The asymmetric synthesis of (S,S)-methylphenidate hydrochloride via ring-opening of an enantiopure aziridinium intermediate with phenylmagnesium bromide

Article abstract of DOI:10.1016/j.tet.2019.130713

The key step in our synthetic strategy towards (S,S)-methylphenidate hydrochloride employs the ring-opening of an in situ formed aziridinium intermediate. Treatment of an α-hydroxy-β-amino ester with methanesulfonic anhydride promoted aziridinium formation and the subsequent addition of phenylmagnesium bromide resulted in stereospecific and regioselective ring-opening to give the corresponding α-phenyl-β-amino ester with overall retention of configuration. Subsequent functional group manipulation followed by N-deprotection and cyclisation generated the piperidine ring within the target compound, and transesterification gave (S,S)-methylphenidate hydrochloride, in only 8 steps from 1,5-pentanediol, in 15% overall yield. These results demonstrate the synthetic utility of enantiopure aziridinium intermediates as substrates for the generation of stereodefined C–C bonds, and crucially this methodology provides access to α-substituted-β-amino ester substrates that are not accessible via enolate alkylation chemistry. The strategy reported herein is potentially applicable to all possible stereoisomers of methylphenidate as well as differentially substituted analogues.

Full text of DOI:10.1016/j.tet.2019.130713

Journal Pre-proof
The asymmetric synthesis of (S,S)-methylphenidate hydrochloride via ring-opening of
an enantiopure aziridinium intermediate with phenylmagnesium bromide
Stephen G. Davies, Ai M. Fletcher, Matthew E. Peters, Paul M. Roberts, James E.
Thomson
PII:
S0040-4020(19)31093-2
https://doi.org/10.1016/j.tet.2019.130713
TET 130713
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 6 September 2019
Revised Date: 3 October 2019
Accepted Date: 17 October 2019
Please cite this article as: Davies SG, Fletcher AM, Peters ME, Roberts PM, Thomson JE, The
asymmetric synthesis of (S,S)-methylphenidate hydrochloride via ring-opening of an enantiopure
aziridinium intermediate with phenylmagnesium bromide, Tetrahedron (2019), doi: https://
doi.org/10.1016/j.tet.2019.130713.
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The asymmetric synthesis of (S,S)-methylphenidate hydrochloride via ring-opening of an enantiopure
aziridinium intermediate with phenylmagnesium bromide
Stephen G. Davies, Ai M. Fletcher, Matthew E. Peters, Paul M. Roberts and James E. Thomson*
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford,
OX1 3TA, U.K.
E-mail: james.thomson@chem.ox.ac.uk

The asymmetric synthesis of (S,S)-methylphenidate hydrochloride via ring-opening of an enantiopure
aziridinium intermediate with phenylmagnesium bromide
Stephen G. Davies, Ai M. Fletcher, Matthew E. Peters, Paul M. Roberts and James E. Thomson*
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford,
OX1 3TA, U.K.
E-mail: james.thomson@chem.ox.ac.uk
Dedicated to Professor Stephen G. Davies in recognition of his outstanding contributions to the field of
organic chemistry.
Abstract
The key step in our synthetic strategy towards (S,S)-methylphenidate hydrochloride employs the ring-
opening of an in situ formed aziridinium intermediate. Treatment of an α-hydroxy-β-amino ester with
methanesulfonic anhydride promoted aziridinium formation and the subsequent addition of
phenylmagnesium bromide resulted in stereospecific and regioselective ring-opening to give the
corresponding α-phenyl-β-amino ester with overall retention of configuration. Subsequent functional group
manipulation followed by N-deprotection and cyclization generated the piperidine ring within the target
compound, and transesterification gave (S,S)-methylphenidate hydrochloride in only 8 steps from 1,5-
pentanediol, in 15% overall yield. These results demonstrate the synthetic utility of enantiopure aziridinium
intermediates as substrates for the generation of stereodefined C–C bonds, and crucially this methodology
provides access to α-substituted-β-amino ester substrates that are not accessible via enolate alkylation
chemistry. The strategy reported herein is potentially applicable to all possible stereoisomers of
methylphenidate as well as differentially substituted analogues.
Key words: methylphenidate; ritalin; asymmetric synthesis; lithium amide; aziridinium; α-aryl-β-amino acid
1. Introduction
Racemic threo-methylphenidate hydrochloride 1ꢀHCl, sold under the tradename Ritalin®, is a dopamine re-
uptake inhibitor commonly prescribed as a treatment for attention deficit hyperactivity disorder (ADHD) in
children and adolescents (Fig. 1).1 Whilst the drug is typically supplied as a racemate, the (+)-enantiomer
1

has been determined to be about thirteen times more pharmacologically active than its antipode.2,3
Furthermore, threo-methylphenidate 1ꢀHCl has also undergone evaluation for its therapeutic potential for the
treatment of cocaine addiction and narcolepsy.4 Several syntheses of enantiopure threo-methylphenidate
hydrochloride 1ꢀHCl have been reported via a number of distinct approaches.5,6 Protocols for the resolution
of threo-methylphenidate 1 by enzymatic hydrolysis as well as classical resolution methods have also been
developed,7 and there have also been reports of various synthetic analogues of methylphenidate
hydrochloride 1ꢀHCl being evaluated for their biological activity.8
Fig. 1. The structure of (±)-threo-methylphenidate hydrochloride (Ritalin®) 1ꢀHCl.
We have previously explored the utility of enantiopure aziridinium species as versatile intermediates in
asymmetric synthesis,9 and envisaged that the stereospecific and regioselective ring-opening of an
aziridinium intermediate with an organometallic reagent could be incorporated as a key step in an
asymmetric synthesis of (S,S)-methylphenidate hydrochloride 1ꢀHCl. This strategy relied upon the
manipulation of a suitably protected α-hydroxy-β-amino ester: substrates which are readily accessible using
our diastereoselective aminohydroxylation protocol.10 ζ-Silyloxy-α-hydroxy-β-amino ester 2 was selected as
a suitable substrate for this synthesis as removal of the O-silyl protecting group would reveal a synthetic
handle for subsequent cyclisation to give the piperidine ring within the target compound. Activation of the α-
hydroxyl group within 2 as a leaving group was expected to promote displacement by the adjacent amino
group [with inversion of configuration at C(2)] to give the corresponding aziridinium 3.9 Subsequent in situ
ring-opening of aziridinium 3 with an organometallic reagent was anticipated to proceed preferentially at the
C(2)-position [again with inversion of configuration at C(2)], distal to the alkyl substituent and proximal to
the electronically activating α-carbonyl of the ester moiety,11 to give the corresponding α-phenyl-β-amino
ester 4 with overall retention of configuration. Subsequent O-silyl deprotection and manipulation of the
resultant hydroxyl group was expected to facilitate cyclisation to give the corresponding piperidine 6, which
could be converted into (S,S)-methylphenidate hydrochloride 1ꢀHCl upon transesterification under acidic
conditions (Fig. 2).
2

Ph
Ph
O-activation then
aziridinium
Ph
N
formation
CO2tBu
Ph
N
TIPSO
CO2tBu
3
2
R
OH
2
3
regioselective
ring-opening at
C(2) with PhMgBr
[R = (CH2)4OTIPS]
Ph
Ph
Ph
O-silyl deprotection
and functional group
manuipulation
Ph
Ph
N
N
CO2tBu
CO2tBu
X
TIPSO
Ph
5
4
N-deprotection
and cyclisation
[X = suitable
leaving group]
NH
NH — HCl
CO2Me
transesterification
CO2tBu
Ph
Ph
6
(S,S)ꢀmethylphenidate
hydrochloride 1—HCl
Fig. 2. Proposed asymmetric synthesis of (S,S)-methylphenidate hydrochloride 1ꢀHCl.
2. Results and discussion
The requisite ζ-silyloxy-α-hydroxy-β-amino ester 2 was prepared in three steps from commercially available
1,5-pentanediol 7. Mono-protection of 7 upon treatment with NaH and TIPSCl gave 8 in 59% yield, and
Swern oxidation of 8 followed by Wittig olefination of the resultant aldehyde gave α,β-unsaturated ester 9 in
93% yield (from 8) and 94:6 dr [(E):(Z)]. The configuration of the major diastereoisomer was assigned from
the diagnostic value of the 3J coupling constant between the two olefinic protons (3J2,3 = 15.6 Hz) in the 1H
NMR spectrum. The mixture of olefin isomers was carried through the next step to give, following
diastereoselective aminohydroxylation upon sequential treatment of 9 with lithium (S)-N-benzyl-N-(α-
methylbenzyl)amide (S)-10 and (+)-(camphorsulfonyl)oxaziridine [(+)-CSO] 11,10 2,3-anti-α-hydroxy-β-
amino ester 2 as a single diastereoisomer (>99:1 dr). Following purification by flash column
chromatography, 2 was isolated in 80% yield and >99:1 dr. The 2,3-anti-relative configuration within 2 was
assigned by analogy to the well-established outcome of this aminohydroxylation procedure,10 and this
assignment was supported by 1H NMR 3J coupling constant analysis (3J2,3 = 1.8 Hz for 2).12 Elaboration of 2
to the corresponding α-phenyl-β-amino ester 4 was undertaken next. Under the optimised conditions for
aziridinium ion formation,9 α-hydroxy-β-amino ester 2 was treated with Ms2O and Et3N then aziridinium
intermediate 3 was reacted with PhMgBr in the presence of CuPF6, which gave α-phenyl-β-amino ester 4 as
the sole reaction product. After chromatographic purification of the crude reaction mixture, 4 was isolated in
68% yield and >99:1 dr (Scheme 1). The relative 2,3-anti-configuration within α-phenyl-β-amino ester 4 was
3

unambiguously established via single crystal X-ray diffraction analysis (Fig. 3),13 with the absolute (S,S,S)-
configuration of 4 being assigned from the known (S)-configuration of the α-methylbenzyl fragment. The
determination of a Flack x parameter14 of −0.02(2) for the structure of 4 confirmed this assignment. The
exclusive formation of 4 in this reaction is entirely consistent with our mechanistic hypothesis, whereby the
Grignard reagent regioselectively reacts at the C(2) position within aziridinium 3.15 This stereospecific C–C
bond forming reaction was conducted on a ~3 g scale, demonstrating the robustness of this methodology for
the α-arylation of β-amino esters, a transformation that is not possible using standard enolate alkylation
chemistry.
Scheme 1.
Fig. 3. X-ray crystal structure of (S,S,S)-4 (selected H atoms have been omitted for clarity).
4

O-Silyl deprotection of 4 upon treatment with TBAF proceeded to give alcohol 12 in 90% isolated yield.
Subsequent treatment of 12 with TsCl in pyridine gave the corresponding tosylate 13 in 45% yield and >99:1
dr. The low yield of this transformation was due to the competitive formation of the corresponding chloride
14, which represented 45% of the crude reaction mixture and was isolated in 27% yield (Scheme 2). We
have previously shown that ω-sulfonyloxy substituted amines undergo cyclisation to the corresponding
quaternary ammonium intermediate followed by SN1-type loss of a benzyl fragment upon heating in
MeCN.16,17 However, under these conditions, tosylate 13 did not react to give either of the potential
piperidine products 15 (R = H) or 16 (R = Me), and only starting material 13 was recovered. With heat-
induced cyclisation of tosylate 13 having proved unsuccessful the next strategy was to convert 13 to the
corresponding primary amine 17 prior to cyclisation. Hydrogenolysis of tertiary amine 13 in the presence of
Pearlman’s catalyst [Pd(OH)2/C] gave primary amine 17, and immediate treatment of the crude reaction
mixture with 2.0 M aq NaOH returned piperidine 6 in 44% yield (from 13) and >99:1 dr (Scheme 2).
Scheme 2.
The generation of piperidine 6 in 20% yield over the three steps from alcohol 12 demonstrates the viability
of this strategy of O-activation, hydrogenolysis, and cyclisation. Efforts therefore turned to increasing the
overall yield of this sequence of reactions. Mesylation of alcohol 12 upon treatment with Ms2O and Et3N
gave 18 (>95:5 dr) as the only observed product in the crude reaction mixture. Subsequent hydrogenolysis of
5

18 followed by treatment of the resultant primary amine 19 with 2.0 M aq NaOH gave piperidine 6 in a
much improved 56% yield over three steps from alcohol 12 (Scheme 3).
Scheme 3.
Finally, transesterification of the tert-butyl ester moiety within 6 upon reaction with SOCl2 and MeOH gave
(S,S)-methylphenidate hydrochloride 1·HCl in quantitative yield and >99:1 dr (Scheme 4). As the lithium
amide reagent used for the conjugate addition reaction was >99:1 er, our sample of 1·HCl was inferred as
being >99:1 er, along with all intermediates en route, as epimerisation was not observed at any stage in the
[α]25
synthesis. The specific rotation of our sample of 1·HCl {
−65.0 (c 1.0 in MeOH)} was in general
D
agreement with literature values {lit.7b
−85.0 (c 1.0 in MeOH); lit.5b
[α]2D0
[α]2D0
−81.8 (c 1.38 in MeOH)},
and the 1H and 13C NMR spectroscopic data for this sample of 1·HCl were also in complete accord with the
literature.5b,7b The assigned relative and absolute configuration of (S,S)-1·HCl were unambiguously
confirmed via single crystal X-ray diffraction analysis (Fig. 4),13 with the Flack x parameter14 for the
structure of 1·HCl being determined as +0.02(3).
Scheme 4.
6

Fig. 4. X-ray crystal structure of (S,S)-methylphenidate hydrochloride (S,S)-1·HCl (selected H atoms have been omitted for
clarity).
3. Conclusion
In conclusion, (S,S)-methylphenidate hydrochloride was synthesised in 15% yield over 8 steps from
commercially available 1,5-pentanediol. The key step in the synthesis employed the regioselective and
stereospecific ring-opening of an enantiopure aziridinium intermediate with phenylmagnesium bromide.
This synthesis demonstrates the synthetic utility of enantiopure aziridiniums as substrates for the generation
of stereodefined C–C bonds, and provides access to substrates that are not accessible via enolate alkylation
chemistry. The strategy reported herein is potentially applicable to all possible stereoisomers of
methylphenidate as well as differentially substituted analogues.
4. Experimental
4.1. General Experimental
Reactions involving organometallic or other moisture-sensitive reagents were carried out under a nitrogen or
argon atmosphere using standard vacuum line techniques and glassware that was flame dried and cooled
under nitrogen before use. BuLi was purchased as a solution in hexanes and titrated against diphenylacetic
acid before use. Solvents were dried according to the procedure outlined by Grubbs and co-workers.20 Water
was purified by an Elix® UV-10 system. All other reagents were used as supplied (analytical or HPLC
grade) without prior purification. Organic layers were dried over MgSO4 or NaSO4. Thin layer
chromatography was performed on aluminium plates coated with 60 F254 silica. Plates were visualised using
UV light (254 nm), iodine, 1% aq KMnO4, or 10% ethanolic phosphomolybdic acid. Flash column
chromatography was performed on Kieselgel 60 silica.
7

Melting points were recorded on a Gallenkamp Hot Stage apparatus. Optical rotations were recorded on a
Perkin-Elmer 241 polarimeter with a water-jacketed 10 cm cell. Specific rotations are reported in 10−1 deg
cm2 g−1 and concentrations in g/100 mL. IR spectra were recorded on a Bruker Tensor 27 FT-IR
spectrometer using an ATR module. Selected characteristic peaks are reported in cm–1. NMR spectra were
recorded on Bruker Avance spectrometers in the deuterated solvent stated. Spectra were recorded at rt. The
field was locked by external referencing to the relevant deuteron resonance. 1H−1H COSY, 1H−13C HMQC,
1
and H−13C HMBC analyses were used to establish atom connectivity. Low-resolution mass spectra were
recorded on either a VG MassLab 20–250 or a Micromass Platform 1 spectrometer. Accurate mass
measurements were run on either a Bruker MicroTOF internally calibrated with polyalanine, or a Micromass
GCT instrument fitted with a Scientific Glass Instruments BPX5 column (15 m × 0.25 mm) using amyl
acetate as a lock mass.
4.2. 5-(Triisopropylsilyloxy)pentan-1-ol 8
1,5-Pentanediol 7 (7.50 g, 72.0 mmol) was added dropwise to a stirred suspension of NaH (60% dispersion
in mineral oil, 2.88 g, 72.0 mmol) in THF (144 mL) at 0 °C, and the resultant mixture was stirred at rt for 45
min. TIPSCl (15.4 mL, 72.0 mmol) was then added at 0 °C and the resultant mixture was allowed to warm to
rt and stirred at rt for 6 h. H2O (125 mL) was then added and the reaction mixture was extracted with Et2O (3
× 125 mL). The combined organic extracts were washed with brine (125 mL), then dried and concentrated in
vacuo. Purification via flash column chromatography (eluent 30−40 °C petrol/Et2O, 5:1 increased to 1:1)
gave 8 as a colourless oil (11.1 g, 59%);18 δH (400 MHz, CDCl3) 0.97−1.16 (21H, m, Si
(CHMe2)3),
1.38−1.48 (2H, m, C(3)H2), 1.51−1.67 (4H, m, C(2)H2, C(4)H2), 3.62−3.73 (4H, m, C(1)H2, C(5)H2).
4.3. tert-Butyl (E)-7-(triisopropylsilyloxy)hept-2-enoate 9
DMSO (12.1 mL, 171 mmol) was added dropwise to a stirred solution of (COCl)2 (7.20 mL, 85.1 mmol) in
CH2Cl2 (190 mL) at −78 °C and the resultant mixture was stirred at −78 °C for 20 min. A solution of 8 (11.1
g, 42.5 mmol) in CH2Cl2 (120 mL) at −78 °C was then added via cannula and the resultant mixture was
stirred at −78 °C for 30 min. Et3N (35.6 mL, 256 mmol) was then added dropwise and the resultant mixture
t
was stirred at −78 °C for 30 min, then allowed to warm to rt and stirred at rt for 30 min. Ph3PCHCO2 Bu
(16.0 g, 42.5 mmol) was then added and the resultant mixture was stirred at rt for 18 h, before being diluted
with H2O (600 mL) and extracted with CH2Cl2 (3 × 300 mL). The combined organic extracts were
8

sequentially washed with satd aq NaHCO3 (300 mL) and brine (300 mL), then concentrated in vacuo.
Purification via flash column chromatography (eluent 30−40 °C petrol/Et2O, 50:1 increased to 5:1) gave 9 as
a yellow oil (14.0 g, 93%, 94:6 dr [(E):(Z)]); νmax 2942 (C−H), 2866 (C−H), 1717 (C=O), 1654 (C=C); δH
(400 MHz, CDCl3) Data for major (E)-diastereoisomer: 1.01−1.14 (21H, m, Si(CHMe2)3), 1.48 (9H, s,
CMe3), 1.48−1.66 (4H, m, C(5)H2, C(6)H2), 2.20 (2H, app qd, J 7.0, 1.6, C(4)H2), 3.63−3.74 (2H, m,
C(7)H2), 5.74 (1H, dt, J 15.6, 1.6, C(2)H), 6.86 (1H, dt, J 15.6, 7.0, C(3)H); δC (100 MHz, CDCl3) Data for
major (E)-diastereoisomer: 11.9 (SiCHMe2), 18.0 (SiCHMe2), 24.5 (C(5)), 28.2 (CMe3), 31.9 (C(4)), 32.4
(C(6)), 63.0 (C(7)), 80.0 (CMe3), 123.1 (C(2)), 148.0 (C(3)), 166.2 (C(1)); m/z (ESI+) 379 ([M+Na]+, 100%);
HRMS (ESI+) C20H40NaO3Si+ ([M+Na]+) requires 379.2639; found 379.2641.
4.4. tert-Butyl (S,S,S)-2-hydroxy-3-[N-benzyl-N-(α-methylbenzyl)amino]-7-
(triisopropylsilyloxy)heptanoate 2
n-BuLi (2.5 M in hexanes, 4.36 mL, 10.9 mmol) was added dropwise to a stirred solution of (S)-N-benzyl-N-
(α-methylbenzyl)amine (S)-10 (13.3 g, 62.9 mmol, >99:1 er) in THF (300 mL) at −78 °C. The resultant
mixture was stirred at −78 °C for 30 min, then a solution of 9 (14.0 g, 39.3 mmol, 94:6 dr [(E):(Z)]) in THF
(90 mL) at −78 °C was added dropwise via cannula. The resultant mixture was stirred at −78 °C for a further
2 h then (+)-CSO 11 (15.4 g, 67.2 mmol) was added. The reaction mixture was allowed to warm to rt and
stirred at rt for 16 h, then concentrated in vacuo. The residue was partitioned between CH2Cl2 (150 mL) and
10% aq citric acid (150 mL). The aqueous layer was extracted with two portions of CH2Cl2 (100 mL) and
the combined organic extracts were washed sequentially with satd aq NaHCO3 (200 mL) and brine (200
mL), then dried and concentrated in vacuo. Purification via flash column chromatography (eluent 30–40 °C
[α]2D5
petrol/Et2O, 13:1) gave 2 as a pale yellow oil (18.5 g, 80%, >99:1 dr);
+21.3 (c 1.0 in CHCl3); νmax
3503 (O−H), 2941 (C−H), 2865 (C−H), 1720 (C=O); δH (400 MHz, CDCl3) 1.03−1.12 (21H, m,
Si(CHMe2)3), 1.30 (3H, d, J 6.9, C(α)Me), 1.43 (9H, s, CMe3), 1.37−1.51 (3H, m, C(6)H2, C(5)HA, C(4)HA)
1.57−1.71 (2H, m, C(5)HB, C(4)HB), 2.89 (1H, d, J 6.0, OH), 3.23 (1H, ddd, J 8.8, 4.5, 1.8, C(3)H),
3.64−3.71 (3H, m, NCHAHBPh, C(7)H2), 3.87 (1H, dd, J 6.0, 1.8, C(2)H), 3.94 (1H, q, J 6.9, C(α)H), 4.26
(1H, d, J 15.5, NCHAHBPh), 7.18−7.50 (10H, m, Ph); δC (100 MHz, CDCl3) 12.1 (Si(CHMe2)3), 18.1
(Si(CHMe2)3), 19.5 (C(α)Me), 23.3 (C(5)), 27.4 (C(4)), 28.0 (CMe3), 33.3 (C(6)), 51.1 (NCH2Ph), 58.4
(C(α)), 58.8 (C(3)), 63.4 (C(7)), 71.2 (C(2)), 82.4 (CMe3), 126.4, 127.0, 128.1, 128.1, 128.2, 128.2 (o,m,p-
9

Ph), 142.6, 143.0 (i-Ph), 174.4 (C(1)); m/z (ESI+) 584 ([M+H]+, 100%); HRMS (ESI+) C35H58NO4Si+
([M+H]+) requires 584.4130; found 584.4139.
4.5. tert-Butyl (S,S,S)-2-phenyl-3-[N-benzyl-N-(α-methylbenzyl)amino]-7-
(triisopropylsilyloxy)heptanoate 4
Ms2O (3.85 g, 25.7 mmol) was added to a stirred solution of 2 (4.30 g, 8.56 mmol, >99:1 dr) and Et3N (4.62
mL, 38.5 mmol) in Et2O (350 mL) and the resultant mixture was stirred at rt for 60 min. The reaction
mixture was then cooled to 0 °C and CuPF6 (1.38 g, 4.28 mmol) and PhMgBr (3.0 M in Et2O, 24.5 mL, 85.6
mmol) were sequentially added, and the resultant mixture was stirred at 0 °C for 2 h. Satd aq NH4Cl (80 mL)
was added, and the reaction mixture was diluted with H2O (400 mL) and extracted with Et2O (3 × 300 mL),
then the combined organic extracts were dried and concentrated in vacuo. Purification via flash column
chromatography (eluent 30−40 °C petrol/Et2O 75:1) gave 4 as a white solid (3.23 g, 68%, >99:1 dr); mp
[α]25
84−86 °C;
−21.9 (c 1.0 in CHCl3); νmax 2942 (C−H), 2865 (C−H), 1726 (C=O); δH (400 MHz, CDCl3)
D
0.48−0.66 (1H, m, C(5)HA), 1.00−1.09 (22H, m, C(4)HA, Si(CHMe2)3), 1.10−1.21 (3H, m, C(5)HB, C(6)H2),
1.24−1.35 (1H, m, C(4)HB), 1.38 (3H, d, J 6.9, C(α)Me), 1.42 (9H, s, CMe3), 3.30−3.43 (2H, m, C(7)H2),
3.39 (1H, d, J 9.7, C(2)H), 3.63 (1H, ddd, J 9.7, 6.9, 4.9, C(3)H), 3.69−3.83 (2H, m, NCH2Ph), 4.14 (1H, q,
J 6.9, C(α)H), 7.12−7.38 (15H, m, Ph); δC (100 MHz, CDCl3) 12.0 (Si(CHMe2)3), 18.1 (Si(CHMe2)3), 20.8
(C(α)Me), 24.3 (C(5)), 28.0 (CMe3), 30.0 (C(4)), 33.3 (C(6)), 50.4 (NCH2Ph), 58.3 (C(2)), 62.0 (C(3)), 62.2
(C(α)), 63.2 (C(7)), 80.1 (CMe3), 126.3, 126.7, 127.0, 127.8, 127.9, 128.1, 128.2, 128.6, 129.1 (o,m,p-Ph),
137.7, 142.7, 144.9 (i-Ph), 172.8 (C(1)); m/z (ESI+) 644 ([M+H]+, 100%); HRMS (ESI+) C41H62NO3Si+
([M+H]+) requires 644.4493; found 644.4480.
4.5.1. X-ray crystal structure determination for tert-butyl (S,S,S)-2-phenyl-3-[N-benzyl-N-(α-
methylbenzyl)amino]-7-(triisopropylsilyloxy)heptanoate 4
Data were collected using an Oxford Diffraction SuperNova diffractometer with graphite monochromated
Cu-Kα radiation using standard procedures at 150 K. The structure was solved by direct methods (SIR92);
all non-hydrogen atoms were refined with anisotropic thermal parameters. Hydrogen atoms were added at
idealised positions. The structure was refined using CRYSTALS.19
X-ray crystal structure data for 4 [C41H61NO3Si]:13 M = 644.03, orthorhombic, space group P 21 21 21,
a = 7.87519(15) Å, b = 11.8183(3) Å, c = 41.2585(6) Å, V = 3840.00(13) Å3, Z = 4,
µ
= 0.811 mm–1,
10

colourless prism, crystal dimensions = 0.11 × 0.11 × 0.23 mm3. A total of 7943 unique reflections were
measured for 4 < < 76 and 7472 reflections were used in the refinement. The final parameters were
θ
wR2 = 0.085 and R1 = 0.039 [I>–3.0σ(I)], with Flack x parameter = –0.02(2).14
4.6. tert-Butyl (S,S,S)-2-phenyl-3-[N-benzyl-N-(α-methylbenzyl)amino]-7-hydroxyheptanoate 12
TBAF (1.0 M in THF, 25.1 mL, 25.1 mmol) was added to a stirred solution of 4 (3.23 g, 5.02 mmol, >99:1
dr) in THF (33 mL) at rt and the resultant mixture was stirred at rt for 24 h. H2O (100 mL) was then added
and the reaction mixture was extracted with CH2Cl2 (3 × 100 mL). The combined organic extracts were then
dried and concentrated in vacuo. Purification via flash column chromatography (eluent 30−40 °C petrol/Et2O
[α]2D5
3:2) gave 12 as a white solid (2.21 g, 90%, >99:1 dr); mp 97−100 °C;
−25.0 (c 1.0 in CHCl3); νmax
3375 (O−H), 3028 (C−H), 2976 (C−H), 1723 (C=O); δH (400 MHz, CDCl3) 0.42−0.54 (1H, m, C(5)HA),
0.84 (1H, app t, J 5.8, C(6)HA), 0.89−1.16 (3H, m, C(4)HA, C(5)HB, C(6)HB), 1.20−1.32 (1H, m, C(4)HB),
1.37 (3H, d, J 7.0, C(α)Me), 1.43 (9H, s, CMe3), 3.27(2H, app q, C(7)H2), 3.39 (1H, d, J 9.8, C(2)H), 3.59
(1H, ddd, J 9.8, 6.7, 4.9, C(3)H), 3.73 (1H, d, J 15.2, NCHAHBPh), 3.85 (1H, d, J 15.2, NCHAHBPh), 4.19
(1H, q, J 7.0, C(α)H), 7.13−7.45 (15H, m, Ph); δC (100 MHz, CDCl3) 20.8 (C(α)Me), 23.9 (C(5)), 28.0
(CMe3), 29.6 (C(4)), 32.7 (C(6)), 49.8 (NCH2Ph), 58.4 (C(2)), 62.4 (C(3)), 62.4 (C(α)), 62.6 (C(7)), 80.2
(CMe3), 126.4, 126.8, 127.1, 127.9, 128.0, 128.2, 128.3, 128.6, 129.0 (o,m,p-Ph), 137.8, 142.7, 144.8 (i-Ph),
172.8 (C(1)); m/z (ESI+) 488 ([M+H]+, 100%); HRMS (ESI+) C32H42NO3 ([M+H]+) requires 488.3159;
+
found 488.3154.
4.7. tert-Butyl (S,S,S)-2-phenyl-3-[N-benzyl-N-(α-methylbenzyl)amino]-7-(p-
toluenesulfonyloxy)heptanoate 13 and tert-butyl (S,S,S)-2-phenyl-3-[N-benzyl-N-(α-
methylbenzyl)amino]-7-chloroheptanoate 14
TsCl (59.0 mg, 0.312 mmol) was added to a stirred solution of 12 (51.0 mg, 0.104 mmol, >99:1 dr) in
pyridine (1.0 mL) and the resultant mixture was stirred at rt for 2 h, then concentrated in vacuo. Purification
via flash column chromatography (eluent 30−40 °C petrol/Et2O 75:1 increased to 10:1) gave 14 as a
[α]2D5
colourless oil (14 mg, 27%, >99:1 dr);
–23.1 (c 1.0 in CHCl3); νmax 3028 (C−H), 2975 (C−H), 1723
(C=O); δH (400 MHz, CDCl3) 0.52−0.67 (1H, m, C(5)HA), 0.93–1.05 (1H, m, C(4)HA), 1.05−1.17 (1H, m,
C(5)HB), 1.19–1.32 (3H, m, C(4)HB, C(6)H2), 1.37 (3H, d, J 7.0, C(α)Me), 1.43 (9H, s, CMe3), 3.07–3.26
(2H, m, C(7)H2), 3.41 (1H, d, J 9.8, C(2)H), 3.54−3.62 (1H, m, C(3)H), 3.74 (1H, d, J 15.2, NCHAHBPh),
11

3.85 (1H, d, J 15.2, NCHAHBPh), 4.19 (1H, q, J 7.0, C(α)H), 7.11–7.42 (15H, m, Ph); δC (100 MHz, CDCl3)
21.2 (C(α)Me), 25.3 (C(5)), 28.2 (CMe3), 29.5 (C(4)), 32.8 (C(6)), 44.9 (C(7)), 50.1 (NCH2Ph), 58.3 (C(2)),
62.3 (C(3)), 62.5 (C(α)), 80.4 (CMe3), 126.6, 127.0, 127.3, 128.1, 128.2, 128.2, 128.4, 128.6, 129.1 (o,m,p-
Ph), 137.8, 142.8, 144.8 (i-Ph), 172.9 (C(1)); m/z (ESI+) 506 ([M(35Cl)+H]+, 100%); HRMS (ESI+)
+
C32H4135ClNO2 ([M(35Cl)+H]+) requires 506.2820; found 506.2820. Further elution (eluent 30−40 °C
[α]2D5
petrol/Et2O 10:1) gave 13 as a colourless oil (30 mg, 45%, >99:1 dr);
−26.8 (c 1.0 in CHCl3); νmax
3028 (C−H), 2974 (C−H), 1722 (C=O); δH (400 MHz, CDCl3) 0.40−0.56 (1H, m, C(5)HA), 0.79−1.02 (2H,
m, C(5)HB, C(4)HA), 1.04−1.29 (3H, m, C(6)H2, C(4)HB), 1.33 (3H, d, J 7.0, C(α)Me), 1.42 (9H, s, CMe3),
2.45 (3H, s, ArMe), 3.37 (1H, d, J 9.7, C(2)H), 3.52 (1H, ddd, J 9.7, 7.0, 4.6, C(3)H), 3.65 (2H, app tt, J 6.7,
3.3, C(7)H2), 3.69 (1H, d, J 15.2, NCHAHBPh), 3.81 (1H, d, J 15.2, NCHAHBPh), 4.14 (1H, q, J 7.0, C(α)H),
7.03−7.84 (19H, m, Ar, Ph); δC (100 MHz, CDCl3) 21.0 (C(α)Me), 21.6 (ArMe), 23.5 (C(5)), 28.0 (CMe3),
28.8 (C(6)), 29.4 (C(4)), 50.0 (NCH2Ph), 58.0 (C(2)), 61.9 (C(3)), C(α)), 70.3 (C(7)), 80.3 (CMe3), 126.5,
126.9, 127.1, 127.9, 128.0, 128.0, 128.3, 128.4, 128.9, 129.8 (Ar, o,m,p-Ph), 137.6, 142.6, 144.5, 144.7 (Ar,
i-Ph), 172.7 (C(1)); m/z (ESI+) 642 ([M+H]+, 100%); HRMS (ESI+) C39H48NO5S+ ([M+H]+) requires
642.3248; found 642.3249.
4.8. tert-Butyl (S,S)-2-phenyl-2-(piperidin-2'-yl)ethanoate 6
Method A: A mixture of 13 (135 mg, 0.210 mmol, >99:1 dr) and Pd(OH)2/C (50.0 mg, 20% w/w) in
MeOH/H2O/AcOH (20:2:1, 4.00 mL) was stirred under H2 (1 atm) for 16 h then filtered through celite
(eluent MeOH) and concentrated in vacuo. The residue was dissolved in CH2Cl2 (10 mL) and washed with
2.0 M aq NaOH (5 mL). The aqueous layer was extracted with CH2Cl2 (3 × 10 mL), and the combined
organic extracts were dried and concentrated in vacuo. Purification via flash column chromatography (eluent
[α]2D5
CHCl3/MeOH 60:1) gave 6 as a pale yellow oil (25 mg, 44% from 13, >99:1 dr);
−33.7 (c 1.0 in
CHCl3); νmax 2931 (C−H), 2854 (C−H), 1720 (C=O); δH (400 MHz, CDCl3) 0.93−1.05 (1H, m, C(3')HA),
1.12−1.27 (2H, m, C(3')HB, C(4')HA), 1.35 (9H, s, CMe3), 1.38−1.49 (1H, m, C(5')HA), 1.54−1.60 (1H, m,
C(5')HB), 1.61−1.72 (1H, m, C(4')HB), 2.48 (1H, app s, NH), 2.70 (1H, td, J 11.8, 2.9, C(6')HA), 3.04–3.10
(2H, m, C(6')HB, C(2')H), 3.37 (1H, d, J 10.0, C(2)H), 7.21−7.33 (5H, m, Ph); δC (100 MHz, CDCl3) 24.4
(C(4')), 25.9 (C(5')), 27.9 (CMe3), 29.7 (C(3')), 46.9 (C(6')), 59.0 (C(2')), 59.4 (C(2)), 81.1 (CMe3), 127.2,
128.5, 128.5 (o,m,p-Ph), 137.0 (i-Ph), 172.7 (C(1)); m/z (ESI+) 276 ([M+H]+, 100%); HRMS (ESI+)
+
C17H26NO2 ([M+H]+) requires 276.1958; found 276.1956.
12

Method B − Step 1: Ms2O (267 mg, 1.53 mmol) was added to a stirred solution of 12 (250 mg, 0.510 mmol,
>99:1 dr) and Et3N (0.30 mL, 2.3 mmol) in Et2O (5.0 mL) at rt and stirred at rt for 2 h. The reaction mixture
was then diluted with H2O (10 mL) and extracted with Et2O (3 × 10 mL). The combined organic extracts
were dried and concentrated in vacuo to give 18 as a pale yellow oil (290 mg, >95:5 dr); δH (400 MHz,
CDCl3) 0.48−0.62 (1H, m, C(5)HA), 0.94–1.08 (2H, m, C(4)HA, C(5)HB), 1.15–1.31 (3H, m, C(4)HB,
C(6)H2), 1.36 (3H, d, J 6.9, C(α)Me), 1.43 (9H, s, CMe3), 2.89 (3H, s, SO2Me), 3.41 (1H, d, J 9.7, C(2)H),
3.52–3.60 (1H, m, C(3)H), 3.74 (1H, d, J 15.2, NCHAHBPh), 3.80–3.90 (3H, m, C(7)H2, NCHAHBPh), 4.19
(1H, q, J 6.9, C(α)H), 7.02–7.54 (15H, m, Ph).
Method B − Step 2: The sample of 18 from the previous step was dissolved in MeOH/AcOH/H2O (20:2:1, 5
mL). Pd(OH)2/C (100 mg, 20% w/w) was added and the reaction mixture was stirred under H2 (1 atm) at rt
for 16 h then filtered through celite (eluent MeOH) and concentrated in vacuo. The residue was dissolved in
CH2Cl2 (10 mL) and the resultant solution was washed with 2.0 M aq NaOH (5 mL). The aqueous layer was
extracted with CH2Cl2 (3 × 10 mL), and the combined organic extracts were dried and concentrated in vacuo.
Purification via flash column chromatography (eluent CHCl3/MeOH 75:1) gave 6 as a yellow oil (79 mg,
56% from 12, >99:1 dr).
4.9. Methyl (S,S)-1-phenyl-2-[N-(1')-piperidin-2'-yl]ethanoate hydrochloride [(S,S)-methylphenidate
hydrochloride] 1ꢀHCl
Method A: SOCl2 (50 ꢁL, 0.63 mmol) was added to a stirred solution of 6 (68 mg, 0.21 mmol, >99:1 dr) in
MeOH (5.0 mL) at 0 °C and the resultant mixture was stirred at 0 °C for 30 min. The reaction mixture was
then heated at 50 °C for 16 h before being concentrated in vacuo to give (S,S)-methylphenidate
hydrochloride 1ꢀHCl as a white solid (67 mg, quant, >99:1 dr); mp 214−219 °C; {lit.5b mp 222−224 °C; lit.7b
[α]25
[α]2D0
[α]2D0
−81.8 (c 1.38
mp 219−221 °C};
−65.0 (c 1.0 in MeOH); {lit.5b
−85.0 (c 1.0 in MeOH); lit.7b
D
in MeOH)}; νmax 3657 (N−H) 2981 (C−H), 1740 (C=O); δH (400 MHz, MeOH-d4) 1.17–1.34 (1H, m,
C(3')HA), 1.32–1.48 (2H, m, C(5')HA, C(3')HB), 1.50–1.65 (1H, m, C(4')HA), 1.66–1.75 (1H, m, C(5')HB),
1.79 (1H, d, J 14.6, C(4')HB), 3.01 (1H, td, J 12.8, 3.3, C(6')HA), 3.34 (1H, m, C(6')HB), 3.63 (3H, s, OMe),
3.69–3.81 (2H, m, C(2)H, C(2')H), 7.15–7.36 (5H, m, Ph); δC (100 MHz, MeOH-d4) 22.8 (C(4')), 23.4
(C(5')), 27.8 (C(3')), 46.7 (C(6')), 53.4 (OMe), 55.4 (C(2)), 59.3 (C(2')), 129.6, 129.8, 130.5 (o,m,p-Ph),
+
135.1 (i-Ph), 173.3 (C(1)); m/z (ESI+) 234 ([M−Cl]+, 100%); HRMS (ESI+) C14H20NO2 ([M−Cl]+) requires
234.1489; found 234.1488.
13

Method B: SOCl2 (35 ꢁL, 0.44 mmol) was added to a stirred solution of 6 (44 mg, 0.14 mmol) in MeOH (3.5
mL) at 0 °C and the resultant mixture was stirred at 0 °C for 30 min. The reaction mixture was then heated at
50 °C for 16 h before being concentrated in vacuo. The residue was dissolved in H2O (5 mL) and the
resultant solution was washed with Et2O (10 mL). 1.0 M aq NH4OH (5 mL) was added to the aqueous layer,
which was then extracted with CH2Cl2 (3 × 10 mL). The combined organic extracts were washed with brine
(10 mL), then dried and concentrated in vacuo. Purification via flash column chromatography (eluent
[α]2D5
CHCl3/MeOH, 75:1) gave (S,S)-methylphenidate 1 as a colourless oil (18 mg, 48% from 6, >99:1 dr);5i
−54.1 (c 0.68 in MeOH); {lit.5i
−58.8 (c 0.68 in MeOH)}; νmax 3657 (N−H), 2981 (C−H), 2854 (C−H),
[α]2D6
1728 (C=O); δH (400 MHz, CDCl3) 0.81–1.03 (1H, m, C(3')HA), 1.14–1.29 (2H, m, C(5')HA, C(3')HB), 1.33–
1.47 (1H, m, C(4')HA), 1.51–1.63 (1H, m, C(4')HB), 1.62–1.74 (1H, m, C(5')HB), 1.98 (1H, app s, NH), 2.69
(1H, td, J 11.9, 2.9, C(6')HA), 3.00–3.18 (2H, m, C(2')H, C(6')HB), 3.44 (1H, d, J 10.0, C(2)H), 3.64 (3H, s,
OMe), 7.20–7.37 (5H, m, Ph); δC (100 MHz, CDCl3) 24.5 (C(5')), 26.3 (C(4')), 30.2 (C(3')), 47.1 (C(6')),
52.1 (OMe), 58.9 (C(2)), 59.1 (C(2')), 127.6, 128.7, 128.8 (o,m,p-Ph), 136.6 (i-Ph), 174.0 (C(1)); m/z (ESI+)
234 ([M+H]+, 100%); HRMS (ESI+) C14H20NO2 ([M+H]+) requires 234.1489; found 234.1488. A sample of
+
1 (16.9 mg) was treated with HCl (2.0 M in Et2O) and concentrated in vacuo to give (S,S)-methylphenidate
[α]25
hydrochloride 1ꢀHCl as a white solid (19.5 mg, quant from 1, >99:1 dr);
−85.0 (c 1.0 in MeOH); lit.7b
−81.8 (c 1.38 in MeOH)}.
–67.0 (c 1.0 in MeOH); {lit.5b
D
[α]2D0
[α]2D0
4.9.1. X-ray crystal structure determination for (S,S)-methylphenidate hydrochloride 1·HCl
Data were collected using an Oxford Diffraction SuperNova diffractometer with graphite monochromated
Cu-Kα radiation using standard procedures at 150 K. The structure was solved by direct methods (SIR92);
all non-hydrogen atoms were refined with anisotropic thermal parameters. Hydrogen atoms were added at
idealised positions. The structure was refined using CRYSTALS.19
X-ray crystal structure data for 1·HCl [C14H20ClNO2]:13 M = 269.77, monoclinic, space group P 21,
a = 9.3195(4) Å, b = 7.2618(3) Å, c = 11.0016(7) Å, β = 109.277(6)°, V = 702.80(7) Å3, Z = 2,
mm–1, colourless block, crystal dimensions = 0.12 × 0.18 × 0.18 mm3. A total of 2916 unique reflections
were measured for 4 < < 77 and 2710 reflections were used in the refinement. The final parameters were
wR2 = 0.135 and R1 = 0.088 [I>–3.0σ(I)], with Flack x parameter = +0.02(3).14
µ = 2.36
θ
14

References and notes
1
Volkow, N. D.; Ding, Y.-S.; Fowler, J. S.; Wang, G.-J.; Logan, J.; Gatley, J. S.; Dewey, S.; Ashby, C.;
Libermann, J.; Hitzemann, R.; Wolf, A. P. Arch. Gen. Psychiatry 1995, 52, 456.
2
Schweri, M. M.; Skolnick, P.; Rafferty, M. F.; Rice, K. C.; Janowsky, A. J.; Paul, S. M. J. Neurochem.
1985, 45, 1062.
3
Maxwell, R. A.; Chaplin, E.; Eckhardt, S. B.; Soares, J. R.; Hite, G. J. Pharmcol. Exp. Ther. 1970, 173,
158.
4
(a) Khantzian, E. J.; Gawin, F.; Kleber, H. D.; Riordan, C. E. J. Subst. Abuse Treat. 1984, 1, 107; (b)
Gawin, F.; Riordan, C.; Kleber, H. Am. J. Drug Alcohol Abuse 1985, 11, 193; (c) Levin, F. R.; Evans, S. M.;
McDowell, D. M.; Kleber, H. D. J. Clin. Psychiatry 1998, 59, 300.
5
(a) Axten, J. M.; Krim, L.; Kung, H. F.; Winkler, J. D. J. Org.Chem. 1998, 63, 9628; (b) Thai, D. L.;
Sapko, M. T.; Reiter, C. T.; Bierer, D. E.; Perel, J. M. J. Med. Chem. 1998, 41, 591; (c) Davies, H. M. L.;
Hansen, T.; Hopper, D. W.; Panaro, S. A. J. Am. Chem. Soc.1999, 121, 6509; (d) Matsumura, Y.; Kanda, Y.;
Shirai, K.; Onomura, O.; Maki, T. Org. Lett. 1999, 1, 175; (e) Prashad, M.; Kim, H.-Y.; Lu, Y.; Liu, Y.; Har,
D.; Repic, O.; Blacklock, T. J.; Giannousis, P. J. Org. Chem. 1999, 64, 1750; (f) Axten, J. M.; Ivy, R.; Krim,
L.; Winkler, J. D. J. Am. Chem. Soc. 1999, 121, 6511; (g) Prashad, M.; Liu, Y.; Kim, H.-Y.; Repic, O.;
Blacklock, T. J. Tetrahedron:Asymmetry 1999, 10, 3479; (h) Matsumura, Y.; Kanda, Y.; Shirai, K.;
Onomura, O.; Maki, T. Tetrahedron 2000, 56, 7411; (i) Davies, H. M. L.; Venkataramani, C.; Hansen, T.;
Hopper, D. W. J. Am. Chem. Soc. 2003, 125, 6462; (j) Krishna, P. R.; Lopinti, K. Synlett 2007, 1742; (k)
Wang, G.; Chen, D.; Sun, Y.; Cao, Q.; Li, B.; Li, J. Int. J. Chem. 2016, 8, 28; (l) Li, C.; Ji, Y.; Cao, Q.; Li,
J.; Li, B. Synth. Commun. 2017, 47, 1301.
6 For a review of the syntheses of enantiopure threo-methylphenidate hydrochloride 1ꢀHCl, see: Prashad, M.
Adv. Synth. Catal. 2001, 343, 379.
7 (a) Patrick, K. S.; Caldwell, R. W.; Ferris, R. M.; Breese, G. R. J. Pharmcol. Exp. Ther. 1987, 241, 152; (b)
Prashad, M.; Har, D.; Repic, O.; Blacklock, T. J.; Giannousis, P. Tetrahedron: Asymmetry 1998, 9, 2133; (c)
Prashad, M.; Har, D.; Repic, O.; Blacklock, T. J.; Giannousis, P. Tetrahedron: Asymmetry 1999, 10, 3111;
(d) Prashad, M. Hu, B.; Repič, O.; Blacklock, T. J.; Giannousis P. Org. Proc. Res. Dev. 2000, 4, 55.
8 (a) Gatley, S. J.; Pan, D.; Chen, R.; Chaturvedi, G.; Ding, Y.-S. Life Sci. 1996, 58, 231; (b) Deutsch, H. M.;
Shi, Q.; Gruszecka-Kowalik, E.; Schweri, M. M. J. Med. Chem. 1996, 39, 1201; (c) Froimowitz, M.;
Deutsch, H. M.; Shi, Q.; Wu, K.-M.; Glaser, R.; Adin, I.; George, C.; Schweri, M. M. Bioorg. Med. Chem.
15

Lett. 1997, 7, 1213; (d) Wayment, H. K.; Deutsch, H.; Schweri, M. M.; Schenk, J. O. J. Neurochem. 1999,
72, 1266; (e) Deutsch, H. M.; Collard, D. M.; Zhang, L.; Burnham, K. S.; Deshpande, A. K.; Holtzman, S.
G.; Schweri, M. M. J. Med. Chem.1999, 42, 882; (f) Meltzer, P. C.; Wang, P.; Blundell, P.; Madras, B. K. J.
Med. Chem. 2003, 46, 1538.
9
(a) Davies, S. G.; Fletcher, A. M.; Frost, A. B.; Roberts, P. M.; Thomson, J. E. Tetrahedron 2014, 70,
5849; (b) Davies, S. G.; Fletcher, A. M.; Frost, A. B.; Roberts, P. M.; Thomson, J. E. Org. Lett. 2015, 17,
2254; (c) Davies, S. G.; Fletcher, A. M.; Frost, A. B.; Kennedy, M. S.; Roberts, P. M.; Thomson, J. E.
Tetrahedron 2016, 72, 2139; (d) Davies, S. G.; Fletcher, A. M.; Greenaway, C. J.; Kennedy, M. S.; Mayer,
C.; Roberts, P. M.; Thomson, J. E. Tetrahedron 2018, 74, 5049; (e) Davies, S. G.; Fletcher, A. M.; Linsdall,
S. M.; Roberts, P. M.; Thomson, J. E. Org. Lett. 2018, 20, 4135.
10
For reviews concerning the utility of our diastereoselective aminohydroxylation procedure, see: (a)
Davies, S. G.; Smith, A. D. Price, P. D.; Tetrahedron: Asymmetry 2005, 16, 2833; (b) Davies, S. G.;
Fletcher, A. M.; Roberts, P. M.; Thomson, J. E. Tetrahedron: Asymmetry 2012, 23, 1111; (c) Davis, S. G.;
Fletcher, A. M.; Roberts, P. M.; Thomson, J. E. Tetrahedron: Asymmetry 2017, 28, 1842.
11 The regioselectivity of ring-opening of 2,3-disubstituted aziridinium ions is a complex process, which can
be affected by a range of factors including electronic, stereoelectronic and steric effects. We have also shown
that the relative configuration of the C(2) and C(3) stereogenic centres is important in determining the
regioselectivity of ring-opening for this class of aziridinium ions. See Ref 9d.
12
1
3
For anti-α-hydroxy-β-amino esters H NMR J2,3 coupling constants of ∼4.0 Hz are usually observed
whereas values of ∼10.0 Hz are indicative of syn-α-hydroxy-β-amino esters; see: Ref 9c.
13
Crystallographic data (excluding structure factors) for 1·HCl and 4 have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 1951733 and
1951734, respectively.
14
(a) Flack, H. D. Acta Crystallogr., Sect. A: Found. Crystallogr. 1983, 39, 876. (b) Flack, H. D.;
Bernardinelli, G. J. Appl. Crystallogr. 2000, 33, 1143.
15
The regioselectivity in this reaction is in contrast to that of ring-opening of similar aziridinium species
with H2O, which is presumably dictated by electronic effects in the positively charged transition state; see
Refs 9a and 9d.
16 For example, see: Ref 9e.
16

17
For examples of alternative tandem cyclisation and N-debenzylation procedures, see: (a) Davies, S. G.;
Fletcher, A. M.; Hughes, D. G.; Lee, J. A.; Price, P. D.; Roberts, P. M.; Russell, A. J.; Smith, A. D.;
Thomson, J. E.; Williams, O. M. H. Tetrahedron 2011, 67, 9975; (b) Davies, S. G.; Fletcher, A. M.; Foster,
E. M.; Houlsby, I. T. T.; Roberts, P. M.; Schofield, T. M.; Thomson, J. E. Org. Biomol. Chem. 2014, 12,
9223; (c) Davies, S. G.; Fletcher, A. M.; Foster, E. M.; Houlsby, I. T. T.; Roberts, P. M.; Schofield, T. M.;
Thomson, J. E. Chem. Commun. 2014, 50, 8309; (d) Davies, S. G.; Foster, E. M.; Lee, J. A.; Roberts, P. M.;
Thomson, J. E. J. Org. Chem. 2014, 79, 9686.
18 Crimmins, M. T.; Vanier, G. S. Org. Lett. 2006, 8, 2887.
19 Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, C. K.; Watkin, D. J. J. Appl. Crystallogr. 2003,
36, 1487.
20 Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics 1996, 15,
1518.
17

•
•
•
•
Asymmetric synthesis of (S,S)-methylphenidate hydrochloride in 15% overall yield in only 8
steps from 1,5-pentanediol
Stereospecific and regioselective ring-opening of an in situ formed aziridinium intermediate with
phenylmagnesium bromide
Conversion of an
overall retention of configuration
Enantiopure aziridinium intermediates as substrates for the generation of stereodefined C–C
bonds, providing access to -substituted- -amino ester substrates that are not accessible via
enolate alkylation chemistry
α-hydroxy-β-amino ester into the corresponding α-phenyl-β-amino ester with
α
β

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: