formation by SN2 reaction with inversion by hydroxy
group activation was examined using the now readily available
trans-hydroxy ester 10. Hydrolysis of the methyl ester of 10
with KOH in MeOH at 60 °C provided the required trans-
hydroxy acid 15. Wu and Sun examined the lactonization of
acyclic ꢀ-hydroxy acids with inversion. This necessitated
activation of the alcohol without also activating the carboyxlic
acid because lactonization by acid activation will give the other
stereoisomer.7 trans-Hydroxy acid 15 would have to form a
highly strained trans-fused ꢀ-lactone by reaction of the alcohol
with an activated acyl group. Therefore, there is no need to
selectively activate the hydroxy group. Treatment of 15 with
MsCl and Et3N in CH2Cl2 provided the mesylate mixed
anhydride 16. Hydrolysis of the more reactive mixed anhydride
with NaHCO3 in aqueous THF gave mesylate carboxylate 19,
which reacted further by an intramolecular SN2 reaction with
inversion (red arrow) to provide the desired lactone 18 in 33%
overall yield from hydroxy ester 10. Unfortunately, Grob
fragmentation of 19 with loss of CO2 (blue arrows) to give triene
17 in 46% overall yield from 10 was the major reaction. An
even greater percentage of 17 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 ꢀ-lactone synthesis.7 This fragmentation process is
quite distinct from the well-known decarboxylation of ꢀ-lactones
that occurs on heating14 since lactone 18 does not lose carbon
dioxide to give triene 17 under the reaction conditions. The low
yield of ꢀ-lactone 18 from trans-hydroxy ester 10 suggested
that 7 would not be a good precursor for vibralactone (1).
To our delight, lactone formation from cis-hydroxy ester 9,
the minor product from the NaBH4 reduction, proceeded cleanly
and in high yield. Hydrolysis of the methyl ester of 9 with KOH
in MeOH at 60 °C afforded the hydroxy acid. Treatment of the
(10) Castells, J.; Palau, J. J. Chem. Soc. 1964, 4938–4941.
(11) (a) Magnus, P.; Tavares, F.; Westwood, N. Tetrahedron Lett. 1997, 38,
1341–1344. (b) Magnus, P.; Westwood, N.; Spyvee, M.; Frost, C.; Linnane, P.;
Tavares, F.; Lynch, V. Tetrahedron 1999, 55, 6435–6452.
(12) Nakata, T.; Tani, Y.; Hatozaki, M.; Oishi, T. Chem. Pharm. Bull. 1984,
32, 1411–1415.
(13) 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.
(15) Adam, W.; Baeza, J.; Liu, J. C. J. Am. Chem. Soc. 1972, 94, 2000–
2006.
(16) (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.
(17) Corey, E. J.; Danheiser, R. L.; Chandrasekaran, S.; Siret, P.; Keck, G. E.;
Gras, J.-L. J. Am. Chem. Soc. 1978, 100, 8031–8034.
(18) Hannick, S. M.; Kishi, Y. J. Org. Chem. 1983, 48, 3833–3835.
(14) Mulzer, J.; Pointner, A.; Chucholowski, A.; Bru¨ntrup, G. J. Chem. Soc.,
Chem. Commun. 1979, 52–54.
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Zhou and Snider
SCHEME 3. Synthesis of (()-Vibralactone (1)
SCHEME 4. Attempted Formation of trans-Hydroxy Acid 7
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 ꢀ-lactone of omuralide.21
Reduction of vibralactone C (2) with NaBH4 in 100:1 DME/
H2O for 40 min at 0-25 °C gave (()-vibralactone (1) in 78%
yield with spectral data identical to those reported.1
Unsuccessful Attempts To Convert 10 to (()-Vibralac-
tone (1). The conversion of cis-hydroxy ester 9 to vibralactone
(1) proceeded very efficiently, but the reduction of ketone 13
to 9 with Me4NBH4 was much less selective than the reduction
of 13 to trans-hydroxy ester 10 with either Zn(BH4)2 or NaBH4
and CaCl2. Therefore, we decided to convert 10 to trans-hydroxy
acid 7 and examine its conversion to 1 despite the competing
fragmentation to give 17 that was observed in the conversion
of trans-cyclohexene hydroxy acid 19 to give ꢀ-lactone 18.
Hydrolysis of 10 followed by iodolactonization as described
for the preparation of 20 and 21 gave iodolactones 25 and 26,
with unknown side chain stereochemistry, in 54% and 26%
yield, respectively (see Scheme 4). Ozonolyis and aldol reaction
as described for the preparation of cyclopentenals 22 and 23
afforded cyclopentenals 27 (73%) and 28 (82%), respectively.
Unfortunately, retro-iodolactonization of either 27 or 28 to give
trans-hydroxy acid 7 was not as clean as the retro-iodolaction-
ization of either 22 or 23 to give cis-hydroxy acid 6. For reasons
that are not clear, we obtained complex mixtures containing at
best about 50% of 7 and uncharacterized side products. Attempts
prenyl acid 6 without pinacol coupling of the aldehyde.19 Acid
6 decomposes if the concentration of HOAc is too high.
Therefore, during work up, the reaction was partially concen-
trated, diluted with heptane, and concentrated to remove the
2:1 heptane-acetic acid azeotrope that boils at 92 °C.20
We chose to prepare the ꢀ-lactone prior to reduction of the
aldehyde because this would not require the use of a protecting
group for the primary alcohol. Treatment of crude 6 with TsCl
in pyridine for 12 h at 0-4 °C afforded mixed anhydride 24,
which cyclized to give ꢀ-lactone 2, which has since been isolated
and named vibralactone C, in 50% overall yield from 22 and
53% overall yield from 23. Unfortunately, reduction of the
aldehyde of vibralactone C (2) under standard conditions
(NaBH4 in MeOH) also hydrolyzed the unstable ꢀ-lactone to
(21) (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.
(19) Hara, A.; Sekiya, M. Chem. Pharm. Bull. 1972, 20, 309–312.
(20) Gordon, A. J.; Ford, R. A. The Chemist’s Companion: A Handbook of
Practical Data, Techniques, and References; Wiley: New York, 1972; p 24.
8052 J. Org. Chem. Vol. 73, No. 20, 2008

Synthesis of (()- and (-)-Vibralactone
SCHEME 5. Reductive Alkylation of 29
SCHEME 6. Synthesis of (-)-Vibralactone (1)
at forming 2 from this mixture by ꢀ-lactone formation with
inversion by an SN2 reaction were not promising.
Synthesis of (-)-Vibralactone (1). We now turned to the
synthesis of (-)-vibralactone (1) using the Schultz asymmetric
Birch reductive alkylation.22,23 Reductive alkylations of
2-alkoxymethylpyrrolidine 2-methoxybenzamides proceed in
excellent yield with very high diastereoselectivity. Treatment
of 2-methoxymethylpyrrolidine 2-methoxybenzamide (29) with
K in liquid NH3 at -78 °C, addition of prenyl bromide, and
slow warming to 25 °C afforded cyclohexadiene 30 in 65% yield
as a single diastereomer whose stereochemistry was assigned
by analogy to the products obtained with other alkylating agents
(see Scheme 5).22,23 Spectroscopic analysis of this mixture was
complicated by the presence of amide rotamers. Hydrolysis of
the enol ether of 30 with methanolic HCl gave ketone 31 in
75% yield. Unfortunately, all attempts at hydrolysis of the amide
were unsuccessful. Acid hydrolysis cannot be used because of
the reactivity of the side chain double bond. Base treatment
will lead to a retro-Dieckmann reaction. Iodolactonization with
the ring double bond has been used to cleave similar amides
but was unsuccessful with 31 or 32.11,23g-i The reduction of
keto amide of 31 was even more selective for the undesired
trans-hydroxy amide than the reduction of keto ester 13.11 No
reaction occurred with Me4NBH4 in 1:1 THF/MeOH. Reduction
with Me4NBH4 in MeOH at 25 °C afforded a 1:4 mixture of
the cis- (desired) and trans-hydroxy amides 32.
with methanolic HCl gave ketone 35. In acid, hydroxy amide
35 rearranged to the ammonium ester 36. Treatment with
NaHCO3 and methyl chloroformate provided carbamate ester
37 in 55% overall yield from 34. We also obtained 15-20% of
carbamate ester 39 in which MeOH had added to the side chain
double bond during the MOM ether hydrolysis. Unfortunately,
keto ester 13 was not formed on treatment of ester 37 with
NaOMe in MeOH. A complex mixture, presumably resulting
from retro-Dieckmann cyclization, was formed. Protection of
the ketone as the enol ether with trimethyl orthoformate and
sulfuric acid in MeOH, followed by ester exchange with NaOMe
in MeOH afforded optically pure keto ester 14, an intermediate
in the synthesis of (()-vibralactone (1). Unfortunately, the length
of this sequence was not appealing.
Reduction of 37 with Me4NBH4 in 1:1 THF/MeOH was very
slow, but in pure MeOH we obtained a 3:2 mixture of
cis-hydroxy ester 38 and the trans diastereomer. Flash chroma-
tography afforded pure 38 in 39% yield along with 48% of a
1:3 mixture of 38 and the diastereomer, which was recycled by
Dess-Martin oxidation to afford 37 in 91% yield. Reduction
of keto esters 13 and 37 is much more selective for the desired
cis-hydroxy esters 9 and 38 (3:2) than the reduction of keto
amide 31 to 32 (1:4). We hoped that the selectivity could be
improved by the asymmetric reduction of 37, a strategy that
Reductive alkylation of 2-(methoxymethoxymethyl)pyrroli-
dine 2-methoxybenzamide (33) provided a solution to this
problem as described by Schultz.23b-d Treatment of 33 with K
in liquid NH3 at -78 °C, addition of prenyl bromide, and slow
warming to 25 °C afforded cyclohexadiene 34 in 76% yield as
a single diastereomer whose stereochemistry was assigned by
analogy to the products obtained with other alkylating agents
(see Scheme 6). Hydrolysis of the MOM and enol ethers of 34
(22) For reviews, see: (a) Schultz, A. G. Acc. Chem. Res. 1990, 23, 207–
213. (b) Schultz, A. G. Chem. Commun. 1999, 1263–1271.
(23) (a) Schultz, A. G.; Sundararaman, P.; Macielag, M.; Lavieri, F. P.;
Welch, M. Tetrahedron Lett. 1985, 26, 4575–4578. (b) Schultz, A. G.; Puig, S.
J. Org. Chem. 1985, 50, 915–916. (c) Schultz, A. G.; Lavieri, F. P.; Macielag,
M.; Plummer, M. J. Am. Chem. Soc. 1987, 109, 3991–4000. (d) McCloskey,
P. J.; Schultz, A. G. Heterocycles 1987, 25, 437–447. (e) Schultz, A. G.;
Macielag, M.; Sundararaman, P.; Taveras, A. G.; Welch, M. J. Am. Chem. Soc.
1988, 110, 7828–7841. (f) Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1991,
113, 4931–4936. (g) Schultz, A. G.; Guzzo, P. R.; Nowak, D. M. J. Org. Chem.
1995, 60, 8044–8050. (h) Schultz, A. G.; Holoboski, M. A.; Smyth, M. S. J. Am.
Chem. Soc. 1996, 118, 6210–6219. (i) Khim, S.-K.; Dai, M.; Zhang, X.; Chen,
L.; Pettus, L.; Thakkar, K.; Schultz, A. G. J. Org. Chem. 2004, 69, 7728–7733.
(j) Paul, T.; Malachowski, W. P.; Lee, J. J. Org. Chem. 2007, 72, 930–937.
J. Org. Chem. Vol. 73, No. 20, 2008 8053

Zhou and Snider
aqueous sodium thiosulfate solution, water, and brine and dried
(MgSO4). The solvent was removed under reduced pressure to give
2.44 g of crude 14 as a yellow oil. Flash chromatography (20:1
hexanes/EtOAc) gave 1.10 g (77%) of pure 14: 1H NMR 5.88 (dt,
1, J ) 9.6, 3.3), 5.42 (br d, 1, J ) 9.6), 4.94 (t, 1, J ) 7.6), 4.83
(dd, 1, J ) 3.7, 3.7), 3.70 (s, 3), 3.52 (s, 3), 2.86 (dddd, 1, J )
22.4, 3.7, 3.3, 3.0), 2.77 (dddd, 1, J ) 22.4, 3.7, 3.3, 3.0), 2.73
(dd, 1, J ) 14.4, 7.6), 2.43 (dd, 1, J ) 14.4, 7.6), 1.66 (s, 3), 1.59
(s, 3); 13C NMR 174.1, 152.8, 133.7, 126.9, 126.4, 119.3, 93.3,
54.2, 52.4, 51.8, 33.3, 26.4, 26.0, 17.9; IR (neat) 1735, 1689, 1235;
HRMS (EI) calcd for C14H20O3 (M+) 236.1413, found 236.1415.
The 22.4 Hz geminal coupling constant is characteristic of 1,4-
cyclohexadienes.26
was not applicable to racemic keto ester 13. Unfortunately, 37
was too hindered to react with chiral oxazaborolidine catalysts.24
Benzylquininium and benzylquinidinium borohydrides reduce
ketones with modest enantiomeric excess.25 These reagents are
very similar to Me4NBH4, the optimal reagent for obtaining the
cis-hydroxy ester. We hoped that we would obtain a higher yield
of 38 with the matched reagent. Unfortunately, the same 3:2
mixture of 38 and the diastereomer was obtained with both
benzylquininium and benzylquinidinium borohydrides.
The conversion of cis-hydroxy ester 38 to vibralactone
proceeded uneventfully. Hydrolysis with KOH in aqueous
MeOH afforded the hydroxy acid that was obtained from methyl
ester 9. Iodolactionization afforded (-)-iodolactone 20 in 56%
yield and (-)-iodolactone 21 in 27% yield. The absolute
stereochemistry of (-)-21 was confirmed by an X-ray crystal
structure determination (for details, see the Supporting Informa-
tion). Ozonolysis and aldol cyclization as in the racemic series
afforded (-)-22 and (-)-23, which were treated with Zn to give
hydroxy acid 6 which was treated with TsCl and pyridine to
give (-)-vibralactone C (2). Reduction as in the racemic series
Methyl (1R*,6S)-6-Hydroxy-1-(3-methyl-2-butenyl)-2-cyclohex-
enecarboxylate (9). Me4NBH4 (166 mg, 1.86 mmol) was added to
a solution of ketone 13 (207 mg, 0.93 mmol) in MeOH (5 mL)
and THF (5 mL) at 0 °C. The ice bath was removed, and the
reaction was stirred at 25 °C for 12 h. The solvent was removed
under reduced pressure. The residue was diluted with EtOAc, and
the resulting solution was washed with 10% aqueous HCl, water,
and brine. The organic layer was dried (MgSO4) and concentrated
to give 220 mg of crude 9 and 10. Flash chromatography (12:1
hexanes/EtOAc) gave 85 mg (40%) of a 2:1 mixture of 10 and 9
afforded (-)-vibralactone (1). The rotation of synthetic 1, [R]25
D
1
) -129 (c 0.27, CHCl3), is very close to that of natural 1, [R]26
followed by 88 mg (42%) of 9: H NMR 5.78 (ddd, 1, J ) 9.8,
D
3.7, 3.7), 5.67 (br d, 1, J ) 9.8), 5.07 (dd, 1, J ) 7.2, 7.2), 3.79
(ddd, 1, J ) 9.2, 9.2, 3.0), 3.71 (s, 3), 3.28 (d, 1, J ) 9.2, OH),
2.52-2.40 (m, 2), 2.25-2.05 (m, 2), 1.95-1.86 (m, 1), 1.84-1.73
(m, 1), 1.70 (br s, 3), 1.62 (br s, 3); 13C NMR 176.2, 135.2, 128.5,
127.6, 118.3, 71.1, 52.3, 52.0, 35.8, 27.4, 26.0, 23.5, 17.9; IR 3509,
3029, 1728, 1713; HRMS (EI) calcd for C13H20O3 (M+) 224.1413,
found 224.1415.
) -135.1 (c 0.52, CHCl3). This confirms the assignment of
stereochemistry based on the B3LYP/aug-cc-pVDA//B3LYP/
6-31G* computational method.1 The rotation of synthetic 2,
[R]25 ) -126.5 (c 0.4, CHCl3), has the same sign but is not
D
close to that of natural 2, [R]17 ) -288.9 (c 0.08, CHCl3).
D
However, the latter value may not be very accurate because of
the very low concentration.
(3S*,5R,10S)-10-Hydroxy-3-(1-iodo-1-methylethyl)-2-oxa-
spiro[4.5]dec-6-en-1-one (20) and (3R*,5R,10S)-10-Hydroxy-3-
(1-iodo-1-methylethyl)-2-oxaspiro[4.5]dec-6-en-1-one (21). A solu-
tion of hydroxy ester 9 (316 mg, 1.41 mmol) in MeOH (15 mL)
and 6 mL of 3.6 M aqueous KOH solution was heated at 60 °C for
3 h and cooled. The MeOH was removed under reduced pressure.
The residue was neutralized with 10% aqueous HCl to pH 1-2
and then treated with solid sodium bicarbonate until CO2 evolution
ceased. THF (15 mL), KI (468 mg, 2.82 mmol), and I2 (716 mg,
2.82 mmol) were then added. The mixture was stirred overnight,
quenched with 10% aqueous sodium thiosulfate solution, and
extracted with EtOAc. The extracts were washed with water and
brine, dried (MgSO4), and concentrated to give 645 mg of crude
lactones 20 and 21. Flash chromatography (2:1 hexanes/EtOAc)
gave 297 mg (63%) of 20 followed by 153 mg (32%) of 21. A
sample of 21 was recrystallized for X-ray crystal structure deter-
mination by dissolution in Et2O at 25 °C and cooling to 4 °C for
2 d.
In conclusion, we have developed a 10-step synthesis of (()-
vibralactone (1) from methyl 2-methoxybenzoate and prenyl
bromide that proceeds in 9% (higher if recycled 10 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. Starting with 2-methoxymethoxymeth-
ylpyrrolidine 2-methoxybenzamide (33) we have prepared (-)-
vibralactone (1) in 11 steps and 4.8% (higher if recycled trans-
hydroxy ester is included) overall yield. This synthesis is readily
amenable to analogue preparation. Vibralactone C (2) was
prepared, prior to its isolation,4 as the ultimate precursor to
vibralactone.
Experimental Section
Methyl 2-Methoxy-1-(3-methyl-2-butenyl)-2,5-cyclohexadiene-
1-carboxylate (14). t-BuOH (0.44 g, 6.0 mmol) was added to a
solution of methyl 2-methoxybenzoate (12) (1.0 g, 6.0 mmol) in
dry THF (5 mL), and the solution was cooled to -78 °C. Liquid
ammonia (60 mL) was condensed into this mixture under nitrogen,
and potassium was added until the reaction mixture maintained a
deep blue coloration for 5 min. 1,3-Pentadiene was added dropwise
(2-20 drops) until the solution turned yellow-brown. Anhydrous
lithium iodide (1.8 g, 13 mmol) was added, and the solution was
stirred for 1 h at -78 °C. A solution of prenyl bromide (2.69 g, 18
mmol) in dry THF (6 mL) was added. The resulting light yellow
solution was stirred for another 1 h. The reaction was allowed to
warm to 25 °C, and the ammonia was removed with a stream of
nitrogen. Brine was added, and the reaction mixture was extracted
with Et2O. The combined Et2O extracts were washed with 10%
1
Data for 20: mp 92-93 °C dec; H NMR 5.93 (ddd, 1, J )
10.0, 3.7, 3.7), 5.58 (br d, 1, J ) 10.0), 4.17 (dd, 1, J ) 10.4, 6.4),
3.76 (ddd, 1, J ) 10.4, 7.6, 2.5), 2.56 (dd, 1, J ) 12.4, 10.4),
2.46-2.38 (m, 1), 2.35 (d, 1, J ) 7.6, OH), 2.33-2.26 (m, 1),
2.26 (dd, 1, J ) 12.4, 6.4), 2.22-2.12 (m, 1), 2.00 (s, 3), 1.98 (s,
3), 1.91-1.83 (m, 1); 13C NMR 177.0, 130.9, 123.7, 84.0, 70.8,
51.4, 46.8, 38.6, 34.1, 31.4, 26.6, 23.9; IR 3444, 1752; HRMS (EI)
calcd for C12H17IO3 (M+) 336.0229, found 336.0223.
1
Data for 21: mp 104-107 °C dec; H NMR 5.96 (ddd, 1, J )
10.0, 4.8, 2.4), 5.45 (br d, 1, J ) 10.0), 3.87-3.78 (m, 2), 2.54
(dd, 1, J ) 13.6, 7.2), 2.37-2.13 (m, 3), 2.26 (dd, 1, J ) 13.6,
9.0), 2.00 (s, 3), 1.92 (s, 3), 1.88 (d, 1, J ) 5.6, OH), 1.84-1.75
(m, 1); 13C NMR 177.0, 131.2, 126.7, 85.3, 75.2, 52.0, 50.6, 42.6,
33.2, 33.0, 27.4, 24.3; IR 3448, 1749; HRMS (EI) calcd for
C12H17IO3 (M+) 336.0229, found 336.0221.
(24) (a) Corey, E. J.; Cheng, X.-M.; Cimprich, K. A.; Sarshar, S. Tetrahedron
Lett. 1991, 32, 6835–6838. (b) Yeung, Y.-Y.; Chein, R.-J.; Corey, E. J. J. Am.
Chem. Soc. 2007, 129, 10346–10347.
(25) (a) Colonna, S.; Fornasier, R. J. Chem. Soc., Perkin Trans. 1 1978,
371–373. (b) Hofstetter, C.; Wilkinson, P. S.; Pochapsky, T. C. J. Org. Chem.
1999, 64, 8794–8800.
(3S*,5R,9S)-3-(1-Iodo-1-methylethyl)-9-hydroxy-1-oxo-2-oxa-
spiro[4.4]non-6-ene-7-carboxaldehyde (22). A solution of 20 (170
mg, 0.50 mmol) in a mixture of dry CH2Cl2 (10 mL) and MeOH
(10 mL) was ozonolyzed at -78 °C until the solution turned light
blue and then purged with oxygen until the blue color disappeared.
8054 J. Org. Chem. Vol. 73, No. 20, 2008

Synthesis of (()- and (-)-Vibralactone
The solution was then treated with PPh3 (157 mg, 0.60 mmol) and
allowed to slowly warm to 25 °C. To this solution was added 40
mL of dry benzene, and the solution was then concentrated to 5
mL. Another 10 mL of dry benzene was added, and the solution
was concentrated to 5 mL again. Finally, another 10 mL of dry
benzene and Bn2NH·TFA (30 mg, 0.10 mmol) was added, and
the solution was stirred overnight. The solvent was removed under
reduced pressure to give crude 22. Flash chromatography (2:1
hexanes/EtOAc) gave 140 mg (80%) of pure 22: 1H NMR 9.73 (s,
1), 6.61 (br s, 1), 4.52 (ddd, 1, J ) 8.4, 8.4, 8.8), 4.20 (dd, 1, J )
9.7, 6.7), 3.01 (dd, 1, J ) 16.4, 8.4), 2.76 (br dd, 1, J ) 16.4, 8.4),
2.76 (d, 1, J ) 8.8, OH), 2.59 (dd, 1, J ) 13.6, 6.7), 2.52 (dd, 1,
J ) 13.6, 9.7), 2.02 (s, 3), 1.99 (s, 3); 13C NMR 188.8, 174.7,
147.7, 144.8, 85.5, 79.0, 61.7, 45.6, 37.4, 36.2, 34.1, 31.3; IR 3460,
1763, 1683, 1188; HRMS (CI) calcd for C12H16IO4 (MH+)
351.0094, found 351.0091.
136.0, 122.5, 117.2, 78.4, 75.1, 61.4, 37.3, 27.6, 25.8, 18.0; IR
3407, 1815, 1110; HRMS (CI) calcd for C12H17O3 (MH+) 209.1178,
found 209.1176.
An identical reaction with (-)-2 afforded (-)-1: [R]25D ) -129
(c 0.27, CHCl3) [lit.1 [R]26 ) -135.1 (c 0.52, CHCl3)].
D
(2S)-2-[(Methoxymethoxy)methyl]-1-[[(1R)-2-methoxy-1-(3-methyl-
2-butenyl)-2,5-cyclohexadien-1-yl]carbonyl]pyrrolidine (34). A so-
lution of benzamide 3323c (540 mg, 1.93 mmol) and t-BuOH (143
mg, 1.93 mmol) in THF (5 mL) and liquid ammonia (60 mL) at
-78 °C was treated with potassium metal in small pieces until the
reaction mixture maintained a deep blue coloration for 20 min. A
solution of prenyl bromide (863 mg, 5.79 mmol) in THF (4 mL)
was added. The reaction was stirred at -78 °C for 1 h and was
allowed to slowly warm to 25 °C while the ammonia was
evaporated. Water was added, and the reaction was extracted with
EtOAc. The combined extracts were washed with brine, dried
(Na2SO4), and concentrated to give 1.32 g of crude prenyl amide
34. Flash chromatography (3:1 hexanes/EtOAc) gave 517 mg (76%)
An identical reaction with (-)-20 afforded (-)-22: [R]25
-66.1 (c 0.95, CHCl3).
)
D
(1R*,5S)-1-(3-Methyl-2-buten-1-yl)-7-oxo-6-oxabicyclo[3.2.0]hept-
2-ene-3-carboxaldehdye (Vibralactone C, 2). A slurry of iodolactone
23 (128 mg, 0.36 mmol) in THF (6 mL) and activated Zn (351
mg, 5.4 mmol) was treated with AcOH (1.5 mL). The mixture was
stirred at 0 °C for 15 min, diluted with EtOAc, and filtered through
a pad of silica gel. The combined filtrates were concentrated under
reduced pressure to about 5 mL volume. A 20 mL portion of
heptane was added, and the resulting solution was again concen-
trated under reduced pressure to give 126 mg of crude hydroxy
acid 6. Addition of heptane and reconcentration aided in the removal
of acetic acid.
of pure 34 as a 3:1 mixture of rotamers: [R]25 ) -40.3 (c 1.62,
D
1
CHCl3); H NMR 5.84 (dt, 1, J ) 9.6, 3.3), 5.38 (br d, 0.75 × 1,
J ) 9.6), 5.35 (br d, 0.25 × 1, J ) 9.6), 4.99 (dd, 1, J ) 7.6, 7.6),
4.71 (dd, 1, J ) 3.7, 3.7), 4.63 (d, 1, J ) 5.6), 4.61 (d, 0.75 × 1,J
) 5.6), 4.59 (d, 0.25 × 1, J ) 5.6), 4.40-4.26 (m, 1), 3.77 (dd,
0.75 × 1, J ) 9.5, 3.5), 3.73 (dd, 0.25 × 1, J ) 9.5, 3.5), 3.70-3.62
(m, 1), 3.54-3.23 (m, 2), 3.48 (s, 0.25 × 3), 3.47 (s, 0.75 × 3),
3.36 (s, 0.75 × 3), 3.35 (s, 0.25 × 3), 2.89-2.69 (m, 3), 2.49 (dd,
0.75 × 1, J ) 14.4, 6.8), 2.38 (dd, 0.25 × 1, J ) 14.4, 6.8),
1.94-1.69 (m, 4), 1.65 (s, 3), 1.56 (s, 3); 13C NMR 170.94 (0.25
× 1), 170.45 (0.75 × 1), 153.18 (0.75 × 1), 153.79 (0.25 × 1),
133.19 (0.25 × 1), 133.14 (0.75 × 1), 127.11 (0.25 × 1), 126.53
(0.75 × 1), 125.83 (0.75 × 1), 125.53 (0.25 × 1), 120.03 (0.75 ×
1), 119.99 (0.25 × 1), 96.79 (0.75 × 1), 96.63 (0.25 × 1), 92.58
(0.25 × 1), 92.51 (0.75 × 1), 67.57 (0.75 × 1), 67.44 (0.25 × 1),
58.26 (0.75 × 1), 58.05 (0.25 × 1), 55.15 (0.25 × 1), 55.10 (0.75
× 1), 54.04 (0.25 × 1), 54.00 (0.75 × 1), 52.2, 46.35 (0.25 × 1),
46.13 (0.75 × 1), 34.9, 26.80 (0.75 × 1), 26.76 (0.25 × 1), 26.66
(0.25 × 1), 26.59 (0.75 × 1), 26.1, 24.83 (0.75 × 1), 24.77 (0.25
× 1), 17.86 (0.75 × 1), 17.84 (0.25 × 1); IR (neat) 1685, 1635;
HRMS (EI) calcd for C20H31NO4 (M+) 349.2253, found 349.2256.
A solution of crude hydroxy acid 6 in dry pyridine (6 mL) was
cooled at 0 °C, and TsCl (103 mg, 0.54 mmol) was added. The
mixture was stirred at 0 °C for 1 h and then sealed and placed in
a refrigerator (4 °C) overnight. The mixture was poured onto
crushed ice and extracted with EtOAc. The combined extracts were
washed with saturated NaHCO3, water, and brine, dried (MgSO4),
and concentrated to give 51 mg of crude 2. Flash chromatography
on MeOH-deactivated silica gel (4:1 hexanes/EtOAc) gave 40 mg
(53%) of 2: 1H NMR 9.84 (s, 1), 6.67 (s, 1), 5.12 (br t, 1, J ) 7.2),
4.90 (d, 1, J ) 6.1), 3.06 (d, 1, J ) 19.6), 2.90 (dd, 1, J ) 19.6,
6.1), 2.75 (dd, 1, J ) 15.2, 7.6), 2.59 (dd, 1, J ) 15.2, 7.6), 1.74
(br s, 3), 1.66 (br s, 3); 13C NMR 188.9, 170.0, 146.8, 144.6, 137.2,
116.2, 78.0, 76.6, 34.2, 27.3, 25.8, 18.0; IR 1819, 1684, 1612, 1106;
HRMS (EI) calcd for C12H14O3 (M+) 206.0943, found 206.0942.
Methyl (2S)-2-[[[[(1R)-1-(3-Methyl-2-butenyl)-6-oxo-2-cyclohexen-
1-yl]carbonyl]oxy]methyl]-1-pyrrolidinecarboxylate (37). A solution
of 34 (375 mg, 1.07 mmol) in methanol (3 mL) and 10% aqueous
HCl (1.5 mL) in a sealed tube was irradiated in a microwave oven
at 65 °C for 8 min and cooled to 25 °C. The solution was then
neutralized with saturated NaHCO3 to pH 6 and concentrated. The
residue was extracted with CH2Cl2 (20 mL × 3). The combined
CH2Cl2 layers were washed with brine, dried (Na2SO4), and
concentrated to give 449 mg of crude amine 36, which was
immediately dissolved in dry CH2Cl2 (6 mL). This solution was
cooled to 0 °C and treated with solid NaHCO3 (90 mg, 1.07 mmol)
and methyl chloroformate (100 µL, 1.28 mmol). The solution was
stirred 1 h at 0 °C and another 2 h at 25 °C. Water was added, and
the reaction mixture was extracted with CH2Cl2. The organic layers
were washed with brine, dried (Na2SO4), and concentrated to give
300 mg of crude 37. Flash chromatography (2:1 hexanes/EtOAc)
gave 206 mg (55%) of pure 37, which is a 1:1 mixture of rotamers:
An identical reaction with (-)-23 afforded (-)-2: [R]25
)
D
-126.5 (c 0.4, CHCl3) [lit.4 [R]17 ) -288.9 (c 0.08, CHCl3)].
D
Following the procedure for conversion of 23 to 2, a slurry of
iodolactone 22 (89 mg, 0.25 mmol) in THF (6 mL) and activated
Zn (330 mg, 5.0 mmol) was treated with AcOH (1.5 mL) to give
91 mg of crude hydroxy acid 6. A solution of crude hydroxy acid
6 in dry pyridine (6 mL) was cooled at 0 °C and treated with TsCl
(96 mg, 0.50 mmol) to give 53 mg of crude 2. Flash chromatog-
raphy on MeOH-deactivated silica gel (4:1 hexanes/EtOAc) gave
26 mg (50%) of 2.
An identical reaction with (-)-22 afforded (-)-2: [R]25
)
D
-126.5 (c 0.4, CHCl3) [lit.4 [R]17 ) -288.9 (c 0.08, CHCl3)].
D
(1R*,5S)-3-(Hydroxymethyl)-1-(3-methyl-2-buten-1-yl)-6-oxa-
bicyclo[3.2.0]hept-2-en-7-one (Vibralactone, 1). NaBH4 (8 mg, 0.2
mmol) was added to a stirred solution of aldehyde 2 (20 mg, 0.1
mmol) in DME (5 mL) and H2O (two drops) at 0 °C. The solution
was stirred for 10 min and allowed to warm to 25 °C over 30 min.
The solvent was removed under reduced pressure. The residue was
taken up in EtOAc, and the solution was washed with water and
brine, dried (MgSO4), and concentrated to give 22 mg of crude 1.
Flash chromatography (2:1 hexanes/EtOAc) gave 15.6 mg (78%)
27
1
[R]25 ) -81.8 (c 1.16, CHCl3); H NMR 6.07 (br, 1, W1/2
)
D
20.0), 5.69 (br d, 1, J ) 9.6), 4.97 (br, 1, W1/2 ) 14.0), 4.28-3.94
(m, 3), 3.70 (br s, 0.5 × 3), 3.69 (br s, 0.5 × 3), 3.53-3.26 (m, 2),
2.78-2.37 (m, 6), 2.03-1.71 (m, 4), 1.66 (br s, 3), 1.60 (br s, 3);
13C NMR 207.0, 170.7, 155.4, 135.5, 129.3, 128.5, 118.0, (65.5,
65.1), 60.3, (55.9, 55.2), (52.4, 52.3), (46.9, 46.5), 38.0, 33.5, (28.6,
27.7), 25.9, 25.4, (23.8, 22.9), 17.9; IR (neat) 1740, 1702, 1450,
1385, 1214; HRMS (EI) calcd for C19H27NO5 (M+) 349.1889, found
349.1888.
1
of pure vibralactone (1): H NMR 5.62 (br s, 1), 5.13 (br dd, 1, J
) 7.6, 7.6), 4.81 (d, 1, J ) 4.4), 4.25 (br d, 2, J ) 4.8), 2.77 (dd,
1, J ) 19, 4.4), 2.75 (d, 1, J ) 19), 2.62 (dd, 1, J ) 15.2, 7.6),
2.43 (dd, 1, J ) 15.2, 7.6), 1.72 (br s, 3), 1.64 (br s, 3), 1.65-1.63
(1, OH, partially obscured by Me group); 13C NMR 172.9, 146.5,
(26) Rabideau, P. W.; Wetzel, D. M.; Paschal, J. W. J. Org. Chem. 1982,
47, 3993–3994.
J. Org. Chem. Vol. 73, No. 20, 2008 8055

Zhou and Snider
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 No. 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.
sion of the crystal structures and X-ray crystallographic data
1
(CIF files) for both (()- and (-)-21 and H and 13C NMR
spectral data. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO8015743
(27) For reports of similar carbamates as 1:1 mixtures or rotamers, see: (a)
Maia, H. L.; Orrell, K. G.; Rydon, H. N. J. Chem. Soc., Perkin Trans. 2 1976,
761–763. (b) Cox, C.; Lectka, T. J. Org. Chem. 1998, 63, 2426–2427. (c) Vargas-
Sanchez, M.; Lakhdar, S.; Couty, F.; Evano, G. Org. Lett. 2006, 8, 5501–5504.
Supporting Information Available: Experimental proce-
dures for all reactions not in the Experimental Section. Discus-
8056 J. Org. Chem. Vol. 73, No. 20, 2008