Asymmetric intermolecular C-H functionalization of benzyl silyl ethers mediated by chiral auxiliary-based aryldiazoacetates and chiral dirhodium catalysts

Article abstract of DOI:10.1021/jo051747g

C-H functionalization of benzyl silyl ethers by means of rhodium-catalyzed insertions of aryldiazoacetates can be achieved in a highly diastereoselective and enantioselective manner by judicious choice of chiral catalyst or auxiliary. The dirhodium tetrap

Full text of DOI:10.1021/jo051747g

Asymmetric Intermolecular C-H Functionalization of Benzyl Silyl
Ethers Mediated by Chiral Auxiliary-Based Aryldiazoacetates and
Chiral Dirhodium Catalysts
Huw M. L. Davies,* Simon J. Hedley, and Brooks R. Bohall
Department of Chemistry, University at Buffalo, The State University of New York,
Buffalo, New York 14260-3000
hdavies@acsu.buffalo.edu
Received August 18, 2005
C-H functionalization of benzyl silyl ethers by means of rhodium-catalyzed insertions of aryl-
diazoacetates can be achieved in a highly diastereoselective and enantioselective manner by judicious
choice of chiral catalyst or auxiliary. The dirhodium tetraprolinates such as Rh2((S)-DOSP)4 have
been widely successful as chiral catalysts in the C-H functionalization chemistry of aryldiazoac-
etates, but give poor enantioselectivity in the reactions of aryldiazoacetates with benzyl silyl ether
derivatives. The use of (S)-lactate as a chiral auxiliary resulted in C-H functionalization with
moderately high diastereoselectivity (79-88% de) and enantioselectivity (68-85% ee). The best
results (91-95% de, 95-98% ee), however, were achieved using Hashimoto’s Rh2((S)-PTTL)4 catalyst.
Introduction
asymmetric induction in this intermolecular C-H func-
tionalization: the first approach relies on the use of (S)-
lactate as a chiral auxiliary 4, whereas the second
involves the employment of Hashimoto’s N-phthaloyl-
based Rh2((S)-PTTL)4 catalyst 5.
Intermolecular C-H functionalization by means of a
rhodium carbenoid-induced C-H insertion is an attrac-
tive strategic reaction for organic synthesis.1 A key
requirement for a successful C-H functionalization
methodology has been the use of carbenoids flanked by
an acceptor and a donor group (1).2 Moreover, when the
C-H functionalization is catalyzed by dirhodium proli-
nates such as Rh2((S)-DOSP)4 23 or bridged catalyst
Rh2((S)-biTISP)2 3,4 high asymmetric induction can be
achieved with a wide range of substrates.1,2 The reaction
has been developed as a new disconnection strategy,
equivalent to some of the classic reactions of organic
synthesis such as the aldol reaction,5 the Mannich
reaction,6 the Michael reaction,7 and the Claisen rear-
rangement.8 During studies on the C-H functionalization
of benzyl silyl ether derivatives, we found that the
generally reliable Rh2(DOSP)4 catalyst failed to achieve
high levels of asymmetric induction. In this paper, we
describe two alternative strategies for obtaining high
(1) Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861.
(2) (a) Davies, H. M. L.; Antoulinakis, E. J. Organomet. Chem. 2001,
617, 47. (b) Davies, H. M. L. J. Mol. Catal. A: Chem. 2002, 189, 125.
(3) Davies, H. M. L.; Bruzinski, P. R.; Lake, D. H.; Kong, N.; Fall,
M. J. J. Am. Chem. Soc. 1996, 118, 6896.
(4) Davies, H. M. L.; Panaro, S. A. Tetrahedron Lett. 1999, 40, 5287.
(5) (a) Davies, H. M. L.; Beckwith, R. E. J.; Antoulinakis, E. G.; Jin,
Q. J. Org. Chem. 2003, 68, 6126. (b) Davies, H. M. L.; Antoulinakis,
E. G. Org. Lett. 2000, 2, 4153. (c) Davies, H. M. L.; Antoulinakis, E.
G.; Hansen, T. Org. Lett. 1999, 1, 383.
10.1021/jo051747g CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/17/2005
J. Org. Chem. 2005, 70, 10737-10742
10737

Davies et al.
TABLE 1. Rh2((R)-DOSP)4-Catalyzed C-H
Functionalization of Benzyl tert-Butyldimethylsilyl
Ethers 6a-e
case, no improvement in enantioselectivity was obtained
when the reaction was conducted at 0 °C (entry 2). At
even lower temperatures (entry 3), the yield of the C-H
functionalization product 8a drops precipitously. 2,2-
Dimethylbutane has been demonstrated to be an excel-
lent solvent for C-H functionalization reactions,12 us-
ually providing high asymmetric induction in Rh2(DOSP)4-
catalyzed reactions, and the same trends are seen here
(entries 1 and 4-6). The use of a TMS group instead of
a TBS group does not have much impact on the enanti-
oselectivity (entry 7), whereas the larger silicon protect-
ing group TIPS results in a much lower yield and
enantioselectivity of C-H functionalization. A very in-
teresting effect was observed with the use of tert-butyl
ester 9 instead of methyl ester 7 because much higher
enantioselectivity was obtained, and furthermore, the
product 10c was obtained with the 2S,3S configuration
(entry 9). This trend is opposite to what has been
previously seen, which is that a bulky ester group results
in lower enantioselectivity in Rh2(DOSP)4-catalyzed reac-
tions.3,12
Chiral Auxiliary-Mediated C-H Functionaliza-
tion Reactions. The above studies demonstrate that the
dirhodium tetraprolinate-catalyzed C-H functionaliza-
tion of benzyl silyl ethers comprises a very unusual
system, displaying very different trends in enantioselec-
tivity compared to all the other substrates previously
studied.1-9 As the enantioselectivity was unsatisfactory
with chiral catalysis, the use of methyl (S)-lactate as a
chiral auxiliary was examined. R-Hydroxyesters such as
(S)-lactate were discovered to be excellent chiral auxil-
iaries for rhodium carbenoid cyclopropanations,13 and
since then, they have been applied to various rhodium
carbenoid-mediated reactions,14 including a recent ex-
ample of intramolecular C-H insertion as a key step in
the total synthesis of (-)-ephedradine A.14l-n However,
to the best of our knowledge, these chiral auxiliaries have
not been utilized in an intermolecular C-H insertion
reaction, and hence this procedure could be very benefi-
cial as a fall-back strategy when chiral catalysis is
ineffective. The feasibility of such an approach was
determined by the reaction of diazoacetate 11 with 6a
(Scheme 1). The chiral auxiliary did not interfere with
the efficiency of the C-H functionalization, as 12a was
formed in 83% yield and as a 12.9:1 ratio of syn and anti
diastereomers. The asymmetric induction for the syn
diastereomer was determined to be 79% ee, by reduction
entry
compound
R
yield (%)
de (%)
ee (%)
1
2
3
4
5
a
b
c
d
e
OMe
Me
H
85
84
83
88
74
88
91
91
94
93
35
30
17
10
30
Cl
CF3
Results and Discussion
Dirhodium Prolinate-Catalyzed Reactions. We
have previously shown that benzylic C-H functionaliza-
tion at methylene and methyl sites is a very effective
process, resulting in high asymmetric induction when the
reaction is catalyzed by Rh2((S)-DOSP)4.9 To employ this
chemistry in the synthesis of podophyllotoxin ana-
logues,10 we needed to achieve an effective C-H func-
tionalization of benzyl silyl ethers. Consequently, we
undertook model studies of the Rh2((R)-DOSP)4-catalyzed
decomposition of methyl phenyldiazoacetate 7 with a
range of benzyl silyl ethers 6. We found it was a very
effective transformation, resulting in the desired product
8 in high yield (74-88%) and diastereoselectivity favoring
the syn isomer (88-94% de). However, the enantiomeric
excess of the major isomer arising from this reaction was
consistently low (10-35% ee).11
The results in Table 1 were unexpected because
Rh2((R)-DOSP)4 has generally been shown to be an
effective catalyst for intermolecular C-H functionaliza-
tion with methyl phenyldiazoacetate 7 for virtually all
substrates previously examined; ordinarily, the reaction
products are isolated with high enantioselectivity, whereas
the diastereoselectivity is variable and strongly substrate
specific.1,2 To understand why 8 was formed with such
low enantioselectivity, we conducted a study to determine
the effect of modifying the silyl substituent, the ester
group on the diazoacetate, and the reaction conditions
(Table 2). Analogous studies have shown that conducting
Rh2((R)-DOSP)4-catalyzed reactions at lower temperature
tends to improve the enantioselectivity,3,4,7,12 but in this
(13) Davies, H. M. L.; Huby, N. J. S.; Cantrell, W. R., Jr.; Olive, J.
L. J. Am. Chem. Soc. 1993, 115, 9468.
(6) (a) Davies, H. M. L.; Venkataramani, C.; Hansen, T.; Hopper,
D. W. J. Am. Chem. Soc. 2003, 125, 6462. (b) Davies, H. M. L.; Hansen,
T.; Hopper, D.; Panaro, S. A. J. Am. Chem. Soc. 1999, 121, 6509. (c)
Davies, H. M. L.; Venkataramani, C. Org. Lett. 2001, 3, 1773. (d)
Davies, H. M. L.; Venkataramani, C. Angew. Chem., Int. Ed. 2002,
41, 2197.
(14) (a) Davies, H. M. L.; Ahmed, G.; Churchill, M. R. J. Am. Chem.
Soc. 1996, 118, 10774. (b) Davies, H. M. L.; Matasi, J. J.; Hodges, L.
M.; Huby, N. J. S.; Thornley, C.; Kong, N.; Houser, J. H. J. Org. Chem.
1997, 62, 1095. (c) Davies, H. M. L.; Ahmed, G.; Calvo, R. L.; Churchill,
M. R.; Churchill, D. G. J. Org. Chem. 1998, 63, 2641. (d) He, M.;
Tanimori, S.; Ohira, S.; Nakayama, M. Tetrahedron 1997, 53, 13307.
(e) Moore, J. D.; Hanson, P. R. Tetrahedron: Asymmetry 2003, 14, 873.
(f) Moore, J. D.; Sprott, K. T.; Wrobleski, A. D.; Hanson, P. R. Org.
Lett. 2002, 4, 2357. (g) Ye, T.; McKervey, M. A.; Bandes, B.; Doyle, M.
P. Tetrahedron Lett. 1994, 35, 7269. (h) Landais, Y.; Planchenault, D.;
Weber, V. Tetrahedron Lett. 1994, 35, 9549. (i) Landais, Y.; Planchenault,
D. Tetrahedron 1997, 53, 2855. (j) Bulugahapitiya, P.; Landais, Y.;
Parra-Rapado, L.; Planchenault, D.; Weber, V. J. Org. Chem. 1997,
62, 1630. (k) Doyle, M. P.; Yan, M. Tetrahedron Lett. 2002, 43, 5929.
(l) Kurosawa, W.; Kan, T.; Fukuyama, T. Synlett 2003, 1028. (m)
Kurosawa, W.; Kan, T.; Fukuyama, T. J. Am. Chem. Soc. 2003, 125,
8112. (n) Kurosawa, W.; Kobayashi, H.; Kan, T.; Fukuyama, T.
Tetrahedron 2004, 60, 9615.
(7) Davies, H. M. L.; Ren, P. J. Am. Chem. Soc. 2001, 123, 2071.
(8) Davies, H. M. L.; Ren, P.; Jin, Q. Org. Lett. 2001, 3, 3587.
(9) (a) Davies, H. M. L.; Ren, P.; Jin, Q.; Kovalevsky, A. Y. J. Org.
Chem. 2002, 67, 4165. (b) Davies, H. M. L.; Jin, Q. Tetrahedron:
Asymmetry 2003, 14, 941.
(10) Ward, R. S. Nat. Prod. Rep. 1999, 16, 75.
(11) Relative stereochemistry was assigned on the basis of the
distinctive proton NMR chemical-shift differences: Davies, H. M. L.;
Ren, P. Tetrahedron Lett. 2001, 42, 3149. Absolute stereochemistry
was determined later by X-ray crystallographic analysis of compound
23 (see ref 23 and the Supporting Information), and the configuration
of the other reaction products was assigned by analogy from these data.
(12) Davies, H. M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem.
Soc. 2000, 122, 3063.
(15) Davies, H. M. L.; Kong, N. Tetrahedron Lett. 1997, 38, 4203.
10738 J. Org. Chem., Vol. 70, No. 26, 2005

C-H Functionalization of Benzyl Silyl Ethers
TABLE 2. C-H Functionalization of p-Methoxybenzyl tert-Butyldimethylsilyl Ether 6a: Optimization of Reaction
Conditions
yield
(%)
de
(%)
entry
product
SiR3
R
conditions
ee (%)
1
2
3
4
5
6
7
8
9
8a
TBS
TBS
TBS
TBS
TBS
TBS
TMS
TIPS
TBS
Me
Me
Me
Me
Me
Me
Me
Me
t-Bu
2,2-DMB,a 23 °C
2,2-DMB, 0 °C
2,2-DMB, -40 °C
CH2Cl2, 23 °C
toluene, 23 °C
PhCF3, 23 °C
2,2-DMB, 23 °C
2,2-DMB, 23 °C
2,2-DMBa 23 °C
85
81
34
69
67
51
71
46
73
88
91
35 (2R,3R)
31 (2R,3R)
34 (2R,3R)
<1
24 (2R,3R)
35 (2R,3R)
38 (2R,3R)
15 (2R,3R)
72 (2S,3S)b
8a
8a
90
8a
62
8a
83
8a
63
10a
10b
10c
83
>95
78
a 2,2-DMB ) 2,2-dimethylbutane. b % ee determined by chiral HPLC of the corresponding alcohol 13a.
SCHEME 1
lectivity. As previously shown in Table 2, 2,2-dimeth-
ylbutane was a far superior solvent than dichloromethane
for this reaction, and even though double stereodiffer-
entiation was observed with chiral catalysts, the enan-
tioselectivity for even the matched reaction with Rh2((S)-
DOSP)4 (entry 5) was not as high as the outcome with
Rh2(OOct)4. Similar behavior was observed in our earlier
studies in the asymmetric cyclopropanation, in which
catalysts with increasingly bulky ligands reduced the
enantioselectivity when chiral auxiliaries were em-
ployed.13
With an effective method for the C-H functionalization
reaction of benzyl silyl ether derivatives with high
asymmetric induction in hand, we decided to investigate
the scope of this transformation. Additionally, it was felt
that a direct one-pot reaction comprising C-H function-
alization followed by reduction would provide a more
attractive route to synthetically useful building blocks.
We were delighted to find that in all cases, the products
13-17 were isolated with much higher enantioselectivity
than could be achieved using chiral catalysis with
Rh2((R)-DOSP)4 (see Table 4). Although the enantiose-
lectivity of the C-H functionalization reaction was shown
to be optimal at 0 °C for a benzyl silyl ether with a
strongly electron-donating substituent 6a, when the less
activated substrate 6b was subjected to these conditions,
a low yield (35%) of 13b was obtained, and hence the
majority of these reactions were carried out at room
temperature. Aryldiazoacetates containing an electron-
rich aromatic ring required elevated temperatures in
order to induce an efficient reaction toward products 14
and 15.
Rh2((S)-PTTL)4-Catalyzed C-H Functionalization
Reactions. Although the development of the chiral
auxiliary approach constituted a more-than-suitable
alternative protocol, modern synthetic chemistry de-
mands that a truly efficient process utilizes a chiral
catalyst. With this in mind, a series of dirhodium
catalysts was investigated for comparison to the already-
studied Rh2((R)-DOSP)4 (Table 5). The Rh2((S)-biTISP)2
(3)-catalyzed reaction resulted in considerably higher
enantioselectivity than the Rh2((R)-DOSP)4-catalyzed
reaction, but the diastereoselectivity was inferior (entry
TABLE 3. C-H Functionalization of
para-Methoxybenzyl tert-Butyldimethylsilyl Ether 6a
with Ethyl (S)-Lactate-Based Aryldiazoacetate 11
yield
entry
conditions
(%) syn/anti ee (%)a
1
2
3
4
5
6
Rh2(OOct)4, 2,2-DMB, 23 °C
Rh2(OOct)4, 2,2-DMB, 0 °C
Rh2(OOct)4, 2,2-DMB, -78 °C
Rh2(OOct)4, CH2Cl2, 23 °C
Rh2((S)-DOSP)4, 2,2-DMB, 23 °C 69
Rh2((R)-DOSP)4, 2,2-DMB, 23 °C 67
83
64
35
43
12.9:1
14.4:1
6.3:1
1.9:1
5.4:1
8.0:1
79
83
81
33
61
10
a % ee determined by chiral HPLC of the corresponding alcohol
13a.
of ester 12a to the alcohol 13a followed by chiral HPLC
analysis of compound 13a.
Further studies to elucidate the optimum conditions
(Table 3) revealed that a decrease in temperature to 0
°C furnished 12a with a moderate improvement in
enantioselectivity, albeit in lower yield. A further de-
crease in temperature to -78 °C resulted in an even
lower product yield, and no improvement in enantiose-
J. Org. Chem, Vol. 70, No. 26, 2005 10739

Davies et al.
TABLE 4. One-Pot Combined Chiral
Auxiliary-Mediated C-H Functionalization Reaction and
Reduction
TABLE 6. Optimization of Rh2((S)-PTTL)4-Catalyzed
C-H Functionalization of para-Methoxybenzyl
tert-Butyldimethylsilyl Ether 6a
entry
solvent
temp (°C)
yield (%)
de (%)
ee (%)
R1
R2
product temp (°C) yield (%) de (%) ee (%)
1
2
3
2,2-DMB
CH2Cl2
PhCF3
50
23
23
78
28
51
89
50
81
91
4
OMe
OMe
Me
Me
H
Cl
CF3
H
13a
13a
13b
13b
13c
13d
13e
14
23
0
23
0
23
23
23
50
50
23
23
70
62
86
35
69
91
89
65
66
63
65
83
87
79
80
88
88
82
84
85
82
80
79
83
80
86
84
82
85
68
82
82
76
76
H
H
H
H
H
H
8a in exceptionally high levels of diastereoselectivity and
enantioselectivity, which was even higher than for any
other process, including the Rh2((S)-biTISP)2-catalyzed
and the (S)-lactate-mediated approach. Inspired by this
result, we also examined Mu¨ller’s Rh2((S)-NTTL)4 cata-
lyst 19, which has been shown to outperform Rh2((S)-
PTTL)4 in some reactions,19 and Pirrung’s Rh2((S)-BNP)4
20.20 However, Rh2((S)-NTTL)4 gave a very poor yield of
product 8a, and Pirrung’s phosphonate based catalyst
Rh2((S)-BNP)4 was even less satisfactory.
OMe Me
OMe OMe
OMe Br
15
16
OMe CF3
17
TABLE 5. Investigation of Dirhodium Catalysts in C-H
Functionalization of p-Methoxybenzyl
tert-Butyldimethylsilyl Ether 6a
entry
Rh cat
yield (%) de (%) ee (%) abs. conf.
1
2
3
4
5
Rh2((S)-biTISP)2 3
18
Rh2((S)-PTTL)4 5
Rh2((S)-NTTL)4 19
Rh2((S)-BNP)4 20
82
61
64
8
38
14
91
65
43
69
40
97
57
nda
2S,3S
2R,3R
2R,3R
2R,3R
nd
2
a Not determined.
4). A very surprising result obtained in this study was
the formation of 8a with opposite asymmetric induction,
because all previous studies have shown that Rh2((S)-
biTISP)2- and Rh2((R)-DOSP)4-catalyzed reactions provide
the same enantiomer of the product.4,11 Prior to the
development of the Rh2((S)-biTISP)2 catalyst, we had
reported a bridged catalyst 18.15 In comparison with the
Rh2((S)-biTISP)2 result, the product was isolated with low
diastereoselectivity, but unlike the former result, high
enantioselectivity was not observed with catalyst 18.
Hashimoto’s Rh2((S)-PTTL)4 catalyst 5 has shown excel-
lent utility in intramolecular carbenoid cyclization reac-
tions,16 including examples involving C-H insertion at
a benzylic ether site,17 but has not been reported to be
particularly effective at general intermolecular C-H
insertion reactions.18 In this study, the Rh2((S)-PTTL)4
catalyst 5 provided the C-H functionalization product
From these results, it was determined that Rh2((S)-
PTTL)4 was the superior catalyst for this system, and
accordingly, optimization of the reaction conditions using
this catalyst was the next logical step (Table 6). Similar
to earlier results (Tables 2 and 3), 2,2-dimethylbutane
was the best solvent for this reaction, and conducting the
reaction under reflux allowed isolation of the product 8a
(18) To the best of our knowledge, Rh2((S)-PTTL)4 has not been
reported in the literature as a catalyst for an intermolecular cyclopro-
panation or intermolecular C-H insertion reaction. However, for an
example of the use of the related N-phthaloyl-based catalyst Rh2((S)-
PTPA)4 in intermolecular cyclopropanation and C-H insertion reac-
tions see: Mu¨ller, P.; Tohill, S. Tetrahedron 2000, 56, 1725. It reported
that the Rh2((S)-PTPA)4-mediated decomposition of 7 in the presence
of cyclohexene provided a 1:1 ratio of C-H insertion product (6% de,
45% ee for the S enantiomer) to cyclopropane product in a combined
yield of 45%. The corresponding Rh2((S)-DOSP)4-catalyzed reaction was
demonstrated to proceed in 73% yield, with a 79:21 ratio of C-H
insertion product to cyclopropane product, with the former isolated
with poor diastereoselectivity but excellent enantioselectivity (93% ee,
R enantiomer: ref 8).
(16) (a) Hashimoto, S.; Watanabe, N.; Ikegami, S. Tetrahedron Lett.
1990, 31, 5173. (b) Takahashi, T.; Tsutsui, H.; Tamura, M.; Kitagaki,
S.; Nakajima, M.; Hashimoto, S. Chem. Commun. 2001, 1604. (c)
Anada, M.; Hashimoto, S. Tetrahedron Lett. 1998, 39, 79. (d) Anada,
M.; Watanabe, N.; Hashimoto, S. Chem. Commun. 1998, 1517. (e)
Hashimoto, S.; Watanabe, N.; Ikegami, S. Synlett 1994, 353.
(17) Saito, H.; Oishi, H.; Kitagaki, S.; Nakamura, S.; Anada, M.;
Hashimoto, S. Org. Lett. 2002, 4, 3887.
(19) Mu¨ller, P.; Bernardinelli, G.; Allenbach, Y. F.; Ferri, M.; Flack,
H. D. Org. Lett. 2004, 6, 1725.
(20) Pirrung, M. C.; Zhang, J. Tetrahedron Lett. 1992, 33, 5987.
10740 J. Org. Chem., Vol. 70, No. 26, 2005

C-H Functionalization of Benzyl Silyl Ethers
TABLE 7. Scope of the Rh2((S)-PTTL)4-Catalyzed C-H
SCHEME 2
Functionalization of Benzyl Silyl Ether Derivatives 6
entry
compound
R
yield (%)
de (%)
ee (%)
1
2
3
4
5
a
b
c
d
e
OMe
Me
H
78
84
95
84
90
89
94
>95
>95
>95
91
98
98
97
95
Cl
CF3
in higher yield while still maintaining the excellent
selectivity (Table 6, entry 1). As observed with the Rh2-
((R)-DOSP)4-catalyzed and chiral auxiliary-mediated re-
actions, dichloromethane was a poor solvent for the
reaction (entry 2), generating the product 8a in very low
yield as an almost racemic mixture.
With the optimum conditions determined, we examined
the scope of the Rh2((S)-PTTL)4-catalyzed reaction (Table
7). As for the Rh2((R)-DOSP)4-catalyzed and (S)-lactate-
mediated reactions, the conditions are compatible with
electron-rich, neutral, and electron-deficient aromatic
rings, generating the desired product in high yield along
with exceptional levels of asymmetric induction with
much higher enantioselectivity than any method previ-
ously employed. Additionally, the reaction works well
with electron-rich and electron-deficient aryldiazoac-
etates (eq 1).
TBAF in order to furnish diol 23 (eq 2). Recrystallization
of diol 23 generated suitable crystals for X-ray crystal-
lographic analysis, which confirmed the absolute stereo-
chemistry as 1R,2S.22 This result means that the chiral
auxiliary model,14 which has been an excellent predictor
for enantioselective cyclopropanation reactions, gave the
wrong result in this C-H functionalization.
To further establish whether the chiral auxiliary
behaves differently in C-H functionalization chemistry
compared to cyclopropanation chemistry, a second sub-
strate was examined that had already been shown to give
excellent enantiocontrol in a Rh2((S)-DOSP)4-catalyzed
C-H functionalization. Rh2((S)-DOSP)4-catalyzed decom-
position of 7 in the presence of the cinnamyl silyl ether
25 followed by reduction furnished the alcohol 25 in
>95% de and 75% ee, and the absolute configuration was
determined to be 2R,3R5 (Scheme 2). In comparison, the
reaction of the (S)-lactate derivative 11 with the silyl
ether 24 was examined, and this reaction again pro-
ceeded in high diastereoselectivity and enantioselectivity;
however, the absolute configuration of product 25 was
opposite to that of the Rh2((S)-DOSP)4-catalyzed reaction.
This result clearly indicates that the influence of the
chiral auxiliary in cyclopropanation reactions13 is very
different from that which occurs in the C-H functional-
ization reactions.
Determination of Absolute Stereochemistry. Rh2-
((S)-DOSP)4 catalyst has been shown to furnish products
with the same sense of asymmetric induction as the (S)-
lactate chiral auxiliary in several different examples of
cyclopropanation reactions of vinyldiazoacetates3,13 and
Si-H insertions.14h-j,21 From our previous studies on
enantioselective C-H functionalization with aryldiaz-
oacetates, the Rh2((S)-DOSP)4 catalyst predictably directs
attack to the re face of the carbenoid,1 generally with high
asymmetric induction. The current study is very anoma-
lous because the enantioselectivity of the reactions
conducted with Rh2((S)-DOSP)4 is low, and the (S)-chiral
catalyst and (S)-chiral auxiliary approaches lead to
opposite asymmetric inductions. Therefore, it was deemed
necessary to unambiguously determine the absolute
configuration of the reaction products. This was achieved
by treatment of 16 (derived from reduction of Rh2((S)-
PTTL)4-catalyzed C-H functionalization product 21) with
Conclusions
In conclusion, these results demonstrate that although
the established dirhodium tetraprolinates such as Rh2-
((S)-DOSP)4 and Rh2((R)-DOSP)4 are generally excellent
catalysts for intermolecular C-H functionalization reac-
tions, in the case of benzyl silyl ethers, the observed
(22) The crystal structure has been deposited at the Cambridge
Crystallographic Data Centre, and the deposition number CCDC
277546 has been allocated (Gerlits, O. O.; Coppens, P. Personal
communication).
(21) Davies, H. M. L.; Hansen, T.; Rutberg, J.; Bruzinski, P. R.
Tetrahedron Lett. 1997, 38, 1741.
J. Org. Chem, Vol. 70, No. 26, 2005 10741

Davies et al.
(2C), 127.3, 113.2, 76.7, 61.7, 55.1, 51.6, 25.4, 17.8, -5.0, -5.8;
IR (CHCl3) 2953, 2929, 2856, 1736, 1612, 1512 cm-1; m/z (ESI)
423 (MNa+, 65%), 270 (14%), 269 (100%). Anal. Calcd for
C23H32O4Si: C, 68.96; H, 8.05. Found: C, 68.94; H, 8.08. HPLC
analysis: 91% ee (Chiralcel OD-H, 1% i-PrOH in hexane, 1.0
mL/min, λ ) 254 nm, tR ) 4.8 min, minor; tR ) 5.7 min, major).
Synthesis of (2S,3R)-3-(tert-Butyldimethylsilanyloxy)-
3-(4-methoxyphenyl)-2-phenylpropan-1-ol (13a). A solu-
tion of Rh2(OOct)4 (3.9 mg, 0.005 mmol, 0.01 equiv) and
compound 6a (126 mg, 0.50 mmol, 1.00 equiv) in degassed 2,2-
dimethylbutane (5 mL) was heated under reflux for 45 min,
and then allowed to cool to room temperature. A solution of
compound 11 (262 mg, 1.00 mmol, 2.00 equiv) in degassed 2,2-
dimethylbutane (9 mL) was added via syringe pump over 3 h.
After addition was complete, the reaction mixture was stirred
for 1 h, and then cooled to 0 °C. Diisobutylaluminum hydride
(1.0 M in toluene, 3.0 mL, 3.00 mmol, 6.00 equiv) was added,
and the reaction mixture was stirred for 2 h at 0 °C and then
for 10 h at room temperature. The reaction mixture was then
poured into a 1:1 mixture (50 mL) of Et2O and saturated
sodium potassium tartrate solution. The biphasic mixture was
stirred for 45 min. The layers were separated, and the aqueous
layer was further extracted with Et2O (2×). The combined
organic fractions were dried (Na2SO4), and concentrated in
vacuo. Diastereoselectivity (83% de) was determined by 1H
NMR of the crude reaction mixture, and the product was
purified by flash chromatography on silica gel using 10:1
hexane/Et2O as eluant to isolate a mixture of the anti and syn
isomers as a colorless oil (53 mg), and the pure syn isomer as
a colorless oil (78 mg). Total mass: 131 mg (70%). Syn
isomer: [R]D +38.2 (ee 79%) (c 1.22, CHCl3); 1H NMR (500
MHz, CDCl3) δ 7.26-7.21 (m, 3H), 7.08-7.05 (m, 2H), 6.99
(d, 2H, J ) 8.5 Hz), 6.77 (d, 2H, J ) 8.5 Hz), 4.91 (d, 1H, J )
6.0 Hz), 3.88 (dd, 1H, J ) 11.0, 7.5 Hz), 3.80 (s, 3H), 3.77 (dd,
1H, J ) 11.0, 7.0 Hz), 3.15 (dd, 1H, J ) 13.0, 7.0 Hz), 1.21 (br
s, 1H), 0.79 (s, 9H), -0.10 (s, 3H), -0.27 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 158.8, 139.1, 134.4, 129.3, 128.0, 127.9,
126.8, 113.1, 77.0, 63.7, 56.4, 55.1, 25.7, 18.0, -4.8, -5.5; IR
(CHCl3) 3456, 2958, 1512, 1248, 1083 cm-1; m/z (EI) 373 (M+,
1%), 357 (36%), 251 (100%). Anal. Calcd for C22H32O3Si: C,
70.92; H, 8.66. Found: C, 70.81; H, 8.62. HPLC analysis: 79%
ee (R,R-Whelk-O1, 3% i-PrOH in hexane, 1.0 mL/min, λ ) 254
nm, tR ) 10.1 min, minor; tR ) 11.9 min, major).
enantioselectivity was uniformly rather poor. Further-
more, these substrates display anomalous behavior when
compared to previously studied systems. This paper
described two approaches that solved the problem of low
enantioselectivity. Initially, we developed the readily
available R-hydroxyester chiral auxiliary-based aryldia-
zoacetates, which allow for efficient C-H functionaliza-
tion to furnish the products in high enantioselectivity.
After this work, we also found that Hashimoto’s Rh2((S)-
PTTL)4 catalyst served as an excellent catalyst for this
reaction, providing the desired product in high yield,
diastereoselectivity, and enantioselectivity. These two
approaches can be considered as useful general alterna-
tive strategies when Rh2((S)-DOSP)4 does not work well
in an intermolecular C-H insertion.
Experimental Section
General considerations, experimental procedures, and spec-
tral data for all new compounds, including X-ray data for diol
23, are included in the Supporting Information.
Synthesis of (2R,3R)-3-(tert-Butyldimethylsilanyloxy)-
3-(4-methoxyphenyl)-2-phenylpropionic Acid Methyl Es-
ter (8a). Procedure A. A solution of methyl phenyldiazoac-
etate 7 (352 mg, 2.00 mmol, 2.00 equiv) in degassed 2,2-
dimethylbutane (8 mL) was added via syringe pump over 2 h
to a solution of Rh2((R)-DOSP)4 (19 mg, 0.01 mmol, 0.01 equiv)
and compound 6a (252 mg, 1.00 mmol, 1.00 equiv) in degassed
2,2-dimethylbutane (1 mL). After the addition was complete,
the reaction mixture was stirred for 1 h and then concentrated
in vacuo. Diastereoselectivity (88% de) was determined by 1H
NMR of the crude reaction mixture, and the products were
purified by flash chromatography on silica gel using 18:1
hexane/Et2O as eluant to provide the anti isomer as a white
solid (15 mg), a mixture of anti and syn isomers as a white
solid (41 mg), and pure syn isomer as a white solid (283 mg),
with a total yield of 85%. Procedure B. A solution of methyl
phenyldiazoacetate 7 (176 mg, 1.00 mmol, 2.00 equiv) in
degassed 2,2-dimethylbutane (6 mL) was added to a solution
of Rh2((S)-PTTL)4 (6 mg, 0.005 mmol, 0.01 equiv), compound
6a (126 mg, 0.50 mmol, 1.00 equiv), and degassed 2,2-
dimethylbutane (3 mL) under reflux via syringe pump at a
rate of 2 mL/h. After the addition was complete, the reaction
mixture was stirred at 50 °C for 30 min, allowed to cool to
room temperature, and concentrated in vacuo. Diastereose-
lectivity (89% de) was determined by 1H NMR of the crude
reaction mixture, and the products were purified by flash
chromatography on silica gel using 18:1 hexane/Et2O as eluant
to provide a mixture of anti and syn isomers as a white solid
(9 mg), and pure syn isomer as a white solid (147 mg), with a
total yield of 78%). Syn isomer: mp 62-64 °C; [R]D +75.9 (ee
91%) (c 1.16, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.42 (d,
2H, J ) 7.5 Hz), 7.34-7.21 (m, 5H), 6.81 (d, 2H, J ) 9.0 Hz),
5.06 (d, 1H, J ) 9.0 Hz), 3.79 (s, 3H), 3.78 (d, 1H, J ) 9.0 Hz),
3.43 (s, 3H), 0.61 (s, 9H), -0.37 (s, 3H), -0.39 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 172.2, 158.9, 136.6, 135.0, 129.3, 128.1
Acknowledgment. Financial support from the Na-
tional Science Foundation (CHE-0350536) is gratefully
acknowledged. We thank Ms. Oksana O. Gerlits for the
X-ray crystallographic studies, which allowed for the
determination of the absolute stereochemistry of diol 23.
We thank Dr. Evan Antoulinakis for technical as-
sistance with the early studies in this project.
Supporting Information Available: Experimental pro-
cedures and spectral data for all novel compounds and X-ray
data for diol 23. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO051747G
10742 J. Org. Chem., Vol. 70, No. 26, 2005