Reductive desilylation

Aliphatic thiols may be prepared from the corresponding halides via a procedure which involves preparation of a-trimethylsiloxy-sulphides followed by extremely mild, two-step, reductive desilylation (Scheme 52). 6 Polymer-supported diaryl selenoxides (35a) and telluroxides... 

Scheme 10-42 Radical cyclization and reductive desilylation allows stereospecific methylation of steroids and formation of a cis or a trans ring junction.

Although the biosynthetic cascade hypothesis predicts the co-occurrence of endiandric acids D (4) and A (1) in nature, the former compound was not isolated until after its total synthesis was completed in the laboratory (see Scheme 6). Our journey to endiandric acid D (4) commences with the desilylation of key intermediate 22 to give alcohol 31 in 95% yield. The endo side chain is then converted to a methyl ester by hydrolysis of the nitrile to the corresponding acid with basic hydrogen peroxide, followed by esterification with diazomethane to afford intermediate 32 in 92% overall yield. The exo side chain is then constructed by sequential bromination, cyanide displacement, ester hydrolysis (33), reduction, and olefination (4) in a straight-... 

In this section primarily reductions of aldehydes, ketones, and esters with sodium, lithium, and potassium in the presence of TCS 14 are discussed closely related reductions with metals such as Zn, Mg, Mn, Sm, Ti, etc., in the presence of TCS 14 are described in Section 13.2. Treatment of ethyl isobutyrate with sodium in the presence of TCS 14 in toluene affords the O-silylated Riihlmann-acyloin-condensation product 1915, which can be readily desilylated to the free acyloin 1916 [119]. Further reactions of methyl or ethyl 1,2- or 1,4-dicarboxylates are discussed elsewhere [120-122]. The same reaction with trimethylsilyl isobutyrate affords the C,0-silylated alcohol 1917, in 72% yield, which is desilylated to 1918 [123] (Scheme 12.34). Likewise, reduction of the diesters 1919 affords the cyclized O-silylated acyloin products 1920 in high yields, which give on saponification the acyloins 1921 [119]. Whereas electroreduction on a Mg-electrode in the presence of MesSiCl 14 converts esters such as ethyl cyclohexane-carboxylate via 1922 and subsequent saponification into acyloins such as 1923 [124], electroreduction of esters such as ethyl cyclohexylcarboxylate using a Mg-electrode without Me3SiCl 14 yields 1,2-ketones such as 1924 [125] (Scheme 12.34). 

The reaction of the aldehyde 174, prepared from D-glucose diethyl dithio-acetal by way of compounds 172 and 173, with lithium dimethyl methyl-phosphonate gave the adduct 175. Conversion of 175 into compound 176, followed by oxidation with dimethyl sulfoxide-oxalyl chloride, provided diketone 177. Cyclization of 177 with ethyldiisopropylamine gave the enone 178, which furnished compounds 179 and 180 on sodium borohydride reduction. 0-Desilylation, catalytic hydrogenation, 0-debenzyIation, and acetylation converted 179 into the pentaacetate 93 and 5a-carba-a-L-ido-pyranose pentaacetate (181). 

Enones and enoates undergo 1,2-reduction [115, 191]. Lipshutz et al. reported the effective protection of carbonyl functions by the triisopropylsilyl acyl silane group (TIPS), which allowed the selective conversion of alkenes or alkynes to the corresponding zirconocene complexes [24]. The aldehyde could subsequently be regenerated by desilylation with TBAF [186]. 

Evidently, an increase in steric hindrance around the reduced fragment requires the presence of ammonium fluoride in the reaction mixture. It should be noted that potassium fluoride has no effect. It is highly probable that ammonium fluoride is required for slow elimination of HF, which gradually desilylates the nitroso acetal fragment thus facilitating its reduction. As can be seen from Scheme 3.284, many reduction products are derivatives of unnatural amino acids. Since the initial nitroso acetals can be prepared by silylation of simple acyclic AN, possibilities have been opened for the synthesis of unnatural amino acids from available AN. 

On the other hand, the use of [Rh(CO)2Cl]2 as a catalyst results in ring opening of the siloxycyclopropanes 13 to the silyl enol ethers 14 with high stereoselectivity [10]. The 2-siloxyrhodacyclobutane 15a is proposed to undergo j8-elimination to give jr-allylrhodium 16a followed by reductive elimination to the silyl enol ether 14a. 1-Trimethylsiloxybicyclo[n.l.0]alkanes serve as / -metallo-carbonyl compounds via desilylation with a variety of transition metals [11]. The palladium-catalyzed reaction of the siloxycyclopropanes 17 under carbon monoxide in chloroform provides a route to the 4-keto pimelates 18. In the presence of aryl triflates, the 1,4-dicarbonyl compounds 19 are... 

The same basic strategy was applied to the synthesis of the smaller fragment benzyl ester 28 as well (Scheme 4). In this case, aldehyde 22 prepared from (S)-2-hydroxypentanoic acid [9] was allylated with ent-10 and tin(IV) chloride, and the resulting alcohol 23 was converted to epimer 24 via Mitsunobu inversion prior to phenylselenenyl-induced tetrahydrofuran formation. Reductive cleavage of the phenylselanyl group, hydrogenolysis of the benzyl ether, oxidation, carboxylate benzylation, and desilylation then furnished ester 28. 

With both building blocks 103 and 109 in hand, the total synthesis of lb was completed as shown in Scheme 17. Coupling of acid 103 and alcohol 109 under Yamaguchi conditions to give ester 110 and subsequent desilylation followed by chemoselective oxidation provided hydroxy acid 111. Lactonization of the 2-thiopyridyl ester derived from 111 in the presence of cupric bromide produced the macrodiolide 112 in 62% yield, which was finally converted to pamamycin-607 (lb) via one-pot azide reduction/double reductive AT-methylation. In summary, 36 steps were necessary to accomplish the synthesis of lb from alcohols 88 and 104, sulfone 91, ketone 93, and iodide rac-97. 

Perlmutter used an oxymercuration/demercuration of a y-hydroxy alkene as the key transformation in an enantioselective synthesis of the C(8 ) epimeric smaller fragment of lb (and many more pamamycin homologs cf. Fig. 1) [36]. Preparation of substrate 164 for the crucial cyclization event commenced with silylation and reduction of hydroxy ester 158 (85-89% ee) [37] to give aldehyde 159, which was converted to alkenal 162 by (Z)-selective olefination with ylide 160 (dr=89 l 1) and another diisobutylaluminum hydride reduction (Scheme 22). An Oppolzer aldol reaction with boron enolate 163 then provided 164 as the major product. Upon successive treatment of 164 with mercury(II) acetate and sodium chloride, organomercurial compound 165 and a second minor diastereomer (dr=6 l) were formed, which could be easily separated. Reductive demercuration, hydrolytic cleavage of the chiral auxiliary, methyl ester formation, and desilylation eventually led to 166, the C(8 ) epimer of the... 

Synthesis of a C(8)-C(18) segment of the larger fragment of lb using the same basic strategy is depicted in Scheme 25. Here, hydroxy ketone 176 was subjected to syn-selective (dr of crude product=90 10) reductive amination [42] with sodium cyanoborohydride and benzylamine followed by tetrahydro-oxazine formation using aqueous formaldehyde. The resulting heterocycle 182 was then converted to unsaturated ester 184 by successive desilylation, oxidation, and entirely (Z)-selective Horner-Wadsworth-Emmons olefination. Re-... 

Reductive y-lactone ring opening, with concomitant desilylation at the tertiary position by LiAlH4, gave triol 17 in 80% yield. Finally, acetonide formation followed by oxidation with tetra-n-propylammonium perruthenate/A-methylmorpholine / /-oxide oxidation, led to the target aldehyde 19 in 80% overall yield. 

The cationic complex [Ir(CO)(ic -N,N,N-(S,S)- Pr-pybox)][PF,5] [50] was also found to be catalytically active in the addition of Ph2SiPt2 to acetophenone, with complete conversion of the ketone into the corresponding silyl ether (I) at room temperature after 72 h of reaction. However, desilylation of the product (I) led to racemic 1-phenylethanol, which means that the reduction took place without asymmetric induction. 

In the hopes of accessing similar molecules that would contain C-6 functionalization, our group explored the cycloisomerization of such alkyne hemiketals as 152.70 Compound 152 was prepared by addition of ethynyltrimethylsilane to 5-0-terf-butyl-diphenylsilyl-2,3-0-isopropylidene-D-ribonolactone (151), followed by desilylation (25% over two steps). Trie thy lamine-mediated cycloisomerization71 provided an oxepinone, compound 153, in 41% yield. 1,2-Reduction of the enone functionality followed by acetylation under standard conditions provided 154 in 56% yield over two steps as a 3 1 ratio of diasteromers (the favored diastereomer is shown in Scheme 24). A small group of oxepines were prepared by this method. Variability in the yield of the cyclization step, which was moderate at best, has prevented this route from being applied more generally for the preparation of oxepines. 

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