Synergistic organocatalysis in the kinetic resolution of secondary thiols with concomitant desymmetrization of an anhydride

Article abstract of DOI:10.1038/nchem.584

Kinetic resolution is an important method for the separation of racemates into their component enantiomers. Thiols are precursors to a variety of organosulfur compounds, with high utility in both chemistry and chemical biology, yet there is a surprising dearth of methodologies for their direct and efficient catalytic kinetic resolution. Here, we demonstrate an organocatalytic process involving the highly enantioselective desymmetrization of an achiral electrophile with the simultaneous kinetic resolution of a racemic thiol. The preparative potential of the methodology is exemplified by the synthesis of a drug precursor antipode in excellent yield and enantioselectivity as a by-product of a process that also resolves a sec-thiol substrate with a selectivity of S = 226 (that is, both thiol antipodes produced in 95% ee at 51% conversion). In a second example a racemic sec-thiol representing the stereocentre-containing core of the anti-asthma drug (R)-Montelukast was resolved with synthetically useful selectivity under mild conditions.

Full text of DOI:10.1038/nchem.584

ARTICLES
PUBLISHED ONLINE: 14 MARCH 2010 | DOI: 10.1038/NCHEM.584
Synergistic organocatalysis in the kinetic
resolution of secondary thiols with concomitant
desymmetrization of an anhydride
Aldo Peschiulli, Barbara Procuranti, Cornelius J. O’ Connor and Stephen J. Connon
*
Kinetic resolution is an important method for the separation of racemates into their component enantiomers. Thiols are
precursors to a variety of organosulfur compounds, with high utility in both chemistry and chemical biology, yet there is a
surprising dearth of methodologies for their direct and efficient catalytic kinetic resolution. Here, we demonstrate an
organocatalytic process involving the highly enantioselective desymmetrization of an achiral electrophile with the
simultaneous kinetic resolution of a racemic thiol. The preparative potential of the methodology is exemplified by the
synthesis of a drug precursor antipode in excellent yield and enantioselectivity as a by-product of a process that also
resolves a sec-thiol substrate with a selectivity of S 5 226 (that is, both thiol antipodes produced in >95% ee at 51%
conversion). In a second example a racemic sec-thiol representing the stereocentre-containing core of the anti-asthma drug
(R)-Montelukast was resolved with synthetically useful selectivity under mild conditions.
ne of the most convenient methods for the rapid isolation of afforded (S)-1 in a substantially diminished enantiomeric excess
enantiopure secondary alcohols is the kinetic resolution of 84.5%, despite considerable care taken to avoid a competing
O
(KR) of the corresponding racemic materials through enan- SN1 substitution pathway. Although it was clear at the outset that
tioselective acylation1,2. Initially this was carried out using biological there were particular difficulties associated with the development
catalysts3,4. However, in recent years, several efficient and selective of an organocatalytic enantioselective acylation protocol for thiol
artificial organocatalysts have become available for these pro- substrates relative to alcohols (for example, ‘softer’ nucleophile,
cesses5–14. Although the KR of alcohols is now a mature and greater distance between the reacting heteroatom and the stereocen-
useful technology, perhaps surprisingly no analogous direct tre, and lower heteroatom pKa), the paucity of methodologies avail-
methods exist for the highly selective, direct catalytic KR of able in the literature for the catalytic asymmetric synthesis of
racemic thiols, despite the importance of thiols and organosulfur enantio-enriched thiols—and for the KR of thiols in particular—
compounds in organic chemistry15,16 and chemical biology17–19
Baker’s yeast has been used to resolve a chiral thiol in the presence
.
encouraged us to focus on the problem.
of glucose, but the resolved material was isolated in trace amounts Results and discussion
only and with low enantioselectivity (40% ee)20. To the best of our Recently, we demonstrated bifunctional thiourea-modified cinchona
knowledge, only two other reports have appeared concerning the alkaloid organocatalysts24 to be capable of catalysing the efficient
KR of thiols. In these, Cesti and colleagues21 and Hult and col- and selective desymmetrization of meso glutaric anhydrides25–28
leagues22 have developed indirect methodologies based on lipase- with achiral alcohol29 and thiol30 nucleophiles (a process first reported
catalysed transesterification of thioesters derived from racemic using artificial catalysts by Nagao and colleagues31) at ambient
thiols. Under optimal conditions the thiol products can be obtained temperature using low catalyst loadings32,33. For the case of
with high enantioselectivity (up to 95% ee); however, only three ring opening with thiols, we observed significantly higher enantio-
thioester substrates were resolved and the methodology required selectivity using bulkier, secondary achiral thiols than with
long reaction times (up to 200 h) and high mass loadings of the primary analogues30. This led us to postulate that if catalyst–nucleo-
enzyme catalyst. It is noteworthy that attempts to use one of the phile steric interactions have a significant role in determining the
lipases to promote the direct acylative KR of thiols failed to efficacy of the desymmetrization process from a stereoselectivity
produce enantio-enriched products22.
standpoint, then these putative interactions could potentially also
Although enantio-enriched thiols can be synthesized from the be used to discriminate between enantiomers of a racemic chiral
corresponding alcohols, this simply makes one reliant on (and thiol nucleophile.
limited by) the availability of the desired alcohol substrate in an
To test this hypothesis, in preliminary experiments we carried
enantiopure form. In addition, care must be taken23 where a sub- out the acylative KR of the racemic sec-thiol 1 with glutaric anhy-
strate (or its derivatives) is capable of racemization. For example, dride (2a) in the presence of bifunctional (thio)urea-derived orga-
before this study could begin a sample of thiol 1 (Table 1) in an nocatalysts 5–7 and sulfonamide 8, which we29,30 and Song and
enantiopure form was required so that both enantiomers of (rac)-1 colleagues32,33, respectively, have demonstrated to be capable of pro-
could be unambiguously identified by chiral stationary phase- moting the addition of achiral alcohols to cyclic anhydrides
(CSP) HPLC analysis. Commercially available (R)-1-phenyl-2- (Table 1). Initial results were far from encouraging—acylation pro-
methyl-propanol (.99% ee) was therefore taken and subjected to a ceeded smoothly at a low catalyst loading (5 mol%), but resulted in
sequence involving mesylation, substitution with thioacetate ion products of low enantiomeric excess (entries 1–4). Of the four cat-
(dry DMSO solvent, rt) and deprotection with LiAlH4, which alysts tested, sulfonamide 8 proved to be superior to the (thio)urea
Centre for Synthesis and Chemical Biology, School of Chemistry, University of Dublin, Trinity College, Dublin 2, Ireland. e-mail: connons@tcd.ie
*
380
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Table 1 | Kinetic resolution of thiol 1 with simultaneous desymmetrization of achiral anhydrides.
O
R
O
O
SH
SH
S
S
2a R = H
2c R = -Bu
2b R = Me 2d R = Ph
R
O
R
O
catalyst, 24 h
CO2H
CO2H
3a R = H
3c R = -Bu
3b R = Me 3d R = Ph
4a R = H
4c R = -Bu
4b R = Me 4d R = Ph
( )-1
(R)-1
A
OMe
OMe
N
N
S
H
N
H
B
N
S
N
H
O
X
N
N
( )-14
CO2H
O
O
O
8
B = 3,5-(CF3)2-C6H3
F3C
CF3
9 B = C6F5
O
10 B = 4-CH3-C6H4
11 B = 2,4,6-(CH3)3-C6H2
12 B = CH3
O
O
O
5 X = S, A = C2H3
6 X = O, A = C2H3
7 X = S, A = C2H5
O
13 B = 2,4,6-(i-Pr)3-C6H2
15
16
Entry
Anhydride
(equiv.)
Catalyst
(mol%)
Solvent
T
(8C)
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
0
–30
–30
–30
–30
Conv.
(%)*
dr†
eeesterA
eeesterB
eedesym
eethiol
Sk
1.2
1.3
1.2
1.5
1.5
2.1
—
(%)‡
(%)‡
(%)‡§
(%)‡
1
2
3
4
5
6
7
8
2a (0.5)
2a (0.5)
2a (0.5)
2a (0.5)
2a (0.5)
2a (0.5)
2a (0.5)
2b (0.5)
2b (0.5)
2c (0.5)
2d (0.5)
2b (0.5)
2b (0.5)
2b (0.5)
2b (0.5)
2b (0.5)
2b (0.5)
2b (0.75)
2b (0.75)
15 (0.75)
16 (0.75)
2a (0.75)
5 (5)
6 (5)
7 (5)
8 (5)
8 (5)
8 (5)
8 (5)
8 (5)
8 (1)
MTBE
MTBE
MTBE
MTBE
Et2O
49
50
50
50
50
39
16
50
49
50
50
49
47
44
48
48
43
62
54
33
4
—
—
—
—
—
—
—
6.5
9
6
13
14
—
—
—
—
—
—
—
91
88
n.d.
n.d.
87
93
90
84
68
78
90
84
—
—
—
—
—
—
—
—
92
94
n.d.
n.d.
94
96
96
92
90
96
94
96
—
7
9
6
13
14
17
—
33
33
21
26
41
41
45
44
60
THF
27
n.d.
95
97
n.d.
n.d.
97
97
97
95
95
98
95
98
n.d.
n.d.
n.d.
CH2Cl2
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
66.5:33.5
67:33
n.d.
2.7
2.7
1.8
9
10
11
8 (5)
8 (5)
9 (5)
60:40
70:30
73:27
79:21
75:25
89:11
89:11
79:21
89:11
—
2.3
3.9
4.0
5.6
4.3
8.5
13.6
11.6
25.5
17.9
n.d.
10.7
12
13
14
15
16
17}
18}
19#
20#
21#
22#
10 (5)
11 (5)
12 (5)
13 (5)
13 (5)
13 (10)
13 (10)
13 (10)
13 (10)
13 (10)
58
93
90
42 (85)**
n.d.
—
—
—
—
—
—
50
68 (68)**
*Conversion was determined using CSP-HPLC, where conversion ¼ 100 ꢀ eethiol/(eethiol þ eethioester); the value of eethioester was calculated using all four thioester stereoisomers. †Diastereomeric ratio ¼
(3a–d þ ent-3a–d):(4a–d þ ent-4a–d). ‡Determined by CSP-HPLC, see Supplementary Information. §Desymmetrization efficiency: the enantiomeric excess of the desymmetrized product if the combined
thioester products were substituted by an achiral (non-hydroxide) nucleophile, calculated as 100 ꢀ [(3a–d þ 4a–d)–(ent-3a–d þ ent-4a–d)]/[(3a–d þ 4a–d) þ (ent-3a–d þ ent-4a–d)]. kS ¼
enantioselectivity (kfast/kslow, see ref. 1). }48 h. #72 h. **Values in parentheses refer to the ee of the thiol obtained after deprotection through cleavage of the combined thioester products. rt ¼ room
temperature; n.d. ¼ not determined.
derivatives and could promote KR with a very modest selectivity 2b–d. Although this complicated matters considerably, as control
(kfast/kslow)1 of 1.5 (13% ee at 50% conv., entry 4). Further exper- over the formation of four possible thioester diastereomers is then
imentation identified methyl tert-butylether (MTBE) as the required, we knew that organocatalytic, stereoselective additions of
optimal solvent overall, although the KR of 1 was slower but more achiral nucleophiles to 3-substituted glutaric anhydrides were poss-
selective in tetrahydrofuran (THF) (entries 4–7).
ible25–34 and therefore posited that the additional control associated
Although these results represented the first examples of direct with the catalyst guiding the nucleophile to a single prochiral carbo-
catalytic asymmetric KR of a thiol, the selectivity achieved was not nyl group of the anhydride could result in improved potential for
at a synthetically useful level. Faced with this failure, we attempted enantio discrimination of the thiol nucleophile. In addition, it
the KR reactions using 3-substituted achiral anhydride electrophiles allowed for the possibility of a conceptually novel type of catalytic
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381

NATURE CHEMISTRY DOI: 10.1038/NCHEM.584
ARTICLES
process in which both KR and anhydride desymmetrization occur
simultaneously. Gratifyingly, this proved to be the case, with the
use of anhydrides 2b–d resulting in more enantioselective acylations
(entries 8–11), with methyl glutaric anhydride (2b) proving
optimal. Using this electrophile, the resolved thiol could be isolated
in 33% ee at 50% conversion (using either 1 or 5 mol% of catalyst 8),
corresponding to S ¼ 2.7. Furthermore, product esters 3b and 4b
were both formed with excellent enantioselectivity (.90% ee) and
with encouraging diastereocontrol (67:33 dr, entry 8). With
respect to the anhydride, the desymmetrization aspect of the reac-
tion was highly selective. The parameter eedesymm (Table 1) rep-
resents the percentage excess of products derived from attack of
thiol 1 at one prochiral anhydride carbonyl moiety over the other
(that is, the enantiomeric excess of the desymmetrized product if
the combined thioester diastereomers were substituted by an
achiral (non-hydroxide) nucleophile without racemization). It is
also noteworthy that in the presence of triethylamine as an achiral
catalyst the diastereoselectivity is reversed, with (+)-14 as the
major diastereomer.
The steric and electronic characteristics of the catalyst were then
systematically varied through the synthesis and evaluation of sulfo-
namides 9–12. Although the electron-deficient pentafluorophenyl-
substituted catalyst fared a little better than 8, less acidic analogues
10–12 had enhanced selectivity profiles (entries 12–15). Given the
superiority of the hindered promoter 11, it was decided to accentu-
ate the steric bulk of the sulfonamide further through the synthesis
of the novel catalyst 13, which proved almost as active as 8, yet pro-
moted the acylation with a synthetically useful KR selectivity of 8.5
(entry 16). Further optimization of the reaction conditions (entries
17–19) resulted in the KR of thiol 1 with outstanding selectivity (S ¼
25.5)—allowing the isolation of resolved (R)-1 in 90% ee at 54%
conversion, along with ester 3a (formed as the major diastereomer,
89:11 dr) in 98% ee, with an excellent attendant eedesymm of 96%
(entry 19). Thus, under optimum conditions, 13 is capable of med-
iating the highly efficient and selective KR of a substrate class pre-
viously outside the orbit of direct enantioselective catalytic acylation,
with the simultaneous desymmetrization of a synthetically useful
class of inexpensive achiral anhydride acylating agent, also with excel-
lent enantioselectivity. To demonstrate that the desymmetrization and
KR processes are synergistic, we next carried out the process under
optimum conditions using the non-prochiral anhydrides 2a, 15 and
16 (entries 20–22). KR either was too slow or proceeded with lower
enantioselectivity using these electrophiles.
Table 2 | Evaluation of substrate scope.
R
2b (X equiv.)
13 (10 mol%)
S
SH
SH
( )
Ar
O
Ar
R
Ar
R
MTBE, –30 °C
CO2H
Entry Substrate
X
Time Conv. eethiol
(h)
(%)* (%)†
S‡
Abs.
config.§
SH
1
0.75 68
0.75 74
0.75 68
0.75 96
63
56
54
52
97
91
14.5
(R)
17
SH
2
19.0
25.5
51.5
(R)
(R)
(R)
18
SH
3k
90
94
1
SH
4}
19
SH
5
6
0.75 72
65
56
95
87
10.7
15.0
(R)
(R)
Cl
20
SH
0.90 120
MeO
21
SH
7
0.75 74
0.75 72
58
45
82
59
9.7
(R)
(R)
8#
22
11.8
HS
9**
10
0.75 96
51
90
36.6
(R)
23
SH
0.75 48
0.75 48
50
50
95 (94)‡‡ 126.0 (R)
98 (96)‡‡ 265.0 (R)
24
Attention now turned to the question of substrate scope (Table 2).
It was found that variation of the steric bulk of both the aromatic and
aliphatic substituent is well tolerated by the catalyst—for example,
a-Me, -Et, -iPr and -tBu derivatives of benzyl mercaptan (that is, 1
and 17–19, entries 1–4) could be resolved with excellent selectivity
(up to S . 50), resulting in the isolation of the unreacted thiol with
.90% ee at ꢁ50% conversion. A strong correlation between increas-
ing aliphatic substituent bulk and selectivity was observed; however, it
is noteworthy that even the challenging substrate 17 (where the steric
discrepancy between the two carbon-based substituents is smallest)
could be resolved with synthetically useful selectivity. Variation of
the characteristics of the aromatic substituent produced interesting
results—substitution in the para-position either slightly reduces or
has no impact on enantioselectivity (20–22, entries 5–8), whereas
steric bulk at the ortho-position dramatically improved the KR.
In optimum cases this resulted in levels of enantio-discrimination
(S ꢂ 100) more usually associated with the enzymatic KR of alcohols
(23–25, entries 9–12).
11††
SH
12§§
0.75 48
43
75 (98)‡‡ 275.0 (R)
25
*Refers to conversion, determined using CSP-HPLC, where conversion ¼ 100 ꢀ eethiol/(eethiol
þ
eethioester). †Determined by CSP-HPLC, see supporting information. ‡S ¼ enantioselectivity
(kfast/kslow,
see ref. 1). §Refers to the absolute configuration of the recovered thiol product
(see Supplementary Information). kData from Table 1. }A repeat of this experiment (conv. 52%,
S ¼ ’50.4) resulted in the isolation of the unreacted (R)-thiol in 47% yield and 95% ee after
chromatography. After aminolysis of the combined thioester products the (S)-thiol was obtained in
43% isolated yield and 86% ee. #Reaction at 240 8C. **A repeat of this experiment in which the
combined thioester diastereomers were aminolysed resulted in the isolation of the corresponding
hemiamide in 93% ee. ††A repeat of this experiment (conv. 51%, S ¼ 249.0) resulted in the
isolation of the unreacted (R)-thiol in 48% yield and 99.6% ee after chromatography. After
aminolysis of the combined thioester products, the (S)-thiol was obtained in 44% isolated yield
and 95% ee. ‡‡Values in parentheses refer to the ee of the thiol obtained after deprotection via
cleavage of the combined thioester products. §§Reaction at 245 8C.
To demonstrate the potential utility of this methodology, we
carried out the KRof thiol 25 (0.80 mmol) with catalyst 13 in the pres- diastereomers) was then treated with aqueous ammonia, resulting in
ence of achiral anhydride 2c, which furnished (R)-25 (0.39 mmol, its cleavage to afford the other thiol enantiomer (S)-25 (96% ee,
99% ee) and the ring-opened product 26 (0.40 mmol) with excellent 0.35 mmol) and the aminolysed product (S)-27 (97% ee,
efficiency at 51% conversion (Fig. 1). Thioester 26 (as a mixture of 0.38 mmol), again with high efficiency. Hemiamide (S)-27 is a
382
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.584
ARTICLES
O
O
SH
SH
S
13 (10 mol%)
O
MTBE, –30 °C, 48 h
CO2H
O
S = 226
C = 50.8%
26 (0.40 mmol)
2c (0.60 mmol)
( )-25 (0.80 mmol)
(R)-25 99%
(0.39 mmol)
NH3 (aq.)
rt, 4 h
NH2
SH
NH2
1 step
(ref. 34)
O
CO2H
(R)-Pregabalin
CO2H
(S)-25 96%
(0.35 mmol)
(S)-27 97%
(0.38 mmol)
Figure 1 | Kinetic resolution of thiol 28 with simultaneous enantioselective synthesis of an (R)-Pregabalin precursor. Racemic thiol 25 can be reacted with
anhydride 2c in the presence of catalyst 13 to produce the unreacted (R)-enantiomer in excellent enantiomeric excess and isolated yield (based on a
maximum of 50%), together with the mixture of thioesters 26. When 26 are cleaved by aminolysis, both the (S)-thiol enantiomer and (S)-27 can be isolated
in excellent yield and .95% ee. Hemiamide (S)-27 is a precursor (one step) from the (R)- enantiomer of the anticonvulsive drug Pregabalin. In this process
(in contrast to the situation in most acylative KR processes where the acylating agent is discarded once cleaved from the fast-reacting substrate enantiomer),
the acylating agent is thus converted to a value-added compound with excellent enantioselectivity although the thiol substrate is being resolved.
Br
SH
Br
SH
13 (10 mol%)
HO2C
2b (0.75 equiv.)
OBn
OBn
Br
O
S
MTBE, –30 °C, 48 h
OBn
S = 9.4
C = 65%
( )-28
(R)-28 35%, 93%
29
Cl
OH
HO
O
S
N
(R)-Montelukast
Figure 2 | Synthesis of the (R)-Montelukast structural core via a catalytic thiol kinetic resolution. Racemic thiol 28, which can be readily synthesized from
o-bromohydrocinammic acid, is resolvable with synthetically useful levels of enantioselectivity through acylation with anhydride 2b in the presence of 13. The
resolved thiol (R)-28 constitutes the stereocentre-containing core of the anti-asthma drug (R)-Montelukast.
precursor that can be converted in a single step to the (R)-antipode of with catalyst 8 by Song and colleagues33 we propose that catalyst
the anticonvulsive agent Pregabalin34 (Fig. 1) and thusthis sequence— 13 operates through a bifunctional mechanism in which stabiliz-
in addition to serving as a highly efficient KR of 25—constitutes a ation of developing positive charge on the thiol sulfur atom and
rapid and convenient formal synthesis of the ‘blockbuster’ drug35 developing negative charge on the anhydride carbonyl moiety
(marketed as ‘Lyrica’) antipode.
undergoing nucleophilic attack is mediated by the basic quinucli-
In a similar fashion we also resolved thiol 28, which constitutes dine ring and the hydrogen-bond-donating sulfonamide moiety,
the structural (stereocentre-containing) core of the leukotriene respectively. It is interesting to note that the less acidic sec-pheny-
receptor antagonist (R)-Montelukast—a drug used in the treatment lethanol (the alcohol analogue of 17) did not open anhydride 2b
of asthma and seasonal allergies (marketed as ‘Singulair’). Racemic in the presence of 13, which would strongly support a considerable
thiol 28 proved to be a challenging substrate that could nonetheless degree of proton transfer to the quinuclidine ring in the rate-deter-
be smoothly resolved in the presence of catalyst 13 and anhydride mining transition state of these reactions.
2b to afford the pharmaceutically relevant (R)-thiol antipode in
excellent enantiomeric excess (Fig. 2).
Conclusions
By analogy with both earlier work from Oda36, and more recent We have developed the novel sulfonamide catalyst 13, which pro-
computational studies concerning the alcoholysis of anhydrides motes the highly enantioselective (S . 10) direct acylative KR of
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383

NATURE CHEMISTRY DOI: 10.1038/NCHEM.584
ARTICLES
20. Fronza, G., Fuganti, C., Grasselli, P., Pedrocchi-Fantoni, G. & Servi, S. Minor
synthetic capacities of baker’s yeast towards unnatural substrates. Pure Appl.
Chem. 64, 1099–1101 (1992).
sec-thiols allowing their isolation in .90% ee at ꢁ50% conversion.
Under optimum conditions at low catalyst loadings, the selectivity
(kfast/kslow) of these processes is in the range 50–275. Using the arti-
ficial catalyst 13 it is therefore possible to achieve levels of enantio-
discrimination more usually associated with acylative KR by biologi-
cal catalysts, using a substrate class not hitherto demonstrated to be
generally amenable to enzyme-mediated direct acylative KR. In
addition, the thiol KR is accompanied by a synergistic, simultaneous
desymmetrization of an achiral anhydride electrophile, which
21. Bianchi, D. & Cesti, P. Lipase-catalyzed stereoselective thiotransesterification of
mercapto esters. J. Org. Chem. 55, 5657–5659 (1990).
¨
22. Ohrner, N., Orrenius, C., Mattson, A., Norin, T. & Hult, K. Kinetic resolutions of
amine and thiol analogues of secondary alcohols catalyzed by the Candida
Antarctica lipase B. Enz. Microb. Tech. 19, 328–331 (1996).
23. Strijtveen, B. & Kellogg, R. M. Synthesis of (racemization prone) optically active
thiols by SN2 substitution using cesium thiocarboxylates. J. Org. Chem. 51,
3664–3671 (1986).
occurs with excellent levels of enantioselectivity on a par with 24. Connon, S. J. Asymmetric catalysis with bifunctional cinchona alkaloid-based
urea and thiourea organocatalysts. Chem. Commun. 2499–2510 (2008).
25. Spivey, A. C. & Andrews, B. I. Catalysis of the asymmetric desymmetrization of
those associated with the best anhydride desymmetrization method-
ologies in the literature37–40. This catalytic desymmetrization of an
cyclic anhydrides by nucleophilic ring-opening with alcohols. Angew. Chem. Int.
Ed. 40, 3131–3134 (2001).
electrophile while it kinetically resolves a nucleophile is, to the
best of our knowledge, a hitherto unreported phenomenon that
has excellent potential as a tool to considerably improve on both
the synthetic utility and atom economy of acylative KR processes.
Studies aimed at further exploration of the scope of this strategy
are under way in our laboratories.
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Methods
Tandem KR–desymmetrization procedure. A 20 ml reaction vial containing a
stirring bar was charged with 3-methylglutaric anhydride (2b) (28.8 mg,
0.225 mmol) and 13 (17.7 mg, 0.030 mmol). The reaction vial was flushed with
argon and fitted with a septum. MTBE was then added using a syringe (1.5 ml,
0.2 M) and the solution was cooled to 230 8C. The relevant thiol (0.30 mmol) was
added with a syringe, and the resulting solution was stirred for the time indicated in
Table 2. The reaction mixture was then subjected to column chromatography and
the separated unreacted thiol and thioester products were then derivatized (as their
acrylonitrile Michael adduct and o-nitrophenyl ester, respectively) to render them
suitable for CSP-HPLC analysis (see Supplementary Information for details).
Received 21 July 2009; accepted 3 February 2010;
published online 14 March 2010
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for the methanolytic desymmetrization of cyclic anhydrides: prevention of
catalyst aggregation. Angew. Chem. Int. Ed. 47, 7872–7875 (2008)
34. Hoekstra, M. S. et al. Chemical development of CI-1008, an enantiomerically
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Acknowledgements
This material is based on work supported by Science Foundation Ireland, The European
Research Council and The Irish Research Council for Science, Engineering
and Technology.
Author contributions
S.J.C., B.P. and A.P. designed the research. S.J.C. analysed the data and prepared the
manuscript. B.P., A.P. and C.J.O’C. performed the experimental work. All authors
discussed the results and commented on the manuscript.
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Chemistry and Biology (Springer, 1991).
Additional information
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18. Moran, L. K., Gutteridge, J. M. & Quinlan, G. J. Thiols in cellular redox
signalling and control. Curr. Med. Chem. 8, 763–762 (2001).
19. Pachamuthu, K. & Schmidt, R. R. Synthetic routes to thiooligosaccharides and
thioglycopeptides. Chem. Rev. 106, 160–187 (2006).
The authors declare no competing financial interests. Supplementary information and
chemical compound information accompany this paper at www.nature.com/
naturechemistry. Reprints and permission information is available online at
http://npg.nature.com/reprintsandpermissions/. Correspondence and requests for materials
should be addressed to S.J.C.
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