Scheme 1. Retrosynthetic Analysis
to install the desired benzylic alcohol enantioselectively.
Alternative approaches have involved resolution or chro-
matographic separation of diastereomeric mixtures.8,9
related example demonstrates the capture/release purification
of ethanolamines with acidic ion-exchange resin.10
ilized formaldehyde adduct,13 proved unsuccessful. We
therefore investigated the possibility of aminomethylation
followed by displacement of dimethylamine with an oxygen
nucleophile to furnish the desired diol motif. Work by
Ungaro et al. showed that phenols could be condensed with
Eschenmoser’s salt catalyzed by potassium carbonate to yield
exclusively the ortho-substituted products (Scheme 3, eq 1).14
However, distillation or recrystallization were generally
required to purify the products. We envisaged that condensa-
tion of 4-hydroxyacetophenone 6 with a resin-bound meth-
yleneiminium salt would eliminate the need for purification,
and acid-catalyzed displacement from the resin with acetic
anhydride would cleanly furnish the protected diol 3. Thus,
4-hydroxyacetophenone 6 was added to a stirred suspension
of resin-bound piperazinomethylpolystyrene15 and formal-
dehyde. Filtration yielded a resin which, when refluxed with
pTSA and acetic anhydride in toluene, released diacetate 3
in 14% yield (Scheme 3, eq 2). Attempted optimization of
the reaction conditions and the use a range of commercially
available secondary amine resins failed to improve the initial
yield.
A
We envisaged that a diastereoselective reduction of ben-
zylic ketone 2, available from the saligenin derivative 3, with
borohydride exchange resin (BER) directed by a labile
N-linked chiral auxiliary, would afford the desired amino
alcohol. Completion of the synthesis could then be achieved
by a reductive amination with aldehyde 4 and cleavage of
the auxiliary by hydrogenolysis (Scheme 1).
Aldehyde 4 was synthesized cleanly in three steps from
4-phenylbutanol 5 in excellent overall yield. Bromination
or mesylation was readily achieved by known procedures11,3a
and the resultant leaving group displaced with excess water-
soluble hexane 1,6-diol to prevent dimerization. Oxidation
with alumina-supported pyridinium chlorochromate then
quantitatively afforded aldehyde 4 (Scheme 2).
We then investigated the use of a polymeric base to
catalyze the condensation. Treatment of 6 with Eschen-
moser’s salt and carbonate exchange resin cleanly afforded
the desired tertiary amine 7 after filtration and evaporation
without the need for further purification (Scheme 3, eq 3).
Interestingly, alkylation of a range of other substituted
phenols (Table 1) under identical conditions yielded exclu-
sively the mono-ortho-substituted products, suggesting a tight
ion pair intermediate. Even in the case where both ortho
positions were blocked, no para substitution was observed
(Table 1, entry 8).
Scheme 2. Synthesis of Aldehyde 4
Displacement of dimethylamine from 7 with acetic anhy-
dride and catalytic sulfonic acid resin followed by a highly
selective monobromination with polyvinylpyridinium bro-
mide perbromide resin furnished diacetate protected R-bro-
moketone 8 in good yield (Scheme 4).16 Treatment of 8 with
(8) Skidmore, I. F.; Lunts, L. H. C.; Finch, H.; Naylor, A. patent
US4992474, February 12, 1991.
(9) Evans, B. patent EP-A 422889, April 17, 1991.
(10) Shuker, A. J.; Siegel, M. G.; Matthews, D. P.; Weigel, L. O.
Tetrahedron Lett. 1997, 37, 6149.
Initial attempts to form ketone 3 via a condensation of
4-hydroxyacetophenone 6 with formaldehyde,12 or a stab-
(5) Nials, A. T.; Coleman, R. A.; Johnson, M.; Vardey, C. J. Am. ReV.
Resp. Dis. 1994, 149, A481.
(6) Procopiou, P. A.; Morton, G. E.; Todd, M.; Webb, G. Tetrahedron:
Asymmetry 2001, 12, 2005.
(11) Hodge, P.; Khoshdel, E. J. Chem. Soc., Perkin Trans. 1 1984, 195.
(12) Schlosser, M.; Jenny, T.; Guggisberg, Y. Synlett 1991, 704.
(13) Maruoka, K.; Concepcion, A. B.; Murase, N.; Oishi, M.; Hirayama,
N.; Yamamoto, H. J. Am. Chem. Soc. 1993, 115, 3943.
(14) Pochini, A.; Puglia, G.; Ungaro, R. Synthesis 1983, 906.
(7) Hett, R.; Stare, R.; Helquist, P. Tetrahedron Lett. 1994, 35, 9375.
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