Asymmetric synthesis of secondary benzylic alcohols via arene chromium tricarbonyl complexes

Article abstract of DOI:10.1016/j.tet.2018.08.033

(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

Full text of DOI:10.1016/j.tet.2018.08.033

Accepted Manuscript
Asymmetric synthesis of secondary benzylic alcohols via arene chromium tricarbonyl
complexes
M. Rute G. da Costa, M. João M. Curto, Stephen G. Davies, Fátima C. Teixeira,
James E. Thomson
PII:
S0040-4020(18)30999-2
10.1016/j.tet.2018.08.033
TET 29753
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 9 July 2018
Revised Date: 21 August 2018
Accepted Date: 23 August 2018
Please cite this article as: da Costa MRG, Curto MJoãM, Davies SG, Teixeira FáC, Thomson JE,
Asymmetric synthesis of secondary benzylic alcohols via arene chromium tricarbonyl complexes,
Tetrahedron (2018), doi: 10.1016/j.tet.2018.08.033.
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ACCEPTED MANUSCRIPT
Asymmetric synthesis of secondary benzylic alcohols via arene chromium tricarbonyl complexes
M. Rute G. da Costa,a M. João M. Curto,a Stephen G. Davies,*,b Fátima C. Teixeiraa,b and James E.
Thomsonb
a
Laboratório Nacional de Energia e Geologia, I.P., Estrada do Paço do Lumiar, 22, 1649-038 Lisboa,
Portugal
b Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford,
OX1 3TA, U.K.
E-mail: steve.davies@chem.ox.ac.uk

ACCEPTED MANUSCRIPT
Asymmetric synthesis of secondary benzylic alcohols via arene chromium tricarbonyl complexes
M. Rute G. da Costa,a M. João M. Curto,a Stephen G. Davies,*,b Fátima C. Teixeiraa,b and James E.
Thomsonb
a
Laboratório Nacional de Energia e Geologia, I.P., Estrada do Paço do Lumiar, 22, 1649-038 Lisboa,
Portugal
b Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford,
OX1 3TA, U.K.
E-mail: steve.davies@chem.ox.ac.uk
Abstract
(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.
Key words: arene chromium tricarbonyl; secondary alcohols, asymmetric synthesis; hydroxylamines
1. 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 non-
racemic 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
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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
(η6-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
(~60:40
dr)
upon
formation
of
the
new
benzylic
stereogenic
centre, and this low diasteroselectivity can be explained by the absence of steric or electronic control
elements. We have observed similarly low diastereoselectivity,5f,g,j when the anion derived from
(S)-[(α-methylbenzyloxy)benzene]tricarbonylchromium(0) and the anion derived from [diphenyl
sulfoxide]tricarbonylchromium(0) were reacted with benzaldehyde to afford ~65:35 mixtures of the
corresponding benzylic alcohols.
MeO
(i)
F
N
Cr(CO)3
Cr(CO)3
Ph
1
(R)-2, 56%
(ii)
O
H
Li
MeO
MeO
N
N
89:11 dr
Cr(CO)3
Cr(CO)3
Ph
Ph
(1pS, R)-4, 82%, >99:1 dr
3
Scheme 1. Reagents and conditions: (i) (R)-O-methyl-N-(α-methylbenzyl)hydroxylamine, BuLi, THF, –78 °C to rt, 16 h;
(ii) t-BuLi, Et2O, –78 °C, 2 h then HCO2Et, –78 °C to rt, 16 h.
It was envisaged that the addition of an organometallic reagent to the carbonyl group within ortho-
substituted (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
2

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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
9, respectively (Figure 1).
Figure 1. Proposed strategy to create benzylic stereogenic centres.
2. Results and discussion
2.1. 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
1
–78 °C, which induced a change in the red colour of the solution to yellow. The H NMR spectrum of the
crude reaction mixture showed the presence of a single product (>99:1 dr), and purification via
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recrystallisation gave 10 in 81% yield and >99:1 dr (Scheme 2). The relative (1pRS,1'SR,αSR)-
configuration7 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.
Scheme 2. Reagents and conditions: (i) MeMgBr, Et2O –78 °C, 30 min.
Figure 2. X-ray crystal structure of (1pRS,1'SR,αSR)-10.
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
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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.
Scheme 3. Reagents and conditions: (i) PhMgBr, Et2O, –78 °C, 30 min; (ii) 2-furyllithium, Et2O, –78 °C, 30 min.
[2-Fur = 2-furyl].
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 1H 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
only 16 in 25% isolated yield; the formation of 16 in this case is consistent with reduction8 of the aldehyde
functionality by the Grignard reagent. Repetition of the reaction followed by immediate decomplexation of
the crude reaction mixture (by exposing it to air and sunlight for 24 h as a solution in Et2O) gave a 60:9:31
mixture of 13 (95:5 dr), 14 (95:5 dr) and 16, respectively. Purification via flash column chromatography
gave 13 in 32% yield and >99:1 dr, and 16 in 29% yield (Scheme 4). The relative configurations of 13 and
14 were again assigned by analogy to the corresponding reaction using MeMgBr.
Scheme 4. Reagents and conditions: (i) t-BuMgCl, Et2O, –78 °C, 30 min; (ii) O2, hν, Et2O, rt, 24 h.
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)-
176 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
1
decomplexed as before, by exposing it to air and sunlight as a solution in Et2O. In this case, H NMR
spectroscopic analysis of the crude reaction mixture after decomplexation revealed the presence of a 19:78:3
mixture of 19, 20 and 22, respectively, corresponding to a diastereoselectivity of 97:3 dr [(19+20):(21+22)]
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upon formation of the intermediate complexes 18 and 10. Purification via flash column chromatography
gave 20 as a single diastereoisomer (>99:1 dr) in 77% isolated yield (Scheme 5). The relative configurations
within the decomplexed amino alcohols 19–22 were established upon decomplexation of authentic samples
of the epimeric complexes 18 and 10.
Scheme 5. Reagents and conditions: (i) LiBHEt3, Et2O, –78 °C, 30 min; (ii) O2, hν, Et2O, rt, 24 h.
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
1
complete decomplexation had been achieved. For the reduction of complex 24 (R = 2-Fur), H NMR
spectroscopic analysis of the crude decomplexed mixture revealed a 15:10:45:30 mixture of 31, 33, 35 and
38, respectively, corresponding to a diastereoselectivity of 25:75 dr [(31+33):(35+38)] upon formation of the
intermediate complexes 27 and 12; it was not possible to separate the diastereoisomers via flash column
chromatography in this case. Likewise, for the reduction of complex 25 (R = t-Bu), only compounds 13 and
36 were produced in a 25:75 diastereoisomeric ratio; as before, all attempts to separate these epimers by
flash column chromatography failed (Scheme 6). Comparison of the 1H NMR spectra of these samples with
those of authentic samples, which were prepared upon addition of either 2-furyllithium or t-BuMgCl to
ortho-substituted aldehyde complex (1pRS,αSR)-4 followed by decomplexation, established the identity of
the major diastereoisomer in each case. The reduction of (aryl ketone)-chromium tricarbonyl complexes 24
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(R = 2-Fur) and 25 (R = t-Bu) proved to be less selective than the other reactions investigated and in fact
proceeded with the opposite sense of diastereoselectivity. Interestingly, complexes 24 (R = 2-Fur) and
25 (R = t-Bu) are yellow whereas all the other ortho-formyl and ortho-acyl complexes investigated are red,
which is indicative of the carbonyl group being in conjugation with the complexed aryl ring. The opposite
stereochemical outcomes upon reduction of 24 (R = 2-Fur) and 25 (R = t-Bu) could therefore be explained if
the carbonyl groups within 24 (R = 2-Fur) and 25 (R = t-Bu) do not lie in the same plane as the complexed
aromatic ring.
Scheme 6. Reagents and conditions: (i) LiBHEt3, Et2O, –78 °C, 30 min; (ii) O2, hν, Et2O, rt, 24 h. [a isolated in 9% yield and
>99:1 dr; b isolated in 76% yield and >99:1 dr; 2-Fur = 2-furyl].
2.2. 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
1
solution in Et2O. H NMR spectroscopic analysis of the crude reaction mixture indicated the presence of a
10:90 mixture of 22 and 21, respectively. The crude reaction mixture was purified via flash column
chromatography and 21 was isolated in 70% yield and >99:1 dr. The decomplexation procedure was
repeated using iodine as oxidant, which gave an 85:15 mixture of 22 and 21, respectively. Purification by
flash column chromatography afforded 22 in 67% yield and 21 in 9% yield, as single diastereoisomers
(>99:1 dr) in each case. The reaction was also repeated by exposing a solution of 10 and
(fluorobenzene)tricarbonylchromium(0) 1 (3.0 equiv) in Et2O to air and sunshine for 5 days, as it was shown
that the addition of (fluorobenzene)tricarbonylchromium(0) 1 promoted complete N–O bond cleavage under
these conditions. Following purification of the crude reaction mixture, 21 was isolated in 93% yield and
>99:1 dr (Scheme 7).
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Scheme 7. Reagents and conditions: (i) O2, hν, Et2O, rt, 24 h; (ii) I2, THF, 0 °C, 3 h; (iii) (fluorobenzene)Cr(CO)3 1, O2, hν, Et2O,
5 days.
With a procedure for removal of the chromium tricarbonyl fragment having already been achieved without
compromising the stereochemical integrity of the newly formed benzylic stereogenic centre, our attention
turned to removal of the auxiliary. Some procedures exist for removal of the benzylic bond of the auxiliary
by treatment with sodium and liquid ammonia9 or by hydrogenolysis.10 The use of sodium in ammonia9 for
the deprotection of (1′RS,αRS)-22 gave only N–O bond cleavage, giving (1′RS,αRS)-21 in quantitative yield
with none of the desired product (RS)-40 being formed. Various attempts at the hydrogenolysis of
(1′RS,αRS)-22 were evaluated with the optimal conditions being the hydrogenolysis of (1′RS,αRS)-22 in the
presence of Pd(OH)2/C in EtOH at 30 °C, which gave (RS)-1-(2-aminophenyl)ethanol (RS)-40 in 75% yield
after purification via preparative TLC. Hydrogenolytic deprotection of secondary amine (1′RS,αRS)-21
under the same conditions gave (RS)-40 in 77% isolated yield (Scheme 8).
Scheme 8. Reagents and conditions: (i) Na, NH3, EtOH, THF, –78 °C, 20 min; (ii) Pd(OH)2/C, H2 (5 atm), EtOH, 30 °C, 48 h.
2.3. Synthesis of enantiopure (R)-1-(2-aminophenyl)ethanol
With this methodology established and optimized for the preparation of racemic complexes, it was extended
to enantiomerically pure complex (1pS,αR)-4, which was prepared as previously reported.6 A solution of
complex (1pS,αR)-4 in Et2O at –78 °C was treated with MeMgBr to give (1pS,1'R,αR)-10 as a single
diastereoisomer (>99:1 dr). Purification of the crude reaction mixture via recrystallisation afforded
1
13
(1pS,1'R,αR)-10 in 94% yield and >99:1 dr (Scheme 9). The H and C NMR spectroscopic data for this
enantiopure sample were identical to those of the authentic racemic sample (1pRS,1'SR,αSR)-10 prepared
previously.
8

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Scheme 9. Reagents and conditions: (i) MeMgBr, Et2O, –78 °C, 30 min.
Subsequent decomplexation of (1pS,1'R,αR)-10 was performed under the conditions optimised for the
racemic series of compounds. A solution of (1pS,1'R,αR)-10 in Et2O was treated with excess I2 for 3.5 h, and
purification of the crude reaction mixture via flash column chromatography allowed isolation of (1′R,αR)-22
in 84% yield and >99:1 dr. Alternatively, the decomplexation procedure was repeated by exposing a solution
of (1pS,1'R,αR)-10 and (fluorobenzene)tricarbonylchromium(0) 1 in Et2O to air and sunshine for 4 days, and
after purification via flash column chromatography (1′R,αR)-21 was isolated in 99% yield and >99:1 dr.
Hydrogenolysis of both (1′R,αR)-22 and (1′R,αR)-21 in the presence of Pd(OH)2/C at 30 °C under a pressure
of 5 atm of H2 gave, after purification via flash column chromatography, (R)-1-(2-aminophenyl)ethanol
(R)-40 in 75 and 70% yield, respectively. In each case, the NMR spectra of (1′R,αR)-21, (1′R,αR)-22 and
(R)-40 were identical to the authentic racemic samples,11,12 and (R)-40 {[α] D23 –6.0 (c 0.1 in MeOH); lit.13
1
for (S)-40: [α] 2D3 +4.5 (c 16.2 in MeOH)} was assessed to be >99:1 er as determined by H NMR
spectroscopic analysis in the presence of the chiral solvating agent (R)-1-(9-anthryl)-2,2,2-trifluoroethanol14
and comparison with an authentic racemic standard (Scheme 10).
Scheme 10. Reagents and conditions: (i) I2, THF, 0 °C, 3 h; (ii) (fluorobenzene)Cr(CO)3 1, O2, hν, Et2O; (iii) Pd(OH)2/C,
H2 (5 atm), EtOH, 30 °C, 48 h.
3. 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
9

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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.
4. Experimental
4.1. 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 cm2g–1. Infrared spectra were recorded using a Perkin-Elmer 172SX Fourier Transform or a
1
Perkin-Elmer 781 spectrometer. H NMR spectra were recorded at 200 MHz on a Varian Gemini 200 or a
13
Bruker AC 200, at 300 MHz on a General Electrical QE-300, and at 500 MHz on a Bruker AMX 500. 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
13
possible to record their C NMR spectra. Mass spectra (m/z) were recorded on a Kratos 25 RF, a VG
MicromassLab ZAB 1F, a VG MassLab 20-250 or an APCI Plataform spectrometer. High resolution mass
10

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spectra (HRMS) were obtained on a VG AutoSpect instrument. Elemental analyses were performed on a
Carlo Erba 1106 elemental analyser.
4.2. 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.
4.3. 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.
4.4. (1pRS,1'SR,αSR)-{1-[O-Methyl-N-(α-methylbenzyl)hydroxylamino]-2-(1'-
hydroxyethyl)benzene}tricarbonylchromium(0) (1pRS,1'SR,αSR)-10
MeMgBr (0.08 mL, 3.0 M in Et2O, 0.250 mmol) was added to a stirred solution of (1pRS,αSR)-4 (49 mg,
0.125 mmol, >99:1 dr) in Et2O (5 mL) at –78 °C and the resultant mixture was stirred at –78 °C for 30 min,
according to general procedure 1, to give (1pRS,1'SR,αSR)-10 in >99:1 dr. Purification via recrystallisation
(40–60 °C petrol/Et2O) gave (1pRS,1'SR,αSR)-10 as a yellow crystalline solid (41 mg, 81%, >99:1 dr);
C20H21CrNO5 requires C, 59.0; H, 5.2; N, 3.4%; found: C, 59.0; H, 5.1; N, 3.3%; mp 90 °C (dec.); νmax
(KBr) 3400 (O–H), 3091, 3032 (C–H, Ar), 2980, 2936 (C–H), 1963, 1882 (C≡O), 1605, 1520, 1496, 1453
(C=C); δH (500 MHz, CDCl3) 1.49 (3H, d, J 6.7, C(α)Me), 1.52 (3H, d, J 6.2, C(2')H3), 3.33 (3H, s, OMe),
3.46 (1H, s, OH), 4.16 (1H, q, J 6.7, C(α)H), 5.03 (1H, br q, J 6.2, C(1')H), 5.33–5.37 (3H, m, Ar), 5.78 (1H,
d, J 6.2, Ar), 7.29–7.45 (5H, m, Ph); m/z (ESI+) 408 ([M+H]+, 100%).
11

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4.4.1. X-ray crystal structure determination for (1pRS,1'SR,αSR)-10
C20H21CrNO5, M = 407.39, monoclinic, a = 12.468(1) Å, b = 9.137(2) Å, c = 18.232(2) Å,
β = 109.92(1)°,
V = 1952.7(5) Å3, space group P 21/c, Z = 4,
µ
= 51.53 cm–1. Colourless prism, crystal dimensions
0.19 × 0.29 × 0.74 mm.
Enraf-Nonius MACH3 diffractometer,
speed 2.2–10.1° min–1, graphite-monochromated Cu/Kα radiation (
measured (2 < < 60, 0, h, 0, k; –1.1), 2702 unique, giving 1993 with I>3.0
ω
-2
θ
scan mode with the
ω
scan width = 1.03 + 0.33tan
= 1.54180 Å), 3060 reflections were
(I).
θ, ω scan
λ
θ
σ
Direct Methods, full-matrix least-squares refinement with all non-hydrogen atoms in anisotropic
approximation. All hydrogen atoms were located in the difference Fourier maps and included in the final
refinement with fixed positional and thermal parameters [only atom H(4) attached to O(4) was refined
isotropically]. Chebychev weighting scheme16 with parameters 25.6, –14.5 and 17.0 was applied.
Corrections for Lorenz and polarisation effects as well as empirical absorption correction based on azimuthal
scan data17 were applied. Final R and R' values are 0.046 and 0.053. All crystallographic calculations were
carried out using the CRYSTALS18 program package on PC/AT-486. Neutral atom scattering factors were
taken from the usual sources.19
Crystallographic data (excluding structure factors) for (1pRS,1'SR,αSR)-10 have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication number CCDC 1853734. Copies of
these data can be obtained free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif
4.5. (1pRS,1'SR,αSR)-{1-[O-Methyl-N-(α-methylbenzyl)hydroxylamino]-2-
(phenylhydroxymethyl)benzene}tricarbonylchromium(0) (1pRS,1'SR,αSR)-11
PhMgBr (0.26 mL, 3.0 M in Et2O, 0.77 mmol) was added to a stirred solution of (1pRS,αSR)-4 (150 mg,
0.38 mmol, >99:1 dr) in Et2O (20 mL) at –78 °C and the resultant mixture was stirred at –78 °C for 40 min,
according to general procedure 1, to give (1pRS,1'SR,αSR)-11 in 96:4 dr. Purification via recrystallisation
(n-hexane/Et2O) gave (1pRS,1'SR,αSR)-11 as a yellow crystalline solid (139 mg, 77%, >99:1 dr);
C25H23CrNO5 requires C, 64.0; H, 4.9; N, 3.0%; found: C, 64.2; H, 4.9; N, 2.9%; mp 93 °C (dec.); νmax
(KBr) 3359 (O–H), 3092, 3067, 3030 (C–H, Ar), 2983, 2937, 2820 (C–H), 1960, 1904, 1893 (C≡O), 1604,
1497, 1455, 1423 (C=C); δH (300 MHz, CDCl3) 1.37 (3H, d, J 6.9, C(α)Me), 3.35 (3H, s, OMe), 3.93 (1H, q,
J 6.9, C(α)H), 4.00 (1H, s, OH), 5.08 (1H, d, J 6.3, Ar), 5.29 (1H, app t, J 6.0, Ar), 5.38 (1H, app t, J 6.0,
12

ACCEPTED MANUSCRIPT
Ar), 5.82 (1H, d, J 6.3, Ar), 5.88 (1H, s, C(1')H), 7.30–7.42 (10H, m, Ph); m/z (FAB+) 469 ([M]+, 10%), 452
([M–OH]+, 1), 353 ([M–C4H4O4]+, 62), 336 ([M–C4H5O5]+, 20), 275 ([M–C10H10O4]+, 100], 247
([M–C11H10O5] +, 18), 195 ([M–C11H10CrO5]+, 4).
4.6. (1pRS,1'SR,αSR)-{1-[O-Methyl-N-(α-methylbenzyl)hydroxylamino]-2-(2''-
furylhydroxymethyl)benzene}tricarbonylchromium(0) (1pRS,1'SR,αSR)-12
BuLi (0.35 mL, 1.4 M in hexanes, 0.492 mmol) was added dropwise to a stirred solution of furan (40 µL,
0.49 mmol) and TMEDA (0.10 mL, 0.74 mmol) in Et2O (5 mL) at –20 °C. The reaction mixture was stirred
at –20 °C for 2 h, then cooled to –78 °C and added dropwise to a solution of (1pRS,αSR)-4 (45 mg, 0.11
mmol, >99:1 dr) in Et2O (5 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 30 min, according
to general procedure 1, to give (1pRS,1'SR,αSR)-12 in 92:8 dr. Purification via flash column
chromatography (eluent 40–60 °C petrol/Et2O, 9:1), followed by recrystallisation (n-hexane/Et2O) gave
(1pRS,1'SR,αSR)-12 as a yellow crystalline solid (47 mg, 81%, >99:1 dr); C23H21CrNO6 requires C, 60.1;
H, 4.6; N, 3.05%; found: C, 60.3; H, 4.8; N, 2.95%; mp 85 °C (dec.); νmax (KBr) 3448 (O–H), 3081, 3032
(C–H, Ar), 2984, 2937, 2809 (C–H), 1977, 1885, 1865 (C≡O), 1603, 1518, 1498, 1451, 1435 (C=C); δH (300
MHz, CDCl3) 1.27 (3H, d, J 6.6, C(α)Me), 2.99 (1H, d, J 2.4, OH), 3.23 (3H, s, OMe), 3.80 (1H, q, J 6.6,
C(α)H), 5.37–5.41 (2H, m, Ar), 5.58 (1H, dd, J 5.7, 1.5, Ar), 5.80 (1H, dd, J 5.7, 1.2, Ar), 6.14 (1H, d, J 2.4,
C(1')H), 6.29 (1H, d, J 3.0, C(3'')H), 6.35 (1H, dd, J 2.7, 1.5, C(4'')H), 7.33 (5H, m, Ph), 7.47 (1H, app s,
C(5'')H); m/z (FAB) 459 ([M]+, 11%), 442 ([M–OH]+, 4), 343 ([M–C4H4O4]+, 94), 326 ([M–C4H5O5]+, 13),
275 ([M–C8H8O5]+, 100), 247 (([M–C9H8O6]+, 12), 195 ([M–C9H8CrO5]+, 10).
4.7. (1'RS,αRS)-1'-[2-N-(α-Methylbenzyl)aminophenyl]-2',2'-dimethylpropan-1'-ol (1'RS,αRS)-13 and
(RS)-{2-[O-methyl-N-(α-methylbenzyl)hydroxylamino]phenyl}methanol (RS)-16
t-BuMgCl (0.13 mL, 2.0 M in Et2O, 0.27 mmol) was added to a stirred solution of (1pRS,αSR)-4 (52 mg,
0.133 mmol, >99:1 dr) in Et2O (5 mL) at –78 °C and the resultant mixture was stirred at –78 °C for 2 h,
according to general procedure 1. The crude reaction mixture was dissolved in Et2O (10 mL) and the
resultant mixture was exposed to air and sunlight for 24 h to give a 60:9:31 mixture of 13 (95:5 dr), 14 (95:5
dr) and 16, respectively. Purification via flash column chromatography (eluent 40–60 °C petrol/Et2O, 9:1),
followed by recrystallisation (40–60 °C petrol/Et2O) gave (1'RS,αRS)-13 (12 mg, 32%, >99:1 dr) and
(RS)-16 as white crystalline solids (10 mg, 29%).
13

ACCEPTED MANUSCRIPT
Data for (1'RS,αRS)-13: C19H25NO requires C, 80.5; H, 8.9; N, 4.9%; found: C, 80.5; H, 8.8; N, 5.0%.; mp
78 °C; νmax (KBr) 3405 (N–H and O–H), 2956, 2868 (C–H), 1604, 1584, 1511, 1451 (C=C); δH (500 MHz,
CDCl3) 1.07 (9H, s, CMe3), 1.54 (3H, d, J 6.8, C(α)Me), 2.18 (1H, br s, NH), 4.47 (1H, q, J 6.8, C(α)H),
4.56 (1H, s, C(1')H), 5.51 (1H, br s, OH), 6.39 (1H, d, J 8.2, C(6)H), 6.58 (1H, app dt, J 7.4, 1.0, C(4)H),
6.98 (1H, app dt, J 7.5, 1.6, C(5)H), 7.01 (1H, d, J 7.6, C(3)H), 7.22–7.25 (1H, m, Ph), 7.31–7.37 (4H, m,
Ph); δC (125 MHz, CDCl3) 25.3 (C(α)Me), 26.8 (CMe3), 37.5 (CMe3), 53.4 (C(α)), 83.0 (C(1')), 112.3, 115.3
(C(4), C(6)), 124.0 (C(2)), 125.7, 126.7, 128.1, 128.6, 129.9 (C(3), C(5), o,m,p-Ph), 145.8, 145.9 (C(1),
i-Ph); m/z (ESI+) 284 ([M+H]+, 100%).
Data for (RS)-16: mp 75 °C; νmax (KBr) 3370 (O–H), 3062, 3031 (C–H, Ar), 2978, 2934, 2891, 2808 (C–H),
1601, 1583, 1494, 1452 (C=C); δH (500 MHz, CDCl3) 1.41 (3H, d, J 6.8, C(α)Me), 3.34 (3H, s, OMe), 4.02
(1H, br t, J 5.6, OH), 4.24 (1H, q, J 6.8, C(α)H), 4.75 (1H, dd, J 13.3, 5.6, CHAHBOH), 4.86 (1H, dd, J 13.3,
5.0, CHAHBOH), 7.17–7.36 (8H, m, Ar, Ph), 7.43 (1H, d, J 8.1, Ar, Ph); δC (125 MHz, CDCl3) 17.8
(C(α)Me), 60.4 (C(α)), 63.9 (CH2OH), 67.2 (OMe), 123.4, 126.5, 127.4, 127.6, 128.1 (C(3), C(4), C(5),
C(6), o,m,p-Ph), 135.8 (C(2)), 141.4, 147.5 (C(1), i-Ph); m/z (CI+) 258 ([M+H]+, 6%), 228 ([M+H–CH2O]+,
12), 108 ([C7H8O]+, 100), 105 ([PhCHCH3]+, 78); HRMS (CI+) C16H20NO2 ([M+H]+) requires 258.1489;
+
found 258.1494.
4.8. (1'RS,αSR)-1'-{2-[O-Methyl-N-(α-methylbenzyl)hydroxylamino]phenyl}ethanol (1'RS,αSR)-20
Super-Hydride® (0.24 mL, 1.0 M in THF, 0.24 mmol) was added to a stirred solution of (1pRS,αSR)-17 (48
mg, 0.119 mmol, >99:1 dr) in Et2O (5 mL) at –78 °C and the resultant mixture was stirred at –78 °C for 30
min, according to general procedure 2. The crude reaction mixture was dissolved in Et2O (10 mL) and the
resultant solution was exposed to air for 19 hours on a cloudy day to give a 19:78:3 mixture of 19, 20 and
22, respectively. Purification via flash column chromatography (eluent 40–60 °C petrol/Et2O, 9:1) gave
(1'RS,αSR)-20 as a white crystalline solid (25 mg, 77%, >99:1 dr); C17H21NO2 requires C, 75.25; H, 7.8;
N, 5.2%; found: C, 75.2; H, 7.8; N, 5.2%; mp 82 °C; νmax (film) 3608–3403 (O–H), 3063, 3031 (C–H, Ar),
2976, 2933, 2892, 2808 (C–H), 1601, 1482, 1452 (C=C); δH (500 MHz, CDCl3) 1.42 (3H, d, J 6.8, C(α)Me),
1.53 (3H, d, J 6.5, C(2')H3), 3.36 (3H, s, OMe), 3.72 (1H, br s, OH), 4.23 (1H, q, J 6.8, C(α)H), 5.39 (1H, dq,
J 6.5, 2.4, C(1')H), 7.20–7.43 (9H, m, Ar, Ph); δC (125 MHz, CDCl3) 19.0 (C(α)Me), 23.8 (C(2')), 60.3
(C(α)), 66.0 (OMe), 67.8 (C(1')), 123.6, 125.6, 127.0, 127.4, 127.9, 128.0, 128.2 (C(3), C(4), C(5), C(6),
14

ACCEPTED MANUSCRIPT
o,m,p-Ph), 141.0, 141.5, 146.6 (C(1), C(2), i-Ph); m/z (CI+) 272 ([M+H]+, 8%), 241 ([M+H–CH3O]+, 16),
240 ([M–CH3O]+, 37), 226 ([M+H–C2H6O]+, 34), 224 ([M+H–C2H7O2]+, 100), 105 ([PhCHCH3]+, 64).
Data for 19: νmax (KBr) 3391 (O–H, N–H), 3062, 3027 (C–H, Ar), 2975, 2927, 2869 (C–H), 1607, 1587,
1515, 1505, 1494, 1455 (C=C); δH (300 MHz, CDCl3) 1.54 (3H, d, J 6.6, C(α)Me), 1.69 (3H, d, J 6.6,
C(2')H3), 4.49 (1H, q, J 6.6, C(α)H), 5.00 (1H, q, J 6.6, C(1')H), 6.39 (1H, d, J 8.1, C(6)H), 6.59 (1H, app dt,
J 7.2, 0.9, C(4)H), 6.99 (1H, app dt, J 7.8, 1.5, C(5)H), 7.05 (1H, dd, J 7.2, 0.9, C(3)H), 7.18–7.39 (5H, m,
Ph); δC (75 MHz, CDCl3) 21.3 (C(α)Me), 25.3 (C(2')), 53.1 (C(α)), 70.7 (C(1')), 112.3 (C(6)), 116.2 (C(4)),
127.2 (C(2)), 125.7, 126.4, 126.7, 128.5, 128.6 (C(3), C(5) o,m,p-Ph), 145.5, 145.7 (C(1), i-Ph); m/z (CI+)
242 ([M+H]+, 7%), 224 ([M–OH]+, 10), 105 ([PhCHCH3]+, 100); HRMS (CI+) C16H20NO+ ([M+H]+)
requires 242.1539; found 242.1533.
4.9. (1'RS,αSR)-Phenyl[2-N-(α-methylbenzyl)aminophenyl]methanol (1'RS,αSR)-30
and (1'RS,αSR)-Phenyl{2-[O-methyl-N-(α-methylbenzyl)hydroxylamino]phenyl}methanol
(1'RS,αSR)-32
Step 1: Super-Hydride® (0.21 mL, 1.0 M in THF, 0.21 mmol) was added to a stirred solution of (1pRS,αSR)-
23 (50 mg, 0.11 mmol, >99:1 dr) in Et2O (5 mL) at –78 °C and the resultant mixture was stirred at –78 °C
for 30 min, according to general procedure 2, to give 26 in 98:2 dr. Data for 26: δH (300 MHz, CDCl3) 1.37
(3H, d, J 6.6, C(α)Me), 3.30 (3H, s, OMe), 4.30 (1H, q, J 6.6, C(α)H), 4.45 (1H, d, J 6.6, OH), 5.20 (1H, dd,
J 6.0, 1.2, Ar), 5.29 (1H, app t, J 6.0, Ar), 5.38 (1H, app dt, J 6.0, 1.2, Ar), 5.77 (1H, d, J 6.6, Ar), 5.86 (1H,
d, J 6.3, C(1')H), 7.28–7.37 (6H, m, Ph), 7.43 (2H, t, J 7.5 Ph), 7.61 (2H, d, J 7.5, Ph).
Step 2: The crude reaction mixture from the previous step was dissolved in Et2O (10 mL) and the resultant
solution was exposed to air and light for 2 cloudy days. Purification via flash column chromatography
(eluent 40–60 °C petrol/Et2O, 9:1) gave (1'RS,αSR)-30 as a white crystalline solid (3 mg, 9%) and
(1'RS,αSR)-32 as a colourless oil (27 mg, 76%).
Data for (1'RS,αSR)-32: C22H23NO2 requires C, 79.25; H, 6.95; N, 4.2%; found: C, 79.0; H, 6.9; N, 4.0%;
νmax (film) 3401 (O–H), 3063, 3030 (C–H, Ar), 2978, 2933, 2893, 2810 (C–H), 1601, 1583, 1494, 1452
(C=C); δH (200 MHz, CDCl3) 1.38 (3H, d, J 6.8, C(α)Me), 3.35 (3H, s, OMe), 4.14 (1H, q, J 6.8, C(α)H),
4.46 (1H, br s, OH), 6.28 (1H, s, C(1')H), 7.06–7.21 (2H, m, Ar, Ph), 7.25–7.49 (12H, m, Ar, Ph); δC (50
MHz, CDCl3) 18.1 (C(α)Me), 60.4 (C(α)), 67.3 (OMe), 72.9 (C(1')), 123.8, 126.7, 127.1, 127.4, 127.9,
15

ACCEPTED MANUSCRIPT
128.1, 128.1, 128.3 (C(3), C(4), C(5), C(6), o,m,p-Ph), 138.8 (C(2)), 141.4, 143.6, 147.2 (C(1), i-Ph);
m/z (ESI+) 334 ([M+H]+, 100%).
Data for (1'RS,αSR)-30: C21H21NO requires C, 83.1; H, 7.0; N, 4.6%; found: C, 83.1; H, 6.95; N, 4.7%; mp
85–86 °C; νmax (KBr) 3347 (O–H and N–H), 3082, 3060, 3025 (C–H)Ar, 2986, 2935, 2860 (C–H), 1606,
1588, 1511, 1494, 1467, 1453 (C=C); δH (500 MHz, CDCl3) 1.39 (3H, d, J 6.7, C(α)Me), 2.51 (1H, br s,
NH), 4.45 (1H, q, J 6.7, C(α)H), 5.05 (1H, br s, OH), 5.94 (1H, s, C(1')H), 6.38 (1H, d, J 8.1, C(6)H), 6.63
(1H, app dt, J 7.4, 1.0, C(4)H), 6.93–6.94 (2H, m, Ph), 7.04 (1H, app dt, J 7.7, 1.6, C(5)H), 7.08 (1H, dd, J
7.5, 1.6, C(3)H), 7.13–7.46 (8H, m, Ph); δC (125 MHz, CDCl3) 25.1 (C(α)Me), 52.5 (C(α)), 76.0 (C(1')),
112.5 (C(6)), 116.1 (C(4)), 126.3 (C(2)), 125.6, 126.3, 126.6, 127.4, 128.3, 128.4, 128.9, 129.1 (C(3), C(5),
o,m,p-Ph), 141.9, 145.1, 145.1 (C(1), i-Ph); m/z (CI+) 304 ([M+H]+, 62%), 286 ([M–OH]+, 100), 105
([PhCHCH3]+, 61).
4.10. Reaction of (1pRS,αSR)-24 with Super-Hydride® followed by decomplexation
Super-Hydride® (0.53 mL, 1.0 M in THF, 0.526 mmol) was added to a stirred solution of (1pRS,αSR)-24
(120 mg, 0.263 mmol, >99:1 dr) in Et2O (15 mL) at –78 °C and the resultant mixture was stirred at –78 °C
for 30 min, according to general procedure 2. The crude reaction mixture was dissolved in Et2O (20 mL)
and the resultant mixture was exposed to air and light for 24 h to give an inseparable 15:10:45:30 mixture of
31, 33, 35 and 38, respectively. Data for 31: δH (500 MHz, CDCl3) 1.48 (3H, d, J 6.7, C(α)Me), 4.50 (1H, q,
J 6.7, C(α)H), 5.94 (1H, s, OH), 6.30–7.47 (13H, m, C(1')H, Ar, Ph). Data for 33: δH (500 MHz, CDCl3)
1.34 (3H, d, J 6.9, C(α)Me), 3.33 (3H, s, OMe), 4.16 (1H, q, J 6.9, C(α)H), 6.18–7.47 (13H, m, C(1')H, Ar,
Ph).
4.11. Reaction of complex (1pRS,αSR)-25 with Super-Hydride® followed by decomplexation
Super-Hydride® (0.22 mL, 1.0 M in THF, 0.22 mmol) was added to a stirred solution of (1pRS,αSR)-25 (50
mg, 0.112 mmol, >99:1 dr) in Et2O (5 mL) at –78 °C and the resultant mixture was stirred at –78 °C for 18
h, according to general procedure 2. The crude reaction mixture was dissolved in Et2O (10 mL) and the
resultant mixture was exposed to air and light for 19 h to give an inseparable 25:75 mixture of 13 and 36,
respectively. Data for 13: δH (500 MHz, CDCl3) 1.09 (9H, s, CMe3), 1.54 (3H, d, J 6.8, C(α)Me), 2.14 (1H,
br s, NH), 4.42 (1H, q, J 6.8, C(α)H), 4.59 (1H, s, C(1')H), 5.50 (1H, br s, OH), 6.39 (1H, d, J 8.2, Ar), 6.58
16

ACCEPTED MANUSCRIPT
(1H, app dt, J 7.4, 1.0, Ar), 6.98 (1H, app dt, J 7.0, 1.7, Ar), 7.02 (1H, dd, J 7.5, 1.4, Ar), 7.21–7.26 (1H, m,
Ph), 7.31–7.41 (4H, m, Ph).
4.12. (1'RS,αRS)-1'-[2-N-(α-Methylbenzyl)aminophenyl]ethanol 21 and
(1'RS,αRS)-1'-{2-[O-methyl-N-(α-methylbenzyl)hydroxylamino]phenyl}ethanol 22
Method A: A solution of (1pRS,1'SR,αSR)-10 (32 mg, 0.079 mmol, >99:1 dr) in Et2O (10 mL) was exposed
to air and sunlight for 24 h to give a 10:90 mixture of 22 and amine 21, respectively. Purification via flash
column chromatography (eluent 40–60 °C petrol/Et2O, 9:1) gave (1'RS,αRS)-21 as a colourless oil (13.3 mg,
70%, >99:1 dr); νmax (KBr) 3392 (O–H and N–H), 3025 (C–H, Ar), 2970, 2927 (C–H), 1605, 1586, 1514,
1451 (C=C); δH (200 MHz, CDCl3) 1.56 (3H, d, J 6.7, C(α)Me), 1.68 (3H, d, J 6.6, C(2')H3), 4.55 (1H, q, J
6.7, C(α)H), 5.03 (1H, q, J 6.6, C(1')H), 6.43 (1H, d, J 8.2, C(6)H), 6.62 (1H, app dt, J 7.3, 0.9, C(4)H),
6.98–7.11 (2H, m, C(3)H, C(5)H), 7.18–7.39 (5H, m, Ph); δC (50 MHz, CDCl3) 21.5 (C(α)Me), 25.2 (C(2')),
52.9 (C(α)), 69.8 (C(1')), 112.3 (C(6)), 116.2 (C(4)), 127.2 (C(2)), 125.8, 126.1, 126.7, 128.6, 128.7 (C(3),
C(5), o,m,p-Ph), 145.4, 145.7 (C(1), i-Ph); m/z (CI+) 242 ([M+H]+, 39%), 224 ([M–OH]+, 100),
223 ([M–H2O]+, 16), 208 (M–CH5O]+, 28), 105 ([PhCHCH3]+, 69); HRMS (CI+) C16H20NO+ ([M+H]+)
requires 242.1539; found 242.1543.
Method B: A solution of I2 (65 mg, 0.26 mmol) in THF (10 mL) was added to a stirred solution of
(1pRS,1'SR,αSR)-10 (52 mg, 0.13 mmol, >99:1 dr) in THF (10 mL) at 0 °C. The reaction mixture was stirred
at rt for 4 h then concentrated in vacuo. The residue was extracted with Et2O (3 × 30 mL) and the combined
organic extracts were washed sequentially with satd aq Na2S2O5 (3 × 35 mL), satd aq NaHCO3 (3 × 35 mL)
and brine (3 × 35 mL), then dried and concentrated in vacuo. Purification by preparative TLC (eluent 40–60
°C petrol/Et2O, 9:1) gave (1'RS,αRS)-22 as a white crystalline solid (23 mg, 67%) and (1'RS,αRS)-21 as a
colourless oil (2.7 mg, 9%).
Data for compound 22: C17H21NO2 requires C, 75.25; H, 7.8; N, 5.2%; found: C, 75.6; H, 7.9; N, 4.8%; mp
115–116 °C; νmax (film) 3360 (O–H), 3029 (C–H, Ar), 2981, 2968, 2940, 2929, 2855, 2806 (C–H), 1602,
1584, 1491, 1461, 1451 (C=C); δH (300 MHz, CDCl3) 1.38 (3H, d, J 6.9, C(α)Me), 1.56 (3H, d, J 6.6,
C(2')H3, 3.30 (3H, s, OMe), 4.24 (1H, q, J 6.9, C(α)H), 4.35 (1H, br s, OH), 5.34 (1H, q, J 6.6, C(1')H),
7.20–7.45 (9H, m, Ar, Ph); δC (75 MHz, CDCl3) 17.9 (C(α)Me), 24.1 (C(2')), 60.3 (C(α)), 66.6 (OMe), 67.2
(C(1')), 123.7, 125.7, 126.8, 127.4, 127.8, 128.1, 128.1 (C(3), C(4), C(5), C(6), o,m,p-Ph), 140.6, 141.7,
146.5 (C(1), C(2), i-Ph); m/z (ESI+) 272 ([M+H]+, 100%).
17

ACCEPTED MANUSCRIPT
Method C:
A
solution of (1pRS,1'SR,αSR)-10 (104 mg, 0.255 mmol, >99:1 dr) and
(fluorobenzene)tricarbonylchromium(0) 1 (178 mg, 0.765 mmol) in Et2O (20 mL) was exposed to air and
sunlight for 5 days. Purification via flash column chromatography (eluent 40–60 °C petrol/Et2O, 9:1) gave
(1'RS,αRS)-21 as a colourless oil (57.7 mg, 93%).
Method D: NH3 (2 mL) was condensed at –78 °C and subsequently dried by addition of sodium until the
solution remained deep blue. The resultant mixture was carefully warmed and the dried ammonia was
recondensed at –78 °C. EtOH (0.1 mL) was added, followed by sodium (7 mg, 0.30 mmol) and the resultant
mixture was stirred at –78 °C for 15 min. A solution of (1'RS,αRS)-22 (44 mg, 0.16 mmol, >99:1 dr) in THF
(0.4 mL) was then added and the resultant mixture was stirred at –78 °C for 10 min, which caused
decolourisation. Two further portions of sodium (2 × 7.5 mg) were added until the solution remained blue.
After 10 min, analysis by TLC showed no evidence of starting material. NH4Cl was added and the reaction
mixture was allowed to warm to rt, then concentrated in vacuo. The residue was dissolved in CH2Cl2 and the
resultant solution was filtered and concentrated in vacuo to afford (1'RS,αRS)-21 as a pale yellow oil (39 mg,
quant).
4.13. (RS)-1-(2-Aminophenyl)ethanol (RS)-4011,12
Method A: 20% Pd(OH)2/C (5 mg, 20% w/w) was added to a solution of (1'RS,αRS)-22 (25 mg, 0.092
mmol) in EtOH (5 mL) and the resultant mixture was vigorously stirred at 30 °C for 48 h under H2 (5 atm).
The reaction mixture was then filtered through a plug of Celite (eluent EtOAc) and concentrated in vacuo.
Purification by preparative TLC (petroleum ether/Et2O, 1:1) gave (RS)-40 as a white crystalline solid (9.4
mg, 75%); mp (54–56 °C); {lit.11b mp 58 °C}; δH (300 MHz, CDCl3) 1.59 (3H, d, J 6.6, C(2´)H3), 4.92 (1H,
q, J 6.6, C(1´)H), 6.65–6.75 (2H, m, C(4)H and C(6)H) 7.07–7.09 (2H, m, C(3)H and C(5)H).
Method B: 20% Pd(OH)2/C (5 mg, 20% w/w) was added to a solution of (1'RS,αRS)-21 (26 mg, 0.108 mmol,
>99:1 dr) in EtOH (5 mL) and the resultant mixture was vigorously stirred at 30 °C for 48 h under H2 (5
atm). The reaction mixture was then filtered through a plug of Celite (eluent EtOAc) and concentrated in
vacuo. Purification by preparative TLC (petroleum ether/Et2O, 1:1) gave (RS)-40 as a white crystalline solid
(11.4 mg, 77%).
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4.14. (1pS,1′R,αR)-{1-[O-Methyl-N-(α-methylbenzyl)hydroxylamino]-2-(1'-
hydroxyethyl)benzene}tricarbonylchromium(0) (1pS,1′R,αR)-10
MeMgBr (0.33 mL, 3.0 M in Et2O, 1.00 mmol) was added to a stirred solution of (1pS,αR)-4 (130 mg, 0.332
mmol, >99:1 dr, >99:1 er) in Et2O (15 mL) at –78 °C and the resultant mixture was stirred at –78 °C for 10
min, according to General Procedure 1, to give (1pS,1'R,αR)-10 in >99:1 dr. Purification via
recrystallisation (40–60 °C petrol/Et2O) gave (1pS,1'R,αR)-10 as a yellow crystalline solid (126 mg, 94%,
>99:1 dr); mp 90 °C (dec.); [α] 2D3 –28.4 (c 0.63 in CHCl3).
4.15. (1'R,αR)-1'-{2-[O-methyl-N-(α-methylbenzyl)hydroxylamino]phenyl}ethanol (1'R,αR)-22
A solution of I2 (67 mg, 0.26 mmol) in THF (10 mL) was added to a stirred solution of (1pS,1′R,αR)-10 (54
mg, 0.132 mmol, >99:1 dr) in THF (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 3.5 h then
concentrated in vacuo. The residue was extracted with Et2O (3 × 30 mL) and the combined organic extracts
were washed with satd aq Na2S2O5 (50 mL), then dried and concentrated in vacuo. Purification via flash
column chromatography (eluent 40–60 °C petrol/Et2O, 9:1) gave (1′R,αR)-22 as a white crystalline solid (30
mg, 84%, >99:1 dr); mp 138–139 °C; [α] 2D3 +98.7 (c 0.45 in CHCl3).
4.16. (1'R,αR)-1'-[2-N-(α-Methylbenzyl)aminophenyl]ethanol (1'R,αR)-21
A solution of (1pS,1′R,αR)-10 (73 mg, 0.18 mmol, >99:1 dr) and (fluorobenzene)tricarbonylchromium(0) 1
(125 mg, 0.538 mmol) in Et2O (20 mL) was exposed to air and sunlight for 4 days. Purification via flash
column chromatography (eluent 40–60 °C petrol/Et2O, 9:1) gave (αR,1′R)-21 as a colourless oil (43 mg,
99%, >99:1 dr); [α] 2D3 –96.0 (c 1.17 in CHCl3).
4.17. (R)-1-(2-Aminophenyl)ethanol (R)-4013,20
Method A (from 22): 20% Pd(OH)2/C (4 mg, 20% w/w) was added to a solution of (1′R,αR)-22 (20 mg,
0.074 mmol, >99:1 dr) in EtOH (5 mL) and the resultant mixture was stirred vigorously at 30 °C for 24 h
under H2 (5 atm). The reaction mixture was then filtered through a plug of Celite (eluent EtOAc) and
concentrated in vacuo. Purification via flash column chromatography (eluent 40–60 °C petrol/Et2O, 1:1)
gave (R)-40 as a white crystalline solid (7.6 mg, 75%, >99:1 er); mp 50–52 °C; {lit.13 mp 49–54 °C};
[α] 2D3 –6.0 (c 0.1 in MeOH); {lit.13 for (S)-40: [α] 2D3 +4.5 (c 16.2 in MeOH)}.
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Method B (from 21): 20% Pd(OH)2/C (8 mg, 20% w/w) was added to a solution of (1′R,αR)-21 (40 mg,
0.166 mmol) in EtOH (5 mL) and the resultant mixture was stirred vigorously at 30 °C for 24 h under
H2 (5 atm). The reaction mixture was then filtered through a plug of Celite (eluent EtOAc) and
concentrated in vacuo. Purification via flash column chromatography (eluent 40–60 °C petrol/Et2O, 1:1)
gave (R)-40 as a white crystalline solid (16 mg, 70%, >99:1 er).
Acknowledgements
We thank Fundação para a Ciência e a Tecnologia (Programa Praxis XXI) for provision of funding (to
F.C.T., Praxis XXI BD/5433/95 JNICT). We also thank Dr. A. N. Chernega, and the Oxford Chemical
Crystallography Service for X-ray crystal structure determination and the use of their diffractometers.
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21