Phosphine-catalyzed formation of carbon-sulfur bonds: Catalytic asymmetric synthesis of γ-thioesters

Article abstract of DOI:10.1021/ja101251d

A method for catalytic asymmetric γ sulfenylation of carbonyl compounds has been developed. In the presence of an appropriate catalyst, thiols not only add to the γ position of allenoates, overcoming their propensity to add to the - position in the absence of a catalyst, but do so with very good enantioselectivity. Sulfur nucleophiles are now added to the three families of nucleophiles (carbon, nitrogen, and oxygen) that had earlier been shown to participate in catalyzed γ additions. The phosphine catalyst of choice, TangPhos, had previously only been employed as a chiral ligand for transition metals, not as an efficient enantioselective nucleophilic catalyst.

Full text of DOI:10.1021/ja101251d

Published on Web 03/11/2010
Phosphine-Catalyzed Formation of Carbon-Sulfur Bonds: Catalytic
Asymmetric Synthesis of γ-Thioesters
Jianwei Sun and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received February 11, 2010; E-mail: gcf@mit.edu
Table 1. Effect of Reaction Parameters on the Catalytic
Asymmetric γ Addition of Thiols to Allenoatesa
Chiral sulfur-containing compounds have important applications
in many areas of chemistry and biology, serving, for example, as
antibiotics, as ligands for metal-based catalysts, as catalysts
themselves, and as chiral auxiliaries.1 With respect to the catalytic
enantioselective synthesis of sulfur-containing molecules, the
conjugate addition of thiols to the ꢀ position of R,ꢀ-unsaturated
carbonyl compounds has been the focus of intense interest.2
Furthermore, there has been recent progress in catalytic asymmetric
sulfenylation R to a carbonyl group.3 In contrast, we are not aware
of any methods for catalytic enantioselective sulfenylation of the
γ position of carbonyl compounds.4
Trost and others have established that phosphines can catalyze
certain γ additions of carbon, nitrogen, and oxygen nucleophiles
to 2,3-allenoates and/or 2-alkynoates;5-8 on the other hand, the
corresponding γ additions of sulfur nucleophiles have not been
achieved. In this report, we describe a method that not only
accomplishes γ functionalizations with this new family of nucleo-
philes but also provides highly enantioenriched products (eq 1).9-12
entry
change from the “standard conditions”
yield (%)b
ee (%)
c
1
2
3
4
5
6
7
no (+)-1, no 2
-
92
-
0
none
89
<5
<5
<5
81
80
no 2
PhOH instead of 2
(S)-3 instead of (+)-1
(S)-4 instead of (+)-1
1.1 instead of 3 equiv of thiol
-
-
80
92
b
a All data are averages of two experiments. Determined by H NMR
analysis with dibromomethane as an internal standard. c Addition occurred
predominantly at the ꢀ position.
1
Table 2. Catalytic Asymmetric γ Addition of Thiols to Allenoates:
Scope with Respect to the Allenoatea
In the case of the carbon, nitrogen, and oxygen nucleophiles that
have previously been employed in phosphine-catalyzed γ additions,
there is generally no reaction between the nucleophile and an
allenoate at room temperature in the absence of a catalyst. In
contrast, thiols do react with allenoates, but not to afford the
γ-addition product (Table 1, entry 1); instead, the uncatalyzed
process leads to addition of the thiol at the ꢀ position.
Nevertheless, through the use of an appropriate catalyst, the
regioselectivity of the addition process can be altered to generate the
desired γ-addition product not only in good yield but also with very
good enantioselectivity. In particular, chiral bisphosphine TangPhos
(1), originally developed by Zhang as a ligand for Rh-catalyzed
asymmetric hydrogenations of olefins,13 along with a carboxylic acid
additive,14 serves as a useful catalyst system, furnishing the γ-sulfe-
nylated product in 89% yield and 92% ee (Table 1, entry 2). To the
best of our knowledge, this is the first application of 1 as an effective
chiral nucleophilic catalyst.15,16
In the absence of carboxylic acid 2, or when 2 is replaced by
phenol,5d very little γ-addition product is observed (Table 1, entries 3
and 4). Other chiral phosphines (e.g., see entries 55d and 67d) give
lower yields and/or ee. Use of 1.1 equiv of thiol leads to a small loss
in yield and no change in enantioselectivity (entry 7).
a All data are averages of two experiments. b Yield of purified product.
bond formation occurs with high ee in the presence of a variety of
functional groups, including alkenes, alkynes, ethers, acetals, esters,
and halides.
This phosphine-catalyzed asymmetric γ addition of thiols proceeds
This method for the catalytic asymmetric synthesis of sulfides
is versatile with respect to the thiol as well as the allenoate (Table
in good yield for an array of allenoates (Table 2).17 Thus, carbon-sulfur
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4568 J. AM. CHEM. SOC. 2010, 132, 4568–4569
10.1021/ja101251d  2010 American Chemical Society

C O M M U N I C A T I O N S
3). A variety of substituted benzyl thiols, including hindered
substrates, add to the γ position in good yield and ee (entries 1-5).
Furthermore, heterocycles are compatible with the reaction condi-
tions (entries 6 and 7). TangPhos also efficiently catalyzes the
asymmetric γ addition of thiols that are not benzylic (entries 8-11);
for the substrate illustrated in entry 11, exclusive γ addition by
sulfur (none by oxygen7) is observed.
(carbon, nitrogen, and oxygen) that had earlier been shown to
participate in catalyzed γ additions. The phosphine catalyst of choice,
TangPhos, had previously only been employed as a chiral ligand for
transition metals, not as an efficient enantioselective nucleophilic
catalyst. The development of additional phosphine-catalyzed asym-
metric reactions is underway.
Acknowledgment. Support was provided by the National
Institutes of Health (National Institute of General Medical Sciences,
Grant R01-GM57034), Merck, and Novartis. We thank Dr. Ying
Kit Chung for preliminary studies.
Table 3. Catalytic Asymmetric γ Addition of Thiols to Allenoates:
Scope with Respect to the Thiola
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) For some leading references, see: (a) Sulphur-Containing Drugs and Related
Organic Compounds; Damani, L. A., Ed.; Wiley: New York, 1989. (b)
Organosulfur Chemistry in Asymmetric Synthesis; Toru, T., Bolm, C., Eds.;
Wiley-VCH: Weinheim, Germany, 2008. (c) Chiral Sulfur Ligands:
Asymmetric Catalysis; Pellissier, H., Ed.; Royal Society of Chemistry:
Cambridge, U.K., 2009.
(2) For a recent review, see: (a) Enders, D.; Lu¨ttgen, K.; Narine, A. A. Synthesis
2007, 959. For a recent example, see: (b) Liu, Y.; Sun, B.; Wang, B.;
Wakem, M.; Deng, L. J. Am. Chem. Soc. 2009, 131, 418.
(3) For a pioneering study, see: Marigo, M.; Wabnitz, T. C.; Fielenbach, D.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 794.
(4) For a catalytic asymmetric method for the addition of nitrogen at the γ
position of aldehydes, see: Bertelsen, S.; Marigo, M.; Brandes, S.; Diner,
P.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 12973.
(5) For some examples of the use of carbon nucleophiles, see: (a) Trost, B. M.;
Li, C.-J. J. Am. Chem. Soc. 1994, 116, 3167. (b) Zhang, C.; Lu, X. Synlett
1995, 645. (c) Chen, Z.; Zhu, G.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X.
J. Org. Chem. 1998, 63, 5631. (d) Smith, S. W.; Fu, G. C. J. Am. Chem.
Soc. 2009, 131, 14231.
(6) For some examples of the use of nitrogen nucleophiles, see: (a) Trost, B. M.;
Dake, G. R. J. Org. Chem. 1997, 62, 5670. (b) Liu, B.; Davis, R.; Joshi,
B.; Reynolds, D. W. J. Org. Chem. 2002, 67, 4595. (c) Lu, C.; Lu, X.
Org. Lett. 2002, 4, 4677.
(7) For some examples of the use of oxygen nucleophiles, see: (a) Trost, B. M.;
Li, C.-J. J. Am. Chem. Soc. 1994, 116, 10819. (b) Reference 5b. (c) Alvarez-
Ibarra, C.; Csaky, A. G.; de la Oliva, C. G. Tetrahedron Lett. 1999, 40,
8465. (d) Chung, Y. K.; Fu, G. C. Angew. Chem., Int. Ed. 2009, 48, 2225.
(8) For a review of catalytic enantioselective reactions of allenoates, see:
Cowen, B. J.; Miller, S. J. Chem. Soc. ReV. 2009, 38, 3102.
(9) For previous studies of catalytic enantioselective γ additions to allenoates/
alkynoates wherein a γ stereocenter is produced, see refs 5d and 7d.
(10) For an investigation of catalytic enantioselective γ additions to allenoates/alkynoates
with control of the stereochemistry of the δ carbon, see ref 5c.
(11) For a discussion of the difficulty in synthesizing this family of products,
their utility, and an alternative route for their synthesis from triazolyated
thiols, see: Armstrong, A.; Challinor, L.; Moir, J. H. Angew. Chem., Int.
Ed. 2007, 46, 5369.
a All data are averages of two experiments. b Yield of purified product.
(12) Allenoates are readily formed by treating acid chlorides with Wittig reagents.
(13) Tang, W.; Zhang, X. Angew. Chem., Int. Ed. 2002, 41, 1612.
(14) The potential benefit of additives such as carboxylic acids is described in
the initial report by Trost.5a
(15) For reviews and leading references on nucleophilic catalysis by phosphines,
see: (a) Methot, J. L.; Roush, W. R. AdV. Synth. Catal. 2004, 346, 1035.
(b) Ye, L.-W.; Zhou, J.; Tang, Y. Chem. Soc. ReV. 2008, 37, 1140. (c) Lu,
X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535.
(16) For a review of enantioselective catalysis by chiral phosphines, see:
Marinetti, A.; Voituriez, A. Synlett 2010, 174.
The enantioenriched sulfides produced via phosphine-catalyzed
γ additions to allenoates can be transformed into other useful
compounds. For example, the sulfide can be converted into a thiol
(eq 2), or highly stereoselective functionalizations of the olefin can
be achieved (eq 3).
(17) Notes: (a) In all cases, the Z isomer of the product was not detected. (b) On a
gram scale, the reaction illustrated in entry 3 of Table 2 proceeded in 87% yield
(purified product) and 91% ee. (c) At partial conversion, no kinetic resolution of
the allenoate was observed. (d) By 31P NMR spectroscopy, we determined that
TangPhos is not protonated by acid 2 in toluene at room temperature. 31P NMR
spectroscopy at -40 °C indicated that when TangPhos (10%), acid 2 (50%), and
an allenoate are mixed, two compounds may be predominant [neither is TangPhos
itself; compound 1: δ 79 (d), 57 (d); compound 2: δ 64 (s)]; upon addition of a
thiol, both appear to be transformed into the γ-addition product, with liberation of
TangPhos. Under the standard reaction conditions, the same resonances were
observed by 31P NMR spectroscopy during the reaction (upon cooling to -40 °C;
there was no resonance due to TangPhos), and TangPhos reappeared when the
reaction was complete. (e) TangPhos is susceptible to oxidation: after exposure to
air for 3 days at room temperature, quantitative conversion to the bis(phosphine
oxide) was observed by 31P NMR spectroscopy. The bis(phosphine oxide) is not
an effective catalyst for γ additions of thiols to allenoates. (f) In an initial
investigation, γ additions of ArSH proceeded in low yields under our standard
conditions. (g) Preliminary studies with truncated (monophosphine) relatives of
TangPhos furnished little of the γ-addition product.
In summary, the first method for catalytic asymmetric γ sulfeny-
lation of carbonyl compounds has been developed. Thus, in the
presence of an appropriate catalyst, thiols not only add to the γ position
of allenoates, overcoming their propensity to add to the ꢀ position in
the absence of a catalyst, but do so with very good enantioselectivity.
Sulfur nucleophiles are now added to the three families of nucleophiles
JA101251D
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