Asymmetric synthesis cyclopropane derivatives

Strained molecules such as cyclopropanes and cyclobutanes have emerged as important intermediates in organic synthesis. We have already demonstrated here that cyclobutane derivatives can indeed serve as starting materials for the synthesis of natural as well as unnatural products. Unlike cyclopropanes, which can be prepared asymmetrically in a number of ways 175 -182>, the asymmetric synthesis of cyclobutane derivative has received less attention, and, to our best knowledge, very few reports were recorded recently 183). Obviously, the ready availability of chiral cyclobutane derivatives would greatly enhance their usefulness in the enantioselective synthesis of natural products. The overcome of this last hurdle would allow cyclobutane derivatives to play an even more important role in synthetic organic chemistry. 

A second example of the use of ionic chiral auxiliaries for asymmetric synthesis is found in the work of Chong et al. on the cis.trans photoisomerization of certain cyclopropane derivatives [33]. Based on the report by Zimmerman and Flechtner [34] that achiral tmns,trans-2,3-diphenyl-l-benzoylcyclopropane (35a, Scheme 7) undergoes very efficient (0=0.94) photoisomerization in solution to afford the racemic cis,trans isomer 36a, the correspondingp-carboxylic acid 35b was synthesized and treated with a variety of optically pure amines to give salts of general structure 35c (CA=chiral auxiliary). Irradiation of crystals of these salts followed by diazomethane workup yielded methyl ester 36d, which was analyzed by chiral HPLC for enantiomeric excess. The results are summarized in Table 3. 

Starting from optically active 1-chlorovinyl p-tolyl sulfoxide derived from 2-cyclohex-enone, the asymmetric synthesis of cyclopropane derivative (85) was realized (equation 23) . Addition reaction of lithium enolate of tert-butyl acetate to 83 gave the adduct (84) in 96% yield with over 99% ee. Treatment of the latter with i-PrMgCl in a similar way as described above afforded optically pure (15,6/ )-bicyclo[4.1.0]hept-2-ene (85) in 90% yield. 

Treatment of diethyl malonate and related compounds with 1,2-dihaloethane in the presence of base constitutes a classical method of cyclopropane synthesis296"300. The reaction can be conveniently carried out under PTC conditions. An improved method utilizing solid-liquid phase transfer catalysis has been reported298. The reaction of dimethyl or diethyl malonate with 1,2-dibromoalkanes except for 1,2-dibromethane tends to give only low yields of 2-alkylcyclopropane-l, 1-dicarboxylic esters. By the use of di-tm-butyl malonate, their preparations in satisfactory yields are realized (equation 134)297. The 2-alkylcyclopropane derivatives are also obtained from the reaction of dimethyl malonate and cyclic sulfates derived from alkane-1,2-diols (equation 135)301. Asymmetric synthesis... 

This collection begins with a series of three procedures illustrating important new methods for preparation of enantiomerically pure substances via asymmetric catalysis. The preparation of 3-[(1S)-1,2-DIHYDROXYETHYL]-1,5-DIHYDRO-3H-2.4-BENZODIOXEPINE describes, in detail, the use of dihydroquinidine 9-0-(9 -phenanthryl) ether as a chiral ligand in the asymmetric dihydroxylation reaction which is broadly applicable for the preparation of chiral dlols from monosubstituted olefins. The product, an acetal of (S)-glyceralcfehyde, is itself a potentially valuable synthetic intermediate. The assembly of a chiral rhodium catalyst from methyl 2-pyrrolidone 5(R)-carboxylate and its use in the intramolecular asymmetric cyclopropanation of an allyl diazoacetate is illustrated in the preparation of (1R.5S)-()-6,6-DIMETHYL-3-OXABICYCLO[3.1. OJHEXAN-2-ONE. Another important general method for asymmetric synthesis involves the desymmetrization of bifunctional meso compounds as is described for the enantioselective enzymatic hydrolysis of cis-3,5-diacetoxycyclopentene to (1R,4S)-(+)-4-HYDROXY-2-CYCLOPENTENYL ACETATE. This intermediate is especially valuable as a precursor of both antipodes (4R) (+)- and (4S)-(-)-tert-BUTYLDIMETHYLSILOXY-2-CYCLOPENTEN-1-ONE, important intermediates in the synthesis of enantiomerically pure prostanoid derivatives and other classes of natural substances, whose preparation is detailed in accompanying procedures. 

Asymmetric synthesis of cyclopropanes, The reaction of dimethyloxosnifonium methylide with (E)-(2R,3S)-6-alkylidene-3,4-dimethyl-2-phenylperhydro-l,4-oxazepine-5,7-diones (1) yields cyclopropane derivatives (2) and dihydrofuranes (3). The ratio of the products depends on the solvent and temperature. Use of THF at 25° favors formation of 2, whereas formation of 3 is favored by use of DMF at -61°. The products (2 and 3) can be converted into optically pure cyclopropane-1,1-dicarboxylic acids (4) and 3-substituted y-butyrolactones (5), respectively. 

The most popular lands of the diols for asymmetric synthesis are bis-secondary diols that have a C2 axis of symmetry [212]. The presence of the symmetry axis avoids the formation of diastereoisomeric esters or acetals [213], (1R, 27 )-Cyclohexanediol 1.34 (n = 1) has been used as an auxiliary in asymmetric cyclopropanation [214] and (IS, 2S)-cycloheptanediol 1.34 (n = 2) in 1,4-addition of cuprates[157], Dioxolane derivatives of 1.34 have been used for asymmetric P-ketoester alkylations [215] and cuprate 1,4-additions [216]. Linear 1,2-diols 1.35 (R = Me, i-Pr, c-CgH j, Ph) and functionalized 1,2-diols 1.36 (Y = COOalkyl, CONR 2, CH2OR ) are readily available from optically active tartaric acids 1.36 (Y = COOH). Acetals derived from these diols are valuable reagents m asymmetric synthesis [173, 213, 217], as the related 1,3-diols 1.37. Acetals of 1,3-butanediol 137 (R = Me, R = H) have also been used. When these acetals are formed from aldehydes under thermodynamic conditions, one 1,3-di-oxane stereoisomer often predominates. In this favored isomer, the substituent from the aldehyde and the methyl group from 1.37 are both in equatorial orientar... 

Numerous other examples of asymmetric intramolecular cyclopropanations with chirally mod-ified rhodium catalysts have been reported 116 125. Asymmetric eyclopropanation of 1,3-di-enes leads to chiral vinyl cyclopropanes and products derived thereof126,127. Asymmetric eyclopropanation is also used in the synthesis of chiral cyclopropanes starting from unsymmet-rically substituted alkynes128. Polymer-supported rhodium catalysts of this type can be recov-... 

The hunt for strained molecules is maintained by the competitive ambition to find the most unusual structures and by the enormous synthetic potential of small-ring compounds. Following the general trend of recent years asymmetric syntheses are at the cutting edge of this research. [1] Despite all advances the synthesis of enantiomerically and diastereomerically pure cyclopropane derivatives remains a considerable challenge, especially when particular functional groups are required. The most... 

Asymmetric cyclopropanation reactions have been developed by using diiodomethane and diethyl zinc in the presence of a chiral Lewis acid. A particularly effective chiral Lewis acid, introduced by Charette, is the dioxaborolane 112, which induces high levels of optical purity in the resultant cyclopropanes derived from allylic alcohols (4.90). This methodology has been used in natural product synthesis, such as in the preparation of the antifungal agent FR-900848 (4.91). ... 

In addition to its occurrence in many natural and bioactive products, cyclopropanes are key moieties in many important reactions, due to its inherent ring strain. Thus, the asymmetric synthesis of cyclopropane derivatives is the subject of intense research activity. The most widely enantioselective methods are the transition metal (mainly copper or... 

A proline-derived catalyst effectively works for the asymmetric synthesis of cyclopropanes fi om a-chloroketones. Ye and coworkers reported that a-chloroacetophenone derivatives underwent asymmetric MIRC cyclopropanation by treatment with substituted cinnamaldehyde in the presence of chiral pyrrolidine 3 and that optically active cyclopropanes 5 were obtained in good yields (Scheme 1.3) [6]. 

The use of catalytic amounts of a chiral source is important to improve the efficiency of asymmetric induction. Charette and coworkers used 10mol% of chiral phosphoric acid 116, derived from a binaphthol derivative, and achieved catalytic asymmetric cyclopropanation to form allylic alcohols 117 (Scheme 1.57) [96]. Walsh and cowoikers reported that the efficient asymmetric synthesis of cyclopropylmethyl alcohol... 

---