Stereoselective oxymercuration

The approach to polyketide synthesis described in Scheme 5.2 requires the relatively nontrivial synthesis of acid-sensitive enol acetals 1. An alternative can be envisioned wherein hemiacetals derived from homoallylic alcohols and aldehydes undergo dia-stereoselective oxymercuration. Transmetallation to rhodium could then intercept the hydroformylation pathway and lead to formylation to produce aldehydes 2. This proposal has been reduced to practice as shown in Scheme 5.6. For example, Yb(OTf)3-cata-lyzed oxymercuration of the illustrated homoallyhc alcohol provided organomercurial 14 [6]. Rhodium(l)-catalyzed hydroformylation of 14 proved successful, giving aldehyde 15, but was highly dependent on the use of exactly 0.5 equiv of DABCO as an additive [7]. Several other amines and diamines were examined with variation of the stoichiometry and none proved nearly as effective in promoting the reaction. This remarkable effect has been ascribed to the facilitation of transmetallation by formation of a 2 1 R-HgCl DABCO complex and the unique properties of DABCO when both amines are complexed/protonated. 

Since segment A (4) is a somewhat large molecule, it was subdivided into Aj (5) and A2 (6). The 2-acetoxyglucal (7) was first converted to 10 via 8 and 9. Stereoselective oxymercuration of the double bond in 10 and subsequent reduction with sodium borohydride gave the diol (11). After protection of the diol, the acetal was cleaved and oxidized to give the lactone (segment A 5) [5a, c]. 

Stereoselective intramolecular oxymercuration of carbohydrate derivatives was proposed as the key reaction for efficient preparation of mono- and dihydroxylated unsymmetrical bis-tetrahydrofuran skeletons present in naturally occurring biologically active acetogenins. The trans- and. mz-selective intramolecular oxymercurations were explored in an enantioselective synthesis of the bis-tetrahydrofuran skeleton of mucoxin (Fig. 57).73... 

Subsequent isolation of solvomercuration products has supplied information about the stereoselectivity of the mercury addition and at the same time has shown that these reactions can give 1,2- and/or 1,4-addition products. In particular, the identification by XH NMR spectroscopy of a 1,4-adduct from 1,3-pentadiene and mercury(II)nitrate in methanol has provided155 the first direct evidence that oxymercuration of conjugated dienes can proceed by 1,4-addition. Furthermore, the observed Z,E-isomerization of the diene has shown that the 1,4-oxymercuration is a reversible process. 

Access to the corresponding enantiopure hydroxy esters 133 and 134 of smaller fragments 2 with R =Me employed a highly stereoselective (ds>95%) Evans aldol reaction of allenic aldehydes 113 and rac-114 with boron enolate 124 followed by silylation to arrive at the y-trimethylsilyloxy allene substrates 125 and 126, respectively, for the crucial oxymercuration/methoxycarbonylation process (Scheme 19). Again, this operation provided the desired tetrahydrofurans 127 and 128 with excellent diastereoselectivity (dr=95 5). Chemoselective hydrolytic cleavage of the chiral auxiliary, chemoselective carboxylic acid reduction, and subsequent diastereoselective chelation-controlled enoate reduction (133 dr of crude product=80 20, 134 dr of crude product=84 16) eventually provided the pure stereoisomers 133 and 134 after preparative HPLC. 

Only scattered information is available on oxymercuration of alkynes. Alkylphe-nylacetylenes were found to undergo stereoselective anti addition.500 Diphenylace-tylene, in contrast, gives only syn adducts.501... 

Cyclization of a variety of y-allenic alcohols with silver nitrate proceeds by 5-exo cyclization to form 2-alkenyltetrahydrofurans (equation 87).205c 206 Little stereoselectivity is seen in cyclizations of secondary alcohols. Cyclization by intramolecular oxypalladation/methoxycarbonylation or oxymercuration followed by transmetallation and methoxycarbonylation also showed no stereoselectivity (equation 88 and Table 24, entries 1 and 2).50 207 However, cyclization of the corresponding r-butyldimethylsilyl ether derivatives with mercury(II) trifluoroacetate followed by transmetallation/methoxycarbonylation pro-... 

Descotes et al. developed a stereoselective photocyclisation procedure of hydrox-alkyl glycosides to give spiro orthoesters [135]. By oxymercuration of the glycal 154... 

Polyene cyclization. Cyclization of dienes by oxymercuration ordinarily is not stereoselective. However, the presence of an allylic hydroxyl groups can increase the stereoselectivity. Thus oxymercuration-demercuration of linalool (1) under the best conditions leads mainly to the iridanols 2 and 3, which constitute 85% of the... 

The stereoselectivities in the cleavage of the C—Hg bond with NaBHa depend upon the nature of the radical intermediates and the reaction conditions. Recent attempts to find optimal conditions for this stereoselective cleavage have been published. " The principle is given in Scheme 27 for the oxymercur-ation-demercuration of a,P-unsaturated esters, generating two asymmetric centers in the 3-alkoxy-2-alkyl ester. 

Zhao and co-workers 48) reported the first synthesis of homoharringtonine (3) in 1980 (Scheme 20). Unsaturated keto acid 151, prepared either from 5,5-dimethyl-5-valeroIactone 150, or by chain extension from the commercially available bromide 149, was esterified with cephalotaxine to give the cephalotaxyl derivative 152, which reacted with methyl bromoacetate under Reformatsky conditions to yield a mixture of epimers of dehydro-homoharringtonine 153. This mixture was converted to homoharringtonine and its epimer by means of oxymercuration, as well as by acid catalysis. As in the aforementioned syntheses of harringtonine, the Reformatsky reaction proceeded with no stereoselectivity, and diastereomeric mixtures resulted from all of these approaches. 

Fig. 7). The ring closure also proved to be remarkably stereoselective. Thus intramolecular oxymercuration, followed by reductive demercuration, provided the tetrahydropyran (22, ring A of X-206) with the desired 2,6-cis-relative stereochemistry in excellent overall yield as a single diastereomer. 

In preliminary studies we have found that this is also a powerful approach to the preparation of enantiomerically pure complex spiroacetals (Fig. 22 [23,24]). Intramolecular oxymercuration of 84 proceeds efficiently, although without any stereoselectivity. 

Scheme 9. Stereoselective intramolecular oxymercuration-demercuration approach (46). Reagents and conditions (a) Hg(OAc) (b) aq. NaOH NaBU, n-Bu4NOH.

The challenge to the synthetic chemist that was posed by these structures was the control of C6 stereochemistry. An early solution to this problem involved the intramolecular oxymercuration-demercuration approach, as illustrated in Scheme 9 (46,58). Thus, the stereoselective cyclization of 38 to the tricycUc cannabinoid skeleton by means of the intramolecular oxymercuration-demercuration reaction (58,61) gave the 6P-isomer predominantly (6P 6a = 85 15). The enantiomers were separated by chiral high-performance liquid chromatography (HPLC) using Chiralpak OD columns. The probable... 

Stereoselectivity in the oxymercur-ation-demercurationof 2,3-dimeth-ylcyclopentene. 

In the oxymercuration step, water and mercuric acetate add to the double bond in the demercuration step, sodium borohydride reduces the acetoxymercury group and replaces it with hydrogen. The net addition of H — and —OH takes place with MaJ-kovnikov t oselectivity and generally takes place without the complication of rearrangements, as sometimes occurs with acid-catalyzed hydration of alkenes. The overall alkene hydration is not stereoselective because even though the oxymercuration step occurs with anti addition, the demercuration step is not stereoselective (radicals are thought to be involved), and hence a mixture of syn and anti products results. 

In the first step, boron and hydrogen undergo syn addition to the alkene in the second step, treatment with hydrogen peroxide and base replaces the boron with — OH with retention of configuration. The net addition of —H and —OH occurs with autl-Markovnikov regioselectivity and syn stereoselectivity. Hydroboration-oxidation, therefore, serves as a useful regiochemical complement to oxymercuration-demercuration. 

The synthesis began with Yb(OTf)3-catalyzed oxymercuration [88] of ho-moallyUc alcohol 204 [89], prepared by asymmetric allylation with Brown s reagent, to generate organomercury chloride 205. Rh(I)-catalyzed formy-lation [90] of 205 in the presence of DABCO (0.5 equiv.) furnished aldehyde 206. Stereoselective crotylation of 206 via Brown s reagent, followed by regioselective Rh(I)-catalyzed hydroformylation provided lactol 203. Dia-... 

The 2,6-czs-dihydropyran 340 was synthesized by the Panek-modified Prins reaction between the chiral aldehyde 338 and the chiral syn-allylsilane 339 mediated by triflic acid. The key point of the stereoselectivity is the sterically hindered electron-withdrawing mesylsulfonate, which induced the chair-like transition state 341. Cyanation, regioselective oxymercuration, and... 

The fact that the oxymercuration step is both regioselective and anti stereoselective has led chemists to propose the following mechanism, which is closely analogous to that for the addition of Btj and CI2 to an alkene (Section 6.3D). 

Oxymercuration-Reduction (Section 6.3F) Oxymercuration-reduction is used to convert alkenes to alcohols. The mechanism involves reaction of the alkene tt bond with an HgOAc+ to give a bridged mercurinium ion intermediate (a cation) that is, in turn, attacked by HjO from the backside to give a new intermediate, which loses a proton. In a second step, NaBH is added to replace the Hg atom with H.The first step is anti stereoselective because HgOAc and OH add from opposite faces of the alkene. However, the NaBH reduction step scrambles the stereochemistry as H replaces Hg, so the overall process is scrambled... 

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