Efficient tin hydride-mediated radical cyclisation of secondary amides leading to substituted pyrrolidinones. Part 2. Application to the synthesis of aromatic kainic acid analogues

Article abstract of DOI:10.1039/a905809e

An enantioselective synthesis of phenyl allokainoid, starting from D-serine, is reported. Tin-mediated cyclisation of a secondary amide was used in the key step to produce a trisubstituted pyrrolidinone in excellent yield (ca. 80%). The predominant format

Full text of DOI:10.1039/a905809e

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Efficient tin hydride-mediated radical cyclisation of secondary
amides leading to substituted pyrrolidinones. Part 2. Application
to the synthesis of aromatic kainic acid analogues
Justin S. Bryans,a Jonathan M. Largeb and Andrew F. Parsons*b
a Parke-Davis Neuroscience Research Centre, Cambridge University Forvie Site, Robinson Way,
Cambridge, UK CB2 2QB
b Department of Chemistry, University of York, Heslington, York, UK YO10 5DD
Received (in Cambridge, UK) 19th July 1999, Accepted 31st August 1999
An enantioselective synthesis of phenyl allokainoid, starting from -serine, is reported. Tin-mediated cyclisation of
a secondary amide was used in the key step to produce a trisubstituted pyrrolidinone in excellent yield (ca. 80%).
The predominant formation of the all-trans diastereoisomer is consistent with a reversible cyclisation to give the
thermodynamically more stable product.
Introduction
Substituted pyrrolidines and pyrrolidinones are attractive syn-
thetic targets because of their widespread occurrence and
diverse range of important biological activities. One important
family of naturally occurring pyrrolidines are the kainoid
amino acids which possess anthelmintic, insecticidal and most
importantly, neuroexcitatory properties.1 This is attributed to
their action as conformationally restricted analogues of the
neurotransmitter -glutamic acid. Numerous syntheses of the
parent member, kainic acid 1, and the C-4 epimer, allokainic
Scheme 1
precursor 4, required for an enantioselective synthesis of 3,
could be prepared from the amino acid -serine.
To test the feasibility of this approach, the preparation of
benzylic chloride 6, containing a silyl protected alcohol, was
then carried out starting from -serine (Scheme 2). Reaction
acid 2, have been reported1 and interest has now turned
towards the preparation of (C-4) aromatic analogues 3.2 These
aromatic amino acids have been shown to exhibit the most
potent neuroexcitatory activity of this family of compounds.
Our earlier work had shown that trisubstituted pyrrol-
idinones could be isolated in good yield from radical cyclisation
of secondary haloamides.3 We envisaged that this type of cyclis-
ation could be employed to construct the 5-membered ring
present in the kainoid amino acids. As shown in the retro-
synthetic analysis (Scheme 1), reaction of a halide precursor of
type 4 with tributyltin hydride could allow the preparation
of pyrrolidinone 5. Steric interactions were expected to give
predominantly the trans-C-4–C-5 isomer. Elaboration to the
amino acid would then include oxidation of the primary alco-
hol and reduction of the lactam carbonyl. An aromatic
substituent (R = Ph) at the site of radical generation was of
particular interest as this is required for the preparation of bio-
logically important aromatic analogues 3. The chiral cyclisation
Scheme 2
of the TBDPS derivative 6 with tin hydride in boiling toluene
yielded three separable pyrrolidinones 7–9 in a combined yield
of 84% after column chromatography. Simple reduction, to give
J. Chem. Soc., Perkin Trans. 1, 1999, 2905–2910
This journal is © The Royal Society of Chemistry 1999
2905

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ethanamide 10, was only observed in low yield (8%). A similar
result was obtained using the corresponding TBDMS-protected
alcohol to give the related pyrrolidinones (as an 8.6:4.5:1
mixture of isomers) in a combined 85% yield.
The formation of three pyrrolidinone diastereomers, 7–9, in
the ratio 8.9:3.5:1 can be compared to the cyclisation of a
similar N-benzyl precursor 11 which gave a 1:1:1 mixture of
of large substituents slows the radical ring opening reaction
leading to more of the cis-isomer.†
The successful formation of trisubstituted pyrrolidinones,
bearing a protected alcohol side chain, suggested that this
cyclisation method could be applied to the synthesis of kainoid
amino acids. This was investigated using -serine methyl ester
hydrochloride 16 which was initially N-protected and converted
to the α,β-unsaturated ester 17 via Wittig reaction of the inter-
mediate α-amino aldehyde (Scheme 3). The 1H NMR spectrum
pyrrolidinone isomers.4 This marked change in diastereo-
selectivity can be explained by steric effects—the size of the
nitrogen protecting group could influence the reversibility of
the radical cyclisation process. A bulky benzyl substituent on
nitrogen could lower the rate of ring opening of the pyrrol-
idinone radical leading to less of the trans-pyrrolidinone iso-
mer. In order to investigate this, the N-methyl and N-benzyl
precursors, 12b and 12c were prepared by acylation of the
corresponding secondary amines. These were reacted with
Bu3SnH and the ratio of diastereomers for pyrrolidinones 13b
and 13c was compared to that obtained from cyclisation of the
corresponding secondary amide 12a.3 The presence of an N-Me
substituent was shown to lower the diastereoselectivity from
8.5:1 (for 13a) to 5.5:1 for 13b and this was lowered further
(to 4.1:1) using the N-benzyl precursor 13c. These results
clearly show that the size of the N-protecting group influ-
ences the diastereoselectivity of the cyclisation; the smaller
the group the greater the proportion of the trans-isomer. This
is consistent with a faster rate of ring opening for a
pyrrolidinone methyl radical with no nitrogen protecting group.
Reaction of the N–Me precursor 12b with tin hydride added
in one portion (rather than over 1 h) was shown, as expected,
to lead to more simple reduction. However, pyrrolidinone 13b
was formed and analysis of the crude 1H NMR spectrum
showed the diastereomer ratio was 3:1, rather than 5.5:1,
observed when the tin hydride was added over 1 h. This is
further evidence for a reversible cyclisation reaction; in the
presence of a high concentration of tin hydride the rate of
trapping of the pyrrolidinone methyl radical will be increased
leading to less ring opening and consequently more of the
cis-isomer of 13b.
The introduction of substituents in a carbocyclic chain has
also been shown to increase the rate of 5-exo radical cyclisation
onto a double bond. Substrates bearing geminal dimethyl or
diester substituents, for example, have been shown to cyclise
very rapidly.5,6 For the (reversible) cyclisation of benzylic
radicals, these substituents have also been shown to influence
the cyclopentane diastereoselectivity; whereas the 1-phenylhex-
5-enylradical 14 gave only the trans-cyclopentane,7 the related
diester precursor 15 (in which the benzylic radical was gener-
ated by a 1,5-hydrogen atom transfer) afforded the cyclo-
pentane as a 47:53 mixture of cis:trans isomers.6 As for the
pyrrolidinone system, it appears that the rate of ring opening is
influenced by substitution within the chain — the introduction
Scheme 3 Reagents and conditions: (i) (Boc)2O, Et3N, CH2Cl2 (85%);
(ii) TBDPSCl, DMAP (cat.), Et3N, CH2Cl2 (87%); (iii) DIBAL-H, tolu-
ene, Ϫ78 ЊC; (iv) Ph3P᎐CHCO2Et, CH2Cl2 (74% over two steps); (v)
᎐
TFA, CH2Cl2, 0 ЊC to room temp.; (vi) PhCH(Cl)COCl, Et3N, Et2O,
0 ЊC to room temp. (81% over two steps); (vii) Bu3SnH, AIBN, toluene,
heat (79%; dr 8.9:3.5:1).
showed the exclusive formation of the trans-double bond iso-
mer (J = 16 Hz). In order to investigate if any racemisation of
the α-centre had taken place during these reactions, the silyl
ether 18 was deprotected using TBAF and the resultant alcohol
reacted with either (ϩ)- or ( )-MTPA [α-methoxy-α-(trifluoro-
methyl)phenyl] chloride at 0 ЊC in the presence of DMAP.
1
Analysis of the H and 19F NMR spectra of the crude esters
indicated an ee of ≥95%. For example, two peaks (of approxi-
mately the same ratio) were observed in the 19F NMR spectrum
at Ϫ69.50 and Ϫ70.75 ppm for the ester derived from ( )-
MTPA chloride while only one of these (at Ϫ70.75 ppm) was
present in the spectrum of the ester prepared from (ϩ)-MTPA
chloride.‡ N-Deprotection of 17 using TFA followed by acyl-
ation of the crude primary amine afforded chloroamide 18 in
excellent yield. Treatment of 18 with tin hydride, added over
1 h, gave the trisubstituted pyrrolidinone 19 in similar yield
and diastereoselectivity to that observed earlier (in the racemic
studies). The cyclisation reaction was carried out a number of
times using 0.2–1.8 mmol of 18 and in some cases the product
of simple reduction was observed but only in ≤8% yield. The
stereochemistry of the three pyrrolidinone diastereomers was
deduced from comparison of the 1H and 13C NMR spectra with
that of related compounds4 and confirmed by base-induced
epimerisation experiments. For example, the cis-C-3–C-4 iso-
mer [of type 8] could be isomerised (in 75% yield) to the more
stable all trans-diastereomer 20 (Scheme 4) on heating with
DBU in toluene.
The trans-pyrrolidinone 20 was then converted to the N-Boc
derivative so as to facilitate lactam reduction. Under the basic
conditions used for the N-protection, epimerisation occurred to
† This is well documented for ring opening of cyclobutylmethyl
radicals. The cyclobutylmethyl radical ring opens 1.6 times faster than
the 3,3-dimethylcyclobutylmethyl radical at 60 ЊC.8
‡ The 19F NMR spectra were referenced to residual ( )-MTPA chloride
at Ϫ70.45 ppm.
2906
J. Chem. Soc., Perkin Trans. 1, 1999, 2905–2910

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Radical cyclisation of alkene 6
Following the general radical cyclisation procedure, the alkene
6 (155 mg, 0.21 mmol) (prepared in the same manner as the
enantiomerically pure alkene 18) in degassed toluene (9 cm3)
was treated with tributyltin hydride (67 mg, 0.23 mmol) and
azobisisobutyronitrile (7 mg, 0.04 mmol) in toluene (17 cm3)
over a 1 h addition period, and the reaction mixture stirred at
reflux for a further 18 h. Column chromatography (dichloro-
methane–ethyl acetate, 4:1) afforded the 3-phenyl-4-(ethoxy-
carbonylmethyl)-5-(tert-butyldiphenylsilyloxymethyl)pyrro-
lidin-2-ones 7, 8 and 9 (90 mg, 84%) as colourless oils in a ratio
of 8.9:3.5:1, together with reduced product 10 (4 mg, 4%) as a
colourless oil.
(3R*,4S*,5S*) Major diastereoisomer 7: Rf 0.3 (dichloro-
methane–ethyl acetate, 4:1); νmax/cmϪ1 (CHCl3) 3429 (w), 3008
(w), 2931 (w), 2862 (w), 1705 (s), 1427 (w), 1111 (w), 706 (w);
δH (270 MHz, CDCl3) 7.60–7.51 (4H, m, aromatics), 7.39–7.08
(11H, m, aromatics), 6.21 (1H, br s, NH), 3.85–3.66 (3H, m,
CO2CH2, NHCH), 3.59–3.50 (2H, m, CH2OSi), 3.39 (1H, d,
J = 10, PhCH), 2.45 (1H, m, CHCH2CO2), 2.37 (2H, d, J = 7,
CH2CO2), 1.00 (9H, s, SiC(CH3)3), 0.98 (3H, t, J = 7,
CO2CH2CH3); δC (67.5 MHz, CDCl3) 177.4, 171.4 (CONH,
CO Et), 138.0 (C᎐CH), 136.0 (CH᎐C), 133.2 (C᎐CH), 130.4,
᎐
᎐
᎐
2
129.9, 128.9, 128.3, 127.9 (CH᎐C), 66.4 (CH OSi), 61.1 (CO -
᎐
2
2
CH2), 59.8 (PhCH), 54.8 (NHCH), 43.1 (CHCH2CO2), 37.3
(CH2CO2), 27.3 (SiC(CH3)3), 19.6 (SiCMe3), 14.4 (CO2-
CH2CH3); m/z (CI, NH3) 516 (M ϩ Hϩ, 100%), 458 (28)
(Found: M ϩ Hϩ, 516.2563. C31H37NO4Si requires for M ϩ Hϩ,
516.2570).
(3R*,4R*,5R*) Minor diastereoisomer 8: Rf 0.4 (dichloro-
methane–ethyl acetate, 4:1); νmax/cmϪ1 (CHCl3) 3429 (w), 2958
(w), 2862 (w), 1705 (s), 1600 (w), 1427 (w), 1111 (w), 779 (w);
δH (270 MHz, CDCl3) 7.60–7.55 (4H, m, aromatics), 7.39–7.16
(9H, m, aromatics), 7.05–7.02 (2H, m, aromatics), 6.11 (1H, br
s, NH), 3.91–3.83 (3H, m, CO2CH2, PhCH), 3.70 (1H, dd,
J = 10, 5, CHAHBOSi), 3.59 (1H, m, CHAHBOSi), 3.46 (1H, m,
NHCH), 2.85 (1H, m, CHCH2CO2), 2.01 (1H, dd, J = 16.5, 7.5,
CHAHBCO2), 1.81 (1H, dd, J = 17, 8, CHAHBCO2), 1.04 (3H, t,
J = 7, CO2CH2CH3), 0.95 (9H, s, SiC(CH3)3); δC (67.5 MHz,
Scheme 4 Reagents and conditions: (i) (Boc)2O, Et3N (2 equiv.),
DMAP, CH2Cl2, (75%); (ii) BH3ؒDMS (6 equiv.), THF, heat (75%); (iii)
BH3ؒDMS (2 equiv.), THF, heat (49%); (iv) TBAF, THF (50%); (v)
TBAF, THF (90%); (vi) RuCl3ؒH2O, NaIO4, MeCN, H2O, CCl4; (vii)
CH2N2, Et2O (44% over two steps); (viii) HCl2, H2O, 70 ЊC (93%).
give a mixture of the C-4 epimers 21 and 22. It is of interest
to note that whereas isomerisation of the cis-C-3–C-4 NH
isomer [of type 8] to 20 occurred readily on heating with
DBU, the corresponding N-Boc compound 22 was more
resistant and a mixture of 21 and 22 (in the ratio 1:1) was
isolated under the same conditions. Presumably epimerisation
of 21 occurs after N-protection and this phenomenon has
previously been observed for alkylated N-Boc pyrogluta-
mates.9 Reduction of lactam 22 using two equivalents of
borane–dimethyl sulfide complex gave the pyrrolidine in
moderate yield and subsequent desilylation to alcohol 23 was
achieved in a similar yield. The deprotection of related com-
pounds, with alternative protecting groups, has previously
been reported as a route to phenylkainic acid.1,2 A much
cleaner transformation was observed when 21 was reacted
with six equivalents of borane–dimethyl sulfide complex to
promote both lactam and ester reduction. The product alco-
hol 24 was then desilylated and oxidised to the dicarboxylic
acid. For ease of characterisation, this was reacted with
diazomethane and the dimethyl ester was isolated in reasonable
yield. This could be efficiently deprotected using hot aqueous
HCl to afford the amino acid salt 25 in 13 steps (4.5% overall
yield) from serine methyl ester 16. The spectroscopic data for
25 was consistent with that reported previously for related
compounds.2b
CDCl ) 177.0, 171.6 (CONH, CO Et), 135.5 (CH᎐C), 135.1,
᎐
3
2
132.7 (C᎐CH), 130.2, 129.3, 128.8, 127.9, 127.5 (CH᎐C),
᎐
᎐
66.4 (CH2OSi), 60.5 (CO2CH2), 59.5 (PhCH), 51.1 (NHCH),
37.9 (CHCH2CO2), 34.6 (CH2CO2), 26.8 (SiC(CH3)3), 19.2
(SiCMe3), 14.0 (CO2CH2CH3); m/z (CI, NH3) 516 (M ϩ Hϩ,
100%), 458 (11) (Found: M ϩ Hϩ, 516.2560. C31H37NO4Si
requires for M ϩ Hϩ, 516.2570).
(3R*,4S*,5R*) Minor diastereoisomer 9: the presence of this
was indicated by NMR spectroscopy; δH (270 MHz, CDCl3)
7.61–7.50 (4H, m, aromatics), 7.39–7.21 (11H, m, aromatics),
3.97–3.79 (4H, m, CO2CH2, NHCH, CHAHBOSi), 3.66 (1H,
app. d, J = 5, CHAHBOSi), 3.63 (1H, d, J = 10, PhCH), 2.93
(1H, m, CHCH2CO2), 2.67 (1H, dd, J = 17, 10.5, CHAHBCO2),
2.48 (1H, dd, J = 17, 5, CHAHBCO2), 1.06 (3H, t, J = 7,
CO2CH2CH3), 1.00 (9H, s, SiC(CH3)3).
Phenylethanamide 10: Rf 0.7 (dichloromethane–ethyl acetate,
4:1); δH (270 MHz, CDCl3) 7.43–7.21 (15H, m, aromatics), 6.75
(1H, dd, J = 16, 16, 5, CH᎐CHCO ), 5.90 (1H, d, J = 8, NH),
᎐
2
5.73 (1H, dd, J = 16, 2, CH᎐CHCO ), 4.60 (1H, m, NHCH),
᎐
2
4.13 (2H, q, J = 7, CO2CH2), 3.64–3.54 (2H, m, CH2OSi), 3.63
(2H, s, PhCH2), 1.21 (3H, t, J = 7, CO2CH2CH3), 1.03 (9H, s,
SiC(CH3)3).
This work has shown that secondary haloamides bearing a
protected alcohol side chain can produce trisubstituted pyrrol-
idinones in excellent yield. Elaboration of the cyclised product
has demonstrated a novel approach to an aromatic allokainoid
amino acid.
1,4-Dimethyl-3-phenylpyrrolidin-2-one 13b. (3R*,4S*) Major
diastereoisomer: Oil; 39%; Rf 0.3 (ethyl acetate); νmax/cmϪ1
(CHCl3) 3003 (m), 2929 (m), 2873 (m), 1689 (s), 1496 (s), 1454
(s), 1405 (s), 1267 (s), 1240 (m), 1151 (w), 698 (m); δH (270
MHz, CDCl3) 7.36–7.15 (5H, m, aromatics), 3.51 (1H, dd,
J = 10, 8, NCHAHB), 3.16 (1H, d, J = 10, PhCH), 3.04 (1H, app.
t, J = 9.5, NCHAHB), 2.92 (3H, s, NCH3), 2.38 (1H, m,
Experimental
For general experimental and a procedure for radical cyclis-
ation see the preceding paper.3
J. Chem. Soc., Perkin Trans. 1, 1999, 2905–2910
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CHCH3), 1.15 (3H, d, J = 7, CHCH3); δC (67.5 MHz, CDCl3)
174.7 (NCO), 138.7 (C᎐CH), 128.5, 128.3, 126.9 (CH᎐C), 56.6
CH᎐CHCO ), 5.96 (1H, dd, J = 16, 2, CH᎐CHCO ), 4.89 (1H,
᎐
᎐
2
2
br s, NH), 4.41 (1H, m, NHCH), 4.20 (2H, q, J = 7, CO2CH2),
3.78 (1H, dd, J = 10, 4.5, CHAHBOSi), 3.69 (1H, dd, J = 10, 4.5,
CHAHBOSi), 1.45 (9H, s, NHCO2C(CH3)3), 1.29 (3H, t, J = 7,
CO2CH2CH3), 1.05 (9H, s, SiC(CH3)3); δC (67.5 MHz, CDCl3)
᎐
᎐
(PhCH), 54.8 (NCH2), 37.2 (CHCH3), 29.9 (NCH3), 17.4
(CHCH3); m/z (CI, NH3) 190 (M ϩ Hϩ, 100%) (Found:
M ϩ Hϩ, 190.1228. C12H15NO requires for M ϩ Hϩ, 190.1232).
(3R*,4R*) Minor diastereoisomer: the presence of this was
indicated by NMR spectroscopy; δH (270 MHz, CDCl3) 3.75
(1H, d, J = 8.5, PhCH), 2.97 (3H, s, NCH3), 2.74 (1H, m,
CHCH3), 0.68 (3H, d, J = 7.5, CHCH3); δC (67.5 MHz, CDCl3)
166.0 (CO Et), 155.1 (NHCO), 146.2 (CH᎐CHCO ), 135.5
᎐
2
2
(CH᎐C), 132.9, 137.7 (C᎐CH), 129.9, 127.7 (CH᎐C), 122.0
᎐
᎐
᎐
(CH᎐CHCO ), 79.8 (NHCO CMe ), 65.4 (CH OSi), 60.4
᎐
2
2
3
2
(CO2CH2), 53.1 (NHCH), 28.3 (NHCO2C(CH3)3), 26.8, 26.5
(SiC(CH3)3), 19.2 (SiCMe3), 14.2 (CO2CH2CH3); m/z (CI, NH3)
498 (M ϩ Hϩ, 12%), 442 (32), 398 (76), 381 (90), 364 (50), 320
(50), 274 (20), 216 (62), 196 (100), 142 (16), 79 (24) (Found:
M ϩ Hϩ, 498.2675. C28H39NO5Si requires for M ϩ Hϩ,
498.2676).
175.0 (NCO), 136.1 (C᎐CH), 129.1, 128.3, 126.7 (CH᎐C), 55.1
᎐
᎐
(NCH2), 52.7 (PhCH), 31.8 (CHCH3), 29.7 (NCH3), 15.2
(CHCH3).
1-Benzyl-4-methyl-3-phenylpyrrolidin-2-one 13c. (3R*,4S*)
Major diastereoisomer: Oil; 57%; Rf 0.4 (petroleum ether–ethyl
acetate, 1:1); νmax/cmϪ1 (CHCl3) 3064 (m), 3001 (s), 2873 (m),
1675 (s), 1492 (s), 1442 (s), 1358 (w), 1259 (s), 908 (m), 771 (m),
754 (s), 721 (s), 700 (s); δH (270 MHz, CDCl3) 7.39–7.18 (10H,
m, aromatics), 4.60 (1H, d, J = 14.5, NCHAHBPh), 4.11 (1H, d,
J = 14.5, NCHAHBPh), 3.39 (1H, dd, J = 10, 8, NCHAHBCH),
3.22 (1H, d, J = 9.5, PhCH), 2.90 (1H, dd, J = 9.5, 8.5,
NCHAHBCH), 2.36 (1H, septet of t, J = 8, 1.5, CHCH3), 1.09
(3H, d, J = 7, CHCH3); δC (67.5 MHz, CDCl3) 174.5 (NCO),
(4S)-Ethyl (E)-4-(2-chloro-2-phenylethanamido)-5-(tert-butyl-
diphenylsilyloxy)pent-2-enoate 18
To a stirred solution of the protected amine 17 (224 mg, 0.45
mmol) in dichloromethane (5 cm3) at 0 ЊC was added trifluoro-
acetic acid (0.41 cm3, 5.40 mmol) and the solution was stirred
for 0.5 h, before warming to room temp. and stirring for a
further 16 h. The solvent was removed in vacuo and the remain-
ing acid removed via its azeotrope with chloroform to afford the
crude amine salt as a brown oil (210 mg); δH (400 MHz, CDCl3)
7.66–7.58 (4H, m, aromatics), 7.46–7.37 (6H, m, aromatics),
138.6, 136.5 (C᎐CH), 128.6, 128.4, 128.1, 127.5, 127.0, 126.8
᎐
(CH᎐C), 56.8 (PhCH), 51.9, 46.8 (NCH Ph, NCH CH), 37.1
᎐
2
2
(CHCH3), 17.4 (CHCH3); m/z (CI, NH3) 266 (M ϩ Hϩ, 100%),
91 (10) (Found: M ϩ Hϩ, 266.1542. C18H19NO requires for
M ϩ Hϩ, 266.1545).
6.80 (1H, dd, J = 16, 6.5, CH᎐CHCO ), 6.06 (1H, d, J = 16,
᎐
2
CH᎐CHCO ), 4.14 (2H, q, J = 7, CO CH ), 4.05 (1H, m,
᎐
2
2
2
NHCH), 3.86–3.78 (2H, m, CH2OSi), 1.22 (3H, t, J = 7,
CO2CH2CH3), 1.06 (9H, s, SiC(CH3)3). The crude amine was
treated with 2-chloro-2-phenylacetyl chloride (0.08 cm3, 0.50
mmol) and triethylamine (0.14 cm3, 0.99 mmol) in diethyl ether
(7 cm3). Column chromatography (petroleum ether–diethyl
ether, 1:1) afforded the alkene 18 (200 mg, 81% over two steps)
as a colourless oil; Rf 0.3 (petroleum ether–diethyl ether, 1:1);
[α]D20 Ϫ13.6 (c 0.5, CHCl3); νmax/cmϪ1 (CHCl3) 3413 (m), 3008
(s), 2958 (s), 2862 (s), 1712 (s), 1678 (s), 1512 (s), 1469 (m), 1307
(m), 1277 (m), 1184 (m), 1111 (s), 983 (m), 702 (s); δH (270
MHz, CDCl3) 7.76–7.70 (4H, m, aromatics), 7.60–7.44 (11H,
(3R*,4R*) Minor diastereoisomer: Oil; Rf 0.3 (petroleum
ether–ethyl acetate, 1:1); νmax/cmϪ1 (CHCl3) 3016 (m), 2873 (w),
1676 (s), 1602 (w), 1494 (w), 1433 (w), 1263 (w); δH (270 MHz,
CDCl3) 7.37–7.03 (10H, m, aromatics), 4.65 (1H, d, J = 14.5,
NCHAHBPh), 4.50 (1H, d, J = 14.5, NCHAHBPh), 3.80 (1H, d,
J = 9, PhCH), 3.40 (1H, dd, J = 10, 8.5, NCHAHBCH), 2.93
(1H, dd, J = 9, 6, NCHAHBCH), 2.70 (1H, m, CHCH3), 0.64
(3H, d, J = 7, CHCH3); δC (67.5 MHz, CDCl3) 174.7 (NCO),
136.6, 136.3 (C᎐CH), 129.2, 128.7, 128.2, 127.7, 127.5, 127.0
᎐
(CH᎐C), 53.0 (PhCH), 52.3, 46.8 (NCH Ph, NCH CH), 32.0
᎐
2
2
(CHCH3), 15.2 (CHCH3); m/z (CI, NH3) 266 (M ϩ Hϩ, 100%),
176 (5), 91 (11) (Found: M ϩ Hϩ, 266.1541. C18H19NO requires
for M ϩ Hϩ, 266.1545).
m, aromatics), 6.83 (1H, m, CH᎐CHCO ), 6.03 and 5.98 (1H,
᎐
2
2 × d, J = 16, CH᎐CHCO ), 5.55 and 5.53 (1H, 2 × s, PhCH),
᎐
2
4.60 (1H, m, NHCH), 4.17–4.07 (2H, m, CO2CH2), 3.77–3.04
(2H, m, CH2OSi), 1.24–1.09 (3H, m, CO2CH2CH3), 0.97 (9H, s,
SiC(CH3)3); δC (67.5 MHz, CDCl3) 167.2, 165.3 (CONH,
(4S)-Ethyl (E)-4-(tert-butoxycarbonylamino)-5-(tert-butyl-
diphenylsilyloxy)pent-2-enoate 17
CO Et), 144.2 (CH᎐CHCO ), 136.7 (C᎐CH), 135.5 (CH᎐C),
᎐ ᎐ ᎐
2 2
132.3 (C᎐CH), 130.0, 129.1, 128.9, 128.7, 127.7 (CH᎐C), 122.7
᎐
᎐
A solution of (3S)-methyl 2-(tert-butoxycarbonylamino)-3-
(tert-butyldiphenylsilyloxy)propanoate10 (265 mg, 0.58 mmol)
in toluene (5 cm3) at Ϫ78 ЊC was treated with diisobutyl-
aluminium hydride (1.45 cm3, 1.45 mmol, 1 M in toluene),
via a syringe pump over 1 h. After stirring for 1 h, 10%
aqueous citric acid (25 cm3) and ethyl acetate (25 cm3) were
added and the mixture stirred for 1 h. The organic layer was
separated and washed with brine, dried (magnesium sulfate)
and concentrated in vacuo to afford the crude aldehyde (195 mg)
as an oil; Rf 0.55 (petroleum ether–ethyl acetate, 2:1); δH (270
MHz, CDCl3) 9.59 (1H, s, CHO), 7.64–7.50 (4H, m, aromatics),
7.42–7.27 (6H, m, aromatics), 5.35 (1H, br s, NH), 4.22 (1H, m,
NHCH), 4.05 (1H, dd, J = 10, 3, CHAHBOSi), 3.92 (1H, dd,
J = 10, 3, CHAHBOSi), 1.39 (9H, s, NHCO2C(CH3)3), 0.96 (9H,
s, SiC(CH3)3).
Thealdehydewasthentreatedwithethoxycarbonylmethylene-
triphenylphosphorane (300 mg, 0.87 mmol) in dichloromethane
(5 cm3). The organic layer was separated and washed with brine,
dried (magnesium sulfate) and concentrated in vacuo. Column
chromatography (petroleum ether–ethyl acetate, 5:1) afforded
the alkene 17 (214 mg, 74% over two steps) as a colourless oil;
Rf 0.35 (petroleum ether–ethyl acetate, 5:1); [α]D20 Ϫ14.8 (c 0.52,
CHCl3); νmax/cmϪ1 (CHCl3) 3381 (w), 2940 (w), 1705 (s), 1512
(m), 733 (w); δH (270 MHz, CDCl3) 7.68–7.57 (4H, m, aro-
matics), 7.48–7.32 (6H, m, aromatics), 6.91 (1H, dd, J = 16, 6,
(CH᎐CHCO ), 64.7 (CH OSi), 61.7 (PhCH), 60.5 (CO CH ),
᎐
2
2
2
2
52.0 (NHCH), 26.7 (SiC(CH3)3), 19.2 (SiCMe3), 14.2 (CO2-
CH2CH3); m/z (CI, NH3) 552 (37M ϩ Hϩ, 20%), 550 (35M ϩ Hϩ,
46), 516 (100), 492 (27), 472 (60), 458 (23), 438 (10), 391 (26),
352 (7), 323 (7), 274 (12), 260 (23) (Found: 35M ϩ Hϩ, 550.2181.
C31H36ClNO4Si requires for 35M ϩ Hϩ, 550.2180).
(3R,4S,5S)-1-(tert-Butoxycarbonyl)-3-phenyl-4-(ethoxy-
carbonylmethyl)-5-(tert-butyldiphenylsilyloxymethyl)pyrrolidin-
2-one 21
To a stirred solution of the lactam 20 (220 mg, 0.43 mmol) in
dry dichloromethane (5 cm3) under an atmosphere of nitrogen
was added triethylamine (0.06 cm3, 0.43 mmol), di-tert-butyl
dicarbonate (186 mg, 0.85 mmol) and 4-dimethylaminopyridine
(52 mg, 0.43 mmol) and the solution was stirred at room temp.
for 24 h. Concentration in vacuo and column chromatography
(dichloromethane–ethyl acetate, 49:1) afforded 21 (131 mg,
50%) and the 3S isomer 22 (67 mg, 25%) as pale yellow oils.
21; Rf 0.2 (dichloromethane–ethyl acetate, 49:1); [α]D20 Ϫ22.7
(c 0.38, CHCl3); νmax/cmϪ1 (CHCl3) 3012 (w), 2931 (w), 1782 (s),
1728 (s), 1473 (w), 1369 (w), 1307 (w), 1153 (m), 1114 (m), 706
(m); δH (270 MHz, CDCl3) 7.73–7.65 and 7.55–7.32 (15H,
2 × m, aromatics), 4.16 (1H, dd, J = 10, 5.5, CHAHBOSi), 4.09–
3.94 (3H, m, CO2CH2, NCH), 3.87 (1H, dd, J = 10.5, 2, CHAHB-
2908
J. Chem. Soc., Perkin Trans. 1, 1999, 2905–2910

View Article Online
OSi), 3.74 (1H, d, J = 9, PhCH), 3.15 (1H, m, CHCH2CO2),
2.67 (1H, dd, J = 15, 5, CHAHBCO2), 2.56 (1H, dd, J = 15, 7.5,
CHAHBCO2), 1.55 (9H, s, NCO2C(CH3)3), 1.20 (3H, t, J = 7,
afford crude product, which was purified by column chrom-
atography (petroleum ether–ethyl acetate, 3:2) to give the
alcohol 23 (10 mg, 50%) as a colourless oil; Rf 0.3 (petroleum
ether–ethyl acetate, 3:2); δH (500 MHz, CDCl3) 7.41–7.22 (5H,
m, aromatics), 4.09 (2H, app. t, J = 7, CO2CH2), 3.82–3.72 and
3.62–3.58 (6H, 2 × m, NCH2, NCH, CH2OH, PhCH), 2.62
(1H, m, CHCH2CO2), 2.20 (1H, dd, J = 16.5, 6.5, CHAHBCO2),
1.94 (1H, dd, J = 16.5, 7.5 CHAHBCO2), 1.51 (9H, s, NCO2-
C(CH3)3), 1.22 (3H, t, J = 7, CO2CH2CH3); m/z (CI, NH3) 391
(11%), 364 (M ϩ Hϩ, 13), 308 (100), 290 (17), 264 (65), 246 (21),
232 (90), 218 (27) (Found: M ϩ Hϩ, 364.2130. C20H29NO5
requires for M ϩ Hϩ, 364.2124).
CO2CH2CH3), 1.16 (9H, s, SiC(CH3)3); δC (67.5 MHz, CDCl3)
t
173.3, 170.9 (NCO, CO Et), 150.0 (NCO Bu), 137.4 (C᎐CH),
᎐
2
2
135.5 (CH᎐C), 132.9 (C᎐CH), 132.7, 129.8, 128.7, 127.8, 127.4
᎐
᎐
(CH᎐C), 83.2 (NCO CMe ), 61.9 (CH OSi), 61.5 (PhCH), 60.7
᎐
2
3
2
(CO2CH2), 54.6 (NCH), 37.6 (CHCH2CO2), 37.2 (CH2CO2),
27.9, 26.8 (NHCO2C(CH3)3, SiC(CH3)3), 19.3 (SiCMe3), 13.9
(CO2CH2CH3); m/z (CI, NH3) 616 (M ϩ Hϩ, 18%), 558 (45),
533 (7), 516 (100), 458 (17) (Found: M ϩ Hϩ, 616.3094.
C36H45NO6Si requires for M ϩ Hϩ, 616.3094).
22; Rf 0.35 (dichloromethane–ethyl acetate, 49:1); [α]D20 Ϫ66.0
(c 0.30, CHCl3); νmax/cmϪ1 (CHCl3) 3012 (w), 2962 (w), 1781 (s),
1728 (s), 1369 (m), 1307 (s), 1111 (s), 705 (m); δH (270 MHz,
CDCl3) 7.77–7.64 and 7.52–7.21 (total 15H, 2 × m, aromatics),
4.74 (1H, d, J = 10, PhCH), 4.19–3.95 (5H, m, CO2CH2, NCH,
CH2OSi), 3.20 (1H, m, CHCH2CO2), 2.23 (1H, dd, J = 17, 11,
CHAHBCO2), 2.03 (1H, dd, J = 17, 4.5, CHAHBCO2), 1.52 (9H,
s, NCO2C(CH3)3), 1.20 (3H, t, J = 7, CO2CH2CH3), 1.15 (9H, s,
(2S,3S,4R)-1-(tert-Butoxycarbonyl)-2-(tert-butyldiphenyl-
silyloxymethyl)-3-(2-hydroxyethyl)-4-phenylpyrrolidine 24
To a stirred solution of lactam 21 (167 mg, 0.27 mmol) in dry
THF (3 cm3) at reflux (under an atmosphere of nitrogen) was
added borane–dimethyl sulfide complex (0.82 cm3, 1.62 mmol,
2 M in THF) and the reaction mixture stirred at reflux for 24 h.
Diethyl ether (10 cm3) and saturated ammonium chloride (10
cm3) were added and the organic layer separated, before further
extraction of the aqueous layer with diethyl ether (20 cm3). The
combined organic extracts were washed with 5% aqueous HCl,
5% aqueous NaHCO3 and brine, dried (magnesium sulfate) and
concentrated in vacuo to give crude product, which was purified
by column chromatography (petroleum ether–ethyl acetate,
9:1) to give the pyrrolidine 24 (103 mg, 75%) as a colourless oil;
Rf 0.45 (petroleum ether–ethyl acetate, 1:1); [α]D20 Ϫ18.5 (c 0.29,
CHCl3); νmax/cmϪ1 (CHCl3) 3614 (w), 2931 (w), 1681 (s), 1411
(m), 1169 (w), 760 (s), 709 (m); δH (270 MHz, toluene-d8) 7.72–
7.63 (4H, m, aromatics), 7.20–6.78 (11H, m, aromatics), 4.33
(1H, m, NCH), 4.00 (1H, m, PhCH), 3.76 (1H, app. d, J = 8,
CHAHBOH), 3.60 (1H, m, CHCH2CH2), 3.30 (1H, app. t, J = 8,
CHAHBOH), 3.10 (2H, app. td, J = 5, 1, CH2OSi), 2.80 (1H,
m, NHAHB), 2.60 (1H, m, NCHAHB), 1.44–1.35 (11H, m,
NCO2C(CH3)3, CH2CH2OH), 1.09 (9H, s, SiC(CH3)3); δC (67.5
SiC(CH3)3); δC (67.5 MHz, CDCl3) 174.5, 172.3 (NCO, CO2Et),
t
150.6 (NCO Bu), 136.0 (CH᎐C), 134.9 (CH᎐C), 133.0 (CH᎐C),
᎐
᎐
᎐
2
130.4, 129.0, 128.4, 127.9 (CH᎐C), 83.6 (NCO CMe ), 65.3
᎐
2
3
(CH2OSi), 62.8 (PhCH), 61.1 (CO2CH2), 52.7 (NCH), 37.2
(CHCH2CO2), 36.1 (CH2CO2), 28.5, 27.3 (NCO2C(CH3)3,
SiC(CH3)3), 19.7 (SiCMe3), 14.5 (CO2CH2CH3); m/z (CI, NH3)
616 (M ϩ Hϩ, 12%), 558 (50), 533 (16), 516 (100), 458 (9), 136
(5), 94 (5) (Found: M ϩ Hϩ, 616.3102. C36H45NO6Si requires
for M ϩ Hϩ, 616.3094).
(2S,3S,4S)-1-(tert-Butoxycarbonyl)-2-(hydroxymethyl)-3-
(ethoxycarbonylmethyl)-4-phenylpyrrolidine 23
To a solution of lactam 22 (90 mg, 0.15 mmol) in dry THF (3
cm3) at reflux under an atmosphere of nitrogen was added
borane–dimethyl sulfide complex (0.22 cm3, 0.44 mmol, 2 M in
THF) and the reaction mixture stirred at reflux for 18 h. Diethyl
ether (10 cm3) and saturated ammonium chloride (10 cm3) were
added and the organic layer was separated, before further
extraction of the aqueous layer with diethyl ether (20 cm3). The
combined organic extracts were washed with 5% HCl, 5%
aqueous sodium bicarbonate and brine, dried (magnesium
sulfate) to give crude material. Purification by column chrom-
atography (petroleum ether–ethyl acetate, 9:1) afforded the
protected pyrrolidine (44 mg, 49%) as a colourless oil; Rf 0.3
(petroleum ether–ethyl acetate, 9:1); νmax/cmϪ1 (CHCl3) 3012
(w), 2931 (w), 1728 (s), 1685 (s), 1403 (s), 758 (m), 733 (m), 706
(m); δH (270 MHz, toluene-d8) 7.78–7.65 (4H, m, aromatics),
7.22–6.92 (11H, m, aromatics), 4.22 (1H, dd, J = 10, 3,
CHAHBOSi), 3.91 (2H, q, J = 7, CO2CH2), 3.99–3.62 (5H, m,
NCH2, PhCH, NCH, CHAHBOSi), 3.16 (1H, m, CHCH2CO2),
2.18 (1H, dd, J = 16, 7, CHAHBCO2), 1.94 (1H, dd, J = 16, 5,
CHAHBCO2), 1.34 (9H, s, NCO2C(CH3)3), 1.20 (3H, t, J = 7,
t
MHz, CDCl3) (mixture of conformers) 153.8 (NCO2 Bu), 140.4
(C᎐CH), 135.6 (CH᎐C), 133.2 (C᎐CH), 129.8, 129.6, 129.4,
᎐
᎐
᎐
128.7, 128.5, 128.4, 127.8, 127.0 (CH᎐C), 79.5, 79.2 (NCO2-
᎐
CMe3), 64.0 (PhCH), 64.2, 62.6 (CH2OH), 61.2, 61.0 (CH2OSi),
55.2, 54.0 (NCH2), 51.0, 50.8 (NCH), 45.1, 43.3 (CHCH2-
CH2OH), 36.5, 36.0 (CH2CH2OH), 28.5, 28.4, 26.9, 26.8
(NCO2C(CH3)3, SiC(CH3)3), 19.4, 19.3 (SiCMe3); m/z (CI,
NH3) 560 (M ϩ Hϩ, 32%), 504 (19), 460 (100), 446 (23), 391
(17), 190 (37) (Found: M ϩ Hϩ, 560.3193. C34H45NO4Si
requires for M ϩ Hϩ, 560.3196).
Phenylallokainic acid 25
A solution of 24 (95 mg, 0.17 mmol) in THF (3 cm3) at room
temp. was treated dropwise with tetrabutylammonium fluoride
(0.51 cm3, 0.51 mmol, 1 M in THF) and stirred for 18 h. The
solvent was removed in vacuo and column chromatography
(ethyl acetate–petroleum ether, 2:1) afforded the diol (49 mg,
90%) as a colourless oil; Rf 0.2 (ethyl acetate–petroleum ether,
2:1); [α]D20 Ϫ17.0 (c 0.08, CHCl3); νmax/cmϪ1 (CHCl3) 3610 (m),
2981 (m), 1666 (m), 1412 (s), 1164 (m), 756 (s); δH (270 MHz;
CDCl3) (mixture of conformers) 7.28–7.14 (5H, m, aromatics),
5.08 (1H, br s, OH), 3.91–3.64 and 3.41–3.13 (8H, 2 × m,
PhCH, NCH2, NCH, CH2OH, CHCH2OH), 2.84 (1H, app. q,
J = 10, CHCH2CH2OH), 2.06 (1H, br s, OH), 1.66 (2H, app. q,
CO2CH2CH3), 1.10 (9H, s, SiC(CH3)3); δC (67.5 MHz, CDCl3)
t
172.5 (CO2Et), 154.5 (NCO2 Bu), 139.5 (CH᎐C), 138.8
᎐
(C᎐CH), 134.8 (CH᎐C), 133.5 (C᎐CH), 129.7, 128.8, 128.6,
᎐
᎐
᎐
128.2, 127.9, 127.7, 127.2, 126.8 (CH᎐C), 79.4 (NCO CMe ),
᎐
2
3
66.4 (CH2OSi), 63.3 (PhCH), 60.4 (CO2CH2), 50.7, 49.2
(NCH2), 44.8, 43.7 (NCH), 42.4, 41.2 (CHCH2CO2), 34.2
(CH2CO2), 28.5, 26.9 (NCO2C(CH3)3, SiC(CH3)3), 19.2
(SiCMe3), 14.1 (CO2CH2CH3); m/z (CI, NH3) 602 (M ϩ Hϩ,
100%), 572 (10), 546 (42), 502 (89) (Found: M ϩ Hϩ, 602.3296.
C36H47NO5Si requires for M ϩ Hϩ, 602.3302).
J = 6, CH2CH2OH), 1.39 (9H, s, NCO2C(CH3)3); δC (67.5 MHz,
t
CDCl ) 156.2 (NCO Bu), 139.5 (C᎐CH), 128.8, 127.7, 127.3
᎐
3
2
A stirred solution of the pyrrolidine (17 mg, 0.028 mmol) in
THF (2 cm3) at room temp. was treated dropwise with
tetrabutylammonium fluoride (0.04 cm3, 0.042 mmol, 1 M in
THF) and stirred for 18 h. The mixture was then poured into
saturated aqueous ammonium chloride and extracted three
times with dichloromethane. The combined organic extracts
were dried (magnesium sulfate) and concentrated in vacuo to
(CH᎐C), 80.5 (NCO CMe ), 66.6 (CHCH OH), 65.9 (PhCH),
᎐
2 3 2
60.3 (CH2CH2OH), 54.4 (NCH2), 50.3 (CHCH2CH2OH), 45.0
(CHCH2OH), 35.0 (CH2CH2OH), 28.4 (NCO2C(CH3)3); m/z
(CI, NH3) 322 (M ϩ Hϩ, 100%), 283 (8), 266 (76), 222 (28),
191 (40) (Found: M ϩ Hϩ, 322.2018. C18H27NO4 requires for
M ϩ Hϩ, 322.2018).
To a solution of the diol (25 mg, 0.08 mmol) in a mixture of
J. Chem. Soc., Perkin Trans. 1, 1999, 2905–2910
2909

View Article Online
carbon tetrachloride (250 µl), acetonitrile (250 µl) and water
(400 µl) was added sodium periodate (100 mg, 0.47 mmol) and
ruthenium trichloride monohydrate (catalytic amount) and the
reaction stirred for 24 h. The aqueous phase was separated and
extracted with dichloromethane (×3), ethyl acetate (×3) and
acidified to pH 3 using 3 M aqueous HCl before re-extraction
using ethyl acetate. The combined organic extracts were dried
(magnesium sulfate) and concentrated in vacuo to give the crude
acid as an oil; δH (270 MHz, CDCl3) 8.00 (2H, br s, 2 × CO2H),
7.39–7.22 (5H, m, aromatics), 4.05–3.85 (2H, m, CHCO2H,
NCHAHB), 3.53 (1H, m, NCHAHB), 3.10–2.92 (2H, m, PhCH,
CHCH2CO2H), 2.54–2.31 (2H, m, CH2CO2H), 1.25 (9H, s
NCO2C(CH3)3).
gum; δH (270 MHz, CDCl3) 7.44–7.30 (5H, m, aromatics), 4.52
(1H, d, J = 10, CHCO2), 3.75 (1H, app. t, J = 6, NCHAHB), 3.56
(1H, m, NCHAHB), 3.47 (1H, app. d, J = 10, PhCH), 2.83 (1H,
m, CHCH2CO2), 2.66 (1H, dd, J = 17, 5, CHAHBCO2), 2.57
(1H, dd, J = 17, 6, CHAHBCO2); δC (125 MHz, CD3OD) 172.9
(CO ), 170.4 (CO ), 137.3 (C᎐CH), 130.3, 129.4, 129.1 (CH᎐C),
᎐
᎐
2
2
64.0 (CHCO2), 52.1, 50.6 (PhCH, NCH2), 47.3 (CHCH2CO2),
34.9 (CH2CO2); m/z (FAB) 284 (M ϩ 2NH3ϩ, 22%), 267
(M ϩ NH3ϩ, 100), 253 (6), 221 (67), 158 (20), 140 (22), 118 (15),
104 (12), 91 (20).
Acknowledgements
The crude acid was dissolved in diethyl ether (2 cm3) at 0 ЊC
and treated with a solution of diazomethane in diethyl ether
(generated from Diazald). After 1 h, glacial ethanoic acid was
added to quench the excess diazomethane and concentration
gave crude product, purified by column chromatography
(dichloromethane–ethyl acetate, 10:1) to give the diester as a
colourless oil (13 mg, 44% from the diol); Rf 0.6 (dichloro-
We thank Parke-Davis Neuroscience and The University of
York for a research studentship (to J. M. L.). We would also
like to thank Dr T. A. Dransfield, Miss H. Fish and Mrs B.
Chamberlain for expert assistance with MS and NMR studies.
References
1 A. F. Parsons, Tetrahedron, 1996, 52, 4149.
methane–ethyl acetate, 10:1); [α]D20 Ϫ22.6 (c 0.1, CHCl3); νmax
/
cmϪ1 (CHCl3) 2979 (m), 1739 (s), 1691 (s), 1407 (w), 1367 (w),
1232 (w), 1167 (s), 775 (s), 748 (s); δH (270 MHz, CDCl3) (mix-
ture of conformers) 7.39–7.23 (5H, m, aromatics), 4.07 (1H, m,
CHCO2), 3.95 (1H, m, NCHAHB), 3.78 and 3.76 (3H, 2 × s,
CO2CH3), 3.52 (1H, app. t, J = 12, NCHAHB), 3.45 and 3.42
(3H, 2 × s, CO2CH3), 3.05 (1H, m, PhCH), 2.71 (1H, m,
CHCH2CO2), 2.45 (2H, app. d, J = 10, CH2CO2), 1.46 and 1.42
2 (a) J. E. Baldwin, A. M. Fryer, M. R. Spyvee, R. C. Whitehead and
M. E. Wood, Tetrahedron, 1997, 53, 5273; (b) J. E. Baldwin, S. J.
Bamford, A. M. Fryer, M. P. Rudolf and M. E. Wood, Tetrahedron,
1997, 53, 5255.
3 J. S. Bryans, J. M. Large and A. F. Parsons, preceding paper.
4 (a) A. F. Parsons and R. J. K. Taylor, J. Chem. Soc., Chem.
Commun., 1993, 1224; (b) A. F. Parsons and R. J. K. Taylor,
J. Chem. Soc., Perkin Trans. 1, 1994, 1945.
5 A. L. J. Beckwith and T. Lawrence, J. Chem. Soc., Perkin Trans. 2,
1979, 1535.
6 D. P. Curran and W. Shen, J. Am. Chem. Soc., 1993, 115, 6051.
7 C. Walling and A. Cioffari, J. Am. Chem. Soc., 1972, 94, 6064.
8 A. L. J. Beckwith and G. Moad, J. Chem. Soc., Perkin Trans. 2, 1980,
1083.
9 (a) J. Ezquerra, C. Pedregal, A. Rubio, B. Yruretagoyena, A.
Escribano and F. Sánchez-Ferrando, Tetrahedron, 1993, 49, 8665;
(b) J. Ezquerra, C. Pedregal, B. Yruretagoyena, A. Rubio, M. C.
Carreño, A. Escribano and J. L. García Ruano, J. Org. Chem., 1995,
60, 2925.
10 K. C. Nicolaou, K. Koide and M. E. Bunnage, Chem. Eur. J., 1995,
1, 454.
(9H, 2 × s, NCO2C(CH3)3); δC (67.5 MHz, CDCl3) 172.8, 172.6
t
(2 × CO CH ), 153.2 (NCO Bu), 137.5, 137.4 (C᎐CH), 128.8,
᎐
2
3
2
128.0, 127.7 (CH᎐C), 80.4, 80.3 (NCO CMe ), 64.6, 64.2
᎐
2
3
(NCHCO2Me), 53.7, 53.0 (NCH2), 52.3, 52.1, 51.6 (2 ×
CO2CH3), 50.1, 49.3, 47.5, 46.8 (PhCH, CHCH2CO2), 35.6,
35.3 (CH2CO2), 28.4, 28.3 (NCO2C(CH3)3); m/z (CI, NH3) 378
(M ϩ Hϩ, 9%), 322 (25), 278 (100), 218 (20) (Found: M ϩ Hϩ,
378.1912. C26H27NO6 requires for M ϩ Hϩ, 378.1917).
A solution of the diester (10 mg, 0.026 mmol) in 6 M HCl (5
cm3) containing anisole (catalytic amount) was heated at 70 ЊC
for 5 h. Water (5 cm3) was added and the aqueous solution was
washed with ethyl acetate (×3). The aqueous phase was then
concentrated and the product was triturated with diethyl ether
to give the hydrochloride salt 25 (7 mg, 93%) as an off-white
Paper 9/05809E
2910
J. Chem. Soc., Perkin Trans. 1, 1999, 2905–2910