Highly Diastereoselective Conjugate Addition to Alkylidene Bis(Sulfoxides): Asymmetric Synthesis of (+)-erythro-Roccellic Acid

Article abstract of DOI:10.1002/anie.200352356

Facial stereocontrol is possible in Michael additions of nucleophiles (Nu) to alkylidene bis(sulfoxides), which proceed via nonchelated (A) or chelated (B) intermediates depending on the addition of an appropriate Lewis acid (LA). This intriguing reactivi

Full text of DOI:10.1002/anie.200352356

Communications
Stereoselective Conjugate Addition
Highly Diastereoselective Conjugate Addition to
Alkylidene Bis(Sulfoxides): Asymmetric
Synthesis of (+)-erythro-Roccellic Acid**
Franck Brebion, BØnØdicte DelouvriØ, Francisco Nµjera,
Louis Fensterbank,* Max Malacria,* and
Jacqueline Vaissermann
The conjugate addition of a nucleophile to an electron-
deficient olefin is a key transformation for the synthesis of
highly functionalized molecules.[1] Facial control relying on an
appended chiral auxiliary as an electron-withdrawing moiety
has been extensively studied,[2] and, despite recent advances
in catalytic asymmetric processes,[3] this strategy still has
important advantages such as predictability and generality.
Whereas most methods for conjugate additions to olefins
have dealt with chiral acrylic systems,[4] sulfoxides and
congener auxiliaries have also been subject to versatile
applications.[5] However, in the latter case, high diastereo-
selectivities have generally been reached when the acceptor is
part of a ring, and/or an extra carbonyl moiety has been
introduced so that additional steric constraints or chelation
controls can operate.[6]
In this context alkylidene bis(sulfoxides) are appealing
candidates[7] for asymmetric conjugate additions. Two types of
these compounds have been developed: namely the 1,1-bis-p-
tolyl derivatives[8] and the cyclic dithioacetal dioxides, which
were studied more extensively by Aggarwal et al.[9] While
these compounds have been utilized mainly as highly
diastereoselective chiral ketene equivalents in cycloaddi-
tion[10] and epoxidation reactions,[11] their behavior as Michael
acceptors has not been exploited.
Our approach has relied on (S,S)-bis-p-tolylsulfinyl
acceptors 1 because of their direct availability from (À)-
[*] Dr. L. Fensterbank, Prof. Dr. M. Malacria, F. Brebion, B. DelouvriØ,
Dr. F. Nµjera
Laboratoire de Chimie Organique
UMR 7611 CNRS, Case 229
UniversitØ Pierre et Marie Curie
4, place Jussieu, 75252 Paris Cedex 05 (France)
Fax: (+33)1-4427-7360
E-mail: fensterb@ccr.jussieu.fr
malacria@ccr.jussieu.fr
Dr. J. Vaissermann
Laboratoire de Chimie Inorganique et MatØriaux MolØculaires
UMR 7071 CNRS
UniversitØ Pierre et Marie Curie
4, place Jussieu, 75252 Paris Cedex 05 (France)
[**] We thank the Minist›re de la Recherche for PhD grants to F.B. and
B.D., and the CNRS for a Poste Rouge to F.N. as well as for their
financial support. We also thank Carine Taboret for technical
assistance, Patrick Herson (UPMC) for the X-ray analysis of 1c, and
Dr. Bernold Hasenknopf (UPMC) for helpful discussions. We are
very grateful to Professor N. P. Argade (NCL Pune, India) for
providing us with NMR spectra of erythro-roccellic acid.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
5342
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200352356
Angew. Chem. Int. Ed. 2003, 42, 5342 –5345

Angewandte
Chemie
menthol as a cheap chiral source.[8d] Moreover, structural
examination of these substrates based on X-ray analysis of 1a
and 1c[12] provided valuable information (see Figure 1 for the
X-ray structure of 1a). By introducing a dummy ligand (LP)
Scheme 1. Dual mode of stereoselection.
Figure 1. X-ray structure of 1a.
in the structures of 1a and 1c in place of the lone pair, it was
possible to deduce a dihedral angle C2-C1-S2-LP of 288 for 1a
and 148 for 1c, which suggests that the lone pair of one
sulfinyl group is quasi-eclipsing the syn R group on the
alkene. Then, C2-C1-S1-O1 dihedral angles (48 for 1a and 138
for 1c) were even more consistent with an s-cis conformation
of the other sulfinyl group. An additional intriguing feature of
this s-cis arrangement is the interaction between the vinylic
following mode A. These amino adducts proved also to be
versatile precursors of enantiopure amino esters and amino
alcohols, as demonstrated by the transformation of 3 into (S)-
5 and (S)-6[17] via the Pummerer adduct 4 (Scheme 2).
The addition of oxygenated nucleophiles required some
optimization. Sodium alkoxides were the best nucleophiles
and afforded adducts in high yields with total stereoselectivity
following mode A, which sets an S absolute configuration at
the a-alkoxy center.[18] It is worthy of note that products 10
À
proton and the O1 atom (d(H O1) = 2.28 Š for 1a and 1c). It
is remarkable that these data corroborate the ab initio
calculations by Tietze et. al on simpler vinylsulfoxides.[13]
Finally, intramolecular p-stacking interactions between p-
tolyl groups were established based on the following values[14]
(distance between centroids: 3.53 Š for 1a, 3.66 Š for 1c, and
ring normal–centroid vector angles of 258 for 1a, and 278 for
1c).
All these observations indicated to us that a dual mode (A
or B) of diastereoselection was possible. If we assume that the
conformations in solution are the same as those in the solid
state, then the two interacting p-tolyl groups should lock the
lower re face and promote the attack of the incoming
nucleophile from the opposite si face (mode A, Scheme 1).
In contrast, in presence of a proper Lewis acid (LA), a new
organization of the reacting system based on chelation by the
two sulfinyl groups should take place (mode B). This would
favor attack from the re face, which minimizes steric
interactions with the p-tolyl group present on the si face.
Finally, a further attractive feature of this system is that the
bis-sulfinyl moiety can serve as a masked carbonyl group,[15]
which could be liberated after a Pummerer reaction.[8d]
To probe these points, we initially focused on the addition
of amines to 1a and 1b. In contrast with the known reactivity
of simple vinylsulfoxides,[16] this process provided amino
adducts 2a and 2b more efficiently (quantitative yield at
À608C) and in a completely diastereoselective manner
Scheme 2. Diastereoselective addition of amines to compounds 1a
and 1b and derivatizations. dias=diastereomer, LAH=lithium
aluminum hydride, RT= room temperature, TFAA=trifluoroacetic
anhydride.
Angew. Chem. Int. Ed. 2003, 42, 5342 –5345
www.angewandte.org
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5343

Communications
and 11 are promising building blocks for the preparation of
enantiopure diols and furan or pyran derivatives, respectively
(Scheme 3, Table 1).
Scheme 5. Addition of copper reagents leads to a reversed diastereo-
selection.
Scheme 3. Diastereoselective addition of alkoxides.
precluded on the si face because of the steric hindrance
from the close p-tolyl group. Thus, addition reactions
proceeded smoothly, affording products 16a, 16c–e,and 17
in good yields and as single diastereomers with R absolute
configuration at the newly alkylated center (Table 2).[23]
Table 1: Addition of sodium alkoxides to Michael acceptors 1.
Precursor
R’
Prod.
Yield [%]
d.r., abs. conf.[a]
1a
1c
1c
1c
1c
Me
Me
Et
Bn
7
8
9
10
11
90
94
93
84
82
>98:2, S
>98:2, S
>98:2, S
>98:2, S
>98:2, S
Table 2: Addition of copper reagents to alkylidene acceptors 1.
Precursor
R’
Prod.
Yield [%]
d.r., abs. conf.[a]
propargyl
1a
1c
1d
1e,
Me
Me
Me
16a
16c
16d
89
96
85
>98:2, R
>98:2, R
>98:2, R
[a] abs. conf.: absolute configuration of the a-alkoxy center.
Me
16e
17
98
77
>98:2, R
>98:2, R
To further extend the scope of these Michael additions, we
1c
nBu
À
examined C C bond formation with stabilized carbon
[a] abs. conf.: absolute configuration of the alkylated center.
nucleophiles such as sodium dimethylmalonate. High yields
and complete stereoselectivity based on mode A were also
observed (adducts 12[19] and 13, Scheme 4). More interest-
Derivatization of alkylidene 16e through a Pummerer
reaction and saponification provided the R enantiomer of
fenoprofen (Scheme 6). R Enantiomers of profens have
recently found applications in rheumatology,[24] and several
members of this family should be readily available by this
approach.
Scheme 6. Application to the synthesis of (R)-fenoprofen.
Finally, exposure of alkylidene acceptor 1 f to the lithium
enolate of Heathcock's ester[25] 18 afforded adduct 19 (79%
yield) accompanied by minor diasteromers (10% yield;
Scheme 7). The major diastereomer 19 was then engaged in
a Pummerer reaction, followed by a double saponification to
result in the first asymmetric synthesis of (+)-erythro-roccellic
acid. Isolated from lichens,[26] and recently synthesized in a
racemic form by Argade et al.,[27] roccellic acid exhibits a
palette of biological activities such as plant growth promo-
tion/inhibition and antituberculosis activity.[27] Remarkably,
the succinate motif is found in a myriad of biologically
relevant derivatives,[28] which this chemistry should render
easily accessible.
À
Scheme 4. Diastereoselective C Cbond formation.
ingly, when the sodium anion of bromomalonate was used, the
intriguing cyclopropane derivatives 14 and 15, whose struc-
ture and absolute configuration were confirmed by X-ray
analysis,[12] were also obtained in the same fashion.
Because of the known complexation of copper salts with
bis(sulfoxides) through sulfinyl oxygen atoms,[20] and previous
results by Posner et al.,[21] we consider copper-based reagents
to be good in Michael additions under chelation control
(mode B, Scheme 5). Presumably also, formation of the initial
Cu/olefin p-complex[22] with the double bond would be
5344
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 5342 –5345

Angewandte
Chemie
[10] For a review, see: B. DelouvriØ, L. Fensterbank, F. Nµjera, M.
Malacria, Eur. J. Org. Chem. 2002, 3507.
[11] V. K. Aggarwal, J. K. Barrell, J. M. Worrall, R. Alexander, J.
Org. Chem. 1998, 63, 7128.
[12] CCDC 213619–213621 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from
the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB21EZ, UK; fax: (+ 44)1223-336-033; or deposit@
ccdc.cam.ac.uk).
[13] L. F. Tietze, A. Schuffenhauer, P. R. Schreiner, J. Am. Chem.
Soc. 1998, 120, 7952.
[14] C. Janiak, J. Chem. Soc. Perkin Trans. 1 2000, 3885.
[15] For the concept of chiral acyl anion, see : a) L. Colombo, C.
Gennari, C. Scolastico, G. Guanti, E. Narisano, J. Chem. Soc.
Chem. Commun. 1979, 591; b) C. Gaul, K. Schꢀrer, D. Seebach,
J. Org. Chem. 2001, 66, 3059, and references therein.
[16] a) S. G. Pyne, P. Bloem, S. L. Chapman, C. E. Dixon, R. Griffith,
J. Org. Chem. 1990, 55, 1086; b) D. J. Abbott, S. Colonna, J. M.
Stirling, J. Chem. Soc. Perkin Trans. 1 1976, 492.
[17] The S absolute configurations of 5 and 6 were determined by
correlation: (R)-5 was made independently from (R)-phenyl-
glycinol, and LAH reduction of 6 afforded (S)-5 with no loss of
optical purity and with completely opposite optical activity, see
the Supporting Information.
[18] The absolute configuration of 7 was determined by chemical
correlation, see the Supporting Information.
[19] The absolute configuration of 12 was determined by chemical
correlation with a compound described by G. Tsuchihashi, S.
Mitamura, S. Inoue, K. Ogura, Tetrahedron Lett. 1973, 14, 323,
see the Supporting Information.
Scheme 7. Synthesis of (+)-erythro-roccellic acid.
In conclusion, we have shown that alkylidene bis(sulf-
oxide) derivatives are exceptional partners in high-yielding
and totally diastereoselective Michael additions. The use of
heteronucleophiles (amines and alkoxides) paves the way to
enantiopure a-amino and a-hydroxy acids as well as b-amino
À
alcohols and diols. C Cbond formation can also be achieved
and the stereoselection conveniently controlled by means of
chelation or lack of chelation by the choice of the counterion
(Li+, Na+ vs. Cu+). A new route to enantiopure succinate
derivatives is also open, as demonstrated by the first
asymmetric synthesis of (+)-erythro-roccelic acid, which
relies on the highly diastereoselective addition of a lithium
ester enolate to an appropriate, readily available bissulfinyl
acceptor.
[20] S. K. Madan, C. M. Hull, L. J. Herman, Inorg. Chem. 1968, 7,
491.
[21] a) G. H. Posner, T. P. Kogan, M. Hulce, Tetrahedron Lett. 1984,
25, 383; b) G. H. Posner, J. P. Mallamo, K. Miura, J. Am. Chem.
Soc. 1981, 103, 2886.
Received: July 11, 2003 [Z52356]
[22] For the mechanism of copper-mediated addition reactions, see:
S. Mori, E. Nakamura in Modern Organocopper Chemistry (Ed.:
N. Krause), Wiley-VCH, Weinheim, 2002.
[23] The R absolute configurations of 16a and 16d were determined
by chemical derivatization. Pummerer reactions followed by
reduction provided known enantiopure alcohols (see the Sup-
porting Information).
[24] G. Geisslinger, S. Grꢁsch, PCT Int. Appl. WO 02/24190A1,
2002.
[25] C. H. Heathcock, M. C. Pirrung, S. H. Montgomery, J. Lampe,
Tetrahedron 1981, 37, 4087.
[26] a) The Merck Index, 12th Edition, 1996, article 8405; b) S.
Huneck, J. Schmidt, A. Porzel, Z. Naturforsch. B 1994, 49, 561,
and references therein.
[27] S. Mangaleswaran, N. P. Argade, J. Chem. Soc. Perkin Trans. 1
2001, 1764.
Keywords: allylic compounds · asymmetric synthesis ·
Michael addition · sulfoxides · total synthesis
.
[1] P. Perlmutter, Conjugate Addition Reactions in Organic Syn-
thesis, Pergamon, Oxford, 1992.
[2] H.-G. Schmalz in Comprehensive Organic Synthesis, Vol. 4 (Ed.:
M. F. Semmelhack), Pergamon, Oxford, 1991, pp. 199 – 236.
[3] For reviews: a) M. P. Sibi, S. Manyem, Tetrahedron 2000, 56,
8033; b) N. Krause, A. Hoffmann-Roder, Synthesis 2001, 171;
c) A. Alexakis, C. Benhaim, Eur. J. Org. Chem. 2002, 3221.
[4] B. E. Rossiter, N. M. Swingle, Chem. Rev. 1992, 92, 771.
[5] M. C. Carreæo, Chem. Rev. 1995, 95, 1717.
[6] a) G. H. Posner, Acc. Chem. Res. 1987, 20, 72. For a radical
version of this, see: b) N. Mase, Y. Watanabe, Y. Ueno, T. Toru, J.
Org. Chem. 1997, 62, 7794; c) N. Mase, N. Watanabe, T. Toru, J.
Org. Chem. 1998, 63, 3899.
[28] For an illustration of this, see: M. P. Sibi, H. Hasegawa, Org. Lett.
2002, 4, 3347.
[7] For an approach involving a phosphoryl sulfinyl alkylidene, see:
W. H. Midura, M. Mikołajczyk, Tetrahedron Lett. 2002, 43, 3061.
[8] a) Y. Arai, S. Kuwayama, Y. Takeuchi, T. Koizumi, Synth.
Commun. 1986, 16, 233; b) G. SolladiØ, F. Colobert, P. Ruiz, C.
Hamdouchi, M. C. Carreæo, J. L. García Ruano, Tetrahedron
Lett. 1991, 32, 3695; c) J. C. Carretero, J. L. García Ruano, L. M.
Martín Cabrejas, Tetrahedron: Asymmetry 1997, 8, 409; d) B.
DelouvriØ, F. Nµjera, L. Fensterbank, M. Malacria, J. Organo-
met. Chem. 2002, 643–644, 130.
[9] For recent contributions of this group, see: a) V. K. Aggarwal,
S. J. Roseblade, J. K. Barrell, R. Alexander, Org. Lett. 2002, 4,
1227; b) V. K. Aggarwal, R. M. Steele, Ritmaleni, J. K. Barrell,
I. Grayson, J. Org. Chem. 2003, 68, 4087, and references therein.
Angew. Chem. Int. Ed. 2003, 42, 5342 –5345
www.angewandte.org
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5345