Asymmetric synthesis of secondary benzylic alcohols via arene chromium tricarbonyl complexes

(Aryl aldehyde)- and (aryl ketone)-chromium tricarbonyl complexes ortho -substituted with the chiral auxiliary O -methyl- N -( α -methylbenzyl)hydroxylamine undergo diastereoselective addition of Grignard reagents and Super-Hydride ® , respectively, to give the corresponding secondary alcohols in high diastereoisomeric purity. These compounds may be easily decomplexed and deprotected to give the corresponding enantiopure amino alcohols.


Introduction
Compounds bearing optically active secondary alcohols are an important group of molecules, being present in many natural products and biologically active compounds, and also as intermediates in the synthesis of other organic functionalities. 1,2 Over the years, there have been a number of studies on the synthesis of nonracemic secondary alcohols from achiral carbonyl compounds via asymmetric induction. 3 The two major methods for the enantioselective synthesis of non-racemic secondary alcohols are the enantioselective nucleophilic addition to aldehydes and the enantioselective reduction of unsymmetrical ketones. 1,3,4 In these cases, a chiral reducing agent or catalyst interacts with a prochiral substrate. Stereoselective nucleophilic additions to ortho-substituted (aryl aldehyde)-and (aryl ketone)-chromium tricarbonyl complexes have been achieved with achiral reducing agents, because the carbonyl group is already in a chiral environment.
Usually, these nucleophilic additions occur with very high diastereoselectivities, as a result of attack on the carbonyl group from the uncomplexed face of the arene, since the chromium tricarbonyl unit sterically blocks the other face of the carbonyl group. The conformation of the carbonyl, which could have the oxygen anti or syn to the ortho-substituent, can be predicted on the basis of known effects such as steric hindrance, dipolar repulsion or hydrogen bonding, leading to the preferred diastereoisomer upon nucleophilic addition. 5 We have recently reported the synthesis of (aryl aldehyde)-and (aryl ketone)-chromium tricarbonyl complexes ortho-substituted with the chiral auxiliary O-methyl-N-(α-methylbenzyl)hydroxylamine. 6 For example, enantiomerically pure complex (1pS,αR)-4 was prepared upon deprotonation of (R)-O-methyl-N-(α-methylbenzyl)hydroxylamine with BuLi followed by addition of the resultant lithium amide to (η 6 -fluorobenzene)tricarbonylchromium(0) 1, which gave (R)-2 in 56% yield. Subsequently, a solution of (R)-2 in Et2O at -78 °C was treated with t-BuLi to effect diastereoselective ortho-deprotonation to give lithiated aryl anion 3, which was reacted with ethyl formate to give ortho-formyl substituted complex (1pS,αR)-4 in 82% yield as a single diastereoisomer (>99:1 dr) after chromatographic purification (Scheme 1). Unfortunately, reaction of lithiated aryl anion 3 with aldehydes gave relatively poor diastereoselectivity It was envisaged that the addition of an organometallic reagent to the carbonyl group within orthosubstituted (aryl aldehyde)-chromium tricarbonyl complex 4 may be a selective alternative procedure to create a benzylic stereogenic centre, and that reduction of the corresponding ortho-substituted (aryl ketone)chromium tricarbonyl complexes 7 (R′ ≠ H) with hydride reagents may also provide complementary diastereoselectivity. By comparison with the X-ray crystal structure for the corresponding ortho-methyl substituted complex, 6 it was anticipated that ortho-formyl substituted complex 4 and ortho-acyl substituted complexes 7 would adopt conformations 5 and 8 in which (i) the nitrogen atom is pyramidalised and its lone pair is approximately in the same plane as the complexed arene ring, whilst pointing towards the ortho-acyl substituent to minimise 1,3-allylic strain; (ii) the methoxy group (as opposed to the bulky α-methylbenzyl fragment) projects towards the chromium tricarbonyl moiety; and (iii) the conformation with respect to rotation about the N-C(α) bond is staggered and the C(α)-H atom is placed in between the arene ring and methoxy substituent. The ortho-acyl fragment can then be expected to adopt a conformation where the carbonyl group lies in the plane of the complexed aryl ring and is anti to the chiral auxiliary due to minimisation of dipolar repulsion. In each case, the nucleophiles would then be expected to approach complexes 5 and 8 anti to the bulky chromium tricarbonyl moiety, giving rise to the epimeric adducts 6 and

Nucleophilic additions to (aryl aldehyde)-and (aryl ketone)-chromium tricarbonyl complexes
Our initial investigations were optimised on a racemic model system. ortho-Substituted aldehyde complex (1pRS,αSR)-4 was prepared as a single diastereoisomer (>99:1 dr), following our previously reported procedure, 6 upon deprotonation of (RS)-2 with t-BuLi followed by reaction of the resultant carbanion with ethyl formate. MeMgBr was subsequently added dropwise to a solution of (1pRS,αSR)-4 in Et2O at -78 °C, which induced a change in the red colour of the solution to yellow. The 1 H NMR spectrum of the crude reaction mixture showed the presence of a single product (>99:1 dr), and purification via recrystallisation gave 10 in 81% yield and >99:1 dr (Scheme 2). The relative (1pRS,1'SR,αSR)configuration 7 within 10 was unambiguously determined by single crystal X-ray diffraction analysis ( Figure   2). Within the solid state structure of 10, the O-methyl-N-(α-methylbenzyl)hydroxylamino chiral auxiliary adopts a conformation in complete accordance with our predictions: the α-methylbenzyl group is anti to the bulky chromium tricarbonyl unit and the nitrogen of the hydroxylamine is pyramidalised with the lone pair pointing towards the ortho-substituent to minimise 1,3-allylic strain, forcing the nitrogen atom to adopt an (S)-configuration; an intramolecular O-H···N hydrogen-bond is also present between the hydroxyl group and the nitrogen atom.  PhMgBr was added dropwise to a solution of (1pRS,αSR)-4 in Et2O at -78 °C, which again induced a change in colour from red to yellow, to give 11 (R = Ph) in 96:4 dr. Recrystallisation of the crude reaction mixture (n-hexane/Et2O) afforded 11 as a single diastereoisomer (>99:1 dr) in 77% yield. The reaction was repeated using 2-furyllithium (which was synthesised in situ by deprotonation of furan with BuLi/TMEDA), which gave 12 (R = 2-Fur) in 92:8 dr. In this case, purification of the crude reaction mixture via flash column chromatography gave 12 in 81% yield and >99:1 dr (Scheme 3). The stereochemical outcomes of these reactions were assigned by analogy to the corresponding reaction using MeMgBr as the nucleophile, for which the relative configuration of the product 10 had been unambiguously assigned. In a similar manner, the nucleophilic addition to (1pRS,αSR)-4 with t-BuMgCl was attempted, although the diastereoselectivity could not be determined in this case because the 1 H NMR spectrum of the crude reaction mixture was very broad and it was impossible to discern the peaks due to major and minor diastereoisomers.
Purification via flash column chromatography promoted partial decomplexation during the elution, giving The epimeric secondary alcohols with the opposite configuration at the benzylic position were next targeted by reduction of the corresponding (aryl ketone)-chromium tricarbonyl complexes. Reduction of (1pRS,αSR)-17 6 with Super-Hydride ® gave a complex mixture of products which was found to undergo rapid decomplexation in solution. Due to the instability of the products, the crude reaction mixture was decomplexed as before, by exposing it to air and sunlight as a solution in Et2O. In this case, 1  Similarly, reduction of (1pRS,αSR)-23 (R = Ph) with Super-Hydride ® in THF at -78 °C gave 26 in 98:2 dr.
As complex 26 was not sufficiently stable to be isolated (unlike its epimer 11) it was decomplexed prior to attempting purification. After decomplexation and purification via flash column chromatography 30 and 32 were isolated in 9 and 76% yield, respectively, as single diastereoisomers (>99:1 dr) in each case. The reduction of the ketone complexes (1pRS,αSR)-24 (R = 2-Fur) 6 and (1pRS,αSR)-25 (R = t-Bu) 6 with Super-Hydride ® were also performed under the same conditions. As before, the adducts were found to be unstable with respect to decomplexation and so the reaction diastereoselectivities were determined only after complete decomplexation had been achieved. For the reduction of complex 24 (R = 2-Fur), 1

Optimising the deprotection procedures
Decomplexation of (1pRS,1'SR,αSR)-10 was achieved by exposing it to air and sunlight for 24 h as a solution in Et2O. 1

Conclusions
The use of O-methyl-N-(α-methylbenzyl)hydroxylamine as a chiral auxiliary in arene tricarbonyl chromium complexes has been shown to be efficient for the stereoselective synthesis of diastereomerically pure secondary alcohols. Diastereoselective addition of Grignard reagents and Super-Hydride ® to (aryl aldehyde)and (aryl ketone)-chromium tricarbonyl complexes, respectively, ortho-substituted with the chiral auxiliary, proceed with complementary diastereoselectivity to give both epimers at the benzylic position. The stereochemical outcomes of these processes are consistent with nucleophilic addition to the exo face of the carbonyl in the anti-conformation. The decomplexation of the resultant amino alcohol complexes was investigated and complementary procedures have been identified, which proceed without disruption of the new alcohol bearing stereogenic centre. Application of this methodology to an enantiopure target gave (R)-1-(2-aminophenyl)ethanol in 65% overall yield and >99:1 er.

General Experimental
All reactions involving air sensitive reagents and organometallic complexes, as well as their purifications, were performed under an atmosphere of dry nitrogen and all solvents were degassed before use. All solvents were distilled under a nitrogen atmosphere. Et2O and THF were distilled from Na/benzophenone ketyl.
Reagents were used as purchased and when necessary were purified according to standard procedures. 15 BuLi and t-BuLi were used as solutions in hexanes and titrated against diphenylacetic acid immediately before use. Flash column chromatography was performed on silica gel (Kieselgel 60, 230-400 Mesh).
Melting points were determined on a Reichert Thermovar or on a Gallenkamp melting point apparatus and are uncorrected. Optical rotations were measured using a Perkin-Elmer 241 polarimeter with a thermally water-jacketed 10 cm cell. Concentrations (c) are given in g/100 mL and specific rotation values are given in units of 10 -1 deg cm 2 g -1 . Infrared spectra were recorded using a Perkin-Elmer 172SX Fourier Transform or a Perkin-Elmer 781 spectrometer. 1 H NMR spectra were recorded at 200 MHz on a Varian Gemini 200 or a Bruker AC 200, at 300 MHz on a General Electrical QE-300, and at 500 MHz on a Bruker AMX 500. 13 C NMR spectra were recorded at 50 MHz on a Bruker AC 200 and at 125 MHz on a Bruker AMX 500. NMR spectra were recorded in CDCl3, using tetramethylsilane (δH 0.00 ppm) or residual chloroform (δH 7.26 ppm; δC 77.0 ppm) as internal standards. Chemical shifts (δ) are reported in ppm and coupling constants (J) in Hz.
Since some hydroxylamine complexes were found to be unstable with respect to decomplexation, it was not possible to record their 13 C NMR spectra. Mass spectra (m/z) were recorded on a Kratos 25 RF, a VG spectra (HRMS) were obtained on a VG AutoSpect instrument. Elemental analyses were performed on a Carlo Erba 1106 elemental analyser.

General procedure 1: reaction of aryl aldehyde complex 4 with organometallic reagents
The requisite organometallic reagent (2.0 equiv) was added dropwise to a stirred solution of aryl aldehyde complex 4 (1.0 equiv) in Et2O at -78 °C and the resultant mixture was stirred at -78 °C for 30 min. MeOH (0.5 mL) was then added and the reaction mixture was allowed to warm to rt, then concentrated in vacuo.
The residue was dissolved in Et2O and the resultant solution was filtered through a plug of alumina (eluent Et2O) and concentrated in vacuo.

General procedure 2: reaction of aryl ketone complexes with Super-Hydride ®
Super-Hydride ® (2.0 equiv) was added dropwise to a stirred solution of the requisite aryl ketone complex (1.0 equiv) in Et2O at -78 °C and the resultant mixture was stirred at -78 °C for 30 min. MeOH (0.5 mL) was then added added and the reaction mixture was allowed to warm to rt, then concentrated in vacuo. The residue was dissolved in Et2O and the resultant solution was filtered through a plug of alumina (eluent Et2O) and concentrated in vacuo.