Organocatalytic asymmetric addition of alcohols and thiols to activated electrophiles: Efficient dynamic kinetic resolution and desymmetrization protocols

Article abstract of DOI:10.1021/jo801158g

(Chemical Equation Presented) Bifunctional urea-based cinchona alkaloid derivatives have been shown to promote highly efficient DKR reactions of azalactones using an alcohol nucleophile. The optimum catalyst is remarkably insensitive to the steric bulk of the amino acid residue, allowing alanine-, methionine-, and phenylalanine-derived azalactones to undergo DKR with unprecedented levels of enantioselectivity using a synthetic catalyst. The first DKR of these substrates by thiols and the highly enantioselective desymmetrization of a meso-glutaric anhydride by thiolysis are also reported.

Full text of DOI:10.1021/jo801158g

Organocatalytic Asymmetric Addition of Alcohols
and Thiols to Activated Electrophiles: Efficient
Dynamic Kinetic Resolution and
Desymmetrization Protocols
Aldo Peschiulli, Cormac Quigley, Sea´n Tallon,
Yuri K. Gun’ko, and Stephen J. Connon*
Centre for Synthesis and Chemical Biology, School of
Chemistry, UniVersity of Dublin,
Trinity College, Dublin 2, Ireland
connons@tcd.ie
ReceiVed May 28, 2008
FIGURE 1. Catalytic DKR of azalactones by alcoholysis.
dipeptides,5 and chiral 4-N,N-dialkylaminopyridine nucleophilic
catalysts.6 While some of these methodologies allowed the
synthesis of the ring-opened adducts with high levels of product
enantiomeric excess (>80% ee), in general, their applicability
is mitigated by narrow substrate scope and/or low activity
leading to long reaction times.
Recently, Berkessel7 has exploited the hydrogen-bonding
ability of (thio)urea derivatives8 in the use of a suite of
bifunctional catalystssof which Takemoto’s catalyst 19 and an
improved second-generation promoter 2 (Figure 1) are represen-
tativeswhich promote the enantioselective addition of allyl
alcohol to azalactones. It was proposed that the catalysts operate
via the simultaneous activation of the reaction’s electrophilic
and nucleophilic components by hydrogen bonding and general
base catalysis, respectively. Excellent levels of enantioselectivity
(>90% ee) were obtained using hindered valine and (in
particular) tert-leucine-derived azalactones at the expense of
Bifunctional urea-based cinchona alkaloid derivatives have
been shown to promote highly efficient DKR reactions of
azalactones using an alcohol nucleophile. The optimum
catalyst is remarkably insensitive to the steric bulk of the
amino acid residue, allowing alanine-, methionine-, and
phenylalanine-derived azalactones to undergo DKR with
unprecedented levels of enantioselectivity using a synthetic
catalyst. The first DKR of these substrates by thiols and the
highly enantioselective desymmetrization of a meso-glutaric
anhydride by thiolysis are also reported.
(3) For examples of the use of enzymes (which are generally only selective
at temperatures of 37 °C or above, depending on the particular enzyme) to
asymmetrically ring-open azalactones with high levels of enantioselectivity, see:
(a) S. A. Brown, S. A.; Parker, M.-C.; Turner, N. J. Tetrahedron: Asymmetry
2000, 11, 1687. (b) Crich, J. Z.; Brieva, R.; Marquant, P.; Gu, R. L.; Flemming,
S.; Sih, C. J. J. Org. Chem. 1993, 58, 3252. (c) Gu, R. L.; Lee, I.-S.; Sih, C. J.
Tetrahedron Lett. 1992, 33, 1953.
The catalytic dynamic kinetic resolution (DKR)1 of R-sub-
stituted azalactones by alcoholysis is a potentially useful route
to the facile, enantioselective synthesis of orthogonally protected
R-amino acid derivatives. While principally a kinetic resolution
process in which one enantiomer of the racemic starting material
reacts perferentially with an alcohol nucleophile in the presence
of a chiral catalyst, the acidity of the R-hydrogen of the
azalactone (pKa ) ca. 9, H2O, 25 °C)2 allows a maximum
theoretical yield of almost 100% through the continuous
regeneration of the fast-reacting antipode if the catalyst is of
sufficient basicity to ensure that the racemization rate is
considerably greater than that of the alcoholysis of the slow
reacting enantiomer (i.e. kfast . kslow and krac . kslow, Figure
1). Several strategies involving de novo designed catalysts3 have
been employed to bring about the selective DKR of azalactone
substrates including the use of Ti-based complexes,4 cyclic
(4) (a) Seebach, D.; Jaeschke, G.; Gottwald, K.; Mastsuda, K.; Formisano,
R.; Chaplin, D. A. Tetrahedron 1997, 53, 7539. (b) Gottwald, K.; Seebach, D.
Tetrahedron 1999, 55, 723.
(5) Xie, L.; Hua, W.; Chan, A. S. C.; Leung, Y.-C. Tetrahedron: Asymmetry
1999, 10, 4715.
(6) Liang, J.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1998, 63, 3154.
(7) (a) Berkessel, A.; Cleeman, F.; Mukherjee, S.; Mu¨ller, T. N.; Lex, J.
Angew. Chem. 2005, 44, 807. (b) Berkessel, A.; Mukherjee, S.; Cleemann, F.;
Mu¨ller, T. N.; Lex, J. Chem. Commun. 2005, 1898. (c) Berkessel, A.; Mukherjee,
S.; Mu¨ller, T. N.; Cleeman, F.; Roland, K.; Brandenburg, M.; Neudo¨rfl, J.-M.;
Lex, J. Org. Biomol. Chem. 2006, 4, 4319.
(8) For selected recent reviews on the use of hydrogen bonding in catalysis,
see: (a) Doyle, A. G.; Jacobsen, E. N. Chem. ReV. 2007, 107, 5713. (b) Akiyama,
T.; Itoh, J.; Fuchibe, K. AdV. Synth. Catal. 2006, 348, 999. (c) Taylor, M. S.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520. (d) Connon, S. J. Chem.
Eur. J. 2006, 12, 5418. (e) Connon, S. J. Angew. Chem., Int. Ed. 2006, 45,
3909. (f) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299. (g) Pihko, P. M.
Angew. Chem., Int. Ed. 2004, 43, 2062. (h) Schreiner, P. R. Chem. Soc. ReV.
2003, 32, 289.
(1) (a) Faber, K. Chem. Eur. J. 2001, 7, 5004. (b) Pellissier, H. Tetrahedron
2003, 59, 8291.
(9) (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125,
12672.
(2) De Jersey, J.; Zerner, B. Biochemistry 1969, 8, 1967.
10.1021/jo801158g CCC: $40.75
Published on Web 07/23/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6409–6412 6409

TABLE 1. Initial Catalyst Screening
entry lactone cat.
x
solvent conca (M) convb (%) eec (%)
FIGURE 2. Bifunctional alkaloid-derived catalysts.
1
2
3
4
6a
6a
6b
6c
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
none
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
4a
4a
4b
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0.4
0.4
0.4
0.4
1.0
0.2
0.2
0.2
0.4
0.2
0.1
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0
n.d.
82
81
78
62
83
84
83
82
84
85
83
n.d.
n.d.
77
87
67
85
84
77
n.d.
5
92
79
92
>98
75
62
83
95
89
78
26
2
31
71
52
100
99
94
100
47
5
5
5
5
5
5
product yield, whereas electrophiles with a lower steric require-
ment underwent smooth ring-opening with reduced10 (yet still
on a par with previous benchmarks4–6) enantiopurity.
5
6
7d
8e
9
While remarkable progress toward the development of a
general catalytic asymmetric system for these potentially useful
transformations has been made, some challenges remainsin
particular, the need to address the sensitivity of the methodology
to substrate steric bulk and the expansion of the reaction scope
to include nonalcoholic nucleophiles. We therefore became
interested in the evaluation of the cinchona alkaloid-derived
urea- and thiourea-based catalysts (Figure 2) in this reaction.
These bifunctional materials promote a variety of asymmetric
addition reactions of acidic pronucleophiles to hydrogen-bond
accepting electrophiles,11,12 and in particular, we were encour-
aged by recently finding that they are capable of mediating
highly efficient and enantioselective additions of alcohols to
meso-anhydrides.13
Our investigation began with the DKR of valine-derived
azalactones 6a-c with allyl alcohol in the presence of the urea-
based catalyst 3a at ambient temperature (Table 1).14 These
initial experiments revealed that 3a is an active catalyst capable
of promoting both racemization and enantioselective (>80%
ee) ring opening of these substrates (no reaction was observed
in the absence of the catalyst) at loadings of 5 mol %. As
expected, the more activated azalactone 6c underwent faster and
10 CH2Cl2
10 CH2Cl2
10 CH2Cl2
10
11
12
13
14
15
16f
17g
18h
19i
20g
21j
5
5
5
5
MTBE
THF
Et2O
PhMe
10 CH2Cl2
5
5
CH2Cl2
CH2Cl2
10 CH2Cl2
5
5
CH2Cl2
CH2Cl2
a Refers to the concentration of the azalactone. b Conversion: deter-
mined by 1H NMR spectroscopy. c Enantioselectivity (% ee, determined
by CSP-HPLC; see the Supporting Information). d 1.0 equiv of 8. e 2.0
equiv of 8. f 2.0 equiv of 7, at -20 °C, conversion after 72 h. g 2.0
equiv of 8, conversion after 65 h. h 2.0 equiv of 8, conversion after
34 h. i 2.0 equiv of 8, at -20 °C, conversion after 72 h. j 2.0 equiv of 8,
conversion after 24 h.
slightly less selective DKR than either 6a or 6b (entries 1-4).
The influence of concentration and nucleophile loading was next
examinedseither 1.5 or 2.0 equiv of allyl alcohol at 0.2 M
reaction concentration provided a convenient balance between
rate and enantioselectivity (entries 5-11). Dichloromethane was
determined to be superior to either ethereal solvents or toluene
(entries 6 and 12-15), while carrying out the reaction at -20
°C resulted in a small improvement in enantioselectivity (87%
ee), albeit with reduced conversion even after extended reaction
time (entry 16). Interestingly, urea derivative 3a is a better
catalyst under these conditions than its thiourea analogue 3b,15
while the corresponding dihydroquinine-derived (thio)urea
derivatives 4a,b possesses similar selectivity but better activity
profiles than their quinine-derived counterparts 3a,b (entries
17-20). Thus, 4a (at 5 mol % levels) emerged from these initial
optimization studies as a readily prepared, active catalyst capable
of the highly enantioselective (85% ee), almost quantitative
conversion of the hindered substrate 6a to 7a at ambient
temperature.
Having established 4a as the optimum catalyst, we next turned
to the determination of the substrate scope (Table 2). We were
pleased to find 4a to be relatively insensitive to the steric bulk
of the azalactone alkyl substituent: both unhindered azalactones
(entries 1-4) and more bulky analogues (entries 5-7) under-
went enantioselective DKR to furnish orthogonally protected
amino acids with very good enantioselectivity. To the best of
our knowledge, this represents the most selective DKR of
azalactones 8-10 by alcoholysis with a synthetic catalyst to
date.
(10) For example, the levels of enantiomeric excess obtained with alanine
and phenylalanine-derived substrates using catalyst 2 and allyl alcohol was 80
and 78% ee, respectively7b).
(11) For a review of the applications of this class of catalyst, see: Connon,
S. J. Chem. Commun. 2008, 2499.
(12) (a) Li, B.-J.; Jang, L.; Liu, M.; Chen, Y.-C.; Ding, L.-S.; Wu, Y. Synlett
2005, 603. (b) Vakulya, B.; Varga, S.; Csa´mpai, A.; Soo´s, T. Org. Lett. 2005,
7, 1967. (c) McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed. 2005, 44,
6367. (d) Ye, J.; Dixon, D. J.; Hynes, P. S. Chem. Commun. 2005, 4481. (e)
Tillman, A. L.; Ye, J.; Dixon, D. J. Chem. Commun. 2006, 1191. (f) McCooey,
S. H.; McCabe, T.; Connon, S. J. J. Org. Chem. 2006, 71, 7494. (g) Mattson,
A. E.; Zuhl, A. M.; Reynolds, T. E.; Scheidt, K. A. J. Am. Chem. Soc. 2006,
128, 4932. (h) Wang, J.; Li, H.; Zu, L.; Jiang, W.; Xie, H.; Duan, W.; Wang,
W. J. Am. Chem. Soc. 2006, 128, 12652. (i) Song, J.; Wang, Y.; Deng, L. J. Am.
Chem. Soc. 2006, 128, 6048. (j) Wang, Y.-Q.; Song, J.; Hong, R.; Li, H.; Deng,
L. J. Am. Chem. Soc. 2006, 128, 8156. (k) Bode, C. M.; Ting, A.; Schaus, S. E.
Tetrahedron 2006, 62, 11499. (l) Hamza, A.; Schubert, G.; Soo´s, T.; Pa´pai, I.
J. Am. Chem. Soc. 2006, 128, 13151. (m) Liu, T.-Y.; Li, R.; Chai, Q.; Long, J.;
Li, B.-J.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. Chem. Eur. J. 2007, 13, 319. (n)
Amere, M.; Lasne, M.-C.; Rouden, J. Org. Lett. 2007, 9, 2621. (o) Hynes, P. S.;
Stranges, D.; Stupple, P. A.; Guarna, A.; Dixon, D. A. Org. Lett. 2007, 9, 2107.
(p) Liu, T.-Y.; Cui, H.-Lei.; Chai, Q.; Long, J.; Li, B.-J.; Wu, Y.; Ding, L.-S.;
Chen, Y.-C. Chem. Commun. 2007, 2228. (q) Biddle, M. M.; Lin, M.; Scheidt,
K. A. J. Am. Chem. Soc. 2007, 129, 3830. (r) Gu, C.-L.; Liu, L.; Sui, Y.; Zhao,
J.-L.; Wang, D.; Chen, Y. J. Tetrahedron: Asymmetry 2007, 18, 455. (s) Song,
J.; Shih, H.-W.; Deng, L. Org. Lett. 2007, 9, 603. (t) Wang, B.; Wu, F.; Wang,
Y.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2007, 129, 768. (u) Zu, L.; Wang, J.;
Li, H.; Xie, H.; Jiang, W.; Wang, W. J. Am. Chem. Soc. 2007, 129, 1036. (v)
Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.; Mazzanti, A.; Sambri, L.;
Melchiorre, P. Chem. Commun. 2007, 722.
(13) Peschiulli, A.; Gun’ko, Y.; Connon, S. J. J. Org. Chem. 2008, 73, 2454.
(14) Allyl alcohol proved the optimum alcohol nucleophile; for example,
use of the more acidic 2,2,2-trichloroethanol under conditions otherwise identical
to those in Table 1, entry 6, furnished the product with 85% conversion and
33% ee after 24 h. Phenol was a similarly unsuitable nucleophile.
6410 J. Org. Chem. Vol. 73, No. 16, 2008

TABLE 2. Investigation of Substrate Scope
TABLE 3. Catalytic DKR Using Thiol Nucleophiles
a Isolated yield. b Enantioselectivity (% ee, determined by CSP-HPLC).
c Refers to conversion. d At -30 °C with 10 mol % of 4a.
SCHEME 2. Desymmetrization of a meso-Anhydride by
Thiolysis
Gratifyingly, preliminary experiments revealed that while the
unhindered benzyl mercaptan provided the thioester product with
low enantioselectivity, use of the more hindered cyclohexyl
thiol18 resulted in more selective desymmetrization (Table 3,
entries 1-4). Under optimum conditions using catalyst 4a, the
challenging unhindered racemic azalactone substrate 8 could
be converted to thioesters 16 and 17 with moderate/good levels
of enantiomeric excess (entry 5).
a Isolated yield. b Enantioselectivity (% ee, determined by CSP-HPLC;
see the Supporting Information). c Reaction at rt with 5 mol % catalyst.
SCHEME 1. One-Pot DKR from a N-Benzoylamino Acid
Finally, the compatibility of thiols with catalyst 4a led us to
postulate that these cinchona alkaloid derivatives could promote
the efficient desymmetrization of meso-anhydrides by thiolysis.19
Treatment of meso-glutaric anhydride 18 with cyclohexyl thiol
in the presence of thiourea 3b (1 mol%) afforded the syntheti-
cally useful hemithioester 19 in excellent yield and >90% ee
(Scheme 2).20 This represents the most selective organocatalytic
thiolysis of this electrophile to date.
The robust nature of catalyst 4a also allowed us to develop
a convenient, organocatalyzed one-pot DKR protocol starting
from N-protected racemic alanine which gives the corresponding
enantioenriched allyl ester in excellent isolated yield and
enantioselectivity (Scheme 1).
In summary, readily synthesized bifunctional cinchona alka-
loid derived catalysts promote the highly efficient DKR of
azalactones with allyl alcohol. Urea derivatives are superior to
their thiourea analogues in these reactions, and most usefully,
the catalysts are insensitive to the steric bulk of the amino acid
residue, allowing alanine-, methionine-, and phenylalanine-
derived azalactones to undergo DKR with unprecedented levels
of enantioselectivity using a synthetic catalyst. The compatibility
of these catalysts with thiol nucleophiles was exploited in the
first enantioselective catalytic DKR of azalactones by thiolysis
to furnish enantioenriched amino acid thioesters of potential use
The broad applicability of catalyst 4a in these reactions
prompted us to investigate the use of thiol nucleophiles in these
processes for the first time. Such a DKR process would be
particularly attractive synthetically as it could allow the direct
synthesis of enantioenriched unnatural amino acid thioesters for
use in native chemical ligation (NCL),16 a powerful coupling
tool in contemporary chemical biology.17
(15) This superiority of urea over thiourea derivatives is unusual but not
unprecedented; for other examples, see: (a) Vachal, P.; Jacobsen, E. N. Org.
Lett. 2000, 2, 867. (b) Curran, D. P.; Kuo, L. H. J. Org. Chem. 1994, 59, 3259.
(c) Maher, D. J.; Connon, S. J. Tetrahedron Lett. 2004, 45, 1301. (d) Kavanagh,
S. A.; Piccinini, A.; Fleming, E. M.; Connon, S. J. Org. Biomol. Chem. 2008, 6,
1339. (e) Fleming, E. M.; Quigley, C.; Rozas, I.; Connon, S. J. J. Org. Chem.
2008, 73, 948.
(18) Use of tert-butyl thiol did not result in further improvements.
(19) Only one such protocol has been reported: Honjo, T.; Sano, S.; Shiro,
M.; Nagao, Y. Angew. Chem., Int. Ed. 2005, 44, 5838.
(20) Early experiments indicate that succinic anhydrides are inferior substrates
in these reactions.
(16) Dawson, P. E.; Muir, T. W.; Clark-Lewis, I.; Kent, S. B. Science 1994,
266, 776.
(17) Macmillan, D. Angew. Chem., Int. Ed. 2006, 45, 7668.
J. Org. Chem. Vol. 73, No. 16, 2008 6411

as a solution in CH2Cl2 (0.5 mL), and the resulting mixture was
cooled to -20 °C. Allyl alcohol (41 µL, 0.6 mmol) was then added
in a dropwise manner via syringe, and the reaction was stirred at
-20 °C for 24 h. After filtration of the white dicyclohexylurea
precipitate, the product was purified by flash chromatography and
obtained as a white solid (66.0 mg, 94%, 88% ee). For characteriza-
tion data, see the Supporting Information.
in NCL processes. Further experimentation revealed that this
catalysis mode could be extended to the ambient-temperature
efficient desymmetrization of a meso-glutaric anhydride by
thiolysis with excellent enantioselectivity using a little as 2 mol
% of catalyst. Experiments to further develop the wide scope
of these catalysts in DKR and desymmetrization reactions are
underway.
Acknowledgment. We thank Science Foundation Ireland and
The School of Chemistry, TCD, for generous financial support.
Experimental Section
One-Pot DKR from N-Benzoylalanine. A 5 mL reaction vial
containing a stirring bar was charged with N-benzoylalanine (58.0
mg, 0.3 mmol), flushed with argon, and fitted with a septum. CH2Cl2
(0.5 mL) was added followed by a solution of DCC (65.0 mg, 0.315
mmol) in CH2Cl2 (0.5 mL) via syringe, and the mixture was stirred
at room temperature for 2 h. 4a (17.4 mg, 0.03 mmol) was added
Supporting Information Available: General experimental
procedures, 1H and 13C NMR spectra, characterization data, and
HPLC assays. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO801158G
6412 J. Org. Chem. Vol. 73, No. 16, 2008