The first synthesis of tonkinecin, an annonaceous acetogenin with a C-5 carbinol center

Article abstract of DOI:10.1021/ol990062y

(formula presented) Reported herein is the first synthetic approach to tonkinecin (1) which uses a palladium-catalyzed cross-coupling reaction between the tetrahydrofuran unit (4) and the butenolide (3) as the key step for constructing the backbone of 1. The stereogenic centers at C-5, C-21, C-22, and C-36 were derived from D-xylose, D-glucose, and L-lactate, respectively, whereas those at C-17, and C-18 were generated using Sharpless asymmetric dihydroxylation.

Full text of DOI:10.1021/ol990062y

ORGANIC
LETTERS
1999
Vol. 1, No. 3
399-401
The First Synthesis of Tonkinecin, an
Annonaceous Acetogenin with a C-5
Carbinol Center
Tai-Shan Hu, Qian Yu, Qi Lin, Yu-Lin Wu,* and Yikang Wu
State Key Laboratory of Bio-organic & Natural Products Chemistry and
Shanghai-Hong Kong Joint 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 April 28, 1999
ABSTRACT
Reported herein is the first synthetic approach to tonkinecin (1) which uses a palladium-catalyzed cross-coupling reaction between the
tetrahydrofuran unit (4) and the butenolide (3) as the key step for constructing the backbone of 1. The stereogenic centers at C-5, C-21, C-22,
and C-36 were derived from D-xylose, D-glucose, and L-lactate, respectively, whereas those at C-17, and C-18 were generated using Sharpless
asymmetric dihydroxylation.
Tonkinecin 1 is a monotetrahydrofuran acetogenin with a
hydroxyl group at C-5 recently isolated from roots of UVaria
tonkinesis by Yu and co-workers. This compound has
demonstrated potent cytotoxity against the Bel 7402 (hep-
toma), BGC (gastrocarcinoma), HCT-8 (colon adenocari-
noma), and HL-60 (leukemia) human tumor cell lines.1
Because among the several hundreds of known acetogenins
only a few2 have a hydroxyl at C-5 and (to the best of our
(1) Chen, Y.; Yu, D.-Q. J. Nat. Prod. 1996, 59, 507.
(2) Hisham, A.; Pieters, L. A. C.; Claeys, M.; Esmans, E.; Dommisse,
R.; Vlietink, A. J. Phytochemistry 1991, 30, 545. (b) Hisham, A.; Pieters,
L. A. C.; Claeys, M.; Esmans, E.; Dommisse, R.; Vlietink, A. J.
Phytochemistry 1991, 30, 2373. (c) Raynaud, S.; Fourneau, C.; Hoc-
quemiller, R.; Sevenet, T.; Hadio, H. A.; Cave, A. Phytochemistry 1997,
46, 321.
(3) Yao, Z.-J.; Wu, Y.-L. Tetrahedron Lett. 1994, 35, 157.
(4) Yadav, J. S.; Barma, D. K. Tetrahedron 1996, 52, 4457.
(5) (a) Kang, S. K.; Kim, S. G.; Park, D. C.; Lee, J. S.; Yoo, W. J.; Pak,
C. S. J. Chem. Soc., Perkin Trans. 1 1993, 9. (b) Wu, W.-L.; Li, J.; Wu,
Y.-L. Chin. J. Chem. 1994, 12, 562.
(6) Wu, W.-L.; Wu, Y.-L. J. Org. Chem. 1993, 58, 3586.
(7) Brandsma, L. PreparatiVe Acetylenic Chemistry, 2nd ed.; Elsevier:
Amsterdam, 1988; p 245.
(8) Yu, Q.; Wu, Y.-K.; Ding, H.; Wu, Y.-L. J. Chem. Soc., Perkin Trans.
1 1999, 1183.
(9) Hoye, T. R.; Hanson, P. R.; Kovelesky, A. C.; Ocain, T. D.; Zhuang,
Z. P. J. Am. Chem. Soc. 1991, 113, 9369.
(10) Marshall, J. A.; Hinkle, K. W. J. Org. Chem. 1997, 62, 5989.
Figure 1.
10.1021/ol990062y CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/25/1999

Scheme 1a,b
A
B
a Reagents and conditions for part A: (a) (i) Ph3PdCHCO2Et, benzoic acid (cat.), THF, reflux; (ii) acetone, concentrated H2SO4 (cat.),
CuSO4, room temperature, 52%; (b) Mg, CH3OH, reflux, 61%; (c) MOMCl, i-Pr2NEt, CH2Cl2, 0 °C f room temperature, 98%; (d) (i)
LDA, THF-HMPA (6:1,v/v), -78 °C; then (S)-O-tetrahydropyranyl lactal, 71%; (ii) Ac2O, Py, room temperature, 90%; (e) H5IO6, Et2O,
room temperature, 84%. b Reagents and conditions fot part B: (a) LiNH2, NH3 (liquid), n-C4H9Br, 72%; (b) KAPA, 1,3-diaminopropane,
73%; (c) DHP, PPTS (cat.), CH2Cl2, room temperature, 95%; (d) (i) Bu3SnH, AIBN (cat.), 130 °C; I2, Et2O; (ii) PTSA (cat.), CH3OH, room
temperature, 94%; (e) PPh3, CBr4, CH2Cl2, 0 °C f room temperature, 90%; (f) PPh3, CH3CN, reflux, quantitative; (g) LiHMDS, THF-
HMPA (6:1, v/v), -78 °C, then 5, 31%.
knowledge) no synthesis has been done on these compounds,
development of synthetic routes to such compounds is
warranted. Herein, we describe the first total synthesis of
one of them, tonkinecin (1).
and subsequent glycol cleavage by periodic acid in one-pot6
led to chiral aldehyde 5 in 84% yield.
Phosphonium salt 6 was prepared from prop-2-yn-1-ol and
1-bromobutane via a series of transformations. First, an
alkylation of prop-2-yn-1-ol with 1-bromobutane gave acety-
lenic alcohol 11 in 72% yield. The latter was then subjected
to the acetylene zipper reaction7 with potassium 3-amino-
propylamide (KAPA) in 3-aminopropylamine to give the
terminal acetylene 12 in 71% yield. After protection as THP
ether, compound 13 was treated with tributyltin hydride and
iodine. The subsequent cleavage of THP group in 13 afforded
alcohol 14 (89% overall yield from 12). Substitution of the
OH with Br using PPh3/CBr2 gave bromide 15, which was
then converted to the phosphonium salt 6 before being
subjected to further coupling with aldehyde 5 and concomi-
tant elimination of acetate ester to afford the desired
butenolide unit 3 in 31% yield. The low yield at the
Wittig reaction step is believed to be caused by elimination
of the vinyl iodide under the basic conditions, and better
alternatives are currently under exploration.
Our retrosynthesis of 1 is illustrated in Figure 1. Thus the
key precursor 2 would be synthesized by the Pd(0)-catalyzed
cross-coupling reaction of tetrahydrofuran unit 4 with vinyl
iodide 3. The chiral center C-5(S) of 1 was derived from
D-xylose, C-17(R) and C-18(R) from D-glucose, and C-36-
(S) from (S)-ethyl lactate, respectively, while the desired
stereochemistries at C-21(R) and C-22(R) were established
by Sharpless asymmetric dihydroxylation.
As shown in Scheme 1, the butenolide unit 3 was furnished
by Wittig reaction of the chiral aldehyde 5 and the Wittig
reagent 6. The synthesis of chiral aldehyde 5 began with
D-xylose and involved construction of a γ-lactone moiety
utilizing the methodology3 developed by us. Thus D-xylose
was converted to R,â-unsaturated ester 7 in 52% yield
according to a known procedure.4 Reductive cleavage of this
R,â-unsaturated ester with Mg in methanol5 provided the
δ-hydroxyl ester 8 in 61% yield which was then protected
as MOM ether. Condensation of the enolate derived from 9
with (S)-O-tertrahydropyranyl lactal from (+)-ethyl lactate,
followed by acetylation of the resulting â-hydroxy group,
gave compound 10 as a mixture of diastereoisomers. Selec-
tive removal of isopropylidene acetal and THP group in 10
The tertrahydrofuran part of 4 was constructed (Scheme
2) from D-glucose via epoxide 16 employing a sequence
reported8 by us earlier. Ring opening of this epoxide with
lithiotrimethysilyacetylide in the presence of boron trifloride
etherate afforded the alkynol, which after removal of the
TMS group at the triple bond terminal and protecting the
400
Org. Lett., Vol. 1, No. 3, 1999

reaction9 between the tertrahydrofuran unit 4 and the
butenolide unit 3, which occurred smoothly giving 2 in 93%
yield (Scheme 3). Selective hydrogenation with diimide10
Scheme 2a
Scheme 3a
a Reagents and conditions: (a) ref 8; (b) i. trimethylsilylacetylene,
n-BuLi, BF3‚Et2O then 16, THF; ii. n-Bu4NF, THF, 90%; iii.
i
MOMCl, Pr2NEt, CH2Cl2, 86%.
OH as MOM ether gave the tetrahydrofuran unit 4. Unlike
in our previous8 work, where 4 was used directly in the
subsequent reaction, this time we isolated this compound and
subjected it to full characterization.
The completion of the construction of the entire carbon
skeleton was achieved by Pd(0)-catalyzed cross-coupling
(11) Physical and spectroscopic data. For 3 (as a 1:5 mixture of cis and
1
trans isomers): IR (film) 1747, 1651 cm-1; H NMR (300 MHz, CDCl3)
a Reagents and conditions: (a) (PPh3)2PdCl2, CuI, Et3N, room
temperature, 93%; (b) TsNHNH2, NaOAc‚3H2O, DME, reflux,
64%; (c) BF3‚Et2O, Me2S, 0 °C, 81%.
δ 7.02 (s, 1H), 6.49 (dt, J ) 14.3, 7.1 Hz, 0.83 H, from one proton in the
trans isomer), 6.17 (m, 0.33 H, from two olefinic protons in the cis isomer),
5.99 (d, J ) 14.3 Hz, 0.83 H, from one proton in the 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),
4.39 (m, 1H), 3.37 (s, 3H), 2.36 (m, 2H), 2.07 (m, 4H), 1.92-1.65 (m,
2H), 1.41 (d, J ) 6.6 Hz, 3H), 1.45-1.31 (m, 4H). For 4: [R]D 23.0 (c 0.5,
CHCl3); EI MS (m/z) 365 (M+ - MOM); 1H NMR (300 MHz, CD3COCD3)
δ 4.82 (d, J ) 6.7 Hz, 1H), 4.75 (s, 2H), 4.61 (d, J ) 6.7 Hz, 1H), 4.12 (m,
1H), 3.97 (m, 1H), 3.60 (m, 1H), 3.44 (m, 1H), 3.35 (s, 3H), 3.32 (s, 3H),
2.43 (m, 3H), 1.98 (m, 2H), 1.70 (m, 2H), 1.30-1.20 (m, 22H), 0.87 (t, J
) 6.6 Hz, 3H). For 2: ESI MS (m/z) 756 (M+ + Na); 1H NMR (300 MHz,
CDCl3) δ 7.02 (d, J ) 1.4 Hz, 1H), 6.03 (dt, J ) 15.8, 7.1 Hz, 1H), 5.60
(dt, J ) 10.7, 7.4 Hz, 1H), 5.43 (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, 1H), 4.48 (d, J ) 6.6 Hz, 1H), 4.40 (m, 1H), 4.13 (m,
1H), 4.00 (m, 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). For 1: [R]D 21.0
(c 0.57, CHCl3) (lit.1 [R]D 26.54 (c 0.09, CHCl3)); EI MS (m/z) 609, 391,
373, 339, 321, 155; ESI MS (m/z) 632 (M+ + Na), 610 (M + 1), 592 (M
and removal of the MOM protecting group with boron
trifloride etherate in the presence of dimethyl sulfide gave
tonkinecin 1.11 The physical data of our synthetic sample
are identical to those of the natural one.
Acknowledgment. This work was supported by the State
Committee of Science and Technology of China, Chinese
Academy of Sciences (KJ-951-A1-504-04, KJ-952-S1-503)
and the National Science Foundation of China (29472070,
29790126). We are grateful to Professor De-Quan Yu of
Institute of Materia Medica, Chinese Academy of Medical
Sciences for comparing the spectra of our 1 with those of
the natural one.
1
+ 1 - H2O), 556 (M + 1 - 3H2O); H 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.
OL990062Y
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