Use of lithiated chiral o -sulfinylbenzyl carbanions for the one-pot building of linear fragments containing up to four connected stereocenters

Article abstract of DOI:10.1021/jo3025434

The reaction of o-sulfinylbenzyl carbanions with prochiral Michael acceptors, such as differently sized cycloalkenones, proceeded with high levels of stereoselectivity, generating molecules containing up to three asymmetric carbon centers in just one synthetic step. All these reactions involved the use of either a proton or an acylating reagent as the final electrophile. Furthermore, the trapping of the enolate resulting from Michael addition with prochiral electrophiles, such as aldehydes or N-sulfonylimines, allowed the highly stereoselective synthesis of densely functionalized compounds containing four chiral centers in just a one-pot sequence, the stereochemical outcome of the sequence being controlled by the sulfinyl auxiliary.

Full text of DOI:10.1021/jo3025434

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Article
Use of Lithiated Chiral ortho-Sulfinyl Benzyl Carbanions for the One-pot
Building of Linear Fragments Containing up to Four Connected Stereocenters
José Luis García Ruano, Esther Torrente, and Ana M. Martin-Castro
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo3025434 • Publication Date (Web): 20 Dec 2012
Downloaded from http://pubs.acs.org on December 30, 2012
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Use of Lithiated Chiral orthoꢀSulfinyl Benzyl
Carbanions for the One-pot Building of Linear
Fragments Containing up to Four Connected
Stereocenters.
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José Luis García Ruano,* Esther Torrente, and Ana M. Martín-Castro*
Departamento de Química Orgánica; Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid,
Spain.
joseluis.garcia.ruano@uam.es; martin.castro@uam.es
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
Dedicated to the memory of Dr. Christian G. Claessens
SYNOPSIS TOC (TABLE OF CONTENTS GRAPHIC)
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n
*
H
CN
O
E
O
1
2
3
4
5
6
7
R
*
Me
*
Me
Me
*
*
1. LiHMDS (1.1 equiv)
XH
1. LiHMDS (1.1 equiv)
THF, -78 ºC
H
H
R
THF, -78 ºC
CN
CN
*
*
H
O
R
O
2.
2.
SOTol
SOTol
(1.3 equiv)
SOTol
(1.3 equiv)
3.
R
H
8
9
n
3. E+
X (X = O, NSO2Tol)
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R = H, Me; n = 1-3; E+ = H+ (52-75%, up to 96:4 dr)
R = Me; n = 1; E+ = R'COCl (64-72%, 96:4 dr)
R = O (60-80%, up to 91:9 dr)
R = NSO2Tol (86-74%, up to 90:10 dr)
ABSTRACT.
The reaction of orthoꢀsulfinyl benzyl carbanions with prochiral Michael acceptors, such as differently
sized cycloalkenones, proceeded with high levels of stereoselectivity, generating molecules containing
up to three asymmetric carbon centers in just one synthetic step. All these reactions involved the use of
either a proton or an acylating reagent as the final electrophile. Furthermore, the trapping of the enolate
resulting from Michael addition with prochiral electrophiles, such as aldehydes or Nꢀsulfonyl imines,
allowed the highly stereoselective synthesis of densely functionalized compounds containing four chiral
centers in just a oneꢀpot sequence, the stereochemical outcome of the sequence being controlled by the
sulfinyl auxiliary.
KEYWORDS: asymmetric synthesis, quaternary carbons, benzyl carbanions, Michael addition,
sulfoxides, remote stereocontrol.
Introduction
Molecular fragments containing several connected stereogenic carbon atoms are present in many
natural products. Asymmetric cycloadditions provide the most efficient method for the simultaneous
creation of up to four asymmetric centers in only one synthetic step and have been widely used in the
synthesis of cyclic substrates.1ꢀ14 By contrast, the preparation of linear fragments containing more than
two connected asymmetric centers in only one synthetic step, usually requires the concatenation of two
(or more) reactions susceptible to be applied in oneꢀpot sequence. A very simple strategy for achieving
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these processes would involve the trapping of the intervening enolates resulting from the Michael
reactions with suitable electrophiles (Scheme 1). Hence, the Michael reactions of prochiral carbanions
with activated olefins would provide enolates containing two stereocenters, and the trapping of such
enolates with prochiral electrophiles would provide acyclic compounds with up to four connected
asymmetric carbon atoms.
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Scheme1. Strategy for obtaining linear fragments containing up to four connected stereocenters.
Despite the apparent simplicity of this strategy, to our knowledge, there are no reported papers
illustrating it. Two main problems limit the application of this strategy to the synthesis of acyclic
compounds. One of them is the difficulty of finding proper prochiral nucleophiles capable of reacting
stereoselectively in Michael additions. The second one derives from the required stereocontrol of the
second step, which imposes the regioselective formation of the enolate and the facial discrimination of
the favored regioisomer. We have recently reported that the orthoꢀsulfinyl group is an efficient
stereoselectivity controller of the configuration of benzyl carbanions in their reactions with different
electrophiles (Equation 1a, Scheme 2).15 Amongst them, 2ꢀpꢀtolylsulfinyl derivatives of ethylbenzene
and benzyl fluoride have been satisfactorily used as precursors of the nucleophiles used in Michaelꢀtype
processes with sulfonylethylenes and unsaturated tꢀbutyl esters (Equation 1b, Scheme 2).16 However, all
the attempts starting from unsaturated carbonyl compounds proved to be unsuccessful and afforded
complex mixtures as the result of a competence between the 1,2ꢀ and 1,4ꢀaddition processes (ethyl
esters also gave similarly complex mixtures).
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Scheme 2. Reported strategies for the asymmetric construction of two vicinal stereocenters based on the
use of a sulfinyl group as remote chiral inductor.
On the other hand, we have also reported the high efficiency of the orthoꢀsulfinyl group for the
configurational stabilization of the benzyl carbanions derived from αꢀalkyl phenylacetonitriles (I)
(Equation 2, Scheme 3), allowing the construction of quaternary stereocenters in their reactions with
alkylating17 and acylating18 reagents. Taking into account that these tertiary carbanions are softer than
the previously commented secondary ones (Equation 1b, Scheme 2), and, therefore, presumably more
efficient in Michaelꢀtype processes, we decided to use compounds 1 as precursors of the nucleophiles
depicted in Scheme 1. This would determine the formation of linear fragments with up to four
stereogenic centers, the first one being quaternary, in a oneꢀpot process (Equations 3, Scheme 3), which
would be an even more relevant synthetic challenge.19, 20 Moreover, the stability of the enolates resulting
from these Michael reactions could be substantially stabilized by chelation (A in Equation 3, Scheme 3),
thus preventing or minimizing the retroꢀMichael processes, and fixing one conformation of the enolate
with their two faces sterically very well differenciated and, therefore, susceptible to evolve
stereoselectively in the presence of appropriate electrophiles.
We report herein the results obtained in the Michael reactions of cyclic and acyclic enones with
the anion derived from 2ꢀmethylꢀ[2ꢀ(pꢀtolylsulfinyl)phenyl]acetonitrile (1) affording ketones with two
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connected asymmetric centers, one of them quaternary (Equation 3a, Scheme 3). Additionally, the in
situ trapping of the enolates formed in these reactions with acylating reagents (one-pot Michaelꢀ
acylation processes, Equation 3b, Scheme 3) as well as with aldehydes or aldimines (one-pot Michaelꢀ
aldol processes, Equation 3c, Scheme 3), allowing the simultaneous creation highly functionalized
linear fragments containing three or four connected asymmetric centers in only one synthetic step, will
also be presented.
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Scheme 3. Proposed strategies for the asymmetric synthesis of fragments containing two, three or four
connected stereocenters, the first one being quaternary.
Results and Discussion
Initially we studied the reaction of 2ꢀmethylꢀ[2ꢀ(pꢀtolylsulfinyl)phenyl]acetonitrile,17 as an
epimeric 50:50 mixture at the benzylic carbon atom (1 + 1’), with cyclopentꢀ2ꢀenone under different
experimental conditions (Table 1, entries 1ꢀ4). The use of THF as the solvent afforded the best
conversions into diastereomerically enriched mixtures of isomers 2a and 2b (Table 1, entries 1ꢀ3), 2a
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being the major product under all the assayed conditions. The highest yield (75%) and
diastereoselectivity (dr 95:5) were obtained with LiHMDS (Table 1, entry 3). A substantial erosion of
both reactivity (40% conversion) and stereoselectivity (dr 80:20) was observed in the presence of 12ꢀ
crownꢀ4 ether, which suggests that a relevant role should be played by the cation Li+ in the course of the
process (Table 1, entry 4). These reactions conducted under NaHMDS (dr 80:20, Table 1, entry 2) or
KHMDS (dr 85:15, Table 1, entry 1) gave lower stereoselectivities.
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When the size of the cycloalkenone ring became larger, the stereoselectivity decreased. Thus, the
reactions of 1 + 1’ with cyclohexꢀ2ꢀenone (Table 1, entry 5) and cycloheptꢀ2ꢀenone (Table 1, entry 6),
both under LiHMDS, also afforded mixtures of two diastereoisomers, with 85:15 and 82:18 dr,
respectively. The use of 2ꢀmethylꢀ2ꢀcyclopentenone as the electrophile afforded a mixture of only two
isomers, 5a and 5b, despite an additional stereocenter was created in the reaction (Table 1, entry 7). The
stereoselectivity was similar (96:4 dr) to that observed in the reaction with cyclopentenone (compare
entries 3 and 7, Table 1), which suggests that the resulting isomers in both reactions should be epimers
at the same carbon. Unfortunately, the reaction of 1 + 1’ with 3ꢀmethylcyclopentꢀ2ꢀenone, which would
provide adducts containing two adjacent quaternary stereocentres, proved to be unsuccessful and the
unaltered starting materials were recovered after long reaction times.
Table 1. Reactions of 2ꢀmethylꢀ[2ꢀ(pꢀtolylsulfinyl)phenyl]acetonitrile (1 + 1’) with different
cycloalkenones.
entry
base (additive)
KHMDS
NaHMDS
time (min) product
n
R
Yield (%)a d.r. (a:b)
1
5
5
1
H
68
65
85:15
80:20
2a + 2b
2a + 2b
2
1
H
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3
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5
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7
LiHMDS
5
1
1
2
3
1
H
H
H
H
91
n.d.b
95:5
2a + 2b
2a + 2b
3a + 3b
4a + 4b
5a + 5b
1
2
3
4
5
6
7
8
LiHMDS (12ꢀcrownꢀ4 ether) 15
80:20
85:15
82:18
96:4
LiHMDS
LiHMDS
LiHMDS
5
5
5
70
52
Me 67
aIsolated yield for diastereoisomeric a + b mixtures. b40% Conversion.
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14
The behavior of the benzylic carbanion derived from 1 + 1’ in the presence of acyclic Michael
acceptors, such as α,βꢀunsaturated methyl ketones and esters, was investigated next. These reactions
also gave mixtures of only two diastereoisomers under mild experimental conditions (ꢀ78 ºC), in good
yields (Table 2). The reaction with methyl vinyl ketone afforded a 85:15 mixture of 6a and 6b (Table 2,
entry 1), which should be obviously epimeric at the benzylic carbon, since this is the only stereocenter
formed in the reaction. The dr value was identical to that obtained in the reaction with cyclohexanone
(Table 1, entry 6). The reaction with ethyl acrylate was even more stereoselective, and yielded a mixture
of epimers 8a and 8b (Table 2, entry 3) with identical dr value (95:5) to that obtained from
cyclopentenone (Table 1, entry 3). The reactions of 1 + 1’ with both βꢀsubstituted enonic and acrylic
systems also afforded mixtures of two diastereoisomers, despite two asymmetric carbon atoms were
simultaneously created in the reaction. Mixtures of 7a + 7b (80:20 dr) and 9a + 9b (85:15 dr) were
obtained from (E)ꢀpentꢀ3ꢀenꢀ2ꢀone and ethyl crotonate, respectively (Table 2, entries 2 and 4). The
similar dr values obtained in the reactions of Tables 1 and 2 suggest that the obtained diastereoisomers
differ in all the cases in the configuration of the quaternary carbon atom. This suggestion is supported
by the fact that similar dr’s had been obtained in reactions of 1 + 1’ with alkylating17 and acylating18
reagents.
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Table 2. Reactions of 2ꢀmethylꢀ[2ꢀ(pꢀtolylsulfinyl)phenyl]acetonitrile (1 + 1’) with acyclic Michael
acceptors.
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entry
product
6a + 6b
R1
R2
Me
Yield (%)a
d.r. (a:b)
85:15
80:20 b
1
2
3
4
H
78
65
76
80
Me
H
Me
7a + 7b
8a + 8b
9a + 9b
OEt
95:5
85:15 b
Me
OEt
aIsolated yield for diastereoisomeric a + b mixtures. bThe configuration of Cꢀβ relative to carbonyl group was
not determined.
We next investigated tandem processes involving the trapping of some of the enolate
intermediates generated in the Michel addition reactions collected in Table 1, with a variety of
electrophiles different from proton. The reaction of 1 + 1’ with cyclopentꢀ2ꢀenone and further addition
of MeI was unsuccessful. Fortunately, the addition of acetyl chloride produced the expected products. A
diastereoisomeric 1:1 mixture was obtained in the reaction of the intermediate enolate generated from
cyclopentenone, whereas the enolate derived from 2ꢀmethylcyclopentꢀ2ꢀenone evolved in a highly
stereoselective manner (96:4 dr) when it was trapped by acetyl chloride or methyl chloroformate,
affording 10a and 11a, respectively (Scheme 4). The similarity between the stereochemical results of
this reaction with those observed when proton was used as the electrophile (Table 1, entry 7) suggests
that the stereochemical outcome is not dependent on the nature of the electrophile used in the second
step and, therefore, the resulting adducts do not differ in the configuration of the αꢀcarbonyl quaternary
stereocenter. So, the formation of fragments containing three connected stereogenic carbons, two of
them quaternary, is possible from these reactions.
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Me
Me
Me
Me
Tol
COR
Me
Tol
1
2
3
4
5
6
7
COR
CN
CN
H
a); b)
c)
O ;
a); b)
c)
∗
O ;
CN
O
O
O
H
S
O
O
S
S
Tol
1 + 1´
10a (R = Me) (64%; 96:4 dr)
11a (R = OMe) (72%; 96:4 dr)
R = Me (70%; 50:50 dr)
8
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Conditions: a) LiHMDS (1.2 equiv), THF, -78 ºC; b) enone (1.3 equiv); c) RCOCl (2.5 equiv)
Scheme 4. Tandem Michael addition/acylation sequences resulting from reactions of 1 + 1’ with
cyclopentꢀ2ꢀenone or 2ꢀmethylcyclopentꢀ2ꢀenone, and then with R’COCl.
Finally, the intermediate enolates of the conjugate addition were treated with prochiral
electrophiles (aldehydes and aldimines),21 so that chiral compounds with four contiguous stereocenters
could be formed in only one synthetic step (one-pot Michael addition/aldol reaction sequence), the
stereoselectivity of which would be controlled by the sulfinyl group present in the initially formed
carbanion. Thus, the enolate resulting from the reaction of 1 + 1’ with cyclopentꢀ2ꢀenone reacted with
an excess amount of a variety of both aliphatic and aromatic aldehydes yielding mixtures of only two
isomers, a and b, one of them being clearly predominant in all the cases (Table 3). The reactivity with
aliphatic aldehydes was seemingly dependent on the steric size of the aldehyde, iꢀPrꢀCHO being the less
reactive (Table 3, entry 3), whereas the stereoselectivity was similar for compounds 12ꢀ15 and the dr
values ranged between 87:13 and 91:9 (Table 3, entries 1ꢀ4). The reactivity of the aryl aldehydes (Table
3, entries 5ꢀ7) was dependent on the electronic density at the aromatic ring. As expected, it was lower
when electronꢀdonating groups were present in the aromatic ring (Table 3, entry 6). The presence of an
electronꢀwithdrawing NO2 substituent also slowed down the reaction although to lower extent (Table 3,
entry 7); this result was probably due to the fact that in this aldehyde the carbonyl group is no longer
conjugated with the aromatic ring and other effects rather than the electrostatic ones are playing a role.
The stereoselectivity was also lower (dr’s ranged between 86:14 and 80:20) than that observed for the
aliphatic aldehydes. Taking into account that a substantially higher dr had been obtained in the reaction
of 1 + 1’ with cyclopentꢀ2ꢀenone (95:5, Table 1, entry 3), the factors determining the composition of the
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diastereomeric mixtures must be different in both sets of reactions.
1
2
3
4
5
6
7
8
9
Our next goal was to apply the methodology described above to the development of the tandem
Michael addition / aldol reaction sequence to trapping the intervening enolates with Nꢀsulfonyl imines
(Table 3, entries 8ꢀ10). When the enolate formed in the reaction of 1 + 1’ with cyclopentꢀ2ꢀenone was
treated with both aliphatic (Table 3, entries 8ꢀ9) and aromatic (Table 3, entry 10) Nꢀsulfonyl aldimines,
mixtures of only two diastereoisomers were obtained with very good stereoselectivities (dr’s ranged
between 87:13 and 90:10) and a similar reactivity to that of the aliphatic aldehydes. The attempts to
perform the reactions of the intermediate enolate resulting from the reaction of 1 + 1’ with 2ꢀ
methylcyclopentꢀ2ꢀenone with aldehydes and Nꢀsulfonyl imines failed.
10
11
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Table 3. One-pot Michael addition/aldol reaction of 1 + 1’ with cyclopentꢀ2ꢀenone and then with
aldehydes and Nꢀsulfonyl imines.
HX
CN
R
CN
R
XH
C
C
H
H
Me
Me
Me
1) LiHMDS (1.2 equiv.),
THF, -78 ºC
H
H
∗
CN
O
O
O
H
H
S
2)
O
O
O
S
S
Tol
1 + 1´
(1.3 equiv.); -78 ºC
Tol
Tol
H
R
3)
a
b
X
-78 ºC
entry
electrophile
time (min.)a
product
d.r. (a : b)b Yield (%)c
R; X (equiv.)
1
2
3
4
5
6
7
8
9
Me; O (2.5)
5
12a + 12b 87:13
13a + 13b 90:10
14a + 14b 87:13
15a + 15b 91:9
16a + 16b 86:14
17a + 17b 85:15
79
80
65
72
77
60
75
68
72
Et; O (2.5)
5
iꢀPr; O (2.5)
180
5
iꢀBu; O (2.5)
Ph; O (5.0)
5
pꢀMeOC6H4; O (5.0)
pꢀNO2C6H4; O (2.5)
180
30
60
60
80:20
90:10
87:13
18a + 18b
19a + 19b
20a + 20b
nꢀPent; NSO2Tol (1.5)
iꢀPr; NSO2Tol (1.5)
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Ph; NSO2Tol (1.5)
5
89:11
74
21a + 21b
1
2
3
4
5
6
7
8
9
10
aReaction time in the presence of the electrophile (aldehyde or Nꢀsulfonyl imine). Diastereomeric ratio
b
1
determined by integration of wellꢀseparated signals of the H NMR spectra and by HPLC analysis of the
crude reaction. cYield of the diastereomeric mixture.
Chromatographic separation of the mixtures obtained in reactions of Tables 1ꢀ3 allowed us to
obtain the major a isomers in their diastereomerically pure form. However, usually the minor b isomers
could not be obtained as pure isomers (see S.I. for some exception) and their characterization was
performed from the spectroscopic data obtained from diastereomeric mixtures containing them.
11
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Configurational assignments
The impossibility of obtaining good crystals from the major diastereoisomers 2a and 5a
prevented us from assigning their absolute configurations by Xꢀray analysis. Fortunately, sulfones 22a
and 23a, prepared by oxidation of 2a and 5a, respectively, afforded suitable crystals, which allowed us
to unequivocally establish their absolute configurations as 2R,1´S and 2R,1’S,2’R, respectively, by Xꢀ
ray diffraction studies. As the sulfur configuration of sulfoxides 2a and 5a was previously known, its
absolute configurations were, therefore, unequivocally established as 2R,1’S,(S)S and 2R,1’S,2’R,(S)S,
respectively (Scheme 5).22 Since the stereochemical pathway of the conjugate addition should be similar
for all the assayed cycloalkenones, the absolute configuration 2R,1’S,(S)S was assigned to the major
isomers 3a and 4a (Table 1). The similar NOE effects between the Me and the H indicated in Scheme 5
(Eq. 2) observed for compounds 5a and 10a, indicative of a syn spatial arrangement of both groups in
the cyclopentenone fragment, suggest that both compounds have the same relative arrangement of the
substituents, although the stereochemical notation is different [2R,1’R,2’R,(S)S for 10a, see Scheme 5].
Since a similar stereochemical evolution must be predicted for reactions affording 10a and 11a, the
absolute configuration of 11a should be the same as that assigned to 10a.
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CN
CN
Me
Me
1
2
3
4
5
6
7
8
(S)
(S)
O
O
(R)
(R)
m-CPBA (1.5 equiv.)
H
H
O
[Eq. 1]
SO2Tol
(S)S
CH2Cl2, rt
(78%)
Tol
(2R,1´S)-22a
[2R,1´S,(S)S]-2a
determined by X-ray analysis
9
10
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CN
CN
CN
Me
H
Me
Me
Me
H
COMe
Me
m-CPBA (1.5 equiv.)
Me
NOE
NOE
(R)
(R)
(R)
(R)
(R)
(R)
O
O
O
[Eq. 2]
(S)
(R)
(S)
CH2Cl2, rt
(80%)
H
H
H
O
O
SO2Tol
(S)S
Tol
[2R,1´S,2'R,(S)S]-5a
(S)S
Tol
[2R,1´R,2'R,(S)S]-10a
(2R,1´S,2'R)-23a
determined by X-ray analysis
Scheme 5. Configurational assignment of the adducts from Michael additions and tandem Michael
addition/acylation sequences.
The absolute configurations of 14a [2R,1’S,2’S,1”R,(S)S] and 21a [2R,1’S,2’S,1”S,(S)S] were
unequivocally established by XꢀRay diffraction analysis.22 Therefore, all the major diastereoisomers
12a-18a (Table 3) should exhibit the same absolute configuration as 14a (although the R/S notation for
the Cꢀ1” stereocenter will be dependent on the nature of the R substituent of the corresponding
aldehyde). Analogously, the configurations of 19a and 20a should be identical to that of 21a.
Finally, from the assumption of a similar stereochemical evolution for all the reactions of Tables
1 and 2, we assigned the same configuration of the benzylic carbon atom to all the major isomers a
collected in both Tables. Thus, the absolute configurations of 6a and 8a were established as 2R,(S)S,
whereas those for 7a and 9a must be 2R,1’R,(S)S, with the configuration at Cꢀ1’ different to that of
adducts 2a-4a, because of the different stereochemistry of the double bonds of the respective starting
materials (Z in cycloalkenones and E in pentꢀ3ꢀenꢀ2ꢀone and ethyl crotonate).
The configuration of the isomers b at Table 1 was tentatively assigned as 2S,1’S,(S)S by NMR
(see S. I.), differing from that for the epimers a in the configuration of the benzylic quaternary carbon
atom. This assignment was mainly supported by the fact that the stereoselectivity observed in reactions
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of 1 + 1’ with cycloalkenones (Table 1) was similar to that obtained with methyl vinyl ketone and
1
2
3
methyl acrylate (Table 2, entries 1 and 3, respectively), where only one stereocenter was formed.
4
5
6
7
8
From the above configurational assignments, it can be concluded that the reactions affording 2,
5, 10 and 11, always produce epimeric mixtures at the benzylic Cꢀ2 carbon atom. This suggests a
completely stereoselective reaction of the intermediate enolate with the electrophile (proton or acyl
derivative) in those processes using 2ꢀmethylcyclopentꢀ2ꢀenone (synthesis of 5, 10 and 11,
respectively), which can be understood by assuming the thermodynamic equilibration of the carbanions
obtained in the conjugate addition step (Scheme 6). The carbanion exhibiting a cis arrangement between
the lone electron pair and the quaternary carbon atom, regardless of the configuration of the latter, must
be clearly favored in the equilibrium in order to avoid unstabilizing Me/quaternary carbon interactions.
Furthermore, species A and B could be additionally stabilized (with respect to A’ and B’) by formation
of chelated species with the sulfinyl oxygen, such as depicted in Scheme 6. Therefore, the electrophile
(H+ in Scheme 6) should approach the face exhibiting the electron pair in the anions derived both from
the major (anion A) and the minor (anion B) isomers. Consequently, the isomers a and b of compounds
2, 5, 10, and 11 will differ only in the configuration at the benzylic carbon Cꢀ2.
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11
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Scheme 6. Proposed thermodynamic intermediate equilibrium accounting for the stereoselectivity of the
reactions of 1 + 1’ and 2ꢀmethylcyclopentꢀ2ꢀenone.
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The results collected in Table 3 are indicative of a lower diastereoselectivity for the one-pot
Michael addition/aldol reaction sequences (< 90:10 dr) than that observed for the conjugate addition to
cyclopentꢀ2ꢀenone (95:5 dr, Table 1, entry 3), which is the first step common to all these sequences.
This different stereochemical outcome suggests that the isomers a and b obtained in the reactions of
Table 3 would differ in the configuration of one of the two stereocenters created in the reaction of the
intermediate enolate with the prochiral electrophile (aldehyde or imine), and both (a and b) should
exhibit the same configuration at the quaternary benzylic carbon atom (the compounds with the opposite
configuration at this center should be present in too low proportion as to be detected).
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Mechanistic proposal.
The stereochemical results obtained in the above described reactions can be explained as
follows. The reaction of 1 + 1’ with LiHMDS initially generates the boatꢀlike chelated sp3 carbanionic
species Ia (more stable than Ib from a steric and electrostatic viewpoint, Scheme 7) predominantly,17
with the metal associated to both the sulfinyl oxygen and the benzylic carbon atom. Such as it had been
postulated for the acylation processes of these carbanions,18 the carbonyl oxygen atom of
cycloalkenones may coordinate with the cation Li+, thus breaking the initial boatꢀlike chelate Ia and
generating a new intermediate species IIa. Intramolecular addition from IIa would afford IIIa with the
R configuration at the benzylic stereocenter, coincident with that observed for the major
diastereoisomers a. Simultaneously, the S configuration of the Cꢀβ atom at the cycloalkenone ring can
also be predicted from this approach (Scheme 7). The formation of the chelated species IIIa, with the
lithium doubly stabilized, can be considered as crucial for the chemical success of these reactions,
because it is responsible for the shifting of the equilibrium involved in the Michael addition toward the
final product (otherwise, the steric demand of the quaternary center would favor the retroꢀMichael
process). Additionally, it is also determinant of the stereochemical control of the electrophilic approach,
which will take place to the less hindered face of the intermediate, generating the major
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diastereoisomers a in all the cases. Thus, when the electrophile is a proton, compounds 2aꢀ4a are
formed (Scheme 5). With prochiral electrophiles (aldehydes or imines) two new stereocenters will be
formed. The configuration at Cꢀα of the cyclopentenone ring will be S, such as can be predicted from
the stereochemical model proposed for the process, in complete agreement with the unequivocal
configurational assignment for 12a-21a (see above) and 12bꢀ21b (Scheme 7). The configuration of CꢀX
in these epimers will depend on the face of the C=X bond favoured for the approach of IIIa.
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3
4
5
6
7
8
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Scheme 7. Mechanistic proposal accounting for the stereochemical outcome of Michaelꢀtype additions
of carbanion derived from 1 + 1’ to cycloalkenones, and subsequent reaction with a proton or a prochiral
electrophile (aldehyde or imine).
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The A and B approaches of the electrophile (Scheme 7), both arranging the CꢀH bond inward the
cyclopentanone ring in order to minimize the steric interactions, are plausible. The smaller dipolar
repulsion in the approach A would make easier the formation of epimers a, thus justifying their
formation as the major products in reactions with acyclic enones (Table 2) and with 2ꢀmethylcyclopentꢀ
2ꢀenone.23, 24
1
2
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5
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From all the above results we can conclude that the orthoꢀsulfinyl group has proved to be highly
efficient as a stabilizer of the configuration of tertiary benzylic carbanions in their reactions with
Michael acceptors affording compounds bearing quaternary centers connected to other asymmetric
carbons. Additionally, the capture of the resulting enolates with acyl chlorides (one pot Michael
addition/acylation process) and aldehydes or Nꢀsulfonylimines (one pot Michael addition/aldolic
reaction) has allowed us the preparation of structural fragments respectively containing three connected
stereocenters (two quaternary carbons joined to the same tertiary carbon) and four consecutive
stereocentres (quaternaryꢀtertiaryꢀtertiaryꢀtertiary) in high enantiomeric purities. We are now extending
the scope of this methodology to the reactions to orthoꢀsulfinylated benzylcyanohydrins and
benzylamino nitriles and using this methodology for the preparation of natural product fragments.
EXPERIMENTAL SECTION
GENERAL PROCEDURES
1
NMR spectra were registered (300 and 75 MHz for H and 13C NMR, respectively) in CDCl3
solutions. 13C NMR spectra were acquired on a broad band decoupled mode. Melting points were
measured in open capillary tubes. Mass spectra (MS) were determined by EI, FAB and ESI, as indicated
in each case. High resolution mass spectra (HRMS) were performed by using a magneticꢀsector mass
analyzer (for FAB ionization mode) or timeꢀofꢀflight (TOF) mass analyzer (for EI and ESI ionization
modes), as indicated for each compound. All reactions were carried out in anhydrous solvents under
argon atmosphere. Commercially available anhydrous tetrahydrofuran (THF) and ethyl ether (Et2O)
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were dried over 4Å molecular sieves. Analytical thin layer chromatography (TLC) was performed using
preꢀcoated aluminiumꢀbacked plates and visualized by ultraviolet irradiation or KMnO4 stain.
Purification of reaction products was carried out by flash column chromatography using silica gel (230ꢀ
400 mesh) or by Combiflash system using normal phase column (ISCO). The diastereomeric excess (de)
of products was determined by chiral stationary phase HPLC. Commercially available Michael
acceptors and aldehydes were used without further purification.
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General
procedure
for
Michael
addition
reaction
of
2-methyl-[2-(p-
tolylsulfinyl)phenyl]acetonitrile. To a solution of diastereoisomerc 50:50 mixture of 2ꢀmethylꢀ[2ꢀ(pꢀ
tolylsulfinyl)phenyl]acetonitrile (1 + 1’, 40.0 mg, 0.15 mmol) in anhydrous THF (1.5 mL) at ꢀ78 °C
under argon was added LiHMDS (1M in THF) (162 ꢀL, 0.18 mmol). The mixture was stirred at ꢀ78 °C
for 5 min. and then 0.19 mmol of the corresponding Michael acceptor was added dropwise. The reaction
was monitored by TLC. Upon transformation of the starting material, the reaction was hydrolyzed using
the method indicated in each case. The mixture was extracted with CH2Cl2 (3 × 5 mL), dried (Na2SO4)
and the solvent was evaporated. The diastereoisomeric mixture was purified by flash column
chromatography or by Combiflash system using a normal phase column (ISCO), the used eluent was
indicated in each case.
[2R,1´S,(S)S] and [2S,1´S,(S)S]-2-(3´-Oxocyclopentyl)-2-[2-(p-tolylsulfinyl)phenyl]propanenitrile
(2a + 2b). Cyclopentꢀ2ꢀenone was used as the electrophile. The reaction mixture was stirred at ꢀ78 °C
for 5 min. following by hydrolysis with saturated aqueous NH4Cl (1 mL), to give a diastereoisomeric
95:5 mixture of 2a + 2b, from which 2a was separated and purified by flash column chromatography
using a Combiflash system (EtOAcꢀhexane gradient 10:90 to 100:0). Yield 91%, 47.9 mg (mixture 2a +
2b). Diastereoisomer [2R,1´S,(S)S]ꢀ2a: colorless oil; [α]20 ꢀ146.9 (c 1.2, CHCl3); IR (film): 3468,
D
1
2253, 1746, 1216, 1046, 729 cm−1; H NMR: δ 8.01ꢀ7.98 (m, 1H), 7.75ꢀ7.59 (m, 1H), 7.57ꢀ7.53 (m,
2H), 7.45 and 7.28 (AA´BB´ system, 4H), 2.99ꢀ2.89 (m, 1H), 2.47ꢀ2.21 (m, 2H), 2.38 (s, 3H), 2.05 (s,
13
3H), 1.91ꢀ1.73 (m, 2H), 1.64ꢀ1.59 (m, 2H) ppm; C NMR: δ 214.5, 143.7, 141.9, 140.9, 137.6, 132.2,
130.2 (2C), 129.7, 127.7, 126.0 (2C), 121.5, 77.2, 47.3, 46.9, 40.9, 38.2, 26.2, 25.3, 21.3 ppm; MS
(FAB+) m/z 352 [M+H]+ (100), 259 (15); HRMS (ESI+) calcd. for C21H22NO2S: 352.1371; found:
352.13800. Diastereoisomer [2S,1´S,(S)S]ꢀ2b (significant chemical shifts obtained from an epimeric
86:14 mixture 2a + 2b): 1H NMR: δ 7.95ꢀ7.91 (m, 1H), 7.89ꢀ7.85 (m, 1H), 3.43 (m, 1H), 2.65 (m, 1H),
1.65ꢀ1.59 (m, 1H), 2.10 (s, 3H) ppm. The diastereoisomeric excess was determined by HPLC and by
1
integration of wellꢀdefined H NMR signals of the crude reaction. HPLC analysis: Chiralpack AD
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[hexaneꢀiPrOH (80:20) eluent; flow = 1 mL/min]; major diastereoisomer 2a: tR = 26.8 min. (95%) and
minor diastereoisomer 2b: tR = 30.6 min. (5%).
1
2
3
4
5
6
7
8
9
[2R,1´S,(S)S] and [2S,1´S,(S)S]-2-(3´-Oxocyclohexyl)-2-[2-(p-tolylsulfinyl)phenyl]propanenitrile
(3a + 3b). Cyclohexꢀ2ꢀenone was used as the electrophile. The reaction mixture was stirred at ꢀ78 °C for
5 min. and then it was hydrolyzed with saturated aqueous NH4Cl (1 mL), to give a diastereoisomeric
86:14 mixture 3a + 3b, which was purified by flash column chromatography using a Combiflash system
(EtOAcꢀhexane gradient 10:90 to 100:0). Yield 70%, 38.3 mg (mixture 3a + 3b, colorless oil).
Diastereoisomer [2R,1´S,(S)S]ꢀ3a: IR (film): 3356, 2401, 1714, 756 cm−1; 1H NMR (86:14 mixture 3a +
3b): δ 7.95 (dd, J 3.2 and 5.9 Hz, 1H), 7.78ꢀ7.69 (m, 1H), 7.55ꢀ7.45 (m, 2H), 7.36 and 7.25 (AA´BB´
system, 4H), 2.76ꢀ2.64 (m, 1H), 2.52ꢀ2.10 (m, 4H), 2.37 (s, 3H), 2.03 (s, 3H), 1.96ꢀ1.86 (m, 1H), 1.64ꢀ
10
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60
13
1.55 (m, 2H), 1.12ꢀ0.95 (m, 1H) ppm; C NMR (86:14 mixture 3a + 3b): δ 208.4, 143.6, 141.8, 141.0,
138.1, 132.1, 130.2 (2C), 129.9, 128.2, 125.9 (2C), 125.4, 121.6, 77.2, 44.4, 40.6, 27.5, 26.7, 24.1, 23.8,
21.3 ppm; MS (FAB+) m/z 366 [M+H]+ (100), 225 (14); HRMS (ESI+) calcd. for C22H24NO2S:
366.1527; found: 366.1528. Diastereoisomer [2S,1´S,(S)S]ꢀ3b (significant chemical shifts obtained from
1
an epimeric 86:14 mixture 3a + 3b): H NMR: δ 7.89ꢀ7.86 (m, 1H), 7.78ꢀ7.69 (m, 1H), 7.55ꢀ7.45 (m,
2H), 7.38 and 7.26 (AA´BB´ system, 4H), 2.86 (tt, J 4.2 and 11.6 Hz, 1H), 2.38 (s, 3H), 2.00 (s, 3H),
1.81ꢀ1.67 (m, 2H), 0.91ꢀ0.82 (m, 1H) ppm; 13C NMR: δ 208.1, 143.7, 141.7, 140.4, 137.9, 130.7, 130.3,
130.1 (2C), 130.0, 128.1, 126.1 (2C), 121.4, 46.1, 43.1, 40.7, 26.6, 24.5, 23.6, 21.3 ppm. The
1
diastereoisomeric excess was determined by HPLC and by integration of wellꢀdefined H NMR signals
of the crude reaction. HPLC analysis: Chiralpack AD [hexaneꢀiPrOH (80:20) eluent; flow = 1 mL/min];
major diastereoisomer 3a: tR = 27.6 min. (86%) and minor diastereoisomer 3b: 30.0 min. (14%).
[2R,1´S,(S)S] and [2R,1´S,(S)S]-2-(3´-Oxocycloheptyl)-2-[2-(p-tolylsulfinyl)phenil]propanenitrile
(4a + 4b). Cycloheptꢀ2ꢀenone was used as the electrophile. The reaction mixture was stirred at ꢀ78 °C
for 5 min. and then it was hydrolyzed with saturated aqueous NH4Cl (1 mL), to give a diastereoisomeric
82:18 mixture 4a + 4b, from which 4a was separated and purified by flash column chromatography
using a Combiflash system (EtOAcꢀhexane gradient 10:90 to 100:0). Yield 52%, 29.6 mg (mixture 4a +
4b). Diastereoisomer [2R,1´S,(S)S]ꢀ4a: colorless oil; [α]20 ꢀ106.6 (c 0.8, CHCl3); IR (film): 3322,
D
2360, 1703, 1214, 754 cm−1; 1H NMR: δ 7.77ꢀ7.74 (m, 1H), 7.54 and 7.29 (AA´BB´ system, 4H), 7.52ꢀ
7.40 (m, 3H), 3.11ꢀ2.95 (m, 1H), 2.62ꢀ2.54 (m, 1H), 2.47ꢀ2.31 (m, 2H), 2.39 (s, 3H), 2.24ꢀ2.03 (m, 1H),
13
2.01ꢀ1.90 (m, 2H), 1.92 (s, 3H), 1.57ꢀ1.33 (m, 3H), 0.94ꢀ0.91 (m, 1H) ppm; C NMR: δ 211.4, 145.0,
141.5, 140.3, 138.2, 132.0, 130.5, 130.0 (2C), 127.2, 125.8 (2C), 125.6, 123.2, 77.2, 44.4, 43.9, 43.2,
33.0, 29.7, 28.7, 24.7, 21.3 ppm; MS (FAB+) m/z 380 [M+H]+ (100), 362 (15), 259 (17); HMRS
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(FAB+) calcd. for C23H26NO2S: 380.1684; found: 380.1678. Diastereoisomer [2S,1´S,(S)S]ꢀ4b
1
2
3
1
(significant chemical shifts obtained from an epimeric 82:18 mixture 4a + 4b): H NMR: δ 7.70ꢀ7.65
4
5
6
(m, 1H), 3.11ꢀ2.95 (m, 1H), 1.95 (s, 3H) ppm. The diastereoisomeric excess was determined by HPLC
1
and by integration of wellꢀdefined H NMR signals of the crude reaction. HPLC analysis: Chiralpack
7
8
9
AD [hexaneꢀiPrOH (80:20) eluent; flow = 1 mL/min]. Major diastereoisomer 4a: tR = 28.3 min. (82%)
and minor diastereoisomer 4b: tR = 32.6 min. (18%).
10
11
12
13
14
15
16
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20
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[2R,1´S,2´R,(S)S] and [2S,1´S,2´R,(S)S]-2-(2´-Methyl-3´-oxocyclopentyl)-2-[2-(p-tolylsulfinyl)
phenyl]propanenitrile (5a + 5b). 2ꢀMethylcyclopentꢀ2ꢀenone was used as the electrophile. The
reaction mixture was stirred at ꢀ78 °C for 5 min. and then it was hydrolyzed with saturated aqueous
NH4Cl (1 mL), to give a diastereoisomeric 96:4 mixture 5a + 5b, from which 5a was separated and
purified by flash column chromatography using a Combiflash system (EtOAcꢀhexane gradient 10:90 to
100:0). Yield 67%, 36.7 mg (mixture 5a + 5b). Diastereoisomer [2R,1´S,2´R,(S)S]ꢀ5a: colorless oil;
1
[α]20 ꢀ177.7 (c 1.0, CHCl3); IR (film): 3324, 2234, 1742, 1461, 811 cm−1; H NMR: δ 7.93ꢀ7.90 (m,
D
1H), 7.68ꢀ7.65 (m, 1H), 7.55ꢀ7.49 (m, 2H), 7.48 and 7.27 (AA´BB´ system, 4H), 2.76 (m, 1H), 2.38 (s,
3H), 2.34ꢀ2.31 (m, 1H), 2.20ꢀ2.14 (m, 1H), 2.10 (s, 3H), 2.03ꢀ1.84 (m, 1H), 1.80ꢀ1.71 (m, 2H), 0.98 (d,
J 6.9 Hz, 3H) ppm; 13C NMR: δ 217.4, 144.2, 141.8, 140.7, 138.3, 132.1, 130.1 (3C), 130.0, 127.2,
125.9 (2C), 122.3, 77.2, 53.1, 46.1, 36.5, 24.7, 24.0, 21.3, 15.7 ppm; MS (FAB+) m/z 366 [M+H]+
(100), 348 (17), 259 (12), 225 (20); HMRS (FAB+) calcd. for C22H24NO2S: 366.1537; found: 366.1541.
Diastereoisomer [2R,1´S,2´R,(S)S]ꢀ5b (significant chemical shifts obtained from an epimeric 82:18
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mixture 5a + 5b): H NMR: δ 7.75ꢀ7.70 (m, 1H), 3.01 (m, 1H), 0.48 (d, J 7.0 Hz, 3H) ppm. The
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diastereoisomeric excess was determined by HPLC and by integration of wellꢀdefined H NMR signals
of the crude reaction. HPLC analysis: Chiralpack AD [hexaneꢀiPrOH (80:20) eluent; flow = 1 mL/min].
Major diastereoisomer 5a: tR = 20.7 min. (96%) and minor diastereoisomer 5b: tR = 35.2 min. (4%).
[2R,(S)S] and [2S,(S)S]-2-Methyl-5-oxo-2-[2-(p-tolylsulfinyl)phenyl]hexanenitrile (6a + 6b).
Methyl vinyl ketone was used as the electrophile. The reaction mixture was stirred at ꢀ78 °C for 5 min.
and then it was hydrolyzed with saturated aqueous NH4Cl (1 mL), to give a diastereoisomeric 92:8
mixture 6a + 6b, from which 6a was separated and purified by flash column chromatography using
EtOAcꢀhexane (1:1) as the eluent. Yield 78%, 39.7 mg (mixture 6a + 6b). Diastereoisomer
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[2R,1´S,2´R,(S)S]ꢀ6a: white solid; m.p. 94ꢀ96 °C (EtOAcꢀhexane); [α]20 −111.3 (c 1.2, CHCl3); H
D
NMR: δ 7.89ꢀ7.86 (m, 1H), 7.61ꢀ7.58 (m, 1H), 7.56 and 7.27 (AA´BB´ system, 4H), 7.59ꢀ7.48 (m, 2H),
2.70ꢀ2.58 (m, 1H), 2.55ꢀ2.43 (m, 2H), 2.43ꢀ2.30 (m, 1H), 2.37 (s, 3H), 2.07 (s, 3H), 1.99 (s, 3H) ppm;
13C NMR: δ 205.8, 144.9, 141.5, 140.8, 138.0, 132.1, 130.1 (2C), 130.0, 129.8, 126.9, 125.9 (2C),
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123.3, 41.6, 39.4, 36.2, 29.8, 26.9, 21.3 ppm; MS (FAB+) m/z 340 [M+H]+ (100), 322 (12); HMRS
(FAB+) calcd. for C20H22NO2S: 340.1371; found: 340.1373. Diastereoisomer [2S,(S)S]ꢀ6b (significant
chemical shifts obtained from an epimeric 92:8 mixture 6a + 6b): 1H NMR: δ 2.14 (s, 3H), 1.95 (s, 3H)
ppm.
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[2R,3S,(S)S] and [2S,3S,(S)S]-2,3-Dimethyl-5-oxo-2-[2-(p-tolylsulfinyl)phenyl]hexanenitrile (7a +
7b). (E)ꢀPentꢀ3ꢀenꢀ2ꢀone was used as the electrophile. The reaction mixture was stirred at ꢀ78 °C for 5
min. and then it was hydrolyzed with saturated aqueous NH4Cl (1 mL), to give a diastereoisomeric 92:8
mixture 7a + 7b, which was purified by flash column chromatography using EtOAcꢀhexane (1:1) as the
eluent. Yield 65%, 34.4 mg (mixture 7a + 7b, colorless oil). Diastereoisomer [2R,3S,(S)S]ꢀ7a: 1H NMR
(from a 92:8 mixture 7a + 7b): δ 7.76ꢀ7.65 (m, 2H), 7.53 and 7.27 (AA´BB´ system, 4H), 7.52ꢀ7.40 (m,
2H), 3.16 (dqd, J 2.5, 6.4 and 12.9 Hz, 1H), 2.59 (dd, J 10.7 and 16.9 Hz), 2.40ꢀ2.34 (m, 1H), 2.38 (s,
3H), 2.08 (s, 3H), 2.06 (s, 3H), 1.15 (d, J 6.4 Hz, 3H) ppm; 13C NMR (from a 92:8 mixture 7a + 7b): δ
206.0, 145.0, 141.3, 140.7, 138.8, 131.8, 130.7, 130.1 (2C), 129.3, 127.9, 125.6 (2C), 122.1, 46.9, 39.1,
30.6, 30.1, 24.7, 21.3, 15.3 ppm; MS (FAB+) m/z 354 [M+H]+ (100), 336 (10); HMRS (FAB+) calcd.
for C21H24NO2S: 354.1528; found: 354.1536. Diastereoisomer [2S,3S,(S)S]ꢀ7b (significant chemical
shifts obtained from an epimeric 92:8 mixture 7a + 7b): 1H NMR: δ 8.01ꢀ7.88 (m, 1H), 2.65 (dd, J 10.5
and 17.1 Hz, 1H), 2.12 (s, 3H), 2.05 (s, 3H), 1.10 (d, J 6.6 Hz, 3H) ppm.
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[4R,(S)S] and [4S,(S)S] Ethyl 4-Cyano-4-[2-(p-tolylsulfinyl)phenyl]pentanoate (8a + 8b). Ethyl
acrylate was used as the electrophile. The reaction mixture was stirred at ꢀ78 °C for 5 min. and then it
was hydrolyzed with saturated aqueous NH4Cl (1 mL), to give a diastereoisomeric 83:17 mixture 8a +
8b, which was purified by flash column chromatography using EtOAcꢀhexane (1:2) as the eluent. Yield
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76%, 42.1 mg (mixture 8a + 8b, colorless oil). Diastereoisomer [2R,3S,(S)S]ꢀ8a: H NMR (from an
83:17 mixture 8a + 8b): δ 7.84ꢀ7.81 (m, 1H), 7.59ꢀ7.51 (m, 1H), 7.50ꢀ7.46 (m, 2H), 7.49 and 7.26
(AA´BB´ system, 4H), 4.15ꢀ4.04 (m, 2H), 2.68ꢀ2.62 (m, 1H), 2.56ꢀ2.47 (m, 2H), 2.37 (s, 3H), 2.28ꢀ2.21
(m, 1H), 2.03 (s, 3H), 1.22 (t, 3H, J 7.1 Hz) ppm; 13C NMR (from an 83:17 mixture 8a + 8b): δ 171.5,
144.9, 141.4, 140.8, 137.9, 132.1, 130.1, 129.9 (2C), 127.0, 125.9, 125.7 (2C), 123.1, 60.8, 41.7, 37.4,
30.5, 26.7, 21.3, 14.1 ppm; MS (FAB+) m/z 370 [M+H]+ (100), 352 (14); HMRS (FAB+) calcd. for
C21H24NO3S: 370.1477; found: 370.1460. Diastereoisomer [2S,(S)S]ꢀ8b (significant chemical shifts
obtained from an epimeric 83:17 mixture 8a + 8b): 1H NMR: δ 1.95 (s, 3H), 1.24 (t, 3H, J 7.2 Hz) ppm.
[3S,4R,(S)S] and [3S,4S,(S)S] Ethyl 4-Cyano-3-methyl-4-[2-(p-tolylsulfinyl)phenyl]pentanoate (9a
+ 9b). Ethyl (E)ꢀbutꢀ2ꢀenoate was used as the electrophile. The reaction mixture was stirred at ꢀ78 °C
for 5 min. and then it was hydrolyzed with saturated aqueous NH4Cl (1 mL), to give a diastereoisomeric
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82:18 mixture 9a + 9b, which was purified by flash column chromatography using EtOAcꢀhexane (1:2)
as the eluent. Yield 80%, 46.0 mg (mixture 9a + 9b, colorless oil). Diastereoisomer [2R,3S,(S)S]ꢀ9a: 1H
NMR (from an 82:18 mixture 9a + 9b): δ 7.91ꢀ7.84 (m, 1H), 7.74ꢀ7.66 (m, 1H), 7.57 and 7.27 (AA´BB´
system, 4H), 7.50ꢀ7.42 (m, 2H), 4.18ꢀ4.04 (m, 2H), 3.18ꢀ3.09 (m, 1H), 2.46ꢀ2.26 (m, 2H), 2.38 (s, 3H,
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s, 3H), 1.90 (s, 3H), 1.28ꢀ1.18 (m, 3H), 0.94 (d, 3H, J 6.7 Hz) ppm; C NMR (from an 82:18 mixture
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9a + 9b): δ 171.2, 144.9, 141.6, 141.0, 138.8, 132.0, 131.0, 130.1, 129.9, 129.8 (2C), 127.7, 125.8 (2C),
121.6, 60.7, 47.8, 40.4, 38.3, 27.1, 21.3, 14.1 ppm; MS (FAB+) m/z 384 [M+H]+ (100), 366 (10);
HMRS (FAB+) calcd. for C22H26NO3S: 384.1633; found: 384.1625. Diastereoisomer [3S,4S,(S)S]ꢀ9b
(significant chemical shifts obtained from an epimeric 82:18 mixture 9a + 9b):1H NMR: δ 7.54 and 7.28
(AA´BB´ system, 4H), 4.18ꢀ4.04 (m, 2H), 3.31ꢀ3.18 (m, 1H), 2.65 (dd, J 4.1 and 15.6 Hz, 1H), 2.46ꢀ
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2.26 (m, 2H), 2.04 (s, 3H), 1.02 (d, 3H, J 6.7 Hz) ppm; C NMR: δ 171.3, 144.7, 141.4, 140.5, 138.4,
131.9, 130.0 (2C), 128.0, 125.5 (2C), 121.9, 60.8, 48.6, 39.7, 37.2, 24.8, 21.3, 14.1 ppm.
General procedure for tandem Michael addition/acylation sequences of 2-methyl-[2-(p-
tolylsulfinyl)phenyl]acetonitrile. To a solution of a diastereoisomeric 50:50 mixture of 2ꢀmethylꢀ[2ꢀ(pꢀ
tolylsulfinyl)phenyl]acetonitrile (1 + 1’, 40.0 mg, 0.15 mmol) in anhydrous THF (1.5 mL) at ꢀ78 °C
under argon was added LiHMDS (1M in THF) (162 ꢀL, 0.18 mmol). The mixture was stirred at ꢀ78 °C
for 5 min. and then 2ꢀmethylcyclopentꢀ2ꢀenone (18.2 mg, 0.19 mmol) was added dropwise. The reaction
mixture was stirred at this temperature for 5 min. and then the corresponding electrophile was added.
The reaction was monitored by TLC. Upon transformation of the substrate (5 min.), the reaction was
hydrolyzed with saturated aqueous NH4Cl (1 mL). The layers were separated and the aqueous layer was
extracted with CH2Cl2 (3 × 5 mL), dried (Na2SO4) and the solvent was evaporated under vacuum. The
diastereoisomeric mixture was purified by flash column chromatography using the eluent indicated in
each case.
[2R,1´R,2´R,(S)S]
and
[2S,1´R,2´R,(S)S]-2-(2´-Acetyl-2´-methyl-3´-oxocyclopentyl)-2-[2-(p-
tolylsulfinyl)phenyl]propanenitrile (10a + 10b). Acetyl chloride (0.18 mmol), was used as the
electrophile. The reaction mixture was stirred at ꢀ78 °C for 5 min. to give a diastereoisomeric 96:4
mixture 10a + 10b, from which 10a was separated and purified by flash column chromatography using
EtOAcꢀhexane (1:2) as the eluent. Yield 64%, 39.1 mg (mixture 10a + 10b). Diastereoisomer
[2R,1´R,2´R,(S)S]ꢀ10a: colorless oil; [α]20 ꢀ107.7 (c 2.0, CHCl3); 1H NMR: δ 7.66ꢀ7.65 (m, 1H), 7.62
D
and 7.33 (AA´BB´ system, 4H), 7.44ꢀ7.40 (m, 3H), 3.97 (m, 1H), 2.76ꢀ2.60 (m, 1H), 3.44ꢀ2.34 (m, 2H),
2.38 (s, 3H), 2.33ꢀ2.14 (m, 1H), 2.12 (s, 3H), 1.90 (s, 3H), 0.83 (s, 3H) ppm; 13C NMR: δ 215.8, 168.1,
149.1, 146.6, 141.0, 140.9, 138.8, 131.6, 130.4, 129.8 (2C), 126.9, 125.3 (2C), 121.0, 77.2, 55.3, 44.2,
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30.2, 25.7, 21.3, 20.6, 20.2, 11.9 ppm; MS (FAB+) m/z 408 [M+H]+ (100), 366 (20); HMRS (FAB+)
calcd. for C24H26NO3S: 408.1633; found: 408.1624. Diastereoisomer [2S,1´R,2´R,(S)S]ꢀ10b (significant
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chemical shifts obtained from an epimeric 96:4 mixture 10a + 10b): H NMR: δ 7.89ꢀ7.85 (m, 1H),
7.65ꢀ7.63 (m, 1H), 2.02 (s, 3H), 1.88 (s, 3H), 0.81 (s, 3H) ppm.
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[1S,5R,1´R,(S)S] and [1S,5R,1´S,(S)S] Methyl 5-{1´-Cyano-1´-[2-(p-tolylsulfinyl)phenylethyl]}-1-
methyl-2-oxocyclopentanecarboxylate (11a + 11b). Methyl chloroformate (0.18 mmol), was used as
electrophile. The reaction mixture was stirred at ꢀ78 °C for 5 min. to give a diastereoisomeric 96:4
mixture 11a + 11b, from which 11a was separated and purified by flash column chromatography using
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EtOAcꢀhexane (1:2) as the eluent. Yield 72%, 45.7 mg (mixture 11a + 11b). Diastereoisomer
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[1S,5R,1´R,(S)S]ꢀ11a: white solid; m.p. 103ꢀ105 °C (CH2Cl2ꢀhexane); [α]20 ꢀ141.5 (c 0.8, CHCl3); H
D
NMR: δ 7.69ꢀ7.67 (m, 1H), 7.62 and 7.27 (AA´BB´ system, 4H), 7.44ꢀ7.41 (m, 3H), 4.06 (m, 1H), 3.82
(s, 3H), 2.73ꢀ2.67 (m, 1H), 2.49ꢀ2.36 (m, 2H), 2.38 (s, 3H), 2.28ꢀ2.20 (m, 1H), 1.96 (s, 3H), 0.96 (s, 3H)
ppm; 13C NMR: δ 220.1, 152.8 , 148.9, 146.6, 141.0, 140.8, 138.7, 131.6, 130.5, 129.8 (2C), 126.8,
125.3 (2C), 121.3, 77.2, 55.2, 55.0, 44.2, 29.7, 25.6, 21.3, 20.1, 11.8 ppm; MS (FAB+) m/z 424 [M+H]+
(100), 406 (15), 225 (11); HMRS (FAB+) calcd. for C24H26NO4S: 424.1583; found: 424.1569.
Diastereoisomer [1S,5S,1´R,(S)S]ꢀ11b (significant chemical shifts obtained from an epimeric 96:4
mixture 11a + 11b): 1H NMR: δ 3.80 (s, 3H) ppm.
General procedure for tandem Michael addition/aldol reaction of 2-methyl-[2-(p-
tolylsulfinyl)phenyl]acetonitrile with aldehydes and N-sulfonyl imines. To a solution of a
diastereoisomerc 50:50 mixture of 2ꢀmethylꢀ[2ꢀ(pꢀtolylsulfinyl)phenyl]acetonitrile (1 + 1’, 40.0 mg,
0.15 mmol) in anhydrous THF (1.5 mL) at ꢀ78 °C under argon was added LiHMDS (1M in THF) (162
ꢀL, 0.18 mmol). The mixture was stirred at ꢀ78 °C for 5 min. and then 2ꢀmethylcyclopentꢀ2ꢀenone (18.2
mg, 0.19 mmol) was added dropwise. The reaction mixture was stirred at this temperature for 5 min.
and then the corresponding electrophile was added. The reaction was monitored by TLC. Upon
transformation of the substrate, the reaction was hydrolyzed with a methanolic HCl solution (1 mL).
The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 × 5 mL), dried (Na2SO4)
and the solvent was evaporated under vacuum. The diastereoisomeric mixture was purified by flash
column chromatography using the eluent indicated in each case.
[2R,1´S,2´S,1´´R,(S)S] and [2R,1´S,2´R,1´´R,(S)S]-2-[(1´´-Hydroxyethyl)-3´-oxocyclopentyl]-2-[2-
(p-tolylsulfinyl)phenyl]propanenitrile (12a + 12b). A 1.78 M solution of acetaldehyde (0.37 mmol) in
anhydrous THF was used as the electrophile. The reaction mixture was stirred at ꢀ78 °C for 5 min. and
then it was hydrolyzed with a methanolic HCl solution to give a diastereoisomeric 83:17 mixture 12a +
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12b, from which 12a was separated and purified by flash column chromatography using a mixture
EtOAcꢀhexane (2:1) as the eluent. Yield 79%, 46.8 mg (mixture 12a + 12b). Diastereoisomer
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[2R,1´S,2´S,1´´R,(S)S]ꢀ12a: colorless oil; [α]20 ꢀ116.3 (c 1.6, CHCl3); IR (film): 3416, 2972, 2233,
D
1741, 755 cm−1; 1H NMR: δ 7.63 and 7.33 (AA´BB´ system, 4H), 7.56ꢀ7.43 (m, 4H), 3.76ꢀ3.69 (m, 1H),
3.46ꢀ3.38 (broad s, 1H), 3.03ꢀ2.96 (m, 1H), 2.41 (s, 3H), 2.41ꢀ2.33 (m, 4H), 1.93 (s, 3H), 1.94ꢀ1.92 (m,
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1H), 1.10 (d, J 6.5 Hz, 3H) ppm; C NMR: δ 216.3, 145.4, 141.8, 138.5, 138.3, 132.5, 132.3, 130.8,
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130.2 (2C), 126.1, 125.5 (2C), 123.6, 77.2, 67.4, 54.6, 46.8, 39.6, 24.4, 21.4 (2C), 20.4 ppm; MS (ESI+)
m/z 396 [M+H]+ (100), 378 (76), 352 (26), 225 (30); HMRS (ESI+) calcd. for C23H26NO3S: 396.1627;
found: 396.1647. Diastereoisomer [2R,1´S,2´R,1´´S,(S)S]ꢀ12b (significant chemical shifts obtained from
an epimeric 87:13 mixture 12a + 12b): 1H NMR: δ 7.79ꢀ7.75 (m, 1H), 7.64ꢀ7.62 (m, 1H), 2.37 (s, 3H),
2.06 (s, 3H), 1.12 (d, J 6.5 Hz, 3H) ppm. The diastereoisomeric excess was determined by HPLC and by
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integration of wellꢀdefined H NMR signals of the crude reaction. HPLC analysis: Chiralpack AD
[hexaneꢀiPrOH (80:20) eluent; flow = 1 mL/min.]. Major diastereoisomer 12a: tR = 15.0 min. (87%) and
minor diastereoisomer 12b: tR = 16.6 min. (13%).
[2R,1´S,2´S,1´´R,(S)S] and [2R,1´S,2´R,1´´R,(S)S]-2-[2´-(1´´-Hydroxypropyl)-3´-oxocyclopentyl]-2-
[2-(p-tolylsulfinyl)phenyl]propanenitrile (13a + 13b). Propionaldehyde (0.37 mmol) was used as the
electrophile. The reaction mixture was stirred at ꢀ78 °C for 5 min. and then it was hydrolyzed with a
methanolic HCl solution to give a diastereoisomeric 90:10 mixture 13a + 13b, from which 13a was
separated and purified by flash column chromatography using a mixture EtOAcꢀhexane (1:1) as the
eluent. Yield 80%, 49.1 mg (mixture 13a + 13b). Diastereoisomer [2R,1´S,2´S,1´´R,(S)S]ꢀ13a: colorless
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oil; [α]20 ꢀ118.4 (c 1.2, CHCl3); IR (film): 3523, 3280, 2236, 1739, 759 cm−1; H NMR: δ 7.63 and
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7.33 (AA´BB´ system, 4H), 7.65ꢀ 7.52 (m, 1H), 7.54ꢀ7.43 (m, 3H), 3.81ꢀ3.74 (m, 1H), 3.44 (broad s,
1H), 2.61ꢀ2.45 (m, 1H), 2.43ꢀ2.27 (m, 3H), 2.41 (s, 3H), 2.00ꢀ1.88 (m, 2H), 1.95 (s, 3H), 1.61ꢀ1.40 (m,
2H), 0.65 (t, J 7.3 Hz, 1H) ppm; 13C NMR: 215.9, 145.9, 141.8, 138.7, 138.5, 132.4, 130.7, 130.6, 130.1
(2C), 126.2, 125.5 (2C), 123.5, 77.2, 73.3, 52.7, 46.9, 39.9, 26.9, 24.4, 21.3 (2C), 10.7 ppm; MS
(FAB+) m/z 410 [M+H]+ (100), 392 (96), 352 (15), 225 (44); HMRS (FAB+) calcd. for C24H28NO3S:
410.1789; found: 410.1790. Diastereoisomer [2R,1´S,2´R,1´´R,(S)S]ꢀ13b (significant chemical shifts
obtained from an epimeric 90:10 mixture 13a + 13b): 1H NMR: δ 7.79ꢀ7.75 (m, 1H), 3.98ꢀ3.92 (m, 1H),
0.47 (t, J 7.3 Hz, 1H) ppm. The diastereoisomeric excess was determined by HPLC and by integration
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of wellꢀdefined H NMR signals of the crude reaction. HPLC analysis: Chiralpack AD [hexaneꢀiPrOH
(80:20) eluent; flow = 1 mL/min]. Major diastereoisomer 13a: tR = 13.5 min. (90%) and minor
diastereoisomer 13b: tR = 25.7 min. (10%).
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[2R,1´S,2´S,1´´R,(S)S] and [2R,1´S,2´R,1´´R,(S)S]-2-[2´-(1´´-Hydroxyisopropyl)-3´-oxocyclopentyl]-
2-[2-(p-tolylsulfinyl)phenyl]propanenitrile (14a + 14b). Isobutiraldehyde (0.37 mmol) was used as
the electrophile. The reaction mixture was stirred at ꢀ78 °C for 180 min. and then it was hydrolyzed with
a methanolic HCl solution to give a diastereoisomeric 83:17 mixture 14a + 14b, from which 14a was
separated and purified by flash column chromatography using a mixture EtOAcꢀhexane (1:1) as the
eluent. Yield 65%, 41.2 mg (mixture 14a + 14b). Diastereoisomer [2R,1´S,2´S,1´´R,(S)S]ꢀ14a: white
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solid; m.p. 113ꢀ115 °C (hexaneꢀiPrOH); [α]20 ꢀ134.5 (c 0.9, CHCl3); IR (KBr): 2962, 2218, 1739, 810
D
cm−1; 1H NMR: δ 7.68ꢀ7.61 (m, 1H), 7.66 and 7.32 (AA´BB´ system, 4H), 7.55ꢀ7.52 (m, 3H), 3.90ꢀ3.77
(m, 1H), 3.71 (broad s, 1H), 2.43ꢀ2.27 (m, 3H), 2.40 (s, 3H), 2.16ꢀ1.74 (m, 4H), 1.96 (s, 3H), 0.64 (d, J
13
6.3 Hz, 3H), 0.58 (d, J 6.3 Hz, 3H) ppm; C NMR: δ 215.6, 145.6, 141.7, 138.7, 138.6, 132.9, 130.6,
130.1 (3C), 125.4, 125.0 (2C), 123.6, 77.6, 77.2, 50.0, 47.1, 40.3, 30.0, 24.4, 21.4, 19.8, 19.5 ppm.; MS
(FAB+) m/z 424 [M+H]+ (60), 406 (64); HMRS (FAB+) calcd. for C25H30NO3S: 424.1940; found:
424.1949. Diastereoisomer [2R,1´S,2´R,1´´R,(S)S]ꢀ14b (significant chemical shifts obtained from an
1
epimeric 87:13 mixture 14a + 14b): H NMR: δ 7.79ꢀ7.75 (m, 1H), 1.65 (m, 1H), 0.56 (d, J 6.4 Hz,
3H), 0.47 (d, J 6.4 Hz, 3H) ppm. The diastereoisomeric excess was determined by HPLC and by
1
integration of wellꢀdefined H NMR signals of the crude reaction. HPLC analysis: Chiralpack AD
[hexaneꢀiPrOH (80:20) eluent; flow = 1 mL/min]. Major diastereoisomer 14a: tR = 10.6 min. (87%) and
minor diastereoisomer 14b: tR = 20.7 min. (13%).
[2R,1´S,2´S,1´´R,(S)S]
and
[2R,1´S,2´R,1´´R,(S)S]-2-[2´-(1´´-Hydroxy-3´´-methylbutyl)-3´-
oxocyclopentyl]-2-[2-(p-tolylsulfinyl)phenyl]propanenitrile (15a + 15b). 2ꢀMethylbutiraldehyde
(0.37 mmol) was used as the electrophile. The reaction mixture was stirred at ꢀ78 °C for 5 min. and then
it was hydrolyzed with a methanolic HCl solution to give a diastereoisomeric 91:9 mixture 15a + 15b,
from which 15a was separated and purified by flash column chromatography using a mixture EtOAcꢀ
hexane (1:1) as the eluent. Yield 72%, 47.2 mg (mixture 15a + 15b). Diastereoisomer
[2R,1´S,2´S,1´´R,(S)S]ꢀ15a: colorless oil; [α]20 ꢀ106.4 (c 1.2, CHCl3); IR (film): 2975, 2223, 1760, 775
D
1
cm−1; H NMR: δ 8.01ꢀ7.98 (m, 1H), 7.74ꢀ7.70 (m, 1H), 7.57ꢀ7.43 (m, 2H), 7.44 and 7.27 (AA´BB´
system, 4H), 2.99ꢀ2.90 (m, 1H), 2.47ꢀ2.39 (m, 1H), 2.40 (s, 3H), 2.33ꢀ2.21 (m, 2H), 2.16ꢀ2.02 (m, 2H),
2.05 (s, 3H), 1.97ꢀ1.71 (m, 2H), 1.68ꢀ1.60 (m, 2H), 0.97 (d, J 6.2 Hz, 3H), 0.96 (d, J 6.2 Hz, 3H) ppm;
13C NMR: δ 214.6, 143.6, 142.0, 140.8, 137.7, 132.2, 130.2 (2C), 130.0, 129.9, 127.7, 126.0 (2C),
121.6, 77.2, 47.2, 46.9, 40.9, 38.2, 26.2, 26.0, 25.4, 25.2, 22.3, 21.3 ppm; MS (FAB+) m/z 424 [M+H]+
(60), 406 (64); HMRS (FAB+) calcd. for C25H30NO3S: 424.1940; found: 424.1949. Diastereoisomer
[2R,1´S,2´R,1´´R,(S)S]ꢀ15b (significant chemical shifts obtained from an epimeric 91:9 mixture 15a +
15b): 1H NMR: δ 7.97ꢀ7.95 (m, 1H), 7.79ꢀ7.75 (m, 1H), 3.46 (m, 1H), 0.98 (d, J 6.4 Hz, 3H) ppm. The
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1
diastereoisomeric excess was determined by HPLC and by integration of wellꢀdefined H NMR signals
of the crude reaction. HPLC analysis: Chiralpack AD [hexaneꢀiPrOH (80:20) eluent; flow = 1 mL/min].
Major diastereoisomer 15a: tR = 26.5 min. (91%) and minor diastereoisomer 15b: tR = 30.0 min. (9%).
1
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3
4
5
6
7
[2R,1´S,2´S,1´´S,(S)S]
and
[2R,1´S,2´R,1´´S,(S)S]-2-{2´-[1´´-Hydroxy(phenyl)methyl]-3´-
8
9
oxocyclopentyl}-2-[2-(p-tolylsulfinyl)phenyl]propanenitrile (16a + 16b). Benzaldehyde (0.37 mmol)
was used as the electrophile. The reaction mixture was stirred at ꢀ78 °C for 5 min. and then it was
hydrolyzed with a methanolic HCl solution to give a diastereoisomeric 86:14 mixture of 16a + 16b,
from which 16a was separated and purified by flash column chromatography using a mixture EtOAcꢀ
hexane (1:1) as the eluent. Yield 77%, 52.8 mg (mixture 16a + 16b). Diastereoisomer
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11
12
13
14
15
16
17
18
19
20
21
22
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[2R,1´S,2´S,1´´S,(S)S]ꢀ16a: colorless oil; [α]20 ꢀ104.1 (c 1.8, CHCl3); IR (film): 3062, 2877, 2237,
D
1
1793, 809 cm−1; H NMR: δ 8.09ꢀ8.06 (m, 1H), 7.87ꢀ7.84 (m, 1H), 7.72ꢀ7.70 (m, 1H), 7.50ꢀ7.45 (m,
2H), 7.42 and 7.28 (AA´BB´ system, 4H), 7.55ꢀ7.31 (m, 4H), 5.30 (m, 1H), 3.28ꢀ3.23 (m, 1H), 2.74 (m,
13
1H), 2.52 (m, 1H), 2.40 (s, 3H), 2.15ꢀ2.03 (m, 1H), 1.68ꢀ1.60 (m, 2H), 1.41 (s, 3H) ppm; C NMR: δ
219.0, 141.7, 141.5, 140.7, 138.3, 132.1, 130.1 (3C), 129.9, 128.8 (2C), 128.3, 128.2 (2C), 125.8 (2C),
125.7 (2C), 122.3, 77.2, 74.7, 58.5, 45.7, 37.8, 24.9, 21.3 (2C) ppm; MS (FAB+) m/z 458 [M+H]+ (47),
440 [MꢀOH] (100); HMRS (FAB+) calcd. for C28H26NO2S [MꢀOH]: 440.1684; found: 440.1672.
Diastereoisomer [2R,1´S,2´R,1´´R,(S)S]ꢀ16b (significant chemical shifts obtained from an epimeric
86:14 mixture 16a + 16b): 1H NMR: δ 7.93ꢀ7.90 (m, 1H), 5.35 (m, 1H), 3.33ꢀ3.29 (m, 1H), 2.38 (s, 3H)
1
ppm. The diastereoisomeric excess was determined by HPLC and by integration of wellꢀdefined H
NMR signals of the crude reaction. HPLC analysis: Chiralpack AD [hexaneꢀiPrOH (80:20) eluent; flow
= 1 mL/min]. Major diastereoisomer 16a: tR = 20.8 min. (86%) and minor diastereoisomer 16b: tR =
27.2 min. (14%).
[2R,1´S,2´S,1´´S,(S)S] and [2R,1´S,2´R,1´´S,(S)S]-2-{2´-[1´´-Hydroxy(p-methoxyphenyl)methyl]-3´-
oxocyclopentyl}-2-[2-(p-tolylsulfinyl)phenyl]propanenitrile (17a + 17b). pꢀMethoxybenzaldehyde
(0.74 mmol) was used as the electrophile. The reaction mixture was stirred at ꢀ78 °C for 180 min. and
then it was hydrolyzed with a methanolic HCl solution to give a diastereoisomeric 85:15 mixture 17a +
17b, which was purified by flash column chromatography using a mixture EtOAcꢀhexane (2:1) as the
eluent. Yield 60%, 43.7 mg (mixture 17a + 17b, colorless oil). Diastereoisomer [2R,1´S,2´S,1´´S,(S)S]ꢀ
1
17a: H NMR (from an 85:15 mixture 17a + 17b): δ 7.91ꢀ7.82 (m, 1H), 7.56ꢀ7.46 (m, 3H), 7.45 and
7.28 (AA´BB´ system, 4H), 7.25 and 6.86 (AA´BB´ system, 4H), 5.22 (broad s, 1H), 3.76 (s, 3H), 3.30ꢀ
3.20 (m, 1H) 2.90 (d, J 5.6 Hz), 2.75ꢀ2.71 (m, 1H), 2.57ꢀ2.42 (m, 2H), 2.39 (s, 3H), 2.34ꢀ2.28 (m, 1H),
13
2.05 (s, 3H) ppm; C NMR (from an 85:15 mixture 17a + 17b): δ 217.2, 160.1, 141.8, 140.2, 138.4,
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137.7, 134.1, 132.2, 130.5, 130.1 (2C), 128.2, 126.7 (2C), 126.4, 113.5 (2C), 113.1 (2C), 120.8, 77.1,
73.8, 56.1, 55.8, 51.9, 45.6, 37.7, 28.9, 21.4, 21.3 ppm; MS (FAB+) m/z 470 [M+HꢀOH] (100), 352
(65); HMRS (FAB+) calcd. for C29H28NO3S: 470.1789; found: 470.1773. Diastereoisomer
[2R,1´S,2´R,1´´S,(S)S]ꢀ17b (significant chemical shifts obtained from an epimeric 85:15 mixture 17a +
1
2
3
4
5
6
7
8
1
17b): H NMR: δ 8.01ꢀ7.98 (m, 1H), 7.45 and 7.28 (AA´BB´ system, 4H), 7.25 and 6.75 (AA´BB´
9
system, 4H), 3.74 (s, 3H), 3.30ꢀ3.20 (m, 1H), 2.38 (s, 3H), 2.04 (s, 3H), 2.11ꢀ1.99 (m, 1H) ppm. The
10
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1
diastereoisomeric excess was determined by HPLC and by integration of wellꢀdefined H NMR signals
of the crude reaction. HPLC analysis: Chiralpack AD [hexaneꢀiPrOH (80:20) eluent; flow = 1 mL/min].
Major diastereoisomer 17a: tR = 27.8 min. (85%) and minor diastereoisomer 17b: tR = 30.1 min. (15%).
[2R,1´S,2´S,1´´S,(S)S] and [2R,1´S,2´R,1´´S,(S)S]-2-{2´-[1´´-Hydroxy(p-nitrophenyl)methyl]-3´-
oxocyclopentyl}-2-[2-(p-tolylsulfinyl)phenyl]propanenitrile (18a + 18b). pꢀNitrobenzaldehyde (0.23
mmol) was used as the electrophile. The reaction mixture was stirred at ꢀ78 °C for 30 min. and then it
was hydrolyzed with a methanolic HCl solution to give a diastereoisomeric 80:20 mixture of 18a + 18b,
which was purified by flash column chromatography using a mixture EtOAcꢀhexane (1:1) as the eluent.
Yield 75%, 56.5 mg (mixture 18a + 18b, colorless oil). Diastereoisomer [2R,1´S,2´S,1´´S,(S)S]ꢀ18a: 1H
NMR (from an 80:20 mixture 18a + 18b): δ 8.10 and 7.23 (AA´BB´ system, 4H), 7.77ꢀ7.71 (m, 1H),
7.68ꢀ7.65 (m, 1H), 7.59ꢀ7.57 (m, 1H), 7.45 and 7.28 (AA´BB´ system, 4H), 7.43ꢀ7.40 (m, 1H), 5.22
(broad s, 1H), 4.83 (m, 1H), 3.44ꢀ3.40 (m, 1H), 2.75ꢀ2.71 (m, 1H), 2.60ꢀ2.52 (m, 2H), 2.41 (s, 3H),
2.33ꢀ2.31 (m, 1H), 2.29ꢀ2.18 (m, 1H), 1.55 (s, 3H) ppm; 13C NMR (from an 80:20 mixture 18a + 18b):
δ 218.2, 141.8, 140.2, 138.4, 137.7, 134.1, 132.2, 130.5, 130.1 (2C), 128.2, 126.7 (2C), 126.4, 125.6
(2C), 123.9 (2C), 123.7, 120.8, 77.2, 73.9, 51.9, 45.6, 37.7, 28.9, 21.4, 21.3 ppm; MS (FAB+) m/z 503
[M+H]+ (100), 485 (48); HMRS (FAB+) calcd. for C28H27N2O5S: 503.1640; found: 503.1631.
Diastereoisomer [2R,1´S,2´R,1´´S,(S)S]ꢀ18b (significant chemical shifts obtained from an epimeric
1
80:20 mixture of 18a + 18b): H NMR: δ 8.22 and 7.17 (AA´BB´ system, 4H), 7.57ꢀ7.55 (m, 1H), 7.44
and 7.28 (AA´BB´ system, 4H), 7.43ꢀ7.40 (m, 1H), 5.50 (m, 1H), 4.85 (m, 1H), 3.32ꢀ3.27 (m, 1H),
2.69ꢀ2.65 (m, 1H), 2.60ꢀ2.52 (m, 2H), 2.52ꢀ2.45 (m, 1H), 2.29ꢀ2.18 (m, 1H), 2.39 (s, 3H), 1.57 (s, 3H)
ppm. 13C NMR: δ 218.3, 133.7, 130.3, 129.0, 127.7, 125.3 (2C), 123.8, 70.8, 50.4, 32.2, 29.4 ppm. The
1
diastereoisomeric excess was determined by HPLC and by integration of wellꢀdefined H NMR signals
of the crude reaction. HPLC analysis: Chiralpack AD [hexaneꢀiPrOH (80:20) eluent; flow = 1 mL/min].
Major diastereoisomer 18a: tR = 33.6 min. (80%) and minor diastereoisomer 18b: tR = 29.7 min. (20%).
[1R,1´S,2´S,1´´R,(S)S]
and
[1R,1´R,2´S,1´´R,(S)S]-N-[1-(2´-{1´´-Cyano-1´´-[2-(p-tolyl
sulfinyl)phenyl]ethyl}-5´-oxocyclopentyl)-1-hexyl]-p-toluenesulfonamide (19a + 19b). (Z)ꢀNꢀ
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hexylideneꢀpꢀtoluenesulfonamide (0.23 mmol dissolved in 0.5 mL of anhydrous THF) was used as the
electrophile. The reaction mixture was stirred at ꢀ78 °C for 60 min. and then it was hydrolyzed with
saturated aqueous NH4Cl (1 mL), to give a diastereoisomeric 90:10 mixture of 19a + 19b, from which
19a was separated and purified by flash column chromatography using a mixture EtOAcꢀhexane (2:1) as
1
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3
4
5
6
7
8
the eluent. Yield 68%, 61.6 mg (mixture 19a + 19b). Diastereoisomer [1R,1´S,2´S,1´´R,(S)S]ꢀ19a:
1
colorless oil; [α]20 ꢀ82.4 (c 1.7, CHCl3); IR (film): 3024, 2236, 1740, 1080, 750 cm−1; H NMR: δ
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D
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16
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7.84ꢀ7.82 (m, 1H), 7.67 and 7.33 (AA´BB´ system, 4H), 7.64 and 7.25 (AA´BB´ system, 4H), 7.56ꢀ7.51
(m, 3H), 5.22 (broad s, 1H), 3.62 (m, 1H), 3.43ꢀ3.39 (m, 1H), 2.52 (m, 1H), 2.41ꢀ2.30 (m, 1H), 2.40 (s,
3H), 2.38 (s, 3H), 2.18ꢀ2.03 (m, 1H), 2.03ꢀ1.94 (m, 1H), 1.96 (s, 3H), 1.67 (m, 1H), 1.33ꢀ1.20 (m, 4H),
13
0.99ꢀ0.82 (m, 4H), 0.67 (t, J 7.0 Hz, 3H) ppm; C NMR: δ 217.6, 144.1, 143.2, 141.6, 139.6, 137.6,
137.5, 132.4, 130.7, 130.0 (3C), 129.5 (2C), 127.2 (3C), 125.9 (2C), 123.5, 77.2, 55.2, 54.9, 46.4, 38.3,
30.9 (2C), 25.6, 24.9, 22.2, 21.3 (3C), 13.6 ppm; MS (FAB+) m/z 605 [M+H]+ (100), 434 (20), 352
(28); HMRS (FAB+) calcd. for C34H41N2O4S2: 605.2508; found: 605.2517. Diastereoisomer
[1R,1´R,2´S,1´´R,(S)S]ꢀ19b (significant chemical shifts obtained from an epimeric 90:10 mixture 19a +
19b): 1H NMR: 7.75ꢀ7.70 (m, 1H), 1.63 (m, 1H), 0.68 (t, J 7.0 Hz, 3H) ppm.
[1R,1´S,2´S,1´´R,(S)S]
and
[1R,1´R,2´S,1´´R,(S)S]
N-[1-(2´-{1´´-Cyano-1´´-[2-(p-tolyl
sulfinyl)phenyl]ethyl}-5´-oxocyclopentyl)-2-methylpropyl]-p-toluenesulfonamide (20a + 20b). (Z)ꢀ
(E)ꢀNꢀ(2ꢀMethylpropylidene)ꢀpꢀmethylphenyltoluenesulfonamide (0.23 mmol dissolved in 0.5 mL of
anhydrous THF) was used as the electrophile. The reaction mixture was stirred at ꢀ78 °C for 60 min. and
then it was hydrolyzed with saturated aqueous NH4Cl (1 mL), to give a diastereoisomeric 87:13 mixture
of 20a + 20b, from which 20a was separated and purified by flash column chromatography using a
mixture EtOAcꢀhexane (2:1) as the eluent. Yield 72%, 62.2 mg (mixture 20a + 20b). Diastereoisomer
1
[2R,1´S,2´S,1´´S,(S)S]ꢀ20a: colorless oil; [α]20 ꢀ82.4 (c 1.7, CHCl3); H NMR: δ 7.98ꢀ7.95 (m, 1H),
D
7.72ꢀ7.68 (m, 1H), 7.67 and 7.29 (AA´BB´ system, 4H), 7.63 and 7.26 (AA´BB´ system, 4H), 7.54ꢀ7.50
(m, 2H), 4.82 (m, 1H), 3.59 (c, J 8.2 Hz, 1H), 3.36 (dd, J 7.9 and 9.5 Hz, 1H), 2.69ꢀ2.66 (m, 1H), 2.39
(s, 3H), 2.37 (s, 3H), 2.35ꢀ2.32 (m, 1H), 2.16ꢀ1.85 (m, 2H), 2.06 (s, 3H), 1.72ꢀ1.67 (m, 1H), 0.77 (d, J
13
6.6 Hz, 3H), 0.46 (d, J 6.8 Hz, 3H) ppm; C NMR: δ 217.3, 144.6, 143.5, 141.6, 140.8, 138.0, 137.7,
132.1, 130.7, 130.1 (3C), 129.5 (2C), 129.4, 127.1 (2C), 126.1 (2C), 122.3, 77.2, 61.1, 54.8, 48.2, 38.4,
31.8, 25.0, 21.4 (2C), 21.3, 20.7, 18.7 ppm; MS (FAB+) m/z 577 [M+H]+ (100), 352 (31), 226 (23);
HMRS (FAB+) calcd. for C32H37N2O4S2: 577.2195; found: 577.2222. Diastereoisomer
[1R,1´R,2´S,1´´R,(S)S]ꢀ20b (significant chemical shifts obtained from an epimeric 83:17 mixture of 20a
+ 20b): 1H NMR: 7.80ꢀ7.75 (m, 1H), 7.46ꢀ7.41 (m, 1H), 1.60 (m, 1H), 0.81 (d, J 6.7 Hz, 3H), 0.38 (d, J
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6.8 Hz, 3H) ppm.
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4
[1S,1´S,2´S,1´´R,(S)S]
and
[1S,1´R,2´S,1´´R,(S)S]
N-[1-(2´-{1´´-Cyano-1´´-[2-(p-tolyl
sulfinyl)phenyl]ethyl}-5´-oxocyclopentyl)-1-(phenyl)methyl-p-toluenesulfonamide (21a + 21b). (E)ꢀ
NꢀBenzylideneꢀpꢀtoluenesulfonamide (0.23 mmol dissolved in 0.5 mL of anhydrous THF) was used as
the electrophile. The reaction mixture was stirred at ꢀ78 °C for 5 min. and then it was hydrolyzed with
saturated aqueous NH4Cl (1 mL) to give a diastereoisomeric 89:11 mixture of 21a + 21b, from which
21a was separated and purified by flash column chromatography using a mixture EtOAcꢀhexane (1:1) as
the eluent. Yield 74%, 67.7 mg (mixture 21a + 21b). Diastereoisomer [1S,1´S,2´S,1´´R,(S)S]ꢀ21a: white
5
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solid; m.p. 131ꢀ133 °C (hexaneꢀiPrOH); [α]20 ꢀ69.6 (c 0.3, CHCl3); IR (KBr): 3050, 2230, 1728, 1027,
D
1
756 cm−1; H NMR: δ 7.92ꢀ7.89 (m, 1H), 7.71ꢀ7.68 (m, 1H), 7.54ꢀ7.42 (m, 5H), 7.14ꢀ7.04 (m, 8H),
6.93ꢀ6.90 (m, 2H), 6.82 (d, J 9.2 Hz, 1H), 4.53 (m, 1H), 2.96ꢀ2.89 (m, 1H), 2.82ꢀ2.78 (m, 1H), 2.37ꢀ
2.21 (m, 2H), 2.34 (s, 3H), 2.31 (s, 3H), 2.08 (s, 3H), 1.58ꢀ1.48 (m, 2H) ppm; 13C NMR: δ 219.4, 143.1,
141.7, 140.3, 137.5, 136.7, 132.4, 130.3, 130.0, 129.9 (2C), 129.3 (2C), 128.8 (2C), 128.1, 127.9 (2C),
126.8 (3C), 125.7 (3C), 121.8, 77.2, 58.9, 55.1, 47.2, 39.0, 24.5 , 21.3 (2C), 21.2 ppm; MS (FAB+) m/z
611 [M+H]+ (100), 440 (70); HMRS (FAB+) calcd. for C35H35N2O4S2: 611.2038; found: 611.2023.
Diastereoisomer [1S,1´R,2´S,1´´R,(S)S]ꢀ21b (significant chemical shifts obtained from an epimeric
89:11 mixture of 21a + 21b): 1H NMR: δ 7.98ꢀ7.95 (m, 1H), 4.61 (m, 1H), 2.72ꢀ2.65 (m, 1H) ppm.
General procedure for oxidation of sulfoxides to sulfones (22a and 23a).
To a solution of the corresponding sulfinyl nitrile (2a or 5a) (0.11 mmol) in 1.0 mL of anhydrous
dichloromethane, cooled at 0 ºC, was slowly added mꢀCPBA (0.16 mmol, 1.5 equiv.). The reaction
mixture was stirred initially at 0 ºC and then warmed to room temperature. The reaction was monitored
by TLC. Upon transformation of starting material, it was quenched with a NaHSO3 solution (40% w/v,
5 mL). The organic layer was washed with saturated NaHCO3 (3 mL) and the aqueous layers were
extracted with CH2Cl2 (3 × 5 mL), dried (Na2SO4) and evaporated. The residue was purified by flash
column chromatography using a mixture of EtOAcꢀhexane (2:1) as the eluent.
(2R,1´S)-2-(3´-Oxocyclopentyl)-2-[2-(p-tolylsulfonyl)phenyl]propanenitrile (22a). [2R,1´S,(S)S]ꢀ2ꢀ
(3´ꢀOxocyclopentyl)ꢀ2ꢀ[2ꢀ(pꢀtolylsulfinyl)ꢀphenyl]propanenitrile (2a) was used as the starting material.
1
Yield 78%, 31.5 mg; white solid; m.p. 82ꢀ84 °C (CH2Cl2ꢀhexane); [α]20 ꢀ41.6 (c 0.8, CHCl3); H
D
NMR: δ 8.05ꢀ8.02 (m, 1H), 7.80ꢀ7.73 (m, 1H), 7.74 and 7.36 (AA´BB´ system, 4H), 7.61 (dt, J 1.5 and
7.7 Hz), 7.40 (dt, J 1.1 and 8.2 Hz, 1H), 4.41ꢀ4.32 (td, J 4.6 and 10.2 Hz), 4.15 (td, J 3.6 and 11.1 Hz,
1H), 3.79 (m, 1H), 2.89 (dd, J 5.5 and 10.1 Hz, 1H), 2.59 (dd, J 6.4 and 11.1 Hz, 1H), 2.45 (s, 3H), 2.02
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The Journal of Organic Chemistry
(s, 3H), 1.80ꢀ1.74 (m, 1H), 1.73ꢀ1.60 (m, 1H) ppm; 13C NMR: δ 169.7, 145.1, 140.1, 138.2, 137.2,
133.4, 133.3, 131.4, 130.1 (2C), 129.1, 127.8 (2C), 121.4, 77.2, 67.8, 37.5, 32.8, 26.1, 23.6, 21.6 ppm;
MS (ESI+) m/z 368 [M+H]+ (100), 286 (75), 259 (35); HMRS (ESI+) calcd. for C21H22NO3S: 368.1314;
found: 368.1298.
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(2R,1´S,2´R)-2-(2´-Methyl-3´-oxocyclopentyl)-2-[2-(p-tolylsulfonyl)phenyl]propanenitrile
(23a).
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[2R,1´S,(S)S]ꢀ2ꢀ(2´ꢀMethylꢀ3´ꢀoxocyclopentyl)ꢀ2ꢀ[2ꢀ(pꢀtolylsulfinyl)phenyl]propanenitrile (5a) was
used as the starting material. Yield 80%, 33.5 mg; white solid; m.p. 149ꢀ151 °C (CH2Cl2ꢀhexane);
[α]20 ꢀ27.5 (c 0.4, CHCl3); 1H NMR: δ 8.09ꢀ8.06 (m, 1H), 7.95ꢀ7.92 (m, 1H), 7.74 and 7.34 (AA´BB´
D
system, 4H), 7.61 (dt, J 1.5 and 7.6 Hz, 1H), 7.46 (dt, J 1.1 and 7.8 Hz, 1H), 3.57 (m, 1H) 2.44 (s, 3H),
2.37ꢀ2.27 (m, 2H), 2.17 (s, 3H), 2.21ꢀ1.92 (m, 1H), 1.65ꢀ1.52 (m, 2H), 1.28 (d, J 6.8 Hz, 3H) ppm.
ACKNOWLEDGMENT: Financial support of this work by the Ministerio de Ciencia y
Tecnología (CTQ2012ꢀ35957), UAMꢀComunidad de Madrid (CCG08UAM/PPQꢀ4235) and Comunidad
de Madrid (AVANCAT, Sꢀ2009ꢀPPQꢀ1634) are gratefully acknowledged. E. T. thanks Ministerio de
Ciencia e Innovación for a predoctoral fellowship.
SUPPORTING INFORMATION PARAGRAPH
13
1H and CꢀNMR for sulfinyl derivatives 2a, 3a + 3b, 4a-6a, 7a + 7b, 8a, 9a + 9b, 10a, 11a-21a,
1
sulfonyl derivatives 22a and 23a, bidimensional H NMR experiment for compound 11a and
crystallographic data for compounds 14a, 21a, 22a and 23a are described in the supporting information.
This material is available free of charge via the Internet at http://pubs.acs.org.
REFERENCES
1. Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033.
2. Krause, N.; HoffmannꢀRoder, A. Synthesis 2001, 171.
3. Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221.
4. Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105.
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