Catalytic conjugate additions of geminal bis(sulfone)s: Expanding the chemistry of sulfones as simple alkyl anion equivalents

Article abstract of DOI:10.1002/chem.200902094

The value of cyclic gem-bis-(sulfone) 4 as a simple alkyl nucleophile equivalent in catalytic C-C bondforming reactions is demonstrated. The 1,4-type nucleophilic additions of bis-(sulfone) 4 to α,β-unsaturated ketones take place by assistance of catalyti

Full text of DOI:10.1002/chem.200902094

DOI: 10.1002/chem.200902094
Catalytic Conjugate Additions of Geminal BisACTHNUTRGENUG(N sulfone)s: Expanding the
Chemistry of Sulfones as Simple Alkyl Anion Equivalents
Aitor Landa, ꢀngel Puente, J. Ignacio Santos, Silvia Vera, Mikel Oiarbide, and
Claudio Palomo*[a]
Dedicated to Professor Josep Font on the occasion of his 70th birthday
Abstract: The value of cyclic gem-bis-
ACHTUNGTRENNUNG(sulfone) 4 as a simple alkyl nucleo-
phile equivalent in catalytic C–C bond-
forming reactions is demonstrated. The
1,4-type nucleophilic additions of bis-
tion of adducts gives rise to the corre-
sponding b-methyl aldehydes, as well
as the derived alcohols, acetals, and
methyl esters after simple (Mg,
MeOH) well-established protocols. Ap-
plication of the procedure to the syn-
thesis of biologically relevant pheneth-
yl building blocks is shown. Most inter-
estingly, a-alkylation of initially ob-
highly enantioselective access to b-
branched aldehydes, alcohols, or esters
is possible. Further exploration of the
method includes the use of chiral a,b-
unsaturated aldehydes derived from
citronellal as the Michael acceptor
partners. In these instances, the sense
of the conjugate addition of 4 is con-
trolled by the chirality of the pyrroli-
dine catalyst, thus allowing for a ste-
reochemically predictable access to 1,3-
dimethyl arrays, such as those present
in deoxygenated polyketide-type natu-
ral products. The intramolecular varia-
tion of this technology by using doubly
unsaturated aldehyde–ester 22 illustrat-
ed the site selectivity of the procedure
and its potential for tandem processes
leading to highly substituted polycyclic
systems, such as 24.
ACHTUNGTRENNUNG(sulfone) 4 to a,b-unsaturated ketones
take place by assistance of catalytic
guanidine base. On the other hand,
pyrrolidines are able to catalyze the
conjugate addition of 4 to both enones
and enals, likely by means of iminium
ion activation. Upon exploration of the
best chiral pyrrolidine catalyst, it has
been found that the addition of 4 to
enals catalyzed by diphenylprolinol
silyl ether 10 proceeds with very high
tained bisACTHNUGRTENUNG(sulfone) adducts can be
done even with less reactive alkylating
reagents, such as long linear-chain or
branched-chain alkyl halides. Accord-
ingly, upon the desulfonation process, a
general, experimentally simple and
enantioselectivity
(b-aryl-substituted
Keywords: alkylation · asymmetric
catalysis · enals · Michael addition ·
sulfones
enals >95% ee; b-alkyl substituted
enals up to 94% ee; ee=enantiomeric
excess). Further reductive desulfona-
Introduction
geminal sulfonyl groups (gem-bisACTHUGNETRNNU(G sulfonyl)s) may be regard-
ed as synthetic equivalents of nucleophilic alkyl units with
multiple applications in the field of natural product synthe-
sis.[2] For years, realization of this concept has mainly relied
on 1) irreversible generation of the sulfonyl a-carbanion by
treatment with stoichiometric base in a separate step, 2) sub-
sequent reaction with the corresponding electrophile; and
3) final reductive elimination of the sulfonyl group by action
of metallic sodium or magnesium.[1–3] Although more ad-
vanced, direct methods capable of merging steps (1) and (2)
by means of catalytic activation of the substrates still remain
challenging. To date, sulfone-based direct catalytic C–C
bond-forming methods are confined to either a-fluoro bi-
s(phenylsulfonyl)methane[4] or monosulfones bearing an ad-
ditional carbonyl, ester, or nitrile group at the a-position
(Scheme 1).[5] Here we describe the first general catalytic,
Sulfones are very attractive compounds in synthesis.[1] For
example, alkylsulfones can function as C nucleophiles owing
to a-carbanion stabilization by the electron-withdrawing sul-
À
fonyl group, whereas the C SO2Ar group can be trans-
À
formed in a number of ways, particularly into C H through
reductive desulfonation. Accordingly, alkanes bearing two
[a] Dr. A. Landa, ꢀ. Puente, Dr. J. I. Santos, S. Vera,
Prof. Dr. M. Oiarbide, Prof. Dr. C. Palomo
Departamento de Quꢁmica Orgꢂnica I, Universidad del Paꢁs Vasco
Apdo. 1072, 20080, San Sebastiꢂn (Spain)
Fax : (+34)943015270
E-mail: claudio.palomo@ehu.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902094.
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FULL PAPER
Table 1. Base-catalyzed conjugate additions of gem-bisACTHNUTRGNEUG(N sulfone)s.
Entry
R
Bis
(sulfone)
Base
Conv/yield [%][b]
1
2
3
4
Me
1
2
3
4
any
any
any
Et3N
0
0
0
0
Scheme 1. Sulfones as C nucleophiles in catalytic C–C bond-forming re-
actions and their synthetic equivalence.
5
6
pyrrolidine
DBU
quant./88
0
sulfone-based simple alkyl nucleophile equivalent concept
as defined in Scheme 1, which may help to expand the use
of sulfones in synthesis.
7
8
9
10
11
TBD
quant./91
–
0
quant./90
0
[c]
H
1
3
4
5
DBU or TBD
pyrrolidine
pyrrolidine
pyrrolidine
Results and Discussion
[a] Reactions conducted at 1 mmol scale in CH2Cl2 (2 mL) at RT for
16 h. [b] Yield of 1,4-addition product after column chromatography.
[c] Only unidentified products detected.
Preparation of gem-bisACTHUNRGTNE(NUG sulfone)s and a working plan: Sul-
fones 2 and 5 used in this study can be prepared by alkyla-
tion of the corresponding unsubstituted sulfones 1, which is
commercially available, and 4, respectively. The latter can
be prepared by the method of Kꢄndig[6] and 3 by simple oxi-
addition adduct was obtained in 91% yield (entry 7). Inter-
estingly, the reaction also proceeded to completion with
20 mol% pyrrolidine (88% isolated yield, entry 5), which in-
dicated that not only Brønsted base mediated activation, but
also an iminium ion activation mechanism is possible. Subse-
quent experiments by using cyclic bisACTHNUTRGNEUNG(sulfone) 4 and cinna-
maldehyde as the acceptor confirmed this trend and, with
pyrrolidine as the catalyst, 90% of the addition aldehyde
adduct was obtained (entry 10).
Catalyst screening for asymmetric conjugate additions to
enals: Based on the above assumptions, the enantioselective
version of the reaction between 4 and a,b-unsaturated alde-
hydes was explored (Scheme 2 and Table 2). First evaluation
dation of the corresponding bisACTHNUTRGNEUGN(sulphide) with meta-chloro-
perbenzoic acid (mCPBA).
The viability of the proposal was first assessed for base-
catalyzed conjugate addition reactions, by using a selection
of the reaction between cinnamaldehyde and bis
in the presence of chiral imidazolidinones 8 and 9, which are
ACHTUNGTRENUN(NG sulfone) 4
of prototypical Michael acceptors and gem-bisACHTNUTRGNE(NUG sulfone)s 1–
5. Because of the easy removal of the sulfonyl group, that is,
Mg/MeOH,[7] success in this goal would represent an attrac-
tive way for the installation of formal alkyl fragments at the
b-position of the carbonyl function. In addition, by proper
choice of a chiral non-racemic organic catalyst, the C–C
bond-forming process could be rendered enantioselective.[8]
Initial experiments, however, revealed that both 1 and 2 did
not react[9] with either cinnamaldehyde or benzylidenace-
tone regardless of the amine (Et3N, pyrrolidine), amidine
(1,5-diazabicyclo
(1,5,7-triazabicyclo
triazabicyclo
[4.4.0]dec-5-ene (MTBD))[10] used as the cata-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
lyst (20 mol% loading). No improvement was observed by
changing to the more acidic bis(trifluoromethyl) analogue 3
(Table 1, entries 1–3). Complete failure was also met in at-
tempted reactions of 4 with benzylideneacetone when Et3N
or DBU were employed (entries 4, 6). However, in the pres-
ence of 20 mol% TBD, quantitative conversion was ob-
served in CH2Cl2 at room temperature and the conjugate
Scheme 2. Catalytic enantioselective conjugate addition of bis
ACHTUNGTRENNUNG(sulfone) 4
to enals. a) NaBH4, EtOH, 08C; b) In(OTf)3, (MeO)3CH, CH2Cl2, RT;
AHCTUNGTRENNUNG
c) i) NaClO2, KH2PO4, H2O2/MeOH, CH3CN, H2O; ii) CHN2SiMe3,
MeOH, C6H6.
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11955

C. Palomo et al.
Table 2. Scope of the amine-catalyzed enantioselective addition of bis-
ACHTUNGTRENNUNG
(sulfone) 4 to enals.[a]
sulfones 1 or 3 and either cinnamaldehyde or crotonalde-
hyde under these catalytic conditions. Since the cyclic/acyclic
Entry
R
Product
t [h]
Yield [%][b]
ee [%][c]
nature of the bis
on the acidity of the pronucleophilic CH group, we believe
that the divergent behavior of both types of bis(sulfone)s in
ACHTUNGTRENUN(NG sulfone) should have minute influence only
1
2
3
4
5
6
7
8
9
a
Ph
13
14
15
13
13
13
14
13
13
13
24
24
24
24
24
24
24
48
48
48
80
71
80
67
62
68
75
62
72
82
98 (99)[d]
99
(99)
95 (98)
96 (98)
96 (98)
99
AHCTUNGTRENNUNG
these catalytic reactions is due to the higher nucleophilicity
of the cyclic anion.[13]
b
c
d
e
f
4-MeC6H4
2-naphthyl
4-ClC6H4
4-NO2C6H4
CH3
Standard desulfonation of adducts provided useful build-
ing blocks in an essentially enantiopure form. For instance,
treatment of 13b with magnesium in MeOH led to alcohol
16b (Scheme 3), which is a key precursor of several sesqui-
terpenes,[14] such as (S)-(+)-curcumene and (E)-(S)-(+)-nu-
ciferal. In terms of operational convenience, the desulfona-
tion step may be carried out from the aldehyde adduct 12.
In this instance, concomitant reduction of the formyl group
takes place to give the desired alcohols 16 in one pot. Inter-
81 (85)
g
h
CH3CH2
CH
89[e]
10
G
94[e]
[a] Reactions conducted at 1 mmol scale in CH2Cl2 (2 mL) at RT by
using cat. 10 and PhCO2H (10 mol% each). Ratio of aldehyde/bis-
ACHTUNGTRENNUNG(sulfone) 2:1 for R=aryl (3:1 for R=alkyl). [b] Overall yield of 13–15
after chromatography. [c] Determined by HPLC analysis. Data in paren-
theses refer to solid product washed once with warm Et2O. [d] Reaction
run at 5 mmol scale. [e] Oil.
the standard catalysts in reac-
tions through iminium ion acti-
vation,[11] were unsuccessful and
unmodified starting materials
were recovered. After several
attempts, it was gratifying to
find that pyrrolidines 10 and
11,[12] which are also proven cat-
alysts in iminium ion mediated
processes, were effective. With
catalyst 10, and after in situ re-
duction of the 1,4-addition
adduct, alcohol 13a was ob-
tained in 80% yield and, most
significantly, 98% ee (ee=enan-
Scheme 3. Hydrodesulfonation of adducts yields enantiopure phenethyl building blocks.
tiomeric excess). Catalyst 11
was less active for this transfor-
mation although equally selec-
tive (71% conversion after 48 h; 60% yield and 96% ee). A
brief screening of solvents revealed CHCl3 as an alternative,
whereas THF and DMF led to higher ee values but lower
yields, and MeOH was unsuitable.
estingly, these reductive conditions are also tolerant with
substrates bearing a chlorine substituent as judged by con-
version of 12d into 16d. The nitro group in adduct 12e,
however, did not survive. On the other hand, transformation
of starting enals into b-substituted aldehydes could be car-
ried out without intervention of any reduction/oxidation of
the respective ester/alcohol intermediate. Thus, desulfona-
tion of the aldehyde adduct in its dimethyl acetal form 14b
proceeded smoothly and the subsequent mild acid hydrolysis
afforded aldehyde 17, a precursor of (S)-(+)-turmerone.
Further evidence of the functional-group compatibility of
the desulfonation process was provided by the transforma-
tion of ester 15a into the phenethyl derivative 18.
The potential of the method is further illustrated in situa-
tions of double stereodifferentiation (Scheme 4). Thus, cata-
lytic conjugate addition of 4 to chiral enal (R)-19, derived
from citronellal,[15] followed by one-pot reduction and desul-
fonation of the resulting aldehyde, led to 20 in 70% overall
yield and with complete diastereocontrol (dr>50:1; dr=dia-
stereomeric ratio). The same sequence applied to (S)-19 af-
Enal scope and synthetic applications: Further examples
under optimized conditions demonstrate that excellent
levels of enantioselectivity may be regularly achieved in the
reactions of 4 with a variety of enals. The aldehyde adducts
12 were systematically transformed into the corresponding
alcohols 13 to facilitate ee determination. The adducts from
the catalytic addition could also be isolated as the corre-
sponding dimethyl acetals 14 or esters 15 by using estab-
lished procedures.
As the results in Table 2 show, the respective products 13–
15 were obtained in high selectivity for a range of aromatic
enals regardless of the electron-poor or -rich nature of the
aryl system. With aliphatic enals, longer times were required
for complete conversion while slightly lower ee values were
attained. Again, no reaction was observed between acyclic
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Chem. Eur. J. 2009, 15, 11954 – 11962

Catalytic Conjugate Additions of Geminal BisACHTNUTRGNE(UNG sulfone)s
FULL PAPER
cy.[19,20] Interestingly, by just avoiding benzoic acid as the co-
catalyst, the simple addition adduct 25 was isolated in 78%
yield. These two latter examples involving substrates with
more than one reactive site susceptible of nucleophilic
attack showcase the remarkable site selectivity of our
method, an aspect that is inherently difficult to be addressed
by using, inter alia, simple Grignard or alkylzinc-based
methodologies.
a-Alkylation of bisACTHNUTRGNEUNG(sulfone) adducts—generalization of the
concept of a simple alkyl nucleophile equivalent: Finally, we
also investigated the behavior of a-substituted gem-bis-
Scheme 4. Double stereodifferentiation by using chiral enals as a stereo-
controlled entry to 1,3-dimethyl arrays.
AHCTUNGTREG(NNNU sulfone) 5, with the aim of getting a more general proce-
dure for the catalytic and stereocontrolled formal b-alkyla-
tion of enals. However, this sulfone proved to be resistant
towards the 1,4-addition reaction under a variety of condi-
tions. Alternatively, it was found that the a-alkylation of
forded alcohol 21 in 73% yield and with a dr>15:1. The
latter transformations represent a new and stereochemically
predictable approach to 1,3-dimethyl arrays, commonly
found in deoxygenated polyketide-type natural products.[16]
either bisACTHNUTRGNEUG(N sulfone) adducts 13 or 14 with both reactive and
less reactive long chain alkyl halides, according to the proce-
Intramolecular version: A tandem Michael–Michael pro-
cess: Complementing the above potential, extended synthet-
ic opportunities are at hand if the enamine intermediate
that catalytically generates during the conjugate addition
step is trapped by the proper electrophile. For instance, in-
tramolecular trapping of the enamine generated upon cata-
dure of Kꢄndig,[6] is feasible (Scheme 6). Thus, a convenient
lytic addition of bisACHTUNGTRENUN(G sulfone) 4 to enal 22, and subsequent
desulfonation of the intermediate 23, led to trisubstituted
indane derivative 24 with the ester group transesterified and
featuring an unusual cis,trans substitution pattern
(Scheme 5).[17,18] This catalytic tandem Michael–Michael
Scheme 6. One-pot a-alkylation of bisACTHNUTRGENUGN(sulfone) adducts enabling installa-
tion of superior alkyl units (RCH2) at Cb of enals.
and stereocontrolled access to products bearing alkyl side
chains other than methyl is provided, as exemplified by pro-
tected alcohol products 26–28 and aldehydes 30 and 31.
Conclusions
In summary, an unprecedented reactivity of cyclic gem-bis-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Scheme 5. Tandem Michael–Michael approach to trisubstituted indanes
turated aldehydes catalyzed by prolinol silyl ethers takes
place with almost perfect enantioselectivity and remarkable
site selectivity, enabling novel sequence-selective tandem
Michael–Michael processes. Reductive desulfonation of ad-
ducts provides a quick entry to valuable building-blocks,
whereas sulfonyl a-alkylation and subsequent desulfonation
can be applied with broad functional-group tolerance and
initiated by catalytic conjugate addition of bisACTHNUTRGNE(UNG sulfone) 4.
process involves a cyclopentane anulation with the genera-
tion of two new C–C bonds and three contiguous stereocen-
ters in one pot, a reaction in which a survey of pronucleo-
philes are anticipated to be involved with equal efficien-
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11957

C. Palomo et al.
(essentially pure aldehyde 12) (ꢀ1.0 mmol) was dissolved in a mixture of
MeOH (5.0 mL), CH3CN (5.0 mL), and water (5.0 mL). The solution was
cooled down to 08C and KH2PO4 (380 mg, 2.77 mmol) and NaClO2
(225 mg, 2.10 mmol) were added. After the injection of H2O2 (35% solu-
tion, 3.0 mL), the mixture was warmed up to RT and stirred for 2 h. The
pH was adjusted to 3 with HCl (1m) and saturated Na2SO3 solution
(20 mL) was added. The resulting mixture was extracted with CH2Cl2 (3ꢅ
30 mL) and the combined organic layers were washed with water
(30 mL) and dried over MgSO4. The organic layer was concentrated in
vacuum and the residue was dissolved in toluene (5.0 mL) and methanol
(15.0 mL). Trimethylsilyl diazomethane (0.5 mL, 1 mmol, 2.0m in n-
hexane) was then added dropwise to the resulting solution. The solution
was stirred for an additional 10 min and quenched with four drops of
concentrated AcOH. The solvents were evaporated under vacuum. The
crude product was subjected to flash column chromatography on silica
gel (eluent: EtOAc/hexane 1:2).
generality with respect to the alkylating agent, aspects that
reinforce the applicability of the method in synthesis. Of im-
portance, some of these functional-group tolerance/chemo-
selectivity patterns are inherently difficult to match with al-
kylmetal-based methodologies. Hence, the use of gem-bis-
ACHTUNGTRENNUNG(sulfone)s as simple alkyl nucleophile equivalents is consid-
erably expanded and new applications can be predicted.
Experimental Section
General methods and materials: The 1H NMR and 13C NMR spectra
were recorded at 300 and 75 MHz respectively. 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=77.0 ppm) for
13C NMR spectra. Purification of reaction products was carried out by
flash column chromatography by using ROCC silica gel 60 (0.040–
0.063 mm, 230–400 mesh). Visualization was accomplished with a solution
of phosphomolybdic acid (1 g) in 100 mL of ethanol (limited lifetime),
followed by heating. Analytical HPLC was performed on a Waters 600E
device, equipped with diode array UV detector, by using Daicel Chiral-
pak IC and IA columns. Optical rotations were recorded on a Jasco P-
2000 polarimeter. MS spectra were recorded on an ESI-ion-trap mass
spectrometer (Agilent 1100 series LC/MSD, SL model). All solvents
were of p.a. quality and were dried by standard procedures prior to use if
necessary.
(S)-3-[(BenzoACTHNUTRGENUGN[1,3]dithiole-1,1,3,3-tetraoxide)-2-yl]-3-phenyl-1-propanol
(13a): Prepared according to the general procedure (method A) by start-
ing from cinnamaldehyde 7a, 4 (1 mmol), and catalyst 10. White solid;
yield: 280 mg, 0.8 mmol (overall, 80%); m.p. 178–1808C; [a]2D3 =+10.8
(c=1.00 in CH2Cl2, 98% ee (S)); 1H NMR (CDCl3): d=8.07–7.48 (m,
9H; Ar), 4.96 (d, J=11.4 Hz, 1H), 4.15–4.06 (m, 1H), 3.72–3.63 (m, 1H),
3.59–3.47 (m, 1H), 2.65–2.55 (m, 1H), 2.20–2.31 ppm (m, 1H); 13C NMR
(CDCl3): d=135.1, 134.9, 129.2, 128.9, 128.5, 122.4, 77.6, 59.2, 38.4,
35.3 ppm; HRMS: m/z: calcd for C16H16O5S2: 353.0517 [M+H]+; found:
353.05175; HPLC (Daicel Chiralpak IC, hexane/2-propanol 50:50): flow
rate=0.5 mLminÀ1; t1 =25.5 (major enantiomer), t2 =34.6 min (minor en-
antiomer).
(S)-3-[(BenzoACTHNUTRGNE[UNG 1,3]dithiole-1,1,3,3-tetraoxide)-2-yl]-3-(4-methylphenyl)-1-
Starting materials: Unless otherwise specified, materials were obtained
from commercial sources and were used without purification. Cinnamal-
dehyde and crotonaldehyde were purified by distillation before usage
and stored in the fridge at À308C under nitrogen. The remaining a,b-un-
saturated aldehydes were prepared by following the procedure described
in the literature.[22] 1,3-Benzodithiole tetraoxide 4 was prepared according
to a published procedure.[6] Benzylideneacetone, Et3N, DBU, pyrrolidine,
guanidines TBD/MTBD, and catalysts 8, 9, 10, and 11 were purchased
from Aldrich and used as supplied. For the preparation of compounds 19
and 22, see the Supporting Information.
propanol (13b): Prepared according to the general procedure (meth-
od A) by starting from 4-methyl-cinnamaldehyde 7b, 4 (0.42 mmol), and
catalyst 10. White solid; yield: 225 mg, 0.67 mmol (overall, 67%); m.p.
74–768C; [a]2D3 =+10.2 (c=0.50 in CH2Cl2, 96% ee (S)); 1H NMR
(CDCl3): d=8.08–7.25 (m, 8H; Ar), 4.94 (d, J=11.4 Hz, 1H), 4.09–4.03
(m, 1H), 3.67–3.69 (m, 1H), 3.65–3.57 (m, 1H), 2.61–2.51 (m, 1H), 2.41
(s, 3H), 2.41–2.19 ppm (m, 1H); 13C NMR (CDCl3): d=138.2, 134.9,
131.8, 129.7, 129.0, 122.5, 77.6, 59.3, 38.1, 35.4, 21.2 ppm; HRMS: m/z:
calcd for C17H18O5S2: 367.0664 [M+H]+; found: 367.0674; HPLC (Daicel
Chiralpak IC, hexane/2-propanol 50:50): flow rate=0.5 mLminÀ1; t1 =
29.5 (major enantiomer), t2 =32.2 min (minor enantiomer).
General procedure for the catalytic asymmetric addition of 4 to enals:
Sulfone 4 (1 mmol, 218 mg) and benzoic acid (6.1 mg, 0.10 mmol, 10
mol%) were successively added to a mixture of catalyst 10 (32 mg,
0.10 mmol, 10 mol%) and the corresponding a,b-unsaturated aldehyde 7
(3 mmol for aliphatic enals; 2 mmol for aromatic enals) in CH2Cl2
(2 mL). The mixture was stirred at RT for the specified time. The solid
product could be purified at this stage by filtration and washing with
warm diethyl ether or, alternatively, subjected to either of the following
protocols:
(S)-3-[(BenzoACTHNUTRGENUGN[1,3]dithiole-1,1,3,3-tetraoxide)-2-yl]-3-(naphtha-2-yl)-1-
propanol (13c): Prepared according to the general procedure (method A)
by starting from 3-(naphth-2-yl)-propenal 7c, 4 (1 mmol), and catalyst 10.
White solid; yield: 104 mg, 0.62 mmol (overall, 62%); m.p. 94–968C;
[a]2D3 =+8.2 (c=0.50 in CH2Cl2, 96% ee (S)); 1H NMR (CDCl3): d=
8.08–7.51 (m, 11H; Ar), 5.11–5.07 (d, J=11.4 Hz, 1H), 4.33–4.25 (m,
1H), 3.75–3.61 (m), 3.59–3.47 (m, 1H), 2.71–2.62 (m, 1H), 2.43–2.20 ppm
(m, 1H); 13C NMR (CDCl3): d=138.3, 137.3, 135.1, 134.9, 129.2, 128.8,
128.1, 127.8, 125.8, 122.4, 59.1, 38.4, 35.2, 29.7 ppm; HRMS: m/z: calcd
for C20H18O5S2: 403.0661 [M+H]+; found: 403.0674; HPLC (Daicel Chir-
alpak IC, hexane/2-propanol 50:50): flow rate=0.5 mLminÀ1; t1 =29.1
(major enantiomer), t2 =32.9 min (minor enantiomer).
Method A (derivatization to alcohols 13): The reaction mixture was
cooled at 08C, diluted with EtOH (2 mL), and then a suspension of
NaBH4 (18.9 mg, 0.5 mmol) in EtOH (2 mL) was added dropwise. The
reaction was stirred at the same temperature for 30 min and afterwards
quenched with H2O (20 mL) and extracted with CH2Cl2 (3ꢅ30 mL). The
combined organic layers were washed with brine and dried (MgSO4).
The solvent was evaporated and the crude compound 13 was purified by
flash chromatography (eluent: EtOAc/hexane 1:2).
(S)-3-[(BenzoACTHNUTRGNE[UNG 1,3]dithiole-1,1,3,3-tetraoxide)-2-yl]-3-(4-chlorophenyl)-1-
propanol (13d): Prepared according to the general procedure (meth-
od A) by starting from 4-chloro-cinnamaldehyde 7d, 4 (1 mmol), and cat-
alyst 10. Yellow solid; yield: 262 mg, 0.64 mmol (overall, 68%); m.p.
108–1118C; [a]2D3 =+4.1 (c=1.00 in CH2Cl2, 96% ee (S)); 1H NMR
(CDCl3): d=8.88–7.42 (m, 8H; Ar), 4.94 (d, J=11.4 Hz, 1H), 4.15–4.06
(m, 1H), 3.70–3.63 (m, 1H), 3.55–3.47 (m, 1H), 2.66–2.50 (m, 1H), 2.17–
2.28 ppm (m, 1H); 13C NMR (CDCl3): d=135.2, 135.0, 130.6, 129.1,
122.5, 77.4, 58.9, 37.8, 35.2 ppm; HRMS: m/z: calcd for C16H15ClO5S2:
387.0118 [M+H]+; found: 387.0128; HPLC (Daicel Chiralpak IC,
hexane/2-propanol 50:50): flow rate=0.5 mLminÀ1; t1 =18.1.5 (major en-
antiomer), t2 =20.6 min (minor enantiomer).
Method B (derivatization to dimethyl acetals 14): The reaction mixture
was filtered and the collected white solid was washed with Et2O. CH2Cl2
(5 mL) was added to this solid (essentially pure aldehyde 12) followed by
the sequential addition of trimethylorthoformate (2 equiv) and In-
[23]
ACHTUNGTRENNUNG(OTf)3 (0.5 mol%) to the resulting suspension under a nitrogen atmos-
phere. The reaction mixture was stirred at RT for 15 min. Afterwards, a
further portion of In(OTf)3 (0.5 mol%) was added and the colorless solu-
ACHTUNGTRENNUNG
tion was stirred for a further 15 min. The mixture was then passed
through a short plug of neutral alumina which was washed with CH2Cl2.
Evaporation of the solvent under reduced pressure gave essentially pure
dimethyl acetal adduct.
(R)-3-[(BenzoACTHNUTRGENUGN[1,3]dithiole-1,1,3,3-tetraoxide)-2-yl]-1-butanol (13 f): Pre-
pared according to the general procedure (method A) by starting from
crotonaldehyde 7 f, 4 (1 mmol), and catalyst 10. White solid; yield:
179 mg, 0.62 mmol (overall, 62%); [a]2D3 =+0.9 (c=0.50 in CHCl3,
Method C (derivatization to methyl esters 15): The reaction mixture was
filtered and the collected white solid was washed with Et2O. This solid
11958
www.chemeurj.org
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 11954 – 11962

Catalytic Conjugate Additions of Geminal BisACHTNUTRGNE(UNG sulfone)s
FULL PAPER
85% ee (R)); 1H NMR (CDCl3): d=8.03–7.89 (m, 4H), 4.65 (d, J=
10.5 Hz, 1H), 3.90 (m, 2H), 3.02 (m, 1H), 2.10 (m, 2H), 1.48 ppm (d, J=
6.6 Hz, 1H); 13C NMR (CDCl3): d=138.0, 137.7, 135.1, 135.0, 122.4, 78.2,
59.2, 34.7, 27.7, 15.6 ppm; HRMS (TOF MS Cl+): m/z: calcd for
C11H14O5S2: 291.0361 [M+H]+; found: 291.0352; HPLC (Daicel Chiral-
Celite and washed with CH2Cl2. The solvent was concentrated and the
residue obtained was partitioned between H2O (20 mL) and CH2Cl2
(20 mL). The aqueous layer was extracted three times with CH2Cl2
(20 mL) and the organic layers were combined and dried with MgSO4.
Evaporation of solvent under reduced pressure gave a crude product as
colorless oil.
pak IC, hexane/2-propanol 50:50): flow rate=0.5 mLminÀ1
(major enantiomer), t2 =25.0 min (minor enantiomer).
; t1 =20.3
(S)-3-Phenylbutan-1-ol (16a): From adduct 13a (0.47 mmol). Colorless
oil; yield: 62 mg, 0.41 mmol (88%); [a]2D0 =+13.3 (c=1.00 in CHCl3,
96% ee (S)), lit.[25] [a]D20 =+13.67 (c=1.02 in CHCl3, 93% ee (S));.
1H NMR (CDCl3): d=7.37–7.24 (m, 5H), 3.58 (m, 2H), 2.93 (sextet, J=
6.9 Hz, 1H), 1.89 (q, J=6.9 Hz, 2H), 1.31 ppm (d, J=6.9 Hz, 3H);
13C NMR (CDCl3): d=146.8, 128.4, 126.9, 126.1, 61.2, 41.0, 36.4,
22.3 ppm; HPLC (Daicel Chiralpak OD-H, hexane/2-propanol 98:2):
(R)-3-[(BenzoACHTUNGTRENNUNG[1,3]dithiole-1,1,3,3-tetraoxide)-2-yl]-1-pentanol (13g): Pre-
pared according to the general procedure (method A) by starting from
(E)-2-pentenal 7g, 4 (1 mmol), and catalyst 10. Colorless oil; yield:
218 mg, 0.72 mmol (overall, 72%); [a]2D3 =+1.21 (c=1.4 in CHCl3,
89% ee (R)); 1H NMR (CDCl3): d=8.04–7.89 (m, 4H), 4.83 (d, J=
10.8 Hz, 1H), 3.88 (t, J=6.00 Hz, 2H), 2.29 (m, 1H), 2.19–1.87 (m, 4H),
1.08 ppm (t, J=7.50 Hz); 13C NMR (CDCl3): d=138.0, 137.7, 135.1,
135.0, 122.4, 122.3, 76.8, 59.3, 33.2, 29.7, 21.1, 9.8 ppm; HRMS: m/z: calcd
for C12H16O5S2: 305.0517 [M+H]+; found: 305.0523; HPLC (Daicel Chir-
alpak IC, hexane/2-propanol 50:50): flow rate=0.5 mLminÀ1; t1 =18.3
(major enantiomer), t2 =24.4 min (minor enantiomer).
flow rate=1.0 mLminÀ1
; t1 =18.2 (minor enantiomer), t2 =21.9 min
(major enantiomer).
(S)-3-p-Tolylbutan-1-ol (16b): From adduct 13b (0.74 mmol). Colorless
oil; yield: 101 mg, 0.61 mmol (83%); [a]2D0 =+29.8 (c=1.00 in CHCl3,
96% ee (S)), lit.[26] [a]D20 =+30.1 (c=1.00 in CHCl3, 99% ee (S));
1H NMR (CDCl3): d=7.12 (s, 4H), 3.60–3.54 (m, 2H), 2.90–2.83 (m,
1H), 2.33 (s, 3H), 1.88–1.82 (m, 2H), 1.27 ppm (d, J=6.9 Hz, 3H);
13C NMR (CDCl3): d=143.8, 135.5, 129.1, 126.8, 61.3, 41.0, 36.1, 22.5,
20.9 ppm; HPLC (Daicel Chiralpak OD-H, hexane/2-propanol 98:2):
(R)-3-[(Benzo
G
(13h):
Prepared according to the general procedure (method A) by starting
from 7h, 4 (0.5 mmol), and catalyst 10. Colorless oil; yield: 159 mg,
0.41 mmol (overall, 82%); [a]2D3 =À2.3 (c=1.00 in CHCl3, 94% ee (R));
1H NMR (CDCl3): d=8.03–7.88 (m, 4H), 4.85 (d, J=10.5 Hz, 1H), 3.88
(t, J=6.60 Hz, 2H), 2.93 (m, 1H), 2.16–0.87 ppm (m, 19H); 13C NMR
(CDCl3): d=138.0, 137.7, 135.0, 134.9, 122.4, 122.3, 77.1, 59.6, 32.1, 31.8,
30.1, 29.4, 29.2, 28.0, 25.5, 22.6, 14.1 ppm; HPLC (Daicel Chiralpak IC,
hexane/2-propanol 50:50): flow rate=0.5 mLminÀ1; t1 =16.1 (major enan-
tiomer), t2 =19.0 min (minor enantiomer).
flow rate=0.5 mLminÀ1
;
t1 =17.50 (minor enantiomer), t2 =21.64 min
(major enantiomer).
(S)-3-(4-Chlorophenyl)butan-1-ol
(16d):[27]
From adduct 13d
(0.19 mmol). Colorless oil; yield: 29 mg, 0.16 mmol (85%); 1H NMR
(CDCl3): d=7.26 (d, J=8.5 Hz, 2H), 7.14 (d, J=8.5 Hz, 2H), 3.65–3.49
(m, 2H), 2.95–2.84 (m, 1H), 1.87–1.76 (m, 2H), 1.51 (brs, 1H), 1.26 ppm
(d, J=7.0 Hz, 3H).
(S)-3-[(BenzoACHTUNGTRENNUNG[1,3]dithiole-1,1,3,3-tetraoxide)-2-yl]-3-(phenyl) propanal-
(S)-Methyl 3-phenylbutanoate (18):[28] From adduct 15a (77 mg,
0.20 mmol). Colorless oil; yield: 32 mg, 0.18 mmol (88%); [a]2D3 =+20.1
(c=1.00 in CHCl3, 99% ee (S)), lit.[28] [a]D20 =À15.5 (c=0.7 in CHCl3,
99% ee (R)); HPLC (Daicel Chiralpak OJ-H, hexane/2-propanol 95:5):
flow rate=0.5 mLminÀ1; t1 =9.2 (minor enantiomer), t2 =9.5 min (major
enantiomer); all other spectroscopic data were in agreement with the lit-
erature.
dehyde dimethyl acetal (14a): Prepared according to the general proce-
dure (method B) by starting from cinnamaldehyde 7a, 4 (3.5 mmol), and
catalyst 10. White solid; yield: 996 mg, 2.51 mmol (overall, 71%); m.p.
133–1358C; [a]2D3 =+10.6 (c=1.00 in CHCl3, 99% ee (S)); 1H NMR
(CDCl3): d=8.03–7.39 (m, 9H), 4.74 (d, J=11.4 Hz, 1H), 4.04 (m, 1H),
4.05 (dd, J=8.4, 3.4 Hz, 1H), 3.95 (dt, J=3.4, 11.4 Hz, 1H), 3.32 (s, 3H),
3.23 (s, 3H), 2.74 (m, 1H), 2.15 ppm (m, 1H); 13C NMR (CDCl3): d=
138.0, 137.2, 135.0, 134.9, 129.1, 128.8, 128.4, 122.3, 100.6, 77.5, 53.2, 51.3,
37.7, 34.9 ppm; HPLC (Daicel Chiralpak IA, hexane/2-propanol 50:50):
flow rate=0.5 mLminÀ1; t=23.5 min. (major enantiomer).
Sequential a-alkylation–desulfonation of bisACTHNUTRGENUG(N sulfone) alcohol adducts
Silylation of 13a: 4-N,N-Dimethylaminopyridine (DMAP; 1.2 equiv,
0.88 g, 7.2 mmol) and tBuPh2SiCl (1 equiv, 1.7 mL, 6.6 mmol) were added
to a solution of 13a (1 equiv, 2.11 g, 6 mmol) in CH2Cl2 (30 mL) under a
N2 atmosphere. The mixture was stirred at RT for 3 h and then water was
added (10 mL). The organic layer was separated and washed with HCl
(0.1n, 25 mL) and with saturated NaHCO3 (25 mL). The organic layer
was dried over MgSO4 and concentrated under reduced pressure. The
crude product was purified by silica flash chromatography (eluent:
hexane/EtOAc 90:10). White solid; yield: 2.76 g, 4.68 mmol (78%);
(S)-3-[(BenzoACHTUNGTRENNUNG[1,3]dithiole-1,1,3,3-tetraoxide)-2-yl]-3-(4-nitrophenyl)pro-
panaldehyde dimethyl acetal (14e): Prepared according to the general
procedure (method B) by starting from 4-nitro-cinnamaldehyde 7e, 4
(1 mmol), and catalyst 10. White solid; yield: 330 mg, 0.75 mmol (overall,
75%); m.p. 70–728C; [a]2D3 =+8.65 (c=2.00 in CHCl3, 99% ee (S));
1H NMR (CDCl3): d=8.27 (d, J=8.7 Hz, 2H), 8.11–7.88 (m, 4H), 7.63
(d, J=8.4 Hz, 2H), 4.76 (d, J=11.4 Hz, 1H), 4.10 (dt, J=3.4, 11.4 Hz,
1H), 4.01 (dd, J=3.4, 8.4 Hz, 1H), 3.31 (s, 3H), 3.23 (s, 3H), 2.78 (m,
1H), 2.16 ppm (m, 1H); 13C NMR (CDCl3): d=148.0, 142.7, 137.7, 137.3,
135.3, 135.2, 130.3, 124.0, 122.5, 100.4, 76.9, 53.5, 51.2, 37.7, 34.8 ppm;
HPLC (Daicel Chiralpak IA, hexane/2-propanol 50:50): flow rate=
0.5 mLminÀ1; t1 =52.6 (minor enantiomer), t2 =97.0 min (major enantio-
mer).
1
[a]2D0 =+5.02 (c=0.5 in CHCl3, 99% ee (S)); H NMR (CDCl3): d=8.08–
7.30 (m, 19H; Ar), 4.76 (d, J=11.4 Hz, 1H), 4.30–4.21 (m, 1H), 3.65–
3.56 (m, 1H), 3.50–3.42 (m, 1H), 2.85–2.74 (m, 1H), 2.16–2.03 (m, 1H),
1.10 ppm (s, 9H); 13C NMR (CDCl3): d=138.3, 137.4, 135.6, 135.5, 134.9,
133.4, 128.7, 128.3, 127.7, 127.5, 122.4, 78.1, 59.7, 38.1, 35.3, 26.8,
19.2 ppm.
(S)-Methyl 3-[(BenzoACHTUNGTRENNUNG[1,3]dithiole-1,1,3,3-tetraoxide)-2-yl]-3-phenylpro-
One-pot a-alkylation–desulfonation: NaH (60 mg, 60% in mineral oil)
was placed in a flask and washed twice with dried hexane. After removal
of the solvent, a solution of silylated adduct (1 equiv, 0.59 g, 1 mmol) in
dried DMF (4 mL) was added. The mixture was cooled at 08C under a
N2 atmosphere and then the corresponding alkyl halide (1.5 equiv, MeI,
panoate (15a): Prepared according to the general procedure (method C)
by starting from cinnamaldehyde 7a, 4 (0.63 mmol), and catalyst 10.
White solid; yield: 205 mg, 0.54 mmol (overall yield: 85%); m.p. 156–
1588C; [a]2D3 =+7.14 (c=1.00 in CHCl3, 99% ee (S)); 1H NMR (CDCl3):
d=8.05–7.38 (m, 9H; Ar), 5.10 (d, J=11.4 Hz, 1H), 4.28 (m, 1H), 3.58
(s, 3H), 3.27 (dd, J=3.6, 16.2 Hz, 1H), 3.11 ppm (dd, J=9.6, 16.2 Hz,
1H); 13C NMR (CDCl3): d=170.0, 138.0, 136.9, 135.2, 135.0, 129.0, 128.9,
128.7, 128.6, 122.4, 122.3, 76.0, 51.8, 37.6, 37.5 ppm. HPLC (Daicel Chiral-
pak IA, hexane/2-propanol 50:50): flow rate=0.5 mLminÀ1; t=36.0 min
(major enantiomer).
Desulfonation of adducts:[24] Mg (turnings) (24 mg, 1 mmol, 10 equiv),
Me3SiCl (1 drop), and 1,2-dibromoethane (1 drop) were added succes-
sively to a solution of the corresponding adducts 13–15 (0.2 mmol) in
MeOH (5 mL) under a N2 atmosphere,. This solution was stirred for 16–
24 h at RT. The reaction mixture was then filtered through a plug of
BnBr, allyl iodide, CH3ACHTUNRGTENNGU(CH2)2I, CH3ACHUTGNTREN(NNGU CH2)5I) was added dropwise. After
stirring the mixture at RT (in the case of hexyl iodide at 508C) for 16 h,
the reaction mixture was poured into water (15 mL) and the product was
extracted from the water phase three times with CH2Cl2. The organic
phase was then dried with anhydrous MgSO4. Evaporation of the solvents
gave the alkylated crude product, which was dissolved in MeOH
(10 mL). Then, Mg (240 mg, 10 equiv, 10 mmol), tetramethylsilyl chlroide
(TMSCl) (1 drop), and Br2ACTHNUTRGNEUNG(CH2)2 (1 drop) were sequentially added. This
suspension was stirred for an additional 16 h at RT and afterwards fil-
tered through a short plug of Celite and washed with Et2O (25 mL). The
solvent was concentrated and the residue obtained was partitioned be-
Chem. Eur. J. 2009, 15, 11954 – 11962
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11959

C. Palomo et al.
tween saturated NaCl (20 mL) and Et2O (20 mL). The organic layer was
washed again twice with saturated brine (20 mL), dried over MgSO4, and
concentrated under reduced pressure. The crude product was purified by
silica flash chromatography (eluent: hexane/EtOAc 90:10).
7.84 Hz), 3.31 (s, 3H), 3.25 (s, 3H), 2.81 (m, 1H), 2.51–2.48 (m, 2H),
2.11–1.86 ppm (m, 4H); 13C NMR (CDCl3): d=144.6, 142.6, 128,3, 127.7,
126.3, 125.8, 52.9, 52.6, 41.5, 39.7, 38.7, 33.7 ppm.
(S)-3-Phenylhept-6-enal dimethyl acetal (29, R’: CH2CH=CH2): Colorless
oil; yield: 159 mg, 0.68 mmol (68%); [a]2D3 =+9.04 (c=0.50 in CHCl3);
1H NMR (CDCl3): d=7.36–7.20 (m, 5H; Ar), 5.84–5.73 (m, 1H), 5.01–
4.95 (m, 2H), 4.12 (dd, 1H, J=3.93, 7.91 Hz), 3.31 (s, 3H), 3.27 (s, 3H),
2.78–2.72 (m, 1H), 2.07–1.65 ppm (m, 6H). 13C NMR (CDCl3): d=144.6,
138.6, 128,4, 127.7, 126.3, 114.5, 102.9, 52.8, 52.5, 41.1, 39.6, 36.1, 31.6,
29.7 ppm.
tert-Butyldiphenyl [(S)-3-phenylpentyloxy]silane (26): Colorless oil;
1
yield: 300 mg, 0.75 mmol (overall, 75%); H NMR (CDCl3): d=7.66–7.13
(m, 15H; Ar), 3.66–3.51 (m, 2H), 2.77–2.68 (m, 1H), 1.94–1.49 (m, 4H),
1.08 (s, 9H), 0.83 ppm (t, 3H, J=7.37 Hz); 13C NMR (CDCl3): d=145.3,
135.5, 134.5, 129.4, 128.1, 127.8, 127.5, 125, 8, 61.9, 43.8, 39.1, 26.6, 27.0,
19.2, 12.1 ppm; determination of the enantiomeric excess was realized on
the desilylated alcohol;[29] thus, 26 was treated with pyridium fluoride in
THF at RT overnight to give the corresponding alcohol.
(S)-3-Phenylpentan-1-ol:[30] Colorless oil; yield: 88 mg, 0.53 mmol (72%);
[a]2D3 =+10.07 (c=0.25 in CHCl3, 99% ee (S)); 1H NMR (CDCl3): d=
7.34–7.19 (m, 5H; Ar), 3.60–3.43 (m, 2H), 2.66–2.58 m, 1H), 2.06–1.59
(m, 4H), 0.83 ppm (t, 3H, J=7.37 Hz); 13C NMR (CDCl3): d=144.9,
128.5, 127.7, 126.1, 61.3, 44.3, 39.3, 29.8, 12.1 ppm; the resulting adduct
was determined to be of 99% ee by HPLC (Daicel Chiralpak OD-H,
hexane/2-propanol 98:2): flow rate=1.0 mLminÀ1; t1 =15.8 (minor enan-
tiomer), t2 =19.5 min (major enantiomer).
Hydrolysis of acetals 29: Concentrated HCl (1 mL) was added to a solu-
tion of the corresponding acetal 29 (0.2 mmol) in acetone (1.5 mL) and
the mixture was stirred for 30 min at RT. After this time, the solvent was
evaporated under reduced pressure and CH2Cl2 (5 mL) and water (5 mL)
were added. The two phases were separated and the organic layer was
dried over MgSO4 and concentrated under reduced pressure.
(S)-3,5-Diphenylpentanal (30): Colorless oil; yield: 45 mg, 0.19 mmol
(96%); [a]2D3 =+3.1 (c=0.5 in CHCl3); 1H NMR (CDCl3): d=9.68
(s,1H), 7.40–7.13 (m, 10H; Ar), 3.30–3.22 (m.1H), 2.78–2.76 (m, 3H),
2.55–2.51 (m, 3H), 2.10–1.96 ppm (m, 2H); 13C NMR (CDCl3) d 201.6,
143.35, 144.1, 128.7, 128.3, 127.6, 126.8, 125.9, 50.7, 39.7, 38.1, 33.4 ppm.
(S)-tert-Butyldiphenyl(3-phenylheptyloxy)silane (27): Colorless oil; yield:
313 mg, 0.72 mmol (overall, 72%); 1H NMR (CDCl3): d=7.69–7.13 (m,
15H; Ar), 3.77–3.49 (m, 2H), 2.84–2.74 (m, 1H), 2.21–1.56 (m, 4H),
1.10–1.31 (m, 2H), 1.08 (s, 9H), 0.87 ppm (t, 3H, J=7.37 Hz); 13C NMR
(CDCl3): d=145.4, 135.5, 129.4, 128.1, 127.7, 127.5, 125,7, 61.9, 41.9, 39.5,
36.5, 29.7, 26.9, 22.7, 19.2, 14.0 ppm; determination of the enantiomeric
excess was realized on the desilylated alcohol;[29] thus, 27 was treated
with pyridium fluoride in THF at RT overnight to give the corresponding
alcohol.
(S)-3-Phenylhept-6-enal (31): Colorless oil; yield: 35 mg, 0.18 mmol
(94%); [a]2D3 =À16.7 (c=1.0 in CHCl3); 1H NMR (CDCl3): d=9.70
(s,1H), 7.37–7.21 (m, 5H; Ar), 5.84–5.74 (m, 1H), 5.02–4.97 (m, 2H),
3.31–3.22 (m, 1H), 2.76 (dd, 2H, J=1.79, 7.34 Hz), 1.95–1.78 (m, 2H),
1.75–1.61 ppm (m, 2H); 13C NMR (CDCl3): d=201.3, 137.16, 128.7,
127.5, 126.7, 114.9, 50.5, 39.5, 35.6, 31.3 ppm.
Catalytic addition of 4 to (R)-19 and double reduction to 20: Sulfone 4
(1 mmol, 218 mg) and benzoic acid (11 mg, 0.10 mmol, 10 mol%) were
successively added to a mixture of catalyst 10 (0.10 mmol, 10 mol%) and
a,b-unsaturated aldehyde (R)-19 (2.87 mmol) in CH2Cl2 (2 mL). The mix-
ture was stirred at RT until disappearance of starting sulfone (3 days),
and then the solid product was filtered and subjected to the general de-
sulfonation procedure (Mg (240 mg, 10 mmol), TMSCl (1 drop), Br2-
(S)-3-Phenylheptan-1-ol:[31] Colorless oil; yield: 95 mg, 0.5 mmol (63%);
[a]2D3 =+5.53 (c=0.50 in CHCl3, 99% ee (S)); 1H NMR (CDCl3): d=
7.35–7.19 (m, 5H; Ar), 3.64–3.46 (m, 2H), 2.78–2.64 (m, 1H), 1.97–1.82
(m, 2H), 1.65–1.59 (m, 2H), 1.15–1.30 (m, 4H), 0.87 ppm (t, 3H, J=
7.37 Hz); 13C NMR (CDCl3): d=145.6, 128.4, 127.6, 126.1, 61.3, 42.5,
39.7, 36.7, 29.7, 22.1, 14.6 ppm; the resulting adduct was determined to be
of 99% ee by HPLC (Daicel Chiralpak OD-H, hexane/2-propanol 98:2):
AHCTUNGTRENNG(NU CH2)2 (1 drop)) to give 20. Colorless oil; yield: 105 mg, 0.52 mmol (over-
all, 70%); [a]2D3 =+6.57 (c=0.56 in CHCl3); 1H NMR (CDCl3): d=5.11
(t, J=7.20 Hz, 1H), 3.70 (m, 2H), 1.97 (m, 2H), 1.69 (s, 3H), 1.61 (s,
3H), 1.63–0.97 (m, 8H), 0.90 (d, J=5.70 Hz, 3H), 0.88 ppm (d, J=
6.30 Hz, 3H); 13C NMR (CDCl3): d=131.0, 124.9, 61.2, 45.2, 39.9, 36.8,
29.7, 26.9, 25.7, 25.4, 20.2, 20.1, 17.6 ppm; HRMS: m/z: calcd for
C13H27O: 199.2062 [M+H]+; found: 199.2074.
flow rate=1.0 mLminÀ1
; t1 =12.8 (minor enantiomer), t2 =15.4 min
(major enantiomer).
(S)-tert-Butyldiphenyl(3-phenyldecyloxy)silane (28): Colorless oil; yield:
330 mg, 0.76 mmol (overall, 76%); [a]2D3 =À12.02 (c=0.50 in CHCl3);
1H NMR (CDCl3): d=7.71–7.16 (m, 15H; Ar), 3.71–3.44 (m, 2H,), 2.89–
2.79 (m, 1H,), 2.23–1.51 (m, 4H,), 1.45–1.25 (m,10H), 1.06 (s, 9H,),
0.87 ppm (t, 3H, J=7.37 Hz,); 13C NMR (CDCl3): d=145.8, 135.7, 134.1,
129.6, 127.7, 125,7, 83.1, 61.9, 39.5, 36.9, 29.8, 29.3, 26.9, 22.8, 19.3 ppm.
Catalytic addition of 4 to (S)-19 and double reduction to 21: The same
procedure as for (R)-19 was applied by starting from the enantiomeric
(S)-19. Product 21 was obtained as the major diastereomer (dr>15:1 as
determined by 1H NMR spectroscopy). Colorless oil; yield:112 mg,
0.56 mmol (73%); [a]2D3 =+7.45 (c=1.62 in CHCl3); 1H NMR (CDCl3):
d=5.10 (t, J=7.20 Hz, 1H), 3.69 (m, 2H), 1.98 (m, 2H), 1.69 (s, 3H),
1.61 (s, 3H), 1.55–1.10 (m, 8H), 0.87 (d, J=5.70 Hz, 3H), 0.85 ppm (d,
J=6.60 Hz, 3H); 13C NMR (CDCl3): d=131.0, 124.9, 61.2, 44.8, 40.9,
37.9, 29.7, 26.9, 25.7, 25.5, 19.4, 19.4, 17.6 ppm; HRMS: m/z: calcd for
C13H27O: 199.2062 [M+H]+; found: 199.2048.
Sequential a-alkylation–desulfonation of bisACTHNUTRGNEUG(N sulfone) acetal adducts
a-Alkylation of 14a: NaH (120 mg 60% in mineral oil) was placed in a
flask and washed twice with dried hexane. After removal of the solvent,
a solution of 14a (1 equiv, 1 mmol) in dried DMF (4 mL) was added. The
mixture was cooled at 08C under a N2 atmosphere and then the corre-
sponding alkyl halide (BnBr or allyl iodide, 3 equiv) was added dropwise.
After stirring the mixture at RT for 7 h, the reaction mixture was poured
into water (15 mL) and the product was extracted from the water phase
three times with CH2Cl2. The organic phase was then dried with anhy-
drous MgSO4. Evaporation of the solvents gave the alkylated crude prod-
uct, which was dissolved in MeOH (10 mL). Then, Mg (240 mg, 10 equiv,
Tandem Michael–Michael reaction involving 22 and 4 to give 23: Enal 22
(1.5 equiv, 1.5 mmol, 345 mg) and bisACTHUNGTRNEN(UG sulfone) 4 (1 equiv, 1 mmol,
218.25 mg) were added to a mixture of catalyst 10 (10 mol%, 0.2 mmol,
65.1 mg) and PhCO2H (10 mol%, 0.2 mmol, 24.5 mg) in CH2Cl2 (1 mL).
After stirring the mixture at RT for 72 h (reaction completion), the sol-
vent was removed under reduced pressure and the crude product was pu-
rified by gradient flash column chromatography (hexane/EtOAc from
90:10 to 70:30). White foam; yield: 282.6 mg, 0.63 mmol (63%); ratio of
10 mmol), TMSCl (1 drop), and Br2ACHTNUGRTNEG(UN CH2)2 (1 drop) were sequentially
added. This suspension was stirred for an additional 24 h at RT and after-
wards, filtered through a short plug of Celite and washed with Et2O
(25 mL). The solvent was concentrated and the residue obtained was par-
titioned between saturated NaCl (20 mL) and Et2O (20 mL). The organic
layer was washed again twice with saturated brine (20 mL), dried over
MgSO4, and concentrated under reduced pressure. The crude product
was purified by silica flash chromatography (eluent: hexane/AcOEt
90:10).
diastereomers 85:15 as determined by NMR spectroscopic analysis;
1
À
H NMR (300 MHz, CDCl3): d=9.92 (d, J=0.7 Hz, 1H; CHO), 9.77 (d,
J=1.2 Hz, 1H; minor diastereomer), 8.08–7.27 (m, 8H; Ar), 4.85 (m,
À
À À
À
2H; CH
G
,
ACHTUNGTRENNUNG
À
À
1H; CHCH2), 3.89 (m, 1H; CHCHO), 2.87 (dd, J1 =3.5, J2 =7.1 Hz,
2H; CH2CO2-), 1.27 (t, J=7.1 Hz, 3H; CH3); 13C NMR (75 MHz,
À
À
À
À
(S)-3,5-Diphenylpentanal dimethyl acetal (29, R’: CH2Ph): Colorless oil;
yield: 112 mg, 0.39 mmol (79%). [a]2D3 =+9.07 (c=0.50 in CHCl3);
1H NMR (CDCl3): d=7.40–7.14 (m, 10H; Ar), 4.13 (dd, 1H, J=3.97,
CDCl3): d=199.9 (minor diastereomer), 198.6 (-CHO), 171.8 ( CO2 ),
171.3 (minor diastereomer), 143.8 (minor diastereomer), 137.2 (minor
diastereomer), 135.6 (C Ar), 135.5 (C Ar), 129.8 (C Ar), 129.7 (minor
11960
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ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 11954 – 11962

Catalytic Conjugate Additions of Geminal BisACHTNUTRGNE(UNG sulfone)s
FULL PAPER
diastereomer), 128.4 (C Ar), 128.2 (minor diastereomer), 127.3 (minor
diastereomer), 127.0 (C Ar), 125.0 (C Ar), 123.5 (minor diastereomer),
formed a-sulfonyl carbanions, see: b) S. Nakamura, N. Hirata, T.
Kita, R. Yamada, D. Nakane, N. Shibata, T. Toru, Angew. Chem.
2007, 119, 7792–7794; Angew. Chem. Int. Ed. 2007, 46, 7648–7650;
c) S. Nakamura, N. Hirata, R. Yamada, T. Kita, N. Shibata, T. Toru,
Chem. Eur. J. 2008, 14, 5519–5527; d) C. Ni, L. Zhang, J. Hu, J. Org.
Chem. 2008, 73, 5699–5713.
À
122.8 (C Ar), 122.7 (C Ar), 77.7 ( CH
G
À
61.3 ( OCH2CH3), 61.1 (minor diastereomer), 57.0 ( CHCHO), 55.4
(minor diastereomer), 41.6 (minor diastereomer), 41.3 ( CHCH2), 40.5
( CH2CO2), 39.8 (minor diastereomer), 39.5 ( CHCH
(minor diastereomer), 29.9 (minor diastereomer), 21.2 (minor diastereo-
À
[4] By using organobifunctional catalysts: a) G. K. S. Prakash, F. Wang,
T. Stewart, T. Mathew, G. A. Olah, Proc. Natl. Acad. Sci. USA 2009,
106, 4090–4094; by using phase-transfer catalysis (PTC) and stoi-
chiometric base: b) S. Mizuta, N. Shibata, Y. Goto, T. Furukawa, S.
Nakamura, T. Toru, J. Am. Chem. Soc. 2007, 129, 6394–6395; c) T.
Furukawa, N. Shibata, S. Mizuta, S. Nakamura, T. Toru, M. Shiro,
Angew. Chem. 2008, 120, 8171–8174; Angew. Chem. Int. Ed. 2008,
47, 8051–8054; by using Pd catalysis and stoichiometric base: d) T.
Fukuzumi, N. Shibata, M. Sugiura, H. Yasui, S. Nakamura, T. Toru,
Angew. Chem. 2006, 118, 5095–5099; Angew. Chem. Int. Ed. 2006,
45, 4973–4977; by using iminium activation: e) A.-N. Alba, X. Com-
panyꢆ, A. Moyano, R. Rꢁos, Chem. Eur. J. 2009, 15, 7035–7038;
f) H. W. Moon, M. J. Cho, D. Y. Kim, Tetrahedron Lett. 2009, 50,
4896–4898; g) F. Ullah, G.-L. Zhao, L. Deiana, M. Zhu, P. Dziedzic,
I. Ibrahem, P. Hammar, J. Sun, A. Cordova, Chem. Eur. J. 2009, 15,
10013–10017. For a review on fluoroalkylations, see: h) G. K. S.
Prakash, J. Hu, Acc. Chem. Res. 2007, 40, 921–930.
[5] For examples with a-functionalized sulfones, see: a-arylketone (phe-
nacyl) through iminium ion catalysis: a) J. Pulkkinen, P. S. Aburel,
N. Halland, K. A. Jørgensen, Adv. Synth. Catal. 2004, 346, 1077–
1080; b) M. Nielsen, C. B. Jacobsen, M. W. Paix¼o, N. Holub, K. A.
Jørgensen, J. Am. Chem. Soc. 2009, 131, 10581–10586; a-aryl-a-ni-
triles through cinchona alkaloid catalysis: c) M. B. Cid, J. Lꢆpez-
Cantarero, S. Duce, J. L. G. Ruano, J. Org. Chem. 2009, 74, 431–434.
a-Esters via PTC catalysis: d) C. Cassani, L. Bernardi, F. Fini, A.
Ricci, Angew. Chem. 2009, 121, 5804–5807; Angew. Chem. Int. Ed.
2009, 48, 5694–5697.
À
mer), 14.4 ppm ( CH3); HRMS: m/z: calcd for C21H21O7S2: 449.0729
[M+H]+; found: 449.0743; the enantiomeric excess of the major diaste-
reomer was determined to be 99% by HPLC; HPLC (Chiralpack IA
column at 260 nm; eluent: hexane/iPrOH 50:50): flow rate=
0.5 mLminÀ1; t1 =33.02 (major), t2 =44.85 min (minor).
Direct desulfonation–reduction–transesterification of 23 to give 24: The
general desulfonation procedure was employed by starting from adduct
23 (224.26 mg, 0.5 mmol). The resulting product 24 was purified by gradi-
ent flash column chromatography (hexane/EtOAc from 80:20 to 50:50).
Yellow oil; yield: 60.9 g, 0.26 mmol (52%); an analytical sample of the
major diastereomer was obtained by preparative TLC; [a]2D5 =À9.0 (c=
1
0.62 in CH2Cl2); H NMR (300 MHz, CDCl3): d=7.26–7.12 (m, 4H; Ar),
À
3.80–3.74 (m, 2H; CH2OH, CO2CH3), 3.49 (dd, J1 =7.9, J2 =13.1 Hz,
1H; CHCH2CO2), 3.05–2.94 (m, 1H; CHCH3), 2.89 (dd, J1 =5.0, J2 =
16.5 Hz, 1H; CHCH2CO2), 2.63 (dd, J1 =8.5, J2 =16.5 Hz, 1H;
À
À
À
À
À
CHCH2CO2), 2.29 (brs, 1H; OH), 1.93–1.80 (m, 1H; CHCH2OH),
1.35 ppm (d, J=6.9 Hz, 3H; CHCH3); 13C NMR (75 MHz, CDCl3): d=
À
À
174.3 ( CO2CH3), 146.8 (C Ar), 143.8 (C Ar), 127.1 (C Ar), 126.7 (C
Ar), 123.6 (C Ar), 123.3 (C Ar), 64.0 ( CH2OH), 57.7 ( CHCH2OH),
51.9 ( CO2CH3), 42.6 ( CHCH2CO2), 40.9 ( CHCH3), 39.9
À
À
À
À
À
À
(
À
CHCH2CO2), 19.9 ppm ( CHCH3); HRMS: calcd for C14H19O3: 235.1334
[M+H]+; found: 235.1333.
Site-selective catalytic conjugate addition of 4 to 22 to give 25: Enal 22
(1.5 equiv, 1.5 mmol, 345 mg) was added to a mixture of catalyst 10 (10
mol%, 65.1 mg, 0.2 mmol) in CH2Cl2 (1 mL). Then sulfone 4 (1 equiv,
218.25 mg, 1 mmol) was added. The mixture was stirred at RT for 48 h.
The solvent was then removed under reduced pressure and the crude
product was purified by gradient flash column chromatography (hexane/
EtOAc from 90:10 to 70:30) to give 25. White foam; yield: 349.8 mmg,
0.78 mmol (78%); [a]D25 =+14.0 (c=1 in CH2Cl2, 99% ee); 1H NMR
(300 MHz, CDCl3): d=9.65 (s, 1H), 8.36–7.30 (m, 8H), 6.42 (d, J=
15.7 Hz, 1H), 5.21 (d, J=11.1 Hz, 1H), 4.81–4.60 (m, 1H), 4.31 (q, J=
7.1 Hz, 2H), 3.42–3.35 (m, 2H), 1.37 ppm (t, J=7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=197.3, 166.3, 141.5, 137.9, 136.9, 135.4, 135.1, 134.2,
130.0, 128.9, 128.2, 122.8, 122.5, 122.4, 75.9, 60.6, 5.1, 31.7, 14.3 ppm; the
enantiomeric excess was determined to be 99% by HPLC; HPLC (Chir-
alpack IA column at 260 nm; eluent: hexane/iPrOH 50:50): flow rate=
[6] E. P. Kꢄndig, A. F. Cunningham, Jr., Tetrahedron 1988, 44, 6855–
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0.5 mLminÀ1
; t1 =33.72 (major), t2 =40.17 min (minor); HRMS: m/z:
calcd for C21H21O7S2: 449.0729 [M+H]+; found: 449.0740.
[9] A previous version of the manuscript was submitted on June 5th as
a communication to another journal. One week later (June 12th) the
amine-catalyzed enantioselective conjugate addition of 1 to aliphatic
enals in the presence of 100 mol% LiOAc as the reaction coadju-
vant was reported (J. L. Garcꢁa-Ruano, V. Marcos, J. Alemꢂn, Chem.
Commun. 2009, 4435–4437). Adducts with selectivities ranging from
80 to 96% ee were obtained, though the method was limited to
alkyl-substituted enals and applicable to formal b-methylation only.
On this basis, one referee suggested us to submit a Full Paper of the
manuscript.
Acknowledgements
This work was financially supported by Universidad del Paꢁs Vasco
(UPV/EHU), Gobierno Vasco (GV), and Ministerio de Educaciꢆn y
Ciencia (MEC CTQ2007-68095, Spain). A.L. thanks the MEC and the
European Social Foundation for a Ramꢆn y Cajal contract. S.V. thanks
the MEC and A.P. thanks GV for a fellowship. Authors thank Dr. C.
Masdeu for experimental assistance.
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Received: July 28, 2009
Published online: September 24, 2009
11962
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ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 11954 – 11962