Polar Effects in Organic Reactions

Abstract

Attempts to gauge the effect of polar substituents on organic reaction rates by means of "inductive substituent constants" are based on the assumption that these effects are independent of the type of reaction observed. The measured rate constants of nucleophilic substitution reactions show, however, that this assumption is only partly justified even for saturated molecules. It is invalid if the substituent and the reaction center are an electron donor and an electron acceptor, respectively, which are hyperconjugated by way of o-bonds. In extreme cases the resulting polarization can lead to heterolytic fragmentation.

Synthetic studies directed toward naturally occurring cyclooctanoids. 1. A total synthesis of (.+-.)-ceroplastol I.

“…eagents: (a) NaOCH3 (18 equiv), CH3OH, , 6 h; (b) KN(TMS)3 (4 equiv), THF, -78 °C -25 °C then Lil (1.2 equiv), collidine, 155 °C, 30 min; (c) LDA (1.1 equiv), THF, -78 °C, 20 min, followed by Pd(OAc)2 (1.1 equiv), CH3CN, 0 °C -25 °C, 2 h; (d) 21, HMPT (2 equiv), THF/Et20 (1:1), -40 °C, 2 h; (e) TsNHNH2 (1.3 equiv), (C02H)2 (5 equiv), C2H5OH, 25 °C, 24 h; (f) ZnCl2 (4 equiv), NaCNBH3 (8 equiv), CH3OH, 90 °C, 4 h. created via a stereoelectronically controlled addition of the mixed cuprate 11 to 10*1 and careful methanolysis of the resulting dienol lactone which provided the readily separable epimeric ketoesters (16) The exclusive formation of the homoannular trienol lactone 10 was unfortunate and surprising in light of our model studies.11 Stereoelectronically controlled axial addition of the cuprate to 10 is the expected result and creates the requisite trans relationship at the Cl0-Cn ring junction in 1. 12 and 13 (6:1) in 65% yield.17 The final ring junction stereocenter C6 was established by Na/NH3 reduction of keto ester 12.…”

“…The primary alcohol was protected [/-Bu(Me)2SiCl/ imidazole/DM F/room temperature] not only to differentiate it from the alcohol produced in the next reaction but also to protect the 0-siIyloxyketone from elimination upon treatment with Grignard reagents. 21 The ketone was then treated with me• thylmagnesium bromide (Et2O/0 °C -*• room temperature) to give a 13:1 mixture of tertiary alcohols favoring the desired 13 in 68% overall yield from 12. At this stage, and in the earlier tin hydride reduction, the relative stereochemistry of the products was assigned by analogy to the model system1 contain functionalized eight-membered rings led us to consider the relatively small group of sesterterpenes exemplified by ceroplastol I (l),1 the closely related structures ceroplastol II (2),2 albolic acid (3),3 and the ophiobolins, such as ophiobolin C (4).4…”