A Catalytic Approach for Enantioselective Synthesis of Homoallylic Alcohols Bearing a Z-Alkenyl Chloride or Trifluoromethyl Group. A Concise and Protecting Group-Free Synthesis of Mycothiazole

Abstract

A protecting group-free strategy is presented for diastereo-and enantioselective routes that can be used to prepare a wide variety of Z-homoallylic alcohols with significantly higher efficiency than is otherwise feasible. The approach entails the merger of several catalytic processes and is expected to facilitate the preparation of a wide range of bioactive organic molecules. More specifically, Z-Chloro-substituted allylic pinacolatoboronate is first obtained through stereoretentive cross-metathesis between Z-crotyl-B(pin) (pin = pinacolato) and Z-dichloroethene, both of which are commercially available. The organoboron compound may then be used in the central transformation of the entire approach, namely, an α-, and enantioselective addition to an aldehyde, catalyzed by a proton-activated, chiral aminophenol-boryl catalyst. Catalytic crosscoupling can then furnish the desired Z-homoallylic alcohol in high enantiomeric purity. The olefin metathesis step can be carried out with substrates and a Mo-based complex that can be purchased. The aminophenol compound that is needed for the second catalytic step can be prepared in multi-gram quantities from inexpensive starting materials. A significant assortment of homoallylic alcohols bearing a Z-F 3 C-substituted alkene can be prepared with similarly high efficiency and regio-, diastereo-, and enantioselectivity. What is more, trisubstituted Z-alkenyl chloride moiety can also be accessed with similar efficiency albeit with somewhat lower αselectivity and enantioselectivity. The general utility of the approach is underscored by a succinct and protecting group-free, and enantioselective total synthesis of mycothiazole, a naturally occurring anticancer agent through a sequence that contains a longest linear sequence of nine steps (12 steps total), seven of which are catalytic, and generates mycothiazole in 14.5% overall yield.

Regio‐ and Enantioselective Synthesis of Trifluoromethyl‐Substituted Homoallylic α‐Tertiary NH2‐Amines by Reactions Facilitated by a Threonine‐Based Boron‐Containing Catalyst

“…The above findings insinuated that it might be possible to exploit steric factors to improve e.r. We recently showed that additions of Z ‐disubstituted allyl boronates to ketones or aldehydes are more enantioselective probably because the substituent at the stereogenic carbon center of the chiral allyl boronate (e.g., Me unit in VI , Scheme a) prefers to be oriented pseudo‐axially, away from the catalyst framework . Accordingly, we investigated the reaction with Z ‐crotyl–B(pin) (( Z )‐ 3 ).…”

“…We opted for aminophenol‐based boryl systems to serve as catalysts. These are easy to prepare and modifiable entities that at the time had been used for enantioselective additions to aldimines, ketones, and aldehydes, but not the far less reactive NH‐ketimines.…”

“…We thus chose to investigate N-trimethylsilyl ketimines,s table entities accessible in multigram quantities by reactions between ketones and lithium bis(trimethylsilyl)amide (1.5 h, 50-95 %y ield) [11] in sufficiently high purity for N-trimethylsilyl ketimines to be directly usable (no purification). Whether in situ NHketimine formation would occur readily or the minimally electrophilic NH-ketimines would react efficiently and enantioselectively,w ed id not know.W eo pted for aminophenolbased boryl systems to serve as catalysts.T hese are easy to prepare and modifiable entities that at the time had been used for enantioselective additions to aldimines, [12] ketones, [13] and aldehydes, [14] but not the far less reactive NH-ketimines.…”

Metathesis Reactions in Natural Product Fragments and Total Syntheses

“…Hoveyda, Romiti, and co‐workers developed the protecting group free and concise total synthesis of mycothiazole 1033 (Scheme 160). [342] In this vital synthetic approach, stereoretentive CM was one of the key steps utilized to forge the compound 1032 with Z ‐selectivity. Negishi‐type coupling between vinyl chloride 1028 and boronate 1029 in presence of Pd‐catalyst facilitated the triene derivative 1030 , which was then subjected to stereoretentive cross CM with Z ‐alkene 1031 in presence of Grubbs catalyst 7 to deliver a primary alcohol 1032 in 77% yield with >98% Z ‐selectivity.…”

Copper-Catalyzed Highly Enantioselective 1,4-Protoboration of Terminal 1,3-Dienes

“…Due to the utility of allylic boron reagents in organic synthesis, chemists are increasingly attentive to their preparations. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] Usually, basic main-group organometallics, such as organolithium or Grignard reagent, are necessary for traditional methods to make allylboranes. [19][20][21][22][23][24][25] The disadvantage of these strategies is their incompatibility with electrophilic functional groups.…”