Chiral N-acylethylenediamines as new modular ligands for the catalytic asymmetric addition of alkylzinc reagents to aldehydes

Article abstract of DOI:10.1021/jo0347516

Chiral N-acylethylenediamines represent a new class of modular ligands for the catalytic asymmetric addition of alkylzinc reagents to aldehydes. The N-acylethylenediamine moiety serves as a metal binding site, while attached amino acids provide the source of chirality. Three sites of diversity on the ligands were optimized to enhance the enantioselectivity of the catalysts using an iterative optimization procedure. The most effective ligand, 4k, was synthesized in a single reaction step from inexpensive and commercially available starting materials. This ligand (10 mol %) catalyzed the addition of Me2Zn to 2-naphthaldehyde, benzaldehyde, and 4-chlorobenzaldehyde to give the corresponding alcohol products in 86%, 84% and 81% ee, respectively.

Full text of DOI:10.1021/jo0347516

Ch ir a l N-Acyleth ylen ed ia m in es a s New Mod u la r Liga n d s for th e
Ca ta lytic Asym m etr ic Ad d ition of Alk ylzin c Rea gen ts to Ald eh yd es
Christopher M. Sprout and Christopher T. Seto*
Department of Chemistry, Brown University, 324 Brook Street, Box H, Providence, Rhode Island 02912
christopher_Seto@brown.edu
Received J une 3, 2003
Chiral N-acylethylenediamines represent a new class of modular ligands for the catalytic asymmetric
addition of alkylzinc reagents to aldehydes. The N-acylethylenediamine moiety serves as a metal
binding site, while attached amino acids provide the source of chirality. Three sites of diversity on
the ligands were optimized to enhance the enantioselectivity of the catalysts using an iterative
optimization procedure. The most effective ligand, 4k , was synthesized in a single reaction step
from inexpensive and commercially available starting materials. This ligand (10 mol %) catalyzed
the addition of Me2Zn to 2-naphthaldehyde, benzaldehyde, and 4-chlorobenzaldehyde to give the
corresponding alcohol products in 86%, 84% and 81% ee, respectively.
In tr od u ction
the structure of each of the subunits that make up the
catalyst can be modified easily.
Over the last several years, a number of investigators
have been applying the techniques of combinatorial
chemistry to problems in asymmetric catalysis.1 One
advantage of this strategy is that a large number of
catalysts can be synthesized and screened for stereose-
lectivity in a relatively short period of time. As a result,
combinatorial methods may help to increase the efficiency
by which chiral catalysts are discovered.
Here, we report on the synthesis of a new class of
modular ligands that are based upon an N-acylethylene-
diamine core (eq 1). The N-acylethylenediamine structure
constitutes a metal binding site, while an attached amino
acid provides a source of chirality.5 Three subunits within
the ligands, the tertiary amine (R1), the amino acid side
chain (R2), and the acyl group on the N-terminus (R3),
can be modified to investigate their influence on the
stereoselectivity of catalyzed reactions. We have initially
applied these ligands to the asymmetric addition of
alkylzinc reagents to aldehydes,6,7 although in the long
term, we envision that they may be applicable to a variety
of other synthetic transformations that involve organo-
metallic reagents. In analogy to the â-amino alcohol class
of ligands, we expect that the N-acylethylenediamines
will be deprotonated by diethylzinc to give a five-
membered chelate in which the tertiary amine and the
anion of the amide are coordinated to zinc.
If a large number of catalysts are to be screened, this
approach requires a method for rapidly measuring the
enantiomeric excess of a large number of chiral samples.2
A variety of methods for doing so have been reported in
the literature,3 including an enzyme-based method that
was developed in our own laboratories.4 A second re-
quirement is the design of ligands or catalysts that can
be synthesized in a modular fashion. With modular
ligands, many catalysts can be synthesized rapidly, and
(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.
Resu lts a n d Discu ssion
The simple one- to three-step synthesis of the ligands
is outlined in Scheme 1. This procedure allows easy
(2) For reviews, see ref 1a and the following: Reetz, M. T. Angew.
Chem., Int. Ed. 2002, 41, 1335.
(3) (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.
(4) Abato, P.; Seto, C. T. J . Am. Chem. Soc. 2001, 123, 9206.
(5) This ligand architecture is related to the wide variety of ligands
that have been developed by Hoveyda and Snapper. For recent
examples, see: (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.
(6) 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.
10.1021/jo0347516 CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/09/2003
7788
J . Org. Chem. 2003, 68, 7788-7794

N-Acylethylenediamines as New Modular Ligands
TABLE 1. Effect of Liga n d R2 Su bstitu en t on th e
Ad d ition of Et2Zn to Ben za ld eh yd ea
SCHEME 1 a
%
%
%
%
ligand amino acid eeb yield ligand amino acid eeb yield
4a
4b
4c
Val
55
54
48
39
75
79
82
82
75
4fd
4g
Chae
t-Leu
o-Cl-Phe
Ala
t-Bu-Thr
38
19
18
12
6
82
Phe
78f
83
a
Reagents: (a) (R1)2NCH2CH2NH2, O-(benzotriazol-1-yl)-
Chgc
t-Bu-Tyr
4h d
4id
4j
N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU), di-
4d
78
isopropylethylamine (DIEA); (b) TFA; (c) R3COCl, triethylamine.
4ed
p-NO2-Phe 41
88f
a
Experiments performed in duplicate unless noted otherwise.
variation of all three diversity elements, R1-R3, within
the ligands so that the enantioselectivity of the catalysts
can be optimized using an iterative process. Boc-protected
amino acids were first coupled to a variety of N,N-
dialkylethylenediamines to yield the corresponding amides.
To vary the R3 substituent, the Boc protecting group was
removed with trifluoroacetic acid, followed by coupling
of the free amine with an acid chloride or a chloroformate
to give the final ligands.
b
% ee of (R)-1-phenyl-1-propanol as measured by HPLC (Chiralcel
OD). c Chg ) cyclohexylglycine. Based on one experiment. e Cha
d
) cyclohexylalanine. f Reactions complete after 4 h.
TABLE 2. Effect of Liga n d R3 Su bstitu en t on th e
Ad d ition of Et2Zn to Ben za ld eh yd ea
Ligand 4b, which is based upon phenylalanine, was
used to optimize the reaction conditions for the addition
of alkylzinc reagents to aldehydes. Noncoordinating
solvents such as hexanes and toluene gave both higher
enantioselectivities and faster reactions when compared
to coordinating solvents such as THF and Et2O. The
stereoselectivity of the reaction was mildly sensitive to
temperature. With ligand 4b, lowering the temperature
of the reaction from 0 to -45 °C resulted in a modest
increase in enantioselectivity from 54% to 63% ee.
However, the reactions were significantly slower at the
lower temperature. Equation 2 shows the final conditions
%
%
%
%
ligand
R3
eeb yield ligand
R3
eeb yield
1a
O-t-Bu
t-Bu
59 83
53 82
42 72
1f
CH2NHBoc 28 43
1bc
1c
1g
1h c
1i
OMe
27 77
22 63
16 79e
adamantyl
4-Me-C6H5
OBn
4-NO2-C6H5
1d
1e
OCH2-fluorenyl 37 82
O-i-Bu
34 76d
1jc
9
48
a
Experiments performed in duplicate unless noted otherwise.
b
% ee of (R)-1-phenyl-1-propanol as measured by HPLC (Chiralcel
OD). c Based on one experiment. Reaction run for 48 h. e Reaction
d
run for 72 h.
(4e) substituents on Phe decreased the ee by approxi-
mately 15%, while a chloro substituent at the ortho-
position (4h ) resulted in a much larger decrease in
enantioselectivity. Very large amino acid side chains,
such as t-Leu (4g) and t-Bu-Thr (4j), and small side
chains, such as Ala (4i), are also detrimental to the
stereoselectivity of the alkylation reaction.
that were chosen for the alkylation reactions, which
included 3 equiv of alkylzinc and 10 mol % ligand in
hexanes at 0 °C.
In the next stage of optimization, the R3 substituent
of the ligands was varied, while the R2 position was held
constant as the isopropyl side chain of valine and ethyl
was chosen for the R1 position (Table 2). Both carbamates
and amides are well tolerated at R3. Again, steric effects
are the most important factor in determining enantiose-
lectivity across this series of ligands. Compounds with
the bulky Boc (1a ) and pivaloyl amide (1b) groups gave
the highest ee values in the alkylation reaction, while
the ligands with adamantyl (1c) and fluorenyl (1d )
groups were somewhat less stereoselective. Ligands with
small aliphatic or aromatic groups at the R3 position
(1e-j) gave low stereoselectivity.
Equation 1 shows a bidentate binding mode between
the zinc atom and a monoanionic ligand. However, we
observe that the steric bulk of the R3 substituent, which
is remote from the site of catalysis, is important for
determining stereoselectivity. This observation suggests
the possibility that the dianionic form of the ligand could
bind zinc in a tridentate fashion, as shown in Figure 1.
Tridentate chelation would bring the R3 substituent into
closer proximity with the zinc atom and provides a
We first examined how the amino acid side chain (R2)
of the ligands influence the stereoselectivity of the
addition reaction, while the R1 and R3 groups were held
constant as methyl and tert-butoxy, respectively (Table
1). Steric factors appear to play the dominant role in
determining enantioselectivity in this series of ligands.
Amino acid side chains that contain â-branching such as
valine (4a ) and cyclohexylglycine (4c), along with the
unsubstituted aromatic ring of phenylalanine (4b), gave
the highest % ee. Electron-donating (4d ) or -withdrawing
(7) 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.
J . Org. Chem, Vol. 68, No. 20, 2003 7789

Sprout and Seto
TABLE 4. Va r ia tion of Su bstr a te a n d Dia lk ylzin c
Rea gen t Usin g Op tim ized Liga n d 4k a
ee
%
ee
%
F IGUR E 1. Possible trivalent binding mode of zinc to the
ligands.
b
b
entry
R
R′
%
yieldc entry
R
R′
%
yieldc
1
2
3
4
5
6
2-naphthyl Me 86 72
2-naphthyl Et 73 94
9
1-naphthyl
Et 24 89
10 trans-PhCHCH Me 25 24e
11 trans-PhCHCH Et 61 89
TABLE 3. Effect of Liga n d R1 Su bstitu en t on th e
Ad d ition of Et2Zn to Ben za ld eh yd ea
Ph
Ph
Me 84 68
Et 68 84
Me 81 77
Et 77 100
Et 90 79
12 C(CH3)3
Et 57f 7g
Et 40 88
Et 17f 81
4-Cl-Ph
4-Cl-Ph
13 4-MeO-Ph
14 cyclohexyl
15 PhCH2CH2
7d 4-Cl-Ph
Et
0
78
8
1-naphthyl Me 76 73
a
b
All experiments performed in duplicate. % ee of (R)-alcohol
%
%
%
%
as measured by HPLC (Chiralcel OD-H). c Reactions were allowed
ligand
R1
eeb yield ligand
R1
eeb yield
d
to proceed from 17 to 72 h. Reaction performed at -48 °C for 72
h. e 30% conversion after 48 h. f Determined using the correspond-
4k
4l
4m
1a
-(CH2)2O(CH2)2- 68
86
68
74
83
4a
Me
55 75
ing (R)-R-methoxy-R-trifluoromethylphenyl ester by 19F NMR
-(CH2)4-
-(CH2)5-
Et
67
66
59
4n c
4o
n-Bu 40 49
i-Pr
g
30 93d
spectroscopy. Neopentyl alcohol is a major side product in this
reaction.
a
Experiments performed in duplicate unless noted otherwise.
b
% ee of (R)-1-phenyl-1-propanol as measured by HPLC (Chiralcel
matic aldehydes was generally higher than with aliphatic
aldehydes. Substrates including 2-naphthaldehyde, ben-
zaldehyde, and 4-chlorobenzaldehyde react with dimeth-
ylzinc in the presence of ligand 4k to give the correspond-
ing alcohol product with 81-86% ee. Aliphatic aldehydes
(entries 12, 14, and 15) and aromatic aldehydes with
electron-donating substituents (entry 13) gave lower
stereoselectivity. Finally, entry 7 shows that for the
reaction between 4-chlorobenzaldehyde and dimethylzinc
the enantioselectivity of the reaction can be increased
from 77% to 90% ee by reducing the temperature of the
reaction from 0 to -48 °C.
OD). c Based on one experiment. Reaction run for 43 h.
d
reasonable explanation for its influence on the stereose-
lectivity.8 The use of tridentate or tetradentate ligands
for zinc to promote the asymmetric alkylation of alde-
hydes has been described by several investigators, in-
cluding Corey9 and Polt.10 An alternate explanation for
the influence of the R3 substituent is that bulky R3 groups
may restrict the population of amide bond rotamers in
the ligands, and this may lead to an enhancement of
stereoselectivity.
In the final round of optimization, we examined the
influence of the tertiary amine component of the ligands
(R1) on stereoselectivity (Table 3). Ligands with a cyclic
tertiary amine including morpholine (4k ), pyrrolidine
(4l), and piperidine (4m ) were the most selective. The
morpholine ring system appears as a common structural
motif in a variety of other amino alcohol-based chiral
ligands.11,12 By contrast, noncyclic amines gave ee values
that were approximately 10-30% lower than the cyclic
analogues. The sterically hindered diisopropylamino
analogue showed the lowest selectivity in this series.
Ligand 4k gives the highest stereoselectivity for the
addition of diethylzinc to benzaldehyde. Therefore, we
have screened this ligand against a variety of other
aldehydes using both diethylzinc and dimethylzinc (Table
4). Several trends have emerged from these experiments.
First, the reactions with diethylzinc were significantly
faster than reactions with dimethylzinc. Second, di-
methylzinc generally gave products with higher ee values
when compared to diethylzinc. The only exception to this
trend is in the case of trans-cinnamaldehyde (entries 10
and 11), where the reaction with diethylzinc was more
stereoselective. Third, the enantioselectivity with aro-
Con clu sion s
In summary, we have developed a new class of modular
ligands that consist of an N-acylethylenediamine metal-
binding moiety coupled to an amino acid that serves as
a source of chirality. Three sites within the ligands were
varied in order to optimize enantioselectivity. This
process resulted in the valine-based ligand 4k , which
catalyzes the addition of dimethylzinc to benzaldehyde,
2-naphthaldehyde, and 4-Cl-benzaldehyde with reason-
able enantioselectivity. Our future work will involve the
development of libraries of chiral ligands that are based
upon the N-acylethylenediamine motif in order to im-
prove further their stereoselectivity and to investigate
their application to other reactions.
Exp er im en ta l Section
Syn th esis of Liga n d s 4a -o, 1a , 1d , a n d 1i. Gen er a l
P r oced u r e. To the appropriate N-protected amino acid (1.5
equiv) were added HBTU (2.2 equiv), DIEA (3.0 equiv), and
enough DMF to dissolve all the solids. After stirring for 5 min,
the appropriate N,N-dialkylethylenediamine (1.0 equiv) was
added. The reaction was stirred at room temperature for 1 h
and then diluted with H2O. The aqueous phase was then
extracted with EtOAc and the organic phase washed with H2O
and brine. The organic layer was dried over Na2SO4, the
solvent removed, and the crude product purified by column
chromatography.
(8) When 2 equiv of diethylzinc are added to a solution of ligand 4k
in toluene-d8, the 1H NMR spectrum shows the disappearance of both
of the NH protons and formation of ethane.
(9) Corey, E. J .; Yuen, P.-W.; Hannon, F. J .; Wierda, D. A. J . Org.
Chem. 1990, 55, 784.
(10) Dangel, B. D.; Polt, R. Org. Lett. 2000, 2, 3003.
(11) Nugent, W. A. J . Chem. Soc., Chem. Commun. 1999, 1369.
(12) Cho, B. T.; Kim, N. J . Chem. Soc., Perkin Trans. 1 1996, 2901.
[1-(2-(Dim eth ylam in o)eth ylcar bam oyl)-2-m eth ylpr opyl]-
ca r ba m ic Acid ter t-Bu tyl Ester 4a . Compound 4a was
7790 J . Org. Chem., Vol. 68, No. 20, 2003

N-Acylethylenediamines as New Modular Ligands
prepared as described above from Boc-Val-OH (0.570 g, 2.62
mmol) and N,N-dimethylethylenediamine (0.432 mL, 3.94
mmol). Chromatography (0.7:6.3:93 30% aqueous NH4OH/
MeOH/CH2Cl2) of the crude material yielded a white solid
(0.159 g, 0.553 mmol, 21%): mp 88-90 °C; 1H NMR (300 MHz,
CDCl3) δ 6.45 (br s, 1 H), 5.15 (br d, 1 H), 3.89 (dd, J ) 8.7,
6.3 Hz, 1 H), 3.33 (dt, J ) 5.9, 5.6 Hz, 2 H), 2.41 (dt, J ) 6.1,
1.9 Hz, 2 H), 2.22 (s, 6 H), 2.10 (m, 1 H), 1.45 (s, 9 H), 0.94
(dd, J ) 11.6, 6.9 Hz, 6 H); 13C NMR (75 MHz, CDCl3) δ 172.5,
156.4, 80.4, 60.6, 58.3, 45.2, 36.5, 31.3, 28.7, 19.6, 18.3; HRMS-
ESI (M + H+) calcd for C14H30N3O3 288.2287, found 288.2294;
δ 170.7, 155.6, 147.3, 145.3, 130.7, 124.0, 80.7, 57.8, 55.8, 45.3,
39.2, 37.1, 28.6; HRMS-ESI (M + H+) calcd for C18H29N4O5
25
381.2138, found 381.2126; [R]D ) +3.4 (c ) 1.0, CHCl3).
[2-Cycloh exyl-1-(2-(d im eth yla m in o)eth ylca r ba m oyl)-
eth yl]ca r ba m ic Acid ter t-Bu tyl Ester 4f. Compound 4f was
prepared as described above from Boc-Cha-OH (0.198 g, 0.728
mmol) and N,N-dimethylethylenediamine (0.120 mL, 1.09
mmol). Chromatography (0.5:4.5:95 30% aqueous NH4OH/
MeOH/CH2Cl2) of the crude material yielded a white solid
(0.160 g, 0.468 mmol, 65%): mp 64-66 °C; 1H NMR (300 MHz,
CDCl3) δ 6.58 (br s, 1 H), 4.96 (br d, 1 H), 4.14 (m, 1 H), 3.35
(dt, J ) 5.9, 5.4 Hz, 2 H), 2.45 (t, J ) 6.0 Hz, 2 H), 2.27 (s, 6
H), 1.83-1.64 (m, 7 H), 1.46 (s, 9 H), 1.34-1.27 (m, 4 H), 0.95
(m, 2 H); 13C NMR (75 MHz, CDCl3) δ 173.0, 155.9, 80.2, 58.1,
52.8, 45.5, 40.8, 37.1, 34.5, 34.0, 33.1, 28.7, 26.8, 26.7, 26.5;
HRMS-ESI (M + H+) calcd for C18H36N3O3 342.2757, found
25
[R]D ) +1.4 (c ) 1.0, CHCl3).
[1-(2-(Dim eth yla m in o)eth ylca r ba m oyl)-2-p h en yleth yl]-
ca r ba m ic Acid ter t-Bu tyl Ester 4b. Compound 4b was
prepared as described above from Boc-Phe-OH (0.725 g, 2.73
mmol) and N,N-dimethylethylenediamine (0.500 mL, 4.56
mmol). Chromatography (1:9:90 30% aqueous NH4OH/MeOH/
CH2Cl2) of the crude material yielded a white solid (0.708 g,
2.11 mmol, 77%): mp 113-114 °C; 1H NMR (300 MHz, CDCl3)
δ 7.33-7.21 (m, 5 H), 6.19 (br s, 1 H), 5.18 (br s, 1 H), 4.31 (d,
J ) 6.7 Hz, 1 H), 3.23 (t, J ) 10.3 Hz, 2 H), 3.10 (dd, J ) 13.5,
6.0 Hz, 1 H), 3.02 (m, 1 H), 2.29 (m, 1 H), 2.23 (m, 1 H), 2.13
(s, 6 H), 1.43 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ 171.4, 155.6,
137.3, 129.7, 129.0, 127.2, 80.3, 57.7, 56.4, 45.3, 39.6, 36.9, 28.7;
HRMS-ESI (M + H+) calcd for C18H30N3O3 336.2287, found
25
342.2749; [R]D ) -12 (c ) 1.1, CHCl3).
[1-(2-(Dim et h yla m in o)et h ylca r ba m oyl)-2,2-d im et h yl-
p r op yl]ca r ba m ic Acid ter t-Bu tyl Ester 4g. Compound 4g
was prepared as described above from Boc-t-Leu-OH (0.078 g,
0.337 mmol) and N,N-dimethylethylenediamine (0.044 mL,
0.404 mmol). Chromatography (30:70 MeOH/CH2Cl2) of the
crude material yielded a yellow solid (0.055 g, 0.182 mmol,
54%): mp 127-133 °C; 1H NMR (300 MHz, CDCl3) δ 6.36 (br
s, 1 H), 5.34 (d, J ) 9.1 Hz, 1 H), 3.82 (d, J ) 9.4 Hz, 1 H),
3.34 (m, 2 H), 2.43 (m, 2 H), 2.23 (s, 6 H), 1.44 (s, 9 H), 0.99 (s,
9 H); 13C NMR (75 MHz, CDCl3) δ 171.1, 156.2, 79.9, 62.8,
57.9, 45.4, 36.9, 35.0, 28.7, 27.0; HRMS-ESI (M + H+) calcd
25
336.2281; [R]D ) +15 (c ) 1.0, CHCl3).
25
for C15H32N3O3 302.2444, found 302.2439; [R]D ) +15 (c )
[C y c lo h e x y l-(2-(d im e t h y la m in o )e t h y lc a r b a m o y l)-
m eth yl]ca r ba m ic Acid ter t-Bu tyl Ester 4c. Compound 4c
was prepared as described above from Boc-Chg-OH (0.302 g,
1.17 mmol) and N,N-dimethylethylenediamine (0.219 mL, 1.99
mmol). Chromatography (0.5:4.5:95 30% aqueous NH4OH/
MeOH/CH2Cl2) of the crude material yielded a white solid
0.81, CHCl3).
[2-(2-Ch lor oph en yl)-1-(2-(dim eth ylam in o)eth ylcar bam -
oyl)eth yl]ca r ba m ic Acid ter t-Bu tyl Ester 4h . Compound
4h was prepared as described above from Boc-Phe(2-Cl)-OH
(0.319 g, 1.06 mmol) and N,N-dimethylethylenediamine (0.198
mL, 1.81 mmol). Chromatography (gradient of 0.5:4.5:95 to
0.8:7.2:92 30% aqueous NH4OH/MeOH/CH2Cl2) of the crude
material yielded a white solid (0.258 g, 0.697 mmol, 66%): mp
132-133 °C; 1H NMR (300 MHz, CDCl3) δ 7.36 (m, 1 H), 7.27
(m, 1 H), 7.19 (m, 2 H), 6.24 (br s, 1 H), 5.25 (d, J ) 7.3 Hz, 1
H), 4.43 (dd, J ) 15.0, 7.4 Hz, 1 H), 3.21 (m, 4 H), 2.31 (m, 1
H), 2.22 (m, 1 H), 2.13 (s, 6 H), 1.38 (s, 9 H); 13C NMR (75
MHz, CDCl3) δ 171.2, 155.6, 135.4, 134.8, 132.0, 129.9, 128.7,
127.3, 80.3, 57.8, 55.0, 45.4, 37.3, 37.1, 28.7; HRMS-ESI (M +
1
(0.213 g, 0.650 mmol, 71%): mp 112-114 °C; H NMR (300
MHz, CDCl3) δ 6.50 (br s, 1 H), 5.17 (br d, 1 H), 3.87 (dd, J )
8.5, 6.7 Hz, 1 H), 3.33 (dt, J ) 5.9, 5.5 Hz, 2 H), 2.40 (dt, J )
6.0, 2.2 Hz, 2 H), 2.22 (s, 6 H), 1.73-1.65 (m, 5 H), 1.44 (s, 9
H), 1.28-0.96 (m, 6 H); 13C NMR (75 MHz, CDCl3) δ 171.9,
156.2, 80.0, 59.9, 58.1, 45.5, 41.2, 37.1, 30.1, 28.7, 26.5, 26.4;
HRMS-ESI (M + H+) calcd for C17H34N3O3 328.2600, found
25
328.2601; [R]D ) +9.6 (c ) 1.0, CHCl3).
H+) calcd for C18H29N3O3Cl 370.1897, found 370.1882; [R]D
) +11 (c ) 1.0, CHCl3).
25
[2-(4-ter t-Bu t oxyp h en yl)-1-(2-(d im et h yla m in o)et h yl-
car bam oyl)eth yl]car bam ic Acid ter t-Bu tyl Ester 4d. Com-
pound 4d was prepared as described above from Boc-Tyr(tert-
Bu)-OH (0.349 g, 1.04 mmol) and N,N-dimethylethylenediamine
(0.171 mL, 1.55 mmol). Chromatography (0.5:4.5:95 30%
aqueous NH4OH/MeOH/CH2Cl2) of the crude material yielded
[1 -(2 -(D i m e t h y l a m i n o )e t h y l c a r b a m o y l )e t h y l ]-
ca r ba m ic Acid ter t-Bu tyl Ester 4i. Compound 4i was
prepared as described above from Boc-Ala-OH (2.02 g, 10.7
mmol) and N,N-dimethylethylenediamine (1.76 mL, 16.0
mmol). Chromatography (0.5:4.5:95 30% aqueous NH4OH/
MeOH/CH2Cl2) of the crude material yielded a white solid
(0.360 g, 1.39 mmol, 22%): mp 61-64 °C; 1H NMR (300 MHz,
CDCl3) δ 6.64 (br s, 1 H), 5.14 (br s, 1 H), 4.15 (t, J ) 6.9 Hz,
1 H), 3.34 (m, 2 H), 2.45 (t, J ) 6.0 Hz, 2 H), 2.25 (s, 6 H), 1.45
(s, 9 H), 1.36 (d, J ) 7.0 Hz, 3 H); 13C NMR (75 MHz, CDCl3)
δ 173.2, 155.8, 80.3, 58.1, 50.6, 45.5, 37.1, 28.7, 19.2; HRMS-
ESI (M + H+) calcd for C12H26N3O3 260.1974, found 260.1986;
1
a white solid (0.245 g, 0.601 mmol, 60%): mp 76-77 °C; H
NMR (300 MHz, CDCl3) δ 7.11 (d, J ) 8.4 Hz, 2 H), 6.92 (d, J
) 7.7 Hz, 2 H), 6.27 (br s, 1 H), 5.16 (d, J ) 6.3 Hz, 1 H), 4.28
(d, J ) 7.2 Hz, 1 H), 3.24 (m, 2 H), 3.00 (t, J ) 6.4 Hz, 2 H),
2.28 (m, 2 H), 2.14 (s, 6 H), 1.42 (s, 9 H), 1.34 (s, 9 H); 13C
NMR (75 MHz, CDCl3) δ 171.5, 155.7, 154.6, 132.0, 130.1,
124.6, 80.3, 78.8, 57.9, 56.4, 45.4, 38.8, 37.1, 29.2, 28.7; HRMS-
ESI (M + H+) calcd for C22H38N3O4 408.2862, found 408.2861;
25
[R]D ) -11 (c ) 3.5, CHCl3).
[2-ter t-Bu toxy-1-(2-(d im eth yla m in o)eth ylca r ba m oyl)-
p r op yl]ca r ba m ic Acid ter t-Bu tyl Ester 4j. Compound 4j
was prepared as described above from Boc-Thr(t-Bu)-OH
(0.372 g, 1.35 mmol) and N,N-dimethylethylenediamine (0.223
mL, 2.03 mmol). Chromatography (0.5:4.5:95 30% aqueous
NH4OH/MeOH/CH2Cl2) of the crude material yielded a white
solid (0.216 g, 0.625 mmol, 46%): mp 65-67 °C; 1H NMR (300
MHz, CDCl3) δ 7.33 (br s, 1 H), 5.68 (d, J ) 5.0 Hz, 1 H), 4.12-
4.08 (m, 2 H), 3.35 (dt, J ) 6.5, 5.3 Hz, 2 H), 2.41 (m, 2 H),
2.24 (s, 6 H), 1.46 (s, 9 H), 1.25 (s, 9 H), 1.05 (d, J ) 6.1 Hz, 3
H); 13C NMR (75 MHz, CDCl3) δ 170.2, 156.0, 79.9, 75.3, 67.3,
58.9, 58.0, 45.5, 37.4, 28.8, 28.6, 18.1; HRMS-ESI (M + H+)
25
[R]D ) +13 (c ) 1.1, CHCl3).
[1-(2-(Dim e t h yla m in o)e t h ylca r b a m oyl)-2-(4-n it r o-
p h en yl)eth yl]ca r ba m ic Acid ter t-Bu tyl Ester 4e. Com-
pound 4e was prepared as described above from Boc-Phe(p-
NO2)-OH (0.356 g, 1.15 mmol) and N,N-dimethylethylenedi-
amine (0.214 mL, 1.95 mmol). Chromatography (0.5:4.5:95 30%
aqueous NH4OH/MeOH/CH2Cl2) of the crude material yielded
a yellow solid (0.243 g, 0.639 mmol, 56%): mp 117-119 °C;
1H NMR (300 MHz, CDCl3) δ 8.17 (dd, J ) 6.9, 1.8 Hz, 2 H),
7.40 (dd, J ) 7.0, 1.7 Hz, 2 H), 6.52 (br s, 1 H), 5.33 (d, J ) 8.5
Hz, 1 H), 4.39 (dd, J ) 14.9, 7.2 Hz, 1 H), 3.21 (m, 4 H), 2.31
(m, 2 H), 2.13 (s, 6 H), 1.40 (s, 9 H); 13C NMR (75 MHz, CDCl3)
25
calcd for C17H36N3O4 346.2706, found 346.2697; [R]D ) +38
(c ) 3.4, CHCl3).
J . Org. Chem, Vol. 68, No. 20, 2003 7791

Sprout and Seto
[2-Meth yl-1-[2-m or p h olin -4-yleth ylca r ba m oyl)p r op yl]-
ca r ba m ic Acid ter t-Bu tyl Ester 4k . Compound 4k was
prepared as described above from Boc-Val-OH (1.02 g, 4.69
mmol) and 2-morpholin-4-ylethylamine (0.681 mL, 5.19 mmol).
Chromatography (0.5:4.5:95 30% aqueous NH4OH/MeOH/CH2-
Cl2) of the crude material yielded a white solid (1.18 g, 3.58
mmol, 76%, mp 92-95 °C). It was found that in some instances
the material that was purified by chromatography required
recrystallization from EtOAc/hexanes to provide a colorless
ligand that produced the highest ee values for the dialkylzinc
(dd, J ) 8.4, 5.8 Hz, 1 H), 3.35 (m, 2 H), 3.20 (t, J ) 6.2 Hz, 2
H), 2.78 (m, 2 H), 2.17 (m, 1 H), 1.44 (s, 9 H), 1.12 (d, J ) 6.6
Hz, 12 H), 0.96 (d, J ) 6.8 Hz, 3 H), 0.90 (d, J ) 6.9 Hz, 3 H);
13C NMR (75 MHz, CDCl3) δ 173.4, 156.2, 80.3, 60.4, 49.8, 44.8,
38.2, 31.1, 28.7, 20.5, 19.7, 18.0; HRMS-ESI (M + H+) calcd
25
for C18H38N3O3 344.2913, found 344.2912; [R]D ) -0.73 (c )
3.4, CHCl3).
[1-(2-(Dieth yla m in o)eth ylca r ba m oyl)-2-m eth ylp r op yl]-
ca r ba m ic Acid ter t-Bu tyl Ester 1a . Compound 1a was
prepared as described above from Boc-Val-OH (5.00 g, 23.0
mmol) and N,N-diethylethylenediamine (4.85 mL, 34.5 mmol).
Chromatography (0.7:6.3:93 30% aqueous NH4OH/MeOH/CH2-
Cl2) of the crude material yielded a white solid (6.88 g, 21.8
mmol, 95%): mp 78-80 °C; 1H NMR (300 MHz, CDCl3) δ 6.76
(br s, 1 H), 5.13 (d, J ) 7.9 Hz, 1 H), 3.88 (dd, J ) 8.2, 6.1 Hz,
1 H), 3.40 (m, 2 H), 2.71 (m, 6 H), 2.10 (m, 1 H), 1.45 (s, 9 H),
1.09 (t, J ) 7.2 Hz, 6 H), 0.95 (dd, J ) 10.3, 6.9 Hz, 6 H); 13C
NMR (75 MHz, CDCl3) δ 172.7, 156.3, 80.3, 60.6, 52.4, 47.3,
36.8, 31.2, 28.7, 19.6, 18.3, 11.5; HRMS-ESI (M + H+) calcd
1
addition to aldehydes. H NMR (300 MHz, CDCl3) δ 6.39 (br
s, 1 H), 5.11 (d, J ) 7.2 Hz, 1 H), 3.89 (dd, J ) 8.7, 6.3 Hz, 1
H), 3.72 (t, J ) 4.5 Hz, 4 H), 3.38 (m, 2 H), 2.48 (m, 6 H), 2.11
(m, 1 H), 1.45 (s, 9 H), 0.95 (t, J ) 7.4 Hz, 6 H); 13C NMR (75
MHz, CDCl3) δ 171.9, 156.2, 80.1, 67.3, 60.4, 57.2, 53.7, 36.0,
31.5, 28.7, 19.6, 18.4; HRMS-ESI (M + H+) calcd for C16H32N3O4
25
330.2393, found 330.2408; [R]D ) -3.8 (c ) 1.0, CHCl3).
[2-Meth yl-1-[2-p yr r olid in -1-yleth ylca r ba m oyl)p r op yl]-
ca r ba m ic Acid ter t-Bu tyl Ester 4l. Compound 4l was
prepared as described above from Boc-Val-OH (0.515 g, 2.37
mmol) and 2-pyrrolidin-1-yl-ethylamine (0.451 mL, 3.56 mmol).
Chromatography (0.7:6.3:93 30% aqueous NH4OH/MeOH/
CH2Cl2) of the crude material yielded a yellow solid (0.263 g,
0.839 mmol, 35%): mp 98-103 °C; 1H NMR (300 MHz, CDCl3)
δ 6.58 (br s, 1 H), 5.18 (br d, 1 H), 3.88 (dd, J ) 8.7, 6.3 Hz, 1
H), 3.38 (dt, J ) 6.4, 5.3 Hz, 2 H), 2.63 (dt, J ) 6.1, 1.5 Hz, 2
H), 2.55 (br s, 4 H), 2.09 (m, 1 H), 1.79 (m, 4 H), 1.44 (s, 9 H),
0.94 (dd, J ) 10.0, 6.9 Hz, 6 H); 13C NMR (75 MHz, CDCl3) δ
172.0, 156.3, 80.1, 60.4, 54.9, 54.2, 38.3, 31.5, 28.7, 23.8, 19.6,
18.3; HRMS-ESI (M + H+) calcd for C16H32N3O3 314.2444,
25
for C16H34N3O3 316.2600, found 316.2600; [R]D ) -0.57 (c )
3.5, CHCl3).
[1-[2-(Dieth yla m in o)eth ylca r ba m oyl)-2-m eth ylp r op yl]-
ca r ba m ic Acid 9H-F lu or en -9-ylm eth yl Ester 1d . Com-
pound 1d was prepared as described above from Fmoc-Val-
OH (0.804 g, 2.37 mmol) and N,N-diethylethylenediamine (0.50
mL, 3.55 mmol). Chromatography (0.4:3.6:96 30% aqueous
NH4OH/MeOH/CH2Cl2) of the crude material yielded a white
solid (0.908 g, 2.07 mmol, 88%): mp 109-110 °C; 1H NMR
(300 MHz, CDCl3) δ 7.78 (d, J ) 7.4 Hz, 2 H), 7.62 (d, J ) 7.3
Hz, 2 H), 7.41 (t, J ) 7.4 Hz, 2 H), 7.35 (t, J ) 6.7 Hz, 2 H),
6.62 (br s, 1 H), 5.60 (d, J ) 8.7 Hz, 1 H), 4.40 (m, 2 H), 4.23
(t, J ) 7.0 Hz, 1 H), 3.99 (dd, J ) 8.4, 6.7 Hz, 1 H), 3.35 (t, J
) 4.5 Hz, 2 H), 2.59 (m, 6 H), 2.13 (m, 1 H), 1.00 (m, 12 H);
13C NMR (75 MHz, CDCl3) δ 171.5, 156.8, 144.3, 144.2, 141.7,
129.2, 128.1, 127.5, 125.6, 125.5, 121.4, 120.4, 120.2, 67.5, 61.0,
51.8, 47.6, 47.4, 47.0, 37.1, 31.7, 19.5, 18.5, 12.1, 11.9; HRMS-
ESI (M + H+) calcd for C26H36N3O3 438.2757, found 438.2753;
25
found 314.2450; [R]D ) +3.9 (c ) 0.33, CHCl3).
[2-Meth yl-1-(2-p ip er id in -1-yleth ylca r ba m oyl)p r op yl]-
ca r ba m ic Acid ter t-Bu tyl Ester 4m . Compound 4m was
prepared as described above from Boc-Val-OH (1.07 g, 4.92
mmol) and 2-piperidin-1-ylethylamine (1.05 mL, 7.39 mmol).
Chromatography (0.5:4.5:95 30% aqueous NH4OH/MeOH/
CH2Cl2) of the crude material yielded a white solid (1.137 g,
3.47 mmol, 70%, mp 91-93 °C). It was found that in some
instances the material that was purified by chromatography
required recrystallization from EtOAc/hexanes to provide a
colorless ligand that produced the highest ee values for the
dialkylzinc addition to aldehydes. 1H NMR (300 MHz, CDCl3)
δ 6.69 (br s, 1 H), 5.15 (d, J ) 6.8 Hz, 1 H), 3.88 (dd, J ) 8.1,
6.1 Hz, 1 H), 3.42 (m, 2 H), 2.59 (m, 6 H), 2.10 (m, 1 H), 1.64
(m, 4 H), 1.52 (m, 2 H), 1.46 (s, 9 H), 0.96 (t, J ) 7.3 Hz, 6 H);
13C NMR (75 MHz, CDCl3) δ 172.5, 156.4, 80.4, 60.6, 57.7, 54.7,
36.0, 31.3, 28.7, 25.8, 24.1, 19.5, 18.4; HRMS-ESI (M + H+)
25
[R]D ) -7.2 (c ) 1.0, CHCl3).
[1-(2-(Dieth yla m in o)eth ylca r ba m oyl)-2-m eth ylp r op yl]-
ca r ba m ic Acid Ben zyl Ester 1i. Compound 1i was prepared
as described above from Cbz-Val-OH (0.894 g, 3.56 mmol) and
N,N-diethylethylenediamine (0.750 mL, 5.34 mmol). Chroma-
tography (0.6:5.4:94 30% aqueous NH4OH/MeOH/CH2Cl2) of
the crude material yielded a white solid (0.725 g, 2.07 mmol,
58%): mp 104-106 °C; 1H NMR (300 MHz, CDCl3) δ 7.34 (m,
5 H), 6.68 (br s, 1 H), 5.47 (br d, 1 H), 5.11 (s, 2 H), 3.96 (dd,
J ) 8.3, 6.1 Hz, 1 H), 3.37 (dt, J ) 5.6, 5.2 Hz, 2 H), 2.63 (m,
6 H), 2.11 (m, 1 H), 1.05 (t, J ) 7.1 Hz, 6 H), 0.96 (dd, J ) 9.7,
6.9 Hz, 6 H); 13C NMR (75 MHz, CDCl3) δ 171.9, 156.9, 136.6,
129.0, 128.6, 128.4, 67.4, 61.1, 52.0, 47.1, 36.8, 31.5, 19.6, 18.3,
11.6; HRMS-ESI (M + H+) calcd for C19H32N3O3 350.2444,
25
calcd for C17H34N3O3 328.2600, found 328.2597; [R]D ) +2.0
(c ) 2.5, CHCl3).
[1-(2-(Dibu tyla m in o)eth ylca r ba m oyl)-2-m eth ylp r op yl]-
ca r ba m ic Acid ter t-Bu tyl Ester 4n . Compound 4n was
prepared as described above from Boc-Val-OH (0.930 g, 4.28
mmol) and N,N-dibutylethylenediamine (1.35 mL, 6.42 mmol).
Chromatography (0.4:3.6:96 30% aqueous NH4OH/MeOH/CH2-
Cl2) of the crude material yielded a white solid (0.721 g, 1.94
mmol, 45%): mp 43-46 °C; 1H NMR (300 MHz, CDCl3) δ 7.05
(br s, 1 H), 5.07 (d, J ) 6.4 Hz, 1 H), 3.88 (m, 1 H), 3.56-3.46
(m, 2 H), 3.02 (m, 2 H), 2.84 (br s, 4 H), 2.13 (m, 1 H), 1.57 (m,
4 H), 1.46 (m, 9 H), 1.37 (m, 4 H), 0.96 (m, 12 H); 13C NMR
(75 MHz, CDCl3) δ 174.3, 156.5, 80.6, 60.8, 55.0, 54.1, 36.5,
30.9, 28.7, 27.5, 20.5, 19.6, 18.3, 14.1; HRMS-ESI (M + H+)
calcd for C20H42N3O3 372.3226, found 372.3216; [R]D25 ) 0.0 (c
) 4.0, CHCl3).
[1-(2-(Diisop r op 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 4o. Compound 4o
was prepared as described above from Boc-Val-OH (0.627 g,
2.89 mmol) and N,N-diisopropylethylenediamine (0.750 mL,
4.30 mmol). Chromatography (0.5:4.5:95 30% aqueous NH4-
OH/MeOH/CH2Cl2) of the crude material yielded a white solid
(0.880 g, 2.56 mmol, 89%): mp 114-118 °C; 1H NMR (300
MHz, CDCl3) δ 6.86 (br s, 1 H), 5.08 (d, J ) 8.5 Hz, 1 H), 3.95
25
found 350.2440; [R]D ) +2.6 (c ) 0.93, CHCl3).
Syn th esis of Liga n d s 1b, 1c, 1e, 1 g, 1h , a n d 1j. Gen er a l
P r oced u r e. Ligand 1a was treated with CF3CO2H (10 equiv)
in CH2Cl2 at 0 °C and allowed to warm to room temperature.
The reaction was monitored by TLC (1.5:13.5:85 30% aqueous
NH4OH/MeOH/CH2Cl2), and after the disappearance of start-
ing material, the reaction was diluted with CH2Cl2 followed
by rotary evaporation. The crude material was dissolved in
EtOAc and treated with small aliquots of saturated aqueous
Na2CO3 until the aqueous layer tested basic. The aqueous layer
was further extracted with fresh EtOAc and the combined
organic layers were dried over Na2SO4. The crude material
was used immediately upon isolation, without further purifica-
tion unless otherwise noted. The crude free amine from ligand
1a , 2-amino-N-(2-(diethylamino)ethyl)-3-methylbutyramide,
(1.0 equiv) was dissolved in EtOAc and treated with DIEA
(1.2-3.6 equiv) followed by the appropriate acid chloride or
chloroformate (1.0 equiv). After a few hours the reaction was
quenched with H2O and extracted into EtOAc. The organic
layer was washed with brine and dried over Na2SO4. The crude
product was then purified by column chromatography.
7792 J . Org. Chem., Vol. 68, No. 20, 2003

N-Acylethylenediamines as New Modular Ligands
N-(2-(Diet h yla m in o)et h yl)-2-(2,2-d im et h ylp r op ion y-
la m in o)-3-m eth ylbu tyr a m id e 1b. Compound 1b was pre-
pared as described above using 2,2-dimethylpropionyl chloride
(0.079 mL, 0.64 mmol) and 2-amino-N-(2-(diethylamino)ethyl)-
3-methylbutyramide (0.125 g, 0.581 mmol). Chromatography
(0.5:4.5:95 30% aqueous NH4OH/MeOH/CH2Cl2) of the crude
material yielded a white solid (0.133 g, 0.44 mmol, 76%): mp
123-126 °C; 1H NMR (300 MHz, CDCl3) δ 6.49 (br s, 1 H),
6.34 (d, J ) 8.3 Hz, 1 H), 4.25 (dd, J ) 8.4, 6.4 Hz, 1 H), 3.34
(m, 2 H), 2.56 (m, 6 H), 2.11 (m, 1 H), 1.24 (s, 9 H), 1.04 (t, J
) 7.1 Hz, 6 H), 0.95 (dd, J ) 6.8, 2.9 Hz, 6 H); 13C NMR (75
MHz, CDCl3) δ 178.7, 171.5, 58.5, 51.7, 46.9, 39.3, 37.0, 31.9,
28.0, 19.5, 18.6, 11.9; HRMS-ESI (M + H+) calcd for C16H34N3O2
N-[1-(2-(Dieth yla m in o)eth ylca r ba m oyl)-2-m eth ylp r o-
p yl]-4-m eth ylben za m id e 1h . Compound 1h was prepared
as described above using 4-methylbenzoyl chloride (0.189 mL,
1.43 mmol) and 2-amino-N-(2-(diethylamino)ethyl)-3-methyl-
butyramide (0.307 g, 1.43 mmol). Chromatography (0.5:4.5:
95 30% aqueous NH4OH/MeOH/CH2Cl2) of the crude material
yielded an amorphous solid (0.0918 g, 0.275 mmol, 19%): 1H
NMR (300 MHz, CDCl3) δ 7.70 (d, J ) 8.2 Hz, 2 H), 7.22 (d, J
) 8.0 Hz, 2 H), 6.98 (m, 2 H), 4.40 (dd, J ) 7.9, 7.1 Hz, 1 H),
3.91 (br s, 1 H), 3.38 (dt, J ) 6.0, 5.7 Hz, 2 H), 2.67 (m, 6 H),
2.38 (s, 1 H), 2.19 (m, 1 H), 1.02 (m, 12 H); 13C NMR (75 MHz,
CDCl3) δ 172.0, 167.9, 142.6, 131.4, 129.6, 127.5, 59.7, 52.1,
47.2, 36.8, 31.8, 21.9, 19.6, 19.0, 11.5; HRMS-ESI (M + H+)
25
25
300.2651, found 300.2657; [R]D ) -9.0 (c ) 2.8, CHCl3).
calcd for C19H32N3O2 334.2495, found 334.2488; [R]D ) +30
(c ) 0.45, CHCl3).
Ad a m a n ta n e-1-ca r boxylic Acid [1-(2-(Dieth yla m in o)-
eth ylca r ba m oyl)-2-m eth ylp r op yl]a m id e 1c. Compound 1c
was prepared as described above using adamantane-1-carbonyl
chloride (0.437 g, 2.20 mmol) and 2-amino-N-(2-(diethylamino)-
ethyl)-3-methylbutyramide (0.473 g, 2.20 mmol). Chromatog-
raphy (0.5:4.5:95 30% aqueous NH4OH/MeOH/CH2Cl2) of the
crude material yielded a white solid (0.210 g, 0.556 mmol,
25%): mp 150-210 °C dec; 1H NMR (300 MHz, CDCl3) δ 6.93
(br s, 1 H), 6.33 (br d, 1 H), 4.27 (dd, J ) 8.5, 6.4 Hz, 1 H),
3.36 (m, 2 H), 2.61 (m, 6 H), 2.09 (m, 1 H), 2.06 (m, 3 H), 1.91
(m, 6 H), 1.73 (d, J ) 2.4 Hz, 6 H), 1.06 (t, J ) 7.2 Hz, 6 H),
0.94 (t, J ) 6.6 Hz, 6 H); 13C NMR (75 MHz, CDCl3) δ 178.3,
171.9, 58.2, 51.7, 46.8, 41.2, 39.7, 39.6, 37.1, 36.9, 36.7, 31.8,
N-[1-(2-(Dieth yla m in o)eth ylca r ba m oyl)-2-m eth ylp r o-
p yl]-4-n itr oben za m id e 1j. Compound 1j was prepared as
described above using 4-nitrobenzoyl chloride (0.192 mL, 1.04
mmol) and 2-amino-N-(2-(diethylamino)ethyl)-3-methylbutyra-
mide (0.223 g, 1.04 mmol). Chromatography (0.7:6.3:93 30%
aqueous NH4OH/MeOH/CH2Cl2) of the crude material yielded
1
a yellow solid (0.157 g, 0.431 mmol, 42%): mp 89-94 °C; H
NMR (300 MHz, CDCl3) δ 8.29 (dt, J ) 8.9, 2.1 Hz, 2 H), 8.00
(dt, J ) 8.9, 2.1 Hz, 2 H), 7.24 (d, J ) 8.4 Hz, 1 H), 6.68 (br s,
1 H), 4.47 (dd, J ) 8.4, 6.7 Hz, 1 H), 3.36 (m, 2 H), 2.56 (m, 6
H), 2.20 (m, 1 H), 1.03 (m, 12 H); 13C NMR (75 MHz, CDCl3)
δ 170.9, 165.6, 150.0, 140.2, 128.8, 124.2, 59.5, 51.5, 46.9, 37.2,
32.3, 19.5, 18.9, 12.0; HRMS-ESI (M + H+) calcd for C18H29N4O4
28.6, 28.5, 19.7, 18.5, 11.3; HRMS-ESI (M + H+) calcd for
25
25
365.2189, found 365.2193; [R]D ) +36 (c ) 1.5, CHCl3).
C
22H40N3O2 378.3121, found 378.3127; [R]D ) -2.9 (c ) 4.7,
{ [ 1 - ( 2 - ( D i e t h y l a m i n o ) e t h y l c a r b a m o y l ) - 2 -
m et h ylp r op ylca r b a m oyl]m et h yl}ca r b a m ic Acid ter t-
Bu tyl Ester 1f. 2-Amino-N-(2-(diethylamino)ethyl)-3-meth-
ylbutyramide (0.180 g, 0.83 mmol) was coupled to Boc-glycine
(0.122 g, 0.695 mmol) using the general procedure used to
synthesize ligands 4a -o. Chromatography (0.7:6.3:93 30%
aqueous NH4OH/MeOH/CH2Cl2) of the crude material yielded
1f as a white solid (0.024 g, 0.064 mmol, 9%): mp 127-130
CHCl3).
[1-(2-(Dieth yla m in o)eth ylca r ba m oyl)-2-m eth ylp r op yl]-
ca r ba m ic Acid Isobu tyl Ester 1e. Compound 1e was
prepared as described above using isobutyl chloroformate
(0.142 mL, 1.09 mmol) and 2-amino-N-(2-(diethylamino)ethyl)-
3-methylbutyramide (0.473 g, 2.20 mmol). Chromatography
(0.5:4.5:95 30% aqueous NH4OH/MeOH/CH2Cl2) of the crude
material yielded a white solid (0.102 g, 0.323 mmol, 30%): mp
85-88 °C; 1H NMR (300 MHz, CDCl3) δ 6.59 (br s, 1 H), 5.34
(br d, 1 H), 3.95 (dd, J ) 8.8, 6.2 Hz, 1 H), 3.85 (d, J ) 6.7 Hz,
2 H), 3.33 (dt, J ) 6.8, 5.1 Hz, 2 H), 2.55 (m, 6 H), 2.10 (m, 1
1
°C; H NMR (300 MHz, CDCl3) δ 6.79 (d, J ) 8.7 Hz, 1 H),
6.59 (br s, 1 H), 5.24 (br s, 1 H), 4.26 (dd, J ) 8.7, 6.4 Hz, 1
H), 3.89 (dd, J ) 16.8, 5.8 Hz, 1 H), 3.79 (dd, J ) 16.8, 5.6 Hz,
1 H), 3.32 (m, 2 H), 2.55 (m, 6 H), 2.12 (m, 1 H), 1.47 (s, 9 H),
1.03 (t, J ) 7.2 Hz, 6 H), 0.95 (dd, J ) 6.7, 5.3 Hz, 6 H); 13C
NMR (75 MHz, CDCl3) δ 170.9, 169.7, 156.4, 80.7, 58.8, 51.6,
47.0, 44.8, 37.1, 31.7, 28.7, 19.5, 18.4, 12.0; HRMS-FAB (M
+ Na+) calcd for C18H36N4O4Na 395.2634, found 395.2628;
H), 1.92 (m, 1 H), 1.02 (t, J ) 7.1 Hz, 6 H), 0.95 (m, 12 H); 13
C
NMR (75 MHz, CDCl3) δ 171.6, 157.2, 71.7, 60.8, 51.7, 47.0,
37.0, 31.6, 28.4, 19.6, 19.4, 18.3, 12.0; HRMS-ESI (M + H+)
25
calcd for C16H34N3O3 316.2600, found 316.2598; [R]D ) -2.1
(c ) 1.0, CHCl3).
25
[R]D ) -3.1 (c ) 2.4, CHCl3).
[1-(2-(Dieth yla m in o)eth ylca r ba m oyl)-2-m eth ylp r op yl]-
ca r ba m ic Acid Meth yl Ester 1g. Ligand 1a (0.760 g, 2.41
mmol) was treated with CF3CO2H in CH2Cl2 at 0 °C. After
the reaction was complete, the organic layer was washed with
saturated Na2CO3, and the solvent was removed by rotary
evaporation. Chromatography (1.5:13.5:85 30% aqueous NH4-
OH/MeOH/CH2Cl2) gave the intermediate free amine 2-amino-
N-(2-(diethylamino)ethyl)-3-methylbutyramide as a viscous
oil: 1H NMR (300 MHz, CDCl3) δ 7.46 (br s, 1 H), 3.33 (dt, J
) 6.3, 5.9 Hz, 2 H), 3.21 (d, J ) 4.1 Hz, 1 H), 2.57 (m, 6 H),
2.26 (m, 1 H), 1.50 (br s, 2 H), 1.03 (t, J ) 7.2 Hz, 6 H), 0.99
(d, J ) 7.0 Hz, 3 H), 0.85 (d, J ) 6.9 Hz, 3 H); 13C NMR (75
MHz, CDCl3) δ 175.5, 60.8, 51.9, 47.4, 36.0, 31.5, 20.1, 16.6,
10.7; HRMS-ESI (M + H+) calcd for C11H26N3O 216.2076, found
216.2078.
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 allowed to stir for 10 min at room temper-
ature and then cooled to 0 °C followed by the addition of
benzaldehyde (0.60 mmol). After 24 h the reaction was
quenched with saturated aqueous NH4Cl and extracted with
Et2O. The combined organic extractions were washed with
saturated aqueous NaHCO3, dried (MgSO4), filtered through
a plug of SiO2, and concentrated in vacuo. The crude alcohol
was analyzed without further purification by chiral HPLC
(Chiralcel OD or OD-H).
(R)-1-P h en yl-1-p r op a n ol: 68% ee by HPLC analysis
(Chiralcel OD-H column eluted with hexanes:2-propanol (97.5:
2.5) at 1.0 mL/min and detection at 219 nm), tR ) 12.4 min
for (R) and tR ) 14.0 min for (S).13
(R)-1-P h en yl-1-eth an ol: 84% ee by HPLC analysis (Chiral-
cel OD-H column eluted with hexanes:2-propanol (97.5:2.5) at
1.0 mL/min and detection at 219 nm), tR ) 12.5 min for (R)
and tR ) 16.3 min for (S).14
(R)-1-(1′-Na p h th yl)-1-p r op a n ol: 24% ee by HPLC analy-
sis (Chiralcel OD-H column eluted with hexanes:2-propanol
Compound 1g was prepared as described above using 1.1
equiv of methyl chloroformate (0.127 mL, 1.65 mmol) and
2-amino-N-(2-(diethylamino)ethyl)-3-methylbutyramide (0.322
g, 1.50 mmol), yielding an amorphous solid (0.231 g, 0.845
mmol, 57%) without the need for further purification: 1H NMR
(300 MHz, CDCl3) δ 6.54 (br s, 1 H), 5.35 (d, J ) 7.7 Hz, 1 H),
3.94 (dd, J ) 8.4, 6.4 Hz, 1 H), 3.68 (s, 3 H), 3.33 (m, 2 H),
2.57 (m, 6 H), 2.10 (m, 1 H), 1.02 (t, J ) 7.1 Hz, 6 H), 0.95 (dd,
J ) 10.2, 6.9 Hz, 6 H); 13C NMR (75 MHz, CDCl3) δ 171.4,
157.4, 60.8, 52.7, 51.6, 47.0, 37.1, 31.6, 19.6, 18.2, 12.1; HRMS-
ESI (M + H+) calcd for C13H28N3O3 274.2131, found 274.2138;
(13) Dai, W.-M.; Zhu, H.-J .; Hao X.-J . Tetrahedron: Asymmetry
2000, 11, 2315.
(14) Palmer, M. J .; Kenny, J . A.; Walsgrove, T.; Kawamoto, A. M.;
Wills, M. J . Chem. Soc., Perkin Trans. 1 2002, 416.
25
[R]D ) -9.1 (c ) 1.0, CHCl3).
J . Org. Chem, Vol. 68, No. 20, 2003 7793

Sprout and Seto
(97.5:2.5) at 1.0 mL/min and detection at 219 nm), tR ) 21.2
min for (S) and tR ) 43.7 min for (R).13
(R)-1-(1′-Na p h th yl)-1-eth a n ol: 76% ee by HPLC analysis
(Chiralcel OD-H column eluted with hexanes:2-propanol (97.5:
2.5) at 1.0 mL/min and detection at 219 nm), tR ) 27.5 min
for (S) and tR ) 44.0 min for (R).14
(R)-1-(2′-Na p h th yl)-1-p r op a n ol: 73% ee by HPLC analy-
sis (Chiralcel OD-H column eluted with hexanes:2-propanol
(97.5:2.5) at 1.0 mL/min and detection at 219 nm), tR ) 23.2
min for (S) and tR ) 25.9 min for (R).13
(R)-1-(2′-Na p h th yl)-1-eth a n ol: 86% ee by HPLC analysis
(Chiralcel OD-H column eluted with hexanes:ethanol (95.0:
5.0) at 0.5 mL/min and detection at 219 nm), tR ) 25.8 min
for (S) and tR ) 27.5 min for (R).14
(R)-1-P h en ylp en t-1-(E)-en -3-ol: 61% ee by HPLC analysis
(Chiralcel OD-H column eluted with hexanes:2-propanol (97.5:
2.5) at 1.0 mL/min and detection at 219 nm), tR ) 18.7 min
for (R) and tR ) 31.3 min for (S).13
(R)-4-P h en yl-4-bu t-3-(E)-en -2-ol: 25% ee by HPLC analy-
sis (Chiralcel OD-H column eluted with hexanes:2-propanol
(97.5:2.5) at 1.0 mL/min and detection at 219 nm), tR ) 25.0
min for (R) and tR ) 44.2 min for (S).15
(R)-1-(4′-Meth oxyp h en yl)-1-p r op a n ol: 40% ee by HPLC
analysis (Chiralcel OD-H column eluted with hexanes:2-
propanol (97.5:2.5) at 1.0 mL/min and detection at 219 nm),
tR ) 16.7 min for (R) and tR ) 19.7 min for (S).13
(R)-1-(4′-Ch lor op h en yl)-1-p r op a n ol: 77% ee by HPLC
analysis (Chiralcel OD-H column eluted with hexanes:2-
propanol (97.5:2.5) at 1.0 mL/min and detection at 219 nm),
tR ) 10.6 min for (S) and tR ) 11.3 min for (R).13
(R)-1-(4′-Ch lor op h en yl)-1-eth a n ol: 81% ee by HPLC
analysis (Chiralcel OD-H column eluted with hexanes:2-
propanol (97.5:2.5) at 1.0 mL/min and detection at 219 nm),
tR ) 12.2 min for (S) and tR ) 13.2 min for (R).17
(R)-2,2-Dim eth ylp en ta n -3-ol: 57% ee by 19F NMR analy-
sis of the (R)-MTPA ester; [R]D23 ) +1.2 (c )5.35, CHCl3) {lit.18
22
[R]D ) -32.6 (c ) 2.38, CHCl3) for 98% ee (S)}.
Ack n ow led gm en t . C.M.S. was supported by a
GAANN Fellowship from the Department of Education
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 and HPLC column conditions/
retention times for all alcohol products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(R)-1-P h en yl-3-pen tan ol: 0% ee by HPLC analysis (Chiral-
cel OD-H column eluted with hexanes:2-propanol (97.5:2.5) at
1.0 mL/min and detection at 219 nm), tR ) 13.8 min for (R)
and tR ) 21.0 min for (S).16
(R)-1-Cycloh exyl-1-p r op a n ol: 17% ee by 19F NMR analy-
sis of the (R)-MTPA ester; [R]D23 ) +1.5 (c )1.84, CHCl3) {lit.13
J O0347516
24
[R]D ) -6.39 (c ) 1.05, CHCl3) for 97% ee (S)}.
(17) Kwong, F. Y.; Yang, Q.; Mak, T. C. W.; Chan, A. S. C.; Chan,
K. S. J . Org. Chem. 2002, 67, 2769.
(18) Watanabe, M.; Araki, S.; Butsugan, Y. J . Org. Chem. 1991, 56,
2218.
(15) Cherng, Y.-J .; Fang, J .-M.; Lu, T.-J . J . Org. Chem. 1999, 64,
3207.
(16) Paquette, L. A.; Zhou, R. J . Org. Chem. 1999, 64, 7929.
7794 J . Org. Chem., Vol. 68, No. 20, 2003