Stereoselective functionalisation of cis- and trans-2-ferrocenyl-3- pivaloyl-4-alkyl-1,3-oxazolidin-5-ones: Asymmetric synthesis of (R)- and (S)-2-alkyl-2-aminopent-4-enoic acids and (2R,3S)-2-amino-2-methyl-3-hydroxy-3- phenylpropanoic acid

Article abstract of DOI:10.1039/b814453b

Treatment of a range of cis- and trans-2-ferrocenyl-3-pivaloyl-4-alkyl-1,3- oxazolidin-5-ones with LDA followed by the addition of allyl bromide promotes highly stereoselective allylation (>98% de) at the 4-position of the oxazolidinone ring anti to the s

Full text of DOI:10.1039/b814453b

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Stereoselective functionalisation of cis- and trans-2-ferrocenyl-3-pivaloyl-
4-alkyl-1,3-oxazolidin-5-ones: asymmetric synthesis of (R)- and (S)-2-alkyl-2-
aminopent-4-enoic acids and (2R,3S)-2-amino-2-methyl-3-hydroxy-
3-phenylpropanoic acid†
Francisco Alonso,‡ Stephen G. Davies,* Almut S. Elend, Michael A. Leech, Paul M. Roberts, Andrew D. Smith
and James E. Thomson
Received 19th August 2008, Accepted 22nd September 2008
First published as an Advance Article on the web 4th December 2008
DOI: 10.1039/b814453b
Treatment of a range of cis- and trans-2-ferrocenyl-3-pivaloyl-4-alkyl-1,3-oxazolidin-5-ones with
LDA followed by the addition of allyl bromide promotes highly stereoselective allylation (>98% de)
at the 4-position of the oxazolidinone ring anti to the stereodirecting 2-ferrocenyl group. Hydrolysis
of the resultant 4,4-disubstituted oxazolidinones (>98% de) yields enantiomeric (R)- and
(S)-2-alkyl-2-aminopent-4-enoic acids in high ee. Furthermore, the aldol reaction of the lithium
enolate of cis-2-ferrocenyl-3-pivaloyl-4-methyl-1,3-oxazolidin-5-one with benzaldehyde followed by
in situ O-protection affords O-protected aldol products in >98% de, with hydrolysis affording
(2R,3S)-2-amino-2-methyl-3-hydroxy-3-phenylpropanoic acid in >98% de.
an efficient chiral template for the asymmetric synthesis of
a range of a-alkyl-a-methyl-a-amino acids in high ee.5a,b In
Introduction
the preceding manuscript6 we demonstrated that both cis- and
trans-2-ferrocenyl-3-pivaloyl-4-methyl-1,3-oxazolidin-5-ones can
be prepared stereoselectively under thermodynamic and kinetic
control respectively from imines derived from a-amino acids.
We detail herein the elaboration of these cis- and trans-2-
ferrocenyl-3-pivaloyl-4-methyl-1,3-oxazolidin-5-ones to the asym-
metric synthesis of (R)- and (S)-2-alkyl-2-aminopent-4-enoic acids
in enantiomerically pure form from the same amino acid starting
material. The further application of this strategy to the synthesis
of (2R,3S)-2-amino-2-methyl-3-hydroxy-3-phenylpropanoic acid
is also delineated.
Enantiomerically pure a,a-disubstituted a-amino acids are recog-
nised as important building blocks in the de novo design of peptides
and proteins,1 with their synthesis presenting a considerable
challenge for chemists due to the stereogenic quaternary carbon
contained within their structure.2 Among the many methods used
for their preparation in homochiral form, the self-regeneration
of stereocentres (SRS) concept introduced by Seebach3 using
oxazolidinones and imidazolidinones as effective chiral templates
is perhaps the most widely applied in synthesis.4 Although of
widespread synthetic utility, this strategy is inherently limited.
Primarily, cyclisation of the a-amino acid derived imine to yield the
parent oxazolidinone proceeds with incomplete stereoselectivity,
requiring purification of the predominant cis-oxazolidinones to
homogeneity before their use in synthesis. Only the cis-isomer is
generally available in sufficient quantity by this route for synthetic
applications, although access to both cis- and trans-oxazolidinones
in a highly stereoselective fashion would be advantageous, leading
to either enantiomer of the desired quaternary amino acid from
the same enantiomer of the starting a-amino acid. Further-
more, the disubstituted oxazolidinone products from alkylation
require relatively forcing hydrolysis conditions to liberate the free
a,a-disubstituted a-amino acid.
Results and discussion
Stereoselective allylation reactions of cis- and trans-2-ferrocenyl-
3-pivaloyl-4-alkyl-1,3-oxazolidin-5-ones: asymmetric synthesis of
(R)- and (S)-2-alkyl-2-aminopent-4-enoic acids
Unsaturated a-amino acids can be considered useful chiral
synthons7 and important building blocks in the synthesis of
biologically active peptides and peptides isosteres.8 In particular,
a-allyl-a-amino acids have been synthesised by alkylation of
glycine and alanine synthons9 or using chiral auxiliaries,10 among
other methods.11
Initial studies within this area focused upon the stereoselective
allylation of the cis- and trans-2-ferrocenyl-3-pivaloyl-4-methyl
oxazolidinones 1 and 3, which were prepared under thermody-
namic and kinetic control, respectively, from the alanine derived
ferrocenyl imine and pivaloyl chloride. Deprotonation of cis-
oxazolidinone 1 with 1.0 eq of◦LDA at -78 ◦C, followed by
addition of allyl bromide at -78 C and subsequent warming to
rt overnight, generated (2S,4R)-2-ferrocenyl-3-pivaloyl-4-allyl-4-
methyl-1,3-oxazolidin-5-one 2 in >98% de,12 and in 85% yield as
In order to solve these inherent limitations and extend the utility
of this powerful strategy, previous investigations from this labo-
ratory on 2-ferrocenyl-1,3-oxazolidin-5-ones5 have introduced cis-
(2S,4S)-2-ferrocenyl-3-pivaloyl-4-methyl-1,3-oxazolidin-5-one as
Department of Chemistry, Chemistry Research Laboratory, University of
Oxford, Mansfield Road, Oxford, UK OX1 3TA.
E-mail: steve.davies@chem.ox.ac.uk
† CCDC reference numbers 679349 (11) and 679348 (22). For crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/b814453b
‡ Present address: Departamento de Qu´ımica Orga´nica, Universidad de
Alicante, Apdo. 99, E-03080 Alicante, Spain
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 527–536 | 527
©

View Article Online
a single diastereoisomer after purification. Following an identical
procedure, allylation of the enolate of trans-oxazolidinone 3 gave
(2R,4S)-2 in >98% de, and in 90% yield and >98% de after
purification (Scheme 1).
with LDA to give the corresponding enolates, and subsequently
alkylated with allyl bromide. In each case, analysis of the crude
reaction product indicated good conversion to the desired 4-alkyl-
4-allyl oxazolidinones in >98% de, with subsequent purification
giving 11–14 in 85–90% yield and as single diastereoisomers in
each case (Scheme 3).
t
˚
˚
Scheme 1 Reagents and conditions: (i) BuCOCl (1.0 eq), CH2Cl2, 4 A
◦
t
molecular sieves, -15 C to rt, 16 h; (ii) BuCOCl (1.0 eq), CH2Cl2, 4 A
molecular sieves, -78 ◦C, 16 h; (iii) LDA (1.5 eq), THF, -78 ◦C then allyl
bromide (1.5 eq), THF, -78 ◦C to rt.
Subsequent hydrolysis of oxazolidinones (2S,4R)-2 and
(2R,4S)-2 with the acidic ion exchange resin Amberlyst-155b gave
(R)- and (S)-2-amino-2-methylpent-4-enoic acid 4 in 95 and 77%
yield respectively (Scheme 2). Amino acids (R)- and (S)-4 showed
spectroscopic properties consistent with the literature {for (R)-4:
mp 296–299 ◦C; lit.13 mp 300 ◦C (dec.); [a]2D5 +24.1 (c 0.7 in MeOH);
for (S)-4: [a]2D5 -29.0 (c 0.4 in MeOH; lit.14 [a]2D0 -25.7 (c 0.8 in
MeOH)}, consistent with this deprotection protocol proceeding
without racemisation of the amino acid fragment.
Scheme 3 Reagents and conditions: (i) LDA (1.5 eq), THF, -78 ◦C then
allyl bromide (1.5 eq), THF, -78 ◦C to rt.
In the racemic series, single crystal X-ray crystallographic
analysis of 11 (obtained by stereoselective allylation of (2RS,4SR)-
5 using the standard protocol) confirmed the assigned relative
configuration (Fig. 1).
Subsequent hydrolysis of the enantiomeric oxazolidinones
(2S,4R)- and (2R,4S)-11, and (2S,4R)- and (2R,4S)-12 with
Amberlyst-155b under standard conditions gave (R)- and (S)-2-
amino-2-ethylpent-4-enoic acid 15, and (R)- and (S)-2-amino-2-
propylpent-4-enoic acid 16, respectively, in good yield. The ee of
amino acids 15 and 16 was assigned as >98% ee on the assumption
that no racemisation of the amino acid fragment had occurred
during this acid catalysed deprotection step (Scheme 4).
Attempted hydrolysis of oxazolidinone (2R,4R)-13 under these
standard conditions proved problematic giving, at 80% con-
version, an approximate 50 : 50 mixture of the desired (R)-2-
amino-2-benzylpent-4-enoic acid 17 (isolated in 25% yield after
purification) and N-pivaloyl (R)-2-amino-2-benzylpent-4-enoic
acid 18. Fortunately, N-pivaloyl 18 could be converted to the
desired free amino acid (R)-17 by refluxing in HCl, giving 17
in 53% yield after ion exchange chromatography (Scheme 5). As
the ready hydrolysis of oxazolidinones in this system is thought
to be due to neighbouring group participation of the ferrocenyl
group,5b the isolation of N-pivaloyl amino acid 18 indicates that
other hydrolysis manifolds may compete with the neighbouring
group participation mechanism in this case (Scheme 5).5b
Scheme 2 Reagents and conditions: (i) Amberlyst-15 at pH 2–4, ace-
tone : H2O (9 : 1), rt, 16 h then ion exchange chromatography.
The synthesis of (R)- and (S)-2-amino-2-methylpent-4-enoic
acid in this manner indicates that both enantiomers of 2-alkyl-2-
aminopent-4-enoic acids are available from a single enantiomer of
a given a-amino acid using this methodology. In order to demon-
strate the generality of this approach, a range of cis- and trans-
2-ferrocenyl-3-pivaloyl-4-alkyl oxazolidinones 5–106 were treated
528 | Org. Biomol. Chem., 2009, 7, 527–536
This journal is
The Royal Society of Chemistry 2009
©

View Article Online
Scheme
5
Reagents and conditions: (i) Amberlyst-15 at pH 2–4,
acetone : H2O (9 : 1), rt, 16 h; (ii). HCl, reflux then ion exchange
chromatography.
Following the successful allylation reaction protocol, depro-
tonation of cis-1 with LDA at -78 ◦C, followed by addition
of benzaldehyde and subsequent warming to rt gave only a
complex mixture of decomposition products. Assuming these
decomposition products were the result of an initial aldol reaction,
followed by a retro-aldol decomposition pathway, a range of
reactive electrophiles designed to trap the initially formed aldol
product were added after the addition of benzaldehyde to the
enolate. In this protocol, the use of acetyl chloride and pivaloyl
chloride gave 50% and 75% conversion respectively to the cor-
responding aldol products 19 and 20 as single diastereoisomers
in each case. However, the use of tert-butyldimethylsilyl chloride,
benzyl chloroformate, or dibenzyl dicarbonate as the O-protecting
agent proved superior, giving approximately 90% conversion to
the desired O-protected aldol products 21 and 22 as single
diastereoisomers (Scheme 6).
Fig. 1 Chem 3D representation of the X-ray crystal structure of
(2RS,4SR)-11 (some H atoms omitted for clarity).
Scheme 6 Reagents and conditions: (i) LDA (1.0 eq), THF, -78 ◦C then
PhCHO (1.3 eq), THF, -78 ◦C; (i◦i) MeCOCl (1.3 eq), THF, -78 ◦C to rt;
(iii) tBuCOCl (1.3 eq), THF, -78 C to rt; (iv) tBuMe2SiCl (1.3 eq), THF,
-78 ◦C to rt; (v) BnOCOCl (1.3 eq), THF, -78 ◦C to rt; (vi) (BnOCO)2O
(1.3 eq), THF, -78 ◦C to rt; (vii) recrystallisation.
Scheme 4 Reagents and conditions: (i) Amberlyst-15 at pH 2–4, ace-
tone : H2O (9 : 1), rt, 16 h then ion exchange chromatography.
Stereoselective aldol reactions of (2S,4S)-cis-2-ferrocenyl-3-
pivaloyl-4-methyl-1,3-oxazolidin-5-one: asymmetric synthesis of
(2R,3S)-2-amino-2-methyl-3-hydroxy-3-phenylpropanoic acid
Crystallisation of the crude reaction product from the use
of benzyl chloroformate in this reaction protocol afforded
(2S,4R,1¢S)-22 as a single diastereoisomer in 87% yield (Scheme 6).
X-Ray crystallographic analysis of 22 confirmed the relative cis-
configuration of the 2-ferrocenyl and the 4-methyl oxazolidinone
substituents, with the absolute (2S,4R,1¢S)-configuration of the
aldol product 22 following from the known (S)-configuration of
the C(2) stereocentre (Fig. 2).
Having demonstrated stereoselective allylation of the enolate
derived from both cis- and trans-2-ferrocenyl-3-pivaloyl-4-methyl
oxazolidinones, the ability of the enolate derived from cis-1 to
undergo stereoselective aldol reactions was investigated. It was
envisaged that this approach would allow the stereoselective
synthesis of the b-hydroxy-a-amino acid molecular class, a
component of a number of biologically active compounds,15 to
which only limited asymmetric routes have been developed.16,17
The stereoselective formation of 22 as the only diastereoisomer
in this aldol protocol is consistent with the stereochemical outcome
of related aldol reactions of oxazolidinone enolates described by
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 527–536 | 529
©

View Article Online
the addition of allyl bromide, promotes highly stereoselective ally-
lation (>98% de) at the 4-position of the oxazolidinone ring anti to
the stereodirecting 2-ferrocenyl group. Hydrolysis of the resultant
4,4-disubstituted oxazolidinones (>98% de) yields enantiomeric
(R)- and (S)-2-alkyl-2-aminopent-4-enoic acids in high ee. The
aldol reaction of the lithium enolate of cis-2-ferrocenyl-3-pivaloyl-
4-methyl-1,3-oxazolidin-5-one with benzaldehyde followed by in
situ O-protection affords O-protected aldol products in >98% de,
with hydrolysis affording (2R,3S)-2-amino-2-methyl-3-hydroxy-3-
phenylpropanoic acid in >98% de. The further application of this
strategy for the asymmetric synthesis of enantiomerically pure
stereodefined chiral building blocks is currently underway in this
laboratory.
Fig. 2 Chem 3D representation of the X-ray crystal structure of
(2S,4R,1¢S)-22 (some H atoms omitted for clarity).
Experimental
General experimental
Seebach et al.18 The configurations within aldol products 19–21
were assigned by analogy to that proven for 22.
All reactions were performed under a nitrogen atmosphere. THF
and diethyl ether were distilled under nitrogen from sodium
benzophenone ketyl. Methanol was distilled from Mg(OMe)2.
Petroleum refers to light petroleum (bp 40–60 ◦C) and was
redistilled before use. All ethanol used was ‘absolute ethanol’. Allyl
bromide and benzaldehyde were distilled before use. Diisopropy-
lamine was distilled from and stored over potassium hydroxide
pellets.
The further application of this aldol protocol using either ac-
etaldehyde or pivalaldehyde gave complex mixtures of products, so
subsequent investigations focused upon deprotection of 21 and 22
to (2R,3S)-2-amino-2-methyl-3-hydroxy-3-phenylpropanoic acid.
Hydrolysis of O-TBDMS protected aldol product 21 (>98% de)
with Amberlyst-15 under standard conditions yielded O-pivaloyl
ester 23 in 72% yield and >98% de,19 which upon treatment with
conc. HCl at reflux gave (2R,3S)-25 in >98% de and 67% yield
after purification by ion exchange chromatography. Treatment of
O-Cbz protected aldol product 22 (>98% de) with Amberlyst-15
gave N-pivaloyl-O-Cbz 24 in 82% yield and >98% de, which also
gave (2R,3S)-25 upon treatment with conc. HCl at reflux in >98%
de and 62% yield after ion exchange chromatography (Scheme 7).
Melting points (mp) were obtained using a ThermogalenTM III,
Griffin Gallenkamp or Swiss Flawil melting point apparatus and
are uncorrected.
Optical rotations were measured with a Perkin-Elmer 241
polarimeter with a thermally jacketted 10 cm cell. Concentrations
(c) are given in g/100 mL and specific rotations [a] are given
in units of 10-1 deg cm2 g-1.
Infrared spectra were recorded as KBr discs on a Perkin-
Elmer 1750 Fourier Transform spectrometer. Absorptions are
recorded in wavenumbers (cm-1). Only diagnostic peaks are
quoted.
1H NMR spectra were recorded at 200 MHz on a Varian
Gemini 200 or a Bruker AC200 spectrometer, at 300 MHz on
a Bruker WH300 spectrometer, at 400 MHz on a Bruker AC400
spectrometer and at 500 MHz on a Bruker AM500 or AMX500
spectrometer. Chemical shifts (dH) are quoted in parts per million
(ppm) downfield from tetramethylsilane and are referenced to the
residual solvent peak. Spectra recorded in D2O are referenced
to internal 1,4-dioxane. Coupling constants (J) were recorded in
Hertz to the nearest 0.5 Hz. Carbon magnetic resonance spectra
(13C NMR) were recorded at 50.3 MHz on a Varian Gemini 200 or
a Bruker AC200 spectrometer, at 100.6 MHz on a Bruker AC400
spectrometer and at 125.7 MHz on a Bruker AM500 or AMX500
spectrometer using DEPT editing. Chemical shifts (dC) are quoted
in ppm downfield from tetramethylsilane and referenced to the
corresponding deuterated solvent.
Scheme 7 Reagents and conditions: (i) Amberlyst-15 at pH 2–4, ace-
tone : H2O (9 : 1), rt, overnight; (ii) HCl, reflux then ion exchange
chromatography.
Low resolution mass spectra (m/z) were recorded on a VG
Micromass ZAB 1F, a VG Masslab 20–250, a GCMS Trio-1, a VG
BIO Q, an APCI Platform or a Finnigan MAT95S spectrometer,
with only molecular ions (M+), fragments from molecular ions
and major peaks being reported. Accurate mass analyses (HRMS)
were performed on a VG AutoSpec spectrometer.
Conclusions
In conclusion, treatment of a range of cis- and trans-2-ferrocenyl-
3-pivaloyl-4-alkyl-1,3-oxazolidin-5-ones with LDA, followed by
530 | Org. Biomol. Chem., 2009, 7, 527–536
This journal is
The Royal Society of Chemistry 2009
©

View Article Online
=
CHAHBCH CH2), 4.20–4.32 (4H, m, Cp), 4.23 (5H, s, Cp¢), 5.12
(1H, d, J 12.0, CH CHAHB), 5.13 (1H, d, J 17.0, CH CHAHB),
Microanalyses were performed on a Carlo Erba 1106 combus-
tion elemental analyser.
=
=
=
Thin layer chromatography was performed on Merck alu-
minium sheets coated with 0.2 mm silica gel 60 F254. Column
chromatography was performed on silica gel (Kieselgel 60),
Amberlyst-15 (wet) or Dowex (50WX8-200) resin.
Diastereomeric excesses were determined by 1H NMR analysis
of the crude reaction mixtures.
5.47–5.61 (1H, m, CH CH2), 6.66 (1H, s, C(2)H); dC (50 MHz,
=
CDCl3) 22.9 (C(4)Me), 28.7 (CMe3), 39.6 (CH2CH CH2), 41.1
(CMe3), 64.7 (C(4)), 67.4, 68.1, 69.1, 69.2 (Cp, Cp¢), 86.5 (C(2)),
89.8 (Cp), 120.0 (CH CH2), 131.6 (CH CH2), 175.5, 176.0 (C(5),
NCO); m/z (EI+) 410 ([M + H]+, 13%), 409 (73), 280 (37), 121
(57), 57 (100).
=
=
Crystallographic analyses. The crystal was mounted on a
glass fibre using a drop of perfluropolyether oil. It was then
plunged into a cold nitrogen stream using an Oxford Cryosystems
CRYOSTREAM cooling system. The data were collected on
an Enraf-Nonius DIP 2020 image-plate diffractometer (w scans,
DIP 2000 software) and the images were processed using the
DENZO20 and SCALEPACK suite of programs. Data were
corrected for Lorentz and polarisation effects. A partial absorption
correction is implied by multi-frame scaling of the image-plate data
using equivalent reflections. The structure was solved by direct
methods (SIR92)21 giving all non-hydrogen atom positions. The
structure was refined using full-matrix least-squares procedures
with anisotropic thermal parameters for all non-hydrogen atoms.
The hydrogen atoms were placed in calculated positions during
the final cycles of refinement. A three parameter Chebychev22
weighting scheme and corrections for anomalous dispersion were
applied to all data. All crystallographic calculations were carried
out using CRYSTALS23 on a PC/AT computer. Neutral atom
scattering factors were taken from International Tables for X-ray
Crystallography.24
(2R,4S)-2-Ferrocenyl-3-pivaloyl-4-allyl-4-methyl-1,3-oxazolidin-5-
one (2R,4S)-2
Following general procedure 1, 3 (100 mg, 0.27 mmol) gave (◦2R,4S)-
2 as orange crystals (100 mg, 90%, >98% de); mp 116–119 C; [a]D25
+214 (c 0.1 in CHCl3).
(2S,4R)-2-Ferrocenyl-3-pivaloyl-4-allyl-4-ethyl-1,3-oxazolidin-5-
one (2S,4R)-11
Following general procedure 1, 5 (0.63 g, 1.64 mmol) gave (2S,4R)-
11 as orange crystals (0.62 g, 90%, >98% de); Found C, 65.0; H,
6.9; N, 3.2%; C23H29FeNO3 requires C 65.3, H 6.9, N 3.3%; mp
General procedure 1 for allylation of oxazolidinones
◦
103–107 C; [a]2D5 -209 (c 0.2 in CHCl3); nmax (KBr) 3080, 2973
BuLi (1.6 M in hexanes, 1.0 eq for 1, 5 and 6, 1.5 eq for 3 and 7–
10) was added dropwise to a stirred solution of diisopropylamine
(1.1 eq for 1, 5 and 6, 1.65 eq for 3 and 7–10) in THF at 0 ◦C and
stirred for 15 min. The resulting solution was cooled to -78 ◦C and
=
=
(C–H), 1786 (OC O), 1641 (NC O), 1360, 1180; dH (400 MHz,
CDCl3) 1.03 (9H, s, CMe3), 1.11 (3H, t, J 7.5, CH2CH3), 2.35–2.44
=
(2H, m, CH2CH3), 2.57 (1H, dd, J 13.5, 6.0, CHAHBCH CH2),
=
◦
3.27 (1H, dd, J 13.5, 9.0, CHAHBCH CH2), 4.22–4.35 (4H, m,
then transferred via cannula to a precooled (-78 C) solution of
=
Cp), 4.26 (5H, s, Cp¢), 5.11 (1H, s, CH CHAHB), 5.15 (1H, d,
the corresponding oxazolidinone (1.0 eq) in THF. Allyl bromide
(1.3 eq) was added dropwise and the solution was stirred overnight
and allowed to warm to rt. The reaction mixture was concentrated
in vacuo. Several portions of Et2O were added and quickly passed
through a sinter containing layers of celite and silica. The Et2O
solution was concentrated in vacuo. The product was purified by
washing with cold pentane.
=
=
J 4.0, CH CHAHB), 5.50–5.61 (1H, m, CH CH2), 6.58 (1H, s,
C(2)H); dC (100 MHz, CDCl3) 9.3 (CH2CH3), 28.6 (CMe3), 29.7
=
(CH2CH3), 37.3 (CH2CH CH2), 41.2 (CMe3), 67.8, 68.7 (Cp),
68.9 (C(4)), 69.0, 69.1 (Cp), 69.3 (Cp¢), 86.8 (C(2)), 89.0 (Cp),
=
=
120.2 (CH CH2), 131.8 (CH CH2), 174.1, 176.3 (C(5), NCO);
m/z (APCI+) 424 ([M + H]+, 100%), 294 (29), 215 (30), 122 (27).
(2R,4S)-2-Ferrocenyl-3-pivaloyl-4-allyl-4-ethyl-1,3-oxazolidin-5-
one (2R,4S)-11
(2S,4R)-2-Ferrocenyl-3-pivaloyl-4-allyl-4-methyl-1,3-oxazolidin-5-
one (2S,4R)-2
Following general procedure 1, 7 (0.67 g, 1.75 mmol) gave (2R,4S)-
11 as orange crystals (0.66 g, 89%, >98% de); mp 98–101 ◦C; [a]D25
+213 (c 0.2 in CHCl3).
Following general procedure 1, 1 (2.25 g, 6.09 mmol) gave (2S,4R)-2
as orange crystals (2.12 g, 85%, >98% de); C22H27FeNO3 requires
C, 64.6; H, 6.7; N, 3.4%; found C, 64.5; H, 6.9; N, 3.4%; mp
◦
167–169 C; [a]2D5 -218 (c 1.0 in CHCl3); nmax (KBr) 3090 (C–
X-Ray crystal structure data for (2RS,4SR)-11
=
=
=
H), 1795 (OC O), 1651 (NC O), 1640 (C C), 1353, 1186; dH
(300 MHz, CDCl3) 1.05 (9H, s, CMe3), 1.92 (3H, s, C(4)Me), 2.53
¯
[C23H29Fe1N1O3]: M = 423.3, triclinic, space group P1, a =
◦
˚
˚
˚
=
(1H, dd, J 14.0, 6.0, CHAHBCH CH2), 3.36 (1H, dd, J 14.0, 9.0,
9.462(1) A, b = 10.432(1) A, c = 11.673(1) A, a = 73.144(3) ,
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 527–536 | 531
©

View Article Online
◦
◦
3
˚
3.90 (1H, d, J 13.0, CHAHBPh), 3.88–3.92 (1H, m, Cp), 4.05–
4.06 (1H, m, Cp), 4.15–4.17 (1H, m, Cp), 4.31–4.33 (1H, m, Cp),
b = 85.380(3) , g = 65.358(3) , V = 1001.21 A , Z = 2, m =
0.77 mm-1, yellow block crystal dimensions 0.25 ¥ 0.20 ¥ 0.20 mm.
A total of 4752 reflections were measured for 5 < q < 27 and 2799
reflections were used in the refinement. Refinement on F: the final
parameters were wR2 = 0.0463 and R1 = 0.0488 [I > 4s(I)]. CCDC
679349.
=
4.16 (5H, s, Cp¢), 5.19 (1H, d, J 14.0, CH CHAHB), 5.23 (1H,
=
=
dd, J 14.0, 2.0, CH CHAHB), 5.64–5.72 (1H, m, CH CH2), 6.27
(1H, s, C(2)H), 7.28–7.35 (5H, m, Ph); dC (125 MHz, CDCl3) 27.5
=
(CMe3), 39.3, 41.7 (CH2Ph, CH2CH CH2), 40.7 (CMe3), 67.2,
67.4, 68.7 (Cp), 69.2 (Cp¢), 71.2 (Cp), 71.7 (C(4)), 86.3 (Cp), 88.1
=
=
(C(2)), 120.9 (CH CH2), 127.2, 128.5, 130.8, 131.3 (CH CH2, p-,
o-, m-Ph) 136.6 (i-Ph), 173.1, 177.2 (C(5), NCO); m/z (APCI+)
486 ([M + H]+, 100%); HRMS (FI+) C28H31FeNO3 ([M]+) requires
485.1653; found 485.1643.
(2S,4R)-2-Ferrocenyl-3-pivaloyl-4-allyl-4-propyl-1,3-oxazolidin-5-
one (2S,4R)-12
(2R,4R)-2-Ferrocenyl-3-pivaloyl-4-allyl-4-(indol-3¢-ylmethyl)-1,3-
oxazolidin-5-one (2R,4R)-14
Following general procedure 1, 6 (432 mg, 1.09 mmol) gave
(2S,4R)-12 as orange crystals (428 mg, 90%, >98% de); mp 123–
125 ◦C; [a]2D3 -292 (c 0.1 in CHCl3); nmax (KBr) 2971 (C–H), 1783
=
=
(OC O), 1634 (NC O), 1353, 1179; dH (400 MHz, CDCl3) 0.98
(3H, t, J 7.5, CH2CH2CH3), 1.02 (9H, s, CMe3), 1.43–1.55 (1H,
m, CH2CHAHBCH3), 1.62–1.71 (1H, m, CH2CHAHBCH3), 2.26
(1H, dt, J 13.0, 4.5, CHAHBCH2CH3), 2.34 (1H, dt, J 13.0, 5.0,
Following general procedure 1, 10 (168 mg, 0.35 mmol) gave, after
purification via flash column chromatography (eluent 30–40 ◦C
petrol/Et2O, 8 : 2), (2R,4R)-14 as orange crystals (147 mg, 81%,
>98% de); mp 59–63 ◦C; [a]D23 +257 (c 0.8 in CHCl3); nmax (KBr)
3325 (N–H), 2958, 2917 (C–H), 1786 (OC O), 1637 (NC O),
1372, 1303, 1190; dH (500 MHz, CDCl3) 0.97 (9H, s, CMe3), 2.60
=
CHAHBCH2CH3), 2.55 (1H, dd, J 13.5, 6.0, CHAHBCH CH2),
=
3.29 (1H, dd, J 13.5, 9.0, CHAHBCH CH2), 4.22–4.35 (4H, m,
Cp), 4.25 (5H, s, Cp¢), 5.11 (1H, s, CH CHAHB), 5.14 (1H, d, J 3.5,
CH CHAHB), 5.49–5.60 (1H, m, CH CH2), 6.57 (1H, s, C(2)H);
dC (100 MHz, CDCl3) 14.3 (CH2CH2CH3), 17.9 (CH2CH2CH3),
28.5 (CMe3), 37.6, 38.7 (CH2CH2CH3, CH2CH CH2), 41.1
(CMe3), 67.7 (Cp), 68.4 (C(4)), 68.7, 68.8, 68.9 (Cp), 69.2 (Cp¢),
86.7 (C(2)), 88.9 (Cp), 120.1 (CH CH2), 131.7 (CH CH2), 174.1,
176.2 (C(5), NCO); m/z (FAB+) 437 ([M]+, 100%), 196 (18), 57
(27); HRMS (ESI+) C24H32FeNO3 ([M + H]+) requires 438.1731;
found 438.1745.
=
=
=
=
=
=
(1H, dd, J 15.5, 5.5, CHAHBCH CH2), 3.46 (1H, dd, J 13.5, 9.5,
=
=
CHAHBCH CH2), 3.64 (1H, d, J 14.5, CHAHBInd), 3.77–4.28
(4H, m, Cp), 4.00 (5H, s, Cp¢), 4.07 (1H, d, J 14.5, CHAHBInd),
=
=
=
=
5.17–5.22 (2H, m, CH CH2), 5.63–5.72 (1H, m, CH CH2), 6.31
(1H, s, C(2)H), 7.11 (1H, d, J 2.5, Ar), 7.13, 7.21 (2H, 2dt, J 7.5,
1.0, Ar), 7.42 (1H, dd, J 7.5, 1.0, Ar), 7.78 (1H, d, J 7.5, Ar),
8.35 (1H, br s, NH); dC (125 MHz, CDCl3) 27.8 (CMe3), 32.2,
=
39.0 (CH2Ind, CH2CH CH2), 40.9 (CMe3), 67.3, 67.5, 68.3, 70.8
(2R,4S)-2-Ferrocenyl-3-pivaloyl-4-allyl-4-propyl-1,3-oxazolidin-5-
one (2R,4S)-12
(Cp), 69.1 (Cp¢), 71.5 (C(4)), 86.7 (Cp), 87.9 (C(2)), 110.6, 110.8,
=
119.8, 120.1 (Ar), 120.7 (CH CH2), 122.1, 124.7, 128.4 (Ar), 131.7
+
=
(CH CH2), 135.8 (Ar), 174.2, 177.2 (C(5), NCO); m/z (APCI )
525 ([M + H]+, 100%); HRMS (FI+) C30H32FeN2O3 ([M]+) requires
524.1762; found 524.1749.
General procedure 2 for hydrolysis of oxazolidinones 2
Following general procedure 1, 8 (164 mg, 0.41 mmol) gave (2R,4S)-
A column was filled with distilled water and Amberlyst-15 was
added slowly and in several portions into the column. The
column was prepared by washing with distilled water up to
pH 2–4 and then with acetone/water 9 : 1. The corresponding
oxazolidinone 2 was dissolved in acetone/water 9 : 1; a gentle
warming was sometimes required to complete dissolution. The
resulting solution was poured into the column and left for 12 h. The
Amberlyst column was eluted with acetone/water 9 : 1, the acetone
was concentrated in vacuo and the aqueous solution was extracted
with ether. The ether solution was concentrated in vacuo and
the residue was purified by flash column chromatography (silica
gel, petroleum/ether 9 : 1) to yield ferrocenecarboxaldehyde. The
Amberlyst column was also eluted with 2 M NH4OH. The aqueous
solution was concentrated in vacuo to yield the free a-amino acid,
which was purified by ion-exchange column chromatography using
Dowex (50WX8-200), to yield the expected (R)- and (S)-2-alkyl-
2-aminopent-4-enoic acids 4.
◦
12 as orange crystals (160 mg, 89%, >98% de); mp 122–125 C;
[a]2D5 +270 (c 0.1 in CHCl3).
(2R,4R)-2-Ferrocenyl-3-pivaloyl-4-allyl-4-benzyl-1,3-oxazolidin-5-
one (2R,4R)-13
Following general procedure 1, 9 (0.96 g, 2.16 mmol) gave (2R,4◦R)-
13 as orange crystals (901 mg, 86%, >98% de); mp 120–123 C;
[a]2D6 +324 (c 0.2 in CHCl3); nmax (KBr) 2965 (C–H), 1786 (OC O),
=
=
1640 (NC O), 1362, 1298, 1186; dH (500 MHz, CDCl3) 0.93 (9H, s,
CMe3), 2.53 (1H, dd, J 13.5, 5.5, CHAHBCH CH2), 3.35 (1H, d,
=
=
J 13.0, CHAHBPh), 3.40 (1H, dd, J 13.5, 9.5, CHAHBCH CH2),
532 | Org. Biomol. Chem., 2009, 7, 527–536
This journal is
The Royal Society of Chemistry 2009
©

View Article Online
(R)-2-Amino-2-methylpent-4-enoic acid (R)-413,25
Following general procedure 3, (2S,4R)-11 (420 mg, 0.99 mmol)
gave ferrocenecarboxaldehyde (168 mg,◦79%) and (R)-15 as white
crystals (102 mg, 72%); mp 237–241 C; [a]2D7 +36.2 (c 0.3 in
=
MeOH); nmax (KBr) 3426 (br, N–H), 3031 (br, O–H), 1603 (C O),
1394; dH (500 MHz, D2O) 0.88 (3H, t, J 7.5, CH2CH3), 1.68–1.77
(1H, m, CHAHBCH3), 1.82–1.92 (1H, m, CHAHBCH3), 2.41 (1H,
dd, J 14.5, 8.5, C(3)HAHB), 2.60 (1H, dd, J 14.5, 6.5, C(3)HAHB),
5.21 (1H, s, C(5)HAHB), 5.23 (1H, s, C(5)HAHB), 5.65–5.73 (1H, m,
C(4)H); dC (125 MHz, D2O) 7.3 (CH2CH3), 28.9 (CH2CH3), 40.3
(C(3)), 65.2 (C(2)), 121.4 (C(5)), 130.6 (C(4)), 175.4 (C(1)); m/z
(APCI+) 144 ([M + H]+, 100%), 102 (97); HRMS (ESI+) C7H14NO2
([M + H]+) requires 144.1024; found 144.1026.
Following general procedure 2, (2S,4R)-2 (1.84 g, 4.50 mmol) gave
ferrocenecarboxaldehyde (0◦.82 g, 85%) and (R)-4 as white crystals
(0.55 g, 95%); mp 296–299 C; {lit.25 mp 308 ◦C, lit.13 mp 300 ◦C
(dec.)}; [a]2D5 +24.1 (c 0.7 in MeOH); {lit.25 [a]2D0 +14.2 (c 1.0 in 1 M
=
HCl)}; nmax (KBr) 3509 (N–H, br), 3021 (O–H, br), 1645 (C O),
1575, 1545; dH (200 MHz, D2O) 1.47 (3H, s, CH3), 2.43 (1H, dd, J
14.5, 8.0, C(3)HAHB), 2.65 (1H, dd, J 14.5, 6.5, C(3)HAHB), 5.25
(1H, d, J 18.0, C(5)HAHB), 5.26 (1H, d, J 13.0, C(5)HAHB), 5.64–
5.83 (1H, m, C(4)H); dC (125 MHz, D2O) 21.9 (CH3), 41.3 (C(3)),
60.9 (C(2)), 121.3 (C(5)), 130.6 (C(4)), 176.4 (C(1)); m/z (CI+)
130 ([M + H]+, 100%), 88 (21), 84 (17); HRMS (ESI+) C6H12NO2
([M + H]+) requires 130.0868; found 130.0865.
(S)-2-Amino-2-ethylpent-4-enoic acid (S)-15
(S)-2-Amino-2-methylpent-4-enoic acid (S)-413,14,25
Following general procedure 3, (2R,4S)-11 (372 mg, 0.88 mmol)
gave ferrocenecarboxaldehyde (148 mg, 79%) and (S)-15 as white
crystals (93 mg, 74%); mp 225–228 ◦C; [a]D27 -36.2 (c 0.3 in MeOH).
Following general procedure 2, (2R,4S)-2 (346 mg, 0.85 mmol)
gave ferrocenecarboxaldehyde (134◦mg, 74%) and (S◦)-4 as white
crystals (84 mg, 77%); mp 262–266 C; {lit.25 mp 308 C, lit.13 mp
300◦C (dec.)}; [a]2D5 -29.0 (c 0.4 in MeOH); {lit.25 [a]2D0 -14.4 (c 1.3
in 1 M HCl); lit.25 [a]D20 -28.5 (c 1.3 in H2O); lit.13 [a]2D0 -17.6 (c 1.3
in 1 M HCl); lit.13 [a]2D0 -25.7 (c 0.8 in MeOH).
(R)-2-Amino-2-propylpent-4-enoic acid (R)-1626
General procedure 3 for hydrolysis of oxazolidinones 11–13
Following general procedure 3, (2S,4R)-12 (531 mg, 1.21 mmol)
gave ferrocenecarboxaldehyde (205 mg, 79%) and (R)-16 as
The corresponding oxazolidinone was dissolved in acetone/water
9 : 1; a gentle warming was sometimes required to complete
dissolution. Amberlyst-15 was prepared by washing with distilled
water up to pH 2–4, then with acetone/water 9 : 1 and added to the
solution of the oxazolidinone. The reaction mixture was placed un-
der argon and, to ensure the complete exclusion of oxygen, argon
was bubbled through the reaction mixture for 10 min. The reaction
mixture was left under a positive pressure of argon for 12 h and
then poured into a column. The Amberlyst column was eluted with
acetone/water (9 : 1) and the acetone was concentrated in vacuo.
The aqueous solution was extracted with ether and the ether solu-
tion was concentrated in vacuo to yield ferrocenecarboxaldehyde,
sometimes together with traces of the corresponding N-pivaloyl
2-alkyl-2-aminopent-4-enoic acid. At any rate, they could be
separated and purified by flash column chromatography (silica gel,
petroleum/ether 9 : 1, followed by ethyl acetate/methanol 4 : 1).
The Amberlyst column was also eluted with 2 M NH4OH. The
aqueous solution was concentrated in vacuo to yield the free 2-
aminopent-4-enoic acid, which was purified by Dowex (50WX8-
200) ion-exchange column chromatography.
◦
white crystals (118 mg, 62%); mp 215–218 C; {lit.26 mp 208–
◦
210 C}; [a]2D2 +14.5 (c 0.2 in MeOH); nmax (KBr) 3436 (N–
=
H, br), 3140 (O–H, br), 2963 (C–H), 1607 (C O), 1392; dH
(500 MHz, D2O) 0.87 (3H, t, J 7.0, CH2CH2CH3), 1.14–1.22
(1H, m, CH2CHAHBCH3), 1.31–1.38 (1H, m, CH2CHAHBCH3),
1.68 (1H, dt, J 13.5, 4.5, CHAHBCH2CH3), 1.80 (1H, dt, J 13.5,
4.5, CHAHBCH2CH3), 2.43 (1H, dd, J 14.5, 8.5, C(3)HAHB), 2.61
(1H, dd, J 14.5, 6.5, C(3)HAHB), 5.21 (1H, m, C(5)HAHB), 5.24
(1H, s, C(5)HAHB), 5.65–5.74 (1H, m, C(4)H); dC (125 MHz,
D2O) 13.3 (CH2CH2CH3), 16.7 (CH2CH2CH3), 37.9, 40.6 (C(3),
CH2CH2CH3), 64.7 (C(2)), 121.5 (C(5)), 130.5 (C(4)), 175.5
(C(1)); m/z (APCI+) 158 ([M + H]+, 8%), 116 (12), 112 (100);
HRMS (ESI+) C8H16NO2 ([M + H]+) requires 158.1181; found
158.1180.
(S)-2-Amino-2-propylpent-4-enoic acid (S)-1626
(R)-2-Amino-2-ethylpent-4-enoic acid (R)-15
Following general procedure 3, (2R,4S)-12 (321 mg, 0.73 mmol)
gave ferrocenecarboxaldehyde (127 mg, 81%) and (S)-16 as white
◦
crystals (74 mg, 64%); mp 238–243 C; {lit.26 mp 208–210 ◦C};
[a]2D5 -31.5 (c 0.3 in MeOH).
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 527–536 | 533
©

View Article Online
(R)-2-Amino-2-benzylpent-4-enoic acid (R)-1727
(35%), 330 (100), 289 (45), 144 (74); HRMS (ESI+) C32H44FeNO4Si
([M + H]+) requires 590.2389; found 590.2380.
(2S,4R,1¢S)-4-[1¢-(Benzyloxycarbonyloxy)benzyl]-2-ferrocenyl-3-
pivaloyl-4-methyl-1,3-oxazolidin-5-one 22
Following general procedure 3, (2R,4R)-13 (560 mg, 1.15 mmol)
gave ferrocenecarboxaldehyde (193 mg, 78%) and (R)-17 as white
crystals (59 mg, 25%); mp 165–168 ◦C; [a]D22 -19.6 (c 1.0 in H2O);
{lit.27 for (S)–enantiomer [a]D +27.3 (c 1.0 in H2O)}; nmax (KBr)
=
3401 (br, N–H), 3140, 3048 (br, O–H), 1621 (C O), 1496, 1403;
dH (500 MHz, CD3OD) 2.49 (1H, dd, J 14.5, 8.5, C(3)HAHB),
2.78 (1H, dd, J 14.5, 6.5, C(3)HAHB), 2.95 (1H, d, J 14.0,
CHAHBPh), 3.31 (1H, d, J 14.0, CHAHBPh), 5.23–5.29 (2H, m,
C(5)H2), 5.83–5.91 (1H, m, C(4)H), 7.21–7.39 (5H, m, Ph); dC
(125 MHz, CD3OD) 42.1, 42.9 (C(3), CH2Ph), 65.9 (C(2)), 121.4
(C(5)), 128.6, 129.8, 131.4, 131.5 (C(4), Ph), 135.8 (i-Ph), 174.6
(C(1)); m/z (APCI+) 206 ([M + H]+, 100%), 189 (10), 164 (21),
145 (28); HRMS (ESI+) C12H16NO2 ([M + H]+) requires 206.1181;
found 206.1183. Unreacted (2R,4R)-13 and the corresponding N-
pivaloyl amino acid were also isolated and converted into the free
a-amino acid in 46 and 53% yield, respectively, by refluxing in
concentrated HCl overnight.
Following general procedure 4, 1 (1.55 g, 4.20 mmol), BuLi (1.6 M
in hexanes, 2.62 mL, 4.20 mmol), diisopropylamine (0.65 mL,
4.62 mmol), benzaldehyde (0.55 mL, 5.46 mmol) and benzyl
chloroformate (0.78 mL, 5.46 mmol) gave 22 as yellow needles
(2.23 g, 87%, >98% de); Found C, 67.1; H, 5.9; N, 2.1%;
◦
C34H35FeNO6 requires C, 67.0; H, 5.8; N, 2.3%; mp 157–159 C;
[a]2D3 +168 (c 0.5 in CHCl3); nmax (KBr) 3090, 2970 (C–H), 1791
=
=
=
(OC O), 1755 (O2C O), 1628 (NC O), 1258; dH (200 MHz,
CDCl3) 0.85 (9H, s, CMe3), 2.17 (3H, s, C(4)Me), 4.20–4.28 (4H,
m, Cp), 4.27 (5H, s, Cp¢), 5.12 (1H, d, J 12.0, CHAHBPh), 5.21 (1H,
d, J 12.0, CHAHBPh), 5.91 (1H, s, CHPh), 6.59 (1H, s, C(2)H),
7.27–7.38 (5H, m, Ph); dC (50 MHz, CDCl3) 20.7 (C(4)Me), 28.0
(CMe3), 41.1 (CMe3), 66.5 (C(4)), 68.0, 68.5, 68.6, 69.4 (Cp, Cp¢),
69.9 (CH2Ph), 77.7 (CHPh), 86.3 (C(2)), 89.0 (Cp), 127.8, 128.5,
128.6, 129.4 (p-, o-, m-Ph), 135.3, 135.6 (i-Ph), 154.5, 171.3, 177.1
(C(5), NCO, OCOO); m/z (APCI+) 610 ([M + H]+, 100%), 475
(10), 330 (39), 229 (14). HRMS (ESI+) C34H36FeNO6 ([M + H]+)
requires 610.1892; found 610.1900.
General procedure 4 for aldol reaction of (2S,4S)-2-ferrocenyl-
3-pivaloyl-4-methyl-1,3-oxazolidin-5-one 1
1.6 M n-Butyl lithium (1.0 eq) was added dropwise to a stirred
solution of diisopropylamine (1.1 eq) in THF at 0 ◦C and stirred
for 15 min. The resulting solution was cooled to -78 ◦C and then
transferred via cannula to a precooled (-78 ◦C) solution of 1 (1.0
eq) in THF. Then, benzaldehyde (1.3 eq) was added dropwise and
the solution was stirred for 3 h at -78 ◦C. The corresponding
trapping agent (1.3 eq) was added and the solution was stirred
overnight and allowed to warm up to room temperature. The
reaction mixture was concentrated in vacuo. Several portions of
ether were added and quickly passed through a sinter containing
layers of celite and silica. The ether solution was concentrated
in vacuo to yield the corresponding aldol products 19–22. Then
the product was purified by flash column chromatography and/or
recrystallisation.
X-Ray crystal structure data for (2S,4R,1¢S)-22
[C34H35Fe1N1O6]: M = 609.5, monoclinic, space group P 21, a =
◦
˚
˚
˚
11.422(1) A, b = 8.778(1) A, c = 15.357(1) A, b = 107.526(3) ,
3
-1
˚
V = 1468.41 A , Z = 2, m = 0.56 mm , orange block crystal
dimensions 0.40 ¥ 0.30 ¥ 0.20 mm. A total of 8634 reflections were
measured for 5 < q < 27 and 3143 reflections were used in the
refinement. Refinement on F: the final parameters were wR2 =
0.0372 and R1 = 0.0373 [I > 3s(I)]. CCDC 679348.
(2S,4R,1¢S)-4-[1¢-(tert-Butyldimethylsilyloxy)benzyl]-2-
ferrocenyl-3-pivaloyl-4-methyl-1,3-oxazolidin-5-one 21
(2R,3S)-2-Amino-2-methyl-3-pivaloyloxy-3-phenylpropanoic
acid 23
Following general procedure 4, 1 (1.76 g, 4.77 mmol), BuLi (1.6 M
in hexanes, 2.98 mL, 4.77 mmol), diisopropylamine (0.73 mL,
5.24 mmol), benzaldehyde (0.63 mL, 6.20 mmol) and TBDMSCl
(0.93 g, 6.20 mmol) gave 21 in >98% de. The crude product
was washed with cold pentane and purified via flash column
chromatography (silica gel, petroleum/ether 9 : 1) to yield 21 as a
waxy solid, contaminated with trace amounts of impurities (2.45 g,
87%); dH (200 MHz, CDCl3) 0.26 (3H, s, SiMe), 0.29 (3H, s, SiMe),
0.95 (9H, s, SiCMe3), 1.22 (9H, s, COCMe3), 1.37 (3H, s, C(4)Me),
4.14 (5H, s, Cp¢), 4.36–4.66 (4H, m, Cp), 5.80 (1H, s, CHPh),
6.21 (1H, s, C(2)H), 7.26–7.49 (5H, m, Ph); m/z (APCI+) 476
Following general procedure 3, 21 (471 mg, 0.80 mmol) gave
ferrocenecarboxaldehyde (138 mg, 81%) and (2R,3S)-23 as white
◦
crystals (161 mg, 72%); mp 113–115 C; [a]2D2 -33.5 (c 0.8 in
=
MeOH); nmax (KBr) 3382, 2964 (br, N–H, O–H, C–H), 1720 (C O),
=
1624 (C O), 1050 (C–O), 703; dH (200 MHz, D2O) 0.84 (9H, s,
CMe3), 1.38 (3H, s, C(2)Me), 4.98 (1H, s, C(3)H), 7.00–7.24 (5H,
m, Ph); dC (125 MHz, CD3OD) 21.4 (C(2)Me), 27.7 (CMe3), 39.8
(CMe3), 64.0 (C(2)), 77.1 (C(3)), 128.3, 128.6, 128.7 (p-, o-, m-
Ph), 142.6 (i-Ph), 178.8, 179.9 (C(1), OCOtBu); m/z (APCI-) 278
([M - H]-, 11%), 172 (100); HRMS (ESI+) C15H22NO4 ([M + H]+)
requires 280.1548; found 280.1540.
534 | Org. Biomol. Chem., 2009, 7, 527–536
This journal is
The Royal Society of Chemistry 2009
©

View Article Online
(2R,3S)-2-Methyl-2-pivaloylamino-3-benzyloxycarbonyloxy-3-
phenylpropanoic acid 24
Bernd Schweizer, P. Seiler and G. Stucky, Helv. Chim. Acta, 1992, 75,
913; M. Gander-Cooper and D. Seebach, Helv. Chim. Acta, 1988, 71,
224; E. Altmann, K. Nebel and M. Mutter, Helv. Chim. Acta, 1991, 74,
800; K. Nebel and M. Mutter, Tetrahedron, 1988, 44, 4793; D. Seebach,
E. Juaristi, D. D. Miller, C. Schickli and T. Weber, Helv. Chim. Acta,
1987, 70, 237.
5 (a) F. Alonso and S. G. Davies, Tetrahedron: Asymmetry, 1995, 6, 353;
(b) F. Alonso, S. G. Davies, A. S. Elend and J. L. Haggitt, J. Chem.
Soc., Perkin Trans. 1, 1998, 257; (c) F. Alonso, S. G. Davies and C. A. P.
Smethurst, J. Organomet. Chem., 1998, 553, 463.
6 F. Alonso, S. G. Davies, A. S. Elend and A. D. Smith, Org. Biomol.
Chem., 2008, 6, DOI: 10.1039/b814450h.
7 D. Guillerm, K. Lavrador and G. Guillerm, Synth. Commun., 1995, 25,
877; I. Ojima, M. Tzamarioudaki and M. Eguchi, J. Org. Chem., 1995,
60, 7078; K. David, A. Greiner, J. Gore´ and B. Cazes, Tetrahedron Lett.,
1996, 37, 3333.
8 See, for instance: C. A. Hutton and J. M. White, Tetrahedron Lett.,
1997, 38, 1643; M. S. Plummer, A. Shahripour, J. S. Kaltelbronn, E. A.
Lunney, B. A. Steinbaugh, J. M. Hamby, H. W. Hamilton, T. K. Sawyer,
C. Humblet, A. M. Doherty, M. D. Taylor, G. Hingorani, B. L. Batley
and S. T. Rapundalo, J. Med. Chem., 1995, 38, 2893; Dolbeare, G. F.
Pontoriero, S. K. Gupta, R. K. Mishra and R. L. J. Johnson, J. Med.
Chem., 2003, 45, 727.
Following general procedure 3, 22 (0.96 g, 1.58 mmol) gave
ferrocenecarboxaldehyde (0.26 g, 78%) and (2R,3S)-24 as light
◦
brown solid (0.54 g, 82%); mp 114–122 C; [a]2D4 -28.3 (c 0.9
in MeOH); nmax (KBr) 3390 (br, N–H, O–H), 2962 (C–H), 1756
=
(OC O), 1656 (amide I), 1516 (amide II), 1254; dH (200 MHz,
CDCl3) 1.15 (9H, s, CMe3), 1.60 (3H, s, C(2)Me), 5.21 (1H,
d, J 12.0, CHAHBPh), 5.21 (1H, d, J 12.0, CHAHBPh), 6.28
(1H, s, C(3)H), 7.31–7.41 (10H, m, Ph); dC (50 MHz, CDCl3) 18.9
(C(2)Me), 27.3 (CMe3), 39.2 (CMe3), 64.1 (C(2)), 70.1 (CH2Ph),
81.7 (C(3)), 128.0, 128.2, 128.7, 129.2 (p-, o-, m-Ph), 135.2, 136.0
+
=
(i-Ph), 155.1 (O2C O), 178.2, 178.9 (C(1), NCO); m/z (APCI )
414 ([M + H]+, 9%), 262 (100), 134 (34); HRMS (ESI+) C23H28NO6
([M + H]+) requires 414.1916; found 414.1937.
9 See, for instance: J. P. Geneˆt, S. Juge, S. Achi, S. Mallart, J. Ruiz Montes
and G. Levif, Tetrahedron, 1988, 44, 5263.
10 See, for instance: R. A. Hamon and P. Razzino, Tetrahedron, 1995,
51, 4183; S. Hanessian and R.-Y. Yang, Tetrahedron Lett., 1996, 37,
8997.
(2R,3S)-2-Amino-2-methyl-3-hydroxy-3-phenylpropanoic
acid 2517,28,29
11 M. Alco´n, A. Moyano, M. A. Perica`s and A. Riera, Tetrahedron:
Asymmetry, 1999, 10, 4639; W. J. III Drury, D. Ferraris, C. Cox, B.
Young and T. Lectka, J. Am. Chem. Soc., 1998, 120, 11006; X. Fang, M.
Johannsen, S. Yao, N. Gathergood, R. G. Hazell and K. A. Jørgensen,
J. Org. Chem., 1999, 64, 4844; B. M. Trost and X. Ariza, J. Am. Chem.
Soc., 1999, 121, 10727.
12 All diastereoisomeric excesses were determined by peak integration of
23 (357 mg, 1.28 mmol) was dissolved in concentrated HCl
(50 mL) and refluxed. The crude product was purified by ion-
exchange column chromatography using Dowex (50WX8-200) to
give (2R,3S)-25 as white crystals (167 mg, 67%); mp 215–216 ◦C;
{lit.28 mp 249 ◦C (dec.); lit.29 mp 243 ◦C (dec.)}; [a]2D6 +19.3 (c 0.4
in MeOH); {lit.17 [a]D25 +33.0 (c 0.35 in H2O)}; nmax (KBr) 3154 (br,
1H NMR spectra.
13 Q. B. Broxterman, B. Kaptein, J. Kamphuis and H. E. Schoemaker,
J. Org. Chem., 1992, 57, 6286.
14 A. Frauer, M. Mehlfu¨hrer, K. Thirring and H. Berner, J. Org. Chem.,
1994, 59, 4215.
15 W. S. Horn, J. L. Smith, G. F. Bills, S. L. Raghoobar, G. L. Helms,
M. B. Kurtz, J. A. Marrinan, B. R. Frommer, R. A. Thornton and
S. M. Mandala, J. Antibiot., 1992, 45, 1692; A. V. R. Rao, M. K.
Gurjar, T. R. Devi and K. R. Kumar, Tetrahedron Lett., 1993, 34, 1653;
S. Omura, T. Fujimoto, K. Otoguro, K. Matsuzaki, R. Moriguchi,
H. Tanaka and Y. Sasaki, J. Antibiot., 1991, 44, 113; S. Omura, K.
Matsuzaki, T. Fujimoto, K. Kosuge, T. Furuya, S. Fujita and A.
Nakagawa, J. Antibiot., 1991, 44, 117; T. Sunazuka, T. Nagamitsu,
K. Matsuzaki, H. Tanaka and S. Omura, J. Am. Chem. Soc., 1993,
115, 5302; E. J. Corey and S. Choi, Tetrahedron Lett., 1993, 34,
6969.
16 For select examples, see: D. Seebach and T. Weber, Tetrahedron Lett.,
1983, 24, 3315; D. Seebach and T. Weber, Helv. Chim. Acta, 1984,
67, 1650; U. Scho¨llkopf, U. Groth, K.-O. Westphalen and C. Deng,
Synthesis, 1981, 969; U. Scho¨llkopf, U. Groth and W. Hartwig, Liebigs
Ann. Chem., 1981, 2407; U. Scho¨llkopf, Tetrahedron, 1983, 39, 2085;
F. A. Davis, H. Liu and G. V. Reddy, Tetrahedron Lett., 1996, 37,
5473.
=
O–H, N–H), 1634 (C O), 1497, 1394, 1363, 708; dH (200 MHz,
D2O) 1.08 (3H, s, C(2)Me), 4.93 (1H, s, C(3)H), 7.21–7.28 (5H, m,
Ph); dC (125 MHz, D2O) 19.0 (C(2)Me), 65.3 (C(2)), 75.3 (C(3)),
127.6, 129.0, 129.2 (p-, o-, m-Ph), 137.6 (i-Ph), 175.8 (C(1)); m/z
(APCI-) 194 ([M–H]-, 100%), 111 (7); HRMS (ESI+) C10H14NO3
([M + H]+) requires 196.0973; found 196.0980.
24 (320 mg, 0.77 mmol), when subjected to the above hydrolysis
procedure, al◦so yielded (2R,3S)-25 as white crystals (94 mg, 62%);
mp 217–220 C; [a]D23 +21.0 (c 0.6 in MeOH).
Acknowledgements
We thank the Ministerio de Educacio´n y Cultura of Spain and
the British Council for a Fleming Fellowship (F. A.), the DTI and
EPSRC for a LINK studentship (A. S. E.) and Oxford Asymmetry
Ltd. for support.
17 A. Avenoza, C. Cativiela, F. Corzana, J. M. Peregrina and M. M.
Zurbano, Tetrahedron: Asymmetry, 2000, 11, 2195.
18 D. Seebach, E. Juaristi, D. D. Miller, C. Schickli and T. Weber,
Helv. Chim. Acta, 1987, 70, 237; D. Seebach, S. G. Mu¨ller, U.
Gysel and J. Zimmermann, Helv. Chim. Acta, 1988, 71, 1303; D.
Blaser and D. Seebach, Liebigs Ann. Chem., 1991, 1067; D. Seebach,
H. M. Bu¨rger and C. P. Schickli, Liebigs Ann. Chem., 1991, 669;
D. Blaser, S. Y. Ko and D. Seebach, J. Org. Chem., 1991, 56,
6230.
19 O-Pivaloyl ester 21 presumably arises by a mechanism involving initial
hydrolysis of the TBDMS group and neighbouring group participation
from the ferrocenyl group to give an intermediate N-acyliminium
cation. N- to O-pivaloyl transfer and subsequent imine hydrolysis
generates O-pivaloyl ester 21.
References
1 W. F. DeGrado, Z. R. Wasserman and J. D. Lear, Science, 1989, 243,
622; M. Mutter, Angew. Chem., Int. Ed. Engl., 1989, 28, 535.
2 For reviews on this topic, see: K. Fuji, Chem. Rev., 1993, 93, 2037.
3 For a review, see: D. Seebach, A. R. Sting and M. Hoffmann, Angew.
Chem., Int. Ed. Engl., 1996, 35, 2708.
4 For selected examples of this approach, see: D. Seebach, B. Lamatsch,
R. Mastutz, A. K. Beck, M. Dobler, M. Egli, R. Fitzi, M. Gautschi,
B. Herradon, P. C. Hibder, J. I. Irwin, R. Locher, M. Maestro, T.
Maetzke, A. Mourino, E. Pfammatter, D. A. Plattner, C. Schickli, W.
20 Z. Otwinowski and W. Minor, DENZO – Processing of X-Ray Diffrac-
tion Data Collected in Oscillation Mode, Methods in Enzymology, 1996,
276.
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 527–536 | 535
©

View Article Online
21 A. Altomare, G. Cascarano, G. Giacovazzo, A. Guagliardi, M. C.
Burla, G. Polidori and M. Camalli, SIR92- a program for automatic
solution of crystal structures by direct methods, J. Appl. Crystallogr.,
1994, 27, 435.
25 Y. N. Belokon, V. I. Bakhmutov, N. I. Chernoglazova, K. A. Kochetkov,
S. V. Vitt, N. S. Garbalinskaya and V. M. Belikov, J. Chem. Soc., Perkin
Trans. 1, 1988, 305.
26 M. Aidene, F. Barbot and L. Miginiac, J. Organomet. Chem., 1997, 534,
22 D. J. Watkin and J. R. Carruthers, Acta Crystallogr., Sect. A, 1979, 35,
117.
698.
27 T. M. Zydowsky, E. de Lara and S. G. Spanton, J. Org. Chem., 1990,
23 D. J. Watkin, C. K. Prout, J. R. Carruthers, and P. Betteridge,
CRYSTALS Issue 10, 1996, Chemical Crystallography Laboratory,
University of Oxford.
55, 5437.
28 S. H. Pines, S. Karady and M. Sletzinger, J. Org. Chem., 1968, 33,
1758.
24 International Tables for Crystallography, 1979, vol. 4, Kynoch Press,
29 S. H. Pines, S. Karady, M. A. Kozlowski and M. Sletzinger, J. Org.
Birmingham.
Chem., 1968, 33, 1762.
536 | Org. Biomol. Chem., 2009, 7, 527–536
This journal is
The Royal Society of Chemistry 2009
©