Lactol intermediates

Scheme 1.57). Although the natural donor aldehyde is D-2-deoxyribose-5-phosphate, non-phosphorylated donor aldehydes are also tolerated and the enzyme displays some flexibility towards both donor and acceptor. Importantly, as both donor and acceptor substrates are aldehydes, the enzyme can perform sequential aldol reactions allowing the preparation of a key lactol intermediate to the atorvastatin side chain in a single step. Following substantial modification, this approach is now operated on an industrial scale to... 

Recently, Ma and co-workers [41] reported a related Michael-acetalization sequence between (S,7-unsaturated a-ketoesters and cyclic 2-oxo aldehydes with a cinchona alkaloid-based organocatalyst (Scheme 16.20). The lactol intermediates were oxidized to the desired spirolactones obtained in good yields and excellent stereoselectivities. Hong et al. [42] used 2-hydroxynitrostyrenes instead of unsaturated ketoesters exploiting the same strategy for the synthesis of spirolactones with similar efficiency. 

Ernest, Woodward and colleagues employed the related lactol intermediate (10a) [21]. This was synthesized from the tricyclic lactone (4) prepared from c/s-1,3,5-cyclohexanetriol and glyoxylic acid which was converted in three steps... 

Later, Ramachary and Sakthidevi reported for the first time the organo-catal)Aic cascade approach to the asymmetric synthesis of functionalised chromans via Barbas-List aldol-acetalisation reaction, as depicted in Scheme 2.28. The reaction of acetone with 2-hydro ybenzaldehyde under trans-4-OH-L-proline-catalysis in NMP as solvent furnished the corresponding aldol/lactol intermediate which upon treatment with p-TSA in methanol in one-pot furnished the selectively frans-2-metho y-2-methyl-chroman-4-ol in 55% yield and 77% ee, as shown in Scheme 2.28. 

Allenyl analogues (182) and (183) of the F, - and E-series have been synthesized by the Syntex group starting from the lactol intermediate (9) from Corey s PG synthesis (Scheme 39). ... 

The two 2,6-cis THP rings present in the monomeric unit of the dimeric diolide (-t)-SCH 351448 offered Backes and Koert an opportunity to exploit stereoselective lactol reductiOTi (Scheme 70) [128]. Lewis acid activation of ketones 266 and 268 with BF3-OEt2, followed by closure with the pendant silyl ether, provides lactol intermediates. Subsequent oxocarbenium ion formation and hydride delivery by triethylsilane afforded the 2,6-cis THP rings 267 and 269 in high yields (98 % and 93 %, respectively) as single diastereomers. 

Dujardin et al. have reported the synthesis of simple optically pure mevalonolactone derivatives via a hetero Diels-Alder cycloaddition [92] (Scheme 48). The lanthanide Lewis acid-catalyzed hetero Diels-Alder cycloaddition of ferf-butyloxymethylenepyruvate 230 with a vinyl ether derived from mandelic acid 231 afforded a cycloadduct, which on hydrogenolysis gave the saturated adduct 232. This intermediate was then transformed into the mevalonolactone derivative 234 in a few steps through oxidation of a lactol intermediate 233. 

Conjugate addition of methyl magnesium iodide in the presence of cuprous chloride to the enone (91) leads to the la-methyl product mesterolone (92) Although this is the thermodynamically unfavored axially disposed product, no possibility for isomerization exists in this case, since the ketone is once removed from this center. In an interesting synthesis of an oxa steroid, the enone (91) is first oxidized with lead tetraacetate the carbon at the 2 position is lost, affording the acid aldehyde. Reduction of this intermediate, also shown in the lactol form, with sodium borohydride affords the steroid lactone oxandrolone... 

In addition to its other properties, interest in the potential use of the vasodilative properties of prostaglandin El, alprostadil ( ), has led to several conceptually different syntheses.For this purpose, the classic Corey process has to be modified by reversing the order of addition of the side chains to allow for convenient removal of the unwanted double bond in the upper side chain. For example, Corey lactone is protected with dihydropyran (acid catalysis), reduced to the lactol with diisobutyaluminum hydride, and then subjected to the usual Wittig reaction to give intermediate This is... 

With the co side chain at C-12 in place, we are now in a position to address the elaboration of the side chain appended to C-8 and the completion of the syntheses. Treatment of lactone 19 with di-isobutylaluminum hydride (Dibal-H) accomplishes partial reduction of the C-6 lactone carbonyl and provides lactol 4. Wittig condensation8 of 4 with nonstabilized phosphorous ylide 5 proceeds smoothly and stereoselectively to give intermediate 20, the bistetra-hydropyranyl ether of ( )-1, in a yield of -80% from 18. The convergent coupling of compounds 4 and 5 is attended by the completely selective formation of the desired cis C5-C6 olefin. 

Although it may not be obvious, putative intermediate 12 could conceivably be fashioned in one step from lactol 13. Of course, 13 can be regarded as a latent aldehyde that should be amenable to an a-chelation-controlled carbonyl addition reaction21 with ethyl-magnesium bromide. This event could secure the formation of the indicated stereocenter in intermediate 12. It seems reasonable to suppose that the sequential action of aqueous acid and 1,1-... 

Subjection of intermediate 16 to the action of 3 n aqueous HC1 in THF results in the formation of monocyclic lactol 14. In the presence of aqueous acid, the internal acetal grouping in intermediate 16 is hydrolyzed and lactol 14 is produced after the liberated secondary hydroxyl group attacks the terminal aldehyde carbonyl positioned five atoms away (see intermediate 15). Protection of the free aldehyde function in 14 with 1,1-dimethylhydrazine proceeds smoothly under dehydrating conditions and affords intermediate 13 in an overall yield of 72 %. 

The completion of the synthesis of key intermediate 2 requires only a straightforward sequence of functional group manipulations. In the presence of acetone, cupric sulfate, and camphorsulfonic acid (CSA), the lactol and secondary hydroxyl groups in 10 are simultaneously protected as an acetonide (see intermediate 9). The overall yield of 9 is 55 % from 13. Cleavage of the benzyl ether in 9 with lithium metal in liquid ammonia furnishes a diol (98% yield) which is subsequently converted to selenide 20 according to Grie-co s procedure22 (see Scheme 6a). Oxidation of the selenium atom... 

The synthesis of key intermediate 6 begins with the asymmetric synthesis of the lactol subunit, intermediate 8 (see Scheme 3). Alkylation of the sodium enolate derived from carboximide 21 with allyl iodide furnishes intermediate 26 as a crystalline solid in 82 % yield and in >99 % diastereomeric purity after recrystallization. Guided by transition state allylic strain conformational control elements5d (see Scheme 4), the action of sodium bis(trimethylsilyl)amide on 21 affords chelated (Z)-enolate 25. Chelation of the type illustrated in 25 prevents rotation about the nitrogen-carbon bond and renders... 

Similarly, (A )-( )-3-(2-methoxymethyl-l-pyrrolidinyl)-l-phenylpropene118 121, after lithia-tion and addition of acetone, acidic hydrolysis and oxidation of the intermediate lactol, gives (5)-dihydro-5,5-dimethyl-4-phenyl-2(3/f)-furanone with 98% ee and 54% overall yield. Thus, these sequences constitute asymmetric homoaldol addition. 

MISCELLANEOUS BENZOHETEROCYCLES Partial reduction of lactone 166 (using for example diisobutylaluminum hydride in the cold) affords lactol 167. Condensation with nitromethane leads to the corresponding alkylated tetrahydrobenzopyran 170. The sequence probably starts by aldol reaction of the hydroxylactone form of the lactol (168) with nitrome thane to give the vinyl nitro intermediate 169 ... 

A simple cyclization was carried out to test the ability of chloro azidoalkene cyclization to generate quinolizidines. Reduction of 6-valerolactone to the corresponding lactol was followed by a Wittig reaction onto the carbonyl function employing an appropriate phosphonium salt, and the intermediate primary alcohol thus formed afforded the chloro... 

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