Enantioselective, facially selective carbomagnesation of cyclopropenes

Article abstract of DOI:10.1021/ja058101q

Described is the facially selective and enantioselective addition of carbon nucleophiles to prochiral 3-hydroxymethylcyclopropenes. The process creates up to four stereocenters in a tandem addition/capture sequence that combines three simple materials to give complex and diverse products. The asymmetry is induced by the inexpensive and recoverable ligand (S)-N-methylprolinol. The enantioselectivity (90-98% ee with MeMgCl) is high for a range of cyclopropenes and electrophiles. Importantly, the diastereoselectivity is complementary to that obtained by enantioselective cyclopropanation with aryldiazoacetates. High enantioselectivities are obtained only when methoxide is included in the reaction. Evidence is provided that at least two chiral ligands are involved in the enantioselectivity-determining step. Copyright

Full text of DOI:10.1021/ja058101q

Published on Web 04/11/2006
Enantioselective, Facially Selective Carbomagnesation of Cyclopropenes
Xiaozhong Liu and Joseph M. Fox*
Brown Laboratories, Department of Chemistry and Biochemistry, UniVersity of Delaware, Newark, Delaware 19716
Received November 29, 2005; E-mail: jmfox@udel.edu
Scheme 1. Effect of Air on the Enantioselective Carbometalation
The ability to rapidly transform simple materials into complex
molecules is at the core of medicinal research in academia and
industry. Multicomponent transformations1sthose that couple three
or more reagents in a single reaction vesselsare especially
important, and those that can produce single enantiomer compounds
in a regio- and stereoselective manner have broad influence on
combinatorial, high throughput, and traditional syntheses. In the
context of our program to use the unusual reactivity of high-strain
molecules to quickly generate stereochemical complexity and
structural diversity,2 we became attracted to the development of
enantioselective carbometalation/electrophilic capture cascades of
prochiral cyclopropenes 1scompounds that can be prepared easily
from diazocompounds and TMS acetylene.3
The carbometalation of cyclopropenes was first discovered in
1967,4,5 and occurs more readily and with greater generality than
the analogous reactions of unstrained alkenes.6 An impressive body
of work that deals with enantio- and diastereoselective addition
reactions of cyclopropenone ketals has been developed in Naka-
mura’s group.7 We recently demonstrated that a wide range of
Grignard reagents add to chiral 3-hydroxymethylcyclopropenes
under Cu-catalyzed conditions.2a The significance of this work is
strengthened by the emergence of general strategies for obtaining
enantiomerically enriched cyclopropene carboxylic acids.2b,c,8 Con-
current with our carbometalation work, Gevorgyan’s group reported
stereoselective hydro, sila-, and stannastannations of cyclopropenes,9a
followed by more recent and very elegant catalytic enantioselective
hydroborations9b and hydrostannations9c of cyclopropenes. Cyclo-
propanes are important synthetic intermediates,10 and diastereose-
lective addition reactions of cyclopropenes constitute an attractive
alternative to more mainstream routes to nonracemic cyclopro-
panes,11 especially when highly functionalized molecules are
required or if convergency of synthesis is a premium considera-
tion.
a Additional MeMgCl was added to deprotonate 1a and the ligand. bFor
reactions with ligands other than N-methylprolinol, MeOH was included.
c6 equiv of MeMgCl were used.
Table 1. Enantio- and Diastereoselective Cyclopropene
Carbometalations
We began our study by showing that a variety of Grignard
reagents can simply be combined with 1a at room temperature to
give racemic carbometalation products in high yield and excellent
diastereoselectivity. Cyclopropene 1a is sufficiently reactive so that
CuI is not needed to catalyze the addition.12 We then identified
through screening efforts that inexpensive N-methylprolinol can
induce high enantioselectivity for the addition of MeMgCl. Pre-
equilibration of MeMgCl (7 equiv) with the chiral ligand (3 equiv)
in toluene gives a complex that deprotonates and adds to 1a to
give 2 in good yield after aqueous quench (Scheme 1). However,
different enantioselectivities were observed with different bottles
of MeMgCls“old” bottles gave the best results. Further studies
showed that adventitious air has a beneficial effect. Thus, a solution
of MeMgCl from a freshly opened container gave 2 in only 67-
75% ee. However, if that same solution of MeMgCl was first
sparged with air, the product 2 could reproducibly be obtained in
73% yield and 93% ee.
It is well-known that Grignard reagents rapidly reduce oxygen
as shown in eq 1.13a
O2
MeMgCl
9
8 MeOOMgCl MeMgCl8 2 MeOMgCl (1)
We therefore rationalized that the role of the oxygen is to produce
methoxide, and subsequent experiments showed that an equivalent
result could be obtained by replacing air with methanol.13b,c The
optimized protocol is shown in Table 1. Significantly, the introduc-
9
5600
J. AM. CHEM. SOC. 2006, 128, 5600-5601
10.1021/ja058101q CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
high diastereoselectivity. Although the enantioselectivities of those
reactions are moderate at this point (Scheme 2), the ability of
methoxide to improve enantioselectivity is general. Future studies
will further our mechanistic understanding so that we can improve
the enantioselectivity under catalytic conditions and increase the
range of nucleophiles that add to prochiral cyclopropenes with
excellent enantioselectivity.
Figure 1. Complementary enantioselective syntheses of cyclopropanes.
Acknowledgment. This work was supported by NIH Grant
GM068640-01A1 and by P20 RR017716-01 from the NIH COBRE
Program of the NCRR.
Supporting Information Available: Full experimental and char-
acterization details and 1H and 13C NMR spectra; X-ray data for
stereochemical assignments. This material is available free of charge
via the Internet at http://pubs.acs.org.
Figure 2. Nonlinear dependence of product ee on ligand ee.
References
(1) (a) Posner, G. H. Chem. ReV. 1986, 86, 831. (b) Marko, I. E.; Mekhalfia,
A.; Murphy, F.; Bayston, D. J.; Bailey, M.; Janousek, Z.; Dolan, S. Pure
Appl. Chem. 1997, 69, 565.
Scheme 2. Enhancement of Enantioselectivity by MeOH Is
General
(2) (a) Liao, L.-a.; Fox, J. M. J. Am. Chem. Soc. 2002, 124, 14322. (b) Liao,
L.-a.; Zhang, F.; Dmitrenko, O.; Bach, R. D.; Fox, J. M. J. Am. Chem.
Soc. 2004, 126, 4490. (c) Liao, L.-a.; Zhang, F.; Yan, N.; Golen, J.; Fox,
J. M. Tetrahedron 2004, 60, 1803. (d) Pallerla, M. K.; Fox, J. M. Org.
Lett. 2005, 7, 3593.
(3) Preparations of 1 were based on footnote 9a and references therein.
(4) Welch, J. G.; Magid, R. M. J. Am. Chem. Soc. 1967, 89, 5300.
(5) (a) Fox, J. M.; Yan, N. Curr. Org. Chem. 2004, 9, 719. (b) Halton, B.;
Banwell. M. G. In The Chemistry of the Cyclopropyl Group; Patai, S.,
Rappoport, Z., Eds.; Wiley: Chichester, 1987; p 1224. (c) Baird, M. S.
Top. Curr. Chem. 1988, 144, 139. (d) Baird, M. S.; Schmidt, T. In
Carbocyclic Three-Membered Ring Compounds; de Meijere, Ed.; Georg
Thieme Verlag: Stuttgart, 1996; p 114.
tion of electrophiles creates all three stereocenters in high enantio-
selectivity for diverse types of tetrasubstituted cyclopropenes as
shown in Table 1. Interestingly, we observed that the enantio-
selectivities differed slightly (and usually advantageously) when
electrophiles other than proton are used to quench the reaction. We
attribute this to slight kinetic differences in reactivity between the
electrophiles toward the diasteromeric cyclopropylmetal/ligand
adducts.14 Also significant is that the reactions in Table 1 proceed
with excellent diastereoselectivity that is complementary to the
Davies enantioselective cyclopropanation15 (Figure 1). The practical
nature of the method is underscored by the straightforward synthesis
of the cyclopropene starting materials and the use of an inexpensive
chiral ligand [(S)-N-methylprolinol]. (R)-N-Methylprolinol is readily
prepared in one step. Furthermore, the N-methylprolinol can be
recovered in high yield (91%) at the completion of the reaction.
High enantioselectivities for the carbometalation reaction are
obtained when the deprotonated ligand and MeMgCl are used in a
1:1 ratio (as measured after deprotonations) and in 3-fold excess.
Reactions with smaller excess of the ligand/Grignard complex give
products of lower ee. Thus, the reaction proceeds in only 79% ee
when the ligand and Grignard reagent are in 2-fold excess, and
further decreases to 45% ee when the ratio of deprotonated ligand/
MeMgCl/substrate is 1.2:1.2:1. Furthermore, there is a negative
nonlinear dependence16 of ligand ee on the ee of 2, as shown in
Figure 2. Taken together, these observations imply the involvement
of at least two chiral ligands in the enantioselectivity-determining
step. It is plausible that separate ligand-metal complexes serve
both as the nucleophilic delivery agent and as a Lewis acid activator
for the cyclopropene.
(6) Reviews of enantioselective alkene carbometalation: (a) Marek, I. J. Chem.
Soc., Perkin Trans. 1 1999, 535. (b) Hoveyda, A. H.; Morken, J. P. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1263.
(7) Nakamura, M.; Isobe, H.; Nakamura, E. Chem. ReV. 2003, 103, 1295.
(8) Lead references to enantioselective cyclopropenation: (a) Doyle, M. P.;
Protopopova, M.; Mu¨ller, P.; Ene, D.; Shapiro, E. A. J. Am. Chem. Soc.
1994, 116, 8492. (b) Doyle, M. P.; Ene, D. G.; Peterson, C. S.; Lynch, V.
Angew. Chem., Int. Ed. 1999, 38, 700. (c) Mu¨ller, P; Imoga¨ı, H.
Tetrahedron: Asymmetry 1998, 9, 4419. (d) Davies, H. M. L.; Lee, G.
H. Org. Lett. 2004, 6, 1233. (e) Lou, Y.; Horikawa, M.; Kloster, R. A.;
Hawryluk, N. A.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 8916.
(9) (a) Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2002, 124,
11566. (b) Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc.
2003, 125, 7198. (c) Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem.
Soc. 2004, 126, 3688.
(10) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.; Tanko, J.; Hudlicky,
T. Chem. ReV. 1989, 89, 165.
(11) Lead references to the synthesis of nonracemic cyclopropanes: (a) Davies,
H. M. L.; Antoulinakis, E. G. Org. React. 2001, 57, 8. (b) Doyle, M. P.;
Forbes, D. C. Chem. ReV. 1998, 98, 911. (c) Charette, A.; Beauchemin,
A. Org. React. 2001, 58, 33. (d) Methoden der Organischen Chemie
(Houben Weyl); de Meijere, Ed.; Georg Thieme Verlag: Stuttgart, 1996;
Vol E17a.
(12) Cu-catalysis is needed for 1-alkyl-3-hydroxymethylcyclopropenes,2a but
not for 1a. The likely explanation for the lower reactivity of the former
(without Cu) is that alkyl substitution considerably increases the strength
of the cyclopropene CdC bond. See ref 5a.
(13) (a) Walling, C.; Buckler, S. A. J. Am. Chem. Soc. 1955, 77, 6032. For
examples of alkoxide-promoted enantioselective reactions of dialkylzinc
and organolithium reagents, see: (b) Vogl, E. M.; Gro¨ger, G.; Shibasaki,
M. Angew. Chem., Int. Ed. 1999, 38, 1570. (c) Funabashi, K.; Jackmann,
M.; Kanai, M.; Shibasaki, M. Angew. Chem. Int. Ed. 2003, 42, 5489. (d)
Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 445. (e) Trost, B. M.;
Pissot-Soldermann, C.; Chen, I.; Schroeder, G. M. J. Am. Chem. Soc.
2004, 126, 4480.
(14) The adduct from 3-hydroxymethyl-3-phenylcyclopropene gave the lactol
in 98% ee after DMF quench (Table 1). Also observed was <10% of 2
in 50% ee. The low ee for 2 is consistent with enantiomeric enrichment
via kinetic resolution.
(15) Nowlan, D. T., III; Gregg, T. M.; Davies, H. M. L.; Singleton, D. A. J.
Am. Chem. Soc. 2003, 125, 15902.
(16) Blackmond, D. G. Acc. Chem. Res. 2000, 33, 402.
While the studies reported here focus on the additions of
MeMgCl to cyclopropenes, other Grignard reagents also add with
JA058101Q
9
J. AM. CHEM. SOC. VOL. 128, NO. 17, 2006 5601