Enantioselective semireduction of allenes

Rh-hydride catalysis solves a synthetic challenge by affording the enantioselective reduction of allenes, thereby yielding access to motifs commonly used in medicinal chemistry. A designer Josiphos ligand promotes the generation of chiral benzylic isomers, when combined with a Hantzsch ester as the reductant. This semireduction proceeds chemoselectively in the presence of other functional groups, which are typically reduced using conventional hydrogenations. Isotopic labelling studies support a mechanism where the hydride is delivered to the branched position of a Rh-allyl intermediate.

I n nature, chemo-and stereocontrolled reduction of unsaturated bonds are catalysed by enzymes and mediated by cofactors such as nicotinamide adenine dinucleotide phosphate (NAD(P)H) 1 . Inspired by this cofactor, chemists have used Hantzsch esters as mild reagents to solve various challenges in asymmetric reductions 2 . It occurred to us that this cofactor mimic could be combined with Rh-hydride catalysis to enable a valuable strategy for reducing allenes to generate benzylic motifs, which are traditionally made by an allylic substitution between an allylic electrophile and an organometallic reagent [3][4][5][6][7] or a hydride source [8][9][10][11][12][13][14] (Fig. 1a). As allenes are readily accessible 15 , a method to access these motifs through a semireduction of allenes would avoid the pre-installation of a suitable leaving group. Allenes are challenging functional groups for reduction because of problems with chemo-, regio-, and stereoselectivity. Both π-bonds can be reduced to the corresponding alkane (Fig. 1b), or one π-bond can be reduced to afford one or a mixture of alkene isomers (Fig. 1c). Before studies in the regioselective semireduction of allenes have shown that the less substituted π-bond is typically reduced to  [16][17][18] . Existing methods that reduce the more substituted π-bond are limited to monosubstituted and symmetrical allenes, which give rise to achiral terminal alkenes 19,20 .
The generation of electrophilic metal-allyl species from allenes using iridium-and rhodium-hydrides is an emerging strategy in allene hydrofunctionalisation 21,22 . These intermediates can undergo allylic substitution with various nucleophiles to afford branched allylated products. We envisioned that a Rh-hydride catalyst would transform an allene to an electrophilic Rh-allyl intermediate, which can then be trapped with a hydride nucleophile [23][24][25][26] . Given that allenes are known to isomerise to dienes in the presence of transition metal-hydrides 27 , we recognise that a key challenge would be identifying a catalyst that promotes semireduction over isomerisation.
Herein, we demonstrate an asymmetric semireduction of allenes enabled by Rh-hydride catalysis as a complementary approach to allylic alkylation and allylic reduction to generate chiral benzylic motifs. Using a designed Josiphos ligand and a Hantzsch ester reductant, various allenes are reduced to the corresponding chiral terminal alkenes with high selectivities.
Mechanistic studies. To shed light on the mechanism of this semireduction, we performed deuterium-labelling experiments using deuterated analogues of Hantzsch ester 5a. Semireduction of 1a with 5b afforded 2ab, where the deuterium label was completely transferred to the allylic carbon (Fig. 5a). In addition to its mechanistic significance, this experiment demonstrates a method to prepare chiral isotopically labelled stereogenic centres that complements allylic deuteration using formic acid-d 2 29, 30 . Using 5c, 2ac was obtained, where the deuterium label was incorporated into the internal vinylic carbon (Fig. 5b) groups of the Hantzsch ester 5c (31% D) and the pyridine byproduct (6% D) presumably as a statistical mixture of products 31 .
On the basis of our observations and literature precedence, we propose the mechanism shown in Fig. 6. To initiate catalysis, the Rh(I) precursor undergoes oxidative addition to generate a Rh (III)-hydride species A. The insertion of allene 1 with A forms an electrophilic Rh(III)-allyl intermediate B, which undergoes allylic substitution with Hantzsch ester 5a to furnish the terminal alkene 2 and regenerate the catalyst.

Discussion
As a complementary approach to allylic alkylation and allylic reduction, we have demonstrated a Rh-catalysed regio-and enantioselective semireduction of allenes as a strategy to generate chiral benzylic motifs. The high reaction selectivities are enabled by a designed Josiphos ligand and a Hantzsch ester reductant. Given the significance of deuterated pharmaceuticals [32][33][34] , new strategies for asymmetric hydride delivery are especially relevant. Our approach allows access to isotopically labelled stereogenic centres and occurs with excellent chemo-and stereocontrol in the presence of functional groups that are sensitive to conventional hydrogenations.

Methods
General procedure for the semireduction of allenes. In a N 2 -filled glovebox, [Rh(COD)Cl] 2 (2.0 mg, 0.0040 mmol, 2 mol%), (PhO) 2 P(O)(OH) (2.0 mg, 0.0080 mmol, 4 mol%), Josiphos L6 (9.1 mg, 0.0080 mmol, 4 mol%), Hantzsch ester 5a (101.3 mg, 0.40 mmol, 2.0 equiv), allene 1 (0.20 mmol, 1 equiv), and anhydrous CH 2 Cl 2 (0.20 mL, 1 M) were added to a 1 dram vial equipped with a magnetic stir bar. The vial was then sealed with a Teflon-lined screw cap and stirred at 30°C for 18 h. The reaction mixture was cooled to rt and concentrated in vacuo. Regioselectivities were determined by 1 H NMR analysis of the unpurified reaction mixture. The terminal alkene product 2 was purified by preparatory thin-layer chromatography. The enantioselectivities were determined by chiral SFC analysis. All new products were fully characterised. For the full experimental procedures and characterisation, including NMR spectra, of the new compounds in this article, see Supplementary Figs. 1-167.
Data availability. The authors declare that the data supporting the conclusions of this study are available within the article and its Supplementary Information file or from the authors upon reasonable request.