Enantioselective C-C bond formation by rhodium-catalyzed tandem ylide formation/[2,3]-sigmatropic rearrangement between donor/acceptor carbenoids and allylic alcohols

Article abstract of DOI:10.1021/ja9075293

The rhodium-catalyzed reaction of racemic allyl alcohols with methyl phenyldiazoacetate or methyl styryldiazoacetate results in a two-step process, an initial oxonium ylide formation followed by a [2,3]-sigmatropic rearrangement. This process competes favorably with the more conventional O-H insertion chemistry as long as donor/acceptor carbenoids and highly substituted allyl alcohols are used as substrates. When the reactions are catalyzed by Rh₂(S-DOSP)₄, tertiary R-hydroxycarboxylate derivatives with two adjacent quaternary centers are produced with high enantioselectivity (85-98% ee).

Full text of DOI:10.1021/ja9075293

Published on Web 12/08/2009
Enantioselective C-C Bond Formation by Rhodium-Catalyzed
Tandem Ylide Formation/[2,3]-Sigmatropic Rearrangement
between Donor/Acceptor Carbenoids and Allylic Alcohols
Zhanjie Li and Huw M. L. Davies*
Department of Chemistry, Emory UniVersity, 1515 Dickey DriVe, Atlanta, Georgia 30322
Received September 7, 2009; E-mail: hmdavie@emory.edu
Abstract: The rhodium-catalyzed reaction of racemic allyl alcohols with methyl phenyldiazoacetate or methyl
styryldiazoacetate results in a two-step process, an initial oxonium ylide formation followed by a [2,3]-
sigmatropic rearrangement. This process competes favorably with the more conventional O-H insertion
chemistry as long as donor/acceptor carbenoids and highly substituted allyl alcohols are used as substrates.
When the reactions are catalyzed by Rh2(S-DOSP)4, tertiary R-hydroxycarboxylate derivatives with two
adjacent quaternary centers are produced with high enantioselectivity (85-98% ee).
aryl sulfides and propargyl aryl sulfides.10,11 The resulting sulfur
ylides undergo a [2,3]-sigmatropic rearrangement with moderate
Introduction
Metal-catalyzed reactions of diazo compounds result in a
variety of useful transformations such as cyclopropanations,
C-H insertions, and various transformations that are initiated
by reactions of carbenoids with heteroatoms to form ylides.1
For some time we have been exploring the rhodium-catalyzed
reactions of donor/acceptor carbenoids.2 We have developed
highly enantioselective processes for cyclopropanation and C-H
insertion,2 but the studies by us and others on enantioselective
reactions involving ylide intermediates, have resulted in limited
success. Chiral rhodium catalysts gave no asymmetric induction
in O-H and N-H insertions of aryldiazoacetates.3-6 Similarly,
no asymmetric induction was obtained in rhodium-catalyzed
epoxidation7 or the three-component coupling between aryldi-
azoacetates, alcohols and aldehydes (or imines).8,9 The only
exception to date is the reaction of aryldiazoacetates with allyl
asymmetric induction (∼70% ee).
We hypothesized that in order to obtain high asymmetric
inductions in ylide transformations of rhodium carbenoid 1, two
critical issues need to be controlled (Scheme 1). The first would
be to avoid reactions in which the metal associated ylide 2
undergoes a proton transfer, since this would likely result in
the formation of achiral enol intermediate 3 and consequent loss
of any asymmetric induction.12 The second would be to avoid
(5) For references on enantioselective N-H insertion via copper-catalyzed
decomposition of diazo carbonyl compounds, see: (a) Bachmann, S.;
Fielenbach, D.; Jørgensen, K. A. Org. Biomol. Chem. 2004, 2, 3044.
(b) Liu, B.; Zhu, S.-F.; Zhang, W.; Chen, C.; Zhou, Q.-L. J. Am. Chem.
Soc. 2007, 129, 5834. (c) Lee, E. C.; Fu, G. C. J. Am. Chem. Soc.
2007, 129, 12066.
(6) Diastereoselective O-H and N-H insertions using dirhodium catalysis
have been generally unsuccessful. For leading references see: (a) Aller,
E.; Cox, G. G.; Miller, D. J.; Moody, C. J. Tetrahedron Lett. 1994,
35, 5949. (b) Aller, E.; Brown, D. S.; Cox, G. G.; Miller, D. J.; Moody,
C. J. J. Org. Chem. 1995, 60, 4449. (c) Miller, D. J.; Moody, C. J.;
Morfitt, C. N. Aust. J. Chem. 1999, 52, 97. (d) Doyle, M. P.; Yan, M.
Tetrahedron Lett. 2002, 43, 5929. (e) Bolm, C.; Saladin, S.; Classen,
A.; Kasyan, A.; Veri, E.; Raabe, G. Synlett 2005, 461. (f) Im, C. Y.;
Okuyama, T.; Sugimura, T. Chem. Lett. 2005, 34, 1328. (g) Im, C. Y.;
Okuyama, T.; Sugimura, T. Eur. J. Org. Chem. 2008, 285. (h) Davis,
F. A.; Fang, T.; Goswami, R. Org. Lett. 2002, 4, 1599.
(1) (a) Padwa, A.; Hornbuckle, S. F. Chem. ReV. 1991, 91, 263. (b) Doyle,
M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds: From Cyclopropanes to
Ylide; Wiley: New York, 1998. (c) Lydon, K. M.; McKervey, M. A.
Compr. Asymmetric Catal. I-III; Springer: Berlin, 1999; Vol. 2, p 539.
(d) Davies, H. M. L. Compr. Asymmetric Catal., Suppl.; Springer:
Berlin, 2004; Vol. 1, p 83. (e) Davies, H. M. L.; Walji, A. M. Modern
Rhodium-Catalyzed Organic Reactions; Wiley: New York, 2005; p
301. (f) Wee, A. G. H. Curr. Org. Synth. 2006, 3, 499. (f) Zhang, Z.;
Wang, J. Tetrahedron 2008, 64, 6577. (g) Padwa, A. J. Org. Chem.
2009, 74, 6421.
(7) DeMeese, J.; Davies, H. M. L. Tetrahedron Lett. 2001, 42, 6803.
(8) (a) Lu, C.; Liu, H.; Chen, Z.; Hu, W.; Mi, A. Org. Lett. 2005, 7, 83.
(b) Huang, H.; Guo, X.; Hu, W. Angew. Chem., Int. Ed. 2007, 46,
1337.
(2) For leading reviews and latest references, see: (a) Davies, H. M. L.;
Beckwith, R. E. J. Chem. ReV. 2003, 103, 2861. (b) Davies, H. M. L.;
Manning, J. R. Nature 2008, 451, 417. (c) Schwartz, B. D.; Denton,
J. R.; Lian, Y.; Davies, H. M. L.; Williams, C. M. J. Am. Chem. Soc.
2009, 131, 8329. (d) Denton, J. R.; Davies, H. M. L. Org. Lett. 2009,
11, 787. (e) Ventura, D. L.; Li, Z.; Coleman, M. G.; Davies, H. M. L.
Tetrahedron 2009, 65, 3052.
(9) Even though dirhodium catalysts gave no asymmetric induction in
the three component coupling, excellent enantioselectivity was achieved
with chiral phosphoric acid or ZrIV/BINOL as co-catalyst. For
references, see: (a) Hu, W.; Xu, X.; Zhou, J.; Liu, W.-J.; Huang, H.;
Hu, J.; Yang, L.; Gong, L.-Z. J. Am. Chem. Soc. 2008, 130, 7782. (b)
Zhang, X.; Huang, H.; Guo, X.; Guan, X.; Yang, L.; Hu, W. Angew.
Chem., Int. Ed. 2008, 47, 6647.
(3) (a) Ferris, L.; Haigh, D.; Moody, C. J. Tetrahedron Lett. 1996, 37,
107. (b) Bulugahapitiya, P.; Landais, Y.; Parra-Rapado, L.; Planchenault,
D.; Weber, V. J. Org. Chem. 1997, 62, 1630.
(10) (a) Zhang, X.; Qu, Z.; Ma, Z.; Shi, W.; Jin, X.; Wang, J. J. Org.
Chem. 2002, 67, 5621. (b) Liao, M.; Wang, J. Green Chem. 2007, 9,
184. (c) Zhang, X.; Ma, M.; Wang, J. Tetrahedron: Asymmetry 2003,
14, 891.
(4) For references on enantioselective O-H insertion via copper-catalyzed
decomposition of diazo carbonyl compounds, see: (a) Maier, T. C.;
Fu, G. C. J. Am. Chem. Soc. 2006, 128, 4594. (b) Chen, C.; Zhu,
S.-F.; Liu, B.; Wang, L.-X.; Zhou, Q.-L. J. Am. Chem. Soc. 2007,
129, 12616. (c) Zhu, S.-F.; Chen, C.; Cai, Y.; Zhou, Q.-L. Angew.
Chem., Int. Ed. 2008, 47, 932.
(11) A highly stereoselective [2,3]-sigmatropic rearrangement of sulfur ylide
generated from aryldiazoacetate and allyl/propargyl sulfides was
achieved with Cu(I) catalyst. For reference, see: Ma, M.; Peng, L.;
Li, C.; Zhang, X.; Wang, J. J. Am. Chem. Soc. 2005, 127, 15016.
9
396 J. AM. CHEM. SOC. 2010, 132, 396–401
10.1021/ja9075293  2010 American Chemical Society

Enantioselective C-C Bond Formation
A R T I C L E S
Scheme 1
Figure 1. Structures of chiral dirhodium catalysts.
donor/acceptor carbenoids, C-H functionalization at the methyl
group preferentially occurs.
conditions that would favor dissociation of the rhodium catalyst
from the metal associated ylide 2 to form the free ylide 4 prior
to the subsequent reactions as this would likely cause erosion
in asymmetric induction.8 We proposed that the most favorable
conditions for achieving such results would be to conduct the
reactions in nonpolar solvents under the mildest conditions
possible.13 In this paper, we describe the discovery of highly
enantioselective rhodium-catalyzed ylide transformations of
donor/acceptor carbenoids.
To overcome the problem with competing C-H functionaliza-
tion, we became intrigued with the possibility of using allyl alcohols
as substrates. The missing methyl group would be expected to make
the oxygen functionality more accessible for oxygen ylide formation
and the favorable C-H functionalization site would no longer be
present. However, allyl alcohols have not previously been used as
substrates for [2,3]-sigmatropic rearrangements in carbenoid reac-
tions because it is well established that alcohols undergo O-H
insertion, by means of ylide formation followed by proton transfer.1
To explore the feasibility of avoiding the O-H insertion process,
the reaction of diazo compounds with racemic allyl alcohol 8 was
examined using the established chiral catalyst Rh2(S-DOSP)4
(Figure 1).2a The reaction with ethyl diazoacetate 9 generated the
O-H insertion product 10 in 67% yield without any evidence of
a [2,3]-sigmatropic rearrangement product (eq 2). A more promis-
ing result was obtained with methyl diazomalonate 11. Even though
the O-H insertion product 12 still dominated, a significant amount
of the [2,3]-sigmatropic rearrangement product 13 was also
observed (eq 3). The outcome was quite different when the reaction
was conducted with a donor/acceptor carbenoid. The reaction with
phenyldiazoacetate 6 gave a 86% combined yield of products, in
which the [2,3]-sigmatropic rearrangement product 14 was the
major product favored over the O-H insertion product 15 by a
ratio of 6:1 (eq 4). Promisingly, 14 was produced with good
asymmetric induction (86% ee), even though the starting alcohol
8 was racemic.15,16
Results and Discussion
The most promising system to date for enantioselective ylide
transformations of donor/acceptor carbenoids has been the
reaction of aryldiazoacetates with aryl allyl sulfides.10 However,
sulfides tend to poison the rhodium catalysts and consequently
tend to require relatively forcing conditions. Furthermore, sulfur
ylides are relatively stable; thus, dissociation of the rhodium
complex from the ylide would be expected to be quite favorable.
Therefore, we decided to explore the use of other allylic systems
containing less nucleophilic heteroatoms. The reaction of allyl
methyl ether 5 with methyl phenyldiazoacetate 6 was examined
but this failed to give the desired [2,3]-sigmatropic rearrange-
ment product (eq 1). Instead, it gave the C-H insertion product
7 as a 2:1 mixture of diastereomers.14 Even though this was a
failure in terms of the ylide chemistry, it is still a most
compelling example of the complementary influence of steric
and electronic effects on the regioselectivity of C-H
functionalization.2e The allylic site is electronically highly
activated, but, due to the overwhelming steric influence with
(15) For reviews on the [2,3]-sigmatropic rearrangement of ylides, see: (a)
Hodgson, D. M.; Pierard, F. Y. T. M.; Stupple, P. A. Chem. Soc. ReV.
2001, 30, 50. (b) Clark, J. S. in Nitrogen, Oxygen and Sulfur Ylide
Chemistry: A Practical Approach; Oxford University Press: Oxford,
2002.
(12) Studies from the Wood group have shown that the reaction of
R-diazoketones with propargylic or allylic alcohols proceeds through
enol intermediates, which subsequently undergo a Claisen rearrange-
ment. For references, see: (a) Wood, J. L.; Stoltz, B. M.; Dietrich,
H.-J. J. Am. Chem. Soc. 1995, 117, 10413. (b) Wood, J. L.; Moniz,
G. A.; Pflum, D. A.; Stoltz, B. M.; Holubec, A. A.; Dietrich, H.-J.
J. Am. Chem. Soc. 1999, 121, 1748. (c) Wood, J. L.; Moniz, G. A.
Org. Lett. 1999, 1, 371. (d) Moniz, G. A.; Wood, J. L. J. Am. Chem.
Soc. 2001, 123, 5095. (e) Drutu, I.; Krygowski, E. S.; Wood, J. L. J.
Org. Chem. 2001, 66, 7025. It would be reasonable to propose that a
similar enol mechanism routinely occurs in rhodium-catalyzed O-H
insertions, but for simple alcohols the enol intermediates tautomerize
to the isolated keto products.
(16) For general references on the [2,3]-sigmatropic rearrangement of
oxonium ylides formed by catalytic diazo decomposition, see: (a)
Pirrung, M. C.; Werner, J. A. J. Am. Chem. Soc. 1986, 108, 6060. (b)
Roskamp, E. J.; Johnson, C. R. J. Am. Chem. Soc. 1986, 108, 6062.
(c) Marmsater, F. P.; West, F. G. J. Am. Chem. Soc. 2001, 123, 5144.
(d) Hodgson, D. M.; Petroliagi, M. Tetrahedron: Asymmetry 2001,
12, 877. (e) Marmsater, F. P.; Vanecko, J. A.; West, F. G. Org. Lett.
2004, 6, 1657. (f) Clark, J. S.; Fessard, T. C.; Wilson, C. Org. Lett.
2004, 6, 1773. (g) Quinn, K. J.; Biddick, N. A.; DeChristopher, B. A.
Tetrahedron Lett. 2006, 47, 7281. (h) Clark, J. S.; Walls, S. B.; Wilson,
C.; East, S. P.; Drysdale, M. J. Eur. J. Org. Chem. 2006, 323. (I)
Clark, J. S.; Fessard, T. C.; Whitlock, G. A. Tetrahedron 2006, 62,
73. (j) Clark, J. S.; Guerot, C.; Wilson, C.; Blake, A. Chem. Commun.
2007, 4134. (k) Hodgson, D. M.; Angrish, D.; Erickson, S.; Kloesges,
J.; Lee, C. H. Org. Lett. 2008, 10, 5553. (l) Shimada, N.; Nakamura,
S.; Anada, M.; Shiro, M.; Hashimoto, S. Chem. Lett. 2009, 38, 488.
(13) Davies, H. M. L.; Bruzinski, P. R.; Lake, D. H.; Kong, N.; Fall, M. J.
J. Am. Chem. Soc. 1996, 118, 6897–6907.
(14) The Rh2(S-MEOX)4-catalyzed reaction of cinnamyl methyl ether with
ethyl diazoacetate results in ylide formation followed by a [2,3]-
sigmatropic rearrangement with high asymmetric induction; see: Doyle,
M. P.; Forbes, D. C.; Vasbinder, M. M.; Peterson, C. S. J. Am. Chem.
Soc. 1998, 120, 7653.
9
J. AM. CHEM. SOC. VOL. 132, NO. 1, 2010 397

A R T I C L E S
Li and Davies
Table 1. Effect of Dirhodium Catalysts and Solvent on the Ratio of
14/15
entry
Rh(II)
solvent
14/15b yield of (14 + 15), %c ee of 14, %d
1
2
3
4
5
6
7
8
9
Rh2(S-DOSP)4 pentane 5:1
94
75
65
69
86
82
94
92
67
49
84
83
74
-37
78
Rh2(S-DOSP)4 toluene
Rh2(S-DOSP)4 CH2Cl2
Rh2(S-biTISP)2 CH2Cl2
3:1
1:1
1:1
Rh2(S-PTAD)4 pentane 2:1
Rh2(OAc)4
Rh2(OOct)4
Rh2(tfa)4
pentane 1:6
pentane 1:5
pentane 1:4
pentane 1:1
pentane 2:1
Rh2(OPiv)4
10 Rh2(esp)2
a All reactions were performed with 8 (1.0 mmol, 2 equiv) and Rh(II)
(0.005 mmol, 1 mol %) in 1 mL of solvent under the addition of 6 (0.50
mmol) in 5 mL of solvent over 1 h at room temp. b Determined by
crude 1H NMR spectroscopy. c Isolated yield. d Determined by chiral
HPLC.
The next series of experiments explored the effect of the allyl
alcohol structure on the outcome of this chemistry. These
reactions were conducted in pentane with Rh2(S-DOSP)4 as
catalyst. The reaction of the highly substituted allyl alcohol 16a
gave the [2,3]-sigmatropic rearrangement product 17a in 72%
yield and 79% ee (eq 5). No trace of the O-H insertion product
was observed. In contrast the parallel reaction of the unsubsti-
tuted allyl alcohol 16h with 6 gave the O-H insertion product
18h as the only identifiable product in 63% yield (eq 6). As is
typical of rhodium catalyzed O-H insertions, this material was
formed without any asymmetric induction. The extension of this
study to a range of methyl-substituted allyl alcohols is sum-
marized in Table 2. As long as the allyl alcohols 16 are relatively
highly substituted, the [2,3]-sigmatropic rearrangement products
dominate (entries 1-4), but relatively less substituted allyl
alcohols 16e-h favor the O-H insertion products 18e-h
(entries 5-8).
Having discovered that the ylide formed from the reaction
of 6 with 8 is capable of undergoing a [2,3]-sigmatropic
rearrangement, a systematic study was conducted to find the
optimal conditions for this process. The effects of catalyst and
solvent are summarized in Table 1. As the reaction between 6
and 8 appeared to be a very effective reaction, the optimization
studies were conducted using just 2 equiv of the allyl alcohol
8. The solvent had a significant effect on the amount of the
[2,3]-sigmatropic rearrangement product 14 formed versus the
O-H insertion product 15. The reaction in pentane favored 14
over 15 by a 5:1 ratio, but in toluene the ratio was 3:1, and in
dichloromethane the ratio had degraded to 1:1 (entries 1-3).
The two other most prominent chiral rhodium catalysts for the
reactions of aryldiazoacetates are Rh2(S-PTAD)4 and Rh2(S-
biTISP)2 (Figure 1).17,18 Neither of these catalysts were as
effective as Rh2(S-DOSP)4 at favoring the formation of 14 over
15, and both catalysts gave lower levels of asymmetric induction
compared to Rh2(S-DOSP)4 (entries 4 and 5). Interestingly the
common achiral dirhodium catalysts favored the formation of
the O-H insertion product 15 (entries 6-9). The only exception
was Du Bois’ Rh2(esp)2 catalyst,19 which gave a 2:1 preference
of 14 over 15 (entry 10). From these results, it can be concluded
that Rh2(S-DOSP)4 and nonpolar solvents are the optimal
conditions for the selective formation of 14.
One of the most unexpected features of the [2,3]-sigmatropic
rearrangement was the high asymmetric induction obtained, even
though the starting allyl alcohol was racemic. To explore this
further, reactions were conducted in which a stoichiometric
amount of the alcohol 8 was used. The reaction with racemic
(R/S)-8 with 6 gave a 69% isolated yield of the [2,3]-sigmatropic
rearrangement product (S)-14 in 88% ee (Table 3). The
formation of 14 in >50% yield indicated that both enantiomers
of 8 were capable of generating (S)-14. This was confirmed by
conducting the reaction with enantioenriched allyl alcohol 8.
The reaction of (R)-8 (83% ee) generated (S)-14 in 59% isolated
yield and 94% ee while the reaction with (S)-8 (84% ee) gave
(S)-14 in 61% isolated yield and 85% ee. All the reactions went
with high conversion and the moderate isolated yields are due
to the slight difficulty in the chromatographic separation of 14
from the O-H insertion side-product, formed in 10-15% yield.
The control reaction of (R/S)-8 with Rh2(R-DOSP)4 as catalyst,
inverted the asymmetric induction and (R)-14 was obtained in
(17) (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, 6509. (c) Davies, H. M. L.; Venkataramani,
C. Org. Lett. 2003, 5, 1403. (d) Davies, H. M. L.; Lee, G. H. Org.
Lett. 2004, 6, 2117.
(18) (a) Reddy, R. P.; Lee, G. H.; Davies, H. M. L. Org. Lett. 2006, 8,
3437. (b) Reddy, R. P.; Davies, H. M. L. Org. Lett. 2006, 8, 5013. (c)
Denton, J. R.; Sukumaran, D.; Davies, H. M. L. Org. Lett. 2007, 9,
262. (d) Reddy, R. P.; Davies, H. M. L. J. Am. Chem. Soc. 2007, 129,
10312. (e) Denton, J. R.; Cheng, K.; Davies, H. M. L. Chem. Commun.
2008, 1238.
(19) (a) Zalatan, D. N.; Du Bois, J. J. Am. Chem. Soc. 2009, 131, 7558.
(b) Trost, B. M.; Malhotra, S.; Olson, D. E.; Maruniak, A.; Du Bois,
J. J. Am. Chem. Soc. 2009, 131, 4190. (c) Fiori, K. W.; Espino, C. G.;
Brodsky, B. H.; Du Bois, J. Tetrahedron 2009, 65, 3042. (d) Olson,
D. E.; Du Bois, J. J. Am. Chem. Soc. 2008, 130, 11248.
9
398 J. AM. CHEM. SOC. VOL. 132, NO. 1, 2010

Enantioselective C-C Bond Formation
A R T I C L E S
Table 2. Effect of Allyl Alcohols on the Formation of [2,3]-Sigmatropic Rearrangement Productsa
entry
R1
R2
R3
R4
alcohol
17/18b
major product
yield, %c
ee, %d
1
2g
3
4
5
6
7
8
Me
Me
H
Me
H
Me
H
H
Me
H
H
H
H
Me
Me
H
Me
Me
Me
H
H
H
Me
Me
Me
Me
Me
H
16a
16b
16c
16d
16e
16f
>20:1
>20:1
5: 1
4:1
1:14
1:16
1:>20
1:>20
17a
17b
17c
17d
18e
18f
72
79
40
66
61
84
72
63
79
88, 65e,g
79
90, 85f
<5
<5
H
H
H
H
16g
16h
18g
18h
<5
<5
a All reactions were performed with 16a-h (2.0 mmol, 4 equiv) and Rh2(S-DOSP)4 (0.005 mmol, 1 mol %) in 1 mL of pentane under the addition of
6 (0.50 mmol) in 5 mL of pentane over 1 h at room temp. b Determined by 1H NMR spectroscopy of the crude reaction mixture. c Isolated yield of
major poduct. d Determined by chiral HPLC. e Ratio of 4:1 diastereomers. f Ratio of 1:1 diastereomers. g The reaction was performed at 40 °C.
Table 3. Reaction of Phenyldiazoacetate 6 with Chiral Allyl Alcohol
A relatively highly substituted allyl alcohol is still a require-
ment for the [2,3]-sigmatropic rearrangement to occur. For
example, simply changing the substrate to allyl alcohol 16f,
caused a total change in the reaction, and O-H insertion product
22 was formed in 74% isolated yield (eq 8). Once again, the
enantioselectivity for the O-H insertion is negligible (<5% ee)
8a
entry configuration of 8
Rh(II)
configuration of 14 yield, %b ee, %c
1
2
3
4
(R/S)
Rh2(S-DOSP)4
Rh2(S-DOSP)4
Rh2(S-DOSP)4
Rh2(R-DOSP)4
(S)
(S)
(S)
(R)
69
61
59
74
88
85
94
87
(S) 84% ee
(R) 83% ee
(R/S)
a All reactions were performed with chiral allyl alcohol 8 (0.5 mmol,
1 equiv) and Rh(II) (0.005 mmol, 1 mol %) in 1 mL of pentane under
the addition of 6 (0.5 mmol) in 5 mL of pentane over 1 h at room temp.
b Isolated yield. c Determined by chiral HPLC.
A variety of different racemic secondary allylic alcohols
23a-i was reacted with styryldiazoacetate 19 and gave [2,3]-
sigmatropic rearrangement products 24a-i with excellent enan-
tioselectivity (92-98% ee) (Table 4). A range of alkyl groups
such as iso-propyl, iso-butyl, tert-butyl, and n-hexyl can be
tolerated on the allyl alcohol. Other more functionalized groups
such as ketal, TBS-protected alcohols, and trimethylsilyl are
also compatible with this reaction. In all the cases, the [2,3]-
sigmatropic rearrangement products dominated over the O-H
insertion products by a ratio of 10:1 to >20:1. Even an allyl
alcohol with an unencumbered terminal double bond (23e) is a
suitable substrate, generating the [2,3]-sigmatropic rearrange-
ment products 24e in 69% yield with 95% ee.20 A selective
O-H insertion versus cyclopropanation has been observed
previously with R-diazocarbonyl compounds.21 The absolute
configuration of 24c was determined to be (R) by X-ray
crystallography (see Supporting Information22). The drawn
absolute configuration of the other products is the tentatively
assigned stereochemistry, assuming that a similar mode of
asymmetric induction occurs for all the substrates.
74% yield with 87% ee. These studies indicate that the
asymmetric induction is dominated by the influence of the chiral
catalyst and both enantiomers of a racemic alcohol can lead to
the preferential formation of the same enantiomer of the product.
Having established the [2,3]-sigmatropic rearrangement of
allyl alcohols with phenyldiazoacetate 6, the studies were then
broadened to include another type of donor/acceptor carbenoid.
Vinyldiazoacetates are highly effective donor/acceptor carbenoid
precursors, and on testing a typical system, the styryldiazoacetate
19, it quickly became apparent that this system was even better
than 6 (eq 7). The Rh2(S-DOSP)4 catalyzed reaction could be
efficiently conducted with 19 using a single equivalent of the
racemic alcohol 8. The [2,3]-sigmatropic rearrangement product
20 was favored over the O-H insertion product 21 by a 15:1
ratio and 20 was formed with very high asymmetric induction
(98% ee).
Excellent chemo- and enantioselectivities were also observed
in the reactions of the tertiary allyl alcohols 16a and 16c (Table
5). The reaction with alcohol 16c illustrates the enhanced
selectivity of styryldiazoacetate 19 compared to phenyldiazo-
acetate 6. The reaction of 19 with 16c showed no evidence of
(20) When 1 equiv of allyl alcohol 24e was used, the isolated yield of
product 25e decreased to 32% but the enantioselectivity increased to
97% ee.
(21) Shi, G.-Q.; Cao, Z.-Y.; Cai, W.-l. Tetrahedron 1995, 5, 5011.
(22) The X-ray crystallographic data has been deposited in the Cambridge
Crystallographic Database.
9
J. AM. CHEM. SOC. VOL. 132, NO. 1, 2010 399

A R T I C L E S
Li and Davies
Table 4. Reaction of Styryldiazoacetate 19 with Racemic Allyl Alcoholsa
a All reactions were performed with 23a-j (0.5 mmol, 1.0 equiv) and Rh2(S-DOSP)4 (0.005 mmol, 1 mol %) in 1 mL of pentane under the addition
of 19 (0.55 mmol, 1.1 equiv) in 5 mL of pentane over 1 h at 0 °C. b Determined by crude 1H NMR spectroscopy. c Isolated yield of 24. d Determined
by chiral HPLC. e A total of 4 equiv alcohol 23e was used.
Table 5. Reactions of Styryldiazoacetate 19 with Tertiary Allyl Alcoholsa
entry
R
alcohol
[2,3]-sigmatropic rearrangement/O-H insertionb
product
yield, %c
ee, %d
1
2
Me
H
16a
16c
>20:1
>20:1
25a
25b
62
45
93
96
a All reactions were performed with 16a and 16c (0.5 mmol, 1.0 equiv) and Rh2(S-DOSP)4 (0.005 mmol, 1 mol %) in 1 mL of pentane under the
b
addition of 19 (0.55 mmol, 1.1 equiv) in 5 mL of pentane over 1 h at 0 °C. Determined by H NMR of the crude reaction mixture. c Isolated yield of
1
25. d Determined by chiral HPLC.
an O-H insertion product, while the reaction of 6 with 16c
generated only a 5:1 ratio of the [2,3]-sigmatropic rearrangement
versus O-H insertion (Table 3).
any evidence of O-H insertion. The major diastereomer formed
in this case was 28, in which the tertiary alcohol carbon has
the (S) configuration. This study illustrates that the chirailty of
the catalyst is the dominant influence of the asymmetric
induction in this chemistry.
To showcase the synthetic potential of the ylide formation/
[2,3]-sigmatropic rearrangement, the effect of the chiral catalyst
was examined on the reaction of styryldiazoacetate 19 with the
commercially available monoterpene, cis-(1R,5R)-(-)-pulegol
26.23 When Rh2(S-DOSP)4 was used as catalyst, the reaction
gave a 6:1 diastereomeric mixture of [2,3]-sigmatropic rear-
rangement products as the major products, from which the major
diastereomer 27 was selectively recrystallized from hexanes.
Both its relative and absolute configuration was determined by
X-ray crystallography (see Supporting Information22). The
observed (R) configuration at the tertiary alcohol carbon in 27
is consistent with the (R) configuration determined for 24c,
supporting the assumption that a similar mode of asymmetric
induction occurs for all the substrates. The reaction of 19 and
26 with Rh2(R-DOSP)4 as catalyst gave a 10:1 diastereomeric
mixture of [2,3]-sigmatropic rearrangement products, without
Conclusion
A novel oxonium ylide/[2,3]-sigmatropic rearrangement reac-
tion of racemic allyl alcohols with methyl phenyldiazoacetate
or methyl styryldiazoacetate was discovered. This process
competes favorably with the more conventional O-H insertion
chemistry when donor/acceptor carbenoids and highly substi-
tuted allyl alcohols are used as substrates. When the reactions
are catalyzed by Rh2(S-DOSP)4, tertiary R-hydroxycarboxylate
derivatives with two adjacent quaternary centers are produced
with high enantioselectivity. The reaction is presumed to occur
via a rhodium-associated oxonium ylide intermediate, which
undergoes the [2,3]-sigmatropic rearrangement with effective
transfer of chirality. In systems capable of double stereodiffer-
entiation, the asymmetric induction by the catalyst dominates
over the chirality of the substrate. These studies demonstrate
(23) Dams, I.; Bialonska, A.; Ciunik, Z.; Wawrzenczyk, C. Eur. J. Org.
Chem. 2004, 2662.
9
400 J. AM. CHEM. SOC. VOL. 132, NO. 1, 2010

Enantioselective C-C Bond Formation
A R T I C L E S
Scheme 2. Reaction of Styryldiazoacetate 19 with cis-(1R,5R)-(-)-Pulegol 26
s), 1.00 (3H, d, J ) 6.8 Hz), 0.99 (3H, d, J ) 6.8 Hz). 13C NMR
(100 MHz, CDCl3): δ 175.2 (C), 137.0 (C), 136.9 (CH), 132.5 (CH),
130.9 (CH), 128.7 (CH), 127.8 (CH), 127.4 (CH), 126.8 (CH), 81.9
(C), 52.9 (CH3), 44.1 (C), 31.6 (CH), 23.0 (CH3), 22.9 (CH3). IR
(neat): 3511, 1722, 1237, 1135, 974, 755, 740, 692 cm-1. HRMS
(+APCI) Calcd for C19H25O2 ([M-OH]+): 285.1849. Found:
285.1850. Anal. Calcd for C19H26O3: C, 75.46; H, 8.67. Found: C,
75.25; H, 8.73. HPLC analysis: 97% ee, CHIRALCEL OD-H, 0.3%
isopropanol/hexanes, 1.0 mL/min. UV: 254 nm. tR: 14.7 min
(major), 16.1 min (minor).
that the intermolecular ylide chemistry of rhodium carbenoids
is capable of highly enantioselective reactions.
Experimental Section
Representative Example. A solution of Rh2(S-DOSP)4 (10 mg,
0.005 mmol, 1 mol %) and allyl alcohol 23a (64 mg, 0.5 mmol) in
1 mL of degassed pentane was cooled to 0 °C with ice bath under
argon. Styryldiazoacetate 19 (113 mg, 0.55 mmol, 1.1 equiv) in 5
mL of degassed pentane was added by syringe pump over 1 h.
The syringe was rinsed with another 1 mL of degassed pentane
and added to the reaction mixture. After addition, the solution was
stirred for 30 min at 0 °C, then concentrated under vacuum. The
crude material was purified by flash chromatography on silica gel
eluting with pentane/diethyl ether (20:1) to give compound 24a as
a clear oil (0.103 g, 68% yield). [R]20D -26.3° (c 1.0, CHCl3). Rf,
Acknowledgment. Support of this work by the National Science
Foundation (CHE-07502730) is gratefully acknowledged. We thank
Ken Hardcastle for the X-ray crystallographic structural determination.
1
Supporting Information Available: Full experimental and
X-ray data for 24c and 27. This material is available free of
charge via the Internet at http://pubs.acs.org.
0.33 (pentane/diethyl ether 10:1). H NMR (400 MHz, CDCl3): δ
7.41 (2H, d, J ) 7.2 Hz), 7.33 (2H, t, J ) 7.2 Hz), 7.27-7.23 (1H,
m), 6.84 (1H, d, J ) 16.0 Hz), 6.50 (1H, d, J ) 16.0 Hz), 5.55
(1H, dd, J ) 16.0, 1.2 Hz), 5.40 (1H, dd, J ) 16.0, 9.2 Hz), 3.80
(3H, s), 3.45 (1H, s), 2.33-2.28 (1H, m), 1.15 (3H, s), 1.07 (3H,
JA9075293
9
J. AM. CHEM. SOC. VOL. 132, NO. 1, 2010 401