Full text of DOI:10.1016/S0040-4020(01)00546-4

TETRAHEDRON
Pergamon
Tetrahedron 57 )2001) 6539±6555
Synthesis by conjugate radical addition of new heterocyclic amino
acids with nucleobase side chains
Raymond C. F. Jones,p,² Didier J. C. Berthelot and James N. Ileyp
Department of Chemistry, The Open University, Walton Hall, Milton Keynes MK7 6AA, UK
Received 15 February 2001; revised 23 March 2001; accepted 9 April 2001
AbstractÐN-)2-iodoethyl) and N-)3-iodopropyl)pyrimidines and purines undergo stereoselective conjugate radical addition with an opti-
cally active oxazolidinone acceptor to give syn-adducts that can be converted into amino acids carrying pyrimidine and purine )nucleobase)
side chains. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
a-PNA3) of the latter, do not demonstrate hybridisation with
DNA, and insuf®cient ¯exibility of the polypeptide chain
has been suggested as the cause.4 In contrast, triplex form-
ation between tetrapeptides of type 4 and poly)dT) or
poly)dU) has been reported.5
Peptide-based nucleic acid analogues )PNAs; sometimes
called `Peptide Nucleic Acids') have attracted much atten-
tion as molecules with the potential to interact with nucleic
acid chains.1 Suggested applications include antisense prop-
erties.2 Indeed, Nielsen's classical PNA 1 )Bˆpyrimidine or
purine base) has been shown to form duplexes with the
complementary DNAs )with higher af®nity than the corre-
sponding DNA±DNA), and to self-hybridize, or to form
triplexes PNA±PNA±DNA )or ±PNA).1 In contrast, DNA
recognition using analogues with a `real' peptide backbone
has proved more elusive. It has been reported that the sub-
stituted alanine oligomers 2 and 3, and homologue 4 )termed
Our interest in unusual amino acids led us to propose the
homologous amino acids 6 carrying the nucleic acid bases
)nucleobases) with a 3- or 4-methylene tether to the peptide
backbone, as components for PNA variants 5. Residues 6
are also analogues of naturally occurring bioactive pyrimi-
dine and purine amino acids such as discadenine 7.6 We
report herein our ¯exible methodology which is based on
stereoselective radical chemistry.7,8
Keywords: nucleic acid analogues; amino acids; radical reactions.
Corresponding authors. Tel.: 144-1509-222557; fax: 144-1509-223926; e-mail: r.c.f.jones@lboro.ac.uk
Current address: Department of Chemistry, Loughborough University, Leicestershire LE11 3TU, UK.
p
²
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020)01)00 546-4

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R. C. F. Jones et al. / Tetrahedron 57 &2001) 6539±6555
9 and 10 )57% overall from S-methyl-)R)-cysteine). syn-
Sulfone 9 was formed as a 10:1.5 mixture with its anti-
diastereoisomer 10, again estimated from the 1H NMR
spectrum )SO2Me singlets for major isomer d 3.09, minor
isomer d 2.87), that was easily separated by column chro-
matography;11 major isomer syn-9 was further crystallised
to ensure diastereomeric purity. The syn con®guration was
supported by nOe studies, inter alia mutual enhancements
between C±2)H) and C±4)H), and is in accord with other
related reports. The minor isomer anti-10 lacked this inter-
action and instead displayed mutual enhancements between
C±4)H) and the tert-butyl group. Base treatment )DBU,
CH2Cl2, 08C, 1 h) of major sulfone 9 afforded )S)-oxazoli-
dinone 11 )96%) as a crystalline solid [the )R)-enantiomer
would be available either from unnatural S-methyl-)S)-
cysteine, or from minor sulfone 10].
Scheme 1.
2. Results and discussion
In contrast to published routes to residues with two-carbon
tethers,3,5,9 we determined to link preformed heterocycles
with the peptide backbone by forming a carbon±carbon
bond in the tether, and proposed the analysis shown in
Scheme 1; this generates the C)b)±C)g) bond by conjugate
radical addition to chiral acceptor 8.10 The N-benzyloxycar-
bonyl )Z) acceptor was selected in order to ultimately
provide Z-amino acids suitable for peptide couplings.
The radical precursors for additions to acceptor 11 were to
be haloalkyl pyrimidines and purines, prepared from the
appropriately protected heterocyclic base and v-haloalco-
hols by a Mitsunobu procedure.12 Thus 3-benzoylthymine
1213 was prepared by treatment of thymine with benzoyl
chloride )2.2 mol equiv., MeCN±pyridine 5:2 v/v, 208C)
to afford 1,3-dibenzoylthymine, which was not isolated
but treated directly with base )K2CO3, dioxane±water) to
complete selective mono-debenzoylation )67% overall) at
N-1. 3-Benzoylthymine 12 was then coupled with 2-
bromoethanol or 3-bromopropanol )DIAD, Ph3P, 0!208C)
to afford the 1-)v-bromoalkyl) derivatives 13a )89%) and
13b )92%), respectively )Scheme 3). Our attempts to gener-
ate radicals from these bromides proved fruitless )using
method B, see below), so they were converted directly to
the corresponding iodoalkyl compounds 13c and 13d,
respectively )NaI, propanone re¯ux; each 95%).
The )S)-acceptor 11 was prepared from S-methyl-)R)-
cysteine as outlined in Scheme 2, by adaptation of a
sequence published for synthesis of the N-benzoyl ana-
logue.11 Thus S-methyl-)R)-cysteine as its dried sodium
carboxylate salt was converted into a Schiff base )ButCHO,
hexane, Dean±Stark water removal) that when acylated
with benzyl chloroformate underwent cyclization to afford
the 4-methylthiomethyloxazolidinones as an inseparable
mixture of diastereomers, estimated as 10:1.3 based on the
1
SMe singlets in the H NMR spectrum )major isomer d
2.10, minor isomer d 2.02). These were oxidised )oxonew,
MeCN) to generate the corresponding mixture of sulfones
Scheme 2. Reagents: i, NaOH aq.; ii, ButCHO, Dean±Stark; iii, PhCH2OCOCl )ZCl); iv, oxonew, MeCN±H2O; v, DBU.
Scheme 3. Reagents: i, HO)CH2)nBr, PriO2CNvNCO2Pri, Ph3P; ii, NaI, Me2CO re¯ux; iii, Method C: 11 )1 mol equiv.), Bu3SnH )1 mol equiv.), AIBN
)0.1 mol equiv.), toluene re¯ux; method D: 11 )2 mol equiv.), Bu3SnCl )0.3 mol equiv.), NaBH3CN )2 mol equiv.), AIBN )0.1 mol equiv.).

R. C. F. Jones et al. / Tetrahedron 57 &2001) 6539±6555
6541
Scheme 4. Reagents: i, ii as in Scheme 3; iii, Method D.
Iodide 13c was treated under two protocols differing in the
method for generation of a radical,10 namely )1) method C
)see Section 3): with oxazolidinone 11 )1 mol equiv.) in
toluene at re¯ux containing AIBN )0.1 mol equiv.) and
dropwise addition of Bu3SnH )1 mol equiv.); or )2) method
D: with oxazolidinone 11 )2 mol equiv.), Bu3SnCl
)0.3 mol equiv.), NaBH3CN )2 mol equiv.) and AIBN
)0.1 mol equiv.) in tert-BuOH at re¯ux. Method C )concen-
tration of iodide 13c approx. 0.01 M) afforded the conjugate
addition product 14a )26%) and reduction product 15a
)24%). On the other hand, method D after 16 h afforded
54% of conjugate addition products consisting of the adduct
14a )24%) and the 3-debenzoylated derivative 14b )30%),
with no reduced material. The extent of debenzoylation was
time dependent; a reaction time of 40h led to 14b as the sole
addition product )47%). This tentatively suggests the deacy-
lation may be via hydride-mediated reduction of the out-of-
plane benzoyl carbonyl group, a possibility supported by
observations of a decrease in debenzoylation when less
NaBH3CN is used in method D, and that debenzoylation
of 13 occurs in the presence of NaBH3CN alone. When 1-
iodopropylthymine derivative 13d was treated under
method D for 40h, adduct 14c was not found and deacylated
adduct 14d was isolated )25%) along with reduction product
15b )21%).
derivatives 17a and 17b as suitable precursors for the
radical addition reactions, using the Mitsunobu protocol
with 2-bromoethanol or 3-bromopropanol as above )82
and 84%, respectively) followed by iodide substitution for
bromide )each 96%) )Scheme 4).
Conjugate addition method D when applied to iodoethyl
compound 17a with a reaction time of 7 h afforded addition
product 18a )47%) and reduction product 15c )46%). When
the reaction was left for 40h, deacylated addition product
18b )51%) was isolated and no benzoylated material was
observed; reduction product was present but not puri®ed
from this reaction. Homologue 17b after 40h gave debenzo-
ylated adduct 18d )44%) with reduced material 15d )51%).
The yield of 18d could be increased to 62% by using
5 mol equiv. of acceptor 11 in method D, but we preferred
to routinely use 2 mol equiv. of this valuable optically
active intermediate. When less than 2 mol equiv. NaBH3CN
was used, some of the benzoylated adduct 18c was isolated,
for example, 1 mol equiv. NaBH3CN affording after 8 h 18c
)21%) and reduction product 3-benzoyl-1-propyluracil 15e
)27%).
During our investigations of the effect of using less
NaBH3CN in reactions with iodopropyluracil 17b, an
unexpected result was observed. From a reaction using
method D but with less oxazolidinone 11 )1.2 mol equiv.)
and less NaBH3CN )0.3 mol equiv.), and after a reaction
time of only 30min, unchanged acceptor 11 )82%) and
iodo compound 17b )80%) were recovered along with the
pyrrolopyrimidinedione 19 )87% based on recovered 17b),
the result of a 5-exo trig cyclisation of the radical formed
from the iodoalkyl compound, followed by hydrogen atom
We elected to extend these standard conjugate radical
addition protocols )methods C and D; method D preferred)
to other pyrimidines and purines rather than to separately
optimise each conjugate addition. 3-Benzoyluracil 1612 was
prepared from uracil )62% overall) using similar methods as
for 3-benzoylthymine, i.e. dibenzoylation with benzoyl
chloride )2.2 mol equiv., MeCN±pyridine 5:2 v/v, 08C)
and mono-debenzoylation )K2CO3, dioxane±water). The
3-benzoyluracil 16 was converted into the 1-iodoalkyl
Scheme 5. Reagents: i, Bu3SnH )1 mol equiv.), AIBN )0.1 mol equiv.),
toluene re¯ux.

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R. C. F. Jones et al. / Tetrahedron 57 &2001) 6539±6555
Scheme 6. Reagents: i and ii as in Scheme 3; iii, Methods C or D )see text).
capture. In a further experiment using the method C for
radical generation but in the absence of any oxazolidinone
11, the pyrrolopyrimidinedione 19 was isolated in 53%
yield )Scheme 5). Related cyclizations have been reported,14
although in those cases the initial radical from intramol-
ecular conjugate addition underwent oxidation or led to
ipso substitution.
Finally, a protected guanine 24a16 was prepared )53% over-
all) by treatment of guanine with excess acetic anhydride
)3 mol equiv., DMF, re¯ux) followed by reaction of the
9,N2-diacetylguanine with 2-)4-nitrophenyl)ethanol under
Mitsunobu conditions )DIAD, Ph3P, 0!208C) and
monodeacetylation by selective hydrolysis )H2O±dioxane
1:1 v/v, re¯ux). The guanine derivative 24a was converted
into the 9-iodoethyl derivative 24b as usual by Mitsunobu
coupling with 2-bromoethanol )67%) and substitution of
iodide for bromide )85%) )Scheme 7). Conjugate addition
by method C led to adduct 25 )21%) and reduction to 26
)20%).
In the purine series, adenine was treated with excess 2-
methylpropionic anhydride )3 mol equiv., DMF, re¯ux)
followed by removal of one 2-methylpropionyl group
)H2O±EtOH, 1:1 v/v, re¯ux) to afford N6-)2-methylpro-
pionyl)adenine 2015 )71% overall) and the 9-iodoalkylade-
nines 21a and 21b were prepared from protected adenine 20
in the standard way, by Mitsunobu coupling with 2-
bromoethanol or 3-bromopropanol as above )each 76%)
followed by iodide substitution for bromide )86 and 81%,
respectively) )Scheme 6). Application of method D with a
16 h reaction time to iodoethyl compound 21a led to the
expected mixture of conjugate addition [40%; acylated
22a )26%) and deacylated 22b )14%)] and reduction
[36%; acylated 23a )17%) and deacylated 23b )19%)].
The deacylated adduct 22b and acylated reduction product
23a were isolated as an inseparable mixture, the contents of
which were quanti®ed from the result of the subsequent
hydrolysis step )see below). The iodopropyl derivative
21b similarly gave adducts using method D for 16 h
[22%; acylated 22c )12%) and deacylated 22d )10%)]
along with reduced compounds [24%; acylated 23c )11%)
and deacylated 23d )23%)]. For comparison, method C
when applied to iodopropyl compound 21b led to acylated
adduct 22c )23%) and reduction product 23c )45%).
The illustrated conjugate radical addition products were all
syn-adducts, as determined by nOe studies, in which for
example mutual enhancements were observed between
C±2)H) and C±4)H). Only one diasteroisomer was visible
1
in the H- and 13C NMR spectra. The diastereoselectivity
has been found to be dependent on the nature of the N-sub-
stituent in the oxazolidinone;10 a preference for syn-adducts,
i.e. hydrogen atom capture from the face of the presumed
radical intermediate )after conjugate addition) opposite
Scheme 7. Reagents: i and ii as in Scheme 3; iii, Method C.

R. C. F. Jones et al. / Tetrahedron 57 &2001) 6539±6555
6543
to the tert-butyl substituent, is expected for N-carbamate
derivatives.
Amino acid 27j was obtained after hydrogenolysis of
Z-amino acid 27f for 5 h; prolonged hydrogenolysis for
16 h led to the 5,6-dihydrouracil amino acid 30 )88%).
The syn-oxazolidinones could be easily and ef®ciently
converted into the corresponding N-benzyloxycarbonyl-
)S)-amino acids )suitable for peptide coupling technology)
by base hydrolysis )2 mol equiv. LiOH, H2O±THF, 3:1 v/v,
08C, 30±60 min). Thus the three thymine-substituted
Z-amino acids 27a±c )having 3- or 4-carbon tethers for
the pyrimidine) were prepared from the adducts 14a, 14b,
and 14d )92, 96 and 87%, respectively). The uracil Z-amino
acids 27d±f were likewise prepared from adducts 18b±d
)69, 96 and 52%, respectively), as were adenine derivatives
28a±d from adducts 22a±d )72, 87, 89 and 86%, respect-
ively) and guanine Z-amino acid 29 from adduct 25 )87%).
To monitor optical purity, the benzyloxycarbonyl group was
removed by hydrogenolysis )Pd±C, EtOH±H2O 7:3 v/v;
8 h) to afford the amino acids 27g±j )74, 79, 75, and 90%,
respectively), 28e and 28f )75 and 61%, respectively).
The amino acids were analysed by esteri®cation )AcCl,
EtOH, re¯ux) and subsequent conversion to the `Mosher
amides' 31 [)R)-3,3,3-tri¯uoro-2-methoxy-2-phenylpropanoyl
chloride, Et3N, CH2Cl2, 208C].17 In some cases diamide
derivatives were also isolated and used for spectral analysis.
A very major and a rather minor diastereoisomer were
1
observed in the H NMR spectra, and analysis of the CF3
signals in the 19F NMR spectra revealed very good enantio-
meric excesses for the amino acids 27g )85%), 27h )88%),
27i )90%), 27j )89%) and 28f )86%).18
We have thus made available a range of novel optically
active pyrimidinyl and purinyl amino acids for application,
for example, in PNA variants.
3. Experimental
3.1. General
Melting points were determined using a Ko¯er hot-stage
apparatus and are uncorrected. Infrared spectra were
recorded using a Perkin±Elmer 1710FT-IR spectrometer.
19F NMR spectra were obtained at 376 MHz on a JEOL
1
JNM-EX400 spectrometer. H and 13C NMR spectra were
recorded at 300 MHz or at 75 MHz, respectively, on a JEOL
JNM-LA300 spectrometer. Low resolution mass spectra
were recorded on a VG Micromass VG20-250 spectrometer,
or by the EPSRC National Mass Spectrometry Service
Centre )University of Wales Swansea) who also performed
the accurate mass measurements. All reagents were puri®ed
by distillation or recrystallisation where appropriate, or
according to standard procedures.19 Column chroma-
tography was carried out using Fluka Silica Gel 60)220±
440mesh).
3.1.1. (2S,4R)-3-Benzyloxycarbonyl-2-tert-butyl-4-(methyl-
sulfonylmethyl)oxazolidin-5-one 9 and (2R,4R)-isomer 10.
S-Methyl-)R)-cysteine )27 g, 0.2 mol) was treated with
3
aqueous sodium hydroxide )8.0g, 0.2 mol, in 130cm
water), and after 5 min the solution was evaporated to
dryness under reduced pressure to leave a white solid. A
solution of 2,2-dimethylpropanal )21.7 cm3, 17.2 g,
0.2 mol) in hexane )300 cm3) was added, and the suspension
was stirred and heated under re¯ux with Dean±Stark water
removal for 24 h. The reaction mixture was then evaporated
to dryness under reduced pressure, and the white solid
suspended in dry dichloromethane )250cm 3). Benzyl

6544
R. C. F. Jones et al. / Tetrahedron 57 &2001) 6539±6555
chloroformate )42.8 cm3, 51.1 g, 0.3 mol) was added drop-
wise to the stirred suspension at 08C over 3 h. After stirring
the mixture at room temperature for a further 36 h, aqueous
sodium bicarbonate )10% w/v, 100 cm3) was added and
rapid stirring was continued for 4 h. The layers were then
separated and the dichloromethane solution was dried
)MgSO4), ®ltered and evaporated. To the residue stirred in
acetonitrile )200 cm3) was added oxonew )95 g, 0.15 mol) in
water )500 cm3). After 24 h at room temperature, water
)200 cm3) was added, the mixture was extracted with
dichloromethane )3£200 cm3), and the combined extracts
were dried)MgSO4), ®ltered and evaporated. Careful puri®-
cation by column chromatography )hexane±ethyl acetate,
9:1 to 3:1 v/v) gave the title compounds )42 g, 57% overall
yield), syn-diastereoisomer 9 as an oil, white crystals from
hexane, mp 151±1528C )38.19 g, 52%) that was used in
the following step without further puri®cation, and anti-
diastereoisomer 10 as a clear oil )3.80g, 5%). )2 S,4R)-3-
)300 MHz; CDCl3) 0.93 )9H, s, CMe3), 5.27 )2H, s,
CH2Ph), 5.63 )2H, s, CvCH2), 5.71 )1H, s, CHCMe3),
7.26±7.39 )5H, m, ArH); dC )75 MHz; CDCl3) 24.3
)CMe3), 38.6 )CMe3), 68.7 )CH2Ph), 93.9 )CHCMe3),
104.2 )CvCH2), 128.65, 128.7 and 128.81 )ArCH),
130.2 and 134.7 )CvCH2 and ArC), 152.3 and 164.5
)CvO).
3-Benzoylthymine 12 and 3-benzoyluracil 16 were prepared
by the method of Reese et al.13 N6-)2-Methylpropionyl)-
adenine 2015 and N2-acetyl-O6-[2-)4-nitrophenyl)ethyl]-
guanine 24a16 were prepared according to the methods of
Shevlin et al.
3.2. General procedure for Mitsunobu reaction, for
preparation of N-(v-bromoalkyl) nucleobase derivatives
(method A)12
Benzyloxycarbonyl-2-tert-butyl-4-)methylsulfonylmethyl)-
ˆ
To a suspension of suitably protected nucleobase )1 mol
equiv.), triphenylphosphine )1.2 mol equiv.) and the
v-bromoalcohol )1.2 mol equiv.) in dry dioxane at 08C
was added DIAD )1.2 mol equiv.) dropwise over 3 h. The
mixture was then stirred under argon at room temperature
overnight to yield a clear solution. The solvent was removed
and the residue puri®ed by column chromatography to give
the N-)v-bromoalkyl) nucleobase derivative.
22
oxazolidin-5-one 9 )major syn diastereoisomer): [a]D
127.0) c, 2.00 in EtOH); Found: MH1 370.1323.
C17H23NO6S requires: MH 370.1324; nmax )®lm/cm21
)
3441, 3056, 2980, 2877, 1796, 1729, 1635, 1397, 1316,
1266, 1131 and 1041; dH )300 MHz; CDCl3) 0.95 )9H, s,
CMe3), 3.11 )3H, s, SO2Me), 3.41 )1H, dd, Jˆ3.80,
15.20Hz, C HHSO2Me), 3.59 )1H, dd, Jˆ8.01, 15.20 Hz,
CHHSO2Me), 4.99 )1H, dd, Jˆ3.80, 8.01 Hz, CHCH2),
5.23 )2H, 2£d, Jˆ11.91 Hz, CH2Ph), 5.62 )1H, s,
CHCMe3) and 7.33±7.43 )5H, m, ArH); dC )75 MHz;
CDCl3) 24.6 )CMe3), 37.2 )CMe3), 42.5 )SO2CH3), 53.5
)CHCH2), 57.2 )CH2SO2Me), 68.9 )CH2Ph), 96.8 )CHO),
128.7, 128.8 and 128.8 )ArCH), 134.8 )ArC), 155.3 and
170.65 )CO). )2R,4R)-3-Benzyloxycarbonyl-2-tert-butyl-4-
)methylsulfonylmethyl)oxazolidin-5-one 10 )minor anti-
3.3. General procedure for conversion of N-(v-bromoalkyl)
nucleobase derivatives into N-(v-iodoalkyl) derivatives
(method B)
The N-)v-bromoalkyl) nucleobase derivative )1 mol equiv.)
and dry sodium iodide )5 mol equiv.) were heated in dry
acetone )100 cm3) at re¯ux under argon overnight in the
dark )aluminium foil). After cooling, the acetone was
removed under reduced pressure and the residue taken up
in ethyl acetate )100 cm3) and water )100 cm3). The organic
layer was separated and washed with aqueous sodium thio-
sulfate solution )2% w/v, 2£50cm 3). The solution was dried
)MgSO4) and the solvent removed under reduced pressure to
yield the N-)v-iodoalkyl) derivative.
22
diastereoisomer): [a]D ˆ172.8 )c, 0.32 in EtOH);
Found: MH1 370.1319. C17H23NO6S requires: MH
370.1324; nmax )®lm/cm21) 3415, 3056, 2973, 2877, 1797,
1713, 1639, 1413, 1354, 1317, 1266, 1127, 1035, 1015 and
975; dH )300 MHz; CDCl3) 0.94 )9H, s, CMe3), 2.91 )3H, s,
SO2Me), 3.57 )2H, d, Jˆ14.1 Hz, CH2SO2Me), 4.45 )1H, br
s, CHCH2), 5.00 )2H, 2£d, Jˆ11.90Hz, C H2Ph), 5.68 )1H,
s, CHCMe3) and 7.23±7.47 )5H, m, ArH); dC )75 MHz;
CDCl3) 24.7 )CMe3), 39.3 )CMe3), 43.7 )SO2CH3), 53.6
)CHCH2), 61.2 )CH2SO2Me), 68.3 )CH2Ph), 96.0)CHO),
128.7, 128.7 and 129.0)ArCH), 134.9 )ArC), 152.9 and
170.4 )CO).
3.3.1. 3-Benzoyl-1-(2-bromoethyl)thymine 13a. Prepared
following method A, using 3-benzoylthymine 12 )4.0g,
17.4 mmol), triphenylphosphine )5.47 g, 20.9 mmol),
2-bromoethanol )1.48 cm3, 2.61 g, 20.9 mmol), dioxane
)150cm 3) and DIAD )4.11 cm3, 4.22 g, 20.9 mmol). Puri®-
cation by column chromatography )hexane±ethyl acetate
6:4 v/v) gave the title compound 13a as a white amorphous
solid )5.22 g, 89%), mp 183±1848C; Found: MNH41 )79Br;
CI) 354.0453. C14H1379BrN2O3 requires: MNH4 354.0455;
3.1.2. (2S)-3-Benzyloxycarbonyl-2-tert-butyl-4-methyl-
eneoxazolidin-5-one 11. )2S,4R)-3-Benzyloxycarbonyl-2-
tert-butyl-4-)methylsulfonylmethyl)oxazolidin-5-one 9
)2.85 g, 7.72 mmol) in dry dichloromethane )40cm 3) was
treated dropwise with DBU )1.39 cm3, 1.41 g, 9.27 mmol)
and stirred at 08C for 1 h before addition of water )40cm 3).
The layers were separated and the dichloromethane solution
was washed with water, dried )MgSO4), ®ltered and evapo-
rated under reduced pressure. The crude product was ®ltered
through a short column of silica gel to give a colourless oil
crystallised from hexane to yield the title compound 11
)2.13 g, 95%) as a colourless crystalline solid, mp 69±
n
max )KBr/cm21) 2926, 2854, 2723, 1752, 1700, 1659, 1441,
1378 and 1360; dH )300 MHz; CDCl3) 1.95 )3H, d,
Jˆ1.1 Hz, CH3), 3.64 and 4.09 )each 2H, t, Jˆ5.9 Hz,
CH2CH2), 7.18 )1H, q, Jˆ1.1 Hz, CHvCCH3), 7.50)2H,
m, ArH), 7.65 )1H, m, ArH) and 7.92 )2H, m, ArH); dC
)75 MHz; CDCl3) 12.35 )CH3), 29.3 and 50.7 )CH2),
110.3 )C-5), 129.2, 130.4, 131.4 and 135.2 )ArCH and C-
6), 140.9 )ArC), 149.6, 163.1 and 168.8 )CO); m/z )EI)
339.1 )MH; 81Br, 100%), 337.1 )MH; 79Br, 96), 310.1
)93), 308.1 )100), 268.1 )28), 266 )31).
718C, [a]D ˆ265.4 )c, 0.4 in EtOH); Found: MH1
20
290.1394. C16H19NO4 requires: MH 290.1392; nmax )KBr/
cm21) 3093, 3068, 3052, 1790, 1724, 1680, 1391, 1369,
1329, 1272, 1257, 1162, 1133, 1095, 1036 and 1012; dH
3.3.2. 3-Benzoyl-1-(2-iodoethyl)thymine 13c. Prepared

R. C. F. Jones et al. / Tetrahedron 57 &2001) 6539±6555
6545
following method B, using 3-benzoyl-1-)2-bromoethyl)-
thymine 13a )4.0g, 11.4 mmol) and sodium iodide
)8.56 g, 57.1 mmol) to yield the title compound 13c as a
yellow powder )4.32 g, 95%), mp 138±1398C; Found:
MH1 385.0049. C14H13IN2O3 requires: MH 385.0053;
nmax )KBr/cm21) 3119, 1754, 1746, 1694, 1650, 1434,
1364 and 1193; dH )300 MHz; CDCl3) 1.95 )3H, s, CH3),
3.4 and 4.07 )each 2H, t, Jˆ6.2 Hz, CH2CH2), 7.14 )1H, s,
CHvCCH3), 7.52 )2H, m, ArH), 7.66 )1H, m, ArH) and
7.93 )2H, m, ArH); dC )75 MHz; CDCl3) 12.35 )CH3), 41.85
and 50.85 )CH2), 110.4 )C-5), 129.2, 130.4, 131.4 and 135.1
)ArCH and C-6), 141.1 )ArC), 149.7, 163.1 and 168.7 )CO);
m/z 385 )MH1, 62%), 356 )100), 314 )18), 229 )20) and 202
)60).
7.31 )each 1H, d, Jˆ7.70Hz, CH vCHCO), 7.48 )2H, m,
ArH), 7.65 )1H, m, ArH), 7.93 )2H, m, ArH); dC )75 MHz;
CDCl3) 29.4 and 51.1 )CH2), 101.8 )C-6), 129.25, 130.5,
131.3 and 135.3 )ArCH and C-5), 144.9 )ArC), 149.6, 162.3
and 168.45 )CO); m/z 324 )M1, 81Br, 100%) and 322 )M1,
79Br, 100).
3.3.6. 1-(2-Iodoethyl)-3-benzoyluracil 17a. Prepared follow-
ing method B, using 3-benzoyl-1-)2-bromoethyl)uracil )5.0g,
15.5 mmol) and sodium iodide )11.64 g, 77.6 mmol) to yield
the title compound 17a as a yellow powder )5.52 g, 96%), mp
190±1918C; Found: MH1 )CI) 370.9892. C13H11IN2O3
requires: MH 370.9892; nmax )KBr/cm21) 3109, 1743, 1700,
1663, 1447, 1344 and 1178; dH )300 MHz; CDCl3) 3.44 and
4.13 )each 2H, t, Jˆ6.16 Hz, CH2CH2), 5.84 and 7.23 )each
1H, d, Jˆ7.90Hz, CH vCHCO), 7.49 )2H, m, ArH), 7.66
)1H, m, ArH) and 7.95 )2H, m, ArH); dC )75 MHz; CDCl3)
21.9 and 51.5 )CH2), 101.9 )C-5), 129.25, 130.5, 131.3, 135.2
)ArCH and C-6), 144.3 )ArC), 149.5, 162.25 and 168.44
)CO); m/z 370)MH 1, 4%), 342 )100), 277 )30), 215 )40),
188 )60) and 155 )50).
3.3.3. 3-Benzoyl-1-(3-bromopropyl)thymine 13b. Prepared
following method A, using 3-benzoylthymine 12 )3.0g,
13.0mmol), triphenylphosphine )4.11 g, 15.7 mmol), 3-
bromo-1-propanol )1.42 cm3, 2.18 g, 15.7 mmol) in dry
dioxane )150cm 3) and DIAD )3.08 cm3, 3.17 g,
15.7 mmol). Puri®cation by column chromatography )hex-
ane±ethyl acetate 1:1 v/v) gave the title compound 13b as a
white solid )4.20g, 92%), mp 89±90 8C; Found: MH1 )CI)
351.0343. C15H15BrN2O3 requires MH 351.0344; nmax )KBr/
cm21) 3079, 2966, 1753, 1698, 1664, 1648, 1597, 1463, 1348,
1257 and 1179; dH )300 MHz, CDCl3) 1.97 )3H, d, 1.0Hz,
CH3), 2.28 )2H, apparent quintet, Jˆ6.58 Hz, CH2CH2CH2),
3.91 )2H, t, Jˆ6.22 Hz, CH2Br), 4.09 )2H, t, Jˆ6.78 Hz,
NCH2), 7.18 )1H, q, Jˆ1.0Hz, C HvCCH3), 7.50)2H, m,
ArH), 7.65 )1H, m, ArH) and 7.92 )2H, m, ArH); dC
)75 MHz; CDCl3) 12.35 )CH3), 29.3, 31.0and 50.7 )CH 2),
110.3 )C-5), 129.2, 130.4, 135.2 and 131.4 )ArCH and C-6),
140.9 )ArC), 149.6, 163.1 and 168.8 )CO); m/z 351 )M1,
10%), 322 )100), 282 )40), 243 )80), 229 )10) and 216 )25).
3.3.7. 3-Benzoyl-1-(3-bromopropyl)uracil. Prepared follow-
ing method A, using 3-benzoyluracil 16 )3.5 g, 16.2 mmol),
triphenylphosphine )5.10g, 19.4 mmol) and 3-bromo-1-
propanol )1.77 cm3, 2.70g, 19.4 mmol) in dry dioxane
)150cm 3) and DIAD )3.08 cm3, 3.83 g, 19.4 mmol). Puri®-
cation by column chromatography )hexane±ethyl acetate, 1:1
v/v) gave the title compound as a white solid )4.57 g, 84%),
mp 89±908C; Found: MH1 )CI) 337.0188. C14H13BrN2O3
requires: MH 337.0188; nmax )KBr/cm21) 1738, 1699, 1654,
1598, 1446, 1389, 1341 and 1256; dH )300 MHz; CDCl3) 2.28
)2H, apparent quintet, Jˆ6.40Hz, CH 2CH2CH2), 3.44 )2H, t,
Jˆ6.07 Hz, CH2Br), 3.94 )2H, t, Jˆ6.61 Hz, NCH2), 5.80and
7.35 )each 1H, d, Jˆ8.05 Hz, CHvCHCO), 7.51 )2H, m,
ArH), 7.65 )1H, m, ArH) and 7.93 )2H, m, ArH); dC
)75 MHz; CDCl3) 29.7, 30.95 and 47.9 )CH2), 102.2 )C-5),
129.2 and 130.45 )ArCH), 131.4 )ArC), 135.2 and 144.5
)ArCH and C-6), 149.8, 162.35 and 168.75 )CO); m/z 337
)MH1, 40%), 276 )30), 259 )40), 172 )100), 155 )46), 139
)44) and 105 )34).
3.3.4. 3-Benzoyl-1-(3-iodopropyl)thymine 13d. Prepared
following method B, using 3-benzoyl-1-)3-bromopropyl)-
thymine 13b )4.0g, 11.4 mmol) and sodium iodide
)8.56 g, 57.1 mmol) to yield the title compound 13d as a
yellow powder )4.32 g, 95%), mp 91±928C; Found: MH1
399.0213. C15H15IN2O3 requires: MH 399.0205; nmax )KBr/
cm21) 3479, 1746, 1651, 1600, 1439, 1353, 1239 and 1176;
dH )300 MHz; CDCl3) 1.97 )3H, s, CH3), 2.25 )2H, apparent
quintet, Jˆ6.90Hz, CH 2CH2CH2), 3.21 )2H, t, Jˆ6.43 Hz,
CH2I), 3.82 )2H, t, Jˆ6.79 Hz, NCH2), 7.17 )1H, s,
CHvCCH3), 7.45 )2H, m, ArH), 7.62 )1H, m, ArH) and
7.93 )2H, m, ArH); dC )75 MHz; CDCl3) 1.6 )CH2I) 12.4
)CH3), 31.8 and 49.5 )CH2), 110.9 )C-5), 129.1, 130.4 and
131.5 and 135.0)ArCH and C-6), 140.2 )ArC), 149.8, 163.0
and 168.9 )CvO); m/z 398 )M1, 15%), 370 )30), 328 )20),
277 )100), 243 )60) and 167 )18).
3.3.8. 3-Benzoyl-1-(3-iodopropyl)uracil 17b. Prepared
following method B, using 3-benzoyl-1-)3-bromopropyl)-
uracil )4.5 g, 13.4 mmol) and sodium iodide )10.0 g,
67.0mmol) to yield the title compound 17b as a yellow
gum )5.0g, 96%); Found: MH 1 385.0052. C14H13IN2O3
requires: MH 385.0049; nmax )KBr/cm21) 3056, 1751,
1708, 1669, 1440 and 1266; dH )300 MHz; CDCl3) 2.21
)2H, apparent quintet, Jˆ6.61 Hz, CH2CH2CH2) 3.14 )2H,
t, Jˆ6.61 Hz, CH2I), 3.82 )2H, t, Jˆ6.79 Hz, NCH2), 5.74
and 7.33 )each 1H, d, Jˆ7.97 Hz, CHvCHCO), 7.49 )2H,
m, ArH), 7.65 )1H, m, ArH) and 7.91 )2H, m, ArH); dC
)75 MHz; CDCl3) 1.53, 31.7 and 49.7 )CH2), 102.0 )C-5),
129.2 and 130.3 )ArCH), 131.3 )ArC), 135.2 and 144.6
)ArCH and C-6), 149.7, 162.3 and 168.8 )CO); m/z 384
)M1, 8%), 356 )50), 328 )8), 314 )10), 263 )100) and 257
)65).
3.3.5. 3-Benzoyl-1-(2-bromoethyl)uracil. Prepared follow-
ing method A, using 3-benzoyluracil 16 )4.2 g, 19.4 mmol),
triphenylphosphine )6.12 g, 23.3 mmol) and 2-bromoethanol
)1.65 cm3, 2.92 g, 23.3 mmol) in dry dioxane )150cm 3) and
DIAD )4.59 cm3, 4.72 g, 23.3 mmol). Puri®cation by column
chromatography )hexane±ethyl acetate 6:4 v/v) gave the title
compound as a white solid )5.15 g, 82%), mp 183±1848C;
Found: MNH4 )ES1; 79Br) 340.0290. C13H1179BrN2O3
3.3.9. 9-(2-Bromoethyl)-N6-(2-methylpropionyl)adenine.
Prepared following method A, using N6-)2-methylpropionyl)-
adenine 20 )5.0g, 24.4 mmol), triphenylphosphine )7.68 g,
29.3 mmol), 2-bromoethanol )2.07 cm3, 3.66 g, 29.3 mmol),
1
requires: MNH4 340.0297; nmax )KBr/cm21) 3110, 1744,
1699, 1664, 1449, 1349 and 1258; dH )300 MHz; CDCl3)
3.65 and 4.13 )each 2H, t, Jˆ5.88 Hz, CH2CH2), 5.74 and

6546
R. C. F. Jones et al. / Tetrahedron 57 &2001) 6539±6555
dioxane )150cm 3) and DIAD )5.76 cm3, 5.92 g, 29.3 mmol).
Puri®cation by column chromatography )hexane±ethyl ace-
tate, 4:1 v/v) gave the title compound as a white solid
)5.76 g, 76%), mp 148±1498C )from ethanol); Found:
MH1 312.0462. C11H14N5OBr requires: MH 312.0460;
nmax )KBr/cm21) 3339, 3281, 3117, 2973, 1689, 1611,
1516, 1489, 1201 and 1152; dH )300 MHz; CDCl3) 1.34
)6H, d, Jˆ6.93 Hz, CHMe2), 3.28 )1H, septet, Jˆ6.93 Hz,
CHMe2), 3.79 and 4.69 )each 2H, t, Jˆ5.88 Hz, CH2CH2),
8.12 and 8.70)each 1H, s, 2-CH and 8-CH), 9.06 )1H, s,
CONH); dC )75 MHz; CDCl3) 19.4 )CH3), 29.65 )CH2Br),
36.0) CHMe2), 45.8 )NCH2), 122.3 and 143.0)ArC), 149.5
and 151.4 )C-2 and C-8), 152.6 )ArC) and 176.4 )CO); m/z
313 )M1, 100%), 311 )M1, 100%), 270 )12) and 268 )20).
)CH3), 32.3 )CH2), 36.1 )CHMe2), 44.5 )CH2), 122.3
)ArC), 142.9 )CH), 149.4 and 151.6 )ArC), 152.57 )CH)
and 176.9 )CO); m/z 373 )M1, 10%), 277 )80), 199 )28),
149 )54) and 77 )100).
3.3.13. 9-(2-Bromoethyl)-N2-acetyl-O6-[2-(4-nitrophenyl)-
ethyl]guanine. Prepared following method A, using N2-
acetyl-O6-[2-)4-nitrophenyl)ethyl]guanine 24a )5.0g,
14.6 mmol), 2-bromoethanol )1.24 cm3, 2.19 g, 17.5 mmol),
triphenylphosphine )4.6 g, 17.5 mmol), dioxane )100 cm3)
and DIAD )3.54 g, 3.45 cm3, 17.5 mmol). Puri®cation by
¯ash chromatography )EtOAc±hexane, 4:1 v/v) gave the
title compound as a white solid )4.39 g, 67%), mp 181±
1828C; Found: MH1 )FAB) 449.0573. C17H17BrN6O4
requires: MH 449.0579; nmax )KBr/cm21) 3206, 3133,
1665, 1610, 1589, 1510, 1460, 1415, 1383, 1352, 1327,
1309, 1226 and 1025; dH )300 MHz; DMSO-d6) 1.97 )3H,
s, CH3 ArCH2), 3.28 )2H, t, Jˆ6.80Hz, ArC H2), 3.95 and
4.55 )each 2H, t, Jˆ6.04 Hz, NCH2CH2Br), 4.77 )2H, t,
Jˆ6.80Hz, OCH 2), 7.60and 8.20)each 2H, d,
Jˆ8.21 Hz, ArH), 8.29 )1H, s, 8-CH), 10.42 )1H, s,
NHCO); dC )75 MHz; DMSO-d6) 24.7 )CH3), 31.0, 34.2,
44.85 and 66.4 )CH2), 116.65 )ArC), 123.4, 130.3 and 142.8
)ArCH), 146.21, 146.4, 152.0, 152.9 and 159.6 )ArC) and
169.10)CO); m/z 449 )MH1, 65%), 343 )20), 300 )75), 258
)35), 178 )50), 151 )100) and 133 )52).
3.3.10. 9-(2-Iodoethyl)-N6-(2-methylpropionyl)adenine 21a.
Prepared following method B, using 9-)2-bromoethyl)-N6-
)2-methylpropionyl)adenine )5.0g, 16.1 mmol) and sodium
iodide )12.0g, 80.4 mmol) to yield the title compound 21a
as a yellow powder )4.96 g, 86%), mp 162±1638C; Found:
MH1 360.0315. C11H14N5OI requires MH 360.0321; nmax
)KBr/cm21) 3339, 2871, 3040, 3064, 2971, 2928, 2363,
1794, 1611, 1527, 1471, 1348, 1322, 1237, 1191, 1152
and 1111; dH )300 MHz; CDCl3) 1.33 )6H, d, Jˆ6.89 Hz,
CHMe2), 3.24 )1H, septet, Jˆ6.89, CHMe2), 3.63 and 4.64
)each 2H, t, Jˆ6.52 Hz, CH2CH2), 8.14 and 8.71 )each 1H,
s, 2-CH and 8-CH) and 8.93 )1H, s, NHCO); m/z 359 )M1,
20%), 289 )20), 205 )20), 135 )100) and 108 )15).
3.3.14.
9-(2-Iodoethyl)-N2-acetyl-O6-[2-(4-nitrophenyl)-
ethyl]guanine 24b. Prepared using a modi®cation of
method B. 9-)2-Bromoethyl)-N2-acetyl-O6-[2-)4-nitro-
phenyl)ethyl]guanine )0.77 g, 1.72 mmol) and dry sodium
iodide )1.29 g, 8.58 mmol) in dry acetone )50cm 3) was
heated at re¯ux in the dark )aluminium foil) under argon
overnight. After cooling, the acetone was removed under
reduced pressure and the residue taken up in dichloro-
methane )50cm 3) and water )50cm 3). The organic layer
was separated and washed with aqueous sodium thiosulfate
solution )2% w/v, 2£25 cm3), dried )MgSO4) and the
solvents were removed under reduced pressure to yield the
title compound 24b as a yellow gum )0.72 g, 85%); Found:
MH1 )FAB) 497.0412. C17H17IN6O4 requires: MH
497.0408; nmax )KBr/cm21) 3387, 3093, 1685, 1677, 1656,
1605, 1515, 1493, 1381, 1344, 1327, 1213, 1048 and 1023;
dH )300 MHz; DMSO-d6) 2.25 )3H, s, CH3), 3.32 )2H, t,
Jˆ6.80Hz, ArC H2), 3.70and 4.51 )each 2H, t, Jˆ6.58 Hz,
NCH2CH2I), 4.79 )2H, t, Jˆ6.80Hz, OCH 2,), 7.56 and 8.18
)each 2H, d, Jˆ8.29 Hz, ArH), 8.26 )1 H, s, 8-CH), 10.42
)1H, s, NHCO); dC )75 MHz; DMSO-d6) 3.65 )CH2), 24.7
)CH3), 34.2, 45.3 and 66.35 )CH2), 116.8 )ArC), 123.3,
130.3 and 142.6 )ArCH), 146.2, 146.4, 152.9, 152.8 and
159.6 )ArC) and 169.0)CO); m/z 497 )MH1, 75%), 348
)55), 279 )26), 193 )65), 151 )100) and 107 )73).
3.3.11. 9-(3-Bromopropyl)-N6-(2-methylpropionyl)adenine.
Prepared following method A, using N6-)2-methylpropionyl)-
adenine 20 )4.5 g, 22.0mmol), triphenylphosphine )6.91 g,
26.3 mmol), 3-bromo-1-propanol )2.39 cm3, 3.66 g,
26.3 mmol), dioxane )170cm 3) and DIAD )5.19 cm3,
5.33 g, 26.3 mmol). Puri®cation by column chromatography
)hexane±ethyl acetate 4:1 v/v) gave the title compound as a
white solid )5.42 g, 76%), mp 110±1118C )from toluene);
Found: MH1 )ES1) 326.0621. C12H16N5OBr requires: MH
326.0616; nmax )KBr/cm21) 3283, 3137, 3068, 3047, 2970,
2930, 1689, 1663, 1485, 1406, 1350, 1234 and 1227; dH
)300 MHz; CDCl3) 1.31 )6H, d, Jˆ6.50Hz, CH Me2), 2.49
)1H, septet, Jˆ6.50Hz, C HMe2), 3.30)2H, apparent quin-
tet, CH2CH2CH2), 3.37 )2H, t, Jˆ6.22 Hz, CH2Br), 4.49
)2H, t, Jˆ6.58 Hz, NCH2), 8.14 and 8.73 )each 1H, s, 2-
CH and 8-CH) and 8.85 )1H, s, NHCO); dC )75 MHz;
CDCl3) 19.25 )CH3), 29.5 and 31.7 )CH2), 36.0) CHMe2),
42.3 )CH2), 122.4 )ArC), 143.1 )CH), 149.5 and 151.7
)ArC), 152.5 )CH) and 176.6 )CO); m/z 325 )M1, 20%),
257 )20), 205 )20), 176 )40), 149 )100) and 71 )38).
3.3.12. 9-(3-Iodopropyl)-N6-(2-methylpropionyl)adenine
21b. Prepared following method B, using 9-)3-bromo-
propyl)-N6-)2-methylpropionyl)adenine )5.3 g, 16.3 mmol)
and sodium iodide )12.2 g, 81.5 mmol) to yield the title
compound 21b as a yellow gum )4.93 g, 81%); Found:
MH1 )ES1) 374.0473. C12H16N5OI requires: MH
374.0478; nmax )®lm/cm21) 3413, 2981, 2360, 2342, 1610,
1588, 1459 and 908; dH )300 MHz, CDCl3) 1.31 )6H, d,
Jˆ6.69 Hz, CHMe2), 2.43 )1H, septet, Jˆ6.69 Hz,
CHMe2), 3.12 )2H, t, Jˆ6.61 Hz, CH2I), 3.24 )2H, apparent
quintet, Jˆ6.61 Hz, CH2CH2CH2), 4.42 )2H, t, Jˆ5.58 Hz,
NCH2), 8.09 and 8.73 )each 1H, s, 2-CH and 8-CH), 8.75
)1H, s, NHCO); dC )75 MHz; CDCl3) 1.65 )CH2), 19.2
3.4. General procedure for conjugate radical addition to
oxazolidinone 11 (method C)
To the iodoalkyl derivative )1.0mol equiv.), )2 S)-3-benzyl-
oxycarbonyl-2-tert-butyl-4-methyleneoxazolidin-5-one 11
)1.2 mol equiv.) and AIBN )0.1 mol equiv.) in degassed
toluene )200 cm3), warmed to 808C and stirred under a
positive atmosphere of argon, was added tributyltin hydride
)1.2 mol equiv.) dropwise via syringe pump over 2 h. Heat-
ing and stirring were continued until re¯ux and for a further

R. C. F. Jones et al. / Tetrahedron 57 &2001) 6539±6555
6547
12 h. After cooling, the toluene was removed under reduced
pressure and the residue puri®ed by ¯ash column chroma-
tography )EtOAc±hexane, 1:4 to 4:1 v/v) to give the conju-
gate adduct.
)0.29 mmol), but heating at re¯ux for 16 h to yield the
conjugate adduct 14a as a colourless oil )1.29 g, 24%)
identical with the sample prepared by method C, and the
debenzoylated conjugate adduct 14b as a white solid
)0.391 g, 30%), mp )decomp.) 78±808C. No reduced
products were isolated. )2S,4S)-3-Benzyloxycarbonyl-2-
tert-butyl-4[3-)1-thyminyl)propyl]oxazolidin-5-one 14b:
Found: MH1 )CI) 444.2132. C23H29N3O6 requires: MH
444.2134; nmax )KBr/cm21) 3204, 3037, 2964, 1792, 1708,
1680, 1467, 1397, 1363, 1348, 1229, 1198 and 1125; dH
)300 MHz; CDCl3) 0.95 )9H, s, CMe3), 1.85±1.99 )7H, m,
CH2CH2 and CHvCCH3), 3.68 and 3.76 )each 1H, m,
NCH2), 4.32 )1H, t, Jˆ6.79 Hz, CHCH2), 5.18 )2H, 2£d,
Jˆ11.93 Hz, CH2Ph), 5.56 )1H, s, CHBut), 7.00 )1H, s,
CHvCCH3), 7.34±7.38 )5H, m, ArH) and 9.57 )1H, s,
NH); dC )75 MHz; CDCl3) 12.3 )CHvCCH3), 24.9
)CMe3), 25.8 )NCH2CH2CH2), 29.8 )CHCH2), 36.9
)CMe3), 47.4 )NCH2), 56.7 )CHCH2), 68.6 )PhCH2), 96.5
)CHBut), 110.8 )CHvCCH3), 128.6, 128.7 and 128.8
)ArH), 135.0)ArC), 14.02 ) CHvCCH3), 172.3, 171.2,
164.5 and 156.1 )CO); m/z 443 )M1, 60%), 386 )70), 308
)75), 286 )100), 264 )35), 250 )35), 208 )80) and 194 )48).
3.5. General procedure for conjugate radical addition to
oxazolidinone 11 (method D)
The iodoalkyl derivative )1.0mol equiv.), )2 S)-3-benzyloxy-
carbonyl-2-tert-butyl-4-methyleneoxazolidin-5-one 11
)2 mol equiv.), tributyltin chloride )0.3 mol equiv.), sodium
cyanoborohydride )2 mol equiv.) and AIBN )0.1 mol
equiv.) in tert-butanol )40cm 3/g of 11) per were heated at
re¯ux under a positive atmosphere of argon for 40h. After
cooling, the solvent was removed under reduced pressure
and the residue puri®ed by ¯ash column chromatography
)EtOAc±hexane, 1:4 to 4:1 v/v) to yield the conjugate
adduct.
3.5.1. (2S,4S)-3-Benzyloxycarbonyl-2-tert-butyl-4-[3-(3-
benzoyl-1-thyminyl)propyl]oxazolidin-5-one 14a. Per-
formed following method C, using 3-benzoyl-1-)2-
iodoethyl)thymine 13c )0.66 g, 17.2 mmol), )2S)-3-benzyl-
oxycarbonyl-2-tert-butyl-4-methyleneoxazolidin-5-one 11
)497 mg, 17.2 mmol), AIBN )ca. 10mg) and tributyltin
hydride )0.555 cm3, 0.60 g, 20.6 mmol) to give the conju-
gate adduct 14a as a colourless oil )244 mg, 26%) and 3-
benzoyl-1-ethylthymine 15a as a white solid )106 mg, 24%),
mp 169±1718C. )2S,4S)-3-Benzyloxycarbonyl-2-tert-butyl-
4-[3-)3-benzoyl-1-thyminyl)propyl]oxazolidin-5-one 14a:
Found: MH1 )CI) 548.2387. C30H33N3O7 requires: MH
548.2397; nmax )neat/cm21) 3431, 2361, 2342, 1790, 1749,
1701, 1657, 1440 and 1266; dH )300 MHz; CDCl3) 0.94
)9H, s, CMe3), 1.74±2.04 )7H, m, 2£NCH2CH2CH2 and
CHvCCH3), 3.69 and 3.81 )each 1H, m, NCH2), 4.31
)1H, t, Jˆ6.79 Hz, CHCH2), 5.17 )2H, s, CH2Ph), 5.56
)1H, s, CHBut), 7.11 )1H, s, CHvCCH3), 7.34±7.38 )5H,
m, ArH), 7.49 )2H, m, ArH), 7.64 )1H, m, ArH) and 7.91
)2H, m, ArH); dC )75 MHz; CDCl3) 12.4 )CHvCCH3), 24.9
)CMe3), 25.8 )NCH2CH2CH2), 29.9 )CHCH2), 36.9 )CMe3),
47.7 )NCH2), 56.6 )CHCH2), 68.7 )CH2Ph), 96.5 )CHBut),
110.9 )CHvCCH3), 128.6, 128.8, 128.8, 129.1, 130.4 and
131.7 )ArCH), 134.95 and 135.0)ArC), 139.9
)CHvCCH3), 149.8, 156.1, 163.1, 169.0and 172.3 )CO);
m/z 547 )M1, 100%), 490 )50), 442 )30), 398 )60), 315 )70)
and 286 )45). 3-Benzoyl-1-ethylthymine 15a: Found: )CI)
259.1083. C14H14N2O3 requires: MH1 259.1082; nmax )KBr/
cm21) 1366, 1346, 1266, 1248 and 1193; dH )300 MHz)
1.30)3H, t, Jˆ7.15 Hz, CH2CH3), 1.95 )3H, s, CHvCCH3),
3.77 )2H, q, Jˆ7.15 Hz, CH2CH3), 7.12 )1H, s,
CHvCCH3), 7.49 )2H, m, ArH), 7.64 )1H, m, ArH) and
7.91 )2H, m, ArH); m/z 258 )M1, 15%), 230 )100) and 188
)40).
When the reaction time was extended to 40h, using 3-
benzoyl-1-)2-iodoethyl)thymine 13c )6.84 g, 17.8 mmol),
)2S)-3-benzyloxycarbonyl-2-tert-butyl-4-methyleneoxazo-
lidin-5-one )10.3 g, 35.6 mmol), tributyltin chloride
)1.45 cm3, 1.74 g, 5.34 mmol), sodium cyanoborohydride
)2.24 g, 35.6 mmol) and AIBN )1.78 mmol), puri®cation
by column chromatography gave only the adduct 14b as a
white solid )3.68 g, 47%), data as above. Reduced products
were not isolated.
3.5.3. (2S,4S)-3-Benzyloxycarbonyl-2-tert-butyl-4-[4-(1-
thyminyl)butyl]oxazolidin-5-one 14d. Prepared following
method D, using 3-benzoyl-1-)3-iodopropyl)thymine 13d
)3.12 g, 7.84 mmol), )2S)-3-benzyloxycarbonyl-2-tert-butyl-
4-methyleneoxazolidin-5-one 11 )4.53 g, 15.7 mmol), tri-
butyltin chloride )0.638 cm3, 0.765 g, 2.35 mmol), sodium
cyanoborohydride )0.98 g, 15.7 mmol) and AIBN
)0.78 mmol) to yield the debenzoylated conjugate adduct
14d as a thick oil )900 mg, 25%) and 1-propylthymine
15b as a white solid )276 mg, 21%), mp 134±1358C.
)2S,4S)-3-benzyloxycarbonyl-2-tert-butyl-4-[4-)1-thyminyl)-
butyl]oxazolidin-5-one 14d: Found: MH1 458.2287.
C24H31N3O6 requires: MH 458.2291; nmax )®lm/cm21
)
3489, 3201, 3068, 2964, 1789, 1710, 1690, 1480, 1398,
1348, 1289, 1269, 1225, 1125, 1043 and 1013; dH
)300 MHz; CDCl3) 0.95 )9H, s, CMe3), 1.56±2.05 )9H, m,
CH)CH2)3CH2N and CHvCCH3), 3.49±3.69 )2H, m,
NCH2), 4.23±4.28 )1H, t, Jˆ6.79 Hz, CHCH2), 5.17 )2H,
s, CH2Ph), 5.55 )1H, s, CHBut), 6.89 )1H, s, CHvCCH3),
7.32±7.44 )5H, m, ArH) and 9.08 )1H, s, NH); dC )75 MHz;
CDCl3) 12.3 )CHvCCH3), 23.2 )CH2), 24.9 )CMe3), 28.4
and 32.6 )CH2), 37.0) CMe3), 48.2 )NCH2), 56.8 )CHCH2),
68.5 )CH2Ph), 96.4 )CHBut), 110.7 )CCH3), 128.5, 128.55
and 128.7 )ArCH), 135.2 )ArC), 140.4 )CHvCCH3), 150.8,
156.0, 164.3 and 172.6 )CO); m/z 457 )M1, 10%), 400 )20),
300 )30), 91 )25), 84 )100) and 47 )20). 1-Propylthymine
15b:20 Found: MH1 169.0980. C8H12N2O2 requires: MH
169.0977; nmax )KBr/cm21) 3163, 3099, 3027, 2970, 1704,
1649 and 1245; dH )300 MHz; CDCl3) 0.94 )3H, t,
Jˆ7.51 Hz, CH2CH3), 1.71 )2H, apparent sextet,
3.5.2. (2S,4S)-3-Benzyloxycarbonyl-2-tert-butyl-4-[3-(3-
benzoyl-1-thyminyl)propyl]oxazolidin-5-one 14a and
(2S,4S)-3-benzyloxycarbonyl-2-tert-butyl-4[3-(1-thy-
minyl)propyl]oxazolidin-5-one 14b. Performed following
method D, using 3-benzoyl-1-)2-iodoethyl)thymine 13c
)1.13 g, 2.94 mmol), )2S)-3-benzyloxycarbonyl-2-tert-butyl-
4-methyleneoxazolidin-5-one 11 )1.70g, 5.89 mmol), tri-
butyltin chloride )0.239 cm3, 0.287 g, 0.882 mmol), sodium
cyanoborohydride )0.370 g, 5.89 mmol) and AIBN

6548
R. C. F. Jones et al. / Tetrahedron 57 &2001) 6539±6555
Jˆ7.33 Hz, NCH2CH2CH3), 1.93 )3H, s, CHvCCH3), 2.91
)2H, t, Jˆ6.25 Hz, NCH2CH2), 6.99 )1H, s, CHvCCH3)
and 9.37 )1H, s, NH); dC )75 MHz; CDCl3) 10.9
)CH2CH3), 12.3 )CHvCCH3), 22.35 )CH2CH3), 50.05
)NCH2), 110.5 )CHvCCH3), 140.5 )CHvCCH3), 151.1
and 164.4 )CO); m/z 168 )M1, 90%), 126 )90), 96 )100),
55 )37) and 41 )40).
)1H, d, Jˆ7.54 Hz, CHvCHCO), 7.32±7.34 )6H, m, ArH
and CHvCHCO) and 9.92 )1H, s, NH); dC )75 MHz;
CDCl3) 24.9 )CMe3), 26.7 )CH2CH2CH2N), 28.9
)CHCH2), 36.8 )CMe3), 47.6 )NCH2), 56.7 )CHCH2), 68.9
)CH2Ph), 96.8 )CHBut), 102.5 )CHCO), 128.7, 135.0
)ArCH), 146.15 and 147.1 )ArC), 151.4 )CHvCHCO),
156.4, 165.5, 171.0and 173.3 )CO); m/z 430)MH
30%), 279 )20), 254 )100), 238 )30) and 220 )90).
1
,
3.5.4. (2S,4S)-3-Benzyloxycarbonyl-2-tert-butyl-4-[3-(3-
benzoyl-1-uracilyl)propyl]oxazolidin-5-one 18a. Prepared
following method D, using 3-benzoyl-1-)2-iodoethyl)uracil
17a )0.76 g, 2.05 mmol), )2S)-3-benzyloxycarbonyl-2-tert-
butyl-4-methyleneoxazolidin-5-one 11 )1.19 g, 4.11 mmol),
tributyltin chloride )0.167 cm3, 0.201 g, 0.616 mmol), sodium
cyanoborohydride )0.258 g, 4.11 mmol) and AIBN
)0.205 mmol), but heating at re¯ux for 7 h to yield the conju-
gate adduct 18a as a colourless oil )510mg, 47%) and 3-
benzoyl-1-ethyluracil 15c as a white amorphous gum
)230mg, 46%) that was incompletely characterized. No
debenzoylated products were observed in the mixture.
)2S,4S)-3-Benzyloxycarbonyl-2-tert-butyl-4-[3-)3-benzoyl-1-
uracilyl)propyl]oxazolidin-5-one 18a: Found: MH1 )CI)
534.2237. C29H31N3O7 requires: MH 534.2240; nmax )®lm/
cm21) 3404, 3369, 1790, 1749, 1704, 1665, 1497, 1439,
1392, 1347, 1255, 1235 and 1041; dH )300 MHz; CDCl3)
0.94 )9H, s, But), 1.82±2.01 )4H, m, CHCH2CH2), 3.69±
3.85 )2H, m, NCH2), 4.30)1H, t, Jˆ6.79 Hz, CHCH2), 5.16
)2H, s, CH2Ph), 5.56 )1H, s, CHBut), 5.75 )1H, d, Jˆ7.87 Hz,
CHvCHCO), 7.24±7.40)6H, m, ArH and C HvCHCO),
7.46±7.52 )2H, m, ArH), 7.61±7.67 )1H, m, ArH) and 7.90
)2H, m, ArH); dC )75 MHz; CDCl3) 24.9 )CMe3), 25.7
)CH2CH2CH2N), 29.8 )CHCH2), 36.9 )CMe3), 48.0)NCH 2),
56.6 )CHCH2), 68.7 )CH2Ph), 96.5 )CHBut), 102.15 )CHCO),
128.4, 128.6, 128.8, 128.8, 129.2 and 130.4 )ArCH), 131.5
and 135.1 )ArC), 144.1 )CHvCHCO), 149.8, 156.1, 162.4,
168.8 and 172.3 )CO); m/z 533 )MH1, 20%), 476 )30), 404
)25), 376 )50), 301 )40) and 198 )50). 3-Benzoyl-1-ethyluracil
15c: nmax )®lm/cm21) 3413, 3058, 2984, 2328, 2178, 1788,
1749, 1665, 1601, 1485, 1439, 1391, 1346, 1266, 1178 and
1122; dH )300 MHz; CDCl3) 1.29 )3H, t, Jˆ7.15 Hz,
NCH2CH3), 3.79 )2H, q, Jˆ7.15 Hz, NCH2CH3), 5.81 )1H,
d, Jˆ7.90Hz, 5-CH), 7.20±7.52 )4H, m, ArH and 6-CH),
7.89 )2H, m, ArH); m/z 244 )M1, 5%), 216 )30 ), 199 )20 ),
183 )15), 105 )100) and 77 )88).
3.5.6. (2S,4S)-3-Benzyloxycarbonyl-2-tert-butyl-4-[4-(3-
benzoyl-1-uracilyl)butyl]oxazolidin-5-one 18c. Prepared
following a modi®ed method D, using 3-benzoyl-1-)3-iodo-
propyl)uracil 17b )2.40g, 6.25 mmol), )2 S)-3-benzyloxycar-
bonyl-2-tert-butyl-4-methyleneoxazolidin-5-one 11 )1.51 g,
5.21 mmol), tributyltin chloride )0.424 cm3, 0.509 g,
1.56 mmol), sodium cyanoborohydride )0.427 g, 6.79 mmol)
and AIBN )0.52 mmol) but heated at re¯ux in degassed etha-
nol )50cm 3) for 8 h to yield the conjugate adduct 18c as a
colourless oil )598 mg, 21%) and 3-benzoyl-1-propyluracil
15e as a white gum )362 mg, 27%) that was incompletely
characterized. )2S,4S)-3-Benzyloxycarbonyl-2-tert-butyl-4-
[4-)3-benzoyl-1-uracilyl)butyl]oxazolidin-5-one 18c: Found:
MH1 )CI) 548.2390. C30H33N3O7 requires: MH 548.2397;
n
max )KBr/cm21) 2962, 2362, 1791, 1749, 1703, 1664, 1438,
1371, 1348, 1256 and 1235; dH )300 MHz; CDCl3) 1.00
)9H, s, CMe3), 1.64±2.02 )6H, m, CH)CH2)3CH2N), 3.74
)2H, m, NCH2), 4.31 )1H, t, Jˆ6.97 Hz, CHCH2), 5.21
)2H, s, CH2Ph), 5.60)1H, s, C HBut), 5.81 and 7.25 )each
1H, d, Jˆ7.44 Hz, CHvCHCO), 7.42±7.44 )5H, m, ArH),
7.55 )2H, m, ArH) 7.70)1H, m, ArH) and 7.97 )2H, m,
ArH); dC )75 MHz; CDCl3) 22.0)CH ), 24.8 )CMe3), 28.1
2
and 32.4 )CH2), 36.81 )CMe3,), 48.7 )NCH2), 53.4
)CHCH2), 68.3 )CH2Ph), 96.3 )CHBut), 101.9 )CHCO),
128.4, 128.6, 128.7, 129.1 and 130.3 )ArCH), 131.4
)ArC), 135.0)ArCH), 135.1 )ArC), 144.2 ) CHvCHCO),
149.6, 155.8, 162.35, 168.8 and 172.4 )CO); m/z 547 )M1,
20%), 490 )50), 446 )30), 418 )50), 390 )60), 286 )40) and
198 )100). 3-Benzoyl-1-propyluracil 15e: dH )300 MHz,
CDCl3) 0.96 )3H, t, Jˆ7.51 Hz, CH2CH3), 1.72 )2H, appar-
ent sextet, Jˆ7.36 Hz, NCH2CH2CH3), 3.68 )2H, t,
Jˆ7.33 Hz, NCH2), 5.80and 7.20)each 1H, d,
Jˆ7.05 Hz, CHvCHCO) and 7.47±7.68 )5H, m, ArH).
3.5.7. (2S,4S)-3-Benzyloxycarbonyl-2-tert-butyl-4-[4-(1-
uracilyl)butyl]oxazolidin-5-one 18d. Prepared following
method D, using 3-benzoyl-1-)3-iodopropyl)uracil 17b
)1.98 g, 5.16 mmol), )2S)-3-benzyloxycarbonyl-2-tert-butyl-
4-methyleneoxazolidin-5-one 11 )2.98 g, 10.3 mmol), tributy-
ltin chloride )0.420 cm3, 503 mg, 1.55 mmol), sodium cyano-
borohydride )648 mg, 10.3 mmol) and AIBN )0.516 mmol)
to yield the debenzoylated conjugate adduct 18d as an
amorphous solid )1.00 g, 44%), mp )decomp.) 151±1538C,
and 1-propyluracil 15d as a white gum )0.405 g, 51%).
)2S,4S)-3-Benzyloxycarbonyl-2-tert-butyl-4-[4-)1-uracilyl)-
butyl]oxazolidin-5-one 18d: Found: MH1 444.2125.
C23H29N3O6 requires: MH 444.2134; dH )300 MHz;
CD3OD) 0.93 )9H, s, CMe3), 1.52±2.01 )6H, m,
CH)CH2)3CH2N), 3.58±3.73 )2H, m, NCH2), 4.35 )1H, t,
Jˆ7.54 Hz, CHCH2), 5.16 )2H, s, CH2Ph), 5.56 )1H, s,
CHBut), 5.62 )1H, d, Jˆ7.69 Hz, CHvCHCO) and 7.30±
7.50)6H, m, ArH and C HvCHCO); dC )75 MHz; CD3OD)
24.2 )CH2), 25.4 )CMe3), 29.2 and 33.8 )CH2), 37.8
)CMe3,), 48.5 )NCH2), 58.2 )CHCH2), 69.4 )CH2Ph), 97.8
3.5.5. (2S,4S)-3-Benzyloxycarbonyl-2-tert-butyl-4-[3-(-1-
uracilyl)propyl]oxazolidin-5-one 18b. Prepared following
method D, using 3-benzoyl-1-)2-iodoethyl)uracil 17a
)5.45 g, 14.7 mmol), )2S)-3-benzyloxycarbonyl-2-tert-butyl-
4-methyleneoxazolidin-5-one 11 )8.51 g, 29.5 mmol), tribu-
tyltin chloride )1.20cm 3, 1.44 g, 4.42 mmol), sodium
cyanoborohydride )1.85 g, 29.5 mmol) and AIBN
)1.47 mmol) to yield the debenzoylated conjugate adduct
18b as a colourless oil )3.24 g, 51%). No benzoylated
product was isolated; reduction product was present but
not puri®ed from this experiment. )2S,4S)-3-Benzyloxycar-
bonyl-2-tert-butyl-4-[3-)-1-uracilyl)propyl]oxazolidin-5-
1
one 18b: Found: MNH4 )ES1) 447.2255. C22H27N3O6
requires: MNH4 447.2244; nmax )®lm/cm21) 3691, 3055,
2360, 2342, 1791, 1713, 1689 and 1266; dH )300 MHz;
CDCl3) 0.92 )9H, s, But), 1.83±2.10)4H, m, CHC H2CH2),
3.26±3.82 )2H, m, NCH2), 4.43 )1H, t, Jˆ6.75 Hz,
CHCH2), 5.16 )2H, s, CH2Ph), 5.54 )1H, s, CHBut), 5.82

R. C. F. Jones et al. / Tetrahedron 57 &2001) 6539±6555
6549
)CHBut), 102.2 )CHvCHCO), 128.75, 129.5 and 129.6
)ArCH), 137.1 )ArC), 147.3 )CHvCHCO), 152.8, 157.9,
166.8 and 174.6 )CO); m/z 444 )MH1, 80%) and 430 )20).
1-Propyluracil 15d: Found: M1 )EI) 154.0734. C7H10N2O2
requires: M 154.0742; dH )300 MHz, CDCl3) 0.91 )3H, t,
Jˆ7.33 Hz, CH2CH3), 1.72 )2H, sextet, Jˆ7.33 Hz,
NCH2CH2CH3), 3.70)2H, t, Jˆ7.33 Hz, NCH2CH2), 5.72
)1H, d, Jˆ7.88 Hz, CHvCHCO), 7.16 )1H, d, Jˆ7.88 Hz,
CHvCHCO) and 9.20)1H, s, NH); dC )75 MHz; CDCl3)
10.9 )CH2CH3), 22.3 )CH2CH3), 50.45 )NCH2), 102.0 )C-5),
144.7 )C-6), 164.0and 171.2 )CO); m/z 154 )M1, 50%), 126
)15), 112 )60), 82 )100), 69 )50) and 55 )40).
2-tert-butyl-4-methyleneoxazolidin-5-one 11 )5.30g,
18.3 mmol), tributyltin chloride )0.746 cm3, 895 mg,
2.75 mmol), sodium cyanoborohydride )1.15 g, 18.3 mmol)
and AIBN )0.92 mmol) but heated at re¯ux for 16 h to yield
the conjugate adduct 22a as a colourless oil )1.17 g, 26%), a
mixture of deacylated conjugate adduct 22b )580mg, 14%,
calculated from the following hydrolysis step) and 9-ethyl-N6-
)2-methylpropionyl)adenine 23a )360mg, 17%, calculated
from the hydrolysis step), and 9-ethyladenine 23b )280mg,
19%) as a white solid, mp 180±1828C )lit.,21 184±1868C).
)2S,4S)-3-Benzyloxycarbonyl-2-tert-butyl-4-{3-[N6-)2-
methylpropionyl)-9-adeninyl]propyl}oxazolidin-5-one 22a:
Found: MH1 523.2670. C27H34N6O5 require: MH 523.2669;
dH )300 MHz; CDCl3) 0.91 )9H, s, CMe3), 1.33 )6H, d,
Jˆ6.97 Hz, CHMe2), 1.87±2.24 )4H, m, CHCH2CH2), 3.28
)1H, septet, Jˆ6.79 Hz, CHMe2), 4.27±4.34 )3H, m, CHCH2
and NCH2), 5.15 )2H, s, CH2Ph), 5.52 )1H, s, CHBut), 7.26
)5H, m, ArH), 8.12 and 8.71 )each 1H, s, adenine-H), 9.74
)1H, s, NH); dC )75 MHz; CDCl3) 19.0)CH Me2), 24.6
)CMe3), 26.7 )CHCH2CH2), 29.0)CH CH2), 33.85 )CHMe2),
35.8 )CMe3), 43.2 )NCH2), 56.5 )CHCH2), 68.6 )CH2Ph), 96.5
)CHBut), 122.0)ArC), 128.5, 128.65 and 128.7 )ArCH), 134.9
)ArC), 143.0)ArCH), 149.55 and 151.7 )ArC), 152.4 )ArCH),
156.1, 172.25 and 176.8 )CO); m/z 522 )M1, 2%), 395 )2),
359 )25) and 91 )100). )2S,4S)-3-Benzyloxycarbonyl-2-tert-
butyl-4-[3-)9-adeninyl)propyl]oxazolidin-5-one 22b )data
from the mixture of 22b and 23a): dH )300 MHz; CDCl3)
0 .91 )9H, s, CMe3), 1.79±2.25 )4H, m, CHCH2CH2), 4.22
)2H, t, Jˆ6.97 Hz, NCH2), 4.36 )1H, m, CHCH2), 5.15 )2H,
s, CH2Ph), 5.56 )1H, s, CHBut), 7.26±7.38 )5H, m, ArH), 7.83
and 8.36 )each 1H, s, adenine-H). 9-Ethyl-N6-)2-methyl-
propionyl)adenine 23a )data from the mixture of 22b and
23a): dH )300 MHz; CD3OD) 1.26 )6H, d, Jˆ6.96 Hz,
CHMe2), 1.51 )3H, t, Jˆ7.33 Hz, CH2CH3) 2.91 )1H, septet,
Jˆ6.96 Hz, CHMe2) and 4.31 )2H, q, Jˆ7.33 Hz, CH2CH3),
8.37 and 8.63 )each 1H, s, 2-CH and 8-CH); dC )75 MHz;
CD3OD) 15.6 and 19.7 )CH3), 37.1 )CHMe2), 40.3 )CH2CH3),
127.05 )ArC), 145.3 )C-2 or C-8), 150.6 )ArC), 152.9 )C-8 or
C-2), 153.2 )ArC) and 178.23 )CO). 9-Ethyladenine 23b:21
Found: M1 )EI) 163.0857. C7H9N5 requires: M 163.0858;
nmax )KBr/cm21) 3268, 3191, 1675, 1601, 1573, 1480,
1415, 1327, 1308, 1249, 1214 and 1197; dH )300 MHz;
CDCl3) 1.62 )3H, t, Jˆ7.32 Hz, CH2CH3), 4.26 )2H, q,
Jˆ7.32 Hz, CH2CH3), 6.09 )2H, s, NH), 7.86 and 8.37
)each 1H, s, 2-CH and 8-CH); dC )75 MHz; CD3OD) 15.55
)CH3), 38.9 )CH2), 121.0)ArC), 140.0)C-2 or C-8), 150.4
)ArC), 152.8 )C-8 or C-2) and 155.5 )ArC); m/z 163 )M1,
60%), 135 )100) and 108 )70).
This experiment was repeated but using 5 mol equiv. of
acceptor 11, i.e. 3-benzoyl-1-)3-iodopropyl)uracil 17b
)1.98 g, 5.16 mmol), )2S)-3-benzyloxycarbonyl-2-tert-butyl-
4-methyleneoxazolidin-5-one 11 )7.45 g, 25.8 mmol), tributy-
ltin chloride )0.420 cm3, 503 mg, 1.55 mmol), sodium cyano-
borohydride )648 mg, 10.3 mmol) and AIBN )0.516 mmol)
to yield the debenzoylated conjugate adduct 18d as an
amorphous solid )1.42 g, 62%), identical to the above
sample.
3.5.8. 2-Benzoyloctahydropyrrolo[1,2-c]pyrimidine-1,3-
dione 19. Prepared following method D, using 3-benzoyl-
1-)3-iodopropyl)uracil 17b )0.86 g, 2.24 mmol), )2S)-3-
benzyloxycarbonyl-2-tert-butyl-4-methyleneoxazolidin-5-
one 11 )777 mg, 2.69 mmol), tributyltin chloride
)0.182 cm3, 219 mg, 0.67 mmol), sodium cyanoborohydride
)42 mg, 0.67 mmol) and AIBN )0.2 mmol) but heated at
re¯ux for 30min. to yield recovered oxazolidinone 11
)640mg, 82%) and uracil 17b )690mg, 80%), and the
title compound 19 )99 mg, 17%; 87% based on recovered
uracil 17b) as a white amorphous solid, mp 157±1588C;
Found: MH1 )CI) 259.1084. C14H14N2O3 requires: MH
259.1083; nmax )KBr/cm21) 3963, 3926, 2361, 1743, 1704,
1681, 1438, 1370, 1349, 1278, 1258, 1240 and 980; dH
)300 MHz, CDCl3) 1.64±1.76 )1H, m, COCH2CHCHH),
1.94±2.00 and 2.09±2.15 )each 1H, ddddd, Jˆ2.37, 4.78,
6.97, 9.70and 11.93 Hz, NCH CH2), 2.32±2.38 )1H, m,
2
COCH2CHCHH), 2.57 )1H, dd, Jˆ13.22 and 15.95 Hz,
COCHH), 2.95 )1H, dd, Jˆ3.85 and 15.95 Hz, COCHH),
3.50±3.71 )2H, m, NCH2), 3.91±3.95 )1H, m, NCH), 7.49
)2H, m, ArH), 7.62 )1H, m, ArH) and 7.89±7.92 )2H, m,
ArH); dC )300 MHz, CDCl3) 23.2 )NCH2CH2CH2), 33.2
)CHCH2), 38.3 )COCH2), 45.3 )NCH2), 52.9 )CH), 129.2
and 130.5 )ArCH), 132.7 )ArC), 134.5 )ArCH), 149.9, 168.9
and 170.0 )CO).
An experiment following method C, using 3-benzoyl-1-)3-
iodopropyl)uracil 17b )0.43 g, 1.12 mmol), AIBN )ca.
3.5.10. (2S,4S)-3-Benzyloxycarbonyl-2-tert-butyl-4-{4-
[N6-(2-methylpropionyl)-9-adeninyl]butyl}oxazolidin-5-
one 22c. Prepared following method C, using 9-)3-iodo-
3
10mg), toluene )150ml) and tributyltin hydride )0.361 cm
,
0.391 g, 1.34 mmol), but without using the chiral acceptor
11, gave the title compound 19 as a colourless oil )152 mg,
53%), having spectral data as above. The reduction product
3-benzoyl-1-propyluracil was not observed.
propyl)-N6-)2-methylpropionyl)adenine
21b
)2S)-3-benzyloxycarbonyl-2-tert-butyl-4-
)0.31 g,
8.31 mmol),
methyleneoxazolidin-5-one 11 )240mg, 8.31 mmol),
AIBN )ca. 10mg) and tributyltin hydride )0.268 ml,
0.290 g, 9.97 mmol) to give the conjugate adduct 22c as a
colourless oil )102 mg, 23%) and N6-)2-methylpropionyl)-
9-propyladenine 23c as a white gum )92.4 mg, 45%).
)2S,4S)-3-Benzyloxycarbonyl-2-tert-butyl-4-{4-[N6-)2-
methylpropionyl)-9-adeninyl]butyl}oxazolidin-5-one 22c:
Found: MH1 537.2811. C28H36N6O5 requires: MH
537.2747; nmax )KBr/cm21) 3343, 3055, 2975, 2875, 2359,
3.5.9. (2S,4S)-3-Benzyloxycarbonyl-2-tert-butyl-4-{3-[N6-
(2-methylpropionyl)-9-adeninyl]propyl}oxazolidin-5-one
22a and (2S,4S)-3-benzyloxycarbonyl-2-tert-butyl-4-[3-(9-
adeninyl)propyl]oxazolidin-5-one 22b. Prepared following
method D, using 9-)2-iodoethyl)-N6-)2-methylpropionyl)-
adenine 21a )3.29 g, 9.16 mmol), )2S)-3-benzyloxycarbonyl-

6550
R. C. F. Jones et al. / Tetrahedron 57 &2001) 6539±6555
1790, 1718, 1615, 1586, 1462, 1402, 1372, 1349 and 1267;
dH )300 MHz; CDCl3) 0.94 )9H, s, CMe3), 1.31 )6H, d,
Jˆ6.87 Hz, CHMe2), 1.52±2.03 )6H, m, CHCH2CH2CH2),
3.22 )1H, septet, Jˆ6.87 Hz, CHMe2), 4.18±4.26 )3H, m,
CHCH2 and NCH2), 5.15 )2H, s, CH2Ph), 5.54 )1H, s,
CHBut), 7.29±7.39 )5H, m, ArH), 7.92 and 8.55 )each 1H,
s, 2-CH and 8-CH) and 8.72 )1H, s, CONH); dC )75 MHz;
CD3OD) 19.7 )CHMe2), 24.4 )CHCH2CH2), 25.6 )CMe3),
30.2 )CHCH2CH2CH2), 33.65 )CHCH2), 37.15 )CHMe2),
37.8 )CMe3), 44.75 )NCH2), 58.1 )CHCH2), 69.3 )CH2Ph),
97.7 )CHBut), 129.5, 129.6 and 129.9 )ArCH), 137.0)ArC),
143.0)ArCH), 149.8 and 150.7 )ArC), 153.1 )ArCH), 153.4
)ArC), 157.8, 174.55 and 176.25 )CO); m/z 537 )MH1,
100%), 515 )6), 379 )15), 260 )16), 202 )16) and 148
)25). N6-)2-Methylpropionyl)-9-propyladenine 23c: Found:
MH1 248.1511. C12H17N5O requires: MH 248.1516; dH
)300 MHz; CD3OD) 0.94 )3H, t, Jˆ7.15 Hz, CH2CH3),
1.38 )6H, d, Jˆ6.86 Hz, CHMe2), 1.88 )2H, sextet,
Jˆ7.15 Hz, CH2CH2CH3), 3.31 )1H, septet, Jˆ6.86 Hz,
CHMe2), 4.29 )2H, t, Jˆ7.15 Hz, NCH2CH2), 8.38 and
8.62 )each 1H, s, 2-CH and 8-CH); dC )75 MHz; CD3OD)
11.3 )CH2CH3), 19.65 )CHMe2), 24.2 )CH2CH3), 37.1
)CHMe2), 46.7 )NCH2), 124.0)ArC), 145.75 )ArCH),
150.65 )ArC), 152.9 )ArCH), 153.4 )ArC) and 178.2
)CO); m/z 247 )M1, 50%), 177 )60), 149 )58), 138 )100),
108 )30) and 84 )30).
1474, 1418, 1327, 1266 and 896; dH )300 MHz; CDCl3)
0.94 )3H, t, Jˆ7.15 Hz, CH2CH3), 1.90)2H, sextet,
Jˆ7.15 Hz, CH2CH2CH3), 4.20)2H, t, Jˆ7.15 Hz, NCH2),
6.23 )2H, s, NH2), 7.82 and 8.35 )each 1H, s, 2-CH and 8-
CH); dC )75 MHz; CD3OD) 11.2 )CH2CH3), 22.8
)CH2CH3), 46.6 )NCH2), 119.6 )ArC), 140.45 )ArCH),
150.1 )ArC), 152.9 )ArCH) and 155.7 )ArC); m/z 177
)M1, 55%), 148 )88), 135 )100) and 108 )60).
3.5.12. (2S,4S)-3-Benzyloxycarbonyl-2-tert-butyl-4-(3-{N2-
acetyl-O6-[2-(4-nitrophenyl)ethyl]-9-guaninyl}propyl)oxa-
zolidin-5-one 25. Prepared following method C, using 9-)2-
iodoethyl)-N2-acetyl-O6-[2-)4-nitrophenyl)ethyl]guanine 24b
)1.0g, 2.02 mmol), )2 S)-3-benzyloxycarbonyl-2-tert-butyl-4-
methyleneoxazolidin-5-one 11 )587 mg, 2.02 mmol), AIBN
3
)ca. 10mg) and tributyltin hydride )0.651 cm , 0 .70 4 g,
2.42 mmol)) in toluene )200 cm3) to give the conjugate
adduct 25 as a yellow oil )279 mg, 21%) and 9-ethyl-N2-
acetyl-O6-[2-&4-nitrophenyl)ethyl]guanine 26 as a white
solid )149 mg, 20%). )2S,4S)-3-Benzyloxycarbonyl-2-tert-
butyl-4-)3-{N2-acetyl-O6-[2-)4-nitrophenyl)ethyl]-9-gua-
ninyl}propyl)oxazolidin-5-one 25: Found: MH1 )CI)
660.2787. C33H37N7O8 requires: MH 660.2782; dH
)300 MHz; CDCl3) 0 .91 )9 H, s, CMe3), 1.72±2.13 )4 H, m,
CHCH2CH2), 2.53 )3H, s, CH3CO), 3.32 )2H, t, Jˆ6.70Hz,
CH2Ar), 4.18 )2H, m, NCH2), 4.37 )1H, t, Jˆ7.54 Hz,
CHCH2), 4.79 )2H, t, Jˆ6.70Hz, OCH 2), 5.16 )2H, s,
CH2Ph), 5.56 )1H, s, CHBut), 7.29±7.35 )5H, m, ArH), 7.50
)2H, d, Jˆ8.62 Hz, ArH), 7.77 )1H, s, guanine-H), 7.85 )1H,
s, CONH) and 8.19 )1H, d, Jˆ8.62 Hz, ArH); dC )75 MHz;
CDCl3) 24.9 )CMe3), 25.2 )COCH3), 26.6 )CHCH2CH2),
30.05 )CHCH2), 35.1 )CH2), 36.9 )CMe3), 43.1 )NCH2),
56.5 )CHCH2), 66.9 )CH2), 68.7 )CH2Ph), 96.5 )CHBut),
117.75 )ArC), 123.8, 128.6, 128.7 and 128.8 )ArCH) 128.9
)ArC), 130.0 )ArCH), 134.9 )ArC), 141.6 )ArCH), 145.7,
146.9, 152.0and 153.15 )ArC), 156.1, 16.06 and 172.25
)CO); m/z 660)MH 1, 20%), 602 )100), 511 )60), 480 )40),
410 )40), 368 )30), 261 )70) and 193 )80). 9-Ethyl-N2-acetyl-
O6-[2-)4-nitrophenyl)ethyl]guanine 26: Found: M1 )EI)
370.1390. C17H18N6O4 requires: M 370.1390; nmax )KBr/
cm21); dH )300 MHz; CDCl3) 3.60)3H, t, Jˆ7.30Hz,
CH2CH3), 2.53 )3H, s, CH3CO), 3.31 )2H, t, Jˆ6.60Hz,
CH2Ar), 4.22 )2H, q, Jˆ7.30Hz, C H2CH3), 4.78 )2H, t,
Jˆ6.60Hz, OCH 2), 7.50)2H, d, Jˆ8.56 Hz, ArH), 7.82
)1H, s, guanine-H), 7.87 )1H, s, CONH) and 8.18 )2H, d,
Jˆ8.56 Hz, ArH); m/z 370)MH 1, 100%), 341 )20), 328
)70), 277 )50), 262 )40) and 234 )84).
3.5.11. (2S,4S)-3-Benzyloxycarbonyl-2-tert-butyl-4-{4-
[N6-(2-methylpropionyl)-9-adeninyl]butyl}oxazolidin-5-
one 22c and (2S,4S)-3-benzyloxycarbonyl-2-tert-butyl-4-
[4-(9-adeninyl)butyl]oxazolidin-5-one 22d. Prepared
following method D, using 9-)3-iodopropyl)-N6-)2-methyl-
propionyl)adenine 21b )1.86 g, 4.99 mmol), )2S)-3-benzyl-
oxycarbonyl-2-tert-butyl-4-methyleneoxazolidin-5-one 11
)2.88 g, 9.97 mmol), tributyltin chloride )0.406 cm3,
487 mg, 1.50mmol), sodium cyanoborohydride )627 mg,
9.97 mmol) and AIBN )0.5 mmol) but heated at re¯ux for
16 h to yield the conjugate adduct 22c as a colourless oil
)0.31 g, 12%), deacylated conjugate adduct 22d as a colour-
less oil )0.22 g, 14%), N6-)2-methylpropionyl)-9-propylade-
nine 23c as a white gum )0.13 g, 11%) and 9-propyladenine
23d also as a white gum )0.2 g, 23%). Data for )2S,4S)-3-
Benzyloxycarbonyl-2-tert-butyl-4-{4-[N6-)2-methylpro-
pionyl)-9-adeninyl]butyl}oxazolidin-5-one 22c and for N6-
)2-methylpropionyl)-9-propyladenine 23c were identical to
those given above. )2S,4S)-3-Benzyloxycarbonyl-2-tert-
butyl-4-[4-)9-adeninyl)butyl]oxazolidin-5-one 22d: Found:
MH1 )ES1) 467.2401. C24H30N6O4 requires: MH 467.2407;
n
max )KBr/cm21) 3323, 3300, 2874, 1790, 1718, 1645, 1600,
3.6. General procedure for conversion of 4-substituted
oxazolidinones into N-benzyloxycarbonyl-(S)-amino
acids by base hydrolysis (method E)
1481, 1396, 1348 and 1082; dH )300 MHz; CD3OD) 0.91
)9H, s, CMe3), 1.35±2.22 )6H, m, CHCH2CH2CH2), 4.15
)2H, t, Jˆ6.96 Hz, NCH2), 4.32 )1H, t, Jˆ6.97 Hz,
CHCH2), 5.10)2H, s, C H2Ph), 5.54 )1H, s, CHBut), 7.24±
7.35 )5H, m, ArH), 8.04 and 8.19 )each 1H, s, adenine-H);
dC )75 MHz; CD3OD) 24.4 )CHCH2CH2), 25.4 )CMe3),
30.4 )CHCH2CH2CH2), 33.7 )CHCH2), 37.8 )CMe3), 44.6
)NCH2), 58.15 )CHCH2), 69.3 )CH2Ph), 97.7 )CHBut),
120.1 )ArC), 129.5, 129.6 and 129.9 )ArCH), 137.0
)ArC), 142.7 )ArCH), 150.7 )ArC), 153.7 )ArCH), 157.3
)ArC), 157.8 and 174.55 )CO); m/z 466 )M1, 80%), 409
)100), 365 )40) and 287 )70). 9-Propyladenine 23d:21
Found: MH1 )ES1) 178.1091. C8H11N5 requires: MH
178.1092; nmax )®lm/cm21) 3408, 3055, 2985, 2361, 1636,
The oxazolidinone conjugate adduct in THF±water )3:1
v/v, 40cm 3) was cooled in an ice-bath and treated with
lithium hydroxide monohydrate )2 mol equiv.). After
stirring for 1 h at 08C, water was added )50cm 3) and the
THF removed under reduced pressure. The solution was
acidi®ed to pH 2±3 by careful addition of 1 M hydro-
chloric acid, and the mixture was extracted with ethyl
acetate )3£50cm 3). The combined organic extracts were
dried )MgSO4), ®ltered, and evaporated to give the
Z-amino acids.

R. C. F. Jones et al. / Tetrahedron 57 &2001) 6539±6555
6551
3.6.1. (2S)-Benzyloxycarbonylamino-5-(3-benzoyl-1-
thyminyl)pentanoic acid 27a. Prepared following method
E, using )2S,4S)-3-benzyloxycarbonyl-2-tert-butyl-4-[3-)3-
benzoyl-1-thyminyl)propyl]oxazolidin-5-one 14a )210mg,
0.384 mmol) and lithium hydroxide monohydrate
)0.768 mmol, 32 mg) to yield the title compound 27a
)0.170 g, 92%) as a thick colourless oil that was incom-
3.6.4. (2S)-Benzyloxycarbonylamino-5-(1-uracilyl)pen-
tanoic acid 27d. Prepared following method E, using
)2S,4S)-3-benzyloxycarbonyl-2-tert-butyl-4-[3-)-1-thymi-
nyl)propyl]-oxazolidin-5-one 18b )2.34 g, 5.45 mmol) and
lithium hydroxide monohydrate )687 mg, 16.4 mmol) to
yield the title compound 27d )1.35 g, 69%) as a thick oil;
[a]D ˆ271.6 )c, 0 .10 in EtOH); Found: MH362.1352.
C17H19N3O6 requires: MH 362.1352; nmax )®lm/cm21) 3426,
3056, 1660 and 1266; dH )300 MHz; CD3OD) 1.55±1.82 )4H,
m, CHCH2CH2), 3.65 )2H, t, Jˆ6.43 Hz, NCH2), 4.11 )1H, m,
CHCH2), 4.98 )2H, s, CH2Ph), 5.52 )1H, d, Jˆ7.80Hz,
CHvCHCO), 7.17±7.26 )5H, m, ArH) and 7.51 )1H, d,
Jˆ7.80Hz, C HvCHCO); dC )75 MHz; CD3OD) 21.5
)CH2CH2CH2), 29.65 )CH2CH2CH2N), 48.7 )CH2CH2CH2N),
54.8 )CHCH2), 67.6 )CH2Ph), 102.3 )CHvCHCO), 128.8,
129.0and 129.5 )ArCH), 138.2 )ArC), 147.15
)CHvCHCO), 152.8, 158.6, 166.7 and 175.4 )CO); m/z
361 )M1, 100%), 344 )40), 318 )55) and 296 )20).
25
1
25
pletely characterized; [a]D ˆ213.3 )c, 0.24 in EtOH);
dH )300 MHz; CDCl3) 1.62±1.96 )7H, m, CHCH2CH2 and
CHvCCH3], 3.65±3.74 )2H, t, Jˆ6.61 Hz, NCH2), 4.20
)1H, m, NHCHCH2), 5.10)2H, s, C H2Ph), 5.58 )1H, d,
Jˆ7.90Hz, N HCHCH2), 7.09 )1 H, s, CHvCCH3),
7.30±7.34 )5H, m, ArH), 7.44 )2H, m, ArH), 7.61 )1H, m,
ArH), 7.87 )2H, m, ArH); dC )75 MHz; CDCl3) 12.3
)CHvCCH3), 24.8 )CH2CH2CH2), 29.2 )CH2CH2CH2N),
48.1 )CH2CH2CH2N), 53.0) CHCH2), 67.2 )CH2Ph),
110.0 )CHvCCH3), 125.3, 128.1, 128.2, 128.6, 129.0
and 129.2 )ArCH), 130.4 and 135.15 )ArC), 140.4
)CHvCCH3), 150.0, 156.3, 163.3, 169.1 and 175.0
)CO).
3.6.5. (2S)-Benzyloxycarbonylamino-6-(3-benzoyl-1-
uracilyl)hexanoic acid 27e. Prepared following method
E, using )2S,4S)-3-benzyloxycarbonyl-2-tert-butyl-4-[4-)3-
benzoyl-1-uracilyl)butyl]oxazolidin-5-one 18c )112.6 mg,
0.206 mmol) and lithium hydroxide monohydrate )17 mg,
0.412 mmol) to yield the title compound 27e as a thick
3.6.2. (2S)-Benzyloxycarbonylamino-5-(1-thyminyl)pen-
tanoic acid 27b. Prepared following method E, using
)2S,4S)-3-benzyloxycarbonyl-2-tert-butyl-4-[3-)1-thyminyl)-
propyl]oxazolidin-5-one 14b )210mg, 0.474 mmol) and
lithium hydroxide monohydrate )0.948 mmol, 40 mg) to
yield the title compound 27b )0.170 g, 96%) as a
white amorphous solid, mp )decomp.) 199±1008C;
1
colourless oil )95 mg, 96%); Found: MNH4 497.2038.
C25H25N3O7 requires: MNH4 497.2036; nmax )KBr/cm21
)
3436, 2096, 1654 and 1266; dH )300 MHz, CDCl3) 1.23±
2.04 )6H, m, CHCH2CH2CH2), 3.66 )2H, m, NCH2), 4.32
)1H, m, CHCH2), 5.02 )2H, s, CH2Ph), 5.59 and 6.98 )each
1H, d, Jˆ7.99 Hz, CHvCHCO), 7.13±7.32 )5H, m, ArH),
7.46 )2H, m, ArH) 7.72 )1H, m, ArH) and 7.87 )2H, m,
ArH); dC )75 MHz; CDCl3) 21.8, 28.1 and 31.4 )CH2),
48.6 )NCH2), 53.3 )CHCH2), 67.1 )CH2Ph), 101.8
)CHvCHCO), 128.0, 128.2, 128.5, 129.2 and 130.3
)ArCH), 131.2 )ArC), 135.2 )ArCH), 136.0)ArC), 144.6
)CHvCHCO), 149.7, 156.2, 162.8, 168.8 and 175.38
)CO). m/z 479 )M1, 15%), 374 )20), 153 )25) and 121 )100).
[a]D ˆ211.3 )c, 0.32 in EtOH); Found: MNH4 )ES1)
393.1777. C18H21N3O6 requires: MNH4 393.1774; nmax
)KBr/cm21) 3306, 3191, 3062, 3035, 2959, 1654, 1531,
1358, 1217, 1133, 1066 and 910; dH )300 MHz; CDCl3)
1.55±1.84 )7H, m, CHCH2CH2 and CHvC)CH3), 3.65±
3.81 )2H, t, Jˆ6.61 Hz, NCH2), 4.27 )1H, m, NHCHCH2),
5.02 )2H, s, CH2Ph), 5.99 )1H, d, Jˆ7.69 Hz, NHCHCH2),
7.00 )1H, s, CHvCCH3), 7.23±7.47 )5H, m, ArH), 10.25
)1H, s, CONH); dC )75 MHz; CDCl3) 12.2 [CHvC)CH3)],
21.1 )CH2CH2CH2), 29.2 )CH2CH2CH2N), 48.0
)CH2CH2CH2N), 53.2 )CHCH2), 67.0) CH2Ph), 110.95
)CHvCCH3), 128.0, 128.2 and 128.5 )ArCH), 136.2
)ArC), 141.0) CHvCCH3), 151.5, 165.2, 156.4 and 151.5
)CO); m/z 393 )MNH41, 100%), 376 )80), 349 )55), 332 )40)
and 285 )70).
25
1
3.6.6. (2S)-Benzyloxycarbonylamino-6-(1-uracilyl)hexa-
noic acid 27f. Prepared following method E, using
)2S,4S)-3-benzyloxycarbonyl-2-tert-butyl-4-[4-)1-uracilyl)-
butyl]oxazolidin-5-one 18d )250mg, 0.564 mmol) and
lithium hydroxide monohydrate )47 mg, 1.13 mmol) to
yield the title compound 27f as a white solid )110mg,
3.6.3. (2S)-Benzyloxycarbonylamino-6-(1-thyminyl)hex-
anoic acid 27c. Prepared following method E, using
)2S,4S)-3-benzyloxycarbonyl-2-tert-butyl-4-[4-)1-thyminyl)-
butyl]oxazolidin-5-one 14d )310mg, 0.678 mmol) and
lithium hydroxide monohydrate )85 mg, 2.04 mmol) to
yield the title compound 27c as a thick colourless oil
25
52%), mp )decomp.) 182±1838C; [a]D ˆ2150) c, 0.032
in EtOH); Found: MH1 376.1513. C18H21N3O6 requires:
MH 376.1508; nmax )KBr/cm21) 3213, 2364, 1715, 1688,
1541, 1466, 1364, 1257, 1200 and 1072; dH )300 MHz,
DMSO-d6) 1.15±1.56 )6H, m, CH CH2CH2CH2), 3.62
)2H, t, Jˆ6.79 Hz, NCH2), 3.89 )1H, m, CHCH2), 5.02
)2H, s, CH2Ph), 5.50)1H, d, Jˆ7.85 Hz, CHvCHCO),
7.31±7.34 )5H, m, ArH), 7.55 )1H, d, Jˆ7.78 Hz, CHNH)
7.61 )1H, d, Jˆ7.85 Hz, CHvCHCO) and 11.21 )1H, s,
uracil-NH); dC )75 MHz; CDCl3) 22.4, 27.9 and 30.3
)CH2), 47.1 )NCH2), 53.6 )CHCH2), 65.3 )CH2Ph), 100.7
)CHvCHCO), 127.6, 127.7 and 128.2 )ArCH), 136.9
)ArC), 145.55 )CHvCHCO), 150.8, 156.0, 163.6 and
173.7 )CO); m/z 376 )MH1, 80%), 332 )70), 285 )90),
268 )100), 244 )100) and 226 )50).
1
)230mg, 87%); Found: MNH 4 407.1940. C19H23N3O6
requires: MNH4 407.1931; nmax )®lm/cm21) 3430, 2959,
2348, 1657, 1546, 1501, 1467, 1129 and 1070; dH
)300 MHz; CDCl3) 1.21±1.88 )9H, m, CH)CH2)3CH2N
and CHvCCH3), 3.66 )2H, m, NCH2), 4.37 )1H, m,
CHCH2), 5.79 )1H, d, Jˆ7.87 Hz, NHCH), 6.98 )1H, s,
CHvCCH3), 7.26±7.37 )5H, m, ArH) and 10.17 )1H, s,
CONH); dC )75 MHz; DMSO-d6) 12.2 )CHvCCH3),
21.7, 28.35 and 31.7 )CH2), 48.0)NCH ), 53.4 )CHCH2),
2
67.0) CH2Ph), 110.9 )CHvCCH3), 128.0, 128.15 and 128.5
)ArCH), 136.3 )ArC), 140.9 )CHvCCH3), 151.45, 156.2,
165.1 and 175.6 )CO); m/z 390)M 1, 75%), 363 )90), 346
)100), 299 )88) and 282 )80).
3.6.7. (2S)-Benzyloxycarbonylamino-5-[N6-(2-methylpro-
pionyl)-9-adeninyl]pentanoic acid 28a. Prepared following

6552
R. C. F. Jones et al. / Tetrahedron 57 &2001) 6539±6555
method E, using )2S,4S)-3-benzyloxycarbonyl-2-tert-butyl-4-
{3-[N6-)2-methylpropionyl)-9-adeninyl]propyl}oxazolidin-5-
one 22a )0.91 g, 1.74 mmol) and lithium hydroxide mono-
hydrate )219 mg, 5.23 mmol) to yield the title compound
28a as a white amorphous solid )0.57 g, 72%), mp )decomp.)
147±1508C; Found: MH1 455.2043; C22H26N6O5 requires:
MH 455.2052; dH )300 MHz; CDCl3) 1.28 )6H, d,
Jˆ6.78 Hz, CHMe2), 1.74±2.27 )4H, m, CHCH2CH2), 3.03
)1H, septet, Jˆ6.78 Hz, CHMe2), 4.36 )2H, m, NCH2), 4.52
)1H, m, CHCH2), 5.11 )2H, s, CH2Ph), 5.73 )1H, d,
Jˆ7.51 Hz, CHNH), 7.33 )5H, m, ArH), 8.17 and 8.69
)each 1H, s, 2-CH and 8-CH); dC )75 MHz; CDCl3) 19.2
)CHMe2), 25.5 )CHCH2CH2), 28.6 )CHCH2), 36.0
)CHMe2), 43.4 )NCH2), 53.5 )CHCH2), 67.1 )CH2Ph), 122.0
)ArC), 128.1, 128.3 and 128.6 )ArCH), 136.8 )ArC), 143.1
)ArCH), 149.3 and 151.6 )ArC), 152.9 )ArCH), 156.2, 172.8
and 176.5 )CO); m/z 455 )M1H, 70%), 347 )100), 277 )30),
206 )62) and 196 )70)
m/z 469 )MH1, 100%), 399 )40), 361 )50), 335 )30) and
291 )42).
3.6.10. (2S)-Benzyloxycarbonylamino-6-(9-adeninyl)hex-
anoic acid 28d. Prepared following method E, using
)2S,4S)-3-benzyloxycarbonyl-2-tert-butyl-4-[4-)9-adeninyl)-
butyl]oxazolidin-5-one 22d )0.27 g, 0.579 mmol) and
lithium hydroxide monohydrate )73 mg, 1.74 mmol) to
yield the title compound 28d as a white amorphous gum
)0.197 g, 86%); Found: MH1 )ES1) 399.1778.
C19H22N6O4 requires: MH 399.1781; nmax )KBr/cm21
)
3327, 2971, 2361, 2342, 1704, 1515, 1266 and 1202; dH
)300 MHz; CD3OD) 1.38±1.98 )6H, m, CHCH2CH2CH2),
4.14 )1H, m, CHCH2), 4.25 )2H, t, Jˆ6.96 Hz, NCH2), 5.06
)2H, s, CH2Ph), 7.25±7.33 )5H, m, ArH), 8.18 and 8.26
)each 1H, s, 2-CH and 8-CH); dC )75 MHz; CD3OD) 23.9
)CHCH2CH2), 30.45 )CHCH2CH2CH2), 32.1 )CHCH2),
44.9 )NCH2), 55.0) CHCH2), 67.6 )CH2Ph), 126.15, 128.8,
129.0and 129.5 )ArCH), 138.2, 139.2 and 143.9 )ArC),
150.2 )ArCH), 155.0 )ArC),158.6 and 176.15 )CO); m/z
399 )MH1, 100%), 355 )15), 291 )60), 265 )60) and 247
)40).
3.6.8. (2S)-Benzyloxycarbonylamino-5-(9-adeninyl)pen-
tanoic acid 28b. Prepared following a modi®ed method E,
using a mixture )see earlier) calculated to comprise )2S,4S)-
3-benzyloxycarbonyl-2-tert-butyl-4-[3-)9-adeninyl)propyl]-
oxazolidin-5-one 22b )580mg, 1.28 mmol), 9-ethyl- N6-)2-
methylpropionyl)adenine 23a )360mg, 1.55 mmol) and
lithium hydroxide monohydrate )162 mg, 3.85 mmol), and
extracting with dichloromethane )3£20cm 3) to yield 9-
ethyl-N6-)2-methylpropionyl)adenine 23a )360mg, 17%
based on iodo-compound 21a). Acidi®cation and extraction
of the aqueous layer as usual gave the title compound 28b as
a white solid )430mg, 87%), mp 193±94 8C; Found: MH1
)ES1) 385.1629. C18H20N6O4 requires: MH 385.1624; nmax
)KBr/cm21) 3395, 1611, 1542, 1459, 1408, 1323 and 1221;
dH )300 MHz; CD3OD) 1.61±2.05 )4H, m, CHCH2CH2),
4.22 )1H, m, CHCH2), 4.43 )2H, m, NCH2), 5.02 )2H, s,
CH2Ph), 7.23±7.31 )5H, m, ArH), 8.50and 8.58 )each 1H, s,
2-CH and 8-CH); dC )75 MHz; CD3OD) 27.4 and 29.4
)CH2), 45.1 )NCH2), 54.8 )CHCH2), 67.6 )CH2Ph), 119.8
)ArC), 128.6, 128.9 and 129.4 )ArCH), 138.0)ArC), 145.1
and 145.7 )ArCH), 150.0 and 151.2 )ArC), 158.5 and 174.0
)CO); m/z 385 )MH1, 15%), 251 )5), 190)46), 126 )70), 111
)100) and 84 )90).
3.6.11. (2S)-Benzyloxycarbonylamino-5-{N2-acetyl-O6-
[2-(4-nitrophenyl)ethyl]-9-guaninyl}pentanoic acid 29.
Prepared following method E, using )2S,4S)-3-benzyloxy-
carbonyl-2-tert-butyl-4-)3-{N2-acetyl-O6-[2-)4-nitrophenyl)-
ethyl]-9-guaninyl}propyl)oxazolidin-5-one 25 )60mg,
0.091 mmol) and lithium hydroxide )10 mg, 0.18 mmol)
to yield the title compound 29 as a yellow solid )47 mg,
87%), mp 143 ± 1448C; Found: MH1 592.2156.
C28H29N7O8 requires; MH 592.2154; nmax )KBr/cm21
)
3466, 2961, 2363, 2345, 1719, 1687, 1664, 1610, 1518,
1345 and 1236; dH )300 MHz; DMSO-d6) 1.45±1.85 )4H,
m, CHCH2CH2), 2.20)3H, s, CH 3CO), 3.35 )2H, t,
Jˆ6.70Hz, CH 2Ar), 3.60)1H, m, C HCH2), 4.20)2H, m,
NCH2), 4.75 )2H, t, Jˆ6.70Hz, OCH 2), 4.97 )2H, br s,
CH2Ph), 6.43 )1H, s, guanine-H), 7.20±7.40 )5H, m,
ArH), 7.60and 8.19 )each 2H, d, Jˆ8.60Hz, ArH) and
10.35 )1H, s, CONH); m/z 592 )MH1, 60%), 562 )40),
546 )38), 516 )100), 484 )40) and 428 )65).
3.7. General procedure for removal of a benzyloxy-
carbonyl group (Z) by hydrogenolysis to afford amino
acids (method F)
3.6.9. (2S)-Benzyloxycarbonylamino-6-[N6-(2-methylpro-
pionyl)-9-adeninyl]hexanoic acid 28c. Prepared following
method E, using )2S,4S)-3-benzyloxycarbonyl-2-tert-butyl-
4-{4-[N6-)2-methylpropionyl)-9-adeninyl]butyl}oxazolidin-
5-one 22c )0.32 g, 0.597 mmol) and lithium hydroxide mono-
hydrate )84 mg, 0.199 mmol) to yield the title compound 28c
as a white amorphous solid )0.250 g, 89%), mp 147±1508C;
Found: MH1 )ES1) 469.2208; C23H28N6O5 requires: MH
469.2199; nmax )KBr/cm21) 3322, 3054, 2974, 2556, 1723,
1683, 1609, 1590, 1540, 1457, 1402, 1350, 1072, 1050 and
968; dH )300 MHz; CD3OD) 1.28 )6H, d, Jˆ6.88 Hz,
CHMe2), 1.34±2.21 )6H, m, CHCH2CH2CH2), 2.91 )1H,
septet, Jˆ6.88 Hz, CHMe2), 4.14 )1H, m, CHCH2), 4.31
)2H, t, Jˆ6.96 Hz, NCH2), 5.04 )2H, s, CH2Ph), 7.26±7.32
)5H, m, ArH), 8.35 and 8.63 )each 1H, s, 2-CH and 8-
CH); dC )75 MHz; CD3OD) 19.2 )CHMe2), 23.9, 28.9 and
32.11 )CH2), 37.1 )CHMe2), 44.8 )NCH2), 53.73
)CHCH2), 67.6 )CH2Ph), 123.75 )ArC), 128.7, 128.9 and
129.4 )ArCH), 138.15 )ArC), 145.6 )ArCH), 150.5 )ArC),
152.9 )ArCH), 153.3 )ArC), 158.6, 175.7 and 178.2 )CO);
The Z-protected amino acid )1 mol equiv.) in ethanol
)140cm 3) and water )60cm 3) was degassed with a stream
of argon for 15 min. Palladium-charcoal catalyst )10mol%,
0.1 mol equiv.) was added and a stream of hydrogen was
passed through the solution under vigorous stirring for 8h.
The solution was then again degassed with a stream of argon
for 15 min, and the catalyst was ®ltered and washed with a
small amount of ethanol and water. The solvents were
removed under reduced pressure, toluene )20cm 3) was
added and removed under reduced pressure )3 times) to
eliminate traces of water. The crude residue was dried
under vacuum to yield the free amino acid.
3.7.1. (2S)-Amino-5-(1-thyminyl)pentanoic acid 27g.
Prepared following method F, using )2S)-benzyloxycar-
bonylamino-5-)1-thyminyl)pentanoic acid 27b )1.61 g,
4.29 mmol) and Pd±C )200 mg) to yield the title compound

R. C. F. Jones et al. / Tetrahedron 57 &2001) 6539±6555
6553
27g as a white solid )760mg, 74%), mp )decomp.) 124±
1258C; Found: MH1 )ES1) 242.1144. C10H15N3O4 requires:
MH 242.1141; nmax )KBr/cm21) 3448, 3153, 3034, 2362,
1685, 1674, 1600, 1475, 1460, 1420 and 1220; dH
)300 MHz, D2O) 1.57±1.91 )7H, m, CHCH2CH2 and
CHvCCH3), 3.57±3.71 )2H, m, NCH2), 3.85 )1H, t,
Jˆ5.50Hz, C HCH2) and 7.29 )1 H, s, CHvCCH3); dC
)75 MHz; D2O) 11.7 )CHvCCH3), 24.3 )CHCH2CH2CH2),
27.2 )CHCH2CH2CH2), 48.2 )CH2N), 53.45 )CHCH2),
111.3 )ArC), 143.4 )CHvCCH3), 152.7, 167.3 and 173.1
)CO); m/z 242 )MH1, 50%), 198 )100), 169 )53), 146 )52),
127 )54), 113 )44) and 70)70).
Pd±C )200 mg) to yield the title compound as a white
solid )100 mg, 75%), mp )decomp.) 110±1128C; Found:
MH1 )ES1) 321.1680. C14H20N6O3 requires: MH
321.1675; nmax )KBr/cm21) 3386, 2971, 2934, 2377, 1794,
1774, 1611, 1459, 1219 and 966; dH )300 MHz; D2O) 1.13
)6H, d, Jˆ6.97 Hz, CHMe2), 1.58 )2H, m, CHCH2CH2),
1.77 )2H, m, CHCH2), 2.75 )1H, septet, Jˆ6.97 Hz,
CHMe2), 3.35 )1H, m, CHCH2), 4.22 )2H, m, NCH2),
8.27 and 8.53 )each 1H, s, 2-CH and 8-CH); dC )75 MHz;
CD3OD) 26.9 )CHCH2CH2), 29.3 )CHCH2), 37.1 )CHMe2),
44.65 )NCH2), 49.0) CHCH2), 124.5 )ArC), 128.8 and 129.4
)ArCH), 145.7 and 151.0)ArC), 153.0and 178.0)CO); m/z
321 )MH1, 35%), 206 )30), 165 )55), 152 )65), 133 )64) and
115 )72).
3.7.2. (2S)-Amino-6-(1-thyminyl)hexanoic acid 27h. Pre-
pared following method F, using )2S)-benzyloxycarbonyl-
amino-6-)1-thyminyl)hexanoic acid 27c )1.32 g, 3.39 mmol)
and Pd±C )300 mg) to yield thetitle compound 27h as a white
solid )680mg, 79%), mp 219±220 8C; Found: MH1 )ES1)
256.1296. C11H17N3O4 requires: MH 256.1297; nmax )KBr/
cm21) 3432, 3050, 2955, 2362, 1685, 1476, 1413, 1356
and 1130; dH )300 MHz; D2O) 1.21±1.29 )2H, m,
CHCH2CH2), 1.52±1.62 )2H, apparent quintet, Jˆ7.36 Hz,
CHCH2CH2CH2), 1.66±1.75 )5H, m, CHCH2 and
CHvCCH3), 3.48 )1H, t, Jˆ6.61 Hz, CHCH2), 3.61 )2H, t,
Jˆ6.98 Hz, NCH2) and 7.33 )1 H, s, CHvCCH3); dC
)75 MHz; D2O) 12.1 )CHvCCH3), 22.2 )CHCH2CH2CH2),
28.6 )CHCH2CH2CH2), 30.9 )CHCH2), 48.9 )CH2N), 55.2
)CHCH2), 111.5 )ArC), 144.0) CHvCCH3), 153.2, 167.9
and 175.6 )CO); m/z 256 )MH1, 70%), 212 )100), 197 )30),
183 )34), 169 )60), 146 )28), 127 )28) and 84 )42).
3.7.6. (2S)-Amino-6-[N6-(2-methylpropionyl)-9-adeninyl]-
hexanoic acid 28f. Prepared following method F, using
)2S)-benzyloxycarbonylamino-6-[N6-)2-methylpropionyl)-
9-adeninyl]hexanoic acid 28c )230mg, 0.491 mmol) and
Pd±C )200 mg) to yield the title compound as a white
hygroscopic solid )100 mg, 61%); Found: MH1 )ES1)
335.1824. C15H22N6O3 requires: MH 335.1831; dH
)300 MHz; D2O) 0.60 )6H, d, Jˆ6.87 Hz, CHMe2), 1.28
)2H, m, CHCH2CH2), 1.06±1.31 )4H, m, CHCH2 and
NCH2CH2), 2.20)1H, septet, Jˆ6.87 Hz, CHMe2), 3.07
)1H, t, Jˆ5.86 Hz, CHCH2), 3.61 )2H, t, Jˆ7.15 Hz,
NCH2), 7.66 and 7.87 )each 1H, s, 2-CH and 8-CH); dC
)75 MHz; D2O) 19.25 )CHCH2CH2), 22.4 )NCH2CH2CH2),
30.7 )CHCH2), 36.7 )CHMe2), 44.5 )NCH2), 55.3 )CHCH2),
123.6 )ArC), 146.1 )ArCH), 149.2 )ArC), 152.0)ArCH)
152.2 )ArC), 176.5 and 181.2 )CO); m/z 335 )MH1, 80%),
291 )80), 265 )100), 221 )90), 204 )60), 178 )100), 149 )40)
and 136 )80).
3.7.3. (2S)-Amino-5-(1-uracilyl)pentanoic acid 27i. Pre-
pared following method F, using )2S)-benzyloxycarbonyl-
amino-5-)1-uracilyl)pentanoic acid 27d )1.23 g, 3.41 mmol)
and Pd±C )150mg) to yield the title compound 27i as a white
solid )580mg, 75%), mp 208±209 8C; Found: M2H )ES2)
226.0833. C9H13N3O4 requires: M-H 226.0828; nmax )KBr/
cm21) 3513, 3457, 3090, 1692, 1673, 1609, 1418, 1387,
1249 and 1237; dH )300 MHz; D2O) 1.47±1.82 )4H, m,
CHCH2CH2), 3.59 )1H, t, Jˆ5.86 Hz, CHCH2), )2H, m,
NCH2), 5.67 and 7.48 )each 1H, d, Jˆ7.81 Hz, CHvCH);
dC )75 MHz; D2O) 24.6 )CHCH2CH2), 27.9 )CHCH2), 48.9
)CH2N), 54.9 )CHCH2), 102.2 and 147.8 )CHvCH), 152.9,
167.5 and 174.8 )CO); m/z 226 )M-H, 58%), 183 )20), 153
)30), 121 )100), 11 )40) and 90 )60).
3.7.7.
(2S)-Amino-6-(5,6-dihydro-1-uracilyl)hexanoic
acid 30. This was prepared following method F, using
)2S)-benzyloxycarbonylamino-6-)1-uracilyl)hexanoic acid
27f )150 mg, 0.40 mmol) and Pd±C )100 mg) but for 16 h
to yield the title compound 30 as a white solid )86 mg, 88%),
mp )decomp.) 219±2208C; Found: MH1 )ES1) 244.1297.
C10H17N3O4 requires: MH 244.1297; nmax )KBr/cm21
)
3484, 2954, 2931, 2344, 2362, 1729, 1466, 1288, 1275,
1044 and 971; dH )300 MHz, D2O) 1.10±1.75 )6H, m,
CHCH2CH2CH2), 2.63 )2H, t, Jˆ7.16 Hz, CH2CO), 3.22
)2H, t, Jˆ7.33 Hz, CH2N), 3.35 )2H, t, Jˆ7.16 Hz,
CH2CH2CO) and 3.94 )1H, m, CHCH2); dC )75 MHz;
D2O) 22.5 )CHCH2CH2), 27.1 )CHCH2CH2CH2), 30.7
)CH2CO), 31.5 )CHCH2), 42.5 )CH2CH2CO), 47.5
)CH2N), 51.4 )CHCH2), 155.0and 175.1 )CO); m/z 244
)MH1, 18%), 198 )20), 155 )30), 141 )40), 116 )34) and
84 )100). Traces of )2S)-amino-6-)1-uracilyl)hexanoic acid
27f were also isolated.
3.7.4. (2S)-Amino-6-(1-uracilyl)hexanoic acid 27j. Prepared
following method F, using )2S)-benzyloxycarbonylamino-6-
)1-uracilyl)hexanoic acid 27f )110mg, 0.293 mmol) and Pd±
C )30mg) for 5 h to yield the title compound 27j as a white
solid )60mg, 90%), mp )decomp.) 187±205 8C, that was
incompletely characterized; nmax )KBr/cm21); dH )300 MHz,
D2O) 1.26±1.93 )6H, m, CHCH2CH2CH2), 3.67 )1H, t,
Jˆ6.43 Hz, CHCH2), 3.74 )2H, t, Jˆ7.33 Hz, NCH2), 5.75
and 7.58 )each 1H, d, Jˆ7.81 Hz, CHvCH); dC )75 MHz;
D2O) 22.1 )CHCH2CH2), 28.5 )CHCH2CH2CH2), 30.8
)CHCH2), 49.3 )CH2N), 55.4 )CHCH2), 102.3 and 148.1
)CHvCH), 153.2, 167.7 and 175.4 )CO).
3.8. General method for conversion of an amino acid into
a (S)-3,3,3-tri¯uoro-2-methoxy-2-phenylpropanamide
(Mosher amide) (method G)
Acetyl chloride )10mol equiv.) was added dropwise at 0 8C
3
to the amino acid )t50mg) stirred in ethanol )50cm ). The
3.7.5. (2S)-Amino-5-[N6-(2-methylpropionyl)-9-adeninyl]-
pentanoic acid 28e. Prepared following method F, using
)2S)-benzyloxycarbonylamino-5-[N6-)2-methylpropionyl)-
9-adeninyl]pentanoic acid 28a )190mg, 0.419 mmol) and
mixture was then stirred overnight at 258C, heated at
re¯ux for 4 h, cooled and the solvent evaporated under
reduced pressure to give the ethyl ester hydrochloride
salt which was further dried under vacuum overnight.

6554
R. C. F. Jones et al. / Tetrahedron 57 &2001) 6539±6555
)R)-3,3,3-Tri¯uoro-2-methoxy-2-phenylpropanoyl chloride
)MTPA-Cl) was added dropwise at room temperature to
the ester hydrochloride stirred in dichloromethane )4 cm3)
and triethylamine )4 cm3). The mixture was stirred over-
night, water )20cm 3) was added and the mixture extracted
with ethyl acetate )3£20cm 3). The combined ethyl acetate
layers were washed with saturated sodium bicarbonate solu-
tion )3£10cm 3), dried with magnesium sulphate and evapo-
rated under reduced pressure. The crude material was then
puri®ed by column chromatography )ethyl acetate/hexane)
to yield the desired Mosher amide.
3.49 )6H, s, 2£OCH3), 3.61 )2H, t, Jˆ6.79 Hz, NCH2),
4.21 )2H, q, Jˆ7.15 Hz, CH2CH3), 4.62 )1H, dt, Jˆ5.13
and 8.17 Hz, CHCH2), 6.91 and 6.99p )1H, s, CHvCCH3),
7.17 )1H, d, Jˆ8.17 Hz, NHCH), 7.26±7.45 )6H, m, ArH),
7.54±7.57 )2H, m, ArH) and 7.68±7.71 )2H, m, ArH); dC
)75 MHz; CDCl3) 12.3 )CHvCCH3), 14.1 )CH2CH3), 22.1,
28.2 and 31.85 )CH2), 48.4 )NCH2), 51.6 )CHCH2), 54.7
and 55.3 )OCH3), 61.9 )CH2CH3), 110.55 )CHvCCH3),
127.3, 128.3, 128.5, 128.6 and 129.65 )ArCH), 132.8 and
131.2 )ArC), 139.9 )CHvCCH3), 149.2, 162.6, 166.4, 171.5
and 171.9 )CO); m/z 716 )M1, 16%), 517 )100), 500)80),
468 )50), 391 )20), 337 )65) and 286 )70). dF )376 MHz;
CDCl3) minor diastereoisomer 269.206 and 270.136,
major diastereoisomer 268.830and 270.017, ee: 88%.
3.8.1. Ethyl (2S)-amino-5-(1-thyminyl)pentanoate (S)-
MTPA amide. Prepared following method G from amino
acid 27i to yield the title compound as a colourless oil;
Found: MH1 )ES1) 486.1856. C22H26F3N3O6 requires:
3.8.3. Ethyl (2S)-amino-5-(1-uracilyl)pentanoate (S)-
MTPA amide. Prepared following method G from amino
acid 27l to yield the title compound as a colourless oil;
MH 486.1852; dH )300 MHz, CDCl3) major and minorp
p
diastereoisomers: 1.30and 1.26
)3H, t, Jˆ7.06 Hz,
Found: MNH4 )ES1) 489.1959. C21H24F3N3O6 requires:
1
CH2CH3), 1.53±1.96 )7H, m, CHCH2CH2 and CHvCCH3),
3.45 and 3.35p )3 H, s, OCH3), 3.56±3.78 )2H, m, NCH2),
4.24 )2H, q, Jˆ7.06 Hz, CH2CH3), 4.66 )1H, dt, Jˆ4.60and
8.26 Hz, CHCH2), 6.85 and 7.05p )1H, s, CHvCCH3),
7.35±7.44 )4H, m, NHCH and ArH), 7.54±7.57 )2H, m,
ArH), 9.04 and 9.00p )1H, s, ArNH); dC )75 MHz; CDCl3)
major diastereomer 12.3 )CHvCCH3), 14.1 )CH2CH3),
24.9 )CHCH2CH2), 29.5 )CHCH2CH2), 47.4 )NCH2), 51.1
)CHCH2), 55.3 )OCH3), 62.1 )CH2CH3), 110.8
)CHvCCH3), 127.2, 128.6 and 129.6 )ArCH), 132.8
)ArC), 140.2 )CHvCCH3), 150.8, 164.2, 166.7 and 171.2
)CO); m/z 486 )M1, 10%), 296 )100), 268 )20), 222 )90),
189 )70) and 105 )80); dF )376 MHz, CDCl3) minor dia-
stereoisomer 269.074, major diastereoisomer 268.790, ee:
85%.
MNH4 489.1961; dH )300 MHz, CDCl3) major and minorp
p
diastereoisomer: 1.30and 1.26
)3H, t, Jˆ7.06 Hz,
CH2CH3), 1.50±1.96 )4H, m, CHCH2CH2), 3.45 and 3.34p
)3H, s, OCH3), 3.48±3.77 )2H, m, NCH2), 4.23 )2H, q,
Jˆ7.06 Hz, CH2CH3), 4.67 )1H, m, CHCH2), 5.54 and
5.69p )1H, d, Jˆ7.78 or 7.88p Hz, CHvCHCO), 6.92 and
7.21p )1H, Jˆ7.78 or 7.88p Hz, CHvCHCO), 7.34±7.59
)5H, m, ArH) and 9.38 )1H, s, ArNH); dC )75 MHz;
CDCl3) major diastereomer 14.1 )CH2CH3), 24.6
)CHCH2CH2), 29.5 )CHCH2), 47.9 )NCH2), 50.85
)CHCH2), 55.2 )OCH3), 62.2 )CH2CH3), 101.9
)CHvCHCO), 128.55, 128.7 and 129.5 )ArCH), 132.6
)ArC), 143.9 )ArCH), 149.1, 161.7, 166.8 and 171.1 )CO);
m/z 472 )MH1, 65%), 398 )100), 346 )80) and 296 )28); dF
)376 MHz; CDCl3) minor diastereoisomer 269.737, major
diastereoisomer 269.122, ee: 90%.
3.8.2. Ethyl (2S)-amino-6-(1-thyminyl)hexanoate (S)-
MTPA amide and ethyl (2S)-amino-6-(1-thyminyl)hex-
anoate (S)-MTPA diamide. Prepared following method
G from amino acid 27j to yield the title monoamide and
the title diamide, both as colourless oils. Ethyl )2S)-
amino-6-)1-thyminyl)hexanoate )S)-MTPA amide: Found:
MH1 )ES1) 500.2019. C23H28F3N3O6 requires: MH
500.2008; dH )300 MHz; CDCl3) major and minorp diaster-
eoisomers: 1.28 and 1.21p )3H, t, Jˆ7.15 Hz, CH2CH3),
1.59±1.97 )9H, m, CHCH2CH2CH2 and CHvCCH3),
3.34p and 3.54 )3H, s, OCH3), 3.61 )2H, t, Jˆ6.79 Hz,
NCH2), 4.16 )2H, q, Jˆ7.15 Hz, CH2CH3), 4.56 )1H, dt,
Jˆ5.13 and 8.15 Hz, CHCH2), 6.89 and 6.98p )1H, s,
CHvCCH3), 7.10)1H, d, Jˆ8.15 Hz, NHCH), 7.31±7.36
)3H, m, ArH), 7.61±7.63 )2H, m, ArH) and 8.51 )1H, s,
ArNH); dC )75 MHz; CDCl3) major diastereomer 12.3
)CHvCCH3), 14.1 )CH2CH3), 22.1, 28.3 and 31.6 )CH2),
47.8 )NCH2), 51.7 )CHCH2), 55.3 )OCH3), 61.84
)CH2CH3), 110.8 )CHvCCH3), 127.2, 128.5 and 129.6
)ArCH), 133.0)ArC), 140.1 ) CHvCCH3), 150.7, 163.9,
166.45 and 171.5 )CO); m/z 499 )M1, 100%), 426
)70)374 )30), 354 )20), 338 )40) and 324 )28). dF
)376 MHz, CDCl3) minor diastereoisomer 269.325, major
diastereoisomer 268.869, ee: 88%. Ethyl )2S)-amino-6-)1-
3.8.4. Ethyl (2S)-amino-6-(1-uracilyl)hexanoate (S)-
MTPA amide. Prepared following method G from amino
acid 27n to yield the title compound as a colourless oil,
1
incompletely characterized; Found: MNH4 491.2117.
C21H24N3O6F3 requires: MNH4 491.2111; dF )376 MHz,
CDCl3) minor diastereoisomer 269.134, major diastereo-
isomer 268.869, ee: 89%.
3.8.5. Ethyl (2S)-amino-6-(9-adeninyl)hexanoate (S)-
MTPA diamide. Prepared following method G from
amino acid 28f to give the title compound; Found: MH)
)ES1) 725.2516. C33H34N6O6F6 requires: MH 725.2522;
dH )300 MHz; CDCl3) minorp and major diastereoisomers:
1.26p and 1.29 )3H, t, Jˆ7.15 Hz, CH2CH3), 1.58±1.91 )6H,
m, CHCH2CH2CH2), 3.32p and 3.46 )3H, s, OCH3), 3.47 and
3.52p )3H, s, OCH3), 3.76 )2H, m, NCH2), 4.22 )2H, q,
Jˆ7.15 Hz, CH2CH3), 4.58 )1H, dt, Jˆ5.32 and 8.17 Hz,
NHCHCH2), 7.13 )1H, d, Jˆ8.17 Hz, NHCH), 7.37±7.67
)10H, m, ArH), 7.92 and 8.00p )1H, s, ArH), 8.78 and 8.80p
)1H, s, ArH) and 9.60)1H, s, NH); dC )75 MHz; CDCl3)
major diastereomer 14.2 )CH2CH3), 22.4, 29.3 and 31.7
)CH2), 47.7 )NCH2), 51.6 )CHCH2), 55.3 and 55.6
)OCH3), 122.8 )ArC), 127.2, 127.7, 128.4, 128.5, 128.75
and 129.6 )ArCH), 131.7 and 132.9 )ArC), 143.1 )ArCH),
148.2 and 152.2 )ArC), 152.5 )ArCH), 163.7, 166.4 and
171.4 )CO); m/z 725 )MH1, 100%), 535 )5), 189 )20) and
105 )8); dF )376 MHz; CDCl3) major diastereoisomer
1
thyminyl)hexanoate )S)-MTPA diamide: Found: MNH4
)ES1) 733.2668. C33H35F6N3O8 requires: MNH4 733.2672;
dH )300 MHz; CDCl3) major and minorp diastereoisomers:
1.26 and 1.22p )3H, t, Jˆ7.15 Hz, CH2CH3), 1.61±1.94 )9H,
m, CHCH2CH2CH2 and CHvCCH3), 3.34p and 3.45 and

R. C. F. Jones et al. / Tetrahedron 57 &2001) 6539±6555
6555
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268.871 and 269.423; minor diastereoisomer 269.181 and
269.277; ee. 86%.
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Acknowledgements
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We thank the Open University for ®nancial support )com-
petitive studentship to D. J. C. B.) and the EPSRC National
Mass Spectrometry Service Centre )Swansea) for some MS
data.
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