Synthesis of enantiopure allylamines by reductive alkylation of amino epoxides with organolithium reagents

Article abstract of DOI:10.1021/ol0529602

Transformation of enantiopure (2R,1′S)-2-(1-aminoalkyl)epoxides 1 into the corresponding allylamines 2 is described. The opening of the epoxide ring with different organolithium compounds takes place with total selectivity and in high yields.

Full text of DOI:10.1021/ol0529602

ORGANIC
LETTERS
2
006
Vol. 8, No. 2
49-351
Synthesis of Enantiopure Allylamines by
Reductive Alkylation of Amino Epoxides
with Organolithium Reagents
3
Jos e´ M. Concell o´ n,* Jos e´ Ram o´ n Su a´ rez, and Virginia del Solar
Departamento de Qu ´ı mica Org a´ nica e Inorg a´ nica, Facultad de Qu ´ı mica UniVersidad
de OViedo, Juli a´ n ClaVer ´ı a, 8, 33071 OViedo, Spain
jmcg@unioVi.es
Received December 7, 2005
ABSTRACT
Transformation of enantiopure (2R,1′S)-2-(1-aminoalkyl)epoxides 1 into the corresponding allylamines 2 is described. The opening of the
epoxide ring with different organolithium compounds takes place with total selectivity and in high yields.
Chiral allylamines are important building blocks and have
been used as synthetic precursors to prepare a number of
important classes of compounds, such as R- and â-amino
developed in comparison with the racemic synthesis. The
synthesis of chiral allylamines is generally achieved by (a)
7
amination of enantiopure allyl alcohols or their derivatives,
1
2
3
8
acids, alkaloids, carbohydrate derivatives, and other com-
(b) asymmetric amination of nonfunctional alkenes, or (c)
from R-amino aldehydes. However, general methods to
4
9
pounds.
5
In addition, allylamines are also of industrial interest. For
prepare allylamines with an enantiomeric excess (ee) > 99%,
these reasons, many efficient methods for the racemic
synthesis of allylamines have been reported. However, the
asymmetric synthesis of allylamines has not been so well
in which only one regioisomer is obtained and the double
6
(7) Examples of asymmetric synthesis of allylamines from allyl alcohols
derivatives. From allyl imidates: (a) Celter, M.; Hollis, T. K.; Overman,
L. E.; Ziller, J.; Zipp, G. G. J. Org. Chem. 1997, 62, 1449-1456. (b) Metz,
P.; Mues, C.; Schoop, A. Tetrahedron 1992, 48, 1071-1080. By amination
of allylic esters catalyzed by transition metal complexes: (c) Togni, A.;
Burckhardt, U.; Gramlich, V.; Pregosin, P. S.; Salzmann, R. J. Am. Chem.
Soc. 1996, 118, 1031-1037. (d) Burckhardt, U.; Baumann, M.; Trabesinger,
G.; Gramlich, V.; Togni, A. Organometallics 1997, 16, 5252-5259. (e)
Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1994, 116, 4089-4090. (f)
Evans, P. A.; Robinson, J. E.; Nelson, J. D. J. Am. Chem. Soc. 1999, 121,
6761-6762. (g) Wang, Y.; Ding, K. J. Org. Chem. 2001, 66, 3238-3241.
(h) Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 15164-15165.
(i) Tollabi, M.; Framery, E.; Goux-Henry, C.; Sinou, D. Tetrahedron:
Asymmetry 2003, 14, 3329-3333. (j) Faller, J. W.; Wilt, J. C. Org. Lett.
2005, 7, 633-636. From vinyl epoxides: (k) Trost, B. M.; Bunt, R. C.
Angew. Chem., Int. Ed. Engl. 1996, 35, 99-102. From allyl ethers: (l)
Enders, D.; Finkam, M. Synlett 1993, 401-402.
(
1) (a) Hayashi, T.; Yamamoto, A.; Ito, Y.; Nishioka, E.; Miura, H.;
Yanagi, K. J. Am. Chem. Soc. 1989, 111, 6301-6311. (b) Jumnah, R.;
Williams, J. M. J.; Williams, A. C. Tetrahedron Lett. 1993, 34, 6619-
6
622. (c) Bower, J. F.; Jumnah, R.; Williams, A. C.; Williams, J. M. J. J.
Chem. Soc., Perkin Trans. 1 1997, 1411-1420. (d) Burgess, K.; Liu, L.
T.; Pal, B. J. Org. Chem. 1993, 58, 4758-4763.
(2) (a) Magnus, P.; Lacour, J.; Coldham, I.; Mugrage, B.; Bauta, W. B.
Tetrahedron 1995, 51, 11087-11110. (b) Trost, B. M. Angew. Chem., Int.
Ed. 1989, 28, 1173-1192.
(3) Trost, B. M.; Van Vranken, D. L. J. Am. Chem. Soc. 1993, 115,
4
44-458.
(4) Aminoallylsilanes: (a) Franciotti, M.; Mordini, A.; Taddei, M. Synlett
1
992, 137-138. Aminoepoxides: (b) Luly, J. R.; Dellaria, J. F.; Plattner,
J. J.; Soderquist, J. L.; Yi, N. J. Org. Chem. 1987, 52, 1487-1492. (c)
Romeo, S.; Rich, D. H. Tetrahedron Lett. 1993, 34, 7187-7190. (d) Albeck,
A.; Persky, R. J. Org. Chem. 1994, 59, 653-657. (e) Branat, J.; Kvarnstr o¨ m,
I.; Classon, B.; Samuelson, B.; Nilroth, U.; Danielson, H.; Karl e´ n, A.;
Halberg, A. Tetrahedron Lett. 1997, 38, 3483-3486. Iodocyclocarbam-
ates: (f) Kobayashi, S.; Isobe, T.; Ohno, M. Tetrahedron Lett. 1984, 25,
(8) To see some examples by asymmetric nitrene insertion reaction: (a)
N a¨ geli, I.; Baud, C.; Bernardinelli, G.; Jacquier, Y.; Moran, M.; M u¨ ller, P.
HelV. Chim. Acta 1997, 80, 1087-1105. Based on the ene reaction: (b)
Takada, H.; Nishibayashi, Y.; Ohe, K.; Uemura, S.; Baird, C. P.; Sparey,
T. J.; Taylor, P. C. J. Org. Chem. 1997, 62, 6512-6518. (c) Kurose, N.;
Takahashi, T.; Koizumi, T. J. Org. Chem. 1996, 61, 2932-2933. (d) Braun,
H.; Felber, H.; Kresse, G.; Ritter, A.; Schmidtchen, F. P.; Schneider, A.
Tetrahedron 1991, 47, 3313-3328.
5
2
079-5082. Isoxazolines: (g) Nishi, T.; Moreisawa, Y. Heterocycles 1989,
9, 1835-1842.
(5) Akutagawa, S.; Tani, K. In Catalytic Asymmetric Synthesis, 2nd ed.;
(
Ojima, I., Ed.; Wiley: Weinheim, Germany, 2000; p 145.
(9) To see two reviews of olefination of R-aminoaldehydes: (a) Reetz,
M. T. Chem. ReV. 1999, 99, 1121-1162. (b) Wei, Z.-Y.; Knaus, E. E.
Synthesis 1994, 1463-1465.
(
6) For see a review: Johannsen, M.; Jørgensen, K. A. Chem. ReV. 1998,
9
8, 1689-1708.
1
0.1021/ol0529602 CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/30/2005

bond is generated with total stereoselectivity by using method
a) or (b) are very scarce. In addition, syntheses of enan-
(
Table 1. Synthesis of (2R,3S)-1,3-Diaminoalkan-2-ols 3
tiopure allylamines involving the Wittig olefination reaction
entry
2
R1
R2
T (h)
yield (%)
a
of R-amino aldehydes10 are limited by the possibility that
4
b
racemization may occur during the Wittig reaction.
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
Me
Me
Me
Me
Me
Me
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
Ph
Me
6
81
79
95
i-Pr
n-Bu
s-Bu
t-Bu
Ph
0.5
0.5
0.5
0.5
6
For this reason, a general synthesis of enantiopure allyl-
amines with complete regio- and stereoselectivity would be
still desirable.
Previously, the olefin formation with alkylation of ep-
oxides using organolithiums has been described by Crandall
and Lin,11 and a number of research groups have subse-
quently made contributions to this field.12
b
75
84
75
79
77
86
Me
6
i-Pr
n-Bu
s-Bu
t-Bu
Ph
0.5
0.5
0.5
0.5
6
b
In the past, we have reported the synthesis of enantiopure
allylamines by successive reaction of R-amino aldehydes with
chloromethyllithium generated in situ and further lithiation
10
76
1
1
1
1
1
1
1
2
3
4
5
6
78
89
75
88
91
85
89
93
Me
6
13
with lithium powder. However, by using this method, it is
possible to prepare only allylamines with the CdC double
bond in the terminal position.
Ph
Ph
Ph
Ph
i-Pr
n-Bu
s-Bu
t-Bu
Ph
0.5
0.5
0.5
0.5
6
b
Previously, we reported an efficient synthesis of enan-
tiopure (2R,1′S)- or (2S,1′S)-2-(1-aminoalkyl)epoxides by
total stereoselective reduction of the easily available, from
natural R-amino acids, R-amino-R′-chloroketones with
17
18
Ph
a
Isolated yield after column chromatography based on the starting amino
epoxide 1. b A mixture of two diastereoisomers in a 1:1 relationship was
obtained when s-Buli was used.
LiAlH
4
, or by highly stereoselective addition of in situ
generated iodomethyllithium (from diiodomethane and me-
thyllithium) to R-aminoaldehydes.
14
reaction was performed with different amino epoxides,
derived from alanine (Table 1, entries 1-6), leucine (entries
As part of a program concerned with the development of
a new synthesis of enantiopure compounds, we wish to report
herein a new easy and general access to enantiopure
allylamines by treatment of enantiopure (2R,1′S)-(1-amino-
alkyl)epoxides with alkyllithium which takes place in high
yield, with complete E-stereoselectivity.
7
-12), and phenylalanine (entries 13-18) and various
primary, secondary, and tertiary alkyllithium and aryllithium
compounds.
When less reactive organolithium compounds, such as
methyllithium or phenyllithium, were used, longer reaction
times were necessary to obtain the corresponding allylamine
The reaction of different (2R,1′S)-(1-aminoalkyl)epoxides
2
in high yield (Table 1, entries 1, 6, 7, 12, 13, and 18).
1
with various organolithium compounds at 0 °C during 30
The complete stereoselectivity of the reaction was deter-
min afforded the corresponding enantiopure allylamine in
1
mined by H NMR spectroscopy (300 MHz) of the crude
reaction, showing the presence of a single diastereoisomer.
The E-stereochemistry of the double CdC bond of
allylamines 2 was assigned on the basis of the value of the
high yields (>74%) with complete E-stereoselectivity (Scheme
1
and Table 1).15
1
Scheme 1. Synthesis of Allylamines 2
H NMR coupling constant of olefinic protons (ranging
between 15.4 and 16.1 Hz according to the average literature
1
6
values).
The enantiomeric purity of 2h was determined by chiral
HPLC analysis, showing an ee < 99%. To exclude the
possibility of coelution of both enantiomers, a racemic
mixture of 2h was prepared and analyzed by HPLC.17
As is shown in Table 1, transformation of amino epoxides
1
into allylamines 2, seems to be general. Therefore, the
(13) Concell o´ n, J. M.; Baraga n˜ a, B.; Riego, E. Tetrahedron Lett. 2000,
4
1, 4361-4362.
(
10) R-Amino aldehydes are often susceptible to racemization: (a)
(14) (a) Barluenga, J.; Baraga n˜ a, B.; Alonso, A.; Concell o´ n, J. M. J.
Fehrentz, J. A.; Castro, B. Synthesis 1983, 676-678. (b) Rettle, K. E.;
Hommick, C. F.; Ponticello, G. S.; Evans, B. E. J. Org. Chem. 1982, 47,
016-3018. (c) Lubell, W. D.; Rapoport, H. J. Am. Chem. Soc. 1988, 110,
447-7455.
Chem. Soc., Chem. Commun. 1994, 969-970. (b) Barluenga, J.; Baraga n˜ a,
B.; Concell o´ n, J. M. J. Org. Chem. 1995, 60, 6696-6699.
3
7
(15) Representative Experimental Procedure. To a stirred solution of
the corresponding amino epoxide 1 (0.2 mmol), in THF (1 mL), was added
the corresponding alkyllithium (3 equiv) at 0 °C. After the solution was
stirred at this temperature until the reaction finished (see Table 1), an
aqueous saturated solution of NH4Cl (5 mL) was added, and the mixture
was stirred at room temperature for 5 min. Then, the aqueous phase was
extracted with diethyl ether (3 × 5 mL), and the combined organic layers
were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo.
Flash column chromatography on silica gel (hexane/EtOAc 10:1) provided
pure compounds 2.
(
11) (a) Crandall, J. K.; Lin, L.-H. C. J. Am. Chem. Soc. 1967, 89, 4526-
4
4
527. (b) Crandall, J. K.; Lin, L.-H. C. J. Am. Chem. Soc. 1967, 89, 4527-
528. (c) Crandall, J. K.; Apparu, M. Org. React. 1983, 29, 345-443.
(12) Reviews: (a) Satoh, T. Chem. ReV. 1996, 96, 3303-3325. (b) Doris,
E.; Dechoux, L.; Mioskowski, C. Synlett 1998, 337-343. To see examples
of development of this methodology: (c) Dechoux, L.; Doris, E.; Miosk-
owski, C. J. Chem. Soc., Chem. Commun. 1996, 549-550. (d) Hodgson,
D. M.; Stent, M. A. H.; Wilson, F. X. Org. Lett. 2001, 3, 3401-3403. (e)
Hodgson, D. M.; Maxwell, C. R.; Miles, T. J.; Paruch, E.; Stent, M. A. H.;
Matthews, I. R.; Wilson, F. X.; Witherington, J. Angew. Chem., Int. Ed.
(16) Silverstein, R. M.; Bassler, G. C.; Morrill, T. C. Spectrometric
Identification of Organic Compounds; John Wiley and Sons: New York,
1991; Chapter 4, Appendix F, p 221.
2
002, 41, 4313-4316.
350
Org. Lett., Vol. 8, No. 2, 2006

This transformation and the observed stereochemistry of
the products 2 may be explained by assuming that after
lithiation of epoxide ring, at the less hindered side, would
produce the oxiranyl anion intermediate 3. This anion 3 could
suffers an R-elimination affording an R-alkoxycarbenoid
intermediate 4, which could react with a second equivalent
of the organometallic compounds to give the dianion 5.
Finally, lithium oxide is then eliminated to afford allylamines
Scheme 3. Reaction with the Anti Amino Epoxide 6
2
(Scheme 2).
In both cases, the corresponding allylamines2 were
obtained with total E-selectivity in yields (78 and 76%,
respectively) similar to those obtained from the syn-amino
epoxide (Table 1, entries 3 and 5, respectively). Then, the
described transformation was not affected by the stereo-
chemistry of the starting amino epoxide.
Scheme 2. Proposed Mechanism
In conclusion, in this paper, we have presented an easy,
simple, general, and efficient preparation of enantiopure
allylamines by reaction of (2R,1′S)-2-(1-aminoalkyl)epoxides
1
with different organolithium compounds. This transforma-
tion takes place in high yield, with complete E-stereoselec-
tivity of the double CdC bond formation.
Acknowledgment. We thank the Ministerio de Ciencia
y Tecnolog ´ı a (CTQ2004-1191/BQU) for financial support
and Vicente del Amo for his revision of the English. J.M.C.
thanks Carmen Fern a´ ndez-Fl o´ rez for her time. V.d.S. thanks
Principado de Asturias for a contract investigation.
An indirect support for this proposed mechanism is
provided by the isolation of a 1:1 mixture of the starting
amino epoxide and the corresponding allylamine when the
reaction was carried out by using only 1 equiv of organo-
lithium compound.
We here also performed the reaction starting from the anti-
amino epoxide 6 with n-BuLi and t-BuLi under the same
reaction conditions (Scheme 3).
Supporting Information Available: General methods,
1
3
spectroscopic data of 2, and C NMR spectra of 2. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) Chiracel OD, UV detector 210 nm, 0.5 mL/min, hexane, rt: 2h
1
8.826 min; rt: enantiomer of 2h 13.737 min.
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