One-pot catalytic enantio- and diastereoselective syntheses of anti-, syn-cis-disubstituted, and syn-vinyl cyclopropyl alcohols

Article abstract of DOI:10.1021/ja907781t

Highly enantio- and diastereoselective methods for the synthesis of a variety of cyclopropyl alcohols are reported. These methods represent the first one-pot approaches to syn-vinyl cyclopropyl alcohols, syn-cis-disubstituted cyclopropyl alcohols, and anti-cyclopropyl alcohols from achiral precursors. The methods begin with enantioselective C-C bond formations promoted by a MIB-based zinc catalyst to generate allylic alkoxide intermediates. The intermediates are then subjected to in situ alkoxide-directed cyclopropanation to provide cyclopropyl alcohols. In the synthesis of vinyl cyclopropyl alcohols, hydroboration of enynes is followed by transmetalation of the resulting dienylborane to zinc to provide dienylzinc reagents. Enantioselective addition to aldehydes generates the requisite dienyl zinc alkoxides, which are then subjected to in situ cyclopropanation to furnish vinyl cyclopropyl alcohols. Cyclopropanation occurs at the double bond allylic to the alkoxide. Using this method, syn-vinylcyclopropyl alcohols are obtained in 65-85% yield, 76-93% ee, and >19:1 dr. To prepare anti-cyclopropanols, enantioselective addition of alkylzinc reagents to conjugated enals provides allylic zinc alkoxides. Because direct cyclopropanation provides syn-cyclopropyl alcohols, the intermediate allylic alkoxides were treated with TMSCl/Et₃N to generate intermediate silyl ethers. In situ cyclopropanation of the allylic silyl ether resulted in cyclopropanation to form the anti-cyclopropyl silyl ether. Workup with TBAF affords the anti-cyclopropyl alcohols in one pot in 60-82% yield, 89-99% ee, and g10:1 dr. For the synthesis of cis-disubstituted cyclopropyl alcohols, in situ generated (Z)-vinyl zinc reagents were employed in asymmetric addition to aldehydes to generate (Z)-allylic zinc alkoxides. In situ cyclopropanation provides syn-cis-disubstituted cyclopropyl alcohols in 42-70% yield, 88-97% ee, and >19:1 dr. These one-pot procedures enable the synthesis of a diverse array of cyclopropyl alcohol building blocks with high enantio- and diastereoselectivities.

Full text of DOI:10.1021/ja907781t

Published on Web 12/02/2009
One-Pot Catalytic Enantio- and Diastereoselective Syntheses
of anti-, syn-cis-Disubstituted, and syn-Vinyl Cyclopropyl
Alcohols
Hun Young Kim, Luca Salvi, Patrick J. Carroll, and Patrick J. Walsh*
P. Roy and Diana T. Vagelos Laboratories, Department of Chemistry, UniVersity of
PennsylVania, 231 South 34th Street, Philadelphia, PennsylVania 19104-6323
Received September 13, 2009; E-mail: pwalsh@sas.upenn.edu
Abstract: Highly enantio- and diastereoselective methods for the synthesis of a variety of cyclopropyl
alcohols are reported. These methods represent the first one-pot approaches to syn-vinyl cyclopropyl
alcohols, syn-cis-disubstituted cyclopropyl alcohols, and anti-cyclopropyl alcohols from achiral precursors.
The methods begin with enantioselective C-C bond formations promoted by a MIB-based zinc catalyst to
generate allylic alkoxide intermediates. The intermediates are then subjected to in situ alkoxide-directed
cyclopropanation to provide cyclopropyl alcohols. In the synthesis of vinyl cyclopropyl alcohols, hydroboration
of enynes is followed by transmetalation of the resulting dienylborane to zinc to provide dienylzinc reagents.
Enantioselective addition to aldehydes generates the requisite dienyl zinc alkoxides, which are then subjected
to in situ cyclopropanation to furnish vinyl cyclopropyl alcohols. Cyclopropanation occurs at the double
bond allylic to the alkoxide. Using this method, syn-vinylcyclopropyl alcohols are obtained in 65-85% yield,
76-93% ee, and >19:1 dr. To prepare anti-cyclopropanols, enantioselective addition of alkylzinc reagents
to conjugated enals provides allylic zinc alkoxides. Because direct cyclopropanation provides syn-cyclopropyl
alcohols, the intermediate allylic alkoxides were treated with TMSCl/Et3N to generate intermediate silyl
ethers. In situ cyclopropanation of the allylic silyl ether resulted in cyclopropanation to form the
anti-cyclopropyl silyl ether. Workup with TBAF affords the anti-cyclopropyl alcohols in one pot in 60-82%
yield, 89-99% ee, and g10:1 dr. For the synthesis of cis-disubstituted cyclopropyl alcohols, in situ generated
(Z)-vinyl zinc reagents were employed in asymmetric addition to aldehydes to generate (Z)-allylic zinc
alkoxides. In situ cyclopropanation provides syn-cis-disubstituted cyclopropyl alcohols in 42-70% yield,
88-97% ee, and >19:1 dr. These one-pot procedures enable the synthesis of a diverse array of cyclopropyl
alcohol building blocks with high enantio- and diastereoselectivities.
of three approaches.5,11,16-18 Tremendous advances have recently
been documented in enantioselective organocatalytic approaches
to cyclopropane synthesis,5,19-23 many of which proceed via
Michael addition initiated ring-closure sequences.5,19,24-26 Like-
1. Introduction
Cyclopropane containing compounds exhibit a broad spectrum
of biological properties1-5 and are present in over 100 thera-
peutic agents.5-7 They are commonly encountered in natural
products, including pheromones, steroids, terpenes, fatty acid
metabolites, and amino acids.4,5 These strained structural motifs
are also valuable building blocks in organic chemistry3,8-12 that
can be elaborated to provide functionalized cyclopropanes or
ring-opened products.10,13-15 The synthetic utility and medicinal
properties of enantioenriched cyclopropanes have inspired many
investigations into their preparation, which generally follow one
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402 J. AM. CHEM. SOC. 2010, 132, 402–412
10.1021/ja907781t  2010 American Chemical Society

Enantio-/Diastereoselective Syntheses of Cyclopropyl Alcohols
A R T I C L E S
Scheme 1. Tandem Approaches to Enantio- and Diastereoenriched Cyclopropyl Alcohols
wise, impressive progress has been made in the area of metal-
catalyzed cyclopropanation of olefins with diazoesters and
related precursors to afford enantio- and diastereoenriched
cyclopropanes.5,27-29 The third pillar in cyclopropane synthesis
is halomethylmetal-mediated cyclopropanation reactions (the
Simmons-Smith reaction).12,17,30-32 In contrast to organocata-
lytic and diazo-based approaches to cyclopropanes, progress in
the catalytic asymmetric Simmons-Smith cyclopropanation of
olefins33,34 and allylic alcohols11,35-41 has been limited. Cata-
lysts for the Simmons-Smith cyclopropanation have been beset
by moderate enantioselectivities, high catalyst loadings (typically
10-25 mol %),11,42 or mediocre substrate generality.43 While
some exceptions are emerging,43 these problems underscore the
complexity of asymmetric Simmons-Smith cyclopropana-
tions.42
experiences,41 we pondered alternative approaches for the
stereoselective synthesis of cyclopropanes. Rather than direct
enantioselective cyclopropanation, we chose to perform a
tandem reaction involving an asymmetric addition to an
aldehyde as the first step. The key intermediate in our approach
was envisioned to be an enantioenriched allylic zinc alkoxide
that could be subjected to a diastereoselective directed cyclo-
propanation (Scheme 1). To generate enantioenriched allylic zinc
alkoxides, two complementary carbonyl additions were studied.
The first involved an asymmetric addition of alkylzinc reagents
to enals followed by diastereoselective cyclopropanation to
afford cyclopropyl alcohols (Scheme 1A).44 A complementary
C-C bond formation was chosen for the second approach,
which entailed an enantioselective vinyl addition to a saturated
aldehyde followed by cyclopropanation (Scheme 1B).44
Considering the well documented difficulties in catalytic
asymmetric Simmons-Smith reactions, as well as our own
Nugent’s amino alcohol (-)-MIB45,46 (4 mol %) was
employed to generate the catalyst for both additions (Scheme
1). With one exception enantioselectivities in the carbonyl
addition step exceeded 90% and the cyclopropanation proceeded
with excellent diastereoselectivity (dr’s >20:1). Although dias-
tereoselective cyclopropanations of chiral allylic alcohols had
been studied,47-49 these were the first examples of the assembly
of enantio- and diastereoenriched cyclopropyl alcohols from
achiral precursors in a one-pot procedure.44 A modified protocol
based on these methods was subsequently developed for the
highly enantio- and diastereoselective iodo-, bromo-, and
chlorocyclopropanations of allylic zinc alkoxides to generate
halocyclopropyl alcohols with up to four stereocenters.44,50
The methods illustrated in Scheme 1 enable the efficient
synthesis of a variety of simple cyclopropyl alcohols with syn
relationships between the hydroxyl and cyclopropane groups.
In their current form, however, these methods cannot be used
to access the diastereomeric anti-cyclopropyl alcohols. Both syn-
(26) Vicario, J. L.; Badia, D.; Carrillo, L. Synthesis 2007, 2065–2092.
(27) Rovis, T.; Evans, D. A. Prog. Inorg. Chem. 2001, 50, 1–150.
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(29) Doyle, M. P.; McKervey, M. A. J. Chem. Soc., Chem. Commun.
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(30) Denmark, S. E.; Christenson, B. L.; O’Connor, S. P.; Noriaki, M.
Pure Appl. Chem. 1996, 68, 23–27.
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15626.
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(34) Long, J.; Du, H.; Li, K.; Shi, Y. Tetrahedron Lett. 2005, 46, 2737–
2740.
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123, 12168–12175.
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(45) Nugent, W. A. J. Chem. Soc., Chem. Commun. 1999, 1369–1370.
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2005, 82, 87–92.
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Kobayashi, S. Tetrahedron 1995, 51, 12013–12026.
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(47) Ratier, M.; Castaing, M.; Godet, J.-Y.; Pereyre, M. J. J. Chem. Res.,
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(41) Balsells, J.; Walsh, P. J. J. Org. Chem. 2000, 65, 5005–5008.
(42) Charette, A. B. In The Chemistry of Organozinc Compounds;
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A R T I C L E S
Kim et al.
transform spectrometers at the University of Pennsylvania NMR
facility. Chemical shifts are reported in units of parts per million
downfield from tetramethylsilane, and all coupling constants are
reported in hertz. The infrared spectra were obtained using a Perkin-
Elmer 1600 series spectrometer. Mass spectra were recorded on a
Waters LCTOF- Xe Premier Mass spectrometer. Silica gel (230-400
mesh, Silicycle) was used for air-flashed chromatography. Deac-
tivated silica gel was made by combining silica gel with 2.5 wt %
NEt3.
2.2. Cautionary Note. Dialkylzinc reagents, tert-butyllithium,
and diethylborane are pyrophoric. Extreme caution should be used
in their handling, and proper laboratory attire is highly recommended.
Figure 1. Structures of members of the oxylipin natural products, which
contains both syn and anti cyclopropyl alcohol motifs.
2.3. General Procedure A. (4E,6E)-2,7-Dimethylundeca-4,6-
dien-3-ol (1a). (E)-4-Methyloct-3-en-1-yne (80 mg, 0.65 mmol) and
diethylborane (0.65 mL, 0.65 mmol, 1.0 M in toluene) were added
to a dry flask under nitrogen and stirred at room temperature for
30 min. The reaction flask was then cooled to -78 °C, and (-)-
MIB (11.75 mg, 0.05 mmol, 10 mol %) was added followed by
Et2Zn (0.75 mL, 1.0 M in hexanes, 0.75 mmol). The reaction
mixture was then warmed to -10 °C, and a solution of isobutyral-
dehyde (45 µL, 0.5 mmol in 3 mL hexanes) was added dropwise
for 20 min. The reaction was stirred at -10 °C for 10 h until vinyl
addition was complete by TLC and quenched with a saturated
solution of NH4Cl (10 mL). The organic and aqueous layers were
separated, and the aqueous layer was extracted with 3 × 15 mL of
dichloromethane. The combined organic layers were then washed
with brine, dried over MgSO4, and filtered. The filtrate was
concentrated in Vacuo, and the residue was purified by column
chromatography on silica (5% ethyl acetate in hexanes) to afford
and anti-cyclopropyl alcohols are encountered in natural prod-
ucts, as exemplified by members of the oxylipin family,51,52
which includes constanolactone A and B, solandelactones E and
F, halicholactone, and eicosanoid (Figure 1). Furthermore, the
asymmetric vinylation method outlined in Scheme 1B provides
access to only the (E)-allylic alkoxide intermediates and is not
applicable to the synthesis of the (Z)-analogues. Thus, cis-
disubstituted cyclopropanes are not accessible using the pro-
cedures in Scheme 1B. Finally, the utility of the method in
Scheme 1B would be greatly broadened if it could be adapted
to the synthesis of vinyl cyclopropanes (VCPs). VCPs are useful
synthetic intermediates that undergo a variety of transforma-
tions.18,53-55 Their synthesis in highly enantio- and diastereo-
enriched form, however, is not trivial.
20
the title compound as a colorless oil in 88% yield. [R]D ) -5.3
(c ) 0.5, CHCl3); 1H NMR (CDCl3, 300 MHz): δ 6.44 (dd, 1H, J
) 15.3, 11.0 Hz), 5.85 (d, 1H, J ) 11.0 Hz), 5.59 (dd, 1H, J )
15.3, 7.5 Hz), 3.90 (dd, 1H, J ) 7.5, 6.6 Hz), 2.07 (m, 2H), 1.90
(br s, 1H), 1.77 (m, 3H), 1.72 (m, 1H), 1.37 (m, 4H), 0.96 (d, 3H,
J ) 6.6 Hz), 0.92 (t, 3H, J ) 7.1 Hz), 0.91 (d, 3H, J ) 6.6 Hz);
13C NMR (CDCl3, 75 MHz,): δ 140.3, 132.1, 128.7, 124.2, 78.7,
40.0, 34.4, 30.4, 22.8, 18.7, 18.5, 17.0, 14.4; IR (neat): 3383 (OH),
2954, 2850, 1452, 1399, 1288, 1118, 1068, 1020, 987 cm-1; HRMS-
CI m/z 178.1720 [(M - H2O)+; calcd for C13H22: 178.1722].
Herein we introduce highly enantio- and diastereoselective
methods to prepare vinyl cyclopropyl alcohols, anti-cyclopropyl
alcohols, and cyclopropyl alcohols with cis-disubstituted cy-
clopropane motifs.
2. Experimental Section
Representative procedures and characterization of the products
are described herein. Full experimental details and characterization
of all compounds are provided in the Supporting Information.
2.1. General Methods. All reactions were carried out under a
nitrogen atmosphere with oven-dried glassware. The progress of
reactions was monitored by thin-layer chromatography on Whatman
precoated silica gel 60 F-254 plates and visualized by ultraviolet
light or by staining with ceric ammonium molybdate stain. All
manipulations involving dialkylzinc reagents were carried out under
an inert atmosphere in a Vacuum Atmosphere drybox with an
attached MO-40 Dritrain or by using standard Schlenk or vacuum
line techniques. Unless otherwise specified, all chemicals were
obtained from Aldrich, Acros, or GFS chemicals, and solvents were
purchased from Fischer Scientific. Dialkylzinc compounds, except
dimethyl- and diethylzinc, which are commercially available, were
prepared according to literature methods.56,57 Dichloromethane and
hexanes were dried through alumina columns. All aldehydes were
2.4. General Procedure B. 2-Methyl-1-(2-((E)-2-methylhex-1-
enyl)cyclopropyl)propan-1-ol (1b). An oven-dried 10 mL Schlenk
flask that had been thoroughly purged with N2 was charged with
(E)-4-methyloct-3-en-1-yne (80 mg, 0.65 mmol) and diethylborane
(0.65 mL, 0.65 mmol, 1.0 M in toluene) and stirred at room
temperature for 30 min. After the reaction flask was cooled to -78
°C, (-)-MIB (11.75 mg, 0.05 mmol, 10 mol %) was added,
followed by Et2Zn (0.75 mL, 1.0 M in hexanes, 0.75 mmol), and
the resulting solution was stirred at this temperature for 10 min.
The reaction mixture was then warmed to -10 °C, and a solution
of isobutyraldehyde (45 µL, 0.5 mmol in 3 mL hexanes) was added
dropwise for 20 min. The reaction mixture was stirred at -10 °C
for 10 h until vinyl addition was complete by TLC. The solvent
and byproduct Et3B were removed in Vacuo at 0 °C, and 2 mL of
hexanes were added. This step was done three times to remove
byproduct Et3B completely. A solution of Et2Zn (1.0 mL, 1.0 M in
hexanes, 1.0 mmol) and diiodomethane (81 µL, 1.0 mmol) were
added at 0 °C, and then the reaction mixture was warmed to room
temperature. The flask was covered with aluminum foil to exclude
light and stirred at room temperature for 20 h. The reaction mixture
1
distilled prior to use and stored under N2. The H and 13C{1H}
NMR spectra were obtained on Bruker 500 or 300 MHz Fourier
(51) Gerwick, W. H. Chem. ReV. 2002, 93, 1807–1823.
(52) Kumaraswamy, G.; Padmaja, M. J. Org. Chem. 2008, 73, 5198–
5201.
(53) Baldwin, J. E. Chem. ReV. 2003, 103, 1197–1212.
(54) Davies, H. M. L.; Kong, N.; Churchill, M. R. J. Org. Chem. 1998,
63, 6586–6589.
(55) Sebelius, S.; Olsson, V. J.; Wallner, O. A.; Szabo, K. J. J. Am. Chem.
Soc. 2006, 128, 8150–8151.
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Enantio-/Diastereoselective Syntheses of Cyclopropyl Alcohols
A R T I C L E S
was then quenched with a saturated solution of NH4Cl (15 mL).
The organic and aqueous layers were separated, and the aqueous
layer was extracted with 3 × 20 mL of dichloromethane. The
combined organic layers were then washed with brine, dried over
MgSO4, and filtered. The filtrate was concentrated in Vacuo, and
the residue was purified by column chromatography on silica (5%
ethyl acetate in hexanes) to afford the title compound as a colorless
oil in 75% yield. [R]D ) -18.3 (c ) 0.4, CHCl3); H NMR
(CDCl3, 300 MHz): δ 4.56 (d, 1H, J ) 9.2 Hz), 2.70 (dd, 1H, J )
9.1, 6.2 Hz), 1.95 (m, 2H), 1.78 (m, 1H), 1.68 (s, 2H), 1.48 (br s,
1H), 1.32 (m, 5H), 1.02 (m, 1H), 0.98 (d, 3H, J ) 7.0 Hz), 0.95
(d, 3H, J ) 7.0 Hz), 0.88 (t, 3H, J ) 7.2 Hz), 0.81 (m, 1H), 0.68
(m, 1H), 0.49 (m, 1H); 13C NMR (CDCl3, 75 MHz): δ 135.3, 126.7,
81.6, 39.6, 35.0, 30.5, 25.5, 22.7, 19.0, 18.9, 17.5, 16.7, 14.4, 11.4;
IR (neat): 3400 (OH), 2875, 2778, 1054, 976, 897 cm-1; HRMS-
CI m/z 193.1963 [(M - H2O)+; calcd for C14H24: 193.1962].
solution in pentane) was added dropwise at -78 °C, and the reaction
mixture stirred for 60 min. The solution was warmed to room
temperature and stirred for an additional 60 min during which time
a precipitate formed. Diethylzinc (0.275 mL, 0.55 mmol, 2 M
solution in hexanes) was slowly added to the reaction mixture at
-78 °C and stirred for 20 min. Addition of TEEDA (14 µL, 0.066
mmol) and hexanes (4 mL) were performed at -78 °C. The solution
was warmed to 0 °C, and (-)-MIB (166 µL, 0.017 mmol, 0.1 M
solution in hexanes) and isobutyraldehyde (30 µL, 0.332 mmol)
were added. The reaction mixture was then slowly warmed to room
temperature and stirred for 12-16 h. After the reaction was
complete by TLC analysis, the temperature was lowered to 0 °C
and ZnEt2 (0.83 mL, 1.66 mmol, 2 M solution in hexanes) was
added. Next, CF3CH2OH (120 µL, 1.65 mmol) was added dropwise.
After stirring at 0 °C for 10 min, CH2I2 (135 µL, 1.67 mmol) was
added. The reaction mixture was stirred with light exclusion at room
temperature for 24 h. It was then quenched with a saturated solution
of NH4Cl. The organic and aqueous layers were separated, and the
aqueous layer was extracted with dichloromethane (3 × 5 mL).
The combined organic layers were then washed with brine, dried
over MgSO4, and filtered. The filtrate was concentrated in Vacuo,
and the crude product was purified by column chromatography on
deactivated silica gel (5% ethyl acetate in hexanes) to afford the
title compound (92.1 mg, 70% yield) as an oil. [R]2D0 ) +4.41 (c
20
1
2.5. General Procedure C. 1-(2-Phenylcyclopropyl)propan-1-
ol (11). A 10 mL Schlenk flask was charged with (-)-MIB (2.9
mg, 0.012 mmol) and cooled to 0 °C. A solution of Et2Zn (0.45
mL, 1.0 M in hexanes) was added, followed by dropwise addition
of trans-cinnamaldehyde (38 µL, 0.3 mmol). The reaction mixture
was stirred at 0 °C for 8 h until alkyl addition was complete by
TLC. Trimethylsilyl chloride (1.5 equiv, 0.45 mmol) and triethyl
amine (1.5 equiv, 0.45 mmol) were added with 2 mL of dichlo-
romethane at 0 °C. The reaction flask was slowly warmed to room
temperature and stirred for 14 h. Next, 5 equiv of Et2Zn (0.75 mL,
2.0 M in dichloromethane) and 5 equiv CF3CH2OH (108 µL, 1.5
mmol) were added slowly at 0 °C. After stirring at 0 °C for 10
min, 5 equiv of CH2I2 (120 µL, 1.5 mmol) were added. The reaction
mixture was stirred with light exclusion at room temperature for
24 h. It was then quenched with 3-4 drops of water and 2 equiv
of TBAF (1 M solution in THF) at 0 °C. After stirring for 1 h, 5
mL of saturated NH4Cl solution were added. The organic and
aqueous layers were separated, and the aqueous layer was extracted
three times with 10 mL of dichloromethane. The combined organic
layers were then washed with brine, dried over MgSO4, and filtered.
The filtrate was concentrated in Vacuo, and the residue was purified
by column chromatography on deactivated silica (10% ethyl acetate
in hexanes) to afford the title compound as a colorless oil in 75%
1
) 0.026, CHCl3); H NMR (CDCl3, 500 MHz): δ 0.05 (m, 1H),
0.67 (m, 1H), 0.93 (m, 2H), 0.98 (t, J ) 7.9 Hz, 6H), 1.1 (m, 9H),
1.23 (m, 1H), 1.3 (d, J ) 3.6 Hz, 1H), 1.74 (m, 1H), 1.91 (m, 1H),
2.96 (m, 1H), 3.76 (m, 2H), 7.42 (m, 6H), 7.7 (m, 4H); 13C{1H}
NMR (CDCl3, 125 MHz): δ 8.9, 14.8, 17.6, 19.2, 19.4, 21.1, 27.1,
32.8, 34.7, 64.5, 76.7, 127.8, 129.8, 134.2, 135.8; IR (neat): 3599,
3411, 3134, 3070, 3050, 3013, 2952, 2912, 2895, 2858, 2739, 2319,
1958, 1888, 1823, 1589, 1486, 1471, 1428, 1362, 1331, 1306, 1260,
1235, 1187, 1157, 1110 1029, 1007 cm-1; HRMS calcd for
C25H36O2NaSi (M + Na)+: 419.2382, found 419.2377.
3. Results and Discussion
3.1. Synthesis of syn-Vinylcyclopropyl Alcohols. The chem-
istry of vinylcyclopropanes is very rich.10,58,59 VCPs are
found in biologically active compounds1,7,60-62 and natural
products,2,63-65 such as carenes, sesquicarenes, sirenines,
dictyopterenes, pyrethrine, and ambruticin.9,66-68 Being useful
intermediates in organic synthesis,10,11,53,69-71 the chemistry of
20
1
yield. [R]D ) +12.6 (c ) 0.50, CHCl3); H NMR (CDCl3, 500
MHz): δ 7.36 (m, 2H), 7.26 (m, 1H), 7.16 (m, 2H), 3.24 (m, 1H),
1.93 (m, 1H), 1.86 (br s, 1H), 1.78 (m, 2H), 1.34 (m, 1H), 1.10 (t,
3H, J ) 7.5 Hz), 1.06 (m, 2H); 13C{1H} NMR (CDCl3, 125 MHz,):
δ 142.7, 128.6, 126.1, 125.9, 77.2, 30.5, 29.5, 21.4, 13.3, 10.3; IR
(58) Wang, S. C.; Tantillo, D. J. J. Organomet. Chem. 2006, 691, 4386–
4392.
(59) Khusnutdinov, R. I.; Dzhemilev, U. M. J. Organomet. Chem. 1994,
471, 1–18.
(neat); 3385 (OH), 3057, 2950, 1459, 1299, 1071, 924, 720 cm-1
.
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2.6. General Procedure D. (Z)-1-(2-(2-(tert-Butyldiphenylsily-
loxy)ethyl)cyclopropyl)-2-methylpropan-1-ol (17). Dicyclohexyl-
borane (88 mg, 0.5 mmol) was weighed into a Schlenk flask under
nitrogen, and dry t-BuOMe (1 mL) was added. tert-Butyl-(4-chloro-
but-3-ynyloxy)-diphenyl-silane (160 µL, 0.5 mmol) was then added
slowly to the reaction mixture at 0 °C. After 15 min the reaction
mixture was warmed to room temperature and stirred for 45 min
resulting in a clear solution. t-BuLi (0.365 mL, 0.55 mmol, 1.5 M
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N.; Okuhara, M.; Kohsaka, M.; Horikoshi, K. J. Antibiot. 1990, 43,
748–754.
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Tetrahedron 2003, 59, 6819–6832.
(67) Doyle, M. P. Chem. ReV. 1986, 86, 919–939.
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Soc. 1999, 121, 5467–5480.
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1956–1958.
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P. J. Org. Chem. 1996, 61, 8229–8243.
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(71) Murelli, R. P.; Catalán, S.; Gannon, M. P.; Snapper, M. L.
Tetrahedron Lett. 2008, 49, 5714–5717.
9
J. AM. CHEM. SOC. VOL. 132, NO. 1, 2010 405

A R T I C L E S
Kim et al.
Scheme 2. Asymmetric Cyclopropanation of Dienols by Charette
and Barrett
Scheme 3. Synthesis of VCPs
Table 1. Optimization of the Dienyl Addition to Aldehydes
VCPs has been studied in detail in several laboratories, including
those of Wender,72,73 de Meijere,74 and Trost.75,76
Accessing enantioenriched vinylcyclopropanes is often
challenging.20,77,78 Davies’ pioneering route involved the cata-
lytic asymmetric cyclopropanation of alkenes with vinyldiazo-
acetates. Good to excellent enantioselectivities were obtained,
although trans-disubstituted alkenes were inert to cyclopropa-
nation under these conditions.79,80 Conversely, use of simple
diazoesters in the cyclopropanation of dienes can lead to VCPs
with high enantio- and diastereoselectivity.81 Organocatalytic
routes have also been used with increasing success.19,24 The
enantioselective Simmons-Smith reactions have been employed
with two dienol substrates (Scheme 2). Barrett82 used Fujisa-
wa’s83 diethyl tartrate-based system to prepare, with moderate
enantioselectivity, a VCP (R ) CH2OTBDPS) for use in the
synthesis of FR-900848. They also prepared the bis(cyclopro-
panes) with moderate to excellent diastereoselectivity in the
cyclopropanation of both CdC double bonds. Charette84
reported the highly enantioselective cyclopropanation of a dienol
(R ) Ph) using a boron-based tartrate additive (Scheme 2). Both
reactions required stoichiometric tartrate-derived Lewis acids.
Given the importance of VCPs and the limited variety that
can be easily prepared under catalytic conditions with high
enantio- and diastereoselectivity, we turned our attention to their
synthesis. We envisioned adapting the tandem aldehyde viny-
lation/cyclopropanation sequence outlined in Scheme 1B to the
synthesis of VCPs,44 as shown in Scheme 3. In place of the
terminal alkyne of Scheme 1B, however, an enyne would be
required.
(-)-MIB
(mol %)
T
(°C)
ee
(%)
entry
borane
ZnR2
1
2
3
4
5
6
Et2BH
Et2BH
Et2BH
Cy2BH
Et2BH
Et2BH
4
4
10
4
4
10
ZnEt2
ZnEt2
ZnEt2
ZnEt2
ZnMe2
ZnEt2
–10
–30
–10
–10
–10
–10
84
88a
89
84
83
93b
a Over 24 h reaction time. b Slow addition of aldehyde in hexanes.
related examples of dienylation of aldehydes have not been
reported to our knowledge. Reductive coupling reactions of
enynes with aldehydes91,92 and ketones93,94 and related
reactions95-97 allow access to dienols with high enantioselec-
tivities in some cases. In prior work from our laboratories, the
vinylation and dienylation of ketones was investigated.98-100
In this case, Oppolzer’s method failed to provide the desired
alcohols with high levels of enantioselectivity and yield. We
found it necessary to use Wipf’s101 hydrozirconation/transmeta-
lation procedure to accomplish the dienylation reaction to afford
enantioenriched dienols containing tertiary alcohols.99
The first step in advancing the catalytic asymmetric synthesis
of VCPs was to optimize the yield and enantioselectivity in the
dienylation of aldehydes (Table 1). In our initial investigations,
we applied the optimized conditions for the asymmetric viny-
lation outlined in Scheme 1B. Thus, using the enyne 4-methyl-
3-decen-1-yne, hydroboration with diethylborane at 25 °C
occurred with high chemo- and regioselectivity to form the
3.1.1. Synthesis of Enantioenriched Dienols. Although a
variety of terminal alkynes have been employed in the asym-
metricvinylationofaldehydesbasedonOppolzer’sprocedure,85-90
(72) Wender, P. A.; Gamber, G. G.; Williams, T. J. In Modern Rhodium-
Catalyzed Organic Reactions; Evans, P. A., Ed.; Wiley: Weinheim,
2005; p 263.
(73) Wegner, H. A.; de Meijere, A.; Wender, P. A. J. Am. Chem. Soc.
2005, 127, 6530–6531.
(86) Oppolzer, W.; Radinov, R. N.; El-Sayed, E. J. Org. Chem. 2001,
66, 4766–4770.
(87) Hussain, M. H.; Walsh, P. J. Acc. Chem. Res. 2008, 41, 883–893.
(88) Rowley Kelly, A.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc.
2005, 127, 14668–14674.
(74) Kurahashi, T.; de Meijere, A. Synlett 2005, 2619–2622.
(75) Trost, B. M.; Shen, H. C.; Horne, D. B.; Toste, F. D.; Steinmetz,
B. G.; Koradin, C. Chem.sEur. J. 2005, 11, 2577–2590.
(76) Trost, B. M.; Yasukata, T. J. Am. Chem. Soc. 2001, 123, 7162–7163.
(77) Zheng, J.-C.; Liao, W.-W.; Tang, Y.; Sun, X.-L.; Dai, L.-X. J. Am.
Chem. Soc. 2005, 127, 12222–12223.
(89) Lurain, A. E.; Carroll, P. J.; Walsh, P. J. J. Org. Chem. 2005, 70,
1262–1268.
(90) Jeon, S.-J.; Chen, Y. K.; Walsh, P. J. Org. Lett. 2005, 7, 1729–1732.
(91) Miller, K. M.; Luanphaisarnnont, T.; Molinaro, C.; Jamison, T. F.
J. Am. Chem. Soc. 2004, 126, 4130–4131.
(92) Mahandru, G. M.; Liu, G.; Montgomery, J. J. Am. Chem. Soc. 2004,
126, 3698–3699.
(78) Deng, X.-M.; Cai, P.; Ye, S.; Sun, X.-L.; Liao, W.-W.; Li, K.; Tang,
Y.; Wu, Y.-D.; Dai, L.-X. J. Am. Chem. Soc. 2006, 128, 9730–9740.
(79) Davies, H. M. L.; Bruzinski, P. R.; Lake, D.; Kong, N.; Fall, M.
J. Am. Chem. Soc. 1996, 118, 6897–6907.
(93) Komanduri, V.; Krische, M. J. J. Am. Chem. Soc. 2006, 128, 16448–
16449.
(94) Miller, K. M.; Jamison, T. F. Org. Lett. 2005, 7, 3077–3080.
(95) Kong, J. R.; Krische, M. J. J. Am. Chem. Soc. 2006, 128, 16040–
16041.
(80) Davies, H. M. L.; Panaro, S. A. Tetrahedron Lett. 1999, 40, 5287–
5290.
(81) Lowenthal, R. E.; Masamune, S. Tetrahedron Lett. 1991, 32, 7373–
7376.
(96) Yu, C.-M.; Lee, S.-J.; Jeon, M. J. Chem. Soc., Perkin Trans. 1 1999,
3557–3558.
(82) Barrett, A. G. M.; Tustin, G. J. J. Chem. Soc., Chem. Commun. 1995,
355, 356.
(97) Yu, C.-M.; Yoon, S.-K.; Lee, S.-J.; Lee, J.-Y.; Yoon, S.-K.; Kim,
S. S. Chem. Commun. 1998, 2749–2750.
(83) Ukaji, Y.; Nishimura, M.; Fujisawa, T. Chem. Lett. 1992, 61–64.
(84) Charette, A. B.; Juteau, H.; Lebel, H.; Molinaro, C. J. Am. Chem.
Soc. 1998, 120, 11943–11952.
(98) Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 6538–6539.
(99) Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 8355–8361.
(100) Anaya de Parrodi, C.; Walsh, P. J. Synlett 2004, 2417–2420.
(101) Wipf, P.; Ribe, S. J. Org. Chem. 1998, 63, 6454–6455.
(85) Oppolzer, W.; Radinov, R. N. HelV. Chim. Acta 1992, 75, 170–173.
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Enantio-/Diastereoselective Syntheses of Cyclopropyl Alcohols
A R T I C L E S
Table 2. Substrate Scope for the Asymmetric Addition of Dienyl
Groups to Aldehydes
intermediate dienylborane. Transmetalation with diethylzinc
generated the dienylzinc intermediate. In the presence of catalyst
derived from (-)-MIB, the dienylation of isobutyraldehyde was
conducted at -10 °C (Table 1, entry 1) and afforded the dienol
product with good enantioselectivity (84%). The enantioselec-
tivity in the dienylation, however, was significantly less than
that observed in the vinylations in Scheme 1B (91-99% ee).44
We suspected that the more electron-rich π-system of the
dienyl group resulted in greater nucleophilicity over vinyl groups
and that the increased rate of the background reaction was
eroding the enantioselectivity. To decrease the impact of the
background reaction, the temperature was lowered to -30 °C.
Although the enantioselectivity increased to 88%, the reaction
time was greatly extended (entry 2). Raising the catalyst loading
to 10 mol % resulted in a slightly higher enantioselectivity (89%,
entry 3) and a more rapid reaction. Use of dicyclohexyl borane
in place of diethyl borane (entry 4) or dimethylzinc instead of
diethylzinc (entry 5) did not result in any improvement in
enantioselectivity. Finally, use of 10 mol % MIB and dropwise
addition of isobutyraldehyde (in a solution of hexanes) resulted
in an increase in enantioselectivity to 93% (entry 6). We
proposed that the slow addition ensures that a greater percentage
of the catalyst is available to promote the aldehyde dienylation,
reducing the contribution of the uncatalyzed background
reaction.
3.1.2. Substrate Scope of the Asymmetric Dienylation of
Aldehydes. With the optimized conditions for the dienylation
outlined in Table 1 (entry 6), the substrate scope was explored
(Table 2). Use of 4-methyl-3-decen-1-yne with isobutyraldehyde
and cyclohexane carboxaldehyde provided the dienols in 93 and
92% ee with 88 and 90% yields, respectively (entries 1 and 2).
Using ethynylcyclohexene with isobutyraldehyde and cyclo-
hexane carboxaldehyde provided products with 89% ee and 85%
yield and 90% ee and 80% yield, respectively (entries 3 and
4). Pivaldehyde underwent dienylation with a slightly lower ee
(80%) but high yield (85%, entry 5). Aromatic aldehydes
underwent addition with 84-91% yield and enantioselectivities
between 93-94% (entries 6 and 7). The silyl protected enynol
participated in the addition to branched aldehydes with 90%
enantioselectivity and g90% yield (entries 8 and 9) and
dihydrocinnamaldehyde with 76% enantioselectivity and 79%
yield (entry 10). These dienylations were next incorporated into
the tandem synthesis of VCPs.
a Isolated yield. b Determined by HPLC (see Supporting Information).
EtZnCH2I, which was employed in Scheme 1B.104,105 Reactions
with 2 equiv of this carbenoid were thwarted by low conver-
sions, possibly due to decomposition of the carbenoid, while
those with 5 equiv led to generation of bis(cyclopropyl) alcohol
(1:1 dr). On the basis of these results, we explored portion-
wise addition of 4 equiv of EtZnCH2I (see General Procedure
B and the Supporting Information). This mode of addition
resulted in formation of the desired vinyl cyclopropyl alcohols
with excellent diastereoselectivity (dr >19:1). Under these
reaction conditions, the enynes and aldehyde partners employed
in Table 2 were subjected to the tandem asymmetric dienylation/
diastereoselective cyclopropanation reactions (Scheme 3, Table
3). In all cases, the optimized conditions for the cyclopropa-
nation generated only one diastereomer of the vinyl cyclopropyl
alcohols (65-85% yield). Initially we were concerned that
cyclopropanation of the electron-rich trisubstituted olefins in
entries 1-5 might be competitive with cyclopropanation of the
allylic double bonds. Fortunately, this was not the case. For
3.1.3. Tandem Enantioselective Dienylation/Diastereoselective
Cyclopropanation: Synthesis of VCPs. With the conditions
established for the asymmetric dienylation of aldehydes, we
proceeded to explore the possibility of a tandem enantioselective
dienylation/chemo- and diastereoselective cyclopropanation. As
shown in Scheme 2, alkoxide directed cyclopropanation at allylic
double bonds is faster than cyclopropanation at more remote
positions.82,84 The carbenoid CF3CH2OZnCH2I was successfully
employed in our cyclopropanation reactions outlined in Scheme
1A.44 Unfortunately, with our dienyl zinc alkoxides (Scheme
3), the bis(cyclopropyl) alcohol was also generated with poor
diastereoselectivity (1:1 dr) despite efforts to optimize the VCP
synthesis. Screening other zinc carbenoids, such as IZnCH2I102
and Zn(CH2I)2, was also unsuccessful.103 To overcome these
problems we examined the milder alkylzinc carbenoid,
(104) Furukawa, J.; Kawabata, K.; Nishimura, J. Tetrahedron Lett. 1966,
(102) Charette, A. B.; Marcoux, J. F. J. Am. Chem. Soc. 1996, 118, 4539–
4549.
28, 3353–3354.
(105) Furukawa, J.; Kawabata, K.; Nishimura, J. Tetrahedron 1968, 24,
(103) Denmark, S. E.; Edwards, J. P. J. Org. Chem. 1991, 56, 6974–6981.
53–58.
9
J. AM. CHEM. SOC. VOL. 132, NO. 1, 2010 407

A R T I C L E S
Kim et al.
Table 3. Scope of the One-Pot Asymmetric Dienylation/
Diastereoselective Cyclopropanation (Scheme 3)
Table 4. Synthesis of anti-Cyclopropyl Silyl Ethers by Charette and
Lacasse
Table 5. Optimization of the Asymmetric Addition/Silylation
Procedure
entry
silyl reagent
equiv
comment
1
2
3
4
5
6
7
8
9
TBDPS-Cl
TBDPS-Cl
TIPS-Cl
TBS-Cl
2.0
2.0
2.0
2.0
2.0
2.0
2.0
5.0
1.5
very low conversiona
low conversion
low conversion
incomplete
incomplete
50% yield
TES-Cl
a
TIPS-OTf
TES-OTf
TBS-Cl
1
Determined by H NMR of the crude product.
35% yield
75% yield
completeb
reasons that are not clear, the tandem asymmetric dienylation/
diastereoselective cyclopropanation with benzaldehyde and
4-fluorobenzaldehyde did not result in formation of the desired
product. These substrates exhibited low conversions and were
complicated by formation of the bis(cyclopropane) and elimina-
tion byproducts. Similarly, problems were encountered in
Scheme 1B with aromatic aldehydes.44
3.2. Approaches toward the Synthesis of anti-Cyclopropyl
Alcohols. The ability of the alkoxy functionality in chiral allylic
alkoxides to direct106 the cyclopropanation of neighboring
double bonds with control of the incipient stereochemistry has
been investigated and applied in synthesis.5 With acyclic (E)-
and (Z)-allylic alcohols, the directed Simmons-Smith reaction
is highly syn selective. Although the excellent directing ability
of allylic alkoxides greatly facilitates synthesis of the syn
cyclopropyl alcohols, efficient syntheses of the anti diastereo-
mers remain challenging.107,108
An early approach to anti-cyclopropyl alcohols by Lautens
involved reduction of the corresponding cyclopropyl ketones,
which gave high anti-selectivity with trisubstituted and (Z)-
disubstituted cyclopropyl ketones.109-111 Charette and co-
workers found that enantioenriched allylic alcohols underwent
cyclopropanation to generate the anti-cyclopropyl alcohols in
the presence of stoichiometric enantioenriched tartrate-derived
TMS-Cl
a No NEt3 added. b Isolation and purification resulted in partial loss
of the TMS group.
dioxaborolanes.112 A different strategy was developed by
Charette and Lacasse that involved protection of allylic alcohols
with bulky silyl groups followed by cyclopropanation (Table
4).107 The silyl group is believed to inhibit coordination of the
zinc carbenoid to the allylic oxygen. Cyclopropanation is
proposed to occur through a transition state that minimizes
interaction between the silyl ether and carbenoid, affording the
anti-stereoisomer, rather than through a directed pathway.
Although this discovery represents a significant advance, the
preparation of anti-cyclopropyl alcohols remains inefficient,
involving the (1) synthesis of the allylic alcohol, (2) silyl ether
formation, (3) cyclopropanation, and (4) deprotection, not to
mention purifications after each step.
3.2.1. Development of a One Pot Synthesis of anti-Cyclopro-
pyl Alcohols. Our approach to anti-cyclopropyl alcohols blends
our one-pot synthesis of syn-cyclopropyl alcohols (Scheme 1A)
(109) Delanghe, P. H. M.; Lautens, M. Tetrahedron Lett. 1994, 35, 9513–
9516.
(110) Lautens, M.; Delanghe, P. H. M. J. Org. Chem. 1995, 60, 2474–
2487.
(106) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307–
1370.
(111) Kazuta, Y.; Abe, H.; Yamamoto, T.; Matsuda, A.; Shuto, S. J. Org.
Chem. 2003, 68, 3511–3521.
(107) Charette, A. B.; Lacasse, M.-C. Org. Lett. 2002, 4, 3351–3354.
(108) Zohar, E.; Marek, I. Org. Lett. 2004, 6, 341–343.
(112) Charette, A. B.; Lebel, H.; Gagnon, A. Tetrahedron 1999, 55, 8845–
8856.
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408 J. AM. CHEM. SOC. VOL. 132, NO. 1, 2010

Enantio-/Diastereoselective Syntheses of Cyclopropyl Alcohols
A R T I C L E S
Scheme 4. Tandem Sequence to Afford anti-Cyclopropyl Alcohols with High Enantio- and Diastereoselectivity (Table 6)
Table 6. Examples of anti-Cyclopropyl Alcohols Prepared in
Scheme 4 in One Pot
agent (entries 4 and 5). More reactive TIPS-OTf and TES-OTf
resulted in complete consumption of the alkoxide. The reactions
were not clean, however, due to formation of elimination
byproducts, and the silyl ethers were isolated in 50 and 35%
yield, respectively (entries 6 and 7). Increasing the equivalents
of TBS-Cl to 5 resulted in complete silylation. Unfortunately,
the excess TBS-Cl caused difficulties in the subsequent cyclo-
propanation step. Finally we employed 1.5 equiv of TMS-Cl
(trimethylsilyl chloride) with 1.5 equiv of triethylamine (entry
9). Isolation of the silylated product did not accurately reflect
the conversion, because TMS silyl ethers are very sensitive to
cleavage of the Si-O bond. Nonetheless, we found that the silyl
protection was complete by TLC in 18 h.
The optimized asymmetric addition/silylation was then com-
bined with the diastereoselective cyclopropanation as illustrated
in Scheme 4. The cyclopropanation employing excess EtZnCH2I
was sluggish. Use of Shi’s more reactive CF3CH2OZnCH2I (5
equiv),113 however, generated the anti-cyclopropyl alcohols with
high diastereoselectivity and yield in 24 h. The cyclopropanated
silyl ether intermediates were desilylated by addition of 2 equiv
of TBAF upon workup. Following Scheme 4, ethyl addition to
cinnamaldehyde, R-methyl cinnamaldehyde, 3-methyl-2-butenal,
and cyclohexene carboxaldehyde resulted in anti-cyclopropyl
alcohol formation with high enantioselectivities (89-99%), good
yields (67-82%), and excellent dr (>19:1, Table 6, entries 1-4).
Methyl addition to R-methyl cinnamaldehyde followed by
silylation, cyclopropanation, and deprotection furnished the anti-
cyclopropyl alcohol 15 in 80% yield with 95% ee and >19:1 dr
(entry 5). The slightly lower dr of 16 (10:1) in entry 6 is likely
aresultofdifficultiesingeneratingtheorganozinccompound.114,115
The results in Table 6 demonstrate that anti-cyclopropyl alcohols
can be prepared with high selectivities and good yields in an
efficient one-pot procedure. The yields in Table 6 are only
slightly lower than those reported by Charette in Table 4 for
the diastereoselective cyclopropanation of racemic silyl ethers.
To date, we have been unsuccessful employing the asymmetric
vinylation of aldehydes44,50 (Scheme 1B) in tandem with the
anti-cyclopropanation procedure. The enal alkylation/anti-
cyclopropanation method of Scheme 4 is complementary to our
syn-cyclopropanation chemistry shown in Scheme 1. In the next
section we explore a method to couple generation of (Z)-allylic
alkoxides with diastereoselective cyclopropanation.
a Ee’s determined by GC or HPLC. b Determined by 1H NMR
analysis of the crude reaction mixture.
with Charette’s synthesis of anti-cyclopropyl alcohols via
silylated allylic alcohols.107
The key to success was development of an in situ silylation
of the intermediate allylic zinc alkoxide that was compatible
with the diastereoselective cyclopropanation. For this study,
cinnamaldehyde and diethylzinc were employed with various
silylating reagents (Table 5). On the basis of Charette’s success
with bulky silyl groups,107 we initiated our studies with TBDPS-
Cl (tert-butyl diphenylsilyl chloride). Surprisingly, reaction of
the zinc allylic alkoxide with 2 equiv of TBDPS-Cl was very
slow and only trace silylated products were observed (entry 1).
We hypothesized that the reactivity of the zinc alkoxide product
might be attenuated by formation of aggregates. To disrupt
aggregation, we added 1.5 equiv of triethylamine. In the
presence of amine, conversion improved but remained low (entry
2). Similar results were observed with TIPS-Cl (triisopropylsilyl
chloride, entry 3). The smaller TBS-Cl (tert-butyl dimethylsilyl
chloride) and TES-Cl (triethylsilyl chloride) exhibited greater
reactivity toward the allylic zinc alkoxide, but full conversion
to the silyl ether was not observed with 2 equiv of the silylating
3.3. Generation of cis-Disubstituted Cyclopropyl Alcohols.
Two approaches to cis-disubstituted cyclopropyl alcohols can
be envisioned as illustrated in Scheme 5. They begin with
(113) Yang, Z. Q.; Lorenz, J. C.; Shi, Y. Tetrahedron Lett. 1998, 39, 8621–
8624.
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9
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A R T I C L E S
Kim et al.
proceed smoothly to generate (Z)-allylic alcohols.126 Using this
method, a variety of racemic (Z)-allylic alcohols were prepared in
high yields. Unfortunately, attempts toward enantioselective ver-
sions in the presence of (-)-MIB furnished only racemic products
due to the rapid LiCl promoted background reaction. To suppress
this background reaction, we inhibited the LiCl byproducts with
tetraethylethylene diamine (TEEDA),124,127,128 which chelates to
the lithium center and likely forms catalytically inactive four-
coordinate oligomeric [TEEDA•LiCl]n complexes with bridging
chlorides.129,130 In the presence of the diamine inhibitor,
enantioselectivities as high as 98% were recorded (Scheme 6,
bottom left).116
Scheme 5. Two Routes to cis-Disubstituted Cyclopropyl Alcohols
To prepare enantio- and diastereoenriched cis-disubstituted
cyclopropyl alcohols, the (Z)-vinylation outlined in Scheme 6
was incorporated into the tandem (Z)-vinylation/cyclopropana-
tion sequence in Scheme 7. Thus, hydroboration of the chlo-
roalkyne and addition of tert-butyllithium generated the (Z)-
vinyl borane. Transmetalation with diethylzinc was followed
by addition of the diamine inhibitor (TEEDA), (-)-MIB, and
the aldehyde. The resulting allylic alkoxide was then subjected
to diastereoselective cyclopropanation with 5 equiv of CF3CH2-
OZnCH2I under conditions similar to those used in Scheme 1B.
After the usual workup, the desired syn-cis-disubstituted cy-
clopropyl alcohols were isolated in 42-70% yield with dr’s
>19:1 (Table 7). As shown in entries 1-3 of Table 7,
chloroalkynes bearing TBDPS ethers underwent additions to
saturated, aromatic, and heteroaromatic aldehydes with enan-
tioselectivities g 90% and yields for the tandem reaction ranging
from 52-65%. Likewise, 1-chloro-substituted chloroalkynes
were also good substrates, furnishing the cyclopropyl alcohols
in 55-70% yield with 88-94% ee (entries 4-6). 1-Chloro-
phenyl acetylene and benzaldehyde were excellent substrates,
affording the cis cyclopropyl alcohol in good yield and enantio-
and diastereoselectivity (65% yield, 97% ee, dr > 19:1).
2-Thiophenecarboxaldehyde proved more difficult, and the
tandem reaction exhibited low yield but a useful ee (92%) and
dr (>19:1).
asymmetric alkyl addition to (Z)-enals or asymmetric (Z)-
vinylation to saturated aldehydes. The resulting (Z)-allylic
alkoxide would then be subjected to diastereoselective syn-
cyclopropanation. Both routes have challenges. (Z)-Enals can
be difficult to prepare with high diastereopurity, and they
isomerize readily to the thermodynamically favored (E)-isomer.
It is also difficult to prepare diastereopure (Z)-vinyl organome-
tallic reagents. The latter method, however, is more versatile,
because there are many more commercially available aldehydes
compared to (Z)-enals.
As outlined in Scheme 1B, using Oppolzer’s procedure85 we
generated (E)-vinylzinc reagents as intermediates in the synthesis
of trans-disubstituted cyclopropyl alcohols. This procedure,
however, does not permit generation of diastereomeric cis-
disubstituted cyclopropyl alcohols, which would be formed from
(Z)-disubstituted vinylzinc reagents. To circumvent this defi-
ciency, we recently developed a method to generate enantioen-
riched (Z)-allylic alcohols starting from 1-chloro-1-alkynes
(Scheme 6).116 Initial hydroboration of 1-chloro-1-alkynes with
dicyclohexylborane generated 1-chloro-1-alkenylboranes with
excellent regioselectivity. It is known that nucleophiles react
with 1-halo-1-alkenylboron derivatives, first adding to the open
coordination site on boron followed by migration of the
nucleophile117,118 or a boron alkyl to the vinylic position with
inversion at the vinylic center.118-124 We used t-BuLi, which
had been demonstrated to act as a hydride source in this process
by Molander,118 in the formation of (Z)-vinylboranes. Vinylbo-
ranes are not very reactive toward carbonyl additions, however.
On the basis of the work of Srebnik125 and Oppolzer85 we knew
that (Z)-vinyl boranes would undergo boron to zinc transmeta-
lation with dialkylzincs to generate more reactive (Z)-vinylzinc
reagents. The increased nucleophilicity of vinylzinc reagents over
their vinylborane counterparts enabled additions to aldehydes to
To confirm the relative stereochemistry of the cyclopropyl
alcohols, 23 (Table 7, entry 7) was derivatized with (-)-
camphanic acid chloride, the resulting ester crystallized by slow
evaporation from a solution of hexanes and dichloromethane,
and the structure determined by X-ray crystallography. Both
the syn relationship between the hydroxyl and cyclopropane and
cis geometry of the cyclopropane were found (Figure 2).
By using our method for the enantioselective (Z)-vinylation
of aldehydes116 in tandem with the in situ cyclopropanation
reaction, a variety of cis-disubstituted cyclopropyl alcohols
(17-24) can be prepared in a one-pot procedure in respectable
yields. This method circumvents the synthesis of thermody-
namically unstable (Z)-enals and the isolation of (Z)-vinylzinc
species. It is complementary to those cyclopropyl alcohol
syntheses in Schemes 1, 3, and 4.
(116) Salvi, L.; Jeon, S.-J.; Fisher, E. L.; Carroll, P. J.; Walsh, P. J. J. Am.
Chem. Soc. 2007, 129, 16119–16125.
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71–79.
(119) Zweifel, G.; Arzoumanian, H. J. Am. Chem. Soc. 1967, 89, 5086–
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(120) Negishi, E.; Yoshida, T. J. Chem. Soc., Chem. Commun. 1973, 606–
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(123) Chen, Y. K.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 3702–3703.
(124) Kerrigan, M. H.; Jeon, S.-J.; Chen, Y.; Salvi, L.; Carroll, P. J.; Walsh,
P. J. J. Am. Chem. Soc. 2009, 131, 8434–8445.
(125) Srebnik, M. Tetrahedron Lett. 1991, 32, 2449–2452.
245–248.
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410 J. AM. CHEM. SOC. VOL. 132, NO. 1, 2010

Enantio-/Diastereoselective Syntheses of Cyclopropyl Alcohols
A R T I C L E S
Scheme 6. Enantioselective Generation of (Z)-Allylic Alcohols in the Presence of TEEDA Inhibitor
Scheme 7. One-Pot Synthesis of cis-Disubstituted Cyclopropyl
Alcohols
Table 7. Substrate Scope of the Synthesis of cis-Disubstituted
Cyclopropyl Alcohols
4. Summary and Outlook
Thousands of cyclopropane containing natural products and
their derivatives have been described in the literature.2-4,9,14,65
Their interesting biological properties and rigid structures131
have made cyclopropanes a platform for the development of
new therapeutic agents. Nature’s cyclopropanes are often
enantioenriched and exhibit diverse substitution patterns and
stereochemistries. Their efficient syntheses, therefore, require
different approaches.
The cyclopropyl alcohols described herein all contain three
stereogenic centers and possess distinct substitution patterns and
stereochemical relationships. Their enantio- and diastereose-
lective syntheses have been designed to provide only the desired
stereoisomer. The methods we have introduced for their
a Ee’s determined by GC or HPLC. b Determined by 1H NMR
analysis of the crude reaction mixture.
syntheses are based on initial enantioselective CsC bond
formations catalyzed by a (-)-MIB-based zinc catalyst. In the
case of vinyl cyclopropyl alcohols, hydroboration of an enyne
affords a dienyl borane. Boron to zinc transmetalation is
followed by asymmetric aldehyde additions to form dienyl zinc
alkoxides. Addition of EtZnCH2I results in an alkoxide-directed
cyclopropanation of the allylic CdC double bond to afford vinyl
cyclopropyl alcohols with high enantio- and diastereoselectivity.
The zinc alkoxy group not only controls the chemoselectivity
but also directs the cyclopropanation to afford the syn stereo-
chemical relationship between the carbinol and cyclopropane.
To prepare the anti-diastereomers, the strong directing ability
of the allylic alkoxide must be overridden. Based on work by
Figure 2. X-ray structure of the camphanic ester of compound 23.
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A R T I C L E S
Kim et al.
Charette,107 we incorporated a silylation step into the tandem
reaction to force cyclopropanation to occur on the opposite
double bond face. Key to this procedure was addition of Et3N
to facilitate silyl ether formation. Thus, asymmetric addition of
an organozinc reagent to an enal was followed by silylation of
the allylic zinc alkoxide to generate an allylic silyl ether.
Cyclopropanation of the allylic silyl ether with CF3CH2OZnCH2I
followed by TBAF workup provided the anti-cyclopropyl
alcohols with excellent ee and dr. Selective formation of the
syn- or anti-cyclopropyl alcohols is now readily achieved in
one pot.44 Previous methods to prepare these compounds
required several synthetic steps and purifications.
the desired diastereomer with high enantio- and diastereoselec-
tivities and moderate yields. The three methods introduced
herein facilitate the synthesis of cyclopropyl alcohols with
different stereochemical relationships. These compounds were
not previously accessible in a synthetically efficient fashion.
Given the rapid increase in molecular complexity with defined
stereochemical outcomes, we anticipate that these methods will
be useful in enantioselective synthesis.
Acknowledgment. We thank the NSF (CHE-065210 and
0848467) and NIH (National Institute of General Medical Sciences
GM58101) for partial support of this work. We are also grateful to
the NIH for the purchase of a Waters LCTOF- Xe Premier ESI
mass spectrometer (Grant No. 1S10RR23444-1).
We have previously employed Oppolzer’s85 alkyne hydrobo-
ration/transmetalation to zinc and asymmetric addition to
aldehydes to prepare cyclopropyl alcohols containing trans-
disubstituted cyclopropanes (Scheme 1B).44 To access the cis-
isomer, our asymmetric (Z)-vinylation of aldehydes116 was
followed by cyclopropanation with CF3CH2OZnCH2I to provide
Supporting Information Available: Procedures, full charac-
terization of new compounds, and structure of the camphanic
ester of 23. This material is available free of charge via the
Internet at http://pubs.acs.org.
(131) Reichelt, A.; Martin, S. F. Acc. Chem. Res. 2006, 39, 433–442.
JA907781T
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