Catalytic asymmetric addition of dialkylzinc reagents to α-aldiminoesters

Article abstract of DOI:10.1021/ol0602093

The first catalytic, enantioselective addition of organozinc reagents to α-aldiminoesters is described. The use of a Lewis acid/Lewis base containing bifunctional catalyst preorganizes both reactive substrates to promote enantioselective addition over the

Full text of DOI:10.1021/ol0602093

ORGANIC
LETTERS
2006
Vol. 8, No. 13
2659-2662
Catalytic Asymmetric Addition of
Dialkylzinc Reagents to
r
-Aldiminoesters
Sandeep Basra, Michael W. Fennie, and Marisa C. Kozlowski*
Department of Chemistry, Roy and Diana Vagelos Laboratories, UniVersity of
PennsylVania, Philadelphia, PennsylVania 19104
marisa@sas.upenn.edu
Received January 24, 2006
ABSTRACT
The first catalytic, enantioselective addition of organozinc reagents to
r-aldiminoesters is described. The use of a Lewis acid/Lewis base
containing bifunctional catalyst preorganizes both reactive substrates to promote enantioselective addition over the racemic background
reaction and alternative addition modes. Alcohol additives were found to enhance the enantioselection. The addition product was also found
to cyclize with remaining substrate to provide imidazolidines.
Optically active natural and non-natural amino acids are
versatile building blocks for a range of biologically important
molecules.1 Enantioselective addition to R-iminoesters as a
route to the synthesis of important chiral amino acids has
been achieved2 via the imino-ene reaction,3 Friedel-Crafts
reaction,4 enol ether addition,5 and enolizable ketone6 and
aldehyde7 addition.
congeners of R-amino acids, has not been reported. While
related diastereomeric processes have been forthcoming,8 the
enantioselective processes have proven to be more difficult.
To date, only enantioselective additions of stoichiometric
allyl zinc reagents have appeared.9
On the other hand, the corresponding aldimine additions
have met with greater success.10 R-Iminoesters are signifi-
cantly more challenging due to their higher reactivity and
the presence of a bicoordinate metal binding site (Figure 1);
In comparison, the enantioselective addition of unstabilized
anions to R-iminoesters, which provides entry to key
(1) For selected reviews on R-amino acid synthesis, see: (a) Williams,
R. M. Synthesis of Optically ActiVe R-Amino Acids; Pergamon: Oxford,
1989. (b) Hanessian, S.; McNaughton-Smith, G.; Lombardt, H.-G.; Lubell,
W. D. Tetrahedron 1997, 53, 12789. (c) Kotha, S. Acc. Chem. Res. 2003,
36, 342. (d) Maruoka, K.; Ooi, T. Chem. ReV. 2003, 103, 3013.
(2) For reviews, see: (a) Taggi, A. E.; Hafez, A. M.; Lectka, T. Acc.
Chem. Res. 2003, 36, 10. (b) Co´rdova, A. Acc. Chem. Res. 2004, 37, 102
and references therein.
(3) (a) Drury, W. J., III; Ferraris, D.; Cox, C.; Young, B.; Lectka, T. J.
Am. Chem. Soc. 1998, 120, 11006. (b) Yao, S.; Fang, X.; Jørgensen, K. A.
J. Chem. Soc., Chem. Commun. 1998, 2547. (c) Elder, A. M.; Rich, D. H.
Org. Lett. 1999, 1, 1443.
(4) (a) Sabby, S.; Fang, X.; Gathergood, N.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2000, 39, 4114. (b) Saaby, S.; Bayon, P.; Aburel, P. S.;
Jørgensen, K. A. J. Org. Chem. 2002, 67, 4352.
(5) (a) Hagiwara, E.; Fujii, A.; Sodeoka, M. J. Am. Chem. Soc. 1998,
120, 2474. (b) Kobayashi, S.; Matsubara, R.; Kitagawa, H. Org. Lett. 2002,
4, 143. (c) Saaby, S.; Nakama, K.; Lie, M. A.; Hazell, R. G.; Jorgensen, K.
A. Chem.sEur. J. 2003, 9, 6145.
(6) (a) Juhl, K.; Gathergood, N.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2001, 40, 2995. (b) Co´rdova, A.; Notz, W.; Zhong, G.; Betancort, J.
M.; Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1844.
(7) Chowdari, N. S.; Suri, J. T.; Barbas, C. F., III. Org. Lett. 2004, 6,
2507.
(8) (a) Bertrand, M. P.; Feray, L.; Nouguier, R.; Perfetti, P. Synlett 1999,
1148. (b) Bertrand, M. P.; Coantic, S.; Feray, L.; Nouguier, R.; Perfetti, P.
Tetrahedron 2002, 56, 3951. (c) Singh, N.; Anand, R. D.; Trehan, S.
Tetrahedron Lett. 2004, 45, 2911. (d) Wipf, P.; Stephenson, C. R. J. Org.
Lett. 2003, 5, 2449.
(9) Hanessian, S.; Yang, R.-Y. Tetrahedron Lett. 1996, 37, 8997.
(10) (a) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J.
Am. Chem. Soc. 2001, 123, 984. (b) Porter, J. R.; Traverse, J. F.; Hoveyda,
A. H.; Snapper, M. L. J. Am. Chem. Soc. 2001, 123, 10409. (c) Wei, C.;
Li, C.-J. J. Am. Chem. Soc. 2002, 124, 5638. (d) Fujihara, H.; Nagai, K.;
Tomioka, K. J. Am. Chem. Soc. 2000, 122, 12055. (e) Dahmen, S.; Brase,
S. J. Am. Chem. Soc. 2002, 123, 5940. (f) Boezio, A. A.; Charette, A. B.
J. Am. Chem. Soc. 2003, 125, 1692.
10.1021/ol0602093 CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/02/2006

have resulted in 1,4-additions, whereas Zn-mediated additions
lead to mainly 1,2-additions (Figure 3).12
Upon screening aldiminoester substrates (Figure 3, R )
H) against metal adducts of bifunctional salens 1-4, we
found that PMP (para-methoxyphenyl)-protected aldimi-
noester 6 gave only 1,2-addition (eq 1) and was chosen for
further exploration. Pure 6 can be synthesized on a large
scale by condensation of ethylglyoxylate and para-meth-
oxyaniline and subsequent distillation.13
Figure 1. Metal binding to aldimines versus R-iminoesters.
both factors lead to substantial racemic background pro-
cesses.
We have previously reported the enantioselective addition
of Et2Zn to R-ketoesters using salen-derived independent
Lewis acid/Lewis base bifunctional catalysts.11 In these
systems, the electrophile coordinates to the Lewis acid, while
the electronically decoupled Lewis base activates the nu-
cleophile. These independent moieties facilitate enantiose-
lective addition (Figure 2). Here we report the first enantio-
Importantly, treating 6 with Et2Zn at -40 °C in the
absence of catalyst led to the formation of significant racemic
addition product within 2 h. Thus, these substrates are much
more challenging than most aldehydes (no background
reaction) and parallel the reactivity encountered with the
R-ketoesters.11 Thus, an effective catalyst for this process
needs to (1) control the enantioselective addition of Et2Zn
to 6, and (2) be more rapid than the background reaction.
Conventional ligands used in the enantioselective addition
of Et2Zn to aldehydes, such as (-)-MIB,14 are not effective,
providing little product and no selectivity.
Figure 2. Proposed transition state.
selective addition of organozinc reagents to R-iminoesters
using these bifunctional catalysts.
Our initial experiments showed that the addition of Et2Zn
to R-ketiminoesters (Figure 3, R * H) proceeded with poor
Gratifyingly, a screen with the bifunctional salen cata-
lysts11,15 revealed that regio- and enantioselective additions
to this problematic substrate class are viable. A number of
metals were investigated using the (R,R)-piperidine ligand
(1) (Table 1, entries 1-4); Ti(Oi-Pr)2 was clearly superior
and was used in the screening of other salens (2-5) (entries
5-8). Importantly, the ligand with a t-Bu group (5) exhibited
practically no stereochemical control (Table 1, entry 8),
confirming the need for a Lewis base moiety. Overall, the
Figure 3. Regioselection and chemoselection in additions of
organometallic reagents to R-iminoesters.
(12) (a) Chiev, K. P.; Roland, S.; Mangeney, P. Tetrahedron: Asymmetry
2002, 13, 2205. (b) Yamamoto, Y.; Ito, W. Tetrahedron 1988, 44, 5415
and references therein. For Et2AlCl additions, see: (c) Niwa, Y.; Shimizu,
M. J. Am. Chem. Soc. 2003, 125, 3720. (d) Shimizu, M.; Niwa, Y.
Tetrahedron Lett. 2001, 42, 2829.
regioselectivity, yielding 1,2-addition, 1,4-addition, and
reduction. A survey of prior work revealed similar regiose-
lectivity problems. Mg-, Al-, and Cu-mediated alkylations
(13) See Supporting Information and the following: Manhas, M. S.;
Ghosh, M.; Bose, A. K. J. Org. Chem. 1990, 55, 575.
(14) Nugent, W. A. J. Chem. Soc., Chem. Commun. 1999, 1369.
(15) DiMauro, E. F.; Mamai, A.; Kozlowski, M. C. Organometallics
2003, 22, 850.
(11) (a) DiMauro, E. F.; Kozlowski, M. C. Org. Lett. 2002, 4, 3781. (b)
DiMauro, E. F.; Kozlowski, M. C. J. Am. Chem. Soc. 2002, 124, 12668.
(c) Fennie, M. W.; DiMauro, E. F.; O’Brien, E. M.; Annamalai, V.;
Kozlowski, M. C. Tetrahedron 2005, 61, 6249.
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Org. Lett., Vol. 8, No. 13, 2006

Table 1. Addition of Diethylzinc to R-Aldiminoester 6 (eq 1)
Using Metal Complexes of Salens 1-5
Table 2. Effect of Additives on the Addition of Diethylzinc to
R-Aldiminoester 6 (eq 2)
entry
ligand
metal
ee (%)a
1
2
3
4
5
6
7
8
1
1
1
1
2
3
4
5
Zn
Mg
28 (S)
57 (S)
22 (S)
62 (S)
36 (S)
40 (S)
40 (S)
4 (S)
Al(Oi-Pr)
Ti(Oi-Pr)2
Ti(Oi-Pr)2
Ti(Oi-Pr)2
Ti(Oi-Pr)2
Ti(Oi-Pr)2
a Determined by HPLC (see Supporting Information).
Ti(Oi-Pr)2-(R,R)-piperidine salen catalyst provided the best
metal-ligand combination (Table 1, entry 4).
To improve the reaction, the effect of temperature on
enantioselectivity (eq 1) was examined. The optimal tem-
perature was -40 °C as a loss of selectivity was observed
at both higher (-10 °C) and lower (-78 °C) temperatures.
Upon increasing catalyst loading from 10 to 20 or 100 mol
%, no selectivity improvements were observed. This key
experiment indicates that none of the inherent selectivity (at
100 mol %) from the catalyst is lost under turnover
conditions (10 mol %). A catalyst loading of 10 mol % at
-40 °C was used in all further studies.
Additives have been reported to modulate catalytic activity
and increase enantioselectivity in many transformations.16
For the related case of Et2Zn addition to R-ketoesters, we
have shown that the use of excess Ti(Oi-Pr)4 leads to
enhancement of enantioselectivity,11c and Hoveyda and co-
workers have shown the benefit of H2NPO(OEt)2 addition.17
Unfortunately, with R-aldiminoesters, the addition of either
excess Ti(Oi-Pr)4 (Table 2, entry 2) or H2NPO(OEt)2 (Table
2, entry 3) resulted in reduced enantioselection. A range of
other additives, including acids (Table 2, entry 4), amines
(Table 2, entries 6-8), phenols (Table 2, entries 9-11), and
alcohols (Table 2, entries 12-22), was then explored.
The temperature at which the additive was introduced
proved crucial. In the case of CF3CH2OH, high enantiose-
lectivities were achieved on addition at -40 °C (Table 2,
entry 13). If the additive was introduced at room temperature,
however, the enantioselectivity was drastically reduced to
7% ee. Apparently, the selective catalyst is not an equilibrated
species, but rather a kinetic adduct.
a Determined by HPLC (see Supporting Information).
mismatched cases were observed with certain chiral alcohols
(Table 2, entries 21 and 22). Apparently, a chiral alcohol
with a relatively small aromatic substituent, as in (R)-
trifluoromethyl benzyl alcohol, optimizes the stereochemical
environment.
Once the selectivity screening was completed, the scope
and yields were examined using the best catalyst combina-
tion: 10 mol % of Ti(Oi-Pr)2-(R,R)-piperidine salen at -40
°C with alcohols having a pKa between 12 and 14 (Table
3). Upon purification of the 1,2-addition product, a dimer
was also observed that likely arises from an intermolecular
reaction of the initially formed amide anion with the starting
material (Scheme 1). The cis stereochemistry of 8 was
established by crystallographic analysis. The selectivity of
8 is comparable to that of 7, suggesting that 8 is formed
from 7. Even so, monomeric adduct 7 was the predominant
adduct and could be obtained with moderate to good yield
and up to 80% ee (Table 3).
Of all the additives investigated, alcohols with a pKa range
of 12-1418 were superior (Table 2, entries 12 and 13) and
were screened further (Table 2, entries 15-22). Matched and
(16) For a review on additives in asymmetric catalysis, see: Vogl, E.
M.; Groger, H.; Shibasaki, M. Angew. Chem., Int. Ed. 1999, 38, 1570.
(17) Wieland, L. C.; Deng, H.; Snapper, M. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2005, 127, 15453.
(18) Additives of Table 3 entries 2-6: (a) Lide, D. R. Dissociation
Constants of Organic Acids and Bases. In Handbook of Chemistry and
Physics, 85th ed.; CRC Press: Boca Raton, FL, 2004-2005; Vol. 1. (b)
AdVanced Chemistry DeVelopment (ACD/Labs) Software, version 8.14
for Solaris; ACD/labs, 1994-2005; CA Registry File (Scifinder Scholar),
CAS RN 75-89-8, 100-51-6, 98-85-1, 91-01-0 (accessed December
2005).
Modification of the R-iminoester substrate by changing
from the ethyl ester to methyl ester had very little effect on
Org. Lett., Vol. 8, No. 13, 2006
2661

Table 3. Addition of Diethylzinc to R-Iminoester (eq 3): Substrate Scope
a Determined by HPLC (see Supporting Information). b Isolated yields. c Ti(Oi-Pr)2-(S,S)-piperidine salen used. d 0.25 equiv of additive used.
the selectivity (Table 3, entries 9-11). It is interesting to
note that the enantioselectivities for the methyl ester do not
vary on addition of additive. When the N-PMP was replaced
with N-diphenylmethyl, none of the cyclization product 8
was obtained. However, poorer enantioselectivities were
observed (Table 3, entries 12-14), although use of additive
did provide an increase in selectivity even in this system.
The first enantioselective addition of Et2Zn to R-aldimi-
noesters has been reported. Independent bifunctional catalysts
have been shown to facilitate this addition with moderate
selectivity. The use of additives has also been shown to
further enhance enantioselectivity under specific conditions.
Alcohols with a pKa of 12-14 were found to be most
effective. A cyclized product was also obtained with
complete diastereocontrol. Further results with organozinc
reagents lacking â-hydrogens and with R-ketiminoesters are
promising and will be reported in due course.
Scheme 1. Proposed Mechanism for the Formation of 8
Acknowledgment. We are grateful to the NIH (GM
59945) and the GAANN program (M.W.F. fellowship) for
financial support. We thank Carla Taylor for the synthesis
of the substrate used in Table 3 (entries 12-14).
Supporting Information Available: Experimental details
and characterization of all new compounds are provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0602093
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Org. Lett., Vol. 8, No. 13, 2006