Asymmetric synthesis of C-aliphatic homoallylic amines and biologically important cyclohexenylamine analogues

Article abstract of DOI:10.1021/jo048903o

An efficient method for the asymmetric synthesis of C-aliphatic homoallylic amines with up to 94% yield and 80% de is reported. Ring-closing metathesis of several chiral homoallylic amines using the second-generation Grubbs catalyst provided easy access t

Full text of DOI:10.1021/jo048903o

SCHEME 1. Ba r bier Allyla tion of Im in es
Asym m etr ic Syn th esis of C-Alip h a tic
Hom oa llylic Am in es a n d Biologica lly
Im p or ta n t Cycloh exen yla m in e An a logu es
Chi-Lik Ken Lee, Hui Yvonne Ling, and Teck-Peng Loh*
allylic bromides, such as prenyl and cinnamyl, produced
undesirable aldehyde products. For that reason, develop-
ment of an efficient method for the assembly of chiral
C-aliphatic amines in a stereocontrolled manner with a
wider variety of allylic bromides is in high demand.
Herein, we report an asymmetric synthesis of homoallylic
amines via the zinc-mediated allylation of C-aliphatic
imines using optically pure (S)-phenylglycine acid methyl
ester as the chiral auxiliary,7-11 which can subsequently
be removed with ease.12
Our initial studies revealed that relatively high asym-
metric induction can be accomplished using a variety of
allylic bromides (Table 1). When cyclohexanecarbox-
aldehyde was used as the corresponding aldehyde moiety
for the construction of chiral imine 1a , the reactions with
allylic bromides generally provided satisfactory to excel-
lent yields. In fact, crotylation and prenylation of chiral
imine 1a provided excellent yields with good selectivities
and syn:anti ratios (Table 1, entries 1 and 2). As expected,
this Zn-mediated allylation using THF as the solvent of
choice gave the desired homoallylic amines derived from
3-phenylpropanal, though in modest yields, except when
prenyl and cinnamyl bromides were used (Table 1, entries
5 and 6). Nonetheless, good diastereoselectivities and
syn:anti ratios were achieved in all cases.
When this methodology was expanded to 4-pentenal
and cis-hept-4-enal (imines 1c and 1d , respectively),
considerable variation of allylic bromides is possible
without any significant loss in efficiency of diastereocon-
trol (up to 92% yield and 80% de). A relatively high ratio
of syn adducts was obtained in all cases. Prenyl bromide
proved again to be the allylic bromide of choice as it gave
the desired chiral homoallylic amine with excellent yields
and impressive diastereoselectivities (Table 1, entries 8
and 11). It is interesting to note that the reactions of
cinnamyl bromide with chiral imines 1a and 1b produced
Department of Chemistry, National University of Singapore,
3 Science Drive 3, Singapore 117543
chmlohtp@nus.edu.sg
Received J une 30, 2004
Abstr a ct: An efficient method for the asymmetric synthesis
of C-aliphatic homoallylic amines with up to 94% yield and
80% de is reported. Ring-closing metathesis of several chiral
homoallylic amines using the second-generation Grubbs
catalyst provided easy access to a wide variety of cyclo-
hexenylamines.
The enantio- and diastereoselective construction of
homoallylic amines1 has become a significant goal in the
field of medicinal chemistry and organic synthesis.
Within the realm of biologically active compounds, the
homoallylic amine functional array is an important
structural subunit2 and a key intermediate in the syn-
thesis of alkaloid natural products and nitrogen hetero-
cycles.3 The development of new methods for the asym-
metric synthesis of homoallylic amines is therefore of
considerable importance.
Among the most frequently employed methods for
accessing chiral homoallylic amines is the Barbier ally-
lation4 of chiral imines (Scheme 1). Although the metal-
mediated allylation of C-aromatic imines has been very
successful,1,2 the development using C-aliphatic imines
has been less explored. While innovative and notable
advances have been documented,5 a truly convenient and
general method remains elusive.
Despite the emergence of the convenient Barbier-type
allylation using indium metal, most of the effective
examples documented mainly involve allyl bromide.6 The
search for an extension of this protocol to more complex
(1) For some representative examples, see: (a) Yamamoto, Y.; Asao,
N. Chem. Rev. 1993, 93, 2207. (b) Kleinman, E. F.; Volkmann, R. A.
In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon
Press: New York, 1991; Vol. 2, Chapter 4.3, pp 975-1066. (c)
Kobayashi, S.; Ishitani, I. Chem. Rev. 1999, 99, 1069.
(2) (a) Ovaa, H.; Stragies, R.; van der Marcel, G. A.; van Boom, J .
H.; Blechert, S. Chem. Commun. 2000, 1501. (b) Enders, D.; Reinhold,
U. Tetrahedron: Asymmetry 1997, 8, 1895. (c) Bloch, R. Chem. Rev.
1998, 98, 1407 and references therein.
(3) (a) Martin, S. F.; Ru¨eger, H.; Williamson, S. A.; Grzejszczak, S.
J . Am. Chem. Soc. 1987, 109, 6124. (b) Felpin, F. X.; Girard, S.; Giang,
V.-T.; Robins, R. J .; Villie´ras, J .; Lebreton, J . J . Org. Chem. 2001, 66,
6305 and references therein.
(4) For a discussion of the mechanism, see: Molle, B. J . Am. Chem.
Soc. 1982, 104, 3481.
(5) (a) van der Marcel, S.; Dalmolen, J .; Lange, B.; Kaptein, B.;
Kellogg, R. M.; Broxterman, Q. B. Org. Lett. 2001, 3, 3943. (b) Shibata,
I.; Nose, K.; Sakamoto, K.; Yasuda, M.; Baba, A. J . Org. Chem. 2004,
69, 2185.
(7) (a) Yamamoto, Y.; Nishii, S.; Maruyama, K.; Komatsu, T.; Ito,
W. J . Am. Chem. Soc. 1986, 108, 7778. (b) Yamamoto, Y.; Ito, W.
Tetrahedron 1988, 44, 5415. (c) Neumann, W.; Rogic, M. M.; Dunn, T.
J . Tetrahedron Lett. 1991, 32, 5865. (d) Beuchet, P.; Le Martec, N.;
Mosset, P. Tetrahedron Lett. 1992, 33, 5959.
(8) (a) Wu, M.-J .; Pridgen, L. N. Synlett 1990, 636. (b) We, M.-J .;
Pridgen, L. N. J . Org. Chem. 1991, 56, 1340. (c) Dembe´le´, Y. A.; Belaud,
C.; Villie´ras, J . Tetrahedron: Asymmetry 1992, 3, 511.
(9) (a) Tanaka, H.; Inoue, K.; Pokorski, U.; Taniguchi, M.; Torii, S.
Tetrahedron Lett. 1990, 31, 3023. (b) Dembe´le´, Y. A.; Belaud, C.;
Hitchcock, P.; Villie´ras, J . Tetrahedron: Asymmetry 1992, 3, 351. (c)
Giammaruco, M.; Taddei, M.; Ulivi, P. Tetrahedron Lett. 1993, 34,
3635. (d) Bhuyan, P. J .; Prajapati, D.; Sandhu, J . Tetrahedron Lett.
1993, 34, 7975.
(10) (a) Laschat, S.; Kunz, H. Synlett 1990, 51. (b) Laschat, S.; Kunz,
H. J . Org. Chem. 1991, 56, 5883.
(11) (a) Alvaro, G.; Martelli, G.; Savoia, D. J . Chem. Soc., Perkins
Trans. 1998, 1, 777. (b) Bocoum, A.; Savoia, D.; Umani-Ronchi, A. J .
Chem. Soc., Chem. Commun. 1993, 1542. (c) Razavi, H.; Polt, R. J .
Org. Chem. 2000, 65, 5693.
(6) (a) Tirayut, V.; Chutima, W.; Tetsuro, S.; Yasufumi, O. Tetra-
hedron Lett. 2001, 42, 9073. (b) Legros, J .; Meyer, F.; Coliboeuf, M.;
Crousse, B.; Bonnet-Delpon, D.; Be´gue´, J . P. J . Org. Chem. 2003, 68,
6444. (c) Alvaro, G.; Savoia, D. Synlett 2002, 651 and references
therein.
(12) The removal of the (S)-phenylglycine acid methyl ester chiral
auxiliary has been achieved in an overall yield of 89% from two steps
(reduction of the ester moiety using DIBAL-H and a subsequent
oxidative cleavage using Pb(OAc)4).
10.1021/jo048903o CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/05/2004
J . Org. Chem. 2004, 69, 7787-7789
7787

TABLE 1. Zn -Med ia ted Allyla tion of Ch ir a l Im in es 1 Usin g Differ en t Allylic Br om id es 2a ,b
homoallylic
amine
yield
(%)
entry
imine
R
R1
R2
dr (S,R:S,S)c
syn:antid
75:25e
1
2
3
4
5
6
7
8
9
1a
1a
1a
1b
1b
1b
1c
1c
1c
1d
1d
1d
c-C6H5
c-C6H5
c-C6H5
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
3a
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
6c
Me
Me
Ph
Me
Me
Ph
Me
Me
Ph
Me
Me
Ph
H
Me
H
H
Me
H
H
Me
H
H
Me
H
94
92
65
39
72
58
59
72
62
53
92
67
80:20
89:11
88:12
78:22
89:11
88:12
75:25
89:11
90:10
80:20
90:10
90:10
82:18f
79:21e
90:10f
86:14e
CH2dCH(CH2)2
CH2dCH(CH2)2
CH2dCH(CH2)2
CH3CH2CHdCH(CH2)2
CH3CH2CHdCH(CH2)2
CH3CH2CHdCH(CH2)2
95:5e
10
11
12
81:19e
88:12e
a
The reactions were performed in THF (5 mL) with 1 mmol of chiral imine by using excess Zn (3.2 mmol) and allylic bromide (3.0
mmol). Allylic bromides used (crotyl and cinnamyl) were predominantly trans. c Determined by 1H NMR and 13C NMR, except in some
b
cases where the diastereomers can be well separated by flash column chromatography. Determined by H NMR and 13C NMR; syn:anti
ratios refer to only the major diastereomer (S,R). e No linear homoallylic amine was observed. f Traces of linear homoallylic amines were
isolated.
d
1
TABLE 2. Rin g-Closin g Meta th esisa of Hom oa llylic
Am in es 5a -c
trace amounts of the linear homoallylic amine adducts
formed. When the same bromide was injected into either
chiral imines 1c or 1d , no such side products were
observed.6c
To illustrate the synthetic potential of our methodol-
ogy, homoallylic amines (5a -c), synthesized from 1c,
were converted to the corresponding cyclohexenylamines13
using a ring-closing metathesis approach.14 These chiral
cyclohexenylamines are important building blocks for
homoallylic
amine
T
(°C)
time
(h)
yield
(%)
several alkaloids, such as sarain A,15 aphanorphine,16
hetisine,17 and some of the Securinega group.18 More
interestingly, some of these cyclohexenylamines, in the
presence of inorganic pyrophosphate, have been reported
to show strong cooperative inhibition with trichodiene
synthase.19
entry
R1
R2
H
product
1
2
3
5a
5b
5c
Me
Me Me
Ph
40b
25
6
12
6
7a
7b
7c
84
92
86
H
40b
a
The reactions were performed in CH2Cl2 (10 mL) with 0.1
mmol of chiral homoallylic amine by using 0.01 mmol of Grubbs’
second-generation catalyst, unless otherwise stated. Reactions
were reflux at 40 °C if the TLC showed starting material after 12
h of stirring at room temperature.
b
As revealed in Table 2, the homoallylic amines under-
went ring-closing metathesis to afford excellent yields.20
(13) (a) Maier, M. E.; Lapeva, T. Synlett 1998, 891. (b) Quirante,
J .; Vila, X.; Escolano, C.; Bonjoch, J . J . Org. Chem. 2002, 67, 2323.
(14) For excellent reviews on the RCM with nitrogen-containing
compounds, see: (a) Philips, A. J .; Abell, A. D. Aldrichimica Acta 1999,
32, 75. For a more general review, see: (b) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413. For recent examples, see: (c) Fu¨rstner,
A.; Thiel, O. R. J . Org. Chem. 2000, 65, 1738. (d) Cook, G. R.; Shanker,
P. S.; Peterson, S. L. Org. Lett. 1999, 1, 615. (e) Kigoshi, H.; Suzuki,
Y.; Aoki, K.; Uenura, D. Tetrahedron Lett. 2000, 41, 3927. (f) Wallace,
D. J .; Cowden, C. J .; Kennedy, D. J .; Ashwood, M. S.; Cottrell, I. F.;
Dolling, U.-H. Tetrahedron Lett. 2000, 41, 2027. (g) Grigg, R.; Sridha-
ran, V.; York, M. Tetrahedron Lett. 1998, 39, 4139. (h) Voigtmann, U.;
Blechert, S. Org. Lett. 2000, 2, 3971. (i) Maldaner, A. O.; Pilli, A. A.
Tetrahedron Lett. 2000, 41, 7843.
(15) (a) Denhart, D. J .; Griffith, D. A.; Heathcock, C. H. J . Org.
Chem. 1998, 63, 9616. (b) Irie, O.; Samizu, K.; Henry, J . R.; Weinreb,
S. M. J . Org. Chem. 1999, 64, 587. (c) Downham, R.; Ng, F.-W.;
Overman, L. E. J . Org. Chem. 1998, 63, 8096. (d) Sung, M. J .; Lee, H.
I.; Chong, Y.; Cha, J . K. Org. Lett. 1999, 1, 2017.
(16) Tamura, O.; Yanagimachi, T.; Kobayashi, T.; Ishibashi, H. Org.
Lett. 2001, 3, 2427 and references therein.
These ring-closing reactions were performed by stirring
a dichloromethane solution of the homoallylic amines in
the presence of 10 mol % Grubbs’ second-generation
catalyst for up to 12 h. In all cases, the cyclohexenylamine
derivatives can be obtained in very good yields.21 It is
important to note that most of the homoallylic amines
needed reflux conditions to allow their full depletion
(Table 2, entries 1 and 3). Notably, homoallylic amine
5b afforded the desired product 7b in excellent yield
(92%) with 10 mol % catalyst when the mixture was
stirred at ambient temperature.
Dibromo adduct 8 was synthesized according to Scheme
2, and on the basis of its X-ray crystallographic analysis
(Figure 1),22 the absolute configuration of the major
(17) Kwak, Y.-S.; Winkler, J . D. J . Am. Chem. Soc. 2001, 123, 7429.
(18) Liras, S.; Davoren, J . E.; Bordner, J . Org. Lett. 2001, 3, 703
and references therein.
(19) (a) Mcgready, P.; Pyun, H.-J .; Coates, R. M.; Croteau, R. Arch.
Biochem. Biophys. 1992, 299, 63. (b) Cane, D. E.; Yang, G.-Y.; Coates,
R. M.; Pyun, H.-J .; Hohm, T. M. J . Org. Chem. 1992, 57, 3454.
(20) Only the major (S,R)-diastereomer was allowed to undergo ring-
closing metathesis.
(21) Fu¨rstner, A.; Langemann, K. Synthesis 1997, 792.
(22) Only pure isomer 7c was used to synthesize 8, and the latter
was obtained as a single isomer based on 1H NMR and 13C NMR
analyses.
7788 J . Org. Chem., Vol. 69, No. 22, 2004

lamines by the ring-closing metathesis reaction has also
been demonstrated. This course offers a valuable alterna-
tive to the Diels-Alder strategy to cyclohexenes with an
electon-donating substituent in the homoallylic position.
The combination of the ring-closing metathesis reaction
with transannular cyclization should provide access to
interesting natural products.
Exp er im en ta l Section
Gen er a l P r oced u r e for th e P r ep a r a tion of Im in es 1. To
a stirred solution of aldehyde (1 mmol, 1 equiv) and Na2SO4 (0.5
g) in dichloromethane (3 mL, 0.33 M) under nitrogen at 0 °C
was added (S)-phenylglycine methyl ester (1.5-2.0 mmol, 1.5-
2.0 equiv). The reaction mixture was stirred for 5 h. The
resulting reaction mixture was then filtered and concentrated
in vacuo. The crude product obtained was used without purifica-
tion for subsequent steps.
Gen er a l P r oced u r e for th e P r ep a r a tion of Hom oa llylic
Am in es 3-6. To a stirred suspension of the chiral imine (1
mmol) in THF (5 mL) and “activated” Zn powder (3.2 mmol) was
added the allylic bromide (3.0 mmol) at 0 °C, and the mixture
was stirred for up to 7 h. The reaction mixture was then
quenched with saturated NaHCO3 (10 mL) before being ex-
tracted with CH2Cl2 (3 × 10 mL). The mixture was then washed
with water (2 × 10 mL) before being dried with Na2SO4 and
concentrated in vacuo. The crude product was purified by flash
column chromatography.
F IGURE 1. X-ray structure of 8.
SCHEME 2. Dibr om in a tion of Cycloh exen yla m in e
7c
Gen er a l P r oced u r e for th e P r ep a r a tion of Cycloh ex-
en yla m in es 7. To a stirred suspension of the chiral homoallylic
amine (1 mmol) in CH2Cl2 (100 mL) was added Grubbs’ second-
generation catalyst (0.1 mmol) in two portions (interval of 30
min) at 25 °C, and the mixture was stirred for up to 12 h.
Reactions were reflux at 40 °C if the TLC showed the starting
material after 12 h of stirring at room temperature. The reaction
mixture was then filtered through a pad of Celite before being
concentrated in vacuo. The crude product was purified by flash
column chromatography.
homoallylic amine diastereomers can therefore be estab-
lished as (S,R). By simply employing a retrosynthetic
study, we recognized the major homoallylic amine dias-
tereomer with a substituent (methyl or phenyl group) at
the γ-position as the syn adduct.
In summary, we have successfully described an ef-
ficient allylation of chiral C-aliphatic imines, affording
the desired aliphatic homoallylic amines in high diaste-
reoselectivities. This methodology enabled the prepara-
tion of a larger variety of chiral C-aliphatic homoallylic
amines, including those inaccessible by conventional
systems. By analyzing the X-ray crystallographic data
of 8, we are able to establish the absolute configuration
of the homoallylic amines obtained. Importantly, the syn
and anti isomers can be unambiguously established. The
simple synthesis of biologically important cyclohexeny-
Ack n ow led gm en t. We thank the National Univer-
sity of Singapore for generous financial support. We also
thank Professor Koh Lip Lin and Ms. Tan Geok Kheng
for determining the crystal structure of 32. C.-L.K.L. is
grateful to the Agency for Science Technology and
Research (A*STAR) for a doctorate scholarship.
Su p p or t in g In for m a t ion Ava ila b le: Experimental
details and characterization data for the products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O048903O
J . Org. Chem, Vol. 69, No. 22, 2004 7789