Chiral synthesis of functionalized tetrahydropyridines: γ-aminobutyric acid uptake inhibitor analogues

Article abstract of DOI:10.1021/jo0508200

A convenient preparation of functionalized chiral tetrahydropyridine-3- carboxylates from nitriles in 68-90% enantiomeric excess (ee) via allylboration, followed by a conjugate addition-elimination and ring-closing metathesis, has been developed. Thus, th

Full text of DOI:10.1021/jo0508200

Chiral Synthesis of Functionalized Tetrahydropyridines:
γ-Aminobutyric Acid Uptake Inhibitor Analogues
P. Veeraraghavan Ramachandran,* Thomas E. Burghardt, and Layla Bland-Berry
Herbert C. Brown Center for Borane Research, Department of Chemistry, Purdue University,
560 Oval Drive, West Lafayette, Indiana 47907-2084
chandran@purdue.edu
Received April 22, 2005
A convenient preparation of functionalized chiral tetrahydropyridine-3-carboxylates from nitriles
in 68-90% enantiomeric excess (ee) via allylboration, followed by a conjugate addition-elimination
and ring-closing metathesis, has been developed. Thus, the treatment of the acetate derived from
vinylalumination of formaldehyde by use of [R-(ethoxycarbonyl)vinyl]diisobutylaluminum with chiral
â-substituted and â-unsubstituted homoallylic amines, prepared in >98% diastereomeric excess
(de) and 68-90% ee via allylboration of the corresponding N-aluminoimines, furnished functionalized
aminodienes, which underwent ring-closing metathesis to provide chiral C5-C6 disubstituted
tetrahydropyridine-3-carboxylates. This methodology has been applied for the synthesis of a chiral
C6-substituted tetrahydropyridine with known GABA-inhibiting properties at low concentrations.
Introduction
gic receptors. Unfortunately, high in vitro activity of 1
and 2 did not extend to the in vivo action.7 Among several
evaluated analogues, compounds such as SKF 100330-A
(3, IC50 ) 0.21 µM)8 and 4 (IC50 ) 0.1 µM)4 were found to
provide good results in GABA inhibition, and 3 was
reported to have high bioavailability as well.2c,9 Subse-
quent studies have shown that a modification at the C6
position (as in compound 5) eliminated the GABA-uptake
inhibition, but inhibition of M1 and M2 muscarinic
receptors at 100 nM was observed (Figure 1).10
Unfortunately, a systematic study of such compounds
has been limited, probably, due to the somewhat cumber-
some routes for their preparation.11 Indeed, to the best
of our knowledge, preparation and biological evaluation
of C6-chiral analogues of guvacine has never been re-
ported.
One of the major mammalian inhibitory neurotrans-
mitters is γ-aminobutyric acid (GABA).1 A plethora of
diseases, such as Parkinson’s, Huntington’s, epilepsy, and
schizophrenia, has been linked to dysfunction of GABAer-
gic synapses.1,2 The tetrahydropyridine moiety3 has been
identified as the pharmacophore for GABA inhibition
with the aid of computer modeling, and these results have
been confirmed by in vitro studies.4 Among the evaluated
compounds, nipecotic acid (1, IC50 ) 1.7 µM),5 guvacine
(2, IC50 ) 4.9 µM),6 and various guvacine derivatives
showed the best results in their activity toward GABAer-
(1) (a) GABA in Nervous System Function; Roberts, E., Chase, T.
R., Tower, D. B., Eds.; Raven Press: New York, 1976. (b) Roberts, E.
In Nervous System; Tower, D. B., Ed.; Raven Press: New York, 1975.
(2) (a) Czapinski, P.; Blaszczyk, B.; Czuczwar, S. J. Curr. Top. Med.
Chem. 2005, 5, 3 and references therein. (b) Dalby, N. O. Eur. J.
Pharmacol. 2003, 479, 127. (c) Bohme, I.; Luddens, H. Curr. Med.
Chem. 2001, 8, 1257. (d) Krogsgaard-Larsen, P.; Frolund, B.; Fryden-
vang, K. Curr. Pharm. Des. 2000, 6, 1193.
(7) Frey, H.-H.; Popp, C.; Lo¨scher, W. Neuropharmacology 1979, 18,
581.
(8) Yunger, L. M.; Fowler, P. J.; Zarevics, P.; Setler, P. E. J.
Pharmacol. Exp. Ther. 1984, 228, 109.
(9) Ali, F. E.; Bondinell, W. E.; Dandridge, P. A.; Frazee, J. S.;
Garvey, E.; Girard, G. R.; Kaiser, C.; Ku, T. W.; Lafferty, J. J.;
Moonsammy, G. I.; Oh, H.-J.; Rush, J. A.; Setler, P. E.; Stringer, O.
D.; Venslavsky, J. W.; Volpe, B. W.; Yunger, L. M.; Zirkle, C. L. J.
Med. Chem. 1985, 28, 653.
(10) Bisel, P.; Gies, J. P.; Schlewer, G.; Wermuth, C. G. Bioorg. Med.
Chem. Lett. 1996, 6, 3025.
(3) (a) Mateeva, N. N.; Winfield, L. L.; Redda, K. K. Curr. Med.
Chem. 2005, 12, 551. (b) Felpin, F.-X..; Lebreton, J. Curr. Org. Synth.
2004, 1, 83.
(4) N’Goka, V.; Schlewer, G.; Linget, J.-M.; Chamborn, J.-P.; Wer-
muth, C.-G. J. Med. Chem. 1991, 34, 2547.
(5) Johnston, G. A. R.; Krogsgaard-Larsen, P.; Stephanson, A. L.;
Twitchin, B. J. Neurochem. 1976, 26, 1029.
(6) Johnston, G. A. R.; Allen, R. D.; Kennedy, S. M. G.; Twitchin, B.
In GABA-Neurotransmitters: Pharmacochemical, Biochemical and
Pharmacological Aspects; Krogsgaard-Larsen, P., Scheel-Krilger, J.,
Kofod, H., Eds.; Munksgaard: Copenhagen, Denmark, 1978; p 147.
(11) (a) Zhu, X.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125,
4617. (b) Clinch, K.; Marquez, C. J.; Parrott, M. J.; Ramage, R.
Tetrahedron 1989, 45, 239. (c) Langlois, Y.; Potier, P. Tetrahedron
1975, 31, 419.
10.1021/jo0508200 CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/30/2005
J. Org. Chem. 2005, 70, 7911-7918
7911

Ramachandran et al.
FIGURE 2. R-Pinene-based reagents for allylboration of
N-aluminoimines.
SCHEME 2. Preparation of Acetate 12 via
Vinylaluminationa
a Reagents and conditions: (a) DIBAL-H (1.5 equiv), NMO (1.8
equiv); THF, 0 °C, 1 h. (b) (1) HCHO (excess); THF, 50 °C, 0.5 h;
(2) aq. dil. HCl; (c) AcCl (1.2 equiv); pyridine (0.8 equiv), CH2Cl2,
1 h, 0 °C.
FIGURE 1. GABA-uptake inhibitors.
SCHEME 1. Retrosynthetic Analysis
developed in our laboratory over the past few years, is
an attractive alternative for the Baylis-Hillman proto-
col17 as it furnishes similar or the same products, while
reaction times are significantly shortened and a broader
range of carbonyl compounds is tolerated. Although
anhydrous formaldehyde had to be generated for the
vinylalumination, the reaction was cleaner, workup and
purification were significantly easier, and the product
was obtained in satisfactory yield (Scheme 2).18 The
obtained alcohol 13 was acetylated under standard
conditions to yield 12.
Partial reduction of benzonitrile (15a) with 1 equiv of
diisobutylaluminum hydride (DIBAL-H) at 0 °C fur-
nished the corresponding N-aluminoimine, which was
added to an ether-pentane solution of 8 at -100 °C,
followed by 1 equiv of methanol. Upon completion of the
reaction, as shown by the disappearance of the peak at
δ 78 and the appearance of a peak at δ 47 in 11B NMR
spectra, and alkaline oxidative workup, followed by
purification, the desired homoallylic amine 16a was
obtained in 90% yield and 88% enantiomeric excess (ee)
(Scheme 3).15 Addition of 16a to the acetate 12 furnished
the desired aminodiene 17a in 92% yield (Scheme 4).
The commercially available ruthenium-based alky-
lidene catalyst 18 (Figure 3),19 devised by Grubbs and
co-workers, is stable to air and moisture and it tolerates
acidic environment. It is widely used for the synthesis of
various cycloalkenes, even from densely substituted
dienes,20 including aminodienes.13 Recent modification of
this catalyst achieved in Hoveyda’s laboratory furnished
19 (Figure 3),21 which was reported to show more
reactivity toward densely substituted dienes and was
herein evaluated on selected aminodienes.
We envisaged a convenient preparation of such mol-
ecules via the conjugate addition-elimination reaction12
of the acetate obtained from the alcohol synthesized via
vinylalumination or Baylis-Hillman reaction with chiral
homoallylic amines to furnish aminodienes, which would
then undergo ring-closing metathesis (RCM) reaction to
yield the desired products. The RCM reaction of amino-
dienes has been previously applied for the syntheses of
numerous piperidine and pyrrolidine alkaloids.13 How-
ever, to the best of our knowledge, RCM has never been
used for the preparation of tetrahydropyridine-3-carboxy-
lic acids such as 2-5 and their esters. We were also
curious to know the effect of the carboxylate on the alkene
during the RCM reaction. Accordingly, we undertook
such a study and our general retrosynthetic analysis for
the preparation of tetrahydropyridine-3-carboxylates is
presented in Scheme 1.
Results and Discussion
Recently, we reported the preparation of chiral ho-
moallylic amines from nitriles via the allylboration or
crotylboration of N-aluminoimines with (-)-B-allyldiiso-
pinocampheylborane (8, Figure 2)14 or the “allyl” “ate”
complexes (9-11, Figure 2) in the presence of 1 equiv of
methanol.15 We adopted this protocol for the current
project.
For the synthesis of the required acetate (12), we chose
to synthesize ethyl 2-(hydroxymethyl)acrylate (13) via
[R-(ethoxycarbonyl)vinyl]diisobutylaluminum (14).16 This
vinylalumination reaction, which has been modified and
(16) (a) Ramachandran, P. V.; Rudd, M. T.; Burghardt, T. E.; Reddy,
M. V. R. J. Org. Chem. 2003, 45, 9310. (b) Ramachandran, P. V.; Reddy,
M. V. R.; Rudd, M. T. Chem. Commun. 1999, 1979.
(17) (a) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev.
2003, 103, 811. (b) Baylis, A. B.; Hillman, M. E. D. Chem. Abstr. 1972,
77, 34174q.
(18) It is noteworthy that the preparation of alcohol 13 via the
Baylis-Hillman reaction of formaldehyde with ethyl acrylate always
resulted in the formation of a significant amount of the dimerized
product. Basavaiah, D.; Krishnamacharyulu, M.; Rao, A. J. Synth.
Commun. 2000, 30, 2061.
(19) Scholl, M.; Ding, S.; Lee, W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(12) This reaction is referred to as an SN2′ reaction in the literature
(see ref 17a). However, this is a conjugated addition-elimination that
is giving an SN2′ product.
(13) For reviews, see (a) Felpin, F.-X.; Lebreton, J. Eur. J. Org.
Chem. 2003, 3693. (b) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104,
2199.
(14) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092.
(15) Ramachandran, P. V.; Burghardt, T. E. Chem. Eur. J. 2005,
11, 4387.
(20) For recent reviews, see (a) Grubbs, R. H. Tetrahedron 2004,
60, 7117. (b) Astruc, D. New J. Chem. 2005, 29, 42.
(21) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J.
Am. Chem. Soc. 2000, 122, 8168.
7912 J. Org. Chem., Vol. 70, No. 20, 2005

GABA-Uptake Inhibitor Analogues
SCHEME 3. Synthesis of Homoallylic Amines via Allylboration of N-Aluminoimines
SCHEME 4. Preparation of Chiral Tetrahydropyridine-3-carboxylatesa
a Reagents and conditions: (a) (1) DIBAL-H (1.0 equiv); pentane, 0 °C, 1 h. (2) 8 (1.2 equiv); pentane. (3) MeOH (1.0 equiv); -100 f
-78 °C (for 15a), -78 °C (for 15b), or -55 °C (for 15c), 3 h. (4) NaOH/H2O2; -78 °C f RT, 14 h. (b) 12 (1.0 equiv); CH2Cl2, 0 °C, 12 h.
(c) HCl (1.2 equiv); Et2O, RT, 0.5 h. (d) Boc2O (1.2 equiv); Et2O, RT, 12 h. (e) Aqueous HCHO (7.0 equiv), NaBH3CN (2.0 equiv); CH3CN,
14 h, RT. (f) 18 or 19 (0.1 equiv); CHCl3, 60 °C, 14 h or PhMe, 100 °C, 14 h.
acrylates prepared from homoallylic alcohols have yielded
R-pyrones without the loss of optical activity.23
Next, this protocol was applied for the preparation of
other chiral C5-substituted GABA inhibitor analogues.
Thus, allylboration of the N-aluminoimines obtained from
3,3-diphenylpropanenitrile (15b) and cyclohexanecarbo-
nitrile (15c) with 1.2 equiv of 8 in the presence of 1.0
FIGURE 3. Catalysts for ring-closing metathesis.
equiv of methanol yielded the corresponding homoallylic
amines 16b and 16c in 64% and 86% yield, respectively,
The RCM reaction using Grubbs’ second-generation
catalyst (18) on the aminodiene containing free secondary
amine (17a) failed to provide any cyclized product (Table
1, entry 1). This may be expected since the chelation
between the catalyst and basic nitrogen atom might
render 18 inactive.22 Three methods for circumventing
this deficiency of RCM were examined: (1) conversion
of the amine to an ammonium salt, (2) conversion of the
secondary amine to a tertiary one, and (3) protection of
the amine. Thus, 17a was treated with ethereal HCl to
obtain the ammonium salt 20a, which was refluxed with
0.1 equiv of 18 in CHCl3 for 14 h and then neutralized
with aqueous NaHCO3. Purification on silica gel provided
the desired amine 21a in 72% yield (Table 1, entry 2).
Similarly, the reaction of 20a with 0.1 equiv of catalyst
19 in toluene at 100 °C yielded the desired tetrahydro-
pyridine 21a in 70% yield (Table 1, entry 3). Preparation
of the N-methylamine (20a′) was achieved in 86% yield
by the reductive amination of aqueous formaldehyde with
17a in the presence of NaBH3CN in dilute acetonitrile.
The compound 20a′ underwent RCM to furnish 21a′ in
85% yield; however, elevated reaction temperature was
required (Scheme 4; Table 1, entries 4 and 5). Protection
of 17a with Boc2O furnished a quantitative yield of 20a′′,
which, after RCM in refluxing CHCl3, provided 21a′′ in
73% yield (Table 1, entry 6).
and both in 68% ee (Scheme 4). Compounds 16b,c were
reacted with acetate 12 to furnish the corresponding
aminodienes 17b,c in 87% and 86% yield, respectively.
Since the RCM on the ammonium salt appeared to be
the most convenient protocol, the aminodienes 17b,c
were converted to their hydrochloride salts 20b,c, fol-
lowed by RCM in the presence of 0.1 equiv of 18 in
toluene at 100 °C for 14 h. Upon completion of the
reaction, the free amines were recovered by neutraliza-
tion with NaHCO3 and purified on silica gel to provide
the corresponding tetrahydropyridine-3-carboxylates 21b
and 21c in 62% and 63% yield, respectively (Scheme 4;
Table 1, entries 7 and 8). We are assuming 68% ee for
21b and 21c since we have previously observed no loss
of optical activity during the RCM reaction.23 The ester
21b is a chiral analogue of the tetrahydropyridine
carboxylic acid 4, which was shown to have GABA-uptake
inhibitory properties at low concentrations.4
Upon successful preparation of a series of C6-substi-
tuted guvacine analogues from nitriles, the synthesis of
compounds with functionalization at C5 and C6 was
attempted. The reagent-controlled crotylboration24 of
N-aluminoimines by use of boron “ate” complexes 9-11
(Figure 2)15 would furnish â-substituted homoallylic
amines in high diastereomeric excess (de) and ee.15
Hence, crotylboration of N-aluminoimines prepared by
The ee of the prepared tetrahydropyridine-3-carboxy-
lates 21a, 21a′, and 21a′′ is assumed to be 88% on the
basis of our earlier demonstration that similar RCM of
(23) For review, see Ramachandran, P. V.; Reddy, M. V. R.; Brown,
H. C. Pure Appl. Chem. 2003, 75, 1263.
(24) (a) Hoffmann, R. W.; Zeiss, H. J. J. Org. Chem. 1981, 46, 1309.
(b) Brown, H. C.; Bhat, K. S. J. Am Chem. Soc. 1986, 108, 293. (c)
Brown, H. C.; Jadhav, P. K.; Bhat, K. S. J. Am. Chem. Soc. 1988, 110,
1535.
(22) Philips, A. J.; Abell, A. D. Aldrichim. Acta 1999, 32, 75 and
references therein.
J. Org. Chem, Vol. 70, No. 20, 2005 7913

Ramachandran et al.
TABLE 1. Preparation of Chiral Tetrahydropyridine-3-carboxylates
aminodiene
tetrahydropyridine
entry
nitrile no.
no.
R
P
yield,a %
temp (°C)
no.
P
yield,a %
ee,b %
1
2
3
4
5
6
7
8
15a
15a
15a
15a
15a
15a
15b
15c
17a
20a
20a
20a′
20a′
20a′′
20b
20c
Ph
Ph
Ph
Ph
Ph
Ph
H
92c
92c
92c
86
60
60
100
60
100
60
100
100
21a
21a
21a
21a′
21a′
21a′′
21b
21c
H
d
HCl
HCl
Me
H
72
70e
d
88
88
88
88
88
68
68
H
Me
Me
Boc
H
Me
86
85
73
62
63
Boc
HCl
HCl
98
Ph2CH(CH2)2
Chx
87c
86c
H
a All yields are of pure isolated products. b The values are on the basis of the starting homoallylic amines, whose enantiomeric excess
was verified by 19F NMR spectroscopy after conversion to Mosher amides and/or obtained by HPLC analysis on a Chiracel OD-H column.
c The yields are given for the free aminodienes; hydrochloride salts were not isolated. d No reaction; most of the unreacted starting material
was recovered. e Catalyst 19 was used.
SCHEME 5. Preparation of C5-C6 Functionalized Tetrahydropyridine-3-carboxylatesa
a Reagents and conditions: (a) (1) DIBAL-H (1.0 equiv); pentane or THF, 0 °C, 1 h. (2) 9, 10, or 11 (1.2 equiv); pentane or THF. (3)
MeOH (1.0 equiv); -78 °C, 3 h. (4) NaOH/H2O2; -78 °C f RT, 14 h. (b) 12 (1.0 equiv); CH2Cl2, 0 °C, 6-12 h. (c) HCl (1.2 equiv); Et2O,
RT, 0.5 h. (d) Boc2O (1.2 equiv); Et2O, RT, 12 h. (e) Aqueous HCHO (7.0 equiv), NaBH3CN (2.0 equiv); CH3CN, 14 h, RT. (f) 18 or 19 (0.1
equiv); PhMe, 100 °C, 14 h
partial reduction of 15a and 15b with DIBAL-H, by use
of the reagent 9, in the presence of 1.0 equiv of methanol,
provided the corresponding anti-â-methyl homoallylic
amines 22a and 22b in 80% and 64% yield, respectively,
and in >98% de and 89% ee (Scheme 5).15 Similarly, syn-
â-methyl homoallylic amine 23a was prepared from 15a
in 78% yield, >98% de, and 90% ee by use of the reagent
10 (Scheme 5). Alkoxyallylboration of the N-alumi-
noimine obtained from 15a by use of the reagent 11, in
the presence of 1 equiv of methanol, furnished syn-â-
ethoxy homoallylic amine 24a in 72% yield, >98% de, and
89% ee (Scheme 5).15
These â-substituted homoallylic amines (22a,b, 23a,
and 24a), upon the conjugate addition-elimination reac-
tion with acetate 12, yielded the corresponding amino-
dienes 25a,b, 26a, and 27a in 78-88% yields. The RCM
reactions of the aminodienes 25a, 26a, and 27a as their
ammonium salts (28a, 29a, and 30a, respectively) did
not proceed satisfactorily even with 0.2 equiv of 18 in
toluene and produced only low amounts of the desired
tetrahydropyridine-3-carboxylates within 24 h, when
decomposition of the starting materials was observed
(Scheme 5; Table 2, entries 1 and 5). However, RCM of
28b (the hydrochloride salt of the aliphatic aminodiene
25b) furnished the desired tetrahydropyridine-3-carboxy-
late 31b in 64% isolated yield (Scheme 5; Table 2, entry
4). Again, on the basis of our previously demonstrated
work with RCM on similar dienes,23 we assume that there
is no loss of optical activity during the RCM reaction. The
prepared compound 31b is a C5-functionalized analogue
of 21b, a chiral analogue of compound 4.4
The aminodienes 25a, 26a, and 27a, upon treatment
with formaldehyde in the presence of NaBH3CN, pro-
vided the corresponding N-methyl compounds 28a′, 29a′,
and 30a′ in 89-92% yields. The tertiary amines 28a′ and
29a′, upon reaction with 0.1 equiv of 18 in toluene at 100
°C, provided the corresponding densely functionalized
tetrahydropyridine-3-carboxylates 31a′ and 32a′ in 75%
and 70% yield, respectively (Scheme 5; Table 2, entries
2 and 6). The N-methylaminodiene 28a′ underwent RCM
in the presence of 0.1 equiv of the catalyst 19 in toluene
at 100 °C, providing the required product 31a′ in 74%
isolated yield (Scheme 5; Table 2, entry 3). Unfortunately,
compound 30a′ did not undergo RCM and only the
starting material was recovered. Although attempted
protection of aminodienes 25a and 26a with Boc2O,
according to numerous published procedures,25 did not
provide the expected N-Boc protected amines 28a′′ and
29a′′, the â-alkoxy aminodiene 27a reacted smoothly and
furnished 30a′′ in 96% yield. To our dismay, RCM on the
â-alkoxy aminodienes 30a, 30a′, and 30a′′ failed to
proceed. The reaction would not advance despite the use
of up to 0.3 equiv of 18 or 19, added in portions over 3
days to a mixture stirring at 100 °C. In all of these cases,
7914 J. Org. Chem., Vol. 70, No. 20, 2005

GABA-Uptake Inhibitor Analogues
TABLE 2. Preparation of C5-C6 Densely Functionalized Tetrahydropyridine-3-carboxylates
aminodiene
R1
tetrahydropyridine
entry
no.
R
R2
P
yield,a %
no.
P
yield,b %
dec (%)
eed (%)
1
2
3
4
5
6
7
8
9
28a
28a′
28a′
28b
29a
29a′
30a
30a′
30a′′
Ph
Ph
Ph
Me
Me
Me
Me
H
H
HCl
Me
86e
79
H
f
98
98
89
89
89
89
90
90
89
89
89
H
31a′
31a′
31b
Me
Me
H
75
74g
64
f
H
H
Me
Me
OEt
OEt
OEt
Me
79
98
Ph2CH(CH2)2
HCl
HCl
Me
HCl
Me
Boc
78e
87e
77
>98
>98
>98
>98
>98
>98
Ph
Ph
Ph
Ph
Ph
H
Me
H
Me
Boc
H
32a′
70
f, h
f, h
f, h
H
88e
79
H
H
84
a All yields are of pure isolated products, obtained over two steps from homoallylic amines. b All yields are of pure isolated products.
c Diastereomeric excess was verified by 1H NMR analysis. d The values are for the starting homoallylic amines. Enantiomeric excess was
verified by 19F NMR spectroscopy after conversion to Mosher amides and/or obtained by HPLC analysis on a Chiracel OD-H column.
e The ammonium salts were not isolated; the yields of free aminodienes are given. f No reaction, most of the unreacted starting material
was recovered. g Catalyst 19 was used. h No reaction with catalysts 18 or 19.
Then, ethyl propiolate (1.1 mL, 11.2 mmol) was added and the
mixture was stirred for 1 h to generate [R-(ethoxycarbonyl)-
vinyl]diisobutylaluminum (14). Paraformaldehyde (10 g) was
heated at 180 °C and the condensing anhydrous formaldehyde
was transferred to the reaction mixture (warmed to 50 °C)
through a short cannula. The reaction was stirred for 0.5 h at
50 °C, cooled to 0 °C, and quenched with HCl (10% in H2O; 5
mL). The product was extracted with Et2O (3 × 50 mL),
solvents were evaporated under reduced pressure, and the
residue was filtered through silica gel to furnish ethyl 2-(hy-
droxymethyl)acrylate (13; 0.7 g, 5.7 mmol, 51% yield). To the
obtained 13, diluted with CH2Cl2 (40 mL) and cooled to 0 °C,
were added pyridine (0.6 mL, 7.4 mmol) and acetyl chloride
(0.7 mL, 9.8 mmol). The reaction was stirred for 1 h at room
temperature (RT), followed by quenching of the excess pyridine
with HCl (10% in H2O; 5 mL). The product was extracted with
CH2Cl2 (1 × 20 mL) and Et2O (2 × 30 mL), the solvents were
evaporated, and the residue was purified on silica gel (95:5
hexanes/ethyl acetate) to yield 12 (1.0 g, 5.7 mmol, 50% yield).
1H NMR (300 MHz, CDCl3, δ) 1.30 (t, J ) 7.1 Hz, 3H), 2.09 (s,
3H), 4.23 (q, J ) 7.1 Hz, 2H), 4.79 (s, 2H), 5.82 (d, J ) 1.0 Hz,
1H), 6.34 (s, 1H); 13C NMR (75 MHz, CDCl3, δ) 14.1, 20.8, 60.9,
62.5, 127.1, 135.6, 165.1, 170.3.
the starting aminodienes were recovered and no product
formation was observed by TLC analysis (Table 2, entries
7-9).
In conclusion, we have developed a novel methodology
for the preparation of chiral functionalized tetrahydro-
pyridine-3-carboxylates in 68-90% ee, such as those
present in GABA and muscarinic inhibitors. The meth-
odology involves the preparation of homoallylic amines
in high ee and de via allylboration of N-aluminoimines,
followed by the conjugate addition-elimination reaction
of an allylic acetate and ring-closing metathesis with
Grubbs’ second-generation catalyst. Substitutions on the
nitrogen and C6, as well as methyl group at C5, are easily
introduced in the tetrahydropyridines. Carboxylic esters
on the double bond are accommodated during the ring-
closing metathesis. We believe that our protocol will find
wide application among organic and bioorganic chemists
as it allows for a convenient synthesis of densely func-
tionalized chiral nitrogen heterocycles.
Experimental Section
Preparation of (1S)-1-Phenylbut-3-en-1-amine (16a). To
a solution of benzonitrile (15a; 0.52 mL, 5.05 mmol) in Et2O
(5 mL) cooled to 0 °C was added DIBAL-H (0.89 mL, 5.0 mmol),
and the mixture was stirred for 1 h to provide the intermediate
N-aluminoimine. For the spectroscopic analysis, the solvent
was removed under reduced pressure. 1H NMR (300 MHz,
CDCl3, δ) 0.14-0.19 (m, 3H), 0.76-1.07 (m, 12H), 1.79 (m qn,
J ) 6.6 Hz, 3H), 7.48-7.80 (m, 5H), 9.00 (s, 1H); 13C NMR (75
MHz, CDCl3, δ) 22.7, 22.8, 26.3, 26.5, 28.2, 28.3, 28.5, 28.7,
129.4, 129.5, 132.4, 132.8, 133.0, 137.1, 174.5, 175.0. The
obtained N-aluminoimine was transferred via cannula to a
solution of 8 (1 M in pentane; 6 mL, 6 mmol) diluted with Et2O
(7 mL) and cooled to -100 °C, followed by a slow addition of
methanol (0.20 mL, 5.0 mmol). The mixture was stirred for 1
h, while it was allowed to slowly warm from -100 to -78 °C
and it was oxidized with NaOH (3 M in H2O; 2 mL) and
(slowly!) H2O2 (30% in H2O; 1.2 mL) and was left stirring under
positive N2 pressure while it slowly warmed to RT. The product
was then extracted with Et2O (3 × 50 mL), treated with HCl
(20% in H2O; 5 mL), and stirred for 0.2 h. To the mixture was
added water (50 mL) to extract the product. After removal of
the organic layer, the aqueous solution of amine hydrochloride
was neutralized with NaOH until pH ∼ 8. The resulting amine
was extracted with Et2O (3 × 50 mL), the solvent was removed
under reduced pressure, and the residue was purified on silica
gel (hexanes/ethyl acetate/triethylamine 84.5:15:0.5) to afford
Preparation of homoallylic amines, vinylalumination, and
ring-closing metathesis were carried out under nitrogen
atmosphere. Tetrahydrofuran (THF) was distilled from sodium
benzophenone ketyl prior to use; all other chemicals and
solvents were purchased commercially and used as such.
Benzonitrile (15a) and cyclohexanecarbonitrile (15c) were
purchased commercially, and 3,3-diphenylpropionitrile (15b)
was prepared from commercially available 3,3-diphenylpropan-
1-ol via the corresponding mesylate. The NMR chemical shifts
(δ) are reported in parts per million (ppm). The enantiomeric
excess of the homoallylic amines was obtained from high-
performance liquid chromatography (HPLC) analysis (Chiracel
OD-H column) and/or 19F and 1H NMR after conversion to
Mosher amides.
Preparation of Ethyl 2-[(Acetyloxy)methyl]acrylate
(12) via Vinylalumination. To a slurry of 4-methylmorpho-
line-N-oxide (2.5 g, 21.3 mmol) in THF (40 mL), cooled to 0
°C, was added DIBAL-H (3.0 mL, 16.8 mmol), and the mixture
was stirred for 0.5 h, wherein DIBAL-H went into solution.
(25) (a) Ohmori, Y.; Yamashita, A.; Tsujita, R.; Yamamoto, T.;
Taniuchi, K.; Matsuda, A.; Shuto, S. J. Med. Chem. 2003, 46, 5326.
(b) Ewert, K.; Ahmad, A.; Evans, H. M.; Schmidt, H.-W.; Safinya, C.
R. J. Med. Chem. 2002, 45, 5023. (c) Lindsay, K. B.; Pyne, S. G. J.
Org. Chem. 2002, 67, 7774. (d) Kamabe, M.; Miyazaki, T.; Hashimoto,
K.; Shirahama, H. Heterocycles 2002, 56, 105. (e) Burg, D.; Filippov,
D. V.; Hermanns, R.; van der Marel, G. A.; van Boom, J. H.; Mulder,
G. J. Bioorg. Med. Chem. 2002, 10, 195. (f) Ma, D.; Sun, H. J. Org.
Chem. 2000, 65, 6009.
1
16a (0.66 g, 4.5 mmol, 90% yield) with 88% ee. H NMR (300
MHz, CDCl3, δ) 1.69 (br s, 2H), 2.32-2.50 (m, 2H), 4.00 (d, J
) 8.0 Hz, 1H), 5.07-5.15 (m, 2H), 5.69-5.82 (m, 1H), 7.22-
J. Org. Chem, Vol. 70, No. 20, 2005 7915

Ramachandran et al.
7.37 (m, 5H); 13C NMR (75 MHz, CDCl3, δ) 44.2, 55.4, 117.7,
126.4, 127.0, 128.5, 135.5, 145.8. MS (EI) m/z 128, 106 (Ph-
CH-NH2), 79; MS (CI) m/z 148 (M + H), 131 (M - NH3); high-
resolution mass spectrometry (HRMS) 148.1126 (calcd),
was stirred for 14 h at RT. The solvent was removed under
reduced pressure and the residue was purified on silica gel
(flash; 97:3 hexanes/ethyl acetate) to yield 20a′ (0.07 g, 0.3
1
mmol, 86% yield). H NMR (300 MHz, CDCl3, δ) 1.38 (t, J )
20
148.1129 (actual). [R]D ) +39 (CHCl3, c ) 0.10) [lit.26 +42
7.1 Hz, 3H), 2.22 (s, 3H), 2.58-2.82 (m, 2H), 3.14 (d, J ) 14.7
Hz, 1H), 3.36 (d, J ) 14.4 Hz, 1H), 3.70 (t, J ) 6.9 Hz, 1H),
4.28 (q, J ) 7.0 Hz, 2H), 4.99-5.10 (m, 2H), 5.71-5.79 (m,
1H), 5.84 (s, 1H), 6.28 (s, 1H), 7.31-7.42 (m, 5H).
(CHCl3, c ) 0.5)].
Preparation of (1R)-1-(3,3-Diphenylpropyl)but-3-eny-
lamine (16b). To a solution of 3,3-diphenylpropionitrile (15b;
1.03 g, 5.0 mmol) in Et2O (10 mL), cooled to 0 °C, was added
DIBAL-H (0.89 mL, 5.0 mmol), and the mixture was stirred
for 1 h. The obtained intermediate N-aluminoimine was
transferred via a cannula to a solution of 8 (1 M in pentane;
7.0 mL, 7.0 mmol) in Et2O (7 mL), cooled to -78 °C, followed
by a slow addition of methanol (0.20 mL, 5.0 mmol). The
mixture was stirred for 6 h and it was oxidized with NaOH (3
M in H2O; 2 mL) and (slowly!) H2O2 (30% in H2O; 1.2 mL),
and was left stirring under positive N2 pressure while it slowly
warmed to RT. The product was extracted with Et2O (3 × 30
mL), the solvent was removed under reduced pressure, and
the residue was purified on silica gel (hexanes/ethyl acetate/
triethylamine 84.5:15:0.5) to afford 16b (0.8 g, 3.2 mmol, 64%
Preparation of Ethyl (6S)-6-Phenyl-1,2,5,6-tetrahydro-
pyridine-3-carboxylate (21a). To 17a (0.05 g, 0.2 mmol),
diluted with Et2O (2 mL), was added HCl (1 M in Et2O; 0.3
mL, 0.3 mmol), and the mixture was stirred for 0.5 h at RT to
generate 20a, followed by the addition of chloroform (250 mL),
warming to 60 °C, and addition of 18 (0.02 g, 0.02 mmol, 0.1
equiv) and stirring for 14 h at 60 °C. The mixture was
concentrated to approximately 20 mL, when it was neutralized
with NaHCO3 (saturated aqueous; 3 mL) and vigorously
stirred for 1 h at RT. The product was extracted with Et2O (3
× 20 mL), the solvents were removed under reduced pressure,
and the residue was purified on silica gel (flash; hexanes/ethyl
acetate 2:1) to furnish 21a (0.03 g, 0.14 mmol, 72% yield). 1H
NMR (300 MHz, CDCl3, δ) 1.38 (t, J ) 7.1 Hz, 3H), 3.76-3.95
(m, 3H), 4.30 (q, J ) 7.1 Hz, 2H), 7.18 (br s, 1H), 7.34-7.45
(m, 5H); 13C NMR (75 MHz, CDCl3, δ) 14.6, 34.6, 45.5, 57.1,
60.7, 126.9, 127.9, 129.0, 130.1, 138.1, 166.2. MS (EI) m/z 231
(M+), 202 (M - C2H5), 158, 104; MS (CI) m/z 232 (M + H),
1
yield) with 68% ee. H NMR (300 MHz, CDCl3, δ) 1.25-1.48
(m, 2H), 1.92-2.27 (m, 4H), 2.78-2.87 (m, 3H), 3.89 (t, J )
7.8 Hz, 1H), 5.01-5.11 (m, 2H), 5.67-5.81 (m, 1H), 7.16-7.32
(m, 10H); 13C NMR (75 MHz, CDCl3, δ): 32.6, 36.2, 42.5, 50.9,
51.8, 117.9, 126.4, 128.0, 128.8, 135.8, 145.1, 145.3. MS (EI)
m/z 265 (M+), 224 (M - C3H5), 91 (C7H7+); MS (CI) m/z 266
155; HRMS (EI) 231.1259 (calcd), 231.1257 (actual). [R]20
+68 (CHCl3, c ) 0.1).
)
D
20
(M + H), 224 (M - C3H4), 188. [R]D ) +8 (CDCl3, c ) 0.6).
(1S)-1-Cyclohexylbut-3-en-1-amine (16c). 1H NMR (300
MHz, CDCl3, δ) 0.94-1.30 (m, 6H), 1.37 (br s, 2H), 1.67-1.78
(m, 5H), 1.93-2.01 (m, 1H), 2.25-2.31 (m, 1H), 2.56 (q, J )
4.2 Hz, 1H), 5.06-5.12 (m, 2H), 5.73-5.84 (m, 1H); 13C NMR
(75 MHz, CDCl3, δ) 26.5, 26.6, 26.7, 28.4, 29.8, 39.5, 43.5, 55.4,
117.2, 136.7. MS (EI) m/z 152 (M - H), 112 (M - C3H5), 95,
70; MS (CI) m/z 154 (M + H), 112; HRMS 154.1596 (calcd),
Ethyl (6S)-1-Methyl-6-phenyl-1,2,5,6-tetrahydropyri-
dine-3-carboxylate (21a′). 1H NMR (300 MHz, CDCl3, δ) 1.31
(t, J ) 7.1 Hz, 3H), 2.12 (s, 3H), 2.48-2.56 (m, 2H), 3.08 (dq,
J ) 3.2 and 18.0 Hz, 1H), 3.21 (dd, J ) 5.1 and 8.5 Hz, 1H),
3.70 (dd, J ) 1.3 and 16.9 Hz, 1H), 4.23 (q, J ) 7.1 Hz, 2H),
7.06 (d, J ) 2.2 Hz, 1H), 7.35-7.27 (m, 5H). 13C NMR (75 MHz,
CDCl3, δ) 14.6, 36.0, 43.5, 54.4, 60.7, 65.0, 127.9, 128.2, 128.9,
129.3, 137.6, 142.5, 166.0. MS (EI) m/z 245 (M+), 118; MS (CI)
m/z 246 (M + H); HRMS (EI) 245.1416 (calcd), 245.1417
20
154.1599 (actual). [R]D ) +9 (CHCl3, c ) 0.37).
Ethyl 2-({[(1S)-1-Phenylbut-3-enyl]amino}methyl)-
acrylate (17a). To 16a (0.6 g, 4.0 mmol) diluted with CH2Cl2
(10 mL) was added 12 (0.7 g, 4.0 mmol), and the mixture was
stirred for 12 h at RT. The solvent was evaporated under
reduced pressure and the residue was purified on silica gel
(flash; 95:5 hexanes/ethyl acetate) to yield 17a (1.0 g, 3.9 mmol,
92% yield). 1H NMR (300 MHz, CDCl3, δ) 1.31 (t, J ) 7.0 Hz,
3H), 1.96 (br s, 1H), 2.34-2.42 (m, 2H), 3.19 (d, J ) 14.6 Hz,
1H), 3.39 (d, J ) 14.6 Hz, 1H), 3.67 (dd, J ) 8.8 and 11.5 Hz,
1H), 4.21 (q, J ) 10.7 Hz, 2H), 5.03-5.13 (m, 2H), 5.58 (s, 1H),
5.63-5.81 (m, 1H), 6.22 (s, 1H), 7.19-7.33 (m, 5H); 13C NMR
(75 MHz, CDCl3, δ) 14.5, 43.5, 48.4, 60.9, 61.2, 117.9, 126.5,
127.4, 127.6, 128.7, 135.7, 138.9, 143.8, 167.0.
20
(actual). [R]D ) -59 (CHCl3, c ) 1.1).
Preparation of 1-tert-Butyl 3-Ethyl (6S)-6-Phenyl-5,6-
dihydropyridine-1,3(2H)-dicarboxylate (21a′′). To a solu-
tion of 17a (0.08 g, 0.3 mmol) in Et2O (10 mL) was added di-
tert-butyl dicarbonate (0.07 g, 0.3 mmol), and the mixture was
stirred for 14 h at RT. Filtration through silica gel furnished
the desired N-Boc protected amine 20a′′ (0.10 g, 0.3 mmol, 99%
yield). The obtained 20a′′ was diluted with chloroform (250
mL) and heated to 60 °C, and 18 (0.03 g, 0.03 mmol) was
added. The solution was refluxed for 14 h, when the solvent
was evaporated and the residue was purified on silica gel
(flash; 95:5 hexanes/ethyl acetate) to yield 21a′′ (0.07 g, 0.2
mmol, 71% yield from 17a). 1H NMR (300 MHz, CDCl3, δ) 1.27
(t, J ) 7.1 Hz, 3H), 1.51 (s, 9H), 2.78-2.81 (m, 2H), 3.41 (dd,
J ) 2.4 Hz and 18.5 Hz, 1H), 4.17 (q, J ) 7.1 Hz, 2H), 4.55 (d,
J ) 18.7 Hz, 1H), 5.61-5.62 (m, 1H), 7.17-7.31 (m, 6H); 13C
NMR (75 MHz, CDCl3, δ) 14.5, 28.3, 28.8, 39.4, 50.1, 60.9, 80.7,
127.0, 127.6, 128.6, 128.6, 136.1, 140.2, 155.2, 165.4. MS (EI)
m/z 331 (M+), 57 (C4H9+); MS (CI) m/z 332 (M + H), 276 (M +
H - C6H8); HRMS (EI) 331.1784 (calcd), 331.1782 (actual).
Ethyl2-{[(1R)-1-(3,3-Diphenylpropyl)but-3-enylamino]-
1
methyl}acrylate (17b). H NMR (300 MHz, CDCl3, δ) 1.30
(t, J ) 7.1 Hz, 3H), 1.37-1.45 (m, 2H), 2.07-2.25 (m, 5H),
2.63 (qn, J ) 5.9 Hz, 1H), 3.39 (br s, 2H), 3.89 (t, J ) 7.7 Hz,
1H), 4.22 (q, J ) 7.1 Hz, 2H), 5.05-5.10 (m, 2H), 5.63 (s, 1H),
5.69-5.78 (m, 1H), 6.23 (s, 1H), 7.16-7.32 (m, 10H); 13C NMR
(75 MHz, CDCl3, δ) 14.5, 43.5, 48.4, 60.9, 61.2, 117.9, 126.5,
127.4, 127.6, 128.7, 135.7, 138.9, 143.8, 167.0.
20
Ethyl 2-({[(1S)-1-Cyclohexylbut-3-enyl]amino}methyl)-
[R]D ) -5 (CHCl3, c ) 0.08).
1
acrylate (17c). H NMR (300 MHz, CDCl3, δ) 1.00-1.53 (m,
Ethyl (6R)-6-(3,3-Diphenylpropyl)-1,2,5,6-tetrahydro-
1
11H), 1.75-1.84 (m, 4H), 2.09-2.19 (m, 1H), 2.27-2.46 (m,
2H), 3.50 (s, 2H), 4.29 (q, J ) 7.2 Hz, 2H), 5.10-5.17 (m, 2H),
5.77 (s, 1H), 5.82-5.91 (m, 1H), 6.29 (s, 1H); 13C NMR (75
MHz, CDCl3, δ) 14.2, 26.7, 26.8, 28.9, 29.3, 35.4, 40.5, 48.4,
60.7, 136.7, 139.3, 166.9.
pyridine-3-carboxylate (21b). H NMR (300 MHz, CDCl3,
δ) 1.28 (t, J ) 7.0 Hz, 3H), 1.95-2.23 (m, 6H), 2.66-2.82 (m,
2H), 3.49 (d, J ) 17.1 Hz, 1H), 3.68 (d, J ) 17.0 Hz, 1H), 3.88
(t, J ) 7.6 Hz, 1H), 4.19 (q, J ) 7.1 Hz, 2H), 6.98 (br s, 1H),
7.15-7.31 (m, 10H); 13C NMR (75 MHz, CDCl3, δ): 14.6, 32.6,
35.1, 36.4, 42.8, 44.8, 51.8, 60.6, 117.7, 126.5, 128.1, 128.7,
128.8, 136.1, 138.0, 145.1, 166.4. MS (EI) m/z 349 (M+), 167,
154, 80; (CI) m/z 350 (M + H), 155; HRMS (EI) 349.2042
Preparation of Ethyl 2-({Methyl[(1S)-1-phenylbut-3-
enyl]amino}methyl)acrylate (20a′). To a solution of 17a
(0.08 g, 0.3 mmol) in CH3CN (60 mL) cooled to 0 °C was added
formaldehyde (37% in H2O; 0.15 mL, 2.0 mmol), followed by
NaBH3CN (1 M in THF; 0.6 mL, 0.6 mmol), and the mixture
20
(calcd), 349.2045 (actual). [R]D ) +9 (CDCl3, c ) 0.2).
Ethyl (6S)-6-Cyclohexyl-1,2,5,6-tetrahydropyridine-3-
1
carboxylate (21c). H NMR (300 MHz, CDCl3, δ) 1.05-1.32
(m, 9H), 1.76-3.18 (m, 8H), 2.42-2.51 (m, 1H), 3.49 (d, J )
24.0 Hz, 1H), 3.75 (d, J ) 24.0 Hz, 1H), 4.19 (q, J ) 10.6 Hz,
(26) Basile, T.; Bocoum, A.; Savoia, D.; Umani-Ronchi, A. J. Org.
Chem. 1994, 59, 7766.
7916 J. Org. Chem., Vol. 70, No. 20, 2005

GABA-Uptake Inhibitor Analogues
2H), 7.01 (s, 1H); 13C NMR (75 MHz, CDCl3, δ) 15.6, 27.5, 27.7,
29.9, 30.5, 43.4, 45.9, 57.8, 61.2, 116.8, 138.5, 144.0, 170.3. MS
(EI) m/z 237 (M+), 154 (M - C6H11), 80; MS (CI) m/z 238 (M +
mmol) in THF (5 mL) cooled to -78 °C was added sec-
butyllithium (1.4 M in cyclohexane; 3.6 mL, 5.0 mmol), and
the mixture was stirred for 1 h at -78 °C. To the generated
anion was added (-)-B-methoxydiisopinocampheylborane (2.28
g, 7.2 mmol) in THF (5 mL), and the mixture was stirred for
1 h at -78 °C. To thus generated “ate” complex 11 was added
via a cannula the N-aluminoimine [prepared as follows: to 15a
(0.52 mL, 5.0 mmol) diluted with THF (5 mL) and cooled to 0
°C was added DIBAL-H (0.89 mL, 5.0 mmol), and the mixture
was stirred for 1 h] at -78 °C, followed by a dropwise addition
of methanol (0.20 mL, 5.0 mmol). The reaction was stirred for
8 h at -78 °C and was oxidized with NaOH (3 M in H2O; 2
mL) and H2O2 (30% in H2O; 1.2 mL) and was allowed to warm
to RT under positive N2 pressure. The product was extracted
with Et2O (3 × 30 mL), the solvents were evaporated, and the
residue was purified on silica gel (ethyl acetate/hexanes/
triethylamine 20:79:1) to furnish 24a (0.58 g, 3.6 mmol, 72%
yield). 1H NMR (300 MHz, CDCl3, δ) 1.21 (t, J ) 7.0 Hz, 3H),
1.84 (br s, 2H), 3.31-3.41 (m, 1H), 3.56-3.64 (m, 1H), 3.72 (t,
J ) 7.2 Hz, 1H), 3.90 (d, J ) 7.5 Hz, 1H), 5.01-5.10 (m, 2H),
5.49-5.58 (m, 1H), 7.24-7.36 (m, 5H); 13C NMR (75 MHz,
CDCl3, δ) 15.6, 60.7, 64.9, 86.4, 118.1, 127.7, 128.2, 128.3,
128.5, 136.4. MS (EI) m/z 144 (M - OEt), 106, 79; MS (CI)
192 (M + H), 175 (M + H - NH3), 146 (M + H - HOEt), 129,
20
H), 192, 155; HRMS 237.1729 (calcd), 237.1725 (actual). [R]D
) +104 (CDCl3, c )1.0).
Preparation of (1S,2S)-2-Methyl-1-phenylbut-3-en-1-
amine (22a). To potassium tert-butoxide (1 M in THF; 6 mL,
6 mmol) diluted with THF (6 mL) and cooled to -78 °C was
added trans-butene (1 mL, 11 mmol) and n-butyllithium (2.5
M in hexanes; 2.4 mL, 6.0 mmol). The mixture was stirred for
0.1 h at -78 °C, followed by 0.3 h at -55 °C, and cooled again
to -78 °C, when a solution of (-)-B-methoxydiisopinocam-
pheylborane (2.28 g, 7.2 mmol) in THF (5 mL) was added, and
the reaction was stirred for 1 h at -78 °C. To thus generated
9 was added via cannula N-aluminoimine [prepared as fol-
lows: to 15a (0.52 mL, 5.05 mmol) diluted with THF (5 mL)
and cooled to 0 °C was added DIBAL-H (0.89 mL, 5.0 mmol),
and the mixture was stirred for 1 h], followed by methanol
(0.20 mL, 5.0 mmol), and the mixture was stirred for 3 h at
-78 °C, when it was oxidized with NaOH (3 M in H2O; 2 mL)
and (slowly!) H2O2 (30% in H2O; 1.2 mL); and the reaction was
left stirring under positive N2 pressure while it slowly warmed
to RT. The product was extracted with Et2O (3 × 50 mL) after
the acid-base manipulation, the solvent was removed under
reduced pressure, and the crude material was purified on silica
gel (hexanes/ethyl acetate/triethylamine 84.5:15:0.5) to afford
22a (0.64 g, 4.0 mmol, 80% yield). 1H NMR (300 MHz, CDCl3,
δ) 0.83 (d, J ) 6.7 Hz, 3H), 1.53 (br s, 2H), 2.37 (q, J ) 7.4 Hz,
1H), 3.65 (d, J ) 8.5 Hz, 1H), 5.10-5.20 (m, 2H), 5.69-5.81
(m, 1H), 7.26-7.33 (m, 5H); 13C NMR (75 MHz, CDCl3, δ) 17.7,
20
106. [R]D ) -8 (CHCl3, c ) 0.7).
Ethyl 2-({[(1S,2S)-2-Methyl-1-phenylbut-3-enyl]amino}-
1
methyl)acrylate (25a). H NMR (300 MHz, CDCl3, δ) 1.04
(d, J ) 6.6 Hz, 3H), 1.37 (t, J ) 7.4 Hz, 3H), 1.91 (br s, 1H),
2.51-2.60 (m, 1H), 3.21 (d, J ) 14.7 Hz, 1H), 3.48 (d, J ) 15.0
Hz, 1H), 3.67 (d, J ) 5.1 Hz, 1H), 4.28 (q, J ) 7.0 Hz, 2H),
5.03-5.08 (m, 2H), 5.65 (s, 1H), 5.73-5.84 (m, 1H), 6.28 (s,
1H), 7.27-7.41 (m, 5H).
46.4, 60.7, 115.9, 127.1, 127.3, 128.3, 141.8, 144.7. MS (EI)
20
m/z 160 (M - H), 106, 79; MS (CI) m/z 162, 145, 106. [R]D
+76 (CHCl3, c ) 0.92).
)
Ethyl 2-({[(1R,2S)-1-(3,3-Diphenylpropyl)-2-methylbut-
1
3-enyl]amino}methyl)acrylate (25b). H NMR (300 MHz,
Preparation of (1R,2S)-1-(3,3-Diphenylpropyl)-2-
methylbut-3-enylamine (22b). To potassium tert-butoxide
(1 M in THF; 6 mL, 6 mmol), diluted with pentane (12 mL)
and cooled to -78 °C was added trans-butene (1 mL, 11 mmol)
and n-butyllithium (2.5 M in hexanes; 2.4 mL, 6.0 mmol). The
mixture was stirred for 0.1 h at -78 °C, followed by 0.3 h at
-55 °C, and cooled again to -78 °C, when a solution of (-)-
B-methoxydiisopinocampheylborane (2.28 g, 7.2 mmol) in
pentane (5 mL) was added, and the reaction was stirred for 1
h at -78 °C. To thus generated reagent 9 was added via a
cannula the N-aluminoimine [prepared as follows: to 15b (1.03
g, 5.0 mmol) diluted with pentane (10 mL) and cooled to 0 °C
was added DIBAL-H (1 M in hexanes; 5.0 mL, 5.0 mmol), and
the mixture was stirred for 1 h], followed by methanol (0.20
mL, 5.0 mmol); the mixture was stirred for 3 h at -78 °C, when
it was oxidized with NaOH (3 M in H2O; 2 mL) and (slowly!)
H2O2 (30% in H2O; 1.2 mL) and was left stirring under positive
N2 pressure while it slowly warmed to RT. The product was
extracted with Et2O (3 × 50 mL), the volatiles were removed
under reduced pressure, and the residue was purified on silica
gel (hexanes/ethyl acetate/triethylamine 84.5:15:0.5) to afford
CDCl3, δ) 0.92 (d, J ) 6.5 Hz, 3H), 1.26-1.44 (m, 5H), 2.03-
2.10 (m, 2H), 2.28-2.38 (m, 2H), 3.27 (d, J ) 14.7 Hz, 1H),
3.40 (d, J ) 14.0 Hz, 1H), 3.85 (t, J ) 7.6 Hz, 1H), 4.19 (q, J
) 7.0 Hz, 2H), 4.98-5.03 (m, 2H), 5.58 (s, 1H), 5.56-5.65 (m,
1H), 6.19 (s, 1H), 7.16-7.30 (m, 10H); 13C NMR (75 MHz,
CDCl3, δ) 14.5, 16.4, 28.7, 31.2, 40.8, 48.4, 51.9, 60.3, 60.8,
61.0, 115.3, 126.1, 126.4, 128.1, 128.7, 139.3, 142.1, 145.5,
167.1.
Ethyl 2-({[(1S,2R)-2-Methyl-1-phenylbut-3-enyl]amino}-
1
methyl)acrylate (26a). H NMR (300 MHz, CDCl3, δ) 0.74
(d, J ) 6.8 Hz, 3H), 1.30 (t, J ) 7.2 Hz, 3H), 2.10 (br s, 1H),
2.29-2.37 (m, 1H), 3.06 (d, J ) 14.7 Hz, 1H), 3.27 (d, J ) 8.8
Hz, 1H), 3.35 (d, J ) 14.6 Hz, 1H), 4.20 (q, J ) 6.9 Hz, 2H),
5.07-5.19 (m, 2H), 5.50 (s, 1H), 5.59-5.68 (m, 1H), 6.20 (s,
1H), 7.24-7.35 (m, 5H).
Ethyl 2-({[(1R,2R)-2-Ethoxy-1-phenylbut-3-enyl]amino}-
1
methyl)acrylate (27a). H NMR (300 MHz, CDCl3, δ) 1.20
(t, J ) 7.0 Hz, 3H), 1.30 (t, J ) 7.1 Hz, 3H), 2.68 (br s, 1H),
3.11-3.39 (m, 3H), 3.54-3.62 (m, 1H), 3.69 (q, J ) 8.6 Hz,
1H), 4.21 (q, J ) 7.1 Hz, 2H), 4.89-5.01 (m, 2H), 5.41-5.52
(m, 1H), 5.56 (s, 1H), 6.22 (s, 1H), 7.23-7.30 (m, 5H); 13C NMR
(75 MHz, CDCl3, δ) 14.5, 15.6, 48.8, 60.9, 64.7, 66.2, 85.6, 118.2,
126.3, 127.7, 128.4, 129.1, 136.1, 138.9, 140.2, 167.0.
1
22b (0.9 g, 3.4 mmol, 64% yield) with 89% ee, >98% de. H
NMR (300 MHz, CDCl3, δ) 0.97 (d, J ) 6.8 Hz, 3H), 1.16-
1.31 (m, 3H), 2.06-2.33 (m, 3H), 2.58-2.63 (m, 1H), 3.90 (t, J
) 7.7 Hz, 1H), 4.15 (q, J ) 7.2 Hz, 1H), 5.00-5.06 (m, 2H),
5.63-5.75 (m, 1H), 7.20-7.30 (m, 10H); 13C NMR (75 MHz,
CDCl3, δ) 17.1, 25.6, 32.6, 33.7, 44.0, 51.8, 55.6, 115.7, 126.3,
128.0, 128.4, 128.7, 141.0, 145.4. MS (EI) m/z 279 (M+), 224,
Ethyl 2-({[(1S,2S)-2-Methyl-1-phenylbut-3-enyl]amino}-
1
methyl)acrylate (28a′). H NMR (300 MHz, CDCl3, δ) 1.12
(d, J ) 6.6 Hz, 3H), 1.31 (t, J ) 7.1 Hz, 3H), 2.10 (s, 3H), 2.85-
2.92 (m, 1H), 3.05 (d, J ) 15.0 Hz, 1H), 3.14 (d, J ) 15.0 Hz,
1H), 3.30 (d, J ) 9.9 Hz, 1H), 4.21 (q, J ) 7.0 Hz, 2H), 4.79-
4.90 (m, 2H), 5.52-5.63 (m, 1H), 5.73 (s, 1H), 6.18 (s, 1H),
7.13-7.33 (m, 5H); 13C NMR (75 MHz, CDCl3, δ) 14.5, 18.3,
30.0, 37.5, 38.8, 55.2, 60.9, 73.5, 114.6, 125.6, 127.2, 127.9,
129.8, 137.3, 139.0, 142.0, 167.7.
20
129, 91; MS (CI) m/z 280 (M + H), 224, 202. [R]D ) +11
(CHCl3, c ) 0.05).
(1S,2R)-2-Methyl-1-phenylbut-3-en-1-amine (23a). Ob-
tained similarly to 22a, however, the reagent 10 was used:
1H NMR (300 MHz, CDCl3, δ) 1.06 (d, J ) 7.2 Hz, 3H), 1.65
(br s, 2H), 2.57 (q, J ) 8.6 Hz, 1H), 3.96 (d, J ) 5.1 Hz, 1H),
Ethyl 2-({[(1S,2R)-2-Methyl-1-phenylbut-3-enyl]amino}-
5.08-5.11 (m, 2H), 5.70-5.76 (m, 1H), 7.28-7.36 (m, 5H); 13
C
1
methyl)acrylate (29a′). H NMR (300 MHz, CDCl3, δ) 0.80
NMR (75 MHz, CDCl3, δ) 15.3, 45.0, 60.2, 115.3, 127.1, 127.4,
(d, J ) 6.6 Hz, 3H), 1.30 (t, J ) 7.3 Hz, 3H), 2.09 (s, 3H), 2.84-
2.97 (m, 1H), 3.15 (s, 2H), 3.41 (d, J ) 9.9 Hz, 1H), 4.26 (q, J
) 7.1 Hz, 2H), 5.01-5.12 (m, 2H), 5.84 (d, J ) 1.5 Hz, 1H),
5.90-6.01 (m, 1H), 6.25 (s, 1H), 7.22-7.42 (m, 5H); 13C NMR
20
128.3, 141.3, 144.5. [R]D ) -27 (CDCl3, c ) 2.46).
Preparation of (1R,2R)-2-Ethoxy-1-phenylbut-3-en-1-
amine (24a). To a solution of allyl ethyl ether (0.57 mL, 5.0
J. Org. Chem, Vol. 70, No. 20, 2005 7917

Ramachandran et al.
(75 MHz, CDCl3, δ) 14.6, 17.9, 37.2, 39.2, 55.1, 60.8, 73.7, 113.0,
125.7, 127.3, 128.1, 129.4, 137.3, 138.8, 143.5, 167.7.
Ethyl (5R,6S)-1,5-Dimethyl-6-phenyl-1,2,5,6-tetrahy-
dropyridine-3-carboxylate (32a′). 1H NMR (200 MHz,
CDCl3, δ) 0.87 (d, J ) 6.8 Hz, 3H), 1.32 (t, J ) 7.1 Hz, 3H),
2.06 (s, 3H), 2.28-2.30 (m, 1H), 2.66-2.67 (m, 1H), 2.97 (d, J
) 25.2 Hz, 1H), 3.73 (d, J ) 26.1 Hz, 1H), 4.23 (q, J ) 7.1 Hz,
2H), 6.89 (br s, 1H), 7.25-7.33 (m, 5H); 13C NMR (50 MHz,
CDCl3, δ) 15.6, 18.8, 30.9, 40.4, 44.6, 55.5, 61.4, 73.8, 127.8,
128.8, 143.1, 163.1. MS (EI) m/z 259 (M+), 230 (M - C2H5),
118 (C9H10+); MS (CI) m/z 260 (M + H), 169; HRMS (EI)
Ethyl (5S,6S)-1,5-Dimethyl-6-phenyl-1,2,5,6-tetrahy-
dropyridine-3-carboxylate (31a′). 1H NMR (300 MHz,
CDCl3, δ) 0.97 (d, J ) 7.5 Hz, 3H), 1.40 (t, J ) 7.1 Hz, 3H),
2.31 (s, 3H), 2.92-3.00 (m, 1H), 3.38 (s, 2H), 3.76 (d, J ) 4.5
Hz, 1H), 4.32 (q, J ) 7.0 Hz, 2H), 7.23-7.39 (m, 5H); 13C NMR
(75 MHz, CDCl3, δ) 14.6, 16.4, 36.0, 43.5, 50.9, 60.8, 67.9, 100.3,
127.8, 128.3, 128.7, 129.9, 143.2, 166.0. MS (EI) m/z 259 (M+),
244 (M - CH3), 230 (M - CH2CH3), 118; MS (CI) m/z 260 (M
+ H), 214, 169; HRMS (EI) 259.1572 (calcd), 259.1576 (actual).
20
259.1572 (calcd), 259.1576 (actual). [R]D ) +10 (CDCl3, c )
1.0).
20
[R]D ) +59 (CDCl3, c ) 0.23).
Acknowledgment. Financial assistance from the
Herbert C. Brown Center for Borane Research27 is
gratefully acknowledged.
Supporting Information Available: All 1H and 13C NMR
spectra of the compounds described (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
Ethyl (5S,6R)-6-(3,3-Diphenylpropyl)-5-methyl-1,2,5,6-
tetrahydropyridine-3-carboxylate (31b). 1H NMR (300
MHz, CDCl3, δ) 0.95 (d, J ) 7.1 Hz, 3H), 1.21-1.37 (m, 5H),
1.56-1.68 (m, 2H), 2.04-2.30 (m, 3H), 3.43 (d, J ) 17.3 Hz,
1H), 3.64 (d, J ) 17.3 Hz, 1H), 3.89 (t, J ) 7.5 Hz, 1H), 4.19
(q, J ) 7.0 Hz, 2H), 6.76 (s, 1H), 7.17-7.28 (m, 10H); 13C NMR
(75 MHz, CDCl3, δ) 15.1, 30.5, 32.6, 36.4, 44.5, 52.1, 60.8, 67.1,
126.0, 127.6, 128.3, 134.5, 139.9, 143.3, 162.1. MS (EI) m/z 363
(M+), 179, 168, 94, 56; MS (CI) m/z 364 (M + H), 169; HRMS
(EI) 363.2198 (calcd), 363.2797 (actual). [R]D20 ) +86 (CDCl3,
c ) 1.2).
JO0508200
(27) Publication number 37 from the Herbert C. Brown Center for
Borane Research.
7918 J. Org. Chem., Vol. 70, No. 20, 2005