Dichloroketene, 1,4-cycloaddition

A variety of synthetic studies focused on clinical CNS candidate 1 are described. The original medicinal chemistry route (Scheme 1) is described, and issues which precluded its scale-up are discussed. An Ullman route to 2-fluoro-4-methoxyaniline (Scheme 4) was developed to avoid a non-selective nitration reaction. The first GMP bulk canpaign utilized a ring expansion strategy via a dichloroketene [2+2] cycloaddition (Scheme 6) to prepare cycloheptane-1,3-dione. While effective on laboratory scale, several issues arose upon scale-up the mechanistic basis for these issues was determined to be competition between desilylation and dechlorination of dichlorocyclobutanone 22 (Scheme 11). These issues led us to develop a third synthesis of 1, in which c3reloheptane-1,3-dione is avoided. Two variants of this Friedel-Crafts strategy are described (Schemes 13 and 14). 

Similar difacial selectivity is observed for dichloroketene cycloadditions to steroidal exocyclic alkenes. For example, dichloroketene adducts 4,5 5,5 65 and 76 were obtained as the major products from the corresponding steroidal alkenes. 

The application of chiral auxiliary groups which can be removed after the cycloaddition has met with limited success. The chiral auxiliary can be attached to either the ketene or alkene moiety. In a study of dichloroketene cycloadditions with a series of enol ethers 18, to which a chiral alkoxy group is attached, diastereoselectivities ranged from 55 to 90%,n with the choice of chiral auxiliary being crucial to obtaining the desired diastereoselectivity. 

Oh, J. Synthesis of a-D-C-glucoside employing dichloroketene cycloaddition and Baeyer-Villiger oxidation. Tetrahedron Lett. 1997, 38, 3249-3250. 

Haima and coworkers used a [2+2] cycloaddition approach for the preparation of precursor en route to forskolin. Dichloroketene cycloaddition with glycal 301 was followed by reductive dechlorination to give 302 in 80% overall yield. Several steps were required to convert 302 into the forskolin (304) Diels-Alder precursor 303 (Scheme 54) [81]. 

Thus, conversion of the olefin to the corresponding dichlorocyclobutanone using the well established method of dichloroketene cycloaddition is followed by conversion into the mono-chloro enol acetate (Bu Li-Ac20) and finally cleavage using... 

Some straightforward, efficient cyclopentanellation procedures were developed recently. Addition of a malonic ester anion to a cyclopropane-1,1-dicarboxylic ester followed by a Dieckmann condensation (S. Danishefsky, 1974) or addition of iJ-ketoester anions to a (l-phenylthiocyclopropyl)phosphonium cation followed by intramolecular Wittig reaction (J.P, Marino. 1975) produced cyclopentanones. Another procedure starts with a (2 + 21-cycloaddition of dichloroketene to alkenes followed by regioselective ring expansion with diazomethane. The resulting 2,2-dichlorocyclopentanones can be converted to a large variety of cyclopentane derivatives (A.E. Greene. 1979 J.-P. Deprds, 1980). 

The present procedure, based on the last method, is relatively simple and uses inexpensive starting materials. Step A exemplifies the 2 + 2 cycloaddition of dichloroketene to an olefin, " and the specific cycloadduct obtained has proved to be a useful intermediate in other syntheses. Step B has been the subject of several mechanistic studies, and its yield has been greatly improved by the isolation technique described above. This synthesis has also been extended to the preparation of various tropolone derivatives. " ... 

Scheme 6.8 gives some examples of ketene-alkene cycloadditions. In Entry 1, dimethylketene was generated by pyrolysis of the dimer, 2,2,4,4-tetramethylcyclobutane-l,3-dione and passed into a solution of the alkene maintained at 70° C. Entries 2 and 3 involve generation of chloromethylketene by dehydrohalo-genation of a-chloropropanoyl chloride. Entry 4 involves formation of dichloroketene. Entry 5 is an intramolecular addition, with the ketene being generated from a 2-pyridyl ester. Entries 6, 7, and 8 are other examples of intramolecular ketene additions. 

Enantioselective [2 + 2 cycloaddition.2 The chiral allylic ether (1), prepared from (lS,2R)-( + )-2-phenylcyclohexanol, undergoes enantioselective cycloaddition with dichloroketene to furnish, after one crystallization, optically pure (-)-2. This cyclobutanone after ring expansion and exposure to chromium(II) perchlorate gives... 

Dechlorination of 4,4-dichlorocyclobutenones.2 These products of [2 + 2] cycloaddition of dichloroketene with alkynes (9, 153) can be reduced satisfactorily and without isomerization by zinc dust in ethanol containing 5 equiv. each of acetic acid and a tertiary amine (preferably TMEDA). 

Greene and co-workers used a dichloroketene/enol ether cycloaddition and a Beckmann ring expansion as key reactions en route to (+)-preussin [76]. 

All of the above-mentioned [2+2] cycloadducts presumably arise via intermediate 1,4-diradicals in a stepwise manner [104, 131]. However, cycloadducts 174 and 175 of 1 to chloro- and dichloroketene most likely arise from a concerted [n s+n a] cycloaddition mode (Scheme 38) [104,130]. 

A significant synthetic achievement this year is Fleming s conversion (Scheme 4) of trimethylsilylcyclopentadiene (135) into the racemic aglucone acetate (136) which has already been converted into loganin (Vol. 1, pp. 20, 21 Vol. 4, p. 26). Cycloaddition of (135) to dichloroketen yields the adduct (137), ° whose conversion into the acetate (138) is straightforward the key steps are the clean... 

Tropolone has been made from 1,2-cycloheptanedione by bromination and reduction, and by reaction with N-bromosuccinimide from cyclo-heptanone by bromination, hydrolysis, and reduction from diethyl pimelate by acyloin condensation and bromination from cyclo-heptatriene by permanganate oxidation from 3,5-dihydroxybenzoic acid by a multistep synthesis from 2,3-dimethoxybenzoic acid by a multistep synthesis from tropone by chlorination and hydrolysis, by amination with hydrazine and hydrolysis, or by photooxidation followed by reduction with thiourea from cyclopentadiene and tetra-fluoroethylene and from cyclopentadiene and dichloroketene. - The present procedure, based on the last method, is relatively simple and uses inexpensive starting materials. Step A exemplifies the 2 + 2 cycloaddition of dichloroketene to an olefin, " and the specific oycloadduot obtained has proved to be a useful intermediate in other syntheses. " Step B has been the subject of several mechanistic studies, " and its yield has been greatly improved by the isolation technique described above. This synthesis has also been extended to the preparation of various tropolone derivatives. - " ... 

Cycloadditions give better efficiency and stereocontrol for ring formation. A high regioselectivity (95 5) for the cycloaddition of dichloroketene to a cyclohexene en route to synthetic eriolanin [164] has been observed. It appears that the allylic methoxy group play a dominant role. Note that the proximal sp2-carbon is a donor by virtue of its 1,3-relationship with the oxygen function. 

Steroids represent rigid chiral systems which are convenient substrates for mechanistic studies of geometric details. Early studies on the difacial selectivity of ketene to steroidal alkene cycloadditions led to the preparation of optically pure cyclobutanones. The addition of dichloroketene to 2- or 3-methyl-5a-cholcst-2-ene (1) generates the cyclobutanones 2 and 3 with regio- and stereoselectivity. The cycloadditions proceed to give the adducts resulting from ketene approach to the a-face.4... 

Ketene itself and simple alkylketenes are inert towards nonactivated alkenes. F or the preparation of cyclobutanones formally derived from ketene or an alkylketene and nonactivated alkenes, the more reactive dichloroketene or alkylchloroketenes can be used. The corresponding a,a-dichloro- or oc-chlorocyclobutanones can readily be dechlorinated by treatment with zinc in acetic acid, or tributyltin hydride in near quantitative yields. F or example cycloaddition of substituted cyclohexene to dichloroketene gave dichlorocyclobutanone 1 which was dechlorinated to 2 with zinc.13,18 Likewise cycloaddition of cycloalkcnes to chloro(methyl)ketene gave 3 which was dechlorinated to 4.14... 

The [2 + 2] cycloaddition of dichloroketene to an alkene is probably the most common non-photolytic method for cyclobutane synthesis (see Sections 1.3.1., 1.3.5. and 5.1.2.3.). The 2,2-dichlorocyclobutanones thus obtained readily undergo reductive dechlorination. Two... 

Cyclobntane. A few examples of cyclobutane derivatives have been described in the carbohydrate series. Formation of this type of ring involves a 2+2 cycloaddition. Relevant examples of cycloaddition of dichloroketene on glucals, explored by Redlich [195] and Lallemand [196,197], and significant transformations of the four-membered ring, such as ketone 165a, are given in Scheme 56. 

In an extension of this method, the cycloaddition of dichloroketene to the heterocyclic aminomethyleneketone (341) yields the dihydropyranone which is dehydrochlorinated with DBN to the fused pyran-2-one (Scheme 104) (78JHC181). Similar behaviour is shown by the benzologue of the enamine. 

Cycloaddition to a cyclic allyl ether The key step in a synthesis of lineatin (3), the aggregation pheromone of the bark beetle, is the addition of dichloroketene to the alkene 1. Under usual conditions (POCl3, 8,156) the desired adduct is obtained in 7% yield. Fortunately, substitution of 1,2-dimethoxyethane for POCl3 increases the yield of 2 to 50-60%. 

Cycloaddition to vinyl sulfoxides, y-butyrolactones/ Dichloroketene (best generated by zinc reduction of trichloroacetyl chloride, 8,156) reacts with vinyl sulfoxides to form a-dichloro-y-butyrolactones in 50 80% yield. A polar mechanism involving a Pummercr-type rearrangement has been suggested. 

An ab initio study of the 2 + 2-cycloadditions of allene to isocyanic acid and ketene to vinylimine found the reactions to be concerted and mostly asynchronous.28,29 The diastereoselective 2 + 2-cycloaddition of dichloroketene with a chiral enol ether (26) produced the cyclobutanone (27), which leads to a key intermediate (28) in (g) the total synthesis of the natural alkaloid (-)-Swainsonine (29) (Scheme 8).30 The... 

Unlike ordinary alkenes, ketenes do 2 + 2 cycloadditions with themselves—the dimerisation above—and with other alkenes.1 Reaction of dichloroketene with cyclobutadiene 11 to give the... 

A [2+2] cycloaddition reaction of l-[azet-l(277)-yl]-2,3-dimethylpropan-l-one 596 to dichloroketene leading to cycloadduct 597 has been described <2006TL6377>. An immediate reduction of the ketone group in the unstable cycloadduct afforded cyclobutanol-fused azetidine 598 (Scheme 78). 

The cycloaddition of 2-azetine 530 and dichloroketene gave the alcohol 531 in three steps which, in two further steps, gave the lactones 532 (mainly) and 533 <2006TL6377>. 

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