Catalytic asymmetric synthesis of γ-substituted vinyl sulfones

Article abstract of DOI:10.1002/chem.201003177

A fast new entry for the stereoselective construction of γ-substituted vinyl sulfones is presented. The key for success is the use of a readily available chiral secondary amine catalyst that allows the use of base-sensitive β-nitroethyl sulfones as masked β-sulfonyl vinyl anions in conjugate additions. The method performed in a three-step one-pot operation gives access to a great variety of vinyl sulfones in good yields and with excellent enantioselectivities. The method has also been extended to other relatively base-sensitive β-electron-withdrawing-substituted nitroalkanes to afford products with manifold functionality, providing a quick entry to very attractive synthetic intermediates for organic synthesis.

Full text of DOI:10.1002/chem.201003177

DOI: 10.1002/chem.201003177
Catalytic Asymmetric Synthesis of g-Substituted Vinyl Sulfones
Rosa Lꢀpez, Maitane Zalacain, and Claudio Palomo*[a]
Dedicated to Professor Antonio Garcꢀa Martinez on the occasion of his 70th birthday
Abstract: A fast new entry for the ste-
The method performed in a three-step
one-pot operation gives access to a
great variety of vinyl sulfones in good
yields and with excellent enantioselec-
reoselective construction of g-substitut-
ed vinyl sulfones is presented. The key
for success is the use of a readily avail-
able chiral secondary amine catalyst
that allows the use of base-sensitive b-
nitroethyl sulfones as masked b-sulfo-
nyl vinyl anions in conjugate additions.
tivities. The method has also been ex-
tended to other relatively base-sensi-
tive b-electron-withdrawing-substituted
nitroalkanes to afford products with
Keywords: amino acids · asymmet-
ric synthesis · iminium activation ·
nitroalkanes · sulfones
manifold functionality, providing
a
quick entry to very attractive synthetic
intermediates for organic synthesis.
Introduction
effective inhibitors of sortases[3a] and tyrosine phosphata-
ses[3b] and III[4] and IV[5] of cysteine proteases, respectively.
Strikingly, whereas the inhibition mechanism is generally
accepted as a 1,4-conjugate addition of the thiol group of
the cysteine active site to the vinyl sufones, much less
known is about the structural requirements for an effective
enzyme recognition.
Antibiotics have a long standing history of success in the
treatment of bacterial infections. Nevertheless, due to the
antibiotic resistance increase, a great effort toward the iden-
tification and validation of new drugs that target essential
and, specially, virulence factors is of crucial interest.[1] Struc-
turally diverse vinyl sulfones have recently been shown to
potently inhibit a variety of enzymatic processes providing
unique properties for drug design and medicinal chemistry
(Scheme 1).[2] For instance, vinyl sulfones I and II behave as
Recent findings, by McCafferty[3a] and Zhang,[3b] support
the notion that even the simple phenyl vinyl sulfone I holds
promise for in vivo applications and shows that further elab-
oration of vinyl sulfone scaffolds are expected to lead to the
identification of more specific inhibitors. In addition, several
vinyl sulfones have recently been identified, by using high-
throughput screens, that have provided insight into the
mechanism of microbial pathogenesis.[6] Despite their bio-
logical interest and their chemical versatility in asymmetric
synthesis,[7] the preparation of vinyl sulfones almost remains
restricted to the addition of sulfonyl-stabilized carbanions to
the corresponding carbonyl compound.[2a,7] Herein, we
report a practical synthetic methodology for the preparation
of vinyl sulfones bearing a g-stereogenic center that could
help to fulfill this gap.
Results and Discussion
Scheme 1. Representative examples of structurally diverse small vinyl sul-
fone enzyme inhibitors.
Challenges and working plan: We envisioned that base-pro-
moted addition of b-nitroethyl sulfones[8] to the proper
carbon-centered electrophile, inter alia a,b-unsaturated car-
bonyl compounds,[9] followed by nitrous acid elimination[10]
would represent a practical short stereoselective route to
functionalized g-substituted vinyl sulfones (Scheme 2). First,
both the carbon–carbon bond and the new stereogenic
center would be generated concurrently in a single synthetic
operation, a notable advantage over traditional methods.
Second, new vinyl sulfone scaffolds with different substitu-
tion patterns would be made feasible from simple and readi-
[a] Dr. R. Lꢀpez, M. Zalacain, Prof. Dr. C. Palomo
Department of Organic Chemistry I
Universidad del Paꢁs Vasco, Apdo. 1072
Manuel de Lardizabal 3, 20018 San Sebastiꢂn (Spain)
Fax : (+34)943-015-270
E-mail: claudio.palomo@ehu.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003177.
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FULL PAPER
The optimum results were achieved by using catalyst 6,
which proved to be the most efficient for both b-alkyl and
b-aryl-substituted a,b-enals.[17] Thus, treatment of 2-pentenal
with a slight excess of b-nitroethyl sulfone 1 in the presence
of 10 mol% of 6, in methylene chloride at room tempera-
ture, and subsequent one-pot protection of the resulting al-
dehyde adduct and base-promoted nitrous acid elimination
furnished 7a in 79% yield and 94% ee. As illustrated in
Table 1, the method is tolerant with a range of aldehydes
Table 1. g-Substituted vinyl sulfones from nitroethyl sulfones 1–4 and
enals 5 promoted by 6.[a]
Scheme 2. Conjugate addition of formal b-sulfonyl vinyl anions to p-defi-
cient olefins. EWG: CHO, CO2Me; R: Me, Et; R3N: DBU, DABCO, qui-
nine, Takemotoꢄs thiourea, dibenzylamine, pyrrolidine.
ly available achiral starting materials. Third, the process
might be realized in a one-pot operation that would be at-
tractive from the economy viewpoint, and finally, the result-
ing products would broaden the pool of available vinyl sul-
fones as synthetic intermediates and as potential protease
inhibitors.
Two critical issues to consider in the realization of this
goal are 1) the ability of the catalyst to promote the forma-
tion of the carbon–carbon bond before any elimination of
nitrous and/or sulfinic acid in the starting b-nitroethylsul-
fone may occur[11] and 2) the tendency of a,b-unsaturated
sulfones to undergo base-promoted isomerization to b,g-un-
saturated products.[12] Thus, initial experiments to assess this
crucial point by using b-nitroethylsulfone 1 (R1 =Ph) and
several p-deficient olefin/amine base combinations revealed
that products from the conjugate addition of phenyl sulfinic
acid were in fact produced for most of the combinations
screened (Scheme 2). For instance, in reactions of 2-pente-
nal, methyl 2-butenoate, and crotonoyl oxazolidinone, em-
Entry Sulfone Enal, R1
T [8C], t [h][b] Yield [%][c] ee [%][d]
1
1
5a, Et
RT, 2
RT, 1
RT, 2
RT, 15
RT, 15
0, 24
7a 79
7b 71
7c 90
7d 60
7e 80
7 f 67
7g 56
7h 57
7i 60
94
94
95
95
93
98
98
97
94
95
96
94
93
96
93
2
5b, Me
3
4
5
6
5c, nBu
5d, iPr[e]
5e, nOct[f]
5 f, Ph
7
8
5g, 4-Cl-C6H4
5h, 4-Me-C6H4
0, 24
0, 24
9
5i, 4-MeO-C6H4 0, 48
10
11
12
13
14
15
2
5a, Et
RT, 1
RT, 24
RT, 6
0, 24
RT, 15
RT, 15
8a 62
8d 51
8e 92
8 f 70
9a 40[h]
10a 75
5d, iPr
5e, nOct[g]
5 f, Ph
5a, Et
5a, Et
3
4
[a] Reactions carried out at 0.5 mmol enal scale by using 1.3–1.5 equiv of
b-nitroethylsulfone, 10 mol% catalyst 6 in CH2Cl2 (1 mL). Nitrous acid
elimination was carried out by employing DBU for adducts with alkyl
substituents and MgACTHNUTRGNEUNG(OMe)2 for aromatic substituents. [b] Reaction time
ploying catalytic amounts of 1,8-diazabicyclo
ene (DBU), the addition of phenyl sulfinic acid was exclu-
sively produced, whereas 1,4-diazobicyclo[2.2.2]octane
ACHTUNGTREN[NGNU 5.4.0]undec-7-
for the b-nitroethyl sulfone addition. [c] Yield of isolated product. [d] ee
was determined by chiral HPLC analysis. [e] Reaction carried out at the
4 mmol scale. [f] 5 mol% catalyst. [g] Reaction carried out at 2 mmol
scale. [h] Adduct 9a partially decomposes during purification.
AHCTUNGTRENNUNG
(DABCO), quinine, and the Takemotoꢄs thiourea[13] afford-
ed mixtures of variable complexity.[14] Gratifyingly, further
screening led to the identification of secondary amines, such
as pyrrolidine and dibenzylamine, as successful promoters of
the reaction of 1 with 2-pentenal to afford the addition
product cleanly. This result suggested that the reaction
should proceed through the activation of the enal acceptor
by in situ generation of the corresponding iminium species
rather than Brønsted base-promoted addition. Early obser-
vations that carbon–carbon bond-forming reactions, includ-
ing conjugate additions, may be efficiently promoted by
using iminium catalysis[15] provided further support for this
proposal.
with varying steric demand to give vinyl sulfones with no
loss of efficiency or enantiocontrol. Aliphatic enals, inde-
pendent of the chain length, reacted within a few hours at
room temperature, whereas aromatic ones required some-
what longer reaction times and lower temperatures, typically
08C. Whilst DBU-promoted nitrous acid elimination was
tolerant for b-alkyl-substituted adducts, a milder base, such
as magnesium methoxide, was required for b-aromatic-sub-
stituted adducts.[18]
This approach also appears to be general with respect the
sulfone moiety. b-Nitroethyl(2-pyridyl)sulfone (2) reacts
with both aliphatic and aromatic enals in the presence of
10% mol of catalyst 6 to afford, after aldehyde protection
and nitrous acid elimination, vinyl sulfones 8 with good
overall yields and excellent enantiomeric excesses. Likewise,
Catalyst screening and conditions: Upon the above assump-
tion, we examined the ability of chiral secondary amines to
promote the reaction enantioselectively and, to our delight,
standard chiral pyrrolidines were found to be effective.[16]
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2451

C. Palomo et al.
b-nitroethylalkylsulfones behaved as b-sulfonyl vinyl anion
equivalents in such a reaction to provide the corresponding
g-substituted vinyl sulfones 9 and 10 with equal chemical
and stereochemical efficiency than their aromatic counter-
parts.[19] The catalyst loading, on the other hand, could be
reduced to 5 mol% (Table 1, entry 5), whereas the use of
1 mol% of 6 resulted in a considerable decrease in both
yield and enantioselectivity. Of practical interest, reactions
can be run at the 10 mmol scale without compromising se-
lectivity or yield (R=Ph, R1 =Oct, 90% yield, 93% ee).
The mild reaction conditions employed allow base-sensi-
tive b-nitroethylsulfones to act, for the first time, as formal
practical vinyl anions in a process that provides sulfones
with different substitution patterns at the sulfone moiety,
with good overall yields over the three steps and enantio-
meric excesses in the 93–98% range. The fact that small
vinyl sulfone inhibitors of serine, cysteine, and threonine
proteases,[2,20] as well as those that specifically block the sor-
tase-catalyzed transpeptidation reaction are highly appeal-
ing, strongly supports the utility of this method to increase
the pool of available sulfones, especially with regard to sub-
stitution patterns distinct to those derived from (native) a-
amino acids.
action time.[21] Most significantly, under these conditions, the
reaction proceeds with good yields and without loss of enan-
tioselectivity.
To expand the scope of this concept, we prepared the b-
nitropropanamide 13[22] with the hope that b-acyl vinyl de-
rivatives might be prepared by simply adding Grignard re-
agents to a common single intermediate.[23] Once again, the
conjugate addition of 13 to the enal 5a carried out by em-
ploying standard conditions, as described for the addition of
methyl b-nitropropanoate 11, afforded adduct 14 in very
high chemical and stereochemical efficiency over the three
steps (Scheme 3). The a,b-unsaturated ketones 15 and 16
were obtained by treatment of intermediate 14 with the cor-
responding aryl/alkyl Grignard reagents.
Scope and versatility: Further exploration revealed that this
approach is also applicable to other related vinyl anion
equivalents. For example, methyl b-nitro propanoate 11
reacts with a,b-enals in the presence of catalyst 6 to afford,
after aldehyde protection and nitrous acid elimination, ad-
ducts 12 with very high chemical efficiency over the three
steps (Table 2).
Scheme 3. Conjugate addition of b-nitroethyl Weinreb amides to a,b-
enals.
The distinct functionality of the resulting adducts gives
additional versatility to this procedure. For instance, simple
elaboration of the acetal group in adducts 7 and 12, as
shown in Scheme 4, provided vinyl sulfones 20 and 21 and
a,b-unsaturated ester 22. Compounds that, to the best of
our knowledge, constitute new vinylogous amino sulfone
and amino acid scaffolds. Additionally, as already shown for
peptides containing vinylogous amino acids,[24] these new
types of b2-vinylogous amino acids could exhibit intramolec-
Table 2. Representative g-substituted crotonates prepared.[a]
Entry
Enal, R1
T [8C], t [h][b]
Yield [%][c]
ee [%][d]
1
2
3
4
5a, Et
40, 24
40, 48
40, 48
10, 24
12a 79
12c 92
12e 88
12 f 67
92
91
96
93
5c, nBu
5e, nOct[e]
5 f, Ph
[a] Reactions carried out at 0.5 mmol enal scale by using 1.3 equiv of 11
(2.0 equiv for enal 5 f), 20 mol% catalyst 6 in MeOH (1 mL). Nitrous
acid elimination was carried out by employing DBU for adducts with
alkyl substituents and MgACHTNURTGNEUNG(OMe)2 for aromatic substituents. [b] Reaction
time for the addition of 11. [c] Yield of isolated product. [d] ee deter-
mined by chiral HPLC analysis. [e] Reaction carried out at 4 mmol scale.
It is worth noting the different reactivity displayed by b-
nitroethyl sulfones 1–4 and methyl b-nitro propanoate 11 in
the present reaction. Whilst b-nitroethyl sulfones appear to
be quite sensitive to the reaction conditions, probably as a
result of its high tendency to eliminate the corresponding
sulfinic acid, 11 allows the conjugate addition to be carried
out at 408C to afford the products in a reasonably short re-
Scheme 4. Preparation of surrogates of b2-amino acids.
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Chem. Eur. J. 2011, 17, 2450 – 2457

Catalytic Asymmetric Synthesis of g-Substituted Vinyl Sulfones
FULL PAPER
ular specific interactions and provide defined secondary
structures when incorporated into peptides.[25,26]
Synthetic applications: In addition to the interest in vinyl
sulfone scaffolds for potential drug development, their
chemical utility was also explored. We anticipated that
acetal hydrolysis and aldehyde reduction in the adducts
would provide configurationally defined tetrahydrofuran
products as a result of a concurrent intramolecular oxa-Mi-
chael reaction,[27] the stereochemistry of which should be
dictated by the resident stereocenter in the starting adduct
(Scheme 5). For instance, aldehyde deprotection in adducts
Scheme 6. Intramolecular cycloisomerization towards 4,5-disubstituted
cyclopentane carbaldehydes.
Conclusion
In summary, we have presented an operationally simple
method for the conjugate addition of b-nitroethylsulfones as
bench-storable readily available new formal b-sulfonyl vinyl
anions.[34] The method bears several advantages: 1) it is per-
formed in a one-pot three-step operation without the need
for intermediate isolation, 2) no chiral materials are re-
quired, except the pyrrolidine catalyst that is employed in
substoichiometric quantities, 3) very high chemical efficiency
is attained, and 4) it provides a broad range of vinyl sulfone
scaffolds, important targets for potential drug development.
The key of this method is the ability of the catalyst to pro-
Scheme 5. Application of adducts 7 and 12 in the synthesis of enantioen-
riched 2,3-disubstituted tetrahydrofurans and 3-substituted homoprolines.
d.r.: diastereomeric ratio.
À
mote the C C bond construction before any nitrous acid
7c and 7d provided the corresponding aldehydes that were
subjected to reduction with NaBH4 to afford 23c and 23d
and, as expected, with excellent diastereomeric ratios.
Therefore, this procedure opens a simple way of access to
2,3-disubstituted tetrahydrofurans that nicely complements
previously reported asymmetric methodology.[28] Likewise,
aldehyde deprotection in 12c and 12e, subsequent imine for-
mation, and reduction gave 24c and 24e in good overall
yields and, essentially, as single diastereomers. Thus, the ap-
proach also provides a concise stereocontrolled access to 3-
substituted b3-homoprolines, a class of b-amino acids that
may be of interest in the field of b-peptide foldamers.[25,29]
In each case, the configuration of the newly created stereo-
genic center was determined by NOE experiments that
showed a 1,2-trans relationship between the two substituents
of the respective heterocyclic ring.[14]
The present study is also interesting in that acetal depro-
tection and Wittig olefination provides Rauhut–Currier
building blocks that allow the establishment of the effect of
a stereogenic center upon reaction stereochemistry. Thus, by
following Roush[30] and Krishe[31] cycloisomerization of sub-
strates 25 and 26, 4,5-disubstituted cyclopentene carbalde-
hydes may be accessed in diastereomeric ratios of up to
75:25 (Scheme 6).[32] Therefore, this method provides an at-
tractive and quick entry for the stereoselective synthesis of
suitable substrates to expand the Rauhut–Currier reac-
tion.[33]
and/or sulfinic acid elimination in the starting reagents may
occur, an aspect that further expands the field of iminium
catalysis. Interestingly, the method may also be extended to
other relatively base-sensitive b-electron-withdrawing-substi-
tuted nitroalkanes to afford products with manifold func-
tionality, and provides a quick entry to building blocks that
are very attractive for organic synthesis.
Experimental Section
General considerations: All catalytic reactions were carried out in round-
bottomed vials stopped with a septum and provided with efficient mag-
netic stirring. All solvents were of p. a. quality and were dried by stan-
dard procedures prior to use if necessary. Unless otherwise specified, ma-
terials were obtained from commercial sources and used without purifica-
tion. Purification of reaction products was carried out by flash column
chromatography by using silica gel 60 (0.040–0.063 mm, 230–400 mesh).
Visualization was accomplished with UV light and a solution obtained by
admixing in 470 mL of water ammonium molybdate (21.0 g), cerium sul-
phate (1.0 g), and concentrated sulphuric acid (31 mL), followed by heat-
ing. Melting points were determined with a Buchi SMP-20 capillary appa-
ratus and are uncorrected. H and 13C NMR spectra were recorded at 300
1
and 75 MHz, respectively, on a Bruker Advance-DPX-300. The chemical
shifts are reported in ppm relative to CDCl3 (d=7.26 ppm) for 1H NMR
spectra and relative to the central resonances of CDCl3 (d=77.23 ppm)
for 13C NMR spectra. Optical rotations were recorded on a Jasco P-2000
polarimeter. Analytical HPLC was performed on Waters 600E device
and Hewlett Packard series 1050 chromatographs, equipped with diode
array UV detector by using capilary columns (25 cm). MS spectra were
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2453

C. Palomo et al.
recorded on an ESI-ion trap mass spectrometer (Agilent 1100 series LC/
MSD, SL model). a,b-Unsaturated aldehydes 5g and 5h[35] and methyl 3-
nitropropionate 11[36] were prepared according to reported procedures.
The synthesis of b-nitroethylsulfones (1–4), catalyst 6, b-nitropropana-
mide 13, ketones 15 and 16, as well as the characterization data for com-
pounds 17–19, 20–22, 23, 24, 25, 26, 27, 28, and 29 are described in the
Supporting information.
7.79 (m, 2H), 7.65–7.44 (m, 3H), 6.82 (dd, J=10.0, 15.0 Hz, 1H), 6.30 (d,
J=15.1 Hz, 1H), 4.16 (dd, J=4.3, 7.5 Hz, 1H), 3.23 (s, 3H), 3.19 (s, 3H),
2.25–2.10 (m, 1H), 1.88–1.80 (m, 1H), 1.78–1.50 (m, 2H), 0.87 ppm (dd,
J=6.8, 10.0 Hz, 6H); 13C NMR (75 MHz, CDCl3): d=149.0, 141.2, 133.4,
131.6, 129.5, 127.7, 103.2, 53.5, 52.9, 44.6, 34.6, 32.1, 20.5, 19.3 ppm;
Chiral HPLC (Chiralpak AS-H column; hexane/iPrOH 80:20;
0.75 mLminÀ1, 210 nm): t
RACHTNUTRGENN(UG major)=21.7, tRACHUTNGTREN(NUGN minor)=17.2 min; 95% ee;
HRMS (TOF MS CI): m/z: calcd for C18H29O4S: 341.1787 [M+C2H5]+;
found: 341.1770.
General procedure for the synthesis of adducts 7–10: The corresponding
b-nitroethylsulfone (1–4) (0.65 mmol, 1.3 equiv for aliphatic enals;
0.75 mmol, 1.5 equiv for aromatic enals) was added to a solution of cata-
lyst 6 (0.05 mmol, 0.1 equiv) and the corresponding enal 5 (0.5 mmol,
1 equiv) in dry CH2Cl2 (1 mL). The reaction mixture was stirred at the in-
dicated temperature and when enal consumption was detected by
AHCTUNGTERG(NNUN R,E)-5,5-Dimetoxy-3-octyl-1-phenylsulfonylpent-1-ene (7e): The title
compound was prepared according to the general procedure by starting
from enal 5e (0.220 mL, 1.0 mmol). Yield: 0.306 g (80%); yellow oil;
[a]2D5 =À7.82 (c=1.01 in CH2Cl2); 1H NMR (300 MHz, CDCl3): d=7.90–
7.87 (m, 2H), 7.65–7.47 (m, 3H), 6.79 (dd, J=9.5, 15.1 Hz, 1H), 6.29 (d,
J=15.1 Hz, 1H), 4.21 (dd, J=4.8, 6.9 Hz, 1H), 3.23 (s, 3H), 3.21 (s, 3H),
2.43–2.26 (m, 1H), 1.82–1.74 (m, 1H), 1.64–1.54 (m, 1H), 1.50–1.07 (m,
14H), 0.88 ppm (t, J=6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=
150.6, 141.0, 133.4, 130.5, 129.4, 127.6, 102.7, 53.2, 52.9, 38.4, 37.2, 34.4,
31.9, 29.5, 29.5, 29.3, 27.17, 22.8, 14.2 ppm; Chiral HPLC (Chiralpak AS-
1H NMR spectroscopy, MeOH (2.5 mL), HC
ACTHNUTRGNEU(NG OMe)3 (0.11 mL, 1 mmol,
2 equiv), and p-toluensulfonic acid (0.02 g, 0.1 mmol, 0.2 equiv) were suc-
cessively added. The reaction mixture was stirred at room temperature,
typically for 1 h, and then subjected to the following protocol: Method A
(for aliphatic enals): DBU (0.15 mL, 1 mmol, 2 equiv) was added at 08C
and the reaction mixture was stirred for 1 h while reaching room temper-
ature. Method B (for aromatic enals): Mg
3 mmol) was added and the reaction mixture was stirred at 408C for 2 h
(for adduct 8 f, 4 equiv Mg(OMe)2, room temperature). Then, HCl (0.1n,
2 mL) was added and the aqueous phase extracted with CH2Cl2 (3ꢅ
5 mL). The combined organic phases were dried (MgSO4) and the solvent
eliminated to afford the crude product, which was purified by flash
column chromatography (eluent mixtures EtOAc/hexanes).
(OMe)2 (0.26 g, 6 equiv,
H column; hexane/iPrOH 85:15; 0.75 mLminÀ1, 210 nm): t
17.9, tRA(minor)=15.2 min; 93% ee; HRMS (TOF MS CI): m/z: calcd for
C23H39O4S: 411.2569 [M+C2H5]+; found: 411.2573.
AHCTUNGTERG(NNUN R,E)-5,5-Dimetoxy-3-phenyl-1-phenylsulfonylpent-1-ene (7 f): The title
RACHTUNGTRENNUNG(major)=
CTHUNGTRENNUNG
AHCTUNGTRENNUNG
compound was prepared according to the general procedure by starting
from enal 5 f (0.063 mLg, 0.5 mmol). Yield: 0.116 g (67%); yellow oil;
1
[a]2D5 =À22.39 (c=0.14 in CH2Cl2); H NMR (300 MHz, CDCl3): d=7.90–
A
7.82 (m, 2H), 7.67–7.48 (m, 3H), 7.40–7.23 (m, 3H), 7.20–7.08 (m, 3H),
6.28 (dd, J=1.4, 15.1 Hz, 1H), 4.14 (dd, J=5.0, 6.7 Hz, 1H), 3.70–3.62
(m, 1H), 3.28 (s, 3H), 3.24 (s, 3H), 2.18–1.96 ppm (m, 2H); 13C NMR
(75 MHz, CDCl3): d=149.0, 140.8, 140.2, 133.5, 130.5, 129.4, 129.2, 128.0,
127.8, 127.6, 102.4, 53.5, 53.0, 43.9, 37.8 ppm; Chiral HPLC (Chiralpak
compound was prepared according to the general procedure by starting
from enal 5a (0.050 mL, 0.5 mmol). Yield: 0.118 g (79%); yellow oil;
[a]2D5 =À5.6 (c=1.12 in CH2Cl2); 1H NMR (300 MHz, CDCl3): d=7.92–
7.82 (m, 2H), 7.65–7.47 (m, 3H), 6.79 (dd, J=9.4, 15.1 Hz, 1H), 6.31 (d,
J=15.1 Hz, 1H), 4.22 (dd, J=4.8, 6.9 Hz, 1H), 3.23 (s, 3H), 3.21 (s, 3H),
2.35–2.23 (m, 1H), 1.83–1.75 (m, 1H), 1.66–1.31 (m, 3H), 0.83 ppm (t,
J=7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=150.2, 140.9, 133.3,
130.7, 129.3, 127.5, 102.7, 53.1, 52.9, 39.8, 36.7, 27.2, 11.5 ppm; Chiral
AS-H column; hexane/iPrOH 80:20; 0.75 mLminÀ1, 235 nm): t
34.1, tRA(minor)=28.6 min; 98% ee; HRMS (TOF MS CI): m/z: calcd for
C21H27O4S: 375.1630 [M+C2H5]+; found: 375.1638.
AHCTUNGTERG(NNUN R,E)-5,5-Dimetoxy-3-(4-chloro)phenyl-1-phenylsulfonylpent-1-ene (7g):
RACHTUNGTRENNUNG(major)=
CTHUNGTRENNUNG
HPLC (Chiralpak AS-H column; hexane/iPrOH 80:20; 0.75 mLminÀ1
,
The title compound was prepared according to the general procedure by
starting from enal 5g (0.083 g, 0.5 mmol). Yield: 0.107 g (56%); yellow
oil; [a]2D5 =À13.85 (c=0.65 in CH2Cl2); 1H NMR (300 MHz, CDCl3): d=
7.93–7.82 (m, 2H), 7.70–7.51 (m, 2H), 7.3–7.26 (m, 3H), 7.17–7.04 (m,
3H), 6.28 (dd, J=1.4, 15.1 Hz, 1H), 4.14 (dd, J=4.9, 6.7 Hz, 1H), 3.70–
3.63 (m, 1H), 3.29 (s, 3H), 3.26 (s, 3H), 2.18–1.94 ppm (m, 2H);
13C NMR (75 MHz, CDCl3): d=148.3, 140.6, 138.7, 133.6, 130.9, 129.5,
129.4, 129.3, 127.8, 102.3, 53.5, 53.1, 43.2, 37.7 ppm; Chiral HPLC (Chiral-
210 nm): tRACHTUNGTRENNUNG(major)=26.5, tRAHCTUNGTRENN(UGN minor)=21.1 min; 94% ee; HRMS (TOF
MS CI): m/z: calcd for C17H27O4S: 327.1630 [M+C2H5]+; found:
327.1616.
ACHTUNGTRENNUNG(R,E)-5,5-Dimetoxy-3-methyl-1-phenylsulfonylpent-1-ene (7b): The title
compound was prepared according to the general procedure by starting
from enal 5b (0.041 mL, 0.5 mmol). Yield: 0.101 g (71%); yellow oil;
[a]2D5 =À26.9 (c=0.60 in CH2Cl2); 1H NMR (300 MHz, CDCl3): d=7.95–
7.78 (m, 2H), 7.69–7.44 (m, 3H), 6.95 (dd, J=7.1, 15.1 Hz, 1H), 6.29 (dd,
J=1.1, 15.1 Hz, 1H), 4.30 (t, J=5.8 Hz, 1H), 3.29 (s, 3H), 3.28 (s, 3H),
2.63–2.52 (m, 1H), 1.73–1.69 (m, 2H), 1.09 ppm (d, J=6.8 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=151.4, 140.9, 133.5, 129.4, 127.8, 102.7,
53.1, 38.5, 32.6, 19.4 ppm; Chiral HPLC (Chiralpak IC column; hexane/
pak IC column; hexane/iPrOH 50:50; 0.5 mLminÀ1, 235 nm): t
27.7, tRA(minor)=26.9 min; 98% ee; HRMS (TOF MS CI): m/z: calcd for
C21H26O4SCl: 409.1240 [M+C2H5]+; found: 409.1256.
(R,E)-5,5-Dimetoxy-3-(4-methyl)phenyl-1-phenylsulfonylpent-1-ene (7h):
RACHTUNGTRENNUNG(major)=
CTHUNGTRENNUNG
AHCTUNGTRENNUNG
The title compound was prepared according to the general procedure by
starting from enal 5h (0.073 g, 0.5 mmol). Yield: 0.103 g (57%); yellow
oil; [a]2D5 =À23.34 (c=0.36 in CH2Cl2); 1H NMR (300 MHz, CDCl3): d=
7.91–7.76 (m, 2H), 7.65–7.44 (m, 3H), 7.14–7.00 (m, 5H), 6.24 (dd, J=
1.4, 15.1 Hz, 1H), 4.12 (dd, J=4.9, 6.7 Hz, 1H), 3.64–3.57 (m, 1H), 3.26
(s, 3H), 3.22 (s, 3H), 2.34 (s, 3H), 2.13–1.91 ppm (m, 2H); 13C NMR
(75 MHz, CDCl3): d=149.3, 140.9, 137.3, 137.1, 133.5, 130.3, 129.9, 129.4,
127.8, 127.8, 102.4, 53.5, 53.0, 43.5, 37.8, 21.2 ppm; Chiral HPLC (Chiral-
pak AS-H column; hexane/iPrOH 80:20; 0.75 mLminÀ1, 235 nm): tR-
iPrOH 95:5; 1.0 mLminÀ1
, 210 nm): tRACHTUGNTREN(UNGN major)=111.1, tRACHTNUGRETNNUG(minor)=
107.9 min; 94% ee; HRMS (TOF MS CI): m/z: calcd for C16H25O4S:
313.1474 [M+C2H5]+; found: 313.1482.
ACHTUNGTRENNUNG(R,E)-3-Butyl-5,5-dimetoxy-1-phenylsulfonylpent-1-ene (7c): The title
compound was prepared according to the general procedure by starting
from enal 5c (0.580 mL, 4.0 mmol). Yield: 1.175 g (90%); yellow oil;
[a]2D5 =À4.2 (c=0.78 in CH2Cl2); 1H NMR (300 MHz, CDCl3): d=7.90–
7.77 (m, 2H), 7.64–7.40 (m, 3H), 6.75 (dd, J=9.5,15.1 Hz, 1H), 6.26 (d,
J=15.1 Hz, 1H), 4.17 (dd, J=5.1, 6.5 Hz, 1H), 3.18 (d, J=1.0 Hz, 3H),
3.16 (d, J=0.9 Hz, 3H), 2.35–2.25 (m, 1H), 1.81–1.48 (m, 2H), 1.47–1.03
(m, 6H), 0.79 ppm (t, J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=
150.6, 141.0, 133.3, 130.5, 129.3, 127.6, 102.8, 53.1, 52.9, 38.3, 37.2, 34.0,
29.2, 22.6, 13.9 ppm; Chiral HPLC (Chiralpak AS-H column; hexane/
iPrOH 80:20; 0.75 mLminÀ1, 210 nm): tR (major)=18.7, tR (minor)=
15.5 min; 95% ee; elemental analysis calcd (%) for C17H26O4S (326.45): C
62.55, H 8.03, S 9.82; found: C 62.40, H 8.21, S 10.21.
A
RACHTUNGTRENUN(NG minor)=24.9 min; 97% ee; HRMS (TOF MS CI): m/z:
AHCTUNGTRENNUNG
(7i): The title compound was prepared according to the general proce-
dure by starting from enal 5i (0.081 g, 0.5 mmol). Yield: 0.113 g (60%);
1
yellow oil; [a]2D5 =À8.0 (c=0.82 in CH2Cl2); H NMR (300 MHz, CDCl3):
d=7.87–7.79 (m, 2H), 7.62–7.48 (m, 3H), 7.14–7.00 (m, 3H), 6.87–6.83
(m, 2H), 6.23 (dd, J=1.4, 15.1 Hz, 1H), 4.12 (dd, J=4.9, 6.8 Hz, 1H),
3.79 (s, 3H), 3.62–3.55 (m, 1H), 3.25 (s, 3H), 3.21 (s, 3H), 2.14–1.88 ppm
(m, 2H); 13C NMR (75 MHz, CDCl3): d=159.0, 149.4, 140.8, 133.5, 132.0,
130.2, 129.4, 129.0, 127.8, 114.6, 102.4, 55.5, 53.5, 53.0, 43.0, 37.8 ppm;
Chiral HPLC (Chiralpak AS-H column; hexane/iPrOH 80:20;
ACHTUNGTRENNUNG(S,E)-5,5-Dimetoxy-3-isopropyl-1-phenylsulfonylpent-1-ene (7d): The
title compound was prepared according to the general procedure by start-
ing from enal 5d (0.060 mL, 0.5 mmol). Yield: 0.094 g (60%); yellow oil;
[a]2D5 =À12.8 (c=0.42 in CH2Cl2); 1H NMR (300 MHz, CDCl3): d=7.97–
2454
www.chemeurj.org
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 2450 – 2457

Catalytic Asymmetric Synthesis of g-Substituted Vinyl Sulfones
FULL PAPER
0.75 mLminÀ1, 235 nm): t
(major)=61.9, t
E
hexane/iPrOH
RA(minor)=34.4 min; 96% ee; HRMS (TOF MS CI): m/z: calcd for
C12H23O3S: 247.1368 [M+H-CH3OH]+; found: 247.1363.
(R,E)-5,5-Dimetoxy-3-ethyl-1-propylsulfonylpent-1-ene (10a): The title
98:2;
0.75 mLminÀ1
,
210 nm):
tRACHTNGUTERN(UNG major)=27.3,
HRMS (TOF MS CI): m/z: calcd for C22H29O5S: 405.1736 [M+C2H5]+;
t CHTUNGTRENNUNG
found: 405.1739.
ACHTUNGTRENNUNG(R,E)-5,5-Dimetoxy-3-ethyl-1-(2-pyridyl)sulfonylpent-1-ene (8a): The
AHCTUNGTRENNUNG
title compound was prepared according to the general procedure by start-
ing from enal 5a (0.058 mL, 0.50 mmol). Yield: 0.136 g (62%); yellow
oil; [a]2D5 =À4.5 (c=0.95 in CH2Cl2); 1H NMR (300 MHz, CDCl3): d=
8.70 (d, J=4.7 Hz, 1H), 8.08 (d, J=7.9 Hz, 1H), 7.93 (td, J=1.7, 7.8 Hz,
1H), 7.49 (ddd, J=1.1, 4.7, 7.6 Hz ,1H), 6.90 (dd, J=9.4, 15.2 Hz, 1H),
6.52 (dd, J=0.5, 15.2 Hz, 1H), 4.28 (dd, J=4.7, 7.1 Hz, 1H), 3.23 (s, 3H),
3.22 (s, 3H), 2.42–2.25 (m, 1H), 1.84–1.76 (m, 1H), 1.67–1.31 (m, 3H),
0.84 ppm (t, J=7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=158.9,
153.4, 150.4, 138.3, 128.1, 127.2, 121.9, 102.8, 53.2, 53.1, 40.3, 36.8, 27.3,
11.6 ppm; Chiral HPLC (Chiralpak AS-H column; hexane/iPrOH 70:30;
compound was prepared according to the general procedure by starting
from enal 5a (0.050 mL, 0. 50 mmol). Yield: 0.099 g (75%); yellow oil;
[a]2D5 =À11.0 (c=1.04 in CH2Cl2); 1H NMR (300 MHz, CDCl3): d=6.69
(dd, J=9.3, 15.2 Hz, 1H), 6.24 (d, J=15.2 Hz, 1H), 4.30 (dd, J=4.9,
6.7 Hz, 1H), 3.27 (s, 6H), 2.96–2.86 (m, 2H), 2.39–2.25 (m, 1H), 1.87–
1.72 (m, 3H), 1.67–1.32 (m, 3H), 1.04 (t, J=7.4 Hz, 3H), 0.87 ppm (t, J=
7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=152.5, 128.3, 102.8, 56.7,
53.3, 52.9, 40.0, 36.2, 27.3, 16.5, 13.2, 11.6 ppm; Chiral HPLC (Chiralpak
AS-H column; hexane/iPrOH 80:20; 0.75 mLminÀ1, 210 nm): t
30.3, tRA(minor)=26.7 min; 93% ee; HRMS (TOF MS CI): m/z: calcd for
C11H21O3S: 233.1211 [M+H-CH3OH]+; found: 233.1216.
RACHTUNGTRENNUNG(major)=
CTHUNGTRENNUNG
0.75 mLminÀ1, 210 nm): t
RACHTNUTRGENN(UG major)=22.1, tRACHUTNGTREN(NUGN minor)=16.2 min; 95% ee;
elemental analysis calcd (%) for C14H21NO4S (299.12): C 56.16, H 7.07, N
4.68, S 10.71; found: C 56.65, H 7.57, N 5.15, S 10.97.
General procedure for the synthesis of adducts 12 and 14: The same pro-
cedure described for the preparation of adducts 7--10 was followed by
employing 20 mol% catalyst 6.
ACHTUNGTRENNUNG(S,E)-5,5-Dimetoxy-3-isopropyl-1-(2-pyridyl)sulfonylpent-1-ene (8d): The
title compound was prepared according to the general procedure by start-
AHCTUNGERTG(NNUN R,E)-Methyl 4-ethyl-6,6-dimethoxyhex-2-enoate (12a): The title com-
ing from enal 5d (0.075 mL, 0.75 mmol). Yield: 0.080 g (51%); pale-
pound was prepared according to the general procedure by starting from
1
yellow oil; [a]2D5 =À6.2 (c=1.04 in CH2Cl2); H NMR (300 MHz, CDCl3):
enal 5a (0.050 mL, 0.5 mmol). Yield: 0.085 g (79%); yellow oil; [a]D25
=
d=8.70 (d, J=4.7 Hz, 1H), 8.09 (dt, J=1.0, 7.9 Hz, 1H), 7.93 (td, J=1.7,
7.8 Hz, 1H), 7.49 (ddd, J=1.1, 4.7, 7.6 Hz, 1H), 6.94 (dd, J=10.0,
15.2 Hz, 1H), 6.50 (d, J=15.2 Hz, 1H), 4.23 (dd, J=4.1, 7.8 Hz, 1H),
3.24 (s, 3H), 3.21 (s, 3H) 2.33–2.19 (m, 1H), 1.91–1.81 (m, 1H), 1.79–1.54
(m, 2H), 0.88 ppm (dd, J=6.8, 10.9 Hz, 6H); 13C NMR (75 MHz,
CDCl3): d=158.8, 152.0, 150.2, 138.1, 128.6, 127.0, 121.7, 102.9, 53.2, 52.7,
44.8, 34.3, 31.8, 20.3, 19.1 ppm; Chiral HPLC (Chiralpak AS-H column;
1
À19.7 (c=1.34 in CH2Cl2); H NMR (300 MHz, CDCl3): d=6.74 (dd, J=
9.4, 15.7 Hz, 1H), 5.81 (d, J=15.7 Hz, 1H), 4.30 (dd, J=4.4, 7.4 Hz, 1H),
3.73 (s, 3H), 3.30 (s, 3H), 3.28 (s, 3H), 2.31–2.16 (m, 1H), 1.83–1.72 (m,
1H), 1.66–1.28 (m, 3H), 0.86 ppm (t, J=7.4 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=167.2, 152.7, 121.4, 103.0, 53.0, 53.0, 51.6, 40.5, 37.1, 27.6,
11.6 ppm; Chiral HPLC (Chiralpak OD-H OD column; hexane/iPrOH
99:1; 0.30 mLminÀ1
, 209.8 nm): tRACHTUGNTREN(UNGN major)=38.3, tRACHTUNGTNUER(NG minor)=49.8 min;
hexane:iPrOH 80:20; 0.75 mLminÀ1
tRACHTUNGTRENNUNG(minor)=20.4 min; 96% ee; HRMS (TOF MS CI): m/z: calcd for
,
210 nm):
tRACHTNGUTERN(UNG major)=27.6,
92% ee.
C14H20NO3S: 282.1164 [M+HÀCH3OH]+; found: 282.1164.
AHCTUNGTERG(NNUN R,E)-Methyl 4-(2,2-dimethoxyethyl)oct-2-enoate (12c): The title com-
pound was prepared according to the general procedure by starting from
enal 5c (0.072 mL, 0.5 mmol). Yield: 0.113 g (92%); pale-yellow oil;
[a]2D5 =À7.5 (c=1.08 in CH2Cl2); 1H NMR (300 MHz, CDCl3): d=6.72
(dd, J=9.5, 15.6 Hz, 1H), 5.78 (d, J=15.7 Hz, 1H), 4.29 (dd, J=4.4,
7.4 Hz, 1H), 3.70 (s, 3H), 3.27 (s, 3H), 3.26 (s, 3H), 2.36–2.22 (m, 1H),
1.80–1.69 (m, 1H), 1.61–1.49 (m, 1H), 1.48–1.14 (m, 6H), 0.84 ppm (t,
J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=167.1, 153.0, 121.1,
102.7, 52.9, 52.8, 51.6, 38.8, 37.4, 34.4, 29.3, 22.8, 14.1 ppm; Chiral HPLC
ACHTUNGTRENNUNG(R,E)-5,5-Dimetoxy-3-octyl-1-(2-pyridyl)sulfonylpent-1-ene (8e): The
title compound was prepared according to the general procedure by start-
ing from enal 5e (0.396 mL, 2.0 mmol). Yield: 0.705 g (92%); yellow oil;
[a]2D5 =À2.7 (c=1.45, CH2Cl2); 1H NMR (300 MHz, CDCl3): d=8.66 (d,
J=4.7 Hz, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.90 (td, J=1.7, 7.8 Hz, 1H),
7.46 (ddd, J=1.1, 4.7, 7.6 Hz, 1H), 6.86 (dd, J=9.5, 15.2 Hz, 1H), 6.47
(d, J=15.2 Hz, 1H), 4.23 (dd, J=4.7, 7.1 Hz, 1H), 3.19 (s, 3H), 3.18 (s,
3H) 2.48–2.30 (m, 1H), 1.81–1.70 (m, 1H), 1.62–1.51 (m, 1H), 1.47–1.32
(m, 2H), 1.27–1.07 (m, 12H), 0.82 ppm (t, J=6.8 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=158.8, 153.6, 150.2, 138.2, 127.8, 127.1, 121.8, 102.7,
53.1, 52.9, 38.7, 37.1, 34.3, 31.9, 29.5, 29.5, 29.2, 27.0, 22.7, 14.2 ppm;
Chiral HPLC (Chiralpak AS-H column; hexane/iPrOH 80:20;
(Chiralpak OD OD-H column; hexane/iPrOH 99:1; 0.30 mLminÀ1
,
209.8 nm): tRACHTNUTRGENNGU(major)=33.0, tRAHCTUNGTRENN(UGN minor)=40.5 min; 91% ee; HRMS (TOF
MS CI): m/z: calcd for C12H22O3: 213.1491 [M+HÀCH3OH]+; found:
213.1485.
0.75 mLminÀ1, 210 nm): t
RACHTNUTRGENN(UG major)=23.4, tRACHUTNGTREN(NUGN minor)=19.1 min; 94% ee;
AHCTUNGERTG(NNUN R,E)-Methyl 4-(2,2-dimethoxyethyl)dodec-2-enoate (12e): The title
compound was prepared according to the general procedure by starting
from enal 5e (0.110 mL, 0.5 mmol). Yield: 0.138 g (88%); colorless oil;
[a]2D5 =+2.0 (c=0.3 in CH2Cl2); 1H NMR (300 MHz, CDCl3): d=6.75
(dd, J=9.5, 15.6 Hz, 1H), 5.81 (d, J=15.6 Hz, 1H), 4.31 (dd, J=4.4,
7.4 Hz, 1H), 3.73 (s, 3H), 3.30 (s, 3H), 3.29 (s, 3H), 2.40–2.25 (m, 1H),
1.83–1.71 (m, 1H), 1.64–1.55 (m, 1H), 1.24 (s, 14H), 0.87 ppm (t, J=
6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=167.2, 153.1, 121.2, 103.0,
53.1, 53.0, 51.6, 38.9, 37.5, 34.8, 32.1, 29.8, 29.7, 29.5, 27.2, 22.9, 14.3 ppm;
Chiral HPLC (Chiralpak OD OD-H column; hexane:iPrOH 99:01;
HRMS (TOF MS CI): m/z: calcd for C19H30NO3S: 352.1946
[M+HÀCH3OH]+; found: 352.1955.
(R,E)-5,5-Dimetoxy-3-phenyl À1-(2-pyridyl)sulfonylpent-1-ene (8 f): The
title compound was prepared according to the general procedure by start-
ing from enal 5 f (0.063 mL, 0.50 mmol). Yield: 0.121 g (70%); yellow
oil; [a]2D5 =+3.0 (c=0.18 in CH2Cl2); 1H NMR (300 MHz, CDCl3): d=
8.71 (d, J=4.7 Hz, 1H), 8.05 (d, J=7.9 Hz, 1H), 7.92 (td, J=1.7, 7.8 Hz,
1H), 7.50 (ddd, J=1.1, 4.7, 7.6 Hz, 1H), 7.36- 7.14 (m, 6H), 6.52 (dd, J=
1.4, 15.2 Hz, 1H), 4.17 (dd, J=5.2, 6.6 Hz, 1H), 3.75–3.65 (m, 1H), 3.27
(s, 3H), 3.23 (s, 3H), 2.18–1.98 ppm (m, 2H); 13C NMR (75 MHz,
CDCl3): d=158.7, 151.8, 150.4, 140.1, 138.3, 129.2, 128.1, 127.9, 127.6,
127.2, 122.0, 102.3, 53.4, 53.0, 44.2, 37.7 ppm; Chiral HPLC (Chiralpak
0.30 mLminÀ1, 209.8 nm): t
RACHTNUTRGENN(UG major)=31.5, tRACHUTNGTREN(NUGN minor)=37.2 min; 96% ee;
HRMS (TOF MS CI): m/z: calcd for C19H37O4: 329.2692 [M+C2H5]+;
found: 329.2708.
AS-H column; hexane/iPrOH 80:20; 0.75 mLminÀ1, 210 nm): t
RACTHNUTRGNEU(GN major)=
AHCTUNGTERG(NNUN R,E)-Methyl 6,6-dimethoxy-4-phenylhex-2-enoate (12 f): The title com-
50.6, tRACHTUNGTRENNUNG(minor)=40.6 min; 93% ee; HRMS (TOF MS CI): m/z: calcd for
pound was prepared according to the general procedure by starting from
enal 5 f (0.063 mL, 0.5 mmol). Yield: 0.086 g (67%); yellow oil; [a]2D5 =+
1.9 (c=0.60 in CH2Cl2); 1H NMR (300 MHz, CDCl3): d=7.38–7.18 (m,
5H), 7.10 (dd, J=7.7, 15.7 Hz, 1H), 5.83 (dd, J=1.3, 15.7 Hz, 1H), 4.22
(t, J=5.9 Hz, 1H), 3.73 (s, 3H), 3.67–3.57 (m, 1H), 3.31 (s, 3H), 3.30 (s,
3H), 2.17–1.99 ppm (m, 2H); 13C NMR (75 MHz, CDCl3): d=167.1,
151.4, 141.5, 129.1, 128.0, 127.2, 120.8, 102.5, 53.2, 52.9, 51.7, 44.4,
37.8 ppm; Chiral HPLC (Chiralpak OD OD-H column; hexane/iPrOH
C17H18NO3S: 316.1007 [M+HÀCH3OH]+; found: 316.0995.
ACHTUNGTRENNUNG(R,E)-5,5-Dimetoxy-3-ethyl-1-tert-butylsulfonylpent-1-ene (9a): The title
compound was prepared according to the general procedure by starting
from enal 1a (0.050 mL, 0.5 mmol). Yield: 0.050 g (40%); yellow oil;
[a]2D5 =À6.0 (c=0.94 in CH2Cl2); 1H NMR (300 MHz, CDCl3): d=6.70
(dd, J=9.3, 15.2 Hz, 1H), 6.24 (dd, J=0.7, 15.2 Hz, 1H), 4.33 (dd, J=4.8,
6.9 Hz, 1H), 3.30 (s, 3H), 3.29 (s, 3H), 2.44–2.30 (m, 1H), 1.86–1.76 (m,
1H), 1.70–1.39 (m, 3H), 1.36 (s, 9H), 0.90 ppm (t, J=7.4 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=154.4, 124.2, 102.9, 58.5, 53.4, 53.0, 40.4,
36.9, 27.5, 23.6, 11.7 ppm; Chiral HPLC (Chiralpak AD-H column;
99:01; 0.30 mLminÀ1, 209.8 nm): t
RACTHNUTRGENNUG(major)=76.9, tRCAHTUNGTREN(NUGN minor)=66.2 min;
93% ee; HRMS (TOF MS CI): m/z: calcd for C14H17O3: 233.1178
[M+HÀCH3OH]+; found: 233.1177.
Chem. Eur. J. 2011, 17, 2450 – 2457
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2455

C. Palomo et al.
A
General procedure for the synthesis of 4,5-disubstituted cyclopentane
carbaldehydes (27, 28): HCl (6n, 3 mLmmolÀ1) was added to a solution
of the corresponding crude adduct (7c, 8e) in acetone (6 mLmmolÀ1) at
room temperature and the reaction mixture was stirred for 1 h. Then,
H2O (3 mLmmolÀ1) was added, the organic solvent eliminated under re-
duced pressure, and the aqueous phase was extracted with CH2Cl2 (2ꢅ
5 mL). The combined organic layers were dried (MgSO4), filtered, and
the solvent eliminated to afford the crude aldehyde in quantitative yield.
The aldehyde was added dropwise in CHCl3 (1.7 mL) at 08C to a solution
of formylmethylenetriphenylphosphorane (0.417 g, 1.38 mmol, 2 equiv) in
CHCl3 (5 mL). The resulting mixture was stirred at the same temperature
for 2 h, warmed up to 508C, and stirred for 24 h. Upon reaction comple-
tion, the solvent was removed under reduced pressure and the crude
product was purified by flash column chromatography (eluent mixtures
EtOAc/hexanes 50:50) to afford the corresponding pure aldehyde (25/26)
as an E/Z mixture. Tributylphosphine (0.008 mL, 0.032 mmol, 0.2 equiv)
was added to a solution of the corresponding aldehyde (0.16 mmol) in
CH2Cl2 (1 mL) and the reaction mixture was stirred at room temperature
for 15 h. Then, H2O (3 mL) was added, the organic solvent eliminated
under reduced pressure, and the aqueous phase was extracted with
CH2Cl2 (2ꢅ5 mL). The combined organic layers were dried (MgSO4), fil-
tered, and the solvent eliminated to afford the corresponding pure cyclo-
pentane carbaldehyde.
compound 14 was prepared according to the general procedure by start-
ing from enal 5a (0.100 mL, 1.00 mmol). Yield: 0.214 g (87%); pale-
yellow oil; [a]2D5 =À17.2 (c=1.10 in CH2Cl2); 1H NMR (300 MHz,
CDCl3): d=6.75 (dd, J=9.4, 15.4 Hz, 1H), 6.40 (d, J=15.4 Hz, 1H), 4.34
(dd, J=4.3, 7.6 Hz, 1H), 3.69 (s, 3H), 3.31 (s, 3H), 3.29 (s, 3H), 3.24 (s,
3H), 2.35–2.21 (m, 1H), 1.84–1.73 (m, 1H), 1.66–1.56 (m, 1H), 1.56–1.30
(m, 2H), 0.87 ppm (t, J=7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=
167.0, 150.8, 119.3, 103.1, 61.9, 53.1, 53.0, 40.6, 37.2, 32.6, 27.7, 11.7 ppm;
Chiral HPLC (Chiralpak AS-H column; hexane/iPrOH 98:02;
0.70 mLminÀ1, 209.8 nm): t
RACHTNUTRGENN(UG major)=26.0, tRACHUTNGTREN(NUGN minor)=22.8 min; 97% ee;
HRMS (TOF MS CI): m/z: calcd for C14H28NO4: 274.2018 [M+C2H5]+;
found: 274.2024.
General procedure for the preparation of surrogates of b-aminoacids 20–
22: Jones reagent[37] (1.5 equiv) was added dropwise to a solution of the
corresponding adduct in acetone (10 mLmmolÀ1) at 08C. The reaction
mixture was then stirred at room temperature for 15 h. Excess isopropa-
nol was added and the mixture stirred for an additional 2 h. Then, the
mixture was filtered and the solvent was removed in the filtrate. The resi-
due was dissolved in EtOAc and washed with HCl (2n). The aqueous
phase was extracted twice with EtOAc and then the organic layers were
combined and dried (MgSO4). The organic solvent was eliminated to
afford the corresponding carboxylic acids 17–19 that were purified by
column chromatography (eluent mixtures EtOAc/hexanes). Phenyl di-
chlorophosphate (2.0 equiv) was added to a stirred suspension of the cor-
responding carboxylic acid (1 equiv), pyridine (5 equiv), and sodium
azide (2 equiv) in dry CH2Cl2 (6 mLmmol À1) at 208C. The reaction mix-
ture was stirred for 15–24 h at 208C and then the solvent was removed
under an argon atmosphere. The crude product was dissolved in dry
tBuOH (6 mLmmol À1) and the solution heated to reflux for 2 h. Then,
the solvent was eliminated and the crude compound was purified by
column chromatography by using EtOAc/hexanes mixtures.
Acknowledgements
This work was financially supported by the University of the Basque
Country (UPV/EHU) and Ministerio de Ciencia e Innovaciꢀn (grant no.
CTQ 2007-68095-C02, Spain). A predoctoral grant to M.Z. (MEC) is ac-
knowledged. We are grateful to SGiker (UPV) for NMR and HRMS fa-
cilities.
General procedure for the synthesis 2,3-disubstituted tetrahydrofurans
23: HCl (6n, 3 mLmmolÀ1) was added to a solution of the corresponding
crude adduct 7 in acetone (6 mLmmolÀ1) at room temperature and the
reaction mixture was stirred for 1 h. Then, H2O (3 mLmmolÀ1) was
added and the organic solvent eliminated under reduced pressure and
the aqueous phase was extracted with CH2Cl2. The combined organic
layers were dried (MgSO4), filtered, and the solvent eliminated to afford
the crude aldehyde in quantitative yield. NaBH4 (4 equiv) in EtOH
(3 mLmmolÀ1) was added to a solution of the corresponding aldehyde in
EtOH (5 mLmmolÀ1) at À208C. The reaction mixture was stirred for 24–
48 h, quenched with H2O, and the organic solvent eliminated under re-
duced pressure. The aqueous phase was extracted with CH2Cl2, the com-
bined organic layers dried (MgSO4), and the solvent eliminated to afford
the crude product that was purified by flash column chromatography
(eluent mixtures EtOAc/hexanes) to afford the pure 2,3-disubstituted tet-
rahydrofuran.
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www.chemeurj.org
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 2450 – 2457

Catalytic Asymmetric Synthesis of g-Substituted Vinyl Sulfones
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Received: November 4, 2010
Published online: January 19, 2011
Chem. Eur. J. 2011, 17, 2450 – 2457
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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