Asymmetric syntheses of a GPR40 receptor agonist via diastereoselective and enantioselective conjugate alkynylation

Article abstract of DOI:10.1016/j.tet.2010.04.019

Two asymmetric methods to synthesize a potent GPR40 receptor agonist are reported. Both synthetic routes utilize readily available, inexpensive starting materials and reagents. The first route relies on a highly diastereoselective conjugate alkynylation of an ephedrine-derived oxazepanedione acceptor. The second route features the enantioselective alkynylation of a Meldrum's acid-derived acceptor mediated by a chiral zinc cinchonidine reagent.

Full text of DOI:10.1016/j.tet.2010.04.019

Tetrahedron 66 (2010) 4730e4737
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric syntheses of a GPR40 receptor agonist via diastereoselective
and enantioselective conjugate alkynylation
*
*
Jacqueline C.S. Woo, Sheng Cui , Shawn D. Walker , Margaret M. Faul
Department of Chemical Process Research and Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Two asymmetric methods to synthesize a potent GPR40 receptor agonist are reported. Both synthetic
routes utilize readily available, inexpensive starting materials and reagents. The first route relies on
a highly diastereoselective conjugate alkynylation of an ephedrine-derived oxazepanedione acceptor.
The second route features the enantioselective alkynylation of a Meldrum’s acid-derived acceptor me-
diated by a chiral zinc cinchonidine reagent.
Received 1 March 2010
Received in revised form
2 April 2010
Accepted 2 April 2010
Available online 9 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
GPR40
Conjugate addition
Diastereoselective
Enantioselective
Oxazepanedione
Cinchonidine
b-Alkynyl acid
Zincate
1. Introduction
Me
Me
classical
O
O
The recent recognition of the function of the G-protein coupled
receptor GPR401 in modulating insulin secretion has provided
insight into regulation of carbohydrate and lipid metabolism in
vertebrates, and further provided targets for the development of
therapeutic agents for disorders such as obesity, diabetes, cardio-
vascular disease, and dyslipidemia.
Recent efforts at Amgen led to the discovery of the potent GPR40
receptor agonist 1.2 To supply toxicological and clinical studies,
a scalable synthesis of 1 was developed. This convergent nine-step
route relied on the synthesis and coupling of two key fragments,
resolution
OH
OH
F3C
Me
(+)-3
(
)-3
HO
HO
O
Br
OH
F3C
O
2
1
Scheme 1. First generation synthetic route.
biaryl bromide 2 and the chiral
b
-alkynyl acid (þ)-3 (Scheme 1).3
Enantioselective conjugate alkynylation
O
Due to the lack of suitable methods for asymmetric alkynylation
on large-scale, (þ)-3 was initially prepared by racemic synthesis
followed by resolution via diastereomeric salt formation. Although
this process was suitable for kilogram-scale preparation of 1,
the use of classical resolution limited the theoretical yield to 50%
(actual yield 35%) and an asymmetric route was desired.
Ar
O
Me
Me
[M]*
Me
+
O
O
Br
Me
O
6
OH
1
Me
N
O
We now report the development of two new asymmetric
syntheses of 1 employing inexpensive raw materials and reagents
(Scheme 2). The first route relies on the diastereoselective
Me
Ph
O
4
Me
M
+
+
Ar
O
7
O
F3C
B(OH)2
Diastereoselective conjugate alkynylation
Scheme 2. Retrosynthetic analysis.
5
* Corresponding authors. Tel.: þ1 805 313 5143/5152; fax: þ1 805 375 4531;
e-mail addresses: scui@amgen.com (S.C), walkers@amgen.com (S.D.W).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.019

J.C.S. Woo et al. / Tetrahedron 66 (2010) 4730e4737
4731
conjugate alkynylation of an ephedrine-derived oxazepanedione
acceptor 7. The second approach features a practical and highly
enantioselective conjugate alkynylation of Meldrum’s acid-derived
acceptors 6 employing cinchonidine, an inexpensive and recyclable
chiral mediator (<$100/kg).4 Both of these strategies relied on
the preparation and cross-coupling of the key chiral intermediate
(Scheme 4). The removal of the chiral auxiliary proved challenging,
as commonly used strong acid and basic conditions caused signif-
icant decomposition.9 Eventually cleavage of the auxiliary and
transformation to the target 1 was accomplished using a mild
multi-step sequence. Hydrolysis of the ester moiety of 11 with
n-Bu4NOH in tBuOH (rt, 6 h) led to an intermediate acid, which was
decarboxylated in DMSO at 100 ꢁC to furnish 12. The high dr of 12
mirrored the Z/E ratio of the acceptor 10, which attests to the
excellent facial selectivity of the conjugate addition step. In
agreement with literature, the stereochemistry of the adduct
was consistent with the acceptor reacting through a boat-like
conformation with attack of the Grignard reagent occurring from
the convex face, syn to the substituents on the ring.7a Without
purification, the crude acyclic amide 12 was coupled with boronic
acid 5 using a Pd/PCy3 catalyst10 to afford 13 in 74% yield over four
steps. Treatment of 13 with a mixture of sodium methoxide and
dimethyl carbonate11 resulted in net cleavage of the amide bond to
provide the methyl ester of 1. Following ester hydrolysis, 1 was
isolated as the corresponding sodium salt in 72% yield for the three-
step sequence.
4 with boronic acid 5.
b-Alkynyl acid 4 was considered attractive
since the optical purity of scalemic material could be readily
upgraded via crystallization of the corresponding
benzylamine salt.
a-methyl-
2. Results and discussion
2.1. Diastereoselective conjugate alkynylation
The oxazepanedione 8 was first introduced by Mukaiyama5 as
an effective chiral auxiliary for a number of asymmetric trans-
formations.6 Recently, Carreira and co-workers7 reported the dia-
stereoselective conjugate addition of in situ generated zinc
alkynylides to chiral oxazepanedione acceptors to provide access to
enantiomerically enriched b-alkynyl acids. However, in this case,
Me
N
Me
N
Me
N
Me
Ph
Me
Ph
Me
Ph
the substrate scope was limited to aliphatic acceptors and additions
to acceptors with aromatic residues did not proceed, presumably
due to the weak nucleophilicity of the in situ prepared zinc alky-
nylide. Therefore, we speculated that a stronger nucleophile, such
as an alkynyl Grignard reagent, could resolve this issue.
O
O
H
O
Me
Me
OH
O
O
O
O
1)
Me
MgBr
2) nBu4NOH, rt
THF, -35 ºC
> 99%
3) DMSO, 100 ºC
Oxazepanedione 8 was conveniently prepared in a three-step
sequence from (ꢀ)-ephedrine and dimethylmalonate (Scheme 3).8
Condensation of 8 with aldehyde 9 was performed in the presence
1.05 equiv of TiCl4 and pyridine to provide a mixture of geometric
isomers favoring the (Z)-alkylidene 10 in ratios of 1e10:16b As-
suming high facial selectivity in the conjugate addition step, control
of E- versus Z-olefin geometry would be critical to obtaining a high
optical purity of the final product. Although the isomers could be
separated by chromatography, for operational ease we desired
a chromatography-free process to 10. With this goal in mind,
additional experimentation revealed that a >95:5 Z/E ratio could be
obtained for crude 10 when 5 equiv of TiCl4 were used in the
condensation reaction. After further process refinement, a crystal-
lization driven thermal isomerization was developed, which took
advantage of the solubility difference between the Z/E-isomers in
isopropanol. For example, heating a 1:1 Z/E-mixture in isopropanol
at 90 ꢁC for 2 h, followed by cooling and filtration, provided 10 as
a crystalline solid in 81% yield and 99.5:0.5 Z/E ratio.
O
O
O
Br
>99% dr
Br
Br
12
11
10
99.5% Z
RMgBr
O
Me
N
Me
H
Ph
H
4) PCy3, Pd(OAc)2
THF, 70 oC, 4h
Ar
O
74% (4 steps)
O
F3C
B(OH)2
H
5
O
1)
Me
Me
MeO OMe
O
NaOMe, DCM
N
Me
Ph
35 oC, 16h
1
2) NaOH, EtOH
HCl workup
3) NaOH, MeCN
72% (3 steps)
99.6% ee
OH
CF3
O
13
Scheme 4. Synthesis of 1 via diastereoselective conjugate alkynylation.
OHC
Br
Despite the superb stereoselectivity, this route was considered
unattractive for long-term development due to the length of the
overall sequence and difficulty to recover the chiral auxiliary.
Me
N
O
O
Me
N
9
O
O
O
OH
Ph
NHMe
Me
Ph
Me
Ph
TiCl4, Pyridine, THF
3 steps
Me
Br
-55 ºC to rt
2.2. Enantioselective conjugate alkynylation
O
O
8
crude 10
Z/E = 1:1 to 10:1
The enantioselective conjugate alkynylation of an ester-derived
acceptor represents a particularly direct route to the target molecule
1. Meldrum’s acid-derived acceptors 6 are attractive substrates for
such processes since they can be readily prepared by Knoevenagel
condensation of Meldrum’s acid12 with aldehydes, and challenges
associated with the control and influence of olefin geometry are
absent. Furthermore, the conjugate addition products can be easily
O
Me
N
O
Br
O
Me
Ph
IPA, 90 oC, 2 h
81% (2 steps)
O
10
O
99.5% Z
converted to the corresponding b
-alkynyl acids in high yield.13
Scheme 3. Preparation of chiral oxazepanedione acceptor.
An article by Carreira and co-workers describing the first catalytic
enantioselective conjugate additions to Meldrum’s acid-derived
acceptors employed phenylacetylene and a Cu/QUINAP derived
catalyst14 and a recent contribution from the Fillion group used a Rh/
xylyl-MeOBiPHEP catalyst to promote TMS-acetylene additions.15
However, despite considerable effort that has been devoted to
The addition of propynylmagnesium bromide to acceptor 10
proceeded smoothly at ꢀ35 ꢁC to room temperature, furnishing
the adduct 11 in >99% yield as a mixture of diastereomers (3:1) due
to non-selective enolate protonation at the
Ca stereocenter

4732
J.C.S. Woo et al. / Tetrahedron 66 (2010) 4730e4737
Table 2
developing enantioselective conjugate alkynylation processes over
the last decade,16 a general and practical method remains elusive and
few successful reports of aliphatic alkynes as nucleophiles have
appeared. We recently reported a general, asymmetric alkynylation
Counterion effect on asymmetric conjugate alkynylation
Me
O
Br
1) 2.4 equiv Me2Zn
O
Br
2.9 equiv R*OH
O
O
1.9 equiv ROH
procedure for the preparation of b-alkynyl acids using a chiral zincate
O
Me
as the mediator.4 Herein, our efforts leading to the discovery and
development of this method, and application to the synthesis of 1
are described.
O
2)
Me
M
O
O
O
Me
Me
2.4 equiv
Me
O
THF/Tol, -40 ºC-rt
14
Following an extensive screen,17 we identified that treatment of
14 with a Znealkynylide species, prepared by treatment of
MeC^CMgCl with a chiral zinc alkoxide reagent generated by the
reaction of Me2Zn with 2 equiv of (1R,2S)-N-methylephedrine,
afforded 15 in 95% yield and 49% ee (Table 1, entry 2).18 During
preparation of the requisite zinc alkoxide, the ratio of Me2Zn to
aminoalcohol proved to be critical for the enantioselectivity: a 1:2
Entry
M
R
*
OH
ROH
%eea (% Yieldb)
1
2
3
4
MgBr
MgBr
MgCl
Li
(1R,2S)-N-methylephedrine
(1R,2S)-N-methylephedrine
(1R,2S)-N-methylephedrine
(1R,2S)-N-methylephedrine
MeOH
29 (96)
44 (95)
54 (96)
0 (7)
CF3CH2OH
CF3CH2OH
CF3CH2OH
a
Determined by chiral HPLC.
Assay yields determined by quantitative HPLC.
b
ratio was superior to 1:1 (entries 1 and 2), suggesting that a Zn(OR )
*
2
H
H
precursor is superior toZn(OR )(Me). Interestingly, through addition
*
OCH3
OCH3
OH
OH
OH
of the achiral additive trifluoroethanol, 1 equiv of chiral amino-
alcohol was sufficient to ensure comparable enantioselectivity
without diminishing the efficiency of the process (entry 3).19
H
N
N
H
Me
Me
Me
N
NBu2
OH
NMe2
OH
N
N
Quinine
Quinidine
Y: 90%
Y: 95%
ee: -77%
Y: 98%
Y: 92%
Table 1
Y: 86%
ee: -49%
ee: -61%
Zn-mediated asymmetric conjugate alkynylation
ee: 73%
ee: -89%
Me
H
H
1) Me2Zn, R*OH/ROH
2)
THF/Tol, -40 ºC-rt
OH
Br
O
O
OH
N
OH
Br
NMe2
OH
Me
MgCl
O
O
Me
Me
H
N
N
H
O
O
Me
Me
N
OH
OH
Me
Me
O
O
Me
N
N
O
O
Ph
=
Cinchonidine
Y: 95%
Y: 95%
Y: 96%
Y: 98%
14
Cinchonine
R*OH
15
N
ee: 43%
ee: 76%
ee: 80%
Y: 93%
Me
Me
ee: 90%
ee: -89%
Entry
Conditions
% eea (% Yieldb)
Figure 2. Survey of chiral ligands.
1
2
3
C3H3MgCl:Me2Zn:R
C3H3MgCl:Me2Zn:R
C3H3MgCl:Me2Zn:R
*
*
*
OH¼1:1:1
OH¼1:1:2
12 (94)
49 (95)
51 (95)
alcohols and carboxylic acids (Fig. 3) also offered comparable
enantioselectivity and yield. Ultimately, trifluoroethanol was se-
lected for further optimization studies due to its low cost and easy
removal by distillation.21
OH:CF3CH2OH¼1:1:1:1
a
Determined by chiral HPLC.
Assay yields determined by quantitative HPLC.
b
Encouraged by these preliminary results, a systematic study was
Me
1) 2.4 equiv Me2Zn
2.9 equiv cinchonidine
1.9 equiv Additive
Br
performed to optimize the reaction parameters. We envisioned that
both the enantioselectivity and yield could be further improved by
tuning the structure of the chiral zincate20 by altering the chiral
ligand, achiral additive, and counterion (Fig. 1).
O
O
Br
O
O
O
O
Me
Me
2)
Me
MgCl
2.4 equiv
THF/Tol, -40 ºC-rt
Me
Me
O
O
O
O
14
15
Chiral ligand
Me
CF3CF2CH2OH
Y: 95%
(S)-CF3CH(CH3)OH
Y: 96%
(CH3)3CCOOH
Y: 93%
(rac)-Mosher acid
Y: 95%
CH3COOH
Y: 89%
ee: 89%
ee: 87%
ee: 90%
ee: 90%
ee: 97%
*RO
Zn
Counterion
M
(Alkyne source)
OR
Figure 3. Additive effect on asymmetric conjugate alkynylation.
Achiral additive
Throughout the course of the reaction, the observed enantio-
selectivity did not significantly change with time, and it was also
not strongly dependent on the reaction temperature. Reactions at
0 ꢁC and 30 ꢁC gave 92% ee and 88% ee, respectively. However, no
reaction was detected below ꢀ30 ꢁC and full conversion was
generally reached at room temperature. The optimal ratio of chiral
to achiral alcohol was determined to be 1.5:1 (Table 3). A slight
increase in enantioselectivity was observed when the ratio of chiral
to achiral alcohol increased, but the reaction rate and yield
diminished.22 Reactions were slower in the absence of tri-
fluoroethanol. For instance, the reaction in entry 2, reached 100%
conversion in 4 h at room temperature. However, the use of zincate
derived from 2 equiv of cinchonidine relative to Zn (with no achiral
additive) furnished the product in 94% ee but required 24 h to reach
e95% conversion (entry 4). Interestingly, addition of a coordinating
solvent, such as NMP (entry 5) led to much lower enantioselectivity,
presumably due to the disruption of the chiral zincate structure.
Figure 1. Zincate design parameters.
A marked counterion effect was observed (Table 2, entries 2e4)
and the use of MeC^CMgCl proved superior to MgBr or Li counter-
ions. As expected, the selection of chiral aminoalcohol had a dramatic
effect on the enantioselectivity of the process. Our initial success with
N-methylephedrine prompted us to focus our attention on related
ligands and further screening (Fig. 2) indicated that cinchonidine was
the mostselective ligand (90%eeand95% yield). Notably, the opposite
enantiomer of the product was obtained with similar asymmetric
induction by using the pseudoenantiomer cinchonine. Another in-
teresting observation was that the product chirality was completely
dictated by the alcohol chiral center of the ligand.
A large selectivity disparity was observed by using different
achiral additives (Table 2, entries 1 and 2), which prompted an in
depth investigation. Compared to trifluoroethanol, a variety of

J.C.S. Woo et al. / Tetrahedron 66 (2010) 4730e4737
4733
Table 3
O
F3C
Ratio of chiral to achiral alcohols
1) K2CO3, DMF
2) Meldrum's acid
cat. DMAP, THF
H
Me
O
O
Br
Br
HO
1) 2.4 equiv Me2Zn
R*OH + ROH =
4.8 equiv
O
O
Br
18
O
O
92% (2 steps)
Me
Me
+
O
O
O
O
Me
Me
2)
Me
MgCl
2.4 equiv
THF/Tol, rt
19
Me
O
O
14
O
O
15
O
2
Me
F3C
F3C
Me
O
Entry
Cinchonidine/CF3CH2OH
%eea (% Yieldb)
Note
1) 1.2 equiv Me2Zn
O
O
1) DMF/H2O
1.5 equiv cinchonidine
0.9 equiv CF3CH2OH
1
2
3
4
5
1:1
1.5:1
2:1
No CF3CH2OH
1.5:1þ5 equiv NMP
76 (98)
90 (96)
92 (95)
94 (92)
56 (97)
Complete in 2 h, rt
Complete in 4 h, rt
Complete in 16 h, rt
95% Conv. 24 h, rt
Complete in 4 h, rt
90 ºC, 2 h
1
O
2) NaOH/ACN
90 % (2 steps)
Me
Me
2)
Me
MgCl
1.2 equiv
THF/Tol, rt, 24 h
O
16
97% Y, 89% ee
Cryst Acetone/H2O
>99% ee, >99 wt%
Overall yield: 82%
a
Determined by chiral HPLC.
Assay yields determined by quantitative HPLC.
b
Scheme 6. Second generation synthesis of 1.
Under the optimized conditions shown in Figure 3 with tri-
fluoroethanol as the additive, the product 15 was isolated in 85%
yield and >99% ee after a single crystallization from acetone/water.
Notably, cinchonidine could be recovered from the aqueous layer in
95% yield by simple pH adjustment and filtration.
3. Conclusion
In summary, two asymmetric methods to synthesize the potent
GPR40 receptor agonist 1 have been developed. Both synthetic routes
made use of readily available inexpensive starting materials and
reagents. The first route relies on the highly diastereoselective
conjugate alkynylation of an ephedrine-derived oxazepanedione
acceptor. The second approach involved a highly enantioselective
conjugate alkynylation of Meldrum’s acid-derived acceptors
employing the inexpensive and recyclable chiral mediator cinchoni-
dine. Overall, the firstgeneration synthesis of1 (ninesteps, 35%yield),
was replaced by this efficient, second generation asymmetric process
(five steps, 65% yield), which was suitable for long-term application.
With the adduct 15 in hand, strategies for the transformation to
the target 1 were explored (Scheme 5). Our initial plan was to per-
form a cross-coupling reactionwith 16, followed by decarboxylation
and sodium salt formation. Unfortunately, a variety of Suzu-
kieMiyaura coupling conditions were investigated, but the best
isolated yield of 16 was only 17% using S-Phos/Pd(OAc)2 as the
catalyst.23 Alternatively, an efficient telescoped sequence was de-
veloped to achieve our goal. Thus, heating a solution of 15 in n-BuOH
at reflux gave rise to the n-butyl ester 17 in 98% yield. The cross-
coupling reaction of 17 with boronic acid 5 proceeded smoothly in
the presence of catalytic Pd/PCy3, leading to the corresponding butyl
ester of 1, which was not isolated but rather directly hydrolyzed by
adding aqueous NaOH to the mixture. After work-up and a final
sodium salt formation step in acetonitrile/water, pure 1 was isolated
in 75% yield over four steps. Notably, the whole sequence (15/1)
could be performed in a single solvent (n-BuOH) without the need
for distillative solvent switches or purification of intermediates.
4. Experimental section
4.1. General information
Reactions were carried out under an atmosphere of dry nitro-
gen. All reagents were purchased from suppliers and used as
received unless noted otherwise. Anhydrous solvents were
purchased from Aldrich in Sure/SealÔ bottles. Propynylmagnesium
chloride was freshly prepared by reaction of a solution of propyne
in THF with n-butylmagnesium chloride (2.0 M in THF) at 0 ꢁC
followed by stirring at rt for 16 h. The final concentration was ad-
justed to 0.5e0.7 M by diluting with THF. The concentration of
organometallic reagents was titrated by the method reported by
Knochel and coworkers.24
Me
O
1.5% S-Phos/Pd(OAc)2,
F3C
THF, K3PO4.H2O, 50 ºC
O
Me
1.1 equiv 5
O
O
O
17%
Me
Me
1) DMF/H2O
16
100 ºC, 40 min
2) 10 N NaOH/ACN
91 % (2 steps)
Br
O
O
The racemates of 15 or 16 were prepared by the reaction of
propynylmagnesium bromide (2.0 equiv) with 14 or 19 at room
temperature.
1
O
Me
Me
O
O
15
1H NMR spectra were recorded on a 400 MHz spectrometer.
Chemical shifts are reported in parts per million (ppm) from
tetramethylsilane with the solvent resonance as the internal stan-
Me
2) 1% Pd(OAc)2, 2% PCy3,
K3PO4, 70 ºC, 1.1 equiv 5
Br
3) 2.5 N NaOH
O
1) n-Butanol
reflux
4) NaOH/ACN
OBu
dard (CDCl3:
d 7.27). Data are reported as follows: chemical shift,
75 % (4 steps)
O
17
multiplicity (s¼singlet, d¼doublet, t¼triplet, q¼quartet, br¼broad,
m¼multiplet), coupling constants (hertz) and integration. 13C NMR
spectra were recorded on a 100 MHz spectrometer with proton
decoupling. Analytical thin layer chromatography (TLC) was per-
formed using JT Baker silica gel plates precoated with a fluorescent
indicator. Standard flash chromatography was performed on
a Biotage MPLC system. Melting points are uncorrected. Optical
rotations were recorded in cells with 1 dm path length. Enantio-
meric excess was determined by HPLC or SFC analysis. All columns
are 250ꢂ4.6 mm. Mass spectra analyses and high-resolution mass
spectral analyses were measured by means of fast-atom bom-
bardment (FAB) or electrospray ionization (ESI).
Scheme 5. Conversion of the adduct 15 to 1.
The broad substrate scope of the enantioselective conjugate
alkynylation process4 encouraged us to attempt a more concise
synthetic route. As shown in Scheme 6, a fully elaborated olefin
acceptor was prepared from 2, 18, and Meldrum’s acid in 92% yield.
The olefin 19 was subjected to our chiral zincate mediated alky-
nylation procedure affording 16 in 97% assay yield and 89% ee.
Crystallization from acetone/water provided optically pure (>99%
ee) 16 in 82% overall yield. Sequential decarboxylation and sodium
salt formation concluded the five-step synthesis of 1.

4734
J.C.S. Woo et al. / Tetrahedron 66 (2010) 4730e4737
4.2. (2R,3S)-3,4-Dimethyl-2-phenyl-1,4-oxazepane-5,7-dione 8
organic layers were washed with a solution of water (10 mL) and
brine (10 mL), dried over MgSO4, and concentrated under reduced
pressure to afford the product as a foam (1.08 g, quantitative). The
product was used directly in the next step without purification.
Compound 8 was prepared according to literature procedure:
(ꢀ)-(1R,2S)-ephedrine was treated with dimethylmalonate at 80 ꢁC
for 16 h25 and the resulting mixture was hydrolyzed with LiOH to
yield the free acid.26 Cyclization was performed with N-methyl-2-
chloropyridinium tosylate (2-chloropyridine and methyltosylate
were stirred neat at 60 ꢁC for 16 h) as reported.5
4.6. (S)-3-(4-(3-Bromobenzyloxy)phenyl)-N-((1R,2S)-1-
hydroxy-1-phenylpropan-2-yl)-N-methylhex-4-ynamide 12
To a slurry of 11 (875 mg, 1.60 mmol, 1.0 equiv) in tert-butanol
(15 mL) at rt was added a solution of n-Bu4NOH (40% in water,
5.19 mL, 8.0 mmol, 5.0 equiv). The pale yellow solution turned or-
ange immediately. The reaction was aged at rt for 16 h, quenched
with an aqueous solution of saturated ammonium chloride (20 mL),
and extracted with CH2Cl2 (20 mL, then 2ꢂ15 mL). The combined
extracts were dried over MgSO4 and concentrated under reduced
pressure. The resulting foam was dissolved in DMSO (7.5 mL) and
heated at 100 ꢁC for 4.5 h. After the reaction was cooled to rt, CH2Cl2
(20 mL) and water (20 mL) were added. The organic layer was
separated and washed with water (2ꢂ20 mL), dried over MgSO4,
and concentrated under reduced pressure to afford an orange oil.
The crude product was used directly in the next step without
purification.
4.3. 4-(3-Bromobenzyloxy)benzaldehyde 9
A
mixture of 4-hydroxybenzaldehyde (2.5 g, 20.47 mmol,
1.0 equiv), K2CO3 (3.68 g, 26.61 mmol, 1.3 equiv), and DMF (9 mL)
was aged at rt for 5 min, and 3-bromobenzyl bromide (5.63 g,
22.52 mmol, 1.1 equiv) was charged in one portion. The resulting
mixture was aged at 60 ꢁC for 19 h. After cooling to rt, water
(27 mL) was added to dissolve the K2CO3, and the solution was
extracted with isopropyl acetate (2ꢂ27 mL). The combined organic
layers were washed with water (20 mL), dried over MgSO4, and
concentrated under reduced pressure. The residue was crystallized
from 20% isopropyl acetate in heptane to afford the product as
white solids (4.7 g, 79%). Mp 65e69 ꢁC. 1H NMR (400 MHz, CDCl3,
d
): 5.11 (s, 2H), 7.07 (d, J¼8.8 Hz, 2H), 7.24e7.31 (m, 1H), 7.35 (d,
J¼7.6 Hz, 1H), 7.48 (d, J¼7.8 Hz, 1H), 7.60 (s, 1H), 7.85 (d, J¼8.8 Hz,
2H), 9.89 (s, 1H). 13C NMR (100 MHz, CDCl3,
): 190.7, 163.3, 138.2,
132.0, 131.3, 130.3, 130.2, 125.8, 122.8, 115.1, 69.2. HRMS (m/z):
[MþH]þ calcd for C14H11BrO2, 290.99424; found, 291.00065.
4.7. (S)-N-((1R,2S)-1-Hydroxy-1-phenylpropan-2-yl)-N-
methyl-3-(4-((40-(trifluoromethyl)biphenyl-3-yl)methoxy)
phenyl)hex-4-ynamide 13
d
A 75 mL Schlenk tube with a septum was charged with Pd(OAc)2
(7.2 mg, 0.032 mmol, 0.02 equiv), PCy3 (17.9 mg, 0.064 mmol,
0.04 equiv), 4-(trifluoromethyl)phenylboronic acid (456 mg,
2.4 mmol, 1.5 equiv), and K3PO4$H2O (737 mg, 3.2 mmol, 2.0 equiv,
finely ground with mortar and pestle). The reaction vessel was
purged with N2 for 10 min, and a solution of 12 (1.60 mmol from
last step) in THF (200 ppm water, degassed by bubbling with N2 for
10 min, 8 mL) was added. The septum was replaced with a screw-
cap and the reaction was heated in a 70 ꢁC oil bath for 4 h. HPLC
analysis indicated reaction was complete. After cooling to rt, the
suspension was filtered through a pad of Celite, concentrated under
reduced pressure, and purified by flash chromatography (silica gel,
4.4. (2R,3S,Z)-6-(4-(3-Bromobenzyloxy)benzylidene)-3,4-
dimethyl-2-phenyl-1,4-oxazepane-5,7-dione 10
To a solution of 8 (1.03 g, 4.41 mmol, 1.0 equiv), 9 (1.41 g,
4.85 mmol, 1.1 equiv), and pyridine (892 mL, 11.05 mmol, 2.5 equiv)
in THF (22 mL) at ꢀ55 ꢁC was added TiCl4 (508
mL, 4.63 mol,
1.05 equiv) dropwise. The pale yellow solution became dark brown
immediately. The suspension was stirred for 16 h, warming to rt.
HPLC analysis indicated a 1:1 mixture of diastereomers. The sus-
pension was filtered through a pad of Celite and the filtrate was
concentrated. The yellow oil was dissolved in CH2Cl2 (20 mL),
washed consecutively with an aqueous solution of HCl (0.1 N,10 mL)
and water (10 mL), dried over MgSO4, and concentrated under re-
duced pressure. Isopropanol (10 mL) was added to the resulting oil,
and the mixture was aged at 90 ꢁC for 4.5 h. The suspension was
cooled and filtered to afford the product as a white solid (1.81 g,
81%). HPLC analysis indicated the E/Z ratio of the product was
2e100% ethyl acetate in hexanes gradient) to afford the product as
25
a yellow oil (0.69 g, 74% over four steps from 10). [
a
]
D
þ5.7 (c 1.0,
MeOH). 1H NMR (400 MHz, CDCl3,
d
): (a mixture of rotamers was
observed) 0.98 (d, J¼6.5 Hz, 3H, minor rotamer), 1.11 (d, J¼7.2 Hz,
3H), 1.76 (d, J¼2.2 Hz, 3H, minor), 1.80 (d, J¼2.2 Hz, 3H) 2.57 (s, 3H),
2.52e2.63 (m, 2H, minor), 2.57 (s, 3H, minor), 2.65e2.76 (m, 2H),
3.35 (d, J¼3.1 Hz, 1H, minor), 3.73e3.85 (m, 1H, minor), 3.96e4.04
(m, 1H, minor), 4.10e4.21 (m, 2H), 4.45e4.57 (m, 1H), 4.77 (t,
J¼3.4 Hz, 1H), 5.06 (s, 2H, minor), 5.08 (s, 2H), 6.89 (d, J¼8.6 Hz, 2H,
minor), 6.94 (d, J¼8.6 Hz, 2H), 7.16e7.70 (m, 15H). 19F NMR
0.5:99.5 (230 nm). Mp 188e196 ꢁC. 1H NMR (400 MHz, CDCl3,
d):
1.26 (d, J¼6.5 Hz, 3H), 3.11 (s, 3H), 3.66 (q, J¼6.7 Hz, 1H), 5.03 (s, 2H),
6.15 (s, 1H), 6.90 (d, J¼8.6 Hz, 2H), 7.20e7.26 (m, 1H), 7.28e7.34 (m,
1H), 7.37 (t, J¼7.04 Hz, 1H), 7.41e7.52 (m, 7H), 7.55 (s, 1H), 7.88 (s,
4H). 13C NMR (100 MHz, CDCl3,
d): 167.3, 162.0, 160.4, 145.9, 138.6,
(377 MHz, CDCl3,
d
): ꢀ62.73 (major rotamer), ꢀ62.26 (minor
136.0, 132.1, 131.2, 130.2, 128.8, 128.6, 126.0, 125.9, 125.8, 124.4, 122.7,
78.5, 75.1, 69.1, 63.9, 35.8, 11.6. HRMS (m/z): [MþH]þ calcd for
C27H24BrNO4, 506.08887; found, 506.09561.
rotamer). 13C NMR (100 MHz, CDCl3,
d
): (a mixture of rotamers was
observed) 3.5, 3.6, 11.9, 14.2, 28.2, 32.9, 33.5, 41.6, 42.7, 57.5, 58.1,
69.7, 75.7, 76.8, 77.7, 78.2, 80.2, 80.6, 114.7, 114.8, 120.1, 122.8, 125.5
(q, 4.0 Hz), 125.9, 126.1, 126.7, 127.0, 127.1, 127.2, 127.8, 128.2 (q,
53.7 Hz), 128.3, 128.4, 129.3 (q, 30.3 Hz), 34.1, 134.2, 134.4, 137.8,
137.8, 139.9, 141.6, 141.9, 144.2, 157.4, 157.5, 170.4. HRMS (m/z):
[MþH]þ calcd for C36H34F3NO3, 586.24908; found, 586.25648.
4.5. (2R,3S)-6-((S)-1-(4-(3-Bromobenzyloxy)phenyl)but-2-
ynyl)-3,4-dimethyl-2-phenyl-1,4-oxazepane-5,7-dione 11
To a suspension of 10 (1.0 g, 1.97 mmol, 1.0 equiv) in THF (15 mL)
at ꢀ45 ꢁC was charged a solution of 1-propynylmagnesium bromide
in THF (0.5 M, 5.94 mL, 2.96 mmol, 1.5 equiv) dropwise. The reaction
temperature was maintained below ꢀ35 ꢁC during the addition. The
reaction was aged for 16 h while warming to rt. HPLC analysis of
the yellow solution indicated starting material was consumed. To the
reaction mixture was added an aqueous solution of saturated am-
monium chloride (10 mL) and water (10 mL), and the mixture was
extracted with CH2Cl2 (1ꢂ20 mL, then 2ꢂ10 mL). The combined
4.8. Conversion of the adduct 13 to 1
To a solution of 13 (320 mg, 0.55 mmol, 1.0 equiv) in CH2Cl2
(6.4 mL) was added dimethyl carbonate (345 mL, 4.1 mmol, 7.5 equiv)
and a solution of sodium methoxide (25% in methanol, 1.18 mL,
5.46 mmol, 10 equiv). The resulting solution was heated at 35 ꢁC for
16 h. After cooling to rt, the reaction was acidified with an aqueous
solution of HCl (1 N, 10 mL) and extracted with CH2Cl2 (3ꢂ10 mL).

J.C.S. Woo et al. / Tetrahedron 66 (2010) 4730e4737
4735
The combined organic layers were washed with a solution of brine
(10 mL) and water (10 mL), dried over MgSO4, and concentrated to
afford the methyl ester as a yellow oil. Ethanol (2 mL) and an
silica). The cake was washed with n-BuOH (2ꢂ5 mL). The combined
n-BuOH solution was used for the next reaction directly without
further purification.
aqueous solution of NaOH (2.5 N, 320
m
L, 0.87 mmol, 2 equiv) were
NaOH (2.5 N, 4.8 mL, 12 mmol, 2 equiv) was slowly added to the
above solution over 10 min at rt. The reaction mixture was stirred at
rt for 16 h to reach >99 A% conversion (by HPLC). Ethyl acetate
(60 mL) and 10% aqueous HCl solution were added and the phases
were separated. The aqueous phase was extracted with ethyl ace-
tate (3ꢂ20 mL) and the combined organic layers were dried over
MgSO4. The solvents were evaporated under reduced pressure and
the remaining residue (a thick yellow oil) was used in the next step
without further purification.
added. After stirring at rt for 16 h, the ethanol was evaporated, iso-
propyl acetate (5 mL) and an aqueous solution of HCl (1 N, 5 mL)
were added. The separated aqueous layer was extracted with iso-
propyl acetate (3ꢂ2 mL). The combined organic layers were washed
with water (10 mL), dried over MgSO4, and concentrated under
reduced pressure to afford the crude acid product as a brown oil.
Acetonitrile (7 mL) was added to dissolve the oil, and an aqueous
solution of sodium hydroxide (5 N,100 mL, 0.55 mmol, 1.0 equiv) was
added dropwise. The resulting slurry was aged at rt for 16 h and
filtered to afford product 1 as an off-white solid (182 mg, 72%).
To a stirred solution of the crude acid from the last step in dry
acetonitrile (22 mL) at rt was added a 10 N aqueous NaOH solution
(0.57 mL, 5.7 mmol, 0.95 equiv) dropwise over 15 min (a volumi-
nous white ppt formed). The resulting mixture was stirred at rt
overnight and filtered onto a fine sintered glass filter funnel. The
product cake was dried in a vacuum oven at 70 ꢁC overnight to
afford 1 (2.1 g, 75%) as a white solid. Mp 139e142 ꢁC. Enantiomeric
excess was determined by HPLC analysis [Chiracel AD-RH 5 micron,
4.6ꢂ150 mm; solvents: A: water (0.1% TFA), B: 80:20 MeOH/ACN
(0.1% TFA) Gradient tR (major)¼8.2 min, tR (minor)¼9.4 min]. 1H
4.9. General procedure for enantioselective conjugate
alkynylation optimization (Tables 2 and 3 and Figs. 2 and 3)
Reactions were typically carried out using 1 mmol substrate 14.
Chiral aminoalcohol (2.9 mmol, 2.9 equiv) and additive (1.9 mmol,
1.9 equiv) were slurried in dry THF (typically contain 30e150 ppm
water, 3.5 mL) and then the mixture was cooled to 0 ꢁC. Diethylzinc
(2.4 mL, 1.0 M in toluene, 2.4 mmol, 2.4 equiv) was added dropwise
via a syringe over 5 min while the temperature was maintained
below 20 ꢁC. The mixture was aged at 20 ꢁC for 1 h to provide
a colorless clear solution. The mixture was cooled to 0 ꢁC and a so-
lution of chloromagnesium acetylide (4.8 mL, 0.5 M in THF,
2.4 mmol, 2.4 equiv) was added dropwise via a syringe over 2 min
while the temperature was maintained below 20 ꢁC. The mixture
was aged at 20 ꢁC for 1 h and the substrate 9 (1 mmol) was added as
a solid. After stirring at 22 ꢁC for 24 h, the mixture was cooled to 0 ꢁC,
1.0 M aqueous HCl (10 mL) was added followed by ethyl acetate
(20 mL), and the layers were separated. The aqueous phase was
extracted with ethyl acetate (1ꢂ20 mL). The combined organic ex-
tracts were washed with brine (1ꢂ20 mL), dried over Na2SO4, and
concentrated under reduced pressure. The crude product was puri-
fied by flash chromatography (silica gel, 75% hexanes/acetone) to
afford, after concentration of the appropriate fractions, the desired
product 15 as a white crystalline. Mp 134e136 ꢁC. Enantiomeric
excess was determined by HPLC analysis [Chiralpak AS-RH, water/
NMR (400 MHz, DMSO-d6,
d
): 7.90 (d, J¼8.2 Hz, 2H), 7.82 (d,
J¼8.2 Hz, 2H), 7.81 (br s, 1H), 7.69 (dt, J¼6.3, 1.9 Hz, 1H), 7.53 (t,
J¼6.3 Hz, 1H), 7.52 (d, J¼6.3 Hz, 2H), 7.26 (d, J¼8.6 Hz, 2H), 6.93 (d,
J¼8.6 Hz, 2H), 5.15 (s, 2H), 4.01 (m, 1H), 2.33 (dd, J¼14.7, 6.9 Hz, 1H),
2.18 (dd, J¼14.7, 7.3 Hz, 1H), 1.74 (d, J¼2.3 Hz, 3H). 13C NMR
(100 MHz, DMSO-d6, d): 174.2, 156.6, 143.9, 138.7, 138.3, 136.1, 129.3,
128.3, 127.9 (q, 2JC-F¼31.7 Hz), 127.6, 127.5, 127.0 (q, 1JC-F¼271.9 Hz),
126.5, 126.2, 125.8 (q, 3JC-F¼3.8 Hz),114.4, 83.3, 76.4, 69.0, 47.5, 33.9,
3.3. HRMS (m/z): [MH]þ calcd for C26H20F3NaO3, 461.1335 found,
461.1326; IR (KBr pellet): 3590, 3064, 1640e1500, 1413, 1328, 1124,
1112, 1071, 789 cmꢀ1
.
Time (min)
%B
0
4
14
15
18
50
90
90
50
50
acetonitrile/ethanol/H3PO4 (40:30:30:0.05), 0.5 mL/min: tR (major)¼
25
31.57 min, tR (minor)¼34.60 min]. [
a
]
þ30.7 (c 0.6, acetone). 1H
D
4.11. 2,2-Dimethyl-5-(4-((40-(trifluoromethyl)biphenyl-3-yl)
NMR (400 MHz, CDCl3, d): 7.58 (s, 1H), 7.47e7.43 (m, 3H), 7.33 (d,
methoxy)benzylidene)-1,3-dioxane-4,6-dione 19
J¼8.0 Hz, 1H), 7.23 (d, J¼8.0 Hz, 1H), 6.91 (d, J¼8.0 Hz, 2H), 5.01 (s,
2H), 3.83 (d, J¼4.0 Hz, 1H), 1.88 (d, J¼4.0 Hz, 3H), 1.71 (s, 3H), 1.62 (s,
3H). 13C NMR (100 MHz, CDCl3,
d): 164.1, 163.4, 157.9, 139.3, 131.0,
4-Hydroxybenzaldehyde 18 (8.6 g, 70.0 mmol),
2 (24.3 g,
77.0 mmol), and K2CO3 (14.5 g, 105.0 mmol) were combined in a 2 L
round bottom flask. DMF (220 mL) was added to the mixture of
solids, and the heterogeneous mixture was stirred for 16 h before
quenched by pouring the mixture into water (200 mL). The mixture
was stirred for an additional 2 h to allow agglomeration to occur.
The resulting precipitate was filtered and dried under vacuum at
ambient temperature to give 4-((40-(trifluoromethyl)biphenyl-3-yl)
methoxy)benzaldehyde as a yellow solid (24.7 g). The material was
used directly in the next reaction.
130.3, 130.2, 129.9, 125.8, 122.7, 114.7, 105.2, 81.2, 76.1, 69.1, 53.0, 36.1,
28.4, 27.8, 3.8. HRMS (m/z): [MþNa]þ calcd for C23H21BrO5,
479.0470; found, 479.0481. IR (neat): 3003, 1921, 1784, 1746, 1510,
1292, 1177 cmꢀ1
.
4.10. Procedure for conversion of the adduct 15 to (S)-3-[4-
(40-trifluoromethyl-biphenyl-3ylmethoxy)-phenyl]-hex-4-
ynoic acid sodium salt (1)
The crude aldehyde from the previous step, Meldrum’s acid
(12.1 g, 84.0 mmol), and DMAP (0.85 g, 7.0 mmol) were combined in
THF (100 mL). The solution was stirred at room temperature for 24 h.
The product was isolated by diluting the mixture with water (150 mL)
and extracting with ethyl acetate (2ꢂ150 mL). The combined organic
extracts were concentrated to dryness to yield a yellow solid. The
yellow solid was purified by slurrying in acetone/water (1:2, 700 mL)
at rt for 3 h. The mixture was filtered, the filter cake was dried under
vacuum at ambient temperature to afford 19 (31.1 g, 92% yield over
Compound 15 (2.74 g, 6 mmol) was dissolved in n-BuOH
(27.5 mL, typically 300e500 ppm water) and heated at reflux for
16 h. The reaction was monitored by HPLC to reach >99 A%
conversion. To this solution at rt were added boronic acid 5 (1.4 g,
7.2 mmol, 1.2 equiv), Pd(OAc)2 (13.5 mg, 0.06 mmol, 0.01 equiv),
PCy3 (33.7 mg, 0.12 mmol, 0.02 equiv), and K3PO4 (2.55 g, 12 mmol,
2.0 equiv) sequentially. The reaction mixture was degassed three
times (vacuum/nitrogen cycle) and stirred at 75 ꢁC for 18 h to reach
>99 A% conversion (by HPLC). To the resulting mixture was added
1 g of charcoal and the mixture was agitated for 1 h at 65 ꢁC. The
mixture was cooled to rt and filtered through a silica pad (e10 g
two steps) as a yellow solid.1H NMR (400 MHz, CDCl3,
8.23 (d, J¼8.0 Hz, 2H), 7.70 (s, 4H), 7.66 (s, 1H), 7.59 (d, J¼8.0 Hz, 1H),
d): 8.38 (s,1H),

4736
J.C.S. Woo et al. / Tetrahedron 66 (2010) 4730e4737
7.54e7.46 (m, 2H), 7.08 (d, J¼8.0 Hz, 2H), 5.25 (s, 2H), 1.79 (s, 6H). 13
C
Supplementary data
NMR (100 MHz, CDCl3, d): 164.0, 163.6, 160.5, 157.7, 144.2, 140.4, 137.6,
136.7, 129.9 (q, 1JC-F¼220.0 Hz), 129.5, 127.5, 127.4, 127.3, 126.4, 125.8
(q, 3JC-F¼4.0 Hz),125.4 (q, 2JC-F¼47.0 Hz),115.2,111.3,104.2, 70.2, 27.6.
HRMS (m/z): [M]þ calcd for C27H21F3O5, 482.1341; found, 482.1349. IR
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.04.019.
(neat): 3003, 1921, 1784, 1746, 1510, 1292, 1177 cmꢀ1
.
References and notes
4.12. (S)-2,2-Dimethyl-5-(1-(4-((40-(trifluoromethyl)biphenyl-
3-yl)methoxy)phenyl)but-2-ynyl)-1,3-dioxane-4,6-dione 16
1. Bharate, S. B.; Nemmani, K. V. S.; Vishwakarma, R. A. Expert Opin. Ther. Pat. 2009,
19, 237 and references therein.
2. Akerman, M.; Houze, J.; Lin, D. C. H.; Liu, J.; Luo, J.; Medina, J. C.; Qiu, W.;
Reagan, J. D.; Sharma, R.; Shuttleworth, S. J.; Sun, Y.; Zhang, J.; Zhu, L. Int. Appl.
PCT, WO 2005086661, 2005.
Cinchonidine (853.8 mg, 2.9 mmol, 1.45 equiv) and tri-
3. Walker, S. D., Borths, C.; DiVirgilio, E.; Faul, M. M.; Huang, L.; Liu, P.; Woo, J. C. S.,
in preparation.
fluoroethanol (140 mL, 1.9 mmol, 0.95 equiv) were slurried in dry
THF (typically contain 30e150 ppm water, 3.5 mL) and then the
mixture was cooled to 0 ꢁC. Diethylzinc (2.4 mL, 1.0 M in toluene,
2.4 mmol, 1.2 equiv) was added dropwise via a syringe over 5 min
while the temperature was maintained below 20 ꢁC. The mixture
was aged at 20 ꢁC for 1 h to provide a colorless clear solution. The
mixture was cooled to 0 ꢁC and a solution of propynylmagnesium
chloride (4.8 mL, 0.5 M in THF, 2.4 mmol, 1.2 equiv) was added
dropwise via a syringe over 5 min while the temperature was
maintained below 20 ꢁC. The mixture was aged at 20 ꢁC for 1 h
and the substrate 19 (965 mg, 2 mmol, 1.0 equiv) was added as
a solid. After stirring at 22 ꢁC for 24 h, the mixture was cooled to
0 ꢁC, 1.0 M aqueous HCl (25 mL) was added followed by ethyl
acetate (60 mL), and the layers were separated. The aqueous
phase was extracted with ethyl acetate (2ꢂ20 mL). The combined
organic extracts were washed with brine (2ꢂ20 mL), dried over
Na2SO4, and concentrated under reduced pressure. The crude
product was crystallized from acetone/water (3:1) to afford the
desired product 16 (857 mg, 82% yield, >99 wt %, >99% ee) as
a white crystalline solid. Mp 139e142 ꢁC. Enantiomeric excess
was determined by HPLC analysis [Chiralpak AS-RH, 4.6ꢂ150 mm,
4. Partof thisworkhasbeencommunicated:Cui, S.;Walker, S. D.;Woo,J. C. S.;Borths,
C. J.; Mukherjee, H.; Chen, M. J.; Faul, M. M. J. Am. Chem. Soc. 2010, 132, 436.
5. Mukaiyama, T.; Takeda, T.; Osaki, M. Chem. Lett. 1977, 1165.
6. (a) Mukaiyama, T.; Hirako, Y.; Takeda, T. Chem. Lett. 1978, 461; (b) Mukaiyama,
T.; Takeda, T.; Fujimoto, K. Bull. Chem. Soc. Jpn. 1978, 51, 3368; (c) Takeda, T.;
HoshiKo, T.; Mukaiyama, T. Chem. Lett. 1981, 797; (d) Tietze, L. F.; Brand, S.;
Pfeiffer, T. Angew. Chem., Int. Ed. Engl. 1985, 24, 784; (e) Tietze, L. F.; Brand, S.;
Pfeiffer, T.; Antel, J.; Harms, K.; Sheldrick, G. M. J. Am. Chem. Soc. 1987, 109, 921;
(f) Trost, B. M.; Yang, B. W.; Miller, M. L. J. Am. Chem. Soc. 1989, 111, 6482; (g)
Brown, R. T.; Ford, M. J. Tetrahedron Lett. 1990, 31, 2033; (h) Li, W.; Thottathil, J.;
Murphy, M. Tetrahedron Lett. 1994, 35, 6591.
€
7. (a) Knopfel, T. F.; Boyall, D.; Carreira, E. M. Org. Lett. 2004, 6, 2281; For examples
of asymmetric conjugate alkynylation using other chiral auxiliaries, see: (b)
Elzner, S.; Maas, S.; Engel, S.; Kunz, H. Synthesis 2004, 13, 2153; (c) Fujimori, S.;
Carreira, E. M. Angew. Chem., Int. Ed. 2007, 46, 4964.
8. See Experimental Section.
9. (a) Intramolecular cyclization of alkynyl acids is a potential decomposition
pathway, see: Woo, J. C. S.; Walker, S. D.; Faul, M. M. Tetrahedron Lett. 2007, 48,
5679; (b) Thermal and base-mediated alkyne isomerization are also potential
side-reactions, see: Jones, E. R. H.; Mansfield, E. H.; Whiting, M. C. J. Chem. Soc.
1954, 3208; (c) For a review see: Iwai, I. Mechanisms of Molecular Rearrange-
ments 1969, 2, 72e116.
10. Kudo, N.; Perseghini, M.; Fu, G. C. Angew. Chem., Int. Ed 2006, 45, 1282 and
references therein.
11. Kanomata, N.;Maruyama, S.;Tomono, K.;Anada,S. TetrahedronLett. 2003, 44, 3599.
12. For the review of the Meldrum’s acids, see: (a) Chen, B. C. Heterocycles 1991, 32,
529 For recent examples of other conjugate additions using Meldrum’s acids
water (0.1% NH4Ac)/MeCN (58:42), 0.8 mL/min: tR (major)¼
25
13.3 min, tR (minor)¼18.5 min]. [
a
]
D
þ29.3 (c 0.53, acetone). 1H
derived acceptors as the substrates, see: (b) Watanabe, T.; Knopfel, T. F.; Car-
€
reira, E. M. Org. Lett. 2003, 5, 4557; (c) Fillion, E.; Wilsily, A. J. Am. Chem. Soc.
2006, 128, 2774; (d) Fillion, E.; Wilsily, A.; Liao, E.-T. Tetrahedron: Asymmetry
2006, 17, 2957; (e) Fillion, E.; Carret, S.; Mercier, L. G.; Trépanier, V. É Org. Lett.
2008, 10, 437; (f) Wilsily, A.; Fillion, E. Org. Lett. 2008, 10, 2801; (g) Dumas, A.
M.; Fillion, E. Org. Lett. 2009, 11, 1919; (h) Wilsily, A.; Lou, T.; Fillion, E. Synthesis
2009, 2066.
NMR (400 MHz, CDCl3,
d): 7.69 (s, 4H), 7.64 (s, 1H), 7.55 (d,
J¼8.0 Hz, 1H), 7.50e7.43 (m, 4H), 6.95 (d, J¼8.0 Hz, 2H), 5.12 (s,
2H), 4.85 (s, 1H), 3.83 (d, J¼4.0 Hz, 1H), 1.88 (d, J¼4.0 Hz, 3H), 1.71
(s, 3H), 1.62 (s, 3H). 13C NMR (100 MHz, CDCl3,
d): 164.1, 163.4,
2
158.2, 144.4, 140.2, 137.9, 130.2, 129.9, 129.5 (q, JC-F¼32.0 Hz),
€
13. Knopfel, T. F.; Carreira, E. M. J. Am. Chem. Soc. 2003, 125, 6054 and references
3
129.3, 127.5, 127.2, 126.9, 126.3, 125.7 (q, JC-F¼4.0 Hz), 124.3 (q,
therein.
1JC-F¼274.0 Hz), 114.7, 105.2, 81.2, 76.1, 69.9, 53.0, 36.1, 28.4, 27.8,
3.8. HRMS (m/z): [MþNa]þ calcd for C30H25F3O5, 545.1552; found,
545.1552. IR (neat): 3003, 2254, 1785, 1747, 1510, 1324, 1292,
€
14. Knopfel, T. F.;Zarotti,P.;Ichikawa,T.;Carreira,E.M.J.Am. Chem.Soc. 2005,127, 9682.
15. Fillion, E.; Zorzitto, A. K. J. Am. Chem. Soc. 2009, 131, 14608.
16. For recent reviews of asymmetric conjugate alkynylation, see: (a) Fujimori, S.;
€
Knopfel, T. F.; Zarotti, P.; Ichikawa, T.; Boyall, D.; Carreira, E. M. Bull. Chem. Soc.
1165 cmꢀ1
.
Jpn. 2007, 80, 1635; (b) Trost, B. M.; Weiss, A. H. Adv. Synth. Catal. 2009, 351, 963
For examples of 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; (e) Yamashita, M.; Yamada, K.; Tomioka,
K. Org. Lett. 2005, 7, 2369; (f) 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; (i) Larionov, O. V.; Corey, E. J. Org. Lett. 2010, 12, 300 For
an example of rhodium-catalyzed enantioselective conjugate alkynylation of
enals, see: (j) Nishimura, T.; Sawano, T.; Hayashi, T. Angew. Chem., Int. Ed. 2009,
48, 8057 For the example of rhodium-catalyzed asymmetric rearrangement of
alkynyl alkenyl carbinols: synthetic equivalent to asymmetric conjugate alky-
nylation of enones, see: (k) Nishimura, T.; Katoh, T.; Takatsu, K.; Shintani, R.;
Hayashi, T. J. Am. Chem. Soc. 2007, 129, 14158 For the example of organocatalytic
formal alkynylation of enals, see: (l) Nielsen, M.; Jacobsen, C. B.; Paixão, M. W.;
Holub, N.; Jørgensen, K. A. J. Am. Chem. Soc. 2009, 131, 10581.
4.13. Conversion of the adduct 16 to 1
Compound 16 (523 mg, 1.0 mmol) was dissolved in DMF
(2.2 mL) and water (0.2 mL) and heated to 90 ꢁC for 2 h. The re-
action mixture was then cooled to rt, diluted with ethyl acetate
(15 mL), and washed with brine (3ꢂ10 mL). The organic layer was
dried over MgSO4, filtered, and concentrated under reduced pres-
sure to afford the free acid of 1 as colorless oil. The crude product
was directly used in the next step.
To a stirred solution of the crude acid in dry acetonitrile (3.3 mL)
at rt was added a 5 N aqueous NaOH solution (0.2 mL, 1.0 equiv)
dropwise over 15 min (a voluminous white ppt formed). The
resulting mixture was stirred at rt overnight and filtered onto a fine
sintered glass filter funnel. The product cake was dried in a vacuum
oven at 70 ꢁC overnight to afford 1 (414 mg, 90%) as a white solid.
17. A variety of other chiral ligands and metals including copper, rhodium and
lithium were also evaluated and gave lower yield and enantioselectivity.
18. The method to generate chiral alkynylzinc reagents played a key role. Chiral
alkynylzinc reagents produced by transmetalation provided superior reactivity
to in situ generated chiral zinc alkynylides by ZnII/R3N.
19. For similar zinc species see: (a) Enders, D.; Zhu, J.; Raabe, G. Angew. Chem., Int. Ed.
1996, 35, 1725; (b) Enders, D.; Zhu, J.; Kramps, L. Liebigs Ann. 1997, 1101; (c) Dosa,
P. I.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 445; (d) Uchiyama, M.; Kameda, M.;
Mishima, O.; Yokoyama, N.; Koike, M.; Kondo, Y.; Sakamoto, T. J. Am. Chem. Soc.
1998, 120, 4934; (e) Tan, L.; Chen, C.; Tillyer, R. D.; Grabowski, E. J. J.; Reider, P. J.
Angew. Chem., Int. Ed. 1999, 38, 711; (f) Chen, C.; Tan, L. Enantiomer 1999, 4, 599.
20. Zincate is depicted as a monomer for clarity. Preliminary NMR studies indicate
that several different zincate species exist in solution.
Acknowledgements
We are grateful to Dr. Tsang-Lin Hwang for NMR structural
work. We thank Maosheng Chen, Bo Shen, and Judith Ostovic for
the chiral HPLC analysis.
21. For full details, see Ref. 4.

J.C.S. Woo et al. / Tetrahedron 66 (2010) 4730e4737
4737
22. (a) Other solvents (Me-THF, MTBE, DME, toluene) evaluated provided lower ee
(<80%) and yield (<90%); (b) Me2Zn and Et2Zn were equally efficient; (c)
Enantioselectivity was not dependent on the concentration (0.04e0.2 M); (d)
The order of addition of reagents during preparation of the zincate (Et2Zn/
trifluoroethanol/cinchonidine) had no effect.
23. Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew. Chem., Int. Ed.
2004, 43, 1871.
24. Krasovskiy, A.; Knochel, P. Synthesis 2006, 5, 890.
25. Tietze, L. F.; Brand, S.; Pfeiffer, T. Angew. Chem., Int. Ed. Engl. 1985, 24, 784.
26. Brown, R. T.; Ford, M. J. Synth. Commun. 1988, 18, 1801.