Diastereoselective cyclopropanation by using Camphorpyrazolidinone derived  ,  - Unsaturated Amides and Ylide

: High to moderate diastereoselectivity and high chemical yield are observed in the Michael addition of ylide and chiral camphorpyrazolidinone ylide to an optically pure  unsaturated carboxylic acid derivatives derived from a chiral camphorpyrazolidinone and  unsaturated carbonyl respectively. A novel route to the asymmetric synthesis of cyclopropanation derivatives is described.

It is well known, that sulfur ylides 14 react with carbonyl groups or with electron deficient carbon-carbon double bond in a two-step reaction to afford epoxide or cyclopropanes, respectively. 15 Sulfur ylide in situ generated by treatment of ethyl dimethyl sulfonium acetate bromide with DBU, were reacted with ab cyclic enones, 16,17 chiral enones 18 and with N-enoyl oxazolidinones in presence of Lewis acids 19 are reported in the literature.
However, the use of chiral auxiliary unsaturated ester or amide with stabilised sulfur ylide is limited. So far few methods has been reported, such as using pyroglutamic acid (O,N-acetal and N-Boc-pyrrolinone) as a chiral auxiliary  unsaturated amide with stabilized sulfur ylide. 12,20 However the Diastereoselectivity is very poor. Still there are demands for better Diastereoselectivity methods. Therefore, development of new methods for stereoselective cyclopropanation of the unsaturated ester or amide which bear an appropriate chiral auxiliary continues to be an important area of research.

Present Work:
Part-A: Cyclopropanation from Chiral unsaturated carbonyls with simple ylides: We have found recently that unsaturated carbonyl camphor pyrazolidinone, an efficient chiral auxiliary that allows its use for Aziridination 21 and Epoxidation 22 . Now we describe here an approach to asymmetric cyclopropanation involving the use of optically pure -unsaturated carboxylic acid derivatives derived from a chiral camphorpyrazolidinone as a Michael accepter of ethyl (dimethylsulfuranylidene) acetate.
The mechanism undoubtedly was a nucleophilic attack by ylide carbon (step-1) followed by ring closure with elimination of dimethyl sulfide (step-2). The cyclopropanation reaction is not stereoselective, either diastereomer 23 may be obtained from the diastereomeric mixture. The outcome of stereoselectivity totally depends on chiral substrate and solvent polarity. The carboethoxy methylene transfer to the unsaturated double bond is reminiscent of the methylene transfer with Dimethyl oxo-sulfonium methylide 24 .
The cyclopropanation of olefin and with ethyl (dimethylsulfuranylidene) acetate has been studied as a model for this reaction. We screened different solvents (see Fig. S1) and found that the toluene at higher temperature and acetonitrile at room temperature are ideal one. and 30% in acetonitrile respectively. After purification, one product 6a is confirmed as 1R,2R by ORTEP. The less reactivity of the camphorsultam toward cyclopropanation may be due to the electrostatic repulsion between the sulfone functionality in the chiral auxiliary with the nucleophilic sulfur ylide 25 . The beta phenyl substrate, 2b gives exclusive 7a and  The cyclopropanation by using chiral ylide 3d with methacrylate has been studied as a model for this reaction. We screened different solvents and found that the acetonitrile at room temperature is ideal one and gives good chemical yield and diastereoselectivity (Fig.   S2). where characterized as 1R,2S by ORTEP where the methyl ester group is cis to chiral amide. The acrylaldehyde also 3 products 21a, 21b and 21c after repeated recrystallizations, no crystals were formed, whereas the acrylonitrile gives full spectrum of four possible products 22a, 22b, 22c and 22d. The vinyl methyl ketone gives mixture of products 23 which are inseparable. These multiple products formations can be explained that chiral ylide can be attack from either side of simple -unsaturated carbonyl substrates. As expected, fumarate gives 9b, (1S, 2R) as major product, but surprisingly, the maleate also gives same 9b (1R, 2S) as major product. This can be explained the esters groups are in cis orientation is most stable than anti orientation. Surprisingly, the hexenaldehyde is gives more selective product 24b with chiral ylide. To improve the selectivity, we generated in situ chiral sulfide from chiral diazo 28 in presence of Rh2 (OAc)4 and diphenyl sulfide 29 , however it is limited to olefin only (Fig.S3). In this method the stereoselectivity is excellent for amides but not esters but other possible diastereomers can be synthesised.

Part-C: Cyclopropanation from Chiral ylide and Chiral unsaturated carbonyls:
After studying the cyclopropanation reaction by using chiral unsaturated carbonyls and chiral ylide, we studied the combined reaction of chiral unsaturated carbonyls (2a-2l) with chiral ylide 3c. Steric hinderance play major rule than stereoselectivity in this type of reactions. Chiral olefin 2a on reaction with chiral ylide 3c, in various solvents and found that acetonitrile at room temperature is the best choice and gives good chemical yield and diastereoselectivity (Fig. S4). In the class of reaction only olefin and beta-ester are effective. In olefin, the products 25b stereoselectivity is increases to 93% in contrast to beta-ester 26b, where its stereo selectivity decreases. Surprisingly, the beta-alkyl is ineffective and as expected substituted or disubstituted substrate are unreactive due to steric hinderance. The 1,3-elimination occurred preferentially from the carbonyl side of chiral camphorpyrazolidinone, leading to the formation of the major diastereoisomer. Diazo acetamide, 3d goes in similar mechanism, except in situ generated ylide (Fig. S5). In most of the cases trans structure was assigned to the major compound with the help of 1 H NMR spectroscopy and ORTEP.
After studying various cyclopropanation approaches, we came to conclusion, that method-A is give better diastereomer products, than chiral ylide (method-B), whereas diazo in presence of sulfide is limited to unsubstituted  -unsaturated carbonyl only. As expected in Method-C, steric hindrance is played major role than stereoselectivity.