Catalytic asymmetric synthesis of allylic thiol derivatives

Article abstract of DOI:10.1021/ol8002942

(Chemical Equation Presented) The palladium(II) complex [(Rp, S)-COP-Cl]₂ and its enantiomer catalyze the rearrangement of linear prochiral O-allyl carbamothioates under mild conditions to provide branched S-allyl carbamothioates in high yield

Full text of DOI:10.1021/ol8002942

ORGANIC
LETTERS
2008
Vol. 10, No. 7
1485-1488
Catalytic Asymmetric Synthesis of
Allylic Thiol Derivatives
Larry E. Overman,* Scott W. Roberts, and Helen F. Sneddon§
Department of Chemistry, 1102 Natural Sciences II, UniVersity of California,
IrVine, California 92697-2025
leoVerma@uci.edu
Received February 8, 2008
ABSTRACT
The palladium(II) complex [(Rp,S)-COP-Cl]2 and its enantiomer catalyze the rearrangement of linear prochiral O-allyl carbamothioates under
mild conditions to provide branched S-allyl carbamothioates in high yield and high enantiomeric purity.
Catalytic methods for enantioselective construction of C-S
bonds are less well developed than those for forming C-C,
C-O, and C-N linkages. Among the most powerful
methods are enantioselective palladium(0)-catalyzed dis-
placements of allylic ester or carbonate precursors with
sulfinate, thiolate, and thiocarboxylate nucleophiles and
mechanistically related rearrangements of O-allyl sulfinates
and carbamothioates.1-3 However, these methods are only
useful for accessing products derived from symmetrically
substituted η3-allylpalladium precursors because of low
regioselection in the capture of unsymmetrical η3-allylpal-
ladium intermediates by sulfur nucleophiles.2c,3
pounds, promoted thermally4 or by metal-catalyzed cyclization-
induced rearrangement mechanisms,5,6 typically is not
complicated by issues of regioselection. However, to date,
catalytic enantioselective variants of such rearrangements
have not been reported. Herein, we disclose that the com-
mercially available palladium(II) complex [(Rp,S)-COP-Cl]2
(1)7 and its enantiomer catalyze the rearrangement of linear
prochiral O-allyl carbamothioates to provide branched S-allyl
carbamothioates in high yield and high enantiomeric purity,
products that are readily transformed to the parent allylic
thiols.3c,d
Because of the success of palladium(II) complexes of the
COP family for catalyzing enantioselective [3,3]-sigmatropic
The formation of allylic sulfur compounds by [3,3]-
sigmatropic rearrangements of allylic thiocarbonyl com-
(4) For a brief review, see: Kocovsky, P.; Stary, I. In Handbook of
Organopalladium Chemistry for Organic Synthesis; Negishi, E., de Meijere,
A., Eds.; Wiley: New York, 2002; Vol. II, pp 2014-2015.
(5) Overman, L. E. Angew. Chem., Int. Ed. 1984, 23, 579-586.
(6) Hg(II), Pd(II), Pt(II), Rh(I), and Ir(I) complexes have been employed.
See inter alia.: (a) Overman, L. E.; Campbell, C. B.; Knoll, F. M. J. Am.
Chem. Soc. 1978, 100, 4822-4834. (b) Tamaru, Y.; Kagotani, M.; Yoshida,
Z. J. Org. Chem. 1980, 45, 5221-5223. (c) Auburn, P. R.; Whelan, J.;
Bosnich, B. Organometallics 1986, 5, 1533-1537. (d) Auburn, P. R.;
Whelan, J.; Bosnich, B. Israel J. Chem. 1986, 27, 250-254.
§ Current address: GlaxoSmithKline Pharmaceuticals Medicines Research
Centre, Gunnels Wood Road, Stevenage, Herts, SG1 2NY, United Kingdom.
(1) Friesen, R. W. In Science of Synthesis; Thieme: Stuttgart, 2001;
version 3.4, Vol 1, pp 201-208.
(2) (a) Hiroi, K.; Makino, K. Chem. Lett. 1986, 617-620. (b) Hiroi, K.;
Makino, K. Chem. Pharm. Bull. 1988, 36, 1744-1749. (c) Eichelmann,
H.; Gais, H.-J. Tetrahedron: Asymmetry 1995, 6, 643-646. (d) Trost, B.
M.; Krische, M. J.; Radinov, R.; Zanoni, G. J. Am. Chem. Soc. 1996, 118,
6297-6298.
(3) For representative examples, see: (a) Trost, B. M.; Organ, M. G.;
O’Doherty, G. A. J. Am. Chem. Soc. 1995, 117, 9662-9670. (b) Valk, J.
M.; Claridge, T. D. W.; Brown, J. M. Tetrahedron: Asymmetry 1995, 6,
2597-2610. (c) Bo¨hme, A.; Gais, H.-J. Tetrahedron: Asymmetry 1999,
10, 2511-2514. (d) Gais, H.-J.; Bo¨hme, A. J. Org. Chem. 2002, 67, 1153-
1161. (e) Lu¨ssem, B. J.; Gais, H.-J. J. Org. Chem. 2004, 69, 4041-4052.
(7) (a) Stevens, A. M.; Richards, C. J. Organometallics 1999, 18, 1346-
1348. (b) Anderson, C. E.; Kirsch, S. F.; Overman, L. E.; Richards, C. J.;
Watson, M. P. Org. Synth. 2007, 84, 148-155. (c) Anderson, C. E.;
Overman, L. E.; Richards, C. J.; Watson, M. P; White, N. Org. Synth. 2007,
84, 139-147. (d) Both enantiomers of [COP-Cl]2 are available from Aldrich
Chemical Co. (products # 661791 and 646636).
10.1021/ol8002942 CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/13/2008

Table 1. Performance of Various Palladium(II) COP Catalysts
in the Enantioselective Rearrangement of O-2-Hexenyl
Methylxanthates 6 and 7
entry xanthatea
catalyst
convn. %b ee %c
1
2
3
4
5
6
7
8
9
6
6
6
6
6
7
7
7
7
7
[COP-Cl]2 (1)
COP-acac (4)
90
75
42
45
35
27
14
14
12
5
66
50
31
30
10
50
49
35
10
6
[COP-OPiv]2 (3)
[COP-OAc]2 (2)
[COP-NHCOCl3]2 (5)
[COP-Cl]2 (1)
[COP-OPiv]2 (3)
[COP-OAc]2 (2)
COP-acac (4)
10
[COP-NHCOCl3]2 (5)
Figure 1. COP palladium(II) catalysts.
a Substrate concentration ) 0.25 M. bAt 20 h, by GC analysis.
cDetermined by HPLC analysis using a chiral stationary phase.
rearrangements of prochiral allylic imidates to allylic amides,8
we examined the complexes depicted in Figure 1 as catalysts
for the rearrangement of (E)- and (Z)-O-2-hexenyl methyl-
xanthates 6 and 7 (Table 1).7,9 Chloride-bridged dimer
[(Rp,S)-COP-Cl]2 (1) proved to be the most effective catalyst.
With a catalyst loading of 1 mol %, S-methylcarbonodithioate
8 was formed in 66% ee and 90% conversion after 20 h at
40 °C from E precursor 6 (entry 1).10 As expected for a
cyclization-induced rearrangement,8d the Z stereoisomer
rearranged more slowly (entries 6-10).11 Again, COP
complex 1 was the best of the catalysts surveyed in terms
of both reaction rate and enantioselection (entry 6).
Table 2. [COP-Cl]2-Catalyzed Rearrangements of
(E)-O-2-Hexenyl Carbamothioates 10
product
catalyst
abs. conf. compd
yield
%
ee %c
b
entry
R2
Me2 (10a)
(abs. conf.)d
1
2
3
4
5
Sp,R
Sp,R
Sp,R
Rp,S
Rp,S
11a
11b
11c
11d 100
11e 71
72
78
98
82e (R)
59f (R)
83 (R)
57 (S)
76f (S)
To further optimize enantioselection, the nature of the
thiocarbonyl substituent was varied. A series of (E)-O-2-
hexenyl carbamothioates were prepared from (E)-2-hexenol
(9),12,13 and their rearrangement in the presence of 1 mol %
of [(Rp,S)-COP-Cl]2 at 40 °C in CH2Cl2 was examined (Table
2). Although no trend in reaction rate was apparent, enan-
tioselectivity was highest in the rearrangements of O-
Et2 (10b)
1-azetinyl (10c)
1-pyrrolidinyl (10d)
1-piperidinyl (10e)
a Substrate concentration ) 0.2-0.5 M. bYield of product after purifica-
c
tion by column chromatography. Determined by HPLC or SFC analysis
using a chiral stationary phase. dSee the Supporting Information for
determination of absolute configuration. eDetermined by GC analysis using
a chiral stationary phase. fThe corresponding S-benzothioates prepared from
11b and 11e were analyzed (see the Supporting Information).
(8) (a) Anderson, C. E.; Overman, L. E. J. Am. Chem. Soc. 2003, 125,
12412-12413. (b) Overman, L. E.; Owen, C. E.; Pavan, M. M.; Richards,
C. J. Org. Lett. 2003, 5, 1809-1812. (c) Kirsch, S. F.; Overman, L. E.;
Watson, M. P. J. Org. Chem. 2004, 69, 8101-8104. (d) Watson, M. P.;
Overman, L. E.; Bergman, R. G. J. Am. Chem. Soc. 2007, 129, 5031-
5044.
(9) The preparation and characterization of COP complexes 3 and 5 will
be described in a forthcoming publication.
(10) The half-life of the thermal background reaction is ∼60 h under
these conditions, which likely contributed somewhat to lowering enantio-
selection.
(11) The thermal background reaction for rearrangement of (Z)-O-2-
hexenyl methylxanthate 7 was negligible.
(12) O-Hexenyl carbamothioate 10a was prepared by reaction of alcohol
9 with commercially available dimethylthiocarbamoyl chloride, whereas
substrates 10b-e were prepared by reaction of (E)-O-2-hexenyl methyl
xanthate 6 with the corresponding secondary amine. Details can be found
in the Supporting Information.
carbamothioates containing the smallest nitrogen substitu-
ents: dimethylamino (10a) and 1-azetidinyl (10c) (entries 1
and 3). Subjection of 10a and 10c to the same reaction
conditions in the absence of catalyst resulted in recovery of
starting material, establishing that the thermal rearrangement
of these substrates was negligible under these conditions.14
(14) The (E)-O-2-hexenyl carbamothioate containing an NHPh substitu-
ent, prepared from the reaction of allylic alcohol 9 with phenyl isothiocy-
anate, rearranged in low enantioselectivity. The O-benzothioate derivative
of 9 rearranged with good enantioselectivity; however, its relative instability
led to low yields of the product, S-hex-1-en-3-yl benzothioate.
(13) Barrett, A. G. M.; Prokopiou, P. A.; Barton, D. H. R. J. Chem.
Soc., Perkin Trans. 1 1981, 1510-1515.
1486
Org. Lett., Vol. 10, No. 7, 2008

Having determined that O-allyl carbamothioates having
dimethylamino or 1-azetinyl substituents rearranged with
higher enantioselectivity, we turned our attention to develop-
ing an optimized general procedure for the [COP-Cl]2-
catalyzed rearrangement of O-allyl methyl- and 1-azetinyl-
carbamothioates. As expected, increasing the catalyst loading
from 1 to 5 mol % significantly reduced reaction times.
However, the higher catalyst loadings complicated the
purification of the transposed allyl S-carbamothioates,
with traces of COP complexes contaminating the product.
Simply adding ethylenediamine (0.5 equiv) to the crude
reaction solution at the conclusion of the reaction15 allowed
pure products to be isolated reproducibly in high
yields.16,17
in one step and high yields by the reaction of dimethyl-
thiocarbamoyl chloride with the appropriate allylic alcohol.18
Yields of the branched S-allyl carbamothioate products were
generally excellent (85-99%). Two exceptions were products
14e and 14f that contain hydroxyl and Boc-protected aniline
substituents, which were formed in lower yields (55-77%
yield) (entries 8-10). Products containing linear or branched
hydrocarbon substituents (entries 1-3), or homoallylic
TBDMS- and TIPS-protected alcohol substituents (entries
3-6), were obtained in high enantiomeric purities (80-88%
ee). Enantioselectivity was somewhat reduced in rearrange-
ments of substrates containing unprotected allylic alcohol
or a keto substituent at C5 (entries 8 and 11). Carrying out
the rearrangement reported in entry 1 with the [(Sp,R)-
COP-Cl]2 (ent-1) provided ent-11c in 83% ee and 98% yield.
Although the reaction time was longer (67 h), the rearrange-
ment of 10c (entry 1) with ent-1 could be readily carried
out at room temperature, giving ent-11c in 82% ee and 96%
yield. The catalyst loading could be reduced to 1 mol %,
although the reaction had to be run for a longer time. For
example, carrying out the rearrangement reported in entry 1
for 47 h at 40 °C at 1 mol % catalyst loading provided 11c
in 76% ee and 95% yield. Absolute configurations of 11a-e
were determined by chemical correlation with (R)-S-hex-1-
yn-3-yl benzothioate, which was prepared by Mitsonobu
reaction of (S)-hex-1-yn-3-ol with S-benzothiotic acid.18,19
The absolute configuration of other S-allyl carbamothioates
products was assigned by analogy.
Using this optimized procedure, the catalytic asymmetric
rearrangement of various O-allyl dimethyl- and 1-azetidi-
nylcarbamothioates was surveyed (Table 3). The starting
Table 3. Scope of the [(Rp,S)-COP-Cl]2-Catalyzed
Rearrangement of (E)-O-Allyl Carbamothioates
product
In summary, a new catalytic asymmetric method for
preparing allylic thiol derivatives has been developed. It is
the first catalytic asymmetric method that provides branched
allylic thiol derivatives in high regioselectivity from prochiral
linear allylic precursors. Attractive features of the method
include the ready synthesis of (E)-S-allyl carbamothioates
from allylic alcohol precursors, the high yields and good
enantioselection observed in their catalytic asymmetric
rearrangement with [COP-Cl]2, and the ability to transform
the branched allyl S-carbamothioate product to the corre-
sponding enantioenriched branched allylic thiol by reduction
with lithium aluminum hydride.3c,d,18
time,
hc
yield ee
d
e
entry
R1
R2
compd
%
%
1b
2b
3
4
5
6
7
8
9
n-Pr
n-Pr
1-azetinyl
Me2
15
18
42
20
18
42
42
13
44
43
11
ent-11c
ent-11a
14a
98
72
85
85
97
99
86
55
68
77
85
83
82
80
88
CH2CH(CH3)2 1-azetinyl
CH2OTBDMS 1-azetinyl
CH2OTBDMS Me2
CH2OTIPS
CH2OTBDPS 1-azetinyl
CH2OH 1-azetinyl
CH2NPh(Boc) 1-azetinyl
CH2NPh(Boc) Me2
(CH2)2COMe
14b
15a
14c
14d
14e
14f
15b
14g
87f,g
87f
76f
61
1-azetinyl
71
81
76
10
11
1-azetinyl
Acknowledgment. We thank the NSF (CHE-0200786)
and the National Heart, Lung, and Blood Institute (HL-
25854) for financial support and the Royal Commission for
the Exhibition of 1851 for postdoctoral fellowship support
of H.F.S. NMR and mass spectra were determined at UC
Irvine using instruments acquired with the assistance of NSF
a Substrate concentration ) 0.5 M. bSp,R enantiomer of [COP-Cl]2 was
used. cTime for disappearance of starting material by TLC analysis. dYield
e
of product after purification by column chromatography. Determined by
SFC analysis using a chiral stationary phase; results from duplicate
experiments agreed within (1%. fDetermined after conversion of the product
to alcohol 14e. gDetermined by GC analysis using a chiral stationary phase;
results from duplicate experiments agreed within (2%.
(17) Many literature reports address the removal of palladium residues
from reaction mixtures. See inter alia: (a) Larsen, R. D.; King, A. O.; Chen,
C. Y.; Corley, E. G.; Foster, B. S.; Roberts, F. E.; Yang, C.; Lieberman, D.
R.; Reamer, R. A.; Tschaen, D. M.; Verhoeven, T. R.; Reider, P. J.; Lo, Y.
S.; Rossano, L. T.; Brookes, A. S.; Meloni, D.; Moore, J. R.; Arnett, J. F.
J. Org. Chem. 1994, 59, 6391-6394. (b) Rosso, V. W.; Lust, D. A.; Bernot,
P. J.; Grosso, J. A.; Modi, S. P.; Rusowicz, A.; Sedergran, T. C.; Simpson,
J. H.; Srivastava, S. K.; Humora, M. J.; Anderson, N. G. Org. Process Res.
DeV. 1997, 1, 311-314. (c) Chen, C.; Dagneau, P.; Grabowski, E. J. J.;
Oballa, R.; O’Shea, P.; Prasit, P.; Robichaud, J.; Tillyer, R.; Wang, X. J.
Org. Chem. 2003, 68, 2633-2638.
1-azetidinecarbamothioates 10c and 12 were prepared in good
overall yields (54-97%) from (E)-allylic alcohol precursors
by reaction of O-methylxanthate intermediates with azetidine
hydrochloride and triethylamine at room temperature.18
O-Allyl dimethylcarbamothioates 10a and 13 were prepared
(15) Urawa, Y.; Miyazawa, M.; Ozeki, N.; Ogura, K. Org. Process Res.
DeV. 2003, 7, 191-195.
(16) Adding polymer-supported ethylenediamine, followed by filtration,
was initially attempted. However, the product still contained ∼5% of a
palladium impurity.
(18) See the Supporting Information for details.
(19) Corey, E. J.; Cimprich, K. A. Tetrahedron Lett. 1992, 33, 4099-
4102.
Org. Lett., Vol. 10, No. 7, 2008
1487

and NIH Shared Instrumentation Programs. We thank Nicole
White (UCI) and Professor Neil Garg (UCLA) for assistance
with SFC analysis.
traces used to establish the enantiopurity of (E)-S-allylic
carbamothioate products; and details of chemical correlations
to establish absolute configuration of products. This material
is available free of charge via the Internet at http://pubs.acs.org.
Supporting Information Available: Experimental pro-
cedures; characterization data for new compounds (1H, 13C,
and HMQC NMR spectra); copies of SFC, GC, and HPLC
OL8002942
1488
Org. Lett., Vol. 10, No. 7, 2008