The first total synthesis of annonacin, the most typical monotetrahydrofuran annonaceous acetogenins.

Article abstract of DOI:10.1021/ol005504g

The first total synthesis of annonacin (1) was achieved by a highly convergent synthetic strategy. All the stereogenic centers were derived from three natural hydroxy acids respectively, except that those at C19 and C20 were produced from a Sharpless AD reaction.

Full text of DOI:10.1021/ol005504g

ORGANIC
LETTERS
2000
Vol. 2, No. 7
887-889
The First Total Synthesis of Annonacin,
the Most Typical Monotetrahydrofuran
Annonaceous Acetogenins
Tai-Shan Hu, 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 January 3, 2000
ABSTRACT
The first total synthesis of annonacin (1) was achieved by a highly convergent synthetic strategy. All the stereogenic centers were derived
from three natural hydroxy acids respectively, except that those at C19 and C20 were produced from a Sharpless AD reaction.
Annonacin (1), the first monotetrahydrofuran acetogenin
discovered, was isolated by Cassady and co-workers from
the stembark of Annona densicoma in 19871 and subse-
quently was also found in more than 10 other species of
Annonaceae.2 This compound demonstrated 9ASK (astro-
cytoma reversal) activity and high cytotoxicity against KB
cells (human nasopharyngeal carcinoma) and P388 cells
(mouse leukemia).1,2a Although to some extent the structure
of annonacin seems to be simple, the construction of the
seven chiral centers, especially the two isolated at C4 and
C10, still presents a challenge. To date there is no report on
the synthesis of annonacin, although the synthesis3 of a
diastereomer of annonacin A, the C-20 epimer of annonacin,
has recently been achieved. In this Letter, we describe the
first total synthesis of annonacin 1.
Our retrosythetic analysis of 1 is illustrated in Figure 1.
Thus, the key precursor 2 was dissected into two major
(1) McCloud, D. J.; Smith, D. L.; Chang, C.-J.; Cassady, J. M.
Experientia 1987, 59, 947.
(2) For other isolations, see: (a) Alkofahi, A.; Rupprecht, J. K.; Smith,
D. L.; Chang, C.-J.; Maclaughlin, J. L. Experientia 1988, 44, 83. (b) Chen,
W.-S.; Yao, Z.-J.; Wu, Y.-L. Youji Huaxue 1995, 15, 85. (c) Jossang, A.;
Dubaele, A.; Cave, A.; Bartoli, M.-H.; Beriel, H. Tetrahedron Lett. 1990,
Figure 1.
31, 1861. (d) Ye, Q.; Zeng, L.; Zhang, Y.; Zhao, G.-X.; Maclaughlin, J.
L.; Woo, M. H. and Evert, D. R. J. Nat. Prod. 1995, 58, 1398. (e) Zhang,
L.-L.; Yang, R.-Z.,; Wu, S.-J. Acta Botanica Sinica (Zhiwu Xuebao) 1993,
building blocks, the THF unit 3 and the epoxide 4. The THF
35, 390.
(3) Hanessian, S.; Grillo, T. A. J. Org. Chem. 1998, 63, 1049.
fragment 3 could be prepared from D-glucono-δ-lactone via
10.1021/ol005504g CCC: $19.00 © 2000 American Chemical Society
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by an acid-catalyzed ring closure reaction gave lactone 10.
A subsequent multistep transformation with the Sharpless
asymmetric dihydroxylation reaction as a key step to
introduce the C19 and C20 chiral centers, reported by us
earlier,6 was adapted to furnish the THF acetylene 3.
Scheme 1a
The synthesis of epoxide 4 is summarized in Scheme 2.
The R-hydroxy ester7 11 obtained from L-ascorbic acid was
protected as the MOM ether before the chain was elongated
by two carbons to give ester 15 using a four-step sequence.
The reduction of 12 with LAH gave alcohol 13. Swern
oxidation of 13 followed by a Wittig reaction with carbe-
thoxymethylenetriphenyphosphorane led to R,â-unsaturated
ester 14. Subsequent hydrogenation afforded the correspond-
8
ing saturated ester 15, which was then treated with H5IO6
to give the chiral aldehyde 5.
On the other hand, 11 was converted to 2-deoxy ester 16
according to a known procedure.9 Reduction with LAH of
16 followed by Swern oxidation, a Wittig reaction, and
hydrogenation gave ester 17 as mentioned above for the
preparation of 15. After reduction with LAH, the resultant
alcohol 18 was converted to iodide 20 by tosylation, followed
by substitution with iodide. The latter, upon reaction with
PPh3, afforded phosphonium salt 6. Treatment of 6 with
NaHMDS generated the corresponding ylide, which reacted
with aldehyde 5 to give olefin 21. Hydrogenation and
cleavage of the isopropylidene group in 22 with aqueous
HOAc led to 1,2-diol 23, which was transformed selectively
to primary tosylate 24 by Bu2SnO-catalyzed tosylation.10
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 6.
a multiple-step sequence, while epoxide 4 could be synthe-
sized from L-ascorbic acid via phosphonium salt 6 and
aldehyde 5.
The THF fragment 3 was prepared as shown in Scheme
1. The D-glucono-δ-lactone-derived R-hydroxyl ester4 7 was
deoxygenated using the PPh3/I2/imidazole system5 to give
2-deoxy ester 8, which was treated with LiHMDS to produce
R,â-unsaturated ester 9. Catalytic hydrogenation followed
Scheme 2a
i
a Reagents and conditions: (a) MOMCl, Pr2NEt, CH2Cl2, 0 °C f rt, 88%; (b) LAH, THF, 0 °C f rt, 96%; (c) (i) oxalyl chloride,
DMSO, iPr2NEt; (ii) PPh3dCHCO2Et, CH2Cl2, reflux, 81%; (d) H2/Pd-C, EtOH, rt, 97%; (e) H5IO6, Et2O, rt, 71%; (f) ref 9; (g) (i) LAH,
THF, 0 °C f rt; (ii) oxalyl chloride, DMSO, Et3N; (iii) PPh3dCHCO2Et, CH2Cl2, reflux, 73% for three steps; (iv) H2/Pd-C, EtOH, rt,
95%; (h) (i) LAH, THF, 0 °C f rt, 95%; (ii) p-TsCl, Et3N, CH2Cl2, 0 °C f rt, 94%; (iii) NaI, acetone, rt, 98%; (i) PPh3, Na2CO3, CH3CN,
quantitative; (j) NaHMDS, THF, 0 f -78 °C, then 5, 81%; (k) H2/Pd-C, NaHCO3, EtOH, rt, 97%; (l) (i) 60% aqueous HOAc, 97%; (ii)
p-TsCl, Et3N, Bu2SnO (cat.), CH2Cl2, 81%; (m) DBU, CH2Cl2, rt, 97%.
888
Org. Lett., Vol. 2, No. 7, 2000

Thus, the lithiated derivative of THF alkyne 3 was reacted
with epoxide 4 in the presence of BF3‚Et2O to afford alkynol
25. Catalytic hydrogenation of 25 with PtO2 in ethanol gave
the corresponding alcohol, which was then protected as the
MOM ether 2. It is noteworthy that hydrogenation of 25 over
Pd/C led to ca. a 1:1 ratio of the desired alcohol and the
10-deoxygenated byproduct. Subsequent construction of the
butenolide segment of 1 was furnished using the method
developed by us.11 Accordingly, the enolate derived from 2
was condensed with (S)-O-THP lactal prepared from (+)-
ethyl lactate to give the aldol product, which was subjected
to acidic cleavage of the THP group and dehydration with
trifluoroacetic anhydride and triethylamine12 to give the R,â-
unsaturated lactone 26. The final removal of all of the MOM
protecting groups with boron trifloride etherate in the
presence of dimethyl sulfide afforded annonacin 1,13 whose
Rf value and spectroscopic data are identical to those reported
for the natural product.
Scheme 3a
Acknowledgment. This research was supported by the
State Ministry of Science and Technology of China
(970211006-6), the Chinese Academy of Sciences (KJ-951-
A1-504-04, KJ-952-S1-503), and the National Natural Sci-
ence Foundation of China (29472070, 29790126).
a Reagent and conditions: (a) BuLi, THF, -78 °C, 1 h, then
BF3‚Et2O, 30 min, then 4, 77%; (b) (i) PtO2, EtOH, rt, 93%; (ii)
OL005504G
i
MOMCl, Pr2NEt, CH2Cl2, 0 °C f rt, 95%; (c) (i) LDA, THF,
(7) (a) Wei, C. C.; De Bernardo, S.; Tengi, J. P.; Borgese, J.; Weigele,
M. J. Org. Chem. 1985, 50, 3462. (b) Jung, M. E.; Shaw, T. J. J. Am.
Chem. Soc. 1980, 102, 6304.
(8) Wu, W.-L.; Wu, Y.-L. J. Org. Chem. 1993, 58, 3586.
(9) Tanaka, A.; Yamashida, K. Synthesis 1987, 570.
-78 °C, then O-THP lactaldehyde; (ii) HOAc/THF/H2O (4:2:1);
(iii) (CF3CO)2O, Et3N, 0 °C f rt, 41% for three steps; (d) BF3‚Et2O,
Me2S, 0 °C f rt, 85%.
(10) Martinelli, M. J.; Nayyar, N. K.; Moher, E. D.; Dhokte, U. P.;
Pawlak, J. M.; Vaidyanathan, R. Org. Lett. 1999, 1, 447.
(11) (a) Yao, Z.-J.; Wu, Y.-L. Tetrahedron Lett. 1994, 35, 157. (b) Yao,
Z. J.; Wu, Y. L. J. Org. Chem. 1995, 60, 1170.
Then the momotosylate was treated with DBU to afford the
epoxide 4 in excellent yield.
With the two major fragments 4 and 3 in hand, we
proceeded to complete the carbon skeleton of 1 (Scheme 3).
(12) Marshall, J. A.; Jiang, H. J. Org. Chem. 1999, 64, 971.
(13) Physical data for synthetic annonacin: white solid; mp 69-71 °C;
[R]D ) +21 (c 0.51, CHCl3) {lit.2e [R]D ) 20.78 (c 5.05 CHCl3)}; [R]D
)
+19 (c 0.40, CH3OH) {lit.2b [R]D ) 11.4 (c 0.04 CH3OH)}; 1H NMR (600
MHz CDCl3) δ 7.18 (s, 1H), 5.06 (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.
(4) Regeling, H.; Rouville, E.; Chittenden, G. J. F. Recl. TraV. Chim.
Pays-Bas 1987, 106, 461.
(5) Rauter, A. P.; Fernandes, A. C.; Figueiredo, J. A. J. Carbohydr. Chem.
1998, 17, 1037.
(6) (a) Yu, Q.; Wu, Y.-K.; Ding, H.; Wu, Y.-L. J. Chem. Soc., Perkin
Trans. 1 1999, 1183. (b) Hu, T.-S.; Yu, Q.; Lin, Q.; Wu, Y.-L.; Wu, Y.
Org. Lett. 1999, 1, 399.
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