Acetogenins of annonaceae. Part 86: Synthesis of a highly functionalized precursor of (-)-4-deoxygigantecin, an annonaceous acetogenin

Article abstract of DOI:10.1039/b000236o

A highly functionalized precursor of (-)-4-deoxygigantecin possessing six stereogenic centers has been prepared in 14 steps from tridecanal. The key steps are (i) enantioselective aldolization, (ii) diastereoselective C- glycosylation and (iii) diastereoselective aldolization reactions, all of them using 2-trimethylsilyloxyfuran as nucleophile. This strategy would allow us to prepare squamostatin D as well, another acetogenin of Annonaceae possessing two nonadjacent tetrahydrofuran rings and a closely related tetrahydrofuran pattern.

Full text of DOI:10.1039/b000236o

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Acetogenins of annonaceae. Part 86:¤ synthesis of a highly
functionalized precursor of (Ô)-4-deoxygigantecin, an annonaceous
acetogenin
Magali Szlosek, Jean-Francois Peyrat, Christophe Chaboche, Xavier Franck, Reynald
Hocquemiller and Bruno Figadere*
L aboratoire de Pharmacognosie [CNRS UPRES-A (BIOCIS)], Universite de Paris-Sud,
Faculte de Pharmacie, 5 rue Jean-Baptiste Clement, F-92296 Chatenay-Malabry, France.
E-mail: Bruno.Figadere=cep.u-psud.fr; Fax: ]33 1 46 83 53 99
Received (in Freiburg, Germany) 10th January 2000, Accepted 22nd February 2000
Published on the Web 12th April 2000
A highly functionalized precursor of ([)-4-deoxygigantecin possessing six stereogenic centers has been prepared in
14 steps from tridecanal. The key steps are (i) enantioselective aldolization, (ii) diastereoselective C-glycosylation
and (iii) diastereoselective aldolization reactions, all of them using 2-trimethylsilyloxyfuran as nucleophile. This
strategy would allow us to prepare squamostatin D as well, another acetogenin of Annonaceae possessing two
nonadjacent tetrahydrofuran rings and a closely related tetrahydrofuran pattern.
Since the Ðrst isolation of uvaricin in 1982,2 more than 300
new natural acetogenins of Annonaceae have been isolated
from either the bark, leaves, or seeds of 30 di†erent Annona-
ceae species,3a,b,4a and exclusively from this botanical family.
They all are supposed to derive from lacceroic (C32) or
ghedoic acids (C34), further substituted by oxygenated func-
tions [e.g., tetrahydrofuran(s), tetrahydropyran, hydroxy(s),
epoxide(s), etc.] and possessing at one terminus a c-methyl-c-
lactone. A tentative classiÐcation has been proposed,5 based
on biogenetic hypotheses, and recent isolation of the *n, n`4
and the *n, n`4, n`8 di- and tri-unsaturated compounds6 (type
E acetogenins) has conÐrmed the biogenetic hypothesis. Tetra-
hydropyran (THP) containing acetogenins were also isolated.7
Insecticide, antiparasitic and immunosuppressive activities
have been reported for some acetogenins,3 but most acetoge-
nins have displayed cytotoxicity against several cancer cells,8
and some of them have shown in vivo antitumor activity.3 The
antitumor and cytotoxic activities have been rationalized as
involving the inhibition of NADH oxidases both at the mito-
chondrial level4b and on the cytoplasmic membranes of cancer
cells,9 resulting in decreased biosynthesis of ATP and conse-
quently cell proliferation, which may ultimately contribute to
programmed death (apoptosis).10 Interestingly, growth inhibi-
tion was also observed for the cancer cells expressing a multi-
drug resistant (MDR) phenotype.3a,b,11,12 Because this
mechanism of action has no equivalent, to our knowledge,
among the anticancer chemotherapeutic agents currently in
use, we have decided to synthesize natural acetogenins of
Annonaceae and related analogs, and report herein our results
concerning the preparation of a precursor of ([)-4-deoxy-
gigantecin, 1a,b.
bis-THF annonaceous acetogenins, (])-4-deoxygigantecin
and (])-squamostatin D, have been recently described in the
literature.18,19 Our retrosynthetic approach is based on the
repeated use of 2-trimethylsilyloxyfuran as a four-carbon-
atom building block, for chain elongation together with
control of the absolute and relative conÐgurations at the
newly created chiral centers (Scheme 1).
The Ðrst step consists in the autoinductive enantioselective
aldolization reaction between 2-TMSOF and tridecanal20 to
a†ord 2,3-dehydromuricatacin, 2, in 80% yield as a 60 : 40
diastereomeric mixture in favor of the desired threo derivative
with [96% e.e. (S,S) (Scheme 2). The absolute conÐguration
of the major product was deduced from comparison of the
speciÐc rotation of the hydrogenated product 3 with reported
values.21 The best result, in terms of chemical yield and e.e.,
was obtained when 2-TMSOF and tridecanal were added in
four portions (6.5, 18.5, 25 and 50 mol%, with 30, 60 and 90
min delays, respectively, and further stirring for 180 min at
[20 ¡C in Et O).20c Natural muricatacin 3 was then obtained
2
after separation and quantitative hydrogenation of 2 over pal-
ladium on charcoal. The large scale preparation of 3 from
L-glutamic acid,21 in 4 steps and 50% overall yield, further
conÐrmed the relative and absolute conÐgurations of 3
obtained through the aldolization procedure.
Protection of the hydroxy group of 3 was then carried out
by treatment with TBDMSCl in the presence of imidazole in
DMF with a catalytic amount of DMAP to a†ord the desired
silyl ether 4 in 98% yield. Reduction of 4 at [78 ¡C by
DIBAL-H in toluene yielded the corresponding lactol 5,
which was treated with acetic anhydride in the presence of
triethylamine to a†ord the anomeric acetates 6 in 95% yield.
Then, addition at 0 ¡C of 2-TMSOF to an etheral solution of
the acetates 6 in the presence of a catalytic amount of TrClO
4
led to a 60 : 40 mixture of the sole erythro-trans-threo and
Results and discussion
threo-trans-threo butenolides 7 and 8, respectively, in 90%
overall yield.22 Interestingly, none of the cis isomers were iso-
lated. Separation of both compounds was performed by
column chromatography and the major undesired isomer was
Several total syntheses13 of mono-THF,14 adjacent bis-THF,15
tris-THF16 and THF-THP17 annonaceous acetogenins have
been reported, whereas only two syntheses of nonadjacent
then treated by Et N at 54 ¡C for 12 h to give in quantitative
3
yield a 60 : 40 mixture of 7 and 8. Separation of both com-
¤ For Part 85, see ref. 1.
pounds allowed us to obtain the desired threo compound 8 in
DOI: 10.1039/b000236o
New J. Chem., 2000, 24, 337È342
337
This journal is ( The Royal Society of Chemistry and the Centre National de la Recherche ScientiÐque 2000

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Scheme 1 Retrosynthetic scheme for the ([)-4-deoxygigantecin precursors
58% overall yield (a second epimerization of the undesired
epimer could eventually further increase the total yield of 8).
8 was then quantitatively reduced by hydrogenation over
palladium on charcoal to give the corresponding butanolide 9.
LiOH treatment of the latter in DME, followed by diazo-
tation (CH N , Et O, 0 ¡C) and protection of the hydroxyl as
Separation of both diastereomers is expected to be accom-
plished in a later stage of the synthesis, based on our know-
ledge of natural acetogenin isolation processes (e.g., by HPLC
and CPC methods).1,3,6 Furthermore, completion of the syn-
thesis with the undesired isomer would allow us to prepare an
unnatural acetogenin, whose biological activity will be evalu-
ated and compared with the natural one. Thus, in order to
gain some information on the structure-cytotoxicity relation-
ship, several intermediates were tested against two cell lines23
and the results are reported in Table 1.
Interestingly, compounds 3 and 9º (obtained from 9 after
TBAF deprotection of the hydroxy group) showed similar
activity against cancer cells (KB) in the lM range, whereas 3
is much less active against normal cells. Moreover, compound
2 showed lower activity against cancer cells, compared to the
known natural muricatacin 3. For comparison, natural (])-4-
deoxygigantecin shows a cytotoxicity against three di†erent
cancer cell lines24 in the range of 0.04 to 8.6 lM, indicating
that our intermediates exhibit a biological activity closely
related to the natural acetogenins, even though they do not
possess the terminal a,b-unsaturated c-methyl-c-lactone.
In conclusion, we have succeeded in the synthesis, from tri-
decanal, of a highly functionalized precursor of ([)-4-deoxy-
gigantecin, as a 1 : 1 bis-epimeric mixture, in 14 steps and
1.4% overall yield (and thus 78% yield per step). 2-TMSOF
was used in enantioselective and diastereoselective reactions
to demonstrate the versatility this reagent. Further C-
glycosylation and introduction of the unsaturated butyrolac-
tone through known procedures25 should lead to the target
molecule in a limited number of chemical steps. The biological
activity of some of our intermediates may positively contrib-
ute to the study of the structure-activity relationship in the
acetogenins of Annonaceae.
2
2
2
a silyl ether (TBDMSCl, imidazole and catalytic DMAP in
DMF) a†orded the corresponding ester 10 in 42% yield for
the last three steps. 10 was reduced by Dibal-H in dichloro-
methane to the primary alcohol, which was oxidized into the
corresponding aldehyde 11 by PDC treatment in the presence
of a catalytic amount of PTA in 78% overall yield for the last
two steps. An aldolization reaction between 2-TMSOF and
the aldehyde 11 was best performed by treatment at [78 ¡C
in CH Cl with BF OEt to a†ord an unseparable mixture of
2
2
3
2
two diastereomers, 1a and 1b, among the four possible ones.
The stereochemical relationships were determined as threo for
both compounds, from comparison with NMR data for
related products. It is worth noting that the use of TiCl as
4
Lewis acid a†orded a more complicated mixture, whereas no
reaction occured in the presence of the (R)-Binol ÈTi(OPri)
2
4
complex.
Table 1 Cytotoxic activity of various compounds
Compound
KBa EC b/lM
VEROc EC b/lM
50
50
2
24.8
17.6
14.1
1.3
28.3
38.7
19.8
3
9º
Taxold
Vinblastined
\11.9
1.2 ] 10~3
\3.7
a Human epidermoid carcinoma. b When EC values were not preci-
50
sely determined, results are expressed as the limits of the range tested.
c African green monkey (Cercopithecus aethiops) kidney epithelial
cells. d Although the modes of action are di†erent, taxol and vinblas-
tine were tested for comparison.
Experimental
Solvents were puriÐed according to the procedures previously
338
New J. Chem., 2000, 24, 337È342

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Scheme 2 Synthesis of the ([)-4-deoxygigantecin precursors 1a,b
described.26 Infrared spectra were recorded on a PerkinÈ
Elmer 257 apparatus (l expressed in cm~1). 1H and 13C NMR
spectra were recorded with Bruker AC-200 (200 MHz) and
Bruker AM-400 (400 MHz) spectrometers. Chemical shifts (d)
are referenced to the protonated solvent. Patterns are
described according to Hoye et al.27 and coupling constants
(J) are given in Hz. Mass spectra (MS) have been recorded on
a NermagÈSidar R10-10C apparatus in either CI mode with
CH or NH or EI mode at 70 eV. Electrospray ionization
(ESI) mass spectra were recorded on a Bruker Esquire
spectrometer. Flash chromatography was performed with
silica gel 60 (9385 Merck), silica gel S (31607 Riedel-de-Haen),
and silica gel 60H (7736 Merck). TLC was performed on
last addition of aldehyde (50 mol%, 0.25 mmol) and TMSOF
(50 mol%, 0.375 mmol) was made. After stirring an additional
180 min, the reaction was hydrolyzed by addition of a saturat-
ed aqueous NH Cl solution and the organic layer extracted
4
by EtOAc (3]). The combined organic layers were washed
with brine, dried over MgSO , Ðltered then concentrated.
4
Flash column chromatography on silica gel (cyclohexaneÈ
EtOAc 70 : 30) led to 113 mg of the two threo and erythro
diastereomers in a 60 : 40 ratio (80% yield). IR (CHCl ) l:
4
3
3
3905È3510, 1730 cm~1. CI-MS (CH ) m/z: 283 (MH~`, 100%),
4
265 (27%), 199 (21%). 1H NMR (400 MHz, CDCl ) d: 7.54
3
(1H, dd, J \ 5.8, J \ 1.5, H erythro), 7.45 (1H, dd, J \ 5.8,
4
J \ 1.5, H threo), 6.15 (1H, m, H ), 4.99 (1H, m, H threo),
4
3
5
plates coated with silica gel 60F
(554 Merck).
4.97 (1H, m, H erythro), 4.50 (1H, m, OH), 3.85 (1H, m, H
254
5
1{
erythro), 3.75 (1H, m, H threo), 1.55 (2H, m, H ), 1.25 (20H,
1{
2{
Synthesis and characterization
m, CH ), 0.87, (3H, t, J \ 6.5, H ). 13C NMR (50 MHz,
13{
2
CDCl ) d: 172.97 (C ), 153.85 (threo), 153.56 (erythro), 122.76
3
2
(1ºS,5S)-5-(1º-Hydroxydodecanyl)furan-2-(5H)-one, (2). To
(erythro), 122.62 (threo) 86.16 (C ), 71.73 (threo), 71.48
5
a solution of (R)-Binol (57 mg, 0.2 mmol) in Et O (2 mL),
(erythro), 33.19, 31.87, 29.59, 29.30, 25.46, 22.64, 14.06 (C ).
2
13{
under N atmosphere was added at room temperature
Anal. C
H
O : calcd C 67.89, H 9.49%; found C 68.01, H
2
17 30
3
Ti(OPri) (29.5 ll, 0.1 mmol), leading to an intense orange-
colored solution. After stirring for 1 h at room temperature,
9.54%. Analysis of the major (threo) diastereomer by 1H
NMR in the presence of the chiral shift reagent, europium
tris[3-(heptaÑuoropropylhydroxymethylene)-(])-camphorate]
4
the solution was cooled to [20 ¡C and the Ðrst addition of
aldehyde (6.5 mol%, 0.0325 mmol), followed by TMSOF (6.5
mol%, 0.048 75 mmol) was made. After 30 min, the second
addition of aldehyde (18.5 mol%, 0.0925 mmol) and TMSOF
(18.5 mol%, 0.138 mmol) was made. Then again after 60 min,
the third addition of aldehyde (25 mol%, 0.125 mmol) and
TMSOF (25 mol%, 0.1875 mmol) was made. After 90 min, the
(Eu(hfc) ), showed [96% e.e. and 90% for the erythro isomer.
3
(4S,5S)-5-Hydroxyheptadecan-4-olide
[(+ )-muricatacin],
(3). Palladium on charcoal (6.5 mg) was added to a solution of
2 (65 mg, 0.23 mmol) in 2 mL of toluene. The solution was
then vigorously stirred under H atmosphere for 10 h. The
2
New J. Chem., 2000, 24, 337È342
339

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crude reaction mixture was then passed through a short pad
of celite, the solvents evaporated and the crude puriÐed by
Ñash chromatography on silica gel (cyclohexaneÈAcOEt
13C NMR (50 MHz, CDCl ) d: 98.8 (C ), 98.3 (C ), 80.7
3
1a
1b
(C ), 74.7 (C ), 74.2 (C ), 34.9, 34.3, 33.2, 32.7, 31.9, 29.8, 29.6,
4
5a
5b
29.3, 25.9 (But), 25.5, 24.7, 24.1, 22.7, 18.2 (CÈBut), 14.1 (C ),
17
70 : 30) to a†ord 3 (65 mg, 99%). [a] 20: ]24.6 (c \ 1.7,
[4.3 (CH Si), [4.5 (CH Si).
D
3
3
MeOH); lit:21 ]23.6 (c \ 1.50, CHCl ). IR (CHCl ) l: 3580È
3
3
(1SR,4S,5S)-1-Acetoxy-5-tert-butyldimethylsilyloxy-1,4-
epoxy-heptadecane, (6). 5 (4.0 g, 10 mmol) was poured into
anhydrous triethylamine (Et N, 30 mL) under N atmosphere.
3440, 2920, 2840, 1770, 1460, 1375, 1260, 1170, 980, 910 cm~1.
EI-MS m/z: 199 (1%), 125 (4%), 97 (6%), 87 (11%), 86 (100%),
85 (13%), 69 (16%), 57 (13%), 55 (11%), 43 (15%), 41 (17%).
3
2
Then at room temperature acetic anhydride (9.45 mL, 10
equiv.) was added, followed by a catalytic amount of DMAP.
After 12 h of stirring, solvents were evaporated. Flash chroma-
tography (CH Cl ÈEt N 90 : 10) puriÐcation on silica gel led
CI-MS (NH ) m/z: 285 (MH`, 31%), 268 (23%), 267 (100%),
3
265 (18%), 249 (7%), 239 (32%), 199 (25%), 143 (9%), 130
(23%), 125 (36%), 123 (11%), 115 (21%), 113 (26%), 112 (26%),
111 (49%), 109 (16%). 1H NMR (200 MHz, CDCl ) d: 4.41
2
2
3
3
to 6 (4.25 g, 95%). IR (CHCl ) l: 2930, 2845, 1730, 1440, 1360,
(1H, td, J \ 4.6, J \ 7.4, H ), 3.66È3.47 (1H, m, H ), 2.72È2.44
3
4
5
1240, 1120 cm~1. EI-MS m/z: 383 (4%), 326 (22%), 325 (100%),
(2H, m, H ), 2.33È1.88 (3H, m, H , OH), 1.64È1.45 (2H, m,
2
3
117 (70%), 75 (64%), 73 (70%). CI-MS (NH ) m/z: 460, (M~
H ), 1.45È1.15 (20H, br s, CH ), 0.87 (3H, t, J \ 6.4, H ). 13C
17
3
] NH `, 23%), 401 (36%), 400 (MH~` [ acetyl, 100%), 383
4
6
2
NMR (50 MHz, CDCl ) d: 177.4 (C ), 83.0 (C ), 73.5 (C ),
3
1
4
5
17
(35%). 1H NMR (200 MHz, CDCl ) d: 6.39È6.18 (1H, m, H ),
32.9, 31.6, 29.6, 29.5, 29.3, 28.6, 25.4, 24.0, 22.6, 14.0 (C ).
3
1
4.30È4.12 (0.5H, m, H ), 4.08È3.98 (0.5H, m, H ), 3.74È3.51
Anal. C
11.40%.
H
O : calcd C 71.78, H 11.33%; found C 71.64, H
4a
4b
CH acetyl a or b), 1.25 (22H, m, CH ), 1.01È0.74 (12H, m, But
17 32
3
(1H, m, H ), 2.22È1.67 (4H, m, H , H ), 2.05 and 2.01 (3H, 2s,
5
2
3
2
3
and H ), 0.17 [3H, s, (CH ) Si], 0.12 [3H, s, (CH ) Si], 0.07
17 3 2 3 2
[6H, s, (CH ) Si]. 13C NMR (50 MHz, CDCl ) d: 170.4 (CO,
3 2
acetyl), 170.1 (CO, acetyl), 99.3 (C ), 98.5 (C ), 85.0 (C ), 82.3
1a 1b 4a
(C ), 75.2 (C ), 73.8 (C ), 32.9, 32.8, 32.1, 31.9, 29.6, 29.3,
(4S,5S)-5-tert-Butyldimethylsilyloxyheptadecan-4-olide, (4).
3 (0.811 g, 2.85 mmol) was poured into anhydrous DMF (15
3
mL) under N atmophere. Then at room temperature imid-
2
azole (10 equiv., 28.5 mmol, 1.94 g) was added, followed by
4b
5a
5b
25.9 (But), 25.7, 25.2, 24.5, 23.9, 22.6, 21.3 (CH , acetyl), 18.1
(C, But), 14.1 (C ), [4.3 (CH Si), [4.8(CH Si).
TBDMSCl (5 equiv., 14.25 mmol, 2.15 g) and a catalytic
amount of DMAP. The reaction mixture was stirred at 25 ¡C
for 12 h prior to addition of water (30 mL), followed by
organic layer extraction with EtOAc. The combined organic
3
17
3
3
(4R,5S,8S,9S)- and (4S,5S,8S,9S)-9-tert-Butyldimethylsilyl-
oxy-5,8-epoxyhenicos-2-en-4-olide, (7) and (8). 6 (0.509 g, 1.15
mmol) was poured into Et O (10 mL) under N atmosphere.
layers were dried over MgSO , Ðltered and concentrated. The
4
2
2
crude was puriÐed by Ñash chromatography on silica gel
The solution was cooled to 0 ¡C and TrClO (39.4 mg, 0.115
4
(cyclohexaneÈAcOEt 90 : 10) to a†ord 4 (1.11 g, 98%). [a]20:
mmol) was added, followed by 2-trimethylsilyloxyfuran
D
]22.7 (c \ 1.72, MeOH). IR (CHCl ) l: 2920, 2850, 1780,
3
(TMSOF, 0.386 mL, 2 equiv.). After 30 min at 0 ¡C a saturated
1555, 1460, 1250, 1175, 1130 cm~1. EI-MS m/z: 383 (1%), 342
aqueous NaHCO solution (10 mL) was added. After extrac-
3
(20%), 341 (77%), 323 (18%), 313 (42%), 297 (60%), 143 (25%), 75
tion with EtOAc, the combined organic layers were dried over
(84%), 73 (100%), 55 (30%). CI-MS (NH ) m/z: 400 (MH~`,
MgSO , Ðltered and concentrated. PuriÐcation by Ñash chro-
3
4
10%), 399 (22%), 383 (14%), 342 (30%), 341 (100%), 297
matography on silica gel (cyclohexaneÈAcOEt 85 : 15) a†ord-
(68%), 267 (18%), 143 (37%). 1H NMR (200 MHz, CDCl ) d:
ed 7 (285 mg) and 8 (189 mg) (90% overall yield, erythro (7):
3
4.47 (1H, ddd, J \ 13.9, J \ 4.4, J \ 1.3, H ), 3.77È3.59 (1H,
4
threo (8) \ 60 : 40).
m, H ), 2.68È2.26 (2H, m, H ), 2.25È1.97 (2H, m, H ), 1.69È
7: [a]20: ]22 (c \ 0.3, MeOH). IR (CHCl ) l: 2930, 2855,
5
2
3
D
3
1.50 (2H, m, H ), 1.49È1.12 (20H, br s, CH ), 1.00È0.53 (12H,
1755, 1380, 1255, 1185 cm~1. EI-MS m/z: 466 (M~`, 2%), 422
6
2
m, But and H ), 0.08 and 0.07 [6H, 2s, (CH ) Si)]. 13C NMR
17 3 2
(50 MHz, CDCl ) d: 177.2 (C ), 81.4 (C ), 74.2 (C ), 32.6, 31.8,
(5%), 409 (65%), 383 (50%), 313(100%), 269 (10%), 153 (90%),
115 (50%), 83 (30%). 1H NMR (200 MHz, CDCl ) d: 7.58 (1H,
3
1
4
5
3
29.6, 29.3, 28.5, 25.7 (But), 25.2, 23.6, 22.6 (C or C ), 18.0 (CÈ
dd, J\5.60, J\1.35, H ), 6.15 (1H, dd, J\5.60, J\1.80, H ),
2
3
3
2
But), 14.0 (C ), [4.5 (CH Si).
4.85 (1H, dt, J \ 7.0, J \ 1.75, H ), 3.95 (1H, m, H ), 3.88 (1H,
17
3
4
8
m, H ), 3.53 (1H, m, H ), 2.20È1.60 (6H, m, H , H , H ), 1.32
10
(20H, br s, CH ), 0.80 (12H, br s, ButSi, H ), 0.05 and 0.04
21
[6H, 2s, (CH ) Si]. 13C NMR (50 MHz, CDCl ) d: 177.83
3 2
(C ), 155.00 (C ), 122.10 (C ), 85.20 (C ), 83.12 (C ), 79.32 (C ),
5
9
6
7
(1SR,4S,5S)-1-Hydroxy-5-tert-butyldimethylsilyloxy-1,4-
epoxyheptadecane, (5). 4 (obtained from L-glutamic acid
through the procedure described in ref. 21) (4.65 g, 11.65
mmol) was poured into CH Cl (20 mL) under N atmo-
2
3
1
3
2
4
8
5
75.00 (C ), 33.24, 32.00, 29.80, 29.60, 29.33, 29.19, 27.46, 25.92,
2
2
2
9
sphere. At [78 ¡C Dibal-H (1 M in toluene, 12.8 mL, 1.1
25.41, 22.67, 18.23 (CÈBut), 14.11 (C ), [4.20 (CH Si), [4.57
21
3
equiv.) was then added dropwise. Stirring was maintained for
(CH Si).
3
40 min, then saturated aqueous NH Cl solution (3 mL) was
8: [a]20: ]14 (c \ 0.5, MeOH). IR (CHCl ) l: 2930, 2855,
4
D
3
added and the solution was allowed to reach room tem-
1760, 1465, 1380, 1255, 1185 cm~1. EI-MS m/z: 466 (M~`,
5%), 422 (10%), 409 (30%), 383 (20%), 313 (60%), 269 (40%),
243 (50%), 153(100%), 115 (60%), 83 (20%). 1H NMR (200
MHz, CDCl ) d: 7.39 (1H, dd, J \ 5.7, J \ 1.5, H ), 6.15 (1H,
perature. The solution was Ðltered on silica gel and the solid
washed with EtOAc. The combined organic layers were dried
over MgSO , Ðltered and concentrated. Flash chromatog-
4
3
3
raphy (cyclohexaneÈAcOEt 90 : 10) puriÐcation of the crude
dd, J \ 5.0, J \ 2.0, H ), 5.05 (1H, dt, J \ 4.0, J \ 6.8, H ),
2
4
8
material a†orded 5 (4.40 g, 95%). IR (CHCl ) l: 3600È3100,
4.23 (1H, ddd, J \ 4, J \ 6.8, J \ 7, H ), 3.88 (1H, m, H ),
3
5
2920, 2930, 2840, 1460, 1255, 1245, 1190 cm~1. EI-MS m/z: 367
3.52 (1H, m, H ), 2.20È1.58 (6H, m, H , H , H ), 1.25 (20H,
10
br s, CH ), 1.00È0.75 (12H, br s, ButSi, H ), 0.03 [6H, s,
21
(CH ) Si]. 13C NMR (50 MHz, CDCl ) d: 173.50 (C ), 153.56
3 2
(C ), 122.61 (C ), 84.72 (C ), 83.26 (C ), 77.50 (C ), 74.79 (C ),
9
6
7
(2%), 343 (9%), 326 (14%), 325 (52%), 313 (52%), 115 (27%),
2
75 (92%), 73 (100%). CI-MS (NH ) m/z: 399 (1%), 384 (21%),
3
3
8
1
383 (M~` [ H O, 50%), 381 (11%), 367 (9%), 343 (36%), 326
2
3
2
4
5
9
(22%), 325 (83%), 314 (18%), 313 (62%), 299 (10%), 251 (15%),
32.98, 31.85, 29.75, 29.57, 29.28, 27.71, 27.33, 25.88, 25.48,
233 (11%), 171 (59%), 145 (32%), 131 (100%), 121 (31%), 115
22.61, 18.19 (CÈBut), 14.05 (C ), [4.30 (CH Si), [4.63
21
3
(48%). 1H NMR (200 MHz, CDCl ) d: 5.60È5.48 (0.5H, m,
(CH Si).
3
3
H ), 5.38 (0.5H, dd, J \ 10.0, J \ 3.5, H ), 4.22 (1H, m, H ),
1a
1b
4
3.96 (0.5H, d, J \ 10.0, OH), 3.53 (1H, m, H ), 2.65 (0.5H, m,
OH), 2.12È1.60 (6H, m, H , H , H ), 1.58È1.01 (20H, m, CH ),
0.98È0.78 (12H, m, But and H ), 0.12 [0.5 É 6H, s, (CH ) Si cis
or trans], 0.06 and 0.05 [0.5 É 6H, 2s, (CH ) Si cis or trans].
(4S,5S,8S,9S)-9-tert-Butyldimethylsilyloxy-5,8-epoxy-
5
henicosan-4-olide, (9). (obtained from several previous
8
2
3
17
6
2
experiments) (1 g, 2.15 mmol) was poured into EtOAc (15
mL). Palladium on charcoal (0.1 g) was then added and the
3 2
3 2
340
New J. Chem., 2000, 24, 337È342

View Article Online
reaction mixture was stirred 18 h under a hydrogen atmo-
sphere at room temperature. The solution was then Ðltered on
celite and the solid washed with EtOAc. The combined
H , H ), 2.40 (2H, m, AB system, H ), 1.90È1.56 (8H, m, H ,
4
9
1
3
H , H , H ), 1.24 (20H, br s, CH ), 0.86 (21H, br s, 2 ButSi,
6
7
10
2
H
), 0.05 and 0.03 [12H, 2s, (CH ) Si]. 13C NMR (50 MHz,
21
3 2
organic layers were dried over MgSO , Ðltered and concen-
CDCl ) d: 174.25 (C ), 81.80 (C , C ), 74.61 (C ), 73.76 (C ),
51.42 (Me), 32.74, 31.92, 30.35, 29.83, 29.61, 29.35, 27.83, 27.35,
27.16, 26.76, 25.92, 23.45, 23.21, 22.68, 22.34, 21.94, 21.09,
4
3
1
8
5
9
4
trated to a†ord the corresponding butanolide 9 (1 g, 99%).
[a]20: ]20 (c \ 0.5, MeOH). IR (CHCl ) l: 2930, 2855, 1785,
D
3
1465, 1360, 1175, 1110 cm~1. EI-MS m/z: 468 (M~`, 5%), 410
20.83, 19.77, 18.15 (CÈBut), 14.10 (C ), 7.39, 1.00, [3.95
21
(70%), 383 (20%), 313 (100%), 243 (90%), 155 (40%), 115
(CH Si), [4.31 (CH Si), [4.52 (CH Si), [4.73 (CH Si).
3
3
3
3
(70%), 85 (80%). 1H NMR (200 MHz, CDCl ) d: 4.45 (1H,
3
ddd, J \ 7.40, J \ 5.85, J \ 2.50, H ), 4.04 (1H, ddd, J \ 10.0,
4
(4S,5S,8S,9S)-4,9-Di-tert-butyldimethylsilyloxy-5,8-epoxy-
henicosanal, (11). 10 (0.043 g, 0.068 mmol) was poured into
CH Cl , under N atmosphere. The temperature was brought
J \ 7.40, J \ 2.50, H ), 3.95 (1H, m, H ), 3.52 (1H, dt, J \ 5.0,
5
8
J \ 2.50, H ), 2.70È2.41 (2H, m, H ), 2.20 (2H, m, H ), 1.95
9
2
3
(2H, m, H ), 1.66 (2H, m, H ), 1.25 (22H, br s, CH ), 0.88 (12H,
2
2
2
to [40 ¡C and Dibal-H (1 M in toluene, 0.4 mL, 0.4 mmol)
7
6
2
br s, ButSi, H ), 0.05 [6H, s, (CH ) Si]. 13C NMR (50 MHz,
was added. After 1 h of stirring at room temperature, an
21 3 2
CDCl ) d: 177.47 (C ), 82.76 (C ), 81.25 (C ), 80.58 (C ), 74.81
aqueous NH Cl solution was added to form a gel. The reac-
3
1
8
4
5
(C ), 33.25, 31.85, 29.83, 29.60, 29.57, 29.53, 29.50, 29.27, 28.11,
4
tion mixture was Ðltered over a short pad of silica gel and the
9
27.87, 27.63, 25.88, 24.52, 22.60, 18.13 (CÈBut), 14.02 (C ),
[4.36 (CH Si), [4.60 (CH Si).
solid washed with a cyclohexaneÈEtOAc (90 : 10) mixture. The
21
combined organic layers were then dried over MgSO , Ðltered
3
3
4
and concentrated to a†ord the expected primary alcohol
(4S,5S,8S,9S)-9-Hydroxy-5,8-epoxyhenicosan-4-olide, (9º). 9
(0.035 g, 88%). [a]20: [11.5 (c \ 1.04, CHCl ). IR (CHCl ) l:
D
3
3
(0.05 g, 0.106 mmol) was poured into anhydrous THF (3 mL)
3685È3130, 2935, 2860, 1715, 1645, 1460, 1360, 1255 cm~1.
under N atmosphere. After the temperature was brought to
CI-MS (CH ) m/z: 587 (MH~`, 100%), 571 (51%), 529 (M~`
2
4
0 ¡C, 0.21 mL of 1 M tetrabutylammoniun Ñuoride solution
[ But, 71%), 397 (74%), 323 (65%), 133 (20%), 115 (31%), 97
was added and the mixture stirred for 2 h. Then water (5 mL)
(35%). 1H NMR (200 MHz, CDCl ) d: 3.97 (2H, m, H , H ),
3
5
8
was added and the solution extracted with EtOAc (3 ] 10
3.65 (4H, m, H , H , H ), 1.77È1.54 (10H, m, H , H , H , H ,
1
4
9
2
3
6
7
mL). The combined organic layers were dried over MgSO ,
H
), 1.27 (20H, br s, CH ), 0.89 (21H, br s, 2 ButSi, H ), 0.08
21
and 0.06 [12H, 2s, (CH ) Si]. 13C NMR (50 MHz, CDCl ) d:
3 2
81.79 (C , C ), 74.67 (C , C ) 63.12 (C ), 32.70, 31.92, 29.85,
4
10
2
Ðltered, concentrated and puriÐed by Ñash chromatography
3
(cyclohexaneÈEtOAc 50 : 50) to a†ord 9º (32 mg, 86%). [a]20:
D
8
5
9
4
1
]8.3 (c \ 1.33, CHCl ). IR (CHCl ) l: 3700È3500, 2930, 2855,
29.64, 29.34, 29.07, 27.36, 27.24, 25.94, 25.70, 22.67, 20.97, 18.17
3
3
1775, 1180, 1075 cm~1. CI-MS (NH ) m/z: 372 (M~ ] NH `,
(CÈBut), 14.09 (C ), 7.56, 0.98, [3.06 (CH Si), [4.42 (CH Si),
3
4
21
3
3
100%), 337 (15%), 269 (16%), 174 (16%), 138 (44%), 130
(25%), 111 (18%). EI-MS m/z: 269 (20%), 155 (54%), 138
(100%), 111 (55%), 97 (24%), 83 (34%). 1H NMR (200 MHz,
CDCl ) d: 4.47 (1H, ddd, J \ 8.0, J \ 5.0, J \ 3.0, H ), 4.05
[4.69 (CH Si).
3
The thus-obtained alcohol (0.035 g, 0.059 mmol) was
poured into CH Cl and pyridinium dichromate (PDC) (0.102
2
2
g, 0.273 mmol) was added at room temperature, followed by a
catalytic amount of pyridinium triÑuoroacetate (PTA). After 3
h of stirring the reaction mixture was directly Ðltered through
a short pad of silica gel and the solid washed with a
cyclohexaneÈEtOAc (90 : 10) mixture. The combined organic
3
4
(1H, dt, J \ 7.5, J \ 3.0, H ), 3.84 (1H, dt, J \ 7.5, J \ 5.5,
H ), 3.39 (1H, m, H ), 2.65 (2H, m, H ), 2.45È2.30 (3H, br m,
5
8
3
9
2
H
and OH), 2.25È2.00 (2H, m, H ), 1.72È1.60 (2H, m, H ),
7
6
1.25 (22H, br s, CH ), 0.86 (3H, t, J \ 6.8, H ). 13C NMR (50
2
21
MHz, CDCl ) d: 177.35 (C ), 83.50 (C ), 81.20 (C ), 80.77 (C ),
layers were dried over MgSO , Ðltered and concentrated to
3
1
8
4
5
4
73.64 (C ), 33.77, 31.90, 29.33, 28.17, 25.58, 24.65, 22.67, 14.10.
a†ord 11 (0.034 g, 97%). [a]20: [11 (c \ 1.46, CHCl ). IR
9
D
3
(CHCl ) l: 3675È3370, 2960, 2930, 2855, 2735, 1720, 1605, 1460,
3
1360, 1255, 1210 cm~1. CI-MS (CH ) m/z: 585 (MH~`, 66%),
(4S,5S,8S,9S)-Methyl-4,9-di-tert-butyldimethylsilyloxy-5,8-
epoxyhenicosanoate, (10). 9 (0.090 g, 0.191 mmol) was poured
into dimethoxyethane (DME, 1.5 mL) and an aqueous LiOH
solution (1 M, 0.96 mL, 0.96 mmol) was added at room
temperature. After 35 min of stirring a 10% molar aqueous
citric acid solution was added and organic layer extracted
with EtOAc. The combined organic layers were dried over
4
570 (63%), 527 (M~` [ But, 100%), 453 (79%), 383 (21%), 313
(59%), 285 (14%), 255 (4%), 201 (12%), 171 (12%), 149 (10%),
133 (36%), 115 (59%), 97 (25%). 1H NMR (200 MHz, CDCl )
3
d: 9.78 (1H, br s, H ), 3.95 (2H, m, H , H ), 3.73È3.50 (3H, m,
1
5
8
H
, H , H ), 2.50 (1H, m, H ), 1.99È1.53 (8H, m, H , H ,
2a
7
4
9
2b
3
6
21
H , H ), 1.25 (20H, br s, CH ), 0.90 (21H, br s, 2 ButSi, H ),
10
2
0.06 and 0.05 [12H, 2s, (CH ) Si]. 13C NMR (50 MHz,
MgSO , Ðltered and concentrated. The crude residue was
3 2
8
CDCl ) d: 202.54 (C ), 81.74 (C , C ), 74.64 (C ), 73.71 (C ),
4
poured into Et O (2 mL) and CH N in Et O (0.1 g per 100
3
1
5
9
4
32.80, 32.68, 31.92, 31.16, 30.50, 30.16, 29.65, 29.35, 29.22,
28.73, 27.32, 27.22, 26.89, 25.91, 25.55, 25.07, 22.68, 18.06 (CÈ
But), 14.09 (C ), 6.73, 0.99, [3.95 (CH Si), [4.11 (CH Si),
2
2
2
2
mL, 8 mL, 0.195 mmol) was added dropwise at 0 ¡C. After 30
min of stirring, a 10% aqueous citric acid solution was added
and the organic layer extracted with EtOAc. The combined
21
3
3
[4.31 (CH Si), [4.71 (CH Si).
organic layers were dried over MgSO , Ðltered and concen-
3
3
4
trated. The crude residue was poured into DMF and imid-
azole (0.130 g, 1.9 mmol) was added, followed by TBDMSCl
(0.144 g, 0.95 mmol) and a catalytic amount of DMAP. After
15 h of stirring at room temperature, water was added and the
organic layer extracted with EtOAc. The combined organic
(4SR,5SR,8S,9S,12S,13S)-5-Hydroxy-8,13-di-tert-butyl-
dimethylsilyl-9,12-epoxypentacosan-4-olide, (1a,b). 11 (0.034 g,
0.058 mmol) was poured into CH Cl under N atmosphere,
2
2
2
the temperature was brought to [78 ¡C and TMSOF (15 lL,
layers were dried over MgSO , Ðltered and concentrated.
0.09 mmol) was added, followed by BF É Et O (7 lL, 0.058
mmol). After 4 h of stirring, an aqueous NH Cl solution was
added and the organic layers extracted by EtOAc. The com-
4
3
2
4
PuriÐcation of the crude mixture by Ñash chromatogtaphy on
silica gel (cyclohexaneÈEtOAc 90 : 10) a†orded 10 (0.05 g,
42% from 9). [a]20: [10 (c \ 0.4, CHCl ). IR (CHCl ) l:
bined organic layers were dried over MgSO , Ðltered and
D
3
3
4
3655È3465, 2960, 2930, 2855, 1775, 1730 1685, 1460, 1360, 1250
concentrated. PuriÐcation of the crude mixture by Ñash chro-
cm~1. CI-MS (CH ) m/z: 615 (MH~`, 39%), 614 (M~`, 17%),
matography on silica gel (cyclohexaneÈEtOAc 80 : 20) a†orded
an unseparable mixture of the desired butenolides (0.014 g,
38.5%, with [95% of the threo derivatives). 1H NMR (400
MHz, CDCl ) d: 7.46 (0.5H, dd, J \ 4.6, J \ 0.8, H ), 7.45
4
599 (M~` [ Me, 58%), 557 (M~` [ But, 100%), 483 (79%),
465 (20%), 425 (21%), 383 (11%) 313 (20%), 255 (9%), 231
(23%), 171 (10%), 149 (16%), 84 (18%). 1H NMR (200 MHz,
CDCl ) d: 3.90 (2H, m, H , H ), 3.65 (3H, s, Me), 3.58 (2H, m,
3
4
(0.5H, dd, J \ 4.6, J \ 0.6, H ), 6.17 (1H, br d, J \ 2.8, H ),
3
5
8
4
3
New J. Chem., 2000, 24, 337È342
341

View Article Online
6
7
C. Gleye, S. Raynaud, R. Hocquemiller, A. Laurens, C. Fourneau,
O. Laprevote, L. Serani, F. Roblot, M. Leb…uf, B. Figadere and
A. Cave, Phytochemistry, 1998, 47, 749.
(a) G. Shi, D. Alfonso, M. O. Fatope, L. Zeng, Z.-M. Gu, K. He,
J. M. McDougal and J. L. McLaughlin, J. Am. Chem. Soc., 1995,
117, 10409; (b) G. Shi, J. F. Kozlowski, J. T. Schwedler, K. V.
Wood, J. M. McDougal and J. L. McLaughlin, J. Org. Chem.,
1996, 61, 7988.
D. Cortes, B. Figadere and A. Cave, Phytochemistry, 1993, 32,
1467.
D. J. Morre, R. deCabo, C. Farley, N. H. Oberlies and J. L.
McLaughlin, L ife Sci., 1995, 56, 343.
5.02 (0.5H, m, H ), 4.97 (0.5H, m, H ), 3.93 (2H, m, H , H ),
5{ 8{
3.78 (1H, m, H ), 3.66 (1H, m, H ), 3.56 (1H, m, H ), 1.87
1{ 4{ 9{
(2H, m, H , H ) 1.77È1.47 (8H, m, H , H , H , H
6{a 7{a 2{ 3{ 6{b 7{b
5
5
,
H
), 1.26 (20H, br s, CH ), 0.89 (21H, br s, ButSi, H ), 0.09,
10{
2
21{
0.08, 0.06 and 0.05 (12H, 4s, (CH ) Si]. 13C NMR (50 MHz,
3 2
CDCl ) d: 175.65 (C ), 154.23 (C ), 122.67 (C ), 86.80 (C ),
3
2
4
3
5a
85.41 (C ), 81.61 (C ), 81.41 (C or C ), 74.62 (C ), 73.98
5b
5{
5{
8{
4{
8
9
(C ), 71.91 (C ), 43.75, 37.08, 36.02, 33.28, 32.86 31.89, 31.22,
9{
1{
30.53, 29.85, 29.64, 29.34, 28.68, 28.50, 27.70, 27.26, 25.92,
25.49, 22.64, 18.19 (CÈBut), 14.09 (C ), 7.02, 0.87, [3.86
21{
(CH Si), [4.34 (CH Si), [4.83 (CH Si). ESI-MS m/z: 686
10 D. Decaudin, I. Marzo, C. Brenner and G. Kroemer, Int. J.
Oncol., 1998, 12, 141.
11 N. H. Oberlies, V. L. Croy, M. L. Harrison and J. L. McLaugh-
lin, Cancer L ett., 1997, 115, 73.
12 S. Raynaud, F. Nemati, L. Miccoli, P. Michel, M. F. Poupon, C.
Fourneau, A. Laurens and R. Hocquemiller, L ife Sci., 1999, 65,
525.
13 Reviews: (a) B. Figadere, Acc. Chem. Res., 1995, 28, 359; (b) B.
Figadere and A. Cave, in Studies in Natural Products Chemistry,
ed. Atta-ur-Rahman, Elsevier, Amsterdam, 1996, vol. 18, pp. 193È
227; (c) J. A. Marshall, K. W. Hinkle and C. E. Hagedorn, Isr. J.
Chem., 1997, 37, 97; (d) R. Hoppe and H. D. Scharf, Synthesis,
1995, 1447.
14 Since 1998: (a) J. A. Marshall and H. Jiang, T etrahedron L ett.,
1998, 39, 1493; (b) S. Hanessian and T. Abad Grillo, J. Org.
Chem., 1998, 63, 1049; (c) Q. Yu, Z. J. Yao, X. G. Chen and Y. L.
Wu, J. Org. Chem., 1999, 64, 2440; (d) W. Kuriyama, K. Ishigami
and T. Kitahara, Heterocycles, 1999, 50, 981; (e) Q. Yu, Y. Wu,
H. Ding and Y. L. Wu, J. Chem. Soc., Perkin T rans. 1, 1999,
1183; ( f ) T. S. Hu, Q. Yu, Y. L. Wu and Y. Wu, Org. L ett., 1999,
1, 399; (g) Z. M. Wang, S. K. Tian and M. Shi, T etrahedron:
Asymmetry, 1999, 10, 667.
3
3
3
(M~ ] NH `, 60%), 669 (MH~`, 100%).
The unseparable mixture of the butenolides (0.014 g, 0.02
4
mmol) was then poured into EtOAc (2 mL) and palladium on
charcoal (0.0014 g) was added. After 18 h of stirring at room
temperature under a hydrogen atmosphere, the reaction
mixture was directly Ðltered through a short pad of silica gel
and the solid washed with EtOAc. The combined organic
layers were dried over MgSO , Ðltered and concentrated to
4
a†ord a mixture of 1a,b (0.014 g, 99%). 1H NMR (200 MHz,
CDCl ) d: 4.40 (1H, m, H ), 3.90 (2H, m, H , H ), 3.73 (1H,
3
4
9
12
m, H ), 3.68È3.48 (2H, m, H , H ), 2.50 (3H, m, H , H ),
5
8
13
2.36 (1H, m, H ), 2.10È1.39 (10H, m, H , H , H , H , H ),
3b 10 11 14
1.26 (18H, br s, CH ), 0.88 (21H, br s, 2 ButSi, H ), 0.07 and
25
0.05 [12H, 2s, (CH ) Si]. 13C NMR (50 MHz, CDCl ) d:
3 2
176.41 (C ), 82.77 (C ), 82.38 (C or C ), 82.08 (C or C
12 12
73.55 (C ), 72.95 (C ), 68.22 (C ), 43.11, 38.11, 34.80, 34.01,
2
3a
6
7
2
3
)
1
13
4
8
9
5
9
33.44, 32.28, 31.89, 31.16, 30.00, 29.64, 29.31, 29.20, 28.01,
27.13, 25.91, 25.31, 24.43, 23.07, 22.65, 18.43 (CÈBut), 18.12 (CÈ
But), 14.85 (C ), 6.96, [4.09 (CH Si), [4.25 (CH Si), [4.38
15 Since 1998: (a) J. A. Marshall and K. W. Hinkle, T etrahedron
L ett., 1998, 39, 1303; (b) S. Sasaki, K. Maruta, H. Naito, R.
Maemura, E. Kawahara and M. Maeda, Chem. Pharm. Bull.,
1998, 46, 154; (c) A. Yazbak, S. C. Sinha and E. Keinan, J. Org.
Chem., 1998, 63, 5863; (d) Z. M. Wang, S. K. Tian and M. Shi,
T etrahedron L ett., 1999, 40, 977; (e) J. A. Marshall and H. Jiang,
J. Org. Chem., 1999, 64, 971; ( f ) U. Emde and U. Koert, T etra-
hedron L ett., 1999, 40, 5979; (g) J. A. Marshall and H. Jiang, J.
Nat. Prod., 1999, 62, 1123; (h) A. Sinha, S. C. Sinha, S. C. Sinha
and E. Keinan, J. Org. Chem., 1999, 64, 2381.
25
3
3
(CH Si), [4.90 (CH Si). ESI-MS m/z: 688 (M~ ] NH `,
3
3
4
59%), 671 (MH~`, 100%).
Acknowledgements
M.S. and C.C. thank the French Ministry of Research
(MENRT), J.-F.P. the Ligue contre Le Cancer and X.F.
lÏAssociation pour la Recherche contre le Cancer for a fellow-
ship. J.-C. Jullian and J. Mahuteau are gratefully acknow-
ledged for NMR experiments and S. Mairesse for elemental
analyses.
16 Since 1998: S. C. Sinha, A. Sinha, S. C. Sinha and E. Keinan, J.
Am. Chem. Soc., 1998, 120, 4017.
17 Since 1998: (a) S. E. Schaus, J. Branalt and E. N. Jacobsen, J.
Org. Chem., 1998, 63, 4876; (b) P. Neogi, T. Doundounlakis, A.
Yazbak, S. C. Sinha, S. C. Sinha and E. Keinan, J. Am. Chem.
Soc., 1998, 120, 11279; (c) S. Takahashi and T. Nakata, T etra-
hedron L ett., 1999, 40, 723; (d) S. Baurle, S. Hoppen and U.
Koert, Angew. Chem., Int. Ed. Engl., 1999, 38, 1263; (e) W. Q.
Yang and T. Kitahara, T etrahedron L ett., 1999, 40, 7827.
18 (a) H. Makabe, A. Tanaka and T. Oritani, T etrahedron L ett.,
1997, 38, 4247; (b) H. Makabe, A. Tanaka and T. Oritani, T etra-
hedron, 1998, 54, 6329.
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19 J. A. Marshall and H. Jiang, J. Org. Chem., 1998, 63, 7066.
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