Preparation of 2,3,4-trisubstituted piperidines by a formal hetero-ene reaction of amino acid derivatives

Article abstract of DOI:10.1021/jo951482d

N-Benzyl- or N-tosyl-N-(4-methyl-3-pentenyl)amino aldehyde benzylimines, which are obtained from alanine, leucine, or phenylalanine methyl esters in five steps, can be cyclized diastereoselectively in the presence of Lewis acids to give 3-amino-2,4-dialkyl-substituted piperidines. The product distribution and diastereoselectivity depends on the type of Lewis acid and nitrogen-protecting group. Benzyl-protected imines give 2-alkyl-3-(benzylamino)-4-isopropenyl piperidines with FeCl₃ and 2-alkyl-3-(benzylideneamino)-4-isopropylpiperidines with TiCl₄. Tosyl-protected imines show a decreased level of selectivity. The relative configurations of the piperidines were established by NMR and X-ray crystal structure analyses. Iminium ion cyclization followed by two competitive ionic pathways, i.e. either proton elimination or hydride transfer are discussed for these reactions.

Full text of DOI:10.1021/jo951482d

J . Org. Chem. 1996, 61, 2829-2838
2829
P r ep a r a tion of 2,3,4-Tr isu bstitu ted P ip er id in es by a F or m a l
Heter o-En e Rea ction of Am in o Acid Der iva tives†
Sabine Laschat,* Roland Fro¨hlich, and Birgit Wibbeling
Organisch-Chemisches Institut der Universita¨t Mu¨nster, Corrensstrasse 40, D-48149 Mu¨nster, Germany
Received August 9, 1995X
N-Benzyl- or N-tosyl-N-(4-methyl-3-pentenyl)amino aldehyde benzylimines, which are obtained from
alanine, leucine, or phenylalanine methyl esters in five steps, can be cyclized diastereoselectively
in the presence of Lewis acids to give 3-amino-2,4-dialkyl-substituted piperidines. The product
distribution and diastereoselectivity depends on the type of Lewis acid and nitrogen-protecting
group. Benzyl-protected imines give 2-alkyl-3-(benzylamino)-4-isopropenyl piperidines with FeCl3
and 2-alkyl-3-(benzylideneamino)-4-isopropylpiperidines with TiCl4. Tosyl-protected imines show
a decreased level of selectivity. The relative configurations of the piperidines were established by
NMR and X-ray crystal structure analyses. Iminium ion cyclization followed by two competitive
ionic pathways, i.e. either proton elimination or hydride transfer are discussed for these reactions.
In tr od u ction
significant pharmacological properties. For example, the
piperidine alkaloid pseudodistomin A 1, which was
isolated from tunicates, exhibits calmodulin antagonistic
activity, and therefore strongly depresses tumor growth
in vitro.11 The racemic compound CP-99,994 2 was
recently discovered as the most potent antagonist of
substance P,12 an undecapeptide, which acts as a neu-
rotransmitter in the central and peripheral nervous
system and is involved in smooth muscle contraction and
regulation of immune responses.13 During our ongoing
The piperidine ring is one of the most abundant
skeletons in natural products and synthetic compounds
with biological activity.1 Therefore a large amount of
synthetic effort has been spent on the stereoselective
construction of piperidines, for example the intramolecu-
lar nucleophilic substitution of imines,2 hetero-Diels-
Alder reactions using imines either as dienophiles3 or as
dienes,4 addition of organometallic reagents to pyridines
followed by photooxygenation,5 Eschenmoser contrac-
tion,6 electrophile- or Lewis acid-induced cyclizations of
imines (or iminium ions).7-10 The 3-aminopiperidine
system has received increasing attention due to its
† Dedicated to Prof. Siegfried Hu¨nig, Univ. Wu¨rburg, on the occasion
of his 75th birthday.
X Abstract published in Advance ACS Abstracts, March 15, 1996.
(1) (a) Strunz, G. M.; Findlay, J . A. The Alkaloids; Academic Press:
New York, 1985; Vol. 26, p 89. (b) Pinder, A. R. Nat. Prod. Rep. 1993,
10, 491. (c) Baliah, V.; J eyaraman, R.; Chandrasekaran, L. Chem. Rev.
1983, 83, 379.
investigations on Lewis acid-catalyzed hetero-ene reac-
tions of prolinal-derived N-benzylimines toward R-amino-
substituted indolizidines,14 we were interested in whether
this reaction type could be extended to the syntheses of
2,3,4-trisubstituted piperidines 3 bearing an amino group
at C-3 (Scheme 1). In order to achieve that goal, imines
4 derived from various acyclic amino acids 5 had to be
used as precursors. Although the cyclization can be
formally considered as a hetero-ene reaction,15,16 it was
shown by previous mechanistic studies in the indolizidine
(2) Wasserman, H. H.; Rodriques, K.; Kucharczyk, R. Tetrahedron
Lett. 1989, 30, 6077.
(3) (a) Hattori, K.; Yamamoto, H. Synlett 1993, 129. (b) Hattori, K.;
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F.; Valdes, C.; Cabal, M.-P. J . Org. Chem. 1993, 58, 3391. (d) Akiba,
K. Y.; Motoshima, T.; Ishimaru, K.; Yabuta, K.; Hirota, H.; Yamamoto;
Y. Synlett 1993, 657. (e) Pfrengle, W.; Kunz, H. J . Org. Chem. 1989,
54, 4261. (f) Kunz, H.; Pfrengle, W. Angew. Chem., Int. Ed. Engl. 1989,
28, 1067. (g) Devine, P. N.; Reilly, M.; Oh, T. Tetrahedron Lett. 1993,
34, 5827. (h) Waldmann, H.; Braun, M.; Dra¨ger, M. Angew. Chem.,
Int. Ed. Engl. 1990, 29, 1468. (i) Waldmann, H.; Braun, M.; Dra¨ger,
M. Tetrahedron Asym. 1991, 2, 1231. (j) Waldmann, H.; Braun, M. J .
Org. Chem. 1992, 57, 4444. (k) Ishihara, K.; Miyata, M.; Hattori, K.;
Tada, T.; Yamamoto, Y. J . Am. Chem. Soc. 1994, 116, 10520. (l) Fujii,
T.; Kimura, T.; Furukawa, N. Tetrahedron Lett. 1995, 36, 4813.
(4) (a) Chen, Y.-S.; Ho, E.; Mariano, P. S.; Ammon, H. L. J . Org.
Chem. 1985, 50, 5678. (b) Trione, C.; Toledo, L. M.; Kuduk, S. D.;
Fowler, F. W.; Grierson, D. S. J . Org. Chem. 1993, 58, 2075.
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349.
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Snider, R. M. J . Med. Chem. 1992, 35, 4911. (b) Rosen, T.; Seeger, T.
F.; McLean, S.; Desai, M. C.; Guarino, K. J .; Bryce, D.; Pratt, K.; Heym,
J .; Chalabi, P. M.; Windels, J . H.; Roth, R. W. J . Med. Chem. 1993,
36, 3197.
(13) (a) Nicoll, R.; Schenker, C.; Leeman, S. E. Annu. Rev. Neurosci.
1980, 3, 227. (b) Otsuka, M.; Yanagisawa, M. Trends Pharmacol. Sci.
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D. G.; Brewster, D. R.; Goetzl, E. J . J . Immunol. 1984, 133, 3260. (e)
Payan, D. G.; Brewster, D. R.; Goetzl, E. J . J . Immunol. 1983, 131,
1613.
(14) (a) Laschat, S.; Grehl, M. Angew. Chem., Int. Ed. Engl. 1994,
33, 458. (b) Laschat, S.; Grehl, M. Chem. Ber. 1994, 127, 2023.
(15) Reviews on carbonyl-ene reactions: (a) Mikami, K.; Terada, M.;
Narisawa, S.; Nakai, T. Synlett 1992, 255. (b) Mikami, K.; Shimizu,
M. Chem. Rev. 1992, 92, 1021. (c) Snider, B. B. In Comprehensive
Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991;
Vol. 2, p 527.
(6) Munchhoff, M. J .; Meyers, A. I. J . Am. Chem. Soc. 1995, 117,
5399.
(7) (a) De Kimpe, N.; Boelens, M. J . Chem. Soc., Chem. Commun.
1993, 916. (b) De Kimpe, N.; Boelens, M.; Piqueur, J .; Baele; J .
Tetrahedron Lett. 1994, 35, 1925. (c) Grigg, R.; Markandu, J .; Perrior,
T.; Qiong, Z.; Suzuki, T. J . Chem. Soc., Chem. Commun. 1994, 1267.
(8) Overman, L. E.; Sarkar, A. K. Tetrahedron Lett. 1992, 33, 4103.
(9) (a) Tietze, L. F.; Bratz, M. Chem. Ber. 1989, 122, 997. (b) Tietze,
L. F.; Bratz, M.; Pretor, M. Chem. Ber. 1989, 122, 1955. (c) Tietze, L.
F.; Bratz, M. Synthesis 1989, 439. (d) Tietze, L. F.; Bratz, M. Liebigs
Ann. Chem. 1989, 559.
(10) (a) Yang, T.-K.; Teng, T.-F.; Lin, J .-H.; Lay, Y.-Y. Tetrahedron
Lett. 1994, 35, 3581. (b) Yang, T.-K.; Hung, S.-M.; Lee, D.-S.; Hong,
A.-W.; Cheng, C.-C. Tetrahedron Lett. 1989, 30, 4973. (c) Castro, P.;
Overman, L. E.; Zhang, X.; Mariano, P. S. Tetrahedron Lett. 1993, 34,
5243.
(16) Review on imino-ene reactions: Borzilleri, R. M.; Weinreb, S.
M. Synthesis 1995, 347.
0022-3263/96/1961-2829$12.00/0 © 1996 American Chemical Society

2830 J . Org. Chem., Vol. 61, No. 8, 1996
Laschat et al.
Sch em e 1
Sch em e 3
Sch em e 2
series that the reaction proceeds by a stepwise iminium
ion cyclization followed by either proton elimination or
intermolecular hydride migration depending on the type
of Lewis acid used.14 In this paper we describe the
diastereoselective synthesis of 3-aminopiperidines 3. In
addition the acyclic precursor 4 presents the opportunity
to study the influence of the electronic nature of the
second nitrogen atom on the stereoselectivity of the
cyclization. The results concerning the “mechanistic
tuning” by proper choice of the protecting group Y are
also presented here.
Resu lts a n d Discu ssion
As was mentioned above the use of acyclic amino acids
5 for the imino ene cyclization required the introduction
of a protecting group Y on nitrogen, which should be
stable to Lewis acid conditions. For this purpose N-
benzyl and N-tosyl groups were chosen. Thus, amino acid
esters 6 were N-alkylated with 4-methyl-3-pentenyl
bromide in DMF in the presence of CaO to afford
monoalkylated esters 7 in moderate to good yields
(Scheme 2).17 In the case of the phenylalanine derivative
6c, 5% of the transesterification product 8 was also
obtained. The esters 7 were then treated with benzyl
bromide under phase transfer conditions to give N-
benzyl-protected compounds 9 or reacted with tosyl
chloride/triethylamine to give N-tosyl derivatives 10
(Scheme 3). Reduction with LiAlH4 of 9 and 10 gave the
corresponding alcohols 13 and 14, respectively. Swern
oxidation18 of 13 and 14 followed by treatment with
benzylamine gave the desired imines 15 and 16. It was
anticipated that the yields could be improved by revers-
ing the reaction sequence. Therefore N-benzylleucine
methyl ester 17 was cleanly prepared by reductive
amination (Scheme 4).19 However this approach turned
out to be unsuccessful, because the corresponding N-
alkylation with K2CO3 gave 9b in only 15% yield. When
CaO or other bases were used, none of the desired
product 9b was obtained.
Sch em e 4
As outlined in Scheme 5 and Table 1, Lewis acid-
catalyzed cyclization of N-benzylimines 15 gave two cis-
configurated 2-alkyl-3-(N-benzylamino)-4-isopropenylpi-
peridines 18, 19, and two cis-configurated 2-alkyl-3-(N-
benzylidene)amino-4-isopropylpiperidines 20, 21. Con-
cerning both diastereoselectivity and yields, FeCl3 and
TiCl4 showed the best results. FeCl3 favors the formation
of product 18 (entries 2, 7, 11), whereas TiCl4 favors the
formation of 20 (entries 6, 10, 14). Thus the same
reversal of the constitution is observed in the piperidine
synthesis as was already discovered in the indolizidine
series.14 However, contrary to the indolizidines, the
relative configuration between the newly formed stereo-
centers at C-3 and C-4 in products 18-21 is always cis.
(17) Alanine butyl ester 6a was used instead of the corresponding
methyl ester for synthetic convenience, because the latter is both
volatile and water soluble.
(18) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(19) Ando, A.; Shiorii, T. Tetrahedron 1989, 45, 4969.

Piperidines by a Formal Hetero-Ene Reaction
J . Org. Chem., Vol. 61, No. 8, 1996 2831
Ta ble 1. Cycliza tion of N-Ben zyl-P r otected Im in es 15 w ith Va r iou s Lew is Acid sa
ratio of productsb
amino
acid
Lewis
acid
time
[h]
conversion
[%]
yieldc
[%]
entry
imine 15
R1
18
19
20
21
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ala
a
a
a
a
a
a
b
b
b
b
c
c
c
c
Me
Me
Me
Me
Me
Me
i-Bu
i-Bu
i-Bu
i-Bu
Bn
SnCl4
FeCl3
TMSOTf
EtAlCl2
Et2AlCl
TiCl4
16
19
144
22
18
21
17
19
19
18
19
19
16
21
62
79
5
27.5
62.2
90.4
0.4
-
-
72.5
28.8
9.4
-
-
60
-
3.0
7.0
(18a )
-
0.7
-
-
8.9
0.7
3.7
1.8
-
96
98
98
89
93
86
92
100
86
73
92
75.3
82.7
96.6
13.1
46.6
85.8
97.0
13.1
64.6
65.7
75.4
23.6
17.3
3.4
-
58
80
66
-
(20a )
(20a )
(18b)
-
Leu
Phe
FeCl3
69.1
1.3
10.5
1.2
75.2
-
8.9
EtAlCl2
Et2AlCl
TiCl4
51.4
-
-
11.7
35.4
34.3
24.6
-
56
41
-
(20b)
(18c)
FeCl3
-
Bn
Bn
Bn
EtAlCl2
Et2AlCl
TiCl4
-
-
-
-
-
-
50, 17
(20c, 21c)
a
b
Reaction conditions: 2.5 equiv of Lewis acid, CH2Cl2, rt. Conversion and product ratios were determined by capillary GC of the
crude mixtures. c Yields of isolated products.
Sch em e 5
Fortunately, X-ray crystal structure analyses were
obtained for both phenylalanine-derived N-tosylpiper-
idines 22c, 23c (Figures 2, 3).20 In addition to the
relative configuration of C-2/C-3/C-4 being established,
the structures revealed some important features. Both
N-tosylpiperidines 22c, 23c adopt a chair conformation
in the solid state in which the benzylamino (or benzyl-
ideneamino) group at C-3 and the benzyl group at C-2
are axial. The reason for this conformation might be that
the number of favourable gauche interactions N-C-C-C
and N-C-C-N is maximized.21 The same stereoelec-
tronic effect might be operating in the N-benzylpiperidine
series. In addition, the dihedral angle N2-C20-C21-
C26 is 173.0(0.2)° [N2-C20-C21-C22 10.4(0.3)°], sug-
gesting that the phenyl ring and the imino group of the
benzylideneamino moiety are slightly twisted by about
7-10°. This small twist, which can be explained by the
preferred overlap of the aromatic π-system with the lone-
pair on nitrogen, is in good agreement with X-ray crystal
structure analyses and calculations by Bu¨rgi and Dunitz
on benzylidene aniline.22
Sch em e 6
With these results in hand, the mechanistic scheme
previously proposed14 must be modified for acyclic imines
15, 16 in the following way (Scheme 7). Addition of the
Lewis acid to imines 15, 16 results in the formation of
the iminium ions 24, which cyclize to the tertiary cations
25, 26 depending on the protecting group on nitrogen.
Thus 25 is formed for Y ) Bn, whereas 26 is formed for
Y ) Ts. The cation 25 (or 26 respectively) can undergo
two competing pathways, i.e. proton elimination followed
by cleavage of the Lewis acid (path A) and reprotonation
to give 18 (or 22 respectively), or an intermolecular
hydride migration followed by cleavage of the Lewis acid
The results in Table 1 follow a general trend; an increase
in diastereoselectivity occurs with the increasing size of
the R1 substituents (e.g. entries 2, 7, 11). In addition,
monodentate Lewis acids such as TMSOTf gave only very
low conversions (entry 3).
When N-tosylimines 16 were treated with Lewis acids,
a mixture of 3-aminopiperidine 22 and the 3-iminopiper-
idine 23 (Scheme 6, Table 2) was obtained. Regardless
of the amino acid, the ratio of 22:23 remained almost
constant at 4:1 f 7:1 for both TiCl4 (entries 4, 7, 10) and
FeCl3 (entries 1, 5, 8). When EtAlCl2 was employed the
diastereoselectivity was low (entries 3, 6, 9). Remark-
ably, both N-tosylpiperidines 22, 23 were trans-configu-
rated at C-2/C-3 and cis-configurated at C-3/C-4, whereas
the corresponding N-benzylpiperidines 18, 20 show an
all-cis-configuration at C-2/C-3/C-4.
The relative configuration of the N-benzylpiperidines
18, 20 was determined by 1D NOE experiments on the
alanine-derived cyclization products 18a , 20a (Figure 1).
The NOE enhancement between 2-H and 4-H in both
isomers supports the axial orientation of the benzylamino
(or benzylideneamino) group. The corresponding chair
conformer with the benzylamino group equatorial should
be strongly disfavored due to the 1,3-diaxial interaction
between methyl and isopropenyl group.
(20) The authors have deposited atomic coordinates for these
structures with the Cambridge Crystallographic Data Centre. The
coordinates can be obtained on request from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
UK.
(21) Ab initio calculations by Wiberg and Murcko on 1,2-dihalo-
ethanes and 1,2-haloethanols showed that the gauche conformation
of X-C-C-Y systems is about 1-2 kcal/mol more stable than the
antiperiplanar conformation. A similar preference for the gauche
orientation of the C-C-C-O and C-C-O-C fragment contributes
to the anomeric effect in 2-methoxytetrahydropyran and related
systems. (a) Wiberg, K. B.; Murcko, M. A. J . Mol. Struct. 1988, 163, 1.
(b) Wiberg, K. B.; Murcko, M. A. J . Phys. Chem. 1987, 91, 3616. (c)
Wiberg, K. B.; Murcko, M. A. J . Am. Chem. Soc. 1989, 111, 4821. For
a general discussion of stereoelectronic effects and the anomeric effect
see: (d) Deslongchamps, P. Stereoelectronic Effects in Organic Chem-
istry; Pergamon Press: Oxford, 1983; p 302. (e) Graczyk, P. P.;
Mikolajczyk, M. Top. Stereochem. 1994, 21, 159.
(22) (a) Bu¨rgi, H. B.; Dunitz, J . D. Helv. Chim. Acta 1970, 53, 1747.
(b) Bu¨rgi, H. B.; Dunitz, J . D. Helv. Chim. Acta 1971, 54, 1255.

2832 J . Org. Chem., Vol. 61, No. 8, 1996
Ta ble 2. Cycliza tion of N-Tosyl-P r otected Im in es 16 w ith Va r iou s Lew is Acid sa
ratio of productsb
Laschat et al.
entry
amino acid
Ala
imine 16
R1
Lewis acid
time [h]
22
23
yieldc [%]
1
2
3
4
5
6
7
8
9
a
a
a
a
b
b
b
c
c
c
Me
Me
Me
Me
i-Bu
i-Bu
i-Bu
Bn
FeCl3
62
64
64
63
87
22
25
17
19
18
87.8
67.2
73.2
82.1
82.3
73.7
81.3
82.7
49.4
81.9
12.2
32.8
26.7
17.9
17.7
26.5
18.7
17.3
50.6
18.1
-
-
Et2AlCl
EtAlCl2
TiCl4
FeCl3
EtAlCl2
TiCl4
FeCl3
EtAlCl2
TiCl4
-
42
(22a )
(22b)
(22b, 23b)
(22b)
(22c)
Leu
Phe
76
41, 12
58
52
44
Bn
Bn
(23c)
(22c)
10
48
a
b
See Table 1, footnote a. Ratio of products was determined by 1H NMR of the crude products. c See Table 1, footnote c.
hydride migration requires the presence of a second
electron-rich nitrogen atom, which chelates the Lewis
acid and thus reduces the electron withdrawal of the
Lewis acid from the N-CH2Bn bond.23,24 As soon as the
donor ability of the piperidino nitrogen atom is decreased,
e.g. by the electron-withdrawing tosyl group, the electron
density of the N-CH2Bn bond is decreased as well and
the hydride is less likely to be abstracted. The origin of
the different stereocontrol in these acyclic imines 15, 16
depends on the protecting group Y, but still remains
unclear. Factors, such as forming chelate complexes
whenever possible, maximizing the number of C-C-
F igu r e 1.
C-N (and C-C-N-C and N-C-C-N) gauche interac-
tions may contribute to the observed results.
As mentioned above, the N-benzyl protected imines 15
were used initially because the electron density of the
nitrogen atom is not decreased by the benzyl group, thus
allowing a chelation-control of the diastereoselectivity.
In addition, the N-benzyl group provides the opportunity
to remove both protecting groups from the piperidines
18-21 simultaneously. Such a hydrogenation/hydro-
genolysis sequence could be achieved by treatment with
PdCl2 in methanol under 1 atm of hydrogen. For
example, if a (1:1) mixture of piperidines 18b, 20b was
subjected to these conditions, the fully deprotected
2-isobutyl-3-amino-4-isopropylpiperidine (27) was ob-
tained in almost quantitative yield (Scheme 8).25,26
F igu r e 2. X-ray crystal structure of N-tosylpiperidine 22c.
In conclusion, a diastereoselective Lewis acid-catalyzed
cyclization of acyclic amino acid-derived benzylimines
toward 2,3,4-trisubstituted piperidines was developed.
Although the reaction can be formally treated as a hetero-
ene reaction, it probably follows two stepwise competetive
pathways. The type of Lewis acid and the electronic
nature of the nitrogen atom play a role in which pathway
is preferred.
(23) In order to further support this hypothesis 3,3,7-trimethyl-6-
octenal benzylimine was treated with various Lewis acids under the
above mentioned conditions. In all cases N-benzyl-3,3-dimethyl-6-
isopropenylcyclohexylamine (trans/cis ratios: FeCl3 98.3/1.7, TiCl4 97.2/
2.8, SnCl4 97.4/2.6) was observed as the only product. No traces of the
corresponding N-benzylidene-3,3-dimethyl-6-isopropylcyclohexylamine
could be detected. See also: (a) Demailly, G.; Solladie, G. Tetrahedron
Lett. 1977, 18, 1885. (b) Demailly, G.; Solladie, G. J . Org. Chem. 1981,
46, 3102.
(24) The question, why TiCl4 and FeCl3 favor different pathways,
remains unsolved. One reason might be the stronger Lewis acidity of
TiCl4 compared to FeCl3.
(25) N-Tosyl groups might be cleaved with sodium or lithium in
liquid ammonia or with sodium naphthalenide: (a) Yamazaki, N.;
Kibayashi, C. J . Am. Chem. Soc. 1989, 111, 1396. (b) Schultz, A. G.;
Mc Closkey, P. J .; Court, J . J . J . Am. Chem. Soc. 1987, 109, 6493. (c)
J i, S.; Gortler, L. B.; Waring, A.; Battisti, A.; Bank, S.; Closson, W. D.;
Wriede, P. J . Am. Chem. Soc. 1967, 89, 5311.
F igu r e 3. X-ray crystal structure of N-tosylpiperidine 23c.
(path B) to give 20 (or 23 respectively). For the N-benzyl
protected cation 25 the Lewis acid determines which
pathway is preferred. FeCl3 favors path A, whereas TiCl4
favors path B. However in the case of the N-tosyl
protected cation 26, both FeCl3 and TiCl4 show a prefer-
ence for path A. That means, that the Lewis acid-
determined reaction pathways A and B are strongly
influenced by the stereoelectronic effect of nitrogen. The
(26) For a detailed discussion concerning removal of N-tosyl and
N-benzyl groups see: Kocienski, P. J . Protecting Groups, Thieme
Verlag: Stuttgart, 1994; p 212.

Piperidines by a Formal Hetero-Ene Reaction
J . Org. Chem., Vol. 61, No. 8, 1996 2833
Sch em e 7
washings were poured into ice-water (200 mL). Extraction
with Et2O (4 × 100 mL), followed by drying over MgSO4 and
evaporation of the solvent yielded a yellow oil, which was
purified by flash chromatography on SiO2 (hexanes/ethyl
acetate 10:1 f 4:1).
Sch em e 8
(S)-N-(4-Meth yl-3-p en ten yl)a la n in e Bu tyl Ester (7a ):
2.87 g (12.6 mmol, 42%) of a colorless oil (99% pure by GC, tR
) 16.4 min); [R]22 -10.6 (c ) 1.00; CHCl3); IR (film) 3323,
D
1
1734, 1177 cm-1; H NMR (200 MHz, CDCl3) δ 5.03 (dd, J )
7.0 Hz, 1 H), 4.06 (dd, J ) 6.5 Hz, 1 H), 3.26 (ddd, J ) 7.0 Hz,
1 H), 2.54-2.37 (m, 2 H), 2.28-2.06 (m, 2 H), 1.63 (s, 3 H),
1.56 (s, 3 H), 1.49-1.02 (m, 5 H), 1.22 (d, J ) 7.0 Hz, 3 H),
0.87 (dd, J ) 7.2 Hz, 3 H); 13C NMR (50 MHz, CDCl3) δ 175.7,
133.4, 121.5, 64.3, 56.6, 47.7, 30.6, 28.8, 25.6, 19.0, 18.9, 17.7,
13.5; MS (EI) m/ z 227 (M, 3), 158 (32), 126 (33), 102 (30), 83
(43), 56 (100); HRMS (CI) calcd for C13H25NO2 + H+ 228.1963,
found 228.1982. Anal. Calcd for C13H25NO2: C, 68.68; H,
10.08; N, 6.16. Found: C, 68.68; H, 10.14; N, 6.17.
(S)-N-(4-Meth yl-3-p en ten yl)leu cin e Meth yl Ester (7b):
3.31 g (14.6 mmol, 73%) of a colorless oil (98% pure by GC, tR
) 16.2 min); [R]22D -4.6 (c ) 1.00; CHCl3); IR (film) 3335, 1738,
1167 cm-1; 1H NMR (200 MHz, CDCl3) δ 5.04 (dd, J ) 7.1 Hz,
1 H), 3.67 (s, 3 H), 3.24 (dd, J ) 7.2 Hz, 1 H), 2.57-2.37 (m,
2 H), 2.10 (ddd, J ) 7.4 Hz, 2 H), 1.65 (d, J ) 1.2 Hz, 3 H),
1.57 (d, J ) 0.7 Hz, 3 H), 1.69-1.60 (m, 1 H), 1.45-1.39 (m, 3
H), 0.88 (d, J ) 6.7 Hz, 3 H), 0.85 (d, J ) 6.4 Hz, 3 H); 13C
NMR (50 MHz, CDCl3) δ 176.4, 133.3, 121.9, 121.5*, 60.1, 51.6,
51.2*, 48.0, 42.8*, 28.9, 25.7, 24.9, 22.6, 22.4, 22.3, 17.8, 17.7*;
MS (EI) m/ z 228 (M + H+, 6), 212 (6), 168 (36), 158 (66), 130
(40), 102 (100), 83 (40); HRMS (DCI, NH3) 228.1964 calcd for
Exp er im en ta l Section
Gen er a l Exp er im en ta l.14b All reactions were carried out
under an argon atmosphere using standard Schlenk technique.
Solvents were dried and deoxygenated by standard procedures.
Analytical TLC was performed on precoated Merck Si 254 F
plates (0.25 mm thickness) and visualized with a solution of
phosphomolybdic acid in EtOH (5%, v/v). Flash chromatog-
raphy was carried out with Merck silica gel 60 (230-400
mesh). NMR spectra were performed at 200 and 300 MHz
(1H), 50 and 75 MHz (13C). Multiplets in 13C NMR spectra
were determined by DEPT and APT experiments. Melting
points were uncorrected. Optical rotations: 1 dm-cells, 1 mL
capacity, room temp. Mass spectra (EI and CI) were obtained
at 70 eV, NH3 was used as reactant gas for CI spectra. GC
analysis: HP5 fused silica capillary column (ID 0.32 mm,
length 25 m), a temperature program was run from 80 °C with
8 °C min-1 up to 280 °C. Amino acid methyl esters 6b,c and
n-butyl ester 6a were obtained by esterification with thionyl
chloride/methanol or n-butanol respectively according to lit-
erature procedures.27 Signals in the 13C NMR spectra of
compounds 7b, 10b, 17 with * refer to a second rotamer.
Gen er a l P r oced u r e for th e N-Alk yla tion of Am in o
Acid Ester s 6. To a solution of ester 6 (20.0 mmol) in DMF
(40 mL) were subsequently added CaO (2.47 g, 44.0 mmol) and
4-methyl-3-pentenyl bromide (3.26 g, 20.0 mmol), and the
resulting suspension was heated at 60 °C for 62 h. After
dilution with Et2O (40 mL), Celite was poured under vigorous
stirring into the mixture, which was then filtered through a
short column (eluent: Et2O). The combined filtrates and
C13H25NO2 + H+, found 228.1897. Anal. Calcd for C13H25
-
NO2: C, 68.68; H, 10.08; N, 6.16. Found: C, 68.70; H, 10.05;
N, 6.19.
(S)-N-(4-Meth yl-3-p en ten yl)p h en yla la n in e Meth yl Es-
ter (7c): 3.13 g (12.0 mmol, 60%) of a colorless oil (99% pure
by GC, tR ) 21.4 min); [R]22D +14.2 (c ) 1.00; CHCl3); IR (film)
3324, 1737, 1454, 1200, 1169, 745, 700 cm-1 1H NMR (200
;
MHz, CDCl3) δ 7.27-7.10 (m, 5 H), 4.98 (dd, J ) 7.2 Hz, 1 H),
3.58 (s, 3 H), 3.49 (dd, J ) 7.0 Hz, 1 H), 2.90 (d, J ) 7.0 Hz,
1 H), 2.59-2.36 (m, 2 H), 2.09 (ddd, J ) 7.1 Hz, 2 H), 1.61 (d,
J ) 0.8 Hz, 3 H), 1.55 (s, 3 H), 1.50 (s, broad, 1 H); 13C NMR
(50 MHz, CDCl3) δ 174.8, 137.2, 133.3, 128.9, 128.2, 126.5,
121.4, 62.9, 51.3, 47.8, 39.5, 28.6, 25.5, 17.6; MS (EI) m/ z 261
(M, 31), 202 (62), 192 (50), 178 (44), 165 (43), 98 (76), 91 (C7H7,
68), 83 (100); HRMS calcd for C16H23NO2 261.1729, found
261.1724. Anal. Calcd for C16H23NO2: C, 73.53; H, 8.87; N,
5.36. Found: C, 73.54; H, 8.91; N, 5.28.
(S)-N-(4-Meth yl-3-p en ten yl)p h en yla la n in e 4-Meth yl-3-
p en ten yl Ester (8): 330 mg (1.00 mmol, 5%) of a yellow oil
(98% pure by GC, tR ) 27.1 min); [R]22 +11.8 (c ) 1.00;
D
CHCl3); IR (film) 3324, 1733, 1454, 1170, 746, 700 cm-1; H
1
NMR (200 MHz, CDCl3) δ 7.25-7.13 (m, 5 H), 5.01-4.96 (m,
2 H), 3.97 (dd, J ) 7.1 Hz, 2 H), 3.48 (dd, J ) 7.1 Hz, 1 H),
2.94-2.89 (m, 2 H), 2.61-2.43 (m, 2 H), 2.21-2.05 (m, 5 H),
1.66 (d, J ) 1.0 Hz, 3 H), 1.63 (d, J ) 1.0 Hz, 3 H), 1.57 (s, 6
(27) Brenner, M.; Mu¨ller, H. R.; Pfister, R. W. Helv. Chim. Acta
1950, 33, 568.

2834 J . Org. Chem., Vol. 61, No. 8, 1996
Laschat et al.
H); 13C NMR (50 MHz, CDCl3) δ 174.5, 137.3, 134.5, 133.4,
129.1, 128.3, 126.6, 121.5, 119.1, 64.1, 63.0, 47.8, 39.7, 28.7,
27.5, 25.6, 17.7; MS (EI) m/ z 330 (M + 1, 3), 290 (9), 260 (21),
202 (21), 178 (21), 91 (22), 83 (100), 55 (100); HRMS (DCI)
calcd for C21H31NO2 + H+ 330.2433, found 330.2454. Anal.
Calcd for C21H31NO2: C, 76.55; H, 9.48; N, 4.25. Found: C,
76.70; H, 9.49; N, 4.20.
Gen er a l P r oced u r e for th e N-Ben zyla tion of Am in o
Acid Ester s 7. To a solution of ester 7 (1.00 mmol) in DMF
(1 mL) were sucessively added K2CO3 (138 mg, 1.00 mmol),
tetrabutylammonium iodide (369 mg, 1.00 mmol), and then
benzyl bromide (171 mg, 1.00 mmol). The resulting mixture
was stirred at room temperature for 4 h and then heated to
100 °C for 48 h. The dark brown mixture was then diluted
with toluene (10 mL) and azeotropically codistilled (3×) under
high vacuum. The remaining brown solid was diluted in
pentane (10 mL) and purified by flash chromatography over
SiO2 (hexanes/ethyl acetate 25:1).
(S)-N-Ben zyl-N-(4-m eth yl-3-pen ten yl)alan in e Bu tyl Es-
ter (9a ): 1.39 g (4.37 mmol, 84%) of a colorless oil (98% pure
by GC, tR ) 25.0 min); [R]22D -80.3 (c ) 1.00; CHCl3); IR (film)
1732, 1144, 730, 697 cm-1; 1H NMR (200 MHz, CDCl3) δ 7.25-
7.07 (m, 5 H), 4.95 (dd, J ) 7.0 Hz, 1 H), 3.98 (dd, J ) 6.5 Hz,
2 H), 3.75 (d, J ) 14.3 Hz, 1 H), 3.52 (d, J ) 14.3 Hz, 1 H),
3.38 (ddd, J ) 7.2 Hz, 1 H), 2.59-2.33 (m, 2 H), 2.07-1.91
(m, 2 H), 1.53 (s, 3 H), 1.42 (s, 3 H), 1.58-1.37 (m, 2 H), 1.36-
1.19 (m, 2 H), 1.15 (d, J ) 7.2 Hz, 3 H), 0.82 (dd, J ) 7.3 Hz,
3 H); 13C-NMR (50 MHz, CDCl3) δ 174.1, 140.5, 132.2, 128.4,
128.0, 126.6, 122.2, 63.9, 57.5, 55.1, 50.7, 30.8, 27.5, 25.6, 19.2,
17.6, 15.4, 13.6; MS (EI) m/ z 317 (M, 1), 274 (6), 248 (35), 220
(9), 192 (7), 117 (20), 91 (100), 83 (17); HRMS (CI) calcd for
C20H31NO2 318.2433, found 318.2442. Anal. Calcd for
C20H31NO2: C, 75.67; H, 9.84; N, 4.41. Found: C, 75.68; H,
9.81; N, 4.45.
H), 7.23 (d, J ) 7.3 Hz, 2 H), 4.99 (dd, J ) 7.3 Hz, 1 H), 4.60
(ddd, J ) 7.3 Hz, 1 H), 3.89 (dd, J ) 6.5 Hz, 2 H), 3.24-2.92
(m, 2 H), 2.38 (s, 3 H), 2.46-2.11 (m, 2 H), 1.64 (s, 3 H), 1.58
(s, 3 H), 1.40 (d, J ) 7.3 Hz, 3 H), 1.53-1.19 (m, 4 H), 0.86
(dd, J ) 7.2 Hz, 3 H); 13C NMR (50 MHz, CDCl3) δ 171.5, 143.1,
137.3, 134.3, 129.4, 127.3, 120.1, 65.0, 55.3, 45.4, 30.3, 30.0,
25.6, 21.4, 19.0, 17.7, 16.9, 13.6; MS (EI) m/ z 380 (M, 6), 312
(14), 280 (7), 225 (21), 198 (31), 155 (39), 91 (79), 83 (100), 56
(97); HRMS calcd for C20H31NO4S 381.1974, found 381.1982.
Anal. Calcd for C20H31NO4S: C, 62.96; H, 8.19; N, 3.67.
Found: C, 62.78; H, 8.25; N, 3.66.
(S)-N-(4-Meth yl-3-p en ten yl)-N-tosylleu cin e Meth yl Es-
ter (10b): 382 mg (1.00 mmol, quant) of a colorless oil; [R]22
D
-58.3 (c ) 1.00; CHCl3); IR (KBr) 1749, 1730, 1338, 1147, 731,
660 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.65 (d, J ) 8.1 Hz, 2
H), 7.22 (d, J ) 8.1 Hz, 2 H), 5.00 (dd, J ) 7.4 Hz, 1 H), 4.53
(dd, J ) 9.1, 5.7 Hz, 1 H), 3.40 (s, 3 H), 3.22-3.11 (m, 1 H),
3.06-2.93 (m, 1 H), 2.49-2.35 (m, 1 H), 2.37 (s, 3 H), 2.23-
2.09 (m, 1 H), 1.77-1.55 (m, 3 H), 1.64 (s, 3 H), 1.59 (s, 3 H),
0.93 (d, J ) 6.5 Hz, 3 H), 0.91 (d, J ) 6.5 Hz, 3 H); 13C NMR
(75 MHz, CDCl3) δ 171.8, 143.0, 136.8, 134.3, 129.2, 127.4,
120.2, 120.1*, 57.9, 51.7, 51.6*, 45.4, 39.4, 30.1, 25.5, 24.3, 22.7,
21.4, 17.7; MS (EI) m/ z 381 (M, 3), 322 (22), 312 (37), 284
(35), 256 (87), 186 (39), 155 (68), 91 (100); HRMS (DCI) calcd
for C20H31NO4S + H+, 382.2052 found 382.2071. Anal. Calcd
for C20H31NO4S: C, 62.96; H 8.19; N 3.67. Found: C, 63.08;
H, 8.24; N, 3.90.
(S )-N -(4-Me t h yl-3-p e n t e n yl)-N -t osylp h e n yla la n in e
Meth yl Ester (10c): 1.71 g (4.11 mmol, 90%) of a colorless
oil; [R]22 -40.6 (c ) 1.00; CHCl3); IR (film) 1742, 1455, 1436,
D
1342, 1221, 1204, 1161, 1092, 727, 700 cm-1
;
1H NMR (200
MHz, CDCl3) δ 7.59 (d, J ) 8.3 Hz, 2 H), 7.27-7.16 (m, 7 H),
5.01 (dd, J ) 7.3 Hz, 1 H), 4.78 (dd, J ) 8.2, 7.0 Hz, 1 H), 3.46
(s, 3 H), 3.34-3.12 (m, 3 H), 2.98-2.87 (dd, J ) 13.9, 7.0 Hz,
1 H), 2.38 (s, 3 H), 2.37-2.12 (m, 2 H), 1.67 (s, 3 H), 1.60 (s, 3
H); 13C NMR (50 MHz, CDCl3) δ 170.9, 143.1, 137.0, 136.6,
134.4, 129.3, 129.0, 128.5, 127.3, 126.7, 119.9, 60.8, 51.8, 45.4,
36.8, 29.3, 25.5, 21.3, 17.7; MS (EI) m/ z 415 (M, 11), 356 (19),
346 (33), 286 (88), 259 (26), 155 (71), 130 (69), 91 (100), 83
(51), 55 (86); HRMS calcd for C23H28NO4S (M - H+) 414.1731,
found 414.1739. Anal. Calcd for C23H29NO4S: C, 66.48; H,
7.03; N, 3.37. Found: C, 66.39; H, 7.21; N, 3.36.
Gen er a l P r oced u r e for LiAlH4 Red u ction of Ester s 9,
10. To an ice-cooled suspension of LiAlH4 (44 mg, 1.14 mmol)
in Et2O (1 mL) was added dropwise N-benzyl or N-tosyl ester
9 or 10, respectively (1.04 mmol), in Et2O (2 mL). Then the
ice-bath was removed, and the resulting suspension was
stirred at room temperature for 4 h and then carefully
hydrolyzed by the addition of ethyl acetate (5 mL) and H2O
(2.5 mL). Stirring was continued for 1 h and then were added
H2O (50 mL) and Et2O (50 mL). After separation of the organic
layer, the aqueous layer was extracted with Et2O (50 mL), and
the combined organic layers were dried over MgSO4 and
evaporated to yield an oil, which was used without further
purification.
(S)-N-Ben zyl-N-(4-m et h yl-3-p en t en yl)leu cin e Met h yl
Ester (9b): 280 mg (0.88 mmol, 96%) of a pale yellow oil (99%
pure by GC, tR ) 25.2 min); [R]22 -97.2 (c ) 1.00; CHCl3); IR
D
1
(film) 1735, 1147, 733, 698 cm-1; H NMR (300 MHz, CDCl3)
δ 7.30-7.13 (m, 5 H), 5.02 (dd, J ) 7.2 Hz, 1 H), 3.90 (d, J )
14.2 Hz, 1 H), 3.65 (s, 3 H), 3.50 (d, J ) 14.2 Hz, 1 H), 3.38
(dd, J ) 8.8, 6.4 Hz, 1 H), 2.63-2.54 (m, 1 H), 2.47-2.39 (m,
1 H), 2.17-1.96 (m, 2 H), 1.62 (d, J ) 1.2 Hz, 3 H), 1.51 (s, 3
H), 1.78-1.37 (m, 3 H), 0.82 (d, J ) 6.7 Hz, 3 H), 0.69 (d, J )
6.7 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 174.1, 140.4, 132.3,
128.7, 128.1, 126.7, 122.3, 60.3, 55.2, 50.7, 39.0, 27.5, 25.6, 24.5,
23.1, 21.7, 17.7; MS (DCI, NH3) m/ z 318 (M + 1, 100), 261
(4), 248 (13), 190 (44), 170 (11); HRMS (DCI) calcd for C20H31
-
-
NO2 + H+ 318.2433, found 318.2457. Anal. Calcd for C20H31
NO2: C, 75.67; H, 9.84; N, 4.41. Found: C, 75.69; H, 9.87; N,
4.35.
(S)-N-Ben zyl-N-(4-m et h yl-3-p en t en yl)p h en yla la n in e
Meth yl Ester (9c): 1.45 g (4.11 mmol, 90%) of a colorless oil
(99% pure by GC, tR ) 30.1 min); [R]22 -102.9 (c ) 1.00;
D
CHCl3); IR (film) 1733, 735, 697 cm-1
;
1H NMR (300 MHz,
CDCl3) δ 7.17-6.96 (m, 10 H), 4.92 (dd, J ) 7.1 Hz, 1 H), 3.87
(d, J ) 14.4 Hz, 1 H), 3.55 (s, 3 H), 3.54 (dd, J ) 6.9 Hz, 1 H),
3.47 (d, J ) 14.4 Hz, 1 H), 2.98 (dd, J ) 13.8, 7.5 Hz, 1 H),
2.80 (dd, J ) 13.8, 7.5 Hz, 1 H), 2.66-2.32 (m, 2 H), 2.04-
1.91 (m, 2 H), 1.55 (s, 3 H), 1.44 (s, 3 H); 13C NMR (50 MHz,
CDCl3) δ 172.9, 139.8, 138.5, 132.3, 129.3, 128.5, 128.1, 127.9,
126.6, 126.1, 122.0, 64.0, 55.1, 50.9, 50.5, 36.1, 27.1, 25.6, 17.6;
MS (EI) m/ z 351 (M, 1), 282 (38), 260 (12), 222 (19), 91 (100),
83 (16); HRMS (DCI) calcd for C23H29NO2 + H+ 352.2276,
found 352.2293. Anal. Calcd for C23H29NO2: C, 78.60; H, 8.32;
N, 3.98. Found: C, 78.62; H, 8.33; N, 4.02.
Gen er a l P r oced u r e for th e N-Tosyla tion of Am in o
Acid Ester s 7. A solution of ester 7 (1.00 mmol) and NEt3
(111 mg, 1.10 mmol) in CH2Cl2 (2 mL) was treated with tosyl
chloride (200 mg, 1.05 mmol) and then stirred at room
temperature for 22 h. Evaporation of the solvent gave an oily
residue, which was purified by flash chromatography on SiO2
(hexanes/ethyl acetate 10:1).
(S)-N-Ben zyl-N-(4-m eth yl-3-pen ten yl)alan in ol (13a): 217
mg (0.88 mmol, 88%) of a colorless oil (98% pure by GC, tR
23.0 min); [R]22D +53.1 (c ) 1.00; CHCl3); IR (film) 3440, 1452,
1375, 1145, 1074, 1041, 1030, 731, 698 cm-1 1H NMR (200
)
;
MHz, CDCl3) δ 7.28-7.17 (m, 5 H), 4.96 (dd, J ) 5.7 Hz, 1 H),
3.77 (d, J ) 13.6 Hz, 1 H), 3.31 (d, J ) 13.6 Hz, 1 H), 3.31 (m,
2 H), 3.18 (s, broad, 1 H), 2.98-2.87 (m, 1 H), 2.52-2.27 (m,
2 H), 2.07 (ddd, broad, J ) 7.0 Hz, 2 H), 1.63 (d, J ) 1.1 Hz,
3 H), 1.52 (s, 3 H), 0.86 (d, J ) 6.6 Hz, 3 H); 13C NMR (50
MHz, CDCl3) δ 139.6, 132.9, 128.7, 128.2, 126.9, 122.0, 62.6,
55.3, 53.4, 48.4, 27.2, 25.5, 17.7, 8.8; MS (EI) m/ z 229 (M - 1
- H2O, 5), 216 (4), 205 (7), 178 (40), 160 (35), 146 (21), 134
(20), 91 (100), 83 (75); HRMS (DCI) calcd for C16H25NO + H+
248.2014, found 248.2020. Anal. Calcd for C16H25NO: C,
77.68; H, 10.19; N, 5.66. Found: C, 77.69; H, 10.22; N, 5.43.
(S)-N-Ben zyl-N-(4-m eth yl-3-pen ten yl)leu cin ol (13b): 246
mg (0.85 mmol, 97%) of a colorless oil (99% pure by GC, tR
)
(S)-N-(4-Meth yl-3-p en ten yl)-N-tosyla la n in e Bu tyl Es-
25.9 min); [R]22D +77.0 (c ) 1.00; CHCl3); IR (film) 3428, 1096,
1071, 1028, 730, 698 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.29-
7.17 (m, 5 H), 4.95 (dd, J ) 7.1 Hz, 1 H), 3.77 (d, J ) 13.6 Hz,
1 H), 3.71 (s, broad, 1 H), 3.43 (dd, J ) 10.5, 5.0 Hz, 1 H), 3.32
ter (10a ): 1.74 g (4.57 mmol, 88%) of a colorless oil; [R]22
D
-52.1 (c ) 1.00; CHCl3); IR (film) 1738, 1341, 1175, 1154, 729,
655 cm-1; 1H NMR (200 MHz, CDCl3) δ 7.68 (d, J ) 7.3 Hz, 2

Piperidines by a Formal Hetero-Ene Reaction
J . Org. Chem., Vol. 61, No. 8, 1996 2835
(d, J ) 13.6 Hz, 1 H), 3.26 (dd, J ) 10.5, 10.5 Hz, 1 H), 2.82-
2.75 (m, 1 H), 2.55-2.45 (m, 1 H), 2.40-2.32 (m, 1 H), 2.07
(ddd, broad, J ) 6.9 Hz, 2 H), 1.63 (d, J ) 1.2 Hz, 3 H), 1.51
(s, 3 H), 1.49-1.32 (m, 2 H), 1.09-1.00 (m, 1 H), 0.87 (d, J )
6.4 Hz, 3 H), 0.83 (d, J ) 6.2 Hz, 3 H); 13C NMR (75 MHz,
CDCl3) δ 139.7, 133.0, 128.8, 128.2, 126.9, 122.0, 61.1, 58.1,
53.7, 48.8, 34.3, 25.5, 25.3, 23.8, 22.0, 17.7; MS (DCI, NH3)
m/ z 290 (M + 1, 100), 258 (1), 220 (7), 200 (1); HRMS (DCI)
calcd for C19H31NO + H+ 290.2484, found 290.2463. Anal.
Calcd for C19H31NO: C, 78.84; H, 10.79; N, 4.84. Found: C,
78.83; H, 10.85; N, 4.76.
NEt3 (3 mL) was added over 30 min, and the mixture was
warmed to room temperature and stirred for another 1 h. The
mixture was subsequently washed with H2O (3 × 50 mL), dried
with Na2SO4, and concentrated to yield a crude oil (>95% pure
by 13C NMR), which was immediately used without further
purification.
(S)-N-Ben zyl-N-(4-m eth yl-3-pen ten yl)alan in al (11a): 246
mg (1.00 mmol, quant) of a yellow oil; [R]22 -28.3 (c ) 1.00;
D
CHCl3); IR (film) 1730, 1452, 1376, 909, 735, 698 cm-1
;
1H
NMR (300 MHz, C6D6) δ 9.69 (s, 1 H), 7.38-7.18 (m, 5 H),
5.14 (dd, J ) 7.2 Hz, 1 H), 3.66 (d, J ) 14.1 Hz, 1 H), 3.42 (d,
J ) 14.1 Hz, 1 H), 3.13 (ddd, J ) 6.9 Hz, 1 H), 2.54-2.42 (m,
2 H), 2.12 (ddd, broad, J ) 7.2 Hz, 2 H), 1.72 (s, 3 H), 1.57 (s,
3 H), 1.04 (d, J ) 7.2 Hz, 3 H); 13C NMR (75 MHz, C6D6) δ
203.1, 140.0, 132.4, 128.9, 128.5, 127.4, 122.4, 64.3, 55.8, 51.1,
27.8, 25.7, 17.7, 7.6; MS (EI) m/ z 245 (M, 5), 216 (M - CHO,
26), 177 (23), 160 (20), 148 (38), 109 (36), 91 (100); HRMS calcd
for C16H23NO 245.1780, found 245.1774.
(S)-N-Ben zyl-N-(4-m et h yl-3-p en t en yl)p h en yla la n in ol
(13c): 1.33 g (4.12 mmol, 99%) of a yellow oil (99% pure by
GC, tR ) 32.5 min); [R]22 +23.0 (c ) 1.00; CHCl3); IR (film)
D
3442, 1495, 1454, 1039, 1029, 731, 699 cm-1
;
1H NMR (200
MHz, CDCl3) δ 7.23-6.99 (m, 10 H), 4.95 (dd, J ) 7.0 Hz, 1
H), 3.83 (d, J ) 13.5 Hz, 1 H), 3.36 (d, J ) 13.5 Hz, 1 H), 3.35-
3.22 (m, 2 H), 3.01-2.85 (m, 2 H), 2.62-2.33 (m, 3 H), 2.26
(dd, J ) 13.0, 9.6 Hz, 1 H), 2.07 (ddd, J ) 7.0 Hz, 2 H), 1.61
(s, 3 H), 1.49 (s, 3 H); 13C NMR (50 MHz, CDCl3) δ 139.4, 139.2,
133.2, 128.8, 128.4, 128.3, 127.0, 126.0, 121.9, 62.2, 60.3, 53.9,
48.7, 31.9, 27.4, 25.6, 17.7; MS (EI) m/ z 323 (M, 4), 305 (M -
H2O, 13), 292 (20), 254 (54), 232 (28), 117 (50), 91 (100), 83
(32); HRMS calcd for C22H27N (M - H2O) 305.2143, found
305.2136. Anal. Calcd for C22H29NO: C, 81.69; H, 9.04; N,
4.33. Found: C, 81.70; H, 9.10; N, 4.29.
(S)-N-Ben zyl-N-(4-m eth yl-3-pen ten yl)leu cin al (11b): 761
mg (2.65 mmol, quant) of a brown oil; [R]22 +64.6 (c ) 1.00;
D
CHCl3); IR (film) 1729, 736, 698 cm-1
;
1H NMR (200 MHz,
C6D6) δ 9.55 (s, 1 H), 7.29-7.06 (m, 5 H), 5.04 (dd, J ) 7.1 Hz,
1 H), 3.64 (d, J ) 14.0 Hz, 1 H), 3.50 (d, J ) 14.0 Hz, 1 H),
3.02 (dd, J ) 7.0 Hz, 1 H), 2.54-2.31 (m, 2 H), 2.09-1.98 (ddd,
J ) 7.2 Hz, 2 H), 1.74-1.13 (m, 3 H), 1.58 (s, 3 H), 1.46 (s, 3
H), 0.90 (d, J ) 6.5 Hz, 3 H), 0.70 (d, J ) 6.5 Hz, 3 H); 13C
NMR (50 MHz, C6D6) δ 202.9, 140.3, 132.4, 129.0, 128.6, 127.5,
122.5, 66.5, 55.9, 51.1, 33.8, 28.2, 25.3, 22.8, 22.6, 17.7; MS
(EI) m/ z 287 (M, 3), 266 (8), 258 (M - CHO, 34), 218 (36),
(S)-N-(4-Meth yl-3-p en ten yl)-N-tosyla la n in ol (14a ): 1.13
g (3.64 mmol, quant) of a colorless oil; [R]22 +39.7 (c ) 1.00;
D
CHCl3); IR (film) 3520, 1334, 1151, 1091, 656 cm-1; H NMR
1
(200 MHz, CDCl3) δ 7.67 (d, J ) 8.4 Hz, 2 H), 7.24 (d, J ) 8.4
Hz, 2 H), 5.02 (dd, J ) 7.3 Hz, 1 H), 3.97-3.81 (m, 1 H), 3.61-
3.44 (m, 3 H), 3.20-2.84 (m, 2 H), 2.36 (s, 3 H), 2.31 (ddd, J )
7.7 Hz, 2 H), 1.64 (s, 3 H), 1.59 (s, 3 H), 0.85 (d, J ) 7.0 Hz, 3
H); 13C NMR (50 MHz, CDCl3) δ 143.2, 137.6, 134.7, 129.5,
127.0, 120.1, 64.6, 55.5, 43.3, 30.2, 25.5, 21.3, 17.7, 14.2; MS
(EI) m/ z 312 (M + 1, 2), 280 (4), 242 (45), 155 (43), 91 (75), 83
(22), 70 (100); HRMS (CI) calcd for C16H25NO3S + H+ 312.1633,
found 312.1584. Anal. Calcd for C16H25NO3S: C, 61.71; H,
8.09; N, 4.50. Found: C, 61.78; H, 7.97; N, 4.53.
190 (28), 176 (26), 91 (100), 83 (47); HRMS calcd for C19H29
NO 287.2249, found 287.2242.
-
(S)-N-Ben zyl-N-(4-m et h yl-3-p en t en yl)p h en yla la n in a l
(11c): 1.31 g (4.08 mmol, quant) of a brown oil; [R]22 -115.8
D
(c ) 1.00; CHCl3); IR (film) 1730, 1453, 910, 742, 698 cm-1; 1H
NMR (200 MHz, C6D6) δ 9.49 (s, 1 H), 7.16-7.02 (m, 10 H),
5.01 (dd, J ) 7.1 Hz, 1 H), 3.62 (d, J ) 14.0 Hz, 1 H), 3.41 (d,
J ) 14.0 Hz, 1 H), 3.31 (dd, J ) 6.7, 7.1 Hz, 1 H), 3.00 (dd, J
) 13.8, 7.1 Hz, 1 H), 2.61 (dd, J ) 13.8, 6.0 Hz, 1 H), 2.51-
2.37 (m, 2 H), 2.01 (ddd, J ) 7.2 Hz, 2 H), 1.60 (s, 3 H), 1.44
(s, 3 H); 13C NMR (50 MHz, C6D6) δ 201.0, 140.0, 139.9, 132.5,
129.7, 128.9, 128.6, 128.5, 127.4, 126.3, 122.4, 70.3, 55.8, 51.0,
30.6, 28.0, 25.8, 17.7; MS (EI) m/ z 321 (M, 2), 292 (M - CHO,
24), 252 (51), 224 (24), 202 (34), 91 (100), 83 (45); HRMS calcd
for C21H26N (M - CHO) 292.2065, found 292.2057.
(S)-N-(4-Meth yl-3-p en ten yl)-N-tosylleu cin ol (14b): 1.13
g (3.21 mmol, 92%) of a colorless oil; [R]22 +10.5 (c ) 1.00;
D
CHCl3); IR (KBr) 3526, 1332, 1151, 1092, 756, 658 cm-1; H
1
NMR (300 MHz, CDCl3) δ 7.71 (d, J ) 8.6 Hz, 2 H), 7.24 (d, J
) 8.6 Hz, 2 H), 5.00 (dd, J ) 7.4 Hz, 1 H), 3.82-3.72 (m, 1 H),
3.51-3.43 (m, 2 H), 3.15-2.96 (m, 2 H), 2.37 (s, 3 H), 2.36-
2.23 (m, 3 H), 1.64 (s, 3 H), 1.59 (s, 3 H), 1.44-1.29 (m, 1 H),
1.25-1.06 (m, 2 H), 0.73 (d, J ) 6.7 Hz, 3 H), 0.70 (d, J ) 6.7
Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 143.2 137.8, 134.5,
129.5, 127.3, 120.1, 63.6, 58.2, 43.7, 38.6, 30.1, 25.5, 24.6, 22.5,
22.4, 21.4, 17.7; MS (DCI) m/ z 371 (M + NH4+, 9), 354 (M +
H+, 100), 196 (93), 168 (100), 130 (100); HRMS (DCI) calcd for
C19H31NO3S + H+ 354.2103, found 354.2121. Anal. Calcd for
C19H31NO3S: C, 64.55; H, 8.84; N, 3.96. Found: C, 64.46; H,
8.80; N, 3.92.
(S)-N-(4-Meth yl-3-pen ten yl)-N-tosylalan in al (12a):28 1.10
g (3.57 mmol, quant) of a pale brown oil; [R]22D -3.5 (c ) 1.00;
CHCl3); IR (film) 1736, 1337, 1155, 1092, 815, 732, 658 cm-1
;
1H NMR (200 MHz, C6D6) δ 9.46 (s, 1 H), 7.60 (d, J ) 8.3 Hz,
2 H), 6.90 (d, J ) 8.3 Hz, 2 H), 4.87 (dd, J ) 7.2 Hz, 1 H),
4.66-4.57 (m, 1 H), 3.04-2.78 (m, 2 H), 2.10 (ddd, J ) 7.5
Hz, 2 H), 2.00 (s, 3 H), 1.53 (s, 3 H), 1.43 (s, 3 H), 0.89 (d, J )
7.7 Hz, 3 H); 13C NMR (50 MHz, C6D6) δ 199.0, 142.9, 137.8,
134.1, 129.4, 127.0, 119.9, 61.7, 45.4, 28.9, 25.2, 20.7, 17.2, 11.7;
MS (EI) m/ z 309 (M, 5), 281 (6), 280 (M - CHO, 19), 240 (30),
212 (26), 155 (41), 91 (73), 83 (57), 55 (100); HRMS (CI) calcd
for C16H23NO3S + H+ 310.1477, found 310.1435.
(S )-N -(4-Me t h yl-3-p e n t e n yl)-N -t osylp h e n yla la n in ol
(14c): 1.59 g (4.12 mmol, quant) of a pale yellow oil; [R]22
D
-45.1 (c ) 1.00; CHCl3); IR (film) 3526, 1324, 1153, 1092, 700,
658 cm-1; 1H NMR (200 MHz, CDCl3) δ 7.64 (d, J ) 8.3 Hz, 2
H), 7.23-7.16 (m, 5 H), 7.01-6.96 (m, 2 H), 5.03 (dd, J ) 6.0
Hz, 1 H), 4.12-3.85 (m, 1 H), 3.59-3.54 (m, 2 H), 3.33-3.02
(m, 2 H), 2.75-2.54 (m, 2 H), 2.37 (s, 3 H), 2.34 (ddd, J ) 7.7
Hz, 2 H), 1.10 (s, broad, 1 H), 1.67 (d, J ) 0.9 Hz, 3 H), 1.62
(s, 3 H); 13C NMR (50 MHz, CDCl3) δ 143.2, 137.6, 134.7, 129.5,
128.9, 128.5, 127.2, 126.5, 120.1, 62.4, 62.0, 44.5, 36.2, 29.9,
25.6, 21.4, 17.8; MS (EI) m/ z 387 (M, 9), 372 (15), 356 (22),
318 (37), 300 (35), 155 (91), 91 (100), 55 (99); HRMS (DCI)
calcd for C22H29NO3S + H+ 388.1946, found 388.1936. Anal.
Calcd for C22H29NO3S: C, 68.18; H, 7.54; N, 3.61. Found: C,
68.05; H, 7.51; N, 3.72.
(S)-N-(4-Meth yl-3-p en ten yl)-N-tosylleu cin a l (12b): 1.13
g (3.21 mmol, quant) of a yellow oil; [R]22 -115.4 (c ) 1.00;
D
CHCl3); IR (film) 1735, 1339, 1156, 736, 659 cm-1; H NMR
1
(200 MHz, C6D6) δ 9.34 (s, 1 H), 7.67 (d, J ) 8.4 Hz, 2 H), 6.79
(d, J ) 8.4 Hz, 2 H), 4.93 (dd, J ) 7.3 Hz, 1 H), 4.25 (dd, J )
9.3, 4.6 Hz, 1 H), 3.15-3.07 (m, 1 H), 2.99-2.91 (m, 1 H), 2.25-
2.09 (m, 2 H), 1.69-1.43 (m, 2 H), 1.35-1.18 (m, 1 H), 1.91 (s,
3 H), 1.56 (d, J ) 1.0 Hz, 3 H), 1.50 (s, 3 H), 0.77 (d, J ) 6.3
Hz, 3 H), 0.72 (d, J ) 6.3 Hz, 3 H); 13C NMR (50 MHz, C6D6)
δ 199.6, 143.2, 138.4, 134.6, 129.7, 127.6, 120.4, 65.0, 46.7, 36.1,
30.1, 25.6, 24.5, 23.0, 21.5, 21.1, 17.7; MS (EI) m/ z 351 (M,
2), 322 (M - CHO, 8), 226 (27), 196 (10), 155 (35), 91 (100), 83
(73), 55 (100); HRMS calcd for C19H29NO3S 351.1868, found
351.1861.
Sw er n Oxid a tion of Alcoh ols 13, 14. A solution of DMSO
(907 mg, 11.6 mmol) in CH2Cl2 (2 mL) was added dropwise
over 30 min at -45 °C to a solution of oxalyl chloride (737
mg, 5.80 mmol) in CH2Cl2 (8 mL). After stirring the mixture
for 15 min a solution of the alcohol 13, 14 (3.36 mmol) in
CH2Cl2 (5 mL) was added dropwise over 30 min, and the
resulting mixture was stirred for another 8 h at -45 °C. Then
N-(4-Meth yl-3-p en ten yl)-N-tosylp h en yla la n in a l (12c):
28
1.58 g (4.12 mmol, quant) of a brown oil; [R]22 -1.5 (c )
D
(28) Unexpectedly, almost complete racemization of the N-tosyl-
protected aldehydes 12a ,c occurred during Swern oxidation. This was
determined by NMR as described in ref 29.

2836 J . Org. Chem., Vol. 61, No. 8, 1996
Laschat et al.
1.00; CHCl3); IR (film) 1737, 1338, 1156, 1092, 737, 660 cm-1
;
(S)-N-(4-Met h yl-3-p en t en yl)-N-t osylleu cin a l Ben zyl-
1H NMR (200 MHz, C6D6) δ 9.75 (d, J ) 0.6 Hz, 1 H), 7.69 (d,
J ) 8.2 Hz, 2 H), 7.19-7.07 (m, 5 H), 6.93 (d, J ) 8.2 Hz, 2
H), 5.04 (dd, J ) 6.9 Hz, 1 H), 4.52 (dd, J ) 7.6, 6.1 Hz, 1 H),
3.46 (dd, J ) 14.5, 6.1 Hz, 1 H), 3.25-3.03 (m, 2 H), 2.82 (dd,
J ) 14.5, 8.0 Hz, 1 H), 2.31 (ddd, J ) 7.6 Hz, 2 H), 1.96 (s, 3
H), 1.71 (s, 3 H), 1.62 (s, 3 H); 13C NMR (50 MHz, C6D6) δ
198.3, 143.2, 138.4, 137.9, 129.8, 129.4, 128.8, 127.6, 126.7,
120.3, 68.2, 46.6, 33.5, 29.3, 25.7, 17.7, 12.3; MS (EI) m/ z 385
(M, 4), 356 (M - CHO, 19), 316 (25), 155 (37), 91 (100), 83
(99), 55 (93); HRMS (DCI) calcd for C22H27NO3S + H+
386.1790, found 386.1796.
im in e (16b): 1.41 g (3.21 mmol, quant) of a yellow oil; [R]22
D
-57.7 (c ) 1.00; CHCl3); IR (film) 1668, 1340, 1155, 733, 698,
1
659 cm-1; H NMR (200 MHz, C6D6) δ 7.80 (d, J ) 8.3 Hz, 2
H), 7.51-7.48 (m, 1 H), 7.20-7.09 (m, 5 H), 6.79 (d, J ) 8.3
Hz, 2 H), 5.04 (dd, J ) 7.3 Hz, 1 H), 4.78-4.67 (m, 1 H), 4.29
(s, 2 H), 3.25-3.12 (m, 2 H), 2.69-2.31 (m, 2 H), 1.93 (s, 3 H),
1.98-1.72 (m, 2 H), 1.65-1.22 (m, 1 H), 1.61 (d, J ) 0.7 Hz, 3
H), 1.57 (s, 3 H), 0.90 (d, J ) 6.3 Hz, 3 H), 0.86 (d, J ) 6.3 Hz,
3 H); 13C NMR (50 MHz, C6D6) δ 163.9, 142.7, 139.2, 139.0,
134.2, 129.5, 128.6, 128.1, 127.8, 127.1, 120.9, 64.7, 59.4, 45.2,
39.1, 30.8, 25.7, 24.6, 23.0, 22.2, 21.1, 17.8; MS (EI) m/ z 440
(M, 1), 285 (7), 215 (28), 125 (17), 91 (100), 83 (35); HRMS
(DCI) calcd for C26H36N2O2S + H 441.2575, found 441.2560.
(S)-N-(4-Meth yl-3-pen ten yl)-N-tosylph en ylalan in al Ben -
Gen er a l P r oced u r e for th e P r ep a r a tion of Ben zyl-
im in es 15, 16. To a solution of aldehyde 15, 16 (1.00 mmol)
and N-benzylamine (1.00 mmol) in CH2Cl2 (10 mL) was added
powdered, freshly activated 4 Å molecular sieves (500 mg), and
the mixture was stirred at room temperature for 12-24 h. The
mixture was then filtered via a fritted funnel through Celite,
and the resulting filtrate was concentrated at room temper-
ature to give an oil (>95% pure by 13C NMR), which was used
immediately without further isolation or purification.
(S)-N-Ben zyl-N-(4-m eth yl-3-p en ten yl)a la n in a l Ben zyl-
im in e (15a ): 335 mg (1.00 mmol, quant) of a pale yellow oil;
[R]22D -59.4 (c ) 1.00; CHCl3); IR (film) 1667, 1494, 1452, 1375,
zylim in e (16c): 1.95 g (4.12 mmol, quant) of a yellow oil; [R]22
D
-1.4 (c ) 1.00; CHCl3); IR (film) 1668, 1599, 1495, 1453, 1338,
1
1158, 1092, 735, 698, 660 cm-1; H NMR (200 MHz, C6D6) δ
7.64 (d, J ) 8.2 Hz, 2 H), 7.21-7.03 (m, 11 H), 6.75 (d, J ) 8.2
Hz, 2 H), 5.13-4.88 (m, 2 H), 3.50 (dd, J ) 14.0, 8.0 Hz, 1 H),
3.27-3.17 (m, 2 H), 2.82 (dd, J ) 14.0, 6.4 Hz, 1 H), 2.52-
2.28 (m, 4 H), 1.94 (s, 3 H), 1.61 (d, J ) 0.8 Hz, 3 H), 1.53 (d,
J ) 0.7 Hz, 3 H); 13C NMR (50 MHz, C6D6) δ 162.9, 142.7,
139.3, 138.8, 138.7, 134.2, 129.8, 129.6, 128.5, 128.2, 127.6,
127.1, 126.4, 120.8, 64.6, 62.5, 45.2, 35.9, 30.3, 25.7, 21.1, 17.8;
MS (EI) m/ z 474 (M, 2), 405 (17), 383 (12), 319 (22), 249 (42),
158 (30), 91 (100), 81 (39); HRMS calcd for C29H34N2O2S
474.2341, found 474.2351.
1
1028, 733, 698 cm-1; H NMR (200 MHz, C6D6) δ 7.70-7.67
(ddd, J ) 3.2, 1.4, 1.4 Hz, 1 H), 7.39-7.06 (m, 10 H), 5.11 (dd,
J ) 7.1, 1.4 Hz, 1 H), 4.42 (s, 2 H), 3.67 (d, J ) 14.1 Hz, 1 H),
3.46 (d, J ) 14.1 Hz, 1 H), 3.49-3.42 (m, 1 H), 2.54-2.37 (m,
2 H), 2.14-2.05 (ddd, J ) 7.1 Hz, 2 H), 1.63 (d, J ) 1.0 Hz, 3
H), 1.47 (s, 3 H), 1.19 (d, J ) 6.7 Hz, 3 H); 13C NMR (50 MHz,
C6D6) δ 167.7, 141.1, 140.3, 132.0, 128.9, 128.6, 128.5, 128.1,
127.1, 126.9, 123.0, 65.0, 58.6, 55.3, 50.6, 27.9, 25.8, 17.8, 11.3;
MS (EI) m/ z 334 (M, 13), 263 (15), 188 (19), 173 (19), 147 (19),
120 (20), 91 (100), 83 (24); HRMS calcd for C23H30N2 334.2409,
found 334.2394.
(S)-N-Ben zylleu cin e Meth yl Ester (17). To an ice-cooled
solution of leucine methyl ester 7b (795 mg, 5.48 mmol) in
MeOH (2 mL) were added NaCNBH3 (314 mg, 5.00 mmol) and
freshly distilled benzaldehyde (636 mg, 6.00 mmol), and the
pH was adjusted to 6 by careful addition of acetic acid. The
resulting mixture was stirred at room temperature for 17 h,
cooled with a MeOH/ice bath, and hydrolyzed by careful
addition of K2CO3 (20 mL of a 40% solution in H2O). Extrac-
tion with Et2O (3 × 50 mL), washing of the combined organic
layers with brine (2 × 50 mL), and drying over Na2SO4 yielded
a colorless oil, which was purified by flash chromatography
on SiO2 (hexanes/ethyl acetate 7.5:1) to give 1.20 g (93%) of a
(S)-N-Ben zyl-N-(4-m eth yl-3-p en ten yl)leu cin a l Ben zyl-
im in e (15b): 996 mg (2.65 mmol, quant) of a yellow oil; [R]22
D
-33.7 (c ) 1.00; CHCl3); IR (film) 1665, 1495, 1452, 733, 697
1
cm-1; H NMR (200 MHz, C6D6) δ 7.63 (d, J ) 4.8 Hz, 1 H),
7.43-7.08 (m, 10 H), 5.15 (dd, J ) 7.2 Hz, 1 H), 4.48 (s, 2 H),
3.73 (d, J ) 14.0 Hz, 1 H), 3.67 (d, J ) 14.0 Hz, 1 H), 3.46
(ddd, J ) 4.8 Hz, 1 H), 2.59 (d, J ) 7.5 Hz, 2 H), 2.19 (ddd, J
) 7.5 Hz, 2 H), 1.92-1.71 (m, 1 H), 1.64 (s, 3 H), 1.64-1.45
(m, 2 H), 1.50 (s, 3 H), 0.87 (d, J ) 6.1 Hz, 3 H), 0.80 (d, J )
6.1 Hz, 3 H); 13C NMR (50 MHz, C6D6) δ 166.1, 141.1, 140.4,
132.1, 129.1, 128.6, 128.4, 128.1, 127.1, 127.0, 123.0, 65.3, 60.8,
55.4, 50.7, 37.7, 28.1, 25.8, 25.1, 23.0, 22.9; MS (EI) m/ z 376
(M, 3), 307 (19), 285 (4), 188 (17), 146 (26), 91 (100), 83 (23);
HRMS calcd for C26H36N2 376.2878, found 376.2870.
colorless oil (99% pure by GC, tR ) 19.9 min); [R]22 -40.7 (c
D
) 1.00, CHCl3); IR (film) 3333, 1736, 1196, 1171, 1152, 738,
1
699 cm-1; H NMR (300 MHz, CDCl3) δ 7.27-7.15 (m, 5 H),
3.73 (d, J ) 12.9 Hz, 1 H), 3.63 (s, 3 H), 3.53 (d, J ) 12.9 Hz,
1 H), 3.23 (dd, J ) 7.3 Hz, 1 H), 1.77-1.65 (m, 2 H), 1.40 (dd,
J ) 7.3 Hz, 2 H), 0.83 (d, J ) 6.7 Hz, 3 H), 0.77 (d, J ) 6.7 Hz,
3 H); 13C-NMR (75 MHz, CDCl3) δ 176.4, 139.9, 128.2, 126.9,
59.2, 59.1*, 52.1, 51.5, 51.4 *, 42.8, 24.8, 22.7, 22.0; MS (EI)
m/ z 235 (M, 3), 176 (49), 106 (16), 91 (100); HRMS (DCI) calcd
for C14H21NO2 + H+ 236.1651, found 236.1621. Anal. Calcd
for C14H21NO2: C, 71.46; H, 8.99; N, 5.95. Found: C, 71.44;
H, 8.90; N, 5.93.
(S)-N-Ben zyl-N-(4-m et h yl-3-p en t en yl)p h en yla la n in a l
Ben zylim in e (15c): 1.67 g (4.08 mmol, quant) of a pale brown
oil; [R]22 -35.4 (c ) 1.00; CHCl3); IR (film) 1666, 1495, 1453,
D
733, 697 cm-1; H NMR (200 MHz, C6D6) δ 7.61 (d, J ) 3.8
1
P r ep a r a tion of 9b fr om 17. To a solution of 17 (235 mg,
1.00 mmol) in DMF (1 mL) were sucessively added K2CO3 (138
mg, 1.00 mmol), tetrabutylammonium iodide (369 mg, 1.00
mmol), and then 4-methyl-3-pentenyl bromide (163 mg, 1.00
mmol), and the resulting mixture was stirred at room tem-
perature for 4 h and then heated to 100 °C for 48 h. The
reaction mixture was then diluted with toluene (10 mL) and
azeotropically codistilled (3×) under high vacuum. The re-
maining brown solid was diluted in pentane (10 mL) and
purified by flash chromatography on SiO2 (hexanes/ethyl
acetate 10:1 f 4:1) to give 48 mg (15%) of a pale yellow oil.
Gen er a l P r oced u r e for th e Lew is Acid -Ca ta lyzed Cy-
cliza tion of Ben zylim in es 15, 16.29 To an ice-cooled solution
of imine 15, 16 (1.00 mmol) were added dropwise in CH2Cl2
(28 mL) and the Lewis acid (2.50 mmol), and the mixture was
stirred at room temperature (see Tables 1, 2) for 24 h. Then
2 N NaOH (50 mL) was added, and the mixture was extracted
with CH2Cl2 (3 × 100 mL). After drying the combined organic
Hz, 1 H), 7.32-7.08 (m, 15 H), 5.12 (dd, J ) 7.4 Hz, 1 H), 4.36
(s, 2 H), 3.75 (d, J ) 14.2 Hz, 1 H), 3.72-3.66 (m, 1 H), 3.62
(d, J ) 14.2 Hz, 1 H), 3.25 (dd, J ) 13.7, 7.9 Hz, 1 H), 2.89
(dd, J ) 13.7, 5.8 Hz, 1 H), 2.69-2.59 (m, 2 H), 2.15 (ddd, J )
7.4 Hz, 2 H), 1.66 (s, 3 H), 1.50 (s, 3 H); 13C NMR (50 MHz,
C6D6) δ 165.1, 140.8, 140.7, 140.1, 132.1, 128.9, 128.6, 128.4,
128.4, 128.1, 127.1, 126.9, 126.0, 122.9, 65.1, 64.7, 55.3, 50.6,
33.7, 28.1, 25.8, 17.8; MS (EI) m/ z 410 (M, 20), 341 (28), 319
(24), 292 (23), 250 (36), 188 (31), 159 (47), 91 (100); HRMS
calcd for C29H34N2 410.2722, found 410.2711.
(()-N-(4-Met h yl-3-p en t en yl)-N-t osyla la n in a l Ben zyl-
im in e (16a ): 400 mg (1.00 mmol, quant) pale brown oil; IR
(film) 1669, 1495, 1453, 1382, 1338, 1155, 1092, 814, 734, 699,
1
659 cm-1; H NMR (200 MHz, C6D6) δ 7.76 (d, J ) 8.3 Hz, 2
H), 7.57-7.56 (m, 1 H), 7.19-7.01 (m, 5 H), 6.83 (d, J ) 8.3
Hz, 2 H), 5.13 (dd, J ) 7.2 Hz, 1 H), 4.62 (ddd, J ) 6.9 Hz, 1
H), 4.31 (s, 2 H), 3.31-2.90 (m, 2 H), 2.41-2.18 (m, 2 H), 1.95
(s, 3 H), 1.61 (d, J ) 0.9 Hz, 3 H), 1.49 (s, 3 H), 1.14 (d, J )
6.9 Hz, 3 H); 13C NMR (50 MHz, C6D6) δ 164.6, 142.8, 140.8,
138.9, 134.1, 129.7, 129.2, 128.6, 128.1, 127.4, 120.8, 64.5, 56.6,
51.4, 44.5, 25.7, 21.1, 17.7; MS (EI) m/ z 398 (M, 3), 329 (6),
243 (21), 173 (43), 91 (100), 83 (61); HRMS calcd for
C23H30N2O2S 398.2028, found 398.2019.
(29) The enantiomeric purity of the cyclization products 18a -c,
20a -c, 22a ,b, and 23b (>98% ee) was determined by 1H NMR (200
MHz) using 1 mol equiv of (-)-(R)-1-(9-anthryl)-2,2,2-trifluoroethanol
as shift reagent: Pirkle, W. H., Sikkenga, D. L.; Pavlin, M. S. J . Org.
Chem. 1977, 42, 384.

Piperidines by a Formal Hetero-Ene Reaction
J . Org. Chem., Vol. 61, No. 8, 1996 2837
layers with MgSO4 and evaporation of the solvent, the crude
products were purified by flash chromatography on SiO2
(hexanes/ethyl acetate/NEt3, 97:3:1).
0.65 (d, J ) 6.2 Hz, 3 H, 10-H); 13C NMR (75 MHz, CDCl3) δ
159.4 (HCdN), 139.9 (C-1′′), 136.6 (C-1′), 130.2, 129.2, 128.5,
128.3, 128.0, 126.5, 73.5 (C-3), 60.3 (C-2), 55.8 (NCH2Ph), 52.9
(C-6), 49.2 (C-4), 28.7 (C-8), 23.3 (C-5), 20.4 (C-9), 19.9 (C-7),
18.4 (C-10); MS (EI) m/ z 334 (M, 37), 291 (36), 231 (38), 202
(47), 188 (60), 91 (100), 83 (41); HRMS calcd for C23H30N2
334.2409, found 334.2401. Anal. Calcd for C23H30N2: C, 82.59;
H, 9.04; N, 8.37. Found: C, 82.58; H, 9.10; N, 8.32.
(2S,3S,4R)-N-Ben zyl-3-(N-ben zyla m in o)-4-isop r op en yl-
2-m eth ylp ip er id in e (18a ): 200 mg (0.60 mmol, 60%) of a
yellow oil; [R]22D +35.9 (c ) 1.00; CHCl3); IR (film) 3432, 1495,
734, 698 cm-1; 1H NMR (200 MHz, CDCl3) δ 7.45-7.22 (m, 10
H, 2 x Ph), 4.85 (dd, J ) 2.0, 0.6 Hz, 1 H, 9a-H), 4.77 (d, J )
0.6 Hz, 1 H, 9b-H), 4.04 (d, J ) 13.5 Hz, 1 H, NHCH2Ph), 3.86
(d, J ) 11.1 Hz, 1 H, NCH2Ph), 3.76 (d, J ) 11.1 Hz, 1 H,
NCH2Ph), 3.09 (d, J ) 13.5 Hz, 1 H, NHCH2Ph), 2.81 (d, broad,
J ) 1.7 Hz, 2 H, 4a-H, 1-H), 2.44 (ddd, J ) 6.5, 6.5, 2.0 Hz, 1
H, 2-H), 1.93-1.88 (m, 4 H, 6-H, 4b-H, 5a-H, NH), 1.78 (s, 3
H, 10-H), 1.37-1.28 (m, 1 H, 5b-H), 1.32 (d, J ) 6.5 Hz, 3 H,
7-H); 13C NMR (50 MHz, CDCl3) δ 147.5 (C-8), 141.5 (C-1′′),
139.8 (C-1′), 128.8, 128.4, 128.2, 128.0, 126.6, 110.3 (C-9), 62.8
(C-2), 60.6 (C-1), 57.5 (NHCH2Ph), 55.5 (NCH2Ph), 53.3 (C-4),
49.1 (C-6), 25.0 (C-5), 22.5 (C-10), 19.1 (C-7); MS (EI) m/ z 334
(M, 25), 319 (6), 289 (24), 200 (35), 188 (41), 173 (40), 105 (35),
91 (100); HRMS calcd for C23H30N2 334.2409, found 334.2401.
Anal. Calcd for C23H30N2: C, 82.59; H, 9.04; N, 8.37. Found:
C, 82.54; H, 9.12; N, 8.34.
(2S,3S,4R)-N-Ben zyl-3-(N-ben zylid en ea m in o)-3-isop r o-
pyl-2-(2-m eth ylpr opyl)piper idin e (20b): 282 mg (0.75 mmol,
56%) of a yellow oil; [R]22 -61.3 (c ) 1.00; CHCl3); IR (film)
D
1644, 1494, 1451, 1384, 1366, 758, 731, 694 cm-1
;
1H NMR
(300 MHz, CDCl3) δ 8.22 (s, 1 H, HCdN), 7.86-7.82 (m, 2 H,
2′′-H, 6′′-H), 7.48-7.18 (m, 8 H), 4.05 (d, J ) 14.8 Hz, 1 H,
NCH2Ph), 3.68 (d, J ) 14.8 Hz, 1 H, NCH2Ph), 3.42 (s, 1 H,
3-H), 3.15-3.06 (m, 2 H, 2-H, 6eq-H), 2.73 (dd, J ) 12.5 Hz, 1
H, 6ax-H), 2.21-2.05 (m, 1 H), 1.82-1.79 (m, 1 H), 1.51-1.44
(m, 1 H), 1.37-1.31 (m, 4 H, 4-H, 5-H, 7-H, 8-H, 11-H), 1.00
(d, J ) 6.7 Hz, 3 H, 12-H), 0.92 (d, J ) 6.7 Hz, 3 H, 13-H),
0.90 (d, J ) 6.0 Hz, 3 H, 9-H), 0.87 (d, J ) 6.0 Hz, 3 H, 10-H);
13C NMR (75 MHz, CDCl3) δ 158.4 (HCdN), 141.9, 136.7 (2 x
C-i), 128.6, 128.1, 126.3, 71.8 (C-3), 62.3 (C-2), 51.8 (NCH2-
Ph), 50.9 (C-6), 49.9 (C-4), 39.8 (C-5), 29.1 (C-11), 24.1, 23.4,
22.4, 20.4, 19.8 (C-12, C-13, C-8, C-9, C-10), 19.8 (C-7); MS
(EI) m/ z 376 (M, 8), 333 (6), 319 (8), 272 (7), 238 (13), 91 (100);
HRMS calcd for C26H36N2 376.2878, found 376.2866. Anal.
Calcd for C26H36N2: C, 82.93; H, 9.64; N, 7.44. Found: C,
82.94; H, 9.61; N, 7.51.
(2S,3S,4R)-N-Ben zyl-3-(N-ben zyla m in o)-3-isop r op en yl-
2-(2-m eth ylp r op yl)p ip er id in e (18b): 329 mg (0.88 mmol,
66%) of a yellow oil; [R]22 +16.3 (c ) 1.00; CHCl3); IR (film)
D
3322, 1456, 738, 699 cm-1; 1H NMR (200 MHz, CDCl3) δ 7.28-
7.07 (m, 10 H, 2 x Ph), 4.77 (s, broad, 1 H, 12a-H), 4.63 (s,
broad, 1 H, 12b-H), 3.68 (d, J ) 13.3 Hz, 1 H, NHCH2Ph), 3.56
(d, broad, J ) 3.5 Hz, 2 H, NCH2Ph), 3.45 (d, J ) 13.3 Hz, 1
H, NHCH2Ph), 2.89-2.81 (m, 1 H, 2-H), 2.55-2.41 (m, 2 H),
2.12 (d, broad, J ) 13.8 Hz, 1 H), 1.87-1.63 (m, 1 H), 1.51 (s,
3 H, 13-H), 1.40-1.23 (m, 5 H), 0.77 (d, J ) 6.0 Hz, 3 H, 9-H),
0.68 (d, J ) 6.0 Hz, 3 H, 10-H); 13C NMR (50 MHz, CDCl3) δ
147.6 (C-11) 141.2, 140.0, 128.5, 128.2, 128.0, 126.7, 126.5,
110.2 (C-12), 58.7 (NHCH2Ph), 56.3 (C-2), 55.3 (C-3), 52.1
(NCH2Ph), 45.6 (C-6), 40.6 (C-4), 31.8 (C-8), 25.8 (C-5), 24.4
(C-7), 23.8 (C-9), 22.0 (C-10), 21.9 (C-13); MS (EI) m/ z 376
(M, 5), 238 (14), 202 (17), 188 (18), 158 (20), 91 (100), 83 (23);
HRMS calcd for C26H36N2 376.2878, found 376.2866. Anal.
Calcd for C26H36N2: C, 82.93; H, 9.64; N, 7.44. Found: C,
82.88; H, 9.60; N, 7.52.
N-Ben zyl-2-(2-b en zyl)-3-(N-b en zylid en ea m in o)-3-iso-
p r op ylp ip er id in e (20c, 21c): 70 mg (0.17 mmol, 17%) of a
yellow oil as first fraction (95.2% 21c by GC, tR ) 31.3 min)
and 205 mg (0.50 mmol, 50%) of a yellow oil as second fraction
(98.7% 20c by GC, tR ) 34.7 min). GC conditions: isotherm
at 280 °C.
(2S,3S,4R)-Isom er 20c: [R]22 -8.0 (c ) 1.00; CHCl3); IR
D
(film) 1642, 1494, 1451, 732, 696 cm-1
;
1H NMR (200 MHz,
CDCl3) δ 8.01 (s, broad, 1 H, HCdN), 7.77-7.73 (m, 2 H),
7.40-7.35 (m, 3 H), 7.26-7.06 (m, 10 H, 3 x Ph), 4.03 (d, J )
14.5 Hz, 1 H, NCH2Ph), 3.70 (d, J ) 14.5 Hz, 1 H, NCH2Ph),
3.29 (s, broad, 1 H, 3-H), 3.23 (dd, J ) 8.2 Hz, 1 H, 2-H), 3.01
(dd, J ) 13.4, 3.4 Hz, 1 H), 2.88 (dd, J ) 14.2, 6.2 Hz, 1 H),
2.63-2.47 (m, 2 H), 2.08-1.84 (m, 1 H), 1.66-1.47 (m, 1 H),
1.31-1.14 (m, 3 H), 0.71 (d, J ) 5.8 Hz, 3 H, 9-H), 0.65 (d, J
) 5.8 Hz, 3 H, 10-H); 13C NMR (50 MHz, CDCl3) δ 159.7
(HCdN), 141.0, 139.4, 136.5 (3 x C-i), 130.3, 129.3, 128.9,
128.6, 128.3, 128.1, 128.0, 126.4, 125.9, 69.9 (C-3), 65.6 (C-2),
53.4 (C-6), 51.5 (NCH2Ph), 49.6 (C-4), 37.2 (C-7), 28.9 (C-8),
20.4 (C-5), 20.3 (C-9), 19.9 (C-10); MS (EI) m/ z 410 (M, 3),
365 (4), 319 (37), 214 (29), 202 (15), 91 (100); HRMS calcd for
C29H34N2 410.2722, found 410.2711. Anal. Calcd for
C29H34N2: C, 84.83; H, 8.35; N, 6.82. Found: C, 84.83; H, 8.40;
N, 6.77.
(2S,3S,4R)-N-Ben zyl-2-(2-ben zyl)-3-(N-ben zyla m in o)-3-
isop r op en ylp ip er id in e (18c): 168 mg (0.41 mmol, 41%) of
a yellow oil; [R]22 -15.7 (c ) 1.00; CHCl3); IR (film) 3317,
D
1494, 1453, 736, 698 cm-1; 1H NMR (200 MHz, CDCl3) δ 7.39-
7.16 (m, 8 H), 7.06-7.03 (m, 3 H), 6.94-6.89 (m, 2 H), 6.78-
6.75 (m, 2 H, 3 x Ph), 4.78 (s, 1 H, 9a-H), 4.66 (s, 1 H, 9b-H),
3.75 (s, broad, 2 H, NCH2Ph), 3.40 (d, J ) 13.2 Hz, 1 H,
NHCH2Ph), 3.08 (d, J ) 13.2 Hz, 1 H, NHCH2Ph), 3.12-3.05
(m, 1 H, 2-H), 2.92 (dd, J ) 13.1, 3.7 Hz, 1 H, 6eq-H), 2.70-
2.60 (m, 3 H, NH, 7-H), 2.41 (s, broad, 1 H, 3-H), 2.32 (d, broad,
J ) 13.0 Hz, 1 H, 5eq-H), 1.97-1.75 (m, 2 H, 4-H, 6ax-H),
1.45 (d, broad, J ) 13.0 Hz, 1 H, 5ax-H), 1.28 (s, 3 H, 10-H);
13C NMR (50 MHz, CDCl3) δ 146.4 (C-8), 140.6, 140.2, 139.3
(3 x C-i), 128.7, 128.5, 128.4, 128.3, 128.1, 127.7, 126.9, 126.2,
125.6 (3 x C-p), 109.9 (C-9), 61.8 (C-2), 59.9 (C-2), 58.8 (NHCH2-
Ph), 51.7 (C-3), 51.3 (NCH2Ph), 46.2 (C-6), 40.2 (C-4), 28.4 (C-
7), 24.6 (C-5), 21.4 (C-10); MS (EI) m/ z 410 (M, 6), 319 (39),
303 (6), 224 (26), 214 (34), 200 (32), 91 (100), 83 (34); HRMS
calcd for C29H34N2 410.2722, found 410.2711. Anal. Calcd for
C29H34N2: C, 84.83; H, 8.35; N, 6.82. Found: C, 84.80; H, 8.39;
N, 6.81.
(2S,3R,4S)-Isom er 21c: [R]22 -83.4 (c ) 1.00; CHCl3); IR
D
(film) 1643, 732, 695 cm-1; 1H NMR (200 MHz, CDCl3) δ 7.86
(s, broad, 1 H, HCdN), 7.63-7.58 (m, 2 H), 7.27-6.94 (m, 13
H, 3 x Ph), 3.78 (s, broad, 1 H, NCH2Ph), 3.76 (s, broad, 1 H,
NCH2Ph), 3.24 (s, broad, 2 H, 7-H), 3.20-2.45 (m, 3 H), 1.96
(ddd, J ) 12.9, 12.9, 4.8 Hz, 2 H), 1.57-1.13 (m, 3 H), 0.78 (d,
J ) 6.4 Hz, 3 H, 9-H), 0.62 (d, J ) 6.4 Hz, 3 H, 10-H); 13C
NMR (50 MHz, CDCl3) δ 158.4 (HCdN), 140.8, 140.2, 137.0
(3 x C-i), 130.0, 129.1, 128.6, 128.4, 128.2, 128.0, 127.9, 126.5,
125.7, 67.4 (C-3), 66.9 (C-2), 59.3 (C-6), 46.8 (NCH2Ph), 42.3
(C-4), 32.8 (C-7), 28.8 (C-8), 23.4 (C-5), 20.6 (C-9), 19.9 (C-10);
MS (EI) m/ z 410 (M, 4), 367 (3), 319 (41), 214 (31), 202 (14),
158 (24), 91 (100); HRMS calcd for C29H34N2 410.2722, found
410.2711. Anal. Calcd for C29H34N2: C, 84.83; H, 8.35; N,
6.82. Found: C, 84.87; H, 8.38; N, 6.75.
1H and 13C NMR signals of the minor isomers 19a -c, 21a ,b,
and 23a from crude products were only incompletely visible.
(2S,3S,4R)-N-Ben zyl-3-(N-ben zylid en ea m in o)-3-isop r o-
p yl-2-m eth ylp ip er id in e (20a ): 267 mg (0.80 mmol, 80%) of
a yellow oil; [R]22 -58.3 (c ) 1.00; CHCl3); IR (film) 1642,
D
1451, 1384, 757, 732, 706, 693 cm-1
;
1H NMR (300 MHz,
(2SR,3RS,4SR)-3-(N-Ben zyla m in o)-2-(2-m eth yl)-3-iso-
p r op en yl-N-tosylp ip er id in e (22a ): 167 mg (0.42 mmol, 42%)
of an orange oil; IR (film) 3397, 1456, 1336, 1156, 1095, 667,
657 cm-1; 1H NMR (200 MHz, CDCl3) δ 7.65 (d, J ) 8.1 Hz, 2
H, 2′-H, 6′-H), 7.16-7.04 (m, 7 H, 3′-H, 5′-H, Ph), 4.74 (s, broad,
1 H, 9a-H), 4.51 (s, broad, 1 H, 9b-H), 4.28 (ddd, J ) 6.8 Hz,
1 H, 2-H), 3.73 (d, J ) 13.3 Hz, 1 H, HNCH2Ph), 3.53 (dd, J )
12.6, 12.6 Hz, 1 H, H-6eq), 3.41 (d, J ) 13.3 Hz, 1 H, HNCH2-
Ph), 3.67-3.36 (m, 1 H, 3-H), 3.27-2.94 (m, 2 H, 6ax-H, NH),
CDCl3) δ 8.06 (s, 1 H, HCdN), 7.67-7.64 (m, 2 H), 7.27-7.03
(m, 8 H), 3.80 (d, J ) 14.0 Hz, 1 H, NCH2Ph), 3.31 (d, J )
14.0 Hz, 1 H, NCH2Ph), 3.12 (s, broad, 1 H, 3-H), 2.90 (ddd, J
) 11.4, 3.5, 2.9 Hz, 1 H, 6a-H), 2.60 (dddd, J ) 6.7, 6.7, 6.7,
2.1 Hz, 1 H, 2-H), 2.20 (ddd, J ) 12.6, 12.6, 2.8 Hz, 1 H, 6b-
H), 1.88 (dddd, J ) 12.9, 2.4, 2.4, 2.4 Hz, 1 H, 5a-H), 1.33 (dd,
J ) 12.9, 2.4 Hz, 1 H, 5b-H), 1.17-1.02 (m, 2 H, 8-H, 4-H),
0.89 (d, J ) 6.7 Hz, 3 H, 7-H), 0.67 (d, J ) 6.4 Hz, 3 H, 9-H),

2838 J . Org. Chem., Vol. 61, No. 8, 1996
Laschat et al.
2.85 (ddd, J ) 13.1, 13.1, 2.8 Hz, 1 H, 4-H), 2.52-2.22 (m, 1
H, 5eq-H), 2.21 (s, 3 H, tosyl-CH3), 1.81-0.80 (m, 1 H, 5ax-
H), 1.40 (s, 3 H, 10-H), 0.93 (d, J ) 6.8 Hz, 3 H, 7-H); 13C NMR
(50 MHz, CDCl3) δ 145.7 (C-8), 142.6, 140.2 (2 x C-i), 138.3,
129.3, 128.2, 128.1, 127.0, 126.7, 111.6 (C-9), 56.2 (C-2), 51.1
(HNCH2Ph), 49.6 (C-3), 40.0 (C-4), 39.5 (C-6), 23.7 (C-5), 21.6
(Tosyl-CH3), 21.3 (C-10), 14.7 (C-7); MS (EI) m/ z 398 (M, 7),
375 (4), 360 (6), 321 (5), 243 (37), 200 (39), 155 (27), 138 (53),
91 (100); HRMS calcd for C23H30N2O2S 398.2028, found
398.2019. Anal. Calcd for C23H30N2O2S: C, 69.31; H, 7.59;
N, 7.03. Found: C, 69.52; H, 7.50; N, 7.11.
(50 MHz, CDCl3) δ 159.9 (HCdN), 142.2, 138.6 (2 x C-i), 136.3,
130.5, 129.2, 128.5, 128.4, 127.7, 68.6 (C-3), 58.7 (C-2), 41.6
(tosyl-CH3), 40.8 (C-6), 39.6 (C-5), 28.3 (C-4), 24.9 (C-11), 23.9
(C-7), 22.8, 21.5 (C-8, C-9, C-10), 20.4 (C-12), 19.8 (C-13); MS
(EI) m/ z 440 (M, 7), 383 (15), 285 (95), 182 (100), 155 (32),
100 (55), 91 (96), 83 (30); HRMS calcd for C26H36N2O2S
440.2497, found 440.2487. Anal. Calcd for C26H36N2O2S: C,
70.87; H, 8.23; N, 6.36. Found: C, 70.85; H, 8.27; N, 6.39.
(2SR,3RS,4SR)-2-(2-Ben zyl)-3-(N-b en zylid en ea m in o)-
3-isop r op yl-N-tosylp ip er id in e (23c): 209 mg (0.44 mmol,
44%) of a yellow, amorphous solid; [R]22 -1.3 (c ) 1.00;
D
CHCl3); IR (film) 1644, 1320, 1157, 1093, 696, 687, 656 cm-1
;
(2S,3R,4S)-3-(N-Ben zyla m in o)-2-(2-m et h ylp r op yl)-3-
isop r op en yl-N-tosylp ip er id in e (22b): 334 mg (0.76 mmol,
1H NMR (200 MHz, CDCl3) δ 7.83 (s, broad, 1 H, HCdN), 7.58
(d, J ) 8.3 Hz, 2 H, 2′-H, 6′-H), 7.47-7.42 (m, 2 H), 7.29-6.94
(m, 8 H, 2 x Ph), 6.98 (d, J ) 8.3 Hz, 2 H, 3′-H, 5′-H), 4.02-
3.94 (m, 1 H, 3-H), 3.64 (dd, J ) 13.4, 2.6 Hz, 1 H, 2-H), 3.28
(m, 1 H), 3.24-3.11 (m, 1 H), 3.03-2.91 (m, 2 H), 2.19 (s, 3 H,
tosyl-CH3), 1.78 (ddd, J ) 12.8, 12.8, 4.7 Hz, 1 H), 1.54-1.40
(m, 3 H), 0.73 (d, J ) 6.6 Hz, 3 H, 9-H), 0.59 (d, J ) 6.6 Hz, 3
H, 10-H); 13C NMR (50 MHz, CDCl3) δ 160.1 (HCdN), 142.3,
138.3, 136.2 (3 x C-i), 130.4, 129.4, 129.1, 128.6, 128.3, 128.2,
127.3, 126.5, 65.2 (C-3), 62.1 (C-2), 41.2 (C-4), 41.2 (C-7), 37.3
(C-6), 28.1 (C-8), 23.9 (C-5), 21.4 (tosyl-CH3), 19.7 (C-9), 17.7
(C-10); MS (EI) m/ z 474 (M, 7), 459 (8), 383 (69), 319 (35),
266 (33), 227 (51), 91 (100), 83 (48); HRMS calcdfor C29H34N2O2S
474.2341, found 474.2351. Anal. Calcd for C29H34N2O2S: C,
73.38; H, 7.22; N, 5.90. Found: C, 73.39; H, 7.30; N, 5.92.
(2S,3S,4R)-3-Am in o-4-isop r op yl-2-(2-m eth ylp r op yl)p i-
p er id in e (27). To a (1:1) mixture of piperidines 18b and 20b
(400 mg, 1.06 mmol) in MeOH (10 mL) was added under argon
PdCl2 (188 mg, 1.06 mmol), and the remaining mixture was
presaturated (3×) with H2 and then stirred under H2 at 1 atm
for 48 h at room temperature. The mixture was filtered
through Celite via a fritted funnel, and the solvent was
76%) of a yellow oil; [R]22 +60.1 (c ) 1.00; CHCl3); IR (film)
D
3330, 1336, 1154, 1094, 736, 667, 663 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.81 (d, J ) 8.3 Hz, 2 H, 2′-H, 6′-H), 7.41-7.09 (m,
5 H, Ph), 7.16 (d, J ) 8.3 Hz, 2 H, 3′-H, 5′-H), 4.86 (dd, J )
1.2, 1.5 Hz, 1 H, 12a-H), 4.60 (d, J ) 1.4 Hz, 1 H, 12b-H), 4.37
(dd, broad, J ) 6.7 Hz, 1 H, 2-H), 3.92 (d, J ) 13.3 Hz, 1 H,
NHCH2Ph), 3.60 (d, J ) 13.3 Hz, 1 H, NHCH2Ph), 2.97 (ddd,
J ) 10.5, 10.5, 2.9 Hz, 1 H, 6eq-H), 2.61 (dd, J ) 2.2 Hz, 1 H,
6ax-H), 2.35 (s, 3 H, tosyl-CH3), 1.81-1.53 (m, 3 H, 3-H, 4-H,
NH), 1.53 (s, 3 H, 13-H), 1.33-1.21 (m, 2 H, 7-H), 1.09-0.97
(m, 2 H, 8-H, 5eq-H), 0.94 (d, J ) 6.6 Hz, 3 H, 9-H), 0.88 (d, J
) 6.6 Hz, 3 H, 10-H), 0.78 (dd, J ) 8.6 Hz, J ) 6.7 Hz, 1 H,
5ax-H); 13C NMR (75 MHz, CDCl3) δ 145.8 (C-11), 142.5, 140.3
(2 x C-i), 138.6, 129.2, 128.2, 127.3, 126.7, 111.4 (C-12), 68.6
(C-2), 58.7 (C-3), 54.4 (C-4), 52.7 (NCH2Ph), 40.6 (tosyl-CH3),
40.0 (C-6), 38.3 (C-5), 25.1 (C-8), 23.3 (C-7), 22.7 (C-9, C-10),
21.6 (C-13); MS (EI) m/ z 440 (M, 6), 383 (4), 285 (19), 200
(33), 180 (53), 91 (100); HRMS calcd for C26H36N2O2S 440.2497,
found 440.2487. Anal. Calcd for C26H36N2O2S: C, 70.87; H,
8.23; N, 6.36. Found: C, 70.90; H, 8.25; N, 6.32.
(2SR,3RS,4SR)-2-(2-Ben zyl)-3-(N-b en zyla m in o)-3-iso-
p r op en yl-N-tosylp ip er id in e (22c): 247 mg (0.52 mmol, 52%)
evaporated to yield 210 mg (quant) of a pale yellow oil; [R]22
D
of a yellow oil; [R]22 -0.8 (c ) 1.00; CHCl3); IR (film) 3318,
-3.7 (c ) 1.00; MeOH); IR (film) 3381, 1469, 1027 cm-1; H
1
D
1304, 1279, 1266, 1156, 1149, 1093, 816, 752, 716 cm-1
;
1H
NMR (200 MHz, CD3OD) δ 5.26 (s, 3 H), 3.68-3.62 (m, 1 H),
3.51-3.14 (m, 2 H), 3.08-2.95 (m, 1 H), 2.14-2.01 (m, 1 H),
1.87-1.52 (m, 5 H), 1.28-1.20 (m, 1 H), 0.99-0.89 (m, 9 H)
0.88 (d, J ) 6.6 Hz, 3 H); 13C NMR (50 MHz, CD3OD) δ 54.1,
50.8, 40.9, 38.7, 37.8, 28.3, 25.6, 23.1, 22.6, 21.6, 21.1, 20.7;
MS (EI) m/ z 198 (M, 41), 170 (64), 141 (60), 128 (66), 114 (81),
99 (81), 83 (81), 56 (100). In order to obtain correct elemental
analysis the amine 27 was converted to the corresponding
hydrobromide. Anal. Calcd for C12H27N2Br: C, 51.61; H, 9.75;
N, 10.03. Found: C, 51.68; H, 9.71; N, 10.14.
NMR (200 MHz, CDCl3) δ 7.61 (d, J ) 8.2 Hz, 2 H, 2′-H, 6′-
H), 7.19-6.99 (m, 10 H, 2 x Ph), 6.71-6.69 (m, 2 H, 3′-H, 5′-
H), 4.70 (s, broad, 1 H, 9a-H), 4.48 (s, broad, 1 H, 9b-H), 4.35
(dd, J ) 7.5 Hz, 1 H, 2-H), 3.66-3.50 (m, 1 H), 3.53 (d, J )
13.7 Hz, 1 H, HNCH2Ph), 3.09 (d, J ) 13.7 Hz, 1 H, HNCH2-
Ph), 2.97 (dd, J ) 10.5 Hz, 1 H), 2.79 (s, broad, 1 H, 7a-H),
2.75 (s, broad, 1 H, 7b-H), 2.43 (s, broad, 1 H, 4-H), 2.30-2.19
(m, 1 H), 1.66 (ddd, J ) 13.0, 13.0, 4.6 Hz, 1 H), 1.55-1.08
(m, 2 H), 1.14 (s, 3 H, 10-H); 13C NMR (50 MHz, CDCl3) δ 145.8
(C-8), 142.7, 140.0 (2 x C-i), 138.4, 129.4, 129.1, 128.7, 128.4,
127.9, 127.2, 126.5, 111.4 (C-9), 56.2 (C-2), 50.6 (HNCH2Ph),
50.6 (C-3), 40.5 (C-7), 40.4 (C-4), 35.9 (C-6), 23.4 (C-5), 21.4
(tosyl-CH3), 21.2 (C-10); MS (EI) m/ z 474 (M, 14), 383 (20),
319 (28), 214 (67), 200 (57), 155 (29), 91 (100); HRMS calcd
for C29H34N2O2S 474.2341, found 474.2351. Anal. Calcd for
C29H34N2O2S: C, 73.38; H, 7.22; N, 5.90. Found: C, 73.41; H,
7.23; N, 5.88.
(2S,3R,4S)-3-(N-Ben zylid en ea m in o)-3-isop r op yl-2-(2-
m eth ylp r op yl)-N-tosylp ip er id in e (23b): 52 mg (0.12 mmol,
12%) of a colorless oil; [R]22D +66.5 (c ) 1.00; CHCl3); IR (film)
1645, 1150, 715, 696, 656 cm-1; 1H NMR (200 MHz, CDCl3) δ
8.31 (s, 1 H, HCdN), 7.76 (d, J ) 8.2 Hz, 2 H, 2′′-H, 6′′-H),
7.42-7.39 (m, 2 H), 7.25-7.24 (m, 3 H), 7.11 (d, J ) 8.2 Hz, 2
H, 3′′-H, 5′′-H), 3.96 (dd, J ) 7.3 Hz, 1 H, 2-H), 3.60 (dd, J )
13.5, 3.3 Hz, 1 H, 6eq-H), 3.38 (s, broad, 1 H, 3-H), 3.16 (dt, J
) 13.3, 3.0 Hz, 1 H, 7b-H), 2.35 (s, 3 H, tosyl-CH3), 1.85-1.07
(m, 7 H), 1.00 (d, J ) 6.2 Hz, 3 H, 12-H), 0.97 (d, J ) 6.2 Hz,
3 H, 13-H), 0.78 (dd, J ) 6.4 Hz, 6 H, 9-H, 10-H); 13C NMR
Ack n ow led gm en t. Generous financial support by
the Alfried Krupp von Bohlen und Halbach-Stiftung and
the Fonds der Chemischen Industrie is gratefully ac-
knowledged. S.L. thanks the Wissenschaftsministerium
des Landes Nordrhein-Westfalen for a Lise Meitner-
fellowship. We would like to thank Marianne Kalic,
Karin Busse, and Dirk Ro¨ttger for performing the NMR
experiments.
Su p p or tin g In for m a tion Ava ila ble: 13C NMR (APT)
spectra of compounds 11a -c, 12a -c, 15a -c, and 16a -c (13
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS, see any current
masthead page for ordering information.
J O951482D