Highly functionalised organolithium and organoboron reagents for the preparation of enantiomerically pure α-amino acids

Article abstract of DOI:10.1016/j.tet.2004.10.097

Homochiral, highly functionalised organolithium reagents derived from l-serine have been generated and reacted with electrophiles. The novel enantiomerically pure adducts thus obtained were then converted, through β-amino alcohols, into novel non-proteinogenic α-amino acids. The methodology also made available a novel boronic acid which was then employed as a Suzuki cross-coupling partner, elaborating a new pathway to phenylalanine analogues.

Full text of DOI:10.1016/j.tet.2004.10.097

Tetrahedron 61 (2005) 3403–3417
Highly functionalised organolithium and organoboron reagents
for the preparation of enantiomerically pure a-amino acids
Christopher W. Barfoot,a Joanne E. Harvey,a Martin N. Kenworthy,a John Paul Kilburn,a
Mahmood Ahmedb and Richard J. K. Taylora,
*
aDepartment of Chemistry, University of York, Heslington, York YO10 5DD, UK
bGlaxoSmithKline, New Frontiers Science Park (North), Third Avenue, Harlow, Essex CM19 5AW, UK
Received 27 July 2004; accepted 15 October 2004
Available online 10 December 2004
Abstract—Homochiral, highly functionalised organolithium reagents derived from L-serine have been generated and reacted with
electrophiles. The novel enantiomerically pure adducts thus obtained were then converted, through b-amino alcohols, into novel non-
proteinogenic a-amino acids. The methodology also made available a novel boronic acid which was then employed as a Suzuki cross-
coupling partner, elaborating a new pathway to phenylalanine analogues.
q 2004 Elsevier Ltd. All rights reserved.
Nucleophilic alanine equivalents have attracted a great deal
of attention in recent years.1–6 These reagents are particu-
larly useful for the preparation of enantiopure proteinogenic
and non-proteinogenic a-amino acids,1 as well as enantio-
pure a-amino alcohols, and other related ‘chiral building
blocks’ used in natural product synthesis. Prominent
examples of these reagents include aspartate-derived anion
1,2 related sulfonyl reagent 2,3 Wittig reagents 34 and 4,5
and the organonickel reagent 5.6 Although ground-breaking
and potentially valuable, these reagents have not been
widely employed in organic synthesis, possibly due to the
difficulty of preparation, the additional steps needed to
remove the anion-stabilising/activating group or to readjust
the oxidation level and, in the case of reagent 5, its low
reactivity.
The organozinc reagent 6 designed and prepared by Jackson
and his group,7 has proved particularly versatile and has
been successfully adopted by other researchers for prepa-
ration of a number of natural products and medicinally
active compounds.8 This reagent can be employed in a
variety of coupling procedures (e.g., to aryl halides and acyl
halides7a), and its copper derivative also undergoes allyla-
tion or conjugate additions.7b Unfortunately, due to its low
nucleophilicity, reaction with simple aldehydes/ketones is
not possible (Fig. 1).
During synthetic efforts towards the synthesis of scyphos-
tatin9a and aranorosin,9b we required a highly reactive
organometallic reagent, i.e. 7, capable of 1,2-addition to
cyclic ketones. In this paper we describe the successful
Figure 1. Alanine anion equivalents.
Keywords: Cross-coupling; a-Amino acids; Organolithium; Suzuki; Alanine anions.
* Corresponding author. Tel.: C44 1904 432606; fax: C44 1904 434523; e-mail: rjkt1@york.ac.uk
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.097

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C. W. Barfoot et al. / Tetrahedron 61 (2005) 3403–3417
development and application of such highly functionalised
organolithium reagents 7.10 The novel homochiral adducts
are then manipulated into proteinogenic and non-proteino-
genic a-amino acids. We also outline the synthesis of a new
alkylboron reagent 8,11 which is employed in Suzuki cross-
coupling reactions. Thus, two new alanine anion equivalents
are described.
indicating the possibility that an additional coordinating site
in the protecting group might be advantageous. The
unprotected alcohol 10 gave no product, nor did the TBS
ether 11a. The failure of silyl-protected 11a was presumably
due to susceptibility to intramolecular Brook-type
rearrangement, although this could not be verified by
analysis of the crude product mixture. No further work was
carried out with the THP-protected 11b in view of the
diastereomeric nature of the adducts.
As might be anticipated,15 preliminary deprotection studies
showed the SEM ether 13d could be deprotected more
easily than MOM ether 13c, although many standard
methods15 led to decomposition. N-Br-Catecholborane
cleanly converted MOM-protected 13c into alcohol 13e,
but only in a disappointing 58% yield. It should be pointed
out that deprotection of the SEM ether employing TBAF
(in THF16 and DMPU17) failed at room temperature, and
decomposition ensued on heating at elevated temperatures.
Fortunately, deprotection of SEM ether 13d could be
performed cleanly using 0.1 M HCl in MeOH18 over 3 h
at room temperature, delivering 13e (PZH) in an excellent
79% yield. Unfortunately, this reaction time (3 h) led to
incomplete conversion, and so starting material was
recovered (see Table 2 footnote). Extended reaction times
led to substantial cleavage of the Boc group.
1. Preparation and application of functionalised
organolithium reagents (7)
We first embarked on a program to explore the preparation
of organolithium reagents 7 commencing from a readily
available proteinogenic a-amino acid (Scheme 1).12 Stan-
dard conditions were employed to convert L-serine via ester
913 into chloro-alcohol 10. Protection of alcohol 10 was
undertaken using a number of different groups, giving the
key lithiation precursors 11a–d.
With precursors 10 and 11a–d in hand we were able to
investigate the generation of organolithium reagents 12a–e
(Scheme 1). Due to the required anion 7 having a b-hetero-
atom it was obviously crucial to generate a dianionic species
in order to impede b-elimination. We therefore employed
the n-butyllithium/lithium naphthalenide (LiNp) combi-
nation pioneered by Yus et al. for b-chloroamide lithia-
tion.14 This protocol was employed with the unprotected
alcohol 10 and with the protected derivatives 11a–d, the
reaction mixture was then quenched with cyclohexanone
with the aim of assessing the procedure in terms of the yield
of adducts 13a–e (Table 1).
Due to the success of the SEM group in the deprotection
studies, it was therefore chosen for further investigation and
a range of electrophiles were used to trap the organolithium
reagent 12d (Table 2). Thus, in addition to cyclohexanone
(entry i), cyclobutanone, benzaldehyde, Weinreb amides,
carbon dioxide, trimethylsilyl chloride, CD3OD and tribu-
tyltin chloride were all successfully employed as electro-
philic trapping agents delivering adducts 15, 18, 21, 23, 25,
27, 30 and 33, respectively, in yields ranging from 51 to
98% (entries ii–viii).
Table 1. Metallation-trapping of 11a–d and 10a
Entry
Precursor
Productb
i
ii
iii
iv
vc
11a, PZTBS
11b, PZTHP
11c, PZMOM
11d, PZSEM
10
13a, PZTBS, 0%
13b, PZTHP, 57%
13c, PZMOM, 82%
13d, PZSEM, 82%
13e, PZH, 0%
Cleavage of the SEM-protecting groups proceeded
smoothly, in most cases, delivering alcohols 13e, 16, 19,
28 and 31 in unoptimised but reasonable yields (entries i–iii,
vi–vii). The main exceptions (entry iv) involved metha-
nolysis of ketone adducts 21 and 23 where the only observed
products were the furans 22 and 24, respectively, resulting
from a cyclocondensation–aromatisation sequence. In
addition (entry v), the alcohol resulting from deprotection
of ester 25 underwent partial lactonisation, and a second
a THF, K78 8C: (i) n-BuLi (1.1 equiv), (ii) LiNp (2.5–3.0 equiv), (iii) EC
(1.5–2.5 equiv).
b Isolated yields.
c 2.1 equiv of n-BuLi was employed.
We were encouraged by the promising results with THP,
MOM and SEM protecting groups (Table 1, entries ii–iv),
Scheme 1. Initial studies.

C. W. Barfoot et al. / Tetrahedron 61 (2005) 3403–3417
Table 2. Metallation-trapping–methanolysis–oxidation of 11da
3405
Electrophile (EC
)
Adduct
Methanolysis product
Oxidation product
i
13d, 82%
13e, 88%b
14 Method A, 69%
ii
15, 81%
16, 76%b
17 Method A, 74%
iii
PhCHO
19, 79%b
20 Method B, 47%,
Method C, 44%
18, 98%
(3:2) ratio
—
-
22, RZMe,c
24, RZPhc
RZMe
RZPh
iv
21 RZMe, 82%,
23 RZPh, 80%
CO2, then
TMSCHN2
v
—
25, 70%
26, 65%b,d
vi
Me3SiCl
CD3OD
Bu3SnCl
27, 78%
30, 87%
33, 51%
28, 72%
29 Method B, 68%
vii
32 Method C, 61%
31, 70%
viii
—
—
a Trapping of 12d using the electrophile indicated; deprotection using 0.1 M HCl in MeOH for 3 h; oxidation/esterification using Method A: PDC, DMF,
Method B: (i) PDC, DMF, (ii) TMSCHN2 or Method C: (i) RuCl3 (cat.), NaIO4, CCl4/H2O/CH3CN, (ii) TMSCHN2; isolated yields are shown.
b Based on recovered starting material (isolated yields were 13e, 79%; 16, 65%; 19, 64%; 26, 50%).
c The desired deprotected product was not observed. Due to the volatility of 22 and 24 isolated yields were not obtained; these were the only products observed
by TLC and 1H NMR spectroscopy.
d Lactonisation to give 26 was completed by treatment with CSA in PhH.19
treatment of the crude material with CSA in benzene19a
completed lactonisation to give the known g-lactone 26.19
The standard deprotection method failed to effect clean
removal of the SEM from the tributyltin adduct 33 (entry
viii).
The Boc-protected b-amino alcohol derivatives obtained by
SEM-deprotection were then oxidised to the corresponding
Boc-protected a-amino acids which were converted into
their methyl esters using trimethylsilyl diazomethane. Thus,
fully protected a-amino acids 20,20 29 and 32 were obtained

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C. W. Barfoot et al. / Tetrahedron 61 (2005) 3403–3417
Scheme 2. Preparation of phosphonate a-amino acid 36.
in reasonable yields (entries iii and vi–vii). Oxidation of
18/38 diols 13e and 16 under these PDC oxidation conditions
gave the spirocyclic lactones 14 and 17, respectively, by in
situ lactonisation (entries i and ii). It should be noted that the
problems with methanolysis of the SEM–ketone adducts,
such as 21 and 23, were overcome by double oxidation of
the deprotected benzaldehyde adduct 19, therefore allowing
the synthesis of b-keto-a-amino acid 20 (entry iii).20
The subsequent alcohol 35 was converted into the protected
a-amino acid 36 in the manner described above.
Hydrolysis of the protected amino acids 19, 28 and 31 was
straightforward (Scheme 3). Thus, treatment of the N-Boc
amino ester 19 with 4.5 M HCl at 70 8C for 3 h gave the
hydrochloride salt 37 in 92% yield. The optical rotation was
in good agreement with the published value {[a]2D1ZC35.6
(c 0.1, 6 M HCl); lit.21 C34.7 (c 0.1, 6 M HCl)}. Similarly,
trimethylsilylalanine was obtained as its hydrochloride salt
38 from 28 in 80% yield {[a]2D1ZC35.2 (c 1.1, 1 M HCl);
lit.22 C31 (c 0.51, 4 M HCl)}. The deutero-alanine HCl salt
39 was obtained in 95% yield from 31 in the same manner
{[a]2D1ZC11.7 (c 1.2, 6 M HCl)}. This labelled amino acid
has been observed in the reaction of alanine with hydroxyl
radicals,23 but has never been isolated and characterised.
A more demanding electrophile such as diethyl chlorophos-
phate could also be employed. Reaction of organolithium
12d with diethyl chlorophosphate delivered a good yield of
the phosphonate 34 (Scheme 2), although reduced reaction
times were required to minimise side reactions. SEM-
deprotection was then carried out efficiently by means of
0.1 M ethanolic HCl, avoiding trans-esterification problems.
Scheme 3. Preparation of (C)-a-amino acids.

C. W. Barfoot et al. / Tetrahedron 61 (2005) 3403–3417
3407
Scheme 4. Preparation of aspartic acid mimic (C)-44.
Future employment of this deuterated amino acid (C)-39
could be envisaged in biological studies.
oxidations led to decomposition. Fortunately, sequential
Dess–Martin periodinane/sodium chlorite oxidations gave
the crude carboxylic acid28 which was directly deprotected
using 4.5 M HCl. The crude hydrogen chloride salt of
the amino acid could then be purified on silica gel eluting
L-2-Amino-3-phosphonopropionic acid 40 has been shown
to be an antagonist of the metabotropic glutamate
receptor.24a This can lead to inhibition of phosphoserine
phosphatase, which catalyses the final step in the major
pathway of L-serine biosynthesis in the brain. The synthesis
of phosphonic acid 40 was achieved through global
deprotection of the phosphonate 36 in 6 M HCl under
reflux, followed by treatment with propylene oxide (Scheme
3).24b The optical rotation value {[a]2D1ZC16.3 (c 0.4, 1 M
NaOH)} of amino acid 40 was in good agreement with that
reported by Smith et al. {lit.24b C13.8 (c 2, 1 M NaOH)}.
29
with 2:1 EtOH–14 M NH3 to deliver the aspartic acid
mimic (C)-44, {[a]D21ZC33.0 (c 0.2, 4.5 M HCl)}.30 This
constitutes the first asymmetric synthesis of the aspartic acid
mimic (C)-44, increasing its potential in future biological
studies.
2. Preparation and application of functionalised
organoboron reagents (8)
We also employed this novel methodology to complete
the first asymmetric synthesis of the aspartic acid mimic
(C)-44, in which the b-carboxylic acid has been substituted
by a boronic acid (Scheme 4). This compound has already
been synthesised as a racemate,25,26 and in one case
resolution was performed by separation of a dipeptide
derivative.26 It is a member of the increasing number of
biomolecules which synthetic chemists have altered by
incorporation of boron-containing moieties.27
Recently, we have explored the use of complex alkyl-borane
Suzuki cross-coupling partners derived from readily
available chiral-pool starting materials. The homoalanine
and bis-homoalanine alkyl-organoboranes 45 and 46,12
obtained by hydroboration of alkenyl-precursors, were
employed in cross-coupling reactions delivering a variety
of novel non-proteinogenic a-amino acids (Fig. 2).
Attempts to synthesise alanine-organoborane derivatives
(47, BR2Z9-BBN) had previously been made, but unfortu-
nately hydroboration of the dehydro-amino acid derivatives
failed.31 The synthesis of boronic acid 41 (Scheme 4) raises
the possibility of its application as the lower homologue of
45 and 46. Application of this lower homologue to Suzuki
cross-coupling would expand the scope of the methodology.
An added benefit is that boronic acid 41 is stable and
presumably has a low level of toxicity,32 compared to the
organoboranes 45 and 46,12 both of which need to be
prepared immediately before use.
Reaction of the functionalised organolithium reagent 12d
with triisopropylborate followed by treatment with mild
acid delivered the boronic acid 41 in 80% yield (Scheme 4).
In order to manipulate the boronic acid adduct 41,
protection as the (K)-pinane-diol boronate ester was
undertaken. This was followed by methanolysis of the
SEM ether 42, giving the alcohol 43 in reasonable yield.
The oxidation of alcohol 43 was found to be sensitive to the
reagent used, for example, both PDC/DMF and ‘RuO4’
Figure 2. Suzuki cross-coupling substrates.

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C. W. Barfoot et al. / Tetrahedron 61 (2005) 3403–3417
Traditionally, Suzuki cross-coupling reactions with alkyl
boronic acids were thought to be non-viable, due to their
low nucleophilicity and tendency for b-hydride elimination
after transmetallation.32 Over recent years this has been
proved to be wrong with pioneering work by Falck,33
Molander34 and Fu,35 who have shown that, by judicious
choice of catalyst and conditions, clean Suzuki cross-
coupling of alkyl-boronic acids is possible.
out that the maximum yield of coupled products from
boronic acid 41 is 82%, due to 18% of the starting alkyl
boronic acid being lost during reduction of the
PdII precatalyst to Pd0. A variety of aryl halides were
found to react smoothly in the coupling procedure, from
electron-rich p-bromoanisole (entry ii) to the electron-
deficient o, m and p-nitrobromobenzenes (entries iii–v).
Unsurprisingly iodobenzene also reacted well, but chlor-
obenzene failed to react. Rather unexpectedly, phenyl
trifluoromethanesulfonate (PhOTf) failed, despite these
conditions previously being employed effectively with
triflates.33 The presence of carbonyl groups in the aryl
halide was found to be tolerated (entries vi and vii). A
doubly coupled product 49 was isolated in a modest 35%
yield by reaction of the boronic acid with 0.5 equiv of 1,4-
diiodobenzene (entry ix).
We first wished to discover if our highly functionalised
boronic acid 41 was applicable to Suzuki cross-coupling with
aryl halides, and whether we could then transform the adducts
into phenylalanine analogues. Through optimisation11 we
were able to devise conditions delivering good yields of the
coupled products 48a–h and 49 (Table 3). Employment of
modified Falck33 conditions (PdIICl2(dppf).CH2Cl2/K2CO3/
Ag2O/THF) gave a clean conversion into the coupled
products 48a–h, 49 at 70 8C over 21 h. It should be pointed
The bromobenzene and p-bromonitrobenzene systems were
Table 3. Suzuki cross-coupling of alkyl boronic acid 35 with aryl halidesa
Entry
ArX
Yield (%)b
72/73/0/0
Product
48a
i
65
48b
ii
iii
65
70
48c
48d
iv
v
67
48e
68
52
48f
vi
48g
vii
73
48h
49
viii
ix
35c
a All performed on 0.10–0.13 mmol scale at ca. 0.1 mol LK1 concentration.
b Yields are based on boronic acid 41.
c 0.5 equiv of dihalide used; doubly coupled product 49 formed:
49.

C. W. Barfoot et al. / Tetrahedron 61 (2005) 3403–3417
3409
Scheme 5. Preparation of (K)-phenylalanine hydrochloride 52.
demonstrated to be amenable to a modest scale-up (ca.
0.5 mmol), giving a reasonable 63% yield of 48a and a
better 71% yield of 48c, respectively. No problems are
foreseen in further scale-ups.
deuterated solvent. An external sample of BF3$OEt2 was
used to calibrate 11B NMR spectra. Infrared spectra were
recorded on a ThermoNicolet IR100 spectrometer with
NaCl plates. Optical rotation values were measured on a
JASCO DIP-370 digital polarimeter using a sodium lamp.
Low-resolution electron impact (EI) mass spectra were
recorded on a Kratos MS 25 spectrometer. Chemical
ionisation (CI) and high-resolution mass spectra were
recorded on a Micromass Autospec spectrometer. Melting
points were recorded on Gallenkamp apparatus and are
uncorrected. Thin layer chromatography was performed on
To demonstrate the synthetic utility of these adducts and to
prove that no racemisation occurred during the coupling
process we transformed the phenyl adduct 48a into (K)-
phenylalanine 52 (Scheme 5). A two-step deprotection
procedure was used, whereby both SEM and Boc groups
were removed to deliver the b-amino alcohol, which was
reprotected with Boc, giving 50. A two-step Dess–Martin
periodinane/sodium chlorite oxidation was then employed
to deliver the amino acid, which was again protected as a
methyl ester, producing the fully protected phenylalanine
51. This was then globally deprotected as before with 6 M
HCl, this time including anisole as a cation trap. The optical
rotation of the so-obtained HCl salt, 52, matched the known
data {[a]2D3ZK8.1 (c 0.91, H2O); [lit.36 [a]2D3ZK8.2 (c 1,
H2O)]}.
aluminium plates coated with Merck silica gel 60 F254
.
Flash column chromatography was carried out using Fluka
flash silica gel 60 and the eluent is specified. Where
necessary, ether and THF were distilled from sodium
benzophenone ketyl immediately before use and CH2Cl2
distilled from calcium hydride. Except where specified, all
reagents were purchased from commercial sources and used
without further purification.
3.2. Synthesis of (R)-[2-chloro-1-(2-trimethylsilanyl-
ethoxymethoxymethyl)-ethyl]-carbamic acid tert-butyl
ester (11d)
In summary, we have prepared a number of highly
functionalised organolithium reagents from L-serine using
the Yus procedure in the key lithiation step and established
that they can be employed as alaninol/alanine anion
equivalents. The optimum SEM-protected reagent 11d has
been used to prepare a range of novel adducts which were
hydrolysed to give alaninol derivatives and then oxidised to
give known and novel non-proteinogenic amino acids as
their protected derivatives. A selection of these compounds
was converted into the amino acid hydrochloride salts.
We were also able to undertake the first asymmetric
synthesis of the aspartic acid mimic (C)-44. In addition,
the alkyl boronic acid 41 was employed as a b-alanine anion
equivalent in Suzuki cross-coupling reactions with aryl
halides. One of the cross-coupled adducts was then
manipulated into (K)-phenylalanine hydrochloride 52.
3.2.1. 2-(R)-tert-Butoxycarbonylamino-3-chloro-propio-
nic acid methyl ester. A solution of triphenylphosphine
(19.2 g, 73.2 mmol) and hexachloroethane (17.3 g,
73.2 mmol) in dichloromethane (50 mL) was added in one
portion to a solution of N-Boc-serine methyl ester 912
(14.6 g, 66.5 mmol) in dichloromethane (250 mL) under an
atmosphere of argon. The reaction was stirred at room
temperature for 2 h, then quenched with a saturated solution
of sodium hydrogen carbonate (50 mL). The organic phase
was separated and washed with brine (100 mL), dried
(MgSO4), evaporated then triturated with Et2O (300 mL).
After filtration and evaporation the subsequent residue was
purified on silica gel, eluting with petrol(40–60)–EtOAc
5:1, delivering 2-tert-butoxycarbonylamino-3-chloro-pro-
pionic acid methyl ester (13.2 g, 84%) as a white solid, mp
62–64 8C; Rf 0.31 (4:1, petrol(40–60)–Et2O); nmax(film)/
cmK1 3362 (NH), 2982 (CH), 1721 (CO); [a]2D1ZC37.8
(c 1.5, CHCl3); dH (400 MHz; CDCl3) 5.37 (1H, brd, JZ
7.5 Hz), 4.65 (1H, m), 3.90 (1H, dd, JZ3 Hz, 11.5), 3.78
(1H, dd, JZ3.5, 11.5 Hz), 3.73 (3H, s), 1.40 (9H, s); dC
(100 MHz; CDCl3) 169.6, 154.9, 80.5, 54.4, 52.9, 45.5,
3. Experimental
3.1. General experimental
NMR spectra were recorded on a Jeol EX-270 or Jeol EX-
400 instrument (specified below); chemical shifts are quoted
in parts per million (ppm) calibrated to residual non-

3410
C. W. Barfoot et al. / Tetrahedron 61 (2005) 3403–3417
28.2. (Found: MNH4C, 255.1110. C8H16NO435Cl requires
MNH4, 255.1112 (0.8 ppm)).
ammonium chloride (20 mL). The layers were separated
and the aqueous layer was extracted with ether (2!10 mL).
The combined organics were dried (MgSO4), filtered and
evaporated to give a crude product which was purified by
flash column chromatography on silica gel, eluting with
diethyl ether–petrol ether (40–60) to give the product.
3.2.2. (2-(R)-Chloro-1-hydroxymethyl-ethyl)-carbamic
acid tert-butyl ester 10. Lithium borohydride (1.18 g,
54.1 mmol) was added in portions to a stirred solution of
the above ester (12.9 g, 54.1 mmol) in ethanol–THF 9:1
(700 mL) at 0 8C under an atmosphere of argon. The
reaction was stirred for 18 h at room temperature then
quenched with a saturated solution of ammonium chloride
(10 mL). The organics were then evaporated and the residue
partitioned between water (300 mL) and Et2O (300 mL).
After separation, the aqueous was further extracted with
Et2O (300 mL). The combined organics were dried
(MgSO4) and evaporated to give a gummy residue which
was purified on silica gel, eluting with petrol(40–60)–Et2O
2:1, giving the alcohol 10 (8.1 g, 81%) as a gum; Rf 0.42
(1:2, petrol(40–60)–Et2O); nmax(film)/cmK1 3353 (OH),
2978 (CH), 1689 (CO); [a]2D1ZK4.6 (c 0.7, CHCl3); dH
(400 MHz; CDCl3) 4.94 (1H, br s), 3.86 (1H, br s), 3.8–3.55
(4H, m), 1.42 (9H, s); dC (100 MHz; CDCl3) 155.6, 80.2,
62.0, 52.5, 44.2, 28.3. (Found: MHC, 210.0889.
C8H16NO335Cl requires MH, 210.0897 (4.0 ppm)).
3.3.1. [2-(1-Hydroxy-cyclohexyl)-1-(S)-(2-trimethylsila-
nyl-ethoxymethoxymethyl)-ethyl]-carbamic acid tert-
butyl ester 13d. 149 mg, 82%. Colourless oil; Rf 0.10
(2:1, petrol(40–60)–Et2O); nmax(film)/cmK1 3448 (OH),
2932, 2867 (CH), 1691 (CO); [a]2D1ZK5.0 (c 0.6, CHCl3);
dH (400 MHz; CDCl3) 5.13 (1H, br s), 4.65 (2H, s), 3.95
(1H, br s), 3.6–3.5 (4H, m), 2.98 (1H, br s), 1.65–1.2 (21H,
m), 0.94 (2H, t, JZ8.5 Hz), 0.01 (9H, s); dC (100 MHz;
CDCl3) 156.3, 95.3, 79.8, 71.9, 70.4, 65.5, 46.8, 44.6, 38.5,
37.9, 29.5, 26.0, 22.4, 22.3, 18.2, K1.3. (Found: MHC,
404.2831. C20H41NO5Si requires MH, 404.2832 (0.4 ppm)).
3.3.2. [2-(1-Hydroxy-cyclobutyl)-1-(S)-(2-trimethylsila-
nyl-ethoxymethoxymethyl)-ethyl]-carbamic acid tert-
butyl ester 15. 204 mg, 81%. Colourless oil; Rf 0.18 (1:1,
petrol(40–60)–Et2O); nmax(film)/cmK1 3397 (OH), 2977,
2953, 2934 (CH), 1686 (CO); [a]2D1ZK1.6 (c 0.2, CHCl3);
dH (270 MHz; CDCl3) 5.19 (1H, br d, JZ8 Hz), 4.68 (2H,
s), 4.41 (1H, br s), 3.97 (1H, br m), 3.7–3.6 (4H, m), 2.2–1.8
(6H, m), 1.7–1.5 (2H, m), 1.44 (9H, s), 0.96 (2H, t, JZ
8.5 Hz), 0.03 (9H, s); dC (100 MHz; CDCl3) 156.3, 95.3,
80.1, 73.3, 71.6, 65.4, 47.3, 42.5, 35.9, 35.6, 28.4, 18.1,
13.0, K1.5. (Found: MHC, 376.2521. C18H37NO5Si
requires MH, 376.2519 (K0.4 ppm)).
3.2.3.
[2-(R)-Chloro-1-(2-trimethylsilanyl-ethoxy-
methoxymethyl)-ethyl]-carbamic acid tert-butyl ester
11d. SEMCl (1.27 mL, 7.2 mmol) was added dropwise to
a stirred solution of alcohol 10 (1.58 g, 7.57 mmol)
and Hunig’s base (1.44 mL, 8.29 mmol) in dichloromethane
(20 mL) at 0 8C under an atmosphere of argon. The
reaction was allowed to warm to room temperature and
stirred for 18 h. The reaction was evaporated and partitioned
between Et2O (50 mL) and water (30 mL). After separation,
further extraction with Et2O (2!40 mL), the combined
organics were dried (MgSO4) and evaporated. The sub-
sequent crude residue was purified on silica gel, eluting with
petrol(40–60)–Et2O 4:1, giving the ether 11d (2.31 g, 95%)
as a colourless oil; Rf 0.30 (4:1, petrol(40–60)–Et2O);
nmax(film)/cmK1 3346 (NH), 2955, 2932, 2893 (CH), 1719
(CO); [a]2D1ZC12.4 (c 0.4, CHCl3); dH (400 MHz; CDCl3)
5.03 (1H, br d, JZ8.0 Hz), 4.67 (2H, s), 4.01 (1H, br s), 3.80
(1H, dd, JZ4, 10 Hz), 3.71 (1H, dd, JZ4, 11 Hz), 3.6–3.5
(4H, m), 1.44 (9H, s), 0.95 (2H, t, JZ9 Hz), 0.02 (9H, s);
dC (100 MHz; CDCl3) 155.4, 95.4, 80.2, 66.4, 65.8,
51.1, 44.3, 28.7, 18.4, K1.1. (Found: MHC, 340.1711.
C14H30NO345ClSi requires MH, 340.1711 (0.0 ppm)).
3.3.3. [3-(RS)-Hydroxy-3-phenyl-1-(S)-(2-trimethylsila-
nyl-ethoxymethoxymethyl)-propyl]-carbamic acid tert-
butyl ester 18. 162 mg, 98%. Crude ratio 3:2.
Diastereomer 1. Colourless oil; Rf 0.25 (1:1, petrol(40–60)–
Et2O); nmax(film)/cmK1 3422 (OH), 2954, 2894 (CH), 1689
(CO); [a]2D1ZK0.3 (c 0.6, CHCl3); dH (400 MHz; CDCl3)
7.5–7.2 (5H, m), 5.29 (1H, br d, JZ8 Hz), 4.8–4.6 (3H, m),
4.46 (1H, d, JZ3.5 Hz), 4.10 (1H, br s), 3.7–3.5 (4H, m),
1.93 (1H, m), 1.75 (1H, m), 1.48 (9H, s), 0.93 (2H, t, JZ
8.5 Hz), 0.00 (9H, s); dC (100 MHz; CDCl3) 156.3, 144.1,
128.2, 127.0, 125.5, 95.2, 80.1, 70.8, 69.9, 65.4, 47.5, 43.3,
28.3, 18.0, K1.5. (Found: MHC, 412.2519. C21H37NO5Si
requires MH, 412.2519 (0.0 ppm)).
Diastereomer 2. Colourless oil; Rf 0.12 (1:1, petrol(40–60)–
Et2O); nmax(film)/cmK1 3373 (OH), 2953, 2893 (CH), 1696
(CO); [a]2D1ZC17.0 (c 0.3, CHCl3); dH (400 MHz; CDCl3)
7.4–7.2 (5H, m), 5.10 (1H, br d), 4.78 (1H, t, JZ6.5 Hz),
4.65 (2H, s), 3.89 (1H, br s), 3.7–3.5 (4H, m), 3.26 (1H, br
s), 1.97 (2H, t, JZ6.5 Hz) 1.43 (9H, s), 0.93 (2H, t, JZ
8.5 Hz), 0.00 (9H, s); dC (100 MHz; CDCl3) 155.8, 144.6,
128.4, 127.4, 125.7, 95.1, 79.5, 72.0, 70.2, 65.4, 48.6, 42.0,
28.4, 18.0, K1.5.
3.3. General lithiation procedure
n-BuLi (0.21 mL, 0.42 mmol, 1.98 M solution in hexanes,
1.1 equiv) was added dropwise to a stirred solution of
chloride 11d (128 mg, 0.38 mmol, 1.0 equiv) in THF (5 mL,
w12 mL/mmol) at K78 8C under an atmosphere of argon.
Stirring was continued for 15 min, followed by the dropwise
addition of LiNp14 (2.2 mL, 1.1 mmol, 0.5 M solution in
THF, 2.5–3.0 equiv) over 5 min. The dark solution was
stirred at K78 8C for 2 h. Subsequently electrophile
(1.1 mmol, 1.5–3.0 equiv) was added dropwise to the
solution causing decolourisation. The reaction mixture
was kept cold (ca. K78 to K40 8C) overnight then
quenched with a saturated solution of ammonium chloride
(w1 mL) and allowed to warm to room temperature. The
reaction was diluted with ether (20 mL) and saturated
3.3.4. [3-Oxo-1-(S)-(2-trimethylsilanyl-ethoxymethoxy-
methyl)-butyl]-carbamic acid tert-butyl ester 21.
170 mg, 82%. Colourless oil; Rf 0.09 (2:1, petrol(40–60)–
Et2O); nmax(film)/cmK1 3348 (NH), 2954 (CH), 1715 (CO);
[a]2D1ZK2.3 (c 1.2, CHCl3); dH (400 MHz; CDCl3) 5.15
(1H, br d, JZ7 Hz), 4.63 (2H, s), 4.11 (1H, br m), 3.7–3.5

C. W. Barfoot et al. / Tetrahedron 61 (2005) 3403–3417
3411
(4H, m), 2.8–2.65 (2H, m), 2.15 (3H, s), 1.42 (9H, s), 0.93
(2H, t, JZ8.5 Hz), 0.02 (9H, s); dC (100 MHz; CDCl3)
207.5, 155.4, 95.3, 79.6, 69.2, 65.5, 47.1, 44.9, 30.5, 28.5,
18.2, K1.3. (Found: MHC, 348.2201. C16H33NO5Si
requires MH, 348.2206 (1.4 ppm)).
ester 33. 174 mg, 51%. Colourless oil; Rf 0.31 (9:1,
petrol(40–60)–Et2O); nmax(film)/cmK1 3350 (NH), 2954,
2914 (CH), 1716 (CO); [a]2D1ZK8.6 (c 0.9, CHCl3); dH
(400 MHz; CDCl3) 4.66–4.62 (3H, m), 3.92 (1H, bs),
3.63–3.59 (2H, m), 3.49–3.41 (2H, m), 1.60–1.25 (22H, m),
0.96–0.83 (19H, m), 0.02 (9H, s); dC (100 MHz; CDCl3)
155.1, 95.2, 79.1, 72.8, 65.3, 49.6, 29.3, 28.6, 27.5,
18.2, 13.8, 13.4, 9.4, K1.3. (Found: MHC, 592.3141.
C26H57NO4Si116Sn requires MH, 592.3153 (1.9 ppm)).
3.3.5. [3-Oxo-3-phenyl-1-(S)-(2-trimethylsilanyl-ethoxy-
methoxymethyl)-propyl]-carbamic acid tert-butyl ester
23. 214 mg, 80%. Colourless oil; Rf 0.39 (1:1, petrol(40–
60)–Et2O); nmax(film)/cmK1 3356 (NH), 2954 (CH), 1715,
1688 (2!CO); [a]2D1ZC6.6 (c 1.0, CHCl3); dH (400 MHz;
CDCl3) 7.96 (2H, d, JZ7.5 Hz), 7.56 (1H, t, JZ7.5 Hz),
7.45 (2H, t, JZ7.5 Hz), 5.32 (1H, br d, JZ7.5 Hz), 4.63
(2H, s), 4.28 (1H, br m), 3.75 (1H, dd, JZ4, 9.5 Hz), 3.64
(1H, dd, JZ5, 9.5 Hz), 3.54 (2H, t, JZ8.5 Hz), 3.36 (1H, br
m), 3.23 (1H, dd, JZ7, 16.5 Hz), 1.42 (9H, s) 0.89 (2H, t,
JZ8.5 Hz), K0.03 (9H, s); dC (100 MHz; CDCl3) 199.0,
155.6, 137.2, 133.6, 129.0, 128.4, 95.5, 79.7, 69.3, 65.7,
47.7, 39.9, 28.7, 18.4, K1.1. (Found: MHC, 410.2362.
C21H35NO5Si requires MH, 410.2363 (0.3 ppm)).
3.3.10.
[2-(R)-(tert-Butoxycarbonylamino-3-(2-tri-
methylsilanyl-ethoxymethoxy)-propyl]-phosphonic acid
diethyl ester 34. 136 mg, 70%. Colourless oil; Rf 0.32 (2:1,
EtOAc–petrol(40–60)); nmax(film)/cmK1 3298 (NH), 2978,
2955, 2931 (CH), 1714 (CO), 1249 (PZO), 1174 (PO);
[a]2D1ZK8.8 (c 1.2, CHCl3); dH (400 MHz; CDCl3) 5.23
(1H, br d, JZ6.0 Hz), 4.64 (2H, s), 4.10–4.05 (5H, m), 3.69
(1H, dd, JZ4.0, 10.0 Hz), 3.67–3.54 (3H, m), 2.08 (2H,
dd, JZ6.0, 18.0 Hz), 1.40 (9H, s), 1.29 (6H, t, JZ7.0 Hz),
0.95 (2H, t, JZ8.5 Hz) 0.02 (9H, s); dC (100 MHz; CDCl3)
3
155.1, 95.3, 79.5, 69.7 (d, JC,PZ7.5 Hz), 65.5, 61.9
2
2
(d, JC,PZ7.0 Hz), 61.8 (d, JC,PZ6.0 Hz), 46.4, 27.8
3.3.6. 3-(S)-tert-Butoxycarbonylamino-4-(2-trimethyl-
silanyl-ethoxymethoxy)-butyric acid methyl ester 25.
An excess of TMSCHN2 (w1.2 equiv, 2 M in ether) was
added to the crude carboxylic acid in MeOH–PhMe at 0 8C.
The reaction was then evaporated delivering the crude ester,
which was purified on silica gel.
1
3
(d, JC,PZ131.0 Hz), 18.1, 16.5 (d, JC,PZ6.0 Hz) K1.3.
(Found: MHC, 442.2386. C19H40NO7SiP requires MH,
442.2390 (0.9 ppm)).
3.4. General SEM deprotection procedure
102 mg, 70%. Colourless oil; Rf 0.16 (2:1, petrol(40–60)–
Et2O); nmax(film)/cmK1 3356 (NH), 2954 (CH), 1741, 1718
(2!CO); [a]2D1ZK2.2 (c 0.9, CHCl3); dH (400 MHz;
CDCl3) 5.19 (1H, br d, JZ8 Hz), 4.65 (2H, s), 4.13 (1H,
br s), 3.67 (3H, s), 3.65–3.5 (4H, m), 2.7–2.5 (2H, m), 1.43
(9H, s), 0.93 (2H, t, JZ8.5 Hz), 0.02 (9H, s); dC (100 MHz;
CDCl3) 172.0, 155.3, 95.3, 79.6, 69.1, 65.5, 51.8, 47.4, 36.2,
28.5, 18.2, K1.3. (Found: MHC, 364.2154. C16H33NO6Si
requires MH, 364.2155 (0.4 ppm)).
0.1 M HCl18 in methanol (2 mL, w6 mL/mmol) was added
to a SEM-ether (0.28 mmol). The subsequent reaction
mixture was stirred at room temperature for 3 h. Excess
triethylamine (w0.1 mL) was then added and the volatiles
were removed under reduced pressure to deliver a crude
mixture, this was then purified by flash column chroma-
tography on silica gel, eluting with diethyl ether to give the
product.
3.3.7. [2-Trimethylsilanyl-1-(R)-(2-trimethylsilanyl-
ethoxymethoxymethyl)-ethyl]-carbamic acid tert-butyl
ester 27. 158 mg, 78%. Colourless oil; Rf 0.11 (6:1,
petrol(40–60)–Et2O); nmax(film)/cmK1 3360 (NH), 2954,
2897 (CH), 1716 (CO); [a]2D1ZK11.6 (c 1.0, CHCl3); dH
(400 MHz; CDCl3) 4.7–4.65 (3H, m), 3.88 (1H, br s), 3.61
(2H, m), 3.55–3.4 (2H, m), 1.43 (9H, s), 0.94 (2H, m), 0.85
(2H, d, JZ7 Hz), 0.04 (9H, s), 0.02 (9H, s); dC (100 MHz;
CDCl3) 155.0, 95.1, 79.0, 72.5, 65.2, 47.7, 28.5, 20.6, 18.1,
K1.0, K1.4. (Found: MHC, 378.2497. C17H39NO4Si2
requires MH, 378.2496 (K0.4 ppm)).
3.4.1. [2-(1-Hydroxy-cyclohexyl)-1-(S)-hydroxymethyl-
ethyl]-carbamic acid tert-butyl ester 13e. 62 mg, 79%,
9% s.m. recovered, 88% b.s.m.r. Colourless oil; Rf 0.20
(Et2O); nmax(film)/cmK1 3348 (OH), 2933, 2861 (CH), 1689
(CO); [a]2D1ZK5.8 (c 0.8, CHCl3); dH (270 MHz; CDCl3)
5.31 (1H, br s), 3.83 (1H, br m), 3.66 (1H, dd, JZ5, 11 Hz),
3.58 (1H, dd, JZ4, 11 Hz), 1.7–1.35 (21H, m); dC
(67.5 MHz; CDCl3) 156.2, 79.8, 71.1, 66.4, 49.2, 43.1,
38.0, 37.8, 28.4, 25.6, 22.2, 22.1. (Found: MHC, 274.2016.
C14H27NO4 requires MH, 274.2018 (0.8 ppm)).
3.4.2. [2-(1-Hydroxy-cyclobutyl)-1-(S)-hydroxymethyl-
ethyl]-carbamic acid tert-butyl ester 16. 86 mg, 65%,
11% s.m. recovered, 76% b.s.m.r. Colourless oil; Rf 0.20
(Et2O); nmax(film)/cmK1 3339 (OH), 2980, 2935 (CH), 1682
(CO); [a]2D1ZK0.5 (c 0.4, CHCl3); dH (400 MHz; CDCl3)
5.22 (1H, br s), 4.27 (1H, br s), 3.81 (1H, br m), 3.51 (2H, br
m), 3.45 (1H, br s), 2.15–2.05 (2H, m), 1.89 (1H, dd, JZ9,
14 Hz), 1.85–1.7 (2H, m), 1.58 (1H, m), 1.42 (9H, s); dC
(100 MHz; CDCl3) 156.8, 80.0, 73.9, 65.7, 49.4, 41.2, 36.2,
35.8, 28.4, 12.7. (Found: MHC, 246.1703. C12H23NO4
requires MH, 246.1705 (0.9 ppm)).
3.3.8. [1-(S)-Deuteromethyl-2-(2-trimethylsilanyl-ethoxy-
methoxy)-ethyl]-carbamic acid tert-butyl ester 30.
101 mg, 87%. Colourless oil; Rf 0.40 (2:1, petrol(40–60)–
Et2O); nmax(film)/cmK1 3351 (NH), 2954 (CH), 1715 (CO);
[a]2D1ZK13.6 (c 1.0, CHCl3); dH (400 MHz; CDCl3) 4.78
(1H, br s), 4.65 (2H, s), 3.91 (1H, br s), 3.60 (2H, t, JZ
8.5 Hz), 3.48 (2H, m), 1.42 (9H, s), 1.15 (2H, m), 0.93 (2H,
t, JZ8.5 Hz), 0.00 (9H, s); dC (100 MHz; CDCl3) 155.5,
92.2, 79.2, 71.4, 65.3, 46.3, 28.5, 18.2, 17.8 (t, JZ19.8 Hz,
CH2D), K1.3. (Found: MHC, 307.2162. C14H31NDO4Si
requires MH, 307.2163 (0.5 ppm)).
3.4.3. (3-(RS)-Hydroxy-1-(S)-hydroxymethyl-3-phenyl-
propyl)-carbamic acid tert-butyl ester 19. 87 mg, 64%,
15% s.m. recovered, 79% b.s.m.r.
3.3.9. [2-Tributylstannanyl-1-(R)-(2-trimethylsilanyl-
ethoxymethoxymethyl)-ethyl]-carbamic acid tert-butyl

3412
C. W. Barfoot et al. / Tetrahedron 61 (2005) 3403–3417
Diastereomer 1. Colourless oil; Rf 0.29 (Et2O);
nmax(film)/cmK1 3382 (NH, OH), 2978, 2932 (CH), 1683
(CO); [a]2D1ZK7.5 (c 2.0, CHCl3); dH (400 MHz; CDCl3)
7.4–7.2 (5H, m), 5.18 (1H, br d, JZ7.5 Hz), 4.73 (1H, br d,
JZ8.5 Hz), 4.11 (1H, br s), 3.95 (1H, br m), 3.72 (1H, br d,
JZ8.5 Hz), 3.63 (1H, dd, JZ4, 10.5 Hz), 2.60 (1H, br s),
1.82 (2H, m), 1.46 (9H, s); dC (100 MHz; CDCl3) 157.3,
144.1, 128.4, 127.3, 125.5, 80.2, 70.4, 65.4, 49.7, 42.3, 28.3.
(Found: MHC, 282.1711. C15H24NO4 requires MH,
282.1705 (K1.8 ppm)).
62.1 (d, 2JC,PZ5.0 Hz), 62.1 (d, 2JC,PZ5.0 Hz), 48.3, 28.5,
1 3
27.8 (d, JC,PZ133.5 Hz), 16.5 (d, JC,PZ6.0 Hz). (Found:
MHC, 312.1576. C12H26NO6P requires MH, 312.1576
(0.0 ppm)).
3.5. General oxidation procedures
3.5.1. Method A. PDC (1.1 mmol, 6 equiv) was added to a
stirred solution of the diol (0.18 mmol, 1 equiv) in
anhydrous dimethylformamide (1.5 mL, w8 mL/mmol).
The reaction mixture was stirred for 6 h, then water
(5 mL) was added and the mixture was extracted with
dichloromethane (2!15 mL). The combined extracts were
then washed with water (2!20 mL) and brine (20 mL), then
dried (MgSO4) and evaporated under reduced pressure. The
crude residue was purified on silica gel, eluting with
petrol(40–60)–Et2O 1:1, delivering the product.
Diastereomer 2. Colourless oil; Rf 0.17 (Et2O); nmax(film)/
cmK1 3358 (NH, OH), 2976, 2931 (CH), 1686 (CO);
[a]2D1ZC33.8 (c 0.8, CHCl3); dH (400 MHz; CDCl3) 7.35–
7.25 (5H, m), 5.25 (1H, br s), 4.84 (1H, br d, JZ7 Hz), 3.78
(1H, br s), 3.67 (2H, br s), 3.30 (1H, br s), 2.03 (1H, ddd, JZ
4.6, 15 Hz), 1.92 (1H, ddd, JZ6.5, 9, 15 Hz), 1.45 (9H, s);
dC (100 MHz; CDCl3) 156.5, 144.4, 128.8, 127.9, 125.8,
79.9, 71.9, 65.9, 51.0, 41.3, 28.5. (Found: MHC, 282.1700.
C15H24NO4 requires MH, 282.1705 (2.0 ppm)).
3.5.1.1. (S)-(2-Oxo-1-oxa-spiro[4.5]dec-4-yl)-carba-
mic acid tert-butyl ester 14. Method A (34 mg, 69%)
white foam; Rf 0.20 (1:1, petrol(40–60)–Et2O); nmax(film)/
cmK1 3365 (NH), 2937, 2863 (CH), 1778, 1697 (2!CO);
[a]2D1ZC17.7 (c 1.1, CHCl3); dH (400 MHz; CDCl3) 5.05
(1H, br s), 4.51 (1H, br s), 2.73 (1H, br t, JZ10 Hz), 1.8–1.4
(20H, m); dC (100 MHz; CDCl3) 175.0, 155.8, 84.9, 80.8,
51.0, 41.4, 38.6, 36.1, 28.6, 25.2, 22.9, 22.8. (Found:
MNHC4 , 287.1977. C14H23NO4 requires MNH4, 287.1971
(K2.1 ppm)).
3.4.4. (S)-(5-Oxo-tetrahydro-furan-3-yl)-carbamic acid
tert-butyl ester 26. Crude mixture was treated with CSA
(w10 mol%) in benzene at 80 8C overnight. Evaporation
and purification on silica gel, eluting with Et2O–petrol(40–
60) 1:2, gave the product (27 mg, 50%, 15% s.m. recovered,
65% b.s.m.r.). Colourless blades, mp 109–110 8C (Et2O),
(lit.19b 113–114 8C); nmax(film)/cmK1 3317 (NH), 1767,
1
1687 (CO); [a]2D1ZK64.2 (c 0.5, CHCl3); H NMR was
identical to that reported in the literature.19b
3.5.1.2. (S)-(6-Oxo-5-oxa-spiro[3.4]oct-7-yl)-carbamic
acid tert-butyl ester 17. Method A (63 mg, 74%)
amorphous solid; nmax(film)/cmK1 3321 (NH), 2976, 2945
(CH), 1761, 1712 (2!CO); [a]2D1ZC1.2 (c 1.1, CHCl3); dH
(400 MHz; CDCl3) 5.06 (1H, br s), 4.41 (1H, br m), 2.95
(1H, br m), 2.63 (1H, q, JZ10 Hz), 2.36 (1H, q, JZ10 Hz),
2.25–1.95 (3H, m), 1.88 (1H, m), 1.67 (1H, m), 1.45 (9H, s);
dC (100 MHz; CDCl3) 174.8, 155.8, 83.2, 80.9, 50.9, 41.5,
34.6, 28.7, 28.3, 12.7. (Found: MHC, 242.1398. C12H19NO4
requires MH, 242.1392 (K2.3 ppm)).
3.4.5. (1-(R)-Hydroxymethyl-2-trimethylsilanyl-ethyl)-
carbamic acid tert-butyl ester 28. 71 mg, 72%. Colourless
oil; Rf 0.48 (Et2O); nmax(film)/cmK1 3256 (OH), 2954 (CH),
1695 (CO); [a]2D1ZK14.6 (c 0.8, CHCl3); dH (400 MHz,
CDCl3) 4.51 (1H, br s), 3.79 (1H, br s), 3.63 (1H, br d, JZ
9 Hz), 3.44 (1H, dd, JZ6.5, 10.5 Hz), 2.47 (1H, br s), 1.44
(9H, s), 0.74 (2H, m), 0.05 (9H, s); dC (100 MHz; CDCl3)
156.6, 80.0, 69.1, 50.6, 28.8, 20.1, K0.72. (Found: MHC,
248.1679. C11H25NO3Si requires MH, 248.1682 (1.2 ppm)).
3.5.2. Method B. PDC (1.2 mmol, 6 equiv) was added to a
stirred solution of alcohol (0.29 mmol, 1 equiv) in anhy-
drous dimethylformamide (3 mL, w8 mL/mmol). The
reaction mixture was stirred for 18 h, then quenched with
water (5 mL) and extracted with EtOAc (2!20 mL). The
combined extracts were then washed with water (2!
20 mL) and brine (20 mL), then dried (MgSO4) and
evaporated under reduced pressure to deliver the crude
carboxylic acid. This was then dissolved in MeOH–toluene
(3 mL, 1:1) and treated with TMSCHN2 (0.29 mL,
0.58 mmol, 2.0 M solution in hexanes) at 0 8C. The reaction
was stirred for 1 h then all volatiles were removed under
reduced pressure to deliver a crude mixture, which was then
purified by flash column chromatography on silica gel,
eluting with Et2O–petrol(40–60) 1:2 to give the product.
3.4.6. (2-Hydroxy-1-(S)-deuteromethyl-ethyl)-carbamic
acid tert-butyl ester 31. 34 mg, 70%. Colourless oil; Rf
0.42 (Et2O); nmax(film)/cmK1 3361 (OH), 2978, 2936 (CH),
1690 (CO); [a]2D1ZK12.6 (c 1.1, CHCl3); dH (400 MHz;
CDCl3) 4.71 (1H, br s), 3.68 (1H, br s), 3.55 (1H, m), 3.43
(1H, dd, JZ6.0, 10.5 Hz), 3.00 (1H, br s), 1.38 (9H, s), 1.07
(2H, m); dC (100 MHz; CDCl3) 156.6, 79.8, 67.4, 48.6, 28.5,
17.2 (t, JZ19 Hz, CH2D). (Found: MHC, 177.1353.
C8H17NDO3 requires MH, 177.1350 (2.2 ppm)).
3.4.7. (2-(R)-tert-Butoxycarbonylamino-3-hydroxy-pro-
pyl)-phosphonic acid diethyl ester 35. 0.1 M HCl in
ethanol was employed in this deprotection using the general
procedure described above. (54 mg, 66%, 10% s.m.
recovered, 76% b.s.m.r.). Colourless oil; Rf 0.30 (9:1,
EtOAc–MeOH); nmax(film)/cmK1 3358 (OH, NH), 2978,
2933 (CH), 1713 (CO), 1249 (PZO), 1172 (PO); [a]2D1Z
C14.9 (c 0.7, CHCl3); dH (400 MHz; CDCl3) 5.23 (1H, br d,
JZ8.0 Hz), 4.11–4.07 (4H, m), 3.94–3.89 (1H, m), 3.78
(1H, dd, JZ4.0, 11.5 Hz), 3.66 (1H, dd, JZ4.0, 11.5 Hz),
2.21–2.01 (2H, m), 1.41 (9H, s), 1.31 (6H, t, JZ7.0 Hz); dC
3.5.2.1. 2-(S)-tert-Butoxycarbonylamino-4-oxo-4-phe-
nyl-butyric acid methyl ester 20. Method B (36 mg,
47%) colourless oil; Rf 0.25 (1:1, petrol(40–60)–Et2O);
nmax(film)/cmK1 3383 (NH), 2979, 2932 (CH), 1748, 1714
(2!CO); [a]2D1ZC59.9 (c 1.1, DCM); H NMR spectrum
1
identical to literature.20 m/z 308 (10, MC), 252 (40,
MKtBu), 208 (100, MKBoc).
3
(100 MHz; CDCl3) 155.7, 79.7, 64.8 (d, JC,PZ6.0 Hz),

C. W. Barfoot et al. / Tetrahedron 61 (2005) 3403–3417
3413
3.5.2.2. 2-(R)-tert-Butoxycarbonylamino-3-trimethyl-
silanyl-propionic acid methyl ester 29. Method B (54 mg,
68%) colourless waxy solid, mp 40–42 8C; Rf 0.34 (2:1,
petrol(40–60)–Et2O); nmax(film)/cmK1 3373 (NH), 2977,
2955 (CH), 1745, 1715 (2!CO); [a]2D1ZC10.8 (c 1.2,
CHCl3); dH (400 MHz; CDCl3) 4.84 (1H, br s), 4.28 (1H, br
m), 3.67 (3H, s), 1.37 (9H, s), 1.05 (1H, dd, JZ6, 9.5 Hz),
0.88 (1H, dd, JZ9.5, 14.5 Hz), 0.00 (9H, s); dC (100 MHz;
CDCl3) 174.3, 154.9, 79.8, 52.1, 50.6, 28.4, 21.4, K1.3.
(Found: MHC, 276.1633. C12H25NO4Si requires MH,
276.1631 (K0.6 ppm)).
3.6.1. 2-(S)-Amino-4-oxo-4-phenyl-butyric acid hydro-
chloride 37. 24 mg, 92%. White powder, mp w200 8C
decomposed (lit.21 mp 207–209 8C decomposed); [a]2D1Z
C35.6 (c 0.104, 6 M HCl), lit.21 [a]DZC34.7 (c 0.098,
1
6 M HCl); H NMR spectrum identical to literature.21
3.6.2. (R)-Trimethylsilanylalanine hydrochloride 38.
31 mg, 80%. White solid, mp w180 8C decomposed;
[a]2D2ZC35.2 (c 1.1, 1 M HCl), lit.23 [a]DZC31 (c 0.51,
4 M HCl); dH (400 MHz; D2O) 4.01 (1H, dd, JZ5.5,
10.5 Hz), 1.22 (1H, dd, JZ10.5, 14.5 Hz), 1.16 (1H, dd, JZ
5.5, 14.5 Hz), 0.08 (9H, s); dC (100 MHz; D2O) 17.3, 51.7,
19.3, K2.3; m/z (ESI) 176 (100%, MC), 162 (35%, MKCl).
3.5.2.3. 2-(R)-tert-Butoxycarbonylamino-3-(diethoxy-
phosphoryl)-propionic acid methyl ester 36. Method B
(61 mg, 60%) colourless oil, Rf 0.50 (9:1, EtOAc–MeOH);
nmax(film)/cmK1 3371 (NH), 2982, 2929 (CH), 1751 (CO),
1716 (CO), 1249 (PZO), 1166 (PO); [a]2D1ZC12.8 (c 1.0,
CHCl3); dH (400 MHz; CDCl3) 5.68 (1H, br d, JZ7.5 Hz),
4.58–4.46 (1H, m), 4.10–4.03 (4H, m), 3.73 (3H, s), 2.34–
2.27 (2H, m), 1.41 (9H, s), 1.29 (6H, t, JZ7.0 Hz); dC
3.6.3. (S)-Deuteroalanine hydrochloride 39. 31 mg, 95%.
Off-white wax; [a]2D1ZC11.7 (c 1.2, 6 M HCl); dH
(400 MHz, D2O) 4.09 (1H, t, JZ7.5 Hz), 1.50 (2H, d, JZ
7.5 Hz); dC (100 MHz; D2O) 172.8, 48.7, 15.0 (t, JZ20 Hz,
CH2D). (Found: MKClC, 91.0620. C3H7NClO2D requires
MKCl, 91.0618 (1.9 ppm)).
3
(100 MHz; CDCl3) 171.5 (d, JC,PZ8.0 Hz), 155.3, 80.2,
2
2
62.1 (d, JC,PZ4.0 Hz), 62.1 (d, JC,PZ3.0 Hz), 52.7, 49.2
3.6.4. 2-(S)-Amino-3-phosphono-propionic acid 40. The
protected amino acid 36 (61 mg, 0.18 mmol) was heated
with 6 M HCl (w3 mL) under reflux for 21 h. After cooling,
the aqueous phase was diluted with water (5 mL) and
washed with ethyl acetate (2!5 mL). The aqueous phase
was then evaporated under reduced pressure delivering an
off-white solid which was triturated with diethyl ether. After
decanting and drying, the salt was obtained as an off-white
solid. Propylene oxide (w1 mL) was added dropwise to a
suspension of the salt in EtOH (w1 mL) at 0 8C and the
resulting mixture was stirred at room temperature for 18 h.
The solvent was removed under reduced pressure delivering
a white solid. Recrystallisation from 50% EtOH/H2O
followed by trituration with EtOH gave the phosphate 40
(18 mg, 59%) as a white solid, mp w225 8C decomposed,
lit.24b 224–226 8C decomposed; [a]2D1ZC16.3 (c 0.4, 1 M
NaOH), lit.24b [a]D24ZC13.8 (c 2, 1 M NaOH); dH
(d, 2JC,PZ5.0 Hz), 28.4, 28.0 (d, 1JC,PZ141.5 Hz), 16.5 (d,
3JC,PZ2.0 Hz), 16.4 (d, JC,PZ2.0 Hz). (Found: MHC,
340.1523. C13H26NO7P requires MH, 340.1525 (0.6 ppm)).
3
3.5.3. Method C.
3.5.3.1. (S)-N-Boc-deuteroalanine methyl ester 32.
Ruthenium chloride (4 mg, 21 mmol, 5 mol%) was added
to a stirred suspension of alcohol 31 (75 mg, 0.43 mmol)
and sodium periodate (273 mg, 1.28 mmol) in CH3CN–
H2O–CCl4 (3 mL, 2:3:2) at room temperature. The reaction
mixture went dark after 30 min. Stirring was continued for
12 h in total then the reaction was diluted with a saturated
solution of ammonium chloride (10 mL) and EtOAc
(10 mL). After separation the aqueous was extracted again
with EtOAc (2!10 mL). The combined organic extracts
were dried (MgSO4) and evaporated under reduced pressure
to deliver the crude carboxylic acid. This was then dissolved
in MeOH–toluene (2 mL, 1:1) and treated with TMSCHN2
(0.42 mL, 0.85 mmol, 2.0 M solution in hexanes) at 0 8C.
The reaction was stirred for 1 h then all volatiles were
removed under reduced pressure to deliver a crude mixture,
which was then purified by flash column chromatography on
silica gel, eluting with Et2O–petrol(40–60) 1:2 to give the
protected amino acid 32 (53 mg, 61%) as a colourless oil; Rf
0.20 (2:1, petrol(40–60)–Et2O); nmax(film)/cmK1 3382
(NH), 2980 (CH), 1748, 1716 (2!CO); [a]2D1ZK43.5 (c
1.4, CHCl3); dH (400 MHz; CDCl3) 5.03 (1H, br s), 4.31
(1H, br m), 3.74 (3H, s), 1.44 (9H, s), 1.36 (2H, br d, JZ
7.5 Hz); dC (100 MHz; CDCl3) 174.0, 155.2, 80.0, 52.3,
49.2, 28.5, 18.6 (t, JZ20 Hz, CH2D). (Found: MHC,
205.1296. C9H17NDO4 requires MH, 205.1299 (1.3 ppm)).
(400 MHz; D2O) 4.17–4.12 (1H, m), 2.36–2.26 (1H, m),
3
2.14–2.04 (1H, m); dC (100 MHz; D2O) 172.1 (d, JC,P
Z
Z
2
1
13.0 Hz), 49.9 (d, JC,PZ4.5 Hz), 28.2 (d, JC,P
131.0 Hz); m/z ESI (Kve) 168 ([MKHC]K, 100%).
3.7. Synthesis of aspartic acid mimic 44
3.7.1.
[2-Borono-1-(S)-(2-trimethylsilanyl-ethoxy-
methoxymethyl)-ethyl]-carbamic acid tert-butyl ester
41. n-BuLi (0.48 mL, 0.95 mmol, 1.97 M solution in
hexanes) was added dropwise to a stirred solution of
chloride 11d (291 mg, 0.89 mmol) in THF (5 mL) at
K78 8C under an atmosphere of argon. Stirring was
continued for 15 min, followed by the dropwise addition
of LiNp (5.7 mL, 2.83 mmol, 0.5 M solution in THF) over
5 min. The dark solution was stirred at K78 8C for 2 h.
Subsequently triisopropylborate (0.5 mL, 2.15 mmol) was
added dropwise to the solution. The reaction mixture was
kept cold (ca. K78 to K40 8C) overnight then quenched
with a saturated solution of ammonium chloride (1 mL),
then allowed to warm to room temperature. To the mixture
was then added an aqueous solution of 0.5 M HCl (5 mL,
saturated with NaCl), and stirring was continued for 30 min.
The solution was then extracted with petrol(40–60) (3!
20 mL). The combined organics were then extracted with
3.6. General amino acid deprotection procedure
The protected amino acid (w50 mg, 0.25 mmol) was heated
at 70 8C with 4.5 M HCl (w2 mL) for 3 h. After cooling, the
aqueous phase was diluted with water (10 mL) and washed
with diethyl ether (10 mL). The aqueous phase was then
evaporated under reduced pressure delivering a solid which
was triturated with diethyl ether. After decanting and
drying, the product was obtained.

3414
C. W. Barfoot et al. / Tetrahedron 61 (2005) 3403–3417
2 M NaOH (3!15 mL). These extracts were combined and
acidified (wpH 1–2) with 4.5 M HCl, then extracted again
with Et2O (3!30 mL). The final combined organics were
dried (MgSO4), filtered and evaporated under reduced
pressure to give the boronic acid 41 (238 mg, 80%) as a light
yellow oil. dH (400 MHz; acetone-d6) 6.95–6.8 (1H, br),
6.55–6.45 (1H, br), 5.88 (1H, br s), 4.63 (2H, s), 3.88 (1H, br
m), 3.63 (2H, m), 3.53 (1H, dd, JZ5.5, 9.5 Hz), 3.47 (1H,
dd, JZ5.5, 9.5 Hz), 1.5–1.35 (9H, several singlets), 1.07
(1H, dd, JZ6, 16 Hz), 1.00 (2H, m), 0.05–0.00 (9H, several
singlets). Due to the many possible solution structures of the
boronic acid, the compound was better characterised as the
boronate ester 42.
(10 mL), dried (Na2SO4) and evaporated. The crude mixture
was then dissolved in t-butanol (3 mL) and treated with a
solution of 2-methyl-2-butene (1.5 mL, 3.1 mmol, 2 M in
THF). A solution of NaH2PO4 (167 mg, 1.07 mmol) and
NaClO2 (125 mg, 1.38 mmol) in water (2 mL) was added
and the reaction was stirred for 1 h. The t-butanol was
evaporated in vacuo and the residue was partitioned
between 0.5 M HCl (5 mL) and EtOAc (10 mL). After
separation and further extraction (EtOAc 2!5 mL), the
combined extracts were dried (MgSO4) and evaporated. The
subsequent residue was heated at 70 8C with 4.5 M HCl
(3 mL) for 3 h. After cooling the aqueous solution was
washed with dichloromethane (2!2 mL). The aqueous
solution was then evaporated in vacuo. The crude residue
was purified on silica gel, eluting with 2:1 EtOH–14 M NH3,
delivering the 2-amino-3-boronopropionic acid 44 (15 mg,
74%) as a white solid. After trituration with acetone the
product was obtained as a white powder, mp O290 8C
decomposed. dH (400 MHz; D2O) 3.94 (1H, br t, JZ
9.5 Hz), 1.08 (1H, br dd, JZ9.5, 13 Hz), 0.79 (1H, br dd,
JZ10.5, 12 Hz); dC (100 MHz; D2O) 178.0, 53.4, 20.4 (br);
3.7.2. [2-(K)-Pinaneboronate-1-(S)-(2-trimethylsilanyl-
ethoxymethoxymethyl)-ethyl]-carbamic acid tert-butyl
ester 42. (K)-Pinane diol (47 mg, 0.28 mmol) was added
to a stirred solution of 41 (88 mg, 0.25 mmol) and powdered
˚
4 A molecular sieves (w100 mg) in dry dichloromethane
(3 mL) under an atmosphere of argon. The reaction mixture
was stirred for 18 h then filtered and evaporated. The
subsequent residue was purified on silica gel, eluting with
petrol(40–60)–Et2O 3:1, delivering boronate ester 42
(113 mg, 95%) as a colourless oil; Rf 0.26 (3:1, petrol(40–
60)–Et2O); nmax(film)/cmK1 2926 (CH), 1718 (CO);
[a]2D1ZK200 (c 0.1, CHCl3); dH (400 MHz; CDCl3) 5.06
(1H, br d, JZ7 Hz), 4.65 (2H, s), 4.25 (1H, dd, JZ2, 9 Hz),
4.01 (1H, br s), 3.60 (2H, t, JZ8.5 Hz), 3.53 (2H, d, JZ
4.5 Hz), 2.32 (1H, m), 2.20 (1H, m), 2.03 (1H, t, JZ5 Hz),
1.9–1.8 (2H, m), 1.43 (9H, s), 1.37 (3H, s), 1.28 (3H, s),
1.2–1.05 (2H, m), 0.93 (2H, t, JZ8.5 Hz), 0.9–0.8 (4H, m),
0.02 (9H, s); dC (100 MHz; CDCl3) 155.4, 95.1, 85.8, 77.8,
71.5, 65.3, 51.4, 39.6, 38.3, 36.2, 35.6, 29.2, 28.7, 28.6,
27.2, 26.6, 24.2, 22.8, 18.2, K1.3. (Found: MHC, 484.3271.
C24H46NBO6Si requires MH, 484.3266 (K1.1 ppm)).
11
dB (160 MHz; D2O) 16.38; m/z ESI (-ve) 160 ([MK
HC]K, 75%), 343 ((2[MKHC]CNaC)K, 100%). HCl
salt30 [a]2D1ZC33.0 (c 0.2, 4.5 M HCl); dH (400 MHz,
D2O) 4.15 (1H, dd, JZ7, 10 Hz), 1.35 (1H, dd, JZ7,
15 Hz), 1.19 (1H, dd, JZ10, 15 Hz); dC (125 MHz; D2O)
11
175.3, 52.4, 18.6 (br); dB (160 MHz; D2O) 24.85.
3.8. General procedure for Suzuki coupling of boronic
acid 41
The boronic acid 41 (ca. 0.12 mmol), K2CO3 (3.0 equiv),
PdCl2(dppf).CH2Cl2 (0.09 equiv) and Ag2O (2.4 equiv)
were placed under Ar. Tetrahydrofuran (1.0 mL) and the
aryl halide (2 equiv) were added and the resulting mixture
was refluxed for 21 h. The reaction mixture was filtered
through a 0.5 cm pad of Celitee and eluted with diethyl
ether (40 mL). The filtrate was concentrated to afford an oil.
Subjection of this material to flash chromatography on silica
gel and concentration of the appropriate fractions provided
the coupled product.
3.7.3. (2-(K)-Pinaneboronate-1-(S)-hydroxymethyl-
ethyl)-carbamic acid tert-butyl ester 43. 0.1 M HCl in
methanol (2 mL, w6 mL/mmol) was added to SEM-ether
42 (99 mg, 0.21 mmol). The subsequent reaction mixture
was stirred at room temperature for 3 h. Excess triethyl-
amine (w0.1 mL) was then added and the volatiles were
removed under reduced pressure to deliver a crude mixture,
which was then purified by flash column chromatography on
silica gel, eluting with petrol(40–60)–Et2O 1:2 to give
starting material (4 mg, 4%) and the alcohol 43 (49 mg,
68%) as a colourless oil; Rf 0.51 (Et2O); nmax(film)/cmK1
3420 (OH), 2975, 2929, 2872 (CH), 1694 (CO); [a]2D1Z
K148 (c 0.9, CHCl3); dH (400 MHz; CDCl3) 5.01 (1H, br s),
4.24 (1H, d, JZ2, 9 Hz), 3.89 (1H, br s), 3.60 (1H, br d, JZ
10.5 Hz), 3.51 (1H, m), 2.31 (1H, m), 2.19 (1H, m), 2.02
(1H, m), 1.95–1.75 (2H, m), 1.41 (9H, s), 1.35 (3H, s), 1.26
(3H, s), 1.25 (1H, m), 1.15–1.0 (2H, m), 0.81 (3H, s).
(Found: MHC, 354.2452. C18H32NBO5 requires MH,
354.2452 (K0.2 ppm)).
3.8.1. [1-(S)-2-Phenyl-1-(2-trimethylsilanylethoxy-
methoxymethyl)ethyl]carbamic acid tert-butyl ester
(48a). 72%. Colourless oil; Rf 0.25 (4:1, petrol(40–60)–
Et2O); nmax/cmK1 (thin film) 3352, 2953, 1714, 1497;
[a]2D0ZK14.4 (c 1.1, CHCl3); dH (270 MHz, CDCl3) 7.31–
7.18 (complex m, 5H), 4.95 (1H, broad d, JZ7 Hz), 4.67
(2H, m), 3.94 (1H, br m), 3.63 (2H, m), 3.49 (1H, dd, JZ10,
4 Hz) 3.45 (1H, dd, JZ10, 4 Hz), 2.91 (1H, br dd, JZ13.5,
5 Hz), 2.82 (1H, dd, JZ13.5, 8 Hz), 1.41 (9H, s), 0.94 (2H,
m), 0.03 (9H, s); dC (100 MHz, CDCl3) 155.5, 138.3, 129.5,
128.5, 126.5, 95.4, 79.4, 68.6, 65.5, 51.8, 38.1, 28.5, 18.2,
K1.3. (Found (CIC) MHC, 382.2413. C20H36NO4Si
requires MHC, 382.2414 (0.0 ppm)).
3.7.4. 2-(S)-Amino-3-boronopropionic acid 44. Dess–
Martin periodinane (78 mg, 0.18 mmol) was added to a
stirred solution of 43 (54 mg, 0.15 mmol) in dichloro-
methane (2 mL) under an atmosphere of argon. After 2 h,
1 M sodium sulfite (5 mL) was added and the mixture was
extracted with Et2O (2!10 mL). The combined organic
extracts were washed with 1 M sodium hydrogen carbonate
3.8.2. [1-(S)-2-(4-Methoxyphenyl)-1-(2-trimethylsilanyl-
ethoxymethoxymethyl)ethyl]carbamic acid tert-butyl
ester (48b). 65%. Pale yellow oil; Rf 0.18 (3:1, petrol(40–
60)–Et2O); nmax/cmK1 (thin film) 3359, 2953, 1714, 1613,
1513, 1248, 1173; [a]2D0ZK13.1 (c 0.9, CHCl3); dH
(400 MHz, CDCl3) d 7.13 (2H, d, JZ8 Hz), 6.82 (2H, d,
JZ8 Hz), 4.92 (1H, br d, JZ8.0 Hz), 4.68 (2H, m), 3.89

C. W. Barfoot et al. / Tetrahedron 61 (2005) 3403–3417
3415
(1H, br m), 3.78 (3H, s), 3.63 (2H, m), 3.46 (2H, m), 2.86
(1H, dd, JZ13, 5 Hz), 2.75 (1H, dd, JZ13, 8 Hz), 1.42 (9H,
s), 0.95 (2H, m), 0.03 (9H, s); dC (100 MHz, CDCl3) 158.3,
155.5, 130.5, 130.3, 114.0, 95.4, 79.3, 68.6, 65.5, 55.4,
51.9, 37.1, 28.5, 18.2, K1.3. (Found (CIC): 412.2520.
C21H38NO5Si requires (MHC): 412.2519 (0.1 ppm)).
K1.3. (Found (CIC): 424.2536. C22H38NO5Si requires
(MHC): 424.2519 (3.9 ppm)).
3.8.7. [1-(S)-2-(4-Carbomethoxyphenyl)-1-(2-trimethyl-
silanylethoxymethoxymethyl)ethyl]carbamic acid tert-
butyl ester (48g). 52%. Colourless oil; Rf 0.26 (2:1,
petrol(40–60)–Et2O); nmax/cmK1 (thin film) 3365, 2953,
1723, 1612, 1504, 1280; [a]2D0ZK16.5 (c 1.4, CHCl3); dH
(400 MHz, CDCl3) d 7.95 (2H, d, JZ8 Hz), 7.29 (2H, d, JZ
8 Hz), 4.99 (1H, br d, JZ8 Hz), 4.67 (1H, d, JZ10.5 Hz),
4.65 (1H, d, JZ10.5 Hz), 3.96 (1H, br m), 3.90 (3H, s), 3.62
(2H, m), 3.46 (2H, d, JZ3.5 Hz), 2.96 (1H, dd, JZ13,
6.5 Hz), 2.89 (1H, dd, JZ13, 8 Hz), 1.40 (9H, s), 0.94 (2H,
m), 0.02 (9H, s); dC (68.5 MHz, CDCl3) 167.2, 155.4, 143.9,
129.8, 129.6, 128.5, 95.5, 79.5, 68.7, 65.6, 52.1, 51.6, 38.1,
28.5, 18.2, K1.3. (Found (CIC): 440.2468. C22H38NO6Si
requires (MHC): 440.2468 (0.0 ppm)).
3.8.3. [1-(S)-2-(4-Nitrophenyl)-1-(2-trimethylsilanyl-
ethoxymethoxymethyl)ethyl]carbamic acid tert-butyl
ester (48c). 65%. Colourless oil; Rf 0.30 (2:1, petrol(40–
60)–Et2O); nmax/cmK1 (thin film) 3412, 2953, 2894, 1714,
1604, 1522, 1346; [a]2D0ZK34.2 (c 1.4, CHCl3); dH
(400 MHz, CDCl3) d 8.14 (2H, d, JZ8.5 Hz), 7.39 (2H, d,
JZ8.5 Hz), 5.04 (1H, br d, JZ8 Hz), 4.67 (2H, m), 3.97
(1H, br m), 3.63 (2H, m), 3.50 (2H, d, JZ4 Hz), 3.02–2.92
(2H, complex m), 1.38 (9H, s), 0.94 (2H, m), 0.02 (9H, s);
dC (100 MHz, CDCl3) 155.4, 146.8, 146.4, 130.3, 123.7,
95.5, 79.7, 68.9, 65.7, 51.5, 38.2, 28.4, 18.2, K1.3. (Found
(CIC): 427.2266. C20H35N2O6Si requires (MHC): 427.2264
(0.5 ppm)).
3.8.8. [1-(S)-2-(Naphthalen-1-yl)-1-(2-trimethylsilanyl-
ethoxymethoxymethyl)ethyl]carbamic acid tert-butyl
ester (48h). 73%. Colourless oil; Rf 0.25 (4:1, petrol(40–
60)–Et2O); nmax/cmK1 (thin film) 3451, 3351, 2953, 2893,
1713, 1495; [a]2D0ZK34.1 (c 1.7, CHCl3); dH (400 MHz,
CDCl3) d 8.39–8.09 (1H, br m), 7.85 (1H, d, JZ8 Hz), 7.74
(1H, d, JZ8.5 Hz), 7.57 (1H, m), 7.48 (1H, m), 7.41–7.35
(2H, complex m), 5.17 (1H, br d, JZ7.5 Hz), 4.72–4.65
(2H, complex m), 4.13 (1H, br m), 3.73–3.62 (2H, complex
m), 3.54–3.18 (4H, complex m), 1.50–1.23 (9H, m), 0.96
(2H, m), 0.04 (9H, s); dC (100 MHz, CDCl3) 155.4, 134.6,
134.0, 132.5, 128.7, 127.8, 127.4, 126.4, 125.7, 125.5,
124.3, 95.6, 79.3, 68.6, 65.7, 51.1, 35.3, 28.5, 18.2, K1.3.
(Found (CIC): 432.2575. C24H38NO4Si requires (MHC):
432.2570 (1.0 ppm)).
3.8.4. [1-(S)-2-(2-Nitrophenyl)-1-(2-trimethylsilanyl-
ethoxymethoxymethyl)ethyl]carbamic acid tert-butyl
ester (48d). 70%. Pale yellow oil; Rf 0.17 (2:1, petrol(40–
60)–Et2O); nmax/cmK1 (thin film) 3351, 2954, 2892, 1713,
1610, 1528, 1453; [a]2D0ZK22.9 (c 1.0, CHCl3); dH
(400 MHz, CDCl3) d 7.91 (1H, d, JZ8 Hz), 7.52 (1H, dd,
JZ8 Hz, 7.5), 7.42–7.34 (2H, complex m), 5.03 (1H, br d,
JZ9 Hz), 4.68 (2H, m), 4.14 (1H, br m), 3.66–3.58 (4H,
complex m), 3.22 (1H, dd, JZ13.5, 5 Hz), 3.09 (1H, dd, JZ
13.5, 9.5 Hz), 1.30 (9H, s), 0.95 (2H, m), 0.03 (9H, s); dC
(100 MHz, CDCl3) 155.3, 150.1, 133.8, 132.9, 127.6, 124.9,
95.4, 79.3, 70.1, 65.6, 51.3, 35.4, 28.4, 18.2, K1.3 (one C
obscured). (Found (CIC): 427.2264. C20H35N2O6Si requires
(MHC): 427.2264 (0.0 ppm)).
3.8.9. 1,4-Bis-[2-(S)-20-(S)-2-(tert-butoxycarbonyla-
mino)-3-(2-trimethylsilanylethoxymethoxy)propyl]-ben-
zene (49). 35%. Colourless oil; Rf 0.09 (2:1, petrol(40–60)–
Et2O); nmax/cmK1 (thin film) 3350, 2952, 2894, 1713, 1514,
1503; [a]2D0ZK16.4 (c 0.7, CHCl3); dH (270 MHz, CDCl3)
d 7.13 (4H, s), 4.94 (2H, br d, JZ8 Hz), 4.66 (4H, m), 3.90
(2H, br m), 3.63 (4H, m), 3.46 (4H, d, JZ3.5 Hz), 2.86 (2H,
partially obscured dd, JZ13.5, 6.5 Hz), 2.78 (2H, dd, JZ
13.5, 8 Hz), 1.41 (18H, s), 0.94 (4H, m), 0.03 (18H, s); dC
(100 MHz, CDCl3) 155.5, 136.3, 129.6, 95.4, 79.3, 68.6,
65.5, 51.7, 37.6, 28.5, 18.2, K1.2. (Found (CIC): 707.4103.
C34H64N2O8Si2Na requires (MCNaC): 707.4099
(0.6 ppm)).
3.8.5. [1-(S)-2-(3-Nitrophenyl)-1-(2-trimethylsilanyl-
ethoxymethoxymethyl)ethyl]carbamic acid tert-butyl
ester (48e). 67%. Colourless oil; Rf 0.21 (2:1, petrol(40–
60)–Et2O); nmax/cmK1 (thin film) 3346, 2954, 2930, 2894,
1714, 1531, 1504, 1453; [a]2D0ZK19.8 (c 1.1, CHCl3); dH
(400 MHz, CDCl3) d 8.09–8.07 (2H, complex m), 7.59 (1H,
d, JZ7.3 Hz), 7.46 (1H, m), 5.04 (1H, broad d, JZ8.2 Hz),
4.68 (2H, m), 3.97 (1H, br m), 3.64 (2H, m), 3.51 (2H, m),
2.97 (2H, m), 1.37 (9H, s), 0.95 (2H, m), 0.02 (9H, s);
dC(100 MHz, CDCl3) 155.4, 148.4, 140.3, 135.8, 129.4,
124.4, 121.7, 95.5, 79.7, 68.9, 65.7, 51.6, 38.0, 28.4, 18.2,
K1.3. (Found (CIC): 427.2268. C20H35N2O6Si requires
(MHC): 427.2264 (0.9 ppm)).
3.9. Synthesis of phenylalanine hydrochloride 52
3.9.1. Deprotection of 48a.
3.8.6. [1-(S)-2-(4-Acetylphenyl)-1-(2-trimethylsilanyl-
ethoxymethoxymethyl)ethyl]carbamic acid tert-butyl
ester (48f). 68%. Colourless oil; Rf 0.21 (2:3, petrol(40–
60)–Et2O); nmax/cmK1 (thin film) 3352, 2954, 1712, 1681,
1607, 1517; [a]2D0ZK19.7 (c 1.5, CHCl3); dH (400 MHz,
CDCl3) d 7.88 (2H, d, JZ8 Hz), 7.32 (2H, d, JZ8 Hz), 5.00
(1H, br d, JZ8 Hz), 4.68 (1H, d, JZ10.5 Hz), 4.65 (1H, d,
JZ10.5 Hz), 3.96 (1H, br s), 3.63 (2H, m), 3.47 (2H, d, JZ
3.5 Hz), 2.98 (1H, dd, JZ13, 6.5 Hz), 2.90 (1H, dd, JZ13,
8 Hz), 2.58 (3H, s), 1.40 (9H s), 0.94 (2H, m), 0.03 (9H, s);
dC(100 MHz, CDCl3) 198.0, 155.4, 144.2, 135.6, 129.7,
128.6, 95.4, 79.5, 68.7, 65.6, 51.6, 38.2, 28.4, 26.7, 18.2,
3.9.1.1. [1-(S)-2-Phenyl-1-(hydroxymethyl)ethyl]car-
bamic acid tert-butyl ester (50). The SEM-protected
phenylalaninol 48a (54 mg, 0.14 mmol) was treated with a
0.1 M solution of HCl in MeOH (1.4 mL). After 8 h stirring
under N2 at room temperature, the reaction mixture was
concentrated under reduced pressure to a white solid. To this
residue was added THF (0.70 mL), triethylamine
(0.060 mL, 0.43 mmol) and di-tert-butyldicarbonate
(43 mg, 0.20 mmol) and the resulting mixture was stirred
under N2 at room temperature for 16 h. Water (10 mL) was
added and the aqueous layer was extracted with EtOAc (3!
10 mL). The combined organic phases were washed with

3416
C. W. Barfoot et al. / Tetrahedron 61 (2005) 3403–3417
brine (10 mL), then dried (MgSO4), filtered and concen-
trated under reduced pressure to afford a yellow oil.
Subjection of this material to flash chromatography (2:1,
Et2O–petroleum(40–60) elution) provided the title com-
pound as a white solid (27 mg, 75%), mp 94–95 8C (lit.37
were mixed and heated at 70 8C for 5 h. The resulting
mixture was then cooled to room temperature and treated
with water (15 mL). The aqueous phase was washed with
EtOAc (2!15 mL) and the separated aqueous layer was
concentrated under reduced pressure to a white solid
(22 mg, 100%), mp (dec.) 215–216 8C [lit.36 mp 241–
243 8C]. nmax/cmK1 (thin film) 3385, 2947, 2616, 1731,
1605, 1485; [a]D20ZK8.1 (c 0.91, H2O) [lit.36 [a]2D0ZK8.2
(c 1, H2O)]; dH (400 MHz, CDCl3) d 7.42–7.32 (3H,
complex m), 7.30 (2H, d, JZ7.5 Hz), 4.25 (1H, dd, JZ7.5,
5.5 Hz), 3.32 (1H, dd, JZ14.5, 5.5 Hz), 3.18 (1H, dd, JZ
14.5, 7.5 Hz); dC(100 MHz, CDCl3) 171.8, 134.3, 129.5,
129.3, 128.0, 55.4, 35.8.
mp 94.5–95.5 8C); Rf 0.25 (1:2, petrol(40–60)–Et2O); nmax
/
cmK1 (thin film) 3352, 2961, 2937, 1683, 1526; [a]2D0Z
K22.0 (c 1.0, CHCl3), lit.38 [a]D20ZK24.0 (c 1, CHCl3)]; dH
(270 MHz, CDCl3) d 7.34–7.19 (5H, complex m), 4.71 (1H,
br s), 3.87 (1H, br m), 3.66 (1H, m), 3.55 (1H, m), 2.84 (2H,
d, JZ7.5 Hz), 2.23 (1H, br s), 1.41 (9H, s); dC (68.5 MHz,
CDCl3) 156.2, 138.0, 129.4, 128.6, 126.6, 79.8, 64.0, 53.8,
37.5, 28.4. (Found (CIC): 252.1603. C14H22NO3 requires
(MHC): 252.1600 (1.3 ppm)).
3.9.2. Oxidation of 50.
Acknowledgements
3.9.2.1. Methyl 2-(S)-2-[(tert-butoxycarbonyl)amino]-
3-phenylpropanoate (51). A solution of phenyl alaninol 50
(36 mg, 0.14 mmol) in dichloromethane (1.5 mL) under N2
at room temperature was treated with Dess–Martin period-
inane (67 mg, 0.16 mmol). After 1.5 h the cloudy suspen-
sion was treated sequentially with saturated aqueous
NaHCO3 solution (3 mL), 1 M aqueous NaS2O3 solution
(10 mL) and Et2O (10 mL). The biphasic mixture was
stirred for 15 min, then partitioned. The aqueous layer was
re-extracted with Et2O (2!10 mL) and the combined
organic layers were dried (MgSO4), filtered and concen-
trated under reduced pressure to afford a white solid. This
residue was dissolved in t-BuOH (3.0 mL), and a 2 M
solution of 2-methyl-2-butene in THF (1.40 mL,
2.80 mmol) was added. A solution of sodium chlorite
(117 mg, 1.29 mmol) and sodium dihydrogen orthopho-
sphate (165 mg, 1.06 mmol) in water (1.40 mL) was
cautiously added dropwise. After 1.5 h, the reaction mixture
was concentrated and saturated aqueous NaHCO3 solution
(10 mL) was added. The aqueous layer was washed with
EtOAc (10 mL) and then acidified to pH 1 with 10% HCl
solution. The resulting acidic aqueous phase was extracted
with EtOAc (3!10 mL). The combined organic phases
were dried (MgSO4), filtered and concentrated under
reduced pressure to afford a colourless oil. This crude
carboxylic acid was dissolved in toluene (0.7 mL) and
MeOH (0.7 mL) and cooled to 0 8C under an atmosphere
of N2, before being treated with a 2 M ethereal solution
of (trimethylsilyl)diazomethane (0.14 mL, 0.28 mmol). The
reaction mixture was maintained at 0 8C for 40 min, and
then was concentrated to afford a colourless oil. This oil was
subjected to flash chromatography (1:3, Et2O–petrol(40–60)
elution) to provide the title compound as a colourless oil
We thank Elsevier Science (M. N. K.) and the Ramsay
Memorial Fellowships Trust (J. E. H.) for postdoctoral
support, Novo Nordisk for research leave funding (J. P. K.),
BBSRC and GSK (C. W. B.) for funding and CASE support.
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