Dearomatising cyclisation of lithiated 1-naphthamides with a phenylglycinol-derived chiral auxiliary: Asymmetric synthesis of an arylkainoid and a kainoid-like pyroglutamate

Article abstract of DOI:10.1016/S0040-4039(01)00502-0

1-Naphthamides of N-benzylphenylglycinols undergo a diastereoselective dearomatising cyclisation on treatment with t-BuLi and DMPU or HMPA. A new pyrrolidinone ring is formed bearing three new stereogenic centers of defined absolute stereochemistry. Removal of the phenylglycinol auxiliary gives enantiomerically pure substituted lactams exhibiting the stereochemistry of the kainoids. These may be converted to kainoid-like pyroglutamates, or alternatively, using the method of the previous paper, to analogues of acromelic acid.

Full text of DOI:10.1016/S0040-4039(01)00502-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3411–3414
Dearomatising cyclisation of lithiated 1-naphthamides with a
phenylglycinol-derived chiral auxiliary: asymmetric synthesis of
an arylkainoid and a kainoid-like pyroglutamate
Ryan A. Bragg,a Jonathan Clayden,a,* Michael Bladonb and Osamu Ichiharab
aDepartment of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
bOxford Asymmetry International, 151 Milton Park, Abingdon, Oxfordshire OX14 4SD, UK
Received 22 February 2001; revised 15 March 2001; accepted 19 March 2001
Abstract—1-Naphthamides of N-benzylphenylglycinols undergo a diastereoselective dearomatising cyclisation on treatment with
t-BuLi and DMPU or HMPA. A new pyrrolidinone ring is formed bearing three new stereogenic centers of defined absolute
stereochemistry. Removal of the phenylglycinol auxiliary gives enantiomerically pure substituted lactams exhibiting the stereo-
chemistry of the kainoids. These may be converted to kainoid-like pyroglutamates, or alternatively, using the method of the
previous paper, to analogues of acromelic acid. © 2001 Elsevier Science Ltd. All rights reserved.
In the preceding paper,1 we reported the synthesis of an
important analogue2 1 of acromelic acid (in racemic
form) by use of a dearomatising anionic cyclisation of a
lithiated naphthamide.3 In this paper, we describe the
development of an asymmetric version of this cyclisa-
tion using a phenylglycinol-derived chiral auxiliary. The
asymmetric cyclisation allows the synthesis, in high
enantiomeric excess, of an intermediate 2 in our route
to the acromelic analogue 1, constituting a formal
enantioselective synthesis of 1. We also describe the use
of the asymmetric dearomatising cyclisation in the syn-
thesis of an analogue 3 of (R)-pyroglutamate 4 with
kainoid-like substituents and relative stereochemistry.
Both kainoids and pyroglutamates are important neuro-
excitatory amino acids, and there is interest in
combining features of the two classes of molecules.4
stereospecific, with the meso diastereoisomer of 5 yield-
ing a different diastereoisomer of the cyclized product,
although the origin of the stereospecificity was com-
plex.7 It was clear at that stage that the stereogenic
center of 5 which remains exocyclic in 6 had little effect
on the cyclisation. Nonetheless, this position-the non-
cyclizing N-substituent-seemed the obvious place to
attach a chiral auxiliary, and in an attempt to promote
an asymmetric cyclisation we lithiated 8 and treated it
with DMPU at −50°C.8 Two products, 11a and 11b,
were obtained in a 60:40 ratio (Scheme 1), and an
X-ray crystal structure (Fig. 1) of the minor product
proved their relative stereochemistry. A similar result
was obtained with the analogous compound 9.
Hoping that coordination of lithium by oxygen might
improve the selectivity of the reaction, we made 10
from (R)-phenylglycine (R)-14 by the route described
below (Scheme 2). Exposing doubly lithiated 10 to
DMPU at −35°C8 promoted its cyclisation to 13 as a
10:1 ratio of diastereoisomers. The stereochemistry of
13a was proved by its reduction to 11a.
We first noted the dearomatising anionic cyclisation of
N-benzyl-1-naphthamides5 when attempted ortholithia-
tion of 5 gave only a small amount of the expected 7:
the major product was 6, formed as
a single
diastereoisomer.6 We later showed that the reaction was
O
CO2H
CO2Me
H
H
HO
MeO2C
OMe
O
O
O
CO2Me
CO2H
CO2H
N
H
1
N
H
2
N
N
H
4
Boc
3
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00502-0

3412
R. A. Bragg et al. / Tetrahedron Letters 42 (2001) 3411–3414
Ph Ph
Me
Me
Ph
Ph
Me
Ph
Me
O
N
O
O
N
N
(i), (ii)
Me
Ph
Me
+
Me
Me
H
5
6 40%
7 20%
Ar
R
R
O
R
O
Ar
Ar
Ph
O
N
Ph
(iii), (iv)
N
N
H
H
Ph
+
H
H
(v), (vi)
86%, 60:40 11a:11b
86%, 60:40 12a:12b
81%, 91:9 13a:13b
8 R = H; Ar = Ph
9 R = H; Ar = 1-naphthyl 12a R = H; Ar = 1-naphthyl
10 R = OH; Ar = Ph 13a R = OH; Ar = Ph
11a R = H; Ar = Ph
11b R = H; Ar = Ph
12b R = H; Ar = 1-naphthyl
13b R = OH; Ar = Ph
Scheme 1. Cyclisation of chiral 1-naphthamides. (i) s-BuLi, THF, −78°C; (ii) MeI; (iii) t-BuLi (1.3 equiv. for 8 and 9; 2.3 equiv.
for 10), THF, −78°C, 2 h, then DMPU (6 equiv.), −50°C (for 8 and 9) or −35°C (for 10), 16 h; (iv) NH4Cl, H2O; (v) MsCl, Et3N,
CH2Cl2 (60%); LiBHEt3, THF, D (traces).
synthesis of (S)-21 using the more valuable 4-methoxy-
naphthoyl chloride1 we chose to ensure monoacylation
at N by selective silylation of (S)-17 at O.
The amides (R)-20 and (S)-21 were cyclized by a mod-
ification of the method used for amide 10: HMPA was
used in place of DMPU, which gave low yields with
p-methoxybenzylamides. The stereoselectivities of the
reactions and the yields of single, pure stereoisomers of
13a, 22 and 23 isolated after flash chromatography are
shown in Scheme 3.
Figure 1. X-Ray crystal structure of 11b.
Products 13a and 22 were relieved of their chiral auxil-
iary by a route developed by Vernon14 and by
In the light of these results, we chose to work with
Villie´ras15 for the removal of the phenylglycinol pro-
tecting group, as shown in Scheme 3.16 Mesylation of
the primary hydroxyl groups of 13a and 22 gave 24 and
25; base-promoted elimination gave acyl enamines 26
and 27 which hydrolyzed to the lactams 28 and 29.17
phenylglycinol as our chiral auxiliary,9 and constructed
a further small group of amides, as shown in Scheme 2,
for use as starting materials for a series of dearomatis-
ing cyclisations. (R)- and (S)-phenylglycinol 15 were
made from (R)- and (S)-phenylglycine 14 by the meth-
ods of Abiko10 or Hruby.11 They were alkylated12 with
benzyl bromide or p-methoxybenzyl chloride to give
(R)-16 and both (R)- and (S)-17. (R)-16 and (R)-17
were doubly acylated with 1-naphthoyl chloride to give
(R)-18 and (R)-19. Ester hydrolysis gave amides (R)-10
and (R)-20: we were unable to find conditions for direct
formation of the hydroxyamide from 16.13 For the
Enol ether 23 was readily hydrolyzed to the ketone 30,
but attempted deprotection of 30 by the mesylation
method failed at the elimination step, possibly due to
competing enolization. Instead, 30 was converted to the
selenide 3118 and oxidized to a selenoxide which under-
went rapid elimination19 to the acylenamine 32. Hydroly-
Ar
OH
(R)
R1
Ph
OH
O
O
Ph
(R)
(R)
HO2C
Ph (i) or (ii)
Ph
NH2
(iii)
(iv)
(v)
(R)
R1
(R)
R1
Ph
HO
O
N
NH2
HN
O
N
Ar
(R)-16 (R1 = H) 66%
(R)-17 (R1 = OMe) 90%
(S)-17 (R1 = OMe) 58%
(R)-18 (R1 = H)c
(R)-14
(S)-14
(R)-15 50%a
(S)-15 77%b
(R)-10 (R1 = H; R2 = H) 79%
(R)-20 (R1 = OMe; R2 = H) 60%
(S)-21 (R1 = OMe; R2 = OMe) 89%
(R)-19 (R1 = OMe)c
R2
(vi), (vii)
Scheme 2. Synthesis of phenylglycinol-derived naphthamides. a From (R)-14 using method (i); b From (S)-14 using method (ii);
c Ar=1-naphthyl; (i) NaBH4, H2SO4, THF; (ii) LiBH4, Me3SiCl, THF; (iii) BnBr or p-MeOC6H4CH2Cl, DBU, toluene; (iv)
1-naphthoyl chloride (2 equiv.), Et3N, CH2Cl2; (v) K2CO3, MeOH; (vi) Me3SiCl (2 equiv.), imidazole, CH2Cl2; (vii) 4-methoxy-
naphthoyl chloride (1 equiv.), Et3N, CH2Cl2 then H2O.

R. A. Bragg et al. / Tetrahedron Letters 42 (2001) 3411–3414
3413
MsO
HO
O
Ph
Ph
Ph
NH
H
O
O
O
H
N
N
N
(R)-10
(R)-20
(S)-21
(i), (ii)
(iii)
(iv)
(v)
H
H
H
R1
H
H
H
R1
R1
R1
R2
24 (R1 = H) 65%
26 (R1 = H) 41%
28 (R1 = H) 92%
13a (R1 = H; R2 = H) 10:1a; 66%b
22 (R1 = OMe; R2 = H) >10:1a; 52%b
25 (R1 = OMe) 70%
27 (R1 = OMe) 86%
29 (R1 = OMe) 83%
23c (R1 = OMe; R2 = OMe) 2:1a; 32%b
HO
O2N
Se
Ph
Ph
O
O
N
N
(vii)
(vi)
H
H
H
H
OMe
OMe
OMe
30 80%
31 54%d
O
O
O
Ph
NH
O
H
N
(viii)
(v)
H
H
H
32 86%
OMe
2 65%; 99% eee
O
O
Scheme 3. Cyclisation and transformation of the cyclized products. a Crude ratio of diastereoisomers (exocyclic center relative to
ring); b isolated yield of one single, pure diastereoisomer; c shown as its enantiomer; d absolute and relative stereochemistry
confirmed by X-ray crystal structure; e determined by HPLC on chiral stationary phase [(R,R)-b-GEM, Regis]; (i) t-BuLi, THF,
−78°C, 2 h then DMPU, −35°C (or HMPA, −30°C for 20, 21), 16 h; (ii) NH4Cl, H2O; (iii) MsCl, Et3N, CH2Cl2; (iv) t-BuOK,
t-BuOH, THF; (v) 3 M HCl (aq.), EtOH, D; (vi) 1 M HCl (aq.), THF; (vii) o-NO2C6H4SeCN, Bu3P, THF; (viii) H2O2, THF, −40
to 25°C.
The tricyclic lactams 28, 29 and 2 contain a pyrogluta-
mate ring bearing substituents with relative stereochem-
istry identical to that of the kainoid series20 of natural
and unnatural products. Lactam 2 is itself an intermedi-
ate in our synthesis of the acromelic acid analogue 4.1
The enantiomeric purity (99% ee) of 2 was confirmed
by HPLC on a chiral stationary phase, and the synthe-
sis of 2 therefore constitutes a formal asymmetric syn-
thesis of the acromelic acid analogue 1.21
A simple transformation leading to ring cleavage of the
central six membered ring of the lactam 29 allowed us
to make an enantiomerically pure pyroglutamate ana-
logue 3 bearing features of the kainoid series (Scheme
4).4 We protected 29 as its N-t-butoxycarbonyl deriva-
tive 33.22 Ruthenium-catalysed oxidation of 33 using
Shioiri’s modification23 of Sharpless’s conditions24 gave,
Figure 2. X-Ray crystal structure of 31.
after a trimethylsilyldiazomethane quench, the triester 3
in 60% yield. Pyrrolidinone 3 has the same relative
stereochemistry as the kainoids, but opposite absolute
stereochemistry, and its synthesis demonstrates that
sis of 32 gave the lactam 2. An X-ray crystal structure
(Fig. 2) of selenide 31 confirmed our assignment of
absolute and relative stereochemistry.
O
O
O
NH
H
NBoc
NBoc
CO2Me
CO2Me
MeO2C
H
H
(i)
OMe
(ii, iii)
OMe
H
29
33
3
Scheme 4. Synthesis of a pyroglutamate bearing kainoid features. (i) Boc2O, Et3N, DMAP, CH2Cl2; (ii) cat. RuCl3, NaIO4 (100
equiv.), MeCN, EtOAc, H2O (1:1:34); (iii) Me3SiCHN2, MeOH, benzene.

3414
R. A. Bragg et al. / Tetrahedron Letters 42 (2001) 3411–3414
dearomatising anionic cyclisation onto naphthamides is
a versatile means of producing new kainoid-like
structures.
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Acknowledgements
We are grateful to the EPSRC for a studentship (to
R.A.B.) and to Dr. Madeleine Helliwell for determining
the X-ray crystal structures of 11b and 31.
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