Straightforward synthesis of chiral non-racemic a -boryl isocyanides

A straightforward concise synthesis of chiral non-racemic aliphatic a -boryl isocyanides, relay intermediates for boron-based bioactive molecules by using multicomponent reaction, is presented. The short synthetic sequence comprises as key steps copper-catalysed asymmetric borylation of imine, simultaneous nitrogen formylation/boron-protecting group interconversion and final formamide dehydration reaction.


Introduction
Boron containing molecules (BCMs) gained much attention due to their usefulness as building blocks in organic synthesis, mainly as preferred reagents in palladium-catalysed C-C bond forming reactions. 1In addition, in the last decade, several BCMs with biological activity have been surfaced from academia and pharmaceutical companies as new therapeutic agents.Indeed, a cyclic boronic acid (vaborbactam) has been approved as novel b-lactamase inhibitor to fight bacterial antibiotic resistance and two dipeptidyl boronic acids (bortezomib and ixazomib) have been approved as proteasome inhibitors for the treatment of multiple myeloma.1b,2 The latter type of BCMs belongs to the boron-containing peptides, where the carboxylate of the last AA is replaced by a boronic acid group.The boropeptide synthesis carried out started with the synthesis of chiral enantiopure aaminoboronic unit obtained by the Matteson homologation protocol,1b,3 or by borylations of chiral sulfinylimines.1b,4 These a-aminoboronates are then sequentially coupled with the corresponding amino acids or simple carboxylic acids, through the traditional peptide coupling chemistry. 5Recently, an attractive methodology appeared in literature, where the boropeptide has been synthesised exploiting a multicomponent reaction (MCR), 6 thus envisioning a rapid exploration of chemical space for such peptidomimetics.As a matter of fact, Yudin and co-workers introduced for the first time the synthesis of stable 7 a-boryl isocyanide rac-1, 8 as a suitable reagent for the Passerini (P3CR), 9 and Ugi (U4CR) 10 multicomponent reactions.Remarkably, protected racemic bortezomib was synthesised in one step from the selected carboxylic acid, aldehyde, ammonia and a-boryl isocyanide rac-1 under U4CR condition.In addition, a-acyloxy carboxamides were successfully obtained from rac-1, under P3CR condition. 8Given the high atom economy, the operational simplicity and the high convergent character of this synthetic approach, the accessibility of a-boryl isocyanides 1 in enantiopure form should maximise the efficiency of the overall process.In the cited work, racemic a-Boryl isocyanides rac-1 were synthesised by a six steps synthetic sequence starting from the corresponding alkenylboronic acid (Scheme 1, top). 11Scheme 1. Rational design behind the synthesis of chiral enantiopure a-Boryl isocyanides 1.

Results and discussion
For the isobutyl derivative, the synthetic sequence commenced with the borylation of the t-butylsulfinyl imine 4a, 13 as chiral enantiopure auxiliary used for the diastereomeric borylations in the optimised condition reported by Ellman and co-workers in 2014 (Scheme 2). 4 The crude borylated adduct was directly hydrolysed with HCl 4M in dioxane, in dry methanol for 2h to attain 3a in very good yield from the sulfinyl imine 4a by simple trituration (85%, Scheme 2).
The next step involved a one pot/two-steps procedure where the ammonium salt 3a underwent a simultaneous boronprotecting group interconversion and C-N bond formation to obtain the related N-formyl -B-MIDA adduct 2a.
An extensive optimisation was conducted, and representative resulted are reported in table 1: formylating agent and the use of a DMF in combination with the increase of temperature were screened.After the optimization we were able to merge both the Nformylating and B-Pin à B-MIDA processes in a one pot fashion by using triethylortoformate as formylating/mild dehydrating agent and MIDA, in DMF, obtaining 2a with 65% yield, by simple precipitation (Scheme 2, centre).The final step involved the dehydration of the formyl derivative 2a.In Table 2 a short optimisation performed for the dehydration step is shown.POCl3 in combination with Et3N proved to be the reagents of choice for the synthesis of the corresponding isocyanide 1a, with good results in terms of yield and easy to handle purification.As highlighted in Scheme 2 (bottom) performing the reaction with an excess of POCl3 and triethylamine at 0 °C afforded the isocyanide 1a with 75 % yield, by extracting with CH2Cl2 and washing the organic phase with saturated NaHCO3.The isocyanide was found spectroscopically pure and quite Please do not adjust margins Please do not adjust margins suitable for a multicomponent reaction.To address a possible racemisation during the last two-steps, compound 1a was analysed by using Pirkle's alcohol as CSA (Chiral Shifts Agents) with 1 H NMR technique (See ESI for more details). 1H doublet at 4.12 ppm, belonging to one of the diastereotopic hydrogen of the MIDA group, was chosen as a suitable signal for the CSA splitting (enlargement b, Figure 1).The enlargement c (Figure 1) shows a 98:2 ratio between 1a and ent-1a, this result has been validated by adding a small amount of ent-1a to the sample 1a : Pirkle's alcohol 1:20 (enlargement d, Figure 1).The enantiomeric ratio of 1a remained 98:2 along the synthetic sequence confirming the mild reaction conditions of the two final steps.Starting from imine 4a, chiral enantiopure isocyanide 1a was synthesised for the first time in three synthetic steps, with an overall yield of 41%, overcoming late-stage column chromatography purification, potentially detrimental for the efficiency of the process.With the overall synthetic sequence established, several substrates have been chosen to broaden the scope of the process (Scheme 3).The diastereomeric borylation/hydrolysis resulted to be quite robust, the corresponding ammonium salts ent-3a, 3b-f were isolated by simple trituration of the crude with a minimum amount of MTBE/n-hexane, a relatively nontoxic mixture.Several substrates have been used bearing an alkyl chain with different degree of steric hindrance and in presence of aromatic or heteroaromatic rings.Primary and secondary b-branching aliphatic a-ammoniumboronic acid pinacol esters ent-3a, 3b-f were obtained in satisfactory to excellent yields over two synthetic steps from the imines ent-4a, 4b-f 14 (Scheme 3, top).This two-steps procedure was suitable even for an aromatic substituent directly attached to the carbon-boron moiety with 84% yield; unfortunately, this compound was not suitable for further modification (vide infra).In addition, the borylation of tertiary a-branched imine, under aqueous condition, did not take place, probably due to steric hindrance. 15Scheme 3. Substrate scope for the synthesis of chiral non-racemic a-boryl isocyanide ent-1a, 1b-f, starting from t-butylsulfinylimine ent-4a, 4b-f.a Opposite enantiomer ent-4a was obtained from the condensation of isovaleraldehyde with (S)-sulfinyl amide.b Reaction conditions.Borylation: reactions were carried out using 1.8-7.1 mmol of ent-4a, 4b-f.c Reaction conditions.Hydrolysis: reactions were carried out using crude Nprotected B-pin adducts.d Opposite enantiomer.e Reactions were carried out using 0.4-1.4mmol of 3a-f.f Reactions were carried out using 0.1-0.4mmol of 2a-f.The subsequent step involved the transformation of ammonium salts ent-3a, 3b-f into N-formyl-B-MIDA adducts ent-2a, 2b-f.The procedure was quite sturdy for substrates bearing an aliphatic group attached to the alpha carbon: ent-2a, 2b-f were Please do not adjust margins Please do not adjust margins attained at reflux (150 °C), after the stated time (2-5 h), with moderated to good yields, by precipitating the crude mixture by using CH2Cl2/diethyl ether mixture (Scheme 3, centre).Aromatic substrate was not suitable for the formylation/B-MIDA transformation conditions and only deboronated side products were recovered at the end of several attempts.The final step for the synthesis of a-boryl isocyanide ent-1a, 1bf regarded an easy-to-handle dehydration of formyl derivatives ent-2a, 2b-f by using and excess of POCl3 and Et3N. 16The corresponding products were isolated from the crude by extracting with CH2Cl2 and washing the organic phase with saturated NaHCO3.The isocyanides were found spectroscopically pure and suitable for a multicomponent reaction.

Conclusions
Straightforward concise reaction sequence is introduced to access chiral non-racemic a-boryl isocyanides ent-1a, 1a-f with overall 17-37% yield over four synthetic steps from the corresponding aldehyde, with convenient purification procedures.Several a-ammonium boronic acid pinacol esters 3a-f were easily attained, and then by introducing a novel simultaneous functional group interconversion at the boron atom and a N-formylation reaction we opened a new path towards the synthesis of chiral non-racemic aliphatic a-boryl isocyanide 1, one of the most desired relay building blocks to use in MCR, for the synthesis of boron-based b-lactamases and proteasome inhibitors.The straightforward synthetic sequence could trigger the design and the easy access of several boron containing inhibitor libraries.

General Synthetic procedures
Borylation of imines 4a-f and subsequent hydrolysis for the synthesis of 3a-f.In a 25 ml round bottomed flasks with magnetic stirring bar, PCy3•HBF4 (1.2 mol%) in toluene (0.06 M) was added.Then an aqueous solution of CuSO4 (1.2 mol%, 0.03M) and benzylamine (5 mol%) were added.The flask is closed and left under stirring for 15 minutes.Afterward t-butylsulfinylimine 4a-f (1 eq., 1.8 -7.1) in toluene (0.5 M) and B2Pin2 (2 eq.) were sequentially added.The flask is kept stirring with a refrigerator at 20°C for 24h.Water (10ml per mmol of imine) was poured in the crude mixture and extracted with AcOEt (3x10ml per mmol of imine).The organic phase was washed with water (10ml per mmol of imine) and brine (10ml per mmol of imine), dried over MgSO4, filtered and evaporated under reduced pressure.The crude mixture was dissolved in dry CH3OH (0.5 M) and cooled down to 0°C and treated with anhydrous HCl 4M in dioxane (1 eq.) under argon.The resulting solution is left for 2h at 20 °C.After the stated time the crude mixture was evaporated under reduced pressure and the crude ammonium salts was triturated with MTBE/n-hexane to afford 3a-f as pale yellow solid and then used for the next step.
Direct one pot/two-steps C-N bond formation and FGI from compounds 3a-f to N-formyl adducts 2a-f.In a Schlenk tube, with magnetic stirring bar, were added 3a-f (1eq.) and MIDA (1.1 eq.) under argon.Then triethylortoformate (4.0 eq.) and dry DMF (2.5 M) were sequentially added.The resulting mixture is warmed up until reflux (150°C).After the stated time (2-5 h) the reaction mixture is cooled down, diluted with CH2Cl2 and solvents were evaporated under reduced pressure.The is then solubilised with the minimum amount of CH2Cl2 and precipitated with diethyl ether.The pale-yellow solid is further triturated with diethyl ether to obtain spectroscopically pure N-formyl adducts 2a-f.Synthesis of a-boryl isocyanide 1a-f from N-formyl adducts 2a-f by using POCl3 and Et3N.In a pear-shaped flask, with magnetic stirring bar, compounds 2a-f (1 eq., 0.1-0.67 mmol) and CH2Cl2 (0.1 M) were sequentially added.The solution was kept at 0°C for 5 minutes.Then Et3N (5.0 eq.) was slowly added followed by POCl3 (1.5 eq.).The reaction mixture was stirred at 0°C for 1.5 h.Afterwards the reaction was quenched with saturated NaHCO3 (3 ml) and stirred for 10 minutes.The organic layer was separated and the aqueous one was extracted with CH2Cl2 (3 x 3 ml).The reunited organic phases were added 500 ml of Et3N, washed with saturated NaHCO3 (3 x 10 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain aboryl isocyanide 1a-f.Compounds 1a-f resulted to be spectroscopically pure.
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Table 1 .
Representative results from the optimisation of compounds 2a.
a 0.5 ml of DMF per mmol of 3a was used b In parenthesis is reported the isolated yield of compound

Table 2 .
Representative results for the dehydration of 2a to obtain isocyanide 1a.