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Preparation of Highly Alkoxy‐Substituted Naphthaldehyde Derivatives – A Regioselective Approach to Building Blocks for the Synthesis of Rubromycins
Author(s) -
Sörgel Sebastian,
Azap Cengiz,
Reißig HansUlrich
Publication year - 2006
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.200600353
Subject(s) - regioselectivity , chemistry , cycloaddition , aryne , aldehyde , yield (engineering) , derivative (finance) , amide , combinatorial chemistry , alkyne , sequence (biology) , acetal , formylation , stereochemistry , organic chemistry , catalysis , materials science , economics , financial economics , biochemistry , metallurgy
An efficient synthesis of highly substituted naphthaldehyde derivatives 8 was required for the planned synthesis of compounds of the rubromycin family. Three different routes towards this goal were attempted. Route I started with 1,5‐dihydroxynaphthalene ( 10 ), and the pentaalkoxy‐substituted naphthaldehyde 17 was obtained in a straightforward sequence in moderate overall yield. Route II employed an aryne cycloaddition to generate the functionalized naphthalene skeleton. This sequence smoothly provided the bromonaphthalene derivative 19 , which served as a very suitable precursor of aldehyde 24 , boronic acid 25 , and finally the unsymmetrically substituted hexaalkoxynaphthalene derivative 18 . Unfortunately, though, the regioselective formylation of 18 to provide the desired aldehyde 8a was not possible, this key compound being obtained only in low yield. Whereas an attempted Claisen rearrangement of O ‐allylated derivative 30 furnished the wrong regioisomer 33 , the ortho ‐Fries rearrangement of the easily available carbamate 34 smoothly afforded the expected amide 35 , which turned out to be essentially inert and could not be converted into the corresponding naphthaldeyde 8b . We therefore developed Route III, involving an alternative aryne cycloaddition and a subsequent regioselective ring‐opening of the tricyclic adduct 41 . This sequence enabled us to efficiently prepare acetal 44 , which was transformed into the desired highly substituted and regioselectively protected naphthaldehyde derivative 8b . The synthesis of this key compound could be achieved in a 12‐step sequence in an overall yield of 9 %. Our planned rubromycin synthesis was successfully verified by the conversion of 8b into the protected α‐hydroxy enone 7b by addition of lithiated methoxyallene followed by hydrolysis and subsequent silylation of intermediate 7a . (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)