1.4- benzoxathiins, synthesis

The key structural features of compound 1 are the chiral cis-diaryl benzox-athiin fused ring system, two phenols, and one phenol ether linkage with the pyrrolidinylethanol. Originally, SERM 1 was prepared by medicinal chemists from a key ketone intermediate 5 shown in Scheme 5.1. Compound 5 was prepared in four steps with rather low yield [4a], Among these steps, the high temperature de-methylation step and the use of extremely toxic MOM-C1 were not particularly suitable for scale-up. The ketone 5 was then brominated with PhMe3NBr3 (PTAB) and coupled with thiophenol 7 to produce adduct 8. The key step of the synthesis was the conversion of adduct 8 to cis-diaryl benzoxathiin 9 under the Kursanov-Parne reaction conditions (TFA/Et3SiH). This novel reaction allowed the formation... 

The cis-2,3-diaryl-2,3-dihydro-l,4-benzoxathiin is a very unique structural motif. Other than scattered reports in the literature on the formation of this scaffold, there was no effective asymmetric synthesis for it [6]. We explored two major synthetic approaches to realize the key chiral as-diaryl dihydrobenzoxathiin scaffold, as shown in Scheme 5.3. One was the quinone ketal route in which the quinone ketal 13 and the chiral mercaptol alcohol 14 were the key intermediates. The other approach was the stereo- and enantioselective reduction of the diaryl benzoxathiin 16. The key mercaptol alcohol 14 and the diaryl benzoxathiin 16 were both envisioned to be prepared from the key, common iodoketone intermediate 15. 

The asymmetric reduction of the benzoxathiin is very appealing because of its simplicity (Scheme 5.3). It was envisioned that intermediate 16 could be prepared from thiol-phenol 7 and bro moke tone 17. Scheme 5.8 summarized the synthesis for 16. The l,3-benzoxathiol-2-one 35 was prepared from 1,4-benzoquinone and thiourea following a literature procedure with minor modifications. Benzylation of 35 with benzyl bromide in the presence of KI gave benzyl ether 36 as a crystalline solid. It was observed that the benzylation gave better results when the reaction was run under anaerobic conditions. Hydrolysis of thiocarbonate 36 gave free thiophenol 7 which was used directly in the next reaction. 

We have developed the efficient synthesis of the SERM drug candidate 1 and successfully demonstrated the process on a multiple kilogram scale to support the drug development program. A novel sulfoxide-directed borane reduction of vinyl sulfoxides was discovered. The mechanistic details of this novel reaction were explored and a plausible mechanism proposed. The sequence of asymmetric oxidation of vinyl sulfoxides followed by stereospecific borane reduction to make chiral dihydro-1,4-benzoxathiins was applied to the asymmetric synthesis of a number of other dihydro-1,4-benzoxathiins including the sweetening agent 67. 

Synthesis of 1,4-dihydro-2,3-benzoxathiin 3-oxide as a useful precursor of o-quinodimethane The sultine l,4-dihydro-2,3-benzoxathiin 3-oxide 9 and substituted derivatives are ideal reagents for the in situ synthesis of o-quinodimethanes (o-xylylenes) 170 because they decompose smoothly in refluxing benzene at ca. 80°C and do not... 

A simple and flexible synthesis of benzoxathiin-2-one from phenols has been reported. The key step in this synthesis is a hitherto unknown anionic rearrangement under direct metallation conditions <2004T5215, 2003SL1474>. 

Benzoxathiin 2,2-dioxides 237 can be prepared from 2-acylphenols by reacdon with a sulfonyl chloride, R1CH2S02C1, followed by base-catalyzed cyclization of the sulfonate ester 236 (Scheme 135). For additional examples of the synthesis of 1,2-benzoxathiin 2,2-dioxides see CHEC-III . 

A related synthesis of benzoxathiins has been reported, in which benzothiete (82) was ring-opened, and the unstable product (83) trapped with electron deficient carbonyl compounds (Scheme 33) <90CB1143>. Yields are extremely dependent upon the nature of the carbonyl compound. 

Thermal decomposition of l,4-dihydro-2,3-benzoxathiin 3-oxides generates o-xylylenes which can be trapped by methyl 2-acetamidoacrylate yielding tetralin-based a-amino acids <04S558>. A phosphazene base [EtN=P(NMe2)2(N=P(NMe)2)3)] is used to generate the ylide from chiral oxathiane 74 in a two-step asymmetric synthesis of aziridines from tosylimines <04JOC1409>. 

A [2+4] cycloaddition of o-thioquinones 55 with pentafulvenes 56 constitutes an efficient protocol for the synthesis of benzoxathiins 57 (Scheme 7.13) [15]. 

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