Stereoselective Synthesis of Highly Functionalized Cyclopropanes. Application to the Asymmetric Synthesis of (1S,2S)-2,3-Methanoamino Acids

Abstract

One-pot palladium(0)-catalyzed alkylation and S(N)(') cyclization of 1,4-dichlorobut-2-ene 1 by the anion of alpha-substituted carbonitriles 2a-d can provide highly functionalized cyclopropanes (E)-4a-d, diastereoselectivity, (de 88-100%). Several attempts to achieve the asymmetric synthesis of the 1-amino-2-ethenylcyclopropanecarbonitrile (E)-9, by means of this new procedure, i.e., using chiral palladium ligands, chiral aminoacetonitriles (-)- and (+)-12 (from 1-hydroxypinanone) or chiral allyl chlorides (4S)-20b-d and (4R)-20e (from (2S) ethyl lactate) have pointed up the reversibility of the palladium-catalyzed cyclization step, responsible for the low enantioselectivity observed (ee </= 32%) and for the formation of byproducts, i.e., azepine derivatives 8a,b arising from subsequent aza Cope ring expansion. Molecular mechanics calculations using a modified MM2 type force field adapted to the pi-allyl palladium complexes have explained these results. However, when performed under the Mitsunobu reaction conditions (DEAD, PMe(3)), therefore, in the absence of palladium catalyst, the S(N)(') cyclization occurred also diastereoselectively (de > 88%) and provided the enantiomerically enriched 1-amino-2-propenylcyclopropanecarbonitrile (E)-22 (ee > 83%) suitable precursor of (1S,2S)-2,3-methanoamino acids.

Synthetic Applications of Intermolecular Cyclopropanation of Carboxylic Esters with Dialkoxytitanacyclopropane Reagents

“…[56] Deacetalization of 38 and standard transformation of the aldehyde group into the Salaün and co-workers elaborated a convenient approach to the synthesis of 1-aminocyclopropanecarboxylic acids (2,3-methanoamino acids) by exploiting the ability of sulfonates of 1-alkenylcyclopropanols to undergo palladiumcatalyzed stereoselective reactions with azides, which leads to the formation of the corresponding 1-alkenyl-1-azido cyclopropanes. [57,58] 2-Ethyl-1-aminocyclopropanecarboxylic acid (coronamic acid) (39) and other 2,3-methanoamino acids [59,60] have been successfully synthesized in this way. Because the cyclopropanation of acyclic α,β-unsaturated carboxylic esters with dialkoxytitanacyclopropane reagents gave low yields, the key 1-(1-alkenyl)cyclopropanol derivative 40 was obtained by the cyclopropanation of ethyl 3,3-diethoxypropionate 41 with the titanacyclopropane reagent 42, followed by the deprotection of acetal 43 and the condensation of aldehyde 44 with malonic acid under microwave irradiation.…”

Titanium-Mediated Diastereoselective Formation of (E)- or (Z)-2-Substituted 1-Vinylcyclopropanols: Scope and Limitation, Applications

“…H 2 O 2 ) [52] then afforded the diastereomerically pure coronamic acid [(E)-62] [53] in 77% overall yield, (Scheme 14) Scheme 14. Synthesis of (E)-2,3-methanoamino acids Although the cyclopropanation of the chiral ester 30, derived from (S)-malate, was unfortunately not sufficiently diastereoselective (Table 2, entry 10) to achieve a convenient asymmetric synthesis of coronamic acid [(E)-62], it must, however, be underlined that resolution of such 2,3-methanoamino acids should be achievable by simple enzymic or chemical methods.…”

“…ref. [53] ]. On the other hand, similar Pd 0 -catalysed azidation (NaN 3 , [15]-crown-5 ether) of the allylic mesylates (Z)-56a and (Z)-56b, which probably took place by way of the π-allyl palladium complexes 63a and 63b, afforded the 2-ethyl-1-(prop-1-enyl)-and 1-(but-1-enyl)-2-ethylcyclopropyl azides (Z)-64a and (Z)-64b, respectively, which, being extremely volatile, were used crude for the following steps (Scheme 15).…”

“…Chromatography of the residue on silica gel (eluent pentane/diethyl ether, 9:1) gave 2.99 g (11.68 mmol, 73% yield) of (Z)-2-(2-tert-butyldimethylsiloxyethyl)-1-(prop-1-enyl)cyclopropanol as a colourless oil. (E)-1-Amino-2-ethylcyclopropanecarboxylic Acid (Coronamic Acid) (62): [53,65] 1,3-Propanedithiol (440 mg, 4.4 mmol, 4 equiv.) and triethylamine (610 mg, 4.4 mmol) were added to a solution of the azidocyclopropane (E)-61 (180 mg, 1.1 mmol) in methanol (3 mL).…”

Silyl Effect on the Regioselective Synthesis of Silylated Alkylidenecyclopropanes

“…The regio-and stereoselective formation of (Z)-14 with sodium formate resulted likely from the approach of the hydride (S N'i substitution) towards the more accessible side of the alkylidenecyclopropane moiety, involving the sterically favoured trans relationship with the bulky trimethylsilyl group in s-13. On the other hand, formation of the 1.4:1 diastereomeric mixture of (Z,E)-14 with n-BuZnCl seemed to indicate a lack of diastereomeric effect on the s-complexes 15 and 16; unless the recently evidenced palladium(0) catalyzed (E) AE (Z) isomerization of vinylcyclopropanes occurred also under these conditions 22,23. Substitution of the p-complex 12 by soft nucleophiles, for instance by the anion of dimethyl (or diethyl) malonates 8a,b occurred regio-and diastereoselectively, providing from 8a (R=H) in 67% yield a 24:1 diastereomeric mixture of (E)-17a and (Z)-18a (d.e.…”