ligand design and ynamide synthesis for

Ligand Design and Ynamide Synthesis for [5+2] Cycloisomerizations

…………………………………………………………………………………………………………………………………….......

Summer Project

Joseph B Parry Worcester College

Supervisor: Dr Edward Anderson

University of OxfordDepartment of Chemistry

August 2015

Ligand Design and Ynamide Synthesis for [5+2] cycloisomerizations Joseph Parry

Contents

Acknowledgements…………………………………………….2

Abbreviations…………………………………………………..3

Stereochemical Notation…………………...…...…..….............4

Results and Discussion………….……………………...………5

Introduction.....................................................................................5

Ligand Synthesis..............................................................................6

Ynamide Synthesis...........................................................................7

Future Work....................................................................................9

References.......................................................................................9

Experimental..............................................................................11

Data for Selected Compounds...................................................19

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Acknowledgments

My thanks go first and foremost to Dr Edward Anderson for the opportunity to work on this project, and for his guidance and support over the past 9 weeks.

To all the members of the EAA group – Yao, Bobby, Marius, Haraldur, Mujahid, Christian and especially Guilhem and Rob – for their extra help and guidance within the Lab.

Also, I am grateful for the generosity of Worcester College whose funding has made my stay in Oxford possible.

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Abbreviations

Ac acetylAtm atmospheresbr broadBu butylcalcd calculated chemical shiftCOSY correlation spectroscopyd doublet2,4-DNP2,4-DinitrophenylhydrazineDCM dichloromethane DMAP 4-(N,N-dimethylamino)pyridine DMF dimethylformamide DMSO dimethyl sulfoxide DPPA diphenylphosphoryl azideee enantiomeric excess eq equivalent(s)Et ethylESI electrospray ionisationFmoc FluorenylmethyloxycarbonylFmocOH Fluorenylmethyloxycarbonyl alcoholg gram(s)h hour(s)HRMS High resolution mass spectrometry iPr isopropylJ coupling constant LiHMDS lithiumbis(trimethylsily)amideMe methylmg milligram(s)MS mass spectrometry min minute(s)mL milliliter(s)M molarmols molesmmol millimole(s)m multipletm/z mass to charge ratioNMR nuclear magnetic resonanceo orthop parappt precipitate Ph phenylPy pyridineq quartetrecryst recrystallisation Red-Al sodiumbis(2-methoxyethoxy)aluminium hydriderbf round bottom flaskr.t. room temperatureRf retention factors singlet(S)-binol (S)-(-)-1,1’-bi(2-napthol)t tripletTEMPO 2,2,6,6-tetramethylpiperidine-1-oxylTHF tetrahydrofuranTs tosylvacuo vacuumw.t weightwrt with respect to

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Stereochemical Notation

Throughout this report, to aid in the recognition of absolute and relative stereochemical configurations, the Maehr convention has been adopted. Thus, solid and broken lines denote racemates, whilst solid and broken wedges imply absolute configurations. For the latter, the narrowing of both solid and broken wedges denotes an increasing distance of that bond from the viewer and widening the opposite.

Racemate Single enantiomer Relative stereochemistry Absolute stereochemistry

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Results and Discussion

Introduction

The chemistry of ynamides has rapidly developed since Zaugg et al first synthesised them in 1958, and they are now becoming routinely used in modern organic chemistry as useful synthetic building blocks[1].

Figure 1. Scheme illustrating the scope of ynamide reactivity. 1, Bronsted acid catalysed addition[2]. 2, transition metal catalysed addition[3]. 3, [4+2] Rh catalysed cycloaddition[4]. 4, ring-closing metathesis[5].

Ynamines, like ynamides take part in various selective transformations but as they lack a nitrogen based EWG they are difficult to prepare and handle, and they show great sensitivity (e.g. they undergo rapid hydrolysis). This is why dampening the electron donating ability of the nitrogen and therefore reducing the overall polarisation of the triple bond increases the curiosity surrounding ynamide chemistry over ynamines.

Figure 2. Top, difference in structure between ynamines

and ynamides. Bottom, most common classes of EWG.

Not only does the EWG increase stability and

ease of use, it also allows for sp differentiation along the triple bond which increases the library of compounds accessible from ynamides and further enriches their chemistry. Figure 3. How the EWG allows for sp differentiation in ynamides by altering their observed reactivity with different reagents.

Amongst the chemistry depicted above, pericyclic reactions, and specifically cycloisomerizations are of particular interest. They are commonly mediated by transition metal complexes and are incredibly atom efficient; every atom in the starting substrate is present in the product. The first example of such a reaction was in 1989 by Trost et al.[6]. As expected, the reaction is rather enantiomerically non-selective, but as chemistry has advanced there have been ways to increase selectivity. Such ways include:- substrate design, transition metal complex design and more recently the addition of a ligand.

Scheme 1. First example of a transition metal mediated cycloisomerization by Trost et al.

Phosphoramidites have emerged as highly accessible ligands whose flexible design enables them to be altered to the requirement of a specific catalytic reaction. This ease of re-design allows for a vast catalogue of ligands to be produced and enables rapid optimisation of enantioselectivity, particularly effective when used in tandem with cyclic substrates. Incorporating chirality into the ligand can increase the overall selectivity of asymmetric reactions. Even if chirality is present, minor alterations to the ligand can have a detrimental effect to a reactions %ee. This can be seen by the alterations made by Straker et al (unpublished). Changing the (S)-binol for the (R)-binol leads to a decrease in ee by 43%. ‘A transition state model is used to identify the importance of an 2-bound arene’ in the reaction mechanism. The electronic and stereochemical character of this arene thus affects the reactions %ee[7]. The data collected

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and reactions carried out in this report concern the illustrated reaction below. Scheme 2. Differences in %ee of a [5+2] cycloisomerization due to ligand alteration.Ligand Synthesis

The electronic structure of the 2-bound arene has a profound effect on the reactions overall selectivity and reaction time. For example, fluoro-ligand L2 enhances the rate and selectivity of cyclisation while methoxy-ligand L3 reduces it.

Scheme 3

Ligands were synthesised where only 1 arene was substituted with group X and also where only one ring was aromatic, the 2nd ring was completely saturated. The synthetic route for the ligand synthesis is shown in scheme 4. The whole process is essentially a reductive amination where a chiral amine is condensed with a ketone (or aldehyde) to give an intermediate imine. Unfortunately the effect of E/Z selectivity in the imine formation step is not possible to evaluate as the imine formed with the substrates used is very unstable and can not be isolated and analysed. This intermediate imine then undergoes a stereoselective reduction to give the amine product. When the reduction selectivity is poor, recrystallisation is required to produce the diastereomerically pure product.

Scheme 4 – overall reductive amination process

The selection of amines synthesised is summarised in figure 4. Only 2 out of the 4 products were actually isolated. The decrease in yield from 1a to 1b is most likely due to the decrease in substrate reactivity. The chiral amine used in 1b was a CF3 para substituted arene. The CF3 group is strongly electron withdrawing, this strong –I effect will pull electron density away from the amine portion of the arene reducing the substrates overall

nucleophilicity and the overall effectiveness of the condensation. A solution to this problem would be to position the CF3 group in the same position on the aromatic ketone equivalent. The LUMO coefficient of the ketone would be increased with the presence of the CF3 group, this overall increase in ketone electrophilicity should increase the extent of the condensation. The main issue with the above solution is the

commercial expense of the suggested ketone. Figure 4

Amine 1d was also not isolated. At first the reaction was carried out using the hydrogenation technique described in the synthesis of 1a but when this failed an alternative was used, possible causes of failure were the imine reduction or the reduction of one of the functional groups on the substrate which could interfere with the imine reduction. Some of the possible outcomes of the nitro ketone reduction are shown in scheme 5.

Scheme 5

None of the above compounds were observed after the reduction; only the starting ketone was isolated. With no clear reason why the reaction failed the focus moved on to the synthesis of a phosphoramidite ligand.

The formation and overall purification of ligand 1e only results in a yield of 20%. The yield is low as the oxidation of P(III) to P(V) in the crude compound is rapid in air. To minimise the loss of pure compound the crude was columned

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quickly, only after several fractions were collected was TLC analysis carried out to identify which fractions contained 1e; once purified the ligand was no longer air sensitive.The mechanism for ligand formation is shown in scheme 6. The reaction consists of multiple SN2 steps leading to the overall formation of the phosphoramidite ligand.

Scheme 6

Ynamide Synthesis

As with most synthetic pathways, starting with a substrate that is cheap and whose various oxidation levels are easily accessible is desirable. The route to ynamide 2i is shown in scheme 7.The formation of aldehyde 2a using TEMPO and NaOCl is favoured over metal-based oxidations such as the Jones oxidation as catalytic amounts of oxidant can be used making the process more ‘green’ and as the aldehyde is desired, TEMPO allows for greater oxidation level selectivity; CrO3 and H2SO4 would lead to over oxidation resulting in the formation of the carboxylic acid [8]. The selective reduction of 2b to the E – alkene 2c is achieved with Red – Al. Red – Al reacts with propargylic alcohols first via co-ordination to the aluminium centre followed by an intramolecular hydride transfer that proceeds through a chair-like transition state. The positioning of both the phenyl and cyclopropyl groups in equatorial positions leads to the selective formation of the E – alkene, scheme 8 depicts this transformation.

Scheme 8 – Chair like transition state for the intramolecular hydride shift that results in overall E – alkene formation.

The yield achieved in acetylation of 2c to 2d is lower than expected, as the reaction is

extremely water sensitive. All compounds, vessels and syringes must be anhydrous to ensure Ac2O hydrolysis doesn’t occur. The transformation occurring in the formation of 2e is an Ireland - Claisen rearrangement. The rearrangement first proceeds via the production of an enolate. The enolate produced in the formation of 2e has no E/Z geometry preference therefore the positioning of the phenyl and cyclopropyl groups determines the overall alkene stereochemistry in the product. The mechanism is a [3,3] sigmatropic shift or suprafacial, pericyclic when described by Woodward – Hoffmann rules. The transition state that leads to the overall E – alkene is shown in scheme 9. The phenyl and cyclopropyl groups are both placed in equatorial positions to reduce 1,3 diaxial interactions, such interactions would raise the energy of the transition state and would not lead to the formation of a product.

Scheme 9

To investigate how enolate geometry affects the overall stereochemistry of the product 2c was also reacted with isovaleryl chloride to create ester 2h. Due to various laboratory difficulties ester 2h was only isolated with a yield of 17% and due to the scale used there was an inadequate amount of mass to work with. Scheme 10 shows the transition states possible if ester 2h was subjected to Ireland – Claisen conditions.

Scheme 10

Amine 2f was synthesised using the Curtius – rearrangement. Scheme 11 shows the key intermediates in the reaction. Upon deprotonation the carboxylate anion adds into DPPA and displaces an azide anion in a SN2 reaction. The addition into the carbonyl to form the acyl azide is aided by the stability of the diphenyl phosphate anion whose resonance stabilisation drives the reaction forward. The acyl azide rapidly rearranges to liberate N2(g) and the reactive isocyanate intermediate is created. To increase the electrophilicity of the isocyanate a Lewis acid is


added, the co-ordinated species is then trapped and worked up with Fmoc alcohol to obtain amine 2f.

Scheme 11

To remove the Fmoc group in 2f Et2NH is used. The major issue with this is the preferential tosylation of excess Et2NH over the amine substrate. This problem was observed when the reaction was carried out in the lab so the tosylated amine 2g was not isolated. Scheme 7 – Synthetic pathway to target molecule

As the target molecules highlighted above have already been synthesised, a new synthetic route was created where the phenyl group was replaced with a hydroxyl group. The aim of this was to see which enatiomer, if any, was favoured by the substrate upon

cycloisomerization. The portion of the synthetic pathway carried out is shown in scheme 12.

Scheme 12

The allylated amine 3a was isolated with a high yield even though a fraction of the double allylated product was formed. Both SN2 and SN’ mechanistic pathways give the desired product, a possible mechanistic pathway for the formation of the double allylated product is mono allylation followed by carbamate deprotection to form a second anion, this anion is then quenched with another equivalent of allyl bromide. Like the previous route, a cyclopropyl group is required in the substrate in order for the cycloisomerization to occur, to add this motif into the substrate an aldehyde was required, Ozonolysis and dihydroxylation followed by diol cleavage was investigated.Treatment of 3a with OsO4 and NaIO4 failed so instead of repeating, which would mean using more expensive OsO4, the cheaper and quicker ozonolysis reaction was attempted. Aldehyde 3a was isolated in an almost stoichiometric quantity, combining this with a very short reaction time (~5 minutes to form the intermediate ozonide and almost immediate completion after addition of reductant) and that purification was not required makes this step incredibly advantageous. The aldehyde isolated was unstable with respect to silica as confirmed by 2D TLC analysis.

Addition into 3a proved difficult as once both alcohols 3d and 3e were created a fraction of them would undergo a 5 – exo – trig cyclization to form the corresponding oxazolidone, minimal oxazolidone was seen in the crude NMR’s but once separated via column, more was produced. The acidity of the silica gel could potentially be acting as a Lewis acid and co-ordinating to the methyl ester carbonyl to

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accelerate the cyclization. Additions with both cyclopropyl acetylene and phenyl acetylene were used to investigate whether the alkyne group affected whether or not oxazolidone formation occurred, its formation occurred with both. Compound 3d was the last to be isolated in the route due to time constraints on laboratory time.

Future Work

The synthesis of the hydroxy substituted cycloisomerization product and further phosphoramidite ligands is the natural course of progression for this work. How the hydroxy group affects the preference of the adjacent H stereocentre and how further advances in ligand design effect %ee would be of great interest to investigate.

From alcohol 3d the Red – Al reduction carried out in the previous route could be problematic. The Red – Al could either react solely with the alkyne group or 2 equivalents could be consumed by it also reacting with the methyl ester, if this did occur, methyl ester removal would have to be carried out first then the reduction of the alkyne. The proposed route to finish the synthesis is shown in scheme 13.

Scheme 13 – Final steps in ynamide synthesis

As the oxazolidone that was produced was isolated, to increase the yield of alcohol formation the oxazolidone could be ring opened by reacting with K2CO3 and MeOH to produce the desired alcohol. Subjecting the oxazolidone to the same conditions used for ynamide synthesis as the acyclic alkyne would not work, the allenamide formed cannot isomerise into the desired ynamide, this was seen by Huang et al in 2002 [10], scheme 14 demonstrates this issue.

A start was made on an alternative route to ynamide synthesis that involved the addition into bromo acetate; this route is shown in scheme 15.

The first step in the scheme was carried out but a large number of spots were seen when the

reaction was analysed via TLC. Even though the electrophilicity of an ester carbonyl is less than that of a ketone, the Lewis acid was added to polarise the carbonyl to drive the addition reaction. 1 possible reason as to why the reaction failed is that a rapid SN2 reaction occurred at the alpha position, such an addition is rapid due to the mixing of the * C=O and the * C–Br to create a new lower energy LUMO in the reactive conformation. Once the ketone has been reduced, the alcohol formed could potentially undergo a rapid, spontaneous 3 – exo – tet cyclisation to form the epoxide, if this occurs the epoxide could be regioselectively ring opened under basic conditions with TsNH2 to form the desired amine alcohol.

Investigating and performing chemistry on molecules that contain multiple sites of functionality is still a challenge even for the most experienced organic chemist. Absolute substrate control has become more of a necessity than a requirement for modern synthetic chemistry and this can be achieved with ynamides. They possess a vast capacity to undergo many transformations and when combined with appropriate reagents, such transformations are incredibly stereo and enantiomerically specific.

References[1] H. E. Zaugg, L. R. Swett, G. R. Stone, J. Org. chem. 1958, 23, 1389-1390.[2] Hsung et al. J Org let. 2003, 5, 1547.[3] J. Oppenheimer, W. L. Johnson, M. R. Tracey, R. P. Hsung, P.- Y. Yao, R. Liu, K. Zhao, Org. Lett. 2007, 9, 2361 – 2364. [4] B. Witulski, J. Lumtscher, U. Bergstraßer, Synlett 2003, 708 – 710.

Scheme 15


[5] M. Mori, D. Tanaka, N. Sato, Y. Sato, Organometallics 2008, 27, 6313 – 6320.

[6] Trost, B. M., Lee, D. C., Rise, F. Tetrahedron Lett. 1989, 30, 651. [7] Robert Straker et al, unpublished. [8] Kenneth Bowden, I. M. Heilbron, E. R. H. Jones, B. C. L. Weedon, J. Chem. Soc., 1946, 39-45.[9] Huang et al. Org. Lett. 2002, 4, 2417.

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