A highly enantioenriched, configurationally stable α-thioallyllithium compound and the stereochemical course of its electrophilic alkylation

Article abstract of DOI:10.1021/ol991134o

matrix presented The first highly enantioenriched, configurationally stable a-thioallyllithium compound (9) was generated by deprotonation of the S-cyclohex-2-enyl thiocarbamate 8. The methylation of 9 in both the α- and γ-positions proceeds antarafacially with a high degree of chirality transmission, as was elucidated by X-ray analysis of thiocarbamates 10 and 11. The optically active S-allyl thiocarbamate 8 was prepared by enantiospecific [3,3]sigmatropic rearrangement of the corresponding Oallyl thiocarbamate 7.

Full text of DOI:10.1021/ol991134o

ORGANIC
LETTERS
1999
Vol. 1, No. 13
2081-2083
A Highly Enantioenriched,
Configurationally Stable
r-Thioallyllithium Compound and the
Stereochemical Course of Its
Electrophilic Alkylation
,†
Felix Marr, Roland Fro1hlich,‡ 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 October 8, 1999
ABSTRACT
The first highly enantioenriched, configurationally stable r-thioallyllithium compound (9) was generated by deprotonation of the S-cyclohex-
2-enyl thiocarbamate 8. The methylation of 9 in both the r- and γ-positions proceeds antarafacially with a high degree of chirality transmission,
as was elucidated by X-ray analysis of thiocarbamates 10 and 11. The optically active S-allyl thiocarbamate 8 was prepared by enantiospecific
[3,3]sigmatropic rearrangement of the corresponding O-allyl thiocarbamate 7.
Enantioenriched R-heteroatom-substituted alkyllithium com-
pounds are valuable chiral carbanion equivalents.1 Electro-
philic substitution of these chiral building blocks is generally
stereospecific. Some R-oxy- and R-amino-substituted orga-
nolithium compounds have proven to be configurationally
stable,2 whereas vinylic, aryl, R-thio,3,4 and R-seleno5 sub-
stituents at the carbanionic center usually lead to rapid
racemization even at low temperatures (e.g. -78 °C).
A configurationally stable, moderately enantioenriched
R-thioalkyllithium compound (R)-1 was synthesized in our
laboratory, which showed no detectable racemization at -78
°C in etheral solution (Scheme 1).6 Later we discovered the
highly enantioenriched R-thiobenzyllithium compound (S)-2
with unusually high configurational stability. Even warming
† Fax: (+49)251/8339772.
‡ For details of the X-ray structure analysis, contact R. Fro¨hlich.
(1) Reviews: (a) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. Engl.
1997, 36, 2282. (b) Beak, P.; Basu, A.; Gallagher, D. J.; Park, J. S.;
Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552. (c) Aggarwal, V. K.
Angew. Chem., Int. Ed. Engl. 1994, 33, 175.
(2) See references in reviews given in refs 1a-c for relevant examples.
(3) (a) Dress, R. K.; Ro¨lle, T.; Hoffmann, R. W. Chem. Ber. 1995, 128,
673. (b) Hoffmann, R. W.; Dress, R. K.; Ruhland, T.; Wenzel, A. Chem.
Ber. 1995, 128, 861. (c) Ahlbrecht, H.; Harbach, J.; Hoffmann, R. W.;
Ruhland, T. Liebigs Ann. 1995, 211.
Scheme 1. Lithiated Monothiocarbamatesa
(4) (a) Reich, H. J.; Dykstra, R. R. Angew. Chem., Int. Ed. Engl. 1993,
32, 1469. (b) Reich, H. J.; Dykstra, R. R. J. Am. Chem. Soc. 1993, 115,
7041. (c) Reich, H. J.; Kulicke, K. J. J. Am. Chem. Soc. 1995, 117, 6621.
(d) Reich, H. J.; Kulicke, K. J. J. Am. Chem. Soc. 1996, 118, 273.
(5) (a) Ruhland, T.; Dress, R.; Hoffmann, R. W. Angew. Chem., Int. Ed.
Engl. 1993, 32, 1467. (b) Hoffmann, R. W.; Klute, W. Chem. Eur. J. 1996,
2, 694. (c) See refs 3a,c and 4a.
a Ligands (TMEDA and Et2O) at the lithium center are omitted
for the sake of clarity.
(6) Kaiser, B.; Hoppe, D. Angew. Chem., Int. Ed. Engl. 1995, 34, 323.
10.1021/ol991134o CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/10/1999

the etheral solution of (S)-2 (>99% ee) to 0 °C led to
unchanged high ee values in the trapping products (g97 up
to g99% ee).7
Encouraged by these results we set out to survey allylic
systems wherein the double bond allows for further trans-
formations. To avoid complications caused by E/Z-isomer-
ization in the allylic anion, a cyclic N-monoalkyl thiocar-
bamate8 was selected to suppress E/Z-isomerization. The
required S-allylic thiocarbamates 3 can easily be generated
from the corresponding O-esters 4 (Scheme 2). Rearrange-
a kinetic resolution of a racemic cyclohexenol precursor by
lipase-catalyzed enantioselective transesterfication13 [(R)]
with an ee up to 95%. (R)-O-(2-Cyclohexenyl) N-isopropyl-
thiocarbamate (7, 95% ee)14 was readily prepared in 93%
yield and subjected to a thermal rearrangement in a neat state
at 105 °C for 3 h. (S)-S-(2-Cyclohexenyl) N-isopropylthio-
carbamate (8) was isolated in 88% yield with 92% ee,
indicating a high level of chirality transfer (Scheme 3).15,16
Scheme 3. Carbamoylation and Rearrangementa
Scheme 2
a This sequence was performed with both enantiomers. Re-
agents: (a) (i) NaH, THF, 0 °C; (ii) i-PrNCS, then H3O+; (b) 105
°C, 3 h.
ment of thiocarbamates has been extensively investigated9,10
for achiral or racemic substrates.11 The O-esters 4 are
prepared by the addition of isothiocyanates onto allylic
alcohols 5,10 which are accessible in enantioenriched form
via different routes.
Enantioenriched cyclohex-2-en-1-ol (6) had been prepared
either by a base-mediated rearrangement of cyclohexene
oxide with chiral lithium amide bases12 [(R) and (S)] or via
In extensive deprotonation experiments, different solvents,
bases, and ligands were employed. When the deprotonation
was performed in the presence of TMEDA in THF at -78
°C, formation of the dianionic species 9 was visible by the
appearance of a yellow color when the addition of the second
equivalent of s-BuLi started. The reaction was complete
within 5 min. The use of a variety of electrophiles provided
optically active products, fortunately the ee values of the
methylation products 10 and 11 could be determined by GC
and HPLC (Scheme 4).17
(7) Hoppe, D.; Kaiser, B.; Stratmann, O.; Fro¨hlich, R. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2784.
(8) This carbamoyl moiety was chosen with the aim of smooth depro-
tection under mild conditions. O-Allyl N-monoalkylcarbamates were already
converted to the N,C-dilithiated species and employed in synthesis, see:
Hanko, R.; Hoppe, D. Angew. Chem., Int. Ed. Engl. 1981, 20, 127.
(9) (a) Hackler, R. E.; Balko, T. W. J. Org. Chem. 1973, 38, 2106. (b)
Hayashi, T. Tetrahedron Lett. 1974, 15, 339. (c) Nakai, T.; Shiono, H.;
Okawara, M. Tetrahedron Lett. 1974, 15, 3625. (d) Nakai, T.; Ari-Izumi,
A. Tetrahedron Lett. 1976, 17, 2355.
Scheme 4. Lithiation of (R)-8 and Methylationa,c
(10) (a) Harayama, H.; Kozera, T.; Kimura, M.; Tanaka, S.; Tamaru, Y.
Chem. Lett. 1996, 543. (b) Harayama, H.; Nagahama, T.; Kozera, T.;
Kimura, M.; Fugami K.; Tanaka, S.; Tamaru, Y. Bull. Chem. Soc. Jpn.
1997, 70, 445.
(11) Harayama reported low de values for the thermally activated
rearrangement of O-6-carvyl N-methylthiocarbamates, see ref 10b. However,
the rearrangement of O-allyl imidazolethiocarboxylic esters has been applied
in the stereospecific synthesis of (a) ansamycin derivatives and (b) the
oligosaccharide fragment of calicheamicin γ1R: (a) Schnur, R. C.; Corman,
M. L. J. Org. Chem. 1994, 59, 2581. (b) Nicolaou, K. C.; Groneberg, R.
D. J. Am. Chem. Soc. 1990, 112, 4085.
(12) (a) Asami, M.; Ishizaki, T.; Inoue, S. Tetrahedron: Asymmetry 1994,
5, 793. (b) Bhuniya, D.; DattaGupta, A.; Singh, V. K. J. Org. Chem. 1996,
61, 6108. (c) So¨dergren, M. J.; Andersson, P. G. J. Am. Chem. Soc. 1998,
120, 10760.
aThis sequence was also performed with (S)-8, see Table 1, entry
4. b Corrected for the enantiomeric purity of used (S)-8. c Reagents:
(a) 2.5 equiv of s-BuLi/TMEDA, THF, -78 °C; (b) 1.5 equiv of
1.0 N MeI/THF, -78 °C, then H3O+. Ligands (TMEDA and THF)
at the lithium center are omitted for the sake of clarity.
(13) (a) Fukazawa, T.; Hashimoto, T. Tetrahedron: Asymmetry 1993,
4, 2323. (b) Fukazawa, T.; Shimoji, Y.; Hashimoto, T. Tetrahedron:
Asymmetry 1996, 6, 1649.
(14) [R]20 ) +156 (c 1.13 in CHCl3).
D
(15) The slight loss of enantioenrichment is probably due to a noncon-
certed rearrangement. Pd(II) catalysis of the rearrangement led here to
marked loss of ee. Moreover, Pd(0) catalysis is assumed to follow a reaction
pathway of dissociation, involving a stabilized allyl cation, and therefore
should furnish racemic S-esters. See ref 13b.
(16) During the course of this research, a high-yielding protocol for the
Pd(0)-catalyzed rearrangement of rac-O-allyl thiocarbamates under efficient
desymmetrization by external chiral induction was published. One of three
examples is the rearrangement of O-(2-cyclohexenyl) N-methylthiocarba-
mate. See: Bo¨hme, A.; Gais, H.-J. Tetrahedron: Asymmetry 1999, 10, 2511.
Deprotonation of 8 in toluene occurred very sluggishly;
the R-product 10 isolated after methylation showed a low
ee whereas the γ-product 11 was almost racemic (entry 1).
Deprotonation of 8 in ether yields thiocarbamates 10 and
11 showing a remarkable loss of enantioenrichment (entry
3). Running the reaction in THF18 yields carbamate 10 with
89% ee, what is equivalent to 97% conservation of the
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Org. Lett., Vol. 1, No. 13, 1999

original enantioenrichment. The electrophilic attack on the
γ-carbon is less stereospecific and forms 11 with 68% ee/
74% stereospecificity (Table 1, entry 4). On deprotonation
in toluene, the addition of methyl iodide after a shorter
reaction time leads to a marked improvement of ee (entry
2), clearly indicating that racemization takes place on the
stage of carbanion 9 under these conditions. In contrast to
this, prolonged reaction times in THF did not cause any
decrease in the ee values (entries 5 and 6). Consequently, it
is concluded that here the partial racemization is caused by
incomplete stereospecificity in the alkylation step.
here the steric demands of the carbon skeleton and the
carbamoyl moiety are lower, and compared to species 1 and
2, racemization in ether occurs more readily than for 1 and
2. The observed high solvent dependence of the racemization
rate matches with results by Reich et al., who reported that
the enantiomerization rate of R-thio-substituted organolithium
reagents decreases with increasing ion pair separation.4a
The stereochemical outcome of the methylation of (R)-9
was elucidated by X-ray analysis (Figure 1).19 From (R)-8,
Table 1. Results of Methylations
stereospecificity, %a
entry
solvent
time/min
10
11
1
2
3
4b
5
6
toluene
toluene
Et2O
THF
THF
270
45
60
5
60
270
3 (41)
56 (6)
61 (46)
97 (21)
96 (19)
96 (17)
0 (22)
nd
58 (26)
74 (44)
73 (28)
74 (21)
THF
a Carbamate (R)-8 with 72-82% ee was employed as starting material.
Isolated yields are given in parentheses. b (S)-8 with 92% ee was the starting
material.
The high configurational stability may be due to the
branched carbanionic center, as we have found previously
by comparing lithiated S-n-alkyl thiocarbamates with lithiated
R-branched S-alkyl thiocarbamates (1).6 Hoffmann et al.
verified some marked steric effects on the enantiomerization
rate of some racemic R-thioaryl-substituted alkyllithium
compounds, wherein branching and bulky substituents at the
sulfur atom cause increased configurational stability.3b Hence,
Figure 1. Crystal structures of carbamates (S)-10 and (S)-11,
achieved from starting material (R)-8. O: red. N: blue. S: yellow.
(17) All compounds were characterized by 1H NMR, 13C NMR, IR, MS,
and elemental analysis.
(18) Representative Procedure (Table 1, entry 4): A solution of (S)-8
(100 mg, 0.50 mmol, 92% ee (determined by GC on a â-DEX 120 column
the R-product (S)-10 is formed in addition to (S)-11,
indicating that the methylation takes place with stereoinver-
sion or in an anti-SE′-process, respectively. Methylation
proceeds, corresponding to electrophilic substitution reactions
of lithiated configurationally unstable O-allyl N,N-diisopro-
pylcarbamates,20 with inversion of configuration.
In summary we have found the first configurationally
stable, highly enantioenriched R-thioallyllithium compound,
showing a marked solvent dependence of its racemization
rate. Both the R- and γ-methylation of the dianionic species
by methyl iodide take place with inversion of configuration.
The work was supported by the Deutsche Forschungsge-
meinschaft and the Fonds der Chemischen Industrie by a
grant for F.M.
[Supelco]), [R]20 ) -194 (c 1.01 in CHCl3), mp ) 92 °C (petroleum
D
ether)), and TMEDA (151 mg, 1.30 mmol, 2.59 equiv) in dry THF (5.0
mL) under Ar in a flask, sealed with a rubber septum, was cooled to -78
°C. s-BuLi (1.02 mL, 1.25 mmol, 2.50 equiv, 1.23 N) was added dropwise
over a period of 5 min through a precooled needle. The yellow reaction
mixture was stirred for additional 5 min, and MeI/THF (0.76 mL, 0.76
mmol, 1.5 equiv, 1.0 N) was added dropwise over a period of 3 min through
a precooled needle. The flask was sealed, and after an additional 12 h of
stirring, HOAc/Et2O (1.25 mL, 1.25 mmol, 2.50 equiv, 1.00 N) was added.
The reaction mixture was brought to approximately 0 °C, and a saturated
NaHCO3 solution (3 mL) and Et2O (10 mL) were added. The phases were
separated, and the aqueous phase was extracted with Et2O (2 × 5 mL).
The combined organic phases were washed with brine (3 mL), dried
(MgSO4), filtered, and concentrated in vacuo to afford a pale yellow oil
which was subjected to column chromatography (silica gel, EtOAc/
cyclohexane gradient). (R)-10 (22 mg) (89% ee (determined by GC on a
R-DEX 120 column [Supelco]), [R]20D ) +159 (c 0.615 in CHCl3), mp )
103 °C (cyclohexane)) and 47 mg of (R)-11 (68% ee (determined by HPLC
on a ZWE-805 column [Bayer], [R]20D ) +5.6 (c 0.970 in CHCl3), mp )
79 °C (cyclohexane)) were isolated as white crystals.
Supporting Information Available: Crystal data for
compounds 10 and 11 and detailed experimental procedures
with spectroscopic data for compounds 7, 8, 10, and 11. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(19) Crystals suitable for X-ray diffraction analyses were grown by vapor
diffusion of pentane into an etheral solution of 10 or 11.
(20) First example: (a) Hoppe, D.; Zschage, O. Angew. Chem., Int. Ed.
Engl. 1989, 28, 67. (b) Revised configuration: Zschage, O.; Hoppe, D.
Tetrahedron 1992, 48, 5657. (c) Paulsen, H.; Graeve, C.; Hoppe, D.
Synthesis 1996, 141. (d) Behrens, K.; Fro¨hlich, R.; Meyer, O.; Hoppe, D.
Eur. J. Org. Chem. 1998, 2397.
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