Synthesis and reactivity of 4-oxo-5-trimethylsilanyl derived α-amino acids

Article abstract of DOI:10.1016/j.tet.2014.11.059

A Lewis-acid promoted one-carbon homologation of an aspartic acid semialdehyde with trimethylsilyldiazomethane has led to the efficient synthesis of two silicon-containing α-amino acids. The use of trimethylaluminium or catalytic tin(II) chloride gave nov

Full text of DOI:10.1016/j.tet.2014.11.059

Tetrahedron 71 (2015) 245e251
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and reactivity of 4-oxo-5-trimethylsilanyl derived
a-amino acids
*
Caroline M. Reid, Kate N. Fanning, Lindsay S. Fowler, Andrew Sutherland
WestCHEM, School of Chemistry, The Joseph Black Building, University of Glasgow, Glasgow G12 8QQ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 October 2014
Received in revised form 14 November 2014
Accepted 24 November 2014
Available online 28 November 2014
A Lewis-acid promoted one-carbon homologation of an aspartic acid semialdehyde with trimethylsi-
lyldiazomethane has led to the efficient synthesis of two silicon-containing -amino acids. The use of
trimethylaluminium or catalytic tin(II) chloride gave novel 4-oxo-5-trimethylsilanyl derived amino acids
in yields of 71e88%. An investigation into the reactivity of these highly functional -amino acids showed
that selective cleavage of the CeSi bond could be achieved under mild basic conditions to give a pro-
tected derivative of the naturally occurring amino acid, 4-oxo- -norvaline. Alternatively, Peterson olefi-
nation with aryl or alkyl aldehydes resulted in the formation of E-enone derived -amino acids.
a
a
L
Keywords:
a
a
-Amino acids
Ó 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license
Peterson olefination
Homologation
(http://creativecommons.org/licenses/by/3.0/).
4-Oxo-L-norvaline
2-Oxosilanes
1. Introduction
a
-Amino acids are the structural building blocks of life, serving
as the key components of all proteins and enzymes.1 They also
play an important role in many enzymatic reactions and in signal
induction pathways. This importance in combination with the
rapid and continual advances in the biomedical sciences has re-
quired the development of novel approaches to optically active a-
amino acids and in particular functional, non-proteinogenic ana-
logues.2 As well as being used to probe the mechanism of en-
zymes and study the bioactive conformations of peptides and
proteins, these compounds often have significant pharmacological
properties.
In this regard, unnatural silicon-containing a-amino acids and
Fig. 1. Silicon-containing a-amino acids and peptides.
peptides have found many applications in structural biology and
medicinal chemistry.3 The inclusion of a silicon-containing group
has been shown to improve lipophilicity, while silicon analogues of
proteinogenic
a-amino acids such as b
-trimethylsilyl alanine (1)4
carbonyl for the generation of a highly potent angiotensin-
converting enzyme inhibitor 3.6
and
g
-(dimethylsila)proline (2)5 have demonstrated increased re-
sistance to proteolytic degradation and increased cellular uptake,
respectively (Fig. 1). A number of silicon-containing bio-isosteres
with enhanced stability have been utilised for the development of
therapeutically active peptides.3 For example, a disilanol analogue
of phenylalanine has been used as a transition-state-like hydrated
Despite their enhanced stability and advantageous pharmaco-
logical properties, synthetic routes towards silicon-containing
amino acids are still relatively limited in number.3,7 Noteworthy
approaches include the use of a reverse aza-Brook rearrangement
of allyl and furyl N-trialkylsilyl amines for the synthesis of
a-tri-
alkylsilyl
prepared
a
-amino acids.8 More recently, Cavelier and co-workers
g
-silylated a-amino acids by a platinum-catalysed
hydrosilylation of unsaturated precursors,7b while Ramesh and
Reddy used a zinc mediated allylation of a chlorosilane as the key
* Corresponding author. Tel.: þ44 141 330 5936; fax: þ44 141 330 4888; e-mail
address: Andrew.Sutherland@glasgow.ac.uk (A. Sutherland).
http://dx.doi.org/10.1016/j.tet.2014.11.059
0040-4020/Ó 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).

246
C.M. Reid et al. / Tetrahedron 71 (2015) 245e251
step for the preparation of unusual 5,5-trans fused
derivative 4 (Fig. 1).7h
a-amino acid
quantitative yield. Using the steric bulk of the bis-protected amine,
regioselective reduction of the -methyl ester was then achieved
b
During a recent study into the synthesis of
bearing ketone side-chains, we unexpectedly formed stable 4-oxo-
5-trimethylsilanyl compounds derived from -aspartic acid. Fol-
lowing further investigation of this serendipitous result, we now
report the highly efficient synthesis of these compounds by the
one-carbon homologation of N-Boc-protected aspartic acid semi-
aldehydes with trimethylsilyldiazomethane in the presence of
a Lewis acid. We also describe a preliminary study of the reactivity
a
-amino acids
using DIBAL-H. This allowed the isolation of aspartic acid semi-
aldehyde 8 in 87% yield.
L
With semialdehyde 8 in hand, methods for conversion to the
corresponding 4-oxo-5-trimethylsilanyl derivative 9 were next in-
vestigated. In 1987, Aoyama and Shioiri demonstrated that 2-
oxotrialkylsilanes could be formed from the reaction of aldehydes
with trimethylsilyldiazomethane in the presence of magnesium
bromide.10 More recently, Lee and co-workers reported a similar
reaction using catalytic indium(III) chloride (2 mol %) that gave high
yields of 2-trimethylsilyl ketones.11 In these transformations, the
Lewis acid-activated aldehyde is subjected to nucleophilic attack by
trimethysilyldiazomethane. The resulting intermediate then un-
dergoes a 1,2-hydride shift with simultaneous extrusion of nitrogen
and formation of the 2-oxotrialkylsilane. In both of these studies,
quenching the reaction with dilute acid or purification by silica gel
flash chromatography was avoided to prevent protodesilylation
and formation of the corresponding methyl ketones.12 Using the
Aoyama procedure with semialdehyde 8, trimethylsilyldiazo-
methane and a stoichiometric amount of magnesium bromide
returned mainly starting material. However, the use of a stronger
Lewis acid such as trimethylaluminium13 allowed clean conversion
to 4-oxo-5-trimethylsilane 9 (Scheme 2). Surprisingly, 9 was found
to be stable to protodesilylation. Work-up of this reaction with an
acid wash (0.1 M HCl) and purification by silica gel flash chroma-
tography gave 4-oxo-5-trimethylsilane 9 in 71% yield. A less pyro-
phoric Lewis acid was then investigated and the use of catalytic
tin(II) chloride14 (5 mol %) resulted in the isolation of 4-oxo-5-
trimethylsilane 9 in an optimal yield of 85%.
of these compounds with a novel synthesis of a 4-oxo-
L-norvaline
derivative, and the preparation of E-enone derived
via Peterson olefination.
a-amino acids
2. Results and discussion
As outlined in Scheme 1, our proposed approach to 4-oxo-5-
trimethylsilanyl derived -amino acids involved the rapid and ef-
ficient protection of -aspartic acid (5) using a protecting group
strategy that would allow the selective reduction of the -carbonyl
a
L
b
moiety. The resulting aspartic acid semialdehyde would then be
used to investigate the formation of the target oxotrialkylsilane by
a one-carbon homologation reaction with trimethylsilyldiazo-
methane. Once this step had been optimised, it was proposed that
these types of compounds could be used as building blocks for the
preparation of more elaborate side-chains.
While the synthesis of 4-oxo-5-trimethylsilane 9 was success-
fully achieved, we were concerned that subsequent reactions with
this intermediate may be limited. Di-N-Boc-protected
esters are known to racemise more easily under basic conditions
due to the acidic nature of the
-hydrogen.15 Furthermore, the
steric bulk associated with the two N-Boc groups of -amino acid
a-amino
a
Scheme 1. Proposed approach to 4-oxo-5-trimethylsilanyl derived
L-aspartic acid (5).
a
-amino acids from
a
derivatives can hinder reactions of the side-chain.9g,16 Therefore,
a mono-N-Boc-protected analogue of 9 was prepared (Scheme 3).
Selective removal of one of the Boc protecting groups from aspartic
acid semialdehyde 8 was achieved using lithium bromide under the
conditions reported by Martín and co-workers.17 This generated the
mono-N-Boc-protected analogue 10 in 92% yield. Reaction of 10
with trimethylsilyldiazomethane and tin(II) chloride (5 mol %) gave
4-oxo-5-trimethylsilane 11 in an excellent 88% yield. Like di-N-Boc
analogue 9, 4-oxo-5-trimethylsilane 11 was isolated using an acidic
It was decided to use di-Boc aspartic acid semialdehyde 8, the
synthesis of which was first reported by Martín and co-workers9a
and has been used by others for the preparation of a range of un-
natural
dimethyl ester (7) was initially prepared in two steps from
a L-aspartic acid
-amino acids.9 N,N0-Di-tert-butoxycarbonyl
L-
aspartic acid (5) (Scheme 2). A one-pot esterification and mono-N-
Boc protection was followed by further reaction with di-tert-butyl
dicarbonate and a catalytic amount of DMAP, which gave 7 in
work-up (0.1
M
HCl) and purified by silica gel flash
Scheme 3. Synthesis of 4-oxo-5-trimethylsilane 11 and conversion to 4-oxo-L-norva-
line derivative 13.
Scheme 2. Four-step synthesis of 4-oxo-5-trimethylsilanyl derived a-amino acid 9.

C.M. Reid et al. / Tetrahedron 71 (2015) 245e251
247
chromatography. The relative stability of the di-N-Boc-protected 4-
oxo-5-trimethylsilane 9 was reasoned due to the substantial steric
bulk associated with the two Boc protecting groups. However, the
facile and high yielding synthesis of mono-N-Boc-protected 4-oxo-
5-trimethylsilane 11 shows that unhindered oxotrialkylsilanes of
this type are stable enough to be isolated.18
Having prepared 4-oxo-5-trimethylsilanyl derived amino acid
11, we were interested in examining the reactivity of this com-
pound for the synthesis of biologically and synthetically useful
amino acids. The first target was 4-oxo- -norvaline, a rare ketone-
substituted -amino acid produced as a metabolite from orni-
thine by Clostridium sticklandii and in bone marrow by -amino-
a-
L
a
a
levulinic acid synthetase.19 The biological importance of this
a-
amino acid has resulted in a number of syntheses,13b,20 as well as an
investigation into its use as an inhibitor of oligosaccharyltransfer-
ase.20f It was proposed that protodesilylation of 4-oxo-5-
trimethylsilane 11 would result in a short synthesis of 4-oxo-L-
norvaline derivatives (Scheme 3). While protodesilylation is nor-
mally performed under acidic conditions,10 we wanted to maintain
the N-Boc protecting group. Therefore, initial attempts at cleavage
of the CeSi bond were conducted under basic conditions. Treat-
ment of 4-oxo-5-trimethylsilane 11 with TBAF led to complete
decomposition. However, selective removal of the trimethylsilyl
group in the presence of the methyl ester was efficiently achieved
Scheme 4. Synthesis of E-enone derived
of 4-oxo-5-trimethylsilane 11.
a-amino acids 18e20 via Peterson olefination
with 5% potassium hydroxide, which gave 4-oxo-L-norvaline de-
a stepwise deprotection approach. Hydrolysis of the ester using
caesium carbonate, followed by TFA-mediated removal of the Boc
group under mild conditions gave after recrystallisation, enone
rivative 12 in 92% yield. The two-step, one-carbon homologation
converting semialdehyde 10 to methyl ketone 12 represents
a simple and highly efficient alternative to standard multi-step
protocols.10 Hydrolysis of 12 using caesium carbonate then gave
derived
This approach also has the advantage of generating the N-Boc-
protected -amino acids after the first step, which could have direct
a-amino acids 18e20 in 93e98% yield over the two steps.
N-Boc-protected 4-oxo-
L
-norvaline 13 in 94% yield. This is a form of
a
4-oxo-
L
-norvaline that is used for peptide synthesis20f and the ap-
application in peptide synthesis.
proach described here allows a seven-step preparation in 61%
overall yield.
A study has also been performed to evaluate the use of 4-oxo-5-
trimethylsilane 11 as a substrate in the Peterson olefination for the
3. Conclusions
In summary, two novel 4-oxo-5-trimethylsilanyl derived
a-
synthesis of E-enone derived a-amino acids. a-Amino acids bearing
amino acids have been prepared by the reaction of aspartic acid
semialdehydes with trimethylsilyldiazomethane in the presence of
Lewis acids. In particular, the use of catalytic tin(II) chloride allowed
the synthesis of these compounds in excellent yields. Unlike simi-
lar 2-oxo-trimethylsilanes, these compounds were found to be
relatively stable to protodesilylation and could be isolated using
a dilute acid work-up and purified by silica gel flash column chro-
matography. Based on this relative stability, preliminary studies
into the synthetic utility of these compounds have been conducted.
Selective cleavage of the CeSi bond of 4-oxo-5-trimethylsilane 11
was achieved under mild basic conditions generating derivatives of
an enone side-chain have many applications.21 These include their
use in 6-endo- or 6-exo-trig cyclisations for the stereoselective
synthesis of highly substituted pipecolic acids.22 Initial attempts at
Peterson olefination of 4-oxo-5-trimethylsilane 11 with benzalde-
hyde using either lithium diisopropylamide (LDA) or lithium
bis(trimethylsilyl)amide (LiHMDS) led to only substantial de-
composition of 11. After careful experimentation, it was found that
the order of reagent addition was crucial for success. In situ for-
mation of LDA and dropwise addition via cannula to a THF solution
of 4-oxo-5-trimethylsilane 11 at ꢀ78 ꢁC, followed by the addition of
benzaldehyde gave E-enone 14 in 48% yield (Scheme 4). At this
stage, the enantiopurity of enone 14 was determined to check that
the integrity of the stereocentre had been retained during the stages
of the synthetic route where di-N-Boc compounds has been gen-
erated and through the use of LDA. A comparison of (2S)-14 and
the non-proteinogenic
a-amino acid, 4-oxo-L-norvaline. Alterna-
tively, Peterson olefination of 11 with LDA and various aldehydes
led to the preparation of E-enones as the sole products in good
yields. Work to investigate further synthetic and biological appli-
cations of the 4-oxo-5-trimethylsilanyl derived
a-amino acids
racemic-14 (prepared from
D/L-aspartic acid) using chiral HPLC
generated from this study, including their use as structural ana-
logues in therapeutic peptides, is currently underway.
showed the enantiomeric excess of (2S)-14 was >99% ee, confirm-
ing that no racemisation had taken place during the synthetic
route.23 Following this result, the scope of the Peterson reaction was
extended to two further analogues. Reaction of 11 with 4-
bromobenzaldehyde and hydrocinnamaldehyde gave the corre-
sponding enones 15 and 16 in comparable yields. NMR spectroscopy
of the crude material from the Peterson reactions showed only the
presence of the E-isomer, demonstrating a highly selective process.
Methods for the deprotection of enones 14e16 were then in-
vestigated. For example, a one-step procedure was demonstrated
for removal of both the Boc protecting group and hydrolysis of the
methyl ester of enone 14 using 6 M HCl under reflux conditions
(Scheme 4). Following recrystallisation, amino acid 17 was isolated
in 62% yield. However, a more efficient approach was possible using
4. Experimental section
4.1. General methods
All reagents and starting materials were obtained from com-
mercial sources and used as received. All dry solvents were purified
using a PureSolv 500 MD solvent purification system. All reactions
were performed under an atmosphere of argon unless otherwise
mentioned. Brine refers to a saturated solution of sodium chloride.
Flash column chromatography was carried out using Fisher matrix
silica 60. Macherey-Nagel aluminium-backed plates pre-coated

248
C.M. Reid et al. / Tetrahedron 71 (2015) 245e251
with silica gel 60 (UV254) were used for thin layer chromatography
and were visualised by staining with KMnO4. 1H NMR and 13C NMR
spectra were recorded on a Bruker DPX 400 spectrometer with
chemical shift values in parts per million (ppm) relative to TMS (dH
0.00 and dC 0.0) or residual chloroform (dH 7.28 and dC 77.2) as
standard. Proton and carbon assignments are based on two-
dimensional COSY and DEPT experiments, respectively. Mass
spectra were obtained using a JEOL JMS-700 spectrometer. Infrared
spectra were obtained neat using a Shimadzu IRPrestige-21 spec-
trometer. Melting points were determined on a Reichert platform
melting point apparatus. Optical rotations were determined as
4.4. Methyl (2S)-2-(di-tert-butoxycarbonylamino)-4-
oxobutanoate (8)9a
Dimethyl
(2S)-2-(di-tert-butoxycarbonylamino)butane-1,4-
dioate (7) (6.90 g, 19.1 mmol) was dissolved in diethyl ether
(150 mL) and cooled to ꢀ78 ꢁC. DIBAL-H (26.8 mL, 26.8 mmol) was
added dropwise and the solution was allowed to stir at ꢀ78 ꢁC for
24 h. A saturated solution of ammonium chloride was added
(40 mL) and the reaction mixture was allowed to warm to room
temperature. It was filtered through a pad of CeliteÒ with diethyl
ether (300 mL) and concentrated in vacuo. Following purification
by column chromatography (10% ethyl acetate in petroleum ether),
methyl (2S)-2-(di-tert-butoxycarbonylamino)-4-oxobutanoate (8)
was obtained as a colourless oil (5.50 g, 87%). nmax (NaCl) 3132, 2796
solutions irradiating with the sodium D line (
l
¼589 nm) using
an Autopol
V
polarimeter.
.
[a]
values are given in units
D
10ꢀ1 deg cm2 gꢀ1
(CH), 1782 (C]O), 1678, 1199, 1072 cmꢀ1; [
a
]
D
26 ꢀ49.2 (c 3.4, CHCl3),
25
lit.9a
[
a]
ꢀ54.9 (c 2.0, CHCl3); dH (400 MHz, CDCl3) 1.53 (18H, s,
D
4.2. Dimethyl (2S)-2-(tert-butoxycarbonylamino)butane-1,4-
t
2ꢂ Bu), 2.86 (1H, ddd, J 18.0, 6.0, 1.2 Hz, 3-HH), 3.45 (1H, ddd, J 18.0,
6.8, 1.2 Hz, 3-HH), 3.76 (3H, s, OMe), 5.57 (1H, dd, J 6.8, 6.0 Hz, 2-H),
9.82 (1H, br t, J 1.2 Hz, 4-H); dC (101 MHz, CDCl3) 27.9 (6ꢂCH3), 45.0
(CH2), 52.6 (CH3), 52.9 (CH), 83.7 (2ꢂC), 151.7 (2ꢂC), 170.2 (C), 198.4
(C); m/z (CI) 332 (MHþ, 8%), 276 (60), 236 (51), 220 (100), 192 (98),
176 (86), 132 (26); HRMS (CI): MHþ, found 332.1708. C15H26NO7
requires 332.1709.
dioate (6)9a
Chlorotrimethylsilane (21.2 mL, 165.4 mmol) was added slowly
to a stirred suspension of -aspartic acid (5) (5.00 g, 37.6 mmol) in
L
methanol (100 mL) at 0 ꢁC. The reaction mixture was allowed to
stir for 1 h at 0 ꢁC and then at room temperature for 24 h. Trie-
thylamine (34.0 mL, 244.4 mmol) and di-tert-butyl dicarbonate
(9.02 g, 41.4 mmol) were added slowly and the mixture stirred for
2 h. The reaction mixture was concentrated in vacuo and the
resulting residue dissolved in diethyl ether (200 mL) and filtered
to remove the white precipitate. The filtrate was concentrated in
vacuo and purified using flash column chromatography (35% ethyl
acetate in petroleum ether) to yield dimethyl (2S)-2-(tert-butox-
ycarbonylamino)butane-1,4-dioate (6) as a white solid (9.81 g,
4.5. Methyl (2S)-2-(di-tert-butoxycarbonylamino)-4-oxo-5-
(trimethylsilanyl)pentanoate (9)
Methyl (2S)-2-(di-tert-butoxycarbonylamino)-4-oxobutanoate
(8) (0.10 g, 0.30 mmol) was added to a solution of trimethylalu-
minium (0.20 mL, 0.40 mmol) in dichloromethane (10 mL) at
ꢀ78 ꢁC. Trimethylsilyldiazomethane (0.20 mL, 0.30 mmol) was
added and the reaction mixture stirred at ꢀ78 ꢁC for 1 h and then at
ꢀ40 ꢁC for 1 h. The solution was then poured into 0.1 M hydro-
chloric acid (10 mL) and extracted using dichloromethane
(3ꢂ15 mL). The organic layers were combined, dried (MgSO4) and
concentrated in vacuo. Purification by flash chromatography (20%
ethyl acetate in petroleum ether) gave methyl (2S)-2-(di-tert-
butoxycarbonylamino)-4-oxo-5-(trimethylsilanyl)pentanoate (9)
100%). Mp 58e60 ꢁC; nmax (NaCl) 3406 (NH), 2927 (CH), 2360,
25
1704 (C]O), 1458, 1159, 1045 cmꢀ1; [
a
]
þ35.8 (c 1.0, CHCl3),
D
25
lit.9a
[
a
]
þ30.8 (c 2.1, CHCl3); dH (400 MHz, CDCl3) 1.47 (9H, s,
D
tBu), 2.85 (1H, dd, J 16.8, 4.2 Hz, 3-HH), 3.03 (1H, dd, J 16.8, 4.2 Hz,
3-HH), 3.72 (3H, s, OMe), 3.78 (3H, s, OMe), 4.58e4.61 (1H, m, 2-
H), 5.50 (1H, br d, J 8.4 Hz, NH); dC (101 MHz, CDCl3) 28.3 (3ꢂCH3),
36.7 (CH2), 49.9 (CH), 52.1 (CH3), 52.8 (CH3), 80.2 (C), 155.4 (C),
171.5 (C), 171.6 (C); m/z (CI) 262 (MHþ, 15%), 206 (100), 162 (36),
85 (13); HRMS (CI): MHþ, found 262.1293. C11H20NO6 requires
262.1291.
as a pale yellow oil (0.09 g, 71%). nmax (NaCl) 2980 (CH),1795 (C]O),
25
1747 (C]O), 1144, 853 cmꢀ1; [
a]
ꢀ72.5 (c 0.4, CHCl3); dH
D
t
(400 MHz, CDCl3) 0.01 (9H, s, SiMe3), 1.56 (18H, s, 2ꢂ Bu), 2.08 (1H,
d, J 10.4 Hz, 5-HH), 2.13 (1H, d, J 10.4 Hz, 5-HH), 2.62 (1H, dd, J 18.0,
5.6 Hz, 3-HH), 3.22 (1H, dd, J 18.0, 6.8 Hz, 3-HH), 3.56 (3H, s, OMe),
5.35e5.40 (1H, m, 2-H); dC (101 MHz, CDCl3) 0.0 (3ꢂCH3), 29.1
(6ꢂCH3), 39.3 (CH2), 46.7 (CH2), 53.5 (CH), 55.2 (CH3), 84.4 (2ꢂC),
152.9 (2ꢂC), 172.0 (C), 206.2 (C); m/z (CI) 418 (MHþ, 16%), 346 (53),
318 (78), 262 (95), 234 (99), 218 (25), 190 (100), 146 (89); HRMS
(CI): MHþ, found 418.2262. C19H36NO7Si requires 418.2261.
4.3. Dimethyl (2S)-2-(di-tert-butoxycarbonylamino)butane-
1,4-dioate (7)9a
Dimethyl
(2S)-2-(tert-butoxycarbonylamino)butane-1,4-
dioate (0.90 g, 3.50 mmol) (6) was dissolved in acetonitrile
(50 mL). 4-Dimethylaminopyridine (0.08 g, 0.70 mmol) and di-
tert-butyl dicarbonate (0.80 g, 3.80 mmol) were added and the
reaction mixture was allowed to stir at room temperature for 3 h.
A
further quantity of di-tert-butyl dicarbonate (0.40 g,
1.90 mmol) was added and the mixture was allowed to stir at
room temperature for 24 h. The solvent was removed in vacuo
and the crude product was purified using flash column chroma-
tography (20% ethyl acetate in petroleum ether) to yield dimethyl
(2S)-2-(di-tert-butoxycarbonylamino)butane-1,4-dioate (7) as
4.6. Methyl (2S)-2-(di-tert-butoxycarbonylamino)-4-oxo-5-
(trimethylsilanyl)pentanoate (9)
Methyl (2S)-2-(di-tert-butoxycarbonylamino)-4-oxobutanoate
(8) (0.10 g, 0.30 mmol) was dissolved in dichloromethane
(10 mL). Tin(II) chloride (0.003 g, 0.015 mmol) and trimethylsi-
lyldiazomethane (0.15 mL, 0.30 mmol) were added and the solution
was allowed to stir at room temperature for 0.5 h. The reaction was
quenched with 0.1 M hydrochloric acid (10 mL) and extracted with
dichloromethane (20 mL). The organic layers were combined,
washed with brine (20 mL), dried (MgSO4) and concentrated in
vacuo. Purification by flash chromatography (20% ethyl acetate in
petroleum ether) gave methyl (2S)-2-(di-tert-butoxycarbonyl
amino)-4-oxo-5-(trimethylsilanyl)pentanoate (9) as a pale yellow
oil (0.09 g, 85%). Spectroscopic data as reported above.
a white solid (1.25 g, 100%). Mp 55e57 ꢁC; nmax (NaCl) 2857 (CH),
25
1747 (C]O), 1458, 1375, 1145 cmꢀ1; [
a
]
ꢀ61.5 (c 2.0, CHCl3),
D
25
lit.9a
[
a
]
ꢀ61.0 (c 2.0, CHCl3); dH (400 MHz, CDCl3) 1.53 (18H, s,
D
t
2ꢂ Bu), 2.77 (1H, dd, J 16.4, 6.4 Hz, 3-HH), 3.29 (1H, dd, J 16.4,
7.2 Hz, 3-HH), 3.73 (3H, s, OMe), 3.76 (3H, s, OMe), 5.48 (1H, dd, J
7.2, 6.4 Hz, 2-H); dC (101 MHz, CDCl3) 28.0 (6ꢂCH3), 35.7 (CH2),
52.0 (CH3), 52.6 (CH3), 54.9 (CH), 83.6 (2ꢂC), 151.6 (2ꢂC), 170.3
(C), 171.1 (C); m/z (CI) 362 (MHþ, 6%), 306 (38), 250 (33), 206
(100), 162 (50); HRMS (CI): MHþ, found 362.1819. C16H28NO8
requires 362.1815.

C.M. Reid et al. / Tetrahedron 71 (2015) 245e251
249
4.7. Methyl (2S)-2-(tert-butoxycarbonylamino)-4-oxobutanoate
190 (100), 147 (67), 89 (23); HRMS (FAB): MHþ, found 246.1343.
C11H20NO5 requires 246.1341.
(10)17
Lithium bromide (2.33 g, 26.8 mmol) was added to a stirring
solution of methyl (2S)-2-(di-tert-butoxycarbonylamino)-4-
oxobutanoate (8) (2.90 g, 8.75 mmol) in acetonitrile (100 mL).
The mixture was then heated at 65 ꢁC for 14 h before being con-
centrated under reduced pressure. Purification by flash chroma-
tography (30% ethyl acetate in hexane) gave methyl (2S)-2-(tert-
butoxycarbonylamino)-4-oxobutanoate (10) as a colourless oil
4.10. (2S)-2-(tert-Butoxycarbonylamino)-4-oxopentanoic acid
(13)20f
Methyl
(2S)-2-(tert-butoxycarbonylamino)-4-oxopentanoate
(12) (0.20 g, 0.70 mmol) was dissolved in a 1:1 mixture of metha-
nol and water (20 mL). Caesium carbonate (0.30 g, 0.90 mmol) was
added and the reaction mixture stirred at room temperature for
24 h. The mixture was acidified with 1 M hydrochloric acid (10 mL)
and extracted with dichloromethane (3ꢂ10 mL). The organic layers
were combined, dried (MgSO4) and concentrated in vacuo to give
(2S)-2-(tert-butoxycarbonylamino)-4-oxopentanoic acid (13) as
a viscous colourless oil (0.15 g, 94%). Spectroscopic data were
(1.86 g, 92%). [
a
]
D þ20.4 (c 1.0, CHCl3), lit.17
[
a
]
D þ16.4 (c 5.0, CHCl3);
dH (400 MHz, CDCl3) 1.38 (9H, s, tBu), 2.95 (1H, dd, J 18.4, 4.6 Hz, 3-
HH), 3.05 (1H, dd, J 18.4, 5.0 Hz, 3-HH), 3.69 (3H, s, OMe), 4.51e4.56
(1H, m, 2-H), 5.33 (1H, br d, J 7.6 Hz, NH), 9.67 (1H, br s, 4-H); dC
(101 MHz, CDCl3) 27.3 (3ꢂCH3), 45.0 (CH2), 47.5 (CH), 51.8 (CH3),
79.3 (C), 154.4 (C), 170.5 (C), 198.4 (C); m/z (CI) 232 (MHþ, 45%), 176
(100), 132 (79); HRMS (CI): MHþ, found 232.1181. C10H18NO5 re-
quires 232.1185.
consistent with the literature.20f nmax (neat) 3357 (NH), 3030 (CH),
1743 (C]O), 1688, 1456, 1138 cmꢀ1; [
a]
þ26.1 (c 0.3, CHCl3); dH
27
D
(400 MHz, CDCl3) 1.38 (9H, s, tBu), 2.13 (3H, s, 5-H3), 2.88 (1H, dd, J
18.2, 4.8 Hz, 3-HH), 3.14 (1H, dd, J 18.2, 3.6 Hz, 3-HH), 4.46 (1H, ddd,
J 8.4, 4.8, 3.6 Hz, 2-H), 5.48 (1H, br d, J 8.4 Hz, NH); dC (101 MHz,
CDCl3) 28.3 (3ꢂCH3), 30.0 (CH3), 45.1 (CH2), 49.3 (CH), 80.5 (C),
155.8 (C),175.1 (C), 207.3 (C); m/z (CI) 232 (MHþ,18%),176 (100),158
(33), 132 (95), 130 (36), 73 (40); HRMS (CI): MHþ, found 232.1189.
4.8. Methyl (2S)-2-(tert-butoxycarbonylamino)-4-oxo-5-(tri-
methylsilanyl)pentanoate (11)
Tin(II) chloride (0.004 g, 0.021 mmol) was dried in an oven at
110 ꢁC overnight and then under vacuum at 100 ꢁC for 3 h in
a round bottomed flask equipped with a stirrer bar. After the flask
was cooled to room temperature and flushed with argon, a 2.0 M
solution of trimethylsilyldiazomethane in diethyl ether (0.22 mL,
0.43 mmol) was added. A solution of methyl (2S)-2-(tert-butox-
ycarbonylamino)-4-oxobutanoate (10) (0.10 g, 0.43 mmol) in
dichloromethane (4 mL) was then added dropwise with stirring.
The mixture was stirred at room temperature for 1 h before water
(5 mL) was added. The reaction was quenched with 0.1 M hydro-
chloric acid (3 mL) and extracted with diethyl ether (3ꢂ10 mL). The
organic layers were combined, dried (MgSO4) and concentrated in
vacuo. Purification by flash chromatography (30% ethyl acetate in
petroleum ether) gave methyl (2S)-2-(tert-butoxycarbonylamino)-
4-oxo-5-(trimethylsilanyl)pentanoate (11) as a pale yellow oil
C10H18NO5 requires 232.1185.
4.11. Methyl (2S,5E)-2-(tert-butoxycarbonylamino)-4-oxo-6-
phenylhex-5-enoate (14)21f
To a solution of diisopropylamine (0.12 mL, 0.84 mmol) in tet-
rahydrofuran (4 mL) at ꢀ78 ꢁC was added dropwise, a solution of
2.5 M n-butyllithium in hexane (0.33 mL, 0.84 mmol). The mixture
was stirred for 0.15 h before being added by cannula to a solution of
methyl (2S)-2-(tert-butoxycarbonylamino)-4-oxo-5-(trimethylsi-
lanyl)pentanoate (11) (0.12 g, 0.38 mmol) in tetrahydrofuran (5 mL).
After 1 h, benzaldehyde (0.04 mL, 0.38 mmol) in tetrahydrofuran
(3 mL) was added and the reaction mixture stirred for 5 h at ꢀ78 ꢁC.
The reaction was quenched by addition of a saturated solution of
ammonium chloride (2.0 mL) and the mixture was warmed to room
temperature. The solution was extracted with ethyl acetate (40 mL),
washed with brine (20 mL), dried (MgSO4) and concentrated in
vacuo. Purification by flash chromatography (10% ethyl acetate in
petroleum ether) gave methyl (2S,5E)-2-(tert-butoxycarbonyl
amino)-4-oxo-6-phenylhex-5-enoate (14) a colourless oil (0.061 g,
(0.12 g, 88%). nmax (NaCl) 3370 (NH), 2955 (CH), 1716 (C]O), 1499,
26
1253, 1168, 854 cmꢀ1; [
a]
þ31.6 (c 1.0, CHCl3); dH (400 MHz,
D
t
CDCl3) 0.00 (9H, s, SiMe3), 1.31 (9H, s, Bu), 2.08 (2H, s, 5-H2), 2.79
(1H, dd, J 18.4, 4.0 Hz, 3-HH), 3.02 (1H, dd, J 18.4, 4.0 Hz, 3-HH), 3.60
(3H, s, OMe), 4.28e4.31 (1H, m, 2-H), 5.43 (1H, d, J 8.4 Hz, NH); dC
(101 MHz, CDCl3) 0.0 (3ꢂCH3), 29.5 (3ꢂCH3), 39.2 (CH2), 47.2 (CH2),
50.7 (CH), 53.7 (CH3), 81.0 (C), 156.7 (C), 173.2 (C), 208.4 (C); m/z (CI)
318 (MHþ, 12%), 279 (31), 262 (100), 218 (46), 207 (71), 146 (21);
HRMS (CI): MHþ, found 318.1740. C14H28NO5Si requires 318.1737.
48%). nmax (NaCl) 3368 (NH), 2979 (CH), 1747 (C]O), 1713 (C]O),
17
1663 (C]C), 1496, 1367, 1168 cmꢀ1; [
a]
þ56.9 (c 1.0, CHCl3); dH
D
(400 MHz, CDCl3) 1.44 (9H, s, tBu), 3.33 (1H, dd, J 17.8, 4.3 Hz, 3-HH),
3.44 (1H, dd, J 17.8, 4.1 Hz, 3-HH), 3.75 (3H, s, OMe), 4.62 (1H, ddd, J
8.5, 4.3, 4.1 Hz, 2-H), 5.60 (1H, d, J 8.5 Hz, NH), 6.71 (1H, d, J 16.1 Hz,
5-H), 7.38e7.42 (3H, m, ArH), 7.52e7.55 (2H, m, ArH), 7.57 (1H, d, J
16.1 Hz, 6-H); dC (101 MHz, CDCl3) 28.3 (3ꢂCH3), 42.4 (CH2), 49.6
(CH), 52.6 (CH3), 79.9 (C), 125.6 (CH), 128.4 (2ꢂCH), 129.2 (2ꢂCH),
130.9 (CH), 134.1 (C), 143.9 (CH), 155.6 (C), 172.0 (C), 197.6 (C); m/z
(CI) 334 (MHþ, 9%), 320 (4), 278 (100), 234 (13); HRMS (CI): MHþ,
found 334.1653. C18H24NO5 requires 334.1654.
4.9. Methyl (2S)-2-(tert-butoxycarbonylamino)-4-
oxopentanoate (12)24
Methyl
(2S)-2-(tert-butoxycarbonylamino)-4-oxo-5-(trime-
thylsilanyl)pentanoate (11) (0.10 g, 0.30 mmol) was dissolved in
a 5% solution of potassium hydroxide in methanol (10 mL). This
mixture was allowed to stir at room temperature for 1 h. The sol-
vent was then removed under vacuum. The residue was dissolved
in ethyl acetate (20 mL), dried (MgSO4) and concentrated in vacuo.
Purification by flash chromatography (50% ethyl acetate in petro-
leum ether) gave methyl (2S)-2-(tert-butoxycarbonylamino)-4-
4.12. Methyl (2S,5E)-2-(tert-butoxycarbonylamino)-6-(40-bro-
mophenyl)-4-oxohex-5-enoate (15)21f
oxopentanoate (12) as a pale yellow oil (0.067 g, 92%). [
a
]
25 þ30.8
The reaction was performed as described above, using (2S)-2-
(tert-butoxycarbonylamino)-4-oxo-5-(trimethylsilanyl)pentanoate
(11) (0.80 g, 2.52 mmol) and 4-bromobenzaldehyde (0.56 g,
3.0 mmol). Purification by flash chromatography (20% ethyl acetate
in petroleum ether) gave methyl (2S,5E)-2-(tert-butoxycarbonyl
amino)-6-(40-bromophenyl)-4-oxohex-5-enoate (15) as a white
solid (0.48 g, 46%). Mp 78e79 ꢁC; nmax (NaCl) 3437 (NH), 3370, 2978
D
(c 2.1, CHCl3), lit.24
[a
]
22 þ32.7 (c 1.0, CHCl3); nmax (neat) 3420 (NH),
D
3082 (CH), 1774 (C]O), 1612, 1466, 1111, 945 cmꢀ1
; dH (400 MHz,
CDCl3) 1.47 (9H, s, tBu), 2.20 (3H, s, 5-H3), 2.98 (1H, dd, J 18.4, 4.2 Hz,
3-HH), 3.22 (1H, dd, J 18.4, 4.4 Hz, 3-HH), 3.76 (3H, s, OMe),
4.49e4.54 (1H, m, 2-H), 5.53 (1H, br d, J 8.4 Hz, NH); dC (101 MHz,
CDCl3) 28.3 (CH3), 29.9 (3ꢂCH3), 45.4 (CH2), 49.4 (CH), 52.7 (CH3),
80.1 (C), 155.6 (C), 171.9 (C), 206.7 (C); m/z (FAB) 246 (MHþ, 45%),
(CH), 1747 (C]O), 1712 (C]O), 1666 (C]C), 1611, 1488, 1168 cmꢀ1
;

250
C.M. Reid et al. / Tetrahedron 71 (2015) 245e251
[
a
]
20 þ42.4 (c 1.0, CHCl3); dH (400 MHz, CDCl3) 1.44 (9H, s, tBu), 3.22
organic layers were concentrated in vacuo. To a solution of the
resulting residue (0.16 mmol) in dichloromethane (2 mL) was
added trifluoroacetic acid (0.80 mmol) and the reaction mixture
was stirred at room temperature under argon for 3 h. The reaction
mixture was concentrated in vacuo to give the TFA salts, which
were purified by recrystallisation from chloroform and methanol.
D
(1H, d, J 17.8 Hz, 3-HH), 3.41 (1H, d, J 17.8 Hz, 3-HH), 3.75 (3H, s,
OMe), 4.58e4.64 (1H, m, 2-H), 5.56 (1H, d, J 8.0 Hz, NH), 6.69 (1H, d,
J 16.0 Hz, 5-H), 7.40 (2H, d, J 8.0 Hz, ArH), 7.46e7.56 (3H, m, 6-H and
ArH); dC (101 MHz, CDCl3) 28.3 (3ꢂCH3), 42.6 (CH2), 49.6 (CH), 52.7
(CH3), 80.0 (C), 125.2 (C), 126.0 (CH), 129.8 (2ꢂCH), 132.3 (2ꢂCH),
133.0 (C), 142.5 (CH), 155.6 (C), 172.0 (C), 197.5 (C); m/z (FAB) 412
(MHþ, 22%), 358 (100), 356 (89), 314 (23), 278 (22), 234 (7); HRMS
(FAB): MHþ, found 412.0755. C18H2379BrNO5 requires 412.0760.
4.15.1. (2S,5E)-2-Amino-4-oxo-6-phenylhex-5-enoic
acid
tri-
fluoroacetate (18).21f Using the general procedure above gave
(2S,5E)-2-amino-4-oxo-6-phenylhex-5-enoic acid trifluoroacetate
(18) as a white solid (0.13 g, 95%). Mp 112e114 ꢁC (decomposition);
4.13. Methyl (2S,5E)-2-(tert-butoxycarbonylamino)-4-oxo-8-
phenyloct-5-enoate (16)21f
nmax (neat) 3028 (NH), 2914 (CH), 1738 (C]O), 1655 (C]C), 1495,
19
1184, 1134 cmꢀ1; [
a]
þ23.3 (c 1.0, MeOH); dH (400 MHz, CD3OD)
D
The reaction was performed as described above, using (2S)-2-
(tert-butoxycarbonylamino)-4-oxo-5-(trimethylsilanyl)pentanoate
(11) (0.80 g, 2.52 mmol) and 3-phenylpropionaldehyde (0.40 g,
3.0 mmol). Purification by flash chromatography (15% ethyl acetate
in petroleum ether) gave methyl (2S,5E)-2-(tert-butox-
ycarbonylamino)-4-oxo-8-phenyloct-5-enoate (16) as a colourless
oil (0.46 g, 53%). nmax (NaCl) 3439 (NH), 3371, 3027, 3004, 2978
3.43 (1H, dd, J 18.5, 6.1 Hz, 3-HH), 3.48e3.56 (1H, m, 3-HH),
4.22e4.28 (1H, m, 2-H), 6.92 (1H, d, J 16.2 Hz, 5-H), 7.40e7.48 (3H,
m, ArH), 7.62e7.69 (2H, m, ArH), 7.74 (1H, d, J 16.2 Hz, 6-H); dC
(101 MHz, CD3OD) 40.9 (CH2), 50.2 (CH), 126.1 (CH), 129.7 (2ꢂCH),
130.2 (2ꢂCH), 132.1 (CH), 135.6 (C), 146.0 (CH), 171.8 (C), 198.0 (C);
m/z (FAB) 220 (MHþ, 42%), 175 (7), 148 (16), 132 (12); HRMS (FAB):
MHþ, found 220.0973. C12H14NO3 requires 220.0974.
(CH), 2952, 2930, 2859, 1749 (C]O), 1714 (C]O), 1672, 1630, 1584
19
(C]C), 1497, 1367, 1167 cmꢀ1; [
a
]
þ47.4 (c 1.0, CHCl3); dH
4.15.2. (2S,5E)-2-Amino-6-(40-bromophenyl)-4-oxohex-5-enoic acid
trifluoroacetate (19).21f Using the general procedure above gave
(2S,5E)-2-amino-6-(40-bromophenyl)-4-oxohex-5-enoic acid tri-
fluoroacetate (19) as a white solid (0.14 g, 93%). Mp 151e152 ꢁC
D
t
(400 MHz, CDCl3) 1.44 (9H, s, Bu), 2.46e2.63 (2H, m, 7-H2), 2.79
(2H, t, J 7.7 Hz, 8-H2), 3.06 (1H, dd, J 18.0, 4.0 Hz, 3-HH), 3.30 (1H, dd,
J 18.0, 4.0 Hz, 3-HH), 3.73 (3H, s, OMe), 4.42e4.64 (1H, m, 2-H), 5.53
(1H, br d, J 8.8 Hz, NH), 6.10 (1H, dt, J 16.0,1.4 Hz, 5-H), 6.88 (1H, dt, J
16.0, 6.8 Hz, 6-H), 7.11e7.37 (5H, m, ArH); dC (101 MHz, CDCl3) 28.3
(CH3), 34.2 (CH2), 34.3 (CH2), 41.8 (CH2), 49.5 (CH), 52.6 (CH3), 79.9
(C), 126.3 (CH), 128.3 (2ꢂCH), 128.6 (2ꢂCH), 130.3 (CH), 140.5 (C),
147.8 (CH), 155.6 (C), 172.0 (C), 197.7 (C); m/z (FAB) 362 (MHþ, 14%),
306 (94), 262 (100), 203 (11), 176 (14), 160 (34), 93 (35), 90 (32);
HRMS (FAB): MHþ, found 362.1974. C20H28NO5 requires 362.1967.
(decomposition); nmax (neat) 3364 (NH), 3061, 1684 (C]O), 1607
(C]C), 1547, 1487, 1397, 1339 cmꢀ1; [
a]
þ55.0 (c 0.3, MeOH); dH
18
D
(400 MHz, CD3OD) 3.23 (1H, dd, J 18.8, 9.3 Hz, 3-HH), 3.46 (1H, dd, J
18.8, 3.4 Hz, 3-HH), 3.95 (1H, dd, J 9.3, 3.4 Hz, 2-H), 6.91 (1H, d, J
16.3 Hz, 5-H), 7.56e7.62 (4H, m, ArH), 7.67 (1H, d, J 16.3 Hz, 6-H); dC
(101 MHz, CD3OD) 40.9 (CH2), 50.2 (CH), 126.2 (C), 126.7 (CH), 131.3
(2ꢂCH), 133.4 (2ꢂCH), 134.8 (C), 144.6 (CH), 171.5 (C), 197.7 (C); m/z
(FAB) 298 (MHþ, 31%), 292 (16), 254 (12), 243 (21), 209 (18), 155
(29), 138 (15); HRMS (FAB): MHþ, found 298.0067. C12H1379BrNO3
requires 298.0079.
4.14. (2S,5E)-2-Amino-4-oxo-6-phenylhex-5-enoic acid hy-
drochloride (17)
To a solution of methyl (2S,5E)-2-(tert-butoxycarbonylamino)-
4-oxo-6-phenylhex-5-enoate (14) (0.20 g, 0.60 mmol) in methanol
(3.0 mL) was added 6.0 M hydrochloric acid (15 mL) and the re-
action mixture heated under reflux for 24 h. The mixture was
allowed to cool to room temperature and then extracted with
diethyl ether (2ꢂ20 mL). The aqueous layer was concentrated in
vacuo to give a yellow solid. Recrystallisation from chloroform and
methanol gave (2S,5E)-2-amino-4-oxo-6-phenylhex-5-enoic acid
hydrochloride (17) as an off-white solid (0.095 g, 62%). Mp
4.15.3. (2S,5E)-2-Amino-4-oxo-8-phenyloct-5-enoic
acid
tri-
fluoroacetate (20).21f The general two-step procedure described
above was used except that a 1:1 acetonitrile/water solution was
used for the hydrolysis step. This gave (2S,5E)-2-amino-4-oxo-8-
phenyloct-5-enoic acid trifluoroacetate (20) as a white solid
(0.10 g, 98%). Mp 94e96 ꢁC (decomposition); nmax (neat) 3161 (NH),
3030, 2918 (CH), 1736 (C]O), 1661 (C]C), 1640, 1604, 1497,
18
1180 cmꢀ1; [
a]
þ10.2 (c 0.3, MeOH); dH (400 MHz, CD3OD)
D
2.54e2.63 (2H, m, 7-H2), 2.82 (2H, t, J 7.4 Hz, 8-H2), 3.20 (1H, dd, J
18.8, 8.0 Hz, 3-HH), 3.28e3.37 (1H, m, 3-HH), 4.11 (1H, dd, J 8.0,
3.6 Hz, 2-H), 6.17 (1H, dt, J 16.0, 1.4 Hz, 5-H), 7.03 (1H, dt, J 16.0,
6.9 Hz, 6-H), 7.12e7.31 (5H, m, ArH); dC (101 MHz, CD3OD) 35.3
(CH2), 35.5 (CH2), 40.4 (CH2), 50.5 (CH), 127.3 (CH), 129.5 (2ꢂCH),
129.6 (2ꢂCH), 130.8 (CH), 142.1 (C), 150.5 (CH), 172.5 (C), 198.1 (C);
m/z (FAB) 248 (MHþ, 14%), 247 (2), 203 (8), 176 (12), 160 (8), 132 (4),
100 (1), 90 (3), 76 (4); HRMS (FAB): MHþ, found 248.1289.
151e153 ꢁC (decomposition); nmax (neat) 3058 (NH), 2976 (CH),
1736 (C]O), 1649 (C]C), 1174, 1126, 854 cmꢀ1; [
a]
þ35.8 (c 1.0,
24
D
MeOH); dH (400 MHz, CD3OD) 3.38e3.58 (2H, m, 3-H2), 4.36 (1H,
dd, J 6.6, 4.2 Hz, 2-H), 6.92 (1H, d, J 16.3 Hz, 5-H), 7.38e7.50 (3H, m,
ArH), 7.63e7.71 (2H, m, ArH), 7.76 (1H, d, J 16.3 Hz, 6-H); dC
(101 MHz, CD3OD) 40.7 (CH2), 49.3 (CH), 126.0 (CH), 129.8 (2ꢂCH),
130.2 (2ꢂCH), 132.2 (CH), 135.6 (C), 146.2 (CH), 171.3 (C), 197.6 (C);
m/z (CI) 220 (MHþ, 84%), 205 (100), 203 (61), 159 (53), 147 (34), 113
(21), 97 (20), 81 (50), 69 (61); HRMS (CI): MHþ, found 220.0978.
C14H18NO3 requires 248.1287.
C
12H14NO3 requires 220.0974.
Acknowledgements
4.15. General procedure for the deprotection of enones 14, 15
and 16
The authors are grateful to the University of Glasgow (student-
ship to K.N.F.), Engineering and Physical Sciences Research Council
(EP/P503582/1) (studentship to L.S.F.) and Pfizer for financial
support.
To
a solution of N-Boc-protected amino methyl ester
(0.16 mmol) in 1:1 methanol/water (4 mL) was added caesium
carbonate (0.21 mmol). The resultant suspension was stirred at
room temperature for 48 h. The reaction mixture was concentrated
in vacuo and the residue was dissolved in water (10 mL) and
acidified to pH 1 with hydrochloric acid (1 M). The aqueous layer
was washed with dichloromethane (3ꢂ20 mL) and the combined
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.11.059.

C.M. Reid et al. / Tetrahedron 71 (2015) 245e251
251
12. In the study by Aoyama and Shioiri (Ref. 10), the reactions leading to the 2-
oxotrialkylsilanes were worked-up with water and the compounds purified
by distillation. Quenching the reactions with dilute acid (10% HCl) gave the
methyl ketones as the main product in 43e89% yield. In the procedure reported
by Lee and co-workers (Ref. 11), the reaction mixtures were concentrated under
vacuum and the yields of 2-oxotrialkylsilanes calculated using an internal
standard. In the experimental procedure, the authors specifically highlight the
avoidance of silica gel flash chromatography.
References and notes
1. For reviews see: (a) Wagner, I.; Musso, H. Angew. Chem., Int. Ed. Engl. 1983, 22,
816; (b) Greenstein, J. P.; Winitz, M. Chemistry of the Amino Acids; R. E. Krieger:
Malabar, FL, 1984, Vols. 1e3; (c) Barrett, G. C. In Chemistry and Biochemistry of
the Amino Acids; Chapman and Hall: London, UK, 1985; (d) O’Donnell, M. J., Ed.
a
-Amino Acid Synthesis Tetrahedron 1988, 44, 5253; (e) Williams, R. M. Syn-
thesis of Optically Active -Amino Acids; Pergamon: Oxford, UK, 1989, Vol. 7.
2. (a) Ohfune, Y. Acc. Chem. Res. 1992, 25, 360; (b) Sutherland, A.; Willis, C. L. Nat.
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Org. Biomol. Chem. 2007, 5, 406; (f) Smits, R.; Cadicamo, C. D.; Burger, K.;
a
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Werner, R. M.; Shokek, O.; Davis, J. T. J. Org. Chem. 1997, 62, 8243.
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€
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Koksch, B. Chem. Soc. Rev. 2008, 37, 1727.
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J. S.; Vederas, J. C. Org. Biomol. Chem. 2005, 3, 4402.
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Rev. 2009, 38, 1002; (b) Franz, A. K.; Wilson, S. O. J. Med. Chem. 2013, 56, 388.
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E. J. Am. Chem. Soc. 2006, 128, 8479.
6. (a) Sieburth, S. McN.; Chen, C.-A. Eur. J. Org. Chem. 2006, 311; (b) Nielson, L.;
Lindsay, K. B.; Faber, J.; Nielsen, N. C.; Skrydstrup, T. J. Org. Chem. 2007, 72,
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ꢀ
17. Hernandez, J. N.; Ramírez, M. A.; Martín, V. S. J. Org. Chem. 2003, 68, 743.
18. A mono-Boc-protected 4-oxo-5-trialkylsilanyl derived amino acid has been
prepared previously (see Ref. 7e), using a base-mediated ring opening reaction
of a 2-amino-3-methyl-4-silylmethylene-g-butyrolactone. However, the rela-
tive stability of this compound may be due to the use of a more hindered tert-
butyldimethylsilyl group.
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23. For full details, see Supplementary data.
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