Synthesis of (15S,16S,21R)-4-deoxyrollicosin analog

Article abstract of DOI:10.1016/j.tetlet.2003.08.088

Synthesis of 4-deoxy rollicosin analog 2 was completed in nine steps, which was based on palladium-catalyzed coupling of two building blocks 3 and 4. Lactone 3 was synthesized from 5-hexyn-1-ol, and vinyl iodide 4 was accessed from L-glutamate and 1-hexyne.

Full text of DOI:10.1016/j.tetlet.2003.08.088

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7833–7835
Synthesis of (15S,16S,21R)-4-deoxyrollicosin analog
Jeng-Lin Lee,a,c Chi-Fong Lin,a Ling-Yu Hsieh,a Wan-Ru Lin,a Huey-Fen Chiu,b Yang-Chang Wu,b
Kun-Sheng Wanga and Ming-Jung Wua,c,
*
aSchool of Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
bGraduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
cGraduate Institute of Pharmaceutical Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
Received 21 May 2003; revised 3 August 2003; accepted 8 August 2003
Abstract—Synthesis of 4-deoxy rollicosin analog 2 was completed in nine steps, which was based on palladium-catalyzed coupling
of two building blocks 3 and 4. Lactone 3 was synthesized from 5-hexyn-1-ol, and vinyl iodide 4 was accessed from L-glutamate
and 1-hexyne.
© 2003 Elsevier Ltd. All rights reserved.
Annonaceous acetogenins are a class of rapid growing
natural products. More than 350 acetogenins have been
isolated from various annonaceae plants because of
their unique structure and wide scope of biological
activities.1 Annonaceous acetogenin showed remarkable
cytotoxicity against human cancer, acting as a blocker
of NADH-ubiquinone oxidoreductase (complex I) of
the mitochondrial electron transport system (ETS).2
Rollicosin 1,3 isolated from the unripe fruit of
annonaceae plant, Rollina mucosa Baill, possesses a
partial skeleton of annonaceous acetogenins containing
two g-lactone moieties on both sides of an aliphatic
chain. The subtype structure of annonaceous ace-
togenons may be generated from oxidative cleavage of
classical acetogenins resulting in special feature of two
lactone moieties. It is considered that the new discov-
ered metabolite of acetogenins will receive a highlight
attention with biological activities and chemical prob-
ing. Hence, we report herein a general route to prepare
the 4-deoxy rollicosin domain 2 with stereochemical
construction as 15S,16S,21R.
The lactone fragment 3 was constructed as shown in
Scheme 2. The synthesis was started from 5-hexyn-1-ol,
which was treated with trimethylsilyl chloride to give
As illustrated in Scheme 1, the retrosynthetic strategy
of 2 was based on a convergent process including
palladium-catalyzed coupling reaction of lactone 3 and
vinyl iodide 4. Compound 3 could be synthesized from
5-hexyn-1-ol. Generation of intermediate 4 could be
accomplished by using
starting materials.
L-glutamic acid and 1-hexyne as
* Corresponding author. Tel.: 886-7-3121101 ext 2220; fax: 886-7-
3125339; e-mail: mijuwu@cc.kmu.edu.tw
Scheme 1.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.088

7834
J.-L. Lee et al. / Tetrahedron Letters 44 (2003) 7833–7835
Scheme 2. Reagents and conditions: (a) (i) n-BuLi, THF, 0°C, 40 min; (ii) TMSCl, 0°C to rt, 2 h, 80%; (b) PCC, CH2Cl2, rt, 4
h, 60%; (c) vinylmagnesium bromide, THF, −78°C, 1 h, 71%; (d) CH3CH2COOH, CH3C(OEt)3, 180°C, 2 h, 84%; (e) AD-MIX-a,
CH3SO2NH2, t-BuOH/H2O, 0°C, 24 h, 62%; (f) TBAF, THF, 0°C, 5 h, 73%.
alcohol 5. Compound 5 was converted to aldehyde 6
via oxidation with pyridinium chlorochromate. Addi-
tion of vinylmagnesium bromide to 6 resulted in the
formation of the allylic alcohol 7. Reaction of 7 with
triethyl orthoacetate and propionic acid proceeded
through orthoacetate Claisen rearrangement4 to afford
g,d-unsaturated ester 8, followed by Sharpless AD
reaction5 to give lactone 9. Finally, protecting group
was removed by tetra-n-butylammonium fluoride to
liberate terminal acetylene to give 3.
of the silylether, tosylation of the alcohol, and iodina-
tion. The butanolide 4 was obtained by alkylation of
the enolate prepared by mixing 138 and LDA with
diiodide 12 (Scheme 3).
Palladium-catalyzed coupling9 of the terminal alkyne
3 with the vinyl iodide 4 afforded eneyne 14. Hydro-
genation of 14 using Wilkinson’s catalyst gave the
corresponding saturated product 15. Finally, oxida-
tion of compound 15 with m-CPBA provided a sulf-
oxide intermediate, followed by thermal elimination
to afford rollicosin analog 210 (Scheme 4). Compound
2 was obtained as white power and the absolute
configuration of 2 demonstrated by X-ray11 shown in
Figure 1.
The butanolide portion 4 of the target molecule was
prepared according to the process reported by
Keinan6 with slight modification. Applying 1-hexyne
with n-butylithium in tetrahydrofuran resulted in for-
mation of acetylenic lithium salt, subsequent exposure
to paraformaldehyde solution gave internal alkyne 10.
Isomerization7 of 10 was promoted in the presence of
potassium hydride in 1,3-diaminopropane to provide
terminal acetylene 11. Conversion of 11 to diiodide
12 was performed using Keinan’s procedure, including
protection of the alcohol as a silylether, hydrostannyl-
ation of the terminal alkyne, iodolysis, deprotection
In conclusion, we have reported a convergent synthe-
sis of deoxy rollicosin analog 2, which may serve as a
building block for the synthesis of a series of 4-deoxy
acetogenins. The application of this method to syn-
thesize a variety of deoxy rollicosin analogs with vari-
ant main carbon chains is currently under
investigation.
Scheme 3. Reagents and conditions: (a) (i) n-BuLi, THF, −78°C, 1 h, (ii) (CH2O)n, −78°C to rt, 18 h, 99%; (b) 30% KH,
1,3-diaminopropane, 10–15°C, 1.5 h, 67%; (c) (i) LDA, THF, 13, 0°C, 30 min; (ii) 12 and HMPA, reflux, 70%.

J.-L. Lee et al. / Tetrahedron Letters 44 (2003) 7833–7835
7835
Scheme 4. Reagents and conditions: (a) PdCl2(PPh3)2, Et3N, CuI, 24 h, 67%; (b) RhCl(PPh3)3, H2, benzene/MeOH 1:1, 24 h, 87%;
(c) (i) m-CPBA, CH2Cl2, 30 min, (ii) toluene, reflux, 4 h, 46% (two steps).
Figure 1. X-Ray structure of compound 2.
Acknowledgements
Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L. J.
Am. Chem. Soc. 1992, 57, 2768.
6. Yazbak, A.; Sinha, S. C.; Keinan, E. J. Org. Chem. 1998,
63, 5863–5868.
We thank the National Science Council of the Republic
of China for financial support of this program.
7. Gensler, W. J.; Prasad, R. S.; Chaudhuri, A. P.; Alam, I.
J. Org. Chem. 1979, 44, 3643–3652.
8. (a) Harmange, J.-C.; Figade`re, B.; Hocquemiller, R. Tet-
rahedron: Asymmetry 1991, 2, 347; (b) Preparation of 13
was completed by following process:
References
1. For recent reviews of annonaceous acetogenins, see: (a)
Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod.
1999, 62, 504–540. (b) Zafra-Polo, M. C.; Figade´re, B.;
Gallardo, T.; Tormo, J. R.; Cortes, D. Phytochemistry
1998, 48, 1087–1117. (c) Cave´, A.; Figade´re, B.; Laurens,
A.; Cortes, D. In Progress in the Chemistry of Organic
Natural Products: Acetogenins from Annonaceae; Herz,
W., Eds; Springer-Verlag: New York, 1997; Vol. 70, pp.
81–288.
9. Hu, T.-S.; Yu, Q.; Wu, Y.-L.; Wu, Y. J. Org. Chem.
2001, 66, 853–861.
10. Data for 2: mp 103–104°C; [h]2D5=−13.6 (c 0.01, CHCl3);
1H NMR (CDCl3, 400 MHz) l: 6.98 (1H, d, J=1.6 Hz),
5.01–4.95 (1H, m), 4.41 (1H, td, J=7.6 Hz, 4.4 Hz),
3.58–3.54 (1H, m), 2.60–2.48 (2H, m) 2.28–2.21 (3H, m),
2.15–2.08 (1H, m), 1.73 (1H, br), 1.57–1.41 (6H, m), 1.39
(3H, d, J=6.8 Hz), 1.37–1.19 (16H, m). 13C NMR
(CDCl3, 100 MHz) l: 177.2, 173.9, 148.9, 134.2, 82.9,
77.4, 73.57, 32.9, 29.5 (3C), 29.4 (3C), 29.2, 29.1, 28.6,
27.3, 25.4, 25.1, 24.0, 19.16. HRMS (EI) calcd for
C22H36O5: 380.2563. Found: 380.2559.
2. Oberlies, N. H.; Chang, C. J.; McLaughlin, J. L. J. Med.
Chem. 1997, 40, 2102–2106.
3. Liaw, C. C.; Chang, F. R.; Wu, M. J.; Wu, Y. C. J. Nat.
Prod. 2003, 66, 279–281.
4. Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brock-
som, T. J.; Li, T.-t; Faulkner, D. J.; Petersen, M. R. J.
Am. Chem. Soc. 1970, 92, 741.
5. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino,
11. The deposition number provided by CCDC is 216122.
G. A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.;