Synthesis of enantiomerically enriched tertiary 2-cyclohexene-1-thiols via configurationally stable α-thio-substituted allyllithium compounds

Article abstract of DOI:10.1021/ol0266828

(Equation presented) (S)-S-(2-Cyclohexenyl) N,N-diisopropylmonothiocarbamate [(-)-(S)-8] was deprotonated by sec-butyllithium/TMEDA to form a configurationally stable lithium compound (S)-9, which is the first example of a new class of α-thio-substituted

Full text of DOI:10.1021/ol0266828

ORGANIC
LETTERS
2002
Vol. 4, No. 24
4217-4220
Synthesis of Enantiomerically Enriched
Tertiary 2-Cyclohexene-1-thiols via
Configurationally Stable
r-Thio-Substituted Allyllithium
Compounds
Felix Marr and Dieter Hoppe*
Organisch-chemisches Institut der UniVersita¨t, Westfa¨lische Wilhelms-UniVersita¨t
Mu¨nster, Corrensstrasse 40, D-48149 Mu¨nster, Germany
dhoppe@uni-muenster.de
Received August 6, 2002
ABSTRACT
(S)-S-(2-Cyclohexenyl) N,N-diisopropylmonothiocarbamate [(−)-(S)-8] was deprotonated by sec-butyllithium/TMEDA to form a configurationally
stable lithium compound (S)-9, which is the first example of a new class of r-thio-substituted organolithium compounds with improved
properties. It is regioselectively alkylated by alkyl halides with complete stereoinversion to form the monothiocarbamates (+)-10 which afford
highly enantioenriched tertiary 2-cyclohexene-1-thiols (+)-6 on reductive cleavage.
The family of R-heteroatom-substituted organolithium com-
pounds has found widespread application in organic synthe-
sis.1 A number of enantioenriched, configurationally stable
R-oxy-2 and R-amino-substituted3 organolithium compounds
have been found, whereas only a few configurationally stable
R-thio-substituted organolithium compounds are known. On
the basis of the first two examples 14 and 25 (Figure 1) of
this class of compounds we recently synthesized the allyl-
lithium compounds 3a and 3bsshowing a marked solvent
dependence of their configurational stabilitysand applied
them in stereoselective electrophilic substitution reactions
(Scheme 1).6
Highly enantioenriched R- and γ-substitution products 4
and 5 are isolated in good yields. Their ratio depends on the
reaction conditions and the employed electrophilesthe
* Address correspondence to this author. Telefax: (+49)251/83-36531.
(1) Reviews: (a) Hodgson, D. M., Ed. Topics in Organometallic
Chemistry; Springer-Verlag: Heidelberg, Germany, 2002; in press. (b) Basu,
A.; Thayumanavan, S. Angew. Chem. 2002, 114, 740; Angew. Chem., Int.
Ed. 2002, 41, 717. (c) Aggarwal, V. K. Angew. Chem. 1994, 106, 185;
Angew. Chem., Int. Ed. Engl. 1994, 33, 175.
(2) Reviews: (a) Hoppe, D.; Marr, F.; Bru¨ggemann, M. In Enantio-
selective Synthesis by Lithiation Adjacent to O and Electrophile Incorpora-
tion, in ref 1a. (b) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. Engl. 1997,
36, 2282.
(3) Review: Beak, P.; Basu, A.; Gallagher, D. J.; Park, J. S.; Tha-
yumanavan, S. Acc. Chem. Res. 1996, 29, 552.
Figure 1. Configurationally stable R-thio-substituted organolithium
compounds. Ligands (TMEDA and Et2O) at the lithium center are
omitted for the sake of clarity.
(4) Kaiser, B.; Hoppe, D. Angew. Chem. 1995, 107, 344; Angew. Chem.,
Int. Ed. Engl. 1995, 34, 323.
10.1021/ol0266828 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/29/2002

Scheme 1. Electrophilic Substitution of Dilithiated
Scheme 2. Synthesis of Tertiary 2-Cyclohexene-1-thiolsa,b
Thiocarbamates (ref 6)a
a Reagents and conditions: (a) (i) solution of ElX, -78 °C; (ii)
sat. NaHCO3, 0 °C.
γ-products generally represent the main products, often
dominating considerably (Scheme 1).6b
To the best of our knowledge, there is no general access
to enantioenriched tertiary allylic thiols. Consequently we
were interested in modifying the lithiation/substitution
methodology toward an R-selective protocol.
Since we have found that the regioselectivity is influenced
by the employed carbamoyl moiety,6b we tried different
substitution patterns. The N,N-diisopropylcarbamoyl group
was easily introduced to racemic cyclohex-2-enethiol (rac-
7) with commercially available N,N-diisopropylcarbamoyl
chloride to yield the corresponding monothiocarbamate rac-
8. Enantioenriched monothiocarbamate (S)-8 was synthesized
from enantioenriched (S)-thiol (Scheme 2).7,8
a Reagents and conditions: (a) (i) NaH, THF, reflux; (ii)
Cl(CdO)NiPr2, THF, reflux; (iii) H2O. (b) s-BuLi/TMEDA, solvent,
-78 °C. (c) (i) ElX, -78f 0 °C; (ii) NH4Cl, rt. (d) (i) LiAlH4 in
ether, ZnCl2 in ether, then 10 in THF, 0f rt; (ii) HCl (aq). bLigands
(TMEDA and Et2O) at the lithium center are omitted for the sake
of clarity.
Lithiation of 9 with sec-butyllithium/TMEDA occurs
smoothly in toluene, ether, or THF at -78 °C.9,10 Alkylations
by alkyl halides take place with complete R-selectivity11 in
very good yields (Table 1), markedly improved in compari-
son to the N-monoalkyl-substituted, dilithiated monothio-
carbamates 3. Further, in contrast to dilithiated species (S)-
3a where for synthetic application useful configurational
stability is achieved in THF solution only,12 interestingly,
no solvent dependence of the configurational stability was
found for lithium compound (S)-9. Methylations in THF,
diethyl ether, or toluene, respectively, lead generally to high
chirality transfer of 99-100% (96-97% ee of product (+)-
(R)-10b, determined on the stage of the thiol (+)-(R)-6b by
GC; Table 1, entries 4-6).
Hexylation, benzylation, and allylation of allyllithium (S)-9
furnished optically active products in good yields (Table 1,
entries 8, 10, and 12). The ee of allylation product (+)-(S)-
10e (er g98:2; g96% ee) and hexyl-substituted thiocarbam-
ate (+)-(S)-10c (er g97:3; g94% ee) were concluded from
the corresponding thiols (all ee values were determined by
GC) and are equally high, indicating an almost quantitative
conservation of the enantioenrichment throughout the reac-
tion sequence. Unfortunately, the ee of benzyl-substituted
thiocarbamate (+)-(S)-10d or its corresponding thiol could
not be determined because no suitable conditions for separa-
tion of enantiomers by GC or HPLC were found.13
(5) (a) Hoppe, D.; Kaiser, B.; Stratmann, O.; Fro¨hlich, R. Angew. Chem.
1997, 109, 24, 2872; Angew. Chem., Int. Ed. Engl. 1997, 36, 2784. (b)
Stratmann, O.; Kaiser, B.; Fro¨hlich, R.; Meyer, O.; Hoppe, D. Chem. Eur.
J. 2001, 7, 423.
(6) (a) Marr, F.; Fro¨hlich, R.; Hoppe, D. Org. Lett. 1999, 1, 2081. (b)
Marr, F.; Fro¨hlich, R.; Wibbeling, B.; Diedrich, C.; Hoppe, D. Eur. J. Org.
Chem. 2002, 2790.
(7) Enantioenriched (S)-cyclohex-2-enethiol was achieved from saponi-
fication of (S)-S-(2-cyclohexenyl) N-methylmonothiocarbamate, which was
synthesized by Pd0-catalyzed deracemization, see: (a) Bo¨hme, A.; Gais,
H.-J. Tetrahedron: Asymmetry 1999, 10, 2511. (b) Gais, H.-J.; Bo¨hme, A.
J. Org. Chem. 2002, 67, 1153. The N,N-diisopropylcarbamoyl group can
be introduced directly by replacement of the N-methylmonothiocarbamoyl
group in a two-step, one-pot reaction with good yield.
(8) The corresponding monothiocarbamate with the N,O-acetal type
2,2,5,5-tetramethyl-1,3-oxazolidin-3-yl-carbonyl group was synthesized
analogously. This protecting group was removed quantitatively from
secondary allyl thiols with a mild, acid/base-mediated two-step reaction
sequence (see: Hintze, F.; Hoppe, D. Synthesis 1992, 1216). However,
severe problems arose in the cleavage of this group on tertiary allyl thiols.
(9) For deprotonations of achiral S-alkyl N,N-dimethylmonothiocarbam-
ates with s-BuLi, see: Beak, P.; Becker, P. D. J. Org. Chem. 1982, 47,
3855. See also ref 4.
Deprotection of N,N-diisopropylcarbamates is usually
carried out with a large excess of diisobutylaluminum hydride
(ca. 10 equiv).14 However, this protocol suffers from the large
amounts of aluminum salts formed during aqueous workup
and was not useful for monothiocarbamates 10. The N,N-
(12) Benzyllithium (S)-2 is configurationally stable in ethereal solution;
however, in contrast to the proposed racemization mechanism (see refs 5a
and 6b), in THF solution some racemization is detected; see ref 5b.
(13) The enantioenrichment should be equally high, because methylation,
benzylation, and allylation of the related dilithiated species 3a take place
with the constantly high stereospecificity of 96%.6b
(10) For deprotonations of achiral S-allyl N,N-dimethylmonothiocarbam-
ates with LDA, see: (a) Nakai, T.; Mimura, T.; Ari-Izumi, A. Tetrahedron
Lett. 1977, 2425. (b) Hoppe, D.; Hanko, R.; Bro¨nneke, A.; Lichtenberg,
F.; van Hu¨lsen, E. Chem. Ber. 1985, 118, 2822.
(11) As the only exception, from the allylation with allyl bromide 5%
of the corresponding γ-product was isolated (16:1 regioselectivity).
(14) Tomooka, K.; Komine, N.; Sasaki, T.; Shimizu, H.; Nakai, T.
Tetrahedron Lett. 1998, 39, 9715.
4218
Org. Lett., Vol. 4, No. 24, 2002

Table 1. Results of Electrophilic Substitution Reactions of Allyllithium 9
entry
substrate
solvent
time,a min
El(X)
yield
1
2
3
rac-8
rac-8
rac-8
Et2O
THF
Et2O
45
10
60
D(OMe)
D(OMe)
Me(I)
66% rac-10a + 34% γ-isomer
28% rac-10a + 72% γ-isomer
99% rac-10b
4
5
6
7
(-)-(S)-8, 97% ee
(-)-(S)-8, 97% ee
(-)-(S)-8, 97% ee
rac-8
toluene
Et2O
THF
120
60
30
Me(I)
Me(I)
Me(I)
n-C6H13(I)
96% (+)-(R)-10b, 97% ee,b [R]D +166c
95% (+)-(R)-10b, 96% ee,b [R]D +164c
87% (+)-(R)-10b, 97% ee,b [R]D +165c
82% rac-10c
Et2O
60
8
9
(-)-(S)-8, 97% ee
rac-8
(-)-(S)-8, 97% ee
rac-8
(-)-(S)-8, 97% ee
rac-8
rac-8
toluene
Et2O
toluene
Et2O
toluene
Et2O
Et2O
120
100
125
90
120
45
n-C6H13(I)
Bn(Br)
Bn(Br)
CH2dCH-CH2(Br)
CH2dCH-CH2(Br)
PhCHdCH-CH2(Br)
geranyl(Br)
67% (+)-(R)-10c,d g94% ee,b [R]D +120c
84% rac-10d
91% (+)-(S)-10d ,d ee n.d.,e [R]D +114c
78% rac-10e
80% (+)-(S)-10e,d g96% ee,b [R]D +153c
90% rac-10f
58% rac-10g
10
11
12
13
14
45
a Time of deprotonation at -78 °C. b Determined on the stage of the corresponding thiol. c c ) 1.0-1.8 in CHCl3. d Absolute configuration assigned in
analogy to (+)-(R)-10b. e Not determined.
diisopropylcarbamoyl group can also be cleaved by nucleo-
philic attack of methyllithium; 3 equiv of MeLi are required
and LDA is formed as a byproduct.15 When using base-
sensitive substrates problems have to be expected.16 Further
reducing and nucleophilic reagents have been tried for
deprotection of monothiocarbamates 10: lithium aluminum
column chromatography on silca gel under an argon atmos-
phere delivered the pure thiols in satisfactory yields (Table
2).
The ee values of enantioenriched thiols (+)-(R)-6b,c and
(+)-(S)-6e could be determined by GC. The determined
g96% ee values for thiols (+)-(R)-6b,e are indicating g99%
stereospecificity for the reaction sequence deprotonation/
alkylation/deprotectionsthis is evidence for an enantiospe-
cific reaction pathway and deprotection without loss of
enantiomeric purity (Table 2, entries 2 and 7).
Table 2. Results of Deprotections of Monothiocarbamates 10
to Yield Tertiary Thiols 6
entry substrate
El
yielda
1
2
3
4
5
6
7
8
rac-10b
(+)-(R)-10b Me
rac-10c n-C6H13
(+)-(R)-10cc n-C6H13
Me
59% rac-6b
83% (+)-(R)-6b, g96% eeb
85% rac-6c
90% (+)-(R)-6c,c 94% eeb
86% rac-6d
86% rac-6e
76% (+)-(S)-6e,c 96% eeb
Scheme 3. Stereochemical Correlationa
rac-10d
Bn
rac-10e
CH2dCH-CH2
(+)-(S)-10ec CH2dCH-CH2
rac-10f
PhCHdCH-CH2 78% rac-6f
a Isolated yields. b Determined by GC. c Absolute configuration assigned
in analogy to (+)-(R)-10b.
hydride in THF,17 lithium triethylboron hydride (super-
hydride) in ether, and pent-1-ynyllithium in hexane.15 In those
cases no reaction or decomposition of the substrates occurred.
A mixture of solutions of LiAlH4 and zinc chloride, both
commercially available, is superior.18 Deprotections were
achieved by adding a solution of thiocarbamates 10 in THF
at 0 °C and stirring overnight at room temperature. Aqueous
workup with diluted hydrochloric acid followed by flash
a Reagents and conditions: (a) MeI, -78 °C. (b) (i) 1.0 N NaOH
(aq), rt; (ii) 2.0 N HCl (aq), rt. (c) (i) LiAlH4 in ether, ZnCl2 in
ether, then 10b in THF, 0f rt; (ii) HCl (aq).
The stereochemical course of the alkylations was eluci-
dated by chemical correlation: Methylation of dilithiated
monothiocarbamate (S)-3a leads to thiocarbamate (R)-11, as
(15) Madec, D.; Henryon, V.; Fe´re´zou, J.-P. Tetrahedron Lett. 1999, 40,
8103.
(16) An excess of MeLi here led to deprotonation of allylic positions
whereas deprotection failed with less than 3 equiv of MeLi.
(17) (a) Paetow, M.; Kotthaus, M.; Grehl, M.; Fro¨hlich, R.; Hoppe, D.
Synlett 1994, 1034. (b) Marko, I. E.; Leroy, B. Tetrahedron Lett. 2000, 41,
7225.
(18) This mixture presumably forms alane; see: (a) Ashby, E. C.;
Sanders, J. R.; Claudy, P.; Schwartz, R. J. Am. Chem. Soc. 1973, 95, 6485.
(b) Brower, F. M.; Matzek, N. E.; Reigler, P. F.; Rinn, H. W.; Roberts, C.
B.; Schmidt, D. L.; Snover, J. A.; Terada, K. J. Am. Chem. Soc. 1975, 98,
2450.
Org. Lett., Vol. 4, No. 24, 2002
4219

was determined by X-ray crystal structure analysis.6 Saponi-
fication furnished the tertiary thiol (+)-(R)-6b. Methylation
of allyllithium (S)-9 forms monothiocarbamate (+)-10b,
which was deprotected to yield thiol (+)-(R)-6b (Scheme
3). Consequently, the (R) configuration is assigned to N,N-
diisopropylmonothiocarbamate (+)-10b. Thus alkylation of
(S)-9 with methyl iodide proceeded with stereoinversion of
configuration as was found previously for the N-isopropyl
species (S)-3a.6
In summary we have found a convenient access to tertiary
allyllic thiols. This synthesis of highly enantioenriched thiols
employs a configurationally stable R-thioallyllithium com-
pound, which is alkylated with essentially complete regio-
and stereoselectivity in high yield, taking place with stereo-
inversion of configuration. Smooth deprotection of the
intermediary monothiocarbamates with lithium aluminum
hydride/zinc chloride occurs without loss of enantiomeric
purity and provides the thiols in good yield.
Acknowledgment. The work was supported by the
Deutsche Forschungsgemeinschaft and the Fonds der Che-
mischen Industrie.
Supporting Information Available: Detailed experi-
mental procedures with spectroscopic data for monothiocar-
bamates 10 and thiols 6. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL0266828
4220
Org. Lett., Vol. 4, No. 24, 2002