Cyclopropanation strategies

Using this cyclopropanation strategy, Yamada et al. have stereoselectively synthesized a side chain segment of an antitumor marine steroid, aragusterol. [34]... 

While this cyclopropanation strategy is usually limited to the use of diazo compounds there has been one recent report of the use of phenyliodonium ylides as the carbene source. In this example the ylide generated from methyl nitroacetate (9.13) and iodosobenzene reacts with styrenes and also 1,3-butadiene in the presence of the copper complex derived from bis-oxazoline (9.14). ... 

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. 

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. 

Internal cyclopropane ring-opening reactions have also been developed using hydroxyl-substituted cyclopropanes. A typical example of this strategy comes from the reaction of the polycylic alcohol 131, which reacts quantitatively with Hg(OAc)2 to yield the acetal 132 (Equation (45)).165 Carbonate moieties can also be used as internal nucleophiles as, for example, in the case of 133, which affords 134 in a 60% yield upon reaction with Hg(OCOCF3) (Equation (46)).166... 

A variety of functionalized [3]radialenes have been prepared starting from the appropriately substituted cyclopropanes or cyclopropenes. West and Zecher have pioneered the chemistry of [3]radialenes with quinoid substituents. The general strategy of this synthesis is outlined in Scheme 513. A tris(4-hydroxyphenyl)cyclopropenylium... 

Two strategies have been adopted for asymmetric cyclopropanation. First, there are auxiliary-based methods, involving a covalently attached adjacent chiral moiety on either the olefin or the cyclopropylating agent. The second process, on the other hand, employs a chiral ligand on a metal catalyst. This method is more applicable to route b or c, and this is an issue that warrants further discussion. 

The most elegant strategy for the preparation of enantiomerically enriched cyclopropanes is based on the use of chiral catalysts (for recent reviews, see [1072-... 

Wade and co-workers used a similar strategy for the synthesis of fran5-l,2-dinitrospiro-pentane (10), which is prepared in 43 % yield by treating the dianion of l,l-few(nitromethyl)-cyclopropane (9) with iodine in DMSO the latter prepared by treating the corresponding diamine (8) with excess ozone while absorbed onto the surface of silica gel. 

Vicinally donor-acceptor-substituted cyclopropanol carboxylic esters have been proven to be versatile synthetic building blocks in organic synthesis [11]. They readily undergo a retroaldol reaction, thus creating a stable enolate that at the same time can be considered as a homoenolate in relation to the newly formed carbonyl function. Shimada et al. applied this strategy to the preparation of y-substituted lactones starting from cyclopropane 21 (Scheme 3) [12]. 

The cyclopropane moiety is a fundamental class of functional group present in both natural products and numerous therapeutic agents. It has provided the impetus for significant breakthroughs in the use of metal carbenoids [151] and organocatalytic ylide intermediates [152, 153] such that rehable methods exist for most disconnective strategies on this ring system. 

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]. 

The key problem in the preparation of 296, 297 undoubtedly is the stereoselective assembly of the chains of four to five contiguous cyclopropyl groups. The strategies of all total syntheses known so far rely on auxiliary-directed stereoselective cyclopropanations of double bonds [111a, 163,164]. The chemistry of bicyclopropylidene (1), namely its capability to be functionalized (Schemes 8, 9), dimerized (Scheme 15), and stereoselectively reduced (Scheme 53) opens up new perspectives to approach the assembly of quatercyclopropyl derivatives. 

Only three of the six possible trisadducts were obtained upon cyclopropanation of e-4. Especially, the adducts with the addition patterns e,e,-trans-l (I) and e,e,-trans-1 (11) did not form [20]. Access to corresponding adducts requires trans-1 precursors and/or tether strategies (Section 10.3.3). Although the relative yield of e,e,e-8 constitutes about 35-40% of the trisadducts formed and the yield of e,trans-3,trans- 2-12 is higher, the preferred mode of addition is e relative to the... 

To improve the yield of six-times cyclopropanated adducts such as Tfj-C55(COOEt)i2 (17) a very efficient one-pot method has been developed (Scheme 10.7) [1, 25, 26, 58, 59]. The lynchpin of this strategy was the discovery that 9,10-dimethylanthracene... 

Finally, an entirely different approach to milnacipran (2) was recently reported in the literature (Scheme 14.6). In this case, the general strategy is based on position-selective deprotonation of cyclopropane carboxamides. Thus, cyclopropane amide 27, which was easily prepared from commercially available cyclopropane carboxylic acid, underwent... 

Functionalized zinc carbenoids have been prepared from carbonyl compounds by an indirect strategy. The deoxygenation of a carbonyl compound to an organozinc carbenoid can be induced by a reaction with zinc and TMSCl. Therefore, the aldehyde or ketone, when treated with TMSCl or l,2-bis(chlorodimethylsilyl)ethane in the presence of an alkene, generates the cyclopropanation product. This method is quite effective for the production of alkoxy-substituted cyclopropane derivatives. A 55% yield of the... 

An alternate strategy to access cyclopropanol derivatives from an acyclic precursor has been reported by Imai and coworkers (equation 79). Alkyne hydroboration followed by treatment of the resulting boronic acid with tetramethyltartramide produced the cyclopropanation precursor. A subsequent diastereofacial cyclopropanation afforded the... 

Another example is the indirect acetonylation of a 1,2,3,4-tetrahydropyridine derivative at the (3-position of the enamide system [99]. The reaction involves a double alkylation to furnish an acetylcyclopropane which undergoes fragmentation on acid treatment. It is noted that polarity alternation and ring strain relief allow the facile and regiospecific C-C bond cleavage to proceed, the intervention of a cyclopropane intermediate also leads to disjoint system. This is a fundamental strategy [100] which has been frequently employed to gain access to compounds with disjoint functionalities. 

STRATEGY We need to plot ln[cyclopropane]( as a function of t and see whether we obtain a straight line. If we do get a straight line, the reaction is first order and the slope of the graph is the value of —k. 

---