Synthesis of (+/-) - oxohexahydrofuro[3,2-b]pyrroles (pyrrolidine-trans-lactones) via a reduction - Alkylation protocol

Article abstract of DOI:10.1055/s-1998-1966

A synthesis of pyrrolidine-trans-lactones is described commencing from 1-(benzyloxycarbonyl)-3-oxo-2-pyrrolidineacetic acid ethyl ester. cis-Reduction of the oxo-pyrrolidine followed by hydroxyl inversion with benzoic acid in a Mitsunobu reaction gave the trans-benzoate ester which was converted into its corresponding silyl ether. After allylation α to ethyl ester, silyl deprotection, saponification and trans-lactonisation gave pyrrolidine-trans-lactones. Stereoselective allylation of trans-1-(benzyloxycarbonyl)- 3-hydroxy-2-pyrrolidine-acetic acid ethyl ester is feasible to give predominantly the desired diastereomer.

Full text of DOI:10.1055/s-1998-1966

1378
LETTERS
SYNLETT
Synthesis of (+/-) - Oxohexahydrofuro[3,2-b]pyrroles (Pyrrolidine-trans-lactones) via a
Reduction - Alkylation Protocol
*
Simon J.F. Macdonald, John G Montana, Doreen M Buckley and Michael D. Dowle
Enzyme Chemistry II, GlaxoWellcome Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UK
Fax: +(0) 1438 763 616
Received 8 October 1998
4,5
6
Abstract: A synthesis of pyrrolidine-trans-lactones is described
commencing from 1-(benzyloxycarbonyl)-3-oxo-2-pyrrolidineacetic
acid ethyl ester. cis-Reduction of the oxo-pyrrolidine followed by
hydroxyl inversion with benzoic acid in a Mitsunobu reaction gave the
trans-benzoate ester which was converted into its corresponding silyl
ether. After allylation α to ethyl ester, silyl deprotection, saponification
and trans-lactonisation gave pyrrolidine-trans-lactones. Stereoselective
allylation of trans-1-(benzyloxycarbonyl)- 3-hydroxy-2-pyrrolidine-
acetic acid ethyl ester is feasible to give predominantly the desired
diastereomer.
(Scheme 1). After numerous attempts to reduce 2a to 4 efficiently,
we used the stereochemical preference for the cis product to our
advantage by a reduction-Mitsunobu protocol (Scheme 2). Thus
reduction of 2 with NaBH /CeCl (to prevent over-reduction), rapid
4
3
work-up (to avoid extensive cyclisation of the intermediate cis-
hydroxyalcohol to 3), and treatment with benzoic acid under Mitsunobu
conditions gave after chromatography, the trans-benzoate 5a in 62%
yield. The deprotection of the benzoate 5a and reprotection as its
7,8
TBDMS ether 6a was easily achieved.
Inhibitors of serine proteases are currently being explored as therapies
1
for respiratory and cardiovascular diseases amongst others. As new
scaffolds for inhibitors of serine proteases are rare, our introduction of a
new scaffold known as pyrrolidine trans-lactones 1 (and their analogous
2
lactams) is a significant and important contribution in this area. These
compounds were developed during our research programme exploring
inhibitors of human neutrophil elastase (HNE). Efficient and
stereoselective routes to these highly unusual strained structures were
critical to our progress.
7
The silyl ether 6a (or 6b ) is readily alkylated (Scheme 3) and proved
invaluable for the preparation of compounds 7 with a substituent
9
adjacent to the ester. From medicinal chemical studies the allyl group
7f was adopted as the preferred substituent and so this chemistry was
carried out on >50g scale. Deprotonation and allylation of 6a gave an
10,11
inseparable 1:1 mixture of α and β allyl diastereomers 7f.
Standard
deprotections gave the hydroxyacid 8. Trans-lactonisation was achieved
12
initially with the Mukaiyama conditions
but the Yamaguchi
13
We describe here a route to racemic trans-lactones which addresses the
conditions (shown) at ca 0.01M dilution gave a higher yield (62-82%)
2
lack of stereoselectivity associated with our previous route and which
of 1:1 β:α allyl trans-lactones
1
and 9, separable by flash
1
is applicable on large scale (giving > 10g of lactone 1). Due to the strain
of the trans-lactone system, we elected to form the lactone ring as a
chromatography. Their structures were confirmed by H-NMR
2
2,14
studies.
final synthetic step from the precursor hydroxyacid in turn prepared
from the known keto-ester 2. Initially this chemistry was developed
Deprotection of the benzyl carbamate 1 and allyl reduction by
hydrogenation with Pearlman’s catalyst followed by salt formation with
3
with the pyrrolidine N protected as its ethyl carbamate, but to facilitate
the preparation of derivatives of the pyrrolidine N for our medicinal
chemistry programme, the preferred protecting group was the benzyl
carbamate (CBZ).
ethereal hydrogen chloride gave the lactone 10 as a key intermediate in
15
our medicinal chemical programme.
The free base of 10 is
surprisingly stable and can be stored for several months without
decomposition. However once degradation commences, it appears to be
autocatalytic leading to rapid breakdown. Mass spectral evidence
suggested the degradation products are the oligomeric dimers, trimers
and tetramers arising from acylation of the nitrogen by the trans-
16
lactone. The hydrochloride is stable indefinitely.
The β-allyl/propyl lactone analogues are preferred as they are more
2
potent HNE inhibitors in vitro than the α-allyl analogues. We therefore
17
attempted to epimerise the α-epimer 9. This was unsuccessful, leading
to recovered 9 and/or degradation products. Presumably deprotonation
of 9 gives a configurationally stable carbanion as formation of the ester
enolate is disfavoured due to increased ring strain.
Scheme 1
18
Our initial challenge was the reduction of ketone 2a; treatment with
We then discovered a simpler introduction of the allyl group which
NaBH gave a 5:1 ratio of cis-lactone 3 to trans-hydroxyester 4a
avoids TBDMS protection/deprotection and which gives
a
4

December 1998
SYNLETT
1379
stereoselective preference for the β product. Reaction of the unprotected
hydroxyester 4a with LHMDS (2eq) and allyl bromide (1eq) at –70 C
References and Notes
o
(1) Vender, R.L. J. Invest. Med. 1996, 44, 531; Ripka, W.C. Curr.
Opin. Chem. Biol. 1997, 1, 242.
for 30min and then warmed to room temperature over 1h gave a 32%
19
yield (unoptimised) of a 4:1 ratio of β:α allyl isomers 11 (Scheme 4).
(2) Macdonald, S.J.F., Belton, D.J., Buckley, D.M., Spooner, J.E.,
Anson, M.S., Harrison, L.A., Mills, K., Upton, R.J., Dowle, M.D.,
Smith, R.A., Risley, C., Molloy, C.J. J. Med. Chem., in press.
In an attempt to improve this yield, the reaction was allowed to warm
much more slowly to room temperature over 18h. This did indeed
improve the yield to 45% but also led to a decrease in stereoselectivity
giving a 1.5:1 ratio of β:α allyl isomers. The stereochemical ratio of the
allyl group in 11 was determined by inspection of HPLC traces of the
(3) The keto-ester 2a was prepared from the ethyl ester of β-alanine
by (i) CBZCl, NaHCO , H O, dioxan, 98%. (ii) NaH, diethyl
fumarate, PhMe, 60-80%. (iii) brine, DMSO, 65-71%. Based on
Geissmann, T.A.; Waiss, A.C. J. Org. Chem. 1962, 27, 139.
3
2
1
19
crude products and by analysis of the crude H-NMR spectra.
Assignment of the β and α isomers of 11 was determined by their
conversion into the trans-lactones for comparison with pure samples of
(4) Reductive amination of 2a to access precursors to the analogous
pyrrolidine trans-lactams gave similar results; cis-lactams were
2
known α and β allyl lactones. Thus a 4:1 isomer ratio of 11 was
the only products isolated.
converted into a 3.6:1 ratio of β:α lactones 1 and 9. The origins of this
1
(5) Data for 3: H-NMR (250MHz, CDCl ) δ 7.42-7.29 (m, 5H),
stereoselectivity and variability with reaction conditions are unclear, but
3
2
5.23-5.04 (m, 3H), 4.52 (m, 1H), 3.95-3.75 (m, 1H), 3.43 (sextet, J
have been observed in an analogous series.
= 5.5Hz, 1H), 2.97-2.67 (m, 2H), 2.33 (dd, J = 12.5, 5.5Hz, 1H),
-1
2.15-1.97 (m, 1H); IR (CHCl ) ν
1785, 1698 cm .
3
C=O
1
Data for 4a: H-NMR (250MHz, CDCl ) δ 7.40-7.28 (m, 5H),
3
5.14 (bs, 2H), 4.28-4.21 (bs, 1H), 4.20-4.00 (m, 3H), 3.73-3.58
(m, 3H), 3.53-3.40 (m, 1H), 3.15-2.78 (m, 2H), 2.30-1.85 (m, 3H),
1.23 (t, J = 7Hz, 3H).
(6) Other attempts included (i) Ph SiH , (PPh ) RhCl. (ii) Na,
2
2
3 3
naphthalene. (iii) Et SiH, (PPh ) RhCl. (iv) SmI . (v)
3
3 3
2
t
LiAl(O Bu) H. (vi) H , Pd-C. Attempts to tether a reducing agent
3
2
Scheme 4
to the corresponding acid of 2, also failed.
(7) The CBZ series gave better yields than the ethyl carbamate series.
1
NB. All new compounds gave satisfactory H-NMR, IR and
The yields for the ethyl carbamates (4b, 5b and 6b) are: step (i) to
5b 47%; step (ii) to 4b 42%; step (iii) to 6b 96%.
microanalytical data or accurate mass measurements.
1
(8) Data for 6a: H-NMR (250MHz, CDCl ) δ 7.40-7.29 (m, 5H),
3
Acknowledgements: We are grateful for analytical and spectroscopic
assistance from Trevor Cholerton, Steve Richards, Dave O’Brien,
Richard Upton, Ian Davidson and Dave Paul. We also thank Lee
Harrison and Professor Tim Gallagher for advice in the preparation of
this manuscript.
5.18 (s, 1H), 5.15 (s, 1H), 4.25-4.22 (m, 1H), 4.21-3.99 (m, 2H),
3.68-3.45 (m, 2H), 2.94-2.66 (m, 1H), 2.27-2.13 (m, 1H), 2.02-
1.87 (m, 1H), 1.86-1.72 (m, 1H), 1.31-1.21 (m, 3H), 0.87 (s, 9H),
0.07 (s, 6H).
(9) Only bis-alkylation giving 7e proceeded in poor yield (Scheme 3).
All the esters 7 were converted into the corresponding trans-
lactones using the protocol described for 7f. The medicinal
chemistry of these compounds will be described elsewhere.

1380
LETTERS
SYNLETT
(10) Protection of the alcohol 4a as its TBDMS ether can be replaced
by protection as the TMS ether in situ. Thus treatment of 4a with
LHMDS followed by addition of TMSCl, then a further
by addition of the resultant enolate to excess allyl bromide gives
only the expected β-allyl cis-lactone in 64% yield resulting from
reaction from the less hindered exo-face. (Addition of the allyl
bromide to the enolate gave a mixture of mono- and bis-
allylation.) However we were then faced with the non-trivial
conversion of the cis-lactone into its trans-lactone.
equivalent of LHMDS and allyl bromide, gave after work-up, the
ethyl ester of 8. This sequence proceeded in lower yield (50%
yield) but avoids two extra steps.
1
(11) Data for 7f: H-NMR (250MHz, CDCl ) δ 7.40-7.26 (m, 5H),
3
(19) Preparation of 11 (β:α 4:1). To trans-1-(benzyloxycarbonyl)-3-
5.86-5.53 (m, 1H), 5.24-4.91 (m, 4H), 4.37-3.92 (m, 4H), 3.77-
3.27 (m, 2H), 3.14-2.15 (m, 3H), 2.14-1.68 (m, 2H), 1.28-1.18 (m,
3H), 0.84 (s, 9H), 0.06 (s, 6H).
hydroxy-2-pyrrolidineacetic acid ethyl ester (1.00g, 3.25mmol) in
dry THF (10mL) at –70 C under nitrogen, was added lithium
o
hexamethyldisilazide (1M in THF) (6.7mL, 6.67mmol) dropwise
over 5min. After 30min, allyl bromide (0.28mL, 3.25mmol) was
(12) Mukaiyama, T. Angew. Chem., Int. Ed. 1979, 18, 707.
o
added dropwise over 5 min. After stirring at –70 C for 1h, the
(13) Inanaga, J.; Katsuki, S.; Takimoto, S.; Ouchida, S.; Inone, K.;
Nakano, A.; Okukuda, N.; Yamaguchi, M. Chem. Lett. 1979,
1021.
cooling bath was removed. After a further 1h, the reaction was
quenched with 2M hydrochloric acid (25mL) and extracted with
EtOAc (3 x 25mL). The combined extracts were washed with
(14) Trans-lactone carbonyls characteristically show higher infra-red
stretching frequencies when compared with the analogous cis-
lactone carbonyls. For example the carbonyl frequencies of 1 and
brine (25mL), dried (MgSO ) and concentrated. Flash
4
chromatography on silica (Merck 9385) eluting with 4:1
ether:hexane afforded the allylester (0.368g, 32%) as a colourless
-1
-1
3 are 1791cm and 1785cm .
1
gum. Although the H-NMR spectrum of 11 at room temperature
1
(15) Data for 10: H-NMR (250MHz, d6 DMSO) δ 9.22 (s, 2H), 4.18
in CDCl is complicated by the existence of 11 as rotamers,
3
(ddd, J = 10.5, 10.5, 5.5Hz, 1H), 3.83-3.56 (m, 2H), 3.28-3.17 (m,
1H), 2.57-2.46 (m, 1H, hidden by DMSO peak), 2.43-2.30 (m,
1H), 2.20 (quintet, J = 9.5Hz, 1H), 1.87-1.71 (m, 1H), 1.60-1.35
(m, 3H), 0.94 (t, J = 7Hz, 3H).
integration of a pair of singlets at δ 4.43 (α isomer) and 4.35 (β
1
isomer) gives the isomer ratio. Data for 4:1 β:α 11: H-NMR
o
(400MHz, d6 DMSO, 100 C) δ 7.39-7.28 (m, 5H β+α), 5.72 (m,
1H β+α), 5.11 (m, 2H, β+α), 5.09-4.93 (m, 2H β+α), 4.79 (s,
1Hβ), 4.74 (s, 1Hα), 4.17 (s, 1Hβ+α), 4.06 (m, 2Hβ), 4.03 (m,
2Hα), 3.93 (ddd, J = 6, 1, 1Hz, 1Hα), 3.88 (ddd, J = 7.5, 1, 1Hz,
1Hβ), 3.57 (m, 1Hβ+α), 3.33 (ddd, J = 10.5, 9, 3.5Hz, 1Hα), 3.28
(ddd, J = 9, 9, 3.5Hz, 1Hβ), 2.73 (m, 1Hβ+α), 2.36 (m, 1Hβ+α),
2.25 (m, 1Hβ), 2.16 (m, 1Hα), 1.96 (m, 1Hβ+α), 1.78 (m,
1Hβ+α), 1.17 (t, J = 7Hz, 3Hβ), 1.16 (t, J = 7Hz, 3Hα); HPLC
(16) The mass spectum (thermospray) of a degraded sample of the free
+
+
+
base of 10 showed ions at 170 (MH ), 339 (2MH ), 508 (3MH )
+
and 677 (4MH ).
o
(17) Epimerisation conditions: DBU, DMF, 45 C, 3 days - degradation
o
of 9; Et N, DMF, 45 C, 3 days – no change in 9; LHMDS, THF –
3
o
o
85 C , no change in 9; KOH, EtOH, H O, 45 C, 4h, α-epimer of
2
8.
Column ODS2-IK5 isochratic 40% MeCN in H O with 0.1%
2
(18) An alternative approach to access the β-allyl products via the cis-
lactone 3 was attempted. Treatment of 3 with LHMDS followed
H PO eluting 1mL/min at 215nm; the β isomer elutes at
3 4
19.12min and the α at 17.29min.