Cyclopropanations chiral auxiliaries

These early studies on zinc carbenoids provide an excellent foundation for the development of an asymmetric process. The subsequent appearance of chiral auxiliary and reagent-based methods for the selective formation of cyclopropanes was an outgrowth of a clear understanding of the achiral process. However, the next important stage in the development of catalytic enantioselective cyclopropanations was elucidation of the structure of the Simmons-Smith reagent. 

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. 

The discovery of viable substrate-direction represents a major turning point in the development of the Simmons-Smith cyclopropanation. This important phenomenon underlies all of the asymmetric variants developed for the cyclopropanation. However, more information regarding the consequences of this coordinative interaction would be required before the appearance of a catalytic, asymmetric method. The first steps in this direction are found in studies of chiral auxiliary-based methods. 

The powerful influence of an oxygen substituent on the rate and stereoselectivity of cyclopropanation augured well for the development of a chiral auxiliary based approach to asymmetric synthesis [54]. The design of the chiral auxiliary would take into account ... 

Upon removal of the auxiliary, an enantioenriched product could be obtained. The application of chiral auxiliary-based methods to Simmons-Smith cyclopropanation not only provided a useful synthetic strategy, but it also served to substantiate earlier mechanistic hypotheses regarding the directing influence of oxygen-containing functional groups on the zinc reagent [6dj. 

The Davies group has described several examples of a rhodium-catalyzed decomposition of a diazo-compound followed by a [2+1] cycloaddition to give divinyl cyclopropanes, which then can undergo a Cope rearrangement. Reaction of the pyrrol derivative 6/2-51 and the diazo compound 6/2-52 led to the tropane nucleus 6/2-54 via the cyclopropane derivative 6/2-53 (Scheme 6/2.11) [201]. Using (S)-lactate and (R)-pari lolaclorie as chiral auxiliaries at the diazo compound, a diastereoselectivity of around 90 10 could be achieved in both cases. 

The reaction was first carried out with the substrate bearing the chiral auxiliary. Scheme 5-64 shows the asymmetric cyclopropanation reaction using 2,4-pentandiol as a chiral auxiliary.115 Scheme 5-65 illustrates the use of optically pure 1,2-frafts-cyclohexanediol as a chiral auxiliary in asymmetric Simmons-Smith cyclopropanation.116 Excellent yield and diastereoselectivity are obtained in most cases. 

The inter- or intramolecular cyclopropanation of achiral alkenes with enantiome-rically pure diazoacetic esters [1016,1363,1364] or amides [1365,1366] does not usually proceed with high diastereoselectivity. A chiral auxiliary which occasionally gives good results is pantolactone (3-hydroxy-4,4-dimethyltetrahydro-2-furanone) [1016,1367,1368]. 

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. 

The full structure and absolute configuration of FR 900848 104 has been determined to be (6R,8S,9R,11S,12S,14R,15S,17R) from X-ray crystallographic study [133]. Strategies for its enantioselective total synthesis are based on an iterative cyclopropanation [134], and on the use of chiral auxiliaries [135]. It has also been prepared by fermentation and isolated from cultures of Streptoverticillium fervens to be considered as an agrochemical microbicide [136]. 

Section 14.2 describes the highly stereoselective cyclopropanation chemistry of the donor/acceptor-carbenoids (Fig. 14.1a) [16]. This section introduces the range of vinyl, aryl, alkynyl, and heteroaryl functionalities that have been used as donor groups in this chemistry. Also, chiral auxiliaries and chiral catalysts that achieve high asymmetric induction in this chemistry are described [25]. The next two sections cover chemistry that is unique to the vinylcarbenoid system, namely [3-t4] cycloaddition with dienes (Fig. 14.1b see also Section 14.3) [13] and [3-1-2] cycloaddition with vinyl... 

I 74 Rhodium (ll)-Stabilized Carbenoids Containing Both Donor and Acceptor Substituents Tab. 14.2 Asymmetric cyclopropanation using (R)-pantolactone as the chiral auxiliary. 

An internal diastereoselective alkylation reaction leading to cyclopropane formation 24 has been reported40. Although the 2-oxazolidinone moiety employed was not chiral, it should be possible to perform this reaction using a chiral auxiliary of the oxazolidinone type. 

D. Stereoselective Cyclopropanation of Alkenes using Chiral Auxiliaries. . . 266... 

FIGURE 6. Carbohydrate derived chiral auxiliaries for the cyclopropanation of aUylic alcohols... 

Chiral acetals have also been used as chiral auxiliaries for the enantioselective cyclopropanation of a,/3-unsaturated carbonyl derivatives (Figure 7). Yamamoto s tartrate derived auxiliaries (15) based on the ether-directed cyclopropanation allowed the efficient preparation of cyclopropylcarboxaldehyde derivatives The reaction proceeded with high diastereocontrol, and the auxiliary could be cleaved under mild acidic conditions (equation 73). 

Other chiral auxiliaries for the cyclopropanation of a,/ -unsaturated aldehydes have also been developed (Figure 7, 16-18) . a,/3-Unsaturated chiral amides have also been used in auxiliary-based reactions but the addition of diethyl tartrate as chiral additives was necessary for high diastereoselectivities ". 

A chiral auxiliary-based approach has been developed for the preparation of chiral, non-racemic cyclopropyhnethylamines that are not protected with electron-withdrawing groups. The cyclopropanation of ally he tertiary amines bearing a -hydroxide occurred... 

A very useful class of chiral auxiliaries has been developed for alkenes substituted with a heteroatom. These auxiliaries, attached to the heteroatom, allow for the preparation of enantiomerically enriched cyclopropanols, cyclopropylamines and cyclopropylboronic acids. Tai and coworkers have developed a method to efficiently generate substituted cyclopropanol derivatives using the cyclopropanation of a chiral enol ether (equation 78) . The reaction proceeds with very high diastereocontrol with five- to eight-membered ring sizes as well as with acyclic enol ethers. The potential problem with the latter is the control of the double bond geometry upon enol ether formation. A detailed mechanistic study involving two zinc centers in the transition structure has been reported. ... 

Asymmetric ethylidene transfer has been achieved in the reactions of 1-cyclohexenyl ethers carrying a chiral auxiliary with 1,1-diodoethane/diethylzinc 39. Asymmetric induction in the reaction of diazofluorene with fumaric esters bearing chiral alcohol moieties has been investigated (equation 84)140,141. Kinetics of intramolecular cyclopropanation in... 

Asymmetric cyclopropanations of Michael acceptors with ylides have been explored for a number of substrates modified with chiral auxiliaries. The reactions of 47 with Ph3P=CMe2,48 (equation 119)259 and of 49 with 50 (equation 120)260-261 proceed with excel-... 

Stereosectivity is a broad term. The stereoselectivity in cyclopropanation which has been discussed in the above subsection, in fact, can also be referred to as diastereoselectivity. In this section, for convenience, the description of diastereoselectivity will be reserved for selectivity in cyclopropanation of diazo compounds or alkenes that are bound to a chiral auxiliary. Chiral diazoesters or chiral Ar-(diazoacetyl)oxazolidinone have been applied in metal catalysed cyclopropanation. However, these chiral diazo precursors and styrene yield cyclopropane products whose diastereomeric excess are less than 15% (equation 129)183,184. The use of several a-hydroxy esters as chiral auxiliaries for asymmetric inter-molecular cyclopropanation with rhodium(II)-stabilized vinylcarbenoids have been reported by Davies and coworkers. With (R)-pantolactone as the chiral auxiliary, cyclopropanation of diazoester 144 with a range of alkenes provided c yield with diastereomeric excess at levels of 90% (equation 130)1... 

There are several possibilities for asymmetric synthesis in catalysed cyclopropanation and very substantial progress has already been made especially with catalyst development. The option of covalently attaching chiral auxiliaries to diazo compounds or to substrates, e.g. alkenes for cyclopropanation, has been discussed above in the subsection on diastere-oselectivity. The fact that many of the processes require metal catalysis makes the alternative option of using chiral catalysts particularly attractive and potentially more rewarding for commercial exploitation. The double option of combining the use of a chiral catalyst with a diazo compound carrying a chiral auxiliary is also available. For convenience, the double option is also included in this subsection. 

The range of alkenes that may be used as substrates in these reactions is vast Suitable catalysts may be chosen to permit use of ordinary alkenes, electron deficient alkenes such as a,(3-unsaturated carbonyl compounds, and very electron rich alkenes such as enol ethers. These reactions are generally stereospecific, and they often exhibit syn stereoselectivity, as was also mentioned for the photochemical reactions earlier. Several optically active catalysts and several types of chiral auxiliaries contained in either the al-kene substrates or the diazo compounds have been studied in asymmetric cyclopropanation reactions, but diazocarbonyl compounds, rather than simple diazoalkanes, have been used in most of these studies. When more than one possible site of cyclopropanation exists, reactions of less highly substituted alkenes are often seen, whereas the photochemical reactions often occur predominantly at more highly substituted double bonds. However, the regioselectivity of the metal-catalyzed reactions can be very dependent upon the particular catalyst chosen for the reaction. 

Despite the stepwise pathway for these reactions, some cyclopropanations using ylides may be stereo-specific.132 Successful efforts have also been reported for the development of enantioselective cyclopropanations through use of, for example, optically active ylides related to (ll)136 and of alkene substrates bearing chiral auxiliaries. 

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,... 

Table 13.3 Chiral auxiliaries for halomethylzinc-derived cyclopropanations...

Stereoselective cyclopropanation of cyclic enones dihydrobenzoin-derived chiral auxiliary... 

In the same publication, an enantioselective process was attempted wherein commercially available (2f ,3/ )-butane-2,3-diol was used to generate the chiral cyclopentene 57, which was cyclopropanated to afford gcm-dibromocyclopropane 58 (Scheme 4.20). Unfortunately, when this substrate was subjected to the reaction conditions outlined above, product 59 was obtained as a 1 1 mixture of diastereomers. This result implies that selectivity in these trapping processes is unaffected by the presence of a chiral auxiliary on the remote carbon of the cyclopentane framework. 

Takagi, R., Nakamura, M., Hashizume, M., Kojima, S., and Ohkata, K. (2001) Stereoselective cyclopropanation of 3-aryl-2-phosphonoacrylates induced by the (—)-8-phenylmethyl group as a chiral auxiliary. Tetrahedron Letters, 42, 5891—5895. 

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