5.37 Introduction to Organic Synthesis Laboratory

Transcription

1 MIT penourseware Introduction to rganic Synthesis Laboratory Spring 2009 For information about citing these materials or our Terms of Use, visit:

2 Massachusetts Institute of Technology hemistry 5.37 Professor ick L. Danheiser Lecture 5 The Invention of ycloaddition and Annulation Strategies May 12, 2008 The Diels-Alder eaction istorical Background.... I consider the teaching and study of the historical development of science as indispensable.... ur textbooks fail in this respect.... ichard Willstätter.... Science is not an abstract thing, but rather, as a product of human labor, is tightly bound in its development to the particularity and fate of the individuals who dedicate themselves to it. Emil Fischer

3 Discovery and Invention Alternate Paths for the Development of New Synthetic hods Discovery: to find something not previously known Invention: deriving from a deliberate attempt to solve a problem The Diels-Alder eaction 1 The single most powerful ring-forming reaction in the arsenal of organic chemistry!

4 Invention of New Annulation Strategies for 1 [4 1] Annulation Strategy Invention of New Annulation Strategies for 1 [3 2] Annulation Strategy

5 Annulation Strategies for the Synthesis of arbocyclic and eterocyclic ompounds Annulation strategies previously developed in our laboratory LiTMP, Et 2 l l l 2 2 n-buli TF-exane-MPT 0-25 [41] Annulation Strategy Stereocontrolled synthesis of fivemembered carbocycles based on anion-accelerated vinylcyclopropane rearrangements W 3 Lewis acid W 3 [32] Annulation Strategy Stereocontrolled synthesis of fivemembered carbocycles and heterocyclic compounds based on allenylsilanes and allylsilanes eaction of arbenes with 1,3-Dienes Potential Basis for a [4 1] Annulation Strategy

6 eaction of arbenes with 1,3-Dienes Potential Basis for a [4 1] Annulation Strategy not observed The Vinylcyclopropane earrangement Potential Basis for a [4 1] Annulation Strategy 1,3-sigmatropic rearrangement 68% mmg vapor phase pyrolysis 10% 22%

7 Stereocontrolled [4 1] Annulation Strategy Anion-accelerated Vinylcyclopropane earrangement LiTMP, Et 2 l l l equiv n-buli TF-exane-MPT % > 50 : 1 > 50 : 1 > 50 : 1 > 50 : 1 = 2 2 Ph > 50 : 1 Invention of New Annulation Strategies for 1 [3 2] Annulation Strategy

8 Invention of New Annulation Strategies for Allyl Anions Allyl ations xyallyl Anions omoenolate Anions Vinylcarbenes Allylmetal ompounds Electrophilic yclopropanes Trimethylenemethane Diradicals Trimethylenemethane witterions Invention of New Annulation Strategies for [3 2] Annulation Strategy Based on Allylmetal ompounds

9 Invention of New Annulation Strategies for Electrophilic addition of alkene to nucleophilic allylmetal compound arbocation stabilized by the! effect Invention of New Annulation Strategies for eversible 1,2-shift of metal group

10 Invention of New Annulation Strategies for ing closure furnishes five-membered ring Stereocontrolled [3 2] Annulation Strategy 1 equiv equiv Til 4, 2 l 2-78 to 0 Me 89% Si(i-Pr)Me Til 4, 2 l 2 then 30% 2 2, K 3 Me-TF 74% 11.5 : 1 stereoisomers

11 Stereocontrolled [3 2] Annulation Strategy Application to the Synthesis of Five-Membered eterocycles X X X X =, S, N = N, X X Stereocontrolled [3 2] Annulation Strategy Application to the Synthesis of Five-Membered eterocycles ept Sit-BuMe eq NBF 4, 3 N, -30 ; then add Br 2, l 4 72% 3 Br N ept Ph l Sit-BuMe 2 Et 3 All 3, 2 l 2, h 80% Ph 3 Sit-BuMe 2 Et