Cyclic ketene acetals, synthesis

Cyclic ketene acetals, which have utility as co-polymers with functional groups capable of cross-linking, etc., have been prepared by the elimination of HX from 2-halomethyl-l,3-dioxolanes. Milder conditions are used under phase-transfer conditions, compared with traditional procedures, which require a strong base and high temperatures. Solid liquid elimination reactions frequently use potassium f-butoxide [27], but acceptable yields have been achieved with potassium hydroxide and without loss of any chiral centres. The added dimension of sonication reduces reaction times and improves the yields [28, 29]. Microwave irradiation has also been used in the synthesis of methyleneacetals and dithioacetals [30] and yields are superior to those obtained with sonofication. 

For this reason, a reinvestigation of the cyclic ketene acetal, 2-methylene-l,3-dioxolane (I), that had been prepared by McElvain and Curry (14) was undertaken. Although McElvain and Beyerstedt (15) reported that benzoyl peroxide had no appreciable effect on diethyl ketene acetal, no such study was reported (14) for the 2-methylene-l,3-dioxolane (I). The synthesis was carried out as follows (6) ... 

This indicates the possibility of making addition polymers biodegradable by the introduction of ester linkages in to the backbone. Since the free radical ring-opening polymerization of cyclic ketene acetals, such as 2-methylene-1,3-dioxepane (1, Scheme I), made possible the introduction of ester groups into the backbone of addition polymers, this appeared to be an attractive method for the synthesis of biodegradable addition polymers. 

Fig. 2 Synthesis of aliphatic polyester by ROP of cyclic ketene acetals I radical initiator...

Agarwal S (2010) Chemistry, chances and limitations of the radical ring-opening polymerization of cyclic ketene acetals for the synthesis of degradable polyesters. Polym Chem 1 953-954... 

Free radical polymerization of cyclic ketene acetals has been used for the synthesis of polyfy-butyrolactone), which cannot be prepared by the usual lactone route due to the stability of the five-membered ring. The polymerization of 2-methylene-l,3-dioxalane at high temperatures (above 120 °C) gave a high molecular mass polyester [59,79]. Only 50% of the rings opened when the polymerization was carried out at 60 °C, and this led to the formation of a random copolymer. The presence of methyl substituents at the 4- or 5-position facilitated the reaction. The free radical initiators generally used in such polymerizations are ferf-butyl hydroperoxide, ferf-butyl peroxide, or cumene hydroperoxide. The various steps involved are described in Scheme 5 [59]. 

Cyclizations of enediynes under the action of electrophiles 13KGS129. Cyclization reactions of l,l-bis(trimethylsilyloxy)ketene acetals (synthesis of lactones, cyclic anhydrides, lactone-bridged N-heterocycles, lactone-annulated N-heterocycles) 12SL1283. 

A methylenation of cyclic carbonates such as 6/4-132 using dimethyltitanocene to give a ketene acetal, followed by a subsequent Claisen rearrangement, allowed the synthesis of medium-ring lactones such as 6/4-133 in good yields these are otherwise difficult to obtain. In this transformation, 6/4-133 is formed as a l l-mix-ture of the two atropisomers 6/4-133a and 6/4-133b (Scheme 6/4.33). The substrate... 

The Claisen rearrangement has been instrumental in the synthesis of a number of natural products.279-289 Many useful derivatives have been prepared using the Claisen-type rearrangement including enol ethers,290 amides,291-293 esters and orthoesters,294-296 acids,297-298 oxazolines,299 ketene acetals,300-301 and thioesters.302 Many of these variants use a cyclic primer to control relative and absolute stereochemistry. The Claisen and oxy Cope provide the best candidates for scale up as a result of the irreversible nature of these reactions. 

The [2+2]photocycloaddition of 5-arylfuran-2,3-diones (496) to trimethylsilyl-oxyethylenes (495) occurs with high regio- and stereoselectivity to efficiently yield polyfunctionalised cyclobutanes (497). ° A convenient four step stereoselective synthesis of ( + )-norasteriscanolide (500) has used the [2+2]photoadduct (499) from 2-cyclopentenone and the trimethylsilyl enol ether (498) to assemble the 5/8 ring system present in many terpenoids. 2-Naphthaldehyde undergoes regio-and stereoselective [2+2]photoadditon to the cyclic ketene silyl acetals (501) to... 

Reaction of dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate with 6-methoxy-l,2,3,4-tetrahy-dropyridine gives dimethyl l,2,3,4-tetrahydropyrido[2,3-<5f]pyridazine-5,8-dicarboxylate. Apparently the lactim ether is in tautomeric equilibrium with the corresponding cyclic ketene A,O-acetal, which acts as the dienophile, the final step being the elimination of methanol.73 For a related synthesis, see ref 74. 

Spiroketals have been obtained by RCM of cyclic ketals 18 without loss of stereochemical integrity at the spiro linkage <04TL5505> and a stereoselective solid-phase synthesis of 6,6-spiroketals has been reported in which aldol reactions of boron enolates are the key feature <04AG(E)3195>. Spiro orthoesters are accessible from thiophenyl ketene acetals and diols (Scheme 5) <04SL2013>. 

Cyclic ketene silyl acetal 536 has been used in a synthesis of the chiral -lactone 541 (Scheme 76). The chelation-controlled aldol reaction of 536 with 464 gives 5y -adduct 537 as the sole product [173]. 

With a cyclic substrate, for example in which three or more atoms of the allyl vinyl ether are constrained in aring, then the boat-shaped transition state maybe favoured. Formation of the silyl ketene acetal from the lactone 295 and rearrangement on warming gave the carboxylic acid 296 (3.190). The reaction occurs via a boatshaped transition state and was used in a synthesis of the sesquiterpene widdrol. 

Following the synthesis of substituted indole A-oxides via a TiC -mediated MBH reaction of a-oxo cyclic ketene-S ,iS -acetal with 2-nitrobenzaldehydes, Dong and Liu and their co-workers further developed a novel method to rapidly synthesize indolizines from MBH adducts 509, which in turn were prepared from the reaction of a-EWG ketene S ,A-acetals with 2-pyridinecarbaldehyde... 

E)-4-hydroxyenestannanes, with 2 extra C-atoms 44, 850 a-hydroxyketones 43,1 P-hydroxyketones 44,627 hydroxynitriles, synthesis 43, 558 2-hydroxythioethers 43,450 rran5-l,2-iodohydrins 44 922 ketene acetals, cyclic 44, 575... 

Burke et al. employed a cyclic variant of the glycolate Ireland-Claisen rearrangement in the asymmetric synthesis of (-I-)-breynolide (Scheme 4.128) [122]. The rearrangement of the Z-silyl ketene acetal via a boat transition state generated the C3,C4 stereochemistry of the natural product in high yield and stereoselectivity. 

Knight et al. have employed a ring contraction via the Ireland-Claisen rearrangement of an aryl lactone to generate a 2,3,4-trisubstituted tetrahydrofuran intermediate in the synthesis of ( )-samin (Scheme 4.143) [138], The rearrangement proceeded via a boat transition state of the cyclic -silyl ketene acetal. 

The same stereoselectivity due to a boat-hke transition state has been observed by Lallemand [16] during an approach in the synthesis of antifeedent compound clerodine. Interestingly, a chemical correlation has been done with the products resulting from a Claisen-Ireland rearrangement in the open chain series. Accordingly, the E-ester enolate obtained after deprotonation and silylation of ester 64 [17] afforded, via a chair-like transition state, a compound which was correlated via 63 with the cyclic orthoester product 62 which resulted from a necessarily Z-ketene acetal. Consistently the E-ester enolate gave rise to a diastereomer 65 after the same sequence of reactions (Scheme 6.8). 

This case study highlights the formidable challenge posed by epimerization en route to the synthesis of nonpeptidic fragments of cyclic peptide natural products. (3S,4R,7S)-HTMMD was prepared from (R)-4-methyl-5-valerolactone 74 in nine steps (Scheme 8.6a). After convenient synthesis of aldehyde 77 and its asymmetric aldol condensation with the ketene acetal 79, HTMMD skeleton 80 was isolated as a single isomer. After installation of allyl ester, the alcohol was coupled with Fmoc-Ala-Cl in the presence of DMAP/DIPEA (4-dimethylaminopyridine/diisopropylethylamine) followed by fluorenylmethyloxy-carbonyl (Fmoc) deprotection to afford the ester segment 81b in excellent yield. The amount of DMAP and temperature (—15 °C) were critical to avoid racemiza-tion. Modified Tsunoda s diastereoselective aza-Claisen rearrangement [145] was used as the key step in the 13-step synthesis of N-methylhydroxyisoleucine 86b... 

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