Addition of Cl2C: To (-)-O-menthyl acrylate under sonication-phase-transfer catalysis. Efficient synthesis of (+)- and (-)-(2-chlorocyclopropyl)methanol

Article abstract of DOI:10.1021/jo0480186

Dichlorocyclopropanation of (-)-O-menthyl acrylate under conditions of phase-transfer catalysis (CHCl₃, KOH, tetramethylammonium bromide), with sonication, gives excellent yields (85-94%) of the corresponding dichlorocyclopropanecarboxylate est

Full text of DOI:10.1021/jo0480186

Under the PTC conditions used for dichlorocyclopropa-
nation of 1 (CHCl3, 2 mol % Me4NBr, NaOH aq),1 we
found no reaction with (-)-5. Under more forcing condi-
tions (90-120 °C, sealed bomb, 36 h), disappointing yields
of the diastereomeric dichlorocyclopropanecarboxylate
esters 6a and 6b were obtained (∼56%, 1:1 dr), but only
after 24-36 h.3 Presumably, slower addition of Cl2C: to
the bulkier menthyl acrylate ester allowed competition
by undesirable side reactions of both product and starting
material. Subsequently, we found these side-products
could be bypassed through the use of PTC under condi-
tions of insonation propagated by ultrasound acoustics
[sonication, )))]. This report describes a rapid and high-
yielding dichlorocyclopropanation of (-)-5 under mild
sonication conditions to provide 6 in up to 94% yield,
followed by a facile separation of the crystalline diaste-
reomer, (+)-6a, and its subsequent transformation into
(+)-4a. This study also revealed insights into the mech-
anism of PTC-catalyzed addition of Cl2C: from measure-
ments of initial reaction rates. Our observation of a
significant deuterium isotope effect during the latter
reaction suggests that the rate-limiting step involves
deprotonation of CHCl3, probably within the bulk organic
phase.
Addition of Cl2C: to (-)-O-Menthyl
Acrylate under Sonication-Phase-Transfer
Catalysis. Efficient Synthesis of (+)- and
(-)-(2-Chlorocyclopropyl)methanol
Makoto N. Masuno, Douglas M. Young,
Alexander C. Hoepker, Colin K. Skepper, and
Tadeusz F. Molinski*
Department of Chemistry, University of California,
Davis, California 95616
tfmolinski@ucdavis.edu
Received November 7, 2004
Dichlorocyclopropanation of (-)-O-menthyl acrylate under
conditions of phase-transfer catalysis (CHCl3, KOH, tetram-
ethylammonium bromide), with sonication, gives excellent
yields (85-94%) of the corresponding dichlorocyclopropan-
ecarboxylate ester compared to thermal conditions (90 °C,
56%). No diastereoselectivity was observed, but one isomer
was isolated pure by fractional crystallization. The measured
kinetic isotope effect (initial rate (CHCl3)/rate (CDCl3) ∼1.7)
suggests deprotonation of CHCl3 as the rate-limiting step.
The use of ultrasound in promotion of PTC reactions
has met with success in some reactions.4 Only one report
describes the use of ultrasound for promotion of dihalo-
cyclopropanation of styrenes and terminal olefins with
heterogeneous haloform-trihalomethane mixtures under
thermal PTC conditions,5 but to the best of our knowledge
there are no accounts of ultrasound-promoted dichloro-
cyclopropanation of electrophilic alkenes.
Sonication of chloroform solutions of (-)-5 in the
presence of alkali metal hydroxides at ambient temper-
atures (25 °C) gave efficient conversion to the dichloro-
carbene adducts 6a,b (73-94%) within 90 min. A survey
of PTC catalytic addition of Cl2C: to (-)-5 with ultra-
sound (Table 1) revealed that the yields of dichlorocyclo-
propanation of (-)-5 were highly dependent upon the
structure of the PTC, in consonance with the findings of
Jonczyk and co-workers with tert-butyl acrylate esters.1
The best catalysts appear to be TMAB and dibenzo-18-
crown-6. Catalyst loading was important: high catalyst
concentration (20 mol %) seemed to suppress the reaction,
but loadings as low as 2% were effective. No detectable
product was formed when catalyst was absent or when
Triton B (N-benzyltrimethylammonium hydroxide, 40%
w/v in MeOH) or Ba(OH)2 was substituted for alkali
metal hydroxide. Yields were significantly higher when
solid sodium or potassium hydroxide was used instead
of 50% w/v aqueous solutions. The best yield of 6a,b (94%,
entry 7) was obtained with Me4N+Br- (5 mol %) and solid
KOH; however, high yields were also observed with
The use of phase-transfer catalysis in organic synthesis
results in dramatic improvement in yield for many
reactions, including alkylation of alcohols (Williamson
ether synthesis), conjugate additions, and dihalocarbene
addition. For example, the preparation of 2,2-dichloro-
cyclopropanecarboxylate esters has been achieved1 by
PTC-catalyzed heterogeneous reactions of chloroform
solutions of O-acrylate esters in the presence of strong
aqueous alkali (NaOH) (Figure 1). The reaction was
reported to be highly sensitive to the structure and
lipophilicity of the PT catalyst. Heating O-tert-butyl
acrylate (1) in the presence of CHCl3, aqueous NaOH
(50% w/v) and Me4N+Br- (2 mol %, 45-50 °C, 8 h) gave
a modest yield of the corresponding (()-O-tert-butyl 2,2-
dichlorocyclopropylcarboxylate ester (2, ∼57%).1 Use of
longer chain N-tetraalkylammonium salts (e.g., n-Bu4N+-
HSO4-) under the same conditions gave product mix-
tures, predominately the Michael adduct of the CCl3
anion to 1 and compounds that arise from subsequent
side reactions.
To fulfill a need for both optically pure enantiomers of
trans-(2-chlorocyclopropyl)methanol (4) we investigated
the addition of Cl2C: to (-)-O-menthyl acrylate [(-)5].2
(2) Meth-Cohn, O. J. Chem. Soc., Chem. Commun. 1986, 695-697.
(3) Caution! High pressure. One trial reaction of 5 with CHCl3 and
50% w/v aq NaOH contained in a heavy glass pressure vessel at
elevated temperature (∼100-120 °C) led to an explosive failure of the
glass vessel. We surmised the cause was either excessive solvent vapor
pressure or an unidentified exotherm (“runaway” reaction).
(4) Cains, P. W.; Martin, P. D.; Price, C. J. Org. Proc. Res. Dev. 1998,
2, 34-38.
* To whom correspondence should be addressed. Tel: (530) 752-
6358. Fax: (530) 752-8995.
(1) (a) Fedoryn´ski, M.; Ziołkowska, W.; Jon´czyk, A. J. Org. Chem.
1993, 58, 6120-6121. (b) Dehmlow, E. V. Liebigs Ann. Chem. 1972,
758, 148-154.
(5) Xu, L.; Tao, F. Synth. Commun. 1988, 18, 2118-2121.
10.1021/jo0480186 CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/21/2005
4162
J. Org. Chem. 2005, 70, 4162-4165

FIGURE 1. PTC-catalyzed addition of Cl2C: to acrylate esters.
TABLE 1. Phase-Transfer Catalyst-Promoted
Dichlorocarbene Additions to Acrylate Ester (-)-5 under
Sonication To Give 6a,b
[(-)-5]a
base
mol yieldb
entry
1
(M)
solvent (17 equiv)
catalystd
TMAB
%
(%)
0.60
CHCl3 NaOH
(50% w/w)
20 68
2
3
0.60
0.60
0.60
0.60
0.60
0.60
0.60
0.60
0.60
0.60
0.20
0.05
CHCl3 KOH (s)
CHCl3 KOH (s)
CHCl3 NaOH (s)
CHCl3 Triton Bc
CHCl3 NaOH (s)
CHCl3 KOH (s)
DB-18-c-6
DB-18-c-6
10 43
5
84
4
cetyl-TMAB 10 17
5
5
5
0
6
TMAB
TMAB
80
7
5
88 (94d)
8
CHCl3 Ba(OH)2 (s) TMAB
5
10
10
0
0
9
CHCl3 KOH (s)
CHCl3 NaOH (s)
CHCl3 KOH (s)
CHCl3 KOH (s)
CHCl3 KOH (s)
18-c-6
7
10
11
11
12
0
0
TMAB
TMAB
5
5
83
52e
a (-)-O-Menthyl acrylate [(-) 5, 0.6 M, 0.6 mmol] in CHCl3
solution (21 equiv of CHCl3). The mixture was sonicated in a
tightly sealed borosilicate glass scintillation vial (20 mL capacity)
for 90 min, and products were analyzed by GCMS (DB-5MS 30 m
× 320 µm i.d., 0.2 m film, He ∼1 mL/min. internal standard )
1,2,4,5-tetramethylbenzene). Temperature was not controlled (ul-
trasound bath, T ) 22-35 °C). b % yields were determined from
GC integrations and comparison with standard 6a,b. c Abbrevia-
tions: TMAB, tetramethylammonium bromide; DB-18-c-6, dibenzo-
18-crown-6; cetyl-TMAB, N-cetyl-N-trimethylammonium bromide;
Triton-B, N-benzyl-N-trimethylammonium hydroxide (40% w/v in
MeOH). d Isolated yield, preparative run (47.5 mmol). e 60 min
reaction.
FIGURE 2. Rate of formation of 6a,b from (-)-5 (initial c)
0.05M in CHCl3 or CDCl3) in the presence of solid KOH and
Me4NBr (5 mol %), T ) 24 °C.8 Data were averaged from
duplicate samples at each time point. Error bars are (1 σ.
reaction was substantially slower (apparent initial rate
) 4.5 × 10-6 mol‚L-1‚s-1; kinetic isotope effect, ∼1.7)
which suggested the rate-determining step involved
deprotonation of CHCl3 by HO-.
Several possible mechanisms are consistent with the
results; however, we favor the pathway shown in (Figure
3) for the following reasons. The reaction proceeds by PTC
mediated-transport of HO- into bulk CHCl3 phase to
produce tetralkylammonium ion pairs that rapidly attain
steady-state concentration under sonication in accord
with the Makosza model for PTC alkylation using te-
tralkylammonium salts of low lipophilicity.7 Rate-limited
deprotonation of CHCl3 (possibly also at the phase
interface) and ion-exchange gives a steady-state concen-
tration of Me4N+ Cl3C- anion. Rapid decomposition of the
latter by loss of Cl- generates dichlorocarbene (Cl2C:),
which diffuses from the collapsed Me4N+ Cl- ion pair and
adds to the CdC double bond of the acrylate ester. The
role of ultrasound, in addition to exposing reactive KOH
surface through physical dispersive effects associated
with cavitation,4 may also promote the reaction by
providing the energy for reorganization of the solvated
tetraalkylammonium ion pairs which is necessary to
allow deprotonation of CHCl3 and ion-exchange. We
attach important significance to the observation that high
Me4N+Br- (solid NaOH) and dibenzo-18-crown-6 (solid
KOH). Diastereoselectivity was not observed under any
of the reaction conditions, which is not surprising since
ultrasound reaction conditions are highly enthalpic and
predisposed to stochastic outcomes with no diastereose-
lection.4 Attempts to induce asymmetric control with the
chiral PT catalyst N-benzylcinchonidinium chloride, (7,
entry 10) were unsuccessful.
Although the two diastereomers 6a,b were difficult to
separate by silica chromatography, fractional crystalliza-
tion in pentane at -78 °C cleanly resolved the mixture
to provide crystalline (+)-6a [>95% de, mp 76 °C, [R]D )
+1.88 (c 1.17, CHCl3)]. Diastereomerically enriched (-)-
6b was recovered from the supernatant [75% de, oil, [R]D
-89.2 (c 1.42, CHCl3)].
The mechanism of the reaction was briefly investigated
by measurement of initial rates and isotope effects. A
brief kinetic investigation, carried out under “isothermal
conditions” (bath temperature maintained at 24 °C) using
(-)-5 (initial c ) 0.05 M) and other conditions similar to
those of entry 7 (Table 1). The initial rate of reaction with
CHCl3 (Figure 2), under conditions similar to those in
entry 7,6 follows apparent zero-order kinetics in (-)-5
(apparent initial rate ) 7.5 × 10-6 mol‚L-1‚s-1). When
CDCl3 was substituted for CHCl3, the initial rate of
(6) Although only initial rates were used for calculation of the isotope
effect, progression of the reaction in the presence of KOH and CDCl3
resulted in accumulation of DOH, HO-, and rising concentration of
CHCl3 through deuteron exchange. Consequently, the apparent isotope
effect (kH/kD ∼ 1.7) may be underestimated in these experiments.
(7) Makosza, M. Pure App. Chem. 1975, 43, 439.
J. Org. Chem, Vol. 70, No. 10, 2005 4163

FIGURE 3. Proposed mechanism of ultrasound-promoted PTC dichlorocyclopropanation of (-)-5.
catalyst loading (20 mol %) suppresses the yield of the
reaction, which suggests a partitioning of reaction path-
ways, or more likely, sequestration of Cl3C- anion as
aggregated ion-pairs. Aggregation of tetralkylammonium
ion-pairs may further stabilize Cl3C- anion and slow the
decomposition to Cl2C:, or possibly impede the diffusion
of the carbene to the acrylate substrate. An alternate
mechanism for formation of (6a,b conjugate addition of
trichloromethyl anion, followed by intramolecular SN2
displacement of chloride by the incipient tetralkylam-
monium enolate) is ruled out. Reaction of (-)-5 with
CCl3- generated independently (spontaneous decarboxy-
lation of NaO2CCCl3 in anhydrous DMF)8 gave only the
conjugate addition product 8 and no detectable 6a,b
(NMR).
lectivity. Reduction of the corresponding diastereomer
(-)-6b gave the enantiomeric alcohol (-)-4b.
Since both diastereomers of 6 are made accessible by
the combination of PTC-promoted sonication of acrylate
(-)-5 followed by facile resolution by crystallization, the
processstogether with subsequent LiAlH4 reductions
constitutes an efficient, scalable two-step synthesis of (+)-
4a or (-)-4b. The procedure represents a marked im-
provement both in yield and number of steps over
previous methods, which were achieved by enzymatic
resolution or asymmetric transformation.10
Diastereoselective reduction of (+)-6a, with concomi-
tant mono-dechlorination, was effected using literature
conditions (LiAlH4, THF, 56 °C, 2-4 days)9 to give the
known trans alcohol, (+)-(1R,2S)-4a,9b exclusively ([R]24
D
+59 (c 0.57, CHCl3; lit. [R]27 +58 (c 1.0, CHCl3)9b). The
D
latter provided proof for the configuration of (+)-6a.
Under literature conditions, reduction was sluggish and
the yields variable. Examination of the time-course of the
reduction (GLC) showed that ester reduction to the
corresponding 2,2-dichlorocyclopropylmethanol occurred
relatively rapidly, but the reductive displacement of Cl
was rate-limiting. We presume that SN2 displacement of
the Cl bond occurs by an intramolecular SN2 mechanism
through an O-menthoxyhydridoaluminate intermediate
as the product is exclusively trans. We also surmised the
slow reaction is due to the bulky menthoxyl group which
impedes collinear backside attack at the C-Cl bond and
that it might be possible to compensate by raising the
temperature of the reduction. Indeed, when (+)-6a was
treated with LiAlH4 in refluxing DME, the reaction was
complete in less than 16 h and the product (+)-4a was
obtained cleanly (91% yield) with no erosion of stereose-
In summary, an efficient dichlorocyclopropanation of
(-)-menthyl acrylate (1) followed by reduction of the
product (+)-6a provides an efficient two-step preparation
of enantiopure (+)-4a. Kinetic evidence supports a mech-
anism of PTC-promoted dichlorocarbene addition to acry-
late esters through a mechanism in which the rate-
dependent step involves deprotonation of CHCl3 by
tetralkylammonium hydroxide, probably in bulk chloro-
form phase, although we cannot rule out the possibility
of a reaction that is rate-limited at the solid-liquid
interface.
Experimental Section
All chemicals were of reagent grade purity or better and were
used without further purification. Chloroform was distilled prior
to use to remove ethanol preservative (EtOH-CHCl3 azeotrope)
(8) The mild conditions for generation of Cl3C- anion, first noted
by Corey and co-workers, had been exploited for preparation of
trichloromethylcarbinols by 1,2-addition of Cl3C- to aldehydes. Corey,
E. J.; Link, J. O.; Shao, Y. Tetrahedron Lett. 1992, 33, 3435-3438. In
our study, addition of a solution of 5 (0.21 M) in DMF to a mixture of
stirred anhydrous NaO2CCl3 (1.5 equiv) in DMF at room temperature
lead to rapid initial spontaneous evolution of CO2 within minutes, but
formation of 8 took place more slowly (∼quant, after about 12 h). These
results attest to a remarkable stability of Cl3C-Na+ at ambient
temperatures under these conditions.
(9) (a) Nadim. A. M.; Romashin, Y. N.; Kulinkovich, O. G. J. Org.
Chem USSR 1992, 1419-1422. (b) Olivo, H. F.; Velaquez, F.; Trevisan,
H. C. Org. Lett. 2000, 2, 4055-4058. The Supporting Information for
ref 9b states an erroneous CIP description - (1S,2R) - in the title for
preparation of (+)-4 [(+)-4a, in our numbering], it should be (+)-(1R,
2S)-4.
(10) The Olivo preparation (ref 9b) of (+)-4 from 1 was achieved
using a four-step procedure which required two separate reduction
steps in order to exploit an efficient lipase-catalyzed kinetic resolution
of the primary alcohol. Paterson and co-workers prepared optically
enriched 4 (98% ee) in two steps from epichlorohydrin (Paterson, I.;
Davies, R. D. M.; Marquez, R. Angew. Chem., Int. Ed. 2001, 40, 603-
607). The volatile aldehyde corresponding to 4 has also been prepared
by Evans (five-step procedure from 1,2:5,6-di-O-cyclohexylidene-D-
mannitol: Evans, D. A.; Burch, J. D. Org. Lett. 2001, 3, 503-505) and
Trost (seven-step synthesis from di-O-menthyl fumarate: Trost, B. M.;
Gunzer, J. L.; Dirat, O.; Rhee, Y. H. J. Am. Chem. Soc. 2002, 124,
10396-10415).
4164 J. Org. Chem., Vol. 70, No. 10, 2005

and stored in the dark in a sealed amber bottle. CH2Cl2 and
THF were dried by passage through commercial alumina solvent
purification cartridges. GC analyses were performed on a
capillary column instrument and GC-MS determinations on an
ion-trap GC-MS instrument. Specific rotations, [R]D, were
measured at T ) 24 °C and concentration c expressed in g/100
mL. Assignment of 1H and 13C NMR signals was made by
interpretation of gCOSY, NOESY, DEPT, and gHSQC NMR
experiments and comparison with the assigned chemical shifts
of (-)-menthol. The enantiomeric purity of 4a,b was carried out
by by GC using a Cyclodex B column (10.5% â-cyclodextrin in
DB1701, 0.25 µm film × 30 m). Other procedures can be found
elsewhere.11
Hz, H4a), 1.91 (dd, 1H, J ) -6.8, 2.8 Hz, H7′), 1.85 (dd, 1H, J
) 10.0, 7.2 Hz, H4b), 1.38 (m, 1H, H5′), 0.92 (d, 3H, J ) 7.0 Hz,
H10′), 0.90 (d, 3H, J ) 7.0 Hz, H8′ or H9′), 0.76 (d, 3H, J ) 7.2
Hz); 13C NMR (CDCl3) δ 166.6 (s, C1), 76.4 (d, C1′), 57.7 (s, C3),
47.0 (d, C2′), 41.1 (t, C6′), 33.6 (d, C2), 31.6 (d, C5′), 26.3 (d,
C7′), 26.1 (t, C4), 23.5 (t, C3′), 22.1 (q, C10′), 20.9 (q, C8′ or C′9′),
16.4 (q, C9′ or C8′); HR DCIMS m/z 310.1350 [M + NH4]+ (calcd
C14H26Cl2NO2 310.1335). 6b: oil; [R]D ) -89.2 (c 1.42, CHCl3);
IR (NaCl) ν 2956, 2928, 2870, 1734, 1371 cm-1; 1H NMR (CDCl3)
δ 4.74 (dt, 1H, dt, J ) 10.8, 4.4 Hz, H1′), 2.55 (dd, 1H, J ) 10.0,
8.0 Hz, H2), 2.07 (dd, 1H, J ) 8.0, 7.2 Hz, H4a), 1.91 (hd, J )
6.8, 2.8 Hz, 1H, H7′), 1.83 (dd, 1H, J ) 10.0, 7.2 Hz, H4b), 0.91
(d, 3H, J ) 6.8 Hz, H10′), 0.90 (d, 3H, J ) 6.8 Hz, H8′ or H9′),
0.76 (d, 3H, J ) 6.8 Hz, H9′ or H8′); 13C NMR (CDCl3) δ 166.1
(s, C1), 76.0 (d, C1′), 57.4 (s, C3), 46.9 (t, C6′), 34.1 (t, C4′), 33.6
(d, C2), 31.4 (d, C5′), 26.1 (d, H7′), 26.0 (t, C4), 23.3 (t, C3′), 22.0
(q, C10′), 20.7 (q, C8′ or C9′), 16.2 (q, C9′ or C8′); HR DCIMS
m/z 310.1329 [M + NH4]+ (calcd C14H26Cl2NO2 310.1335).
Reduction of (+)-6a. (+)-Chlorocyclopropylmethanol
(4a). Reduction of the menthyl ester (+)-6a was carried out with
LiAlH4 using a modification of the procedure described by Nadim
and co-workers.9a A mixture of LiAlH4 (0.64 g, 17 mmol) in dry
DME (15 mL) was heated at reflux for 6 h before dropwise
addition of a solution of (+)-6a (800 mg, 2.73 mmol) in DME (4
mL). After 12 h, the mixture was cooled in an ice-water bath
and the excess hydride quenched by addition of wet ether
(Caution! Evolution of hydrogen) followed by 4 M NaOH aq.
Extractive workup of the reaction mixture with Et2O followed
by careful flash chromatography (silica, 95:5 CH2Cl2/Et2O) and
removal of solvent at atmospheric pressure gave essentially pure
(+)-(1R,2S)-4a (91%). Chiral GC analysis showed the product
to have >99% ee [([R]24D +59 (c 0.57, CHCl3) (lit.9b [R]27D +58 (c
1.0, CHCl3) for (+)-4]. 1H and 13C NMR spectral properties
matched those of literature values.9b
(-)-Menthyl Acrylate [(-)-5]. Ester (-)-5 was prepared by
base-promoted transesterification according to a modification
of a literature procedure.2 Briefly, lithium menthoxide, pre-
pared by addition of n-butyllithium in hexanes (2.8 M) to (-)-
menthol in dry THF, was treated with O-methyl acrylate in THF
(0 °C to rt). After completion of the reaction and extractive
workup, (-)-5 was obtained in 66% yield ([R]24 -96.4 (c 1.5,
D
CHCl3) [lit.12 -85.4 (c 0.97, CH2Cl2)]. Standard esterification
conditions (acryloyl chloride, (-)-menthol, pyridine, DMAP) gave
inferior yields of (-)-5 (<20%).
Preparative-Scale Dichlorocarbene Addition. Menthyl
Dichlorocyclopropylcarboxylates (+)-6a and (-)-6b. A
solution of (-)-5 (10.0 g, 47.5 mmol) in CHCl3 (final concentration
) 0.6 M) in a 250 mL round-bottom flask was treated with
TMAB (0.366 g, 2.38 mmol, 5 mol %) and powdered KOH (89 g,
1.5 mol, 33 equiv). The flask was immediately sealed with a
rubber septum and the mixture sonicated by immersion in an
ultrasonic cleaning bath (Fisher FS60, 40 kHz, 150 W) contain-
ing ice-water (initial temperature: 0 °C, rising to 25 °C over 3
h), with occasional venting (Caution! Exotherm). The mixture
was cooled and diluted with 1:3 MTBE/hexane, and the filtered
solution washed with aqueous sodium phosphate buffer (0.1 M,
pH 7.5). After drying, the combined extracts (Na2SO4) were
concentrated, and the crude product was purified by silica
chromatography (1:5 CH2Cl2/n-hexane) to give the diastereo-
meric mixture 6a,b (1:1, 13.1 g, 94%). The mixture was dissolved
in pentane (13% w/v) and placed in a low-temperature freezer
(-80 °C) for 1-3 days whereupon crystals of pure (+)-6a (mp
Reduction of (-)-6a. (-)-Chlorocyclopropylmethanol
(4b). Reduction of (-)-6b (88% de, GC) was carried out using
LiAlH4 in refluxing DME, as described for (+)-6a, to give (-)-
4b ([R]27 -54 (c 0.44, CHCl3)).
D
Acknowledgment. We thank J. Berg (UC Davis,
Department of Chemistry) and S. Stanley (Equine
Analytical Chemistry Laboratory, UC Davis, CA) for
help with GCMS measurements, C. Liu for initial
preparation of 6a,b mixtures, and R. New (UC River-
side) for high-resolution mass spectra. This work was
funded by the NIH (CA 85602).
1
76 °C, >95% de, H NMR integration) were deposited, leaving
behind 6b (∼75-88% de) in the mother liquors. 6a: mp 76 °C;
[R]D ) +1.88 (c 1.17, CHCl3); IR (NaCl) ν 2952, 2930, 2870, 1728,
1
1385 cm-1; H NMR (CDCl3) δ 4.74 (td, J ) 10.8, 4.4 Hz, H1′),
2.54 (dd, 1H, J ) 10.0, 8.0 Hz, H2), 2.07 (dd, 1H, J ) 8.0, 7.2
Supporting Information Available: 1H and 13C NMR
spectra of (+)-6a and (-)-6b. This material is available free
of charge via the Internet at http://pubs.acs.org.
(11) Searle, P. A.; Molinski, T. F. J. Org. Chem. 1993, 58, 7578-
7580.
(12) Lee-Ruff, E.; Xi, F.; Qie, J. H. J. Org. Chem. 1996, 61, 1547-
1550. (b) Moureu, C.; Murat, M.; Tampier, L. C. R. Hebd. Seances Acad.
Sci. 1921, 172, 1269.
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