Absolute configuration of α-phthalimido carboxylic acid derivatives from circular dichroism spectra

Article abstract of DOI:10.1016/S0957-4166(99)00521-2

It is demonstrated that the Cotton effects due to the 220 nm phthalimide π-π* transition observed for a series of derivatives of α- phthalimidocarboxylic acids unequivocally reflect the amino acid absolute configuration. This method is based on the exciton coupling of the allowed transitions of the phthalimide and the carboxylic acid derivative chromophores. (C) 1999 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(99)00521-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 4585–4590
Absolute configuration of α-phthalimido carboxylic acid
derivatives from circular dichroism spectra
P. Skowronek ∗ and J. Gawron´ski
Department of Chemistry, Adam Mickiewicz University, Poznan´, Poland
Received 28 October 1999; accepted 18 November 1999
Abstract
It is demonstrated that the Cotton effects due to the 220 nm phthalimide π–π* transition observed for a series
of derivatives of α-phthalimidocarboxylic acids unequivocally reflect the amino acid absolute configuration. This
method is based on the exciton coupling of the allowed transitions of the phthalimide and the carboxylic acid
derivative chromophores. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Optically active α-aminocarboxylic acids play an important role in organic chemistry and biochemistry
and determination of their configuration is a crucial part of their asymmetric synthesis. However, in the
literature there are only few examples of using CD spectra of α-amino acid chromophoric derivatives
for determining absolute configuration. Although the carboxyl chromophore (and its derivatives) did
not find many applications in the exciton coupling method, mainly due to the high energy of the π–π*
transition placed below 190 nm, examples of the CD spectra of N-salicylidene1 and N-(4-bromobenzoyl)2
derivatives of α-amino acids show that exciton coupling with the carboxyl chromophore can be effective.
The phthaloyl group is one of the most frequently used protecting groups in amino acid chemistry, but
surprisingly to date this derivative has not been used for the determination of the absolute configuration
of α-amino acids. Recently we have demonstrated that the phthaloyl group is an excellent chromophoric
derivative for the non-empirical determination of the absolute configuration of diamines, aminoalcohols,
and arylamines, based on the exciton coupling mechanism.3,4
∗
Corresponding author.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00521-2
tetasy 3156

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2. Results and discussion
In this report we show that N-phthaloyl α-amino acids and their derivatives exhibit Cotton effects at ca.
220 nm, i.e. at the maximum absorption for the π–π* transition of the phthalimide chromophore, whose
sign unequivocally reflects the absolute configuration of the α-amino acids or its derivative. Both acyclic
1a–1g and cyclic 2a–2c, 3a, 3b derivatives of S configuration (i.e. belonging to the L configurational
series) are characterized by a negative Cotton effect at 220 nm (Scheme 1).†
Scheme 1.
The negative π–π* transition Cotton effect of α-phthalimido carboxylic acid and derivatives results
from the excited state interaction of the electric dipole transition moments of the phthalimide (polarized
along the C2 axis of the chromophore)3,4 and the carboxylic chromophore (Scheme 2).
Scheme 2. Minimum energy conformations of α-phthalimido carboxylic acid derivatives
In the case of acyclic amino acid derivatives, molecular mechanics calculations suggest that confor-
mation A is preferred. The preferred conformation of acyclic compounds 1a–1g is similar to that found
for α-amino acids5 and for α-hydroxyacids both in solution5 and in the solid state,6 as well as for α-
phenylacids.7 Minimum energy conformations of the cyclic compounds 2a–2c were determined as B and
for 3a,3b as C by molecular mechanics calculations and proved by measurement of the 3JHα,Hβ coupling
constants (2a: 9.3, 10.7; 2b: 9.9, 9.9; 2c: 7.0, 13.0; 3a: 5.8, 7.0; 3b: 5.3, 12.7 Hz). These data correspond
well with the conformation reported for derivatives of homoserine lactone8,9 and for substituted glutaric
anhydride and glutarimides.10–13
†
The CD spectrum of the thiolactone 2c is more complicated due to the contribution of the thiolactone σ–π* transition at
around 235 nm. Nevertheless, a negative Cotton effect at ca. 230 nm (∆ε −3.0) was found by subtracting the CD spectrum of
L-homocysteine thiolactone hydrochloride from the CD spectrum of 2c.

P. Skowronek, J. Gawron´ski / Tetrahedron: Asymmetry 10 (1999) 4585–4590
4587
The negative helicity of the two-dipole system results in a negative Cotton effect at 220–225 nm (the
other part of the couplet is expected to appear below 200 nm, i.e. where the carboxylic acid derivative
π–π* absorption band is located). Calculation of the sign of the rotational strength14 for the long
wavelength chromophore as a function of the dihedral angle N–C*–C(O)–X gives negative rotational
strength for all negative values of the dihedral angle (Fig. 1). This result is in agreement with the sign of
the experimental Cotton effects for the phthalimide chromophore at 220–225 nm in derivatives 1–3.
Fig. 1. Calculated rotational strength of the phthalimide 220 nm transition as a function of the N–C*–C(O)–X angle
The CD spectra of N-phthaloyl amino acids are affected by the solvent; however in all cases studied a
negative Cotton effect at 220–225 nm was consistently observed (Fig. 2).
Fig. 2. CD spectra of N-phthaloyl-l-alanine 1a in various solvents
In the case of the solution in borate buffer (pH 9.2) the amino acid derivative is ionized; the carboxylate
ion transition, occurring at a longer wavelength than that of the carboxylic acid, gives rise to a weak
Cotton effect at ca. 245 nm (Fig. 2). This Cotton effect is apparently due to the coupling of the carboxylate
transition dipole to the dipole of the 240 nm phthalimide transition, polarized perpendicularly to the
chromophore C2 axis.3,4
3. Conclusion
In summary, we have shown that the absolute configuration of an α-amino acid or its derivative can
be readily determined from the CD spectrum of its N-phthaloyl derivative. The sign of long-wavelength

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Cotton effect at 220 nm directly reflects the helicity of the bichromophoric system, i.e. for a negative
sign of Cotton effect the absolute configuration of the N-phthaloyl-α-amino acid or its derivative is S.
This statement is straightforward and insensitive to additional non-chromophoric substituents for rigid
cyclic derivatives of N-phthaloyl-α-amino acids as well as for acyclic N-phthaloyl-α-amino acids or
its esters. In doubtful cases a conformational analysis is necessary to establish the correct helicity of
bichromophoric systems. Further applications are now under development.
4. Experimental
IR spectra were recorded with a FT IR Bruker IFS 113v spectrophotometer. 1H NMR were recorded
on a Varian EM-360 spectrometer in CDCl3 solutions unless noted otherwise. CD spectra were taken
with a Jobin-Yvon III dichrograph in acetonitrile solutions. Optical rotations were measured with a
Perkin–Elmer 243B polarimeter. The enantiomeric purity of the compounds 1a–c was better than 92%,
as determined by HPLC analysis on a DAICEL OD-H 250/4 column. Melting points are uncorrected.
4.1. N-Phthaloyl-L-amino acids
The title compounds were synthesized according to literature procedures.15,16
4.1.1. N-Phthaloyl-L-alanine 1a
M.p. 148–149°C (lit. 144–146°C15); [α]D −25.7, c=10, EtOH (lit. [α]D −24.2, c=3, EtOH15).
4.2. N-Phthaloyl-L-valine and N-phthaloyl-L-leucine
The title compounds were synthesized by melting 1 equiv. of the amino acid with 1 equiv. of phthalic
anhydride at 140°C. Crude N-phthaloylamino acids were purified by crystallization from cyclohexane.
4.2.1. N-Phthaloyl-L-valine 1b
M.p. 110–112°C (lit. 114–115°C16); [α]D −71.7, c=1.46, EtOH (lit. [α]D −68.5, EtOH16).
4.2.2. N-Phthaloyl-L-leucine 1c
M.p. 118–120°C (lit. 118–119°C16); [α]D −24.2, c=3, EtOH (lit. [α]D −22.1, EtOH16).
4.3. N-Phthaloyl-L-amino acid methyl esters
The title compounds were prepared from N-phthaloyl-L-amino acid chlorides.17 Acid chlorides were
used without purification. Methyl esters were obtained from acid chlorides by dissolving in methanol at
0°C. Products were purified by column chromatography on silica gel.
4.3.1. N-Phthaloyl-L-alanine methyl ester18 1d
Yield 87%; m.p. 33–34°C; [α]D −17.1, c=1, MeOH; 1H NMR δ 1.7 (d, J=7.4 Hz, 3H), 3.75 (s, 3H),
4.98 (q, J=7.4 Hz, 1H), 7.2–7.8 (m, 4H); IR (KBr) 2957, 1708, 1748, 1714, 1391, 1245, 1147, 1072, 883,
718, 530 cm−1
.

P. Skowronek, J. Gawron´ski / Tetrahedron: Asymmetry 10 (1999) 4585–4590
4589
4.3.2. N-Phthaloyl-L-valine methyl ester 1e
Yield 89%; oil; [α]D −69.3, c=1, MeOH (lit. [α]D −66.7, c=1.2, MeOH19); 1H NMR δ 0.9 (d, J=6.8
Hz, 3H), 1.15 (d, J=6.7 Hz, 3H), 2.76 (m, 1H), 3.7 (s, 3H), 4.5 (d, J=8.4 Hz, 1H), 7.7–7.9 (m, 4H.); IR
(film) 2963, 1769, 1714, 1467, 1383, 1354, 1332, 1073, 719 cm−1
.
4.3.3. N-Phthaloyl-L-leucine methyl ester 1f
Yield 95%; oil; [α]D −30.2, c=1, MeOH (lit. [α]D −20.8, c=5.6, CHCl320); 1H NMR δ 0.93 (d, J=6.4
Hz, 3H), 0.96 (d, J=5.9 Hz, 3H), 1.5 (m, 1H), 1.96 (ddd, J=4.4, 10, 14.1 Hz, 1H), 2.3 (ddd, J=4.1, 11.6,
14.2 Hz, 1H), 3.37 (s, 3H), 5.0 (dd, J=4.4, 11.5 Hz, 1H), 7.7–7.9 (m, 4H); IR (film) 2958, 2872, 1776,
1746, 1715, 1387, 1255, 720, 530 cm−1
.
4.3.4. N-Phthaloyl-L-cysteine methyl ester 1g
Obtained by treatment of N-phthaloyl-L-cysteine with excess diazomethane in methanol solution, oil;
[α]D −105.5, c=1, CHCl3; 1H NMR δ 2.11 (s, 3H), 3.35 (d, J=7.6 Hz, 2H), 3.77 (s, 3H), 5.04 (t, J=8.0
Hz, 1H), 7.82 (m, 4H); IR (film) 1770, 1715, 1385, 1245, 1100, 715 cm−1
.
4.3.5. (S)-N-Phthaloyl-α-amino-γ-butyrolactone 2a
N-Carboethoxyphthalimide (87 mg, 0.4 mmol) was dissolved in DMF (1 ml) and α-amino-γ-
butyrolactone hydrochloride (55 mg, 0.4 mmol) and Et3N (40 mg, 0.4 mmol) were added. The mixture
was stirred for 4 h at room temperature. Half of the solvent was evaporated in vacuo and water (1 ml)
was added to give 55 mg (62%) of 2a, m.p. 181–182°C; [α]D −29.2, c=1, CHCl3 (lit. [α]D −39.5, c=1,
1
MeCN21); H NMR δ 2.6 (m, 1H), 2.8 (m, 1H), 4.4 (m, 1H), 4.6 (dt, J=2.2, 9.0 Hz, 1H), 5.1 (dd, 9.0,
10.0 Hz, 1H), 7.7–7.9 (m, 4H); IR (KBr) 3473, 2991, 2924, 1788, 1773, 1713, 1469, 1403, 1387, 1230,
1204, 1124, 1089, 1033, 1015, 1007, 895, 798, 717, 531 cm−1
.
4.3.6. (S)-N-Phthaloyl-α-amino-γ-butyrolactam 2b
L-2,4-Diaminobutyric acid dihydrochloride (195 mg, 1.02 mmol) and HMDS (4 ml) were refluxed in
acetonitrile (5 ml) for 72 h.22 The solvents were evaporated and the residue was dissolved in CHCl3.
After filtration the clear solution was evaporated to give 89 mg of crystalline α-amino-γ-butyrolactam
(yield 88%).
To the lactam (39 mg, 0.39 mmol) in DMF (0.5 ml) N-carboethoxyphthalimide (85 mg, 0.39 mmol)
was added and the solution was stirred for 4 h at room temperature. Half of solvent was evaporated and
water (1 ml) was added to give 61 mg (68%) of 2b, m.p. 192–194°C; [α]D −56.2, c=0.445, CHCl3; 1H
NMR δ 2.56 (m, 2H), 3.5 (q, J=7.9, 9.3 Hz, 1H), 3.6 (t, J=7.9 Hz, 1H), 4.95 (t, J=9.9 Hz, 1H), 6.9 (s, 1H),
7.7–7.9 (m, 4H); IR (KBr) 3431, 3353, 2929, 1773, 1704, 1466, 1425, 1395, 1292, 1265, 1192, 1135,
1044, 1027, 898, 802, 722, 640, 562, 525 cm−1
.
Racemic form of the compound 2b was reported.23
4.3.7. (S)-N-Phthaloyl-α-amino-γ-butyrothiolactone 2c
N-Phthaloyl-L-methionine21,24 (72 mg, 0.48 mmol) was dissolved in CH2Cl2 (3 ml) and SOCl2 (3
ml) was added. After 2 h of refluxing, the solution was evaporated to dryness. Crude acid chloride was
dissolved in CS2 (10 ml) and after addition of 3 equivalents SnCl4 in CS2 (10 ml) the solution was
refluxed with stirring for 4 h.25 Afterwards ice (0.5 g) and 2N HCl (4 ml) were added to the solution. The
product was extracted with benzene and purified by column chromatography; 2c was obtained as an oil,
yield 48 mg (40%); [α]D −56, c=1, CHCl3 (lit. [α]D −4.5, c=0.85, CHCl326); 1H NMR δ 2.6 (m, 1H),
2.9 (m, 1H), 3.5 (m, 2H), 5.0 (dd, J=7.2, 13.0 Hz, 1H), 7.76–7.87 (m, 4H); IR (KBr) 3040, 2900, 1720,
1680, 1380, 1100, 710 cm−1
.

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4.3.8. N-Phthaloyl-L-glutamic acid anhydride 3a
To N-phthaloyl-L-glutamic acid27 (40 mg, 0.14 mmol) in THF (1 ml) DCC (33 mg, 0.16 mmol) in
THF (1 ml) was added. After removal of dicyclohexylurea by filtration the anhydride 3b crystallized,
yield 26 mg (71%); m.p. 190–193°C (lit. 200–202°C28); [α]D −36.4, c=1, dioxane (lit. [α]D −47.0, c=1,
dioxane28); 1H NMR (acetone-d6) 2.3 (ddd, J=3.0, 5.7, 13.1 Hz, 1H), 2.8 (ddd, J=5.0, 13.1, 13.1 Hz, 1H),
3.15 (ddd, J=3.0, 5.0, 17.8 Hz, 1H), 3.3 (ddd, J=5.7, 13.1, 17.8 Hz, 1H), 5.45 (dd, J=5.8, 7.0 Hz, 1H), 7.9
(s, 4H).
4.3.9. (S)-N-Phthaloyl-α-aminoglutarimide (thalidomide 3b)
This compound was obtained according to the recorded procedure,29 m.p. 268–270°C; [α]D −54.4,
c=1, DMF (lit. −64.2, c=1, DMF29).
Acknowledgements
This work was supported by the Committee for Scientific Research (KBN), grant no. 3T09A/08/10.
References
1. Smith, H. S. Chem. Rev. 1983, 83, 359–377.
2. Molinski, T. F.; Ireland, C. M. J. Org. Chem. 1988, 53, 2103–2105.
3. Kaz´mierczak, F.; Gawron´ska, K.; Rychlewska, U.; Gawron´ski, J. Tetrahedron: Asymmetry 1994, 5, 527–530.
4. Gawron´ski, J.; Kaz´mierczak, F.; Gawron´ska, K.; Rychlewska, U.; Nordén, B.; Holmén, A. J. Am. Chem. Soc. 1998, 120,
12083–12091.
5. Craig, J. C.; Pereira Jr., W. E. Tetrahedron 1970, 26, 3457–3460.
6. Gawron´ski, J.; Gawron´ska, K.; Skowronek, P.; Rychlewska, U.; Warz˙ajtis, B.; Rychlewski, J.; Hoffman, M.; Szarecka, A.
Tetrahedron 1997, 53, 6113–6144.
7. Klyne, W.; Scopes, P. M.; Thomas, R. N.; Dahn H. Helv. Chim. Acta 1971, 54, 2420–2430.
8. Son, J.-K.; Kalvin, D.; Woodart, R. W. Tetrahedron Lett. 1988, 29, 4045–4048.
9. Meguro, H.; Konno, T.; Tuzimura, K. Tetrahedron Lett. 1972, 3165–3168.
10. Połon´ski, T. J. Chem. Soc., Perkin Trans. 1 1988, 639–648.
11. Allen, F. H.; Trotter, J. J. Chem. Soc. (B) 1971, 1073–1075.
12. Caira, M. R.; Botha S. A.; Falangan D. R. J. Chem. Crystallography 1994, 24, 95–99.
13. Reepmayer, J. C.; Rhodes, M. O.; Cox, D. C.; Silverton, J. V. J. Chem. Soc., Perkin Trans. 2 1994, 2063–2067.
14. Rodger, A.; Nordén, B. Circular Dichroism and Linear Dichroism; Oxford University Press: Oxford, 1997; pp. 66–89.
15. Bose, A.; Greer, F.; Price, C. J. Org. Chem. 1958, 23, 1335–1338.
16. Fling, M.; Minard, F. N.; Fox, S. W. J. Am. Chem. Soc. 1947, 69, 2466–2468.
17. Juaristi, E.; Beck, A. K.; Hansen, J.; Matt, T.; Mukhopadhyay, T. Synthesis 1993, 1271–1290.
18. Griesbeck, A. G.; Mauder, H.; Mueller, I. Chem. Ber. 1992, 125, 2467–2476.
19. Griesbeck, A. G.; Mauder, H. Angew. Chem. 1992, 104, 97–99.
20. Marshall, J. A.; Garofalo, A. W. J. Org. Chem. 1993, 58, 3675–3680.
21. Griesbeck, A. G.; Hirt, J. Liebigs Ann. Chem. 1995, 1957–1961.
22. Pellegata, R.; Pinza, M.; Pifferi, G. Synthesis 1987, 614–616.
23. Reppe, W. Liebigs Ann. Chem. 1955, 596, 158–188.
24. Guttmann, S.; Boissannas, R. A. Helv. Chim. Acta 1958, 41, 1852–1867.
25. Fleš, D.; Markovac-Prpic, A.; Tomasic, V. J. Am. Chem. Soc. 1958, 80, 4654–4655.
26. Dehmlow, E. V.; Westerheide, R. Synthesis 1993, 1225–1226.
27. Nefkens, G. H. L. Rec. Trav. Chim. Pay-Bas 1960, 79, 688–698.
28. Echavarren, A. M.; Castano, A. M. Tetrahedron 1995, 51, 2369–2378.
29. Reepmayer, J. C. Chirality 1996, 8, 11–17.