Intramolecular cyclizations of imines bearing the 2-(thiomethyl)-3-trimethylsilyl-1-propenyl terminator. An efficient new procedure for the stereocontrolled synthesis of functionalized pyrrolidine derivatives

Full text of DOI:10.1021/jo0015366

J . Org. Chem. 2001, 66, 5237-5240
5237
Sch em e 1
In tr a m olecu la r Cycliza tion s of Im in es
Bea r in g th e
2-(Th iom eth yl)-3-tr im eth ylsilyl-1-p r op en yl
Ter m in a tor . An Efficien t New P r oced u r e
for th e Ster eocon tr olled Syn th esis of
F u n ction a lized P yr r olid in e Der iva tives
David Duncan and Tom Livinghouse*
Department of Chemistry and Biochemistry,
Montana State University, Bozeman, Montana 59717
livinghouse@chemistry.montana.edu.
Received October 30, 2000
At the commencement of this investigation, no pre-
paratively general methods for the synthesis of molecules
containing the 2-(thiomethyl)-3-trimethylsilyl-1-propenyl
subunit were available. After some experimentation, the
following procedure was developed for the synthesis of
amine 7 and was later shown to be extendable to the
preparation of related intermediates. Sequential treat-
ment of 3-butyn-1-ol (3a ) with n-BuLi (2 equiv) followed
by MeSSMe provided 4-methylthio-3-butyn-1-ol (79%),
which was subsequently converted to phthalimide 4
under Mitsunobu conditions [PPh3/phthalimide/DIAD,
(86%)]. Exposure of 4 to gaseous HCl followed by treat-
ment of the resulting vinyl chloride 5 with (Me3SiCH2)2-
Zn (1.5 equiv, prepared from Me3SiCH2MgCl + ZnCl2 in
situ) in the presence of 7 mol % PdCl2(PPh3)2 (THF, rt)
then gave phthalimide 6 (87% overall). Final PHT
cleavage with N2H4‚H2O (EtOH, reflux), afforded 7 as a
7:1 mixture of E- and Z-isomers (92% from 6).5 Conden-
sation of amine 7 with a variety of aldehydes was readily
achieved in the presence of 4 Å molecular sieves (THF,
rt) to provide the corresponding imines 1a -g as pure
E-isomers about the CdN bond6 in quantitative yield
(Scheme 2).
Cycliza tion Stu d ies. The TiCl4-mediated cyclization
of imines 1a -g could be readily accomplished by the
procedure described previously by us for imines bearing
the 2-propylidene-1,3-bis(silane) terminator.4a Accord-
ingly, simple exposure of these substrates to TiCl4 (1.0
equiv) in CH2Cl2 at -78 °C followed by stirring at -20
°C for 10 h and final inverse addition to saturated
aqueous KHCO3 provided optimal conversion to the 1,2-
disubstituted pyrrolidines 2a -g, typically with excellent
trans-selectivity and in good isolated yield. In the case
of 2f, a 1.3:7.0 ratio of isomeric pyrrolidines was obtained.
This mixture was converted to the corresponding N-TFA
derivatives (TFAA-pyridine) to facilitate chromatographic
separation of the cis and trans isomers. Sequential amide
hydrolysis of the pure isomers (K2CO3, MeOH) followed
by N-tosylation (TsCl, Py, CH2Cl2, 0 °C f rt) provided
the pure isomeric tosamides 2f(Ts)cis and 2f(Ts)trans. NOE
spectroscopic analyses of the individual isomers provided
compelling evidence for the relative stereochemical ori-
entation of the substituents at positions 2 and 3. Specif-
ically, irradiation of the C-3 methine (H(3)) of the major
isomer (2f(Ts)cis) gave rise to a 13.4% NOE enhancement
The nucleophilic addition of allylsilanes, vinylsilanes,
and related species to carbon-based electrophiles has
come to be regarded as a particularly versatile and
efficient means for the construction of strategic bonds.1
It is therefore surprising that there have been relatively
few instances of highly diastereoselective cyclizations
involving intramolecular additions of this variety to
azomethine moieties.2,3 We have previously shown that
2-propylidene-1,3-bis(silane) assemblages undergo ste-
reodefined intramolecular aminoalkylations in the pres-
ence of TiCl4 to provide functionalized pyrrolidine and
isotropane derivatives.4a As part of a parallel study, it
was discovered that corresponding cyclizations involving
simple (Z)-allylsilanes proceed with diminished stereo-
selectivity and cyclization efficiency, thereby rendering
this process synthetically unattractive.4c In principle, the
installation of a thioalkyl substituent at the 2-position
of an allylsilane should augment the nucleophilicity of
the conjugated π-system with an attendant increase in
coupling efficiency. We now describe an electronically
modified allylsilane terminator of this type for intramo-
lecular imine-alkylations that provides excellent levels
of cyclization stereocontrol under comparatively mild
reaction conditions. As an additional feature, cyclizations
of the type described herein result in the formation of
products possessing a synthetically versatile vinyl sulfide
moiety (Scheme 1).2g
(1) (a) Langkopf, E.; Schinzer, D. Chem. Rev. 1995, 95, 1375. (b)
The Electrophilic Substitution of Allylsilanes and Vinylsilanes. Flem-
ing, I.; Dunogue`s, J .; Smithers, R. In Organic Reactions; Kende, A. S.,
Ed.; J ohn Wiley and Sons: New York, 1989; Vol. 37, Chapter 2, p 57.
(2) (a) Heerding, D. A.; Hong, C. Y.; Kado, N.; Look, G. C.; Overman,
L. E. J . Org. Chem. 1993, 58, 6947. (b) Hong, C. Y.; Kado, N.; Overman,
L. E. J . Am. Chem. Soc. 1993, 115, 11028. (c) Hiemstra, H.; Fortgens,
H. P.; Speckamp, W. N. Tetrahedron Lett. 1985, 26, 3155. (d) Hiemstra,
H.; Sno, M. H. A. M.; Vijn, R. J .; Speckamp, W. N. J . Org. Chem. 1985,
50, 4014. (e) An account addressing stereoselective cyclizations of
allylsilanes with iminium ions generated by a Beckmann rearrange-
ment has appeared: Schinzer, D.; Bo, Y. Angew. Chem., Int. Ed. Engl.
1991, 30, 687. (f) A related intramolecular cyclization initiated by a
TiCl4-activated imine has recently appeared: Frank, K. E.; Aube, J .
J . Org. Chem. 2000, 65, 655. (g) The intermolecular addition of
2-methylthio-3-trimethylsilyl-1-propene to simple imines has been
described: Narasaka, K.; Shibata, T.; Hayashi, Y. Bull Soc. Chem. J pn.
1992, 65, 1392.
(3) (a) J in, J .; Smith, D. T.; Weinreb, S. M. J . Org. Chem. 1995, 60,
5366. (b) Borzilleri, R. M.; Parvez M.; Weinreb, S. M. J . Am. Chem.
Soc. 1994, 116, 9789.
(4) (a) Kercher, T.; Livinghouse, T. J . Am. Chem. Soc. 1996, 118,
4200. (b) For cyclizations involving the intramolecular coupling of
C-acylnitrilium ions with 2-propylidene-1,3-bis(silane)s, see: Kercher,
T.; Livinghouse, T. J . Org. Chem. 1997, 62, 805. (c) Li, J . M.S. Thesis,
Montana State University, 2001.
(5) All new compounds have been fully characterized by 1H and 13C
NMR and IR and possess satisfactory exact mass.
(6) Aldimine geometrical constitution was determined by 300 MHz
1H NMR.
10.1021/jo0015366 CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/04/2001

5238 J . Org. Chem., Vol. 66, No. 15, 2001
Notes
Sch em e 2
(a) (1) n-BuLi, (2) MeSSMe; (b) PPh3/phthalimide/DIAD; (c) HClg; (d) (TMSCH2)2Zn, (Ph3P)2PdCl2 (7 mol %), THF, rt; (e) N2H4‚H2O,
EtOH, reflux; (f) RCHO, 4 Å mol. sieves, THF, rt.
F igu r e 1.
Sch em e 3
at H(2). Corresponding irradiation of H(3) of the minor
isomer (2f(Ts)trans) led to a much smaller (2.6%) NOE
signal at H(2) (Figure 1). The stereochemical assignment
for N-tosylpyrrolidines 2e(Ts) were derived by an analo-
gous NOE study. For N-tosylpyrrolidines 2a -d (Ts), the
observation of characteristically small NOEs in the range
of 2-5% was considered diagnostic for the selective
formation of the indicated trans isomers. In the case of
2c, the sense of relative stereoinduction was established
by NOE enhancement studies performed on the corre-
sponding oxazolidinone 8 that was prepared by sequen-
tial desilylation (TBAF) followed by carbonyldiimidazole
treatment (Scheme 3). A summary of the results obtained
for the TiCl4-mediated cyclizations of imines 1a -g
(Scheme 1) is provided in Table 1.
In consonance with our earlier findings in the 2-pro-
pylidine-1,3-bis(silane) series,4a TiCl4-mediated cycliza-
tion of the ketimine 9 derived from 7 and ethyl levulinate
furnished the pyrrolizidine derivative 10 directly with
excellent and reversed stereoselectivity (cis/trans >
50:1) in 83% yield (Scheme 4).
In conclusion, this study has demonstrated that the
2-(thiomethyl)-3-trimethylsilyl-1-propenyl terminator
serves as an effective nucleophile in efficient and stereo-
selective annulations leading to functionalized pyrroli-
dines. The utilization of this cyclization strategy for the
stereodefined synthesis of bioactive substances is under
current investigation.
Exp er im en ta l Section
Gen er a l. All experiments were carried out under an argon
atmosphere in oven-dried glassware. Tetrahydrofuran (THF) and
diethyl ether (Et2O) were distilled from sodium-benzophenone
ketyl. All other reagents were either prepared according to
published procedures or were available from commercial sources.
Column flash chromatography was performed on Merck silica
gel 60 (230-400 mesh) or Aldrich neutral alumina (∼150 mesh).
N-(4-Meth ylth io)bu t-3-yn ylp h th a lim id e (4). A 100-mL
flame-dried round-bottomed flask equipped with a Teflon-coated

Notes
J . Org. Chem., Vol. 66, No. 15, 2001 5239
Ta ble 1. TiCl4-Med ia ted Cycliza tion s
residue was subjected to flash chromatography (20% ethyl
acetate/hexane for elution) to afford the title compound as a
white solid (5.06 g, 86%). Mp: 70-72 °C. 1H NMR (300 MHz,
CDCl3): δ 7.81 (m, 2H, ArH), 7.68 (m, 2H, ArH), 3.82 (t, 2H,
J ) 7.0 Hz, NCH2CH2-), 2.65 (t, 2H, J ) 7.0 Hz, -CH2CH2C-),
2.24 (s, 3H, -SCH3). 13C NMR (75 MHz, CDCl3): δ 168.4, 134.4,
132.4, 89.2, 73.1, 37.1, 20.4, 19.3. IR (film): 3251, 1767, 1706,
1430, 1400, 1369, 1335, 1114, 996, 867, 724 cm-1. HRMS (EI)
m/z 245.0516 (calcd for C13H11NO2S, 245.0511), ppm error )
-2.1.
N-[4-Ch lor o-4-(m eth ylth io)bu t-3-en yl]p h th a lim id e (5). A
250-mL flame-dried round-bottomed flask equipped with
a
Teflon-coated magnetic stirring bar and a rubber septum was
charged with N-[(4-methylthio)but-3-ynyl]phthalimide (4) (5.00
g, 20.4 mmol) and chloroform (100 mL). The solution was cooled
to 0 °C, and HCl(g) was bubbled through the reaction mixture
until the starting material had been consumed (the consumption
of starting material was monitored by GC analysis). The reaction
mixture was concentrated, dissolved in a minimal amount of 20%
ethyl acetate/hexane, and filtered through a plug of silica gel
(20% ethyl acetate/hexane as eluent). The solvent was then
removed under reduced pressure to afford the title compound
as a viscous oil (5.60 g, 98%) that was used without further
1
purification. H NMR (300 MHz, CDCl3): δ 7.83 (m, 2H, ArH),
7.69 (m, 2H, ArH), 5.88 (t, 1H, J ) 7.0 Hz, -CH2CHd), 3.76 (t,
2H, J ) 6.8 Hz, NCH2CH2-), 2.62 (dt, 2H, J ) 7.0, 6.8 Hz,
-CH2CH2CHd), 2.26 (s, 3H, -SCH3). 13C NMR (75 MHz,
CDCl3): δ 168.6, 134.4, 131.2, 127.2, 123.7, 36.7, 29.5, 16.9. IR
(KBr): 3467, 3279, 2926, 1773, 1712, 1611, 1466, 1436, 1360,
1187, 1046, 970, 862, 793, 719 cm-1. HRMS (EI) m/z 281.0280
(calcd for C13H11ClNO2Si, 281.0277), ppm error ) -1.1.
N-[4-(Meth ylth io)-5-(tr im eth ylsilyl)p en t-3-en yl]p h th a l-
im id e (6). A 50-mL flame-dried round-bottomed flask equipped
with a Teflon-coated magnetic stirring bar and a rubber septum
was charged with a solution of anhydrous ZnCl2 (3.69 mL of 1.06
M in THF, 3.91 mmol). The solution was cooled to 0 °C, and a
solution of TMSCH2MgCl (4.76 mL of 1.64 M in THF, 7.81 mmol)
was added dropwise over a 15-min period. The gray reaction
mixture was stirred for 15 min at 0 °C, and PdCl2(PPh3)2 (350
mg, 0.50 mmol, 7 mol %) was added in one portion. After 15
min of stirring at 25 °C, N-[4-chloro-4-(methylthio)but-3-enyl]-
pthalimide (5) (2 g, 7.10 mmol) in THF (20 mL) was added
dropwise to the black/brown reaction mixture over a 40 min
period, which was stirred at 25 °C for 7 h and poured into a
solution of cold, saturated ammonium chloride (50 mL). Both
phases were decanted into a separatory funnel, and the organic
phase was removed. The aqueous phase was extracted with ether
(3 × 25 mL), and the combined organic extracts were washed
with brine, dried over magnesium sulfate, and concentrated. The
residue was triturated with pentane and filtered through a pad
of Celite. The pentane was removed, and the residue was
purified by flash chromatography (20% ethyl acetate/hexane for
elution) to afford the title compound as a yellowish, viscous oil
(2.06 g, 87%). 1H NMR (300 MHz, CDCl3): δ 7.80 (m, 2H, ArH),
7.67 (m, 2H, ArH), 4.85 (app t, 1H, J ) 7.1 Hz, -CH2CHd), 3.69
(t, 2H, J ) 6.5 Hz, NCH2CH2-), 2.40 (dt, 2H, J ) 7.1, 6.5 Hz,
NCH2CH2-), 2.17 (s, 3H, -SCH3), 1.70 (s, 2H, dCCH2Si(CH3)3)),
0.01 (s, 9H, -Si(CH3)3). 13C NMR (75 MHz, CDCl3): δ 168.77,
137.47, 134.27, 132.55, 123.55, 117.58, 38.15, 35.10, 29.73, 23.62,
-0.54. IR (KBr): 3251, 1771, 1710, 1465, 1396, 1364, 1337, 1114,
867, 744 cm-1. HRMS (EI) m/z 333.1225 (calcd for C17H23NO2-
SSi, 333.1219), ppm error ) -1.8.
a
As determined by 1H NMR.
magnetic stirring bar and a rubber septum was charged with
THF (50 mL), 4-(methylthio)but-3-yn-1-ol (3.00 g, 0.024 mol),
phthalimide (3.83 g, 0.026 mol), and triphenylphosphine (6.82
g, 0.026 mol). The homogeneous solution was cooled to 0 °C and
treated dropwise with diisopropyldiazocarboxylate (5.26 g, 0.026
mol) over a 10-min period. The solution was allowed to warm to
ambient temperature and stirred for 12 h. Evaporation of solvent
at reduced pressure afforded a viscous oil, which was triturated
with 20% ethyl acetate/hexane and filtered through a pad of
silica gel. The filtrate was concentrated, and the resulting
Sch em e 4

5240 J . Org. Chem., Vol. 66, No. 15, 2001
Notes
4-(Meth ylth io)-5-(tr im eth ylsilyl)p en t-3-en yla m in e (7). A
2
h
at room temperature. A solution of aqueous KHCO3
100-mL flame-dried round-bottomed flask equipped with
a
(saturated, 2 mL) was added, and the biphasic mixture was
stirred vigorously for 1 h. The organic phase was removed and
the aqueous phase was extracted with CH2Cl2 (3 × 2 mL). The
combined organic phases were dried (MgSO4) and concentrated
in vacuo to give a deep yellow oil. The residue was subjected to
flash chromatography on silica gel (10% ethyl acetate/hexanes
for elution) to afford the title compound as a colorless, viscous
oil (52 mg, 76%). 1H NMR (300 MHz, CDCl3): δ 7.86 (d, 2H,
J ) 8.3 Hz, ArH), 6.83 (d, 2H, J ) 8.3 Hz, ArH), 4.54 (app s,
1H, -C(CH3S)dCHH), 4.12 (app s, 1H, -C(CH3S)dCHH), 3.99
(dd, 1H, J ) 4.9, 4.8 Hz, -CH2NCHCH-), 3.44 (m, 1H,
-NCHHCH2-), 3.15 (m, 1H, -NCHHCH2), 2.57 (m, 1H,
-CHCdCH2), 2.55 (m, 1H, -CH(CH3)3), 1.92 (s, 3H, ArCH3),
1.63 (s, 3H, SCH3), 1.52 (m, 1H, -NCHCHH), 1.41 (m, 1H,
-NCHCHH), 1.04 (d, 3H, J ) 7.0 Hz, -CH(CH3)2), 0.95 (d, 3H,
J ) 6.9 Hz, -CH(CH3)2). 13C NMR (75 MHz, CDCl3): δ 149.8,
143.4, 137.8, 129.6, 103.2, 69.9, 49.5, 47.8, 33.7, 32.5, 21.2, 19.7,
17.03, 14.3. IR (film): 2972, 2915, 2867, 1593, 1464, 1339, 1152,
1089, 1046, 998, 840 cm-1. HRMS (EI): 339.1329 m/z (calcd for
Teflon-coated magnetic stirring bar, reflux condenser, and a
rubber septum was charged with N-[(4-methylthio)-5-(trimeth-
ylsilyl)pent-3-enyl]pthalimide (6) (1.5 g, 4.5 mmol) and ethanol
(50 mL). The reaction mixture was treated with hydrazine
monohydrate (0.48 g, 9.50 mmol) and heated to reflux temper-
atures with stirring for 8 h. The heterogeneous mixture was
cooled to ambient temperature and filtered through a pad of
Celite. The filtrate was concentrated, and the residue was
triturated with pentane, filtered through a pad of Celite, and
concentrated. The residue was purified by bulb-to-bulb distilla-
tion (120 °C at 0.25 Torr) to afford the title compound as a
colorless liquid (0.84 g, 92%), which consisted of 2 inseparable
isomers (7:1 E/Z isomeric ratio) (major isomer only). 1H NMR
(300 MHz, CDCl3): δ 4.86 (app t, 1H, J ) 7.2 Hz, -CH2CHd),
2.68 (t, 2H, J ) 7.0 Hz, H2NCH2CH2-), 2.17 (s, 3H, -SCH3),
2.16 (m, 2H, H2NCH2CH2CHd), 1.75 (s, 2H, -CH2Si(CH3)3), 1.28
(bs, 2H, -NH2), 0.05 (s, 9H, -CH2Si(CH3)3). 13C NMR (75 MHz,
CDCl3): δ 135.9, 115.2, 42.7 34.31, 23.6, 15.5, 0.48. IR (film):
3370, 3299, 2952, 2919, 1618, 1438, 1424, 1247, 1156, 958, 856,
C
17H25NO2S2, 339.1327), ppm error ) -0.7.
724 cm-1. HRMS (EI+) (M + 1) 204.1232 m/z (calcd for C9H22
NSSi, 204.1242), ppm error ) 5.1.
-
P yr r olizid in on e (10). A 25-mL flame-dried round-bottomed
flask containing a Teflon-coated magnetic stirring bar and a
rubber septum was charged with 4-(methylthio)-5-(trimethylsi-
lyl)pent-3-enylamine (7) (203 mg, 1.00 mmol), 4 Å molecular
sieves, and CH2Cl2 (2 mL). Ethyl levulinate (144 mg, 1.00 mmol)
was added to the reaction mixture and stirred for 12 h at
ambient temperature. The reaction mixture was diluted with
hexane and filtered through a plug of Celite. The filtrate was
concentrated, and the residue was dissolved in CH2Cl2 (10 mL).
This solution was cooled to -78 °C and treated dropwise over a
2-min period with TiCl4 (1.50 mL of mL 0.70 M in toluene, 1.00
mmol) via syringe. The resulting deep orange solution was
stirred for 3 h at -78 °C followed by an additional 12 h at -20
°C. The reaction mixture was transferred dropwise via cannula
into a vigorously stirred, saturated aqueous solution of KHCO3
cooled to 0 °C. The biphasic mixture was stirred for 30 min at
ambient temperature. The organic phase was removed, and the
aqueous phase was extracted with CH2Cl2 (2 × 5 mL). The
combined organic phases were then dried with Na2SO4, filtered,
and concentrated to give a thick oil, which was subjected to flash
chromatography (20% ethyl acetate/hexane followed by 90%
ethyl acetate/hexane for elution) to give the title compound as a
colorless oil (175 mg, 83%). 1H NMR (300 MHz, C6D6): δ 4.76
(app s, 1H, -C(CH3S)dCHH), 4.44 (app s, 1H, -C(CH3S)dCHH),
3.88 (app dt, 1H, J ) 6.8, 7.4 Hz, -NCHHCH2), 2.76 (ddd, 1H,
J ) 1.0, 7.4, 11.3 Hz, -NCHHCH2-), 2.46 (m, 1H, OdCCHH-),
2.32 (app t, 1H, J ) 6.6 Hz, dCCH-), 2.30 (m, 1H, OdCCH2-
CHH-), 2.05 (app dt, 1H, J ) 9.9, 12.8 Hz, OdCCHH-), 1.85
(m, 1H, OdCCH2CHH), 1.81 (m, 1H -NCH2CHH-), 1.79 (s, 3H,
-SCH3), 1.44 (ddd, 1H, J ) 2.5, 9.3, 15.3 Hz, OdCH2CHH), 1.04
(s, 3H, -CCH3). 13C NMR (75 MHz, C6D6): δ 173.9, 148.19,
103.7, 69.2, 53.8, 40.3, 33.3, 31.9, 28.9, 27.8, 14.1. IR (film): 2967,
2918, 1692, 1392, 1244, 842 cm-1. HRMS (EI+): 211.1027 (calcd
for C11H17NOS, 211.1031), ppm error ) 1.7.
N-(2-Meth ylp r op ylid en e)-4-m eth ylth io-5-tr im eth ylsilyl-
3-p en ten -1-a m in e (1a ). The following serves as a general
experimental procedure used for the preparation of aldimines.
A 10-mL single-necked, round-bottomed flask equipped with a
Teflon-coated magnetic stirring bar and a rubber septum was
charged with activated 4 Å molecular sieves (700 mg), 4-(meth-
ylthio)-5-(trimethylsilyl)pent-3-enylamine (7) (0.203 g, 1.00 mmol),
and CH2Cl2 (2 mL). Freshly distilled isobutyraldehyde (0.087 g,
1.20 mmol) was added to the reaction mixture and stirred for
12 h at ambient temperature. The reaction mixture was diluted
with hexane (∼5 mL) and filtered through
a Celite pad.
Evaporation of the solvent and excess aldehyde in vacuo afforded
the title aldimine (0.252 g, 98%) as a colorless oil, which was
used immediately in the next step (2a (Ts)). Crude aldimines (1a -
g, and the ketimine precursor for 10) were prepared using this
procedure.
Tr a n s-N-tosyl-2-isop r op yl-3-[(2-m eth ylth io)eth en yl]p yr -
r olid in e (2a (Ts)). The following represents the general experi-
mental procedure used for the preparation of pyrrolidines from
the corresponding aldimines. A 5-mL flame-dried round-bot-
tomed flask containing a Teflon-coated magnetic stirring bar and
a rubber septum was charged with a solution of freshly prepared
aldimine 1a (52 mg, 0.20 mmol) in CH2Cl2 (2 mL). The solution
was cooled to -78 °C and treated dropwise over a 2 min period
with TiCl4 (0.32 M in toluene, 0.63 mL, 0.20 mmol). The resulting
deep orange solution was stirred for 3 h at -78 °C followed by
an additional 12 h at -20 °C. The reaction mixture was
transferred dropwise via cannula into a vigorously stirred,
saturated aqueous solution of KHCO3 cooled to 0 °C. The
biphasic mixture was stirred for 30 min at ambient temperature
and decanted into a separatory funnel. The organic phase was
removed, and the aqueous phase was extracted with CH2Cl2
(2 × 5 mL). The combined organic phases were then dried with
MgSO4, filtered, and concentrated to give a thick yellow oil. For
the purposes of complete and accurate characterization as well
as NOE analysis, the pyrrolidine was immediately converted to
the corresponding N-tosylate via the following procedure. A 25-
mL flame-dried round-bottomed flask containing a Teflon-coated
magnetic stirring bar and a rubber septum was charged with
the crude pyrrolidine (0.20 mmol calc), pyridine (0.65 µL, 0.80
mmol), and CH2Cl2 (2 mL). The reaction mixture was cooled to
0 °C, and TsCl (38 mg, 0.20 mmol) was added in one portion.
The mixture was stirred at 0 °C for 2 h followed by an additional
Ack n ow led gm en t. Generous financial support for
this research by a grant from the National Institutes of
Health is gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and listings of 1H and 13C NMR, IR, and HRMS
composition data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O0015366