Synthesis of functionally diverse bicyclic sulfonamides as constrained proline analogues and application to the design of potential thrombin inhibitors

Article abstract of DOI:10.1016/S0040-4020(03)00919-0

Bicyclic sulfonamides were synthesized from 4-alkenyl N-alkenylsulfonyl L-prolines using a ring-closure metathesis reaction. Three types of bicyclic sulfonamides varying in the size of the second ring (5,5; 5,6; 5,7) were synthesized. A sulfonamide counte

Full text of DOI:10.1016/S0040-4020(03)00919-0

Tetrahedron 59 (2003) 7047–7056
Synthesis of functionally diverse bicyclic sulfonamides as
constrained proline analogues and application to the design of
potential thrombin inhibitors
*
Stephen Hanessian, Helen Sailes and Eric Therrien
´ ´ ´
Department of Chemistry, Universite de Montreal, C. P. 6128, Succursale Centre-Ville, Montreal, P. Q., Canada H3C 3J7
Received 24 May 2003; revised 9 June 2003; accepted 10 June 2003
Dedicated to Professor K. C. Nicolaou, chemist extraordinaire, and master molecule builder, wishing him the best in chemistry and in life
Abstract—Bicyclic sulfonamides were synthesized from 4-alkenyl N-alkenylsulfonyl L-prolines using a ring-closure metathesis reaction.
Three types of bicyclic sulfonamides varying in the size of the second ring (5,5; 5,6; 5,7) were synthesized. A sulfonamide counterpart of an
indolizidinone 2-carboxylic acid was synthesized and evaluated for its activity against the enzyme thrombin.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
first generation Grubbs catalyst (benzylidene-bis(tricyclo-
hexylphosphine) dichlororuthenium).12 To the best of our
knowledge, bicyclic enantiopure and functionalized
sulfonamides have not been reported utilizing a direct
ring-closure metathesis reaction. A route to oligomeric
bicyclic sulfonamides has been recently reported via a ring-
opening metathesis reaction.13 We describe herein the
synthesis of diversely functionalized bicyclic sulfonamides
as constrained proline analogues. We also report on a
sulfonamide surrogate of an indolizidinone 2-carboxylic
acid patterned after a low nanomolar prototypical thrombin
inhibitor.14,15
The acyclic sulfonamide group has been extensively used as
a surrogate for an amide function in the design of
peptidomimetic structures.1 Indeed, the sulfonamide group
can be considered as a transition state isostere for
proteases.2,3 A large number of such replacements can be
found in the synthesis of potential enzyme inhibitors and
antagonists with widespread applications in pharmaceutical
research.4 Cyclic sulfonamides (sultams) can be considered
to be the functional analogues of the corresponding lactam
structures.5 Their incorporation in peptidic motifs can lead
to conformational restriction in that substructure similar to
the corresponding lactams. Although cyclic sulfonamides,
including aromatic variants, are not found in nature, a
recently introduced drug for the treatment of glaucoma
(brinzolamide, Azopt),6 incorporates such a functionality as
a bicyclic thiophene analogue. Cyclic sulfonamides have
also found applications as agrochemicals,7 and as potential
chemotherapeutic agents.8
2. Results and discussion
The known 4-cis-(2-propenyl)-N-Boc-L-proline benzyl
ester16 3 was treated with trifluoroacetic acid, then with
ethenesulfonyl chloride prepared from 2-chloroethylsul-
fonyl chloride and triethylamine,17 to give 5 in excellent
overall yield. Treatment of 5 under the conditions of ring-
closure metathesis with the first generation Grubbs catalyst
A11 gave the bicyclic sulfonamide 6 albeit in 22% yield
only. Hydrogenation afforded the corresponding carboxylic
acid 7. When the catalyst was changed to the more reactive
second generation version B, and the cyclization conducted
on the 2-TBDPS ether analogue 10, the corresponding
bicyclic sulfonamide 11 was obtained in 79% yield. Its
structure was determined unambiguously by a single crystal
X-ray analysis. Cleavage of the TBDPS group afforded the
corresponding alcohol 12.
Monocyclic and polycyclic sultams can be prepared by a
variety of methods relying on intramolecular cyclizations.9
The advent of the ring-closure metathesis reaction10
especially utilizing the Grubbs catalysts,11 has considerably
facilitated the synthesis of such sultams, and expanded the
scope of their applications. A variety of monocyclic
sulfonamides can be accessed in excellent yields with the
Keywords: ring-closure metathesis; sulfonamide; sulfonamide carbanion;
alkylation; azidation; thrombin inhibitors.
*
Corresponding author. Tel.: þ1-514-343-6738; fax: þ1-514-343-5728;
e-mail: stephen.hanessian@umontreal.ca
The synthesis of the 6-membered homologue is shown in
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00919-0

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S. Hanessian et al. / Tetrahedron 59 (2003) 7047–7056
Scheme 1. Reagents and conditions: (a) TFA, CH2Cl2, 89%; (b) ethenesulfonyl chloride, Et3N, CH2Cl2, 08C to rt, 81%; (c) A, 6 mol%, reflux, 48 h, 22%;
(d) H2, Pd/C, MeOH, 48 h, 74%; (e) TMSOTf, i-Pr2NEt, CH2Cl2, 08C, 94%; (f) ethenesulfonyl chloride, Et3N, Ch2Cl2, 08C to rt, 47%; (g) B, 5 mol%, toluene,
reflux, 48 h, 79%; (h) TBAF, THF, 57%.
Scheme 2. Thus, N-sulfonylation of 4 afforded 13 which
was subjected to ring-closure metathesis with reagent A to
give 14 in quantitative yield. The structure and position of
the double bond was unequivocally determined by single
crystal X-ray analysis. Hydrogenation led to the carboxylic
acid 15. It was also possible to cleave the benzyl ester
selectively using conditions of catalytic transfer hydrogen-
ation to afford the acid 16. Reduction of the benzyl ester
group in 14 gave the alcohol 17.
metathesis of 18 afforded the bicyclic sulfonamide 19 in
excellent yield, which upon hydrogenation gave the
saturated acid 20. Compound 19 could be converted to the
corresponding free acid 21 by treatment with LiOH in this
case without affecting the double bond, as confirmed by a
single crystal X-ray structure.
A noteworthy feature in the three bicyclic sulfonamide
products obtained by ring-closure metathesis in Schemes
1–3 is the disposition of the double bond which does not
migrate from its original position in the six and seven-
membered ring systems. The X-ray crystal structures show
The 7-membered analogue of 16 was prepared using the
same protocol as shown in Scheme 3. Thus, ring-closure
Scheme 2. Reagents and conditions: (a) prop-2-ene-1-sulfonyl chloride, Et3N, CH2Cl2, 08C, 63%; (b) A, 3 mol%, CH2Cl2, 3 h, 98%; (c) H2, Pd/C, MeOH/
EtOAc, 1 h, 99%; (d) cyclohexadiene, Pd/C, EtOAc, 6 h, 90%; (e) DiBAL-H, THF/toluene, 2788C to rt, 1.5 h, 85%.
Scheme 3. Reagents and conditions: (a) but-3-ene-1-sulfonyl chloride, Et3N, CH2Cl2, 08C, 1 h, 55%; (b) A, 6 mol%, CH2Cl2, 2 h, 81%; (c) H2, Pd/C, MeOH,
1 h, 86%; (d) LiOH, H2O/THF, 16 h, 85%.

S. Hanessian et al. / Tetrahedron 59 (2003) 7047–7056
7049
Scheme 4. Reagents and conditions: (a) prop-2-ene-1-sulfonyl chloride, Et3N, CH2Cl2, 08C 63%; (b) A, 3 mol%, CH2Cl2, reflux, 15 h, 93%; (c) H2, Pd/C,
EtOAc, 99%; (d) t-BuLi, BnBr, THF, 2788C, 87%; (e) t-BuLi, trisyl-azide, THF, 2788C, 26 (40%), epimer (24%); (f) TBAF, THF, 86%; (g) Dess-Martin,
CH2Cl2; (h) NaO2Cl, NaH2PO4, 2-methyl-butene, t-BuOH/H2O; (i) EDC, HOBt, i-Pr2NEt, N-Boc aminomethylbenzamidine, DMF, 65%; (j) H2, Pd/C, MeOH;
(k) HCl (3N)/MeOH (1:1), 60%.
interesting conformational features in 14 and 21, respect-
ively. Clearly these exquisitely functionalized bicyclic
sulfonamide analogues of constrained prolines can find
many applications as turn mimetics,18 lactam comple-
ments,19 and scaffolds for further diversity.20 In this context,
we describe the stereocontrolled functionalization of the
sultam related to an indolizidinone 2-carboxylic acid.14,21,22
Thus, compound 9 was N-sulfonylated to 22, then subjected
to ring-closure metathesis to give 23 in 93% yield
(Scheme 4). Hydrogenation to 24 followed by treatment
with t-BuLi gave the a-sulfonyl carbanion, which was
benzylated with benzyl bromide to give 25 as a mixture of
epimers.14 Formation of the corresponding a-sulfonyl
carbanion23 with t-BuLi, and treatment with trisyl
azide14b,24 afforded a 1.2:1 mixture of epimeric tertiary
azides. The modestly prevalent isomer 26 was characterized
by a single X-ray structure. It should be noted that the azide
group adopts a pseudo equatorial orientation in the six-
membered chair-like sultam subunit.
Catalytic hydrogenation and treatment with acid gave the
bicyclic sulfonamide 29 as the bis-hydrochloride salt.
We have previously reported on the synthesis of corre-
sponding indolizidinone analogues 1 and 2 (Fig. 1) as
inhibitors of thrombin14a and Factor VIIa,14b respectively.
When tested against thrombin, compound 29 showed
considerably weaker inhibition (IC50 494 nM) compared
to 1 (IC50 20 nM) and 1a (IC50 4 nM),25 inspite of the
presence of a more favored amino group at C-3. It is not
known whether the loss of antithrombin activity is due to
poorer binding of the sulfone group to Gly 216,15 compared
to the lactam carbonyl analogues in 1 or 2. Clearly more
studies are needed to assess the H-bonding capacity of
cyclic a-amino sulfonamides such as 29 compared to their
lactam analogues.2,19
It is of interest to compare the azidation of the closely
related indolizidinones 3014b and 3125 under the same
conditions (Scheme 5). In the case of 30, the major product
was the desired 3R ‘up’ azide 32, probably due to the
approach of the electrophile from the convex face of the
bicyclic system, because the pseudoaxial 5-methoxy group
Cleavage of the TBDPS group from 26 afforded 27 which
was oxidized to the carboxylic acid, and the latter converted
to the p-N-Boc amidino benzylamide derivative 28.
Figure 1. Constrained proline analogues as inhibitors of thrombin.

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S. Hanessian et al. / Tetrahedron 59 (2003) 7047–7056
Scheme 5.
on the concave face exerts a steric influence towards the
approach of the electrophile from that side. In the absence of
such a substituent as in 31, the azidation led to a 1:2 mixture
of 33 (minor) and its epimer. Presumably the bulky TBDPS
group has a more dominant influence in this case compared
to the substituted counterpart 30. Based on extensive studies
on a-alkyl sulfonyl carbanions,23,26 we can assume that the
lithium anion 25a is pyramidal, with the cation near the
sulfonyl oxygens. Therefore the approach of the electrophile
will be subject to two inherently opposing factors, namely
the TBDPS group on the convex face and the topology of
the concave side, probably bearing a pseudo-equatorially
disposed benzylic substituent, resulting in a mixture of
tertiary azides. More studies are needed to better understand
the stereochemical preferences in the reaction with various
carbon and hetero-atom based electrophiles of these
constrained sulfonamide carbanions.
Low and high-resolution mass spectra were recorded on VG
Micromass, Ael-MS902 or Kratos MS-50 spectrometers
using fast atom bombardment (FAB) technique. Optical
rotations were measured at 258C at the sodium line.
4.1.1. (2S,5S)-5-cis-Propenyl-pyrrolidine-2-carboxylic
acid benzyl ester (4). To a solution of 3 (1.14 g,
3.30 mmol) in CH2Cl2 (20 mL) was added trifluoroacetic
acid (5 mL, 66.0 mmol). The reaction mixture was stirred at
room temperature for 1 h then quenched with solid NaHCO3
until no further effervescence was observed. The mixture
was partitioned between water and CH2Cl2, the organic
phases were dried over Na2SO4 and evaporated. The yellow
residue was purified by column chromatography (50%,
EtOAc/hexanes) to furnish the title compound 2 (720 mg,
89%) as a pale yellow oil: [a]D¼246.2 (c 2.3, CHCl3); 1H
NMR (400 MHz, CDCl3) d 1.44–1.52 (m, 1H), 1.66 (dd,
J¼1.2, 6.9 Hz, 3H), 1.87–1.98 (m, 2H), 2.25–2.32 (m, 1H),
2.36 (br, 1H), 3.94–4.05 (m, 1H), 4.07–4.11 (m, 1H), 5.17
(s, 2H), 5.33–5.38 (m, 1H), 5.47–5.54 (m, 1H), 7.32–7.40
(m, 5H); 13C NMR (75 MHz, CDCl3) d 13.1, 29.5, 32.0,
54.4, 59.1, 66.6, 125.4, 128.1, 128.2, 126.5, 133.2, 135.7,
175.6; nmax/cm21 3351, 2965, 1735, 1190; HRMS calcd for
C15H20NO2 (Mþ1) 246.14940; found 246.14860.
3. Conclusion
We have described practical syntheses of enantiopure
bicyclic sulfonamides endowed with sites for functional
diversity. These compounds can be functionalized next to
the sulfonamide group via carbanion formation. The facile
alkylation and azidation at this site are unprecedented
examples within this class of bicyclic sulfonamides. It is
hoped that such functionalized bicyclic sulfonamides
containing two or more sites for diversification will find
application in the design of prototypical bioactive
molecules.
4.1.2. (2S,5S)-1-Ethenesulfonyl-5-cis-propenyl-pyrroli-
dine-2-carboxylic acid benzyl ester (5). To a solution of
chloroethanesulfonylchloride17a (0.140 mL, 1.33 mmol) in
CH2Cl2 (3 mL), was added Et3N (0.185 mL, 1.33 mmol) at
2788C under argon. The reaction mixture was allowed to
slowly warm to 08C over 2 h then a solution of 4 (326 mg,
1.33 mmol) in CH2Cl2 (3 mL) and Et3N (0.19 mL,
1.33 mmol) were added. The reaction mixture was allowed
to warm to room temperature, stirred for a further 2 h, and
then was partitioned between 10% HCl (aq.) and CH2Cl2.
The organic phases were combined, washed with brine,
dried over Na2SO4 and evaporated. The residue was purified
by column chromatography (10%, EtOAc/hexanes) to yield
the title compound 5 (360 mg, 81%) as a colorless oil:
[a]D¼þ26.9 (c 2.7, CHCl3); 1H NMR (400 MHz, CDCl3) d
1.64–1.71 (m, 4H), 1.96–2.00 (m, 1H), 2.26–2.39 (m, 2H),
4.40–4.42 (m, 1H), 4.73–4.77 (m, 1H), 5.22 (m, J¼11.1,
14 Hz, 2H), 5.37–5.43 (m, 1H), 5.53–5.61 (m, 1H), 5.86
(dd, J¼1.3, 9.9 Hz, 1H), 6.18 (dd, J¼1.3, 16.6 Hz, 1H), 6.59
(ddd, J¼1.3, 9.9, 16.6 Hz, 1H), 7.34–7.38 (m, 5H); 13C
4. Experimental
4.1. General
Flash chromatography was performed on 230–240 mesh
silica gel.27 Thin-layer chromatography (TLC) was per-
formed on glass plates coated with 0.02 mm layer of silica
gel 60 F254. All solvents were distilled freshly before use.
400-MHz 1H NMR, 100-MHz 13C NMR spectra were
determined in CDCl3 unless otherwise noted. Wherever
necessary, 1H NMR assignments were supported by
appropriate homonuclear correlation experiments (COSY).

S. Hanessian et al. / Tetrahedron 59 (2003) 7047–7056
7051
NMR (100 MHz, CDCl3) d 12.9, 29.1, 31.7, 55.8, 61.0,
67.0, 126.3, 126.4, 128.1, 128.3, 128.5, 130.1, 135.4, 136.1,
172.5; nmax/cm21 2957, 1746, 1345, 1148; HRMS calcd for
C17H22NO4S (Mþ1) 336.12695; found 336.12590.
dry CH2Cl2 (7.3 mL). The mixture was slowly warmed to
08C over a period of 1.5 h and the amine 9 (1.04 g,
2.74 mmol) in CH2Cl2 (2.0 mL) and Et3N (0.40 mL,
2.90 mmol) were added via canula. The mixture was stirred
for 15 h, quenched with the addition of 1N HCl, and the
resulting solution was extracted with CH2Cl2 and processed
as usual. The resulting residue was purified by column
chromatography (30–50% CH2Cl2/hexanes) to afford 10
(607 mg, 47%) as a colorless oil: [a]D¼þ50.1 (c 0.5,
CHCl3); 1H NMR (400 MHz, CDCl3) d 1.12 (s, 9H), 1.54–
1.63 (m, 1H), 1.71–1.75 (m, 3H), 2.04–2.09 (m, 1H), 2.15–
2.23 (m, 2H), 3.59–3.68 (m, 2H), 4.00–4.03 (m, 1H), 4.70
(t, J¼6.9 Hz, 1H), 5.35 (t, J¼10.5 Hz, 1H), 5.58–5.62 (m,
1H), 5.76 (dd, J¼5.3, 9.9 Hz, 1H), 6.03 (dd, J¼4.4, 16.6 Hz,
1H), 6.42 (dd, J¼9.9, 16.6 Hz, 1H), 7.39–7.47 (m, 6H),
7.68–7.71 (m, 4H); 13C NMR (100 MHz, CDCl3) d 13.4,
19.7, 27.2, 27.4, 31.0, 57.3, 60.5, 66.0, 125.9, 127.4, 128.1,
130.0, 130.1, 133.9, 134.0, 136.0, 136.1, 136.5; nmax/cm21
2933, 2858, 1473, 1428, 1348, 1151, 1113; HRMS calcd for
C26H36NO3SSi (Mþ1) 470.21852; found 470.21640.
4.1.3. (6S)-1,1-Dioxo-3a,4,5,6-tetrahydro-1H-1l6-pyr-
rolo[1,2-b]-isothiazole-6-carboxylic acid benzyl ester
(6). To a de-gassed solution of 5 (174 mg, 0.52 mmol) in
CH2Cl2 (52 mL), Grubbs’ catalyst A (26 mg, 0.031 mmol)
was added under argon. The solution was refluxed for 48 h
then evaporated. The residue was purified by filtration
through a pad of Florisil followed by column chromato-
graphy (50%, EtOAc/hexanes) to furnish the title compound
1
6 (33 mg, 22%): [a]D¼221.8 (c 1.14, CHCl3) H NMR
(400 MHz, CDCl3) d 1.73–1.80 (m, 1H), 2.21–2.36 (m,
3H), 4.62 (t, J¼6.7 Hz, 1H), 4.68–4.72 (m, 1H), 5.23 (ABq,
J¼12.4 Hz, sep. J¼19.8 Hz, 2H), 6.68 (dd, J¼2.3, 6.5 Hz,
1H), 6.79 (dd, J¼2.0, 6.5 Hz, 1H), 7.31–7.44 (m, 5H); 13C
NMR (75 MHz, CDCl3) d 30.0, 30.2, 60.8, 67.2, 67.3,
127.6, 128.1, 128.3, 128.6, 135.3, 139.3, 170.6; nmax/cm21
1746, 1306, 1154; HRMS calcd for C14H16NO4S (Mþ1)
294.08002; found 294.07940.
4.1.7. (6S)-6-(tert-Butyl-diphenyl-silanyloxymethyl)-
3a,4,5,6-tetrahydro-pyrrolo[1,2-b]isothiazole 1,1-dioxide
(11). Grubbs second generation’s catalyst B (10 mg,
0.28 mmol) was added to a solution of diene 10 (100 mg,
0.21 mmol) in toluene (20 mL) and the mixture was heated
at reflux 2 days. The solution was concentrated in vacuo and
the resulting residue was purified by column chromato-
graphy (20% EtOAc/hexanes) to afford 11 (72 mg, 79%) as
4.1.4. (6S)-1,1-Dioxo-hexahydro-1l6-pyrrolo[1,2-b]-iso-
thiazole-6-carboxylic acid (7). A solution of 6 (13.4 mg,
0.046 mmol) in methanol (0.5 mL) was stirred under an
atmosphere of hydrogen in the presence of a catalytic
amount of 10% palladium-on-charcoal for 48 h. The
suspension was then filtered through a Celite pad and the
filtrate was evaporated to yield the title compound 7 (7 mg,
74%) as a white semi-solid: [a]D¼270.8 (c 0.36, MeOH);
1H NMR (400 MHz, CD3OD) d 1.67–1.77 (m, 1H),
2.01–2.11 (m, 1H), 2.16–2.25 (m, 2H), 2.36–2.44 (m,
1H), 2.51–2.60 (m, 1H), 3.02–3.10 (m, 1H), 3.23–3.29 (m,
1H), 4.09–4.15 (m, 1H), 4.37 (t, J¼7.8 Hz, 1H); 13C NMR
(75 MHz, CD3OD) d 27.0, 31.5, 32.6, 46.0, 63.4, 63.9,
175.6; nmax/cm21 2927, 1728, 1317, 1151; HRMS calcd for
C7H12NO4S (Mþ1) 206.04870; found 206.04450.
1
a pale brown oil: [a]D¼26.2 (c 0.13, CHCl3); H NMR
(400 MHz, CDCl3) d 1.10 (s, 9H), 1.65 (m, 1H), 1.97 (m,
1H), 2.12 (m, 1H), 2.22 (m, 1H), 3.67 (dd, J¼6.1, 10.3 Hz,
1H), 3.78 (dd, J¼5.3, 10.3 Hz, 1H), 4.15 (m, 1H), 4.53 (t,
J¼7.7 Hz, 1H), 6.61 (dd, J¼2.6, 6.5 Hz, 1H), 6.77 (dd,
J¼1.9, 6.4 Hz, 1H), 7.39–7.47 (m, 6H), 7.70–7.73 (m, 4H);
13C NMR (100 MHz, CDCl3) d 19.7, 27.2, 30.1, 30.9, 61.7,
67.0, 67.9, 127.9, 128.2, 133.6, 133.7, 136.0, 136.1, 139.2,
139.8; nmax/cm21 2931, 2858, 1306, 1155, 1113; HRMS
calcd for C23H30NO3SSi (Mþ1) 428.17157; found
428.17181.
4.1.5. (2S,5S)-2-(tert-Butyl-diphenylsilanyloxymethyl)-5-
cis-propenyl-pyrrolidine (9). TMSOTf (0.63 mL,
3.51 mmol) was added to a 08C solution of 8 (1.40 g,
2.92 mmol) and i-Pr2NEt (1.02 mL, 5.85 mmol) in CH2Cl2
(20 mL). The solution was stirred for 1.5 h, quenched with
saturated aqueous NaHCO3 (15 mL), extracted with
CH2Cl2, dried over Na2SO4, filtered and concentrated in
vacuo. The residue was purified by column chromatography
(50% EtOAc/hexanes) to afford 9 (1.04 g, 94%) as a
colorless oil: [a]D¼þ12.1 (c 2.7, CHCl3); 1H NMR
(400 MHz, CDCl3) d 1.05 (s, 9H), 1.64 (d, J¼6.9 Hz, 3H),
1.68–1.82 (m, 2H), 2.10–2.15 (m, 2H), 3.64–3.68 (m, 1H),
3.77–3.90 (m, 2H), 4.33–4.39 (m, 1H), 5.47–5.52 (m, 1H),
5.61–5.66 (m, 1H), 7.36–7.45 (m, 6H), 7.61–7.67 (m, 4H);
13C NMR (100 MHz, CDCl3) d 13.0, 19.0, 26.6, 26.8, 31.6,
55.7, 59.3, 64.3, 127.3, 127.7, 129.3, 129.8, 132.6, 132.7,
135.5, 135.6; nmax/cm21 2959, 2860, 1683, 1429, 1202,
1135, 1114; HRMS calcd for C24H33NOSi (Mþ)
379.233143; found 379.233444.
4.1.8. (6S)-(1,1-Dioxo-3a,4,5,6-tetrahydro-1H-1l6-pyr-
rolo[1,2-b]isothiazol-6-yl)-methanol (12). TBAF (1 M in
THF, 0.70 mL, 0.70 mmol) was added dropwise to a
solution of 11 (200 mg, 0.47 mmol) in THF (2.4 mL).
After stirring for 1.5 h, a saturated solution of NaHCO3
(10 mL) was added and extracted with EtOAc. The organic
layer was processed as usual to yield a residue which was
purified by column chromatography (75–100% EtOAc/
hexanes) to give the title compound (12) (51 mg, 57%) as a
clear, colorless oil; [a]D¼þ24.8 (c 1.53, CHCl3). 1H NMR
(400 MHz, CDCl3): d 1.60–1.70 (m, 1H), 1.96–2.06 (m,
1H), 2.12–2.19 (m, 1H), 2.23–2.30 (m, 1H), 2.49 (br, 1H),
3.59 (dd, J¼5.7, 11.5 Hz, 1H), 3.75 (dd, J¼5.7, 11.5 Hz,
1H), 4.04 (m, 1H), 4.57 (td, J¼1.9, 6.8 Hz, 1H), 6.61 (dd,
J¼2.0, 6.4 Hz, 1H), 6.83 (dd, J¼2.0, 6.5 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 29.8, 31.3, 62.2, 65.0, 68.1, 127.5,
140.1; nmax/cm21 3509 (br), 2923, 1606, 1280, 1147;
HRMS calcd for C7H12NO3S (Mþ1) 190.05379; found
190.05430.
4.1.6. (2S,5S)-2-(tert-Butyl-diphenyl-silanyloxymethyl)-
1-ethenesulfonyl-5-cis-propenyl-pyrrolidine (10). Dry
Et3N (0.40 mL, 2.90 mmol) was added to a 2788C solution
of chloroethanesulfonylchloride (0.30 mL, 2.90 mmol) in
4.1.9. (2S,5S)-1-(Prop-2-ene-1-sulfonyl)-5-cis-propenyl-
pyrrolidine-2-carboxylic acid benzyl ester (13). To a

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S. Hanessian et al. / Tetrahedron 59 (2003) 7047–7056
solution of 4 (336 mg, 1.37 mmol) in CH2Cl2 (10 mL) at
08C were added Et3N (0.191 mL, 1.37 mmol) and prop-2-
ene-1-sulfonylchloride17b (192 mg, 1.37 mmol) under
argon. After 1 h the reaction mixture was partitioned
between CH2Cl2 and saturated aqueous NaHCO3. The
combined organic phases were washed with 10% HCl then
brine, dried over Na2SO4 and evaporated. Purification of the
residue by column chromatography (10% EtOAc/hexanes)
yielded the title compound 13 (301 mg, 63%) as a colorless
oil: [a]D¼242.5 (c 2.4, CHCl3); 1H NMR (400 MHz,
CDCl3) d 1.64–1.67 (m, 1H), 1.77 (dd, J¼1.7, 7.0 Hz, 3H),
1.94–1.99 (m, 1H), 2.23–2.42 (m, 2H), 3.77 (d, J¼7.3 Hz,
2H), 4.40–4.42 (m, 1H), 4.92–4.97 (m, 1H), 5.19 (ABq,
J¼12.3 Hz, sep. J¼14.5 Hz, 2H), 5.36–5.43 (m, 3H), 5.61–
5.69 (m, 1H), 5.87–5.98 (m, 1H), 7.31–7.39 (m, 5H); 13C
NMR (75 MHz, CDCl3) d 13.4, 29.4, 31.9, 56.0, 59.1, 59.3,
62.7, 62.9, 67.4, 77.5, 123.7, 127.7, 128.7, 129.0, 130.7,
136.0, 173.0; nmax/cm21 2958, 1747, 1341, 1144; HRMS
calcd for C18H23NO4S (Mþ1) 350.14261; found 350.14340.
suspension was stirred at room temperature for 6 h then
filtered through a Celite pad and evaporated to afford the
title compound 16 (78 mg, 90%) as a white, crystalline
solid: mp.1808C decomp., [a]D¼258.6 (c 0.63, MeOH);
1H NMR (400 MHz, CD3OD) d 1.92–1.98 (m, 1H),
2.05–2.13 (m, 1H), 2.25–2.40 (m, 2H), 3.57–3.64 (m,
1H), 3.87–3.93 (m, 1H), 4.30–4.35 (m, 1H), 4.67–4.70 (m,
1H), 5.75–5.80 (m, 1H), 5.83–5.88 (m, 1H); 13C NMR
(75 MHz, CD3OD) d 29.6, 31.5, 44.4, 62.4, 64.9, 122.2,
129.7, 175.7; nmax/cm21 1745, 1327, 1137; HRMS calcd for
C8H12NO4S (Mþ1) 218.025230; found 218.026072.
4.1.13. (7S)-(1,1-Dioxo-1,2,4a,5,6,7-hexahydro-1l6-pyr-
rolo[1,2-b][1,2]thiazin-7-yl)-methanol (17). To a solution
of 14 (27 mg, 0.087 mmol) in THF (2 mL) at 2788C under
argon was slowly added diisobutylaluminium hydride
(0.23 mL, 1.5 M solution in toluene, 0.35 mmol). The
reaction mixture was allowed to warm to room temperature
over 1.5 h, quenched with methanol (0.1 mL), then treated
with a saturated aqueous solution of potassium sodium
L-tartrate tetrahydrate (5 mL) for 1.5 h. Extraction with
ethyl acetate and usual processing yielded the title
compound 17 (15 mg, 85%) as a white solid after column
chromatography (50% EtOAc/hexanes): mp 688C;
[a]D¼243.3 (c 0.58, CHCl3); 1H NMR (400 MHz,
CDCl3) d 1.81–1.91 (m, 2H), 1.99–2.10 (m, 1H), 2.16–
2.26 (m, 1H), 2.32 (br., 1H), 3.53–3.72 (m, 5H), 4.65–4.66
(m, 1H), 5.66–5.69 (m, 1H), 5.77–5.81 (m, 1H); 13C NMR
(100 MHz, CDCl3) d 26.3, 29.7, 42.3, 61.9, 63.8, 66.1,
119.9, 129.3; nmax/cm21 3515, 1336, 1157; HRMS calcd for
C8H14NO3S (Mþ1) 204.06944; found 204.07030.
4.1.10. (7S)-1,1-Dioxo-1,2,4a,5,6,7-hexahydro-1l6-pyr-
rolo[1,2-b][1,2]thiazine-7-carboxylic acid benzyl ester
(14). To a de-gassed solution of 13 (100 mg, 0.29 mmol)
in CH2Cl2 (29 mL) under argon was added Grubbs’ catalyst
A (7 mg, 0.0087 mmol). The mixture was stirred at room
temperature for 3 h then evaporated. The residue was
purified by filtration through a pad of Florisil followed by
column chromatography (25% EtOAc/hexanes) to furnish
the title compound 14 (87 mg, 98%) as a white solid: mp
1
1398C; [a]D¼255.5 (c 2.1, CHCl3); H NMR (400 MHz,
CDCl3) d 1.83–1.89 (m, 1H), 2.01–2.08 (m, 1H), 2.17–
2.34 (m, 2H), 3.54–3.70 (m, 2H), 4.29 (dd, J¼3.0, 9.2 Hz,
1H), 4.72–4.74 (m, 1H), 5.20 (s, 2H), 5.68–5.79 (m, 2H),
7.29–7.38 (m, 5H); 13C NMR (100 MHz, CDCl3) d 28.4,
30.6, 43.9, 61.1, 63.0, 67.1, 119.9, 128.0, 128.2, 128.5,
129.0, 135.4, 171.2; nmax/cm21 2957, 1750, 1346, 1156;
HRMS calcd for C15H18NO4S (Mþ1) 308.09564; found
308.09630.
4.1.14. (2S,5S)-1-(But-3-ene-1-sulfonyl)-5-cis-propenyl-
pyrrolidine-2-carboxylic acid benzyl ester (18). To a
solution of 4 (68 mg, 0.28 mmol) in CH2Cl2 (5 mL) at 08C
under argon were added Et3N (0.059 mL, 0.42 mmol) and
but-3-ene-1-sulfonylchloride17c (65 mg, 0.42 mmol). The
reaction mixture was allowed to warm to room temperature
and stirred overnight. The solution was then partitioned
between CH2Cl2 and 10% HCl, and the combined organic
phases were washed with brine, dried over Na2SO4 and
evaporated. Purification of the residue by column chroma-
tography (10% EtOAc/hexanes) yielded the title compound
18 (50 mg, 55%) as a colorless oil: [a]D¼215.0 (c 4.4,
CHCl3); 1H NMR (400 MHz, CDCl3) d 1.65–1.72 (m, 1H),
1.76 (dd, J¼1.7, 7.0 Hz, 3H), 1.98–2.01 (m, 1H), 2.25–2.57
(m, 4H), 3.08–3.12 (m, 2H), 4.42–4.44 (m, 1H), 4.89–4.94
(m, 1H), 5.04–5.16 (m, 2H), 5.19 (ABq, J¼12.3 Hz, sep.
J¼13.8 Hz, 2H), 5.37–5.43 (m, 1H), 5.58–5.66 (m, 1H),
5.73–5.83 (m, 1H), 7.31–7.39 (m, 5H); 13C NMR
(100 MHz, CDCl3) d 12.9, 27.5, 29.0, 31.5, 53.3, 55.3,
61.9, 67.0, 116.6, 127.1, 128.1, 128.2, 128.5, 129.9, 134.4,
135.5, 172.5; nmax/cm21 2957, 1746, 1341, 1143; HRMS
calcd for C19H26NO4S (Mþ1) 364.15826; found 364.15910.
4.1.11. (7S)-1,1-Dioxo-octahydro-1l6-pyrrolo[1,2-b]-
[1,2]thiazine-7-carboxylic acid (15). A solution of 14
(28 mg, 0.092 mmol) in methanol (1 mL) and ethyl acetate
(1 mL) was stirred at room temperature under an atmos-
phere of hydrogen in the presence of a catalytic amount of
10% palladium-on-charcoal for 1 h. The reaction mixture
was filtered through a pad of Celite and evaporated to yield
the title compound 15 as a white solid (20 mg, 99%):
mp.1508C decomp., [a]D¼246.4 (c 0.88, MeOH); 1H
NMR (400 MHz, CD3OD) d 1.37–1.48 (m, 1H), 1.57–1.63
(m, 1H), 1.77 (dd, J¼7.5, 12.5 Hz, 1H), 2.00–2.06 (m, 1H),
2.14–2.25 (m, 3H), 2.45–2.55 (m, 1H), 2.92–2.99 (m, 1H),
3.04–3.09 (m, 1H), 4.04–4.10 (m, 1H), 4.31 (dd, J¼2.3,
10.2 Hz, 1H); 13C NMR (75 MHz, CD3OD) d 24.3, 28.2,
29.2, 31.7, 47.8, 61.4, 63.1, 176.3; nmax/cm21 3236, 2920,
1763, 1323, 1129, 1113; HRMS calcd for C8H14NO4S
(Mþ1) 220.06436; found 220.06480.
4.1.15. (8S)-1,1-Dioxo-2,3,5a,6,7,8-hexahydro-1H-1l6-
pyrrolo[1,2-b][1,2]thiazepine-8-carboxylic acid benzyl
ester (19). To a de-gassed solution of 18 (28 mg,
0.077 mmol) in CH2Cl2 (8 mL) under argon was added
Grubbs’ catalyst A (4 mg, 0.0046 mmol). The solution was
stirred at room temperature for 2 h then evaporated. The
residue was purified by filtration through a pad of Florisil
followed by column chromatography (50% EtOAc/hexanes)
4.1.12. (7S)-1,1-Dioxo-1,2,4a,5,6,7-hexahydro-1l6-pyr-
rolo[1,2-b][1,2]thiazine-7-carboxylic acid (16). A suspen-
sion of 10% palladium-on-charcoal (200 mg) in ethyl
acetate (7 mL) and 1,4-cyclohexadiene (5 mL) was stirred
at room temperature for 15 min. A solution of 14 (124 mg,
0.40 mmol) in ethyl acetate (3 mL) was then added. The

S. Hanessian et al. / Tetrahedron 59 (2003) 7047–7056
7053
to furnish the title compound 19 (20 mg, 81%) as a colorless
oil: [a]D¼236.6 (c 4.4, CHCl3); 1H NMR (400 MHz,
CDCl3) d 1.78–1.86 (m, 1H), 1.96–2.05 (m, 1H),
2.22–2.34 (m, 2H), 2.46–2.62 (m, 2H), 3.02–3.09 (m,
1H), 3.28–3.34 (m, 1H), 4.29 (d, J¼7.8 Hz, 1H), 4.55 (br,
1H), 5.19 (s, 2H), 5.55–5.59 (m, 1H), 5.85–5.92 (m, 1H),
7.27–7.38 (m, 5H); 13C NMR (100 MHz, CDCl3) d 22.2,
28.8, 31.7, 52.5, 56.7, 60.4, 66.9, 128.0, 128.1, 128.4, 130.3,
135.4, 136.0, 171.8; nmax/cm21 2954, 1750, 1340, 1139;
HRMS calcd for C16H20NO4S (Mþ1) 322.11130; found
322.10990.
(m, 1H), 3.63–3.76 (m, 2H), 3.84–3.89 (m, 1H), 4.01 (dd,
J¼3.6, 10.0 Hz, 1H), 4.64–4.69 (m, 1H), 5.31–5.42 (m,
3H), 5.62–5.69 (m, 1H), 5.83–5.94 (m, 1H), 7.36–7.46 (m,
6H), 7.66–7.69 (m, 4H); 13C NMR (100 MHz, CDCl3) d
12.9, 19.2, 26.4, 26.9, 30.4, 56.1, 58.2, 61.6, 65.1, 122.7,
126.5, 127.5, 127.6, 129.4, 129.6, 133.4, 133.5, 135.5,
135.6; nmax/cm21 2959, 1344, 1145, 1113; HRMS calcd for
C27H38NO3SSi (Mþ1) 484.23416; found 484.23530.
4.1.19. (7S)-7-(tert-Butyl-diphenyl-silanyloxymethyl)-
4a,5,6,7-tetrahydro-2H-pyrrolo[1,2-b][1,2]thiazine 1,1-
dioxide (23). To a de-gassed solution of 22 (90 mg,
0.19 mmol) in CH2Cl2 (19 mL) under argon was added
Grubbs’ catalyst A (5 mg, 0.0056 mmol). The mixture was
heated at reflux for 16 h then evaporated, the residue was
purified by filtration through a pad of Florisil followed by
column chromatography (20% EtOAc/hexanes) to furnish
the title compound 23 (78 mg, 93%) as a colorless oil:
[a]D¼246.4 (c 3.5, CHCl3); 1H NMR (400 MHz, CDCl3) d
1.08 (s, 9H), 1.75–1.80 (m, 1H), 1.93–2.18 (m, 3H), 3.46–
3.84 (m, 5H), 4.57–4.58 (m, 1H), 5.63–5.66 (m, 1H), 5.74–
5.79 (m, 1H), 7.37–7.46 (m, 4H), 7.63–7.69 (m, 6H); 13C
NMR (100 MHz, CDCl3) d 19.2, 25.6, 26.8, 29.3, 42.3,
61.5, 63.2, 66.6, 120.2, 127.6, 129.4, 129.6, 133.8, 135.4;
4.1.16. (8S)-1,1-Dioxo-octahydro-1l6-pyrrolo[1,2-
b][1,2]thiazepine-8-carboxylic acid (20). A solution of
19 (39.8 mg, 0.12 mmol) in methanol (5 mL) was stirred at
room temperature under an atmosphere of hydrogen gas, in
the presence of a catalytic amount of 10% palladium-on-
charcoal for 1 h. The suspension was filtered through a
Celite pad and the filtrate evaporated to yield the title
compound 20 (24 mg, 86%) as a white crystalline solid: mp
1
1478C; [a]D¼286.8 (c 1.1, CHCl3); H NMR (400 MHz,
CDCl3) d 1.42–1.57 (m, 1H), 1.69–2.13 (m, 7H), 2.16–
2.25 (m, 1H), 2.31–2.41 (m, 1H), 2.93–3.00 (m, 1H), 3.25–
3.31 (m, 1H), 3.94–3.97 (m, 1H), 4.34–4.42 (m, 1H),
10.18–10.68 (br, 1H); 13C NMR (75 MHz, CDCl3) d 22.7,
24.1, 28.7, 31.7, 32.3, 53.9, 57.8, 61.9, 178.2; nmax/cm21
2938, 1716, 1335, 1307, 1142; HRMS calcd for C9H16NO4S
(Mþ1) 234.08000; found 234.08080.
n
max/cm21 2932, 2858, 1347, 1157, 1112; HRMS calcd for
C24H32NO3SSi (Mþ1) 442.18723; found 442.188850.
4.1.20. (7S)-7-(tert-Butyl-diphenyl-silanyloxymethyl)-
hexahydro-2H-pyrrolo[1,2-b][1,2]thiazine 1,1-dioxide
(24). A solution of 23 (61 mg, 0.14 mmol) in methanol
(10 mL) was stirred at room temperature under an
atmosphere of hydrogen gas, in the presence of a catalytic
amount of 10% Pd/C for 2 h. The suspension was then
filtered through a Celite pad and evaporated to yield the title
compound 24 (60 mg, 97%) as a colorless oil: [a]D¼228.9
(c 2.95, CHCl3); 1H NMR (400 MHz, CDCl3) d 1.08 (s, 9H),
1.23–1.35 (m, 1H), 1.56–1.64 (m, 2H), 2.05–2.16 (m, 4H),
2.22–2.33 (m, 1H), 2.75 (td, J¼3.9, 13.2 Hz, 1H), 3.07 (dt,
J¼3.4, 13.2 Hz, 1H), 3.54–3.59 (m, 1H), 3.84–3.88 (m,
2H), 3.94–3.99 (m, 1H), 7.36–7.44 (m, 6H), 7.65–7.70 (m,
4H); 13C NMR (100 MHz, CDCl3) d 19.2, 23.1, 25.6, 26.8,
27.6, 30.2, 46.7, 60.9, 61.1, 66.9, 127.6, 129.6, 133.4, 133.5,
135.5, 135.6; nmax/cm21 2933, 2858, 1333, 1146, 1113;
HRMS calcd for C24H34NO3SSi (Mþ1) 444.20288; found
444.20360.
4.1.17. (8S)-1,1-Dioxo-2,3,5a,6,7,8-hexahydro-1H-1l6-
pyrrolo[1,2-b][1,2]thiazepine-8-carboxylic acid (21). A
solution of 19 (41 mg, 0.13 mmol) in THF (1 mL) and water
(1 mL) was treated with lithium hydroxide (8 mg,
0.19 mmol) at room temperature overnight. The solvent
was removed and the residue partitioned between diethyl
ether and water. The aqueous phase was treated dropwise
with conc. HCl to pH 2 and extracted with ethyl acetate. The
organic phases were dried over Na2SO4 and evaporated to
yield the title compound 21 (25 mg, 85%) as a white,
crystalline solid: mp 1308C; [a]D¼254.0 (c 0.49, CHCl3);
1H NMR (400 MHz, CDCl3) d 1.88–1.90 (m, 1H), 2.14–
2.23 (m, 1H), 2.28–2.41 (m, 2H), 2.48–2.65 (m, 2H), 3.05–
3.12 (m, 1H), 3.32–3.38 (m, 1H), 4.27 (d, J¼8.0 Hz, 1H),
4.57 (br, 1H), 5.57–5.61 (m, 1H), 5.87–5.94 (m, 1H);
13C NMR (75 MHz, CDCl3) d 22.2, 29.0, 31.9, 52.6, 57.1,
60.3, 130.3, 136.0, 176.9; nmax/cm21 1723, 1337, 1137;
HRMS calcd for C9H14NO4S (Mþ1) 232.06436; found
232.06540.
4.1.21. (7S)-2-Benzyl-7-(tert-butyl-diphenyl-silanyloxy-
methyl)-hexahydro-pyrrolo[1,2-b][1,2]thiazine 1,1-dioxide
(25). The substrate 24 (279 mg, 0.63 mmol) was dissolved
in THF (3.2 mL) and cooled to 2788C under argon
atmosphere. t-BuLi (1.7 M in pentane, 0.41 mL,
0.69 mmol) was added dropwise and the resulting yellow
mixture was stirred at 2788C for 45 min. Benzyl bromide
(0.09 mL, 0.82 mmol) was slowly added at 2788C and
stirring was continued for another hour at 2788C. Saturated
aqueous NaHCO3 (10 mL) was added and the aqueous
phase was extracted with EtOAc. The organic phase was
dried over Na2SO4, filtered and evaporated. The resulting
residue was purified by column chromatography (10%
EtOAc/hexanes) to afford 25 (291 mg, 87%) as a colorless
oil: [a]D¼253.6 (c 0.97, CHCl3); 1H NMR (400 MHz,
CDCl3) d 1.12 (s, 9H), 1.30 (m, 1H), 1.57 (m, 2H), 1.94 (m,
2H), 2.13 (m, 3H), 2.68 (t, J¼13.0 Hz, 1H), 2.91 (m, 1H),
4.1.18. (2S,5S)-1-(Prop-2-ene-1-sulfonyl)-2-(tert-butyl-
diphenylsilanyloxymethyl)-5-cis-propenyl-pyrrolidine
(22). To a solution of amine 9 (132 mg, 0.35 mmol) in
CH2Cl2 (4 mL) at 08C under argon were added Et3N
(0.049 mL, 0.35 mmol) and prop-2-ene-1-sulfonyl-
chloride17b (79 mg, 0.56 mmol) in CH2Cl2 (2 mL). After
2 h the reaction mixture was partitioned between CH2Cl2
and 10% HCl. The combined organic phases were washed
with brine, dried over Na2SO4 and evaporated. Purification
of the residue by column chromatography (5% EtOAc/
hexanes) yielded the title compound 22 (107 mg, 63%) as a
colorless oil: [a]D¼26.5 (c 2.6, CHCl3); 1H NMR
(400 MHz, CDCl3) d 1.09 (s, 9H), 1.51–1.56 (m, 1H),
1.75 (dd, J¼1.7, 6.9 Hz, 3H), 2.01–2.17 (m, 3H), 3.54–3.58

7054
S. Hanessian et al. / Tetrahedron 59 (2003) 7047–7056
3.53 (dd, J¼2.6, 13.4 Hz, 1H), 3.62 (t, J¼8.1 Hz, 1H),
3.90–3.97 (m, 3H), 7.24 (m, 2H), 7.28 (m, 1H), 7.35 (m,
2H), 7.44 (m, 6H), 7.74 (m, 4H); 13C NMR (100 MHz,
CDCl3) d 26.2, 27.4, 28.4, 29.6, 30.6, 34.4, 59.1, 61.4, 61.5,
67.4, 127.3, 128.2, 129.1, 129.9, 130.1, 133.8, 136.0, 136.1,
137.3; nmax/cm21 2932, 1472, 1324, 1205, 1149, 1113,
1031, 760, 701; HRMS calcd for C31H39NO3SSi (Mþ)
533.24202; found 533.24179.
saturated aqueous NaHCO3 and Na2S2O3 and extracted with
CH2Cl2. The combined organic phases were dried over
Na2SO4 and evaporated to dryness to yield a crude aldehyde
which was dissolved in t-BuOH (1.4 mL), cooled to 08C
and 2-methyl-2-butene (0.67 mL, 1.3 mmol) was added. A
solution of NaH2PO4 (101 mg, 0.73 mmol) and NaO2Cl
(60 mg, 0.67 mmol) in H2O (1.4 mL) was added dropwise.
After stirring for 45 min, 1N HCl (2 mL) was added and the
aqueous phase was extracted with EtOAc. The combined
organic phases were dried, filtered and evaporated to yield a
colorless foam. To a solution of crude acid in DMF (3.0 mL)
were successively added EDC (30 mg, 0.16 mmol), HOBt
(21 mg, 0.16 mmol) and i-Pr2NEt (0.05 mL, 0.26 mmol).
After stirring for 20 min, N-Boc aminomethyl benzamidine
(39 mg, 0.16 mmol) was added, the resulting mixture was
stirred overnight then evaporated to dryness. The residue
was dissolved in saturated aqueous NaHCO3 and extracted
with EtOAc. The combined organic phases were dried over
Na2SO4, filtered and concentrated. Purification by column
chromatography (2% MeOH/EtOAc) afford 28 (49 mg,
4.1.22. (2S,7S)-2-Azido-2-benzyl-7-(tert-butyl-diphenyl-
silanyloxymethyl)-hexahydro-pyrrolo[1,2-b][1,2]thia-
zine 1,1-dioxide (26). The substrate 25 (500 mg,
0.94 mmol) was dissolved in THF (4.7 mL) and cooled to
2788C under argon atmosphere. t-BuLi (1.7 M in pentane,
0.72 mL, 1.22 mmol) was added dropwise and the resulting
yellow mixture was stirred at 2788C for 55 min. Trizyl
azide (436 mg, 1.41 mmol) in THF (0.5 mL) was slowly
added and stirring was continued for 6 h at 2788C.
Saturated aqueous NaHCO3 (15 mL) was added and the
aqueous phase was extracted with EtOAc, the organic phase
was dried over Na2SO4, filtered and evaporated. The
resulting residue was purified by column chromatography
(40% hexanes/CH2Cl2) to afford 26 (217 mg, 40%) as a
colorless oil which was crystallized from CH2Cl2: mp
1
65%) as a colorless oil: [a]D¼þ4.2 (c 0.65, CHCl3); H
NMR (400 MHz, CDCl3) d 1.53 (s, 9H), 1.67–1.72 (m, 1H),
1.78–1.86 (m, 1H), 1.89–1.92 (m, 2H), 2.16–2.23 (m, 1H),
2.25–2.34 (m, 1H), 2.38–2.43 (m, 2H), 2.85 (d, J¼14.1 Hz,
1H), 3.20 (d, J¼14.0 Hz, 1H), 4.15–4.16 (m, 1H),
4.42–4.55 (m, 3H), 7.14 (t, J¼5.9 Hz, 1H), 7.26–7.37
(m, 7H), 7.78 (d, J¼8.1 Hz, 2H); 13C NMR (100. MHz,
CDCl3) d 27.3, 28.0, 28.1, 28.2, 28.7, 30.6, 35.8, 42.9, 60.3,
64.0, 79.0, 79.5, 127.0, 127.7, 128.5, 130.2, 132.7, 133.8,
1
1448C; [a]D¼24.5 (c 0.85, CHCl3); H NMR (400 MHz,
CDCl3) d 1.11 (s, 9H), 1.26–1.33 (m, 1H), 1.59–1.71 (m,
2H), 1.84–1.90 (m, 2H), 2.17–2.35 (m, 3H), 2.91 (d,
J¼14.1 Hz, 1H), 3.22 (d, J¼14.1 Hz, 1H), 3.61 (dd, J¼7.6,
10.1 Hz, 1H), 3.83 (dd, J¼3.7, 10.2 Hz, 1H), 4.03–4.08 (m,
2H), 7.27–7.47 (m, 6H), 7.68–7.72 (m, 4H); 13C NMR
(100 MHz, CDCl3) d 19.7, 26.3, 27.3, 28.4, 29.5, 30.6, 36.4,
60.3, 63.5, 67.0, 79.1, 128.1, 128.2, 129.0, 130.2, 130.9,
133.7, 134.0, 136.0, 136.1; nmax/cm21 2955, 2858, 2107,
1428, 1333, 1154, 1112; HRMS calcd for C31H39N4O3SSi
(Mþ1) 575.24342; found 575.24304.
141.9, 171.0;
n
max/cm21 2108, 1616, 1281, 1142;
HRMS calcd for C28H36N7O5S (Mþ1) 582.2499; found
582.2512.
4.1.25. (2S,7S)-2-Amino-2-benzyl-1,1-dioxo-octahydro-
1l6-pyrrolo[1,2-b][1,2]thiazine-7-carboxylic acid 4-car-
bamimidoyl-benzylamide (29). The substrate 28 (6.3 mg,
0.01 mmol) was dissolved in MeOH (1 mL) and Pd/C
(20 mg) was added. The suspension was hydrogenated
overnight under 40 psi, after which it was filtered through a
pad of Celite (MeOH rinse), and concentrated to give a
colorless oil which was dissolved in MeOH (1 mL) and 6N
HCl (1 mL) was added. The solution was stirred at room
temperature overnight. The solvent was removed by high
vacuum evaporation and gave the desired compound 29
(3.6 mg, 73%) as a hydrochloride salt: [a]D¼238.9 (c 0.18,
4.1.23. (2S,7S)-(2-Azido-2-benzyl-1,1-dioxo-octahydro-
1l6-pyrrolo[1,2-b][1,2]thiazin-7-yl)-methanol (27). The
substrate 26 (190 mg, 0.33 mmol) was dissolved in dry THF
(3.5 mL) at room temperature and TBAF (1 M in THF,
0.66 mL, 0.66 mmol) was added dropwise. After stirring for
1.25 h, a saturated aqueous solution of NaHCO3 (20 mL)
was added. The aqueous phase was extracted with EtOAc,
dried over Na2SO4, filtered and concentrated in vacuo. The
resulting residue was purified by column chromatography
(70% EtOAc/hexanes) to afford 27 (96 mg, 86%) as a
colorless oil: [a]D¼þ34.2 (c 1.22, CHCl3); 1H NMR
(400 MHz, CDCl3) d 1.69–1.76 (m, 2H), 1.83–1.89 (m,
2H), 2.07–2.10 (m, 1H), 2.25–2.30 (m, 3H), 2.97 (d,
J¼14.1 Hz, 1H), 3.21 (d, J¼14.1 Hz, 1H), 3.64–3.73 (m,
3H), 4.02–4.05 (m, 2H), 7.27–7.35 (m, 5H); 13C NMR
(100 MHz, CDCl3) d 26.7, 28.3, 29.5, 31.2, 36.5, 60.9, 64.1,
66.4, 79.5, 128.1, 129.0, 130.8, 133.8; nmax/cm21 2959,
2104, 1454, 1329, 1150, 699; HRMS calcd for
C15H20N4O3S (Mþ) 336.12565; found 336.12598.
1
CH3OH); H NMR (400 MHz, CD3OH) d 1.70–1.73 (m,
1H), 1.82–1.91 (m, 2H), 1.93–1.98 (m, 1H), 2.16–2.28 (m,
2H), 2.37–2.43 (m, 1H), 2.60 (s, 1H), 2.90–2.99 (m, 1H),
3.09 (dd, J¼4.6, 13.6 Hz, 1H), 3.57–3.70 (m, 2H), 4.19–
4.25 (m, 1H), 4.29–4.38 (m, 1H), 7.16–7.24 (m, 5H), 7.33
(d, J¼8.0 Hz, 2H), 7.78 (d, J¼8.1 Hz, 2H); nmax/cm21
3059, 1680, 1560; HRMS calcd for C23H29N5O3S (Mþ)
455.57313; found 455.57297.
4.1.24. (2S,7S)-[Amino-(4-{[(2-azido-2-benzyl-1,1-dioxo-
octahydro-1l6-pyrrolo[1,2-b][1,2]thiazine-7-carbonyl)-
amino]-methyl}-phenyl)-methylene]-carbamic acid tert-
butyl ester (28). To a stirred solution of alcohol 27 (45 mg,
0.13 mmol) in dry CH2Cl2 (1.0 mL) was added Dess–
Martin periodinane (74 mg, 0.17 mmol). The resulting
suspension was stirred 1 h, quenched with 1:1 mixture of
Acknowledgements
¨
We thank NSERC of Canada and AstraZeneca (Molndal,
Sweden) for generous financial assistance and the
enzymatic assays, and Dr Michel Simard for X-ray crystal-
lographic analysis. We also acknowledge stimulating
discussions with Dr Ingemar Nilsson (AstraZeneca).

S. Hanessian et al. / Tetrahedron 59 (2003) 7047–7056
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