Short, Enantioselective Total Synthesis of Highly Oxidized Taxanes

Abstract

In the realm of natural product chemistry, few isolates have risen to the level of fame justifiably accorded to Taxol (1) and its chemical siblings. This report describes the most concise route to date for accessing the highly oxidized members of this family. As representative members of taxanes containing five oxygen atoms, decinnamoyltaxinine E (2) and taxabaccatin III (3), have succumbed to enantioselective total synthesis for the first time in only 18 steps from a simple olefin starting material. The strategy holistically mimics natures approach (two-phase synthesis) and features a carefully choreographed sequence of stereoselective oxidations and a remarkable redox-isomerization to set the key trans-diol present in 2 and 3. This work lays the critical groundwork necessary to access even higher oxidized taxanes such as 1 in a more practical fashion, thus empowering a medicinal chemistry campaign that is not wedded to semi-synthesis.[ + ] These authors contributed equally.Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under http://dx.

Synthesis of a Biomimetic Tetracyclic Precursor of Aspochalasins Allowing a Formal Synthesis of Trichoderone A

“…In conclusion, we were able to perform the synthesis of a key synthetic precursor (5) of tetracyclic aspochalasan natural products and derivatives, the structure of which could be confirmed by X-ray analysis of an epoxide product (26). Compound 5 constitutes a good entry to perform the "oxidase" phase in the bio-inspired synthesis of natural products such as trichoderone A (3) and trichodermone (4). In particular, this work constitutes a formal synthesis of 3.…”

“…General remarks (1S,2R)-1,2-Dihydroxy-1-methylcycloheptane (13) (2S)-2-Trimethylsilyloxy-2-methylcycloheptan-1-one (15) (7S)-7-Hydroxy-7-methyl-1-trifluoromethanesulfonyloxycyclohept-1-ene (12) (7S)-7-Acetoxy-7-methyl-1-trifluoromethanesulfonyloxycyclohept-1-ene (16) (7S)-7-Acetoxy-7-methyl-1-[(1E,3E)-3-methylpenta-1,3-dien-1-yl]cyclohept-1-ene (10), as a 4:1 mixture with the 1Z isomer 1E,3E)-3-methylpenta-1,3-dien-1-yl)cyclohept-2-en-1-yl]acetyl}-3phenylselenyl-2-pyrrolidone (mixture of stereoisomers 23) (3S,3aR,4S,6aS,8aS,13bR)-5-Benzoyl-4-isobutyl-2,3,13-trimethyl-4,5,8,8a,9,10,11,12-octahydro-3Hcyclohepta [3,4]benzo [1,2-d]isoindole-6,7(3aH,13bH)-dione (endo product 24) (3R,3aR,4S,6aS,8aS,13bS)-5-Benzoyl-4-isobutyl-2,3,13-trimethyl-4,5,8,8a,9,10,11,12-octahydro-3Hcyclohepta [3,4]benzo [1,2-d]isoindole-6,7(3aH,13bH)-dione (exo product 25) (3S,3aR,4S,6aS,8aS,13bR)-4-Isobutyl-2,3,13-trimethyl-4,5,8,8a,9,10,11,12-octahydro-3H-cyclohepta [3,4]benzo [1,2d]isoindole-6,7(3aH,13bH)-dione (5) (3S,3aR,4S,6aS,8aS,13R,13aR,13bR)-5-Benzoyl-13,13a-epoxy-4-isobutyl-2,3,13-trimethyl-4,5,8,8a,9,10,11,12-octahydro-3Hcyclohepta [3,4]benzo [1,2-d]isoindole-6,7(3aH,13bH)-dione (26) (3S,3aR,4S,6aS,8aS,13S,13aS,13bR)-5-Benzoyl-13,13a-epoxy-4-isobutyl-2,3,13-trimethyl-4,5,8,8a,9,10,11,12-octahydro-3Hcyclohepta [3,4]…”

“…1 This intermediate is then engaged in a second stage involving functional decorations, also called "oxidation phase" when it comes to selective oxidative functionalization, which aims to produce the final natural products. Highly complex natural products have been achieved by this strategy, [1][2][3][4][5][6][7][8][9] with the two-phase synthesis of taxol recently achieved by Baran and co-workers standing as a feat in total synthesis. 10 These examples most often concern terpenoids, while biosynthetic oxidative functionalizations are ubiquitous in natural products.…”

Concise Construction of the ACDE Ring System of Calyciphylline A Type Alkaloids by a [5+2] Cycloaddition

“…Consideringt he yield andr eaction time, DABCO was employed as ab ase for further investigations.C ombining DABCO with acetic acid instead of TFAr esulted in al ower yield (entry 13). Various oxidation conditions, including H 2 O 2 / HCO 2 H, [18] MoO 5 ·pyridine complex, [19] and PhNO, [20] were tested, but compound 25 did not react at all under these conditions. These results indicated that the bulkiness and basicity of the amine werei mportant for this [5+ +2] cycloaddition.N otably, this established sequence including a[5+ +2] cycloaddition readily furnished the ADE ring core bearingt he spiro structure and vicinal quaternary carbon centers from commerciallya vailable materialt hrough eight steps and three purifications using silica gel chromatography.…”

“…Intramolecular nucleophilic attack of the amine was used to form unstablee naminone 24,w hich was then trapped using CbzCl as ad ienamide 25 in 72 %y ield. Various oxidation conditions, including H 2 O 2 / HCO 2 H, [18] MoO 5 ·pyridine complex, [19] and PhNO, [20] were tested, but compound 25 did not react at all under these conditions. Furthermore, using 3-chloroperoxybenzoic acid (mCPBA) [21] or NBS [22] resulted in the decomposition of startingm aterial 25.…”