Conjugate addition to (α,β)(α,β)-diendioate esters by lithium (α- methylbenzyl)benzylamide: Tandem addition-cyclisation versus double addition

Article abstract of DOI:10.1016/S0957-4166(99)00170-6

Strategies for obtaining either the products from tandem conjugate addition-cyclisation or from double addition in the highly stereoselective addition of lithium (R)-(β-methylbenzyl)benzylamide to (α,β)(α,β)- diendioate esters are demonstrated.

Full text of DOI:10.1016/S0957-4166(99)00170-6

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1637–1641
Conjugate addition to (α,β)(α0,β0)-diendioate esters by lithium
(α-methylbenzyl)benzylamide: tandem addition–cyclisation
versus double addition
Julio G. Urones,a Narciso M. Garrido,a,∗ D. Díez,a Sara H. Dominguez a and
Stephen G. Davies b
aDepartamento de Química Orgánica, Universidad de Salamanca, Plaza de los Caídos 1-5, 37008 Salamanca, Spain
bThe Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QY, UK
Received 19 April 1999; accepted 4 May 1999
Abstract
Strategies for obtaining either the products from tandem conjugate addition–cyclisation or from double addition
in the highly stereoselective addition of lithium (R)-(α-methylbenzyl)benzylamide to (α,β)(α0,β0)-diendioate
esters are demonstrated. © 1999 Elsevier Science Ltd. All rights reserved.
(α,β)(α0,β0)-Diendioate esters are potential substrates for tandem conjugate addition–cyclisation
processes or for double conjugate addition reactions (Scheme 1): which reaction manifold is followed will
obviously depend on the rate of intramolecular cyclisation of the intermediate ester enolate formed in the
first addition versus the rate of intermolecular conjugate addition to the second α,β-unsaturated ester.
Conjugate addition–cyclisation reactions with (α,β)(α0,β0)-diendioate esters as substrates have been
studied in the racemic series using lithium (benzyl)trimethylsilylamide as initiating nucleophile for the
generation of cyclopentane and cyclohexane derivatives.1 Asymmetric versions have also been reported
for (α,β)(α0,β0)-diendioyl derivatives of chiral auxiliaries.2 The double addition manifold has not been
reported although monoaddition without cyclisation has been reported for an (E,E)-deca-2,5-diendioate
ester with lithium (benzyl)trimethylsilylamide rather than cyclisation to a cycloheptane derivative.1 The
diamino bisadducts obtained are very versatile intermediates3 due to the fact that a class of C2-symmetric
molecules that contains 1,n-diamino functions (n=3−5) as structural features has been found to efficiently
inhibit HIV-protease.4 C2-Symmetric diamines are also of importance in asymmetric synthesis as ligands
and ligand building blocks for transition metal catalysts.5
We have demonstrated the use of homochiral lithium (α-methylbenzyl)benzylamide 1 to initiate
the asymmetric conjugate addition–cyclisation of dimethyl (E,E)-octa-2,5-dienoate 2 to generate the
∗
Corresponding author. E-mail: nmg@gugu.usal.es
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00170-6

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Scheme 1.
homochiral cyclopentane derivative 3 with complete control over the configuration of C-1 and C-2 and
excellent control over C-5 with only a small amount of the C-5 epimer 4 being formed6 (Scheme 2).
Scheme 2.
Addition of dimethyl (E,E)-octa-2,5-dienoate 2 to a large excess (12 equiv.) of the lithium amide (R)-1
similarly resulted in the exclusive formation of the cyclised products 3 and 4 with no double addition
product 5 being found.
Whereas (E)-α,β-unsaturated esters are very susceptible to conjugate addition, their (Z)-counterparts
are highly susceptible to γ-deprotonation.1b,7 This suggested a strategy towards the monoadduct 6 from
di-3-pentyl (E,Z)-octa-2,6-diendioate 7. Addition of 7 to an excess (3 equiv.) of (R)-1 generated, in 76%
yield after work-up, the (E)-β,γ-unsaturated monoadduct 8, [α]D26=−12.8 (c 1.54, CHCl3),8 as expected
from α-protonation of the intermediate dienoate 9, which on treatment with base under protic conditions
rearranged to the (E)-α,β-unsaturated ester monoadduct 6 in 72% yield (Scheme 3). The bisadduct 10
[α]D26=−2.8 (c 0.21, CHCl3), was now accesssible in 51% yield by subsequent conjugate addition of
(R)-1 to 6.
Scheme 3.

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1639
Addition of a slight excess of lithium amide (R)-1 to dimethyl (E,E)-nona-2,7-diendioate 11 gave (+)-
(1R,2R,6R,αR)-12, [α]D26=+3.9 (c 1.86, CHCl3), as the sole product completely stereoselectively in 72%
yield. The absolute configuration of the α-methylbenzyl centre derives from (R)-1, while that of C-2 is
assigned by analogy with all other conjugate additions of (R)-1 to α,β-unsaturated esters.9 The absolute
1
configurations of C-1 and C-6 are assigned by determining their configurations relative to C-2 by H
NMR spectroscopy including two-dimensional homonuclear COSY, heteronuclear HMQC and HMBC,
NOE and ROESY experiments. The C-1 configuration is consistent with the established anti-addition to
the first α,β-unsaturated ester initiated by the lithium amide10 (Scheme 4).
Scheme 4.
On the other hand, addition of dimethyl (E,E)-nona-2,7-diendioate 11 to a large excess (12 equiv.) of
the lithium amide (R)-1 generated a 40:60 mixture of the cyclised adduct (1R,2R,6R,αR)-12 to the double
addition product (+)-13, [α]D26=+7.4 (c 2.00, CHCl3) in 70% yield (Scheme 5).
Scheme 5.
When lithium amide (R)-1 (1.2 equiv.) was added to di-3-pentyl (E,E)-deca-2,8-diendioate 14, no
cyclisation products were obtained, with only the monoaddition product 15, [α]D26=+6.2 (c 0.62,
CHCl3), being formed in 25% yield (Scheme 6) and 65% of 14 was recovered. Addition of 14 to a
large excess (12 equiv.) of lithium amide (R)-1 generated the bisadduct (+)-16, [α]D26=+7.1 (c 0.86,
1
CHCl3), as the sole product in 67% isolated yield. Analysis of the crude product by H NMR (400
MHz) confirmed it to be diastereomerically pure (>95% d.e.) as no trace was found of any of the
other (β,β0)-stereoisomers independently prepared11 by adding (R)-α-methylbenzylamine to 14 non-
stereoselectively.9a,12 Bisadduct (+)-16 was also obtained on addition of (R)-1 to the monoadduct 15.
The bisadduct 17, precursor to the meso-diaminodiacid derivative was obtained on treatment of 15 with
(S)-1 in 71% yield, [α]D26=−0.1 (c 0.86, CHCl3). Reduction of (+)-16 and 17 with LiAlH4 generated the
diols: (−)-18, [α]D26=−47.5 (c 1.57, CHCl3) and 19, in 84% and 77% yields, respectively.
The analogous series of reactions starting from (S)-1 generated (−)-16, [α]D26=−6.6 (c 3.80, CHCl3),
and, by reduction, the diol (+)-18, [α]D26=+46.2 (c 1.18, CHCl3).
In conclusion, we have demonstrated strategies for obtaining either the products from tandem
conjugate addition–cyclisation (cyclopentane and cyclohexane derivatives) or from double addition
in the highly stereoselective addition of (R)- and (S)-(α-methylbenzyl)benzylamide to (α,β)(α0,β0)-

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Scheme 6.
diendioate esters. In this way the asymmetric synthesis of precursors to all three stereoisomers of (β,β0)-
diaminodiacids is achieved in good yield.
Acknowledgements
We thank the Spanish Ministerio de Educación y Ciencias (DGES PB97-1323) and the British Council
for accion integrada HB155.
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†
By reaction of 14 with (R)-α-methylbenzylamide in EtOH at reflux, the monoaddition product 21 together with the diaddition
product 20 were obtained. Subsequent benzylation of the secondary amines gave 22 from 21 and the mixture of three
stereoisomers, (+)-(3R,8R,αR,α0R)-16, (3R,8S,αR,α0R)-16 and (3S,8S,αR,α0R)-16, from 20. Treatment of 22 with (R)-1 gave
the mixture: (+)-(3R,8R,αR,α0R)-16 and (3R,8S,αR,α0R)-16.