Three-component catalytic asymmetric synthesis of aliphatic amines [12]

Full text of DOI:10.1021/ja0118744

J. Am. Chem. Soc. 2001, 123, 10409-10410
10409
Scheme 1
Three-Component Catalytic Asymmetric Synthesis of
Aliphatic Amines
James R. Porter, John F. Traverse, Amir H. Hoveyda,* and
Marc L. Snapper*
Department of Chemistry
Merkert Chemistry Center, Boston College
Chestnut Hill, Massachusetts 02467
Table 1. Three-Component Catalytic Asymmetric Synthesis of
ReceiVed August 2, 2001
Arylaminesa
Discovery and development of efficient catalytic asymmetric
methods for the preparation of nonracemic amines is an important
objective in organic synthesis. In this context, there have been
notable advances involving catalytic enantioselective hydrogena-
tions and hydrogen transfer reactions involving imine1 and
enamine substrates.2 Protocols for catalytic enantioselective
alkylations of imines have also emerged. Earlier reports include
the catalytic enantioselective additions of alkyllithiums,3 promoted
by chiral amines, in up to 82% ee. More recently, Tomioka4 and
co-workers disclosed Cu-catalyzed asymmetric additions of
Et2Zn to N-tosylimines, while research in our laboratories has
resulted in the development of a method for Zr-catalyzed
asymmetric additions of a range of alkylzinc reagents to o-anisidyl
imines.5 Nonetheless, the large majority of the above advances
(both hydrogenations and alkylations), deals with transformations
of aromatic imines and enamines.6 Herein, we report the results
of our studies regarding the Zr-catalyzed asymmetric addition of
alkylzincs to aliphatic imines by a single-vessel, three-component
catalytic asymmetric procedure that obviates the need for isolation
of unstable imine starting materials (Scheme 1). The requisite
chiral ligands are peptide-based7 and can be synthesized through
coupling (and reduction) of commercially available aromatic
aldehydes and amino acids valine and phenylalanine.8
a Conditions: 6 equiv Et2Zn, toluene, 0 °Cf22 °C, 48 h for entry
1-2, 24 h for entry 3, 96 h for entry 4. b Isolated yields after silica gel
chromatography. c Determined by chiral HPLC in comparison with
authentic racemic material (Chiralcel OD).
likely that the presence of the acidic R-protons, together with the
activating effect of the o-anisidyl unit, leads to formation of the
enamines and the corresponding homocoupling products (e.g.,
aldol- and Mannich-type additions).9 To circumvent the above
complication, we set out to examine the possibility of three-
component asymmetric amine synthesis involving imine formation
from an appropriate aldehyde and o-anisidine, followed by in situ
catalytic alkylation. The viability of such an approach was first
investigated with aromatic aldehydes. As illustrated in entry 1 of
Table 1, we established that treatment of benzaldehyde with
o-anisidine, 10 mol % dipeptide Schiff base ligand 1 and
Zr(Oi-Pr)4‚HOi-Pr and six equiv of Et2Zn leads to the facile
formation of amine 2 in 82% ee and 90% isolated yield.10 Reaction
efficiency and enantioselectivity improved when dipeptide amine
3 was employed (entry 2). Two more examples, involving
Our initial attempts to examine the catalytic alkylations of
aliphatic o-anisidyl imines were thwarted by their lack of stability
upon isolation. In contrast to the derived aromatic imines, it is
(1) For a review on catalytic asymmetric additions to imines, see: (a)
Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895-1946. (b)
Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069-1094.
(2) For representative examples, see: (a) Lee, N. E.; Buchwald, S. L. J.
Am. Chem. Soc. 1994, 116, 5985-5986. (b) Burk, M. J.; Wang, Y. M.; Lee,
J. R. J. Am. Chem. Soc. 1996, 118, 5142-5143. (c) Li, W.; Zhang, X. J. Org.
Chem. 2000, 65, 5871-5874.
(3) (a) Denmark, S. E.; Nakajima, N.; Nicaise, O. J.-C. J. Am. Chem. Soc.
1994, 116, 8797-8798. (b) Denmark, S. E.; Nicaise, O. J.-C. Chem. Commun.
1996, 999-1004. (c) Denmark, S. E.; Stiff, C. M. J. Org. Chem. 2000, 65,
5875-5878. (d) Tomioka, K.; Inoue, I.; Shindo, M.; Koga, K. Tetrahedron
Lett. 1991, 32, 3095-3098.
(4) Fujihara, H.; Nagai, K.; Tomioka, K. J. Am. Chem. Soc. 2000, 122,
12055-12056.
(5) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J. Am.
Chem. Soc. 2001, 123, 984-985.
(6) For catalytic asymmetric additions of alkyllithiums to aliphatic imines
(in the presence of 20 mol % (-)-sparteine), see: ref 3a. For an example of
catalytic asymmetric hydrogenation of imines derived from nonaromatic
ketones, see: Hansen, M. C.; Buchwald, S. L. Org. Lett. 2000, 2, 713-715.
(7) For other catalytic asymmetric C-C bond forming reactions promoted
by this class of peptide-based ligands, see: Ti-catalyzed addition of cyanide
to aldehydes: (a) Nitta, H.; Yu, D.; Kudo, M.; Mori, A.; Inoue, S. J. Am.
Chem. Soc. 1992, 114, 7969-7975. Ti-catalyzed cyanide addition to ep-
oxides: (b) Cole, B. M.; Shimizu, K. D.; Krueger, C. A.; Harrity, J. P. A.;
Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1996, 35, 1668-
1671. (c) Shimizu, K. D.; Cole, B. M.; Krueger, C. A.; Kuntz, K. W.; Snapper,
M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1997, 36, 1704-1707.
Ti-catalyzed cyanide addition to imines: (d) Krueger, C. A.; Kuntz, K. W.;
Dzierba, C. D.; Wirschun, W. G.; Gleason, J. D.; Snapper, M. L.; Hoveyda,
A. H. J. Am. Chem. Soc. 1999, 121, 4284-4285. (e) Porter, J. R.; Wirschun,
W. G.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc.
2000, 122, 2657-2658. Cu-catalyzed conjugate additions of dialkylzincs to
enones: (f) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc.
2001, 123, 755-756. Cu-catalyzed allylic substitutions of allyl phosphates
with dialkylzincs: (g) Luchaco-Cullis, C. A.; Mizutani, H.; Murphy, K. E.;
Hoveyda, A. H. Angew. Chem., Int. Ed. 2001, 40, 1456-1460.
(8) Boc-L-Val and Boc-L-Phe are commercially available at $0.15 and $0.19
per mmol from Advanced Chemtech; the corresponding D-isomers can be
purchased at $1.22 and $0.86 per mmol.
2-furaldehyde and 3-pyridine carboxaldehyde11 are illustrated in
Table 1 (entries 3-4). Additional issues regarding the data in
Table 1 merit mention: (i) In all cases shown, analysis of the
400 MHz1H NMR spectra did not indicate any products from
alkylations of aldehydes (<2%). (ii) Although appreciable asym-
metric induction is observed, the selectivities shown in Table 1
are somewhat lower than those obtained with purified imine
substrates.5
Since we expected nonselective (noncatalytic) background
alkylations to be less favored with the less reactive aliphatic
imines, the data in Table 1 proved encouraging despite the lower
levels of enantioselectivity (in comparison to the two-vessel
procedure5). This expectation was substantiated when we estab-
(9) This class of aliphatic imines undergo decomposition upon concentra-
tion.
(10) See the Supporting Information for the methods used to establish the
identity of major enantiomers in this study.
(11) In contrast to reactions with PhCHO (entries 1-2), with 3-pyridine
carboxaldehyde, ligand 1 provides superior enantioselectivity and efficiency
(77% ee and 64% with 3).
10.1021/ja0118744 CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/02/2001

10410 J. Am. Chem. Soc., Vol. 123, No. 42, 2001
Communications to the Editor
Table 2. Three-Component Catalytic Asymmetric Synthesis of
lished that treatment of 1-pentanal and o-anisidine with 10 mol
% 3 and Zr(Oi-Pr)4‚HOi-Pr and six equiV of Et2Zn (0 °Cf22
°C) leads to the formation of amine 7 in 97% ee and 69% isolated
yield after silica gel chromatography (entry 1, Table 2). Similar
results were obtained when heptanal was used as the starting
material (f8; entry 2, Table 2), and reaction efficiency signifi-
cantly improved in the catalytic asymmetric synthesis of 9 (>98%
yield; entry 3). Synthesis of unsaturated amine 10 (entry 4)
proceeds with high enantioselectivity (>98% ee) in 60% isolated
yield; ligand screening led us to establish that reaction efficiency
improves when dipeptide 6 is used (10 is obtained in 72% yield
and 92% ee). Highly enantioselective syntheses of 11 (entry 5)
and cyclopropylamine 12 (entry 6) indicate that the three-
component catalytic alkylation is effective with aldehydes bearing
an R- or a â-alkyl substituent. Zr-catalyzed alkylation with
6-bromo-hexanal, shown in entry 7 of Table 2, proceeds ef-
fectively to afford 13 in 95% ee and 57% yield together with
13% of the cyclized product 16 (by addition to imine formed
through intramolecular alkylation by the derived enamine).12
Optically enriched amino alcohols 14 and 15 (entries 8-9) are
obtained with excellent enantioselectivity from three-component
catalytic alkylations that employ siloxy aldehydes (tert-butyl-
diphenylsilyl and tert-butyldimethylsilyl ethers, respectively; 48%
and 64% overall yields for two steps).
Alkylaminesa
An important attribute of the previously reported Zr-catalyzed
alkylations of aromatic imines5 is that alkylzinc reagents other
than Et2Zn can be employed for enantioselective C-C bond
formation. As the representative examples in Scheme 2 indicate,
this advantage is available to reactions of aliphatic imines as well.
The three-component catalytic asymmetric processes involving
Me2Zn with aldehyde 17 delivers 18 in 88% ee and 68% isolated
yield;13 in a similar fashion, amine 20 is obtained from the reaction
of 19 and (4-methylpentyl)2Zn in 97% ee and 80% yield.
a Conditions: 6 equiv Et2Zn, toluene, 0 °Cf22 °C, 24 h (48 h for
entry 9). b >98% conv in all cases. Isolated yields after silica gel
chromatography. c Determined by chiral HPLC in comparison with
authentic racemic material (Chiralcel OD). d With 6 as the chiral ligand,
10 is obtained in 78% yield and 92% ee. e 13% 16 was also isolated.
f Overall yields after alkylation and deprotection of silyl ethers (see
Supporting Information for details).
Scheme 2
We thus disclose a general catalytic asymmetric method for
alkylations of aliphatic imines, where prior isolation of imines is
not necessary. The metal salts employed are inexpensive and the
chiral ligands can be easily prepared and modified. The use of
dialkylzinc reagents other than Et2Zn is effective and allows for
the preparation of aliphatic amines of high optical purity that are
not otherwise readily available. The above factors, together with
the significance of three-component approaches16 to combinatorial
synthesis,17 collectively render the present technology of notable
utility. Future studies will involve study of mechanism and
applications to target-oriented synthesis.18
Although optically enriched o-anisidylamines are of potential
utility in synthesis, facile and efficient removal of the N-activating
group to yield the unfunctionalized amines is important as well.
Toward this end, we discovered that the protocol employed pre-
viously for unmasking of aromatic amines yields5 the desired ali-
phatic products in <35% yield. Accordingly, the oxidative method
represented in eq 1 was developed,14 where the optically enriched
acylated amine is obtained with higher efficiency and without
any detectable loss of enantiopurity (chiral GLC and HPLC).15
Supporting Information Available: Experimental procedures, ster-
eochemical assignments and spectral and analytical data for all products
(PDF). This material is available free of charge via the Internet at
http//:www.acs.pubs.org.
JA0118744
(12) Amine 16 is formed in 53% ee. The reason for the lower level of
enantioselectivity is unclear and will be addressed in the course of upcoming
mechanistic studies.
(16) For representative recent reports regarding multicomponent asymmetric
catalysis, see: (a) Ikeda, S.; Cui, D.-M.; Sato, Y. J. Am. Chem. Soc. 1999,
121, 4712-4713. (b) Yamasaki, S.; Iida, T.; Shibasaki, M. Tetrahedron 1999,
55, 8857-8867. (c) Fujii, A.; Hagiwara, E.; Sodeoka, M. J. Am. Chem. Soc.
1999, 121, 5450-5458. (d) Ishitani, H.; Komiyama, S.; Hasegawa, Y.;
Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 762-766. (e) List, B. J. Am.
Chem. Soc. 2000, 122, 9336-9337. For a related nonasymmetric example,
see: (f) Wipf, P.; Kendall, C.; Stephenson, C. R. J. J. Am. Chem. Soc. 2001,
123, 5122-5123.
(13) Lower reactivity of Me2Zn requires that larger amounts of this
alkylmetal reagent be employed.
(14) For related oxidative procedures, see: (a) Pelter, A.; Elgendy, S.
Tetrahedron Lett. 1988, 29, 677-680. (b) Barret, R.; Daudon, M. Tetrahedron
Lett. 1990, 31, 4871-4872. (c) Kinugawa, M.; Masuda, Y.; Arai, H.;
Nishikawa, H.; Ogasa, T.; Tomioka, S.; Kasai, M. Synthesis 1996, 633-636.
(d) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S.; Sugita, K. Angew. Chem.,
Int. Ed. 2001, 40, 2145-2149.
(15) The present procedure is more effective for the unmasking of alkylation
products of aromatic imines as well. For example, 2 was deprotected in 75%
isolated yield (vs 65% by protocol in ref 5).
(17) (a) Lutz, W.; Illgen, K.; Almstetter, M. Synlett 1999, 366-374. (b)
Lee, D.; Sello, J. K.; Schreiber, S. L. Org. Lett. 2000, 2, 709-712.
(18) Financial support was provided by the NIH (GM-57212).