Solid-phase synthesis of chiral N-acylethylenediamines and their use as ligands for the asymmetric addition of alkylzinc and alkenylzinc reagents to aldehydes

Article abstract of DOI:10.1021/jo049160+

A solid-phase procedure has been developed for the synthesis of chiral N-acylethylenediamine ligands. The ligands are obtained in good yield and purity, without the need for chromatography or other purification methods. Several new and previously reported ligands were prepared using this procedure. These compounds were examined as catalysts for the enantioselective addition of alkylzinc reagents to aldehydes. In all cases, the crude ligands from the solid-phase syntheses catalyzed the reactions with similar yields and stereoselectivities when compared to reactions using ligands that had been purified by standard methods. Preliminary studies were also performed with ligands 3a and 3f as catalysts for the addition of alkenylzinc reagents to aldehydes to give chiral allylic alcohols. Ligand 3f was found to catalyze this addition reaction in up to 76% ee.

Full text of DOI:10.1021/jo049160+

Solid -P h a se Syn th esis of Ch ir a l N-Acyleth ylen ed ia m in es a n d Th eir
Use a s Liga n d s for th e Asym m etr ic Ad d ition of Alk ylzin c a n d
Alk en ylzin c Rea gen ts to Ald eh yd es
Christopher M. Sprout,† Meaghan L. Richmond,† and Christopher T. Seto*
Department of Chemistry, Brown University, 324 Brook Street Box H, Providence, Rhode Island 02912
christopher_seto@brown.edu
Received May 18, 2004
A solid-phase procedure has been developed for the synthesis of chiral N-acylethylenediamine
ligands. The ligands are obtained in good yield and purity, without the need for chromatography
or other purification methods. Several new and previously reported ligands were prepared using
this procedure. These compounds were examined as catalysts for the enantioselective addition of
alkylzinc reagents to aldehydes. In all cases, the crude ligands from the solid-phase syntheses
catalyzed the reactions with similar yields and stereoselectivities when compared to reactions using
ligands that had been purified by standard methods. Preliminary studies were also performed with
ligands 3a and 3f as catalysts for the addition of alkenylzinc reagents to aldehydes to give chiral
allylic alcohols. Ligand 3f was found to catalyze this addition reaction in up to 76% ee.
In tr od u ction
Combinatorial chemistry is becoming an important tool
in the development of new catalysts for asymmetric
reactions.1,2 The methods of combinatorial chemistry have
the potential to increase the efficiency by which success-
ful chiral catalysts are discovered. However, to realize
this goal several challenges must be met. First, ligands
must be designed that can be assembled in a modular
fashion. Second, the ligands need to be effective catalysts
for a synthetically useful transformation. Third, an
economical synthesis of the ligands has to be developed
that allows for easy incorporation of diversity elements
into the modular structure and that requires little or no
purification of the final products. Finally, a high-
throughput method must be available to evaluate the
stereoselectivity of the catalyst library.
F IGURE 1. Reactions catalyzed by 10 mol % of ligands 1 and
2.
As part of our efforts to develop and screen libraries
of enantioselective catalysts, we have recently reported
two different types of modular ligands that catalyze the
asymmetric addition of dialkylzinc reagents to aldehydes
(Figure 1).3,4 Both types of ligands incorporate an N-
acylethylenediamine subunit that, upon deprotonation,
provides a binding site for zinc. Ligand 1 includes a chiral
center on an attached amino acid and was found to
promote the reaction between Me2Zn or Et2Zn and a
variety of aromatic aldehydes with up to 90% ee. Ligand
2, which incorporates a chiral center on the ethylenedi-
amine bridge, catalyzes the addition of Et2Zn to cyclo-
hexane carboxaldehyde in 99% ee. These and other
related ligands were prepared using standard solution-
phase methods. In some cases, we found that it was
necessary to recrystallize the ligand in order to obtain
the highest % ee in the catalyzed reactions. For both
types of ligands, amino acids provided the initial source
of chirality.
† These two authors contributed equally to this work.
(1) For selected reports, see: (a) Reetz, M. T. Angew. Chem., Int.
Ed. 2001, 40, 284. (b) Huttenloch, O.; Laxman, E.; Waldman, H. Chem.
Eur. J . 2002, 8, 4767. (c) Gilbertson, S. R.; Wang, X. Tetrahedron 1999,
55, 11609. (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. (e) Francis, M. B.; J acobsen, E. N. Angew. Chem., Int. Ed.
1999, 38, 937. (f) Chataigner, I.; Gennari, C.; Piarulli, U.; Ceccarelli,
S. Angew. Chem., Int. Ed. 2000, 39, 916. (g) Cole, B. M.; Shimizu, K.
D.; Kruger, C. A.; Harrity, J . P.; Snapper, M. L.; Hoveyda, A. Angew.
Chem., Int. Ed. 1996, 35, 1668. (h) Krattiger, P.; McCarthy, C.; Pfaltz,
A.; Wennemers, H. Angew. Chem., Int. Ed. 2003, 42, 1722. (i) Gennari,
C.; Piarulli, U. Chem. Rev. 2003, 103, 3071.
We have also developed a high-throughput method for
determining the enantiomeric excess of chiral alcohols5
(2) (a) Murphy, K. E.; Hoveyda, A. H. J . Am. Chem. Soc. 2003, 125,
4690. (b) J osephsohn, N. S.; Snapper, M. L.; Hoveyda, A. H. J . Am.
Chem. Soc. 2003, 125, 4018. (c) Hird, A. W.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2003, 42, 1276.
(4) Sprout, C. M.; Seto, C. T. J . Org. Chem. 2003, 68, 7788.
(5) Abato, P.; Seto, C. T. J . Am. Chem. Soc. 2001, 123, 9206.
(3) Richmond, M. L.; Seto, C. T. J . Org. Chem. 2003, 68, 7505.
10.1021/jo049160+ CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/28/2004
6666
J . Org. Chem. 2004, 69, 6666-6673

Solid-Phase Synthesis of Chiral N-Acylethylenediamines
SCHEME 1. Solid -P h a se Syn th esis of N-Acyleth ylen ed ia m in e Liga n d sa
a
Reagents: (a) HBTU, DIEA, N-Boc-protected amino acid, DMF, double coupling; (b) diamines 6-9, CH2Cl2 or CH3CN; (c) isocyanate
resin, CH2Cl2; (d) 25% TFA, CH2Cl2; (e) 10% DIEA, CH2Cl2; (f) R4COCl, 10% DIEA, CH2Cl2.
and allylic acetates.6 This technique is called EMDee for
an enzymatic method for determining enantiomeric
excess. In this method, the products from a catalytic
asymmetric reaction that are of unknown stereochemical
composition are analyzed using an enzyme. The enzyme
stereospecifically recognizes and processes only one of the
two possible enantiomers in the sample. As a result, the
rate of the enzyme-catalyzed reaction can be used to
determine the % ee of the sample. This method and a
variety of other methods that have been reported in the
literature7,8 provide useful tools for screening libraries
of asymmetric catalysts.
species shown in eq 1 is reasonable, it is only one of
several possible chelate structures.
Resu lts a n d Discu ssion
The solid-phase protocol that we have developed for
the synthesis of the ligands is shown in Scheme 1. It
begins with coupling of a Boc-protected amino acid to an
oxime-functionalized resin to give intermediate 5.13 To
optimize and quantitate the yield of this step, we coupled
Boc-Val-OH to the oxime resin under a variety of condi-
tions and then cleaved the amino acid from the solid
support using methanol and DBU to give Boc-Val-OMe.14
Single or double coupling reactions using DIC, DMAP,
HOBt, and Boc-Val-OH gave unsatisfactory yields. By
contrast, a double coupling procedure using HBTU
provided Boc-Val-OMe in 72% yield. This coupling pro-
cedure was used in subsequent syntheses of the ligands.
In our current work, we are focusing on two of the
remaining challenges in the development of such librar-
ies. The first challenge is the design of an efficient
synthesis that can be used to generate a large number
of ligands in a parallel fashion and that does not require
chromatographic purification of the final products. It is
equally important to broaden the synthetic utility of the
ligands by examining new reactions in which they
function as enantioselective catalysts. To accomplish
these goals, we have developed a solid-phase synthesis
of the N-acylethylenediamine-based ligands and exam-
ined the crude ligands from this synthesis as catalysts
for the enantioselective addition of alkylzinc reagents to
aldehydes.9,10 In all cases, we find that the crude ligands
give similar yields and stereoselectivities when compared
to those of ligands that have been purified by chroma-
tography or recrystallization. We have also examined two
of the ligands as enantioselective catalysts for the reac-
tion between alkenylzinc reagents, generated via the
Oppolzer method,11 and aldehydes to yield chiral allylic
alcohols. Finally, we have used the solid-phase protocol
to synthesize ligands with the general structure 3 (eq 1)
that are hybrids of ligands 1 and 2.12 These compounds
(6) Onaran, M. B.; Seto, C. T. J . Org. Chem. 2003, 68, 8136.
(7) For reviews, see ref 1a and the following: Reetz, M. T. Angew.
Chem., Int. Ed. 2002, 41, 1335.
(8) For selected reports, see: (a) Guo, J .; Wu, J .; Siuzdak, G.; Finn,
M. G. Angew. Chem., Int. Ed. 1999, 38, 1755. (b) Korbel, G. A.; Lalic,
G.; Shair, M. D. J . Am. Chem. Soc. 2001, 123, 361. (c) Reetz, M. T.;
Kuhling, K. M.; Deege, A.; Hinrichs, H.; Belder, D. Angew. Chem., Int.
Ed. 2000, 39, 3891. (d) Ding, K.; Ishii, A.; Mikami, K. Angew. Chem.,
Int. Ed. 1999, 38, 497. (e) Reetz, M. T.; Becker, M. H.; Kuhling, K. M.;
Holzwarth, A. Angew. Chem., Int. Ed. 1998, 37, 2647. (f) Reetz, M. T.;
Zonta, A.; Schimossek, K.; Liebeton, K.; J aeger, K.-E. Angew. Chem.,
Int. Ed. 1997, 36, 2830. (g) Reetz, M. T.; Becker, M. H.; Klein, H.-W.;
Stockigt, D. Angew. Chem., Int. Ed. 1999, 38, 1758. (h) Taran, F.;
Gauchet, C.; Mohar, B.; Meunier, S.; Valleix, A.; Renard, P. Y.;
Creminon, C.; Grassi, J .; Wagner, A.; Mioskowski, C. Angew. Chem.,
Int. Ed. 2002, 41, 124.
(9) For reviews, see: (a) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101,
757. (b) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833. (c) Soai, K.;
Shibata, T. Comprehensive Asymmetric Catalysis; J acobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Berlin, 1999; Vol. 2,
pp 911-922. (d) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl.
1991, 30, 49.
(10) For selected reports, see: (a) Yoshioka, M.; Kawakita, T.; Ohno,
M. Tetrahedron Lett. 1989, 30, 1657. (b) Lutz, C.; Graf, C.-D.; Knochel,
P. Tetrahedron 1998, 54, 10317. (c) Balsells, J .; Walsh, P. J . J . Am.
Chem. Soc. 2000, 122, 3250. (d) Schmidt, B.; Seebach, D. Angew. Chem.,
Int. Ed. 1991, 30, 99. (e) Wipf, P.; Wang, X. Org. Lett. 2002, 4, 1197.
(f) Ko, D.-H.; Kim, K. H.; Ha, D.-C. Org. Lett. 2002, 4, 3759. (g) Nugent,
W. A. Org. Lett. 2002, 4, 2133. (h) Liu, D.-X.; Zhang, L.-C.; Wang, Q.;
Da, C.-S.; Xin, Z.-Q.; Wang, R.; Choi, M. C. K.; Chan, A. S. C. Org.
Lett. 2001, 3, 2733. (i) Dahmen, S.; Brase, S. J . Chem. Soc., Chem.
Commun. 2002, 26. (j) Schinneri, M.; Seitz, M.; Kaiser, A.; Reiser, O.
Org. Lett. 2001, 3, 4259. (k) Vidal-Ferran, A.; Bampos, N.; Moyano,
A.; Pericas, M. A.; Riera, A.; Sanders, J . K. M. J . Org. Chem. 1998,
63, 6309. (l) Brouwer, A. J .; Linden, H. J .; Liskamp, R. M. J . J . Org.
Chem. 2000, 65, 1750.
(11) (a) Oppolzer, W.; Radinov, R. N. Helv. Chim. Acta 1992, 75,
170. (b) Oppolzer, W.; Radinov, R. N. J . Am. Chem. Soc. 1993, 115,
1593. (c) Oppolzer, W.; Radinov, R. N.; El-Sayed, E. J . Org. Chem. 2001,
66, 4766. (d) Oppolzer, W.; Radinov, R. N. Tetrahedron Lett. 1988, 29,
5645. (e) Oppolzer, W.; Radinov, R. N. Tetrahedron Lett. 1991, 32, 5777.
(12) This ligand architecture is related to the wide variety of ligands
that have been developed by Hoveyda and Snapper. For recent
examples, see ref 2.
incorporate stereochemical elements on both the ethyl-
enediamine bridge and on an attached amino acid. They
have four potential diversity elements (R1-R4) that each
can be easily modified in order to investigate their
influence on the stereoselectivity of the catalyzed reac-
tions. In analogy with previously reported ligands, we
expect that compounds such as 3 will be deprotonated
by alkylzinc reagents to give a zinc chelate as the
catalytically active species. Although the zinc chelate
(13) (a) DeGrado, W. F.; Kaiser, E. T. J . Org. Chem. 1980, 45, 1295.
(b) DeGrado, W. F.; Kaiser, E. T. J . Org. Chem. 1982, 47, 3258.
J . Org. Chem, Vol. 69, No. 20, 2004 6667

Sprout et al.
give the corresponding amide. Cleavage of this amide
from the solid support with diamine 8 and scavenging of
the excess diamine gave ligand 3e in 73% overall yield
(Table 1). Additional amino acids can also be incorporated
to further extend the ligand architecture (Scheme 2).
After loading the oxime resin 4 with Boc-L-Val-OH and
subsequently removing the Boc protecting group with
TFA, the resin-bound amine 11 was treated twice with
Boc-L-Cys(Trt)-OH under HBTU coupling conditions.
Displacement of the ligand was performed using diamine
6. Removal of excess diamine was accomplished with an
aqueous workup to provide ligand 3f in 84% yield.
Reaction of intermediate 5 (Scheme 1) with chiral
diamine 93 gave ligands 3g-l that incorporate two
stereocenters. We found that, unlike diamines 6-8, the
more sterically hindered diamine 9 required heating at
reflux in methylene chloride to effect both efficient
displacement of the amino acid from the resin and
scavenging of the residual diamine with isocyanate resin
after the reaction was complete. Other investigators have
noted similar difficulty in displacing peptides from an
oxime resin using R-branched nucleophiles.16,17 The reac-
tion between diamine 9 and resin-bound Boc-D-Val was
particularly problematic and required heating at 80 °C
in acetonitrile to obtain a good yield of ligand 3h .
The solid-phase procedure can be further modified to
synthesize the carbamate-containing ligand 13 (Scheme
3). The oxime resin was double coupled using methyl
chloroformate in the presence of DIEA and DMAP to give
intermediate 14. This compound was reacted with an
excess of diamine 9 in refluxing acetonitrile to give, after
scavenging of the remaining diamine with isocyanate
resin, ligand 13 in excellent yield and purity.
F IGURE 2. Structures of diamines used in the synthesis of
the N-acylethylenediamine ligands.
TABLE 1. Solid -P h a se Syn th esis of Liga n d s 3a -l
R3
)
reaction
condi-
lig-
and
amino acid
%
R1
R2 side chain
R4
tionsa yield
3a -(CH2)2O(CH2)2- H
3b -(CH2)2O(CH2)2- H
L-Val
L-Phe
L-Val
L-Val
L-Val
O-t-Bu
O-t-Bu
O-t-Bu
O-t-Bu
t-Bu
1
1
1
1
1
86
73
88
92
73
3c -(CH2)5-
3d Et
H
H
H
3e Et
3f -(CH2)2O(CH2)2- H
L-Val
1
84
3g -(CH2)2O(CH2)2- s-Bu
3h -(CH2)2O(CH2)2- s-Bu
3i -(CH2)2O(CH2)2- s-Bu
3j -(CH2)2O(CH2)2- s-Bu
3k -(CH2)2O(CH2)2- s-Bu
3l -(CH2)2O(CH2)2- s-Bu
L-Val
D-Val
L-Phe
D-Phe
L-Ala
D-Ala
O-t-Bu
O-t-Bu
O-t-Bu
O-t-Bu
O-t-Bu
O-t-Bu
2
3
2
2
2
2
62
83
69
64
65
59
The crude ligands that resulted from the solid-phase
syntheses were examined as enantioselective catalysts
for the addition of dialkylzinc reagents to aldehydes
(Table 2). The % ee of the alcohol products from these
reactions were compared to the results of similar reac-
tions performed using ligands that had been purified by
chromatography or recrystallization. We found that the
two sets of reactions gave comparable enantioselectivi-
ties. Many of the reactions gave essentially identical %
ee values using crude and purified ligands (entries 2, 3,
and 5), while the largest decrease of 9% ee was observed
with ligand 3e (entry 6). The results shown in entries 2
and 14 illustrate that the solid-phase ligands can catalyze
the dialkylzinc addition with good enantioselectivity.
Yields for the reactions catalyzed by a majority of the
ligands (entries 1-6, 8, 12-14) range from good to
excellent.
Because we observe similar % ee values using crude
ligands from the solid-phase synthesis and purified
ligands, we believe that the solid-phase protocol will be
useful for synthesizing large libraries of chiral ligands.
For such libraries, the % ee values obtained during
screening of the crude ligands will provide a clear
indication of the stereoselectivity that would be observed
with purified ligands. Thus, highly enantioselective
catalysts that are discovered through the library screen-
ing process will have a high probability of remaining
a
Reaction conditions for displacement of the ligand from the
solid support with diamines 6-9 (step b in Scheme 1 and step e
in Scheme 2): (1) CH2Cl2, 25 °C, (2) CH2Cl2, 40 °C, (3) CH3CN,
80 °C.
Six different Boc-protected amino acids were coupled.
to the oxime resin: D- and L-Val, D- and L-Phe, and D-
and L-Ala. The resin-bound amino acid was then cleaved
from the solid support using an excess of the N,N-
dialkylethylenediamines 6-8 (Figure 2) at 25 °C to give
ligands 3a -d (Table 1). After the reactions were com-
plete, the remaining N,N-dialkylethylenediamine was
scavenged with an isocyanate resin. Examination of the
1H and 13C NMR spectra of the ligands, without further
purification, showed that the desired products were
obtained in essentially pure form, with only trace impuri-
ties.15 In all cases, the yield for the solid-phase syntheses
was similar to or better than the yield that is obtained
through standard solution-phase methods.4
The solid-phase synthesis can be modified to allow
variation at the R4 position of the ligands. For example,
ligand 3e was prepared by treating intermediate 5
(Scheme 1) with TFA to remove the Boc group, followed
by reaction of the free amine with pivaloyl chloride to
(14) Abbreviations: HBTU, O-(benzotriazol-1-yl)-N,N,N′,N′-tetra-
methyluronium hexafluorophosphate; DIEA, diisopropylethylamine;
DIC diisopropylcarbodiimide; HOBT, 1-hydroxybenzotriazole; DMAP,
4-(dimethylamino)pyridine; TFA, trifluoroacetic acid; DBU 1,8-diaza-
bicyclo[4.5.0]undec-7-ene.
(16) Gilbertson, S. R.; Lan, P. Tetrahedron Lett. 2002, 43, 6961.
(17) Voyer, N.; Lavoie, A.; Pinette, M.; Bernier, J . Tetrahedron Lett.
1994, 35, 355.
(15) See Supporting Information.
6668 J . Org. Chem., Vol. 69, No. 20, 2004

Solid-Phase Synthesis of Chiral N-Acylethylenediamines
SCHEME 2. Solid -P h a se Syn th esis of N-Acyleth ylen ed ia m in e Dip ep tid e Liga n d 3fa
a
Reagents: (a) HBTU, DIEA, N-Boc-Val-OH, DMF, triple coupling; (b) 25% TFA, CH2Cl2; (c) 10% DIEA, CH2Cl2; (d) HBTU, DIEA,
N-Boc-Cys(Trt)-OH, DMF, double coupling; (e) diamine 6, CH2Cl2.
SCHEME 3. Syn th esis of Liga n d 13a
a
Reagents: (a) CH3OCOCl, DMAP, DIEA, CH2Cl2, double coupling; (b) diamine 9, CH3CN, reflux; (c) isocyanate resin, CH2Cl2.
TABLE 2. Use of Liga n d s 3a -l a n d 13 a s Ca ta lysts for
We have also examined ligands 3f-l, which contain
two stereogenic centers, as catalysts for the addition of
diethylzinc to benzaldehyde. However, none of these
ligands catalyzed the reaction with significant enantio-
selectivity. In the case of ligand 3f no reaction occurred.
This result may be caused by the insolubility of the ligand
in hexanes, which was used as the solvent for the
addition reaction. If we examine the absolute configura-
tion of the alcohol products that are obtained using
ligands 3g-l, we find that the sense of stereochemical
induction in the catalyzed reaction is controlled by the
stereochemistry of the side chain on the attached amino
acid of the ligand (R3 position, Table 1), not by the
chirality of the alkyl group on the ethylenediamine bridge
(R2 position, Table 1). Comparison of the results using
ligands 3a , 3b, and 3g-3j shows that when R3 is of the
S configuration (ligands 3a ,b,g, and i), the (R)-alcohol is
the predominate product. Conversely, when R3 has the
R configuration (ligands 3h and 3j), the (S)-alcohol is the
predominate product. The only exception to this trend is
ligand 3k , which shows no stereoselectivity in the
catalyzed reaction.
th e Ad d ition of Dia lk ylzin c Rea gen ts to Ald eh yd esa
% ee
crude ligand
config of from solid-phase purified
entry ligand
R
R′
alcohol
synthesisb,c
ligandb,c
1
2
3
4
5
6
7
8
3a
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ph
Et
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
R
R
R
R
R
R
na
R
S
R
S
na
S
60 (83)
84 (85)d
23 (89)e
61 (89)
58 (83)
44 (86)
nr
18 (81)
24 (52)
16 (58)
29 (48)
0 (73)e
27 (82)
94 (100)f
68 (86)
84 (68)d
25 (86)e
66 (74)
59 (83)
53 (82)
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
9
10
11
12
13
14
3j
3k
3l
30 (54)
99 (93)f
13
cyclo- Et
hexyl
S
a
Experiments performed in duplicate unless noted otherwise.
% ee measured by HPLC (Chiralcel OD-H). c Values in paren-
b
To broaden the overall utility of the N-acylethylene-
diamine ligands, we have performed a preliminary
examination of two of these compounds as potential
catalysts for the asymmetric addition of alkenylzinc
reagents to aldehydes to yield chiral allylic alcohols.
Several investigators, including Oppolzer,11 Walsh,18 and
theses are the % yield. Reaction run for 65 h. e Based on one
experiment. f % ee measured by 19F NMR of the (S)-MPTA ester.
na ) not applicable. nr ) no reaction.
d
“hits” when they are examined in purified form. The
converse is also true. Catalysts that show poor stereo-
selectivity in the screening process are not likely to be
highly selective when purified.
(18) (a) Chen, Y. K.; Lurain, A. E.; Walsh, P. J . J . Am. Chem. Soc.
2002, 124, 12225. (b) Lurain, A. E.; Walsh, P. J . J . Am. Chem. Soc.
2003, 125, 10677.
J . Org. Chem, Vol. 69, No. 20, 2004 6669

Sprout et al.
SCHEME 4. En a n tioselective Syn th esis of Allylic
Alcoh ols Usin g Liga n d s 3a a n d 3fa
from 36% to 59% ee. Ligand 3f gives somewhat higher
stereoselectivities, with allylic alcohol products that
range from 67% to 76% ee. Although the N-acylethyl-
enediamine-based ligands do not yet give high stereose-
lectivity in the alkyenylation of aldehydes, the structures
of the ligands are not yet optimized. However, these
preliminary results show that ligand 3f gives a promising
degree of stereoselectivity and suggest that further
variation of the amino acid components of the ligand is
likely to lead to improved asymmetric catalysts for this
reaction. A library-based approach could be ideal for
performing this type of optimization process. A compari-
son of the % ee values obtained using crude ligands that
come directly from the solid-phase synthesis with purified
ligands (Table 3, entries 1 and 4) shows similar results
for both sets of reactions. This observation provides
further evidence that the solid-phase synthesis protocol
that we have developed yields ligands that are directly
suitable for screening purposes and do not require
purification.
a
Reagents: (a) BH3‚DMS, CH2Cl2, 2 h, 0 °C; (b) RCtCH where
R ) t-Bu, n-Bu, or n-C6H13, 30 min, 0-25 °C; (c) 7.5 mol % ligand
3a or 3f, Et2Zn, -78 °C, 18 h, CH2Cl2; (d) PhCHO, -48 °C, 48 h.
TABLE 3. % ee Va lu es of Allylic Alcoh ol P r od u cts fr om
th e Rea ction of Alk en ylzin c Rea gen ts w ith Ben za ld eh yd e
Ca ta lyzed by Liga n d s 3a a n d 3f (Sch em e 4)a
% ee
crude ligand from
purified
ligandc
entry
ligand
Rb
t-Bu
solid-phase synthesisc
1
2
3
4
5
6
3a
3a
3a
3f
3f
3f
59
54
n-Bu
n-C6H13
t-Bu
n-Bu
n-C6H13
36
41d
67
65
Con clu sion
76e
73d
In summary, we have developed a solid-phase synthe-
sis of our recently reported class of modular chiral
N-acylethylenediamine ligands. The synthetic route uti-
lizes an oxime resin to activate N-protected amino acids,
followed by displacement of the amino acid with either a
commercially available achiral N,N-dialkylethylenedi-
amine or a synthesized chiral diamine. An isocyanate-
based scavenging resin was used to remove the excess
diamine. This procedure provided ligands in good yield
and purity that did not require further purification. By
modification of the N-terminus of the amino acid, this
procedure can generate ligands that incorporate up to
four different diversity sites. The ligands, in crude form,
are suitable for use as catalysts for the addition of both
alkylzinc and alkenylzinc reagents to aldehydes. For the
reactions using alkylzinc reagents, high enantioselectivi-
ties are observed for specific ligands. For the alkenylzinc
reactions, we have obtained allylic alcohol products in
up to 76% ee. Our future work will use this solid-phase
protocol to synthesize a library of N-acylethylenediamine-
based ligands. This library will be screened to discover
optimal catalysts for the alkenylation of aldehydes and
other synthetically useful transformations.
a
Experiments performed in duplicate unless noted otherwise.
Refers to the R group in compounds 17a -c. c % ee measured by
b
d
HPLC (Chiralcel OD-H). The absolute configuration was as-
signed by comparison of the optical rotation with the reported
values of the related compounds (R)-1-phenyl-hept-2-ene-1-ol and
(S)-4,4-dimethyl-1-phenyl-pent-2-en-1-ol (see refs 1 and 2 in Sup-
porting Information). e Based on one experiment.
Chan,19 have developed amino alcohol based catalysts for
this reaction that show good to excellent stereoselectivi-
ties. Brase has examined chiral paracyclophane-contain-
ing catalysts,20 and Wipf and co-workers have developed
aminothiol catalysts for use with alkenylzinc reagents
that are generated via the corresponding alkenyl zir-
conocene species.21 Scheme 4 shows the procedure that
we employed using the N-acylethylenediamine-based
ligands. Reaction of 2 equiv of cyclohexene with borane-
dimethyl sulfide complex gave dicyclohexylborane. This
compound was used to hydroborate three different ter-
minal alkynes to give the vinylboranes 15a -c. Trans-
metalation of the vinylboranes with diethylzinc gave
alkenylzinc intermediates 16a-c, which were then treated
with benzaldehyde in the presence of 7.5 mol % of the
ligand to yield allylic alcohols 17a -c.
Table 3 shows the results from these alkene transfer
reactions using ligands 3a and 3f. Both ligands are
effective catalysts for this reaction, and in all cases the
(R)-allylic alcohol was the predominant product. A com-
parison of the results using ligand 3a as a catalyst for
the reaction of benzaldehyde with alkylzinc reagents
(Table 2) and alkenylzinc reagents (Table 3) shows that
the ligand promotes both of these reactions with the same
sense of stereochemical induction, with (R)-alcohols as
the major product in both cases. The enantioselectivities
observed using ligand 3a are only moderate, and range
Exp er im en ta l Section
Solu tion -P h a se Syn th esis of (1S)-[1-(2-Mor p h olin -4-yl-
eth ylca r ba m oyl)-2-p h en yl-eth yl]ca r ba m ic Acid ter t-Bu -
tyl Ester 3b. To Boc-Phe-OH (0.460 g, 1.73 mmol) were added
HBTU (1.45 g, 3.82 mmol), DIEA (0.91 mL, 5.20 mmol), and
enough DMF to dissolve all of the solids. After 5 min of stirring,
2-morpholin-4-yl-ethylamine (0.273 mL, 2.08 mmol) was added.
The reaction mixture was stirred at 25 °C for 1 h and then
diluted with H2O. The aqueous phase was then extracted with
EtOAc, and the organic phase was washed with H2O and brine.
The organic layer was dried over Na2SO4, the solvent was
removed, and the crude product was purified by column
chromatography (0.5:4.5:95 30% aqueous NH4OH/MeOH/CH2-
Cl2) to yield compound 3b as a white solid (0.444 g, 1.18 mmol,
68%): mp 109-111 °C; 1H NMR (300 MHz, CDCl3) δ 7.31 (m,
1 H), 7.22 (m, 4 H), 6.07 (br s, 1 H), 5.19 (br s, 1 H), 4.28 (m,
1 H), 3.60 (m, 4 H), 3.23 (m, 2 H), 3.11 (dd, J ) 13.4, 6.0 Hz,
1 H), 2.97 (dd, J ) 13.3, 8.4 Hz, 1 H), 2.33 (m, 6 H), 1.44 (s, 9
(19) J i, J .-X.; Qiu, L.-Q.; Yip, C. W.; Chan, A. S. C. J . Org. Chem.
2003, 68, 1589.
(20) Dahmen, S.; Brase, S. Org. Lett. 2001, 3, 4119.
(21) (a) Wipf, P.; Ribe, S. J . Org. Chem. 1998, 63, 6454. (b) Wipf,
P.; J ayasuriya, N.; Ribe, S. Chirality 2003, 15, 208. (c) Wipf, P.;
Kendall, C. Chem. Eur. J . 2002, 8, 1779.
6670 J . Org. Chem., Vol. 69, No. 20, 2004

Solid-Phase Synthesis of Chiral N-Acylethylenediamines
H); 13C NMR (75 MHz, CDCl3) δ 171.2, 155.7, 137.4, 129.7,
129.0, 127.2, 80.4, 67.2, 56.8, 56.6, 53.4, 39.7, 35.7, 28.7; IR
(neat) 3298, 2966, 1704, 1660, 1523, 1454, 1365, 1246, 1168,
1118, 1022 cm-1; HRMS-ESI (M + H+) calcd for C20H32N3O4
ic Acid ter t-Bu tyl Ester 3f. Ligand 3f was prepared by first
loading oxime resin (0.160 g, 0.144 mmol) with a DMF (1.5
mL) solution containing Boc-Val-OH (0.0939 g, 0.432 mmol),
HBTU (0.164 g, 0.432 mmol), and DIEA (0.125 mL, 0.718
mmol). The reaction mixture was shaken for 23 h and
subsequently washed with DMF (5 × 3 mL). The above
procedure was repeated twice, and the resin was washed with
CH2Cl2 (5 × 3 mL). The resin was treated with 25% TFA in
CH2Cl2 (2 mL) and shaken for 2 h at 25 °C. The resin was
then washed with CH2Cl2 (5 × 2 mL), followed by 10% DIEA
in CH2Cl2 (5 × 2 mL) and finally DMF (2 × 3 mL). A solution
of Boc-Cys(Trt)-OH (0.200 g, 0.432 mmol), HBTU (0.164 g,
0.432 mmol), and DIEA (0.125 mL, 0.718 mmol) dissolved in
DMF (1.5 mL) was added to the resin and shaken for 2 h at
25 °C. The resin was then washed with DMF (5 × 3 mL), and
the coupling procedure was repeated a second time, followed
by washes with DMF (5 × 3 mL) and CH2Cl2 (10 × 3 mL).
The resin was finally treated with 2-morpholin-4-yl-ethylamine
(0.042 mL, 0.320 mmol) in CH2Cl2 (2 mL) and shaken for 15 h
at 25 °C. The reaction mixture was then filtered and washed
with CH2Cl2 (6 × 3 mL). The filtrates were combined, washed
twice with H2O, and dried over Na2SO4. Removal of the solvent
provided the crude product as a white solid (0.082 g, 0.121
mmol, 84%): 1H NMR (300 MHz, CDCl3) δ 7.44 (d, J ) 8.3,
1.1 Hz, 6 H), 7.34-7.22 (m, 9 H), 6.49 (br s, 2 H), 4.76 (br d,
1 H), 4.17 (dd, J ) 8.3, 5.9 Hz, 1 H), 3.80 (br s, 1 H), 3.70 (br
s, 4 H), 3.33 (m, 2 H), 2.71 (m, 1 H), 2.61 (dd, J ) 12.4, 5.4 Hz,
1 H), 2.44 (br s, 6 H), 2.25 (m, 1 H), 1.43 (s, 9 H), 0.92 (d, J )
6.8 Hz, 3 H), 0.88 (d, J ) 6.9 Hz, 3 H); 13C NMR (75 MHz,
CDCl3) δ 170.91, 170.87, 156.0, 144.7, 129.9, 128.5, 127.4, 81.0,
67.7, 67.2, 59.0, 57.4, 54.2, 53.7, 36.2, 33.6, 30.5, 28.7, 19.6,
17.9; IR (neat) 3299, 3057, 2964, 1714, 1698, 1647, 1516, 1494,
1450, 1366, 1245, 1169, 1118, 1016 cm-1; HRMS-FAB (M +
Na+) calcd for C38H50N4O5SNa 697.33996, found 697.3378;
378.2393, found 378.2393; [R]26 ) +13 (c ) 0.94, CHCl3).
D
Solid -P h a se Syn th esis of Liga n d s 3a -d . Gen er a l P r o-
ced u r e. To the appropriate N-Boc amino acid (3.0 equiv) were
added HBTU (3.0 equiv), DIEA (4.0 equiv), and enough DMF
to dissolve all of the solids. The DMF solution was added to
the oxime resin (1.0 equiv), and the reaction mixture was
shaken for 3 h. The resin was then washed with DMF (4 × 3
mL), and the coupling procedure was repeated a second time,
followed by washes with DMF (5 × 3 mL) and CH2Cl2 (6 × 3
mL). The resin was suspended in 3-5 mL of CH2Cl2, and the
appropriate N,N-dialkylethylenediamine (2.25-3.00 equiv)
was added at 25 °C. After the reaction mixture was shaken
for 15 h, isocyanate resin (3.75-6.00 equiv) was added at 25
°C, and shaking was continued for an additional 6 h. The
reaction mixture was filtered, the filtrate was collected, and
the solvent was removed. The crude ligands were used without
further purification. In several cases, residual DMF was
removed from the crude ligand via azeotropic distillation with
heptane. Spectroscopic characterization of ligands 3a ,c, and
d
matched the previously reported values.4 Spectroscopic
characterization of ligand 3b matched the data listed above.
(1S)-[2-Met h yl-1-(2-m or p h olin -4-yl-et h ylca r b a m oyl)-
p r op yl]ca r ba m ic Acid ter t-Bu tyl Ester 3a . Ligand 3a was
prepared as described above from oxime resin (0.200 g, 0.180
mmol), Boc-Val-OH (0.117 g, 0.540 mmol), and 2-morpholin-
4-yl-ethylamine (0.072 mL, 0.550 mmol), yielding a white solid
(0.051 g, 0.155 mmol, 86%).
(1S)-[1-(2-Mor p h olin -4-yl-et h ylca r b a m oyl)-2-p h en yl-
eth yl]ca r ba m ic Acid ter t-Bu tyl Ester 3b. Ligand 3b was
prepared as described above from oxime resin (0.217 g, 0.196
mmol), Boc-Phe-OH (0.128 g, 0.587 mmol), and 2-morpholin-
4-yl-ethylamine (0.025 mL, 0.440 mmol), yielding a yellow-
brown solid (0.054 g, 0.143 mmol, 73%).
(1S)-[2-Meth yl-1-(2-piper idin -1-yl-eth ylcar bam oyl)-pr o-
p yl]ca r ba m ic Acid ter t-Bu tyl Ester 3c. Ligand 3c was
prepared as described above from oxime resin (0.215 g, 0.194
mmol), Boc-Val-OH (0.130 g, 0.598 mmol), and 2-piperidin-1-
yl-ethylamine (0.062 mL, 0.437 mmol), yielding a yellow solid
(0.056 g, 0.170 mmol, 88%).
(1S)-[1-(2-(Diet h yla m in o)et h ylca r b a m oyl)-2-m et h yl-
p r op yl]ca r ba m ic Acid ter t-Bu tyl Ester 3d . Ligand 3d was
prepared as described above from oxime resin (0.215 g, 0.194
mmol), Boc-Val-OH (0.130 g, 0.598 mmol), and N,N-diethyl-
ethylenediamine (0.061 mL, 0.437 mmol), yielding a white solid
(0.056 g, 0.178 mmol, 92%).
(2S)-N-(2-(Dieth yla m in o)eth yl)-2-(2,2-d im eth yl-p r op io-
n yla m in o)-3-m eth yl-bu tyr a m id e 3e. Ligand 3e was pre-
pared by first loading oxime resin (0.421 g, 0.379 mmol) with
Boc-Val-OH (0.247 g, 1.14 mmol) using the general procedure
described above for the synthesis of ligands 3a -3d . After Boc-
Val-OH was coupled to the resin, the resin was treated with
25% TFA (20 equiv, 0.581 mL) in CH2Cl2, and the mixture was
shaken for 2 h at 25 °C. The resin was washed with CH2Cl2 (3
× 2 mL) followed by 10% DIEA in CH2Cl2 (3 × 1 mL). The
resin was then treated with 2,2-dimethyl-propionyl chloride
(0.103 mL, 0.835 mmol) in 2 mL of 10% DIEA in CH2Cl2,
shaken for 22 h, and washed with CH2Cl2 (6 × 3 mL). The
resin was treated with N,N-diethylethylenediamine (0.16 mL,
1.14 mmol) in CH2Cl2 and shaken for 16 h, and the excess
diamine was scavenged using isocyanate resin (0.857 g, 1.52
mmol) at 25 °C for 6 h. The reaction mixture was filtered, the
filtrate was collected, and the solvent was removed to yield
compound 3e as a white solid (0.0833 g, 0.278 mmol, 73%).
The ligand was used without further purification. Spectro-
scopic characterization of the crude ligand matched that of
previously reported values.4
[R]25 ) -9.2 (c ) 1.7, CHCl3).
D
(1S)-1-((S)-1-Met h yl-p r op yl)-(2-m or p h olin -4-ylet h yl)-
a m in e 9. [(1S)-1-((S)-1-Methyl-propyl)-(2-morpholin-4yl-eth-
yl)]carbamic acid tert-butyl ester (1.00 g, 3.5 mmol), prepared
as previously described,3 was treated with TFA (5.4 mL, 70
mmol) in CH2Cl2 (20 mL) at 25 °C for 1 h. The excess TFA
was removed by rotary evaporation, and the residue was
treated with DOWEX Monosphere 550A ion-exchange resin
(30 mL) in methanol (100 mL) and allowed to stir overnight.
Removal of the solvent gave compound 9 as a viscous pale
yellow oil (0.615 g, 3.3 mmol, 95%). As an alternate workup
procedure, after the TFA is removed, the residue can be diluted
with water and the pH adjusted to pH 10 with 10% aqueous
KOH. The aqueous solution may then be extracted with CH2-
Cl2 (3 × 10 mL), the organic layers combined and dried (Na2-
CO3), and the solvent removed by rotary evaporation to yield
compound 9: 1H NMR (300 MHz, CDCl3) δ 3.71 (m, 4 H), 2.82
(m, 1 H), 2.58 (m, 2 H), 2.32 (m, 2 H), 2.19 (m, 2 H), 1.67 (br
s, 2 H), 1.49 (m, 1 H), 1.35 (m, 1 H), 1.20 (m, 1 H), 0.90 (m, 6
H); 13C NMR (75 MHz, CDCl3) δ 67.6, 63.3, 54.5, 51.7, 39.4,
25.6, 15.4, 12.0; HRMS-FAB (M + H+) calcd for C10H23N2O
187.1810, found 187.1815; [R]24 ) +48.8 (c ) 1.46, CHCl3).
D
Solid -P h a se Syn th esis of Liga n d s 3g-l. Gen er a l P r o-
ced u r e. To the appropriate N-Boc amino acid (3.0 equiv) was
added HBTU (3.0 equiv), DIEA (4.0 equiv), and enough DMF
to dissolve all of the solids. The DMF solution was added to
the oxime resin (1.0 equiv), and the reaction mixture was
shaken for 3 h. The resin was then washed with DMF (4 × 3
mL), and the coupling procedure was repeated a second time
and shaken for 15 h, followed by washes with DMF (5 × 3
mL) and CH2Cl2 (6 × 3 mL). The resin was transferred into a
round-bottom flask and suspended in CH2Cl2 (5-10 mL).
Diamine 9 (2.0 equiv) was added, and the reaction was heated
at 40 °C under N2 with stirring for 24 h. Isocyanate resin (3
equiv) was then added, and the reaction mixture was heated
at 40 °C with stirring for an additional 14 h. The reaction
mixture was filtered, the filtrate was collected, and the solvent
{1-[2-Meth yl-1-(2-m or p h olin -4-yl-eth ylca r ba m oyl)-(S)-
1-p r opylca r ba m oyl]-2-tr itylsu lfa n yl-(R)-1-eth yl}-ca r ba m -
J . Org. Chem, Vol. 69, No. 20, 2004 6671

Sprout et al.
was removed. The crude ligands were used without further
purification.
1 H), 1.43 (m, 1 H), 1.39 (s, 9 H), 0.97 (m, 1 H), 0.87 (t, J ) 7.0
Hz, 3 H), 0.74 (d, J ) 6.1 Hz, 3 H);
13C NMR (75 MHz, CDCl3)
δ 172.0, 155.9, 137.3, 129.8, 129.0, 127.2, 80.4, 66.3, 58.4, 56.7,
53.6, 49.3, 38.8, 37.6, 28.7, 25.4, 15.2, 12.1; IR (neat) 3307,
2963, 2931, 2871, 1698, 1653, 1522, 1455, 1366, 1249, 1170,
1118, 1018 cm-1; HRMS-FAB (M + Na+) calcd for C24H39N3O4-
[((1S)-1-((S)-1-Meth yl-p r op yl)-2-m or p h olin -4-yl-eth yl-
ca r ba m oyl)-(S)-2-p r op yl-m eth yl]ca r ba m ic Acid ter t-Bu -
tyl Ester 3g. Ligand 3g was prepared as described above from
oxime resin (0.384 g, 0.346 mmol), Boc-Val-OH (0.225 g, 1.04
mmol), and diamine 9 (0.129 g, 0.691 mmol), yielding a white
solid (0.083 g, 0.216 mmol, 62%): 1H NMR (300 MHz, CDCl3)
δ 6.02 (br s, 1 H), 5.13 (d, J ) 7.7 Hz, 1 H), 4.01 (m, 1 H), 3.84
(dd, J ) 8.9, 6.9 Hz, 1 H), 3.64 (br s, 4 H), 2.52 (m, 2 H), 2.09
(m, 4 H), 2.10 (m, 1 H), 1.73 (m, 1 H), 1.44 (s, 9 H), 1.38 (m, 1
H), 1.10 (m, 1 H), 0.93 (m, 12 H); 13C NMR (75 MHz, CDCl3)
δ 171.8, 156.2, 80.1, 67.2, 60.9, 58.9, 54.2, 50.3, 37.3, 31.1, 28.7,
25.6, 19.7, 18.4, 15.1, 12.2; IR (neat) 3323, 2961, 1684, 1644,
1525, 1249, 1177 cm-1; HRMS-FAB (M + H+) calcd for
Na 456.2838, found 456.2831; [R]24 ) +17 (c ) 1.3, CHCl3).
D
[((1S)-1-((S)-1-Meth yl-p r op yl)-2-m or p h olin -4-yl-eth yl-
ca r ba m oyl)-(S)-1-m eth yl-m eth yl]ca r ba m ic Acid ter t-Bu -
tyl Ester 3k . Ligand 3k was prepared as described above from
oxime resin (0.342 g, 0.380 mmol), Boc-Ala-OH (0.216 g, 1.14
mmol), and diamine 9 (0.142 g, 0.762 mmol), yielding a white
solid (0.088 g, 0.247 mmol, 65%): 1H NMR (300 MHz, CDCl3)
δ 6.10 (br s, 1 H), 5.06 (br s, 1 H), 4.16 (m, 1 H), 4.04 (br s, 1
H), 3.69 (br s, 4 H), 2.52 (br s, 2 H), 2.38 (br s, 4 H), 1.72 (m,
1 H), 1.64 (m, 1 H), 1.46 (s, 9 H), 1.38 (d, J ) 7.0 Hz, 3 H),
1.10 (m, 1 H), 0.93 (m, 6 H); 13C NMR (75 MHz, CDCl3) δ 173.0,
155.9, 80.4, 66.9, 59.0, 54.0, 50.6, 50.1, 37.5, 28.7, 25.4, 18.6,
15.3, 12.2; IR (neat) 3309, 2966, 2932, 2874, 1697, 1656, 1524,
1455, 1366, 1249, 1169, 1118 cm-1; HRMS-FAB (M + Na+)
C
20H40N3O4 386.3019, found 386.3014; [R]25 ) +2.5 (c ) 1.3,
D
CHCl3).
[((1S)-1-((S)-1-Meth yl-p r op yl)-2-m or p h olin -4-yl-eth yl-
ca r ba m oyl)-(R)-2-p r op ylm eth yl]ca r ba m ic Acid ter t-Bu -
tyl Ester 3h . Oxime resin (0.302 g, 0.27 mmol) was suspended
in dry DMF (3 mL), and to this solution were added Boc-D-
Val-OH (0.177 g, 0.81 mmol), DIEA (0.190 mL, 1.1 mmol), and
HBTU (0.320 g, 0.81 mmol). After the solution was shaken
for 3 h, the resin was washed with DMF (10 × 5 mL), and the
coupling procedure was repeated. After the second coupling,
the resin was washed with DMF (10 × 5 mL), followed by
washing with CH2Cl2 (20 × 5 mL). The resin was transferred
to a round-bottom flask and suspended in dry CH3CN (10 mL).
Diamine 9 (0.110 g, 0.59 mmol) was dissolved in CH3CN (0.5
mL) and was added to the resin. The solution was brought to
reflux for 24 h and then cooled to 40 °C. Isocyanate resin (0.402
g, 0.96 mmol) and CH2Cl2 (10 mL) were added to the reaction,
and it was maintained at 40 °C with stirring for 24 h. The
reaction mixture was cooled and filtered through a fine glass
fritted Buchner funnel with water aspiration, and the resin
was washed with CH2Cl2 (50 mL). The filtrate was collected,
and the solvent removed to yield a white solid (0.877 g, 0.23
mmol, 84%): 1H NMR (300 MHz, CDCl3) δ 6.36 (s, 1 H), 5.16
(s, 1 H), 4.10 (m, 1 H), 3.91 (m, 1 H), 3.73 (s, 4 H), 2.62-2.39
(m, 5 H), 2.16 (m, 1 H), 1.71 (s, 1 H), 1.44 (s, 9 H), 1.26 (m, 1
H), 1.10 (m, 1 H), 0.94 (m, 12 H); 13C NMR (75 MHz, CDCl3)
δ 172.2, 156.3, 80.2, 66.8, 60.9, 58.5, 53.9, 49.8, 37.4, 31.0, 28.7,
25.5, 19.8, 18.3, 15.4, 12.2; IR (neat) 3326, 2961, 2931, 2871,
calcd for C18H35N3O4Na 380.2525, found 380.2539; [R]26
-6.0 (c ) 3.1, CHCl3).
)
D
[((1S)-1-((S)-1-Meth yl-p r op yl)-2-m or p h olin -4-yl-eth yl-
ca r ba m oyl)-(R)-1-m eth yl-m eth yl]ca r ba m ic Acid ter t-Bu -
tyl Ester 3l. Ligand 3l was prepared as described above from
oxime resin (0.334 g, 0.371 mmol), Boc-D-Ala-OH (0.210 g, 1.11
mmol), and diamine 9 (0.138 g, 0.742 mmol), yielding a white
solid (0.079 g, 0.220 mmol, 59%): 1H NMR (300 MHz, CDCl3)
δ 6.53 (br s, 1 H), 5.26 (br s, 1 H), 4.18 (m, 1 H), 4.10 (m, 1 H),
3.78 (br s, 4 H), 2.69 (br s, 2 H), 2.49 (m, 4 H), 1.66 (m, 1 H),
1.50 (m, 1 H), 1.47 (s, 9 H), 1.39 (d, J ) 7.1 Hz, 3 H), 1.10 (m,
1 H), 0.94 (t, J ) 7.1 Hz, 3 H), 0.90 (d, J ) 6.8 Hz, 3 H); 13C
NMR (75 MHz, CDCl3) δ 173.7, 155.9, 80.4, 66.1, 58.8, 53.6,
51.0, 49.0, 37.9, 28.7, 25.3, 18.8, 15.5, 12.0; IR (neat) 3305,
2965, 1708, 1659, 1518, 1450, 1367, 1246, 1168 cm-1; HRMS-
FAB (M + Na+) calcd for C18H35N3O4Na 380.2525, found
380.2524; [R]25 ) +34 (c ) 0.70, CHCl3).
D
Solid -P h a se Syn th esis of [(1S)-1-((S)-1-Meth yl-p r op yl)-
(2-m or p h olin -4yl-eth yl)]ca r ba m ic Acid Meth yl Ester 13.
To prewashed (3 × 5 mL CH2Cl2) oxime resin (0.452 g, 0.410
mmol) were added DMAP (0.014 g, 0.102 mmol) and DIEA
(0.285 mL, 1.64 mmol) dissolved in CH2Cl2 (0.5 mL). Enough
CH2Cl2 was added to suspend the resin, methyl chloroformate
(0.95 mL, 1.23 mmol) was added, and the reaction was shaken
for 3 h at 25 °C. The resin was washed with CH2Cl2 (10 × 5
mL), and the loading step was repeated. The resin was again
washed with CH2Cl2 (20 × 5 mL) and then transferred to a
round-bottom flask. The resin was suspended in CH3CN (10
mL). Diamine 9 (0.169 g, 0.900 mmol) was dissolved in CH3-
CN (0.5 mL) and added to the resin. The reaction was brought
to reflux for 24 h and then cooled to 40 °C before the isocyanate
resin (0.616 g, 1.48 mmol) was added. After 24 h of stirring at
40 °C, the reaction was cooled and filtered through a fine glass
fritted Buchner funnel with water aspiration, and the resin
was washed with large amounts of CH2Cl2. The filtrate was
collected, and the solvent was removed to yield a yellow oil
(0.100 g, 0.410 mmol, 100%). Spectroscopic characterization
of ligand 13 matched previously reported data.3
2810, 1709, 1659, 1522, 1456, 1366, 1172, 1118, 1010 cm-1
;
HRMS-FAB (M + H+) calcd for C20H40N3O4 386.3019, found
386.3017; [R]24 ) +21.9 (c ) 2.2, CHCl3).
D
[((1S)-1-((S)-1-Meth yl-p r op yl)-2-m or p h olin -4-yl-eth yl-
ca r ba m oyl)-(S)-1-p h en ylm eth yl-m eth yl]ca r ba m ic Acid
ter t-Bu tyl Ester 3i. Ligand 3i was prepared as described
above from oxime resin (0.366 g, 0.406 mmol), Boc-Phe-OH
(0.324 g, 1.22 mmol), and diamine 9 (0.151 g, 0.812 mmol),
yielding a white solid (0.122 g, 0.282 mmol, 69%): 1H NMR
(300 MHz, CDCl3) δ 7.31 (m, 3 H), 7.25 (m, 2 H), 5.99 (br s, 1
H), 5.04 (br s, 1 H), 4.34 (dd, J ) 15.1, 7.2 Hz, 1 H), 3.94 (br
s, 1 H), 3.59 (br s, 4 H), 3.08 (m, 2 H), 2.37 (br s, 2 H), 2.27 (br
m, 4 H), 1.75 (br m, 1 H), 1.44 (s, 9 H), 1.35 (m, 1 H), 1.03 (m,
1 H), 0.90 (t, J ) 7.2 Hz, 3 H), 0.82 (d, J ) 6.8 Hz, 3 H); 13C
NMR (75 MHz, CDCl3) δ 171.5, 155.8, 137.4, 129.9, 129.0,
127.2, 80.5, 66.7, 58.5, 56.4, 53.9, 50.1, 38.4, 37.1, 28.7, 25.3,
15.2, 12.2; IR (neat) 3318, 2964, 1681, 1650, 1524, 1455, 1390,
1370, 1170 cm-1; HRMS-FAB (M + Na+) calcd for C24H39N3O4-
Na 456.2838, found 456.2852; [R]24D ) -1.2 (c ) 0.42, CHCl3).
[((1S)-1-((S)-1-Meth yl-p r op yl)-2-m or p h olin -4-yl-eth yl-
ca r ba m oyl)-(R)-1-p h en ylm et h yl-m et h yl]ca r ba m ic Acid
ter t-Bu tyl Ester 3j. Ligand 3j was prepared as described
above from oxime resin (0.334 g, 0.371 mmol), Boc-D-Phe-OH
(0.294 g, 1.11 mmol), and diamine 9 (0.138 g, 0.742 mmol),
yielding a white solid (0.104 g, 0.239 mmol, 64%): 1H NMR
(300 MHz, CDCl3) δ 7.30 (m, 3 H), 7.23 (m, 2 H), 6.53 (br s, 1
H), 5.36 (br s, 1 H), 4.41 (dd, J ) 14.9, 7.3 Hz, 1 H), 4.09 (br
s, 1 H), 3.78 (m, 4 H), 3.10 (d, J ) 7.4 Hz, 2 H), 2.71 (br s, 2
H), 2.58 (br s, 2 H), 2.45 (br s, 1 H), 2.42 (br s, 1 H), 1.58 (m,
Gen er a l P r oced u r e for Et2Zn Ad d ition to Ald eh yd es.
To an oven-dried vial was added the ligand (0.06 mmol)
followed by a 1.0 M solution of Et2Zn in hexanes (1.8 mmol).
The solution was stirred for 10 min at 25 °C and cooled to 0
°C, and then benzaldehyde (0.60 mmol) was added. After 18
h, the reaction was quenched first with saturated aqueous
NH4Cl and then with 1 N HCl (2 mL), and then it was
extracted with Et2O (2 × 5 mL). The combined organic extracts
were washed with saturated aqueous NaHCO3 solution (5 mL),
dried (Na2SO4), filtered through a plug of silica gel, and
concentrated in vacuo. The crude alcohol was analyzed without
further purification by HPLC (Chiralcel OD-H) using an eluent
of 97.5% hexanes/2-propanol running at 1.0 mL/min.
6672 J . Org. Chem., Vol. 69, No. 20, 2004

Solid-Phase Synthesis of Chiral N-Acylethylenediamines
Gen er a l P r oced u r e for Rea ction of Alk en ylzin c Re-
a gen ts to Ald eh yd es. An oven-dried vial was cooled to 0 °C,
and borane-dimethyl sulfide complex (0.55 mmol) in CH2Cl2
(0.25 mL) was added, followed by cyclohexene (1.1 mmol). This
solution was stirred at 0 °C for 2 h. Next, the alkyne (0.55
mmol) was added, and the reaction was warmed to room
temperature for 30 min. To this solution was added the ligand
(0.038 mmol), and the reaction was cooled to -78 °C. A 1.0 M
solution of Et2Zn in CH2Cl2 (0.625 mmol) was added to the
solution. After 18 h at -78 °C, benzaldehyde (0.50 mmol) was
added, and the reaction was warmed to -48 °C for 48 h. The
reaction was quenched with saturated aqueous NH4Cl and
diluted with diethyl ether. The organic layer was washed with
1 N HCl (3 × 2 mL), water (2 mL), saturated aqueous NaHCO3
(2 × 2 mL), and brine (2 mL) and was dried (MgSO4). The
solvent was removed, and purification was performed by
column chromatography (9:1 hexanes/EtOAc).
Ack n ow led gm en t . C.M.S. was supported by a
GAANN Fellowship from the Department of Education,
and M.L.R. was partially supported by the National
Aeronautic and Space Administration (NASA) through
the Rhode Island Space Grant.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for all new compounds; HPLC column conditions and
retention times for allylic alcohol products. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O049160+
J . Org. Chem, Vol. 69, No. 20, 2004 6673