Chiral cyclopropanation

Whereas the utility of these methods has been amply documented, they are limited in the structures they can provide because of their dependence on the diazoacetate functionality and its unique chemical properties. Transfer of a simple, unsubstituted methylene would allow access to a more general subset of chiral cyclopropanes. However, attempts to utilize simple diazo compounds, such as diazomethane, have never approached the high selectivities observed with the related diazoacetates (Scheme 3.2) [4]. Traditional strategies involving rhodium [3a,c], copper [ 3b, 5] and palladium have yet to provide a solution to this synthetic problem. The most promising results to date involve the use of zinc carbenoids albeit with selectivities less than those obtained using the diazoacetates. 

The compound curacin A 207 is a novel antimitotic agent isolated from the Caribbean cyanobacterium Lyngbya majuscula. The compound consists of a disubstituted thiazoline bearing a chiral cyclopropane ring and an aliphatic side chain. Scheme 5-67 depicts the construction of the cyclopropane ring using an asymmetric cyclopropanation reaction.122... 

Because the chiral cyclopropane subunit is present in a wide range of natural and synthetic products showing important biological properties, asymmetric construction of the cyclopropane moiety via asymmetric cyclopropanation is of commercial interest. Many chiral catalysts and chiral ligands have been pre-... 

A very convenient asymmetric synthesis of cyclopropane or epoxide systems developed by Johnson (184) is based on the use of chiral sulfur ylides as the agents that induce optical activity. Generally, this method consists of the asymmetric addition of a chiral sulfur ylide to the C=C or C=0 bond and subsequent cyclization of the addition product to form a chiral cyclopropane or epoxide system together with chiral sulfinamide. A wide range of chiral... 

In the past few years, new approaches for the enantioselective synthesis of / -benzyl-y-butyrolactones appeared in the literature. Some of these approaches involve the asymmetric hydrogenation of 2-benzyl-2-butenediols (j [34]), the radical mediated rearrangement of chiral cyclopropanes (r [35]), the transition metal catalyzed asymmetric Bayer-Villiger oxidation of cyclobutanones n [36]), or the enzymatic resolution of racemic succinates (g [37]). 

Chiral cyclopropanes. Carrie el al.b l have developed a highly enantioselective synthesis of cyclopropanes from the aldehyde 2, in which the butadiene group is protected as the iron tricarhonyl complex. The complex (2) is resolved by the method of Kelly and Van Rheenan (5, 289-290), and the two optical isomers arc then converted separately into a cyclopropanealdehyde (5a and 5b) as formulated. A sulfur ylide such as (CH3)2S=CHCOOCH3 can be used in place of diazomethane for cyclopropanation. Optical yields are > 90%,... 

In 2003, Mayoral et al. proved that by using this strategy, the productivity of chiral cyclopropanes per molecule of chiral ligands immobilized on a den-drimer greatly increased, which led to an improvement in the ligand economy and the chirality transfer [63]. 

Wang, M.X. and Feng, G.Q. 2000. Enantioselective synthesis of chiral cyclopropane compounds through microbial transformations of fra 5-2-arylcyclopropanecarbonitriles. Tetrahedron letters, 41 6501-5. 

Although many chiral cyclopropanation catalysts are known, this class of complexes is superior for the alkenes containing vinyl, phenyl, or alkoxycarbonyl groups. Some relevant examples are shown in eq 1-5. In eq 5, the enantiomeric excess of the product is not known due to the absence of enantiomerically pure isomer. The absolute configuration is not known. 

The enantiomeric purity of the chiral cyclopropanes may be enhanced by recrystallization of the acid obtained after mild alkaline hydrolysis of the chiral ester when the ee values are over 60%. 

In the literature there exists several theoretical approaches to deal with optical rotations [0]d of (monocyclic) chiral cyclopropanes 1 . In formula I R corresponds to a substituent R attached to the ligand-site i. The enumeration of the skeletal carbon atoms is... 

For the deductions of absolute configurations of cyclopropane hydrocarbons from CD measurements there seems to exist a qualitative rule Apparently, trans-dialkylcyclopropanes (and probably also other polyalkylated chiral cyclopropanes with at least local symmetry C2) will exhibit a positive Cotton effect between 180 nm and 190 nm for molecules with a structure corresponding to (IR, 2R)-( — )-trans-dimethylcyclopropane (1). 

Chiral electrophilic cyclopropanes (63) are prepared in high enantiomeric excess starting from butadiene-iron tricarbonyl complexes (60) containing a non-complexed double bond. Reaction with diazomethane and decomposition of the resulting pyrazolines (61) in the presence of Ce" gave the corresponding chiral cyclopropanes (62). Breakdown of the dienic substituent of electrophilic cyclopropane (62) by means of ozonization resulted in the formation of formyl-substituted electrophilic cyclopropane (63) still carrying the asymmetric centre (equation 10) " . ... 

Chiral cyclopropanes geminally substituted with two EWGs (259) are obtained when alkenes, complexed with Fe carbonyls (257), are treated which sulphur ylides bearing an EWG (equation 78). Reaction of cyanosulphoniummethylide (260) with electron-... 

The diastereoselective and enantioselective preparation of cyclopropanes has attracted attention since chiral cyclopropanes were found to occur in many natural products [11]. Moreover, cyclopropanes are useful intermediates in organic synthesis. There are many methods of cyclopropane ring opening that transfer stereochemical information from the substrate to acyclic products in a stereocontrolled manner [12]. Among the methods used for the preparation of cyclopropanes from olehns, the Simmons-Smith and related reactions as well as reactions of diazoalkanes catalyzed by rhodium, copper and cobalt salts have frequently been applied [13]. The preparatively simple Makosza reaction [14] has scarcely been used. 

An efficient asymmetric synthesis of chiral cyclopropanes has been described by Charette et al. [15], who treated allyl (3-D-glucopyranosides 1 with an excess of diethyl zinc/diiodomethane (Scheme 10.1). Cyclopropanes 2 were obtained in high yield and high diastereoselectivity (Table 10.1). 

The reduction of chiral 1-substituted l-halo-2,2-diphenylcyclopropanes at a mercury cathode to the chiral cyclopropanes has been reported by some workers [387-389]. 

The precursor to the Rh-carbene complex is a dirhodium system that typically has four bidentate ligands attached. One example of the dirhodium complex is shown as structure 63, which was discovered by Doyle and co-workers and is abbreviated Rh2(5.S -MEPY)4,76 Here the 5.S-MEPY ligand is chiral carboxami-date, which is derived from the amino acid L-proline. The use of 63 and similar complexes makes it possible to induce chirality into the cyclopropane product. Equation 10.51 is an example of an intramolecular chiral cyclopropanation... 

In the course of developing the melatonin agonist 1 (Fig. 1), potentially indicated for the treatment of sleep disorders, we evaluated approaches to the chiral cyclopropane intermediates 2 a and 2 b based on both classical resolution and asymmetric induction. Conceptually, these intermediates could be derived from di-hydrobenzofurans 3, 4 and 5 each of these was used at one stage or another during our research and development work. 

In this account, we describe how several documented methodologies for the preparation of chiral cyclopropane derivatives were applied across various stages of development and we present insights into the considerations that ultimately drove the selection of the process technology for long-term commercial use. 

Having identified 5 as a preferred intermediate, we chose to focus on two approaches to reach the desired chiral cyclopropane derivative the preparation of chiral epoxide 19, and direct asymmetric cyclopropanation to afford 2 b (Fig. 5). While the latter appeared more direct, several issues needed to be resolved before scale-up and thus it required more extensive development work. Therefore, initial efforts focused on developing a process based on epoxide 19 and subsequent conversion into 20 via a modified Wadsworth-Emmons procedure [8]. Two approaches were explored to convert 5 into 19. 

While the Sharpless asymmetric dihydroxylation procedure proved effective in making the desired chiral cyclopropane acid intermediate from 5, several unit operations were required to make the key intermediate 2 b. Overall efficiency, however, is the key criterion for developing a long-term, cost-effective manufacturing process. Asymmetric cyclopropanation [18] certainly offered the most direct approach starting from 5, and so a number of catalyst systems known to effect this type of reaction were screened. Three catalytic systems were examined in detail for potential, as outlined in Tab. 1. 

The usefulness of this transformation first became apparent when it was discovered that some chiral cyclopropane-containing pyrethroids were highly effective insecticides. More importantly, the biological activity of these compounds was directly related to the cyclopropane stereochemistry [4]. One of the most ef-... 

For example, it has been used to elaborate the chiral cyclopropanes subunits of Curacin A[60], and of the structurally fascinating FR-900848 [61] and U-106305 [62]. The chiral dioxaborolane-derived ligand was also effective to synthesize 1,2,3-substituted cyclopropanes [63]. Excellent to outstanding diastere-oselectivities and enantioselectivities were observed when a variety of allylic alcohols were treated with the reagent formed by mixing 1,1 -diiodoethane and di-ethylzinc. It was also shown that functionalized 1,1-diiodoalkanes could also be used in this reaction. 

The discovery of the chiral copper carbenoid reaction in Kyoto has led to the introduction of a chiral cyclopropane production in Sumitomo. However, at the present time, the catalysts in our hands are not as selective as those of natural origin. The Pyrethrum flower is still much more skillful and beautiful in chry-santhemic acid synthesis. Further endeavors should be exerted to complete the man-made asymmetric catalysis [42,43,44,45]. 

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 cyclopropanation of cinnamyl alcohol is a good example of the use of dioxaborolane ligand 3 as chiral additive to synthesize chiral cyclopropanes. 

Steroids are members of a large class of lipid compounds called terpenes. Using acetate as a starting material, a variety of organisms produce terpenes by essentially the same biosynthetic scheme (Fig. 8). The self-condensation of two molecules of acetyl coenzyme A (CoA) forms acetoacetyl CoA. Condensation of acetoacetyl CoA with a third molecule of acetyl CoA, then followed by an NADPH-mediated reduction of the thioester moiety produces mevalonic acid [150-97-0] (72). Phosphorylation of (72) followed by concomitant decarboxylation and dehydration processes produce isopentenyl pyrophosphate. Isopentenyl pyrophosphate isomerase establishes an equilibrium between isopentenyl pyrophosphate and 3,3-dimethylallyl pyrophosphate (73). The head-to-tail addition of these isoprene units forms geranyl pyrophosphate. The addition of another isopentenyl pyrophosphate unit results in the sesquiterpene (C15) famesyl pyrophosphate (74). Both of these head-to-tail additions are catalyzed by prenyl transferase. Squalene synthetase catalyzes the head-to-head addition of two achiral molecules of famesyl pyrophosphate, through a chiral cyclopropane intermediate, to form the achiral triterpene, squalene (75). 

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