Diastereoselective allylation of chiral imines and a stereocontrolled route to 4-hydroxy-N-tosylpipecolic acid derivatives

Article abstract of DOI:10.1016/S0957-4166(02)00542-6

We report an asymmetric route to non-proteogenic amino acids, based on Lewis acid-mediated diastereoselective additions of allyltrimethylsilane to iminoglyoxylic acid derivatives bearing ester or amide chiral auxiliaries. Reactions of allyltrimethylsilane

Full text of DOI:10.1016/S0957-4166(02)00542-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2061–2069
Diastereoselective allylation of chiral imines and a
stereocontrolled route to 4-hydroxy-N-tosylpipecolic acid
derivatives
Anna Kulesza,a Adam Mieczkowskia and Janusz Jurczaka,b,
*
aDepartment of Chemistry, Warsaw University, Pasteura 1, PL-02-093 Warsaw, Poland
bInstitute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, PL-01-224 Warsaw, Poland
Received 25 July 2002; accepted 4 September 2002
Abstract—We report an asymmetric route to non-proteogenic amino acids, based on Lewis acid-mediated diastereoselective
additions of allyltrimethylsilane to iminoglyoxylic acid derivatives bearing ester or amide chiral auxiliaries. Reactions of
allyltrimethylsilane with N-tosyl- and N-phenyliminoglyoxylates of (R)-8-phenylmenthol proceeded with excellent diastereoselec-
tivity (d.e. 98%). In contrast, the reactions of N-benzyliminoglyoxylates occurred with low diastereoselectivities and in poor yields.
We have applied our methodology to develop a short synthesis of (2S,4R)-4-hydroxypipecolic acid derivatives. © 2002 Published
by Elsevier Science Ltd.
1. Introduction
lective fashion (external ligands like oxazolidinones7 or
ephedrines8) or a chiral nucleophile (allylboranes9) led
to improvement in the selectivity and yield.
Chiral non-proteogenic amino acids and their deriva-
tives are important building blocks in organic synthe-
sis.1 They also play a crucial role as structural features
in bioactive natural products and pharmaceutically
important compounds. Many enantio- and diastereose-
lective 1,2-nucleophilic additions of organometallic
compounds to imines involving Grignard reagents and
organozinc compounds have been exploited.2 In such
reactions, the use of highly nucleophilic organometallic
reagents is dictated by the low electrophilicity of the
CꢀN group in comparison to the CꢀO group. In many
cases, the choice of nucleophile is very limited as a
result of the possibility of enamine formation and
reduction to an amine.
Another factor complicating additions to the imine
functionality is the possibility of geometric isomers
around the carbonꢁnitrogen double bond as each of
these isomers may lead to a different stereoisomer of
the product.10
Hetero-Diels–Alder reactions of N-tosyl imines of N-
glyoxyloyl-(2R)-bornano-10,2-sultam with various
dienes were recently investigated in our group and
showed very good diastereofacial differentiation.11 In
our previous reports on the stereoselectivity of the
nucleophilic addition12 and hetero-Diels–Alder reac-
tions of N-glyoxyloyl-(2R)-bornano-10,2-sultam13,14 we
described a stereochemical rationalization for the asym-
metric induction and the advantages of (2R)-bornano-
10,2-sultam as a chiral auxiliary. The 10-N,N-dicyclo-
hexylsulfamoyl-(R)-isobornyl glyoxylate was found to
be less beneficial (in terms of diastereoselectivity) in the
nucleophilic addition of the allyltrimethylsilane to the
carbonyl group.15 Recently, we have also published the
preliminary results from our study into the addition
of allyltrimethylsilane to the N-tosylimine of (R)-8-
phenylmenthyl glyoxylate.16
Several methods have been developed to overcome this
problem. Activation of the CꢀN bond by incorporation
of electron-withdrawing substituents and coordination
of nitrogen with a Lewis acid has been investigated.3
The use of organometallic nucleophiles of low basicity
such as organocerium or organocuprate reagents4
instead of Grignard and lithium reagents, use of the
Barbier procedure,5 and an allyltin nucleophile6 have
been examined. Introduction of a ligand that would
chelate the organometallic nucleophile in an enantiose-
Thus, we decided to examine the asymmetric 1,2-addi-
tion of allyltrimethylsilane to glyoxylimines as a poten-
* Corresponding author. Tel.: +48-22-823-0944; fax: +48-22-822-5996;
e-mail: jjurczak@chem.uw.edu.pl
0957-4166/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0957-4166(02)00542-6

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A. Kulesza et al. / Tetrahedron: Asymmetry 13 (2002) 2061–2069
tial method for the stereoselective synthesis of a-allyl-
phenylmenthyl ester 2b. Comparable chemical yields,
with substantially lower diastereoselectivities, were
obtained in the addition of allyltrimethylsilane to the
imine of N-glyoxyloyl-(2R)-bornano-10,2-sultam 2a.
Addition to the N-tosylimine of the glyoxylate of 10-
N,N-dicyclohexylsulfamoyl-(R)-isobornyl 2c led to an
excess of the (2%R)-diastereoisomer with good
diastereoselectivity.
amino acids.
2. Results and discussion
2.1. Preparation of imines
The N-tosylimines were obtained from the correspond-
ing derivatives of glyoxylic acid by a method intro-
duced recently by Holmes et al.17 The reaction of
compounds 1a, 1b, and 1c with p-toluenesulfonyl isocy-
anate in refluxing toluene afforded the expected imines
2a, 2b, and 2c, respectively (Scheme 1).
N-Benzyl imines 3a, 3b and 3c were obtained according
to the method introduced by Stella18 using the trifluoro-
acetic acid-catalyzed reaction of glyoxylates and benzyl-
Scheme 2.
amine in methylene chloride as
a solvent. N-
The absolute configurations—(2%S) of 6a and (2%R) of
5c—were determined by X-ray analysis (Figs. 1 and 2,
respectively). The relative configuration of adduct 6b
was obtained by converting it into the known com-
pound 7 (Scheme 3).
Phenylimines 4a, 4b and 4c were obtained by reacting
the corresponding glyoxylates with aniline, in the pres-
,
ence of 4 A molecular sieves as a dehydrating agent.
2.2. Addition of allyltrimethylsilane to imines
The N-tosyl-, N-benzyl-, and N-phenylimines, obtained
according to the above procedures, were used in situ for
the nucleophilic addition. We investigated several Lewis
acids as imine-activating agents (Table 1, Scheme 2) for
additions to N-tosylimines. The representative data is
presented in Table 1. Stronger, chelating Lewis acids
(ZnBr2, ZnCl2, SnCl4, TiCl4) generally gave better
yields and selectivities than weaker, non-chelating ones
(e.g. BF3·Et2O). Among chiral auxiliaries, the best yield
and total diastereoselectivity was obtained for (R)-8-
Scheme 3.
In contrast to N-tosylimines, reaction of allyltrimethyl-
silane with N-benzylimines 3a, 3b and 3c gave lower
yields and diastereoselectivities (Scheme 4, Table 2).
Scheme 1.

A. Kulesza et al. / Tetrahedron: Asymmetry 13 (2002) 2061–2069
Table 1. Results of the addition of allyltrimethylsilane to N-tosylimines
2063
Lewis acid
N-Tosyl imine
Yielda (%)
D.e. (%)
Abs. conf.
Yielda (%)
D.e. (%)
Abs. conf.
Yielda (%)
D.e. (%)
Abs. conf.
BF3·Et2O
ZnCl2
ZnBr2
TiCl4
35
60
65
60
90
60
80
78
52
68
S
S
S
S
S
25
60
50
72
60
8
96
96
96
96
S
S
S
S
S
0
61
60
56
0
66
60
52
R
R
R
SnCl4
a Yields calculated for two steps: formation of imine and addition of allyltrimethylsilane.
Figure 1. Crystal structure of (S)-N-tosylallylglycine (2R)-bornano-10,2-sultam imide 6a.
However, compound 3b (with an (R)-8-phenylmenthyl
auxiliary), seemed to provide the best diastereoselectivi-
ties. No product was observed in the reaction with
imine 3a derived from Oppolzer’s chiral auxiliary. In all
of these reactions, the main by-product was the amine
of the type A resulting from reduction of the CꢀN
bond.
The N-phenylimines 4a, 4b, and 4c were reacted with
allyltrimethylsilane in the presence of SnCl4 giving the
allyl-adduct as the major product (Scheme 5, Table 3).
We also detected traces of tetrahydroquinoline deriva-
tives of type B. Formation of this compound was reported
in the reactions of allyltrimethylsilane to diphenylimines
19
,
in the presence of Lewis acid and 4 A molecular sieves.
Scheme 4.

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A. Kulesza et al. / Tetrahedron: Asymmetry 13 (2002) 2061–2069
Figure 2. Crystal structure of (R)-N-tosylallylglycine 10-N,N-dicyclohexylosulfamoyl-(2R)-isobornyl ester 5c.
Table 2. Results of the addition of allyltrimethylsilane to
N-benzylimines
Table 3. Results of the addition of allyltrimethylsilane to
N-phenylimines
N-Benzylimine
Yield (%)
D.e. (%)
N-Phenylimine
Yield (%)
D.e. (%)
3a
3b
3b
0
23
20
–
72
15
4a
4b
4c
60
71
55
62
\95
10
Several concepts can be considered for the rationaliza-
tion of diastereoselectivities in the reactions of gly-
oxylimines with allyltrimethylsilane described in this
work. One explanation, concerning reaction with the
N-tosylimine of N-glyoxyloyl-(2R)-bornano-10,2-sul-
tam 2a, is analogous to the proposed rationale for the
hetero Diels–Alder reaction that was based on two
concepts (Fig. 3): (a) the sterically controlled approach
of the thermodynamically more stable SO2/CO
antiperiplanar, CO/CHNTs s-cis planar conformer C,
as proposed by Oppolzer et al.20 and by Curran et al.21
for N-acryloyl- and N-crotonoyl-(2R)-bornano-10,2-
sultam; and (b) the high reactivity of the less stable
SO2/CO synperiplanar, CO/CHNTs s-cis planar con-
former D, reinforced by the cooperative stereoelectronic
effect, as recently formulated by Chapuis et al.13,14 for
N-glyoxyloyl-(2R)-bornano-10,2-sultam 1a. The con-
formational equilibrium may be even more complicated
in view of, as recently proposed by Pindur et al.,22 the
reactive SO2/CO antiperiplanar, CO/CHNTs s-trans
planar conformation E.
Since the sultam ring in N-glyoxyloyl-(2R)-bornano-
10,2-sultam 1a has a large impact on the conformation
in the transition state (due to both electronic and steric
effects), we decided to use an auxiliary that lacks the
rigidity of sultam 1a in the stereodifferentiating moiety,
the 10-N,N-dicyclohexylsulfamoyl-(R)-isobornyl gly-
oxylate 1c (Fig. 4). The electronic interactions between
SO2 and CO that determine the conformation of 2a
Scheme 5.

A. Kulesza et al. / Tetrahedron: Asymmetry 13 (2002) 2061–2069
2065
Figure 3.
unsaturated reacting site. We postulate the same model
for addition of allyltrimethylsilane to N-tosyl-,
N-benzyl- and N-phenylimines of (R)-8-phenylmenthyl
glyoxylate 1b to explain the approach from the pro-S
side of the CꢀN bond, which is the most favorable
because the pro-R side is effectively shielded by the aryl
moiety.
have no influence on the conformation of 2c. The
reaction center, being subject to less steric restriction,
has the pro-R side of the reacting site less hindered.
Another stereodifferentiating effect has its origin in the
p–p stacking effect of the (R)-8-phenylmenthyl moiety
(Fig. 5). It provides excellent asymmetric induction in
the reactions of its various derivatives such as acrylates,
acetamidoacrylates, glyoxylates and many others.23 The
excellent stereoselection is believed to benefit from face
to face p–p interaction between the aryl moiety and the
2.3. Diastereoselective synthesis of (2S,4R)-4-hydroxy-
pipecolic acid derivatives
Pipecolic acid derivatives are useful intermediates for
the preparation of many biologically important
compounds such as immunosuppressants, enzyme
inhibitors, cyclopeptide antibiotics,24 virginiamycin S2,
as well as NMDA antagonists.25 The naturally
occurring (2S,4R)-4-hydroxypipecolic acid 12 (Fig. 6)
was used as a building block in the synthesis of
palinavir 13, a potent HIV protease inhibitor.26 In the
past few years several stereoselective preparations of 12
have been reported.27
Having in hand the allylic adduct bearing a chiral
auxiliary, we subjected it to cyclization conditions to
obtain in one step the corresponding derivative of
(2%S,4%R)-4-hydroxypipecolic acid 14 in 65% yield
(Scheme 6). We also obtained its 4%-epimer 15 as the
minor diastereoisomer (d.e. ratio 1.7:1). The reaction
pathway involves formation of an acyliminium cation,
followed by cyclization that produces a carbocation at
C-4%. The carbocation transition state affects and
eventually lowers the stereoselectivity at the newly
formed stereogenic center. The long-distance steric
interactions with the chiral auxiliary have no influence
on the asymmetric induction.
Figure 4.
Figure 5.
Figure 6.

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A. Kulesza et al. / Tetrahedron: Asymmetry 13 (2002) 2061–2069
Scheme 6.
The relative configuration of the newly formed stereo-
genic center was established unambiguously by a series
of 1H NMR experiments. The J-coupling constants
indicate an axial position for H-4% and, accordingly, the
4%R-configuration was assigned.
moyl-(2R)-isobornyl glyoxylate 1c (146 mg, 0.32 mmol)
in DCM or toluene, TiCl4 (1 M, 5 ml, 0.32 ml, 0.32
mmol) was added at rt (the reactions with other Lewis
acids were carried out according to this procedure).
After 5 min, AllSiMe3 (0.64 mmol, 0.1 ml) was added
dropwise at rt. The reaction was stirred for 12 h and
then worked up with NaHCO3, and extracted with
DCM. The organic extracts were combined, dried over
MgSO4, and evaporated under reduced pressure. The
product was purified by flash chromatography using 5%
EtOAc–toluene as eluent affording the separate
diastereoisomers.
3. Experimental
Reagent grade solvents (CH2Cl2, hexanes, EtOAc,
THF) were distilled prior to use. All reported NMR
spectra were recorded on a Varian Gemini spectrometer
at 200 MHz (1H NMR) and 50 MHz (13C NMR).
Chemical shifts are reported as l values relative to
TMS peak defined at l=0.00 (1H NMR) or l=0.0 (13C
NMR). IR spectra were obtained on a Perkin–Elmer
1640 FTIR. Mass spectra were obtained on an AMD-
604 Intectra instrument using the EI or LSIMS tech-
nique. Chromatography was performed on silica (Kiesel
Gel 60, 200–400 mesh). Optical rotations were recorded
using a JASCO DIP-360 polarimeter with a thermally
jacketed 10 cm cell. All air- or moisture-sensitive reac-
tions were carried out in flame-dried glassware under
an atmosphere of argon.
3.1.4.1. (R)-N-Tosylallylglycine (2R)-bornano-10,2-
sultam imide, 5a. Mp 154–157°C (hexane–EtOAc);
[h]2D0=−28.2 (c 1, CHCl3); IR (KBr): 3438, 2960, 2921,
1
1692 cm−1; H NMR (200 MHz, CDCl3): l 5.74–5.53
(m, 1H), 5.39 (d, 1H), 5.14–5.01 (m, 2H), 4.70–4.60 (m,
1H), 3.68–3.62 (m, 1H), 3.44 (qAB, 2H), 2.72–2.47 (m,
1H); 13C NMR (200 MHz, ppm): 170.4, 143.5, 136.4,
131.8, 129.5, 127.6, 119.4, 65.3, 54.4, 52.8, 48.8, 47.7,
44.4, 37.9, 36.3, 32.8, 26.3, 21.5, 20.5, 19.9; EIMS m/e
(%) 489 (M+Na)+ (100), 467 (M+H)+ (5), 260 (22), 224
(50), 105 (40), 91 (12); HR EIMS calcd for
C22H30N2NaS2O5 (M+Na): 489.1494. Found: 489.1489.
Anal. calcd for C22H30N2O5S2: C, 56.7; H, 6.4; N, 6.0;
S, 13.7. Found: C, 56.5; H, 6.5; N, 5.8; S, 13.5%.
3.1. Preparation of N-substituted imines
3.1.1. General procedure for preparation of N-tosyl-
imines 2a, 2b, and 2c. To a solution of the correspond-
ing glyoxylic acid derivative (1.5 mmol) in toluene (10
ml) was added tosyl isocyanate (1.5 mmol, 0.23 ml)
under argon and the reaction mixture was refluxed for
24 h. The obtained imines were used in situ for allyla-
tion reactions.
3.1.4.2. (S)-N-Tosylallylglycine (2R)-bornano-10,2-
sultam imide, 6a. Mp 120–123°C (hexane–EtOAc);
[h]2D0=−34.6 (c 1, CHCl3); 1H NMR (200 MHz,
CDCl3): l 5.76–5.55 (m, 1H), 5.46–5.38 (m, 1H), 5.19–
5.11 (m, 2H), 4.44 (dt, 1H), 3.89 (t, 1H), 3.53 (qAB,
2H), 2.69–2.54 (m, 1H), 2.40 (m, 3H), 2.36–2.25 (m,
1H), 2.08–1.77 (m, 6H), 1.44–1.22 (m, 2H), 1.04 (s, 3H),
0.95 (s, 3H); 13C NMR (200 MHz, CDCl3): l 170.2,
143.4, 131.1, 129.6, 127.5, 119.9, 107.0, 65.0, 55.6, 52.8,
48.8, 47.8, 44.5, 38.8, 38.1, 32.8, 26.4, 21.6, 20.7, 19.9.
3.1.2. General procedure for preparation of N-ben-
zylimines 3a, 3b, and 3c. To a solution of the corre-
sponding glyoxylic acid derivative (1.5 mmol) in 10 ml
,
of DCM, containing molecular sieves 4 A, benzylamine
was added (3 mmol, 0.33 ml) at 0°C and the reaction
3.1.4.3. (S)-N-Tosylallylglycine 8-(R)-phenylmenthyl
ester, 6b. Oil; [h]D20=+20.6 (c 1, CHCl3); IR (KBr):
3282, 2955, 2923, 1726 cm−1; 1H NMR (200 MHz,
CDCl3): l 7.74–7.70 (m, 2H), 7.33–7.11 (m, 7H), 5.6–
5.4 (m, 1H), 5.1–4.94 (m, 2H), 4.72 (d, J=8.6, NH),
4.55 (dt, J1=10.8, J2=4, 1H), 3.45–3.35 (m, 1H), 2.42
(s, 3H), 2.42–1.15 (m, 9H), 1.07 (s, 3H), 1.04 (s, 3H),
0.83 (d, J=6.4, 3H); 13C NMR (200 MHz, CDCl3): l
169.8, 151.9, 143.3, 137.2, 131.6, 128.5, 128.1, 127.2,
125.3, 125.1, 124.9, 119.2, 76.7, 54.8, 40.8, 39.1, 37.3,
34.4, 31.1, 28.9, 26.2, 23.2, 21.6, 21.5; EIMS m/e (%)
484 (M+H)+ (8), 391 (14), 270 (56), 215 (26), 155 (10),
149 (25), 119 (70), 105 (100), 91 (26); HR EIMS calcd
for C28H37NNaO4S (M+Na): 506.2336. Found:
506.2364. Anal. calcd for C28H37NO4S: C, 69.6; H,
7.7; N, 2.9; S, 6.6. Found: C, 69.2; H, 7.7; N, 2.9; S,
6.6%.
mixture was stirred for 0.5 h.
3.1.3. General procedure for preparation of N-phenyl-
imines 4a, 4b, and 4c. To a stirred solution of glyoxylic
,
acid derivative (1 mmol), in toluene containing 4 A
molecular sieves, was added aniline (1 mmol, 0.11 ml).
The reaction was quenched with 1 M HCl. The reaction
mixture was washed with NaHCO3, extracted with
DCM, dried over MgSO4, and evaporated. The product
was purified by flash chromatography using 10%
EtOAc–toluene afforded 80% yield.
3.1.4. General procedure for addition of allyltrimethylsi-
lane to N-tosylimines. To a solution of the N-tosylimine
of 10-N,N-dicyclohexylosulfamoyl-(R)-isobornyl gly-
oxylate 2c obtained from 10-N,N-dicyclohexylosulfa-

A. Kulesza et al. / Tetrahedron: Asymmetry 13 (2002) 2061–2069
2067
3.1.4.4. (R)-N-Tosylallylglycine 10-N,N-dicyclohexyl-
osulfamoyl-(2R)-isobornyl ester, 5c. Mp 171–172°C;
[h]2D0=−29.2 (c 1, CHCl3); IR: 3281, 2932, 2855, 1737,
3.1.6.1. (RS)-N-Benzylallylglycine 8-(R)-phenylmen-
thyl esters, 8b and 9b. Mixture of diastereoisomers
1
82:18; IR: 3343, 3061, 3029, 2954, 2924, 1725 cm−1; H
1
1642, 1598 cm−1; H NMR (200 MHz, CDCl3): l 7.71
NMR (200 MHz, CDCl3): l 7.34–7.01 (m, 5H), 5.73–
5.53 (m, 1H), 5.12–4.88 (m, 2H), 4.83 (dt, J1=4.2,
J2=10.8, 1H), 3.68 (qAB, 2H), 2.74–2.68 (m, 1H),
2.24–1.89 (m, 5H), 1.72–1.62 (m, 3H), 1.28 (s, 3H), 1.21
(s, 3H), 1.15–1.00 (m, 2H), 0.87 (d, J=6.4, 3H); 13C
NMR (200 MHz, CDCl3): l 173.7, 151.7, 140.0, 133.8,
128.4, 128.2, 127.9, 127.0, 125.3, 125.1, 117.7, 75.3,
59.4, 51.9, 50.2, 41.6, 39.6, 37.3, 34.6, 31.3, 27.9, 26.6,
25.2, 21.8; EIMS m/e (%) 419 (M)+ (35), 378 (66), 164
(36), 160 (100), 119 (24), 105 (32), 91 (73); HR EIMS
calcd for C28H37NO2 (M): 419.2824. Found: 419.2832.
Anal. calcd for C28H37NO2: C, 56.5; H, 6.7; N, 5.5; S,
12.6. Found: C, 56.5; H, 6.9; N, 5.3; S, 12.5%.
(d1/2AB, J=8.2, 2H), 7.26 (d1/2AB, J=8.2, 2H), 5.82–
5.58 (m, 1H), 5.38 (d, J=9.0, 1H), 5.22–5.10 (m, 2H),
4.72–4.61 (m, 1H), 3.97–3.82 (m, 1H), 3.36–3.08 (m,
3H), 2.68–2.46 (m, 3H), 2.40 (s, 3H), 1.94–0.96 (m,
27H), 0.86 (s, 3H), 0.84 (s, 3H); 13C NMR (200 MHz,
CDCl3): l 169.3, 143.6, 136.8, 131.4, 129.7, 127.4,
120.2, 80.2, 57.6, 55.2, 54.0, 49.3, 49.2, 44.4, 39.4, 37.4,
33.3, 32.3, 30.9, 27.0, 26.4, 26.3, 25.1, 21.5, 20.4, 20.0;
EIMS m/e (%): 658 M+ (33), 607 (15), 380 (55), 298
(100), 224 (71), 216 (12), 180 (32); HR EIMS calcd for
C34H52N2NaO6S2 (M+Na): 671.3154. Found: 671.3154.
Anal. calcd for C34H52N2O6S2: C, 62.9; H, 8.1; N, 4.3;
S, 9.9. Found: C, 62.7; H, 7.9; N, 4.2; S, 10.1%.
3.1.6.2. (RS)-N-Benzylallylglycine 10-N,N-dicyclo-
hexylosulfamoyl-(2R)-isobornyl esters, 8c and 9c. Mix-
3.1.4.5. (S)-N-Tosylallylglycine 10-N,N-dicyclohexyl-
osulfamoyl-(2R)-isobornyl ester, 6c. Mp 167–168°C;
[h]2D0=−14.0 (c 1, CHCl3); 1H NMR (200 MHz,
CDCl3): l 7.72 (d1/2AB, J=8.2, 2H), 7.23 (d1/2AB,
J=8.2, 2H), 5.75–5.53 (m, 1H), 5.25 (d, J=8.2, 1H),
5.15–5.00 (m, 2H), 4.83–4.73 (m, 1H), 4.28–4.16 (m,
1H), 3.32–3.20 (m, 3H), 2.65 (d, J=13.8, 1H), 2.40 (s,
3H), 2.25–1.11 (m, 27H), 0.97 (s, 3H), 0.87 (s, 3H); 13C
NMR (200 MHz, CDCl3): l 169.6, 143.4, 137.6, 131.5,
129.8, 126.8, 199.7, 80.6, 57. 697, 55.4, 54.2, 49.6, 49.2,
44.4, 39.4, 37.2, 33.0, 32.7, 30.7, 26.9, 26.5, 26.4, 25.2,
21.6, 20.3, 20.0.
1
ture of diastereoisomers; H NMR (200 MHz, CDCl3):
l 7.45–7.20 (m, 5H), 5.95–5.72 (m, 1H), 5.23–5.10 (m,
2H), 5.09–5.00 (m, 1H), 3.65–3.98 (m, 2H), 3.65–3.35
(m, 3H), 2.75–2.60 (m, 1H), 2.59–2.48 (m, 1H), 2.22–
1.45 (m, 21H), 1.43–1.05 (m, 9H), 1.02–0.97 (m, 2H),
1.02 (s, 3H), 0.92 (s, 3H); 13C NMR (200 MHz,
CDCl3): l 171.6, 141.0, 132.0, 129.6, 128.8, 118.5,
118.2, 113.6, 113.2, 79.5, 61.3, 55.6, 55.4, 53.7, 49.4,
49.2, 49.1, 44.6, 42.9, 39.5, 36.4, 36.3, 33.2, 32.9, 32.6,
32.4, 30.7, 30.4, 26.9, 26.3, 25.1, 20.3, 20.0, 19.9; EIMS
m/e (%) 584 (M)+ (10), 543 (28), 380 (30), 160 (100),
135 (48), 91 (62); HR EIMS calcd for C34H52N2O4S
(M): 584.3648. Found: 584.3631. Anal. calcd for
C34H52N2O4S: C, 56.5; H, 6.7; N, 5.5; S, 12.6. Found:
C, 56.5; H, 6.9; N, 5.3; S, 12.5.
3.1.5. Reduction of (S)-N-tosylallylglycine 8-(R)-phenyl-
menthyl ester, 6b. To a stirred solution of 6b (1 mmol,
484 mg) in THF, LAH was added (2 mmol, 76 mg).
The reaction was quenched after 12 h with water and 1
M NaOH, then extracted with DCM, dried over
MgSO4, and evaporated. The product was purified
using flash chromatography 30% EtOAc–toluene as an
eluent to afford the product (204 mg) in 80% yield.
3.1.7. General procedure for addition of allyltrimethylsi-
lane to N-phenylimines. To a stirred solution of imine (1
mmol) in toluene, SnCl4 was added (1 M, 1 ml, 1
mmol), followed by AlSiMe3 (2 mmol, 0.32 ml). The
reaction was stirred for 3 h, then quenched with
NaHCO3, extracted with DCM, dried over MgSO4, and
evaporated. The product was purified by flash chro-
matography using 10% EtOAc–hexane.
3.1.5.1. (S)-N-Tosylallylglycinol, 7. Mp 40–43°C;
[h]2D0=+17.0 (c 1, CHCl3); 1H NMR (200 MHz,
CDCl3): l 7.78–7.74 (m, 2H), 7.34–7.30 (m, 2H), 5.62–
5.41 (m, 1H), 5.12–5.04 (m, 2H), 4.74 (d, J=7.6, 1H),
3.69–3.49 (m, 2H), 3.36–3.21 (m, 1H), 2.44 (s, 3H), 2.18
(t, J=6.2, 2H); 13C NMR (200 MHz, CDCl3): l 143.8,
137.5, 132.4, 129.8, 127.1, 119.7, 53.3, 47.0, 36.5, 21.6;
EIMS m/e (%) 256 (M+H)+ (100), 214 (38), 155 (32), 91
(26); HR EIMS calcd for C12H18NO3S (M): 256.1007.
Found: 256.0997. Anal. calcd for C12H18NO3S: C, 56.5;
H, 6.7; N, 5.5; S, 12.6. Found: C, 56.5; H, 6.9; N, 5.3;
S, 12.5%.
3.1.7.1. (RS)-N-Phenylallylglycine (2R)-bornano-10,2-
sultam imides, 10a and 11a. Mixture of diastereoisomers
81:19; IR: 2416, 3391, 2986, 2943, 1695, 1605, 1516,
1
1324 cm−1; H NMR (500 MHz, CDCl3): l 7.18–7.08
(m, 2H), 6.77–6.69 (m, 3H), 5.93–5.83 (m, 0.19H),
5.82–5.72 (m, 0.81H), 5.21–5.14 (m, 2H), 4.84–4.80 (m,
0.81H), 4.79–4.75 (m, 0.19H), 3.93–3.86 (m, 1H), 3.58–
3.45 (m, 2H), 2.80–2.72 (m, 1H), 2.64–2.56 (m, 1H),
2.08–1.97 (m, 2H), 1.97–1.81 (m, 4H), 1.44–1.36 (m,
1H), 1.35–1.28 (m, 1H), 1.16 (s, 3×0.81H), 1.09 (s,
3×0.19H), 0.97 (s, 3×0.81H), 0.95 (s, 3×0.19H); 13C
NMR (500 MHz, CDCl3): l 173.4, 172.8, 146.4, 146.3,
133.3, 132.4, 129.3, 129.2, 119.3, 118.9, 118.7, 118.5,
114.4, 114.0, 65.5, 65.1, 56.1, 55.6, 53.5, 53.1, 53.0, 48.8,
48.7, 47.8, 47.8, 44.5, 44.4, 38.3, 38.3, 37.5, 36.3, 32.9,
32.7, 26.4, 26.3, 20.7, 20.5, 19.9, 19.9; EIMS m/e (%)
488 (M)+ (45), 347 (30), 216 (10), 146 (100), 104 (30), 77
(20); HR EIMS calcd for C21H28N2O3S (M): 388.1821.
3.1.6. General procedure for addition of allyltrimethylsi-
lane to N-benzylimines. The reaction mixture was
cooled to −78°C, and the following reagents were added
under an argon atmosphere: trifluoroacetic acid (3
mmol, 0.23 ml), BF3·Et2O (3 mmol, 0.38 ml) and
AllSiMe3 (6 mmol, 1 ml). The reaction mixture was
stirred for 12 h at 0°C and quenched with NaHCO3,
extracted with DCM, dried over MgSO4, and evapo-
rated. The product was purified by flash chromatogra-
phy using 5% EtOAc–toluene as eluent, affording the
corresponding products.

2068
A. Kulesza et al. / Tetrahedron: Asymmetry 13 (2002) 2061–2069
Found: 388.1825. Anal. calcd for C21H28N2O3S: C,
65.0; H, 7.2; N, 7.2; S, 8.3. Found: C, 64.8; H, 7.3; N,
7.4; S, 8.1%.
1H NMR (500 MHz, CDCl3): l 7.72–7.69 (m, 2H),
7.37–7.33 (m, 2H), 7.30–7.25 (m, 4H), 7.21–7.16 (m,
1H), 4.65 (td, J1=4.3, J2=10.8, 1H), 4.16–4.12 (m,
1H), 3.82–3.76 (dquint., 1H), 3.33 (tt, J1=4.2, J2=11.4,
1H), 3.09 (td, J1=2.8, J2=13.3, 1H), 2.45 (s, 3H),
2.09–2.01 (m, 1H), 1.84–1.71 (m, 4H), 1.70–1.63 (m,
1H), 1.61–1.25 (m, 3H), 1.24 (s, 3H), 1.18 (s, 3H),
1.15–1.05 (m, 1H), 0.9–0.86 (m, 2H), 0.84 (d, J=6.6,
3H); 13C NMR (200 MHz, CDCl3): l 168.8, 151.9,
143.2, 137.4, 129.4, 128.2, 127.3, 125.2, 125.1, 75.9,
65.9, 55.1, 50.3, 41.4, 41.0, 39.3, 36.2, 34.5, 34.2, 31.2,
29.1, 26.3, 23.0, 21.7, 21.6.
3.1.7.2. (S)-N-Phenylallylglycine 8-(R)-phenylmenthyl
ester, 11b. Oil; [h]D20=+24.3 (c 1, CHCl3); 1H NMR (200
MHz, CDCl3): l 7.36–7.15 (m, 5H), 6.80–6.71 (m, 1H),
6.56–6.51 (m, 2H), 5.74–5.54 (m, 1H), 5.10–5.00 (m,
2H), 4.85 (dt, J1=4.4, J2=10.8, 1H), 4.06 (d, J=7.8,
1H), 3.42–3.33 (m, 1H), 2.45–2.32 (m, 1H), 2.23–2.10
(m, 2H), 1.91–1.41 (m, 6H), 1.34 (s, 3H), 1.23 (s, 3H),
1.16–1.00 (m, 1H), 0.91 (d, J=6.2, 3H); 13C NMR (200
MHz, CDCl3): l 172.3, 152.2, 146.7, 133.1, 129.3,
128.3, 125.5, 125.3, 118.6, 118.0, 113.7, 75.7, 55.3, 50.3,
41.6, 39.7, 36.4, 34.7, 31.4, 29.3, 26.5, 23.8, 22.0; EIMS
m/e (%) 405 (M)+ (14), 364 (41), 215 (31), 146 (99), 119
(52), 105 (100), 91 (20); HR EIMS calcd for C27H35NO2
(M): 405.2668. Found: 405.2675.
3.2. X-Ray analyses of 5c and 6a
X-Ray single-crystal diffraction experiments were car-
ried out with an Enraf–Nonius CAD44 diffractometer
(CAD4-EXPRESS program28) using Cu Ka radiation
,
(1.54178 A). The program used to solve and refine was
3.1.7.3. (RS)-N-Phenylallylglycine 10-N,N-dicyclo-
hexylosulfamoyl-(2R)-isobornyl esters, 10c and 11c.
Mixture of diastereoisomers 55:45; IR: 3393, 3054,
SHELX-97.29
Compound 6a: C22H30N2O5S2, M=466.60, orthorhom-
bic, a=15.035(3), b=21.214(4), c=7.2830(10), space
group P212121, Z=4, Dcalcd=1.334 mg/m−3, v(Cu
Ka)=2.377 mm−1, 1859 reflections measured, 1659
unique reflections (Rint=0.0555), which were used in all
calculations. Data/restraints/parameters: 1652/0/318.
1
2935, 2856, 1738 cm−1; H NMR (500 MHz, CDCl3): l
7.16–7.00 (m, 2H), 6.73–6.70 (m, 1H), 6.61–6.59 (m,
2H), 5.95–5.70 (m, 1H), 5.21–5.12 (m, 2H), 4.99 (dd,
J1=1.2, J2=3.2, 0.55H), 4.93 (dd, J1=1.2, J2=3.2,
0.45H), 4.25 (bs, 1H), 4.11 (bs, 1H), 3.30–3.21 (m, 3H),
2.80–2.50 (m, 3H), 2.04–1.90 (m, 2H), 1.84–1.45 (m,
21H), 1.43–1.05 (m, 9H), 1.02–0.97 (m, 2H), 0.89 (s,
3H), 0.87 (s, 3H); 13C NMR (200 MHz, CDCl3): l
171.6, 146.3, 132.8, 129.2, 119.2, 118.7, 118.2, 117.0,
113.6, 113.2, 79.6, 57.5, 55.6, 55.5, 53.7, 49.4, 49.2, 49.1,
44.3, 39.9, 39.5, 36.4, 36.3, 33.2, 32.9, 32.6, 32.4, 30.7,
30.4, 26.9, 26.3, 25.1, 20.3, 20.0, 19.8; EIMS m/e (%)
402 (M+Na)+ (5), 380 (M+H)+ (30), 246 (15), 228 (25),
146 (90), 135 (100), 83 (50); HR EIMS calcd for
C33H50N2NaO4S (M): 593.3389. Found: 593.3360.
The final R1=0.0916 (all data), s=−0.02. Residual
−3
,
electron density: 0.218 and −0.226 e A .
Compound 5c: C34H51N2O6S2, M=647.89, orthorhom-
bic, a=14.444, b=15.223, c=16.003, space group
P212121, Z=4, Dcalcd=1.223 mg/m−3, v(Cu Ka)=1.728
mm−1, 2653 reflections measured, 2653 unique reflec-
tions (Rint=0.0000), which were used in all calculations.
Data/restraints/parameters: 2653/0/398. The final R1=
0.0525 (all data), s=−0.05. Residual electron density:
−3
,
0.178 and −0.209 e A .
3.1.8. Preparation of N-tosyl-(2S,4R)-4-hydroxy-
pipecolic acid (R)-8-phenylmenthyl ester, 14. Compound
6b was dissolved in THF (0.5 ml) and aqueous (CHO)n
(2 ml) was added, followed by TFA (0.1 ml). The
mixture was stirred for 48 h and quenched by the
addition of NaHCO3. The product was then extracted
with DCM, dried over MgSO4, and evaporated to
afford pure 14 as an oil; [h]2D0=−12.8 (c 1, CHCl3); IR:
Crystallographic data (excluding structure factors) for
the structures reported in this paper have been
deposited with the Cambridge Crystallographic Data
Centre under the deposition numbers CCDC 192272
and 192273 for 5c and 6a, respectively.
1
3531. 2956, 2926, 1740, 1347, 1159 cm−1; H NMR (500
Acknowledgements
MHz, CDCl3): l 7.74 (d, J=8, 2H), 7.37–7.32 (m, 2H),
7.32–7.25 (m, 5H), 7.19–7.14 (m, 1H), 4.65 (td, J1=4.2,
J2=10.8, 1H), 4.00–3.95 (m, 2H), 3.60–3.54 (m, 1H),
3.45 (td, J1=2.9, J2=13.1, 1H), 2.42 (s, 3H), 2.06 (td,
J1=2.1, J2=12.2, 1H), 1.93–1.88 (m, 1H), 1.83–1.76
(m, 1H), 1.70–1.53 (m, 7H), 1.47–1.36 (m, 1H), 1.23 (s,
3H), 1.17 (s, 3H), 0.91–0.83 (m, 2H), 0.82 (d, J=6.6,
3H); 13C NMR (200 MHz, CDCl3): l 169.7, 152.2,
143.0, 137.6, 129.3, 128.2, 127.4, 125.0, 75.7, 63.5, 51.8,
50.4, 41.0, 39.3, 36.7, 34.6, 34.1, 31.5, 31.2, 29.2, 26.3,
23.2, 21.7, 21.6; EIMS m/e (%) 536 (M+Na)+ (40), 254
(28), 176 (100), 105 (60), 91 (39); HR EIMS calcd for
C29H39NNaO5S (M+Na): 536.2447. Found: 536.2434.
This work was supported by Polish State Committee
for Scientific Research, Grant PBZ 6.05/T09/1999
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