Enantioselective syntheses of monotetrahydrofuran annonaceous acetogenins tonkinecin and annonacin starting from carbohydrates

Article abstract of DOI:10.1021/jo005643b

The total synthesis of two mono-THF acetogenins, tonkinecin (1) and annonacin (2), is reported in full detail. Terminal acetylene 3 prepared from D-glucono-δ-lactone and asymmetric dihydroxylation was employed as a common intermediate for both targets 1 and 2. Pd(0)-catalyzed coupling reaction of 3 with vinyl iodides 4 and 5, the chiral centers of which were taken from D-xylose and S-(-)-ethyl lactate, afforded enyne 26 and 27, respectively. Selective hydrogenation of 26 or 27 with diimide followed by removal of MOM ethers completed the synthesis of 1. A coupling reaction between the lithium derivative of 3 and epoxide 6 in the presence of boron trifluoride etherate gave 42. Both chiral centers in epoxide 6 were taken from L-ascorbic acid. Subsequent catalytic hydrogenation and MOM protection led to 43b. Introduction of the butenolide moiety by aldol condensation of protected S-lactal followed by cleavage of all MOM ethers completed the synthesis of 2.

Full text of DOI:10.1021/jo005643b

J . Org. Chem. 2001, 66, 853-861
853
En a n tioselective Syn th eses of Mon otetr a h yd r ofu r a n An n on a ceou s
Acetogen in s Ton k in ecin a n d An n on a cin Sta r tin g fr om
Ca r boh yd r a tes
Tai-Shan Hu, Qian Yu, Yu-Lin Wu,* and Yikang Wu
State Key Laboratory of Bio-organic & Natural Products Chemistry and Shanghai-Hong Kong J oint
Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Road, Shanghai 200032, China
ylwu@pub.sioc.ac.cn
Received September 12, 2000
The total synthesis of two mono-THF acetogenins, tonkinecin (1) and annonacin (2), is reported in
full detail. Terminal acetylene 3 prepared from D-glucono-δ-lactone and asymmetric dihydroxylation
was employed as a common intermediate for both targets 1 and 2. Pd(0)-catalyzed coupling reaction
of 3 with vinyl iodides 4 and 5, the chiral centers of which were taken from D-xylose and S-(-)-
ethyl lactate, afforded enyne 26 and 27, respectively. Selective hydrogenation of 26 or 27 with
diimide followed by removal of MOM ethers completed the synthesis of 1. A coupling reaction
between the lithium derivative of 3 and epoxide 6 in the presence of boron trifluoride etherate
gave 42. Both chiral centers in epoxide 6 were taken from L-ascorbic acid. Subsequent catalytic
hydrogenation and MOM protection led to 43b. Introduction of the butenolide moiety by aldol
condensation of protected S-lactal followed by cleavage of all MOM ethers completed the synthesis
of 2.
In tr od u ction
bis-THF, the nonadjacent bis-THF, and the non-THF
acetogenins. We have synthesized1i-l,2 some mono-THF
acetogenins by convergent approaches and determined
the absolute configuration and activities of 10-isomers
of corossolin.1j We have also synthesized several structur-
ally simplified acetogenin analogues with potential bio-
logical activities have been.3 Herein, we report the total
syntheses of other two mono-THF acetogenins, tokinecin
and annonacin, via a carbohydrate-based1i,l approach.
The Annonaceous acetogenins from the Annonaceae
plants have attracted increasing interest1 because of their
potential biological properties, such as cytotoxic, antitu-
moral, pesticidal, and immunosuppressive activities. Up
to now, over 350 acetogenins have been isolated1a from
37 species of Annonaceae. The majority of these com-
pounds can be classified into four subgroups according
to the number and arrangement of the tetrahydrofuran
rings within the molecule: the mono-THF, the adjacent
(1) For recent comprehensive reviews, see: (a) Alali, F. Q.; Liu, X.-
X.; McLaughlin, J . L. J . Nat. Prod. 1999, 62, 504. (b) Zafra-Polo, M.
C.; Figadere, B.; Gallardo, T.; Tormo, J . R.; Cortes, D. Phytochemistry
1998, 48, 1087. (c) Casiraghi, G.; Zanardi, F.; Battistini, L.; Rassu,
G.; Appendino, G. Chemtracts Org. Chem. 1998, 11, 803. (d) Cave, A.;
Figadere, B.; Laurens, A.; Cortes, D. In Progress in the Chemistry of
Organic Natural Products; Herz, W., Kirby, G.-W., Moor, R. E.,
Steglich, W., Tamm, Ch., Eds.; Springer: New York, 1997; Vol. 70, pp
81-288 and references therein. For recent total synthesis, see: (e)
Hoppen, S.; Baurle, S.; Koert, U. Chem. Eur. J . 2000, 6, 2382. (f) Emde,
U.; Koert, U. Eur. J . Org. Chem. 2000, 1889. (g) Baurle, S.; Peters,
U.; Friedrich, T.; Koert, U. Eur. J . Org. Chem. 2000, 2207. (h) Yang,
W.-Q.; Kitahara, T. Tetrahedron 2000, 56, 1451. (i) Hu, T.-S.; Wu, Y.-
L.; Wu, Y. Org. Lett. 2000, 2, 887. (j) Yu, Q.; Yao, Z.-J .; Chen, X.-G.;
Wu, Y.-L. J . Org. Chem. 1999, 64, 2440. (k) Yu, Q.; Wu, Y.; Ding, H.;
Wu, Y.-L. J . Chem. Soc., Perkin Trans. 1 1999, 1183. (l) Hu, T.-S.; Yu,
Q.; Lin, Q.; Wu, Y.-L.; Wu, Y. Org. Lett. 1999, 1, 399. (m) Marshall, J .
A.; J iang, H. J . Org. Chem. 1999, 64, 971. (n) Sinha, A.; Sinha, S. C.;
Sinha, S. C.; Keina, E. J . Org. Chem. 1999, 64, 2381. (o) Sinha, S. C.;
Sinha, S. C.; Keinan, E. J . Org. Chem. 1999, 64, 7067. (p) Wang, Z.-
M.; Tian, S.-K.; Shi, M. Tetrahedron Lett. 1999, 40, 977. (q) Wang,
Z.-M.; Tian, S.-K.; Shi, M. Tetrahedron: Asymmertry 1999, 10, 667.
(r) Takahahi, S.; Nakata, T. Tetrahedron Lett. 1999, 40, 723; 1999,
40, 727. (s) Hanessian, S. Grillo, T. A. J . Org. Chem. 1998, 63, 1049.
(t) Marshall, J . A.; J iang, H. Tetrahedron Lett. 1998, 39, 1493.
Marshall, J . A.; J iang, H.; J . Org. Chem. 1998, 63, 7066. Marshall, J .
A. and Hinkle, K. W. Tetrahedron Lett. 1998, 39, 1303. (u) Makabe,
H.; Tanaka, A.; Oritani T. Tetrahedron 1998, 54, 6329. (v) Sinha, S.
C.; Sinha, A.; Sinha, S. C.; Keinan, E. J . Am. Chem. Soc. 1998, 120,
4017. Yazbak, A.; Sinha, C. C.; Keinan, E. J . Org. Chem. 1998, 63,
5863. Neogi, P.; Doundoulakis, T.; Yazak, A.; Sinha, S. C.; Sinha, S.
C.; Keinan, E. J . Am. Chem. Soc. 1998, 120, 11279. (w) Schans, S. E.;
Branact, J .; J acobson E. N. J . Org. Chem. 1998, 63, 4876.
Tonkinecin, 1, which was recently isolated4 from the
roots of Uvaria tonkinesis (Annonaceae), is a C-37 mono-
THF acetogenin with a C5 carbinol center (to the best of
our knowledge only six mono-THF acetogenins with C5
secondary hydroxyl5 have been known). Annonacin, 2, the
first and most typical mono-THF acetogenin, was iso-
lated6 from the stem bark of Annona densicoma in 1987.
The differences between structures of 1 and 2 lie in the
(2) Yao, Z.-J .; Wu, Y.-L. Tetrahedron Lett. 1994, 35, 157. Yao, Z.-J .;
Wu, Y.-L. J . Org. Chem. 1995, 60, 1170.
(3) Zeng, B.-B.; Wu, Y.; Yu, Q.; Wu, Y.-L.; Li, Y.; Chen, X.-G. Angew.
Chem., Int. Ed. 2000, 39, 1934.
(4) Chen, Y.; Yu, D.-Q. J . Nat. Prod. 1996, 59, 507.
(5) Pan, X.-P.; Yu, D.-Q. Acta Pharm. Sin. 1997, 32, 286. Chen, Y.;
Chen, R. Y.; Yu, D. Q. Phytochemistry, 1996, 43, 793. Zheng, X. C.;
Yang, R. Z.; Xu, R. S.; Qin, G. W. Acta Botan. Sin. 1994, 36, 557.
10.1021/jo005643b CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/21/2000

854 J . Org. Chem., Vol. 66, No. 3, 2001
Hu et al.
F igu r e 1. Retrosynthetic analysis of 1 and 2.
Sch em e 1a
number of carbon in the alkyl chain between the THF
and the γ-lactone and the number as well as position of
the hydroxyl group on it, which are critical1a to the
biological activities of the acetogenins.
Our retrosynthetic strategy is illustrated in Figure 1.
A key feature of our approach is use of alkyne 3 as a
common key intermediate to both 1 and 2. Thus, the
carbon skeleton of 1 can be constructed by Pd(0)-
catalyzed cross coupling reaction of 3 with vinyl iodide 4
or 5, while that of 2 can be obtained by epoxide opening
reaction between 3 and 6. The intermediates 3, 4, 5, and
6 were prepared from D-glucono-δ-lactone, D-xylose,
S-(-)ethyl lactate and L-ascorbic acid, respectively. The
introduction of butenolide moiety of 1 was arranged at
an early stage of the synthesis. However, butenolide
segment of 2 was introduced at the end of its synthesis
to avoid γ-epimerization of the butenolide segment that
might occur in basic media,1m,7 because a relative strong
base was required to prepare 6.
a
Reagents and conditions: (a) PPh3, I2, imidazole, toluene,
reflux, 69%; (b) LiHMDS, THF, -78 °C, 95%; (c) (i) H2/Pd-C,
MeOH; (ii) acetone, p-TsOH (cat.), 86%; (d) ref 1k, l.
Sch em e 2a
Resu lts a n d Discu ssion
Syn th esis of Alk yn e 3. Deoxygenation of R-hydroxyl
ester 7,8 which was derived from readily available D-glu-
cono-1,5-lactone, by treatment with Ph3P/I2/imidazole in
toluene9 gave ester 8 in 69% yield (Scheme 1). The ester
8 was then treated with LiHMDS in THF to give R,â-
unsaturated ester 9 in 97% yield. Hydrogenation followed
by acid-catalyzed ring closure produced lactone 10 in 86%
yield. Then compound 10 was converted to alkyne 3 via
a multistep procedure described previously1k,l by us.
Syn th esis of Bu ten olid e 4. The two stereogenic
centers of 4 were related to D-xylose and (S)-ethyl lactate,
respectively (Scheme 2). Thus, R,â-unsaturated ester 1110
was treated with Mg in methanol to give δ-hydroxyl ester
12a in 61% yield, which was protected as MOM ether
12b. Condensation of enolate derived from 12b with (S)-
OTHP lactal 132 led to aldol adduct 14a as a mixture of
diastereoisomers in 71% yield. After acetylation of 14a ,
compound 14b was subjected to periodic acid in ether to
afford aldehyde 15 in 76% yield.
a
Reagents and conditions: (a) Mg, CH3OH, reflux, 61%; (b)
i
MOMCl, Pr2NEt, CH2Cl2, 0 °C f rt, 98% (c) LDA, THF-HMPA
(6:1,v/v), -78 °C; then 13, 71%; (d) Ac2O, Py, rt, 90%; (e) H5IO6,
Et2O, rt, 76%.
The synthesis of 19b (Scheme 3) started with hept-6-
yn-1-ol (16), which was prepared10 in two steps from prop-
2-yn-1-ol and 1-bromobutane. Protection of 16, hydrostan-
nation, and iodolysis, and finally removal of the THP
group led to vinyl iodide 18 in 89% yield based on 16.
The primary alcohol was converted first to bromide 19a
before being transformed into the corresponding phos-
(6) McCloud, T. G.; Smith, D. L.; Chang, C.-J .; Cassady, J . M.
Experientia. 1987, 43, 947.
(7) Duret, P.; Figadere, B.; Hocquemiller, R.; Cave, A. Tetrahedron
Lett. 1997, 38, 8849.
(8) Regeling, H.; Rouville, E.; Chittenden, G. J . F. Recl. Trav. Chim.
Pays-Bas 1987, 106, 461.
(9) Rauter, A. P.; Fernandes, A. C.; Figueiredo, J . A. J . Carbohydr.
Chem. 1998, 17, 1037.
(10) Yadav, J . S.; Barma, D. K. Tetrahedron 1996, 52, 4457.

Syntheses of Tonkinecin and Annonacin
J . Org. Chem., Vol. 66, No. 3, 2001 855
Sch em e 3a
Sch em e 5a
a
Reagents and conditions: (a) DHP, PPTS (cat.), CH2Cl2, rt,
95%; (b) (i) Bu3SnH, AIBN (cat.), 130 °C, 2 h, then I2; (ii) PTSA
(cat.), CH3OH, rt, 94%; (c) PPh3, CBr4, CH2Cl2, 0 °C f rt, 90%;
(d) PPh3, CH3CN, reflux, quant; (e) LiHMDS, THF/HMPA (6:1,v/
v), -78 °C, then 15, 31%.
Sch em e 4a
a
Reagent and conditions: (a) (PPh3)2PdCl2, CuI, Et3N, rt, 93%
from 26, 86% from 27; (b) TsNHNH2, NaOAc, DME, reflux, 65%;
(c) BF3‚Et2O, Me2S, 0 °C, 86%.
aldehyde 24, which was treated with CHI3 and CrCl2 to
produce vinyl iodide 5 in 75% yield as a 4:1 mixture of
E/Z isomers.
Syn th esis of Ton k in ecin 1. Treatment of vinyl
iodides 4 and 5 with terminal alkyne 3 in the presence
of (PPh3)2PdCl2 and CuI in NEt3 gave 26 and 27 in 93%
and 86% yield, respectively. Subsequent hydrogenation
of 26 or 27 with diimide12 produced precursor 28 (Scheme
5). Finally, cleavage of the MOM ethers with BF3.OEt2
in SMe213 afford 1 as a waxy solid in 86% yield. The
spectral data of 1 were identical with the reported ones.4
a
Reagents and conditions: (a) NaH, DMF, then p-methoxyl-
benzyl chloride, 44%; (b) PPh3, CBr4, CH2Cl2, 93%; (c) PPh3,
CH3CN, reflux, quant; (d) (i) NaHMDS, THF, 0 °C, then -78 °C,
25, 64%; (ii) H2, Pd/C, EtOH, 97%; (e) (i) -78 °C, THF, LDA, then
13, 96%; (ii) AcOH/THF/H2O (4:2:1), 55 °C; (iii) (CF3CO)2O, Et3N,
66% for two steps; (f) (i) DDQ, CH2Cl2/H2O (v/v 18:1), 78%; (ii)
Dess-Martin periodinane, CH2Cl2, 96%; (g) CHI3, CrCl2, THF,
75%.
Syn th esis of Ep oxid e 6 (C1-C11 Segm en t of 2).
The synthesis of epoxide 6 is summarized in Scheme 6.
Protection of R-hydroxyl ester 2914 derived from L-
ascorbic acid as MOM ether followed by LAH reduction
gave 31 in 84% yield for two steps. 31 was converted to
R,â-unsaturated ester 32 by Swern oxidation followed by
Wittig reaction. It is noteworthy that at the Swern
oxidation step, the choice of base used was crucial.
Considerable epimerization at the R position of the
resultant aldehyde was observed with NEt3 as base,
which was commonly used in Swern oxidation. However,
phonium salt 19b. The following coupling of 19b with
aldehyde 15 and concomitant elimination of acetate ester
afforded the butenolide 4 in 31% yield.
Secon d Ap p r oa ch to C1-C13 Segm en t of 1 (Syn -
th esis of Bu ten olid e 5). A possible reason for the rather
poor yield for Wittig reaction of 19b with 15 is that the
vinyl iodide is eliminated under the basic conditions to
give a terminal alkyne. To overcome this drawback and
also avoid use of tributytin hydride, an alternative route
(Scheme 4) to the C1-C13 segment of 1 was then
explored. Thus, 1,6-hexanediol was protected as mono-
PMB ether 20 in 44% yield, which was converted to
bromide and then to phosphonium salt 21b. Wittig
reaction of the latter with aldehyde 25 prepared from 12b
(eq 1) followed by hydrogenation gave ester 22 in 62%
yield over two steps. Subsequent introduction1m,2 of the
i
with Pr2NEt as base, this problem was overcome. Cata-
lytic hydrogenation afforded 33 in 97% yield. Subsequent
removal of the isopropylidene group and oxidative cleav-
age of the resulting diol with sodium periodate furnished
aldehyde 34 in 73% yield.
Compound 29 was converted to ester 35 according to
a known15 procedure. Two-carbon chain elongation of 35
to give 36 was realized in 69% yield via reduction of 35
with LAH, Swern oxidation followed by Wittig reaction,
and finally catalytic hydrogenation. Treatment of 36 with
LAH afforded alcohol 37 in 95% yield, which was
(11) Brandsma, L. Preparative acetylenic chemistry, 2nd ed.; Elsevi-
er: Amsterdam, 1988; p 245.
(12) Marshall, J . A.; Hinkle, K. W., J . Org. Chem. 1997, 62, 5989.
(13) Naito, H.; Kawahara, E.; Maruta, K.; Maeda, M.; Sasaki, S. J .
Org. Chem, 1995, 60, 4419.
(14) Wei, C. C.; De Bernardo, S.; Tengi, J . P.; Borgese, J .; Weigele,
M. J . Org. Chem. 1985, 50, 3462. J ung, M. E.; Shaw, T. J . J . Am. Chem.
Soc. 1980, 102, 6304.
butenolide unit involved three steps: (1) adol reaction
of 22 with aldehyde 13; (2) acid-catalyzed THP cleavage
and concurrent ring closure; (3) â-elimination in the
presence of F3CCO2H and NEt3. Cleavage of PMB group
in 23 and oxidation of the resulting alcohol afforded
(15) Tanaka, A.; Yamashida, K. Synthesis 1987, 570.

856 J . Org. Chem., Vol. 66, No. 3, 2001
Hu et al.
Sch em e 6a
a
i
Reagents and conditions: (a) MOMCl, Pr2NEt, CH2Cl2, 0 °C to room temperature, 88%; (b) LAH, THF, 0 °C to room temperature,
i
96%; (c) (i) oxalyl chloride, DMSO, Pr2NEt; (ii) PPh3dCHCO2Et, CH2Cl2, reflux, 81%; (d) H2/Pd-C, EtOH, rt, 97%; (e) (i) 60% AcOH, 45
°C, 1 h; (ii) NaIO4, CH2Cl2/H2O, rt, 73% for two steps; (f) Reference 14. (g) (i) LAH, THF, 0 °C to rt; (ii) oxalyl chloride, DMSO, Et3N; (iii)
PPh3dCHCO2Et, CH2Cl2, reflux, 73% for three steps; (iv) H2/Pd-C, EtOH, rt, 95%; (h) LAH, THF, 0 °C to rt, 95%; (i) (i) p-TsCl, Et3N,
CH2Cl2, 0 °C to rt, 94%; (ii) NaI, acetone, rt, 98%; (j) PPh3, Na2CO3, CH3CN, quantitative; (k) NaHMDS, THF, 0 to -78 °C then 34, 81%;
(l) H2/Pd-C, NaHCO3, EtOH, rt, 97%; (m) (i) 60% aq HOAc, 97%; (n) p-TsCl, Et3N, Bu2SnO (cat.), CH2Cl2, 81%; (o) DBU, CH2Cl2, rt, 97%.
Sch em e 7a
converted to tosylate and then to iodide 38a . The latter
was reacted with PPh3 to give phosphonium salt 38b.
Treatment of 38b with NaHMDS and then aldehyde 34
afforded 39 in 81% yield, which, after hydrogenation,
gave ester 40 in 97% yield. Hydrolysis of the acetonide
group afforded diol 41a , which was converted to primary
tosylate 41b in 81% yield by Bu2SnO-catalyzed16 tosyla-
tion. Treatment of 41b with DBU in methylene chloride
gave epoxide in 97% yield.Syn th esis of An n on a cin (2).
Successful accomplishment of epoxide 6 set the stage for
the construction of carbon skeleton of 2. Thus, the
lithiated derivative of alkyne 3 was reacted with epoxide
6 in the presence of BF3‚Et2O to afford alkynol 42 in 77%
yield. To our surprise, catalytic hydrogenation of 42 over
Pd/C led to a mixture of ca. 1:1 ratio of the desired alcohol
43a and 10-deoxgenated byproduct. However, substitu-
tion of Pd/C with PtO2 as catalyst afforded 43a in 93%
yield, which was then protected as MOM ether 43b in
95% yield. In a similar sequence to that from 22 to 23,
a
43a was converted to butenolide 44 in 41% yield. The
final stage of the synthesis, deprotection of the MOM
ethers of 44, was effected in 85% yield with BF3‚Et2O in
the presence of Me2S. The spectral data of the resulting
product 2 were in accord with those reported for the
natural product.6
Reagent and conditions: (a) BuLi, THF, -78 °C, 1 h, then
BF3‚Et2O, 30 min then 4, 77%; (b) PtO2, EtOH, rt, 93%; (c)
i
MOMCl, Pr2NEt, CH2Cl2, 0 °C to rt, 95%; (d) (i) LDA, THF, -78
°C, then O-THP lactaldehyde; (ii) HOAc/THF/H2O (4:2:1); (iii)
(CF3CO)2O, Et3N, 0 °C to rt, 41% for three steps; (e) BF3‚Et2O,
Me2S, 0 °C to rt, 85%.
Exp er im en ta l Section
In conclusion, total synthesis of tonkinecin and an-
nonacin has been achieved via convergent routes using
readily available carbohydrates and hydroxyl acid as
starting materials. The strategy described herein should
be applicable to various analogues of acetogenins. Fur-
ther biological evaluation of 1 and 2 is undergoing.
Gen er a l Meth od s. NMR spectra were recorded in CDCl3
at 300, 400 and 600 MHz, respectively. IR spectra were
recorded on a Perkin-Elmer 983 or IR-440 spetrophotomer.
Mass spectra were obtained on an HP 5989A Mass spectrom-
eter. Optical rotations were measured on a Perkin-Elmer 241
MC autopol polarimeter. Elemental analyses were carried out
at the Microanalytic Laboratory of Shanghai Institute of
Organic Chemistry. Flash column chromatography was per-
formed on silica gel (10-40 µm).
(16) Martinelli, M. J .; Nayyar, N. K.; Moher, E. D.; Dhokte, U. P.;
Pawlak, J . M.; Vaidyanathan, R. Org. Lett. 1999, 1, 447.

Syntheses of Tonkinecin and Annonacin
J . Org. Chem., Vol. 66, No. 3, 2001 857
1
Meth yl (2RS,5R,6R,1′RS,2′S)-2-(1′-Hyd r oxy-2′-tetr a h y-
d r op yr a n yloxyp r op -1′-yl)-6,7-d ih yd r oxy-6,7-O-isop r op yl-
id en e-5-m eth oxym eth oxyh ep ta n oa te (14a ). To a solution
of diisopropylamine (0.2 mL, 1.53 mmol) in THF (8 mL) at 0
°C was added BuLi (0.6 mL, 1.5 mmol). The mixture was
stirred at 0 °C for 10 min and cooled to -78 °C and then was
added HMPA (1 mL). The reaction mixture was stirred at -78
°C for 30 min, and then a solution of ester 12b (0.388 g, 1.22
mmol) in THF (3 mL) was added. After another 30 min, a
solution of aldehyde 13 (0.220 g, 1.39 mmol) in THF (2 mL)
was added. The reaction mixture was stirred at -78 °C for 2
h, quenched with saturated aqueous NH4Cl solution, and
extracted with ether. The extracts were washed with brine and
dried over Na2SO4. After filtration and concentration, the crude
product was purified by column chromatography to afford 14a
(0.376 g, 71%) as a mixture of diasteroisomers: IR (film) 3463,
2856, 1604, 945 cm-1; H NMR (300 MHz, CDCl3) δ 6.49 (dt,
J ) 14.3, 7.1 Hz, 0.8H, from one olefinic proton in the trans
isomer), 6.17 (m, 0.4H, from two olefinic protons in the cis
isomer), 5.97 (ddd, J ) 14.3, 2.2, 1.4 Hz, 0.8H, from one proton
in the trans isomer), 3.62 (m, 2H), 2.18-1.95 (m, 2H), 1.61-
1.25 (m, 6H); EIMS (m/z) 127 (6.15), 113 (9.23).
(EZ)-7-Br om o-1-iod oh ep t -1-en e (19a ). To a mixture of
alcohol 18 (2.605 g, 0.010 mol) and carbon tetrabromide (4.320
g, 0.013 mol) in CH2Cl2 (10 mL) at 0 °C was added a solution
of triphenylphosphine (4.264 g, 0.016 mol) in CH2Cl2 (10 mL).
The reaction mixture was stirred at room temperature for 3
h, concentrated under reduced pressure, and purified by
column chromatography to afford 19a (2.942 g, 90%) as a
colorless oil. IR (film) 3045, 3004, 2930, 2854, 1605 cm-1; H
1
NMR (300 MHz, CDCl3) δ 6.50 (dt, J ) 14.6, 7.1 Hz, 0.78H,
from olefinic proton in the trans isomer), 6.17 (m, 0.44H, from
two olefinic protons in the cis isomer), 6.00 (dt, J ) 14.3, 1.4
Hz, 0.78H, from olefinic proton in the trans isomer), 3.41 (t, J
) 6.9 Hz, 0.44H), 3.40 (t, J ) 6.9, 1.56H), 2.16 (m, 0.44H),
2.06 (m, 1.56H), 1.85 (m, 2H), 1.43 (m, 4H); EIMS (m/z) 303
(21.99), 301 (22.02), 95 (100.00), 127 (4.79). Anal. Calcd for
1
2942, 1734 cm-1; H NMR (300 MHz, CDCl3) δ 4.79 (m, 1H),
4.66 (m, 1H), 4.60 (m, 1H), 4.18 (m, 1H), 3.98 (m, 1H), 3.86
(m, 1H), 3.80-3.42 (m, 5H), 3.69 (s, 3H), 3.39, 3.38 (s, s, 3H),
2.62, 2.50 (m, m, 1H), 1.97 (m, 1H), 1.90-1.62 (m, 3H), 1.40
(s, 3H), 1.34 (s, 3H), 1.59-1.11 (m, 9H); EIMS (m/z) 403 (M+
- CH3O, 0.57), 101 (17.25), 85 (THP, 100), 45 (42.21).
C
17H12BrI: C, 27.75; H, 3.99. Found: C, 27.62; H, 4.02.
(4′Z,10′EZ,5S,3′R)-3-(11′-Iod o-3′-m et h oxym et h oxyu n -
Meth yl (2RS,5R,6R,1′RS,2′S)-2-(1′-Acetoxy-2′-tetr a h y-
d r op yr a n yloxyp r op -1′-yl)-6,7-d ih yd r oxy-6,7-O-isop r op yl-
id en e-5-m eth oxym eth oxyh ep ta n oa te (14b). A mixture of
alcohol 14a (4.500 g, 10.36 mmol) and acetic anhydride (5 mL)
in pyridine (25 mL) was stirred for 16 h at room temperature,
diluted with ether (100 mL), washed with 10% aqueous HCl
solution, H2O, and brine, and dried over Na2SO4. The solvents
were evaporated under reduce pressure, and the residue was
purified by column chromatography to afforded 14b (4.451 g,
d eca -4′,10′-d ien -1′-yl)-5-m eth ylfu r a n -2(5H)-on e (4). A mix-
ture of bromide 19a (0.391 g, 1.23 mmol) and PPh3 (0.629 g,
2.45 mmol) in CH3CN (8 mL) was stirred at 90 °C for 24 h,
concentrated under reduced pressure and washed with Et2O
several times. The phosphonium salt 19b was dried in vacuo,
dissolved in THF (8 mL) and treated with LiHMDS (prepared
from 0.52 mL of BuLi (1.30 mmol) and 0.3 mL of HMDS (1.42
mmol)) in THF (2 mL) at 0 °C. The orange solution was stirred
at 0 °C for 30 min and cooled to -78 °C, and then HMPA (1.5
mL) was added. The mixture was stirred another 30 min, and
a solution of aldehyde 15 (0.265 g, 0.92 mmol) in THF (2.5
mL) was added. The reaction mixture was stirred for 2 h from
-78 °C to room temperature, quenched with saturated aque-
ous NH4Cl solution, and extracted with ether. The extracts
were washed with brine and dried over Na2SO4. Concentration
and chromatography afforded butenolide 4 (0.123 g, 31%) as
a colorless oil: [R]D +89.3 (c 1.22 CHCl3); IR (film) 2929, 1747,
1651, 1449, 954, 922 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.02
(s, 1H), 6.49 (dt, J ) 14.3, 7.1 Hz, 0.83H, from one olefinic
proton of trans isomer), 6.17 (m, 0.33H, from two olefinic
protons of cis isomer), 5.99 (d, J ) 14.3 Hz, 0.83H, from one
olefinic proton of trans isomer), 5.61 (dt, J ) 11.0, 7.2 Hz, 1H),
5.23 (m, 1H), 5.01(dq, J ) 1.8, 6.6 Hz, 1H), 4.66 (d, J ) 6.9
Hz, 1H), 4.48 (d, J ) 6.9 Hz, 1H), 4.39 (m, 1H), 3.37 (s, 3H),
2.36 (m, 2H), 2.07 (m, 4H), 1.88 (m, 1H), 1.72 (m, 1H), 1.41 (d,
J ) 6.6 Hz, 3H), 1.45-1.31 (m, 4H); EIMS (m/z) 389 ([M+-
MOM], 6.27), 45 (100.00); HRMS calcd for C16H22O3I (M -
MOM) 389.0612, found 389.0625.
90%) as a colorless oil: IR (film) 2942, 1740, 1372 cm-1 1H
;
NMR (300 MHz, CDCl3) δ 5.20 (m, 1H), 4.79 (m, 1H), 4.65 (m,
1H), 4.60 (m, 1H), 4.13 (m, 1H), 3.95 (m, 1H), 3.90-3.40 (m,
5H), 3.66 (m, 3H), 3.38 (m, 3H), 2.82-2.58 (m, 1H), 3.04 (m,
3H), 1.70 (m, 5H), 1.58-1.05 (m, 8H), 1.38 (s, 3H), 1.33 (s, 3H);
EIMS (m/z) 85 (73.87), 101 (64.49). Anal. Calcd for C23H40O10
:
C, 57.97; H, 8.46. Found: C, 57.84; H, 8.58.
(2R,3′RS,4′RS,5′S)-4-(4′-Acetoxy-5′-m eth yl-2′-oxotetr ah y-
d r ofu r a n -3′-yl)-2-m eth oxym eth oxybu ta n a l (15). To a solu-
tion of compound 14b (1.113 g, 2.34 mmol) in ether (12 mL)
was added periodic acid (1.065 g, 4.67 mmol). The reaction
mixture was stirred for 20 h at room temperature, filtered,
and concentrated under reduced pressure. The residue was
purified by column chromatography to give 15 (0.511 g, 76%)
1
as a colorless oil: IR (film) 2942, 2826, 1771, 1736; H NMR
(300 MHz, CDCl3) δ 9.61 (d, J ) 1.7 Hz, 1H), 5.12 (m, 0.25H),
4.89 (dd, J ) 6.0, 5.9 Hz, 0.85H), 4.71 (m, 2H), 4.49, 4.37 (m,
m, 1H), 3.91 (m, 1H), 3.40 (s, 3H), 2.70 (m, 1H), 2.10 (m, 3H),
1.85 (m, 4H), 1.39 (m, 3H); MS (m/z) 289 (MH+, 0.50), 227
(71.46), 197 (80.08), 167 (53.72).
(EZ)-7-Iod oh ep t-6-en -1-ol (18). To a solution of alkynol
16 (1.370 g, 0.012 mol) in CH2Cl2 (30 mL) were added DHP
(1.541 g, 0.018 mol) and PPTS (0.129 g). The mixture was
stirred for 12 h at room temperature, diluted with ether (50
mL), washed with H2O, saturated aqueous NaHCO3 solution,
and brine, and dried over Na2SO4. Removal of the solvent
under reduced pressure and purification by column chroma-
tography afforded the product (2.290 g, 95%) as a colorless oil.
A mixture of the above product (2.290 g, 0.012 mol), AIBN (ca.
0.1 g), and tributytin hydride (4.7 mL, 0.017 mol) was stirred
for 2.5 h at 130 °C and then cooled to 0 °C. To it was added
ether (20 mL) and then iodine (3.800 g, 0.015 mol) in portions.
The reaction mixture was stirred at room temperature over-
night, and then solid potassium fluoride (1.200 g, 0.021 mol)
and H2O (1.5 mL) were added to destroy excess tributytin
hydride. After filtration, the filtrate was washed with aqueous
Na2S2O3 solution and brine and dried over Na2SO4. The solvent
was evaporated under reduced pressure, and the residue was
dissolved in methanol. To the mixture was added p-toluene-
sulfonic acid monohydrate (0.222 g). The reaction mixture was
stirred for 24 h at room temperature and neutralized with solid
K2CO3 (1.9 g). Filtration, removal of the solvent, and purifica-
tion by column chromatography afforded 18 (2.631 g, 94%) as
a 4:1 mixture of E and Z isomers: IR (film) 3342, 3047, 2930,
1-Br om o-6-p-m eth oxyben zyloxyh exa n e (21a ). To a sus-
pension of 60% NaH (0.915 g, 0.022 mol) in DMF (22 mL) at
-20 °C was added a solution of 1,6-hexanediol (2.364 g, 0.020
mol) in DMF (14 mL). The mixture was stirred at the same
temperature for 30 min, and a solution of p-methoxybenzyl
chloride (3.451 g, 0.022 mol) in DMF (7 mL) was added. The
reaction mixture was stirred at -20 °C for 2 h and then pooled
into ice-water (100 mL), extracted with ether. The extracts
were washed with brine and dried over Na2SO4. The solvent
was removed, and the residue was purified by chromatography
to afford alcohol 20 (2.080 g, 44%) as a colorless oil: IR (film)
3393, 2935, 2860, 1614, 1587, 1514 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.25 (d, J ) 8.5 Hz, 2H), 6.87 (d, J ) 8.5 Hz, 2H),
4.42 (s, 2H), 3.79 (s, 3H), 3.62 (t, J ) 6.5 Hz, 2H), 3.43 (t, J )
6.6 Hz), 1.56 (m, 4H), 1.37 (m, 4H); MS (m/z) 238 (M+, 3.46),
137 (59.35), 121 (100.00), 77 (9.31).
To a mixture of alcohol 20 (0.800 g, 3.36 mmol) and carbon
tetrabromide (1.337 g, 4.03 mmol) in CH2Cl2 at 0 °C was added
a solution of PPh3 (1.319 g, 5.03 mmol) in CH2Cl2 (3 mL). The
reaction mixture was stirred at room temperature for 1 h,
concentrated under reduced pressure and purified by column
chromatography to afford bromide 21b (0.941 g, 93%): IR
1
(film) 2930, 2857, 1601, 1580 cm-1; H NMR (300 MHz, CD3-
Cl) δ 7.25 (d, J ) 8.7 Hz, 2H), 6.87 (d, J ) 8.7 Hz, 2H), 4.42 (s,

858 J . Org. Chem., Vol. 66, No. 3, 2001
Hu et al.
2H), 3.80 (s, 3H), 3.43 (t, J ) 6.6 Hz, 2H), 3.39 (t, J ) 6.9 Hz,
2H), 1.85 (m, 2H), 1.41 (m, 4H); EIMS (m/z) 302 (2.52), 301
(1.38), 300 (2.70), 137 (8.07), 121 (100), 77 (7.50).
Removal of the solvents gave crude product which, after
chromatography, afforded 23 (0.092 g, 60%) as a colorless oil:
[R]D +25.1 (c 0.59, CHCl3); IR (film) 2933, 2857, 1756, 1614,
1580, 1514, 1465, 1098, 1035 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.27 (d, J ) 8.6 Hz, 2H), 7.03 (s, 1H), 6.89 (d, J ) 8.6 Hz,
2H), 5.01 (m, 1H), 4.68 (d, J ) 7.1 Hz, 1H), 4.65 (d, J ) 7.1
Hz, 1H), 4.44 (s, 2H), 3.81 (s, 3H), 3.57 (m, 1H), 3.44 (t, J )
6.6 Hz, 2H), 3.40 (s, 3H), 2.36 (m, 2H), 1.75 (m, 2H), 1.70-
1.46 (m, 4H), 1.42 (d, J ) 6.6 Hz, 3H), 1.31 (brs, 8H); EIMS
(m/z) 389 (M+ - MOM, 8.92), 261 (11.36), 137 (23.23), 121
(100.00), 77 (5.07), 45 (25.20); HREIMS for C23H33O5 (M-CH3-
OCH2) calcd 389.2328, found 389.2352.
Meth yl (5R)-5-Meth oxym eth oxy-6-oxo-h exa n oa te (25).
To a solution of 12b (1.043 g, 3.77 mmol) in ether (23 mL)
was added periodic acid (1.800 g, 7.90 mmol), and the reaction
mixture was stirred at room temperature for 12 h and filtered.
The filtrate was washed with H2O and brine and dried over
Na2SO4. The solvent was removed under reduced pressure, and
the residue was purified by column chromatography to afford
aldehyde 25 (0.527 g, 68%) as a colorless oil: [R]D +34.5 (c
1
1.02, CHCl3); H NMR (300 MHz, CDCl3) δ 9.62 (d, J ) 1.7
Hz, 1H), 4.72 (d, J ) 6.9 Hz, 1H), 4.68 (d, J ) 6.9 Hz, 1H),
3.98 (m, 1H), 3.67 (s, 3H), 3.37 (s, 3H), 2.33 (t, J ) 7.4 Hz,
2H), 1.75 (m, 2H), 1.50 (m, 2H).
(8S,5′S)-8-Met h oxym et h oxy-10-(5′-m et h yl-2′-oxo-2′,5′-
d ih yd r ofu r a n -3′-yl)d eca n a l (24). To a solution of 23 (0.085
g, 0.196 mmol) in CH2Cl2/H2O (2.1 mL, v/v 20:1) at 0 °C was
added DDQ (0.067 g, 0.294 mmol). The reaction mixture was
stirred at room temperature for 1 h, diluted with ether, washed
with saturated aqueous NaHCO3 solution, and brine, and dried
over Na2SO4. Concentration under reduced pressure and
purification by column chromatography afforded an alcohol
(0.045 g, 73%) as a light yellow oil: [R]D +29.8 (c 0.41, CHCl3);
Meth yl (5S)-5-Meth oxym eth oxy-12-p-m eth oxyben zyl-
oxyd od eca n oa te (22). A mixture of bromide 21a (0.482 g,
1.60 mmol) and PPh3 (0.838 g, 0.32 mmol) in CH3CN (12 mL)
was stirred at 90 °C for 2 days, concentrated under reduced
pressure, and washed with ether several times. The phospho-
nium salt obtained was dried in vacuo, dissolved in THF (14
mL), and treated with NaHMDS (1.6 mL, 1 M solution in THF,
1.6 mmol) at 0 °C. The orange solution was stirred at 0 °C for
30 min and then cooled to -78 °C, and a solution of aldehyde
25 (0.205 g, 1.00 mmol) in THF (8 mL) was added. The reaction
mixture was stirred at -78 °C for 2 h, quenched with brine,
and extracted with ether. The extracts were washed with H2O
and brine and dried over Na2SO4. The solvents were removed
under reduced pressure, and the residue was purified by
column chromatography to afford product (0.260 g, 64%) as a
colorless oil: [R]D +65.7 (c 1.30, CHCl3); IR (film) 2933, 2855,
IR (film) 3450, 2933, 2858, 1754 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 7.03 (d, J ) 1.6 Hz, 1H), 5.01 (qd, J ) 6.9, 1.7 Hz,
1H), 4.68 (d, J ) 6.9 Hz, 1H), 4.65 (d, J ) 6.9 Hz, 1H), 3.64 (t,
J ) 6.6 Hz, 2H), 3.57 (m, 1H), 3.40 (s, 3H), 2.37 (m, 2H), 1.78
(m, 2H), 1.70 (m, 4H), 1.41 (d, J ) 6.6 Hz, 3H), 1.33 (brs, 8H);
EIMS (m/z) 297 (11.56), 283 (16.91), 253 (100.00), 235 (22.93),
199 (2.27), 169 (9.97).
A mixture of the above-obtained alcohol (0.040 g, 0.127
mmol) and Dess-Martin periodinane (0.081 g, 0.190 mmol)
in CH2Cl2 (2 mL) was stirred at room temperature for 50 min,
filtered, and concentrated under reduced pressure. The residue
was purified by column chromatography to afford aldehyde 24
(0.038 g, 96%) as a colorless oil: [R]D +18.6 (c 0.13, CHCl3);
1736, 1610, 1585, 1510 cm-1 1H NMR (300 MHz, CDCl3) δ
;
7.25 (d, J ) 6.9 Hz,2H) 6.88 (d, J ) 6.9 Hz, 2H) 5.59 (dt, J )
10.9, 7.6 Hz, 1H), 5.20 (dd, J ) 10.9, 9.4 Hz, 1H), 4.66 (d, J )
6.6 Hz, 1H), 4.47 (d, J ) 6.6 Hz, 1H), 4.43 (s, 2H), 4,38 (m,
1H), 3.81 (s, 3H), 3.67 (s, 3H), 3.43 (t, J ) 6.5 Hz, 2H), 3.36 (s,
3H), 2.34 (t, J ) 7.2 Hz, 2H), 1.75-1.55 (m, 6H), 1.55-1.30
(m, 6H) EIMS (m/z) 363 (M+ - MOM, 0.90), 346 (1.89), 137
(11.52), 121 (100.00), 45 (16.24). Anal. Calcd for C23H36O6: C,
67.62; H, 8.88. Found: C, 67.76; H, 9.03.
IR (film) 2934, 2858, 1755, 1712 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 9.78 (s, 1H), 7.03 (d, J ) 1.7 Hz, 1H), 5.01 (qd, J )
6.9, 1.7 Hz, 1H), 4.68 (d, J ) 6.9 Hz, 1H), 4.65 (d, J ) 6.9 Hz,
1H), 3.58 (m, 1H), 3.40 (s, 3H), 2.44 (m, 2H), 2.37 (m, 2H),
1.79-1.46 (m, 4H), 1.42 (d, J ) 6.6 Hz, 3H), 1.34 (brs, 8H);
EIMS (m/z) 312 (M+, 0.49), 297 (4.17), 283 (4.37), 267 (20.57),
249 (37.77), 199 (16.90), 169 (31.50), 112 (20.67), 45 (100.00).
(10′EZ,5S,3′S)-3-(11′-Iod o-3′-m et h oxym et h oxyu n d ec-
10′-en -1′-yl)-5-m eth ylfu r a n -2(5H)-on e (5). To a suspension
of CrCl2 (0.081 g, 0.660 mmol) in THF (0.8 mL) at 0 °C was
added a mixture of aldehyde 24 (0.034 g, 0.109 mmol) and
iodoform (0.088 g, 0.224 mmol) in THF (2.5 mL). The reaction
mixture was stirred at 0 °C for 5 h, quenched with H2O, and
extracted with ether. The extracts were washed with brine,
dried, and concentrated. The residue was purified by column
chromatography to afford 5 (0.035 g, 74%) as a 4:1 mixture of
E and Z isomers in the form of an oil. [R]D +37.2 (c 0.20,
CHCl3); 1H NMR (600 MHz, CDCl3) δ 7.03 (d, J ) 1.2 Hz, 1H),
6.52 (dt, J ) 14.4, 7.2 Hz, 0.8 H from one olefinic proton of
trans isomer), 6.18 (m, 0.4 H from two olefinic protons of cis
isomer), 5.98 (dt, J ) 14.4, 1.4 Hz, 0.8 H from one olefinic
proton of trans isomer), 5.01 (qd, J ) 6.6, 1.8 Hz, 1H), 4.67 (d,
J ) 7.2 Hz, 1H), 4.66 (d, J ) 7.2 Hz, 1H), 3.57 (m, 1H), 3.40
(s, 3H), 2.42 (m, 1H), 2.33 (m, 1H), 2.15 and 2.06 (m and m,
together 2 H), 1.81-1.70 (m, 2H), 1.59-1.48 (m, 2H), 1.42 (d,
J ) 6.6 Hz, 3H), 1.42-1.29 (m, 8H); EIMS (m/z) 391 (M+-CH3-
OCH2, 6.92), 375 (47.53), 247 (15.98), 199 (15.81), 167 (31.16),
169 (27.94), 45 (100.00).
To a solution of the above product (0.170 g, 0.42 mmol) in
95% ethanol (4 mL) were added 10% Pd/C (0.025 g) and
triethylamine (0.17 mL, 0.83 mmol). The mixture was stirred
at room temperature for 3 h under 1 atm of pressure of
hydrogen, filtrated through Celite, and concentrated to give
crude product, which was purified by column chromatography
to afford 22 (0.165 g, 97%) as a colorless oil: [R]D +4.29 (c 0.81,
CHCl3); IR (film) 2930, 2853, 1736, 1610, 1510, 1460 cm-1; 1H
NMR (300 MHz, CDCl3) δ 7.27 (d, J ) 8.8 Hz, 2H), 6.89 (d, J
) 8.8 Hz, 2H), 4.65 (s, 2H), 4.44 (s, 2H), 3.82 (s, 3H), 3.68 (s,
3H), 3.54 (m, 1H), 3.42 (t, J ) 6.6 Hz, 2H), 3.39 (s, 3H), 2.34
(t, J ) 7.4 Hz), 1.80-1.45 (m, 8H), 1.31 (brs, 8H); EIMS (m/z)
365 (M+ - MOM, 6.23), 137 (13.82), 121 (100.00), 77 (3.86),
45 (25.77).
(5S,3′S)-3-(3′-Met h oxym et h oxy-10′-p -m et h oxyb en zyl-
oxyd eca n -1′-yl)-5-m eth ylfu r a n -2(5H)-on e (23). To a solu-
tion of diisopropylamine (0.28 mL, 1.98 mmol) in THF (4 mL)
at 0 °C was added BuLi (0.64 mL, 1.6 M solution in hexane,
1.02 mmol). The mixture was stirred at 0 °C for 10 min and
then cooled to -78 °C, and a solution of ester 22 (0.210 g, 0.51
mmol) in THF (4 mL) was added. After 40 min, a solution of
aldehyde 13 (0.162 g, 1.02 mmol) in THF (3 mL) was added.
The reaction was stirred at -78 °C for 1.5 h, quenched with
saturated aqueous NH4Cl solution, and extracted with ether.
The extracts were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified
by column chromatography to afford aldol product (0.280 g,
96%) as a mixture of diastereoisomers. The mixture was
dissolved in AcOH/THF/H2O (10 mL, 4:2:1), stirred at 55 °C
for 2 h, and concentrated in vacuo. To a mixture of the residue
(0.180 g) and triethylamine (0.6 mL, 4.27 mmol) in CH2Cl2 (18
mL) at 0 °C was added trifluoroacetic anhydride (0.36 mL, 2.54
mmol). The reaction mixture was stirred at room temperature
for 20 h, diluted with ether, and washed with saturated
aqueous NaHCO3 solution and brine, dried over Na2SO4.
MOM-P r otected 6,7,12,13,14,14,15,15-Octadeh ydr oton k-
in ecin (26). To a solution of 4 (0.081 g, 0.186 mmol) in Et3N
(8 mL) under N2 were added Pd(PPh3)2Cl2 (9.80 mg, 0.014
mmol) and CuI (7.00 mg, 0.037 mmol). The mixture was stirred
at room temperature for 30 min, and to it was added a solution
of 3 (0.078 g, 0.183 mmol) in Et3N (2 mL). The reaction mixture
was stirred at room temperature for 3 h and concentrated. The
residue was purified by column chromatography to afford 26
1
(0.125 g, 93%) as an oil: [R]D +55.8 (c 0.17, CHCl3); H NMR
(300 MHz, CDCl3) δ 7.02 (d, J ) 1.4 Hz, 1H), 6.03 (dt, J )
15.9, 7.1 Hz, 1H), 5.60 (dt, J ) 10.7, 7.4 Hz, 1H), 5.42 (d, J )
15.8 Hz, 1H), 5.23 (m, 1H), 5.00 (m, 1H), 4.84 (d, J ) 6.9 Hz,
1H), 4.77 (s, 2H), 4.67 (d, J ) 6.9 Hz, 1H), 4.66 (d, J ) 6.6 Hz,

Syntheses of Tonkinecin and Annonacin
J . Org. Chem., Vol. 66, No. 3, 2001 859
1H), 4.48 (d, J ) 6.6 Hz, 1H), 4.40 (m, 1H), 4.13 (m, 1H), 4.00
(m, 1H), 3.64 (q, J ) 5.8 Hz, 1H), 3.47 (m, 1H), 3.41 (s, 3H),
3.39 (s, 3H), 3.36 (s, 3H), 2.65-2.22 (m, 3H), 2.13-1.55 (m,
11H), 1.41 (d, J ) 6.9 Hz, 3H), 1.39 (m, 6H), 1.30-1.18 (m,
20H), 0.87 (t, J ) 6.7 Hz, 3H); ESIMS (m/z) 756 (M + Na+).
Anal. Calcd for C43H72O9: C, 70.48; H, 9.90. Found: C, 70.15;
H, 10.32.
an oil: [R]D -35.2 (c 1.12, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 9.62 (d, J ) 1.5 Hz, 1H), 4.72 (d, J ) 7.0 Hz, 1H), 4.69 (d, J
) 7.0 Hz, 1H), 4.12 (q, J ) 7.1 Hz, 2H), 3.96 (m, 1H), 3.40 (s,
3H), 2.43 (t, J ) 7.3 Hz, 2H), 2.12-1.88 (m, 2H), 1.24 (t, J )
7.1 Hz, 3H); EIMS (m/z) 205 (MH+, 0.25), 173 (M - CH3O,
14.01), 101 (2.87), 45 (100.00).
(2R)-6-Iod o-1,2-O-isop r op ylid en eh exa n e-1,2-d iol (38a ).
To a solution of alcohol 37 (1.540 g, 8.84 mmol) in CH2Cl2 (25
mL) at 0 °C were added triethylamine (2.5 mL), p-toluene-
sulfonyl chloride (3.362 g, 17.68 mmol), and DMAP (cat.). The
reaction mixture was stirred at room temperature for 2 h,
diluted with ether, washed with H2O, saturated aqueous NH4-
Cl solution, and brine, and dried over Na2SO4. The solvents
were removed under reduced pressure, and the residue was
purified by column chromatography to afford a tosylate (2.720,
94%) as a colorless oil: [R]D -7.5 (c 1.1, CHCl3); 1H NMR (300
MHz, CDCl3) δ 7.81 (d, J ) 8.2 Hz, 2H), 7.35 (d, J ) 8.2 Hz,
2H), 4.02 (m, 4H), 3.46 (m, 1H), 2.46 (s, 3H), 1.69 (m, 2H),
1.60-1.36 (m, 4H), 1.38 (s, 3H), 1.34 (s, 3H); EIMS (m/z) 173
(18.96), 155 (11.79), 107 (10.49), 91 (61.06), 85 (100.00).
The above tosylate (2.720 g, 8.28 mmol) was dissolved in
acetone (60 mL), and to it were added sodium iodide (7.422 g,
49.48 mmol) and NaHCO3 (2.064 g, 24.57 mmol). The reaction
mixture was stirred at room temperature overnight. Most of
the solvent was evaporated, and then to the residue was added
ether. The mixture was washed with H2O and brine, dried over
Na2SO4, and concentrated. The crude product was purified by
column chromatography to afford 38a (2.310, 98%) as a
colorless oil: [R]D -8.9 (c 1.75, CHCl3); IR (film) 2981, 2933,
MOM-P r otected 12,13,14,14,15,15-Hexa d eh yd r oton k i-
n ecin e (27). To a solution of 5 (0.035 g, 0.072 mmol) in Et3N
(3 mL) under N2 were added Pd(PPh3)2Cl2 (4.20 mg, 0.006
mmol) and CuI (3.10 mg, 0.016 mmol). The mixture was stirred
at room temperature for 30 min, and to it was added a solution
of 3 (0.036 g, 0.085 mmol) in Et3N (2 mL). The reaction mixture
was stirred at room temperature for 6 h and concentrated. The
residue was purified by column chromatography to afford 27
(0.046 g, 86%) in the form of an oil: [R]D +17.6 (c 0.18, CHCl3);
1H NMR (600 MHz, CDCl3) δ7.02 (d, J ) 1.2 Hz, 1H), 6.04,
5.81 and 5.43 (dt, J ) 15.6, 7.2 Hz, dt, J ) 10.0, 7.2 Hz and
m, together 2H), 5.01 (qd, J ) 6.6, 1.8 Hz, 1H), 4.84 (d, J )
6.6 Hz, 1H), 4.78 (s, 2H), 4.68 (d, J ) 6.6 Hz, 1H), 4.67 (d, J
) 6.6 Hz, 1H), 4.65 (d, J ) 6.6 Hz, 1H), 4.15 (m, 1H), 4.02 (m,
1H), 3.65 (m, 1H), 3.57 (m, 1H), 3.48 (m, 1H), 3.42 (m, 1H),
3.402 (s, 3H), 3.395 (s, 3H), 2.63 (m, 1H), 2.53 (m, 1H), 2.40
(m, 1H), 2.34 (m, 1H), 2.07 (m, 2H), 2.02-1.94 (m, 2H), 1.82-
1.26 (m and brs, 39H), 1.42 (d, J ) 6.6 Hz, 3H); EIMS (m/z)
704 (4.27), 672 (9.07), 642 (15.07), 581 (12.38), 427 (11.99), 397
(20.24), 281 (22.08), 199 (9.00), 169 (11.30).
MOM-P r otected Ton k in ecin (28). To a mixture of enyne
26 (34 mg, 0.047 mmol) and p-toluenesulfony hydrazide (6.010
g, 32 mmol) in dimethoxyethane (6 mL) at reflux was added a
solution of NaOAc‚H2O in H2O over a 2 h period. The reaction
mixture was then cooled to room temperature and extracted
with ether. The extracts were washed with brine and dried
over Na2SO4. Removal of the solvent and purification by
column chromatography afforded 28 (22 mg, 64%) as a
1
2862, 1370 cm-1; H NMR (300 MHz, CDCl3) δ 4.05 (m, 2H),
3.50 (m, 1H), 3.18 (t, J ) 6.9 Hz, 2H), 1.85 (m, 2H), 1.70-1.32
(m, 4H), 1.40 (s, 3H), 1.34 (s, 3H); EIMS (m/z) 269 (M+ - CH3,
25.42), 127 (3.54), 101 (98.26), 43 (100.00). Anal. Calcd for
C9H17O2I: C, 38.04; H, 6.03. Found: C, 38.34; H, 6.18.
Eth yl (5Z,4S,10R)-10,11-Dih yd r oxy-10,11-O-isop r op yl-
id en e-4-m eth oxym eth oxy-5-u n d ecen oa te (39). To a solu-
tion of iodide 38a (0.975 g, 3.43 mmol) in CH3CN (25 mL) were
added PPh3 (1.798 g, 6.86 mmol) and NaHCO3. The mixture
was stirred at 85 °C for 12 h and concentrated under reduced
pressure. To the residue was added CH2Cl2, and the mixture
was filtered and concentrated. The obtained phosphonium salt
was washed with ether several times, dried in vacuo, and
dissolved in THF (30 mL). To it at 0 °C was added NaHMDS
(3.5 mL, 1 M solution in THF, 3.5 mmol). After 30 min, the
reaction mixture was cooled to -78 °C, and a solution of
aldehyde 34 (0.520 g, 2.60 mmol) in THF (6 mL) was added.
The reaction mixture was stirred at -78 °C for 2 h and
quenched with brine, and the solvent was removed under
reduced pressure. To the residue was added ethyl acetate, and
the mixture was washed with ether and brine and dried over
Na2SO4. Removal of the solvent and purification by column
chromatography afforded 39 (0.707 g, 81%) as a colorless oil:
[R]D -87.0 (c 0.97, CHCl3); IR (film) 2982, 2934, 1731, 1449,
1
colorless oil: [R]D +46.6 (c 0.85, CHCl3); H NMR (300 MHz,
CDCl3) δ 7.01 (s, 1H), 4.99 (qd, J ) 6.6, 1.5 Hz, 1H), 4.83 (d,
J ) 6.6 Hz, 2H), 4.65 (m, 4H), 3.96 (m, 2H), 3.55 (m, 1H), 3.45
(m, 2H), 3.38 (s, 9H), 2.45-2.25 (m, 2H), 1.92 (m, 2H), 1.81-
1.57 (m, 4H), 1.57-1.36 (m, 6H), 1.40 (d, J ) 6.6 Hz, 3H), 1.24
(brs, 38), 0.87 (t, J ) 6.2 Hz, 3H); EIMS (m/z) 597 (5.55), 585
(31.29), 573 (32.82), 555(84.89), 403 (42.15), 321 (71.94), 45
(100.00); ESIMS 764 (MNa+). Anal. Calcd for C43H80O9: C,
69.69; H, 10.88. Found: C, 69.56; H, 10.96.
In a similar procedure, 39 mg (0.053 mmol) of compound
27 and 0.682 g (3.64 mmol) of p-toluensulfony hydrazide
afforded 26 mg (66%) of 28.
Ton k in ecin (1). To a solution of 28 (36 mg, 0.0486 mmol)
in dimethyl sulfide (3 mL) at 0 °C was added BF3‚Et2O (0.5
mL). The reaction mixture was stirred at 0 °C for 1.5 h,
quenched with saturated aqueous NaHCO3 solution, and
extracted with ether. The extracts were washed with brine,
dried over Na2SO4, and concentrated under reduced pressure.
The residue was purified by column chromatography to afford
1 (26 mg, 86%) as a waxy solid: [R]D +21.0 (c 0.57, CHCl3)
[lit.4 [R]D +26.54 (c 0.09, CHCl3)]; 1H NMR (600 MHz, CDCl3)
δ 7.03 (d, J ) 1.2 Hz, 1H), 5.01 (dq, J ) 1.2, 6.6 Hz, 1H), 3.81
(m, 2H), 3.60 (m, 1H), 3.41 (m, 2H), 2.46 (m, 1H), 2.38 (m,
1H), 1.99 (m, 2H), 1.76-1.60 (m, 4H), 1.54-1.37 (m, 6H), 1.41
(d, J ) 6.6 Hz, 3H), 1.33-1.24(m, 38H), 0.88 (t, J ) 6.6 Hz,
3H); 13C NMR (150 MHz, CDCl3) δ 174.10, 149.48, 134.08,
82.64, 77.57, 74.10, 70.93, 37.54, 35.40, 33.55, 31.94, 30.00-
29.40 (br), 29.38, 28.80, 25.66, 22.71, 21.52, 19.19, 14.11; EIMS
(m/z) 609, 391, 373, 339, 321, 155; ESIMS (m/z) 632 (MNa+),
610 (MH+), 592 (MH+ - H2O), 556 (MH+ - 3H2O);
Eth yl (4S)-4-Meth oxym eth oxy-5-oxo-p en ta n oa te (34).
Ester 33 (0.965 g, 3.49 mmol) was dissolved in 60% aqueous
AcOH solution, stirred at 45 °C for 1 h, concentrated, and
purified by column chromatography to give the product (0.629
g). The product was dissolved in 21 mL of CH2Cl2/H2O (20:1,
v/v), and to it was added sodium periodate (1.147 g, 5.36
mmol). The reaction mixture was stirred at room temperature
for 1 h, and then Na2SO4 was added. After filtration and
concentration, the residue was purified by column chroma-
tography to afford aldehyde 34 (0.520 g, 73% for two steps) as
1
1371 cm-1; H NMR (300 MHz, CDCl3) δ 5.59 (dt, J ) 10.4,
7.3 Hz, 1H), 5.22 (dd, J ) 11.0, 9.2 Hz, 1H), 4.64 (d, J ) 6.6
Hz, 1H), 4.46 (d, J ) 6.6 Hz, 1H), 4.39 (m, 1H), 4.15-3.98 (m,
4H), 3.48 (m, 1H), 3.34 (s, 3H), 2.39 (t, J ) 7.5 Hz, 2H), 2.11
(m, 2H), 1.95-1.30 (m, 6H), 1.39 (s, 3H), 1.33 (s, 3H), 1.24 (t,
J ) 7.1 Hz, 3H); EIMS (m/z) 329 (M - CH3, 4.23), 101 (14.19),
45 (100.00). Anal. Calcd for C18H32O6: C, 62.77; H, 9.36.
Found: C, 62.73; H, 9.60.
Eth yl (4R,10R)-10,11-Dih ydr oxy-10,11-O-isopr opyliden e-
4-m eth oxym eth oxyu n d eca n oa te (40). A mixture of 39
(1.479 g, 3.42 mmol), 10% Pd/C (0.221 g), and NaHCO3 in
ethanol (25 mL) was stirred at room temperature for 4 h under
1 atm pressure of hydrogen, filtered through Celite, and
washed with ethyl acetate. The filtrate was concentrated under
reduced pressure and purified by column chromatography to
afford 40 (1.440 g, 97%) as a colorless oil: [R]D -18.9 (c 0.76,
CHCl3); IR (film) 2981, 2933, 1731, 1449, 1371 cm-1; 1H NMR
(300 MHz, CDCl3) δ 4.63 (s, 2H), 4.13 (q, J ) 7.1 Hz, 2H), 4.03
(m, 2H), 3.56 (m, 1H), 3.49 (m, 1H), 3.37 (s, 3H), 2.38 (m, 2H),
1.86 (m, 1H), 1.76 (m, 1H), 1.71-1.30 (m, 10H), 1.40 (s, 3H),
1.35 (s, 3H), 1.25 (t, J ) 7.1 Hz, 3H); EIMS (m/z) 331 (M -
CH3, 4.02), 175 (4.43), 101 (8.06), 45 (100.00).

860 J . Org. Chem., Vol. 66, No. 3, 2001
Hu et al.
Eth yl (4R,10R)-10,11-Dih yd r oxy-4-m eth oxym eth oxy-
u n d eca n oa te (41a ). Compound 40 (0.301 g, 0.87 mmol) was
dissolved in 60% aqueous AcOH solution (4.5 mL). The mixture
was stirred at 45 °C for 1 h and concentrated in vacuo. The
crude product was purified by column chromatography to
afford 41a (0.260 g, 98%) a as an oil: [R]D -10.33 (c 1.05,
CHCl3); IR (film) 3398, 2930, 1730, 1448, 1373 cm-1; 1H NMR
(300 MHz, CDCl3) δ 4.62 (s, 2H), 4.12 (q, J ) 7.1 Hz, 2H), 3.68
(m, 2H), 3.55 (m, 1H), 3.42 (m, 2H), 3.36 (s, 3H), 2.37 (t, J )
7.4 Hz, 2H), 2.03 (br, 2H), 1.86 (m, 1H), 1.76 (m, 1H), 1.60-
3478, 2925, 2853, 1731, 1460, 1371 cm-1; 1H NMR (300 MHz,
CDCl3) δ 4.84 (d, J ) 6.6 Hz, 2H), 4.67 (d, J ) 6.6 Hz, 2H),
4.63 (s, 2H), 4.13 (q, J ) 7.1 Hz, 2H), 3.98 (m, 2H), 3.56 (m,
2H), 3.47 (m, 2H), 3.39 (s, 6H), 3.38 (s, 3H), 2.39 (m, 2H), 1.96-
1.22 (m, 49H), 0.88 (t, J ) 6.8 Hz, 3H); ESIMS 742 (MNa+).
Eth yl (4R,10R,15R,2′R,5′R,1′′R)-4,10,15-Tr is(m eth oxy-
m eth oxy)-15-[5′-(1′′-m eth oxym eth oxytr idec-1′′-yl)tetr ah y-
d r ofu r a n -2′-yl]p en ta d eca n oa te (43b). To a mixture of
alcohol 43a (0.172 g, 0.24 mmol) and diisopropylethylamine
(0.82 mL, 4.70 mmol) in CH2Cl2 (3.7 mL) at 0 °C was added
MOMCl (0.27 mL, 3.55 mmol). The mixture was stirred at
room temperature for 5 h, diluted with ether, washed with
H2O and brine, and dried over Na2SO4. The solvent was
removed under reduced pressure, and the residue was purified
by column chromatography to afford 43b (0.174 g, 95%) as a
colorless oil: [R]D +26.30 (c 1.23, CHCl3); IR (film) 2925, 2853,
1.30 (m, 10H), 1.24 (t, J ) 7.1 Hz, 3H); EIMS (m/z) 291 (M+
-
CH3, 0.66), 175 (9.95), 45 (100.00). Anal. Calcd for C15H30O6:
C, 58.80; H, 9.87. Found: C, 58.94; H, 10.12.
Eth yl (4R,10R)-10-Hyd r oxy-4-m eth oxym eth oxy-11-to-
syloxyu n d eca n oa te (41b). To a stirred mixture of 41a (0.140
g, 0.46 mmol) and dibutyltin oxide (0.023 g) in CH2Cl2 (1.5
mL) were added p-toluenesulfonyl chloride (0.091 g, 4.80
mmol) and triethylamine (67 uL). The reaction mixture was
stirred at room temperature for 3 h, diluted with petroleum
ether (3 mL), and chromatographed to afford 41b (0.171 g,
81%) as an oil: [R]D -13.0 (c 0.73, CHCl3); IR (film) 3446, 2934,
1729, 1597, 1449, 1364 cm-1; 1HNMR (300 MHz, CDCl3) δ 7.80
(d, J ) 8.3 Hz, 2H), 7.36 (d, J ) 7.9 Hz, 2H), 4.62 (s, 2H), 4.13
(q, J ) 7.2 Hz, 2H), 4.03 (m, 1H), 3.90-3.78 (m, 2H), 3.52 (m,
1H), 3.37 (s, 3H), 2.46 (s, 3H), 2.38 (m, 2H), 1.95-1.68 (m, 2H),
1.55-1.30 (m, 10H), 1.25 (t, J ) 7.2 Hz, 3H); EIMS (m/z) 443
[(M+ - OH), 2.94], 181 (28.36), 155 (20.48), 91 (44.09), 45
1
1734 cm-1; H NMR (300 MHz, CDCl3) δ 4.83 (d, J ) 6.6 Hz,
2H), 4.66 (d, J ) 6.6 Hz, 2H), 4.635 (s, 2H), 4.631 (s, 2H), 4.13
(q, J ) 7.1 Hz, 2H), 3.98 (m, 2H), 3.60-3.42 (m, 4H), 3.39 (s,
6H), 3.373 (s, 3H), 3.368 (s, 3H), 2.39 (m, 2H), 1.97-1.58 (m,
6H), 1.56-1.22 (m, 43H), 0.88 (t, J ) 6.7 Hz, 3H); EIMS (m/z)
626 (1.83), 594 (8.24), 564 (12.4), 281 (13.69), 45 (100.00). Anal.
Calcd for C42H82O11: C, 66.11; H, 10.83. Found: C, 66.44; H,
10.80.
MOM-P r otected An n on a cin (44). To a solution of diiso-
propylamine (0.13 mL, 0.92 mmol) in THF (1.6 mL) at 0 °C
was added BuLi (0.23 mL, 2.5 M solution in THF, 0.58 mmol).
The mixture was stirred at 0 °C for 10 min and then cooled to
-78 °C, and a solution of ester 42b (0.172 g, 0.23 mmol) in
THF (1.7 mL) was added. After 60 min, a solution of aldehyde
13 (0.080 g, 0.51 mmol) in THF (1 mL) was added. The reaction
was stirred at -78 °C for 2 h, quenched with saturated
aqueous NH4Cl solution, and extracted with ether. The
extracts were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified
with column chromatography to afford aldol product (0.205 g,
98%) as a mixture of diastereoisomers: IR (film) 3461, 2925,
(100.00). Anal. Calcd for
Found: C 57.45, H 7.69.
C22H36O8S: C, 57.37; H, 7.88.
Eth yl (4R,10R)-10,11-Ep oxy-4-m eth oxym eth oxyu n d e-
ca n oa te (6). A mixture of tosylate 41b (0.306 g, 0.66 mmol)
and DBU (0.2 mL) in CH2Cl2 (3 mL) was stirred at room
temperature for 4 h, concentrated and purified by column
chromatography to afford 6 (0.185 g, 97%) as a colorless oil:
[R]D -5.8 (c 1.07, CHCl3); IR (film) 2934, 1731, 1100 cm-1; 1H
NMR (300 MHz, CDCl3) δ 4.63 (s, 2H), 4.13 (q, J ) 7.1 Hz,
2H), 3.56 (m, 1H), 3.38 (s, 3H), 2.90 (m, 1H), 2.75 (dd, J ) 5.0,
3.9 Hz, 1H), 2.46 (dd, J ) 5.0, 2.8 Hz, 1H), 2.39 (m, 2H), 1.95-
1.70 (m, 2H), 1.60-1.31 (m, 10H), 1.26 (t, J ) 7.1 Hz, 3H);
EIMS (m/z) 257 (M+ - CH3O, 1.22), 227 (M+ - MOMO, 15.93),
175 (5.71), 45 (100.00). Anal. Calcd for C15H28O5: C, 62.47; H,
9.79. Found: C, 62.45; H, 9.67.
1
1728, 1466, 1376 cm-1; H NMR (300 MHz, CDCl3) δ 4.83 (d,
J ) 6.6 Hz, 2H) 4.70-4.56 (m, 7H), 4.12 (m, 3H), 3.97 (m, 2H),
3.92-3.52 (m, 3H), 3.47 (m, 4H), 3.39,3.37 (2s, 12H), 2.63 (m,
1H), 2.02-1l.15 (m, 58H), 0.88 (t, J ) 6.6 Hz, 3H); ESIMS
944 (MNa+).
Eth yl (4R,10R,15R,2′R,5′R,1′′R)-4,15-Bis(m eth oxym eth -
oxy)-15-[5′-(1′′-m eth oxym eth oxytr id ec-1′′-yl)tetr a h yd r o-
fu r a n -2′-yl]-10-h yd r oxy-12-p en t a d ecyn oa t e (42). To a
stirred solution of alkyne 3 (72 mg, 0.17 mmol) in THF (1 mL)
at -78 °C was added a solution of BuLi (2.5 M solution in
hexane, 67.5 µL, 0.17 mmol). After 1 h, BF3‚Et2O (21.0 µL,
0.23 mmol) was added. The mixture was stirred for 40 min,
and a solution of epoxide 6 (60 mg, 0.21 mmol) in THF (0.7
mL) was added. The reaction mixture was stirred at -78 °C
for 2 h, quenched with saturated aqueous NH4Cl solution, and
extracted with ether. The extracts were washed with brine,
dried, and concentrated. The residue was purified by column
chromatography to afford 42 (93 mg, 77%) as a colorless oil:
[R]D + 3.5 (c 0.79, CHCl3); IR (film) 3462, 2925, 2852, 1731
The above-obtained mixture (0.200 g, 0.22 mmol) was
dissolved in AcOH/THF/H2O (10 mL, 4:2:1). The reaction
mixture was stirred at 45 °C for 5 h and concentrated in vacuo.
To a mixture of the residue (0.195 g) and triethylamine (0.34
mL, 2.42 mmol) in CH2Cl2 (9.5 mL) at 0 °C was added
trifluoroacetic anhydride (0.20 mL, 1.41 mmol). The reaction
mixture was stirred at room temperature for 20 h, diluted with
ether and washed with saturated aqueous NaHCO3 solution
and brine, dried over Na2SO4. Removal of the solvent gave
crude product which, after chromatography, afforded 44 (0.076
1
g, 45%) as a colorless oil: [R]D +38.0 (c 0.8, CHCl3); H NMR
(300 MHz, CDCl3) δ 7.16 (s, 1H), 5.02 (m, 1H), 4.84 (d, J ) 6.6
Hz, 2H), 4.70-4.61 (m, 6H), 3.97 (m, 2H), 3.82 (m, 1H), 3.58-
3.35 (m, 3H), 3.39 (s, 6H), 3.37 (s, 3H), 3.34 (s, 3H), 2.51 (m,
1H), 2.49 (m, 1H), 1.93 (m, 2H), 1.78-1.20 (m, 45H), 1.39 (d,
J ) 8.0 Hz, 3H), 0.88 (t, J ) 6.6 Hz, 3H); ESIMS 796 (MNa+).
1
cm-1; H NMR (600 MHz, CDCl3) δ 4.88 (d, J ) 6.6 Hz, 1H),
4.78 (d, J ) 6.6 Hz, 1H), 4.74 (d, J ) 6.6 Hz, 1H), 4.66 (d, J )
6.6 Hz, 1H), 4.64 (d, J ) 6.6 Hz, 1H), 4.62 (d, J ) 6.6 Hz, 1H),
4.13 (q, J ) 7.2 Hz, 2H), 4.13 (m, 1H), 4.01 (m, 1H), 3.67 (m,
1H), 3.64 (q, J ) 7.0 Hz, 1H), 3.56 (m, 1H), 3.46 (m, 1H), 3.41
(s, 3H), 3.40 (s, 3H), 3.37 (s, 3H), 2.52 (m, 1H), 2.45-2.34 (m,
4H), 2.23 (ddd, J ) 14.4, 7.8, 2.4 Hz, 1H), 1.96 (m, 2H), 1.88
(m, 1H), 1.76 (m, 2H), 1.66 (m, 1H), 1.57-1.21 (m, 35H), 0.88
(t, J ) 6.9 Hz, 3H); EIMS (m/z) 590 (3.39), 559 (4.34), 213
(24.26), 45 (100.00); ESIMS 738 (MNa+). Anal. Calcd for
An n on a cin (2). To a solution of 62 (66 mg, 0.085 mmol) in
dimethyl sulfide (7.2 mL) at 0 °C was added BF3‚Et2O (1.1
mL). The reaction mixture was stirred room temperature for
40 min, cooled to 0 °C, quenched with saturated aqueous
NaHCO3 solution, and extracted with ethyl acetate. The
extracts were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified
by column chromatography to afford 2 (44 mg, 86%) as a white
solid: mp 69-71 °C; [R]D +21 (c 0.51, CHCl3) [lit.17 [R]D +20.78
(c 5.05 CHCl3)]; [R]D +19 (c 0.40, CH3OH) [lit.18 [R]D ) 11.4 (c
0.04 CH3OH)]; 1H NMR (600 MHz, CDCl3) δ 7.18 (s, 1H), 5.06
C
40H74O10: C, 67.19; H, 10.43. Found: C, 67.42; H, 10.28.
Eth yl (4R,10R,15R,2′R,5′R,1′′R)-4,15-Bis(m eth oxym eth -
oxy)-15-[5′-(1′′-m eth oxym eth oxy-tr id ec-1′′-yl)tetr a h yd r o-
fu r a n -2′-yl]-10-h yd r oxyp en ta d eca n oa te (43a ). A mixture
of 42 (0.210 g, 0.29 mmol) and PtO2 (8 mg) in ethanol (4 mL)
was stirred at room temperature for 3 h under 1 atm pressure
of hydrogen and filtered. The filtrate was concentrated and
purified by column chromatography to afford 43a (0.195 g,
92%) as a colorless oil: [R]D +29.5 (c 0.77, CHCl3); IR (film)
(17) Zhang, L.-L.; Yang, R.-Z.; Wu, S.-J . Acta Botanica Sinica (Zhiwu
Xuebao) 1993, 35, 390.
(18) Chen, W.-S.; Yao, Z.-J .; Wu, Y.-L. Youji Huaxue 1995, 15, 85.

Syntheses of Tonkinecin and Annonacin
J . Org. Chem., Vol. 66, No. 3, 2001 861
(q, J ) 6.6 Hz, 1H), 3.85 (m, 1H), 3.81 (dt, J ) 11.7, 6.6 Hz,
2H), 3.59 (m, 1H), 3.41 (dt, J ) 11.7, 6.0 Hz, 2H), 2.52 (d, J )
14.7 Hz, 1H), 2.40 (dd, J ) 14.7, 7.8 Hz, 1H), 2.04 (br. 4 OH),
1.99 (m, 2H), 1.68 (m, 2H), 1.60-1.20 (m, 40H), 1.43 (d, J )
7.2 Hz, 3H), 0.88 (t, 6.8 Hz, 3H); 13C NMR (150 MHz, CDCl3)
δ 174.58, 151.80, 131.18, 82.67, 82.60, 77.95, 74.05, 73.95,
71.74, 69.90, 37.36, 37.27, 33.48, 33.37, 29.70-29.57 signal
overlap, 29.47, 29.32, 28.72, 25.64, 25.58, 25.48, 22.66, 19.09,
14.08.
ence Foundation of China (29472070, 29790126), and
the Major State Basic Research Development Program
(G2000077502). We are grateful to Professor D. Q. Yu,
Institute of Material Medical, Chinese Academy of
Medical Sciences, for comparing the spectra of 1 with
those of the natural product.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for compounds 8-10, 12a ,b, 30-33, 36, and 37. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Ack n ow led gm en t. This research was supported by
the State Ministry of Science and Technology of China
(970211006-6), Chinese Academy of Sciences (KJ -951-
A1-504-04, KJ -952-S1-503), the National Natural Sci-
J O005643B