Cyclopropanation stereocontrolled

The landmark report by Winstein et al. (Scheme 3.6) on the powerful accelerating and directing effect of a proximal hydroxyl group would become one of the most critical in the development of the Simmons-Smith cyclopropanation reactions [11]. A clear syw directing effect is observed, implying coordination of the reagent to the alcohol before methylene transfer. This characteristic served as the basis of subsequent developments for stereocontrolled reactions with many classes of chiral allylic cycloalkenols and indirectly for chiral auxiliaries and catalysts. A full understanding of this phenomenon would not only be informative, but it would have practical applications in the rationalization of asymmetric catalytic reactions. 

Recently, Charette et al. have also demonstrated this behavior in the stereoselective cyciopropanations of a number of enantiopure acyclic allylic ethers [47]. The high degree of acyclic stereocontrol in the Simmons-Smith cyclopropanation has been extended to synthesis several times, most notably in the synthesis of small biomolecules. Schollkopf et al. utilized this method in their syntheses of cyclopropane-containing amino acids [48 a, b]. The synthesis of a cyclopropane-containing nucleoside was also preformed using acyclic stereocontrol [48c]. 

A stereoselective convergent synthesis of hydroazulenes 538 was also based on a tandem intermolecular cyclopropanation-Cope rearrangement sequence with predictable stereocontrol (equation 211)262. 

Nucleosides such as 178 and 179 containing a cyclopropane ring fused to the sugar portion have shown antiviral activity their stereocontrolled syntheses have recently been achieved, Eq. (69) [233]. 

In an approach to the stereocontrolled creation of the acyclic side-chain of tetracyclic triterpenoids and other natural products, Trost and his colleagues have converted the acyclic starting compound (29) into the cyclopropanoid intermediate (31) via the diazo-ketone (30). The key step in the scheme is the cleavage of the cyclopropane with lithium dimethylcuprate to give (32). The stereochemistry at C-7 is determined by the configuration of the double bond in (29). The c.d. and u.v. spectra of a series of triterpenoid olefins have been measured. The Scott-Wrixon rules can be used to correlate the sign of the c.d. curves with molecular structure. A... 

Beyond these systems, challenges in stereocontrol remain for both inter- and intramolecular cyclopropanation reactions with diazoketones, diazoketoesters (18), diazomalonates, and diazomethane. Although some progress has been made in intramolecular reactions of diazoketones, with selected examples having high % ee values,enantiocontrol is generally low to moderate for these systems. 

The diastereoselective cyclopropanation of acyclic allylic alcohols is a very useful synthetic transformation. It was recognized early on by Pereyre and coworkers that the cyclopropanation of Z-substituted chiral allylic alcohol was highly syn selective (equation 58) °. It was later shown that most zinc carbenoids react with these substrates with high syn stereocontrol. 

The level of diastereoselection in the cyclopropanation of chiral acyclic E-aUylic alcohols is highly dependent upon the choice of the reagent, the stoichiometry and the solvent. Charette has shown that, with simple ii-substituted chiral allylic alcohols, the use of an excess of the Furukawa reagent in dichloromethane provided the highest syn stereocontrol (equation 59). ... 

The fact that the above reactions allow isolation of 4-hydroxyesters, which are often unstable and lactonize quickly, is a merit of the homoenolate chemistry. Mesylation of the hydroxy group followed by appropriate operations provides stereocontrolled routes to y-lactones and cyclopropane carboxylates [19]. Through application of such methodology steroid total synthesis has been achieved (Section 7). 

Tomislav Rovis of Colorado State University has reported (Angew. Chem. Ini. Ed. 2005,44, 3264) the diastereoselective Lewis acid-mediated 1,3-rearrangement of dihydrooxepins such as 10 to the cyclopentene carboxaldehyde II. It is particularly convenient that the precursor aldehyde 9 is also converted into 11 under the same conditions. As there are many ways to construct alkenyl cyclopropanes such as 9 with control of both relative and absolute configuration, this is an important addition to methods for the stereocontrolled construction of cyclopentanes,... 

More recently, an analogous combination of lithium, magnesium, zinc and copper reagents led to the stereocontrolled synthesis of cyclopropanes, illustrated for the synthesis of fran -divinylcyclopropane (equation 33)84. 

Stereocontrol in intermolecular cyclopropanation also depends on the structure of the unsaturated substrate. Early work concerning the influence of substrate on stereoselectivity has been summarized by Doyle2. In general, cyclopropanation of ciy-disubstituted alkenes results in higher stereoselectivity than with monosubstituted alkenes and the steric bulk of the olefinic substituent enhances the stereoselectivity. However, the stereocontrol appears not simply to be caused by a steric factor. In comparable cases, the presence of halogen as an alkene substituent may cause a reversal of the normal stereoselectivity. A few examples which illustrate these effects are shown in equations 124167 172, 74. 

Considerable variation in stereocontrol can also occur, depending on the catalyst employed (equation 125). In general, the various rhodium(II) carboxylates and palladium catalysts show little stereocontrol in intermolecular cyclopropanation162,175. Rhodium(II) acetamides and copper catalysts favour the formation of more stable trans (anti) cyclopropanes162166. The ruthenium bis(oxazolinyl)pyridine catalyst [Ru(pybox-ip)] provides extremely high trans selectivity in the cyclopropanation of styrene with ethyl diazoacetate43. Furthermore, rhodium or osmium porphyrin complexes 140 are selective catalysts... 

The inclusion of a separate chapter on catalysed cyclopropanation in this latest volume of the series is indicative of the very high level of activity in the area of metal catalysed reactions of diazo compounds. Excellent, reproducible catalytic systems, based mainly on rhodium, copper or palladium, are now readily available for cyclopropanation of a wide variety of alkenes. Both intermolecular and intramolecular reactions have been explored extensively in the synthesis of novel cyclopropanes including natural products. Major advances have been made in both regiocontrol and stereocontrol, the latter leading to the growing use of chiral catalysts for producing enantiopure cyclopropane derivatives. 

This process has found occasional use in the synthesis of heterocycles. The major product resulting from the reaction of MeLi on the dibromocarbene adduct (51) is the tetrahydrofuran (52), as shown in equation (105).189 In a novel approach to the synthesis of spiroacetal pheromones, caibene insertion into an acetal C—H bond was studied (equation 106).252 Unfortunately, the reaction proceeds in low yield and the approach is further hampered by the lack of stereocontrol in the ring opening of the cyclopropane. Carbene insertions into N—H and C—H bonds adjacent to nitrogen have been shown to give azabicyclo systems, as shown in equations (107) and (108).188... 

Enantiocontrol with 21-23 is lower than that achieved with chiral copper catalysts for reactions of diazoacetates with styrene and a few other alkenes examined thus far [68], but the carboxamidates display far greater stereocontrol than do the dirhodium(II) carboxylates for the same reactions [69]. However, Hashimoto has reported the use of chiral piperidinonate 24 and found exceptional enantiocontrol in the cyclopropanation of styrene and both mono- and... 

It has also been reported (66, 67) that trans-2-broino-3-methylcyclobutanone 190 undergoes a stereocontrol led ring contraction to form trans-2-methyl-cyclopropane derivatives 192 by using either NH3, aqueous sodium carbonate or water. Inversion of configuration (cf. 191) is again observed. 

In recent years, most of the attention has focused on the stereocontrolled synthesis of cyclopropanes. The isolation of several structurally intriguing natural product has revived the interest of the scientific community for the development of new methods. Several efficient and practical chiral auxiliaries have been developed for the enantioselective cyclopropanation of olefins. The most efficient chiral auxiliaries have been specifically designed for the cyclopropanation of acyclic allylic alcohols (Table 13.3, entry 1, 2, Protocol 8),24 alkenones,25 cycloalkenones26 (Table 13.3, entry 3,4, Protocol 9), vinyl ethers27 (Table 13.3, entry 5, Protocol 10), and vinylboronate esters28 (Table 13.3,... 

From the multitude of synthetic work in the field of cyclopropanation, we will focus on the asymmetric synthesis of cyclopropanes. Besides the known stereocontrolled addition of diazocompounds to olefins (diazo-method) [6] the stereocontrolled Simmons-Smith cyclopropanation has received significant attention in the last ten years. The latter will be discussed further. 

Scheme 6. Stereocontrolled cyclopropanation in the synthesis of cyclopropanated nucleosides...

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