A direct route to 2,2,5-trisubstituted pyrrolidines of relevance to kaitocephalin

Article abstract of DOI:10.1016/j.tetlet.2013.01.130

2,2,5-Trisubstituted pyrrolidines of relevance to the core of kaitocephalin are readily available by an oxime ring closure using substrates derived from aspartic acid.

Full text of DOI:10.1016/j.tetlet.2013.01.130

Tetrahedron Letters 54 (2013) 1987–1990
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Tetrahedron Letters
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A direct route to 2,2,5-trisubstituted pyrrolidines of relevance to kaitocephalin
⇑
Nandkishkor Chandan, Mark G. Moloney
The Department of Chemistry, Chemistry Research Laboratory, The University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
2,2,5-Trisubstituted pyrrolidines of relevance to the core of kaitocephalin are readily available by an
oxime ring closure using substrates derived from aspartic acid.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 11 December 2012
Revised 15 January 2013
Accepted 31 January 2013
Available online 11 February 2013
Keywords:
Kaitocephalin
Pyrrolidines
Ring closure
Kaitocephalin (1) (Fig. 1), isolated from chick telencephalic neu-
rons (10 kg of cell culture gave 9 mg of kaitocephalin),1 is an unu-
sual and potent AMPA receptor antagonist, exhibiting protection of
kainite-induced toxicity at 500 mM at chick primary telencephalic
and rate hippocampal neurons with EC50 values of 0.68 and
2.4 mM, respectively, with no cytotoxic effects,2 as well as against
AMPA/cyclothiazide (500/50 mM) with EC50 values of 0.6 and
0.4 mM, respectively.2 Although its absolute configuration was
established3 and apparently proven by total synthesis,4 later work
indicated this assignment to be in error,5 and this was confirmed
by further total synthesis;6,7 a reinvestigation of the original Letter
has recently appeared.8 Kaitocephalin has subsequently been
synthesised on several occasions.9–13 Its core 2,2,5-trisubstituted
pyrrolidine unit, which has potential as a medicinally relevant
scaffold,14 offers a considerable challenge for synthesis, and has
attracted a high level of attention,14–24 but of interest to us was
the possibility that our recently reported ring closure, based upon
enolate attack at activated oximes, might also be of value for its
rapid construction.25 This approach, which proceeds by an intra-
molecular attack at nitrogen of activated oximes 2, gives pyrrolines
of type 3, which may in turn be reduced to polysubstituted pyrrol-
idines 4 (Scheme 1).
treatment with oxalyl chloride/DMF30–32 gave material which
was immediately used for Stille coupling with tributylvinyltin,33–36
giving the required ketone 6b in 68% yield. Conjugate addition
with diethyl malonate in the presence of base gave adduct 6c in
a good yield of 76%. However, when this was treated with
NH2OHÁHCl and Et3N in ethanol, a mixture of products was ob-
tained, including oxime 7, hydroxamic acid 8a and oxime 8b,
whose identity were all confirmed by mass spectrometry. Unfortu-
nately, isolation of the desired oxime 7 from this mixture was
problematic. This outcome is no doubt due to the high nucleophi-
licity of hydroxylamine, and since changing the temperature for
the reaction gave no improvement in the selectivity, it was clear
that the oxazolidine ring system was too sensitive towards ring-
opening, and that another protecting strategy would be needed.
To avoid this unwanted opening, acid 6a was treated with so-
dium methoxide28 in MeOH at À10 °C, giving a mixture of products
including 9–11 (Scheme 2). This mixture was directly treated with
oxalyl chloride followed by tributylvinyltin and catalytic
PhCH2Pd(PPh3)2Cl to produce the required ketone 1233–36 in mod-
est yield, which was in turn used for the conjugate addition reac-
tion with diethyl malonate in the presence of base (anhydrous
K2CO3 and dry dichloromethane heated to reflux), giving adduct
Fundamental to the application of this methodology would be
to demonstrate that the oxime cyclisation reaction was tolerant
of more elaborate chemical functionality, and that selective manip-
ulation of the resulting gem-dicarbonyl groups could be achieved.
In the first regard, commercially available N-Cbz-L-aspartic acid 5
was converted into N-Cbz-oxazolidinone 6a (Scheme 2) using the
literature approach.26–29 Conversion into the acid chloride by
⇑
Corresponding author. Tel.: +44 (0)1865 275656; fax: +44 (0)1865 285002.
E-mail address: mark.moloney@chem.ox.ac.uk (M.G. Moloney).
Figure 1. Kaitocephalin.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.130

1988
N. Chandan, M. G. Moloney / Tetrahedron Letters 54 (2013) 1987–1990
Scheme 1. General strategy for ring closure.
Scheme 2. Synthetic scheme for ring closure sequence.
13a in excellent yield. Subsequently it was found that adduct 13a
could be synthesised in quantitative yield directly from 6c by
treatment with 5% NaHCO3 in refluxing MeOH26–29 followed by
esterification with thionyl chloride/MeOH.37 Adduct 13a was read-
ily converted into the corresponding oxime 13b under standard
conditions (NH2OHÁHCl and Et3N in ethanol heated to reflux for

N. Chandan, M. G. Moloney / Tetrahedron Letters 54 (2013) 1987–1990
1989
Figure 2. Comparison of NMR data.
1 h) in a very high yield of 92% as inseparable syn- and anti-iso-
mers. This material was directly treated with p-toluenesulfonyl
choride and base (Et3N or pyridine in dry dichloromethane at rt)
to afford the tosyl oxime 13c (87% yield). Treatment of this com-
pound with sodium hydride at reflux gave the desired ring closure
product, pyrroline 14 in a good yield of 64%, which when reduced
(NaBH3CN, MeOH, 2 M HCl in MeOH, rt) afforded 2,2,5-trisubsti-
tuted pyrrolidine 15 (96% yield) with undetermined diastereo-
meric ratio. This clearly demonstrated that the cyclisation
methodology was tolerant of additional system functionality, and
the next key goal was to establish a system in which carbonyl
group differentiation would be possible.
the chemical shift of H-7 in both 15 and 20 was about 0.2–
0.3 ppm lower than the natural product, most likely as a result of
the proximity of the anisotropic carbonyl group at C-4 of the pyr-
rolidine ring.
In conclusion, we have shown that rapid diastereoselective
elaboration of aspartate derivatives into 2,2,5-trisubstituted pyr-
rolidines is feasible in a short, reliable sequence and in good overall
yield, and work to demonstrate its applicability to the synthesis of
kaitocephalin is ongoing.
Acknowledgment
For this purpose, Weinreb malonamide 16 on conjugate addi-
N.C. gratefully acknowledges receipt of a National Overseas
Scholarship from the Indian Ministry of Social Justice and Empow-
erment (GF6-352746).
tion with
a,b-unsaturated ketone 6b and base (anhydrous K2CO3
in dry dichloromethane at rt) gave adduct 6d in 65% yield as a mix-
ture of diastereomers (Scheme 2). Since it was now clear that the
oxazolidinone ring would not be stable towards oxime formation,
it was immediately opened by treatment with 5% NaHCO3 in
MeOH, giving ketone 17a in 76% yield. This material was readily
converted into the corresponding oxime 17b using the standard
conditions (NH2OHÁHCl and Et3N in EtOH heated to reflux for
1 h) in a good yield of 86% as inseparable E and Z isomers. Oxime
17b was reacted with methanesulfonyl chloride and Et3N in dry
dichloromethane to give the mesyl oxime 17c in a very good yield
of 79% as inseparable E and Z isomers, and this was immediately
treated with NaH in dry THF at reflux for 30 min; however,
although the starting material was consumed completely as shown
by TLC and the desired cyclised pyrroline 18 could be detected in
the mass spectrum, its isolation was very difficult. Instead, conver-
sion of the oxime 17b into tosyl oxime 17d by treatment with
p-toluenesulfonyl chloride with Et3N or pyridine in dry dichloro-
methane gave the desired product in 61% yield, and immediate
treatment with NaH in dry THF afforded the desired pyrroline 18
in 49% yield with a diastereomeric ratio of approximately 1:2,
along with unexpected pyrazole 19 in 42% yield with a diastereo-
meric ratio of approximately 1:1. This latter product resulted from
ring formation by an attack of the proximal carbamate nitrogen on
the activated oxime, but both 18 and 19 were easily separated by
chromatography. Of interest is that this pyrazole formation is fully
analogous to a process previously reported by Black.38 The pyrro-
line 18 was readily converted into the 2,2,5-trisubstituted pyrroli-
dine 20 by treatment with NaBH3CN in 2 M MeOH to afford a 97%
yield with a 1:2 diastereomeric ratio (Scheme 2). Comparisons of
the chemical shifts at H-7 and H-9 of kaitocephalin (1) and the
mimics 15 and 20 are shown in Figure 2; similar chemical shift
and coupling patterns were observed in these systems, although
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2013.01.130.
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