Synthesis of unfunctionalized carbonated fragments containing two vicinal chiral centers: Stereocontrolled benzylation of vinylsulfones mediated by a remote sulfinyl group

Article abstract of DOI:10.1002/chem.201001006

One-pot benzylation of (E)-vinylsulfones with optically pure 2-p-tolylsulfinylbenzyl carbanions and desulfinylation with tBuLi, followed by desulfonylation of the resulting 1-sulfonylpropanes, provided acyclic hydrocarbons containing two connected chiral centers in very smooth conditions and almost complete control of the stereoselectivity (see scheme).

Full text of DOI:10.1002/chem.201001006

DOI: 10.1002/chem.201001006
Synthesis of Unfunctionalized Carbonated Fragments Containing Two Vicinal
Chiral Centers: Stereocontrolled Benzylation of Vinylsulfones Mediated by a
Remote Sulfinyl Group
Josꢀ Luis Garcꢁa Ruano,* Christine Schçpping, Cuauhtꢀmoc Alvarado, and
Josꢀ Alemꢂn*[a]
The synthesis of carbon skeletons containing two adjacent
stereogenic centers in a single step is a difficult task, espe-
cially when no functional groups are joined to any of these
centers. The most direct approaches for the synthesis of
these carbonated fragments is the asymmetric hydrogena-
tion of unfunctionalized tetrasubstituted olefins,[1] but only
two main papers have been reported in this field from the
groups of Buchwald[1b] and Pfaltz.[1c] In these papers, only
hydrogenation of endocyclic alkenes (types A and B in
Scheme 1) was reported with good enantiomeric excess (ee)
privileged status as a stereochemical motif in medicinal
chemistry because of their presence in many therapeutic
agents as well as in important nonsteroidal estrogen com-
pounds. However, to the best of our knowledge, no reports
concerning the asymmetric hydrogenation of tetrasubstitut-
ed acyclic alkenes leading to compounds with two chiral
centers have appeared in the literature. Only catalytic hy-
drogenation of compounds C (Scheme 1), yielding com-
pounds with only one chiral center, has been described.[1a–b]
We have recently described the successful asymmetric
benzylation of some electrophiles with substituted benzyl-
carbanions containing a remote ortho-sulfinyl group as a
chiral inducer.[2] This method allowed us to provide almost
complete control of the stereoselectivity at the benzylic
center and, starting from prochiral electrophiles, also at the
chiral carbon joined to the benzylic one. Electrophiles stud-
ied so far involved compounds with C=O[2a] or C=N[2b–c]
bonds and, therefore, at least one of the obtained chiral cen-
ters was functionalized. On these precedents, we reasoned
that conjugated additions of the ortho-sulfinyl benzylcarban-
ions derived from 1 to activated olefins would provide an in-
direct method for the synthesis of nonfunctionalized alkyl
chains with two adjacent stereogenic centers, whenever the
activating group could be easily removed. Vinylsulfones
were chosen for this study because the sulfonyl group can
be easily removed or, which could be even more interesting,
transformed into a diversity of functional groups without af-
fecting the chirality introduced in the first step
(Scheme 2).[3] Herein, we present our results concerning the
reactions indicated in Scheme 2 that allow the synthesis of
alkyl chains with two adjacent stereogenic centers (one of
them benzylic) by the reaction of alkyl-substituted 2-p-tolyl-
sulfinylcarbanions derivatives with (E)-alkyl or aryl vinylsul-
fones and further removal of the sulfur functions.
Scheme 1. Unfunctionalized tetrasubstituted olefins, the catalytic asym-
metric hydrogenation of which has been successfully studied.
values (better for cyclopentenes). Despite the limitations in
the scope, these methods have become highly important be-
cause they are the only ones able to afford unfunctionalized
carbon skeletons with two connected chiral centers in a
short synthetic sequence. Moreover, the obtained com-
pounds have benzylic carbon stereocenters, which are found
in over 5000 isolated natural products and have gained a
[a] Prof. Dr. J. L. Garcꢀa Ruano, C. Schçpping, Dr. C. Alvarado,
Dr. J. Alemꢁn
Department of Organic Chemistry
Universidad Autꢂnoma
28049 Madrid (Spain)
Fax : (+34)914-973-966
E-mail: joseluis.garcia.ruano@uam.es
jose.aleman@uam.es
Conjugated addition (CA) of organometallic reagents to
vinylsulfones has been one of the synthetic procedures most
widely used in asymmetric synthesis for the carbon–carbon
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001006.
8968
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Chem. Eur. J. 2010, 16, 8968 – 8971

COMMUNICATION
70% yield (Table 1, entry 2). Reactions with other 2-arylvi-
nylsulfones (2B–G) were also studied. Results were similar
when an electron-donating group or a naphthyl group were
incorporated (2B, 2C; Table 1, entries 3 and 4, respectively),
whereas the presence of electron-withdrawing groups at the
2-aryl ring decreased the stereoselectivity. Thus, compound
2D (R2 =p-ClC6H4) yielded an 84:16 diastereoisomeric mix-
ture of 3bD and 3’bD (Table 1, entry 5), and 2E (R2 =p-
CNC6H4) evolved in an even lower stereoselective manner,
affording a 72:28 mixture of 3bE and 3’bE (Table 1,
entry 6). These results suggested a significant role of the
electronic factors in the stereochemical course of the reac-
tions. Compounds with substituents at the ortho position
provided better stereoselectivity than those observed with
the same substituent at the para position. Thus, 2F (R2 =o-
ClC6H4) afforded a 92:8 mixture of 3bF and 3’bF (Table 1,
entry 7). Differences between entries 5 and 7 can be ex-
plained by assuming that steric effects, which would increase
as a consequence of the loss of planarity, also have an im-
portant role on the stereoselectivity. In this sense, compound
2G (o-BrC6H4) evolved in a completely stereoselective
manner, only yielding 3bG (Table 1, entry 8), which could
be attributed to the larger size of the bromine.
To broaden the scope of these reactions, we studied the
behavior of 1b with (E)-2-alkyl vinylsulfones (2H–2J). Re-
actions were completely stereoselective with primary (2H)
and secondary (2I) alkyl residues (Table 1, entries 9 and 10),
however, no conversion was observed with the tert-butyl de-
rivative 2J (Table 1, entry 11).[9] Finally, we also studied the
reaction of 1b with the 2-alkenyl derivative 2K (Table 1,
entry 12) for expanding the scope of the reaction and evalu-
ating the 1,4 versus 1,6 addition. The reaction was complete-
ly regio- and stereoselective, only affording the 1,4 addition
product 3bK as a single diastereoisomer in good yield.
To check the influence of the steric effects on the stereo-
selectivity and extend the scope of the reaction, we investi-
gated the behavior of compounds (S)-1c–f acting as precur-
sors of different alkyl benzyl carbanions (Table 2). Their re-
actions with stryrylphenylsulfone 2A evolved in moderate
Scheme 2. Synthesis of alkyl chains with two adjacent stereogenic centers.
LDA=lithium diisopropylamide.
bond formation.[3] In this field, many catalytic methods have
been reported in recent years, mainly from the groups of
Carretero,[4] Feringa,[5] and Charette,[6] allowing hydride re-
duction as well as the arylation and alkylation of the double
bond with enantioselectivity ranging from moderate to very
good. However, as far as we know, the catalytic benzylation
of vinylsulfones has never been reported and the use of pro-
chiral nucleophiles in catalytic conjugated additions, provid-
ing two connected chiral centers in the same step, remains
an unsolved problem. Both facts increased the interest in in-
vestigating the reactions shown in Scheme 2.
Compounds 1 were easily available from 2-bromotoluene
in a two-step sequence (sulfinylation and alkylation) with
very high yields.[7] Vinylsulfones 2 were commercially avail-
able or very easily prepared.[4a] Reaction of equimolecular
amounts of the simplest sulfinyl carbanion derived from (S)-
1a (R1 =H; Table 1, entry 1) with stryrylphenylsulfone 2A,
resulted in the formation of a complex mixture, in which
products of double addition could be present.[8] However,
the reaction of 2A with the methylbenzyl carbanion derived
from (S)-1b (R1 =Me; Table 1, entry 2) as a prochiral nucle-
ophile, was very fast (less than 1 min) and provided 3bA as
only diastereoisomer (diastereomeric excess (de)>98%) in
Table 1. Reactions of (S)-1a and (S)-1b with vinylsulfones 2A–K.[a]
Table 2. Reactions of (S)-1b–f with vinylsulfones.[a]
Sulfoxide R1 R2
Sulfone Product
(yield [%])
d.r. (3/3’)[b]
AHCTUNGTRENNUNG
1
2
3
4
5
6
7
8
9
1a
1b
1b
1b
1b
1b
1b
1b
1b
H
Ph
2A
2A
2B
2C
2D
2E
2F
2G
2H
2I
c.m.[c]
Me Ph
3bA (70)
3bB (71)
3bC (83)
3bD (71)
3bE (83)
3bF (68)
3bG (73
3bH (54)
3bI (59)
n.r.[d]
>98:2
>98:2
>98:2
84:16
72:28
92:8
>98:2
>98:2
>98:2
–
Me p-MeOC6H4
Me 2-naphthyl
Me p-ClC6H4
Me p-CNC6H4
Me o-ClC6H4
Me o-BrC6H4
Me sBu
Me iPr
Me tBu
Me (E)-PhCH=CH 2K
Sulfoxide R1
R2
Sulfone Yield Product
[%]
[%]
1
2
3
4
5
6
7
1c
1d
1e
1 f
1d
1d
1d
CH2CH3
benzyl
allyl
Ph
Ph
Ph
2A
2A
2A
2A
2F
61
59
54
47
58
61
77
3cA
3dA
3eA
3 fA
3dF
3dD
3dE
ꢀ
10 1b
11 1b
12 1b
CH2CH2C CH Ph
2J
benzyl
benzyl
benzyl
o-ClC6H4
p-ClC6H4
p-CNC6H4 2E
3bK (62)
>98:2
2D
[a] All reactions were performed on a 0.4 mmol scale in 0.4 mL of THF
and stopped after 1 min. [b] Diastereomeric ratio determined by NMR
spectroscopy. [c] Complex mixture. [d] No reaction.
[a] All reactions were performed on a 0.4 mmol scale in 0.4 mL of THF
and stopped after 1 min.
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J. L. Garcꢀa Ruano, J. Alemꢁn et al.
or good yields with complete stereoselectivity, regardless of
the saturated (Table 2, entry 1), or unsaturated (Table 2, en-
tries 2–4) character of the alkyl-chain at benzylic position.
This reaction was compatible with the presence of acetylenic
protons (Table 2, entry 4) by increasing the amount of LDA
used (to 2.4 equiv). But the most interesting feature of these
reactions was the substantial increase in the stereoselectivity
observed when the size of the chain at the benzylic position
(R1 in Table 2) was larger than Me. Thus, reactions of 1d
(R1 =Bn) with 2D–2F afforded only one diastereoisomer,
which is in contrast with the incomplete stereoselective evo-
lution of these three vinylsulfones in their reactions with 1b
(Table 1, entries 5–7). This significant improvement could be
a consequence of the increase in size of R1.
nected with the original goal of this paper, was the synthesis
of hydrocarbons by removal of the sulfone group, and the
second one was the preparation of esters, by taking advant-
age of the easy introduction of the functional groups on C-a
of the sulfones. Removal of the sulfonyl groups at 4 can be
made with Mg in MeOH,[13] without affecting the optical
purity of the substrates (Scheme 3A). These reaction condi-
Configurational assignment for compounds 3 was tenta-
tively made from their NMR spectroscopy data (significant
differences between the diastereoisomers of 3 and 3’) and
later unequivocally confirmed by X-ray analysis of com-
pounds 3bB and 3dA[10] (see the Supporting Information).
The obtained compounds 3 could be easily transformed
into desulfinylated product 4 by treatment with tBuLi.[11]
After several trials, we checked that conditions of these re-
actions were also efficient when they were applied to the
crude mixture of the reaction of 1 with 2, which allowed the
direct synthesis of 4 without isolating the sulfinyl derivatives
3. Under the conditions of the “one-pot process”, the ob-
tained yields of 4 were much better than those obtained in
the two-step sequence by isolation of compounds 3.[12] We
have checked the efficiency of these transformations in dif-
ferent cases and the results are shown in Table 3. Benzyla-
tion and desulfinylation took place in high yields in 30 min
and very smooth conditions without epimerization of the
chiral centers (Table 3, entries 1–3). One relevant point of
this sequence was that a multigram scale can be applied to
these processes. Thus, reaction of 1b (1 g, 4.1 mmol) with
2A (0.98 g, 4.0 mmol) and further treatment with tBuLi af-
forded 4bA in 81% yield (Table 3, entry 4), after column
chromatography to remove some impurities.
Scheme 3. Synthesis of acyclic enantiomerically pure compounds with
two connected stereogenic centers from 1b and 4bA.
tions could be applied to the crude reaction mixtures, yield-
ing 4, once liberated from the salts, thus affording hydrocar-
bons 5 in good yields and with complete stereoselectivity
control. These reactions, involving subsequent benzylation,
desulfinylation, and desulfonylation steps, have been studied
in two cases. The first one provided the optically inactive
meso-5bA from 1b and 2A in 70% yield. Compound 5bI,
obtained from 1b and 2I (61% yield), had an identical ee
value to that of the starting sulfoxide 1b.[14] We have also in-
troduced the ester group at 4bA before removal of the sul-
fonyl group by using a two-step procedure, yielding 6bA in
64% yield (Scheme 3B).
Stereochemical results can be explained by assuming that
the chelated structure shown in Scheme 4, with the metal
joined to the benzyllic carbon and the sulfinyl oxygen, is the
most stable one for benzyllic carbanions derived from 1
(supported by theoretical calculations in the case of 1b[15]).
We have studied two applications of compounds 4 that il-
lustrate their large synthetic possibilities. The first one, con-
Table 3. One-pot conversion of (S)-1b and 1e with the vinylsulfone 2A
into desulfinylated compounds 4.[a]
Sulfoxide
R1
R2
Sulfone
Yield [%]
Product [%]
1
2
3
4
1b
1e
1b
1b
Me
allyl
Me
Me
Ph
Ph
iPr
Ph
2A
2A
2I
75
91
4bA
4eA
4bI
71
2A
81[b]
4bA
[a] All reactions were performed on a 0.4 mmol scale in 0.2 mL of THF
and finally stopped after 1 min. [b] This reaction was carried out in a
4.0 mmol scale in 1 mL of THF.
Scheme 4. Diastereoselectivity control in the formation of sulfones 3 and
3’.
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Chem. Eur. J. 2010, 16, 8968 – 8971

Synthesis of Unfunctionalized Carbonated Fragments
COMMUNICATION
Troutman, D. H. Applla, S. L. Buchwald, J. Am. Chem. Soc. 1999,
121, 4916; c) M. G. Schrems, E. Neurmann, A. Pfaltz, Angew. Chem.
2007, 119, 8422; Angew. Chem. Int. Ed. 2007, 46, 8274.
Since Li is blocking the upper face of the carbanion, the
electrophilic attack can only take place from the bottom
face, thus yielding compounds with R configuration at the
benzyllic carbon. Intermediates IA and IIA (Scheme 4) are
presumably the most stable approaches because they only
exhibit two significant gauche interactions (Newman projec-
tions show the hydrogen atoms in antiperiplanar arrange-
ment). Intermediate IA must be favored by steric grounds
(the two aryl groups adopt an antiperiplanar arrangement)
and the repulsion between SO and SO2 functions can be at-
tenuated by the attractive interaction between positively
charged sulfinyl sulfur and the negatively charged sulfonyl
oxygen. Intermediate IIA would be only considered in those
cases in which a stabilizing p–p stacking interaction between
the two aromatic rings could be postulated (X=electron-
withdrawing groups). In the rest of the cases (X=electron-
donating groups and 2-alkyl sulfones) the repulsive steric in-
teractions (Ar/Ar or R/Ar) are predominant and decrease
the stability of the approach IIA. The presence of ortho sub-
stituents at the aromatic ring distorts its planarity, thus de-
creasing the p–p stacking interaction and unstabilizing IIA.
On the other hand, the increase in the size of R1 mainly re-
duces the stability of IIA because the interaction R1/SO2Ph
(Scheme 4) is larger.
[2] For a reaction with carbonyl groups, see: a) J. L. Garcꢀa Ruano,
M. C. CarreÇo, M. A. Toledo, J. M. Aguirre, M. T. Aranda, J. Fisch-
er, Angew. Chem. 2000, 112, 2848; Angew. Chem. Int. Ed. 2000, 39,
2736; with imines, see: b) J. L. Garcꢀa Ruano, J. Alemꢁn, F. Soriano,
Org. Lett. 2003, 5, 677; c) J. L. Garcꢀa Ruano, J. Alemꢁn, Org. Lett.
2003, 5, 4513.
[3] a) J. C. Carretero, R. Gꢂmez-Arrayꢁs, J. Adrio in Organosulfur
Chemistry in Asymmetric Synthesis (Eds.: T. Toru, C. Bolm), Wiley-
VCH, Weinheim, p. 291; b) J. C. Carretero, R. Gꢂmez Arrayꢁs in
Houben–Weyl Methods of Molecular Transformations: Science of
Synthesis Vol. 33 (Ed.: G. Molander), Thieme, Stuttgart, 2007, p. 19.
[4] a) P. Mauleꢂn, J. C. Carretero, Org. Lett. 2004, 6, 3195; b) P. Mau-
leꢂn, J. C. Carretero, Chem. Commun. 2005, 4961; c) P. Mauleꢂn, I.
Alonso, M. Rodrꢀguez-Rivero, J. C. Carretero, J. Org. Chem. 2007,
72, 9924; d) for the catalytic reduction, see: T. Llamas, R. Gꢂmez
Arrayꢁs, J. C. Carretero, Angew. Chem. 2007, 119, 3393; Angew.
Chem. Int. Ed. 2007, 46, 3329.
[5] a) P. H. Bos, A. J. Minnard, B. L. Feringa, Org. Lett. 2008, 10, 4219;
b) P. H. Bos, B. Maciꢁ, M. A. Fernꢁndez-IbꢁÇez, A. J. Minnard, B. L.
Feringa, Org. Biomol. Chem. 2010, 8, 47.
[6] a) J.-N. Desrosiers, W. S. Bechara, A. B. Charette, Org. Lett. 2008,
10, 2315; b) for the reduction, see: J. N. Desrosiers, A. B. Charette,
Angew. Chem. 2007, 119, 6059; Angew. Chem. Int. Ed. 2007, 46,
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[7] J. L. Garcꢀa-Ruano, J. Alemꢁn, M. Aranda, M. J. Arꢄvalo, A.
Padwa, Org. Lett. 2005, 7, 19.
[8] According to the mass spectra, a signal at 719 was detected between
others, indicating the double addition of these carbanions.
[9] To obtain quaternary centers, reactions of the sulfinylcarbanion de-
rived from 1b with b,b-disubstituted-vinylsulfones were also investi-
gated. However, only starting materials could be identified in the
crude mixtures obtained under similar conditions to those used in
the reactions given in Tables 1 and 2.
[10] CCDC-765581 (3bB) and 765582 (3dA) contains the supplementary
crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[11] Y. Arroyo, A. Meana, J. F. Rodriguez, M. Sanz-Tejedor, M. Ascen-
sion; I. Alonso, J. L. Garcia Ruano, J. Org. Chem. 2009, 74, 4127.
[12] Difficulties associated with the isolation of the highly polar com-
pounds 3 are circumvented in the one-pot reactions by obtaining the
less-polar compounds 4, thus explaining the observed improvements
in the yields.
In summary, optically pure hydrocarbons with two con-
nected stereogenic centers can be directly obtained from
easily available 2-p-tolylsulfinylarenes and (E)-2-substituted
vinylsulfones in a sequence involving benzylation–desulfiny-
lation with tBuLi (one-pot process), followed by desulfony-
lation with Mg/MeOH.
Acknowledgements
Financial support from the Spanish Government (CTQ-2009-12168) and
CAM (“programa AVANCAT CS2009/PPQ-1634”) is gratefully acknowl-
edged. J.A. thanks the MICINN for a “Juan de la Cierva contract” and
C.A. thanks the “Consejo Nacional de Ciencia y Tecnologꢀa de Mꢄxico”
for a postdoctoral fellowship”. C.S. thanks the European Community for
an Erasmus fellowship.
[13] C. Nꢁjera, M Yus, Tetrahedron 1999, 55, 10547.
[14] Both sulfoxide 1b and the intermediate 4bI have a 95% ee by chiral
HPLC (see the Supporting Information).
[15] J. L. Garcꢀa Ruano, J. Alemꢁn, I. Alonso, A. Parra, V. Marcos, J.
Aguirre, Chem. Eur. J. 2007, 13, 6179.
Keywords: asymmetric
synthesis · carbanions · remote stereocontrol · vinylsulfones
hydrogenation
·
asymmetric
[1] a) For review in hydrogenation of tetrasubstituted non-funtionalized
Received: April 19, 2010
alkenes, see: X. Cui, K. Burgess, Chem. Rev. 2005, 105, 3272; b) M.
Published online: July 12, 2010
Chem. Eur. J. 2010, 16, 8968 – 8971
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www.chemeurj.org
8971