Catalytic Enantioselective Dihalogenation in Total Synthesis

Abstract

To date, more than 5000 biogenic halogenated molecules have been characterized. This number continues to increase as chemists explore chloride- and bromide-rich marine environments in search of novel bioactive natural products. Naturally occurring organohalogens span nearly all biosynthetic structural classes, exhibit a range of unique biological activities, and have been the subject of numerous investigations. Despite the abundance of and interest in halogenated molecules, enantioselective methods capable of forging carbon-halogen bonds in synthetically relevant contexts remain scarce. Accordingly, syntheses of organohalogens often rely on multistep functional group interconversions to establish carbon-halogen stereocenters. Our group has developed an enantioselective dihalogenation reaction and utilized it in the only reported examples of catalytic enantioselective halogenation in natural product synthesis. In this Account, we describe our laboratory's development of a method for catalytic, enantioselective dihalogenation and the application of this method to the synthesis of both mono- and polyhalogenated natural products. In the first part, we describe the initial discovery of a TADDOL-mediated dibromination of cinnamyl alcohols. Extension of this reaction to a second-generation system capable of selective bromochlorination, dichlorination, and dibromination is then detailed. This system is capable of controlling the enantioselectivity of dihalide formation, chemoselectivity for polyolefinic substrates, and regioselectivity in the case of bromochlorination. The ability of this method to exert control over regioselectivity of halide delivery permits selective halogenation of electronically nonbiased olefins required for total synthesis. In the second part, we demonstrate how the described dihalogenation has provided efficient access to a host of structurally diverse natural products. The most direct application of this methodology is in the synthesis of naturally occurring vicinal dihalides. Chiral vicinal bromochlorides represent a class of >175 natural products; syntheses of five members of this class, including its flagship member, (+)-halomon, have been accomplished through use of the catalytic, enantioselective bromochlorination. Likewise, enantioselective dichlorination has provided selective access to two members of the chlorosulfolipids, a class of linear, acyclic polychlorides. Synthesis of chiral monohalides has been achieved through solvolysis of enantioenriched bromochlorides; this approach has resulted in the synthesis of five bromocyclohexane-containing natural products through an enantiospecific bromopolyene cyclization. In reviewing these syntheses, a framework for the synthesis of chiral organohalogens mediated by catalytic, enantioselective dihalogenation has emerged. The development of a selective dihalogenation method has been highly enabling in the synthesis of halogenated natural products. In this Account, we detail all examples of catalytic, enantioselective halogenation in total synthesis and encourage the further development of synthetically useful halogenation methodologies.

Figure 1

First-Generation Enantioselective Dibromination Design Principles.

Figure 2

Rational Design of a Second-Generation Dihalogenation Platform.

Figure 3

Mechanistic Rationale for Dihalide Stability.

Scheme 1

Selectivity Challenges Associated with Enantioselective Dihalogenation of Alkenes.

Scheme 2

First-Generation System for Enantioselective Dibromination.

Scheme 3

Scope of Catalytic Enantioselective Bromochlorination.

Scheme 4

Proposed Catalytic Cycle for Bromochlorination of Allylic Alcohols.

Scheme 5

Dibromination and Dichlorination with Second-Generation System.

Scheme 6

Syntheses of (+)-Halomon, (+)-Bromochloromyrcene, (−)-Anverene, (−)-Isoplocamenone, and (−)-Plocamenone.

Scheme 7

Synthesis of (−)-Deschloromytilipin A.

Scheme 8

Comparison of Synthetic Strategies for (−)-Danicalipin A.

Scheme 9

Synthesis of (−)-Danicalipin A.

Scheme 10

Summary of Strategies for Catalytic, Enantioselective Dihalogenation in Synthesis.

Scheme 11

A Solvolytic Approach to Monobrominated Natural Products.