Peter A. Wade

Intramolecular 1,3-Dipolar Cycloadditions

The most general approach to synthesis of five-membered heterocyclic compounds involves cycloaddition of a 1,3-dipole to an appropriate unsaturated substrate, the dipolarophile. Intermolecular cycloadditions result in the formation of one new ring only. When the 1,3-dipole and the substrate are part of the same molecule, cycloaddition is intramolecular and leads to a new bicyclic system. Thus, intramolecular cycloadditions are amenable to the construction of inherently more complex products than intermolecular cycloadditions. Markedly different regioselectivity, controlled by the geometric constraints of bringing the 1,3-dipole into correct internal alignment for reaction with the dipolarophile, is often observed in an intramolecular cycloaddition. Sometimes these geometric constraints overwhelm the normal regiochemical preference dictated by electronic factors. The greater steric constraint inherent to intramolecular cycloaddition often affords higher diastereofacial discrimination: accordingly, these reactions can exhibit very high stereoselectivity. Periselectivity can also be different for an intramolecular cycloaddition, leading to formation of unusual bicyclic systems, containing other than five-membered heterocycles.

.alpha.-Nitro sulfones. 2. Convenient new synthesis and selected functional group transformations

X-ray Analysis of 2a. Single crystals of 2a were tetrahedral, space group P43 (for the configuration shown in Figure 1) or P4*, with a = 12.896 (1) A, c = 13.773 (3) A, and d d = 1.300 g for 2 = 4 (C29H2809, mol w t 448.47). The intensity data were measured on a Hilger-Watts diffractometer (Ni-filtered Cu Ka radiation, 8-28 scans, pulse-height discrimination). A crystal measuring approximately 0.30 X 0.6 X 0.6 mm was used for data collection. A total of 1616 reflections was measured for 8 < 57O, of which 1570 were considered to be observed [I > 2.5u(Z)]. The structure was solved by a multiple solution p r ~ e d u r e ’ ~ and was refined by full-matrix least-squares. In the final refinement

Cyanogen chloride N-oxide cycloadditions. A simple, short route to AT-125.

Abstract Addition of AgNO 3 to dichloroformaldoxime in the presence of alkenes provides an efficient procedure for the preparation of 3-chloroisoxazolines including AT-125.

Benzenesulfonylcarbonitrile oxide. 5. Face selectivity of cycloaddition to chiral terminal alkenes

Abstract The diastereomer ratio for cycloaddition of benzenesulfonylcarbonitrile oxide (BSNO) to a series of (S)-vinylglycine-derived alkenes varied from 30:70 to 66:34 depending on the substitutents at the chiral center. Isomer ratios were routinely determined by 1H-NMR; isolation confirmed the results in several cases. Isomer assignment was based on comparison to acivicin where the absolute configuration has been determined by X-ray analysis. The results are interpreted as consistent with competitive cycloaddition to the alkene oriented in two differing conformations.

Generation and in situ Diels–Alder reactions of activated nitroethylene derivatives

Abstract Dienes readily undergo Diels–Alder reaction with CH 2 C(NO 2 )SO 2 Ph ( 2a ), CH 2 C(NO 2 )CO 2 Et ( 2b ), and CH 2 C(NO 2 )COPh ( 2c ), all observed in situ by 1 H NMR. The cycloadducts of 2a undergo S RN 1 reactions.

A new route to 4-oxygenated isoxazolines. Application to the synthesis of 2-deoxy-2-aminobutose derivatives

The THP ether of 4,5-dihydro-3-nitro-4-isoxazolol, prepared by a sequential nitroaldol nitrosative cyclization strategy, was converted to a 4,5-dihydro-3-(dithiolanyl)isoxazole; subsequent LBH reduction gave a 95:5 diastereomeric mixture of 2-deoxy-2-aminothreose and -erythrose derivatives, respectively, which was cyclized to a mixture of tetrahydro-2H-1,3-oxazine-2-ones.

Metal-hydride reduction of isoxazoline-3-carboxylate esters

Abstract The reduction of a series of isoxazolino-3-carboxylate esters with sodium borohydride gave 3-(hydroxymethyl)isoxazolines in 34–98% yield. Reduction with DIBAH gave isoxazoline-3-carboxaldehydes in 63 and 85% yields for the two reactions studied. Isoxazoline-3-carboxaldehydes could also be prepared by Swern oxidation of the corresponding 3-(hydroxymethyl)isoxazolines. The hydroxyl group of 3-(hydroxymethyl)isoxazoline 11b was silylated and the endocyclic double bond was cleaved by ozonolysis to produce a monosilylated triol.

Diastereocontrol in the asymmetric dihydroxylation of chiral 3-alkenyl-4,5-dihydroisoxazoles

Catalytic asymmetric dihydroxylation of 4 afforded virtually one diastereomer using (DHQD)2-PHAL as a chiral auxiliary (matched pair; 96% d.e.); the other diastereomer was heavily predominant with (DHQ)2-PHAL as the chiral auxiliary (mismatched pair; 90% d.e.).

A dihydroisoxazole-based route to 2,3,6-trideoxy-3-aminohexose derivatives

Abstract Acosamine and ristosamine derivatives were prepared via stereoselective reductive cleavage reactions of a benzylidenated dihydroisoxazolyl diol; the diol was prepared from 3-nitro-4,5-dihydroisoxazole via sequential propynylation, Lindlar reduction, and catalytic hydroxylation.

C-alkylation reactions of phenylsulphonylnitromethane. A convenient new α-nitro-sulphone synthesis

Phenylsulphonylnitromethane (1) is C-alkylated by benzylic halides and primary alkyl iodides affording α-nitro-sulphones in 43–75% yield; α-nitro-sulphones (83–90% yield) are also obtained from the corresponding C-alkylation of allylic acetates in the presence of catalytic Pd(PPh3)4.