Optimization of enantiocontrol in cis-selective cyclopropanation reactions
catalyzed by dirhodium(II) tetrakis[alkyl 2-oxaazetidine-4(S)-carboxylates]
Michael P. Doyle,* Simon B. Davies and Wenhao Hu
Department of Chemistry, University of Arizona, Tucson, Arizona, 85721, USA. E-mail: mdoyle@u.arizona.edu
Received (in Corvallis, OR, USA) 18th February 2000, Accepted 7th April 2000
Both intermolecular and macrocyclic intramolecular cyclo-
propanation reactions occur with greater selectivity for the
cis-(Z)-diastereoisomer than for the trans-(E)-diastereomer
in reactions catalyzed by chiral dirhodium(II) azetidinone-
carboxylates; the influence of the catalyst’s ester alkyl group
on enantiocontrol is substantial but appears to be delicately
balanced by steric factors.
application of the dirhodium carboxamidate catalyst 1a.1,9 An
exception is the Ru–salen catalyst recently reported by Katsuki
and co-workers.10 However, the use of chiral azetidinone
catalysts 2 provides a distinct preference for the thermodynam-
ically less stable 3 (Table 1), and enantiocontrol for the favored
isomer is quite respectable. With 4-methylpenta-l,3-diene and
dicyclohexylmethyl diazoacetate (DCDA)11 these same cata-
lysts show exclusive regioselection for addition to the less-
substituted double bond (5 + 6), comparable diastereocontrol to
that obtained with styrene/EDA, and exceptional enantiocontrol
in the formation of 5. The absolute configuration for the major
isomer of 3 (and 5) is (1S, 2R); that for 4 (and 6) is (1S, 2S).
Chiral dirhodium(II) carboxamidate catalysts having the general
structural framework of 1 have been widely employed to
achieve high diastereoselectivity and enantiocontrol in a wide
variety of catalytic metal carbene transformations.1–3 The
Table 1 Stereocontrol in intermolecular asymmetric cyclopropanation
reactions catalyzed by 2a
Ee(%)
Isolated
Catalyst
yield (%)b 3+5(5+6) 3(5)
4(6)
PhCHNCH
2
+ EDA:c
2a
2b
2c
2d
2e
CNCHCHNCH
Rh
2
Rh
2
Rh
2
Rh
2
Rh
2
(4S-IBAZ)
4
62
74
65
69
68
69+31
58+42
55+45
66+34
64+36
76
60
58
67
70
52
32
32
34
50
(4S-BNAZ)
(4S-MEAZ)
(4S-NEPAZ)
(4S-CHAZ)
4
4
4
4
Me
2
2
+ DCDA+d
e
Rh
Rh
Rh
Rh
Rh
a
2
(4S-IBAZ)
(4S-BNAZ)
(4S-MEAZ)
(4S-NEPAZ)
(4S-CHAZ)
4
2a
81
89
86
91
80
54+46
42+58
43+57
49+51
53+47
> 98
> 98
91
> 98
83
66
70
63
70
60
2
2
2
2
4
2b
2c
4
methyl ester has been commonly employed because early
investigations showed no significant difference in enantiocon-
trol with ester variation from methyl to octadecyl and from
isopropyl to neopentyl.4 However, we recently reported the
preparation of two chiral azetidinone-4-carboxylate-ligated
4
2d
2e
4
2 2
Reactions were performed in refluxing CH Cl using 1.0 mol% catalyst.
–6
b
c
Yield of 3 + 4 (or 5 + 6) after chromatography. [Styrene]/[EDA] = 10;
ee values obtained by GC on a 30 m Chiraldex B-DM column with cis-
isomers eluting before trans-isomers. [Diene]/[DCDA] = 4; % ee values
%
dirhodium(II) catalysts, Rh
2
(4S-IBAZ)
4
2a and Rh
2
(4S-
d
BNAZ) 2b, whose ester alkyl group seemed to have a
4
obtained from the methyl esters following saponification and resterification
with analysis on a 30 m Chiraldex G-TA column. Data from ref. 7.
7
e
significant influence on enantiocontrol in cyclopropanation
8
and insertion transformations. We now report, from results
obtained with a broad selection of these catalysts, that the size
of the ester alkyl group has a modest influence on diaster-
eoselectivity but has a substantial, but irregular, effect on
enantiocontrol in addition reactions.
As can be seen from the data in Table 1, diastereoselectivity
and enantioselectivity are responsive to the ester alkyl group of
the catalyst ligand. Larger alkyl groups favor the cis-cyclopro-
panecarboxylate isomer more than do the smaller ones (2b and
2c). In addition to suggesting the potential of 2 for predominant
formation of highly enantioenriched cis-substituted cyclopropa-
The catalytic reaction of ethyl diazoacetate (EDA) with
styrene is the classic transformation with which stereoselectiv-
ity for cyclopropanation is measured and catalyst effectiveness
is determined.1 Products are cis- and trans-2-phenylcyclopro-
panecarboxylate esters 3 and 4.
,9
necarboxylates, however, the data in Table 1 also allow us to
7
correct data previously reported for Rh
2
(4S-BNAZ)
4
which
showed considerably lower enantioselectivities from those
reported in Table 1.
Catalysts 1 have been shown to be particularly suitable for
high enantiocontrol in intramolecular cyclopropanation reac-
tions of allylic diazoacetates, providing the cyclized products in
high yields and with ee values > 94%.1
,3,12
With allyl
1a gives
the corresponding bicyclic lactone 8 in good yield and with
5% ee. In contrast, chiral azetidinones 2 do not have such high
2 4
diazoacetate 7, for example, use of Rh (5S-MEPY)
9
enantiocontrol in reactions with 7 (Table 2), but they do show a
remarkable variation in % ee as a function of the ester alkyl
group on the catalyst.
Chiral copper, ruthenium and cobalt catalysts show a marked
preference for the trans isomer 4, and this is also true for
DOI: 10.1039/b001464h
Chem. Commun., 2000, 867–868
This journal is © The Royal Society of Chemistry 2000
867