Enantioselective syntheses of orthogonally protected tricarballylic acid esters

Article abstract of DOI:10.1016/S0040-4039(99)02264-9

3(S) and 3(R)-Benzyloxycarbonyl-pentanedioic acid mono-tert-butyl esters (6) were obtained as enantiopure orthogonally protected tricarballylic acid (TCA) esters. These were synthesised by alkylation of the sodium enolate derived from chiral but-3-enoylox

Full text of DOI:10.1016/S0040-4039(99)02264-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1261–1264
Enantioselective syntheses of orthogonally protected tricarballylic
acid esters
Nicholas J. S. Harmat, Silvia Mangani,† Enzo Perrotta,∗ Danilo Giannotti, Rossano Nannicini
and Maria Altamura
Chemistry Department, Menarini Ricerche S.p.A., Via Sette Santi 3, 50131 Firenze, Italy
Received 18 October 1999; accepted 7 December 1999
Abstract
3(S) and 3(R)-Benzyloxycarbonyl-pentanedioic acid mono-tert-butyl esters (6) were obtained as enantiopure
orthogonally protected tricarballylic acid (TCA) esters. These were synthesised by alkylation of the sodium enolate
derived from chiral but-3-enoyloxazolidinone imides (3) with tert-butyl bromoacetate; following the hydrolysis to
remove the chiral auxiliary, benzyl esterification afforded the 2-allyl succinic acid diesters (4) that were converted
to protected TCA esters after oxidation of the double bond. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: alkylation; asymmetric synthesis; carboxylic acids; oxazolidinones; protecting groups.
Tricarballylic acid (TCA) (1) has a framework that bears structural similarity to several biologically
active compounds such as citric acid, amino acids,1a toxins1b and enzyme inhibitors.1c In particular,
TCA has attracted the attention of several research groups2a,b because it was found as a fragment in the
mycotoxins, Fumonisins B1 and B2, isolated from the corn pathogen Fusarium moliniforme, which have
been linked to human esophageal cancer in part of China and Southern Africa. To investigate the role
that the TCA framework should play in other biologically active compounds, we decided to use it as a
building block in our medicinal chemistry projects.3 However, major synthetic problems arose from the
necessity to use orthogonal protection on the carboxylic groups of TCA.
Previous syntheses of both enantiomers of dimethyl tricarballylic acid were described by Boyle
and Kishi2a using a modified Hanessian procedure for the asymmetric Michael addition of a chiral
allylphosphonoamide to t-butyl sorbate as a key step.4 However, the resulting TCA dimethyl ester was
not suitable for our purposes due to lack of orthogonality between the two ester groups. Subsequently
∗
†
Corresponding author. Tel: +39 055 5680745; fax: +39 055 5680419.
On leave from Università degli Studi di Firenze.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02264-9
tetl 16192

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Wyatt et al.5 demonstrated that but-3-enoyloxazolidinones (of type 3, Scheme 1) bearing an Evans chiral
auxiliary are able to undergo diastereoselective alkylation by various electrophiles of type Br–CH2–X
(X_CN, COOMe), and the homologue of aspartic acid was synthesized stereoselectively. With this in
mind, the enantioselective synthesis of orthogonally protected TCA was planned as depicted in Scheme
1; t-butyl and benzyl esters were selected as protecting groups,6 leaving the third carboxylic functional
group unprotected (to obtain type 2 molecules). The allylic double bond of but-3-enoyloxazolidinones
3a was used as a masked carboxymethyl group and diastereoselective alkylation was performed using
t-butyl bromoacetate as the electrophile (recently Evans et al. reported a study on this kind of reaction).7
The resulting compound 4a was transformed into the target compound (S)-6 by route ii–iii−iv or iv–v. In
the first route the chiral auxiliary was removed from 4a using LiOH/H2O2/THF and, after work-up, the
resulting crude intermediate was esterified by O-alkylation with benzyl bromide/Cs2CO3. The oxidation
of compound 5 with RuCl3/NaIO4 in a biphasic system8 afforded the target compound (S)-6 in 29%
overall yield after flash chromatography.9
t
Scheme 1. (i) BrCH2CO2 Bu, NaHMDS, THF, −78°C (89%); (ii) LiOH/H2O2, THF, 0°C; (iii) Cs2CO3, BnBr, DMF (66%);
(iv) NaIO4/RuCl3·H2O, CCl4/MeCN/H2O (49%); (v) BnOLi/BnOH, THF
In the alternative route the oxidation of the double bond of compound 4a with the chiral auxiliary in
place gave a poor yield due to the difficulty of extraction of intermediate 7 from inorganic salts. The
subsequent removal of the chiral auxiliary was effected by in situ benzyl esterification10 using freshly
prepared PhCH2OLi in benzyl alcohol/THF. Although this route also furnished the expected compound
6 the separation from side-products and excess PhCH2OH was, however, very tedious and the yield also
low. Using oxazolidinones a, b, c and steps ii–iii–iv both enantiomers (R)-6 and (S)-6 were obtained
(Table 1).
In order to establish the enantiomeric excess of the TCA derivatives the Chiral Derivatising Agents
1
(CDAs) method was used and the resulting diastereoisomer ratio was checked by H NMR. The
derivatisation of both (R)-6 and (S)-6 with D(+)-norephedrine, D(+)-methylbenzylamine and (−)-
menthol did not give unequivocal results due to large overlapping of proton signals and poor magnitude
of the chemical shift differences. To improve the signal shift and to simplify the 1H NMR spectra the free
carboxylate functional group was converted into the corresponding methyl ester and, after deprotection of

1263
Table 1
the benzyl ester, CDAs were used on the free carboxyl group nearest to the stereocentre. The procedure is
described in Scheme 2. The methyl ester signals of compounds 8 and 9 show 1H NMR resonances at 3.59
and 3.69 ppm, respectively, and they were used to determine the ee of (S)-6 and (R)-6.11 Mutual addition
of the NMR sample 8 to 9, and vice versa, confirmed the assignment of the methyl ester resonance
signals. The diastereomeric ratio Ds 8:9 was 92:8 for 8 and 3:97 for 9.
Scheme 2.
The absolute stereochemistry of compound (R)-6 was correlated with a compound of known absolute
30
stereochemistry. Compound (R)-6 was transformed (Scheme 3) in two steps into diol 10: [α]D −1.9
(c=3.2, CHCl3), [α]D −2.7 (c=2.5, CHCl3) lit.2a and [α]D +2.2 (c=2.6, CHCl3) lit.2a for the enantiomer.
The values of the optical rotation are very low and they were intended only from a qualitative point of
view to confirm the sign of optical rotation and so to correlate the absolute configuration of the TCA
derivatives with the reference compound.
Scheme 3.
In conclusion, an easy and approachable synthesis of both enantiomers, with good optical purity, of
tricarballylic acid (TCA) has been described. This synthesis also provides final products with orthogonal
protection in at least two out of the three carboxylic acid groups which renders the TCA moiety amenable
to regioselective insertion into larger molecules. Applications of these enantiomerically enriched TCA
derivatives as chiral building blocks for the synthesis of target compounds of medicinal interest is
currently under investigation

1264
References
1. (a) Christy, M. R.; Barkley, M. R.; Koch, T. H.; Van Buskirk, J. J.; Kirsc, W. M. J. Am. Chem. Soc. 1981, 103, 3935–3937; (b)
Shier, W. T.; Habbes, H. K.; Badria, F. A. Tetrahedron Lett. 1995, 36, 1571–1574; (c) Aoyama; T.; Sato, T.; Yonemoto, M.;
Shibata, J.; Nanoshita, K.; Arai, S.; Kawakami, K.; Iwasawa, Y.; Sano, H.; Tanaka, K.; Monden, Y.; Kodera, T.; Arakawa,
H.; Suzuki-Takahashi, I.; Kamei, T.; Tomimoto, K. J. Med. Chem. 1998, 41, 143–147.
2. (a) Boyle, C. D.; Kishi, Y. Tetrahedron Lett. 1995, 36, 4579–4582; (b) Edwards, O. E.; Blackwell, A. B.; Driega, B. A.;
Bensimon C.; Apsimon, J. W. Tetrahedron Lett. 1999, 40, 763–795.
3. Perrotta, E.; Harmat, N. J. S.; Mangani, S.; Raffaelli, B.; Giannotti, D.; Nannicini R.; Altamura, M.; Poster n.138, ESOC 11,
Goteborg, Sweden, 1999.
4. Hanessian, S.; Gomtsyan, A.; Payne, A.; Hervè, Y.; Beaudoin, S. J. Org. Chem. 1993, 58, 5032–5034.
5. Arvanitis, E.; Motevalli, M.; Wyatt, P. B. Tetrahedron Lett. 1996, 37, 4277–4280.
6. Perrotta, E.; Raffaelli, B.; Giannotti, D.; Harmat, N. J. S.; Nannicini, R.; Altamura, M. Synlett 1999, 144–146.
7. Evans, D. A.; Wu, L. D.; Wiener, J. J. M.; Johnson, J. S.; Ripin, D. H. B.; Tedrow, J. S. J. Org. Chem. 1999, 64, 6411–6417.
8. Carlsen, P. H. J.; Tatsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1981, 46, 3936–3938.
9. Compound (S)-6, pale yellow oil, 1H NMR (200 MHz, CDCl3) δ 1.41 (s, 9H), 2.46–2.90 (m, 4H), 3.18–3.35 (m, 1H), 5.14
(s, 2H), 7.28–7.45 (m, 5H), 8.8 (bs, 1H); 13C NMR (50 MHz, CDCl3) δ 28.0, 35.2, 36.5, 37.6, 66.9, 81.2, 128.1, 128.2,
128.5, 135.7, 170.4, 173.1, 176.5. Anal. calcd for C17H22O6: C, 63.34; H, 6.88. Found: C, 63.23; H, 6.89.
10. Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127–2129.
1
11. Compound 8, colourless oil, H NMR (500 MHz, CDCl3) δ 1.44 (s, 9H), 1.44 (d, J=7.8 Hz, 3H), 2.33–2.45 (m, 2H),
2.61–2.74 (m, 2H), 3.08 (m, 1H), 3.59 (s, 3H), 5.02–5.11 (m, 1H), 6.37 (d, J=7.5 Hz, 1H), 7.20–7.29 (m, 5H); MS ES+
m/z 349.8 (MH+). Anal. calcd for C19H27NO5: C, 65.31; H, 7.79; N, 4.01. Found: C, 65.43; H, 7.84; N, 4.07. Compound 9,
colourless oil, 1H NMR (500 MHz, CDCl3) δ 1.40 (s, 9H), 1.45 (d, J=6.8 Hz, 3H), 2.30–2.74 (m, 2H), 2.52–2.62 (m, 1H),
2.71–2.82 (m, 1H), 3.02–3.12 (m, 1H), 3.69 (s, 3H), 5.02–5.10 (m, 1H), 6.45 (d, J=8.2 Hz, 1H), 7.18–7.30 (m, 5H); MS ES+
m/z 349.8 (MH+). Anal. calcd for C19H27NO5: C, 65.31; H, 7.79; N, 4.01. Found: C, 65.25; H, 7.81; N, 3.97.