Reactivity of cyclic sulfamidates towards sulfur-stabilised enolates. Stereocontrolled synthesis of functionalised lactams

Article abstract of DOI:10.1039/b601804a

A structurally representative series of 1,2- and 1,3-cyclic sulfamidates react with enolates derived from methyl α-phenylthioacetate 9b to give 5- and 6-substituted α-phenylthio lactams 20-24. These products provide, via the corresponding sulfoxides, an e

Full text of DOI:10.1039/b601804a

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Reactivity of cyclic sulfamidates towards sulfur-stabilised enolates.
Stereocontrolled synthesis of functionalised lactams
a
a
a
a
b
b
ˇ
John F. Bower, Suda Chakthong, Jakub Svenda, Andrew J. Williams, Ron M. Lawrence, Peter Szeto and
Timothy Gallagher*a
Received 7th February 2006, Accepted 14th March 2006
First published as an Advance Article on the web 19th April 2006
DOI: 10.1039/b601804a
A structurally representative series of 1,2- and 1,3-cyclic sulfamidates react with enolates derived from
methyl a-phenylthioacetate 9b to give 5- and 6-substituted a-phenylthio lactams 20–24. These products
provide, via the corresponding sulfoxides, an entry to a,b-unsaturated lactams e.g. 12, 27, 29 and their
a-phenylthio analogues e.g. 26 and 30. With the enantiomerically pure 1,2-cyclic sulfamidates 10, 15
and 17, these reactions all proceed with no detectable loss of stereochemical integrity.
has inherent limitations in terms of the range of substrates that
are accessible, and other recent reports have exploited the use
of chiral auxiliaries or directing groups for the synthesis of a
wider range of substituted and unsaturated lactam variants. These
Introduction
Five and six-ring lactams, and the related saturated N-
heterocycles, pyrrolidines and piperidines, represent important
classes of molecules that find widespread applications throughout
include use of (R)- and (S)-a-methyl benzylamine to direct a
range of ring substitution reactions within a bicyclic framework,5
and the exploitation of chiral anthracene cycloadducts (again
incorporating a-methyl benzylamine) to generate 5-substituted
a,b-unsaturated lactams via a retro Diels–Alder fragmentation.6
The asymmetric Mannich reaction between imines and enol ethers
provides a catalytic entry to 6-substituted six-ring lactams, as
exemplified by a synthesis of (−)-sedamine.7
academia, the fine chemicals industry and, in particular, within
the pharmaceutical sector.1 Reports highlighting recent interest
in the medicinal chemistry aspects of functionalised lactams
include the trans-fused bicyclic serine protease inhibitors e.g. 1
reported by MacDonald and co-workers,2 and the incorporation
of a,b-unsaturated lactams units (derived from pyroglutamic acid)
into microcolin A analogues 2 as described by Crews.3 In both
cases, enantiomerically pure substituted lactams represented key
components of these biologically active entities.
Our focus has been upon the application of substituted 1,2- and
1,3-cyclic sulfamidates 5 to the synthesis of enantiomerically pure
substituted N-heterocycles, including lactams.8,9 We have reported
the synthesis of a range of enantiomerically pure scaffolds, such
as piperazinones 6, thiomorpholinones 7,8a and a series of a-
functionalised lactams 8.8b The strategy that we have developed
is outlined in Scheme 1.
We were attracted by two challenges in this area: (i) the synthesis
of enantiomerically pure substituted 5- and 6-ring lactams and
(ii) the ability to provide an entry to more highly functionalised
lactams, such as the a,b-unsaturated variants. Currently, there are
limited methods for accessing enantiomerically pure unsaturated
5- and6-ring lactams 3 and 4. The corresponding x-carboxylic acid
derivatives (pyroglutamic acid as well as the corresponding six-ring
variant)4 provide a valuable entry; pyroglutamic acid provided the
starting point for the synthesis of 2.3 This approach, however,
Scheme 1
This involves the regioselective ring opening of a 1,2- or 1,3-
cyclic sulfamidate with an a-amino ester (including a-substituted
amino esters) or a-thiolester to give 6 and 7, respectively. Al-
ternatively, use of a functionalised enolate as the nucleophilic
component provides a versatile entry to a-functionalised variants
8. This methodology has also recently been applied to an efficient
asymmetric synthesis of (−)-aphanorphine, which itself represents
an entry to 3-benzazepines.9
aSchool of Chemistry, University of Bristol, Bristol, UK BS8 1TS. E-mail:
T.Gallagher@bristol.ac.uk; Fax: +44(0)117 9298611; Tel: +44(0)117
9288260
bChemical Development, GlaxoSmithKline, Medicines Research Centre,
Stevenage, UK SG1 2NY
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have been more successful with cyclic sulfamidates, we have
Results and discussion
=
nevertheless encountered issues in the reactions of 9a (X S(O)Ph)
A strategy for lactam synthesis using cyclic sulfamidates also
offers an entry to a,b-unsaturated lactams and their a-thiophenyl
derivatives based on the use of an a-sulfinyl (or an a-thio) enolate
as the nucleophilic component (Scheme 2). Following ring opening
of the cyclic sulfamidate, and subsequent lactamization, either (i)
thermal elimination of RSOH or (ii) Pummerer oxidation would
provide access to the target systems.
with some 1,2-cyclic sulfamidates which are described below
(Scheme 3).
Cyclic sulfamidate 10, a representative and readily available
substrate, reacted with the enolate derived from ester 9a to
give, after acidic hydrolysis (to cleave the intermediate N-sulfate)
and neutralization (to achieve lactamization), lactam 11 in 48%
yield as a mixture of diastereomers (Scheme 3). Issues associated
with purification of the final product necessitated the use of
a polystyrene-bound phosphine (PS–PPh3)† scavenger for the
subsequent sulfoxide elimination step, and in this way we were
able to obtain 12 in 42% overall yield and in >98% e.e. (as judged
by chiral HPLC). In the absence of a scavenger, alkene migration
was facile and benzylidene derivative 13 was isolated as the major
product; alkene 13 was a single geometric isomer although the
alkene geometry has not been established.
We were, however, unable to generate a lactam adduct from
4,5-disubstituted cyclic sulfamidate 15 using ester 9a because of
competing and premature elimination of PhSOH. Nucleophilic
ring cleavage appeared to proceed as expected, but the elevated
temperatures required to achieve annulation led to problems
associated with competing elimination. For this reason, the
corresponding methyl sulfoxide derivative 9d was investigated.
Using 10 as a test substrate with 9d, unsaturated lactam 12
was obtained in 35% yield although the enantiopurity of this
product was not established. The drawback of the use of 9d was
the prolonged period (4 d) required for thermal elimination of
MeSOH, and alternative reaction conditions (including use of
higher temperatures or microwave-mediated thermolysis) resulted
in unacceptable levels of decomposition. We also isolated signif-
icant amounts of amino alcohol 14 after the initial sulfamidate
opening step using 9d, which is possibly formed via competing
O-alkylation (and subsequent hydrolysis) of the enolate species.
In the case of the sterically more demanding disubstituted
sulfamidate 15, reaction with the enolate derived from 9d led
to poor and irreproducible yields of adduct 16 as a mixture
of diastereomers which was not pursued further. In addition,
we were unable to achieve thermal elimination of MeSOH
from this substrate and the use of sulfoxide-based enolates was
abandoned.
Scheme
sulfamidates.
2
Synthetic approach to unsaturated lactams via cyclic
In this paper we report on the scope and limitations of this
approach to functionalised and unsaturated substituted lactams,
in terms of both the nucleophilic and electrophilic components.
Use of a-sulfinyl substituted enolates
We have previously investigated the ability of enolates derived from
esters 9a–c (see Scheme 3) carrying an a-sulfur-based electron
withdrawing group (SR vs S(O)R vs SO2R) to react with 1,2-
and 1,3-cyclic sulfates,10 and here we had encountered problems
associated with the use of 9a and 9b (i.e. X = S(O)Ph and
X = SPh, respectively). We were not able to achieve the desired
transformations (nucleophilic ring opening of the cyclic sulfate
substrate), although the analogous sulfone-based nucleophile 9c
was successfully employed. Although sulfoxide-stabilised enolates
Use of a-sulfenyl substituted enolates
Enolates derived from a-thioesters have proven to be a more
generally applicable class of nucleophiles, and use of ester 9b
with a series of cyclic sulfamidates (10, 15, 17–19) gave good
yields of the corresponding a-phenylthio substituted lactams 20–
24 A representative example based on cyclic sulfamidate 10 is
illustrated in Scheme 4 and other details for additional substrates
are presented in Table 1.
Certain experimental modifications were necessary in specific
cases and these are detailed within the Experimental section.
It should be noted that in some cases (e.g. formation of 21
and 22) lactamisation occurred upon neutralization (following
Scheme 3 Reagents and conditions: (i), 9a, NaH, DMF, r.t.; (ii), 5 M HCl
then NaHCO3; (iii), PhMe, PS–PPh3, 100 ◦C; (iv), 9d, NaH, DMF, r.t.;
(v), PhMe, NaHCO3, reflux, 4 d; (vi), 9d, KOt-Bu, t-BuOH, reflux.
† To the best of our knowledge PS–PPh3 has not previously been used as a
scavenger for thermal sulfoxide elimination reactions, although it has been
widely applied to other processes, such as the Mitsunobu reaction.11
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Table 1 Synthesis of a-sulfenyl substituted lactams
Entry
1
Cyclic sulfamidatea
C(3)-SPh lactam productb
Yield (%)
98
Comments
2 : 1 mixture of diastereomers at C(3) (see Scheme 4)
2
3
83
62
10 : 1 mixture of diastereomers at C(3); major
isomer shown as determined by 1H NMR
1 : 1 mixture of diastereomers at C(3)
4
5
23
80
3 : 2 mixture of diastereomers at C(3);
1 : 1 mixture of diastereomers at C(3)
a Nucleophilic ring opening of 10, 15, 18 and 19 took place at room temperature, while 17 required 45 ◦C. b Lactamisation to give 21 and 22 took place at
room temperature following neutralisation, whereas formation of 20, 23 and 24 required thermal lactamisation conditions (see the Experimental section).
substrates (10, 15, and 17) employed here were derived using
enantiomerically pure amino alcohols as starting materials.
Lactams 20–24 were all isolated as mixtures of diastereomers
at C(3) and for the major isomer of 21, the stereochemical
assignment was based on correlations with related structures for
which crystallographic data were available.8b
We have examined two transformations of representative a-
Scheme 4 Reagents and conditions: (i), 9b, NaH DMF, r.t.; (ii), 5M HCl
then NaHCO3; (iii), PhMe, reflux. See Table 1 for other substrates studied.
phenylthiolactams shown in Table 1. These involved sulfide
nucleophilic cleavage and acidic hydrolysis) while in other ex-
amples (e.g. formation of 20 and 23) the ring closure step was
significantly slower and was best induced thermally. In the case
of 24, lactamisation was most efficiently achieved under basic
(NaOEt, EtOH, heat) conditions.
The substrates shown in Table 1 represent a range of readily
available cyclic sulfamidate variants, which were chosen in order
to define the scope of the underlying methodology. One limitation
is obvious: use of the 5-benzyl derivative 18 leads to a significant
amount of allylic amine 25, which is the product of b-elimination
of the precursor cyclic sulfamidate 18. This is a side reaction that
we had not previously encountered using 18 with other stabilised
enolates, and this substrate appears to provide a good test as to
the effectiveness of a given nucleophile towards a base sensitive
substrate. It should also be pointed out that both the 1,2-cyclic
sulfamidate 18 and the 1,3-cyclic sulfamidate 19 used in this study
were most conveniently prepared in racemic form, while the other
oxidation followed by either thermal elimination to give the
a,b-unsaturated lactams, or Pummerer reaction of the sulfoxide
intermediate which leads to the corresponding vinyl sulfides (see
Scheme 2 and 5).
With lactams 20 and 21, the key issue of interest associated
with sulfoxide elimination was the enantiomeric integrity of the
unsaturated products obtained. This is of particular significance in
the five-ring series given the obvious possibilities associated with
the allylic nature of C(5) present in e.g. 12 and 27.
The oxidation/sulfoxide elimination reactions proceeded effi-
ciently, and the unsaturated lactams 12, 27 and 29 were obtained
in high yields and for 12 and 27 with essentially no loss of enan-
tiomeric integrity (Scheme 5). The enantiomeric purities of 12 and
27 were readily assessed using chiral HPLC with the corresponding
racemic substrates being used as analytical standards. Generally,
it was more convenient to use a polymer-supported phosphine
to scavenge phenylsulfenic acid, but this was not essential to the
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=
Scheme 6 Reagents and conditions: (i), n-BuLi or CH2 CHMgBr, CuI,
Me3SiCl, HMPA, THF, r.t.
tion leading to enamine 32. It is appropriate to note that work-up
of these conjugate addition reactions involved exposure of the
crude material to TBAF, since substantial amounts of C-silylated
material were formed under the reaction conditions.
Conclusions
In summary, a range of variously substituted 1,2- and 1,3-cyclic
sulfamidates react efficiently with sulfur-substituted enolates to
give a-thiosubstituted lactams, which can then be used to generate
the corresponding enones and vinyl sulfides. Thio-substituted
enolates were the reagents of choice as these proved to be more
generally applicable than the corresponding sulfoxide-substituted
enolates. In cases where enantiomerically pure cyclic sulfamidates
were used, clean inversion (where appropriate) was observed
during the initial nucleophilic ring opening step and no erosion
of enantiomeric integrity was encountered following lactam
formation. In addition a series of other synthetically valuable
reactions based on a,b-unsaturated lactams also proceeded with-
out loss of enantiomeric purity. These transformations of cyclic
sulfamidates demonstrate a new and straightforward approach to
functionalised and enantiomerically pure lactams, and the further
application of this chemistry to specific targets is underway.
Scheme 5 Reagents and conditions: (i), m-CPBA, CH2Cl2, 0 ◦C;
(ii), PhMe, PS–PPh3, 100 ◦C; (iii), (CF3CO)2O, CH2Cl2, r.t.; (iv), NaHCO3,
MeCN, reflux.
success of these reactions. Interestingly, in the case of 21, use of the
resin-based scavenger led to approximately 50% of the enamine
by-product 28, but this side reaction was effectively suppressed
when mildly basic conditions (use of NaHCO3) were employed.
In addition, the sulfoxide intermediate derived from the minor
diastereomer of 21 did not undergo thermal elimination under a
variety of conditions; this reflects upon the trans stereochemical
relationship between the phenyl sulfoxide substituent and the b-
proton. This observation also emphasises the importance of a
favourable stereochemical outcome from the initial sulfamidate
opening step to the overall efficiency of the sequence, as we were
unable to achieve in situ equilibration of this stereocentre under
the elimination conditions used. It is pertinent to point out that
use of a 2-pyridyl variant of 9b (i.e. Rꢀꢀ = S(2-Py)) for the initial
sulfamidate opening/lactamisation sequence provides lactams
which do undergo equilibration at C(3) under the mildly acidic
oxidation conditions employed to form the requisite sulfoxide.
This can be beneficial for the subsequent elimination step in
cases where 9b provides substrates with an unfavourable C(3)
stereochemistry.
Experimental
General
Starting materials sourced from commercial suppliers were used
as received. Dry solvents, where necessary, were obtained by
distillation using standard procedures or by passage through a
column of anhydrous alumina using equipment from Anhydrous
Engineering based on the Grubbs’ design. Petrol refers to the
fraction of petroleum ether boiling in the range of 40–60 ◦C. The
removal of solvents in vacuo was achieved using both a Bu¨chi
rotary evaporator (bath temperatures up to 40 ◦C) at a pressure of
either 15 mmHg (diaphragm pump) or 0.1 mmHg (oil pump),
as appropriate, and a high vacuum line at room temperature.
Reactions requiring anhydrous conditions were run under an
atmosphere of dry nitrogen; glassware, syringes and needles were
either flame dried immediately prior to use or placed in an
oven (150 ◦C) for at least 2 h and allowed to cool either in
a desiccator or under an atmosphere of dry nitrogen; liquid
reagents, solutions or solvents were added via syringe through
rubber septa; solid reagents were added via Schlenk type adapters.
Commercially available Merck Kieselgel 60F254 aluminium backed
plates were used for TLC analysis. Visualisation was achieved
by either UV fluorescence, acidic KMnO4 solution and heat,
ammonium molybdate solution and heat or iodine vapour. Flash
column chromatography (FCC) was performed using Fluorochem
Sulfoxide-based Pummerer reactions also proceeded smoothly
using the representative 5- and 6-ring lactams 20 and 24 to give 26
and 30. In the case of 26, which has an obvious sensitivity towards
racemisation, no degradation of enantiomeric purity was detected
(as judged by chiral HPLC).
It is also appropriate to mention that a,b-unsaturated lactams
are valuable electrophiles in their own right. Accordingly, lactam
12 underwent a diastereoselective copper-mediated 1,4-addition of
=
either n-BuLi or CH2 CHMgBr to provide the 4,5-disubstituted
lactams 31a and 31b (Scheme 6).
Again, no loss of enantiomeric purity was detected for 31a
and 31b (based on chiral HPLC analysis). Similar 1, 4-additions
involving N-alkyl lactams12 have been reported but HMPA was
required for these processes; in the absence of HMPA, the major
product corresponded to base-mediated double bond isomerisa-
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60 silica: 230–400 mesh (40–63 lm). The crude material was
applied to the column as a solution in CH2Cl2 or by pre-adsorption
onto silica, as appropriate. Melting points were determined using
a Reichert melting point table and temperature controller and
are uncorrected. Optical rotations were measured using a Perkin-
Elmer 241 polarimeter. Infra-red spectra were recorded in the
range 4000–600 cm−1 on a Perkin Elmer Spectrum either as neat
films or solids compressed onto a diamond window. Abbreviations
used are: w (weak), m (medium), s (strong) and br (broad).
NMR spectra were recorded on a JEOL GX270, JEOL GX400,
JEOL Lambda 300, JEOL Eclipse 400 or JEOL Eclipse 300
spectrometer. Chemical shifts are quoted in parts per million
(ppm); 1H NMR spectra are referenced to TMS or residual
protium of the deuterated solvent; 13C NMR are referenced
to TMS or the deuterated solvent. Coupling constants (J) are
quoted to the nearest 0.5 Hz. Other abbreviations used are: s
(singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br
0.72 mmol, 60% dispersion in mineral oil) and the resulting
suspension was stirred at r.t. for 10 min to form a pale yellow
solution. Sulfamidate 10 (218 mg, 0.72 mmol) was added and the
mixture was stirred at r.t. for 16 h. Aq. 5 M HCl (0.37 cm3) was then
added and the mixture was stirred at r.t. for 3 h. The mixture was
then neutralised by addition of saturated aq. NaHCO3 (7 cm3)
and extracted with Et2O (3 × 30 cm3). The combined organic
portions were washed with water (3 × 50 cm3), dried (MgSO4) and
concentrated in vacuo. The residue was dissolved in anhydrous
toluene (6 cm3), added to a suspension of PS–PPh3 (932 mg, 1–
1.8 mmol g−1 loading, swelled for 2 h) in anhydrous toluene (4 cm3),
◦
and then heated at 100 C for 2.5 h. The mixture was cooled to
r.t., filtered through Celite, washing with toluene (3 × 15 cm3) and
then CH2Cl2 (2 × 5 cm3), and concentrated in vacuo. The residue
was purified by FCC (Et2O–petrol 7 : 3) to afford alkene 12 (74 mg,
42%, >98% e.e.) as a colourless oil. In the absence of a scavenger,
13 was formed as the major product.
1
(broad). Assignments of H NMR and 13C NMR signals were
Procedure B. PS–PPh3 (173 mg, ca. 3.0 mmol g−1 loading) was
allowed to swell in anhydrous toluene (2 cm3) without stirring for
1.5 h. A solution of phenyl sulfoxide 11 (88 mg, 0.23 mmol) in
anhydrous toluene◦(3 cm3) was added and the resulting mixture
was heated at 100 C for 2 h. The reaction mixture was allowed
to cool to r.t., filtered through Celite, washing with toluene (3 ×
5 cm3) followed by CH2Cl2 (4 × 5 cm3), and concentrated in vacuo.
The residue was purified by FCC (Et2O–hexanes 7 : 3) to afford
the product 12 (67 mg, 99%, >98% e.e.) as a colourless, viscous oil
Data for lactam 12; [a]2D0 −17.9 (c 0.7, CHCl3); mmax/cm−1 (film)
3028 (br w), 1676 (s), 1494 (m), 1405 (m), 1232 (m), 1028 (m); dH
(400 MHz, CDCl3) 2.57 (1 H, d d, J = 13.5 and 9.0, C5–CH2Ph),
3.17 (1 H, d d, J = 13.5 and 5.0, C5–CH2Ph), 4.10 (1 H, d d d d,
J = 9.0, 5.0, 1.5 and 1.5, C5–H), 4.16 (1 H, d, J = 15.0, NCH2Ph),
5.21 (1 H, d, J = 15.0, NCH2Ph), 6.15 (1 H, d d, J = 6.0 and 1.5,
C4–H), 6.89 (1 H, d d, J = 6.0 and 1.5, C5–H), 7.05 (2 H, d t,
J = 6.0 and 2.0, ArCH), 7.18–7.36 (8 H, m ArCH); dC (75 MHz,
CDCl3) 37.6 (C5–CH2Ph), 43.9 (NCH2Ph), 62.8 (C-5), 127.0 (C-
3), 127.1, 127.6, 127.9, 128.6, 128.8 and 129.1 (10 × ArCH), 136.0
and 137.4 (2 × ArC), 147.6 (C-4), 171.3 (C-2); m/z (CI+) 264
([M + H]+, 100%); HRMS: (CI+) Found: [M + H]+ 264.1391,
C18H18NO requires 264.1388.
The enantiomeric purity of this compound was determined
by chiral HPLC (Chiralcel OD, isocratic hexane–i-PrOH 93 : 7,
1.0 cm3 min−1, 20 ◦C); tR (major) = 16.8 min and tR (minor) =
20.4 min.
Data for exoalkene 13; mmax/cm−1 (film) 2920 (w), 1702 (s), 1635
(s), 1418 (m), 1342 (m), 1182 (m); dH (400 MHz, CDCl3) 2.66–2.70
(2 H, m, C3–H), 3.01–3.06 (2 H, m, C4–H), 4.86 (2 H, s, NCH2Ph),
5.78 (1 H, m, C5–CH2Ph), 7.10–7.16 (3 H, m, ArCH), 7.25–7.40
(7 H, m, ArCH); dC (75 MHz, CDCl3) 24.0 (C-4), 29.1 (C-3), 44.0
(NCH2Ph), 104.1 (C5–CHPh), 125.7, 127.4, 127.6, 127.9, 128.6
and 128.9 (ArCH × 10), 136.2 and 136.8 (ArC × 2), 141.7 (C-
5), 175.5 (C-2); m/z (CI+) 264 ([M + H]+, 100%); HRMS: (CI+)
Found: [M + H]+ 264.1382, C18H18NO requires 264.1388.
made where possible, using COSY, DEPT, HMQC and HMBC
experiments. Where, e.g., diastereomers have been characterised
as a mixture, signals associated with the individual isomers are,
where possible, referred to as A and B. Mass spectra were
determined by the University of Bristol mass spectrometry service
by either electron impact (EI) or chemical ionisation (CI) using a
Fisons VG Analytical Autospec spectrometer, or by electrospray
ionisation (ESI) using a Bru¨ker Daltonics Apex IV spectrometer.
Chiral HPLC was performed using the corresponding racemate
as a standard on an Agilent 1100 LC system equipped with a
quaternary pump, diode array detector and column thermostat
under the conditions specified in each case.
For the preparation of cyclic sulfamidates 10, 15, 17, 18 and 19
see earlier publications.8 Lactam-based sulfoxide intermediates,
which were formed as mixtures of 4 diastereomers, have only been
characterised by mass spectrometry due to the complexity of NMR
data obtained.
(5S)-3-Phenylsulfinyl-1,5-dibenzylpyrrolidin-2-one (11)
To a solution of methyl (phenylsulfinyl)acetate 9a (143 mg,
0.72 mmol) in anhydrous DMF (3 cm3) was added NaH (29 mg,
0.72 mmol, 60% dispersion in mineral oil) and the resulting
suspension was stirred at r.t. for 10 min to form a pale yellow
solution. Sulfamidate 10 (218 mg, 0.72 mmol) was added and the
mixture was stirred at r.t. for 16 h. Aqueous 5 M HCl (0.37 cm3)
was added and the mixture was stirred at r.t. for 3 h. The mixture
was neutralised by addition of saturated aq. NaHCO3 (7 cm3)
and extracted with Et2O (3 × 30 cm3). The combined organic
portions were washed with water (3 × 50 cm3), dried (MgSO4) and
concentrated in vacuo. The residue was purified by FCC (Et2O) to
afford sulfoxide 11 (141 mg, 54%) as a colourless foam and as a
mixture of four diastereoisomers; m/z (CI+) 390 ([M + H]+, 15%),
264 (100%).
(S)-1,5-Dibenzyl-1,5-dihydropyrrol-2-one (12) and
1-benzyl-5-benzylidene pyrrolidin-2-one (13)
(5S)-1,5-Dibenzyl-3-methanesulfinylpyrrolidin-2-one and
(2S)-2-benzyl amino-3-phenylpropan-1-ol (14)
Procedure A (one pot procedure from cyclic sulfamidate 10).
To a solution of methyl (phenylsulfinyl)acetate 9a (143 mg,
0.72 mmol) in anhydrous DMF (3 cm3) was added NaH (29 mg,
To a solution of ethyl(methylsulfinyl)acetate 9d (73 mg, 0.49 mmol)
in anhydrous DMF (2 cm3) at r.t. was added NaH (20 mg,
0.49 mmol, 60% dispersion in mineral oil) and the resulting
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colourless suspension was stirred at r.t. for 20 min to form a pale
yellow solution. Sulfamidate 10 (134 mg, 0.44 mmol) was added
and the mixture was stirred at r.t. 18 h. Aqueous 5 M HCl (0.2 cm3)
was added and the resulting suspension was stirred at r.t. for 3 h.
The reaction mixture was neutralised by addition of saturated aq.
NaHCO3, diluted by addition of water (10 cm3) and extracted with
Et2O (3 × 10 cm3). The organic extracts were combined, washed
with water (3 × 10 cm3), dried (MgSO4) and concentrated in vacuo.
The residue was dissolved in toluene (3 cm3) and heated at 80 ◦C
for 12 h, allowed to cool to r.t., and concentrated in vacuo. The
residue was purified by FCC (CH2Cl2–MeOH 19 : 1) to afford (5S)-
1,5-dibenzyl-3-methanesulfinylpyrrolidin-2-one (60 mg, 43%) as a
pale oil and subsequently amino alcohol 14 (15 mg, 14%) as a
colourless solid.
13.5, 6.5 and 6.5, C4–H of A), 1.94 (1 H, d d d, J = 13.5, 8.0 and
8.0, C4–H of B), 2.20 (1 H, d d d, J = 13.5, 9.0 and 3.5, C4–H of
B), 2.26 (1 H, d d, J = 13.0 and 10.0, C5–CH2Ph of A), 2.33 (1 H, d
d d, J = 13.5, 8.5 and 7.5, C4–H of A), 2.60 (1 H, d d, J = 13.5 and
8.0, C5–CH2Ph of B), 2.93 (1 H, d d, J = 13.5 and 4.0, C5–CH2Ph
of B), 3.12 (1 H, d d, J = 13.0 and 4.5, C5–CH2Ph of A), 3.49–3.62
(3 H, m, C5–H of A and B and C3–H of B), 3.84 (1 H, d d, J = 10.0
and 7.5, C3–H of A), 3.97 (1 H, d, J = 15.0, NCH2Ph of B), 4.15
(1 H, d, J = 15.0, NCH2Ph of A), 5.03 (1 H, d, J = 15.0, NCH2Ph
of A), 5.15 (1 H, d, J = 15.0, NCH2Ph of B), 6.97 (2 H, d, J =
6.5, ArCH of A), 7.02 (2 H, d, J = 7.0, ArCH of B), 7.08–7.41
(22 H, m, ArCH), 7.46–7.52 (2 H, m, ArCH), 7.57–7.63 (2 H, m,
ArCH); dC (100 MHz, CDCl3) 31.8 (C-4 of B), 32.0 (C-4 of A),
38.9 (C5–CH2Ph of B), 40.3 (C5–CH2Ph of A), 45.0 (NCH2Ph of
B), 45.4 (NCH2Ph of A), 46.9 (C-3 of B), 47.3 (C-3 of A), 55.7
(C-5 of B), 56.8 (C-5 of A), 126.8, 127.0, 127.7, 127.8 (2 signals),
128.1, 128.2, 128.7, 128.8 (2 signals), 129.0 (2 signals), 129.1, 129.2,
129.3 and 132.7 (16 × ArCH), 133.0 (ArC), 133.3 (2 × ArCH),
134.1, 136.1, 136.5 (2 signals) and 136.9 (ArC), 172.3 (C-2 of
B), 172.8 (C-2 of A); m/z (CI+) 374 ([M + H]+, 100%); HRMS:
(ESI) Found: [M + Na]+ 396.1393, C24H23NOSNa requires
396.1420.
Data for (5S)-1,5-dibenzyl-3-methanesulfinylpyrrolidin-2-one:
m/z (CI+) 328 ([M + H]+, 100%) 264 ([M–SOMe]+, 90).
Data for 14: dH (400 MHz, CDCl3) 2.70–2.88 (2 H, m, C3–H),
2.96 (1 H, m, C2–H), 3.34 (1 H, d d, J = 10.5 and 5.5, C1–H),
3.65 (1 H, d d, J = 10.5 and 4.0, C1–H), 3.77 (2 H, s, NCH2Ph),
7.14–7.36 (10 H, m, ArCH); m/z (CI+) 242 ([M + H]+, 100%).
The spectroscopic properties of this compound were consistent
with the data available in the literature.13
Lactam 20 was oxidised to generate sulfoxide 11 as follows: To a
solution of 20 (96 mg, 0.26 mmol) in CH2Cl2 (8 cm3), at 0 ◦C, was
added m-CPBA (64 mg, ca. 0.26 mmol, 70–75% purity) to form a
colourless solution which was stirred at 0 ◦C for 2 h. The reaction
mixture was quenched by addition of saturated aqueous potassium
metabisulfite (10 cm3). The organic portion was isolated, washed
with saturated aq. NaHCO3 (2 × 10 cm3), dried (Na2SO4) and
concentrated in vacuo to afford the sulfoxide 11 (98 mg, 97%) as
a colourless foam. This was identical to the product obtain by
reaction of 9 with 10 (see above).
(4S,5S)-3-Methanesulfinyl-1,5-dimethyl-4-phenylpyrrolidin-
2-one (16)
To
a solution of ethyl(methylsulfinyl)acetate 9d (173 mg,
1.15 mmol) in anhydrous t-BuOH (6 cm3) at r.t. was added t-BuOK
(136 mg, 1.15 mmol) and the resulting colourless suspension was
stirred at r.t. for 20 min. Sulfamidate 15 (238 mg, 1.10 mmol)
was added and the reaction mixture was heated at reflux for 46 h.
The reaction mixture was allowed to cool to r.t. and aq. 5 M
HCl (0.56 cm3) was added and the mixture was stirred at r.t. for
4 h. The reaction mixture was neutralised by addition of saturated
aq. NaHCO3, diluted by addition of brine (30 cm3) and extracted
with CH2Cl2 (3 × 30 cm3). The organics were combined, dried
(MgSO4) and concentrated in vacuo. The residue was purified by
FCC (CH2Cl2–MeOH 10 : 1) to afford lactam 16 (152 mg, 55%)
as a pale yellow oil and as a mixture of four diastereoisomers; m/z
(CI+) 252 ([M + H]+, 100%).
(4S, 5S)-1,5-Dimethyl-4-phenyl-3-phenylsulfanylpyrrolidin-
2-one (21)
To a solution of methyl(phenylthio)acetate 9b (215 ll, 1.38 mmol)
in anhydrous DMF (8.3 cm3) was added NaH (55 mg, 1.38 mmol,
60% dispersion in mineral oil) and the resulting mixture was stirred
at r.t. for 15 min to form a pale yellow suspension. Sulfamidate
15 (150 mg, 0.69 mmol) was added and the reaction mixture was
stirred at r.t. for 18.5 h. Aq. 5 M HCl (0.69 cm3) was added and
the resulting pale yellow suspension was stirred at r.t. for 3 h.
The reaction mixture was neutralised by addition of saturated aq.
NaHCO3 and extracted with Et2O (3 × 20 cm3). The combined
organic extracts were washed with water (3 × 10 cm3), dried
(MgSO4) and concentrated in vacuo. The residue was purified by
FCC (Et2O) to afford lactam 21 (169 mg, 83%, 10 : 1 d.r. A : ◦B)
as a colourless oil which crystallised on standing; m.p. 93–95 C
(Et2O–petrol); mmax/cm−1 (thin film) 3059 (w), 2969 (w), 1697 (s),
1396 (m), 751 (m), 694 (m); dH (400 MHz, CDCl3) 1.08 (3 H, d,
J = 6.0, C5–CH3 of A), 1.26 (3 H, d, J = 6.5, C5–CH3 of B), 2.77
(2 H, d d, J = 9.0 and 7.0, C4–H of A; 1 H, m, C4–H of B), 2.87
(3 H, s, NCH3 of A), 2.90 (3 H, s, NCH3 of B), 3.40 (1 H, d q, J =
7.0 and 6.5, C5–H of B), 3.51 (1 H, d q, J = 6.0 and 6.0, C5–H
of A), 3.82 (1 H, d, J = 9.0, C3–H of A), 4.13 (1 H, d, J = 8.0,
C3–H of B), 7.12–7.54 (20 H, m, ArCH); dC (100 MHz, CDCl3)
(data for major isomer A only) 18.4 (C5–CH3), 28.1 (NCH3), 53.9
(C-3), 56.3 (C-4), 60.1 (C-5), 127.6, 127.8, 127.9, 128.9 and 129.0
(5S)-1,5-Dibenzyl-3-phenylsulfanylpyrrolidin-2-one (20)
To a solution of methyl(phenylthio)acetate 9b (153 ll, 1.00 mmol)
in anhydrous DMF (6 cm3) was added NaH (40 mg, 1.00 mmol,
60% dispersion in mineral oil) and the resulting mixture was stirred
at r.t. for 20 min to form a colourless suspension. Sulfamidate 10
(150 mg, 0.50 mmol) was added and the reaction mixture was
stirred at r.t. for 20.5 h. Aqueous 5 M HCl (0.5 cm3) was added
and the resulting colourless suspension was stirred at r.t. for 3 h.
The reaction mixture was neutralised by addition of saturated
aq. NaHCO3 and extracted with Et2O (3 × 15 cm3). The organic
extracts were combined, washed with water (3 × 10 cm3), dried
(MgSO4) and concentrated in vacuo. The residue was dissolved in
toluene (8 cm3) and heated at 100 ◦C for 18 h. Solvent was removed
in vacuo and the residue was purified by FCC (Et2O–petrol 1 : 1)
to afford lactam 20 (183 mg, 98%, 2 : 1 d.r.) as a pale yellow oil;
mmax/cm−1 (thin film) 3028 (w), 2924 (w), 1686 (s), 1438 (m), 1249
(m), 733 (s), 691 (m); dH (400 MHz, CDCl3) 1.79 (1 H, d d d, J =
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(8 × ArCH), 133.1 (ArC), 133.6 (2 × ArCH), 139.7 (ArC), 171.3
(C-2); m/z (CI+) 298 ([M + H]+, 100%); HRMS: (ESI) Found:
[M + H]+ 298.1260, C18H20NOS requires 298.1249.
C4–CH2Ph of A), 2.88–3.07 (4 H, m, C4–CH2Ph of A and B and
C5–H of A), 3.11 (1 H, d d, J = 14.5 and 6.0, C5–H of B), 3.54
(1 H, d, J = 7.0, C3–H of A), 3.98 (1 H, d d, J = 14.5 and 6.5,
C3–H of B), 4.28 (1 H, d, J = 14.5, NCH2Ph of B), 4.34 (1 H, d,
J = 14.5, NCH2Ph of A), 4.45 (1 H, d, J = 14.5, NCH2Ph of A),
4.50 (1 H, d, J = 14.5, NCH2Ph of B), 6.95–7.02 (4 H, m, ArCH),
7.09–7.37 (22 H, m, ArCH), 7.54 (2 H, d d, J = 8.5 and 2.0, ArCH
of A), 7.61 (2 H, d d, J = 8.5 and 1.5, ArCH of B); dC (100 MHz,
CDCl3) 35.1 (C-5 of B), 39.1 (C-5 of A), 39.8 (C-4 of B), 40.5 (C-4
of A), 46.9 (NCH2Ph of B), 47.1 (NCH2Ph of A), 49.5 (2 signals)
(C4–CH2Ph of A and B), 126.7, 127.6, 127.7, 127.8, 128.1, 128.2,
128.3, 128.6, 128.7, 128.8 (3 signals), 128.9, 129.1 (2 signals) and
132.4 (28 × ArCH), 132.9 (ArC), 133.7 (2 × ArCH), 134.3, 136.1,
136.3, 138.3 and 139.2 (ArC), 171.6 and 172.3 (C-2); m/z (CI+)
374 ([M + H]+, 100%); HRMS: (CI+) Found: [M + H]+ 374.1577,
C24H24NOS requires 374.1579.
(4S, 5R)-1,5-Dimethyl-4-phenyl-3-phenylsulfanylpyrrolidin-
2-one (22)
To a solution of methyl(phenylthio)acetate 9b (215 lL, 1.38 mmol)
in anhydrous DMF (8.3 cm3) was added NaH (55 mg, 1.38 mmol,
60% dispersion in mineral oil) and the resulting mixture was stirred
at r.t. for 20 min to form a pale yellow suspension. Sulfamidate
17 (150 mg, 0◦.69 mmol) was added and the reaction mixture was
stirred at 45 C for 18 h. Aq. 5 M HCl (0.69 cm3) was added
and the resulting pale yellow suspension was stirred at r.t. for
3 h. The reaction mixture was neutralised by addition of saturated
aq. NaHCO3 and extracted with Et2O (3 × 25 cm3). The organic
extracts were combined, washed with water (3 × 10 cm3), dried
(Na2SO4) and concentrated in vacuo. The residue was purified by
FCC (Et2O–hexanes 1 : 1) to afford lactam 22 (126 mg, 62%, 1 :
1 d.r. A : B) as a colourless, viscous oil; mmax/cm−1 (film) 2929 (br
m), 1687 (s), 1395 (m), 1258 (w), 739 (s), 701 (s); dH (400 MHz,
CDCl3) 0.75 (3 H, d, J = 6.5, C5–CH3 of A), 0.89 (3 H, d, J = 6.5,
C5–CH3 of B), 2.83 (3 H, s, NCH3 of A), 2.87 (3 H, s, NCH3 of
B), 3.61–3.74 (2 H, m, C5–H of A and C4–H of B), 3.89 (1 H, d q,
J = 6.5 and 6.5, C5–H of B), 4.02 (1 H, d, J = 8.0, C3–H of A),
4.27 (1 H, d, J = 8.0, C3–H of B), 7.03–7.36 (16 H, m, ArCH),
7.43–7.56 (4 H, m, ArCH); dC (100 MHz, CDCl3) 15.0 (C5–CH3
of A), 15.7 (C5–CH3 of B), 27.7 and 28.3 (2 × NCH3), 49.4 (C-4
of A), 49.6 (C-4 of B), 52.2 (C-3 of A), 55.2 (C-3 of B), 56.9 (C-5 of
B), 57.5 (C-5 of A), 126.9, 127.4, 127.7, 128.0, 128.2, 128.3, 128.7,
128.8, 129.0, 129.7, 131.4 and 133.5 (20 × ArCH), 133.0, 136.1,
136.5 and 137.5 (4 × ArC), 171.7 and 173.5 (2 × C-2); m/z (CI+)
298 ([M + H]+, 100%); HRMS: (CI+) Found: [M + H]+ 298.1266,
C18H20NOS requires 298.1266.
Data for alkene 25: dH (400 MHz, CDCl3) 1.63 (1 H, br s, NH),
3.42 (2 H, d, J = 6.0, C1–H), 3.82 (2 H, s, NCH2Ph), 6.30 (1 H,
d t, J = 16.0 and 6.0, C2–H), 6.53 (1 H, d, J = 16.0, C3–H),
7.18–7.39 (10 H, m, ArCH); m/z (CI+) 224 ([M + H]+, 100%).
The spectroscopic properties of this compound were consistent
with the data available in the literature.14
1-Benzyl-6-methyl-3-phenylsulfanylpiperidin-2-one (24)
To a solution of methyl(phenylthio)acetate 9b (537 ll, 3.45 mmol)
in anhydrous DMF (21 cm3) was added portionwise NaH (138 mg,
3.45 mmol, 60% dispersion in mineral oil) and the resulting
mixture was stirred at r.t. for 20 min to form a pale yellow
suspension. Sulfamidate 19 (416 mg, 1.73 mmol) was added and
the reaction mixture was stirred at r.t. for 14.5 h. Aq. 5 M HCl
(0.5 cm3) was added and the resulting pale yellow suspension was
stirred at r.t. for 3 h. The reaction mixture was neutralised by
addition of saturated aq. NaHCO3 and extracted with Et2O (3 ×
30 cm3). The organic extracts were combined, washed with water
(3 × 50 cm3), dried (Na2SO4) and concentrated in vacuo. The
residue was dissolved in 0.2 M ethanolic NaOEt (20 cm3) and
heated at reflux for 11 h. The reaction mixture was quenched by
addition of saturated aq. NH4Cl (30 cm3) and was extracted with
CH2Cl2 (2 × 20 cm3). The organic extracts were combined, dried
(Na2SO4) and concentrated in vacuo. The residue was purified by
FCC (Et2O–hexanes 1 : 1) to afford lactam 24 (431 mg, 80%, 1 :
1 d.r.) as a pale yellow oil; mmax/cm−1 (thin film) 2946 (m), 1639
(s), 1439 (m), 745 (m), 694 (m); dH (400 MHz, CDCl3) 1.10 (3 H,
d, J = 6.5, C6–CH3), 1.20 (3 H, d, J = 6.5, C6–CH3), 1.51 (1
H, m, C4–H), 1.74–1.85 (2 H, m, C5–H), 1.89 (1 H, m, C4–H),
2.00–2.09 (2 H, m, C5–H), 2.14–2.32 (2 H, m, C4–H), 3.38–3.50 (2
H, m, C6–H), 3.89–3.98 (3 H, m, NCH2Ph and C3–H × 2), 4.11
(1 H, d, J = 15.0, NCH2Ph), 5.22 (1 H, d, J = 15.0, NCH2Ph),
5.41 (1 H, d, J = 15.0, NCH2Ph), 7.21–7.35 (16 H, m, ArCH),
7.54–7.61 (4 H, m, ArCH); dC (100 MHz, CDCl3) 19.7 and 20.0
(C6–CH3), 24.8 (C-4), 25.6 (C-5), 27.0 (C-4), 28.6 (C-5), 47.4 and
47.9 (NCH2Ph), 48.9 and 49.1 (C-3), 51.0 and 51.6 (C-6), 127.3
(2 signals), 127.6, 127.7 (2 signals), 127.9, 128.6 (2 signals), 128.9,
129.0, 132.8 and 133.1 (ArCH × 20), 134.5, 134.8, 137.5 and 137.7
(ArC), 168.7 and 169.0 (C-2); m/z (CI+) 312 ([M + H]+, 100%);
HRMS: (CI+) Found: [M + H]+ 312.1420, C19H22NOS requires
312.1422.
1,4-Dibenzyl-3-phenylsulfanylpyrrolidin-2-one 23 and
benzyl-(3-phenylallyl)amine (25)
To a solution of methyl(phenylthio)acetate 9b (306 ll, 2.00 mmol)
in anhydrous DMF (12 cm3) was added NaH (80 mg, 2.00 mmol,
60% dispersion in mineral oil) and the resulting mixture was stirred
at r.t. for 20 min to form a pale yellow suspension. Sulfamidate 18
(300 mg, 1.0 mmol) was added and the reaction mixture was stirred
at r.t. for 16.5 h. Aq. 5 M HCl (0.5 cm3) was added and the resulting
pale yellow emulsion was stirred at r.t. for 3 h. The reaction
mixture was neutralised by addition of saturated aq. NaHCO3
and extracted with Et2O (3 × 20 cm3). The combined organic
portions were washed with water (3 × 20 cm3), dried (MgSO4)
and concentrated in vacuo. The residue was dissolved in toluene
(16 cm3) and heated at reflux for 3 h. Solvent was removed in vacuo
and the residue was purified by FCC (Et2O–hexanes 1 : 2 → Et2O
100%) to afford the lactam 23 (84 mg, 23%, 3 : 2 d.r.) as a pale
yellow oil. Continued elution provided alkene 25 (82 mg, 37%) as
a yellow oil.
Data for lactam 23: mmax/cm−1 (thin film) 3027 (w), 2918 (w),
1688 (s), 1438 (m), 1426 (m), 1264 (br m), 740 (s), 698 (s); dH
(400 MHz, CDCl3) 2.44 (1 H, m, C4–H of A), 2.57 (1H, d d, J =
14.5 and 9.5, C5–H of A), 2.57 (1 H, d d, J = 14.5 and 10.0, C5–H
of B), 2.80 (1 H, m, C4–H of B), 2.86 (1 H, d d, J = 10.0 and 6.0,
1874 | Org. Biomol. Chem., 2006, 4, 1868–1877
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(S)-1,5-Dibenzyl-3-phenylsulfanyl-1,5-dihydropyrrol-2-one (26)
to afford the alkene 27 (68 mg, 84%, >98% e.e.) as a colourless,
crystalline solid.
To a solution of phenylsulfoxide 11 (80 mg, 021 mmol) in
anhydrous CH2Cl2 (2 cm3) at 0 ◦C was added, via syringe, TFAA
(59 ll, 0.42 mmol). The resulting clear solution was stirred at r.t.
for 2 h to form a dark red solution which was then diluted by
addition of saturated aq. NaHCO3 (2 cm3) and water (10 cm3)
and extracted with CH2Cl2 (2 × 10 cm3). The combined organic
portions were dried (Na2SO4) and concentrated in vacuo. The
residue was purified by FCC (Petrol–Et2O 4 : 1) to afford the
product 26 (43 mg, 55%, >98% e.e.) as a red oil; [a]2D0 +141.2 (c
0.51, CHCl3); mmax/cm−1 (film) 2923 (br w), 1684 (s), 1406 (m), 1179
(m), 1024 (m); dH (400 MHz, CDCl3) 2.58 (1 H, d d, J = 13.5 and
9.0, C5–CH2Ph), 2.99 (1 H, d d, J = 13.5 and 5.0, C5–CH2Ph),
3.95 (1 H, m, C5–H), 4.11 (1 H, d, J = 15.0, NCH2Ph), 5.18 (1 H,
d, J = 15.0, NCH2Ph), 6.10 (1 H, d, J = 2.0, C3–H), 6.95–6.99 (2
H, m, ArCH), 7.15–7.42 (13 H, m ArCH); dC (100 MHz, CDCl3)
37.7 (C5–CH2Ph), 44.7 (NCH2Ph), 61.5 (C-5), 127.0, 127.7, 128.2,
128.5, 128.6, 128.8, 129.2, 129.5 and 132.7 (15 × ArCH), 134.9,
136.3, 136.6 and 136.9 (3 × ArC and C-3), 136.9 (C-4), 168.2 (C-
2); m/z (CI+) 372 ([M + H]+, 100%); HRMS: (CI+) Found: [M +
H]+ 372.1423, C24H22NOS requires 372.1422.
Data for 27; m.p. 129–131 ◦C (EtOAc–hexanes); [a]2D0 +85.5 (c
1.31, CHCl3); mmax/cm−1 (thin film) 2925 (w), 1672 (s), 1448 (m),
1425 (m), 1395 (m), 767 (m), 693 (m); dH (400 MHz, CDCl3) 1.34
(3 H, d, J = 7.0, C5–CH3), 3.05 (3 H, s, NCH3), 4.51 (1 H, q, J =
7.0, C5–H), 6.34 (1 H, s, C3–H), 7.36–7.48 (5 H, m, ArCH). The
spectroscopic properties of this compound were consistent with
the data available in the literature.15
The enantiomeric purity of this compound (synthesised via
Procedure B) was determined by chiral HPLC (Chiralcel OJ-H,
gradient hexane–i-PrOH 100 : 0–95 : 5 over 90 min, 1.0 cm3 min−1,
20 ◦C); tR (major) = 68.2 min and tR (minor) = 57.4 min.
Data for 28; mmax/cm−1 (thin film) 2960 (m), 1679 (br s), 1447
(m), 1436 (m), 1065 (m), 1023 (m), 764 (m), 696 (s); dH (400 MHz,
CDCl3) 2.18 (3H, t, J = 2.5, C5–CH3), 3.10 (3 H, s, NCH3),
3.34 (2 H, q, J = 2.5, C3–H), 7.17–7.39 (5 H, m, ArCH); dC
(75 MHz, CDCl3) 12.1 (C5–CH3), 26.7 (NCH3), 39.4 (C-3), 112.9
(C-4), 126.2, 127.2 and 128.7 (5 × ArCH), 135.1 and 136.1 (C-
5 and ArC), 176.5 (C-2); m/z (CI+) 188 ([M + H]+, 100%);
HRMS: (CI+) Found: [M + H]+ 188.1068, C12H14NO requires
188.1075.
The enantiomeric purity of this compound was determined
by chiral HPLC (Chiralcel OD, isocratic hexane–i-PrOH 95 : 5,
1.0 cm3 min−1, 20 ◦C); tR (major) = 24.5 min and tR (minor) =
34.5 min.
3-Phenylsulfinyl-1-benzyl-6-methylpiperidin-2-one
To a solution of 24 (341 mg, 1.10 mmol) in CH2Cl2 (25 cm3),
at 0 ◦C, was added m-CPBA (271 mg, ca. 1.10 mmol, 70–75%)
to form a pale yellow solution which was stirred at 0 ◦C for
1 h. The reaction mixture was quenched by addition of saturated
aq. potassium metabisulfite (25 cm3). The organics were isolated,
washed with saturated aq. NaHCO3 (2 × 25 cm3), dried (Na2SO4)
and concentrated in vacuo to afford the corresponding sulfoxide
(344 mg, 96%) as a pale yellow gum; m/z (CI+) 328 ([M + H]+,
100%).
(4S, 5S)-1,5-Dimethyl-4-phenyl-3-phenylsulfinylpyrrolidin-2-one
To a solution of 21 (93 mg, 0.31 mmol) in CH2Cl2 (7 cm3), at
0
◦C, was added m-CPBA (76 mg, ca. 0.31 mmol, 70–75%) to
form a colourless solution which was stirred at 0 ◦C for 1 h.
The reaction mixture was quenched by addition of saturated
aq. potassium metabisulfite (5 cm3). The organics were isolated,
washed with saturated aq. NaHCO3 (2 × 5 cm3), dried (Na2SO4)
and concentrated in vacuo to afford the corresponding sulfoxide
(93 mg, 96%, 10 : 10 : 1 : 1 d.r.) as a colourless foam; m/z (CI+)
314 ([M + H]+, 38%), 188 ([M–SOPh]+, 100).
1-Benzyl-6-methyl-5,6-dihydro-1H-pyridin-2-one (29)
PS–PPh3 (210 mg, ca. 3 mmol g−1 loading) was allowed to
swell in anhydrous toluene (2 cm3) for 3.5 h without stirring.
A solution of 3-phenylsulfinyl-1-benzyl-6-methylpiperidin-2-one
(93 mg, 0.28 mmol) in anhydrous toluene (3 cm3) was added and
the resulting mixture was heated at reflux for 1.5 h. The reaction
mixture was allowed to cool to r.t., filtered through Celite (washing
with toluene (3 × 5 cm3) followed by CH2Cl2 (4 × 5 cm3)) and
concentrated in vacuo. The residue was purified by FCC (Et2O–
hexanes 6 : 1) to afford product 29 (49 mg, 87%) as a colourless
oil; mmax/cm−1 (thin film) 2932 (m), 1664 (s), 1605 (s), 1449 (m),
1141 (m), 830 (m), 717 (m), 697 (m); dH (270 MHz, CDCl3) 1.19
(3 H, d, J = 7.0, C6–CH3), 2.09 (1 H, d d d d, J = 18.0, 6.0, 3.0
and 0.5, C5–H), 2.58 (1 H, d d d d, J = 18.0, 7.0, 2.5 and 2.5,
C5–H), 3.56 (1 H, q d d d, J = 7.0, 7.0, 2.5 and 1.5, C6–H), 3.90
(1 H, d, J = 15.0, NCH2Ph), 5.35 (1 H, d, J = 15.0, NCH2Ph),
6.02 (1 H, d d d, J = 10.0, 3.0 and 0.5, C3–H), 6.44 (1 H, d d d,
J = 10.0, 6.0, 2,5 and 1.5, C4–H), 7.18–7.27 (5 H, m, ArCH); dC
(100 MHz, CDCl3) 17.7 (C6–CH3), 30.9 (C-5), 47.3 (NCH2Ph),
49.8 (C-6), 125.0 (C-4), 127.3, 127.9 and 128.6 (ArCH × 5), 137.2
(C-3), 138.3 (ArC), 163.7 (C-2); m/z (CI+) 202 ([M + H]+, 100%);
HRMS: (CI+) Found: [M + H]+ 202.1230, C13H16NO requires
202.1232.
(5S)-1,5-Dimethyl-4-phenyl-1,5-dihydropyrrol-2-one (27) and
1,5-Dimethyl-4-phenyl-1,3-dihydropyrrol-2-one (28)
Procedure A. PS–PPh3 (310 mg, ca. 3.0 mmol g−1 loading)
was allowed to swell in anhydrous toluene (1.3 cm3) without
stirring for 1.5 h. A solution of (4S, 5S)-1,5-dimethyl-4-phenyl-3-
phenylsulfinylpyrrolidin-2-one (53 mg, 0.17 mmol) in anhydrous
toluene (2 cm3) was added and the resulting mixture was heated at
100 ◦C for 1.5 h. The reaction mixture was allowed to cool to r.t.,
filtered through Celite (washing with toluene (3 × 5 cm3) followed
1
by CH2Cl2 (3 × 5 cm3)) and concentrated in vacuo. H NMR of
the crude material showed 27 : 28 as a 11 : 9 mixture. Analytical
samples were isolated by preparative TLC (Et2O–petrol 1 : 1).
Procedure B.
A suspension of (4S, 5S)-1,5-dimethyl-4-
phenyl-3-phenylsulfinylpyrrolidin-2-one (135 mg, 0.43 mmol) and
NaHCO3 (160 mg, 1.90 mmol) in MeCN (8 cm3) was heated at
reflux for 10 h. The mixture was then cooled to r.t., filtered through
Celite (washing with CH2Cl2 (3 × 5 cm3)) and concentrated in
vacuo. The residue was purified by FCC (EtOAc–hexanes 2 : 1)
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Data for 31a: [a]D20 −16.7 (c 0.48, CHCl3); mmax/cm−1 (film) 2927
(br m), 1686 (s), 1454 (m), 1365 (w); dH (400 MHz, CDCl3) 0.70
(3 H, t, J = 7.5, (CH2)3CH3), 0.82–1.10 (6 H, m, (CH2)3CH3),
1.94–2.03 (2 H, m, C3–H and C4–H), 2.43 (1 H, d d, J = 17.0 and
8.5, C3–H), 2.63 (1 H, d d, J = 13.5 and 8.0, C5–CH2Ph), 2.94 (1
H, d d, J = 13.5 and 4.5, C5–CH2Ph), 3.25 (1 H, d d d, J = 8.0, 4.5
and 2.5, C5–H), 3.89 (1 H, d, J = 15.0, NCH2Ph), 5.12 (1 H, d,
J = 15.0, NCH2Ph), 7.03–7.07 (2 H, m, ArCH), 7.18–7.36 (8 H, m
ArCH); dC (100 MHz, CDCl3) 13.8 ((CH2)3CH3), 22.3, 28.8 and
34.5 ((CH2)3CH3), 35.8 (C-4), 36.5 (C-3), 39.0 (C5–CH2Ph), 44.5
(NCH2Ph), 63.5 (C-5), 126.8, 127.9, 128.3, 128.6, 128.7 and 129.3
(10 × ArCH), 136.7 and 137.3 (2 × ArC), 174.5 (C-2); m/z (CI+)
322 ([M + H]+, 100%); HRMS: (CI+) Found: [M + H]+ 322.2177,
C22H28NO requires 322.2171.
1-Benzyl-6-methyl-3-phenylsulfanyl-5,6-dihydro-1H-pyridin-
2-one (30)
To an ice-cooled (0 ◦C) solution of 3-phenylsulfinyl-1-benzyl-6-
methylpiperidin-2-one (99 mg, 0.30 mmol) in anhydrous CH2Cl2
(3 cm3) was added, dropwise, TFAA (85 ll, 0.60 mmol) to form a
pale yellow solution which was allowed to warm slowly to r.t. and
stirred for 14.5 h. Saturated aq. NaHCO3 (3 cm3) was added, the
reaction mixture was stirred at r.t. for 2 h and then extracted with
CH2Cl2 (3 × 10 cm3). The organic extracts were combined, washed
with aq. 1 M HCl (10 cm3), saturated aq. NaHCO3 (10 cm3),
dried (Na2SO4) and concentrated in vacuo to afford the product 30
(79 mg, 85%) as a pale yellow gum; mmax/cm−1 (thin film) 2968 (m),
1734 (m), 1639 (s), 1603 (s) 1439 (m), 1215 (m), 1073 (m), 1025
(m), 730 (s), 694 (s); dH (400 MHz, CDCl3) 1.21 (3 H, d, J = 6.5,
C6–CH3), 2.06 (1 H, d d d, J = 17.5, 6.5 and 2.5, C5–H), 2.57 (1
H, d d d, J = 17.5, 7.0 and 3.0, C5–H), 3.57 (1 H, q d d d, J =
7.0, 6.5, 3.0 and 1.0, C6–H), 3.97 (1 H, d, J = 14.5, NCH2Ph),
5.36 (1 H, d, J = 14.5, NCH2Ph), 5.79 (1 H, d d d, J = 6.5, 2.5
and 1.0, C4–H), 7.20–7.45 (8 H, m, ArCH), 7.51–7.58 (2 H, d d,
J = 6.0 and 4.5, ArCH); dC (100 MHz, CDCl3) 17.6 (C6–CH3),
31.4 (C-5), 48.0 (NCH2Ph), 50.0 (C-6), 127.3, 127.9, 128.3 and
128.5 (ArCH × 8), 129.4 (C-4), 132.4 and 133.7 (ArC and C-3),
134.3 (ArCH × 2), 137.9 (ArC), 161.6 (C-2); m/z (CI+) 310 ([M +
H]+, 100%); HRMS: (CI+) Found: [M + H]+ 310.1262, C19H20NOS
requires 310.1266.
The enantiomeric purity of this compound was determined by
chiral HPLC (Chiralpak AD, isocratic hexane–i-PrOH 98 : 2,
1.0 cm3/min, 15 ◦C); tR (major) = 21.7 min and tR (minor) =
28.2 min.
(4S,5S)-1,5-Dibenzyl-4-vinylpyrrolidin-2-one (31b)
To a stirred suspensi◦on of CuI (139 mg, 0.73 mmol) in anhydrous
THF (0.6 cm3) at 0 C was added, via syringe, vinyl magnesium
bromide (1 M in THF, 1.40 cm3, 1.40 mmol) to form a brown
suspension. After 10 min the mixture was cooled to −78 ◦C and
TMSCl (43 ll, 0.34 mmol) and HMPA (81 ll, 0.46 mmol) were
sequentially added via syringe. After a further 5 min a solution
of alkene 12 (60 mg, 0.21 mmol) in anhydrous THF (1.0 cm3)
was added, via syringe, and the mixture was stirred at r.t. for
2 h. Saturated aq. NH4Cl (10 cm3) was added and the mixture
was diluted with Et2O (15 cm3). The organic portion was isolated
and washed with saturated aq. NH4Cl (10 cm3) and water (2 ×
10 cm3), dried (Na2SO4) and concentrated in vacuo. The residue
was dissolved in THF (1 cm3), TBAF (1 M in THF, 0.20 cm3,
0.20 mmol) was added and the mixture was stirred at r.t. for 15 min.
The mixture was then diluted with water (5 cm3) and extracted
with Et2O (2 × 5 cm3). The organic extracts were dried (Na2SO4)
and concentrated in vacuo to afford a residue which was purified
by FCC (Et2O–petrol 1 : 1) to yield the lactam 31b (18 mg, 29%,
>98% e.e.) as a colourless oil; [a]2D0 +19.0 (c 0.63, CHCl3); mmax/cm−1
(film) 2926 (br m), 1681 (s), 1420 (m), 1247 (m), 1079 (w), 912 (m);
dH (400 MHz, CDCl3) 2.21 (1 H, d d, J = 17.0 and 4.5, C3–H),
2.47 (1 H, d d d, J = 17.0, 9.0 and 1.0, C3–H), 2.66 (1 H, d
d d d, J = 9.0, 7.5, 4.5 and 3.5, C4–H), 2.76 (1 H, d d, J =
14.0 and 7.5, C5–CH2Ph), 2.95 (1 H, d d, J = 14.0 and 5.0, C5–
CH2Ph), 3.43 (1 H, d d d, J = 7.5, 5.0 and 3.5, C5–H), 3.92
(1 H, d, J = 15.0, NCH2Ph), 4.81 (1 H, d t, J = 17.0 and 1.0,
(4R,5S)-1,5-Dibenzyl-4-butylpyrrolidin-2-one (31a) and
1,5-dibenzyl-1,3-dihydropyrrol-2-one (32)
To a stirred suspension of CuI (209 mg, 1.10 mmol) in anhydrous
THF (1 cm3) at 0 ◦C was added, via syringe, n-BuLi (1.6 M in
hexanes, 1.31 cm3, 2.10 mmol) to form a brown suspension. After
10 min the mixture was cooled to −78 ◦C and TMSCl (65 ll,
0.52 mmol) and HMPA (122 ll, 0.7 mmol) were sequentially
added via syringe. After a further 5 min a solution of alkene 12
(91 mg, 0.35 mmol) in anhydrous THF (1.4 cm3) was added, via
syringe, and the mixture was stirred at r.t. for 2 h. Saturated aq.
NH4Cl (10 cm3) was added and the mixture was diluted with
Et2O (15 cm3). The organic portion was isolated and washed with
saturated aq. NH4Cl (10 cm3) and water (2 × 10 cm3), dried
(MgSO4) and concentrated in vacuo. The residue was dissolved
in THF (1 cm3), TBAF (1 M in THF, 0.25 cm3, 0.25 mmol) was
added and the mixture was stirred at r.t. for 15 min. The mixture
was then diluted with water (5 cm3) and extracted with Et2O (2 ×
5 cm3). The organic extracts were dried (MgSO4) and concentrated
in vacuo to afford a residue which was purified by FCC (Et2O–
petrol 1 : 1) to yield the enamine 32 (5 mg, 6%) as a colourless oil
and continued elution provided lactam 31a (80 mg, 78%, >98%
e.e.) as a colourless oil.
Data for 32; mmax/cm−1 (film) 2925 (br w), 1705 (s), 1646 (m),
1348 (m), 1183 (w); dH (400 MHz, CDCl3) 3.15 (2 H, q, J = 2.5,
C5–CH2Ph), 3.43–3.47 (2 H, m C3–H), 4.59 (2 H, s, NCH2Ph),
4.89–4.91 (1 H, m, C4–H), 7.11–7.19 (4 H, m, ArCH), 7.22–7.35
(6 H, m, ArCH); dC (100 MHz, CDCl3) 34.3 (C-3), 36.9 (C5–
CH2Ph), 43.4 (NCH2Ph), 101.4 (C-4), 126.8, 127.0, 127.4, 128.7
(2 signals) and 128.8 (10 × ArCH), 136.2, 137.8 and 144.3 (C-5 and
2 × ArC), 178.3 (C-2); m/z (CI+) 264 ([M + H]+, 100%); HRMS:
(CI+) Found: [M + H]+ 264.1378, C18H18NO requires 264.1388.
=
=
C4–CH CH2), 4.85 (1 H, d t, J = 10.0 and 1.0, C4–CH CH2),
5.12 (1 H, d, J = 15.0, NCH2Ph), 5.52 (1 H, d d d, J = 17.0,
=
10.0 and 7.5, C4–CH CH2), 7.05–7.07 (2 H, m, ArCH), 7.14–
7.17 (2 H, m ArCH), 7.21–7.34 (6 H, m ArCH); dC (100 MHz,
CDCl3) 35.9 (C-3), 38.4 (C5–CH2Ph), 40.0 (C-4), 44.5 (NCH2Ph),
=
63.2 (C-5), 115.0 (C4–CH CH2), 126.9, 127.7, 128.5, 128.8 (2
signals) and 129.4 (10 × ArCH), 136.5 and 136.9 (2 × ArC), 138.8
+
+
=
(C4–CH CH2), 174.0 (C-2); m/z (CI ) 292 ([M + H] , 100%);
HRMS: (CI+) Found: [M + H]+ 292.1698, C20H22NO requires
292.1701.
The enantiomeric purity of this compound was determined by
chiral HPLC (Chiralpak AD, isocratic hexane–i-PrOH 98 : 2,
1876 | Org. Biomol. Chem., 2006, 4, 1868–1877
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1.0 cm3/min, 15 ◦C); tR (major) = 28.0 min and tR (minor) =
G. G. A. Inglis, D. Bentley and M. D. Dowle, Tetrahedron Lett., 2002,
43, 5057–5060.
3 A. K. Mandal, J. Hines, K. Kuramochi and C. M. Crews, Bioorg. Med.
Chem. Lett., 2005, 15, 4043–4047.
42.3 min.
4 For some recent applications, see: P. Armstrong, S. Feutren, H.
McAlonan, G. O’Mahony and P. J. Stevenson, Tetrahedron Lett., 2004,
45, 1627–1630; J. Marin, C. Didierjean, A. Aubry, J.-R. Casimir, J.-P.
Briand and G. Guichard, J. Org. Chem., 2004, 69, 130–141.
5 D. Franc¸ois, E. Poupon, N. Kunesch and H.-P. Husson, Eur. J. Org.
Chem., 2004, 4823–4829; M. Amat, C. Escolano, N. Llor, M. Huguet,
M. Pe´rez and J. Bosch, Tetrahedron: Asymmetry, 2003, 14, 1679–1683.
6 A. Sanyal, Q. Yuan and J. K. Snyder, Tetrahedron Lett., 2005, 46, 2475–
2478.
Acknowledgements
We thank Argonaut Technologies for a generous gift of resin
bound phosphine reagent, GSK and EPSRC for studentships
(to AJW and JFB), the EU (Erasmus) (to JS), and SC thanks
the Thailand Research Fund for the award of a Royal Golden
Jubilee Scholarship through Professor Somsak Ruchirawat. We
also acknowledge the use of the Chemical Database Service and
the EPSRC Mass Spectrometry Swansea Service Centre.
7 N. S. Josephsohn, M. L. Snapper and A. H. Hoveyda, J. Am. Chem.
Soc., 2004, 126, 3734–3735.
8 (a) A. J. Williams, S. Chakthong, D. Gray, R. M. Lawrence and T.
ˇ
Gallagher, Org. Lett., 2003, 5, 811–814; (b) J. F. Bower, J. Svenda, A. J.
Williams, J. P. H. Charmant, R. M. Lawrence, P. Szeto and T. Gallagher,
Org. Lett., 2004, 6, 4727–4730.
9 J. F. Bower, P. Szeto and T. Gallagher, Chem. Commun., 2005, 46,
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10 M. Eskici and T. Gallagher, SYNLETT, 2000, 1360–1362; B. J. Littler,
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