A new route to hydrophobic amino acids using copper-promoted reactions of serine-derived organozinc reagents

Article abstract of DOI:10.1039/b007032g

Copper-catalysed reaction of the serine-derived zinc reagent 1 with allylic electrophiles gives products arising formally from both S_N2 and S_N2′ pathways. These constitutional isomers can be separated, either directly, or in the case of (2S)-2-tert-butoxycarbonylamino-6-methylhept-5-enoic acid methyl ester (11) and (2S)-2-tert-butoxycarbonylamino-4,4-dimethylhex-5-enoic acid methyl ester (12) by selective epoxidation of 11. Hydrogenation of the double bond, followed by protecting group manipulation, allows the synthesis of the Fmoc-protected amino acids 3-7 ready for automated peptide synthesis. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b007032g

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A new route to hydrophobic amino acids using copper-promoted
reactions of serine-derived organozinc reagents
Hervé J. C. Deboves,a Urszula Grabowska,b Adriana Rizzob and Richard F. W. Jackson*a
1
a Department of Chemistry, Bedson Building, The University of Newcastle, Newcastle upon Tyne,
UK NE1 7RU
b Medivir UK Ltd, Peterhouse Technology Park, 100 Fulbourn Road, Cambridge, UK CB1 9PT
Received (in Cambridge, UK) 30th August 2000, Accepted 4th October 2000
First published as an Advance Article on the web 1st December 2000
Copper-catalysed reaction of the serine-derived zinc reagent 1 with allylic electrophiles gives products arising
formally from both SN2 and SN2Ј pathways. These constitutional isomers can be separated, either directly, or in
the case of (2S)-2-tert-butoxycarbonylamino-6-methylhept-5-enoic acid methyl ester (11) and (2S)-2-tert-butoxy-
carbonylamino-4,4-dimethylhex-5-enoic acid methyl ester (12) by selective epoxidation of 11. Hydrogenation of the
double bond, followed by protecting group manipulation, allows the synthesis of the Fmoc-protected amino acids
3–7 ready for automated peptide synthesis.
The synthesis of unnatural analogues of proteinogenic amino
acids is an important goal in the context of understanding
Results and discussion
In our original work,3 we had employed the stoichiometric
receptor binding.1 We have developed effective methods for the
conversion of readily available enantiomerically pure natural
amino acids (serine, aspartic acid, glutamic acid) into unnatural
amino acids using organometallic chemistry without loss of
stereochemical integrity.2–5 We have established that the zinc–
copper reagent 2, prepared from the zinc reagent 1, reacts
with allylic and propargylic (prop-2-ynyl) electrophiles to give
enantiomerically pure unsaturated amino acids in moderate to
good yields.3 It was therefore of interest to establish whether
this approach might also be amenable to the synthesis of a
range of homologues of valine, leucine and isoleucine, in
which the side chains contain a series of methyl branches. The
Fmoc-protected amino acids 3–7 were therefore identified as
targets, and we have explored a route to these compounds
using the copper-promoted reaction of the zinc reagent 1
with a range of highly substituted allylic electrophiles. The
unprotected analogue of 3 had previously been isolated by
hydrolysis of the peptide antibiotic Longicatenamycin,6,7 along
with the lower and higher homologues.
transmetallation of the zinc reagent 1 to the zinc–copper
reagent 2 using CuCNؒ2LiCl, prior to addition of the electro-
phile. While this process is reliable, the need to exercise
appropriate precautions during the reaction due to the toxicity
of cyanide, and especially during the work-up, is a significant
drawback. This prompted us to explore the use of catalytic
amounts of copper, most specifically CuBrؒDMS, which has
recently been reported to catalyse the reaction between β-amino
zinc reagents and both propargyl and allenyl halides.8,9 In
addition, we were concerned that the electrophiles that we pro-
posed to use, 8–10, might be susceptible to copper-catalysed
isomerisation in the presence of halide ion, which in turn would
lead to mixtures of products provided the usual SN2Ј pathway
was followed in the substitution. The use of catalytic amounts
of copper might be expected to minimise this problem.
Reaction of the zinc–copper reagent, prepared under our
previously described conditions, with 3,3-dimethylallyl chloride
gave a mixture of the constitutional isomers 11 and 12, in
a 58:42 ratio (93%). When the zinc reagent 1 was treated with
3,3-dimethylallyl chloride in the presence of a catalytic amount
of CuBrؒDMS, the two isomers 11 and 12 were isolated in
excellent overall yield (90%), and in a ratio of 55:45. These
results suggest that while the work-up can be much simplified
by the use of catalytic amounts of copper, the regiochemical
outcome of the reaction is not altered. Unfortunately, it did
not prove possible to separate 11 and 12, so we took advantage
of the very well-established higher reactivity of trisubstituted
alkenes, compared with terminal alkenes, towards MCPBA.10
Thus, treatment of the mixture of 11 and 12 with MCPBA
resulted in selective epoxidation of 11 to give 13 (as a mixture
of diastereoisomers), leaving 12 untouched. The separation of
alkene 12 from epoxide 13 proved straightforward, and epoxide
13 was converted back into the terminal alkene 11 by treatment
with the reagent derived from WCl6 and BuLi (Scheme 1).11,12
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J. Chem. Soc., Perkin Trans. 1, 2000, 4284–4292
This journal is © The Royal Society of Chemistry 2000
DOI: 10.1039/b007032g

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Scheme 3 Reagents and conditions: i CuBrؒDMS, (E)-CH3CH᎐C-
᎐
(CH3)CH2OTs; ii H2, Pd/C, EtOH, room temp.; iii LiOH, THF–H2O,
1:1, room, temp.; iv HCl (4 M), dioxane; v FmocCl, Na2CO3, H2O,
dioxane, room temp.
with the bromide 10, prepared by HBr addition to 2,3-dimethyl-
butadiene,16 was investigated. The two constitutional isomers
18 (29%) and 19 (30%) were isolated, and these could be
separated by flash chromatography. This reaction was carried
out on a 30 mmol scale, and demonstrates the capability
of this method to prepare gramme amounts of material. The
unsaturated amino acids 18 and 19 were then converted via
the saturated analogues 20 (isolated as an inseparable mixture
of diastereoisomers) and 21, and the derived Boc-protected
amino acids 22 and 23 into the targets 6 (also isolated as an
inseparable mixture of diastereoisomers) and 7, respectively
(Scheme 4).
Scheme 1 Reagents and conditions: i CuBrؒDMS, (CH3)2C᎐CHCH2Cl;
ii MCPBA, CHCl3, room temp., 2 h; iii separation; iv WCl6–BuLi,
Ϫ78 ЊC, then 0–5 ЊC, 30 min, room temp., 1 h.
᎐
Separate hydrogenation of compounds 11 and 12 proceeded
smoothly to give the saturated analogues 14 and 15. These two
compounds were fully characterised, and then converted into
the Fmoc-protected amino acids 3 and 4 by a series of standard
protecting group manipulations (Scheme 2).
Scheme 2 Reagents and conditions: i H2, Pd/C, EtOH, room temp.;
ii LiOH, THF–H2O, 1:1, room temp.; iii HCl (4 M), dioxane;
iv FmocCl, Na2CO3, H2O, dioxane, room temp.
In order to prepare the two diastereoisomers 5a and 5b,
it was necessary to treat the zinc reagent 1 with the tosylate
9, which was prepared in two steps from 2-methylbut-2-enoic
acid.13,14 Tosylate 9, as reported in the literature,14 is very
unstable, and it is necessary to store the compound in solu-
tion. Nevertheless, the CuBrؒDMS catalysed reaction gave
the separable diastereoisomers 16a (32%) and 16b (19%)
in moderate combined yield. The relative stereochemistry
of the racemic N-acetyl analogues of 16a and 16b, prepared
by a Lewis acid catalysed ene reaction between methyl 2-
acetamidoacrylate and 2-methylbut-2-ene, had been tentatively
assigned by analogy with the outcome of a related reaction.15
We have therefore converted compound 16b into the corre-
sponding N-acetyl derivative, which exhibited identical 13C
NMR data to that reported in the literature.15 Compounds
16a and 16b were then separately converted in an analogous
series of steps to those already described, via the characterised
saturated analogues 17a and 17b, into the target Fmoc-
protected acids 5a and 5b (Scheme 3).
Scheme 4 Reagents and conditions: i CuBrؒDMS, (CH3)2C᎐C(CH3)-
᎐
CH2Br; ii H2, Pd/C, EtOH, room temp.; iii LiOH, THF–H2O, 1:1,
room, temp.; iv HCl (4 M), dioxane; v FmocCl, Na2CO3, H2O, dioxane,
room temp.
Conclusions
It appears that the normal course of substitution reactions
of allylic electrophiles with zinc–copper reagents, in which
the products from the SN2Ј pathway predominate, is no longer
followed when highly substituted electrophiles are used.
Electrophiles in which the SN2Ј pathway would require attack
at a fully substituted position, as is the case for 8 and 10, tend
to give significant amounts of the products formally derived
by the SN2 pathway. At this stage, we cannot rule out the possi-
bility that the products formally derived by the SN2 pathway
actually arise by an initial isomerisation of the electrophile
With the aim of preparing the homologues of compounds
5a and 5b, the copper-catalysed reaction of the zinc reagent 1
J. Chem. Soc., Perkin Trans. 1, 2000, 4284–4292
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(which is known to be promoted by copper salts, even if these
are present only in sub-stoichiometric amounts), rather than an
SN2 pathway.
From a preparative point of view, we have shown how the
copper-catalysed reaction of the serine-derived zinc reagent 1
with substituted allylic electrophiles can be used to good effect
in the preparation of a series of amino acids with branched
hydrophobic side-chains. Although constitutional isomers are
formed, these can be separated.
weighed into a 25 cm3 round bottom flask fitted with a three
way tap and dried gently with a heat gun under vacuum until
CuBrؒDMS changed appearance from a brown powder to
a light green powder. Dry DMF (0.5 cm3) was then added
followed by addition of the electrophile (1-chloro-2-methylbut-
2-ene, toluene-4-sulfonic acid (E)-2-methylbut-2-enyl ester
or 1-bromo-2,3-dimethylbut-2-ene) (1.00 mmol, 1.3 eq.). The
reaction mixture was then cooled to Ϫ15 ЊC. Stirring of the
organozinc reagent solution was stopped to allow the zinc
powder to settle and the supernatant was carefully removed via
syringe (care taken to avoid transferring too much zinc powder)
and added dropwise to the solution of electrophile and copper
catalyst. The cooling bath was removed and the solution was
stirred at room temperature overnight. Ethyl acetate (20 cm3)
was added and stirring was continued for a further 15 min. The
reaction mixture was transferred to a separating funnel and
a further aliquot of EtOAc (30 cm3) was added. The organic
phase was washed successively with 1 M Na2S2O3 (20 cm3),
water (2 × 20 cm3), brine (40 cm3), dried (Na2SO4 or MgSO4)
and filtered. The solvent was removed in vacuo and the crude
product purified by flash chromatography on silica gel as
described.
Experimental
Dry DMF was distilled from calcium hydride and stored over
4 Å molecular sieves. Dry dichloromethane was distilled
from calcium hydride. Dry THF was distilled from potassium
benzophenone ketyl. Petroleum ether refers to the fraction
with a boiling point between 40–60 ЊC. Specific rotations were
measured on a PolAAr 2000 instrument at the stated tem-
perature and are given in units of 10Ϫ1 deg cm2 gϪ1. IR spectra
were recorded on a Nicolet 20PCIR spectrometer at the
University of Newcastle as thin films. Mass spectra (m/z)
(Electrospray) were obtained using a Fisons/VG analytical
system at Medivir UK, Cambridge or measured on a Micro-
mass Autospec M spectrometer in electron impact (EI) mode
at the University of Newcastle. HRMS mass spectra (m/z)
(Electrospray) were recorded using a Q-TOF Micromass
spectrometer by University of Cambridge Spectrometry Service
or a Micromass Autospec M spectrometer in EI mode at the
University of Newcastle. Nuclear magnetic resonance (NMR)
spectra were recorded at the field strength in the solvents indi-
cated, using standard pulse sequences on a DRX-500 machine
by the University of Cambridge NMR Department or on a
Bruker AC 200 (200 MHz) or JEOL LA 500 (500 MHz)
instrument at the University of Newcastle. Chemical shifts are
expressed in parts per million (δ) and are referenced to residual
signals of the solvent. Coupling constants (J) are expressed
in Hz. Elemental analyses were carried out either by University
of Cambridge Microanalysis Service or by University of
Newcastle Microanalysis Service. Unless otherwise specified, all
solvents and reagents were obtained from commercial suppliers
and used without further purification. HPLC samples were
run on a Vydac Phenomenex Jupiter C4 (5µ) 250 × 4.6 mm
analytical column using an automated Gilson 215/233XL. A
gradient of 10–90% B in A, 2–30 min, 1.5 cm3 minϪ1, where
solvent A = 0.1% aq. TFA and solvent B = acetonitrile–10% A,
with UV detection at 215 nm. Thin layer chromatography
(TLC) was performed on precoated plates (Merck aluminium
sheets silica 60 F254, Art. no. 5554). Visualisation of com-
pounds was achieved by illumination under ultraviolet light
(254 nm) or using an appropriate staining reagent. Flash
column chromatography was performed on silica gel 60
(Merck 9385).
Additional general procedures
Hydrogenation of alkenes. The alkene (1.00 mmol) was dis-
solved in ethanol (10 cm3), 10% palladium on carbon (80 mg)
added and hydrogen introduced. Once the reaction was
judged to have reached completion (TLC, HPLC or MS), the
hydrogen was removed, the reaction filtered through Celite
and the catalyst washed with ethanol (30 cm3). The combined
organic filtrate was concentrated in vacuo and the alkane
used directly in the subsequent reaction or purified by flash
chromatography on silica gel as described.
Saponification of methyl esters. The methyl ester (1.00 mmol)
was dissolved in THF (6 cm3) and whilst stirring, a solution
of LiOH (1.20 mmol, 1.2 eq.) in water (6 cm3) was added drop-
wise. Once the reaction was judged to have reached completion
(TLC, HPLC or MS), the THF was removed in vacuo and
diethyl ether (10 cm3) added to the residue. The reaction mix-
ture was acidified with 1.0 M HCl until pH 3. The organic
phase was then removed and the aqueous layer extracted
with diethyl ether (2 × 10 cm3). The combined organic extracts
were dried over magnesium sulfate, filtered and the solvent
removed in vacuo to give the carboxylic acid used directly in the
subsequent reaction or purified by flash chromatography on
silica gel as described.
Removal of N-Boc protecting group. The N-Boc protected
material (1.00 mmol) was cooled to 0 ЊC and 4 M HCl in
dioxane (5 cm3) was added dropwise. When the reaction
was judged to have reached completion (TLC, HPLC or
MS), the solvents were removed in vacuo to yield the amine
hydrochloride which was used directly in the subsequent
reaction.
General procedure for the zinc coupling reactions
Zinc dust (150 mg, 2.29 mmol, 3.0 eq., Aldrich) was weighed
into a 25 cm3 round bottom flask with a side arm and fitted
with a three way tap. The zinc powder was heated with a heat
gun under vacuum and the flask was flushed with nitrogen and
evacuated and flushed a further three times. With the flask
filled with nitrogen, dry DMF (0.5 cm3) was added. Trimethyl-
silyl chloride (0.029 cm3, 0.23 mmol, 0.3 eq.) was added and
the zinc slurry was vigorously stirred for a further 30 min. N-
(tert-Butoxycarbonyl)-3-iodo--alanine methyl ester3 (247 mg,
0.75 mmol, 1.0 eq.) dissolved in dry DMF (0.5 cm3) was added
dropwise, via syringe, to the activated zinc slurry at 0 ЊC
prepared as described above. The reaction mixture was then
allowed to warm up to room temperature and stirred for 1 h to
give the organozinc reagent. Whilst the zinc insertion reaction
was in progress, CuBrؒDMS (21 mg, 0.10 mmol, 0.13 eq.) was
Fmoc protection of amines. The amine hydrochloride
(1.00 mmol) in 1,4-dioxane (2 cm3) was cooled to 0 ЊC and
10% sodium carbonate (2.20 mmol, 2.2 eq., 4 cm3) added.
The biphasic reaction mixture was stirred vigorously and
Fmoc–Cl (1.10 mmol, 1.1 eq.) in dioxane (2 cm3) was added
over 1 h. Once the reaction was judged to have reached com-
pletion (TLC, HPLC or MS), diethyl ether (10 cm3) was added
and the reaction mixture acidified to pH 3 with 1 M HCl. The
organic phase was removed and the aqueous layer extracted
with diethyl ether (2 × 10 cm3). The combined organic extracts
were dried over sodium sulfate, filtered, the solvent removed
in vacuo and the residue purified by flash chromatography using
silica gel.
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J. Chem. Soc., Perkin Trans. 1, 2000, 4284–4292

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(2S)-2-tert-Butoxycarbonylamino-4,4-dimethylhex-5-enoic acid
methyl ester 12, (2S)-2-tert-butoxycarbonylamino-4-[(2S)-3,3-
dimethyloxiranyl]butyric acid methyl ester 13a and (2S)-2-tert-
butoxycarbonylamino-4-[(2R)-3,3-dimethyloxiranyl]butyric acid
methyl ester 13b
((CH3)2C), 79.87 (C(CH3)3), 155.38 (OC(O)NH) and 173.01
(NHCHCO2CH3); HRMS 288.1823 (MHϩ, C14H26NO5 requires
288.1811 (δ 4.2 ppm)); m/z (Electrospray-MS) 288 (91%) and
232 (100%).
(2S)-2-tert-Butoxycarbonylamino-4,4-dimethylhexanoic acid
methyl ester 15
Following the general procedure for zinc coupling reactions,
1-chloro-3-methylbut-2-ene (0.110 cm3, 0.98 mmol) was
coupled to N-(tert-butoxycarbonyl)-3-iodo--alanine methyl
ester (247 mg, 0.75 mmol) in the presence of CuBrؒDMS
(21 mg, 0.10 mmol) to give a residue which was purified by flash
column chromatography over silica gel eluting with EtOAc–
heptane (1:9, v/v). Fractions were pooled and reduced in vacuo
Following the general procedure for alkene hydrogenation,
(2S)-2-tert-butoxycarbonylamino-4,4-dimethylhex-5-enoic acid
methyl ester 12 (93 mg, 0.34 mmol) yielded on purification
by flash column chromatography over silica gel, eluting with
EtOAc–heptane (1:5, v/v), (2S)-2-tert-butoxycarbonylamino-
4,4-dimethylhexanoic acid methyl ester 15 (90 mg, 96%) as
a colourless oil. Analytical HPLC tr = 22.55 min (100%);
[α]D18 Ϫ6.1 (c 0.99 in CH2Cl2); δH (500 MHz; CDCl3) 0.81 (3H,
t, J 7.5, CH3CH2), 0.89 (3H, s, CH3CH2C(CH3)2A), 0.90 (3H,
s, CH3CH2C(CH3)2B), 1.29 (2H, dq, J 7.5 and 1, CH3CH2), 1.38
(1H, dd, J 14.5 and 9, NHCHCH2A), 1.42 (9H, s, C(CH3)3), 1.69
(1H, dd, J 14.5 and 3.5, NHCHCH2B), 3.71 (3H, s, CO2CH3),
4.31 (1H, br m, NHCHCO2CH3) and 4.78 (1H, br d, J 8.5,
NH); δC (125 MHz; CDCl3) 8.66 (CH3CH2), 26.61 (CH3-
CH2C(CH3)2), 28.28 (C(CH3)3), 33.06 (CH3CH2C(CH3)2),
34.40 (CH3CH2), 43.97 (NHCHCH2), 50.84 ((NHCHCH2),
52.13 (CO2CH3), 79.79 (C(CH3)3), 155.08 (OC(O)NH) and
174.46 (NHCHCO2CH3); HRMS 296.1827 (MNa, C14H27-
NO4Na requires 296.1838 (δ 3.7 ppm)); m/z (Electrospray-MS)
274 (69%) and 218 (100%).
1
to give on the basis of H NMR spectroscopy a mixture of
regioisomers (183 mg, 90%) (45:55 formal SN2Ј vs. SN2),
inseparable by column chromatography, as a colourless oil.
To a mixture of isomers 11 and 12 (190 mg, 0.70 mmol)
in chloroform (3 cm3) was added dropwise over 5 min, 3-
chloroperbenzoic acid (164 mg, 85% pure, 0.81 mmol, 1.15 eq.)
in chloroform (2 cm3). The reaction mixture was stirred at room
temperature for a further 2 h. The reaction mixture was then
washed successively with 1 M Na2S2O5 (5 cm3), saturated
sodium bicarbonate solution (5 cm3) and brine (10 cm3). The
organic phase was dried over sodium sulfate, filtered, the
solvent removed in vacuo and the residue was purified by flash
chromatography over silica gel eluting with EtOAc–heptane
(1:9, v/v). Three products were obtained; (2S)-2-tert-butoxy-
carbonylamino-4,4-dimethylhex-5-enoic acid methyl ester 12
was eluted first and further elution afforded an inseparable
mixture of (2S)-2-tert-butoxycarbonylamino-4-[(2S)-3,3-di-
methyloxiranyl]butyric acid methyl ester 13a and (2S)-2-tert-
butoxycarbonylamino-4-[(2R)-3,3-dimethyloxiranyl]butyric
acid methyl ester 13b. Fractions containing the initial com-
ponent were pooled and reduced in vacuo to give (2S)-2-tert-
butoxycarbonylamino-4,4-dimethylhex-5-enoic acid methyl
ester 12 (93 mg, 49%) as a colourless oil. Analytical HPLC
tr = 21.45 min (95%); [α]D18 ϩ18.7 (c 0.32 in CH2Cl2); νmax(film)/
cmϪ1 3369 (s), 3084 (m), 2965 (s), 1748 (s), 1715 (s), 1517 (s),
1167 (s), 1007 (s) and 914 (s); δH (500 MHz; CDCl3) 1.06 (6H,
(2S)-2-tert-Butoxycarbonylamino-4,4-dimethylhexanoic acid.
Following the general procedure for methyl ester saponification,
(2S)-2-tert-butoxycarbonylamino-4,4-dimethylhexanoic acid
methyl ester 15 (90 mg, 0.33 mmol) gave (2S)-2-tert-butoxy-
carbonylamino-4,4-dimethylhexanoic acid (79 mg, 93%) as
crystals which were used directly in the subsequent reaction.
Analytical HPLC tr = 20.90 min (100%); m/z (Electrospray-MS)
260 (33%) and 204 (100%).
(2S)-2-Amino-4,4-dimethylhexanoic acid hydrochloride salt.
Following the general procedure of N-Boc removal using
4 M HCl in dioxane, (2S)-2-tert-butoxycarbonylamino-4,4-
dimethylhexanoic acid (79 mg, 0.31 mmol) gave (2S)-2-amino-
4,4-dimethylhexanoic acid hydrochloride salt (60 mg, 100%)
as a solid, and was used directly in the subsequent reaction;
m/z (Electrospray-MS) 160 (100%).
s, CH ᎐CHC(CH ) ), 1.42 (9H, s, C(CH ) ), 1.55 (1H, dd, J 14
᎐
2
3
2
3 3
and 9, NHCHCH2A), 1.82 (1H, dd, J 14 and 4, NHCHCH2B),
3.69 (3H, s, CO2CH3), 4.30 (1H, br m, NHCHCO2CH3), 4.83
(1H, br d, J 7, NH), 4.97 (2H, m, CH ᎐CH) and 5.78 (1H,
᎐
2
dd, Jtrans 17.5 and Jcis 11, CH ᎐CH); δ (125 MHz; CDCl )
᎐
2
C
3
26.93 (CH ᎐CHC(CH ) ), 28.34 (C(CH ) ), 36.33 (CH ᎐CHC-
᎐
᎐
2
2
3
2
3
3
(CH3)2), 45.06 (NHCHCH2), 51.25 (NHCHCO2CH3), 52.15
(CO2CH3), 79.77 (C(CH3)3), 111.39 (CH ᎐CH), 146.87
᎐
2
(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-4,4-dimethyl-
hexanoic acid 4
(CH ᎐CH), 154.97 (OC(O)NH) and 174.04 (NHCHCO CH );
᎐
2
2
3
HRMS 215.1152 (Mϩ Ϫ C4H8, C10H17NO4 requires 215.1158
(δ 2.8 ppm)); m/z (Electrospray-MS) 272 (40%) and 216 (100%).
Pooling together the fractions containing later-eluting com-
ponents gave a mixture of (2S)-2-tert-butoxycarbonylamino-
4-[(2S)-3,3-dimethyloxiranyl]butyric acid methyl ester 13a
and (2S)-2-tert-butoxycarbonylamino-4-[(2R)-3,3-dimethyloxi-
ranyl]butyric acid methyl ester 13b (55 mg, 27%) as a colourless
oil. (1H NMR spectroscopy showed a mixture of diastereo-
isomers had been obtained in a 3.5:1 ratio. No attempt was
made to establish which isomer was formed preferentially.) [α]D23
ϩ12.0 (c 1.02 in CH2Cl2); νmax(film)/cmϪ1 2976 (br), 2931 (s),
1747 (s), 1716 (s), 1391 (s) and 1367 (s); δH (500 MHz; CDCl3)
1.26 (3H, s, (CH3)2A), 1.31 (3H, s, (CH3)2B), 1.44 (9H, s,
C(CH3)3), 1.52 (1H, m, NHCHCH2CH2A), 1.61 (1H, m,
NHCHCH2CH2B), 1.80 (1H, m, NHCHCH2ACH2), 2.01 (1H,
m, NHCHCH2BCH2), 2.69 (1H, dd, J 7 and 5.5, NHCH(CH2)2-
CH), 3.75 (3H, s, CO2CH3), 4.35 (1H, br m, NHCHCO2CH3)
and 5.20 (1H, br d, J 8, NH); δC (125 MHz; CDCl3) 18.61 and
18.62 ((CH3)2A), 24.77 and 24.79 (NHCHCH2CH2), 24.81
and 25.08 ((CH3)2B), 28.30 (C(CH3)3), 29.51 and 29.61
(NHCHCH2CH2), 52.30 and 52.36 ((CH3)2CCH), 53.08 and
53.27 ((NHCHCH2), 58.55 (CO2CH3), 63.36 and 63.48
Following the general procedure for Fmoc protection of an
amine, (2S)-2-amino-4,4-dimethylhexanoic acid hydrochloride
salt (60 mg, 0.31 mmol) gave on purification by flash chrom-
atography over silica gel, eluting with CHCl3–CH3OH (100:0
to 96:4, v/v), (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-
4,4-dimethylhexanoic acid 4 (63 mg, 54%) as an amorphous
solid, mp 64–65 ЊC. Analytical HPLC tr = 23.63 min (100%);
[α]D18 Ϫ17.4 (c 1.01 in CH2Cl2); δH (500 MHz; CDCl3) 0.82 (3H,
t, J 7.5, CH3CH2), 0.91 (3H, s, CH3CH2C(CH3)2A), 0.92 (3H,
s, CH3CH2C(CH3)2B), 1.29 (2H, br q, J 7.5, CH3CH2), 1.46 (1H,
dd, J 14.5 and 9.5, NHCHCH2A), 1.83 (1H, dd, J 14.5 and
2, NHCHCH2B), 4.20 (1H, t, J 7, H-9Ј), 4.40 (3H, br m,
NHCHCO2H and CH2O), 5.07 (1H, br d, J 7.5, NH), 7.28
(2H, m, H-2Ј and H-7Ј), 7.37 (2H, m, H-3Ј and H-6Ј), 7.56 (2H,
m, H-1Ј and H-8Ј) and 7.74 (2H, d, J 7.5, H-4Ј and H-5Ј);
δC (125 MHz; CDCl3) 8.23 (CH3CH2), 26.62 (CH3CH2-
C(CH3)2), 33.20 (CH3CH2C(CH3)2), 34.37 (CH3CH2), 43.40
(NHCHCH2), 47.14 (CH-9Ј), 51.30 (NHCHCO2H), 67.01
(CH2O), 119.92 (CH-4Ј and CH-5Ј), 124.99 (CH-1Ј and
CH-8Ј), 127.01 (CH-2Ј and CH-7Ј), 127.65 (CH-3Ј and CH-6Ј),
141.27 (C-4aЈ and C-5aЈ), 143.70 (C-1aЈ and C-8aЈ), 155.90
J. Chem. Soc., Perkin Trans. 1, 2000, 4284–4292
4287

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(OC(O)NH) and 177.07 (NHCHCO2H); HRMS 404.1839
(MNa, C23H27NO4Na requires 404.1838 (δ 0.2 ppm)); m/z
(Electrospray-MS) 382 (100%).
amino-6-methylheptanoic acid (88 mg, 92%) as a solid, and
was used directly in the subsequent reaction. Analytical
HPLC tr = 20.04 min (100%); m/z (Electrospray-MS) 260 (8%)
and 204 (100%).
(2S)-2-tert-Butoxycarbonylamino-6-methylhept-5-enoic acid
methyl ester 11
(2S)-2-Amino-6-methylheptanoic acid hydrochloride salt.
Following the general procedure of N-Boc removal using 4 M
HCl in dioxane, (2S)-2-tert-butoxycarbonylamino-6-methyl-
heptanoic acid (88 mg, 0.34 mmol) gave (2S)-2-amino-6-
methylheptanoic acid hydrochloride salt (66 mg, 100%) as
a solid and was used directly in the subsequent reaction;
m/z (Electrospray-MS) 160 (100%).
Hexachlorotungsten (106 mg, 0.30 mmol, 1.4 eq.) was weighed
out into a Schlenk tube under nitrogen and dry THF (0.5 cm3)
was added. A solution of n-BuLi (0.216 cm3, 2.5 M, 0.60 mmol,
2.8 eq.) was added dropwise at Ϫ78 ЊC and the solution was
then left to warm up slowly to room temperature to give a clear
brown solution. It was then recooled to Ϫ78 ЊC and treated
with a solution of (2S)-2-tert-butoxycarbonylamino-4-[(2S)-
3,3-dimethyloxiranyl]butyric acid methyl ester 13a and (2S)-
2-tert-butoxycarbonylamino-4-[(2R)-3,3-dimethyloxiranyl]-
butyric acid methyl ester 13b (55 mg, 0.19 mmol) in THF
(0.2 cm3). The reaction mixture was stirred at 0–5 ЊC for 30 min
and then at room temperature for 1 h to give a clear green
solution. The reaction mixture was poured into a 1:1 solution
of 1.5 M sodium tartrate and 2 M sodium hydroxide (5 cm3).
The organic layer was removed and dried over magnesium
sulfate, filtered and the solvent removed in vacuo to give a crude
oil. The residue was purified by flash chromatography over
silica gel eluting with EtOAc–heptane (1:5, v/v) to give (2S)-2-
tert-butoxycarbonylamino-6-methylhept-5-enoic acid methyl
ester 11 (25 mg, 48%) as a colourless oil. Analytical HPLC
tr = 21.32 min (100%); νmax(film)/cmϪ1 3364 (m), 2977 (m), 1744
(s), 1715 (s), 1516 (s) and 1167 (s); [α]D18 ϩ11.9 (c 1.01 in CH2Cl2);
δH (500 MHz; CDCl3) 1.43 (9H, s, C(CH3)3), 1.59 (3H, s,
(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-6-methylhept-
anoic acid 3
Following the general procedure for Fmoc protection of an
amine (2S)-2-amino-6-methylheptanoic acid hydrochloride salt
(66 mg, 0.34 mmol) gave on purification by flash chrom-
atography over silica gel eluting with CHCl3–CH3OH (100:0 to
95:5, v/v), (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-6-
methylheptanoic acid 3 (70 mg, 54%) as amorphous solid, mp
97–98 ЊC. Analytical HPLC tr = 23.55 min (100%); [α]D23 Ϫ14.6
(c 0.74 in CH3OH); δH (500 MHz; CDCl3) 0.84 (6H, d, J 7,
(CH3)2CH), 1.09 (2H, br m, NHCH(CH2)2CH2), 1.28 (2H, m,
NHCHCH2CH2), 1.46 (1H, qt, J 7 and 6.5, (CH3)3CH), 1.63
(1H, m, NHCHCH2A), 1.84 (1H, m, NHCHCH2B), 4.18 (1H, t,
J 7, H-9Ј), 4.36 (1H, br m, NHCHCO2H), 4.38 (2H, d, J 6.5,
CH2O), 5.27 (1H, br d, J 8, NH), 7.28 (2H, m, H-2Ј and H-7Ј),
7.37 (2H, m, H-3Ј and H-6Ј), 7.57 (2H, m, H-1Ј and H-8Ј) and
7.74 (2H, d, J 7.5, H-4Ј and H-5Ј); δC (125 MHz; CDCl3) 22.43
((CH3)2ACH), 22.53 ((CH3)2BCH), 23.04 (NHCHCH2CH2),
27.71 ((CH3)2CH), 32.44 (NHCHCH2), 38.29 (NHCH-
(CH2)2CH2), 47.09 (CH-9Ј), 53.83 (NHCHCO2H), 67.05
(CH2O), 119.95 (CH-4Ј and CH-5Ј), 125.02 (CH-1Ј and
CH-8Ј), 127.03 (CH-2Ј and CH-7Ј), 127.68 (CH-3Ј and CH-6Ј),
141.26 (C-4aЈ and C-5aЈ), 143.65 (C-1aЈ and C-8aЈ), 156.10
(OC(O)NH) and 176.90 (NHCHCO2H); HRMS 404.1856
(MNa, C23H27NO4Na requires 404.1838 (δ 4.4 ppm)); m/z
(Electrospray-MS) 382 (100%) and 267 (70%).
(CH3)2AC᎐CH), 1.64 (1H, m, NHCHCH CH2A), 1.68 (3H, s,
᎐
2
(CH ) C᎐CH), 1.82 (1H, m, NHCHCH CH ), 2.01 (1H, dd,
᎐
3
2B
2
2B
J 14.5 and 7.5, NHCHCH2A), 2.06 (1H, dd, J 14.5 and 6.5,
NHCHCH2B), 3.73 (3H, s, CO2CH3), 4.30 (1H, br m, NHCH-
CO2CH3), 4.99 (1H, br d, J 7.0, NH) and 5.07 (1H, br t, J 7.0,
(CH ) C᎐CH); δ (125 MHz; CDCl3) 17.65 ((CH3)2AC᎐CH),
᎐
᎐
3
2
C
23.89 (NHCHCH CH ), 25.71 ((CH ) C᎐CH), 28.33 (C-
᎐
3 2B
2
2
(CH3)3), 32.67 (NHCHCH2), 52.19 (CO2CH3), 53.15 (NHCH-
CO CH ), 79.53 (C(CH ) ), 122.68 ((CH ) C᎐CH), 132.89
᎐
3 2
2
3
3
3
((CH ) C᎐CH), 155.21 (OC(O)NH) and 173.24 (NHCH-
᎐
2
3
CO2CH3); HRMS 294.1687 (MNa, C14H25NO4Na requires
294.1681 (δ 1.8 ppm)); m/z (Electrospray-MS) 272 (100%).
(2S,4R)-2-tert-Butoxycarbonylamino-4,5-dimethylhex-5-enoic
acid methyl ester 16a and (2S,4S)-2-tert-butoxycarbonylamino-
4,5-dimethylhex-5-enoic acid methyl ester 16b
(2S)-2-tert-Butoxycarbonylamino-6-methylheptanoic acid
Using the general procedure for the coupling reaction (on six
times the scale), toluene-4-sulfonic acid (E)-2-methylbut-2-enyl
ester (3 ml, 1.8 M solution in DMF, 5.4 mmol) was coupled
to the zinc reagent 1, derived from N-(tert-butoxycarbonyl)-
3-iodo--alanine methyl ester (1.48 g, 4.5 mmol) and zinc
(900 mg, 13.8 mmol), in the presence of CuBrؒDMS (126 mg,
methyl ester 14
Following the general procedure for alkene hydrogenation,
(2S)-2-tert-butoxycarbonylamino-6-methylhept-5-enoic methyl
ester 11 (48 mg, 0.18 mmol) yielded on purification by flash
column chromatography over silica gel, eluting with EtOAc–
heptane (1:10, v/v), (2S)-tert-butoxycarbonylamino-6-methyl-
heptanoic acid methyl ester 14 (48 mg, 100%) as a colourless oil.
Analytical HPLC tr = 22.65 min (100%); [α]D23 Ϫ13.3 (c 0.96
in CH3OH); δH (500 MHz; CDCl3) 0.85 (6H, d, J 6.5, (CH3)2-
CH), 1.16 (2H, m, NHCH(CH2)2CH2), 1.30 (2H, m, NHCH-
CH2CH2), 1.42 (9H, s, C(CH3)3), 1.51 (1H, qt, J 7 and 6.5,
(CH3)3CH), 1.58 (1H, m, NHCHCH2A), 1.74 (1H, m, NHCH-
CH2B), 3.71 (3H, s, CO2CH3), 4.28 (1H, br m, NHCHCO2CH3)
and 4.99 (1H, br d, J 7.5, NH); δC (125 MHz; CDCl3) 22.42
((CH3)2ACH), 22.48 ((CH3)2BCH), 23.01 (NHCHCH2CH2),
27.72 ((CH3)2CH), 28.27 (C(CH3)3), 32.94 (NHCHCH2),
38.33 (NHCH(CH2)2CH2), 52.13 (CO2CH3), 53.39 (NHCH-
CO2CH3), 155.32 (OC(O)NH) and 173.51 (NHCHCO2CH3);
HRMS 296.1836 (MNa, C14H27NO4Na requires 296.1838 (δ 0.7
ppm)); m/z (Electrospray-MS) 274 (53%) and 218 (100%).
1
0.60 mmol) to give a residue. H NMR spectroscopy indicated
that a 1:1 ratio of diastereoisomers had been obtained. This
residue was purified by flash chromatography over silica
gel, eluting with EtOAc–petroleum ether (1:9, v/v), to give
three fractions, the first being (2S,4R)-2-tert-butoxycarb-
onylamino-4,5-dimethylhex-5-enoic acid methyl ester 16a (136
mg, 11%), the second a mixed fraction of 16a and 16b (560 mg,
46%), and the third (2S,4S)-2-tert-butoxycarbonylamino-4,5-
dimethylhex-5-enoic acid methyl ester 16b (70 mg, 6%). The
mixed fractions could be separated by further chromatography.
Diastereoisomer 16a was a colourless oil. Analytical HPLC
tr = 22.52 min (90%); [α]D20 ϩ12.3 (c 1.06 in CHCl3); νmax(film)/
cmϪ1 3382 (m), 3070 (m), 2966 (s), 1746 (s), 1716 (s), 1616 (w),
1507 (s) and 886 (m); δH (500 MHz; CDCl3) 1.06 (3H, d, J
7, CH CH), 1.45 (9H, s, C(CH ) ), 1.58 (1H, m, CH ᎐C-
᎐
2
3
3
3
(CH )CH), 1.68 (3H, s, CH ᎐C(CH )), 1.85 (1H, m, NHCH-
᎐
3
2
3
(2S)-2-tert-Butoxycarbonylamino-6-methylheptanoic
acid.
CH2A), 1.97 (1H, m, NHCHCH2B), 3.73 (3H, s, CO2CH3), 4.29
(1H, m, NHCHCO2CH3), 4.72 (1H, s, CH2A᎐C(CH )), 4.95
Following the general procedure for methyl ester saponification,
(2S)-tert-butoxycarbonylamino-6-methylheptanoic acid methyl
ester 14 (100 mg, 0.37 mmol) gave (2S)-2-tert-butoxycarbonyl-
᎐
3
(1H, d, J 1.5, CH ᎐C(CH )) and 5.04 (1H, br d, J 7, NH);
᎐
2B
3
δC (125 MHz; CDCl ) 18.61 (CH ᎐C(CH )), 21.64 (CH ᎐C-
᎐
᎐
2
3
2
3
4288
J. Chem. Soc., Perkin Trans. 1, 2000, 4284–4292

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(CH )CH(CH )), 28.32 (C(CH ) ), 30.79 (CH ᎐C(CH )CH),
(2S,4R)-2-tert-Butoxycarbonylamino-4,5-dimethylhexanoic
᎐
3
3
3
3
2
3
38.06 (NHCHCH2), 52.00 (NHCHCO2CH3), 52.22 (CO2CH3),
79.53 (C(CH ) ), 110.19 (CH ᎐C(CH )), 144.62 (CH ᎐C(CH )),
155.18 (OC(O)NH) and 173.30 (NHCHCO2CH3); HRMS
294.1684 (MNa, C14H25NO4Na requires 294.1681 (δ 0.8 ppm));
m/z (Electrospray-MS) 272 (26%) and 216 (100%).
Diastereoisomer 16b was isolated as a colourless oil.
Analytical HPLC tr = 22.49 min (95%); [α]D20 ϩ16.0 (c 0.60 in
CHCl3); νmax(film)/cmϪ1 3369 (s), 3073 (m), 2969 (s), 1747 (s),
1717 (s), 1617 (w), 1517 (s) and 893 (m); δH (500 MHz; CDCl3)
1.04 (3H, d, J 7, CH3CH), 1.44 (9H, s, C(CH3)3), 1.55 (1H,
acid and (2S,4S)-2-tert-butoxycarbonylamino-4,5-dimethyl-
hexanoic acid. Following the general procedure for methyl
ester saponification (2S,4R)-2-tert-butoxycarbonylamino-4,5-
dimethylhexanoic acid methyl ester (60 mg, 0.22 mmol) yielded
(2S,4R)-2-tert-butoxycarbonylamino-4,5-dimethylhexanoic
acid (52 mg, 91%) as a colourless oil and was used directly in
the subsequent reaction. Analytical HPLC tr = 20.65 min
(100%); m/z (Electrospray-MS) 260 (18%) and 204 (100%).
Following the general procedure for methyl ester saponific-
᎐
᎐
3
3
2
3
2
3
ation
(2S,4S)-2-tert-butoxycarbonylamino-4,5-dimethylhex-
m, CH ᎐C(CH )CH), 1.67 (3H, s, CH ᎐C(CH )), 1.91 (1H,
m, NHCHCH2A), 2.32 (1H, m, NHCHCH2B), 3.72 (3H, s,
CO2CH3), 4.26 (1H, m, NHCHCO2CH3), 4.75 (1H, d, J 1.5,
anoic acid methyl ester (32 mg, 0.12 mmol) yielded (2S,4S)-
2-tert-butoxycarbonylamino-4,5-dimethylhexanoic acid (30 mg,
100%) as a colourless oil and was used directly in the sub-
sequent reaction. Analytical HPLC tr = 20.45 min (100%); m/z
(Electrospray-MS) 260 (20%) and 204 (100%).
᎐
᎐
2
3
2
3
CH2A᎐C(CH )), 4.79 (1H, d, J 1.5, CH ᎐C(CH )) and 5.46
᎐
᎐
3
2B
3
(1H, br d, J 6, NH); δC (125 MHz; CDCl ) 18.51 (CH ᎐
᎐
2
3
C(CH3)), 20.14 (CH ᎐C(CH )CH(CH )), 28.31 (C(CH3)3),
᎐
2
3
3
30.55 (CH ᎐C(CH )CH), 37.64 (NHCHCH ), 52.17 (NHCH-
᎐
2
3
2
(2S,4R)-2-Amino-4,5-dimethylhexanoic acid hydrochloride
salt and (2S,4S)-2-amino-4,5-dimethylhexanoic acid hydro-
chloride salt. Following the general procedure of N-Boc
removal using 4 M HCl in dioxane, (2S,4R)-2-tert-butoxy-
carbonylamino-4,5-dimethylhexanoic acid (52 mg, 0.20 mmol)
yielded (2S,4R)-2-amino-4,5-dimethylhexanoic acid hydro-
chloride salt (39 mg, 100%) as a solid and was used directly
in the subsequent reaction; m/z (Electrospray-MS) 160 (76%)
and 142 (100%).
Following the general procedure of N-Boc removal using
4 M HCl in dioxane, (2S,4S)-2-tert-butoxycarbonylamino-4,5-
dimethylhexanoic acid (32 mg, 0.12 mmol) yielded (2S,4S)-2-
amino-4,5-dimethylhexanoic acid hydrochloride salt (24 mg,
100%) as a solid and was used directly in the subsequent
reaction; m/z (Electrospray-MS) 160 (80%) and 142 (100%).
CO CH ), 52.22 (CO CH ), 79.74 (C(CH ) ), 111.27 (CH ᎐
᎐
2
2
3
2
3
3
3
C(CH )), 147.94 (CH ᎐C(CH )), 155.36 (OC(O)NH) and
᎐
3
2
3
173.83 (NHCHCO2CH3); HRMS 294.1673 (MNa, C14H25-
NO4Na requires 294.1681 (δ 2.9 ppm)); m/z (Electrospray-MS)
272 (73%) and 216 (100%).
Compound 16b was converted into the corresponding N-
acetyl derivative, which exhibited a signal at δ 111.27 in the
13C NMR spectrum , while the signal for the N-acetyl derivative
of 16a (prepared as a mixture with the N-acetyl derivative
of 16b) was at δ 110.2. These shifts compare very well with
shifts of δ 111.1 and 110.1 reported for the tentatively assigned
syn- and anti-N-acetyl analogues, respectively.15
(2S,4R)-2-tert-Butoxycarbonylamino-4,5-dimethylhexanoic acid
methyl ester 17a and (2S,4S)-2-tert-butoxycarbonylamino-4,5-
dimethylhexanoic acid methyl ester 17b
(2S,4R)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-4,5-di-
methylhexanoic acid 5a and (2S,4S)-2-(9H-fluoren-9-ylmethoxy-
carbonylamino)-4,5-dimethylhexanoic acid 5b
Following the general procedure for alkene hydrogenation,
the first eluted diastereoisomer of (2S,4R)-2-tert-butoxy-
carbonylamino-4,5-dimethylhex-5-enoic acid methyl ester 16a
(63 mg, 0.23 mmol) yielded (2S,4R)-2-tert-butoxycarb-
onylamino-4,5-dimethylhexanoic acid methyl ester 17a (60 mg,
95%) as a colourless oil. Analytical HPLC tr = 22.52 min (90%);
[α]D18 ϩ3.3 (c 0.60 in CH2Cl2); δH (500 MHz; CDCl3) 0.81 (3H,
d, J 7, (CH3)2ACH), 0.84 (3H, d, J 7, (CH3)2CHCH(CH3)),
0.87 (3H, d, J 7, (CH3)2BCH), 1.10 (1H, m, (CH3)2CH), 1.31
(1H, m, (CH3)2CHCH(CH3)), 1.43 (9H, s, C(CH3)3), 1.53
(1H, m, NHCHCH2A), 1.75 (1H, m, NHCHCH2B), 3.72 (3H, s,
CO2CH3), 4.26 (1H, br m, NHCHCO2CH3) and 4.96 (1H, br d,
J 7, NH); HRMS 296.1835 (MNa, C14H27NO4Na requires
296.1838 (δ 1.0 ppm)); m/z (Electrospray-MS) 274 (43%) and
218 (100%).
Following the general procedure for alkene hydrogenation,
the second eluted diastereoisomer of (2S,4S)-2-tert-butoxy-
carbonylamino-4,5-dimethylhex-5-enoic acid methyl ester 16b
(39 mg, 0.14 mmol) yielded (2S,4S)-2-tert-butoxycarbonyl-
amino-4,5-dimethylhexanoic acid methyl ester 17b (39 mg,
100%) as a colourless oil. Analytical HPLC tr = 22.49 min
(98%); [α]D18 ϩ 32.0 (c 0.10 in CH2Cl2); δH (500 MHz; CDCl3)
0.78 (3H, d, J 7, (CH3)2ACH), 0.84 (3H, d, J 7, (CH3)2-
CHCH(CH3)), 0.85 (3H, d, J 7, (CH3)2BCH), 1.37 (1H, m,
NHCHCH2A), 1.43 (9H, s, C(CH3)3), 1.52 (1H, m, (CH3)2CH-
CH(CH3)), 1.64 (1H, m, (CH3)2CH), 1.76 (1H, ddd, J 10, 7
and 6, NHCHCH2B), 3.72 (3H, s, CO2CH3), 4.29 (1H, br m,
NHCHCO2CH3) and 4.94 (1H, br d, J 7, NH); δC (125 MHz;
CDCl3) 15.16 (CH3)2CHCH(CH3)), 17.07 ((CH3)2ACH),
20.00 ((CH3)2BCH), 28.26 (C(CH3)3), 31.03 (CH3)2CH-
CH(CH3)), 34.66 (CH3)2CHCH(CH3)), 37.53 (NHCHCH2),
52.04 (NHCHCO2CH3), 52.12 (CO2CH3), 79.78 (C(CH3)3),
155.17 (OC(O)NH) and 173.89 (NHCHCO2CH3); HRMS
296.1830 (MNa, C14H27NO4Na requires 296.1838 (δ 2.7 ppm));
m/z (Electrospray-MS) 274 (40%) and 218 (100%).
Following the general procedure for Fmoc protection of
an amine, (2S,4R)-2-amino-4,5-dimethylhexanoic acid hydro-
chloride salt (39 mg, 0.20 mmol) gave on purification by flash
chromatography over silica gel, eluting with CHCl3–CH3OH
(100:0 to 95:5, v/v), (2S,4R)-2-(9H-fluoren-9-ylmethoxy-
carbonylamino)-4,5-dimethylhexanoic acid 5a (30 mg, 40%) as
an amorphous solid, mp 53–54 ЊC. Analytical HPLC tr = 23.46
min (100%); [α]D23 Ϫ10.4 (c 1.00 in CH3OH); δH (500 MHz;
CDCl3) 0.85 (9H, m, (CH3)2CHCH(CH3)), 1.34 (1H, m, (CH3)2-
CHCH(CH3)), 1.56 (1H, m, NHCHCH2A), 1.64 (1H, br
m, (CH3)2CHCH(CH3)), 1.89 (1H, m, NHCHCH2B), 4.21 (1H,
t, J 7, H-9Ј), 4.41 (3H, m, CH2O and NHCHCO2H), 5.09
(1H, br d, J 7, NH), 7.29 (2H, m, H-2Ј and H-7Ј), 7.39 (2H, m,
H-3Ј and H-6Ј), 7.56 (2H, m, H-1Ј and H-8Ј) and 7.76 (2H, d,
J 7, H-4Ј and H-5Ј); HRMS 404.1825 (MNa, C23H27NO4Na
requires 404.1838 (δ 3.2 ppm)); m/z (Electrospray-MS) 382
(100%).
Following the general procedure for Fmoc protection of
an amine, (2S,4S)-2-amino-4,5-dimethylhexanoic acid hydro-
chloride salt (24 mg, 0.12 mmol) gave on purification by flash
chromatography over silica gel, eluting with CHCl3–CH3OH
(100:0 to 95:5, v/v), (2S,4S)-2-(9H-fluoren-9-ylmethoxy-
carbonylamino)-4,5-dimethylhexanoic acid 5b (15 mg, 32%) as
an amorphous solid, mp 50–51 ЊC. Analytical HPLC tr = 23.23
min (100%); [α]D18 Ϫ12.8 (c 0.25 in CH3OH); δH (500 MHz;
CDCl3) 0.80 (3H, d, J 6.5, (CH3)2ACH), 0.89 (6H, d, J 6.5,
(CH3)2BCHCH(CH3)), 1.49 (1H, m, NHCHCH2A), 1.52 (1H, br
m, (CH3)2CHCH(CH3)), 1.66 (1H, br m, (CH3)2CHCH(CH3)),
1.91 (1H, br m, NHCHCH2B), 4.22 (1H, t, J 7, H-9Ј), 4.42
(3H, m, CH2O and NHCHCO2H), 5.13 (1H, br d, J 7, NH),
7.32 (2H, m, H-2Ј and H-7Ј), 7.39 (2H, m, H-3Ј and H-6Ј), 7.56
(2H, m, H-1Ј and H-8Ј) and 7.76 (2H, d, J 7, H-4Ј and H-5Ј);
δC (125 MHz; CDCl3) 15.08 ((CH3)2CHCH(CH3)), 16.94
J. Chem. Soc., Perkin Trans. 1, 2000, 4284–4292
4289

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((CH3)2ACH), 20.10 ((CH3)2BCH), 30.94 ((CH3)2CHCH(CH3)),
34.73((CH3)2CHCH(CH3)), 37.13(NHCHCH2), 47.13(CH-9Ј),
52.30 (NHCHCO2H), 66.79 (CH2O), 119.70 (CH-4Ј and
CH-5Ј), 124.78 (CH-1Ј and CH-8Ј), 126.79 (CH-2Ј and CH-7Ј),
127.44 (CH-3Ј and CH-6Ј), 141.05 (C-4aЈ and C-5aЈ), 143.61
(C-1aЈ and C-8aЈ), 155.68 (OC(O)NH) and 178.00 (NHCH-
CO2H); HRMS 404.1841 (MNa, C23H27NO4Na requires
404.1838 (δ 0.7 ppm)); m/z (Electrospray-MS) 382 (100%).
ester 18 (6.78 g, 23.79 mmol) yielded on purification by flash
column chromatography over silica gel, eluting with EtOAc–
heptane (1:9, v/v), an inseparable mixture of (2S,5S)-2-tert-
butoxycarbonylamino-5,6-dimethylheptanoic acid methyl
ester and (2S,5R)-2-tert-butoxycarbonylamino-5,6-dimethyl-
heptanoic acid methyl ester 20 (6.63 g, 97%) as a colourless oil.
Analytical HPLC tr = 24.06 min (100%); [α]D23 Ϫ12.1 (c 1.26
in CH3OH) (Found: C, 62.9; H, 10.1; N, 4.9. C15H29NO4Na
requires C, 62.7; H, 10.2; N, 4.9%); δH (500 MHz; CDCl3)
0.76 (3H, dd, J 7 and 3.5, (CH3)2CHCH(CH3)), 0.78 (3H, dd,
J 7 and 1.5, (CH3)2ACHCH(CH3), 0.83 (3H, dd, J 7 and 1.5,
(CH3)2BCHCH(CH3)), 1.09 (1H, m, NHCHCH2CH2A), 1.26
(1H, m, (CH3)2CHCH(CH3)), 1.37 (1H, m, NHCHCH2CH2B),
1.42 (9H, s, C(CH3)3), 1.53 (1.5H, m, (CH3)2CHCH(CH3) and
0.5 NHCHCH2A), 1.63 (0.5H, m, 0.5 NHCHCH2A), 1.74 (0.5H,
br m, 0.5 NHCHCH2B), 1.84 (0.5H, br m, 0.5 NHCHCH2B),
3.72 (3H, s, CO2CH3), 4.25 (1H, br m, NHCHCO2CH3) and
4.99 (1H, br m, NH); δC (125 MHz; CDCl3) 15.16 and 15.18
((CH3)2CHCH(CH3)), 17.78 and 17.91 ((CH3)2ACHCH(CH3)),
20.06 and 20.14 ((CH3)2BCHCH(CH3)), 28.26 (C(CH3)3), 29.38
and 29.47 (NHCHCH2CH2), 30.60 and 30.75 (NHCHCH2),
31.66 and 31.83 ((CH3)2CHCH(CH3)), 38.07 and 38.27 ((CH3)2-
CHCH(CH3)), 52.10 (NHCHCO2CH3), 53.55 and 53.68
(NHCHCO2CH3), 79.75 (C(CH3)3), 155.306 (OC(O)NH)
and 173.43 and 173.49 (NHCHCO2CH3); HRMS 310.1982
(MNa, C15H29NO4Na requires 310.1994 (δ 4.1 ppm)); m/z
(Electrospray-MS) 288 (68%) and 232 (74%).
(2S)-2-tert-Butoxycarbonylamino-5,6-dimethylhept-5-enoic acid
methyl ester 18 and (2S)-2-tert-butoxycarbonylamino-4,4,5-tri-
methylhex-5-enoic acid methyl ester 19
Following the general procedure for zinc coupling reactions,
1-bromo-2,3-dimethylbut-2-ene (5.45 g, 33.46 mmol) was
coupled to N-(tert-butoxycarbonyl)-3-iodo--alanine methyl
ester (10.00 g, 30.40 mmol) in the presence of CuBrؒDMS
(0.80 g, 3.89 mmol) to give a residue which on purification by
flash chromatography over silica gel eluting with EtOAc–
heptane (1:9, v/v) gave two regioisomers in a ratio of 1:1 as
1
established by H NMR spectroscopy. The first eluted compo-
nent was (2S)-2-tert-butoxycarbonylamino-5,6-dimethylhept-5-
enoic acid methyl ester and further elution afforded (2S)-2-tert-
butoxycarbonylamino-4,4,5-trimethylhex-5-enoic acid methyl
ester. Fractions containing the initial component were pooled
and reduced in vacuo to give (2S)-2-tert-butoxycarbonylamino-
5,6-dimethylhept-5-enoic acid methyl ester 18 (2.51 g, 29%)
as a colourless oil. Analytical HPLC tr = 21.96 min (100%);
[α]D22 ϩ 26.1 (c 1.02 in CH2Cl2) (Found: C, 63.1; H, 9.3; N, 4.9.
C15H27NO4 requires C, 63.1; H, 9.5; N, 4.9%); νmax(film)/cmϪ1
3366 (m), 3154 (m), 2978 (s), 1744 (s), 1718 (s), 1506 (s), 1366 (s)
and 1164 (s); δH (500 MHz; CDCl3) 1.43 (9H, s, C(CH3)3),
(2S,5S)-2-tert-Butoxycarbonylamino-5,6-dimethylheptanoic
acid and (2S,5R)-2-tert-butoxycarbonylamino-5,6-dimethyl-
heptanoic acid 22
1.60 (9H, m, (CH ) C᎐C(CH )), 1.66 (1H, m, NHCHCH2A),
᎐
3
2
3
Following the general procedure for methyl ester saponification,
(2S,5S)-2-tert-butoxycarbonylamino-5,6-dimethylheptanoic
acid methyl ester and (2S,5R)-2-tert-butoxycarbonylamino-5,6-
dimethylheptanoic acid methyl ester 20 (6.60 g, 23.00 mmol)
gave after purification by flash chromatography over silica gel,
eluting with CHCl3–MeOH (95:5, v/v), (2S,5S)-2-tert-butoxy-
carbonylamino-5,6-dimethylheptanoic acid and (2S,5R)-2-tert-
butoxycarbonylamino-5,6-dimethylheptanoic acid 22 (6.28 g,
100%) as a colourless oil. Analytical HPLC tr = 21.44 min
(100%); δH (500 MHz; CDCl3) 0.79 (6H, d, J 6.5, (CH3)2ACH-
CH(CH3)), 0.84 (3H, d, J 7, (CH3)2BCHCH(CH3)), 1.15 (1H,
m, NHCHCH2CH2A), 1.28 (1H, m, (CH3)2CHCH(CH3)), 1.40
(1H, m, NHCHCH2CH2B), 1.44 (9H, s, C(CH3)3), 1.54 (1.5H,
br m, (CH3)2CHCH(CH3) and 0.5 NHCHCH2A), 1.68 (0.5H,
br m, 0.5 NHCHCH2A), 1.79 (0.5H, br m, 0.5 NHCHCH2B),
1.89 (0.5H, br m, 0.5 NHCHCH2B), 4.25 (1H, br m, NHCH-
CO2CH3) and 5.09 (1H, br s, NH); δC (125 MHz; CDCl3) 15.12
((CH3)2CHCH(CH3)), 17.75 and 17.89 ((CH3)2ACHCH(CH3)),
20.12 and 20.23 ((CH3)2BCHCH(CH3)), 28.27 (C(CH3)3), 29.46
and 29.62 (NHCHCH2CH2), 30.30 and 30.48 (NHCHCH2),
31.66 and 31.83 ((CH3)2CHCH(CH3)), 38.09 and 38.34 ((CH3)2-
CHCH(CH3)), 53.81 and 53.99 (NHCHCO2CH3), 80.01
(C(CH3)3), 155.69 (OC(O)NH) and 177.61 (NHCHCO2H);
HRMS 296.1831 (MNa, C14H27NO4Na requires 296.1838
(δ 2.4 ppm)); m/z (Electrospray-MS) 274 (19%) and 218
(100%).
1.85 (1H, m, NHCHCH2B), 2.00 (1H, ddd, J 13, 12.5 and 5,
NHCHCH2CH2A), 2.07 (1H, ddd, J 13, 10.5 and 6, NHCH-
CH2CH2B), 3.72 (3H, s, CO2CH3), 4.25 (1H, br m, NHCH-
CO2CH3) and 5.00 (1H, br d, J 7, NH); δC (125 MHz; CDCl3)
18.14 ((CH ) C᎐C(CH )), 19.92 ((CH3)2AC᎐C(CH )), 20.53
᎐
᎐
3
2
3
3
((CH ) C᎐C(CH )), 28.26 (C(CH ) ), 30.01 (NHCHCH CH ),
᎐
3
2B
3
3
3
2
2
30.86 (NHCHCH2), 52.10 (OCH3), 53.41 (NHCHCO2CH3),
79.74 (C(CH ) ), 125.36 ((CH ) C᎐C(CH )), 125.93 ((CH ) -
᎐
3
3
3
2
3
3 2
C᎐C(CH ), 155.30 (OC(O)NH) and 173.34 (NHCHCO CH );
᎐
3
2
3
HRMS 308.1829 (MNa, C15H27NO4Na requires 308.1838
(δ 2.9 ppm)); m/z (Electrospray-MS) 286 (100%).
Pooling together the fractions containing the later-eluting
component gave (2S)-2-tert-butyloxycarbonylamino-4,4,5-tri-
methylhex-5-enoic methyl ester 19 (2.60 g, 30%) as a colourless
oil. Analytical HPLC tr = 21.02 min (100%); [α]D18 ϩ3.5 (c 0.83 in
CH2Cl2) (Found: C, 62.7; H, 9.3; N, 4.95. C15H27NO4 requires
C, 63.1; H, 9.5; N, 4.9%); νmax(film)/cmϪ1 3368 (s), 3091 (m),
2934 (s), 1748 (s), 1717 (s) and 1516 (s); δH (500 MHz; CDCl3)
1.08 (3H, s, CH ᎐C(CH )C(CH ) ), 1.10 (3H, s, CH ᎐C-
᎐
᎐
2
2
3
3
2A
(CH3)C(CH3)2B), 1.40 (9H, s, C(CH3)3), 1.59 (1H, dd, J 14.5
and 9, NHCHCH2A), 1.73 (3H, d, J 1, H C᎐C(CH )), 1.90
᎐
2
3
(1H, dd, J 14.5 and 4, NHCHCH2B), 3.67 (3H, s, CO2CH3), 4.22
(1H, br m, NHCHCO2CH3), 4.77 (1H, d, J 1, CH2A᎐C(CH ))
᎐
3
and 4.81 (2H, br m, CH ᎐C(CH ) and NH); δ (125 MHz;
᎐
2B
3
C
CDCl ) 19.31 (CH ᎐C(CH )), 27.13 (CH ᎐CC(CH )C(CH )2A),
᎐
᎐
3
2
3
2
3
3
27.54 (CH ᎐CC(CH )C(CH ) ), 28.28 (C(CH ) ), 38.45 ((CH ᎐
᎐
᎐
2
2
3
3
2B
3
3
C(CH3)C(CH3)2), 42.91 (NHCHCH2), 51.29 (NHCHCO2CH3),
52.04 (CO2CH3), 79.64 (C(CH3)3), 110.88 (CH ᎐C(CH )),
(2S,5S)-2-Amino-5,6-dimethylheptanoic acid hydrochloride
salt and (2S,5R)-2-amino-5,6-dimethylheptanoic acid hydro-
chloride salt. Following the general procedure of N-Boc
removal using 4 M HCl in dioxane, (2S,5S)-2-tert-butoxy-
carbonylamino-5,6-dimethylheptanoic acid and (2S,5R)-2-
tert-butoxycarbonylamino-5,6-dimethylheptanoic acid (2.47 g,
9.05 mmol) gave (2S,5S)-2-amino-5,6-dimethylheptanoic acid
hydrochloride salt and (2S,5R)-2-amino-5,6-dimethylheptanoic
acid hydrochloride salt (1.84 g, 97%) as a solid and used in
the subsequent reaction without further purification; m/z
(Electrospray-MS) 174 (100%).
᎐
2
3
150.57 (CH ᎐C(CH )), 154.96 (OC(O)NH) and 174.04 (NHCH-
᎐
2
3
CO2CH3); HRMS 308.1838 (MNa, C15H27NO4Na requires
308.1838 (δ 2.2 ppm)); m/z (Electrospray-MS) 286 (100%).
(2S,5S)-2-tert-Butoxycarbonylamino-5,6-dimethylheptanoic
acid methyl ester and (2S,5R)-2-tert-butoxycarbonylamino-5,6-
dimethylheptanoic acid methyl ester 20
Following the general procedure for alkene hydrogenation, (2S)-
2-tert-butoxycarbonylamino-5,6-dimethylhept-5-enoic methyl
4290
J. Chem. Soc., Perkin Trans. 1, 2000, 4284–4292

View Article Online
(2S,5S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-5,6-di-
methylheptanoic acid and (2S,5R)-2-(9H-fluoren-9-ylmethoxy-
carbonylamino)-5,6-dimethylheptanoic acid 6
4,4,5-trimethylhexanoic acid 23 (5.33 g, 100%) as a colourless
oil. Analytical HPLC tr = 22.91 min (100%); [α]D17 Ϫ19.1 (c 0.70
in CH2Cl2); δH (500 MHz; CDCl3) 0.83 (6H, d, J 7, (CH3)2-
CHC(CH3)2), 0.86 (3H, s, (CH3)2CHC(CH3)2A), 0.90 (3H, s,
(CH3)2CHC(CH3)2B), 1.42 (9H, s, C(CH3)3), 1.43 (1H, m, NH-
CHCH2A), 1.55 (1H, m, (CH3)2CH), 1.82 (1H, br d, J 14.5,
NHCHCH2B), 4.31 (1H, br m, NHCHCO2CH3) and 4.86
Following the general procedure for Fmoc protection of
an amine, (2S,5S)-2-amino-5,6-dimethylheptanoic acid hydro-
chloride salt and (2S,5R)-2-amino-5,6-dimethylheptanoic
acid hydrochloride salt (1.84 g, 8.78 mmol) gave on purifi-
cation by flash chromatography over silica gel eluting with
CHCl3–CH3OH (100:0 to 95:5, v/v), (2S,5S)-2-(9H-fluoren-
9-ylmethoxycarbonylamino)-5,6-dimethylheptanoic acid and
(2S,5R)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-5,6-di-
methylheptanoic acid 6 (1.94 g, 56%) as an amorphous solid,
mp 43–44 ЊC. Analytical HPLC tr = 24.52 min (100%); δH (500
MHz; CDCl3) 0.78 (6H, m, (CH3)2ACHCH(CH3)), 0.84 (3H, d,
J 6.5, (CH3)2BCHCH(CH3)), 1.15 (1H, m, NHCHCH2CH2A),
1.29 (1H, m, (CH3)2CHCH(CH3)), 1.40 (1H, m, NHCHCH2-
CH2B), 1.54 (1H, m, (CH3)2CHCH(CH3)), 1.64 (0.5H, m,
0.5 NHCHCH2A), 1.73 (0.5H, m, 0.5 NHCHCH2A), 1.85 (0.5H,
m, 0.5 NHCHCH2B), 1.94 (0.5H, m, 0.5 NHCHCH2B), 4.22
(1H, t, J 7, H-9Ј), 4.37 (1H, m, NHCHCO2H), 4.41 (2H, br d,
J 7, CH2O), 5.29 (1H, br s, NH), 7.27 (2H, m, H-2Ј and H-7Ј),
7.37 (2H, m, H-3Ј and H-6Ј), 7.56 (2H, m, H-1Ј and H-8Ј)
and 7.75 (2H, d, J 7, H-4Ј and H-5Ј); δC (125 MHz; CDCl3)
15.12 ((CH3)2CHCH(CH3)), 17.70 and 17.94 ((CH3)2ACHCH-
(CH3)), 20.14 and 20.25 ((CH3)2BCHCH(CH3)), 29.44 and
29.58 (NHCHCH2CH2), 30.26 and 30.39 (NHCHCH2), 31.59
and 31.86 ((CH3)2CHCH(CH3)), 38.10 and 38.28 ((CH3)2-
CHCH(CH3)), 47.11 (CH-9Ј), 53.98 and 54.08 (NHCHCO2H),
67.08 and 67.61 (CH2O), 119.72 (CH-4Ј and CH-5Ј), 124.80
(CH-1Ј and CH-8Ј), 126.81 (CH-2Ј and CH-7Ј), 127.46 (CH-3Ј
and CH-6Ј), 141.05 (C-4aЈ and C-5aЈ), 143.47 (C-1aЈ and
C-8aЈ), 155.89 (OC(O)NH) and 177.19 (NHCHCO2H); HRMS
418.1992 (MNa, C24H29NO4Na requires 418.1994 (δ 0.62
ppm)); m/z (Electrospray-MS) 396 (46%) and 267 (100%).
(1H, br d, J 8, NH); δC (125 MHz; CDCl3) 17.23 ((CH3)2A
-
CHC(CH3)2), 17.36 ((CH3)2BCHC(CH3)2), 23.82 ((CH3)2-
CHC(CH3)2A), 24.44 ((CH3)2CHC(CH3)2B), 28.30 (C(CH3)3),
35.41, 35.99 ((CH3)2CHC(CH3)2), 42.42 (NHCHCH2), 50.84
(NHCHCO2CH3), 80.12 (C(CH3)3, 155.44 (OC(O)NH) and
178.93 (NHCHCO2H); HRMS 296.1826 (MNa, C14H27NO4Na
requires 296.1838 (δ 4.1 ppm)); m/z (Electrospray-MS) 274
(38%) and 218 (100%).
(2S)-2-Amino-4,4,5-trimethylhexanoic acid hydrochloride salt.
Following the general procedure of N-Boc removal using
4 M HCl in dioxane, (2S)-2-tert-butoxycarbonylamino-4,4,5-
trimethylhexanoic acid (1.85 g, 6.80 mmol) gave (2S)-2-amino-
4,4,5-trimethylhexanoic acid hydrochloride salt (1.42 g, 100%)
as a solid; m/z (Electrospray-MS) 174 (100%).
(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-4,4,5-tri-
methylhexanoic acid 7
Following the general procedure for Fmoc protection of
an amine, (2S)-2-amino-4,4,5-trimethylhexanoic acid hydro-
chloride salt (1.42 g, 6.78 mmol) gave on purification by flash
chromatography over silica gel eluting with CHCl3–CH3OH
(100:0 to 95:5, v/v), (2S)-2-(9H-fluoren-9-ylmethoxycarbonyl-
amino)-4,4,5-trimethylhexanoic acid 7 (1.23 g, 46%) as an
amorphous solid, mp 61–62 ЊC. Analytical HPLC tr = 24.28
min (100%); [α]D17 Ϫ15.0 (c 0.62 in CH2Cl2); δH (500 MHz;
CDCl3) 0.85 (9H, m, (CH3)2CHC(CH3)2A), 0.91 (3H, s,
(CH3)2CHC(CH3)2B), 1.46 (1H, dd, J 14 and 9, NHCH2A), 1.54
(1H, m, (CH3)2CH), 1.88 (1H, dd, J 14 and 3, NHCH2B), 4.21
(1H, t, J 6.5, H-9Ј), 4.40 (3H, br m, NHCHCO2H and CH2O),
5.10 (1H, br d, J 7.5, NH), 7.27 (2H, m, H-2Ј and H-7Ј), 7.36
(2H, m, H-3Ј and H-6Ј), 7.57 (2H, m, H-1Ј and H-8Ј) and 7.74
(2H, d, J 7, H-4Ј and H-5Ј); δC (125 MHz; CDCl3) 17.01
((CH3)2ACH), 17.16 ((CH3)2BCH), 23.69 ((CH3)2CHC(CH3)2A),
24.27 ((CH3)2CHC(CH3)2B), 35.27 ((CH3)2CHC(CH3)2),
35.73 ((CH3)2CH), 41.88 (NHCHCH2), 46.93 (CH-9Ј), 54.20
(NHCHCO2H), 66.79 (CH2O), 119.70 (CH-4Ј and CH-5Ј),
124.78 (CH-1Ј and CH-8Ј), 126.79 (CH-2Ј and CH-7Ј), 127.44
(CH-3Ј and CH-6Ј), 141.05 (C-4aЈ and C-5aЈ), 143.61 (C-1aЈ
and C-8aЈ), 155.68 (OC(O)NH) and 178.00 (NHCHCO2H);
HRMS 418.1990 (MNa, C24H29NO4Na requires 418.1994
(δ 1.1 ppm)); m/z (Electrospray-MS) 396 (100%).
(2S)-2-tert-Butoxycarbonylamino-4,4,5-trimethylhexanoic acid
methyl ester 21
Following the general procedure for alkene hydrogenation,
(2S)-2-tert-butoxycarbonylamino-4,4,5-trimethylhex-5-enoic
methyl ester 19 (5.85 g, 3.51 mmol) yielded on purification
by flash column chromatography over silica gel, eluting with
EtOAc–heptane (1:5, v/v), (2S)-2-tert-butoxycarbonylamino-
4,4,5-trimethylhexanoic acid methyl ester 21 (5.60 g, 95%) as
a colourless oil. Analytical HPLC tr = 22.91 min (100%);
[α]D17 Ϫ5.7 (c 0.83 in CH2Cl2) (Found: C, 62.7; H, 10.0; N, 4.8.
C15H29NO4 requires C, 62.7; H, 10.2; N, 4.9%); δH (500 MHz;
CDCl3) 0.83 (3H, d, J 7, (CH3)2ACHC(CH3)2), 0.84 (3H, d,
J 7, (CH3)2BCHC(CH3)2), 0.85 (3H, s, (CH3)2CHC(CH3)2A),
0.89 (3H, s, (CH3)2CHC(CH3)2B), 1.40 (1H, dd, J 14.5 and 9,
NHCHCH2A), 1.42 (9H, s, C(CH3)3), 1.54 (1H, q, J 7, (CH3)2-
CH), 1.72 (1H, dd, J 14.5 and 3, NHCHCH2B), 3.71 (3H, s,
CO2CH3), 4.34 (1H, br m, NHCHCO2CH3) and 4.79 (1H, br d,
J 8, NH); δC (125 MHz; CDCl3) 17.22 ((CH3)2ACHC(CH3)2),
17.34 ((CH3)2BCHC(CH3)2), 23.81 ((CH3)2CHC(CH3)2A), 24.41
((CH3)2CHC(CH3)2B), 28.28 (C(CH3)3), 35.33 ((CH3)2CH-
C(CH3)2), 35.94 ((CH3)2CHC(CH3)2), 42.67 (NHCHCH2),
50.69 (NHCHCO2CH3), 52.14 (CO2CH3), 79.80 (C(CH3)3),
155.08 (OC(O)NH) and 174.57 (NHCHCO2CH3); HRMS
310.1987 (MNa, C15H29NO4Na requires 310.1994 (δ 2.4 ppm));
m/z (Electrospray-MS) 288 (48%) and 232 (100%).
Acknowledgements
We thank Medivir (UK) for partial funding of a studentship
(H. J. C. Deboves). We also thank Dr M. N. S. Hill,
Mrs L. Cook, Mr D. Dunbar and Mr S. Addison for obtaining
spectroscopic and other data, and Mr E. Hart for his invaluable
technical assistance.
References
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Following the general procedure for methyl ester saponification,
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J. Chem. Soc., Perkin Trans. 1, 2000, 4284–4292
4291

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J. Chem. Soc., Perkin Trans. 1, 2000, 4284–4292