Cyclopropanes Enamide

Gibson and co-workers reacted tertiary alcohol diamides with SOCI2 to prepare a series of bis(oxazoline) ligands 20a-f that are used as catalysts for asymmetric cyclopropanations. This method was preferred for preparation of 20e-f. Use of a strong acid such as methanesulfonic acid promoted extensive elimination of water to give the corresponding enamides (Scheme 8.9). 

The cyclopropanation of a chiral enamide has been investigated for the preparation of fluoro-substituted cyclopropylamines. Unfortunately, the reaction produced a mixture of all four possible stereoisomers when the chiral starting material was submitted to the a-fluoro iodomethylzinc carbene (equation 80). ... 

Another example is the indirect acetonylation of a 1,2,3,4-tetrahydropyridine derivative at the (3-position of the enamide system [99]. The reaction involves a double alkylation to furnish an acetylcyclopropane which undergoes fragmentation on acid treatment. It is noted that polarity alternation and ring strain relief allow the facile and regiospecific C-C bond cleavage to proceed, the intervention of a cyclopropane intermediate also leads to disjoint system. This is a fundamental strategy [100] which has been frequently employed to gain access to compounds with disjoint functionalities. 

Addition of electrophilic carbenes to enamines usually does not proceed with good efficiency, very likely because of the disturbance by the Lewis basic nitrogen 15). If however the less basic enamide derivatives are used as olefins, high conversions to donor-acceptor cyclopropanes are possible. Thus cyclic carbamate 245, which itself originates from an oxycyclopropane, gives the bicyclic compound 246 almost quantitatively. Its cleavage with aqueous base provides lactone 247 that could be coupled with tryptophyl bromide to afford 248, a direct precursor of the alkaloid eburnamoni-ne 105>. 

Intermolecular cyclopropanation reactions with ethyl diazoacetate have been employed for the construction of the cyclopropane-containing amino acid 7 (equation 25) Thus, rhodium(II) acetate catalysed decomposition of ethyl diazoacetate in the presence of d-cbz-vinylglycine methyl ester 5 afforded cyclopropyl ester 6 in 85% yield. Removal of the protecting group completed the synthesis of 7. Another example illustrating intermolecular cyclopropanation can be found in Piers and Moss synthesis of ( )-quadrone 8" (equation 26). Intermolecular cyclopropanation of enamide or vinyl ether functions using ethyl diazoacetate has also been used in the synthesis of eburnamonine 9", pentalenolactone E ester 10" and ( )-dicranenone A11" (equations 27-29). 

Diastereofacially controlled cyclopropanation of a, -unsaturated carboxamides derived from (+)-(l/l)-camphor was successful in obtaining both enantiomers of /ra s -2-phenylcyclo-propanecarboxylates. The exo-7Vf- (l/ ,25,3/ ,45 )-2-hydroxy-l,7,7-trimethylbicyclo[2.2.1]hept-3-yl -3-phenylprop-2-enamide (exo-lflOa) and its endo-(l/ ,27 ,3iS ,4S)-isomer (enc/o-lOOa) reacted with diethylzinc/diiodomethane to give selectively (l/ ,2i )-102 (de < 80%) and (15,25)-102 (de < 58%), respectively, after hydrolysis. Complete reversal of the stereoselectivity (98% de) was observed when O-triisopropyl derivatives of the amides, i.e. 100b, were used in the cyclopropanation. 

The lack of trichloromethyl anion adducts to acrylates in these processes is possibly due to relatively tight, poorly lipophilic ion pairs Me4N CCI3 which cannot penetrate the organic phase thus, they reside in the interfacial region where the hydrated trichloromethyl anions have low activity. Consequently, dichlorocarbene reacts with acrylates to form 1,1-dichlorocy-clopropanes 2. ( )-A -tert-Butyl but-2-enamide forms the cyclopropane 3 on reaction with dichlorocarbene, generated from chloroform/base/phase-transfer catalyst, with tetramethylam-monium chloride as the catalyst. ... 

An efficient two-step procedure for the introduction of an acetic acid substituent into the 4-posltion of 2-methyl-l(2H)-isoquinollnone Involves reaction with ethyl diazoacetate in the presence of a copper catalyst to give a mixture of exo and endo adducts, which are then isomerlzed t g4-carboethoxymethyl-N-methyl-2(lH)-isoqulnollnog0 with ethanolic HCl. Uracil 5-acetlc acids could be prepared analogously. The cyclopropane adduct from 2-methyl-l(2H)-lsoquinolinone and dichlorocarbene can be ring-contracted to an isolndole, or ring-expanded to a benzazeplnone P The reaction of carbenes with other heterocyclic enamides has been reviewed. 

Chiral oxazolidinone also controlled the stereochemistry of cyclopropanation of enamides 102 (Scheme 1.53) [88]. Cyclopropane 103 was obtained in good yields with high diastereomeric excesses. 

Diastereoselective cyclopropanation progressed in the reaction with sugar-derived glycals 143 (Scheme 1.69) [113]. A new type of spiro cyclopropanes 144 were formed in a highly stereoselective manner. Optically active enamide 145 underwent stereo-controUed cyclopropanation, and amide cyclopropanes 146 were prepared in more than 95 5 selectivity (Scheme 1.70) [114]. Cyclopropanation of 8-oxabicy-clo[3.2. l]octane 147 with diazoalkanes smoothly occurred in the presence of a rhodium or copper catalyst, and exo,exo adduct 148 was isolated in a highly stereoselective manner (Scheme 1.71) [115]. 

---