A facile route to the total synthesis of gigantetrocin A

Article abstract of DOI:10.1016/S0957-4166(99)00039-7

A highly efficient synthetic method of the trans-mono-tetrahydrofuran (THF) ring building block was established and the title compound synthesized in 19 steps from trans-1,4-dichloro-2-butene via a convergent route with a Wittig reaction as the key step.

Full text of DOI:10.1016/S0957-4166(99)00039-7

Pergamon
Tetrahedron: Asymmetry 10 (1999) 667–670
A facile route to the total synthesis of gigantetrocin A
Zhi-Min Wang, Shi-Kai Tian and Min Shi ∗
Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, People’s Republic of China
Received 16 December 1998; accepted 19 January 1999
Abstract
A highly efficient synthetic method of the trans-mono-tetrahydrofuran(THF) ring building block was established
and the title compound synthesized in 19 steps from trans-1,4-dichloro-2-butene via a convergent route with a
Wittig reaction as the key step. © 1999 Elsevier Science Ltd. All rights reserved.
In recent years, the rapidly growing class of naturally occurring Annonaceous acetogenins has received
considerable attention, due to their broad spectrum of biological activities such as cytotoxic, antitumor,
antimicrobial, antimalarial, antifeedant, pesticidal and immunosuppressive effects.1 Gigantetrocin A was
isolated by McLaughlin’s group from Goniothalamus giganteus Hook. f. and Thomas (Annonaceae)2 and
showed significant and selective cytotoxicity to human tumor cells in culture.2,3 Its absolute configuration
has been determined by spectroscopic analysis. The striking characteristics are the existence of four
hydroxyl groups, an α,β-unsaturated γ-lactone and a mono trans-tetrahydrofuran (THF) ring unit
(Fig. 1).
Figure 1.
Although its diasteromer (+)-densicomacin has been synthesized by Cassady’s group,4 no successful
synthesis of this interesting natural product has been achieved to date. Herein we wish to report our facile
route to the first total synthesis of gigantetrocin A.
A Sharpless AD reaction5 on trans-1,4-dichloro-2-butene 1 installed the two primitive obtained
stereogenic centers, with greater than 94% ee,6 in the mono-THF ring backbone. The diol 2 was
subsequently treated with NaH and allylmagnesium chloride in the presence of CuI to produce another
diol 3 in 79% yield which was mono-protected by MOMCl and then oxidatively cyclized to form a mono
∗
Corresponding author. E-mail: mshi@pub.sioc.ac.cn
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00039-7

668
Z.-M. Wang et al. / Tetrahedron: Asymmetry 10 (1999) 667–670
trans-THF ring compound 5 with greater than 95% de7 in 78% yield using Co(modp)28 as a catalyst under
an oxygen atmosphere. Protection of 5 gave benzyl ether 6 which was dihydroxylated and underwent an
oxidative cleavage reaction to afford aldehyde 7. The Horner–Emmons reaction on 7 gave 8, and diol
9 was obtained by the use of a further Sharpless AD reaction. After protection of the diol group by
isopropylidene ketal, aldehyde 11 was produced by reduction with LiAlH4 and Swern oxidation which
then reacted with Wittig salt CH3(CH2)12P+Ph3Br− in the presence of BuLi in THF to give 12 (E-isomer
predominated). The catalytic hydrogenation over Pd/C gave segment 13 in 83% yield (Scheme 1).
Scheme 1.
Preparation of segment 21 is shown in Scheme 2. Epoxide 149 was opened by lithium alkynylide 15 in
the presence of BF3·OEt2 and the resulting alcohol was treated with MOMCl/i-Pr2NEt to give 16. Aldol
condensation of the enolate for 16 and aldehyde 1710 produced compound 18. Protection of the newly
generated hydroxyl group in 18 as a MOM ether and treatment with 9% H2SO4:THF (1:3) afforded
lactone 19.10 Bromination of the propargyl alcohol 19 gave segment 20, which was then reacted with
PPh3 to afford the Wittig salt 21.
The coupling reaction between aldehyde 22, prepared from 13 in situ by Swern oxidation, and the ylide
prepared from 21 gave enyne 23 (Z-isomer predominated) in 28% yield which was hydrogenated over
Wilkinson’s catalyst and then treated with DBU to afford 2411 in 69% yield (Scheme 3). Deprotection of
20
24 by BF3·OEt2 gave the target compound in 59% yield which has a very close specific rotation {[α]
D
+13.1 (c 0.35, CHCl3); lit.3 [α]20 +14.3 (c 0.45, CHCl3)} and the same spectral data as those reported in
D
other literature.2,3

Z.-M. Wang et al. / Tetrahedron: Asymmetry 10 (1999) 667–670
669
Scheme 2.
Scheme 3.
In conclusion, we have developed an efficient procedure for the stereocontrolled synthesis of the THF
ring unit and a convenient route for coupling this key intermediate with other building blocks. The first
total synthesis of gigantetrocin A has been achieved in 19 steps from trans-1,4-dichloro-2-butene (1).
Acknowledgements
We thank the National Natural Sciences Foundation of China for financial support.
References
1. Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z.-M.; He, K.; Mclaughlin, J. L. Nat. Prod. Rep. 1996, 13, 275.
2. Fang, X.-L.; Rupprecht, J.-K.; Alkofahi, A.; Hui, Y.-H.; Liu, Y.-M.; Smith, D. L.; Wood, K. V., Mclaughlin, J. L.
Heterocycles 1991, 32, 11.
3. Rieser, M. J.; Fang, X.-L.; Anderson, J. E.; Miesbauer, L. R.; Smith, D. L.; Mclaughlin, J. L. Helv. Chim. Acta 1993, 76,
2433 and references cited therein.

670
Z.-M. Wang et al. / Tetrahedron: Asymmetry 10 (1999) 667–670
4. Wang, T.-L.; Hu, E.; Cassady, J. M. Tetrahedron Lett. 1995, 36, 9301 and references cited therein.
5. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
6. The ee of the resulting diol 2 {[α]2D0 +11.6 (c 1.70, CH2Cl2)} is determined by comparing the specific optical rotation with
its opposite enantiomer {[α]1D9 −11.1 (c 2.75, CH2Cl2); lit. [α]D −11.7 (c 1.5, CH2Cl2)} reported in literature (Vanhessche,
K. P. M.; Wang, Z.-M.; Sharpless, K. B. Tetrahedron Lett. 1994, 35, 3469).
1
7. No cis-THF ring was formed in this step based on the H NMR (CDCl3, 300 MHz) and 13C NMR (CDCl3, 75 MHz)
spectral analysis. Physical data for compound 5: colorless oil; [α]2D0 −24.1 (c 1.58, CHCl3); 1H NMR (CDCl3, 300 MHz):
δ 1.50–1.76 (m, 4H), 1.89–2.03 (m, 2H), 2.08–2.27 (m, 2H), 3.41 (s, 3H), 3.46–3.55 (m, 2H), 3.62–3.68 (m, 1H), 3.99–4.13
(m, 2H), 4.70 (d, J=6.8 Hz, 1H), 4.81 (d, J=6.8 Hz, 1H), 4.98 (dm, J=10.2 Hz, 1H), 5.04 (dm, J=17.1 Hz, 1H), 5.82 (ddt,
J=17.1, 10.2, 6.6 Hz, 1H); 13C NMR (CDCl3, 75 MHz): δ 27.56, 28.49, 29.62, 30.54, 55.83, 64.79, 79.42, 79.61, 81.37,
96.92, 114.84, 138.45; EIMS: m/z 229 (M−H, 0.63), 215 (0.76), 199 (100); IR (neat): ν 3426, 1639 cm−1. HRMS calcd
for C12H22O4: 230.1518; Found: 230.1521.
8. Inoki, S.; Mukaiyama, T. Chem. Lett. 1990, 67.
9. Vigneron, J. P.; Meric, R.; Larcheveque, M.; Debel, A.; Kunesch, G.; Zagatti, P.; Gallois, M. Tetrahedron Lett. 1982, 33,
5051.
10. Yao, Z.-J.; Wu, Y.-L. J. Org. Chem. 1995, 60, 1170.
11. The spectral data of this compound: colorless oil; [α]2D0 −1.0 (c 0.50, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 0.88 (3H,
t, J=6.8 Hz), 1.20–1.37 (30H, m), 1.37–1.82 (10H, m), 1.38 (6H, s), 1.41 (3H, d, J=7.1 Hz), 1.91–2.08 (2H, m), 2.50
(2H, d, J=5.8 Hz), 3.35–3.44 (6H, m), 3.46–3.66 (3H, m), 3.79–4.05 (3H, m), 4.60–4.75 (3H, m), 4.84 (1H, d, J=6.9 Hz),
4.95–5.05 (1H, m), 7.16–7.18 (1H, m); EIMS: m/z 525 (6), 450 (13), 432 (5); IR (neat): ν 2921, 1756 cm−1.