The double reduction of cyclic sulfonamides for the synthesis of (4S-phenylpyrrolidin-2R-yl)methanol and 2S-methyl-4S-phenylpyrrolidine

Article abstract of DOI:10.1021/jo062189o

The synthesis of (4S-pheny]pyrrolidin-2R-yl)methanol and 2S-methyl-4S-phenylpyrrolidine has been achieved via the double reduction of their cyclic sulfonamide precursors which themselves were prepared following the stereoselective intramolecular Heck reaction of a chiral pool derived 2,5-dihydropyrrole. We have recently described a process whereby cyclic aryl sulfonamides, such as 2, are reductively ring-opened to furnish amino products in which the aryl group is incorporated in the final compound. (Evans, P.; McCabe, T.; Morgan, B. S.; Reau, S. Org. Lett. 2005, 7, 43.) The precursors for this reaction were assembled using an intramolecular Heck reaction followed by reduction of the alkene. Overall, this sequence represents an efficient means to construct molecules of this type in which the aryl sulfonyl moiety acts as both an N-protecting group and as an aryl donor. Use of Benkeser's stronger reducing conditions enables molecules such as 4 to be prepared in which both the sulfonamide functional group and the aromaticity of the aryl substituent have been destroyed.

Full text of DOI:10.1021/jo062189o

SCHEME 1
The Double Reduction of Cyclic Sulfonamides for
the Synthesis of
(4S-Phenylpyrrolidin-2R-yl)methanol and
2S-Methyl-4S-phenylpyrrolidine
Paul Evans
Centre for Synthesis and Chemical Biology, School of Chemistry
and Chemical Biology, UniVersity College Dublin,
Dublin 4, Ireland
paul.eVans@ucd.ie
SCHEME 2
ReceiVed October 21, 2006
The synthesis of (4S-phenylpyrrolidin-2R-yl)methanol and
2S-methyl-4S-phenylpyrrolidine has been achieved via the
double reduction of their cyclic sulfonamide precursors which
themselves were prepared following the stereoselective
intramolecular Heck reaction of a chiral pool derived 2,5-
dihydropyrrole. We have recently described a process
whereby cyclic aryl sulfonamides, such as 2, are reductively
ring-opened to furnish amino products in which the aryl
group is incorporated in the final compound. (Evans, P.;
McCabe, T.; Morgan, B. S.; Reau, S. Org. Lett. 2005, 7,
43.) The precursors for this reaction were assembled using
an intramolecular Heck reaction followed by reduction of
the alkene. Overall, this sequence represents an efficient
means to construct molecules of this type in which the aryl
sulfonyl moiety acts as both an N-protecting group and as
an aryl donor. Use of Benkeser’s stronger reducing conditions
enables molecules such as 4 to be prepared in which both
the sulfonamide functional group and the aromaticity of the
aryl substituent have been destroyed.
we decided to investigate the preparation of enantiopure 4-aryl-
2-substituted pyrrolidines 8 using anti-4-hydroxy-L-proline 5
(Scheme 2). The proposed route utilized a selenium-based
method for the preparation of the enantiopure pyrroline Heck
precursor 6 and has been described for the analogous N-Cbz
and N-Boc series.5 It was expected that the intramolecular Heck
reaction of 6 would proceed in a stereoselective manner and
that the stereogenic center controlling this cyclization would
then be lost following syn-â-hydride elimination. The function-
alized scaffold 7 would then be amenable to further (diastereo-
selective) functionalization via conjugate addition/alkenyl re-
duction or manipulation of the ester functional group, prior to
the double reduction generating species such as 8.
Thus, 4-hydoxy proline 5 was converted to its methyl ester,5
which was then used to prepare sulfonamide 9 (Scheme 3).
Following a three-step sequence, 9 was converted into 6 in an
overall yield of 69%. None of the N-sulfonyl enamine, resulting
from a non-regioselective Cope-type elimination, was observed.
The initial thionyl chloride reaction works most efficiently in
methanol affording the methyl ester. In contrast, it has been
reported for similar N-carbamate examples5 that the mesylate
displacement, under reductive formation of benzene selenonate,
proceeds best in ethanol. As a consequence, trans-esterification
also occurred at this stage and 6 was isolated as the ethyl ester.
At this stage, we investigated the possibility of performing a
stereoselective intramolecular Heck reaction directly to form 7
(Scheme 2). However, under the standard conditions used, this
proved not to be possible since pyrrole 17 rapidly formed,
presumably by a base-mediated sulfinate elimination-isomer-
The type of structural motif accessed using this reaction
appears in several classes of biologically active molecules.2,3
The angiotensin converting enzyme (ACE) inhibitor fosinopril,
for example, contains 3R-cyclohexyl proline as a central
structural motif.4 Following on from these preliminary studies,
(1) Evans, P.; McCabe, T.; Morgan, B. S.; Reau, S. Org. Lett. 2005, 7,
43.
(2) (a) Zelle, R. E.; Hancock, A. A.; Buckner, S. A.; Basha, F. Z.; Tietje,
K.; DeBernardis, J. F.; Meyer, M. D. Bioorg. Med. Chem. Lett. 1994, 4,
1319. (b) Ahn, K. H.; Lee, S. J.; Lee, C.-H.; Hong, C. Y.; Park, T. K.
Bioorg. Med. Chem. Lett. 1999, 9, 1379. (c) Sonesson, C.; Wikstro¨m, H.;
Smith, M. W.; Svensson, K.; Carlsson, A.; Waters, N. Bioorg. Med. Chem.
Lett. 1997, 7, 241.
(3) (a) Parsons, A. Tetrahedron 1996, 52, 4149. (b) Baldwin, J. E.; Fryer,
A. M.; Pritchard, G. J. J. Org. Chem. 2001, 66, 2588.
(4) See: Karanewsky, D. S.; Badia, M. C.; Cushman, D. W.; DeForrest,
J. M.; Dejneka, T.; Lee, V. G.; Loots, M. J.; Petrillo, E. W. J. Med. Chem.
1990, 33, 1459 and references therein.
(5) (a) Robinson, J. K.; Lee, V.; Claridge, T. D. W.; Baldwin, J. E.;
Schofield, C. J. Tetrahedron 1998, 54, 98l. (b) Greenwood, E. S.; Hitchcock,
P. B.; Parsons, P. J. Tetrahedron 2003, 59, 3307.
10.1021/jo062189o CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/26/2007
1830
J. Org. Chem. 2007, 72, 1830-1833

SCHEME 3
SCHEME 4
ization process.6 Since we had been able to use 2,5-dihydro-
pyrroles without 2-substituents effectively in this type of Heck
reaction,1 the ethyl ester 6 was reduced to the corresponding
alcohol 10 using Dibal.7 When 10 was subjected to the standard
Heck reaction protocol, pleasingly none of the 2-substituted
pyrrole was observed. 1H NMR spectroscopy of the crude
material, however, revealed the presence of two compounds (ca.
50:50) that proved to be inseparable. Although assignment of
these compounds was difficult, we had a feeling that they were
regioisomers 12a and 13a resulting from an unselective 6-exo-
trig cyclization at both the 3- and 4-positions.
To probe this hypothesis, we converted the primary alcohol
10 into more sterically demanding derivatives in an attempt to
direct the carbon-carbon bond formation toward the 4-position.
Pleasingly, this proved to be the case, although the reactions
were not completely regioselective. Thus, using the pivaloyl
ester 11 significantly more of the 4-isomer 12b was observed
(12b:13b; 80:20), and although the compounds co-ran on
chromatography, the major isomer 12b proved crystalline and
could be separated from 13b. X-ray crystallography confirmed
the structure and indicated that bond formation had occurred
on the Si-face of the alkene as expected.8 The regioisomer 13b
was not obtained in completely pure form, but we assume that
bond formation occurs from the opposite face to the substituent.
Similarly, using the O-tert-butyldimethylsilyl ether, or O-
triisoproylsilyl ether derivatives, a 70:30 mixture of regioisomers
12c/d and 13c/d were observed which were not crystalline and
again proved to be inseparable by column chromatography.
Hydrogenolysis of 12b (ca. 1 mol % Pd/C) proceeded with high
stereoselectivity and 14 was obtained as a single diastereoisomer
in 90% yield. NOE experiments indicated that reduction had
occurred on the opposite side to the aromatic substituent and
reinvestigation of the X-ray structure indicated that this is the
least sterically congested face of the alkene. Interestingly, during
these studies, it was noticed that reactions performed using ca.
8 mol % of palladium resulted in the formation of an additional
compound. Separation of this impurity initially proved prob-
lematic but could be achieved by column chromatography using
DCM as the eluent (14, 49%; 15, 29%).9 Once separated,
spectroscopic data and X-ray crystallographic studies8 indicated
that this impurity was compound 15. It seems likely that 15
arises from a π-allyl palladium species such as 16 since, as
expected, 14 does not undergo reduction to 15 under the
hydrogenation conditions.10
With the cyclic sulfonamides 14 and 15 in hand, their double
reduction was investigated (Scheme 4). Thus, compound 14 was
added to liquid ammonia and was stirred at -78 °C before
lithium (5 equiv) was added in small pieces. Under these
conditions, 14 smoothly underwent both double reduction of
the aryl sulfonamide motif and O-pivaloyl cleavage. Treatment
of O-pivaloyl esters with ammonia solutions represents a mild
method for their cleavage.11 The resultant amine12 was converted
to the sulfonamide 18 for characterization purposes. Similarly,
the methyl compound 15 was converted into 19 in good yield.13
To confirm the stereochemical assignment of 14, on the basis
of the NOE measurements described above, alcohol 18 was
converted into 19 and the proton and carbon spectra for this
material proved to be identical with those obtained from the
direct reduction of 15. This latter sequence, along with the
(9) Use of 100 mol% of Pd/C gave a 50:50 mixture of 14:15.
(10) For a similar reduction of an allylic ester see: Quijano, L.; Caldero´n,
J. S.; R´ıos, T. Chem. Lett. 1979, 1387.
(11) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
(6) Declerck, V.; Ribiere, P.; Martinez, J.; Lamaty, F. J. Org. Chem.
2004, 69, 8372.
(7) Use of LiAlH4 resulted in significant reduction of the aromatic
bromide.
Synthesis, 3rd ed.; Wiley: New York, 1999.
(12) For a racemic synthesis see: Katsukiyo, M.; Takeshi, H.; Takahiro,
N.; Tatsuyuki, T.; Akira, H. Org. Lett. 2000, 2, 385.
(13) For a racemic synthesis see: Bexrud, J. A.; Beard, J. D.; Leitch,
D. C.; Schafer, L. L. Org. Lett. 2005, 7, 1959.
(8) CCDC references numbers 624659 (12b) and 624660 (15).
J. Org. Chem, Vol. 72, No. 5, 2007 1831

[1-(2-Bromobenzenesulfonyl)-2,5-dihydro-1H-pyrrol-2S-yl]-
methanol 10. Under N2, a solution of 1 M Dibal in hexanes (2.00
mL, 2.00 mmol, 2.2 equiv) was added dropwise to a solution of 6
(0.330 g, 0.92 mmol, 1 equiv) in THF (8 mL) at -78 °C. The
reaction mixture was allowed to warm to 0 °C over 1 h. Saturated
NH4Cl (25 mL) and Et2O (25 mL) were added. Following
separation, the resultant aqueous layer was further extracted with
Et2O (3 × 25 mL). The combined organic extracts were dried over
MgSO4 and were filtered, and the solvent was removed under
reduced pressure. Purification by flash column chromatography
(cyclohexane-EtOAc; 1:1) gave 10 (0.267 mg, 92%) as a colorless
π-allyl palladium chemistry implicated previously, illustrates
the potential for the further functionalization of this series of
chiral pool derived aryl substituted pyrrolidines. In summary,
we have developed a concise route for the preparation of (4S-
phenylpyrrolidin-2R-yl)methanol and 2S-methyl-4S-phenylpyr-
rolidine from 4-hydroxyproline, featuring a stereoselective
intramolecular Heck cyclization and the double reduction of the
aromatic cyclic sulfonamide functionality.
Experimental Section
oil. Rf ) 0.3 (cyclohexane-EtOAc; 1:1); [R]20 -86.0 (c 3.0,
D
1-(2-Bromobenzenesulfonyl)-4S-phenylselanylpyrrolidine-2S-
carboxylic Acid Ethyl Ester. Under N2, a solution of diphenyl
diselenide (0.805 g, 2.58 mmol, 0.53 equiv) was treated with NaBH4
(0.210 g, 5.53 mmol, 1.1 equiv) at 0 °C for 1 h. The mesylate
(2.17 g, 4.91 mmol, 1 equiv) in EtOH (40 mL) was then added
and the mixture was heated to reflux for 3.5 h. The reaction mixture
was cooled to room temperature and stirring was continued for 18
h. The bulk of the solvent was removed under reduced pressure
before Et2O (75 mL) and saturated brine solution (75 mL) were
added. Following separation, the aqueous layer was further extracted
with Et2O (2 × 50 mL) and was dried over MgSO4. On filtration,
silica (ca. 10 g) was added and the solvent was removed under
reduced pressure. Purification by flash column chromatography
(cyclohexane-EtOAc; 9:1 f 3:1) gave the selenoether (2.05 g, 81%)
as a yellow oil. Rf ) 0.35 (cyclohexane-EtOAc; 3:1); [R]20D -18.8
(c 0.5, CHCl3); υmax (neat/cm-1) 3065, 2983, 1742, 1573, 1442,
1342, 1260, 1209, 1162, 1028, 913; m/z (ES+) 537 (MNH4+, Br,81
100%), 535 (MNH4+, Br,79 100%), 520 (MH+, Br,81 80%), 518
(MH+, Br,79 80%); found 517.9526, C19H21NO4SSeBr79 requires
CHCl3); υmax (neat/cm-1) 3518, 3427, 3087, 2923, 2875, 1693,
1570, 1444, 1427, 1334, 1164, 1109; m/z (ES+) 320 (MH+, Br,81
100%), 318 (MH+, Br,79 100%); found 317.9814, C11H12NO3SBr79
1
requires 317.9800 (+4.6 ppm); H NMR (CDCl3, 400 MHz) δ )
2.42-2.61 (s(br), 1H), 3.65 (dd, J ) 4.5, 12.0 Hz, 1H), 3.73 (dd,
J ) 3.25, 12.0 Hz, 1H), 4.24 (dddd, app. ddt, J ) 2.0, 5.75, 14.5
Hz, 1H), 4.39 (dddd, app. dq, J ) 2.25, 14.5 Hz, 1H), 4.74-4.78
(m, 1H), 5.67-5.71 (m, 1H), 5.85-5.89 (m, 1H), 7.41 (dt, J )
1.75, 7.5 Hz, 1H), 7.45 (dt, J ) 1.5, 7.5 Hz, 1H), 7.76 (dd, J )
1.5, 7.5 Hz, 1H), 8.01 (dd, J ) 1.75, 7.5 Hz, 1H); 13C NMR (CDCl3,
100 MHz) δ ) 56.4 (CH2), 64.9 (CH2), 69.3 (CH), 120.4 (C), 126.7
(CH), 127.1 (CH), 127.8 (CH), 131.5 (CH), 133.8 (CH), 136.0 (CH),
138.1 (C).
2,2-Dimethylpropionic Acid 1-(2-Bromobenzenesulfonyl)-2,5-
dihydro-1H-pyrrol-2S-yl Methyl Ester 11. At room temperature,
alcohol 10 (475 mg, 1.494 mmol, 1 equiv) in DCM (10 mL) was
treated with pivaloyl chloride (0.23 mL, 1.862 mmol, 1.25 equiv)
and triethylamine (0.31 mL, 2.224 mmol, 1.5 equiv). After 15 h,
the silica (ca. 3 g) was added and the solvent was removed under
reduced pressure. The residue was then purified by flash column
chromatography (cyclohexane-EtOAc; 9:1 f 3:1) which gave 11
(0.553 mg, 92%) as a colorless oil. Rf ) 0.15 (cyclohexane-EtOAc;
1
517.9540 (-2.7 ppm); H NMR (CDCl3, 400 MHz) δ ) 1.14 (t,
J ) 7.0 Hz, 3H), 2.11-2.18 (m, 1H), 2.74-2.81 (m, 1H), 3.58-
3.63 (m, 2H), 3.95 (dq, J ) 7.0, 10.75 Hz, 1H), 4.01 (dq, J ) 7.0,
10.75 Hz, 1H), 4.08-4.16 (m, 1H), 4.59 (dd, J ) 6.5, 8.5 Hz, 1H),
7.28-7.32 (m, 3H), 7.37 (dt, J ) 2.0, 7.5 Hz, 1H), 7.42 (dt, J )
1.5, 7.5 Hz, 1H), 7.51-7.55 (m, 2H), 7.73 (dd, J ) 1.5, 7.5 Hz,
1H), 8.10 (dd, J ) 2.0, 7.5 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
δ ) 13.9 (CH3), 37.3 (CH), 37.9 (CH2), 55.6 (CH2), 60.6 (CH),
61.5 (CH2), 120.4 (C), 127.4 (CH), 127.6 (C), 128.3 (CH), 129.3
(CH), 132.1 (CH), 133.6 (CH), 134.9 (CH), 135.5 (CH), 139.2 (C),
171.1 (CO).
9:1); [R]20 -129.7 (c 4.2, CHCl3); υmax (neat/cm-1) 3089, 2972,
D
+
2874, 1729, 1571, 1453, 1342, 1283, 1165; m/z (ES+) 421 (MNH4
,
Br,81 100%), 419 (MNH4+, Br,79 100%), 404 (MH+, Br,81 90%),
402 (MH+, Br,79 90%); found 402.0378, C16H21NO4SBr79 requires
1
402.0375 (+0.8 ppm); H NMR (CDCl3, 400 MHz) δ ) 1.18 (s,
9H), 4.03 (dd, J ) 4.75, 11.5 Hz, 1H), 4.22 (dddd, J ) 2.0, 2.5,
5.5, 14.5 Hz, 1H), 4.32-4.37 (m, 2H), 4.96-5.01 (m, 1H), 5.66-
5.69 (m, 1H), 5.83-5.87 (m, 1H), 7.38 (dt, J ) 2.0, 7.5 Hz, 1H),
7.45 (dt, J ) 1.5, 7.5 Hz, 1H), 7.74 (dd, J ) 1.5, 7.5 Hz, 1H), 8.02
(dd, J ) 2.0, 7.5 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ ) 27.1
(CH3), 38.7 (C), 55.9 (CH2), 64.6 (CH2), 66.2 (CH), 120.4 (C),
126.7 (CH), 126.9 (CH), 127.7 (CH), 131.1 (CH), 133.6 (CH), 135.9
(CH), 139.0 (C), 177.9 (CO).
1-(2-Bromobenzenesulfonyl)-2,5-dihydro-1H-pyrrole-2S-car-
boxylic Acid Ethyl Ester 6. A solution of the selenoether (4.30 g,
8.43 mmol, 1 equiv) and pyridine (0.85 mL, 10.57 mmol, 1.25
equiv) in DCM (50 mL) was cooled to 0 °C before 30% w/v H2O2
(2.15 mL, 18.97 mmol, 2.25 equiv) was added. The reaction was
stirred and warmed to room temperature over 15 h. DCM (50 mL),
H2O (50 mL), and 1 M HCl solution (10 mL) were added. On
separation, the resultant aqueous layer was further extracted with
DCM (2 × 50 mL) and the combined organic extracts were dried
over MgSO4. Filtration, solvent removal, and purification by flash
column chromatography (cyclohexane-EtOAc; 3:1) gave 6 (2.71
g, 91%) as a colorless viscous oil which solidified at 5 °C. Mp
2,2-Dimethylpropionic Acid 1S-8,8-Dioxo-8λ6-thia-9-aza-
tricyclo[7.2.1.02,7]dodeca-2,4,6,10-tetraen-10-yl Methyl Ester
12b. Under N2, a mixture of 11 (411 mg, 1.02 mmol, 1 equiv),
Pd(OAc)2 (23 mg, 0.102 mmol, 10 mol %), PPh3 (54 mg, 0.206
mmol, 20 mol %), and K2CO3 (212 mg, 1.53 mmol, 1.5 equiv) in
DMF (25 mL) was heated to 60 °C (oil bath temperature). The
reaction was stirred at this temperature for 15 h before cooling and
addition of Et2O (50 mL) and H2O (50 mL). The aqueous layer
was further extracted with Et2O (4 × 30 mL) and the combined
organics were dried over MgSO4. Filtration, solvent removal, and
purification by flash column chromatography (cyclohexane-EtOAc;
3:1) gave regioisomers 12b and 13b (313 mg, 96%) as an
inseparable mixture (80:20). The major isomer 12b was obtained
as a colorless solid (ca. 200 mg) following crystallization. Mp 122
°C (EtOAc-cyclohexane; 1:1); Rf ) 0.15 (cyclohexane-EtOAc; 9:1);
69-71 °C; Rf ) 0.3 (cyclohexane-EtOAc; 3:1); [R]20 -143.8 (c
D
3.0, CHCl3); υmax (neat/cm-1) 3091, 2983, 2928, 2873, 1750, 1571,
1446, 1343, 1263, 1167, 1027; m/z (ES+) 379 (MNH4+, Br,81 45%),
377 (MNH4+, Br,79 45%), 362 (MH+, Br,81 100%), 360 (MH+, Br,79
100%); found 359.9897, C13H14NO4SBr79 requires 359.9905 (-2.3
ppm); 1H NMR (CDCl3, 400 MHz) δ ) 1.20 (t, J ) 7.0 Hz, 3H),
4.04-4.08 (m, 2H), 4.34 (dddd, app. dq, J ) 2.25, 14.25 Hz, 1H),
4.43 (dddd, app. ddt, J ) 2.0, 5.75, 14.25 Hz, 1H), 5.33-5.36 (m,
1H), 5.76-5.80 (m, 1H), 5.95-5.98 (m, 1H), 7.39 (t, J ) 7.5 Hz,
1H), 7.44 (t, J ) 7.5 Hz, 1H), 7.75 (d, J ) 7.5 Hz, 1H), 8.11 (d,
J ) 7.5 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ ) 13.9 (CH3),
55.7 (CH2), 61.7 (CH2), 68.7 (CH), 120.5 (C), 124.8 (CH), 127.5
(CH), 128.5 (CH), 131.8 (CH), 133.6 (CH), 135.6 (CH), 139.0 (C),
169.5 (CO); found C, 43.03; H, 3.82; N, 3.69%, C13H14NO4SBr
requires C, 43.35; H, 3.92; N, 3.89%.
[R]20 -38.5 (c 1.3, CHCl3); υmax (neat/cm-1) 3075, 2973, 2876,
D
+
1733, 1654, 1476, 1340, 1340, 1283, 1164; m/z (ES+) 339 (MNH4
,
50%), 322 (MH+, 100%); found 322.1100, C16H20NO4S requires
1
322.1113 (-4.1 ppm); H NMR (CDCl3, 400 MHz) δ ) 1.19 (s,
9H), 3.30 (dd, app. t, J ) 3.75 Hz, 1H), 4.15 (dd, J ) 3.75, 11.75
Hz, 1H), 4.54 (d, J ) 11.75 Hz, 1H), 4.91 (ddd, J ) 0.75, 1.75,
1832 J. Org. Chem., Vol. 72, No. 5, 2007

15.0 Hz, 1H), 4.93 (dd, J ) 1.5, 15.0 Hz, 1H), 6.44-6.47 (m, 1H),
7.13 (dd, J ) 1.5, 7.5 Hz, 1H), 7.39 (dt, J ) 1.5, 7.5 Hz, 1H), 7.47
(dt, J ) 1.5, 7.5 Hz, 1H), 7.72 (dd, J ) 1.5, 7.5 Hz, 1H); 13C
NMR (CDCl3, 100 MHz) δ ) 27.1 (CH3), 38.2 (C), 42.5 (CH),
60.9 (CH2), 64.8 (CH2), 125.5 (CH), 127.3 (CH), 129.9 (CH), 131.7
(CH), 131.8 (CH), 134.5 (C), 140.5 (C), 144.0 (C), 177.7 (CO);
found C, 59.85; H, 5.96; N, 4.25%, C16H19NO4S requires C, 59.80;
H, 5.96; N, 4.36%.
(ES+) 332 (MH+, 100%); found 332.1309, C18H22NO3S requires
332.1320 (-3.4 ppm); H NMR (CDCl3, 400 MHz) δ ) 1.84-
1
1.95 (m, 1H), 2.21-2.29 (m, 1H), 2.43 (s, 3H), 2.51-2.62 (m,
1H), 3.36 (dd, app. t, J ) 11.75 Hz, 1H), 3.73 (dd, J ) 5.5, 11.0
Hz, 1H), 3.74-3.81 (m, 1H), 3.86 (dd, J ) 2.75, 11.0 Hz, 1H),
3.89 (ddd, J ) 1.5., 7.5, 11.75 Hz, 1H), 7.07 (d, J ) 7.0 Hz, 2H),
7.21 (t, J ) 7.0 Hz, 1H), 7.26 (t, J ) 7.0 Hz, 2H), 7.36 (d, J ) 8.0
Hz, 2H), 7.79 (d, J ) 8.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz)
δ ) 21.6 (CH3), 36.2 (CH2), 42.7 (CH), 56.0 (CH2), 62.8 (CH),
65.6 (CH2), 126.9 (CH), 127.2 (CH), 127.5 (CH), 128.6 (CH), 130.0
(CH), 134.4 (C), 138.9 (C), 144.1 (C).
2,2-Dimethyl-propionic Acid 1S-8,8-Dioxo-8λ6-thia-9-aza-
tricyclo[7.2.1.02,7]dodeca-2,4,6-trien-10R-yl Methyl Ester 14 and
1S,10S-Methyl-8-thia-9-aza-tricyclo[7.2.1.02,7]dodeca-2,4,6-
triene 8,8-Dioxide 15. 10% w/w Pd/C (84 mg, ca. 0.08 mmol, 8
mol %) was added to a solution of 12b (316 mg, 0.984 mmol, 1
equiv) in EtOAc (20 mL). The mixture was stirred under H2 (1
atm) for 15 h. Filtration through Celite, washing EtOAc (2 × 25
mL), and solvent removal followed by purification and by flash
column chromatography (cyclohexane-DCM: 1:2 f DCM) gave
initially 15 (63 mg, 29%) as a colorless solid followed by 14 (155
mg, 49%) as a viscous oil. Data for 15: Mp 148-150 °C (EtOAc);
2S-Methyl-4S-phenyl-1-(toluene-4-sulfonyl)pyrrolidine 19. As
described above, 15 (53 mg, 0.238 mmol, 1 equiv) was converted
into 19 (54 mg, 72%) which was isolated following purification
by flash column chromatography (cyclohexane-EtOAc: 6:1) as a
colorless oil. Rf ) 0.25 (cyclohexane-EtOAc: 6:1); [R]20D -114.0
(c 0.6, CHCl3); υmax (neat/cm-1) 3031, 2972, 2927, 2878, 1599,
1494, 1454, 1339, 1158, 1091; m/z (ES+) 316 (MH+, 100%); found
1
316.1358, C18H22NO2S requires 316.1371 (-4.2 ppm); H NMR
Rf ) 0.5 (DCM); [R]20 -17.2 (c 1.7, CHCl3); υmax (neat/cm-1
)
(CDCl3, 400 MHz) δ ) 1.46 (d, J ) 6.0 Hz, 3H), 1.65-1.74 (m,
1H), 2.31-2.39 (m, 1H), 2.45 (s, 3H), 2.61-2.70 (m, 1H), 3.35
(dd, app. t, J ) 11.5 Hz, 1H), 3.72-3.81 (m, 1H), 3.74 (ddd, J )
1.25, 7.5, 11.5 Hz, 1H), 7.09-7.12 (m, 2H), 7.21 (t, J ) 7.5 Hz,
1H), 7.29 (t, J ) 7.5 Hz, 2H), 7.35 (d, J ) 8.0 Hz, 2H), 7.79 (d,
J ) 8.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ ) 21.6 (CH3),
22.7 (CH3), 42.2 (CH2), 43.0 (CH), 55.0 (CH2), 57.1 (CH), 126.9
(CH), 127.0 (CH), 127.5 (CH), 128.6 (CH), 129.8 (CH), 135.4 (C),
139.7 (C), 143.4 (C).
D
3045, 2985, 2923, 1449, 1329, 1264, 1168; m/z (ES+) 224 (MH+,
100%); found 224.0740, C11H14NO2S requires 224.0745 (-2.3
ppm); 1H NMR (CDCl3, 400 MHz) δ ) 1.46-1.54 (m, 1H), 1.50
(d, J ) 7.5 Hz, 3H), 2.54-2.62 (m, 1H), 3.24 (dd, J ) 3.25, 7.0
Hz, 1H), 3.32 (dd, J ) 3.25, 12.75 Hz, 1H), 3.83-3.39 (m, 1H),
4.41 (dd, J ) 2.5, 12.75 Hz, 1H), 7.17 (dd, J ) 1.5, 7.5 Hz, 1H),
7.38 (dt, J ) 1.5, 7.5 Hz, 1H), 7.44 (dt, J ) 1.5, 7.5 Hz, 1H), 7.78
(dd, J ) 1.5, 7.5 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ ) 19.4
(CH3), 39.9 (CH2), 41.4 (CH), 58.8 (CH2), 59.0 (CH), 125.7 (CH),
127.1 (CH), 128.2 (CH), 132.6 (CH), 136.7 (C), 142.7 (C); found
C, 59.04; H, 5.85; N, 6.11%, C11H13NO2S requires C, 59.15; H,
Alcohol 18 (75 mg, 0.227 mmol, 1 equiv) in DCM (10 mL)
was treated with MsCl (25 µL, 0.323 mmol, 1.4 equiv) and
triethylamine (63 µL, 0.452 mmol, 2 equiv), and stirring was
continued at room temperature for 15 h. Diethyl ether (15 mL)
and 1 M HCl solution (15 mL) were added and the resultant aqueous
phase was re-extracted with diethyl ether (2 × 15 mL). The
combined organic extracts were dried over MgSO4 and were filtered,
and the solvent was removed under reduced pressure. The mesylate
(ca. 0.227 mmol) was directly dissolved in acetone (15 mL), and
NaI (340 mg, 2.267 mmol, 10 equiv) and 18-crown-6 (ca. 5 mg)
were added. The mixture was heated to reflux for 24 h. On cooling,
acetone was removed under reduced pressure before diethyl ether
(20 mL) and water (20 mL) were added. The aqueous layer was
extracted with diethyl ether (20 mL) and the combined extracts
were dried over MgSO4 and were filtered, and the solvent was
removed. The crude iodide (ca. 0.227 mmol) was taken up in dry
THF (10 mL) and LAH (86 mg, 2.263 mmol, 10 eq.) was added.
The mixture was heated to reflux and was stirred for 1 h. After
cooling to room temperature, saturated NH4Cl (20 mL) and diethyl
ether (20 mL) were added. On phase separation, the aqueous layer
was further extracted with diethyl ether (2 × 20 mL) and the
combined organic extracts were dried over MgSO4. Filtration,
solvent removal, and purification by flash column chromatography
(cyclohexane-EtOAc: 6:1) gave 19 (47 mg, 66%) whose data were
identical to that described above.
5.87; N, 6.30%. Data for 14: Rf ) 0.45 (DCM); [R]20 -33.8 (c
D
1.7, CHCl3); υmax (neat/cm-1) 3055, 2965, 2875, 1727, 1476, 1334,
1285, 1168; m/z (ES+) 324 (MH+, 100%); found 324.1255, C16H22-
NO4S requires 324.1270 (-4.5 ppm); 1H NMR (CDCl3, 400 MHz)
δ ) 1.16 (s, 9H), 1.71 (ddd, J ) 2.0, 6.5, 13.0 Hz, 1H), 2.52 (ddd,
J ) 7.0, 9.75, 13.0 Hz, 1H), 3.31 (dd, J ) 3.25, 7.0 Hz, 1H), 3.34
(dd, J ) 3.25, 12.5 Hz, 1H), 3.99-4.07 (m, 1H), 4.28 (dd, J )
7.0, 12.0 Hz, 1H), 4.39 (dd, J ) 2.25, 12.5 Hz, 1H), 4.65 (dd, J )
6.5, 12.0 Hz, 1H), 7.19 (dd, J ) 1.5, 7.5 Hz, 1H), 7.38 (dt, J )
1.5, 7.5 Hz, 1H), 7.44 (dt, J ) 1.5, 7.5 Hz, 1H), 7.77 (dd, J ) 1.5,
7.5 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ ) 27.0 (CH3), 37.1
(CH2), 38.6 (C), 39.3 (CH), 58.8 (CH2), 60.8 (CH), 63.4 (CH2),
126.0 (CH), 127.1 (CH), 128.4 (CH), 132.8 (CH), 136.2 (C), 142.0
(C), 177.8 (CO).
[4S-Phenyl-1-(toluene-4-sulfonyl)pyrrolidin-2R-yl]methanol
18. A solution of 14 (86 mg, 0.266 mmol, 1 equiv) in THF (10
mL) was added to NH3 (ca. 250 mL) at -78 °C. The mixture was
stirred for 0.25 h before small pieces of Li (9 mg, 1.29 mmol, 4.8
equiv) were added. Stirring was continued for 0.5 h before solid
NH4Cl (ca. 5 g) was added. Following evaporation of ammonia,
Et2O (50 mL) and 1 M KOH (50 mL) were added. The resultant
aqueous phase was further extracted with Et2O (4 × 25 mL) and
the combined organic phases were dried over MgSO4. Filtration
and solvent removal gave the crude product which was taken up
in DCM (3 mL). TsCl (51 mg, 0.268 mmol, 1 equiv) and
triethylamine (56 µL, 0.402 mmol, 1.5 equiv) were added and the
mixture was stirred for 15 h. Silica (ca. 1 g) was added and the
solvent was removed under reduced pressure before purification
by flash column chromatography (cyclohexane-EtOAc; 3:1) gave
18 (78 mg, 89%) as a colorless oil. Rf ) 0.15 (cyclohexane-EtOAc;
Acknowledgment. Dr. H. Mueller-Bunz (UCD) is thanked
for X-ray crystallography and UCD is thanked for their financial
support.
Supporting Information Available: Proton and carbon NMR
spectra and the X-ray structures of 12a and 15. This material is
available free of charge via the Internet at http://pubs.acs.org.
3:1); [R]20 -79.7 (c 2.3, CHCl3); υmax (neat/cm-1) 3475, 3061,
D
3031, 2928, 2889, 1599, 1495, 1452, 1339, 1158, 1092, 1034; m/z
JO062189O
J. Org. Chem, Vol. 72, No. 5, 2007 1833