Enantioselective generation of benzylic stereocenters mediated by a remote sulfoxide

Article abstract of DOI:10.1002/1521-3773(20000804)39:15<2736::AID-ANIE2736>3.0.CO;2-M

Ortho-Sulfinyl-substituted benzyllithium reagents react with aldehydes and ketones to afford, after desulfurization with Raney-Nickel, stereoselective access to benzylic stereocenters [Eq. (1)]. This is the first efficient asymmetric 1,4-induction with mediation by a sulfoxide group. LDA = lithium diisopropylamide; Tol = tolyl; TIPS = triisopropylsilyl.

Full text of DOI:10.1002/1521-3773(20000804)39:15<2736::AID-ANIE2736>3.0.CO;2-M

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1
high ee (98% by H NMR) by Andersen synthesis[11] from
Enantioselective Generation of Benzylic
Stereocenters Mediated by a Remote
Sulfoxide**
ortho-bromo derivatives of ethylbenzene (1) and triisopro-
pylsilyloxymethylbenzene (2). Organomagnesium reagents
were used for the reaction with menthyl p-toluene sulfinate
despite the better yields obtained with lithium analogues,
since these afforded partially racemized 3 and 4.
Regioselective deprotonation of 3 and 4 at the benzylic
position with lithium diisopropylamide (LDA) at À788C[12]
gave carbanions A. Quantitative formation of LDA was
essential to avoid the partial racemization of the sulfoxide that
occurred when traces of BuLi were present. Intermediates A
reacted with electrophiles to give a as the major diastereomers
(Scheme 1, Table 1).
As shown in Table 1, reaction of carbanions derived from 3
and 4 with ethyl chloroformate afforded diastereomerically
pure esters 5a[13] and 6a (entries 1 and 2). In a similar way,
acetone yielded pure diastereomers 7a and 8a from 3 and 4,
respectively (entries 3 and 4).[14] With asymmetrically substi-
tuted electrophiles, such as 2-butanone, compound 3 evolved
Â
Ä
Jose L. García Ruano,* M. Carmen Carreno,*
Â
Miguel A. Toledo, Jose M. Aguirre, M. Teresa Aranda,
and Jean Fischer
À
Enantioselective C C bond formations via benzyllithium
derivatives generated by deprotonation with organolithium
bases has attracted the interest of several groups in the past
two decades.[1] High asymmetric inductions were achieved by
using the lithiation ± substitution sequence when chiral aux-
iliaries are located in a remote position of the aliphatic chain[2]
or by starting from tricarbonyl chromium arene complexes.[3]
(À)-Sparteine[4] has been effectively used as chiral ligand to
promote enantioselective synthesis of benzylic carbanions
from alkylbenzenes bearing ortho substituents such as
R2NCO[5] and tBuCONH.[6] Enantiopure bis(oxazolines)[7]
have also been applied with variable success.
In our continuing search for new applications of sulfoxides
in asymmetric synthesis,[8] we found that association of the
sulfinyl oxygen atom with lithium was essential to achieve
highly diastereoselective 1,2-induction processes such as
aldol-type reactions.[9] These results prompted us to inves-
tigate whether enantiopure ortho-sulfinyl groups[10] can stabi-
lize benzyllithium carbanions and promote diastereoselective
reactions with electrophiles by a 1,4-induction process.
This possibility was evaluated for (S)-2-ethylphenyl p-
tolylsulfoxide (3) and (S)-2-(triisopropylsiloxymethyl)phenyl
p-tolylsulfoxide (4; Scheme 1), which are easily accessible in
Table 1. Reactions of carbanions derived from
(Scheme 1).
3 and 4 with electrophiles
Entry Carbanion Electrophile
Precursor
Products (diastereomer ratio)[a]
Yield
[%]
1
2
3
4
3
4
3
4
ClCO2Et
ClCO2Et
MeCOMe
MeCOMe
75
75
81
78
Scheme 1. Synthesis of 3 and 4 and reaction of their benzyllithium
derivatives with electrophiles. a) Mg/diethyl ether, RT, for 1; 1) nBuLi/
THF, À788C; 2) MgBr2, RT, for 2. b) (S,S)- TolSO2Menthyl, THF, À788C.
c) LDA, THF, À788C. d) Electrophile, THF, À788C. OTIPS ˆ OSiiPr3.
5
6
7
8
3
3
4
3
MeCOEt
PhCHO
PhCHO
81
Ä
[*] Prof. J. L. García Ruano, Prof. M. C. Carreno, Dr. M. A. Toledo,
M. T. Aranda
65[b]
57[d]
75
Â
Departamento de Química Organica (C-I)
Â
Universidad Autonoma
Cantoblanco, 28049-Madrid (Spain)
Fax : (‡349)1-397-3966
E-mail: joseluis.garcia.ruano@uam.es
carmen.carrenno@uam.es
Prof. J. M. Aguirre
Universidad de Lujan, Lujan (Argentina)
Prof. J. Fischer
Â
Lab. de Cristallochimie, Universite Louis Pasteur
67070-Strasbourg (France)
Â
Â
[**] This work was supported by the Direccion General de Investigacion
Â
Científica y Tecnica (Grants PB98-0062 to M.C.C. and PB98-0078 to
J.L.G.R.).
[a] Arˆ (S)-2-p-tolylsulfinylphenyl. [b] Yield of pure 10a. [c] Characterized as
Supporting information for this article is available on the WWW under 50:50 mixture of R1 ˆ OTIPS; R2 ˆ H and R1 ˆ H; R2 ˆ OTIPS. [d] Yield of pure
http://www.wiley-vch.de/home/angewandte/ or from the author.
11a.
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into a 1:1 mixture of carbinols 9a and 9b, which are epimers at
the hydroxy-bearing carbon atom (entry 5). The stereogenic
benzylic center showed the S absolute configuration. Reac-
tions of 3 and 4 with benzaldehyde were more stereoselective.
Starting from 3, an 85:15 mixture of epimeric carbinols 10a
and 10b was formed (entry 6); pure 10a was isolated by
chromatography. Under similar conditions, 4 yielded a 78:22
mixture of diol derivatives 11a and 11b (entry 7). The latter
was characterized as a 50:50 regioisomeric mixture of 1- and
2-TIPS derivatives, which evolved into the diol after treat-
ment with nBu4NF. The rearrangement of silyl groups in
similar 1,2-diols has already been reported.[15] To control the
absolute configuration of both new stereogenic centers, a
double asymmetric induction was performed in the reaction
Scheme 3. Products of desulfurization of 5a, 7a, and 13a. For 14 and 16,
the ee was determined by comparison with reported [a]2D0 values.[17, 18]
Received: February 4, 2000
Revised: April 3, 2000 [Z14652]
between
3 and [2S,(S)R]-2-(p-tolylsulfinyl)cyclohexanone
[1] Review: ªStereoselective Synthesisº: H. Ahlbrecht, Methods of
Organic Chemistry (Houben-Weyl) 4th ed. 1952 ± , Vol. E21a, 1995,
pp. 645 ± 696.
[2] For recent references, see a) M. Magnus, P. Magnus, Nature 1997, 38,
3491; b) A. G. Myers, B. H. Yang, H. Chen, L. McKistry, D. J.
Kopecky, J. L. Gleason, J. Am. Chem. Soc. 1997, 119, 6496 ± 6511;
c) D. J. Pippel, M. D. Curtis, H. Du, P. Beak, J. Org. Chem. 1998, 63,
2 ± 3.
[3] T. Geller, H. G. Schmalz, J. Bats, Tetrahedron Lett. 1998, 39, 1537±
1540, and references therein.
[4] Reviews: a) D. Hoppe, T. Hense, Angew. Chem. 1997, 109, 2376 ± 2410;
Angew. Chem. Int. Ed. Engl. 1997, 36, 2282 ± 2316; b) P. Beak, A. Basu,
D. J. Gallagher, Y. S. Park, S. Thayumanavan, Acc. Chem. Res. 1996,
29, 552 ± 560.
(12).[9] The exclusive formation of diastereoisomer 13a
(entry 8) was consistent with the known stereochemical
behavior of 12 in nucleophilic additions.
According to these results, the new benzylic stereogenic
centers were always generated in a highly diastereoselective
manner and with the same asymmetric induction, independ-
ent of the electrophile. When additional stereogenic centers
were created, the stereoselectivity of the process was electro-
phile-dependent. A plausible mechanism that accounts for
our current observations is shown in Scheme 2. Benzyllithium
[5] S. Thayumanavan, A. Basu, P. Beak, J. Am. Chem. Soc. 1997, 119,
8209 ± 8216, and references therein.
[6] a) A. Basu, P. Beak, J. Am. Chem. Soc. 1996, 118, 1575 ± 1576; b) A.
Basu, D. J. Gallagher, P. Beak, J. Org. Chem. 1996, 61, 5718 ± 5719.
[7] a) N. Komine, L.-F. Wang, K. Tomooka, T. Nakai, Tetrahedron Lett.
1999, 40, 6809 ± 6812; b) N. Komine, L.-F. Wang, K. Tomooka, T.
Nakai, Tetrahedron Lett. 1999, 40, 6813 ± 6816.
[8] Reviews: a) M. C. CarrenÄo, Chem. Rev. 1995, 95, 1717 ± 1760; b) J. L.
García Ruano, M. B. Cid, Top. Curr. Chem. 1999, 204, 1 ± 126.
Â
[9] a) J. L. García Ruano, I. Fernandez, M. del Prado, J. A. Hermoso, J.
Sanz Aparicio, M. Martínez-Ripoll, J. Org. Chem. 1998, 63, 7157 ±
7161; b) J. L. García Ruano, D. Barros, M. C. Maestro, R. Araya-
Maturana, J. Fischer, J. Org. Chem. 1996, 61, 9462 ± 9470.
Scheme 2. Favored transition state for reaction of intermediates A with
electrophiles.
[10] ortho-Lithium heteroaromatic sulfoxides react diastereoselectively
Â
Â
with aldehydes: P. Pollet, A. Truck, N. Ple, G. Queguiner, J. Org.
Chem. 1999, 64, 4512 ± 4515.
derivative A1 must be the most stable among all diastereom-
ers and conformers since it lacks allylic strain.[16] The metal-
assisted pseudoequatorial approach of the electrophile would
yield the observed S configuration at the benzylic center if the
configuration of the carbanion were retained. When the
electrophile is prochiral, the stabilities of the transition states
depend on the relative size of R1 and R2. When they are
similar, equimolar mixtures of two epimers are formed
(entry 5), while higher diastereoselectivies are observed when
R1 and R2 are very different (entries 6 and 7).
Important for preparative applications of this methodology
is the removal of the auxiliary. This was quantitatively
achieved in compounds 5a ± 8a and 13a by reaction with
Raney nickel, which gave 14 ± 18 (Scheme 3). Formation of
known 14[17] and 16[18] confirmed the absolute configuration of
5a and 7a. The enantiomeric purity of desulfurized products
14, 16, and 18 was identical to that of the starting materials.
For OTIPS derivatives 6a and 8a the enantiomeric excess of
the resulting compounds 15 and 17 could be determined
neither by 1H NMR spectroscopy nor by HPLC.
[11] K. K. Andersen, W. Gaffield, N. E. Papanikolau, J. W. Foley, R. I.
Perkins, J. Am. Chem. Soc. 1964, 86, 5637± 5646.
[12] ortho-Lithiation was not observed despite the ortho-directing charac-
ter of the sulfoxide group; see V. Snieckus, Chem. Rev. 1990, 90, 87 9 ±
933.
[13] Characterization of 5a was carried out immediately after crystalliza-
tion since it readily epimerizes at C-2.
[14] The structures of 8a and 10a were established by X-ray diffraction.
Crystallographic data (excluding structure factors) for the structures
reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publications nos.
CCDC-139404 and -139405. Copies of the data can be obtained free of
charge on application to CCDC, 12 Union Road, Cambridge
CB21EZ, UK (fax: (‡44)1223-336-033; e-mail: deposit@ccdc.cam.
ac.uk).
[15] See M. Lalonde, T. H. Chan, Synthesis 1985, 817.
[16] The chelate structure proposed for A1 is consistent with the result
observed when reaction of 3 with acetone (entry 3) was conducted in
the presence of hexamethylphosphoric triamide (6 equiv). Under
these conditions, an 87:13 mixture of 7a and its epimer at the benzylic
carbon atom was isolated.
[17] C. Kashima, I. Fukuchi, A. Hosomi, J. Org. Chem. 1994, 59, 7821 ±
7824.
[18] F. D. Greene, J. Am. Chem. Soc. 1959, 81, 2688 ± 2691.
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