Dynamic kinetic resolution of dehydrocoronamic acid

Article abstract of DOI:10.1039/c4cc01125b

Dehydrocoronamic acid can be racemised by dehydration of an N-acyl derivative to an azlactone, which undergoes facile racemisation. For the N-trifluoroacetyl derivative, the racemisation process was combined with an enzymatic resolution, to achieve a dynamic kinetic resolution process by which the racemate can be converted to either enantiomer. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc01125b

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Dynamic kinetic resolution of dehydrocoronamic
acid†
Cite this: Chem. Commun., 2014,
50, 5858
David A. Chaplin, Martin E. Fox* and Sebastian H. B. Kroll
Received 12th February 2014,
Accepted 8th April 2014
DOI: 10.1039/c4cc01125b
www.rsc.org/chemcomm
Dehydrocoronamic acid can be racemised by dehydration of an N-acyl coupling reactions, amide derivatives of dehydrocoronamic acid 5
derivative to an azlactone, which undergoes facile racemisation. For the cleanly give azlactones 6 (Scheme 1). Subsequent methanolysis of 6
N-trifluoroacetyl derivative, the racemisation process was combined gives the corresponding methyl esters 7. To our surprise, we
with an enzymatic resolution, to achieve a dynamic kinetic resolution discovered the enantiomeric excess of the product ester was lower
process by which the racemate can be converted to either enantiomer. than that of the starting acid.
The rate of racemisation was strongly influenced by the nature of
A family of Hepatitis C NS3 NS4A protease inhibitors which contain the amide group. Thus, the single enantiomer methyl azlactone 6a
the common chiral motif (1R, 2S)-dehydrocoronamic acid 1 (Fig. 1) racemised‡ very slowly at room temperature in acetonitrile, and with
comprises several antiviral drugs and developmental drug t1/2 of 60 minutes at 80 1C. Azlactone 6b with an electron-withdrawing
candidates (Fig. 2).1–9
3-trifluoromethyl substituent racemised more readily, with t1/2 of
Efficient synthesis of this densely functionalised quaternary 7.5 h at 15 1C in acetonitrile. In addition to racemisation, slower
amino-acid as a single enantiomer is challenging. However, a concise cis/trans isomerisation (Schemes 1 and 4) took place. This was
route to the racemate has been developed,10,11 and routes to the detectable both by NMR and by chiral GC after methanolysis, which
single enantiomer based on resolution of both the racemate10 and a showed the trans-isomer 8 formed to be racemic. Rates of cis/trans
malonate precursor12 have been described. Synthesis from the chiral isomerisation of 6a and 6b were almost identical at 80 1C in
pool material butane-1,2,4-triol13 and asymmetric routes employing acetonitrile. Hence the relative rates of racemisation to cis/trans
asymmetric alkylation under chiral phase-transfer catalysis11 and isomerisation were lower for 6a (8.5 : 1 at 80 1C in acetonitrile) than
palladium-catalysed asymmetric allylic alkylation14 have also been 6b (165 : 1 at 15 1C). After in situ formation of 6a from (1R)-5a, heating
published. We reasoned that if a method for racemisation of the off- for 4 h at 80 1C, then methanolysis at ambient temperature, racemic
isomer could be found, this could be combined with the established 7a + 8a (6 : 1) was isolated in quantitative yield. For (1R)-6b, after 1 day
racemic synthesis and a method of resolution to provide an overall at 15 1C, near-racemic (12% ee) 7b + 8b (189 : 1) was isolated in 70%
high-yielding synthesis of this increasingly commercially important yield. This behaviour was in marked contrast to the thermal isomer-
compound. On dehydration with DCC, as an entry to subsequent isation of other dehydrocoronamic acid derivatives, for example, the
benzaldehyde imine 9,9,10 where racemisation was much slower
than cis/trans isomerisation (Scheme 2). For this compound, after
120 minutes at 80 1C in toluene, the enantiomeric excess was 98.1%,
but the ratio of imine 9 to dihydroazepine 11, formed by [3,3]-
sigmatropic isomerisation of the trans-isomer 1010,11 was 5 : 1 (66% de).
Likewise, the N-BOC, cis-ethyl ester 12 underwent more rapid
cis/trans isomerisation than racemisation, reaching 90% ee and
38 : 62 cis/trans after 16 h in o-dichlorobenzene at 150 1C (Scheme 3).
Fig. 1 (1R,2S)-Dehydrocoronamic acid.
These observations can be rationalised if a trans-selective thermal
isomerisation mechanism is possible for all dehydrocoronamic acid
derivatives, but a different and cis-stereospecific isomerisation is
possible for azlactones 6 (Scheme 4). A diradical mechanism15–17 is
widely accepted for cyclopropane thermal isomerisation. For the
intermediate 14, C–C bond rotation is possible, hence this pathway
would give the thermodynamically more stable trans isomer 15
Chirotech Technology Centre, Dr Reddy’s Laboratories EU Ltd., Unit 410 Cambridge
Science Park, Milton Road, Cambridge, CB4 0PE, UK. E-mail: mfox@drreddys.com;
Fax: +44 (0)1223 506710; Tel: +44 (0)1223 728010
† Electronic supplementary information (ESI) available: Experimental procedures
for preparation and isomerisation of 6a, 6b and 10, isomerisation of 12, resolu-
tion of 7b and dynamic kinetic resolution of 6b. GC analytical methods and
chromatograms for 7a–c, 12 and 13. 1H NMR spectra of 1, 5a, 5b, 6a, 6b, 7a, 7b,
7c, 9, 11, 12, 13, 15a, 15b. See DOI: 10.1039/c4cc01125b
5858 | Chem. Commun., 2014, 50, 5858--5860
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Fig. 2 Examples of Hepatitis C NS3 NS4A protease inhibitors.
Scheme 3 Isomerisation of cis-N-BOC dehydrocoronamic acid ethyl ester.
Scheme 1 Racemisation of dehydrocoronamic acid azlactones.
Scheme 4 Proposed mechanisms of azlactone isomerisation.
1
Evidence for this mechanism is provided by the H NMR spec-
trum of 6b (Fig. 3), where in addition to the major signals which can
be assigned to the cyclopropane structure, a minor set of four signals
[dH (400 MHz, CDCl3; Me4Si) 6.18, (1H, dt, J = 11.2, 5.2 Hz, OCH2CH),
5.97 (1H, dtt, J = 11.2, 5.9, 2.2 Hz, OCH2CHCH), 4.72 (2H, d, J =
5.9 Hz, OCH2) and 3.47 (2H, dd, J = 5.2, 2.2 Hz, OCH2CHCHCH2)] is
Scheme 2 Isomerisation of dehydrocoronamic ester imine.
as the main product. For the cis-stereospecific rearrangement, we observed in a 30 : 1 ratio which can be assigned to dihydrooxepine
propose a mechanism which proceeds by concerted [3,3]-sigmatropic 16, present as an equilibrium component.
oxadivinylcyclopropane rearrangement to an achiral dihydrooxepine
Given the ready racemisation of trifluoromethyl azlactone 6b at
intermediate 16, for which C–C bond rotation is not possible. This ambient temperature and the utility of trifluoroacetyl as a removable
mechanism should be energetically more favoured for azlactone 6 nitrogen protecting group,18–21 we were able to apply this discovery to
compared to other dehydrocoronamic acid derivatives owing to the our objective of an asymmetric synthesis of dehydrocoronamic acid.
stabilisation provided by the simultaneous formation of an aromatic The racemisation could be applied in a resolution-based approach
oxazole heterocycle. Increasing the electron-withdrawing power of by recycle of the off-isomer of acid 5 to racemic ester 7 or acid 5. The
the azlactone substituent R1 withdraws electron density from the desired (1R)-ester was obtained by resolution of 7b by enantio-
CQO bond and destabilises the azlactone relative to the oxazole.
selective hydrolysis of the ester group of the (1S)-enantiomer with
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Notes and references
‡ Enantiomeric excesses of 6 determined by methanolysis to ester 7
then chiral GC.
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Scheme 5 Dynamic kinetic resolution of azlactone 6b.
subtilisin A, with an E value of around 100, sufficiently high for an
efficient resolution. However, this enzyme also cleaved the trifluoro-
acetyl group to a significant extent, reducing the possible efficiency
of the recycle of (1S)-5b. Dynamic kinetic resolution of azlactone 6
provides a more direct and attractive approach than resolution/
recycle of ester 7. Dynamic kinetic resolution of azlactones bearing a
single 5-substituent, which can tautomerise to an enol form, by ring-
opening with nucleophiles in the presence of a chiral catalyst is
well-established.22–26 Application of this concept to reaction of the
5,5-disubstituted azlactone 6b with alcohols mediated by enzymes
proved feasible (Scheme 5). On a 7.5 g scale, the isolated yield of rac-
6b from rac-5b was 89%. In the dynamic kinetic resolution, ethanol
gave the best combination of reactivity and selectivity. With
Novozym-435 (immobilised Candida antarctica Lipase B) under
optimised conditions, (100 : 1 w/w MTBE–ethanol at 25 1C) on a
1 g scale, (1S)-7c was obtained in 95% ee and 97% isolated yield after
11 days (E B 40). For (1R)-7c, the isomer required for the antiviral
compounds, the highest enantioselectivity was achieved with
immobilised Lipase PS. On a 1 g scale, under the same conditions,
75% ee and 96% isolated yield was obtained after 18 days (E B 7).
We have discovered a method for racemisation of dehydro-
coronamic acid and applied this to the asymmetric synthesis of
either enantiomer of this commercially significant molecule by
enzyme mediated dynamic asymmetric kinetic resolution. A
concerted [3,3]-sigmatropic mechanism is proposed for this
isomerisation.
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5860 | Chem. Commun., 2014, 50, 5858--5860
This journal is ©The Royal Society of Chemistry 2014