Structural diversification of the aminobicyclo [ 4 . 3 . 0 ] nonane skeleton using alkynylsilyl-derived allylic trichloroacetimidates †

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Introduction
The amino substituted bicyclo[4.3.0]nonanecore is found in various natural products, 1 such as guanidine alkaloid netamine A (1), 2 the antitumour antibiotics (+)-ptilocaulin (2) 3 and kinamycin A (3), 4 as well as the lycopodium alkaloid serratinine (4) (Fig. 1). 5 Amino-indanes, a partially saturated form of the aminobicyclo[4.3.0]nonane scaffold are also found in a diverse range of pharmacologically important compounds including the monoamine transporter inhibitor (+)-indatraline (5) 6 and, rasagiline (6) (Azilect), used for the treatment of Parkinson's disease. 7While there are synthetic methods for the preparation of specific aminobicyclo[4.3.0]nonanes, 8 there are relatively few general strategies for the stereoselective synthesis of this scaffold that is modular, allowing late-stage structural diversification. 9ith the aim of developing new strategies for the preparation of drug-like scaffolds, we reported a one-pot, three-step multi-bond forming process of alkyne derived allylic alcohols that utilised an Overman rearrangement, a ring closing enyne metathesis (RCEYM) step and a Diels-Alder reaction for the general preparation of aminobicyclo[4.3.0]nonanes. 10More recently the diversity of this library was extended by using C-7 substituted hept-2-en-6-yn-1-ols (Scheme 1a). 11As well as yielding aminobicyclo[4.3.0]nonanes with additional functionality, the presence of a C-7 substituent within the allylic trichloroacetimidate substrate, allowed the use of mild palladium(II)catalysed conditions for the Overman rearrangement step. 12lthough diversity could be introduced into the aminobicyclo [4.3.0]nonane core during the final-stage Diels-Alder reaction, the other point of diversity was via a Sonogashira reaction during the first step.This required substantial effort to generate a small library of these compounds with various R-groups.To overcome this limitation, we decided to investigate an alternative C-7 substituent that would be compatible with the synthesis of alkyne-derived allylic trichloroacetimidates, allow a Pd(II)-catalysed Overman rearrangement and be used as a functional handle for late-stage diversification.We now report the use of alkynylsilyl derived allylic trichloroacetimidates as substrates for the one-pot multi-bond forming process and the diastereoselective synthesis of aminobicyclo[4.3.0]nonanesbearing a vinylsilane functional handle (Scheme 1b).We also demonstrate the synthetic utility of a benzyldimethylsilyl (BDMS) analogue for the late-stage synthesis of a small library of novel, drug-like aminobicyclo[4.3.0] nonanes with up to six stereogenic centres.

Results and discussion
The first aim of this project was the synthesis of a hept-2-en-6yn-1-ol bearing a C-7 silyl group.Although a wide-range of silanes have been developed for cross-coupling reactions, 13 the BDMS group 14 was chosen as this was likely to be stable to the various steps required for allylic alcohol synthesis and the conditions of the one-pot process.While the vinyl-BDMS functionality is relatively robust, it has been used in a number of Hiyama-Denmark type couplings. 15To probe the steric requirements of the one-pot three-step process, the tertbutyldimethylsilyl (TBDMS) analogue was also prepared.Initially, pent-4-yn-1-ol bearing a C-5 TBDMS group was prepared in a one-pot operation by silylation of both the alkyne and alcohol moieties, followed by acid-mediated hydrolysis of the silyloxy group (Scheme 2). 16While this allowed rapid access to 5-(tert-butyldimethylsilyl)pent-4-yn-1-ol (8), the overall yield was only 31%.Therefore, preparation of the corresponding BDMS analogue 11 was performed in a stepwise fashion, with protection of the hydroxyl group as a THP ether before silylation of the alkyne with benzyldimethylsilyl chloride under basic conditions. 17Removal of the THP protecting group then gave 5-(benzyldimethylsilyl)pent-4-yn-1-ol (11) in quantitative yield over the three steps.The pent-4-yn-1-ols 8 and 11 were converted to the (E)-α,β-unsaturated ethyl esters 12 and 13 in high yields using a one-pot Swern oxidation and Horner-Wadsworth-Emmons reaction under mild Masamune-Roush condtions. 18,19Reduction of the ester groups using DIBAL-H then gave allylic alcohols 14 and 15 in excellent yields.The highly efficient six-step route (90% overall yield) for the preparation of BDMS-derived allylic alcohol 15 was easily amenable to scale-up, allowing synthesis of multigram quantities of this key substrate.
Having prepared the alkynylsilyl derived allylic alcohols, conditions for an optimal one-pot synthesis of the corresponding aminobicyclo[4.3.0]nonanes were next explored.The TBDMS-analogue that was designed to probe the steric limitation of the one-pot process was initially investigated (Scheme 3).The allylic trichloroacetimidate was formed by reaction of 14 with trichloroacetonitrile and DBU and without purification, 20 this was subjected to the one-pot three-step process.In our previous study that evaluated C-7 substituted alkyne derived allylic alcohols for the one-pot process, it was found that while a relatively bulky substituent prevented coordination of the Pd(II)-catalyst to the alkyne and facilitated an efficient Overman rearrangement, the presence of this group hindered the following RCEYM step.11b With the TBDMS-derived allylic trichloroacetimidate, a similar outcome was observed for both steps.The Pd(II)-catalysed Overman rearrangement proceeded under standard conditions to give the allylic trichloroacetamide after 12 hours, 21 however, the RCEYM reaction required forcing conditions.A combination of the use of 1,7-octadiene (an in situ source of ethylene) to accelerate the reaction, 22 high loading of Grubbs 2 nd generation catalyst (20 mol%) and a 120 hour reaction time was required for complete conversion to the enyne. 23Following the hydrogen bonding directed Diels-Alder reaction with N-phenyl maleimide, aminobicyclo[4.3.0]nonane16 was isolated as a single diastereomer in 19% yield over the four steps.This rela-tively low yield is likely due to the extended RCEYM step and demonstrates the steric limitation of the one-pot process.
Application of the one-pot process using BDMS-allylic alcohol 15 was more straightforward (Scheme 3).Again, allylic trichloroacetimidate formation and Pd(II)-catalysed Overman rearrangement proceeded under standard conditions.The RCEYM reaction did require the presence of 1,7-octadiene, but needed only 7 mol% catalyst loading and was complete after 18 hours.Diels-Alder reaction with N-phenyl maleimide then gave aminobicyclo[4.3.0]nonane 17 as a single diastereomer in 57% yield over the four steps.As previously reported for the Diels-Alder reaction of trichloroacetamide derived cyclic exodienes, the reaction proceeds via a hydrogen bonding controlled endo transition state, forming the syn-products (syn relationship of hydrogen atoms at C-3a, C-8, C-8a and C-8b) with excellent diastereoselectivity (>20 : 1). 10,11Analysis of BDMS-derived aminobicyclo[4.3.0]nonane 17 using difference NOE experiments confirmed the relative stereochemistry and that the Diels-Alder reaction has proceeded in the same manner as other trichloroacetamide derived cyclic exo-diene substrates (Scheme 3). 24aving used the BDMS-group to perform a mild Pd(II)-catalysed Overman rearrangement and efficiently access the aminobicyclo[4.3.0]nonanecore, we next wanted to demonstrate that the resulting vinylsilane could be used for the late-stage synthesis of a wide range of derivatives.Initially, removal of the trialkylsilyl group to access the parent scaffold was investigated (Scheme 4).During introduction of the BDMS-group for cross-coupling reactions, Trost and co-workers showed that BDMS-vinylsilanes were stable to proto-desilylation under typical fluoride conditions. 14This was confirmed on treatment of vinylsilane 17 with TBAF, which showed no reaction.Increasing the temperature or duration of the reaction only led to decomposition.Cleavage of the C-Si bond was achieved under acidic conditions.While the use of dilute hydrochloric acid solutions (2 M or 4 M) gave only partial proto-desilylation, treatment of 17 with 6 M hydrochloric acid at 60 °C gave 18 cleanly, in 74% yield.The reactivity of tri-substituted alkene 18 to oxidation was next studied.Osmium tetroxide mediated dihydroxylation under Donohoe conditions gave the desired diol product 19 as a single diastereomer in 86% yield. 25In a similar fashion, treatment of 18 with m-CPBA proceeded with high selectivity and the major diastereomer 20 was isolated in 73% yield. 26,27The high selectivity for both reactions is a consequence of the relative stereochemistry at the C-3a, C-8, C-8a and C-8b positions of the tricyclic core of 18.This creates a curved shape to the molecule where reactions readily take place at the more exposed convex face.
The final stage of this project then investigated cross-coupling reactions of vinylsilane 17 for the late-stage diversification of the aminobicyclo[4.3.0]nonanecore.Using standard conditions for Hiyama-Denmark reactions with the BDMSgroup, 14 attempts were made to couple 17 with various electron-rich and electron-deficient aryl iodides.However, these reactions showed only decomposition of vinylsilane 17.Due to the inability of 17 to undergo cross-coupling reactions, an alternative strategy was sought using a more reactive vinyl functionality.Iodo-desilylation of vinylsilane 17 was found to proceed readily with iodine monochloride and gave vinyl iodide 21 in 88% yield (Scheme 5). 28This was then used to explore various palladium-catalysed cross-coupling reactions.
After some optimisation, vinyl iodide 21 was found to be an efficient cross-coupling partner for Suzuki-Miyaura reactions.
Using Pd(PPh 3 ) 4 (10 mol%) and phenylboronic acid under typical conditions gave the cross-coupled product 22 in 76% yield.Reaction of an electron-rich variant, p-methoxyphenylboronic acid also proceed smoothly, giving 23 in 53% yield.In previous studies, we have found that the trichloroacetamide group is prone to dechlorination during Pd(0)-catalysed reactions.11b, 29 Similarly, in the Suzuki-Miyaura reactions to form 22 and 23, small amounts of dichloroacetamide analogues of these compounds were observed in the reaction mixture (<10%).This became a more significant issue in attempting a cross-coupling reaction with electron-defficient p-fluorophenylboronic acid, where substantial amounts of the reduced coupled product were also detected (∼20%).However, this byproduct could be minimised (<10%) by using a shorter reaction time, which allowed the synthesis of 24 in 46% yield.To expand the diversity of aminobicyclo[4.3.0]nonanes at the C-5 position, a Sonogashira reaction with phenylacetylene was also performed.For this example, both palladium-mediated coupling and reduction of the trichloroacetamide were found to be rapid, leading to isolation of the dichloroacetamide-derived enyne 25 as the major product, in 48% yield.

Conclusions
In conclusion, two alkynylsilyl derived allylic trichloroacetimidates have been prepared and evaluated as substrates for a one-pot multi-reaction process for the preparation of novel aminobicyclo[4.3.0]nonanes.While a TBDMS-derivative showed the steric limitations of this process, a BDMS-analogue was efficiently converted to the corresponding aminobicyclo [4.3.0]nonane in good overall yield.The BDMS-compound was then explored for the late-stage diversification of the aminobicyclo[4.3.0]nonanecore.Vinylsilane 17 was found to undergo both proto-desilylation and iodo-silylation reactions, leading to derivatives that could undergo a range of oxidation and cross-coupling reactions.Overall, this study has developed a general route to novel, sp 3 -rich aminobicyclo[4.3.0]nonanesincorporating diversity at a late-stage of the synthesis.To exemplify the strategy, the project focused on using a single dienophile, N-phenyl maleimide during the Diels-Alder reaction.However, as shown in previous studies, 11 we believe that other alkenes will react readily with the BDMS-derived diene allowing further late-stage expansion of the compounds that can be formed via this process.Work is currently underway to achieve this goal and explore further reactions of BDMS-derived aminobicyclo[4.3.0]nonanes.

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.Brine refers to a saturated solu-tion of sodium chloride.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 and 13 C NMR spectra were recorded on a Bruker DPX 400 ( 1 H: 400 MHz; 13 C: 101 MHz) spectrometer or a Bruker 500 ( 1 H: 500 MHz; 13 C: 126 MHz) spectrometer with chemical shift values reported in ppm relative to a residual solvent peak and in the solvent stated.Assignment of 1 H NMR signals is based on COSY experiments.Assignment of 13 C NMR signals is based on HSQC and/or DEPT experiments.All coupling constants, J, are quoted in Hz.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.