Application of the Chloro Ketal Claisen Reaction to the Total Synthesis of Squalene

Abstract

Abstract. A short, highly stereoselective (over 97%) synthesis of alltrans squalene is described. Starting with succinaldehyde, a tetraenedichlorodione having the complete squalene skeleton with the four internal trans olefinic bonds has been developed in four steps involving a sequence of two double Claisen rearrangements. Three simple operations convert this intermediate into squalene.In a recent communication1 we showed that certain olefinic ketals like 3, on heating at about 100'C in the presence of 2,4-dinitrophenol, interact with allylic alcohols to produce a,j3-unsaturated ketones, e.g., 2 + 3 -0 4. Although the probability is small that the steps involved in this reaction occur simultaneously at both ends of the molecule, the process may be regarded schematically as follows: (a) ketal exchange with the allylic alcohol to form a mixed ketal; (b) elimination of methanol to give the vinyl ether A; and (c) Claisen rearrangement of this vinyl ether A 4. 0x A Thus, the dienediol 2, which is readily accessible in 54% yield from succinaldehyde, 1, and isopropenyllithium,2 was converted into the diketone 4. This last substance, on reduction with sodium borohydride, gave the tetraenediol 5 in 62% yield from 2. Now we wish to report that an a-chloro ketal like 6 can react under similar conditions with an allylic alcohol, to give a product of a Claisen rearrangement with retention of the chlorine atom. Thus, a mixture of the tetraenediol 5 in toluene that contained a catalytic amount of 2,4-dinitrophenol and excess chloro ketal 6 was heated at 94°C for 24 hr. Chromatography on silica gel gave the tetraenedichlorodione 7 in 60% yield. It is to be noted that a homologous chloro ketal has also been used similarly in a synthesis of the insect juvenile hormone.3 1465

Enantioselective Total Synthesis of the Mexicanolides: Khayasin, Proceranolide, and Mexicanolide

“…With both enantiomers of azedaralide in hand, these could now be applied to either synthesis of (+)- or (−)-cipadonoid B ( 4 ). The known, but rarely applied, ketal–Claisen rearrangement − used in the synthesis of racemic (±)-cipadonoid B ( 4 ) (Scheme ), however, was poorly understood in terms of stereochemical outcome. In brief, when this reaction was performed in the racemic series it produced undesired diastereoisomers (i.e., 13 and 15 ) of the natural product cipadonoid B ( 4 ).…”

Advanced Strategies for the Efficient Production of Squalene by Microbial Fermentation

“…18 However, it should be noticed that the complete reaction contains 7 steps under harsh conditions such as high temperature and pressure, and this will generate some unwanted byproducts and organic reagent residue, affecting the final squalene quality and causing some environmental issues (Figure 2). 13 In the 1980s, Momose et al used (E,E)-farnesyl bromide as raw material and benzene as solvent to synthesize (E,E,E,E)squalene under the catalysis of CoCl(Ph 3 P) 3 with a content of about 55% and (6E,10Z,14Z,18E)-squalene (51% yield) at room temperature for 3 h. 19 Through this strategy, (E,E,E,E)-squalene was stereospecifically synthesized from (E,E)-farnesyl bromide, The reaction can be carried out at room temperature without low-temperature operation, however, the drawback was that the yield was low. In conclusion, it was still difficult to industrially synthesize squalene by chemical synthesis, mainly due to the harsh reaction condition, long synthesis path and low yield.…”

Simultaneous Preparation of Both Enantiomers of Juvenile Hormones Labeled at C-10 with Tritium at High Specific Activity

“…3-Chloro-2,2-dimethoxy-3-methylpentane for use in this Claisen rearrangement (giving the JH I chloroketone) was synthesized as previously described (13). The crude chloroketone product from the Claisen was separated on preparative (1.5 mm) 20 ϫ 20 cm TLC silica gel plates (developed in 10% ethyl acetate/hexane).…”

“…The JH III chloroketone precursor [methyl(2E,6E)-11-chloro-10-oxo-3,7,11-trimethyl-2,6-dodecadienoate] was prepared using a Claisen rearrangement of 6b (synthesis described above) with 2,2-dimethoxy-3-chloro-3-methylbutane (13). The crude chloroketone product was separated on preparative (1.5 mm) 20 ϫ 20 cm TLC silica gel plates (developed in 10% ethyl acetate/hexane).…”