Bidentate chelation-controlled asymmetric synthesis of α-hydroxy esters based on the glycolate enolate alkylation

Article abstract of DOI:10.1016/S0040-4039(00)00031-9

(S)-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl](4-methoxyphenyl)methanol (4b) has been synthesized and evaluated as a chiral auxiliary for the asymmetric synthesis of α-hydroxy esters based on bidentate chelation-controlled alkylation of glycolate enolate. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00031-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1793–1796
Bidentate chelation-controlled asymmetric synthesis of
α-hydroxy esters based on the glycolate enolate alkylation
Ju Eun Jung, Hyunsoon Ho and Hee-Doo Kim ∗
College of Pharmacy, Sookmyung Women’s University, Yongsan-ku, Seoul 140-742, South Korea
Received 5 November 1999; revised 29 November 1999; accepted 1 December 1999
Abstract
(S)-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl](4-methoxyphenyl)methanol (4b) has been synthesized and evaluated
as a chiral auxiliary for the asymmetric synthesis of α-hydroxy esters based on bidentate chelation-controlled
alkylation of glycolate enolate. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric synthesis; chelation; hydroxy acid and derivatives; alkylation.
The widespread use of α-hydroxy esters and their derivatives as chiral synthons in organic synthesis1,2
has grown collaterally with advances in methodology for their asymmetric synthesis.3 One of the most
important strategies for their synthesis is the ester enolate alkylation of chiral glycolate including both
forms of cyclic4–6 and acyclic structures.7–10 As far as acyclic chiral glycolate is concerned, the following
two features are notable from the previous methods: (1) most of the chiral auxiliaries are attached to the
carboxyl group rather than to the hydroxyl group in glycolic acid unit;7 (2) all of their enolates form
cyclic structures by monodentate chelation of the oxygen on α-carbon of glycolate to metal. Herein, we
describe the highly stereoselective method for α-hydroxy esters featuring bidentate chelation-controlled
asymmetric alkylation of chiral glycolate, in which the chiral auxiliary is attached to the hydroxyl group
as ether linkage, as outlined in Scheme 1.
Scheme 1.
However, in consideration of conformational flexibility of ether linkage, acceptable levels of dia-
stereoselection are less likely to be achieved by the previous monodentate chelation-controlled method.
∗
Corresponding author. Fax: +82 2 703 0736; e-mail: hdkim@sdic.sookmyung.ac.kr (H.-D. Kim)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00031-9
tetl 16311

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Thus, it is necessary to construct chiral auxiliary with a molecular architecture that restricts rotation
and shields one of the π-faces of enolates. As our initial attempt, the chiral auxiliaries, such as 2 and
4a, with additional ligation sites were designed for the construction of highly organized polycyclic ring
complexes during the glycolate enolate formation. As shown in Scheme 2, the chiral glycolates 3, 5a and
5b were prepared simply, but stereoselectively, by treatment of (R)-2,3-O-isopropylideneglyceraldehyde
(1)11 with Ph3ZnMgBr2Mg(Cl)Br)12 or organocopper reagent,13 followed by O-alkylation with ethyl bro-
moacetate in good yields. Because both (R)- and (S)-form of 1 are readily available,14 the corresponding
enantiomers can be prepared by the same way.
Scheme 2. (a) Ph3ZnMgBr2Mg(Cl)Br (b) ArMgBr/THF, CuI, DMS; recrystallization (c) NaH/DME; BrCH2CO2Et
With both diastereomers 3 and 5a in hand, our special attention was drawn to the level of stereoselec-
tivity of this glycolate enolate alkylation. Deprotonation of 3 and 5a was accomplished with LDA in THF
at −78°C. Methylation of 3 via its corresponding enolate with CH3I at −78°C for 2 h furnished a 3:1
mixture of 6 and 7 in 36% yield. However, a dramatic changeover in diastereoselectivity was observed
during the alkylation of 5a. The selectivity ratio up to 45 was accomplished.
Scheme 3.
Encouraged with this result, we then set about optimizing the efficiency of this alkylation process. A
22
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minor structural tuning for syn-4a was made at first, then syn-4b with [α] −37.2 (c 0.4, CHCl3) was
finally selected as a chiral auxiliary due to its enhanced crystallizability (mp 46–47°C, recrystallized from
hexane–EtOAc) and the fact that it could be more easily removed from the chiral glycolate after reaction.
To examine the efficiency of syn-4b as a chiral auxiliary in this reaction, the chiral glycolate 5b was
prepared and subjected to alkylation. The following procedure is representative. Compound 5b (324 mg,
1 mmol) in THF (3 ml) was added in a dropwise manner to a solution of LiHMDS (1.8 mmol) in THF (7
ml) at −78°C. After 10 min, benzyl bromide (10 mmol) was added, and the solution was stirred for an
additional 20 min. The reaction was quenched by addition of water, then warmed to room temperature.
Conventional work-up followed by column chromatography (SiO2, 8% ethyl acetate in hexane) afforded

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26
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281 mg (77%) of a diastereomeric mixture of 8b and 9b with [α] −79.1 (c 0.23, EtOH) as an oil. In
comparison with authentic samples, the diastereomeric ratio of 8b to 9b in the crude product was found
to be exceeding 300 by capillary GLC analysis (OV-1). As shown in Table 1, the preferential formation
of 8b over 9b was observed in all cases, and the ratio is seen to be highly dependent on solvent as well
as R groups. THF is the optimal solvent for this reaction. Low chemical yields and diastereoselectivities
in toluene or ether seemed to be associated with the aggregation of lithium enolate. The bulkier and the
more reactive R group becomes, the higher is the selectivity attained in the alkylation (entries 6 and
10). This result is correlated with the observation that prolonged reaction time and use of stronger base
(entries 3 and 6) resulted in lowering the selectivity, presumably due to racemization.
Table 1
Diastereoselective alkylation of 5b and deprotection to 10
The preferential formation of 8b over 9b and the unprecedented high level of stereoselection associated
with this asymmetric alkylation may be rationalized by considering the following plausible transition
state model of highly organized enolate complex, resulted from bidentate chelation of the internal
two oxygens with lithium ion. In this model, the cyclic ring containing enolate is puckered to upside
minimizing the steric interaction with aromatic ring nearby. This transition state model also explains why
the relative configuration of chiral auxiliary is critical to stereoselection and chiral glycolate 3 derived
from anti-2 does not work well, as evidenced in Scheme 3. As shown in Table 1, any external polar
ligands such as HMPA and EtOTf (entries 5 and 8) could destroy the chelation complex, resulting in
lowering the stereoselectivies.
The absolute configurations of newly created chiral center on 8b were assigned after removal of the
chiral auxiliary with CAN and comparison of the optical rotations of the resulting α-hydroxy esters
with literature values.5,15 For example, treatment of the benzylated products (0.11 mmol) in entry 10,
with ceric ammonium nitrate (0.18 mmol) in 10% aqueous CH3CN (1 ml) at room temperature for
21
D
30 min afforded (S)-(−)-ethyl 2-hydroxy-4-phenylpropionate with [α] −25.1(c 1.0, benzene) in 85%

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yield. This hydroxy ester was subjected to HPLC analysis using chiral column (Chiracel OD, hexane/2-
propanol), and found to be enantiomerically pure.
In conclusion, the asymmetric synthesis of α-hydroxy esters using 4b has been successfully carried
out, and the following features are notable: (1) we have developed a new chiral auxiliary entirely different
from the previously reported; (2) the unprecedented high stereoselectivity over 300 is obtained; (3) from
a mechanistic point of view, this is a first example of the bidentate chelation-controlled alkylation of
chiral glycolate, in which the chiral auxiliary played the dual role as a chiral inducer as well as a
protecting group; (4) during the removal of the chiral auxiliary with CAN, 4b was oxidized to the
corresponding ketone, however, which upon treatment with L-selectride,16 can be readily recovered
for reuse. In addition, the convenience for its preparation and mild condition for its removal from the
glycolate without racemization make this method an attractive route to optically active α-hydroxy esters.
Further applications using this chiral auxiliary are currently underway.
Acknowledgements
This work was supported by grant no. 981-0716-127-2 from the Basic Research Program of the
KOSEF. Technical assistance by Young-Kyo Kim is gratefully acknowledged.
References
1. Coppola, G. M.; Schuster, H. F. Hydroxy Acids in Enantioselective Syntheses; VCH: Weinheim, 1997.
2. Hanessian, S. Total Synthesis of Natural Products. The Chiron Approach; Pergamon Press: New York, 1983; Chapter 2.
3. Pansare, S. V.; Ravi, R. G. Tetrahedron 1998, 54, 14549–14564 and references cited therein.
4. Frater, G. Y.; Muller, U.; Gunther, W. Tetrahedron Lett. 1981, 22, 4221–4224.
5. Pearson, W. H.; Cheng, M.-C. J. Org. Chem. 1986, 51, 3746–3748.
6. Ludwig, J. W.; Newcomb, M.; Bergbreiter, D. E. Tetrahedron Lett. 1986, 27, 2731–2734.
7. d’Angelo, J.; Pages, O.; Maddaluno, J.; Dumas, F.; Revial, G. Tetrahedron Lett. 1983, 24, 5869–5872.
8. Helmchen, G.; Wierzchowski, R. Angew. Chem., Int. Ed. Engl. 1984, 23, 60–61.
9. Kelly, T. R.; Arvanitis, A. Tetrahedron Lett. 1984, 25, 39–42.
10. Enomoto, M.; Ito, Y.; Katsuki, T.; Yamaguchi, M. Tetrahedron Lett. 1985, 26, 1343–1344.
11. Schimid, C. R.; Bryant, J. D.; Dowlatzedah, M.; Philips, J. L.; Prather, D. E.; Schantz, R. D.; Sear, N. L.; Vianco, C. S. J.
Org. Chem. 1991, 56, 4056–4058.
12. Sugimura, H.; Watanabe, T. Synlett 1994, 175–176.
13. Sato, F.; Kobayashi, Y.; Takahashi, O.; Chiba, T.; Takeda, Y.; Kusakabe, M. J. Chem. Soc., Chem. Commun. 1985,
1636–1638.
14. Schimid, C. R.; Bryant, J. D. Org. Synth. Coll. Vol. IX. 1998, 450–453; Hubschwerlen, C.; Specklin, J.-L.; Higelin, J. ibid,
454–456.
15. Nakamura, K.; Inoue, K.; Ushio, K.; Oka, S.; Ohno, A. J. Org. Chem. 1988, 53, 2589–2593.
16. Chikashita, H.; Nikaya, T.; Uemura, H.; Itoh, K. Bull. Chem. Soc. Jpn. 1989, 62, 2121–2123.