Chelation-Controlled Additions to Chiral α- and β-Silyloxy, α-Halo, and β-Vinyl Carbonyl Compounds

Abstract

The science and art of preventing and managing disease and prolonging life is dependent on advances in medicine, biology, and biochemistry. Many of these advances will involve interactions of small molecules with biological entities. As such, they will rely on the efficient synthesis of active compounds with very high stereochemical purity. Although enantioselective reactions are important in this regard, most stereocenters in complex molecule synthesis are installed in diastereoselective reactions. Perhaps the most well-known diastereoselective C-C bond-forming reaction is the addition of nucleophiles to carbonyl groups with α- or β-stereogenic centers. Diastereoselective additions of organometallic reagents to protected chiral α- and β-hydroxy aldehydes and ketones are described by either Cram chelation or Felkin-Anh models, which are protecting group (PG)-dependent. Small PGs (X = OMOM, OBn, etc.) favor Cram chelation, wherein both the carbonyl group and the O-PG bind to the Lewis acidic metal, providing syn diol motifs. In contrast, silyl PGs, with the OSiR moiety being both bulky and weakly coordinating, provide anti diols (Felkin addition). It is well-known that exceptions to this paradigm are scarce. Therefore, the choice of PG is based on the desired stereochemical outcome in the addition step and is often inappropriate for the global protection strategy. Thus, it is critical to develop general methods for chelation-controlled additions of organometallics to chiral silyloxy aldehydes and ketones. Once the challenge of developing chelation-controlled additions to silyloxy carbonyl compounds can be met, the next question is what other pendant functional groups can chelate? Herein we introduce the first general methods for the chelation-controlled addition of organometallics to chiral silyloxy aldehydes and ketones. A wide variety of organozinc reagents have been used in these addition reactions, including dialkylzinc reagents that are commercially available or generated using Knochel's methods. Existing protocols for the generation of (E)-di- and -trisubstituted vinylzinc reagents have been employed, and new methods for the generation of (Z)-di- and -trisubstituted vinylzinc reagents have been developed. The generation of 1,1-heterobimetallic reagents based on boron and zinc has been advanced, and the addition of these reagents to silyloxy aldehydes via chelation-control is included. We will first describe the initial discovery and a model to explain the observed diastereoselectivities. A wide array of chelation-controlled additions to chiral α- and β-silyloxy aldehydes and ketones will then be presented. We next describe other functional groups that undergo chelation-controlled additions. α-Halo aldehyde derivatives are well-known to favor Felkin addition (via the Cornforth-Evans model). We introduce a general method for chelation-controlled additions to α-halo aldimines that provides useful precursors to aziridines. Finally, we provide preliminary evidence that even C═C bonds can play the role of chelatin...

Reactions of Allylmagnesium Reagents with Carbonyl Compounds and Compounds with C═N Double Bonds: Their Diastereoselectivities Generally Cannot Be Analyzed Using the Felkin–Anh and Chelation-Control Models

“…In this section, examples of chelation-controlled and nonchelation-controlled additions are documented. These examples will focus on reactions of allylmagnesium reagents; the studies of chelation-controlled additions by other organometallic reagents such as organotitanium or organozinc reagents have been reported elsewhere. − …”

“…By contrast, addition of allylmagnesium bromide gave low stereoselectivity (the configuration was determined after conversion to a cyclic product). Chelated transition states are unlikely, considering that, for most organometallic reagents, chelation to a bulky silyloxy group is normally disfavored 236 (although chelation can be favored with zinc reagents 98,187 ).…”

Synthesis of Enantioenriched (Z)-Disubstituted Allylic Alcohols via Ru-Catalyzed Selective Dehydrogenation

“…Enantioenriched ( E )-allylic alcohols have been readily available through either Sharpless–Katsuki asymmetric epoxidation-based kinetic resolution (KR) or various catalytic asymmetric vinylation protocols of carbonyl compounds. , In contrast, these similar methods were not applicable to prepare enanrioenriched allylic alcohols with thermodynamically less favored ( Z )-alkenes due to the presence of severe allylic strain, and thus, enantioselective syntheses of ( Z )-allylic alcohols are much less developed. Walsh and co-workers reported the a highly efficient generation of ( Z )-disubstitued organometallic vinyl intermediates, which undergoes enantioselective addition to aldehydes, and thus a variety of enantioenriched ( Z )-allylic alcohols can be accessed (Figure a) . Other methods to generate enantioenriched ( Z )-allylic alcohols or analogues include Lindlar hydrogenations of enantioenriched propargylic alcohols, Z -selective cross metathesis of enantioenriched terminal allylic ethers, and Rh-catalyzed reductive coupling of alkynes to α-ketoesters .…”

Synthesis of 1,4- and 1,5-Amino Alcohols via Nucleophilic Addition of Semicyclic N,O-Acetal with Organozinc Reagents

“…In the past decade, functionalized organozinc reagents, which were easily prepared through an insertion reaction of zinc metal into various substituted organic halides, have demonstrated many advantages in modern organic synthesis . Many useful transformations from functionalized organozinc reagents were successfully realized through the addition to carbonyl and nitrones, as well as addition–elimination or addition–migration . More recently, a coupling reaction of organozinc reagents with N , O -acetals was reported .…”