天然有機化合物討論会講演要旨集
Online ISSN : 2433-1856
第59回天然有機化合物討論会実行委員会
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P-01 有機触媒を用いたエストラジオールメチルエーテルのポットエコノミーを指向した全合成
*越野 晴太郎小嶋 かんな林 雄二郎
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会議録・要旨集 オープンアクセス

p. 279-284

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Steroids, with a tetracyclic molecular framework, have versatile, strong and important biological activities. Given their importance in medicine and biology, the efficient synthesis of steroid is still an important subject in synthetic organic chemistry in spite of the many previous synthetic studies. Recently, we proposed the term “pot economy”, since one-pot operations constitute an effective method both for carrying out several transformations and forming several bonds in a single pot, while at the same time eliminating several purification steps, minimizing chemical waste generation, and saving time. Based on this concept, we have reported a one-pot synthesis of (-)-oseltamivir and a three-pots synthesis of PGE1 methyl ester. We have accomplished a total synthesis of estradiol methyl ether (6) via five pots using organocatalyst as follows: One of the key reactions is a domino reaction of diphenylprolinol silyl ether 1 mediated asymmetric Michael reaction between nitroalkane 2 and enal 3, and intramolecular aldol reaction, which afforded bicyclo[4.3.0]nonane derivative 5, possessing A, C, and D rings of steroid with excellent diastereo- and enantioselectivities. The strereochemistry of 5 was found to be identical to that of the steroid. After formation of 5, cyanohydrine formation, protection by xanthate and dehydration afforded compound 10 in the first pot. Compound 10 has been contained all carbons for estradiol methyl ether. Then, nitro group and xanthate moiety was reduced in one-pot to afford 12. The ketone and nitrile moiety of 12 was reduced and protected by silyl ether to afford 18. Then, next six reactions can be conducted sequentially in a single vessel: Pinnick-Kraus oxidation, diastereoselective hydrogenation, acid chloride formation, Friedel-Crafts acylation, deprotection of silyl ether and hydrogenolysis of benzylketone afforded estradiol methyl ether (6). This synthesis is fewest pot synthesis of estradiol methyl ether.

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