Y-Lactols

In contrast to the results obtained with the jS-alkoxy-a-alkyl-y-lactol 16 (vide supra), a chelation-directed, anti-Cram selective nucleophilic addition to the a-methyl-y-lactol 1 was not only observed with methyllithium and methylmagnesium bromide but also with (triisopropoxy)methyl-titanium72. In fact, the highest diastereoselectivity (> 98 % de) was observed with the titanium reagent in dichloromethane as reaction solvent. A seven-membered chelate 3 with the a-methyl substituent in a pscudoequatorial position has been postulated in order to explain the stereochemical outcome. 

The acid-catalyzed reaction of enol ethers 2 (X = OR) and enamines 2 (X = NR2) to form y-lactol derivatives proceeds with great ease even on silica gel chromatography. Vinyl sulfides 2 (X = SR) or vinyl chlorides 2 (X = Cl) are difficult to hydrolyze. 

Irradiation of oxyberberine (58) in benzene in a stream of oxygen afforded directly the y-lactol 371 in 42% yield (Scheme 66). On treatment with methyl... 

Acidic treatment of prechilenine (139) (Section III,C) afforded the imino keto acid 377 via the imminium salt 140 (Scheme 68). Neutralization and work-up furnished the known y-lactol 371 in 90% overall yield from 139 (96, 181). Kondo et al. (183) obtained 139 from the epidioxide 122 by treatment with pyridine hydrochloride in pyridine along with 377 and norhydrastine. The acid 377 was converted to the known imino ester 373 through N,0-dimethylation. 

It has been demonstrated by Pancrazi, Ardisson and coworkers that an efficient kinetic resolution takes place when an excess (2 equivalents) of the racemic titanated alkenyl carbamate rac-334a (R = Me) is allowed to react with the enantiopure )-hydroxyaldehyde 341 or alternatively the corresponding y-lactol 340, since the mismatched pair contributes to a lower extent to the product ratio (equation 91) . Under best conditions, the ratio of the enantiomerically pure diastereomers 3,4-anti-4,5-syn (342) and 3,4-anti-4,5-anti (343) is close to 14 1. Surprisingly, approximately 9% of the iyw,iyw-diastereomer 344 resulted when the starting (ii)-crotyl carbamate was contaminated by the (Z)-isomer. The reasons which apply here are unknown. Extra base has to be used in order to neutrafize the free hydroxy group. The pure awft, awfi-product 345 was obtained with 85% yield from the reaction of the (W-oxy-substituted titanate rac-334b and lactol 340. 345 is an intermediate in the asymmetric synthesis of tylosine . ... 

Strong nucleophiles applied under basic conditions attack epoxides 364a at C(2) with inversion of the configuration, leading to fraw5,rran5-2,3,4-trisubstituted y-lactols 375, which are easily oxidized to the corresponding y-lactones 376 (equation 100) . 

To a solution of 0.50 g of (-)-3a,5a-dihydroxy-2p-[(3RS)-3-hydroxy-3-methyl-trans-octenyl]cyclopentane-la-acetic acid - lactone 3-benzoate in 15 ml of tetrahydrofuran at -78°C under nitrogen was added 10 ml of 10% diisobutylaluminum hydride in toluene. After a gas evolution was ceased, the reaction was quenched by addition of 10 ml of saturated aqueous ammonium chloride. The resulting mixture was stirred at room temperature, filtered through Celite, and extracted with ethyl acetate. Extract was evaporated to give 0.48 g of (-)-3a,5a-dihydroxy-2p-[3-(RS)-3-hydroxy-3-methyl-trans-octenyl]cyclopentane-l-a-acetaldehyde y-lactol 3-benzoate as an oil. 

A convenient route to 1,4-monoprotected dialdehydes, 1,4-ketoaldehydes, y-lactols and v-lactones through radical alkylation of a,p-unsaturated aldehydes in organic and, organic-aqueous media. Tetrahedron, 59, 947-957. 

It should be noted that several sensitive groups (amino, heteroaromatic, etc.) were unaffected [24], The same reagent effected the highly selective oxidation of a number of 1,4-diols to cyclic hemiacetals (y-lactols), a conversion not previously possible in one step, for example [25] ... 

Lactone ring expansion.1 The 7-lactone 2 can be expanded to the protected y-lactol 4, characteristic of mevinic acids, by reaction of the lactol of 2 with this Wittig reagent to provide a vinyl sulfide 3. Conversion of the vinyl sulfide to 4 was... 

Reaction of the enol ether 58 with dimethyl diazomalonate provides the spiro compound 59 in high yield. Reduction and acid catalyzed cyclopropane cleavage gives the unsaturated y-lactol 60 which can be oxidized to p-methylene y-butyro-lactone 61 20). 

Not surprisingly, carbonyl compounds are excellent reaction partners for the ester enolates 104. Since the primary adducts are only isolable in singular cases and the subsequent ring opened products (y-lactols) are very versatile precursors for synthesis of heterocycles, these addition reactions as well as those of electrophiles with a S = C unit will be discussed in a separate paragraph (see section 4.6). 

Synthetically even more versatile trifunctional intermediates result from the addition of carbonyl compounds onto methyl 2-siloxycyclopropanecarboxylates 92). Benzo-phenone, titanium tetrachloride, and 162, for instance, provide an excellent yield of the a-hydroxyalkylated y-oxoester 174, which predominates in the equilibrium with its cyclic hemiacetal 176 (y-lactol). It can undergo elimination to the unsaturated ester 175, but as Scheme 7 illustrates, 174/176 can also serve as the starting material to several highly substituted furan(one) derivatives. 

The synthesis of dihydrofuran derivatives such as 177 has been performed to explore scope and limitations of the Lewis acid promoted hydroxyalkylation of siloxycyclopropanes. Table 6 shows that aromatic as well as aliphatic ketones can efficiently be incorporated. Enolization of ketones does not occur and a 1-methyl group at the cyclopropane is no obstacle for the reaction, which now binds the carbonyl compound to a quartemary center with surprisingly high efficiency (entry 5). Albeit there are some restrictions with regard to the substitution pattern of the cyclopropanes, bicyclic siloxycyclopropanes also give good yields (e.g. entry 6 and Eq. 76). Further examples of the tetrahydrofuran synthesis from intermediate y-lactols with... 

Adduct 180 can be transformed to various furan derivatives (Scheme 9)61). Dehydration is accompanied by cis/trans isomerization giving tra/w-dihydrofuran 186, and oxidation to ketone 187 followed by condensation provides the trisubstituted furan 188. Cyano and allyl trimethylsilane, respectively, lead to tetrahydrofuran derivatives 189 and 190 with high stereoselection, which carry new substituents suitable for further manipulation. These reactions work equally well for the ketone adduct 176 and a bicyclic y-lactol affording 191-193 93). 

In two cases the direct oxidation with PCC of the primary adduct 198 — presumably already contaminated with the corresponding y-lactol — has been tried and surprisingly the P-hydroxylated y-butyrolactones 201 are formed (Eq. 84) 96 b). 

As already discussed above several C-nucleophiles also add smoothly to y-lactols (Eq. 85, Table 9). BF3 is the promotor of choice allowing efficient and highly diastereo-selective reactions with allyl and cyanotrimethylsilane or with bis(trimethylsilyl)ace-tylene which introduce the corresponding substituents at C-5 of the methyl tetra-hydrofuran-3-carboxylates 204, In the case of propargyltrimethylsilane an allenyl group is transferred to the heterocyclic 93). 

The stereoselectivity of this reaction rises when more bulky nucleophiles are employed (compare entries 7, 3,1, and 5). This is most impressively demonstrated by comparison of the y-lactol reduction with its allylation leading to 205 or 206, respectively (Scheme 10). Formation of tetrahydrofuran derivative 208, dihydrofuran 209, or unsaturated a-methylen-y-butyrolactone 207 illustrate that various modes of straightforward work-up procedures provide two different five membered heterocycles 93 b-96). A second example without the geminal dialkyl substitution at C-3 of the siloxy-cyclopropane depicted in Eq. 86 making available the annulated tetrahydrofuran-3-carboxylate 210 underlines the generality of the C-C-bond forming hydroxyalkylation reaction via ester enolates. 

In this reaction only the cyclopropane ring is opened to form III/66. This compound is in equilibrium with the y-lactol III/67, which, in case of R=H, was transformed oxidatively (pyridinium chlorochromate) to the furanone III/68. The synthesis of thiophene derivatives in a similar reaction is shown in Scheme III/ll, also. 

These enol carbamates are stable to acid, but undergo methanolysis in the presence of methanesulfonic acid and Hg(OAc)2 to form y-lactol methyl ethers, with retention of configuration at C, and C4. These products can be oxidized (8, 97) to -y-lactones. The overall process thus provides a route to protected -y-hydroxy aldehydes. 

Cleavage of y-lactols. y-Lactols arc generally more stable than the acyclic hy-... 

Examples of the application of the tandem Wittig conjugate-addition sequence to noncarbohydrate y-lactols are shown below. The tricycle 8 was prepared from the lactol 7 in good yield and highly stereoselectively. Upon thermolysis of 8. a retro-Diels-Alder reaction gave rise to furan and to the chiral dihydrofuran 9 in 94% ee36. 

A complementary entry to hydroxyalkylated products has been opened by deprotonation, carbonyl compound addition and ring-opening as outlined in equation 100 . The resulting y-lactols are precursors to y-butyrolactones or tetrahydrofuran derivatives. 

A bicyclic y-lactol—accessible in a few steps— allows entry into certain vinylcyclopro-panes (equation 117). At high temperature, these suffer a hydrogen shift to 1,4-dienes, which are masked 1,4-dicarbonyl compounds capable of many synthetically valuable selective reactions ". A total synthesis of trisporic acids profits from this approach ". If simple Grignard reagents are added to the y-lactol, manipulation of the resulting cyclopropylcarbinols opens a path to 2-methylenecyclobutanones. ... 

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