Stereoselective Conjugate Addition of Cyanide
A thesis presented by Nicola Jane Con vine
In partial fulfilment of the requirements for the degree of Doctor of Philosophy and the award of the Diploma of Imperial College London
1630442
Heilbron Laboratory Department of Chemistry Imperial College London SW7 2AY Abstract
This thesis describes the development of a diastereoselective conjugate addition of cyanide. Chapter One contains a critical review of reported asymmetric conjugate additions of cyanide and a brief summary of non-asymmetric conjugate additions of cyanide to enones. Chapter Two summarises the initial research objective of this project; namely development of an enantioselective conjugate addition of cyanide to enones. Chapter Three presents the research undertaken to achieve this objective and the evolution of the project to the successful diastereoselective hydrocyanation employing an oxazolidinone as a chiral auxiliary. In Chapter Three, investigation into the ZnI2 and YbCb catalysed addition of TMSCN to cyclohexenone and other carbonyl compounds is detailed. Since enantioselective adaptation of this methodology proved unsuccessful, further research into the hydrocyanation of a,p- unsaturated carbonyl compounds under Sm(O'Pr)3 catalysis with the cheap cyanide source, acetone cyanohydrin, is detailed. This is followed by adaptation of the Sm(O'Pr)3 methodology to chiral a,|3-unsaturated W-acyl oxazolidinones to provide a diastereoselective conjugate addition of cyanide. This section includes a review of reported asymmetric conjugate additions to chiral a,(3-unsaturated 7V-acyl oxazolidinones and continues with a discussion of the substrate scope and possible mechanism of the hydrocyanation. Chapter Three concludes with the application of this stereoselective hydrocyanation to the synthesis of three drug molecules, Pregabalin, Baclofen and Rolipram, and includes a brief review of previously reported syntheses of these molecules. Chapter Four summarises the findings in this thesis and offers suggestions for future development of this work. Chapter Five gives full experimental details along with spectroscopic and physical data for all new compounds. Acknowledgements
Firstly I have to thank Prof. Alan Armstrong for giving me the opportunity to undertake this project and for all his help and guidance throughout. I would also like to thank Dr. Matt Popkin for his support and suggestions for the project, especially during my time at GSK. I would also like to acknowledge EPSRC and GSK for their financial support.
My thanks go to the Armstrong group members (Tom, lan, Jenna, Graham, Fred, Rich C, Chris, Steve, James, Richie, Lizzie, Hans, Nigel, Dave, Nat, Carol, Teika, Rich K, Jamie) for making the whole experience more enjoyable and for their ideas. Special thanks go to Tom and Nigel for their computer support and Dave for proof-reading this thesis. Thanks also to my lab colleagues at GSK Tonbridge for making me welcome during my placement.
I would also like to acknowledge the technical support given by the NMR, MS and X- ray departments at 1C and from the NMR and MS departments at GSK Tonbridge.
Finally I would like to thank my family for all their support throughout. Contents
Abstract...... 2 Acknowledgements...... 3
Abbreviations...... ?
1 Introduction-Stereoselective conjugate addition of carbon nucleophiles...... 9 1.1 Enantioselective conjugate addition to enones...... 9 1.2 Enantioselective conjugate addition of cyanide...... 14 1.3 Diastereoselective conjugate addition of cyanide...... 18 1.4 Non-asymmetric conjugate addition of cyanide to enones...... 20
2 Research Objectives...... 24
3 Results and Discussion...... 25 3.1 Metal-catalysed cyanide addition to enones...... 25 3.1.1 Zinc iodide catalysed reaction...... 25 3.1.1.1 Isomerisation of 1,2-adductto l,4-adduct...... 28 3.1.1.1.1 Investigation of stereospecificity of isomerisation...... 3 1 3.1.1.2 Addition of asymmetric ligands...... 33 3.1.1.3 Znl2 catalysed conjugate addition of TMSCN to other substrates...... 35 3.1.1.3.1 Synthesis of substrates...... 35 3.1.1.3.2 Results of Znb catalysed addition of TMSCN to other
3.1.2 Ytterbium trichloride catalysed reaction...... 42 3.1.2.1 Comparison with other lanthanide catalysts...... 46 3.1.2.2 YbCl3 catalysis of TMSCN addition to other substrates...... 48 3.1.2.3 Yb-catalysed reaction in presence of asymmetric ligands...... 49 3.1.3 Samarium isopropoxide catalysed conjugate addition with acetone cyanohydrin...... 53
3.2 Development of auxiliary-controlled cyanide conjugate addition...... 56 3.2.1 Introduction: Diastereoselective conjugate addition with oxazolidinone auxiliaries...... 56 3.2.2 Diastereoselective conjugate addition of cyanide with Evans' auxiliary...... 60 3.2.2.1 Initial test reactions...... 60 3.2.2.2 Relative stereochemistry of product...... 63 3.2.2.3 Investigation of the Sm-catalysed reaction conditions...... 64 3.2.2.4 Chiral oxazolidinone substrates in other hydrocyanating systems...... 68 3.2.2.5 Effect of auxiliary on stereoselectivity...... 70 3.2.2.6 Scope of substitution of the alkene...... 73 3.2.2.6.1 Synthesis of substrates...... 73 3.2.2.6.2 Hydrocyanation...... 78 3.2.2.7 Mechanistic possibilities...... 82 3.2.2.8 Auxiliary cleavage and product manipulation...... 85 3.2.2.8.1 Hydrolytic auxiliary cleavage...... 85 3.2.2.8.2 Reductive auxiliary cleavage...... 86 3.2.2.8.3 Nitrile reduction with concomitant auxilary cleavage....87
3.3 Application of methodology to drug molecule syntheses...... 90 3.3.1 Introduction...... 90 3.3.1.1 Pregabalin...... 90 3.3.1.2 Baclofen...... 92 3.3.1.3 Rolipram...... 94 3.3.2 e«/-Pregabalinsynthesis...... 98 3.3.3 (5)-Baclofen synthesis...... 101 3.3.4 (5)-Rolipram synthesis...... 104
4 Conclusions...... 107
5 Experimental...... 109 5.1 Znh catalysed conjugate addition of TMSCN...... 111 5.1.1 Preparation of authentic samples of cyclohexenone derived products...... ! 11 5.1.2 Investigation into Znl2 catalysed cyanations...... ! 15 5.1.2.1 Znl2 catalysed cyanation in the presence of chiral additives...... 119 5.1.2.2 Znl2 catalysed cyanation of other substrates...... 121 5.1.2.2.1 Synthesis of a,p-unsaturated compounds...... 121 5.1.2.2.2 Cyanation of substrates...... 125 5.2 YbCls catalysed cyanation...... 129 5.2.1 Cyanation in the presence of pybox Iigands...... l35 5.3 Non-asymmetric Sm(O'Pr)3 catalysed reaction...... 138 5.4 Diastereoselective conjugate addition of cyanide...... 140 5.4.1 Synthesis of initial test substrates...... 140 5.4.2 Asymmetric hydrocyanation of a,p-unsaturated N-acyl
5.4.3 Hydrocyanation of chiral a,p-unsaturated TV-acyl oxazolidinones under alternative conditions...... 149 5.4.4 Effect of auxiliary...... 151 5.4.4.1 Synthesis of substrates...... 151 5.4.4.2 Hydrocyanation...... 153 5.4.5 Scope of substitution on alkene...... 158 5.4.5.1 Synthesis of substrates...... 158 5.4.5.2 Hydrocyanation...... 170 5.4.6 Investigation of mechanism...... 184 5.4.7 Auxiliary cleavage...... 185 5.4.7.1 Hydrolytic cleavage of auxiliary...... 185 5.4.7.2 Reductive auxiliary cleavage...... 187 5.4.7.3 Nitrile hydrogenation with auxiliary cleavage...... 189 5.5 Drug molecule synthesis...... 192 5.5.1 Pregabalin...... l92 5.5.2 Baclofen...... 200 5.5.3 Rolipram...... 204
Appendix...... 2 10 References...... 223 Abbreviations
9BBN 9-borabicyclo[3.3. IJnonane Ac acetyl AMP adenosine monophosphate aq aqueous Ar aryl binap 2,2'-bis(diphenylphosphino)-1,1 '-binaphthyl binol 2,2'-dihydroxy-1,1 '-binaphthyl Bn benzyl boc ?-butyloxycarbonyl br broad Bu butyl c concentration cat. catalytic CI chemical ionisation cone. concentrated d doublet DBU 1,8-diazabicyclo[5.4.0]undecene-7 de diastereomeric excess DIPEA diisopropylethylamine DMAP 4-dimethylaminopyridine DMF dimethylformamide DMSO dimethylsulfoxide dr diastereomeric ratio ee enantiomeric excess ent enantiomeric equiv equivalent Et ethyl FID flame ionisation detector g gram GABA y-aminobutyric acid GC gas chromatography h hour HMDS hexamethyldisilylamine HPLC high performance liquid chromatography HWE Homer-Wadsworth-Emmons / iso IPA propan-2-ol IR infra-red J coupling constant LDA lithium diisopropylamide lit. literature LUMO lowest unoccupied molecular orbital m multiplet m meta m-CP&A /w-chloroperbenzoic acid Me methyl mg milligram 8
MHz megahertz min minutes ml millilitre mmol millimole m.p. melting point m/z mass / charge ratio n normal NMR nuclear magnetic resonance o ortho o/n overnight P para PDE phosphodiesterase pet. petroleum Ph phenyl ppm parts per million Pr propyl q quartet rt room temperature rxn reaction s singlet SM starting material t triplet t tertiary TBDMS /-butyldimethylsilyl TBDPS f-butyldiphenylsilyl temp temperature tert tertiary Tf trifluoromethanesulfonyl THF tetrahydrofuran TLC thin layer chromatography TMS trimethylsilyl tr retention time Ts /7-toluenesulfonyl w/v weight by volume 1 Introduction - Stereoselective conjugate addition of carbon nucleophiles
1.1 Enantioselective conjugate addition to enones
o R1X R1 O 'R chiral catalyst Scheme 1 : Asymmetric conjugate addition to enones
The asymmetric conjugate addition of carbon based nucleophiles to a,p-unsaturated carbonyl compounds (Scheme 1) is a valuable transformation in organic synthesis. Much effort has been expended in developing techniques for this. 1 Very effective approaches have been developed for, among others, the enantioselective addition of alkyl, aryl, and 1,3-dicarbonyl groups to enones. For example, Hoveyda has developed novel peptide based chiral phosphine ligands 1 for the copper catalysed asymmetric conjugate addition of alkyl organozinc reagents to a range of cyclic and acyclic enones (Scheme 2).2~4
la R1 = R3 = H, R2 = "Bu NHR" Ib R1 = Me, R2 = "Bu, R3 = OfBu Ic R1 = Me, R2 = CH2COOMe, R3 = OfBu
2.4 mol% 1a mol% (CuOTf)2-C6H6 n = 1 78%, 97% ee 3 equiv Et2Zn n = 2 98%, 98% ee toluene n = 3 98%, 98% ee -30 °C, 12 h
2.4mol%1b mol% (CuOTf)2.C6H6 O 3 equiv Et2Zn Et O R1 = "pent, R2 = Me 85%, 95% ee —————————»• R1 = Me, R2 = "hex 87%, 90% ee R toluene R1 = "pent, R2 = 'Pr 75%, 90% ee 22 °C, 1 h Scheme 2 : Hoveyda's enantioselective conjugate addition of alkyl groups to enones 10
The generality of the enone scope for these ligands arises from their modular nature which provides easy variation. For example, ligand tuning developed a more effective ligand Ic for the addition of the bulky isopropyl group which had given poorer ee's for cyclic enones (Scheme 3).2
2.4 mol% 1 mol% (CuOTf)2.C6H6 3 equiv 'Pr2Zn la 98%, 72% ee —————————». Ic 98%,91%ee toluene -30 °C, 12 h Scheme 3 : Hoveyda's ligand tuning to improve selectivity
Further ligand tuning developed a simpler phosphine ligand 2 which was most effective for the difficult class of tri-substituted cyclic enones (Scheme 4).4
NHBu
O
6 mol% 2 mol% (CuOTf)2.C6H6 3 equiv Et2Zn "hex toluene 'Et 0°C, 12 h 85%, 97% ee Scheme 4 : Hoveyda's addition of alkyl groups to tri-substituted enones
This utility of this methodology has recently been demonstrated by the total synthesis5 of the antimycobacterial agent erogorgiaene 3, where the enantioselective conjugate addition was utilised in two key steps, the second of which is shown in Scheme 5. 11
12mol%2 5 mol% (CuOTf)2.C6H6 Me2Zn
toluene 4°C,24h
50%, 97 : 3 dr Scheme 5 : A key step in the synthesis of erogorgiaene 3
Complementary to the addition of alkyl groups detailed above, Hayashi has developed excellent methodology for the addition of aryl and alkenyl groups to enones. f\ " R A rhodium(binap) complex catalyses the addition of aryl- or alkenylboronic acids to a range of cyclic and acyclic enones with outstanding selectivities (Scheme 6).
3 mol% Rh(acac)(C2H4)2 (S)-binap 5 PhB(OH)2 —————————»• dioxane/H2O(10:1) 100°C,5h >99%, 97% ee
3 mol% Rh(acac)(C2H4)2 (S)-binap Ph 5 PhB(OH)2 dioxane/H2O(10:1) 100°C,5h 82%, 97% ee Scheme 6 : Hayashi's Rh-catalysed addition of aryl groups to enones
This methodology has been extended to the addition of aryl-9BBN9'10 and organotitanium11 reagents in aprotic solvents which allows for the isolation or trapping of the enolate products (Scheme 7) as opposed to the hydrolysed product, the only product available after the addition of organoboron compounds with water as the co-solvent.
1.6equivPhTi(O'Pr)3 [Rh(OH)((S)-binap)]2 BrCH2CH=CH2 LiO'Pr (3 mol% Rh) ———————>" THF THF Ph 20 °C, 1 h 82%, >99% ee Scheme 7 : Trapping of titanium enolate after asymmetric conjugate addition of aryl group 12
For the asymmetric conjugate addition of 1,3-dicarbonyl compounds to enones (eg Scheme 8 and 9), Shibasaki's multifunctional catalysts have given excellent results. 12'13 The concept of these multifunctional catalysts is very interesting, being designed to simultaneously activate both the electrophile and nucleophile of the reaction in a defined chiral environment (Figure 1).
[ Lewis acid ) Ph .Ph
Q^—[ Lewis acid]
AI-CI Q^"^ [Lewis base )
Bronsted base]
4 ALB 5 Figure 1 : Examples of multifunctional catalysts
The multifunctional catalysts have been applied to a variety of reaction types; for example, cyanosilylation of aldehydes (Scheme 8) can employ the Lewis acid - Lewis base activating complex 4, where the Lewis acidic site activates the aldehyde and the Lewis basic site activates the TMSCN (Figure I). 14 In contrast, the asymmetric conjugate addition of 1,3-dicarbonyl compounds uses catalysts that are Lewis acid - Bronsted base activating complexes such as ALB 5 (Scheme 8). 15 The Lewis acidic site activates the enone and the Bronsted basic site deprotonates the 1,3-dicarbonyl compound (Figure I). 14 13
i) 36 mol% Bu3PO 9 mol% 4 O CH2CI2, -40 °C, 58 h .OH u 1.8TMSCN ^ ii) 2 N HCI
100%, 98%ee
0.3 mol% 5 CO2Me o.27 mol% KOfBu . CO2Me MS 4A, THF rt, 120 h CO2Me
94%, >99% ee Scheme 8 : Examples of the use of multifunctional catalysts
The most practical catalyst for the asymmetric conjugate addition of 1,3-dicarbonyl compounds employs an ether bridged linked binol ligand with a lanthanum centre 6 (Scheme 9). The linked ligand renders the catalyst air-stable, storable (no loss of product yield or ee after four weeks storage) and reusable after recovery. 12 In contrast, the ALB 5 catalyst, whilst using lower catalyst loadings and giving comparable selectivities, is very moisture sensitive. Both these catalysts are most i *y effective with cyclic enones.
CO2Bn 10mol%6 . CO2Bn DME, 4 UC, 85 h CO2Bn
98%, >99% ee Scheme 9 : Shibasaki's practical catalyst for enantioselective conjugate addition of 1,3-dicarbonyls
Despite the successful methodology for the addition of the carbon based nucleophiles detailed above, there is still a need for asymmetric techniques for the conjugate 14 addition of other cheap versatile carbon nucleophiles. The use of cyanide as the nucleophile fulfils these requirements.
1.2 Enantioselective conjugate addition of cyanide
The asymmetric conjugate addition of cyanide to a,p-unsaturated carbonyl compounds can lead to a variety of chiral compounds after manipulation of the nitrile and carbonyl functionalities. Some examples of these manipulations are shown in Scheme 10.
HOOC O
" • \ / s / s / s / / f / / t / O PM© CN 0 II T ^^ff x R X R^^
\ \ \ X X X=OH S \ \ HOOC
Scheme 10 : Potential products from asymmetric conjugate addition of cyanide through manipulation of the difunctional intermediate
Despite the versatility offered by asymmetric conjugate addition of cyanide there are few approaches to this transformation described in the literature. When this work commenced, there had been no published enantioselective conjugate additions of cyanide. To date, only two procedures have been disclosed; Jacobsen16'17 in 2003
I O while this work was in progress and Shibasaki in 2005 after the completion of the work for this thesis. 15
Jacobsen employs his aluminium salen catalyst 7 in the addition of HCN to a,p- unsaturated imide substrates with very good yield and ee (Scheme II). 16
7 Figure 2 : Aluminium salen catalyst employed for enantioselective conjugate addition of cyanide
10mol%7 2.5 equivTMSCN ° ° 2.5 equiv 'PrOH
toluene, rt NC R 26-48 h R -" alkvlalky' 9490 - 98%- 96% ee
Scheme 11 : Jacobsen's enantioselective conjugate addition of cyanide
The substrate scope is limited to alkyl substitution on the alkene and more demanding substituents, such as the bulky f-butyl group or an oxygenated substituent (R = Ct^OBn), require elevated temperatures (45 °C), catalyst loading (15 mol%) and reactant equivalents (4 equiv). The imide moiety is also a necessity. Another limitation is that HCN cannot be used directly, no reaction is observed, but needs to be generated in situ by slow addition of an alcohol to the expensive cyanide source, trimethylsilyl cyanide. This methodology was applied to the synthesis of the p-substituted-y-amino acid drug Pregabalin 8 and the a-substituted-p-amino acid 9.
O X)H H2N Pregabalin 8 9 Figure 3 : Molecules synthesised to demonstrate Jacobsen's enantioselective conjugate addition of cyanide 16
Mechanistic studies suggest that the catalyst acts with a bimetallic dual activation mechanism similar to that found with the (pybox)ytterbium complex that Jacobsen had utilised for the asymmetric addition of cyanide to meso epoxides. 19 It is hypothesised that the chloride in the catalyst 7 is displaced with cyanide upon addition of TMSCN. This aluminium-cyanide complex subsequently delivers cyanide to the imide substrate which is also activated by Lewis acidic complexation of another molecule of catalyst (Figure 4). This bimetallic proposal is supported by the second order kinetic rate dependence on catalyst concentration and spectroscopic studies which reveal two distinct species of the catalyst under the reaction conditions. 16
CN-AI(salen)
Figure 4 : Proposed bimetallic activation in Jacobsen's enantioselective conjugate addition of cyanide
Jacobsen has further developed his enantioselective conjugate addition of cyanide by independently optimising the nucleophile-delivery and Lewis acid activation functions of the catalyst by employing two separate catalysts in the system. 17 The combination of the u-oxo (salen)aluminiiim 10 and (pybox)erbium 11 complexes as cooperative catalysts (Scheme 12) increases reactivity with reduced catalyst loading, reaction time, reagent equivalents and, for slower reacting substrates, reaction temperature. The substrate scope is still limited to alkyl p-substitution of the imide. 17
fBu
11
Bu Figure 5 : Jacobsen's cooperative catalysts for enantioselective conjugate addition of cyanide 17
2 mol% 10 3mol%11 2 equiv TMSCN —————————*• 2 equiv 'PrOH toluene, rt R - h 84 - 94% R " 93 - 97% ee Scheme 12 : Jacobsen's cooperatively catalysed enantioselective conjugate addition of cyanide
Poor conversion rates are obtained when either catalyst is used separately and mechanistic studies reveal a first order rate dependence in both catalysts. Aluminium salen complexes have previously been shown to activate imide substrates for the addition of other nucleophiles (eg azide,20 malononitrile21) and lanthanide pybox
i f\ T) __ complexes have been shown to deliver cyanide to epoxides and aldehydes. These facts suggested that the increase in reactivity is due to the (pybox)erbium catalyst 11 acting as a superior cyanide delivery system while the u-oxo aluminium salen complex 10 activates the imide. 17
Shibasaki's methodology for the enantioselective conjugate addition of cyanide18 was developed from work on the asymmetric Strecker reaction.23"25 Another multifunctional catalyst (see Section 1.1.1) is employed; the protonated complex 12 with two gadolinium centres and three ligands, formed from mixing Gd(O'Pr)3 and the T5 '"J/i ligand 13 in a 1 : 2 ratio in the presence of TMSCN and the protic additive HCN. '
12 13 Figure 6 : Active catalyst complex and ligand for Shibasaki's enantioselective conjugate addition of cyanide
The Gd-CN centre acts as the cyanide source for the a,p~unsaturated compound which is activated by the other more Lewis acidic Gd centre. ' 18
The only a,p-unsaturated compounds that are employed in this reaction are a,p- unsaturated Af-acylpyrroles (Scheme 13).
5-20 mol% Gd(OjPr)3 O 10-40 mol% 12 0.5-1 equiv TMSCN —————————— 2 equiv HCN EtCN, -20 °C 42-139 h 84-94% 78 - 92% ee
Scheme 13 : Shibasaki's enantioselective conjugate addition of cyanide
Alkyl and aryl p-substirution patterns are well tolerated in good yields and stereoselectivity. An a,p-disubstituted substrate is also tolerated in a good yield and enantioselectivity but poor diastereoselectivity results from non-stereoselective protonation of the intermediate enolate. Long reaction times and high catalyst loadings are required for reactivity which seems problematic when the ligand is synthesised in a lengthy eight steps.26
1.3 Diastereoselective conjugate addition of cyanide
While enantioselective reactions are conceptually interesting and efficient, diastereoselective reactions can prove to be of practical superiority without the need to synthesise complicated ligands. Furthermore, the stereoselectivity of the reaction can be more readily measured when diastereomers, as opposed to enantiomers, are formed. There have been limited diastereoselective approaches published to the conjugate addition of cyanide to electron deficient alkenes and some of the more successful methods are reviewed here.
The addition of cyanide to enantiopure chiral a,p-unsaturated oxazolines was reported by Langlois (Scheme 14).27 19
Et2AICN R = Me, 95%, 28% de R = Ph, 60%, 32% de Ph"x rt, 1-3 days
Et2AICN
-N THF, 0°C -N 2 days 88%, 60% de Scheme 14 : Diastereoselective addition of cyanide to a,p-unsaturated oxazolines
At best moderate stereoselectivities were obtained with long reaction times required. This methodology has been applied to the stereoselective synthesis of the drug molecules (/?)-Rolipram 14 and (^)-Baclofen 15 (Scheme 15) but with moderate yields and stereoselectivity in the key cyanide addition steps.28>29
i) NaOH ii) SOCI2 MeOH
iii) NEt3 OMe NC HO. A o VR [HI N R (/0-Rolipram 14 Ph' Ph'*x H
R = aryl NaOH
(tf)-Baclofen 15 Scheme 15 : Langlois' synthesis of drug molecules (/?)-Rolipram and (/?)-Baclofen
A diastereoselective conjugate addition of cyanide to valine derived a'-amino a,p- unsaturated ketones was reported by Benedetti (Scheme 16).30 The TV-protecting group proved key to stereoselectivity with the bulky AyV-dibenzyl groups providing superior selectivity. Acetone cyanohydrin was used as a protic source in the reaction to decompose the intermediate aluminium enolate and render the cyanide addition irreversible. 20
Et2AICN acetone cyanohydrin —————————- Bn2N toluene, 6 h, rt u CN
75%, 6:1 dr Scheme 16 : Benedetti's diastereoselective conjugate addition of cyanide
Ruano employs a tolyl sulfinyl as the chiral auxiliary in the hydrocyanation of alkenyl sulfoxides (Scheme 17).31
R 1 S '" B2AICN to,uene
R1 = H, R2= nBu, 90%, >98% de R 1 = nBu, R2= Me, 72%, >98% de Scheme 17 : Hydrocyanation of alkenyl sulfoxides
The reaction proceeds with good yields and stereoselectivities but the products resulting from auxiliary removal are less versatile than with other auxiliaries. This methodology has been applied to the synthesis of the fungicide CK)-systhane, demonstrating the formation of a chiral quaternary centre. The three diastereoselective systems detailed in this section all utilise Et2AlCN as the cyanide source which is a relatively expensive and moisture sensitive stoichiometric cyanide source.
1.4 Non-asymmetric conjugate addition of cyanide to enones
O either HCN-AIR3 CN O orEt2AICN R Scheme 18 : Nagata's hydrocyanation of enones
Whilst limited approaches to asymmetric conjugate addition of cyanide have been published, the non-asymmetric version has been well developed. 21
Conjugate addition of cyanide to enones has been known since 187332 but it was not until Nagata revealed his methodology (Scheme 18) in 196233 that hydrocyanation became reliable and efficient.34 Previous methodology for hydrocyanation generally suffered from either poor reactivity (HCN or acetone cyanohydrin catalysed by base) or side reactions due to the basicity of the system (metal cyanides).34 Nagata's hydrocyanation in the presence of organoaluminiums provides good reactivity and chemoselectivity with few side reactions. It is widely used as the reagent of choice, as evidenced by the diastereoselective conjugate additions of cyanide in Section 1.3. There are two different Nagata reagents, hydrogen cyanide in combination with an alkylaluminium (HCN-A1R3, method A), or an alkylaluminium cyanide (R2A1CN, method B). These two reagents are mechanistically distinct.34 The combination of HCN and A1R3 (method A) forms the 1,4-adduct irreversibly.34
2 R3A1 R2A1+ + R4A1' (Eq la)
R3A1 + HCN ' H+ + R3A1CN' (Eq Ib) Equation 1 : Dissociations of HCN and A1R3 in solvent for method A hydrocyantion
The dissociation reactions shown in Equations la and Ib, take place in the commonly utilised solvent THF. The enone is initially activated by either R2A1+ or H+, with R3A1CN" acting subsequently as the cyanating agent, delivering cyanide to the p carbon, and the reaction is finally rendered irreversible after subsequent in situ protonation of the intermediate enolate by H+.34 The activating and cyanating species for method B is monomeric R2A1CN which may be associated with one molecule of solvent. The enone is activated by R2A1CN then either rapid reversible 1,2-addition of cyanide can occur from the activating R2A1CN or another R2A1CN species can deliver cyanide to the (3-carbon. The 1,4-addition is slow compared to the 1,2-addition but is not easily reversible. So over time, the aluminium enolate of the 1,4-adduct can be obtained as the major product and that is protonated upon workup.34
If conjugate addition is undertaken instead with the alternative cyanide source, TMSCN, p-cyano silyl enol ethers can be obtained, which is useful as they are versatile intermediates for further transformations. It was thought that TMSCN would 22 not add in a conjugate fashion to enones ' until Utimoto established it would in the 1*7 "* ft presence of stoichiometric organoaluminiums (Scheme 19). J
2.2 equiv TMSCN 2 equiv AIEt3
reflux, 20 h ™SO CN
quantitative yield Scheme 19 : Conjugate addition of TMSCN in the presence of stoichiometric AlEt3
Employing substoichiometric amounts (0.2 equiv) of AlEt3 resulted in the exclusive formation of the 1,2-adduct 16. It was demonstrated that the 1,2-adduct 16 could be converted to the 1,4-adduct 17 (Scheme 20) in the presence of TMSCN and AlEt3,
"2 *7 both reagents being required.
TMSCN MB3
THF, reflux, 3 h TMSO
16 17 Scheme 20 : Isomerisation of the 1,2-adduct to the 1,4-adduct
Utimoto also established that other Lewis acids (eg Aids, BF3.OEt2, Me3SiOTf and Zn^) could be used catalytically (0.1 equiv) in the place of AlEt3 for the conjugate addition of cyanide to enones, but long reaction times or elevated temperatures are required to avoid 1,2-addition products.37'38 A brief survey of substrate scope revealed that with TMSCN and either AlEt3 or catalytic Lewis acids, only cyclic enones or acyclic enones disubstituted at the p-carbon, underwent conjugate addition.37'38
Another method for the conjugate addition of TMSCN to a,p-unsaturated compounds is the use of solid acids such as Sn4+ or Fe3+ ion-exchanged montmorillonite.39'40 These catalysts are more active than AlEt3 or the other Lewis acids and will function at lower temperatures and with shorter reaction times. As before, it was found that in the initial stages of the reaction mostly 1,2-adduct is formed which is isomerised to the 1,4-adduct under the reaction conditions. Again excess TMSCN is required for the conversion. A survey of substrate scope suggested it was similar to the scope 23 shown for the other catalysts for conjugate addition of TMSCN. Solid bases such as calcium oxide or hydroxyapatite only provided the 1,2-adducts.39'40 While the ion- exchanged montmorillonites give excellent results for the conjugate addition of TMSCN, the practicalities of the preparation and use of these catalysts are not simple.
In summary, the asymmetric conjugate addition of carbon based nucleophiles is a fundamental technique in organic synthesis and some excellent methodology has been developed for the addition of alkyl and aryl groups. Although the non-asymmetric conjugate addition of the versatile cyanide nucleophile has been well developed for a variety of cyanide sources, less development is found for the useful asymmetric addition of cyanide and those techniques that do exist have limitations or drawbacks. 24
2 Research Objectives
To date there have only been limited approaches to the asymmetric conjugate addition of cyanide to a,p-unsaturated carbonyl compounds (Chapter 1). Therefore, the initial aim of this project was to investigate the feasibility of a metal catalysed enantioselective conjugate addition of TMSCN to enones. Secondly we sought to examine whether the scope of the catalyst would extend to other 3 Results and Discussion 3.1 Metal-catalysed cyanide addition to enones 3.1.1 Zinc iodide catalysed reaction The initial tasks of the project were to prepare the silyl 1,2-cyano adduct 19 and the silyl enol ether 1,4-cyano adduct 20 of cyclohexenone to use as a GC standards when testing the potential of Lewis acids to produce the conjugate cyano adduct. The 1,2-adduct 19 was prepared by the addition of TMSCN to cyclohexenone under TMSOTf catalysis at -78 °C for two hours (Scheme 21).42 + TMSCN -78 °C, 2 h 18 19, 64% Scheme 21 : Preparation of 1,2-adduct Analysis of the relevant literature for preparative methods for the 1,4-adduct 20 showed that the use of catalytic Zn^ (10 mol%)38'40 gave the product in good yield and with good selectivity over the 1,2-adduct 19. Therefore Znb as the catalyst was used to prepare 20 (Scheme 22)40 rather than the use of stoichiometric AlEta as used *J Q by Utimoto (Section 1 .4), due to synthetic ease of handling of Znl2 compared to the moisture sensitive AlEt3. Thus, cyclohexenone was reacted with excess TMSCN under catalysis by Zn^ in CFbCb at 40 °C for 6 hours and, after an aqueous work-up, 1H NMR of the crude reaction mixture indicated its composition to be mostly 20. 10mol%Znl + 1.6 TMSCN 40°C,6h NC 18 20 Scheme 22 : Synthesis of the 1,4-adduct of cyclohexenone 26 The purification of 20 proved problematic. The 1,4-adduct 20 was inseparable from both the 1,2-adduct 19 and an additional by-product 21 formed during Kugelrohr distillation. On silica and alumina flash columns, even with base washing, a proportion of the 1,4-adduct 20 decomposed to the p-cyano ketone, 3-oxo- cyclohexanecarbonitrile 22. Even with these difficulties, a suitable amount of 1,4- adduct 20 could be obtained to act as a GC standard. The Znl2 catalysed reaction looked interesting and since there are several asymmetric reactions that employ zinc,43"47 it was decided to investigate the reaction further. Under the conditions shown in Scheme 22 the 1,4-adduct 20 was always the major product although trace amounts of by-products were also visible in the 'H NMR of the crude reaction mixtures. Amongst the by-products obtained were the 1,2-adduct 19, the P-cyano ketone 22, the silylated bis-adduct 23 and an unisolated by-product proposed to be 3-trimethylsiloxy-3-cyclohexenecarbonitrile 21 based on !H NMR analysis. NC .OTMS 9 NC OTMS NC 19 22 23 21 Figure 7 : By-products formed in the ZnI2 catalysed conjugate addition of TMSCN to cyclohexenone The p-cyano ketone 22 is formed via the hydrolysis of the 1,4-adduct 20 by any water in the reaction mixture. The bis-adduct 23 is the result of further cyanide addition to 22; proved by placing the p-cyano ketone 22 under the reaction conditions (10 mol% ZnI2, CH2C12, 40 °C, 6 h) in the presence of TMSCN and obtaining the bis-adduct 23. Further investigations into the effect of time, temperature and solvent are detailed in Table 1 and control experiments showed that in the absence of ZnI2 there was no consumption of the starting cyclohexenone 18 at 40 °C or room temperature. 27 OTMS 10mol%Znl2 + 1.6 TMSCN ————————— 18 20 19 Table 1: Cyanosilylation of 2-cyclohexen-l-one 18 under Znl2 catalysis Ratio" Entry Solvent Temp / °C Time3 / h 20:19 1 CH2C12 40 6 1 :0 2 THF 40 6 rxnc 3 ether 40 6 1 : 1 4 toluene 40 6 2: 1 5 CH2C12 25 48 1 :2 6 CH2C12 40 3 3: 1 a) 100% conversion of cyclohexenone 18 obtained over reaction time b) measured by ratio of alkene peaks in 1H NMR of the crude reaction mixture c) some THF was ring opened under ZnI2 catalysis to give 4-iodobutanol Table 1 shows that CH2C12 is the most suitable solvent of those tested (entries 1-4) with other solvents either giving higher proportions of 1,2-adduct or reacting with the catalyst. In addition, Table 1 demonstrates that a lower temperature (entry 5) or reduced reaction time (entry 6) lead to a higher proportion of 1,2-adduct. This result is explained when following the course of the reaction by TLC and is consistent with that found by Utimoto37'38 and Onaka.39'40 That is, cyclohexenone is generally all consumed upon the initial addition of TMSCN to form a small amount of 1,4-adduct but predominantly 1,2-adduct is produced initially which is then isomerised to the 1,4- adduct under the reaction conditions. The isomerisation was confirmed by placing the 1,2-adduct 19 under the same reaction conditions (TMSCN, 10 mol% Znl2, 40 °C, 6 h) and obtaining the 1,4-adduct 20 (Scheme 23). NCV .OTMS 10mol%Znl2 OTMS + 0.6 TMSCN —— 40 °C, 6h 100% conversion 19 20 Scheme 23 : Isomerisation of 1,2-adduct to 1,4-adduct under the reaction conditions 28 The use of other catalysts such as SnCl2 or TMSOTf in place of ZnI2 for the addition of TMSCN to cyclohexenone at 40 °C for 6 hours gave crude reaction mixtures in which the 1,2-adduct predominated as presumably the isomerisation either did not take place or was not as ready. 3.1.1.1 Isomerisation of 1,2-adduct to 1,4-adduct The mechanism for the isomerisation of the 1,2- to the 1,4-adduct was not known so it was interesting to speculate on what it may be. A postulated mechanism is shown in Scheme 24 where cyanide from the 1,2-adduct leaves with assistance from the lone pair of the trimethylsiloxy group, forming the planar intermediate 24. Re-addition of cyanide can then take place in either 1,2- or 1,4-fashion with the thermodynamically favoured 1,4-adduct 20 formed increasingly over time. NCA OTMS 19 24 Scheme 24 : Possible mechanism for isomerisation of 1,2-adduct to 1,4-adduct It was postulated that the 1,2-adduct may serve as the source of cyanide for the re- addition to intermediate 24. If 19 was acting as the direct source of cyanide, there existed the possibility of introducing chirality by employing chiral ketones^ as the parent ketone of a 1,2-adduct. To test this hypothesis, cyclohexenone 18 and 1,2- adduct 19 were separately subjected to the reaction conditions (10% ZnI2, 40 °C, 6 h, CFhCk) in the presence of the 1,2-adduct of methyl vinyl ketone 25 (Scheme 25). No reaction was observed for either substrate which suggests the 1,2-adduct is not the direct source of cyanide during the isomerisation. f Chiral ketones have been extensively employed within the Armstrong group for asymmetric epoxidations4849 29 TMSCX €N 25 NC .OTMS 10mol%Znl2 or 40 °C, 6h 18 19 Scheme 25 : Determining that the source of cyanide for the isomerisation is not the 1,2-adduct Further investigations into the requirements for isomerisation to the 1,4-adduct are summarised in Table 2. NC OTMS catalyst OTMS + reagent 40 °C, 6 h 19 20 Table 2: Investigations into the isomerisation of the 1,2-adduct 19 Entry Catalyst (mol%) Reagent (equiv) Ratioab 19 : 20 1 ZnI2 (10) TMSCN (0.6) 0: 1 2 ZnI2 (10) TMSCN(O.l) 0: 1 3 ZnBr2 (10) TMSCN (0.6) 10: 1 4 Zn(OTf)2 (10) TMSCN (0.6) 1 :0 5 Zn(CN)2 (10) TMSCN (0.6) 1 :0 6 BU4NI (20) TMSCN (0.6) 1 :0 7 Nal (20) TMSCN (0.6) 1 :0 8 TMSI (10) TMSCN (0.6) 15: 1 9 ZnI2 (10) TMSOTf(0.6) decomposition 10 ZnI2 (10) TMSI (0.6) decomposition 11 CsF (20) TMSCN (0.6) 1 :0 12 CsF (20) + TMSCN (0.6) 1 :0 18-crown-6(20) 13 ZnI2 (10) KCN (0.6) 1 :0 14 ZnI2 (10) KCN (0.6) + 1 8-crown-6 (0.6) c a) ratio indicates conversion of 1,2-adduct 19 after 6 h reaction time b) measured by ratio of alkene peaks in 'H NMR of the crude reaction mixture c) predominantly |3-cyano ketone 22 and bis-adduct 23 present in crude 30 Control experiments demonstrated that in the absence of either TMSCN or Znl2 no reaction would take place but full isomerisation would take place within 6 hours with catalytic ZnI2 and only 0.1 equivalents of TMSCN (entry 2). In order to test the catalytic activity of other zinc halides, ZnBr2 was used as the catalyst for isomerisation of the 1,2-adduct. Entry 3 reveals that the isomerisation, although occurring, was incomplete after 6 hours. The ability of ZnBr2 to catalyse the isomerisation albeit at a slower rate than Znl2, is exemplified by the addition of TMSCN to cyclohexenone 18 using 1.6 equivalents of TMSCN in CH2C12 at 40 °C. After 6 hours, 1,2-adduct was still observed in the crude mixture but when the reaction was conducted over 13 hours, all 1,2-adduct had isomerised. Interestingly, as entries 4 and 5 show, other zinc salts, Zn(OTf)2 and Zn(CNh were unable to catalyse the isomerisation suggesting the halide counter ion may play a role. Therefore catalytic tetrabutylammonium iodide (20 mol%) (entry 6) was tested in the place of Znh to probe whether it was the iodide ion that was inducing the isomerisation, however there was no reaction. Sodium iodide (entry 7) was also tested in case a metal iodide was required but again there was no reaction. It was thought that iodotrimethylsilane (TMSI) may be formed in situ by the TMSCN and Znl2 and that may be catalysing the isomerisation. Therefore, TMSI was tested as catalyst (entry 8) in place of Znb, but again little reaction was observed. A small proportion was converted but mostly unreacted 1,2-adduct was recovered. A study by *H and 13C NMR spectroscopy suggested that the mixture of TMSCN and ZnI2 probably does not form TMSI in situ, since no peaks that corresponded to TMSI could be detected in a mixture of TMSCN and Znl2 in deuterated dichloromethane at room temperature or after the mixture was heated to 40 °C. In addition, the inability of Zn(CN)2 (entry 5) itself to catalyse the isomerisation suggests that this is also not the active component being formed in situ. To establish whether it was the combination of Znb and a trimethylsilyl source that effected the isomerisation, TMSOTf was utilised in the place of TMSCN (entry 9) but in this case there was only decomposition of the starting material. The same result was obtained using TMSI as the trimethylsilyl source (entry 10). To investigate whether the use of a fluoride source would stimulate release of cyanide by desilylating the 1,2-adduct and encourage the isomerisation, CsF, alone and in the 31 presence of 18-crown-6, was tested but in both cases no reaction was observed (entries 11 and 12). In the absence of TMSCN, the isomerisation would not occur. To examine whether a different cyanide source would also effect the isomerisation, potassium cyanide was used in the place of TMSCN (entry 13) however, no reaction was observed. It was thought that this absence of reaction may be because the KCN was insoluble in dichloromethane. When KCN was used in combination with solubilizing agent 18- crown-6 under Znlj catalysis (entry 14), reaction was observed with consumption of the starting 1,2-adduct 19 and production of the p-cyano ketone 22 and the bis-adduct 23 in the crude. These must have been formed from the 1,4-adduct 20 and water, which was probably present in the reaction due to the hygroscopic 18-crown-6. This reaction suggests that another cyanide source can effect the isomerisation under the catalysis of Zn^. These investigations summarised in Table 2 do not conclusively reveal the mechanism of isomerisation but they do reveal important aspects; that additional cyanide is required but not necessarily TMSCN and that a zinc halide seems to be required to catalyse the reaction. It is probable that the additional cyanide required for the isomerisation is just used for initiating the reaction. The role of the Znl2 in the isomerisation is not understood. 3.1.1.1.1 Investigation of stereospecificity of isomerisation An investigation was undertaken to determine whether there was any facial selectivity in the isomerisation of the 1,2-adduct to the 1,4-adduct. If this reaction was stereospecific, it was thought that the 1,4-adduct may be produced with appreciable stereoselectivity by synthesising the 1,2-adduct asymmetrically, for which there are a number of known methods.50'51 Any stereospecificity in the isomerisation may be a consequence of an SN2' like mechanism (Scheme 26). If this mechanism was functioning, it may be an alternative explanation for the requirement of additional TMSCN to initiate the isomerisation. 32 Znl2 OTMS CH2CI2 CN 40 °C, 6h Scheme 26 : Possible SN2' mechanism for isomerisation of the 1,2-adduct to the 1,4-adduct If the SN2" mechanism was being employed the syn52 product relative to the starting material, as shown in Scheme 26, might be expected. Although, if the planar intermediate 24 of Scheme 24 operates, then no stereospecificity would be expected. To test this mechanistic hypothesis, 6-methyl-2-cyclohexen-l-one 26 was synthesised and converted to its 1,2-adduct 27 by reaction with TMSCN under TMSOTf catalysis at -78 °C for 2 hours, as shown in Scheme 27. The purpose of using this substrate was that if there was any facial selectivity in the isomerisation, the diastereomeric ratio of the 1,2-adduct would be reflected in the diastereomeric ratio of the 1,4-adduct. OTMS TMSCN TMSQ CN TMSCN cat. TMSOTf 10mol%Znl2 CH CH2CI2,40°C ° -78°C,2h 48%, 95:5 dr 26 27 28 Scheme 27 : Substrate synthesis and investigation of stereospecificity of isomerisation The 1,2-adduct 27 was synthesised in a 95 : 5 dr as determined by GC. The stereochemistry of the major diastereomer has not been identified but generally 1,2- addition to cyclohexenones operates via axial attack with small nucleophiles53'54 which suggests that the diastereomer with the configuration of the cyanide syn to the methyl predominates (Scheme 28). (axial attack) TMSQ Me H 26 27 Scheme 28 : Axial attack of cyanide on 6-methyl-cyclohexenone 33 Thus 27 was subjected to the isomerising reaction conditions (TMSCN, 10 mol% ZnI2, CH2C12, 40 °C, 6 hr) however after 6 hours the diastereomers of 1,4-adduct 28 were not identifiable by GC and the dr of 28 could not be calculated. Instead the isomerisation was repeated under the same conditions but was terminated after only 4 hours with the hope that a cleaner crude reaction mixture would be produced and thus the 1,4-adduct 28 would be more identifiable by GC. After 4 hours a proportion of the starting 1,2-adduct 27 was still present but now 27 had a 1 : 1 dr by GC. There are two possibilities which could explain why the dr is 1 : 1. It is conceivable that the major diastereomer reacts faster and coincidently led to a 1 : 1 dr. The starting material ratio was 95 : 5 therefore the maximum possible yield of 1,2-adduct where this 1 : 1 dr coincidence can occur is at a 10% yield (5 : 5 ratio of major to minor isomers after reaction of 90% of the material and when no reaction of the minor diastereomer has occurred). But the total percentage of 1,2-adduct 27 after 4 hours, as judged by the integration of the methyl peaks in 1H NMR, was 22%; this is greater than maximum 10% yield, therefore there must be scrambling of the stereochemical information of the 1,2-adduct under the isomerisation conditions to lead to a 1 : 1 dr. Therefore it is irrelevant whether there is any facial selectivity in the isomerisation as the stereochemistry of the 1,2-adduct cannot be retained to be passed onto the 1,4- adduct. This experiment suggests that the isomerisation may proceed, not with a SN2' type mechanism (Scheme 26) but via a planar intermediate of the type shown in Scheme 24 with the re-addition of cyanide in a 1,2-fashion causing the loss of the stereochemistry. 3.1.1.2 Addition of asymmetric ligands The Znl2 catalysed addition of TMSCN to cyclohexenone was also carried out in the presence of chiral additives (Scheme 29) (Table 3). These chiral additives are representive of typical classes of chiral ligands that have previously been successfully employed with zinc;43'44 a diol, a diamine, and amino alcohols. 34 20 mol% chiral additive OTMS NQ OTMS 10mol%Znl2 + 1.6TMSCN 40 °C, 6h 18 20 19 Scheme 29 : ZnI2 catalysed addition of TMSCN to cyclohexenone in the presence of chiral additives Table 3: Addition of TMSCN to cyclohexenone 18 under ZnJ.2 catalysis in the presence of chiral additives Entry Chiral additive Ratio3 18 : 20 : 19 eeb'c of 20 1 (/?)-(+)-bmol 0:2:1 0 2 (7S,2S)-(-)-l,2- 1 :0:0 - diphenylethylenediamine 3 (-)-ephedrine 8:3: 16 0 4 (+)-7V-methylephedrine 29 0:2:4 0 a) measured by ratio of alkene peaks in 1U NMR of the crude reaction mixture b) ee of 1,2-adduct 19 not established c) measured by chiral GC These attempts to introduce asymmetry were not successful as all additives produced a rate retardation and no stereoselectivity. Furthermore, with the diamine (entry 2) no reaction was seen. This was not encouraging because ligand accelerated catalysis is desirable to nullify any background reaction catalysed by uncomplexed zinc iodide. The decrease in reaction rate is understandable if Znb is acting solely as a Lewis acid and is not involved in cyanide delivery or extrusion, since co-ordination of the ligands would reduce the Lewis acidity of the zinc. The improved reactivity of 7V- methylephedrine (entry 4) compared to ephedrine (entry 3) supports this assumption as the resulting positive charge after zinc co-ordination on the tertiary amine of 7V- methylephedrine would increase the Lewis acidity relative to the neutral secondary amine of co-ordinated ephedrine. The lack of any stereoselectivity meant no further work was undertaken on introducing asymmetry into the Znh catalysed reaction. Following the disappointing results for stereoselectivity achieved with cyclohexenone and the issue of by-products and purification, attention was turned to the applicability of other substrates for the Znl2 catalysed addition of TMSCN. 35 3.1.1.3 ZnI2 catalysed conjugate addition of TMSCN to other substrates The ZnI2 catalysed addition of TMSCN was tested on other a,p-unsaturated carbonyl compounds (Figure 9) under the same conditions as used for cyclohexenone (1.6 equiv TMSCN, Cl^Cb, 6 hours and 40 °C). The results of this brief survey of scope are shown in Table 4. 3.1.1.3.1 Synthesis of substrates All the substrates were obtained commercially except for the lactam substrates 30, 31 and 32, and the oxazolidinone substrates 33 and 34 (Figure 9). The lactam 30 was synthesised in three steps by the route shown in Scheme 30.55'56 O O O mCPBA i)NaH ^' i)LDA phSexx^/ 0°C— rt ™ ii)Mel "x^x1 ii)PhSeCI {^^ 30 min 91% 63% 35 36 37 Scheme 30 : Synthesis of substrate 7V-methyl-piperidin-2-one Thus 8-valerolactam 35 was alkylated, the resulting lactam 36 phenylselenenylated by treatment with LDA and quenching with phenylselenenyl chloride and finally 7V- methyl-piperidin-2-one 30 was prepared by oxidative elimination with wCPBA. All steps proceeded smoothly except for the final selenide oxidation with in situ elimination. This required a reduction in reaction time from overnight, as suggested in the literature for similar compounds,55"57 to 30 minutes. Leaving the reaction overnight to effect the benzeneselenenic acid elimination resulted in formation of a by-product, proposed to be 38 which was inseparable from the desired TV-methyl- CO piperidin-2-one 30. The by-product presumably arose from the known addition of the eliminated benzeneselenenic acid across the newly formed double bond. The reduction in the reaction time still allowed the reaction to go to completion but suppressed the formation of 38. 36 38 Figure 8 : Proposed structure of by-product from oxidative elimination step The lactam, 3-(^)-ethylidene-l-phenyl-pyrrolidin-2-one 31 was obtained from GlaxoSmithKline (GSK) and the related phenyl substituted lactam 32 was synthesised by a Wittig reaction (Scheme 31) using materials and methodology developed by GSK. i)DBU jj} benzaldehyde 39 32,73% Scheme 31 : Synthesis of lactam substrate a,p-Unsaturated oxazolidinone substrates, 33 and 34 were prepared using Evans' methodology.59 Oxazolidinone 40 was deprotonated with "BuLi at -78 °C and acylated by the appropriate acid chloride (Scheme 32). 9 i)"BuLi, THF, -78 °C O O HN. O ii) a,|3-unsaturated R^^^^N O acid chloride 40 33, R = Me, 56% 34, R = Ph, 57% Scheme 32 : Synthesis of oxazolidinone substrates 37 3.1.1.3.2 Results of ZnI2 catalysed addition of TMSCN to other substrates O O Ph' 18 41 42 43 44 45 46 O O O NH2 OMe O Ph 47 48 49 50 30 51 O Ph' A PhN PhN V^ Ph 33 34 31 32 Figure 9 : Substrates tested for conjugate addition of TMSCN under ZnI2 catalysis 38 Table 4: Addition of 1.6 equiv of TMSCN to a,(3-unsaturated carbonyl compounds under 10% ZnI2 catalysis in CH2C12 at 40 °C Reaction Ratio3 of starting material : Entry Substrate time/h 1,4-adduct : 1,2-adduct 1 2-cyclohexen-l-one 18 6 0: 1 :0 2 2-cyclopenten-l-one 41 6 0 : 1 : Ob 3 3-methyl-2-cyclohexen-l-one 42 6 0 : 1 : Ob 4 mesityl oxide 43 6 0 : 1 : 2b 5 methyl vinyl ketone 44 6 0:0:1 6 (E)-4-hexen-3-one 45 6 0:0: 1 7 (£)-4-phenyl-3-buten-2-one 46 6 0:0:1 8 cinnamamide 47 6 1 : 0 : Oc 9 JVyV-dimethylacrylamide 48 6 1 : 0 : Od 10e 2(5//)-furanone 49 6 decomposition ll e methyl acrylate 50 6 4: l f :0 12e Af-methyl-piperidin-2-one 30 6 6: l f :0 13e methyl acrylate 50 62 3: 4f :0 14e Af-methyl-piperidin-2-one 30 62 0: l f :0 15 5,6-dihydro-2//-pyran-2-one 51 64 1 :l f :08 16 3-(£)-ethylidene- 1 -phenyl- 144 1 :0:0 pyrrolidin-2-one 31 17 3-(£)-benzylidene- 1 -phenyl- 240 1 :0:0 pyrrolidin-2-one 32 18 3-((£)-2-butenoyl)- 54 1 :0:0 -l,3-oxazolidin-2-one 33 19 3 -((£)-2-cinnamoyl)- 144 1 :0:0 -l,3-oxazolidin-2-one 34 measured by ratio of alkene peaks in H NMR of the crude reaction mixture b) other unidentified products present in crude c) small proportion was jV-silylated d) small amount of unidentified product present e) reaction carried out in NMR tube with CD2C12 as solvent and analysed with no work up ^ 1,4-adduct present as hydrolysed 1,4-adduct 8) polymerised material also produced Table 4 demonstrates that the ZnI2 catalysed conjugate addition of TMSCN only works effectively for cyclic enones (entries 1-3). It was seen by TLC that the 1,4- 39 adducts of the cyclic enones were produced by isomerisation of the initially formed 1,2-adduct. Mesityl oxide (entry 4), a P-disubstituted enone, produced a mixture of 1,4- and 1,2-adduct after 6 hours in which the 1,2-adduct predominated. When the reaction time for mesityl oxide was increased to 12 hours, the 1,4-adduct predominated in a ratio of 4 : 1 with the 1,2-adduct, showing that the isomerisation was taking place, just at a slower rate compared to cyclic enones. Enones with mono- or no substitution at the p-carbon produced exclusively the 1,2-adduct under these •30 conditions (entries 5-7). The enone scope seems to conform to that which Utimoto found for AlEts or other Lewis acid catalysis (Section 1.4); i.e. that only cyclic enones or P-disubstituted enones would give the conjugate addition products. The attempts to add TMSCN to the other classes of a,p-unsaturated carbonyl compounds were not very successful (entries 8-19). Employing a,p-unsaturated amides or esters should encourage 1,4-addition over 1,2-addition due to the electron donating properties of the heteroatoms reducing the electrophilicity of the carbonyl carbon. Entry 8 shows that cinnamamide did not react at all except for a small portion that was 7V-silylated. This meant that the other a,p-unsaturated amides tested were TV-substituted to prevent that side reaction. A^-Dimethylacrylamide (entry 9) has limited reaction, though the !H NMR shows a small amount of another unknown compound. Several of these reactions (entries 10-14) were carried out on a NMR scale due to difficulties in obtaining the products from work up. Furanone 49 (entry 10) gave no recognisable products and seems to decompose under the reaction conditions. Interestingly, while methyl acrylate (entry 11) and 7V-methyl-piperidin-2- one (entry 12) displayed limited reaction over six hours, there does seem to be a small proportion of the respective hydrolysed 1,4-adducts (non-silylated p-cyano adducts) in the NMR tube reactions. The presence of the hydrolysed 1,4-adducts is due to the instability of the silylated 1,4-adducts of these substrates and the probable presence of moisture in the NMR tube from hygroscopic Zn^ and deuterated dichloromethane. a,p-Unsaturated amides and esters are deactivated towards nucleophiles compared to enones, due to the electron donating properties of the heteroatoms. This probably explains why only a small proportion of the methyl acrylate and TV-methyl-piperidin- 2-one had reacted after six hours. When the reaction time of the methyl acrylate reaction was increased to 62 hours (entry 13), the hydrolysed 1,4-adduct, 3-cyano- propionic acid methyl ester60 52 was formed in an increased ratio of 4 : 3 to the starting material. When 7V-methyl-piperidin-2-one was left for 62 hours (entry 14) the 40 starting material was completely transformed to the hydrolysed 1,4-adduct, 1-methyl- 2-oxo-piperidine-4-carbonitrile 53. The lactone, 5,6-dihydro-2//-pyran-2-one 51, also had reduced reactivity compared to the enones and after 64 hours the hydrolysed 1,4- adduct 54 had been producd in an isolated 25% yield. A similar amount of starting material was recovered and the mass balance appeared to be polymerised material. No 1,2-adduct was seen for any of the amide and ester substrates. The exocyclic a,p-unsaturated lactams, 31 and 32, (entries 16-17) and the a,p- unsaturated oxazolidinone substrates, 33 and 34, (entries 18-19) were unreactive towards the addition of TMSCN under Znb catalysis. 52 53 54 Figure 10 : Hydrolysed 1,4-adducts produced by the addition of TMSCN under ZnI2 catalysis It was postulated that a higher reaction temperature may encourage 1,4-addition for enone substrates where the 1,2-adduct was the predominant product. Therefore 1,2- dichloroethane (DCE) (b.p. 83 °C) was employed as the solvent. The results of the increased reaction temperature are summarised in Table 5. Table 5: Addition of 1.6 equiv TMSCN to a,p-unsaturated carbonyl compounds under 10% Znk catalysis in DCE at 83 °C for 6 h. Entry Substrate Major products 1 (£)-4-hexen-3-one 45 bis-adduct 55 2 (E)-4-phenyl-3-buten-2-one 46 1,2-adduct 3 mesityl oxide 43 1,4-adduct, bis-adduct, p-cyano ketone 56 41 TMSCX ,CN CN 55 Figure 11 : Bis-adduct of 4-hexen-3-one obtained at an increased reaction temperature When the higher reaction temperature was employed with 4-hexen-3-one (entry 1), the bis-adduct 55 was the only isolable product, in a 54% yield (maximum possible yield is 60% as only 1.6 equiv. of TMSCN used). Conjugate addition must have occurred to furnish this product thus demonstrating that the higher reaction temperature will promote 1,4-addition where none was seen at the lower reaction temperature of 40 °C. However, 4-phenyl-3-buten-2-one still only produced its 1,2-adduct (entry 2) at the higher reaction temperature. This suggests that the stability provided by the conjugation of the a,p-unsaturated system with the phenyl ring in this substrate, is too great for 1,4-addition to occur under these conditions. The higher reaction temperature was also beneficial at promoting conjugate addition when mesityl oxide was the substrate. After 6 hours at the higher reaction temperature, no 1,2-adduct was present in the crude reaction mixture, instead only the conjugate addition products, the 1,4-adduct, the p-cyano ketone 56 and the bis-adduct, were identifiable in the crude reaction mixture. This is in contrast to the reaction at 40°C where the 1,2-adduct predominated after 6 hours. The results with alternative substrates reinforced the limitations of the Znl2 catalysed addition of TMSCN; discouraging chiral additive results, limited substrate scope and formation of by-products. Therefore, it was decided to investigate the potential of other catalysts for the conjugate addition of TMSCN to enones. 42 3.1.2 Ytterbium trichloride catalysed reaction Attention turned to the potential of lanthanide salts for catalysis of the addition of TMSCN to cyclohexenone. Lanthanide salts have multiple co-ordination sites and good potential for ligand optimisation during the development of asymmetric reactions. Ytterbium was a good starting point for a survey of lanthanide salt catalysis. It is comparatively cheap and has previously been used widely in cyanations; for example opening of epoxides19'61'62 or aziridines63 with cyanide, the Strecker reaction64 and cyanohydrin synthesis.22'65"67 In addition, superior stereoselectivities19'22 have been obtained with ytterbium compared to other lanthanides; ytterbium has a small ionic radius and therefore the chiral ligands are held close to the metal centre and chirality transfer is more efficient. YbCb was the ytterbium salt initially employed because it is comparatively cheap and the chlorides of other lanthanides are widely available for comparison of the effect of the metal. YbCla was initially tested under the same conditions as Znh for the addition of TMSCN to cyclohexenone; 10 mol% catalyst in dichloromethane at 40 °C for six hours with 1.6 equiv of TMSCN. The result of this and changes in the reaction variables are shown in Table 6. It was found that the only product when YbCls was employed as the catalyst was the desilylated bis-adduct, l-hydroxy-cyclohexane-1,3- dicarbonitrile 57. Whilst this was not the silyl enol ether 1,4-adduct 20 that was hoped for, the result was still encouraging as the bis-adduct 57 must have been formed from initial conjugate addition. 43 HO, 10mol%YbCI3 + TMSCN ————————- solvent, 40 °C 18 57 Table 6: Cyanation of cyclohexenone by TMSCN with YbCb catalysis Reaction TMSCN Ratio3 18 : Entry Catalyst Solvent time / h equiv 57b 1 hydrate CH2C12 6 1.6 3:2 2 hydrate THF 6 1.6 1 : 1 3 anhydrous CH2C12 6 1.6 1 : 1 4 anhydrous THF 6 1.6 1 : 1 5 hydrate THF 62 3.2 0:1 a) measured by ratio of alkene protons in 18 to 3-H in 57 in H NMR of crude reaction mixture b) equal mixture of diastereomers of 57 Comparison of the two solvents employed, CH2C12 and THF (entries 1-4), showed similar results with regard to completion of the reaction. THF was eventually found to be the superior solvent as it gave better mass recovery of the crude after the work up. Efforts to drive the reaction to completion were hampered by initial mis-identification of the product. Originally it was thought to be the p-cyano ketone 22 because the !H NMR spectra are similar and the bis-adduct, l-hydroxy-cyclohexane-1,3- dicarbonitrile 57, decomposes on the GC and therefore also on GC-MS to 22. Once the product had been correctly identified as 57, it was realised the reaction could not go to completion with only 1.6 equivalents of TMSCN. The use of 3.2 equivalents of TMSCN and a long reaction time (62 hours) managed to drive the reaction to completion (entry 5). As shown with entries 3 and 4, the use of the anhydrous catalyst still resulted in the desilylated bis-adduct 57 as the only product. Rigourous anhydrous conditions, such as drying the anhydrous catalyst by heating under a vacuum prior to use and running the reaction in the presence of molecular sieves, still result in 57 being the only product with no sign of any silylated products. Lowering the reaction temperature to 44 20 °C or -20 °C only affected the reaction rate and not the product obtained; only desilylated bis-adduct 57 was produced albeit at reduced reaction rates. In order to investigate the origin of the bis-adduct 57, 1,4-adduct 20 was placed under the reaction conditions of 1.6 equiv of TMSCN, catalysis by 10 mol% YbCl3.6H2O in THF at 40 °C for 6 hours (Scheme 33). OTMS 10%YbCI3.6H2O + 1.6 TMSCN ————————^ NCT - THF,40°C,6h 1 : 10 : 6 20 20 22 57 Scheme 33 : Investigation into origin of bis-adduct 57 After the 6 hour reaction time, a small proportion of the 1,4-adduct 20 was still present in the reaction mixture and the major product was the p-cyano ketone 22 while the bis-adduct 57 was a minor product. The continued existence of 1,4-adduct 20 in the crude mixture suggests that it is unlikely that 57 is formed via the 1,4-adduct 20 in the reaction from cyclohexenone as the 1,4-adduct 20 is not observed by NMR or TLC. When the P-cyano ketone 22 is placed under the same reaction conditions it converts cleanly to 57 (Scheme 34) indicating that is the most likely intermediate in the reaction from cyclohexenone. 10%YbCI3.6H20 + 1.6 TMSCN ————————— THF, 40 °C, 6h NC" ^^ 100% conversion NC 22 57 Scheme 34 : Investigation into origin of bis-adduct 57 These reactions (Schemes 33-34) suggest that silylated product is not formed under ytterbium catalysis. This is probably due to the high oxophilicity of the lanthanides which means the catalysts are difficult to dry thoroughly. Therefore, water is present to readily hydrolyse the intermediate Yb-enolates before silylation of the enolate can 45 take place. In addition, any transitory silylated products in the reaction mixture would be extremely susceptible to hydrolysis due to the oxophilicity of Yb. In contrast to Znk catalysis, the absence of any products resulting from initial 1,2- addition to the enone suggests that a different form of the cyanide nucleophile may be involved under Yb catalysis. Mixtures of TMSCN and Yb are known to form ytterbium cyanides19'65'66 in situ and if this is acting as the nucleophile it could account for the different reaction pathway. Therefore, the path to bis-adduct 57 is likely to be exclusive rate determining 1,4-addition from an ytterbium cyanide and hydrolysis of the resulting Yb-enolate to give the p-cyano ketone 22. This may be followed by a fast 1,2-addition to the ketone to form the bis-adduct 57 (Scheme 35). 18 -Yb 57 Scheme 35 : Proposed mechanism of formation of bis-adduct 57 Since the silylated products were not being formed using TMSCN, it was decided to test whether a cheaper cyanide source, KCN, could be utilised to produce the same bis-adduct 57. Thus cyclohexenone was reacted with 3.2 equiv of KCN under 10% YbCl3.6H2O catalysis in THF at 40 °C. After 62 hours, the time taken for the reaction with TMSCN to go to completion (entry 5, Table 6), the bis-adduct 57 was present, along with some P-cyano ketone 22 but cyclohexenone was still the major component of the reaction mixture. This result suggests that KCN can be utilised as a less expensive cyanide source however, its reactivity is lower. 46 The bis-adduct 57 is produced as a mixture of diastereomers in the Yb catalysed reaction but if the cyanohydrin portion of the compound is able to decompose to the ketone the useful p-cyano ketone conjugate addition product 22 can be obtained. This would simplify the measurement of the stereoselectivity of the conjugate addition when asymmetry is introduced into the Yb-catalysed reaction. Complete conversion of the bis-adduct to the p-cyano ketone was achieved by treatment of 57 with aqueous in CHCb at room temperature with vigouous stirring for 2.5 hours (Scheme 36).68 HO. ,CN 5% aqueous K2CO3 CHCI3, rt, 2.5 h NCT ^ NC 57 22 Scheme 36 : Decomposition of bis-adduct to |3-cyano ketone 3.1.2.1 Comparison with other lanthanide catalysts A brief survey of other lanthanide catalysts was carried out. A range of lanthanide chlorides and two other ytterbium salts were tested to investigate what effect the metal and the anion had on reactivity. These results are shown in Table 7. 47 HO. €N 10mol% catalyst + 1.6TMSCN solvent 40 °C, 6 h 18 57 Table 7: Cyanation of cyclohexenone 18 under lanthanide catalysis TLn 3+ ionic' Entry Catalyst3 Solvent Ratiob ofl8:57c radius69 / A 1 YC13 1.02 CH2C12 3: 1 2 LaCl3 1.16 CH2C12 norxn 3 CeCl3 1.14 CH2C12 no rxn 4 SmCl3 1.08 CH2C12 norxn 5 DyCl3 1.03 CH2C12 12: 1 6 YbCl3 0.99 CH2C12 1 : 1 7 Yb(O'Pr)3 0.99 CH2C12 3: 1 8 Yb(OTf)3 0.99 CH2C12 d 9 Yb(OTf)3 0.99 THF e a) anhydrous catalysts were employed b) measured by ratio of alkene protons in 18 to 3-H in 57 in JH NMR of crude reaction mixture c) equal mixture of diastereomers of 57 d) hydrolysed 1,2-adduct and 0-cyano ketone 22 recovered in a 2:1 ratio e) cyclohexenone, silylated 1,2-adduct 19 and 1,4-adduct 20 present in crude in ratio of 2 : 8 : 3 A general trend of increasing reactivity with decreasing ionic radius of the metal can be proposed from the data in Table 7 (entries 1-6). Yttrium (entry 1) has the most similar ionic radius to ytterbium (entry 6) and is the closest in reactivity. The lighter and larger lanthanides (entries 2-4) have no reactivity under these conditions while dysprosium has only limited reactivity (entry 5). Presumably the increasing Lewis acidity obtained with decreasing ionic radius enhances the reactivity. Changing the anion to isopropoxide (entry 7) decreases the reactivity and using the triflate counter ion (entries 8 and 9) changes the reactivity to produce a mixture of 1,2- and 1,4- adducts. Possibly, with the triflate counter ion Yb simply acts as a Lewis acid and does not form a ytterbium cyanide for the cyanide delivery which may explain the difference in products. In CH2C12, Yb(OTf)3 catalysis produces the desilylated 1,2- adduct and the p-cyano ketone 22; again there were no silylated products in the crude but in THF the silylated products were present. It may be that the Lewis basic 48 properties of THF reduces the oxophilicity of Yb(OTf)s and allows silylation to occur. It was found that Yb(OTf)3 does not catalyse the isomerisation of the 1,2-adduct to the 1,4-adduct so the 1,4-adduct that was produced must have come from direct initial addition. 3.1.2.2 Yb€l3 catalysis of TMSCN addition to other substrates A brief survey of substrate scope with YbCl3.6H2O catalysis has been carried out for other a,p-unsaturated carbonyl compounds under the same conditions as used for cyclohexenone (3.2 equiv TMSCN, THF and 40 °C). The results are summarised in Table 8. Table 8: Cyanation of a,p-unsaturated carbonyl compounds with 3.2 equiv of TMSCN under 10% YbCl3.6H2O catalysis in THF Rxna Entry Substrate Product (%yield) time/h 1 2-cyclohexen-l-one 18 62 bis-adduct 57 2 2-cyclopenten-l-one 41 12 bis-adduct & P-cyano ketone 58 (59%) 3 (£)-4-hexen-3-one 45 22 P-cyano ketone 59 (64%) 4 mesityl oxide 43 63 p-cyano ketone 56 (57%) 5 (£)-4-phenyl-3-buten-2-one 46 119 P-cyano ketone 60 (33%) & TMS-bis-adduct 61 (25%) 6 5,6-dihydro-2//-pyran-2-one 51 108 hydrolysed 1,4-adduct 54 (34%) 7 7V-methyl-piperidin-2-oneb 30 23 norxn 8 3 -(£)-ethylidene-1 -phenyl- 100 norxn pyrrolidin-2-one 31 9 3 -(TTj-benzy lidene-1 -pheny 1- 100 no rxn pyrrolidin-2-one 32 10 3-((£)-2-butenoyl)- 23 hydrolysed 1,4-adduct 62 -1,3-oxazolidin-2-one 33 (79%)c 11 3-((£)-2-cinnamoyl)- 74 hydrolysed 1,4-adduct 63 (68%) -l,3-oxazolidin-2-one 34 ^reaction time until total consumption of starting material by TLC b) anhydrous YbCl3 used as catalyst c) non-aqueous work-up used; reaction mixture was diluted with ether and filtered through a short pad of silica washing with CH2C12 49 The type of products obtained for each substrate is variable but all are derived from initial conjugate addition although long reaction times are required for consumption of starting material. Apart from cyclohexenone, the only other substrate to produce the desilylated bis-adduct (analogous to 57) was cyclopentenone (entry 2) and that was as an inseparable mixture with the P-cyano ketone. The P-cyano ketone was the predominant type of product; the only product for all other substrates apart from (E)- 4-phenyl-3-buten-2-one 46 (entry 5), which also produced some silylated bis-adduct 61, as a mixture of diastereomers. No 1,2-addition products were seen with YbCl3.6H2O catalysis although the yields of the conjugate addition products were generally only moderate. The lactone (entry 6) produced the hydrolysed 1,4-adduct but in a poor yield and long reaction time. Lactams (entries 7-9) were unreactive in this catalytic system. Encouragingly, the a,p-unsaturated oxazolidinones (entries 10- 11) gave good yields of the hydrolysed 1,4-adducts although lengthy reaction times were required. 3.1.2.3 Yb-catalysed reaction in the presence of asymmetric ligands In the literature19'22 asymmetry has been effectively introduced into Yb-catalysed cyanations by the use of pybox ligands. Therefore, this was the ligand class of choice for attempts to adapt the Yb-catalysed conjugate addition of TMSCN asymmetrically. Jacobsen's methodology was employed to synthesise the Yb-pybox complex from a mixture of YbCl3.6H2O and the free pybox ligand 64. This Yb-pybox catalyst was applied to the reaction of cyclohexenone and TMSCN in THF (Scheme 37). 50 pybox = 9™S HO. £N TMSO 10%Yb-pybox + 3TMSCN ————————^ THF, 40 °C, 42 h NC 3:8:1 18 20 57 19 Scheme 37 : Yb-catalysed reaction of cylohexenone and TMSCN in the presence of pybox ligand The use of the Yb-pybox catalyst resulted in a mixture of products; the silylated 1,4- and 1,2-adducts and the bis-adduct 57 in contrast to the YbCls.6H2O catalysed reaction where the bis-adduct 57 was the sole product. The ee of the 1,4-adduct 20 was unable to be assessed by GC so it was converted to a diastereomeric acetal 65 (Figure 12) by treatment of the crude reaction mixture with the chiral diol, (2R,3R)- 2,3-butanediol, under acid catalysis.70 The cyano acetal 65 was isolated in a 29% yield over the two steps from cyclohexenone, in addition to some bis-adduct 57 and 1,2-adduct 19, which were unaffected by the acetal formation. It had been shown in *71 *j*y the literature ' that the diastereomeric ratio of this cyano acetal 65 could be assessed by 13C NMR, unfortunately it showed that in this case the diastereomeric excess of the cyano acetal 65 was negligible and consequently that the initial conjugate addition of cyanide to cyclohexenone was not stereoselective under the conditions in Scheme 37. NC' 65 Figure 12 : Diastereomeric cyano acetal Jacobsen19 had reported that THF as the solvent gave poorer stereoselectivity and conversion than halogenated solvents for Yb-pybox catalysed openings of meso- epoxides with TMSCN. Therefore the reaction (Scheme 37) was repeated with as the solvent. Surprisingly the reaction required 6.5 days to go to completion 51 (cf to under 2 days with THF) and this time the major, and only recognisable, product was the TMS-bis-adduct 23. While 23 is not particularly useful for further manipulations, analysis by GC showed it to have been formed with a 82 : 18 dr. Although it is probable that the stereoselectivity arises in the 1,2-second addition of cyanide to the p-cyano ketone and there is no stereoselectivity hi the initial conjugate addition. Due to the poor product selectivity encountered during the addition to cyclohexenone in the presence of chiral ligands, attention was turned to a more reliable substrate class, the a,p-unsaturated oxazolidinones, 33 and 34 (Table 9). These had provided good yields of the hydrolysed 1,4-adducts when catalysed by YbCl3.6H2O. v^ -^ ^ N pybox = <^Jl 1 ^N-Y R R CN O O 10%Yb-pybox R1X^^A + 3.2 TMSCN R1X^X^'NO \_7 40 °C Table 9: Reaction of a,p-unsaturated oxazolidinone substrates with 3.2 equiv of TMSCN under 10 mol% Yb-pybox catalysis at 40 °C Rxn % Yield of eea of Entry Substrate R1 R Solvent time / h product product 1 33 Me 'Pr THF 49 28 0 2 33 Me 'Pr CH2C12 68 20 8 3b 33 Me 'Pr CH2C12 48.5 12 7 4 33 Me 'Pr CHC13C 25 24 -18d 5 33 Me 'Pr CHCl3e 51 8 5 6f 33 Me 'Pr CH2C12 118 29g 6 7 33 Me Ph CH2C12 140 16 3 8 34 Ph 'Pr CH2C12 168 36 18 a) ee measured by chiral HPLC (OJ-H column) of purified hydrolysed 1,4-adduct b) order of addition altered. TMSCN added to catalyst prior to substrate as opposed to substrate addition first for other entries c) distilled from molecular sieves d) major enantiomer opposite to that with CH2C12 e) dry CHC1, purchased from Acros 0 3 equiv of IPA added as an additive y) 24% of starting material also isolated 52 The Yb-pybox catalysed reaction in THF (entry 1) gave a poor yield compared to that catalysed by YbCl3.6H2O and an increased reaction time with no stereoselectivity. Employing CH2C12 as the solvent (entry 2), further increased the reaction time and resulted in a poorer yield and negligible selectivity. Premixing TMSCN and the catalyst prior to substrate addition to encourage Yb-CN formation (entry 3), had minor effect on the stereoselectivity. Swapping the solvent to CHCls (entry 4), the optimal solvent reported by Jacobsen,19 resulted in an increase in enantioselectivity to 18% but curiously the major enantiomer was oppposite to that found with Cl^Cfe. Repetition of the reaction with CHCls (entry 5), although the solvent was obtained from a different source, resulted in a longer reaction time, poorer yield, ee and an exchange in major enantiomer. These results (entries 1-5) suggest that the reaction is not reliably reproducible. It was assumed that the lack of a proton source to generate the hydrocyanated product may be leading to the poor yields. Therefore, IPA was added to the reaction as a proton source (entry 6) but this led to reduced reactivity with only minor improvement in the yield. HCN would possibly be a better proton source for this reaction as the alcohol may have co-ordinated to the Yb, thus decreasing its Lewis acidity. The phenyl substituted pybox ligand was also tested (entry 7) but this resulted in a slight decrease in ee. Use of the p-phenyl a,p~ unsaturated oxazolidinone 34 was not much more encouraging (entry 8), as although a slight increase in yield and enantioselectivity was achieved, the reactivity suffered. The poor stereoselectivity encountered with the oxazolidinone substrates may be attributable to the Yb-pybox complex acting as a Lewis acid on the carbonyl so the chirality of the ligand is at too distant from the cyanide delivery at the P-carbon. It was hoped that the Yb-pybox would act as the cyanide delivery agent and thus influence the stereoselectivity at the P-carbon but either the Yb-CN was not delivering or the chirality transfer was not effective. Other ligand classes may have proved more effective at inducing stereoselectivity but these poor selectivity results, yields and reactivity meant that attention was turned to another metal catalysed conjugate addition of cyanide. 53 3.1.3 Samarium isopropoxide catalysed conjugate addition with acetone cyanohydrin 9 HO, .CN 10mol%Sm(0'Pr)3 CN O toluene, rt n Scheme 38 : Hydrocyanation of enones with acetone cyanohydrin Analysis of the literature revealed methodolgy for the conjugate addition of cyanide to enones utilising Sm(O'Pr)3 catalysis and acetone cyanohydrin as the cyanide source (Scheme 38). *yj This__ reagent combination has also been successfully applied to the ring opening of epoxides,62 aziridines62 and cyanohydrin formation from aldehydes and ketones.74 Acetone cyanohydrin is a cheap and easy to handle source of cyanide and since silylation does not usually occur under Yb-catalysis, it is useful to use in place of the more expensive TMSCN. The application of Sm(O'Pr)3 catalysis for the addition of acetone cyanohydrin to Table 10: Cyanation of a,p-unsaturated carbonyl compounds with 2 equiv of acetone cyanohydrin under 10% Sm(O'Pr)3 catalysis at room temperature in toluene Reaction Entry Substrate Product (%yield) time3 / h 1 methyl vinyl ketone 44 15 p-cyano ketone 67 (9%) 2 (£)-4-hexen-3-one 45 15 p-cyano ketone 59 (44%) 3 (£)-4-phenyl-3-buten-2-one 46 68 P-cyano ketone 60 (57%) 4 mesityl oxide 43 41 P-cyano ketone 56 (77%) 5 2-cyclohexen-l-one 18 15 bis-adduct 57 (quantitative) 6 5,6-dihydro-2//-pyran-2-one 51 71 hydrolysed l,4-adduct54 3 -(£)-ethy lidene-1 -pheny 1- 168 Norxn pyrrolidin-2-one 31 8 3-(£)-benzylidene-1 -phenyl- 168 No rxn pyrrolidin-2-one 32 9 3-((£)-2-butenoyl)-l,3- 16.5 hydrolysed l,4-adduct62 oxazolidin-2-one 33 (84%); isopropyl ester 68a (4%); acetone cyanohydrin adduct 69a (6%) 10 3-((£)-2-cinnamoyl)-1,3- 96 hydrolysed l,4-adduct63 oxazolidin-2-one 34 (72%); isopropyl ester 68b (10%) a) reaction time overnight or until total consumption of starting material by TLC b) polymerised material also formed There was no reaction between the a,p-unsaturated carbonyl compounds and acetone cyanohydrin in the absence of Sm(O'Pr)3. Repetition of the reactions carried out in the literature gave contrasting results. For methyl vinyl ketone 44 (entry 1) the yield was very disappointing compared to the »iro _ 80% reported. The literature was not clear whether toluene or THF was used as the solvent but repeating entry 1 in THF made negligible difference to the yield. The acetone cyanohydrin employed for the results in Table 10 was used unpurified, as supplied from commercial sources, and that contained 0.2% FfeSC^ as a stabiliser. Entry 1 was therefore repeated in the presence of sodium bicarbonate to neutralise the 55 H2SO4 in case that was detrimental to the reaction but it gave no difference in the yield. In contrast, (£)-4-hexen-3-one 45 (entry 2) generated a superior, although moderate, yield compared to that in the literature.73 Other acyclic enones (entries 3-4) gave moderate to good yields but a phenyl p-substituent or p-disubstitution reduced the reactivity of the substrate and resulted in longer reaction times. Cyclohexenone again gave the bis-adduct as the sole product in quantitative yield (entry 5). The lactone 51 (entry 6) gave a poor yield of the required hydrolysed 1,4-adduct 54 due to polymerisation. The exocyclic a,p-unsaturated lactams, 31 and 32, again proved unreactive (entries 7-8). Encouragingly, the hydrolysed 1,4-adducts, 62 and 63, from the a,p-unsaturated oxazolidinone substrates, 33 and 34, were isolated in good yields. However, by-products identified as the a,p-unsaturated isopropyl esters, 68a and 68b, and an acetone cyanohydrin adduct 69a were also isolated. CM O rM R = Me, 68a 69a R = Ph, 68b Figure 13 : By-products from the Sm-catalysed addition of acetone cyanohydrin to a,p-unsaturated oxazolidinone substrates The practicalities of the Sm(O'Pr)3 catalysed addition of acetone cyanohydrin are fairly simple as the reactions are run at room temperature with unpurified acetone cyanohydrin and reasonable reaction times. Although Sm(O'Pr)3 was generally stored and weighed out in a nitrogen glove box in order to preserve the catalytic activity of the compound, storage and weighing out under a stream of argon is also sufficient to retain effectiveness. The a,p-unsaturated oxazolidinone class of substrates had given superior yields of the required cyanide conjugate addition products for the Yb- and Sm-catalysed reactions and did not suffer from the product selectivity issues encountered with enone substrates. Therefore, thought turned to pursuing this class of substrate further and introducing asymmetry into the reaction by the use of chiral oxazolidinones as auxiliaries. 56 3.2 Development of auxiliary-controlled cyanide conjugate addition 3.2.1 Introduction: Diastereoselective conjugate addition with oxazolidinone auxiliaries The use of chiral auxiliaries to accomplish asymmetric reactions has long been known. One class of chiral auxiliaries that has been well developed since they were introduced by Evans in 1981 75 are chiral non-racemic 4-substituted l,3-oxazolidin-2- ones. Benefits of these auxiliaries include their versatility and application to a range of reactions, the ready availability from amino acids and the ease of removal and consequently the recyclability of the auxiliaries.76'77 a,p-Unsaturated Af-acyl oxazolidinones are useful as electrophilic substrates for diastereoselective conjugate additions. a,p-Unsaturated Af-acyl oxazolidinones retain better reactivity for conjugate additions compared to simple a,p-unsaturated amides as the nitrogen lone pair is delocalised between the two carbonyl groups thus the whole system is less deactivated. This point is further backed by LUMO calculations which reveal that the reactivity is similar to enones. 7fi The stereoselectivity in reactions employing a,|3-unsaturated N-acyl oxazolidinones arises from the restriction of rotational freedom in the ground state. Lewis acids are generally employed which co-ordinate to the substrate and enhance the electrophilicity. There are four possible conformations (Figure 14) that the co ordinated a,p-unsaturated N-acyl oxazolidinone can occupy that are planar and thus benefit from maximum overlapping of rc-orbitals.59'79 M M tf a 0 ,^4 pi"^ x^4 R R R anti s-cis anti s-trans syn s-cis syn s-trans 70 71 72 73 Figure 14 : The four possible planar rotamers of a,p-unsaturated yV-acyl oxazolidinones 57 The two s-trans conformations, 71 and 73, are disfavoured80 due to non-bonding steric repulsive interactions between the P-carbon and either C-4 of the oxazolidinone, 73, or the oxazolidinone carbonyl, 71. In the case of a monodentate Lewis acid the anti s-cis conformer 70 is the preferred ground state due to favourable dipole opposition, although this leaves the P-carbon of the alkene pointing away from the stereochemistry of the oxazolidinone thus limiting the effect it can have on facial stereoselectivity.79 When a bidentate Lewis acid is employed, the more stable bis- coordinated complex is favoured which results in the syn s-cis conformer 72 being the preferred ground state. The stereochemistry of the €4 substituent of the oxazolidinone is positioned closer to the P-carbon and can thus more readily influence which face the nucleophile approaches from. This bis-coordinated model was first proposed by Evans59 and was later confirmed by NMR studies with Et2AlCl as the Lewis acid.81 The use of a,p-unsaturated JV-acyl oxazolidinones has been extensively studied for cuprate or copper catalysed conjugate additions. The copper catalysed conjugate ft"? addition of Grignard reagents was first demonstrated by Hruby (Scheme 39). It was found that excellent stereoselectivities could be obtained using the 4-phenyl substituted auxiliary but that diastereoselectivity was much reduced when the phenylalanine derived auxiliary (R = Bn) was employed. The predominant diastereomer was consistent with the model proposed for bidentate chelation (72) and delivery of the nucleophile from the less hindered face opposite the oxazolidinone _ __ oo substituent. Further NMR studies confirmed that a Mg-bis-coordinated copper(I) alkene complex, 74, was formed which confirmed the proposed model of selectivity. 00 Ar O O ArMgBr _/ CuBr / Me2S _/ _ _ R = Ph 91%, 98% dr ~ ~V_/~ R = Bn 85%, 10% dr Scheme 39 : Hruby's copper catalysed conjugate addition to a,p-unsaturated A'-acyl oxazolidinones 58 R Br R-CJ Ph' 74 Figure 15 : Copper(I) alkene complex intermediate in copper catalysed conjugate addition Williams has studied the addition of Yamamoto organocopper reagents (RCu.BF3(MgBr2)) which furnish excellent stereoselectivities for the expected diastereomer arising from bis-coordination when the phenyl substituted auxiliary is employed but suprisingly gives the opposite diastereomer with reduced stereoselectivity for the benzyl substituted auxiliary.84 Other copper catalysed additions include the use of organozirconocenes that are prepared in situ. 5 This allows the addition of a wider ranger of functionalised alkyl groups. Bergdahl found that the facial selectivity for the addition of monoorganocuprate reagents (Li[RCuI]) can be manipulated by the use of TMSI as an additive and judicious choice of solvent. 8 f\ " fift In THF, the TMSI^^ preferentially coordinates the substrate which results in the mono-coordinated anti s-cis conformation 70 being presented for the conjugate addition. In EtiO, the lithium ion is less solvated and is available for bidentate chelation of the substrate with conjugate addition taking place o-y from the syn s-cis conformation 72. Bergdahl has also demonstrated the diastereoselective conjugate addition of a silyl group using a related monosilylcuprate o/r OQ reagent (LifPhNfezSiCul]). ' For the addition of monocuprate reagents, the best stereoselectivities are obtained with the phenyl auxiliary although isopropyl and t- butyl substituted auxiliaries gave only slightly reduced stereoselectivities. The superiority of the phenyl 4-substituted auxiliary over the benzyl auxiliary in additions employing copper is attributed to its superior ability to disrupt the formation of the syn isomer (copper on the opposite alkene face) of the initial copper TC- complex90 74 since the benzyl is effectively sterically smaller due to the potential rotational freedom of the C4-benzyl bond thus reducing its ability to disrupt syn-14*2 The reversal in stereoselectivity discovered by Williams cannot yet be adequately explained though may arise from a more complicated view of the potential 59 coordinated retainers than proposed in Figure 14, maybe involving dimeric or bimetallic complexes or non-planar conformations.91'92 Allylsilanes or allylstannanes in the presence of Lewis acids can be used for conjugate additions to a,p-unsaturated 7V-acyl oxazolidinones (Scheme 40).93'94 Interestingly, although the Lewis acids employed (Sc(OTf)3, ZrCU, Sm(OTf)3) are potentially bis- coordinating, the major diastereomer produced is counter to that predicted by the bis- coordinated model 72. 94 Sc(OTf)3 Ph 85%, 10: 1 dr Scheme 40 : Diastereoselective conjugate addition of allylsilane The production of the unexpected diastereomer has been seen in the conjugate addition of an amine to a substrate bearing a similar imidazolidinone chiral auxiliary. 00 The stereoisomer predicted by the biscoordinated model was produced when Et2AlCl was employed but a reversal in selectivity was seen when the usually bidentate chelating TiCU was used. It was proposed that although the TiCU was bis- coordinated, the Ti-O bond lengths forced the Ti out of the plane and this twisting of the structure exposed the opposite face to conjugate addition. OO It is conceivable that a similar effect exists for the Lewis acids employed in the addition of allylsilanes or allylstannanes detailed above. Thiols can be added to o,p-unsaturated N-acy\ oxazolidinones in a conjugate fashion in the presence of catalytic lithium thioaryloxide.95 The expected diastereomer predicted by the lithium bis-coordinated model 72 is produced. The work undertaken on conjugate additions employing Evans* auxiliaries detailed above, suggested there was scope for further development with cyanide as the nucleophile. 60 3.2.2 Diastereoselective conjugate addition of cyanide with Evans* auxiliary 3.2.2.1 Initial test reactions The chiral non-racemic a,p-unsaturated oxazolidinone substrates were prepared in good yield as described in Section 3.1.1.3.1 using Evans' methodology (Table II).59 The 4-substituted l,3-oxazolidin-2-one was deprotonated with "BuLi at -78 °C and acylated by the appropriate acid chloride. Two commonly used and commercially available Evans' auxiliaries were employed for initial test reactions; the valine derived oxazolidinone (R = 'Pr) and the phenyl alanine derived oxazolidinone (R = Bn). 9 i) nBuLi, THF, -78 °C HN A0 -————— ——— Table 11: Synthesis of chiral non-racemic a,p-unsaturated oxazolidinones Entry R1 R Product %yield 1 Me 'Pr 75 88 2 Ph 'Pr 76 94 3 Me Bn 77 70 4 Ph Bn 78 57 The substrates synthesised in Table 11 were subjected to the reaction conditions developed (see Sections 3.1.2 and 3.1.3) for Yb- and Sm-catalysed conjugate cyanations under which a,p-unsaturated oxazolidinones, 33 and 34, had provided good yields, in order to assess whether any stereoselectivity could be achieved (Table 12). 61 00 CM O O cyanide source i » ^ \ _^ / M i R*^ # Table 12: Conjugate hydrocyanation of chiral non-racemic a,p-unsaturated oxazolidinones under either Sm- or Yb-catalysis Product Rxn Product Entry Substrate R1 R Catalysta %yield (SM time / h drb %yield) 1 75 Me 'Pr Sm 0.5 73 19:81 2 75 Me 'Pr Yb 49 81(8) 37:63 3 76 Ph 'Pr Sm 6 68(2) 11 :89 4 76 Ph 'Pr Yb 211 53 (32) 28:72 5 77 Me Bn Sm 0.5 80 25:75 6 77 Me Bn Yb 49 81 37:63 7 78 Ph Bn Sm 180 78 (20) 28:72 8 78 Ph Bn Yb 211 67(2) 25:75 ^ Sm catalysed conditions: 2 equiv acetone cyanohydrin, 10mol% Sm(O'Pr)3, toluene, rt. Yb catalysed conditions: 3 equiv TMSCN, 10mol% YbCl3.6H2O, THF, 40 °C. b) dr measured by isolated mass of separated diastereomers Table 12 shows that the Sm-catalysed reaction (eg entry 1 vs 2) is superior for the chiral non-racemic a,p-unsaturated oxazolidinone class of substrate. The Sm(O'Pr)3 catalysed addition of acetone cyanohydrin provided much better reactivity with shorter reaction times at lower temperatures and generally a superior diastereomeric ratio than the YbCl3.6H2O catalysed addition of TMSCN. The methyl p-substituted substrate bearing the valine derived auxiliary 75 (entry 1) provided the expected hydrocyanated product 79 after just 0.5 hours at room temperature in good yield and dr under the Sm-catalysed conditions. The Yb-catalysed reaction (entry 2) required 49 hours at 40 °C and starting material was still isolated. The inferior diastereoselectivity could be attributed in part to the higher reaction temperature required for reactivity which unfavorably perturbs the distribution of reactive ground state conformers compared to the lower temperature Sm-catalysed reaction or just the inherent mechanistic differences encountered when using different reagents may account for the stereoselectivity difference. 62 Unsurprisingly, the alkyl p-substituted substrates were more reactive than the more stable conjugated Ph p-substituted substrates (entries 1 vs 3 and 2 vs 4 etc) although the Ph substrates did usually provide a superior dr. The isopropyl 4-substituted auxiliary generally provided slightly superior diastereoselectivity compared to the benzyl 4-substituted auxiliary under these reaction conditions. Therefore, due to the superior reactivity and diastereoselectivity, the methyl-isopropyl substrate 75 was chosen as the basis for further investigation of the Sm-catalysed reaction. The diastereomers of the hydrocyanated oxazolidinone products were not separable in ! H NMR spectrum,1^ except for that of the phenyl-benzyl substrate 78. Fortunately, the others were separable by silica flash column chromatography so the diastereomeric ratio could be calculated from the isolated masses of the separated diastereomers. The veracity of the dr calculated by the isolated masses was demonstrated in two ways. 1) The dr calculated by isolated mass (28 : 72) of the phenyl-benzyl products (entry 7) was in good agreement to that found by !H NMR spectrum (27 : 73). 2) The diastereomers of the methyl-benzyl product 80 could be separated by ]H NMR decoupling at 4.72 ppm on a 500 MHz machine, which provides one set of the benzylic protons as separated doublets instead of overlapping double doublets (Figure 16). The dr calculated in the decoupled NMR spectrum was in good agreement with that calculated by isolated masses (23 : 77 vs 24 : 76). 500 MHz *H NMR 500 MHz *H NMR decoupled at 4.72 ppm CN O Q CN O \/ 4.72ppm 8° multiple! 80 H H H H-, I diastereomer A = 2.79ppm overlapping diastereomer A = 2.79ppm separated [ diastereomer B = 2.84ppm double doublets diastereomer B = 2.84ppm doublets Figure 16 : NMR separation of the diastereomers of the Me-Bn hydrocyanated product 80 by 500 MHz 'H NMR decoupled at 4.72 ppm (see appendix) Various deuterated solvents were evaluated on 250, 400 and 500 MHz NMR machines 63 3.2.2.2 Relative stereochemistry of product X-ray crystallography of the major diastereomer of the methyl-benzyl hydrocyanated product 80b (Figure 17) showed that the new stereocentre formed at the p-carbon had an /^-configuration. This stereocentre is consistent with application of the syn s-cis model shown in Figure 14, with the metal bis-coordinated and the enone in the favoured s-cis conformation and approach of the cyanide nucleophile from the least hindered face opposite the 4-substiruent of the oxazolidinone (Scheme 41). This suggests that bidentate chelation is seen for the samarium centre in the reaction. 80b Figure 17 : X-ray crystal structure of the major diastereomer of Me-Bn hydrocyanated product 80b CN O O 'CN01 Ph— • Ph— ' syn s-cis major diastereomer 77 80b "CNe " Scheme 41 : Explanation for formation of the major diastereomer The major diastereomer for the Me-isopropyl hydrocyanated product 79b was isolated as an oil so X-ray crystallography to determine the configuration of the new stereocentre was not possible. However, comparison of the optical rotations of the p- 64 cyano acids obtained from the hydrolytic cleavage (Section 3.2.2.8.1) of the benzyl and isopropyl auxiliaries from the p-hydrocyanated product, 80b and 79b, proved that the isopropyl auxiliary provided the same ^-configuration. In addition, X-ray crystallography of the crystalline minor diastereomer of Me-isopropyl hydrocyanated product 79a showed that it possessed the opposite S-stereocentre at the p-carbon (Figure 18). Therefore the same model as employed for the benzyl auxiliary (Scheme 41) can be used to explain the stereoselectivity encountered with the isopropyl auxiliary. In addition, to evaluate whether the major diastereomer predominates by virtue of equilibration to the more stable isomer, each diastereomer of the Me- isopropyl hydrocyanated product 79 was submitted individually to the Sm-catalysed reaction conditions. It was found that solely the diastereomer submitted was obtained after the completion of the reaction and therefore the cyanide addition is essentially irreversible and no equilibration is taking place. CN O Figure 18 : X-ray crystal structure of the minor diastereomer of Me-isopropyl hydrocyanated product 79a 3.2.2.3 Investigation of the Sm-catalysed reaction conditions The reaction conditions of the Sm-catalysed addition of cyanide were investigated (Table 13) using the Me-isopropyl oxazolidinone substrate 75 that had been found to deliver the best combination of reactivity and stereoselectivity in the initial test reactions (Section 3.2.2.1). Reduction of acetone cyanohydrin equivalents from 2 equiv to 1 equiv resulted in negligible difference in dr and only a slight reduction in yield in the same reaction time (entry 2, Table 13). Similarly it was found that when 5 mol% compared to 10 65 mol% of Sm(O'Pr)3t was employed there was negligible difference in dr, a similar reaction time and even an increase in yield (entry 3, Table 13). 00 CM O O A^ toluene AA^^ A rt 75 x 79 Table 13: Investigation of reactant equivalents for the Sm-catalysed reaction Equiv of acetone Sm(0'Pr)3 Rxn time / %Yield dra Entry cyanohydrin mol% mm 79 1 2 10 30 73 19:81 2 1 10 30 67 18:82 3 2 5 40 85 20:80 a) dr measured by isolated mass of separated diastereomers By-products that are seen with the Sm(O'Pr)3 catalysed reaction include a,p- unsaturated isopropyl esters 68 which were always produced in varying quantities. These are generally formed from the initial reaction between the catalyst and the a,p- unsaturated oxazolidinone substrate prior to the addition of acetone cyanohydrin, as seen by TLC. The p-methyl isopropyl ester 68a is volatile and is not generally isolated after workup but is visible by TLC; for other p-substituted substrates the ester has been isolated in up to a 20% yield but usually less than 10% is seen. This side reaction may explain the increase in yield observed when employing only 5 mol% of Sm(O'Pr)3 (entry 3, Table 13) as the reduction in catalyst means a reduction in the isopropyl ester by-product formation. In addition, the production of this ester also produces the free oxazolidinone 81 as a by-product which can be isolated from the reaction mixture. Another by-product that was occasionally isolated in small quantities (<5%) was the acetone cyanohydrin ester of the hydrocyanated product 69. * Care was required to preserve the activity of the catalyst. Reduction in reactivity was seen with yellowed catalyst after prolonged exposure to air and moisture. 66 O A CN O HN O 68 81 69 Figure 19 : By-products isolated from the Sm-catalysed addition of acetone cyanohydrin to chiral non- racemic a,p-unsaturated oxazolidinone substrates The reactant order of addition was investigated in order to reduce the formation of the isopropyl ester by-product. Usually a toluene solution of the oxazolidinone substrate was added to the Sm(O;Pr)3 to allow Sm-chelation, followed by the acetone cyanohydrin. By TLC, the formation of the isopropyl ester was seen upon addition of the substrate to the catalyst prior to the addition of the acetone cyanohydrin. Therefore, to reduce the by-product formation and increase the yield of the required hydrocyanated product, the acetone cyanohydrin was added to the Sm(O'Pr)3 prior to the substrate. By TLC, there was minimal formation of the isopropyl ester and this gave a much improved 93% yield although poorer stereoselectivity was obtained with a dr of 27 : 73. The origin of the reduction in stereoselectivity is not known. 67 CN O Q 3 NC OH 10%Sm(O'Pr) solvent, rt 75 79 Table 14: Reaction of substrate 75 with 2 equiv of acetone cyanohydrin under 10% Sm(O'Pr)3 catalysis at rt in various solvents %Yield 79 Entry Substrate Solvent3 Rxn time / h drb (%yield 75) 1 75 toluene 0.5 73 19:81 2 75 Et20 0.66 64 20:80 3 75 THF 0.66 78 21 :79 4 75 CH2C12 0.66 71 18:82 5 75 acetone 3 81(11) 23:77 6 75 EtOAc 0.5 74 24:76 7 75 DMF 27 16(41) 39:61 8 75 MeCN 0.5 75 22:78 9 75 'PrOH 0.75 63 17:83 anhydrous solvent b> dr measured by isolated mass of separated diastereomers A survey of solvents showed that there was minimal solvent effect with increasing polarity (Table 14) with similar yields and diastereoselectivity obtained for most solvents. The use of 'PrOH (entry 9) did not result in an excess of isopropyl ester by product 68 and gave only a marginally reduced yield of the required hydrocyanated product 79. DMF (entry 7) was the only unsuitable solvent tested, with poor reactivity. Presumably the Lewis basic characteristics of the solvent impeded the ability of Sm(O'Pr)3 to coordinate to the substrate. The use of acetone (entry 5) as the solvent results in reduced reactivity probably because the decomposition of acetone cyanohydrin to release cyanide results in the formation of acetone (Scheme 47) and this equilibrium is perturbed by the use of acetone as the solvent resulting in the slower reaction. Even so, an increased yield was obtained with acetone. 68 Experiments were also undertaken to investigate whether reducing the reaction temperature would increase the diastereoselectivity. Reduction of the temperature to -78 °C resulted in almost complete loss of reactivity and at -20 °C or 0 °C the reactivity was again reduced with negligible effect on stereoselectivity. 3.2.2.4 Chiral oxazolidinone substrates in other hydrocyanating systems The chiral non-racemic a,p-unsaturated oxazolidinone substrate 75 was also subjected to hydrocyanation with Nagata's reagent,34 Et2AlCN (Table 15), for comparison with 0 CN O O .,- -~ toluene ^ N p + 2 Et2AICN ——————————^ ^ ^^ N p )—' additive ,0—' 75 x 79 Table 15: Reaction of substrate 75 with 2 equiv of diethylaluminium cyanide in toluene Rxn time / %Yield Entry Additive Temp / °C dra h 79 1 - rt 0.5 95 43:57 2 - -78 29 62b 43:57 3 acetone rt 1 96 31 :69 cyanohydrin acetone -78 74 90 38:62 cyanohydrin 5 ZnBr2 rt 0.3 89 39:61 6C ZnBr2 rt 0.75 44d 32:68 dr measured by isolated mass of separated diastereomers b) 11% of (4S)-4-isopropyl-3-(3-methyl-pentanoyl)-l,3-oxazolidin-2-one 82 also isolated as a 1 : 1 mixture of diastereomers c) Et2O used as reaction solvent d) 44% of starting oxazolidinone 75 also isolated Hydrocyanation of oxazolidinone 75 by EtiAlCN at room temperature (entry 1) was complete within 30 minutes and gave a good yield of the required hydrocyanated 69 product 79 but with poor stereoselectivity. To improve stereoselectivity, the reaction temperature was reduced to -78 °C (entry 2). This produced a longer reaction time and poorer yield but had no effect on the stereoselectivity. Also the ethyl adduct 82, formed from the conjugate addition of the ethyl group from Et2AlCN instead of the cyano group, was isolated as a by-product in an 11% yield. O O 82 Figure 20 : By-product of reaction of 75 with Et2AlCN at -78°C Hydrocyanation with Et2AlCN forms the aluminium enolate in a reversible reaction34 (Section 1.4); protonation to the hydrocyanated product occurs upon aqueous workup. This equilibration could be the source of the poor stereoselectivity. To combat this, the addition can be made irreversible by using the alternative Nagata reagent, HCN- AlEt3 or more conveniently by employing an in situ proton source such as acetone "jf\ cyanohydrin (entries 3-4). Although the use of acetone cyanohydrin as a proton source did lead to an increase in stereoselectivity at both room temperature and -78 °C, the dr was still inferior to that found with the Sm-catalysed reaction. Looking for a further increase in stereoselectivity, a stoichiometric amount of ZnBr2 was premixed with the oxazolidinone substrate 75 (entries 5-6)96 to act as a chelating agent and fix 75 in the syn s-cis conformation. In toluene (entry 5), the ZnBr2 was not fully soluble so much of the substrate reacted without ZnBr2 chelation and the diastereoselectivity did not show much improvement over that found with entry 1. When ether, in which ZnBr2 is soluble, was employed there was a drop in reactivity and not much improvement in stereoselectivity. Further study into the use of Et2AlCN was not undertaken due to the reduced stereoselectivity obtained so far, compared to the Sm(O'Pr)3 catalysed reaction, and the expense and the instability of Et2AlCN as the cyanating reagent compared to acetone cyanohydrin. 70 Investigations into the effect of the lanthanide and counter ion of the catalyst were also attempted. Thus the Me-isopropyl oxazolidinone 75 was subjected to the reaction conditions of 2 equiv acetone cyanohydrin in toluene at room temperature with 10 mol% of Yb(O'Pr)3 as the catalyst. In this case there was no reaction observed after several days. It was unclear whether the change in lanthanide or the quality of the catalyst, which may have decomposed, was the reason for the lack of reaction. SmCla was also tested as the catalyst under the same reaction conditions. With no base present, no reaction was observed and when the base triethylamine was added to encourage release of the cyanide ion by decomposition of the acetone cyanohydrin only a trace of conversion to the hydrocyanated product 79 was observed. Further investigation into the effect of the lanthanide and counter ion of the catalyst was not possible due to time constraints. 3.2.2.5 Effect of auxiliary on stereoselectivity Other auxiliaries (oxazolidinone and a sultam) (Figure 21) were assessed for impact on the stereoselectivity of the Sm(O/Pr)3 catalysed reaction. 0 O O If If If HN O HN O HN O \_/ Ph—* Ph" A 81 83 84 O O A A HN O HN O -Ph Ph Ph— 85 86 87 Figure 21 : Auxiliaries tested in the Sm(O'Pr)3 catalysed reaction The 4-isopropyl and 4-benzyl substituted oxazolidinones, 81 and 83, were the initially tested auxiliaries (Section 3.2.2.1). For several copper catalysed conjugate additions the 4-phenyl substituted oxazolidinone 84 has been found to yield superior stereoselectivity when compared to the 4-benzyl and 4-isopropyl substituted oxazolidinones (Section 3.2.1). The 5-ge/w-disubstituted oxazolidinones, 85 and 86, 71 have been developed by Seebach97 and Davies98 in anticipation of being superior auxiliaries compared to the standard oxazolidinones, eg: 81. It is proposed that the 5- gew-disubstituents control the conformation of the 4-substituent on the oxazolidinone and thus enhance the facial shielding properties and stereoselectivity. " Other advantages that these 5-disubstituted auxiliaries, 85 and 86, offer, include the production of more crystalline compounds and cleaner cleavage of the auxiliary because endocyclic cleavage at the oxazolidinone carbonyl is sterically blocked by the 4- and 5-substituents.99'100 Oppolozer's sultam 87 has provided excellent stereoselectivities for conjugate additions in the literature. 101"103 The p-methyl a,p-unsaturated substrates were synthesised by acylation of the deprotonated auxiliary with crotonyl chloride (Table 16). Evans1 methodology59 ("BuLi at -78 °C followed by stirring with crotonyl chloride for 0.75 hours warming to 0 °C) was used for all oxazolidinones except for the 5-gem-dipheny\ substituted oxazolidinone 85 where Seebach's conditions97 of "BuLi at 0 °C were required for complete deprotonation of the oxazolidinone followed by stirring at room temperature overnight for acylation with crotonyl chloride. Literature104 procedure was followed for the sultam auxiliary 87 where deprotonation with NaH was sufficient. i) base Auxiliary ii) crotonyl chloride " aux Table 16: Synthesis of a,(3-unsaturated substrates bearing different auxiliaries Entry Auxiliary Product %Yield 1 (^S)-4-isopropyl-2-oxazolidinone81 75 88 2 (4S)-4-benzyl-2-oxazolidinone 83 77 70 3 (4S)-4-phenyl-2-oxazolidinone 84 88 88 4 (4S)-4-isopropyl-5,5-diphenyl-2-oxazolidinone 85 89 75 5 (4S)-4-benzyl-5,5-dimethyl-2-oxazolidinone 86 90 59 6 (73,2/0-2,1 0-caniphorsultam 87 91 82 These a,|3-unsaturated substrates were reacted with acetone cyanohydrin under Sm(O'Pr)3 catalysis at room temperature and the results are shown in Table 17. 72 O HO CN 10%Sm(QfPr)3 CN O toluene, rt Table 17: Sm(O'Pr)3 catalysed hydrocyanation of a,p-unsaturated substrates bearing different auxiliaries dra Entry Substrate Rxn time/ h Product %yield 1 75 0.5 73 19:81 2 77 0.5 80 25:75 3 88 0.5 69 29:71 4 89 4.5 58 40 : 60b 5 90 0.5 60 33:67 6 91 116 48C -85 : 15d a) dr measured by isolated mass of separated diastereomers b) diastereomers inseparable by flash column chromatography. dr measured by !H NMR of purified mixture of diastereomers c) 23% of starting material also isolated d) diastereomers inseparable by flash column chromatography. dr estimated by 13C NMR of purified mixture of diastereomers As discussed in Section 3.2.2.1, the isopropyl auxiliary 81 gave a superior dr to the benzyl auxiliary 83 (entries 1-2). While the phenyl auxiliary 84 has been found to deliver a superior dr for many copper containing conjugate additions (Section 3.2.1), this was not the case for the Sm(O'Pr)3 catalysed hydrocyanation where a decrease in dr and yield (entry 3) was found compared to the isopropyl auxiliary (entry 1). The use of the 5-disubstituted oxazolidinones, 85 and 86, did not provide the hoped for increase in stereoselectivity. In contrast, the use of the 5-diphenyl substituted auxiliary 85 (entry 4) resulted in a poorer dr and yield, longer reaction time and diastereomers that were inseparable by flash column chromatography. The 5- dimethyl substituted auxiliary 86 (entry 5) also resulted in a decreased yield and dr compared to the isopropyl auxiliary (entry 1). The sultam auxiliary (entry 6) also proved problematic under these reaction conditions. The reactivity of the substrate 91 was much reduced; 23% of starting material still recovered after 116 hours and the diastereomers of the product 92 were inseparable by flash column chromatography. While the dr was slightly superior to that obtained with the isopropyl auxiliary 81, it could not be calculated by ! H NMR spectrum and only estimated by I3C NMR 73 spectrum. To evaluate the major product diastereomer in the mixture and therefore the probable Sm-coordination mode, the sultam auxiliary was hydrolytically cleaved to yield the p-cyano acid. Comparison of the optical rotation revealed that the major enantiomer of the p-cyano acid possesses an S-stereocentre at the p-carbon. This stereoselectivity suggests that samarium also employs a bis-coordination mode for the sultam auxiliary with attack of the cyanide from the least hindered face of the alkene (Figure 22). 101 "CN G" Figure 22 : Bis-coordination of Sm with sultam auxiliary As a result of the superior dr supplied by the isopropyl auxiliary (Table 17), it was employed for further investigations into the scope of p-substitution on the a,p- unsaturated substrates in the Sm(O'Pr)3 catalysed hydrocyanation. 3.2.2.6 Scope of substitution of the alkene 3.2.2.6.1 Synthesis of substrates The a,p-unsaturated oxazolidinone substrates with a range of substitution were generally prepared in good yield as described in Section 3.2.2.1 using Evans1 methodology (Table 18).59 Thus (4S)-4-isopropyl-2-oxazolidinone 81 was deprotonated with "BuLi at -78 °C and acylated by the appropriate acid chloride (Scheme 43). If the acid chloride was not commercially available it was generally synthesised from the a,p-unsaturated carboxylic acid by reaction with oxalyl chloride under DMF catalysis (Scheme 42). 105 74 R2 O oxalyl chloride cat. DMF OH Cl 0°C, 20min Scheme 42 : Synthesis of a,P~unsaturated acid chlorides i) nBuLi, THF, -78 °C ii) 81 Scheme 43 : Synthesis of substituted o,)5-unsaturated substrates Table 18: Synthesis of substituted a,p-unsaturated oxazolidinone substrates Entry R1 R2 R' Product %Yield 1 Me H H 75 88 2 Et H H 93 70 3 'Pr H H 94 90 4 Ph H H 76 94 5 /7-MeOC6H4 H H 95 84 6 p-C!C6H4 H H 96 90 7 Me Me H 97 95 8 Me H Me 98 95 The a,p-unsaturated carboxylic acid was not available for three substrates (Figure 23) and these needed to be synthesised via alternative routes. TBSO MeO Ph \_7 99 v 100 v 101 Figure 23 : Substituted a,p-unsaturated substrates requiring extended synthesis The substrate bearing the TBS protected oxygenated p-substituent 99 was synthesised employing a route (Scheme 44) that had already proved successful, with the benzyl 75 auxiliary, within the research group. 106 The substrate bearing the methoxy |3- substituent 100 was synthesised in an analogous manner (Scheme 44) although monoprotection of the diol was not required as the methoxy alcohol 102 was commercially available. Attempts to synthesise the similar acetoxy oxygenated substrate were not successful and time constraints meant that a further attempt to synthesise that substrate via an alternative route was not possible. O i) "BuLi, THF O O O O O If -78 °C, 15min HN O ———————————»> v_y ii) chloroacetyl chloride Y_J 140 °C, 3h -78 °C, 5 min rt, 30 min 104, 94% 81 103, 82% Horner- Wadsworth- Emmons R= IBS, 99, 31% R= Me, 100, 88% i) NaH, THF Swern rt, 45 min oxidation ii) TBSCI 105 rt, 45 min R=TBS, 106, 61% R= TBS, 107, 58% R= Me, 102, commercial R= Me, 108,31% Scheme 44 : Synthesis of substrates bearing an oxygenated p-substituent Thus the substrates bearing an oxygenated P-substituent were synthesised by a Horner-Wadsworth-Emmons (HWE) reaction between the appropriate aldehyde and the phosphonate 104. Deprotonation of the oxazolidinone by "BuLi and acylation with chloroacetyl chloride, yielded the a-chloro compound 103, which was subjected to an Arbuzov reaction to give the required phosphonate 104. 107 The aldehyde partner was synthesised from 1,3-propane diol, for the OTBS substrate, which was monoprotected 108 then the alcohol oxidized to the aldehyde by a Swern oxidation. 109 The poor yield (31%) for the oxidation of the OMe substrate was attributed to the 76 volatility of the aldehyde 108. The HWE reaction between the phosphonate and aldehyde produced the required a,p-unsaturated oxazolidinones 99 and 100. The poor yield (31%) encountered for the HWE reaction of the OTBS substrate was possibly due to incomplete deprotonation of the phosphonate 104 by the diisopropylethylamine / LiCl combination. Therefore for the HWE reaction of the OMe substrate, the stronger base, sodium hydride, was employed for the deprotonation of the phosphonate 104 and an increased product yield was obtained. To test the feasibility of creating a quaternary centre with the Sm-catalysed hydrocyantion methodology, the dimethyl P-disubstituted substrate 97 was readily synthesised from the commercial a,p-unsaturated acid (Table 18). However, no other p-disubstituted a,p-unsaturated carboxylic acids were readily commercially available to investigate the stereochemical consequences when creating a quaternary chiral centre. Therefore it was planned to synthesise a dialkyl Et-Me p-disubstituted substrate and the potentially less reactive, but more discriminating Ph-Me p- disubstituted substrate 101, via the formation of the a,p-unsaturated ester by a HWE reaction (Scheme 45). A linear route via the ester to the a,p-unsaturated oxazolidinone was choosen rather than a convergent route employing the HWE reaction between the oxazolidinone phosphonate 104 and the appropriate ketone (Scheme 45) because literature precedent110' 111 suggested that the Z/.E-isomers of both esters were separable by flash column chromatography and that the individual isomers were identifiable and previously characterised. The convergent route would have produced novel compounds in a possibly inseparable mixture of Z/£-isomers. 77 O i) hydrolysis OEt ii) acid chloride R2 O O HWE formation 109 R2 O N O iii) auxiliary attachment known separable E-isomer Z/E-isomers R1 = Et or Ph R2 = Me Linear route Convergent route O O O R2 O O ii II II O HWE (EtO)2Px^ NAc R1X^^N O \_y R 1 " R^ R1 = Et or Ph 104 inseparable? Z/E-isomers Scheme 45 : Linear vs convergent route to P-disubstituted a,|3-unsaturated substrates An attempt to synthesise the dialkyl Et-Me p-disubstituted substrate was not successful. In contrast, the synthesis of the presumably less reactive (due to the aryl group) Ph-Me P-disubstituted substrate 101 proceeded smoothly. Acetophenone was reacted with the phosphonate 109 to yield the £-ester 110 after removal of the minor Z-isomer by flash column chromatography. Hydrolysis to the acid 111, conversion to the acid chloride 112, followed by attachment of the auxiliary yielded the disubstituted a,p-unsaturated oxazolidinone substrate 101 (Scheme 46). 78 o 'Me Pri NaH.THF Me O 1N NaOH Me J - ^ O O reflux, 4 h Ph ^^XJEt EtOH Ph 75°C, 1.5h 110, 65%£-isomer 111, 97% 109 XCOCI)2 cat. DMF 0°C, 20min Me O O "BuLi Me O v_y o 112, 99% 101, 76% ^ Scheme 46 : Synthesis of p-disubstituted a,P~unsaturated substrate 101 3.2.2.6.2 Hydrocyanation The substrates synthesised above were reacted with 2 equiv of acetone cyanohydnn under 10 mol% Sm(O'Pr)3 catalysis at room temperature in toluene and the results are shown in Table 19. 79 O Q CN O O NQ OH 10%Sm(O'Pr)3 1 % i iv -\^ " /* R'^ 1 o \ ___ / \ toluene, rt V f\ Table 19: Reaction of a,p-unsaturated substrates with 2 equiv of acetone cyanohydrin under 10% Sm(O/Pr)3 catalysis in toluene atrt Product ixxnP vti Entry Substrate R1 R2 R3 %yield dra time / h (%yield SM) 1 75 Me H H 0.5 73 19:81 2 93 Et H H 0.83 71 17:83 3 94 'Pr H H 0.5 70 13:87 4 113 'Bu H H 1 75b 12:88 5 76 Ph H H 5.75 68 (2)c 11 :89 6 96 P-C1C6H4 H H 23.5 74 (l)d 16:84 7 95 /?-MeOC^6ii4 H H 49 22 (63)e 19:81 8f 95 ^7-JVleOC^6H4 H H 4 73 (l)g 18:82 9 99 (CH2)2OTBS H H 69 46(31)h 0:100 10 100 (CH2)2OMe H H 3.75 80* 22:78 ll f 99 (CH2)2OTBS H H 70 48 (22V 0: 100 12 97 Me Me H 69 60(10)k - 13f 97 Me Me H 47 74(6) - 14 101 Ph Me H 161 20 (60)1 9:91 15m 101 Ph Me H 96 40 (40)" 18:82 16 98 Me H Me 70 7(2)° 47 : 53P dr measured by isolated mass of separated diastereomers b) 12% of auxiliary 81 also isolated c) 20% of isopropyl ester 68b also isolated d) 17% of isopropyl ester 68c and 14% of auxiliary 81 also isolated e) 4% of isopropyl ester 68d and 9% of auxiliary 81 also isolated ^ reaction temperature of 50 °C employed 8) 14% of isopropyl ester 68d, 16% of auxiliary 81 and 3% of cyanohydrin ester 69b also isolated h) 5% of isopropyl ester 68e also isolated 0 10% of isopropyl ester 68f also isolated ^ 8% of isopropyl ester 68e also isolated k) 14% of auxiliary 81 also isolated !) 15% of isopropyl ester 68g also isolated m) 20 mol% Sm(O'Pr)3 employed and order of addition reversed n) 10% of isopropyl ester 68g also isolated 0) see text p) 2 diastereomers inseparable by flash column, dr calculated by !H NMR of purified mixture of diastereomers 80 Table 19 demonstrates that alkyl p-substituents (entries 1-4) are well tolerated in the Sm-catalysed reaction. Increasing steric bulk had little impact on the yield and led to a slight increase in the dr. The reaction times for the p-aliphatic substrates are much reduced compared to Jacobseris16'17 and Shibasaki's18 methodology for stereoselective hydrocyanation (Section 1.1). Aryl p-substituents are also tolerated although with a reduced reactivity (entries 5-7). This is an improvement in scope compared to Jacobsen's16'17 methodolgy where substrates bearing an aryl p-substituent were unreactive. Surprisingly, the Ph p- substituent substrate 76 appeared to be more reactive with a reduced reaction time compared to substrate 96 bearing the electron withdrawing p-chloro group on the phenyl ring. Unsurprisingly, the electron donating /7-methoxy group on the phenyl ring 95 had the most impact with poor reactivity encountered at room temperature (63% recovered starting material after 49 hours). The reactivity for this substrate 95 could be enhanced by increasing the reaction temperature to 50 °C when an increased yield was obtained in a much reduced reaction time with little impact on dr (entry 8). Substrates bearing oxygenated p-substituents were also tested in the reaction conditions (entries 9-10). The TBS protected substrate 99 had quite poor reactivity with 31% of starting material remaining after 69 hours but interestingly it seems as if only one diastereomer of the hydrocyanated product 114 was produced, judging by NMR and TLC. In contrast, the reaction of the methoxy oxygenated substrate 100 was complete within 3.75 hours; probably well within that time since that was the first point at which the reaction was analysed because it was expected to possess similar reactivity to the OTBS substrate 99 and not that of simple p-alkyl substrates. The yield and dr for the OMe substrate 100 was also comparable to that found for the simple p-alkyl substrates. It was wondered if the single diastereomer product and reduced reactivity of the OTBS substrate 99 may be attributable to a different co ordination mode for the Sm; possibly with Sm chelated between the exocyclic carbonyl oxygen and the silyl ether oxygen in an 8-membered ring which could completely shield one diastereopic face of the alkene or delivery of cyanide from a Sm-coordinated to the oxygen of the p-substituent. Although if these were the case, the OMe substrate 100 would have been expected to exhibit similar co-ordination, perhaps even more readily with a less bulky protecting group and more basic alkyl ether oxygen, and therefore show similar diastereoselectivity and reactivity and this 81 was not observed. An attempt to improve the reactivity of the OTBS substrate 99 by raising the reaction temperature to 50 °C (entry 11), was not successful and again only a moderate yield as a single diastereomer was obtained in a similar reaction time. Entry 12 shows that a dialkyl p-di substituted substrate 97 will give the required hydrocyanated product 115 with a quaternary centre although a long reaction time is required to produce a moderate yield. The reaction time and yield can be improved by increasing the reaction temperature to 50 °C (entry 13). The stereoselective hydrocyanation of p-disubstituted compounds is not demonstrated by either Jacobsen or Shibasaki. 16"18 Formation of a chiral quaternary centre was demonstrated by the use of the Ph-Me p-disubstituted substrate 101 (entry 14) although a poor yield was obtained due to the expected poor reactivity of this substrate arising from the combination of aryl and disubstitution at the p-position. The yield was moderately increased to 40% (entry 15) by modifying the reaction conditions to employ 20 mol% Sm(O'Pr)3 and also reversing the reagent order of addition to counter the expected increase in by-product formation from the catalyst increase. Consequently, the previously observed reduction in dr resulting from order reversal was also encountered (Section 3.2.2.3). Two other sets of reaction conditions were tested to improve the reactivity of 101 (50 °C or 20 mol% Sm(O'Pr)3 at 100 °C) but by NMR spectrum and TLC of the crude reaction mixtures they seemed to offer no improvement in conversion compared to entry 15. Further experimentation to improve the yield of this reaction was not possible due to time constraints. An a,p-disubstituted substrate 98 (entry 16) was not suitable for these hydrocyanating conditions and mostly decomposed. Products that were recovered and identified are shown in Figure 24. Presumably some volatile isopropyl ester was also formed. O AO CN O O 98, 2% 116, 7% 47:53 dr 117, 19% 68:32 dr 81, 78% inseparable diastereomers separable diastereomers Figure 24 : Products obtained from attempted hydrocyanation of a-substituted substrate 98 The formation of alternative products to the intended hydrocyanated oxazolidinone product is unsurprising because a-substituted a,p-unsaturated oxazolidiones are 82 known112'113 to exhibit poor reactivity towards nucleophilic conjugate addition due to the alkene twisting out of the plane and breaking conjugation in both rotamers to relieve unfavourable steric interactions between the a-substituent and €4 of the oxazolidinone (Figure 25). Figure 25 : Unfavourable steric interactions in a-substituted planar rotamers 3.2.2.7 Mechanistic possibilities Experimental observations and work in the literature provides clues about the mechanism of hydrocyanation of a,|3-unsaturated carbonyl compounds with acetone cyanohydrin under Sm(O'Pr)3 catalysis and conclusions drawn from this information are detailed below. The stereochemical information (Section 3.2.2.2) implies that the Sm is bis- coordinated to the substrate. It is considered in the literature62 that a mixture of Ln(O'Pr)3 and acetone cyanohydrin forms a lanthanoid cyanide (Ln-CN) and therefore it is likely that the cyanating agent in this conjugate addition of cyanide is a samarium cyanide species (Scheme 47). HO CN NC / L /\ 1 /^~y L O ^^ ^\ Sm-CN Sm-O'Pr om i U A -^-———— LX LX HO'Pr LX W o ™ r^j ® 118 Scheme 47 : Proposed formation of Sm-CN It is uncertain whether the actual cyanating agent62 is Sm(CN)3 or Sm(CN)x(L)3.x. Evidence could be obtained if Sm(CN)3 was employed instead of Sm(O'Pr)3 as the catalyst to establish whether the same result could be obtained. It is unlikely that cyanation occurs in Meerwein-Ponndorf-Verley fashion from the lanthanide cyanohydrin alkoxide (Figure 26) because structure 118 (Scheme 47) would be 83 unstable and susceptible to elimination of cyanide due to the high basicity of the alkoxide resulting from the relatively low electronegativity of the lanthanide. = alkoxideorCN 0 Figure 26 : Unlikely Meerwein-Ponndorf-Verley-type cyanation The combination of Ln(O7Pr)3 and TMSCN is also known to form Ln-CN in situ41' ' 114'115 so corroboration for Sm-CN acting as the cyanating agent is offered by the replacement of acetone cyanohydrin with TMSCN and IPA as a proton source (Scheme 48). Hydrocyanation still takes place with only a slightly reduced yield and dr suggesting that the same cyanating agent, Sm-CN, is formed. The employment of the large Sm(CN)x(L)3.x complex as the cyanating agent may explain why the dr is superior to that expected if the small naked cyanide ion is the cyanating agent. Since the naked cyanide ion is a small nucleophile, it would not be expected to be especially hindered at the P-carbon by the €4 substituent of the oxazolidinone but the Sm-CN nucleophile is bulkier and consequently more likely to be hindered and produce the stereoselectivity. O O 10%Sm(O'Pr)3 CN O O K,' -^ 2equivlPA , ^ , _ . ,. N O + 2 TMSCN ______' ^^ N O ^— rt,toluene 40 min ~~~~"""\^— 75 79, 65% 25:75 dr Scheme 48 : Replacement of acetone cyanohydrin with TMSCN to suggest formation of Sm-CN Work by Jacobsen19 and Shibasaki25'41 has revealed bimetallic mechanisms for Ln-CN cyanations. Therefore, a bimetallic mechanism can be suggested for this cyanation, ie: nucleophilic addition of cyanide by a second Sm-CN to that coordinating the substrate as it is unlikely that the coordinating Sm-CN can reach around to the n* orbitals at the P-carbon to attack the alkene. 84 From the information detailed above a proposed catalytic cycle and mechanism is shown in Scheme 49. Sm(0'Pr)3 0 L = alkoxide or CN O Q Sm(CN)L2 120 119 SmL Sm(CN)L2 Scheme 49 : Possible catalytic cycle and mechanism for Sm(O'Pr)3 catalysed hydrocyanation of a,P~ unsaturated oxazolidinone substrates with acetone cyanohydrin Sm(CN)x(L)3_x is formed by reaction of Sm(O'Pr)3 with acetone cyanohydrin and it co-ordinates to the a,p-unsaturated oxazolidinone substrate 75. The co-ordinated substrate 119 is cyanated by another molecule of Sm-CN to give the cyanated Sm- enolate 120 with loss of a ligand from the co-ordinated Sm. The Sm-enolate 120 undergoes protonation by acetone cyanohydrin which releases another molecule of cyanide and allows regeneration of the catalyst with release of the Sm catalyst from the hydrocyanated product 79. 85 3.2.2.8 Auxiliary cleavage and product manipulation A benefit of employing the Evans' auxiliary is the versatility offered upon its cleavage; a number of functionalities can be revealed. 3.2.2.8.1 Hydrolytic auxiliary cleavage LiOOH is Evans1 preferred reagent for hydrolytic cleavage of the oxazolidinone to reveal the carboxylic acid. 116 LiOOH is an especially useful reagent for the auxiliary cleavage of sterically hindered substrates where the use of another reagent such as LiOH can result in a large proportion of unwanted endocyclic cleavage; that is attack at the carbonyl of the auxiliary and opening to the acyclic amide (eg 122) instead of the required attack at the exocyclic acyl carbonyl. The p-cyano compounds (eg 79) were not suitable substrates for the use of LiOOH which resulted in a mixture of unidentified compounds presumably arising from some hydrolysis of the nitrile. Fortunately, since these compounds were not sterically hindered at the a-position, LiOH117 at -10 °C was found to cleave the auxilary from these cyano compounds (79 and 80) without significant endocyclic cleavage or nitrile hydrolysis to yield the required p-cyano acid 121 and recoverable auxiliary (Scheme 50). The benzyl auxiliary gave only 1% of the endocyclic cleavage product 122 while none was detectable for the isopropyl auxiliary. O LiOH.H2O o A THF-H2° CN O CN O O ————- —— ^ ^ -10 °°C - OH Ph — ^ 1h20min Ph — '" H 80b 121b, 77% 83, 61% 122, 1% CN O O LiOH.H20 O A^O ——————————THF"H2° CN o ^I -10°C,1h 79b 121b, 87% 81, 61% Scheme 50 : Hydrolytic cleavage of auxiliary with LiOH The_ P-cyano acid 121 proved to be an unstable compound 1 1 ft but if used immediately it could be converted to the p-substituted y-amino acid, a useful class of compound, 119 86 when hydrogenated under PtOi catalysis16 although in this example, a long reaction time was required (Scheme 51). HC,.H2N H20, HCI rt, 112h 121b 123, 88% Scheme 5 1 : Hydrogenation of p-cyano acid to give p-substituted y-amino acid 3.2.2.8.2 Reductive auxiliary cleavage Reductive auxiliary cleavage to yield the cyano alcohol is also possible. NaBtLj in THF/F^O has been proven to be effective for the reductive removal of the oxazolidinone auxiliary from compounds containing the nitrile functionality without nitrile reduction. 120 Thus the hydrocyanated product bearing a P-methyl substituent 80b was exposed to NaBtLi in a THF/t^O mixture at room temperature (Scheme 52). CN O ft O JL Jl A THF-H20 CN il ^"^•^N O +4NaBH4 —————————— JL ^ + HN O V_V rt,3.5h /^^^OH \— J 80b 124, 33% 83, 80% Scheme 52 : Reductive cleavage of the auxiliary from a p-methyl substituted compound The required cyano alcohol 124 was isolated in poor yield. The loss of alcohol 124 was proposed to be due to its water solubility during workup. The reductive removal of the auxiliary with NaBRi was therefore demonstrated using the substrate with the more hydrophobic isopropyl p-substituent 125b which furnished the required cyano alcohol 126b in good yield and with recoverable auxiliary 81 (Scheme 53). There was negligble racemisation at the p-carbon with the cyano alcohol 126b recovered in a 98.5% ee as analysed by GC. 87 CN O O 1 THF-H2O N O•™- +• 4^ NaBHI ^«-« i-*l 1^14 \_/ rt, 2.5 h 125b 80%, 98.5% ee 126b Scheme 53 : Reductive cleavage of the auxiliary from the |3-isopropyl substituted compound 3.2.2.8.3 Nitrile reduction with concomitant auxiliary cleavage The concept of reduction of the nitrile functionality with in situ auxiliary cleavage to yield 4-substituted lactams was suggested by work undertaken by Seebach1 ] in which a one pot hydrogenation of similar y-nitro oxazolidinone compounds with in situ cleavage of the auxiliary provided lactam products (Scheme 58). A sample of hydrogenation catalysts was investigated for optimisation of the yield of the lactam 127 and reduction in the formation of the by-product 128 (Table 20). CN O 9 catalysttelyst o O ^-N o H2 —————H2 HrrSA + HN^OA + ° /^AN^O1 u 1 EtOH rt 79b 127 81 128 Table 20: Hydrogenation of 79b Solvent Rxn % Yield % Yield % Yield Entry Catalyst volume / ml time / h 127 81 128 1 10%Pd/C 5 93 43 66 13 2 Raney Nia 5 92 55 81 3.4 3 10%PtO2 15 42.5 69 90 1.7 a) slurry in water; reaction initially with -10% catalyst, -100% catalyst added after 53 h. The optimal yield of lactam 127 and suppression of by-product 128 was obtained with PtC>2 catalysis (entry 3). The formation of 2° amine derived by-products, such as 128, is a well known side reaction for nitrile reductions. 122 The most likely mechanism for the formation of 128 is analogous to that found in other nitrile hydrogenations, 122 namely attack of the newly formed primary amine 130 on another molecule of intermediate imine 129, prior to the trapping of the 1° amine by intramolecular cyclisation. Then formation of the lactam by-product 128 by cyclisation of the resulting secondary amine 131 with loss of one of the oxazolidinone moieties (Scheme 54). \-J 127 81 HN CN O O PtO, A^ Pt° H2 H2 130 79b 129 HNxiA- o o NH-, + O N OIf HN O 81 128 Scheme 54 : Lactam and by-product formation during hydrogenation of nitrile functionality Generally 2° amine formation is suppressed by running the reaction in the presence of acid or ammonia or by trapping of the primary amine with, for example, acetic 89 I AM anhydride. It was hoped that the desired intramolecular cyclisation with loss of the oxazolidinone would function as a trapping mechanism for the primary amine but that was not efficient for Pd/C catalysis (entry 1). Instead PtC>2 catalysis and higher dilution minimised by-product formation 128. The conversion to lactam 127 also provided an alternative route from the hydrocyanated compound to the useful p-substituted y-amino acid 123 via acidic hydrolytic opening of the lactam (Scheme 55), thus avoiding the unstable p-cyano acid encountered during the formation of the amino acid from hydrolytic cleavage of the auxiliary prior to nitrile hydrolysis (Section 3.2.2.8.1). S 6NHCI HCI.H2N HN ) ———————————- I II \_/ 100°c, u.sh ^^^ 127 123,80% Scheme 55 : Hydrolytic opening of the lactam to the P-substituted y-amino acid 90 3.3 Application of methodology to drug molecule syntheses 3.3.1 Introduction The methodology developed in this thesis was applied to the synthesis of three drug molecules, so it is appropriate to review some previous syntheses of these compounds. 3.3.1.1 Pregabalin Pregabalin 8 Figure 27 : Anti-convulsant drug Pregabalin Pregabalin is an anti-convulsant drug that is related to the inhibitory neurotransmitter y-amino butyric acid (GABA)._ 1 OT It is also a promising treatment for neuropathic pain124 and psychotic125 disorders. The pharmacological activity resides in the S- enantiomer of the compound 10^ so asymmetric syntheses are required for its production. The»» original manufacturing route 1 1 ft involved a classical late stage resolution which results in wastage of the /?-enantiomer. This disadvantage can be overcome by the use of a route involving asymmetric hydrogenation as the key 1 ^f i ">o stereoinduction step (Scheme 56). 91 CN CN DABCO CICO2Et pyridine OH OCO2Et 95 97% i) LiOH CN ii) HCI CN CO2Et iii) 'BuNH; 89o/0 'BuNH3+ 83% catalytic 132.Rh(COD)BF4 HoN i) sponge Ni, H2 'BuNH3+ ii) AcOH 100%, 98% ee Pregabalin 8 61%, 99.8% ee Scheme 56 : Asymmetric synthesis of Pregabalin via asymmetric hydrogenation 132 Figure 28 : Me-DuPhos ligand employed in asymmetric hydrogenation in Scheme 56 Other routes to Pregabalin by Jacobsen and Shibasaki include the use of the catalytic enantioselective conjugate addition of cyanide as the key step, as discussed in Section 1.2. In both cases, just two further steps are employed to convert the p-cyano carbonyl compound to Pregabalin; hydrolysis of the carbonyl moiety to the p-cyano acid followed by nitrile hydrogenation (Scheme 57). 1 f\ ' 1 ft 92 CN O NaOH CN O PtO2 R X)H H2 94%, 96% ee Pregabalin 8 92%. 96% ee R= N ^ph °r N H Scheme 57 : Conversion to Pregabalin after enantioselective conjugate addition of cyanide In both syntheses three steps are required to synthesise the a,|3-unsaturated cyanation substrates with the alkenes formed via either a Horner-Wadsworth-Emmons or Wittig olefination. Another approach to Pregabalin is demonstrated by Seebach who employs the diastereoselective Michael addition of chiral A^-acyl-oxazolidinone enolates to nitro olefins as the key step towards the synthesis of lactam 133 (Scheme 58). 121 The opening of the lactam to give Pregabalin is not explicitly stated but this reaction is known. 129 i) TiCI4 ON DIPEA O P Raney-Ni Ph Ho Ph 133, 90% 40%, 92 : 8 dr Scheme 58 : Seebach's approach to the precursor lactam of Pregabalin 3.3.1.2 Baclofen (^)-Baclofen 15 Figure 29 : Anti-spastic agent (^)-Baclofen Baclofen is related to the inhibitory neurotransmitter GABA and is a selective GABAn receptor agonist. It is used as a treatment for spasticity caused by disease of the spinal cord and is currently administered as a racemate. It has been found that the 93 pharmacological activity resides exclusively in the /?-enantiomer so stereoselective synthetic strategies are worthwhile. 130 There have been several different approaches to (^)-Baclofen including chemoenzymatic 131-135" strategies and multistep manipulations of the chiral pool. 136,137 One popular approach is the use of stereoselective conjugate additions. Corey employs an enantioselective conjugate addition of nitromethane to the enone 134 in the presence of a cinchonium salt to give the 1,4-adduct in 70% ee, however, the enantiomeric excess can be improved to 95% ee upon recrystallisation. Three further steps yield (tf)-Baclofen (Scheme 59). 138 0 O9N CsF CH3NO2 89% 134 m-CPBA 0,N 90% (tf)-Baclofen 15 Scheme 59 : Corey's syntheis of (/?)-Baclofen The diastereoselective conjugate addition of nitromethane to a chiral tricarbonyl chromium cinnamate complex is employed by Baldoli as the key step in (^)-Baclofen synthesis. 139 Licandro uses a diastereoselective conjugate addition of the anion of an enantiopure Fischer-type amino carbene to p-chloro-nitrostyrene but multiple steps are required to synthesise the carbene. 140 Helmchen's four step synthesis of (/?)- Baclofen is one of the shortest approaches. 141 '142 This approach utilises methodology based upon Hayashi's enantioselective Rh-catalysed conjugate addition of arylboronic acids6'7 (Section 1.1); in this case to the a,p-unsaturated ester 135. 94 O BocHN. OEt 135 Figure 30 : Substrate for enantioselective conjugate addition enroute to (/?)-Baclofen Other efficient enantioselective approaches to (/?)-Baclofen include Rh catalysed C-H insertions,143'144 asymmetric hydrogenation of a p-keto ester,145 enantioselective deprotonation of a meso cyclobutanone146 and an asymmetric ally lie alkylation using a resin supported ligand147 as the key steps. 3.3.1.3 Rolipram HN H_ Vo OMe (^)-Rolipram 14 Figure 31 : (/?)-Rolipram; an anti-depressant Rolipram is a potent and selective inhibitor of cyclic-AMP specific phosphodiesterase (PDE iv)148'149 and is used as an anti-depressant. PDE IV is the predominant enzyme in a variety of inflammatory cells therefore Rolipram also has great potential as an anti-inflammatory agent for treatment of diseases such as asthma. 150 Again the (R)- enantiomer has been identified as the most active stereoisomer thus there is a need for stereoselective syntheses of Rolipram. 151 Several asymmetric syntheses of Rolipram are found in the literature. Strategies employing an asymmetric conjugate addition as the key step are popular. One of the first asymmetric routes to Rolipram was published by Meyers who uses a diastereoselective conjugate addition of an aryl cuprate to a chiral a,p-unsaturated lactam (Scheme 60) with excellent stereoselectivity. Three further steps lead to (R)- Rolipram. 152 95 O RCuCNLi , R= — oMe >98:2dr Scheme 60 : Meyers1 asymmetric step in the synthesis of (7?)-Rolipram Alvarez-Builla employed a similar diastereoselective addition of the same aryl cuprate; in this case to chiral substrate 136, derived from L-glutamic acid. 153 TBDPSO 136 Figure 32 : Substrate for asymmetric conjugate addition of aryl cuprate An elegant four step synthesis was demonstrated by Mulzer. 154 The diastereoselective addition of an enolate, derived from a chiral 7V-acyl-oxazolidinone, to the appropriate aryl nitro olefin (Scheme 61) leads to (^)-Rolipram after further elaboration. This includes a catalytic hydrogenation which neatly accomplishes the debenzylation of the aryloxy group, reduction of the nitro group and cyclisation with removal of the chiral auxiliary all in one step. OQ P,--W NaHMDS 65%, 94 . 6 dr Scheme 61 : Mulzer's key conjugate addition in the synthesis of (/?)-Rolipram 96 Another example of addition to a nitro olefin is used by Barnes when he demonstrates the efficacy of his enantioselective conjugate addition of dicarbonyl substrates (Scheme 62) by the synthesis of (/?)-Rolipram. 155 NO- Mg(OTf)2 Ar O O O 137 O9N OEt EtO Ar N-methylmorpholine CO2Et 95%, 96% ee Ar = OMe Scheme 62 : Barnes' key conjugate addition in the synthesis of (/?)-Rolipram Another variation on the Michael addition theme is employed by Kanemasa. 156 The addition of nitromethane to an a,p-unsaturated pyrazole acceptor takes place enantioselectively under the "catalytic double activation method" where the combination of a bulky amine and a chiral nickel ligand complex are used as co- catalysts (Scheme 63). O Ni(CIO4)2.6H2O 138 Ar' 2,2,6,6-tetramethylpiperidine Ar MeNO2 91%, 98% ee Ar = OMe Scheme 63 : Kanemasa's key conjugate addition in the synthesis of (^)-Rolipram Helmchen also utilises the same approach to (^)-Rolipram as applied to (/?)-Baclofen (Section 3.3.1.2); namely the addition of a suitable arylboronic acid to the a,p- unsaturated ester 135. 142 97 Alternative stereoselective approaches to (^)-Rolipram include an enantioselective Rh-catalysed C-H insertion,157 an enantioselective deprotonation of a meso cyclobutanone,158 a diastereoselective [3+2] cycloaddition159 and a diastereoselective Pd-catalysed allylic substitution,160 but these strategies are either low yielding or require many steps. In summary, there have been several synthetic routes published to the drugs Pregabalin, (J?)-Baclofen and (7?)-Rolipram but concise strategies to target molecules is still a good way to demonstrate the utility of newly developed methodology. 98 3.3.2 e/f/-Pregabalin synthesis The feasibility of synthesising Pregabalin with Sm(O'Pr)3 catalysed asymmetric hydrocyanation as the key step was demonstrated by the synthesis of the enantiomeric series of Pregabalin (ie; (^)-3-aminomethyl-5-methylhexanoic acid) since the stereoisomer of the auxiliary which led to e/tf-Pregabalin was readily available within the research group. The S-enantiomer could be as easily synthesised by using the opposite enantiomer of the chiral auxiliary. The a,p-unsaturated oxazolidinone substrate 113 for hydrocyanation was synthesised by two routes. Firstly, the appropriate a,p-unsaturated ester 139 was synthesised by a HWE reaction and then converted to the acid 140. Subsequent acid chloride 141 formation, followed by attachment of the auxiliary 81, gave the a,p-unsaturated oxazolidinone substrate 113 in a 49% yield from the phosphonate 109 over four steps (Scheme 64). One advantage of this route is that the expensive chiral auxiliary 81 is only introduced in the last step and therefore the chirality is used as efficiently as possible and not wasted in the earlier manipulations. i) NaH, THF O o 0°C, 15min (EtO)2P- OEt ii) 3 I O 109 reflux, 3 h 140, 73% oxalyl chloride cat. DMF 0°C,20min BuLi, THF O HN^O —\ ™ y 141 113 \ ••• - 81 87% 2 steps Scheme 64 : Synthesis of hydrocyanation substrate for ent-Pregabalin via a,p-unsaturated ester 99 A more stepwise efficient route to the hydrocyanation substrate was developed which required only three steps and had an improved overall yield of 62%. This involved deprotonation of the oxazolidinone 81 by "BuLi and acylation with chloroacetyl chloride, to yield the a-chloro compound 103, which was subjected to an Arbuzov reaction to yield the required phosphonate 104. 107 The HWE reaction between the phosphonate 104 and isovaleraldehyde produced the required a,p-unsaturated oxazolidinone 113 in good yield (Scheme 65). O i) "BuLi, THF o O jf OOP -78 °C, 15 min HN O ———————————»• ii) chloroacetyl chloride — / 140°C,3h -78 °C, 5 min rt, 30 104, 94% 81 103, 82% LiCI, DIPEA MeCN, rt, 21 h \_J 113,81% Scheme 65 : Synthesis of hydrocyanation substrate for ew/-Pregabalin by a shorter route Exposure of substrate 113 to the hydrocyanating conditions (10% Sm(O'Pr)3, 2 equiv acetone cyanohydrin, toluene, rt, 1 h) (Scheme 66) results in a 66% yield of the major (2/?)-diastereomer 142b after separation of the minor (25)-diastereomer 142a (9%) by flash column chromatography. The absolute stereochemistry at the (3-carbon of the major diastereomer 142b was assigned by analogy to the results with the Me-p- substituted substrate 75 and comparison of the sign of the optical rotations with literature values of the lactam1 l 133b and amino acid118 8b obtained in the subsequent steps (Scheme 66). The nitrile reduction with concomitant auxiliary cleavage was accomplished under the PtC>2 catalysed hydrogenation conditions (Section 3.2.2.8.3) to give the lactam 133b in good yield and ee (Scheme 66); as demonstrated by chiral HPLC. This auxiliary 100 cleavage procedure is employed rather than the hydrolytic cleavage (Section 3.2.2.8.1) to avoid the resulting unstable p-cyano acid. Conversion of the lactam 133b to the hydrochloride salt of e/tf-Pregabalin 8b was i *}c\ accomplished by acidic hydrolysis and gave the amino acid in good yield with retention of ee (Scheme 66). The optical rotation of the amino acid (e«/-Pregabalin) 8b is too low for enantiomeric purity determination and reliable comparison with the literature value for Pregabalin ([a]D24 +10 (c 1.1, H2O)),118 therefore the retention of ee was confirmed by partial conversion back to the lactam 133b and analysis by chiral HPLC. 10%Sm(O'Pr)3 CN O acetone cyanohydrin toluene, rt, 1 h 113 142b 66% major diastereomer 10% PtO2 H2, EtOH rt, 70 h HCI.H2N O 4NHCI 125°C, 20 h e«/-Pregabalin 8b 133b 95%, 96% ee 75%, 96% ee [a]D = -6 Scheme 66 : Synthesis of e«/-Pregabalin 101 3.3.3 (5)-Baclofen synthesis As with Pregabalin, the feasibility of synthesising enantiomerically pure Baclofen with the hydrocyanation methodology developed in this thesis was demonstrated by the synthesis of the less active enantiomer, (^-Baclofen. The synthesis of the a,p-unsaturated oxazolidinone substrate 96 for hydrocyanation was simple because the appropriate a,p-unsaturated acid 143 was commercially available. Therefore Evans1 methodolgy59 (Section 3.2.2.6.1) was employed; namely conversion to the acid chloride 144 by treatment with oxalyl chloride and catalytic DMF and acylation with the deprotonated oxazolidinone 81 to give the a,p- unsaturated oxazolidinone substrate 96 in good yield (Scheme 67). oxalyl chloride cat. DMF ————————» 0 °C, 20 min 144 o "BuLi 81 96, 90% 2 steps Scheme 67 : Synthesis of hydrocyanation substrate for (5)-Baclofen Exposure of substrate 96 to the hydrocyanating conditions (10% Sm(O'Pr)3, 2 equiv acetone cyanohydrin, toluene, rt, 23.5 h) (Scheme 68) resulted in a 62% yield of the major (2S)-diastereomer 145b after separation of the minor (2/?)-diastereomer 145a (11 %) by flash column chromatography. The aryl p-substituted substrate 96 was less reactive than that found for the alkyl p-substituted Pregabalin precursor 113, but the reaction was still complete within 23.5 hours. The absolute (S)-stereochemistry at the p-carbon of the major diastereomer 145b was again assigned by analogy to results 102 with the p-Me-substituted substrate 75 (ie: attack of the cyanide at the face opposite to the oxazolidinone substituent with the substrate in the syn s-cis conformation (Scheme 41)) and this was confirmed by X-ray crystallography of the minor diastereomer 145a which had the expected opposite (/0-stereocentre at the p-carbon (Figure 33). 10%Sm(O'Pr)3 acetone cyanohydrin toluene, rt, 23.5 h 145b 62% major diastereomer Scheme 68 : Hydrocyanation of a,p-unsaturated compound enroute to (5)-Baclofen 145a minor (2/?)-diastereomer Figure 33 : X-ray crystal structure of the minor diastereomer produced enroute to (5)-Baclofen An attempt to reduce the nitrile and cleave the auxiliary to form the lactam 146b by PtC>2 catalysed hydrogenation (Section 3.2.2.8.3) was not successful because the required lactam was inseparable from an unidentified by-product, presumably arising from 2° amine formation. Instead, use of the selective nitrile reduction reagent combination of NiCl2.6H2O and NaBH/45'161 gave the primary amine and successfully allowed in situ cyclisation to yield the lactam 146b (Scheme 69). The lactam yield was only 51% for the (^-enantiomer 146b from the major diastereomer but that was successfully raised to a 64% yield for the conversion of the minor diastereomer 145a to the (^)-lactam 146a, due to improved experimental technique upon repetition of the reaction and modification of the workup to include an aqueous NaHCOs basic wash to encourage cyclisation of the primary amine. The lactam 146b was found to have an ee of 99% by chiral HPLC thus demonstrating the absence of racemisation under these reaction conditions. 103 Conversion of the lactam 146b to the hydrochloride salt of (S)-Baclofen 15b was accomplished by acidic hydrolysis145 and gave the amino acid in a good yield with retention of ee (Scheme 69). Again the optical rotation of the amino acid ((5)- Baclofen) 15b is too low for enantiomeric purity determination and reliable comparison with the literature162 ([a]D25 +2 (c 0.2, H2O)), therefore the retention of ee was confirmed by partial conversion back to the lactam 146b and analysis of that by chiral HPLC. NiCI2.6H2O NaBH4 MeOH, rt 1.5h 146b 145b 51%,99%ee 4NHCI 1 00 °C, 24.5 h HCI.H2N O (S)-Baclofen 15b 98%, 99% ee [a]D = +2 Scheme 69 : Synthesis of (5)-Baclofen from the hydrocyanated product 104 3.3.4 (5)-Rolipram synthesis Again the less pharmacologically active enantiomer, (S)-Rolipram, was synthesised to demonstrate the feasibility of employing the asymmetric Sm(O'Pr)3 catalysed hydrocyanation methodology. The oxazolidinone bearing a,p-unsaturated substrate 147 for hydrocyanation was prepared by a HWE reaction between phosphonate 104 and the appropriate aldehyde 148 (Scheme 70). The phosphonate 104 was synthesised as described in Sections 3.2.2.6.1 and 3.3.2, by deprotonation of auxiliary 81, acylation with chloroacetyl chloride and conversion of that a-chloro compound 103 to phosphonate 104 by an Arbuzov reaction. 107 The aldehyde partner 148 was prepared in one step, by quantitative 0-alkylation of the commercially available aldehyde 149 with cyclopentylbromlde.29 Because of the electron rich nature of the aldehyde 148, the HWE reaction required comparatively forcing conditions of NaH deprotonation in THF and reflux for 25.5 hours to provide a moderate yield (61%) of the required a,p- unsaturated compound 147 and 23% of recovered starting aldehyde 148 (Scheme 70). O i) "BuLi, THF o O O O O If -78 °C, 15 min HN O ———————————»~ V_7 ii) chloroacetyl chloride — ' 140 °C, 3h \ —/ -78 °C, 5 min rt, 30 min 104, 94% 81 103, 82% NaH, THF reflux, 25.5 h K2CO3, DMF 100°C, 1.75h MeO 149 148, 99% Scheme 70 : Synthesis of hydrocyanation substrate for (5)-Rolipram 105 Due to the electron donating nature of the aryl p-substituent, substrate 147 was expected to be comparatively unreactive towards the conjugate addition of cyanide. Therefore the hydrocyanation, with Sm(O'Pr)3 catalysis, was undertaken with a reaction temperature of 50 °C instead of the usual room temperature (Scheme 71). With the usual order of addition (ie: substrate added to Sm(O'Pr)3 followed by acetone cyanohydrin) the hydrocyanated product 150 was obtained, after a reaction time of 18 hours, in a 54% yield as a mixture of diastereomers with a dr of 15 : 85. This gave the required (2S)-major diastereomer 150b in a 46% yield after separation of the minor (2J?)-diastereomer 150a (8%) by flash column chromatography. The isopropyl ester 68h was recovered in a 20% yield and 6% of the starting material 147 was also isolated. Reversing the order of addition for the reaction (acetone cyanohydrin added to Sm(O'Pr)3 followed by substrate 147) reduced the formation of the isopropyl ester 68h to a 1% yield and gave the hydrocyanated product 150 in an increased yield of 75% but, as previously found (Section 3.2.2.3), with a reduced dr of 24 : 76 which meant the major (2S)-diastereomer 150b was still only isolated in a moderate yield of 57% after separation of the minor (2/?)-diastereomer 150a (18%). This substrate does reinforce the limitations of the methodology encountered when dealing with electron donating aryl p-substituents but with further optimisation of the reaction conditions, such as further increase in reaction temperature or reduced catalyst loading with original order of addition, improvement in the yield of the required diastereomer may be possible. 10%Sm(O'Pr)3 acetone cyanohydrin toluene, 50 °C MeO 150b normal addition order, 18 h, 46% 150b reverse addition order, 24.5 h, 57% 150b Scheme 71 : Hydrocyanation of substrate leading to (5)-Rolipram For conversion of the hydrocyanated product 150b to the lactam (S)-Rolipram 14b, the same nitrile reduction conditions as employed for Baclofen, the reagent 106 combination of NiCl2-NaBH4 in MeOH at room temperature for 2.5 hours, provided the required lactam, (S)-Rolipram 14b, in a good yield (77%) and recoverable auxiliary 81 (90%) (Scheme 72). The absolute stereochemistry of the lactam 14b was confirmed by comparison of the optical rotation with the literature value152 and the ee was assessed to be >99% by chiral HPLC. NiCI2.6H2O NaBH4 MeOH, rt 2.5 h 150b (5)-Rolipram 14b 77%, 99% ee [a]D = +30 Scheme 72 : Nitrile reduction and auxiliary cleavage of the hydrocyanated product to give (5)- Rolipram 107 4 Conclusions The work described in this thesis details the development of methodology for asymmetric conjugate addition of cyanide. Initial work utilising Zn- and Yb-catalysis for the conjugate addition of TMSCN to enones was not successful. The Zn- and Yb-catalysed reactions suffered from product selectivity issues and attempts to render the reactions enantioselective by use of conventional metal-chiral ligand complexes as catalysts also failed. The Zn-catalysed reaction required specific zinc catalysts to produce the 1,4-adduct through isomerisation of the 1,2-adduct and the presence of chiral ligands did not fulfil that requirement. The Sm(O'Pr)3 catalysed conjugate addition of cyanide using the cheap commercial acetone cyanohydrin was only moderately successful for enones but encouraging results for the Af-acyl a,p-unsaturated oxazolidinones led to the introduction of asymmetry in the cyanide conjugate addition through a diastereoselective reaction using chiral oxazolidinones as auxiliaries. The major diastereomer of the hydrocyanated product has been shown to conform to that predicted by the model for bis-coordination of the catalyst. By-product formation can be minimised by alteration of the reaction conditions including a reduction in amount of catalyst required. Investigation of the scope of reaction has shown that p-alkyl substitution is well tolerated and although the reactivity is reduced for p-aryl substituents they are also tolerated which is an improvement on the scope for Jacobsen's enantioselective conjugate addition of cyanide. 16'17 p-Disubstitution is also tolerated, which was not demonstrated by either Jacobsen16'17 or Shibasaki,18 although more forcing conditions were required and alkyl/aryl disubstitution yields unsatisfactory results under the reaction conditions tested so far. The application of the asymmetric Sm(O/Pr)3 catalysed hydrocyanation with acetone cyanohydrin developed within this thesis has been demonstrated by the synthesis of three drug molecules. The alkyl p-substituted y-amino acid, Pregabalin, has been synthesised in six steps from commercial materials, with the key asymmetric hydrocyanation step providing a good yield with a rapid reaction time at room temperature. The asymmetric synthesis of the similar aryl p-substituted y-amino acid, (5)-Baclofen, has been achieved in five synthetic steps and proved the hydrocyanation 108 methodology was also effective when certain aryl p-substituents were present. The 4- substituted lactam, (5)-Rolipram, has been synthesised in four steps and although the yield of the required major diastereomer after hydrocyantion was only moderate, it demonstrates that modifications of the reaction conditions can increase the yield for the least reactive substrates such as those with electron donating aryl p-subsitituents or p-disubstitution. Future development for this project should include the addition of chiral alkoxide ligands to samarium to develop an enantioselective reaction using the achiral oxazolidinone substrate 33. If, as proposed in the possible mechanism, the samarium acts as the cyanide delivery agent, the chirality transfer to the p-carbon may be effective. As proposed in the mechanism and evidenced by the by-product formation of isopropyl esters, the isopropoxide ligands of Sm(O'Pr)3 are labile but the use of a bidentate chelating ligand such as binol may induce greater ligand stability. 109 5 Experimental Diethyl ether and tetrahydrofuran were freshly distilled before use from sodium- benzophenone ketyl, and dichloromethane from calcium hydride. Other solvents and reagents were purified according to standard procedures where appropriate. Znl2 was dried by heating at 120 °C overnight under vacuum. Excess cyanide reagent was destroyed by treatment with bleach (sodium hypochlorite) solutions before disposal. 163 Hexane solutions of butyl lithium were titrated against diphenylacetic acid before use. Reactions were run under a positive pressure of nitrogen unless otherwise stated and reaction temperatures were recorded as bath temperatures. Flash chromatography was performed using BDH F254 silica gel or BDH active basic or neutral Brockmann grade 1 aluminium oxide. Analytical thin layer chromatography was performed on pre-coated Merck silica gel 60 F254 glass backed plates and visualised by ultraviolet light and potassium permanganate, eerie ammonium nitrate or anisaldehyde stains as appropriate. Gas chromatography was performed on an Agilent 4890D machine with either a HP-5 (crosslinked 5% PHME siloxane) achiral column or a CP-Chirasil-Dex CB chiral column or a ChiraPak gamma-TA chiral column with an FID set at 250 °C using helium as the carrier gas. Chiral HPLC was performed on a Shimadzu HPLC system with Chiracel OJ-H or AD columns using 'PrOH/hexane as the eluent. NMR analyses were performed on Bruker 250, 400 or 500 MHz instruments in CDCls or other appropriate deuterated solvents; chemical shifts are quoted in ppm relative to IMS (as referenced to residual CHC13 OH = 7.26 or CDC13 8c = 77.0 ppm), with coupling constants quoted in Hz. Infrared analyses were recorded as a thin film (produced from evaporation of a dichloromethane solution) on NaCl plates using a Mattson Satellite FTIR spectrometer from 4000 - 600 cm'1 . Mass spectrometry was carried out under CI (ammonia reagent gas) using a Micromass Autospec-Q spectrometer at the Imperial College Mass Spectrometry Service. Optical rotation measurements were performed on an Optical Activity Polarimeter. X-ray crystal structures were obtained at the Imperial College Crystallography Service using a Siemens P4 or Bruker P4 diffractometer. 110 NMR notation and numbering The assignment 3-H denotes the proton(s) attached to the carbon numbered 3. The assignment 3'-H denotes the proton(s) attached to the carbon numbered 3' on a side chain. The assignment 3-H', when 3-H has already been designated, denotes diastereotopic protons and 3-Hf indicates the signal for the second diastereotopic proton attached to the carbon numbered 3. The commonly used numbering of oxazolidinone containing compounds are shown in Figure 34. O 1CN O O 21 R R ct,p-unsaturated hydrocyanated 7V-acyl 7V-acyl oxazolidinone oxazolidinone Figure 34 : Numbering scheme for oxazolidinone containing compounds Where the numbering system is not clear the proton assignment is indicated by the structural group (eg; Me) and, if required, any surrounding functionality to dispel any ambiguities (eg; CHCN). The assigned proton or carbon is indicated by italics when others are present in the assignment notation (eg; C//2Me). When the CH2 is diastereotopic and only one proton is assigned, that is indicated by italicisation of only H and not the subscript 2 (eg; Ill 5.1 ZnI2 catalysed conjugate addition of TMSCN 5.1.1 Preparation of authentic samples of cyclohexenone derived products 1-Trimethylsilyloxy-2-cyclohexenecarbonitrile 19 TMSOTf TMSQ + TMSCN ———• -78 °C, 2 h 18 19 A solution of TMSOTf (56 ul, 0.3 mmol) in CH2C12 (1 ml) was added to a mixture of 2-cyclohexen-l-one 18 (1.45 ml, 15 mmol) and TMSCN (2.40 g, 18 mmol) in CH2C12 (30 ml) at -78 °C under N2. The solution was stirred for 2 hours and quenched by pyridine (0.1 ml). The resulting mixture was poured into saturated NaHCO3(aq) (30 ml) and extracted with ether (3 x 30 ml). The combined organics were dried over Na2SC>4 and the solvent was removed under reduced pressure to yield the crude product that was purified by flash column chromatography (4% EtOAc in pet. spirits 40-60) to yield l-trimethylsilyloxy-2-cyclohexenecarbonitrile 19 (1.86 g, 64%) as a colourless oil; 5H (250 MHz, CDC13) 5.97 (IH, dt, J9.8, 3.7, 3-H), 5.75 (IH, dt, 2.1, 2-H), 2.19-1.73 (6H, m), 0.24 (9H, s, TMS). Consistent with lit.40 3-Trimethylsiloxy-2-cyclohexenecarbonitrile2to 10mol%Znl2 9™s + 1.6 TMSCN 18 A solution of 2-cyclohexen-l-one 18 (96 mg, 1 mmol) in CH2C12 (4 ml) was added to ZnI2 (32 mg, 0.1 mmol) at 0 °C and the mixture stirred under N2 for 15 minutes. 112 TMSCN (212 ul, 1.6 mmol) was then added and the resulting solution was stirred at 40 °C for 6 hours. After the reaction was quenched with NEts (0.5 ml), the solution was diluted with ether (10 ml), water (10 ml) poured into the quenched solution and the organic products extracted with ether (3x10 ml). The combined organics were washed with brine (40 ml) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to yield crude 3-trimethylsiloxy-2- cyclohexenecarbonitrile 20. 6H (250 MHz, CDC13) 4.80 (IH, dt, .74.3, 1.5, 2-H), 3.31 (IH, m, 1-H), 2.20-1.66 (6H, m), 0.20 (9H, s, TMS). Consistent with lit.40 3-Oxo-cyclohexanecarbonitrile 22 OTMS 1NHCI -*• rt, 30 min 20 22 A solution of IN HC1 (0.1 ml) was added to crude 3-trimethylsilyloxy-2- cyclohexenecarbonitrile 20 (0.17 g, 0.85 mmol) in THF (10 ml) and the solution was stirred for 30 min at room temperature under N2. The mixture was worked up with ice water (50 ml) and extracted with ether. The combined organics were washed with saturated NaHCO3(aq), brine and dried over anhydrous Na2SC>4. The solvent was removed under reduced pressure to yield the crude product which was purified by flash column chromatography (2% EtOAc in pet. spirits 40-60) to yield 3-oxo- cyclohexanecarbonitrile 22 (39 mg, 37%) as a colourless oil; SH (250 MHz, CDC13) 3.03 (IH, m, 1-H), 2.72-2.53 (2H, m, 2-H), 2.43-2.38 (2H, m, 4-H), 2.20-1.78 (4H, m, 5-H, 6-H); 6C (62.5 MHz, CDC13) 205.8 (C, 3-C), 120.2 (C, CN), 43.1 (CH2), 40.6 (CH2), 28.6 (CH, 1-C), 28.0 (CH2), 23.7 (CH2). Consistent with lit.164 113 l-Trimethylsilyloxy-cyclohexane-l,3-dicarbonitrile2$ TMSCN 10mol%Znl2 40 °C, 6 h 22 23 A solution of crude 3-oxo-cyclohexanecarbonitrile 22 (0.116 g, 0.95 mmol) in CH2C12 (4 ml) was added to ZnI2 (30 mg, 0.1 mmol) at room temperature under N2 and the mixture stirred for 10 minutes. TMSCN (201 ul, 1.52 mmol) was added and the resulting solution stirred at 40 °C for 6 hours. After the reaction was quenched with NEt3 (0.5 ml), the solution was diluted with ether (10 ml), water (10 ml) added and the organic products extracted with ether (3x10 ml). The combined organics were washed with brine (40 ml), dried over Na2SC>4, filtered and the solvent removed under reduced pressure to yield the crude product that was purified by silica flash column chromatography (15% EtOAc in pet. spirits 40-60) to yield a mixture of diastereomers of l-trimethylsilyloxy-cyclohexane-l,3-dicarbonitrile 23 (0.15 g, 73%) as a colourless oil. The dr was found to be 64 : 36 by achiral GC using the column and conditions detailed below (t^major) = 16.0 min, t^minor) = 16.3 min); vmax/cm l 2957, 2869, 2243, 1449, 1255, 1149, 1072, 1041, 892, 848, 758; 6H (250 MHz, CDC13) 2.83 (IH, m, 3-H), 2.39 (IH, m, 2-H), 2.17-1.46 (7H, m, 2-H', 4-H, 5-H, 6-H), 0.27 (5.8H, s, TMS), 0.26 (3.2H, s, TMS); Diastereomer A: 6C (250 MHz, CDC13) 121.1 (C, CN), 121.0 (C, CN), 66.2 (C, 1-C), 40.4 (CH2), 36.7 (CH2), 28.3 (CH2), 23.1 (CH, 3-C), 19.0 (CH2), 1.0 (CH3, TMS); Diastereomer B: 8C (250 MHz, CDC13) 120.4 (C, CN), 120.3 (C, CN), 69.1 (C, 1-C), 41.1 (CH2), 38.3 (CH2), 28.1 (CH2), 25.7 (CH, 3-C), 21.1 (CH2), 1.3 (CH3, TMS); m/z (CI) 240 (M+NH4+, 100%); Found: M+NH4+, 240.1526. CnH22N3OSi requires: M+NH/, 240.1532. Gas chromatography The products were analysed on the HP-5 (crosslinked 5% PHME siloxane) achiral column employing a ramping programme of increasing temperature, 50 °C to 180 °C 114 at 10 °Cmin'1 then 15 min at 180 °C. The retention times of the 2-cyclohexen-l-one derived products are shown in Table 21. Table 21: GC retention times for cyclohexenone derived products Compound Retention time / min 2-cyclohexen-l-one 18 7.5 l,2-adduct!9 12.2 l,4-adduct20 14.5 3-oxo-cyclohexanecarbonitrile 22 12.5 isomerised l,4-adduct21 14.5 bis-adduct23 16.0 & 16.3 115 5.1.2 Investigation into ZnI2 catalysed cyanations General procedure for the addition of TMSCN to cyclohexenone 18 under ZnI2 catalysis40 (used in Table 1) (General procedure (GP) 1) OTMS 10mol%Znl2 + 1.6 TMSCN —————————^ NC 18 20 19 A solution of 2-cyclohexen-l-one 18 (96 mg, 1 mmol) in solvent (4 ml) was added to Znl2 (32 mg, 0.1 mmol) at 0°C and the mixture stirred under N2 for 15 minutes. TMSCN (212 ul, 1.6 mmol) was then added and the resulting solution was stirred under the conditions given in Table 1. After the reaction was quenched with NEts (0.5 ml), the solution was diluted with ether (10 ml), water (10 ml) poured into the quenched solution and the organic products extracted with ether (3 x 10 ml). The combined organics were washed with brine (40 ml) and dried over anhydrous Na2SC>4. The solvent was removed under reduced pressure to yield the crude products, which were analysed by !H NMR and GC. General procedure for the attempted isomerisation of the 1,2-adduct 19 to the 1,4-adduct 20 with various catalysts and reagents (as used in Table 2) (GP 2) OTMS catalyst 9™S 40 C, 6 h N(r 20 A solution of the 1,2-adduct 19 (0.195 g, 1 mmol) in CH2C12 (4 ml) was added at 0 °C to the catalyst (0.1 - 0.2 mmol) shown in Table 2 and the mixture stirred under N2 for 15 minutes. The other reagent (0.1 - 0.6 mmol), as shown in Table 2, was added and the resulting solution stirred at 40 °C for 6 hours. After the reaction was quenched 116 with NEt3 (0.5 ml), the solution was diluted with ether (10 ml), water (10 ml) poured into the quenched solution and the organic products extracted with ether (3x10 ml). The combined organics were washed with brine (40 ml), dried over anhydrous Na2SC>4 and the solvent was removed under reduced pressure to yield the crude products, which were analysed by ]H NMR and GC. 2-Methyl-2-trimethylsilyloxy-3-butenenitrile25 o 10%Znl2 CH2CI2 NC OTMS + 1.2TMSCN 40 °C, 1.5h 44 25 A solution of 3-buten-2-one 44 (0.56 g, 8.0 mmol) in CtbCb (16 ml) was added at 0 °C to Znl2 (26 mg, 0.8 mmol) and the mixture stirred under N2 for 15 minutes. TMSCN (1.27 ml, 9.2 mmol) was added and the resulting solution stirred at 40 °C for 1 .5 hours. After the reaction was quenched with NEt3 (4 ml), the solution was diluted with ether (40 ml), water (40 ml) poured into the quenched solution and the organic products extracted with ether (3 x 40 ml). The combined organics were washed with brine (100 ml) and dried over anhydrous Na2SC>4. The solvent was removed under reduced pressure to yield the crude product that was purified by flash column chromatography (7% EtOAc in pet. spirits 40-60) to yield 2-methyl-2- trimethylsilyloxy-3-butenenitrile 25 (0.82 g, 61%) a colourless oil; SH (250 MHz, CDC13) 5.85 (IH, dd, J17.1, 10.2, 3-H), 5.58 (IH, d, J17.1, 4-H), 5.27 (IH, d, J10.2, 4-H), 1.65 (3H, s, Me), 0.23 (9H, s, TMS). Consistent with lit. 165 117 Synthesis of the 6-methyl substituted 1,2-adduct 27 6-Methyl-2-cyclohexen-l-one166 26 i)LDA ii) Mel 18 26 A solution of 2.40 M «-butyl lithium (6.25 ml, 15.0 mmol) was added dropwise to a solution of diisopropylamine (2.40 ml, 17.5 mmol) in THF (10 ml) at -40 °C. After the resulting solution had been allowed to stir for 15 min at -40 °C, 2-cyclohexen-l- one 18 (1.2 g, 12.5 mmol) in THF (10 ml) was added dropwise at 0 °C. A further 30 min stirring at 0 °C was followed by rapid addition of Mel (6 ml, 97 mmol). The ice bath was removed and a white precipitate formed during 45 min of stirring at room temperature. The mixture was poured into saturated NaHCCfyaq) and the organic products extracted with pet. spirits 40-60 (3 x 100 ml). The combined organics were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield the crude product that was purified by flash column chromatography (7% Et2O hi pet. spirits 40-60) to yield 6-methyl-2-cyclohexen-l-one 26 (0.53 g, 38 %) as a colourless oil; 5H (250 MHz, CDC13) 6.92 (1H, dtd, .710.1, 4.3, 1.2, 3-H), 5.98 (1H, dt, J10.1, 1.8, 2-H), 2.43-2.35 (3H, m), 2.07 (1H, m), 1.73 (1H, m), 1.13 (3H, d, .77.0, Me). Consistent with lit.167 6-Methyl-l-trimethylsilyloxy-2-cyclohexenecarbonitrile21 TMSCN TMSO cat. TMSOTf -78 °C, 2 h 26 27 A solution of TMSOTf (0.02 g, 0.1 mmol) in CH2C12 (1 ml) was added to a mixture of 6-methyl-2-cyclohexen-l-one 26 (0.53 g, 4.8 mmol) and TMSCN (0.50 g, 5.1 mmol) in CH2C12 (10 ml) at -78 °C. The solution was stirred for 2 hours and quenched by 118 pyridine (0.1 ml). The resulting mixture was poured into saturated NaHCO3(aq) (20 ml) and extracted with ether (3 x 20 ml). The combined organics were dried over Na2SC>4 and the solvent was removed under reduced pressure to yield the crude product that was purified by flash column chromatography (3% EtOAc in pet. spirits 40-60) to yield 6-methyl-l-trimethylsilyloxy-2-cyclohexenecarbonitrile 27 (0.48 g, 48%) as a colourless oil. The dr was calculated to be 5 : 95 by achiral GC (HP-5 (crosslinked 5% PHME siloxane) column, 50 °C to 180 °C at 10 ^min'1 then 15 min at 180 °C, tr(minor) = 13.0 min, tr(major) = 13.4 min); vmjcm l 2963, 2936, 2227, 1653, 1254, 1120, 1106, 844; Major diastereomer 5H (250 MHz, CDC13) 5.91 (IH, dtd, J9.8, 3.7, 0.9, 3-H), 5.69 (IH, dt, J9.8, 2.1, 2-H), 2.15-2.07 (2H, m, 4-H), 1.92- 1.53 (3H, m, 5-H, 6-H), 1.17 (3H, d, J6.7, Me), 0.24 (9H, s, TMS); 6C (62.5 MHz, CDC13) 132.1 (CH), 128.2 (CH), 119.7 (C, CN), 72.8 (C, 1-C), 39.8 (CH, 6-C), 27.0 (CH2), 24.6 (CH2), 16.1 (CH3, Me), 1.5 (CH3, TMS); m/z (CI) 227 (M+NlV, 42%); Found: M+NHi+, 227.1579. CnH23N2OSi requires; M+NlV, 227.1580 119 5.1.2.1 ZnI2 catalysed cyanation in the presence of chiral additives General procedure for the addition of TMSCN to cyclohexenone 18 under ZnI2 catalysis with a chiral additive (as used in Table 3) (GP 3) 20 mol% chiral additive OTMS NC QTMS 10mol%Znl2 40 °C, 6h 18 20 19 A solution of the chiral additive (0.2 mmol) in CH2C12 (1.5 ml) was added to ZnI2 (32 mg, 0.1 mmol) at 0 °C under N2. The mixture was stirred for 10 minutes then a solution of cyclohexenone 18 (96 mg, 1 mmol) in CH2C12 (3 ml) was added at 0 °C and the mixture stirred under N2 for 15 minutes. TMSCN (212 ul, 1.6 mmol) was then added and the resulting solution was stirred at 40 °C for 6 hours. After the reaction was quenched with NEts (0.5 ml), the solution was diluted with ether (10 ml), water (10 ml) poured into the quenched solution and the organic products extracted with ether (3x10 ml). The combined organics were washed with brine (40 ml) and dried over anhydrous Na2SC>4. The solvent was removed under reduced pressure to yield the crude products, which were analysed by ! H NMR and GC. The ee of the 1,4-adduct 20 was evaluated by chiral GC on a CP-Chirasil-Dex CB chiral column employing an isotherm of 140 °C. The retention times of the enantiomers were 9.6 and 10.4 minutes. (+)-(lS,2R)-N-Methylephedrinem 29 HO NHM. HO NMe2 Ph' x reflux, 3 h Ph 29 A mixture of (+)-(7,S,2/?)-ephedrine (0.83 g, 5 mmol) and formic acid (5 ml) was treated with formaldehyde (37% aqueous solution, 5 ml) and the mixture heated at 120 reflux for 3 hours. The acid was removed under reduced pressure, the solution basified (IN NaOH) and the aqueous phase extracted with ether (3 x 30 ml). The combined organic extracts were evaporated and the solid obtained recrystallised from pet. spirits to give (+)-(lS,2R)-N-methylephedrine 29 (0.63 g, 71%) as a colourless solid, m.p. 90-91 °C (lit. 169 86.5-87 °C), [a]D22 +30 (c 1.0, MeOH) (lit. 169 [a]D2° +28 (c 4.5, MeOH)); 6H (250 MHz, CDC13) 7.37-7.20 (5H, m, Ph), 4.94 (IH, d, J3.7, 1-H), 3.60 (IH, br s, OH), 2.52 (IH, qd, J6.7, 3.7, 2-H), 2.35 (6H, s, NMe2), 0.81 (3H, d, J6.7,Me). Consistent with lit.170 121 5.1.2.2 ZnI2 catalysed cyanation of other substrates 5.1.2.2.1 Synthesis of a,p-unsaturated compounds Synthesis of a,p-unsaturated lactam 30 N-Methyl-piperidin-2-one 36 i)NaH ii) Mel 35 36 Sodium hydride (60% mineral dispersion in oil, 1.5 g, 31 mmol) was washed with anhydrous petrol (2 x 20 ml) under a nitrogen atmosphere, resuspended in dry THF (15 ml) and 18-crown-6 (0.1 g, 0.4 mmol) in dry THF (5 ml) added, followed by a solution of 8-valerolactam 35 (2.5 g, 25 mmol) in dry THF (10 ml) at 0 °C and then Mel (2.5 ml, 40 mmol) and the reaction mixture stirred overnight at room temperature. H2O (30 ml) was added and the mixture concentrated. After the addition of cone. NaOH(aq) (30 ml), the mixture was extracted with ether (3 x 60 ml), the organic extracts dried over MgSO4 and the solvent removed under reduced pressure to give N-methyl-piperidin-2-one 36 (2.56 g, 91%) as a colourless oil; 5H (250 MHz, CDC13) 3.28-3.23 (2H, m, 6-H), 2.92 (3H, s, NMe), 2.37-2.32 (2H, m, 3- H), 1 .84-1 .72 (4H, m, 4-H, 5-H). Consistent with lit.171 l-Methyl-3-phenylselenenyl-piperidin-2-one31 O i LDA ii) PhSeCI \/ 36 37 A solution of 1.52 M w-butyl lithium (21.9 ml, 33.3 mmol) was added dropwise to a solution of diisopropylamine (4.9 ml, 35.0 mmol) in THF (35 ml) at -78 °C under nitrogen. This solution was then added dropwise to W-methyl-piperidin-2-one 36 122 (2.56 g, 22.7 mmol) in THF (25 ml) and stirred for 1 hour at -78 °C. A solution of PhSeCl (4.59 g, 24.0 mmol) in THF (25 ml) was added and the solution stirred at -78 °C for 1 hour then warmed to room temperature and stirred for a further 1 hour. The reaction mixture was poured into H2O (100 ml), extracted with ether (3 x 100 ml) and the organic extracts washed successively with 10% NaOH(aq) (100 ml), H2O (100 ml), 10% HC^aq) (100 ml), H2O (100 ml) and brine (100 ml) then dried over Na2SO4 and the solvent removed under reduced pressure to yield the crude product that was purified by silica flash column chromatography (10-100% EtOAc in pet. spirits 40- 60) to yield l-methyl-3-phenylselenenyl-piperidin-2-one 37 (3.67 g, 63%) as a colourless oil; vmax/cm l 2933, 1639, 741; SH (250 MHz, CDC13) 7.72-7.64 (2H, m, Ph), 7.32-7.24 (3H, m, Ph), 4.02 (1H, t, J4.9, 3-H), 3.28 (2H, t, .75.5, 6-H), 2.94 (3H, s, NMe) 2.18-1.60 (4H, m, 4-H, 5-H); 5C (62.5 MHz, CDC13) 167.0 (C, CO), 135.1 (CH, Ph), 129.2 (C, Ph), 129.0 (CH, Ph), 128.0 (CH, Ph), 49.9 (CH2, 6-C), 42.9 (CH, 3-C), 35.2 (CH3, NMe ), 29.1 (CH2), 20.8 (CH2); m/z (CI) 270 (M+H+, 100%); Found M(80Se)+H+, 270.0405. Ci2H16NO80Se requires: M, 270.0397. l-Methyl-5,6-dihydro-lH-pyridin-2-one3Q mCPBA 30 min 37 30 A solution of mCPBA (0.59 M, 15 ml, 9 mmol) in CH2C12 was added to a solution of 37 (1.6 g, 6 mmol) in CH2C12 (20 ml) at 0 °C and stirred for 10 min. The mixture was allowed to warm to room temperature and was stirred for a further 30 min. The solution was poured onto NaHCO3(aq) (50 ml) and extracted with CH2C12 (3 x 100 ml). The organic extracts were washed with NaHCO3(aq) (100 ml), H2O (100 ml) and brine (100 ml), dried over Na2SC>4 and the solvent removed under reduced pressure to yield the crude product that was purified by silica flash column chromatography (60% EtOAc in pet.spirits 40-60) to yield l-methyl-5,6-dihydro-lH-pyridin-2-one 30 (0.28 g, 42%) as a yellow oil; vmjcm l 1661, 1601; 6H (250 MHz, CDC13) 6.52 (1H, dt, .79.8, 4.3, 4-H), 5.91 (1H, dt, .79.8, 1.8, 3-H), 3.40 (2H, t, 77.3, 6-H), 2.98 (3H, s, Me), 123 2.38 (2H, tdd, J73, 4.3, 1.8, 5-H); 8C (62.5 MHz, CDC13) 164.8 (C, CO), 139.2 (CH, 4-C), 125.1 (CH, 3-C), 47.3 (CH2, 6-C), 34.3 (CH3), 23.9 (CH2, 5-C); m/z (CI) 129 (M+NH/, 25%), 112 (M+H+, 100%); Found: M+H+, 112.0756. C6Hi0NO requires: M, 112.0762. 4-Hydroxy-l-methyl-3-phenylselenenyl-piperidin-2-one3% 38 Mainly inseparable by-product in attempted preparation of l-methyl-5,6-dihydro-l//- pyridin-2-one 30. Colourless solid, m.p. 142-143 °C; vmax/cm l 3222, 2927, 2855, 1615, 1462, 1067, 735, 692; 8H (250 MHz, CDC13) 7.71-7.67 (2H, m, Ph), 7.33-7.25 (3H, m, Ph), 4.13 (1H, m, 4-H), 3.69 (1H, dd, J5.5, 0.6, 3-H), 3.45 (1H, m, 6-H), 3.13 (1H, m, 6-H'), 2.92 (3H, s, Me), 2.64 (1H, dd, J2.7, 0.6, OH), 2.27 (1H, m, 5-H), 1.87 (1H, m, 5-H'); 8C (62.5 MHz, CDC13) 168.4 (C, CO), 134.9 (CH, Ph), 129.1 (CH, Ph), 128.7 (C, Ph), 128.3 (CH, Ph), 69.2 (CH, 4-C), 49.2 (CH, 3-C), 45.4 (CH2, 6-C), 35.1 (CH3), 26.2 (CH2, 5-C); m/z (CI) 303 (M+NlV, 8%), 286 (M+H+, 50%), 130 (M- SePh, 95%); Found: M(80Se)+H+, 286.0343. Ci2Hi6NO280Se requires: M, 286.0346. 3-(E)-Benzylidene-l-phenyl-pyrrolidin-2-one32 i) DBU, MeCN, 1 h n)• • \ benzaldehydei i i i i toluene, rt, 2 h 39 32 DBU was added (19.6 ml, 97 mmol) to a stirred suspension of l-phenyl-3- (triphenylphosphine)-pyrrolidin-2-one bromide 39 (44.2 g, 88 mmol) in MeCN (110 ml). After 1 hour, benzaldehyde (8.1 ml, 80 mmol) in toluene (50 ml) was added dropwise keeping the reaction temperature at 20-23 °C. After complete addition, the 124 reaction mixture was stirred at room temperature for a further 2 hours before quenching with water (125 ml). After 30 minutes stirring, the mixture was heated to 40 °C and the layers were separated. The aqueous layer was run off and the organic layer was filtered to yield the crude product which was triturated with IPA (85 ml) to yield 3-(E)-benzylidene-l-phenyl-pyrrolidin-2-one 32 (16.0 g, 73%) as a colourless solid, m.p. 218-220 °C; vmjcm l 1782, 1701, 1394, 1276, 1260, 764, 749; 5H (400 MHz, CDC13) 7.80-7.76 (2H, m, Ph), 7.53-7.32 (8H, m, Ph, C=CH), 7.17 (1H, m, Ph), 3.98-3.94 (2H, m, 5-H), 3.27-3.21 (2H, m, 4-H); 6C (100 MHz, CDC13) 168.2 (C, CO), 139.7 (C), 135.7 (C), 131.4 (CH), 131.3 (C), 129.7 (CH), 128.9 (CH), 128.7 (CH), 128.6 (CH), 124.6 (CH), 119.6 (CH), 45.5 (CH2, 5-C), 24.1 (CH2, 4-C); m/z (CI) 250 (M+H+, 100%), 267 (M+NH4+, 20%); Found M+H+, 250.1228. C17H16NO requires: M, 250.1232. General procedure59 for the preparation of a,p-unsatu rated /V-acyl 1,3- oxazolidin-2-ones 33 and 34 (GP 4) 9 J) nBuLi.THF,-78°C 0 ii) a,p-unsaturated acid chloride 40 33, R - Me 34, R - Ph w-Butyl lithium (31 mmol) was added to a solution of l,3-oxazolidin-2-one 40 (2.61 g, 30 mmol) in THF (100 ml) at -78°C. After 15 min of stirring at -78 °C, the a,p- unsaturated acid chloride (37 mmol) was added. The mixture was stirred at -78 °C for a further 30 min then at 0 °C for 15 min. The reaction was quenched with saturated NHtClfaq) (40 ml) and the resultant slurry was concentrated in vacuo. The residue was diluted with Et2O or Cl^Cb (50 ml) and washed with saturated sodium bicarbonate and brine. The organic layer was dried over MgSCU, filtered and the solvent removed under reduced pressure to yield the crude product that was purified by silica flash column chromatography (25% EtOAc in pet. spirits 40-60). 125 3-((E)-2-Butenoyl)-l,3-oxazolidin-2-one$3 Compound 33 (2.61 g, 56%) isolated as an oily solid, m.p. 31-33 °C (lit. 172 42-43 °C); 6H (400 MHz, CDC13) 7.26 (1H, dq, .715.2, 1.1, 2f-H), 7.18 (1H, dq, 715.2, 6.1, 3'-H), 4.44.4.40 (2H, m, 5-H), 4.09-4.04 (2H, m, 4-H), 1.96 (3H, dd, J6.1, 1.1, Me). Consistent with lit. 173 3-((E)-2-Cinnamoyl)-l,3-oxazolidin-2-one34 Compound 34 (3.69 g, 57%) isolated as a cream solid, m.p. 157-158 °C (lit. 172 151- 152 °C); 8H (400 MHz, CDC13) 7.92 (1H, d, J15.8, 3'-H), 7.82 (1H, d, .715.8, 2'-H), 7.64-7.61 (2H, m, Ph), 7.41-7.39 (3H, m, Ph), 4.48-4.44 (2H, m, 5-H), 4.16-4.12 (2H, m, 4-H). Consistent with lit.174 5.1.2.2.2 Cyanation of substrates General procedure for the addition of TMSCN to other a,fi-unsaturated carbonyl compounds under ZnI2 catalysis (as used in Table 4) (GP 5) A solution of the a,p-unsaturated carbonyl compound (1 mmol) in CH2C12 (4 ml) was added to ZnI2 (32 mg, 0.1 mmol) at 0 °C and the mixture stirred under N2 for 15 minutes. TMSCN (1.6 mmol) was then added and the resulting solution was stirred at 40 °C for the reaction time indicated in Table 4. After the reaction was quenched with NEts (0.5 ml), the solution was diluted with ether (10 ml), water (10 ml) poured into the quenched solution and the organic products extracted with ether (3x10 ml). The combined organics were washed with brine (40 ml) and dried over anhydrous Na2SC>4. The solvent was removed under reduced pressure to yield the crude products that were analysed by !H NMR. General procedure for the addition of TMSCN to a,p-unsaturated carbonyl compounds under Znh catalysis in a NMR tube (as used in Table 4) (GP 5a) The a,p-unsaturated carbonyl compound (0.19 mmol) was added to undried ZnI2 (6 mg, 0.019 mmol) in CD2C12 (0.75 ml) in a NMR tube, then TMSCN (40 ul, 0.3 126 mmol) was added and the mixture heated to 40 °C for the reaction time given in Table 4. After cooling, the reaction mixture was analysed by *H NMR. 3-Cyano-propionic acid methyl ester 52 Prepared according GP 5a (Table 4) in a ratio of 4 : 3 with starting material. Not purified or isolated - tentatively assigned; 8H (250 MHz, CD2C12) 3.71 (3H, s, OMe), 2.72-2.59 (4H, m, 2-H, 3-H). Consistent with lit.60 l-Methyl-2-oxo-piperidine-4-carbonitrile 53 53 Prepared according to GP 5a (Table 4) and not purified or isolated - tentatively assigned; 8H (250 MHz, CD2C12) 3.54 (2H, t, J5.9, 6-H), 3.27 (1H, m, 4-H), 3.04 (3H, s, Me), 2.95 (1H, dd, .717.9, 6.0, 3-H), 2.74 (1H, dd, J17.9, 7.8, 3-H1), 2.34-2.06 (2H, m, 5-H); 8C (62.5 MHz, CD2C12) 170.7 (C, CO), 120.1 (C, CN), 48.2 (CH2, 6-C), 36.2 (CH3, Me), 34.5 (CH2, 3-C), 25.8 (CH2, 5-C), 24.3 (CH, 4-C). 2-Oxotetrahydropyran-4-carbonitrile54 Prepared according to GP 5 (Table 4). Compound 54 (31 mg, 25%) isolated as a colourless oil; v^/cm'1 2962, 2933, 2245, 1736, 1405, 1251, 1162, 1080; 8M (250 127 MHz, CDC13) 4.54 (1H, ddd, 711.9, 6.7, 4.6, 6-H), 4.37 (1H, ddd, 711.9, 7.3, 4.2, 6- H'), 3.21 (1H, apparent qd, 77.6, 5.2, 4-H), 2.94 (1H, dd, 718.0, 7.0, 3-H), 2.81 (1H, dd, 718.0, 7.9, 3-H1), 2.33-2.10 (2H, m, 5-H); 5C (62.5 MHz, CDC13) 166.5 (C, CO), 119.5 (C, CN), 66.7 (CH2, 6-C), 32.1 (CH2), 25.6 (CH2), 22.6 (CH, 4-C); m/z (CI) 143 (M+NH4+, 100%); Found M+NlV, 143.0818. C6HnN2O2 requires: M, 143.0821. General procedure for the addition of TMSCN to a,p-unsaturated carbonyl compounds under ZnI2 catalysis in 1,2-dichloroethane (DCE) (as used in Table 5) (GP6) A solution of the a,p-unsaturated carbonyl compound (1.0 mmol) in DCE (4 ml) was added to ZnI2 (32 mg, 0.1 mmol) at 0 °C and the mixture stirred under N2 for 15 minutes. TMSCN (1.6 mmol) was added and the resulting solution stirred at 83 °C for 6 hours. After the reaction was quenched with NEts (0.5 ml), the solution was diluted with ether (10 ml), water (10 ml) poured into the quenched solution and the organic products extracted with ether (3 x 10 ml). The combined organics were washed with brine (40 ml) and dried over anhydrous Na2SC>4. The solvent was removed under reduced pressure to yield the crude products, which were analysed by *H NMR and GC. 2-Ethyl-4-methyl-2-trimethylsilyloxy-pentane-l,5-dinitrile55 TMSO. CN Prepared according to GP 6 (Table 5). The crude product was purified by silica flash column chromatography (2-5% EtOAc in pet. spirits 40-60) to yield a mixture of diastereomers of 2-ethyl-4-methyl-2-trimethylsilyloxy-pentane-l,5-dinitrile 55 (0.12 g, 54%) as a colourless oil. The dr was calculated to be 40 : 60 by achiral GC of the crude product (HP-5 (crosslinked 5% PHME siloxane) column, 50 °C to 180 °C at 10 128 °Cmin"1 then 15 min at 180 °C, Mminor) = 14.6 min, tr(major) = 14.9 min); vmax/cm l 2975, 2885, 2242,1460,1255,1071,849; Diastereomer A: 5H (250 MHz, CDC13) 2.90 (1H, m, 4-H), 2.16 (1H, dd, .714.3, 9.5, 3- H), 2.02-1.77 (3H, m, 3-H1, CH2Me), 1.44 (3H, d, J7.3, M?CHCN), 1.06 (3H, t, J1.6, CH2M>), 0.29 (9H, s, IMS); 5C (62.5 MHz, CDC13) 122.6 (C, CN), 120.6 (C, CN), 72.6 (C, 2-C), 43.6 (CH2), 34.6 (CH2), 21.1 (CH, 4-C), 19.3 (CH3), 8.5 (CH3), 1.1 (CH3, TMS); Diastereomer B: 8H (250 MHZ, CDC13) 2.85 (1H, m, 4-H), 2.23 (1H, dd, J14.3, 8.9, 3-H), 1.99-1.74 (3H, m, 3-H1, C//2Me), 1.43 (3H, d, J7.0, M?CHCN), 1.07 (3H, t, .77.6, CH2M?), 0.28 (9H, s, TMS); 8C (62.5 MHz, CDC13) 122.1 (C, CN), 120.2 (C, CN), 72.0 (C, 2-C), 43.5 (CH2), 34.2 (CH2), 20.8 (CH, 4-C), 19.4 (CH3), 8.5 (CH3), 1.1(CH3,TMS). m/z (CI) 242 (M+NH/, 100%); Found: M+NH4+, 242.1684. CnH24N3OSi requires: M+NH4+, 242.1689. 129 5.2 YbCl3 catalysed cyanation General procedure for the addition of TMSCN to cyclohexenone 18 under YbCb catalysis (as used in Table 6) (GP 7) O HO, XCN 10mol%YbCI3 + TMSCN ————————— solvent, 40 °C NC 18 57 A solution of cyclohexenone 18 (96 mg, 1.0 mmol) in solvent (4 ml) was added at 0 °C to either anhydrous or hydrated YbCls (0.1 mmol) and the mixture stirred under N2 for 15 minutes. TMSCN (1.6 - 3.2 mmol) was added and the resulting solution stirred for the time shown in Table 6. After the reaction time was completed, the solution was diluted with ether (10 ml), water (15 ml) poured into the diluted solution and the organic products extracted with ether (3 x 15 ml). The combined organics were washed with brine (40 ml) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to yield the crude products, which were analysed by 'H NMR. l-Hydroxy-cyclohexane-l,3-dicarbonitrile51 HO. ON 57 Prepared according to GP 7 (Table 6). A portion of crude product was purified by silica flash column chromatography (2-5% EtOAc in pet. spirits 40-60) to yield two diastereomers of l-hydroxy-cyclohexane-l,3-dicarbonitrile 57 as a colourless oil which could only be partially charaterised due to the instability of the compound; Vmax/cm-1 3410, 2247, 1448, 1145; Diastereomer A: 8M (250 MHz, CDC13) 3.10 (IH, s, OH), 2.94 (IH, tt, Jl 1.9, 4.0, 3- H), 2.44 (IH, m, 2-H), 2.12-1.98 (3H, m, 2-H' & 6-H), 1.89-1.50 (4H, m); 6C (62.5 130 MHz, CDC13) 121.3 (C, CN), 121.2 (C, CN), 65.3 (C, 1-C), 38.2 (CH2), 35.3 (CH2), 28.1 (CH2), 23.0 (CH, 3-C), 18.8 (CH2). Diastereomer B: 6C (250 MHz, CDC13) 120.6 (C, CN), 120.4 (C, CN), 68.1 (C, 1-C), 39.4 (CH2), 36.6 (CH2), 28.0 (CH2), 25.5 (CH, 3-C), 20.9 (CH2). m/z (CI) 168 (M+NH4+, 52%), 141 (M-HCN+NH/, 100%). YbClj catalysis with KCN as the cyanide source HQ £N 10%YbCI3.6H2O + 3.2 KCN ———————————- I I + THF, 40 °C, 58 h 18 A solution of cyclohexenone 18 (96 mg, 1.0 mmol) in THF (4 ml) was added at 0 °C to YbCl3.6H2O (39 mg, 0.1 mmol) and the mixture stirred under N2 for 15 minutes. KCN (208 mg, 3.2 mmol) was added and the resulting solution stirred at 40 °C for 58 hours. After the reaction time was complete, the solution was diluted with ether (10 ml), water (15 ml) poured into the diluted solution and the organic products extracted with ether (3x15 ml). The combined organics were washed with brine (40 ml) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to yield the crude products, which were analysed by !H NMR and GC. Decomposition of l-hydroxy-cyclohexane-l,3-dicarbonitrile 57 to 3-oxo- cyclohexanecarbonitrile68 22 NCV ,OH 5% K2C03 (aq) CHCI3 rt, 2.5 h i-*\^ 22 131 Aqueous potassium carbonate (5% w/v, 2 ml) was added to a solution of crude 1 - hydroxy-cyclohexane-l,3-dicarbonitrile 57 (55 mg) in CHCls (2 ml) under an air atmosphere. The reaction mixture was stirred vigorously at room temperature for 2.5 hours then poured onto water (10 ml) and extracted with CH2Cl2 (3 x 10 ml). The combined organic extracts were dried over NaiSO^ filtered and the solvent removed under reduced pressure to yield crude 3-oxo-cyclohexanecarbonitrile 22 (35 mg). General procedure for the addition of TMSCN to cyclohexenone 18 with other lanthanide catalysis (as used in Table 7) (GP 8) HO. ,CN 10 mol% catalyst + 1.6 TMSCN ————————- solvent 40 °C, 6 h 18 57 A solution of cyclohexenone 18 (96 mg, 1.0 mmol) in solvent (4 ml) was added to the lanthanide catalyst (0.1 mmol) at 0 °C and the mixture stirred under N2 for 15 minutes. TMSCN (212 ul, 1.6 mmol) was added and the resulting solution stirred at 40 °C for 6 hours. The reaction mixture was diluted with ether (10 ml), water (15 ml) poured into the solution and the organic products extracted with ether (3 x 10 ml). The combined organics were washed with brine (40 ml) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to yield the crude products, which were analysed by !H NMR. General procedure for the addition of TMSCN to a,(5-unsaturated carbonyl compounds under YbCfo catalysis (as used in Table 8) (GP 9) A solution of a,p-unsaturated carbonyl compound (1.0 mmol) in THF (4 ml) was added at 0 °C to YbCl3.6H2O (0.1 mmol) and the mixture stirred under N2 for 15 minutes. TMSCN (424 ul, 3.2 mmol) was added and the resulting solution stirred at 40 °C until no starting material was present by TLC. The solution was diluted with ether (10 ml), water (15 ml) poured into the diluted solution and the organic products 132 extracted with ether (3x15 ml). The combined organics were washed with brine (40 ml) and dried over anhydrous Na2SC>4. The solvent was removed under reduced pressure to yield the crude products that were purified by silica flash column chromatography. 3-Oxo-cyclopentanecarbonitrile5S Prepared according to GP 9 (Table 8). Isolated in a mixture with the bis-adduct. SH (250 MHz, CDC13) 3.17 (IH, m, 1-H), 2.65-2.16 (6H, m); 8C (62.5 MHz, CDC13) 212.7 (C, CO), 120.8 (C, CN), 41.3 (CH2), 36.6 (CH2), 27.3 (CH2), 25.5 (CH, 1-C). Consistent with lit. 175 2-Methyl-4-oxo-hexanenitrile 59 Prepared according to GP 9 (Table 8). Compound 59 (0.16 g, 64%) isolated as a colourless oil; 8H (250 MHz, CDC13) 3.07 (IH, sextet, J7.0, 2-H), 2.80 (IH, dd, J18.0, 7.0, 3-H), 2.59 (IH, dd, J18.0, 7.0, 3-H'), 2.41 (2H, q, .77.3, 5-H), 1.26 (3H, d, /7.0, Me), 1.02 (3H, t, J13, 6-H). Consistent with lit.176 2,2-Dimethyl-4-oxo-pentanenitrile56 133 Prepared according to GP 9 (Table 8). Compound 56 (0.14 g, 57%) isolated as a colourless oil; 8H (250 MHz, CDC13) 2.69 (2H, s, 3-H), 2.20 (3H, s, 5-H), 1.43 (6H, s, M?C(CN)M>). Consistent with lit.176 4-Oxo-2-phenyl-pentanenitrile 60 Prepared according to GP 9 (Table 8). Compound 60 (0.12 g, 33%) isolated as a colourless oil; 6H (250 MHz, CDC13) 7.42-7.24 (5H, m, Ph), 4.34 (1H, dd, 77.9, 6.1, 2- H), 3.19 (1H, dd, .718.0, 7.9, 3-H), 2.96 (1H, dd, J18.0, 6.1, 3-H1), 2.18 (3H, s, Me). Consistent with lit. 177 2-Methyl-4-phenyl-2-trimethylsilyloxy-pentanedinitrile 61 NQ DIMS CN 61 Prepared according to GP 9 (Table 8). Both diastereomers (0.14 g, 25%) of 61 were produced but only one could be purified and fully characterised. The other was inseparable from a by-product. One diastereomer: vmax/cm l 2962, 2244, 1710, 1601, 1496, 1258, 1124, 1033, 848, 799, 758, 701; 8H (250 MHz, CDC13) 7.43-7.19 (5H, m, Ph), 4.05 (1H, dd, 79.8, 3.7, 4-H), 2.46 (1H, dd, J14.3, 9.8, 3-H), 2.1 1 (1H, dd, J14.3, 3.7, 3-Hf), 1.66 (3H, s, Me), 0.31 (9H, s, TMS); 8C (62.5 MHz, CDC13) 135.5 (C, Ph), 129.4 (CH, Ph), 128.5 (CH, Ph), 127.8 (CH, Ph), 120.8 (C, CN), 120.5 (C, CN), 68.6 (C, 2-C), 48.9 (CH2, 3-C), 33.3 (CH, 4-C), 29.1 (CH3, Me); m/z (CI) 290 (M+NH4+, 100%); Found M+NH4+, 290.1684. Ci5H24N3OSi requires: M, 290.1689. 134 2-Methyl-4-(l,3-oxazolidm-2-one)-4-oxo-butanenitrileGl CN O O 62 Prepared according to GP 9 (Table 8). Compound 62 (145 mg, 79%) isolated as a colourless solid, m.p. 45-48 °C; vmjcm l 2988, 2928, 2243, 1779, 1699, 1479, 1394, 1291, 1225, 1115, 1039, 760, 703; 8H (400 MHz, CDC13) 4.49-4.45 (2H, m, 5'-H), 4.15-4.00 (2H, m, 4'-H), 3.41-3.31 (1H, m, 2-H), 3.23-3.12 (2H, m, 3-H), 1.42 (3H, d, J7.1, Me); 8C (100 MHz, CDC13) 169.2 (C, 4-C), 153.5 (C, 2'-C), 122.0 (C, CN), 62.5 (CH2, 5f-C), 42.3 (CH2), 39.4 (CH2), 21.0 (CH, 2-C), 17.7 (CH3, Me); m/z (CI) 200 (M+NH4+, 100%); Found M+NH4+, 200.1038. C8H,4N3O3 requires: M, 200.1035. 4-(l,3-Oxazolidin-2-one)-4-oxo-2-phenyl-butanenitrile63 CN O O V_7 63 Prepared according to GP 9 (Table 8). Compound 63 (167 mg, 68%) isolated as a colourless solid, m.p. 79-81 °C; v^/cm'1 1774, 1695, 1390, 1277, 1223, 1116, 1038, 757, 700; 6H (400 MHz, CDC13) 7.42-7.32 (5H, m, Ph), 4.49-4.38 (3H, m, 2-H and 5'- H), 4.15-3.99 (2H, m, 4'-H), 3.68 (1H, dd, .718.1, 9.0, 3-H), 3.46 (1H, dd, .718.1, 5.6, 3-H'); 5C (100 MHz, CDC13) 168.7 (C, 4-C), 153.4 (C, 2'-C), 134.5 (C, Ph), 129.2 (CH, Ph), 128.5 (CH, Ph), 127.5 (CH, Ph), 120.1 (C, CN), 62.5 (CH2, 5'-C), 42.3 (CH2), 41.1 (CH2), 32.4 (CH, 2-C); m/z (CI) 262 (M+NHt+, 100%); Found M+NH4+, 262.1186. Ci3Hi6N3O3 requires: M, 262.1192. 135 5.2.1 Cyanation in the presence of pybox ligands General procedure for the addition of TMSCN to cyclohexenone 18 under ytterbium catalysis in the presence of a chiral non-racemic pybox ligand 64 (GP 10) solvent, 40 °C 18 A mixture of YbCl3.6H2O (39 mg, 0.10 mmol) and 2,6-bis[4-(^)-(+)-isopropyl-2- oxazolin-2-yl]pyridine 64 (36 mg, 0.12 mmol) in THF (6 ml) was stirred at room temperature for 45 min then CHCls (2 ml) was added to precipitate uncomplexed YbCls and the mixture was stirred a further 15 min. The suspension was filtered through a plug of cotton wool and the filtrate was concentrated in vacua to yield a white solid. The solvent (4 ml), cyclohexenone 18 (96 mg, 1 mmol) and TMSCN (424 ul, 3.2 mmol) were added sequentially and the reaction mixture stirred at 40 °C and monitored by TLC. After completion of the reaction time, CFbCb (10 ml) was added and the reaction mixture filtered through a short pad of silica and washed through with CHfeCk (50 ml). The filtrate was concentrated in vacua to yield the crude products which were analysed by *H NMR and GC. (2R,3R)-2,3-Butanediol acetal of 3-cyanocyclohexanone™ 65 11 •. 65 Crude 1,4-adduct 20, obtained according to GP 10, was heated under reflux in a Dean- Stark apparatus with (2/?,3/?)-2,3-butanediol (0.1 ml, 1.1 mmol), /7-toluene sulfonic 136 acid (5 mg) in toluene (20 ml) for 3 hours. The reaction mixture was concentrated in vacuo and the crude reaction mixture purified by silica flash column chromatography (10-40% EtOAc in pet. spirits 40-60) to yield a 1 : 1 mixture of diastereomers of (2R,3R)-2,3-butanediol acetal of 3-cyanocyclohexanone 65 (57 mg, 29%) as a colourless liquid; 5H (400 MHz, CDC13) 3.70-3.55 (2H, m, 8-H, 9-H), 2.83-2.75 (1H, m, 3-H), 2.07-1.98 (2H, m, 2-H), 1.83-1.43 (6H, m, 4-H, 5-H, 6-H), 1.25-1.23 (6H, m, 10-H, 11-H); 5C (100 MHz, CDC13) 122.0 (C, CN), 121.9 (C, CN), 105.8 (C, 1-C), 105.7 (C, 1-C), 78.5 (CH, 8-C or 9-C), 78.4 (CH, 8-C or 9-C), 78.3 (CH, 8-C or 9-C), 78.2 (CH, 8-C or 9-C), 39.8 (CH2, 2S-C), 38.8 (CH2, 2R-C\ 36.1 (CH2, 6tf-C), 35.2 (CH2, 6S-C), 28.7 (CH2, 4-C), 26.5 (CH, 3tf-C), 26.1 (CH, 3S-C), 22.3 (CH2, 55-C), 22.0 (CH2, 5R-C\ 16.9 (CH3, 10-C or 11-C), 16.8 (CH3, 10-C or 11-C), 16.7 (CH3, 10-C or 11-C), 16.6 (CH3, 10-C or 11-C). Consistent with lit.164 General procedure for the addition of TMSCN to a,p-unsaturated /V-acyl oxazolidinone compounds under ytterbium catalysis in the presence of chiral non-racemic pybox ligands19 (as used in Table 9) (GP 11) ligand = O O 10%Yb.ligand CN O O A mixture of YbCl3.6H2O (39 mg, 0.1 mmol) and the pybox ligand (0.12 mmol) in THF (6 ml) was stirred at room temperature for 45 min then CHC13 (2 ml) was added to precipitate uncomplexed YbCl3, and the mixture was stirred a further 1 5 min. The suspension was filtered through a plug of cotton wool and the filtrate concentrated in vacuo to yield a white solid. The solvent (4 ml), substrate (1 mmol) and TMSCN (424 ul, 3.2 mmol) were added sequentially, followed by any additive, and the reaction mixture stirred at 40 °C and monitored by TLC. After completion of the reaction time, CH2C12 (10 ml) was added and the reaction mixture was filtered 137 through a short pad of silica and washed through with CH2C12 (50 ml). The filtrate was concentrated in vacuo to yield the crude products that were purified by silica flash column chromatography to yield products that were consistent with previous spectrally analysis. The ee of the hydrocyanated product was analysed by chiral HPLC (RI= Me, OJ-H column, 30% IPA in hexane, 28 °C, 1 ml/min, 215 nm, tr = 42.9 min and 56.5 min) (Rl= Ph, OJ-H column, 50% IPA in hexane, 35 °C, 0.6 ml/min, 215 nm, tr = 85.6 min and 102.8 min). 138 • 5.3 Non-asymmetric Sm(O'Pr)3 catalysed reaction General procedure for the hydrocyanation of a,|$-unsaturated carbonyl compounds with acetone cyanohydrin under Sm(O'Pr)3 catalysis73 (as used in Table 10) (GP 12) Sm(O'Pr)3 (33 mg, 0.1 mmol) was weighed out in a nitrogen atmosphere glove box and transferred, under an atmosphere of nitrogen, to a fume hood where toluene (1 ml) was added, followed sequentially by the a,p-unsaturated carbonyl compound (1 mmol) and commercial acetone cyanohydrin (182 ul, 2 mmol). The reaction mixture was stirred at room temperature generally until no more starting material was visible by TLC, the mixture diluted with ether (5 ml) and filtered through Celite. The solvent was removed under reduced pressure to yield the crude products that were purified by silica flash column chromatography. 4-Oxo-pentanenitrile 67 Prepared according to GP 12 (Table 10). Compound 67 (8 mg, 9%) isolated as a colourless oil; 5H (250 MHz, CDC13) 2.84 (2H, t, J7.0, 2-H), 2.58 (2H, t, J7.0, 3-H), 2.22 (3H, s, Me). Consistent with lit. 178 Spectral data of other hydrocyanated products prepared according to GP 12 in Table 10 were consistent with previous characterisation. Spectral data of side-products observed in the reaction of acetone cyanohydrin with a,p-unsaturated compounds under Sm(O'Pr)3 catalysis (Table 10, GP 12) are shown below. Isopropyl (E)-crotonate 68a O O 68a 139 Compound 68a (5 mg, 4%); 8H (400 MHz, CDC13) 6.95 (IH, dq, 715.4, 6.9, 3-H), 5.82 (IH, dq, 715.4, 1.8, 2-H), 5.05 (IH, septet, 76.2, MeCtfMe), 1.87 (3H, dd, 76.9, 1.8, 4-H), 1.26 (6H, d, 76.2, MeCHMe). Consistent with lit.179 Acetone cyanohydrin ester of 2-methyl-4-oxo-butanenitrile 69a CN O 69a Compound 69a (10 mg, 6%); vmax/cm l 2998, 2946, 2245, 1750, 1371, 1 142; 6H (400 MHz, CDC13) 3.11 (IH, sextet, 77. 1, 2-H), 2.75 (IH, dd, 716.7, 7.2, 3-H), 2.59 (IH, dd, 716.7, 7.1, 3-H1), 1.80 (3H, s, Me2CCN), 1.79 (3H, s, M>2CCN), 1.41 (3H, d, 7.1, MeCHCN); 8C (100 MHz, CDC13) 167.7 (C, 4-C), 121.2 (C, CN), 1 18.8 (C, CN), 69.5 (C, Me2CCN), 38.1 (CH2, 3-C), 26.9 (CH3, M>2CCN), 26.7 (CH3, M?2CCN), 21.7 (CH, 2-C), 17.6 (CH3, M?CHCN); m/z (CI) 198 (M+NtV, 100%); Found M+NH4+, 198.1247. C9Hi6N3O2 requires: M, 198.1243 Isopropyl (E)-cinnamate 68b O 68b Compound 68ab (19 mg, 10%); 8H (250 MHz, CDC13) 7.67 (IH, d, 716.2, 3-H), 7.54- 7.50 (2H, m, Ph), 7.40-7.35 (3H, m, Ph), 6.42 (IH, d, 716.2, 2-H), 5.14 (IH, septet, 76.4, MeC//Me), 1.31 (6H, d, 76.4, MeCHMe). Consistent with lit. 180 140 5.4 Diastereoselective conjugate addition of cyanide 5.4.1 Synthesis of initial test substrates General procedure59 for the preparation of chiral non-racemic a,p-unsatu rated 7V-acyl l^-oxazolidin-2-ones (as used in Table 11) (GP 13) 9 i) nBuLi,THF.-78°C O " ii) a,p-unsaturated R acid chloride R" w-Butyl lithium (10 mmol) was added to a solution of the chiral 4-substituted 1,3- oxazolidin-2-one (10 mmol) in THF (35 ml) at -78 °C. After 15 min of stirring at -78 °C, the a,p-unsaturated acid chloride (11 mmol) was added. The mixture was stirred at -78 °C for a further 30 min then at 0 °C for 15 min, quenched with saturated NH4Cl(aq) (40 ml) and the resultant slurry concentrated in vacuo. The residue was diluted with Et2O or Ct^Cb (20 ml) and washed with saturated sodium bicarbonate and brine. The organic layer was dried over MgSC>4, filtered and the solvent removed under reduced pressure to yield the crude product. (4S)-3-((E)-2-Butenoyl)-4-isopropyl-l,3-oxazolidin-2-one 75 O O Prepared according to GP 13 (Table 11). The crude product was purified by silica flash column chromatography (15% EtOAc in pet. spirits 40-60) to give (4S)-3-((E)- 2-butenoyl)-4-isopropyl-l,3-oxazolidin-2-one 75 (1.74 g, 88%) as white needles, m.p. 54-56 °C (lit.59 56-56.5 °C), [a]D205 +120 (c 1, CHC13) (lit.59 [a]D +105 (c 1.97, CHC13)); 6H (250 MHz, CDC13) 7.33-7.08 (2H, m, 2'-H, 3'-H), 4.49 (IH, dt, J7.9, 3.7, 4-H), 4.28 (IH, dd, 78.9, 7.9, 5-H), 4.21 (IH, dd, J8.9, 3.4, 5-H'), 2.41 (IH, septet of 141 d, 77.0, 3.9, MeC//Me), 1.96 (3H, dd, 76.4, 1.2, 4'-H), 0.93 (3H, d, 77.0, M?CHMe), 0.88 (3H, d, 77.0, MeCHM?). Consistent with lit.59 (4S)-3-((E)-2-Cinnamoyl)-4-isopropyl-l,3-oxazolidin-2-one 76 O O Prepared according to GP 13 (Table 11). The crude product was purified by silica flash column chromatography (10% EtOAc in pet. spirits 40-60) to give (4S)-3-((E)- 2-cinnamoyl)-4-isopropyl-l,3-oxazolidin-2-one 76 (2.46 g, 94%) as a white solid, m.p. 57-58 °C, [a]D205 +102 (c 1, CHC13) (lit.59 [a]D +95 (c 1.65, CHC13)); 8H (250 MHz, CDC13) 7.96 (1H, d, 715.8, 3'-H), 7.84 (1H, d, .715.8, 2'-H), 7.66-7.59 (2H, m, Ph), 7.43-7.37 (3H, m, Ph), 4.57 (1H, dt, J1.9, 3.7, 4-H), 4.33 (1H, dd, 79.2, 7.9, 5-H), 4.25 (1H, dd, 79.2, 3.7, 5-Hf), 2.46 (1H, septet of d, J7.0, 3.6, MeC//Me), 0.96 (3H, d, 77.0, Me), 0.92 (3H, d, 77.0, Me). Consistent with lit.59 (4S)-4-Benzyl-3-((E)-2-butenoyl)-l,3-oxazolidin-2-onell O Ph— 77 Prepared according to GP 13 (Table 11). The crude product was recrystallised from to give (4S)-4-benzyl-3-((E)-2-butenoyl)-l,3-oxazolidin-2-one 77 (1.71 g, 70%) as a white solid, m.p. 84-86 °C (lit.59 85-86 °C), [a]D31 +82 (c 1, CHC13) (lit.59 [a]D +78 (c 2, CHC13)); 5H (400 MHz, CDC13) 7.36-7.18 (7H, m, 2'-H, 3'-H, Ph), 4.73 (1H, ddt, 79.5, 7.6, 3.2, 4-H), 4.21 (1H, dd, 79.0, 7.6, 5-H), 4.17 (1H, dd, 79.0, 3.2, 5-H'), 3.33 (1H, dd, 713.4, 3.2, C//2Ph), 2.80 (1H, dd, 713.4, 9.5, C//2Ph), 1.99 (3H, d, 75.8, 4'-H). Consistent with lit.59 142 (4S)-4-Benzyl-3-((E)-2-cinnamoyl)-l,3-oxazolidin-2-one 78 O O Ph— ' 78 Prepared according to GP 13 (Table 11). The crude product was recrystallised from CH2Cl2/hexane to give (4S)-4-benzyl-3-((E)-2-cinnamoyl)-l,3-oxazolidin-2-one 78 (1.73 g, 57%) as a white solid, m.p. 133 °C (lit. 181 121 °C), [a]D31 +62 (c 1, CHC13) (lit. 181 [a]D25 +46 (c 1.1, CHC13)); 5H (400 MHz, CDC13) 7.93-7.92 (2H, m, 2f-H, 3'H), 7.66-7.62 (2H, m, Ph), 7.43-7.21 (8H, m, Ph), 4.81 (IH, ddt, 79.5, 7.6, 3.2, 4-H), 4.26 (IH, dd, 79.0, 7.6, 5-H), 4.22 (IH, dd, 79.0, 3.2, 5-H'), 3.38 (IH, dd, 713.4, 3.2, C//2Ph), 2.86 (IH, dd, 713.4, 9.5, C//2Ph). Consistent with lit. 181 143 5.4.2 Asymmetric hydrocyanation of a,p-un saturated 7V-acyl oxazolidinones General procedure for the hydrocyanation of a,f$-unsaturated 7V-acyl " *7^ oxazolidinones with acetone cyanohydrin under Sm(O'Pr)3 catalysis (as used in Table 12) (GP 14) Sm(O'Pr)3 (33 mg, 0.1 mmol) was weighed out in a nitrogen atmosphere glove box and transferred, under an atmosphere of nitrogen, to a fume hood where a solution of a,p-unsaturated 7V-acyl oxazolidinone (1 mmol) in toluene (1 ml) was added followed by commercial acetone cyanohydrin (182 ul, 2 mmol). The reaction mixture was stirred at room temperature generally until no starting material was visible by TLC, the mixture diluted with ether (5 ml) and filtered through Celite. The solvent was removed under reduced pressure to yield the crude products that were purified by silica flash column chromatography. General procedure for the addition of TMSCN to a,p-unsaturated /V-acyl oxazolidinones under YbCl3 catalysis (as used in Table 12) (GP 15) A solution of a,p-unsaturated 7V-acyl oxazolidinone (1.0 mmol) in THF (4 ml) was added at 0 °C to YbCl3.6H2O (0.1 mmol) and the mixture stirred under N2 for 15 minutes. TMSCN (424 ul, 3.2 mmol) was added and the resulting solution stirred at 40 °C generally until no starting material was present by TLC. The solution was diluted with ether (10 ml), water (15 ml) poured into the diluted solution and the organic products extracted with ether (3 x 15 ml). The combined orgam'cs were washed with brine (40 ml) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to yield the crude products that were purified by silica flash column chromatography. Spectral data for products obtained in the hydrocyanation of a,p-unsaturated /V-acyl oxazolidinones according to GP 14 and GP 15 (Table 12). 144 4-((4S)-Isopropyl-l,3-oxazolidin-2-one)-2-(2S)-methyl-4-oxo-butanenitrile 79a Diastereomer A, minor isomer CN O O NA0 79a Compound 79a (31 mg, 14% [Sm-cat]) (63 mg, 30% [Yb-cat]) isolated as a colourless solid, m.p. 70-73 °C, [a]D20 +120 (c 1, CHC13); vmax/cm l 2964, 2243, 1779, 1703, 1390, 1209; 5H (250 MHz, CDC13) 4.47 (IH, dt, 77.9, 3.7, 4f-H), 4.33 (IH, dd, 79.2, 7.9, 5'-H), 4.25 (IH, dd, 79.2, 3.4, 5'-H'), 3.34 (IH, dd, 718.6, 10.1, 3-H), 3.27-3.13 (2H, m, 3-H', 2-H), 2.38 (IH, septet of d, 77.0, 4.0, MeC/flVIe), 1.42 (3H, d, 76.7, Me), 0.93 (3H, d, 77.0, M?CHMe), 0.88 (3H, d, 77.0, MeCHM?); 8C (62.5 MHz, CDC13) 169.1 (C, 4-C), 154.0 (C, 2'-C), 122.1 (C, CN), 63.9 (CH2, 5'-C), 58.5 (CH, 4'- C), 39.8 (CH2, 3-C), 28.4 (CH, MeC//Me), 21.1 (CH, 2-C), 17.9 (CH3), 17.7 (CH3), 14.7 (CH3, MeCHM?); m/z (CI) 242 (M+NlV, 100%); Found M+NH4+, 242.1497. CiiH2oN3O3 requires: M, 242.1505. Structure and relative stereochemistry confirmed by X-ray crystal structure. 4-((4S)-Isopropyl-l,3-oxazolidin-2-one)-2-(2R)-methyl-4-oxo-butanenitrilel9b Diastereomer B, major isomer CN O 9 79b Compound 79b (132 mg, 59% [Sm-cat]) (115 mg, 51% [Yb-cat]) isolated as a colourless oil, [a]D2° +60 (c 1, CHC13); vmax/cm } 2965, 2243, 1779, 1703, 1390, 1209; 8H (250 MHz, CDC13) 4.46 (IH, dt, 77.9, 3.7, 4'-H), 4.31 (IH, dd, 79.2, 7.9, 5'-H), 4.25 (IH, dd, 79.2, 3.4, 5f-Hf), 3.41 (IH, m, 3-H), 3.24-3.07 (2H, m, 2-H, 3-H1), 2.41 (IH, septet of d, 77.0, 4.0, MeC//Me), 1.41 (3H, d, 77.0, Me), 0.93 (3H, d, 77.0, MeCHMe), 0.89 (3H, d, 77.0, MeCHM?); 8C (62.5 MHz, CDC13) 169.0 (C, 4-C), 154.0 (C, 2'-C), 122.1 (C, CN), 63.8 (CH2, 5'-C), 58.4 (CH, 4'-C), 39.6 (CH2, 3-C), 145 28.3 (CH, MeC/TMe), 21.1 (CH, 2-C), 17.8 (CH3), 17.7 (CH3), 14.7 (CH3, MeCHM?); m/z (CI) 242 (M+NH4+, 100%); Found M+NH4+, 242.1498. CnH20N3O3 requires: M, 242.1505. Stereochemistry assigned by analogy to 80b and as opposite to 79a. 4-((4S)-Isopropyl-l,3-oxazolidin-2-one)-4-oxo-2-(2R)-phenyl-butanenitrile 1 5 1 a Diastereomer A, minor isomer CN O O 151a Compound 151a (21 mg, 8% [Sm-cat]) (42 mg, 15% [Yb-cat]) isolated as a colourless solid, m.p. 91-93 °C, [a]D20 +92 (c 1, CHC13); vmax/cm l 2965, 2245, 1781, 1699, 1390, 1266, 1209; 8H (250 MHz, CDC13) 7.42-7.30 (5H, m, Ph), 4.47 (IH, dt, .77.9, 3.7, 4'-H), 4.40 (IH, dd, J8.5, 6.4, 2-H), 4.32 (IH, dd, .79.1, 7.9, 5'-H), 4.23 (IH, dd, .79.1, 3.1, 5'-Hf), 3.61 (IH, dd, J18.0, 8.5, 3-H), 3.51 (IH, dd, J18.0, 6.4, 3-H'), 2.34 (IH, septet of d, .77.0, 4.0, MeC//Me), 0.90 (3H, d, J7.0, MCHMe), 0.80 (3H, d, /7.0, MeCHM?); 5C (62.5 MHz, CDC13) 168.6 (C, 4-C), 153.5 (C, 2'-C), 134.3 (C, Ph), 129.7 (CH, Ph), 128.8 (CH, Ph), 127.5 (CH, Ph), 120.1 (C, CN), 63.9 (CH2, 5'- C), 58.6 (CH, 4'-C), 41.4 (CH2, 3-C), 32.6 (CH, 2-C), 28.3 (CH, MeCtfMe), 17.9 (CH3, MeCHMe), 14.6 (CH3, MeCHM?); m/z (CI) 304 (M+NH4+, 100%); Found M+NH/, 304.1667. Ci6H22N3O3 requires: M, 304.1661. Stereochemistry assigned by analogy to 79a and 145a. 4-((4S)-Isopropyl-l,3-oxazolidin-2-one)-4-oxo-2-(2S)-phenyl-butanenitrile 1 51 b Diastereomer B, major isomer CN O O 151b Compound 151b (162 mg, 60% [Sm-cat]) (109 mg, 38% [Yb-cat]) isolated as a colourless oil, [a]D20 +44 (c 1, CHC13); vmjcm l 2965, 2246, 1780, 1702, 1389, 1302, 1267, 1209, 1 107, 755, 734, 700; 8H (250 MHz, CDC13) 7.41-7.29 (5H, m, Ph), 4.45- 146 4.35 (2H, m, 4'-H, 2-H), 4.27 (IH, dd, J9.2, 7.3, 5f-H), 4.22 (IH, dd, J9.2, 4.2, 5'-H'), 3.71 (IH, dd, J18.0, 8.5, 3-H), 3.44 (IH, dd, .718.0, 5.8, 3-H'), 2.38 (IH, septet of d, /7.0, 4.0, MeCmie), 0.91 (3H, d, /7.0, MeCHMe), 0.87 (3H, d, /7.0, MeCHMe); 6C (62.5 MHz, CDC13) 168.6 (C, 4-C), 153.9 (C, 2'-C), 134.5 (C, Ph), 129.2 (CH, Ph), 128.5 (CH, Ph), 127.6 (CH, Ph), 120.1 (C, CN), 63.8 (CH2, 5'-C), 58.5 (CH, 4'-C), 41.3 (CH2, 3-C), 32.5 (CH, 2-C), 28.3 (CH, MeCHMe), 17.9 (CH3, MeCHMe), 14.7 (CH3, MeCHMe); m/z (CI) 304 (M+NH4+, 100%); Found M+NlV, 304.1652. Ci6H22N3O3 requires: M, 304.1661. Stereochemistry assigned by analogy to 80b and 145a. 4-((4S)-Benzyl-l,3-oxazolidin-2-one)-2-(2S)-methyl-4-oxo-butanenitrile8Qa Diastereomer A, minor isomer CN O O Ph— ' 80a Compound 80a (54 mg, 20% [Sm-cat]) (82 mg, 30% [Yb-cat]) isolated as a colourless oil, [a]D2° +82 (c 1, CHC13); vmjcm l 2988, 2241, 1775, 1697, 1391, 1276, 1211, 1 1 10, 749, 701; 8H (400 MHz, CDC13) 7.37-7.20 (5H, m, Ph), 4.72 (IH, ddt, ,79.6, 7.6, 3.2, 4'-H), 4.27 (IH, dd, J9.2, 7.6, 5'-H), 4.22 (IH, dd, J9.2, 3.2, 5'-H'), 3.38-3.15 (4H, m, C#2Ph, 2-H, 3-H), 2.79 (IH, dd, J13.4, 9.6, C//2Ph), 1.45 (3H, d, J7.0, Me); 6C (100 MHz, CDC13) 169.1 (C, 4-C), 153.4 (C, 2'-C), 134.8 (C, Ph), 129.4 (CH, Ph), 129.0 (CH, Ph), 127.5 (CH, Ph), 122.1 (C, CN), 66.7 (CH2, 5'-C), 55.2 (CH, 4f-C), 39.8 (CH2), 37.8 (CH2), 21.1 (CH, 2-C), 17.8 (CH3, Me); m/z (CI) 290 (M+NlV, 100%); Found M+NlV, 290.1493. Ci5H20N3O3 requires: M, 290.1501. Stereochemistry assigned as opposite to 80b. 4-((4S)-Benzyl-l,3-oxazolidin-2-one)-2-(2R)-methyl-4-oxo-butanenitrile8Qb Diastereomer B, major isomer CN O O Ph— • SOI) 147 Compound 80b (163 mg, 60% [Sm-cat]) (139 mg, 51% [Yb-cat]) isolated as a colourless solid, m.p. 119-121 °C, [a]D2° +50 (c 1, CHC13); vmjcm l 2989, 2244, 1775, 1698, 1392, 1351, 1277, 1260, 1213, 1110, 750, 704; 5H (400 MHz, CDC13) 7.37-7.20 (5H, m, Ph), 4.72 (1H, m, 4'-H), 4.29-4.21 (2H, m, 5'-H), 3.41 (1H, dd, .717.7, 7.8, 3-H), 3.32 (1H, dd, .713.5, 3.2, C7/2Ph), 3.26-3.10 (2H, m, 2-H, 3-H'), 2.84 (1H, dd, J13.5, 9.5, C//2Ph), 1.44 (3H, d, /7.0, Me); 8C (100 MHz, CDC13) 169.1 (C, 4-C), 153.4 (C, 2'-C), 134.8 (C, Ph), 129.4 (CH, Ph), 129.0 (CH, Ph), 127.5 (CH, Ph), 122.1 (C, CN), 66.6 (CH2, 5'-C), 55.0 (CH, 4'-C), 39.7 (CH2), 37.6 (CH2), 21.0 (CH, 2-C), 17.7 (CH3, Me); m/z (CI) 290 (M+NlC, 100%); Found M+NH4+, 290.1496. Ci5H2oN3O3 requires: M, 290.1501. Structure and relative stereochemistry confirmed by X-ray crystal structure. 4-((4S)-Benzyl-l,3-oxazolidin-2-one)-4-oxo-2-(2R)-phenyl-butanenitrile 152a Diastereomer A, minor isomer CN O O Ph— 152a Compound 152a (75 mg, 22% [Sm-cat]) (55 mg, 17% [Yb-cat]) isolated as a colourless solid, m.p. 154-156 °C, [a]D2° +90 (c 1, CHC13); vmax/cm l 3029, 2245, 1782, 1699, 1392, 1274, 1213, 1113, 913, 743, 703; 5H (400 MHz, CDC13) 7.45-7.26 (8H, m, Ph), 7.15-7.13 (2H, m, Ph), 4.73 (1H, m, 4'-H), 4.44 (1H, dd, 79.1, 5.6, 2-H), 4.26 (1H, dd, J9.1, 7.7, 5'-H), 4.21 (1H, dd, .79.1, 2.9, 5'-H'), 3.63 (1H, dd, J18.1, 9.1, 3-H), 3.52 (1H, dd, J18.1, 5.6, 3-H1), 3.26 (1H, dd, .713.4, 3.2, C7/2Ph), 2.76 (1H, dd, ,713.4, 9.4, C//2Ph); 5C (100 MHz, CDC13) 168.7 (C, 4-C), 153.3 (C, 2f-C), 134.7 (C, Ph), 134.4 (C, Ph), 129.4 (CH, Ph), 129.3 (CH, Ph), 129.0 (CH, Ph), 128.6 (CH, Ph), 127.6 (CH, Ph), 127.5 (CH, Ph), 120.1 (C, CN), 66.6 (CH2, 5'-C), 55.1 (CH, 4'-C), 41.5 (CH2), 37.6 (CH2), 32.5 (2-C); m/z (CI) 352 (M+NlV, 100%); Found M+NH/, 352.1663. C2oH22N3O3 requires: M, 352.1661. Stereochemistry assigned by analogy to 151a. 148 4-((4S)-Benzyl-l,3-oxazolidin-2-one)-4-oxo-2-(2S)-phenyl-butanenitrilel52b Diastereomer B, major isomer CN O Q Ph— ' 152b Compound 152b (186 mg, 56% [Sm-cat]) (164 mg, 50% [Yb-cat]) isolated as a colourless solid, m.p. 125-127 °C, [a]D2° +58 (c 1, CHC13); vmax/cm l 2952, 2923, 2854, 2243, 1777, 1699, 1390, 1267, 1213, 1114, 913, 744, 700; 5H (400 MHz, CDC13) 7.43-7.25 (8H, m, Ph), 7.19-7.17 (2H, m, Ph), 4.66 (IH, m, 4'-H), 4.42 (IH, dd, .78.7, 5.8, 2-H), 4.19 (2H, d, J5.8, 5'-H), 3.71 (IH, dd, .718.1, 8.7, 3-H), 3.45 (IH, dd, J18.1, 5.8, 3-Hf), 3.27 (IH, dd, J13.4, 3.2, C//2Ph), 2.83 (IH, dd, J13.4, 9.3, C//2Ph); 8C (100 MHz, CDC13) 168.7 (C, 4-C), 153.3 (C, 2'-C), 134.7 (C, Ph), 134.5 (C, Ph), 129.4 (CH, Ph), 129.3 (CH, Ph), 129.0 (CH, Ph), 128.5 (CH, Ph), 127.6 (CH, Ph), 127.5 (CH, Ph), 120.2 (C, CN), 66.6 (CH2, 5'-C), 55.0 (CH, 4f-C), 41.4 (CH2), 37.6 (CH2), 32.4 (CH, 2-C); m/z (CI) 352 (M+NlV, 100%); Found M+NH/, 352.1667. C2oH22N3O3 requires: M, 352.1661. Stereochemistry assigned by analogy to 151b. 149 5.4.3 Hydrocyanation of chiral a,p-unsatu rated /V-acyl oxazolidinones under alternative conditions General procedure for the reaction of substrate 75 with Et2AlCN (as used in Table 15) (GP 16) 00 CN O K,^ toluene K,^ N p + 2Et2AICN ——————————— N O — ' additive — ' 75 79 Et2AlCN (1M solution in toluene, 2 ml, 2 mmol) was added, after any additive (2 mmol), to a stirred solution of 75 (197 mg, 1 mmol) in toluene (8 ml) at the reaction temperature given in Table 15. The reaction mixture was stirred at the reaction temperature until no starting material was visible by TLC. The reaction was quenched by addition of 10% Na2CC>3(aq), extracted with CH2Cl2 (2 x 10 ml), the combined organic layers dried over Na2SC>4, filtered and the solvent removed under reduced pressure to yield the crude products which were purified by silica flash column chromatography (20% EtOAc in pet. spirits 40-60) to give hydrocyanated products that were consistent with previous spectral analysis. (4S)-4-Isopropyl-3-(3-methyl-pentanoyl)-l,3-oxazolidin-2-one#I By-product 82 (26 mg, 1 1%) isolated from GP 16 (Table 15, entry 2) as 1 : 1 mixture of inseparable diastereomers. Colourless oil; vmSK/cm~l 2964, 2932, 2877, 1783, 1702, 1386, 1302, 1204; 5H (250 MHz, CDC13) 4.50 (1H, dt, .77.9, 3.7, 4-H), 4.26 (1H, dd, J9.1, 7.9, 5-H), 4.19 (1H, dd, .79.1, 3.4, 5-H'), 3.03 (0.5H, dd, J15.9, 5.5, 2'a-H), 2.88 (0.5H, dd, 715.7, 7.6, 2'b-H), 2.80 (0.5H, dd, .71 5.7, 6.4, 2'b-H'), 2.63 (0.5H, dd, J] 5.9, 8.24, 2'a-H'), 2.38 (1H, septet of d, .77.0, 4.0, MeC//Me), 1.97 (1H, m, 3'-H), 1.50- 1.14 (2H, m, 4'-H), 0.97-0.86 (12H, m, MeCHMe. 5'-H. Me); 8C (62.5 MHz, CDC13) 150 172.9 (C, I'-C), 154.0 (C, 2-C), 63.2 (CH2, 5-C), 58.4 (CH, 4-C (one diastereomer)), 58.3 (CH, 4-C (one diastereomer)), 42.1 (CH2, 2'-C (one diastereomer)), 42.0 (CH2, 2'-C (one diastereomer)), 31.4 (CH, 3'-C (one diastereomer), 31.3 (CH, 3'-C (one diastereomer)), 29.5 (CH2, 4'-C (one diastereomer)), 29.2 (CH2, 4'-C (one diastereomer)), 28.4 (CH, MeCHMe), 19.2 (CH3, (one diastereomer)), 19.1 (CH3, (one diastereomer)), 17.9 (CH3, (both diastereomers)), 14.6 (CH3, (one diastereomer)), 14.6 (CH3, (one diastereomer)), 11.2 (CH3, (both diastereomers)); m/z (CI) 228 (M+H+, 55%), 245 (M+NH4+, 100%); Found M+H+, 228.1600. Ci2H22NO3 requires: M, 228.1600. 151 5.4.4 Effect of auxiliary 5.4.4.1 Synthesis of substrates (4S)-3-((E)-2-Butenoyl)-4-phenyl-l,3-oxazolidin-2-one88 O O 88 Prepared similarly to GP 13 using 5 mmol oxazolidinone 84 scale. The crude product was purified by silica flash column chromatography (20% EtOAc in pet. spirits 40- 60) to give (4S)-3-((E)-2-butenoyl)-4-phenyl-l,3-oxazolidin-2-one 88 (1.02 g, 88%) as a colourless solid, m.p. 73-75 °C (lit. 182 77-79 °C), [a]D205 +120 (c 1, CHC13) (lit. 182 [ajo25 +1 12 (c 1.08, CHC13)); 8H (250 MHz, CDC13) 7.42-7.24 (6H, m, Ph, 2'-H), 7.09 (IH, dq, 715.3, 6.7, 3'-H), 5.49 (IH, dd, 78.5, 3.7, 4-H), 4.70 (IH, t, 78.7, 5-H), 4.28 (IH, dd, 78.9, 3.7, 5-Hf), 1 .94 (3H, dd, 76.7, 1 .2, 4'-H). Consistent with lit.182 (4S)-4-Benzyl-3-((E)-2-butenoyl)-5,5-dimethyl-l,3-oxazolidin-2-oneW O O 90 Prepared similarly to GP 1 3 using 2 mmol oxazolidinone 86 scale. The crude product was purified by silica flash column chromatography (10% EtOAc in pet. spirits 40- 60) to give (4S)-4-benzyl-3-((E)-2-butenoyl)-5,5-dimethyl-l,3-oxazolidin-2-one 90 (0.32 g, 59%) as a colourless solid, m.p. 79-81 °C, [a]D22 -48 (c 1, CHC13); v^/cm'1 1775, 1683, 1638, 1385, 1357, 1277, 1236, 1158, 1120, 1093, 760, 720 ; 5H (250 MHz, CDC13) 7.34-7.07 (7H, m, Ph, 2'-H, 3'-H), 4.55 (IH, dd, 79.8, 3.4, 4-H), 3.23 (IH, dd, 714.3, 3.4, C//2Ph), 2.88 (IH, dd, 714.3, 9.8, C//2Ph), 1.96 (3H, d, 76.4, 4'- H), 1.37 (3H, s, CMe2\ 1.35 (3H, s, CM?2); 6C (100 MHz, CDC13) 173.2 (C, l'-C), 165.3 (C, 2'-C), 146.6 (CH, 3'-C), 137.1 (C, Ph), 129.0 (CH, Ph), 128.6 (CH, Ph), 152 126.7 (CH, Ph), 122.2 (CH, 2f-C), 82.1 (C, 5-C), 63.7 (CH, 4-C), 35.2 (CH2, CH2Ph), 28.5 (CH3), 22.3 (CH3), 18.5 (CH3); m/z (CI) 291 (M+NlV, 100%), 274 (M+H+, 40%); Found M+H+, 274.1447. Ci6H2oNO3 requires: M, 274.1443. (4S)-3-((E)-2-Butenoyl)-4-isopropyl-5,5-diphenyl-l,3-oxazolidin-2-one 97 89 o o o i) "BuLi, THF, 0 °C ^ _ /__Ph ii) crotonyl chloride s^ — (--Ph >n rt, o/n ^Vs 85 89 A solution of 2.35 M w-butyl lithium (1.00 ml, 2.35 mmol) was added slowly to a suspension of (4S)-4-isopropyl-5,5-diphenyl-2-oxazolidinone 85 (0.63 g, 2.24 mmol) in THF (10 ml) at 0 °C. Crotonyl chloride (0.26 ml, 2.69 mmol) was added to the resulting clear solution and the mixture was allowed to warm slowly to room temperature overnight. The reaction was quenched with saturated NFLjCl^q) (4 ml) and the resultant slurry concentrated in vacuo. The residue was diluted with ether (10 ml) and washed with saturated sodium bicarbonate and brine. The organic layer was dried over MgSC>4, filtered and the solvent removed under reduced pressure to yield the crude product that was purified by silica flash column chromatography (10% EtOAc in pet. spirits 40-60) to give (4S)-3-((E)-2-butenoyl)-4-isopropyl-5,5-diphenyl- l,3-oxazolidin-2-one 89 (0.59 g, 75%) as a colourless solid, m.p. 132-134 °C, (lit.97 135-136 °C), [a]D22 -230 (c 1, CHC13) (lit.97 [a]Drt -239 (c 1.02, CHC13)); 8H (250 MHz, CDC13) 7.50-7.07 (12H, m, Ph, 2'-H, 3'-H), 5.45 (IH, d, J3.4, 4-H), 1.99 (IH, m, MeC//Me), 1.91 (3H, d, J5.8, 4'-H), 0.89 (3H, d, .77.0, MeCHMe), 0.77 (3H, d, J6.7, MeCHM?). Consistent with lit.97 (-)-N-((E)-2-Butenoyl)bornane-10,2-sultamm 91 i) NaH, toluene rt, 1 h ii) crotonyl chloride toluene, rt, 3 h 87 91 153 A solution of (7S,2tf)-(-)-2,10-camphorsultam 87 (0.86 g, 4.0 mmol) in toluene (10 ml) was added dropwise at room temperature to a stirred suspension of NaH (60% dispersion in mineral oil, 0.24 g, 6.0 mmol). After 1 hour, a solution of crotonyl chloride (0.77 ml, 8.0 mmol) in toluene (20 ml) was added slowly and the mixture stirred at room temperature for a further 3 hours. The reaction was quenched with the addition of H2O (10 ml), the organic layer removed and the aqueous layer extracted with EtOAc (3x10 ml). The combined organic layers were washed with brine, dried over MgSC>4, filtered and the solvent removed under reduced pressure to yield the crude product that was purified by silica flash column chromatography (20% EtOAc in pet. spirits 40-60) and then recrystallised from MeOH to give (-)-N-((E)-2- butenoyl)bornane-10,2-sultam 91 (0.93 g, 82%) as a colourless solid, m.p. 189-190 °C (lit. 183 186-187 °C), [a]D22 -158 (c 1, CHC13) (lit.183 [a]Drt -100 (c 1.04, CHC13)); 8H (250 MHz, CDC13) 7.10 (IH, dq, J14.9, 7.0, Me//C=CH), 6.59 (IH, dq, J14.9, 1.5, MeHC=C//), 3.93 (IH, dd, /7.0, 5.2, NC#), 3.51 (IH, d, J13.7, SC//2), 3.43 (IH, d, .713.7, SC//2), 2.18-2.04 (2H, m), 1.98-1.84 (6H, m), 1.47-1.32 (2H, m), 1.17 (3H, s, Me), 0.97 (3H, s, Me). Consistent with lit.184 5.4.4.2 Hydrocyanation Hydrocyanation of the substrates bearing alternative auxiliaries with acetone cyanohydrin under Sm(O'Pr)3 catalysis was accomplished according to GP 14 (Section 5.4.2) under conditions given in Table 17. Spectral data for the hydrocyanated products :- 2-(2S)-Methyl-4-oxo-4-((4S)-phenyl-l,3-oxazolidin-2-one)-butanenitrile 153a Diastereomer A, minor isomer CN O O PIT 153a Compound 153a (46 mg, 20%) isolated as a yellow oil, [a] D21 +110 (c 1, CHC13); 2243, 1782, 1707, 1389, 1204, 764, 709; 8M (250 MHz, CDC13 ) 7.42-7.26 154 (5H, m, Ph), 5.44 (IH, dd, J8.9, 3.4, 4'-H), 4.72 (IH, t, J8.9, 5f-H), 4.30 (IH, dd, J8.9, 3.4, 5'-Hf), 3.38 (IH, dd, J19.5, 10.4, 3-H), 3.12-2.98 (2H, m, 2-H, 3-H1), 1.31 (3H, d, J6.7, Me); 5C (62.5 MHz, CDC13) 168.9 (C, 4-C), 162.0 (C, 2'-C), 138.7 (C, Ph), 129.4 (CH, Ph), 129.0 (CH, Ph), 126.0 (CH, Ph), 122.1 (C, CN), 70.5 (CH2, 5f-C), 57.5 (CH, 4'-C), 39.9 (CH2, 3-C), 20.9 (CH, 2-C), 17.6 (CH3, Me); m/z (CI) 276 (M+NlV, 100%); Found M+NlV, 276.1338. C,4Hi8N3O3 requires: M, 276.1348. Stereochemistry assigned by analogy with 79a. 2-(2R)-Methyl-4-oxo-4-((4S)-phenyl-l,3-oxazolidin-2-one)-butanenitrile 153b Diastereomer B, major isomer CN O O 153b Compound 153b (112 mg, 49%) isolated as a yellow oil, [a]D205 +56 (c 1, CHC13); Vmax/cm'1 2985, 2243, 1781, 1709, 1390, 1203, 735, 705; 8H (250 MHz, CDC13) 7.41- 7.25 (5H, m, Ph), 5.40 (IH, dd, J8.9, 3.7, 4'-H), 4.67 (IH, t, ^8.9, 5'-H), 4.24 (IH, dd, J8.9, 3.7, 5'-H'), 3.32 (IH, dd, J18.0, 7.3, 3-H), 3.18 (IH, dd, J18.0, 6.4, 3-Hf), 3.06 (IH, sextet, /7.0, 2-H), 1.32 (3H, d, J6.7, Me); 8C (62.5 MHz, CDC13) 168.7 (C, 4-C), 153.7 (C, 2'-C), 138.5 (C, Ph), 129.3 (CH, Ph), 128.9 (CH, Ph), 125.9 (CH, Ph), 121.9 (C, CN), 70.4 (CH2, 5'-C), 57.6 (CH, 4'-C), 39.5 (CH2, 3-C), 20.9 (CH, 2-C), 17.7 (CH3, Me); m/z (CI) 276 (M+NlV, 100%); Found M+NH/, 276.1340. Ci4H18N3O3 requires: M, 276.1348. Stereochemistry assigned by analogy with 79b. 4-((4S)-Isopropyl-5,5-diphenyl-l,3-oxazolidin-2-one)-2-methyl-4-oxo-butanenitrile 154 CN O -Ph Ph 154 A 40 : 60 mixture of inseparable diastereomers (219 mg, 58%). Colourless solid; 3064, 2982, 2965, 2244, 1781, 1714, 1451, 1389, 1373, 1213, 707; 8M (250 155 MHz, CDC13) 7.49-7.26 (10H, m, Ph), 5.39 (IH, m, 4'-H), 3.37 (0.6H, dd, 717.4, 8.2, 3-H (major diastereomer)), 3.23-3.02 (1.8H, m, 2-H (both diastereomers), 3-H & 3-H' (minor diastereomer)), 2.94 (0.6H, dd, 717.4, 5.8, 3-H1 (major diastereomer)), 1.99 (IH, m, MeC//Me), 1.34 (1.2H, d, 77.0, Me (minor diastereomer)), 1.28 (1.8H, d, 77.0, Me (major diastereomer)), 0.91-0.87 (3H, m, M?CHMe), 0.79-0.75 (3H, m, MeCHM?); 8C (62.5 MHz, CDC13) 168.8 (C, 4-C), 152.7 (C, 2f-C), 141.9 (C, Ph (minor diastereomer), 141.7 (C, Ph (major diastereomer), 137.6 (C, Ph), 128.9 (CH, Ph), 128.7 (CH, Ph), 128.6 (CH, Ph), 128.3 (CH, Ph), 128.0 (CH, Ph), 125.7 (CH, Ph (minor diastereomer)), 125.4 (CH, Ph (major diastereomer)), 121.8 (C, CN (major diastereomer)), 121.6 (C, CN (minor diastereomer)), 89.9 (C, 5'-C (minor diastereomer)), 89.7 (C, 5'-C (major diastereomer)), 64.6 (CH, 4'-C), 39.2 (CH2, 3-C), 29.7 (CH), 21.6 (CH3), 21.1 (CH), 17.5 (CH3, (minor diastereomer)), 17.3 (CH3, (major diastereomer)), 16.2 (CH3); m/z (CI) 394 (M+NlV, 100%); Found M+NlV, 394.2118. C23H28N3O3 requires: M, 394.2131. 4-((4S)-Benzyl-5,5-dimethyl-l,3-oxazolidin-2-one)-2-(2S)-methyl-4-oxo- butanenitrile 155a. Diastereomer A, minor isomer 155a Compound 155a (61 mg, 20%) isolated as a colourless solid, m.p. 110-112 °C, [a]D21 -2 (c 1, CHC13); Vmax/cm-1 2244, 1776, 1700, 1393, 1377, 1356, 1279, 1105, 733, 701; 6H (250 MHz, CDC13) 7.35-7.21 (5H, m, Ph), 4.55 (IH, dd, 79.2, 4.3, 4f-H), 3.35 (IH, dd, 719.2, 9.8, 3-H), 3.17-3.05 (3H, m, 2-H, 3-H1, C//2Ph), 2.90 (IH, dd, 714.3, 9.2, C//2Ph), 1.40 (6H, s, CM?2), 1.36 (3H, d, 77.0, M?CHCN); 5C (62.5 MHz, CDC13) 169.2 (C, 4-C), 152.5 (C, 2'-C), 136.5 (C, Ph), 129.0 (CH, Ph), 128.7 (CH, Ph), 126.9 (CH, Ph), 122.1 (C, CN), 83.0 (C, 5'-C), 63.4 (CH, 4'-C), 39.8 (CH2), 35.3 (CH2), 28.5 (CH3), 22.2 (CH3), 21.1 (CH, 2-C), 17.8 (CH3); m/z (CI) 318 (M+NH4+, 100%); Found M+NlV, 318.1817. CnH24N3O3 requires: M, 318.1818. Stereochemistry assigned by analogy with 80a. 156 4-((4S)-Benzyl-5,5-dimethyl-l,3-oxazolidin-2-one)-2-(2R)-methyl-4-oxo butanenitrile 155b. Diastereomer B, major isomer CN Ph— • 155b Compound 155b (121 mg, 40%) isolated as a colourless oil, [a]D21 -46 (c 1, CHC13); Vmax/cm'1 2985, 2244, 1772, 1696, 1394, 1377, 1357, 1279, 1105, 733, 701; 8H (250 MHz, CDC13) 7.36-7.21 (5H, m, Ph), 4.52 (1H, dd, .79.5, 4.0, 4'-H), 3.34 (1H, dd, .719.2, 9.5, 3-H), 3.23-3.05 (3H, m, 2-H, 3-H', C//2Ph), 2.90 (1H, dd, .714.6, 9.5, C//2Ph), 1.40-1.37 (9H, m, CMe2, MCHCN); 5C (62.5 MHz, CDC13) 169.3 (C, 4-C), 152.5 (C, 2'-C), 136.5 (C, Ph), 129.0 (CH, Ph), 128.7 (CH, Ph), 126.9 (CH, Ph), 122.1 (C, CN), 82.9 (C, 5f-C), 63.4 (CH, 4'-C), 39.7 (CH2), 35.1 (CH2), 28.6 (CH3), 22.3 (CH3), 21.0 (CH, 2-C), 17.7 (CH3); m/z (CI) 318 (M+NlV, 100%); Found M+NlV, 318.1821. Ci 7H24N3O3 requires : M, 318.1818. Stereochemistry assigned by analogy with 80b. 4-((-)-N-Bornane-10,2-sultam)-2-methyl-4-oxo-butanenitrile92 CN 92 An ~85 : 15 mixture of inseparable diastereomers (150 mg, 48%). Colourless solid; Vmax/cm'1 3405, 3003, 2983, 2962, 2940, 2246, 1696, 1678, 1389, 1325, 1286, 1237. 1221, 1166, 1137, 1057; 5H (250 MHz, CDC13) 3.86 (1H, dd, .77.3, 5.2, NC7/), 3.52 (1H, d, .713.7, SC772), 3.43 (1H, d, 713.7, SC/fc), 3.26-2.90 (3H, m, 2-H, 3-H), 2.21- 2.02 (2H, m), 1.98-1.77 (3H, m), 1.45-1.21 (5H, m), 1.14 (3H, s, Me), 0.96 (3H, s, Me); 8C (62.5 MHz, CDC13) 167.8 (C, 4-C), 121.8 (C, CN), 65.2 (CH, NCH (major diastereomer)), 62.8 (CH, NCH (minor diastereomer)), 52.8 (CH2, CH2S), 49.5 (C, 157 (minor diastereomer)), 48.7 (C, (major diastereomer)), 47.8 (C, (major diastereomer)), 47,4 (C, (minor diastereomer)), 44.6 (CH), 38.9 (CH2), 38.3 (CH2, (major diastereomer)), 36.0 (CH2, (minor diastereomer)), 32.7 (CH2, (major diastereomer)), 31.9 (CH2, (minor diastereomer)), 26.8 (CH2, (minor diastereomer)), 26.4 (CH2, (major diastereomer)), 21.1 (CH), 20.8 (CH3, (major diastereomer)), 20.4 (CH3, (minor diastereomer)), 19.8 (CH3), 17.6 (CH3); m/z (CI) 328 (M+NH/, 100%); Found , 328.1685. QsI^NsOaS requires: M, 328.1695. 158 5.4.5 Scope of substitution on alkene 5.4.5.1 Synthesis of substrates General procedure105 for the synthesis of a,p-unsaturated acid chloride from the acid (for use in Table 18) (GP 17) R2 o oxalyl chloride R2 o cat. DMF R1 " f ^OH p^3 0 C, 20 min R3 Oxalyl chloride (3.50 ml, 40 mmol) was added to the a,p-unsaturated acid (20 mmol) at 0 °C. After initiation by a drop of DMF, the reaction was stirred at 0 °C for 20 min then slowly warmed to room temperature. The volatiles were removed in vacuo and the product was analysed by *H NMR and used without further purification or isolation. (E)-2-Pentenoyl chloride 156 O 156 6H (250 MHz, CDC13) 7.28 (IH, dt, 715.3, 6.4, 3-H), 6.06 (IH, dt, 715.3, 1.8, 2-H), 2.34 (2H, quintet d, 77.3, 1.8, 4-H), 1.10 (3H, t, 77.3, 5-H). (E)-4-Methyl-2-pentenoyl chloride 157 O 157 6H (250 MHz, CDC13) 7.18 (IH, dd, 715.3, 6.7, 3-H), 6.02 (IH, dd, 715.3, 1.5, 2-H), 2.56 (IH, octet of d, 76.7, 1.2, 4-H), 1.12 (6H, d, 77.0, 5-H, Me). Consistent with lit. 185 159 (E)-4-Methoxy-cinnamoyl chloride 158 MeO 158 5H (250 MHz, CDC13) 7.80 (IH, d, 715.6, 3-H), 7.57-7.51 (2H, m, Ar), 6.98-6.92 (2H, m, Ar), 6.51 (IH, d, 715.6, 2-H), 3.87 (3H, s, OMe). Consistent with lit. 186 (E)-4-Chloro-cinnamoyl chloride 144 144 5H (250 MHz, CDC13) 7.79 (IH, d, 715.6, 3-H), 7.54-7.49 (2H, m, Ar), 7.44-7.39 (2H, m, Ar), 6.62 (IH, d, 715.6, 2-H). 3-Methyl-2-butenoyl chloride 159 O Cl 159 5H (250 MHz, CDC13) 6.06 (IH, septet, 71.2, 2-H), 2.15 (3H, d, 71.2, Me), 1.98 (3H, d, 71.2, Me). Consistent with lit. 187 (E)-2-Methyl-2-butenoyl chloride 160 O Cl 160 160 6H (250 MHz, CDC13) 7.31 (IH, qq, J7.0, 1.2, 3-H), 1.95-1.89 (6H, m, 4-H, Me). Consistent with lit.188 General procedure59 for the preparation of chiral non-racemic a,f$-unsaturated /V-acyl l,3-oxazolidin-2-one (as used in Table 18) (GP 18) O i) nBuLi,THF,-78°C «2 O O X » D-Mn . 9 ii) a,p-unsaturated R N. P > acid chloride R c> 81 tt-Butyl lithium (10 mmol) was added to a solution of (4S)-4-isopropyl-2- oxazolidinone 81 (10 mmol) in THF (35 ml) at -78 °C. After 15 min of stirring at -78 °C, the a,p-unsaturated acid chloride (11 mmol) was added. The mixture was stirred at -78 °C for a further 30 min then at 0 °C for 15 min, quenched with saturated NH4Cl(aq) (40 ml) and the resultant slurry was concentrated in vacuo. The residue was diluted with Et2O or Cl^Cfe (20 ml) and washed with saturated sodium bicarbonate and brine. The organic layer was dried over MgSC>4, filtered and the solvent removed under reduced pressure to yield the crude product that was purified by silica flash column chromatography (EtOAc in pet. spirits 40-60). (4S)-4-Isopropyl-3-((E)-2-pentenoyl)-l,3-oxazolidin-2-one93 Prepared according to GP 18 (Table 18). Compound 93 (1.48 g, 70%) isolated as a yellow oil, [a]D205 +104 (c 1, CHC13) (lit. 189 [a]D +96 (c 1.42. CHC13)); 8H (250 MHz, CDC13) 7.30-7.13 (2H, m, 2'-H, 3'-H), 4.57 (IH, dt, J7.9, 3.7, 4-H), 4.28 (IH, dd, ^9.2, 7.9, 5-H), 4.21 (IH, dd, ,79.2, 3.7, 5-H1), 2.48-2.25 (3H, m, MeC//Me, 4f-H), 161 1.11 (3H, t, /7.6, 5'-H), 0.93 (3H, d, 77.0, M?CHMe), 0.89 (3H, d, .76.7, MeCHM?). Consistent with lit. 189 (4S)-4-Isopropyl-3-((E)-4-methyl-2-pentenoyl)-l,3-oxazolidin-2-one94 Prepared according to GP 18 using 7.5 mmol oxazolidinone 81 scale (Table 18). Compound 94 (1.53 g, 90%) isolated as a yellow oil, [a]D2° +100 (c 1, CHC13); Vmax/an 1 2965, 2933, 2875, 1778, 1686, 1634, 1387, 1365, 1295; 6H (250 MHz, CDC13) 7.21 (1H, d, .715.3, 2'-H), 7.07 (1H, dd, .715.3, 6.4, 3'-H), 4.47 (1H, dt, J7.9, 3.3, 4-H), 4.25 (1H, dd, 79.2, 7.9, 5-H), 4.18 (1H, dd, 79.2, 3.3, 5-Hf), 2.52 (1H, octet, 76.7, 4'-H), 2.38 (1H, septet d, 77.0, 3.9, MeC//Me), 1.07 (6H, d, 77.0, 5-H, Me), 0.91 (3H, d, 77.0, MeCHMe), 0.87 (3H, d, 77.0, MeCHM?); 5C (62.5 MHz, CDC13) 165.4 (C, l'-C), 157.5 (CH, 3'-C), 154.0 (C, 2-C), 117.8 (CH, 2'-C), 63.3 (CH2, 5-C), 58.5 (CH, 4-C), 31.4 (CH), 28.5 (CH), 21.3 (CH3), 18.0 (CH3), 14.7 (CH3); m/z (CI) 243 (M+NH4+, 100%); Found M+NH4+, 243.1705. C,2H23N2O3 requires: M, 243.1709. (4S)-4-Isopropyl-3-((E)-4-methoxy-cinnamoyl)-l,3-oxazolidin-2-one95 MeO 95 Prepared according to GP 18 (Table 18). Compound 95 (2.44 g, 84%) isolated as a cream solid, m.p. 58-60 °C, [a]D22 +96 (c 1, CHC13); vmax/cm ] 3100, 2965, 2936, 1777, 1677, 1600, 1574, 1464, 1423, 1389, 1364, 1346, 1305, 1258, 1229, 1206, 1175, 1060, 1032, 987, 912, 829, 795, 734, 703; 6H (250 MHz, CDC13) 7.79 (2H, s, 2'- H, 3'-H), 7.58-7.52 (2H, m, Ar), 6.91-6.85 (2H, m, Ar), 4.53 (1H, dt, .77.9, 3.4, 4-H), 4.28 (1H, dd, .79.2, 7.9, 5-H), 4.21 (1H, dd, 79.2, 3.4, 5-H1), 3.81 (3H, s, OMe), 2.43 (1H, septet of d, 77.0, 3.9, MeC//Me), 0.93 (3H, d, 77.0, A/eCHMe), 0.88 (3H, d, 162 77.0, MeCHMe); 8C (100 MHz, CDC13) 165.4 (C), 162.0 (C), 154.2 (C, 2-C), 145.9 (CH, 3'-C), 120.4 (CH), 127.4 (C, AT), 114.6 (CH), 114.3 (CH), 63.3 (CH2, 5-C), 58.6 (CH, 4-C), 55.3 (CH3, OMe), 28.6 (CH, MeCHMe), 18.0 (CH3, MeCHMe), 14.7 (CH3, MeCHMe); m/z (CI) 290 (M+H+, 100%); Found M+H+, 290.1385. C16H2oNO4 requires: M, 290.1392. (4S)-3-((E)-4-Chloro-cinnamoyl)-4-isopropyl-l,3-oxazolidin-2-one96 Prepared according to GP 18 (Table 18). Compound 96 (2.65 g, 90%) isolated as a colourless solid, m.p. 109-110 °C, [a]D22 +88 (c 1, CHC13); v^/cm'1 3100, 2965, 1770, 1679, 1621, 1490, 1387, 1364, 1343, 1299, 1231, 1207, 1097, 1060, 1032, 985, 912, 821, 771, 732, 719, 652; 8H (250 MHz, CDC13) 7.90 (1H, d, J15.6, 3'-H), 7.75 (1H, d, J15.6, 2'-H), 7.55-7.49 (2H, m, Ar), 7.36-7.31 (2H, m, Ar), 4.54 (1H, dt, J8.2, 3.4, 4-H), 4.31 (1H, dd, J9.2, 8.2, 5-H), 4.23 (1H, dd, J9.2, 3.4, 5-H'), 2.43 (1H, septet of d, /7.0, 3.9, MeC//Me), 0.93 (3H, d, /7.0, MeCHMe), 0.89 (3H, d, J7.0, MeCHMe); 5C (100 MHz, CDC13) 164.9 (C, I'-C), 154.1 (C, 2-C), 144.6 (CH, 3'-C), 136.5 (C, Ar), 133.1 (C, Ar), 129.7 (CH), 129.1 (CH), 117.6 (CH), 63.4 (CH2, 5-C), 58.6 (CH, 4-C), 28.5 (CH, MeCHMe), 18.0 (CH3, MeCHMe), 14.7 (CH3, MeCHMe); m/z (CI) 294 (M(35C1)+H+, 100%), 296 (M(37C1)+H+, 55%), 311 (M(35C1)+NH4+, 70%), 313 (M(37C1)+NH4+, 40%); Found M(35C1)+H+, 294.0890. C, 5Hi7NO335Cl requires: M, 294.0890; Found M(37C1)+H+, 296.0872. Ci5H17NO337Cl requires: M, 296.0867. (4S)-4-Isopropyl-3-(3-methyl-2-butenoyl)-l,3-oxazolidin-2-one97 O O 97 163 Prepared according to GP 18 using 7.5 mmol oxazolidinone 81 scale (Table 18). Compound 97 (1.52 g, 95%) isolated as a colourless oil, [a]D21 +90 (c 1, CHC13) (lit. 189 [a]D +92 (c 0.5, CHC13)); 5H (250 MHz, CDC13) 6.95 (IH, septet, 71.2, 2'-H), 4.49 (IH, dt, 78.2, 3.7, 4-H), 4.26 (IH, dd, 78.9, 8.2, 5-H), 4.18 (IH, dd, 78.9, 3.7, 5- H'), 2.40 (IH, septet of d, 77.0, 3.9, MeC//Me), 2.17 (3H, d, 71.2, Me), 1.99 (3H, d, 71.2, Me), 0.92 (3H, d, 77.0, MeCHMe), 0.89 (3H, d, 77.0, MeCHM?). Consistent with lit. 189 (4S)-4-Isopropyl-3-((E)-2-methyl-2-butenoyl)-l,3-oxazolidin-2-one98 A^ 98 Prepared according to GP 18 using 7.5 mmol oxazolidinone 81 scale (Table 18). Compound 98 (1.50 g, 95%) isolated as a colourless solid, m.p. 57-58 °C (lit.95 61-62 °C), [a]D22 +100 (c 1, CHC13) (lit.95 [a]D22 +111 (c 1.3, CHC13)); 5H (250 MHz, CDC13) 6.21 (IH, qq, 77.0, 1.2, 3'-H), 4.52 (IH, ddd, 78.5, 5.5, 4.2, 4-H), 4.31 (IH, dd, 79.2, 8.5, 5-H), 4.17 (IH, dd, 79.2, 5.5, 5-H1), 2.36 (IH, septet of d, 77.0, 4.2, MeCmie), 1.91 (3H, quintet, 71.2, 2'-Me), 1.80 (3H, dq, 77.0, 1.2, 4'-H), 0.92 (3H, d, 77.0, MCHMe), 0.90 (3H, d, 77.0, MeCHM?). Consistent with lit.95 Synthesis of substrates with oxygenated sidechain (4S)-3-Chloroacetyl-4-isopropyl-l,3-oxazolidin-2-onem 113 o o o jf i) nBuLi,THF,-78 0C,15min C\^J^ A HN O —————————————————•* Nx P \_/ ii) chloroacetyl chloride N0—' -78 °C, 5 min 81 rt- 30 min 103 164 A solution of 2.48 M w-butyl lithium (24.20 ml, 60 mmol) was added to a solution of (4S)-4-isopropyl-2-oxazolidinone 81 (7.74 g, 60 mmol) in THF (150 ml) at -78 °C. After 15 min of stirring at -78 °C, chloroacetyl chloride (5.28 ml, 66 mmol) was added. The mixture was allowed to warm to room temperature and stirred for a further 30 min. The reaction was quenched with saturated NFLiCl^q) (150 ml) and the mixture extracted with ether (3 x 150 ml). The combined organic phases were washed with saturated sodium bicarbonate and brine. The organic layer was dried over MgSC>4, filtered and the solvent removed under reduced pressure to yield the crude product that was purified by silica flash column chromatography (20% EtOAc in pet. spirits 40-60) to give (4S)-3-chloroacetyl-4-isopropyl-l,3-oxazolidin-2-one 103 (9.92 g, 82%) as a colourless oil, [a]D22 +92 (c 1, CHC13) (lit. 191 [a]D25 +98 (c 1, CHC13)); 8H (250 MHz, CDC13) 4.77 (IH, d, J15.9, C//2C1), 4.70 (IH, d, J15.9, C//2C1), 4.67 (IH, dt, .77.9, 3.7, 4-H), 4.36 (IH, dd, J9.2, 7.9, 5-H), 4.28 (IH, dd, .79.2, 3.7, 5-H'), 2.43 (IH, septet of d, .77.0, 3.7, MeC/TMe), 0.94 (3H, d, .77.0, M?CHMe), 0.89 (3H, d, J7.0, MeCHM?). Consistent with lit. 191 (4S)-3-((Diethylphosphono)acetyl)-4-isopropyl-l,3-oxazolidin-2-one lQ1 1 04 140°C,3h 103 104 A mixture of (4S)-3-chloroacetyl-4-isopropyl-l,3-oxazolidin-2-one 103 (2.79 g, 13.6 mmol) and triethylphosphite (9.29 ml, 54.2 mmol) was heated to 140 °C for 3 hours. After allowing the reaction mixture to cool, silica flash column chromatography (80% EtOAc in pet. spirits 40-60) yielded (4S)-3-((diethylphosphono)acetyl)-4-isopropyl- l,3-oxazolidin-2-one 104 (3.90 g, 94%) as a colourless oil, [a]D22 +58 (c 1, CHC13); 8H (250 MHz, CDC13) 4.47 (IH, dt, .77.9, 3.7, 4-H), 4.28 (IH, dd, .78.9, 7.9, 5-H), 4.24-4.05 (5H, m, 5-H', 2 x C#2OP), 3.86 (IH, dd, .722.3, 14.0, C//2P), 3.72 (IH, dd, .722.3, 14.0, C//2P), 2.39 (IH, septet of d, /7.0, 4.0, MeC//Me), 1.33 (6H, t, /7.0, 2 x M?CH2O), 0.92 (3H, d, /7.0, M?CHMe), 0.90 (3H, d, .77.0, MeCHM?). Consistent with lit. 107 165 3-([tert-butyl(dimethyl)silyl]oxy)propan-l-or*lQ6108 i) NaH, THF rt, 45 min ii) TBSCI, rt 45 min At room temperature, 1,3-propanediol 105 (2.17 ml, 30 mmol) was added dropwise to a suspension of NaH (60% dispersion in mineral oil, 1.20 g, 30 mmol) in THF (60 ml). After 45 min, TBSCI (4.53 g, 30 mmol) in THF (10 ml) was added dropwise and the reaction mixture stirred for a further 45 min. K2CO3(aq) (10% w/v, 50 ml) was added and the mixture extracted with ether (3 x 50 ml). The combined organic layers were washed with brine, dried over MgSC>4, filtered and the solvent removed under reduced pressure to yield the crude product that was purified by silica flash column chromatography (15% EtOAc in pet. spirits 40-60) to give 3-([tert- butyl(dimethyl)silyl]oxy)propan-l-ol 106 (3.47 g, 61%) as a colourless oil; SH (250 MHz, CDC13) 3.84 (2H, t, J5.8, 1-H), 3.80 (2H, t, J5.5, 3-H), 2.58 (1H, br s, OH), 1.78 (2H, quintet, J5.8, 2-H), 0.90 (9H, s, C(M>)5), 0.08 (6H, s, Si(Me)2). Consistent with lit.108 3-([tert-butyl(dimethyl)silyl]oxy)propanalm 107 Swern oxidation 106 107 Dimethyl sulfoxide (3.78 ml, 53.4 mmol) was added dropwise to a solution of oxalyl chloride (2.33 ml, 26.7 mmol) in CH2C12 (38 ml) at -78 °C. After 45 min, 3-([tert- butyl(dimethyl)silyl]oxy)propan-l-ol 106 (3.39 g, 17.8 mmol) in CH2C12 (16 ml) was added and the mixture stirred for a further 45 min. Triethylamine (12.40 ml, 89.0 mmol) was then added dropwise and the mixture stirred for a further 30 min and then allowed to warm to room temperature. Saturated NaHCO3(aq) (50 ml) was added and the resultant mixture extracted with CH2C12 (40 ml). The organic layer was washed with brine, dried over MgSO4, filtered and the solvent removed under reduced 166 pressure to yield the crude product that was purified by silica flash column chromatography (5% EtOAc in pet. spirits 40-60) to give 3-([tert- butyl(dimethyl)silyl]oxy)propanal 107 (1.95 g, 58%) as a colourless oil; 5H (250 MHz, CDC13) 9.80 (1H, t, J2.1, 1-H), 3.98 (2H, t, 76.1, 3-H), 2.60 (2H, td, 76.1, 2.1, 2H), 0.88 (9H, s, C(M?)5), 0.06 (6H, s, Si(M?)2). Consistent with lit. 109 (4S)-3-((E)-5-([tert-butyl(dimethyl)silyl]oxy)-2-pentenoyl)-4-isopropyl-lt3- oxazolidin-2-onem 99 OOP LiCI, DIPEA TBSO MeCN, rt, o/n \_/ 107 99 A solution of (^5)-3-[(diethylphosphono)acetyl]-4-isopropyl-l,3-oxazolidin-2-one 104 (1.92 g, 6.27 mmol) in MeCN (17 ml) was added to a stirred mixture of LiCI (0.34 g, 8.15 mmol) in MeCN (45 ml) followed by diisopropylethylarnine (1.1 ml, 6.27 mmol) dropwise. Finally 3-([tert-butyl(dimethyl)silyl]oxy)propanal 107 (1.18 g, 6.27 mmol) in MeCN (15 ml) was added. The reaction mixture was stirred overnight. Brine (45 ml) was added and the mixture extracted with ether (2 x 45 ml). The combined organic layers were dried over MgSC>4, filtered and the solvent removed under reduced pressure to yield the crude product that was purified by silica flash column chromatography (10% EtOAc in pet. spirits 40-60) to give (4S)-3-(5-([tert- butyl(dimethyl)silyl]oxy)-2-pentenoyl)-4-isopropyl-l,3-oxazolidin-2-one 99 (0.67 g, 31%) as a colourless oil, [a]D21 +60 (c 1, CHC13); vmwi/cm~l 2957, 2929, 2858, 1781, 1688, 1639, 1387, 1365, 1300, 1258, 1197, 1101, 838, 777; 8H (250 MHz, CDC13) 7.32 (1H, dt, 715.6, 1.2, 2'-H), 7.15 (1H, dt, .715.6, 6.7, 3'-H), 4.50 (1H, dt, .77.9, 3.9, 4-H), 4.28 (1H, dd, 79.2, 7.9, 5-H), 4.21 (1H, dd, .79.2, 3.7, 5-Hf), 3.75 (2H, t, 76.4, 5'- H), 2.50 (2H, qd, .76.4, 1.2, 4'-H), 2.41 (1H, septet of d, 77.0, 3.9, MeC//Me), 0.93 (3H, d, 77.0, M?CHMe), 0.88 (3H, d, 77.0, MeCHM>), 0.88 (9H, s, C(Me)3\ 0.05 (6H, s, Si(M?)2); Sc (62.5 MHz, CDC13) 164.8 (C, I'-C), 154.0 (C, 2-C), 148.1 (CH, 3'-C), 121.8 (CH, 2'-C), 63.3 (CH2), 61.5 (CH2), 58.5 (CH, 4-C), 36.1 (CH2, 4'-C), 28.4 (CH, MeCHMe), 25.8 (CH3, C(M?)j), 18.2 (C, C(Me)3), 18.0 (CH3, A/eCHMe), 167 14.7 (CH3, MeCHM?), -5.4 (CH3, Si(M?)2); m/z (CI) 342 (M+H+, 20%), 359 (M+NH4+, 100%); Found M+H+, 342.2106. Ci 7H32NO4Si requires: M, 342.2101. 3-Methoxypropanal 108 Swern oxidation MeO 108 Dimethyl sulfoxide (8.50 ml, 120 mmol) was added dropwise to a solution of oxalyl chloride (5.22 ml, 60 mmol) in CH2C12 (60 ml) at -78 °C. After 45 min, 3-methoxy- propan-1-ol 102 (3.82 ml, 40 mmol) was added and the mixture stirred for a further 40 min. Triethylamine (27.82 ml, 200 mmol) was added dropwise and the mixture stirred for a further 30 min and allowed to warm to room temperature. Saturated NaHCO3(aq) (60 ml) was added and the resultant mixture was extracted with CH2C12 (60 ml). The organic layer was washed with brine, dried over MgSC>4, filtered and the solvent carefully removed under reduced pressure to yield the crude product that was purified by silica flash column chromatography (40% Et2O in pet. spirits 40-60) to give 3-methoxypropanal 108 (1.07 g, 31%) as a colourless oil; 8H (250 MHz, CDC13) 9.79 (1H, t, J1.8, 1-H), 3.73 (2H, t, J6.1, 3-H), 3.36 (3H, s, OMe), 2.67 (2H, td, J6.1, 1.8, 2-H). Consistent with lit. 192 (4S)-4-Isopropyl-3-((E)-5-methoxy-2-pentenoyl)"l,3-oxazolidin-2-one 100 i) NaH, THF, 0°C, 15 min MeO ii) reflux, 4 h 100 Sodium hydride (60% dispersion in mineral oil, 0.20 g, 5 mmol) was added to a solution of the phosphonate 104 (1.54 g, 5 mmol) in THF (10 ml) at 0 °C. After stirring for 15 min, a solution of the aldehyde 108 (1.07 g, 12 mmol) in THF (5 ml) was added and the resulting mixture was stirred at reflux for 4 hours. After cooling, the solvent was removed under reduced pressure and the residue was re-dissolved in 168 CH2C12 (10 ml), washed with water (10 ml) and the organic layer dried over MgSCU, filtered and the solvent removed under reduced pressure to yield the crude product that was purified by silica flash column chromatography (30% EtOAc in pet. spirits 40-60) to give (4S)-4-isopropyl-3-((E)-5-methoxy-2-pentenoyl)-l,3-oxazolidin-2-one 100 (1.08 g, 88%) as a colourless oil, [a]D24 +94 (c 1, CHC13); vmi0i/cm } 1771, 1687, 1634, 1389, 1365, 1204, 1118, 714; 8H (250 MHz, CDC13) 7.34 (IH, dt, .715.5, 1.2, 2'- H), 7.14 (IH, dt, J15.5, 6.7, 3'-H), 4.48 (IH, dt, /7.6, 3.7, 4-H), 4.27 (IH, dd, J9.2, 7.6, 5-H), 4.20 (IH, dd, J9.2, 3.7, 5-H'), 3.53 (2H, t, 76.4, 5'-H), 3.35 (3H, s, OMe), 2.55 (2H, qd, J6.7, 1.2, 4'-H), 2.40 (IH, septet of d, /7.0, 3.7, MeCtfMe), 0.92 (3H, d, /7.0, M?CHMe), 0.88 (3H, d, J7.0, MeCHM?); 8C (100 MHz, CDC13) 164.8 (C, l'-C), 154.0 (C, 2-C), 147.7 (CH, 3'-C), 121.8 (CH, 2'-C), 70.7 (CH2, 5'-C), 63.3 (CH2, 5-C), 58.7 (CH3, OMe), 58.5 (CH, 4-C), 32.9 (CH2, 4'-C), 28.4 (CH, MeCHMe), 18.0 (CH3, MeCHMe), 14.7 (CH3, MeCHMe); m/z (CI) 242 (M+H+, 100%), 259 (M+NH/, 91%); Found M+H+, 242.1397. Ci2H20NO4 requires: M, 242.1392. Synthesis of p-disubstituted substrate 101 Ethyl (E)-3-phenyl-2-butenoate 110 o o i} NaHl THF 0°C,15min EtO ii) acetophenone reflux, 4 h 109 110 NaH (60% dispersion in mineral oil, 3.20 g, 80 mmol) was added to a solution of triethylphosphonoacetate 109 (15.86 ml, 80 mmol) in THF (150 ml) at 0 °C. After stirring for 15 min, acetophenone (9.90 ml, 85 mmol) was added and the resulting mixture stirred at reflux for 4 hours. After cooling, the solvent was removed under reduced pressure and the residue was re-dissolved in hexane (90 ml) and washed with H2O (90 ml), brine, dried over Na2SO4, filtered and the solvent removed under reduced pressure to yield the crude product that was separated from impurities and the minor Z-isomer by silica flash column chromatography (5% Et2O in pet. spirits 40-60) to give ethyl (E)-3-phenyl-2-butenoate 110 (9.95 g, 65%) as a colourless oil; 8M (250 MHz, CDC13) 7.50-7.34 (5H, m, Ph), 6.14 (IH, q, J1.2, 2-H), 4.22 (211, q, ,77.0, 169 OC//2Me), 2.58 (3H, d, J1.2, 4-H), 1.32 (3H, t, .77.0, OCH2M>). Consistent with lit. 111 (E)-3-Phenyl-2-butenoic acid 111 O INNaOH O Pr. ^ ^OEt EtOH,75 0C,1.5h Ph 110 111 A solution of IN NaOH in H2O (104 ml, 104 mmol) was added to ethyl (£)-3-phenyl- 2-butenoate 110 (9.95 g, 52 mmol) in EtOH (100 ml) and the mixture was stirred at 75 °C for 1.5 hours. The EtOH was removed in vacua and the aqueous residue extracted with Et2O (100 ml), acidified to pH 1 with cone. HC1 and extracted with Et2O (3 x 100 ml). The combined latter organic layers were washed with H2O (200 ml), dried over MgSC>4, filtered and the solvent removed under reduced pressure to yield (E)-3-phenyl-2-butenoic acid 111 (8.19 g, 97%) as a colourless solid; SH (250 MHz, CDC13) 11.75 (1H, br s, COOH), 7.54-7.30 (5H, m, Ph), 6.19 (1H, q, J1.2, 2- H), 2.62 (3H, d, J1.2, 4-H). Consistent with lit. 193 (E)-3-Phenyl-2-butenoyl chloride 112 oxalyl chloride catDMF I O ^^ 0 c 20 mjn 111 112 The acid chloride 112 was prepared according to GP 17 using a 25 mmol acid 111 scale. 5H (250 MHz, CDC13) 7.57-7.34 (5H, m, Ph), 6.48 (1H, q, J1.2, 2-H), 2.56 (3H, d, 71 .2, 4-H). (4S)-4-Isopropyl-3-((E)-3-phenyl-2-butenoyl)-l,3-oxazolidin-2-one 101 j? i) "BuLi, THF, -78 °C, 1 5 min A A HN\ _I o n)..wcxo (E)-3-phenyl-2-butenoyl u — rr:~ — , chlorideu, -^ ph^^^N\ _ /o -78 °C, 30 min 81 0°C, 15min 170 Prepared according to GP 18 using 15 mmol oxazolidinone 81 scale. Compound 101 (3.09 g, 76%) isolated as a yellow solid, m.p. 64-66 °C, [a]D22 +104 (c 1, CHC13); Vmax/cm'1 2964, 1774, 1678, 1613, 1387, 1364, 1226, 1203, 1063, 767, 712, 696; SH (250 MHz, CDC13) 7.59-7.54 (2H, m, Ph), 7.43-7.35 (4H, m, Ph, 2f-H), 4.55 (1H, dt, .78.2, 3.4, 4-H), 4.30 (1H, dd, .79.2, 8.2, 5-H), 4.22 (1H, dd, .79.2, 3.4, 5-H1), 2.56 (3H, d, J1.5, 4'-H), 2.45 (1H, septet of d, /7.0, 3.7, MeCtfMe), 0.95 (3H, d, .77.0, M?CHMe), 0.92 (3H, d, .77.0, MeCHM?); 8C (125 MHz, CDC13) 165.3 (C, l'-C), 156.5 (C, 3'-C), 154.1 (C, 2-C), 142.3 (C, Ph), 129.2 (CH, Ph), 128.5 (CH, Ph), 126.6 (CH, Ph), 117.0 (CH, 2'-C), 63.2 (CH2, 5-C), 58.4 (CH, 4-C), 28.6 (CH, MeCHMe), 18.8 (CH3), 18.0 (CH3), 14.8 (CH3, MeCHM?); m/z (CI) 274 (M+H+, 100%), 291 (M+NHU+, 73%); Found M+H+, 274.1445. Ci6H20NO3 requires: M, 274.1443. 5.4.5.2 Hydrocyanation Hydrocyanation, with acetone cyanohydrin under Sm(O'Pr)3 catalysis, of the substrates to demonstrate the scope of substitution of the alkene was accomplished according to GP 14 under conditions given in Table 19. Spectral data for the hydrocyanated products:- 2-(2S)-Ethyl-4-((4S)-isopropyl-l,3-oxazolidin-2-one)-4-oxo-butanenitrile 1 6 1 a Diastereomer A, minor isomer CM O O 161a Compound 161a (29 mg, 12%) isolated as a colourless solid, m.p. 95-97 °C, [a]D205 +104 (c 1, CHC13); Vmax/cm'1 2969, 2937, 2879, 2242, 1782, 1701, 1391, 1210; 8H (250 MHz, CDC13) 4.47 (1H, dt, J7.9, 3.7, 4'-H), 4.33 (1H, dd, .79.2, 7.9, 5'-H), 4.25 (1H, dd, .79.2, 3.4, 5'-H'), 3.33 (1H, dd, J18.0, 9.2, 3-H), 3.16 (1H, dd, J18.0, 5.2, 3- H(), 3.06 (1H, dtd, .79.2, 7.0, 5.2, 2-H), 2.38 (1H, septet of d, .77.0, 3.7, MeC//Me), 1.72 (2H, quintet, 77.3, MeC/72), 1.13 (3H, t, J7.3, Me), 0.92 (3H, d,/7.0, AYeCHMe), 171 0.88 (3H, d, /7.0, MeCHM;); 5C (62.5 MHz, CDC13) 169.2 (C, 4-C), 154.0 (C, 2f-C), 121.2 (C, CN), 63.9 (CH2, 5'-C), 58.5 (CH, 4'-C), 38.0 (CH2, 3-C), 28.5 (CH), 28.4 (CH), 25.2 (CH2, MeCH2), 17.9 (CH3), 14.7 (CH3), 11.5 (CH3); m/z (CI) 256 (M+NH4+, 100%); Found M+NlV, 256.1662. Ci2H22N3O3 requires: M, 256.1661. Stereochemistry assigned by analogy with 79a. 2-(2R)-Ethyl-4-((4S)-isopropyl-l,3-oxazolidin-2~one)-4-oxo-butanenitrile 161b Diastereomer B, major isomer CN O O 161b Compound 161b (140 mg, 59%) isolated as a yellow oil, [a]D205 +52 (c 1, CHC13); Vmax/cm'1 2969, 2937, 2879, 2242, 1782, 1703, 1390, 1210; 8H (250 MHz, CDC13) 4.46 (IH, dt, J7.9, 3.6, 4'-H), 4.31 (IH, dd, .79.2, 7.9, 5f-H), 4.25 (IH, dd, .79.2, 3.4, 5'- Hf), 3.41 (IH, dd, J17.7, 8.5, 3-H), 3.13 (IH, dd, .717.7, 5.2, 3-H1), 3.04 (IH, m, 2-H), 2.41 (IH, septet of d, /7.0, 3.6, MeC7/Me), 1.71 (2H, quintet, .77.3, MeC/6), 1.13 (3H, t, /7.3, M?CH2), 0.92 (3H, d, J7.Q, MeCHMe), 0.89 (3H, d, .77.0, MeCHM?); 5C (62.5 MHz, CDC13) 169.3 (C, 4-C), 154.0 (C, 2f-C), 121.2 (C, CN), 63.8 (CH2, 5'-C), 58.5 (CH, 4f-C), 37.8 (CH2, 3-C), 28.5 (CH), 28.3 (CH), 25.2 (CH2, MeCH2), 17.8 (CH3), 14.6 (CH3), 11.5 (CH3); m/z (CI) 256 (M+NH4+, 100%); Found M+NH4+, 256.1653. Ci2H22N3O3 requires: M, 256.1661. Stereochemistry assigned by analogy with 79b. 4-((4S)-Isopropyl-l,3-oxazolidin-2-one)-2-(2R)-isopropyl-4-oxo-butanenitrile 125a Diastereomer A, minor isomer 125a Compound 125a (23 mg, 9%) isolated as a colourless solid, m.p. 83-84 °C, [a]D21 +116 (c 1, CHC13); vmax/cm'1 2965, 2936, 2878, 2241, 1784, 1703, 1390, 1210; 8,, 172 (250 MHz, CDC13) 4.46 (IH, dt, 77.9, 3.7, 4'-H), 4.32 (IH, dd, 79.2, 7.9, 5'-H), 4.24 (IH, dd, 79.2, 3.4, 5'-H'), 3.32 (IH, dd, 717.7, 10.1, 3-H), 3.14 (IH, dd, 717.7, 4.6, 3- H'), 3.06 (IH, m, 2-H), 2.37 (IH, septet of d, 77.0, 4.0, (Me)2C#CHN), 1.93 (IH, septet of d, 76.7, 4.9, MeC//Me), 1.10 (3H, d, 76.7, M?CHMe), 1.09 (3H, d, 76.7, MeCHM?), 0.92 (3H, d, 77.0, (M?)2CHCHN), 0.87 (3H, d, 77.0, (M?)2CHCHN); 6C (62.5 MHz, CDC13) 169.4 (C, 4-C), 154.0 (C, 2'-C), 120.1 (C, CN), 63.9 (CH2, 5'-C), 58.6 (CH, 4'-C), 36.4 (CH2, 3-C), 34.0 (CH), 30.0 (CH), 28.4 (CH, (Me)2CHCHN), 20.8 (CH3, M?CHMe), 18.6 (CH3, MeCHMe), 17.9 (CH3, (M?)2CHCHN), 14.7 (CH3, (M?)2CHCHN); m/z (CI) 270 (M+NH4+, 100%); Found M+NH4+, 270.1815. Ci3H24N3O3 requires: M, 270.1818. Stereochemistry assigned by analogy with 79a. 4-((4S)-Isopropyl-l,3-oxazolidin-2-one)-2-(2S)-isopropyl-4-oxo-butanenitrile 125b Diastereomer B, major isomer CN O O N O \l 125b *y i Compound 125b (153 mg, 61%) isolated as a colourless oil, [OJD +36 (c 1, CHC13); vmjcm l 2967, 2936, 2878, 2241, 1782, 1702, 1389, 1209; 5H (250 MHz, CDC13) 4.46 (IH, dt, 77.9, 3.7, 4'-H), 4.31 (IH, dd, 79.2, 7.9, 5'-H), 4.24 (IH, dd, 79.2, 3.7, 5'- H'), 3.41 (IH, m, 3-H), 3.15-2.95 (2H, m, 2-H, 3-Hf), 2.41 (IH, septet of d, 77.0, 4.0, (Me)2C//CHN), 1.93 (IH, septet of d, 76.7, 4.9, MeC//Me), 1.11 (3H, d, 76.7, M>CHMe), 1.10 (3H, d, 76.7, MeCHM?), 0.93 (3H, d, 77.0, (M?)2CHCHN), 0.89 (3H, d, 77.0, (M?)2CHCHN); 6C (62.5 MHz, CDC13) 169.5 (C, 4-C), 154.0 (C, 2'-C), 120.2 (C, CN), 63.8 (CH2, 5'-C), 58.6 (CH, 4'-C), 36.3 (CH2, 3-C), 34.0 (CH), 29.8 (CH), 28.3 (CH, (Me)2CHCHN), 20.8 (CH3), 18.5 (CH3), 17.8 (CH3), 14.6 (CH3); m/z (CI) 270 (M+NJV, 100%); Found M+NlV, 270.1812. C,3H24N3O3 requires: M, 270.1818. Stereochemistry assigned by analogy with 79b. 173 2-(2R)-(4-Chlorophenyl)-4-((4S)-isopropyl-l,3-oxazolidin-2-one)-4-oxo- butanenitrile 145a. Diastereomer A, minor isomer CN O 145a Compound 145a (37 mg, 12%) isolated as a colourless solid, m.p. 124-126 °C, [a]o 22 +78 (c 1, CHC13); vmax/cm } 2965, 2245, 1782, 1698, 1494, 1388, 1265, 1209, 1094, 1016, 820, 720; 8H (250 MHz, CDC13) 7.41-7.32 (4H, m, AT), 4.46 (1H, dt, 77.9, 3.4, 4f-H), 4.38 (1H, dd, 78.2, 6.4, 2-H), 4.32 (1H, dd, 79.2, 7.9, 5(-H), 4.23 (1H, dd, 79.2, 3.1, 5'-H'), 3.58 (1H, dd, 717.7, 8.2, 3-H), 3.50 (1H, dd, 717.7, 6.4, 3-H'), 2.32 (1H, septet of d, 77.0, 3.7, MeC//Me), 0.90 (3H, d, 77.0, M>CHMe), 0.80 (3H, d, 77.0, MeCHM?); 6C (62.5 MHz, CDC13) 168.4 (C, 4-C), 153.9 (C, 2f-C), 134.6 (C, Ar), 132.9 (C, Ar), 129.4 (CH, Ar), 128.9 (CH, Ar), 119.6 (C, CN), 63.9 (CH2, 5'-C), 58.6 (CH, 4'-C), 41.1 (CH2, 3-C), 32.1 (CH, 2-C), 28.4 (CH, MeCHMe), 17.8 (CH3, MeCHMe), 14.6 (CH3, MeCHM?); m/z (CI) 338 (M(35C1)+NH4+, 100%), 340 (M(37C1)+NH4+, 35%); Found M(35C1)+NH4+, 338.1277. Ci6H2iN3O335Cl requires: M, 338.1271. Found M(37C1)+NH4+, 340.1251. Ci6H2iN3O337Cl requires: M, 340.1242. Stereochemistry and structure confirmed by X-ray crystal structure. 2-(2S)-(4-Chlorophenyl)-4-((4S)-isopropyl-l,3-oxazolidin-2-one)-4-oxo- butanenitrile 145b. Diastereomer B, major isomer 145b Compound 145b (198 mg, 62%) isolated as a colourless solid, m.p. 105-107 °C, [a]D22 +40 (c 1, CHC13); vmjcm l 2966, 2246, 1781, 1703, 1493, 1388, 1266, 1209, 1094, 1017, 970, 822, 735, 720; 8H (250 MHz, CDC13) 7.38-7.31 (4H, m, Ar), 4.44- 4.34 (2H, m, 2-H, 4'-H), 4.27 (1H, dd, 79.2, 7.6, 5'-H), 4.22 (1H, dd, 79.2, 3.9, 5'-H'), 3.69 (1H, dd, 718.0, 7.9, 3-H), 3.43 (1H, dd, 718.0, 6.1, 3-Hf), 2.37 (1H, septet of d, 174 J7.0, 3.9, MeCtfMe), 0.91 (3H, d, /7.0, MeCHMe), 0.86 (3H, d, J7.0, MeCHMe); 6C (62.5 MHz, CDC13) 168.4 (C, 4-C), 153.9 (C, 2'-C), 134.5 (C, Ar), 133.1 (C, Ar), 129.4 (CH, Ar), 129.0 (CH, Ar), 119.7 (C, CN), 63.9 (CH2, 5'-C), 58.5 (CH, 4'-C), 41.1 (CH2, 3-C), 31.9 (CH, 2-C), 28.3 (CH, MeCHMe), 17.8 (CH3, MeCHMe), 14.6 (CH3, MeCHMe); m/z (CI) 338 (M(35C1)+NH4+, 100%), 340 (M(37C1)+NH4+, 50%); Found M(35C1)+NH4+, 338.1265. C ]6H21N3O335C1 requires: M, 338.1271. Found M(37C1)+NH4+, 340.1239. Ci6H2iN3O337Cl requires: M, 340.1242. Stereochemistry assigned as opposite to 145a. 4-((4S)-Isopropyl-l,3-oxazolidin-2-one)-2-(2R)-(4-methoxy-phenyl)-4-oxo- butanenitrile 162a. Diastereomer A, minor isomer MeOx 162 a Compound 162a (13 mg, 4%) isolated as a colourless oil, [a]D22 +38 (c 0.46, CHC13); Vmax/cm'1 2964, 2936, 2244, 1780, 1698, 1514, 1389, 1266, 1254, 1209, 1182, 1032, 834, 734; 6H (250 MHz, CDC13) 7.34-7.28 (2H, m, Ar), 6.93-6.87 (2H, m, Ar), 4.46 (1H, dt, J7.9, 3.4, 4'-H), 4.37-4.28 (2H, m, 2-H, 5'-H), 4.22 (1H, dd, J9.2, 3.4, 5'-H?), 3.80 (3H, s, OMe), 3.57 (1H, dd, .717.7, 8.5, 3-H), 3.48 (1H, dd, J17.7, 6.4, 3-H), 2.32 (1H, septet of d, /7.0, 3.9, MeC//Me), 0.90 (3H, d, J7.0, MeCHMe), 0.79 (3H, d, /7.0, MeCHMe); 5C (100 MHz, CDC13) 168.7 (C, 4-C), 159.6 (C, 2'-C), 153.9 (C, Ar), 128.7 (CH, Ar), 126.3 (C, Ar), 120.3 (C, CN), 114.6 (CH, Ar), 63.9 (CH2, 5'-C), 58.5 (CH, 4f-C), 55.4 (CH3, OMe), 41.4 (CH2, 3-C), 31.9 (CH, 2-C), 28.3 (CH, MeCHMe), 17.9 (CH3, MeCHMe), 14.6 (CH3, MeCHMe); m/z (CI) 334 (M+NH/, 100%); Found M+NH4+, 334.1765. Ci 7H24N3O4 requires: M, 334.1767. Stereochemistry assigned by analogy with 145a. 175 4-((4S)-Isopropyl-l,3-oxazolidin-2-one)-2-(2S)-(4-methoxy-phenyl)-4-oxo- butanenitrile 162b. Diastereomer B, major isomer MeO 162b Compound 162b (54 mg, 17%) isolated as a colourless solid, m.p. 114-116 °C, [a]D22 +44 (c 1, CHC13); vmjcm l 2965, 2938, 2244, 1781, 1702, 1514, 1389, 1254, 1209, 1182, 1032, 835, 734; 6H (250 MHz, CDC13) 7.34-7.28 (2H, m, Ar), 6.93-6.87 (2H, m, AT), 4.42 (1H, dt, /7.0, 4.3, 4'-H), 4.36-4.19 (3H, m, 2-H, 5'-H), 3.80 (3H, s, OMe), 3.68 (1H, dd, .717.7, 8.2, 3-H), 3.43 (1H, dd, J17.7, 6.1, 3-H'), 2.39 (1H, septet of d, /7.0, 3.9, MeC//Me), 0.92 (3H, d, J7.0, M?CHMe), 0.88 (3H, d, /7.0, MeCHM?); 5C (62.5 MHz, CDC13) 168.7 (C, 4-C), 159.6 (C, 2'-C), 153.9 (C, Ar), 128.7 (CH, Ar), 126.4 (C, Ar), 120.4 (C, CN), 114.5 (CH, Ar), 63.8 (CH2, 5'-C), 58.5 (CH, 4'-C), 55.3 (CH3, OMe), 41.4 (CH2, 3-C), 31.7 (CH, 2-C), 28.3 (CH, MeCHMe), 17.9 (CH3, M?CHMe), 14.7 (CH3, MeCHMe); m/z (CI) 334 (M+NH4+, 100%); Found M+NH4+, 334.1770. CiyH24N3O4 requires: M, 334.1767. Stereochemistry assigned by analogy with 145b. 2-(2-([tert-butyl(dimethyl)silyl]oxy)-ethyl)-4-((4S)-isopropyl'lf3-oxazolidin-2-one)- 4-oxo-butanenitrile 114. Single diastereomer CN O TBSO^^^^-^i i 114 \ Compound 114 (170 mg, 46%) isolated as a colourless oil, [a]D21 +46 (c 1, CHC13); Vmax/cm'1 2958, 2930, 2858, 2243, 1783, 1703, 1389, 1259, 1209, 1106, 837, 778; 6H (250 MHz, CDC13) 4.46 (1H, dt, .77.9, 3.7, 4'-H), 4.30 (1H, dd, J9.2, 7.9, 5'-H), 4.24 (1H, dd, .79.2, 3.4, 5'-H'), 3.79 (2H, dd, .76.7, 4.9, C//2OTBS), 3.48-3.12 (3H, m, 2-H, 3-H), 2.40 (1H, septet of d, J7.0, 4.0, MeC//Me), 1.97-1.75 (2H, m, TBSOCH2C//_?), 0.92 (3H, d, J7.0, MeCHMe), 0.88 (9H, s, SiCM?5), 0.88 (3H, d, 77.0, MeCHMe), 176 0.07 (3H, s, SiMe2), 0.06 (3H, s, SiMe2); 8C (62.5 MHz, CDC13) 169.2 (C, 4-C), 154.0 (C, 2'-C), 121.1 (C, CN), 63.7 (CH2, 5(-C), 59.6 (CH2, CH2OTBS), 58.4 (CH, 4'-C), 38.0 (CH2), 34.5 (CH2), 28.3 (CH, MeCHMe), 25.8 (CH3, SiCMe3), 23.7 (CH, 2-C), 18.2 (C, SiCMe3), 17.9 (CH3, MeCHMe), 14.7 (CH3, MeCHMe), -5.5 (CH3, SiMe2); m/z (CI) 369 (M+H+, 20%), 386 (M+NH/, 100%); Found M+NH/, 386.2479. Ci8H36N3O4Si requires: M, 386.2475. 4-((4S)-Isopropyl-l,3-oxazolidin-2-one)-2-(2S)-(2-methoxy-ethyl)-4-oxo- butanenitrile 163a. Diastereomer A, minor isomer MeO' 163a \ Compound 163a (48 mg, 18%) isolated as a yellow oil, [a]D24 +84 (c 1, CHC13); Vmax/cm'1 2965, 2243, 1782, 1703, 1389, 1209, 1121; 5H (250 MHz, CDC13) 4.47 (IH, dt, 77.9, 3.4, 4'-H), 4.33 (IH, dd, J9.2, 7.9, 5(-H), 4.25 (IH, dd, J9.2, 3.4, 5'-H(), 3.57 (2H, t, J5.8, MeOC//2), 3.41-3.16 (3H, m, 2-H, 3-H), 3.36 (3H, s, OMe), 2.39 (IH, septet of d, /7.0, 3.7, MeCtfMe), 1.93 (2H, q, J5.8, MeOCH2C#2), 0.92 (3H, d, J7.0, MeCHMe), 0.88 (3H, d, /7.0, MeCHMe); 8C (100 MHz, CDC13) 169.1 (C, 4-C), 154.0 (C, 2'-C), 121.1 (C, CN), 69.0 (CH2, MeOCH2), 63.9 (CH2, 5'-C), 58.8 (CH3, OMe), 58.5 (CH, 4'-C), 38.1 (CH2), 31.8 (CH2), 28.4 (CH, MeCHMe), 24.1 (CH, 2-C), 17.9 (CH3, MeCHMe), 14.7 (CH3, MeCHMe); m/z (CI) 286 (M+NH/, 100%); Found M+NH4+, 286.1769. Ci3H24N3O4 requires: M, 286.1767. Stereochemistry assigned by analogy with 79a. 4-((4S)-Isopropyl-l,3-oxazolidin-2-one)-2-(2R)-(2-methoxy-ethyl)-4-oxo- butanenitrile 163b. Diastereomer B, major isomer MeO 163b 177 Compound 163b (166 mg, 62%) isolated as a yellow oil, [a]D22 +70 (c 1, CHC13); Vmax/cm'1 2966, 2243, 1780, 1703, 1389, 1208, 1121; 5H (250 MHz, CDC13) 4.46 (1H, dt, 77.9, 3.7, 4f-H), 4.31 (1H, dd, 79.2, 7.9, 5'-H), 4.24 (1H, dd, 79.2, 3.7, 5'-H'), 3.56 (2H, t, 76.1, MeOC//2), 3.46-3.26 (2H, m, 2-H, 3-H), 3.35 (3H, s, OMe), 3.19 (1H, dd, 716.5, 4.3, 3-H(), 2.40 (1H, septet of d, 77.0, 3.7, MeC//Me), 1.93 (2H, q, 76.1, MeOCH2C//2), 0.92 (3H, d, 77.0, MeCHMe), 0.89 (3H, d, 77.0, MeCHMe); 5C (100 MHz, CDC13) 169.1 (C, 4-C), 154.0 (C, 2'-C), 121.0 (C, CN), 69.0 (CH2, MeOCH2), 63.8 (CH2, 5'-C), 58.8 (CH3, OMe), 58.5 (CH, 4'-C), 37.9 (CH2), 31.7 (CH2), 28.3 (CH, MeCHMe), 24.1 (CH, 2-C), 17.8 (CH3, MeCHMe), 14.7 (CH3, MeCHMe); m/z (CI) 286 (M+NH/, 100%); Found M+NH/, 286.1768. Ci3H24N3O4 requires: M, 286.1767. Stereochemistry assigned by analogy with 79b. 4-((4S)-Isopropyl-l,3-oxazolidin-2-one)-2,2-dimethyl-4-oxo-butanenitrile 115 CN O Q Compound 115 (143 mg, 60%) isolated as a colourless solid, m.p. 59-62 °C, [a]o21 +62 (c 0.88, CHC13); vmax/cm l 2968, 2937, 2878, 2237, 1782, 1706, 1378, 1256, 1209; 8H (250 MHz, CDC13) 4.46 (1H, dt, 77.9, 3.7, 4'-H), 4.29 (1H, dd, 79.2, 7.9, 5'- H), 4.21 (1H, dd, 79.2, 3.4, 5'-H'), 3.23 (1H, d, 717.7, 3-H), 3.14 (1H, d, 717.7, 3-H'), 2.38 (1H, septet of d, 77.0, 4.0, MeC//Me), 1.48 (3H, s, MeC(CN)Me), 1.47 (3H, s, MeC(CN)Me), 0.90 (3H, d, 77.0, MeCHMe), 0.87 (3H, d, 77.0, MeCHMe); 5C (62.5 MHz, CDC13) 168.4 (C, 4-C), 153.9 (C, 2'-C), 124.0 (C, CN), 63.6 (CH2, 5'-C), 58.3 (CH, 4'-C), 44.6 (CH2, 3-C), 29.5 (C, 2-C), 28.3 (CH, MeCHMe), 26.9 (CH3, (Me)2C(CN)), 26.7 (CH3, (Me)2C(CN)), 17.7 (CH3, MeCHMe), 14.6 (CH3, MeCHMe); m/z (CI) 256 (M+NlV, 100%); Found M+NlV, 256.1659. C,2H22N3O3 requires: M, 256.1661. 178 (2R)-4-((4S)-Isopropyl-l,3-oxazolidin-2-one)-2-methyl-2-phenyl-4-oxo butanenitrile 164a. Diastereomer A, minor isomer .CN O O 164a Compound 164a (5 mg, 2%) isolated as a yellow oil, [a]D2° +22 (c 1, CHC13); Vmax/cm'1 2964, 2240, 1778, 1706, 1389, 1373, 1251, 1206, 762, 699; 5H (250 MHz, CDC13) 7.52-7.48 (2H, m, Ph), 7.42-7.28 (3H, m, Ph), 4.33 (IH, m, 4'-H), 4.19 (2H, apparent d, J5.5, 5'-H), 3.82 (IH, d, 718.0, 3-H), 3.53 (IH, d, 718.0, 3-H'), 2.36 (IH, septet of d, 77.0, 3.7, MeC#Me), 1.84 (3H, s, Me), 0.87 (3H, d, 77.0, M?CHMe), 0.86 (3H, d, 77.0, MeCHM?); 8C (125 MHz, CDC13) 168.0 (C, 4-C), 154.1 (C, 2'-C), 139.5 (C, Ph), 129.0 (CH, Ph), 128.0 (CH, Ph), 125.3 (CH, Ph), 122.6 (C, CN), 63.7 (CH2, 5'-C), 58.5 (CH, 4'-C), 45.5 (CH2, 3-C), 39.4 (C, 2-C), 28.4 (CH3, Me), 28.3 (CH, MeCHMe), 17.9 (CH3, MeCHMe), 14.7 (CH3, MeCHMe); m/z (CI) 318 (M+NH4+, 100%); Found M+NH4+, 318.1821. C,7H24N3O3 requires: M, 318.1818. Stereochemistry assigned by analogy with 79a. (2S)-4-((4S)-Isopropyl-l,3-oxazolidin-2-one)-2-methyl-2-phenyl-4-oxo-butanenitrile 164b. Diastereomer B, major isomer O 164b Compound 153a (54 mg, 18%) isolated as a colourless solid, m.p. 94-96 °C, [ MeCHM?); 5C (125 MHz, CDC13) 168.0 (C, 4-C), 154.0 (C, 2'-C), 139.4 (C, Ph), 128.9 (CH, Ph), 127.9 (CH, Ph), 125.3 (CH, Ph), 122.7 (C, CN), 63.7 (CH2, 5'-C), 58.3 (CH, 4'-C), 45.1 (CH2, 3-C), 39.4 (C, 2-C), 28.7 (CH3, Me), 28.3 (CH, MeCHMe), 17.7 (CH3, MeCHMe), 14.5 (CH3, MeCHM?); m/z (CI) 318 (M+NH/, 100%); Found M+NH4+, 318.1815. Ci7H24N3O3 requires: M, 318.1818. Stereochemistry assigned by analogy with 79b. 4-((4S)-Isopropyl-l,3-oxazolidin-2-one)-2,3-dimethyl-4-oxo-butanenitrile 116 CN O O V_y 116 A 47 : 53 mixture of two inseparable diastereomers (16 mg, 7%). Colourless oil; Vmax/cm'1 2967, 2243, 1779, 1699, 1389, 1207; 5H (250 MHz, CDC13) 4.46 (IH, dt, J7.6, 3.4, 4'-H), 4.34-4.20 (2H, m, 5f-H), 4.02 (0.47H, quintet, .77.3, 3-H (minor diastereomer)), 3.86 (0.53H, quintet, J7.3, 3-H (major diastereomer)), 3.08 (0.47H, quintet, /7.3, 2-H (minor diastereomer)), 2.97 (0.53H, quintet, .77.3, 2-H (major diastereomer)), 2.36 (IH, m, MeCHMe), 1.44-1.26 (6H, m, Me, CH(M?)CO), 0.93- 0.84 (6H, m, MeCHMe); 5C (62.5 MHz, CDC13) 173.5 (C, 4-C (one diastereomer)), 173.4 (C, 4-C (one diastereomer)), 153.6 (C, 2(-C (one diastereomer)), 153.4 (C, 2'-C (one diastereomer)), 121.4 (C, CN (one diastereomer)), 121.2 (C, CN (one diastereomer)), 63.5 (CH2, 5'-C (one diastereomer)), 63.4 (CH2, 5'-C (one diastereomer)), 58.7 (CH, 4'-C (one diastereomer)), 58.3 (CH, 4'-C (one diastereomer)), 41.2 (CH, 3-C (one diastereomer)), 40.7 (CH, 3-C (one diastereomer)), 28.2 (CH, (both diastereomers)), 28.1 (CH, (both diastereomers)), 17.9 (CH3, (one diastereomer)), 17.8 (CH3, (one diastereomer)), 16.8 (CH3, (one diastereomer)), 16.1 (CH3, (one diastereomer)), 15.0 (CH3, (one diastereomer)), 14.8 (CH3, (one diastereomer)), 14.6 (CH3, (one diastereomer)), 14.5 (CH3, (one diastereomer)); m/z (CI) 256 (M+NH4+, 100%); Found M+NH4+, 256.1652. Ci2H22N3O3 requires: M, 256.1661. 180 Spectral data of by-products produced in the hydrocyanation of a,|3-unsaturated N- acyl oxazolidinones by acetone cyanohydrin under Sm(O'Pr)3 catalysis (GP 14, Table 19) (see also Section 5.3). Isopropyl (E)-4-chloro-cinnamate 68c Compound 68c (38 mg, 17%) isolated as a yellow oil; vmjcm l 3443, 2979, 1711, 1638, 1492, 1309, 1272, 1203, 1175, 1108, 1099, 1013, 983, 914, 823; 8H (250 MHz, CDC13) 7.61 (IH, d, .716.1, 3-H), 7.48-7.43 (2H, m, AT), 7.38-7.32 (2H, m, AT), 6.39 (IH, d, .716.1, 2-H), 5.14 (IH, septet, .76.4, MeC/TMe), 1.31 (6H, d, J6.4, MeCHMe); 8C (62.5 MHz, CDC13) 166.2 (C, 1-C), 142.8 (CH, 3-C), 136.0 (C, Ar), 133.0 (C, Ar), 129.1 (CH, Ar), 119.4 (CH, 2-C), 67.9 (CH, MeCHMe), 21.9 (CH3, MeCRMe); m/z (CI) 242 (M(35C1)+NH4+, 100%), 244 (M(37C1)+NH4+, 35%); Found M(35C1)+NH4+, 242.0947. Ci2Hi7NO235Cl requires: M, 242.0948. Isopropyl (E)-4-methoxy-cinnamate 68d 68d Compound 68d (9 mg, 4%) isolated as a yellow oil; 5H (250 MHz, CDC13) 7.62 (IH, d, .715.9, 3-H), 7.50-7.44 (2H, m, Ar), 6.92-6.87 (2H, m, Ar), 6.28 (IH, d, .715.9, 2-H), 5.13 (IH, septet, J6.1, MeC/TMe), 3.83 (3H, s, OMe), 1.25 (6H, d, .76.1, MeCHMe). Consistent with lit. 194 Acetone cyanohydrin ester of2-(4-methoxyphenyl)-4-oxo-butanenitrile 69b MeO 69b 181 Compound 69b (8 mg, 3%) isolated as a colourless oil, [a]D22 +2 (c 0.31, CHC13); Vmax/cm'1 2959, 2933, 2245, 2211, 1788, 1751, 1613, 1514, 1254, 1182, 1137; SH (250 MHz, CDC13) 7.31-7.25 (2H, m, Ar), 6.94-6.88 (2H, m, Ar), 4.24 (IH, t, J7.6, 2-H), 3.81 (3H, s, OMe), 3.02 (IH, dd, J16.5, 7.6, 3-H), 2.85 (IH, dd, J16.5, 7.6, 3-H1), 1.76 (3H, s, M?C(CN)Me), 1.69 (3H, s, MeC(CN)M?); Sc (100 MHz, CDC13) 167.3 (C, 4- C), 159.8 (C, Ar), 128.5 (CH, Ar), 125.7 (C, Ar), 119.7 (C, CN), 118.7 (C, CN), 114.7 (CH, Ar), 69.5 (C, MeC(CN)Me), 55.4 (CH3, OMe), 40.1 (CH2, 3-C), 32.3 (CH, 2-C), 26.8 (CH3, M?C(CN)Me), 26.6 (CH3, MeC(CN)M?); m/z (CI) 290 (M+NlV, 100%); Found M+NH/, 290.1515. Ci5H20N3O3 requires: M, 290.1518. Isopropyl (E)-5-([tert-butyl(dimethyl)silyl]oxy)-2-pentenoate68e TBSO 68e Compound 68e (13 mg, 5%) isolated as a colourless oil; vmax/cm } 1719, 1257, 1175, 1109, 836; 8H (250 MHz, CDC13) 6.93 (IH, dt, J15.9, 7.0, 3-H), 5.84 (IH, dt, J15.9, 1.5, 2-H), 5.06 (IH, septet, J6.4, MeC//Me), 3.72 (2H, t, J6.7, 5-H), 2.40 (2H, qd, J6.7, 1.5, 4-H), 1.25 (6H, d, J6.4, MeCHMe}, 0.89 (9H, s, SiCM^), 0.05 (6H, s, SiM?2); 8C (125 MHz, CDC13) 166.0 (C, 1-C), 145.4 (CH, 3-C), 123.5 (CH, 2-C), 67.4 (CH, MeCHMe), 61.6 (CH2, 5-C), 35.7 (CH2, 4-C), 25.9 (CH3, SiCM?5), 21.9 (CH3, MeCHMe), 18.3 (C, SiCMe3), -5.4 (CH3, SiM?2); m/z (CI) 290 (M+NH4+, 100%); Found M+NH4+, 290.2147. Ci4H32NO3Si requires: M, 290.2151. Isopropyl (E)-5-methoxy-2-pentenoate 68f Compound 68f (18 mg, 10%) isolated as a colourless oil; vmax/cm l 2981, 1716, 1657, 1272, 1195, 1179, 1111; 8H (250 MHz, CDC13) 6.92 (IH, dt, J15.6, 7.0, 3-H), 5.86 (IH, dt, .715.6, 1.5, 2-H), 5.04 (IH, septet, J6.4, MeC//Me), 3.49 (2H, t, J6.4, 5-H), 182 3.34 (3H, s, OMe), 2.46 (2H, qd, J6.7, 1.5, 4-H), 1.25 (6H, d, J6.4, MeCHMe); §c (100 MHz, CDC13) 165.9 (C, 1-C), 145.2 (CH, 3-C), 123.4 (CH, 2-C), 70.7 (CH2, 5- C), 67.5 (CH, MeCHMe), 58.7 (CH3, OMe), 32.4 (CH2, 4-C), 21.8 (CH3, MeCHMe); m/z (CI) 190 (M+NH4+, 100%); Found M+NlV, 190.1436. C9H2oNO3 requires: M, 190.1443. Isopropyl (E)-3-phenyl-2-butenoate 68g O Ph' ^c>^ Compound 68g (32 mg, 15%) isolated as a colourless oil; vmax/cm'} 2979, 1711, 1630, 1273, 1173, 1110, 766, 695; 8H (250 MHz, CDC13) 7.50-7.33 (5H, m, Ph), 6.11 (1H, q, J1.2, 2-H), 5.11 (1H, septet, J6.4, MeC//Me), 2.58 (3H, s, 4-H), 1.30 (6H, d, J6.4, MeCHMe); 8C (125 MHz, CDC13) 166.4 (C, 1-C), 155.0 (C), 142.3 (C), 128.9 (CH, Ph), 128.4 (CH, Ph), 126.3 (CH, Ph), 117.8 (CH, 2-C), 67.0 (CH, MeCHMe), 22.0 (CH3, MeCHMe), 17.9 (CH3, 4-C); m/z (CI) 205 (M+H+, 100%), 222 (M+NlV, 69%); Found M+H+, 205.1224. Ci3Hi7O2 requires: M, 205.1229. Acetone cyanohydrin ester of2,3-dimethyl-4-oxo-butanenitrile 117a Diastereomer A, major isomer CN ° J 117a Compound 117a (24 mg, 13%) isolated as a colourless oil; vmax/cm'1 2244, 1750, 1 140; 6H (250 MHz, CDC13) 3.03 (1H, quintet, J7.3, 2-H), 2.62 (1H, quintet, J7.3, 3- H), 1.79 (6H, s, MeC(CN)Me\ 1.40 (3H, d, /7.3, Me), 1.36 (3H, d, J7.3, Me); 6C (62.5 MHz, CDC13) 171.1 (C, 4-C), 120.4 (C, CN), 118.8 (C, CN), 69.3 (C, MeC(CN)Me), 42.7 (CH, 3-C), 28.6 (CH, 2-C), 26.8 (CH3, M?C(CN)Me), 26.6 (CH3, MeC(CN)Me), 16.3 (CH3), 14.7 (CH3); m/z (CI) 212 (M+NH4+, 100%); Found M+NH4+, 212.1402. C, 0Hi 8N3O2 requires: M, 212.1399. 183 Acetone cyanohydrin ester of2,3-dimethyl-4-oxo-butanenitrile 117b Diastereomer B, minor isomer CN O LCN ^^\ nib Compound 117b (12 mg, 6%) isolated as a colourless oil; vma}i/cm l 2991, 2244, 1747, 1137; 5H (250 MHz, CDC13) 2.98 (IH, m, 2-H), 2.75 (IH, m, 3-H), 1.79 (6H, s, M?C(CN)M?), 1.35 (3H, d, 77.0, Me), 1.34 (3H, d, 77.3, Me); 5C (125 MHz, CDC13) 170.6 (C, 4-C), 120.6 (C, CN), 118.8 (C, CN), 69.3 (C, MeC(CN)Me), 42.1 (CH, 3- C), 28.1 (CH, 2-C), 26.8 (CH3, M?C(CN)Me), 26.6 (CH3, MeC(CN)M>), 14.6 (CH3), 13.7 (CH3); m/z (CI) 212 (M+NlV, 100%); Found M+NlV, 212.1396. C 10H18N3O2 requires: M, 212.1399. (S)-4-Isopropyl-2-oxazolidinone 8 1 O If HN O \_7 81 Colourless solid, m.p. 64-66 °C (lit. 195 69-70 °C), [a]D22 +4 (c 1, CHC13) (lit.75 [a]D +15 (c 7, CHC13)); 5H (250 MHz, CDC13) 6.62 (IH, br s, NH), 4.44 (IH, t, 78.5, 5-H), 4.10 (IH, dd, 78.5, 6.1, 5-H(), 3.60 (IH, dt, 78.5, 6.1, 4-H), 1.72 (IH, octet, 76.7, MeC#Me), 0.95 (3H, d, 76.7, MeCHMe), 0.89 (3H, d, 76.7, MeCHM?). Consistent with lit. 195 184 5.4.6 Investigation of mechanism Cyanation of (^5)-3-((£)-2-butenoyl)-4-isopropyI-l,3-oxazolidin-2-one 75 with TMSCN under Sm(O'Pr)3 catalysis in the presence of IPA O O 10%Sm(O'Pr)3 CN O O + 2TMSCN ——————————— ^ toluene rt, 40 min 75 79 Sm((yPr)3 (33 mg, 0.1 mmol) was weighed out in a nitrogen atmosphere glove box and transferred, under an atmosphere of nitrogen, to a fume hood where toluene (1 ml) was added followed by (4S)-3-((£)-2-butenoyl)-4-isopropyl-l,3-oxazolidin-2-one 75 (197 mg, 1 mmol) and TMSCN (266 ul, 2 mmol). The reaction mixture was stirred at room temperature for 40 min. IPA (153 ul, 2 mmol) was added and the reaction stirred for a further 5 min, the mixture diluted with ether (5 ml) and filtered through Celite. The solvent was removed under reduced pressure to yield the crude products that were purified by silica flash column chromatography (20% EtOAc in pet. spirits 40-60) to give 4-((4S)-isopropyl-l,3-oxazolidin-2-one)-2-methyl-4-oxo- butanenitrile, minor diastereomer 79a (36 mg, 16%), major diastereomer 79b (109 mg, 49%), 25 : 75 dr. 185 5.4.7 Auxiliary cleavage 5.4.7.1 Hydrolytic cleavage of auxiliary Representive procedure of hydrolytic auxiliary cleavage with LiOH (R)-3-Cyano-butyric acid111 121b CN O ° LiOH.H2O O j^ THF-H20 CN -10°C,1h ^^^OH \—J y 79b \ 121b \ 81 A solution of 4-((^5)-isopropyl-l,3-oxazolidin-2-one)-2-(2J/?)-methyl-4-oxo- butanenitrile 79b (112 mg, 0.5 mmol) in THF (1.25 ml) was cooled to -10 °C and treated with a solution of LiOH.H2O (30 mg, 0.71 mmol) in H2O (1 ml). Upon completion of the reaction after 1 hour, the THF was removed in vacuo and the aqueous residue was extracted with CH2C12 (3x5 ml). The CH2C12 layer was dried over Na2SO4 and the solvent removed in vacuo to yield the crude product, which was purified by silica flash column chromatography (60% EtOAc in pet. spirits 40-60) to give (S)-4-isopropyl-2-oxazolidinone 81 (39 mg, 61%) as a colourless solid which was consistent with previous characterisation and lit. 195 The aqueous residue was acidified with 2 M HC1 to pH 1 and extracted with EtOAc (3 x 5 ml). The EtOAc layer was dried over Na2SO4 and the solvent removed in vacuo to yield (R)-3-cyano-butyric acid 121b (49 mg, 87%) as a colourless oil, [a]o21 -22 (c 1, CHC13); Vmax/cm'1 3235, 2943, 2247, 1735, 1412, 1197; 5H (250 MHz, CDC13) 8.86 (1H, br s, OH), 3.09 (1H, sextet, 77.0, 3-H), 2.80 (1H, dd, 717.1, 7.3, 2-H), 2.61 (1H, dd, 717.1, 6.7, 2-H1), 1.41 (3H, d, 77.0, 4-H); 8C (62.5 MHz, CDC13) 175.2 (C, 1-C), 121.5 (C, CN), 37.8 (CH2, 2-C), 21.5 (CH, 3-C), 17.6 (CH3, 4-C); m/z (CI) 131 (M+NH4+, 100%); Found M+NH4+, 131.0817. C5HnN2O2 requires: M, 131.0820. 186 Hydrolytic cleavage of the benzyl auxiliary LiOH.H2O CN O O THF-H20 Ph CN O HN A0 -10°C OH AXOH \_y Ph— ' Ph—' 1h20min H SOI) 121b 83 122 A similar reaction with 4-((4S)-beiizyl-l,3-oxazolidin-2-one)-2-(2^)-methyl-4-oxo- butanenitrile 80b (109 mg, 0.4 mmol) yielded (R)-3-cyano-butyric acid 121b (35 mg, 77%) which was consistent with previous characterisation and (S)-4-benzyl-2- oxazolidinone 83 (40 mg, 61%) as a colourless solid, m.p. 81-83 °C (lit. 196 90-91 °C), [a]D205 -70 (c 1, CHC13) (lit. 196 [a]D30 -62 (c 1, CHC13)); 8H (250 MHz, CDC13) 7.38- 7.25 (3H, m, Ph), 7.20-7.15 (2H, m, Ph), 5.35 (IH, br s, NH), 4.47 (IH, t, /7.9, 5-H), 4.19-4.03 (2H, m, 4-H, 5-H1), 2.87 (2H, d, J7.0, CH2Ph). Consistent with lit. 196 Also the endocyclic cleavage product isolated from the CH2C12 extract, 3-cyano-N-((S)-l- hydroxymethyl-2-phenyl-ethyl)-3-methyl-propionamide 122 (1 mg, 1%) as an oil; Vmax/cm'1 3418, 2246, 1650, 1553, 1454, 1095, 1043, 701; 6H (250 MHz, CDC13) 7.36-7.20 (5H, m, Ph), 5.81 (IH, br s, NH), 4.22 (IH, m, NCH), 3.74-3.56 (2H, m, C//2OH), 3.15 (IH, sextet, /7.3, CHCN), 2.90 (2H, d, J1.3, CH2Ph), 2.54 (IH, dd, J14.6, 7.0, C//2CO), 2.35 (IH, dd, J14.9, 7.3, C//2CO), 2.15 (IH, br s, OH), 1.35 (3H, d, /7.3, Me); 8C (125 MHz, CDC13) 168.6 (C, CO), 137.3 (C, Ph), 129.2 (CH, Ph), 128.7 (CH, Ph), 126.8 (CH, Ph), 122.2 (C, CN), 63.7 (CH2, CH2OH), 52.8 (CH, NCH), 40.3 (CH2), 37.0 (CH2), 22.2 (CH, CHCN), 17.7 (CH3); m/z (CI) 247 (M+H+, 100%); Found M+H+, 247.1442. Ci4Hi9N2O2 requires: M, 247.1447. Hydrolytic cleavage of the sultam auxiliary LiOH.H2O CN CN O THF-H2O OH 0 °C, 3h 92 121 87 A similar reaction with 4-((-)-A^-bornane-10,2-sultam)-2-methyl-4-oxo-butanenitrile 92 (-85:15 dr mixture of inseparable diastereomers, 93 mg, 0.3 mmol) yielded 3- 187 cyano-butyric acid 121 (mixture of enantiomers, 32 mg, 93%), [a]D21 +10 (c 1, CHCls), which was consistent with previous characterisation and (lS,2R)-(-)-2,10- camphorsultam 87 (59 mg, 91%) as a colourless solid; 5H (250 MHz, CDC13) 4.21 (IH, d, J6.4, NH), 3.41 (IH, m, C//NH), 3.13 (IH, d, .714.0, C//2SO2), 3.07 (IH, d, J14.0, C#2SO2), 2.03-1.79 (5H, m), 1.48-1.24 (2H, m), 1.12 (3H, s, Me), 0.92 (3H, s, Me). Consistent with lit. 197 (R)-4-Amino-3-methylbutanoic acid hydrochloride 16 123 10%P«02 OH H20, HCI ^ v OH rt, 112 h 121b 123 -3-Cyano-butyric acid 121b (37 mg, 0.33 mmol) was combined with PtO2 (7.5 mg, 0.03 mmol), H2O (5 ml) and cone. HCI (0.5 ml). The flask was evacuated and refilled with hydrogen three times and the reaction allowed to stir vigorously at room temperature and pressure under hydrogen for 112 hours. The reaction mixture was filtered through celite washing with H2O (5 ml), washed with CH2C12 (10 ml) and the water removed in vacua to yield (R)-4-amino-3-methylbutanoic acid hydrochloride 123 (45 mg, 88%). 5H (250 MHz, DMSO-d6) 12.20 (IH, br s, COOH), 7.88 (3H, br s, NH3), 2.87-2.58 (2H, m, 4-H), 2.41 (IH, m), 2.19-2.06 (2H, m), 0.94 (3H, d, J6.1, Me). Consistent with lit.198 5.4.7.2 Reductive auxiliary cleavage Representative procedure of reductive auxiliary cleavage with NaBILi120 (S)-4-Hydroxy-2-isopropyl-butanenitrile 126b CN O ft O U THF-H20 CN jl N 0 + 4 NaBH4 —————————- ^ I . + HN -J rt,2.5h 125b 126b 81 A solution of NaBH4 (61 mg, 1.6 mmol) in H2O (0.4 ml) was added to a solution of 4- ((4S)-isopropyl- 1 ,3-oxazolidin-2-one)-2-(21S)-isopropyl-4-oxo-butanenitrile 125b (101 mg, 0.4 mmol) in THF (1.2 ml) at rt and at a rate to keep the internal temperature at 20-25 °C. Upon completion of the reaction, 2 M HC1 was added (1 ml), and the mixture extracted with EtOAc (3x5 ml). The combined organic layers were washed with brine, dried over Na2SC>4 and the solvent removed in vacua to yield the crude product, which was purified by silica flash column chromatography (30% EtOAc in pet. spirits 40-60) to give (S)-4-kydroxy-2-isopropyl-butanenitrile 126b (41 mg, 80%) as a colourless oil. The ee was determined to be 98.5% by chiral GC (y-TA column, 95 °C isotherm, tr(minor) = 39.4 min, tr(major) = 41.3 min); [a]D22 -34 (c 1, CHC13); Vmax/cm"1 3440, 2965, 2935, 2877, 2239, 1467, 1426, 1392, 1374, 1051, 760 ; 6H (250 MHz, CDC13) 3.89-3.74 (2H, m, 4-H), 2.74 (1H, m, 2-H), 1.96-1.71 (4H, m, 3-H, OH, MeC/flVIe), 1.08 (3H, d, J6.7, MeCHMe), 1.05 (3H, d, J6.7, MeCHM?); 8C (100 MHz, CDC13) 121.0 (C, CN), 59.7 (CH2, 4-C), 35.3 (CH), 32.7 (CH2, 3-C), 30.0 (CH), 20.9 (CH3, MeCHMe), 18.5 (CH3, MeCHM?); m/z (CI) 145 (M+NlV, 100%); Found M+NlV, 145.1337. C7Hi7N2O requires: M, 145.1341. The flash column also yielded (S)-4-isopropyl-2-oxazolidinone 81 (37 mg, 71%) as a colourless solid which was consistent with previous characterisation and lit. l95 Reductive auxiliary cleavage with Me ^-substitution120 (R)-4-Hydroxy-2-methyl-butanenitrile 1 24 CN O ft O A THF-H20 CN Jl O +4NaBH4 —————————— + HN O rt,3.5h Ph— •" Ph— •' 80b 124 83 A similar reaction with 4-((4S)-benzyl-l,3-oxazolidm-2-one)-2-(2/?)-methyl-4-oxo- butanenitrile 80b (109 mg, 0.4 mmol) yielded (R)-4-hydroxy-2-methyl-butanenitrile 124 (10 mg, 33%) as a yellow oil, [a]D2° -48 (c 1, CHC13); v^/cm'1 3398, 2940, 2884, 2244, 1459, 1081, 1052; 8H (250 MHz, CDC13) 3.81 (2H, t, J6.1, 4-H), 2.90 (1H, m, 2-H), 1.93-1.72 (3H, m, 3-H, OH), 1.35 (3H, d, J7.0, Me); 5C (100 MHz, CDC13) 122.8 (C, CN), 59.5 (CH2, 4-C), 36.4 (CH2, 3-C), 22.0 (CH, 2-C), 17.9 (CH3, 189 Me); m/z (CI) 117 (M+NH4+, 25%); Found M+NH4+, 117.1023. C5Hi3N2O requires: M, 117.1028. The flash column also yielded (S)-4-benzyl-2-oxazolidinone 83 (57 mg, 80%) as a colourless solid which was consistent with previous characterisation and lit. 196 5.4.7.3 Nitrite hydrogenation with auxiliary cleavage General procedure for the hydrogenation of 4-((4S)-isopropyl-l,3-oxazolidin-2- one)-2-(2tf)-meth\ l-4-oxo-butanenitrile 79b (as used in Table 20) (GP 19) CN O catalyst EtOH rt and pressure \ -^^ \— / 79b 127 81 128 A solution of 4-((4S)-isopropyl-l,3-oxazolidin-2-one)-2-(2ft)-methyl-4-oxo- butanenitrile 79b (112 mg, 0.5 mmol) in EtOH was added to the catalyst (Pd/C or Raney Ni or PtC>2 (0.05 mmol)) at room temperature under N2. The flask was evacuated and refilled with hydrogen three times and the reaction allowed to stir vigorously at room temperature and pressure under hydrogen. Upon completion, the reaction mixture was filtered through celite washing with EtOAc. The filtrate was concentrated under reduced pressure to yield the crude product that was purified by increasing gradient silica flash column chromatography (80% EtOAc in pet. spirits 40-60 then 100% EtOAc then 30% acetone in EtOAc) to give the products shown in Table 20. (R)-4-Methylpyrrolidin-2-one 127 127 190 Under PtO2 catalysis, compound 127 (34 mg, 69%) obtained as a colourless solid, m.p. 49-51 °C, [a]D21 +28 (c 1, CHC13) (lit.199 [a]D +30 (c 1.1, CHC13)); 5H (250 MHz, CDC13) 6.39 (IH, br s, NH), 3.50 (IH, dd, 79.5, 7.9, 5-H), 2.96 (IH, dd, 79.5, 6.1, 5- H1), 2.62-2.40 (2H, m, 3-H, 4-H), 1.94 (IH, dd, 716.7, 6.7, 3-H'), 1.13 (3H, d, 76.7, Me). Consistent with lit.152 (4S)-Isopropyl-3-(3-(3R)-methyl-4-(N-4-(4R)-methylpyrrolidin-2-one)-l-oxo- butane)-oxazolidin-2-one 128 Under PtO2 catalysis, compound 128 (2.7 mg, 1.7%) obtained as a colourless oil, [a]D22 +74 (c 1, CHC13); vmax/cm l 2962, 2930, 1779, 1688, 1388, 1208; 8H (250 MHz, CDC13) 4.44 (IH, dt, 78.2, 3.4, 4-H), 4.27 (IH, dd, 78.9, 8.2, 5-H), 4.19 (IH, dd, 78.9, 3.0, 5-H'), 3.49 (IH, dd,79.4, 7.6), 3.24 (IH, dd, 713.7, 7.6), 3.17 (IH, dd, 713.7, 6.7), 3.08-2.99 (2H, m), 2.71-2.28 (5H, m), 2.03 (IH, dd, 715.9, 6.4), 1.12 (3H, d, 76.7), 0.96 (3H, d, 76.7), 0.91 (3H, d, 77.0, M?CHMe), 0.87 (3H, d, 77.0, MeCHM?); 5C (125 MHz, CDC13) 175.0 (C, CO), 172.0 (C, CO), 153.9 (C, 2-C), 63.3 (CH2, 5-C), 58.4 (CH, 4-C), 55.0 (CH2, CH2N), 48.2 (CH2, CH2N), 40.1 (CH2CO), 39.4 (CH2CO), 28.6 (CH), 28.4 (CH), 26.6 (CH), 19.7 (CH3), 18.0 (CH3), 17.5 (CH3, M?CHMe), 14.6 (CH3, MeCHM?); m/z (CI) 311 (M+H+, 100%), 328 (M+NlV, 12%); Found M+H+, 311.1986. C16H27N204 requires: M, 311.1971. (R)-4-Amino-3-methylbutanoic acid hydrochloride 123 6N HCI HCI.H2N 100°C,11.5h 127 123 191 A solution of 6N HCl(aq) (0.25 ml) was added to (7?)-4-methylpyrrolidin-2-one 127 (55 mg, 0.55 mmol) and the reaction mixture was heated at 100 °C for 11.5 hours. After cooling, F^O (3 ml) was added and the aqueous layer washed with Cl^Cfe (3 ml). The water was removed in vacua to yield (R)-4-amino-3-methylbutanoic acid hydrochloride 123 (68 mg, 80%) as a colourless solid; 6H (250 MHz, DMSO-d6) 12.24 (1H, br s, COOH), 7.93 (3H, br s, NH3), 2.87-2.58 (2H, m, 4-H), 2.41 (1H, m), 2.19-2.06 (2H, m), 0.94 (3H, d, J6.1, Me); 6C (125 MHz, DMSO-d6) 173.1 (C, 1-C), 43.6 (CH2), 38.1 (CH2), 28.3 (CH, 3-C), 17.1 (CH3, Me). Consistent with lit. 198 192 5.5 Drug Molecule Synthesis 5.5.1 Pregabalin Synthesis of substrate 113 for hydrocyanation-Method A Ethyl (E)-5-methyl-2-hexenoate200 139 i) NaH, THF O O 0°C, 15min OEt EtO ii) isovaleraldehyde OEt reflux, 3 h 109 139 NaH (60% dispersion in mineral oil, 1.20 g, 30 mmol) was added to a solution of triethylphosphonoacetate 109 (5.95 ml, 30 mmol) in THF (70 ml) at 0 °C. After stirring for 15 min, isovaleraldehyde (9.64 ml, 90 mmol) was added and the resulting mixture was stirred at reflux for 3 hours. After cooling, the solvent was removed under reduced pressure, the residue re-dissolved in hexane (30 ml) and washed with H2O (30 ml), brine, dried over Na2SC>4, filtered and the solvent removed under reduced pressure to yield the crude product that was purified by silica flash column chromatography (5% EtOAc in pet. spirits 40-60) to give ethyl (E)-5-methyl-2- hexenoate 139 (3.62 g, 77%) as a colourless oil; 8H (250 MHz, CDC13) 6.94 (IH, dt, J15.6, 7.3, 3-H), 5.80 (IH, dt, J15.6, 1.5, 2-H), 4.18 (2H, q, J7.3, OC//2), 2.09 (2H, td, .77.3, 1.5, 4-H), 1.76 (IH, nonet, .76.7, 5-H), 1.29 (3H, t, .77.3, Me), 0.92 (6H, d, J6.4, MeCHMe). Consistent with lit.200 (E)-5-Methyl-2-hexenoic acid200 140 INNaOH OEt EtOH, rt, 3 h 139 140 A solution of IN NaOH in H2O (45 ml, 45 mmol) was added to ethyl (£)-5-methyl-2- hexenoate 139 (3.52 g, 22.5 mmol) in EtOH (50 ml) and the mixture was stirred at 193 room temperature for 3 hours. The EtOH was removed in vacua and the aqueous residue was diluted with H2O (30 ml), acidified to pH 1 with IN HC1 and extracted with EtOAc (3 x 60 ml). The combined organic layers were dried over Na2SC>4, filtered and the solvent removed under reduced pressure to yield (E)-5-methyl-2- hexenoic acid 140 (2.09 g, 73%) as a colourless oil; vmax/cm l 3071, 2961, 2677, 2553, 1699, 1651, 1422, 1314, 1285, 986; 5H (250 MHz, CDC13) 11.60 (1H, br s, COOH), 7.06 (1H, dt, 715.6, 7.6, 3-H), 5.82 (1H, dt, 715.6, 1.5, 2-H), 2.13 (2H, td, 77.3, 1.5, 4-H), 1.79 (1H, nonet, 76.7, 5-H), 0.93 (6H, d, 76.7, MeCUMe); 8C (62.5 MHz, CDC13) 172.3 (C, 1-C), 151.3 (CH, 3-C), 121.7 (CH, 2-C), 41.5 (CH2, 4-C), 27.7 (CH, 5-C), 22.3 (CH3, M?CHM>); m/z (CI) 146 (M+NHU+, 100%); Found M+NlV, 146.1178. C7Hi6NO2 requires: M, 146.1181. (E)-5-Methyl-2-hexenoyl chloride 141 oxalyl chloride O cat. DMF i O OH 0°C,20min ^ v ^ CI 140 141 The acid chloride 141 was prepared according to GP 17 using a 16 mmol acid 140 scale. 5H (250 MHz, CDC13) 7.20 (1H, dt, 715.3, 7.6, 3-H), 6.07 (1H, dt, 715.3, 1.2, 2- H), 2.18 (2H, ddd, 77.6, 6.7, 1.2, 4-H), 1.84 (1H, nonet, 76.7, 5-H), 0.96 (6H, d, 76.7, MeCHMe). (4S)-4-Isopropyl-3-((E)-5-methyl-2-hexenoyl)-l,3-oxazolidin-2-one 113 9 i) nBuLi,THF,-78 0C ./\. HN. O ii) (E)-5-methyl-2-hexenoyl chloride » , -78 °C, SOmin 81 0°C,15min Prepared according to GP 18. Compound 113 (2.09 g, 87%) isolated as a colourless oil, [a]D22 +88 (c 1, CHC13); vmax/cm ] 2960, 2929, 1779, 1687, 1634, 1387, 1366, 1334, 1203, 716; 5,, (250 MHz, CDC13) 7.30-7.07 (2H, m, 2'-H, 3'-H), 4.49 (1H, dt. 194 .77.9, 3.7, 4-H), 4.28 (1H, dd, J9.2, 7.9, 5-H), 4.21 (1H, dd, J9.2, 3.7, 5-H'), 2.41 (1H, septet of d, .77.0, 4.0, (Me)2C//CHN), 2.17 (2H, td, J7.3, 0.9, 4'-H), 1.80 (1H, nonet, J6.7, 5'-H), 0.94 (3H, d, J6.7, M?CHMe), 0.94 (3H, d, J6.7, MeCHM?), 0.93 (3H, d, ,77.0, (M?)2CHCHN), 0.89 (3H, d, /7.0, (M?)2CHCHN); 5C (62.5 MHz, CDC13) 165.0 (C, I'-C), 154.0 (C, 2-C), 150.5 (CH, 3f-C), 121.3 (CH, 2'-C), 63.3 (CH2, 5-C), 58.5 (CH, 4-C), 41.8 (CH2, 4'-C), 28.5 (CH), 27.9 (CH), 22.3 (CH3), 18.0 (CH3), 14.7 (CH3); m/z (CI) 257 (M+NlV, 100%), 240 (M+H+, 30%); Found M+NlV, 257.1864. C 13H25N2O3 requires: M, 257.1865. Method B106 (4S)-4-Isopropyl-3-((E)-5-methyl-2-hexenoyl)-l,3-oxazolidin-2-one 113 o o LiCI, DIPEA Eto '; r -N—' ~ MeCN, rt, 21 h 104 113 The phosphonate 104 (see Section 5.4.5.1) (614 mg, 2.0 mmol) in MeCN (5.5 ml) was added to a stirred mixture of LiCl (109 mg, 2.6 mmol) in MeCN (15 ml) followed by diisopropylethylamine (347 pi, 2.0 mmol) dropwise. Finally isovaleraldehyde (428 pi, 4.0 mmol) in MeCN (5 ml) was added. The reaction mixture was stirred for 21 hours. Brine (15 ml) was added and the mixture extracted with ether (2x15 ml). The combined organic layers were dried over MgSC>4, filtered and the solvent removed under reduced pressure to yield the crude product that was purified by silica flash column chromatography (20% EtOAc in pet. spirits 40-60) to give (4S)-4-isopropyl- 3-((E)-5-methyl-2-hexenoyl)-l,3-oxazolidin-2-one 113 (386 mg, 81%) as a colourless oil which was consistent with previous characterisation. 195 Hydrocyanation of 113 with acetone cyanohydrin under Sm(O'Pr)3 catalysis 10%Sm(O'Pr)3 CN O O acetone cyanohydrin X^X^X^XX^N^^C toluene, rt, 1 h — v_y 142 Hydrocyanation of 113 was accomplished according to GP 14. The crude products were purified by flash column chromatography (15% EtOAc in pet. spirits 40-60) to yield 142a (25 mg, 9%) and 142b (175 mg, 66%). 4-((4S)-Isopropyl-l,3-oxazolidin-2-one)-2-(2S)-(2-methyl-propyl)-4-oxo- butanenitrile 142a. Diastereomer A, minor diastereomer 142a * Colourless oil, [a]D22 +92 (c 1, CHC13); vmax/cm } 2962, 2242, 1783, 1703, 1390, 1209; 8H (250 MHz, CDC13) 4.46 (1H, dt, 77.9, 3.7, 4'-H), 4.32 (1H, dd, 79.2, 7.9, 5'- H), 4.24 (1H, dd, 79.2, 3.4, 5'-H'), 3.31 (1H, dd, 718.6, 10.1, 3-H), 3.19-3.07 (2H, m, 2-H, 3-Hf), 2.37 (1H, septet of d, 77.0, 3.7, (Me)2C//CHN), 1.88 (1H, m, MeC//Me), 1.70 (1H, ddd, 713.4, 9.8, 4.9, C//2CHCN), 1.35 (1H, ddd, 713.4, 9.2, 4.3, C//2CHCN), 0.97 (3H, d, 76.7, M?CHMe), 0.96 (3H, d, 76.7, MeCHM?), 0.92 (3H, d, 77.0, (M?)2CHCHN), 0.87 (3H, d, 77.0, (Me)2CHCHN); 6C (62.5 MHz, CDC13) 169.2 (C, 4-C), 154.0 (C, 2'-C), 121.4 (C, CN), 63.9 (CH2, 5'-C), 58.6 (CH, 4'-C), 40.7 (CH2), 38.7 (CH2), 28.4 (CH), 26.1 (CH), 25.1 (CH), 22.9 (CH3, M?CHMe), 21.3 (CH3, MeCHM?), 17.9 (CH3, (Me)2CHCHN), 14.7 (CH3, (Mg)2CHCHN); m/z (CI) 284 (M+NlV, 100%); Found M+NH4+, 284.1978. Ci4H26N3O3 requires: M, 284.1974. Stereochemistry was assigned by analogy to 79a and confirmed by subsequent conversion to the known lactam 133a. 196 4-((4S)-Isopropyl-l,3-oxazolidin-2-one)-2-(2R)-(2-methyl-propyl)-4-oxo- butanenitrile 142b. Diastereomer B, major diastereomer CN O O 142b Colourless oil, [a]D22 +62 (c 1, CHC13); v^/cm'1 2962, 2242, 1783, 1703, 1390, 1209; 8H (250 MHz, CDC13) 4.41 (IH, dt, J7.9, 3.7, 4'-H), 4.26 (IH, dd, J9.2, 7.9, 5'- H), 4.19 (IH, dd, J9.2, 3.4, 5'-H'), 3.33 (IH, dd, J19.5, 9.8, 3-H), 3.14-3.01 (2H, m, 2- H, 3-H(), 2.34 (IH, septet of d, 77.0, 3.9, (Me)2C//CHN), 1.82 (IH, m, MeCT/Me), 1.64 (IH, ddd, J13.4, 10.0, 4.9, C//2CHCN), 1.31 (IH, ddd, J13.4, 9.5, 5.2, C//2CHCN), 0.92 (3H, d, J6.4, M?CHMe), 0.91 (3H, d, J6.4, MeCHM?), 0.87 (3H, d, .77.0, (M?)2CHCHN), 0.83 (3H, d, J7.0, (Me)2CHCHN); 5C (62.5 MHz, CDC13) 169.2 (C, 4-C), 154.0 (C, 2'-C), 121.4 (C, CN), 63.8 (CH2, 5f-C), 58.5 (CH, 4f-C), 40.7 (CH2), 38.5 (CH2), 28.3 (CH), 26.1 (CH), 25.1 (CH), 22.8 (CH3, MeCHMe), 21.2 (CH3, MeCHA/e), 17.8 (CH3, (M?)2CHCHN), 14.6 (CH3, (Me)2CHCHN); m/z (CI) 284 (M+NH4+, 100%); Found M+NlV, 284.1971. Ci4H26N3O3 requires: M, 284.1974. Stereochemistry was assigned by analogy to 79b and confirmed by subsequent conversion to the known lactam 133b. Auxiliary cleavage and product manipulation to Pregabalin (R)-4-Isobutylpyrrolidin-2-one 133b CN O EtOH, rt 70h 142b 133b 81 A solution of 4-((^5)-isopropyl-l,3-oxazolidin-2-one)-2-(2^)-(2-methyl-propyl)-4- oxo-butanenitrile 142b (266 mg, 1 mmol) in EtOH (30 ml) was added to platinum oxide (23 mg, 0.1 mmol) at room temperature under N2. The flask was evacuated and 197 refilled with hydrogen three times and the reaction allowed to stir vigorously at room temperature and pressure under hydrogen for 70 hours. Upon completion, the reaction mixture was filtered through Celite, washing with EtOAc and the filtrate concentrated under reduced pressure to yield the crude products that were purified by silica flash column chromatography (40% EtOAc in pet. spirits 40-60 increasing to 70% then 100% EtOAc) to give starting material 142b (28 mg, 11%) and (S)-4- isopropyl-2-oxazolidinone 81 (109 mg, 84%) as a colourless solid which was consistent with previous characterisation and lit. 195 Also (R)-4-isobutylpyrrolidin-2-one 133b (104 mg, 75%) as a colourless oil. The ee was determined to be 96% by chiral HPLC (AD column, 3% IPA in hexane, 26 °C, 1 ml/min, 215 nm, tr(minor) = 16.5 min, tr(major) = 18.0 min); [a]D24 +2 (c 1, CHC13) (lit. 121 [a]D +2 (c 1.1, CHC13)); 8H (250 MHz, CDC13) 6.00 (IH, br s, NH), 3.47 (IH, dd, J9.2, 7.9, 5-H), 2.99 (IH, dd, .79.2, 7.0, 5-H'), 2.64-2.36 (2H, m, 3-H, 4-H), 1.98 (IH, dd, .716.5, 8.5, 3-Hf), 1.58 (IH, nonet, .77.0, MeC//Me), 1.35 (2H, t, ,77.6, C/72CH(Me)2), 0.91 (3H, d, J6.7, MeCHMe), 0.90 (3H, d, .76.7, MeCHM?). Consistent with lit. 121 (S)-4-Isobutylpyrrolidin-2-one 133a CN O O 10%R09 9 ft . HN^O EtOH, rt 86 h 142a x 133a x x 81 A similar reaction of the minor diasteromer 142a (100 mg, 0.4 mmol) yielded starting material 142a (20 mg, 20%) and (S)-4-isopropyl-2-oxazolidinone 81 (29 mg, 60%) as a colourless solid which was consistent with previous characterisation and lit. 195 Also (S)-4-isobutylpyrrolidin-2-one 133a (37 mg, 69%) as a colourless oil, [a]D24 -2 (c 1, CHC13) (lit. 121 for enantiomer [a]D +2 (c 1.1, CHC13)). The ee was determined to be >99% by chiral HPLC (AD column, 3% IPA in hexane, 26 °C, 1 ml/min, 215 nm, tr(major) = 15.8 min) and was consistent with previous characterisation and lit. 121 for the enantiomer. 198 (R)-3-Aminomethyl-5-methyl-hexanoic acid (ent Pregabalin) hydrochloride.•jJ29 8b 133b A mixture of (J/?)-4-isobutylpyrrolidin-2-one 133b (65 mg, 0.5 mmol) and 4N HCl(aq) (5 ml) was heated at 125 °C for 20 hours. After cooling, H2O (5 ml) was added and the mixture was extracted with CH2C12 (3x5 ml). The aqueous layer was shaken with activated charcoal, filtered through Celite and the water removed in vacuo to give (R)-3-aminomethyl-5-methyl-hexanoic acid hydrochloride 8b (86 mg, 95%) as a colourless hygroscopic solid, [a]D24 -6 (c 1, H2O) (lit. 16 for enantiomer [a]D24 +7 (c 1.03, H2O)); 5H (250 MHz, DMSO-d6) 12.20 (1H, br s, COOH), 7.91 (3H, br s, NH), 2.75 (2H, t, J6.7, C/fcN), 2.39 (1H, dd, .716.1, 6.7, 2-H), 2.22 (1H, dd, J16.1, 6.7, 2- H1), 2.08 (1H, septet, J6.7, 3-H), 1.60 (1H, nonet, J6.7, 5-H), 1.27-1.04 (2H, m, 4-H), 0.86 (3H, d, J6.7, M?CHMe), 0.84 (3H, d, J6.7, MeCHM?). Consistent with lit. 16'129 The ee was established to be 96% by re-closure201 of the acid to the lactam 133b which showed retention of ee by chiral HPLC. The acid 8b (10 mg) was heated with NaOH(aq) (10% w/v, 0.5 ml) at 90 °C for 6 hours. Upon cooling, the reaction mixture was diluted with H2O (5 ml) and extracted with CH2C12 (3 x 5ml). The solvent of the combined organic layers was removed under reduced pressure to give crude (R)-4- isobutylpyrrolidin-2-one 133b which was analysed by chiral HPLC and shown to have retained its ee (96%). (S)-3-Aminomethyl-5-methyl-hexanoic acid (Pregabalin) hydrochloride129 8a o H 4N HCI HCI.H2NX Q 125 °C, 20 h A 133a A similar reaction of (S)-4-isobutylpyrrolidin-2-one 133a (18 mg, 0.13 mmol) yielded (S)-3-aminomethyl-5-methyl-hexanoic acid hydrochloride 8a (26 mg, 100%) as a 199 colourless hygroscopic solid, [a]D24 +8 (c 1, H2O) (lit. 16 [a]D24 +7 (c 1.03, H2O)); 6H (250 MHz, DMSO-d6) 2.75 (2H, d, J6.1, C#2N), 2.36 (IH, dd, .715.9, 6.1, 2-H), 2.21 (IH, dd, J15.9, 6.1, 2-Hf), 2.05 (IH, septet, J6.1, 3-H), 1.59 (IH, nonet, .76.7, 5-H), 1.25-1.04 (2H, m, 4-H), 0.85 (3H, d, J6.7, MeCHMe), 0.84 (3H, d, J6.7, MeCHM?). Consistent with lit.16'129 200 5.5.2 Baclofen Synthesis of substrate 96 for hydrocyanation (E)-4-Chloro-cinnamoyl chloride 144 oxalyl chloride cat. DMF 0°C, 20min 143 Acid chloride 144 prepared according to GP 17. See Section 5.4.5.1 for characterisation. (4S)-3-((E)-4-Chloro-cinnamoyl)-4-isopropyl-l,3-oxazolidin-2-one96 O i) nBuLi,THF, -78 °C jf HN O i) (E)-4-chloro-cinnamoyl chloride V_7 -78 °C, 30 min 81 0°C, 15 min Prepared according to GP 18. Compound 96 (2.65 g, 90%) isolated as a colourless solid. See Section 5.4.5.1 for characterisation. Hydrocyanation of 96 with acetone cyanohydrin under Sm(O'Pr)3 catalysis 10%Sm(O'Pr)3 acetone cyanohydrin toluene, rt, 23.5 h Hydrocyanation of 96 was accomplished according to GP 14. The crude products were purified by silica flash column chromatography (15% EtOAc in pet. spirits 40- 60) to yield 145a (37 mg, 12%) and 145b (198 mg, 62%). See Section 5.4.5.2 for characterisation of hydrocyanated products. 201 Auxiliary cleavage and product manipulation to Baclofen (S)-4-(4-Chlorophenyl)pyrrolidin-2-onel45202 146b NaBH4 NiCI2.6H2O MeOH, rt 1.75h 145b 146b 81 NaBILj (148 mg, 4 mmol) was added in four portions to a stirred solution of 2-(2S)- (4-chlorophenyl)-4-((4S)-isopropyl-1,3 -oxazolidin-2-one)-4-oxo-butanenitrile 145b (128 mg, 0.4 mmol) and NiCl2.6H2O (190 mg, 0.8 mmol) in MeOH (3 ml) at room temperature. After stirring for 1.75 hours, the reaction mixture was filtered through Celite washing with MeOH and CHCls. The filtrate was concentrated under reduced pressure to yield the crude products that were purified by silica flash column chromatography (40% EtOAc in pet. spirits 40-60 increasing to 70% then 100% EtOAc) to give (S)-4-isopropyl-2-oxazolidinone 81 (28 mg, 53%) as a colourless solid which was consistent with previous characterisation and lit. 195 Also (S)-4-(4- chlorophenyl)pyrrolidin-2-one 146b (40 mg, 51%) as a colourless solid. The ee was determined to be 99% by chiral HPLC (AD column, 4% IPA in hexane, 27 °C, 0.8 ml/min, 230 nm, tr(minor) = 29.6 min, tr(major) = 34.1 min); m.p. 110-112 °C (lit. 137 112 °C), [a]D22 +38 (c 1, EtOH) (lit. 137 for enantiomer [a]D -39 (c 1, EtOH)); 6H (250 MHz, CDC13) 7.33-7.17 (4H, m, AT), 6.40 (1H, br s, NH), 3.82-3.61 (2H, m, 4-H, 5- H), 3.38 (1H, dd, J9.2, 7.0, 5-H'), 2.74 (1H, dd, J16.8, 8.5, 3-H), 2.45 (1H, dd, J16.8, 8.5, 3-H'). Consistent with lit for enantiomer. 137 202 (R)-4-(4-Chlorophenyl)pyrrolidin-2-onel452()2 146si O NaBH4 NiCI2.6H2O HN \_y\ MeOH, rt 1.5 h 145a 146a 81 Cl NaBH4 (148 mg, 4 mmol) was added in four portions to a stirred solution of 2- (4-chlorophenyl)-4-((^,S)-isopropyl-l,3-oxazolidin-2-one)-4-oxo-butanenitrile 145a (120 mg, 0.37 mmol) and NiCl2.6H2O (190 mg, 0.8 mmol) in MeOH (3 ml) at room temperature. After stirring for 1.5 hours, saturated NaHCOs^q) (3 ml) was added and the reaction mixture extracted with CHCb (3x10 ml). The combined organic layers were washed with brine (30 ml) and concentrated under reduced pressure to yield the crude products that were purified by silica flash column chromatography (50% EtOAc in pet. spirits 40-60 increasing to 70% then 100% EtOAc) to give (S)-4-isopropyl-2- oxazolidinone 81 (34 mg, 70%) as a colourless solid which was consistent with previous characterisation and lit. 195 Also (R)-4-(4-chlorophenyl)pyrrolidin-2-one 146a (46 mg, 64%) as a colourless solid. The ee was determined to be 99% by chiral HPLC (AD column, 4% IPA in hexane, 27 °C, 0.8 ml/min, 230 nm, tr(major) = 29.2 min, tr(minor) = 35.2 min); m.p. 110-112 °C (lit.137 112 °C), [a]D19 -44 (c 1, EtOH) (lit. 137 [a]D -39 (c 1, EtOH)); 5H (250 MHz, CDC13) 7.34-7.17 (4H, m, AT), 5.97 (IH, br s, NH), 3.82-3.62 (2H, m, 4-H, 5-H), 3.38 (IH, dd, 78.9, 6.7, 5-H1), 2.74 (IH, dd, 717.0, 8.9, 3-H), 2.45 (IH, dd, 717.0, 8.5, 3-Hf). Consistent with lit.137 and previous characterisation of enantiomer. (S)-4-Amino-3-(4-chlorophenyl)butanoic acid ((S)-Baclofen) hydrochloride145 15b HCI.H2N 4N HCI ' ° 100°C, 24.5 h 15b 146b 203 A mixture of (S)-4-(4-chlorophenyl)pyrrolidin-2-one 146b (23 mg, 0.12 mmol) and 4N HCl(aq) (0.75 ml) was heated at 100 °C for 24.5 hours. After cooling, the water was removed in vacuo to yield the crude product which was triturated with cold IPA to give (S)-4-amino-3-(4-chlorophenyl)butanoic acid hydrochloride 15b (29 mg, 98%) as a colourless solid, m.p. 190-192 °C (lit. 146 195 °C), [a]D22 +2 (c 1, H2O) (lit. 146 for enantiomer [a]D2° -2 (c 0.6, H2O)); 8H (250 MHz, D2O) 7.24 (2H, d, J8.5, AT), 7.14 (2H, d, J8.5, Ar), 3.28-2.99 (3H, m, 4-H, 5-H), 2.63 (1H, dd, J15.9, 5.8, 3- H), 2.51 (1H, dd, J15.9, 8.9, 3-H'); 5C (125 MHz, D2O) 179.1 (C, 2-C), 140.1 (C, Ar), 136.2 (C, Ar), 132.3 (CH, Ar), 132.1 (CH, Ar), 46.5 (CH2), 42.6 (CH, 4-C), 41.9 (CH2). Consistent with lit. for enantiomer. 146'162 The ee was established to be 99% by re-closure of the acid to the lactam 146b which showed retention of ee by chiral HPLC. The acid 15b (6 mg) was heated with NaOH(aq) (10% w/v, 0.5 ml) at 90 °C for 6 hours. Upon cooling, the reaction mixture was diluted with H2O (5 ml) and extracted with CH2C12 (3 x 5ml). The solvent of the combined organic layers was removed under reduced pressure to give crude (S)-4-(4- chlorophenyl)pyrrolidin-2-one 146b which was analysed by chiral HPLC and shown to have retained its ee (99%). 204 5.5.3 Rolipram Synthesis of substrate 147 for hydrocyanation 3-Cyclopentyloxy-4-methoxybenzaldehyde29 148 K2CO3, DMF H + Br 100°C, 1.75h 149 148 Potassium carbonate (16.56 g, 120 mmol) and cyclopentylbromide were added successively to a solution of isovanillin 149 (6.08 g, 40 mmol) in dry DMF (120 ml). The mixture was stirred at 100 °C for 1.75 hours, cooled to room temperature, saturated NH4Cl(aq) (200 ml) added and stirred for a further 10 minutes. The mixture was extracted with EtOAc (3 x 150 ml) and the organic extracts washed with water (2 x 50 ml), dried over MgSC>4, filtered and the solvent removed under reduced pressure to yield 3-cyclopentyloxy-4-methoxybenzaldehyde 148 (8.80 g, 100%) as a yellow oil; 5H (250 MHz, CDC13) 9.83 (1H, s, CHO), 7.44-7.39 (2H, m, 6-H, 2-H), 6.96 (1H, d, J8.2, 5-H), 4.85 (1H, m, ArOC#), 3.92 (3H, s, OMe), 2.07-1.55 (8H, m, cyclopentyl). Consistent with lit.29 (4S)-3-((E)-3-(3-Cyclopentyloxy-4-methoxy-phenyl)-propenoyl)-4-isopropyl-l,3- oxazolidin-2-one 147 i) NaH, THF, O 0°C, 15min ————————i ii) reflux, 25.5 h MeO Sodium hydride (60% dispersion in mineral oil, 0.20 g, 5 mmol) was added to a solution of the phosphonate 104 (see Section 5.4.5.1) (1.54 g, 5 mmol) in THF (10 ml) at 0 °C. After stirring for 15 min, a solution of the aldehyde 148 (1.10 g, 5 mmol) in THF (5 ml) was added and the resulting mixture was stirred at reflux for 25.5 205 hours. After cooling, the solvent was removed under reduced pressure and the residue was re-dissolved in CH2C12 (10 ml), washed with water (10 ml) and the organic layer dried over MgSC>4, filtered and the solvent removed under reduced pressure to yield the crude product that was purified by silica flash column chromatography (10% EtOAc in pet. spirits 40-60) to give (4S)-3-((E)-3-(3-cyclopentyloxy-4-methoxy- phenyl)-propenoyl)-4-isopropyl-l,3-oxazolidin-2-one 147 (1.13 g, 61%) as a sticky yellow solid, [a]D24 +74 (c 1, CHC13); vmjcm l 1774, 1677, 1614, 1593, 1511, 1365, 1260, 1202, 1137, 131, 847, 805, 699; 8H (250 MHz, CDC13) 7.80 (2H, s, 2'-H, 3'-H), 7.20-7.14 (2H, m, AT), 6.86 (1H, d, 78.2, Ar), 4.82 (1H, m, ArOCfl), 4.56 (1H, dt, 78.2, 3.7, 4-H), 4.31 (1H, dd, .78.9, 8.2, 5-H), 4.24 (1H, dd, 78.9, 3.7, 5-H'), 3.88 (3H, s, OMe), 2.46 (1H, septet of d, 77.0, 3.7, MeCtfMe), 2.06-1.55 (8H, m, cyclopentyl), 0.95 (3H, d, 77.0, MeCHMe), 0.92 (3H, d, 77.0, MeCHM?); 6C (125 MHz, CDC13) 165.4 (C, l'-C), 154.3 (C), 152.6 (C), 147.9 (C), 146.5 (CH, 3f-C), 127.6 (C, Ar), 123.0 (CH), 114.6 (CH), 114.0 (CH), 111.6 (CH), 80.7 (CH, ArOCH), 63.4 (CH2, 5- C), 58.7 (CH, 4-C), 56.0 (CH3, OMe), 32.8 (CH2, cyclopentyl), 28.6 (CH, MeCHMe), 24.1 (CH2, cyclopentyl), 18.0 (CH3, M?CHMe), 14.8 (CH3, MeCHM?); m/z (CI) 374 (M+H+, 100%); Found M+H+, 374.1970. C2 iH28NO5 requires: M, 374.1967. Hydrocyanation of 147 with acetone cyanohydrin under Sm(O'Pr)3 catalysis 10%Sm(O'Pr)3 acetone cyanohydrin toluene, 50 °C MeO 147 Method A:- Sm(O'Pr)3 (33 mg, 0.1 mmol) was weighed out in a nitrogen atmosphere glove box and transferred, under an atmosphere of nitrogen, to a fume hood where a solution of 147 (373 mg, 1 mmol) in toluene (1 ml) was added followed by commercial acetone cyanohydrin (182 ul, 2 mmol). The reaction mixture was stirred at 50 °C for 18 hours, the mixture diluted with ether (5 ml) and filtered through Celite. The solvent was removed under reduced pressure to yield the crude products that were purified by 206 silica flash column chromatography (20% EtOAc in pet. spirits 40-60) to yield starting material 147 (22 mg, 6%), 150a (32 mg, 8%), 150b (180 mg, 46%) and the isopropyl ester 68h (61 mg, 20%). Method B:- Sm(O'Pr)3 (33 mg, 0.1 mmol) was weighed out in a nitrogen atmosphere glove box and transferred, under an atmosphere of nitrogen, to a fume hood where acetone cyanohydrin (182 ul, 2 mmol) and toluene (0.25 ml) were added followed by a solution of 147 (373 mg, 1 mmol) in toluene (0.75 ml). The reaction mixture was stirred at 50 °C for 24.5 hours, the mixture diluted with ether (5 ml) and filtered through Celite. The solvent was removed under reduced pressure to yield the crude products that were purified by silica flash column chromatography (20% EtOAc in pet. spirits 40-60) to yield starting material 147 (31 mg, 9%), 150a (69 mg, 18%), 150b (213 mg, 57%) and the isopropyl ester 68h (2 mg, 1%). 2-(2R)-(3-Cyclopentyloxy-4-methoxy-phenyl)-4-((4S)-isopropyl-l,3-oxazolidin-2- one)-4-oxo-butanenitrile 150a. Diastereomer A, minor diastereomer 150a Yellow oil, [a]D19 +72 (c 1, CHC13); vmjcm l 2694, 2244, 1782, 1699, 1516, 1389, 1258, 1209, 1141; 5H (250 MHz, CDC13) 6.93-6.81 (3H, m, Ar), 4.78 (1H, m, ArOC/f), 4.46 (1H, dt, J8.2, 3.7, C//N), 4.35-4.20 (3H, m, 2-H, C//2O), 3.83 (3H, s, OMe), 3.54 (2H, d, .77.9, 3-H), 2.32 (1H, septet of d, J7.0, 3.7, MeC//Me), 2.04-1.50 (8H, m, cyclopentyl), 0.90 (3H, d, ,77.0, MeCHMe), 0.79 (3H, d, J7.0, MeCHM?); 6C (125 MHz, CDC13) 168.7 (C, 4-C), 153.9 (C, NCOO), 150.1 (C, Ar), 148.1 (C, Ar), 126.6 (C, Ar), 120.3 (C, CN), 119.6 (CH, Ar), 114.1 (CH, Ar), 112.3 (CH, Ar), 80.6 (CH, ArOCH), 63.8 (CH2, CH2O), 58.5 (CH, NCH), 56.1 (CH3, OMe), 41.3 (CH2, 3- C), 32.7 (CH2, cyclopentyl), 32.2 (CH, 2-C), 28.3 (CH, MeCHMe), 24.0 (CH2, cyclopentyl), 17.8 (CH3, MeCHMe), 14.6 (CH3, MeCHM?); m/z (CI) 418 (M+NH4+, 207 100%); Found M+NH4+, 418.2333. C22H32N3O5 requires: M, 418.2342. Stereochemistry was assigned by analogy to 145a and confirmed by subsequent conversion to the known lactam 14a. 2-(2S)-(3-Cyclopentyloxy-4-methoxy-phenyl)-4-((4S)-isopropyl-l,3-oxazolidin-2- one)-4-oxo-butanenitrile 150b. Diastereomer B, major diastereomer 150b Yellow oil, [a]D19 +34 (c 1, CHC13); vmjcm l 2693, 2245, 1782, 1699, 1514, 1388, 1258, 1209, 1141; 8H (250 MHz, CDC13) 6.91-6.80 (3H, m, Ar), 4.78 (IH, m, ArOC//), 4.41 (IH, dt, 77.3, 4.0, C//N), 4.33-4.19 (3H, m, 2-H, C//2O), 3.82 (3H, s, OMe), 3.67 (IH, dd, .717.7, 8.5, 3-H), 3.43 (IH, dd, 717.7, 6.1, 3-H?), 2.38 (IH, septet of d, 77.0, 4.0, MeC/fMe), 2.03-1.53 (8H, m, cyclopentyl), 0.91 (3H, d, 77.0, MeCHMe), 0.87 (3H, d, 77.0, MeCHM?); 8C (125 MHz, CDC13) 168.6 (C, 4-C), 153.8 (C, NCOO), 150.0 (C, Ar), 148.1 (C, Ar), 126.6 (C, Ar), 120.3 (C, CN), 119.7 (CH, Ar), 114.0 (CH, Ar), 112.2 (CH, Ar), 80.6 (CH, ArOCH), 63.7 (CH2, CH2O), 58.4 (CH, NCH), 56.0 (CH3, OMe), 41.3 (CH2, 3-C), 32.7 (CH2, cyclopentyl), 32.0 (CH, 2- C), 28.3 (CH, MeCHMe), 23.9 (CH2, cyclopentyl), 17.8 (CH3, MeCHMe), 14.6 (CH3, MeCHM?); m/z (CI) 418 (M+NlV, 35%); Found M+NH4+, 418.2327. C22H32N3O5 requires: M, 418.2342. Stereochemistry was assigned by analogy to 145b and confirmed by subsequent conversion to the known lactam 14b. Isopropyl (E)-3-(3-cyclopentyloxy-4-methoxy-phenyl)-2-propenoate 68h Me0' ~ 68h 208 Yellow oil; vmax/cm l 2695, 1704, 1634, 1596, 1512, 1304, 1260, 1176, 1137, 1109, 992; 5H (250 MHz, CDC13) 7.59 (1H, d, J15.9, 3-H), 7.08-7.04 (2H, m, 6(-H, 2'-H), 6.83 (1H, d, J8.2, 5'-H), 6.25 (1H, d, J15.9, 2-H), 5.12 (1H, septet, J6.1, MeCtfMe), 4.78 (1H, m, ArOC//), 3.85 (3H, s, OMe), 2.03-1.54 (8H, m, cyclopentyl), 1.30 (6H, d, J6.1, MeCHMe)', 8C (100 MHz, CDC13) 166.8 (C, 1-C), 152.0 (C, Ar), 147.7 (C, Ar), 144.4 (CH, 3-C), 127.3 (C, Ar), 122.2 (CH), 116.1 (CH), 113.2 (CH), 111.5 (CH), 80.4 (CH, ArOCH), 67.5 (CH, MeCHMe), 55.9 (CH3, OMe), 32.7 (CH2, cyclopentyl), 24.0 (CH2, cyclopentyl), 21.9 (CH3, MeCHMe); m/z (CI) 305 (M+H+, 100%); Found M+H+, 305.1766. Ci8H25O4 requires: M, 305.1753. Auxiliary cleavage to Rolipram (S)-4-(3-Cyclopentyloxy-4-methoxy-phenyl)pyrrolidin-2-one ((S)-Rolipram) }45'202 14b NaBH4 NiCI2.6H2O MeOH, rt 2.5 h 150b 14b OMe NaBH4 (111 mg, 3 mmol) was added in four portions to a stirred solution of 2-(2S)- (3 -cyclopentyloxy-4-methoxy-phenyl)-4-((4S)-isopropyl-1,3 -oxazolidin-2-one)-4- oxo-butanenitrile 150b (120 mg, 0.3 mmol) and NiCl2.6H2O (143 mg, 0.6 mmol) in MeOH (3 ml) at room temperature. After stirring for 2.5 hours, Na2CO3(aq) (10% w/v, 3 ml) was added and the reaction mixture extracted with CHC13 (3 x 10 ml). The combined organic layers were washed with brine (30 ml) and concentrated under reduced pressure to yield the crude products that were purified by silica flash column chromatography (100% EtOAc) to give (S)-4-isopropyl-2-oxazolidinone 81 (35 mg, 90%) as a colourless solid which was consistent with previous characterisation and lit. 195 and (S)-4-(3-cyclopentyloxy-4-methoxy-phenyl)pyrrolidin-2-one 14b (64 mg, 77%) as a colourless solid. The ee was determined to be >99% by chiral HPLC (AD column, 2% IPA in hexane, 27 °C, 1 ml/min, 254 nm, tr(minor) = 49.9 min, tr(major) = 54.3 min); m.p. 133-135 °C (lit."152 132 °C), [a]D 21 +30 (c 1, MeOH) (lit. 152~ for 209 enantiomer [a]D -31 (c 1.15, MeOH)); 5H (250 MHz, CDC13) 6.84-6.75 (3H, m, AT), 6.17 (IH, br s, NH), 4.77 (IH, m, ArOC//), 3.83 (3H, s, OMe), 3.75 (IH, t, 78.2, 5- H), 3.63 (IH, quintet, 78.2, 4-H), 3.38 (IH, dd, 78.8, 7.0, 5-H1), 2.71 (IH, dd, 717.1, 8.5, 3-H), 2.47 (IH, dd, 717.1, 8.5, 3-Hf), 1.98-1.55 (8H, m, cyclopentyl); 8C (100 MHz, CDC13) 177.7 (C, 2-C), 149.2 (C, AT), 147.9 (C, Ar), 134.5 (C, Ar), 118.8 (CH, AT), 113.8 (CH, Ar), 112.2 (CH, Ar), 80.6 (CH, ArOCH), 56.1 (CH3, OMe), 49.7 (CH2, 5-H), 40.0 (CH, 4-H), 38.1 (CH2, 3-H), 32.8 (CH2, cyclopentyl), 24.0 (CH2, cyclopentyl). Consistent with lit. for enantiomer.152 (R)-4-(3-Cyclopentyloxy-4-methoxy-phenyl)pyrrolidin-2-one ((R)-Rotipram) l452()2 14a NaBH4 O If NiCI2.6H2O HN O MeOH, rt 2h 150a 81 A similar reaction with 2-(2^)-(3-cyclopentyloxy-4-methoxy-phenyl)-4-((4S)- isopropyl-l,3-oxazolidin-2-one)-4-oxo-butanenitrile 150a (102 mg, 0.26 mmol) yielded (R)-4-(3-cyclopentyloxy-4-methoxy-phenyl)pyrrolidin-2-one 14a (49 mg, 70%) as a colourless solid. The ee was determined to be >99% by chiral HPLC (AD column, 2% IPA in hexane, 27 °C, 1 ml/min, 254 nm, tr(major) = 51.8 min); m.p. 132- 134 °C (lit. 152 132 °C), [a]D22 -30 (c 1, MeOH) (lit. 152 [a]D -31 (c 1.15, MeOH)); 8H (250 MHz, CDC13) 6.84-6.75 (3H, m, Ar), 6.20 (IH, br s, NH), 4.77 (IH, m, ArOC//), 3.83 (3H, s, OMe), 3.75 (IH, t, 78.5, 5-H), 3.63 (IH, quintet, 78.5, 4-H), 3.38 (IH, dd, 78.8, 7.3, 5-H(), 2.71 (IH, dd, 716.8, 8.5, 3-H), 2.47 (IH, dd, 716.8, 8.5, 3-H(), 1.98- 1.54 (8H, m, cyclopentyl). Consistent with lit.152 210 Appendix X-ray crystallographic data 4-((4S)-Isopropyl-l,3-oxazolidin-2-one)-2-(2S)-methyl-4-oxo-butanenitrilel9si CN O \J 0(3) Crystal data and structure refinement for 79a Identification code AA0403 Empirical formula C11H16N2O3 Formula weight 224.26 Temperature 173(2)K Diffractometer, wavelength ODXcalibur3,0.71073 A Crystal system, space group Orthorhombic, P2( 1)2(1)2(1) Unit cell dimensions a = 7.2301(7) A a = 90° b= 17.8212(15) A P = 90° c= 18.8383(16) A y = 90° Volume, Z 2427.3(4) A3, 8 Density (calculated) 1.227 Mg/m3 Absorption coefficient 0.090mm- 1 F(OOO) 960 211 Crystal colour / morphology Colourless needles Crystal size 0.46 x 0.07 x 0.04 mm3 0 range for data collection 4.06 to 32.71° Index ranges -10<=h<=10, -19<=k<=25, -28<=1<=27 Reflns collected / unique 23763 / 8179 [R(int) = 0.0814] Reflns observed [F>4a(F>] 6237 Absorption correction None Refinement method Full-matrix least-squares on F^ Data / restraints / parameters 8179/6/290 Goodness-of-fit on F^ 1.308 Final R indices [F>4o(F)] Rl= 0.1441, wR2 = 0.2311 R1+ = 0.1441, wR2+ = 0.2311 Rl- = 0.1441, wR2- = 0.2311 R indices (all data) Rl - 0.182l,wR2 = 0.2473 Absolute structure parameter x+=l(2),x- = 0(2) Extinction coefficient 0.011(3) Largest diff. peak, hole 0.270,-0.23 leA'3 Mean and maximum shift/error 0.000 and 0.000 Bond lengths [A] and angles [°] for 79a 1.390(5) 1.402(5) 1.470(5) C(2)-0(2) 1.197(5) C(2)-0(3) 1.347(5) 0(3)-C(4) 1.451(5) C(4)-C(5) 1.533(6) 1.536(5) C(6)-0(6) 1.218(5) C(6)-C(7) 1.503(5) C(7)-C(8) 1.538(6) C(8)-C(9) 1.477(6) C(8)-C(10) 1.535(6) C(9)-N(9) 1.141(6) 1.524(6) 1.535(6) 1.397(5) 1.402(5) 1.476(5) C(2')-0(2') 1.205(5) C(2')-O(3') 1.342(5) 0(3')-C(4') 1.425(6) C(4')-C(5') 1.540(6) 1.532(6) C(6')-0(6') 1.202(5) C(6')-C(7') 1.512(5) C(7')-C(8') 1.541(5) C(8')-C(9') 1.477(6) 1.534(6) C(9')-N(9') 1.141(5) 1.490(8) 1.526(6) C(2)-N(1)-C(6) 126.3(3) C(2)-N(1)-C(5) 112.0(3) C(6)-N(1)-C(5) 120.2(3) 0(2)-C(2)-0(3) 122.5(4) 212 0(2)-C(2)-N(1) 128.7(4) 0(3)-C(2)-N(1) 108.8(3) C(2)-0(3)-C(4) 109.8(3) 0(3)-C(4)-C(5) 105.5(3) N(1)-C(5)-C(4) 100.2(3) N(1)-C(5)-C(11) 112.7(3) C(4)-C(5)-C(11) 115.8(3) 0(6)-C(6)-N(1) 118.4(3) 0(6)-C(6)-C(7) 123.5(3) N(1)-C(6)-C(7) 118.2(3) C(6)-C(7)-C(8) 110.4(3) C(9)-C(8)-C(10) 110.3(3) C(9)-C(8)-C(7) 109.7(3) C(10)-C(8)-C(7) 111.4(4) N(9)-C(9)-C(8) 177.7(5) C(13)-C(11)-C(12) 111.9(4) C(13)-C(11)-C(5) 109.4(4) C(12)-C(11)-C(5) 113.3(3) C(2')-N(1')-C(6I) 126.6(3) C(2')-N(r)-C(5') 111.8(3) C(6')-N(1')-C(5') 120.7(3) O(21)-C(2')-O(3I) 122.4(4) O(2')-C(2')-N(1 1) 128.6(4) O(3')-C(2')-N(1') 109.0(3) C(2')-O(3')-C(4') 111.5(3) O(3')-C(4')-C(5') 107.1(4) NO'KXS'KXll 1) 113.0(3) N(r)-C(5')-C(4') 100.5(3) C(11')-C(5')-C(4') 114.4(4) O(6')-C(6')-N(1 ?) 119.0(3) O(6')-C(61)-C(7') 124.0(3) N(r)-C(6')-C(7') 117.0(3) C(6')-C(7')-C(8') 111.0(3) C(9')-C(8')-C(10') 110.5(3) C(9')-C(8')-C(7') 107.5(3) C(10')-C(8')-C(7') 114.0(3) N(9')-C(9')-C(8') 178.3(5) C(13')-C(11')-C(12') 112.0(5) COS'KXll'KXS1) 113.4(5) C(12')-C(ir)-C(5') 110.1(4) Symmetry transformations used to generate equivalent atoms 4-((4S)-Benzyl-l,3-oxazolidin-2-one)-2-(2R)-methyl-4-oxo-butanenitrile8Qb CM O O Ph— ' 213 C(10) C(4) C«13) CI15) CI14) Crystal data and structure refinement for 80b Identification code AA0307 Empirical formula C15H16N2O3 Formula weight 272.30 Temperature 293(2)K Diffractometer, wavelength BrukerP4, 1.54178 A Crystal system, space group Monoclinic, P2(l) Unit cell dimensions a-7.3531(9) A a = 90° b= 11.7125(12) A p= 102.373(18)° c = 8.3351(18) A = 90° Volume, Z 701.17(19) A3, 2 Density (calculated) 1.290Mg/m3 Absorption coefficient 0.746mm- 1 F(OOO) 288 Crystal colour / morphology Colourless blocks Crystal size 0.93 x 0.77 x 0.40 mm3 0 range for data collection 7.30 to 66.00° Index ranges -7<=h<=8, -13<=k<=8, -8<=1<=9 Reflns collected / unique 1364/1304 [R(int) = 0.0403] Reflns observed [F>4a(F)] 1250 Absorption correction None Refinement method Full-matrix least-squares on F^ Data / restraints / parameters 1304/1/170 Goodness-of-fit on F^ 1.083 Final R indices [F>4o(F)] Rl = 0.0444, wR2 = 0.1214 R1+ = 0.0444, wR2+ = 0.1214 Rl- = 0.0446, wR2- = 0.1219 R indices (all data) Rl = 0.0462,wR2 = 0.1237 Absolute structure parameter x+ = 0.0(6), x- = 2.3(6) Absolute structure indeterminate, assigned by internal reference on C(5) Extinction coefficient 0.42(3) Largest diff. peak, hole 0.153,-0.149eA-3 214 Mean and maximum shift/error 0.000 and 0.001 Bond lengths [A] and angles [°] for 80b N(1)-C(2) 1.383(4) N(1)-C(6) 1.391(3) N(1)-C(5) 1.481(4) C(2)-0(2) 1.188(4) C(2)-0(3) 1.358(4) 0(3)-C(4) 1.455(5) C(4)-C(5) 1.528(4) C(5)-C(11) 1.522(4) 0(6)-C(6) 1.205(4) C(6)-C(7) 1.503(4) C(7)-C(8) 1.531(4) C(8)-C(9) 1.457(5) C(8)-C(10) 1.536(5) C(9)-N(9) 1.134(5) C(11)-C(17) 1.517(3) C(12)-C(13) 1.3900 C(12)-C(17) 1.3900 C(13)-C(14) 1.3900 C(14)-C(15) 1.3900 C(15)-C(16) 1.3900 C(16)-C(17) 1.3900 C(2)-N(1)-C(6) 127.3(3) C(2)-N(1)-C(5) 111.2(2) C(6)-N(1)-C(5) 121.3(3) O(2)-C(2)-O(3) 122.9(3) O(2)-C(2)-N(1) 129.0(3) O(3)-C(2)-N(1) 108.1(3) C(2)-O(3)-C(4) 109.7(3) O(3)-C(4)-C(5) 104.2(3) N(1)-C(5)-C(11) 110.7(2) N(1)-C(5)-C(4) 99.0(3) C(11)-C(5)-C(4) 114.2(3) O(6)-C(6)-N(1) 119.2(3) O(6)-C(6)-C(7) 123.7(2) N(1)-C(6)-C(7) 117.0(3) C(6)-C(7)-C(8) 112.8(2) C(9)-C(8)-C(7) 113.4(3) C(9)-C(8)-C(10) 110.1(3) C(7)-C(8)-C(10) 110.1(3) N(9)-C(9)-C(8) 176.4(4) C(17)-C(11)-C(5) 113.0(2) C(13)-C(12)-C(17) 120.0 C(12)-C(13)-C(14) 120.0 C(13)-C(14)-C(15) 120.0 C(16)-C(15)-C(14) 120.0 C(17)-C(16)-C(15) 120.0 C(16)-C(17)-C(12) 120.0 C(16)-C(17)-C(11) 120.56(18) C(12)-C(17)-C(11) 119.41(18) Symmetry transformations used to generate equivalent atoms 215 2-(2R)-(4-Chlorophenyl)-4-((4S)-isopropyl-l,3-oxazolidin-2-one)-4-oxo butanenitrile 145a Crystal data and structure reflnement for 145a Identification code AA0402 Empirical formula C16H17C1N2O3 Formula weight 320.77 Temperature 173(2)K Diffractometer, wavelength OD Xcalibur PX Ultra, 1 .54248 A Crystal system, space group Orthorhombic, P2( 1)2(1)2(1) Unit cell dimensions a = 6.3860(3) A a = 90° b= 11. 0773(5) A c = 22.3704(9) A y = 90 Volume, Z 1582.47(12) A3, 4 Density (calculated) 1.346Mg/m3 Absorption coefficient 2.262mm- 1 F(OOO) 672 Crystal colour / morphology Colourless blocky needles Crystal size 0.28x0.25x0. 19 mm3 9 range for data collection 3.95 to 71. 15° Index ranges -7<=h<=7, -12<=k<=13, -26<=1< 27 Reflns collected / unique 15785 / 2986 [R(int) - 0.0407] Reflns observed [F>4o(F>] 2983 Absorption correction Numeric analytical 216 Max. and min. transmission 0.68524 and 0.58512 Refinement method Full-matrix least-squares on F^ Data / restraints / parameters 2986 / 0 / 200 Goodness-of-fit on F^ 1.046 Final R indices [F>4o(F)] Rl = 0.0283, wR2 - 0.0730 R1+ - 0.0283, wR2+ = 0.0730 Rl- = 0.0500, wR2- = 0.1290 R indices (all data) Rl = 0.0284, wR2 = 0.0730 Absolute structure parameter x+ = 0.014(12), x- = 0.986(12) Extinction coefficient 0.0066(5) Largest diff. peak, hole 0.147,-0.205 eA'3 Mean and maximum shift/error 0.000 and 0.000 Bond lengths [A] and angles |°] for 145a 1.3917(19) 1.3948(19) 1.4768(18) C(2)-0(2) 1.2024(19) C(2)-0(3) 1.3466(19) 0(3)-C(4) 1.4575(18) C(4)-C(5) 1.526(2) C(5)-C(16) 1.538(2) C(6)-0(6) 1.2122(19) C(6)-C(7) 1.514(2) C(7)-C(8) 1.543(2) C(8)-C(9) 1.475(2) C(8)-C(10) 1.523(2) C(9)-N(9) 1.143(2) C(10)-C(15) 1.391(2) 1.396(2) 1.387(2) C(12)-C(13) 1.389(2) C(13)-C(14) 1.377(3) 1.7466(16) C(14)-C(15) 1.389(2) C(16)-C(17) 1.528(2) C(16)-C(18) 1.529(2) C(2)-N(1)-C(6) 127.45(13) C(2)-N(1)-C(5) 111.09(11) C(6)-N(1)-C(5) 121.46(12) 0(2)-C(2)-0(3) 122.83(14) 0(2)-C(2)-N(1) 128.40(14) 0(3)-C(2)-N(1) 108.78(12) C(2)-0(3)-C(4) 109.53(11) 0(3)-C(4)-C(5) 105.15(11) N(1)-C(5)-C(4) 99.28(11) 112.22(12) C(4)-C(5)-C(16) 115.56(13) 0(6)-C(6)-N(1) 118.90(13) 0(6)-C(6)-C(7) 122.93(13) N(1)-C(6)-C(7) 118.17(12) C(6)-C(7)-C(8) 110.18(12) C(9)-C(8)-C(10) 111.80(14) C(9)-C(8)-C(7) 108.62(13) C(10)-C(8)-C(7) 113.00(13) N(9)-C(9)-C(8) 177.53(17) 217 118.82(14) C(15)-C(10)-C(8) 122.22(15) 118.94(14) 120.86(15) 118.89(16) C(14)-C(13)-C(12) 121.38(15) 118.13(13) 120.48(13) C(13)-C(14)-C(15) 119.16(16) C(14)-C(15)-C(10) 120.88(16) C(17)-C(16)-C(18) 111.12(14) C(17)-C(16)-C(5) 113.38(13) C(18)-C(16)-C(5) 109.63(13) Symmetry transformations used to generate equivalent atoms Separation of 80 by NMR spectrum (See Section 3.2.2.1) CN O Q H 80 1^ 2 75 Figure 35 : Overlapping double doublets of HI in 500 MHz *H NMR spectrum of a mixture of diastereomers of the Me-Bn hydrocyanated product 80 218 ~T~ 2.80 Figure 36 : Separated doublets of Hj in 500 MHz 1H NMR spectrum of a mixture of diastereomers of the Me-Bn hydrocyanated product 80 decoupled at 4.72 ppm (H2) NMR spectrum of drug molecules OH 8.5 8.0 7 5 7.0 6.5 60 5.5 5.0 4 5 4.0 3.5 3.0 2 5 2.0 1.5 1.0 0.5 Figure 37 : *H NMR spectrum of e«?-Pregabalin hydrochloride 8b in 219 HCIJ-feN J/ n_ r p-i—i—r T-p-r-i i i [i i i i | i i i i | i i i i j i i i i | • T i | i | i i -—i | i -r i i | i i :—' | • ! --- ' •- i i I i i i i i i i i i i i i i i i i i i i i i t i—r—r 85 *-° 7-S 70 6.5 60 55 50 45 4.0 35 30 25 2.0 1.5 10 0.5 00 Figure 38 : *H NMR spectrum of (5)-Baclofen hydrochloride 15b in D2O OMe 1 ' ' ' ' i ' • ' ' i • ' ^n ' ' i ' ' ' ' i ' c ' • i ' • ' BO 7.5 70 6 ^ 60 55 50 4O 3.5 3.O 2S 1 O 0$ 00 Figure 39 : !H NMR spectrum of (5)-Rolipram 14b in CDC13 220 HPLC traces -1 [J ll •-•el-. .-I Figure 40 : HPLC trace of Pregabalin lactam 133b showing 96% ee Figure 41 : HPLC trace of mixture of Pregabalin lactams 133a and 133b 221 J-t o- O o H =! ; I \:- i I Mil .' I t J .•! Figure 42 : HPLC trace of Baclofen lactam 146b showing 99% ee 5 .?»;! t fo> i.jli. . , 1 . E Figure 43 : HPLC trace of mixture of Baclofen lactams 146a and 146b 222 f! •)ij .ri U s a ? •--.._ —L , -.^-'>" r 11 1111 Figure 44 : HPLC trace of Rolipram lactam 14b showing 99% ee Figure 45 : HPLC trace of mixture of Rolipram lactams 14a and 14b 223 References Armstrong, A.; Convine, N. J., In Comprehensive Organic Functional Group Transformations II, ed., Katritzky, A. R.; Taylor, R. J. K.; Cossy, J., Elsevier Pergamon, Oxford, 2005, Vol. 1, p. 287. 2 Degrade, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc., 2001, 123, 755. 3 Mizutani, H.; Degrade, S. J.; Hoveyda, A. H. J. Am. Chem. Soc., 2002, 124, 779. 4 Degrade, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc., 2002, 124, 13362. 5 Cesati, R. R.; de Armas, J.; Hoveyda, A. H. J. Am. Chem. Soc., 2004, 725, 96. 6 Hayashi, T. Synlett, 2001, 879. 7 Hayashi, T.; Yamasaki, K. Chem. Rev., 2003, 103, 2829. 8 Hayashi, T. Bull. Chem. Soc. Jpn., 2004, 77, 13. 9 Yoshida, K.; Ogasawara, M.; Hayashi, T. J. Am. Chem. Soc., 2002, 124, 10984. 10 Yoshida, K.; Ogasawara, M.; Hayashi, T. J. Org. Chem., 2003, 68, 1901. 11 Hayashi, T.; Tokunaga, N.; Yoshida, K.; Han, J. W. J. Am. Chem. Soc., 2002, 724, 12102. 12 Matsunaga, S.; Ohshima, T.; Shibasaki, M. Adv. Synth. Catal, 2002, 344, 3. 13 Shibasaki, M.; Yoshikawa, N. Chem. Rev., 2002, 702,2187. 14 Shibasaki, M.; Kanai, M. Chem. Pharm. Bull, 2001, 49, 511. 15 Shibasaki, M. Enantiomer, 1999, 4, 513. 16 Sammis, G. M.; Jacobsen, E. N. J. Am. Chem. Soc., 2003, 725,4442. 17 Sammis, G. M.; Danjo, H.; Jacobsen, E. N. J. Am. Chem. Soc., 2004, 725, 9928. 18 Mita, T.; Sasaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc., 2005, 727, 514. 19 Schaus, S. E.; Jacobsen, E. N. Org. Lett., 2000, 2, 1001. 20 Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc., 1999, 727, 8959. 21 Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc., 2003, 725, 11204. 22 Aspinall, H. C.; Greeves, N.; Smith, P. M. Tetrahedron Lett., 1999, 40, 1763. 23 Kato, N.; Suzuki, M.; Kanai, M.; Shibasaki, M. Tetrahedron Lett., 2004, 45, 3 147. 24 Kato, N.; Suzuki, M.; Kanai, M.; Shibasaki, M. Tetrahedron Lett., 2004, 45, 3153. 25 Masumoto, S.; Usuda, H.; Suzuki, M.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc., 2003, 725, 5634. 26 Kato, N.; Tomita, D.; Maki, K.; Kanai, M.; Shibasaki, M. J. Org. Chem., 2004, 69, 6128. 27 Dahuron, N.; Langlois, N. Synlett, 1996, 51. 28 Langlois, N.; Dahuron, N.; Wang, H.-S. Tetrahedron, 1996, 52, 15117. 29 Langlois, N.; Wang, H.-S. Synth. Commun., 1997,27, 3133. 30 Benedetti, F.; Berti, F.; Garau, G.; Martinuzzi, I.; Norbedo, S. Eur. J. Org. Chem., 2003, 1973. 31 Ruano, J. L. G.; Garcia, M. C.; Laso, N. M.; Castro, A. M. M.; Ramos, J. H. R. Angew. Chem. Int. Ed., 2001, 40, 2507. 32 Claus, A.Ann. Chem., 1873, 770, 126. 33 Nagata, W.; Yoshioka, M.; Hirai, S. Tetrahedron Lett., 1962, 77,461. 34 Nagata, W.; Yoshioka, M. Org. React., 1977,25,255. 35 Evans, D. A.; Carroll, G. L.; Truesdale, L. K. J. Org. Chem., 1974, 39, 914. 36 Evans, D. A.; Truesdale, L. K.; Carroll, G. L. Chem. Commun., 1973, 55. 37 Utimoto, K.; Obayashi, M.; Shishiyama, Y.; Inoue, M.; Nozaki, H. Tetrahedron Lett., 1980,27, 3389. 38 Utimoto, K.; Wakabayashi, Y.; Horiie, T.; Inoue, M.; Shishiyama, Y.; Obayashi, M.; Nozaki, H. Tetrahedron, 1983, 39, 967. 39 Higuchi, K.; Onaka, M.; Izumi, Y. Chem. Commun., 1991, 1035. 40 Higuchi, K.; Onaka, M.; Izumi, Y. Bull. Chem. Soc. Jpn., 1993, 66, 2016. 41 Yabu, K.; Masumoto, S.; Yamasaki, S.; Hamashima, Y.; Kanai, M.; Du, W.; Curran, D. P.; Shibasaki, M. J. Am. Chem. Soc., 2001, 723, 9908. 42 Noyori, R.; Murata, S.; Suzuki, M. Tetrahedron, 1981, 37, 3899. 43 Pu, L.; Yu, H.-B. Chem. Rev., 2001, 707, 757. 44 Frantz, D. E.; Fassler, R.; Tomooka, C. S.; Carreira, E. M. Ace. Chem. Res., 2000, 33, 373. 45 Kumagai, N.; Matsunaga, S.; Shibasaki, M. Org. Lett., 2001, 3, 4251. 46 Takahashi, H.; Yoshioka, M.; Shibasaki, M.; Ohno, M.; Imai, N.; Kobayashi, S. Tetrahedron, 1995, 57, 12013. 47 Denmark, S. E.; O'Connor, S. P. J. Org. Chem., 1997, 62, 3390. 48 Armstrong, A.; Ahmed, G.; Dominguez-Fernandez, B.; Hayter, B. R.; Wailes, J. S. J. Org. Chem., 2002,57,8610. 224 49 Armstrong, A.; Hayter, B. R.; Moss, W. O.; Reeves, J. R.; Wailes, J. S. Tetrahedron: Asymmetry, 2000,77,2057. 50 North, M. Tetrahedron: Asymmetry, 2003, 14, 147. 51 Brunei, J.-M; Holmes, I. P. Angew. Chem. Int. Ed., 2004, 43, 2752. 52 Magid, R. M. Tetrahedron, 1980, 36, 1901. 53 Trost, B. M.; Florez, J.; Jebaratnam, D. J. J. Am. Chem. Soc., 1987, 109, 613. 54 Wu, Y.-D.; Houk, K. N.; Florez, J.; Trost, B. M. J. Org. Chem., 1991, 1991, 3656. 55 Gribble, G. W.; Keavy, D. J.; Davis, D. A.; Saulnier, M. G.; Pelcman, B.; Barden, T. C; Sibi, M. P.; Olson, E. R.; BelBruno, J. J. J. Org. Chem., 1992, 57, 5878. 56 Diez, A.; Castells, J.; Forns, P.; Rubiralta, M.; Grierson, D. S.; Husson, H.-P.; Solans, X.; Font- Bardia, M. Tetrahedron, 1994, 50, 6585. 57 Casamitjana, N.; Lopez, V.; Jorge, A.; Bosch, J.; Molins, E.; Roig, A. Tetrahedron, 2000, 56, 4027. 58 Paulmier, C., Selenium Reagents and Intermediates in Organic Synthesis, Pergamon, Oxford, 1986, p!34. 59 Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc., 1988, 770, 1238. 60 Tsay, S. C.; Gani, P.; Hwu, J. R. J. Chem. Soc., Perkin Trans. 1, 1991, 1493. 61 Matsubara, S.; Onishi, H.; Utimoto, K. Tetrahedron Lett., 1990, 31, 6209. 62 Ohno, H.; Mori, A.; Inoue, S. Chem. Lett., 1993, 975. 63 Matsubara, S.; Kodama, T.; Utimoto, K. Tetrahedron Lett., 1990, 31, 6379. 64 Kobayashi, S.; Ishitani, H.; Ueno, M. Synlett, 1997, 115. 65 Matsubara, S.; Takai, T.; Utimoto, K. Chem. Lett., 1991, 1447. 66 Utimoto, K.; Takai, T.; Kasuga, Y.; Matsubara, S. Appl. Organomet. Chem., 1995, 9, 413. 67 Yang, Y.; Wang, D. Synlett, 1997, 1379. 68 Poos, G. I.; Lukes, R. M.; Arm, G. E.; Sarett, L. H. J. Am. Chem. Soc., 1954, 76, 5031. 69 Mikami, K.; Terada, M.; Matsuzawa, H. Angew. Chem. Int. Ed., 2002, 41, 3554. 70 Davies, J.; Jones, J. B. J. Am. Chem. Soc., 1979, 707, 5405. 71 Hiemstra, H.; Wynberg, H. Tetrahedron Lett., 1977, 18, 2183. 72 Lemiere, G. L.; Dommisse, R. A.; Lepoivre, J. A.; Alderweireldt, F. C.; Hiemstra, H.; Wynberg, H.; Jones, J. B.; Toone, E. J. J. Am. Chem. Soc., 1987, 109, 1363. 73 Kawasaki, Y.; Fujii, A.; Nakano, Y.; Sakaguchi, S.; Ishii, Y. J. Org. Chem., 1999, 64, 4214. 74 Ohno, H.; Mori, A.; Inoue, S. Chem. Lett., 1993, 375. 75 Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc., 1981, 103, 2127. 76 Ager, D. J.; Prakash, L; Schaad, D. R. Chem. Rev., 1996, 96, 835. 77 Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichim. Acta, 1997, 30, 3. 78 Matsunaga, S.; Kinoshita, T.; Okada, S.; Harada, S.; Shibasaki, M. J. Am. Chem. Soc., 2004, 126, 7559. 79 Kirn, B. H.; Curran, D. P. Tetrahedron, 1993, 49, 293. 80 Montaudo, G.; Librando, V.; Caccamese, S.; Maravigna, P. J. Am. Chem. Soc., 1973, 95, 6365. 81 Castellino, S.; Dwight, W. J. J. Am. Chem. Soc., 1993, 775,2986. 82 Nicolas, E.; Russell, K. C.; Hruby, V. J. J. Org. Chem., 1993, 58, 766. 83 Lou, B.-S.; Li, G.; Lung, F.-D.; Hruby, V. J. J. Org. Chem., 1995, 60, 5509. 84 Williams, D. R.; Kissel, W. S.; Li, J. J. Tetrahedron Lett., 1998, 39, 8593. 85 Wipf, P.; Takahashi, H. Chem. Commun., 1996,2675. 86 Dambacher, J.; Bergdahl, M. Chem. Commun., 2003, 144. 87 Dambacher, J.; Bergdahl, M. Org. Lett., 2003, 5, 3539. 88 Dambacher, J.; Anness, R.; Pollock, P.; Bergdahl, M. Tetrahedron, 2004, 60, 2097. 89 Dambacher, J.; Bergdahl, M. J. Org. Chem., 2005, 70, 580. 90 Williams, D. R.; Nold, A. L.; Mullins, R. J. J. Org. Chem., 2004, 69, 5374. 91 Williams, D. R.; Kissel, W. S.; Li, J. J.; Mullins, R. J. Tetrahedron Lett., 2002, 43, 3723. 92 Amoroso, R.; Cardillo, G.; Sabatino, P.; Tomasini, C.; Trere, A. J. Org. Chem., 1993, 58, 5615. 93 Wu, M.-J.; Yeh, J.-Y. Tetrahedron, 1994, 50, 1073. 94 Williams, D. R.; Mullins, R. J.; Miller, N. A. Chem. Commun., 2003, 2220. 95 Miyata, O.; Shinada, T.; Ninomiya, L; Naito, T. Tetrahedron, 1997, 53, 2421. 96 Flores-Morales, V.; Fernandez-Zertuche, M.; Ordonez, M. Tetrahedron: Asymmetry, 2003, 14, 2693. 97 Hintermann, T.; Seebach, D. Helv. Chim. Acta, 1998, 81, 2093. 98 Davies, S. G.; Sanganee, H. J. Tetrahedron: Asymmetry, 1995, 6, 671. 99 Gaul, C.; Schweizer, B. W.; Seiler, P.; Seebach, D. Helv. Chim. Acta, 2002, 85, 1546. 100 Davies, S. G.; Sanganee, H. J.; Szolcsanyi, P. Tetrahedron, 1999, 55, 3337. 101 Oppolzer, W.; Mills, R. J.; Pachinger, W.; Stevenson, T. Helv. Chim. Acta, 1986, 69, 1542. 225 102 Oppolzer, W.; Poll, G.; Kingma, A. J.; Starkemann, C.; Bernardinelli, G. Helv. Chim. Acta, 1987, 70,2201. J03 Oppolzer, W.; Kingma, A. J.; Poli, G. Tetrahedron, 1989, 45, 479. Vandewalle, M.; Van der Eycken, J.; Oppolzer, W.; Vullioud, C. Tetrahedron, 1986, 42, 4035. 105 Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc., 1998, 120, 6615. 106 Davies, N. G. M. Ph.D. Thesis, 2002, Imperial College London. 107 Roush, W. R.; Brown, B. B. J. Org. Chem., 1993, 58, 2162. 108 McDougal, P. G.; Rico, J. G.; Oh, Y.-I.; Condon, B. D. J. Org. Chem., 1986, 57, 3388. 109 Vijn, R. J.; Hiemstra, H.; Kok, J. J.; Knotter, M.; Speckamp, W. N. Tetrahedron, 1987, 43, 5019. 110 Hagen, S.; Lwande, W.; Kilaas, L.; Anthonsen, T. Tetrahedron, 1980, 36, 3101. 111 Chen, Y.; Huang, L.; Zhang, X. P. Org. Lett., 2003, 5, 2493. 112 Namy, J. L.; Souppe, J.; Collin, J.; Kagan, H. B. J. Org. Chem., 1984, 49, 2045. 113 Sibi, M. P.; Sausker, J. B. J. Am. Chem. Soc., 2002, 124, 984. 114 Fujii, A.; Sakaguchi, S.; Ishii, Y. J. Org. Chem., 2000, 65, 6209. 115 Tosaki, S.; Tsuji, R.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc., 2005, 727, 2147. 116 Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett., 1987, 28, 6141. 117 Azam, S.; D'Souza, A. A.; Wyatt, P. B. J. Chem. Soc., Perkin Trans. 1, 1996, 621. 118 Hoekstra, M. S.; Sobieray, D. M.; Schwindt, M. A.; Mulhern, T. A.; Grote, T. M.; Huckabee, B. K.; Hendrickson, V. S.; Franklin, L. C.; Granger, E. J.; Karrick, G. L. Org. Proc. Res. Dev., 1997, 7, 26. 119 Silverman, R. B.; Andruszkiewicz, R.; Nanavati, S. M.; Taylor, C. P.; Vartanian, M. G. J. Med. Chem., 1991, 34, 2295. 120 Prashad, M.; Har, D.; Kirn, H.-Y.; Repic, O. Tetrahedron Lett., 1998, 39, 7067. 121 Brenner, M.; Seebach, D. Helv. Chim. Acta, 1999, 82, 2365. 122 Barrett, A. G. M., In Comprehensive Organic Synthesis, ed., Trost, B. M.; Fleming, I., Pergamon Press, Oxford, 1991, Vol. 8, p. 235. 123 Yuen, P.-w.; Kanter, G. D.; Taylor, C. P.; Vartanian, M. G. Bioorg. Med. Chem. Lett., 1994, 4, 823. 124 Field, M. J.; McCleary, S.; Hughes, J.; Singh, L. Pain, 1999, 80, 391. 125 Andruszkiewicz, R.; Silverman, R. B.; Sobieray, D. M.; Franklin, L. C.; Schwindt, M. A., Pat. No. US626120, July 172001. 126 Burk, M. J.; de Koning, P. D.; Grote, T. M.; Hoekstra, M. S.; Hoge, G.; Jennings, R. A.; Kissel, W. S.; Le, T. V.; Lennon, I. C.; Mulhern, T. A.; Ramsden, J. A.; Wade, R. A. J. Org. Chem., 2003, 68, 5731. 127 Burk, M. J.; Goel, O. P.; Hoekstra, M. S.; Mich, T. F.; Mulhern, T. A.; Ramsden, J. A., Pat. No. WOO 155090, August 2 2001. 128 Hoge, G. J. Am. Chem. Soc., 2003, 725, 10219. 129 Puetz, C.; Przewosny, M. T., Pat. No. WO03062185, July 31 2003. 130 Olpe, H.-R.; Demieville, H.; Baltzer, V.; Bencze, W. L.; Koella, W. P.; Wolf, P.; Haas, H. L. Eur. J. Pharmacol, 1978,52, 133. 131 Chenevert, R.; Desjardins, M. Can. J. Chem., 1994, 72, 2312. 132 Brenna, E.; Caraccia, N.; Fuganti, C.; Fuganti, D.; Grasselli, P. Tetrahedron: Asymmetry, 1997, 8, 3801. 133 Mazzini, C.; Lebreton, J.; Alphand, V.; Furstoss, R. Tetrahedron Lett., 1997, 38, 1195. 134 Wang, M.-X.; Zhao, S.-M. Tetrahedron Lett., 2002, 43, 6617. 135 Hayashi, M.; Ogasawara, K. Heterocycles, 2003, 59, 785. 136 Herdeis, C.; Hubmann, H. P. Tetrahedron: Asymmetry, 1992, 3, 1213. 137 Schoenfelder, A.; Mann, A.; Coz, S. L. Synlett, 1993, 63. 138 Corey, E. J.; Zhang, F.-Y. Org. Lett., 2000,2,4257. 139 Baldoli, C.; Maiorana, S.; Licandro, E.; Perdicchia, D.; Vandoni, B. Tetrahedron: Asymmetry, 2000, 77,2007. 140 Licandro, E.; Maiorana, S.; Baldoli, C.; Capella, L.; Perdicchia, D. Tetrahedron: Asymmetry, 2000, 77,975. 141 Meyer, O.; Becht, J.-M.; Helmchen, G. Synlett, 2003, 1539. 142 Becht, J.-M.; Meyer, O.; Helmchen, G. Synthesis, 2003,2805. 143 Anada, M.; Hashimoto, S. Tetrahedron Lett., 1998, 39, 79. 144 Doyle, M. P.; Hu, W. Chirality, 2002, 14, 169. 145 Thakur, V. V.; Nikalje, M. D.; Sudalai, A. Tetrahedron: Asymmetry, 2003, 14, 581. 146 Resende, P.; Almeida, W. P.; Coelho, F. Tetrahedron: Asymmetry, 1999, JO, 2113. 147 Belda, O.; Lundgren, S.; Moberg, C. Org. Lett., 2003, 5,2275. 148 Wachtel, H. J. Pharm. Pharmacol., 1983, 55, 440. 149 Schneider, H. H.; Schmiechen, R.; Brezinski, M.; Seidler, J. Eur. J. Pharmacol., 1986, 727, 105. 226 150 Stafford, J. A.; Veal, J. M; Feldman, P. L.; Valvano, N. L.; Baer, P. G.; Brackeen, M. F.; Brawley, E. S.; Connolly, K. M.; Domanico, P. L.; Han, B.; Rose, D. A.; Rutkowske, R. D.; Sekut, L.; Stimpson, S. A.; Strickland, A. B.; Verghese, M. W. J. Med. Chem., 1995, 38, 4972. 151 Baures, P. W.; Eggleston, D. S.; Erhard, K. F.; Cieslinski, L. B.; Torphy, T. J.; Christensen, S. B. J. Med Chem., 1993, 36, 3274. 152 Meyers, A. L; Snyder, L. J. Org. Chem., 1993, 58, 36. 153 Diaz, A.; Siro, J. G.; Garcia-Navio, J. L.; Vaquero, J. J.; Alvarez-Builla, J. Synlett, 1997, 559. 154 Mulzer, J.; Zuhse, R.; Schmiechen, R. Angew. Chem. Int. Ed, 1992, 31, 870. 155 Barnes, D. M.; Ji, J.; Fickes, M. G.; Fitzgerald, M. A.; King, S. A.; Morton, H. E.; Plagge, F. A.; Preskill, M.; Wagaw, S. H.; Wittenberger, S. J.; Zhang, J. J. Am. Chem. Soc., 2002, 124, 13097. 156 Itoh, K.; Kanemasa, S. J. Am. Chem. Soc., 2002, 124, 13394. 157 Anada, M.; Mita, O.; Watanabe, H.; Kitagaki, S.; Hashimoto, S. Synlett, 1999, 1775. 158 Honda, T.; Ishikawa, F.; Kanai, K.; Sato, S.; Kato, D.; Tominaga, H. Heterocycles, 1996, 42, 109. 159 Barluenga, J.; Fernandez-Rodriguez, M. A.; Aguilar, E.; Fernandez-Mari, F.; Salinas, A.; Olano, B. Chem. Eur. J., 2001, 7, 3533. 160 Braun, M.; Opdenbusch, K.; Unger, C. Synlett, 1995, 1174. 161 Caddick, S.; Judd, D. B.; Lewis, A. K. d. K.; Reich, M. T.; Williams, M. R. V. Tetrahedron, 2003, 59, 5417. 162 Yoshifuji, S.; Kaname, M. Chem. Pharm. Bull, 1995, 43, 1302. 163 Barnes, D. M.; Bhagavatula, L.; DeMattei, J.; Gupta, A.; Hill, D. R.; Manna, S.; McLaughlin, M. A.; Nichols, P.; Premchandran, R.; Rasmussen, M. W.; Tian, Z.; Wittenberger, S. J. Tetrahedron: Asymmetry, 2003, 14, 3541. 164 Willaert, J. J.; Lemiere, G. L.; Dommisse, R. A.; Lepoivre, J. A.; Alderweireldt, F. C. Bull. Soc. Chim. Belg., 1984, 93, 139. 165 Hertenstein, U.; Hunig, S.; Oiler, M. Chem. Ber., 1980, 113, 3783. 166 Cory, R. M.; Chan, D. M. T.; Naguib, Y. M. A.; Rastall, M. H.; Renneborg, R. M. J. Org. Chem., 1980,45,1852. 167 Reich, H. J.; Renga, J. M.; Reich, I. L. J. Am. Chem. Soc., 1975, 97, 5434. 168 Coote, S. J.; Davies, S. G.; Goodfellow, C. L.; Sutton, K. H. Tetrahedron: Asymmetry, 1990, 7, 817. 169 Wu, K. M.; Okamura, W. H. J. Org. Chem., 1990, 55,4025. 170 Miyano, S.; Lu, L. D. L.; Viti, S. M.; Sharpless, K. B. J. Org. Chem., 1985, 50, 4350. 171 Nabeya, A.; Endo, T. J. Org. Chem., 1991, 56, 3194. 172 Soloshonok, V. A.; Cai, C.; Hruby, V. J.; Meervelt, L. V.; Yamazaki, T. J. Org. Chem., 2000, 65, 6688. 173 Kanemasa, S.; Oderaotoshi, Y.; Sakaguchi, S.; Yamamoto, H.; Tanaka, J.; Wada, E.; Curran, D. P. J. Am. Chem. Soc., 1998, 120, 3074. 174 Narasaka, K.; Iwasawa, N.; Inoue, M.; Yamada, T.; Nakashima, M.; Sugimori, J. J. Am. Chem. Soc., 1989, 777, 5340. 175 Farcasiu, D.; Schleyer, P. V. R.; Ledlie, D. B. J. Org. Chem., 1973, 38, 3455. 176 Ahlbrecht, H.; Ibe, M. Synthesis, 1985,421. 177 Diez, E.; Feraandez, R.; Gasch, C.; Lassaletta, J. M.; Llera, J. M.; Martin-Zamora, E.; Vazquez, J. J. Org. Chem., 1991,62,5144. 178 Giese, B.; Thoma, G. Helv. Chim. Acta, 1991, 74, 1143. 179 Fedorynski, M.; Ziolkowska, W.; Jonczyk, A. J. Org. Chem., 1993, 58, 6120. 180 Parrish, J. P.; Dueno, E. E.; Kirn, S.-L; Jung, K. W. Synth. Commun., 2000, 30, 2687. 181 Ruck, K.; Kunz, H. Synthesis, 1993, 1018. 182 Nicolas, E.; Russell, K. C.; Knollenberg, J.; Hruby, V. J. J. Org. Chem., 1993, 58, 7565. 183 Oppolzer, W.; Chapuis, C.; Bernardinelli, G. Helv. Chim. Acta, 1984, 67, 1397. 184 Liang, B.; Carroll, P. J.; Joullie, M. M. Org. Lett., 2000,2,4157. 185 Yamada, T.; Takashima, K.; Miyazawa, T.; Kuwata, S.; Watanabe, H. Bull. Chem. Soc. Jpn., 1978, 57, 878. 186 Lochner, M.; Geneste, H.; Hesse, M. Helv. Chim. Acta, 1998, 81, 2270. 187 Kampmeier, J. A.; Harris, S. H.; Rodehorst, R. M. J. Am. Chem. Soc., 1981, 703, 1478. 188 Hoffinann, H. M. R.; Haase, K. Synthesis, 1981, 715. 189 Galatsis, P.; Millan, S. D.; Ferguson, G. J. Org. Chem., 1997, 62, 5048. 190 Evans, D. A.; Weber, A. J. Am. Chem. Soc., 1986, 108, 6757. 191 Abdel-Magid, A.; Pridgen, L. N.; Eggleston, D. S.; Lantos, I. J. Am. Chem. Soc., 1986, 108, 4595. 192 Juric, S.; Kronja, O. J. Phys. Org. Chem., 2002, 75, 556. 193 Tel Her, F.; Sauvetre, R. Tetrahedron Lett., 1993, 34, 5433. 194 Jacobsen, E. N.; Deng, L.; Furukawa, Y.; Martinez, L. E. Tetrahedron, 1994, 50, 4323. 227 195 Evans, D. A.; Mathre, D. J.; Scott, W. L. J. Org. Chem., 1985, 50, 1830. 196 Wu, Y.; Shen, X. Tetrahedron: Asymmetry, 2000, 11, 4359. Davis, F. A.; Towson, J. C.; Weismiller, M. C.; Lal, S.; Carroll, P. J. J. Am. Chem. Soc., 1988, 110, 8477. 198 Andruszkiewicz, R.; Barrett, A. G. M.; Silverman, R. B. Synth. Commun., 1990, 20, 159. 199 Kamimura, A.; Omata, Y.; Tanaka, K.; Shirai, M. Tetrahedron, 2003, 59, 6291. Gomez-Monterrey, I.; Turcaud, S.; Lucas, E.; Bruetachy, L.; Roques, B. P.; Fournie-Zaluski, M.-C. J. Med. Chem., 1993, 36, 87. 201 Nagarajan, K.; Sivaramakrishnan, H.; Arulselvan, M., Pat. No. WO2004046085, June 3 2004. 202 Camps, P.; Munoz-Torrero, D.; Sanchez, L. Tetrahedron: Asymmetry, 2004, 15, 2039.