Influences of catalyst configuration and catalyst loading on selectivities in reactions of diazoacetamides. Barrier to equilibrium between diastereomeric conformations

Article abstract of DOI:10.1021/ol027157b

(Matrix presented) Stereoelectronic factors present a barrier to equilibrium between diastereomeric conformations resulting in differences in selectivity as a function of catalyst configuration. The bis(trimethylsilyl)-methyl protective group is inert to

Full text of DOI:10.1021/ol027157b

ORGANIC
LETTERS
2003
Vol. 5, No. 4
407-410
Influences of Catalyst Configuration and
Catalyst Loading on Selectivities in
Reactions of Diazoacetamides. Barrier
to Equilibrium between Diastereomeric
Conformations
,†
,‡
Michael P. Doyle,* Wenhao Hu,† Andrew G. H. Wee,* Zhongyi Wang,‡ and
Sammy C. Duncan‡
Department of Chemistry, UniVersity of Arizona, Tucson, Arizona 85721, and
Department of Chemistry, UniVersity of Regina, Regina, Saskatchewan S4S 0A2, Canada
mdoyle@u.arizona.edu; andrew.wee@uregina.ca
Received October 23, 2002
ABSTRACT
Stereoelectronic factors present a barrier to equilibrium between diastereomeric conformations resulting in differences in selectivity as a
function of catalyst configuration. The bis(trimethylsilyl)-methyl protective group is inert to insertion but directs carbon−hydrogen insertion
with enhanced enantiocontrol.
In asymmetric catalysis, standard practice assumes that with
achiral substrates the selectivities achieved with one enan-
tiomeric catalyst under a specified set of conditions will be
equal, but opposite, to those from use of its mirror image.1
This is well established in reactions involving metal carbene
intermediates, and there are no published exceptions.2-4 The
possibility that chiral catalysts of opposite configuration
could induce different outcomes with the same achiral
substrate has not been examined.
transformation are different.6,7 This could occur in reactions
of diazocarbonyl compounds if diastereomeric conformations
are formed from mirror image catalysts (e.g., Scheme 1, 1a
Scheme 1
However, there is growing documentation that, since
flexible achiral and meso ligands possess chiral conforma-
tions,5 interaction with a metal can produce diastereomeric
complexes whose reactivities and selectivities in a chemical
and 1b are diastereomeric in the attached substrate, S). A
test of this concept has been undertaken with conformation-
† University of Arizona.
‡ University of Regina.
(5) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley: New York, 1994.
(6) Mikami, K.; Terada, M.; Korenaga, T.; Matsumoto, Y.; Matsukawa,
S. Acc. Chem. Res. 2000, 33, 391.
(7) (a) Davis, T. J.; Balsells, J.; Carroll, P. J.; Walsh, P. J. Org. Lett.
2001, 3, 2161. (b) Balsells, J.; Walsh, P. J. J. Am. Chem. Soc. 2000, 122,
1802.
(1) Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-
VCH: New York, 2000.
(2) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds; Wiley: New York, 1998.
(3) Davies, H. M. L.; Antoulinakis, E. G. Org. React. (NY) 2001, 57, 1.
(4) Doyle, M. P.; Forbes, D. C. Chem. ReV. 1998, 98, 911.
10.1021/ol027157b CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/21/2003

Table 1. Catalyst-Dependent Reactions of 8 as a Function of Configuration and Loadinga
% eef
% eef
isolated
isolated
catalyst
S/Cb
configurationc
yield, %d
9:10:11e
9
11
configurationc
yield, %d
9:10:11e
9
11
Rh2(MEPY)4
10
100
1000
100
1000
100
R
R
R
R
R
R
98
81
87
48
55
85
1:3:96
10:9:81
12:10:78
35:42:23
18:35:47
10:21:69
3
50
32
62
13
20
S
S
S
S
52
52
66
61
35:30:35
34:28:38
18:32:50
32:33:35
94
95
>95
87
28
22
33
38
88
78
86
82
29
Rh2(MEOX)4
Rh2(MPPIM)4
S
82
8:37:55
64
5
a All reactions were carried out in refluxing dichloromethane containing diazoamide (0.009 M) and catalyst for 5 min (S/C e 100) or 1 h (S/C ) 1000).
b Molar ratio of 8 to catalyst. c Configuration of catalyst. d Yield determined after chromatographic removal of catalyst. e Determined by 1H NMR of reaction
mixture; imine 12 was present in amounts that were 0.8 that of 10. f Determined by HPLC using a Chiralpak OD column; opposite catalyst configurations
give opposite mirror image isomers of 9 and 11.
ally and configurationally well-defined chiral dirhodium(II)
carboxamidates ((S)-forms, 2-5). They have been fully
characterized8-11 and are well-known for their conformational
rigidity.12
configuration of the catalysts (eq 1). For example, with Rh2-
(5R-MEPY)4, aromatic cycloaddition was dominant, and
insertion into the benzhydryl C-H group (or fragmentation
to imine 12) was competitive with insertion into the 1,3-
dioxane ring.
We have previously reported that C-H insertion reactions
from 1,3-dioxan-5-yl diazoacetamide 6 provides a convenient
route to 2-deoxyxylolactams 7 and ent-7, and uses of 2-5
were explored to determine optimum catalysts and condi-
tions.13 The Rh2(MEPY)4 catalysts gave the highest level of
enantiocontrol (85% ee) and the least complications from
competing reactions (5%). However, the benzyl protective
group could not be conveniently removed, and a search for
an alternative led us to evaluate the N-benzhydryl compound
8.
With Rh2(5S-MEPY)4, chemoselectivity, regioselectivity, and
enantioselectivity were greatly different. Similar catalyst
configuration-dependent outcomes were seen with Rh2-
(MEOX)4 and Rh2(MPPIM)4 catalysts (Table 1), and selec-
tivities also varied as a function of catalyst loading.
Increasing the concentration of 8 by 30-fold had very limited
influence on selectivities,14 as did performing this reaction
in refluxing dichloroethane.15
To ensure that these differences were not due to differential
catalyst purity, the same catalyst pairs were used with the
N-benzyl analogue of 6. Here chemoselectivity and enantio-
selectivity did not vary with catalyst configuration. Indeed,
in all reactions previously reported from our laboratories that
used chiral dirhodium(II) carboxamidate catalysts, we did
not observe different outcomes from the use of the (R)- or
(S)-configured catalysts.
However, treatment of 8 with 2-4 and their enantiomeric
forms gave very different results that were dependent on the
(8) Doyle, M. P.; Winchester, W. R.; Hoorn, J. A. A.; Lynch, V.;
Simonsen, S. H.; Ghosh, R. J. Am. Chem. Soc. 1993, 115, 9968.
(9) Doyle, M. P.; Dyatkin, A. B.; Protopopova, M. N.; Yang, C. I.;
Miertschin, C. S.; Winchester, W. R.; Simonsen, S. H.; Lynch, V.; Ghosh,
R. Rec. Tran. Chim. Pays-Bas 1995, 114, 163.
(10) Doyle, M. P.; Zhou, Q.-L.; Raab, C. E.; Roos, G. H. P.; Simonsen,
S. H.; Lynch, V. Inorg. Chem. 1996, 35, 6064.
(11) Doyle, M. P.; Zhou, Q.-L.; Simonsen, S. H.; Lynch, V. Synlett. 1996,
697.
(12) Doyle, M. P.; Ren, T. Prog. Inorg. Chem. 2001, 49, 113.
(13) Doyle, M. P.; Phillips, I. M.; Yan, M.; Timmons, D. J. AdV. Synth.
Catal. 2002, 344, 91.
(14) For Rh2(5R-MEPY)4 at S/C ) 1000 and [8] ) 0.27 M in refluxing
CH2Cl2: % yield ) 75; 9:10:11 ) 9:16:75; % ee 9 ) 81; % ee 11 ) 34.
(15) For Rh2(5R-MEPY)4 at S/C ) 1000 and [8] ) 0.009 M in refluxing
ClCH2CH2Cl: % yield ) 74; 9:10:11 ) 19:15:66; % ee 9 ) 75; % ee
11 ) 7.
408
Org. Lett., Vol. 5, No. 4, 2003

Table 2. Catalyst-Dependent Reactions of 15 as a Function of Configurationa
d
16 at room temperaturec
16 at reflux
catalyst
absolute configuratione
catalyst
configurationb
% yield
% eef
% yield
% eef
(4a,7a)-16
Rh2(MEPY)4
R
S
R
S
R
S
R
S
S
72
82
72
76
g
66
50
84
70
80
84
95
92
62
88
77
80
71
44
43
90
68
1
S,S
R,R
S,S
R,R
Rh2(MEOX)4
Rh2(MPPIM)4
Rh2(MEAZ)4
Rh2(PTTL)4
g
4
81
69
g
78
66
77
70
29
S,S
R,R
R,R
a All reactions were carried out in dry dichloromethane (0.02 M) containing diazoamide and 2.5 mol % Rh(II) catalyst. b Configuration of catalyst ligands.
c Reaction time was 40 min except with Rh2(MEAZ)4 for which the reaction time was 20 min. d Reaction time was 15-20 min except with Rh2(MPPIM)4
(20 h) and Rh2(S-PTTL)4 (3 h). e Configuration assigned based on comparison of [R]D20 of 17, prepared from 16, with known (4S,5S)-17. The configuration
at carbons 4a and 7a in 16 prepared using other Rh(II) catalysts was inferred. f Determined by chiral HPLC analysis using a Chiralcel OD column. g No
reaction at room temperature.
The influences of catalyst configuration and loading on
selectivities can be attributed to basic conformational dif-
ferences in the intermediate metal carbene. Regioselectivities
and chemoselectivities are a function of the populations of
13 and 14 (Scheme 2), and the data demonstrate that the
pathway through 14 is dominant.
achieved within the time scale for insertion, then the
enantioselectivity will differ with the configuration of the
catalyst that is employed. Furthermore, the favored confor-
mation (13a/13b) is dependent on the configuration of the
catalyst so that the conformational distribution of 13 with
Rh2(5S-MEPY)4, for example, will not be the same as that
with Rh2(5R-MEPY)4. And because trapping of diazoaceta-
mide 8 configurations leading to 13 and 14 is a function of
the S/C ratio, selectivities also vary with catalyst loading.16
To focus only on enantiocontrol in C-H insertion, we have
taken advantage of Wee’s recent report of bis(trimethylsilyl)-
methyl (BTMSM) as a nitrogen protective group in diazo
decomposition reactions.17 With Rh2(OAc)4, racemic inser-
tion product 16 (eq 2) was obtained in 72% yield. Catalysts
2-5 were used, and only 16 was produced. Results from
these reactions, reported in Table 2, show significant
differences in enantioselectivity as a function of catalyst
configuration. Unlike 8, however, higher enantioselectivity
was realized for 16 with the (R)-configured catalysts for an
enantiomeric set of Rh(II) carboxamidates when the reaction
was conducted either at room temperature or at reflux. It is
also instructive to compare the levels of enantioselection for
the conversions 8 f 9 and 15 f 16 to the structure of the
catalyst. In the formation of 9, Rh2(MEPY)4 (2) gave good
to excellent enantioselection, whereas for the formation of
16, Rh2(MEOX)4 (3) provided superior results. For catalysts
of type 5, 5a was more effective in providing higher
enantioselection in the formation of 16 than 5b.
Scheme 2
Differences in enantioselectivity, however, are related to
the relative access through competing diastereomeric con-
formations, as through 13a and 13b (Scheme 3). Here, the
Scheme 3
relative energy difference between 13a and 13b is the normal
determinant of the extent of enantiocontrol. However, if
equilibrium between diastereomeric 13a and 13b cannot be
On the other hand, 5b gave a higher % ee for 9 compared to
that for 16. There was a marked difference in the perfor-
mance of Rh2(MPPIM)4 in effecting enantioselection during
Org. Lett., Vol. 5, No. 4, 2003
409

the formation of 9 and 16; for 9, higher ees were realized
with Rh2(4S-MPPIM)4, whereas for 16, an almost racemic
mixture was produced with each of the enantiomeric forms
of this catalyst.
during formation of 16, but interestingly, the sense of
induction is the same as that obtained with (S)-configured
dirhodium(II) carboxamidates.
The absolute configuration at C-4a and C-7a in 16, formed
with Rh2(4R-MEOX)4, was assigned as S,S by conversion
of 16 to the known18 18 (eq 3) and comparison of the specific
20
optical rotation of 18 ([a]D ) +40.9) with the reported18
value ([a]D20) +51.53).
With the use of diazoamide 15 and Rh2(4R-MEOX)4, an
enantioselectivity of 90% ee has been achieved for the C-H
insertion reaction to form 16, and because of the ease of
removal of BTMSM, this methodology is optimal for the
construction of 2-deoxyxylolactam. Applications to other
synthetic targets are presently under investigation.
Thus, the (R)-configured catalysts afforded (4aS,7aS)-16 and
the (S)-configured catalysts gave (4aR,7aR)-16.
Acknowledgment. Support for this research by grants
from the National Science Foundation and National Institutes
of Health (GM-46503) to M.P.D. is gratefully acknowledged.
A.G.H.W. thanks the Natural Sciences and Engineering
Research Council, Canada, and the University of Regina for
support. We thank Professor S.-I. Hashimoto for providing
A.G.H.W. with a sample of Rh2(S-PTTL)4 catalyst for initial
studies on N-BTMSM diazoamide chemistry.
The Hashimoto catalyst 1719 was also evaluated against
15 and found to be not as effective as the dirhodium(II)
carboxamidates [except Rh2(MPPIM)4] for enantiocontrol
(16) The same principles apply to enantioselection in aromatic cycload-
dition. This report is only the second to document enantioselectivity for
aromatic cycloaddition of diazoacetamides and diazoacetates: Doyle, M.
P.; Ene, D. G.; Forbes, D. C.; Pillow, T. H. J. Chem. Soc., Chem. Commun.
1999, 1691.
(17) Wee, A. G. H.; Duncan, S. C. Tetrahedron Lett. 2002, 43, 6173.
(18) Takahata, H.; Banba, Y.; Tajima, M.; Momose, T. J. Org Chem.
1991, 56, 240.
(19) Watanabe, N.; Ogawa, T.; Ohtaka, Y.; Ikegami, S.; Hashimoto, S.
Synlett 1996, 85. This catalyst is readily prepared from (S)-N-phthaloyl-
tert-leucinate and Rh2(OAc)4 via ligand exchange.
Supporting Information Available: Experimental pro-
cedures and product characterizations. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL027157B
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Org. Lett., Vol. 5, No. 4, 2003