A mutually π-facial selective cyclopropanation of chiral enamides using dirhodium(ll) carbenoids

Article abstract of DOI:10.1021/ol702824s

A mutually π-facial selective cyclopropanation of chiral enamides using dirhodium(ll) carbenoids is described here. This work illustrates the influence of enamide substituents on stereoselectivity and reveals insights into this cyclopropanation.

Full text of DOI:10.1021/ol702824s

ORGANIC
LETTERS
2008
Vol. 10, No. 4
541-544
A Mutually
Cyclopropanation of Chiral Enamides
Using Dirhodium(II) Carbenoids
π-Facial Selective
Ting Lu, Zhenlei Song, and Richard P. Hsung*
DiVision of Pharmaceutical Sciences and Department of Chemistry, Rennebohm Hall,
777 Highland AVenue, UniVersity of Wisconsin, Madison, Wisconsin 53705-2222
rhsung@wisc.edu
Received November 21, 2007
ABSTRACT
A mutually
π-facial selective cyclopropanation of chiral enamides using dirhodium(II) carbenoids is described here. This work illustrates the
influence of enamide substituents on stereoselectivity and reveals insights into this cyclopropanation.
Enamides are useful building blocks in organic synthesis.1
Recent development in metal-catalyzed C-N bond forma-
tions2-5 has elicited a strong interest in employing chiral
enamides in a range of stereoselective synthetic transforma-
tions.6-11 High levels of diastereoselectivity can be attained
from these reactions because of the π-facial bias present in
the preferred conformation8a-c,10a of chiral enamides 1
(Scheme 1). Given that cyclopropanation12 via transition-
(1) For reviews of chemistry of enamides, see: (a) Rappoport, Z. The
Chemistry of Enamines in The Chemistry of Functional Groups; John Wiley
and Sons: New York, 1994. (b) Whitesell, J. K.; Whitesell, M. A. Synthesis
1983, 517. (c) Hickmott, P. W. Tetrahedron 1982, 38, 1975 and 3363.
(2) For reviews, see: (a) Dehli, J. R.; Legros, J.; Bolm, C. Chem.
Commun. 2005, 973. (b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int.
Ed. 2003, 42, 5400. (c) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37,
2046. (d) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc.
Chem. Res. 1998, 31, 805.
(3) For a review on the synthesis of enamides, see: Tracey, M. R.; Hsung,
R. P.; Antoline, J. E.; Kurtz, K. C. M.; Shen, L.; Slafer, B. W.; Zhang, Y.
In Science of Synthesis, Houben-Weyl Methods of Molecular Transforma-
tions; Weinreb, S. M., Ed.; Georg Thieme Verlag KG: Stuttgart, 2005;
Chapter 21.4.
(6) For [4 + 2] cycloadditions, see: (a) Gohier, F.; Bouhadjera, K.; Faye,
D.; Gaulon, C.; Maisonneuve, V.; Dujardin, G.; Dhal, R. Org. Lett. 2007,
9, 211. (b) Crawly, S. L.; Funk, R. L. Org. Lett. 2006, 8, 3995. (c) Tardy,
S.; Arnaud Tatiboue¨t, A.; Rollin, P.; Dujardin, D. Synlett 2006, 1425. (d)
Palasz, A. Org. Biomol. Chem. 2005, 3, 3207. (e) Robiette, R.; Cheboub-
Benchaba, K.; Peeters, D.; Marchand-Brynaert, J. J. Org. Chem. 2003, 68,
9809. (f) Abbiati, G.; Clerici, F.; Gelmi, M. L.; Gambini, A.; Pilati, T. J.
Org. Chem. 2001, 66, 6299.
(7) For [2 + 2] cycloadditions of chiral enamides, see: (a) Hegedus, L.
S.; Bates, R. W.; Soderberg, B. C. J. Am. Chem. Soc. 1991, 113, 923. (b)
For a review, see: Hegedus, L. S. Tetrahedron 1997, 53, 4105. (c) Riches,
A. G.; Wernersbach, L. A.; Hegedus, L. S. J. Org. Chem. 1998, 63, 4691.
For Paterno`-Bu¨chi [2 + 2], see: (d) Bach, T.; Schro¨der, J.; Brandl, T.;
Hecht, J.; Harms, K. Tetrahedron 1998, 54, 4507.
(4) For recent enamide syntheses, see: (a) Chechik-Lankin, H.; Livshin,
S.; Marek, I. Synlett 2005, 2098. (b) Han, C.; Shen, R.; Su, S.; Porco, J.
A., Jr. Org. Lett. 2004, 6, 27. (c) Pan, X.; Cai, Q.; Ma, D. Org. Lett. 2004,
6, 1809. (d) Brice, J. L.; Meerdink, J. E.; Stahl, S. S. Org. Lett. 2004, 6,
1845. (e) Langner, M.; Bolm, C. Angew. Chem., Int. Ed., 2004, 43, 5984.
(f) Dehli, J. R.; Bolm, C. J. Org. Chem. 2004, 69, 8518. (g) Jiang, L.; Job,
G. E.; Klapars, A.; Buchwald, S. L. Org. Lett. 2003, 5, 3667. (h) Shen, R.;
Lin, C. T.; Porco, J. A., Jr. J. Am. Chem. Soc. 2002, 124, 5650.
(5) For a synthesis of Z-enamides, see: Zhang, X.; Zhang, Y.; Huang,
J.; Hsung, R. P.; Kurtz, K. C. M.; Oppenheimer, J.; Petersen, M. E.;
Sagamanova, I. K.; Tracey, M. R. J. Org. Chem. 2006, 71, 4170.
(8) For epoxidations, see: (a) Xiong, H.; Hsung, R. P.; Shen, L.; Hahn,
J. M. Tetrahedron Lett. 2002, 43, 4449. (b) Adam, W.; Bosio, S. G.; Wolff,
B. T. Org. Lett. 2003, 5, 819. (c) Sivaguru, J.; Saito, H.; Poon, T.; Omonuwa,
T.; Franz, R.; Jockusch, S.; Hooper, C.; Inoue, Y.; Adam, W.; Turro, N. J.
Org. Lett. 2005, 7, 2089. (d) Koseki, Y.; Kusano, S.; Ichi, D.; Yoshida, K.;
Nagasaka, T. Tetrahedron 2000, 56, 8855.
(9) For R-metalations, see: (a) Lander, P.; Hegedus, L. S. J. Am. Chem.
Soc. 1994, 116, 8126. For cross-couplings, see: (b) Mulder, J. A.; Kurtz, K.
C. M.; Hsung, R. P.; Coverdale, H. A.; Frederick, M. O.; Shen, L.; Zificsak,
C. A. Org. Lett. 2003, 5, 1547. (c) Naud, S.; Cintrat, J.-C. Synthesis 2003,
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10.1021/ol702824s CCC: $40.75
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Published on Web 01/19/2008

from R-diazo esters poses its own π-facial differentiation,
leading to trans- and cis-amidocyclopropanes 3 via two
possible approaches. Although influence of metals, ligands,
and ester substituents on the trans/cis selectivity has been
reported,13,14 this selectivity has not responded to structural
variations on the olefin in a distinct or consistent manner.13a,14
We examined the impact of enamide substituents on the
π-facial preference of approaching metal carbenoids, and we
report herein a mutually π-facial selective cyclopropanation
of chiral enamides employing dirhodium(II) carbenoids.
Scheme 1. π-Facial Selectivities for Reactions of Chiral
Enamides
The feasibility for the cyclopropanation of chiral enamides
using transition-metal-catalyzed decompositions of R-diazo
esters could be quickly established after screening several
metal catalysts.12-14 As shown in Scheme 2, dirhodium(II)
metal-catalyzed decomposition of R-diazo esters13-17 repre-
sents a powerful method for constructing highly function-
alized cyclopropanes and that such cyclopropanations
employing chiral enamides are rare,18 we investigated the
reaction of 1 with metal carbenoids en route to amido
cyclopropanes 3.19,20 While the π-facial preference in 1 may
be high,10a the reactive electrophilic metal carbenoid derived
Scheme 2. Choice of Metal Carbenoids for the
Cyclopropanationa
(10) For cyclopropanations, see: (a) Song, Z.; Lu, T.; Hsung, R. P.; Al-
Rashid, Z. F.; Ko, C.; Tang, Y. Angew. Chem., Int. Ed. 2007, 46, 4069. (b)
Voigt, J.; Noltemeyer, M.; Reiser, O. Synlett 1997, 202. (c) Akiba, T.;
Tamura, O.; Hashimoto, M.; Kobayashi, Y.; Katoh, T.; Nakatani, K.;
Kamada, M.; Hayakawa, I.; Terashima, S. Tetrahedron 1994, 50, 3905.
(d) Seebach, D.; Stucky, G.; Pfammatter, E. Chem. Ber. 1989, 122, 2377.
(e) Seebach, D.; Stucky, G. Angew. Chem., Int. Ed. 1988, 27, 1351.
(11) For other recent transformations, see: (a) Martin, R.; Cuenca, A.;
Buchwald, S. L. Org. Lett. 2007, 9, 5521. (b) Ko, C.; Hsung, R. P.; Al-
Rashid, Z. F.; Feltenberger, J. B.; Lu, T.; Wei, Y.; Yang, J.; Zificsak, C.
A. Org. Lett. 2007, 9, 4459. (c) Barbazanges, Meyer, C.; Cossy, J. Org.
Lett. 2007, 9, 3245. (d) Kim, H.; Lee, C. J. Am. Chem. Soc. 2006, 128,
6336. (e) Martin, R.; Rivero, M. R. A.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2006, 45, 7079. (f) Huntley, R. J.; Funk, R. L. Org. Lett. 2006, 8,
3403. (g) Padwa, A.; Danca, M. D. Org. Lett. 2002, 4, 715.
(12) For a leading review on cyclopropanations, see: Lebel, H.; Marcoux,
J.-F.; Molinaro, C.; Charette, A. B. Chem. ReV. 2003, 103, 977.
(13) For reviews on cyclopropanations via metal-catalyzed decomposi-
tions of diazo esters, see: (a) Doyle, M. P. Chem. ReV. 1986, 86, 919. (b)
Padwa, A.; Krumpe, K. E. Tetrahedron 1992, 48, 5385. (c) Doyle, M. P.;
Forbe, D. C. Chem. ReV. 1998, 98, 911. (d) Davies, H. M. L.; Autoulinakis,
E. Org. React. 2003, 57, 1. (e) Maas, G. Chem. Soc. ReV. 2004, 33, 183.
(f) Doyle, M. P. J. Org. Chem. 2006, 71, 9253.
(14) Also see: Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis With Diazo Compounds; John Wiley and
Sons, Inc.: New York, 1998; Chapter 4 and references therein.
(15) Calter, M. A. Curr. Org. Chem. 1997, 1, 37.
(16) For asymmetric cyclopropanations using R-diazoesters, see (a) refs
12-14. For some recent examples, see: (b) Kanchiku, S.; Suematsu, H.;
Matsumoto, K.; Uchida, T.; Katsuki, T. Angew. Chem., Int. Ed. 2007, 46,
3889. (c) Chen, Y.; Ruppel, J. V.; Zhang, X. P. J. Am. Chem. Soc. 2007,
129, 12074. (d) Bykowski, D.; Wu, K.; Doyle, P. M. J. Am. Chem. Soc.
2006, 128, 16038. (e) Davies, H. M. L.; Walji, M. A. Org. Lett. 2005, 7,
2941.
(17) For examples of some approaches to diastereoselective cyclopro-
panations using R-diazoesters, see: (a) Doyle, M. P.; Dorow, R. L.; Terpstra,
J. W.; Rodenhouse, R. A. J. Org. Chem. 1985, 50, 1663. (b) Piers, E.;
Maxwell, A. R.; Moss, N. Can. J. Chem. 1985, 63, 555. (c) Doyle, M. P.;
Bagheri, V.; Wandless, T. J.; Harn, N. K.; Brinker, D. A.; Eagle, C. T.;
Loh, K. L. J. Am. Chem. Soc. 1990, 112, 1906. (d) Doyle, M. P.;
Protopopova, M. N.; Brandes, B. D.; Davies, H. M. L.; Huby, N. J. S.;
Whitesell, J. K. Synlett 1993, 151. (e) Henry, K. J.; Fraserreid, B.
Tetrahedron Lett. 1995, 36, 8901. (f) Hoberg, J. O.; Claffey, D. J.
Tetrahedron Lett. 1996, 37, 2533. (g) Timmers, C. M.; Leeuwenburgh, M.
A.; Verheijen, J. C.; vander Marel, G. A.; van Boom, J. H. Tetrahedron:
Asymmetry 1996, 7, 49. (h) Haddad, N.; Galili, N. Tetrahedron: Asymmetry
1997, 8, 3367. (i) Gross, Z.; Galili, N.; Simkhovich, L. Tetrahedron Lett.
1999, 40, 1571.
a dr of a:b is designated for the enamide π-facial selectivity.
1
Ratios were assigned using H and/or 13C NMR.
tetraacetate appeared to be the most effective catalyst.14,21
When using 2 mol % of dirhodium(II) tetraacetate at rt,
1
cyclopropanation of chiral enamide 4 (E/Z g95:5 by H
NMR) proceeded smoothly to give amido cyclopropanes
(18) For examples of using enamides, see: (a) Wenkert, E.; Hudlicky,
T. J. Org. Chem. 1988, 53, 1953. (b) Paulini, K.; Reissig, H.-U. Liebigs
Ann. Chem. 1991, 455. (c) Davies, H. M. L.; Saikali, E.; Young, W. B. J.
Org. Chem. 1991, 56, 5696. (d) Arenare, L.; De Carprariis, P.; Marinozzi,
M.; Natalini, B.; Pellicciari, R. Tetrahedron Lett. 1994, 35, 1425. (e)
Jime´nez, J.; Rife´, J.; Ortun˜o, R. M. Tetrahedron: Asymmetry 1996, 7, 537.
For examples of using enimides, see: (f) Aggarwal, V. K.; Vicente, J.;
Bonnert, R. V. Org. Lett. 2001, 3, 2785. (g) Melby, T.; Hughes, E.; Hansen,
T. Synlett 2007, 2277.
(19) For leading reviews on aminocyclopropanes, see: (a) Gnad, F.;
Reiser, O. Chem. ReV. 2003, 103, 1603. (b) Seebach, D.; Matthews, J. L.
Chem. Commun. 1997, 2015. (c) Gellman, S. H. Acc. Chem. Res. 1998,
31, 173. (d) Burgess, K.; Ho, K. K.; Moyesherman, D. Synlett 1994, 575.
(e) Alami, A.; Calmes, M.; Daunis, J.; Jacquier, R. Bull. Soc. Chim. Fr.
1993, 130, 5.
(20) For recent examples, see: (a) Faler, C. A.; Joullie´, M. M. Org. Lett.
2007, 9, 1987. (b) Zeng, X. Z.; Wei, X. D.; Farina, V.; Napolitano, E.; Xu,
Y. B.; Zhang, L.; Haddad, N.; Yee, N. K.; Grinberg, N.; Shen, S.;
Senanayake, C. H. J. Org. Chem. 2006, 71, 8864. (c) Begis, G.; Sheppard,
T. D.; Cladingboel, D. E.; Motherwell, W. B.; Tocher, D. A. Synthesis 2005,
3186.
(21) The only other metal catalysts used were AgSbF6, CuOTf, and Pd-
(OAc)2, and we did not examine other cyclopropanations conditions known
in the literature (see ref 18). In addition, to elimate extra parameters in this
mechanistic based study, we only examined enamides with the oxazolidinone
or Evans’ auxiliary.
542
Org. Lett., Vol. 10, No. 4, 2008

5a/b22 in 67% with a diastereomer ratio of 92:8 (the dr of
a/b designates π-facial selectivity of enamides) and a trans/
cis ratio of 7:1 in favor of trans-5a. The relative stereo-
chemistry of trans-5a was confirmed by X-ray structure of
its aldehyde derivative (Figure 1A), whereas the cis isomer
and 2), whereas enamides with a bulky cyclohexyl (c-hex)
or i-Pr group led to higher ratios (entries 7 and 9) with Bn
and Ph groups providing a ratio in between (entries 4 and
5). When Râ ) t-Bu, the reaction was actually shut down
(entry 11).
Intriguingly, when using tert-butyl R-diazoacetate, while
there was no change in ratio with Râ ) n-pent (entry 3) and
Ph (entry 6), the trans/cis ratio drastically improved relative
to ethyl R-diazoacetate with Râ ) c-hex and i-Pr (entry 7
versus 8 and entry 9 versus 10, respectively). We did have
to use 4 equiv of tert-butyl R-diazoacetate, and reactions were
relatively slower than those using ethyl R-diazoacetate. The
minor cis isomer was assigned via the X-ray structure of
cis-14a (Figure 1B).
In contrast, R-substituents of enamides appeared to have
no significant impact on the trans/cis selectivity. As shown
in Scheme 3, cyclopropanation of chiral enamide 22 with
Figure 1. X-ray structures of trans- and cis-amidocyclopropanes.
(a) Derived from trans-5a via Dibal-H [H] (see the Supporting
Information).
Scheme 3. Impact of the R-Substituent of Chiral Enamides
was unambiguously assigned later using another cyclopro-
panation product (see cis-14a in Table 1).
Table 1. Cyclopropanations of E-Enamides
enamides:
products: yielda
drb
(a/b) trans/cisb
a:
entry
Râ )
R )
(%)
1
2
3
4
5
6
7
8
9
6: CH2CH2OTBS 12a/b: Et
74
66
g95:5
g95:5
g95:5
g95:5
92:8
g95:5
g95:5
g95:5
g95:5
g95:5
2.5:1
2.5:1
2.5:1
4:1
7:1
7:1
7: n-pent
7: n-pent
8: Bn
13a/b: Et
14a/b: t-Bu
15a/b: Et
5a/b: Et
54c
66
RR ) Me afforded 24 with no trans/cis selectivity, and even
when RR ) Ph as in enamide 23, the selectivity remained
low in the cycloadduct 25. The ratio from the cyclopropa-
nation of 22 also implies that the Evans’ chiral oxazolidinone
ring does not play an important role in the trans/cis
selectivity.23 On the other hand, the selectivity was noticeably
improved if a â-substituent was added. For instance, enamide
26 with just an additional methyl group at the â-position
led to a ratio that is already better than enamide 22 and
comparable to that of enamide 23, while enamide 27 gave a
much improved trans/cis ratio.
4: Ph
67
4: Ph
16a/b: t-Bu
17a/b: Et
18a/b: t-Bu
19a/b: Et
20a/b: t-Bu
21a/b: Et
40c
67
9: c-hex
9: c-hex
10: i-Pr
10: i-Pr
11: t-Bu
8:1
62c
91
g19:1
9:1
g19:1
10
11
78c
n.d.c,d
1
a Isolated yields. b Ratios were assigned using H and/or 13C NMR. c 4
equiv of N2CHCO2-t-Bu was used. d n.d.: not determined.
We proceeded to examine cyclopropanations of a range
of â-substituted E-enamides as shown in Table 1. In all cases,
the cycloaddition exhibits an excellent π-facial selectivity
with respect to the enamide (a/b 92:8 to g 95:5). The trans/
cis selectivity, on the other hand, appeared to be directly
correlated with the size of the â-substituent. Simple un-
branched alkyl groups gave a lower trans/cis ratio (entries 1
(23) The ratio of 1:1 isomer ii-a and ii-a′ (the designation of trans/cis
used in the text is not suitable here) obtained from the cyclopropanation of
chiral enamide i further confirms this point.
(22) See the Supporting Information.
Org. Lett., Vol. 10, No. 4, 2008
543

These collective observations imply that a mutually
π-facial selective cyclopropanation has taken place and that
the â-substituent appears to be solely responsible for the
π-facial preference of the approaching dirhodium(II) car-
benoid. These results can be rationalized using a mechanistic
model based on the one proposed by Doyle.24,25 As shown
in Figure 2, the π-facial selectivity observed with respect to
Scheme 4. Cyclopropanations of Z-Enamides
on the trans/cis selectivity, there was no real predictable
order, and cyclopropanations of these enamides have revealed
a distinct influence of Râ substituents.
To further support this model, we examined Z-enamides
30 and 31 (Z/E g95:5 by 1H NMR) as shown in Scheme 4.
Although the yields are inferior to those from cyclopropa-
nations of E-enamides, the trans/cis ratios again reflect the
same preference for the π-face of the dirhodium(II) carbenoid
that would allow the ethoxy carbonyl group to be trans to
the Râ substituent.
Figure 2. Doyle’s model for the observed π-facial selectivity.
Finally, the observed trans/cis selectivity is likely not a
result of thermodynamic equilibration through an epimer-
ization.26 Based on PM3 calculations using Spartan Model,
trans-5a and cis-5a products show virtually identical energies
with ∆E ) -0.2 kcal mol-1, whereas for 14a, cis-14a is
actually more stable than trans-14a by ∼0.7 kcal mol-1.
We have described herein a dirhodium(II) tetracetate
catalyzed stereoselective cyclopropanation of chiral enamides
for constructing highly functionalized amido cyclopropanes.
This work reveals a distinct influence of enamide â-substit-
uents on the π-facial preference of the approaching dirhod-
ium(II) carbenoids, thereby constituting a mutually π-facial
selective cyclopropanation process. Studies involving syn-
thetic applications as well as examining other enamide
systems are currently underway.
chiral enamides is in accordance with the preferred confor-
mation chiral enamide in which the oxazolidinone ring is
coplanar with the olefin,8,10a thereby allowing the metal
carbene to approach favorably from the bottom face of
enamides.
On the other hand, for the π-facial preference of the
approaching the dirhodium(II) carbenoid, a Markovnikov
addition should take place because of the electrophilicity of
metal carbenoids and would likely occur in an unusually
skewed manner in favoring of the â-carbon. This key
assessment is based on the electronic bias posed by the
nitrogen substitution that places a greater partial negative
charge distribution at the â-carbon of enamides. Such a
skewed approach of the carbenoid would still allow a
potential “second-effect” in which the carbonyl oxygen of
the ester group serves to stabilize the pending carbocation
formation at the R-carbon of the enamide (see the maroon
hash line in Figure 2).
Our model is consistent with the observation that Râ exerts
a much greater influence on the trans/cis selectivity than RR.
Such a skewed approach would render the dirhodium(II)
carbenoid more sensitive to the sterics or structural variations
at the â-position of these chiral enamides. While previous
reports23 documented steric influences of olefinic substituents
Acknowledgment. We thank the NIH-NIGMS (GM066-
055) and UWsMadison for financial support. We also thank
Drs. Vic Young and Ben Kucera (University of Minnesota)
for solving X-ray structures.
Supporting Information Available: Experimental de-
tails, characterization data, X-ray structural analysis, and
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL702824S
(24) Doyle, M. P.; Dorow, R. L.; Buhro, W. E.; Griffin, J. H.; Tamblyn,
W. H.; Trudell, M. L. Organometallics 1984, 3, 44.
(25) Doyle, M. P.; Griffin, J. H.; Bagheri, V.; Dorow, R. L. Organo-
metallics 1984, 3, 53.
(26) Epimerization of either trans-14a or cis-14a employing 0.20-5.0
equiv of t-BuOH/tBuOK at temperatures ranging from rt to 80 °C did not
lead to any observable epimerization but recovered starting material and
some decomposition.
544
Org. Lett., Vol. 10, No. 4, 2008