New routes to ss-cycloalkylalanine derivatives using serine-derived organozinc reagents

Article abstract of DOI:10.1039/b512784j

Two distinct routes to β-cycloalkylalanine derivatives have been developed. The first route employs the reaction of the iodoalanine-derived zinc-copper reagent 2 with cycloalk-l-en-3-yl phosphates, and the second uses the palladium-catalysed coupling of t

Full text of DOI:10.1039/b512784j

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A R T I C L E
New routes to b-cycloalkylalanine derivatives using serine-derived
organozinc reagents
Tomas Carrillo-Marquez,a Lorenzo Caggiano,a Richard F. W. Jackson,*a Urszula Grabowska,b
Alastair Raeb and Matthew J. Tozerb
a Department of Chemistry, Dainton Building, University of Sheffield, Brook Hill, Sheffield,
UK S3 7HF. E-mail: r.f.w.jackson@shef.ac.uk
b Medivir UK Ltd, Chesterford Research Park, Little Chesterford, Essex, UK CB10 1XL
Received 4th August 2005, Accepted 8th September 2005
First published as an Advance Article on the web 3rd October 2005
Two distinct routes to b-cycloalkylalanine derivatives have been developed. The first route employs the reaction
of the iodoalanine-derived zinc–copper reagent 2 with cycloalk-1-en-3-yl phosphates, and the second uses the
palladium-catalysed coupling of the iodoalanine-derived zinc reagent 1 with cycloalkenyl triflates; in each case,
catalytic hydrogenation of the unsaturated product leads to the protected b-cycloalkylalanine. The latter route allows
access to a range of cycloalkyl derivatives, with ring sizes of 5–8. b-(1-Methyl-1-cyclohexyl)alanine may be prepared
using reaction of the zinc–copper reagent 2 with 3-methyl-2-cyclohexenyl chloride, followed by hydrogenation. The
corresponding cyclopentyl derivative may be prepared by reaction of the same zinc–copper reagent 2 with diethyl
geranylphosphate, followed by ring-closing metathesis and hydrogenation.
glycine anion chemistry has also been reported.6 A distinctive
Introduction
approach, involving the reaction of 9-alkylborabicyclononane
Non-natural analogues of proteinogenic amino acids are an
derivatives with a glycine cation equivalent, followed by enan-
important tool in the context of exploring receptor binding
tioselective protonation, has been applied to the preparation
and preparing drug-like molecules able to interact with such
of cyclopentyl and cyclohexylalanines with moderate ee (62%).7
receptors. Proteases, enzymes that cleave proteins or polypro-
The copper-catalysed ring-opening of a serinol-derived aziridine
teins at distinct sites, are involved in virtually all biological
by cyclopentylmagnesium chloride, followed by oxidation, has
functions and dysfunctions. They regulate numerous biochem-
also been reported.8 The most general route presently available
ical, physiological and disease processes by controlling protein
to enantiomerically pure cyclopentyl, cycloheptyl and cycloocty-
synthesis and degradation through hydrolysis of specific amide
lalanines involves the electrophilic azidation of chiral imide
bonds in the polypeptide. A number of therapeutic areas have
enolates,3,9 employing the method pioneered by Evans.10
been addressed by the inhibition of proteases and physiological
We have previously reported a new route to lipophilic amino
disorders. For example, a deficiency in cathepsin K can lead
acids using the copper-catalysed reaction of the serine-derived
to pycnodysostosis, an autosomal recessive disorder while
organozinc reagent 1 with allylic halides, or by transmetallation
overexpression of cathepsin K may be responsible for excessive
of zinc reagent 1 to give the zinc–copper reagent 2.11 We now
bone breakdown which is indicative for osteoporosis.1
wish to report the application and extension of this approach
to the preparation of protected derivatives of a range of non-
natural branched amino acids containing a b-cycloalkyl residue,
in which the stereochemistry is derived from serine.
Proteases recognise defined amino acid sequences adjacent to
the cleavage site and the elucidation of this interaction is usually
important in the design of either peptides or peptidomimetic
molecules able to inhibit protease function.2 Such inhibitors,
containing natural and non-natural amino acids, can provide
enhanced information on the best amino acids to fill the various
enzyme pockets.
Whether employed in receptor exploration or peptide/
peptidomimetic construction it is important that constituent
amino acids, natural or non-natural, have a defined stereochem-
istry at the a carbon. Typically this will be the L-stereochemistry
but a number of therapeutics also employ specific amino acids
with D-stereochemistry at this position. Accordingly there is a
need for efficient methodology allowing access to amino acids
with defined stereochemistry at C-a. Although an enormous
amount of effort has been devoted to developing such meth-
ods, substantial challenges still remain. Non-natural branched
amino acids, especially compounds with highly lipophilic side
chains, have recently started to attract attention as components
Synthetic design
of enzyme inhibitors.
The most direct route to the targets above would require simple
alkylation of either zinc reagent 1 or zinc–copper reagent 2 with
the appropriate cycloalkyl halide. While recent significant de-
velopments in the area of palladium12,13 and nickel14–16 catalysed
coupling of organozinc reagents with alkyl halides suggests that
such an approach may be possible, we have initially explored two
different routes which use the unsaturated isomeric compounds
3 and 4, respectively, as intermediates (Scheme 1).
While cyclohexylalanines, important as components of renin
inhibitors,3 may be prepared by catalytic reduction of the
corresponding phenylalanine derivatives,4 routes to cyclopentyl,
cycloheptyl and cyclooctylalanines are less well-developed. A
general route to these compounds using radical addition to dehy-
droalanine derivatives has been developed, yielding the products
as racemates.5 The synthesis of racemic cyclooctylalanine using
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 1 1 7 – 4 1 2 3
4 1 1 7
©

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the yield was modest (36%).19 This general process has since
been employed in the synthesis of neodysiherbaine A.20 Given
the recent improvements in yields that have been observed
by preparing and coupling organozinc reagents in DMF as
solvent,21 further optimisation of this process seemed appropri-
ate. In the event, palladium-catalysed coupling of zinc reagent
1 (prepared in DMF) with a series of cycloalkenyl triflates 6a–
d yielded the expected cycloalkenylalanine derivatives 4a–d in
modest, but consistent, yields. In all cases, the yields are based
on the more valuable iodoalanine starting material from which
the zinc reagent 1 was prepared, with the cycloalkenyl triflate
being used in small excess (1.25 equiv.). When the coupling
reaction between 1 and cycloheptenyl triflate was conducted
on a larger scale (6 mmol) and at room temperature, the yield
of product 4c increased to 58%, again based on iodoalanine.
Catalytic hydrogenation of 4a–d gave the desired products 7a–
d respectively, in excellent yields (Scheme 3). This latter route
ultimately proved to be a more effective and general route to the
targets.
Scheme 1 Retrosynthetic plan.
Results and discussion
Allylation route
Given previous success using the allylation of the zinc–copper
reagent 2, initial efforts were directed towards the synthesis
of the cycloalken-1-en-3-yl diethyl phosphates 5a–c, X =
OP(O)(OEt)2. Phosphorylation, using pyridine and diethyl
chlorophosphate, of the precursor alcohols, straightforwardly
prepared by Luche reduction of the corresponding enones,17
proved challenging. It has been reported that cyclohex-1-en-
3-yl phosphate 5b is not stable to silica gel chromatography,18
but careful chromatographic purification using diethyl ether as
eluent did allow 5b to be isolated in pure form (60%). Prepa-
ration of 5c was straightforward (72%), since it was perfectly
stable to chromatographic purification, but all attempts to pre-
pare the simple cyclopent-1-en-3-yl diethyl phosphate 5a were
unsuccessful.† While it would have been possible to explore the
use of other less good leaving groups, the success of the vinylation
route meant that this was not pursued. Treatment of the allylic
phosphates 5b and 5c with the zinc–copper reagent 2, prepared in
DMF, resulted in the formation of the expected products 3b and
3c as a mixture of diastereoisomers, and in moderate yield. Care-
ful control, especially of the reaction temperature, proved to be
necessary. Catalytic hydrogenation of 3b and 3c gave the desired
products 7b and 7c, respectively, in excellent yield (Scheme 2).
While this route was effective for preparing the cyclohexyl
and cycloheptyl analogues, the careful control of reaction
conditions that was required meant that an alternative route was
desirable.
Scheme 3 Reagents and conditions: i, 1, Pd(PPh3)2Cl2 (5 mol%), DMF,
50 ◦C, 16 h; ii, H2, Pd/C, MeOH.
Tertiary cycloalkyl analogues
In the context of our interest in more highly branched ana-
logues of lipophilic amino acids,11 synthesis of the additionally
methylated cyclopentyl and cyclohexyl compounds 8a and 8b
was considered. Self-evidently, only the allylation approach was
possible, and the presumed enhanced instability of the required
allylic phosphates 9a and 9b, compared to their non-methylated
congeners 5a and 5b (Fig. 1), meant that an alternative was
required.
Fig. 1 (1-Methyl-1-cycloalkyl)alanine derivatives.
The first approach to be explored relied on the prepara-
tion of the cycloalkenyl chorides 10a and 10b. All efforts to
prepare the cyclopentenyl derivative 10a were frustrated, due
to the great instability of the compound. However, it did
prove possible to prepare the cyclohexenyl derivative 10b by
treatment of 3-methyl-2-cyclohexen-1-ol with thionyl chloride–
pyridine in diethyl ether. The product was isolated as a 2.5 :
1 mixture with the product of allylic isomerisation, 11b.
Treatment of this mixture with the zinc–copper reagent 2 gave
a mixture of allylation products 12b (as a 1 : 1 mixture of
diastereoisomers) and 13 (combined yield 53%), which was not
separated but instead subjected to catalytic hydrogenation. The
desired product 8b could then be isolated (62%) straightfor-
wardly. The remainder of the material was a mixture of di-
astereoisomers 14 resulting from hydrogenation of compound 13
(Scheme 4).
Scheme 2 Reagents and conditions: i, (EtO)2POCl, pyridine, CH2Cl2,
0
◦C to rt, 16 h; ii, 2, DMF, −30 ◦C to rt, 16 h; iii, H2, Pd/C, MeOH.
Vinylation route
In earlier work, we had established that the palladium-catalysed
coupling of an analogue of zinc reagent 1 with cyclohexenyl
triflate 6b did yield the expected cyclohexenylalanine, although
† This observation was somewhat unexpected, given the straightforward
preparation of diethyl 2-iodo-2-cyclopentenyl-1-phosphate using the
same method.28
Since it was not possible to prepare the cyclopentenyl deriva-
tive 10a, an entirely new route to 8a was required. It appeared
4 1 1 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 1 1 7 – 4 1 2 3

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The success of this latter route suggests that a variety of
1-alkylcyclopentenes (and 1-alkylcyclopentanes) may also be
prepared by the same strategy. The combination of (catalytic
asymmetric) allylation of organometallic nucleophiles, followed
by RCM, has been used before as a route to cyclopentene
derivatives.23
In conclusion, a variety of routes to cycloalkyl alanine
derivatives has been developed, further extending the breadth
of application of serine-derived organometallic reagents.
Experimental
General experimental procedures have been previously
described.11 Dry DMF was distilled from calcium hydride and
˚
stored over 4 A molecular sieves. Cycloalkenyl triflates were
prepared by literature methods.20,24 3-Methyl-2-cyclohexen-1-ol
was prepared by reduction of 3-methylcyclohex-2-enone using
Luche conditions.17
Scheme 4 Reagents and conditions: i, SOCl2, pyridine, Et2O, 0 ◦C to rt,
16 h; ii, 2, DMF, −30 ◦C to rt, 16 h; iii, H2, Pd/C, MeOH.
General procedure for the synthesis of cycloalken-1-en-3-yl
diethyl phosphates
that unsaturated intermediate 12a could in principle be prepared
by ring-closing metathesis (RCM)22 of the allylation product 15,
itself available by reaction of diethyl geranylphosphate 16 with
the zinc–copper reagent 2.
Diethyl chlorophosphate (1.03 equiv.) was added to a solution
of cycloalken-1-ol (1 equiv.) and pyridine (5.2 equiv.) in CH2Cl2
◦
(5 cm3) at 0 C under a nitrogen atmosphere, and the mixture
stirred for 1 h at 0 ◦C and then overnight at room temperature.
The mixture was diluted with ether (50 cm3) and washed with
hydrochloric acid (3 × 10 cm3, 1 M), brine (1 × 10 cm3)
and saturated sodium bicarbonate (1 × 10 cm3) and dried
over anhydrous magnesium sulfate. The solvent was removed
under reduced pressure and the product purified by flash
chromatography using diethyl ether as solvent.
In the event, treatment of zinc–copper reagent 2 with diethyl
geranyl phosphate 16 yielded a mixture of three compounds, the
formal product of SN2 substitution 17 and the two diastereoiso-
meric SN2ꢀ products 15, with the latter predominating in a ratio
of 88 : 12, and in a combined yield of 47%. These compounds
could not be straightforwardly separated, but since this was
not crucial to the planned route, the mixture was subjected to
RCM using second-generation Grubbs’ catalyst. This yielded
a mixture of the cyclopentenyl adducts 12a as a mixture of
diastereoisomers, as well as a side product tentatively identified
as the alkene 18,11 presumably derived by cross metathesis of
17 with the isopropylidene fragment formed as a side-product
during the RCM of 15. Hydrogenation of this mixture then gave
the desired target 8a, which was separated from compound 19
(derived by hydrogenation of 18), and which was unambiguously
identified by spectroscopic comparison with an authentic sample
of 19 (Scheme 5).11 The overall yield of 8a for the RCM
and hydrogenation steps from 15 was 84%. This route has
been successfully scaled up to give 2 g of the product 8a,
demonstrating its practicality.
Cyclohexen-1-en-3-yl diethyl phosphate 5b25. Following the
above procedure using 2-cyclohexen-1-ol (0.37 g, 3.76 mmol) the
product 5b was obtained as a colourless oil (0.52 g, 60% yield).
dH (400 MHz, CDCl3) 1.28 (6H, t, J 7.0, OCH2CH3), 1.53–1.60
(1H, m, CH2), 1.71–1.75 (1H, m, CH2), 1.80–2.06 (4H, m, CH2),
4.03 (2H, q, J 7.0, OCH2CH3), 4.07 (2H, q, J 7.0, OCH2CH3),
4.82 [1H, br s, CHOP(O)(OEt)2], 5.74 (1H, dd, J 10.0 and 1.5,
CH), 5.88–5.92 (1H, m, CH); dC (100 MHz, CDCl3) 16.0 (d, JCP
7.0, OCH2CH3), 18.3 (CH2), 24.6 (CH2), 29.8 (d, JCP 4.5, CH2),
63.4 (d, JCP 5.0, OCH2CH3), 72.1 [d, JCP 5.5, CHOP(O)(OEt)2],
126.2 (d, JCP 5.0, CH), 132.6 (CH).
Cyclohepten-1-en-3-yl diethyl phosphate 5c. Following the
above procedure using 2-cyclohepten-1-ol (0.46 g, 4.08 mmol)
the product 5c was obtained as a colourless oil (0.73 g, 72%
yield). mmax (liquid film)/cm−1 2984, 2931, 1447, 1395, 1262,
1034, 1011, 981; dH (400 MHz, CDCl3), 1.24 (3H, t, J 7.0,
OCH2CH3), 1.25 (3H, t, J 7.0, OCH2CH3), 1.27–1.34 (1H, m,
CH2), 1.47–1.60 (2H, m, CH2), 1.63–1.72 (1H, m, CH2), 1.81–
1.98 (3H, m, CH2), 2.06–2.14 (1H, m, CH2), 3.99 (2H, q, J 7.0,
OCH2CH3), 4.01 (2H, q, J 7.0, OCH2CH3), 4.88–4.93 [1H,
m, CHOP(O)(OEt)2], 5.65–5.75 (2H, m, CH); dC (100 MHz,
CDCl3) 15.9 (d, JCP 6.5, OCH2CH3), 26.1 (d, JCP 4.5, CH2),
28.3 (CH2), 34.4 (d, JCP 4.5, CH2), 36.6 (CH2), 63.5 (d, JCP 5.5,
OCH2CH3), 78.3 [d, JCP 5.5, CHOP(O)(OEt)2], 131.5 (CH),
133.9 (d, JCP 5.0, CH).
General procedure for the synthesis of cycloalken-2-yl alanine
amino acids 3
Zinc dust (0.294 g, 4.5 mmol) was placed in a 10 cm3 round
bottom flask equipped with a side arm, stirrer bar and fitted
with a 3-way tap. The flask was evacuated and flushed with
nitrogen 3 times. Dry DMF (0.5 cm3) and TMSCl (0.1 cm3) were
added and the mixture was stirred for 35 min under a nitrogen
atmosphere. The solvent was removed by syringe and the zinc
dried under reduced pressure while heating with a heat gun.
A solution of N-(tert-butoxycarbonyl)-3-iodo-L-alanine methyl
ester (0.247 g, 0.75 mmol) in dry DMF (0.3 cm3) was prepared
Scheme 5 Reagents and conditions: i, 2, DMF, −30 ◦C to rt, 16 h;
ii, 2nd generation Grubbs’ catalyst (5 mol%), toluene, 80 ◦C, 16 h;
iii, H2, Pd/C, MeOH.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 1 1 7 – 4 1 2 3
4 1 1 9

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under nitrogen, and this solution was transferred by syringe
to the zinc, and the mixture stirred at 0 ◦C for 20 min. TLC
(heptane : ethyl acetate, 1 : 1) confirmed that zinc insertion was
complete.
132.1 (Aꢀ, CH), 135.7 (A, CH), 136.5 (Aꢀ, CH), 155.3 [A and Aꢀ,
NHCOC(CH)3], 173.8 (A and Aꢀ, CO2CH3).
Synthesis of protected cycloalkyl alanine amino acids 7
In the meantime, a 10 cm3 round bottomed flask equipped
with a side arm and fitted with a 3-way tap was charged with
CuCN (0.75 mmol) and dry lithium chloride (1.5 mmol) under
nitrogen. Dry DMF (0.6 cm3) was added and the resulting
solution was cooled using a dry ice–acetonitrile bath (−30 ◦C).
The solution of zinc reagent prepared previously was transferred
carefully by syringe (avoiding the excess of zinc dust present) to
the mixture of CuCN : LiCl (1 : 2) in DMF. The resulting mixture
was warmed to 0 ◦C, and stirred for 5 min to allow the formation
of the organocopper derivative 2. Finally the electrophile 5
(1 mmol) was added and the mixture placed again in a dry ice–
acetonitrile bath and stirred overnight (temperature increased
slowly from −30 ◦C to room temperature). The reaction mixture
A 0.1 M solution of the protected cycloalken-2-yl alanine amino
acid 3 in methanol was treated with palladium (70 mg mmol−1
of substrate, 10 wt% on activated carbon) and stirred vigorously
under an atmosphere of hydrogen for 24 h. The catalyst was
R
removed by filtration through Celiteꢀ and the solvent removed
under reduced pressure to give the product 7.
(2S)-2-tert-Butoxycarbonylamino-3-cyclohexylpropanoic acid
methyl ester 7b. Following the above procedure using the
mixture of the two diastereoisomers 3b (43 mg, 0.15 mmol)
the product 7b was obtained as colourless oil (41 mg, 96%).
[a]2D2 +2.0 (c 3.92 in CHCl3); m/z (EI) (Found MNa+ 308.1829;
C15H27NO4Na requires 308.1838) MH+ 308 (100%), 252 (3),
186 (19); mmax (liquid film)/cm−1 2924, 1715, 1516, 1366 and
1165; dH (400 MHz, CDCl3) 0.83–0.98 (2H, m, CH2), 1.10–
1.30 (4H, m, CH2), 1.43 [9H, s, C(CH3)3], 1.58–1.75 [6H,
m, CH2 + CHAHBCHNH + CH(CH2)5], 1.80 (1H, br d,
J 13.5, CHAHBCHNH), 3.71 (3H, s, OCH3), 4.27–4.36 (1H,
m, CHCO2CH3), 4.86 (1H, d, J 8.0, NH); dC (100 MHz, CDCl3)
26.1 (CH2), 28.2 [C(CH3)3], 32.4 (CH2), 33.7 [CH(CH2)5], 34.0
(CH2), 40.3 (CH2CHNH), 51.3 (CHCO2CH3), 52.1 (CO2CH3),
79.8 [C(CH3)3], 155.4 [NHCOC(CH)3], 174.4 (CO2CH3).
R
was diluted with ethyl acetate and filtered through Celiteꢀ.
The solvent was removed under reduced pressure, and the
residue was diluted with ethyl acetate (50 cm3) and washed
with saturated aqueous ammonium chloride solution (15 cm3)
and brine (15 cm3). The organic phase was dried over sodium
sulfate and concentrated under reduced pressure. The two
diastereoisomeric products 3 were obtained after purification
by flash chromatography using a mixture of heptane and ethyl
acetate (typically 3 : 1).
(2S,3RS)-2-tert-Butoxycarbonylamino-3-cyclohexen-2ꢀ -enyl-
propanoic acid methyl ester 3b. The product was obtained as
an inseparable mixture of two diastereoisomers (A and Aꢀ, in
53 : 47 ratio) as a colourless oil (83 mg, 40%); m/z (EI) (Found
MNa+ 306.1686; C15H25NO4Na requires 306.1681) 322 (MK+,
100%), MNa+ 306 (6), 184 (16); mmax (liquid film)/cm−1 2929,
1747, 1715, 1517, 1437, 1366 and 1168; dH (400 MHz, CDCl3)
1.18–1.30 (A and Aꢀ, 1H, m, CH2), 1.41 [A, 9H, s, C(CH3)3],
1.42 [Aꢀ, 9H, s, C(CH3)3], 1.47–1.88 (A and Aꢀ, 5H, m, CH2),
1.95–1.99 (A and Aꢀ, 2H, m, CH2), 2.14–2.22 [A and Aꢀ, 1H,
m, CH(CH2)2CHCH], 3.71 (A, 3H, s, OCH3), 3.72 (Aꢀ, 3H, s,
OCH3), 4.34–4.42 (A and Aꢀ, 1H, m, CHCO2CH3) 4.90 (A, 1H,
d, J 8.0, NH), 4.94 (Aꢀ, 1H, d, J 8.0, NH), 5.46 (A, 1H, dd,
J 10.0 and 2.0, CH), 5.60 (Aꢀ, 1H, dd, J 10.0 and 2.0, CH),
5.67–5.73 (A and Aꢀ, 1H, m, CH); dC (100 MHz, CDCl3) 20.9
(A, CH2), 21.0 (Aꢀ, CH2), 25.1 (A and Aꢀ, CH2), 28.2 [A and Aꢀ,
C(CH3)3], 29.1 (A and Aꢀ, CH2), 31.4 [A, CH(CH2)2CHCH],
31.5 [Aꢀ, CH(CH2)2CHCH], 39.3 (A, CH2CHNH), 39.4 (Aꢀ,
CH2CHNH), 51.4 (A, CO2CH3), 51.5 (Aꢀ, CO2CH3), 52.2
(A and Aꢀ, CHCO2CH3), 79.9 [A and Aꢀ, C(CH3)3], 128.0
(A and Aꢀ, CH), 129.9 (A, CH), 130.7 (Aꢀ, CH), 155.4 [A and
Aꢀ, NHCOC(CH)3], 173.8 (A and Aꢀ, CO2CH3).
(2S,3RS)-2-tert-Butoxycarbonylamino-3-cyclohepten-2ꢀ-enyl-
propanoic acid methyl ester 3c. The product was obtained as
an inseparable mixture of two diastereoisomers (A and Aꢀ in a
60 : 40 ratio) as a colourless oil (121 mg, 55%); m/z (EI) (Found
MH+ 298.2017 C16H28NO4 requires 298.2018) MNa+ 320 (11%),
MH+ 298 (6%), 242 (48), 198 (100); mmax (liquid film)/cm−1
2921, 1746, 1716, 1446, 1366 and 1164; dH (400 MHz, CDCl3)
1.12–1.37 (A and Aꢀ, 2H, m, CH2), 1.41 [A, 9H, s, C(CH3)3],
1.42 [Aꢀ, 9H, s, C(CH3)3], 1.49–1.67 (A and Aꢀ, 4H, m, CH2),
1.75–1.92 (A and Aꢀ, 2H, m, CH2), 2.06–2.12 (A and Aꢀ, 2H,
m, CH2), 2.28–2.38 [A and Aꢀ, 1H, m, CH(CH2)2CHCH],
3.71 (A and Aꢀ, 3H, s, OCH3), 4.26–4.35 (A and Aꢀ, 1H, m,
CHCO2CH3), 4.92 (A, 1H, d, J 8.5, NH), 4.96 (Aꢀ, 1H, d,
J 8.5, NH), 5.47 (A, 1H, dd, J 10.5 and 3.5, CH), 5.55 (Aꢀ, 1H,
dd, J 10.5 and 3.5, CH), 5.72–5.81 (A and Aꢀ, 1H, m, CH); dC
(100 MHz, CDCl3) 28.2 [A and Aꢀ, C(CH3)3], 28.4 (A, CH2),
28.5 (Aꢀ, CH2), 29.8 (A, CH2), 29.9 (Aꢀ, CH2), 32.1 (A and
Aꢀ, CH2), 33.5 (A and Aꢀ, CH2), 35.7 [A, CH(CH2)2CHCH],
35.8 [Aꢀ, CH(CH2)2CHCH], 39.5 (A, CH2CHNH), 39.6 (Aꢀ,
CH2CHNH), 51.7 (A and Aꢀ, CHCO2CH3), 52.0 (A, CO2CH3),
52.1 (Aꢀ, CO2CH3), 79.7 [A and Aꢀ, C(CH3)3], 132.0 (A, CH),
(2S)-2-tert-Butoxycarbonylamino-3-cycloheptylpropanoic acid
methyl ester 7c. Following the above procedure using the
mixture of the two diastereoisomers 3c (58 mg, 0.20 mmol) the
product 7c was obtained as colourless oil (57 mg, 98%). [a]2D2 +3.5
(c 6.0 in CHCl3); m/z (EI) (Found MH+ 300.2162; C16H30NO4
requires 300.2175) MNa+ 322 (4%), MH+ 300 (61), 244 (100),
200 (11); mmax (liquid film)/cm−1 2926, 1717, 1507, 1367 and 1168;
dH (400 MHz, CDCl3) 1.15–1.22 (2H, m, CH2), 1.44 (9H, s,
C(CH3)3), 1.36–1.48 (3H, m), 1.52–1.70 (9H, m), 1.72–1.78 (1H,
m, CHAHBCHNH), 3.72 (3H, s, OCH3), 4.26–4.35 (1H, m,
CHCO2CH3), 4.86 (1H, d, J 8.0, NH); dC (100 MHz, CDCl3)
26.5 (CH2), 28.2 (C(CH3)3), 33.7 (CH(CH2)6), 35.2 (CH2), 35.7
(CH2), 40.3 (CH2CHNH), 52.1 (CHCO2CH3), 52.4 (CO2CH3),
80.0 (C(CH3)3), 155.6 (NHCOC(CH)3), 174.5 (CO2CH3).
General procedure for the synthesis of protected cycloalken-
1-yl alanine amino acids 4
Organozinc reagent 1 (1 equiv.) was prepared using the same
procedure described in the preparation of 3. The solution of
organozinc reagent 1 was transferred carefully by syringe (avoid-
ing the excess of zinc dust present) to a separate 25 cm3 round
bottom flask, equipped with a side arm, and which had been
charged previously with dichlorobis(triphenylphosphine) palla-
dium(II) (5 mol%), the cycloalken-1-yl triflate 6 (1.25 equiv.) and
dry DMF (0.4 cm3 per mmol of 1) under a nitrogen atmosphere.
Dry DMF (0.4 cm3 per mmol of 1) was added to the residual zinc
dust and the washings were transferred to the reaction mixture.
The mixture was stirred at 50 ◦C overnight, then cooled, diluted
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with ethyl acetate and filtered through Celiteꢀ. The solvent was
removed under reduced pressure (primarily to remove traces of
DMF which interfere with the aqueous work-up). The residue
was diluted with ethyl acetate (200 cm3) and washed with
saturated aqueous ammonium chloride solution (50 cm3), brine
(50 cm3). The organic phase was dried over sodium sulfate and
concentrated under reduced pressure. The product was obtained
after purification by flash chromatography using heptane and
ethyl acetate (typically 3 : 1) as eluent. In case of contamination
of the product by triphenylphosphine, the crude product was
dissolved in CH2Cl2 and washed with hydrogen peroxide, 10%
aqueous sodium sulfite solution and water. The solution was
dried over sodium sulfate and removed under reduced pressure.
4 1 2 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 1 1 7 – 4 1 2 3

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(2S)-2-tert-Butoxycarbonylamino-3-cyclopent-1ꢀ-enyl-propanoic
acid methyl ester 4a. Following the above procedure
using N-(tert-butoxycarbonyl)-3-iodo-L-alanine methyl ester
(0.247 g, 0.75 mmol) the product 4a was obtained by flash
chromatography as a colourless oil (86 mg, 43% yield); [a]D22
+13.9 (c 2.09 in CHCl3); m/z (EI) (Found MNa+ 292.1521;
C14H23NO4Na requires 292.1525) MNa+ 270 (13%), 214 (100),
169 (19), 153 (33); mmax (liquid film)/cm−1 1747, 1716, 1504
and 1336; dH (400 MHz, CDCl3) 1.43 [9H, s, C(CH3)3], 1.84
(2H, qn, J 7.5, CH2), 2.16–2.31 (4H, m, CH2), 2.47 (1H, dd,
J 14.0 and 8.0, CHAHBCHNH), 2.57 (1H, dd, J 14.5 and
5.5, CHAHBCHNH), 3.71 (3H, s, OCH3), 4.35–4.42 (1H, m,
CHCO2CH3), 4.95 (1H, d, J 7.5, NH), 5.43–5.47 (1H, br s,
CH); dC (100 MHz, CDCl3) 23.5 (CH2), 28.3 [C(CH3)3], 32.4
(CH2), 34.1 (CH2), 34.7 (CH2CHNH), 52.0 (CHCO2CH3),
52.2 (CO2CH3), 79.8 [C(CH3)3], 128.3 (CHCH2), 138.9
[CHC(CH2)2], 155.2 [NHCOC(CH)3], 173.1 (CO2CH3).
6.6 mmol) and dichlorobis(triphenylphosphine)palladium(II)
(210 mg, 0.3 mmol) under nitrogen. The zinc residue was washed
with dry DMF (2 × 1 cm3), and the washings also added
to the reaction mixture. The reaction mixture was stirred for
16 hours at room temperature, and then transferred directly to
a chromatography column, which was eluted with petroleum
◦
ether (bp 60–80 C), 10% EtOAc, 15% EtOAc and finally 20%
EtOAc in petroleum ether. The product 4c, (Rf 0.4, 20% EtOAc
in petroleum ether), was obtained as a colourless oil (1.027 g,
58%) (after separation of mixed fractions using the same solvent
system). The major by-product was N-(tert-butoxycarbonyl)-
L-alanine methyl ester (0.288 g, 24%, Rf 0.3), together with
N-(tert-butoxycarbonyl)-dehydroalanine methyl ester (0.15 g,
12%, Rf 0.45).
(2S)-tert-Butoxycarbonylamino-3-cyclooct-1ꢀ -enyl-propanoic
acid methyl ester 4d. Following the above procedure using
N-(tert-butoxycarbonyl)-3-iodo-L-alanine methyl ester (1 g,
3.04 mmol) the product 4d was obtained as a colourless oil
(435 mg, 46%); [a]2D2 +9.5 (c 0.53 in CHCl3); m/z (EI) (Found
MH+ 312.2169; C17H30NO4 requires 312.2175) MK+ 350 (40%),
MH+ 312 (39), 256 (100), 212 (17); mmax (liquid film)/cm−1
2925, 1747, 1716, 1504, 1366 and 1171; dH (400 MHz, CDCl3)
1.40 [9H, s, C(CH3)3], 1.41–1.45 (8H, m, CH2), 2.05–2.12 (4H,
m, CH2), 2.24 (1H, dd, J 14.0 and 8.5 CHAHBCHNH), 2.48
(1H, dd, J 14.0 and 5.0, CHAHBCHNH), 3.71 (3H, s, OCH3),
4.28–4.38 (1H, m, CHCO2CH3), 4.87 (1H, d, J 7.0, NH), 5.41
(1H, t, J 7.5, CH); dC (100 MHz, CDCl3) 22.8 (CH2), 26.3
(CH2), 26.5 (CH2), 26.6 (CH2), 28.5 [C(CH3)3], 28.7 (CH2), 29.8
(CH2), 40.5 (CH2CHNH), 52.1 (CHCO2CH3), 52.5 (CO2CH3),
80.0 [C(CH3)3], 128.8 (CHCH2), 135.8 [CHC(CH2)2], 155.8
[NHCOC(CH)3], 173.6 (CO2CH3).
(2S)-2-tert-Butoxycarbonylamino-3-cyclohex-1ꢀ-enyl-propanoic
acid methyl ester 4b. Following the above procedure
using N-(tert-butoxycarbonyl)-3-iodo-L-alanine methyl ester
(0.123 g, 0.375 mmol) the product 4b was obtained by
flash chromatography as a colourless oil (43 mg, 41%); [a]D22
+14.5 (c 1.68 in CHCl3); m/z (EI) (Found MNa+ 306.1668;
C15H25NO4Na requires 306.1681) MNa+ 306 (100%), 228 (26),
184 (25); mmax (liquid film)/cm−1 2930, 1747, 1716, 1505, 1366
and 1169; dH (400 MHz, CDCl3) 1.42 [9H, s, C(CH3)3], 1.50–1.55
(2H, m, CH2), 1.56–1.60 (2H, m, CH2), 1.87–1.89 (1H, m,
CH2), 1.94–2.00 (3H, m, CH2), 2.22 (1H, dd, J 13.5 and 8.5,
CHAHBCHNH), 2.39 (1H, dd, J 13.5 and 5.5, CHAHBCHNH),
3.70 (3H, s, OCH3), 4.31–4.39 (1H, m, CHCO2CH3), 4.88 (1H,
d, J 7.0, NH), 5.42–5.48 (1H, br s, CH); dC (100 MHz, CDCl3)
22.1 (CH2), 22.7 (CH2), 25.3 (CH2), 27.8 (CH2), 28.3 [C(CH3)3],
41.4 (CH2CHNH), 51.9 (CHCO2CH3), 52.1 (CO2CH3),
79.8 [C(CH3)3], 125.7 (CHCH2), 132.7 [CHC(CH2)2], 155.2
[NHCOC(CH)3], 173.4 (CO2CH3).
General procedure for the synthesis of protected cycloalkyl
alanine amino acids 7
A 0.1 M solution of the protected cycloalken-1-yl-alanine 4
in methanol was treated with palladium (70 mg mmol−1 of
substrate, 10 wt% on activated carbon) and stirred under an
atmosphere of hydrogen for 24 h. The catalyst was removed
(2S)-2-tert-Butoxycarbonylamino-3-cyclohept-1ꢀ-enyl-propanoic
acid methyl ester 4c. Following the above procedure
using N-(tert-butoxycarbonyl)-3-iodo-L-alanine methyl ester
(1.0 g, 3.04 mmol) the product 4c was obtained by flash
chromatography as a colourless oil (405 mg, 45%); [a]2D2 +7.8 (c
1.15 in CHCl3); m/z (EI) (Found MH+ 298.2013; C16H28NO4
requires 298.2018) MK+ 336 (100%), MH+ 298 (71), 242 (91);
mmax (liquid film)/cm−1 2923, 1747, 1717, 1499, 1418, 1367 and
1167; dH (400 MHz, CDCl3) 1.36 [9H, s, C(CH3)3], 1.37–1.42
(4H, m, CH2), 1.65 (2H, q, J 5.5, CH2), 1.98–2.06 (4H, m,
CH2), 2.18 (1H, dd, J 14.0 and 8.5, CHAHBCHNH), 2.38
(1H, dd, J 14.0 and 5.5, CHAHBCHNH), 3.65 (3H, s, OCH3),
4.21–4.29 (1H, m, CHCO2CH3), 4.84 (1H, d, J 7.0, NH),
5.54 (1H, t, J 6.0, CH); dC (100 MHz, CDCl3) 26.3 (CH2),
28.5 (CH2), 28.6 [C(CH3)3], 33.6 (CH2), 35.2 (CH2), 35.6
(CH2), 41.1 (CH2CHNH), 52.1 (CHCO2CH3), 52.3 (CO2CH3),
80.1 [C(CH3)3], 118.3 (CHCH2), 134.8 [CHC(CH2)2], 155.7
[NHCOC(CH)3], 174.4 (CO2CH3).
R
by filtration through Celiteꢀ and the solvent removed under
reduced pressure to give the product. If traces of water were
observed, the product was redissolved in CH2Cl2 and dried over
sodium sulfate.
(2S)-tert-2-Butoxycarbonylamino-3-cyclopentylpropanoic acid
methyl ester 7a. Following the above procedure using the
protected cyclopenten-1-yl alanine amino acid 4a (42 mg,
0.16 mmol) the product 7a was obtained as a colourless oil
(41 mg, 98%); [a]2D2 +7.5 (c 0.81 in CHCl3); m/z (EI) (Found
MH+ 272.1857; C14H26NO4 requires 272.1862) MH+ 272 (84%),
216 (100), 172 (40); mmax (liquid film)/cm−1 2923, 1747, 1716,
1504 and 1366; dH (400 MHz, CDCl3) 1.03–1.16 (2H, m, CH2),
1.44 [9H, s, C(CH3)3], 1.48–1.68 (6H, m, CH2), 1.73–1.88 [3H,
m, CH2 + CH(CH2)4], 3.73 (3H, s, OCH3), 4.25–4.32 (1H, m,
CHCO2CH3), 4.93 (1H, d, J 7.0, NH); dC (100 MHz, CDCl3)
25.0 (CH2), 28.3 [C(CH3)3], 32.6 (CH2), 36.6 [CH(CH2)4],
39.0 (CH2CHNH), 52.1 (CHCO2CH3), 53.2 (CO2CH3), 79.8
[C(CH3)3], 155.3 [NHCOC(CH)3], 173.8 (CO2CH3).
Larger scale reaction
TMSCl (1.2 cm3) was added to a stirred suspension of zinc dust
(2.34 g, 36 mmol) in dry DMF (4 cm3). The reaction mixture
was stirred for 20 min, the zinc was allowed to settle and the
supernatant then removed by syringe. The activated zinc was
washed with dry DMF (2 × 1 cm3), and then dried under reduced
pressure to give a free flowing powder. N-(tert-Butoxycarbonyl)-
3-iodo-L-alanine methyl ester (1.974 g, 6 mmol) was added as
a solid to a rapidly stirred suspension of the activated zinc in
dry DMF (4 cm3) at room temperature under nitrogen. A strong
exotherm was observed, and this was controlled with the aid of
a water bath. Stirring was continued for 20 minutes, and the zinc
was allowed to settle. The supernatant was then transferred by
syringe into a flask containing cyclohepten-1-yl triflate (1.61 g,
(2S)-tert-2-Butoxycarbonylamino-3-cyclohexylpropanoic acid
methyl ester 7b. Following the above procedure using the
protected cyclohexen-1-yl alanine amino acid 4b (200 mg,
0.71 mmol) the product 7b was obtained as a colourless oil
(194 mg, 96%). The spectroscopic data of this compound
matched that already obtained.
(2S)-tert-2-Butoxycarbonylamino-3-cycloheptylpropanoic acid
methyl ester 7c. Following the above procedure using the
protected cyclohepten-1-yl alanine amino acid 4c (250 mg,
0.84 mmol) the product 7c was obtained as a colourless oil
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 1 1 7 – 4 1 2 3
4 1 2 1

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(248 mg, 99%). The spectroscopic data of this compound
matched that already obtained.
CH2), 24.8 (A, CH2), 24.9 (Aꢀ, CH2), 27.5 (A, CH3), 27.8 (Aꢀ,
CH3), 28.3 [A and Aꢀ, C(CH3)3], 34.1 [A, C(CH2)2CH3], 34.4
[Aꢀ, C(CH2)2CH3], 34.9 (A and Aꢀ, CH2), 44.8 (A, CH2CHNH),
45.2 (Aꢀ, CH2CHNH), 50.9 (A and Aꢀ, CHCO2CH3), 52.1 (A,
CO2CH3), 52.2 (Aꢀ, CO2CH3), 79.7 [A, C(CH3)3], 79.9 [Aꢀ,
C(CH3)3], 126.3 (A and Aꢀ, CH), 135.1 (A, CH), 135.2 (Aꢀ, CH),
155.0 [A and Aꢀ, NHCOC(CH)3], 174.2 (A and Aꢀ, CO2CH3).
(2S)-tert-2-Butoxycarbonylamino-3-cyclooctylpropanoic acid
methyl ester 7d. Following the above procedure using the
protected cycloocten-1-yl alanine amino acid 4d (236 mg,
0.76 mmol) the product 7d was obtained as a colourless oil
(224 mg, 95%); [a]2D2 +6.5 (c 0.5 in CHCl3); m/z (EI) (Found M+
314.2328; C17H32NO4 requires 314.2331) MK+ 352 (27%), MH+
314 (59), 258 (100), 214 (92); mmax (liquid film)/cm−1 2921,
1716, 1513, 1366 and 1172; dH (400 MHz, CDCl3) 1.24–1.32
(2H, m, CH2), 1.43 [9H, s, C(CH3)3], 1.42–1.49 (6H, m, CH2),
1.56–1.68 [9H, m, CH2 + CH(CH2)7], 3.72 (3H, s, OCH3),
4.28–4.37 (1H, m, CHCO2CH3), 4.86 (1H, d, J 8.0, NH); dC
(100 MHz, CDCl3) 25.3 (CH2), 26.5 (CH2), 27.4 (CH2), 28.5
[C(CH3)3], 31.2 (CH2), 33.5 (CH(CH2)7), 41.2 (CH2CHNH),
52.0 (CHCO2CH3), 52.3 (CO2CH3), 80.0 [C(CH3)3], 155.5
[NHCOC(CH)3], 174.3 (CO2CH3).
(2S)-2-tert-Butoxycarbonylamino-3-(1-methyl-cyclohexyl)-
propanoic acid methyl ester 8b. A solution of the mixture
of diastereoisomers 12b (42 mg, 0.141 mmol) in methanol
(1.4 cm3) was treated with palladium (10 mg, 10 wt% on
activated carbon) and stirred under an atmosphere of hydrogen
R
for 24 h. The catalyst was removed by filtration through Celiteꢀ
and the solvent removed under reduced pressure to yield the
product 8b as a colourless oil (27 mg, 62%). [a]2D2 +1.3 (c 1.92
in CHCl3); m/z (ES) (Found MNa+ 322.1998; C16H29NO4Na
requires 322.1994) MNa+ 322 (100%); mmax (liquid film)/cm−1
2927, 2861, 1747, 1714, 1514, 1366 and 1166; dH (400 MHz,
CDCl3) 0.95 (3H, s, CH3), 1.26–1.32 (4H, m, CH2), 1.38–1.43
(6H, m, CH2), 1.42 [9H, s, C(CH3)3] 1.60–1.65 (1H, br d, J 14.0,
CHAHBCHNH), 1.72 (1H, dd, J 14.0 and 3.5, CHAHBCHNH),
3.71 (3H, s, OCH3), 4.34 (1H, dt, J 3.5 and 9.0, CHCO2CH3),
4.82 (1H, d, J 9.0, NH); dC (100 MHz, CDCl3) 21.9 (CH2), 24.6
[C(CH2)3], 26.2 (CH2), 28.3 [C(CH3)3], 33.0 (CH2), 37.8 (CH2),
44.9 (CH2CHNH), 50.4 (CHCO2CH3), 52.2 (CO2CH3), 79.8
[C(CH3)3], 155.1 [NHCOC(CH)3], 174.6 (CO2CH3).
3-Chloro-1-methyl-cyclohexene 10b26.
A solution of 3-
methylcycloalk-2-enol (670 mg, 5.93 mmol) and dry pyridine
(0.45 cm3, 7.41 mmol) in dry diethyl ether (3 cm3) was cooled in
an ice-bath. A solution of thionyl chloride (0.54 cm3, 7.41 mmol)
in dry diethyl ether (2 cm3) was added. The mixture was stirred
for 5 min at 0 ◦C and then for 3 h at room temperature, filtered,
washed three times with aqueous saturated sodium hydrogen
carbonate and brine. Drying over anhydrous magnesium sulfate
and concentration under reduced pressure, gave the product 10b
(408 mg, 53%) as a yellow oil, as a 2.5 : 1 mixture with 3-
chloro-3-methylcyclohexene 11b. This mixture was used in the
subsequent step without any further purification. dH (400 MHz,
CDCl3) 1.70 (3H, d, J 1.0, CH3), 1.84–2.06 (6H, m, CH2), 4.63–
4.68 (1H, m, CHCl), 5.55–5.59 (1H, m, CH); dC (100 MHz,
CDCl3) 18.4 (CH2), 23.7 (CH3), 29.7 (CH2), 32.0 (CH2), 57.0
(CHCl), 122.6 (CH), 139.8 (CH).
Phosphoric acid (E)-3,7-dimethyl-octa-2,6-dienyl ester diethyl
ester 1627. Diethyl chlorophosphate (1.3 cm3, 7.78 mmol) was
added dropwise to a solution of geraniol (1 g, 6.48 mmol) and
pyridine (2.1 cm3, 26 mmol) in CH2Cl2 (5 cm3) at 0 ◦C under
a nitrogen atmosphere, and the mixture was stirred for 1 h at
0
◦C and then overnight at room temperature. The reaction
mixture was diluted with diethyl ether (50 cm3) and washed
with hydrochloric acid (3 × 10 cm3, 1 M), brine (1 × 10 cm3)
and saturated sodium bicarbonate (1 × 10 cm3) and dried
over anhydrous magnesium sulfate. The solvent was removed
under reduced pressure and the product purified by column
chromatography over silica gel using diethyl ether as solvent,
yielding geraniol phosphate 16 as a colourless oil (1.47 g, 78%).
mmax (liquid film)/cm−1 2980, 2912, 1276, 1101 and 1035; dH
(400 MHz, CDCl3) 1.26 (6H, dt, J 7.0 and 1.0, OCH2CH3),
1.52 (3H, d J 0.5, CH3CCH2), 1.60 (3H, d, J 1.0, CH3CHCH3),
1.63 (3H, d, J 1.0, CH3CHCH3), 1.95–2.08 (4H, m, CH2),
4.00–4.07 (4H, m, OCH2CH3), 4.49 (2H, dt, J 7.5 and 0.5,
CHCH2O), 4.98–5.03 (1H, m, CHCH2O), 5.30–5.36 [1H, m,
CHC(CH3)2]; dC (100 MHz, CDCl3) 15.9 (JCP 6.5, OCH2CH3),
16.2 (CH3CCH2), 17.5 (CH3CHCH3), 25.5 (CH2CHC), 26.0
(CH3CHCH3), 39.3 (CH2CCH3), 63.4 (JCP 6.0, OCH2CH3),
63.9 (JCP 5.5, CHCH2O), 118.8 (JCP 6.5, CHCH2O), 123.4
[CHC(CH3)2], 131.7 (CH3CHCH3), 142.3 (CH2CCH3CH).
(2S,3RS)-2-tert-Butoxycarbonylamino-3-(1-methyl-cyclohex-
2-enyl)-propanoic acid methyl ester 12b. Organocopper
derivative
2 was prepared from N-(tert-butoxycarbonyl)-
3-iodo-L-alanine methyl ester (0.247 g, 0.75 mmol) using
the same procedure described in the preparation of 3. The
mixture of 3-chloro-1-methylcyclohex-1-ene and 3-chloro-3-
methylcyclohex-1-ene (130 mg, 1 mmol) was added and the
flask placed again in a dry ice–acetonitrile bath and stirred
◦
overnight (temperature increased slowly from −30 C to room
temperature). The reaction mixture was diluted with diethyl
R
ether (50 cm3) and filtered through Celiteꢀ. The solution was
then washed with saturated aqueous ammonium chloride
(15 cm3) and brine (15 cm3). The organic phase was dried
over magnesium sulfate and concentrated under reduced
pressure. The product was obtained as a mixture of isomers
(118 mg, 53%) after purification of the residue by flash
chromatography using CH2Cl2 and ethyl acetate (10 : 1) as
eluent. 2-tert-Butoxycarbonylamino-3-(1-methyl-cyclohex-2-
enyl)-propanoic acid methyl ester 12b (SN2ꢀ products) and
2-tert-butoxycarbonylamino-3-(3-methyl-cyclohex-2-enyl)-
propanoic acid methyl ester 13 (SN2 product) were obtained
in a ratio of 2.5 : 1. Subsequent purification of the mixture by
flash chromatography using a mixture of CH2Cl2 : ethyl acetate
(4 : 1) did allow the desired products 12b to be isolated as a
mixture of two diastereoisomers A and Aꢀ in a 53 : 47 ratio:
m/z (EI) (Found MH+ 298.2018; C16H28NO4 requires 298.2026)
MH+ 298 (28%), 242 (50), 198 (100); mmax (liquid film)/cm−1; dH
(400 MHz, CDCl3) 1.02 (A, 3H, s, CH3), 1.03 (Aꢀ, 3H, s, CH3),
1.42 [A, 9H, s, C(CH3)3], 1.43 [Aꢀ, 9H, s, C(CH3)3], 1.46–1.66
(A and Aꢀ, 4H, m, CH2), 1.72–1.84 (A and Aꢀ, 2H, m, CH2),
1.90–1.96 (A and Aꢀ, 2H, m, CH2CHNH), 3.70 (A, 3H, s,
OCH3), 3.71 (Aꢀ, 3H, s, OCH3), 4.32–4.41 (A and Aꢀ, 1H, m,
CHCO2CH3), 4.81–4.90 (A and Aꢀ, 1H, m, NH), 5.38–5.43 (A
and Aꢀ, 1H, br d, J 9.0, CH), 5.62 (A and Aꢀ, 1H, dt, J 9.0
and 3.5, CH); dC (100 MHz, CDCl3) 18.8 (A, CH2), 18.9 (Aꢀ,
Coupling of phosphoric acid (2E)-3,7-dimethyl-octa-2,6-dienyl
ester diethyl ester 16 to reagent 2
Organocopper derivative
2 was prepared from N-(tert-
butoxycarbonyl)-3-iodo-L-alanine methyl ester (0.247 g,
0.75 mmol) using the same procedure described in the prepara-
tion of 3. Geraniol phosphate 16 (290 mg, 1 mmol) was added
and the mixture placed again in a dry ice–acetonitrile bath and
stirred overnight (temperature increased slowly from −30 ◦C to
room temperature). The reaction mixture was diluted with ethyl
R
acetate and filtered through Celiteꢀ. The solvent was removed
under reduced pressure (in order to remove residual DMF it was
necessary to heat at 55 ◦C under reduced pressure and to leave
the crude material attached to a vacuum pump for 2 h). The
residue was diluted with ethyl acetate (50 cm3) and washed with
saturated aqueous ammonium chloride solution (15 cm3) and
brine (15 cm3). The organic phase was dried over sodium sulfate
andconcentrated under reducedpressure. A mixture of17 and 15
4 1 2 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 1 1 7 – 4 1 2 3

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(50 : 50 mixture of diastereoisomers) was obtained as colourless
oil (120 mg, 47%) (with a ratio of 17 to 15 of 12 : 88,
as determined by 1H NMR) after purification by flash
chromatography using heptane–ethyl acetate (3 : 1). NMR data
were obtained as follows.
15 and 17, and 84% overall yield based on the amount of 15) as
a colourless oil. [a]2D2 −1.8 (c 0.56 in CHCl3); m/z (EI) (Found
MH+ 286.2024; C15H28NO4 requires 286.2018) MH+ 286 (1.5%),
230 (47), 186 (100); mmax (liquid film)/cm−1 2955, 1715, 1513,
1366 and 1166; dH (400 MHz, CDCl3) 0.96 (3H, s, CH3C), 1.42
[9H, s, C(CH3)3], 1.34–1.45 (4H, m, CH2), 1.53 (1H, dd, J 14.0
and 8.5, CHAHBCHNH), 1.57–1.68 (4H, m), 1.85 (1H, dd, J
13.5 and 4.0, CHAHBCHNH), 3.72 (3H, s, OCH3), 4.36 (1H,
dt, J 4.0 and 8.5, CHCO2CH3), 4.83 (1H, d, J 8.5, NH); dC
(100 MHz, CDCl3) 23.6 (CH2), 24.0 (CH3C), 24.8 (CH3C), 28.3
[C(CH3)3], 39.8 (CH2), 44.9 (CH2CHNH), 51.7 (CHCO2CH3),
52.2 (CO2CH3), 79.8 [C(CH3)3], 155.1 [NHCOC(CH)3], 174.4
(CO2CH3).
(2S,5E)-2-tert-Butoxycarbonylamino-6,10-dimethyl-undeca-
5,9-dienoic acid methyl ester 17. dH (400 MHz, CDCl3) 1.44
[9H, s, C(CH3)3], 1.58 (3H, s, CH3), 1.59 (3H, s, CH3), 1.67
(3H, s, CH3), 1.77–1.88 (2H, m), 1.95–1.99 (2H, m), 2.01–2.08
(4H, m), 3.73 (3H, s, OCH3), 4.24–4.33 (1H, m, CHCO2CH3),
4.96–5.03 (1H, br s, NH), 5.05–5.12 (2H, m).
(2S,4RS)-2-tert-Butoxycarbonylamino-4,8-dimethyl-4-vinyl-
non-7-enoic acid methyl ester 15. Mixture of diastereoisomers
A and Aꢀ obtained in 50 : 50 ratio. dH (400 MHz, CDCl3)
1.04 (A and Aꢀ, 3H, s, CH3CCH2), 1.33 (A and Aꢀ, 2H, t,
J 8.0, CH3CCH2), 1.41 [A, 9H, s, C(CH3)3], 1.42 [Aꢀ, 9H, s,
C(CH3)3], 1.57 (A and Aꢀ, 3H, s, CH3CCH3), 1.66 (A and Aꢀ,
3H, s, CH3CCH3), 1.77–1.90 (A and Aꢀ, 4H, m, CH2CHNH +
CH2CHC), 3.68 (A, 3H, s, OCH3), 3.70 (Aꢀ, 3H, s, OCH3),
4.30 (A and Aꢀ, 1H, m, CHCO2CH3), 4.82 (A and Aꢀ, 1H, d, J
8.0, NH), 4.92–5.02 (A and Aꢀ, 2H, m, CH2CHC), 5.02–5.10
[A and Aꢀ, 1H, m, CHC(CH3)2], 5.66–5.76 (A and Aꢀ, 1H, m,
CH2CHC). dC (100 MHz, CDCl3) 17.8 (A and Aꢀ, CH2CHC),
22.1 (A, CH3CCH3), 22.2 (Aꢀ, CH3CCH3), 22.8 (A, CH3CCH2),
22.9 (Aꢀ CH3CCH2), 25.9 (A and Aꢀ, CH3CCH3), 28.6 [A and
Aꢀ, C(CH3)3], 39.5 (A, CH3CCH2), 39.7 (Aꢀ, CH3CCH2), 41.4
(A, CH3CCH2), 41.5 (Aꢀ, CH3CCH2), 43.8 (A, CH2CHNH),
44.0 (Aꢀ, CH2CHNH), 51.1 (A and Aꢀ, CHCO2CH3), 52.3 (A
and Aꢀ, OCH3), 79.8 [A and Aꢀ, C(CH3)3], 112.7 (A, CH2CHC),
113.1 (Aꢀ, CH2CHC), 124.7 [A and Aꢀ, CHC(CH3)2], 131.6
[A and Aꢀ, CHC(CH3)2], 145.8 (A, CH2CHC), 145.9 (Aꢀ,
CH2CHC), 155.2 [A and Aꢀ, NHCOC(CH)3], 174.3 (A and Aꢀ,
CO2CH3).
Acknowledgements
We thank Medivir (UK) for funding of
(T. Carrillo-Marquez).
a studentship
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R
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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 1 1 7 – 4 1 2 3
4 1 2 3