臺灣博碩士論文加值系統

嗎啡是一個強效的中樞作用止痛劑，它的構造很堅固，共有五個環。多年
來，研究者將嗎啡之結構簡化，亦即減少環的數目，而得到多種仍具有止
痛作用之藥物。在可能的簡化組合中，ANO環系統亦即旋環 [苯駢■
喃-3(2H),4'-六氫■啶]較少受到注意，且至今並無具此環系統的藥物在
臨床使用。本研究中，探討以自由基環化反應來合成具O環的嗎啡部分構
造；並利用鈀金屬催化的Heck反應對ACNO環系統化合物之合成做初步的研
究。我們以鄰-甲基酚為起始物，經過4個步驟，得到主中間體4-[(2'-溴
基-6'-甲氧基苯氧基)甲基]-1-甲基- 1,2,5,6,-四氫■啶(16)；再經偶氮
雙異丁■的催化及氫化三丁基錫作用下，進行自由基環化得到唯一產物旋
環[7-甲氧基苯駢■喃- 3(2H),4'-1'-甲基六氫■啶](17)。上述之5-exo-
trig形式的分子內自由基環化反應也曾在本實驗室被延伸至嗎啡四環ACNO
部分構造的合成為了增加自由基反應在嗎啡 ACNO環系統的反應性，我們
設計了中間體5-(2'-溴基-6'-甲氧基苯氧基)-2-甲基-1-氧
基-1,2,3,4,5,6,7,8-八氫異■ ■(36)，希望藉由 C-1■基的導入使得拉
電子的效應能利於苯基自由基打入立體障礙較大的4a位置而達到環化的目
的。然而反應的結果並不如理想；雖然得到較高產率(30%)的C/N環反式
的9-甲氧基-3-甲基-4-氧基- 2,3,4,4a,5,6,7,7a-八氫-1H-苯駢■喃
[3,2-e]異■ ■(37)而無C/N環順式異構物，但是去溴重排的還原產
物(38)仍被得到，且比例提高不少(26%)。為了進一步改善合成嗎啡ACNO
環系統的效率，我們接著嚐試Heck反應來進行類似的分子內環化反應。將
中間體36，在三苯基■、三乙基胺及催化量的二乙醯氧基鈀作用下，我們
得到39%的預期產物9-甲氧基-3-甲基-4-氧基-2,3,4,6,7,7aa-六氫-1H-苯
駢 [4,5]■喃[3,2-e]異■ ■(41)。而對中間體23進行相似之分子內
Heck反應，則得到48%的9-甲氧基-3-甲基-4-氧基-2,3,5,6,7,7aa-六氫-1
H-苯駢[4,5]■喃[3,2-e]異■ ■(48)。將含enamine的化合物 48可利用
文獻中相關資料，進一步架構至具嗎啡ABCNO五員環的骨架。

Morphine is a potent analgesic alkaloid, its rigid structure
consisting of five rings (ABCNO). Among the partial structures
of morphine, the ANO spiro[benzofuran3(2H),4'-piperidines] and
the ACNO octahydro-1H-benzofuro[3,2-e]isoquinolines have not
been developed for clinical use. We have now developed a novel
synthetic approach to the above-mentioned morphine fragments
4-(2-bromo-6-methoxyphenoxymethyl)-1,2,5,6- tetrahydropyridine
(16) underwent facile 5-exo-trig radical cyclization upon
treatment with Bu3SnH /AIBN (cat) to afford spiro[7-
methoxybenzofuran-3(2H),4'-1'-methylpiperidine] (17) in 96%
yield as the sole product. The above methodology has been
extended to the synthesis of fragments of morphine.As an
attempt to boost the selectivity of the radical synthesis of
the ACNO system, we modified our intermediate 23 by introducing
a carbonyl function at it's C-1. Although the desired trans
isomer 37 was obtained in higher (30%) in the absence of the
cis isomer, the debrominated rearrangement product 38 was also
obtained in higher yield (26%). We then turned our attention to
the construction of oxide- containing morphine fragments via
intramolecular Heck reaction. Preliminary results are
encouraging. Intermediate 36 was treated with Pd(OAc)2, PPh3,
and Et3N in acetonitrile at 130 in a sealed vessel , and
afforded the desired 9-methoxy-3- methyl-4-oxo-2,3,4,6,7,7a-
hexahydro-1H-benzofuro[2,2- e]isoquinoline (41) in 39% yield as
the major product. When intermediate 23 was subjected to the
same reaction condition 36, compound 48 was obtained in 48%
yield . The enamine in 48 can be further elaborated for the
formation of ring B , thus allowing the synthesis of typical
morphine skeleton.