Dynamically resolved peri-substituted 2-formyl naphthamides: A new class of atropisomeric chiral auxiliary

Article abstract of DOI:10.1016/S0040-4039(00)00397-X

2-Formyl-N,N-dialkylnaphthamides are chiral, atropisomeric compounds, provided they are substituted peri to the amide group. They may be obtained as single enantiomers by dynamic resolution on formation of diastereoisomeric aminal derivatives and used as chiral auxiliaries in a new addition/rearrangement strategy. Nucleophilic attack by vinyl anion equivalents in the presence of Lewis acids leads atroposelectively to single diastereoisomers of allylic alcohols, whose derivatives undergo stereospecific [3,3]-sigmatropic rearrangements. Reductive ozonolysis of the rearrangement product returns an enantiomerically pure functionalised alcohol and in principle allows recovery of the atropisomeric auxiliary. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00397-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3279–3283
Dynamically resolved peri-substituted 2-formyl naphthamides:
a new class of atropisomeric chiral auxiliary
Jonathan Clayden,a,∗ Catherine McCarthy a and John G. Cumming b
aDepartment of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, UK
bAstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
Received 28 February 2000; accepted 3 March 2000
Abstract
2-Formyl-N,N-dialkylnaphthamides are chiral, atropisomeric compounds, provided they are substituted peri
to the amide group. They may be obtained as single enantiomers by dynamic resolution on formation of
diastereoisomeric aminal derivatives and used as chiral auxiliaries in a new addition/rearrangement strategy.
Nucleophilic attack by vinyl anion equivalents in the presence of Lewis acids leads atroposelectively to single
diastereoisomers of allylic alcohols, whose derivatives undergo stereospecific [3,3]-sigmatropic rearrangements.
Reductive ozonolysis of the rearrangement product returns an enantiomerically pure functionalised alcohol and
in principle allows recovery of the atropisomeric auxiliary. © 2000 Published by Elsevier Science Ltd. All rights
reserved.
Despite the long history of axially chiral compounds (in particular binaphthyls) as chiral ligands,1
enantiomerically pure non-biaryl atropisomers have only recently found uses in asymmetric synthesis.2
The perpendicular architecture of atropisomeric anilides, naphthamides and benzamides allows these
groups to exert powerful diastereoselective control over new stereogenic centres in the racemic sense,3,4
and recently the anilides 1 have been obtained in enantiomerically enriched form5–8 and employed as chi-
ral auxiliaries to asymmetric enolate alkylations and aldols,5,6 cycloadditions7 and iodolactonisations.8
We9 and others10 have recently reported enantioselective routes to atropisomeric benzamides 2 and
the related naphthamides, but uses for enantiomerically enriched atropisomeric benzamides have been
confined to NADH model studies11 and components of tachykinin NK1 receptor agonists.12 In this letter
we describe the first use of compounds in this class as chiral auxiliaries.
To facilitate removal of the auxiliary, most chiral auxiliaries are linked to their substrates by means
of an ester or amide, with the disadvantage that there are always at least three bond lengths between
the source of asymmetric induction and the newly forming stereogenic centre. We have published13 an
alternative strategy (Scheme 1) in which an aldehyde 3 functions as a C–C bonded chiral auxiliary, allow-
ing a new stereogenic centre to be formed immediately adjacent to the auxiliary’s chiral influence under
Felkin14–Anh15 control. Diastereoselective attack by a vinyl anion equivalent 4 to give 5, followed by
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00397-X
tetl 16677

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stereospecific [3,3]-sigmatropic rearrangement (or its equivalent), leads to an alkene 7 whose ozonolysis
returns the aldehyde auxiliary 3 and a 2-substituted aldehyde 6 as the product.16
Scheme 1. The strategy
The key step is the diastereoselective addition to the aldehyde: originally, we used phenylalanine-
derived 3a because of its highly selective, non-chelation controlled reactions with organolithiums and
Grignard reagents.17 We have recently discovered18 that, in the presence of certain Lewis acids, additions
to 2-formyl-N,N-dialkyl-1-naphthamides 3d (R=H) are among the most diastereoselective additions to
aldehydes known, and we now describe the use of related compounds as chiral auxiliaries in a similar
strategy.
Aldehyde 3d (R=H) is barely atropisomeric and racemises with a half-life of only 12 min at 20°C,
making it unsuitable as a chiral auxiliary.19 However, in a recent study of peri-substituted naphthamides20
we found that heteroatomic 8-substituents (R=NMe2, OMe) provide highly effective barriers to racemi-
sation by incipient donation into the C_O π* orbital. The half life for racemisation of 3c (R=NMe2) is
estimated as 80 days at 20°C; that for 3b (R=OMe) is >10 years at 20°C.21
We decided to use the most stable chiral aldehyde 3b (R=OMe) as the auxiliary. It was made in
racemic form in multi-gram quantities from naphthalic anhydride by a published high-yielding route,22
and was resolved by chromatographic purification of one of a pair of diastereoisomeric aminals 10 and
epi-10 (Scheme 2).23 The aminals were made by refluxing 3b with the diamine 9 (available in four steps
from proline24) in xylene.9 Some interconversion of the atropisomers must have taken place during the
formation of the aminal, because the two diastereoisomers 10 and epi-10 were formed as a 4:1 mixture
in 92% yield. Simply hydrolysing the crude mixture of aminals returned (–)-3b quantitatively, with 62%
ee. Alternatively, 10 could be purified on basic alumina and hydrolysed (HCl, H2O) to give the aldehyde
(–)-3b in 99% ee and 36% overall yield from the racemate. It proved impossible to isolate a pure sample
of the unstable epi-10.
A similar, but complete, interconversion of atropisomers accompanies the formation of homologous
aminals from 3b (R=H). In that case, it is the aminal products which equilibrate, a process which amounts
to a dynamic thermodynamic resolution. However, re-subjecting purified 10 to the conditions of the
reaction gave no epi-10, so the atropisomeric enrichment of 10 in this case appears to represent instead
a dynamic kinetic resolution of 3b, whose racemisation at the temperature of the reaction is estimated to
take place over a matter of a few hours.21,25
For the next step, stereoselective addition of a vinyl anion equivalent, we decided to use the strategy
employed previously13 of adding a lithiated alkyne and reducing the product to an allylic alcohol.
Lithiated octyne added to (–)-3b to give syn-11 (whose relative stereochemistry was proved by an

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Scheme 2. Dynamic resolution of the aldehyde
X-ray crystal structure) relatively unselectively, but in the presence of i-Bu2AlH or Me3Al the same
nucleophile gave anti-11 with >97:3 selectivity (Scheme 3). Alkylaluminiums appear to coordinate to
the aldehyde oxygen, fixing it s-trans to the amide, prevent chelation of the two carbonyls by a metal ion,
and encouraging anti-selective nucleophilic attack.18 The anti product anti-11 was reduced either to the
E-allylic alcohol (+)-E-12 with RedAl® [NaAlH2(OCH2CH2OMe)2] or to the Z-allylic alcohol (+)-Z-12
by hydrogenation over Lindlar’s catalyst.
Scheme 3. Stereoselective construction of allylic alcohols (R=n-hexyl)
The next step in the strategy requires stereospecific allylic rearrangement of 12 to transfer stereo-
chemistry to the stereogenic centre which will remain once the auxiliary is recovered. We chose to use
two variants of the [3,3]-sigmatropic Claisen rearrangement of known stereospecificity. Allylic alcohol
Z-12 was heated with trimethyl orthoacetate to give the ketene acetal 17 which underwent a stereospecific
Johnson–Claisen rearrangement26 in 12 h at 110°C (Scheme 4). The product ester 18 was isolated as a
single diastereoisomer in 84% yield. By contrast, Eschenmoser–Claisen rearrangement27 of Z-12 with
dimethylacetamide dimethoxy acetal in refluxing xylene at 130°C for 20 h gave a mixture of epimers
of the product amide 14. The most reasonable explanation for this is that the higher temperature allows
equilibration of the atropisomeric epimers, particularly in the rearranged product which has a small,
trigonal substituent (a trans double bond) adjacent to the amide axis. The newly formed centre was
nonetheless evidently formed with high stereospecificity, because ozonolysis of 14 with reductive work-
up yielded an optically active alcohol (R)-(–)-15 whose Mosher ester28 16 (formed from (+)-MTPACl)
contained less than 5% of the diastereoisomer formed from the known13 (S)-(+)-15.
Unfortunately, it proved impossible to recover the auxiliary (in its reduced form) from the ozonolysis
step: the only other product turned out to be a benzamide 19 derived from further oxidation of the
naphthalene’s more electron-rich ring.

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Scheme 4. Stereospecific rearrangements and cleavage (R=n-hexyl)
In summary, we have shown that atropisomeric amides may be dynamically resolved by formation
of epimeric aminals, and we have illustrated their use as a new class of chiral auxiliaries by making
a chiral amidoalcohol using an unusual stereoselective addition–stereospecific rearrangement strategy.
In principle, a variety of 2-substituted (including 2-heterosubstituted) alcohols and aldehydes should be
available using this route simply by variation of the nature of the allylic rearrangement. We would hope
that optimisation of the oxidative cleavage step could also allow recovery of the auxiliary.
Acknowledgements
We are grateful to the EPSRC for a studentship (to CMcC), and to Dr. M Helliwell for determining the
X-ray crystal structure of syn-11.
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