Copper acetal deprotection

Copper-based Lewis acids have some advantages for hydrolysis reactions they are mild, nonacidic, and can control reactions due to chelation by the substrate to achieve high selectivity. CuS04 is effective for acetal deprotection (Scheme 47).197 Thioacetals198,199 and selenoacetals200-202 are also hydrolyzed by copper Lewis acids, and dehydration is accelerated by Cu11 Lewis acids under mild conditions.203... 

M[pz(A4)] A = S2ML2. The octakis(.V-R)porphyra/,ines reported by Schramm and Hoffman (2), M[pz(S-R)8 (M = Ni, Cu), (60), can be converted to the octathiolate M[pz(S )g] (Scheme 11) via reductive cleavage of the sulfur-carbon bond when R = benzyl (Bn), and this tetra-bis(dithiolate) can then be peripherally capped with metal-ligand systems to yield peripherally tetrametalated star porphyrazines. The benzyl dinitrile 57 can be macrocyclized around magnesium butoxide to form [Mg[pz(S-Bn)8] (58) (35-40%), which can then be demetalated with trifluoroacetic acid to form 59 (90%), which is subsequently remetalated with nickel or copper acetate to form 60a (95%) and 60b (70%) (Scheme 11) (3, 23, 24). Deprotection of 60a or 60b with sodium in ammonia yields the Ni or Cu tetra-enedithiolates, 61a or 61b to which addition of di-ferf-butyl or n-butyl tin dinitrate produces the peripherally metalated star porphyrazines 62a (37%), 62b (80%), and 62c (41%). 

Afterward, the peptide chain was elongated following the standard Fmoc-based protocol. Before cleavage of the peptide the incorporated Mmt-protected cysteine was deprotected using 1% TFA. Under these very mild conditions the farnesyl moiety was not harmed. Palmitoylation could he achieved using an excess of palmitoyl chloride. Cleavage with copper acetate and methanol as a nucleophile gave the farnesylated and palmitoylated N-Ras sequence with the C-terminal methyl ester 78. ... 

The utility of the phenacyl group is exemplified in the C-terminal deprotection [Scheme 6.70] taken from Schmidt s synthesis of the immunosuppressive and antiviral cyclodepsipeptide Didemnin.113 Here, the phenacyl ester was reduc-tively cleaved with zinc in acetic acid. A similar transformation was used in a synthesis of the potent protein serine/threonine phosphatase inhibitor Motupor-in.lM Zinc-copper couple is an attractive alternative that can be used on a large scale [Scheme 6.71 ]J70... 

Copper Lewis acids have found many applications in the last decade in a variety of organic transformations and more notably in enantioselective reactions. In particular, Cu(OTf)2 and Cu(SbFg)2 in conjunction with chiral bisoxazolines are the chiral Lewis acids of choice for cycloadditions, aldol reactions, ene reactions, and other selective transformations. Moderately Lewis acidic copper salts are also reagents for transesterifications, dehydrations, and hydrolysis. The thiophilic nature of copper makes them ideal for selective deprotection of thio acetals and thioesters and offer practical advantages over mercury salts. 

The mild deprotection of acetal 15 with CUSO4 in acetone was accomplished in high yield [12]. The mildness of copper Lewis acids for the hydrolysis of hydra-zones [13] is advantageous for acid-sensitive substrates (Sch. 5). The /3,a-unsaturated hydrazone 17 was effectively hydrolyzed without conjugation of the double bond to afford 18 in good yield (Sch. 5) [14]. SAMP-Hydrazones can be hydrolyzed without racemization [15]. The two-step alkylation and hydrolysis of 19 provided 20 in 84 % overall yield and 94 % ee. 

Another advantage over other Lewis acids is the thiophilic nature of copper this has led to its utility in the hydrolysis of thioacetals. Copper(II) chloride in conjunction with copper(II) oxide was introduced by Mukaiyama [16] for the deprotection of 1,3-dithianes and this method has found utility in a variety of synthetic protocols (Sch. 6) [17]. This combination, in which copper oxide plays the role of a buffer to prevent the medium from becoming too acidic, has also found application in the hydrolysis of a-heteroatom substituted and vinyl sulfides [18]. Acetals, which are prone to epimerization under acid-catalyzed hydrolysis conditions (21), can be con-... 

The CuCli-CuO promoted hydrolysis is not solely limited to thioacetals—a variety of acetals are also deprotected [21]. Treatment of 26 with the copper catalysts in acetone-water afforded the spiroacetals 27 and 28 via concomitant hydrolysis of the thioacetal and benzylidene dioxy and ethoxyethyl acetals (Sch. 7) [22], Copper(II) chloride dihydrate has also been shown to hydrolyze a variety of acetals [23] and trityl groups can also be removed in the presence of copper sulfate in benzene to afford deprotected alcohols [24]. 

The acylation of alcohols, thiols, and amines with acetic anhydride, or directly with acetic acid, can be accomplished with the aid of catalytic (2.5 mol %) Cu(OTf)2 [40]. Copper(I) and (II) chloride has been used for the acylation of a variety of a,/8-unsaturated acid chlorides (Sch. 17). Copper powder is usually added to prevent polymerization. The A -silylsulfonamide 65 was directly acylated without first deprotection to afford 66 in high... 

In order to synthesize the C5 acetate, dimethoxyacetone obtained by oxidation of acetone is ethynylated to 4,4-dimethoxy-3-methyl-l-butyn-3-ol in the presence of sodium hydroxide. Partial catalytic hydrogenation of the alkynol leads to 4,4-di-methoxy-3-methyl-l-buten-3-ol as the C5 alcohol which rearranges in acetie anhydride to the C5 aeetal ester. Deprotection of the aldehyde funetion necessary before the WiTTIG alkenylation is achieved thermally in the presence of copper(II)-salt as catalyst. 

Subsequently, compound 91 was elaborated to primary alcohol 92 with the H-ring functionality in a similar manner to the Sasaki synthesis (Scheme 11). For the introduction of the triene side chain, a simple and practical method for the stereoselective synthesis of (Z)-vinyl iodide, which is expected to be more reactive than the bromide counterpart, was developed [105]. Thus, PCC oxidation of alcohol 92 followed by treatment of the resultant aldehyde with tetraiodomethane and triphenylphosphine gave diiodoalkene 93. Reduction of 93 with the zinc-copper couple in the presence of acetic acid provided (Z)-vinyl iodide 94 in high yield. Since deprotection of the fully protected... 

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