A one-pot , three-step process for the diastereoselective synthesis of aminobicyclo [ 4 . 3 . 0 ] nonanes using consecutive palladium ( II )-and ruthenium ( II )-catalysis †

A diastereoselective synthesis of highly substituted aminobicyclo[4.3.0]nonanes has been attained using a one-pot multi-bond forming process. A four-step synthetic route was developed for the efficient synthesis of a series of C-7 substituted hept-2-en-6-yn-1-ols. These compounds were then investigated as substrates for a one-pot, three-step tandem process involving a palladium(II)-catalysed Overman rearrangement, a ruthenium(II)-catalysed ring closing enyne metathesis reaction followed by a hydrogen bond directed Diels–Alder reaction. The optimisation of the one-pot process has allowed the rapid preparation of a library of aminobicyclo[4.3.0]nonanes with significant molecular complexity and up to four stereogenic centres.


Introduction
A recent trend in identifying lead-hit compounds and smallmolecule probes for medicinal chemistry and chemical biology has been the replacement of sp 2 -rich aromatic and heteroaromatic compounds with sp 3 -rich compounds. 1Partially saturated compounds with a higher degree of saturation have more suitable physicochemical properties such as solubility and allow a more efficient examination of three-dimensional chemical space. 1,2In this regard, saturated and partially saturated forms of amino substituted bicyclo[4.3.0]nonanes have exhibited wide-ranging biological and pharmacological properties. 3In particular, these compounds are found as components of natural products such as the guanidine alkaloid netamine A (1) 4 and the antitumour antibiotic (+)-ptilocaulin (2) (Fig. 1). 5 Amino-indanes are found as constituents of a range of medicinal agents including (+)-indatraline (3), 6 a monoamine transporter inhibitor and rasagiline (Azilect), a drug used for the treatment of Parkinson's disease. 7Other amino-indane structural analogues can inhibit the proliferation of malignant cells 8 and are used to treat HIV infections and AIDS. 91][12][13] Diastereoselective syntheses have been achieved using an intramolecular 1,3-dipolar cycloaddition between an oxime and a cyclohexene 5 and, using a Ru(I)-catalysed allenic cycloisomerisation of an alkynone, followed by a Diels-Alder reaction of the resulting 2-alkylidene-3-vinylcyclopentenone. 10 Other diastereoselective syntheses include the C-H activation of a hexahydroindene that gave the corresponding secondary organoborane, which was then aminated to give the amino substituted bicyclo [4.3.0]nonane in good overall yield. 11s part of a research programme to develop new methods for rapid access to drug-like polycyclic scaffolds, we recently reported the diastereoselective synthesis of amino substituted bicyclo [4.3.0]nonanes using a one-pot multistep process involving a thermally-mediated Overman rearrangement of alkyne derived allylic alcohols, followed by a ring closing enyne Fig. 1 Biologically active amino bicyclo[4.3.0]nonanes and indanes.† Electronic supplementary information (ESI) available: NOE data for compounds 25-37 and, 1 H and 13 C NMR spectra of all new compounds.CCDC 1429493.For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ob00165c metathesis (RCEYM) reaction of the resulting enyne and a hydrogen bond directed Diels-Alder reaction (Scheme 1). 14sing a range of dienophiles, this allowed the late-stage synthesis of a library of partially saturated indane ring systems.More recently the one-pot method has been extended to include a cross-metathesis step leading to the rapid preparation of C-4 substituted analogues with up to five stereogenic centres. 15While this approach permitted the facile preparation of a range of amino substituted bicyclo[4.3.0]nonanes,we found that some of the one-pot processes required particularly long reaction times and this was in part due to using thermal conditions to implement the Overman rearrangement (36 h). 14,15In previous studies, we found that alkene and alkyne derived allylic trichloroacetimidates would not undergo effective palladium(II)-catalysed rearrangements due to binding of the catalyst to the unsaturated side-chains. 13,16We were interested in exploring the structural requirements of alkyne derived allylic alcohols that could block catalyst side-chain binding and perform a Pd(II)-catalysed Overman rearrangement as part of a more rapid one-pot process leading to new C-5 substituted aminobicyclo[4.3.0]nonanes.We now report the synthesis of a series of C-7 substituted hept-2-en-6yn-1-ols and the evaluation of these compounds to undergo a Pd(II)-catalysed Overman rearrangement.As well as using these allylic alcohols as substrates for a one-pot multistep process for the diastereoselective preparation of novel aminobicyclo-[4.3.0]nonanes,we also report further functionalisation of these products to generate highly substituted sp 3 -rich, druglike polycyclic scaffolds with up to six stereogenic centres.
The ability of hept-2-en-6-yn-1-ols 15-19 to undergo a Pd(II)catalysed Overman rearrangement was next investigated.The study began by exploring the rearrangement of mono-substituted alkyne, (2E)-hept-2-en-6-yn-1-ol (15) (Table 1, entry 1).Allylic alcohol 15 was converted to the corresponding allylic trichloroacetimidate using trichloroacetonitrile and a catalytic amount of DBU. 21Using standard conditions for a Pd(II)-catalysed Overman rearrangement (10 mol% catalyst loading at rt), 22 only small amounts (<10%) of allylic trichloroacetamide 20 could be observed by NMR spectroscopy.A number of reactions were then performed to elucidate the optimal conditions for the preparation of 20.It was found that addition of a second batch of catalyst after 24 h and conducting the entire reaction at 40 °C gave allylic trichloroacetamide 20 in 34% yield after a reaction time of 48 h.The elevated temperature, high catalyst loading and long reaction time are exemplary of the conditions required for metal catalysed rearrangement of allylic trichloroacetamides bearing mono-substituted unsaturated side-chains.The rearrangement of disubstituted alkyne derived allylic trichloroacetamides was next investigated.While a methyl substituent is relatively small, the use of this group was sufficient to partially retard catalyst binding and allow rearrangement using only 10 mol% of catalyst at 20 °C (entry 2).This gave allylic trichloroacetamide 21 in 55% yield after 24 h.Using aryl groups with substantially more bulk proved effective and allowed the efficient synthesis of the corresponding allylic trichloroacetamides 22-24 in high yields after a 12 h reaction time (entries 3-5).Interestingly, the yields were independent of the electronic nature of the aryl groups indicating that the steric bulk of these substituents is primarily responsible for preventing binding of the catalyst to the alkyne moiety.
Having identified the structural requirements and optimal conditions for an efficient Overman rearrangement, these were incorporated into a one-pot multi-reaction process including a Ru(II)-catalysed RCEYM step 23 and a Diels-Alder reaction for the preparation of novel aminobicyclo[4.3.0]nonanes (Scheme 3).Preliminary attempts at the one-pot preparation of 25 from phenyl substituted allylic alcohol 17 using Grubbs 2 nd generation catalyst (7 mol%) 24 for the RCEYM step and N-phenyl maleimide as a dienophile for the Diels-Alder step, under previously developed conditions for these reactions 14,15 gave low yields of 25 (∼25%).Analysis of the 1 H NMR spectrum of the reaction mixture showed the presence of the 1,6-enyne 22, indicating that the RCEYM step had not gone to completion.This was unsurprising as disubstituted, bulky alkynes often show suppressed reactivity during RCEYM reactions. 23Methods for improving this step were investigated.A combination of the use of 1,7-octadiene as an in situ source of ethylene 25 and a higher reaction temperature (from 75 to 90 °C) resulted in an accelerated RCEYM reaction, allowing complete conversion of 1,6-enyne 22 to the corresponding cyclopentyl exo-diene.Using these modified conditions as part of the one-pot process gave 5-phenyl aminobicyclo[4.3.0]nonane 25 as a single diastereomer in 51% overall yield from allylic alcohol 17 (Scheme 3). 26As previously reported for the Diels-Alder reaction of trichloroacetamide derived cyclic exo-dienes, the reaction proceeds via a hydrogen bonding directed endo transition state, generating the syn-products with excellent diastereoselectivity (>20 : 1). 14The relative stereochemistry of 25 was confirmed by difference NOE experiments, which showed the syn relationship of the hydrogen atoms at C-3a, C-8, C-8a and C-8b. 27For comparison, use of the optimised one-pot process was applied to methyl substituted allylic alcohol 16 which gave 26 in 25% overall yield.The significantly lower yield for 26 is a consequence of the less efficient Overman rearrangement for this analogue.Using phenyl derived allylic alcohol 17, the scope of the one-pot multistep process was explored using various dienophiles.In all cases, the compounds were formed as single diastereomers in good yields over the four steps (40-56%).It should be noted that the non-symmetrical dienophile, methyl acrylate gave indane 29 as a single regioisomer.This again is a direct consequence of the hydrogen bonding directed endo transition state. 14s well as developing a one-pot synthesis of aminobicyclo-[4.3.0]nonanes using consecutive Pd(II)-and Ru(II)-catalysis, another major objective of this research programme was to probe the effect of electron-deficient and electron-rich aryl substituted alkynes on the outcome of the RCEYM step and the subsequent one-pot process.While 1,6-enynes bearing electron-deficient alkyne substituents have been shown to have a detrimental effect on RCEYM reactions, 23a,28 examples with electron-poor aryl groups have given excellent yields under forcing conditions. 28Using (2E)-7-(4′-nitrophenyl)hept-2-en-6yn-1-ol (18) as a substrate for the one-pot multistep process and N-phenyl maleimide as the dienophile, gave 4-nitrophenyl substituted aminobicyclo[4.3.0]nonane 30 as a single diastereomer in 69% yield.In a similar fashion, use of 4-phenyl-1,2,4triazole-3,5-dione, tetracyanoethylene or methyl acrylate as dienophiles for the Diels-Alder step allowed the preparation of 4-nitrophenyl substituted aminobicyclo[4.3.0]nonanes31-33 in good overall yields.Despite being sterically encumbered and electron-deficient, the 1,6-enyne produced during these one-pot processes seems able to undergo a highly effective RCEYM reaction under our optimal conditions.A more stable cyclopentyl exo-diene and a cleaner subsequent Diels-Alder reaction may account for the elevated yields of the 4-nitrophenyl series compared to the phenyl-substituted compounds.
Electron-rich allylic alcohol (2E)-7-(4′-methoxyphenyl)hept-2-en-6-yn-1-ol (19) was then converted to the allylic trichloroacetamidate and subjected to the one-pot, three-step process using N-phenyl maleimide as the dienophile.This gave the corresponding 4-methoxyphenyl substituted aminobicyclo-[4.3.0]nonane34 in only 34% yield.Analysis of the individual steps of the one-pot process revealed that while the electronrich cyclopentyl exo-diene was readily formed during our optimised conditions for the RCEYM reaction, the temperature (90 °C) of this transformation was resulting in decomposition of the highly reactive diene.On screening various temperatures for the RCEYM reaction of electron-rich 1,6-enyne 24, it was found that the reaction proceeded to completion at a much lower temperature of 40 °C.Despite application of this optimised RCEYM step, one-pot reactions using allylic alcohol 19 still gave modest yields of the 4-methoxyphenyl substituted aminobicyclo[4.3.0]nonane34.As such, the preparation of this final series of compounds was conducted as two separate processes.Following efficient large-scale preparation of allylic trichloroacetamide 24 (Table 1), this was subjected to a one-pot, two-step process involving the low temperature RCEYM step and a Diels-Alder reaction with various electron-deficient dienophiles (Scheme 4).This allowed the synthesis of 4-methoxyphenyl substituted aminobicyclo[4.3.0]nonanes34-37 as single diastereomers in good yields over the two steps.
Having synthesised a novel library of aminobicyclo[4.3.0]nonanes, a preliminary study was conducted to explore further functionalisation of these compounds and in particular, the reactivity of the tetra-substituted alkene moiety.Initially, hydrogenation of 25 was attempted under standard conditions (Scheme 5).However, after 48 h, partial reduction of the trichloromethyl group was the only change detected, giving the dichloroacetamide in 48% yield.Despite the resistance of the tetra-substituted alkene to undergo hydrogenation, oxidation of the moiety was readily observed.For example, reaction of 25 with osmium tetroxide in the presence of TMEDA under Donohoe conditions 29 gave dihydroxy derivative 39 as a single diastereomer in quantitative yield after only 3 h.Based on the shape of aminobicyclo[4.3.0]nonane 25, it was expected that reactions of the alkene would take place from the more exposed convex face of the molecule.This was confirmed by X-ray crystallography.The (3aS*,5R*,5aR*,8R*,8aR*,8bR*)stereoisomer 39 was found to crystallise in the triclinic space group P1 ˉand the structure clearly shows the syn relationship

Conclusions
In summary, a series of C-7 substituted hept-2-en-6-yn-1-ols have been examined as substrates for the one-pot diastereoselective synthesis of sp 3 -rich aminobicyclo[4.3.0]nonanes.The presence of the C-7 groups allowed an effective Pd(II)-catalysed Overman rearrangement to proceed.Incorporation of this transformation into a one-pot, three-step process involving a Ru(II)-catalysed RCEYM reaction and a hydrogen bonding directed Diels-Alder reaction gave a range of aminobicyclo-[4.3.0]nonanes in good overall yields.The effect of the electronic nature of the aryl substituent on the RCEYM step was also studied and while an electron-poor analogue could be used as a substrate for the one-pot process using forcing conditions for the RCEYM step, the electron-rich cyclopentyl exodiene was found to undergo decomposition during the multistep process.Nevertheless, a series of 4-methoxyphenyl substituted aminobicyclo[4.3.0]nonanes could be prepared efficiently using a one-pot, two-step process from the allylic trichloroacetamide.The reactivity of these novel compounds was also explored and aminobicyclo[4.3.0]nonane 25 was readily oxidised, generating dihydroxy and epoxide derivatives as single diastereomers in high yields.The combination of the one-pot, three-step multireaction process with the oxidations allowed the rapid preparation of these sp 3 -rich, drug-like polycyclic scaffolds with six stereogenic centres.With the development of an effective one-pot synthesis of these compounds using a Pd(II)-catalysed rearrangement, work is currently underway to incorporate chiral Pd(II)-catalysts for their asymmetric synthesis and preparation of natural product targets.

Experimental
All reagents and starting materials were obtained from commercial sources and used as received.All dry solvents were purified using a PureSolv 500 MD solvent purification system.All reactions were performed under an atmosphere of argon unless otherwise mentioned.Flash column chromatography was performed using Fisher matrix silica 60.Macherey-Nagel aluminium-backed plates pre-coated with silica gel 60 (UV254) were used for thin layer chromatography and were visualised by staining with KMnO 4 . 1 H NMR and 13 C NMR spectra were recorded on a Bruker DPX 400 spectrometer with chemical shift values in ppm relative to TMS (δ H 0.00 and δ C 0.0) or residual chloroform (δ H 7.26 and δ C 77.2) as standard.Proton and carbon assignments are based on two-dimensional COSY and DEPT experiments, respectively.Mass spectra were obtained using a JEOL JMS-700 spectrometer for EI and CI or a Bruker Microtof-q for ESI.Infrared spectra were obtained neat using a Shimadzu IRPrestige-21 spectrometer.Melting points were determined on a Reichert platform melting point apparatus.

X-ray procedure for 39
Single crystal diffraction data for 39 were collected by the EPSRC UK National Crystallography Service. 38Data reduction was carried out using Crysalis PRO (Agilent Technologies, 2014).The structure was solved by charge-flipping methods using SuperFlip 39 and refined against F 2 using full-matrix least-squares refinement using SHELX2014 40 within OLEX2. 41ositional and anisotropic atomic displacement parameters (adps) were refined for all non-hydrogen atoms.Hydrogen atoms bound to carbon and nitrogen atoms were placed at calculated positions and refined as part of a riding model except for the MeOH methyl hydrogen and all hydroxyl hydrogen atoms which located in difference Fourier maps and were refined as a rigid rotor.There are two independent molecules of both the compound and of MeOH in the asymmetric unit although the conformation of the two molecules is essentially the same.
of the hydrogen atoms at C-3a, C-8, C-8a and C-8b and the hydroxyl groups at C-5 and C-5a (Fig.2).30,31In a similar fashion, reaction of 25 with m-CPBA gave epoxide 40 as a single diastereomer in 65% yield.

Fig. 2
Fig.2View showing the structure of one of the crystallographically independent molecules of 39.Atomic displacement ellipsoids are drawn at 50% probability level.