Stereoselective synthesis of syn- and anti-1,3- and 1,2-dimethyl arrays via asymmetric conjugate additions

Article abstract of DOI:10.1016/S0040-4039(02)00638-X

Asymmetric conjugate additions have been investigated with enantiopure N-enoyloxazolidinones for efficient construction of syn and anti-1,3-dimethyl arrays on an acyclic carbon backbone. Reactions of Yamamoto organocopper species exhibit characteristics of double asymmetric induction resulting from influences of the 4-substituted chiral auxiliary and features of side chain stereochemistry.

Full text of DOI:10.1016/S0040-4039(02)00638-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3723–3727
Stereoselective synthesis of syn- and anti-1,3- and 1,2-dimethyl
arrays via asymmetric conjugate additions
David R. Williams,* William S. Kissel, Jie Jack Li and Richard J. Mullins
Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, IN 47405-7102, USA
Received 19 February 2002; accepted 22 March 2002
Abstract—Asymmetric conjugate additions have been investigated with enantiopure N-enoyloxazolidinones for efficient construc-
tion of syn and anti-1,3-dimethyl arrays on an acyclic carbon backbone. Reactions of Yamamoto organocopper species exhibit
characteristics of double asymmetric induction resulting from influences of the 4-substituted chiral auxiliary and features of side
chain stereochemistry. © 2002 Published by Elsevier Science Ltd.
Processes of asymmetric conjugate addition to a,b-
unsaturated carbonyl moieties are of crucial importance
in synthesis endeavors.1 This is particularly significant
as applied to problems of formation of new car-
bonꢀcarbon bonds.2 The 1,4-addition of organocopper
reagents to conjugated enoyl systems which incorporate
chiral auxiliaries has received much attention.3
asymmetric conjugate additions for the stereoselective
construction of 1,3-syn- and 1,3-anti-dimethyl arrays.
These efforts also briefly examine the implications for
1,2-dimethyl arrangements.
Initially our experiments examined reactions of the
4-benzyl-N-enoyl-1,3-oxazolidin-2-one 1 with enantio-
pure Yamamoto organocopper species 3a and 3b.11
While the addition of 3a (Table 1; entry A) proceeded
to give 4 in high yield and with good stereoselectivity,
use of the enantiomer 3b led to an interesting reversal
of facial selectivity, albeit with reduced stereocontrol, in
the production of 5 (entry B). Based on the report of
Hruby,3g our utilization of 4-phenyl-1,3-oxazolidin-2-
one 2a in reactions with 3a proved highly successful for
synthesis of the 1,3-anti-dimethyl array in 6 (entry C),
whereas 1,3-syn diastereomer 7 (entry D) was available
from 2b in diminished yield and stereoselectivity.12
Over the past decade, our goals in natural product
synthesis have periodically focused on aspects of conju-
gate addition which would prove effective for the direct
installation of 1,3-syn- and 1,3-anti-dimethyl stereoar-
rangements along an acyclic backbone. Our syntheses
of myxovirescin A1,4 sambutoxin5 and O,O-
dimethylfuniculosin6 are illustrative of these efforts.
Although solutions to this problem are not general, the
hydroxyl-directed reduction of acyclic homoallylic alco-
hols provides access to 1,3-syn-dimethyl constructions
via homogeneous catalysis.7 Additionally, investigators
have also developed successful strategies to this end in
the course of natural product syntheses.8
O
O
R1 R2
O
N
F3B•Cu
OBn
Hoffman has provided significant insights for confor-
mational organization of flexible molecules bearing 1,3-
dimethyl substitution, which may contribute to the
understanding of molecular recognition and biochemi-
cal properties.9 This body of work underscores the need
for adaptable and effective methodology as a funda-
mental tool in the proactive design of molecular archi-
tecture.10 Herein we communicate our studies of
Y
X
1
X = Bn, Y = H
2a X = Ph, Y = H
2b X = H, Y = Ph
3a R1 = H, R2 = CH3
3b R1 = CH3, R2 = H
Based on these results, a general strategy to provide
anti- and syn-1,3-dimethyl constructions was examined.
Efforts explored the differences in selectivity as pro-
moted by the 4-phenyl- and 4-benzyloxazolidinone chi-
ral auxiliaries. In contrast to the addition of the
asymmetric organocopper reagents 3a and 3b, the addi-
tion of a methylcopper species to chiral imides permit-
Keywords: asymmetric organocopper additions; 1,3-stereocontrol.
* Corresponding author. Tel.: 1-812-855-6629; fax: 1-812-855-8300;
e-mail: williamd@indiana.edu
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00638-X

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D. R. Williams et al. / Tetrahedron Letters 43 (2002) 3723–3727
Table 1. Double asymmetric induction reactions of N-enoyl-oxazolidinones and organocopper reagent 3a
Major Product
Entry
A
de (yield)
87 (96%)
Imide R-Cu
O
O
O
O
CH3 CH3
OBn
OBn
OBn
O
O
O
N
N
N
1
1
3a
3b
3a
4
Bn
O
CH3 CH3
51 (83%)
99 (96%)
72 (77%)
B
C
5
Bn
O
CH3 CH3
2a
6
Ph
O
O
CH3 CH3
OBn
O
N
D
2b
3a
7
Ph
(a) All reactions were carried out with Yamamoto organocopper reagent in THF at −78°C.
ted more detailed explorations of the effects of preexist-
ing proximate asymmetry in the conjugate acceptor.
per reagent for the 4(S)-phenyl, the 4(S)-benzyl, and
the 4-unsubstituted oxazolidinones of entries A, B and
C of Table 2. While comparable product yields were
obtained in each of these reactions, evidence for good
diastereoselectivity prevailed only in the case of the
4-phenyl auxiliary.13,14
To evaluate the inherent contributions of the individual
elements of chirality, initial reactions examined the
diastereofacial selectivity in the addition of methylcop-
Table 2. Double asymmetric induction from chiral auxiliary and homoallylic methyla
Entry
de (Yield)
Major Product
Substrate
O
O
O
Y
X
O
OSitBuPh2
OSitBuPh2
85% (85%)
47% (86%)
A (R = Ph, X = CH3, Y = H)
B (R = Bn, X = H, Y = CH3)
O
N
O
N
R
R
O
O
O
O
O
O
CH3
CH3
O
O
CH3 CH3
OSitBuPh2
OSitBuPh2
OSitBuPh2
OSitBuPh2
59% (83%)
C
O
O
N
O
O
N
X
X
CH3
CH3
Y
Y
D (R = Ph, X = H, Y = CH3)
E (R = Bn, X = CH3, Y = H)
>97% (84%)
0% (99%)
N
N
R
R
O
O
O
CH3
O
F (R = Ph, X = CH3, Y = H)
G (R = Bn, X = H, Y = CH3)
H (R = iBu, X = H, Y = CH3)
84% (75%)
74% (96%)
74% (96%)
OSitBuPh2
CH3
OSitBuPh2
O
N
O
N
R
R
O
O
O
N
O
CH3 CH3
O
O
N
O
O
N
N
N
85% (78%)
83% (77%)b
I
Ph
Ph
O
O
O
O
O
N
CH3
O
CH3 CH3
67% (87%)
67% (89%)b
J
Ph
Ph
O
O
CH3 CH3
CH3 CH3 CH3
OBn
OBn
O
O
88% (78%)
K
Ph
Ph
(a) Reactions performed with CH3Cu·BF3(MgBr2) in THF warming from −78 to −20°C. (b) (Et2AlCl)2·oxazolidinone complex added to CH3Cu.

D. R. Williams et al. / Tetrahedron Letters 43 (2002) 3723–3727
3725
Surprisingly, the homochiral 4(S)-benzyloxazolidinone
(entry B) led to a reversal of facial selectivity, albeit
with modest diastereocontrol. The presence of chirality
at the homoallylic site in entry C also yielded results of
moderate diastereofacial selectivity.15
Thus, reactions of the 4(R)-phenyl auxiliary of entry D
yielded the 1,3-syn-dimethyl array with greater than
97% diastereoselectivity. Throughout our investiga-
tions, the 4-phenyl-2-oxazolidinone auxiliary was the
dominant contributor for asymmetric induction leading
to the efficient assembly of the 1,3-syn-dimethyl
arrangements in matched cases (entries D, I and K).
Mismatched substrates (entries F and J) exhibited ero-
sion of diastereofacial selectivity. Overall, the technique
was highly effective for acyclic synthesis as illustrated
by formation of the 1,3,5-stereotriad of entry K.
Throughout our studies, methylcopper reagent16 was
prepared via the addition of methylmagnesium bromide
in ether to a suspension of 1 equiv. of CuBr·DMS
complex, followed by 1 equiv. of freshly distilled boron
trifluoride etherate at −78°C. Subsequently, the starting
N-enoyloxazolidinones were added at −78°C in THF
with careful warming to −20°C. The increase in reac-
tion temperature, compared to efforts of Table 1,
reflects the reduced reactivity of the methyl reagent as
compared to related alkyl, alkenyl or allylic species.3i
A rationalization for the role of the preexisting g-
stereogenic site is based upon 1,4-steric arguments (Fig.
1). For example, the matched scenario of entry D
(Table 2) suggests that conformer A would minimize
nonbonded interactions with a staggered butane geome-
try (alkenyl/methyl). As a result, vinylic Ha and Hb
define a plane whereby the remaining acyclic chain
impedes nucleophilic attack to the a-face of the enoyl
unit, enhancing the role of the chiral auxiliary. Con-
former B is a less stable rotamer introducing the gauche
butane interaction of the homoallylic methyl group and
the b-carbon of the enone. In conformer B, the
siloxymethylene of the acyclic chain is projected above
a plane defined by the 1,3-interaction of Ha and the
methyl group.21 In fact, tert-butyldiphenylsilyl ethers
(R=t-C4H9Ph2Si) provided for higher levels of stereo-
control than we recorded in earlier experiments using
the corresponding benzyl ethers.
We and others have postulated that the reactivity of
populations of Lewis acid complexes of the starting
imides may be reflected in the overall observations of
diastereoselectivity for these reactions. Low tempera-
ture NMR studies have indicated that the six-mem-
bered chelation complex of the syn-s-cis oxazolidinone
conformer is formed exclusively upon addition of 2
equiv. of Et2AlCl.17 Monocoordination of a Lewis acid
provides the anti-s-cis conformer which minimizes car-
bonyl dipoles and nonbonded interactions, while other
possibilities are clearly of higher energy.
The results of Table 2 have demonstrated products
which are consistent with nucleophilic addition to the
bis-chelated syn-s-cis enoyl system via anti-facial selec-
tivity with respect to the 4-phenyl substituent. As a test
of this hypothesis, we have examined the reactions of
preformed (Et2AlCl)2/oxazolidinone complexes (entries
I and J) at −78°C. These results were nearly identical to
examples featuring the 4-phenyl auxiliary using
Yamamoto conditions. However, gaps in this simplified
view are evident from modeling, which clearly shows
that the 4-phenyl cannot sterically impede nucleophilic
attack at the b-carbon of the Michael acceptor. Addi-
tionally, growing evidence suggests that the rate-deter-
mining step of 1,4-cuprate addition to enones involves
reductive elimination of a b-cuprio(III) intermediate.18
Thus, unfavorable interactions of the 4-phenyl sub-
stituent and a carbon-bound copper species arising
from the syn four-centered addition of methylcopper
may explain our stereochemical results. These rational-
izations are also incomplete as evidenced by the reversal
of diastereoselectivity found in the corresponding 4-
benzyl examples of Table 2 (compare entries A versus
B; entries D versus E; entries F versus G). The latter
observations cannot be explained by favorable directive
p-complexation effects with the organocopper species in
reactions of a syn-s-cis chelation complex (R=benzyl)
since the analogous isobutyl derivative (entry H) gave
identical results.19,20
We have also investigated the effects of g-methyl substi-
tution for asymmetric conjugate addition in the prepa-
ration of 1,2-dimethyl arrays. In Scheme 1, reactions
provided 1,2-syn- and 1,2-anti-dimethyl arrays with
moderate to good asymmetric induction, offering
promise for adaptation in the stereocontrolled synthesis
of acyclic systems.22
L
X
R
L
X
Hb
CH3
L
Ha
L
Ha
H
O
H
H
O
N
O
N
O
O
CH3
Hb
O
R
H
H
O
O
H
H
H
X = Mg+2
Conformer A
Conformer B
Figure 1. Conformations of g-methyl substitution.
O
O
O
CH3
CH3Cu•BF3(MgBr2)
OR
OR
Xc
OR
OR
Xc
THF,
–78 to –20 °C
74% de (89%)
CH3
CH3
CH3
O
CH3Cu•BF3(MgBr2)
Xc
Xc
THF,
–78 to –20 °C
87% de (83%)
CH3
CH3
An additional element of chirality is introduced with
the incorporation of the homoallylic methyl substituent
in the N-enoyl side chain. This leads to reinforcing and
opposing factors for asymmetric conjugate additions.
Xc = 4(S)-phenyl-1,3-oxazolidin-2-one; R = SitBuPh2
Scheme 1. Preparation of 1,2-dimethyl array.

3726
D. R. Williams et al. / Tetrahedron Letters 43 (2002) 3723–3727
Indeed, subsequent to our experiments,23 Gerwick and
co-workers have effectively utilized this strategy for
anti-1,2-dimethyl stereoselection in the course of total
synthesis of (+)-kalkitoxin, a novel marine toxin.24
Tetrahedron Lett. 1998, 39, 7823; (d) Ghosh, A. K.; Liu,
C. Org. Lett. 2001, 3, 635.
9. For an overview of conformational analyses, see: Hoff-
mann, R. W. Angew. Chem., Int. Ed. 2000, 39, 2054.
10. Hoffmann, R. W. Chem. Rev. 1989, 89, 1841.
11. (a) For a review: Yamamoto, Y. Angew. Chem., Int. Ed.
1986, 25, 947; (b) The optically pure bromides and Grig-
nard reagents leading to 3ab were prepared from
2(R)- and 2(S)-methyl-3-hydroxy-2-methylpropionates
(Aldrich) via reactions with benzyl 2,2,2-trichloroacetimi-
date, LiAlH4 reduction, tosylation and exchange with
LiBr in DMF at 50°C. (D’Antuono, J. Ph.D. Thesis,
Indiana University, 1988; Earley, J. Ph.D. Thesis, Indi-
ana University, 1996).
In conclusion, asymmetric conjugate addition reactions
have been demonstrated for construction of 1,3-syn-
and 1,3-anti-dimethyl arrays on an acyclic framework
utilizing 4-phenyl-1,3-oxazolidin-2-ones as chiral auxil-
iaries. Limitations have been explored, and the concept
has been extended to also provide 1,2-anti- and 1,2-syn-
dimethyl arrangements. The generality of the methodol-
ogy provides an advance for the synthesis of acyclic
compounds via organocopper-mediated addition
processes.
12. For stereochemical assignments of products of Table 1,
transformations leading to individual diastereomers per-
mitted correlations with isomers derived from asymmetric
crotylations using Roush boronate methodology: Roush,
W. R.; Palkowitz, A. D.; Palmer M. A. J. Org. Chem.
1987, 52, 316. See also Refs. 4 and 5.
Acknowledgements
The authors gratefully acknowledge support from the
National Institutes of Health (GM41560 and
GM42897).
1
13. Diastereomeric excesses (% de) are based upon H NMR
(400 MHz) data of crude products, and yields are for
purified materials.
14. The stereoassignments of entries A and B were proven
following separation of the diastereomers, reduction
(LiBH4), acetylation (AcCl; DMAP; CH2Cl2), and silyl
ether cleavage (TBAF) to give the enantiomeric alcohols
i and ii for comparison with the literature: Thijs, L.;
Stokkingreef, E. H. M.; Lemmons, J. M.; Zwanenburg,
B. Tetrahedron 1985, 41, 2949.
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O
CH3
O
CH3
OH
OH
H3C
O
H3C
O
i
ii
15. syn- and anti-Diastereomeric products of entries
C
through H (Table 2) were clearly distinguished by proton
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