Stereocontrolled synthesis of the taxol C-13 side chain: Methyl (2R,3S)-3-benzoylamino-2-hydroxy-3-phenylpropanoate

Abstract

685α-Hydroxy-β-amino acids are present in a number of biologically active compounds and therefore their stereoselective syntheses were object of many recent investigations [1]. We have already described preparation of several anti-(2S,3S)-α-hydroxy-β-amino esters by stereoselective addition of lithiated methoxyallene to optically active N-benzyl-BOC-protected amino aldehydes followed by ozonolysis [2]. We anticipated that a modification of the N-protecting group could lead to predominant syn-configurated products and therefore we envisaged a synthesis of (2R,3S)-3-benzoylamino-2-hydroxy-3-phenylpropanoic acid (1) Abstract: Addition of lithiated methoxyallene 5 to literatureknown amino aldehyde 3 followed by ozonolysis provided syn-configurated α-hydroxy-β-amino ester 6 in moderate Lithiation of methoxyallene 4 was performed under standard conditions [6] in THF, and to the resulting solution of 5 freshly prepared aldehyde 3 was added to give a mixture of syn-2 (major) and anti-2 (minor). The best yield, highest ratio of diastereomers (85:15), and purity were obtained by reaction of 8 equivalents of 5 with 3 at -25 °C. Lower or higher temperatures and addition of cerium trichloride or diethylaluminum chloride as Lewis acids did not improve the result. Also, an attempt to generate a cuprate from 5 [7] was unsuccessful giving only an intractable product mixture after reaction with aldehyde 3. The crude product syn-2/anti-2 could not be purified, but after ozonolysis under standard conditions a mixture of methyl esters was obtained from which the desired syn-6 could be isolated in pure crystalline form in 28% overall yield. The optical rotation of 6 could be comoverall yield and with an ee of 90%. The predominant formation of syn-compounds may be due to a chelate controlled addition step.

Sugars, Alkaloids, and Heteroaromatics: Exploring Heterocyclic Chemistry with Alkoxyallenes

“…The preparation of spiroketals employs lithiated alkoxyallene as unsaturated acyl anion synthon a . The equivalency of lithiated alkoxyallenes to formyl anion synthon d or homoenolate e has been demonstrated earlier. ,, To our great delight, we also detected less obvious novel synthons, which guided us in unexpected directions (Figure ). The oxidative ring opening of dihydrofurans as described in Scheme demonstrates that lithiated alkoxyallenes are equivalent to the unusual malondialdehyde anion f .…”

Highly Diastereoselective Enolate Addition of O-Protected α-Hydroxyacetate to (SR)-tert-Butanesulfinylimines: Synthesis of Taxol Side Chain

“…The N ,O-protected isoseric acid and β-lactam were commonly used for the semi-synthsis of taxol. 2b,4l, With adduct 4c in hands, our attention was then focused on preparing the isoseric acid 9 and β-lactam 10 by selective manipulating of the protecting groups in 4c . Acid 9 and β-lactam 10 were readily synthesized by the following two steps.…”

“…For this reason, extensive efforts have been focused on semi-synthesis of taxol by the condensation of commercially available 14-β-hydroxy-10-deacetylbacctin III 2 with a side chain such as N -benzoyl-( 2R , 3 S )-3-phenylisoserine 3 (Figure ). Therefore, over the last 20 years, the efficient synthesis of enantiopure side chain 3 has attracted much attention from academic community as well as industry . In this article, we report a highly diastereoselective enolate addition of O -Boc-α-hydroxyacetate to benzylidene ( S R )- tert -butanesulfinamide to lead directly to the formation of N , O -protected ( S R ,2 R ,3 S )-3-phenylisoserine ester 4c in excellent yield.…”

A New Approach to Neuraminic Acid Analogues via 1,2-Oxazines

“…As shown in the retrosynthetic analysis (Scheme ), neuraminic acid analogue A can be obtained from protected α-ketoester B . The corresponding α-hydroxyester C should be available by chain elongation from aldehyde D by using lithiated alkoxyallene E as a C 1 building block . A primary amino alcohol which can be oxidized to the crucial aldehyde D is accessible from 1,2-oxazine F by hydrogenolysis as shown previously by our group .…”