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Volumn 72, Issue 23, 2007, Pages 8824-8830

Synthesis of 4-formyl estrone using a positional protecting group and its conversion to other C-4-substituted estrogens

Author keywords

[No Author keywords available]

Indexed keywords

ESTROGEN 4-CARBOXYESTRONE; ESTRONE;

EID: 35948995254     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo7017075     Document Type: Article
Times cited : (18)

References (38)
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    • For a review on STS inhibitors see
    • For a review on STS inhibitors see: Nussbaumer, P.; Billich, A. Med. Res. Rev. 2004, 24, 529.
    • (2004) Med. Res. Rev , vol.24 , pp. 529
    • Nussbaumer, P.1    Billich, A.2
  • 5
    • 35948934334 scopus 로고
    • Patent 6506542
    • (a) Organon, N. V. Neth. Patent 6506542, 1967.
    • (1967)
    • Organon, N.V.N.1
  • 12
    • 35948952467 scopus 로고    scopus 로고
    • This assumes a yield of 93% for the oxidation step (see ref 7) and 80% for the bromination see ref 10
    • This assumes a yield of 93% for the oxidation step (see ref 7) and 80% for the bromination (see ref 10).
  • 13
    • 35948929497 scopus 로고    scopus 로고
    • Labrie, F.; Provencher, L.; Gauthier, S. Int. Appl. WO2004089971, 2004; Chem. Abstr. 2004, 141, 366369.
    • Labrie, F.; Provencher, L.; Gauthier, S. Int. Appl. WO2004089971, 2004; Chem. Abstr. 2004, 141, 366369.
  • 14
    • 35948949147 scopus 로고    scopus 로고
    • This high level of selectivity for the 4-position is unusual for an electrophilic aromatic substitution (EAS) on E1. All other reported EAS reactions on E1 (not just bromination) always give mixtures of the 2- and 4-isomeric products (plus disubstituted product) and the 2-isomer usually dominates. Other brominating agents do not give the same degree of selectivity as NBA. See: Numazawa, M, Ogura, Y, Kimura, K, Nagaoka, M. J. Chem. Res, Syn. 1985, 11, 348. No explanation has been put forth to explain the high level of selectivity obtained with NBA
    • This high level of selectivity for the 4-position is unusual for an electrophilic aromatic substitution (EAS) on E1. All other reported EAS reactions on E1 (not just bromination) always give mixtures of the 2- and 4-isomeric products (plus disubstituted product) and the 2-isomer usually dominates. Other brominating agents do not give the same degree of selectivity as NBA. See: Numazawa, M.; Ogura, Y.; Kimura, K.; Nagaoka, M. J. Chem. Res., Syn. 1985, 11, 348. No explanation has been put forth to explain the high level of selectivity obtained with NBA.
  • 17
    • 35948967283 scopus 로고    scopus 로고
    • This synthesis of 9 (33% in three steps from E1) is a considerable improvement over the literature synthesis of 9 which was accomplished in a 21% yield over 6 steps starting from estradiol. See ref 17
    • This synthesis of 9 (33% in three steps from E1) is a considerable improvement over the literature synthesis of 9 which was accomplished in a 21% yield over 6 steps starting from estradiol. See ref 17.
  • 27
    • 0032211368 scopus 로고    scopus 로고
    • For a review on the de-tert-butylation of substituted arenes, see: Saleh, S. A.; Tashtoush, H., I. Tetrahedron, 1998, 53, 14157.
    • For a review on the de-tert-butylation of substituted arenes, see: Saleh, S. A.; Tashtoush, H., I. Tetrahedron, 1998, 53, 14157.
  • 30
    • 35948995829 scopus 로고    scopus 로고
    • 3, 2.5 mL of 1.5 M NaOH, 20 mg benzyltriethylammonium chloride in 2.5 mL 95% ethanol then reflux for 20 h. See ref 6). However, even after 24 h reflux, most of the starting material remained unreacted and only a 9% yield of 4-formylated product was obtained. Adding additional base or chloroform at various time intervals and increasing the reaction times did not result in improved yields.
    • 3, 2.5 mL of 1.5 M NaOH, 20 mg benzyltriethylammonium chloride in 2.5 mL 95% ethanol then reflux for 20 h. See ref 6). However, even after 24 h reflux, most of the starting material remained unreacted and only a 9% yield of 4-formylated product was obtained. Adding additional base or chloroform at various time intervals and increasing the reaction times did not result in improved yields.
  • 31
    • 35948968458 scopus 로고    scopus 로고
    • We found that subjecting E1 to these conditions yields a mixture of 2-FE1 (major) and 4-FE1 (minor) as well as unidentified byproducts.
    • We found that subjecting E1 to these conditions yields a mixture of 2-FE1 (major) and 4-FE1 (minor) as well as unidentified byproducts.
  • 32
    • 35948935695 scopus 로고    scopus 로고
    • Triol 15 has been prepared previously by Lovely et al. in five steps starting from E2 in an overall yield of 13, see ref 17, We have achieved its synthesis in 4 steps starting from E1 in 33% yield and we have not attempted to optimize the reduction reaction
    • Triol 15 has been prepared previously by Lovely et al. in five steps starting from E2 in an overall yield of 13% (see ref 17). We have achieved its synthesis in 4 steps starting from E1 in 33% yield and we have not attempted to optimize the reduction reaction.
  • 33
    • 35948938096 scopus 로고    scopus 로고
    • Compound 4 was obtained by Singh et al. as a byproduct in the synthesis of 2-hydroxymethyl estrone. This was achieved by hydroxymethylation of estrone protected at the 17-position with a 1,3-dioxolane ketal followed by removal of the ketal protecting group. The hydroxymethylation gave a 35% yield of the 2- and 4-isomers in a 5:1 ratio which could not be separated until the ketal protecting group was removed. The overall yield of 4 was 6, See ref 8. We have prepared compound 4 in a 55% yield starting from E1
    • Compound 4 was obtained by Singh et al. as a byproduct in the synthesis of 2-hydroxymethyl estrone. This was achieved by hydroxymethylation of estrone protected at the 17-position with a 1,3-dioxolane ketal followed by removal of the ketal protecting group. The hydroxymethylation gave a 35% yield of the 2- and 4-isomers in a 5:1 ratio which could not be separated until the ketal protecting group was removed. The overall yield of 4 was 6%. See ref 8. We have prepared compound 4 in a 55% yield starting from E1.
  • 34
    • 35948996238 scopus 로고    scopus 로고
    • This synthesis of 6 (50% from E1) represents a dramatic improvement over the literature procedure which has been prepared by a multistep procedure in less than 3% yield starting from expensive 19-nortestosterone. See ref 9 and references therein
    • This synthesis of 6 (50% from E1) represents a dramatic improvement over the literature procedure which has been prepared by a multistep procedure in less than 3% yield starting from expensive 19-nortestosterone. See ref 9 and references therein.
  • 38
    • 35948931857 scopus 로고    scopus 로고
    • Inhibition studies with compounds 3-6 and steroid sulfatase are in progress. The results of these studies will be reported elsewhere.
    • Inhibition studies with compounds 3-6 and steroid sulfatase are in progress. The results of these studies will be reported elsewhere.


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.