A novel asymmetric route to succinimides and derived compounds: Synthesis of the lignan lactone (+)-hinokinin

Article abstract of DOI:10.1039/b403193h

A novel approach to chiral succinimides and derived compounds has been developed that involves chiral lithium amide desymmetrisation of an N-ortho-tert-butylphenyl succinimide to generate a putative atropisomeric intermediate enolate, alkylation of which

Full text of DOI:10.1039/b403193h

A novel asymmetric route to succinimides and derived compounds:
synthesis of the lignan lactone (+)-hinokinin
D. Jonathan Bennett,a Paula L. Pickeringb and Nigel S. Simpkins*b
a Organon Laboratories Ltd., Newhouse, Lanarkshire, UK ML1 5SH
b School of Chemistry, The University of Nottingham, University Park, Nottingham, UK NG7 2RD.
E-mail: Nigel.Simpkins@Nottingham.ac.uk; Fax: +44(0) 115 951 3564; Tel: +44(0) 115 951 3533
Received (in Cambridge, UK) 3rd March 2004, Accepted 19th April 2004
First published as an Advance Article on the web 14th May 2004
A novel approach to chiral succinimides and derived com-
pounds has been developed that involves chiral lithium amide
desymmetrisation of an N-ortho-tert-butylphenyl succinimide
to generate a putative atropisomeric intermediate enolate,
alkylation of which enables access to the lignan lactone
(+)-hinokinin.
At the outset we envisaged desymmetrisation of the parent
succinimide 8, having an N-ortho-tert-butyl substituent, as shown
in (Scheme 3).6
A chiral base was anticipated to select between a pair of
enantiotopic protons on the face of the succinimide 8 anti to the
bulky tert-butyl substituent, thus generating an enolate 9 possessed
of a chiral C–N axis. Subsequent face selective electrophilic quench
would then furnish a chiral succinimide product 7, 10–12 (see later
for nature of E).
Preliminary experiments using bis-lithium amide 2 provided
mainly the doubly substituted products 13–16, which were isolated
in good yield, predominantly as the trans isomer shown. This result
demonstrated that the steric effect of the first installed substituent
could over-ride the influence of the remote tert-butyl group, and
thus avoid the second alkylation returning a meso product.7
However, the products from these reactions proved to be almost
racemic, a result that suggests the intermediacy of symmetrical
imide dianions, as documented by Garratt and co-workers.8
To avoid this problem we utilised the mono-lithiated base 3 to
deprotonate 8, and then effected alkylation using reactive alkyl
halides and DMPU, Table 1.†
Previously we have demonstrated a range of applications of chiral
base chemistry in which prochiral starting materials are converted
into useful chiral (non-racemic) products by a process dubbed
‘asymmetric deprotonation’.1 Most recently the focus of this work
has been the asymmetric transformation of various types of cyclic
imide, especially ring-fused succinimides and certain types of
glutarimide.2 For example, asymmetric substitution of glutarimide
1, by deprotonation with bis-lithium amide base 2, gave a range of
substituted products 4, one of which was converted into the drug
substance paroxetine, (Scheme 1).
In much of this chemistry the use of diamine derived base 2, or
the corresponding mono-lithiated derivative 3 has proved crucial
for optimal chemical yield or enantioselectivity.3
A further possibility for the application of the asymmetric
deprotonation strategy to the synthesis of chiral imides became
apparent to us following a report by Taguchi and co-workers.4 As
part of this study, chiral pool access to atropisomeric imides 6 and
7 was reported, starting from (R)-2-methylsuccinic acid 5, Scheme
2.
In each case a mono-alkylated product was obtained as the main
product, principally as the anti isomer shown, although small
amounts of the corresponding syn isomer (not shown) were also
isolated.‡ The chemical yields are moderate, which reflects the
One of the diastereomeric imide products 6 was converted into
the corresponding maleimide, which was shown to undergo a
highly stereocontrolled Diels–Alder reaction.5 Prompted by these
findings we initiated studies aimed at applying the kind of
desymmetrisation shown in Scheme 1 to the asymmetric synthesis
of atropisomeric intermediates such as 6 and 7, the results of which
are described herein.
Scheme 3
Scheme 1
Table 1 Alkylation of 8 to give 7 and 10–12 according to Scheme 3
Product and
yield (%)
Product
ee (%)
By-product
and yield (%)
Entry
Electrophile
1
2
3
4
Methyl iodide
Allyl bromide
Benzylbromide
7 56a
10 55
11 50
85
94
92
95
13 0
14 7
15 6
16 7
Piperonyl bromide 12 40
a The methylated imide corresponds to the enantiomer of 7 in Scheme 2
Scheme 2
C h e m . C o m m u n . , 2 0 0 4 , 1 3 9 2 – 1 3 9 3
1392
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

difficulty in controlling the alkylations of the somewhat unstable
imide enolate, and have not been fully optimised. As in the previous
glutarimide work, illustrated in Scheme 1, the enantiomeric excess
of the monoalkylated product appears to be slightly enhanced in
runs where some dialkylation is evident. This effect is due to a
kinetic resolution of the first formed product being superimposed
on the initial asymmetric deprotonation.9 Thus, in the case of MeI
as electrophile, the ee of the monoalkylated product 7 is a little
lower than for the other electrophiles, since no over-alkylation
occurred.
The absolute configuration of methylated product (2) 7 (entry 1)
was correlated with the enantiomeric imide synthesized previously
by Taguchi and co-workers, generated as shown in Scheme 2. The
absolute configuration of product 12 was also proved by subsequent
transformations, as described below.
It appeared to us that this novel imide alkylation could provide
useful access to a range of target molecules, and we were
particularly attracted to a very simple idea for preparing certain
lignan dibenzyl lactones.10 Initially, we established the viability of
such a process by the three step sequence shown in Scheme 4, using
racemic imide 11.
A second benzylation of imide 11 served to generate 15, identical
to the product that we had obtained previously (Scheme 3), and
subsequent borohydride reduction then furnished the hydrox-
yamide 17. Treatment of this amide with sulfuric acid, according to
a procedure that we had used previously,11 then gave the desired
racemic dibenzyl lactone 19, albeit in moderate yield.
uses a new chiral base desymmetrisation as the pivotal step. A new
and concise synthesis of the lignan lactone hinokinin serves as a
preliminary demonstration of the potential of the new method.
We are grateful to Organon Laboratories, Newhouse, for the
support of P.L.P. and to Dr E. Hutchinson for his input at the early
stages of the project.
Notes and references
† Preparation of (+)-12: A solution of chiral lithium amide base 3 (2.44
mmol) in THF (5 mL) at 278 °C was added by cannula to a solution of
imide 8 (400 mg, 1.73 mmol) in THF (40 mL) at 278 °C. After 1 h DMPU
(0.29 mL, 2.42 mmol) was added, followed by piperonyl bromide (3.72 g,
17.3 mmol) in THF (4 mL), and the reaction mixture stirred at 278 °C for
a further 2 h. Usual workup (saturated aqueous NH4Cl solution and EtOAc
extraction), followed by chromatographic purification gave firstly the bis-
adduct 16 (Rf 0.65, 7 : 3 EtOAc/petroleum ether) as a white solid (60.0 mg,
0.12 mmol, 7%); followed by imide 12 (Rf 0.6, 7 : 3 EtOAc/petroleum ether)
as a solid (250 mg, 0.68 mmol, 40%), m.p. 143–145 °C, [a]D23 +86.7 (c 0.5,
CHCl3); nmax (CHCl3)/cm21 2972, 1711, 1602, 1490, 1444, 1382, 1041; dH
(500MHz, CDCl3) 1.32 (9H, s, C(CH3)3), 2.67 (1H, dd, J 18.7, 4.8, 4-HA),
2.90 (1H, dd, J 18.7, 9.7, 4-HB), 3.09 (1H, dd, J, 13.9, 7.2, 1A-HA), 3.13 (1H,
dd, J, 13.9, 4.8, 1A-HB), 3.28 (1H, dddd, J 9.7, 7.2, 4.8, 4.8, 3-H), 5.98 (2H,
m, OCH2O), 6.61 (1H, dd, J 7.5, 1.3, Ar-H), 6.69 (1H, dd, J 7.8, 1.3, Ar-H),
6.74 (1H, d, J 1.3, Ar-H), 6.80 (1H, d, J 7.8, Ar-H), 7.27 (1H, ddd, J 7.5, 7.2,
1.1, Ar-H), 7.40 (1H, ddd, J 7.8, 7.2, 1.3, Ar-H), 7.59 (1H, dd, J 7.8, 1.1, Ar-
H); dC (125 MHz, CDCl3) 31.7 (CH3), 33.4 (CH2), 35.7 (C), 35.8 (CH2),
41.7 (CH), 101.2 (CH2), 101.7 (CH), 109.7 (CH), 122.6 (CH), 127.5 (CH),
128.9 (CH), 129.9 (CH), 130.3 (2 3 C), 130.7 (CH), 146.9 (C), 148.0 (C),
148.2 (C), 176.6 (CNO), 179.6 (CNO); m/z (EI) (Found M+, 365.1628.
We then conducted an analogous sequence of reactions, starting
with imide (+)-12 of 95% ee, bearing a piperonyl substituent, which
is characteristic of a number of naturally occurring lignan lactones.
Introduction of a further piperonyl unit was accomplished by
enolate alkylation, and reduction and cyclisation then gave
(+)-hinokinin 20, which is the enantiomer of a well-known lignan
natural product. Our spectroscopic data for this compound were in
accord with those reported previously,12 and analysis by HPLC
indicated that the enantiomeric excess of this compound was at the
same level (95% ee) as that of the initially formed chiral
intermediate (+)-12.
C
22H23NO4 requires M, 365.1627). The ee of 12 (95%) was determined by
HPLC analysis using a Chiracel OD column [25 cm 3 0.46 cm i.d.; 8% i-
PrOH in hexane; flow rate, 1.0 mL min21; (2)-12; tR = 35.2 min, (+)-12;
tR = 41.3 min].
‡ This by-product amounted to: 14% (7); 4% (10); 7% (11), and could not
be isolated for 12. We expect that MeI represents a worst case, and that the
observed level of facial selectivity (ca. 10 : 1) will be adequate for synthesis
using most (bulkier) electrophiles.
1 (a) P. O’Brien, J. Chem. Soc., Perkin Trans. 1, 1998, 1439; (b) For a
special journal edition dedicated to chiral lithium amide base chemistry,
see P. O’Brien, Tetrahedron, 2002, 58(23), 4567–4733, Symposium in
Print guest editor; (c) For a very recent report, see C. C. McComas and
D. L. Van Dranken, Tetrahedron Lett., 2003, 44, 8203.
2 (a) C. D. Gill, D. A. Greenhalgh and N. S. Simpkins, Tetrahedron, 2003,
59, 9213; (b) C. D. Gill, D. A. Greenhalgh and N. S. Simpkins,
Tetrahedron Lett., 2003, 44, 7803.
In summary, a conceptually novel approach to the synthesis of
chiral imides, and derived systems, has been demonstrated, which
3 K. Bambridge, M. J. Begley and N. S. Simpkins, Tetrahedron Lett.,
1994, 35, 3391. For recent use of this base, see refs. 1 and 2.
4 K. Kitagawa, H. Izawa, K. Sato, A. Dobashi and T. Taguchi, J. Org.
Chem., 1998, 63, 2634.
5 For the seminal report in this area, see D. P. Curran, H. Qi, S. J. Geib and
N. C. DeMello, J. Am. Chem. Soc., 1994, 116, 3131.
6 For other chiral base mediated desymmetrisation leading to atropi-
somers, see for example: (a) S. Thayumanavan, P. Beak and D. P.
Curran, Tetrahedron Lett., 1996, 37, 2899; (b) H. Koide, T. Hata and M.
Uemura, J. Org. Chem., 2002, 67, 1929; (c) J. Clayden, P. Johnson and
J. Pink, J. Chem. Soc., Perkin Trans. 1, 2001, 371.
7 This result is in contrast to a related alkylation of an amino-substituted
succinimide, see K. Kishikawa, I. Tsuru, S. Kohmoto, M. Yamamoto
and K. Yamada, Chem. Lett., 1994, 1605.
8 K. G. Bilyard, P. J. Garratt, R. Hunter and E. Lete, J. Org. Chem., 1982,
47, 4731.
9 See reference 2a for a range of examples of this kind of kinetic
resolution.
10 (a) R. S. Ward, Nat. Prod. Rep., 1999, 16, 75; (b) For examples of
asymmetric approaches, see J. W. Bode, M. P. Doyle, M. N.
Protopopova and Q-L. Zhou, J. Org. Chem., 1996, 61, 9146; (c) N. Kise,
T. Ueda, K. Kumada, Y. Terao and N. Ueda, J. Org. Chem., 2000, 65,
464; (d) S. Kamlage, M. Sefkow, B. L. Pool-Zobel and M. G. Peter,
Chem. Commun., 2001, 331.
11 D. J. Adams, A. J. Blake, P. A. Cooke, C. D. Gill and N. S. Simpkins,
Tetrahedron, 2002, 58, 4603 and references therein.
12 (+)-Hinokinin was made previously by Doyle and co-workers (ref. 10b)
using an asymmetric C–H insertion process that gave ca., 95% ee. They
report [a]D +29.4 (c 0.9, CHCl3) for the final product, whereas we
observed [a]D +26.9 (c 0.7, CHCl3).
Scheme 4
C h e m . C o m m u n . , 2 0 0 4 , 1 3 9 2 – 1 3 9 3
1393