Asymmetric Aldol Reaction of Thiazole‐Carbaldehydes: Regio‐ and Stereoselective Synthesis of Tubuvalin Analogues

Abstract

The first organocatalytic enantioselective approach to precursors of tubuvaline (pre-Tuv) is presented employing a prolinamide-catalyzed aldol reaction of easily accessible thiazole-carbaldehyde with methyl isopropyl ketone "on water" in excellent yield as well as regio-and enantioselectivities. The analogues of pre-Tuv were achieved using an lproline-catalyzed direct asymmetric aldol reaction of substituted thiazole-carbaldehydes with acetone. A direct and flexible approach to the tubavaline (Tuv) core of tubusylins has been established employing the reductive amination of the pre-Tuv species. The key aldol reaction should greatly expand the potential of this strategy to the synthesis of natural product tubulysins and a range of analogues.Scheme 2. Synthesis of tubuvaline analogues.

Stereoselective access to tubuphenylalanine and tubuvaline: improved Mn-mediated radical additions and assembly of a tubulysin tetrapeptide analog

“…We disclosed our initial studies directed toward synthesis of the tubulysins in 2004, 7 and the first total syntheses were achieved by Ellman (tubulysin D, 2006) 8 and Zanda (tubulysins U and V, 2007). 9 Despite numerous synthetic efforts (which have been reviewed 10 , 11 , 12 and continue to emerge 13 , 14 , 15 ), accessing both of the γ-amino acid subunits tubuvaline (Tuv, Scheme 1 ) and tubuphenylalanine (Tup) with excellent stereocontrol has proven to be a difficult challenge. Prior tubulysin syntheses have been hampered by limited stereoselectivity in alkene or ketone reductions to generate the requisite configuration at the α carbon of the γ-amino acids.…”

Diastereocontrol in Radical Addition to β-Benzyloxy Hydrazones: Revised Approach to Tubuvaline and Synthesis of O-Benzyltubulysin V Benzyl Ester

“…After 2 h at −78 °C, triethylamine (0.086 mL, 0.63 mmol) was added, and the temperature was allowed to rise to 0 °C over a period of 2 h. The reaction mixture at 0 °C was then diluted using 0.3 mL anhydrous ethyl alcohol followed by addition of cysteine methyl ester hydrochloride (18 mg, 0.1 mmol). After 12 h, concentration and flash chromatography (1:1 petroleum ether/ethyl acetate) afforded 35 (24 mg, 77% yield, mixture of diastereomers) as pale yellow oil: (2S,4R)-4-(tert-Butoxycarbonylamino)-2-methyl-5-phenyl-1-pentanol (37). A solution of trifluoroacetyl amino alcohol 36 48 (57 mg, 0.02 mmol) in a suspension of methanol−water (9.5 mL, 5:1) was cooled to 0 °C followed by addition of Ba(OH) 2 •8H 2 O (124 mg, 0.39 mmol).…”

“…The C11 configuration has been addressed by stereocontrolled enolate oxidation, 28 , 29 metalloenamine aldol addition, 30 thiazolyl anion addition, 31 hydride reduction, 32 − 35 hetero-Diels–Alder reactions, 36 and proline-catalyzed aldol reactions. 37 An interesting multicomponent coupling reaction (MCR) rapidly built both C11 and the thiazole, albeit with modest stereocontrol 38 , 39 that was later improved via a catalytic asymmetric Passerini reaction. 40 Most Tuv syntheses begin with precursors having the C13 chiral amine already established from various valine derivatives and their homologues.…”

“…In the diverse slate of creative strategies to prepare Tuv, the main innovations tend to focus on stereocontrol issues (known to impact activity) at the hydroxyl- or acetoxy-bearing center at C11, stereocontrol at the C13 chiral amine, and introduction of the thiazole. The C11 configuration has been addressed by stereocontrolled enolate oxidation, , metalloenamine aldol addition, thiazolyl anion addition, hydride reduction, − hetero-Diels–Alder reactions, and proline-catalyzed aldol reactions . An interesting multicomponent coupling reaction (MCR) rapidly built both C11 and the thiazole, albeit with modest stereocontrol , that was later improved via a catalytic asymmetric Passerini reaction .…”

Recent Advances in Sustainable Organocatalysis

“…The yields varied in the range of 38-88%, being lower with more demanding substrates (67-96% ees). In the same year, Dash developed a novel approach to obtain tubuvaline precursors based on a prolinamide 24 catalysed aldol reaction of thiazole carbaldehydes with ketones 'on water' [36]. Tubuvalin is the core structure of a family of tetrapeptides, the tubulysins, which are the most potent anti-cancer agents known so far.…”