Synthesis of highly epimerizable N-protected α-amino aldehydes of high enantiomeric excess

Article abstract of DOI:10.1016/S0040-4039(99)02293-5

The Dess-Martin periodinane was found to be a superior oxidant for the efficient, epimerization-free synthesis of optically active N-protected α- amino aldehydes from the corresponding N-protected β-amino alcohols. Highly racemization-prone products, including N-Fmoc phenylglycinal and N- trifluoroacetyl α-amino aldehydes, were prepared in ≥95% yield with ≤ 1% epimerization. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02293-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1359–1362
Synthesis of highly epimerizable N-protected α-amino aldehydes
of high enantiomeric excess
Andrew G. Myers,∗ Boyu Zhong, Mohammad Movassaghi, Daniel W. Kung, Brian A. Lanman
and Soojin Kwon
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA
Received 16 November 1999; accepted 29 November 1999
Abstract
The Dess–Martin periodinane was found to be a superior oxidant for the efficient, epimerization-free synthesis
of optically active N-protected α-amino aldehydes from the corresponding N-protected β-amino alcohols. Highly
racemization-prone products, including N-Fmoc phenylglycinal and N-trifluoroacetyl α-amino aldehydes, were
prepared in ≥95% yield with ≤1% epimerization. © 2000 Elsevier Science Ltd. All rights reserved.
Optically active N-protected α-amino aldehydes are widely used synthetic intermediates of importance
in the pharmaceutical and fine chemical industries.1 The facility with which they undergo epimerization
has been noted and strategies have been devised to minimize this propensity, such as Rapoport’s 9-
(9-phenylfluorenyl) substitution of the α-amino group2 and Reetz’ N,N-dibenzyl derivatization.3 In the
course of studies directed toward the synthesis of saframycin A and related alkaloids with antitumor
activity, we were led to prepare a series of chiral α-amino aldehydes with simple, base-labile N-protective
groups such as fluorenylmethoxycarbonyl (Fmoc) and trifluoroacetyl (TFA). Several of these aldehydes
proved to be exceedingly susceptible to base-induced epimerization. In surveying methods for the
preparation of these compounds with maximal enantiomeric enrichment we have consistently found that
oxidation of the corresponding N-protected β-amino alcohols with the Dess–Martin periodinane4 prov-
ides exceptional results, furnishing the desired aldehydes with ≤1% epimerization of the α-stereocenter,
including highly epimerizable products such as N-Fmoc phenylglycinal. Because of the broad utility of
these compounds as intermediates in chemical synthesis, we describe the details of our findings herein.
A large number of optically active N-protected α-amino aldehydes have been described in the
literature.1 These are typically among the less racemization-prone α-amino aldehydes, however, with
α-side-chains such as benzyl, isobutyl, and the like, and can often be prepared in high optical purity by
Swern oxidation of the corresponding N-protected β-amino alcohols.1 There are far fewer references to
α-amino aldehydes with epimerization-enhancing features such as an α-aryl group or a strongly electron-
withdrawing N-protective group. From consideration of literature reports concerning N-protected der-
ivatives of phenylglycinal, it is evident that such compounds can be difficult to prepare and handle.
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02293-5
tetl 16221

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Greene et al. noted that addition of vinyl magnesium bromide to N-benzoyl and N-tert-butoxycarbonyl
phenylglycinal, prepared by Swern oxidation of the corresponding alcohols using diisopropylethylamine
as base, afforded racemic products (adducts of high ee were obtained by an inverse addition protocol).5
Dondoni et al. reported obtaining poor yields upon attempted synthesis of N-benzoyl phenylglycinal
using the same Swern protocol, and instead turned to a semireduction method to produce the aldehyde.
They described the product, N-benzoyl phenylglycinal, as a material which decomposed upon standing
and upon attempted purification by chromatography.6,7
We chose the oxidation of N-Fmoc phenylglycinol (99% ee, determined by direct HPLC analysis
using a Chiralcel OD column) as a focal point for our studies. Attempted Swern oxidation of N-Fmoc
phenylglycinol using triethylamine as base failed to provide any of the desired N-Fmoc phenylglycinal
(1). Thin-layer chromatographic analysis of the reaction mixture showed that dibenzofulvene had been
formed as a product. This was somewhat surprising, for the N-Fmoc group is generally found to be
compatible with Swern oxidation conditions (vide infra). Its instability in this particular instance may be
indicative of enolization of the product aldehyde, promoting internal cleavage of the Fmoc group. Use
of diisopropylethylamine as base in the Swern procedure did provide some of the desired aldehyde (ca.
37% yield, 50±5% ee), but the reaction was prohibitively slow and was in no sense a viable protocol.
In accord with findings from the Abbott process group, TEMPO-catalyzed oxidation (using bleach as
the stoichiometric oxidant) was found to be an effective method,8 affording the desired aldehyde (1)
in 87% yield after aqueous work-up. Consistent with the observations of Dondoni et al.,6 attempted
chromatographic purification of 1 on silica gel led to its decomposition. To determine the enantiomeric
excess of the product, the crude material was reduced with sodium borohydride in ethanol at 23°C. The
resulting N-Fmoc phenylglycinol, isolated in 97% yield, was found by direct HPLC analysis to be of 95%
ee.9 This value was initially considered to be a lower limit, given the possibility that racemization might
have occurred in the reduction step of the ee determination; however, subsequent results established that
the degree of epimerization in the reduction was at most 1%, and, thus, the erosion in optical purity
must be ascribed to racemization during the oxidation or upon work-up. With further experimentation
we found that optimal results in the oxidation were obtained using the Dess–Martin periodinane (2
equiv.)10 in wet dichloromethane11 at 23°C (25 min). Aqueous work-up afforded the crude aldehyde in
>95% yield. Reduction with sodium borohydride, as described above, provided N-Fmoc phenylglycinol
of 99% ee. This finding established both the superiority of the Dess–Martin oxidation protocol and the
validity of the borohydride reduction procedure as a method for determining the ee of the product. N-
Fmoc phenylglycinal prepared in this manner was obtained as a white solid and was shown to be of
1
>90% purity by H and 13C NMR spectroscopy. The efficiency of the conversion was confirmed by
subsequent transformations of the aldehyde to purified products, such as reduction to the alcohol (with
sodium borohydride or diisobutylaluminum hydride) or cyanohydrin formation, affording yields of >90%
for each two-step procedure. Further examination of the Dess–Martin protocol for the epimerization-free
preparation of N-protected α-amino aldehydes leads us to speculate that the procedure may be of general
value.12
Although the N-Fmoc phenylalaninal derivative 2 must clearly be categorized among the less
racemization-prone α-amino aldehydes (it could be prepared without epimerization by Swern oxidation
of the corresponding alcohol using triethylamine as base, see Fig. 1), efforts to prepare the corresponding
N-trifluoroacetyl derivative 3 quickly established that this product exhibited an equal or perhaps even
greater propensity to undergo base-induced epimerization than N-Fmoc phenylglycinal (1). Attempted
preparation of 3 from the corresponding N-trifluoroacetyl β-amino alcohol (92% ee) by Swern oxidation
using triethylamine as base (–40°C, >95% yield, unpurified) afforded nearly racemic product (6% ee,
determined by reduction, Mosher ester formation, then 1H NMR analysis). Using diisopropylethylamine
as base in the Swern oxidation, the rate of reaction was found to be prohibitively slow, and that product

1361
which had formed was shown to be only 45±5% ee. By contrast, Dess–Martin oxidation afforded a
product of 90% ee (1% epimerization) and 95% yield (unpurified). That 3 should exhibit a comparable
or greater propensity to undergo base-induced epimerization relative to 1 must clearly be attributed to the
strongly electron-withdrawing nature of the N-trifluoroacetyl protective group. Correlations such as this
have been previously noted, e.g., in the case of enolization of N-protected α-amino ketones,13 as well as
in the propensities of N-protected α-amino acids to epimerize.14 It is reasonable to propose that the rate
of deprotonation of the α-stereocenter slows as the electron density on the α-amino group increases.
Fig. 1. Preparation of N-protected α-amino aldehydes by oxidation of the corresponding alcohols
As summarized in Fig. 1, further studies directed toward the preparation of N-Fmoc alaninal (4)15
and N-Fmoc (m-methoxyphenyl)alaninal (5) are in keeping with the findings above and suggest the
following generalizations for the preparation of N-protected α-amino aldehydes by oxidation of the
corresponding N-protected β-amino alcohols. Swern oxidation using triethylamine as base is effective
only with the most robust N-protected α-amino aldehydes and leads to a high degree of racemization with
epimerization-prone substrates. Use of diisopropylethylamine as base in the Swern oxidation produces
less racemization, but the rate of oxidation can be unacceptably slow and in epimerization-prone cases
products of high ee are not obtained. The TEMPO-catalyzed oxidation is a practical and efficient method
to produce optically active aldehydes, but does lead to a small degree of racemization (4–6%) with the
most demanding cases that we have explored, whereas the Dess–Martin procedure is highly efficient for
all substrates that we examined, proceeding with minimal epimerization of the α-stereocenter.16

1362
Acknowledgements
Financial support from the National Institutes of Health is gratefully acknowledged. M.M. is supported
by a Roche predoctoral fellowship. D.W.K. and B.A.L. acknowledge predoctoral fellowships from the
National Science Foundation.
References
1. For reviews, see: (a) Jurczak, J.; Golebiowski, A. Chem. Rev. 1989, 89, 149–164. (b) Fisher, L. E.; Muchowski, J. M. Org.
Prep. Proced. Int. 1990, 22, 399–484. (c) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1991, 30, 1531–1546. (d) Sardina, F. J.;
Rapoport, H. Chem. Rev. 1996, 96, 1825–1872. (e) Reetz, M. T. Chem. Rev. 1999, 99, 1121–1162.
2. Lubell, W. D.; Rapoport, H. J. Am. Chem. Soc. 1987, 109, 236–239.
3. Reetz, M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem., Int. Ed. Engl. 1987, 26, 1141–1143.
4. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156. (b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991,
113, 7277–7287.
5. Denis, J.-N.; Correa, A.; Greene, A. E. J. Org. Chem. 1991, 56, 6939–6942.
6. Dondoni, A.; Perrone, D.; Semola, T. Synthesis 1995, 181–186.
7. For other examples of N-protected phenylglycinal derivatives, see: (a) Matsunaga, N.; Harada, H.; Aoyama, T.; Shioiri, T.
Heterocycles 1992, 33, 235–255. (b) Hanessian, S.; Devasthale, P. V. Tetrahedron Lett. 1996, 37, 987–990. (c) Andres, J.
M.; Barrio, R.; Martinez, M. A.; Pedrosa, R.; Perez-Encabo, A. J. Org. Chem. 1996, 61, 4210–4213.
8. Leanna, M. R.; Sowin, T. J.; Morton, H. E. Tetrahedron Lett. 1992, 33, 5029–5032. For comparison of the TEMPO and Swern
procedures, see: Jurczak, J.; Gryko, D.; Kobrzycka, E.; Gruza, H.; Prokopowicz, P. Tetrahedron 1998, 54, 6051–6064.
9. For a prior example employing sodium borohydride in the reduction of phenylglycinal derivatives, see Ref. 6.
10. 2-Iodoxybenzoic acid was prepared by oxidation of 2-iodobenzoic acid according to a recently reported procedure: Frigerio,
M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537–4538. 2-Iodoxybenzoic acid was transformed to the
Dess–Martin periodinane following the Ireland protocol: Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
11. Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549–7552.
12. The superiority of the Dess–Martin periodinane for the preparation of chiral α-fluoro aldehydes has been documented:
Davis, F. A.; Kasu, P. V. N.; Sundarababu, G.; Qi, H. J. Org. Chem. 1997, 62, 7546–7547.
13. (a) Garst, M. E.; Bonfiglio, J. N.; Grudoski, D. A.; Marks, J. Tetrahedron Lett. 1978, 30, 2671–2674. (b) Garst, M. E.;
Bonfiglio, J. N.; Grudoski, D. A.; Marks, J. J. Org. Chem. 1980, 45, 2307–2315.
14. For leading references, see: Kemp, D. S. In The Peptides; Gross, E.; Meienhofer, J., Eds.; Academic: New York, 1979;
Volume 1, Chapter 7.
15. For the preparation of N-Boc and N-Cbz alaninal in ees ranging from 82–99%, using TEMPO, Swern, or Parikh–Doering
oxidations, see: Ref. 8, and Hamada, Y.; Shioiri, T. Chem. Pharm. Bull. 1982, 30, 1921–1924.
16. Procedure for the synthesis of N-Fmoc phenylglycinal (1): The Dess–Martin periodinane (2.56 g, 6.03 mmol, 2.1 equiv.,
see Ref. 10 for preparation) was added to a solution of N-Fmoc-(S)-phenylglycinol (99% ee, 1.01 g, 2.82 mmol, 1 equiv.)
in water-saturated dichloromethane (10 mL, see Ref. 11). The resulting suspension was stirred at 23°C, monitoring the
progress of reaction by TLC analysis (2.5% methanol–dichloromethane). As the rate of conversion of the starting material
slowed, additional 2 mL portions of water-saturated dichloromethane were added (three portions over 15 min). After 25
min, no remaining N-Fmoc phenylglycinol was detected by TLC analysis. The reaction mixture was diluted with ether (10
mL), and a solution of sodium thiosulfate (4.74 g, 30.0 mmol, 11 equiv.) in 80% saturated aqueous sodium bicarbonate
solution (10 mL) was added. The mixture was stirred rapidly for 10 min, until both phases were clear. The layers were
separated and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed sequentially
with saturated aqueous sodium bicarbonate solution (15 mL), water (2×15 mL), and brine (2×15 mL), then dried over
sodium sulfate. Concentration afforded crude N-Fmoc phenylglycinal (1) as a white solid (1.01 g, 100%). A sample of the
product (10 mg, 0.029 mmol, 1 equiv.) was dissolved in ethanol (1 mL) at 23°C, and solid sodium borohydride (12 mg,
0.33 mmol, 12 equiv.) was added in one portion. TLC analysis showed complete conversion to N-Fmoc phenylglycinol
after 5 min. After 15 min, excess hydride was quenched by the addition of saturated aqueous ammonium chloride solution
(5 mL). The resulting mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride solution
(10 mL each). The organic layer was washed sequentially with 10 mL portions of saturated aqueous ammonium chloride
solution and brine, then was dried over sodium sulfate and was concentrated. The residue was purified by flash column
chromatography (0→0.5→1% methanol–dichloromethane), furnishing N-Fmoc phenylglycinol as a white solid (9.5 mg,
91%). HPLC analysis (Chiralcel OD, 50% 2-propanol–hexanes, 0.75 mL/min, 266 nm, tR(N-Fmoc-(S)-phenylglycinol)=8.2
min, tR(N-Fmoc-(R)-phenylglycinol)=24.5 min) established an ee of 99%.