Rhodium(I)-Catalyzed O-H Insertions on O-Protected α-Diazo-ß-Hydroxyesters.

The X-H insertion reaction constitutes a powerful tool to create diversity through the diazo decomposition of diazocarbonyl compounds. However, until now, X-H insertion on α-diazo-ß-aryl-ß-hydroxyester scaffolds, readily prepared by aldol-type addition, remained a challenge for the organic chemist. We report herein the first O-H insertions on O-protected α-diazo-ß-aryl-ß-hydroxyesters, providing straightforward access to a wide range of α,ß-dioxygenated esters through modulation of the alcohol and of the aryl substituent. The key feature to achieving this transformation is the use of Rh(I) catalysts, which proved to be crucial to favor the targeted O-H insertion product over the competing 1,2-H and 1,2-Ar migration products. Overall, 32 O-H insertion products have been prepared, in moderate to good yields, with a diastereoisomeric ratio up to 7.5:1 in favor of the syn diastereoisomer.

Acid-Catalyzed Decomposition of O-Silylated α-Diazo-ß-hydroxy Esters: Access to Mixed Monosilyl Acetals.

Acid-catalyzed decomposition of diazocarbonyl compounds triggers a wide range of transformations leading to synthetically useful building blocks with high diversity. In this field, the chemistry of α-diazo-ß-hydroxy ester substrates is largely dominated by migration processes. We describe herein a new approach to original mixed monosilyl acetals from O-protected α-diazo-ß-hydroxy-ß-aryl esters and alcohols, catalyzed by trimethylsilyl trifluoromethanesulfonate (TMSOTf). The ratio between these original mixed acetals, the symmetric acetals, and the migration products fluctuates depending on the catalyst, the nature of the alcohols, and the substituent on the aromatic ring. Fifty-six examples are reported herein with yields up to 71% and diastereoselectivity up to 6:1. Such mixed monosilyl acetals constitute a synthetic equivalent of α-substituted ß-oxoesters with high potential for further transformations.

TIPS-Diazoacetone Aldol Addition: Mechanistic Aspects and Contribution to the Synthesis.

Aldol addition of α-triisopropylsilyl-α-diazoacetone (TIPS-diazoacetone), promoted by excess lithium diisopropylamide (LDA), was developed and applied to the synthesis of original C-TIPS diazoaldols, C-TIPS diazoketols, and a related Mannich-type product. An unprecedented mechanistic pathway has been proposed, involving a lithiated triazene intermediate resulting from the nucleophilic addition of LDA on the diazo moiety, supported by experimental results and DFT calculations.

Function-Oriented Synthesis toward Peloruside A Analogues.

A convergent and rapid synthesis of original C2,C3-unsaturated, C11,C13-keto-enol macrocycles with a peloruside A skeleton has been developed. These original unsaturated macrocycles constitute valuable platforms to access peloruside A analogues with high diversity. The four-fragment strategy implemented features two aldol-type couplings with the central C12-C14 building block TES-diazoacetone and a late-stage ring-closing metathesis. Enantiopure analogue 18ab showed antiproliferative activity in the low micromolar range on NCI and MCF7 tumor cell lines.

TBAF-Triggered Aldol-Type Addition of α-Triethylsilyl-α-diazoacetone.

Aldol-type addition of α-triethylsilyl-α-diazoacetone was achieved under nucleophilic activation by tetrabutylammonium fluoride (TBAF). The use of a semistoichiometric amount of TBAF (protocol P1) provided the corresponding ß-hydroxy-α-diazoacetone as the sole product. Alternatively, the use of a catalytic amount of TBAF led to a mixture of ß-hydroxy- and ß-silyloxy-α-diazoacetone products, which was cleanly desilylated with Et3N·3HF (protocol P2). The weakly basic conditions employed tolerate a wide range of substrates and constitute a high-yielding, convenient complementary procedure to the low-temperature LDA-promoted aldol-type addition of diazoacetone.

Tandem Payne/Meinwald versus Meinwald rearrangements on the α-hydroxy- or α-silyloxy-spiro epoxide skeleton.

Under Lewis acid activation, the new α-hydroxy-spiro epoxide scaffold 1a underwent an original tandem Payne/Meinwald rearrangement affording the cyclopentyl hydroxymethylketone 6 in a stereospecific manner, while a Meinwald-type epoxide rearrangement occurred when the derived α-trimethylsilyloxy-spiro epoxide 2a was treated with MABR, yielding stereoselectively the cyclohexane carbaldehyde 9.