The total synthesis of chrysotricine

Article abstract of DOI:10.1016/S0040-4039(00)00146-5

Geraniol was converted, using Sharpless oxidations as key steps, into the chiral trans-tri-substituted tetrahydrofuran 10, from which chrysotricine was synthesized in 16 steps (1.1% overall yield). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00146-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2211–2213
The total synthesis of chrysotricine
Jing-Xin Zhang, Guang-Xing Wang, Ping Xie, Shu-Feng Chen and Xiao-Tian Liang ∗
Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050,
PR China
Received 7 December 1999; accepted 18 January 2000
Abstract
Geraniol was converted, using Sharpless oxidations as key steps, into the chiral trans-tri-substituted tetrahydro-
furan 10, from which chrysotricine was synthesized in 16 steps (1.1% overall yield). © 2000 Elsevier Science Ltd.
All rights reserved.
Chrysotricine 14 was isolated from the Chinese herb medicine Hedyotis chrysotricha, and its structural
characterization was first reported in 1997 as only a trace alkaloid (0.00001%) which exhibits an
inhibitory activity against the growth of HL-60 cells in vitro.1 The relative configuration was established
by X-ray structure analysis. (±)-Chrysotricine has been synthesized by our group.2 It possesses a rare
trans-tri-substituted tetrahydrofuran unit as a crucial component.
2,5-Substituted tetrahydrofurans are commonly encountered in many natural products. There are
numerous literature reports dealing with the synthesis of 2,5-di-substituted tetrahydrofurans,3 but, to our
knowledge, the enantioselective synthesis of 2,2,5-tri-substituted tetrahydrofurans is less established.4
Scheme 1 illustrates a synthesis in which each stereogenic center of the tetrahydrofuran section of
chrysotricine is controlled independently. Compound 1, prepared from geraniol by a known procedure,5
was protected by treatment with benzoyl chloride. After deprotecting the THP ether by PPTS, Sharpless
asymmetric epoxidation using (−)DET provided the corresponding epoxy alcohol 3.
The optical purity of 3 was judged to be 90% ee as determined by examination of its 1H NMR spectrum
in the presence of Eu(hfpc)3.6
The hydroxyl group of the epoxide was then converted to the benzyl ether 4. We attempted to use
benzyl bromide and silver oxide in DMF, but the reaction was too slow to reach completion. So we
protected the hydroxyl with NaH and benzyl bromide. In the absence of n-Bu4NI, benzyl ether formation
was also sluggish. Longer exposure of 3 to NaH was detrimental, and the yield decreased dramatically,
probably due to the loss of the benzoyl-protecting group. By shortening this reaction time, we attained
the benzyl ether in a reproducible yield of 64%.
After regioselective reduction by LiAlH4, the desired diol 5 was obtained in satisfactory yield.
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00146-5
tetl 16426

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Scheme 1. (a) DHP, PPTS; (b) SeO2/SiO2, T BHP; (c) BzCl, pyridine; (d) PPTS, EtOH; (e) Ti(iOPr)4, THBP, (−)DET; (f)
BnBr, NaH, n-Bu4NI; (g) LiAlH4; (h) Ti(iOPr)4, TBHP, (+)DET; (i) MsCl, Et3N; (j) LiAlH4; (k) Pd/C, H2; (l) DMSO, (COCl)2
Epoxidation of the double bond of 5 as well as the key ring-closure step was achieved in one step by
a second Sharpless oxidation with (+)DET and gave 6, with a de of 82%. The vicinal diol moiety of 6
was oxidized to the methyl ketone by HIO4, to be treated with a methyl Grignard reagent to get alcohol
8. Unfortunately, the methyl ketone was rather unstable even at a low temperature or under nitrogen.
We, therefore, transformed the primary hydroxyl group into a mesylate followed by treatment of the
intermediary mesylate with LiAlH4 in THF to produce the required tert-hydroxyl compound 8 which
was deprotected to give the alcohol 9. By oxidizing the primary hydroxyl group of 9 into an aldehyde,
we obtained the key intermediate 10. The two Sharpless AEs defined the tetrahydrofuran core to be
(2R,5R). To reach the natural product, we designed the route shown in Scheme 2.
A TFA-catalyzed Picter–Spengler reaction was utilized to form the tetrahydrocarboline 11. On treat-
ment with palladium black in boiling EtOH for 12 h, 11 produced the ring C-dehydrogenated product 12
in 57% yield. The structure assigned was supported by the MS and 1H NMR spectra of 12 in CDCl3. The
crystalline quaternary iminium 13 was prepared smoothly by using CH3I in acetone at 50°C for 2 h.7
1
Finally, treatment of 13 with aqueous NaOH in EtOH furnished the base 14. The H NMR data
and [α]D of 14 are in accordance with that of the literature.1,7 Thus, we could confirm the absolute
configuration of chrysotricine as (2R,5R).
In summary, a concise and straightforward synthesis of the natural compound chrysotricine has been
developed. The total yield for the 16 steps was 1.1%. The strategy capitalized on the enantioselectivity
of the Sharpless asymmetric epoxidation. The key synthon, the trans-tri-substituted tetrahydrofuran, was
obtained in 11 steps and 8.2% yield.8

2213
Scheme 2. (a) TFA, CH2Cl2; (b) Pd/C, EtOH, reflux; (c) CH3I; (d) NaOH/EtOH
References
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K. W. J. Org. Chem. 1997, 62, 5989.
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7. All new compounds gave satisfactory spectroscopic data. Compound 13: 1H NMR (500 MHz, CDCl3): 12.61 (s, 1H, NH),
8.17 (d, J=6.5, 1H), 8.13 (d, J=8.3, 1H), 8.12 (d, J=8.3, 1H), 8.11 (d, J=6.5, 1H), 7.70 (t, J=8.3, 1H), 7.38 (t, J=8.3, 1H), 4.58
(s, 3H), 4.07 (s, 2H), 3.52 (m, 1H), 2.46–1.67 (m, 4H), 1.39 (s, 3H), 1.15 (s, 3H), 1.07 (s, 3H). Compound 14: 1H NMR (500
MHz, CDCl3): 8.16 (d, J=8.0, 1H), 8.06 (d, J=6.5, 1H), 8.00 (d, J=8.0, 1H), 7.58–7.56 (m, 2H), 7.19 (t, 1H, J=8.0), 4.43 (s,
3H), 4.18 (m, 1H), 3.83 (m, 1H), 3.10 (m, 1H), 2.33 (m, 1H), 2.17 (m, 1H), 1.92 (m, 1H), 1.71 (m, 1H), 1.43 (s, 3H), 1.12 (s,
3H), 1.01 (s, 3H). [α]2D1=+30 (MeOH, c 0.049).
8. According to Ref. 1, in methanol the structure 14 is in equilibrium with structure 15. The 1H NMR data of 15 in methanol is
in agreement with those reported in the literature.