Azasugar analogues: Conformationally restricted vicinal diamine derived from (S)-(-)-pyroglutamic acid

Article abstract of DOI:10.1016/S0957-4166(99)00420-6

The preparation of a diamino substituted pyrrolidinone system in a diastereoselectively controlled manner is described. The procedure employed made use of electrophilic amination of a chiral bicyclic γ-lactam, which when subjected to sequential deprotecti

Full text of DOI:10.1016/S0957-4166(99)00420-6

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3887–3891
Azasugar analogues: conformationally restricted vicinal diamine
derived from (S)-(−)-pyroglutamic acid
Philip W. H. Chan,a Ian F. Cottrell b and Mark G. Moloney a,∗
aThe Department of Chemistry, Dyson Perrins Laboratory, University of Oxford, South Parks Rd, Oxford, OX1 3QY, UK
bDepartment of Process Research, Merck Sharp and Dohme Research Laboratories, Hertford Rd, Hoddesdon,
Herts, EN11 9BU, UK
Received 16 September 1999; accepted 21 September 1999
Abstract
The preparation of a diamino substituted pyrrolidinone system in a diastereoselectively controlled manner is
described. The procedure employed made use of electrophilic amination of a chiral bicyclic γ-lactam, which when
subjected to sequential deprotection provided a simple route to a 3,4-diaminopyroglutaminol. The chemoselective
deprotection of the amino functionality was also shown to be possible under mild hydrogenolytic conditions.
© 1999 Elsevier Science Ltd. All rights reserved.
3-Amino- and 4-aminopyrrolidine moieties have been shown to exhibit an impressively broad spec-
trum of biological activity, either as entities in their own right, or as sub-structural units of larger
molecules;1–3 (−)-cucurbitine 1, a possible compound for the treatment for bilharziasis, the neuroex-
citatory amino acid APDC 2,4 emonapride 3,5 an antipsychotic agent, and lactam 4,6 a sub-unit of the
cyclic hexapeptides microsclerodermins A and B, are examples. It was therefore surprising to us to find
that natural products containing a 3,4-diaminopyrrolidinone functionality were virtually unknown, and
perhaps as a consequence synthetic routes to this class of compounds have been little explored; on the
other hand, 1,2-diaminoacids are relatively well described.7–9 One compound of this class was reported
by Eckstein et al.10 in 1959, where the preparation of trans-3,4-diaminopyrrolid-2-one 5 was reported.
We therefore report here the first synthesis of this class of compounds which makes use of electrophilic
amination11 of a chiral γ-lactam in the key step; such compounds might be expected to possess unusual
biological activity, as shown by recent reports of the application of α- or β-aminopyrrolidinones as
peptidomimetics.12
∗
Corresponding author. E-mail: mark.moloney@chem.ox.ac.uk
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00420-6

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In order to extend the synthetic utility of amino substituted cyclic systems of type 6, readily prepared
from enone 7 using chemistry developed within our laboratory,13,14 electrophilic amination at the
C-7 position as a means of accessing a trans-3,4-diamino substituted pyrrolidine was undertaken.
Deprotonation of bicyclic lactam 6 with LDA followed by quenching of the resultant enolate with either
di-tert-butyl azodicarboxylate or dibenzyl azodicarboxylate afforded the corresponding diamino lactams
8 and 9 in excellent yields (70% and 85%, respectively), and as single diastereomers. Although the
stereochemical outcome of these reactions could not be unequivocally determined by standard NOE
spectroscopic techniques due to the presence of rotamers, the stereochemistry at C-6 and C-7 was,
however, believed to be trans, since this was expected to give rise to the most thermodynamically stable
product (Scheme 1) (vide infra).15
Scheme 1. (i) LDA, −78°C, then DBAD for 8 or CBZN_NCBZ for 9, 8 h; (ii) TFA, DCM, rt
Acid-mediated deprotection of both adducts 8 and 9, following standard procedures (TFA, DCM, rt),
furnished the corresponding products 10 and 11 (the latter in 67% yield as a single isomer) but the former
resisted all attempts at purification. Once again, the stereochemistry of both alcohols 10 and 11 could not
1
be unequivocally determined by NOE techniques, although both the H and 13C NMR spectra of 11
indicated that it was a single diastereomer.
Hydrogenolysis of the hydrazine adduct 10 (10% Pd/C, AcOH, 4 bar) afforded 3,4-
diaminopyroglutaminols 12a,b in excellent yield (77%) but as an inseparable mixture of diastereomers
in a ratio of 12a:12b=6:1 after purification by ion exchange chromatography.16 Similarly, the
dibenzylcarbamate derivative 11 was converted to the same product 12 in excellent yield (75%) and also
as a mixture of isomers in a ratio of 12a:12b=5:1 (Scheme 2). Since we had earlier shown that the chiral
integrity of C-3 is unaffected by these conditions,13 we assumed that epimerisation occurred exclusively
at C-4 under the acidic conditions of the reaction; this was later shown to be the case. The relative
stereochemistry of the major adduct 12a could not be unequivocally determined by NOE techniques,
but was tentatively assigned as having the trans-configuration on the basis of a full NOE spectroscopic
analysis of a derivative (vide infra). This epimerisation under the acidic conditions presumably becomes
possible once the bulky N-protecting groups are removed.
Scheme 2. (i) H2(g), Pd/C, glacial acetic acid, 4 bar, rt, 48 h

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Because it was not possible to unequivocally determine the stereochemical outcome of the electrophilic
amination of compound 6 from the analysis of the products 8–12, the chemoselective deprotection of the
diamino substrate 9 using milder conditions was examined. Hydrogenolysis of 9 (10% Pd/C, EtOAc,
4 bar) was found to give three different products depending on the reaction time. After 22 hours, the
partially deprotected hydrazine adducts 13a,b were obtained in good yield and as an inseparable mixture
1
of diastereomers. Careful H NMR examination using dry deuterio-DMSO showed that, of the two
possible benzyloxycarbamate protecting groups, deprotection of the N-alkylated nitrogen centre was
preferential; no evidence for the NH2 group, which would have arisen from the removal of the benzyl
carboxylate protecting group of the terminal nitrogen of the adduct, was observed. After two days, a
mixture of the two products 14a,b and 15a,b was obtained, which could be separated by flash column
chromatography to give 14a,b in good yield and as the major adduct. After one week, a reversal in
the yields of these products was observed; this time the fully deprotected amino derivative 15a,b was
obtained in good yield and as the major product (Scheme 3 and Table 1). NMR spectroscopy indicated
the formation of the hydrazine and amine derivatives 14 and 15, and this was confirmed by mass
spectroscopic analysis which showed molecular ion peaks at 445 and 430, respectively.
Scheme 3. (i) H2(g), Pd/C, EtOAc, 4 bar, rt, and Table 1
Spectroscopic analysis (NOE) of the amino analogue 15a enabled the assignment of the trans-relative
stereochemistry, the absolute stereochemistry being (6R,7S) (Fig. 1). The NOE triad from H-2→H-
4endo→H-6 indicated their spacial proximity on the endo-face; this was confirmed by a 4.5% NOE from
H-5 (endo) to the O-methylene protons, consistent with exo-orientation of this bulky group as expected.
An NOE from H-7 to the N-methylene protons indicated a trans-diamine orientation, i.e. endo-NH2 at
C-7. This therefore also further supported the major intermediate products 13a and 14a as having the
trans-orientation, the absolute stereochemistry also being (6R,7S), and that this result could have only
arisen from initial electrophilic amination of substrate 6 occurring exclusively from the endo-face of the
bicyclic structure, i.e. trans to the bulky C-6 substituent, as expected.
The question arose as to the likely stage of the deprotection at which this epimerisation was occurring.
No stereochemical lability of the starting material 9 has been noted, presumably due to the thermodyna-
mically stable trans-arrangement of the bulky substituents, and the epimerisation observed in the products
12 appeared to be due to stepwise cleavage of the protecting groups in the hydrogenolysis deprotection.
Table 1
Yields and diastereomeric ratios of the hydrogenolysis products 13–15

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P. W. H. Chan et al. / Tetrahedron: Asymmetry 10 (1999) 3887–3891
Figure 1.
Since the partially deprotected adducts 14 and 15 were readily available, the configurational stability of
1
both derivatives (1:1 C6D6/D2O, 24 h, rt) was therefore examined. By careful H NMR spectroscopic
analysis, no change in the epimeric ratio of the amino product 15 was detected, but the ratio of the
major product 14a to that of the minor compound 14b was found to have changed from 8:1 to 2:1,
suggesting that epimerisation could indeed take place at an intermediate stage once cleavage of one of
the benzylcarbamate protecting groups had occurred.
In summary, the development of a route to conformationally restricted diamino functionalised pyrroli-
dines, obtained in excellent yields and with a high degree of diastereocontrol, was shown to be possible
through the electrophilic amination at C-7 of the β-amino chiral template 6. Subsequent elaboration
of these compounds provided an efficient route to the 3,4-diaminopyroglutaminol 12 in excellent yield,
albeit with some loss of chiral integrity at C-4. Although the stereochemistry of some of the intermediates
generated could not be directly determined by conventional analytical protocol, the chemoselective
hydrogenolysis of compound 9 allowed the assignment of the absolute configuration of the major isomers
obtained as well as revealing the source of the observed epimerisation.
Acknowledgements
The authors are grateful to the Engineering and Physical Sciences Research Council and Merck Sharp
and Dohme for providing financial funding to P.C. We wish to acknowledge the use of the EPSRC
Chemical Database Service at Daresbury17 and the EPSRC National Mass Spectrometric Service Centre
at Swansea.
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