Enantioselective addition of vinylzinc reagents to aldehydes catalyzed by modular ligands derived from amino acids

Article abstract of DOI:10.1021/jo051313l

A series of N-acylethylenediamine-based ligands were synthesized from Boc-protected amino acids. The ligands were screened for the ability to catalyze the asymmetric addition of vinylzinc reagents to aldehydes. Three sites of diversity on the ligands were optimized for this reaction using a positional scanning approach. The optimized ligand 3d was found to catalyze the formation of 15 different (E)-allylic alcohols with enantioselectivities that ranged from 52 to 91% ee and yields that ranged from 40 to 90%. This ligand was especially effective for the reaction of aromatic aldehydes with vinylzinc reagents derived from bulky terminal alkynes. Ligand 3d catalyzed the addition of (E)-(3,3-dimethylbut-1-enyl)(ethyl)zinc to 2-naphthaldehyde to give (R,E)-4,4-dimethyl-1-(naphthalene-1-yl)pent-2-en-1-ol in 89% ee. The ee of this product could be increased to 97% through a single recrystallization.

Full text of DOI:10.1021/jo051313l

Enantioselective Addition of Vinylzinc Reagents to Aldehydes
Catalyzed by Modular Ligands Derived from Amino Acids
Meaghan L. Richmond, 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 June 27, 2005
A series of N-acylethylenediamine-based ligands were synthesized from Boc-protected amino acids.
The ligands were screened for the ability to catalyze the asymmetric addition of vinylzinc reagents
to aldehydes. Three sites of diversity on the ligands were optimized for this reaction using a
positional scanning approach. The optimized ligand 3d was found to catalyze the formation of 15
different (E)-allylic alcohols with enantioselectivities that ranged from 52 to 91% ee and yields
that ranged from 40 to 90%. This ligand was especially effective for the reaction of aromatic
aldehydes with vinylzinc reagents derived from bulky terminal alkynes. Ligand 3d catalyzed the
addition of (E)-(3,3-dimethylbut-1-enyl)(ethyl)zinc to 2-naphthaldehyde to give (R,E)-4,4-dimethyl-
1
-(naphthalene-1-yl)pent-2-en-1-ol in 89% ee. The ee of this product could be increased to 97%
through a single recrystallization.
Introduction
method, established4 by Wipf,3 employs Cp
2
ZrHCl
(
Schwartz’s reagent) to accomplish the (E)-selective
Reactions that form optically active secondary allylic
alcohols represent a very useful class of catalytic enan-
tioselective transformations. The resulting chiral allylic
alcohols have many attractive features; they are impor-
hydrozirconation of terminal alkynes, yielding an organo-
zirconium intermediate. Such organozirconium com-
pounds are relatively unreactive toward electrophiles.
However, they undergo smooth transmetalation with
dialkylzinc reagents to give the corresponding vinylzinc
species. After transmetalation, addition of an aromatic
1
tant synthetic precursors and they are found in numer-
ous naturally occurring and biologically active com-
2
pounds. Two general approaches have been used to
prepare chiral allylic alcohols: (a) the enantioselective
reduction of R,â-unsaturated ketones and (b) the enan-
tioselective addition of vinylzinc reagents to aldehydes.
One advantage to the latter approach is that it generates
a new C-C bond concomitant with formation of the chiral
center.
(
2) For recent examples, see: (a) van der Berg, R. J. B. H. N.;
Korevaar, C. G. N.; Overkleeft, H. S.; van der Marel, G. A.; van Boom,
J. H. J. Org. Chem. 2004, 69, 5699-5704. (b) Barboni, L.; Giarlo, G.;
Ricciutelli, M.; Ballini, R.; Georg, G. I.; VanderVelde, D. G.; Himes, R.
H.; Wang, M.; Lakdawala, A.; Snyder, J. P. Org. Lett. 2004, 6, 461-
464. (c) Zannatta, S. D.; White, J. M.; Rizzacasa, M. A. Org. Lett. 2004,
6
, 1041-1044. (d) Magnin-Lachaux, M.; Tan, Z.; Liang, B.; Negishi,
E.-I. Org. Lett. 2004, 6, 1425-1427. (e) Wu, Y.; Shen, X.; Yang, Y.-Q.;
Hu, Q.; Huang, J.-H. J. Org. Chem. 2004, 69, 3857-3865. (f) Vassil-
ikogiannakis, G.; Margaros, I.; Montagnon, T. Org. Lett. 2004, 6, 2039-
Two methods have been developed for the dialkylzinc-
promoted synthesis of chiral (E)-allylic alcohols. The first
2
042. (g) Mehta, G.; Roy, S. Org. Lett. 2004, 6, 2389-2392. (h) Rai, A.
N.; Basu, A. Org. Lett. 2004, 6, 2861-2863. (i) El Sous, M.; Ganame,
D.; Tregloan, P. A.; Rizzacasa, M. A. Org. Lett. 2004, 6, 3001-3004.
(j) Morales, C. A.; Layton, M. E.; Shair, M. D. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 12036.
(3) Wipf, P.; Xu, W. Tetrahedron Lett. 1994, 35, 5197-5200.
(4) (a) Schwartz, J.; Labinger, J. A. Angew. Chem., Int. Ed. Engl.
1976, 15, 333-340. (b) Labinger, J. A. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol 8, pp 667-702.
(
1) For recent examples, see: (a) Drutu, I.; Krygowski, E. S.; Wood,
J. L. J. Org. Chem. 2001, 66, 7025-7029. (b) Griesbeck, A. G.; El-
Idreesy, T. T.; Fiege, M.; Brun, R. Org. Lett. 2002, 4, 4193-4195. (c)
Lambert, W. T.; Burke, S. D. Org. Lett. 2003, 5, 515-518. (d) Yun, H.;
Danishefsky, S. J. J. Org. Chem. 2003, 68, 4519-4522. (e) Weaving,
R.; Roulland, E.; Monneret, C.; Florent, J.-C. Tetrahedron Lett. 2003,
4
4, 2579-2581. (f) Smith, T. E.; Djang, M.; Velander, A. J.; Downey,
C. W.; Carroll, K. A.; van Alphen, S. Org. Lett. 2004, 6, 2317-2320.
1
0.1021/jo051313l CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/24/2005
J. Org. Chem. 2005, 70, 8835-8840
8835

Richmond et al.
or aliphatic aldehyde and a chiral catalyst provides the
E)-allylic alcohol. Wipf and co-workers have used this
SCHEME 1. Synthesis of Modular Amino
a-c
(
Acid-Based Ligands
method, in conjunction with a catalytic amount of a chiral
amino-thiol ligand to provide (E)-allylic alcohols in high
5
ee’s.
The second method, originally described by Oppolzer
and Radinov, begins with the regioselective hydrobora-
6
a
Reagents: (a) O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-
uronium hexafluorophosphate (HBTU), diisopropylethylamine
tion of a terminal alkyne to give a vinylborane. The
vinylborane is transmetalated with dialkylzinc to yield
a mixed (E)-alkeny(alkyl)zinc species. This vinylzinc
species can be subsequently reacted with aldehydes in
the presence of a ligand to provide chiral (E)-allylic
alcohols. Oppolzer and Radinov developed several amino
alcohol ligands that provide the desired chiral allylic
1
(
DIEA), (R )2NH, DMF, 55-96%; (b) (i) BH3-THF, (ii) H2-
3
N(CH2)2NH2, 11-53%; (c) (i) TFA, (ii) R COX (X ) Cl or F), DIEA,
b
CH2Cl2, 48-99%. For the specific structures of compounds 2a-
r, see the Supporting Information. cFor the specific structures of
compounds 3a-r and 4a-k, see Tables 2-4 and 6 and Scheme 2.
SCHEME 2
7
alcohols in good enantioselectivities. Other researchers
have used the Oppolzer protocol, in conjunction with a
variety of Lewis base ligands, to broaden the scope of the
8
reaction. For example, Dahmen and Brase have em-
ployed [2,2]paracyclophane hydroxyketimine ligands,
9
Chan and co-workers have employed an aromatic γ-ami-
no alcohol, and Tseng and Yang10 have used amino thiol
ligands in this reaction. Walsh has developed Nugent’s
isoborneal-based â-amino alcohol ligand (-)-MIB11 as a
catalyst for the Oppolzer protocol. He has further elabo-
rated the resulting chiral allylic alcohols into a number
of products and synthetically useful intermediates in-
acylethylenediamine ligands to the enantioselective ad-
dition of vinylzinc reagents to aldehydes using the
Oppolzer protocol.
12
12
cluding allylic amines, R-amino acids, γ-unsaturated
1
3
14
â-amino acids, hydroxyl enol ethers and epoxy alco-
hols.
Results and Discussion
1
5
We began the synthesis of the ligands by coupling
commercially available Boc-protected amino acids with
a secondary amine to yield the corresponding amides 2
(Scheme 1). The amides were reduced with borane-THF
to give the corresponding diamine as a complex with
boron. The free diamine 3 was liberated by treating the
complex with an excess of ethylenediamine in methanol
solution and heating the reaction to 100 °C for 120 s using
microwave irradiation. Finally, the Boc group was re-
moved with TFA, and the resulting free amine was
reacted with an acid chloride or a chloro- or fluoroformate
We have recently reported the synthesis of modular
N-acylethylenediamine ligands with three sites of diver-
sity and their use as asymmetric catalysts for the
16,17
addition of dialkylzinc reagents to aldehydes.
We
envision that these ligands, in analogy to amino alcohol-
based ligands, react with organozinc reagents by depro-
tonation of the amide or carbamate N-H group to give a
five-membered zinc chelate.18 We have also described an
efficient solid-phase synthesis of these chiral ligands.19
In this report, we describe the application of the N-
2
0
to yield the corresponding amide or carbamate 4.
(
5) (a) Wipf, P.; Ribe, S. J. Org. Chem. 1998, 63, 6454-6455. (b)
Wipf, P.; Jayasuriya, N.; Ribe, S. Chirality 2003, 15, 208-212. (c) Wipf,
P.; Kendall, C. Chem. Eur. J. 2002, 8, 1778-1784.
Other investigators who have developed catalysts for
use in the Oppolzer protocol have employed a variety of
different reaction conditions, including different temper-
(
6) Oppolzer, W.; Radinov, R. N. Helv. Chim. Acta 1992, 75, 170-
1
73.
(
7) (a) Oppolzer, W.; Radinov, R. N. Tetrahedron Lett. 1988, 29,
2 2
atures for the transmetalation, the use of Me Zn or Et -
5
3
1
645-5648. (b) Oppolzer, W.; Radinov, R. N. Tetrahedron Lett. 1991,
2, 5777-5780. (c) Oppolzer, W.; Radinov, R. N. J. Am. Chem. Soc.
993, 115, 1593-1594. (d) Oppolzer, W.; Radinov, R. N.; El-Sayed, E.
Zn, and several methods for the addition of reagents.
Since so many different and conflicting conditions have
been reported, we began our investigations by optimizing
the reaction conditions for the N-acylethylenediamine
class of ligands. In the first series of reactions, the
vinylborane reagent obtained from 1-octyne was added
to a solution of benzaldehyde, dialkylzinc and 10 mol %
of ligand 4a (Scheme 2). The reactions were allowed to
proceed at -48 °C for 48 h, and then they were quenched
with aqueous ammonium chloride solution and the ee
was analyzed by chiral HPLC. At -48 °C, the reaction
between dialkylzinc and benzaldehyde is much slower
than the desired transmetalation/vinyl transfer reaction.
J. Org. Chem. 2001, 66, 4766-4770.
(
(
8) Dahmen, S.; Br a¨ se, S. Org. Lett. 2001, 3, 4119-4122.
9) Ji, J.-X.; Qiu, L.-Q.; Yip, C. W.; Chan, A. S. C. J. Org. Chem.
2
7
1
003, 68, 1589-1590.
(
10) Tseng, S.-L.; Yang, T.-K. Tetrahedron: Asymmetry 2005, 16,
73-782.
(
11) (a) Nugent, W. A. J. Chem. Soc., Chem. Commun. 1999, 1369-
370. (b) Rosner, T.; Sears, P. J.; Nugent, W. A.; Blackmond, D. G.
Org. Lett. 2000, 2, 2511-2513.
(
12) Chen, Y. K.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2002,
24, 12225-12231.
13) Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2003, 125, 10677-
1
1
1
7
7
(
0683.
(
14) Jeon, S.-J.; Chen, Y. K.; Walsh, P. J. Org. Lett. 2005, 7, 1729-
732.
(
15) Lurain, A. E.; Carroll, P. J.; Walsh, P. J. J. Org. Chem. 2005,
2
When Et Zn was employed as the transmetalating
agent and the vinylborane was added quickly to the
0, 1262-1268.
(
16) Richmond, M. L.; Seto, C. T. J. Org. Chem. 2003, 68, 7505-
508.
(
(
17) Sprout, C. M.; Seto, C. T. J. Org. Chem. 2003, 68, 7788-7794.
(19) Sprout, C. M.; Richmond, M. R.; Seto, C. T. J. Org. Chem. 2004,
69, 6666.
(20) For the synthesis and characterization of amides 2a,b,h-i and
ligands 3a,b,h,i, and 4d-i, see ref 16.
1
18) The H NMR spectrum of a mixture of diethylzinc and a related
N-acylethylenediamine-based ligand shows disappearance of the NH
protons and formation of ethane. See ref 17.
8836 J. Org. Chem., Vol. 70, No. 22, 2005

Enantioselective Addition of Vinylzinc Reagents to Aldehydes
TABLE 1. Effect of Catalyst Loading on the % ee of
TABLE 2. Effect of the Ligand Tertiary Amine on the
R,E)-1-Phenyl-2-nonen-1-ola
Addition of Vinylzinc Reagent to Benzaldehyde
a
(
entry
4a (mol %)
eeb,c (%)
1
2
3
4
5
6
2.5
5
7.5
7.5
10
15
9
26
48
ee (%) at ee (%) at yieldd
1
b,c
b,c
entry ligand
N(R )2
-48 °C
-20 °C
(%)
d
66
1
2
3
4
5
3a
3b
3c
3d
3e
N(CH2CH2)2O
N(CH2)5
N(CH2)4
NEt2
85
86
91
90
89
76
82
88
89
78
55
e
48
46
61
61
67
54
a
All experiments performed in duplicate. b Absolute configu-
ration assigned by comparison with literature values. Determined
by chiral HPLC (Chiralcel OD-H). d Reaction conducted in CH2Cl2
as the only solvent. c-Hex ) cyclohexyl.
NMe2
c
a
All experiments performed in duplicate. b Absolute configu-
c
ration assigned by comparison with literature values. Determined
d
by chiral HPLC (Chiralcel OD-H). All yields are for reactions
e
performed at -20 °C unless otherwise noted. Yield for reaction
reaction mixture in a single portion, none of the desired
allylic alcohol was detected. However, when the vinyl-
borane was added slowly to the reaction over a period of
h by syringe pump, the product (R)-allylic alcohol was
obtained in 26% ee. With Me Zn as the transmetalating
agent, no product was observed with fast or slow addition
of the vinylborane.
We next modified the order of addition of the reactants.
The vinylzinc reagent was first prepared by reacting
Me Zn or Et Zn with the vinylborane derived from
2 2
-octyne in the presence of ligand 4a at -78 °C for 1 h.
Benzaldehyde was then added, and the reaction was
incubated at -48 °C for 48 h and quenched. As before,
reactions employing Me
desired product. When Et
performed at -48 °C. c-Hex ) cyclohexyl.
point we did not observe a further increase in product
ee with catalyst loading. Changing the solvent to 100%
1
2
CH
6% ee (entry 4). As a result, all further experiments
were performed using a catalyst loading of 7.5 mol % and
CH Cl as the solvent.
2 2
Cl gave a further increase in enantioselectivity to
6
2
2
With the conditions for the transmetalation, catalyst
loading, and reagent addition in place, we began to
optimize the structure of the modular ligands. We first
investigated the effect of the tertiary amine on product
ee by employing ligands derived from N-Boc-Ile that
incorporated five different tertiary amine groups (Table
1
2
Zn did not yield any of the
Zn was used as the transmeta-
2
2
). All of the ligands gave good enantioselectivities, with
lating agent, and benzaldehyde was added to the pre-
formed vinylzinc reagent over 30 min by syringe pump,
the product allylic alcohol was obtained in 20% ee. By
contrast, when benzaldehyde was added quickly and in
one portion to the vinyl(ethyl)zinc species, we obtained
the allylic alcohol in 48% ee. As a result, we performed
all subsequent reactions by adding the aldehyde in a
single portion to a preformed solution of the mixed
those containing the five-membered pyrrolidine ring and
diethylamine (entries 3 and 4) providing the highest ee.
Increasing the temperature of the reaction from -48 to
-
20 °C allowed us to decrease the reaction time from 48
to 24 h, although it resulted in a small decrease in
enantioselectivity. Ligands 3c and 3d lost only 1-3% ee
with the increase in temperature, while ligands 3a and
3
e showed a larger erosion of product ee of 9 and 11%,
(alkenyl)(ethyl)zinc species and ligand.
respectively.
We have also observed that the quality of the vinylzinc
To determine if there was a difference between the
pyrrolidine ring and the diethylamino group within the
context of ligands derived from other amino acids, we
prepared ligands based upon Phe and Val that contained
these two tertiary amines. For the addition of (E)-(3,3-
dimethylbut-1-enyl)(ethyl)zinc to benzaldehyde (Table 3),
ligands that contained the diethylamino group (entries
2, 4, and 6) gave the same or in some cases significantly
higher ee values for the product allylic alcohol when
compared to ligands that contained the pyrrolidine ring
(entries 1, 3, and 5). In addition, diethylamino-containing
ligands 3d, 3g, and 3i gave higher yields when compared
to pyrrolidine-containing ligands 3c, 3f, and 3h.
We next investigated the effect of the carbamate and
amide groups of the ligand on the stereoselectivity of the
reaction (Table 4). In the first series of reactions (entries
1-8), the amino acid side chain and the tertiary amine
of the ligand were held constant as the side chain of Ile
and morpholine, respectively. All of the modifications that
we explored at the R3 position of the ligands gave
substantially lower enantioselectivities and yields when
compared to ligand 3a, which incorporates an O-tBu
reagent and the subsequent ee of the reaction product
are very sensitive to the temperature of the transmeta-
lation reaction. Walsh and co-workers reported that the
2 2
transmetalation reaction with Me Zn or Et Zn could be
performed at 0 °C, which gave excellent enantioselec-
tivities and yields of the desired products.12 However, in
our hands we found that warming the reaction mixture
containing Et
2
Zn, the vinylborane and ligand above -78
°C was not favorable. When the transmetalation reaction
was allowed to warm from -78 to 0 °C over 1 h, the
solution turned deep brown and the resulting alcohol,
after addition of benzaldehyde, was formed in only 30%
ee. Similar results were obtained when the reaction was
warmed to -48 °C over an hour. When the transmeta-
lation reaction was kept at -78 °C for 1 h, the solution
remained colorless and the ee of the product was in-
creased to 48%.
Finally, we examined the effect of catalyst loading on
the formation of (R,E)-1-phenyl-2-nonen-1-ol (Table 1).
The ee of the product increased from 9 to 48% as the
catalyst was increased from 2.5 to 7.5 mol %. Beyond this
J. Org. Chem, Vol. 70, No. 22, 2005 8837

Richmond et al.
TABLE 3. Comparison between Diethylamino and
Pyrrolidino Substituents on the Liganda
TABLE 5. Effect of Poly(ethylene glycol) Additives on
a
the Reaction of Vinylzinc Reagents with Benzaldehyde
entry ligand N(R )2 R ) side chain of eeb,c (%) yield (%)
1
2
d
1
2
3
4
5
6
3c
3d
3f
3g
3h
3i
N(CH2)4
NEt2
N(CH2)4
NEt2
N(CH2)4
NEt2
Ile
88
89
33
59
35
87
61
67
18
56
40
56
entry
additive
additive (mol %)
eeb,c (%)
Ile
Phe
Phe
Val
Val
1
2
3
4
5
6
7
none
88
79
78
84
81
78
80
MPEG
MPEG
MPEG
DiPEG
DiPEG
DiPEG
1
2.5
5
1
2.5
5
a
All experiments performed in duplicate. b Absolute configu-
c
ration assigned by comparison with literature values. Determined
by chiral HPLC (Chiralcel OD-H). d All yields are for reactions
performed at -20 °C. c-Hex ) cyclohexyl.
a All experiments performed in duplicate. b Absolute configu-
ration assigned by comparison with literature values. c Determined
by chiral HPLC (Chiralcel OD-H). c-Hex ) cyclohexyl.
TABLE 4. Effect of Ligand Carbamate and Amide
Functional Groups on the Addition of Vinylzinc Reagent
a
to Benzaldehyde
2
we observed previously for the addition of Et Zn to
aldehydes,16 amides such as 4g and 4h catalyze the
reaction but give racemic products (entries 6 and 7).
We also examined changes to the tertiary amine
component of ligand 4i (entries 8-10). The ee values for
adamantyl carbamates 4i-k follow the same trend as
was observed for the tert-butyl carbamates 3a, 3c and
3
d (Table 2). These comparisons provide a further
indication that the adamantyl and tert-butyl carbamates
fulfill a similar role within these catalysts.
Bolm21 and Dahmen have examined the effects of
22
MeOPEG (poly(ethylene glycol) monomethyl ether, MW
2000) and DiMPEG (poly(ethylene glycol) dimethyl ether,
MW 2000) on the enantioselective reaction of organozinc
reagents with aldehydes. In many cases, addition of 1-10
mol % of these additives increases the ee of the reaction
by approximately 3-6%. These additives also allow lower
catalyst loadings to be used without a significant decrease
in the enantioselectivity. One of the reactions investi-
gated by Bolm was the arylation of aldehydes using a
mixture of BPh
exchange reactions to give an equilibrium mixture of
organozinc species that includes Ph Zn and PhZnEt.
Since Ph Zn is the more reactive aryl transfer reagent,
3 2
and Et Zn. These reagents undergo
2
2
Bolm has suggested that the additives influence the
stereoselectivity of the reaction by coordinating to this
more reactive species. This coordination reduces the rate
2
of the uncatalyzed addition of Ph Zn to the aldehyde. As
a result, the enantioselectivity of the overall reaction
increases because the competing nonstereoselective reac-
tion pathway is closed down.
These observations have prompted us to examine the
effects of MeOPEG and DiMPEG as additives for the
addition of vinylzinc reagents to aldehydes using ligand
a
All experiments performed in duplicate. b Absolute configu-
c
ration assigned by comparison with literature values. Determined
by chiral HPLC (Chiralcel OD-H). c-Hex ) cyclohexyl.
3
c (Table 5). In all cases, addition of the additive
decreased the stereoselectivity of the reaction. For (vinyl)-
group at R3 (Table 2, entry 1). Even ligands with
additional stereocenters such as (R)- or (S)-menthyl
carbamates 4b and 4c did not change the absolute
stereochemistry of the products or improve the ee. The
only exception to this trend is ligand 4i with an O-
adamantyl group at R (entry 8). Ligands 3a and 4i both
incorporate bulky carbamate groups, and gave similar
ee values in the catalyzed reaction (76% vs 78% ee). As
1
(
alkyl)Zn reagents, H NMR studies have shown that at
65 °C the mixed organozinc species is favored over
-
dialkylzinc and divinylzinc species. As the temperature
is increased, the equilibrium shifts even further toward
3
(
21) Rudolph, J.; Hermanns, N.; Bolm, C. J. Org. Chem. 2004, 69,
3
997-4000.
(22) Dahmen, S. Org. Lett. 2004, 6, 2113-2116.
8838 J. Org. Chem., Vol. 70, No. 22, 2005

Enantioselective Addition of Vinylzinc Reagents to Aldehydes
TABLE 6. Optimization of the Amino Acid Side Chain
LT iAg Ba nL dE 37 d. a Variation of the Vinylzinc Reagent Using
a,b
of the Ligands
b
entry
allylic alcohol
ee (%)
yield (%)
1
2
3
4
5
6
5a, R ) tert-butyl
5b, R ) cyclohexyl
5c, R ) CH2CH2Ph
5d, R ) n-hexyl
89
73
67
65
60
52
67
51
48
49
40
51
5e, R ) n-butyl
2
ee (%)c-e
5f, R ) cyclopropyl
entry
ligand
R ) side chain of
yield (%)
a
All experiments performed in duplicate. b Determined by
1
2
3
4
5
6
7
8
9
3d
3g
3i
Ile
89
67
56
56
29
47
37
51
58
70
50
58
64
Phe
Val
68
chiral HPLC (Chiralcel OD-H). c-Hex ) cyclohexyl.
87
3j
Tle
57
TABLE 8. Variation of Aldehydes Using Ligand 3da
3k
3l
Leu
Cha
Chg
Ala
52
51
3m
3n
3o
3p
3q
3r
73
55
Nle
63
b
entry
allylic alcohol
ee (%)
yield (%)
10
11
12
Dph
D-2-Nal
Met
50
65 (S)
52
1
2
3
4
5
6
7
8
9
6a, R ) 4-chlorophenyl
6b, R ) 2-naphthyl
6b, R ) 2-naphthyl
6c, R ) 4-bromophenyl
5a, R ) phenyl
6d, R ) 4-methylbenzoate
6e, R ) 4-methoxyphenyl
6f, R ) 1-naphthyl
91
89
97
89
89
86
81
70
67
67
86
90
c
a
All experiments performed in duplicate. b Abbreviations: Cha
59
71
67
81
54
81
68
63
33
)
cyclohexylalanine, Chg ) cyclohexylglycine, Nle ) norleucine,
Dph ) diphenylalanine, D-2-Nal )D-3-(2-naphthyl)alanine, c-Hex
cyclohexyl. c Absolute configuration assigned by comparison with
)
d
literature values. Determined by chiral HPLC (Chiralcel OD-
H). e All ligands provided the product with the (R) configuration
6g, R ) trans-CHdCHPh
6h, R ) PhCH2CH2
6i, R ) cyclohexyl
unless otherwise noted.
1
1
0
1
d
39
6
the mixed species. Thus, addition of the additives does
a
b
All experiments performed in duplicate. Determined by
c
not result in an improvement in stereoselectivity. In
addition, the additives may act as weak achiral Lewis
basic ligands that slightly accelerate the nonstereoselec-
tive reaction between the vinylzinc reagent and aldehyde.
chiral HPLC (Chiralcel OD-H). Purified alcohol from entry 2 was
d
recrystallized once from hexanes. Determined using the corre-
19
sponding (R)-R-methoxy-R-trifluoromethylphenyl ester by F NMR
spectroscopy.
The final step in the optimization of the modular
ligands involved variation of the amino acid side chain
that is attached to the ethylenediamine scaffold (Table
vinylzinc reagents derived from other less sterically
demanding alkynes.
While the reaction catalyzed by 3d is fairly limited in
terms of the vinylzinc reagent, it is much more tolerant
of variations of the aldehyde (Table 8). Electron poor
benzaldehyde derivatives gave ee values that range from
6
). A series of ligands were synthesized containing a
diethylamino group at the tertiary amine position, and
a Boc group on the primary amine. Ligands with
â-branched alkyl groups such as the side chains of Ile
8
6 to 91% and yields in the range of 67-86% (entries 1
(3d), Val (3i), and cyclohexylglycine (3m) provide the
and 4-6). 2-Naphthaldehyde is also a good substrate for
the reaction, giving the corresponding allylic alcohol 6b
in 89% ee. The ee of this product could be improved to
highest ee values for the catalyzed reaction. Other
sterically less demanding side chains give lower enantio-
selectivities. In addition, the side chain of tert-leucine (3j),
which is larger than Ile, results in a ligand that is too
bulky to promote the reaction with high stereoselectivity.
All of the catalysts except for 3q were derived from
L-amino acids, and gave the (R)-allylic alcohol as the
major product. Since 3q was derived from D-2-naphthyl-
alanine, the product from the reaction catalyzed by this
ligand had the (S)-configuration.
9
7% by a single recrystallization from hexanes. The
electron-rich 4-methoxybenzaldehyde (entry 7) gave a
lower ee (81%) and yield (54%) when compared to its
electron poor counterparts. The use of aliphatic (entries
1
0 and 11) and other aldehydes also gave lower stereo-
selectivities.
Conclusion
Ligand 3d emerged as the best ligand in this class from
our screening studies. As a result, we examined the scope
of the reactions catalyzed by this ligand by first varying
the structure of the vinylzinc reagent (Table 7). Using
the optimized set of reaction conditions, 3d catalyzed the
addition of (E)-(3,3-dimethylbut-1-enyl)(ethyl)zinc, formed
from tert-butylacetylene and dicyclohexylborane, to benzy-
aldehyde in 89% ee. The reaction is sensitive to the size
of the vinylzinc reagent. Using cyclohexylacetylene, the
ee value drops to 73%. Lower values were obtained with
In summary, we have synthesized and screened a
series of chiral N-acylethylenediamine ligands for the
ability to catalyze the asymmetric addition of vinylzinc
reagents to aldehydes. The modular structure of these
ligands allowed for easy modification of three diversity
sites. Ligand 3d was found to catalyze the addition of
(E)-(3,3-dimethylbut-1-enyl)(ethyl)zinc to a variety of
aromatic aldehydes to yield chiral (E)-allylic alcohols in
81-91% ee and 54-90% yield. In addition, the ee of
J. Org. Chem, Vol. 70, No. 22, 2005 8839

Richmond et al.
allylic alcohol 6b was improved from 89 to 97% ee
through a single recrystallization from hexanes. We are
currently exploring these ligands as asymmetric catalysts
for other synthetically useful transformations.
residue was diluted with water, and the pH was adjusted to
pH 10 with 10% aqueous KOH. The aqueous solution was
extracted with CH
combined and dried (Na
by rotary evaporation. The residue was redissolved in anhy-
drous CH Cl (3 mL), and DIEA (1.5 mmol) was added. The
2
Cl
2
(3 × 10 mL), the organic layers were
2
CO ), and the solvent was removed
3
2
2
Experimental Section
reaction was cooled to 0 °C, the appropriate fluoroformate,
chloroformate or acid chloride (1.1 mmol) was added, and the
solution was warmed to rt and stirred for 1 h. The reaction
General Procedure for the Synthesis of Amides 2c-g
and 2j-r. The Boc-protected amino acid (1 equiv) was
suspended or dissolved in dry DMF. To this solution were
added DIEA (2 equiv) and HBTU (1.5 equiv). After the mixture
was stirred at rt for 1 h, the appropriate secondary amine (1.1
equiv) was added and the reaction was allowed to stir for 1 h.
The reaction was quenched by the addition of 1 N HCl. The
mixture was extracted with EtOAc, and the organic phase was
washed with 1 N HCl and brine and dried (MgSO ). The
4
solvent was removed, and purification was performed by flash
column chromatography.
Amide 2c. Amide 2c was prepared as described above from
Boc-Ile-OH (0.571 g, 2.4 mmol) and pyrrolidine (0.220 mL, 2.6
mmol). Purification (EtOAc/hexanes 5:28) gave a yellow oil
was diluted with CH
2
Cl
2
, washed with water (2 × 10 mL) and
brine (1 × 10 mL), and dried (Na
2
CO ). The solvent was
3
removed by rotary evaporation, and the crude product was
purified by flash column chromatography.
Ligand 4a. (S)-tert-Butyl 1-morpholino-1-oxo-3-phenylpro-
16
pan-2-ylcarbamate 7 (1.05 g, 3.3 mmol) was deprotected and
transformed to 4a as described above using DIEA (0.900 mL,
4.9 mmol) and adamantyl fluoroformate (0.713 g, 3.6 mmol).
Purification (gradient of 0.1:0.9:49 to 0.1:0.9:11.5 30% aqueous
NH OH/CH OH/CH Cl ) gave a white solid (1.30 g, 3.27 mmol,
4
3
2
2
1
9
6
2
3
9%): mp 124-127 °C; H NMR (CDCl , 300 MHz) δ 1.72 (s,
H), 2.16 (s, 6 H), 2.22 (s, 3 H), 2.30 (m, 2 H), 2.44 (m, 4 H),
.84 (dd, J ) 13.5, 6.3 Hz, 1 H), 2.94 (dd, J ) 13.6, 5.3 Hz, 1
1
(
(
0.520 g, 1.85 mmol, 78%): H NMR (CDCl
3
, 300 MHz) δ 0.92
H), 3.83 (t, J ) 4.6 Hz, 4 H), 3.95 (s, 1 H), 4.63 (s, 1 H), 7.19-
m, 6 H), 1.14 (m, 1 H), 1.44 (s, 9 H), 1.56-1.72 (m, 1 H), 1.83-
.99 (m, 4 H), 3.39-3.59 (m, 4 H), 3.68-3.73 (m, 1 H), 4.28
13
7
1
.34 (m, 5 H); C NMR (CDCl
3
, 75 MHz) δ 155.8, 138.2, 130.1,
1
28.7, 126.7, 79.6, 67.4, 61.5, 54.1, 48.6, 42.1, 39.2, 36.6, 31.2;
1
3
(
(
2
1
8
2
dd, J ) 9.4, 7.2 Hz, 1 H), 5.24 (d, J ) 9.3 Hz, 1 H); C NMR
CDCl , 75 MHz) δ 171.4, 156.2, 79.8, 56.8, 47.1, 46.2, 38.4,
9.4, 28.7, 24.6, 15.9, 11.7; IR (neat) 3436, 3287, 2971, 2878,
707, 1636, 1503, 1449, 1366, 1250, 1171, 1044, 1019, 917, 878,
IR (neat) 3332, 2909, 2855, 1680, 1537, 1455, 1265, 1115, 1065
3
-1
+
cm ; HRMS-FAB (M + Na ) calcd for C24
H
34
N
2
O
3
Na 421.2467,
2
4
found 421.2468; [R]
) +15.9 (c ) 1.75, CHCl ).
D 3
Representative Procedure for the Addition of Vinyl-
-
1
+
17, 754 cm ; HRMS-ESI (M + H ) calcd for C15
H
29
N
2
O
3
3
zinc Reagents to Aldehydes. To an oven-dried vial were
2
4
85.2178, found 285.2186; [R]
D
) +1.43 (c ) 0.77, CHCl
).
2 2 3
added dry CH Cl (2.5 mL) and neat BH ‚DMS complex (0.260
General Procedure for the Synthesis of Ligands 3c-g
mL, 2.74 mmol). The solution was cooled to 0 °C, and
cyclohexene (0.550 mL, 5.40 mmol) was added. The reaction
was stirred for 2 h, during which time a white precipitate
formed. After 2 h, 3,3-dimethyl-1-butyne (0.360 mL, 2.95
mmol) was added, and the reaction was slowly warmed to rt.
After addition of the alkyne, the white precipitate dissolved.
However, in a few cases when the precipitate did not dissolve,
the reaction yielded the product with a lower ee than expected.
An aliquot of the above solution (0.735 mL) was transferred
to a vial pre-loaded with ligand 3c (0.0104 g, 0.038 mmol).
The reaction was cooled to -78 °C and a 1 M solution of
and j-r. To a solution of the amide (1 equiv) dissolved in
anhydrous THF was slowly added 1.8 M BH in THF (4 equiv).
The reaction was stirred at rt for 18 h, cooled to 0 °C, and
carefully quenched (evolution of H gas!) with methanol. The
3
2
solvent was removed, and the residue was redissolved in
methanol. To this solution was added ethylenediamine (4
equiv), and the solution was heated by microwave irradiation
for 120 s at 100 °C. The methanol was removed, and the
residue was dissolved in water and extracted with CH
2
Cl
3
2
. The
organic phase was washed with water, dried (Na CO
2
), and
concentrated. The crude product was purified by flash column
chromatography.
Ligand 3c. Amide 2c (0.506 g, 1.8 mmol) was reduced as
3
described above with 1.8 M BH (4.0 mL, 7.1 mmol) followed
by boron exchange with ethylenediamine (0.475 mL, 7.1 mmol).
Purification (gradient of 0.1:0.9:49 to 0.1:0.9:11.5 30% aqueous
diethylzinc in CH
8 h at -78 °C, benzaldehyde (0.050 mL, 0.49 mmol) was
added in one portion, and the reaction was slowly warmed from
78 to -20 °C. After 24 h, the reaction was carefully quenched
with saturated NH Cl solution (0.50 mL). The reaction was
extracted with ether, and the organic phase was washed with
N HCl (2 × 1 mL), H O (1 × 1 mL), saturated NaHCO
) and
2 2
Cl was added (0.640 mL, 0.640 mmol). After
1
-
4
NH
mmol, 51%): H NMR (CDCl
m, 1 H), 1.43 (s, 10 H), 1.75 (s, 5 H), 2.34 (dd, J ) 12.3, 4.7
4
OH/CH
3
OH/CH
2
Cl
2
) gave a yellow oil (0.250 g, 0.925
1
2
3
1
3
, 300 MHz) δ 0.89 (m, 6 H), 1.09
solution (2 × 1 mL), and brine (1 × 1 mL), dried (MgSO
4
(
concentrated in vacuo. The residue was purified by flash
column chromatography (EtOAC/hexanes 1:9) to yield 4,4-
dimethyl-1-phenylpent-2-en-1-ol (0.057 g, 0.30 mmol, 61%).
1
3
Hz, 1 H), 2.45-2.57 (m, 4 H), 3.63 (s, 1 H), 4.72 (s, 1 H);
NMR (CDCl , 75 MHz) δ 156.5, 79.3, 56.6, 54.7, 53.9, 37.7,
8.8, 25.4, 23.9, 15.2, 12.4; IR (neat) 3378, 2962, 2875, 2791,
C
3
2
1
-
1
681, 1517, 1454, 1385, 1363, 1247, 1172, 1058 cm ; HRMS-
Supporting Information Available: HPLC column con-
+
FAB (M + Na ) calcd for C15
H
30
N
2
O
2
Na 293.2205, found
) +18.3 (c ) 1.25, CHCl ).
General Procedure for the Synthesis of Ligands 4a-c
ditions and retention times for all allylic alcohol products;
2
4
2
93.2210; [R]
D
3
1
structures for amides 2a-r; complete experimental details; H
13
and C NMR spectra for all new compounds. This material is
and j-k. To the Boc-protected precursor (1 mmol) was added
trifluoroacetic acid (1 mL) at rt, and the reaction was stirred
for 1 h. The TFA was removed by rotary evaporation, the
available free of charge via the Internet at http://pubs.acs.org.
JO051313L
8840 J. Org. Chem., Vol. 70, No. 22, 2005