Kenzo Yahata

Reversing the Reactivity of Carbonyl Functions with Phosphonium Salts: Enantioselective Total Synthesis of (+)‐Centrolobine

The control of chemoselective transformations irrespective of the individual reactivity of functional groups still remains a largely unanswered challenge. Carbonyl groups, such as aldehydes and ketones, are without doubt the most important functional groups in organic chemistry and their reactions are well known. The order of the reactivity of carbonyl groups toward nucleophiles is generally aldehyde> ketone> ester. Therefore, it is easy to react an aldehyde in the presence of ketones and esters. In contrast, it is difficult to react a ketone prior to an aldehyde. Therefore, protective groups have to be employed for such transformations, which thus become intrusive three-step operations that involve the protection of the aldehyde, transformation of the ketone, and deprotection of the aldehyde. The reversal of the reactivity of functional groups is a challenging theme in chemistry and there are few reports on such transformations. Luche and Gemal reported pioneering and representative work, in which a ketone was selectively reduced in the presence of an aliphatic aldehyde. The conversion of the aldehyde into an acetal, the subsequent reduction of the ketone with NaBH4, and the deacetalization were carried out in one pot by using the CeCl3–MeOH–NaBH4 system. However, this reaction was limited to reductions and is difficult to apply to other reactions. Other methods, such as the use of metal amides, a bulky Lewis acid, and a copper catalyst with a bulky phosphine ligand, were reported. However, these methods have drawbacks, such as lower generality, the need to prepare special reagents, and strict control of stoichiometry because of the use of highly reactive reagents. Therefore, more practical and facile methods for the selective transformation of carbonyl groups are required. Herein we report the convenient and versatile selective one-pot transformation of less-reactive carbonyl groups in the presence of aldehydes (or ketones) by using the combination of PPh3 (or PEt3) and TMSOTf to selectively mask the aldehyde prior to the addition of the nucleophile (Scheme 1). The asymmetric transformation of a less-reactive carbonyl group in the presence of a more-reactive carbonyl group was also accomplished, and was applied to the short asymmetric total synthesis of (+)-centrolobine.

Selective transformations of carbonyl functions in the presence of α,β-unsaturated ketones: concise asymmetric total synthesis of decytospolides A and B.

Enones selectively react with a combination of PPh(3) and TMSOTf to produce phosphonium silyl enol ethers, which work as protective groups of enones during the reduction of other carbonyl functions and can be easily deprotected to regenerate parent enones at workup. Furthermore, the first ketone selective alkylations in the presence of enones were also accomplished. This in situ protection method was applied to concise asymmetric total syntheses of decytospolides A and B.

A concise and unified strategy for synthesis of the C1-C18 macrolactone fragments of FD-891, FD-892 and their analogues: formal total synthesis of FD-891.

A concise and unified strategy for the synthesis of C1-C18 macrolactone fragments of FD-891 and FD-892 as well as their analogues is reported. The strategy includes a stereoselective vinylogous Mukaiyama aldol reaction (VMAR) using chiral silyl ketene N,O-acetal to construct C6-C7 stereocenters, an E-selective ring closing metathesis to construct a C12-C13 olefin, and stereodivergent construction of a C8-C9 epoxide.

Novel Regiocontrolled Protection of 1,2- and 1,3-Diols via Mild Cleavage of Methylene Acetals

The regiocontrolled protection of unsymmetrical 1,2- and 1,3-diols has been developed. Different types of protected diols are available from the methylene acetal in a one-pot procedure. Highly regioselective protection of diols with a silyl group at the less hindered hydroxy group as well as with a MOM group at the more hindered one were achieved. The reaction conditions are mild without affecting other functional groups including acid-labile function.

Fe/Cu-Mediated One-Pot Ketone Synthesis

An Fe/Cu-mediated one-pot ketone synthesis was reported. Unlike Ni- and Pd-mediated one-pot ketone syntheses, the reported Fe/Cu-mediated method allowed selective activation and coupling of alkyl iodides over vinyl iodides. The newly developed one-pot ketone synthesis was applied to a synthesis of vinyl iodide/ketone 13, the left half of halichondrin B, as well as vinyl iodide/ketone 8a, the C20-C26 building block of halichondrins.

Unified Synthesis of Right Halves of Halichondrins A-C

The right halves of halichondrins A-C were synthesized by coupling the common C20-C37 building block 9 with the C1-C19 building blocks 10a-c, respectively. Catalytic, asymmetric Ni/Cr-mediated coupling was used for three C-C bond formations. For all cases, the stereochemistry was controlled with the Cr catalyst prepared from the chiral sulfonamide identified via the toolbox approach. For (3 + 4)-, (6 + 7)-, and (9 + 10)-couplings, the stereoselectivity of 28:1, >40:1, and ∼20:1 was achieved by the Cr catalysts prepared from (S)-H, (S)-I, and (R)-L, respectively. Unlike the first and second couplings, the third coupling used the structurally complex nucleophile. It was demonstrated that the coupling efficiency was excellent even with the electrophile/nucleophile molar ratio = 1.0/1.1. In addition, the third coupling was achieved with the substrate bearing a free hydroxyl group. The products obtained in the Ni/Cr-mediated couplings were converted to the right halves of halichondrins A-C in excellent overall yields. The right halves of halichondrins A-C (1a-c) were synthesized in 28, 24, and 24 steps from commercial d-galactal in 13.4%, 21.1%, and 16.7% overall yield, respectively.

Stereocontrolled Synthesis of Left Halves of Halichondrins

A stereocontrolled synthesis of the left halves of halichondrins was reported. An intramolecular oxy-Michael reaction under basic conditions was used to construct the [6,6]-spiroketal in a stereocontrolled manner. With this approach, the left halves of halichondrins, homohalichondrins, and norhalichondrins were synthesized.