A new synthetic approach towards N-alkylated 2-epi-valienamines via palladium-catalyzed coupling reaction

Article abstract of DOI:10.1016/S0040-4039(00)01150-3

Preparation of N-alkylated 2-epi-valienamines was accomplished by the palladium-catalyzed coupling reaction of the allylic chloride 5 with various amines in the presence of trimethylolpropane phosphite (TMPP). The 2-epi-valienamine precursor (i.e. allylic

Full text of DOI:10.1016/S0040-4039(00)01150-3

Tetrahedron Letters 41 (2000) 6865±6868
A new synthetic approach towards N-alkylated
2-epi-valienamines via palladium-catalyzed coupling reaction
Stanton H. L. Kok and Tony K. M. Shing*
Department of Chemistry, The Chinese University of Hong Kong, Hong Kong, China
Received 10 May 2000; accepted 5 July 2000
Abstract
Preparation of N-alkylated 2-epi-valienamines was accomplished by the palladium-catalyzed coupling
reaction of the allylic chloride 5 with various amines in the presence of trimethylolpropane phosphite
(TMPP). The 2-epi-valienamine precursor (i.e. allylic chloride 5) was obtained from the reaction of diol 2
with Viehe's salt and the diol 2 was readily prepared from (^)-quinic acid in 10 steps. # 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: coupling reactions; enzyme inhibitors; palladium and compounds.
As part of our ongoing program concerning the syntheses of valienamine and its derivatives as
potential glycosidase inhibitors,1 3 we were interested in the preparation of N-alkylated 2-epi-
valienamines. Earlier syntheses of N-alkylated valienamines were reported by Kameda et al.4 and
were based on three classic approaches: (a) alkylation of valienamine with an alkyl halide,5a
(b) condensation of valienamine with an aldehyde (or a ketone) and subsequent reduction of the
resulting Schi€ base,5b and (c) ring-opening of an epoxide with valienamine.5c Halide displacement
and reductive amination reactions often gave poor yields and depended heavily upon the steric
requirement of both coupling partners. The epoxide aminolysis approach su€ers from the
regioselectivity problem, although the trans-diaxial opening of the epoxide ring is more favorable.
In this communication, we wish to report facile, regio- and stereospeci®c syntheses of N-alkylated
2-epi-valienamines based on the Pd-catalyzed coupling6 of allylic chloride 5,7 which was prepared
from vicinal-cis diol 2 and Viehe's salt,8 12 with di€erent aliphatic amines.
The diol 2 was readily prepared from (^)-quinic acid 1 in 10 steps with an overall yield of 45%
according to our recent work.13 Treatment of diol 2 with Viehe's salt in re¯uxing dichloro-
methane in the presence of triethylamine gave the air-stable allylic chloride 5 (Scheme 1). The
mechanism was believed to involve the initial formation of the cyclic iminium salt 4, and the
chloride anion then attacked the more reactive allylic carbon to give a quantitative yield of allylic
chloride 5. The presence of the trans-disposed H1±H2 in the allylic chloride 5 was con®rmed by
2D proton NMR experiments (NOESY and COSY).
* Corresponding author. Tel: +852-2609-6367; fax: +852-2603-5057; e-mail: tonyshing@cuhk.edu.hk
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01150-3

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Scheme 1.
Table 1
Scope of the Pd(dba)2/TMPP-catalyzed amine coupling of allylic chloride 5

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The palladium-catalyzed reactions of various amine nucleophiles with allylic chloride 5 were
carried out and the results are shown in Table 1. Indeed, the reaction proceeded smoothly with
both primary (including amino acids) and secondary amines, although it showed an acute fall in
yields with bulky amines (e.g. dicyclohexylamine or diisopropylamine). In comparison to those
reactions using triphenylphosphine as ligand (entries 3, 5 and 11), we found that the use of
TMPP14 16 increased the overall yields drastically (entries 2, 4 and 10). However, the reaction
involving cyclohexylamine apparently gave no improvement in yields (entries 8 and 9), probably
attributable to steric reasons. The overall retention of con®guration in the present palladium-
catalyzed reactions was indicated by comparing the coupling constant (J1,2) between H1 and H2
in diacetate 3 and chlorocarbamate 5 with that in the newly constructed amines, e.g. benzylamine
16 (Fig. 1). The J1,2 values in 5 and 16 are 8.1 and 6.6 Hz, respectively, whereas the J1,2 value in 3
is less than 3 Hz, thereby indicating the trans-orientation of H1 and H2 in 16. Furthermore, the
spectral and physical data of the known pentaacetate 1713 derived from the corresponding amine
16 (entry 10 of Table 1) was identical with an authentic sample from our previous work.17 This
con®rms the stereochemical outcome of the palladium-catalyzed coupling reaction. All amines
were fully characterized in all aspects. The presence of diene 7 may be explained as a result of
b-elimination of a s-palladium intermediate.18 20
Figure 1. 1H NMR spectra: (a) diacetate 3; (b) chlorocarbamate 5; (c) amine 16 (entry 10 of Table 1)
In summary, we have described regio- and stereospeci®c syntheses of N-alkylated 2-epi-valien-
amines based on a Pd-catalyzed coupling reaction using TMPP as ligand. Application of this
strategy towards the construction of pseudoaminodisaccarides is in progress.
Acknowledgements
Financial support from Hong Kong RGC (Ref. No. CUHK 308/96P) is gratefully acknowledged.
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