Asymmetric halo-Mannich-type reaction provides access to pyrrolidines and β-proline derivatives

Article abstract of DOI:10.1021/jo0509051

A new halo-Mannich-type reaction is reported using cyclopropyl carbonyl-derived enolates and sulfonyl-protected imines. Chiral oxazolidinones auxiliaries were found to be effective for completely controlling the stereochemistry of the products. Variations

Full text of DOI:10.1021/jo0509051

Asymmetric Halo-Mannich-Type Reaction Provides Access to
Pyrrolidines and â-Proline Derivatives
Cody Timmons, Li Guo, Junying Liu, John F. Cannon,† and Guigen Li*
Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas 79409-1061, and
Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602-5700
guigen.li@ttu.edu
Received May 6, 2005
A new halo-Mannich-type reaction is reported using cyclopropyl carbonyl-derived enolates and
sulfonyl-protected imines. Chiral oxazolidinones auxiliaries were found to be effective for completely
controlling the stereochemistry of the products. Variations in the oxazolidinone, protecting group,
and imine components show this to be a quite general reaction. The initial iodo-Mannich products
were found to be readily cyclized in the presence of triethylamine to afford the resulting protected
pyrrolidines, which could be readily deprotected under standard conditions.
Introduction
propyl carbonyl compounds to perform a variety of aldol
and related reactions that result in the formation of
structurally diverse heterocycles.6,7 Recently, we devel-
oped an asymmetric halo aldol reaction utilizing enolates
derived from chiral cyclopropyl-N-acyl oxazolidinones
(Scheme 1).8 High yields and diastereoselectivities were
obtained for a number of aldehyde substrates. Further-
more, the initial products were easily cyclized in the
presence of triethylamine to yield the corresponding
chiral cis-2,3-disubstituted tetrahydrofuran derivatives,
thus complementing the existing methods for the syn-
The asymmetric aldol reaction is among the most
powerful methodologies for the construction of C(sp3)-
C(sp3) bonds and continues to remain an active topic of
study in the organic community.1-3 Unfortunately, tra-
ditional aldol products lack a high number of sites of
functionalization. To increase the synthetic utility of aldol
products, we and others have introduced a number of new
halo aldol reactions in which the aldol framework is
further functionalized by the presence of a halogen that
can be a site for coupling, elimination, and displacement
reactions.4,5 Of particular recent interest in some research
groups has been the use of enolates derived from cyclo-
(4) (a) Li, G.;Wei, H.-X.; Phelps, B. S.; Purkiss, D. W.; Kim, S. H.
Org. Lett. 2001, 3, 823-826. (b) Li, G.; Xu, X.; Chen, D.; Timmons, C.;
Carducci, M. D.; Headley, A. D. Org. Lett. 2003, 5, 329-331.
(5) For recent racemic halo aldol reaction, see: (a) Kataoka, T.; H.
Kinoshita, Kinoshita, S.; Iwamura, T.; Watanabe, S. Angew. Chem.,
Int. Ed. 2000, 39, 2358-2360. (b) Wei, H. X.; Caputo, T. D.; Purkiss,
D. W.; Li, G.; Tetrahedron 2000, 56, 2397-2401. (c) Uehira, S.; Han,
Z.; Shinokubo, H.; Oshima, K. J. Org. Chem. 2001, 66, 7854-7857.
(d) Li, G.; Wei, H.-X.; Caputo, T. D. Tetrahedron Lett. 2000, 41, 1-4.
(e) Shi, M.; Jiang, J.-K.; Feng, Y.-S. Org. Lett. 2000, 2, 2397-2400.
(6) (a) Han, Z.; Uehira, S.; Tsuritani, T.; Shinokubo, H.; Oshima,
K. Tetrahedron 2001, 57, 987-995. (b) Bertozzi, F.; Gustafsson, M.;
Olsson, R. Org. Lett. 2002, 4, 3147-3150. (c) Bertozzi, F.; Gustafsson,
M.; Olsson, R. Org. Lett. 2002, 4, 4333-4336. (d) Huang, W.; O’Donnell,
M.-M.; Bi, G.; Liu, J.; Yu, L.; Baldino, C. M.; Bell, A. S.; Underwood,
T. J. Tetrahedron Lett. 2004, 45, 8511-8514. (e) Kozuka, M.; Inoue,
A.; Tsuchida, T.; Mitani, M. Synlett 2004, 2751.
† Brigham Young University.
(1) (a) Carreira In, E. M. Comprehensive Asymmetric Catalysis;
Jacobsen, E. J., Pfaltz, A., Yamamoto, H., Eds., Springer: Berlin, 1999,
Vol. III, pp 997-1065. (b) Mahrwald, R. Chem. Rev. 1999, 99, 1095-
1120. (c) Arya, P.; Qin, H. Tetrahedron 2000, 56, 917-948. (d) Nelson,
S. G. Tetrahedron Asymmetry 1998, 9, 357-389.
(2) (a) Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem.
1982, 13, 1-115. (b) Kim, B. M.; Williams, S. F.; Masamune, S. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Heathcock,
C. H., Eds.; Pergamon: Oxford, 1991; Vol. 2, Chapter 1.7, pp 239-
275.
(3) For representative references on asymmetric catalytic aldol
reactions, see: (a) Bach, T. Angew. Chem., Int. Ed. Engl. 1994, 33,
417-419. (b) Enders, D.; Ince, S. J. Synthesis 2002, 619-624. (c) Corey,
E. J.; Cywin, C. L.; Roper, T. D.; Tetrahedron Lett. 1992, 33, 6907-
6910. (d) Evans, D. A.; Kozlowski, M. C.; Murray, J. A.; Burgey, C. S.;
Campos, B. T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121, 669-685.
(e) Groger, H.; Vogl, E. M.; Shibasaki, M. Chem Eur. J. 1998, 4, 1137-
1141.
(7) For ring openings of methylene cyclopropanes to construct
N-heterocycles, see: (a) Scott, M. E.; Han, W.; Lautens, M. Org. Lett.
2004, 6, 3309-3312. (b) Shi, M.; Xu, B.; Huang, J.-W. Org. Lett. 2004,
6, 1175-1178.
(8) Timmons, C.; Chen, D.; Cannon, J. F.; Headley, A. D.; Li, G.
Org. Lett. 2004, 6, 2075-2078.
10.1021/jo0509051 CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/13/2005
7634
J. Org. Chem. 2005, 70, 7634-7639

Asymmetric Halo Mannich-Type Reaction
TABLE 1.
SCHEME 1
entry
R1
R2
Pg product yield (%) % de
1
2
Ph
Ph
Ph
Ts
1
2
82
78
78
81
76
79
77
67
69
62
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
i-Pr Ts
3
2-furyl
Ph
Ph
Ts
Bs
Ts
Ts
Bs
Ts
Bs
Ts
3
thesis of heterocycles from cyclopropane ring-opening
reactions.6a,7b,9,10
4
4-Me-C6H4
4-MeO-C6H4 Ph
4
5
5
With these initial results in hand, we explored an
analogous reaction in which imines replaced aldehydes
as electrophilic acceptors. Such a methodology would
presumably initially produce asymmetric Mannich prod-
ucts, which could then be cyclized to the corresponding
pyrrolidines.6e Such pyrrolidines are of significant syn-
thetic utility for a number of reasons. For example, they
have been widely utilized as auxiliaries and ligands for
asymmetric synthesis.11 Additionally, the products of this
process can, after deprotection, be converted into R-sub-
stituted-â-proline derivatives, which are potentially use-
ful for catalysis and peptide studies.12 Furthermore, a
number of natural products, such as indolizidine13 and
pyrrolizidine14 alkaloids, contain the five-membered N-
heterocyclic moiety. In this paper, we are pleased to
report the full details of our study of this new asymmetric
halo aldol-type methodology, as well as an extension of
this methodology in which a number of new â-proline
derivatives have been prepared.
6
4-BnO-C6H4
4-BnO-C6H4
3-BnO-C6H4
4-Cl-C6H4
Ph
Ph
Ph
Ph
Ph
6
7
7
8
8
9
9
10
4-F-C6H4
10
to completion within 9 h at 0 °C to afford the product in
∼80% yield with complete control of diastereoselectivity.
When the amount of imine was decreased to 1.5 equiv,
the same results were obtained; however, the use of 1.0
equiv or less gave rise to longer reaction times and
generally poorer yields. When THF was utilized as
solvent, the yield was decreased by ∼10% for the same
reaction conditions. Of the other solvents tested (toluene,
ether, acetonitrile), only toluene worked well, giving
results similar to those obtained using CH2Cl2. The use
of a slight excess of Et2AlI was found to be necessary for
complete conversion.
With these initial results in hand, a series of imines
was studied.15 When the Bs protecting group was re-
placed by a Ts group, the reaction efficiency was un-
changed for a number of examples. Unfortunately, re-
peated attempts at using the 2-Ns protecting group all
led to complex reaction mixtures containing very low
Results and Discussion
During the past few years, several reports have been
published in which diethylaluminum iodide (Et2AlI) was
used as Lewis acid/halogen donor.4b,5c,6a,8 When excess Et2-
AlI (1.2 equiv) was added to a CH2Cl2 solution of
cyclopropyl starting material at 0 °C, it was indeed found
that within 30 min the enolate was formed, as indicated
by a significant change in the appearance of the CH2 ring
1
yields of the desired product, as evidenced by H NMR
analysis of the crude reaction mixture. The initial forma-
tion of halo-Mannich products is outlined in Table 1.
As can be seen from Table 1, complete control of
diastereoselectivity was achieved in all cases. Both
electron-donating and electron-withdrawing substituents
on the imine work well. Additionally, the oxazolidinone
prepared from valine (entry 2) was found to be as efficient
in controlling diastereoselectivity as the oxazolidinone
prepared from phenylglycine. Entry 3 is an interesting
case in that furyl rings can be considered precursors for
carboxylic acids, thus introducing an additional func-
tionality to the molecule.
1
protons in the H NMR spectrum. Upon decreasing the
reaction temperature to -20 °C, the enolate formation
proceeded slowly such that after 20 h, ∼40% of the
starting material remained.
Initial experiment optimization was carried out using
the benzenesulfonyl (Bs) imine derived from p-tolualde-
hyde. When 2 equiv of the imine were added to the
enolate (preformed as described above), the reaction went
With these initial products in hand, attention was then
turned to focus on cyclization to the corresponding
pyrrolidines. It was found that the reaction could be
conveniently carried out in CH2Cl2 using 5 equiv of Et3N,
without the need for protection in an inert atmosphere.
In all cases the reaction proceeded to completion in 2 h
or less without any epimerization being observed. The
use of an equimolar amount of base resulted in extended
reaction times (ca. 4-5 h), while increasing to 10 equiv
of Et3N showed little improvement of reaction rate. In
all cases, very high yields were obtained after purification
by column chromatography (Table 2). The cis stereo-
(9) Fleming, F. F.; Gudipati, V.; Steward, O. W. J. Org. Chem. 2003,
68, 3943-3946.
(10) For some leading examples of tetrahydrofuran syntheses by
other methods, see: (a) Ito, K.; Yoshitake, M.; Katsuki, T. Heterocycles
1996, 42, 305-317. (b) Takacs, J. M.; Schroeder, S. D.; Han, J.; Gifford,
M.; Jiang, X.-T.; Saleh, T.; Vayalakkada, S.; Yap, A. H. Org. Lett. 2003,
5, 3595-3598. (c) Takami, K.; Mikami, S.; Yorimitsu, H.; Shinokubo,
H.; Oshima, K. Tetrahedron 2003, 59, 6627-6635. (d) Miura, K.;
Hondo, T.; Okajima, S.; Nakagawa, T.; Takahashi, T.; Hosomi, A. J.
Org. Chem. 2002, 67, 6082-6090.
(11) (a) Mukaiyama, T.; Uchiro, H.; Kobayashi, S. Chem. Lett. 1989,
1001. (b) Kobayashi, S.; Sano, T.; Mukaiyama, T. Chem. Lett. 1989,
1319. (c) Kobayashi, S.; Fujishita, Y.; Mukaiyama, T. Chem. Lett. 1989,
2069.
(12) Lelais, G.; Seebach, D. Biopolymers 2004, 76, 206-243.
(13) Daly, J. W.; Spande, T. F. In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1986;
Vol. 4.
(14) Numata, A.; Ibuka, T. In The Alkaloids; Brossi, A., Ed.;
Academic Press: San Diego, 1987; Vol. 31, Chapter 6, p 193.
(15) Imines were readily prepared in high yields according to
literature procedures: Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang,
T.; Fanelli, D. L.; Zhang, H. J. Org. Chem. 1999, 64, 1403-1406.
J. Org. Chem, Vol. 70, No. 19, 2005 7635

Timmons et al.
TABLE 2.
entry
R1
R2
Pg
product
yield (%)
1
2
Ph
Ph
Ph
i-Pr
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ts
Ts
Ts
Bs
Ts
Ts
Bs
Ts
Bs
Ts
11
12
13
14
15
16
17
18
19
20
90
89
95
96
93
94
93
89
97
90
3
2-furyl
FIGURE 2. Proposed model for asymmetric induction.
SCHEME 2
4
4-Me-C6H4
4-MeO-C6H4
4-BnO-C6H4
4-BnO-C6H4
3-BnO-C6H4
4-Cl-C6H4
4-F-C6H4
5
6
7
8
9
10
chemistry of these 2,3-disubstituted pyrrolidines (vide
infra) complements the work of Olsson6b and Lautens,7a
who typically obtained trans products.
Additionally, it was found that purification of the halo-
Mannich intermediate was not necessary for the forma-
tion of the cyclized pyrrolidine product. For a number of
cases, the initial halo aldol reaction was carried out,
quenched with aqueous acid, extracted with CH2Cl2, and
concentrated. Treatment of these crude products with
Et3N formed the cyclized products with typically <10%
diminishment of yield when compared to the two-step
process.
The absolute stereochemistry of this process was
determined by X-ray crystallographic analysis. The chiral-
ity was found to be the same as that of our previous work
in which aldehydes were utilized as electrophiles.8 The
crystal structure diagram is shown in Figure 1. Two
molecules exist in the asymmetric unit, and it is interest-
ing to note that interatomic distances from O2 to C21 of
different molecules are quite small (2.77 and 3.00 Å). Full
crystallographic data can be found in Supporting Infor-
mation.
SCHEME 3
similar to that proposed by Heathcock and co-workers,
who reported similar diastereoselectivity in the standard
oxazolidinone aldol reaction.16
In an effort to demonstrate the utility of these pyrro-
lidine products, a few were deprotected to the corre-
sponding monoprotected â-proline derivatives (Scheme
2). Under standard conditions reported by Evans and co-
workers,17 the chiral auxiliary was cleaved to produce,
after acidic workup, the N-protected R-substituted â-pro-
lines. In all cases, the auxiliary cleavage proceeded in
high yields with minimal purification and no epimeriza-
tion.
Additionally, under conditions reported by Rapoport
and co-workers,18 the Ts group of product 11 was cleaved
to afford the free amine with the auxiliary intact.
Treatment of the N-protected pyrrolidine with 33% HBr/
HOAc in the presence of phenol produced the desired
product without destruction of the chirality. The product
was easily isolated in high yield by simple recrystalliza-
tion (Scheme 3).
The stereochemistry for this reaction can be explained
by the formation of a metal-chelated enolate (Figure 2).
With the auxiliary in an orientation fixed by the chelation
of the enolate and auxiliary carbonyl oxygens, the imine
approaches the less hindered side away from the phenyl
group as shown. Such an open chain transition state is
In summary, a new approach has been developed for
the formation of chiral halo-Mannich products. These
compounds can be easily cyclized to the corresponding
cis-2,3-disubstituted pyrrolidines in excellent yields.
Further manipulation of these pyrrolidine products gives
rise to â-proline derivatives, which are important in
asymmetric synthesis and pharmaceutical research.
(16) Walker, M. A.; Heathcock, C. H. J. Org. Chem. 1991, 56, 5747-
5750.
(17) Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett.
1987, 28, 6141-6144.
(18) (a) Maurer, P. J.; Takahata, H.; Rapoport, H. J. Am. Chem.
Soc. 1984, 106, 1095-1098. (b) Roemmele, R. C.; Rapoport, H. J. Org.
Chem. 1988, 53, 2367-2371.
FIGURE 1. Crystal structure for product 11.
7636 J. Org. Chem., Vol. 70, No. 19, 2005

Asymmetric Halo Mannich-Type Reaction
(m, 2H), 2.81 (s, 3H), 2.22-2.14 (m, 1H), 1.93-1.86 (m, 1H).
13C NMR (125 MHz, CDCl3): 173.3, 158.8, 154.0, 142.6, 138.0,
137.7, 129.8, 129.2, 129.1, 128.5, 127.6, 126.8, 125.4, 113.7,
70.2, 58.2, 58.0, 55.2, 49.0, 33.3, 21.3, 2.2. HRMS MNa+:
expected 671.0683, found 671.0689.
Experimental Section
Typical Procedure for the Preparation of Asymmetric
Halo-Mannich Products. To an oven-dried test tube was
added cyclopropyl starting material (80.0 mg, 0.346 mmol). The
vessel was capped, vacuumed, and flushed with nitrogen. To
this was added 3 mL of CH2Cl2, and the resulting solution was
cooled to 0 °C. To this solution was added Et2AlI (1 M in
toluene, 0.42 mmol, 0.42 mL) dropwise over 5 min. After 30
min, imine was added (0.70 mmol in 2 mL of CH2Cl2) dropwise.
The resulting solution was stirred for 9 h at 0 °C, at which
time the reaction was quenched with 5 mL of 1 N HCl. The
mixture was extracted with CH2Cl2 (3 × 15 mL), washed with
brine, and dried over anhydrous Na2SO4. The dried solution
was concentrated under reduced pressure and subjected to
flash chromatography (EtOAc/hexane 1:4) to afford the pure
products.
Analytical Data for 6. Isolated as 197.1 mg of a white solid
(79%): mp ) 168-170 °C. [R]23D ) +24.4°. FTIR: 3286.4 (N-
H), 1774.2 (CdO), 1701.4 (CdO) cm-1 1H NMR (500 MHz
.
CDCl3): 7.44-7.40 (m, 4H), 7.37-7.33 (m, 3H), 7.30-7.28 (m,
3H), 7.04-7.01 (m, 2H), 6.96 (d, J ) 8.0 Hz, 2H), 6.80-6.77
(m, 2H), 6.60-6.57 (m, 2H), 6.11 (d, J ) 9.5 Hz, 1H), 5.37 (dd,
J ) 3.5 Hz, 8.5 Hz, 1H), 4.97 (s, 2H), 4.66 (t, J ) 8.5 Hz, 1H),
4.56-4.52 (m, 2H), 4.18 (dd, J ) 3.5 Hz, 9.0 Hz, 1H), 3.19-
3.10 (m, 2H), 2.82 (s, 3H), 2.22-2.10 (m, 1H), 1.92-1.82 (m,
1H). 13C NMR (125 MHz, CDCl3): 173.3, 158.1, 154.0, 142.7,
138.0, 137.7, 136.8, 130.1, 129.2, 129.1, 128.7, 128.5, 128.1,
127.2, 127.4, 126.8, 125.5, 114.7, 70.2, 70.0, 58.2, 58.1, 49.0,
33.3, 21.4, 2.2. HRMS MNa+: expected 747.0996, found
747.0996.
Analytical Data for 1. Isolated as 176.1 mg of a white solid
(82%): mp ) 128-130 °C. [R]23D ) +57.5°. FTIR: 3300.6 (N-
H), 1776.7 (CdO), 1700.4 (CdO) cm-1 1H NMR (500 MHz,
.
Analytical Data for 7. Isolated as 190.0 mg of a colorless
CDCl3): 7.36-7.33 (m, 2H), 7.31-7.28 (m, 3H), 7.10-7.06 (m,
1H), 7.00-6.94 (m, 6H), 6.87-6.85 (m, 2H), 6.19 (d, J ) 9.5
Hz, 1H), 5.35 (dd, J ) 3.5 Hz, 8.5 Hz, 1H), 4.66-4.58 (m, 3H),
4.16 (dd, J ) 3.5 Hz, 9.0 Hz, 1H), 3.22-3.12 (m, 2H), 2.27 (s,
3H), 2.23-2.16 (m, 1H), 1.95-1.88 (m, 1H). 13C NMR (125
MHz, CDCl3): 173.3, 153.9, 142.8, 137.9, 137.7, 137.6, 129.3,
129.1, 128.5, 128.4, 127.3, 126.8, 126.5, 125.4, 70.1, 58.5, 58.0,
48.9, 33.3, 21.3, 2.1. HRMS MH+: expected 619.0758, found
619.0755.
oil (77%). [R]23 ) +32.3°. FTIR: 3286.7 (N-H), 1774.4 (Cd
D
O), 1701.4 (CdO) cm-1. 1H NMR (500 MHz CDCl3): 7.46-7.40
(m, 6H), 7.38-7.34 (m, 1H), 7.30-7.24 (m, 4H), 7.14-7.11 (m,
2H), 7.05-7.03 (m, 2H), 6.77-6.73 (m, 2H), 6.57-6.54 (m, 2H),
6.16 (d, J ) 8.5 Hz, 1H), 5.37 (dd, J ) 3.0 Hz, 8.5 Hz, 1H),
4.98 (s, 2H), 4.67 (t, J ) 8.5 Hz, 1H), 4.58-4.52 (m, 2H), 4.19
(dd, J ) 3.5 Hz, 8.5 Hz, 1H), 3.21-3.13 (m, 2H), 2.23-2.15
(m, 1H), 1.94-1.87 (m, 1H). 13C NMR (125 MHz, CDCl3):
173.3, 158.0, 154.0, 140.6, 138.0, 136.8, 131.9, 129.9, 129.3,
128.6, 128.5, 128.5, 128.1, 127.7, 127.4, 126.7, 125.4, 114.8,
70.2, 69.8, 58.3, 58.1, 49.0, 33.2, 2.2. HRMS MNa+: expected
733.0840, found 733.0835.
Analytical Data for 2. Isolated as 158.3 mg of a colorless
oil (78%). [R]23 ) +17.6°. FTIR: 3304.5 (N-H), 1773.7 (Cd
D
O), 1697.1 (CdO) cm-1. 1H NMR (500 MHz CDCl3): 7.39 (d, J
) 8.0 Hz, 2H), 7.09-7.04 (m, 3H), 7.01-6.97 (m, 4H), 6.19 (d,
J ) 10 Hz, 1H), 4.63-4.59 (m, 1H), 4.53-4.48 (m, 1H), 4.40-
4.37 (m, 1H), 4.26 (t, J ) 9.0 Hz, 1H), 4.19 (dd, J ) 2.5 Hz, 9.0
Hz, 1H), 3.13-3.04 (m, 2H), 2.84 (s, 3H), 2.25-2.15 (m, 2H),
1.82-1.75 (m, 1H), 0.86 (d, J ) 7.5 Hz, 3H), 0.62 (d, J ) 7.0
Hz, 3H). 13C NMR (125 MHz, CDCl3): 173.3, 154.5, 142.8,
137.9, 137.6, 129.1, 128.4, 127.5, 126.8, 126.6, 63.4, 59.2, 59.2,
48.9, 33.1, 28.4, 21.3, 18.0, 14.3, 2.2. HRMS MH+: expected
585.0915, found 585.0915.
Analytical Data for 8. Isolated as 167.5 mg of a colorless
oil (67%). [R]23 ) +44.1°. FTIR: 3300.8 (N-H), 1777.8 (Cd
D
O), 1689.9 (CdO) cm-1. 1H NMR (500 MHz CDCl3): 7.42-7.32
(m, 8H), 7.28-7.20 (m, 3H), 6.97-6.92 (m, 5H), 6.72-6.69 (m,
1H), 5.54 (d, J ) 8.0 Hz, 1H), 6.42-6.41 (m, 1H), 6.17 (d, J )
8.5 Hz, 1H), 5.35 (dd, J ) 3.5 Hz, 8.5 Hz, 1H), 4.70-4.59 (m,
5H), 4.14 (dd, J ) 3.5 Hz, 8.5 Hz, 1H), 3.21-3.15 (m, 2H),
2.22-2.17 (m, 4H), 1.95-1.90 (m, 1H). 13C NMR (125 MHz,
CDCl3): 173.3, 158.5, 153.9, 142.8, 139.2, 137.9, 137.7, 136.7,
129.3, 129.1, 128.6, 128.4, 128.0, 127.4, 126.8, 125.2, 119.2,
114.5, 112.3, 70.2, 69.5, 58.5, 58.1, 48.8, 33.1, 21.3, 2.2. HRMS
MNa+: expected 747.0996, found 747.0996.
Analytical Data for 3. Isolated as 160.0 mg of a white solid
(78%): mp ) 140-142 °C (dec). [R]23D ) +44.8°. FTIR: 3304.5
(N-H), 1775.4 (CdO), 1699.4 (CdO) cm-1. 1H NMR (500 MHz
CDCl3): 7.48 (d, J ) 8 Hz, 2H), 7.38-7.30 (m, 3H), 7.19-7.17
(m, 2H), 7.10 (d, J ) 8.0 Hz, 2H), 6.99 (m, 1H), 5.99 (d, J )
10.0 Hz, 1H), 5.96-5.95 (m, 1H), 5.63 (d, J ) 3.5 Hz, 1H), 5.40
(dd, J ) 3.5 Hz, 8.5 Hz, 1H), 4.70 (t, J ) 9.0 Hz, 1H), 4.64-
4.55 (m, 2H), 4.24 (dd, J ) 3.5 Hz, 9.0 Hz, 1H), 3.16-3.12 (m,
2H), 2.33 (s, 3H), 2.24-2.17 (m, 1H), 1.99-1.92 (m, 1H). 13C
NMR (125 MHz, CDCl3): 172.8, 153.7, 150.4, 143.0, 141.9,
138.0, 137.5, 129.3, 129.2, 128.6, 126.8, 125.7, 110.1, 108.2,
70.1, 58.0, 52.5, 46.9, 33.2, 21.4, 1.2. HRMS MNa+: expected
631.0370, found 631.0370.
Analytical Data for 9. Isolated as 152.6 mg of a colorless
oil (69%). [R]23 ) +30.0°. FTIR: 3299.5 (N-H), 1777.9 (Cd
D
O), 1696.3 (CdO) cm-1. 1H NMR (500 MHz CDCl3): 7.51-7.49
(m, 2H), 7.39-7.35 (m, 1H), 7.32-7.27 (m, 3H), 7.23-7.20 (m,
2H), 6.93-6.91 (m, 2H), 6.90-6.87 (m, 2H), 6.30 (d, J ) 10
Hz, 1H), 5.32 (dd, J ) 3.5 Hz, 8.5 Hz), 4.66-4.56 (m, 3H), 4.16
(dd, J ) 3.0 Hz, J ) 9.0 Hz, 1H), 3.24-3.21 (m, 2H), 2.26-
2.18 (m, 1H), 2.04-1.96 (m, 1H). 13C NMR (125 MHz, CDCl3):
173.3, 153.6, 140.5, 137.9, 136.1, 133.2, 132.3, 129.2, 128.7,
128.6, 128.5, 127.7, 126.7, 125.4, 70.1, 57.8, 57.3, 48.6, 33.0,
1.7. HRMS MNa+: expected 661.0031, found 661.0029.
Analytical Data for 4. Isolated as 173.1 mg of a white solid
(81%): mp ) 147-149 °C. [R]23D ) +47.0°. FTIR: 3306.1 (N-
H), 1769.7 (CdO), 1693.9 (CdO) cm-1 1H NMR (500 MHz
.
Analytical Data for 10. Isolated as a white solid (%): mp
) 135-137 °C (dec). [R]23 ) +58.3°. FTIR: 3287.2 (N-H),
D
CDCl3): 7.47-7.45 (m, 2H), 7.31-7.29 (m, 4H), 7.17-7.14 (m,
2H), 7.03-7.01 (m, 2H), 6.77-6.72 (m, 4H), 6.20 (d, J ) 9.5
Hz, 1H), 5.37 (dd, J ) 3.5, J ) 8.0 Hz, 1H), 4.66 (t, J ) 8.5
Hz, 1H), 4.60-4.56 (m, 2H), 4.17 (dd, J ) 3.5, J ) 9.0 Hz,
1H), 3.20-3.14 (m, 2H), 2.24-2.15 (m, 4H), 1.94-1.88 (m, 1H).
13C NMR (125 MHz, CDCl3): 173.3, 154.0, 140.6, 138.0, 137.1,
134.5, 131.8, 129.2, 129.1, 128.4, 128.4, 126.7, 126.4, 125.4,
70.2, 58.5, 58.1, 48.9, 33.2, 21.0, 2.2. HRMS MH+: expected
619.0758, found 619.0742.
1776.9 (CdO), 1698.9 (CdO) cm-1
.
1H NMR (500 MHz
CDCl3): 7.38-7.36 (m, 2H), 7.32-7.29 (m, 3H), 7.01-6.96 (m,
4H), 6.82-6.79 (m, 2H), 6.65-6.61 (m, 2H), 6.20 (d, J ) 10
Hz, 1H), 5.34 (dd, J ) 3.5 Hz, 8.5 Hz, 1H), 4.67-4.53 (m, 3H),
4.18 (dd, J ) 3.5 Hz, 8.5 Hz, 1H), 3.24-3.15 (m, 2H), 2.30 (s,
3H), 2.23-2.16 (m, 1H), 1.98-1.91 (m, 1H). 13C NMR (125
MHz, CDCl3): 173.3, 162.8, 160.9, 153.7, 143.1, 138.0, 137.6,
133.6, 133.5, 129.2, 129.2, 128.6, 128.2, 128.1, 126.8, 125.5,
115.3, 115.1, 70.1, 57.9, 57.5, 48.8, 33.1, 21.3, 1.8. HRMS
MH+: expected 637.0664, found 637.0674.
General Procedure for Cyclization To Afford cis-2,3-
Disubstituted Pyrrolidines. To an oven-dried vial was
added halo-Mannich product (0.20 mmol), CH2Cl2 (3 mL), and
Et3N (ca. 5 equiv, 0.15 mL). This solution was stirred without
inert gas protection for 2 h at room temperature, at which time
Analytical Data for 5. Isolated as 170.5 mg of a colorless
oil (76%). [R]23 ) +30.3°. FTIR: 3286.4 (N-H), 1775.6 (Cd
D
O), 1701.2 (CdO) cm-1. 1H NMR (500 MHz CDCl3): 7.36-7.34
(m, 2H), 7.32-7.29 (m, 3H), 7.04-7.02 (m, 2H), 6.98-6.96 (m,
2H), 6.51-6.48 (m, 2H), 6.12 (d, J ) 9.5 Hz, 1H), 5.37 (dd, J
) 3.0 Hz, 8.5 Hz, 1H), 4.65 (t, J ) 8.5 Hz, 1H), 4.55-4.52 (m,
2H), 4.17 (dd, J ) 3.5 Hz, 8.5 Hz, 1H), 3.73 (s, 3H), 3.19-3.10
J. Org. Chem, Vol. 70, No. 19, 2005 7637

Timmons et al.
it was concentrated and directly subjected to flash chroma-
tography (EtOAc/hexane 1:2) to afford the pure products.
(dd, J ) 4.0 Hz, 8.5 Hz, 1H), 4.93 (s, 2H), 4.57 (t, J ) 4.0 Hz,
1H), 4.19 (dd, J ) 4.0 Hz, 9.0 Hz, 1H), 3.93-3.87 (m, 1H),
3.77-3.73 (m, 1H), 3.20-3.14 (m, 1H), 2.67-2.58 (m, 1H), 2.41
(s, 3H), 1.94-1.88 (m, 1H). 13C NMR (125 MHz, CDCl3): 168.7,
158.3, 153.2, 143.4, 137.7, 137.0, 134.3, 131.2, 129.5, 128.8,
128.8, 128.6, 128.3, 128.0, 127.7, 127.5, 126.1, 114.4, 70.2, 69.7,
63.0, 57.9, 49.6, 47.2, 26.4, 21.5. Elemental analysis (C, H, N)
expected: 68.44 C, 5.41 H, 4.69 N. Found: 68.18 C, 5.13 H,
4.58 N.
Analytical Data for 11. Isolated as 88.3 mg of a white solid
(90%). Recrystallized by slow evaporation (10 days) of a
solution in CH2Cl2/EtOAc/hexane (ca. 1:1:1) for X-ray analy-
sis: mp ) 91-93 °C. [R]23 ) -61.6°. FTIR: 1778.3 (CdO),
D
1704.4 (CdO) cm-1. 1H NMR (500 MHz CDCl3): 7.68-7.66 (m,
2H), 7.29-7.27 (m, 2H), 7.25-7.21 (m, 1H), 7.19-7.15 (m, 2H),
7.09-7.03 (m, 3H), 6.98-6.95 (m, 2H), 6.76-6.74 (m, 2H), 5.49
(d, J ) 9.0 Hz, 1H), 5.13 (dd, J ) 3.5 Hz, 8.5 Hz, 1H), 4.54 (t,
J ) 8.5 Hz, 1H), 4.17 (dd, J ) 4.0 Hz, 9.0 Hz, 1H), 3.91-3.86
(m, 1H), 3.78-3.74 (m, 1H), 3.21-3.15 (m, 1H), 2.65-2.55 (m,
1H), 2.41 (s, 3H), 1.92-1.86 (m, 1H). 13C NMR (125 MHz,
CDCl3): 168.4, 153.3, 143.4, 138.7, 137.6, 134.2, 129.5, 128.9,
128.3, 128.2, 127.7, 127.7, 127.3, 126.0, 70.2, 63.4, 57.9, 49.5,
47.2, 26.2, 21.5. Elemental analysis (C, H, N) expected: 66.11
C, 5.34 H, 5.71 N. Found: 65.88 C, 5.12 H, 5.62 N.
Analytical Data for 17. Isolated as 108.4 mg of a white
solid (93%): mp ) 79-81 °C. [R]23 ) -46.1°. FTIR: 1778.0
D
(CdO), 1703.7 (CdO) cm-1. 1H NMR (500 MHz CDCl3): 7.75-
7.73 (m, 2H), 7.55-7.34 (m, 8H), 7.21-7.18 (m, 3H), 6.79-
6.95 (m, 2H), 6.77-6.75 (m, 2H), 6.60-6.57 (m, 2H), 5.47 (d,
J ) 9.0 Hz, 1H), 5.15 (dd, J ) 4.0 Hz, 9.0 Hz, 1H), 4.93 (s,
2H), 4.56 (t, J ) 9.0 Hz, 1H), 4.18 (dd, J ) 4.0 Hz, 9.0 Hz,
1H), 3.94-3.88 (m, 1H), 3.78-3.74 (m, 1H), 3.25-3.19 (m, 1H),
2.67-2.58 (m, 1H), 1.95-1.89 (m, 1H). 13C NMR (125 MHz,
CDCl3): 168.5, 158.3, 153.2, 137.7, 136.9, 132.6, 130.9, 128.9,
128.8, 128.8, 128.6, 128.3, 128.0, 127.6, 127.5, 126.0, 114.4,
70.2, 69.7, 62.7, 57.9, 49.6, 47.2, 26.3. Elemental analysis (C,
H, N) expected: 68.03 C, 5.19 H, 4.81 N. Found: 68.08 C, 4.89
H, 4.70 N.
Analytical Data for 12. Isolated as 81.3 mg of a white solid
(89%): mp ) 144-146 °C. [R]23D ) -59.3°. FTIR: 1776.8 (Cd
O), 1700.8 (CdO) cm-1. 1H NMR (500 MHz CDCl3): 7.69 (d, J
) 8.5 Hz, 2H), 7.29 (d, J ) 8.0 Hz, 2H), 7.25-7.20 (m, 5H),
5.48 (d, J ) 9.0 Hz, 1H), 4.14-4.10 (m, 3H), 3.93-3.87 (m,
1H), 3.86-3.82 (m, 1H), 3.25-3.20 (m, 1H), 2.76-2.67 (m, 1H),
2.42 (s, 3H), 1.92-1.86 (m, 1H), 1.57-1.51 (m, 1H), 0.66 (d, J
) 7.0 Hz, 3H), 0.49 (m, J ) 7.0 Hz, 3H). 13C NMR (125 MHz,
CDCl3): 168.7, 153.7, 143.4, 139.1, 134.2, 129.6, 128.2, 128.0,
127.7, 127.7, 63.8, 63.7, 58.8, 49.3, 47.5, 28.4, 26.5, 21.5, 18.1,
14.7. HRMS MH+: expected 457.1792, found 457.1791.
Analytical Data for 18. Isolated as 106.2 mg of a colorless
oil (89%). [R]23 ) -31.8°. FTIR: 1778.5 (CdO), 1704.7 (Cd
D
O) cm-1. 1H NMR (500 MHz CDCl3): 7.64-7.62 (m, 2H), 7.39-
7.12 (m, 10H), 6.84 (t, J ) 8.0 Hz, 1H), 6.72-6.68 (m, 4H),
6.63-6.61 (m, 1H), 5.47 (d, J ) 9.5 Hz, 1H), 5.12 (dd, J ) 4.5
Hz, 9.0 Hz, 1H), 4.82 (dd, J ) 11.5 Hz, 13.5 Hz, 2H), 4.52 (t,
J ) 9.0 Hz, 1H), 4.11 (dd, J ) 4.5 Hz, 9.0 Hz, 1H), 3.94-3.88
(m, 1H), 3.74-3.69 (m, 1H), 3.23-3.18 (m, 1H), 2.62-2.53 (m,
1H), 2.38 (s, 3H), 1.91-1.86 (m, 1H). 13C NMR (125 MHz,
CDCl3): 168.4, 158.2, 153.3, 143.3, 140.1, 137.0.6, 136.9, 134.3,
129.5, 129.1, 128.8, 128.5, 128.2, 127.8, 127.6, 127.5, 125.8,
120.2, 114.5, 113.9, 70.1, 69.6, 63.4, 58.0, 49.5, 47.2, 26.4, 21.4.
Elemental analysis (C, H, N) expected: 68.44 C, 5.41 H, 4.69
N. Found: 68.54 C, 5.23 H, 4.54 N.
Analytical Datat for 13. Isolated as 89.0 mg of a white
solid (95%): mp ) 86-88 °C. [R]23 ) -13.8°. FTIR: 1778.2
D
1
(CdO), 1706.4 (CdO) cm-1. H NMR (500 MHz CDCl3): 7.70
(d, J ) 8.0 Hz, 2H), 7.32-7.29 (m, 5H), 7.16-7.14 (m, 2H),
6.55-6.54 (m, 1H), 6.15 (d, J ) 3.0 Hz, 1H), 5.98-5.96 (m,
1H), 5.70 (d, J ) 8.0 Hz, 1H), 5.27 (dd, J ) 4.0 Hz, 8.5 Hz,
1H), 4.63 (t, J ) 9.0 Hz, 1H), 4.32 (dd, J ) 3.5 Hz, 9.0 Hz,
1H), 3.76-3.70 (m, 1H), 3.66-3.62 (m, 1H), 3.18-3.12 (m, 1H),
2.66-2.56 (m, 1H), 2.41 (s, 3H), 1.93-1.88 (m, 1H). 13C NMR
(125 MHz, CDCl3): 167.7, 153.2, 151.4, 143.4, 142.1, 138.0,
134.4, 129.6, 128.9, 128.5, 127.6, 126.7, 109.8, 108.9, 70.3, 57.8,
57.5, 48.2, 46.3, 25.8, 21.5. HRMS MH+: expected 481.1428,
found 481.1417.
Analytical Data for 14. Isolated as 97.9 mg of a white solid
(96%): mp ) 221-223 °C. [R]23D ) -21.7°. FTIR: 1777.0 (Cd
O), 1704.0 (CdO) cm-1. 1H NMR (500 MHz CDCl3): 7.79-7.77
(m, 2H), 7.58-7.54 (m, 1H), 7.50-7.47 (m, 2H), 7.27-7.23 (m,
1H), 7.19-7.15 (m, 2H), 6.92 (d, J ) 8.0 Hz, 2H), 6.80-6.75
(m, 4H), 5.48 (d, J ) 9.0 Hz, 1H), 5.15 (dd, J ) 4.0, J ) 8.5
Hz, 1H), 4.57 (t, J ) 9.0 Hz, 1H), 4.22 (dd, J ) 4.0, J ) 9.0
Hz, 1H), 3.91-3.85 (m, 1H), 3.80-3.76 (m, 1H), 3.24-3.18 (m,
1H), 2.68-2.59 (m, 1H), 2.22 (s, 3H), 1.94-1.88 (m, 1H). 13C
NMR (125 MHz, CDCl3): 168.4, 153.2, 137.6, 137.3, 137.2,
135.6, 132.6, 129.0, 128.9, 128.8, 128.2, 127.6, 127.3, 126.2,
70.2, 63.2, 57.9, 49.5, 47.2, 26.2, 21.2. HRMS MH+: expected
491.1635, found 491.1629.
Analytical Data for 15. Isolated as 100.3 mg of a white
solid (93%): mp ) 186-188 °C. [R]23D ) -34.3°. FTIR: 1778.1
(CdO), 1704.0 (CdO) cm-1. 1H NMR (500 MHz CDCl3): 7.67-
7.64 (m, 2H), 7.29-7.21 (m, 3H), 7.19-7.15 (m, 2H), 6.74-
6.97 (m, 2H), 6.52-6.50 (m, 2H), 5.42 (d, J ) 9.0 Hz, 1H), 5.15
(dd, J ) 4.0 Hz, 9.0 Hz, 1H), 4.55 (t, J ) 9.0 Hz, 1H), 4.17 (dd,
J ) 4.5 Hz, 9.0 Hz, 1H), 3.92-3.86 (m, 1H), 3.77-3.73 (m,
1H), 3.72 (s, 3H), 3.19-3.13 (m, 1H), 2.66-2.57 (m, 1H), 2.41
(s, 3H), 1.93-1.87 (m, 1H). 13C NMR (125 MHz, CDCl3): 168.6,
159.0, 153.2, 143.3, 137.7, 134.2, 130.9, 129.5, 128.8, 128.7,
128.2, 127.7, 126.0, 113.6, 70.2, 62.9, 57.9, 54.9, 49.6, 47.2, 26.3,
21.5. HRMS MH+: expected 521.1741, found 521.1743.
Analytical Data for 19. Isolated as 99.1 mg of a white solid
(97%): mp ) 194-196 °C. [R]23D ) -57.8°. FTIR: 1777.2 (Cd
O), 1703.4 (CdO) cm-1. 1H NMR (500 MHz CDCl3): 7.76-7.74
(m, 2H), 7.60-7.56 (m, 1H), 7.51-7.47 (m, 2H), 7.34-7.30 (m,
1H), 7.27-7.23 (m, 2H), 6.96-6.93 (m, 2H), 6.90-6.87 (m, 2H),
6.83-6.81 (m, 2H), 5.41 (d, J ) 9.5 Hz, 1H), 5.16 (dd, J ) 4.0
Hz, 9.0 Hz, 1H), 4.58 (t, J ) 9.0 Hz, 1H), 4.27 (dd, J ) 4.0 Hz,
9.5 Hz, 1H), 3.98-3.92 (m, 1H), 3.81-3.77 (m, 1H), 3.26-3.20
(m, 1H), 2.63-2.54 (m, 1H), 1.95-1.90, (m, 1H). 13C NMR (125
MHz, CDCl3): 168.3, 153.2, 137.4, 137.1, 133.6, 132.8, 129.0,
129.0, 128.8, 128.7, 128.4, 127.6, 126.2, 70.1, 62.9, 57.8, 49.3,
47.5, 26.4. HRMS MH+: expected 511.1089, found 511.1079.
Analytical Data for 20. Isolated as 94.9 mg of a white solid
(90%): mp ) 160-162 °C. [R]23D ) -42.6°. FTIR: 1778.1 (Cd
O), 1704.2 (CdO) cm-1. 1H NMR (500 MHz CDCl3): 7.66-7.64
(m, 2H), 7.30-7.27 (m, 3H), 7.24-7.20 (m, 2H), 7.01-6.98 (m,
2H), 6.83-6.81 (m, 2H), 6.62-6.58 (m, 2H), 5.40 (d, J ) 9.5
Hz, 1H), 5.15 (dd, J ) 4.0 Hz, 9.0 Hz, 1H), 4.57 (t, J ) 9.0 Hz,
1H), 4.25 (dd, J ) 4.0 Hz, 9.0 Hz, 1H), 3.95-3.90 (m, 1H),
3.79-3.75 (m, 1H), 3.20-3.15 (m, 1H), 2.63-2.54 (m, 1H), 2.42
(s, 3H), 1.92-1.87 (m, 1H). 13C NMR (125 MHz, CDCl3): 168.4,
163.1, 161.1, 153.2, 143.6, 137.5, 134.5, 134.5, 134.0, 129.6,
129.2, 129.1, 128.9, 128.6, 127.7, 126.2, 115.1, 114.9, 70.1, 62.8,
57.8, 49.3, 47.4, 26.3, 21.5. HRMS MH+: expected 509.1541,
found 509.1544.
General Procedure for Auxiliary Cleavage. To a vial
were added pyrrolidine (0.15 mmol), THF (6 mL), and H2O (2
mL). This mixture was cooled to 0 °C, at which time LiOH
(0.3 mmol) and H2O2 (30% in H2O, 0.75 mmol) were added.
The mixture was warmed to room temperature and stirred for
16 h. The crude product mixture was quenched with Na2SO3,
concentrated under reduced pressure, and extracted with CH2-
Cl2. The aqueous layer was acidified to pH 1, extracted with
EtOAc (3 × 15 mL), and dried over anhydrous Na2SO4. When
Analytical Data for 16. Isolated as 112.3 mg of a white
solid (94%): mp ) 77-79 °C. [R]23 ) -58.8°. FTIR: 1777.6
D
(CdO), 1703.1 (CdO) cm-1. 1H NMR (500 MHz CDCl3): 7.67-
7.65 (m, 2H), 7.46-7.41 (m, 4H), 7.38-7.35 (m, 1H), 7.28-
7.26 (m, 2H), 7.21-7.16 (m, 3H), 7.01-6.97 (m, 2H), 6.78-
6.75 (m, 2H), 6.62-6.59 (m, 2H), 5.44 (d, J ) 9.0 Hz, 1H), 5.16
7638 J. Org. Chem., Vol. 70, No. 19, 2005

Asymmetric Halo Mannich-Type Reaction
necessary, recrystallization (benzene/hexane ca. 1:1) afforded
the analytically pure products.
(m, 2H), 7.21 (d, J ) 8.0 Hz, 2H), 7.12-7.10 (m, 1H), 6.26-
6.21 (m, 2H), 5.24 (d, J ) 8.0 Hz, 1H), 3.61-3.57 (m, 1H),
3.48-3.43 (m, 1H), 3.16-3.10 (m, 1H), 2.58-2.49 (m, 1H), 2.40
(s, 3H), 2.17-2.11 (m, 1H). 13C NMR (125 MHz, CDCl3): 172.6,
151.0, 143.3, 142.4, 135.1, 129.5, 127.2, 110.1, 109.3, 57.4, 47.7,
46.5, 25.8, 21.5. HRMS MNa+: expected 358.0720, found
358.0714.
General Procedure for Cleavage of Ts Group. To a 25-
mL round-bottom flask were added pyrrolidine (0.15 mmol),
phenol (50 mg), and 33% HBr in HOAc (15 mL). The flask was
fitted with a reflux condenser and the solution was stirred at
reflux for 8 h. The reaction mixture was cooled to room
temperature, and to this solution was added ice water (∼7 mL).
The resulting mixture was extracted with EtOAc (3 × 15 mL).
The remaining aqueous layer was neutralized by careful
addition of Na2CO3 to pH 8. The resulting mixture was
extracted with EtOAc (3 × 15 mL), and the organic phase was
dried with anhydrous Na2SO4. Recrystallization (CH2Cl2/
hexane ca. 3:1) afforded the pure product.
Analytical Data for 21a. Isolated as 51.8 mg of a white
solid (quant): mp ) 148-150 °C. [R]23 ) -108.0°. FTIR:
D
3199.5, 1736.0, 1716.9 cm-1. 1H NMR (500 MHz CDCl3): 7.59
(d, J ) 8.5 Hz, 2H), 7.26-7.16 (m, 5H), 7.13-7.10 (m, 2H),
5.09 (d, J ) 8.5 Hz, 1H), 3.78-3.74 (m, 1H), 3.43-3.37 (m,
1H), 3.07-3.02 (m, 1H), 2.41 (s, 3H), 2.37-2.28 (m, 1H), 2.00-
1.94. (m, 1H). 13C NMR (125 MHz, CDCl3): 174.2, 143.6, 138.1,
134.9, 129.6, 128.1, 127.9, 127.4, 127.2, 63.9, 49.5, 47.5, 25.3,
21.5. HRMS MH+: expected 346.1107, found 346.1100.
Analytical Data for 21b. Isolated as 51.8 mg of a white
solid (quant): mp ) 52-54 °C. [R]23D ) -97.2°. FTIR: 3246.2,
1
1735.9, 1717.6 cm-1. H NMR (500 MHz CDCl3): 7.71-7.68
(m, 2H), 7.57-7.53 (m, 1H), 7.46-7.42 (m, 2H), 7.02-6.98 (m,
4H), 5.12 (d, J-8.5 Hz, 1H), 3.80-3.76 (m, 1H), 3.64-3.41 (m,
1H), 3.11-3.06 (m, 1H), 2.40-2.29 (m, 4H), 2.04-1.98 (m, 1H).
13C NMR (125 MHz, CDCl3): 173.3, 138.0, 137.6, 135.0, 132.6,
128.9, 128.8, 127.3, 127.2, 63.8, 49.4, 47.5, 25.4, 21.1. HRMS
MH+: expected 346.1107, found 346.1097.
Analytical Data for 22. Isolated as 44.4 mg of a white solid
Analytical Data for 21c. Isolated as 52.3 mg of a white
(88%): mp ) 218-220 °C. [R]23 ) +310.2°. FTIR: 3394.7,
D
solid (96%): mp ) 188-190 °C. [R]23 ) -118.1°. FTIR:
1
1764.3, 1699.5 cm-1. H NMR (500 MHz CD3CN): 7.35-7.32
D
3187.5, 1735.8, 1718.2 cm-1. 1H NMR (500 MHz CDCl3): 7.60-
7.58 (m, 2H), 7.27-7.25 (m, 3H), 7.13-7.10 (m, 2H), 6.91-
6.87 (m, 2H), 5.07 (d, J ) 8.5 Hz, 1H), 3.79-3.75 (m, 1H),
3.42-3.36 (m, 1H), 3.10-3.04 (m, 1H), 2.42 (s, 3H), 2.36-2.27
(m, 1H), 2.02-1.97 (m, 1H). 13C NMR (125 MHz, CDCl3):
173.8, 163.3, 161.4, 143.8, 135.0, 134.1, 134.1, 129.7, 129.0,
128.9, 127.4, 115.1, 114.9, 63.2, 49.5, 47.6, 25.3, 21.5. HRMS
MH+: expected 364.1013, found 364.1006.
(m, 1H), 7.26-7.22 (m, 4H), 7.21-7.15 (m, 3H), 6.73-6.71 (m,
2H), 5.24 (dd, J ) 4.0 Hz, 9.0 Hz, 1H), 5.05 (d, J ) 7.5 Hz,
1H), 4.92-4.88 (m, 1H), 4.63 (t, J ) 9.0 Hz, 1H), 4.01 (dd, J )
4.0 Hz, 9.0 Hz, 1H), 3.56-3.51 (m, 1H), 3.49-3.43 (m, 1H),
2.55-2.48 (m, 1H), 2.44-2.36 (m, 1H). 13C NMR (125 MHz,
CD3CN): 172.2, 154.8, 139.7, 133.9, 129.9, 129.9, 129.8, 128.9,
128.3, 126.4, 71.4, 64.9, 58.6, 46.5, 44.9, 28.5. HRMS MH+:
expected 337.1547, found 337.1542.
Analytical Data for 21d. Isolated as 56.4 mg of a white
solid (86%): mp ) 193-195 °C. [R]23D ) -94.4°. FTIR: 3256.5,
1
Acknowledgment. We gratefully acknowledge fi-
nancial support from the National Institutes of Health
(CA 99995-1) and the Robert A. Welch Foundation (D-
1361).
1736.6, 1711.3 cm-1. H NMR (500 MHz CDCl3): 7.67-7.65
(m, 2H), 7.53-7.49 (m, 1H), 7.42-7.32 (m, 7H), 7.03-7.01 (m,
2H), 6.80-6.77 (m, 2H), 5.10 (s, J ) 9.0 Hz, 1H), 4.99 (s, 2H),
3.77-3.73 (m, 1H), 3.45-3.39 (m, 1H), 3.09-3.04 (m, 1H),
2.40-2.29 (m, 1H), 2.03-1.97 (m, 1H). 13C NMR (125 MHz,
CDCl3): 173.8, 158.4, 138.0, 136.8, 132.6, 130.3, 128.9, 128.6,
128.5, 128.0, 127.5, 127.3, 114.4, 69.9, 63.5, 49.5, 47.4, 25.3.
HRMS MH+: expected 438.1370, found 438.1355.
Supporting Information Available: 1H and 13C NMR for
all new compounds, and crystallographic data in CIF format
for product 11. This material is available free of charge via
the Internet at http://pubs.acs.org.
Analytical Data for 21e. Isolated as 42.3 mg of a white
solid (84%): mp ) 130-131 °C. [R]23D ) -97.9°. FTIR: 3234.4,
1
1735.9, 1718.1 cm-1. H NMR (500 MHz CDCl3): 7.51-7.49
JO0509051
J. Org. Chem, Vol. 70, No. 19, 2005 7639