Asymmetric phase-transfer catalyzed glycolate alkylation, investigation of the scope, and application to the synthesis of (-)-ragaglitazar

Article abstract of DOI:10.1021/jo051568z

Asymmetric glycolate alkylation using a protected acetophenone surrogate under solid-liquid phase-transfer conditions is a new approach to the synthesis of 2-hydroxy esters and acids. Diphenylmethyloxy-2,5-dimethoxyacetophenone 1 with a trifluorobenzyl ci

Full text of DOI:10.1021/jo051568z

Asymmetric Phase-Transfer Catalyzed Glycolate Alkylation,
Investigation of the Scope, and Application to the Synthesis of
(-)-Ragaglitazar
Merritt B. Andrus,* Erik J. Hicken, Jeffrey C. Stephens, and D. Karl Bedke
Department of Chemistry and Biochemistry, Brigham Young University,
C100 BNSN, Provo, Utah 84602-5700
mbandrus@chem.byu.edu
Received July 27, 2005
Asymmetric glycolate alkylation using a protected acetophenone surrogate under solid-liquid phase-
transfer conditions is a new approach to the synthesis of 2-hydroxy esters and acids. Diphenyl-
methyloxy-2,5-dimethoxyacetophenone 1 with a trifluorobenzyl cinchonidinium bromide catalyst
9 (10 mol %) and cesium hydroxide provided S-alkylation products 2 at -35 °C in high yield (80-
99%) and with excellent enantioselectivities using a wide range of electrophiles (80-90% ee).
Alkylated products were elaborated to useful R-hydroxy intermediates 3 using bis-TMS peroxide
Baeyer-Villiger conditions and selective transesterification reactions. The ester products have been
enantioenriched by simple recrystallization from ether to give a single isomer (99% ee). A tight
ion-pair model is proposed for the observed S-stereoinduction that includes van der Waals contacts
between the extended enolate and the isoquinoline of the catalyst. To demonstrate the utility of
the new methodology, the anti-diabetes drug (-)-ragaglitazar 24 was synthesized in six steps from
a key 2-alkoxy-3-p-phenoxypropionic acid 26 that was made using PTC glycolate alkylation.
SCHEME 1. Glycolate Alkylation
Introduction
Phase-transfer catalysis (PTC) is rapidly becoming an
attractive, general approach to asymmetric synthesis.
Under these conditions a reactive enolate, ion-paired with
an enantiopure ammonium ion, partitions to the organic
phase where it can selectively react with a variety of
electrophiles. Successful methods have been developed
for asymmetric glycine alkylations, enone epoxidation,
conjugate additions, and other transformations that now
rival auxiliary and metal-complex-based approaches.1
PTC has numerous attractive features including the use
of inexpensive, cinchona alkaloid catalysts, which are
readily available in both enantiomeric antipodes, simple
hydroxide bases for in situ enolate formation, and mild
conditions that can be run in either liquid-liquid or
liquid-solid mode over an extended temperature range.
The formation of C-C bonds through direct alkylation
of an enolate poses a significant synthetic problem. There
are only a few successes based on catalytic methods using
sp3 hybridized electrophiles.2 The recent report by
Jacobsen is a significant advance in this area.2a In an
effort to develop a process using glycolate intermediates,
we previously reported PTC with oxygenated substrates
using the novel alkoxyacetophenone 1.3 This method
provides a route to a variety of alkylated hydroxy
products 2 formed under mild conditions in high selectiv-
ity (Scheme 1). Previous to this work, known asymmetric
glycolate alkylations were limited to chiral auxiliary
based approaches.4 The resultant PTC product undergoes
(2) (a) Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127,
62-63. (b) Vignola, N.; List, B. J. Am. Chem. Soc. 2004, 126, 450-
451. (c) Imai, M.; Hagihara, A.; Kawasaki, H.; Manabe, K.; Koga, K.
J. Am. Chem. Soc. 1994, 116, 8829-8830.
(3) Andrus, M. B.; Hicken, E. J.; Stephens, J. S. Org. Lett. 2004, 6,
2289-2292.
(1) (a) Maruoka, K.; Ooi, T. Chem. Rev. 2003, 103, 3013-3028. (b)
Kacprzak, K.; Gawronski, J. Synthesis 2001, 961-998. (c) O’Donnell,
M. J. Aldrichimica Acta 2001, 3, 3-15.
10.1021/jo051568z CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/14/2005
9470
J. Org. Chem. 2005, 70, 9470-9479

Phase-Transfer Catalyzed Glycolate Alkylation
SCHEME 2. PTC Glycine Alkylation
SCHEME 4. Phase Transfer Mechanism
SCHEME 3. Phase Transfer Catalysts
Investigated
TABLE 1. PTC Benzylation of Aryl Ketone 1
aryl ketone, Ar )
time (h)
yield (%)
ee (%)
phenyl
26
6
74
82
78
50
87
72
70
83
78
90
83
25
54
66
50
17
62
66
60
55
54
71
p-anisyl
o-anisyl
m-anisyl
N,N-dimethylaniline
o-toluyl
2,4-xylyl
5-methyl-2-anisyl
1-naphthyl
2,4-dimethoxy
2,5-dimethoxy
8
16
13
12
8
11
8
13
7
Baeyer-Villiger-type oxidation to give the aryl ester,
which is readily transesterified to produce the useful
R-hydroxy ester 3. PTC glycolate alkylation also serves
as a starting point to the design of new asymmetric,
catalytic approaches to a variety of oxygenated products
using other electrophiles. We now report a full account
of the development of catalytic glycolate alkylation
including substrate optimization, investigation of the
conditions, the scope of the electrophile, elaboration to
synthetic intermediates, the origin of the stereoinduction,
together with a direct, efficient route to the new diabetes
drug (-)-ragaglitazar.
PTC amino acid synthesis has been facilitated by the
benzophenone imine tert-butyl glycine 4 (Scheme 2),
pioneered by O’Donnell,5 as a result of its extended
enolate conjugation and relatively low pKa value (18.7,
DMSO).1c Cinchonidine-derived catalysts (Scheme 3,
1-10 mol %), bases, and reaction condition variations
have shown steady improvement in selectivity for the
production of S-5 (Scheme 3). Nonnatural chiral bis-
binaphthyl catalysts1a,3f typified by 8 have also demon-
strated success. Asymmetric PTC reactions have been
shown to follow an interfacial-type mechanism, where
enolate formation occurs at the solvent interface boundry
layer and alkylation of the ammonium-enolate ion-pair
in the organic layer is the rate-limiting step (Scheme 4).6
To extend PTC to glycolates, with oxygen now in place
of nitrogen at C-2, reactivity and selectivity must be
addressed in the context of an entirely new substrate.
The key effect is the formation of the organic soluble
glycolate enolate-cinchonidinium tight ion-pair 12 that
selectively reacts with electrophiles.1a,7 The cinchonidin-
ium cation is free to ion exchange with additional metal
enolate 11 at the interface, facilitating further phase
transfer and alkylation. Liquid-solid PTC mode, which
gives improved selectivity with metal hydroxide hydrates
without added water at lower temperatures (-78 to -20
°C), is an important recent advance.3c
(4) Previous asymmetric glycolate alkylations are limited to chiral
auxiliaries: (a) Crimmins, M. T.; Emmitte, K. A.; Katz, J. D. Org. Lett.
2000, 2, 2165-2167. (b) Schmidt, B.; Wildermann, H. J. Chem. Soc.
Perkin Trans. 1 2002, 1050-1060. (c) Chappell, M. D.; Stachel, S. J.;
Lee, C. B.; Danishefsky, S. J. Org. Lett. 2000, 2, 1633-1636. (d) Burke,
S. D.; quinn, K. J.; Chen, V. J. J. Org. Chem. 1998, 63, 8626-8627. (e)
Cardillo, G.; Orena, M.; Romero, M.; Sandri, S. Tetrahedron 1989, 45,
1501-1508. (f) Jung, J. E.; Ho, H.; Kim, H.-D. Tetrahedron Lett. 2000,
41, 1793-1796. (g) Maeda, K.; Oishi, T.; Oguri, H.; Hirama, M. Chem.
Commun. 1999, 1063-1064. (h) Davies, S. G.; Wills, M. J. Organomet.
Chem. 1987, 328, C29-C33. (i) Ludwig, J. W.; Newcomb, M.; Berbre-
iter, D. E. Tetrahedron Lett. 1986, 27, 2731-2734. (j) Enomoto, M.;
Ito, Y.; Katsuki, T.; Yamaguchi, M. Tetrahedron Lett. 1985, 26, 1343-
1344. (k) Helmchen, G.; Wierzchowski, R. Angew. Chem., Int. Ed. Engl.
1984, 23, 60-61. (l) Yu, H.; Ballard, C. E.; Boyle, P. D.; Wang, B.
Tetrahedron 2002, 58, 7663-7679.
(5) (a) O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc.
1989, 111, 2353-2354. (b) O’Donnell, M. J.; Delgado, F.; Hostettler,
C.; Schwesinger, R. Tetrahedron Lett. 1998, 39, 8775-8778. (c) Corey,
E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414-12415.
(d) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38, 8595-8598.
(e) Corey, E. J.; Bo, Y.; Busch-Petersen, J. J. Am. Chem. Soc. 1998,
120, 13000-13001. (f) Ooi, T.; Kameda, K.; Maruoka, K. J. Am. Chem.
Soc. 1999, 121, 6519-6520. (g) Jew, S.; Yoo, M.; Jeong, B.; Park, I. Y.;
Park, H. Org. Lett. 2002, 4, 4245-4248. (h) Park, H.; Jeong, B.; Yoo,
M.; Lee, J.; Park, M.; Lee, Y.; Kim, M.; Jew, S. Angew. Chem., Int. Ed.
2002, 41, 3036-3038.
Results and Discussion
Aryl ketone functionality, with a lower pKa value (∼22),
proved essential for PTC reactivity (Table 1). Glycolate
esters (pKa ∼25) were initially explored without success
even with the use of the more potent phosphazene,
Schwesinger bases BTPP and P2-t-Bu under homoge-
neous conditions.3b tert-Butyl benzyloxyacetate (not shown)
failed to give product with allyl bromide in the presence
of cinchonidinium catalyst and various bases. The cor-
responding thioester gave low yields and selectivities
(6) (a) Hughes, D. L.; Dolling, U. H.; Ryan, K. M.; Schoenewadt, E.
F.; Grabowski, E. J. J. J. Org. Chem. 1987, 52, 4745. (b) Lipkowitz, K.
B.; Cavanaugh, M. W.; Baker, B.; O′Donnell, M. J. J. Org. Chem. 1991,
56, 5181-5192. (c) Starks, C. M. In Phase-Transfer Catalysis; Halpern,
M. E., Ed.; ACS Symposium Series 659; The American Chemical
Society: Washington, DC, 1997; pp 10-28.
(7) Maruoka, K.; Ooi, T. Chem. Rev. 2003, 103, 3013-3028.
J. Org. Chem, Vol. 70, No. 23, 2005 9471

Andrus et al.
TABLE 3. Effect of Solvent, Temperature, and Base
TABLE 2. PTC Benzylation of 2,5-Dimethoxy Ketone 1
solvent
CH2Cl2
CH2Cl2/Et2O 1:1
CH2Cl2/n-hex. 1:1
toluene
temp (°C)
time (h)
yield (%)
ee (%)
P )
time (h)
yield (%)
ee (%)
-40
-40
-40
-40
-40
-40
-40
-40
-40
-40
-20
-30
-60
7
22
13
28
24
23
16
13
39
72
12
12
52
80
84
96
80
50
68
72
50
74
tr
80
86
86
86
60
76
41a
10b
84c
d
Bn
7
9
13
23
10
7
83
83
80
70
84
80
71
68
75
40a
7a
PMB
2-Nap-Me
p-MeO-Ph
methyl
DPM
CHCl3
Tol/CHCl3 7:3
CH2Cl2/n-hex. 1:1
CH2Cl2/n-hex. 1:1
CH2Cl2/n-hex. 1:1
CH2Cl2/n-hex. 1:1
CH2Cl2/n-hex. 1:1
CH2Cl2/n-hex. 1:1
CH2Cl2/n-hex. 1:1
80
a The o-methoxyketone 1 was used.
86
95
69
82
85
84
with catalyst 9 and CsOH‚H2O (29%, 13% ee) and P2-t-
Bu (50 h, 41%, 8% ee). Numerous acetophenones with
various protecting groups 1 were screened (Table 1).
Benzyl-protected substrates 1 were made from benzyloxy
acetyl chloride via the Weinreb amide and displacement
with aryl Grignard reagents.8 Benzyloxyacetophenones
1 were treated with benzyl bromide (5 equiv) and
trifluorobenzyl cinchonidinium bromide 93g (10 mol %)
using CsOH‚H2O (5 equiv) in CH2Cl2 at -40°.9 This
catalyst is conveniently made in three steps from inex-
pensive cinchonidine and can be chromatographed prior
to use. The parent acetophenone 1 (Ar ) Ph) gave product
3 with 25% ee (Chiral HPLC) in 74% yield after 26 h.10
More electron-rich aryl ketones were predicted to show
higher reactivity and selectivity through enhanced ion-
pairing with the catalyst.3c The rate of phase transfer,
ion-pairing, and nonbonded interactions that control
selectivity should all be improved by increasing the
electrostatic interaction of the enolate with the am-
monium ion of the catalyst. The p-methoxy variant 1
improved to 54% ee, and o-anisyl 1 further increased to
66% ee with much shorter reaction times and higher
yields, 6 and 8 h, respectively. Dimethylaniline, tolyl, and
2,4-dimethoxy variants did not show improvement. Fi-
nally, 2,5-dimethoxyacetophenone 1 demonstrated a syn-
ergistic enhancement of reactivity and selectivity, giving
product with 71% ee (83%) in 7 h.
The 2,5-dimethoxyphenyl motif was maintained and
explored with various protecting groups 1 (catalyst 9,
Table 2). The benzyl-, p-methoxybenzyl-, and 2-naphth-
ylmethyl-protected substrates 1 (P ) Bn, PMB, 2-NPM)
all reacted with good yields and selectivities (80-83%,
68-75% ee). With the C2 hydroxyl protected as a p-
methoxyphenyl or a simple methyl ether, the rate of
reaction was decreased and the selectivity was eroded.
The larger benzhydryl (P ) diphenylmethyl, DPM) group
was found to be superior, allowing for efficient reactivity
at -40 °C in CH2Cl2 to give 2 in 80% yield and very good
selectivity of 80% ee (90:10 er). It is interesting to note
that the topology of this group approximates the diphe-
a Corey/Lygo catalyst 7 was used. b Catalyst 8 was used.
c RbOH‚H2O used as base. d Ba(OH)2 used.
nylmethyl imine group of glycine 4. The rate of reaction
with DPM 1 was also significantly faster, being complete
after 7 h at this temperature. Other modifications to
DPM group, including bis(p-methoxyphenyl)methyl and
di-2-naphthylmethyl, did not show enhanced reactivity
(88% and 83%) or selectivity (85% and 84% ee).
Solvent, base, and temperature were explored to
optimize the process (Table 3). Solvents and combinations
1:1 CH2Cl2/Et2O, CH2Cl2/n-hexane, and toluene were
explored again with trifluorobenzyl catalyst 9 and the
insoluble base CsOH‚H2O at -40 °C in liquid-solid mode
with benzyl bromide. Product 2 was obtained with
excellent selectivity using CH2Cl2/Et2O, 86% ee (22 h,
93:7 er). Liquid-liquid mode, with aqueous NaOH or
KOH in toluene, was inferior. The fastest rate was found
in CH2Cl2/n-hexane, giving a 96% yield in 13 h with 93:7
er. Other solvents and combinations were less effective.
In 1:1 CH2Cl2/n-hexane, the 9-anthracenylmethyl cin-
chonidine catalyst 7 gave 2 with 40% ee and the bis-
binaphthyl catalyst 8 gave only 10% ee. Rubidium
hydroxide with 2 showed excellent selectivity; however,
the rate was slow, 39 h, and barium hydroxide failed to
give product. Temperature changes had only a slight
effect on the rate of the reaction. At -20 °C with CsOH‚
H2O, the selectivity dropped slightly to 82% ee. At -30°,
the selectivity improved to 85% ee. At -60 °C the rate of
reaction was very slow, 52 h, and the selectivity was
lowered slightly to 84% ee. Catalyst aggregation or
substrate coordination are the likely causes of this
nonlinear response.13c Changing the reaction concentra-
tion, from 0.1 to 0.05 or 0.6 M, and amount of the benzyl
(11) (a) Kobayashi, S.; Tanaka, H.; Amii, H.; Uneyama, K, Tetra-
hedron 2003, 59, 1547-1552. (b) Boyes, S. A.; Hewson, A. T. J. Chem.
Soc. Perkin Trans. 1 2000, 2759-2765.
(12) (a) Sawanda, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2000, 122, 10521-10532. (b) Go¨ttlich, R.; Yamakoshi, K.; Sasai, H.;
Shibasaki, M. Synlett 1997, 971-974. (c) Trost, B. M.; Terrell, L. R. J.
Am. Chem. Soc. 2003, 125, 338-339.
(13) (a) Andrus, M. B.; Meredith, E. L.; Hicken, E. J. Simmons, B.
L.; Glancey, R. R.; Ma, W. J. Org. Chem. 2003, 68, 8162-8169. (b)
Andrus, M. B.; Mendenhall, K. G.; Meredith, E. L.; Soma Sekhar, B.
B. V. Tetrahedron Lett. 2002, 43, 1789-1792. (c) Andrus, M. B.
Meredith, E. L.; Simmons, B. L.; Soma Sekhar, B. B. V.; Hicken, E. J.
Org. Lett. 2002, 4, 3549-3552. (d) Andrus, M. B. Meredith, E. L.; Soma
Sekhar, B. B. V. Org. Lett. 2001, 3, 259-262.
(8) (a) Sibi, M. P. Org. Prep. Proced. Int. 1993, 25, 15-48. (b)
Sengupta, S.; Mondal, S.; Das, D. Tetrahedron Lett. 1999, 40, 4107-
4110. (c) Williams, R. M. J. Org. Chem. 1987, 52, 2615-2618.
(9) TLC was used to monitor for disappearance of the starting
material.
(10) Comparisons were made with racemic materials formed without
added PTC catalyst at higher temperatures (chiral HPLC, Chiracel
AD column, 10% EtOH/hexane, 0.5 mL/min, 170 psi, R-isomer tR -15.2
min, S-17.0 min, UV 254 nM detection). See Supporting Information.
9472 J. Org. Chem., Vol. 70, No. 23, 2005

Phase-Transfer Catalyzed Glycolate Alkylation
SCHEME 5. Synthesis of Aryl Ketone 1
found to be crystalline, allowing for enhancement of the
enantiopurity through simple recrystallization from warm
ether (>99% ee). Benzoate 15 and other protecting groups
also allow for production of the aryl ester 16 under the
TMS peroxide conditions. This ester 16 was selectively
converted to methyl esters under transesterification
conditions that either maintain the benzoate ester, giving
17, or alternatively generate the methyl ester and give
a free hydroxyl at C2, 18.13 When treated with catalytic
NaOMe (20 mol %) in MeOH, the S-methyl ester ben-
zoate 17 was obtained in 81% isolated yield ([R]D -35.5°
(c 2.0, CHCl3), lit.14 -40.2° (c 1.85, MeOH). Alternatively,
when 16 was treated with excess NaOMe (2.1 equiv) in
methanol for 13 h, S-hydroxy ester 18 ([R]D -8.8° (c 2.0,
CHCl3), lit.15 -7.6° (c 2.0, CHCl3) was obtained in 82%
yield after 13 h without racemization. n-π-Interaction
renders the aryl ester more labile when catalytic sodium
methoxide is used, allowing for selective aryl ester
transesterification in the presence of an alkyl ester.
Asymmetric PTC alkylation of 1 with catalyst 9 (10
mol %) was performed with a number of benzyl, allyl,
and propargyl electrophiles (2-5 equiv, Table 4). All
benzyl and allylic bromides (2 equiv) investigated reacted
in high yield and selectivity (85-90% ee). The yields
indicated and the selectivities (chiral HPLC) are again
reported for isolated materials with comparisons to
racemic materials. Propargyl bromides (3 equiv), includ-
ing those substituted at the 3-position (entries 6 and 7),
were also successful. Allyl iodides, as used with oxazo-
lidinone auxiliary based glycolates,4a also reacted but
with lower selectivity. Reactions with n-alkyl iodides (5
equiv) and tosylates were not successful. Only methyl
iodide reacted at -20 °C with success to give 2 with
moderate results (entry 15, R ) Me, 79%, 66% ee).12,16
tert-Butyl bromoacetate (entry 14), in contrast, gave
product with good yield (70%) and excellent selectivity
(89% ee).
The approach accommodates allylic electrophiles, lead-
ing to unsaturated products where the alkenyl function-
ality is maintained following Baeyer-Villiger oxidation.
Hexenyl ketone, obtained from PTC alkylation with (E)-
1-bromo-2-pentene (entry 3, Table 4) underwent TMS
peroxide oxidation, following DPM removal, to give aryl
ester 19 in 74% yield (Scheme 7). Epoxidation was not
detected in this case. The alkenyl group can also be
readily converted to an alkyl target. As an example of
an indirect approach to n-alkylation, this PTC product
was also hydrogenated and deprotected in one pot to give
the 2-hydroxy product 20.
A model, where the geometry of the enolate and the
cinchonium tight ion-pair arrangement are well-defined,3c
can be used to rationalize the stereoinduction of the
glycolate process. The Z-enolate17 oxygen generated from
1 (Scheme 8), tight ion-paired with the least-hindered
face of the ammonium nitrogen, can adopt various
conformations. This Z-enolate has been generated from
1 under the PTC conditions and trapped with ethyl
SCHEME 6. Elaboration of PTC Product 2
halide, 2 to 10 equiv, also did not greatly effect the
selectivity or reaction rate. These findings are consistent
with the findings that asymmetric PTC reactions are zero
order in substrate and less than first order in alkyl halide
(0.6).13a Variations of the trifluorobenzyl catalyst 9 were
also made and tested without improvement. Changing
the counteranion to BF4-, exchanging the O-allyl ether
for O-benzyl, and maintaining the vinyl group gave 2
with essentially the same selectivity (86% ee). The
important factors that affect reactivity and selectivity are
the substitution patterns of the acetophenone and the
quinuclidine N-substituent of the catalyst. High reactiv-
ity and selectivity were obtained with more electron-rich,
ketones consistent with the enolate-catalyst ion-pairing
model. The optimal conditions with 1 and CsOH‚H2O in
1:1 CH2Cl2/n-hexane have been used many times, includ-
ing on a multigram scale, with reproducible results.
DPM-acetophenone 1 is conveniently made in two steps
(Scheme 5). Benzhydryl alcohol reacts with ethyl bro-
moacetate to give 12 in 95% yield following ester hy-
drolysis with aqueous HCl. One-pot Weinreb amide
formation, followed by treatment of the crude intermedi-
ate with lithiated 1,4-dimethoxybenzene, gives the crys-
talline product 1 in 84% isolated yield.
To establish synthetic utility and the absolute stere-
ochemistry, oxidation and transesterification conditions
were developed to convert the PTC product 2 to known
esters (Scheme 6). The DPM group was easily removed
with TiCl4 (20 min, CH2Cl2, -78°, 91%) to give hydroxy
ketone 13. Alternatives to m-CPBA (m-chloroperbenzoic
acid), the standard reagent for Baeyer-Villiger oxida-
tion,11 were investigated for the formation of the aryl
ester. It was important to use conditions that would not
give epoxidation of alkene-containing substrates. By
avoiding peracids at this point, alkene products from allyl
and propargyl electrophiles with 1 would provide a
significant strategic advantage and expansion of the
scope of the process. A variation of the oxidation condi-
tions developed by Shibazaki12 was developed using bis-
TMS peroxide (2.5 equiv), catalytic SnCl4, dl-trans-
cyclohexanediamine bis-toluenesulfonamide (both at 0.5
equiv), and K2CO3 to give ester 14 in 79% yield. The
reported conditions with excess bis-TMS peroxide (4
equiv) and tin-diamide complex (1.5 equiv) gave lower
yields in this case (20-62%). The phenyl ester 14 was
(14) Burk, M. J.; Kalberg, C. S.; Pizzano, A. J. Am. Chem. Soc. 1998,
120, 4345-4353.
(15) Davis, F. A.; Haque, M. S.; Ulatowski, T. G.; Towson, J. C. J.
Org. Chem. 1986, 51, 2402-2404.
(16) Boeckman, R. K.; Clark, T. J.; Shook, B. C. Org. Lett. 2002, 4,
2109-2112.
(17) Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.; Pirrung, M.
C.; Sohn, J. E.; Lampe, J. J. Org. Chem. 1980, 45, 1066-1081.
J. Org. Chem, Vol. 70, No. 23, 2005 9473

Andrus et al.
TABLE 4. PTC Glycolate Alkylation with Various
Electrophiles
FIGURE 1. Transition-state arrangements of the Z-enolate
from 1 ion-paired with catalyst 9 compared to the ion-pair
model with glycine 4 and catalyst 7.
of the catalyst.18 The extended conjugation of the sub-
strate, made up by the enolate and the dimethoxyphenyl
group, then incurs a π-interaction with the quinoline of
the catalyst. The front re face of the enolate attacks the
electrophile generating the major S-product 2. The elec-
tronegative trifluoro N-benzyl group enhances the ion-
pairing with the electron-rich enolate. In arrangement
B, the dimethoxylphenyl fits between the ligand N-benzyl
without π-stacking and the quinoline group π-stacks with
the DPM group. The electrophile alkylates from the front
si face as shown, generating the minor R product. A
similar model reported by Corey for glycine imine 4
invokes π-stacking with the E-enolate over the quinoline
leading to alkylation to give S-product 5 (Scheme 8).3c
The utility of PTC alkylation is demonstrated by a
direct seven-step synthesis of the important new anti-
diabetes drug ragaglitazar 24, a potent inhibitor of
peroxisome proliferator receptor (PPAr).19 Previous routes,
which all go through a key 2-alkoxy-3-phenylpropionate
23, have relied on hydrolase kinetic resolution catalysis,
a strain of which was found only after screening 80
hydrolases, with racemic materials 22 (Scheme 9). Asym-
metric approaches to R-hydroxy carboxylic acids including
chiral oxaziridines reacted with preformed enolates and
hydrogenation of R-ketoesters were unsuitable for this
target.20 The 2-alkoxy-3-phenylpropionate can be consid-
ered a privileged structure that is common to many new
drugs and current lead compounds in this therapeutic
area.19c
a Reaction was performed at -20 °C.
SCHEME 7. Elaboration of Alkenyl Product 2
SCHEME 8. Formation of Z-Enolate
triflate to give 21. An nOe value of 6% was observed by
1H NMR to confirm the expected Z-geometry. Arrange-
ments A and B with 2 are shown that expose opposite
prochiral faces while maximizing π-stacking van der
Waals contacts between the catalyst and the enolate from
1 with the oxygen pointing directly at the ammonium
nitrogen (Figure 1). In arrangement A, the DPM group
adopts a π-π interaction with the trifluorobenzyl group
(18) Jones, G. B.; Chapman, B. J. Synthesis 1995, 475-497.
(19) (a) Ebdrup, S.; Pettersson, I.; Rasmusse, H. B.; Deussen, H.-J.;
Jense, A. F.; Mortensen, S. B.; Fleckner, J.; Pridal, L.; Nygaard, L.;
Sauerberg, P. J. Med. Chem. 2003, 46, 1306-1317. (b) Saad, M. F.;
Osel, K.; Lewin, A. J.; Patel. N.; Edwards, C. R.; Greco, S.; Nunez, M.;
Huang, W. C.; Reinhardt, R. R. Diabetes 2002, 51 (suppl 2), A35-A36.
(c) Henke, B. R. J. Med. Chem. 2004, 47, 4118-4127.
9474 J. Org. Chem., Vol. 70, No. 23, 2005

Phase-Transfer Catalyzed Glycolate Alkylation
SCHEME 9. Previous Route to Ragaglitazar
SCHEME 10. PTC Route to Ragaglitazar
TABLE 5. Effect of Equivalents and p-Substitution
yield (83% ee) and the excess benzyl bromide was readily
recovered (94%).
Pivaloate-protected benzyl bromide 25 (5 equiv) was
used under the optimized PTC conditions with catalyst
9 (10 mol %) and ketone 1 to give 26, 95%, 83% ee
(Scheme 10). Excess halide 25 was recovered (94%) and
reused on large scale (1 g). The DPM group was removed
and TMS peroxide oxidation gave the aryl ester 27 in
high yield with 96% ee selectivity after a single recrys-
tallization (Et2O). The ethyl ether was formed using
triethyloxonium tetrafluoroborate in chloroform and
transesterification with NaOMe was performed to give
28. No racemation was observed at this point even when
using 3 equiv of base. Ethylation performed using NaH
or silver oxide and EtI or amine bases with ethyl triflate
produced multiple products. Treatment with phenoxazine
mesylate 29 with K2CO3 in warm toluene produced 30
in excellent yield (95% ee). Use of CsCO3 as base also
gave 30 in excellent yield (98%); however, significant
racemization was observed (110 °C), 85% ee. Hydrolysis
with aqueous NaOH, without racemization, completed
the PTC route to this important compound. Each step
from 27 to ragaglitazar in this sequence was shown by
chiral HPLC to maintain high enantiopurity.
In summary, a general approach to catalytic asym-
metric alkylation has been developed. A surrogate benz-
hydryloxy acetophenone reacts with a variety of electro-
philes under phase tranfer conditions to give enantio-
enriched products (80-90% ee). TMS-peroxide generates
the aryl ester, which can be recrystallized to give a single
enantiomeric product (99% ee). Transesterification readily
provides methyl esters that are suitable for multistep
applications. A tight ion-pair model between the enolate
and the cinchonidinium catalyst, which maximizes van
der Waals contacts, can be used to rationalize the
observed S-enantioselectivity. The diabetes drug ragagli-
tazar was made in seven direct steps using a substituted
benzyl bromide electrophile. This success within the
demanding constraints of catalytic alkylation provides a
sound precedent for extending the process further to
include other electrophiles, i.e., aldehydes and unsatur-
The requisite p-alkoxybenzyl electrophile was inves-
tigated as a prelude to the PTC synthesis of (-)-
ragaglitazar (Table 5). This seemingly straightforward
variation was shown to be highly dependent on the
nature of the p-alkoxy protecting group and the stoichi-
ometry of the electrophile. Benzyl bromide (entries 1-3)
used at 2, 5, and 10 equiv gave product 2 with consis-
tently high selectivities. Use of 2 equiv slightly increased
the reaction time and the yield was only slightly lowered.
p-Benzyloxybenzyl bromide used at 1.25 and 5 equiv gave
2 with greatly reduced selectivity, 40% ee. Surprisingly,
use of 2 equiv (entry 5) improved the selectivity (74% ee).
The TIPS (triisopropylsilyl) ether (entry 7) reacted at a
slower rate with only moderate selectivity (70% ee).
4-Benzoate benzyl bromide (entries 8 and 9) also reacted
with slow rates and moderate selectivities. The electroni-
cally deactivated p-pivalate benzyl bromide (entries 10
and 11) finally was found to generate PTC product in
both high yield and selectivity. This electrophile was
conveniently produced from p-hydroxybenzyl alcohol
reacted with pivaloyl chloride followed by treatment with
lithium bromide in the presence of mesyl chloride. With
5 equiv of this electrophile, product was obtained in 95%
(20) (a) Davis, F. A. Chen, B.-C. Chem. Rev. 1992, 92, 919-934. (b)
DeSantis, G.; Zhu, Z.; Greenberg, W. A.; Wong, K.; Chaplin, J.; Hanson,
S. R.; Farwell, B.; Nicholson, L. W.; Rand, C. L.; Weiner, D. P.;
Robertson, D. E.; Burk, M. J. J. Am. Chem. Soc. 2002, 124, 9024-
9025. (c) Tang, L.; Deng, L. J. Am. Chem. Soc. 2002, 124, 2870-2871.
(d) LeBlond, C.; Wang, J.; Liu, J.; Andrews, A. T.; Sun, Y.-K. J. Am.
Chem. Soc. 1999, 121, 4920-4921.
J. Org. Chem, Vol. 70, No. 23, 2005 9475

Andrus et al.
NMR (CDCl3, 75 MHz) δ 197.7, 153.7, 141.8, 128.5, 127.7,
127.5, 125.9, 121.1, 113.7, 113.1, 83.4, 75.1, 56.0, 55.9; mp )
70-72 °C; HRMS (FAB+) found 385.1412 [M + Na]+, calcd
385.1410 for C23H22O4Na. Anal. Calcd for C23H22O4: C, 76.22;
H, 6.12. Found: C, 75.98; H, 6.09.
ated carbonyl compounds, and will aid in the design of
new catalysts for improved selectivity and reactivity.
Experimental Section
Representative Procedure for Phase-Transfer Alky-
lation (Table 4, entry 8). (2S)-2-Benzhydryloxy-1-(2,5-
dimethoxy-phenyl)-4-methyl-pent-4-en-1-one. To a flame-
dried round-bottom flask were added 2-benzhydryloxy-1-(2,5-
dimethoxy-phenyl)-ethanone 1 (0.10 g, 0.276 mmol), O(9)-allyl-
N-2′,3′,4′-triflurorbenzylhydrocinchonidinium bromide (15.7
mg, 0.028 mmol), CH2Cl2 (1.4 mL) and hexane (1.4 mL). The
solution was cooled to -35 °C and then CsOH‚H2O (0.232 g,
1.38 mmol) was added in one portion. The mixture stirred for
10 min at which time benzyl bromide (0.165 mL, 1.38 mmol)
was added dropwise. The mixture stirred at -35 °C for 14 h
at which time the reaction was diluted with Et2O (40 mL) and
H2O (15 mL). The layers were mixed and then separated and
the organic layer was washed with H2O (2 × 15 mL) followed
by a saturated aqueous solution of NaCl and then dried over
MgSO4. The mixture was filtered, the solvent removed in vacuo
and the crude residue purified by column chromatography
(15% EtOAc/hexane) to afford 0.116 g (93%) of the desired
Benzhydryloxy-acetic Acid (12). To an oven-dried round-
bottom flask were added benzhydrol (5.07 g, 27.5 mmol) and
270 mL of benzene. Then tetrabutylammonium hydrogensul-
fate (0.465 g, 1.37 mmol) was added with stirring followed by
50 mL of a 50% aqueous (w/w) NaOH solution. The reaction
was stirred for 30 min then ethyl bromoacetate (4.6 mL, 41.3
mmol) was added dropwise. The solution was allowed to stir
at ambient temperature for 24 h. The resulting thick white
solution was then diluted with H2O and hexanes, the layers
were mixed and then separated. The aqueous layer was then
carefully acidified, while stirring vigorously, with 6 M HCl
until a pH of ∼7 was obtained. Then 1 M HCl was added until
the pH was ∼1.4, as monitored by pH 0-2.5 indicator strips.
Next, the resulting white, cloudy solution was extracted with
CH2Cl2 (5 × 100 mL). The combined organic layers were dried
over MgSO4, filtered and concentrated to provide 6.32 g (95%)
of the title compound as a white powder. Observations by TLC
and 1H NMR concluded that the product was analytically pure
and it was carried on to the next step. 1H NMR (DMSO-d6,
300 MHz) δ 12.76 (bs, 1H), 7.40-7.22 (m, 10H), 5.60 (s, 1H),
3.99 (s, 2H); 13C NMR (DMSO-d6, 75 MHz) δ 171.3, 141.7,
128.4, 127.5, 126.8, 82.1, 65.2.
2-Benzhydryloxy-1-(2,5-dimethoxy-phenyl)-etha-
none (1). To a flame-dried round-bottom flask were added
benzhydryloxy-acetic acid 12 (1.95 g, 8.07 mmol) and 32 mL
of CH2Cl2. The solution was cooled to 0 °C and N,O-dimeth-
ylhydroxylamine hydrochloride (1.20 g, 12.3 mmol) was added
in one portion followed by N,N-diisopropylethylamine (2.10
mL, 12.1 mmol). Then 4-(dimethylamino)pyridine (0.156 g,
1.27 mmol) was added followed by 1-[3-(dimethylamino)-
propyl]-3-ethylcarbodiimide hydrochloride (1.56 g, 8.12 mmol).
The reaction was stirred at 0 °C for 1 h and then warmed to
ambient temperature where it stirred for an additional 24 h.
The solution was then diluted with CH2Cl2 (80 mL) and H2O
(80 mL). The layers were mixed and separated, and the
aqueous layer was extracted with CH2Cl2 (3 × 70 mL). The
combined organic layers were washed with an aqueous 1 M
H3PO4 solution, then with a saturated aqueous NaHCO3
solution, and finally with a saturated aqueous NaCl solution.
The organic layer was then dried over MgSO4, filtered, and
concentrated in vacuo. The crude amide was filtered through
a silica gel plug, eluting with EtOAc, and the filtrate was then
concentrated and thoroughly dried in vacuo, resulting in the
isolation of a pale yellow solid. Dry THF (40.0 mL) was added
to the crude mixture followed by cooling to -40 °C. To a
separate flame-dried round-bottom flask were added 1,4-
dimethoxybenzene (1.46 g, 10.6 mmol) and 18.0 mL of THF.
The solution was cooled to 0 °C, and then, with stirring, n-BuLi
(6.3 mL, 1.6 M in hexanes, 10.1 mmol) was added dropwise
over 30 min to produce a faint yellow solution. The solution
was allowed to stir for 3 h at 0 °C then added via cannula to
the previously described, precooled solution of the crude
2-benzhydryloxy-N-methoxy-N-methyl-acetamide solution. The
resulting solution was allowed to stir for 15 min at -40 °C
and then quenched by the addition of a saturated aqueous
NH4Cl solution (10 mL). The reaction was warmed to ambient
temperature, and the solution was partitioned between a
saturated aqueous NaCl solution and a 1:1 mixture of Et2O/
CH2Cl2. The layers were separated and the aqueous layer
extracted with (1:1) Et2O/CH2Cl2 (3 × 50 mL). The combined
organic layers were dried over MgSO4, filtered and concen-
trated. The crude product was purified via column chroma-
tography (20% EtOAc/hexanes) to produce 2.24 g (84%) of the
desired compound as an off-white crystalline solid. TLC Rf )
0.23 (20% EtOAc/hexanes); 1H NMR (CDCl3, 300 MHz) δ 7.43-
7.20 (m, 11H), 7.00 (dd, J ) 3, 9 Hz, 1H), 6.81 (d, J ) 9 Hz,
1H), 5.62 (s, 1H), 4.71 (s, 1H), 3.75 (s, 3H), 3.69 (s, 3H); 13C
compound as a colorless oil. TLC Rf ) 0.35 (20% EtOAc/
1
hexanes); [R]23 -6.7° (c 2.14, CHCl3); H NMR (CDCl3, 300
D
MHz) δ 7.32-7.07 (m, 14H), 7.00 (dd, J ) 3.0, 9.0 Hz, 1H),
6.88-6.80 (m, 3H), 5.41 (s, 1H), 5.14 (dd, J ) 3.0, 9.6 Hz, 1H),
3.76 (s, 3H), 3.58 (s, 3H), 3.06 (dd, J ) 2.7, 13.8 Hz, 1H), 2.88
(dd, J ) 9.6, 14.1 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 201.2,
153.9, 152.7, 142.7, 141.4, 138.5, 129.9, 128.29, 128.27, 127.8,
127.5, 127.4, 127.3, 127.2, 126.5, 120.5, 114.3, 113.4, 82.8, 82.5,
56.1, 56.0, 39.1; HRMS (EI+) found 452.1982 M+, calcd
452.1988 for C30H28O4. Anal. Calcd for C30H28O4: C, 79.62; H,
6.24. Found: C, 79.59; H, 6.24. The enantioselectivity was
determined by chiral HPLC (DAICEL Chiralpack AD column,
10% EtOH/hexane, 1.0 mL/min, 23 °C, λ ) 254 nm, retention
times: S (major) 7.3 min, R (minor) 6.4 min, 86% ee). The
absolute configuration was determined by elaboration of the
product to known compounds described below.
(2S)-2-Benzhydryloxy-1-(2,5-dimethoxy-phenyl)-pent-
4-en-1-one (Table 4, entries 1 and 2). Following purification
via chromatography the product was obtained in 83% yield as
a colorless oil. TLC Rf ) 0.31 (20% EtOAc/hexanes); [R]23
D
-10.8° (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.40-7.16
(m, 10H), 7.12 (d, J ) 3.0 Hz, 1H), 6.98 (dd, J ) 3.0, 9.0 Hz,
1H), 6.79 (d, J ) 9.0 Hz, 1H), 5.95-5.81 (m, 1H), 5.53 (s, 1H),
5.05-4.97 (m, 3H), 3.75 (s, 3H), 3.55 (s, 3H), 2.55-2.32 (m,
2H); 13C NMR (CDCl3, 75 MHz) δ 202.2, 153.8, 152.6, 142.7,
141.8, 134.5, 128.6, 128.5, 128.2, 128.1, 127.8, 127.7, 127.4,
127.3, 126.7, 120.1, 117.3, 114.2, 113.2, 82.3, 81.4, 56.0, 55.9,
37.2; HRMS (FAB+) found 425.1715 [M + Na]+, calcd 425.1723
for C26H26O4Na. Anal. Calcd for C26H26O4: C, 77.59; H, 6.51.
Found: C, 77.61; H, 6.57. The enantioselectivity was deter-
mined by chiral HPLC (DAICEL Chiralpack AD column, 10%
EtOH/hexane, 0.5 mL/min, 23 °C, λ ) 254 nm, retention times,
S (major) 12.6 min, R (minor) 11.2 min, 83% ee).
(2S)-2-Benzhydryloxy-1-(2,5-dimethoxy-phenyl)-4-meth-
yl-pent-4-en-1-one (Table 4, entry 3). Following purification
via chromatography the product was obtained in 78% yield as
a colorless oil. TLC Rf ) 0.36 (20% EtOAc/hexanes); [R]23
D
-26.5° (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.42-7.16
(m, 11H), 6.98 (dd, J ) 3.3, 9.0 Hz, 1H), 6.79 (d, J ) 9.0 Hz,
1H), 5.52 (s, 1H), 5.12 (dd, J ) 4.8, 7.5 Hz, 1H), 4.82-4.77 (m,
2H), 3.75 (s, 3H), 3.55 (s, 3H), 2.40-2.35 (m, 2H), 1.61 (s, 3H);
13C NMR (CDCl3, 75 MHz) δ 202.5, 153.8, 152.6, 144.0, 142.8,
141.8, 141.7, 128.6, 128.4, 128.3, 128.2, 127.8, 127.7, 127.5,
127.3, 127.2, 126.7, 120.3, 114.3, 113.9, 113.2, 82.2, 80.1, 56.0,
55.9, 41.1, 22.5; HRMS (FAB+) found 439.1878 [M + Na]+,
calcd 439.1880 for C27H28O4Na. The enantioselectivity was
determined by chiral HPLC (DAICEL Chiralpack AD column,
10% EtOH/hexane, 1.0 mL/min, 23 °C, λ ) 254 nm, retention
times, S (major) 5.9 min, R (minor) 5.4 min, 89% ee).
9476 J. Org. Chem., Vol. 70, No. 23, 2005

Phase-Transfer Catalyzed Glycolate Alkylation
1
(S)-1-(2,5-Dimethoxyphenyl)-2-hydroxyheptan-1-one
(20). To a 100-mL round-bottom flask containing (S)-2-
benzhydryloxy-1-(2,5-dimethoxy-phenyl)-hept-4-en-1-one (2,
Table 4, entry 4) (0.150 g, 0.348 mmol) was added dry toluene.
Then 10% Pd on activated carbon (0.030 g) was carefully added
to the solution and the mixture stirred at ambient temperature
under a H2 atmosphere (balloon pressure). After 30 h the
mixture was filtered through a silica gel plug, eluting with
EtOAc. The solvent was removed in vacuo and the residue
dissolved in CH2Cl2 (3.5 mL). Then trifluoroacetic acid (0.060
mL, 0.70 mmol) was added dropwise. The reaction was stirred
at ambient temperature for 30 min and then quenched by the
addition of a saturated aqueous NaHCO3 solution (10 mL). The
layers were separated and the aqueous layer was extracted
with CH2Cl2 (2 × 20 mL). The combined organic layers were
washed with a saturated aqueous NaCl solution, then dried
over MgSO4, filtered and concentrated in vacuo. Chromatog-
raphy (radial, 1 mm plate, 20% EtOAc/hexanes) afforded the
title compound as an off-white powder. H NMR (CDCl3, 300
MHz) δ 6.89-6.76 (m, 6H), 6.42 (d, J ) 7.5 Hz, 2H), 4.30 (obs
q, J ) 6.9, 14.1 Hz, 2H), 4.26 (s, 2H), 1.33 (t, J ) 7.2 Hz, 3H);
13C NMR (CDCl3, 75 MHz) δ 169.4, 145.3, 133.4, 123.6, 121.7,
115.5, 111.7, 61.5, 46.8, 14.2; HRMS (EI+) found 269.1053 M+,
calcd 269.1052 for C16H15O3N.
2-(10H-Phenoxazin-10-yl)ethanol. To a flame-dried 50-
mL round-bottom flask was added lithium aluminum hydride
(95% powder, 0.120 g, 3.15 mmol) and THF (5 mL). Then ethyl
2-(10H-phenoxazin-10-yl)acetate was added as a THF solution
(10 mL + 3 mL rinse) and the mixture stirred at ambient
temperature for 2 h. Then additional lithium aluminum
hydride (95% powder, 0.050 g, 1.32 mmol) was added and the
reaction stirred for 1 h. H2O (50 mL) was then added followed
by 1 M HCl aqueous solution (5 mL). Then mixture was then
extracted with EtOAc (3 × 20 mL) and the combined organic
layers were washed with H2O, a saturated aqueous NaCl
solution then dried over Na2SO4, filtered, and concentrated.
The crude title compound (0.279 g, 97%) was isolated as a pale
orange/brown solid and carried on to the next step without
title compound, 0.074 g (80%), as a colorless oil. TLC Rf ) 0.26
1
(20% EtOAc/hexanes); [R]23 -51.0° (c 1.0, CHCl3); H NMR
D
1
(CDCl3, 500 MHz) δ 7.34 (d, J ) 2.5 Hz, 1H), 7.09 (dd, J )
3.5, 9.0 Hz, 1H), 6.92 (d, J ) 9.0 Hz, 1H), 5.12-5.09 (m, 1H),
3.87 (s, 3H), 3.81 (obs s, 1H), 3.80 (s, 3H), 1.80-1.73 (m, 1H),
1.52-1.18 (m, 7H), 0.85 (t, J ) 7.5 Hz, 3H); 13C NMR (CDCl3,
125 MHz) δ 203.5, 153.8, 153.4, 124.6, 121.5, 114.5, 113.3, 56.1,
56.0, 34.7, 31.8, 25.4, 22.7, 14.2; HRMS (EI+) found 266.1531
M+, calcd 266.1518 for C15H22O4.
further purification. H NMR (CDCl3, 300 MHz) δ 6.83-6.77
(m, 2H), 6.71-6.59 (m, 6H), 3.89 (t, J ) 6.3 Hz, 2H), 3.73 (t,
J ) 6.0 Hz, 2H), 2.07 (bs, 1H); 13C NMR (CDCl3, 75 MHz) δ
144.9, 133.6, 123.8, 121.4, 115.6, 112.0, 59.3, 46.9.
(S)-4-(2-(Benzhydryloxy)-3-(2,5-dimethoxyphenyl)-3-
oxopropyl)phenyl Pivalate (26). To a flame-dried round-
bottom flask were added 2-benzhydryloxy-1-(2,5-dimethoxy-
phenyl)-ethanone 1 (1.0 g, 2.76 mmol), O(9)-allyl-N-2′,3′,4′-
triflurorbenzyl hydrocinchonidinium bromide 9 (0.157 g, 0.28
mmol), CH2Cl2 (14 mL) and hexane (14 mL). The solution was
cooled to -35 °C and then CsOH‚H2O (2.32 g, 13.8 mmol) was
added in one portion. The mixture stirred for 10 min at which
time 4-(bromomethyl) phenyl pivalate 25 (3.74 g, 13.8 mmol)
was added. The mixture stirred at -35 °C for 24 h at which
time the reaction was diluted with Et2O (400 mL) and H2O
(150 mL). The layers were mixed and then separated and the
organic layer was washed with H2O (2 × 50 mL) followed by
a saturated aqueous solution of NaCl, then dried over MgSO4.
The mixture was filtered, the solvent removed in vacuo and
the crude residue purified by column chromatography (10-
20% EtOAc/hexane gradient) to afford 1.45 g (95%) of the
desired compound as a colorless oil. Early column fractions
were collected and concentrated to produce 2.82 g (94%
recovery) of analytically pure 4-(bromomethyl)phenyl pivalate.
4-(Hydroxymethyl)phenyl Pivalate. To a flame-dried
500-mL round-bottom flask were added NaH (dry 95%, 2.13
g, 88.9 mmol) and 400 mL of THF. The suspension was cooled
to 0 °C under N2. Then 4-hydroxybenzyl alcohol (10.06 g, 80.9
mmol) was added in one portion. The mixture stirred at 0 °C
until bubbling ceased at which time the reaction was warmed
to ambient temperature and stirred for an additional 30 min.
The mixture was again cooled to 0 °C and trimethylacetyl
chloride (10.95 mL, 88.9 mmol) was added slowly. After
stirring for 30 min at 0°C the mixture was warmed to ambient
temperature and stirred for 2 h. Then 100 mL of a saturated
aqueous NaHCO3 solution was added followed by 300 mL of
H2O. The mixture was extracted with EtOAc (3 × 100 mL),
the combined organic layers were washed with a saturated
aqueous NaCl solution, dried over MgSO4, filtered, and
concentrated. The crude product was purified via column
chromatography (40% EtOAc/hex) to afford 13.40 g (80%) of
the title compound as a pale yellow oil which solidified in cold
storage. 1H NMR (CDCl3, 300 MHz) δ 7.38-7.36 (m, 2H),
7.06-7.03 (m, 2H), 4.67 (s, 2H), 1.84 (bs, 1H), 1.37 (s, 9H).
[R]23 +14.0° (c 1.3, CHCl3); 1H NMR (CDCl3, 500 MHz) δ
D
7.32-6.81 (m’s, 17H), 5.42 (s, 1H), 5.12 (dd, J ) 3.0, 10.0 Hz,
1H), 3.76 (s, 3H), 3.56 (s, 3H), 3.03 (dd, J ) 3.0, 14.0 Hz, 1H),
2.86 (dd, J ) 10.0, 13.5 Hz, 1H), 1.37 (s, 9H); 13C NMR (CDCl3,
125 MHz) δ 202.0, 177.4, 154.0, 152.8, 150.0, 142.7, 141.3,
135.9, 130.8, 128.5, 128.4, 127.9, 127.7, 127.4, 127.3, 121.4,
120.7, 114.3, 113.6, 82.7, 82.6, 56.1, 56.0, 39.3, 38.5, 27.5;
HRMS (FAB+) found 575.2420 [M + Na]+, calcd 575.2404 for
C35H36O6Na; The enantioselectivity was determined by chiral
HPLC (DAICEL Chiralpack AD column, 10% EtOH/hexane,
1.0 mL/min, 23 °C, λ ) 254 nm, retention times, S (major) 7.9
min, R (minor) 6.1 min, 91.4:8.6 er, 83% ee). The absolute
configuration was determined by elaboration of the product
to known compounds described below.
4-(Bromomethyl)phenyl Pivalate (25). To an oven-dried
500-mL round-bottom flask was added LiBr (55.84 g, 643
mmol), THF (120 mL), and NEt3 (22.4 mL, 160.8 mmol). Then
4-(hydroxymethyl)phenyl pivalate (13.4 g, 64.3 mmol) was
added as a THF solution (200 mL). The mixture was cooled to
0 °C and methanesulfonyl chloride (10.45 mL, 135 mmol) was
added dropwise. The solution stirred at 0 °C for 2 h at which
time H2O (200 mL) was added. The solution was warmed to
ambient temperature and extracted with CH2Cl2 (3 × 100 mL).
The combined organic layers were washed with a saturated
aqueous NaHCO3 solution, dried over MgSO4, filtered and
concentrated. The crude product was purified via column
chromatography (10% EtOAc/hex) to provide 14.15 g (81%) of
(S)-4-(3-(2,5-Dimethoxyphenyl)-2-hydroxy-3-oxoprop-
yl)phenyl Pivalate. To a 250 mL-round-bottom flask con-
taining (S)-4-(2-(benzhydryloxy)-3-(2,5-dimethoxyphenyl)-3-
oxopropyl)phenyl pivalate 26 (1.315 g, 2.38 mmol) was added
CH2Cl2 (48 mL) and the solution was cooled to -78 °C. Then
TiCl4 (1.0 M in CH2Cl2, 2.38 mL) was added dropwise over 5
min and the reaction stirred at -78 °C for 20 min. Then a
saturated aqueous NaHCO3 solution was added (50 mL) and
the mixture warmed to ambient temperature. The layers were
separated and the aqueous phase extracted with CH2Cl2 (3 ×
30 mL). The combined organic layers were washed with a
saturated aqueous NaCl solution, dried over Na2SO4, filtered
and concentrated. The crude product was purified via radial
chromatography (4 mm plate, 20% EtOAc/hex) to afford 0.843
1
the desired compound as a white solid. Mp ) 58-60 °C; H
NMR (CDCl3, 500 MHz) δ 7.41-7.40 (m, 2H), 7.05-7.03 (m,
2H), 4.50 (s, 2H), 1.36 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ
177.1, 151.2, 135.3, 130.4, 122.1, 39.3, 33.0, 27.3; HRMS (EI+)
found 270.0255 M+, calcd 270.0255 for C12H15O2Br.
Ethyl 2-(10H-Phenoxazin-10-yl)acetate. To a flame-dried
25-mL round-bottom flask was added phenoxazine (0.300 g,
1.64 mmol) followed by 1-methyl-2-pyrrolidinone (5.50 mL).
Ethyl bromoacetate (0.910 mL, 8.20 mmol) was then added
and the reaction warmed to 70 °C where it stirred for 20 h.
The reaction mixture was then purified directly by column
chromatography (10% Et2O/hex) to afford 0.343 g (78%) of the
J. Org. Chem, Vol. 70, No. 23, 2005 9477

Andrus et al.
g (92%) of the title compound as a colorless viscous oil. [R]23
excess was determined by chiral HPLC (DAICEL Chiralpack
AD column, 10% EtOH/hexane, 1.0 mL/min, 23 °C, λ ) 254
nm, retention times, S (major) 10.1 min, R (minor) 8.3 min,
95% ee).
D
-34.4° (c 1.4, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.34 (d, J
) 3.5 Hz, 1H), 7.17-7.11 (m, 3H), 6.97-6.94 (m, 3H), 5.38-
5.37 (m, 1H), 3.89 (s, 3H), 3.87 (obs m, 1H), 3.81 (s, 3H), 3.13
(dd, J ) 3.0, 14.0 Hz, 1H), 2.73 (dd, J ) 7.0, 14.0 Hz, 1H),
1.35 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ 201.9, 177.2, 154.0,
153.5, 149.9, 135.2, 130.5, 124.4, 122.1, 121.2, 114.7, 113.4,
77.5, 56.2, 56.0, 40.3, 39.2, 27.3; HRMS (FAB+) found 409.1613
[M + Na]+, calcd 409.1622 for C22H26O6Na.
(S)-Methyl 2-Ethoxy-3-(4-hydroxyphenyl)propanoate
(28). To a 25-mL round-bottom flask containing (S)-2,5-
dimethoxyphenyl 2-ethoxy-3-(4-pivalatephenyl)propanoate
(0.078 g, 0.181 mmol) was added THF (1.80 mL) and the
solution was cooled to 0 °C. Then a freshly prepared NaOMe/
MeOH (0.1 M, 5.45 mL) solution was added and the mixture
was allowed to slowly warm to ambient temperature over 2h.
The reaction was stirred at ambient temperature for 24 h at
which time a saturated aqueous NH4Cl solution (10 mL) was
added followed by H2O (10 mL). The solution was then
extracted with EtOAc (3 × 15 mL), the combined organic layers
were then dried over Na2SO4, filtered, and concentrated. The
product was isolated via radial chromatography (1 mm plate,
20% EtOAc/hex) to provude 0.038 g (94%) of the title compound
as a yellow oil with 95.0% ee. [R]23D -18.7° (c 1.0, CHCl3); 1H
NMR (CDCl3, 500 MHz) δ 7.10-7.08 (m, 2H), 6.75-6.73 (m,
2H), 5.12 (m, 1H), 4.01 (dd, J ) 6.0, 7.5 Hz, 1H), 3.71 (s, 3H),
3.63 (m, 1H), 3.39-3.33 (m, 1H), 2.98-2.91 (m, 2H), 1.17 (t, J
) 7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 173.4, 154.6,
130.7, 129.2, 115.4, 80.6, 66.5, 52.1, 38.7, 15.2; HRMS (EI+)
found 224.1043 M+, calcd 224.1049 for C12H16O4. The enan-
tiomeric excess was determined by chiral HPLC (DAICEL
Chiralpack AD column, 10% EtOH/hexane, 0.5 mL/min, 23 °C,
λ ) 254 nm, retention times, S (major) 14.8 min, R (minor)
14.1 min, 95% ee).
2-(10H-Phenoxazin-10-yl)ethyl Methanesulfonate (29).3
To a 100-mL round-bottom flask containing 2-(10H-phenox-
azin-10-yl)ethanol (0.274 g, 1.20 mmol) were added CH2Cl2 (24
mL) and NEt3 (0.835 mL, 6.0 mmol). Then methanesulfonyl
chloride (0.390 mL, 5.04 mmol) was added dropwise and the
reaction stirred at ambient temperature for 2 h. Then H2O
(25 mL) was added and the layers separated. The organic layer
was washed with another 25 mL of H2O, then dried over
MgSO4, filtered and concentrated. The crude product was then
purified by radial chromatography (2 mm plate, 3:1:6 CH2Cl2/
Et2O/hex mixture) to afford 0.318 g (86%) of the desired
compound as a fluffy off-white solid. Mp ) 90-92 °C; 1H NMR
(CDCl3, 500 MHz) δ 6.85-6.81 (m, 2H), 6.73-6.70 (m, 2H),
6.67 (dd, J ) 1.5, 7.5 Hz, 2H), 6.58 (d, J ) 7.5 Hz, 2H), 4.42 (t,
J ) 7.0 Hz, 2H), 3.95 (t, J ) 7.0 Hz, 2H), 3.00 (s, 3H); 13C
NMR (CDCl3, 125 MHz) δ 145.0, 132.7, 124.0, 122.0, 116.0,
111.7, 64.5, 43.6, 37.8; HRMS (EI+) found 305.0721 M+, calcd
305.0722 for C15H15O4NS.
(S)-2,5-Dimethoxyphenyl 2-Hydroxy-3-(4-phenylpiv-
alate)propanoate (27). To a flame-dried round-bottom flask
were added activated 4 Å molecular sieves (0.500 g), trans-
N,N-bis(p-toluenesulfonyl)-1,2-cyclohexanediamine (0.840 g,
1.99 mmol), K2CO3 (0.550 g, 3.98 mmol) and 15.0 mL of CH2-
Cl2. The mixture was cooled to 0 °C and SnCl4 (2.0 mL, 1.0 M
in CH2Cl2) was added followed by bis(trimethylsilyl)peroxide
(0.855 mL, 3.98 mmol). The mixture was stirred at 0 °C for 5
min, then (S)-4-(3-(2,5-dimethoxyphenyl)-2-hydroxy-3-oxopro-
pyl)phenyl pivalate (0.770 g, 1.99 mmol) was added as a CH2-
Cl2 solution (16.0 mL + 4.0 mL round-bottom rinse). The
reaction stirred at 0 °C for 75 min, at which time the reaction
was quenched by the addition of a saturated aqueous NaHCO3
(20 mL) followed by a saturated aqueous Na2S2O3 solution (15
mL). The mixture was warmed to ambient temperature and
filtered through a Celite pad. The product was rinsed off the
Celite with CH2Cl2 (150 mL) and the layers were then
separated. The organic layer was washed with a saturated
aqueous NaCl solution, dried over Na2SO4, filtered, concen-
trated and purified via flash column chromatography (50%
Et2O/hexanes) to provide 0.665 g (83%) of the title compound
as a fluffy white solid. Then, 0.510 g of the white solid was
dissolved in a minimal amount of warm Et2O/hexanes (1:1)
and the product was allowed to recrystalize overnight. Re-
moval of the residual solvent and subsequent drying of the
needlelike crystals provided 0.380 g (75%) of the title com-
pound with 95.8% ee. [R]23D -7.3° (c 1.0, CHCl3); mp ) 94-96
°C; 1H NMR (CDCl3, 500 MHz) δ 7.38-7.37 (m, 2H), 7.05-
7.02 (m, 2H), 6.92 (d, J ) 8.5 Hz, 1H), 6.77 (dd, J ) 3.0, 9.0
Hz, 1H), 6.59 (d, J ) 3.0, 1H), 4.73-4.70 (m, 1H), 3.78 (s, 3H),
3.76 (s, 3H), 3.34 (dd, J ) 3.5, 14.0 Hz, 1H), 3.15 (dd, J ) 7.0,
14.0 Hz, 1H), 2.79-2.76 (m, 1H), 1.36 (s, 9H); 13C NMR (CDCl3,
125 MHz) δ 177.2, 172.4, 153.9, 150.3, 145.2, 139.8, 133.9,
130.9, 121.6, 113.6, 112.1, 109.3, 71.4, 56.6, 56.0, 40.0, 39.3,
27.3; HRMS (FAB+) found 425.1583 [M + Na]+, calcd 425.1571
for C22H26O7Na. The enantiomeric excess was determined by
chiral HPLC (DAICEL Chiralpack AD column, 10% IPA/
hexane, 1.9 mL/min, 23 °C, λ ) 254 nm, retention times, S
(major) 14.4 min, R (minor) 11.4 min, 96% ee).
(S)-Methyl
3-(4-(2-(10H-Phenoxazin-10-yl)ethoxy)-
(S)-2,5-Dimethoxyphenyl 2-Ethoxy-3-(4-pivalatephen-
yl)propanoate. To a flame-dried 25-mL round-bottom flask
was added (S)-2,5-dimethoxyphenyl 2-hydroxy-3-(4-phenylpiv-
alate)propanoate 27 (0.200 g, 0.497 mmol) and CHCl3 (10.0
mL). The solution was cooled to 0 °C and proton sponge (0.425
g, 1.99 mmol) was added followed by triethyloxonium tet-
rafluoroborate (0.380 g, 1.99 mmol). The mixture was stirred
for 60 min at 0 °C then warmed to ambient temperature where
it stirred for 24 h. The mixture was then quickly passed
through a small silica gel plug, eluting with EtOAc (75 mL).
The eluent was then concentrated and purified via column
chromatography (30% Et2O/hex) to afford 0.169 g (79%) of the
title compound as a white solid with 94.8% ee. TLC Rf ) 0.40
phenyl)-2-ethoxypropanoate (30). To a 25-mL round-bot-
tom flask containing (S)-methyl 2-ethoxy-3-(4-hydroxyphenyl)
propanoate 28 (0.069 g, 0.308 mmol) were added toluene (4.0
mL) and K2CO3 (0.085 g, 0.620 mmol). Then 2-(10H-phenox-
azin-10-yl)ethyl methanesulfonate 29 (0.125 g, 0.400 mmol)
was added and the mixture warmed to 100-105 °C where it
stirred for 45 h, with additional toluene being added at various
intervals to maintain the reaction volume. The reaction was
then cooled to ambient temperature where H2O was added (10
mL) followed by a saturated aqueous NH4Cl solution (10 mL).
The mixture was then extracted with EtOAc (3 × 20 mL). The
combined organic layers were washed with a saturated aque-
ous NaCl solution, dried over MgSO4, filtered and concen-
trated. The crude product was purified via radial chromatog-
raphy (1 mm plate, 10% EtOAc/hex) to afford 0.113 g (85%) of
the desired product as an off-white solid in 94.6% ee. TLC Rf
) 0.44 (50% Et2O/hex); [R]23D -9.6° (c 1.9, CHCl3); mp ) 96-
98 °C; 1H NMR (CDCl3, 500 MHz) δ 7.17-7.15 (m, 2H), 6.85-
6.79 (m, 4H), 6.70-6.63 (m, 6H), 4.18 (t, J ) 7.0 Hz, 2H), 4.00
(dd, J ) 5.5, 7.5 Hz, 1H), 3.97 (t, J ) 7.0 Hz, 2H), 3.72 (s, 3H),
3.64-3.58 (m, 1H), 3.39-3.33 (m, 1H), 3.01-2.93 (m, 2H), 1.18
(t, J ) 7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 173.1, 157.4,
145.0, 133.3, 130.6, 130.0, 123.8, 121.5, 115.7, 114.5, 111.8,
80.5, 66.5, 63.6, 52.0, 44.1, 38.6, 15.2; HRMS (FAB+) found
(30% EtOAc/hex); [R]23 -1.4° (c 1.9, CHCl3); mp ) 100-102
D
°C; 1H NMR (CDCl3, 500 MHz) δ 7.37-7.34 (m, 2H), 7.04-
7.01 (m, 2H), 6.90 (d, J ) 9.0 Hz, 1H), 6.74 (dd, J ) 3.0, 9.0
Hz, 1H), 6.52 (d, J ) 3.0 Hz, 1H), 4.27 (dd, J ) 4.0, 8.0 Hz,
1H), 3.85-3.76 (obs m, 1H), 3.76 (s, 3H), 3.75 (s, 3H), 3.50-
3.44 (m, 1H), 3.23 (dd, J ) 5.0, 14.0 Hz, 1H), 3.15 (dd, J )
9.0, 14.0 Hz, 1H), 1.36 (s, 9H), 1.22 (t, J ) 7.0 Hz, 3H); 13C
NMR (CDCl3, 125 MHz) δ 177.2, 170.6, 154.0, 150.2, 145.4,
140.2, 134.8, 130.7, 121.5, 113.8, 112.0, 109.4, 80.1, 66.7, 56.7,
56.0, 39.3, 39.0, 27.4, 15.3; HRMS (FAB+) found 453.1892 [M
+ Na]+, calcd 453.1884 for C24H30O7Na. The enantiomeric
9478 J. Org. Chem., Vol. 70, No. 23, 2005

Phase-Transfer Catalyzed Glycolate Alkylation
456.1797 [M + Na]+, calcd 456.1781 for C26H27O5NNa. The
enantiomeric excess was determined by chiral HPLC (DAICEL
Chiralpack AD column, 5% IPA/hexane, 1.0 mL/min, 23 °C, λ
) 254 nm, retention times, S (major) 11.1 min, R (minor) 10.4
min, 95% ee).
δ 9.74 (bs, 1H), 7.18 (d, J ) 7.5 Hz, 1H), 6.85-6.79 (m, 4H),
6.70-6.63 (m, 6H), 4.17 (t, J ) 7.0 Hz, 2H), 4.05 (dd, J ) 4.5,
8.0 Hz, 1H), 3.97 (t, J ) 7.0 Hz, 2H), 3.66-3.60 (m, 1H), 3.46-
3.40 (m, 1H), 3.08 (dd, J ) 4.5, 14.5 Hz, 1H), 2.97 (dd, J )
8.5, 14.0 Hz, 1H), 1.19 (t, J ) 7.0 Hz, 3H); 13C NMR (CDCl3,
125 MHz) δ 176.4, 157.5, 145.0, 133.3, 130.8, 129.5, 123.8,
121.5, 115.7, 114.6, 111.8, 79.9, 67.0, 63.6, 44.1, 38.1, 15.2.
(-)-Ragaglitazar. To a 25-mL round-bottom flask contain-
ing (S)-methyl 3-(4-(2-(10H-phenoxazin-10-yl)ethoxy)phenyl)-
2-ethoxypropanoate 30 (0.10 g, 0.230 mmol) was added MeOH
(2.30 mL) followed by 3 N NaOH (2.0 mL). The reaction
mixture was stirred at ambient temperature for 6 h at which
time H2O (35 mL) was added and the mixture washed with
Et2O (15 mL). Then 1 M HCl was added dropwise until a pH
of 2 was obtained. The mixture was then extracted with EtOAc
(3 × 20 mL). The combined organic layers were washed with
H2O followed by a saturated aqueous NaCl solution, then dried
over Na2SO4, filtered and concentrated to provide 0.089 g (92%)
of the title compound as a foaming viscous oil that solidified
into a white solid, which matched the following reported
values. [R]23D -8.7° (c 1.0, CHCl3); 1H NMR (CDCl3, 500 MHz)
Acknowledgment. We are grateful to the American
Chemical Society, Petroleum Research Fund-AC (41552-
AC1) and the BYU Cancer Research Center for funding.
Supporting Information Available: Experimental pro-
cedures and characterization for all compounds, and NMR
spectral and HPLC data. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO051568Z
J. Org. Chem, Vol. 70, No. 23, 2005 9479