N-Benzyloxycarbonyl-L-serine b-Lactone

(R = NH-Cbz) (1)

[26054-60-4]  · C11H11NO4  · N-Benzyloxycarbonyl-L-serine b-Lactone  · (MW 221.21) (R = NH-Boc) (2)

[98541-64-1]  · C8H13NO4  · N-t-Butoxycarbonyl-L-serine b-Lactone  · (MW 187.20) (R = NH3+ OTs-) (3)

[112839-95-9]  · C10H13NO5S  · L-Serine b-Lactone Tosylate  · (MW 259.28)

(reagent for the synthesis of b-substituted alanines1,2)

Alternate Name: (S)-3-(N-benzyloxycarbonyl)aminooxetan-2-one.

Physical Data: (1): mp 133-134 °C, [a]25D = -26.8° (c = 1, MeCN); (2): mp 119.5-120.5 °C, [a]25D = -26.2° (c = 1, MeCN, 24 °C); (3): mp 133-135 °C (darkening), dec. 173 °C, [a]25D = -15.9° (c = 2.2, DMF).

Solubility: (1) and (2) sol most organic solvents; (3) sol polar aprotic organic solvents and H2O.

Form Supplied in: white solids.

Preparative Methods: (1) is easily made by cyclization of commercially available N-Cbz-L-serine (4) under modified Mitsunobu conditions, using a preformed complex of dimethyl azodicarboxylate (DMAD) and Triphenylphosphine (eq 1).3 The reaction proceeds via hydroxy group activation, and labeling studies show that the 3-hydroxy group is lost in a 4-exo-tet cyclization mechanism.5 The b-lactone must be separated quickly from the reaction mixture,3 and a slight excess of DMAD improves the yield because unreacted triphenylphosphine can cause polymerization.6 The Boc (t-butoxycarbonyl) analog (2) is prepared similarly, and the p-toluenesulfonate (tosylate) salt (3) is synthesized from (2) by acidic cleavage.4

Purification: see Pansare et al.3,4

Handling, Storage, and Precautions: the b-lactones (1)-(3) are stable for many months at 4 °C in dry form. Neutral or slightly acidic solutions of (1) and (2) are stable for at least 1 day; (3) must be used in situ; basic and strongly acidic solutions rapidly decompose these b-lactones. They should be handled in a fume hood.

Ring-Opening Reactions.

N-Cbz-b-lactone (1) is a very useful tool for the synthesis of optically active a-amino acids. Unlike other well established procedures,2 this method does not generate the chiral center at the a-carbon but rather homologates optically pure serine derivatives at the b-carbon. Although this review is limited to the use of N-Cbz-L-serine b-lactone to generate L-amino acids in most applications, the corresponding D-serine b-lactones are available analogously from inexpensive D-serine derivatives. Ring-opening of b-lactones can occur in two different modes. Soft nucleophiles (e.g. carboxylate, thiolate) usually attack the b-carbon, whereas hard nucleophiles (e.g. hydroxide, methoxide, organolithium compounds) tend to target the carbonyl group. In certain cases, altering the conditions (e.g. N-substituent, solvent) directs the mode of addition. For example, ammonia in THF at 0 °C attacks the b-position of (1) to give the protected a,b-diaminopropanoic acid (6), whereas the same nucleophile in acetonitrile reacts with acyl oxygen cleavage to produce serine amide (5) (eq 2).7 However, acetonitrile enhances b-attack by ammonia in the case of the N-Boc lactone (2).8

A variety of heteroatom nucleophiles have proven suitable for the desired ring-opening at the b-position (eq 3), such as Nu- = NH3, NMe3, OAc-, SBn-, Cl-, Br-, pyrazole, and thiourea (S-attack).7 Sulfur nucleophiles appear to require protic solvent for good results in this process.

Carbon-carbon bond formation can be achieved with copper-catalyzed Grignard reagents (eq 4), or less cleanly with organolithium-derived cuprate reagents (R2CuLi or R2Cu(CN)Li2).9 Thus Cbz-serine b-lactones behave like chiral enone equivalents, with 1,4-attack of the carbanion at the b-position leading to amino acids and 1,2-attack leading to ketones or even alcohols. Hard organometallics, such as copper-free organolithium or Grignard reagents, react primarily at the carbonyl group, but the organocuprates add at the b-carbon to produce the desired amino acids (8) in good to moderate yields. The magnesium plays a key role in this reaction in terms of regioselectivity, optical purity (>99.4 % ee), and yield. The lithium cuprate reagents show less regioselectivity and in certain cases (e.g. R = Ph) can lead to some epimerization at the a-carbon. Temperature control (-23 °C is often ideal) is critical in reactions of (1) with organometallic reagents.

Acyl-oxygen cleavage of the serine b-lactone, although not desired in most cases, has been employed for the synthesis of (S)-2-methyl-4-benzyloxycarbonylaminopyrazolidine (10). Methylhydrazine in dichloromethane adds regioselectively to the carbonyl group of (1) to afford the hydrazide (9), which after several steps affords (10) (eq 5).10

The anionic polymerization of N-benzyloxycarbonyl-L-serine b-lactone leads to poly(N-acyl-L-serine ester) (Mw = ca. 40 000), from which poly(L-serine ester hydrochloride) can be obtained by hydrogenation.11

Other 3-Aminooxetanones.

Various other a-amino-b-lactones have been prepared and used in amino acid syntheses. The Boc derivative (2),6-9,12-14 the tosylate salt (3),4,15 and the recently published N-Fmoc-L-serine b-lactone16 generally exhibit similar reactivity towards nucleophiles (e.g. phosphites14,16), and the choice of b-lactone can often be determined by requirements of subsequent synthetic steps. However, some differences have been observed. In addition to the ammonia reaction described above,7,8 the condensation of b-mercaptoethylamine (11) with (1) results in nucleophilic attack by nitrogen leading to (12), whereas the same nucleophile attacks the tosylate salt (3) with reverse chemoselectivity giving the corresponding amino acid (13) (eq 6).7,15 The salt (3) has the advantage of producing free amino acids in cases where deprotection of nitrogen may affect the b-substituent.

The L-threonine b-lactone (14), in contrast to the serine b-lactones, has been synthesized by carboxyl group activation (4-exo-trig).17 Initial experiments have shown that ring opening of such b-substituted lactones tends to proceed by attack at the carbonyl except with certain nucleophiles (e.g. thiourea, halides). However, correct choice of N-protecting group allows the synthesis of a range of other b-substituted a-amino-b-lactones,17b,c such as the antiobiotic obaflourin (15).18

In summary, ring opening of serine-b-lactones is an attractive method for generating optically pure b-substituted alanines; the synthesis usually occurs with little or no epimerization.

Related Reagents.

Diketene; b-Ethynyl-b-propiolactone; b-Methyl-b-propiolactone; b-Propiolactone.


1. For a review on b-lactone chemistry, see: Pommier, A.; Pons, J.-M. S 1993, 441.
2. For a review on amino acid synthesis, see: Williams, R. M. Synthesis of Optically Active a-Amino Acids; Pergamon: Oxford, 1989.
3. Pansare, S. V.; Huyer, G.; Arnold, L. D.; Vederas, J. C. OS 1991, 70, 1.
4. Pansare, S. V.; Arnold, L. D.; Vederas, J. C. OS 1991, 70, 10.
5. Ramer, S. E.; Moore, R. N.; Vederas, J. C. CJC 1986, 64, 706.
6. Lodwig, S. N.; Unkefer, C. J. J. Labelled Compds. Radiopharm. 1991, 31, 95.
7. Arnold, L. D.; Kalantar, T. H.; Vederas, J. C. JACS 1985, 107, 7105. Ratemi, E. S.; Vederas, J. C. TL 1994, 35, 7605.
8. Kucharczyk, N.; Badet, B.; Le Goffic, F. SC 1989, 19, 1603.
9. Arnold, L. D.; Drover, J. C. G.; Vederas, J. C. JACS 1987, 109, 4649.
10. Kim, K. S.; Ryan, P. C. H 1990, 31, 79.
11. (a) Zhou, Q.-X.; Kohn, J. Macromol. 1990, 23, 3399. (b) Gelbin, M. E.; Kohn, J. JACS 1992, 114, 3962.
12. Soucy, F.; Wernic, D.; Beaulieu, P. JCS(P1) 1991, 2885.
13. Rosenberg, S. H.; Spina, K. P.; Woods, K. W.; Polakowski, J.; Martin, D. L.; Yao, Z.; Stein, H. H.; Cohen, J.; Barlow, J. L.; Egan, D. A.; Tricarico, K. A.; Baker, W. R.; Kleinert, H. D. JMC 1993, 36, 449.
14. Smith, E. C. R.; McQuaid, L. A.; Paschal, J. W.; DeHoniesto, J. JOC 1990, 55, 4472.
15. Arnold, L. D.; May, R. G.; Vederas, J. C. JACS 1988, 110, 2237.
16. Hutchinson, J. P. E.; Parkes, K. E. B. TL 1992, 33, 7065.
17. (a) Pansare, S. V.; Vederas, J. C. JOC 1989, 54, 2311; (b) Pu, Y.; Martin, F. M.; Vederas, J. C. JOC 1991, 56, 1280. (c) Rao, M. N.; Holkar, A. G.; Ayyangar, N. R. CC 1991, 1007.
18. Lowe, C.; Pu, Y.; Vederas, J. C. JOC 1992, 57, 10. Pu, Y.; Lowe, C.; Sailer, M.; Vederas, J. C. JOC 1994, 59, 3642.

Michael Klinge & John C. Vederas

University of Alberta, Edmonton, AB, Canada



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