Asymmetric synthesis Claisen rearrangement

The /V-allylketene N,O-acetal rearrangement methodology has been successfully applied in natural product synthesis. For example, an asymmetric aza-Claisen rearrangement of the cyclic substrate 14 [ 5,6) rearrangement] is the key step in the total synthesis of (+ )-dihydropalles-censin-2 (isolated from the marine sponge Dysidea fragilis)648. 

Corey et al. used the asymmetric Ireland-Claisen rearrangement in the synthesis of j8-elemene (Scheme 4.131) [124], Rearrangement of the Z-(0)-B-ketene acetal via the chair transition state afforded the trienic acid in good yield with complete diastereo- and enantioselectivity. 

Kurth, M.J. and Soares, C.J. (1987) Asymmetric aza-Claisen rearrangement synthesis of (- -)-dihydropallescensin-2 [( )-penlan-pallescensin]. Tetrahedron Lett., 2, 1031-1034. 

The most recent, and probably most elegant, process for the asymmetric synthesis of (+)-estrone appHes a tandem Claisen rearrangement and intramolecular ene-reaction (Eig. 23). StereochemicaHy pure (185) is synthesized from (2R)-l,2-0-isopropyhdene-3-butanone in an overall yield of 86% in four chemical steps. Heating a toluene solution of (185), enol ether (187), and 2,6-dimethylphenol to 180°C in a sealed tube for 60 h produces (190) in 76% yield after purification. Ozonolysis of (190) followed by base-catalyzed epimerization of the C8a-hydrogen to a C8P-hydrogen (again similar to conversion of (175) to (176)) produces (184) in 46% yield from (190). Aldehyde (184) was converted to 9,11-dehydroestrone methyl ether (177) as discussed above. The overall yield of 9,11-dehydroestrone methyl ether (177) was 17% in five steps from 6-methoxy-l-tetralone (186) and (185) (201). 

Claisen and Carroll rearrangements of hydroxyalkenylsilanes provide an asymmetric synthesis of allylsilanes from optically active secondary alcohols39,40. 

Hemiacetal 25 [(3 ,4S,l E)-3,4-bis(r-butenyl)tetrahydro-2-furanol] is the male pheromone of the spined citrus bug (Biprorulus bibax). Scheme 38 summarizes Mori s synthesis of 25 [61]. Claisen rearrangement (A B) and lipase-catalyzed asymmetric acetylation [meso-C >(5S,6R)-D] were the two key steps of the synthesis. Further purification of D was executed at the stage of its crystalline derivative E. In this particular case, the unnatural (3S,4R,l E)-25 was as active as the natural (3R,4S,VE)-25. Accordingly, a more efficient synthesis of ( )-25 was achieved by the rearrangement of F, avoiding the use of toxic HMPA [62]. 

Scheme 4.22 Asymmetric synthesis of allene 89 by the orthoester Claisen rearrangement.

Scheme 4.23 Chiral allene synthesis via asymmetric aldol reaction and Claisen rearrangement.

Scheme 4.24 Asymmetric synthesis of enprostil 95 via Claisen rearrangement.

Scheme 4.25 Asymmetric synthesis of clavepictines 99 and 100 via Claisen rearrangement.

Monoalkylation of a-isocyano esters by using tert-butyl isocyano acetate (R = fBu) has been reported by Schollkopf [28, 33]. Besides successful examples using primary halides, 2-iodopropane has been reported to produce the a-alkylated product (1) as well by this method (KOfBu in THF). In the years 1987-1991, Ito reported several methods for the monoalkylation of isocyano esters, including the Michael reaction under TBAF catalysis as described earlier [31], Claisen rearrangements [34], and asymmetric Pd-catalyzed allylation [35]. Finally, Zhu recently reported the first example of the introduction of an aromatic substituent by means of a nucleophilic aromatic substitution (Cs0H-H20, MeCN, 0°C) in the synthesis of methyl ot-isocyano p-nitrophenylacetate [36]. 

The most recent, and probably most elegant, process for the asymmetric synthesis of (+)-estrone applies a tandem Claisen rearrangement and intramolecular ene-reaction. Most 19-nonsteroid contraceptive agents are produced by total synthesis from nonsteroidal starting materials. 

The Claisen rearrangement was used in the asymmetric total synthesis of (+)-9(ll)-dehydroestrone methyl ether (5), a versatile intermediate in the synthesis of estrogens5 (Scheme 1. If). The key feature of the synthesis is the successful development of the asymmetric tandem Claisen-ene sequence. Thus, a solution of the cyclic enol ether 6 in toluene was heated in a sealed tube at 180 C for 60 hours to afford the product 9 in 76% isolated yield after deprotection of the silyl enol ether. The Claisen rearrangement of the allyl vinyl ether 6 occurred stereoselectively to give an intermediate (7), in which the 8,14-configuration was 90% syn. The stereoselectivity in the Claisen rearrangement can be explained... 

The cholesteric mesophase formed by cholesteryl p-nitrobenzoate at 200 °C has been used as the solvent to effect an asymmetric synthesis lrans-but-2-enyl p-tolyl ether gave the product of an ortho-Claisen rearrangement, 2-(but-1 -en-3 -yl)-4-methylphenol. This material exhibited circular dichroism, although neither the optical yield nor the configuration of the product is yet known.262 Decarboxylation of ethylphenylmalonic acid in cholesteryl benzoate at 160 °C (cholesteric liquid-crystalline phase) also proceeded with asymmetric induction to give (R)-(—)-2-phenylbutyric acid, with 18% optical yield.263 Electric dipole moments are reported for some esters of 5a-cholest-8(14)-en-3j8-ol there is some slight correlation with melting points.264... 

The final approach was elegantly presented by Panek [44]. Several optically active ( )-crotylsilanes are available via stereoselective Ireland-Claisen rearrangement of enantiomerically pure vinylsilanes. Addition of the chiral crotylsilanes to acetals or to mixtures of aldehyde and trimethylsilyl methyl ether is effected by la to afford homoallylic ethers in exceedingly high diastereo- and enantioselectivity (Sch. 13). Occasionally a stoichiometric amount of la is required for allylation of aliphatic acetals, preserving the excellent level of asymmetric induction. The synthesis of (-F)-macbecin I involving triple use of the strategy imderscores the utility of the la-catalyzed asymmetric allylation [44c]. 

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