Robert V. Hoffman

The preparation of 2-hydrazinyl esters in high optical purity from 2-sulfonyloxy esters

Abstract Chiral 2-triflyloxy esters, prepared from chiral 2-hydroxy esters, react enantiospecifically wilh BocNHNH 2 to produce optically pure 2-hydrazinyl ester derivatives in high yields. The reaction of 2-nosyloxy esters with BocNHNH 2 gives 2-(Bochydrazinyl) esters, thus providing an efficient (albeit slow) method for the conversion of esters to 2-hydrazinyl ester derivatives.

Preparation of (R)-2-azidoesters from 2-((p-nitrobenzene)sulfonyl)oxy esters and their use as protected amino acid equivalents for the synthesis of di- and tripeptides containing D-amino acid constituents

Abstract (R)-2-Azidoesters and their derived (R)-2-azido acids are readily prepared from common amino acids by an inversion methodology that employs (S)-2-nosyloxyesters as key intermediates. The (R)-2- azidoesters can be used as protected amino acid equivalents in peptide synthesis. Basic hydrolysis frees the carboxyl group. Triphenylphosphine/water is used to free the amine group. By these reactions a variety of L- D and D-L dipeptides,L-D-L tripeptides,and depsipeptides can be prepared easily in good yields, and without detectable epimerization.

Highly Stereoselective Synthesis ofanti-N-Protected-α-Amino Epoxides

A simple and efficient method for the synthesis of anti-N-protected amino epoxides from carbamate-protected amino acids is described. The two key steps are the monobromination of a beta-ketoester and chelation-controlled reduction of a bromomethyl ketone intermediate. Good overall yields, high diastereoselectivity, and excellent functional group compatibility are characteristic.

A simple, stereoselective synthesis of ketomethylene dipeptide isosteres

Abstract An exceedingly simple, general, and stereoselective method for the preparation of ketomethylene dipeptide isosteres (5-(carbobenzyloxyamino)-2-alkyl-γ-ketoesters) from Cbz-protected amino acids and scalemic 2-triflyloxy esters has been developed. The method is short (three steps), efficient, and highly diastereoselective and enantioselective.

A simple synthetic approach to Cbz-Phe-Ψ-(Ch2)-Gly-Pro-OMe and related Peptide Isosteres

Abstract A new approach to ketomethylene and hydroxymethylene peptide isosteres has been developed which is simple, direct, and highly convergent. A key feature is construction of the central bond of a ≥-keto ester by alkylation of a t-butyl β-keto ester with an ∠-bromo ester.

A new chiral alkylation methodology for the synthesis of 2-alkyl-4-ketoacids in high optical purity using 2-triflyloxy esters

Abstract Optical active 2-triflyloxy esters are excellent alkylating agents for β-ketoester enolates. Decarboxylation of the alkylation products gives 2-substituted-4-ketoacid derivatives in high optical purities.

Efficient synthesis of N-substituted lactams from (N-arylsulfonyloxy) amines and cyclic ketones

Abstract A new method is reported for the direct preparation of N-substituted lactams from cycloalkanones. N-(p-nitrobenzenesulfonoxyl) methylamine 1a (CH 3 NH-OSO 2 C 6 H 4 NO 2 ) was reacted with a series of cycloalkanones to give good yields of N-methyl lactams. An addition-rearrangement pathway accounts for the ring-expanded lactam products. A series of N-alkyl-N-arylsulfonoxyl amines were generated in situ and reacted with cyclobutanone to give N-alkyl pyrrolidinones in high yields.

A Stereocontrolled Synthesis of Monofluoro Ketomethylene Dipeptide Isosteres.

A simple, stereocontrolled synthesis of monofluoro ketomethylene dipeptide isosteres has been developed. N-Tritylated ketomethylene dipeptide isosteres, prepared from N-tritylated amino acids, are converted to their Z-TMS enol ethers and fluorinated with Selectfluor. There is cooperative stereocontrol between the N-tritylamine group and the alkyl group at C-2. The method is short (six steps), diastereoselective (85 --> 95%), and enantioselective (>95%).

A short, enantiospecific synthesis of a protected seco acid precursor to (R,R)-(−)-pyrenophorin

Abstract Described herein is a four-step enantiospecific synthesis of a protected seco acid precursor of (R,R)-(−)-pyrenophorin in 23% yield from a chiral β-ketoester 3 , which can be prepared in one step from ethyl acetoacetate by a standard procedure.

Generation of N-acyl iminium ions from ionization-rearrangement reactions of N-triflyloxy amides

Abstract N-Triflyloxy amides undergo ionization in refluxing isopropanol to give N-acyliminium ions which can be trapped by addition of allyltrimethylsilane to the reaction mixture. Alternatively they can be converted to N-(isopropoxy)alkyl amides and then back to N-acyliminium ions under a variety of conditions.