Independent Research

I began my independent research career in 1964 with a wide range of synthetic and mechanistic studies over the whole range of organic chemistry. Before the watershed year 1972, there were contributions to synthetic methodology,^21,32,212 to mechanistic understanding,^9,17,22,28 to photochemistry,³⁸ and even to mass spectrometry.¹³ I determine the full structure of chlorophyll, by proving the absolute configuration of the stereogenic centres in the macrocyclic ring,¹² and I made the 8- cycloheptatrienylheptafulvenyl cation,³⁰ which at that time was the most stable known hydrocarbon cation.

I am, however, best known for my work on organosilicon chemistry applied to organic synthesis. This began during a formative sabbatical year, 1971-1972, spent at McGill University in Montreal, where I had time to read. Silicon was almost completely ignored by synthetic organic chemists at that time, but, in the course of my reading, I came across Eaborn's mechanistic work establishing the now well known β-effect of a trimethylsilyl group, and showing that it is a better electrofugal group than a proton. I was able to put what I learned from his papers into a context which provided solutions to problems of regioselectivity and control in organic synthesis, especially in reactions between a C=C π-bond and an electrophile. I began work in this area on my return to Cambridge in the autumn of 1972, and it rapidly became the main topic in my research group. I coined the idea of the trimethylsilyl group as a "super" proton,^PL6 making it clearer how organic chemists should think about the ways in which silicon might be useful. Our early work was specifically designed to illustrate this idea in vivid ways, so that our work was as influential as anyone's in placing in the minds of synthetic organic chemists the idea that silicon was a mainstream element, with a highly coherent and largely predictable chemistry. I was awarded the Tilden lectureship of the Royal Society of Chemistry in 1981 and the Prize for Organic Synthesis in 1983 for the early stages of this work, and in 1993 I was elected a Fellow of the Royal Society largely on the strength of my continuing contributions in this area.

Thus we illustrated how, other things being equal, vinylsilanes would react with electrophiles at the atom to which the silicon was bonded,^68,100 and allylsilanes would react at the γ carbon with reliable allylic shift.^79,100 Although we were not alone in this work, Au-Yeung's loganin synthesis⁷⁷ was the first total synthesis of a non- trivial natural product to use organosilicon chemistry. In order to carry out all this work, we needed to develop methods for the regiocontrolled synthesis of vinylsilanes,^82,210 unsymmetrical allylsilanes,^{61,78,79,97,99,160,161} allenylsilanes,¹⁶⁷ and propargylsilanes.¹⁹⁸ In the course of this work, David Ager introduced the phenyldimethylsilyl-cuprate reagent,⁵¹ which has since been much used by others, because it allows the introduction of a silyl group into a variety of functionalised molecules, such as α,β-unsaturated carbonyl systems,^{81,122,155,180} acetylenes,^82,212 allylic acetates^78,97,161 and allenes.^{135,144,145,179} Subsequently we studied the preparation and reactions of the silyl-lithium reagent itself,^195,196 finding several intriguing reactions with esters,¹⁷⁴ nitriles,¹⁸⁶ arenesulfonamides,¹⁹⁷ and especially with amides.^218,230,234

Ian Paterson stimulated us into some contributions to silyl enol ether chemistry, picking up a hint in Mukaiyama's work, that silyl dienol ethers could solve the problem of getting reasonably reliable, kinetically controlled d⁴ reactivity from α,β-unsaturated carbonyl systems.^63,71

In addition to purely synthetic work, we contributed to mechanistic understanding, including demonstrations that: (i) the protodesilylation of an allylsilane passes through a free carbocation;⁷⁴ (ii) the cationic rearrangement of alcohols can be controlled by a carefully placed silyl group;^{49,70,75,133,225} (iii) 3,3-disubstituted allylsilanes can undergo electrophilic attack with concealed cationic rearrangement;⁸⁰ (iv) thermal sulfoxide elimination is faster when the hydrogen atom is adjacent to a silyl group;⁸⁶ (v) the stereochemistry of both S_E2' reactions^97,149,229 and S_E2" reactions are stereospecifically anti,^127,184,185 adding to Hayashi's work, with the former accurately measured to be highly stereospecific with allyl- and allenylsilanes but not with propargylsilanes;²²⁹ (vi) the stabilisation by a silyl group of a β cation can make the stereochemistry of a 1,2 shift take place anomalously with retention of configuration at the migration origin;²⁰⁶ and (vii) the vinylogous Peterson reaction is syn stereospecific with interesting selectivity about which double bond in the diene product comes out cis when one of them must.²⁰⁹ Chris Urch and Mike Rowley investigated some reactions of tin compounds, specifically to point up the similarities and the differences with the corresponding silicon chemistry, notably fleshing out, and proving the stereospecificity of, the known cyclopropane-forming reactions of γ-stannyl alcohols,¹⁰⁷ and adding substantially to the chemistry of stannyl- cuprates.^{109,135,147,171}

We also invented two devices using silicon to solve problems in organic synthesis that had no existing solution. One was the idea that a silyl group β to a ketone masked the α,β-unsaturation of an α,β-unsaturated ketone, without itself being a nucleofugal group in danger of leaving prematurely.^67,81,84 This has been used by Corey, and extensively by Asaoka and Takei. The second, and more important device, was the idea that a phenyldimethylsilyl group was a masked hydroxy group, without itself being remotely like a hydroxy group.^{96,123,172,181} As a large, relatively unreactive, non-polar electropositive group without lone pairs, a silyl group influences the chemistry in its neighbourhood in a completely different way from the hydroxy group, but a phenyldimethylsilyl group can be converted into a hydroxy group, with retention of configuration, when desired. This reaction has been called the Tamao-Fleming reaction, since Tamao has been equally active in working out and exploiting the oxidation step. Our part, pioneered by Howard Plaut, Rolf Henning and Philip Sanderson was to couple the oxidation, which I knew about from Aylwyn Davies's work, with the removal of the phenyl group. This idea, or a slightly modified version, has now entered the mainstream of organic synthetic methodology, and has been used by many people in total syntheses. Three reviews in 1996, one of them mine,^RCB12 each with approximately 200 references, attest to the importance of this concept.

Our later work, beginning in the 1980s following a key observation made by David Waterson, was on how to use the silyl group, usually a phenyldimethylsilyl group because of its ease of introduction and its potential for being turned into a hydroxy group, to influence the stereochemistry of the events in its neighbourhood.^{155-163,227,228} Alongside this work, we applied our discoveries of high levels of open-chain stereocontrol to the synthesis of a series of relatively small molecules: dihydronepetalactone by Nick Terrett,¹⁹⁹ the Prelog-Djerassi lactone by Hak-Fun Chow,²⁰⁰ thienamycin by Jeremy Kilburn,²⁰¹ a carbacyclin analogue by Dick Higgins,²⁰² tetrahydrolipstatin by Nick Lawrence,²⁰³ the prostaglandin C-15 problem by Stephen Winter,²⁰⁴ lavandulol by Duckhee Lee,²⁰⁵ deoxyribonolactone by Sunil Ghosh,²⁰⁶ phytol by Pranab Maiti,²²⁶ and, most dramatically, nonactin by Sunil Ghosh.^207,208 This work was carried out to illustrate the methods more vividly and to expose the methods to the test of a real synthesis, revealing new problems and new needs. A more ambitious synthesis, of ebelactone A, in which all the stereochemistry was controlled by silicon-based methods, was thwarted by epimerisation of one stereogenic centre at the end of the synthesis.²³¹

Alongside all the organosilicon work, there were a few other projects in which organosilicon chemistry played either no part or only a small part. A synthesis of gelsemine reached an advanced stage of a highly functionalised tricyclic ketone,¹³² with methods for the stereoselective spiroannulation of an oxindole onto a ketone already prepared for it,^111,143 but in the end it was not completed, because no one would fund us to put the two pieces of work together. Right at the end of my career, Chandra Ramarao looked again at decarboxylative elimination using enol triflates to make acetylenic compounds,²³² overcoming a limitation in the decarboxylative eliminations in my PhD work.⁵ The very last project, also without any help from silicon, was Thomas Buttler's stereocontrolled synthesis of racemic sparteine.²³⁵

I have written several reviews on organosilicon chemistry, most notably: (i) a chapter^RCB4 on organosilicon chemistry in Comprehensive Organic Chemistry, which was the first primeron the subject; (ii) an Organic Reactions chapter^RCB7 of over 500 pages on the electrophilic substitution of allyl- and vinylsilanes; (iii) one of the three reviews mentioned above on the silyl-to-hydroxy conversion;^RCB12 and (iv) a review^RCB14 in Chemical Reviews, with nearly 1000 references on the uses of silicon compounds in the control of stereochemistry in organic synthesis.

Key to reference numbers:

PL = Published Lectures, which can be found in the list of published lectures;
RCB = Reviews and Chapters in Books, which can be found in the list of reviews and chapters in books;
and plain superscript numbers are Scientific Papers, which can be found in the publication list.