Generic synthesis of β-sultams via domino alkylation of bromomethanesulfonamides

Article abstract of DOI:10.1139/v03-174

Reaction of N-substituted bromomethanesulfonamides with 2 equiv of potassium carbonate and an α-halo ketone, ester, or nitrile leads directly to 3-substituted β-sultams. The first step is intermolecular and is followed by an intramolecular alkylation. The

Full text of DOI:10.1139/v03-174

113
Generic synthesis of ␤-sultams via domino
alkylation of bromomethanesulfonamides1
William R.S. Barton and Leo A. Paquette
Abstract: Reaction of N-substituted bromomethanesulfonamides with 2 equiv of potassium carbonate and an α-halo
ketone, ester, or nitrile leads directly to 3-substituted β-sultams. The first step is intermolecular and is followed by an
intramolecular alkylation. The process is particularly efficient when diethyl bromomalonate and 3-chloro-2-butanone are
involved. In the latter example, no competitive cyclization to form a six-membered ring is seen. The functional groups
in certain of the β-sultam products can be subsequently manipulated to give bicyclic products.
Key words: β-sultams, intramolecular SN2 displacement, sulfonamides, ring closing metathesis, four-membered
heterocycles.
Résumé : La réaction de bromométhanesulfonamides N-substitués avec deux équivalents de carbonate de potassium et
des cétones, des esters ou des nitriles α-halogénés conduit directement à des β-sultames substitués en position 3. La
première étape est intermoléculaire et elle est suivie par une alkylation intramoléculaire. La méthode est particulière-
ment efficace avec le bromomalonate de diéthyle et la 3-chlorobutan-2-one. Dans ce dernier cas, on n’a pas observé de
cyclisation compétitive conduisant à la formation d’un cycle à six chaînons. Les groupes fonctionnels dans certains β-
sultames formés comme produits peuvent être manipulés subséquemment pour conduire à des produits bicycliques.
Mots clés : β-sultames, déplacement SN2 intramoléculaire, sulfonamides, métathèse avec fermeture de cycle, hétérocy-
cles à quatre chaînons.
[Traduit par la Rédaction] Barton and Paquette 119
Introduction
different transition-state characteristics for these allied reac-
tions are depicted in A and B.
As a result of their close structural similarity to β-lactams,
β-sultams have been rather extensively investigated for their
antibacterial properties. Despite the significantly heightened
reactivity (ca. 103-fold) toward hydrolysis resident in these
strained sulfur analogues (1), none have exhibited truly re-
markable antibiotic features. However, other biological
activities have surfaced. For example, the irreversible inhibi-
tion of human neutrophile elastase has recently been docu-
mented for a member of this class (2). In part, the quest for
more structurally varied β-sultams has been limited by exist-
ing synthetic methodology (3). Since the hydrogen atoms at
C-3 are not activated by any neighboring group, the direct
introduction of substituents at this site has often proven trou-
blesome.
In the intermolecular process A, the field effect exerted by
the two sulfonyl oxygens requires close approach of the
nucleophile to at least one atom of high electron density,
thus strongly decelerating backside attack (5). When intra-
molecularity is involved, as in B, geometric factors conspire
to require orientation of the sulfonyl oxygens as remote as
possible from the attacking nucleophile. As a consequence,
cyclization reactions are facilitated, in line with a coopera-
tive inductive effect (6).
Reported herein is a direct, flexible approach to C-3
functionalized β-sultams. This new methodology is based on
the inertness of α-bromomethanesulfonamides to inter-
molecular SN2 displacement and the contrasting ease of
intramolecular ejection of bromide ion (4). The dramatically
Received 3 September 2003. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 12 December 2003.
This paper is dedicated with respect and admiration to Ed Piers who has provided us with a rich legacy of important milestones in
synthetic methodology and total synthesis.
W.R.S. Barton and L.A. Paquette.2 Evans Chemical Laboratories, The Ohio State University, Columbus, OH 43210, U.S.A.
1This article is part of a Special Issue dedicated to Professor Ed Piers.
2Corresponding author (e-mail: paquette.1@osu.edu).
Can. J. Chem. 82: 113–119 (2004)
doi: 10.1139/V03-174
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Can. J. Chem. Vol. 82, 2004
Scheme 1.
Results and discussion
The sulfonamides 1a–1c were conveniently prepared by
the reaction of readily available bromomethanesulfonyl chlo-
ride (7) with the relevant primary amine in CH2Cl2, contain-
ing both DMAP and Hünig’s base, at –10 °C (8). Treatment
of these sulfonamides with 2 equiv of potassium carbonate
and an α-halo ketone, ester, or nitrile in DMF at various
nonoptimized temperatures generated the β-sultams
4
(Scheme 1). The simple alkylation products 2 can be iso-
lated in high yield if the reaction is performed instead at
room temperature (rt) in the same solvent and quenched af-
ter approximately 3 h. Presumably, further deprotonation en-
sues upon continued reaction to give 3, the nucleophilic site in
which gives indication of being well disposed to cyclization.
The overall process is not limited to activated primary
halides and proceeds with notably high efficiency when di-
ethyl bromomalonate and 3-chloro-2-butanone are involved
(Scheme 2). The latter example holds considerable mecha-
nistic significance. In this case, the closure of 7 with elabo-
ration of β-sultam 9 can a priori be viewed as competitive,
with the formation and cyclization of enolate 8. Were 8 to
experience intramolecular displacement, the six-membered
isomer 10 would result. While no information is available
regarding the possible intervention of 8, it is patently clear
that no 10 is formed. This outcome is regarded to be a re-
flection of the fact that the relatively elongated C—S and
N—S bonds of acyclic α-bromosulfonamides (9) are more
ideally suited to the reaction trajectory defined by 7 than
that prevailing in 8 (10). An impressively regioselective one-
pot, two-step domino (11) alkylative sequence is the result.
dibromide. When 19 was heated with tributyltin hydride in
benzene, 5-exo cyclization (13) operated predominantly, to
deliver bicyclic sultam 28 as a 3:1 mixture of diastereomers
in nonoptimized 47% yield. In contrast, the primary radical
did not enter into homolytic aromatic substitution (14). In-
stead, the kinetically preferred reaction involved fragmenta-
tion of the strained heterocyclic ring with formation of 22.
The direct availability of the functionalized β-sultams 4
provides an unrivaled opportunity to synthesize bicyclic de-
rivatives in a straightforward manner. Several preparative op-
tions that can deliver these targets are illustrated below. As
shown in Scheme 3, the controlled addition of methylma-
gnesium bromide to ester 4f gave rise to a chromato-
graphically separable mixture of 4d and 11, thereby setting
the stage for their independent conversion to diene 12
(Scheme 3). For this purpose, 4d was subjected to a Wittig
olefination with methylenetriphenylphosphorane, and 11
was dehydrated with phosphorus oxychloride in pyridine.
Ring-closing metathesis (RCM) of 12 in the presence of
tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-
dihydroimidazole-2-ylidene][benzylidene]ruthenium(IV)
dichloride (14) (12) was then exploited to generate 13 in
near quantitative yield.
Compound 15 was produced by a related route that in-
volved the condensation of 4f with an equivalent of allyl-
magnesium bromide. The coupling step was followed by
migration of the double bond into conjugation with the
ketone carbonyl. In this way, the stage was set for applica-
tion of RCM technology for the conversion of 15 to 16
(Scheme 4).
Conclusion
N-Substituted bromomethanesulfonamides are amenable
to base-promoted condensation with α-halo ketones, esters,
and nitriles under conditions where a second SN2 displace-
ment, now intramolecular, can operate in tandem fashion.
This domino alkylation sequence exhibits a reactivity order
where ketone > nitrile > ester. Evidence has been obtained
that the formation of four-membered β-sultam products is
kinetically favored over cyclization to give the six-
membered analogs. Although β-lactams have previously
been generated by the stepwise closure of α-haloacetamides
(15), in only one report has azetidinone construction been
described from cyclic precursors in a single operation (16).
The protocol described herein is tailored to the ready intro-
duction of useful functional groups at C-3, such that arrival
at bicyclic β-sultams of varied type is conveniently feasible.
In this connection, the preferred cyclization of 19 to 21 un-
der free-radical conditions without competitive homolytic
fragmentation is noteworthy.
Experimental
When esters 4f and 4h were subjected to the action of so-
dium borohydride in wet THF, alcohols 17a and 17b were
obtained. As shown in Scheme 5, the first of these was con-
veniently transformed via mesylate 18 into primary iodide
19. In the N-benzyl series, bromide 20 was prepared more
directly by reaction of 17b with triphenylphosphine
␤-Sultam 4d
A solution of 1a (100 mg, 0.467 mmol) in DMF (1.5 mL)
was stirred with potassium carbonate (129 mg, 0.934 mmol)
for 20 min, treated with a solution of chloroacetone (48 mg,
0.51 mmol) in DMF (1.5 mL), and allowed to react for 48 h.
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Barton and Paquette
115
Scheme 2.
Scheme 3.
Scheme 4.
3.57 (m, 2 H), 2.29 (s, 3 H). 13C NMR (75 MHz, CDCl3) δ:
203.3, 130.4, 121.0, 60.1, 52.1, 49.5, 25.5. ES-HR-MS (m/z)
([M+Na]+) calcd: 212.0352; obsd: 212.0357.
␤-Sultam 4e
Analogous reaction of 1a (100 mg, 0.467 mmol) with po-
tassium carbonate (130 mg, 0.934 mmol) and phenacyl bro-
mide (93 mg, 0.467 mmol) in DMF (3 mL total) at rt for
1
6 days furnished 95 mg (81%) of 4e as a colorless oil. H
The reaction mixture was quenched with water and extracted
with ethyl acetate (3×). The combined organic layers were
washed with water and brine (2×), dried, and evaporated.
The residue was chromatographed on silica gel (elution with
hexanes – ethyl acetate 3:2) to give 4d as a colorless oil
(53 mg, 59%). 1H NMR (300 MHz, CDCl3) δ: 5.89–5.78 (m,
1 H), 5.40–5.25 (m, 2 H), 4.26 (dd, J = 8.8, 12.7 Hz, 1 H),
4.09 (dd, J = 6.4, 12.7 Hz, 1 H), 3.92–3.84 (m, 1 H), 3.69–
NMR (300 MHz, CDCl3) δ: 7.93–7.88 (m, 2 H), 7.66–7.60
(m, 1 H), 7.53–7.47 (m, 2 H), 5.80 (m, 1 H), 5.34–5.26 (m,
1 H), 5.20–5.16 (m, 1 H), 4.68 (dd, J = 6.5, 8.3 Hz, 1 H),
4.40 (dd, J = 8.3, 12.2 Hz, 1 H), 4.19 (dd, J = 6.5, 12.2 Hz,
1 H), 3.88–3.81 (m, 1 H), 3.75–3.70 (m, 1 H). 13C NMR
(75 MHz, CDCl3) δ: 192.5, 134.5, 134.2, 131.1, 129.2,
128.5, 120.6, 60.9, 48.9, 48.7. ES-HR-MS m/z ([M+Na]+)
calcd: 274.0508; obsd: 274.0523.
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Can. J. Chem. Vol. 82, 2004
Scheme 5.
4 h at 110 °C afforded 1.48 g (70%) of 4h as a colorless oil.
1H NMR (300 MHz, CDCl3) δ: 7.40–7.30 (m, 5 H), 4.46 (d,
J = 14.2 Hz, 1 H), 4.35–4.18 (m, 3 H), 4.17–4.05 (m, 2 H),
␤-Sultam 4f
Compound 1a (2.00 g, 9.34 mmol), ethyl bromoacetate
(1.04 mL, 9.34 mmol), and potassium carbonate (2.84 g,
20.6 mmol) in DMF (80 mL) was stirred overnight at rt and
heated to 105 °C for 3.5 h. Following the predescribed
workup, there was isolated 1.14 g (56%) of 4f as a colorless
3.78 (dd, J = 6.1, 8.1 Hz, 1 H), 1.19 (t, J = 7.1 Hz, 3 H). 13
C
NMR (75 MHz, CDCl3) δ: 167.9, 133.8, 129.0, 128.7, 128.2,
60.5, 49.9, 46.7, 13.9. ES-HR-MS m/z ([M+Na]+) calcd:
292.0614; obsd: 292.0604.
1
oil. H NMR (300 MHz, CDCl3) δ: 5.95–5.82 (m, 1 H),
5.40–5.24 (m, 2 H), 4.33–4.18 (m, 4 H), 3.88–3.71 (m, 3 H),
1.30 (t, J = 7.1 Hz, 3 H). 13C NMR (75 MHz, CDCl3) δ:
168.0, 130.7, 120.5, 62.4, 60.5, 49.0, 46.5, 14.0. ES-HR-MS
m/z ([M+Na]+) calcd: 242.0457; obsd: 242.0458.
␤-Sultam 6a
A mixture of 1a (500 mg, 234 mmol) and potassium car-
bonate (650 mg, 4.68 mmol) in DMF (2.5 mL) was treated
with diethyl bromomalonate (0.38 mL, 2.34 mmol) and
stirred overnight at rt and at 110 °C for 3 h. The reaction
mixture was quenched with water and extracted with ethyl
acetate (3×). The usual workup yielded 0.61 g (89%) of 6a
␤-Sultam 4g
A mixture of 1a (200 mg, 0.934 mmol), bromoacetonitrile
(123 mg, 0.934 mmol), and potassium carbonate (260 mg,
1.87 mmol) was stirred at rt for 72 h and processed as de-
tailed above. There was isolated 98 mg (61%) of 4g as a col-
1
as a colorless oil. H NMR (300 MHz, CDCl3) δ: 6.00–5.87
(m, 1 H), 5.43–5.21 (m, 2 H), 4.50 (s, 2 H), 4.32 (q, J =
7.1 Hz, 4 H), 3.99–3.96 (m, 2 H), 1.32 (t, J = 7.1 Hz, 6 H).
13C NMR (75 MHz, CDCl3) δ: 165.9, 131.7, 119.4, 64.7,
63.3, 57.7, 46.8, 14.0. ES-HR-MS m/z ([M+Na]+) calcd:
314.0667; obsd: 314.0678.
1
orless oil. H NMR (300 MHz, CDCl3) δ: 5.88–5.80 (m, 1
H), 5.52–5.37 (m, 2 H), 4.46 (dd, J = 7.9, 12.7 Hz, 1 H),
4.37 (dd, J = 4.5, 12.7 Hz, 1 H), 4.18 (dd, J = 4.5, 7.9 Hz, 1
H), 3.94–3.79 (m, 2 H). 13C NMR (75 MHz, CDCl3) δ:
129.2, 122.0, 114.8, 62.1, 48.3, 35.7. ES-HR-MS m/z
([M+Na]+) calcd: 195.0199; obsd: 195.0237.
␤-Sultam 9a
Analogous reaction of 1a (100 mg, 0.467 mmol) with 3-
chloro-2-butanone (55 mg, 0.467 mmol) and potassium car-
bonate (129 mg, 0.93 mmol) in DMF (2.5 mL) at rt for
␤-Sultam 4h
Comparable reaction of 1b (2.08 g, 7.87 mmol) with ethyl
bromoacetate (0.87 mL, 7.87 mmol) and potassium carbon-
ate (2.18 g, 15.7 mmol) in DMF (40 mL) for 18 h at rt and
1
7 days provided 94 mg (93%) of 9a as a colorless oil. H
© 2003 NRC Canada

Barton and Paquette
117
NMR (300 MHz, CDCl3) δ: 5.90–5.79 (m, 1 H), 5.44–5.37
(m, 1 H), 5.29–5.24 (m, 1 H), 4.26 (d, J = 12.8 Hz, 1 H),
3.94–3.86 (m, 1 H), 3.81 (d, J = 12.8 Hz, 1 H), 3.51–3.43
(m, 1 H), 2.37 (s, 3 H), 1.50 (s, 3 H). 13C NMR (75 MHz,
CDCl3) δ: 205.5, 131.0, 120.3, 66.6, 57.1, 45.2, 24.2, 17.1.
ES-HR-MS m/z ([M+Na]+) calcd: 226.0508; obsd: 226.0512.
lution of methyltriphenylphosphonium bromide (536 mg,
1.5 mmol) in THF (10 mL) at 0 °C. After being stirred for
20 min in the cold, the reaction mixture was brought to
–42 °C and a solution of 4d (189 mg, 1.0 mmol) in THF
(10 mL) was introduced over 20 min, prior to warming to rt
30 min later. After overnight stirring, saturated NH4Cl solu-
tion was added, and the product was extracted into ether
(3×). The combined organic phases were dried and evapo-
rated to leave a residue that was purified by chromatography
on silica gel. Elution with 5:1 hexanes – ethyl acetate gave
␤-Sultam 9c
Bromomethanesulfonyl chloride (from 20.00
g
(0.107 mmol) of sodium bromomethanesulfonate and 22.20 g
(0.102 mmol) of phosphorus pentachloride) dissolved in
CH2Cl2 (100 mL) was added to aminoacetaldehyde dimethyl
acetal (12.29 mL, 0.112 mmol), DMAP (20 mg), and
triethylamine (15.60 mL, 0.112 mmol) in CH2Cl2 (100 mL)
at 0 °C over 30 min. Stirring was maintained at this cold
temperature for 4 h, at which point the reaction mixture was
allowed to warm to rt, stirred overnight, quenched with satu-
rated NaHSO4 solution, and extracted with CH2Cl2 (3×). The
combined organic phases were washed with brine, dried, and
evaporated to yield 12.97 g (50% over two steps) of 1c as a
1
127 mg (68%) of 12 as a colorless oil. H NMR (300 MHz,
CDCl3) δ: 5.95–5.81 (m, 1 H), 5.43 (dd, J = 1.1, 17.1 Hz, 1
H), 5.23 (dd, J = 1.1, 10.2 Hz, 1 H), 5.16 (s, 1 H), 5.04 (d,
J = 1.1 Hz, 1 H), 4.11 (dd, J = 7.9, 12.2 Hz, 1 H), 3.90 (dd,
J = 6.5, 12.2 Hz, 1 H), 3.77–3.70 (m, 2 H), 3.52 (dd, J = 5.6,
14.8 Hz, 1 H), 1.81 (s, 3 H). 13C NMR (75 MHz, CDCl3) δ:
139.9, 131.3, 119.7, 116.1, 61.7, 52.0, 48.3, 30.3. ES-HR-
MS m/z ([M+Na]+) calcd: 210.0559; obsd: 210.0562.
Dehydration of 11
1
colorless oil. H NMR (300 MHz, CDCl3) δ: 5.05 (t, J =
A solution of 11 (131 mg, 0.64 mmol) in pyridine
(10 mL) was treated dropwise with phosphorus oxychloride
(0.59 mL, 6.40 mmol) over 5 min. The reaction mixture was
stirred overnight at rt, cooled in an ice bath, and cautiously
quenched with warm water. After 30 min, the aqueous layer
was extracted with ether (2×), and the combined organic lay-
ers were washed with 0.5 mol L–1 hydrochloric acid, fol-
lowed by water; dried; and freed of solvent. There was
isolated 110 mg (92%) of 12, identical in all respects to the
material generated in the above section (Olefination of 4d).
6.0 Hz, 1 H), 4.47 (s, 2 H), 4.42 (t, J = 5.0 Hz, 1 H), 3.42 (s,
6 H), 3.31 (dd, J = 6.0, 5.0 Hz, 2 H). 13C NMR (75 MHz,
CDCl3) δ: 102.9, 54.7, 45.3, 41.9. ES-HR-MS m/z
([M+Na]+) calcd: 283.9563; obsd: 283.9548.
To a solution of 1c (123 mg, 0.467 mmol) and 3-chloro-2-
butanone (55 mg, 0.467 mmol) in DMF (25 mL) was added
potassium carbonate (129 mg, 0.734 mmol). The mixture
was stirred at rt for 6 days and processed as described above
to give 89 mg (76%) of 9c as a colorless oil. 1H NMR
(300 MHz, CDCl3) δ: 4.43 (dd, J = 4.1, 6.1 Hz, 1 H), 4.23
(d, J = 12.8 Hz, 1 H), 3.82 (d, J = 12.8 Hz, 1 H), 3.45–3.39
(m, 4 H), 3.35 (s, 3 H), 2.93 (dd, J = 6.1, 14.3 Hz, 1 H),
2.39 (s, 3 H), 1.57 (s, 3 H). 13C NMR (75 MHz, CDCl3) δ:
205.2, 107.8, 66.7, 57.2, 54.7, 54.6, 43.4, 23.5, 16.8.
Ring closing metathesis of 12
β-Sultam 12 (118 mg, 0.63 mmol) dissolved in CH2Cl2
(10 mL) was added to a deoxygenated solution of 14
(27 mg, 0.032 mmol) in the same solvent (40 mL). The reac-
tion mixture was heated to a gentle reflux, periodically evac-
uated to remove ethylene, cooled to rt, and evaporated to
dryness. Chromatography of the residue on silica gel pro-
Addition of methylmagnesium bromide to 4f
A
solution of methylmagnesium bromide in THF
(7.28 mL of 3.0 mol L–1, 21.9 mmol) was added over a
20 min period to a solution of 4f (1.20 g, 5.46 mmol) in the
same solvent (100 mL) previously cooled to –78 °C. The
mixture was stirred in the cold for 5 h, quenched with satu-
rated NH4Cl solution, warmed to rt, and extracted with
CH2Cl2 (2×). The combined organic layers were washed
with brine, dried, and evaporated. The residue was chroma-
tographed on silica gel (elution with hexanes – ethyl acetate
3:2) and afforded 630 mg (61%) of 4d (identical to the sam-
ple prepared above) and 126 mg (11%) of 11 as a colorless
1
vided 96 mg (96%) of 13 as a white solid, mp 85–86 °C. H
NMR (300 MHz, CDCl3) δ: 5.61 (m, 1 H), 4.49–4.41 (m, 2
H), 4.38–4.36 (m, 1 H), 4.09 (ddd, J = 0.7, 3.7, 12.4 Hz, 1
H), 3.76–3.71 (m, 1 H), 1.79–1.77 (m, 3 H). 13C NMR
(75 MHz, CDCl3) δ: 135.8, 125.7, 65.0, 55.7, 54.3, 12.0. ES-
HR-MS m/z ([M+Na]+) calcd: 182.0246; obsd: 182.0253.
Addition of allylmagnesium bromide to 4f
Allylmagnesium bromide (273 mL of 1.0 mol L–1 in THF)
was added over 10 min to 4f (0.20 g, 0.91 mmol) in THF
(20 mL) at –78 °C. The reaction mixture was stirred in the
cold for 3.5 h, quenched carefully with concentrated NH4Cl
solution at –78 °C, warmed to rt, stirred for 3.5 h, and ex-
tracted with ethyl acetate (3×). The customary workup (elu-
tion with 3:1 hexane – ethyl acetate) gave 48 mg (25%) of
1
oil. H NMR (300 MHz, CDCl3) δ: 5.98–5.87 (m, 1 H),
5.42–5.26 (m, 2 H), 4.15 (dd, J = 6.1, 12.4 Hz, 1 H), 4.02
(dd, J = 8.3, 12.4 Hz, 1 H), 3.92 (dd, J = 6.1, 15.5 Hz, 1 H),
3.66–3.58 (m, 1 H), 3.16 (dd, J = 6.1, 8.3 Hz, 1 H), 2.32–
2.30 (m, 1 H), 1.26 (s, 3 H) 1.16 (s, 3 H). 13C NMR
(75 MHz, CDCl3) δ: 132.0, 119.7, 70.3, 58.6, 54.6, 50.7,
27.4, 24.8. ES-HR-MS m/z ([M+Na]+) calcd: 228.0665;
obsd: 228.0667.
1
15. H NMR (300 MHz, CDCl3) δ: 7.17–7.07 (m, 1 H),
6.63–6.56 (m, 1 H), 5.88–5.77 (m, 1 H), 5.39–5.24 (m, 2 H),
4.25 (dd, J = 8.6, 12.5 Hz, 1 H), 4.08 (dd, J = 6.5, 12.5 Hz,
1 H), 3.90–3.80 (m, 2 H), 3.67–3.60 (m, 1 H), 1.98 (dd, J =
1.7, 7.0 Hz, 3 H). 13C NMR (75 MHz, CDCl3) δ: 193.1,
148.0, 130.4, 125.3, 121.1, 60.6, 51.1, 49.4, 18.8. ES-HR-
MS m/z ([M+Na]+) calcd: 238.0508; obsd: 238.0507.
Dienyl sultam 12
Olefination of 4d
A solution of n-butyllithium in hexanes (0.94 mL of
1.6 mol L–1, 1.50 mmol) was added dropwise to a stirred so-
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Can. J. Chem. Vol. 82, 2004
120.6, 67.9, 60.1, 49.0, 45.6, 35.0. ES-HR-MS m/z
Ring closing metathesis of 15
([M+Na]+) calcd: 278.0127; obsd: 278.0125.
To a solution of 15 (43 mg, 0.20 mmol) dissolved in
CH2Cl2 (60 mL) was added a deoxygenated solution of 14
(8.5 mg, 0.001 mmol) in the same solvent (2 mL); this was
gently refluxed during 2.5 h, with periodic evacuation of the
vessel to remove ethylene, and evaporated to dryness. Chro-
matographic purification of the residue on silica gel fur-
nished 22 mg (64%) of 16 as a colorless oil. 1H NMR
(300 MHz, CDCl3) δ: 6.99 (ddd, J = 2.3, 4.0, 10.8 Hz, 1 H),
6.25 (ddd, J = 2.3, 2.4, 10.8 Hz, 1 H), 4.61 (dd, J = 8.3,
12.8 Hz, 1 H), 4.33 (dd, J = 2.8, 12.8 Hz, 1 H), 4.26–4.16
(m, 2 H), 3.93–3.84 (m, 1 H). 13C NMR (75 MHz, CDCl3) δ:
190.8, 146.4, 127.0, 64.6, 45.9, 38.8. ES-HR-MS m/z
([M+Na]+) calcd: 196.0039; obsd: 196.0039.
Formation of iodide 19
A solution of 18 (200 mg, 0.78 mmol) in acetone (15 mL)
was treated with sodium iodide (1.17 g, 780 mmol), heated
to reflux for 24 h in the absence of light, cooled to rt, and
evaporated to dryness. The residue was slurried with ether
(3×) and filtered. The dark oily residue resulting from evap-
oration of the ether was chromatographed on silica gel. Elu-
tion with 10:1 to 6:1 hexane – ethyl acetate afforded 19
(212 mg, 95%) as a colorless oil. 1H NMR (300 MHz,
CDCl3) δ: 5.93–5.82 (m, 1 H), 5.44–5.37 (m, 1 H), 5.30–
5.27 (m, 1 H, 4.21 (dd, J = 12.7, 7.5 Hz, 1 H), 3.91–3.83 (m,
2 H), 3.61 (dd, J = 14.6, 6.4 Hz, 1 H), 3.45–3.39 (m, 2 H),
3.23–3.17 (m, 1 H). 13C NMR (75 MHz, CDCl3) δ: 131.4,
120.4, 64.5, 48.6, 48.5, 5.5. ES-HR-MS m/z ([M+Na]+)
calcd: 309.9369; obsd: 309.9374.
Hydride reduction of 4f
β-Sultam 4f (0.60 g, 2.73 mmol) dissolved in THF (5 mL)
was introduced into a cold (0 °C), vigorously stirred suspen-
sion of sodium borohydride (0.52 g, 13.7 mmol) in THF
(25 mL), followed by the slow addition of water (10 mL),
also at 0 °C. The reaction mixture was stirred at rt for
10 min, treated successively with ethyl acetate and
1.0 mol L–1 hydrochloric acid (20 mL), and agitated for a
further 20 min. The separated aqueous layer was extracted
with ethyl acetate, and the combined organic layers were
washed with saturated NaHCO3 solution and brine, dried,
and evaporated to give 405 mg (84%) of 17a as a colorless
Generation of bromide 20
Alcohol 17b (1.29 g, 5.58 mmol) in CH2Cl2 (10 mL) was
added dropwise to a stirred suspension of triphenyl-
phosphine dibromide (2.59 g, 6.14 mmol) in CH2Cl2
(15 mL) at 0 °C. The mixture was stirred for 30 min,
warmed to rt, stirred for 3 h, quenched with saturated
NaHCO3 solution, and extracted with CH2Cl2 (2×). The
combined organic phases were dried and evaporated. The re-
sulting residue was purified by chromatography on silica gel
1
oil. H NMR (300 MHz, CDCl3) δ: 5.96–5.83 (m, 1 H),
1
5.42–5.35 (m, 1 H), 5.27 (dd, J = 1.1, 10.0 Hz, 1H), 4.16
(dd, J = 6.3, 12.4 Hz, 1 H), 4.06 (dd, J = 7.8, 12.4 Hz, 1 H),
3.90–3.77 (m, 2 H), 3.65 (dd, J = 3.1, 12.1 Hz, 1 H), 3.56
(dd, J = 6.4, 14.6 Hz, 1 H), 3.42–3.37 (m, 1 H), 2.42 (s, 1
H). 13C NMR (75 MHz, CDCl3) δ: 131.7, 120.0, 61.4, 58.9,
48.9, 48.4. ES-HR-MS m/z ([M+Na]+) calcd: 200.0358;
obsd: 200.0353.
to give 605 mg (37%) of 20 as a colorless oil. H NMR
(300 MHz, CDCl3) δ: 7.40–7.32 (m, 5 H), 4.45 (d, J =
14.1 Hz, 1 H), 4.21 (dd, J = 17.7, 7.8 Hz, 1 H), 4.11 (d, J =
14.1 Hz, 1 H), 3.96 (dd, J = 12.7, 5.7 Hz, 1 H), 3.56–3.49
(m, 1 H), 3.23–3.15 (m, 2 H). 13C NMR (75 MHz, CDCl3) δ:
134.3, 129.0 (2 C), 128.8 (2 C), 128.5, 63.0, 49.9, 48.1,
32.7. ES-HR-MS m/z ([M+Na]+) calcd: 311.9664; obsd:
311.9677.
Hydride reduction of 4h
A 0.50 g (1.86 mmol) sample of 4h was reduced with so-
dium borohydride (0.70 g, 18.6 mmol) in the predescribed
manner. After chromatography, there was isolated 335 mg
(78%) of 17b as a colorless oil. 1H NMR (300 MHz, CDCl3)
δ: 7.40–7.30 (m, 5 H), 4.49 (d, J = 13.2 Hz, 1 H), 4.18–4.01
(m, 3 H), 3.49–3.36 (m, 3 H), 2.05 (dd, J = 4.2, 8.0 Hz, 1
H). 13C NMR (75 MHz, CDCl3) δ: 134.8, 129.0, 128.7,
128.4, 61.3, 59.0, 50.1, 49.0. ES-HR-MS m/z ([M+Na]+)
calcd: 250.0508; obsd: 250.0500.
Radical cyclization of 19
A solution of tributylstannane (0.16 mL, 0.60 mmol) and
AIBN (17 mg, 0.10 mmol) in benzene (10 mL) was added to
a solution of 19 (144 mg, 0.503 mmol) in benzene (50 mL)
at the reflux temperature over a period of 12 h. The cooled
reaction mixture was evaporated to dryess and the residue
was chromatographed on silica gel to give 21 as a colorless
oily 3:1 mixture of diastereomers. 1H NMR (300 MHz,
C6D6) δ: 3.65 (dd, J = 12.7, 7.0 Hz, 1 H), 3.56 (dd, J = 12.8,
7.0 Hz, 1 H), 3.23–3.15 (m, 1 H), 3.10 (dd, J = 12.7, 4.9 Hz,
1 H), 3.00–2.96 (m, 1 H), 2.77 (dd, J = 10.2, 7.5 Hz, 1 H),
2.25–2.08 (m, 2 H), 1.77–1.71 (m, 1 H), 1.42–1.23 (m, 2 H),
1.17–1.07 (m, 1 H), 1.00–0.82 (m, 4 H), 0.71 (d, J = 6.5 Hz,
3 H), 0.55 (d, J = 6.4 Hz, 3 H). 13C NMR (75 MHz, C6D6) δ:
(major isomer) 66.0, 55.0, 46.5, 38.6, 34.0, 16.4. ES-HR-MS
m/z ([M+Na]+) calcd: 184.0403; obsd: 184.0411.
Mesylation of 17a
Samples of 17a (0.38 g, 2.14 mmol) and Et3N (0.75 mL,
5.35 mmol) were dissolved in CH2Cl2 (40 mL) and treated
dropwise with a solution of methanesulfonyl chloride
(0.20 mL, 2.57 mmol) in CH2Cl2 (5 mL). The reaction mix-
ture was stirred for 3 h, quenched with water, and extracted
with CH2Cl2 (2×). The combined organic layers were
washed with brine, dried, and freed of solvent to provide
Radical fragmentation of 20
1
0.50 g (91%) of 18 as a colorless oil. H NMR (300 MHz,
A solution of tributylstannane (123 mg, 0.424 mmol) and
AIBN (67 mg, 0.41 mmol) in benzene (2.5 mL) was added
to a solution of 20 (107 mg, 0.369 mmol) in benzene
(20 mL) at the reflux temperature over a period of 9 h.
Workup in the predescribed manner afforded 37 mg (48%)
of 22 as a colorless oil contaminated with a very minor
CDCl3) δ: 5.93–5.82 (m, 1 H), 5.43–5.37 (m, 1 H), 5.32–
5.27 (m, 1 H), 4.40 (dd, J = 4.7, 11.3 Hz, 1 H), 4.30 (dd, J =
4.5, 11.3 Hz, 1 H), 4.20 (dd, J = 8.1, 12.7 Hz, 1 H), 4.04 (m,
J = 5.9, 12.7 Hz, 1 H), 3.90–3.83 (m, 1 H), 3.66–3.54 (m, 2
H), 3.11 (s, 3 H). 13C NMR (75 MHz, CDCl3) δ: 131.2,
© 2003 NRC Canada

Barton and Paquette
119
amount of the uncleaved reduction product. 1H NMR
(300 MHz, C6D6) δ: 7.40–7.23 (m, 5 H), 5.90–5.76 (m, 1 H),
5.38–5.35 (m, 1 H), 5.28–5.21 (m, 1 H), 5.00–4.96 (m, 1 H),
4.27 (d, J = 6.2 Hz, 2 H), 3.64 (dd, J = 8.1, 0.8 Hz, 2 H).
13C NMR (75 MHz, C6D6) δ: 137.7, 128.6, 128.1 (2 C),
128.0 (2 C), 126.4, 122.8, 57.2, 47.1. ES-HR-MS m/z
([M+Na]+) calcd: 234.0539; obsd: 234.0553.
7. M.-J. Brienne, D. Varech, M. Leclercq, J. Jacques, N.
Radembrino, M.-C. Dessalles, G. Mahuzier, C. Gueyouche, C.
Borias, P. Loiseau, and P. Gayral. J. Med. Chem. 30, 2232
(1987).
8. S.M. Leit and L.A. Paquette. J. Org. Chem. 64, 9225 (1999).
9. For an early compilation of crystallographic data, see R.L.
Beddoes, L. Dalton, J.A. Joule, O.S. Mills, J.D. Street, and
C.I.F. Watt. J. Chem. Soc. Perkin Trans. 2, 787 (1986).
10. The situation is reminiscent of that noted in the kinetically
controlled base-promoted cyclization of epoxy nitriles: G.
Stork and J. F. Cohen. J. Am. Chem. Soc. 96, 5270 (1974).
11. For the initial introduction of this term, see L.A. Paquette and
M.J. Wyvratt. J. Am. Chem. Soc. 96, 4671 (1974).
12. For recent reviews, consult: (a) R.H. Grubbs and S. Chang.
Tetrahedron, 54, 4413 (1998); (b) A. Fürstner. Angew. Chem.
Int. Ed. 39, 3012 (2000); (c) T.M. Trnka and R.H. Grubbs.
Acc. Chem. Res. 34, 18 (2001); (d) S.J. Connon and S.
Blechert. Angew. Chem. Int. Ed. 42, 1900 (2003).
Acknowledgment
We thank the S.T. Li Foundation for an unrestricted grant.
Technical assistance has been provided by Claire E. Barton
and Kavita Bhatt.
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© 2003 NRC Canada