A short synthesis of (S)-α-(diphenylmethyl)alkyl amines from amino acids

Article abstract of DOI:10.1016/S0957-4166(99)00095-6

A range of (S)-α-(diphenylmethyl)alkyl amines were prepared from the corresponding (S)-α-amino acid ester hydrochlorides. These amines were derived by direct hydrogenation of their precursor oxazolidinones.

Full text of DOI:10.1016/S0957-4166(99)00095-6

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1189–1192
A short synthesis of (S)-α-(diphenylmethyl)alkyl amines from
amino acids
David O’Hagan ∗ and Mustafa Tavasli
Department of Chemistry, University of Durham, Science Laboratories, South Road, Durham, DH1 3LE, UK
Received 18 February 1999; accepted 12 March 1999
Abstract
A range of (S)-α-(diphenylmethyl)alkyl amines were prepared from the corresponding (S)-α-amino acid ester
hydrochlorides. These amines were derived by direct hydrogenation of their precursor oxazolidinones. © 1999
Elsevier Science Ltd. All rights reserved.
1. Introduction
The synthesis of (S)-α-(diphenylmethyl)pyrrolidine 3 from (S)-proline 1 was recently described1 as
shown in Scheme 1. The key step in the route is the final one where the oxazolidinone 2, when treated
under standard hydrogenation conditions, delivered amine 3, after removal of the elements of carbon
dioxide. Amine 3 emerged as a good chiral solvating agent for enantiomeric analysis of chiral carboxylic
acids and was also used to prepare the diamines 4 and 5, potential bidentate ligands.1
To develop this methodology further we now report the synthesis of the (S)-α-(diphenylmethyl)alkyl
amines 11–15 from appropriate (S)-amino acids. The amines were delivered in a straightforward manner
by an analogous hydrogenation to that of 2 on the corresponding oxazolidinones 6–10.
2. Results and discussion
The general route to these amines is outlined in Scheme 2. Reaction of the ethyl ester ammonium
HCl salts of the starting amino acids, with phenylmagnesium bromide has previously been described for
all of the cases studied,2 and similarly all of the oxazolidinones except 9 (derived from (S)-isoleucine)
have previously been prepared by analogous routes.3 In our case the amino alcohols were treated with
diphosgene to generate the oxazolidinones 6–10 and generally the yields were good to excellent. The
∗
Corresponding author.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00095-6

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D. O’Hagan, M. Tavasli / Tetrahedron: Asymmetry 10 (1999) 1189–1192
Scheme 1.
hydrogenation of the oxazolidinones proved straightforward and the target amines were readily purified
as detailed in the Experimental. Data for characterisation and physical properties of these novel amines
are summarised in Table 1.
Scheme 2.
It was important to determine if the amines 11–15 were enantiomerically pure and that no racemisation
had occurred during the hydrogen process. To this end amine 13 was prepared as a racemate from (RS)-
alanine ethyl ester HCl salt and was then derivatised with (S)-Mosher’s acid chloride4 to generate the
corresponding (R)-Mosher’s amide derivatives 16 and 17, a mixture of diastereoisomers. Fig. 1 illustrates
a comparison of selected regions of the 1H and 19F NMR spectra (OMe and CF3 signals, respectively),
of the amide diastereoisomers 16 and 17, and 16 generated by reaction of (R)-Mosher’s acid chloride
with (S)-13. It is clear that a single diastereoisomer is generated in the latter case and within the level of
detection there is no indication of any racemisation. (R)-Mosher’s amide derivatives were then prepared
for the remaining amines (11, 12, 14 and 15) and in all cases the 1H and 19F NMR spectra indicated the
presence of a single stereoisomer. Thus we are confident that the synthetic sequence outlined in Scheme 2
is not susceptible to racemisation.
These compounds offer a range of new chiral amines for applications in synthesis and as components
for combinatorial libraries.

D. O’Hagan, M. Tavasli / Tetrahedron: Asymmetry 10 (1999) 1189–1192
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Table 1
Physical properties and spectroscopic data for the (S) amines 11–15
3. Experimental
3.1. General hydrogenation method
To a suspension of the oxazolidinones 6–10 (15 mmol) in MeOH:AcOH (10:1) (100 ml) was added Pd
(10%) on carbon (159 mg, 1.5 mmol) and the reaction was shaken for 2 days at 4–5 atm under hydrogen
gas. The catalyst was filtered over Hyflo and the solvent removed under reduced pressure. The residue

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D. O’Hagan, M. Tavasli / Tetrahedron: Asymmetry 10 (1999) 1189–1192
1
Figure 1. Selected regions of the H NMR and 19F NMR spectra of the (R)-Mosher’s amides 16 and 17 prepared from either
(SR)-13 or (S)-13
was stirred with 2 M HCl (50 ml) and the acidic aqueous solution was washed with EtOAc (3×30 ml), and
then made basic by addition of NaOH pellets. The amines were then extracted into ethyl acetate (3×100
ml), dried (MgSO4) and the solvent was removed under reduced pressure to give 11–15 as off-white
amorphous solids (65–87%). When necessary, further purification was carried out by chromatography or
recrystallisation from organic solvent. See Table 1 for characterisation.
Acknowledgements
We thank the Afyon Kocatepe University, Turkey for a Y.O.K Studentship (M.T)
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