Phase-transfer-catalyzed asymmetric glycolate alkylation

Article abstract of DOI:10.1021/ol0491235

Asymmetric surrogate glycolate alkylation has been performed under phase-transfer conditions. Diphenylmethyloxy-2,5-dimethoxyacetophenone with trifluorobenzyl cinchonidinium catalyst and cesium hydroxide provided alkylation products at -35°C in high yield

Full text of DOI:10.1021/ol0491235

ORGANIC
LETTERS
2004
Vol. 6, No. 13
2289-2292
Phase-Transfer-Catalyzed Asymmetric
Glycolate Alkylation
Merritt B. Andrus,* Erik J. Hicken, and Jeffrey C. Stephens
Brigham Young UniVersity, Department of Chemistry and Biochemistry,
C100 BNSN, ProVo, Utah 84602-5700
mbandrus@chem.byu.edu
Received May 13, 2004
ABSTRACT
Asymmetric surrogate glycolate alkylation has been performed under phase-transfer conditions. Diphenylmethyloxy-2,5-dimethoxyacetophenone
with trifluorobenzyl cinchonidinium catalyst and cesium hydroxide provided alkylation products at −35 °C in high yield (80−99%) and with
excellent enantioselectivities (90:10 to 95:5). Useful r-hydroxy products were obtained using bis-TMS peroxide Baeyer−Villiger conditions and
selective transesterification. The intermediate aryl ester can be obtained with >99% ee after a single recrystallization. A tight ion-pair model
for the observed (S)-stereoinduction is proposed.
Phase-transfer catalysis (PTC), through ion pairing of a
reactive anion with an enantiopure ammonium ion, has been
developed for asymmetric glycine alkylations, enone epoxi-
dation, conjugate additions, and other transformations.1
Advantages of this approach include use of inexpensive
cinchona alkaloid-derived catalysts, readily available in both
Using an alkoxyester substrate (pKa ∼28), which would
enantiomeric antipodes, simple hydroxide bases, and mild
conditions that can be run in either liquid-liquid or liquid-
solid mode. Benzophenone imine tert-butyl glycine, with its
extended enolate conjugation and low pKa value (18.7,
DMSO),1c continues to be a popular substrate for amino acid
synthesis and catalyst development.2 As a first step toward
development of PTC reactions with oxygenated substrates,
we now report a novel alkoxyacetophenone 1 that undergoes
highly selective catalytic glycolate alkylation with various
electrophiles (eq 1).3 The resultant product undergoes
Baeyer-Villiger-type oxidation to give the aryl ester, which
is readily transesterified to produce the useful R-hydroxy
ester 3.
provide direct access to glycolate esters, did not give
alkylation products under various PTC conditions. The more
acidic benzyloxy acetophenones (pKa ∼22) were then
screened for reactivity using the Park-Jew trifluorobenzyl
cinchonidinium (CD) bromide catalyst 42f (10 mol %) with
(2) (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. For a related
unsaturated ester, see: (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.
(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.
(3) Previous asymmetric glycolate alkylations are limited to chiral
auxiliaries: Crimmins, M. T.; Emmitte, K. A.; Katz, J. D. Org. Lett. 2000,
2, 2165-2167. and references therein.
10.1021/ol0491235 CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/29/2004

various allyl, propargyl, and benzyl halides (5 equiv) were
performed (Table 2). Allyl bromides (entries 1-3) reacted
Table 1. Asymmetric Glycolate PTC Alkylation
Table 2. PTC Alkylation with Allyl, Propargyl, and Benzyl
Halides
entry
P
Ar
time (h) % yielda
erb
1c
2
3
4
5
6
7
8
9
Bn
Bn
Bn
Bn
Bn
Bn
PMB
Ph
p-anisyl
o-anisyl
o-toluyl
2,4-diMeOPh
2,5-diMeOPh
2,5-diMeOPh
26
6
8
12
13
7
9
13
7
74
82
78
72
90
83
83
80
80
96
63:37
77:23
83:17
81:19
76:24
86:14
84:16
87:13
90:10
93:7
2-NapCH2- 2,5-diMeOPh
DPM
DPM
2,5-diMeOPh
2,5-diMeOPh
10d
13
a Yields are for isolated, chromatographed materials. b Determined by
chiral HPLC with comparison to racemic materials. c Performed with aq
KOH in toluene. d Performed with a mixture of CH2Cl2:n-hex 1:1 as the
solvent.
cesium hydroxide (5 equiv) as a base (Table 1). In the
presence of excess benzyl bromide (5 equiv) with aryl ketone
1, the alkylation product 2 was obtained (entry 1). It was
envisioned that more electron-rich aryl ketones would give
higher reactivity and selectivity consistent with the tight ion-
pair model.2c This turned out to be the case in that the 2,5-
dimethoxy ketone (entry 6) gave an 83% yield after 7 h at
-40 °C with an 86:14 er (enantiomeric ratio, 72% ee). Other
ketones, including naphthyl and xylyl substrates, were less
effective. The 2,5-dimethoxy functionality was maintained,
and various protecting groups at C-2 were explored. Methyl
ether-protected ketone and others, including monoarylmethyl
(entries 7, 8) and aryl ethers, gave lower selectivity. Finally,
the benzhydryl (diphenylmethyl, DPM) ether substrate 1 was
found to be superior, providing product in 7 h with 90:10
enantioselectivity (entry 9). Changing the solvent to 1:1
methylene chloride/n-hexane provided further improvement
in yield and selectivity to 93:7 er (entry 10). With toluene
as a solvent, the selectivity was also high; however, the
reaction rate was greatly slowed, requiring 28 h for comple-
tion. Other solvents and combinations investigated were less
effective. The reactions with RbOH or aqueous KOH as a
base were slow, while Ba(OH)2 and BTPP gave only trace
product formation. Use of the Corey-Lygo 9-anthracenyl
methyl-CD2c,d catalyst in place of 4 gave 70:30 er selectivity
for 2 (P ) DPM, Ar ) 2,5-diMeOPh) and the Maruoka 2,2′-
dinaphthyl-bis-binaphthylammonium PTC catalyst2e gave still
lower selectivity under these conditions. At -60 °C, the
reaction selectivity was not improved (92:8, 52 h, 69%).
Variations of catalyst 4 and further modifications of the
reaction conditions did not lead to improved selectivity.
Using these optimized conditions with aryl ketone 1,
asymmetric glycolate PTC alkylations with catalyst 4 and
a Chromatographed, isolated yields. b Determined by chiral HPLC with
comparison to racemic materials.
with high isolated yields and selectivities in 4-5 h. Allyl
iodide reacted at a faster rate; however, the selectivity was
reduced. Methallyl bromide gave the highest selectivity at
94:6 er. Geranyl bromide was somewhat slower at 8 h.
Propargyl bromides substituted at the γ-position (entries 5,
6) were also effective with high selectivity in 4 h. Yields
and selectivities were uniformly high with benzyl bromides
(entries 7-11), and the reaction times varied depending on
the substitution pattern. Benzyl bromide required 13 h for
completion, while p-tert-butyl BnBr terminated in 5 h with
high selectivity (92:8). o-Phenyl BnBr (entry 9) gave a
quantitative yield after 9 h with 95:5 selectivity (90% ee).
Entries 1 and 7 have been repeated many times, including
on a gram scale with reproducible results. Catalyst 4 can be
recovered in pure form as the chloride salt during the workup
step (71%)4 and excess 2-naphthylmethyl bromide (entry 10)
was easily recovered (75%) upon purification.
The requisite aryl ketones 1, including the optimal
electron-rich substrate (P ) DPM, Ar ) 2,5-dimethoxyphen-
yl, mp 82 °C), were readily made from protected glycolic
(4) See Supporting Information for experimental details.
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Org. Lett., Vol. 6, No. 13, 2004

acid 5 via the Weinreb amide followed by displacement with
the corresponding aryllithium reagent (Scheme 1). This one-
pot operation conveniently converts glycolic acid 5 to 1 in
excellent yield (91%).
converted to the aryl ester 11 using the same oxidation
conditions in 74% yield. No trace of epoxide product was
seen.
Selective transesterification conditions were also developed
for the aryl ester intermediate 9 to establish the stereochem-
istry and to demonstrate multistep utility (Scheme 3).
Scheme 1
Scheme 3
Baeyer-Villiger conversion of the aryl ketone PTC
product to the corresponding aryl ester was then addressed.
PTC product 2 was deprotected using TiCl4 to give alcohol
6 (Scheme 2). Aryl ester 7 (Ar ) 2,5-dimethoxyphenyl) was
Catalytic NaOMe (20 mol %) gave (S)-methyl ester 12 with
the benzoate ester intact without racemization. In comple-
mentary fashion, excess NaOMe (2 equiv) generated (S)-2-
hydroxy methyl ester 3 ([R]D -8.8°).7 A combination of
attenuated lone-pair n-π carbonyl resonance by the O-aryl
oxygen and greater stability of the aryloxy leaving group
appears to be the origin of this useful chemoselectivity
leading to 12.8 A single-crystal X-ray structure was solved
for benzoate 8 that also established the proposed stereo-
chemistry.4
Scheme 2
The stereoinduction of the process can be rationalized
using a modification of the tight-ion pair model proposed
by Corey for asymmetric glycine PTC (Scheme 4).2c The
Scheme 4
then formed in 79% yield under Baeyer-Villiger-type
oxidation conditions using a modification of the reported
conditions with bis-TMS peroxide (2.0 equiv) and SnCl4‚
bis-sulfonamide complex ((1 equiv).5 MCPBA was not
effective for this step. We were pleased to find that a single
recrystallization of hydroxyester 7 (mp 128-130 °C) from
warm Et2O gave further enantioenrichment to an er of >99:1
(>99% ee).4 Alcohol 6 was also protected as the benzoate
ester 8, and oxidation gave 9 in 72% yield. A key benefit of
these peroxide conditions is that, unlike peracids, these
conditions do not effect alkene epoxidation and thus allow
for expansion of the scope of the process to include
unsaturated substrates.6 Benzoate 10, obtained in high
selectivity (entry 3, Table 2), was readily formed and
Z-enolate from 1 was trapped with EtOTf to give vinyl ether
13 under the PTC conditions and confirmed by NMR.4 With
(6) (a) Sawada, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2000,
122, 10521-10532. (b) Yoshikawa, N.; Suzuki, T.; Shibasaki, M. J. Org.
Chem. 2002, 67, 2556-2565.
(7) c 2.0, CHCl3. Lit. -7.6° (c 2.0, CHCl3): Davis, F. A.; Haque, M.
S.; Ulatowski, T. G.; Towson, J. C. J. Org. Chem. 1986, 51, 2402-2404.
(5) Go¨ttlich, R.; Yamakoshi, K.; Sasai, H.; Shibasaki, M. Synlett 1997,
971-974.
Org. Lett., Vol. 6, No. 13, 2004
2291

the oxygen of the Z-enolate of 1 pointing directly at the least
hindered face of the CD nitrogen of 4, two orientations can
be envisioned, A and B. The catalyst is shaded for clarity,
and the enolate oxygen-quinuclidine nitrogen interaction is
highlighted. The extended portion of the enolate in A, made
up of the 2,5-dimethoxyphenyl portion of the substrate,
maximizes van der Waals contact with the isoquinoline of
the catalyst, and the DPM group interacts with the trifluo-
robenzyl group. This arrangement leads to the major product,
(S)-2, as a result of re-face attack. Arrangement B places
the DPM group over the isoquinoline with the 2,5-dimeth-
oxyphenyl group twisted out of resonance, giving (R)-2.
Asymmetric, catalytic glycolate alkylation has been achieved
with high reactivity and selectivity with various alkylating
agents through a surrogate DPM-protected acetophenone
under asymmetric PTC conditions. Applications with other
electrophiles will now open new approaches to a variety of
enantiomerically enriched oxygenated products applicable to
multistep synthesis.
Acknowledgment. This work was funded by the National
Institutes of Health (GM57275) and The Cancer Research
Center at Brigham Young University. We also thank Prof.
John F. Cannon for X-ray chrystallography.
Supporting Information Available: Experimental and
spectral data for all compounds, including X-ray data for
ketone 8 and HPLC chromatograms for selected alkylation
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
(8) For a discussion of base-mediated ester hydrolysis, BAC2, see: Lowry,
T. H.; Richardson, K. S. In Mechanism and Theory in Organic Chemistry,
2nd ed.; Harper and Row; New York, 1981; p 651.
OL0491235
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