Asymmetric syntheses of 2-substituted and 2,5-disubstituted pyrrolidines from (3S,5R,7aR)-5-(benzotriazol-1-yl)-3-phenyl[2,1-b]oxazolopyrrolidine

Article abstract of DOI:10.1021/jo9821426

Benzotriazole, 2,5-dimethoxytetrahydrofuran, and (S)-phenylglycinol in one step gave 80% of (3S, 5R,7aR)-5-(benzotriazol-1-yl)-3-phenyl-[2,1- b]oxazolopyrrolidine (6), whose crystal structure was confirmed by X-ray crystallography. Novel chiral pyrrolidine synthon 6 reacts with organosilicon (allyltrimethylsilanes and vinyloxytrimethylsilanes), organophosphorus, organozinc, and Grignard reagents to afford chiral 2-substituted and 2,5- disubstituted pyrrolidines.

Full text of DOI:10.1021/jo9821426

J . Org. Chem. 1999, 64, 1979-1985
1979
Asym m etr ic Syn th eses of 2-Su bstitu ted a n d 2,5-Disu bstitu ted
P yr r olid in es fr om
(3S,5R,7a R)-5-(Ben zotr ia zol-1-yl)-3-p h en yl[2,1-b]oxa zolop yr r olid in e‡
Alan R. Katritzky,*,§ Xi-Lin Cui,§ Baozhen Yang,§ and Peter J . Steel
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200, and Department of Chemistry, University of Canterbury,
Christchurch, New Zealand
Received October 23, 1998
Benzotriazole, 2,5-dimethoxytetrahydrofuran, and (S)-phenylglycinol in one step gave 80% of (3S,
5R,7aR)-5-(benzotriazol-1-yl)-3-phenyl-[2,1-b]oxazolopyrrolidine (6), whose crystal structure was
confirmed by X-ray crystallography. Novel chiral pyrrolidine synthon 6 reacts with organosilicon
(allyltrimethylsilanes and vinyloxytrimethylsilanes), organophosphorus, organozinc, and Grignard
reagents to afford chiral 2-substituted and 2,5-disubstituted pyrrolidines.
In tr od u ction
additions,5c,d and metal-catalyzed cyclizations.5e,f Ring
syntheses of optically active pyrrolidines are usually
multistep: Rapoport et al. prepared chiral 2,5-disubsti-
tuted pyrrolidines from glutamic acid in 10 or more
steps,5g while Kibayashi et al. made 2,5-disubstituted
pyrrolidines in seven steps starting with D-mannitol.5h
Syntheses in which a preformed pyrrolidine ring is
functionalized6 include stepwise alkylation of N-nitroso-
pyrrolidine via deprotonation R to the nitrogen atom,6a
conjugate addition to R,â-unsaturated 2-pyrrolidinones,6g
and alkylation and reduction of the Lukes-Sorm di-
lactam.6c Such syntheses often derive their chirality
source from an amino acid, e.g., proline6j or pyroglutamic
acid.6d,6e
Endocyclic enamines (1) have been developed as suc-
cessful synthons by Stevens (Figure 1).7 Husson et al.
have used both the 2-cyano-6-oxazolopiperidine synthon
(2b)8 and the lower homologue (2a ) for the synthesis of
chiral 2-substituted and 2,5-disubstituted pyrrolidines9
including (+)-ferruginine.10 Chiral R,â-unsaturated 2-pyr-
rolidinone synthons (311 and 412) have been recently used
Pyrrolidine derivatives are attractive synthetic targets1
because numerous biological compounds possess pyrrol-
idine rings as their framework,2 and some of them are
pharmaceutically important.3 In addition, enantiomeri-
cally pure pyrrolidines are useful chiral auxiliaries.4
Substituted pyrrolidines have been synthesized by (i)
pyrrolidine ring construction5 and (ii) substituent modi-
fication of a preformed ring. Many ring syntheses give
racemic products, e.g., photocyclization of N-chloramines,
reductive amination of 1,4-diketones,5b 1,3-dipolar cyclo-
‡ This paper is dedicated in friendship and with affection to Henk
van der Plas on the occasion of his 70th anniversary.
§ University of Florida.
University of Canterbury.
(1) (a) Braekman, J . C.; Daloze, D. In Studies in Natural Products
Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1990; Vol. 6,
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M.; Figadere, B. Tetrahedron: Asymmetry 1996, 7, 927.
(2) (a) Elbein, A.; Molyneux, R. I. In Alkaloids, Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; J ohn Wiley: New York,
1990; Vol. 5, p 1-54. (b) Attygalle, A. B.; Morgan, E. D. Chem. Soc.
Rev. 1984, 13, 245. (c) Schmeltz, I.; Hoffmann, D. Chem. Rev. 1977,
77, 295.
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Synthesis 1995, 772. (b) Lin, N.-H.; Carrera, G. M., J r.; Anderson, D.
J . J . Med. Chem. 1994, 37, 3542.
(6) For some examples, see the following. Racemic synthesis: (a)
Fraser, R. R.; Passannanti, S. Synthesis 1976, 540. (b) J ones, T. H.;
Blum, M. S.; Fales, H. M. Tetrahedron 1982, 38, 1949. (c) Gessner,
W.; Takahashi, K.; Brossi, A.; Kowalski, M.; Kaliner, M. A. Helv. Chim.
Acta 1987, 70, 2003. Optically active synthesis: (d) Saliou, C.; Fleurant,
A.; Celerier, J . P.; Lhommet, G. Tetrahedron Lett. 1991, 32, 3365. (e)
Haviari, G.; Celerier, J . P.; Petit, H.; Lhommet, G.; Gardette, D.;
Gramain, J . C. Tetrahedron Lett. 1992, 33, 4311. (f) Viso, A.; Lee, N.
E.; Buchwald, S. L. J . Am. Chem. Soc. 1994, 116, 9373. (g) Chan, P.
W. H.; Cottrell, I. F.; Moloney, M. G. Tetrahedron Lett. 1997, 38, 5891.
(h) Bardou, A.; Celerier, J . P.; Lhommet, G. Tetrahedron Lett. 1997,
38, 8507. (i) Blot, J .; Bardou, A.; Bellec, C.; Fargeau-Bellassoued, M.-
C.; Celerier, J . P.; Lhommet, G.; Gardette, D.; Gramain, J .-C. Tetra-
hedron Lett. 1997, 38, 8511. (j) Sudau, A.; Nubbemeyer, U. Angew.
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M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 1, p 64. (b)
Yamamoto, Y.; Hoshino, J .; Fujimoto, Y.; Ohmoto, J .; Sawada, S.
Synthesis 1993, 298. (c) Koh, K.; Ben, R. N.; Durst, T. Tetrahedron
Lett. 1994, 35, 375. (d) Corey, E. J .; Yuen, P.-W.; Hannon, F. J .; Wierda,
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Lijewski, L. Tetrahedron Lett. 1990, 31, 7415. (f) J ones, T. K.; Mohan,
J . J .; Xavier, L. C.; Blacklock, T. J .; Mathre, D. J .; Sohar, P.; J ones, E.
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1991, 56, 763.
(5) For some recent examples, see: Racemic synthesis: (a) J ones,
T. H.; Franko, J . B.; Blum, M. S.; Fales, H. M. Tetrahedron Lett. 1980,
21, 789. (b) J ones, T. H.; Highet, R. J .; Don, A. W.; Blum, M. S. J . Org.
Chem. 1986, 51, 2712. (c) Chastanet, J .; Roussi, G. J . Org. Chem. 1988,
53, 3808. (d) Wittland, C.; Arend, M.; Risch, N. Synthesis 1996, 367.
(e) Backvall, J .-E.; Schink, H. E.; Renko, Z. D. J . Org. Chem. 1990,
55, 826. (f) Cancho, Y.; Martin, J . M.; Martinez, M.; Liebaria, A.;
Moreto, J . M.; Delgado, A. Tetrahedron 1998, 54, 1221. Optically active
synthesis: (g) Shiosaki, K.; Rapoport, H. J . Org. Chem. 1985, 50, 1229.
(h) Machinaga, N.; Kibayashi, C. J . Org. Chem. 1991, 56, 1386. (i)
Meyers, A. I.; Burgess, L. E. J . Org. Chem. 1991, 56, 2294. (j) Lorthiois,
E.; Marek, I.; Normant, J . F. J . Org. Chem. 1998, 63, 2442. (k) Enierga,
G.; Hockless, D. C. R.; Perlmutter, P.; Rose, M.; Sjoberg, S.; Wong, K.
Tetrahedron Lett. 1998, 39, 2813. (l) Sasaki, N. A.; Sagnard, I.
Tetrahedron 1994, 50, 7093. (m) Dockner, M.; Sasaki, N. A.; Potier, P.
Heterocycles 1996, 42, 529.
(7) Stevens, R. V. Acc. Chem. Res. 1977, 10, 193.
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Chem. Soc. 1983, 105, 7754. (b) Bonin, M.; Grierson, D. S.; Royer, J .;
Husson, H.-P. Org. Synth. 1992, 70, 54.
(9) (a) Huang, P.-Q.; Arseniyadis, S.; Husson, H.-P. Tetrahedron Lett.
1987, 28, 547. (b) Royer, J .; Husson, H.-P. Tetrahedron Lett. 1987, 28,
6175. (c) Arseniyadis, S.; Huang, P.-Q.; Husson, H.-P. Tetrahedron Lett.
1988, 29, 631. (d) Arseniyadis, S.; Huang, P.-Q.; Piveteau, D.; Husson,
H.-P. Tetrahedron 1988, 44, 2457.
(10) Gauthier, I.; Royer, J .; Husson, H.-P. J . Org. Chem. 1997, 62,
6704.
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1992, 57, 1059. (b) Luker, T.; Koot, W.-J .; Hiemstra, H.; Speckamp,
W. N. J . Org. Chem. 1998, 63, 220.
10.1021/jo9821426 CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/25/1999

1980 J . Org. Chem., Vol. 64, No. 6, 1999
Katritzky et al.
Sch em e 1. P r ep a r a tion a n d th e X-r a y Str u ctu r e
of Syn th on 6a
a
(i) 0.1 N HCl, 50 °C, 0.5 h; (ii) CH2Cl2, rt, 12 h.
F igu r e 1. Synthons.
by Speckamp and Royer, respectively, for the synthesis
of 3,4-disubstituted and ring-fused pyrrolidines. Despite
these successes, the development of simple synthons, and
thus reliable and flexible routes to complex chiral pyr-
rolidines, is still important.
Benzotriazole is a useful auxiliary group in organic
synthesis.13 Benzotriazole methodology has been applied
by Shankar et al. to synthesize polyhydroxylated piper-
idines as potential glycosidase inhibitors.14 We prepared
chiral 2-substituted and 2,6-disubstituted piperidines
from intermediate 2-benzotriazolyl-6-oxazolopiperidine
(5).15 We now report the details of the preparation of
2-benzotriazolyl-5-oxazolopyrrolidine (6) and its applica-
tion as a pyrrolidine synthon for chiral pyrrolidines (for
a preliminary communication of part of this work see ref
16).
and 2a cannot be prepared by Robinson-Schopf conden-
sation of succinaldehyde with phenylglycinol in the
presence of KCN,8b the method used for 2b. An epimeric
mixture of 2a was produced in 52% yield by the conden-
sation of phenylglycinol, dimethoxytetrahydrofuran, and
aqueous KCN at pH ∼3 over 48 h, followed by refluxing
the crude reaction extract in EtOH for 96 h.9b
Rea ction s of Syn th on 6 w ith Allylsila n es a n d
Vin yloxysila n es To Give 2-Su bstitu ted a n d 2,5-
Disu bstitu ted P yr r olid in es. Synthon 6 with allyltri-
methylsilane in the presence of zinc(II) bromide, tin(IV)
chloride, or boron trifluoride as a Lewis acid gave the
2-substituted product (8) along with the elimination
product (7) (Scheme 2). Boron trifluoride-diethyl ether-
ate cleanly gave 8 in 40-50% yield. Synthon 6 and (2-
methylprop-1-en-3-yl)trimethylsilane gave 15 (Scheme 3),
which has the 2-methylpropenyl substituent at the C-2
pyrrolidine position.
The trans H-3, H-7a relationship of 6 was unchanged
in 8. A 2D shift correlation COSY experiment allowed
assignment of the 1H resonances, and the absolute
configuration (S) of C-5 in 8 was ascertained by the NOE
difference technique (Figure 2). Presaturation of the H-5
resonance resulted in enhancement of the signals for the
H-3 proton.
Hydrogenation of intermediates 8 and 15 cleaved the
chiral auxiliary and reduced the double bond to give the
2-alkylpyrrolidines 11 and 18 in nearly quantitative
yields (Scheme 2 and 3).
Resu lts a n d Discu ssion
P r ep a r a tion a n d Ch a r a cter iza tion of (3S,5R,
7a R)-5-(Ben zot r ia zol-1-yl)-3-p h en yl[2,1-b]oxa zolo-
p yr r olid in e (6). Benzotriazole, (S)-phenylglycinol, and
hydrolyzed 2,5-dimethoxytetrahydrofuran (the equivalent
of succindialdehyde) at room temperature gave crystal-
line (3S,5R, 7aR)-5-(benzotriazol-1-yl)-3-phenyl[2,1-b]-
oxazolopyrrolidine (6) in 80% yield on a 100 mmol scale.
This reaction entails the formation of two heterocyclic
rings and two new chiral centers in one step (Scheme 1)
by double Robinson-Schopf condensation of the dialde-
hyde with the amino group and benzotriazole intercept-
ing the initially formed iminium ion. Concentrations of
HCl greater than 0.1 N or a reaction temperature higher
than ambient led to the formation of byproduct 7 and
lower yields of 6. The 1H and 13C NMR spectra of the
crude product 6 showed only one diastereoisomer; the
detailed structure of 6 was shown by X-ray crystal-
lography to be that in Scheme 1.
Compound 6 is thus even easier to prepare than is its
higher homologue 2-benzotriazolyl-6-oxazolopiperidine
(5).15 By contrast, the cyano derivative (2a )9a,c,d was less
stable than that of its 5,6-membered ring analogue (2b),8a
(12) (a) Baussanne, I.; Royer, J . Tetrahedron Lett. 1998, 39, 845.
(b) Baussanne, I.; Travers, C.; Royer, J . Tetrahedron Asymmetry 1998,
9, 797.
(13) Katritzky, A. R.; Lan, X.; Yang, Z. J .; Denisko, O. V. Chem.
Rev. 1998, 98, 409.
(14) Shankar, B. B.; Kirkup, M. P.; McCombie, S. W.; Ganguly, A.
K. Tetrahedron Lett. 1993, 34, 7171.
(15) Katritzky, A. R.; Qiu, G.; Yang, B.; Steel, P. J . J . Org. Chem.
1998, 63, 6699.
Intermediate 8 was also reacted further with Grignard
reagents to give mixtures of cis and trans epimers 9 and
10 (Table 1), which were easily separated by flash
chromatography. As shown in Scheme 2 and Table 1, only
two isomers were produced in this reaction. Nucleophilic
substitution of the benzotriazole group at the C-2 pyr-
rolidine position gave one stereoisomer, with attack cis
to the phenyl group. Further substitution at the C-5
(16) Katritzky, A. R.; Cui, X.-L.; Yang, B.; Steel, P. J . Tetrahedron
Lett. 1998, 39, 1697.

Asymmetric Syntheses of Substituted Pyrrolidines
J . Org. Chem., Vol. 64, No. 6, 1999 1981
Sch em e 2a
F igu r e 2. NOE effects in 8.
Ta ble 1. Rea ction of In ter m ed ia te 8 w ith Gr ign a r d
Rea gen ts to P r ep a r e 9 a n d 10
total
yield
(%)
[R]20 of 9 [R]20 of 10
D
D
ratio
9:10
(c 1 g/mL,
EtOH)
(c 1 g/mL,
EtOH)
entry
R
a
b
c
d
Me
90
90
90
85
10:90
20:80
15:85
<3:97
-13.0
+31.5
+56.4
-36.7
-20.9
-23.4
-34.6
n-pentyl
PhCH2CH2
Ph
Ta ble 2. Rea ction of Syn th on 6 w ith Excess Gr ign a r d
Rea gen ts to P r ep a r e Com p ou n d s 23 a n d 24
total
yield
(%)
[R]20 of 23 [R]20 of 24
D
D
ratio
23:24
(c 1 g/mL,
EtOH)
(c 1 g/mL,
EtOH)
entry
R
a
b
c
d
e
Ph
Me
n-Pr
n-pentyl
PhCH2CH2
90
76
77
70
90
1:1
3:1
5:2
3:1
2:1
-17.6
+30.1
+20.3
+14.6
+8.2
-3.1
-23.0
-36.7
-42.9
-25.5a
a
Solvent: CHCl3.
Sch em e 3
10 was cleaved to afford the corresponding 2,5-dialkyl
pyrrolidines (12 and 13). When R was a phenyl group,
hydrogenolysis by pyrrolidine ring opening led to the
chiral primary amine (4R)-1-phenyl-4-heptanamine (14).
Thus, starting from 2,5-dimethoxytetrahydrofuran,
optically pure 2,5-disubstituted pyrrolidines were pre-
pared. Trans configuration products 13 dominate, which
could be useful as most natural dialkyl pyrrolidines (e.g.,
ant alkaloids1a,2b) have the trans 2,5-configuration. The
cis/trans stereoselectivities of several other approaches
are low, e.g., 60:40 in the case of the alkylation of
formamidines.18
Synthon 6 reacted with (R-substituted-vinyloxy)tri-
methylsilanes in the presence of boron trifluoride-diethyl
etherate at 0 °C to produce compounds 19, which have a
substituent bearing a carbonyl group at the C-2 pyrrol-
idine position (Scheme 4). Compounds 19a (R ) Me) and
19b (R ) Ph) are potential intermediates for the prepa-
ration of (-)-hygrine and ruspolinone analogues.5k,19
Synthon 6 reacted with 1-methoxy-1-trimethylsiloxy-2-
methyl-1-propene to give compound 20 as an inseparable
mixture of two isomers, in 64% yield.
Rea ction s of Syn th on 6 w ith P h osp h or u s Re-
a gen ts. During the last two decades, considerable efforts
have been made toward the asymmetric synthesis of
phosphonic analogues of naturally occurring R-amino
acids.20 Cyclic phosphonic acids, like their acyclic deriva-
tives, also show interesting properties.
pyrrolidine position gave a mixture of cis and trans
isomers. The mechanism involves initial formation of an
iminium ion by opening the oxazolidine ring and subse-
quent nucleophilic addition, which selectively attacked
at the less hindered face of the molecule. The cis-trans
ratio of 9:10 from alkyl Grignards ranged from 20:80 to
10:90, but for the phenyl group the ratio of 9:10 was <3:
>97; only trans isomer was detected in the crude NMR
spectra.
The stereochemistry of compounds 9 (cis) and 10
(trans) was determined by comparing their NMR spectra
and [R]D with those reported in the literature17 and with
the series cis-23 and trans-24 products derived from
synthon 6 with excess Grignard reagents. The absolute
configuration of 24b has been elucidated by X-ray
crystallography.16 The optical rotations of cis-2,5-dialkyl
substituted 9 and 23 were usually positive, while those
of trans-2,5-dialkyl-substituted 10 and 24 were always
negative, as shown in Tables 1 and 2.
(18) Meyers, A. I.; Edwards, P. D.; Rieker, W. F.; Bailey, T. R. J .
Am. Chem. Soc. 1984, 106, 3270.
(19) (a) Roessler, F.; Ganzinger, D.; J ohne, S.; Schopp, E.; Hesse,
M. Helv. Chim. Acta 1978, 61, 1200. (b) Langenskiold, T.; Lounasmaa,
M. Heterocycles 1983, 20, 671.
(20) For recent asymmetric syntheses see: (a) Smith, A. B., III;
Yager, K. M.; Taylor, C. M. J . Am. Chem. Soc. 1995, 117, 10879. (b)
Maury, C.; Gharbaoui, T.; Royer, J .; Husson, H.-P. J . Org. Chem. 1996,
61, 3687. (c) Maury, C.; Wang, Q.; Gharbaoui, T.; Chiadmi, M.; Tomas,
A.; Royer, J .; Husson, H.-P. Tetrahedron 1997, 53, 3627.
Under hydrogenolytic conditions (Pd(OH)2/C, H2), the
chiral auxiliary attached to the nitrogen atom of 9 and
(17) Higashiyama, K.; Inoue, H.; Takahashi, H. Tetrahedron 1994,
50, 1083.

1982 J . Org. Chem., Vol. 64, No. 6, 1999
Katritzky et al.
Sch em e 4
Sch em e 6
Sch em e 5
the corresponding cis and trans 2,5-disubstituted pyr-
rolidines (25a -d and 26a -d ) in excellent yields.
When phenylmagnesium bromide reacted with 6, the
reaction gave 23a and 24a in a ratio of 1:1. However,
methylmagnesium bromide in this reaction gave a ratio
of 3:1. Similarly, other alkyl Grignard reagents afforded
23 and 24 in ratios of about 3:1. The ratios of cis/trans
23:24 (Table 2) are surprising in contrast to the 9:10
ratios (Table 1), with cis-23 being the major product.
a
Key: (i) P(OEt)3, ZnBr2, CH2Cl2, rt; (ii) Pd/C, H2.
The Arbuzov reaction,21 as previously employed by
Husson et al. to prepare piperidin-2-ylphosphonic acid,20c
converted 6 into the expected 2-substituted pyrrolidine
phosphonate (21) in 77% yield in the presence of the mild
Lewis acid ZnBr2. Both 1H and 13C NMR spectra of 21
indicated that only one diastereoisomer was obtained.
Hydrogenation of 21 gave diethyl (2R)-tetrahydropyrro-
2-ylphosphonate (22) in 63% overall yield (Scheme 5).
We previously found that the C-benzotriazole bond
can be cleaved selectively in the presence of a geminal
C-O bond.22 This, and the results described above,
suggested that two reactive sites in the pyrrolidine ring
of synthon 6 should be discriminated by mild organo-
metallic reagents. Phenyl organozinc reagent and Re-
formatsky reagent did furnish the monosubstituted
products 27 and 28 (a key intermediate to homohygrinic
acid), respectively, but in low yields (10%) and with
disubstituted and elimination byproducts (Scheme 6).
Treatment of synthon 6 with 1 equiv of Grignard reagent
at 0 °C gave mixtures of cis and trans 2,5-disubstituted
pyrrolidines (23 and 24), along with a large amount of
recovered starting material 6. Many attempts, including
addition of Lewis acids such as ZnBr2 to the reaction
mixture to assist the departure of the benzotriazolyl
group, lowering the reaction temperature, and adjusting
the rate of Grignard reagent addition, failed to yield the
desired monosubstituted product in reasonable yield.
This indicates that the two reaction centers, R-aminoben-
zotriazolyl at the C-2 position and R-amino ether at the
The reactivity of synthon 6 toward phosphorus re-
agents differs from that of its homologue 5 and of synthon
2b. Lithium diethyl phosphite was used successfully in
the preparation of piperidin-2-yl phosphonate from 5,15
but it failed to react with 6. Furthermore, attempts to
use the same procedure that gave 2-cyano-6-oxazaphos-
phorinane from synthon 2b20c failed for synthon 6 as
triethyl phosphite in the presence of SnCl4 in room
temperature for 24 h gave a complex mixture.
Rea ction s of Syn th on 6 w ith Gr ign a r d Rea gen ts
a n d Or ga n ozin c Rea gen ts: P r ep a r a tion of 2,5-
Disu bstitu ted P yr r olid in es. When excess (4 equiv)
Grignard reagent was reacted with synthon 6 at 0 °C,
the reactions gave mixtures of the cis products (23a -e)
and trans products (24a -e) in excellent total yields; each
of the diastereoisomeric pairs of 23 and 24 were sepa-
rated by column chromatography. Hydrogenation of
23b-e and 24b-e in the presence of Pd/C catalyst gave
(22) Katritzky, A. R.; Bao, W.; Qi, M.; Fali, C. N.; Prakash, I.
Tetrahedron Lett. 1998, in press.
(21) Bhattacharya, A. K.; Thyagarajan, G. Chem. Rev. 1981, 81, 415.

Asymmetric Syntheses of Substituted Pyrrolidines
J . Org. Chem., Vol. 64, No. 6, 1999 1983
30.2, 40.4, 66.3, 68.0, 73.0, 98.9, 116.4, 126.5, 126.9, 128.4,
135.7, 143.0. Anal. Calcd for C15H19NO: C, 78.56; H, 8.37; N,
6.11. Found: C, 78.35; H, 8.62; N, 6.24.
C-5 position of the pyrrolidine ring, have similar reac-
tivities toward Grignard reagents.
Gen er a l P r oced u r e for Hyd r ogen a t ion . A solution of
starting material (1 mmol) in ethanol (60 mL) with 10%
Pd(OH)2/C (50 mg) was charged with hydrogen at a pressure
of 40 psi at room temperature for 24 h. After filtration of the
catalyst, the filtrate was treated with HCl in EtOAc (2.0 M)
and stirred at room temperature for 30 min. The solvent was
evaporated under vacuum, and the residue was washed with
ethyl ether to provide the crude product, which can be
recrystallized from CHCl3 and hexane or purified by column
chromatography using CH2Cl2/MeOH as eluents.
Con clu sion
Novel chiral pyrrolidine 6, (3S,5R,7aR)-5-(benzotriazol-
1-yl)-3-phenyl[2,1-b]oxazolopyrrolidine, which was pre-
pared from benzotriazole, 2,5-dimethoxytetrahydrofuran,
and (S)-phenylglycinol in one step, can be used as a chiral
synthon for rapid asymmetric syntheses of 2-substituted
and 2,5-disubstituted pyrrolidines.
(2R)-2-P r opylpyr r olidiu m ch lor ide (11): yield 95%; [R]20
D
1
Exp er im en ta l Section
) -3.21 (c 1.34, EtOH); H NMR δ 0.94 (t, J ) 7.2 Hz, 3H),
1.41-1.48 (m, 2H), 1.61-1.79 (m, 2H), 1.92-2.13 (m, 4H),
Gen er a l Com m en ts. Air- and moisture-sensitive reactions
were carried out under inert atmosphere (N2 or Ar). When
necessary, solvents and reagents were dried in the traditional
fashion prior to use. Column chromatography was carried out
on silica gel (230-400 mesh). All melting points were meas-
ured on a hot-stage apparatus and are not corrected. Optical
rotations were measured with a digital polarimeter (a 1 dm
3.27-3.47 (m, 3H), 9.23 (br s, 1H), 9.89 (br s, 1H); 13C NMR δ
13.7, 20.2, 23.5, 30.3, 34.1, 44.4, 60.2; HRMS calcd for C7H16
-
NCl 114.1283 (M - Cl), found 114.1306.
Gen er a l P r oced u r e for 8 Rea cted w ith Gr ign a r d
Rea gen ts To P r ep a r e 9 a n d 10. To a cold solution (ice-
water bath) of 8 (1 mmol) in dry THF (50 mL) was added
Grignard reagent (2 mmol) dropwise under nitrogen. The
reaction mixture was warmed to room temperature and stirred
overnight. The mixture was washed with NaOH (2 N, 3 × 30
mL) and water (2 × 30 mL) before being extracted with
CH2Cl2. The organic layers were dried over anhydrous Na2SO4.
After removal of the solvent, the residue was purified by
column chromatography (silica gel, hexane/ethyl acetate from
20/1 to 5/1 as eluents) to give pure products 9 and 10.
1
cell was used in all cases). The H and 13C NMR spectra were
measured in CDCl3 solution (300 and 75 MHz, respectively),
with TMS or CDCl3 as internal references.
(3S,5R,7a R)-5-(Ben zot r ia zol-1-yl)-3-p h en yl[2,1-b]ox-
a zolop yr r olid in e (6). A mixture of 2,5-dimethoxytetrahy-
drofuran (1.3 mL, 10 mmol) and HCl aqueous solution (40 mL,
0.1 N) was refluxed for 1 h and then cooled to room temper-
ature. A solution of benzotriazole (1.19 g, 10 mmol) and (S)-
phenylglycinol (1.37 g, 10 mL) in methylene chloride (100 mL)
was added to the cooled mixture, which was then stirred
overnight. The reaction mixture was washed with NaOH
aqueous solution (2 N, 3 × 30 mL) and water (2 × 30 mL).
The organic layer was dried over anhydrous Na2SO4. After
removal of the solvent, the residue was recrystallized from
(2S)-2-[(2S,5S)-2-Allyl-5-m eth yltetr a h yd r o-1H-p yr r ol-
1-yl]-2-p h en yl-1-eth a n ol (9a ): yield 9%; [R]20 ) -12.78 (c
D
0.90, EtOH); 1H NMR δ 1.21-1.31 (m, 4H), 1.34-1.45 (m, 2H),
1.68-1.74 (m, 1H), 2.02-2.12 (m, 1H), 2.26-2.31 (m, 1H), 2.60
(br s, 1H), 2.98-3.02 (m, 1H), 3.09-3.16 (m, 1H), 3.66-3.70
(m, 1H), 3.87-3.98 (m, 2H), 5.00-5.06 (m, 2H), 5.70-5.78 (m,
1H), 7.21-7.38 (m, 5H); 13C NMR δ 21.1, 29.2, 32.2, 42.8, 56.7,
61.5, 63.9, 116.5, 127.7, 128.3, 128.9, 136.1, 137.0. Anal. Calcd
for C16H23NO: C, 78.31; H, 9.47; N, 5.71. Found: C, 78.01; H,
9.72; N, 5.80.
ethyl acetate to give crystalline product 6 in 80% yield: mp
139-140 °C; [R]20 ) +89.0 (c 0.57, EtOH); H NMR δ 2.27-
1
D
2.32 (m, 1H), 2.57-2.67 (m, 3H), 3.68-3.75 (m, 1H), 4.48-
4.55 (m, 2H), 5.23-5.24 (m, 1H), 5.98-6.01 (m, 1H), 7.05-
7.20 (m, 5H), 7.26-7.35 (m, 2H), 7.53 (d, J ) 7.1 Hz, 1H), 7.99
(d, J ) 6.9 Hz, 1H); 13C NMR δ 29.6, 30.0, 68.5, 73.2, 82.4,
97.6, 111.0, 111.1, 119.8, 123.8, 126.1, 127.2, 128.4, 131.6,
140.6, 146.8. Anal. Calcd for C18H18N4O: C, 70.55; H, 5.93; N,
18.30. Found: C, 70.16; H, 6.18; N, 18.23.
(2S)-2-[(2S,5R)-2-Allyl-5-m eth yltetr a h yd r o-1H-p yr r ol-
1-yl]-2-p h en yl-1-eth a n ol (10a ): yield 81%; [R]20 ) -36.74
D
(c 0.86, EtOH); 1H NMR δ 1.02 (d, J ) 6.3 Hz, 3H), 1.30-1.37
(m, 1H), 1.44-1.51 (m, 1H), 1.76-1.94 (m, 3H), 2.07-2.12 (m,
1H), 2.64 (br s, 1H), 3.13-3.19 (m, 1H), 3.35-3.40 (m, 1H),
3.72-3.78 (m, 1H), 3.82-3.88 (m, 1H), 3.99-4.04 (m, 1H),
4.88-4.98 (m, 2H), 5.58-5.69 (m, 1H), 7.26-7.40 (m, 5H); 13
C
Crystal data for 6 at -132 °C:
C18H18N4O, M 306.36,
orthorhombic, P212121, a ) 5.6900(1) Å, b ) 9.3343(2) Å, c )
27.1700(5) Å, V ) 1511.53 (5) Å3, Z ) 4, λ (Mo KR) ) 0.710 73
Å, F(000) ) 648, Dc ) 1.346 gcm-3, µ ) 0.087 mm-1, 3082
reflections, 209 parameters, R ) 0.0331, Rw ) 0.0763 for all
data.
NMR δ 19.1, 28.2, 31.7, 39.3, 56.2, 59.1, 62.9, 63.8, 116.4, 127.6,
128.3, 129.3, 136.2, 140.1. Anal. Calcd for C16H23NO: C, 78.31;
H, 9.47; N, 5.71. Found: C, 77.87; H, 9.86; N, 5.73.
(2S)-2-[(2S,5S)-2-Allyl-5-p h en yltetr a h yd r o-1H-p yr r ol-
1-yl]-2-p h en yl-1-eth a n ol (10d ): yield 91%; [R]20 ) -34.59
D
1
(2S)-2-P yr r olyl-2-p h en yleth a n -1-ol (7). The elimination
product of (3S,5R,7aR)-5-(benzotriazol-1-yl)-3-phenyl[2,1-b]-
oxazolopyrrolidine (6) was formed in the presence of Lewis
(c 0.85, EtOH); H NMR δ 1.58-1.61 (m, 1H), 1.65-1.72 (m,
1H), 1.94-2.01 (m, 1H), 2.12-2.18 (m, 1H), 2.21-2.28 (m, 1H),
2.40-2.42 (m, 1H), 3.54-3.66 (m, 3H), 4.05-4.10 (m, 2H),
4.98-5.07 (m, 2H), 5.70-5.76 (m, 1H), 7.11-7.38 (m, 10H);
13C NMR δ 28.1, 33.0, 37.5, 61.5, 63.1, 63.4, 63.8, 116.6, 126.4,
126.9, 127.3, 127.9, 128.2, 129.4, 136.1, 139.1, 146.7; MS m/z
308 (M + 1), 266 (80), 146 (100), 129 (50), 91 (45). Anal. Calcd
for C21H25NO: C, 82.04; H, 8.21; N, 4.56. Found: C, 81.93; H,
8.71; N, 4.71.
acids or at high temperature: [R]20 ) -21.53 (c 0.85, EtOH);
D
1H NMR δ 2.02 (s, 1H), 4.09-4.16 (m, 2H), 5.18-5.22 (t, J )
6.9 Hz, 1H), 6.20 (s, 2H), 6.79 (s, 2H), 7.11-7.14 (d, J ) 6.9
Hz, 2H), 7.27-7.34 (m, 3H); 13C NMR δ 64.8, 65.2, 108.6, 119.9,
126.6, 128.0, 128.7, 138.5. Anal. Calcd for C12H13NO: C, 76.98;
H, 7.00; N, 7.48. Found: C, 76.89; H, 7.31; N, 7.78.
(3S,5S,7a R)-5-Allyl-3-p h en ylh exa h yd r op yr r olo[2,1-b]-
[1,3]oxa zole (8). To a solution of 6 (3.1 g, 10 mmol) in CH2Cl2
(200 mL) was added sequentially allyltrimethylsilane (4.0 mL,
25 mmol) and zinc bromide. The reaction mixture was stirred
at 0 °C for 24 h. Then the reaction was quenched with 2 N
NaOH and the aqueous suspension extracted with CH2Cl2. The
combined organic extracts were washed with brine, dried with
Na2SO4, and evaporated in vacuo. Column chromatography on
silica gel, eluting with hexane/ethyl acetate (10/1), yielded 1.03
(2S)-2-[(2S,5S)-2-Met h yl-5-(2-m et h yl-2-p r op en yl)t et -
r a h yd r o-1H-p yr r ol-1-yl]-2-p h en yl-1-eth a n ol (16): yield 9%;
[R20]D ) +9.52 (c 0.21, EtOH); 1H δ 1.08-1.21 (m, 4H), 1.31-
1.45 (m, 2H), 1.50-1.73 (m, 4H), 1.95-2.08 (m, 1H), 2.20-
2.30 (m, 1H), 3.05-3.08 (m, 2H), 3.64-3.66 (m, 1H), 3.85-
3.91 (m, 2H), 4.58 (s, 1H), 4.66 (s, 1H), 7.17-7.37 (m, 5H); 13
C
NMR δ 19.4, 22.4, 27.8, 31.5, 43.1, 55.9, 57.8, 62.8, 63.8, 111.8,
118.0, 127.6, 128.3, 129.4, 143.9. MS m/z 228 (10), 204 (100),
84 (100); HRMS calcd for C17H25NO 260.2014 (M + 1), found
260.1962.
g (45%) 8 as a colorless oil: [R]20 ) +57.94 (c 2.52, EtOH);
D
1H NMR δ 1.56-1.66 (m, 1H), 1.84-1.95 (m, 1H), 2.02-2.33
(m, 4H), 2.93-3.00 (m, 1H), 3.62 (dd, J ) 6.6 Hz, J ) 8.4 Hz,
1H), 4.20 (t, J ) 6.6 Hz, 1H), 4.37 (t, J ) 7.2 Hz, 1H), 4.94-
5.02 (m, 3H), 5.68-5.80 (m, 1H), 7.20-7.38 (m, 5H); 13C δ 29.9,
(2S)-2-[(2R,5S)-2-Met h yl-5-(2-m et h yl-2-p r op en yl)t et -
r ah ydr o-1H-pyr r ol-1-yl]-2-ph en yl-1-eth an ol (17): yield 86%;
[R]20 ) -4.52 (c 1.26, EtOH); 1H NMR δ 1.04 (d, J ) 6.3 Hz,
D
3H), 1.24-1.59 (m, 2H), 1.48 (s, 3H), 1.75-2.09 (m, 4H), 3.27-

1984 J . Org. Chem., Vol. 64, No. 6, 1999
Katritzky et al.
3.30 (m, 1H), 3.47-3.49 (m, 1H), 3.74-3.79 (m, 1H), 3.84-
3.89 (m, 1H), 3.97-4.04 (m, 1H), 4.55 (s, 1H), 4.65 (s, 1H),
7.24-7.42 (m, 5H); 13C NMR δ 19.0, 22.3, 27.6, 31.4, 42.8, 56.4,
58.3, 63.2, 63.7, 112.0, 118.0, 127.8, 128.4, 129.5, 143.6; HRMS
calcd for C17H25NO 260.2014 (M + 1), found 260.1962.
Dieth yl (3S,5R,7a R)-3-P h en ylh exa h yd r op yr r olo[2,1-b]-
[1,3]oxa zol-5-yl p h osp h on a te (21). To a solution of 6 (3.1
g, 10 mmol) in CH2Cl2 (200 mL) were added sequentially
triethyl phosphite (3.4 mL, 20 mmol) and ZnBr2 (1 mmol). The
reaction mixture was stirred at 0 °C for 20 h. Then the reaction
was quenched with 2 N NaOH, and the aqueous suspension
was extracted with CH2Cl2. The combined organic extracts
were washed with brine, dried with Na2SO4, and evaporated
in vacuo. Column chromatography on silica gel, eluting with
hexane/EtOAc (2/1), yielded 2.57 g (77%) of 21 as a colorless
(2S,5R)-2-P en tyl-5-p r op ylp yr r olid iu m Ch lor id e (12).
From hydrogenation of 9b: yield 90%; [R]20 ) +3.09 (c 2.98,
D
EtOH); 1H NMR δ 0.88 (t, J ) 6.3 Hz, 3H), 0.96 (t, J ) 6.9 Hz,
3H), 1.30-1.50 (m, 8H), 1.80-1.88 (m, 4H), 2.00-2.17 (m, 4H),
3.46-3.47 (m, 2H), 8.93 (br s, 1H), 10.14 (br s, 1H); 13C NMR
δ 13.8, 14.0, 20.2, 22.5, 26.6, 28.5, 28.6, 31.5, 32.2, 34.3, 60.2,
60.4; HRMS calcd for C12H26NCl 184.2065 (M - Cl), found
184.2066.
oil: [R]20 ) +50.02 (c 4.65, EtOH); 1H NMR δ 1.11(t, J ) 7.2
D
Hz, 3H), 1.19 (t, J ) 6.9 Hz, 3H), 2.00-2.18 (m, 2H), 2.22-
2.32 (m, 2H), 3.22-3.25 (m, 1H), 3.63 (t, J ) 9.3 Hz, 1H), 3.82-
3.90 (m, 1H), 3.96-4.05 (m, 3H), 4.30-4.36 (m, 2H), 5.03-
5.04 (m, 1H), 7.20-7.25 (m, 1H), 7.28-7.33 (m, 2H), 7.40-
7.42 (m, 2H); 13C NMR δ 16.2 (J ) 6.2 Hz), 16.3 (J ) 6.0 Hz),
25.1, 30.4 (J ) 6.6 Hz), 61.7 (J ) 31.8 Hz), 62.1 (J ) 10.3 Hz),
63.9, 70.1 (J ) 5.7 Hz), 72.6, 99.0 (J ) 0.7 Hz), 126.6, 126.9,
128.2, 142.0. Anal. Calcd for C16H24NO4P: C, 59.06; H, 7.45;
N, 4.31. Found: C, 58.82; H, 7.72; N, 4.28.
(2R,5R)-2-Meth yl-5-p r op ylp yr r olid iu m Ch lor id e (13a ).
From hydrogenation of 10a : yield 95%; [R]20D ) +1.23 (c 1.14,
EtOH); 1H NMR δ 0.98 (t, J ) 7.2 Hz, 3H), 1.42-1.58 (m, 1H),
1.54 (d, J ) 6.6 Hz, 3H), 1.60-1.76 (m, 4H), 1.92-2.01 (m,
1H), 2.14-2.24 (m, 2H), 3.65-3.70 (m, 1H), 3.76-3.82 (m, 1H),
9.45-9.48 (br s, 1H), 9.56-9.60 (br s, 1H); 13C NMR δ 13.7,
18.0, 20.0, 30.5, 32.2, 34.6, 55.2, 59.2. Anal. Calcd for C8H18
-
Diet h yl (2R)-Tet r a h yd r o-1H -p yr r ol-2-ylp h osp h on a t e
(22). Hydrogenation of 21 through the general procedure gave
NCl: C, 58.70; H, 11.11; N, 8.56. Found: C, 58.53; H, 11.36;
N, 8.30.
22 in 89% yield: [R]20 ) -7.81 (c 2.60, EtOH); 1H NMR δ
D
(4R)-1-P h en yl-4-h ep ta n a m in iu m Ch lor id e (14). From
1.38 (t, J ) 6.6 Hz, 6H), 1.94-2.20 (m, 4H), 3.20-3.35 (m, 2H),
3.60-3.70 (m, 1H), 4.26 (q, J ) 6.9 Hz), 6.46 (br s, 2H); 13C
NMR δ 16.4 (J ) 5.6 Hz), 25.0 (J ) 8.7 Hz), 26.7, 47.5 (J )
6.3 Hz), 52.1, 54.2, 63.0 (J ) 7.1 Hz), 63.2 (J ) 7.2 Hz); HRMS
calcd for C8H19NO3PCl 208.1102 (M + 1), found 208.1112.
Anal. Calcd for C8H19NO3PCl: C, 39.43; H, 7.86; N, 5.75.
Found: C, 39.69; H, 8.29; N, 5.14.
hydrogenation of 10d : yield 70%; [R]20 ) +2.38 (c 0.42,
D
EtOH); 1H NMR δ 0.91 (t, J ) 6.9 Hz, 3H), 1.40-1.51 (m, 2H),
1.62-1.85 (m, 6H), 2.63 (t, J ) 6.6 Hz, 2H), 3.18-3.19 (m, 1H),
7.17-7.29 (m, 5H), 8.40 (br s, 3H); 13C NMR δ 13.7, 18.6, 26.8,
32.4, 34.8, 35.3, 52.3, 111.2, 125.9, 128.4, 141.4; HRMS calcd
for C13H22NCl 192.1752 (M - Cl), found 192.1761.
Gen er a l P r oced u r e for 6 Rea cted w ith Vin yloxytr i-
m eth ylsila n es. To a solution of 6 (1.5 g, 5 mmol) in CH2Cl2
(100 mL) were added sequentially 2-methyl-propenyltrimeth-
ylsilane (1.2 g, 10 mmol) and BF3‚Et2O at 0 °C. The reaction
mixture was warmed to room temperature and stirred over-
night. Then the reaction was quenched with 2 N NaOH, and
the aqueous suspension extracted with CH2Cl2. The combined
organic extracts were washed with brine, dried over Na2SO4,
and evaporated in vacuo. Column chromatography on silica
gel, eluting with hexane/ethyl acetate (10/1), yielded pure 19.
1-[(3S,5S,7a R)-3-P h en ylh exa h yd r op yr r olo[2,1-b][1,3]-
oxa zol-5-yl]a ceton e (19a ): yield 41%; [R]20D ) +55.23 (c 0.88,
EtOH); 1H NMR δ 1.49-1.60 (m, 1H), 1.94-2.10 (m, 1H), 1.97
(s, 3H), 2.13-2.23 (m, 2H), 2.44 (dd, J ) 7.2 Hz, J ) 16.5 Hz,
1H), 2.65 (dd, J ) 5.8 Hz, J ) 19.2 Hz, 1H), 3.39-3.44 (m,
1H), 3.57-3.62 (m, 1H), 4.18 (t, J ) 6.6 Hz, 1H), 4.35 (t, J )
7.2 Hz, 1H), 5.01-5.02 (m, 1H), 7.23-7.33 (m, 5H); 13C NMR
δ 30.0, 30.8, 50.1, 62.4, 68.3, 73.5, 98.6, 108.6, 126.5, 127.0,
128.4, 142.6, 207.9; HRMS calcd for C15H19NO2 246.1494 (M
+ 1), found 246.1419.
Gen er a l P r oced u r e for 6 Rea cted w ith Excess Gr ig-
n a r d Rea gen ts To P r ep a r e 23 a n d 24. A solution of
Grignard reagent (15 mmol) was added dropwise to a cold
solution (ice-water bath) of 6 (1.53 g, 5 mmol) in dry
tetrahydrofuran (100 mL) under nitrogen. It was then warmed
to room temperature and stirred overnight. The reaction
mixture was washed with 2 N NaOH solution (3 × 30 mL)
and water (2 × 30 mL). The organic layer was dried over
anhydrous Na2SO4, and the solvent was evaporated under
reduced pressure. The crude products were separated by
column chromatography on silica gel using hexane/ethyl
acetate (20/1) as eluent to give pure 23 and 24.
(2S)-2-(2R,5R)-2,5-Dip h en yltetr a h yd r o-1H-1-p yr r olyl-
2-p h en yleth a n -1-ol (23a ): yield 45%; [R]20D ) -17.64 (c 0.72,
EtOH); 1H NMR δ 1.68-1.72 (m, 1H), 1.94-2.03 (m, 3H),
3.20-3.28 (m, 1H), 3.42-3.50 (m, 1H), 3.87-4.04 (m, 3H), 7.14
(d, J ) 6.6 Hz, 2H), 7.23-7.47 (m, 9H), 7.57-7.63 (m, 4H);
13C NMR δ 34.6, 35.3, 60.7, 62.2, 63.5, 67.3, 126.5, 127.2, 127.5,
127.6, 127.7, 128.2, 128.9, 129.5, 135.4, 143.4, 148.0; HRMS
calcd for C24H25NO 343.1936, found 344.1938 (M + 1).
(2S)-2-(2R,5S)-2,5-Dip h en yltetr a h yd r o-1H-1-p yr r olyl-
2-p h en yleth a n -1-ol (24a ): yield 45%; [R]20D ) -3.12 (c 0.48,
2-[(3S,5S,7a R)-3-P h en ylh exa h yd r op yr r olo[2,1-b][1,3]-
oxa zol-5-yl]-1-p h en yl-1-eth a n on e (19b): yield 54%; [R]20
D
) +45.78 (c 9.37, EtOH); 1H NMR δ 1.56-1.63 (m, 1H), 1.95-
2.02 (m, 1H), 2.16-2.34 (m, 2H), 2.98 (dd, J ) 8.1 Hz, J )
16.8 Hz, 1H), 3.21 (dd, J ) 4.8 Hz, J ) 16.8 Hz, 1H), 3.56-
3.66 (m, 2H), 4.26 (t, J ) 6.6 Hz, 1H), 4.36 (t, J ) 7.5 Hz, 1H),
5.04-5.05 (m, 1H), 7.18-7.41 (m, 7H), 7.48-7.53 (m, 1H), 7.84
(d, J ) 8.1 Hz, 2H); 13C NMR δ 30.1, 31.0, 45.3, 63.0, 68.3,
73.1, 98.5, 126.5, 126.9, 128.0, 128.3, 128.4, 132.9, 137.1, 142.6,
199.1. Anal. Calcd for C20H21NO2: C, 78.14; H, 6.90; N, 4.56.
Found: C, 77.91; H, 7.03; N, 4.89.
1
EtOH); H NMR δ 1.70-1.80 (m, 2H), 2.01 (br s, 1H), 2.52-
2.67 (m, 2H), 3.46-3.58 (m, 2H), 4.02 (t, J ) 6.6 Hz, 1H), 4.49
(d, J ) 6.3 Hz, 2H), 6.75-6.77 (d, J ) 7.2 Hz, 2H), 7.01-7.37
(m, 13H); 13C NMR δ 33.4, 63.2, 63.3, 65.7, 126.7, 127.2, 127.6,
128.3, 129.5, 138.4, 146.8; HRMS calcd for C24H25NO 343.1936,
Found 344.2014 (M + 1).
(2S)-2-(2R,5S)-2,5-Dim eth yltetr a h yd r o-1H-1-p yr r olyl-
2-p h en yleth a n -1-ol (23b): yield 57%; [R]20D ) +30.10 (c 0.93,
1
EtOH); H NMR δ 1.12 (d, J ) 6.3 Hz, 3H), 1.21 (d, J ) 6.3
Meth yl 2-[3S,7a R)-3-P h en ylh exa h yd r op yr r olo[2,1-b]-
[1,3]oxa zol-5-yl]-2-m eth ylp r op a n oa te (20). The reaction of
6 with 1-methoxy-1-trimethylsiloxy-2-methyl-1-propene, using
the same procedure as for the preparation 19, gave the mixture
of two diastereoisomers in ratio of 2:1. The data for the minor
Hz, 3H), 1.26-1.36 (m, 1H), 1.39-1.46 (m, 2H), 1.67-1.73 (m,
1H), 2.92-2.98 (m, 1H), 3.03-3.10 (m, 1H), 3.50 (br s, 1H),
3.64-3.68 (m, 1H), 3.88-4.01 (m, 2H), 7.20-7.36 (m, 5H); 13
C
NMR δ 21.2, 24.2, 31.8, 32.3, 52.5, 58.3, 61.3, 63.0, 127.6, 128.1,
128.9, 136.8. Anal. Calcd for C14H21NO: C, 76.67; H, 9.65; N,
6.39. Found: C, 76.38; H, 9.78; N, 6.53.
1
isomer are given in brackets. H NMR δ 1.05 (s, 6H) [0.76 (s,
3H), 0.91 (s, 3H)], 1.61-2.11 (m, 4H), 3.24 (s, 3H) [3.55 (s, 3H)],
3.36-3.49 (m, 2H) [3.03-3.06 (m, 2H)], 4.19-4.31 (m, 2H)
[3.97-4.03 (m, 2H)], 4.87-4.88 (m, 1H) [4.97-4.99 (m, 1H)],
7.16-7.30 (m, 5H); 13C NMR δ 21.1 (20.6), 21.6 (22.9), 24.6
(26.4), 31.0 (31.6), 47.9 (48.2), 51.3 (51.5), 66.9 (64.4), 71.5
(72.8), 74.3 (72.9), 99.4 (99.3), 126.2 (126.7), 128.3 (127.9), 128.3
(2S)-2-(2R,5S)-2,5-Dim eth yltetr a h yd r o-1H-1-p yr r olyl-
2-p h en yleth a n -1-ol (24b): yield 19%; [R]20D ) -23.00 (c 0.87,
EtOH); 1H NMR δ 0.93 (d, J ) 6.3 Hz, 6H), 1.31-1.32 (m, 2H),
1.96-2.00 (m, 2H), 3.29-3.33 (m, 2H), 3.73-3.80 (m, 1H),
3.82-3.85 (m, 1H), 3.96 (t, J ) 6.9 Hz, 1H), 7.26-7.40 (m, 5H);
13C NMR δ 20.3, 31.6, 55.5, 63.3, 63.9, 127.5, 128.2, 129.3,
140.4. Anal. Calcd for C14H21NO: C, 76.67; H, 9.65; N, 6.39.
Found: C, 76.57; H, 9.69; N, 6.44.
(129.2), 143.3 (139.6), 177.6 (178.0); HRMS calcd for C17H23
-
NO3 290.1756 (M + 1), found 290.1754.

Asymmetric Syntheses of Substituted Pyrrolidines
J . Org. Chem., Vol. 64, No. 6, 1999 1985
Crystal data for 24b at 23 °C: C14H21NO, M 219.32,
monoclinic, P21, a ) 8.3271(6) Å, b ) 8.2785(5) Å, c )
10.1973(7) Å, â ) 106.761(2)°, V ) 673.10(8) Å3, Z ) 2, λ (Mo
KR) ) 0.710 73 Å, F(000) ) 240, Dc ) 1.082 g cm-3, µ ) 0.067
with ether. The organic layer was dried over anhydrous
Na2SO4 and the solvent evaporated under reduced pressure.
The crude products were separated by column chromatography
on silica gel using hexane/ethyl acetate (20/1) as eluent to give
0.03 g 27 and recovered 0.4 g of starting material 6: yield 8%;
mm-1, 1246 reflections, 149 parameters, R ) 0.0385, Rw
)
[R]20 ) +41.33 (c 0.60, EtOH); 1H NMR δ 1.71-1.78 (m, 1H),
0.1038 for all data.
D
Gen er a l P r oced u r e for Hyd r ogen a tion of 23 a n d 24
To P r ep a r e 25 a n d 26. Compound 23 or 24 (1 mmol) was
dissolved in 60 mL of methanol, and 50 mg of 10% Pd/C
catalyst was added. After hydrogenation at 40 psi of pressure
for 24 h, the catalyst was filtered off, and the filtrate was
treated with concentrated HCl with stirring at room temper-
ature for 30 min. The solvent was evaporated in vacuo, and
the resulting product was washed with ether to give the target
product as a white solid. Recrystallization from CHCl3 and
hexane provided crystalline 25 and 26.
1.91-1.97 (m, 1H), 2.17-2.26 (m, 2H), 3.66 (dd, J ) 5.4 Hz, J
) 8.1 Hz, 1H), 3.95 (dd, J ) 6.0 Hz, J ) 9.6 Hz, 1H), 4.14 (t,
J ) 6.9 Hz, 1H), 4.35 (t, J ) 7.2 Hz, 1H), 5.10-5.12 (m, 1H),
7.08-7.33 (m, 10H); 13C NMR δ 30.4, 35.1, 66.6, 69.5, 72.0,
98.3, 126.4, 126.7, 126.9, 127.1, 128.2, 128.3, 142.8, 143.1.
Eth yl 2-[(3S,5S,7a R)-3-P h en ylh exa h yd r op yr r olo[2,1-b]-
[1,3]oxa zol-5-yl]a ceta te (28). To a solution of 6 (0.6 g, 2
mmol) in dichloromethane (50 mL) was added dropwise freshly
prepared zinc reagent of ethyl 2-bromoacetate (2 mmol) at 0
°C. The reaction mixture was stirred at 0 °C for 24 h. Then
the reaction was quenched with 2 N NaOH, and the aqueous
suspension was extracted with dichloromethane. The combined
organic extracts were washed with brine, dried with Na2SO4,
and evaporated in vacuo. Column chromatography on silica
(2R,5S)-2,5-Dim eth yltetr ah ydr o-1H-1-pyr r olidiu m Ch lo-
1
r id e (25a ): yield 90%; mp 213-215 °C; H NMR δ 1.58 (d, J
) 6.0 Hz, 6H), 1.82-1.87 (m, 2H), 2.15-2.19 (m, 2H), 3.63-
3.67 (m, 2H), 9.11 (br s, 1H), 10.1 (br s, 1H); 13C NMR δ 17.8,
30.7, 56.2. Anal. Calcd for C6H14NCl: C, 53.13; H, 10.40; N,
10.33. Found: C, 52.77; H, 10.66; N, 10.06.
gel, eluting with hexanes/ethyl acetate (5/1), yielded 50 mg of
1
28 (10%): [R]20 ) +93.19 (c 2.79, EtOH); H NMR δ 1.10 (t,
D
(2R,5R)-2,5-Dim eth yltetr ah ydr o-1H-1-pyr r olidiu m ch lo-
r id e (26a ): yield 87%; mp 164-166 °C; [R]20D ) +0.76 (c 1.19,
EtOH); 1H NMR δ 1.53 (d, J ) 6.6 Hz, 6H), 1.65-1.72 (m, 2H),
2.21-2.24 (m, 2H), 3.82-3.84 (m, 2H), 9.58 (br s, 2H); 13C NMR
δ 18.2, 32.2, 54.9. Anal. Calcd for C6H14NCl: C, 53.13; H, 10.40;
N, 10.33. Found: C, 53.09; H, 10.57; N, 10.16.
(3S,5S,7a R)-3,5-Dip h en ylh exa h yd r op yr r olo[2,1-b][1,3]-
oxa zole (27).17 An ether solution of zinc chloride complex (3
mL, 3 mmol) was added dropwise at 0 °C to a solution of
phenylmagnesium bromide (1 mL, 3 mmol) in dry THF (30
mL). The mixture was stirred at 25 °C for 45 min and then
cooled to 0 °C again. A solution of compound 8 (0.91 g, 3 mmol)
in dry tetrahydrofuran (20 mL) was then added dropwise
under nitrogen. The mixture was stirred at room temperature
for another 30 min before being washed with 2 N NaOH
solution (3 × 30 mL) and water (2 × 30 mL) and then extracted
J ) 6.9 Hz, 3H), 1.59-1.68 (m, 1H), 1.94-2.02 (m, 1H), 2.15-
2.35 (m, 3H), 2.45-2.62 (m, 1H), 3.39-3.46 (m, 1H), 3.55-
3.60 (m, 1H), 3.85-3.93 (m, 2H), 4.24 (t, J ) 6.9 Hz, 1H), 4.35
(t, J ) 7.2 Hz, 1H), 4.99-5.02 (m, 1H), 7.22-7.36 (m, 5H); 13
C
NMR δ 14.0, 30.0, 30.4, 41.6, 60.2, 63.6, 68.7, 73.4, 98.7, 126.4,
126.9, 128.3, 142.7, 171.8. Anal. Calcd for C16H21NO3: C, 69.79;
H, 7.70; N, 5.09. Found: C, 70.15; H, 8.08; N, 5.32.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra and CHN analyses or HRMS (if new compounds) for
compounds 15, 18, 9b,c, 10b ,c, 13b ,c, 19c, 23c-e, 24c-e,
25b-d , and 26b-d . This material is available free of charge
via the Internet at http://pubs.acs.org.
J O9821426