Amplification of asymmetric induction in sequential reactions of bis-diazoacetates catalyzed by chiral dirhodium(II) carboxamidates

Article abstract of DOI:10.1021/ol0520121

(Chemical Equation Presented) Two sequential intramolecular carbon-hydrogen insertion or cyclopropanation reactions of bis-diazoacetates using chiral dirhodium(II) carboxamidate catalysts are reported. The initial metal carbene transformation forms an excess of one enantiomer that with the second transformation further enhances stereocontrol (kinetic amplification). Diastereoselectivity and enantioselectivity for product formation are controlled by the catalyst.

Full text of DOI:10.1021/ol0520121

ORGANIC
LETTERS
2005
Vol. 7, No. 22
5035-5038
Amplification of Asymmetric Induction
in Sequential Reactions of
Bis-diazoacetates Catalyzed by Chiral
Dirhodium(II) Carboxamidates
Michael P. Doyle,* Yuanhua Wang, Pejman Ghorbani, and Erhard Bappert
Department of Chemistry and Biochemistry, UniVersity of Maryland,
College Park, Maryland 20742
mdoyle3@umd.edu
Received August 19, 2005
ABSTRACT
Two sequential intramolecular carbon−hydrogen insertion or cyclopropanation reactions of bis-diazoacetates using chiral dirhodium(II)
carboxamidate catalysts are reported. The initial metal carbene transformation forms an excess of one enantiomer that with the second
transformation further enhances stereocontrol (kinetic amplification). Diastereoselectivity and enantioselectivity for product formation are
controlled by the catalyst.
Carbon-hydrogen insertion and cyclopropanation reactions
of diazoacetates catalyzed by chiral dirhodium(II) compounds
are important methodologies for the formation of lactones.
Abundant examples of highly diastereoselective and enan-
tioselective transformations in processes that occur with
monodiazoacetates have been published,1-4 but there are few
examples in which double stereodifferentiation is exhibited.5
results in enhancement of stereocontrol.7 The first applica-
tions with diazoacetates for enhanced selectivity occurred
by reacting chiral, nonracemic diazoacetates with chiral
catalysts,8 match/mismatch effects were observed, often with
surprising results. More recently, the influence of two chiral
centers on the catalyst in close proximity to the metal carbene
reaction center was examined.9 What has yet to be reported
is the outcome of two sequential reactions of a bis-
Amplification of asymmetric induction6 involving sequen-
tial reactions at sites in proximity to each other generally
(6) Amplification of asymmetric induction and double stereodifferen-
tiation are discussed in Eliel, E. L.; Wilen, S. H.; Mander, L. N.
Stereochemistry of Organic Compounds; Wiley: New York, 1994; Chapter
12.5.
(7) Examples of the broad applications of double stereodifferentiation
include: (a) Heathcock, C. H.; White, C. T. J. Am. Chem. Soc. 1979, 101,
7076. (b) Starkmann, B. A.; Young, D. W. J. Chem. Soc., Perkin Trans. 1
2002, 725. (c) Togni, A.; Blumer, R. K.; Pregosin, P. S. HelV. Chim. Acta
2004, 74, 1533.
(8) (a) Martin, S. F.; Spaller, M. R.; Liras, S.; Hartmann, B. J. Am. Chem.
Soc. 1994, 116, 4493. (b) Doyle, M. P.; Dyatkin, A. B.; Kalinin, A. V.;
Ruppar, D. A.; Martin, S. F.; Spallar, M. R.; Liras, S. J. Am. Chem. Soc.
1995, 117, 11021.
(9) Doyle, M. P.; Morgan, J. P.; Fettinger, J.; Colyer, J. T.; Timmons,
D. J.; Carducci, M. J. Org. Chem. 2005, 70, 5291.
(1) (a) Doyle, M. P. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima,
I., Ed.; Wiley-VCH: New York, 2000. (b) Doyle, M. P. In Topics in
Organometallic Chemistry; Dotz, K.-H., Ed.; Springer-Verlag GmbH:
Berlin, Germany, 2004; Vol. 10, p 203. (c) Doyle, M. P. In Modern
Rhodium-Catalyzed Transformations; Evans, P. A., Ed.; Wiley-VCH: New
York, 2005.
(2) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds; Wiley: New York, 1998.
(3) (a) Davies, H. M. L.; Antoulinakis, E. G. Org. React. 2001, 57, 1.
(b) Davies, H. M. L.; Beckwith, R. E. J. Chem. ReV. 2003, 103, 2861.
(4) Doyle, M. P.; Forbes, D. C. Chem. ReV. 1998, 98, 911.
(5) (a) Davies, H. M. L.; Jin, Q. Org. Lett. 2005, 7, 2293. (b) Davies, H.
M. L.; Venkataramani, C. Org. Lett. 2001, 3, 1773.
10.1021/ol0520121 CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/07/2005

Table 1. Chemoselectivity and Enantioselectivity from Catalytic Reactions of 1a
ratiob
2:3:4
yieldc
(%)
ee of 3d
(%)
entry
catalyst
procedure
e
1
2
3
4
5
6
7
8
9
Rh2(OAc)4
A
B
A
B
B
A
B
B
B
20:80:0
11:80:9
11:72:17
1:65:34
6:94:0
59:41:0
48:52:0
48:52:0
32:68:0
60
58
70
81
43
90
91
90
35
Rh2(5S-MEPY)4
Rh2(4R-MEOX)4
Rh2(4S-MEOX)4
Rh2(4S-IBAZ)4
Rh2(4S-MPPIM)4
Rh2(4S-MPPIM)4
Rh2(4S,S-BSPIM)4
Rh2(4S,R-MNACIM)4
95
95
99
96
99
f
99
99
a Reactions were performed by addition of 1 in CH2Cl2 to a refluxing CH2Cl2 solution of the catalyst (procedure A: 1.0 mol % catalyst, addition over
10 h; procedure B: 2.0 mol % catalyst, addition over 2 h). b Determined by 1H NMR in CDCl3. c Isolated yield after column chromatography. d Determined
by GC on Chiraldex B-DM column. e Racemic mixture of 3 and ent-3 was formed. f ent-3 was formed in this case.
diazoacetate in reactions with a chiral dirhodium(II) car-
boxamidate. In such cases, the first transformation forms an
excess of one enantiomer that with the second transformation
further enhances stereocontrol (kinetic amplification).
The preference for formation of five-membered rings in
carbon-hydrogen insertion reactions is well established.1-4,10
This preference is exacting and virtually exclusive in C-H
insertion reactions that occur with cyclohexyl diazoacetates
(Scheme 1).11 The only significant exception occurred in
chiral dirhodium(II) carboxamidates (Table 1). Full charac-
terization of each of these products was provided by their
X-ray structures (Figures 2-4)14 and complimented by
Scheme 1
Figure 1. Chiral dirhodium(II) carboxamidate catalysts.
spectroscopic results. The production of 2 was anticipated
from the configurational outcome of monodiazoacetates
(Scheme 1). This compound is C2-symmetric, but was formed
as the major product only in reactions performed with
sterically encumbered oxaimidazolidine-carboxylate cata-
lysts Rh2(4S-MPPIM)4 and Rh2(4S,S-BSPIM)4 (Table 1,
entries 6-8). Note that the directional outcome of the
insertion reactions is consistent with the trans configuration
of the reactant bis-diazoacetate.
reactions of 3-substituted steroidal diazoacetates where, when
there was a configurational mismatch between substrate and
catalyst, four-membered ring â-lactone was the major
product.12 Consider, then, our surprise in encountering three
insertion products in varying amounts from reactions of the
bis-diazoacetate of trans-1,4-cyclohexanediol13 catalyzed by
(10) Taber, D. F.; Ruckle, R. E., Jr. J. Am. Chem. Soc. 1986, 108, 7686.
(11) (a) Doyle, M. P.; Kalinin, A. V.; Ene, D. G. J. Am. Chem. Soc.
1996, 118, 8837. (b) Doyle, M. P.; Tedrow, J. S.; Dyatkin, A. B.; Spaans,
C. J.; Ene, D. G. J. Org. Chem. 1999, 64, 8907. (c) Doyle, M. P.; Colyer,
J. J. Mol. Catal. A 2003, 196. (d) Doyle, M. P.; Yan, M.; Gau, H.-M.;
Blossey, E. C. Org. Lett. 2003, 5, 561.
Spirolactone 3 was the major product from reactions that
occurred with the more open catalysts Rh2(5S-MEPY)4, Rh2-
(12) Doyle, M. P.; Davies, S. B.; May, E. J. J. Org. Chem. 2001, 66,
8112.
(13) Only products from intermolecular and intramolecular “carbene
dimer” formation were observed from reactions of the bis-diazoacetate of
cis-1,4-cyclohexanediol.
(14) Crystallographic data for 2, 3, and 4 have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication no.
CCDC 279653, 279654, 279655. See Supporting Information for X-ray
crystal data.
5036
Org. Lett., Vol. 7, No. 22, 2005

Figure 4. Crystal structure of 4 with selected bond lengths [Å]
and angles [deg]: O2-C1 1.3587(15), O2-C3 1.5114(13), C1-
C2 1.5025(17), C2-C3 1.5374(17), C3-C4 1.5118(16), C4-C5
1.5251(18), C1-O2-C3 91.11(8), C4-C3-C2 116.60(11), C3-
C4-C5 112.03(10).
Figure 2. Crystal structure of 2 with selected bond lengths [Å]
and angles [deg]: O12-C11 1.347(3), O12-C14 1.465(2), C11-
C12 1.496(3), C12-C13, 1.535(3), C13-C18 1.521(3), C13-C14
1.548(3), C14-C15 1.519(3), C11-O12-C14 112.07(17), O12-
C11-C12 110.54(17), C11-C12-C13 105.48(17), C18-C13-
C14 114.36(16), C12-C13-C14 103.95(16), O12-C14-C13
104.98(15), C15-C14-C13, 113.95(17), C14-C15-C16, 111.16-
(17), C17-C16-C15 111.37(17).
decomposition of the intermediate monodiazoacetate is
slower than that for 1.
(E,E)-2,4-Hexadien-1,6-diyl bis-diazoacetate 5 was se-
lected for examination of double diastereoselection in
dirhodium(II)-catalyzed intramolecular cyclopropanation re-
actions (Table 2). Two diastereomeric products were
(4S/R-MEOX)4, and Rh2(4S-IBAZ)4 (Table 1, entries 2-5),
and enantioselectivities associated with its formation were
exceptional. The bis-spirolactone product 4 was a minor
product only formed in reactions with 1 catalyzed by Rh2-
(MEOX)4 and Rh2(5S-MEPY)4 (Table 1, entries 2-4), and
efforts to increase its production were not successful. The
major competing process in these reactions was “carbene
dimer” formation, especially with the more reactive catalysts,
such as Rh2(OAc)4, Rh2(4S-IBAZ)4, and Rh2(5S-MEPY)4;
only the sterically hindered oxaimidazolidine-ligated cata-
lysts, Rh2(4S-MPPIM)4 and Rh2(4S,S-BSPIM)4, suppressed
the formation of these products. Ordinarily, increasing the
time of addition of the diazo compound to the reaction
mixture containing the catalyst reduces this undesirable
reaction. However, in several instances, decreasing the time
for addition from 10 h (procedure B) to 2 h (procedure A)
led to a reduction in these dimeric and oligomeric products.
Furthermore, changes in addition time changed the ratio of
2:3:4, indicating that the diazoacetate remaining from the
first C-H insertion was being preferentially drawn down
this pathway, further suggesting that the rate for diazo
Table 2. Diastereoselectivity and Enantioselectivity from
Catalytic Double Cyclopropanation Reactions of 5a
yieldb
(%)
ee of 6bd
entry
catalyst
Rh2(OAc)4
6a:6bc
(%)
1
2
3
4
5
6
7
8
9
trace
54
79
21
78
91
90
79
78
Rh2(CAPY)4
48:52
45:55
33:67
24:76
18:82
7:93
Rh2(R/S-MEPY)4
Rh2(4R-MEAZ)4
Rh2(4R-MEOX)4
Rh2(5R-MEPY)4
Rh2(4R-MPPIM)4
Rh2(4S,S-BSPIM)4
Rh2(4S,R-MNACIM)4
11
82
86
96
99
99
99
4:96
5:95
a Reactions were performed by addition of 5 in CH2Cl2 over 10 h to a
refluxing CH2Cl2 solution of the catalyst (1.0 mol %). b Isolated yield after
chromatography. c Determined by 1H NMR in CD3CN. d Determined by
GC on Chiraldex B-DM column.
formed: 6a (1S,5R,6R,1′R,5′S,6′S)-[6,6′]bi(3-oxabicyclo-
[3.1.0]hexyl)-2,2′-dione, which is the meso product, and a
enantiomeric pair of R-6b, (1R,5S,6S,1′R,5′S,6′S)-[6,6′]bi-
[3-oxabicyclo[3.1.0]hexyl]-2,2′-dione, and S-6b, (1S,5R,6R,1′S,
5′R,6′R)-[6,6′]bi[3-oxabicyclo[3.1.0]hexyl]-2,2′-dione. To de-
termine diastereoselectivity for the double cyclopropanation
reaction in the absence of the effects related to chiral ligands
Figure 3. Crystal structure depicting the (3aR,5R,7aR)-3 enanti-
omer with selected bond lengths [Å] and angles [deg]: O2-C1
1.359(3), C1-C2 1.509(4), C2-C3 1.524(4), C3-C8 1.502(4),
C7-C9 1.516(4), C7-C8 1.527(4), C9-C10 1.508(4), C10-O3
1.348(4), C1-C2-C3 85.2(2), C8-C3-C2 117.0(2), C9-C7-
C8 111.0(2), C3-C8-C7 112.5(2), C10-C9-C7 102.2(2).
Org. Lett., Vol. 7, No. 22, 2005
5037

on dirhodium(II), reactions with Rh2(OAc)4 and Rh2(CAPY)4
were performed. With Rh2(OAc)4 compounds 6a and 6b
could only be obtained in trace amounts, but the reaction
with Rh2(CAPY)4 resulted in a modest yield of diastereomers
with a product ratio showing no preference for either
diastereoisomer, indicating that the influence of the first
cyclization on the second cyclization step is relatively small.
When “equal” amounts of the enantiomeric Rh2(MEPY)4
catalysts were used, product diastereoselectivity was the
same, but product yields for 6a + 6b were dramatically
improved.15 The slight preference for the chiral compound
6b in this case is probably due to impurities in one of the
catalyst enantiomers or to the measurement of unequal
amounts of the pure catalysts. The S-configured dirhodium-
(II) catalysts favored the formation of (1R,5S,6S,1′R,5′S,6′S)-
6b (S-6b), and the (1S,5R,6R,1′S,5′R,6′R)-6b (R-6b) was the
dominant product of the R-configured catalysts. Imidazoli-
dinone-based catalysts gave superior enantioselectivities and
low yields of the meso product 6a. Compared to the model
compound, (E)-2-hexen-1-yl diazoacetate (Scheme 2),11c
Scheme 3
to S-7 is 85:15, then one would expect that product ratio for
R-6b:6a:S-6b would be 72:26:2, or 26:74 for 6a:6b and 95%
ee for 6b. Instead, we see from Table 2 that the R-6b:6a:
S-6b product ratio is 80:18:2 with 96% ee, which suggests
that there is synergistic enhancement of selectivity, but that
this enhancement is small.
Scheme 2
In summary, amplification of asymmetric induction in
intramolecular metal carbene transformations has provided
the first examples of competition for formation of meso and
D,L-diastereoisomers. Limiting the formation of the meso
isomer provides enhanced enantioselectivity.
Acknowledgment. The financial support of the National
Institutes of Health (GM 46503) and the National Science
Foundation is gratefully acknowledged. E.B. thanks the
University of Heidelberg through Prof. G. Helmchen for
support of his participation. We are grateful to Doina Ene
and Albert Russell for their efforts in this research.
where only monocyclopropanation occurs, all catalysts
resulted in an higher enantiomeric excess.
As shown in Table 2, the decrease in the relative yield of
the meso product 6a is linked to the increase of enantiose-
lectivity for 6b. This relationship can be understood by
reference to the stepwise process described in Scheme 3. In
the absence of secondary influences, the anticipated ratio of
products from reaction with achiral or racemic catalyst is
25:50:25 for R-6b:6a:S-6b, or 50:50 for 6a:6b, and this is
what is observed. If, in what is expected from reactions
catalyzed by Rh2(5R-MEPY)4 (Scheme 2), the ratio of R-7
Supporting Information Available: Additional experi-
mental details, 1H and 13C NMR spectra, tables of positional
and thermal parameters, and X-ray crystallographic informa-
tion in CIF format. This material is available free of charge
via the Internet at http://pubs.acs.org.
(15) Similar results were obtained with Rh2(R/S-MEOX)4.
OL0520121
5038
Org. Lett., Vol. 7, No. 22, 2005