Palladium(O) catalysed and copper(I) promoted reactions of the secondary zinc reagent derived from L-threonine

Article abstract of DOI:10.1039/b208667k

The preparation of C-3 epimeric secondary zinc reagents from diastereoisomeric iodide using DMF as solvent was discussed and analyzed by NMR methods. Palladium catalysed cross couplings and copper promoted allylations produced protected β-methyl substituted amino acids. It was concluded that the threonine derived zinc reagents were of limited values, but further optimization of copper-promoted reactions make this approach to synthesis of β-methyl substituted α-amino acids more useful.

Full text of DOI:10.1039/b208667k

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Palladium(0) catalysed and copper(I) promoted reactions of the
secondary zinc reagent derived from L-threonine
Ian Wilson and Richard F. W. Jackson*†
1
bromide. A recent report has shown that an analogue of the
zinc reagent derived from iodide 3a (protected as the N-Boc
methyl ester) reacted with phosphorus electrophiles in an
overall non-stereoselective manner,19 and this has prompted us
to report our own synthetic endeavours.
Therefore to address both the stereochemical issues and to
access a range of 3-methyl α-amino acids we aimed to prepare
pure samples of diastereoisomeric iodides 3a/b, and then
using our now optimum conditions (activated zinc dust in
DMF at room temperature) convert them both into the corre-
sponding zinc reagent. Its stability would be apparent through
deuterium quenching, Pd() cross-coupling with aryl halides/
Cu() promoted allylations and 1H/ 13C NMR spectroscopy.
Department of Chemistry, Bedson Building, The University of Newcastle, Newcastle upon Tyne,
UK NE1 7RU. E-mail: r.f.w.jackson@shef.ac.uk
Received (in Cambridge, UK) 6th September 2002, Accepted 22nd October 2002
First published as an Advance Article on the web 19th November 2002
C-3 epimeric secondary zinc reagents 2a/b were prepared from either diastereoisomeric iodide 3a or 3b using DMF
as solvent, and characterised by 1H NMR methods. Palladium catalysed cross couplings and copper promoted
allylations yielded protected β-methyl substituted amino acids.
followed by transmetallation with a source of Cu() and allyl
Introduction
There is continued interest in methodology directed towards the
synthesis of non-proteinogenic amino acids.1,2 To this end we
have prepared a wide range of non-natural enantiomerically
pure α-/β-/γ- amino acids via the palladium()-catalysed cross
couplings and copper() catalysed allylations of zinc reagents
derived from serine, aspartic acid and glutamic acid.3–5
However our methodology cannot yet access C-3 disubstituted
α-amino acids, for example 3-methyl-3-arylalanines.
In view of the interest in modified amino acids that can
confer conformational rigidity in small peptides,6,7 various
groups have investigated the synthesis of 3-methyl-3-aryl-
alanines. Many of those reported have relied on the use
of chiral enolates,8,9 catalytic asymmetric process (i.e. Katsuki–
Jacobsen or Sharpless epoxidations)10,11 or asymmetric hydro-
genation12 to introduce chirality. Despite the attractiveness of
using -threonine as a starting material, to our knowledge only
one report has used this strategy.13
The efficient and reliable palladium and copper()-catalysed
reactions of iodozinc alanine 1 in DMF encouraged us to
extend this methodology to the secondary zinc reagent 2. It was
envisaged that a range of C(3)-methyl substituted α-amino
acids could be accessed using this reagent.
Results and discussion
Iodide 3a was prepared in two steps from commercially
available N-Cbz--threonine 4 (Scheme 1). Selective tert-butyl
However when preparing a secondary alkylzinc reagent
from an optically pure alkyl iodide precursor, stereochemical
Scheme 1 Reagents and conditions: i. tBuBr, benzyltriethylammonium
chloride (BTEAC), K2CO3, DMA, 55 ЊC, 48 h. ii. 2 eq. Me(PhO)3PϩIϪ,
DMF, rt, 4 h.
3
scrambling is usually seen at the secondary Csp –I bond. For
example, Rieke14–16 has shown that optically pure secondary
alkyl bromides yield racemic secondary alkylzinc bromides
when treated with activated zinc dust. Similarly, Knochel17,18
reported that diastereoisomerically pure iodides give a 1:1 mix-
ture of diastereoisomers after treatment with zinc dust,
esterification of 4 with tBuBr, potassium carbonate and
benzyltriethylammonium chloride in dimethylacetamide20
proceeded to give 5 in 50–55% yield after recrystallisation.
Though this method did avoid tert-butyl ether formation
it proved capricious, and was not amenable to scale up beyond
30 mmol.
† Present address: Department of Chemistry, Dainton Building, The
University of Sheffield, Sheffield, UK S3 7HF.
DOI: 10.1039/b208667k
J. Chem. Soc., Perkin Trans. 1, 2002, 2845–2850
This journal is © The Royal Society of Chemistry 2002
2845

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Treatment of
5
with methyl triphenoxyphosphonium
The zinc reagent 2 was prepared as before, but in d7-DMF,
and then transferred to an NMR tube fitted with Youngs’ tap
under a nitrogen atmosphere. The 1H NMR spectrum obtained
∼10 min after formation of zinc reagent confirmed the absence
of the iodide 3a and the formation of a 1:1 mixture of the two
diastereoisomeric zinc reagents 2a/b (Fig. 2). Reduced com-
pound 8 and 9 were present in small amounts (∼5% each). The
diagnostic signals for the zinc reagents 2a/b were two doublets
(1.02 ppm and 1.045 ppm), corresponding to the zinc reagent
methyl group, and two pentets (0.79 ppm and 0.88 ppm)
corresponding to the methine proton adjacent to zinc.
iodide21 in dry DMF at room temperature afforded 3a as a
single diastereoisomer typically in 50–55% yield after chrom-
atography. Formate 6 was isolated as a minor product (2%).
Iodide 3b was prepared by treatment of 3a with sodium
iodide in acetone at room temperature (Scheme 2). A sample
of the pure diastereoisomer 3b was obtained by flash chrom-
atography.
Scheme 2 Reagents and conditions: 2 eq. NaI, acetone, rt.
Fig. 2 Proposed structure of zinc reagents 2a/b in DMF.
Preparation and deuteration of zinc reagent 2
In the 13C spectrum of 2a/b, two signals (174.46 and 174.54
ppm) corresponding to the ester carbonyls were observed, each
shifted downfield from the signal (169.0) due to the ester
carbonyl in the starting iodide 3a. These shifts are indicative
of diastereoisomeric zinc reagents with internal Zn–O co-
ordination, in a similar manner to that observed with the
serine-derived reagent 1.
In order to assess the stability of the reagents 2a/b, a second
1H NMR spectrum was obtained 2 hours later, and this proved
to be essentially identical to the original spectrum. Thus, the
secondary zinc reagents 2a/b appeared to be stable at room
temperature.
Zinc reagent 2 was generated in dry DMF using activated zinc
dust (Scheme 3). TLC analysis of the reaction, as a means to
verify that 3a had been transformed to the zinc reagent, proved
ineffective. A slight exotherm that ensued as 3a reacts became a
more reliable sign that zinc reagent 2 had formed. Consumption
of 3a was complete after 2 min at room temperature. Immediate
quenching of the zinc reagent with d1-acetic acid (2 eq.) led to
a 1:1 mixture of 7 and 8, as judged from integration of
their C(2)H protons. 13C and MS data confirmed deuterium
incorporation. The overall sequence of forming zinc reagent
2 and its quench to give 7 gave a 1:1 mixture of C-3 epimeric
deuterated compounds, as evident from the C(3)H proton
signal integrals. N-Cbz--vinylglycine tert-butyl ester 9 was
formed in small amounts (∼5%) on all occasions, though it
proved to be inseparable from protonated zinc reagent 8.
Synthesis of 3-methyl-3-arylalanines
Palladium catalysed cross coupling of reagents 2a/b with a
series of aryl iodides was effected using the catalyst prepared
in situ from Pd2(dba)3 and tri-o-tolylphosphine (Scheme 4).
Scheme 4 Reagents and conditions: (i) Zn* in DMF. (ii) iodide 3a or
3b in DMF, 2 min. (iii) ArI (1.33 eq.), Pd2(dba)3 (2.5 mol%),
P(o–MeC6H4)3 (10 mol%), room temp., 3 h.
Scheme 3 Reagents and conditions: (i) Zn* (prepared from Zn dust
using 1,2-dibromoethane followed by Me3SiCl in DMF). (ii) Iodide 3a
in DMF 2 min then 2 eq. CH3COOD.
Compounds 10a/b and 11a/b were formed as a 1:1 mixture of
C-3 epimers in modest yields (see Table 1). Diastereoisomers
with a polar aromatic substituent (i.e. p-nitro and p-methoxy,
10a/b and 11a/b) were separable by careful chromatography
on silica gel with an appropriate petrol–ethyl acetate gradient.
In these reactions reduced compound 8 was typically formed in
30–35% yield, along with inseparable 9 in ∼5% yield. Absolute
configurations at C-3 were assigned by comparison with those
reported for N-acetyl methyl ester analogues,22 for which in all
cases the (2S,3S) diastereoisomer displayed its C(3)H signal
downfield from that of the corresponding signal in the (2S,3R)
diastereoisomer. Our best, albeit still modest, yield (for 11a/b)
was obtained from a reaction on a 2.3 mmol scale, the largest
scale that we employed.
Reactions with iodobenzene and 4-iodotoluene did produce
the expected products as mixtures of diastereoisomers, but it
proved not to be possible to isolate analytically pure samples of
the products. No cross-coupled product was obtained when
using 1-iodonaphthalene or 1-iodo-4-bromobenzene, the major
product in these cases being 8, formed by protonation. Reaction
of iodide 3b under the same conditions again gave a 1:1 mixture
of diastereoisomers (entry 2, Table 1). The low yields reflect the
small scale (0.17 mmol) on which this reaction was carried out,
and again the major by-product was 8.
Longer time lapse before addition of Dϩ led to a relatively
smaller amount of the deuterated compound 7, with the
protonated compound 8 being the major decomposition
product. Though these reactions proceeded with complete
conversion of the iodide, only 60–65% recovery of material was
the norm.
NMR experiments: structure and stability of secondary zinc
reagent 2
We have previously reported that the 13C NMR spectrum
of zinc reagent 1 in DMF-d7 indicates the presence of
intramolecular ester carbonyl-zinc() coordination (Fig. 1),
as evidenced by a substantial (∼5 ppm) downfield shift of
the ester carbon signal following zinc insertion.5
Fig. 1 Proposed structure of N-Boc iodozincalanine methyl ester 1 in
DMF.
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J. Chem. Soc., Perkin Trans. 1, 2002, 2845–2850

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Table 1 Preparation of 3-methyl-3-arylalanines 10a/b, 11a/b
Aryl iodide
Alkyl iodide
Ar
Products
Yield (%)a
Yield 8a
4–NO2–C6H4I
4–NO2–C6H4I
4–MeO–C6H4I
3a
3b
3a
4–NO2–C6H4
4–NO2–C6H4
4–MeO–C6H4
10a/b
10a/b
11a/b
37
17
44
31
11
7
a Based on starting iodide 3a or 3b.
Table 2 Preparation of 3-methyl 3-alkenyl substituted α-amino acids
reactions, may render this approach to the synthesis of
β-methyl substituted α-amino acids more practically useful.
The difficulties in separating the products of the reaction from
the by-products 8 and 9 is a major limitation at present.
Electrophile
R
Product
Yield (%)
CH2᎐᎐CHCH2Br
CH2᎐᎐C(Br)CH2Br
CH2᎐᎐C(CO2Et)CH2Br
H2C᎐CHCH2
13a/b
14a/b
38
34
36
᎐
H2C᎐C(Br)CH2
᎐
CH2᎐᎐C(CO2Et)CH2 15a/b
Experimental
Melting points were determined on a Linkham HFS91 heating
stage, with a TC92 controller. Optical rotations were deter-
mined with a PolAAR 2001 instrument. Mass spectra were
obtained using a Micromass Autospec M machine in E.I.
mode. Infra red spectra were obtained using a Nicolet 20PCIR
instrument. 1H NMR spectra were acquired at 500 MHz with a
JEOL Lambda spectrometer and at 200 MHz with a Bruker
WP-200. Chemical shifts (δ) are given in ppm, relative to
tetramethylsilane (0 ppm), and coupling constants are given in
Hz. 13C NMR spectra were acquired at 125 MHz with the
JEOL Lambda spectrometer and at 50 MHz with the Bruker
WP-200. All chemical shifts (δ) are given in ppm, and are
referenced to tetramethylsilane (0 ppm) or CDCl3 (77.0 ppm).
DMF, DMA and toluene were distilled from calcium hydride
and stored over 4 Å molecular sieves. TLC analysis was per-
formed on aluminium plates coated with Kieselgel 60 F254 (0.25
mm). TLC plates were analysed by UV (254 nm) where
appropriate, otherwise plates were developed by treatment with
aqueous ammonium molybdate followed by heating.
Chemicals were purchased from the Aldrich or Lancaster Syn-
thesis chemical companies, and used as supplied.
Formation of zinc reagent 2 from bromide 12, prepared as a
single diastereoisomer from 5 using CBr4/PPh3 in toluene,
required a slightly elevated temperature (35 ЊC) (Scheme 5).
Scheme 5 Reagents and conditions: (i) CBr4/PPh3, toluene, rt 5 h. (ii)
Zn*, DMF. (iii) bromide 5 in DMF, 1 h 35 ЊC. (iv) 4–NO2–C6H4I (1.33
eq.), Pd2(dba)3 (2.5 mol%), P(o–MeC6H4)3 (10 mol%), room temp., 3 h.
Subsequent Pd() cross coupling with p-iodonitrobenzene led
to the isolation of 10a/b and 8 in 30% yield each, though vinyl
glycine derivative 9 was not formed. This represented no
improvement on using iodide 3a.
Our conclusion from these results is that the zinc reagent 2a/b
is perfectly stable at room temperature, but that it reacts
substantially more slowly with aryl iodides under palladium
catalysis than the analogous zinc reagent 1. We therefore turned
our attention to the possibility of copper-catalysed reactions.
tert-Butyl (2S,3R)-2-(benzyloxycarbonyl)amino-3-hydroxy-
butanoate (5)
Copper(I) catalysed reactions
N-Benzyloxycarbonyl--threonine 4 (2.53 g, 10 mmol) was
dissolved in N,N-dimethylacetamide (75 cm3) at room temper-
ature in the presence of benzyltriethylammonium chloride
(2.28 g, 10 mmol). Anhydrous potassium carbonate (35.9 g,
260 mmol) was added to the stirred solution, followed by the
addition of tert-butyl bromide (55 cm3, 480 mmol). The mixture
was stirred at 55 ЊC for 24 h. The reaction was allowed to cool,
poured into water (1000 cm3) and the product extracted with
ethyl acetate (250 cm3). The organic layer was separated,
washed with water (2 × 100 cm3), dried (MgSO4) and concen-
trated under reduced pressure to give a pale yellow solid.
Recrystallisation from diethyl ether–hexane afforded ester 5 as
colourless needles (1.57 g, 3.1 mmol, 51%). Mp 66 ЊC. (Found
Treatment of alkylzinc halides with Cu() salts gives more
reactive organometallics which can be trapped with allylic or
propargylic halides.4 We have previously employed Hiemstra’s
variant23 using a catalytic amount of Cu()BrؒDMS (0.1 eq.) in
dry DMF with α-amino acid zinc reagents.24 Extension of
this methodology to iodide 3a permitted the preparation
of 3 examples of 3-methyl 3-alkenyl substituted α-amino acids
13a/b–15a/b (Scheme 6) in typically 30–40% yield (Table 2).
Mϩ Ϫ C4H8, 253.0954. C12H15NO5 requires 253.0950); [α]2D0
ϩ
Ϫ3.8 (c. 1.0, CH2Cl2); νmax/cmϪ1 (KBr disc) 1514, 1740, 2975,
3407; δH (500 MHz, CDCl3) 1.24 (3H, d, J 6.5), 1.47 (9H, s),
1.94 (1H, br s), 4.15–4.23 (1H, m), 5.12 (2H, s), 5.51 (1H, br s),
7.26–7.37 (5H, m); δC (125 MHz, CDCl3) 20.0, 28.0, 59.7, 67.1,
68.4, 82.6, 128.1 (2×), 128.2, 136.3, 156.7, 170.0; m/z (EI) 253
(Mϩ Ϫ C4H8, 4%), 209 (97), 164 (25), 148 (75), 107 (30), 91 (96),
57 (100). Anal. Calc’C16H23O5N: C 62.10%, H 7.49%, N 4.53%.
Found C 62.20%, H 7.46%, N 4.43%.
Scheme 6 Reagents and conditions: (i) Zn*, DMF. (ii) CuBrؒSMe2
(0.1 eq.), Ϫ10 ЊC, electrophile, warm to room temp., 3 h.
In this case, products were isolated as inseparable 1:1
mixtures of diastereoisomers. Significantly lower amounts of
reduced compound 8, typically 5–10%, were isolated from these
Cu() promoted reactions along with nearly equal amounts of
inseparable vinyl glycine 9.
tert-Butyl (2R,3S )-2-(benzyloxycarbonyl)amino-3-iodo-
butanoate (3a)
Conclusions
(2S,3R)-tert-Butyl
2-(benzyloxycarbonyl)amino-3-hydroxy-
Our final conclusion from this work is that the threonine
derived zinc reagents 2a/b are of limited synthetic value, but
that further optimisation, particularly of the copper-promoted
butanoate 5 (2.1 g, 5 mmol) was added in four portions over
10 minutes to a solution of methyltriphenoxyphosphonium
iodide (4.52 g, 10 mmol) in anhydrous N,N-dimethylformamide
J. Chem. Soc., Perkin Trans. 1, 2002, 2845–2850
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(15 cm3) under nitrogen at room temperature. The flask was
covered with foil and the mixture stirred at room temperature
for 3 h. Methanol (15 cm3) was added and the reaction left to
stir for a further 15 minutes. The reaction mixture was poured
into water (75 cm3) and extracted with ether (2 × 50 cm3). The
combined organic fractions were washed with water (2 × 75
cm3), 5% NaOH (25 cm3), water (3 × 50 cm3) and dried
(MgSO4). Concentration under reduced pressure gave a pale
yellow oil. Flash chromatography on silica gel using petrol–
ethyl acetate (20:1) gave 3a as a pale yellow oil (1.14 g, 2.72
νmax/cmϪ1 (cap. film) 1394, 1506, 1725, 3034, 3348; δH (500
MHz, CDCl3) 1.50 (9H, s), 1.81 (3H, d, J 7), 4.37 (1H, dq, J 3
and 7), 4.46 (1H, dd, J 3 and 8), 5.12 (2H, s), 5.65 (1H, d, J 8),
7.30–7.40 (5H, m); δC (125 MHz, CDCl3) 23.0, 28.0, 50.0, 60.0,
67.3, 83.5, 128.1, 128.2, 128.6, 136.1, 155.6, 167.4. m/z (EI) 315
(Mϩ Ϫ tBu, 70%), 272 (11), 264 (13), 191 (100) 91 (100), 57 (31).
Preparation of protected ꢀ-methylarylalanines (10a/b–13a/b).
General procedure
Zinc dust (0.294 g, 4.5 mmol, 6.0 eq.) was weighed into a 50 cm3
round bottom flask that was repeatedly evacuated and flushed
with nitrogen. Dry DMF (0.5 cm3) and 1,2-dibromoethane (19
µL, 0.225 mmol) were added via syringe and the mixture was
stirred vigorously. The mixture was then heated until ethane
was evolved before being allowed to attain room temperature.
Trimethylsilylchloride (15 µL, 0.115 mmol) was added to the
mixture and stirred for 30 min. Iodide 3a or 3b (0.314 g, 0.75
mmol) was dissolved in dry DMF (0.5 cm3) under nitrogen. The
iodide solution was added to the activated zinc at room tem-
perature in a water bath via syringe. After 2 minutes aryl iodide
(1.0 mmol), Pd2(dba)3 (0.0228 g, 0.025 mmol, 0.025 eq.) and
tri-o-tolyl-phosphine (0.0304 g, 0.10 mmol, 0.10 eq.) were
added in that order to the reaction mixture. The reaction
mixture was left to stir at room temperature for 3 h and then
diluted with ethyl acetate (50 cm3). The organic extract was
washed with brine (50 cm3), water (50 cm3) and dried (MgSO4).
ϩ
mmol, 54%). (Found: [MHϩ Ϫ C4H9], 362.9972. C12H14NO4
requires 362.9968); [α]2D2 40.2 (c. 1.05, CH2Cl2); νmax/cmϪ1 (cap.
film) 1394, 1504, 1724, 2978, 3033; δH (500 MHz, CDCl3) 1.51
(9H, s), 1.99 (3H, d, J 7), 4.19 (1H, dd, J 8 and 3.5), 4.44
(1H, dq, J 7 and 3.5), 5.12 (2H, m), 5.61 (2H, d, J 8), 7.31–7.39
(5H, s); δC (125 MHz, CDCl3) 25.3, 28.1, 60.7, 67.2,
83.6, 128.1, 128.3, 128.6, 129.6, 136.1, 155.6, 167.6; m/z (EI) 363
t
(MHϩ Ϫ Bu, 30%), 318 (42), 292 (9), 236 (40), 107 (33), 91
(100), 57 (40).
tert-Butyl (2S,3S )-2-(benzyloxycarbonyl)amino-3-formyloxy-
butanoate (6)
Isolated as a pale yellow oil from the above reaction (33 mg,
ϩ
0.1 mmol, 2%). (Found: [MHϩ Ϫ C4H9] 281.0907. C13H15NO6
requires 281.0899); [α]3D0 5.9 (c. 1.5, CH2Cl2); νmax/cmϪ1 (cap.
film) 1155, 1522, 1726, 2938, 2980 3350; δH (500 MHz, CDCl3)
1.32 (3H, d, J 6.5), 1.48 (9H, s), 4.56 (1H, dd, J 8 and 3),
5.11 (2H, s), 5.30–5.35 (1H, m), 5.56 (1H, d, J 8), 7.17–7.36
(5H, m), 8.01 (1H, s); δC (125 MHz, CDCl3) 16.9, 30.0, 57.3,
67.2, 70.6, 83.3, 128.2 (×2), 128.5, 136.1, 155.9, 160.2, 167.9.
m/z (EI) 281 (Mϩ Ϫ C4H8, 9%), 236 (4), 107 (9), 91 (100), 57
(31).
tert-Butyl (2S,3R/S )-2-(benzyloxycarbonyl)amino-3-(p-nitro-
phenyl)butanoate (10a/b)
Treatment with p-iodonitrobenzene (0.249 g, 1.0 mmol)
followed by flash chromatography on silica gel using petrol–
ethyl acetate (8:1) yielded (2S,3R) diastereoisomer 10a (52 mg,
0.13 mmol, 17%) as a thick dark oil. (Found: Mϩ 414.1799.
tert-Butyl (2R,3R)-2-(benzyloxycarbonyl)amino-3-iodo-
butanoate (3b)
C22H26N2O6 requires 414.1791); [α]2D2 16.3 (c. 0.27, CH2Cl2);
ϩ
νmax/cmϪ1 (cap. film) 1347, 1521, 1724, 2935, 2978, 3340. δH (500
MHz, CDCl3) 1.33 (3H, d, J 7), 1.35 (9H, s), 3.33 (1H, pent,
J 6.5), 4.51 (1H, dd, J 6 and 9), 4.99 (1H, d, J 12), 5.09 (1H, d,
J 12), 5.37 (1H, d, J 9), 7.28–7.40 (7H, m), 8.12 (2H, m); δC (125
MHz, CDCl3) 16.1, 27.9, 42.8, 59.1, 67.1, 82.9, 123.9, 128.2,
128.4, 128.6, 128.9, 137.9, 147.0, 149.6, 155.9, 169.9. m/z (EI)
414 (Mϩ, 15%), 358 (10), 313 (45), 151 (6), 91 (100), 57 (9%).
(2S,3S) Diastereoisomer 10b (63 mg, 0.15 mmol, 20%).
Iodide 3a (3.06 g, 7.3 mmol) was added to a stirred solution of
sodium iodide (3.29 g, 20 mmol, 2.7 eq.) in acetone (200 cm3)
under nitrogen at room temperature then heated at reflux for
24 h. The reaction mixture was concentrated under reduced
pressure. Residue was extracted into ethyl acetate (200 cm3),
washed with brine (250 cm3), 1 M sodium thiosulfate solution
(100 cm3) and water (250 cm3). Concentration of the organic
layer gave a 2:1 mixture of the (2R,3R)- and (2R,3S)-diastereo-
isomers as a pale yellow oil. Flash chromatography on silica gel
using petrol–ethyl acetate gave 3b (0.37 g, 0.88 mmol, 12%) and
a 1:1 mixture of 3a/b (1.824 g, 4.35 mmol, 60%). (Found: Mϩ,
419.0594. C16H22NO4Iϩ requires 419.0593); [α]2D2 Ϫ14.4 (c. 1.2,
CH2Cl2); νmax/cmϪ1 (cap. film) 1394, 1507, 1728, 2978; δH (500
MHz, CDCl3) 1.49 (9H, s), 1.92 (3H, d, J 7), 4.17 (1H, dd, J 2.5
and 9.5), 4.69 (1H, dq, J 7 and 2.5), 5.14 (2H, s), 5.44 (1H, d,
J 9.5), 7.26–7.40 (5H, m); δC (125 MHz, CDCl3) 26.0, 28.0, 29.6,
60.2, 67.3, 83.2, 128.1, 128.2, 128.5, 136.1, 156.6, 168.5; m/z
(EI) 419 (Mϩ, 28%), 363 (40), 318 (28), 236 (5), 192 (65), 107
(13), 91 (100), 57 (30).
t
ϩ
(Found Mϩ
Ϫ CO2 Bu 313.1193. C17H17N2O4 requires
313.1188); [α]2D2 15.9 (c. 0.27, CH2Cl2); νmax/cmϪ1 (cap. film)
1346, 1718, 2935, 2978, 3342; δH (500 MHz, CDCl3) 1.40 (9H,
s), 1.80 (3H, d, J 7), 3.43 (1H, pent, J 6.5), 4.51 (1H, dd, J 5.5
and 8.5), 5.05 (1H, d, J 12), 5.09 (1H, d, J 12), 5.26 (1H, d, J 9),
7.25–7.45 (7H, m), 8.14 (2H, m); δC (125 MHz, CDCl3) 16.6,
28.0, 42.4, 59.1, 67.1, 82.9, 123.4, 128.0, 128.3, 128.5, 128.8,
136.0, 146.9, 149.1, 156.0, 169.6; m/z (EI) 358 (MHϩ Ϫ Bu,
t
0.3%), 313 (1), 223 (1), 151 (6), 107 (30), 91 (100).
tert-Butyl (2S,3R/S )-2-(benzyloxycarbonyl)amino-3-
(p-methoxyphenyl)butanoate (11a/b)
Using iodide 3a (0.98 g, 2.34 mmol) to generate the organozinc
reagent 2a/b and p-methoxyiodobenzene (0.73 g, 3.12 mmol)
followed by flash chromatography on silica gel using petrol–
ethyl acetate 8:1 gave (2S,3S) diastereoisomer 11a (221 mg, 0.55
mmol, 24%) as a dark red oil. [α]2D1 16.3 (c. 0.27, CH2Cl2).
νmax/ cmϪ1 (cap. film) 1514, 1726, 3344. δH (500 MHz, CDCl3)
1.33 (3H, d, J 7), 1.41 (9H, s), 3.30 (1H, pent, J 6.5), 3.76 (3H,
s), 4.44 (1H, dd, J 9 and 5), 5.07 (2H, s), 6.81 (2H, m), 7.11 (2H,
m), 7.25–7.30 (5H, m); δC (125 MHz, CDCl3) 17.9, 27.9, 41.3,
55.2, 59.8, 66.8, 81.6, 113.7, 128.0, 128.1 (×2), 128.8, 133.0,
136.4, 156.2, 158.6, 170.5. m/z (EI) 400 (MHϩ, 0.1%), 344 (0.5),
327 (0.1), 298 (1.3), 248 (5), 135 (100), 91 (52), 57 (12%).
tert-Butyl (2R,3S )-2-(benzyloxycarbonyl)amino-3-bromo-
butanoate (12)
Carbon tetrabromide (0.958 g, 2.89 mmol) and triphenyl-
phosphine (0.758 g, 2.89 mmol) were dissolved in anhydrous
toluene (16 cm3) in a dry flask under nitrogen at room temper-
ature. Ester 5 (0.618 g, 2.00 mmol) was added in four portions
over 30 minutes. The reaction was stirred at room temperature
for 3 hours, then filtered and the solid washed with toluene
(20 cm3). The filtrate was concentrated under reduced pressure
to give a pale yellow oil. Flash chromatography on silica gel
using petrol–ethyl acetate (3:1) gave tert-butyl (2R,3S)-2-
(benzyloxycarbonyl)amino-3-bromobutanoate 12 as a yellow
oil (0.373 g, 1.00 mmol, 50%); (Found MHϩ Ϫ C4H9 315.0091,
C12H14NO4Brϩ requires 315.0106); [α]2D2 31.0 (c. 1.05, CH2Cl2);
Also (2S,3R) diastereoisomer 11b (190 mg, 0.48 mmol, 20%)
ϩ
as a dark red oil. (Found Mϩ 399.2022. C23H29NO5 requires
399.2046); [α]2D1 16.3 (c. 0.27, CH2Cl2); νmax/ cmϪ1 (cap. film)
2848
J. Chem. Soc., Perkin Trans. 1, 2002, 2845–2850

View Article Online
1155, 1248, 1514, 1725, 3341. δH (500 MHz, CDCl3) 1.30 (9H, s,
tBu), 1.31 (3H, d, J 6.5), 3.08 (1H, pent, J 7), 3.76 (3H, s), 4.41
(1H, dd, J 7 and 9), 5.08 (2H, m), 5.37 (1H, d, J 9), 6.81 (2H,
m), 7.12 (2H, m), 7.30–7.36 (5H, m); δC (125 MHz, CDCl3)
17.3, 27.7, 42.2, 55.1, 59.7, 66.7, 81.7, 113.6, 128.0, 128.4. 128.8
(×2), 133.6, 136.3, 155.8, 158.5, 170.6. m/z (EI) 399 (Mϩ,
0.01%), 343 (0.05), 298 (1.3), 207 (0.7), 163 (0.5, 135 (100), 91
(37).
tert-Butyl (2S,3R/S )-2-(benzyloxycarbonyl)amino-5-bromo-3-
methylhex-5-enoate (14a/b)
Treatment with 2,3-dibromopropene followed by followed by
flash chromatography on silica gel (10:1 petrol–ethyl acetate)
gave 14a/b (104 mg, 0.25 mmol, 34%) as a pale yellow oil.
(Found Mϩ Ϫ C4H9 Ϫ CO2, 310.0443. C14H17NO2Brϩ requires
310.0443). δH (500 MHz, CDCl3) 0.87 (3H, d, J 7), 0.93 (3H, d,
J 7), 1.48 (9H, s), 1.49 (9H, s), 2.21 (2H, m), 2.40 (1H, m), 2.49
(2H, m), 2.58 (1H, m), 4.32 (2H, m), 5.10 (4H, m), 5.26 (1H, d,
J 9), 5.34 (1H, d, J 8), 5.48 (2H, m), 5.63 (2H, s), 7.30–7.38 (5H,
m). δC 13.5, 15.1, 28.0,* 34.5, 35.0, 44.1, 45.2, 57.0, 57.9, 67.0,
67.2, 82.3, 82.6, 118.9, 119.1, 128.2,* 128.5 (×2),* 132.0,*
136.2,* 156.1, 156.3, 170.5, 170.9 (* indicates signals common
tert-Butyl (2S )-2-(benzyloxycarbonyl)aminobutanoate (8)
Obtained as a by product in all palladium() couplings as result
of protonation of the zinc reagent 2. Isolated from those
reactions as an inseparable mixture with N-Cbz--vinylglycine
tert-butyl ester 9. The title compound was prepared as a pure
compound as follows: (2R,3S)-tert-butyl 2-(benzyloxycarb-
onyl)amino-3-iodobutanoate 3a was dissolved in a small
amount of DMF, acetic acid was then added followed by zinc
dust. A strong exotherm then ensued. After filtration of the zinc
dust and aqueous work up the title compound was isolated as a
to both diastereoisomers). m/z (EI) 266 ([MH Ϫ C4H8
Ϫ
PhCH2]ϩ, 5.5%), 232 (7), 91 (100), 57 (14).
tert-Butyl (2S,3R/S )-2-(benzyloxycarbonyl)amino-3-methyl-5-
methylenehexanedioic acid 6-ethyl ester (15a/b)
Treatment with ethyl 2-bromomethylacrylate (0.14 cm3, 1 mmol)
followed by flash chromatography on silica gel (10:1 petrol–
ethyl acetate) gave the title compounds 15a/b (95 mg, 0.27
mmol, 36%) as a 1:1 mixture of diastereoisomers. (Found Mϩ Ϫ
C4H8 349.1523. C18H23NO6ϩ requires 349.1525). νmax/cmϪ1 (cap.
film) 1158, 1218, 1521, 1717, 2935, 2978, 3556. δH (500 MHz,
CDCl3) 0.84 (3H, d, J 7), 0.90 (3H, d, J 7), 1.30 (3H, t, J 7), 1.46
(9H, s), 1.48 (9H, s), 2.05–2.14 (2× 1H, m), 2.22 (1H, m), 2.29
(1H, m), 2.45 (2× 1H, m), 4.14–4.24 (2× 2H, m), 4.31 (1H, dd,
J 3 and 9), 5.11 (2H, m, PhCH2), 5.30 (1H, d, J 9), 5.46 (1H, d,
J 8), 5.60 (2H, s), 6.23 (2H, d, J 7.5), 7.30–7.40 (10H, m).
δC (125 MHz, CDCl3) 14.2, 14.3, 15.7,* 28.0,* 35.0,* 35.5, 35.9,
57.4, 58.4, 60.7, 60.8, 66.9, 67.0, 82.1, 82.3, 126.8, 127.2, 128.1,*
128.5,* 136.4,* 138.4,* 156.1, 156.4, 166.9,* 170.7, 171.1
(* indicates signals common to both diastereoisomers; two
signals obscured between 128.0 and 128.5). m/z (EI) 349 (Mϩ Ϫ
C4H8, 1.3%), 332 (0.4), 304 (20), 260 (40), 91 (100), 57 (13).
ϩ
pale yellow oil. (Found Mϩ Ϫ C4H8, 237.1011. C12H15NO4
requires 237.1001); [α]2D4 6.2 (c. 1.25, CH2Cl2). νmax/cmϪ1 (cap.
film) 3340, 3091, 2976, 1723, 1524, 1157. δH (500 MHz, CDCl3)
0.91 (3H, t, J 7.5), 1.45 (9H, s), 1.66–1.75 (1H, m), 1.82–1.90
(1H, m), 4.20–4.26 (1H, m), 5.10 (2H, s), 5.33 (1H, d, J 7.5),
7.30–7.38 (5H, m). δC (125 MHz, CDCl3) 9.2, 26.0, 28.0, 55.3,
66.8, 81.9, 128.1, 128.5 (×2), 136.4, 155.8, 171.5. m/z (EI) 237
(4%, Mϩ Ϫ C4H8), 192 (12), 148 (17) 91 (100), 57 (20).
Copper(I)-promoted couplings. General procedure
Zinc dust (0.150 g, 2.3 mmol, 3 eq.) was weighed into a 50 cm3
round bottom flask which was evacuated four times (twice with
heating) and flushed with nitrogen four times. Dry DMF (0.5
cm3) was added via syringe and the reaction stirred vigorously.
Trimethylsilylchloride (30 cm3, 0.23 mmol) was added to the
mixture and stirred for 30 min. (2R,3S)-tert-butyl 2-(benzyl-
oxycarbonyl)amino-3-iodobutanoate 3a (0.314 g, 0.75 mmol)
was dissolved in dry DMF (0.5 cm3) under nitrogen and added
to the activated zinc at room temperature. An exotherm after
2–3 min corresponded to the formation of the zinc reagent after
which the stirring was stopped and zinc allowed to settle. The
supernatent and further dry DMF (5 cm3) used to wash the zinc
was transferred to a solution of copper() bromide dimethyl
sulfide complex (20 mg, 0.1 mmol, 0.1 eq.) and electrophile
(1 mmol). The reaction mixture was stirred at Ϫ15 ЊC for 5 min
then allowed to warm to room temperature, and left to stir
overnight. The reaction mixture was diluted with ethyl acetate
(50 cm3), washed with 1 M sodium thiosulfate (20 cm3), water
(2 × 20 cm3), brine (40 cm3) and dried (MgSO4).
Acknowledgements
We thank Dr M. Mitchell and Dr P. D. Tiffin, Roche, Welwyn,
for helpful discussion, and Roche Products Ltd. (Welwyn
Garden City) and the EPSRC for the award of an Industrial
CASE studentship (IW).
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(cap. film) 1156, 1222, 1368, 1511, 1723, 3347. δH (500 MHz,
CDCl3) 0.85 (3H, d, J 7) and 0.94 (3H, d, J 7), 1.46 and 1.47
(9H, s), 1.86–2.23 (3H, m), 4.20 (1H, dd, J 4.5 and 8.5), 4.26
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(1H, d, J 8.5). δC (125 MHz, CDCl3) 14.2, 15.6, 28.2,* 36.1,
36.5, 37.0, 37.7, 57.7, 58.3, 67.2,* 82.0, 82.2, 116.8, 116.9,
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171.2 (* indicates signals common to both diastereoisomers);
m/z 277 ([MHϩ Ϫ C4H8], 0.3%), 232 (13), 91 (100), 57 (22).
Anal. Calc’d for C19H27NO4: C 68.4%, H 8.2%, N 4.4%. Found
C 68.37%, H 8.31%, N 4.36%.
ϩ
ϩ
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