Enantioselective synthesis of chiral sulfones by Rh-catalyzed asymmetric addition of boronic acids to α,β-unsaturated 2-pyridyl sulfones

Article abstract of DOI:10.1021/jo7016197

(Chemical Equation Presented) A general and efficient method for the rhodium-catalyzed enantioselective catalytic conjugate addition of organoboronic acids to α,β-unsaturated sulfones is described. The success of the process relies on the use of α,β-unsat

Full text of DOI:10.1021/jo7016197

Enantioselective Synthesis of Chiral Sulfones by Rh-Catalyzed
Asymmetric Addition of Boronic Acids to r,â-Unsaturated 2-Pyridyl
Sulfones
Pablo Mauleo´n, Ine´s Alonso, Marta Rodr´ıguez Rivero, and Juan C. Carretero*
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias. UniVersidad Auto´noma de Madrid,
28049 Madrid, Spain
juancarlos.carretero@uam.es
ReceiVed August 1, 2007
A general and efficient method for the rhodium-catalyzed enantioselective catalytic conjugate addition
of organoboronic acids to R,â-unsaturated sulfones is described. The success of the process relies on the
use of R,â-unsaturated 2-pyridyl sulfones as key metal-coordinating substrates; typical sulfones such as
vinyl phenyl sulfones are inert under the reaction conditions. Among a variety of chiral ligands, Chiraphos
provided the best asymmetric induction. This rhodium [Rh(acac)(C2H4)2]/Chiraphos catalyst system has
a broad scope, being applicable to the addition of both aryl and alkenyl boronic acids to cis and trans
R,â-unsaturated 2-pyridyl sulfones. In most cases, especially in the addition of aryl boronic acids, the
reactions take place cleanly and with high enantioselectivity, affording chiral â-substituted 2-pyridyl
sulfones in good yields and enantioselectivities (70-92% ee). The sense and magnitude of this
enantioselectivity have been studied by DFT theoretical calculations of the aryl-rhodium insertion step.
These calculations strongly support the formation of a five-membered pyridyl-rhodium chelated species
as the most stable complex after the insertion into the CdC bond. These highly enantioenriched chiral
sulfones are very appealing building blocks in enantioselective synthesis. For instance, the straightforward
elimination of the 2-pyridylsulfonyl group by either Julia-Kociensky olefination or alkylation/
desulfonylation sequences provides a variety of functionalized chiral compounds, such as allylic substituted
alkenes or â-substituted ketones and esters.
Introduction
the rhodium-catalyzed conjugate addition of boronic acids to
R,â-unsaturated sulfones had not been previously described. In
Since the first report described by Miyaura et al. in 1997,1a
the Rh(I)-catalyzed asymmetric conjugate addition of boronic
acids to electron-deficient olefins has gained increasing impor-
tance, becoming one of the most useful and versatile tools for
the introduction of both aryl and alkenyl fragments at the
â-position of such substrates in a highly enantioselective
fashion.1 The current state of the art includes the extension of
the methodology to a wide variety of Michael acceptors, such
as R,â-unsaturated ketones,2 esters,3 amides and imides,4 ni-
troalkenes,5 phosphonates,6 and aldehydes.7 However, despite
the well-known importance of sulfones in organic synthesis,8
(2) (a) Takaya, Y.; Ogasawara, M.; Sakai, M.; Hayashi, T.; Miyaura, N.
J. Am. Chem. Soc. 1998, 120, 5579. (b) Reetz, M. T.; Moulin, D.; Gosberb,
A. Org. Lett. 2001, 3, 4083. (c) Kuriyama, M.; Nagai K.; Yamada K.-i.;
Miwa, Y.; Taga, T.; Tomioka, K. J. Am. Chem. Soc. 2002, 124, 8932. (d)
Boiteau, J. G.; Imbos, R.; Minnaard A. J.; Feringa, B. L. Org. Lett. 2003,
5, 681 and 1385. (e) Boiteau, J. G.; Minnaard, A. J.; Feringa, B. L. J. Org.
Chem. 2003, 68, 9481. (f) Iguchi, Y.; Itooka, R.; Miyaura, N. Synlett 2003,
7, 1040. (g) Hayashi, T.; Ueyama K.; Tokunaga, N.; Yoshida, K. J. Am.
Chem. Soc. 2003, 125, 11508. (h) Defieber, C.; Paquin, J.-F.; Serna S.;
Carreira, E. M. Org. Lett. 2004, 6, 3873. (i) Otomoru, Y.; Okamoto, K.;
Shintani, R.; Hayashi, T. J. Org. Chem. 2005, 70, 2503. (j) Chen, Q.;
Kuriyama, M.; Soeta, T.; Hao, X.; Yamada, K.; Tomioka, K. Org. Lett.
2005, 7, 4439. (k) Chen, F.-X.; Kina, A.; Hayashi, T. Org. Lett. 2006, 8,
341. (l) Vandyck, K.; Matthys, B.; Willen, M.; Robeyns, K.; Van Meervelt,
L.; Van der Eycken, J. Org. Lett. 2006, 8, 363. (m) Kina, A.; Iwamura, H.;
Hayashi, T. J. Am. Chem. Soc. 2006, 128, 3904. (n) Monti, C.; Gennari,
C.; Piarulli, U. Chem. Eur. J. 2007, 13, 1547. (o) Duan, W.-L.; Iwamura,
H.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2007, 129, 2130.
(1) For a pioneering contribution in the area, see: (a) Sakai, M.; Hayashi,
H.; Miyaura, N. Organometallics 1997, 16, 4229. For general reviews on
enantioselective Rh-catalyzed addition of boronic acids, see: (b) Hayashi,
T. Synlett 2001, 879. (c) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103,
2829. (d) Fagnou, K.; Lautens, M. Chem. ReV. 2003, 103, 169.
10.1021/jo7016197 CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/30/2007
9924
J. Org. Chem. 2007, 72, 9924-9935

EnantioselectiVe Synthesis of Chiral Sulfones
SCHEME 1
fact, to the best of our knowledge, the only precedent on the
use of R,â-unsaturated sulfones and carbon nucleophiles in
enantioselective Rh-catalyzed addition reactions was reported
by Hayashi et al. in 2003, which described that the reaction
with aryltitanium species provided a cine-substitution alkene
product instead of the 1,4-addition product.9
Removable metal-coordinating groups have been often used
in metal-catalyzed transformations to accelerate or even enable
reactions that would otherwise be extremely sluggish, the
coordination of such ancillary groups with late transition metals
rendering these processes pseudo intramolecular.10 For example,
heterocyclic nitrogen coordinating groups such as 2-pyridyl,
2-pyridyldimethylsilyl, or 2,6-pyrimidylsulfenyl have been
widely employed in highly efficient C-C bond-forming reac-
tions catalyzed by transition metals, mainly Pd, Ru, Rh, and
Cu.11 As part of an ongoing research program dealing with
potentially metal-coordinating R,â-unsaturated sulfones in tran-
sition-metal-catalyzed processes, our research group has reported
that the o-(dimethylamino)phenyl sulfonyl group allowed
intermolecular Heck reactions on R,â-unsaturated sulfones,12
and the 2-pyridyl sulfonyl group played a key role in the
SCHEME 2
development of the Cu-catalyzed asymmetric reduction of â,â-
disubstituted vinyl sulfones.13
In a previous communication we reported that this kind of
chelation-controlled strategy can also be applied to the enan-
tioselective 1,4-addition of boronic acids to R,â-unsaturated
sulfones, especially utilizing a 2-pyridyl sulfone as the key
auxiliary coordinating group.14 Herein, we report a full account
of the scope of this Rh-catalyzed asymmetric conjugate addition
of boronic acids to â-substituted R,â-unsaturated sulfones with
regard to the substitution at the boronic acid and vinyl sulfone,
cis/trans stereochemistry of the vinyl sulfone, nature of the chiral
ligand, and synthetic applications of the resulting enantioen-
riched â-chiral 2-pyridyl sulfones. A DFT theoretical study to
rationalize the origin of the enantioselectivity of the process,
presumably through the participation of the chelated Rh-N
species I (Scheme 1), is also presented.
(3) (a) Takaya, Y.; Senda, T.; Kurushima, H.; Ogasawara M.; Hayashi,
T. Tetrahedron: Asymmetry 1999, 10, 4047. (b) Sakuma, S.; Sakai, M.;
Itooka, R.; Miyaura, N. J. Org. Chem. 2000, 65, 5951. (c) Shintani, R.;
Ueyama, K.; Yamada, I.; Hayashi, T. Org. Lett. 2004, 6, 3425. (d) Paquin,
J.-F.; Stephenson, C. R. J.; Defieber, C.; Carreira, E. M. Org. Lett. 2005,
7, 3821. (e) Chen, G.; Tokunaga, N.; Hayashi, T. Org. Lett. 2005, 7, 2285.
(f) See also ref 2h.
(4) (a) Sakuma, S.; Miyaura, N. J. Org. Chem. 2001, 66, 8944. (b) Senda,
T.; Ogasawara, M.; Hayashi, T. J. Org. Chem. 2001, 66, 6852. (c) Shintani,
R.; Duan, W.-L.; Nagano, T.; Okada, A.; Hayashi, T. Angew. Chem., Int.
Ed. 2005, 44, 4611. (d) Shintani, R.; Duan, W.-L.; Hayashi, T. J. Am. Chem.
Soc. 2006, 128, 5628. (e) Hargrave, J. D.; Bishb, G.; Frost, C. G. Chem.
Commun. 2006, 4389.
(5) Hayashi, T.; Senda, T.; Ogasawara, M. J. Am. Chem. Soc. 2000, 122,
10716.
(6) (a) Hayashi, T.; Senda, T.; Takaya, Y.; Ogasawara, M. J. Am. Chem.
Soc. 1999, 121, 11591. (b) Nishimura, T.; Hirabayashi, S.; Yasuhara, Y.;
Hayashi, T. J. Am. Chem. Soc. 2006, 128, 2556.
(7) Paquin, J.-F.; Defieber, C.; Stephenson, C. R. J.; Carreira, E. M. J.
Am. Chem. Soc. 2005, 127, 10850.
(8) Simpkins, N. S. In Sulphones in Organic Synthesis; Pergamon
Press: Oxford, 1993. For some reviews on sulfone chemistry, see: (a)
Simpkins, N. S. Tetrahedron 1990, 46, 6951. (b) Rayner, C. M. Contemp.
Org. Synth. 1996, 3, 499.
Results and Discussion
1. Preparation of the Model Aryl and Heteroaryl 1-Pro-
penyl Sulfones. It is surprising that, despite the well-established
utility of the sulfonyl group, the vast majority of the reactions
reported to date with R,â-unsaturated sulfones refer exclusively
to the use of the traditional phenyl or p-tolyl sulfones. Thus, as
a starting point in our agenda, we set out to develop an efficient
synthetic route to heteroaryl vinyl sulfones. As a first approach,
we studied the addition of a heteroaryl methyl sulfone to an
aldehyde and further dehydration. For that purpose, we chose
methyl 2-pyridyl sulfone as starting material, which was
prepared by methylation of the commercially available 2-mer-
captopyridine and further oxidation at sulfur15 (Scheme 2).
However, deprotonation of methyl 2-pyridyl sulfone with n-BuLi
(THF, -78 °C) and in situ treatment with acetaldehyde led to
a complex reaction mixture, most likely due to competitive self-
condensation reactions of the aldehyde.
In light of these results, we turned to the Horner-Wad-
sworth-Emmons olefination as a plausible approach to the
synthesis of this type of functionalized alkenes. As a first
alternative to prepare the required phosphonate, we tried the
direct phosphorylation of the lithium anion of methyl 2-pyridyl
sulfone (prepared by treatment with n-BuLi, THF, -78 °C) with
diethyl chlorophosphate. Unfortunately, a complex mixture was
observed by 1H NMR. Then, a two-step sequence was studied:
(9) Yoshida, K.; Hayashi, T. J. Am. Chem. Soc. 2003, 125, 2872.
(10) For general reviews on organometallic reactions controlled by
chelation with auxiliary coordinating groups, see: (a) Hoveyda, A. H.;
Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307. (b) Beak, P.; Basu,
A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996,
29, 552.
(11) For some selected recent publications on nitrogen coordinating
groups in organometallic reactions, see: (a) Inoue, S.; Yokota, K.;
Tatamidani, H.; Kukumoto, Y.; Chatani, N. Org. Lett. 2006, 8, 2519. (b)
Park, Y. J.; Jo, E.-A.; Jun, C.-H. Chem. Commun. 2005, 1185. (c) Itami,
K.; Ohashi, Y.; Yoshida, J.-i. J. Org. Chem. 2005, 70, 2778. (d) Itami, K.;
Ushiogi, Y.; Nokami, T.; Ohashi, Y.; Yoshida, J.-i. Org. Lett. 2004, 6, 3695.
(e) Itami, K.; Mitsudo, K.; Fujita, K.; Ohashi, Y.; Yoshida, J.-i. J. Am.
Chem. Soc. 2004, 126, 11058. (f) Park, Y. J.; Kwon, B; Ahn, J.-A.; Lee,
H.; Jun, C.-H. J. Am. Chem. Soc. 2004, 126, 13892. (g) Han, H.; Bae, I.;
Yoo, E. J.; Lee, J.; Do, Y.; Chang, S. Org. Lett. 2004, 6, 4109. (h) Itami,
K.; Mineno, M.; Muraoka, N.; Yoshida, J.-i. J. Am. Chem. Soc. 2004, 126,
11778. (i) Tatamidani, H.; Yokota, K.; Kakiuchi, F.; Chatani, N. J. Org.
Chem. 2004, 69, 5615. (j) Stadler, A.; von Schenck, H.; Vallin, K. S. A.;
Larhed, M.; Hallberg, A. AdV. Synth. Catal. 2004, 346, 1773. (k) Nilsson,
P.; Larhed, M.; Hallberg, A. J. Am. Chem. Soc. 2003, 125, 3430. (l) Itami,
K; Kamei, T.; Yoshida, J. J. Am. Chem. Soc. 2003, 125, 14670. (m) Lee,
D.-Y.; Hong, B.-S.; Cho, E.-G.; Lee, H.; Jun, C.-H. J. Am. Chem. Soc.
2003, 125, 6372. (n) Ko, S.; Han, H.; Chang, S. Org. Lett. 2003, 5, 2687.
(o) Ko, S.; Han, H.; Chang, S. J. Org. Chem. 2003, 68, 1607.
(12) (a) Mauleo´n, P.; Alonso, I.; Carretero, J. C. Angew. Chem., Int. Ed.
2001, 40, 1291. (b) Mauleo´n, P.; Nun˜ez, A. A.; Alonso, I.; Carretero, J. C.
Chem. Eur. J. 2003, 9, 1511.
(13) Llamas, T.; Go´mez Arraya´s, R.; Carretero, J. C. Angew. Chem.,
Int. Ed. 2007, 46, 3329.
(14) (a) Mauleo´n, P.; Carretero, J. C. Org. Lett. 2004, 6, 3195. For the
enantioselective formation of quaternary stereocenters through Rh-catalyzed
addition to â,â-disubstituted 2-pyridyl vinyl sulfones, see: (b) Mauleo´n,
P.; Carretero, J. C. Chem. Commun. 2005, 4961.
(15) Blacklock, T. J.; Sohar, P.; Butcher, J. W.; Lamanec, T.; Grabowski,
E. J. J. J. Org. Chem. 1993, 58, 1672.
J. Org. Chem, Vol. 72, No. 26, 2007 9925

Mauleo´n et al.
TABLE 1. Rh-Catalyzed Addition of PhB(OH)2 to (E)-1-Propenyl
Aryl Sulfones
SCHEME 3
a SN2 reaction of the commercially available diethyl iodom-
ethylphosphonate with an aromatic thiol16 and further oxidation
of the thioether to the sulfone. As outlined in Scheme 3, in the
presence of K2CO3 as base (THF, reflux) the reaction of diethyl
iodomethylphosphonate with a set of five heteroaromatic thiols
took place in good yields (59-75%). The oxidation of the so
formed thioethers (1) to the corresponding sulfones (2) was
effected by adding 3 equiv of hydrogen peroxide in the presence
of catalytic amounts of Na2WO4 in ethyl acetate.15 In all cases,
the oxidation took place cleanly, without any competitive
formation of N-oxides, providing the required phosphonates in
excellent yields (96-99%). With these sulfonyl phosphonates
in hand, we studied the Horner-Wadsworth-Emmons olefi-
nation with acetaldehyde. After trying a number of reaction
conditions, testing different solvents and bases, we found as
optimal conditions the use of inexpensive K2CO3 as base and
CH2Cl2 as solvent, at room temperature. Under these conditions,
the olefination process gave rise to the desired 1-propenyl
heteroaryl sulfones 3 in good yields (64-85%, except for the
pyrimidylsulfonyl derivative 3e) and with complete (E) stereo-
selectivity.
a
Reaction conditions: PhB(OH)2 (500 mol %), [Rh] (3 mol %), Binap
(3 mol %), dioxane/H2O (10:1), 100 °C, 12 h. b Estimated by 1H NMR
analysis of the crude reaction mixtures. c In pure isolated product after
chromatography.
SCHEME 4
2. Rh-Catalyzed Addition of PhB(OH)2 to Aryl and
Heteroaryl 1-Propenyl Sulfones: Effect of the Substitution
at the Sulfone. Having prepared a variety of 1-propenyl
sulfones, ranging from the simple non-coordinating phenyl
sulfone (3a) to the substrate bearing an o-N,N-dimethylami-
nophenyl moiety (3b) or the previously mentioned heteroaro-
matic sulfones17 (3c-g), we studied the Rh-catalyzed reactions
of all of these substrates with PhB(OH)2 under the conditions
originally described by Miyaura and Hayashi for the addition
to enones2a [Rh(acac)(C2H4)2 as catalyst, racemic Binap as
ligand, in dioxane/H2O at 100 °C] (Table 1).
(imidazoyl group) or 3g (pyridyl group) was used as substrate,
leading to the desired â-phenylsubstituted sulfone as the sole
detected product. Among both substrates, the 2-pyridyl sulfone
3g proved to be more efficient than the imidazoyl homologue
3f, affording the addition product in 12 h in 98% isolated yield
(as opposed to 74% yield).
At this point we decided to clarify if the high reactivity
observed with the sulfone 3g was due to merely the electron-
withdrawing effect of the pyridyl group or if, as first envisaged,
it would be the result of the participation of Rh-N five-
membered chelated species (such as I in Scheme 1). With that
purpose in mind, and following the reaction sequence optimized
for the synthesis of R,â-unsaturated heteroaryl sulfones, we
prepared the pyridyl sulfone 3h, a structural isomer of 3g that
presents the nitrogen atom in position 4 at the pyridine unit.
As such, the electronic properties of both isomers should be
very similar, but in the case of 3h the nitrogen atom in position
4 makes the formation of chelated Rh-N species unfeasible.
Interestingly, unlike the high reactivity observed for 3g, no
reaction took place when 3h was treated with PhB(OH)2 under
the standard Rh-catalyzed reaction conditions, 3h being fully
recovered after 12 h (Scheme 4). This result substantiates our
hypothesis that the high reactive profile of 3g could be due to
chelation Rh-N effects rather than mere electronic factors.
Not unexpectedly,9 the simple phenyl sulfone 3a proved to
be unreactive under the reaction conditions. Unfortunately, no
evolution was observed from the sulfones 3b, 3c, or 3d, bearing
2-(dimethylamino)phenyl (3b), tetrazoyl (3c), and benzothiazo-
2-yl (3d) groups (entries 2-4), and an incomplete conversion
occurred in the case of the 2,6-pyrimidyl sulfone 3e (entry 5).18
However, a very smooth and clean reaction took place when 3f
(16) Erian, A.; Kwonno, A.; Fuchigami, T. J. Org. Chem. 1995, 60, 7654.
(17) See supporting information for details on the preparation of
substrates 3.
(18) Although we previously found that sulfone 3e does not react with
phenylboronic acid,14a we have recently observed that this substrate is
slightly reactive when a very fresh sample of Rh(acac)(C2H4)2 is used as
catalyst.
9926 J. Org. Chem., Vol. 72, No. 26, 2007

EnantioselectiVe Synthesis of Chiral Sulfones
TABLE 2. Ligand Screening for Rh-catalyzed Enantioselective
Addition of PhB(OH)2 to Model Sulfone 3g
TABLE 3. Horner-Wadsworth-Emmons Olefination of 2g with
Various Aldehydes
entrya
ligand
(R)-Binap
(R)-Tol-Binap
(S,S)-Chiraphos
(R)-Norphos
(R)-Phanephos
Josiphos 1
Josiphos 2
Taniaphos
Mandyphos
Fesulphos 1
Fesulphos 2
Phosphoramidite
conv (%)b
yield (%)c
ee (%)d
entrya
R
E/Z ratiob
3, yield (%)c
1
2
3
4
5
6
7
8
9
>98
>98
>98
10
<10
73
<10
<10
<10
87
70
39
97
92
97
73 (R)
60 (R)
81 (S)
1
2
3
4
Me
>98/<2
>98/<2
>98/<2
>98/<2
3g, 85
3i, 72
3j, 76
3k, 78
n-pent
i-Pr
â-naphth
a Reaction conditions: RCHO (1.5 equiv), K2CO3 (1.5 equiv), CH2Cl2,
rt, 24-48 h. b Estimated by 1H NMR analysis of the crude reaction mixtures.
c In pure isolated product.
68
41 (R)
10e
11e
12
78
66
31
76 (S)
81 (S)
73 (S)
successfully used in many reported Rh-catalyzed additions, in
our case it was found that (S,S)-Chiraphos afforded a better result
(81% ee, entry 3) than (R)-Binap (73% ee, entry 1) or (R)-Tol-
Binap (60% ee, entry 2). Also worth noting are the high levels
of enantioselectivity obtained with the P,S-Fesulphos ligands,
recently developed in our group,19 albeit their reactivity was
significantly lower than that exhibited by (S,S)-Chiraphos. The
absolute configuration of the addition product 4g was unequivo-
cally determined by chemical correlation with a known chiral
compound, as will be discussed later (compound 20 in Table
7).
a Reaction conditions: PhB(OH)2 (500 mol %), [Rh] (3 mol %), ligand
(3 mol %), dioxane/H2O (10:1), 100 °C, 12 h. b Estimated by 1H NMR
analysis of the crude reaction mixtures. c In pure isolated product after
chromatography. d Determined by chiral HPLC (Chiralpak AD). e 6 mol
% of ligand and Rh catalyst were used.
4. Scope of the Catalytic Asymmetric Addition of Aryl
and Alkenyl Boronic Acids to R,â-Unsaturated 2-Pyridyl
Sulfones. (a) Synthesis of (E) and (Z) R,â-Unsaturated
2-Pyridyl Sulfones. To address the effect of the substitution at
the vinyl sulfone, a series of substrates with sterically different
substitution at the â position were prepared. Thus, in addition
to the model substrate 3g, substrates 3i, 3j, and 3k (bearing
n-pentyl, isopropyl, and â-naphthyl groups, respectively) were
readily obtained in good yields (72-78%) and complete (E)
stereoselectivity by Horner-Wadsworth-Emmons olefination
of 2-pyridylsulfonyl phosphonate 2g and the corresponding
aldehyde (Table 3).
The (Z)-propenyl 2-pyridyl sulfone (3l) was prepared to study
the effect of the configuration at the CdC bond. This compound
was easily synthesized taking advantage of the fact that the
Horner-Wadsworth-Emmons reaction of the sulfenyl phos-
phonate 1g is (Z)-stereoselective, instead of highly (E)-stereo-
selective as in the case of the sulfonyl phosphonate 2g. Thus,
the reaction of 1g with acetaldehyde employing KHMDS as
base (DME, -78 °C) provided the (Z) isomer as the major
product (Z:E ) 70:30). After chromatographic separation and
sulfur oxidation (Na2WO4·2H2O/H2O2) the sulfone 3l was
obtained in 45% overall yield (Scheme 5).
Finally, in addition to all the previous acyclic vinyl 2-pyridyl
sulfones, we also prepared the cyclic vinyl sulfone 3m. This
compound was readily prepared in two steps by the known
Pummerer rearrangement of cyclohexyl 2-pyridyl sulfoxide,20
followed by tungsten/H2O2 oxidation of the resulting sulfide
(Scheme 6).
FIGURE 1. Chiral ligands tested.
3. Rh-Catalyzed Asymmetric Addition of PhB(OH)2 to
1-Propenyl 2-Pyridyl Sulfone: Effect of the Chiral Ligand.
With the 2-pyridyl sulfone 3g as optimal substrate, we next
studied the enantioselectivity of the process in the presence of
a variety of structurally different chiral ligands (Table 2, Figure
1).
To establish appropriate reactivity comparisons, all the
reactions were conducted for 12 h. Complete conversions were
only observed when certain P,P-bisphosphines were employed,
namely, Binap, Tol-Binap, and Chiraphos (entries 1-3, respec-
tively). On the other hand, other bidentate ligands with P,P
coordination (entries 4, 5, and 7), or P,N coordination (entries
8 and 9) almost completely inhibited the process. An intermedi-
ate situation was observed in the cases of Josiphos 1 (entry 6),
Fesulphos 1 and 2 (entries 10 and 11), and the monodentate
Feringa’s phosphoramidite (entry 12). In all of these cases,
incomplete conversions were obtained after 12 h. Regarding
the enantioselectivity of the process, despite Binap having been
(19) (a) Priego, J.; Garc´ıa Manchen˜o, O.; Cabrera, S.; Go´mez Arraya´s,
R.; Llamas, T.; Carretero, J. C. J. Org. Chem. 2003, 68, 3679. (b) Cabrera,
S.; Go´mez Arraya´s, R.; Carretero, J. C. Angew. Chem., Int. Ed. 2004, 43,
3944. (c) Garc´ıa Manchen˜o, O.; Go´mez Arraya´s, R.; Carretero, J. C. J.
Am. Chem. Soc. 2004, 126, 456. (d) Cabrera, S.; Go´mez Arraya´s, R.;
Carretero, J. C. J. Am. Chem. Soc. 2005, 127, 16394. (e) Cabrera, S.; Go´mez
Arraya´s, R.; Alonso, I.; Carretero, J. C. J. Am. Chem. Soc. 2005, 127, 17938.
(f) Cabrera, S.; Garc´ıa Manchen˜o, O.; Go´mez Arraya´s, R.; Alonso, I.;
Mauleo´n, P.; Carretero, Juan C. Pure Appl. Chem. 2006, 78, 257.
J. Org. Chem, Vol. 72, No. 26, 2007 9927

Mauleo´n et al.
TABLE 4. Rh-Catalyzed Enantioselective Conjugate Addition of Aryl Boronic Acids to (E)-2-Pyridyl r,â-Unsaturated Sulfones
entrya
sulfone
R1
R2
ligand
product
yield (%)b
ee (%)c
1d
2d
3g
3g
3g
3g
3g
3g
3i
3i
3i
3i
3j
3j
3j
3j
3k
3k
3k
3k
Me
Me
Me
Me
Me
Me
n-pent
n-pent
n-pent
n-pent
i-Pr
i-Pr
i-Pr
i-Pr
â-naphth
â-naphth
â-naphth
â-naphth
Ph
Ph
B
C
B
C
B
C
B
C
C
C
B
C
C
C
B
C
C
C
4g
4g
5
5
6
6
7
7
8
97
98
98
98
97
89
98
98
73 (R)
81 (S)
76 (R)
84 (S)
54 (R)
77 (S)
74 (R)
84 (S)
87 (S)
81 (S)
76 (R)
78 (S)
85 (S)
76 (S)
76 (S)
87 (R)
92 (R)
85 (R)
3d
p-FC6H4
p-FC6H4
p-MeOC6H4
p-MeOC6H4
Ph
4d
5
6
7
8
9
10
11e
12e
13e
14e
15e
16e
17e
18e
Ph
p-FC6H4
p-MeOC6H4
Ph
94
92
9
10
10
11
12
13
13
14
15
62 (89)f
93
Ph
p-FC6H4
p-MeOC6H4
Ph
93
74 (94)f
76 (95)f
96
Ph
p-FC6H4
p-MeOC6H4
97
84 (94)f
a Reaction conditions: R2B(OH)2 (5 equiv), Rh(acac)(C2H4)2 (3 mol %), L* (3 mol %), dioxane/H2O (10:1), 24 h. B: (R)-Binap, C: (S,S)-Chiraphos. b In
pure isolated product. c Determined by chiral HPLC (Chiralpak AD or Chiralcel OD). d Reaction time 12 h. e 5 mol % of ligand and Rh catalyst were used.
f In converted product.
SCHEME 5
TABLE 5. Rh-Catalyzed Enantioselective Addition of Aryl
Boronic Acids to (Z)-r,â-Unsaturated 2-Pyridyl Sulfone 3l
SCHEME 6
entrya
Ar
prod, yield (%)b
ee (%)c
(b) Catalytic Asymmetric Addition of Aryl Boronic Acids
to R,â-Unsaturated 2-Pyridyl Sulfones. In Tables 4 and 5 are
shown the results of the Rh-catalyzed addition of three elec-
tronically different aryl boronic acids [PhB(OH)2, p-MeOC6H4B-
(OH)2, and p-FC6H4B(OH)2] to the four (E) vinyl sulfones 3
g-k (Table 4) and the (Z) substrate 3l (Table 5). For comparison
purposes and because Chiraphos is not a very common chiral
ligand in Rh-catalyzed conjugate additions (unlike Binap), we
decided at this point to study more systematically the asymmetric
performance of Binap versus Chiraphos.
Certain important conclusions can be extracted from these
results: (a) Yields above 90% in pure isolated product and
moderate to high asymmetric inductions, ranging 69-92% ee,
were obtained regardless of the substitution at the vinyl sulfone
and the boronic acid. Only in the reaction of the bulkier
substrates 3j and 3k with p-MeOC6H4B(OH)2 were the yields
1
2
3
Ph
4g, 97
5, 94
6, 92
70 (R)
74 (R)
69 (R)
pFC6H4
pMeOC6H4
a Reaction conditions: ArB(OH)2 (500 mol %), [Rh] (3 mol %), (S,S)-
Chiraphos (3 mol %), dioxane/H2O (10:1), 100 °C, 12 h. b In pure isolated
product. c Determined by chiral HPLC (Chiralpak AD).
slightly lower as a result of incomplete conversions (entries 11,
14, 15, and 18). Addition of methyl boronic acid over 3i was
also attempted; however, no reaction at all was observed under
the optimized conditions. (b) (S,S)-Chiraphos (ligand C in Table
4) proved to be more efficient than (R)-Binap (ligand B in Table
4) in all of the tested reactions (enantioselectivities from 2 to
23 points higher with Chiraphos than with (R)-Binap). This
effect is particularly remarkable in the case of the addition of
p-methoxyphenyl boronic acid to the sulfone 3g (entries 5 and
6, 54% and 77% ee, respectively). Additionally, in the case of
the more bulky substrates the chemical yields obtained using
(20) Shimazaki, M.; Hikita, M.; Hosoda, T.; Ohta, A. Heterocycles 1991,
32, 937.
9928 J. Org. Chem., Vol. 72, No. 26, 2007

EnantioselectiVe Synthesis of Chiral Sulfones
TABLE 7. Julia-Kocienski Olefination of Chiral 2-Pyridyl
Sulfones Having a â-Tertiary Stereocenter
SCHEME 7
entrya
R1
Me
Me
Me
Me
Me
R2
R3
E/Z ratiob prod, yieldc (%)
TABLE 6. Rh/Chiraphos-Catalyzed Enantioselective Addition of
Alkenylboronic Acids to 3g
1
2
3
4
5
6
Ph
Ph
Ph
Ph
Ph
>99/<1
90/10
20, 93
21, 81
22, 89d
23, 48
24, 92
25, 91
p-FC6H4
PhC2H2
i-Pr
87/13
65/35
p-FC6H4 Ph
Ph
>99/<1
n-pent Ph
>99/<1
entrya
R
prod, yield (%)b
ee (%)c
a Reaction conditions: KHMDS (1.5 equiv), DME, -78 °C, 2 h.
1
2
3
Me
Ph
CH2Ph
17, 91
18, 94
19, 93
43 (S)
45 (S)
92 (S)
b Estimated by H NMR analysis of the crude reaction mixtures. c In pure
1
(E) olefin after flash chromatography. d As a mixture of (E/Z) isomers (87:
13).
a Reaction conditions: RCHdCHB(OH)2 (500 mol %), [Rh] (3 mol %),
(S,S)-Chiraphos (3 mol %), dioxane/H2O (10:1), 100 °C, 24 h. b In pure
isolated product. c Determined by chiral HPLC (Chiralpak AD).
elimination by direct Julia-Kociensky reaction21 provides a
practical alternative for the introduction of a CdC bond.
As shown in Table 7, the treatment of the 2-pyridyl sulfones
having a tertiary stereocenter at â-position with KHMDS (DME
at -78 °C), followed by the addition of the aldehyde, either
aromatic (entries 1, 2, 5, and 6), R,â-unsaturated (entry 3), or
aliphatic (entry 4), afforded the corresponding alkene in
excellent yields (81-93%), usually with very high or complete
(E) stereoselectivity (except entry 4). In addition, we confirmed
that, as expected, this olefination reaction takes place without
erosion of the optical purity of the product. For instance, starting
from an enantioenriched sample of substrate 4g (81% ee), the
known alkene (R)-2022 was obtained with the same enantiomeric
excess (HPLC, Chiralcel OD), allowing also for the unequivocal
assignment of the absolute configuration of the stereogenic
center created in the Rh-catalyzed conjugate addition step.
From a synthetic point of view, this reaction sequence
(conjugate addition to an R,â-unsaturated 2-pyridyl sulfone and
Julia-Kocienski olefination) constitutes a complementary al-
ternative to the enantioselective metal-catalyzed allylic substitu-
tion of allylic acetates and related compounds.23 Interestingly,
unlike processes involving π-allyl intermediates, this two-step
procedure avoids any regiochemical uncertainty in the formation
of the CdC bond, allowing the unequivocal substitution at
positions 1 and 3 at the alkene. This point is clearly illustrated
in Table 7 by the synthesis of both 1,3-diaryl regioisomers 21
and 24 (entries 2 and 5, respectively).
Binap were significantly lower than those obtained with
Chiraphos (entries 11 and 15 vs 12 and 16). (c) As expected
for a process involving the participation of Rh-N chelated
species in the addition step, the reaction of the (E/Z) diastere-
omeric olefins 3g (entries 2, 4, and 6, Table 4) and 3l (Table 5)
employing (S,S)-Chiraphos as chiral ligand led to opposite
enantiomers (â-re face addition in the case of 3g and â-si face
addition for 3l), albeit the enantioselectivity provided by the
(Z) isomer 3l was somewhat lower than that of the (E) isomer
3g (69-74% ee vs 77-84% ee).
We also explored the behavior of an ortho-substituted
arylboronic acid, a substitution pattern that has scarcely been
studied in Rh-catalyzed conjugate additions (Scheme 7). Thus,
under the standard conditions, the reaction of 2-fluorophenyl
boronic acid with sulfone 3g provided the addition product 16
in 93% yield and 76% ee.
(c) Addition of Alkenyl Boronic Acids. As a complementary
study devoted to broadening the scope of the reaction, we also
explored the behavior of some commercially available alkenyl
boronic acids as nucleophilic partners in the reaction with the
model substrate 3g (Table 6).
Again, excellent yields were obtained in the three cases (91-
94%). However, regarding the enantioselectivity of the process,
the results were not as consistent. Thus, whereas trans-propenyl
or trans-styryl boronic acids afforded modest enantioselectivities
(43% and 45% ee, entries 1 and 2), the reaction of 3-phenyl-
1-propenyl boronic acid was much more enantioselective,
affording 19 in 92% ee (entry 3).
Finally, the reactivity of 1-cyclohexenyl 2-pyridyl sulfone
(3m) was studied. Unfortunately, no reaction was observed after
treatment with phenyl and trans-styryl boronic acids, using either
Binap or Chiraphos (3-10 mol %), for 24 h at 100 °C, showing
that the substitution at R-position has a deep detrimental effect
in the reactivity of the vinyl 2-pyridyl sulfone.
5. Synthetic Applications: Removal of the 2-Pyridyl
Sulfonyl Group by Julia-Kociensky Olefination and Reduc-
tive Elimination. Because of the versatility of the sulfonyl group
in organic synthesis, the enantioenriched sulfones obtained in
the addition of boronic acids to vinyl sulfones are very appealing
intermediates in the formation of C-C and CdC bonds. In this
context the 2-pyridylsulfonyl group plays a dual role: not only
is it essential for achieving the Rh-catalyzed addition, but its
Finally, to further highlight the chemical versatility of these
â-substituted enantioenriched sulfones in the preparation of
differently functionalized chiral compounds,13 the conversion
of (S)-4g (of 94% ee) into the benzylated compound (R)-26,
the known â-substituted ester (R)-27,24 and the known â-sub-
stituted ketone (R)-28,25 is shown in Scheme 8. All these
straightforward transformations are based on the generation of
the highly nucleophilic R-sulfonyl carbanion, formation of the
(21) For a review on the Julia-Kocienski olefination, see: (a) Blakemore,
P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563. For some recent references,
see: (b) Charette, A. B.; Berthelette, C.; St-Martin, D. Tetrahedron Lett.
2001, 42, 5149. Corrigendum: Charette, A. B.; Berthelette, C.; St-Martin,
D. Tetrahedron Lett. 2001, 42, 6619. (c) Alonso, D. A.; Na´jera, C.; Varea,
M. Tetrahedron Lett. 2004, 45, 573.
(22) Knochel, P.; Schwink, L. Chem.-Eur. J. 1998, 4, 950.
(23) Recent reviews: (a) Trost, B. M.; Van Vranken, D. L. Chem. ReV.
1996, 96, 395. (b) Trost, B. M.; Carawheg, M. L. Chem. ReV. 2003, 103,
2921. (c) Graening, T.; Schmalz, H.-G. Angew. Chem., Int. Ed. 2003, 42,
2580.
J. Org. Chem, Vol. 72, No. 26, 2007 9929

Mauleo´n et al.
SCHEME 8. Further Functional Group Transformations
SCHEME 9. Mechanistic Proposal (L2*) (S,S)-Chiraphos)
C-C bond by reaction with an appropriate carbon electrophile
and final desulfonylation.26 Thus, R-deprotonation of (S)-4g with
n-BuLi and reaction with benzyl bromide, ethyl chloroformate,
or benzoyl chloride afforded the corresponding functionalized
R-substituted sulfones as mixtures of epimers at the R-position.
Subsequent desulfonylation with Na(Hg) or Zn led to the final
chiral compounds (R) 26-28 in good overall yields (69-80%).
6. Mechanistic Hypothesis and DFT Theoretical Studies.
The mechanism of the rhodium-catalyzed conjugate addition
of aryl boronic acids to enones has been deeply studied by
Hayashi.27 It has been proposed that the catalytic cycle involves
the following steps: (a) initial transmetallation of an aryl group
from boron to rhodium, (b) coordination with the CdC bond,
(c) insertion of the alkene into the aryl-rhodium bond to
generate an oxa-π-allyl rhodium intermediate, and (d) hydrolysis
of this rhodium enolate to give the â-aryl addition product and
regeneration of the hydroxorhodium catalyst. According to this
well accepted catalytic cycle, we postulate a similar transmeta-
lation/coordination/insertion/hydrolysis sequence for the con-
jugate addition to vinyl pyridyl sulfones, which would presum-
ably involve the formation of a five-membered pyridyl-rhodium
chelate in the insertion step (Scheme 9).
To shed some light on the origin of the enantioselectivity in
the addition to vinyl pyridyl sulfones and the role of the nitrogen
atom at the pyridine ring, the stereochemically key coordination
and insertion steps were theoretically studied at DFT (B3LYP)28
level by using the Gaussian03 program.29 The standard 6-31G-
(d)30 basis set was used for all of the atoms except Rh, for which
LANL2DZ31 was employed. Harmonic frequencies were cal-
culated at the same level of theory to characterize the stationary
points and to determine the zero-point energies (ZPE). Sulfone
3g was used as model substrate, whereas ligand (S,S)-Chiraphos
was simplified, changing phenyl by methyl groups (modL*).
The molecular structures and relative energies of the possible
phenyl-rhodium complexes formed by coordination of 3g
through pyridyl nitrogen (A), sulfonyl oxygen (B), or olefin
(C) are shown in Figure 2.32 The rhodium complexes coordi-
nated to nitrogen and especially to oxygen were much less stable
than those coordinated with the olefin (C1). This result could
be ascribed to the fact that in these complexes the rhodium atom
does not show any electrophilic character; indeed it is negatively
charged (-0.11 to -0.12 au). Probably because of this reason
the pentacoordinated electron-rich rhodium complex D could
not be found. Regarding the alkene coordinated complexes, the
most stable, C1re and C1si, showed the CdC bond in a
perpendicular arrangement with regard to the coordination plane
of the metal [Ph-Rh-(CdC) dihedral angle being 112.2° and
-110.5°, respectively]. However, in the conformers C2re and
C2si the alkene moiety is in a quasi coplanar arrangement [Ph-
Rh-(CdC) dihedral angle being -26.3° and 28.6°, respec-
tively], and so these complexes were considered as starting
points of the insertion step. The stability of these coordinated
complexes, especially the π-complexes C, seems to be directly
related to an important stabilizing electrostatic interaction
between the closest sulfonyl oxygen and phosphorus atom
(located at an interatomic distances of 3.33-3.74 Å), the
corresponding natural charges being -0.98 to -0.99 and 1.07
to 1.08 au, respectively.33
The insertion steps through the â-re face, to afford the major
enantiomer (S)-4g, and through the â-si face, to afford the minor
(29) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels,
A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson,
B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03,
Revision B.05; Gaussian, Inc.: Pittsburgh PA, 2003.
(24) Appella, D. H.; Moritani, Y.; Shintani, R.; Ferreira, E. M.; Buchwald,
S. L. J. Am. Chem. Soc. 1999, 121, 9473.
(25) Kanazawa, Y.; Tsuchiya, Y.; Kobayashi, K.; Shiomi, T.; Itoh, J-i.;
Kikuchi, M.; Yamamoto, Y.; Nishiyama, H. Chem. Eur. J. 2006, 12, 63.
(26) Na´jera, C.; Yus, M. Tetrahedron 1999, 55, 10547.
(30) (a) Ditchfield, R.; Hehre, W. J.; Pople, J. A. J. Chem. Phys. 1971,
54, 724. (b) Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972,
56, 2257. (c) Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28,
213.
(27) (a) Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am.
Chem. Soc. 2002, 124, 5052. (b) Kina, A.; Iwamura, H.; Hayashi, T. J.
Am. Chem. Soc. 2006, 128, 3904. (c) See also ref 2c.
(28) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785. (b)
Becke, A. D. J. Chem. Phys. 1993, 98, 1372.
(31) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 270.
(32) Slight differences in energy were observed depending upon the
conformation of the pyridyl ring that always locates the nitrogen atom in
anti arrangement with respect to one of the sulfonyl oxygens, probably in
order to minimize dipole interactions.
9930 J. Org. Chem., Vol. 72, No. 26, 2007

EnantioselectiVe Synthesis of Chiral Sulfones
FIGURE 3. Energy profile for the insertion step through the â-re face
to give the major enantiomer (S)-4g. Relative energies (kcal mol-1
)
evaluated with respect to RhPh(H2O)(modL*)+3g-H2O. ZPE correction
included.
FIGURE 2. Relative energies (kcal mol-1) evaluated with respect to
RhPh(H2O)(modL*)+3g-H2O. ZPE correction included. The closest
P-O distances (Å) are also indicated. Hydrogen atoms have been
omitted for clarity.
enantiomer (R)-4g, were studied from C2re and C2si respec-
tively. The corresponding energy profiles are shown in Figures
3 and 4. In the formation of the new C-C bond through TSre
and TSsi the initial CdC/Ph distance in C2re and C2si is
strongly shortened [d(CdC)/Ph from 2.65 Å in C2re to 2.07 Å
in TSre and from 2.78 Å in C2si to 2.07 Å in TSsi]. However
the distance variation of the C-Rh bond being broken is quite
small [d(Rh-Ph) is only lengthened from 2.11 Å in C2re to
2.20 Å in TSre and from 2.12 Å in C2si to 2.19 Å in TSsi].
This is in agreement with the fact that the first intermediate
found after the formation of the new C-C bond was E1 in
which the free coordination site of the Rh atom was occupied
by a C-C bond of the aromatic ring. This moiety is displaced
by the nitrogen atom of the pyridyl unit to give the much more
stable N-complexes F1 and F2, the later having an additional
stabilizing interaction by π-stacking between phenyl and pyridyl
groups (distance between centroids 3.97 and 4.04 Å for F2re
and F2si, respectively).
FIGURE 4. Energy profile for the insertion step through the â-si face
to give the minor enantiomer (R)-4g. Relative energies (kcal mol-1
)
evaluated with respect to RhPh(H2O)(modL*)+3g-H2O. ZPE correction
included.
The activation energy is similar for re-face and si-face
(33) Natural bond orbital method of Weinhold: Reed, A. E.; Curtiss, L.
A.; Weinhold, F. Chem. ReV. 1988, 88, 899.
approximations (9.2 and 9.7 kcal mol-1, respectively), and the
J. Org. Chem, Vol. 72, No. 26, 2007 9931

Mauleo´n et al.
fones: Synthesis of (S)-2-Phenyl-1-((2-pyridyl)sulfonyl)propane
(4g). A 1 mL portion of anhydrous 1,4-dioxane and 0.1 mL of water
were sequentially added to a mixture of [Rh(acac)(C2H4)2 (3.9 mg,
0.015 mmol), (S,S)-chiraphos (6.4 mg, 0.015 mmol), PhB(OH)2 (303
mg, 2.5 mmol), and the R,â-unsaturated sulfone 3g (91.5 mg, 0.500
mmol), previously placed under argon or nitrogen in a Schlenk tube.
The pale yellow solution was stirred at 100 °C for 12 h, after which
time the resulting orange mixture was cooled to room temperature,
diluted with CH2Cl2 (ca. 3 mL) and filtered through a short pad of
silica gel (eluent CH2Cl2). After concentration of the filtrate, the
residue was purified by flash chromatography (AcOEt/hexanes, 2:3)
to give 4g as a white solid (128 mg, 0.49 mmol, 98% yield). Mp:
1
90-92 °C. H NMR (300 MHz): 8.73-8.69 (m, 1H), 7.84-7.74
(m, 2H), 7.41 (ddd, J ) 1.2, 4.2 and 7.5 Hz, 1H), 7.18-7.03 (m,
5H), 3.89 (dd, J ) 6.5 and 14.2 Hz, 1H), 3.58-3.42 (m, 2H), 1.41
(d, J ) 6.9 Hz, 3H). 13C NMR (75 MHz): 157.5, 150.0, 143.3,
137.8, 128.5, 127.0, 126.7, 122.0, 58.7, 35.0, 22.1. HRMS (FAB+,
m/z): calcd for C14H16NO2S [M+H]+, 262.0901; found, 262.0903.
[R]D ) +9.6 (c 0.5, CHCl3). HPLC: 81% ee [Daicel Chiralpak
AD column, hexane/isopropanol 90:10, 0.6 mL min-1, λ ) 254
nm; tR/min ) 25.7 (R) and 29.1 (S)].
(S)-2-(4-Fluorophenyl)-1-((2-pyridyl)sulfonyl)propane (5). White
solid. Mp: 96-98 °C. 1H NMR (300 MHz): 8.62 (dt, J ) 1.2 and
4.7 Hz, 1H), 7.83-7.76 (m, 2H), 7.46-7.42 (m, 1H), 7.07-7.00
(m, 2H), 6.85-6.77 (m, 2H), 3.98 (dd, J ) 6.9 and 13.7 Hz, 1H),
3.56-3.41 (m, 2H), 1.39 (d, J ) 6.9 Hz, 3H). 13C NMR (75 MHz,
full list of peaks including C-F coupling): 163.1, 157.6, 150.0,
138.9, 137.9, 128.6, 128.5, 127.0, 122.0, 115.4, 115.1, 58.7, 34.4,
22.3. HRMS (FAB+, m/z): calcd for C14H15NO2SF [M + H]+,
280.0807; found, 280.0808. [R]D ) +10.4 (c 0.51, CHCl3).
HPLC: 84% ee [Daicel Chiralpak AD column, hexane/isopropanol
90:10, 0.6 mL min-1, λ ) 254 nm; tR/min ) 35.5 (R) and 40.1
(S)].
FIGURE 5. Molecular structures of transition states TSre and TSsi.
Distances (Å) between selected atoms are also indicated. Hydrogen
atoms have been omitted for clarity.
difference in energy content between TSre and TSsi is 1.8 kcal
mol-1. This value predicts that products of this model reaction,
at 100 °C, will be formed in about 84% ee, indeed close to the
experimental value obtained (81% ee) employing Chiraphos as
chiral ligand. The difference in energy between both TSs may
be due to the attractive electrostatic interaction between P and
O atoms indicated before (shorter for TSre than TSsi; see P1-
O1 distance in Figure 5), as well as a somewhat greater steric
interaction between the Me group present in 3g and the Me
group bonded to the anti P atom in TSsi than in TSre (shorter
C1-C2 distance for TSsi than TSre). This steric interaction
would become more important as a function of the size of the
group bonded to the vinyl sulfone, which might explain the
slight enhancement of the enantioselectivity observed with the
increasing steric bulk of the â-substituent.
(S)-2-(4-Methoxyphenyl)-1-((2-pyridyl)sulfonyl)propane (6).
1H NMR (300 MHz): 8.63 (dt, J ) 1.2 and 4.4 Hz, 1H), 7.83-
7.74 (m, 2H), 7.44 (ddd, J ) 2.0, 4.4 and 6.4 Hz, 1H), 7.00-6.95
(m, 2H), 6.63-6.68 (m, 2H), 3.85 (dd, J ) 6.9 and 14.1 Hz, 1H),
3.72 (s, 3H), 3.55-3.35 (m, 2H), 1.38 (d, J ) 6.9 Hz, 3H). 13C
NMR (75 MHz): 158.2, 157.6, 149.9, 137.8, 135.4, 128.0, 126.8,
122.0, 113.8, 59.0, 55.2, 34.2, 22.2. HRMS (FAB+, m/z): calcd
Conclusions
In summary, we have developed a general procedure for the
Rh-catalyzed asymmetric conjugate addition of boronic acids
to vinyl sulfones. The success of this strategy heavily relies on
two factors: (a) the use of vinyl 2-pyridyl sulfones as key
Michael acceptors and (b) the use of Chiraphos as chiral ligand.
Under these conditions the addition of aryl and alkenyl boronic
acids to â-substituted vinyl sulfones shows a broad scope,
providing the sulfonylated conjugate addition products with a
chiral tertiary stereocenter in very good yields and moderate to
high enantioselectivities (up to 92% ee). The sense and
magnitude of this high enantioselectivity has been explained
by DFT theoretical calculations. The difference in energy for
the key transition states of the Rh-Ph insertion step, through
both re and si olefin faces of the vinyl sulfone, seems to be
determined by a combination of steric interactions and a strong
electrostatic interaction between the closest sulfonyl oxygen in
the substrate and one of the phosphorus atoms in the ligand. A
five-membered pyridyl-rhodium chelated species is formed as
the most stable complex after insertion into the CdC bond.
Taking advantage of the versatile reactivity inherent to the
2-pyridyl sulfonyl group, the enantioenriched addition products
are very interesting building blocks in the straightforward
enantioselective synthesis of other chiral functionalized com-
pounds, such as allylic derivatives (by Julia-Kocienski olefi-
nation) or â-substituted esters and ketones (by an acylation/
desulfonylation sequence).
for C15H18NO3S [M + H]+, 292.1007; found, 292.1010. [R]D
)
-29.2 (c 0.59, CHCl3). HPLC: 77% ee [Daicel Chiralpak AD
column, hexane/isopropanol 90:10, 0.6 mL min-1, λ ) 254 nm;
tR/min ) 43.4 (R) and 51.2 (S)].
(S)-2-Phenyl-1-((2-pyridyl)sulfonyl)heptane (7). White solid.
1
Mp: 85-87 °C. H NMR (300 MHz): 8.56 (dt, J ) 1.2 and 4.4
Hz, 1H), 7.71-7.64 (m, 2H), 7.34 (q, J ) 4.4 Hz, 1H), 7.09-6.94
(m, 5H), 3.94 (dd, J ) 6.9 and 15.0 Hz, 1H), 3.55 (dd, J ) 5.3 and
15.0 Hz, 1H), 3.26-3.20 (m, 1H), 1.85-1.71 (m, 1H), 1.68-1.52
(m, 1H), 1.27-0.96 (m, 6H), 0.84-0.73 (m, 3H). 13C NMR (75
MHz): 157.4, 149.8, 141.3, 137.6, 128.2, 127.7, 126.7, 126.6,
122.0, 57.7, 40.6, 36.3, 31.3, 26.5, 22.3, 13.9. HRMS (FAB+,
m/z): calcd for C18H24NO2S [M + H]+, 318.1527; found, 318.1520.
[R]D ) -29.4 (c 0.51, CHCl3). HPLC: 84% ee [Daicel Chiralcel
OD column, hexane/isopropanol 90:10, 0.6 mL min-1, λ ) 254
nm; tR/min ) 26.7 (R) and 36.3 (S)].
(S)-2-(4-Fluorophenyl)-1-((2-pyridyl)sulfonyl)heptane (8). White
solid. Mp: 65-67 °C. 1H NMR (300 MHz): 8.56 (dt, J ) 1.2 and
4.9 Hz, 1H), 7.75-7.63 (m, 2H), 7.40-7.35 (m, 1H), 6.96-6.89
(m, 2H), 6.77-6.69 (m, 2H), 3.92 (dd, J ) 9.3 and 15.0 Hz, 1H),
3.52 (dd, J ) 4.9 and 15.0 Hz, 1H), 3.26-3.20 (m, 1H), 1.82-
1.67 (m, 1H), 1.64-1.48 (m, 1H), 1.25-0.96 (m, 6H), 0.84-0.72
(m, 3H). 13C NMR (75 MHz, full list of peaks including C-F
coupling): 163.0, 159.7, 157.4, 149.8, 137.6, 137.0, 136.9, 129.3,
129.2, 126.7, 121.9, 115.1, 114.8, 57.7, 40.0, 36.4, 31.3, 26.4, 22.3,
13.8. HRMS (FAB+, m/z): calcd for C18H23NO2SF [M + H]+,
336.1433; found, 336.1434. [R]D ) -30.5 (c 1, CHCl3). HPLC:
87% ee [Daicel Chiralcel OD column, hexane/isopropanol 90:10,
0.6 mL min-1, λ ) 254 nm; tR/min ) 18.1 (R) and 28.1 (S)].
Experimental Section
Typical Procedure for the Rh-Catalyzed Enantioselective
Addition of Boronic Acids to R,â-Unsaturated Pyridyl Sul-
9932 J. Org. Chem., Vol. 72, No. 26, 2007

EnantioselectiVe Synthesis of Chiral Sulfones
(S)-2-(4-Methoxyphenyl)-1-((2-pyridyl)sulfonyl)heptane (9).
1H NMR (300 MHz): 8.58 (dt, J ) 1.2 and 4.9 Hz, 1H), 7.73-
7.65 (m, 2H), 7.39-7.33 (m, 1H), 6.91-6.86 (m, 2H), 6.61-6.56
(m, 2H), 3.92 (dd, J ) 8.9 and 14.6 Hz, 1H), 3.72 (s, 3H), 3.53
(dd, J ) 5.3 and 14.6 Hz, 1H), 3.24-3.18 (m, 1H), 1.82-1.67 (m,
1H), 1.64-1.48 (m, 1H), 1.25-0.96 (m, 6H), 0.84-0.72 (m, 3H).
13C NMR (75 MHz): 158.1, 157.6, 149.8, 137.5, 133.3, 128.7,
126.6, 122.1, 113.6, 58.1, 55.1, 39.9, 36.4, 31.4, 26.5, 22.3, 13.9.
HRMS (FAB+, m/z): calcd for C19H26NO3S [M + H]+, 348.1633;
found, 348.1643. [R]D ) +30.5 (c 0.38, CHCl3). HPLC: 81% ee
[Daicel Chiralcel OD column, hexane/isopropanol 90:10, 0.5 mL
min-1, λ ) 254 nm; tR/min ) 32.1 (R) and 42.3 (S)].
(R)-2-(4-Fluorophenyl)-2-(2-naphthyl)-1-((2-pyridyl)sulfonyl)-
ethane (14). White solid. Mp: 123-125 °C. 1H NMR (300
MHz): 8.49 (ddd, J ) 0.8, 1.6 and 4.5 Hz, 1H), 7.74-7.65 (m,
2H), 7.63-7.50 (m, 3H), 7.48-7.37 (m, 3H), 7.22-7.11 (m, 4H),
6.89-6.79 (m, 2H), 4.83 (t, J ) 7.3 Hz, 1H), 4.38 (dd, J ) 7.7
and 15.0 Hz, 1H), 4.28 (dd, J ) 7.3 and 15.0 Hz, 1H). 13C NMR
(75 MHz, full list of peaks including C-F coupling): 163.2, 159.9,
157.0, 149.7, 138.1, 137.2, 136.7, 133.0, 132.2, 129.5, 129.4, 128.5,
127.7, 127.4, 126.5, 126.3, 126.2, 126.0, 125.8, 122.1, 115.5, 115.2,
56.7, 45.4. HRMS (FAB+, m/z): calcd for C23H19NO2SF [M +
H]+, 392.1120; found, 392.1113. [R]D ) -35.9 (c 0.51, CHCl3).
HPLC: 92% ee [Daicel Chiralpak AD column, hexane/isopropanol
90:10, 0.6 mL min-1, λ ) 254 nm; tR/min ) 63.7 (R) and 81.8
(S)].
(R)-2-(4-Methoxyphenyl)-2-(2-naphtyl)-1-((2-pyridyl)sulfonyl)-
ethane (15). 1H NMR (300 MHz): 8.43 (ddd, J ) 0.8, 1.6 and 5.0
Hz, 1H), 7.71-7.64 (m, 2H), 7.59-7.53 (m, 2H), 7.54-7.45 (m,
1H), 7.46-7.32 (m, 3H), 7.21-7.08 (m, 4H), 6.71-6.66 (m, 2H),
4.78 (t, J ) 7.3 Hz, 1H), 4.39 (dd, J ) 7.7 and 14.5 Hz, 1H), 4.24
(dd, J ) 6.9 and 14.5 Hz, 1H), 3.71 (s, 3H). 13C NMR (75 MHz):
158.4, 157.1, 149.7, 138.5, 137.1, 133.1, 132.2, 128.8, 128.3, 127.7,
127.4, 126.3, 126.2, 126.1, 126.0, 125.9, 122.2, 114.0, 56.9, 55.2,
45.4. HRMS (FAB+, m/z): calcd for C24H22NO3S [M + H]+,
404.1320; found, 404.1312. [R]D ) -21.1 (c 0.75, CHCl3).
HPLC: 85% ee [Daicel Chiralpak AD column, hexane/isopropanol
90:10, 0.7 mL min-1, λ ) 254 nm; tR/min ) 86.6 (R) and 110.2
(S)].
(S)-2-(2-Fluorophenyl)-1-((2-pyridyl)sulfonyl)propane (16). 1H
NMR (300 MHz): 8.62 (dt, J ) 1.2 and 4.7 Hz, 1H), 7.88-7.75
(m, 2H), 7.46-7.40 (m, 1H), 7.13-7.00 (m, 2H), 6.99-6.88 (m,
1H), 6.85-6.76 (m, 1H), 4.04-3.89 (m, 1H), 3.70-3.53 (m, 2H),
1.42 (d, J ) 6.9 Hz, 3H). 13C NMR (75 MHz, full list of peaks
including C-F coupling): 162.0, 158.7, 157.2, 150.0, 137.8, 129.9,
129.8, 129.0, 128.9, 128.5, 128.4, 124.1, 124.0, 122.0, 115.7, 115.4,
57.1, 30.0, 20.7. HRMS (FAB+, m/z): calcd for C14H15NO2SF [M
+ H]+, 280.0807; found, 280.0794. [R]D ) -1.6 (c 0.61, CHCl3).
HPLC: 76% ee [Daicel Chiralpak AD column, hexane/isopropanol
90:10, 0.6 mL min-1, λ ) 254 nm; tR/min ) 25.5 (R) and 27.7
(S)].
(S)-3-Methyl-2-phenyl-1-((2-pyridyl)sulfonyl)butane (10). White
solid. Mp: 87-89 °C. 1H NMR (300 MHz): 8.53 (dt, J ) 1.2 and
4.4 Hz, 1H), 7.62-7.50 (m, 2H), 7.32-7.27 (m, 1H), 7.00-6.85
(m, 5H), 4.08 (dd, J ) 10.9 and 15.0 Hz, 1H), 3.65 (dd, J ) 3.6
and 15.0 Hz, 1H), 3.05-2.98 (m, 1H), 1.92-1.87 (m, 1H), 0.96
(d, J ) 6.9 Hz, 3H), 0.71 (d, J ) 6.9 Hz, 3H). 13C NMR (75
MHz): 157.2, 149.7, 139.5, 137.4, 128.6, 127.8, 126.5, 126.4,
122.1, 55.5, 47.4, 33.4, 20.5, 19.7. HRMS (FAB+, m/z): calcd for
C16H20NO2S [M + H]+, 290.1214; found, 290.1213. [R]D ) +22.2
(c 0.51, CHCl3). HPLC: 78% ee [Daicel Chiralpak AD column,
hexane/isopropanol 90:10, 0.6 mL min-1, λ ) 254 nm; tR/min )
33.6 (R) and 46.5 (S)].
(S)-2-(4-Fluorophenyl)-3-methyl-1-((2-pyridyl)sulfonyl)bu-
1
tane (11). H NMR (300 MHz): 8.55 (ddd, J ) 0.8, 1.6 and 4.9
Hz, 1H), 7.65 (dt, J ) 1.6 and 7.7 Hz, 1H), 7.53 (dt, J ) 1.2 and
8.1 Hz, 1H), 7.35 (ddd, J ) 1.2, 4.9 and 7.7 Hz, 1H), 6.89-6.80
(m, 2H), 6.71-6.61 (m, 2H), 4.05 (dd, J ) 11.3 and 15.0 Hz, 1H),
3.69 (dd, J ) 3.6 and 15.0 Hz, 1H), 3.05-2.98 (m, 1H), 1.90-
1.82 (m, 1H), 0.95 (d, J ) 6.9 Hz, 3H), 0.69 (d, J ) 6.9 Hz, 3H).
13C NMR (75 MHz, full list of peaks including C-F coupling):
163.0, 159.7, 157.3, 149.8, 137.5, 135.3, 130.2, 130.1, 126.6, 122.1,
114.7, 114.5, 55.6, 46.7, 33.4, 20.6, 19.7. HRMS (FAB+, m/z):
calcd for C16H19NO2SF [M + H]+, 308.1120; found, 308.1111. [R]D
) +29.3 (c 0.67, CHCl3). HPLC: 85% ee [Daicel Chiralcel OD
column, hexane/isopropanol 90:10, 0.5 mL min-1, λ ) 254 nm;
tR/min ) 23.8 (R) and 41.3 (S)].
(2E,4S)-3-Methyl-5-[(2-pyridyl)sulfonyl]-2-pentene (17). Col-
1
orless oil. H NMR (300 MHz): 8.74 (d, J ) 5.2 Hz, 1H), 8.05
(S)-2-(4-Methoxyphenyl)-3-methyl-1-((2-pyridyl)sulfonyl)bu-
(dt, J ) 1.3 and 7.9 Hz, 1H), 7.79 (dt, J ) 1.8 and 7.7 Hz, 1H),
7.52 (ddd, J ) 1.2, 4.4 and 7.4 Hz, 1H), 5.38 (m, 1H), 5.11 (m,
1H), 3.55 (dd, J ) 7.2 and 14.2 Hz, 1H), 3.24 (dd, J ) 6.4 and
14.4 Hz, 1H), 2.81 (m, 1H), 1.46 (d, J ) 6.9 Hz, 3H), 1.12 (d, J
) 6.7 Hz, 3H). HRMS (FAB+, m/z): calcd for C11H16NO2S [M
+ H]+, 226.0901; found, 226.0905. [R]D ) -30.1 (c 0.84, CHCl3).
HPLC: 45% ee [Daicel Chiralpak AD Column, hexane/isopropanol
80:20, 0.5 mL min-1, λ ) 254 nm; tR/min ) 17.4 (R) and 18.9
(S)].
1
tane (12). H NMR (300 MHz): 8.56 (ddd, J ) 0.8, 1.6 and 4.9
Hz, 1H), 7.61 (dt, J ) 1.6 and 7.7 Hz, 1H), 7.51 (d, J ) 7.7 Hz,
1H), 7.31 (ddd, J ) 1.2, 4.9 and 7.7 Hz, 1H), 6.81-6.76 (m, 2H),
6.53-6.48 (m, 2H), 4.06 (dd, J ) 10.9 and 15.0 Hz, 1H), 3.70 (s,
3H), 3.63 (dd, J ) 3.6 and 15.0 Hz, 1H), 3.00-2.94 (m, 1H), 1.90-
1.82 (m, 1H), 0.95 (d, J ) 6.9 Hz, 3H), 0.71 (d, J ) 6.9 Hz, 3H).
13C NMR (75 MHz): 158.0, 157.4, 149.7, 137.4, 131.4, 129.7,
126.4, 122.2, 113.2, 55.9, 55.1, 46.6, 33.4, 20.6, 19.7. HRMS
(FAB+, m/z): calcd for C17H22NO3S [M + H]+, 320.1320; found,
320.1306. [R]D ) +31.6 (c 0.49, CHCl3). HPLC: 76% ee [Daicel
Chiralcel OD column, hexane/isopropanol 90:10, 0.6 mL min-1, λ
) 254 nm; tR/min ) 33.4 (R) and 46.4 (S)].
(1E,3S)-3-Methyl-1-phenyl-4-((2-pyridyl)sulfonyl)-1-butene (18).
1H NMR (300 MHz): 8.77-8.70 (m, 1H), 8.09-8.00 (m, 1H),
7.79 (dt, J ) 1.6 and 7.7 Hz, 1H), 7.42 (ddd, J ) 1.2, 4.9 and 6.7
Hz, 1H), 7.36-7.06 (m, 5H), 6.33 (d, J ) 15.8 Hz, 1H), 5.82 (dd,
J ) 8.1 and 15.8 Hz, 1H), 3.77 (dd, J ) 7.7 and 14.6 Hz, 1H),
3.41 (dd, J ) 6.1 and 14.6 Hz, 1H), 3.14-3.06 (m, 1H), 1.29 (d,
J ) 6.9 Hz, 3H). 13C NMR (75 MHz): 157.9, 150.0, 138.0, 136.6,
131.7, 130.2, 128.3, 127.4, 127.0, 126.1, 122.1, 57.4, 32.7, 20.6.
HRMS (FAB+, m/z): calcd for C16H18NO2S [M + H]+, 288.1058;
found, 288.1056. [R]D ) -40.7 (c 0.73, CHCl3). HPLC: 45% ee
[Daicel Chiralpak AD column, hexane/isopropanol 90:10, 0.6 mL
min-1, λ ) 254 nm; tR/min ) 28.0 (R) and 33.0 (S)].
(2E,4S)-1-Phenyl-4-methyl-5-[(2-pyridyl)sulfonyl]-2-pen-
tene (19). Colorless oil. 1H NMR (300 MHz): 8.72 (m, 1H), 8.04
(m, 1H), 7.89 (dt, J ) 1.6 and 7.6 Hz, 1H), 7.51 (ddd, J ) 1.1, 4.4
and 7.5 Hz, 1H), 7.32-7.08 (m, 5H), 5.56 (m, 1H), 5.31 (m, 1H),
3.56 (dd, J ) 6.6 and 14.1 Hz, 1H), 3.31 (dd, J ) 6.6 and 14.1 Hz,
1H), 3.19 (d, J ) 6.6 Hz, 2H), 2.85 (m, 1H), 1.17 (d, J ) 6.7 Hz,
(R)-2-(2-Naphthyl)-2-phenyl-1-((2-pyridyl)sulfonyl)ethane (13).
1
White solid. Mp: 127-129 °C. H NMR (300 MHz): 8.47 (ddd,
J ) 0.8, 1.6 and 5.0 Hz, 1H), 7.71-7.65 (m, 2H), 7.59-7.53 (m,
2H), 7.49 (dt, J ) 1.2 and 8.1 Hz, 1H), 7.46-7.37 (m, 2H), 7.33
(dt, J ) 1.6 and 8.1 Hz, 1H), 7.24-7.05 (m, 7H), 4.83 (t, J ) 7.3
Hz, 1H), 4.45 (dd, J ) 8.1 and 15.0 Hz, 1H), 4.26 (dd, J ) 6.9
and 15.0 Hz, 1H). 13C NMR (75 MHz): 156.9, 149.7, 140.9, 138.1,
137.1, 133.0, 132.1, 128.6, 128.3, 127.7, 127.6, 127.3, 126.9, 126.5,
126.4, 126.1, 126.0, 125.9, 122.1, 56.7, 46.2. HRMS (FAB+,
m/z): calcd for C23H20NO2S [M + H]+, 374.1214; found, 374.1201.
[R]D ) -23.6 (c 0.5, CHCl3). HPLC: 87% ee [Daicel Chiralpak
AD column, hexane/isopropanol 90:10, 0.6 mL min-1, λ ) 254
nm; tR/min ) 63.3 (R) and 70.4 (S)].
J. Org. Chem, Vol. 72, No. 26, 2007 9933

Mauleo´n et al.
3H). HRMS (FAB+, m/z): calcd for C17H20NO2S [M + H]+,
302.4122; found, 302.4126. [R]D ) -41.5 (c 0.91, CHCl3).
HPLC: 92% ee [Daicel Chiralpak AD Column, hexane/isopropanol
80:20, 0.5 mL min-1, λ ) 254 nm; tR/min ) 19.9 (R) and 21.5
(S)].
The resulting orange solution was stirred for 30 min at -78 °C
before benzyl bromide (25 µL, 0.21 mmol) was added. The mixture
was stirred at -78 °C for 2 h, and then aqueous saturated NH4Cl
(10 mL) was added. The organic layer was separated, and the
aqueous layer was extracted with EtOAc (2 × 15 mL). The
combined organic layers were dried (MgSO4), filtered, and con-
centrated. The residue was dissolved in MeOH (5 mL) and treated
with 5% Na(Hg) (230 mg) and Na2HPO4 (93 mg, 0.6 mmol). The
resulting suspension was stirred for 5 h at room temperature before
it was poured into CH2Cl2 (10 mL), filtered, and washed with water
(2 × 5 mL). The aqueous phase was extracted with CH2Cl2 (3 ×
5 mL), and the combined organic phase was dried (MgSO4), filtered,
and concentrated. The residue was purified by flash chromatography
Typical Procedure for the Julia-Kocienski Olefination:
Synthesis of (1E,3R)-1,3-Diphenyl-1-butene (R)-20. To a stirred
solution of the starting chiral nonracemic 2-pyridyl sulfone 4g (46
mg, 0.176 mmol, 81% ee) dissolved in anhydrous DME (4.6 mL,
0.033 M) under argon and cooled at -78 °C was added via syringe
(530 µL, 0.264 mmol) a solution of potassium hexamethyldisilazide
(0.5 M in toluene). The yellow-orange solution was stirred for 3
min, then benzaldehyde (27 µL, 0.264 mmol) was added, and the
mixture was stirred at -78 °C for 2 h. The pale yellow solution
was quenched with saturated NH4Cl at the same temperature, the
mixture was diluted with CH2Cl2 (5 mL), and the aqueous layer
was extracted with CH2Cl2 (3 × 10 mL). The combined organic
layers were dried over anhydrous Na2SO4, the solvent was removed
in vacuo, and the resulting pale yellow oil was purified by column
chromatography (hexanes) to give (R)-20 (34 mg, 0.163 mmol,
(hexanes/EtOAc 100:1), to afford 26 as a colorless oil; yield: 30
1
mg (75%). [R]20 ) +9.2 (c 0.7, CHCl3), 94% ee. H NMR (300
D
MHz): δ 7.45-7.35 (m, 5H), 7.20-7.09 (m, 5H), 2.59 (sextuplet,
J ) 7.1 Hz, 1H), 2.48 (t, J ) 7.9 Hz, 2H), 2.08-1.65 (m, 2H),
1.22 (d, J ) 7.1 Hz, 3H). 13C NMR (75 MHz): δ 139.7, 139.4.
128.7, 128.4, 128.3, 128.1 126.1, 125.8, 42.5, 41.4, 33.1, 21.2.
HRMS (FAB+): calcd for C16H19, 211.1409; found, 211.1420.
1
93% yield). H NMR (300 MHz): 7.51-7.30 (m, 10H), 6.61-
Ethyl (R)-3-Phenylbutyrate (27).24 To a solution of sulfone 3a
(50 mg, 0.19 mmol, 94% ee) in THF (5 mL), cooled to -78 °C,
was added a 2.5 M solution of n-BuLi in hexane (84 µL, 0.21
mmol). The resulting orange solution was stirred at -78 °C for 30
min before ethyl chloroformate (21 µL, 0.21 mmol) was added.
The mixture was stirred at -78 °C for 2 h, and then saturated
aqueous NH4Cl (10 mL) was added. The organic phase was
separated, and the aqueous layer was extracted with EtOAc (2 ×
10 mL). The combined organic phase was dried (MgSO4), filtered,
and concentrated. The residue was dissolved in THF (2 mL) and
added to a suspension of activated Zn (350 mg) in THF (4 mL)
and aqueous saturated NH4Cl (4 mL). The mixture was stirred for
12 h at room temperature before it was filtered through Celite and
washed with CH2Cl2 (2 × 10 mL). The combined organic phase
was dried (MgSO4), filtered, and concentrated. The residue was
purified by flash chromatography (hexanes/EtOAc 4:1) to afford
27 as a colorless oil; yield 29.4 mg (80%). [R]20D ) -17.9 (c 0.8,
CHCl3), 94% ee; [R]Dlit (for the (S)-isomer of 90% ee) ) +19.0 (c
6.49 (m, 2H), 3.83-3.74 (m, 1H), 1.62 (d, J ) 7.0 Hz, 3H).
13C NMR (75 MHz): 145.6, 137.6, 135.2, 128.6, 128.4, 127.3,
127.0, 126.2, 126.1, 42.5, 21.2. HRMS (EI+, m/z): calcd for
C16H16 [M]+, 208.1252; found, 208.1243. [R]D ) +32.0 (c 0.4,
CHCl3). HPLC: 81% ee (this ee was identical to that of the
starting sulfone (S)-4g). The absolute (R) configuration was
determined by comparison of the optical rotation and chiral HPLC
lit
data with the literature values22 [[R]D (S)-20 ) -39.3 (c 2.51,
CHCl3), 93% ee. Daicel Chiralcel OD column, hexane/isopropanol
99.5:0.5, 0.2 mL min-1, λ ) 215 nm; tR/min ) 29.6 (S) and 31.8
(R)].
(E)-1-(4-Fluorophenyl)-3-phenyl-1-butene (21). Colorless oil.
1H NMR (300 MHz): 7.36-7.20 (m, 7H), 7.01-6.96 (m, 2H),
6.42-6.27 (m, 2H), 3.69-3.59 (m, 1H), 1.45 (d, J ) 6.9 Hz, 3H).
13C NMR (75 MHz): 163.7, 160.4, 145.5, 135.0, 133.7, 128.5,
127.6, 127.5, 127.4, 127.3, 126.3, 115.5, 115.2, 42.5, 21.2. HRMS
(EI+, m/z): calcd for C16H15F [M]+, 226.1157; found, 226.1147.
1
(1E,3E)-1,5-Diphenyl-1,3-hexadiene (22). Obtained as a mixture
of isomers [87:13, (E,E):(E,Z)]. (E,E) isomer: 1H NMR (300
MHz): 7.47-7.29 (m, 10H), 6.78 (dd, J ) 10.1 and 15.4 Hz),
6.49 (d, J ) 15.4 Hz), 6.19 (dd, 10.1 and 15.0 Hz, 1H), 6.01 (dd,
J ) 6.9 and 15.0 Hz, 1H), 3.64-3.55 (m, 1H), 1.49-1.39 (d, J )
6.9 Hz, 3H). (E,Z) isomer (representative signals): 1H NMR (300
MHz): 6.58 (d, J ) 15.8 Hz, 1H), 6.17 (t, J ) 10.5 Hz, 1H), 5.64
(t, J ) 10.5 Hz, 1H), 4.08 (m, 1H).
1.1, CHCl3). H NMR (300 MHz): δ 7.32-7.27 (m, 2H), 7.22-
7.17 (m, 3H), 4.07 (q, J ) 7.1 Hz, 2H), 3.28 (sextet, J ) 7.6 Hz,
1H), 2.61 (dd, J ) 7.0, 15.0 Hz, 1H), 2.53 (dd, J ) 8.0, 15.0 Hz,
1H), 1.31 (d, J ) 7.1 Hz, 3H), 1.18 (t, J )7.1 Hz, 3H). 13C NMR
(75 MHz): δ 172.3, 145.7, 128.4, 126.7, 126.3, 60.2, 42.9, 36.5,
21.7, 14.1.
(R)-1,3-Diphenylbutan-1-one (28).25 To a solution of sulfone
3a (50 mg, 0.19 mmol, 94% ee) in THF (5 mL), cooled to
-78 °C, was added a 2.5 M solution of n-BuLi in hexane (84 µL,
0.21 mmol). The resulting orange solution was stirred for 30 min
at -78 °C before benzoyl chloride (24 µL, 0.21 mmol) was added.
The resulting solution was stirred at -78 °C for 2 h, and then
aqueous saturated NH4Cl (10 mL) was added. The organic phase
was separated, and the aqueous phase was extracted with EtOAc
(2 × 10 mL). The combined organic phase was dried (MgSO4),
filtered, and concentrated. The residue was dissolved in THF (2
mL) and added to a suspension of Zn activated (350 mg) in THF
(4 mL) and aqueous saturated NH4Cl (4 mL). The mixture was
stirred for 12 h at room temperature before it was filtered through
Celite and washed with CH2Cl2 (2 × 10 mL). The combined organic
phase was dried (MgSO4), filtered, and concentrated. The residue
was purified by flash chromatography (hexanes/EtOAc 3:1), to
afford 28 as a white solid; yield 29.2 mg (69%). Mp ) 51-52 °C.
1
(E)-5-Methyl-2-phenyl-3-hexene (23). Colorless oil. H NMR
(300 MHz): 7.30-7.00 (m, 5H), 5.54 (ddd, J ) 1.2, 6.5 and 15.4
Hz, 1H), 5.41 (ddd, J ) 0.8, 6.5 and 15.4 Hz, 1H), 3.46-3.37 (m,
1H), 2.30-2.22 (m, 1H), 1.33 (d, J ) 6.9 Hz, 3H), 0.98 (d, J )
6.5 Hz, 3H), 0.97 (d, J ) 6.5 Hz, 3H). 13C NMR (75 MHz): 146.7,
136.4, 131.9, 128.3, 127.2, 125.9, 42.1, 31.0, 29.7, 22.6, 21.6.
(E)-3-(4-Fluorophenyl)-1-phenyl-1-butene (24). Colorless oil.
1H NMR (300 MHz): 7.45-7.21 (m, 7H), 7.09-7.02 (m, 2H),
6.49-6.35 (m, 2H), 3.69 (dq, J ) 6.9 and 14.2 Hz, 1H), (d, J )
6.9 Hz, 3H). 13C NMR (75 MHz): 163.0, 159.8, 141.2, 137.4,
135.0, 128.8, 128.7, 128.6, 128.5, 127.1, 126.1, 115.3, 115.0, 41.8,
21.3. HRMS (EI+, m/z): calcd for C16H15F [M]+, 226.1157; found,
226.1150.
1
(E)-1,3-Diphenyl-1-octene (25). Colorless oil. H NMR (300
MHz): 7.44-7.20 (m, 10H), 6.49-6.35 (m, 2H), 3.46 (q, J ) 7.3
Hz, 1H), 1.92-1.78 (m, 2H), 1.47-1.24 (m, 6H), 1.01-0.84 (m,
3H). 13C NMR (75 MHz): 144.7, 137.6, 134.5, 129.2, 128.4, 127.6,
127.0, 126.1, 49.2, 35.8, 31.8, 27.3, 22.5, 14.1. HRMS (EI+, m/z):
calcd for C20H24F [M]+, 264.1878; found, 264.1869.
(R)-1,3-Diphenylbutane (26). To a solution of sulfone 3a (50
mg, 0.19 mmol, 94% ee) in THF (5 mL), cooled to -78 °C, was
added a 2.5 M solution of n-BuLi in hexane (84 mL, 0.21 mmol).
[R]20 ) -16.2 (c 0.7, CHCl3), 94% ee; [R]D (for a sample of
lit
D
82% ee) ) -13.5 (c 1.0, CCl4). 1H NMR (300 MHz): δ 7.93 (dd,
J ) 0.9, 8.0 Hz, 2H), 7.57-7.52 (m, 1H), 7.44 (dt, J ) 1.8, 8.2
Hz, 2H), 7.33-7.27 (m, 4H), 7.22-7.17 (m, 1H), 3.51 (sextet, J
) 7.2 Hz, 1H), 3.31 (dd, J ) 5.8, 16.5 Hz, 1H), 3.16 (dd, J ) 8.1,
16.2 Hz, 1H), 1.34 (d, J ) 6.8 Hz, 3H). 13C NMR (75 MHz): δ
199.0, 146.5, 132.9, 128.5, 128.2, 128.0, 126.8, 126.2, 47.0, 35.5,
9934 J. Org. Chem., Vol. 72, No. 26, 2007

EnantioselectiVe Synthesis of Chiral Sulfones
21.8. HPLC: Daicel Chiralcel OD, i-PrOH/hexane 2:98, 1 mL
min-1, tR/min ) 17.6 (S) and 19.9 (R), 210 nm.
allocation of computer time at the Centro de Computacio´n
Cient´ıfica de la UAM is also acknowledged.
Acknowledgment. Financial support of this work by the
Ministerio de Educacio´n y Ciencia (projects BQU2003/0508
and CTQ2006-01121) is gratefully acknowledged. P.M. thanks
the Ministerio de Educacio´n y Ciencia for a predoctoral
fellowship. The authors also thank Dr. Toma´s Llamas for some
synthetic applications from chiral 2-pyridyl sulfones, Johnson
Matthey PLC for a generous loan of [Rh(cod)Cl]2, and Solvias
for a gift of several chiral ferrocene ligands. A generous
Supporting Information Available: Experimental procedures
for the preparation of the starting vinyl sulfones and characterization
1
data. Copies of H NMR and 13C NMR of the new compounds.
Cartesian coordinates for all optimized structures and their absolute
energies. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO7016197
J. Org. Chem, Vol. 72, No. 26, 2007 9935