Intermolecular C-H functionalization versus cyclopropanation of electron rich 1,1-disubstituted and trisubstituted alkenes

Article abstract of DOI:10.1016/j.tet.2008.11.059

Rhodium(II)-catalyzed reactions of aryldiazoacetates with electron rich 1,1-disubstituted and trisubstituted alkenes were systematically studied. The regio-, diastereo- and enantioselectivity of the chemistry was profoundly influenced by the nature of the

Full text of DOI:10.1016/j.tet.2008.11.059

Tetrahedron 65 (2009) 3052–3061
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Intermolecular C–H functionalization versus cyclopropanation of electron
rich 1,1-disubstituted and trisubstituted alkenes
,
Dominic L. Ventura b, Zhanjie Li a, Michael G. Coleman b, Huw M.L. Davies a
*
a Department of Chemistry, Emory University, Atwood Hall, 1515 Dickey Drive, Atlanta, GA 30322, United States
b Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY 14260, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Rhodium(II)-catalyzed reactions of aryldiazoacetates with electron rich 1,1-disubstituted and tri-
substituted alkenes were systematically studied. The regio-, diastereo- and enantioselectivity of the
chemistry was profoundly influenced by the nature of the substrates and the catalyst. Conditions were
developed for either selective cyclopropanation or C–H insertion. Both reactions can be achieved with
high diastereo- and enantioselectivity (for C–H insertion: >90% de, up to 96% ee, for cyclopropanation:
>94% de, up to 95% ee). For the 1,1-disubstituted vinyl ethers, cyclopropanation occurs with variable
diastereoselectivity but in optimized systems the cyclopropane is formed in >94% de and up to 98% ee.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 15 September 2008
Received in revised form 15 November 2008
Accepted 19 November 2008
Available online 25 November 2008
Dedicated to Professor Justin Du Bois in
recognition of his receipt of the Tetrahedron
Young Investigator Award
1. Introduction
illustrate how the catalyst and substrates can have a profound in-
fluence on which reaction pathway is preferred.
Aryldiazoacetates are widely recognized as useful precursors to
rhodium carbenoid intermediates.1 The resulting donor/acceptor-
substituted carbenoids are more stabilized than conventional
carbenoids. Consequently, they are capable of a range of highly
stereoselective reactions, including cyclopropanation,2 cyclo-
propenation,3 N–H,4 O–H,5 and C–H6 insertions, and ylide
transformations.7 For some time we have explored the C–C bond-
forming reactions of the donor/acceptor-substituted carbenoids
with particular emphasis on intermolecular C–H insertion6 and
cyclopropanation.2a–e Substrates with an allylic moiety have two
potentially competing pathways: cyclopropanation and allylic C–H
insertion.8 Thus, as the donor/acceptor carbenoids chemistry has
evolved, a natural question has arisen: what controls the selectivity
between these two reaction pathways (Fig. 1)? This study will
The donor/acceptor carbenoids act as sterically demanding
electrophiles. When they react with electron neutral alkenes, only
monosubstituted, 1,1-disubstituted and, less favorably, cis-1,2-
disubstituted alkenes can be cyclopropanated. More highly
substituted alkenes will be susceptible to allylic C–H insertion,
while competing cyclopropanation and C–H insertion often occurs
in the reactions of cis-1,2-disubstituted alkenes. Recently, we dis-
covered that electron rich trans-1,2-disubstituted alkenes can be
stereoselectively cyclopropanated by aryldiazoacetates.9 The com-
petition between cyclopropanation and C–H insertion was con-
trolled by a delicate balance between the substrates and the
catalysts. This led to the current study, which explores the com-
petition between C–H insertion to form 2 and cyclopropanation to
form 3 of trisubstituted alkenes 1 (Scheme 1). The unexpected
stereochemical outcome of cyclopropane 3 expanded the study to
the cyclopropanation chemistry of 1,1-disubstituted alkenes
(Scheme 2).
The synthetic chemistry of the donor/acceptor carbenoids has
been greatly enriched by the availability of chiral dirhodium
carboxylates capable of highly enantioselective reactions. The
standard catalyst has been dirhodium tetraprolinate Rh2(S-
DOSP)4, which has by now seen broad application in carbenoid
reactions.6 Another effective catalyst is the bridged prolinate
catalyst, Rh2(S-biTISP)2,10 while the most recent is Rh2(S-PTAD)4.11
This study also gives a detailed analysis on how these highly
effective catalysts can impact the outcome of this chemistry
(Fig. 2).
C–H insertion
R1
R2
R3
Cyclopropanation
Figure 1. Two competing reaction pathways for carbenoid reactions at allylic systems.
* Corresponding author. Tel.: þ1 404 727 6839; fax: þ1 404 727 7766.
E-mail address: hmdavie@emory.edu (H.M.L. Davies).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.059

D.L. Ventura et al. / Tetrahedron 65 (2009) 3052–3061
3053
N2
and 2,2-dimethylbutane (2,2-DMB) as solvent. When Rh2(S-
DOSP)4 was used as catalyst, allylic C–H insertion and cyclo-
propanation occurred (Table 1, entries 1–3). Cyclopropane 10a was
favored by a 4:1 ratio with 7a, containing the smallest silicon
protecting group, (entry 1), while 7c with the largest silyl group
favored the C–H insertion product 9c by a 2:1 ratio (entry 3). The
C–H insertion products 9a–c were formed with good diaster-
eocontrol (82–88% de) and moderate enantiocontrol (54–73% ee)
while the cyclopropanes 10a–c were formed with excellent dia-
stereocontrol (>94% de) and good enantiocontrol (78–91% ee).
When the sterically more rigid catalyst, Rh2(S-biTISP)2, was used,
the C–H insertion products 9a–c were preferred over the cyclo-
propanes 10a–c in ratios varying from 2:1 to 7:1 (Table 1, entries
4–6). The diastereoselectivity for 9a–c (75–84% de) was similar to
that observed with Rh2(S-DOSP)4, but the enantioselectivity was
greatly improved (90–92% ee). Both series of compounds 9a–c and
10a–c were formed with opposite asymmetric induction to
the reactions catalyzed by Rh2(S-DOSP)4. This switch in asym-
metric induction between the two-prolinate catalysts is well
established.10
R2
OR1 R2
OR1
Ar
CO2Me
Rh(II)
CO2Me
and/or
R1O
Ph
Ar
CO2Me
Ph
Ph
R2
Ar
1
2
3
R1= TMS, TBS, TBDPS
R2= H, Me
Scheme 1. Reaction of aryldiazoacetates with trisubstituted vinyl ethers.
N2
Ar1
RO
Ar2
RO
Ar1
Ar2
Ar2 CO2Me
Rh(II)
OR
CO2Me
Ar1
CO2Me
4
5
6
R= TMS, TBS, TBDPS
Scheme 2. Reaction of aryldiazoacetates with 1,1-disubstituted vinyl ethers.
2. Results and discussion
The most impressive results were obtained in the reactions of
7a–c catalyzed by Rh2(S-PTAD)4. This catalyst is gaining signifi-
cance because it has been shown to be an effective catalyst in
various reactions of donor/acceptor carbenoids.11 Furthermore,
in certain systems it can give superior diastereoselectivity and
The preliminary studies focused on the reaction of TMS-, TBS-,
and TBDPS-protected silyl enol ethers 7a–c. The standard reaction
used p-bromophenyldiazoacetate 8 as the carbenoid precursor
R
N
H
O
H
O
O
Rh
Rh
H
O
H
O
O
Rh
Rh
Rh
Rh
O
O
O
N
N
N
R
O
H
H
SO2C6H4C12H25
4
2
4
i
Rh2(S-DOSP)4
R = SO2-2,4,6-tri PrC6H2
Rh2(S-PTAD)4
Rh2(S-biTISP)2
Figure 2. Chiral dirhodium catalysts.
Table 1
Optimization of the Rh(II) catalyzed reactions of 7a–c with aryldiazoacetate
Et
OR
N2
OR
CO2Me
RO
Ph
Ph(p-Br)
Rh(II) (1 mol %)
2,2-DMB, rt, 3 h
Ph
(p-Br)Ph
CO2Me
+
+
Ph
CO2Me
Ph(p-Br)
9a-c
7a-c
8, 2 equiv.
10a-c
R: TMS (7a), TBS (7b), TBDPS (7c)
Entry
Substrate
Rh(II)
9/10b
9
10
Yieldc (%)
deb (%)
eed,e (%)
Yieldc (%)
deb (%)
eed,e (%)
1
2
3
7a
7b
7c
7a
7b
7c
7a
7b
7c
7c
Rh2(S-DOSP)4
Rh2(S-DOSP)4
Rh2(S-DOSP)4
Rh2(S-biTISP)2
Rh2(S-biTISP)2
Rh2(S-biTISP)2
Rh2(S-PTAD)4
Rh2(S-PTAD)4
Rh2(S-PTAD)4
Rh2(S-PTAD)4
1/4
1/1
2/1
2/1
7/1
7/1
1/1
8/1
14
49
64
40
66
70
28
77
89
89
84
88
82
75
82
84
85
>94
92
92
73
54
65
75
42
23
22
9
9
35
6
>94
>94
>94
68
N.D.
N.D.
90
N.D.
N.D.
N.D.
91
80
78
ꢀ60
ꢀ74
ꢀ77
34
47
N.D.
N.D.
4a
5a
6a
7
ꢀ90
ꢀ92
ꢀ91
ꢀ83
ꢀ91
ꢀ86
ꢀ93
8
9
>15/1
>15/1
N.D.
N.D.
10f
a
CH2Cl2 was used as solvent.
de was determined from the 1H NMR of the crude reaction mixture.
Reported yields are of isolated products.
b
c
d
e
f
ee was determined by chiral HPLC.
Negative value signifies the opposite enantiomeric series.
Reaction was conducted at 0 ꢁC.

3054
D.L. Ventura et al. / Tetrahedron 65 (2009) 3052–3061
Table 3
enantioselectivity compared to the standard catalyst Rh2(S-
DOSP)4. In the reactions of 7a–c with Rh2(S-PTAD)4 the ratios of
9/10 were very sensitive to the size of the siloxy group (Table 1,
entries 7–9). In the case of the TMS derivative 7a, a 1:1 mixture
of 9a and 10a was formed. Increasing the size of the siloxy group,
increased the preference for the C–H insertion product 9, and in
the case of the TBDPS derivative 7c, 9c was the only product and
was isolated in 89% yield with 92% de and 86% ee. The reaction of
7c was also conducted at 0 ꢁC, and under these conditions, the
yield and diastereoselectivity of 9c were retained while the
enantioselectivity improved to 93% ee. Previous studies have
shown that reactions catalyzed by Rh2(S-PTAD)4 can give either
the same or the opposite enantioinduction to Rh2(S-DOSP)4.11
Rh2(S-PTAD)4 and Rh2(S-DOSP)4 produced the C–H insertion
products 9a–c with opposite asymmetric induction. In contrast,
the same absolute configuration of cyclopropanes 10a and 10b is
obtained with both catalysts, although the enantioselectivity is
quite low (34–47% ee) in the Rh2(S-PTAD)4-catalyzed reactions.
The Rh2(S-PTAD)4-catalyzed C–H insertion of the TBDPS de-
rivative 7c can be extended to a range of aryldiazoacetates 11a–f
with excellent results (Table 2). The C–H insertion products 12a–f
were cleanly formed with little evidence of the competing
cyclopropanation pathway. Lower yields, however, were obtained
with 11d and 11e, primarily because these diazo compounds
were only partially soluble under the reaction conditions. No
product was obtained in the reaction of 7c with p-methoxy-
phenyldiazoacetate 11g. This indicates that a reasonably reactive
electrophilic carbenoid is required for an effective C–H insertion
with this substrate.
Cyclopropanation of 14a–c by aryldiazoacetate 8
N2
OR
RO
Ph
Ph(p-Br)
Rh(II) (1 mol %)
2,2-DMB, rt, 3 h
(p-Br)Ph
CO2Me
+
CO2Me
Ph
8, 2 equiv.
13a-c
14a-c
R: TMS (13a), TBS (13b), TBDPS (13c)
Entry
Substrate
Rh(II)
14
Yieldc (%)
deb (%)
eed,e (%)
1
2
3
13a
13b
13c
13a
13b
13c
13a
13b
13c
Rh2(S-DOSP)4
Rh2(S-DOSP)4
Rh2(S-DOSP)4
Rh2(S-biTISP)2
Rh2(S-biTISP)2
Rh2(S-biTISP)2
Rh2(S-PTAD)4
Rh2(S-PTAD)4
Rh2(S-PTAD)4
88f
70f
84f
79g
68f
61h
90f
86f
67i
>94
>94
>94
72
>94
49
90
>94
85
92
89
95
ꢀ72
ꢀ88
ꢀ69
ꢀ26
ꢀ43
4
4a
5a
6a
7
8
9
a
CH2Cl2 was used as solvent.
b
c
d
e
f
de was determined from the 1H NMR of the crude reaction mixture.
Reported yields are of isolated products.
ee was determined by chiral HPLC.
Negative value indicates the opposite enantiomeric series.
Ratio of cyclopropane: C–H insertion product was >15:1.
Ratio of cyclopropane: C–H insertion product was 11:1.
Ratio of cyclopropane: C–H insertion product was 2:1.
g
h
i
Ratio of cyclopropane: C–H insertion product was 3.7:1; the C–H insertion
product was obtained in 20% isolated yield with 93% ee.
The stereoselective formation of pentasubstituted cyclopro-
panes broadens the synthetic range of donor/acceptor-
substituted carbenoids. In order to optimize this reaction further,
the propene derivatives 13a–c were examined as substrates. It is
well established that the C–H insertion by donor/acceptor car-
benoids is controlled by a delicate balance of steric and electronic
effects.6a In general methyl allylic sites are much harder to
functionalize than methylene allylic sites. Substrates 13a–c would
be expected to be much more selective toward cyclopropanation
than substrates 7a–c, and this was indeed the case, as summa-
rized in Table 3. The Rh2(S-DOSP)4-catalyzed reaction of 8 with
The relative configurations of the C–H insertion products 9a–c
and 12a–f are assigned on the basis of the distinctive shielding of
the vinyl proton,8b,c,12 while their absolute configurations are ten-
tatively assigned by analogy to related established Rh2(S-DOSP)4-
catalyzed C–H insertions8b and the predictive model that has been
developed for Rh2(S-DOSP)4-catalyzed reactions.6a The initial as-
signment of the relative configuration of the cyclopropanes 10a–c
assumed that the cyclopropanation occurred with retention of the
alkene geometry. The 1H NMR of 10 showed a distinctive shielding
of the methyl ester group to
d 3.2 ppm, which is diagnostic of
a methyl ester cis to the C-2 phenyl. This stereochemical arrange-
ment is opposite to that obtained in the cyclopropanation of less
substituted styryl derivatives. Even the reaction of aryldiazoace-
tates with trans-1-aryl-1-propenes gives a single cyclopropane di-
astereomer, which has a trans arrangement between the C-2 aryl
and the methyl ester.2,9
Table 2
Optimized conditions for C–H functionalization of 7c
TBDPSO
Ph
Rh2(S-PTAD)4
N2
OTBDPS
(1 mol %)
CO2Me
+
Ar
CO2Me
Ph
2,2-DMB,
0 °C, 3 h
Ar
12a-g
11a-g, 2equiv.
7c
Entry
Substrate
Ar
12
Yielda (%)
deb (%)
eec (%)
1
2
3
4
5
6
7
11a
11b
11c
11d
11e
11f
p-ClPh
p-IPh
p-CF3Ph
p-TfOPh
3,4-diClPh
Ph
p-MeOPh
64
65
83
40
42
87
>90
>90
>90
80
>90
>90
90
96
93
90
84
72
11g
No reaction
a
Reported yields are of isolated products.
b
c
de was determined from the 1H NMR of the crude reaction mixture.
ee was determined by chiral HPLC.
Figure 3. Crystallographic data of 14c.

D.L. Ventura et al. / Tetrahedron 65 (2009) 3052–3061
3055
OMe
Ph(p-Br)
CO2Me
16
Figure 3. This not only confirmed the assigned relative config-
uration, but also, gave an assignment of the absolute
configuration.
N2
OTBS
OMe
TBSO
Ph
Rh(II) (1 mol %)
2,2-DMB, rt, 3h
+ (p-Br)Ph
CO2Me
Ph
Further studies were then conducted to expand the types of
pentasubstituted cyclopropanes that could be formed. The reaction
of the highly electron rich alkene 15 gave a highly diaster-
eoselective cyclopropanation in both Rh2(S-DOSP)4 and Rh2(S-
PTAD)4-catalyzed reactions. The two catalysts gave opposite
asymmetric induction with Rh2(S-PTAD)4 giving the highest
enantioselectivity (92% ee). The cis relationship between the C-2
phenyl and the methyl ester was again evident from the distinctive
shielding of the methyl ester protons (Scheme 3).
15
8
Rh2(S-DOSP)4
Rh2(S-PTAD)4
69% yield (>94% de, +73% ee)
72% yield (>94% de, -92% ee)
Scheme 3. Synthesis of cyclopropane 16.
Monosubstituted vinyl ethers and styrene undergo highly
diastereoselective cyclopropanations with donor/acceptor car-
benoids. Thus, it is not clear whether the unusual stereocontrol
is due to the methyl group on the trisubstituted vinyl ether or
the steric competition between the phenyl and the siloxy
groups. Therefore, it became of interest to determine what
would be the effect of changing the alkene geometry of the
trisubstituted vinyl ether. The chemistry of the E-vinyl ether 17
was very different from the Z-vinyl ethers 13a–c. The Rh2(S-
DOSP)4-catalyzed reaction of 17 with 8 was not a high yielding
process, resulting in only a 30% conversion (Scheme 4). The
major product was the C–H insertion product 18, while the two
minor products were tentatively assigned as the cyclopropanes
19 and 20. In this case, the cyclopropanation is not diaster-
eoselective. The absolute configuration of 18–20 has not been
unambiguously assigned, but are drawn assuming the pre-
dictive model for the asymmetric induction is still operational
for this system.6a,8b
The profound difference between the reactions of E-vinyl
ether 17 and Z-vinyl ethers 13a–c indicate that the regio- and
stereocontrol involve the subtle influences of all three sub-
stituents. In order to further understand these influences the
reactions of 1-aryl vinyl ethers 21a–c were examined. With these
substrates only cyclopropanation can occur but the diaster-
eoselectivity is still an issue as summarized in Table 4. The nature
of the silyl group has very little influence on the diaster-
eoselectivity as seen in entries 1–9. In contrast, the catalyst has
a more significant influence. The Rh2(S-DOSP)4-catalyzed reaction
favors the E-isomer 23 by about a 2:1 ratio (entries 1–3), while
the Rh2(S-PTAD)4-catalyzed reaction favors the Z-isomer 22 by
N2
8
(p-Br)Ph
CO2Me
Ph
OTBS
CO2Me
Rh2(S-DOSP)4 (1 mol %)
TBSO
Ph
2,2-DMB, rt, 3 h
Ph(p-Br)
17
18, 24% yield
TBSO
Ph(p-Br)
CO2Me
Ph
Ph(p-Br)
+
+
Ph
TBSO
CO2Me
19, 3% yield
Scheme 4. Reaction of E-vinyl ether 17 with aryldiazoacetate 8.
20, 3% yield
the vinyl ethers 13a–c gave predominantly the cyclopropanes
14a–c in high yield (70–88% yield) and with excellent stereo-
control (>94% de, 89–95% ee) (entries 1–3). Even the very bulky
TBDPS derivative 13c was capable of generating the cyclopropane
14c in 84% isolated yield with >94% de and 95% ee. The other two
catalysts, Rh2(S-biTISP)2 and Rh2(S-PTAD)4 were once again less
selective toward the cyclopropanation, but in all cases the cy-
clopropanes 14a–c were the dominant products. In the case of
the TMS derivative 13a, the cyclopropane 14a was the exclusive
product.
The unexpected relative configuration of the cyclopropanes
prompted an effort to confirm the assignment by X-ray crys-
tallography. The cyclopropane 14c from the Rh2(S-DOSP)4-cata-
lyzed reaction was isolated as a solid and one recrystallization
from hexanes generated enantiomerically pure crystals (>99%
ee). The results of the X-ray diffraction analysis are shown in
Table 4
Effect of catalyst and silyl group on the cyclopropanation of aryl vinyl ethers
N2
RO
Ph
Ph(p-Br)
Ph
Ph(p-Br)
OR
Rh(II) (1 mol %)
2,2-DMB, rt, 2 h
+
(p-Br)Ph
CO2Me
+
CO2Me
RO
CO2Me
Ph
21a-c
8, 2equiv.
22a-c
23a-c
R: TMS (21a), TBS (21b), TBDPS (21c)
Entry
Substrate
Rh(II)
22/23b
22
23
Yieldc (%)
eed (%)
Yieldc (%)
eed,e (%)
1
2
3
21a
21b
21c
21a
21b
21c
21a
21b
21c
Rh2(S-DOSP)4
Rh2(S-DOSP)4
Rh2(S-DOSP)4
Rh2(S-biTISP)2
Rh2(S-biTISP)2
Rh2(S-biTISP)2
Rh2(S-PTAD)4
Rh2(S-PTAD)4
Rh2(S-PTAD)4
1/2
1/2
1/2
1/1
1/1
3/1
3/1
7/1
4/1
33
25
27
43
45
58
63
77
73
82
69
51
ꢀ92
ꢀ90
ꢀ91
ꢀ91
ꢀ90
ꢀ84
39
46
51
46
46
23
24
10
18
75
83
85
4a
5a
6a
7
ꢀ20
ꢀ4
ꢀ30
ꢀ64
ꢀ75
ꢀ83
8
9
a
CH2Cl2 was used as solvent.
de was determined from the 1H NMR of the crude reaction mixture.
Reported yields are of isolated products.
b
c
d
e
ee was determined by chiral HPLC.
Negative value indicates the opposite enantiomeric series.

3056
D.L. Ventura et al. / Tetrahedron 65 (2009) 3052–3061
Table 5
Effect of catalyst and substrate electronics on the cyclopropanation of aryl vinyl ethers
N2
OTBS
TBSO
Ar
Ph(p-Br)
Ar
Ph(p-Br)
Rh(II) (1 mol %)
2,2-DMB, rt, 2 h
+
(p-Br)Ph
CO2Me
+
CO2Me
TBSO
CO2Me
Ar
24a-c
8, 2 equiv.
25a-c
26a-c
Entry
Substrate
Ar
Rh(II)
25/26a
25
26
Yieldb (%)
eec,d (%)
Yieldb (%)
eec,d (%)
1
2
3
4
5
6
24a
24a
24b
24b
24c
24c
(p-MeO)Ph
(p-MeO)Ph
(p-Br)Ph
(p-Br)Ph
(p-CF3)Ph
(p-CF3)Ph
Rh2(S-DOSP)4
2/1
7/1
1/2
>15/1
1/2
61
67
25
84
26
69
74
27
9
49
N.D.
44
73
Rh2(S-PTAD)4
Rh2(S-DOSP)4
Rh2(S-PTAD)4
Rh2(S-DOSP)4
Rh2(S-PTAD)4
ꢀ74
ꢀ90
66
50
ꢀ94
74
ꢀ97
N.D.
84
N.D.
>15/1
N.D.
de was determined from the 1H NMR of the crude reaction mixture.
Reported yields are of isolated products.
ee was determined by chiral HPLC.
Negative value indicates the opposite enantiomeric series.
a
b
c
d
diastereo- and enantiocontrol. A secondary allylic site is more
favorable for C–H insertion compared to a primary allylic site.
Rh2(S-DOSP)4 is the best catalyst to favor cyclopropanation while
Rh2(S-PTAD)4 favors C–H insertion. The size of the silyl group is
another important controlling feature with the TMS group favoring
cyclopropanation and the bulky TBDPS group favoring C–H in-
sertion. The nature of the catalyst and substrate also greatly in-
fluences the diastereoselectivity of the cyclopropanation of 1-aryl
vinyl ethers, with Rh2(S-PTAD)4 and electron withdrawing groups
on the aryl group strongly favoring the formation of the (Z)-tetra-
substituted cyclopropanes. These studies define some of the con-
trolling influences of the reactivity of donor/acceptor carbenoids,
which will help to guide their application in more elaborate
systems.
Table 6
Optimized conditions for the stereoselective cyclopropanation of 1-aryl vinyl ethers
Rh2(S-PTAD)4,
N2
TBSO
CO2Me
Ar
OTBS
(1 mol %)
+
2,2-DMB, rt, 2 h p-BrPh
Ar
CO2Me
11, 2 equiv.
p-BrPh
24b
27a-d
Entry
Substrate
Ar
Product
27
Yielda (%)
deb (%)
eec (%)
1
2
3
4
11a
11f
11g
11h
p-ClPh
Ph
p-MeOPh
p-MePh
27a
27b
27c
27d
92
87
89
91
>94
>94
>94
>94
95
95
98
95
a
b
c
Reported yields are of isolated products.
de was determined from the 1H NMR of the crude reaction mixture.
ee was determined by chiral HPLC.
4. Experimental
4.1. General
a 3–7:1 ratio (entries 7–9). The diastereomers can be readily
distinguished on the basis of the chemical shift in the 1H NMR for
the methyl ester protons. Further optimization of the diaster-
eoselectivity was possible by adding an electron withdrawing
group to the aryl vinyl ether (Table 5). The reaction of 24b and
24c, containing p-Br and p-CF3 substituents greatly increased the
formation of the Z-cyclopropane 25. Indeed, the Rh2(S-PTAD)4-
catalyzed reaction of 8 with 24c generates essentially a single
diastereomer of 25c in 69% yield and 97% ee. The absolute con-
figuration of the cyclopropanes is assigned using the predictive
model that has been developed for Rh2(S-DOSP)4-catalyzed
reactions.6a In Table 4, the Rh2(S-DOSP)4-catalyzed reactions give
the opposite asymmetric induction to the Rh2(S-PTAD)4- and
Rh2(S-biTISP)2-catalyzed reactions.
Once the optimized conditions were determined, highly enan-
tioselective cyclopropanation of 1-aryl vinyl ethers can be pre-
dictably achieved (Table 6). Rh2(S-PTAD)4-catalyzed reaction of
a range of aryldiazoacetates (11a, 11f–h) with p-bromophenyl vinyl
ether 24b generated cyclopropanes 27a-d in 87–92% yield, >94% de
and 95–98% ee.
General methods for spectral and analytical procedures, the
preparation of starting materials, and the X-ray crystallographic
data for 14c are described in Supplementary data.
4.2. General procedure for rhodium(II)-catalyzed
decompositions of methyl aryldiazoacetates in the presence
of alkenes
Methyl aryldiazoacetate (0.4–2.0 mmol, 1.5–2.0 equiv) in 6–
12 mL of degassed 2,2-dimethylbutane (2,2-DMB) was added
dropwise by syringe pump over 2–3 h to a solution of alkene (0.2–
1.0 mmol,1.0 equiv) and Rh(II) (0.01 equiv) in 3–6 mL of 2,2-DMB at
rt under Ar. In the Rh2(S-PTAD)4-catalyzed reactions, tri-
fluorotoluene (0.2 mL) was added to the 2,2-DMB to increase the
solubility of the catalyst. After the addition is complete, the solution
was stirred for an additional 16 h, then concentrated under vac-
uum. The crude product was purified by flash chromatography on
silica using pentane/Et2O as eluent to give the desired product.
3. Conclusions
4.2.1. (2R,3S,Z)-Methyl 2-(4-bromophenyl)-3-methyl-5-phenyl-5-
(trimethylsilyloxy)pent-4-enoate (9a) and (1S,2S,3R)-methyl 1-
(4-bromophenyl)-3-ethyl-2-phenyl-2-(trimethylsilyloxy)-
cyclopropanecarboxylate (10a)
Purification by silica gel chromatography eluting with pentane/
Et2O (30:1) enabled the separation of 9a and 10a. Compound 9a:
clear oil; Rf 0.50 (pentane/Et2O 5:1); 1H NMR (500 MHz, CDCl3):
The reactions of electron rich trisubstituted alkenes and 1,1-di-
substituted alkenes with aryldiazoacetates catalyzed by dirhodium
carboxylate catalysts illustrate the subtle factors that control
cyclopropanation versus C–H insertion chemistry. Electron rich
trisubstituted alkenes can either undergo cyclopropanation to
generate pentasubstituted cyclopropanes or C–H insertion. Both
types of products can be obtained with excellent levels of
d
7.39 (d, J¼8.5 Hz, 2H), 7.27–7.23 (m, 7H), 4.75 (d, J¼9.0 Hz, 1H),
3.69 (s, 3H), 3.44–3.39 (m, 2H), 1.15 (d, J¼5.5 Hz, 3H), 0.07 (s, 9H);

D.L. Ventura et al. / Tetrahedron 65 (2009) 3052–3061
3057
13C NMR (75 MHz, CDCl3): 173.6 (C), 150.0 (C), 139.1 (C), 136.9 (C),
131.1 (CH), 130.4 (CH), 127.9 (CH), 127.6 (CH), 125.8 (CH), 121.1 (C),
113.2 (CH), 57.7 (CH), 51.9 (CH3), 34.3 (CH), 19.6 (CH3), 0.6 (CH3); IR
(neat) 1737, 1648, 1489, 1298, 1164, 1064, 846 cmꢀ1; ESI-HRMS:
(MþNa) m/z, found: 469.0809; calcd (C22H27O3BrSiNa): 469.0805;
Data are consistent with the reference.8b Compound 10c: clear oil;
Rf 0.38 (pentane/Et2O 5:1); 1H NMR (500 MHz, CDCl3):
7.57 (d,
d
J¼8.5 Hz, 2H), 7.44 (d, J¼8.5 Hz, 2H), 7.38–7.31 (m, 4H), 7.24 (t,
J¼7.0 Hz, 2H), 7.18–7.12 (m, 5H), 7.06 (t, J¼7.0 Hz, 4H), 3.17 (s, 3H),
2.48 (t, J¼7.0 Hz, 1H), 1.54–1.41 (m, 2H), 1.02 (t, J¼7.0 Hz, 3H), 0.76
(s, 9H); 13C NMR (75 MHz, CDCl3): 171.2 (C), 138.2 (C), 136.5 (CH),
136.0 (CH), 134.9 (CH), 133.4 (C), 133.2 (C), 132.9 (C), 131.1 (CH),
130.6 (CH), 129.6 (CH), 129.3 (CH), 128.0 (CH), 127.4 (CH),127.0 (CH),
126.9 (CH), 121.3 (C), 71.5 (C), 52.1 (CH3), 42.5 (C), 35.4 (CH), 27.3
(CH3), 19.6 (C), 18.2 (CH2), 14.2 (CH3); IR (neat) 1724, 1489, 1244,
1146, 1111, 1072, 699 cmꢀ1; EI-HRMS: m/z, found: 612.1671; calcd
HPLC: (R,R)-whelk-01, 0.5% iPrOH/hexane, 1.0 mL minꢀ1
, UV
254 nm, tR: 6.7 min (major), 10.9 min (minor), ꢀ90% ee with Rh2(S-
23
biTISP)4; [
a
]
þ95.7 (c 1.0, CHCl3). Compound 10a: clear oil; Rf 0.41
D
(pentane/Et2O 5:1); 1H NMR (500 MHz, CDCl3):
d
7.51–7.48 (m, 4H),
7.38–7.30 (m, 5H), 3.23 (s, 3H), 2.60 (dd, J¼8.0, 5.0 Hz,1H),1.59–1.51
(m, 1H), 1.29–1.22 (m, 1H), 1.19 (t, J¼7.0 Hz, 3H), ꢀ0.18 (s, 9H); 13C
NMR (75 MHz, CDCl3): 171.2 (C), 138.9 (C), 134.1 (CH), 133.2 (C),
130.6 (CH), 129.6 (CH), 128.2 (CH), 128.0 (CH), 120.9 (C), 70.4 (C),
52.0 (CH3), 42.0 (C), 34.2 (CH), 17.9 (CH2), 13.7 (CH3), 1.2 (CH3); IR
(neat) 1724, 1488, 1250, 1073, 890, 844 cmꢀ1; ESI-HRMS: (MþNa)
m/z, found: 469.0808; calcd (C22H27O3BrSiNa): 469.0805; HPLC:
i
(C35H37O3BrSi): 612.1690; HPLC: (R,R)-whelk-01, 0.5% PrOH/hex-
ane, 1.0 mL minꢀ1, UV 254 nm, tR: 10.4 min (major), 28.4 min (mi-
23
nor), 78% ee with Rh2(S-DOSP)4; [
a
]
þ32.1 (c 1.3, CHCl3).
D
4.2.4. (2S,3R,Z)-Methyl 5-(tert-butyldiphenylsilyloxy)-2-(4-
chlorophenyl)-3-methyl-5-phenylpent-4-enoate (12a)
i
(R,R)-whelk-01, 0.5% PrOH/hexane, 1.0 mL minꢀ1, UV 254 nm, tR:
23
7.9 min (major), 17.7 min (minor), 91% ee with Rh2(S-DOSP)4; [
a
]
Purification by silica gel chromatography eluting with pentane/
D
þ133.7 (c 1.0, CHCl3).
Et2O (20:1) to give 12a as a clear oil. Rf 0.44 (pentane/Et2O 5:1); 1H
NMR (500 MHz, CDCl3):
d
7.52 (t, J¼6.0 Hz, 4H), 7.42–7.23 (m, 8H),
4.2.2. (2R,3S,Z)-Methyl 2-(4-bromophenyl)-5-(tert-butyldimethyl-
silyloxy)-3-methyl-5-phenylpent-4-enoate (9b) and (1S,2S,3R)-
methyl 1-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)-3-ethyl-
2-phenylcyclopropanecarboxylate (10b)
Purification by silica gel chromatography eluting with pentane/
Et2O (30:1 to 20:1) enabled the separation of 9b and 10b. Com-
pound 9b: clear oil; Rf 0.55 (pentane/Et2O 5:1); 1H NMR (500 MHz,
7.18–7.16 (d, J¼8.0 Hz, 2H), 7.01 (t, J¼7.5 Hz, 1H), 6.95–6.90 (m, 4H),
4.50 (d, J¼10.0 Hz, 1H), 3.68 (s, 3H), 3.50–3.45 (m, 1H), 3.33 (d,
J¼10.0 Hz,1H),1.08 (s, 9H), 0.97 (d, J¼6.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3): 173.5 (C),150.7 (C),138.9 (C),136.6 (C),135.7 (CH),135.6 (CH),
133.4 (C),133.2 (C),132.8 (C),130.0 (CH),129.5 (CH),128.2 (CH),127.3
(CH), 127.2 (CH), 126.9 (CH), 114.0 (CH), 57.7 (CH), 51.8 (CH3), 34.6
(CH), 26.9 (CH3),19.8 (C),19.2 (CH3); IR (neat) 1737,1652,1491,1428,
CDCl3):
d
7.38 (d, J¼8.5 Hz, 2H), 7.25–7.21 (m, 5H), 7.17–7.15 (m, 2H),
1337, 1113, 1073, 699 cmꢀ1
;
ESI-HRMS: (MþNa) m/z, found:
4.61 (d, J¼10.0 Hz, 1H), 3.69 (s, 3H), 3.50–3.44 (m, 1H), 3.37 (d,
J¼10.5 Hz, 1H), 1.15 (d, J¼6.5 Hz, 3H), 1.01 (s, 9H), ꢀ0.04 (s, 3H),
ꢀ0.20 (s, 3H); 13C NMR (75 MHz, CDCl3): 173.6 (C), 150.2 (C), 139.5
(C), 137.0 (C), 131.0 (CH), 130.4 (CH), 127.8 (CH), 127.6 (CH), 126.3
(CH), 121.0 (C), 113.9 (CH), 57.9 (CH), 51.9 (CH3), 34.0 (CH), 25.8
(CH3), 19.6 (CH3), 18.2 (C), ꢀ3.9 (CH3), ꢀ4.2 (CH3); IR (neat) 1737,
1650, 1489, 1339, 1257, 1059 cmꢀ1; ESI-HRMS: (MþNa) m/z, found:
511.1264; calcd (C25H33O3BrSiNa): 511.1275; HPLC: (R,R)-whelk-01,
591.2075; calcd (C35H37O3ClSiNa): 591.2093; HPLC: (R,R)-whelk-01,
i
0.5% PrOH/hexane, 0.8 mL minꢀ1, UV 254 nm, tR: 8.3 min (major),
23
16.4 min (minor), 90% ee with Rh2(S-PTAD)4;
(c 1.0, CHCl3).
[a
]
þ38.1
D
4.2.5. (2S,3R,Z)-Methyl 5-(tert-butyldiphenylsilyloxy)-2-(4-
iodophenyl)-3-methyl-5-phenylpent-4-enoate (12b)
Purification by silica gel chromatography eluting with pentane/
i
0.5% PrOH/hexane, 0.8 mL minꢀ1, UV 254 nm, tR: 7.4 min (major),
Et2O (15:1) to give 12b as a clear oil. Rf 0.47 (pentane/Et2O 5:1); 1H
23
11.7 min (minor), ꢀ91% ee with Rh2(S-PTAD)4; [
a
]
þ66.5 (c 1.1,
NMR (500 MHz, CDCl3):
d
7.58 (d, J¼8.0 Hz, 2H), 7.52 (d, J¼8.0 Hz,
D
CHCl3). Compound 10b: clear oil; Rf 0.43 (pentane/Et2O 5:1); 1H
NMR (500 MHz, CDCl3): 7.50–7.48 (m, 4H), 7.37–7.31 (m, 5H), 3.24
4H), 7.42–7.26 (m, 6H), 7.03–6.90 (m, 7H), 4.50 (d, J¼10.0 Hz, 1H),
3.67 (s, 3H), 3.49–3.44 (m, 1H), 3.30 (d, J¼10.0 Hz, 1H), 1.08 (s, 9H),
0.96 (d, J¼6.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): 173.3 (C), 150.7
(C), 138.9 (C), 137.8 (C), 137.1 (CH), 135.7 (CH), 135.6 (CH), 133.4 (C),
133.2 (C), 130.7 (CH), 129.5 (CH), 127.3 (CH), 127.2 (CH), 126.9 (CH),
114.0 (CH), 92.5 (C), 57.8 (CH), 51.8 (CH3), 34.5 (CH), 26.9 (CH3), 19.8
(C), 19.2 (CH3); IR (neat) 1737, 1652, 1485, 1428, 1337, 1299, 1113,
1072, 699 cmꢀ1; ESI-HRMS: (MþNa) m/z, found: 683.1456; calcd
d
(s, 3H), 2.58 (dd, J¼8.0, 5.5 Hz, 1H), 1.61–1.56 (m, 1H), 1.41–1.35 (m,
1H), 1.21 (t, J¼7.5 Hz, 3H), 0.61 (s, 9H), ꢀ0.25 (s, 3H), ꢀ0.34 (s, 3H);
13C NMR (75 MHz, CDCl3): 171.3 (C), 138.9 (C), 134.5 (CH), 132.8 (C),
130.7 (CH), 130.2 (CH), 128.4 (CH), 128.1 (CH), 120.9 (C), 70.5 (C),
52.1 (CH3), 42.0 (C), 34.9 (CH), 25.6 (CH3), 18.3 (C), 17.9 (CH3), 14.1
(CH3), ꢀ3.0 (CH3), ꢀ3.4 (CH3); IR (neat) 1724, 1489, 1247, 1072, 886,
837 cmꢀ1; EI-HRMS: m/z, found: 488.1377; calcd (C25H33O3BrSi):
(C35H37O3ISiNa): 683.1449; HPLC: (R,R)-whelk-01, 0.5% PrOH/hex-
i
i
488.1377; HPLC: (R,R)-whelk-01, 0.5% PrOH/hexane, 0.8 mL minꢀ1
,
ane, 0.8 mL minꢀ1, UV 254 nm, tR: 9.3 min (major), 17.9 min (mi-
23
UV 254 nm, tR: 10.3 min (major), 31.8 min (minor), 80% ee with
nor), 96% ee with Rh2(S-PTAD)4; [
a]
þ39.3 (c 1.0, CHCl3).
D
23
Rh2(S-DOSP)4; [
a]
þ94.3 (c 1.1, CHCl3).
D
4.2.6. (2S,3R,Z)-Methyl 5-(tert-butyldiphenylsilyloxy)-3-methyl-5-
phenyl-2-(4-(trifluoromethyl)phenyl)pent-4-enoate (12c)
4.2.3. (2R,3S,Z)-Methyl 2-(4-bromophenyl)-5-(tert-butyldiphenyl-
silyloxy)-3-methyl-5-phenylpent-4-enoate (9c) and (1S,2S,3R)-
methyl 1-(4-bromophenyl)-2-(tert-butyldiphenylsilyloxy)-
3-ethyl-2-phenylcyclopropanecarboxylate (10c)
Purification by silica gel chromatography eluting with pentane/
Et2O (20:1) to give 12c as a clear oil. Rf 0.45 (pentane/Et2O 5:1); 1H
NMR (500 MHz, CDCl3):
d 7.53–7.52 (m, 6H), 7.41–7.35 (m, 4H),
Purification by silica gel chromatography eluting with pentane/
Et2O (30:1) enabled the separation of 9c and 10c. Compound 9c:
clear oil; Rf 0.48 (pentane/Et2O 5:1); 1H NMR (500 MHz, CDCl3):
7.31–7.26 (m, 4H), 7.01 (t, J¼7.0 Hz, 1H), 6.93 (t, J¼7.5 Hz, 2H), 6.87
(d, J¼7.0 Hz, 2H), 4.49 (d, J¼10.0 Hz, 1H), 3.69 (s, 3H), 3.55–3.50 (m,
1H), 3.41 (d, J¼10.0 Hz, 1H), 1.08 (s, 9H), 0.98 (d, J¼6.5 Hz, 3H); 13C
NMR (75 MHz, CDCl3): 173.2 (C), 150.8 (C), 142.1 (C), 138.9 (C), 135.7
(CH), 135.6 (CH), 133.3 (C), 133.1 (C), 129.6 (CH), 129.0 (CH), 127.4
(CH), 127.3 (CH), 127.3 (CH), 126.9 (CH), 125.0 (CH), 124.9 (CH), 113.8
(CH), 58.2 (CH), 51.9 (CH3), 34.7 (CH), 26.9 (CH3),19.8 (C),19.1 (CH3);
19F NMR (376 MHz, CDCl3): ꢀ62.2; IR (neat) 1737, 1653, 1326, 1166,
1115, 1069, 699 cmꢀ1; ESI-HRMS: (MþNa) m/z, found: 625.2356;
calcd (C35H37O3F3SiNa): 625.2356; HPLC: (R,R)-whelk-01, 0.5%
d
7.52–7.50 (m, 4H), 7.42–7.26 (m, 8H), 7.10 (d, J¼8.5 Hz, 2H), 7.02–
6.99 (m, 1H), 6.95–6.89 (m, 4H), 4.51 (d, J¼10.0 Hz, 1H), 3.68 (s, 3H),
3.46 (m, 1H), 3.31 (d, J¼10.0 Hz, 1H), 1.08 (s, 9H), 0.96 (d, J¼6.5 Hz,
3H); 13C NMR (75 MHz, CDCl3): 173.4, 150.7, 138.9, 137.1, 135.7,
135.6,133.4,133.2,131.1,130.4,129.5,127.3,127.2,126.9,120.9,114.0,
i
57.8, 51.8, 34.5, 26.9, 19.8, 19.2; HPLC: (R,R)-whelk-01, 0.2% PrOH/
hexane, 1.0 mL minꢀ1, UV 254 nm, tR: 9.5 min (major), 23.0 min
23
(minor), ꢀ93% ee with Rh2(S-PTAD)4; [
a]
þ38.4 (c 1.0, CHCl3).
iPrOH/hexane, 0.8 mL minꢀ1
, UV 254 nm, tR: 7.3 min (major),
D

3058
D.L. Ventura et al. / Tetrahedron 65 (2009) 3052–3061
23
10.3 min (minor), 93% ee with Rh2(S-PTAD)4; [
CHCl3).
a
]
þ15.2 (c 1.0,
128.0 (CH), 121.0 (C), 70.3 (C), 52.0 (CH3), 41.9 (C), 26.5 (CH), 10.4
(CH3), 0.9 (CH3); IR (neat) 1724, 1248, 1057, 1012, 874, 842 cmꢀ1
ESI-HRMS: (MþH) m/z, found: 433.0826; calcd (C21H26O3BrSi):
433.0829; HPLC: (R,R)-whelk-01, 0.7% iPrOH/hexane, 0.6 mL minꢀ1
UV 254 nm, tR: 12.6 min (major), 24.4 min (minor), 92% ee with
D
;
4.2.7. (2S,3R,Z)-Methyl 5-(tert-butyldiphenylsilyloxy)-3-methyl-5-
phenyl-2-(4-(trifluoromethylsulfonyloxy)phenyl)pent-4-enoate
(12d)
,
23
Rh2(S-DOSP)4; [
a
]
þ138.5 (c 1.0, CHCl3). Minor diastereomer: clear
D
Purification by silica gel chromatography eluting with pentane/
oil; Rf 0.48 (pentane/Et2O 5:1); 1H NMR (500 MHz, CDCl3):
d 7.23 (d,
Et2O (20:1) to give 12d as a clear oil. Rf 0.40 (pentane/Et2O 5:1); 1H
J¼7.0 Hz, 2H), 7.18–7.12 (m, 5H), 7.05 (d, J¼8.5 Hz, 2H), 3.69 (s, 3H),
2.27 (q, J¼6.5 Hz, 1H), 1.62 (d, J¼6.5 Hz, 3H), ꢀ0.03 (s, 9H); 13C NMR
(75 MHz, CDCl3): 169.1 (C), 138.9 (C), 136.9 (C), 131.9 (CH), 130.6
(CH), 128.4 (CH), 127.8 (CH), 127.7 (CH), 120.6 (C), 68.7 (C), 51.7
(CH3), 43.5 (C), 26.2 (CH), 10.4 (CH3), 1.1 (CH3); IR (neat) 1734, 1490,
1448, 1433, 1308, 1251, 1213, 1025, 1010, 876, 844 cmꢀ1; ESI-HRMS:
(MþNa) m/z, found: 455.0651; calcd (C21H25O3BrSiNa): 455.0649.
NMR (500 MHz, CDCl3):
d
7.55 (d, J¼7.0 Hz, 2H), 7.50 (d, J¼7.0 Hz,
2H), 7.41–7.37 (m, 2H), 7.34–7.27 (m, 6H), 7.16 (d, J¼8.5 Hz, 2H), 7.02
(t, J¼7.0 Hz,1H), 6.94 (t, J¼7.5 Hz, 2H), 6.87 (d, J¼7.5 Hz, 2H), 4.44 (d,
J¼10.0 Hz, 1H), 3.69 (s, 3H), 3.49–3.44 (m, 1H), 3.35 (d, J¼10.0 Hz,
1H), 1.07 (s, 9H), 0.94 (d, J¼6.5 Hz, 3H); 13C NMR (75 MHz, CDCl3):
173.2 (C), 150.9 (C), 148.6 (C), 138.9 (C), 138.7 (C), 135.7 (CH), 135.6
(CH), 133.3 (C), 133.2 (C), 130.5 (CH), 129.6 (CH), 129.6 (CH), 127.4
(CH), 127.4 (CH), 127.3 (CH), 126.9 (CH), 120.8 (CH), 113.8 (CH), 57.8
(CH), 51.9 (CH3), 34.8 (CH), 26.9 (CH3), 19.8 (C), 19.1 (CH3); IR (neat)
1737, 1653, 1426, 1214, 1141, 888, 700 cmꢀ1; APCI-HRMS: (MþH)
m/z, found: 683.2107; calcd (C36H38O6F3SSi): 683.2110; HPLC: (R,R)-
whelk-01, 0.6% iPrOH/hexane, 0.8 mL minꢀ1, UV 254 nm, tR: 9.2 min
(major), 12.1 min (minor), 90% ee with Rh2(S-PTAD)4.
4.2.11. (1S,2S,3R)-Methyl 1-(4-bromophenyl)-2-(tert-butyldimethyl-
silyloxy)-3-methyl-2-phenylcyclopropanecarboxylate (14b)
Purification by silica gel chromatography eluting with pentane/
Et2O (20:1) enabled the separation of 14b as a clear oil. Rf 0.36
(pentane/Et2O 5:1); 1H NMR (300 MHz, CDCl3):
d 7.72–7.69 (m, 4H),
7.58–7.52 (m, 5H), 3.42 (s, 3H), 3.01 (q, J¼6.3 Hz, 1H), 1.35 (d,
J¼6.3 Hz, 3H), 0.84 (s, 9H), 0.13 (s, 3H), ꢀ0.37 (s, 3H); 13C NMR
(75 MHz, CDCl3): 171.2, 139.2, 134.7, 132.4, 130.7, 129.7, 128.2, 128.1,
121.0, 70.2, 52.0, 41.7, 26.9, 25.6, 18.2, 10.5, ꢀ3.9, ꢀ4.2; IR (neat)
1725, 1489, 1462, 1448, 1434, 1250, 1132, 1058, 1013, 863, 839, 777,
4.2.8. (2S,3R,Z)-Methyl 5-(tert-butyldiphenylsilyloxy)-2-(3,4-
dichlorophenyl)-3-methyl-5-phenylpent-4-enoate (12e)
Purification by silica gel chromatography eluting with pentane/
Et2O (20:1) to give 12e as a clear oil. Rf 0.47 (pentane/Et2O 5:1); 1H
701 cmꢀ1; EI-HRMS: m/z, found: 475.1281; calcd (C24H32O3BrSi):
i
NMR (500 MHz, CDCl3):
d
7.54 (d, J¼8.0 Hz, 2H), 7.50 (d, J¼8.0 Hz,
475.1299; HPLC: (R,R)-whelk-01, 2.0% PrOH/hexane, 0.8 mL minꢀ1
,
2H), 7.41 (d, J¼2.0 Hz, 1H), 7.39–7.35 (m, 2H), 7.30–7.27 (m, 6H),
7.05–7.00 (m, 2H), 6.95–6.90 (m, 4H), 4.46 (d, J¼10.0 Hz, 1H), 3.68
(s, 3H), 3.46–3.41 (m, 1H), 3.28 (d, J¼10.0 Hz, 1H), 1.07 (s, 9H), 0.92
(d, J¼6.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): 173.0 (C), 151.0 (C),
138.9 (C), 138.3 (C), 135.7 (CH), 135.6 (CH), 133.3 (C), 133.2 (C), 132.1
(C), 131.1 (C), 130.5 (CH), 129.9 (CH), 129.6 (CH), 129.5 (CH), 128.2
(CH), 127.4 (CH), 127.4 (CH), 127.3 (CH), 126.9 (CH), 113.7 (CH), 57.4
(CH), 51.9 (CH3), 34.5 (CH), 26.9 (CH3), 19.8 (C), 19.1 (CH3); IR (neat)
1737, 1652, 1472, 1428, 1336, 1113, 1072, 699 cmꢀ1; EI-HRMS: m/z,
found: 602.1796; calcd (C35H36O3Cl2Si): 602.1805; HPLC: (R,R)-
UV 254 nm, tR: 7.3 min (major), 16.4 min (minor), 89% ee with
23
Rh2(S-DOSP)4; [
a
]
þ85.3 (c 1.1, CHCl3).
D
4.2.12. (1S,2S,3R)-Methyl 1-(4-bromophenyl)-2-(tert-butyl-
diphenylsilyloxy)-3-methyl-2-phenylcyclopropanecarboxylate (14c)
Purification by silica gel chromatography eluting with pentane/
Et2O (30:1 to 20:1) enabled the separation of the two di-
astereomers of 14c. Major diastereomer: clear oil; Rf 0.32 (pentane/
Et2O 5:1); 1H NMR (500 MHz, CDCl3):
d
7.65 (d, J¼8.5 Hz, 2H), 7.48
(d, J¼8.0 Hz, 2H), 7.43–7.34 (m, 4H), 7.27 (t, J¼7.5 Hz, 2H), 7.22–7.12
(m, 7H), 7.06 (d, J¼7.0 Hz, 2H), 3.21 (s, 3H), 2.67 (q, J¼6.5 Hz, 1H),
1.05 (d, J¼6.5 Hz, 3H), 0.81 (s, 9H); 13C NMR (75 MHz, CDCl3): 171.0
(C), 138.4 (C), 136.5 (CH), 135.9 (CH), 135.1 (CH), 133.6 (C), 132.8 (C),
132.7 (C), 131.1 (CH), 130.4 (CH), 129.7 (CH), 129.3 (CH), 127.9 (CH),
127.4 (CH), 127.0 (CH), 121.3 (C), 71.4 (C), 52.0 (CH3), 42.1 (C), 27.7
(CH), 27.1 (CH3), 19.6 (C), 11.3 (CH3); IR (neat) 1724, 1489, 1428, 1247,
1133, 1112, 1058, 1013, 911, 853, 735, 700 cmꢀ1; EI-HRMS: m/z,
found: 598.1540; calcd (C34H35O3BrSi): 598.1533; HPLC: (R,R)-
whelk-01, 0.6% iPrOH/hexane, 0.8 mL minꢀ1, UV 254 nm, tR: 8.2 min
(major), 17.2 min (minor), 84% ee with Rh2(S-PTAD)4; [
23
a
]
þ28.7
D
(c 1.1, CHCl3).
4.2.9. (2S,3R,Z)-Methyl 5-(tert-butyldiphenylsilyloxy)-3-methyl-
2,5-diphenylpent-4-enoate (12f)
Purification by silica gel chromatography eluting with pentane/
Et2O/triethylamine (100:1:0.5) to give 12f as a clear oil. Rf 0.51
(pentane/Et2O 5:1); 1H NMR (500 MHz, CDCl3):
d
7.55 (d, J¼7.5 Hz,
whelk-01, 0.5% iPrOH/hexane, 1.0 mL minꢀ1
10.5 min (major), 42.1 min (minor), 95% ee with Rh2(S-DOSP)4;
, UV 254 nm, tR:
2H), 7.50 (d, J¼7.0 Hz, 2H), 7.38–7.35 (m, 2H), 7.27 (t, J¼7.5 Hz, 9H),
6.97 (t, J¼7.0 Hz, 1H), 6.91–6.85 (m, 4H), 4.52 (d, J¼9.5 Hz, 1H), 3.67
(s, 3H), 3.56–3.51 (m,1H), 3.38 (d, J¼10.0 Hz,1H),1.08 (s, 9H), 0.98 (d,
J¼6.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): 173.8, 150.4, 139.1, 138.0,
135.7, 135.6, 133.5, 133.4, 129.5, 129.4, 128.7, 128.1, 127.3, 127.2, 127.1,
127.0, 126.9, 114.4, 58.4, 51.7, 34.4, 26.9, 19.8, 19.2; IR (neat) 1736,
1653, 1429, 1113, 1071, 698 cmꢀ1; EI-HRMS: m/z, found: 534.2585;
23
[a
]
þ40.2 (c 1.0, CHCl3). Minor diastereomer: clear oil; Rf 0.52
D
(pentane/Et2O 5:1); 1H NMR (500 MHz, CDCl3)
d
7.64 (d, J¼6.5 Hz,
2H), 7.42–7.38 (m, 3H), 7.35–7.31 (m, 3H), 7.23 (t, J¼7.5 Hz, 2H), 7.13
(d, J¼8.5 Hz, 2H), 7.08 (d, J¼8.5 Hz, 2H), 6.86–6.81 (m, 3H), 6.69 (t,
J¼7.5 Hz, 2H), 3.83 (s, 3H), 2.07 (q, J¼7.0 Hz, 1H), 1.58 (d, J¼6.5 Hz,
3H), 0.95 (s, 9H); 13C NMR (75 MHz, CDCl3): 169.2 (C), 136.8 (C),
136.7 (C), 136.2 (CH), 135.8 (CH), 134.3 (C), 133.8 (C), 131.3 (CH),
130.7 (CH), 130.5 (CH), 129.3 (CH), 129.2 (CH), 127.4 (CH), 127.1 (CH),
127.0 (CH), 126.9 (CH), 120.6 (C), 69.7 (C), 51.9 (CH3), 43.2 (C), 27.2
(CH3), 26.7 (CH), 19.8 (C), 10.4 (CH3); IR (neat) 1733, 1489, 1429,
1308, 1209, 1112, 1010, 737, 699 cmꢀ1; ESI-HRMS: (MþNa) m/z,
found: 621.1457; calcd (C34H35O3BrSiNa): 621.1431. C–H insertion
product: clear oil; Rf 0.44 (pentane/Et2O 5:1); 1H NMR (500 MHz,
i
calcd (C35H38O3Si): 534.2585; HPLC: (R,R)-whelk-01, 0.5% PrOH/
hexane, 0.8 mL minꢀ1, UV 254 nm, tR: 8.6 min (major), 16.0 min
23
(minor), 72% ee with Rh2(S-PTAD)4; [
a
]
þ15.5 (c 1.2, CHCl3).
D
4.2.10. (1S,2S,3R)-Methyl 1-(4-bromophenyl)-3-methyl-2-phenyl-
2-(trimethylsilyloxy)cyclopropanecarboxylate (14a)
Purification by silica gel chromatography eluting with pentane/
Et2O (30:1 to 15:1) enabled the separation of the two diastereomer
of 14a. Major diastereomer: white solid; Rf 0.38 (pentane/Et2O 5:1);
CDCl3):
d 7.65–7.61 (m, 4H), 7.43–7.27 (m, 10H), 7.17–7.13 (m 3H),
6.92 (d, J¼9.0 Hz, 2H), 4.75 (t, J¼7.0 Hz, 1H), 3.58 (s, 3H), 3.22 (t,
J¼8.0 Hz, 1H), 2.65–2.62 (m, 1H), 2.38–2.33 (m, 1H), 1.02 (s, 9H); 13C
NMR (75 MHz, CDCl3): 173.4 (C), 151.4 (C), 139.0 (C), 137.6 (C), 135.6
(CH), 135.5 (CH), 133.3 (C), 133.2 (C), 131.4 (CH), 129.7 (CH), 129.6
(CH), 127.7 (CH), 127.6 (CH), 127.4 (CH), 126.5 (CH), 121.0 (C), 106.9
1H NMR (500 MHz, CDCl3):
d
7.50–7.48 (m, 4H), 7.35 (t, J¼8.0 Hz,
2H), 7.31–7.28 (m, 3H), 3.20 (s, 3H), 2.80 (q, J¼6.0 Hz, 1H), 1.08 (d,
J¼7.0 Hz, 3H), ꢀ0.20 (s, 9H); 13C NMR (75 MHz, CDCl3): 171.2 (C),
139.1 (C), 134.3 (CH), 132.8 (C), 130.7 (CH), 129.4 (CH), 128.1 (CH),

D.L. Ventura et al. / Tetrahedron 65 (2009) 3052–3061
3059
(CH), 51.9 (CH3), 50.6 (CH), 30.1 (CH2), 26.8 (CH3), 19.8 (C); IR (neat)
1737, 1652, 1488, 1428, 1113, 1074, 700 cmꢀ1; ESI-HRMS: (MþNa)
m/z, found: 621.1420; calcd (C34H35O3BrSiNa): 621.1431; HPLC:
d
7.17 (d, J¼8.5 Hz, 2H), 7.11 (t, J¼8.5 Hz, 3H), 7.08 (t, J¼8.5 Hz, 2H),
6.99 (d, J¼8.5 Hz, 2H), 3.70 (s, 3H), 2.48 (d, J¼7.0 Hz, 1H), 2.12 (d,
J¼6.5 Hz, 1H), 0.05 (s, 9H); 13C NMR (75 MHz, CDCl3): 169.5 (C),
138.7 (C), 134.8 (C), 132.9 (CH), 130.6 (CH), 127.7 (CH), 127.2 (CH),
126.6 (CH), 121.0 (C), 66.5 (CH3), 52.4 (C), 42.9 (CH2), 22.2 (C), 0.7
(CH3); IR (neat) 1731, 1490, 1449, 1434, 1327, 1251, 1240, 1214, 1126,
1076, 1056, 1011, 977, 931, 846, 846, 756, 714, 698, 669 cmꢀ1; EI-
HRMS: m/z, found: 419.0665; calcd (C20H24O3BrSi): 419.0673. Anal.
Calcd for C20H24O3BrSi: C, 57.28; H, 5.53. Found: C, 57.18; H, 5.52.
i
(R,R)-whelk-01, 0.5% PrOH/hexane, 0.8 mL minꢀ1, UV 254 nm, tR:
23
17.4 min (major), 21.2 min (minor), 93% ee with Rh2(S-PTAD)4; [
a]
D
þ43.8 (c 1.0, CHCl3).
4.2.13. (1R,2S,3R)-Methyl 1-(4-bromophenyl)-2-(tert-butyl-
dimethylsilyloxy)-3-methoxy-2-phenylcyclo-
propanecarboxylate (16)
HPLC: (R,R)-whelk-01, 2.0% iPrOH/hexane, 1.0 mL minꢀ1
254 nm, tR: 6.1 min (major), 10.3 min (minor), 82% ee with Rh2(S-
, UV
Purification by silica gel chromatography eluting with pentane/
23
Et2O (20:1) to give 16 as a white solid. Mp 117–119 ꢁC; Rf 0.35 (20%
DOSP)4; [
a
]
þ36.0 (c 1.0, CHCl3). Compound 23a: clear oil; Rf 0.37
D
Et2O/pentane); 1H NMR (300 MHz, CDCl3):
d
7.48–7.44 (m, 4H),
(20% Et2O/pentane); 1H NMR (500 MHz, CDCl3):
d 7.51–7.49 (m,
7.36–7.26 (m, 5H), 5.44 (s, 1H), 3.70 (s, 3H), 3.23 (s, 3H), 0.54 (s, 9H),
ꢀ0.29 (s, 3H), ꢀ0.31 (s, 3H); 13C NMR (75 MHz, CDCl3): 170.0, 138.1,
134.9, 131.0, 130.5, 128.9, 128.2, 128.1, 121.1, 68.9, 68.7, 59.3, 52.0,
42.8, 25.4, 18.1, ꢀ3.9, ꢀ4.2; IR (neat) 1721, 1489, 1448, 1247, 1205,
1089, 1072, 1013, 962, 891, 839, 777, 723, 699 cmꢀ1. Anal. Calcd for
C24H31O4BrSi: C, 58.65; H, 6.36. Found: C, 58.67; H, 6.42. EI-HRMS:
m/z, found: 490.1182; calcd (C24H31O4BrSi): 490.1170; HPLC: (R,R)-
4H), 7.41 (d, J¼8.5 Hz, 2H), 7.36 (t, J¼7.5 Hz, 2H), 7.30 (t, J¼7.5 Hz,
1H), 3.23 (s, 3H), 2.71 (d, J¼6.0 Hz, 1H), 1.70 (d, J¼6.5 Hz, 1H), ꢀ0.22
(s, 9H); 13C NMR (75 MHz, CDCl3): 170.2 (C), 138.8 (C), 135.3 (C),
133.5 (CH), 130.6 (CH), 128.3 (CH), 127.9 (CH), 127.8 (CH), 121.0 (C),
67.0 (C), 52.0 (CH3), 41.4 (C), 24.0 (CH2), 0.4 (3CH3); IR (neat) 1726,
1489, 1448, 1435, 1294, 1252, 1225, 1117, 1086, 1010, 936, 846, 787,
754, 715, 698 cmꢀ1
; EI-HRMS: m/z, found: 419.0683; calcd
whelk-01, 2.0% iPrOH/hexane, 1.0 mL minꢀ1, UV 254 nm, tR: 6.3 min
(C20H24O3BrSi): 419.0673. Anal. Calcd for C20H24O3BrSi: C, 57.28; H,
23
i
(major), 15.0 min (minor), 73% ee with Rh2(S-DOSP)4; [
1.0, CHCl3).
a
]
þ45.9 (c
5.53. Found: C, 56.46; H, 5.43. HPLC: (R,R)-whelk-01, 2.0% PrOH/
D
hexane, 1.0 mL minꢀ1, UV 254 nm, tR: 6.0 min (major), 11.0 min
23
(minor), 75% ee with Rh2(S-DOSP)4; [
a
]
þ79.4 (c 1.0, CHCl3).
D
4.2.14. (R,E)-Methyl 2-(4-bromophenyl)-5-(tert-butyldimethyl-
silyloxy)-5-phenylpent-4-enoate (18), (1S,2S,3S)-methyl 1-(4-
bromophenyl)-2-(tert-butyldimethylsilyloxy)-3-methyl-2-
phenylcyclopropanecarboxylate (19), and (1S,2R,3R)-methyl 1-(4-
bromophenyl)-2-(tert-butyldimethylsilyloxy)-3-methyl-2-
phenylcyclopropanecarboxylate (20)
Purification by silica gel chromatography eluting with pentane/
diethyl ether (100:1 to 50:1) enabled the separation of 18, 19, and
20. Compound 18: clear oil; Rf 0.50 (pentane/Et2O 5:1); 1H NMR
4.2.16. (1S,2R)-Methyl 1-(4-bromophenyl)-2-(tert-butyldimethyl-
silyloxy)-2-phenylcyclopropanecarboxylate (22b) and (1S,2S)-
methyl 1-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)-2-
phenylcyclopropanecarboxylate (23b)
Purification by silica gel chromatography eluting with pentane/
Et2O (20:1) gave 22b. White solid; mp 86–88 ꢁC; Rf 0.48 (20% Et2O/
pentane); 1H NMR (500 MHz, CDCl3):
d 7.14–7.09 (m, 7H), 7.01 (d,
J¼10.5 Hz, 2H), 3.69 (s, 3H), 2.40 (d, J¼8.5 Hz, 1H), 2.11 (d, J¼8.5 Hz,
1H), 0.87 (s, 9H), 0.09 (s, 3H), ꢀ0.26 (s, 3H); 13C NMR (75 MHz,
CDCl3): 169.4 (C), 138.4 (C), 134.9 (C), 132.7 (CH), 130.5 (CH), 127.7
(CH), 127.4 (CH), 127.2 (CH), 120.9 (C), 66.5 (C), 52.4 (CH3), 42.6 (C),
25.5 (3CH3), 21.3 (CH2), 17.8 (C), ꢀ3.9 (CH3), ꢀ4.2 (CH3); IR (neat)
1732,1490,1449,1434,1394,1316,1239,1213,1126,1077,1055,1011,
977, 931, 871, 834, 779, 713, 699 cmꢀ1; EI-HRMS: m/z, found:
460.1067; calcd (C23H29O3BrSi): 460.1064. Anal. Calcd for
C23H29O3BrSi: C, 59.86; H, 6.33. Found: C, 59.96; H, 6.34. HPLC:
(500 MHz, CDCl3):
d
7.41 (d, J¼8.0 Hz, 2H), 7.34–7.28 (m, 5H), 7.11
(d, J¼8.0 Hz, 2H), 4.84 (t, J¼7.5 Hz, 1H), 3.65 (s, 3H), 3.55 (t,
J¼8.0 Hz, 1H), 2.85–2.80 (m, 1H), 2.61–2.55 (m, 1H), 0.88 (s, 9H),
ꢀ0.01 (s, 3H), ꢀ0.03 (s, 3H); 13C NMR (75 MHz, CDCl3): 173.5 (C),
151.8 (C), 137.4 (C), 137.3 (C), 131.6 (CH), 129.8 (CH), 128.2 (CH), 127.9
(C), 127.8 (CH), 121.2 (C), 106.3 (CH), 52.0 (CH), 51.9 (CH3), 31.5
(CH2), 25.6 (CH3), 18.1 (C), ꢀ4.6 (CH3), ꢀ4.7 (CH3); IR (neat) 1738,
1649, 1489, 1252, 1161, 1074, 1012 cmꢀ1; EI-HRMS: m/z, found:
23
i
474.1205; calcd (C24H31O3BrSi): 474.1220; [
a
]
ꢀ17.6 (c 1.0, CHCl3).
(R,R)-whelk-01, 2.0% PrOH/hexane, 1.0 mL minꢀ1, UV 254 nm, tR:
D
23
Compound 19: clear oil; 1H NMR (400 MHz, CDCl3):
d
7.48–7.45 (m,
5.2 min (major), 10.1 min (minor), 69% ee with Rh2(S-DOSP)4; [a]
D
4H), 7.38–7.31 (m, 5H), 3.36 (s, 3H), 2.07 (q, J¼7.2 Hz, 1H), 1.70 (d,
J¼8.5 Hz, 3H), 0.43 (s, 9H), ꢀ0.14 (s, 3H), ꢀ0.52 (s, 3H); 13C NMR
(75 MHz, CDCl3): 170.2 (C), 137.6 (C), 137.4 (C), 133.5 (CH), 130.6
(CH), 129.9 (CH), 128.1 (CH), 127.9 (CH), 120.6 (C), 69.6 (C), 51.6
(CH3), 42.7 (C), 35.7 (CH), 24.9 (CH3), 17.4 (C), 12.2 (CH3), ꢀ4.6 (CH3),
ꢀ4.6 (CH3); APCI-HRMS: (MþH) m/z, found: 475.1301; calcd
(C24H32O3BrSi): 475.1304. Compound 20: clear oil; 1H NMR
þ18.2 (c 1.0, CHCl3). Compound 23b: white solid; mp 69–71 ꢁC; Rf
0.48 (20% Et2O/pentane); 1H NMR (500 MHz, CDCl3):
d 7.52–7.50
(m, 4H), 7.43 (d, J¼11.0 Hz, 2H), 7.39 (t, J¼8.5 Hz, 2H), 7.32 (t,
J¼9.0 Hz, 1H), 3.25 (s, 3H), 2.74 (d, J¼8.0 Hz, 1H), 1.69 (d, J¼8.0 Hz,
1H), 0.54 (s, 9H), ꢀ0.14 (s, 3H), ꢀ0.37 (s, 3H); 13C NMR (75 MHz,
CDCl3): 170.1 (C), 138.5 (C), 135.1 (C), 133.7 (CH), 130.6 (CH), 128.5
(CH), 127.9 (CH), 127.8 (CH), 121.0 (C), 67.0 (C), 51.9 (CH3), 41.2 (C),
25.0 (3CH3), 23.9 (CH2), 17.9 (C), ꢀ4.3 (CH3), ꢀ4.6 (CH3); IR (neat)
1727, 1489, 1472, 1462, 1448, 1435, 1394, 1294, 1257, 1226, 1117,
1086, 1071, 1010, 936, 833, 814, 778, 716, 698 cmꢀ1; EI-HRMS: m/z,
found: 460.1070; calcd (C23H29O3BrSi): 460.1064. Anal. Calcd for
C23H29O3BrSi: C, 59.86; H, 6.33. Found: C, 59.87; H, 6.21. HPLC:
(500 MHz, CDCl3): d 7.53–7.51 (m, 2H), 7.30–7.21 (m, 5H), 6.99–6.97
(m, 2H), 3.68 (s, 3H), 2.56 (q, J¼7.0 Hz, 1H), 1.34 (d, J¼7.0 Hz, 3H),
0.81 (s, 9H), 0.10 (s, 3H), ꢀ0.41 (s, 3H); 13C NMR (75 MHz, CDCl3):
170.6 (C), 138.4 (C), 133.3 (CH), 133.1 (C), 130.8 (CH), 130.1 (CH),
127.9 (CH), 127.9 (CH), 121.1 (C), 66.7 (C), 52.4 (CH3), 43.7 (C), 30.2
(CH), 25.4 (CH3), 17.8 (C), 13.9 (CH3), ꢀ4.2 (CH3), ꢀ4.3 (CH3); APCI-
HRMS: (MþH) m/z, found: 475.1310; calcd (C24H32O3BrSi):
475.1304.
i
(R,R)-whelk-01, 2.0% PrOH/hexane, 1.0 mL minꢀ1, UV 254 nm, tR:
23
5.9 min (major), 16.2 min (minor), 83% ee with Rh2(S-DOSP)4; [
þ107.0 (c 1.0, CHCl3).
a]
D
4.2.15. (1S,2R)-Methyl 1-(4-bromophenyl)-2-phenyl-2-(trimethyl-
silyloxy)cyclopropanecarboxylate (22a) and (1S,2S)-methyl 1-(4-
bromophenyl)-2-phenyl-2-(trimethylsilyloxy)-
4.2.17. (1S,2R)-Methyl 1-(4-bromophenyl)-2-(tert-butyldiphenyl-
silyloxy)-2-phenylcyclopropanecarboxylate (22c) and (1S,2S)-
methyl 1-(4-bromophenyl)-2-(tert-butyldiphenylsilyloxy)-2-
phenylcyclopropanecarboxylate (23c)
cyclopropanecarboxylate (23a)
Purification by silica gel chromatography eluting with pentane/
Et2O (30:1) enabled the separation of 22a and 23a. Compound 22a:
clear oil; Rf 0.46 (20% Et2O/pentane); 1H NMR (500 MHz, CDCl3):
Purification by silica gel chromatography eluting with pentane/
Et2O (25:1) gave 22c. White solid; mp 54–56 ꢁC; Rf 0.53 (20% Et2O/
pentane); 1H NMR (500 MHz, CDCl3):
d
7.53 (d, J¼10.0 Hz, 2H), 7.48

3060
D.L. Ventura et al. / Tetrahedron 65 (2009) 3052–3061
(d, J¼10.0 Hz, 2H), 7.37 (t, J¼9.0 Hz, 1H), 7.27 (t, J¼10.0 Hz, 3H), 7.19
(t, J¼10.0 Hz, 2H), 7.09 (d, J¼10.0 Hz, 2H), 7.01 (d, J¼10.0 Hz, 2H),
6.90–6.80 (m, 5H), 3.76 (s, 3H), 2.33 (d, J¼9.5 Hz, 1H), 1.88 (d, J
9.5 Hz, 1H), 1.00 (s, 9H); 13C NMR (75 MHz, CDCl3): 169.6 (C), 137.6
(C), 136.2 (CH), 136.0 (CH), 135.0 (C), 133.6 (C), 133.5 (C), 132.5 (CH),
130.4 (CH), 129.5 (CH), 129.3 (CH), 127.7 (CH), 127.7 (CH), 127.3 (CH),
127.2 (CH), 127.1 (CH), 120.9 (C), 67.7 (C), 52.5 (CH3), 42.6 (C), 26.9
(3CH3), 21.5 (CH2), 19.3 (C); IR (neat) 1731, 1489, 1428, 1393, 1313,
1240, 1212, 1112, 1079, 1054, 1011, 977, 931, 910, 822, 787, 736,
pentane); 1H NMR (500 MHz, CDCl3):
d
7.26 (d, J¼7.5 Hz, 2H), 7.18 (d,
J¼7.5 Hz, 2H), 7.01 (d, J¼8.0 Hz, 4H), 3.69 (s, 3H), 2.41 (d, J¼7.0 Hz,
1H), 2.06 (d, J¼7.0 Hz,1H), 0.87 (s, 9H), 0.09 (s. 3H), ꢀ0.24 (s, 3H); 13C
NMR (75 MHz, CDCl3): 169.0, 137.8, 134.4, 123.6, 130.8, 130.7, 128.7,
121.4, 121.2, 65.9, 52.4, 42.7, 25.5, 21.4, 17.8, ꢀ3.8, ꢀ4.1; IR (neat)
1732,1490,1472,1434,1395,1331,1239,1213,1103,1075,1056,1010,
977, 931, 871, 835, 779, 717, 669 cmꢀ1; EI-HRMS: m/z, found:
538.0165; calcd (C23H28O3Br2Si): 538.0169; HPLC: (S,S)-whelk-01,
2.0% iPrOH/hexane, 1.0 mL minꢀ1, UV 254 nm, tR: 10.2 min (minor),
23
698 cmꢀ1
;
ESI-HRMS: (MþNa) m/z, found: 607.1285; calcd
26.9 min (major), 66% ee with Rh2(S-DOSP)4; [
a
]
þ26.1 (c 1.0,
(C33H33O3BrNaSi): 607.1275. Anal. Calcd for C33H33O3BrSi: C, 67.68;
CHCl3). Compound 26b: white solid; mp 62–64 ꢁDC; Rf 0.61 (20%
H, 5.68. Found: C, 67.37; H, 5.61. HPLC: (S,S)-whelk-01, 2.0% iPrOH/
Et2O/pentane); 1H NMR (500 MHz, CDCl3):
d 7.47 (m, 4H), 7.35 (m,
hexane, 1.0 mL minꢀ1, UV 254 nm, tR: 6.6 min (minor), 14.8 min
4H), 3.25 (s, 3H), 2.65 (d, J¼6.5 Hz,1H),1.66 (d, J¼6.5 Hz,1H), 0.49 (s,
9H), ꢀ0.21 (s, 3H), ꢀ0.38 (s, 3H); 13C NMR (75 MHz, CDCl3): 170.5,
138.3, 135.3, 134.2, 131.6, 131.3, 130.7, 122.5, 121.8, 66.9, 52.7, 42.1,
25.5, 24.5, 18.0, ꢀ3.5, ꢀ4.0; IR (neat) 1729, 1489, 1472, 1463, 1434,
1394, 1281, 1253, 1215, 1117, 1102, 1074, 1057, 1010, 977, 933, 870,
23
(major), 51% ee with Rh2(S-DOSP)4; [
a
]
þ1.8 (c 0.25, CHCl3).
D
Compound 23c: white solid; mp 100–102 ꢁC; Rf 0.43 (20% Et2O/
pentane); 1H NMR (500 MHz, CDCl3):
7.56 (d, J¼10.5 Hz, 2H), 7.47
d
(d, J¼10.5 Hz, 2H), 7.34–7.28 (m, 4H), 7.21–7.09 (m, 9H), 6.86 (d,
J¼9.5 Hz, 2H), 3.11 (s, 3H), 2.36 (d, J¼8.5 Hz, 1H), 1.58 (d, J¼8.5 Hz,
1H), 0.74 (s, 9H); 13C NMR (75 MHz, CDCl3): 170.0 (C), 138.0 (C),
136.3 (C), 135.7 (CH), 135.1 (C), 134.2 (CH), 133.6 (C), 132.6 (C), 131.0
(CH), 129.6 (CH), 129.4 (CH), 128.8 (CH), 127.5 (CH), 127.4 (CH), 127.2
(CH),127.1 (CH),121.4 (CH), 67.7 (C), 51.9 (CH3), 41.3 (C), 26.6 (3CH3),
24.0 (CH2), 18.8 (C); IR (neat) 1727, 1589, 1488, 1428, 1293, 1255,
1113, 1086, 1010, 935, 822, 801, 737, 699, 670 cmꢀ1; ESI-HRMS:
(MþNa) m/z, found: 607.1258; calcd (C37H31BrNaSi): 607.1250. Anal.
Calcd for C33H33O3BrSi: C, 67.68; H, 5.68. Found: C, 67.14; H, 5.70.
HPLC: (S,S)-whelk-01, 2.0% iPrOH/hexane,1.0 mL minꢀ1, UV 254 nm,
838, 779, 720 cmꢀ1
; EI-HRMS: m/z, found: 538.0154; calcd
i
(C23H28O3Br2Si): 538.0169; HPLC: (S,S)-whelk-01, 2.0% PrOH/hex-
ane, 1.0 mL minꢀ1, UV 254 nm, tR: 12.0 min (minor), 43.7 min (ma-
23
jor), 80% ee with Rh2(S-DOSP)4; [
a
]
þ79.5 (c 1.0, CHCl3).
D
4.2.20. (1S,2R)-Methyl 1-(4-bromophenyl)-2-(tert-butyldimethyl-
silyloxy)-2-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylate
(25c) and (1S,2S)-methyl 1-(4-bromophenyl)-2-(tert-
butyldimethylsilyloxy)-2-(4-(trifluoromethyl)phenyl)-
cyclopropanecarboxylate (25c)
tR: 8.7 min (minor), 40.3 min (major), 85% ee with Rh2(S-DOSP)4;
Purification by silica gel chromatography eluting with pentane/
23
[
a]
þ47.5 (c 0.25, CHCl3).
Et2O (30:1) gave 25c. Clear oil; Rf 0.43 (20% Et2O/pentane); 1H NMR
D
(500 MHz, CDCl3):
d
7.40 (d, J¼8.5 Hz, 2H), 7.24 (d, J¼7.5 Hz, 2H),
4.2.18. (1S,2R)-Methyl 1-(4-bromophenyl)-2-(tert-butyldimethyl-
silyloxy)-2-(4-methoxyphenyl)cyclopropanecarboxylate (25a) and
(1S,2S)-methyl 1-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)-
2-(4-methoxyphenyl)cyclopropanecarboxylate (26a)
7.17 (d, J¼8.0 Hz, 2H), 6.99 (d, J¼8.5 Hz, 2H), 3.70 (s, 3H), 2.49 (d,
J¼7.0 Hz, 1H), 2.15 (d, J¼7.0 Hz, 1H), 0.89 (s, 9H), 0.11 (s, 3H), ꢀ0.25
(s, 3H); 13C NMR (75 MHz, CDCl3): 168.9, 142.9, 134.2, 136.6, 130.8,
129.5 (q, J¼32.0 Hz), 127.3, 124.7 (q, J¼4.0 Hz), 123.9 (q,
J¼270.0 Hz), 121.3, 65.8, 52.5, 43.1, 25.5, 21.6, 17.9, ꢀ3.8, ꢀ4.1; IR
Purification by silica gel chromatography eluting with pentane/
Et2O (25:1) gave 25a. White solid; mp 104–106 ꢁC; Rf 0.60 (20%
(neat) 1728, 1325, 1258, 1167, 1110, 1072, 1011, 934, 833, 780 cmꢀ1
;
Et2O/pentane); 1H NMR (500 MHz, CDCl3):
d
7.16 (d, J¼8.5 Hz, 2H),
EI-HRMS: m/z, found: 528.0941; calcd (C24H28O3BrF3Si): 528.0938;
7.06 (d, J¼9.0 Hz, 2H), 7.04 (d, J¼8.5 Hz, 2H), 6.65 (d, J¼9.0 Hz, 2H),
3.73 (s, 3H), 3.69 (s, 3H), 2.36 (d, J¼6.5 Hz, 1H), 2.04 (s, J¼6.5 Hz,
1H), 0.86 (s, 9H), 0.07 (s, 3H), ꢀ0.27 (s, 3H); 13C NMR (75 MHz,
CDCl3): 169.5, 158.8, 135.1, 132.7, 130.5, 128.6, 120.8, 113.0, 66.4,
55.0, 52.3, 42.5, 25.5, 21.5, 17.8, ꢀ3.9, ꢀ4.2; IR (neat) 1735, 1670,
1608, 1512, 1489, 1463, 1293, 1251, 1208, 1173, 1127, 1110, 1074, 1032,
1010, 838, 779 cmꢀ1; ESI-HRMS: (MþNa) m/z, found: 513.1055;
calcd (C24H31O4BrNaSi): 513.1045; HPLC: (S,S)-whelk-01, 2.0%
HPLC: (S,S)-whelk-01, 2.0% iPrOH/hexane,1.0 mL minꢀ1, UV 254 nm,
tR: 7.0 min (minor), 20.5 min (major), 74% ee with Rh2(S-DOSP)4;
23
[a
]
þ48.2 (c 1.4, CHCl3). Compound 26c: clear oil; Rf 0.39 (20%
D
Et2O/pentane); 1H NMR (500 MHz, CDCl3):
d 7.60 (s, 4H), 7.49 (d,
J¼8.0 Hz, 2H), 7.37 (d, J¼8.5 Hz, 2H), 3.22 (s, 3H), 2.72 (d, J¼6.5 Hz,
1H), 1.72 (d, J¼6.5 Hz, 1H), 0.50 (s, 9H), ꢀ0.21 (s, 3H), ꢀ0.39 (s, 3H);
13C NMR (75 MHz, CDCl3): 169.8, 142.7, 134.6, 133.6, 130.8, 130.1 (q,
J¼32.0 Hz), 128.7, 124.9 (q, J¼4.0 Hz), 124.0 (q, J¼270.0 Hz), 121.4,
66.3, 52.2, 41.8, 25.0, 24.0, 17.5, ꢀ4.1, ꢀ4.5; IR (neat) 1732, 1491,
1435, 1325, 1242, 1216, 1167, 1127, 1110, 1072, 1013, 977, 931, 836,
iPrOH/hexane, 1.0 mL minꢀ1, UV 254 nm, tR: 14.2 min (minor),
23
33.8 min (major), 74% ee with Rh2(S-DOSP)4; [
a
]
þ25.8 (c 1.0,
CHCl3). Compound 26a: white solid; mp 75–77 ꢁDC; Rf 0.60 (20%
810, 780 cmꢀ1
;
EI-HRMS: m/z, found: 528.0931; calcd
Et2O/pentane); 1H NMR (500 MHz, CDCl3):
d
7.47 (d, J¼8.5 Hz, 2H),
(C24H28O3BrF3Si): 528.0938; HPLC: (S,S)-whelk-01, 2.0% iPrOH/
7.38 (d, J¼8.0 Hz, 4H), 6.85 (d, J¼8.5 Hz, 2H), 3.81 (s, 3H), 3.42 (s,
3H), 2.65 (d, J¼6.5 Hz, 1H), 1.61 (d, J¼6.5 Hz, 1H), 0.48 (s, 9H), ꢀ0.19
(s, 3H), ꢀ0.41 (s, 3H); 13C NMR (75 MHz, CDCl3): 170.2, 159.1, 135.3,
133.8, 130.8, 130.6, 129.8, 120.9, 113.2, 66.6, 55.1, 52.0, 41.4, 25.0,
24.2, 17.4, ꢀ4.2, ꢀ4.6; IR (neat) 1726, 1611, 1515, 1489, 1462, 1435,
1304, 1252, 1174, 1117, 1085, 1072, 1035, 1010, 933, 841, 778, 669,
hexane, 1.0 mL minꢀ1, UV 254 nm, tR: 7.7 min (minor), 21.5 min
(major), 84% ee with Rh2(S-DOSP)4; [
23
a
]
þ110.3 (c 0.71, CHCl3).
D
4.2.21. (1R,2S)-Methyl 2-(4-bromophenyl)-2-(tert-butyldimethyl-
silyloxy)-1-(4-chlorophenyl)cyclopropanecarboxylate (27a)
Purification by silica gel chromatography eluting with pentane/
Et2O (15:1) gave 27a. White solid; mp 114–116 ꢁC; Rf 0.54 (20%
619 cmꢀ1
;
ESI-HRMS: (MþNa) m/z, found: 513.1058; calcd
(C24H31O4BrNaSi): 513.1067; HPLC: (S,S)-whelk-01, 2.0% iPrOH/
Et2O/pentane); 1H NMR (500 MHz, CDCl3):
d 7.25 (m, 2H), 7.08–7.00
hexane, 1.0 mL minꢀ1, UV 254 nm, tR: 16.6 min (minor), 81.0 min
(m, 6H), 3.70 (s, 3H), 2.42 (d, J¼7.0 Hz, 1H), 2.07 (d, J¼7.0 Hz, 1H),
0.87 (s, 9H), 0.09 (s, 3H), ꢀ0.24 (s, 3H); 13C NMR (75 MHz, CDCl3):
169.0, 137.8, 133.9, 132.9, 132.2, 130.8, 128.7, 127.7, 121.3, 65.9, 52.3,
42.6, 25.5, 21.4, 17.8, ꢀ3.8, ꢀ4.2; IR (neat) 1732, 1493, 1434, 1331,
1240,1213,1127,1092,1075,1060,1009, 977, 931, 835, 779 cmꢀ1; EI-
HRMS: m/z, found: 495.0741; calcd (C23H29O3BrClSi): 495.0747;
HPLC: (S,S)-whelk-01, 2.0% iPrOH/hexane,1.0 mL minꢀ1, UV 254 nm,
23
(major), 73% ee with Rh2(S-DOSP)4; [
a
]
þ54.0 (c 0.93, CHCl3).
D
4.2.19. (1S,2R)-Methyl 1,2-bis(4-bromophenyl)-2-(tert-butyldime-
thylsilyloxy)cyclopropanecarboxylate (25b) and (1S,2S)-methyl 1,2-
bis(4-bromophenyl)-2-(tert-butyldimethyl-
silyloxy)cyclopropanecarboxylate (26b)
Purification by silica gel chromatography eluting with pentane/
Et2O (20:1) gave 25b. White solid; mp 114–116 ꢁC; Rf 0.66 (20% Et2O/
tR: 7.4 min (major), 19.4 min (minor), 95% ee with Rh2(S-PTAD)4;
23
[a
]
ꢀ57.3 (c 0.96, CHCl3).
D

D.L. Ventura et al. / Tetrahedron 65 (2009) 3052–3061
3061
4.2.22. (1R,2S)-Methyl 2-(4-bromophenyl)-2-(tert-butyldimethyl-
Acknowledgements
silyloxy)-1-phenylcyclopropanecarboxylate (27b)
Purification by silica gel chromatography eluting with pentane/
Financial support of this work by the National Science Founda-
tion (CHE-0750273) is gratefully acknowledged. We thank
Professor Phillip Coppens’ group at the University at Buffalo for the
X-ray crystallographic structure determination.
Et2O (20:1) gave 27b. Clear oil; Rf 0.58 (20% Et2O/pentane); 1H NMR
(500 MHz, CDCl3):
d
7.22 (d, J¼8.0 Hz, 2H), 7.14 (m, 3H), 7.05 (m,
2H), 7.01 (d, J¼8.0 Hz, 2H), 3.70 (s, 3H), 2.41 (d, J¼6.5 Hz, 1H), 2.10
(d, J¼6.5 Hz, 1H), 0.88 (s, 9H), 0.10 (s, 3H), ꢀ0.23 (s, 3H); 13C NMR
(75 MHz, CDCl3): 169.5, 138.2, 135.3, 131.0, 130.6, 128.8, 127.5, 126.9,
121.1, 65.7, 52.3, 43.4, 25.6, 21.4, 17.8, ꢀ3.7, ꢀ4.1; IR (neat) 1731,
1240, 1213,1064, 1009, 977, 931, 834, 778, 752, 699 cmꢀ1; EI-HRMS:
m/z, found: 483.0980; calcd (C25H28O3BrSi): 483.0986; HPLC: (S,S)-
Supplementary data
Detailed experimental for the compounds described in this
paper. Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2008.11.059.
whelk-01, 2.0% iPrOH/hexane, 1.0 mL minꢀ1, UV 254 nm, tR: 7.1 min
(major), 13.6 min (minor), 95% ee with Rh2(S-PTAD)4; [
23
a
]
ꢀ54.8 (c
D
1.12, CHCl3).
References and notes
4.2.23. (1R,2S)-Methyl 2-(4-bromophenyl)-2-(tert-butyldimethyl-
silyloxy)-1-(4-methoxyphenyl)cyclopropanecarboxylate (27c)
Purification by silica gel chromatography eluting with pentane/
Et2O (15:1) gave 27c. White solid; mp 87–89 ꢁC; Rf 0.32 (20% Et2O/
1. Doyle, M. P.; McKervey, M.; Ye, T. Modern Catalytic Methods for Organic Synthesis
with Diazo Compounds: From Cyclopropanes to Ylides; John Wiley & Sons: New
York, NY, 1998.
2. (a) Davies, H. M. L.; Bruzinski, P. R.; Fall, M. J. Tetrahedron Lett. 1996, 37, 4133; (b)
Davies, H. M. L.; Panaro, S. A. Tetrahedron 2000, 56, 4871; (c) Davies, H. M. L.;
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Davies, H. M. L. J. Org. Chem. 2006, 71, 5594; (e) Hedley, S. J.; Ventura, D. L.;
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Xu, Z.-H.; Zhu, S.-N.; Sun, X.-L.; Tang, Y.; Dai, L.-X. Chem. Commun. 2007, 1960;
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3. Davies, H. M. L.; Lee, G. H. Org. Lett. 2004, 6, 1233.
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5. (a) Maier, T. C.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 4594; (b) Chen, C.; Zhu, S.;
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6. (a) Davies, H. M. L.; Beckwith, E. J. Chem. Rev. 2003, 103, 2861; (b) Davies, H. M.
L.; Loe, Ø. Synthesis 2004, 16, 2595; (c) Davies, H. M. L.; Manning, J. R. Nature
2008, 451, 417.
7. (a) Hodgson, D. M.; Pierard, F. Y. T. M.; Stupple, P. A. Chem. Soc. Rev. 2001, 30, 50;
(b) Doyle, M. P.; Hu, W.; Timmons, D. J. Org. Lett. 2001, 3, 933; (c) Lu, C.; Liu, H.;
Chen, Z.; Hu, W.; Mi, A. Org. Lett. 2005, 7, 83; (d) Guo, Z.; Huang, H.; Fu, Q.; Hu,
W. Synlett 2006, 2486.
8. (a) Davies, H. M. L.; Antoulinakis, E. G.; Hansen, T. Org. Lett. 1999, 1, 383; (b)
Davies, H. M. L.; Ren, P. J. Am. Chem. Soc. 2001, 123, 2070; (c) Davies, H. M. L.;
Ren, P.; Jin, Q. Org. Lett. 2001, 3, 3587.
9. Davies, H. M. L.; Coleman, M. G.; Ventura, D. L. Org. Lett. 2007, 9, 4971.
10. (a) Davies, H. M. L.; Panaro, S. A. Tetrahedron Lett. 1999, 40, 5287; (b) Davies,
H. M. L.; Hansen, T.; Hopper, D. W.; Panaro, S. A. J. Am. Chem. Soc. 1999, 121,
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H. M. L.; Lee, G. H. Org. Lett. 2004, 6, 2117.
11. (a) Reddy, R. P.; Lee, G. H.; Davies, H. M. L. Org. Lett. 2006, 8, 3437; (b) Reddy,
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pentane); 1H NMR (500 MHz, CDCl3):
d
7.24 (d, J¼8.5 Hz, 2H), 7.04
(d, J¼8.5 Hz, 2H), 7.01 (d, J¼8.5 Hz, 2H), 6.58 (d, J¼8.5 Hz), 3.69 (s,
3H), 2.37 (d, J¼6.5 Hz, 1H), 2.04 (d, J¼7.0 Hz, 1H), 0.88 (s, 9H), 0.09
(s, 3H), ꢀ0.24 (s, 3H); 13C NMR (75 MHz, CDCl3): 169.8, 158.3, 138.3,
132.0, 130.6, 128.8, 127.3, 121.0, 112.9, 66.4, 55.5, 52.9, 43.2, 26.2,
22.1, 18.4, ꢀ3.2, ꢀ3.5; IR (neat) 1731, 1514, 1463, 1434, 1295, 1250,
1213, 1177, 1126, 1066, 1033, 1009, 978, 931, 836, 800, 779,
749 cmꢀ1; EI-HRMS: m/z, found: 513.1082; calcd (C26H30O4BrSi):
i
513.1091; HPLC: (S,S)-whelk-01, 2.0% PrOH/hexane, 1.0 mL minꢀ1
,
UV 254 nm, tR: 13.0 min (major), 54.0 min (minor), 98% ee with
23
Rh2(S-PTAD)4; [
a
]
ꢀ63.0 (c 0.79, CHCl3).
D
4.2.24. (1R,2S)-Methyl 2-(4-bromophenyl)-2-(tert-butyldimethyl-
silyloxy)-1-p-tolylcyclopropanecarboxylate (27d)
Purification by silica gel chromatography eluting with pentane/
Et2O (5:1) gave 27d. White solid; mp 53–55 ꢁC; Rf 0.54 (20% Et2O/
pentane); 1H NMR (500 MHz, CDCl3):
d
7.24 (d, J¼8.0 Hz, 2H), 7.02
(m, 4H), 6.85(d, J¼8.0 Hz, 2H), 3.68 (s, 3H), 2.37 (d, J¼6.5 Hz,1H), 2.19
(s, 3H), 2.05 (d, J¼7.0 Hz,1H), 0.87 (s, 9H), 0.09 (s, 3H), ꢀ0.24 (s, 3H);
13C NMR (75 MHz, CDCl3): 169.7, 138.3, 136.5, 132.2, 130.7, 130.6,
128.9,128.3,121.0, 65.8, 52.3, 43.0, 25.5, 21.4, 21.0,17.8, ꢀ3.8, ꢀ4.1; IR
(neat) 1732,1434,1332,1240,1218,1208,1183,1126,1103,1062,1009,
978, 931, 836, 779, 746 cmꢀ1; EI-HRMS: m/z, found: 474.1212; calcd
(C24H31O3BrSi): 474.1220; HPLC: (S,S)-whelk-01, 2.0% iPrOH/hexane,
1.0 mL minꢀ1, UV 254 nm, tR: 7.3 min (major),15.9 min (minor), 95%
23
ee with Rh2(S-PTAD)4; [
a
]
ꢀ70.0 (c 0.94, CHCl3).
12. Davies, H. M. L.; Ren, P. Tetrahedron Lett. 2001, 42, 3149.
D