Asymmetric syntheses of N-Boc 2-substituted pyrrolidines and piperidines by intramolecular cyclization

Article abstract of DOI:10.1021/jo981553j

Asymmetric lithiation-substitutions by n-BuLi/(-)-sparteine with the N- Boc-N-(3-halopropyl)allylamines 1-4 provide the N-Boc-2-alkenylpyrrolidines (S)-5, (S)-6, and (S)-7 in yields of 3193% with enantiomeric ratios (ers) from 65:35 to 90:10. These reactions are shown to involve an initial asymmetric deprotonation, but the enantiodetermining step is a subsequent asymmetric cyclization under the influence of the chiral ligand. Extension to formation of a piperidine is illustrated by reaction of N-Boc-(4- chlorobutyl)cinnamylamine (9) to afford (S)-N-Boc-2-(trans-β- styryl)piperidine ((S)-10) in 68% yield with an enantiomeric ratio (er) of 84:16. Analogous reactions with epoxide ring openings of N-Boc-N- (oxaalkenyl)benzylamines 11 and 12 afford the corresponding N-Boc-2-phenyl- 3-(hydroxymethyl)pyrrolidine (13) in 67% yield with a diastereomeric ratio (dr) of 50:50 and ers of 97:3 and 95:5 and the corresponding N-Boc-2-phenyl- 3-(hydroxymethyl)piperidine (14) in 29% yield with a dr of 86:14 and ers of 81:19 and 86:14.

Full text of DOI:10.1021/jo981553j

1160
J . Org. Chem. 1999, 64, 1160-1165
Asym m etr ic Syn th eses of N-Boc 2-Su bstitu ted P yr r olid in es a n d
P ip er id in es by In tr a m olecu la r Cycliza tion
Caterina Serino, Nathan Stehle, Yong Sun Park,1a Saverio Florio,1b and Peter Beak*
Department of Chemistry, University of Illinois at UrbanasChampaign, Urbana, Illinois 61801
Received August 3, 1998
Asymmetric lithiation-substitutions by n-BuLi/(-)-sparteine with the N-Boc-N-(3-halopropyl)-
allylamines 1-4 provide the N-Boc-2-alkenylpyrrolidines (S)-5, (S)-6, and (S)-7 in yields of 31-
93% with enantiomeric ratios (ers) from 65:35 to 90:10. These reactions are shown to involve an
initial asymmetric deprotonation, but the enantiodetermining step is a subsequent asymmetric
cyclization under the influence of the chiral ligand. Extension to formation of a piperidine is
illustrated by reaction of N-Boc-(4-chlorobutyl)cinnamylamine (9) to afford (S)-N-Boc-2-(trans-â-
styryl)piperidine ((S)-10) in 68% yield with an enantiomeric ratio (er) of 84:16. Analogous reactions
with epoxide ring openings of N-Boc-N-(oxaalkenyl)benzylamines 11 and 12 afford the corresponding
N-Boc-2-phenyl-3-(hydroxymethyl)pyrrolidine (13) in 67% yield with a diastereomeric ratio (dr) of
50:50 and ers of 97:3 and 95:5 and the corresponding N-Boc-2-phenyl-3-(hydroxymethyl)piperidine
(14) in 29% yield with a dr of 86:14 and ers of 81:19 and 86:14.
Recent studies have established that reactions of
recrystallization from hexane, the enantiomeric ratio of
7 is increased to 97:3 with a 70% yield for the recrystal-
lization. The absolute configuration of (S)-7 was deter-
mined by oxidative cleavage of the olefin to afford N-Boc-
proline followed by synthesis of the amide derivative for
CSP-HPLC analysis.7 When the 3:1 mixture of trans and
cis 3 was treated with n-BuLi/sparteine in ether at -78
°C for 4 h, the products 6 are obtained in a trans:cis ratio
of 3:1 in 70% yield with ers of 92:8 and 75:25, respec-
tively.
organolithium species complexed to (-)-sparteine can
afford highly enantioenriched products in lithiation-
substitution sequences.2 We have reported an intra-
molecular version in which (S)-N-Boc-2-arylpyrrolidines
are obtained in >91:9 enantiomeric ratios (ers) by the
lithiation-cyclization of the corresponding N-Boc-(3-
chloropropyl)arylmethylamines with s-BuLi/(-)-sparteine.3
We now report enantioselective syntheses of N-Boc-2-
alkenylpyrrolidines, a N-Boc-2-alkenylpiperidine, a N-Boc-
2-phenyl-3-(hydroxymethyl)pyrrolidine, and a N-Boc-2-
phenyl-3-(hydroxymethyl)piperidine by lithiation-
cyclizations of the appropriate N-Boc-allylmethylamine
or N-Boc-arylamine derivative with the n-BuLi/(-)-
sparteine complex.
The lithiation-cyclization of N-Boc-N-(3-chloropropyl)-
allylamine (1) with 1.2 equiv of n-BuLi/sparteine at -78
°C in ether for 3 h provides (S)-5 in 93% yield with an
enantiomeric ratio (er) of 83:17. The cyclization is regio-
specific at the R-position of the allyl group; the possible
seven-membered ring product from cyclization at the
γ-position is not observed.4 With bromine as the leaving
group, 2 affords (S)-5 in 31% yield in toluene with an er
of 65:35. The absolute configuration of (S)-5 is based on
comparison of optical rotation to the N-ethoxycarbonyl
carbamate of previously assigned enantiomers.5
The double bond geometry of the reactant is retained
in the product. Treatment of N-Boc-N-(3-chloropropyl)-
cinnamylamine (4) with n-BuLi/sparteine in Et2O at -78
°C for 2 h followed by warming to -25 °C for 1 h affords
(S)-7 in 85% yield with an er of 90:10.6 After one
(1) (a) Present address: Department of Chemistry, Konkuk Uni-
versity, Seoul, Korea, 143-701. (b) Present address: Dipartimento
Farmaco-Chimico, Universita` di Bari, Via Orabona 4, Bari, Italy.
(2) (a) Beak, P.; Basu, A.; Gallagher, D. J .; Park, Y. S.; Thayumana-
van, S. Acc. Chem. Res. 1996, 29, 552. (b) Hoppe, D.; Hense, T. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2282.
(3) Wu, S.; Lee, S.; Beak, P. J . Am. Chem. Soc. 1996, 118, 715.
(4) Weisenburger, G. A.; Beak, P. J . Am. Chem. Soc. 1996, 118,
12218-12219. Beak, P.; Resek, J . E. Tetrahedron Lett. 1993, 34, 3443.
(5) Sato, T.; Tsujimoto, K.; Matsubayashi, K.; Ishibashi, H.; Ikedo,
M. Chem. Pharm. Bull. 1992, 40, 2308.
The mechanism of lithiation-cyclization of 4 to (S)-7
could involve either an asymmetric deprotonation or an
asymmetric substitution as the enantiodetermining step.2
If an asymmetric deprotonation is operative, a n-BuLi/
(6) When 4 was treated with n-BuLi/(-)-sparteine at -78 °C for 10
h in ether and quenched with water at -78 °C, 7 was produced in
16% yield with an er of 90:10.
10.1021/jo981553j CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/29/1999

N-Boc 2-Substituted Pyrrolidines and Piperidines
J . Org. Chem., Vol. 64, No. 4, 1999 1161
Ta ble 1. Rea ction s of 4 a n d r a c-4-d 1 in Eth er to P r ovid e
7 a n d 7-d 1
racemic tin precusor 8 to generate the racemic lithium
intermediate in the presence of (-)-sparteine to provide
(S)-7 in 41% yield and an er of 89:11. This result confirms
that the asymmetric induction occurs via an asymmetric
substitution.
reactant
diamine
TMEDA
(-)-sparteine
yield (%) product
er
d1 (%)a
4
4
70
85
62
45
rac-7
(S)-7
rac-7-d1
90:10
rac-4-d1 TMEDA
95
73
rac-4-d1 (-)-sparteine
(S)-7-d1 90:10
a
Deuterium incorporation determined by GC/MS.
(-)-sparteine complex would act as a chiral base and
provide an enantioenriched lithium intermediate which
cyclizes faster than it epimerizes. In the case of asym-
metric substitution, deprotonation of 4 with n-BuLi/
(-)-sparteine would provide a racemic organolithium
intermediate either directly or by epimerization, and
this intermediate could then undergo diastereoselective
cyclization under the influence of the (-)-sparteine to give
(S)-7. These possibilities can be distinguished by experi-
ments with rac-4-d1 and rac-8.
If the stereodetermining step is an asymmetric depro-
tonation, significant differences in deuterium contents,
ers, and yields of the products should be observed
between the reaction of 4 and rac-4-d1 (97% d1). If the
asymmetric induction occurs only through asymmetric
substitution and there is no facial selectivity in depro-
tonation, (S)-7-d1 should be formed selectively with a
deuterium content comparable to that of rac-7-d1 due to
the large deuterium isotope effect at -78 °C.3,8
Lithiation-cyclizations of 4 and rac-4-d1 were carried
out in Et2O, and comparison of the deuterium content
for rac-7-d1 and (S)-7-d1 and the enantiomeric ratios for
(S)-7 and (S)-7-d1 are shown in Table 1. The deuterium
content (73%) of (S)-7-d1 is appreciably different from the
deuterium content (95%) of rac-7-d1, a result which
indicates that an asymmetric deprotonation is operative.
The yield is decreased for the lithiation-cyclization of
rac-4-d1 which shows the asymmetric deprotonation by
n-BuLi/(-)-sparteine is retarded by the kinetic isotope
effect. The lower yield, decreased percent deuterium, and
same ers within experimental error ((5%) indicate that
both the deuterium kinetic isotope effect and the enan-
tioselectivity are sufficiently high to limit reaction of rac-
4-d1 and that the facial selectivity in the deprotonation
step can override the kinetic isotope effect. The asym-
metric deprotonation does not, however, determine the
enantiomeric ratio of the product.
The data establish that reaction pathway involves an
initial asymmetric deprotonation. On the basis of our
recent assignment of absolute configuration of N-Boc-N-
(p-methoxyphenyl)-3-phenylallyllithium intermediate,9
this lithiated species can be assumed to have (R) config-
uration. The lithio intermediate must not maintain its
configuration and undergoes epimerization faster than
cyclization as the asymmetric induction arises in a
subsequent asymmetric substitution.
Extension of this methodology to asymmetric synthesis
of a 2-alkenylpiperidine has been demonstrated. The
treatment of N-Boc-(4-chlorobutyl)cinnamylamine (9)
with n-BuLi/sparteine at -78 °C followed by gradual
warming to room temperature affords (S)-10 in 68% yield
with an er of 84:16.10 The absolute configuration of (S)-
10 was determined by oxidative cleavage of the olefin to
give (S)-N-Boc-pipecolic acid and conversion of the acid
to the amide which was analyzed by CSP-HPLC.7
The methodology also can be used intramolecularly to
open an epoxide ring. This approach has been used to
provide the enantioenriched 2-phenyl-3-(hydroxymethyl)-
pyrrolidine (13) and 2-phenyl-3-(hydroxymethyl)piperi-
dine (14) by reactions of the racemic epoxides 11 and 12
with n-BuLi/(-)sparteine for 2 h at -78 °C followed by
slow warming to room temperature.8,11 The pyrrolidine
13 is obtained in 67% yield with a dr (diastereomeric
ratio) of 50:50 by lithiation-cyclization. The ers of two
diastereomers are 97:3 and 95:5. The inseparable two
diastereomers of piperidine 14 are obtained in 29% yield
with a dr of 86:14. The er of major diastereomer is
81:19, and the er of minor diastereomer is 86:14. The
absolute configurations of 2-position are assigned to be
(S) by analogy to the reaction of related N-Boc-benzyl-
amines with n-BuLi/(-)-sparteine.3,8
The ers of the products from the reaction of 4 and rac-
4-d1 with n-BuLi/(-)-sparteine have the same value as
shown in Table 1. This indicates the enantiodetermining
step is the asymmetric substitution. Confirmation of the
pathway has been carried out by the transmetalation of
(9) Pippel, D. J .; Weisenburger, G. A.; Wilson, S.; Beak, P. Angew.
Chem., Int. Ed. Engl. 1998, 37, 2522.
(10) The synthesis of 9 was achieved by use of the Ing-Manske
preparation of primary amines. Ing, H. R.; Manske, R. H. F. J . Chem.
Soc. 1926, 2348. Refluxing potassium pthalamide and cinnamyl
bromide in DMF afforded N-cinnamyl pthalamide in 79% yield. The
amine is then liberated by refluxing pthalamide in EtOH in the
presence of hydrazine and subsequently protected to provide N-Boc-
cinnamylamine in 82% yield. Alkylation to afford 9 in 60% yield is
performed by refluxing the amine with sodium hydride and 1-bromo-
4-chloropropylamine in THF.
(7) The ers and absolute configurations of (S)-7 and (S)-10 were
determined by converting the amino acids to dimethylaniline deriva-
tives. Comparison of CSP-HPLC retension times to those of optically
pure amides from commercially available (S)-amino acids showed the
configuration to be (S). Pirkle, W. H.; McCune, J . E. J . Chromatogr.
1989, 479, 471, 271.
(8) Faibish, N. C.; Park, Y. S.; Lee, S.; Beak, P. J . Am. Chem. Soc.
1997, 119, 11561.
(11) Beak, P.; Wu, S.; Yum, E. K.; J un, Y. M. J . Org. Chem. 1994,
59, 276.

1162 J . Org. Chem., Vol. 64, No. 4, 1999
Serino et al.
tography using Cyclodex-B chiral column (isothermal at 60 °C,
tR ) 266 (minor) and 277 (major)).
Reaction of 2 was carried out using a standard procedure
above in the reaction of 1 (27 mg, 31% yield). The enantiomeric
purity of (S)-5 was determined to be 65:35 er by gas chroma-
tography using Cyclodex-B chiral column.
Deter m in a tion of Absolu te Con figu r a tion of N-(ter t-
bu toxyca r bon yl)-2-vin ylp yr r olid in e (5). To a solution of
(S)-N-(tert-butoxycarbonyl)-2-vinylpyrrolidine (5) (100 mg, 0.51
mmol, 67% ee by GC) in CH2Cl2 (5 mL) was added an excess
of trifluoroacetic acid (0.2 mL, 2.6 mmol). The resulting
mixture was stirred at room temperature for 3 h, and then
10% NaOH (2 mL) was added and followed by extraction with
CH2Cl2 (2 × 5 mL). To this stirred organic solution were added
4 N NaOH (1 mL) and ethyl chloroformate (0.2 mL, 2.1 mmol)
at 0 °C, and the mixture was stirred at the same temperature
for 30 min. The reaction mixture was neutralized with 10%
HCl and extracted with CH2Cl2. The extract was dried over
MgSO4 and concentrated. The residue was chromatographed
The present work provides methodology for the con-
venient preparation of moderately enantioenriched 2-alk-
enyl- or -aryl-substituted pyrrolidines and piperidines by
a lithiation-intramolecular cyclization sequence. Ap-
plication of this methodology and extensions to other
systems are under further study.
(hexane/EtOAc, 9/1) to give a colorless oil (70 mg, 81%): [R]22
Exp er im en ta l Section
D
) -23.3 (c ) 1, EtOH), lit.5 [R]22 ) -22.2 c ) 1, EtOH); 83:
D
P r ep a r a tion of N-(ter t-Bu toxyca r bon yl)-N-(3-ch lor o-
p r op yl)a llyla m in e (1). Sodium hydride (2.55 g, 60% disper-
sion in mineral oil) was washed with three portions of hexane
to remove the mineral oil. The system was filled with nitrogen
followed by THF (15 mL). A solution of N-(tert-butoxycarbonyl)-
allylamine (5 g, 31.85 mmol) in THF (10 mL) and 1-bromo-3-
chloropropane (7.5 g, 47.77 mmol) were then added. The
resulting mixture was stirred at room temperature overnight.
Water (10 mL) was then added, and the mixture was extracted
with ethyl acetate (3 × 20 mL). The combined extracts were
purified by chromatography (Hexane/EtOAc, 9/1) to give 1 as
a colorless oil (3.7 g, 50%): 1H NMR (CDCl3, 300 MHz) δ 1.79
(s, 9H), 2.0 (br, 2H), 3.2 (m, 2H), 3.5 (m, 2H), 3.7 (br, 2H), 5.0
(m, 2H), 5.8 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 27.5, 30.6,
41.6, (43.2-43.6), (48.7-49.5), 78.69, (115.2-115.8), 133.19,
154.48; GC/MS (EI, 70 eV) 177 (M+ - 56), 114 (10), 70 (41),
57 (100). Anal. Calcd for C11H20NO2Cl: C, 56.65; H, 8.58; N,
6.34. Found: C, 56.75; H, 8.87; N, 6.34.
P r epar ation of N-(ter t-Bu toxycar bon yl)-N-(3-br om opr o-
p yl)a llyla m in e (2). A procedure identical with that described
above for preparation of 1 was used to produce 2 (200 mg,
12%); 1H NMR (CDCl3, 300 MHz) δ 1.45 (s, 9H), 2.07 (br, 2H),
3.29-3.33 (t, 2H, J ) 6.35 Hz), 3.37-3.41 (t, 2H, J ) 6.84
Hz), 3.8 (br, 2H), 5.1 (br, 2H), 5.7 (m, 1H); 13C NMR (CDCl3,
100 MHz) δ 28.2, (30.7-30.8), (31.3-31.5), (44.9-45.3), (49.5-
50.3), (79.6) (2), (116.4-116.7), 133.8, 155.3; GC/MS (EI, 70
eV) 221 (M+ - 56, 30), 223 (30), 142 (29), 114 (18), 70 (46), 57
(100). Anal. Calcd for C11H20NO2Br: C, 47.65; H, 7.22; N, 5.05.
Found: C, 47.34; H, 7.11; N, 5.38.
17 er by GC, using cyclodex-B column, isothermal at 60 °C, tR
) 233 (minor) and 251 (major) min; 1H NMR (CDCl3, 300 MHz)
δ 1.25 (t, 3H, J ) 7 Hz), 1.6-2.2 (m, 4H), 3.3-3.6 (m, 2H),
3.9-4.5 (m, 1H), 4.1 (q, 2H, J ) 7 Hz), 4.9-5.3 (m, 2H), 5.8
(ddd, 1H, J ) 17.9, 5.5 Hz); GC/MS (EI, 70 eV) 169 (42), 142
(38), 140 (84), 96 (98), 70 (100), 68 (64).
P r ep a r a tion of N-(ter t-Bu toxyca r bon yl)-N-(2-bu ten yl)-
3-ch lor op r op yla m in e (3). Sodium hydride (0.3 g, 60% dis-
persion in mineral oil) was washed with three portions of
hexane to remove the mineral oil, and the system was filled
with nitrogen followed by THF (20 mL). N-(tert-Butoxycarbo-
nyl)-3-chloropropylamine (1 g, 5.18 mmol) in THF (5 mL) and
crotyl bromide (1.049 g, 6.21 mmol, as a mixture cis/trans 1/3)
were then added under nitrogen. The resulting mixture was
stirred at room temperature overnight. Water (10 mL) was
then added, and the solution was extracted with ethyl acetate
(3 × 20 mL).The combined extracts were dried (MgSO4) and
concentrated in vacuo. The crude product was purified by flash
chromatography (hexane/EtOAc, 9/1) to give 3 as a colorless
oil (1 g, 78%, as a mixture of cis/trans, 1/3): 1H NMR (CDCl3,
400 MHz) δ 1.43 (s, 9H), 1.66 (d, 3H, J ) 6.2 Hz), 1.95 (br,
2H), 3.25-3.29 (m, 2H), 3.49-3.54 (m, 2H), 3.69-3.73 (m, 2H),
5.36-5.40 (m, 1H), 5.52-5.57 (m, 1H, J ) 15.4 Hz); 13C NMR
(CDCl3, 100 MHz) (mixture of cis/trans, 1/3) δ (12.5-17.4),
28.1, (31.1-31.2), (42.2-42.3), (43.0-43.1), (48.5-48.8), (79.2-
79.3), (126.5-126.5), (127.8-128.1), (155.2 (2)); GC/MS (EI,
70 eV) 191 (M+ - 56, 26), 156 (19), 57 (100). Anal. Calcd for
C
12H22NO2Cl: C, 58.29; H, 8.90; N, 5.66; Cl, 14.17. Found: C,
58.29; H, 9.28; N, 5.60; Cl, 14.03.
Cycliza tion s To P r od u ce (S)-N-(ter t-Bu toxyca r bon yl)-
2-vin ylp yr r olid in e ((S)-5). A mixture of (-)-sparteine (200
mg, 0.86 mmol) and n-BuLi (0.41 mL, 1.27 M in cyclohexane)
in 2 mL of Et2O at -78 °C was transferred to a solution of 1
in 1 mL of Et2O. The resulting reaction mixture was stirred
at -78 °C for 2.5 h. Water (5 mL) was added to quench the
reaction. The aqueous layer was extracted with ether (3 × 5
mL), and the combined ether extracts were washed with 0.5
M phosphoric acid (10 mL), dried over MgSO4 (anhydrous),
filtered, and concentrated in vacuo at room temperature. The
crude product was further purified by flash chromatography
(hexane/EtOAc, 9/1) to give (S)-N-(tert-butoxycarbonyl)-2-
vinylpyrrolidine ((S)-5) as a colorless and volatile oil (78 mg,
93%): 1H NMR (CDCl3, 300 MHz) δ 1.43 (s, 9H), 1.50-2.02
(m, 4H), 3.3 (br, 2H), 4.21-4.28 (br, 1H), 5.0 (m, 2H), 5.68-
5.75 (br, 1H); 13C NMR (CDCl3, 75 MHz) δ (23.8-24.2), 28.4,
(32.2-33.5), 47.8, 58.4, 79.4, 116.3, (138.2-139.2), 155.6; GC/
MS (EI, 70 eV) 197 (4), 142 (10), 141 (76), 124 (23), 96 (42), 57
(100). The 1H NMR of product was identical to those of the
authentic material reported previously.12a The enantiomeric
purity of (S)-5 was determined to be 83:17 er by gas chroma-
Cycliza tion of 3 To P r od u ce N-(ter t-Bu toxyca r bon yl)-
2-(p r op en )p yr r olid in e ((S)-6). A mixture of (-)-sparteine
(279 mg, 1.19 mmol) and n-BuLi (0.62 mL, 0.60 mmol), 1.3 M
in cyclohexane) in 3 mL of the appropriate solvent at -78 °C
was transferred to a solution of 3 (0.2 g, 0.81 mmol) in 2 mL
of solvent. The resulting reaction mixture was stirred at -78
°C for 4 h. Water (5 mL) was added to quench the reaction.
The aqueous layer was extracted with ether (3 × 5 mL), and
the combined ether extracts were washed with 0.5 M phos-
phoric acid (10 mL), dried over MgSO4 anhydrous, filtered, and
concentrated in vacuo at room temperature. The crude product
was further purified by flash chromatography (hexane/EtOAc,
9/1) to give (S)-6 as a colorless oil (70%; mixture of trans/cis
3/1): 1H NMR (CDCl3, 400 MHz) δ 1.42 (s, 9H), 1.65-1.67 (d,
3H, J ) 6.7 Hz), 1.69-2.0 (m, 4H), 3.28-3.36 (br, 2H), 4.1-
4.4 (m, 1H), 5.29-5.33 (br, 1H), 5.43-5.49 (br, 1H); 13C NMR
(CDCl3, 100 MHz) δ 17.4, (22.8 (2)), 28.3, 32.3, (45.9 (2)), (58.6
(2)), 78.8, (124.8-124.9), (131.6 (2)), 155; GC/MS (EI, 70 eV)
211 (1), 155 (47), 140 (77), 96 (28), 57 (100). The 1H NMR of
product was identical to those of the authentic material
reported previously.12b The enantiomeric purity of (S)-N-(tert-
butoxycarbonyl)-2-(propen-1-yl)pyrrolidine (6) was determined
to be 85% for trans isomer and 51% for cis isomer by gas
chromatography using Ciclodex-B column (isothermal at 80
°C tR ) 147 (minor) and 154 (major) min for trans and 167
(12) (a) Hassner, A.; Maurya, R.; Padwa, A.; Bullock, W. H. J . Org.
Chem. 1991, 56, 2775. (b) Tietze, L. F.; Burkhardt, O. Synthesis 1994,
1331.

N-Boc 2-Substituted Pyrrolidines and Piperidines
J . Org. Chem., Vol. 64, No. 4, 1999 1163
(minor) and 174 (major) min for cis isomer with 92:8 er for
trans and 75:25 er for cis.
dimethylanilide and racemic 3,5-dimethylanilide were inde-
pendently prepared using the same procedure described above
to confirm the stereochemical assignment and the enantio-
meric ratio by comparison the elution time of the enantiomers
on HPLC.
P r ep a r a tion of N-(ter t-Bu toxyca r bon yl)-N-(3-tr a n s-
p h en yl-2-p r op en yl)-3-ch lor op r op yla m in e (4). A procedure
identical with that described above for preparation of 3 was
used to produce N-(tert-butoxycarbonyl)-N-(3-trans-phenylpro-
pene-2-yl)-3-chloropropylamine (1 g, 63%, as pure trans iso-
mer): 1H NMR (CDCl3, 400 MHz) δ (s, 9H), 1.91-1.94 (br, 2H),
3.27 (br, 2H), 3.43-3.46 (t, 2H, J ) 6.11 Hz), 3.87-3.90 (br,
2H), 6.04-6.06 (br, 1H), 6.35-6.38 (d, 1H, J ) 15.4 Hz), 7.12-
7.28 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 28.0, 31.1, 42.1,
(43.4-43.5), (49.5 (2)), 79.3, 125.0, 126.0, 127.2, 128.2, (131.3
(2)), 136.2, 155.0; GC/MS (EI, 70 eV) 253 (M+ - 56, 59), 208
(44), 138 (32), 116 (100), 57 (49). Anal. Calcd for C17H24NO2-
Cl: C, 66.02; H, 7.76; N, 4.53; Cl, 11.32. Found: C, 65.87; H,
7.85; N, 4.61; Cl, 10.91.
Cycliza tion of 4. Cyclization of 4 was carried out using a
procedure identical with that described above for asymmetric
cyclization of 1 except that reaction was stirred for 2 h at -78
°C and for 1 h at -25 °C. The product N-(tert-butoxycarbonyl)-
2-(2-phenyl)ethenylpyrrolidine ((S)-7) was formed as a white
solid (mp 99-101 °C, 140 mg, 85%): 1H NMR (CDCl3, 300
MHz) δ 1.42 (s, 9H), 1.75-2.06 (m, 4H), 3.41-3.47 (m, 2H),
4.43 (br, 1H), 6.05-6.10 (dd, 1H, J ) 16, 6.4 Hz), 6.37-6.42
(d, 1H, J ) 16 Hz), 7.21-7.36 (m, 5H); 13C NMR (CDCl3, 100
MHz) δ 23.0, 28.4, 32.5, 46.1, 58.9, 79.1, 126.1, 127.2, 128.4,
129.3, 130.6, 136.9, 156.4; GC/MS (EI, 70 eV) 217 (M+ - 56,
47), 200 (14), 172 (70), 130 (100), 57 (48). Anal. Calcd for
Syn th esis of r a c-4-d 1. To a suspension of cinnamyl alde-
hyde (4 g, 30.3 mmol) and MgSO4 (6.7 g, 55.6 mmol) in CH2-
Cl2 (50 mL) was added triethylamine (3.0 mL, 36.2 mmol) and
3-chloropropylamine hydrochloride. The resulting mixture was
stirred overnight at room temperature. The solvent was
evaporated, and the residue was diluted with water (920 mL).
The aqueous layer was extracted with EtOAc (3 × 10 mL),
the organic phases were dried over MgSO4 and filtered, and
the solvent was evaporated to give an imine (2 g, 32%) which
was used in the next step. To a solution of the imine (2 g, 9.7
mmol) in MeOH (20 mL) was added NaBD4 (9.45 g, 10.7 mmol)
in 3 portions at 0 °C for 1 h; the reaction was then warmed to
room temperature and stirred for 2 h. Water (10 mL) was
added, and the aqueous layers were extracted with EtOAc (3
× 10 mL). The organic phase was dried (MgSO4), filtered, and
concentrated in vacuo. The crude product was purified by
column chromatography using EtOAc as the eluent, and the
deuterated amine was obtained as a yellow oil (0.78 g, 38%):
1H NMR (CDCl3, 300 MHz) δ 7.39-7.22 (m, 5H), 6.53 (d, J )
15.9 Hz, 1H), 6.28 (dd, J ) 15.9, 6.3 Hz), 3.64 (t, 2H, J ) 6.4
Hz), 3.40 (d, J ) 6.2 Hz), 2.81 (t, J ) 6.8 Hz, 2H), 1.95 (m, 2H,
1.81 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 136.8, 131.0, 128.3,
128.0, 127.1, 126.0, t (50.9, 51.1, 51.3), 45.9, 42.8, 32.6. A
procedure identical with that described for the preparation of
N-(tert-butoxycarbonyl)allylamine was used for rac-4-d1 (1 g,
87%): 1H NMR (CDCl3, 400 MHz) δ 7.38-7.22 (m, 5H), 6.4
(d, J ) 15.4 Hz, 1H), 6.1 (br, 1H), 3.9 (br, 1H), 3.5 (br, 2H),
3.3 (br, 2H), 2.0 (br, 2H), 1.48 (s, 9H); 13C NMR (CDCl3, 100
MHz) δ 132.3-131.8, 128.5, 127.6, 126.3, 125.3, 79.8, 49.5 (m),
44.2, 42.3, 31.8, 28.4-27.3. The deuterium content for all
products was determined by GC-MS from the M+ - 56 peak.
P r epar ation of r a c-N-(ter t-Bu toxycar bon yl)-N-(3-tr a n s-
p h en yl-1-(t r im et h ylst a n n yl)p r op en -2-yl)-3-ch lor op r o-
p yla m in e (8). To a solution of 4 in Et2O (5 mL) was added
TMEDA (0.12 mL, 0.78 mmol). The solution was cooled to -78
°C followed by addition of n-BuLi (0.5 mL, 1.3 M solution in
cyclohexane). The resulting solution was stirred at -78 °C for
30 min, then trimethyltinchloride (0.65 mL, 1 M in cyclohex-
ane) was added, and the mixture was stirred for 2 h at -78
°C. Water (5 mL) was added, and the aqueous layer was
extracted with EtOAc (3 × 5 mL). The organic phase was dried
(MgSO4), filtered, and concentrated in vacuo. The crude
mixture was purified by flash chromatography to give 8 (50
mg): 1H NMR (CDCl3, 400 MHz) δ 7.32-7.16 (m, 5H), 6.29
(dd, J ) 15.8, 7.7 Hz, 1H), 6.08 (d, J ) 15.8 Hz, 1H), 3.59-
3.32 (m, 5H), 2.00 (m, 2H), 1.47 (s, 9H), 0.09 (s, 9H); 13C NMR
(CDCl3, 100 MHz) δ 156.1, 137.5, 130.9, 128.1, 126.0, 125.5,
122.8, 79.6, 53.9, 46.3, 42.1, 31.4, 28.0, -7.3. In addition,
γ-substituted product (100 mg, 33%) was obtained: 1H NMR
(CDCl3, 400 MHz) δ 7.23 (m, 3H), 7.02 (m, 2H), 5.91 (br, 1H),
5.88 (br, 1H), 3.63-3.39 (br, 5H), 1.98 (br, 2H), 1.48-1.43 (br,
9H), 0.04 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 155.5, 143.7,
128.8, 125.2, 125.4, 124.1, 122.9, 80.6, 46.6, 42.8, 34.7, 31.5,
28.6, -9.2.
C
17H23NO2: C, 74.72; H, 8.42; N, 5.12. Found: C, 75.03; H,
8.48; N, 5.16. The enantiomeric purity of N-(tert-butoxycar-
bonyl)-2-(2-phenyl)ethenylpyrrolidine ((S)-7) was determined
to be 90:10 er by HPLC using chiral Regis (R,R)-â-GEM
column (1% 2-propanol/hexane, flow rate 1.75 mL/min, tR
5.3 min for (S) enantiomer (major) and 7.5 min for (R)
)
enantiomer (minor)).
Deter m in a tion of Absolu te Con figu r a tion of N-(ter t-
Bu toxyca r bon yl)-2-(2-p h en yl)eth en ylp yr r olid in e (7). To
5.8 mL of carbon tetrachloride, 5.8 mL of acetonitrile, and 11.6
mL of water were added 290 mg (1.06 mmol) of (S)-7 and 917
mg (4.1 equiv) of sodium metaperiodate. To this biphasic
solution was added 5.8 mg (2.2 mol %) of ruthenium trichloride
hydrate, and the entire mixture was stirred for 2 h at room
temperature; 10 mL of CH2Cl2 was then added, and the phases
were separated. The (upper) aqueous phase was extracted 3
times with CH2Cl2. The combined organic extracts were dried
(MgSO4) and concentrated. The crude product was purified by
column chromatography (EtOAc) to give N-(tert-butoxycar-
bonyl)proline as a white solid (23 mg, 10%, mp 130-132 °C
[lit.13 134-136 °C]): 1H NMR (CDCl3, 400 MHz) δ 1.47 (s, 6H),
1.51 (s, 3H), 1.87-1.95 (br, 2H), 2.04-2.09 (br, 1H), 2.26-2.29
(br, 1H), 3.34-3.46 (br, 2H), 4.10-4.36 (br, 1H); 13C NMR
(CDCl3, 100 MHz) mixture of rotamers δ (23.52-24.14), (28.1-
28.3), (29.2-30.7), (46.2-46.7), (58.7-58.8), (80.3-80.6), (153.9-
155.4), (176.6-178.4); [R]24 ) -52 (c ) 1, CHCl3), lit.13 [R]25
D
D
) -57.2 (c ) 2.0, AcOH). To N-(tert-butoxycarbonyl)proline
(23 mg, 0.11 mmol) in CH2Cl2 (5 mL) were added dicyclohexyl-
carbodiimide (22 mg, 0.11 mmol), 3,5-dimethylanilide (0.015
mL, 0.12 mmol), and HOBT (16.4 mg, 0.11 mmol). The reaction
mixture was stirred at room temperature for 12 h. The solvent
was removed in vacuo, 10 mL of EtOAc was added, and the
solids were filtered and the EtOAc solution was concentrated
in vacuo and purified by column chromatography (hexane/
EtOAc, 20/1) to give an amide (22 mg, 65%): 1H NMR (CDCl3,
400 MHz) δ 9.35 (br, 0.8H), 8.13 (br, 0.2H), 7.13 (m, 2H), 6.71
(br, 1H), 4.46-4.20 (br, 1H), 3.30-3.75 (br, 2H), 2.27 (s, 6H),
1.60-2.20 (m, 2H), 1.44-1.49 (br, 9H). The enantiomeric
purity of the 3,5-dimethylanilide derivative was determined
to be 99.5% by HPLC on Whelk-O column (5% 2-propanol/
hexane, flow rate ) 2 mL/min). The (R) enantiomer (minor)
had a retention time of 13.65 min, and the (S) enantiomer
(major) had a retention time of 19.17 min. Both pure (S)-3.5-
Tr a n sm eta la tion of 8 To P r ovid e (S)-7. A mixture of (-)-
sparteine (49.6 mg, 0.22 mmol) and n-BuLi (0.08 mL, 1.3 M
solution in cyclohexane) in 2 mL of Et2O was transferred to a
solution of 8 (50 mg, 0.11 mmol) in 1 mL of Et2O. The resulting
mixture was stirred at -78 °C for 2 h, then warmed to -25
°C, and stirred at this temperature for 1 h. Water (5 mL) was
added to quench the reaction, the aqueous layer was extracted
with EtOAc (3 × 5 mL), the combined organic phases were
washed with 0.5 M H3PO4, dried over MgSO4, filtered, and
concentrated in vacuo. The crude product was purified by flash
chromatography (hexane/EtOAc, 9/1) to give (S)-7 as a white
solid (mp 99-102 °C, 12 mg, 41%). The data of (S)-7 were
identical to those of (S)-7 prepared from 4.
Syn th esis of N-(ter t-Bu toxyca r bon yl)-(4-ch lor obu tyl)-
cin n a m yla m in e (9). To a solution of potassium pthalamide
(23.10 g, 124.7 mmol) in DMF (270 mL) was added trans-
(13) Azuse, I.; Tamura, N., Kinomura, K.; Okai, H.; Kouge, K. Bull.
Chem. Soc. J pn. 1989, 62, 3103.

1164 J . Org. Chem., Vol. 64, No. 4, 1999
Serino et al.
cinnamyl bromide (23.72 g, 116.7 mmol), and the resulting
solution was refluxed for 4.5 h. After the reaction was cooled
to room temperature, the reaction mixture was poured over
water (400 mL) and filtered. The collected solid was then
recrystallized from toluene to afford N-cinnamyl pthalamide
as a white solid (24.20 g, 79%): mp 155-156 °C; 1H NMR
(CDCl3) δ 7.86 (m, 2H, 7.72 (m, 2H), 7.35 (m, 2H), 7.29 (m,
2H), 7.22 (m, 1H), 6.66 (d, J ) 15.8 Hz, 1H), 6.26 (dt, J )
15.8, 6.5 Hz, 1H), 4.45 (dd, J ) 6.56, 1.2 Hz, 2H); 13C NMR
(CDCl3) δ 167.9, 136.1, 133.9, 133.7, 132.1, 128.5, 127.8, 126.4,
123.2, 122.6, 39.6. Anal. Calcd for C17H13NO2: C, 77.55; H,
4.98; N, 5.32. Found: C, 77.52; H, 5.06; N, 5.34.
To a solution of N-cinnamyl pthalamide (24.20 g, 91.9 mmol)
in EtOH (360 mL) was added aqueous H2NNH2 (55%, 6.40 mL,
109.8 mmol), and the resulting solution was refluxed for 6.5
h. Upon heating the solution turned a clear yellow color
followed by formation of a white precipitate. After the reaction
was cooled to room temperature, the reaction mixture was
poured over concentrated HCl (aqueous, 100 mL), and the
resulting solid was filtered off and washed with 10% (v/v, 50
mL). The filtrant was then made basic by the addition of 40%
KOH (wt/wt, 200 mL), and the aqueous layer was extracted
with Et2O (5 times, 100 mL). The combined ether extracts were
treated with a solution of (Boc)2O (24.5 g, 112.3 mmol) in Et2O
(25.0 mL). The solution was then stirred at room temperature
for 14 h, and then the Et2O solution was washed with H3PO4
(0.5 M, 2 times, 100 mL), saturated aqueous NaHCO3 (100
mL), and brine (100 mL). The organic layer was concentrated
in vacuo to afford the crude product as an off-white solid. The
material was recrystallized from hexane (2 times, 100 mL) to
afford N-Boc-cinnamylamine as white crystalline solid (17.53
g, 82%): mp 87-88 °C; 1H NMR (CDCl3) δ 7.34 (m, 2H), 7.29
(m, 2H), 7.22 (m, 1H), 6.47 (d, J ) 15.9 Hz, 1H), 6.17 (m, 1H),
4.86 (s, br, 1H), 3.89 (s, br, 2H), 1.47 (s, 9H); 13C NMR (CDCl3)
δ 155.7, 136.5, 131.2, 128.4, 127.4, 126.2, 79.2, 42.6, 28.3. Anal.
Calcd for C14H19NO2: C, 72.07; H,8.21; N, 6.00. Found: C,
72.18;, H, 8.22; N, 6.05.
To a solution of N-Boc-cinnamylamine (11.94 g, 51.2 mmol)
and NaH (60% dispersion in mineral oil, 2.90 g, 72.5 mmol)
in THF (250 mL) under nitrogen was added 1-bromo-4-
chlorobutane (12.65 g, 8.50 mL), 73.8 mmol). The resulting
solution was refluxed for 7.25 h. The solution was allowed to
cool to room temperature, and the solution was treated with
H2O. The material was partitioned between the layers, and
the organic layer was separated. The aqueous layer was
extracted with Et2O (4 times, 50 mL). The combined organic
extracts were dried over MgSO4 and concentrated to afford
the crude product as a yellow oil which was purified by flash
column chromatography to afford 9 as a clear, colorless oil
(10.00 g, 60%): 1H NMR (CDCl3, 400 MHz) δ 7.37 (m, 2H),
7.31 (m, 2H), 7.23 (m, 1H), 6.46 (d, br, J ) 15.9 Hz, 1H), 6.17
(s, br, 1H), 3.97 (s, br, 2H), 3.55 (t, J ) 6.2 Hz, 2H), 3.27 (s,
br, 2H), 1.80-1.53 (m, 4H), 1.48 (s, 9H); 13C NMR (CDCl3, 400
MHz) δ 155.6, 136.8, 132.2 and 131.7 (rotamers), 128.7, 127.7,
126.5, 125.8, 79.8, 49.2 and 48.8 (rotamers), 45.7, 44.8, 29.9,
28.6, 25.7. Anal. Calcd for C18H27NO2Cl: C, 66.76; H, 8.09; N,
4.32. Found: C, 66.68; H, 8.17; N, 4.59.
Syn th esis of (S)-N-(ter t-Bu toxyca r bon yl)-2-(tr a n s-â-
styr yl)p ip er id in e (10). To a solution of the chlorocarbamate
9 (0.4540 g, 1.40 mmol) in Et2O (14.0 mL) cooled to -78 °C
was added a pre-cooled solution of (-)-sparteine (0.66 mL, 2.87
mmol)/n-BuLi (1.75 M, 1.60 mL, 2.80 mmol) in Et2O (14.0
mmol) at -78 °C. The resulting yellow solution was allowed
to stir at -78 °C for 6.5 h and then allowed to warm to room
temperature. After the treatment of the reaction mixture with
water (10 mL), the aqueous layer was extracted with EtOAc
(5 times, 10 mL). The combined organic extracts were washed
successively with H3PO4 (0.5 M, 2 times, 15 mL) and brine
(20 mL). The organic layer was dried over MgSO4 and
concentrated to give the crude product as a yellow oil.
Preparative HPLC purification (2.5% EtOAc/hexane) afforded
(S)-10 as a white solid (0.320 g, 55%): mp 60-62 °C; 1H NMR
(CDCl3) δ 7.37-7.20 (m, 5 H), 6.37 (dd, J ) 16.1, 1.8 Hz, 1H),
6.17 (dd, J ) 16.1, 4.8 Hz, 1H), 4.95 (br, s, 1H), 3.99 (d, br, J
) 2.2 Hz, 1H), 2.90 (d, J ) 13.1 Hz, 1H), 1.46 (s, 9H), 1.81-
1.41 (br, m, 6H); 13C NMR (CDCl3) δ 156.1, 137.7, 131.4, 129.3,
129.2, 128.2, 128.0, 126.9, 80.1, 78.2, 52.9, 40.5, 30.2, 29.2, 26.2,
20.4. Anal. Calcd for C18H25NO2: C, 75.23; H, 8.77; 4.87.
Found: C, 75.28; H, 8.66; N, 4.96. The enantiomeric ratio (S:
R) was determined to be 82:18 by CSP-HPLC (1.75 mL/min,
2.5% 2-propanol/hexane) (Rf of major peak, 9.8 min; Rf minor
peak, 4.6 min).
Deter m in a tion of Absolu te Con figu r a tion of (S)-N-
(ter t-Bu toxyca r bon yl)-2-(tr a n s-â-styr yl)p ip er id in e (10).
To a stirred solution of (S)-10 (0.117 g, 0.41 mmol, 84:16 er)
and 0.0024 g of RuCl3‚xH2O (0.012 mmol) in water (1.2 mL)/
CCl4 (0.8 mL)/CH3CN (0.8 mL) was added NaIO4 (0.400 g, 1.87
mmol). The biphasic reaction mixture was stirred at room
temperature rapidly for 5 h. After 5 h, water (5 mL) and CH2-
Cl2 (5 mL) were added, and the material was partitioned
between the layers. The aqueous layer was extracted with CH2-
Cl2 (5 times, 5 mL), and the combined organic extracts were
dried over MgSO4. The crude product was isolated by concen-
tration in vacuo and purified by flash column using 1% AcOH/
20% EtOAc/hexane to afford (S)-N-Boc-pipecolic acid. Using
standard DCC coupling procedure, (S)-N-Boc-pipecolic acid
(0.0460 g, 0.20 mmol), DCC (0.0458 g, 0.22 mmol), HOBT
(0.0291 g, 0.22 mmol), and 3,5-dimethylaniline (0.03 mL, 0.24
mmol) in CH2Cl2 (8.0 mL) were stirred at room temperature
for 18 h and then worked up by filtering through a plug of
silica gel using 100% EtOAc as the eluent. The product was
purified by flash column (20% EtOAc/hexane) and then by
preparatory HPLC (5% EtOAc/hexane) to afford the anilide
was a sticky oil (0.0514 g, 78%): 1H NMR was in agreement
with the racemic product. The product was obtained in an er
of 84:16 using the Whelk-O column (5% 2-propanol/hexane,
1.50 mL/min; Rf (R)-enantiomer (11.3 min, minor); Rf (S)-
enantiomer (13.3 min, major).
P r ep a r a t ion of N-(ter t-Bu t oxyca r b on yl)-N-(3-oxa -3-
bu ten yl)ben zyla m in e (11). To a solution of N-Boc-N-(3-
butenyl)benzylamine (50 mg) in 5 mL of methylene chloride
was added mCPBA (2.2 equiv), and the resulting solution was
stirred for 10 h at room temperature. saturated NaHCO3
solution (10 mL) was added and the aqueous layer was
extracted with methylene chloride. The combined organic
phase was dried, filtered, and concentrated in vacuo. The crude
mixture was purified by flash chromatograghy to give 11 (41
mg, 78% yield) as a colorless oil: 1H NMR (CDCl3) δ 7.33-
7.23 (m, 5 H), 4.43 (br, 2H), 3.36 (br, 2H), 2.89 (br, 1H), 2.72
(t, 1H, J ) 4.9 Hz), 2.42 (br, 1H), 1.65 (m, 2H), 1.44 (br, 9H);
13C NMR (CDCl3) δ 155.5, 138.3, 128.5, 127.7, 127.2, 79.8, 50.8,
50.2, 46.9, 43.7, 31.4, 28.7; HRMS calcd for C16H24NO3 (M+
1) 278.1756, found 278.1747.
+
N-(ter t-Bu toxyca r bon yl)-2-P h en yl-3-(h yd r oxym eth yl)-
p yr r olid in e (13). The procedure identical with the synthesis
of 10 was used to produce 13. From 20 mg of 11, 13 mg (67%
yield) of an inseparable 50:50 mixture of two diastereomers
was obtained as a colorless oil: 1H NMR (CDCl3, 400 MHz)
less polar product 7.31-7.05 (m, 5H), 4.90 (d, J ) 7.7 Hz, 1H),
3.84 (m, 1H), 3.51 (m, 1H), 3.24 (m, 2H), 2.69 (m, 1H), 1.97
(m, 1H), 1.81 (m, 1H), 1.56 (brs, 9H); more polar product 7.96-
7.05 (m, 5H), 4.52 (br, 1H), 3.72 (m, 4H), 2.35 (m, 1H), 2.06
(m, 1H), 1.77 (m, 1H), 1.56 (s, br, 9H); CIMS m/z 278 (M+
+
1); HRMS calcd for C16H24NO3 (M+ + 1) 278.1756, found
278.1749. The enantiomeric ratio of the less polar product 13
was determined to be 97:3 by chiral HPLC using racemic
material as a standard (Whelk-O column; 10% 2-propanol in
hexane; 1.5 mL/min; the major enantiomer had a retention
time of 7.6 min, and the minor enantiomer had a retention
time of 6.6 min). The enantiomeric ratio of the more polar
product 13 was determined to be 95:5 by chiral HPLC using
racemic material as a standard (Whelk-O column; 10% 2-pro-
panol in hexane; 1.5 mL/min; the major enantiomer had a
retention time of 15.4 min, and the minor enantiomer had a
retention time of 9.1 min).
P r ep a r a t ion of N-(ter t-Bu t oxyca r bon yl)-N-(4-oxa -4-
p en ten yl)ben zyla m in e (12). The procedure identical with
the synthesis of 11 was used to produce 12 (80% yield). The
1H NMR of product was identical to those of the authentic
material reported previously:11 1H NMR (CDCl3) δ 7.33-7.23

N-Boc 2-Substituted Pyrrolidines and Piperidines
J . Org. Chem., Vol. 64, No. 4, 1999 1165
(m, 5 H), 4.20 (br, 2H), 3.20 (br, 2H), 2.89 (br, 1H), 2.72 (t,
1H, J ) 4.3 Hz), 2.43 (br, 1H), 1.60 (m, 4H), 1.45 (br, 9H).
N-(ter t-Bu toxyca r bon yl)-2-P h en yl-3-(h yd r oxym eth yl)-
p ip er id in e (14). The procedure identical with the synthesis
of 10 was used to produce 14. From 208 mg of 12, 60 mg (29%
yield) of an inseparable 86:14 mixture of two diastereomers
was obtained as a colorless oil. The 1H NMR of product was
identical to those of the authentic material reported previ-
ously.11 The enantiomeric ratio of major diastereomer was
determined to be 81:19 by chiral HPLC using racemic material
as a standard (Whelk-O column; 5% 2-propanol in hexane; 1.5
mL/min; the major enantiomer had a retention time of 17.4
min, and the minor enantiomer had a retention time of 12.3
min). The enantiomeric ratio of minor diastereomer was
determined to be 86:14 by chiral HPLC using racemic material
as a standard (Whelk-O column; 5% 2-propanol in hexane; 1.5
mL/min; the major enantiomer had a retention time of 8.3 min,
and the minor enantiomer had a retention time of 7.4 min).
Ack n ow led gm en t. We are grateful to the National
Institute of Health (GM-18874) and National Science
Foundation (CHE-9526355) for support of this work. We
are also grateful for support of Dr. Caterina Serino from
“Stereoselezione in Sintesi Organica. Metodologie ed
Applicazioni” supported by MURST (Rome) and the
University of Bari.
J O981553J