Diastereofacial selectivity cyclopropanes

A double diastereotopic differentiation strategy on a phosphonoacetate template has been described. The approach utilizes Rh2(OAc)4-catalysed intramolecular cyclopropanation (ICP) employing the (R)-pantolactone auxiliary in the ester functionality of the phosphonoacetate (328).The olefinic diastereofacial selectivity is governed by inherent electronic and steric interactions in the reacting carbene intermediate, while the group selectivity is dictated by the chiral auxiliary. This approach is an effective method to access bicyclic P-chiral phos-phonates (329) (Scheme 87). ... 

Recently, the stereochemical definitions of the addition of carbenes to C-C double bonds have been summarized. The term stereoselectivity refers to the degree of selectivity for the formation of cyclopropane products having endo vs. exo or, alternatively, syn vs. anti orientation of the substituents in the carbene species relative to substituents in the alkene substrate. The term stereospecificity refers to the stereochemistry of vicinal cyclopropane substituents originating as double-bond substituents in the starting alkene, i.e. a cyclopropane-forming reaction is stereospecific if the cisjtrans relationship of the double-bond substituents is retained in the cyclopropane product. Diastereofacial selectivity refers to the face of the alkene to which addition occurs relative to other substituents in the alkene substrate. Finally, enantioselectivity refers to the formation of a specific enantiomer of the cyclopropane product. 

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. 

Asymmetric induction in intramolecular cyclopropanation reactions can be achieved by substrate and catalyst control. In the example of 24, a stereogenic center in the tether of the unsaturated diazocarbonyl compound controls the diastereofacial selectivity of the cyclopropanation reaction. In the examples of and 27, the diastereoselectivity of the cycli-zation process is controlled by the siloxy group at the stereogenic center obviously, this group prefers the exo position in the transition state. However, the catalyst is also important, since practically no diastereoselectivity for 26 resulted when bis(Al-tc/-t-butylsalicylaldimato)cop-per(II) was used. 

A polyethylene-bound soluble recoverable dirhodium(II) tetrakis(2-oxapyrrolidine-(55 )-carb-oxylate) was also highly efficient in enantioselective intramolecular cyclopropanation of allyl diazoacetates and could be used repeatedly without significant loss of enantiocontrol. Some enantiomerically pure, secondary allylic diazoacetates showed the expected substrate-induced diastereofacial selectivity in intramolecular cyclopropanation, when they were decomposed with bis(A-n-r/-butylsalicylamidinato)copper(II). ° This selectivity could be significantly enhanced or reversed with the chiral catalyst 30 or its antipode. Furthermore, catalysts 30 and 32 allowed a highly efficient kinetic resolution of racemic secondary allylic diazoacetates. 

The zinc-based Simmons-Smith type procedures frequently require rather harsh conditions in order to provide acceptable cyclopropane yields. Also, the discrimination between allylic alcohols, homoallylic alcohols and olefins without a hydroxyl group is often not very pronounced. These drawbacks are avoided by a new method which substitutes samarium metal (or samarium amalgam) for zinc (Table 4)43. This cnahlcs only allylic alcohols to be cyclo-propanated under very mild conditions, even for highly crowded substrates. The hydroxy-directed diastereofacial selectivity is good to excellent for cyclic olefins. Due to this property, the method has been applied to the stereoselective synthesis of 1,25-dihydroxycholecalciferol44. 

Cyclopropanation of eA o-A-[(lf ,25,3/ ,4S)-2-hydroxy-1,7,7-trimethylbicyclo[2.2.1]hept-3-yl]-3-phenyl-2-propenamide with the diiodomethane/diethylzinc reagent proceeds with moderate diastereofacial selectivity only. However, the corresponding O-triisopropylsilyl-protected compound reacts with excellent but opposite diastereoselectivity the added diethyl tartrate has no influence on the stereoselectivity but only on the rate of the reaction. Similar effects are observed for the related cWo-derivatives of the amino alcohol auxiliary, which induces the opposite absolute configurations at the cyclopropane ring101. 

The diastereofacial selectivity of arylcarbenes has rarely been studied however, there are two reports dealing with enantioselective arylcarbene transfer. Addition of 9-diazofluorene to 2-propenoates or ( )-butendioates, which bear (—)-menthyl or (—)-8-phenylmenthyl groups as optically active auxiliaries, provides cyclopropanecarboxylates with moderate to very good diastcrcoselcctivities9. The best results are obtained with bis(8-phenylmenthyl) ( )-butene-dioate which affords the spiro compound with a d.r. of 95 5. Subsequent saponification and esterification with diazomethane leads to the corresponding spiro ir s[2,3]bis(methoxycarb-onyl)cyclopropane-l,9 -[9/f]-fluorene with 85% ee. 

Chiral tricarbonyl(butadienyl)iron complexes are easily accessible by resolution and show excellent diastereofacial selectivities with a variety of reagents55. The tricarbonyl(trienyl)iron complex 2 and methyl diazoacetate (copper bronze catalysis) give only two cis 7/m -isomeric cyclopropanes 5< These can be separated by column chromatography, and each diastereomer transformed into methyl traits- or 7.r-2-formyl-3.3-dimcthylcyclopropanecarboxylate (hemica-ronic aldehyde) by destructive cleavage of the diene complex auxiliary. The enantiomeric excess in these compounds is above 90%. 

This hydroxy-directed cyclopropanation method is also applicable to homoallylic alcohols27. Thus, f K-2-[(Z)-4-/err-butyldiphenylsilyloxy-1 -butenyl]-l-cyclopentanol and dichlorocarbcne combine to provide the adduct with perfect diastereofacial selectivity. On the other hand, the reaction of the diastereomeric /rau.s-substitutcd cvclopentanol proceeds with only moderate selectivity. 

The sulfonium ylide obtained from dimethyl(trimethylsilylmethyl)sulfonium iodide by deprotonation with 1-methylpropyllithium reacts with 2-cyclohexenone to provide 7-(trimethylsilyl)-bicyclo[4.1 0]heptan-2-one with good exo selectivity10. The diastereofacial selectivity of the ylide is also high, as demonstrated by the conversion of the chiral substituted 2-cyclohexenone into cyclopropane derivative 12. 

A diene system with unsymmetrical 1,4-disubstitution is converted to the iron carbonyl complex 1 which is resolved into its enantiomers. The aldehyde function is conformationally locked in the transoid position and is diastereofacially shielded from the bottom face. Nucleophiles attack from the top face with high selectivity. Alternatively, chain elongation leads to the triene 2 which is reacted with diazomethane. Cerium(IV) oxidation removes the metal and furnishes the substituted cyclopropane 3. 

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