Induced stereoselectivity

The detailed explanation of the reaction mechanism and the stereoselection induced b> transition metal catalysts along with some early examples of Pd-catalyzed chiral conversions. 

The addition of (219) to ,j8-dialkoxynitrones (220) can be rationalized by assuming a transition state model A (Figure 2) similar to that involved in nucleophilic addition to C= (Houk model) <82JA7162>. The reversal of stereoselectivity induced by diethyl aluminum chloride is consistent with a j8-chelation model B. The scope and the synthetic utility of these reactions have been amply demonstrated <95MI 306-01 >. 

Chelated transition state models have been proposed to account for the high stereoselectivities induced by the DiTOX system in many synthetic transformations. These are highlighted below for the case of enolate alkylation. 

The less expensive dibromomethane has been used in the presence of an in situ formed zinc-copper couple. 33 xhe method, however, fails with aromatic annulene compounds.234 The reaction provides good results with functional olefins. The stereoselectivity induced by the hydroxyl group is similar to that of the conventional reaction (Eq. 51).235... 

Chitin is the most abimdant organic macromolecules in the animal field found in invertebrates (12). The in vitro ssmthesis of this important biomacromolecule has been achieved for the first time by enzymatic ring-opening polyaddition of a chitobiose oxazoline monomer (Fig. 3). Chitinase, a hydrolysis enzyme of chitin, regio- and stereoselectively induced the polymerization of the monomer in a basic buffer (38—41). It is postulated that the monomer is preferable as a... 

Table 58.2 also indicates diastereomer ratios for the cyclobutanols formed from some of the ketones. One particularly interesting case involves a-methylbutyrophenone (aMeBP) and valerophenone (VP) forming the same 2-methyl-1-phenylcyclobutanol but with much different stereoselectivity. aMeBP forms a single isomer with the methyl and phenyl groups trans, whereas VP forms a 3 1 ratio favoring that isomer. VP exemplifies stereoselectivity induced by nonbonded interactions created as the two radical sites approach each other, whereas aMeBP exemplifies stereoselectivity induced by pre-existing nonbonded interactions in the biradical. In the former case, selectivity appears to mirror relative product energies in the latter, it mirrors relative biradical conformational preferences. Scheme 6 illustrates both types of selectivity. 

Open-chain 1,5-polyenes (e.g. squalene) and some oxygenated derivatives are the biochemical precursors of cyclic terpenoids (e.g. steroids, carotenoids). The enzymic cyclization of squalene 2,3-oxide, which has one chiral carbon atom, to produce lanosterol introduces seven chiral centres in one totally stereoselective reaction. As a result, organic chemists have tried to ascertain, whether squalene or related olefinic systems could be induced to undergo similar stereoselective cyclizations in the absence of enzymes (W.S. Johnson, 1968, 1976). 

Non-enzymatic cyclizations of educts containing chiral centres can lead to products with additional "asymmetric centres. The underlying effect is called "asymmetric induction . Its systematic exploration in steroid syntheses started when G. Saucy discovered in 1971 that a chiral carbon atom in a cyclic educt induces a stereoselective Torgov condensation several carbon atoms away (M. Rosenberger, 1971, 1972). 

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolate (178) to the scalemic sulfoxide (179). Direct treatment of the cmde Michael adduct with y /i7-chloroperbenzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (180, X = a and PH R = H) in over 90% yield. Similarly to the conversion of (175) to (176), base-catalyzed epimerization of (180) produces an 85% isolated yield of (181, X = /5H R = H). C8 and C14 of (181) have the same relative and absolute stereochemistry as that of the naturally occurring steroids. Methylation of (181) provides (182). A (CH2)2CuLi-induced reductive cleavage of sulfone (182) followed by stereoselective alkylation of the resultant enolate with an allyl bromide yields (183). Ozonolysis of (183) produces (184) (wherein the aldehydric oxygen is by isopropyUdene) in 68% yield. Compound (184) is the optically active form of Ziegler s intermediate (176), and is converted to (+)-estrone in 6.3% overall yield and >95% enantiomeric excess (200). 

A stereoselective determination of enantiomers of 5, its A -oxide and N-desmethyl metabolites in human urine was developed by capillary electrophoresis using laser-induced fluorescence detection and sulfonated /1-cyclodextrin in the running buffer (01JC(B)169). 

A rather unexpected discovery was made in connection to these investigations [49]. When the 1,3-dipolar cycloaddition reaction of la with 19b mediated by catalyst 20 (X=I) was performed in the absence of MS 4 A a remarkable reversal of enantioselectivity was observed as the opposite enantiomer of ench-21 was obtained (Table 6.1, entries 1 and 2). This had not been observed for enantioselective catalytic reactions before and the role of molecular sieves cannot simply be ascribed to the removal of water by the MS, since the application of MS 4 A that were presaturated with water, also induced the reversal of enantioselectivity (Table 6.1, entries 3 and 4). Recently, Desimoni et al. also found that in addition to the presence of MS in the MgX2-Ph-BOX-catalyzed 1,3-dipolar addition shown in Scheme 6.17, the counter-ion for the magnesium catalyst also strongly affect the absolute stereoselectivity of the reac-... 

Stereoselective preparation of CEi-allyl alcohols via radical elimination from ruin -y-phenylthio-fi-nkro alcohols has been reported. The requisiteruin -fi-nitro sulfides are prepared by protonadon of nitronates at low temperanire Isee Chapter 4, and subsequent treatment v/ith Bu-vSnH induces and eliminadon to givelE -alkenes selecdvely IseeEq. 7.112. Unfortunately, it is difficult to get the pure syu-fi-nitro sulfides. Treatment of a rruxnire of syu- and ruin -fi-nitrosulfides v/ith Bu- SnH results in formadon of a rruxnire of (Ey and lZ -alkenes. 

An expedient and stereoselective synthesis of bicyclic ketone 30 exemplifies the utility and elegance of Corey s new catalytic system (see Scheme 8). Reaction of the (R)-tryptophan-derived oxazaboro-lidine 42 (5 mol %), 5-(benzyloxymethyl)-l,3-cyclopentadiene 26, and 2-bromoacrolein (43) at -78 °C in methylene chloride gives, after eight hours, diastereomeric adducts 44 in a yield of 83 % (95 5 exo.endo diastereoselectivity 96 4 enantioselectivity for the exo isomer). After reaction, the /V-tosyltryptophan can be recovered for reuse. The basic premise is that oxazaborolidine 42 induces the Diels-Alder reaction between intermediates 26 and 43 to proceed through a transition state geometry that maximizes attractive donor-acceptor interactions. Coordination of the dienophile at the face of boron that is cis to the 3-indolylmethyl substituent is thus favored.19d f Treatment of the 95 5 mixture of exo/endo diastereo-mers with 5 mol % aqueous AgNC>3 selectively converts the minor, but more reactive, endo aldehyde diastereomer into water-soluble... 

A sequence of straightforward functional group interconversions leads from 17 back to compound 20 via 18 and 19. In the synthetic direction, a base-induced intramolecular Michael addition reaction could create a new six-membered ring and two stereogenic centers. The transformation of intermediate 20 to 19 would likely be stereoselective substrate structural features inherent in 20 should control the stereochemical course of the intramolecular Michael addition reaction. Retrosynthetic disassembly of 20 by cleavage of the indicated bond provides precursors 21 and 22. In the forward sense, acylation of the nitrogen atom in 22 with the acid chloride 21 could afford amide 20. 

The elaboration of the polyunsaturated side chain of asteltoxin requires a stereoselective coupling of aldehyde 2 with a suitable synthetic equivalent for the anion of 4-formyl-1,3-butadiene (see intermediate 3 in Scheme 4). Acid-induced skeletal reorganization of the aldehyde addition product, followed by an intermolecular... 

It was projected that compound 13 could be stereoselectively linked, through its free phenolic hydroxyl group, with the anomeric carbon of intermediate 12 under suitably acidic conditions (see Scheme 8). Gratifyingly, the action of boron trifluoride etherate on a mixture of 12 and 13 in CH2CI2 at -50 °C induces a completely stereoselective glycosidation reaction, providing the desired a-ano-mer 48 in an excellent yield of 95 % from 46. It is presumed that boron trifluoride initiates cleavage of the anomeric trichloroacetimi-... 

The chelated lithium anions 1 and 2, derived from enantiomerically pure tetrahydroisoquino-line-amidines or -oxazolines, exhibit high induced stereoselectivity in alkylation reactions (Section D.l.1.1.1.3.1.). 

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