Diastereodivergent Catalysis

Abstract

Alongside enantioselective catalysis, synthetic chemists are often confronted by the challenge of achieving catalyst control over the relative configuration to stereodivergently access desired diastereomers. Typically, these approaches iteratively or simultaneously control multiple stereogenic units for which dual catalytic methods comprising sequential, relay, and synergistic catalysis emerged as particularly efficient strategies. In this Perspective, the benefits and challenges of catalyst-controlled diastereodivergence in the construction of carbon stereocenters are discussed on the basis of illustrative examples. The concepts are then transferred to diastereodivergent catalysis for atropisomeric systems with twofold and higher-order stereogenicity as well as diastereodivergent catalyst control over E- and Z-configured alkenes.

Figure 1

Key concepts in diastereodivergent catalysis: (A) enzyme catalyzed stereodivergent aldol reaction in gluconeogenesis, (B) schematic energy profiles of an enantioselective and a diastereodivergent reaction, (C) catalytic concepts applied in diastereodivergent catalysis, (D) permutations of catalyst configurations give rise to four stereoisomers in a diastereodivergent dual catalytic reaction, and (E) Horeau principle for the e.r. amplification in a sequence of two stereoselective reactions.

Scheme 1. Iterative Diastereodivergent Control over Deoxypolypropionate Chains by a Conjugate Addition–Chain Prolongation Sequence

Scheme 2. Diastereodivergent Access to Polypropionate Chains by Stepwise Construction of Vicinal Stereocenters

dbcot = dibenzo[a,e]cyclooctene; HG-II = Hoveyda–Grubbs catalyst II; PMP = p-methoxyphenyl.

Scheme 3. Diastereodivergent Aldol Addition Using One Chiral Catalyst for Simultaneous Control over Two Stereocenters

Scheme 4. Representative Examples for Diastereodivergent Catalysis

(A) Pd-catalyzed access to all cyclobutene stereoisomers from racemic starting material and (B) organocatalytic diastereodivergent thia-Michael addition.

Scheme 5. Diastereodivergent Synthesis of Nonproteogenic α-Amino Acids under Aldehyde Catalysis

Scheme 6. Cu-Catalyzed Coupling of 2-Azatriene 27 and Imine 28 Leads to Diastereodivergent Control over 1,2-Diamine 29

Scheme 7. Directed Evolution Enables Diastereodivergent Biocatalysis

(A) Aldol addition and (B) atom transfer radical cyclization.

Scheme 8. Diastereodivergent Sequential Iminium–Enamine Catalysis

Scheme 9. Sequential Dual Catalysis Using Two Chiral Metal Complexes for Stereoselective Allylation and Conjugate Addition

Scheme 10. Relay Catalysis Cascade in the Stereodivergent C–H functionalization/Oxa-Michael Addition between 47 and 48

Scheme 11. Metal–Organo Synergistic Dual Catalysis for Diastereodivergent Reaction Control

(A) Concept, (B) pioneering study on the α-allylation of aldehydes, and (C) diastereodivergent synthesis of amines and alcohols. Pfp = perfluorophenyl.

Scheme 12. Metal–Metal Synergistic Dual Catalytic Systems for the α-Allylation of Carbonyl Compounds

(A) Concept, (B) pioneering Zn/Ir-catalysis, and (C) application in the synthesis of natural products.

Scheme 13. Organo–Organo Synergistic Dual Catalysis Enables Stereodivergent Michael Addition

PfP = perfluorophenyl.

Scheme 14. Iterative Diastereodivergent Control over Oligonaphthylenes with Four Stereogenic Axes by Atroposelective Aldol Condensations

IBX = 2-iodoxybenzoic acid.

Scheme 15. Diastereodivergent Synthesis of Dual Axis Systems Using Sequential Catalyst Control

(A) Sequential double kinetic resolution and (B) diastereodivergent formation of stereocenters and stereospecific oxidation to the atropisomeric system. NCS = N-chlorosuccinimide.

Scheme 16. Diastereodivergent Synthesis of a Dual Axis System 88 by Arene-Forming Aldol Condensations

Scheme 17. Stepwise Diastereodivergent Construction of a Tertiary Stereocenter and a Stereogenic C–N Axis

Scheme 18. Sequential Dual Catalysis for the Stereodivergent Control over Atropisomeric Hydrazides with a Quaternary Carbon Stereocenter

Scheme 19. Diastereodivergent and Enantioselective Arene Formation by [2+2+2] Cycloaddition Giving Rise to Sixfold Stereogenic C(sp²)–C(sp³) Atropisomers

Scheme 20. Catalyst-Controlled Access to All Three Stereoisomers of Atropisomeric Sulfone 98 with a Stereogenic C–S Axis

CHP = cumene hydroperoxide.

Scheme 21. Direct Catalyst Control of the Double Bond Configuration in 1,3-Dienes