Highly diastereoselective formation and reactions of a non-mesomerically stabilized, lithiated α-thiocarbanion

Article abstract of DOI:10.1039/b604029b

A new class of non-mesomerically stabilized, unbranched, configurationally stable lithiated α-thiocarbanion has been synthesized and its stereospecific reactions with several electrophiles were investigated. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b604029b

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Highly diastereoselective formation and reactions of a
non-mesomerically stabilized, lithiated a-thiocarbanion{
Ravindra P. Sonawane, Roland Fro¨hlich{ and Dieter Hoppe*
Received (in Cambridge, UK) 20th March 2006, Accepted 23rd May 2006
First published as an Advance Article on the web 14th June 2006
DOI: 10.1039/b604029b
A new class of non-mesomerically stabilized, unbranched,
configurationally stable lithiated a-thiocarbanion has been
synthesized and its stereospecific reactions with several electro-
philes were investigated.
Asymmetric induction on a prochiral methylene group through
deprotonation followed by electrophilic substitution is one of the
basic asymmetric C–C bond forming reactions.1 Synthetic utility of
this process has been limited to the a-heteroatom substituted
organolithium compounds wherein excellent enantio- and diaster-
eoselectivities have been achieved.1 Especially, a-oxy1b and
a-amino1d organolithium compounds have proved to be highly
Scheme 1 Reagents and conditions: i) 1.2 eq. sec-BuLi, 1.2 eq. TMEDA,
toluene, 278 uC, 3 h; ii) 3.0 eq. electrophile (ElX).
valuable in synthetic organic chemistry. In contrast, a-thio
substituted carbanions are known for their high configurational
instability and rapid epimerization even at low temperatures.1c,2
Configurational stability could be achieved in very few examples3
in which the carbanionic center bears branching which enhances
the barrier of epimerization as proposed by Hoffmann and
coworkers.4 Lack of such a branching at the carbanionic center
results in configurational instability of the lithiated carbanion. In
such cases, one has to rely on post deprotonation enantioenrich-
ment for obtaining useful selectivity.5 In order to find an
unbranched, configurationally stable a-thiocarbanion and estab-
lishing its stereochemical behaviour, we became interested in the
thiocarbamates derived from a-amino acids.
Table 1 Results of the substitution of 2 by various electrophiles
Entry ElX (product) Yield dr
[a]D/deg cm2 g21
1
2
3
4
5
a
TMSCl (3a) 83% .97 : 3 281.5 (c = 1.15, CHCl3)
TBDMSOTf (3b) 65% .97 : 3 288.0 (c = 0.96, CH2Cl2)
MeI (3c)
EtI (3d)
BnBr (3e)
83% .97 : 3 247.7 (c = 1.23, CHCl3)
84% .97 : 3 276.3 (c = 1.17, CHCl3)
98% .97 : 3 24.7 (c = 1.09, CHCl3)
ElX = electrophile; dr = diastereomeric ratio.
whether the selectivity is achieved in the deprotonation step or in
the post-deprotonation reactions, an in situ deprotonation was
carried out wherein the substrate 1 was deprotonated in the
presence of the electrophile tert-butyldimethylsilyl triflate
(TBDMSOTf) (Scheme 2).
Herein, we present the initial results obtained from our
investigations on the deprotonation and stereochemical behaviour
of thiocarbamate 1 derived from (S)-prolinol (Scheme 1).
When thiocarbamate 1 was deprotonated with 1.2 eq. of sec-
BuLi in the presence of achiral additive N,N,N9,N9-tetramethyl-
ethylenediamine (TMEDA), one of the two diastereotopic protons
is abstracted to form the lithiated species 2. Trapping this lithiated
species with various electrophiles afforded the corresponding
substitution products 3 in high yields and excellent diastereoselec-
tivities (Table 1).§
This experiment resulted in the formation of the same
diastereomer (dr . 97 : 3) as is obtained by the normal
deprotonation–substitution sequence. This observation is indica-
tive of the fact that the lithium species 2 is formed by selective
deprotonation and is configurationally stable at 278 uC.6 If 2
would be formed non-selectively, a mixture of two diastereomers
should be obtained.
The results outlined in Table 1 show that the deprotonation–
substitution process takes place in a highly selective manner. In all
cases, no trace of the second diastereomer could be detected by
TLC, NMR, or GC.
In order to gain information regarding the configurational
stability of the intermediate lithium species 2 and to find out
Organisch-Chemisches Institut der Universita¨t, Westfa¨lische Wilhelms-
Universita¨t Mu¨nster, Corrensstrasse 40, 48149, Mu¨nster, Germany.
E-mail: dhoppe@uni-muenster.de
{ Electronic supplementary information (ESI) available: Experimental
details for the preparation of starting material 1, analytical data for
compounds 3a–3e and 5. See DOI: 10.1039/b604029b
Scheme 2 Reagents and conditions: i) 1.2 eq. sec-BuLi, 1.2 eq. TMEDA,
toluene, 278 uC; ii) 3.0 eq. TBDMSOTf; iii) 1.2 eq. sec-BuLi, 1.2 eq.
TMEDA, toluene, 278 uC, 3.0 eq. TBDMSOTf, in situ.
{ Responsible for X-ray crystal structure analysis.
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Chem. Commun., 2006, 3101–3103 | 3101

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opposite stereochemical course to that observed for the
O-carbamate case (1, O for S)8 are presently unknown.
Thus, we have found a new class of unbranched, non-
mesomerically stabilized, configurationally stable a-thiocarbanion9
which undergoes electrophilic substitution with various electro-
philes to furnish the products in good to excellent yields and
excellent diastereoselectivities. This method provides an easy access
to chiral secondary b-amino thiols. The origin of the selectivity,
mode of electrophilic substitution, and further extension of this
protocol to other substrates is currently under investigation.
This work was supported by Sonderforschungsereich 424. R. P.
S. gratefully acknowledges International NRW Graduate School
of Chemistry, Mu¨nster, Germany, for doctoral scholarship.
Excellent experimental assistance from Ms Mareike Renger is
also acknowledged.
Notes and references
§ Typical experimental procedure: In a flame dried 10 mL round bottom
flask was dissolved 1 (100 mg, 0.27 mmol, 1.0 eq.) in 5 mL of absolute
toluene under argon atmosphere. To this was added 37 mg (0.32 mmol,
1.2 eq.) of TMEDA and the reaction flask was cooled to 278 uC. sec-BuLi
(1.36 M, 0.23 mL, 0.32 mmol, 1.2 eq.) was added in a dropwise manner and
the reaction mixture was stirred at 278 uC for 3 hours. Afterwards,
appropriate electrophile (0.81 mmol, 3.0 eq.) was injected and the reaction
mixture was stirred till no starting material could be detected by TLC. The
reaction was then quenched with 2 mL of water, the phases were separated
and the aqueous phase was extracted with diethyl ether (3 6 10 mL). The
collective organic layer was dried over anhydrous MgSO4, filtered through
glass wool, concentrated and subjected to flash column chromatography
(diethyl ether–pentane) to obtain analytically pure product.
Fig. 1 X-Ray crystal structure of triflate salt 4.
" C23H35F3N2O5S2, M 540.65, orthorhombic, space group P212121,
a 8.353(1), b 13.073(1), c 24.181(1) s, U 2640.5(4) s3, Z 4, T 198(2) K,
m(Mo-Ka) 0.259 mm21, 6278 reflections measured, final R1 and wR2
0.0536 and 0.0995. CCDC 602731. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b604029b
Scheme 3 Reagents and conditions: i) 2 eq. Cu(OTf)2, CH2Cl2, rt, 24 h.
The absolute configuration of one of the substitution products,
derived from ethyl iodide (Entry 4, Table 1), was elucidated by
X-ray crystal structure analysis (under anomalous dispersion)" of
its triflate salt 4 (Fig. 1). The triflate salt was obtained by reaction
of 3d with copper(II) triflate in dichloromethane (Scheme 3). The
newly generated stereocenter is conclusively proved to be
S-configured.
1 Reviews: (a) D. Hoppe and T. Hense, Angew. Chem., Int. Ed., 1997, 36,
2282; Angew. Chem., 1997, 109, 2376; (b) D. Hoppe, F. Marr and
M. Bru¨ggemann, Top. Organomet. Chem., 2003, 5, 61–137; (c) T. Toru
and S. Nakamura, Top. Organomet. Chem., 2003, 5, 177–216; (d) P. Beak,
T. Johnson, D. Kim and S. Kim, Top. Organomet. Chem., 2003, 5,
139–176; (e) D. Hoppe and G. Christoph, in The Chemistry of
Organolithium Compounds, ed. Z. Rappoport and I. Marek, Wiley,
Chichester, 2004, pp. 1055–1164.
2 (a) P. G. McDougal, B. Condon, M. Laffose, Jr., A. Lauro and
D. Vanderveer, Tetrahedron Lett., 1988, 29, 2547; (b) P. McDougal and
B. Condon, Tetrahedron Lett., 1989, 30, 789; (c) A. Krief, G. Evrard,
E. Badaoui, V. DeBeys and R. Dieden, Tetrahedron Lett., 1989, 30, 5635;
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3 (a) D. Hoppe, B. Kaiser, O. Stratmann and R. Fro¨hlich, Angew. Chem.,
Int. Ed. Engl., 1997, 36, 2784, Angew. Chem., 1997, 109, 2872; (b)
O. Stratmann, B. Kaiser, R. Fro¨hlich, O. Meyer and D. Hoppe, Chem.-
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(d) F. Marr and D. Hoppe, Org. Lett., 2002, 4, 4217.
Strong evidence was found that the lithium compound 2 has
[2S,2(1S)]-configuration and the substitution with the reported
electrophiles proceeds with retention of configuration: Deuteration
of 2 with CH3OD afforded 5 as a single diastereomer (Scheme 4).
Since the diastereotopic protons HR and HS in 1 have very distinct
1H NMR shifts (supported by quantum-chemical calculations7), 5
could be assigned to the [2S,2(1S)] configuration as deuteration of
chiral lithium carbanions proceeds with retention in all known
examples. The reasons why the deprotonation of 1 takes the
4 (a) R. W. Hoffmann, T. Ruhl and J. Harbach, Liebigs Ann. Chem., 1992,
725; (b) R. W. Hoffmann, M. Julius, F. Chemla, T. Ruhland and
G. Frenzen, Tetrahedron, 1994, 50, 6049; (c) R. W. Hoffmann,
R. K. Dress, T. Ruhland and A. Wenzel, Chem. Ber., 1995, 128, 861;
(d) T. Ruhland, R. Dress and R. W. Hoffmann, Angew. Chem., Int. Ed.
Engl., 1993, 32, 1467, Angew. Chem., 1993, 105, 8487.
5 (a) R. Otte, R. Fro¨hlich, B. Wibbeling and D. Hoppe, Angew. Chem., Int.
Ed., 2005, 44, 5492, Angew. Chem., 2005, 117, 5629; (b) S. Nakamura,
Y. Ito, L. Wang and T. Toru, J. Org. Chem., 2004, 69, 1581; (c)
S. Nakamura, A. Furutani and T. Toru, Eur. J. Org. Chem., 2002, 1690;
(d) S. Nakamura, R. Nagakawa, Y. Watanabe and T. Toru, Angew.
Chem., Int. Ed., 2000, 39, 353, Angew. Chem., 2000, 112, 361; (e)
S. Nakamura, R. Nagakawa, Y. Watanabe and T. Toru, J. Am. Chem.
Soc., 2000, 142, 11342.
Scheme 4 Reagents and conditions: i) 1.2 eq. sec-BuLi, 1.2 eq. TMEDA,
toluene, 278 uC, 3 h; ii) 10.0 eq. CH3OD.
3102 | Chem. Commun., 2006, 3101–3103
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6 An unlikely possiblity remains: If the equilibrium between diastereomers
2 is extremely on the side of [2S,2(1S)]-2 and the equilibration proceeds
extremely rapidly, the same result is expected. All the attempts to
synthesize the opposite diastereomer via lithio-destannylation failed as
a-thio stannanes could not be synthesized. Treatment of 5 with s-BuLi/
TMEDA resulted only in dedeuteration, showing the high kinetic
preference that overrides any possible isotope effect.
7 C. Mu¨ck-Lichtenfeld, unpublished results.
8 B. Weber, J. Schwerdfeger, R. Fro¨hlich, A. Go¨hrt and D. Hoppe,
Synthesis, 1999, 1915.
9 The only example where an unbranched a-thioorganolithium compound
is believed to be stable has been reported by S. Gibson see: S. Gibson (ne´e
Thomas), P. Ham, G. Jefferson and M. Smith, J. Chem. Soc., Perkin
Trans. 1, 1997, 2161.
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