Halide ion effects in the rhodium-catalyzed allylic substitution reaction using copper(I) alkoxides and enolates

Article abstract of DOI:10.1016/j.tetasy.2003.08.044

The transmetallation of lithium alkoxides and enolates with a copper(I) halide salt provides the requisite nucleophiles to accomplish the stereospecific rhodium-catalyzed allylic substitution. These studies demonstrate that the nature of the halide ion derived from the copper(I) salt has a profound effect on regioselectivity and enantiospecificity. This observation was attributed to the trans-effect, by virtue of an in situ modification of the catalyst by the halide ion, which leads to modulated catalytic activity and improved stereospecificity.

Full text of DOI:10.1016/j.tetasy.2003.08.044

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3613–3618
Halide ion effects in the rhodium-catalyzed allylic substitution
reaction using copper(I) alkoxides and enolates
P. Andrew Evans,* David K. Leahy and Laura M. Slieker†
Department of Chemistry, 800 E. Kirkwood Ave., Indiana University, Bloomington, IN 47405, USA
Received 17 July 2003; accepted 6 August 2003
Abstract—The transmetallation of lithium alkoxides and enolates with a copper(I) halide salt provides the requisite nucleophiles
to accomplish the stereospecific rhodium-catalyzed allylic substitution. These studies demonstrate that the nature of the halide ion
derived from the copper(I) salt has a profound effect on regioselectivity and enantiospecificity. This observation was attributed to
the trans-effect, by virtue of an in situ modification of the catalyst by the halide ion, which leads to modulated catalytic activity
and improved stereospecificity.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
unique and useful specificity can be obtained due to the
propensity for the substitution to occur through a
configurationally stable distorted p-allyl or enyl (s+p)
organorhodium intermediate.2–5 The alkali metal salts
of stabilized carbon, nitrogen, and oxygen nucleophiles
provide efficient cross-coupling partners in the
rhodium-catalyzed allylic substitution using malonates,2
tosylamides,3 and phenols.4 Conversely, unstabilized
nucleophiles, as exemplified by alkali metal alkoxides6
and enolates,7 were unsatisfactory due to competing
side reactions and poor selectivity. We anticipated that
the reactivity of alkoxide and enolate nucleophiles
could be modulated through transmetallation with a
copper(I) halide salt, and thereby soften the nucle-
ophile. Indeed, copper(I) alkoxides8 and enolates9
provide optimum nucleophiles for the rhodium-allyl
electrophile, as judged by the excellent specificity.10,11
Herein, we describe a surprising halide effect on
regioselectivity and enantiospecificity in the context of
these reactions.12 We also demonstrate that the allylic
alkylation with copper enolates can be achieved using
significantly reduced catalyst loading (0.5 mol%) with
excellent regioselectivity and enantiospecificity, without
dramatically compromising yield and specificity, mak-
ing this a potentially useful transformation for process
scale synthesis.
The transition metal-catalyzed allylic substitution is an
important method for carbonꢀcarbon and car-
bonꢀheteroatom bond construction, since it allows the
introduction of a wide range of nucleophiles into an
allylic framework (Eq. (1)).1 Stabilized nucleophiles are
typically employed in this type of reaction, due to the
soft nature of the transition metal–allyl electrophile,
whereas unstabilized nucleophiles are less common
since they react through an alternative mechanism
involving direct nucleophilic attack at the metal center.
Nonetheless, the major limitation with this process has
been the necessity to utilize allylic substrates that gener-
ate symmetrical metal–allyl intermediates in order to
circumvent regiochemical infidelity. An equally impor-
tant and challenging aspect of this transformation is the
ability to control the absolute configuration of the
newly formed stereogenic center.
(1)
The stereospecific rhodium-catalyzed allylic substitution
provides a novel approach to this problem, in which
2. Results and discussion
Preliminary studies demonstrated that alkali metal
alkoxides were not suitable nucleophiles for the
rhodium-catalyzed allylic etherification reaction due to
* Corresponding author. Tel.: (812) 855-7368; fax: (812) 856-0184;
e-mail: paevans@indina.edu
† Undergraduate participant.
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.08.044

3614
P. A. E6ans et al. / Tetrahedron: Asymmetry 14 (2003) 3613–3618
extensive side reactions (Table 1, entry 1). However, the
transmetallation of the lithium alkoxide with copper(I)
cyanide led to an efficient etherification, albeit with no
discernable selectivity (entry 2). The utilization of a
copper(I) halide salt led to a significant improvement in
selectivity, in which there was a pronounced halide
effect (I > Br > Cl) on regioselectivity (entries 3–5).13
Additional improvements in the efficiency of the trans-
formation were realized by increasing the steric bulk of
the leaving group to suppress competitive transac-
ylation (entry 6).
Encouraged by the excellent regioselectivity, we turned
our attention to stereospecificity. A general assessment
of the metal-catalyzed allylic alkylation indicates that
the reaction could proceed through either a configura-
tionally stable enyl ii or
a distorted p-allyl iii
organometallic species, as depicted in Figure 1. We had
originally envisioned that the stereospecificity could be
maintained by suppressing the rate of isomerization of
the initial enyl or metal–allyl intermediate relative to
SN2% substitution, by adjusting the electronic environ-
ment and/or coordination sphere of the metal.
Although the dynamics of this isomerization are com-
plex, the ability to control the rate of isomerization
provided the key to the stereospecific metal-catalyzed
allylic substitution reaction. Hence, in order for the
etherification reaction to be stereospecific, nucleophilic
trapping by the copper(I) alkoxide must be faster than
racemization of the rhodium–allyl intermediate (i.e. for
i k2ꢀk1 and for ent-i k2%ꢀk−1) through a (p-s-p) iso-
merization mechanism (Fig. 1).
This halide ion effect is most easily explained through
an in situ salt metathesis reaction between the
rhodium–chloride catalyst and the resulting lithium
cyanide or halide salts.14 Thus, the rhodium–iodide
catalyst appears to be the most effective in terms of
affording the branched product selectively, while the
rhodium–cyanide catalyst shows no preference for
either regioisomer. Additional studies demonstrated the
rhodium-catalyzed allylic etherification is compatible
with primary, secondary, and tertiary copper alkoxides
using an array of substituted secondary allylic
carbonates.10
The examination of the stereospecificity of the etherifi-
cation provided the most dramatic halide effect, as
outlined in Table 2. Treatment of enantiomerically
enriched allylic carbonate (R)-1b (94% ee) under opti-
mized conditions, furnished the allyl ether (R)-2b in
84% yield (2°:1°]99:1), albeit with poor enantiospecifi-
city (41% cee; entry 1). This result represented a signifi-
cant departure from our earlier studies and thus
prompted the examination of the other copper(I) halide
salts. Interestingly, the transmetallation with copper(I)
chloride or bromide, furnished the allylic ether (R)-2b
with significantly improved chirality transfer (entries
2–3). Moreover, the trend for enantiospecificity is
opposite that for regioselectivity, indicating that they
are independent of one another. Additional work
demonstrated that the optimal stereospecificity was
obtained at lower temperature (entry 4).
Table 1. Effect of copper(I) salts on the regioselective
rhodium-catalyzed allylic etherification
Entry
Leaving group
Lga
X
2°:1°
Yield
(%)c
2a:3ab
1
2
3
4
5
6
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
–
9:1
1:1
44:1
72:1
]99:1
]99:1
4
73
58
66
73
96
CN
Cl
Br
I
While it is difficult to completely discount the role of
the halide on the metal center’s ability to influence the
rate of nucleophilic trapping, this cannot be excluded as
a possibility. However, a more likely scenario involves
the halide’s ability to influence the rate of p-s-p isomer-
ization. This phenomenon is supported by the fact that
the amount of racemization caused by the various
rhodium–halide catalysts parallels the strength of the
trans-effect15,16 attributed to each halide ligand (I > Br
> Cl). Thus if the p-component of the enyl ligand is
trans to the halide in the rhodium–allyl intermediate,
then dissociation of the p-component of the enyl inter-
mediate, leading to a s-allyl will be most facile when
the halide ligand is iodide. Although speculative, this
trans-effect adequately explains the observed trend in
enantiospecificity for the etherification reaction.
t
CO2 Bu
I
a All reactions were carried out on a 0.5 mmol reaction scale using 10
mol% of RhCl(PPh3)3 modified with 40 mol% P(OMe)3, 1.9 equiv.
of the lithium alkoxide, and 2.0 equiv. of CuX.
b Ratios of regioisomers were determined by capillary GLC on
aliquots of the crude reaction mixture.
c GLC yields.
In light of the halide effects, we decided to probe the
role of the copper alkoxide and the lithium halide,
derived from the transmetallation, by preparing the
copper alkoxide under salt free conditions, as outlined
in Table 3. Mesityl copper was chosen to provide the
copper(I) alkoxide because the metal halide salts are
removed during its preparation. Interestingly, only a
Figure 1.

P. A. E6ans et al. / Tetrahedron: Asymmetry 14 (2003) 3613–3618
3615
Table 2. Influence of the copper(I) halide salt on enan-
tiospecificity
Table 3. Probing the role of lithium iodide and the cop-
per(I) alkoxide in the allylic etherification
Basea
Additive
2°:1°
Yield
(%)c
Entry
Copper
Temp.
2°:1°
cee
Yield
(%)d
Entry
halide salta
2b:3bb
(%)c
2b:3bb
1
2
3
4
CuI
0°C–RT ]99:1
0°C–RT 91:1
0°C–RT ]99:1
−10°C ]99:1
41
85
88
96
84
86
81
81
1
2
3
4
LiHMDS
Mesityl copper
LiHMDS
CuI
–
LiI
LiI
]99:1
7:1
86:1
84
3
4
CuBr
CuCl
CuCl
Mesityl copper
]99:1
76
a All reactions were carried out on a 0.5 mmol reaction scale.
b Ratios of regioisomers were determined by capillary GLC on the
crude reaction mixture.
a All reactions were carried out on a 0.5 mmol reaction scale.
b Ratios of regioisomers were determined by capillary GLC on the
crude reaction mixture.
c Enantiomeric excess was determined by chiral capillary GLC.
d GLC yields.
c GLC yields.
Treatment of the enantiomerically enriched secondary
allylic carbonate (S)-1b% with the lithium enolate of
acetophenone, transmetallated with copper(I) iodide,
using 10 mol% of the trimethylphosphite-modified
Wilkinson’s catalyst at 0°C, furnished the alkylation
product (R)-4b in 91% yield with excellent regioselectiv-
ity and enantiospecificity (2°:1°]99:1, cee=100%, Eq.
(2)). In light of the immense synthetic utility of this
transformation, additional studies focused on reducing
the catalyst loading to make the reaction more cost
effective. Interestingly, the amount of catalyst was read-
ily reduced without significantly compromising selectiv-
ity, and with similar efficiency, albeit with slightly more
dialkylation (13%).17 Hence, the rhodium-catalyzed
allylic alkylation of (S)-1b% with the copper enolate of
acetophenone was performed on a 100 mmol scale with
only 0.5 mol% catalyst, to afford the ketone (R)-4b in
trace of product was observed in the absence of lithium
iodide (entry 2). Conversely, the addition of lithium
iodide to the lithium alkoxide also furnished a trace
amount of the allylic ether 2b, indicating the necessity
for copper (entry 3). When lithium iodide is added to
the copper alkoxide derived from the alcohol and
mesityl copper, analogous turnover and regioselectivity
are obtained (entry 4 vs 1). This clearly indicates that
the copper alkoxide and lithium iodide are both
required for optimal catalytic activity.
Although the exact role of lithium iodide remains
unclear, it may function to reconstitute a catalytically
inactive rhodium–alkoxide complex into a catalytically
active rhodium–halide complex. The addition of lithium
iodide to the reaction with a lithium alkoxide is catalyt-
ically inferior, proving that the copper is vital to the
reaction. It appears that the copper(I) alkoxide is cru-
cial for nucleophilic trapping of the soft rhodium–allyl
electrophile, while lithium iodide, derived from the
transmetalation, may be involved in regenerating the
active catalyst.
70% yield with excellent selectivity (2°:1° >
6 99:1, cee=
95%).
The concept of modulating the reactivity of a nucle-
ophile through the transmetalation with a copper(I)
halide was extended to enolates with the notion that
this would soften its basic character. We anticipated
that the copper(I) enolate would circumvent problems
associated with the corresponding lithium enolate,
namely polyalkylation, poor regio- and stereocontrol
and poor chemical yield. Preliminary optimization
demonstrated that although the transmetalation is cru-
cial for efficient conversion and selectivity, the nature
of the copper(I) halide salt was inconsequential to the
stereospecificity (IꢁBrꢁCl), in sharp contrast to the
previous studies with copper alkoxides. This is due
presumably to the favorable matching of the nucle-
ophilicity the copper(I) enolate with the rhodium-allyl
intermediate, which results in direct alkylation prior to
equilibration via p-s-p isomerization.
(2)
The stereocontrolled construction of 1,3-carbon stereo-
genic centers, including pseudo C2-symmetrical frag-
ments, represent an important process for organic
synthesis.18 We envisioned that acetophenone could
serve as a linchpin, allowing two sequential allylic
alkylations to provide the ketone 5a, which upon
desymmetrization could afford the potentially useful
synthon 6 in an expeditious manner (Scheme 1). The
second allylic alkylation, using the copper iodide
derived enantiomerically enriched enolate (R)-4b and
the allylic carbonate (S)-1b% (97% ee) proved a consider-
ably more challenging alkylation than expected, provid-
ing 5a/b in 77% yield, albeit with modest diastereo-

3616
P. A. E6ans et al. / Tetrahedron: Asymmetry 14 (2003) 3613–3618
selectivity favoring 5a (ds=5:1, 2°:1°=34:1). Since the
reaction is otherwise identical to the previous alkylation
(Eq. (2)), the poor diastereocontrol is presumably the
result of equilibration of the rhodium–allyl intermedi-
ate, which is due in part to a slower alkylation with the
more sterically hindered enolate of (R)-4b. We antici-
pated that the poor diastereoselectivity could be cir-
cumvented using a different copper(I) halide salt, with
the expectation that the rhodium–allyl intermediate
would be less prone to equilibration. Treatment of the
allylic carbonate (S)-1b% with the copper enolate of
(R)-4b derived from the transmetallation with copper
chloride, furnished 5a in 74% yield, and with excellent
tution. This study also demonstrated that the nature of
the halide ion derived from the copper(I) salt has a
profound effect on regioselectivity and enantiospecific-
ity. This observation was attributed to the trans-effect,
by virtue of an in situ modification of the catalyst by
the halide ion, leading to modulated catalytic activity
and ultimately improved stereospecificity. We also
demonstrated that the catalyst loading could be signifi-
cantly reduced upon scale-up, for the enolate alkyla-
tion, making it a more attractive method for process
development. Overall, this work provides yet another
example of the important role that halides play in
metal-catalyzed reactions.
diastereoselectivity
(ds=24:1,
2°:1°=37:1).
The
improved diastereoselectivity is consistent with the
trend observed using copper(I) alkoxides, wherein the
chloride ion show enhanced stereospecificity as com-
pared to their iodide derived counterparts.
4. Experimental
4.1. General
All reactions were carried out in flame-dried glassware,
and under an atmosphere of argon or nitrogen. Tetra-
hydrofuran (THF) was continuously distilled from
sodium benzophenone ketyl, N,N-dimethylformamide
(DMF) was distilled from CaH2, dimethylsulfoxide
(DMSO) was used without purification or drying.
Trimethyl phosphite was distilled from CaH2 and
,
stored over 4 A molecular sieves. Benzyl alcohol was
distilled from MgSO4 and stored over 3 A molecular
,
sieves. Acetophenone was distilled from MgSO4. All
copper salts were dried in a vacuum at 160°C for 12 h
and stored in the dark. Lithium iodide was dried in a
vacuum at 160°C for 12 h and stored and handled in a
glove box. Mesityl copper was prepared using literature
procedures, stored, and handled in a glove box.20 N-
Bromosuccinimide was recrystallized from water and
dried in a vacuum desiccator over P2O5. All allylic
carbonates were prepared using literature procedures
and distilled before use. All other reagents were pur-
chased from Acros, Aldrich, Fluka, or Lancaster chem-
ical companies and were used without purification
unless otherwise noted. Thin-layer chromatography
(TLC) was performed on Merck 60 F254 precoated silica
gel plates. Flash chromatography was conducted using
Merck Silica Gel 60 (230–400 mesh).
Scheme 1.
This study confirms that the iodide anion either pro-
motes more rapid equilibration of the rhodium–allyl
intermediate or less rapid nucleophilic trapping of that
intermediate compared to the chloride ion. This may be
attributed to the in situ generation of an iodo-rhodium
catalyst from the chloro-rhodium species. Nevertheless,
the iodide anion seems to cause racemization in more
demanding cases where nucleophilic trapping is pre-
sumably slower. The pseudo C2-symmetrical linchpin
alkylation product 5a was then desymmetrized using a
novel bromoetherification reaction, where the addition
of water to the ketone allows for a selective bro-
moetherification followed by elimination of the in situ
silyl protected hemiketal, to furnish 6 in 71% yield with
excellent diastereoselectivity (ds]19:1 by NMR).19 The
stereochemical assignment was made with the aid of an
NOE experiment.
4.2. (R)-3-Methyl-1-phenylpent-4-en-1-one (R)-4b
Trimethyl phosphite (240 mL, 2.0 mmol) was added
directly to a red suspension of Wilkinson’s catalyst
(464.6 mg, 0.50 mmol) in anhydrous THF (20 mL) and
then stirred under an atmosphere of argon. The catalyst
was allowed to form over ca. 15 min resulting in a light
yellow homogeneous solution. Lithium hexamethyldisi-
lyl azide (190 mL, 190 mmol, 1.0 M solution in THF)
was added dropwise over a period of 5 min to a
suspension of copper(I) iodide (38.107 g, 200 mmol,
previously dried in vacuo at 160°C) and acetophenone
(23.3 mL, 200 mmol) in anhydrous THF (500 mL)
under an atmosphere of argon. The enolate was
allowed to form over ca. 5 min until a brown homoge-
neous solution was obtained. The catalyst and the
enolate solutions were then cooled with stirring to 0°C,
and the former added via Teflon cannula to the copper
3. Conclusion
In conclusion, we have demonstrated the transmetalla-
tion of lithium alkoxides and enolates with copper
halide salts provide the requisite nucleophiles to facili-
tate the stereospecific rhodium-catalyzed allylic substi-

P. A. E6ans et al. / Tetrahedron: Asymmetry 14 (2003) 3613–3618
3617
enolate solution, followed by the addition of the allylic
carbonate (S)-1b (13.037 g, 100 mmol, ee=97%) in
anhydrous THF (80.0 mL) via Teflon cannula. The
reaction was allowed to slowly warm to room tempera-
ture over ca. 16 h resulting in a brown heterogeneous
solution (TLC control). The reaction mixture was
quenched with NH4Cl solution (500 mL) and parti-
tioned between diethyl ether and saturated aqueous
NH4Cl solution. The organic layers were combined,
dried (MgSO4), filtered and concentrated in vacuo to
afford a crude oil. Purification by flash chromatogra-
phy (eluting with 1% ethyl acetate/hexanes) furnished
the ketone (R)-4b (12.250 g, 70%) as a colorless oil:
[h]2D4 +1.3 (c 1.35, CHCl3); chiral HPLC analysis
(Diacel® AD-H column) ee=92%, Racemic GC analy-
sis (HP-1 methyl siloxane capillary column) 2°:1°]
99:1; IR (neat) 3082 (w), 2963 (m), 2929 (w), 2857 (w),
(m), 2931 (m), 2871 (w), 1678 (s), 1640 (m), 1596 (m),
1580 (m), 1450 (m), 1420 (w) cm−1; 1H NMR (400
MHz, CDCl3) l 7.91 (dt, J=7.1, 1.7 Hz, 2H), 7.53 (tt,
J=7.4, 1.5 Hz, 1H), 7.43 (t, J=7.6 Hz, 2H), 5.89–5.80
(m, 1H), 5.68 (ddd, J=17.2, 10.2, 8.6 Hz, 1H), 5.08–
4.92 (m, 4H), 3.41 (dd, J=8.8, 5.9 Hz, 1H), 2.78–2.64
(m, 2H), 0.96 (d, J=7.0 Hz, 3H), 0.94 (d, J=6.7 Hz,
3H; 13C NMR (100 MHz, CDCl3) l 203.74 (e), 142.39
(o), 140.72 (o), 139.96 (e), 132.96 (o), 128.76 (o), 128.44
(o), 115.03 (e), 114.81 (e), 55.40 (o), 39.19 (o), 38.94 (o),
19.15 (o), 18.26 (o); HRMS (CI, M+) calcd for C16H20O
228.1514, found 228.1510.
4.4. (2S,3R,1%S)-2-(Bromomethyl)-3-methyl-4-(1-methyl-
prop-2-en-1-yl)-5-phenyl-2,3-dihydrofuran 6
N-Bromosuccinimide (16.7 mg, 0.09 mmol) was added
in one portion to a solution of 5 (20.8 mg, 0.09 mmol)
in DMSO (0.5 mL) and water (1.6 mL, 0.09 mmol) then
stirred under an atmosphere of nitrogen for ca. 1 h
(TLC control). The reaction was then partitioned
between diethyl ether and water. The organic layers
were combined, dried (MgSO4), filtered and concen-
trated in vacuo to afford a crude oil. Purification by
flash chromatography (eluting with 10% ethyl acetate/
hexanes) furnished the epimeric hemiketals (25.1 mg,
85%) as a colorless oil. tert-Butyldimethylsilyl chloride
(33.2 mg, 0.22 mmol) was added in one portion to a
solution of the epimeric hemiketals (31.5 mg, 0.10
mmol) and imidazole (19.2 mg, 0.28 mmol) in DMF
(0.5 mL) then stirred under an atmosphere of nitrogen
for 72 h (TLC control). The reaction was partitioned
between diethyl ether and water. The organic layers
were combined, dried (MgSO4), filtered and concen-
trated in vacuo to afford a crude oil. Purification by
1
1686 (s), 1641 (w), 1598 (m), 1449 (s) cm−1; H NMR
(400 MHz, CDCl3) l 7.94–7.92 (m, 2H), 7.54 (t, J=7.4
Hz, 1H), 7.44 (t, J=7.6 Hz, 2H), 5.83 (ddd, J=17.0,
10.5, 6.5 Hz, 1H), 5.01 (dt, J=17.3, 1.2 Hz, 1H), 4.94
(d, J=10.5 Hz, 1H), 3.01 (dd, A of ABX, JAB=18.2
Hz, JAX=9.0 Hz, 1H), 2.92–2.85 (m, 1H), 2.88 (dd, B
of ABX, JAB=18.0 Hz, JBX=6.9 Hz, 1H), 1.08 (d,
J=6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) l 199.59
(e), 143.27 (o), 137.51 (e), 133.18 (o), 128.79 (o), 128.32
(o), 113.26 (e), 45.36 (e), 33.82 (o), 20.02 (o); HRMS
(CI, M+) calcd for C12H14O 174.1045, found 174.1048.
4.3.
(3S,1%S)-3-Methyl-2-(1-methylprop-2-en-1-yl)-1-
phenylpent-4-en-1-one 5a
Trimethyl phosphite (24 mL, 0.20 mmol) was added
directly to a red suspension of Wilkinson’s catalyst
(46.5 mg, 0.05 mmol) in anhydrous THF (2.0 mL) and
then stirred under an atmosphere of argon. The catalyst
was allowed to form over ca. 15 min resulting in a light
yellow homogeneous solution. Lithium hexamethyldisi-
lyl azide (950 mL, 0.95 mmol, 1.0 M solution in THF)
was added dropwise to a suspension of copper(I) chlo-
ride (89.2 mg, 1.00 mmol, previously dried in vacuo at
160°C) and (R)-4b (178.8 mg, 1.03 mmol, ee=97%,) in
anhydrous THF (3.0 mL) under an atmosphere of
argon and the anion was allowed to form over ca. 2
min until a light yellow/green homogeneous solution
was obtained. The catalyst and the enolate solutions
were then cooled with stirring to 0°C, and the former
added via Teflon cannula to the copper enolate solu-
tion. The allylic carbonate (S)-1b (64.9 mg, 0.50 mmol,
ee=97%) was then added via a tared 500 mL gastight
syringe to the catalyst/enolate mixture, and the reaction
was allowed to slowly warm to room temperature over
ca. 4 h (TLC control) resulting in a tan heterogeneous
solution. The reaction mixture was quenched with
NH4Cl solution (1 mL) and partitioned between diethyl
ether and saturated aqueous NH4Cl solution. The
organic layers were combined, dried (MgSO4), filtered
and concentrated in vacuo to afford a crude oil. Purifi-
cation by flash chromatography (eluting with 1% ethyl
acetate/hexanes) furnished the ketone 5a (84.3 mg,
74%) as a colorless oil: [h]2D5 +38.8 (c 1.16, CHCl3);
racemic GC analysis (HP-1 methyl siloxane capillary
column) 2°:1°=37:1, ds=24:1; IR (neat) 3076 (w), 2969
flash
chromatography
(eluting
with
10%
dichloromethane/hexanes) furnished 6 (25.0 mg, 84%)
as a colorless oil. [h]D25 −43.0 (c 1.01, CHCl3); IR (neat)
3082 (w), 2968 (s), 2929 (m), 2876 (m), 1636 (m), 1602
1
(m), 1494 (m), 1446 (m) cm−1; H NMR (400 MHz,
CDCl3) l 7.48 (dd, J=7.0, 1.5 Hz, 2H), 7.35 (t, J=7.4
Hz, 2H), 7.29 (tt, J=7.3, 2.8 Hz, 1H), 5.89 (ddd,
J=17.2, 10.4, 5.6 Hz, 1H), 5.03 (dt, J=17.2, 1.5 Hz,
1H), 5.01 (dt, J=10.3, 1.4 Hz, 1H), 4.65 (q, J=7.4 Hz,
1H), 3.65 (dd, A of ABX, JAB=10.2 Hz, JAX=6.4 Hz,
1H), 3.55 (dd, B of ABX, JAB=10.2 Hz, JBX=7.9 Hz,
1H), 3.47 (pentet, J=7.1 Hz, 1H), 3.01 (pentet, J=7.2
Hz, 1H), 1.30 (d, J=7.1 Hz, 3H), 1.12 (d, J=7.0 Hz,
3H); 13C NMR (100 MHz, CDCl3) l 149.20 (e), 141.98
(o), 131.66 (e), 128.55 (o), 128.42 (o), 127.86 (o), 119.94
(e), 113.57 (e), 82.85 (o), 40.86 (o), 34.75 (o), 29.74 (e),
19.97 (o), 13.92 (o); HRMS (CI, M+) calcd for
C16H19BrO 306.0619, found 306.0611.
Acknowledgements
We sincerely thank the National Institutes of Health
(GM58877) and the Donors of The Petroleum Research
Fund, administered by the American Chemical Society
for generous financial support. We also thank Johnson
and Johnson for a Focused Giving Award and Pfizer
Pharmaceuticals for the Creativity in Organic Chemistry

3618
P. A. E6ans et al. / Tetrahedron: Asymmetry 14 (2003) 3613–3618
Award. The Camille and Henry Dreyfus Foundation is
thanked for a Camille Dreyfus Teacher-Scholar Award
(P.A.E.), and the Department of Chemistry at Indiana
University for an E. M. Kratz Fellowship (D.K.L.).
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