Practical asymmetric conjugate alkynylation of meldrum's acid-derived acceptors: Access to chiral β-alkynyl acids

Article abstract of DOI:10.1021/ja909105s

(Chemical Equation Presented) The enantioselective conjugate addition of alkynyl nucleophiles has been a long-standing challenge in synthetic chemistry. This paper describes a highly practical asymmetric conjugate alkynylation of Meldrum's acid-derived acceptors using cinchonidine (<$100/kg) as the chiral mediator. The process provides practical access to chiral β-alkynyl acids. Noteworthy attributes of the method are its broad scope, high functional-group compatibility, and ease of scalability. Copyright

Full text of DOI:10.1021/ja909105s

Published on Web 12/18/2009
Practical Asymmetric Conjugate Alkynylation of Meldrum’s Acid-Derived
Acceptors: Access to Chiral ꢀ-Alkynyl Acids
Sheng Cui,* Shawn D. Walker,* Jacqueline C. S. Woo, Christopher J. Borths, Herschel Mukherjee,
Maosheng J. Chen, and Margaret M. Faul
Department of Chemical Process Research and DeVelopment, Amgen Inc., One Amgen Center DriVe, Thousand
Oaks, California 91320
Received August 4, 2009; E-mail: scui@amgen.com; walkers@amgen.com
Table 1. Zn-Mediated Asymmetric Conjugate Alkynylation
Chiral ꢀ-alkynyl acids are an important class of pharmaceutical
compounds with diverse biological activities that include PDE IV
inhibitors, TNF inhibitors, GPR40 receptor agonists, and GRP
receptor antagonists.1 However, because of the lack of available
asymmetric methods, their preparation typically requires racemic
synthesis followed by separation of enantiomers (classical resolution
or chiral chromatography). In this context, the asymmetric conjugate
alkynylation of an ester-derived acceptor represents a particularly
direct route to this target class. Meldrum’s acid-derived acceptors
2 (eq 1) are attractive substrates for such processes because they
can be readily prepared by Knoevenagel condensation of Meldrum’s
acid with aldehydes and the challenges associated with the control
and influence of olefin geometry are absent. Furthermore, the
conjugate-addition products can be easily converted to the corre-
sponding ꢀ-alkynyl acids 1 in high yield.2
% eea
% eea
entry
Additive
(% yieldb) entry
Additive
(% yieldb)
1
2
3
4
5
6
CF3CH2OH
MeOH
90 (96)
64 (95)
7
8
9
(R)-CF3CH(CH3)OH
(S)-CF3CH(CH3)OH
(rac)-CF3CH(CH3)OH 80 (95)
66 (96)
88 (95)
(CH3)3CCH2OH n.d.c (64)
CF3COOH
CH3COOH
(CH3)3CCOOH 90 (93)
75 (86)
87 (89)
10 (R)-Mosher acid
11 (S)-Mosher acid
12 (rac)-Mosher acid
94 (94)
98 (95)
97 (95)
a Determined by chiral HPLC. b Assay yields determined by
quantitative HPLC. c Not determined.
as effectively as trifluoroethanol (entry 1).9 Importantly, as shown in
entries 10-12, it was demonstrated that in addition to the primary
chiral ligand (cinchonidine), a second chiral component (e.g., Mosher
acid) can further modulate the chiral environment around the zinc atom,
resulting in dramatically enhanced enantioselectivity (from 90 to 98%
ee; entries 1 and 11), although the configuration of the additive did
not change the major product configuration (entries 7-12). This novel
finding in regard to tuning of chiral zincate selectivity should be
applicable to other Zn-mediated asymmetric transformations.
Carreira and co-workers3 recently reported the first example of
copper-catalyzed enantioselective conjugate additions to Meldrum’s
acid-derived acceptors, providing a new avenue to optically enriched
ꢀ-alkynyl acids. However, the effective nucleophile was limited to
phenylacetylene, and aliphatic alkynes afforded significantly lower
yield (<30%) and enantioselectivity (<70%) even in the presence of
20 mol % copper-PINAP catalyst. In fact, despite considerable
progress in the area of enantioselective conjugate alkynylation over
the past decade, bulky or electronically activated alkyne nucleophiles
such as silyl- or arylacetylenes remain the alkynes of choice.4 To the
best of our knowledge, synthetically useful yields and enantioselec-
tivities have never been achieved in enantioselective conjugate
alkynylation of ester-derived acceptors with aliphatic alkyne nucleo-
philes. Herein we report a practical, general, and highly enantioselective
conjugate alkynylation of Meldrum’s acid-derived acceptors employing
cinchonidine, an inexpensive and recyclable chiral mediator (<$100/
kg). This process has been readily extended to a variety of alkynylides,
including those possessing aliphatic, aromatic, and silyl groups, to
afford products in both high yield and enantioselectivity.
The enantioselectivity of the process was not strongly dependent
on the reaction temperature, and full conversion was generally
reached at room temperature (rt).10 The optimal ratio of chiral to
achiral alcohol was determined to be 1.5:1. A slight increase in
enantioselectivity was observed when the ratio of chiral to achiral
alcohol was increased, but the reaction rate and yield decreased.11
Little change in the enantioselectivity was observed when the
amount of chiral zincate was reduced from 2.4 to 1.2 equiv.
To demonstrate the practicality of this new method, a reaction
of substrate 2 was carried out on 10 g scale (Scheme 1). A chiral
zincate 412 was generated by treatment of Et2Zn with cinchonidine
and trifluoroethanol followed by addition of the Grignard reagent.
The acceptor 2 was then added, and the mixture was aged for 24 h
at rt. Following workup, the product 3 was isolated in 85% yield
and >99% ee after a single crystallization. Notably, cinchonidine
could be recovered from the aqueous layer in 95% yield by simple
pH adjustment and filtration. Finally, the adduct 3 was readily
converted to the ꢀ-alkynyl acid 1 in 96% yield without racemization.
Having established an optimal protocol, we next investigated the
generality and the scope of the reaction. As the data in entries 1-9 of
Table 2 illustrate, a wide range of functional groups were well-tolerated,
including carbonate, nitrile, ester, and ketone. Altering the electronic
character of the para and meta positions of the phenyl ring did not
Following an extensive screen,5 we identified that reaction of a Zn
alkynylide species prepared by treatment of MeCt CMgCl with a chiral
zinc alkoxide reagent generated by the reaction of Me2Zn with the
chiral amino alcohol cinchonidine and achiral additive trifluoroethanol
afforded 3 in 96% yield and 90% ee (Table 1, entry 1).6-8 Interestingly,
a large selectivity disparity was observed when different achiral
additives were used (entries 1-6), which prompted an in-depth
investigation. While the conjugate addition reaction proceeded slowly
in the presence of the bulky additive neopentanol (entry 3), a variety
of carboxylic acids, including pivalic acid (entries 4-6), performed
9
436 J. AM. CHEM. SOC. 2010, 132, 436–437
10.1021/ja909105s  2010 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1
and recyclable chiral mediator cinchonidine, crystalline nature of the
starting materials and products, excellent functional group compatibility
of the process, wide substrate scope, and ability to prepare either
enantiomer of the product (Table 2, entry 22) make this an attractive
new synthetic method.
Acknowledgment. We are grateful to Dr. Tsang-Lin Hwang
for NMR structural work.
Supporting Information Available: Experimental procedures and
spectral data for all new compounds and crystallographic data (CIF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
Table 2. Substrate Scope of Asymmetric Conjugate Alkynylation
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entry
R1
R2
% yielda
% eeb
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
4-(MeO)Ph (5a)
4-ClPh (5b)
4-BrPh (5c)
Me
87 (76c) (6a)
95 (6b)
96 (86c) (6c)
91 (6d)
90 (6e)
82 (6f)
92 (6g)
95 (6h)
96 (6i)
86 (6j)
85 (6k)
93 (92d) (6l)
91 (6m)
93 (6n)
95 (6o)
89 (6p)
71 (6q)
88 (6r)
81 (6s)
85 (6t)
89 (6u)
96 (6v)
93 (>99c)
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
94
93 (>99c)
93
(2) Kno¨pfel, T. F.; Carreira, E. M. J. Am. Chem. Soc. 2003, 125, 6054, and
references therein.
4-(MeCO)Ph (5d)
4-(MeOOC)Ph (5e)
4-(BocO)Ph (5f)
4-(CN)Ph (5g)
3-(MeO)Ph (5h)
3-CIPh (5i)
1-naphthyl (5j)
2-(MeO)Ph (5k)
2-CIPh (5l)
(3) Kno¨pfel, T. F.; Zarotti, P.; Ichikawa, T.; Carreira, E. M. J. Am. Chem.
Soc. 2005, 127, 9682.
88
94
98
88
88
90
70
(4) For recent reviews of asymmetric conjugate alkynylation, see: (a) Fujimori,
S.; Kno¨pfel, T. F.; Zarotti, P.; Ichikawa, T.; Boyall, D.; Carreira, E. M.
Bull. Chem. Soc. Jpn. 2007, 80, 1635. (b) Trost, B. M.; Weiss, A. H. AdV.
Synth. Catal. 2009, 351, 963. For enantioselective conjugate alkynylation
of enones, see: (c) Chong, J. M.; Shen, L.; Taylor, N. J. J. Am. Chem. Soc.
2000, 122, 1822. (d) Kwak, Y.-S.; Corey, E. J. Org. Lett. 2004, 6, 3385.
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Wu, T. R.; Chong, J. M. J. Am. Chem. Soc. 2005, 127, 3244. (g) Nishimura,
T.; Guo, X.-X.; Uchiyama, N.; Katoh, T.; Hayashi, T. J. Am. Chem. Soc.
2008, 130, 1576. (h) Nishimura, T.; Tokuji, S.; Sawano, T.; Hayashi, T.
Org. Lett. 2009, 11, 3222. For Rh-catalyzed enantioselective conjugate
alkynylation of enals, see: (i) Nishimura, T.; Sawano, T.; Hayashi, T. Angew.
Chem., Int. Ed. 2009, 48, 8057. For Rh-catalyzed enantioselective conjugate
alkynylation of Meldrum’s acid-derived acceptors with TMS-acetylene, see:
(j) Fillion, E.; Zorzitto, A. K. J. Am. Chem. Soc. 2009, 131, 14608. For
Rh-catalyzed asymmetric rearrangement of alkynyl alkenyl carbinols as a
synthetic equivalent to asymmetric conjugate alkynylation of enones, see:
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Chem. Soc. 2007, 129, 14158. For organocatalytic formal alkynylation of
enals, see: (l) Nielsen, M.; Jacobsen, C. B.; Paixa˜o, M. W.; Holub, N.;
Jørgensen, K. A. J. Am. Chem. Soc. 2009, 131, 10581. For asymmetric
conjugate alkynylation using chiral auxiliaries, see: (m) Elzner, S.; Maas,
S.; Engel, S.; Kunz, H. Synthesis 2004, 2153. (n) Kno¨pfel, T. F.; Boyall,
D.; Carreira, E. M. Org. Lett. 2004, 6, 2281. (o) Fujimori, S.; Carreira,
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56 (84d)
82
74
46
45
81
92
92
86
1-thiophyl (5m)
2-furyl (5n)
i-Pr (5o)
Et (5p)
4-BrPh (5c)
4-BrPh (5c)
4-BrPh (5c)
4-BrPh (5c)
4-BrPh (5c)
4-BrPh (5c)
n-C4H9
Ph
t-Bu
TMS
Me
81
-91e
a Isolated yields after chromatography. b Determined by chiral HPLC.
c After one crystallization from acetone/water. d Using 1.9 equiv of (rac)-
Mosher acid instead of CF3CH2OH. e Using cinchonine as the chiral ligand
instead of cinchonidine to obtain the opposite enantiomer of the product.
(5) A variety of other chiral ligands and metals, including copper, rhodium,
and lithium, were also evaluated, but they afforded lower yields and
enantioselectivities.
(6) The method used to generate the chiral alkynylzinc reagents played a key
role. Chiral alkynylzinc reagents produced by transmetalation provided
superior reactivity to in situ-generated chiral zinc alkynylides obtained using
ZnII/R3N. See the Supporting Information for detailed optimization work.
(7) The absolute configuration was determined by single-crystal X-ray crystal-
lographic analysis. See the Supporting Information.
considerably affect the reaction efficiency (82-96% yield) or asym-
metric induction (88-98% ee). Although ortho-substituted arene
acceptors (entries 11 and 12) and aliphatic acceptors (entries 15 and
16) generally provided moderate ee (45-70%), this limitation could
be overcome by use of (rac)-Mosher acid instead of trifluoroethanol
as the additive (entry 12). The process was also suitable for heterocyclic
substrates, such as furyl and thiophyl (entries 13 and 14). A wide
variety of Zn alkynylides, including those possessing aliphatic,
aromatic, and silyl groups, could be employed in the conjugate addition
with high ee (entries 17-22). Remarkably, even with the smallest
alkynyl nucleophile (derived from acetylene), 81% ee and 71% yield
were achieved (entry 17). Importantly, all of the starting materials 5
and products 6 were crystalline, allowing simple isolations and ee
upgrades by crystallization (entries 1 and 3).
In summary, we have developed a highly general, practical
asymmetric alkynylation procedure for the preparation of ꢀ-alkynyl
acids. These results demonstrate for the first time that unactivated
aliphatic alkynes (even acetylene) can be employed in the enantiose-
lective conjugate alkynylation of ester-derived acceptors to afford
products in both high yield and enantioselectivity. The inexpensive
(8) For similar zinc species, see: (a) Enders, D.; Zhu, J.; Raabe, G. Angew.
Chem., Int. Ed. 1996, 35, 1725. (b) Dosa, P. I.; Fu, G. C. J. Am. Chem.
Soc. 1998, 120, 445. (c) Uchiyama, M.; Kameda, M.; Mishima, O.;
Yokoyama, N.; Koike, M.; Kondo, Y.; Sakamoto, T. J. Am. Chem. Soc.
1998, 120, 4934. (d) Tan, L.; Chen, C.; Tillyer, R. D.; Grabowski, E. J. J.;
Reider, P. J. Angew. Chem., Int. Ed. 1999, 38, 711.
(9) Ultimately, trifluoroethanol was selected for further optimization studies
because of its low cost and easy removal by distillation.
(10) No reaction was detected below-30 °C, and reactions at 0 and 30 °C gave
92 and 88% ee, respectively.
(11) (a) Reactions were slower in the absence of trifluoroethanol. For example, the
reaction in Table 1, entry 1, reached 100% conversion in <6 h at rt. When the
reaction was performed with 4.8 equiv of cinchonidine (no CF3CH2OH) at rt
for 24 h, 93% conversion and 94% ee was observed. (b) Other evaluated
solvents (Me-THF, MTBE, DME, toluene) provided lower ee (<80%) and yield
(<90%). (c) Me2Zn and Et2Zn were equally efficient. (d) The enantioselectivity
was not dependent on the concentration (0.04-0.2 M). (e) The order of addition
of reagents during the zincate preparation had no effect.
(12) In Scheme 1, zincate 4 is depicted as a monomer for clarity. Preliminary
NMR studies indicate that several different zincate species exist in solution.
JA909105S
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J. AM. CHEM. SOC. VOL. 132, NO. 2, 2010 437