Modular ligands derived from amino acids for the enantio selective addition of organozinc reagents to aldehydes

Article abstract of DOI:10.1021/jo0349375

A new series of modular chiral ligands that are derived from amino acids were prepared and tested for their ability to catalyze the asymmetric addition of alkylzinc reagents to aromatic and aliphatic aldehydes. The ligands contain a tertiary amine, an amino acid side chain, and a carbamate or amide functional group. One ligand, which was synthesized from Ile, catalyzes the addition of diethylzinc to cyclohexanecarboxaldehyde in 99% ee.

Full text of DOI:10.1021/jo0349375

Mod u la r Liga n d s Der ived fr om Am in o
Acid s for th e En a n tioselective Ad d ition of
Or ga n ozin c Rea gen ts to Ald eh yd es
Meaghan L. Richmond and Christopher T. Seto*
F IGURE 1. General design of ligands.
Department of Chemistry, Brown University,
324 Brook Street, Box H, Providence, Rhode Island 02912
strategy that we have developed recently for screening
the enantiomeric excess of chiral secondary alcohols.4
To gain quick access to a diversity of ligands, a modular
system comprised of simple components is essential.
Utilizing amino acids from the chiral pool allows for the
easy incorporation of chirality into the ligands and opens
the way for a number of straightforward chemical
modifications. Amino acids have been used as the basis
for a variety of catalyst systems,5 and ligands that are
based on proline,6 valine,7 tyrosine,8 tryptophan,9 serine,10
and leucine11 have been reported.
We imposed two important restrictions on the design
of these new modular ligands. First, the components
needed to be simple and readily available in order to
facilitate preparation of a number of different analogues.
Second, the reactions that are employed during their
synthesis must be reliable, and they must be accom-
plished with a reasonable yield. The general structure
of the ligands is illustrated in Figure 1. They are derived
from L-amino acids and incorporate both a tertiary amine
and a carbamate or amide functional group. This class
of ligands mimics the very successful chiral â-amino
alcohol-based ligands that have been developed by Soai
and others.1c We have replaced the alcohol moiety of a
â-amino alcohol with a carbamate or amide N-H
group.12,13 We reasoned that this would be an appropriate
substitution because alcohol and carbamate protons have
similar pKa values.14 Deprotonation of the carbamate
provides, in conjunction with the tertiary amine, a good
christopher_seto@brown.edu
Received J une 30, 2003
Abstr a ct: A new series of modular chiral ligands that are
derived from amino acids were prepared and tested for their
ability to catalyze the asymmetric addition of alkylzinc
reagents to aromatic and aliphatic aldehydes. The ligands
contain a tertiary amine, an amino acid side chain, and a
carbamate or amide functional group. One ligand, which was
synthesized from Ile, catalyzes the addition of diethylzinc
to cyclohexanecarboxaldehyde in 99% ee.
The design of catalysts for the asymmetric addition of
organozinc reagents to aldehydes to give chiral secondary
alcohols has been the focus of intensive research.1 A large
number of catalysts for this reaction have been developed
that rely on either a Lewis acidic or Lewis basic strategy
for catalyzing the reaction.2
We are interested in developing new modular chiral
ligands for this reaction. In the long term, we envision
that these modular ligands could serve as the basis for
synthesizing libraries of catalysts3 for reactions involving
alkylzinc, as well as other organometallic reagents. This
work will then be interfaced with a high-throughput
(1) For comprehensive reviews, see: (a) Noyori, R.; Kitamura, M.
Angew. Chem., Int. Ed. Engl. 1991, 30, 49-69. (b) Soai, K.; Niwa, S.
Chem. Rev. 1992, 92, 833-856. (c) Pu, L.; Yu, H.-B. Chem. Rev. 2001,
101, 757-824.
(4) Abato, P.; Seto, C. T. J . Am. Chem. Soc. 2001, 123, 9206-9207.
(5) For a recent review on amino acids and peptides as catalysts,
see: J arvo, E. R.; Miller, S. J . Tetrahedron 2002, 58, 2481-2495.
(6) (a) Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J . Am. Chem. Soc.
1987, 109, 7111-7115. (b) Yang, X.; Shen, J .; Da, C.; Wang, R.; Choi,
M. C. K.; Yang, L.; Wong, K.-Y. Tetrahedron: Asymmetry 1999, 10,
133-138. (c) Cicchi, S.; Crea, S.; Goti, A.; Brandi, A. Tetrahedron:
Asymmetry 1997, 8, 293-301. (d) List, B. Tetrahedron 2002, 58, 5537-
5590.
(2) For selected reports, see: (a) Oguni, N.; Omi, T. Tetrahedron
Lett. 1984, 25, 2823-2824. (b) Kitamura, M.; Suga, S.; Kawai, K.;
Noyori, R. J . Am. Chem. Soc. 1986, 108, 6071-6072. (c) Fitzpatrick,
K.; Hulst, R.; Kellogg, R. M. Tetrahedron: Asymmetry 1995, 6, 1861-
1864. (d) Kang, J .; Lee, J . W.; Kim, J . I. J . Chem. Soc., Chem. Commun.
1994, 2009-2010. (e) Chelucci, G.; Conti, S.; Falorni, M.; Giacomelli,
G. Tetrahedron 1991, 47, 8251-8258. (f) Asami, M.; Watanabe, H.;
Honda, K.; Inoue, S. Tetrahedron: Asymmetry 1998, 9, 4165-4173. (g)
Schmidt, B.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1991, 30, 99-
101. (h) Mori, M.; Nakai, T. Tetrahedron Lett. 1997, 38, 6233-6236.
(i) Zhang, F.-Y.; Chan, A. S. C. Tetrahedron: Asymmetry 1997, 8, 3651-
3655. (j) Yoshioka, M.; Kawakita, T.; Ohno, M. Tetrahedron Lett. 1989,
30, 1657-1660. (k) Paquette, L. A.; Zhou, R. J . Org. Chem. 1999, 64,
7926-7934. (l) Shi, M.; Sui, W.-S. Tetrahedron: Asymmetry 1999, 10,
3319-3325. (m) Soai, K.; Hirose, Y.; Ohno, Y. Tetrahedron: Asymmetry
1993, 4, 1473-1474.
(3) For selected reports, see: (a) Reetz, M. T. Angew. Chem., Int.
Ed. 2001, 40, 284-310. (b) Huttenloch, O.; Laxman, E.; Waldman, H.
Chem. Eur. J . 2002, 8, 4767-4779. (c) Gilbertson, S. R.; Wang, X.
Tetrahedron 1999, 55, 11609-11618. (d) Burguete, M. I.; Collado, M.;
Garcia-Verdugo, E.; Vicent, M. J .; Luis, S. V.; von Keyserling, N. G.;
Martens, J . Tetrahedron 2003, 59, 1797-1804. (e) J acobsen, E. N.;
Francis, M. B. Angew. Chem., Int. Ed. 1999, 38, 937-941. (f) Chataign-
er, I.; Gennari, C.; Piarulli, U.; Ceccarelli, S. Angew. Chem., Int. Ed.
2000, 39, 916-918. (g) Cole, B. M.; Shimizu, K. D.; Kruger, C. A.;
Harrity, J . P.; Snapper, M. L.; Hoveyda, A. Angew. Chem., Int. Ed.
Engl. 1996, 35, 1668-1671.
(7) Delair, P.; Einhorn, C.; Dinhorn, J .; Luche, J . L. Tetrahedron
1995, 51, 165-172.
(8) Beliczey, J .; Giffels, G.; Kragl, U.; Wandrey, C. Tetrahedron:
Asymmetry 1997, 8, 1529-1530.
(9) (a) Dai, W.-M.; Zhu, H. J .; Hao, X.-J . Tetrahedron: Asymmetry
1995, 6, 1857-1860. (b) Dai, W.-M.; Zhu, H. J .; Hao, X.-J . Tetrahedron:
Asymmetry 2000, 11, 2315-2337.
(10) Sibi, M. P.; Chen, J .-X.; Cook, G. R. Tetrahedron Lett. 1999,
40, 3301-3304.
(11) Kawanami, Y.; Mitsuie, T.; Miki, M.; Sakamoto, T.; Nishitani,
K. Tetrahedron 2000, 56, 175-178.
(12) (a) For a review of phosphonamides and sulfonamides as ligands
for the enantioselective reduction of ketones, see: Zhang, J .; Zhou, H.
B.; Xie, R. G. Curr. Org. Chem. 2002, 6, 865-890. (b) Rhyoo, H. Y.;
Young-Ae, Y.; Park, H.-J .; Chung, Y. K. Tetrahedron Lett. 2001, 42,
5045.
(13) Dangel, B. D.; Polt, R. Org. Lett. 2000, 2, 3003-3006.
(14) Bordwell, F. G.; Zhang, X.-M. J . Org. Chem. 1994, 59, 6456-
6458.
10.1021/jo0349375 CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/20/2003
J . Org. Chem. 2003, 68, 7505-7508
7505

TABLE 1. Ad d ition of Dieth ylzin c to Ben za ld eh yd e
Usin g Liga n d s 5a -g
SCHEME 1. Gen er a l Syn th esis of Am in o Acid
Ba sed Liga n d sa
a
Key: (a) HBTU,15 DIEA, (R1)2NH, DMF, 53-98%; (b) (i) BH3-
THF, (ii) H2N(CH2)2NH2, CH3OH, 23-80%.
binding site for a metal atom such as zinc. The carbamate
group also provides an additional site for diversity within
the ligands. The results presented in this report serve
as a proof of concept for this ligand class and demonstrate
that they can be used to develop enantioselective reac-
tions that proceed with good stereoselectivity.
The general synthesis of the ligands starting from
N-Boc- or N-Cbz-protected amino acids is shown in
Scheme 1.16 The amino acids were coupled to five differ-
ent secondary amines to give the corresponding amides.
Reduction of the amides with BH3-THF17 gave the
desired tertiary amines that were chelated to boron. The
boron was removed with ethylenediamine to give the final
ligands.
We first examined how the structure of the amino acid
side chain affected enantioselectivity for the addition of
Et2Zn to benzaldehyde (Table 1). All of the ligands in this
series (compounds 5a -g) incorporated piperidine as the
tertiary amine component, with a Boc group on the
primary amine. Reactions were performed with 3 equiv
of Et2Zn in hexanes and 10 mol % of the catalyst at 4 °C
for 24 h. Over this period, the benzaldehyde was com-
pletely consumed, and after workup, the product (S)-
(-)-1-phenyl-1-propanol was isolated in satisfactory yield.
Enantioselectivities ranged from 29 to 62% ee, with the
â-branched side chains derived from isoleucine, valine,
and cyclohexylglycine giving the highest ee. The larger
steric bulk of the tert-leucine side chain (entry 7) resulted
in significantly lower enantioselectivity.
a
Absolute configuration assigned by comparison to literature
b
values. Determined by chiral HPLC (Chiralcel OD-H).
TABLE 2. Effect of Ter tia r y Am in e on th e Ad d ition of
Dieth ylzin c to Ben za ld eh yd e
We next investigated how the tertiary amine compo-
nent of the ligands affected stereoselectivity while the
side chain derived from valine was held constant (Table
2). Ligands that contained the six-membered ring of
either morpholine or piperidine gave the highest enan-
tioselectivities, while pyrrolidine and smaller amines
such as dimethylamine were less stereoselective. To
confirm that â-branched side chains were optimal, even
in the presence of the morpholine group, we examined
ligands 6a and 7a -d (Table 3). In this series, the side
chain of isoleucine (entry 1) again gave the highest
enantioselectivity.
With both the tertiary amine and the amino acid side
chain optimized, we next examined the effect of the
(15) HBTU is O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium
hexafluorophosphate.
(16) For a detailed description of the synthesis of ligands 5-8, see
a
the Supporting Information.
Absolute configuration assigned by comparison to literature
b
(17) Roseke, R. W.; Weitl, F. L.; Prasad, K. U.; Thompson, R. M. J .
Org. Chem. 1976, 41, 1260-1261.
values. Determined by chiral HPLC (Chiralcel OD-H).
7506 J . Org. Chem., Vol. 68, No. 19, 2003

SCHEME 2. Syn th esis of Liga n d s 9a -ea
TABLE 3. Op tim a tiza tion of th e Alk yl Sid e Ch a in in th e
Ad d iton of Dieth ylzin c to Ben zla d eh yd e
a
Key: (a) (i) TFA, (ii) R3COX (X ) Cl or F), DIEA, CH2Cl2, 48-
80%.
TABLE 5. Ad d ition of Dieth ylzin c to Ald eh yd es Usin g
Liga n d s 7a a n d 9a
entry
R
ligand
Yield (%)
eea (%)
1
2
3
4
5
6
7
8
9
1-naphthyl
2-naphthyl
trans-cinnamyl
hydrocinnamyl
cyclohexyl
CH3(CH2)4
1-naphthyl
2-naphthyl
7a
7a
7a
7a
7a
7a
9a
9a
9a
9a
9a
9a
70
73
68
72
78
81
79
94
98
74
93
79
53b
70b
64b
81b
99c
83d
64b
76b
58b
72b
99c
74d
a
Absolute configuration assigned by comparison to literature
trans-cinnamyl
hydrocinnamyl
cyclohexyl
b
values. Determined by chiral HPLC (Chiralcel OD-H).
10
11
12
CH3(CH2)4
TABLE 4. Effect of Ca r ba m a te a n d Am id e
F u n tion a lities on th e Ad d ition of Dieth ylzin c to
Ben za ld eh yd e
a
Absolute configuration assigned by comparison to literature
values. Determined by chiral HPLC (Chiralcel OD-H). c Deter-
b
mined by 19F NMR of the (S)-MPTA ester. Determined by chiral
d
HPLC (Chiralcel OD-H) of the corresponding phenyl carbamate.
carbamate or amide functional group on the stereoselec-
tivity of the alkylation reaction. Several carbamates and
amides were synthesized as illustrated in Scheme 2. The
Boc-protecting group on ligand 7a was removed with
TFA, followed by reaction of the resulting primary amine
with the appropriate acid chloride or chloro- or fluoro-
formate to give compounds 9a -e.
Table 4 shows the results of the alkylation reaction
with these ligands. Carbamates 7a (Table 3, entry 1), 8,
9b, and 9c all gave similar stereoselectivity with ee
values that range from 69 to 72%. Interestingly, the
smaller methyl carbamate of 9a consistently gave the
highest stereoselectivity with 80% ee. By contrast, re-
placement of the carbamate functional group with amides
(entries 5 and 6) resulted in a significant decrease in
enantioselectivity.
Finally, we examined the utility of ligands 7a and 9a
for the alkylation of a variety of other aromatic and
aliphatic aldehydes (Table 5). In all of the reactions, the
aldehyde was completely consumed after 24 h. 1- and
2-naphthylaldehyde and trans-cinnamaldehyde gave ee
values that ranged from 53 to 76%. However, the ligands
generally gave higher stereoselectivities with aliphatic
aldehydes. In particular, alkylation of cyclohexanecar-
boxaldehyde using either ligand 7a or 9a yielded (S)-1-
cyclohexyl-1-propanol in 99% ee.
a
Absolute configuration assigned by comparison to literature
In summary, we have developed a new class of modular
ligands that are derived from amino acids for the enan-
b
values. Determined by chiral HPLC (Chiralcel OD-H).
J . Org. Chem, Vol. 68, No. 19, 2003 7507

tioselective addition of diethylzinc to aromatic and ali-
phatic aldehdyes. These ligands can be synthesized in
two to three simple steps from readily available and
inexpensive starting materials. This work paves the way
for the synthesis and evaluation of larger libraries of
ligands that are based upon the same general structure.
supported by the National Aeronautic and Space Ad-
ministration (NASA) through the Rhode Island Space
Grant.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and characterization data, including 1H and 13C NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
Ack n ow led gm en t. We thank Farah Dhun for the
initial investigation of ligands 5a ,d -e. M.L.R. was
J O0349375
7508 J . Org. Chem., Vol. 68, No. 19, 2003