Construction of C-S bonds with a quaternary stereocenter through a formal Michael reaction: Asymmetric synthesis of tertiary thiols

Article abstract of DOI:10.1002/anie.200453889

Quaternary stereocenters that bear a sulfur substituent can be created with nearly perfect stereocontrol through an intramolecular Michael-type process. Lewis acids (L.A.) accelerate the intramolecular sulfur-atom transfer from the oxazolidine-2-thione functionality to the β carbon atom of the β,β-disubstituted enoyl moiety, whereas the chirality of the oxazolidine-2-thione portion controls reaction stereochemistry (see scheme).

Full text of DOI:10.1002/anie.200453889

Angewandte
Chemie
Asymmetric Synthesis
À
Construction of C S Bonds with a Quaternary
Stereocenter through a Formal Michael Reaction:
Asymmetric Synthesis of Tertiary Thiols**
Claudio Palomo,* Mikel Oiarbide, Flavia Dias,
Rosa López, and Anthony Linden
There are several reactions for the asymmetric construction of
À
C S bonds, often with excellent results in terms of efficiency
and selectivity.[1,2] Among them, the Michael reaction, that is,
the conjugate addition of nucleophiles to electron-deficient
olefins,[3] has received special attention. This approach is very
attractive not only because of the availability of a broad range
of Michael acceptors and the suitability of the simultaneous
À
formation of both a new C S bond and a stereocenter, but
also because the conjugate addition step provides a reactive
species that may be trapped by electrophiles leading to
tandem processes of significant synthetic value. Several
approaches have been documented for diastereo-[4] and
enantiocontrol[5,6] in the conjugate addition of sulfur-based
nucleophiles to Michael acceptors. To the best of our knowl-
[7]
À
edge, however, construction of quaternary C S systems
through this reaction remains essentially unexplored within
[*] Prof. Dr. C. Palomo, Prof. Dr. M. Oiarbide, F. Dias, Dr. R. López
Departamento de Química Orgµnica I
Facultad de Química
Universidad del País Vasco
Apdo. 1072, 20080 San Sebastiµn (Spain)
Fax: (+34)943-212-236
E-mail: qoppanic@sc.ehu.es
Dr. A. Linden+
Organisch-chemisches Institut
Universität Zürich
Winterthurerstrasse 190, 8057 Zürich (Switzerland)
[+] crystal structure analysis
[**] We thank The University of the Basque Country (EHU/UPV) and
Ministerio de Ciencia y Tecnología (Spain) for financial support. A
Ramón y Cajal grant to R.L. from Ministerio de Educación Cultura y
Deporte and a predoctoral grant to F.D. from EHU/UPV are
acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 3307 –3310
DOI: 10.1002/anie.200453889
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3307

Communications
the asymmetric endeavor.[8] There are three conceptual
SnCl4 also led to a clean reaction, but longer reaction times
and in general lower diastereoselectivities were obtained. For
a variety of substrates examined (Table 1) the diastereose-
lectivity of the reactions carried out at À308C ranged from
restraints that may be invoked for this omission: a) the
attenuated reactivity of b,b-disubstituted Michael accep-
tors;[9] b) the inherent difficulty in controlling p-facial dia-
stereo- and enantioselectivity in these substrates;[8] and
c) virtual thermodynamic equilibration of the stereoisomeric
products through an addition–elimination mechanism,[10]
which makes kinetic stereocontrol rather challenging. Yet,
the asymmetric construction of quaternary stereocenters,
particularly from b,b-disubstituted Michael acceptors, is a
very difficult synthetic task.[11,12]
Table 1: BF3·Et2O-promoted intramolecular Michael-type addition of
sulfur in b,b-disubstituted enoyl systems 3 leading to tertiary thiols 4.[a]
Compound R1
R2
T [8C] t [h]
d.r.[b]
Yield [%][c]
3a
Me
Ph
À78
À30
25
13
9
52
7
5
9
n.d. <40
>99:1
80
86:14 n.d.
Our hypothesis was that the above restraints might be
counterbalanced if an intramolecular version of the Michael-
type approach could be implemented (Figure 1). In this
3b
3c
3d
4-MeC6H4
4-ClC6H4
4-BrC6H4
À30
97:3
73:27 89[d]
92:8 72
90:10 90[d]
77
25
À30
25
5
À30
72
24
7
120
36
12
10
15
98:2
96:4
76
42
25
3e
3 f
3g
3h
3i
4-MeOC6H4 À30
3-MeOC6H4 À30
52:48 65
93:7
92:8
91:9
98:2
96:4
83
4-CNC6H4
4-NO2C6H4
Ph
À30
À30
À30
À30
73[e]
70
Et
77
68
3j
nBu Ph
[a] Reactions conducted at 0.5 mmol scale and 0.1m substrate concen-
tration. Ratio of 3:BF3·OEt2 1:2. For details, see Supporting Information.
[b] Determined by 1H and/or 13C NMR spectroscopy. [c] Yields of isolated
compound after purification by column chromatography. [d] Yield of
crude product. [e] Reaction performed at 0.2 mmol scale.
Figure 1. Intermolecular and intramolecular variants of the Michael-
type addition of sulfur nucleophiles to enoyl systems as a route to C S
bonds with a quaternary stereocenter.
À
instance, the favorable entropy usually associated with an
intramolecular process might help to solve the reactivity
problem, whilst at the same time, a sufficiently high p-facial
discrimination could also be exerted because of the intra-
molecular nature of the chirality transfer.
very high to essentially perfect, while even at 258C diaster-
eoselectivity remained high in some instances (compounds
3c,d). Curiously, whilst the b-4-methoxyphenyl substituted
enoyl derivative 3e brought about almost no diastereoselec-
tion, the enoyl compound 3 f bearing the 3-methoxyphenyl
substituent showed quite good diastereoselectivity. On the
other hand, from comparison of the results with substrates 3a,
3i, and 3j, it appears that the size of the “small” substituent at
the b position does not influence selectivity very much and
high d.r. values are regularly observed.
To validate this hypothesis, we have formulated the
approach outlined in Scheme 1 on the basis of previous
The assigned configuration for the adducts was estab-
lished by a single-crystal X-ray crystallographic analysis of the
p-nitrobenzoyl derivative 5,[17] and by assuming a uniform
reaction mechanism. In this respect, the sense of the
asymmetric induction can be explained by assuming a
preferential attack of sulfur on the Si face of the enoyl b
carbon atom with no interference of the iPr group (model A),
Figure 2.
Scheme 1. Preparation of Michael acceptors 3 and their intramolecular
reaction leading to tertiary thiols 4. Conditions: a) NaH, THF, À788C.
b) BF3·Et2O then H2O.
In an effort to add some insight into the reaction
mechanism, several substrates with variable E/Z composi-
observations made in our laboratory.[13,14] Accordingly, sev-
eral b,b-disubstituted N-enoyl oxazolidine-2-thiones, 3, were
prepared from 1 and 2, and their intramolecular reaction in
the presence of Lewis acids[15] examined, whereby the chiral
oxazolidine-2-thione moiety was expected to act not only as
the controller of the reaction stereochemistry but also as the
sulfur transfer reagent. We were pleased to find that tertiary
thiols 4 were indeed formed with good to excellent yields and,
most significantly, with high diastereoselectivity under the
action of an appropriate Lewis acid. The most satisfactory
results in terms of both reactivity and stereoselectivity were
obtained with BF3·Et2O. Among the Lewis acids tested,[16]
Figure 2. The attacking trajectories of sulfur onto (A) the Si face and
(B) the Re face of the enoyl b-carbon, showing the distal and proximal
1
2
=
alignments, respectively, of iPr group and (R R C C) moiety, and struc-
ture of 5.
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tions were prepared[18] and the outcomes of their reactions
were examined. Strikingly, it was found that the reaction
diastereoselectivity was essentially the same regardless of the
E/Z composition of the starting enoyl substrate 3,[19] Table 2.
Table 2: Reaction diastereoselectivities obtained from substrates 3 of
variable E/Z compositions.[a]
Compound
R1
R2
Substrate 3
E/Z ratio[b]
Product 4
d.r.[b]
3d
3g
3j
Me
Me
nBu
4-BrC6H4
4-CNC6H4
Ph
100:0
30:70
100:0
83:13
100:0
50:50
0:100
92:8
92:8
92:8
92:8
96:4
96:4
96:4
Scheme 2. Elaboration of adducts into enantiopure sulfanyl-bearing
[a] Reactions conducted at 0.5 mmol scale and 0.1m substrate concen-
tration. Ratio of 3:BF3·OEt2 1:2. [b] Determined by 500 MHz 1H NMR
spectroscopy.
esters and alcohols bearing a quaternary stereocenter, and recycling of
the chiral auxiliary. Conditions: a) Sm(OTf)3, MeOH, RT; b) NaBH4,
THF/H2O. c) Lawesson’s reagent, 1,4-Dioxane, reflux.
The same behavior was also observed for substrate 6
(Figure 3), which bears a structurally different oxazolidine-
2-thione auxiliary.[20] These results show that products with
very high diastereomeric purity may be accessible from
Experimental Section
General Procedure: BF3·Et2O (1.0 mmol, 0.127 mL) was added
dropwise by syringe to a solution of the corresponding N-enoyl
oxazolidine-2-thione (3; 0.5 mmol) in methylene chloride (8 mL)
under a nitrogen atmosphere at À308C (bath temperature) or at the
corresponding temperature (see Table 1). The resulting mixture was
stirred at the same temperature until signals corresponding to starting
material were no longer visible in the 1H NMR spectra of the
extracted samples. The mixture was then poured into a saturated
solution of sodium bicarbonate (20 mL) and the layers were
separated. The organic layer was washed with brine (50 mL), dried
over MgSO4, and the solvent evaporated under reduced pressure. The
crude material was purified by silica gel chromatography by using a
mixture of ethyl acetate and hexane (10:90) as eluent.
Figure 3. Uniform diastereoselectivity sense and level regardless of the
E/Z composition of substrate 6. Conditions: a) BF3·Et2O, À308C then
H2O.
Received: January 30, 2004 [Z53889]
Keywords: asymmetric synthesis · chirality · Lewis acids ·
.
Michael addition · thiols
configurationally nonhomogeneous b,b-disubstituted Michael
acceptors, a feature that is of practical interest.[21]
Although at the present time we do not have a rational
explanation for the above observations,[22] the excellent
diastereoselectivity attained in these reactions is also of
particular interest, since treatment of the thiol adducts such as
4b and 4d with Sm(OTf)3 (Tf = trifluromethanesulfonyl) in
MeOH[23] provides the b,b-disubstituted b-sulfanyl carboxylic
esters 8 and 9, respectively. Likewise, treatment of 4a and 4b
[1] For an updated account on the synthesis of thiols, sulfides, and
derivatives, see: D. J. Procter, J. Chem. Soc. Perkin Trans. 1 2001,
335 – 354 and previous review articles in the series.
À
[2] For a review on metal-catalyzed C S bond formation, see: T.
Kondo, T. Mitsudo, Chem. Rev. 2000, 100, 3205 – 3220.
[3] P. Perlmutter, Conjugate Addition Reactions in Organic Syn-
thesis, Pergamon, Oxford, 1992.
[24]
[4] For recent examples, see: a) D. F. Taber, G. J. Gorski, L. M.
Liable-Sands, A. L. Rheingold, Tetrahedron Lett. 1997, 38,
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M. Nakajima, S. Hashimoto, Tetrahedron 2000, 56, 9589 – 9594;
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with NaBH4 leads to the corresponding 1,3-hydroxythiols
10[25] and 11. In each case, the oxazolidinone 12 is produced
and can be transformed into the oxazolidine-2-thione 2 for
reuse by treatment with Lawesonꢀs reagent (Scheme 2).
In conclusion, it has been shown that b,b-disubstituted N-
enoyl oxazolidine-2-thiones react upon the action of Lewis
acids through
a highly stereoselective intramolecular
Michael-type process. This transformation allows for the
À
construction of C S bonds with a quaternary stereocenter and
results in the formation of functionalized tertiary sulfanyls in
very high enantioselectivity. Further studies are underway to
clarify the mechanism of this reaction.
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Communications
e) S. Kobayashi, C. Ogawa, M. Kawamura, M. Sugiura, Synlett
[20] Note for this case it is the opposite configuration of both the
auxiliary and the resulting tertiary sulfanyl. Also, see refer-
ence [25].
[21] The synthesis of b,b-disubstituted Michael acceptors with either
solely E or solely Z configuration is, in general, not so
straightforward. For further information, see, for instance, N.
Zhu, D. G. Hall, J. Org. Chem. 2003, 68, 6066 – 6069, and
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[6] Reviews on catalytic enantioselective Michael additions: a) N.
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Sibi, S. Manyem, Tetrahedron 2000, 56, 8033 – 8061.
[22] There are two possible rationales: kinetic production of the
observed diastereomer through any reaction pathway involving
À
[7] For the synthesis of quaternary C S systems other than thiols
a
common intermediate reachable from both E- and Z-
asymmetrically, see: Sulfoxides: a) D. A. Evans, G. C. Andews,
Acc. Chem. Res. 1974, 7, 147 – 155; sulfones from rearrangement
of chiral sulfinates: b) K. Hiroi, M. Yamamoto, Y. Kurihara, H.
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rearrangement of sulfur ylides: c) X. Zhang, Z. Qu, Z. Ma, W.
Shi, X. Jin, J. Wang, J. Org. Chem. 2002, 67, 5621 – 5625; sulfides
from rearrangement of allyl xanthates: d) M. S. Chambers, E. J.
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configured enoyl derivatives, and thermodynamic equilibration
of the formed diastereomeric products before final hydrolysis.
Among the possible pathways for the first rationale would be the
virtual E/Z isomerization of the substrate under the reaction
conditions. After analysis by NMR spectroscopy of aliquots
taken for a set of reactions at times corresponding to different
degrees of reaction conversion, however, no detectable E/Z
isomerization could be observed, and this possibility can be ruled
out.
[8] The preparation of
a tertiary arylsulfide is described in
[23] a) E. Lee, E. J. Jeong, E. J. Kang, L. T. Sung, S. K. Hong, J. Am.
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[24] M. Prashad, D. Har, H.-Y. Kim, O. Repic, Tetrahedron Lett. 1998,
39, 7067 – 7070.
reference [5a] (53% yield and 85% ee); another one in
reference [5b] (43% yield and 10% ee).
[9] M. E. Jung in Comprehensive Organic Synthesis, Vol. 4 (Eds.:
B. M. Trost, I. Fleming, M. F. Semmelhack), Pergamon, Oxford,
1991, p. 17.
[10] a) J. A. Marshall, S. L. Crooks, B. S. DeHoff, J. Org. Chem. 1988,
53, 1616 – 1623; b) J. A. Marshall, M. W. Andersen, J. Org.
Chem. 1992, 57, 2766 – 2768.
[25] The enantiomer of 10 is obtained in ꢀ 97% ee from the
reduction of 7 under otherwise identical conditions.
[11] Reviews: a) K. Fuji, Chem. Rev. 1993, 93, 2037 – 2066; b) E. J.
Corey, A. Guzman-Perez, Angew. Chem. 1998, 110, 402 – 415;
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[12] The use of Michael addition reactions in the construction of
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[13] C. Palomo, M. Oiarbide, F. Dias, A. Ortiz, A. Linden, J. Am.
Chem. Soc. 2001, 123, 5602 – 5603.
[14] For further development by others, see: T. Kataoka, H.
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[15] For Lewis acid-assisted cyclization of N-enoyl thioureas leading
to 1,3-thiazines, see: M. Dzurilla, P. Kutschy, P. Kristan, Synthesis
1985, 933 – 934.
[16] While the treatment with SnCl2 led to the recovery of unreacted
3, the reaction with other Lewis acids such as TiCl4, Sm(OTf)3,
AlCl3, AlEt2Cl, BCl3, and BBr3 led to variable quantities of
undesired side products.
[17] CCDC-228804 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB21EZ, UK; fax: (+ 44)1223-336-033; or deposit@
ccdc.cam.ac.uk).
[18] Mixtures of different E/Z composition were obtained by either
column chromatography- or recrystallization-driven enrichment
of the original E/Z mixture. See Supporting Information for
details.
[19] For example, it has been described recently that the conjugate
addition of lithium thiophenolate to an E and Z mixture of a
cyclic enone gives exclusively one diastereomeric addition
product. T. J. Houghton, C. Soongyu, V. H. Rawal, Org. Lett.
2001, 3, 3615 – 3617.
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