Studies toward the total synthesis of YW3699, a sesterterpenoid GPI biosynthesis inhibitor: preparation of the tri-substituted cyclooctene ring using the RCM reaction

Article abstract of DOI:10.1016/j.tetlet.2009.02.163

The preparation of eight-membered carbocycles with tri-substituted double bonds has been attempted using RCM reactions. One of the stereoisomers subjected to the RCM reaction provided a desired compound which will be used for the synthesis of YW3699.

Full text of DOI:10.1016/j.tetlet.2009.02.163

Tetrahedron Letters 50 (2009) 2225–2227
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Studies toward the total synthesis of YW3699, a sesterterpenoid GPI
biosynthesis inhibitor: preparation of the tri-substituted cyclooctene
ring using the RCM reaction
*
Reiko Mizutani, Katsuyuki Nakashima, Yoshinori Saito, Masakazu Sono, Motoo Tori
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation of eight-membered carbocycles with tri-substituted double bonds has been attempted
using RCM reactions. One of the stereoisomers subjected to the RCM reaction provided a desired com-
pound which will be used for the synthesis of YW3699.
Received 13 January 2009
Revised 20 February 2009
Accepted 23 February 2009
Available online 26 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
YW3699 (1)1 is a fungal metabolite isolated in 1998 by Wang et
al. (Fig. 1) and was shown to inhibit the biosynthesis of glycosyl-
phosphatidylinositol (GPI) in tripanosoma.2,3 It has a unique car-
bon skeleton, namely four consecutive five-, eight-, six-, and five-
membered rings, with an ester of C9 hydroxycarboxylic acid. The
absolute configuration is yet to be established. We have been
studying the preparation of carbocycles with tri-substituted
cycloheptenes using the ring-closing methathesis (RCM) reaction.4
Our next challenge was the preparation of eight-membered carbo-
cycles by the RCM reaction. Recently more than ten papers5–13
describing the application of RCM reactions to the synthesis of
eight-membered substances have been reported. However, the
construction of the eight-membered carbocycles especially having
a tri-substituted double bond is still a challenging task in the syn-
thetic work. Syntheses of cyclooctenes are attempted by carefully
planning the precursors. Here we report our preliminary results
on the applications of the RCM reactions to the construction of
the eight-membered carbocycles.
The strategy for the total synthesis of YW3699 (1) is to con-
struct the ring D as well as to introduce the oxygen function of
the ring A at the last step.14 Thus, the target molecule is the simple
tri-cyclic substance like compound 6. We would like to know the
feasibility of the cyclization to the tri-substituted eight-membered
carbocycle. Therefore, we have planned to test the RCM reactions
of the four diastereoisomers with the epoxide ring. The trans rela-
tionship of the eight- and six-membered rings in rings B and C was
realized by the conjugate addition to compound 2. The epoxide
ring was introduced to a five-membered enone as illustrated in
Scheme 1.
chemistry was established based on 2D NMR spectra. Protection of
the primary alcohol as a TBDPS ether, ketalization using the
O
H
14
12
H
O
OH
18
4
8
6
1
H
H
OH
HO
O
Figure 1. Structure of YW3699 (1).
H
H
H
H
O
O
OHC
O
O
O
H
O
2
3
4
H
H
H
H
H
O
O
H
O
O
O
O
O
O
5
6
H
The 1,4-addition of i-PrOSiMe2CH2MgCl in the presence of
CuBr-Me2S and the Tamao reaction15 to enone 216 afforded 7, as
the sole isomer with trans stereochemistry (Scheme 2). The stereo-
OR
H
B
C
D
A
H
H
OH
HO
O
1
* Corresponding author. Tel.: +81 88 602 8462; fax: +81 88 655 3051.
E-mail address: tori@ph.bunri-u.ac.jp (M. Tori).
Scheme 1. Synthetic plan.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.163

2226
R. Mizutani et al. / Tetrahedron Letters 50 (2009) 2225–2227
H
H
H
H
H
H
H
H
c
a
b
H
a
H
H
O
O
O
O
O
O
O
O
H
H
O
O
OH
O
OTBDPS
(80 %)
OTBDPS
O
2
O
7
8
5a
6a
9
H
H
H
H
H
e
f
H
d
H
a
O
O
O
O
H
O
O
O
O
OHC
O
O
H
OH
H
H
OH
H
O
O
O
O
3
10
11
6b or 6d
5b or 5d
H
H
H
g
H
a
O
O
H
H
H
O
O
O
O
H
O
H
H
O
H
H
H
(trace)
+
+
O
O
O
O
h
H
H
O
O
4a: αH
4b: βH
5c
6c
O
H
O
O
H
O
O
O
a
H
5a
5c
H
O
O
O
H
H
H
H
O
O
O
h
O
H
H
O
6d or 6b
O
5d or 5b
H
O
O
H
O
O
2
O
O
H
H
H
5d or 5b
5b or 5d
i, j
O
H
H
O
O
H
5a
+
11
5b
O
O
O
H
H
O
O
O
H
O
Scheme 2. Reagents and conditions: (a) i-PrOSiMe2CH2Cl, Mg, CuBr–Me2S, THF;
then KF, KHCO3, H2O2, 86%: (b) TBDPSCl, NEt3, DMAP, CH2Cl2, 93%; (c) TMS-
OCH2CH2OTMS, TMSOTf, CH2Cl2, 70%; (d) TBAF, THF, 76%; (e) Dess–Martin Oxid.,
99%; (f) trisylhydrazone of 2-allylcyclopentanone, t-BuLi, THF, 90%; (g) Dess–Martin
Oxid., 4a (46%), 4b (37%); (h) H2O2, NaOH; (i) t-BuOOH, VO(acac)2; (j) Dess–Martin
Oxid., 5a (28%), 5b (22%).
O
O
13
14
12
Scheme 3. Reagents and conditions: (a) Grubbs II (30 mol %), CH2Cl2 (0.5 mol %),
reflux, 10 h.
Tsunoda and Noyori method,17 deprotection of the silyl ether
(TBAF), and Dess–Martin periodinane oxidation18 gave aldehyde
3. The trisyl hydrazone of 2-allylcyclopentanone was treated with
t-BuLi19 and was reacted with 3 to produce alcohol 11 as a mixture
of diastereoisomers with a 90% yield.20 The mixture of alcohols 11
was oxidized (Dess–Martin) into separable enones 4a and 4b and
gave yields of 46 and 37%, respectively. Enone 4a was converted
(H2O2, NaOH) into epoxides 5a21 and 5c22 with yields of 67% and
13%, respectively. Enone 4b was also converted into epoxides 5b
and 5d with yields of 65% and 18%, respectively; however, the con-
figuration was not determined at this stage. Alternatively, alcohol
11 was converted into epoxides under Sharpless epoxidation con-
ditions23 followed by oxidation, to generate two diastereoisomeric
epoxides, 5a and 5b, with yields of 28% and 22%, respectively. The
configurations were later assigned by the analysis of the cyclized
compound 6a.
H
a
H
H
H
H
H
O
14
18
O
7
H
O
H
1
O
H
3
O
H
O
O
H
H
15
NOE
6a
Figure 2. The selected NOESY correlations of 6a and methylenation. (a) Tebbe
reagent, THF, 85%.
afforded many products without recovery of the starting material,
which could not be analyzed due to the minute amounts. The prod-
uct 6a had the desired configurations for the synthesis of YW3699
(1). Compound 6a was further efficiently converted to 1530 with
Tebbe reagent (85%) (Fig. 2).31 We then carried out the RCM reac-
tions of compounds 4a and 4b to compare the effect of the epoxide
ring and the double bond at the 3,4-positions. However, the start-
ing material was recovered.
In summary, we have reported the synthetic efforts toward the
sesterterpenoid YW3699 (1). The RCM reaction was successfully
applied to the construction of the tri-substituted cyclooctene ring.
Interestingly, only one diastereoisomer was efficiently cyclized to
the corresponding tri-cyclic compound. This result confirms the
Each epoxide was treated with Grubbs II (30 mol %)24 in CH2Cl2
(1 mM) under reflux for 10 h (Scheme 3). The diene 5a efficiently
afforded the tri-carbocyclic ketone 6a25 with an 80% yield as the
sole product. The structure of 6a was solved by X-ray crystallo-
graphic26 and 2D NMR spectral analysis. The 3D structure is shown
in Figures 2 and 3.
From 5c, cyclized product 6c was obtained only in trace
amounts. However, epoxide 5b (or 5d) provided a ring-contracted
seven-membered compound 12,27–29 dimeric at the terminal vinyl
group 1329 and the styrene adduct 14.29 Epoxide 5d (or 5b)

R. Mizutani et al. / Tetrahedron Letters 50 (2009) 2225–2227
18. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
2227
19. (a) Chamberlin, A. R.; Bloom, S. H. Org. React. 1990, 39, 1–83; (b) Shih, C.;
Swenton, J. S. J. Org. Chem. 1982, 47, 2825–2832; (c) Paquette, L. A.; Combrink,
K. D.; Elmore, S. W.; Rogers, R. D. J. Am. Chem. Soc. 1991, 113, 1335–1344.
20. After oxidation of the diastereoisomers, the ratio was 1:1 due to the isomers at
the C-18, based on the 13C NMR data.
21. Compound 5a: FTIR 1700 cmÀ1 1H NMR (400 MHz, CDCl3) d 5.70 (1H, m), 5.01
;
(1H, m), 4.96 (1H, m), 4.77 (1H, s), 4.71 (1H, m), 3.96 (4H, m), 3.75 (1H, s), 3.08
(1H, ddd, J = 12.6, 11.1, 3.6 Hz), 2.47 (1H, m), 2.37 (1H, m), 2.02–1.95 (2H, m),
1.83–1.75 (3H, m), 1.72 (3H, s), 1.66 (2H, m), 1.57–1.44 (5H, m); 13C NMR
(100 MHz, CDCl3) d 207.8 (C), 146.9 (C), 136.5 (CH), 116.5 (CH2), 111.4 (CH2),
108.2 (C), 69.0 (C), 64.4 (CH2 Â 2), 62.5 (CH), 46.0 (CH), 45.3 (CH), 38.5 (CH2),
37.9 (CH), 34.3 (CH2), 34.1 (CH2), 28.8 (CH2), 25.9 (CH2), 23.3 (CH2), 20.3 (CH3);
MS (Cl) m/z 333 [M+H]+, 315, 209 (base), 181, 165, 99, 86; HRMS (CI). Found m/
z 333.2065 [M+H]+, C20H29O4 requires 333.2066.
22. Compound 5c: FTIR 1700 cmÀ1 1H NMR (400 MHz, CDCl3) d 5.74 (1H, ddt,
;
J = 17.1, 9.9, 7.2 Hz), 5.00 (1H, br d, J = 17.1 Hz), 4.95 (1H, br d, J = 9.9 Hz), 4.69
(1H, m), 4.63 (1H, br s), 3.98 (4H, m), 3.59 (1H, s), 2.97 (1H, ddd, J = 12.3, 11.4,
3.3 Hz), 2.72 (1H, m), 2.36 (1H, dt, J = 11.4, 3.3 Hz), 2.25 (1H, m), 2.04 (3H, m),
1.81–1.74 (3H, s), 1.71 (3H, s), 1.69–1.53 (3H, m), 1.26 (1H, d, t, J = 12.6 Hz),
1.08 (1H, m); 13C NMR (100 MHz, CDCl3) d 208.4 (C), 148.6 (C), 136.5 (CH),
115.9 (CH2), 110.1 (CH2), 108.0 (C), 71.5 (C), 64.4 (CH2 Â 2), 63.6 (CH), 46.3
(CH), 43.3 (CH), 38.1 (CH2), 36.6 (CH2), 34.8 (CH2), 34.4 (CH2), 29.2 (CH2), 27.3
(CH2), 25.3 (CH2), 22.1 (CH3); MS (Cl) m/z 333 [M+H]+ (base), 315, 209, 181, 99,
61; HRMS (CI). Found m/z 333.2057 [M+H]+, C20H29O4 requires 333.2066.
23. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, S.; Sharpless, K. B. J.
Am. Chem. Soc. 1987, 109, 5765–5780.
Figure 3. The 3D structure of compound 6a analyzed by X-ray crystallography.
importance of the conformation of the diene substrate. Namely,
only one of the four possible diastereoisomers, 5a–d, had the suit-
able geometry for cyclization. The total synthesis of YW3699 (1) is
currently under progress in this line.
24. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953–956.
25. Compound 6a: mp 110–111 °C (from hexane); IR 1700, 1612 cmÀ1 1H NMR
;
(600 MHz, CDCl3) d 5.47 (1H, td, J = 9.0, 1.2 Hz, H-16), 3.95–3.90 (4H, m, ketal),
3.41 (1H, s, H-3), 3.36 (1H, td, J = 13.2, 3.6 Hz, H-14), 2.68 (1H, ddd, J = 13.2,
12.9, 4.1 Hz, H-6), 2.44 (1H, ddd, J = 13.1, 9.0, 9.0 Hz, H-17b), 2.33 (1H, t,
J = 12.9 Hz, H-7b), 2.26 (1H, m, H-18), 2.00 (1H, dd, J = 14.3, 8.1 Hz, H-2), 1.93
Acknowledgments
(1H, ddd, J = 13.1, 9.0, 2.9 Hz, H-17a), 1.80 (1H, m), 1.79 (1H, m), 1.77 (1H, m),
We thank Dr. Masami Tanaka and Miss. Yasuko Okamoto, Toku-
shima Bunri University, for acquiring the 600 MHz NMR and MS
spectra, respectively.
1.74 (1H, m), 1.68 (1H,m), 1.67 (1H, m), 1.66 (1H, m), 1.63 (3H, s, H-25), 1.11
(1H, m, H-1); 13C NMR (150 MHz, CDCl3) d 208.9 (C-5), 140.4 (C-15), 124.8 (C-
16), 107.5 (C-8) 72.7 (C-4), 64.3 (ketal X 2), 63.6 (C-3), 55.4 (C-6), 44.8 (C-18),
36.3 (C-14), 34.6 (C-7), 34.3 (C-12), 28.1 (C-17), 27.7 (C-2), 26.3 (C-1), 25.8 (C-
13), 19.1 (CH3); HRMS obs. m/z 304.1673 Calcd for C18H24O4 304.1675; MS (CI)
m/z 305 [M+H]+, 304 [M]+ (base), 287, 243, 164, 99.
References and notes
26. X-ray crystallographic analysis of compound 6a: All diagrams and calculations
were performed using maXus (Bruker Nonius, Delft & MacScience, Japan). Mo
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Ka radiation, k = 0.71073 Å, 8445 measured reflections, 8613 independent
reflections, 6935 observed reflections, Data collection: DIP Image plate,
Program(s) used to refine structure: SHELXL-97 (Sheldrick, 1997); refinement
on F2, full matrix least squares refinement. Crystal data: monoclinic, Cc,
a = 20.554(2) Å, b = 7.1676(7) Å, c = 21.723(2) Å,
a = 90°, b = 103.206(2)°,
c
= 90°, V = 3115.7(6) Å3,
R
(all) = 0.0390, (gt) = 0.0371. Crystallographic
R
data for compound 6a have been deposited at the Cambridge
Crystallographic Data Center as supplementary publication number CCDC
707740. Copies of the data can be obtained, free of charge, via
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291.1579 [M+H]+, C17H23O4 requires 291.1597. 13: d 5.30 (1H, t, J = 4.4 Hz),
4.71 (1H, m), 4.65 (1H, s), 1.69 (3H, s). 14: d 7.33–7.19 (5H, m), 6.37 (1H, d,
J = 15.6 Hz), 6.10 (1H, dt, J = 15.6, 7.5 Hz), 4.73 (1H, m), 4.69 (1H, m), 1.71
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30. Compound 15: FTIR 1630 cmÀ1 1H NMR (400 MHz, CDCl3)
; d 5.44 (1H, t,
J = 8.7 Hz), 4.92 (1H, d, J = 1.2 Hz), 4.83 (1H, d, J = 1.8 Hz), 3.94 (4H, m), 3.12
(1H, br s), 2.91 (1H, br t, J = 11.1 Hz), 2.47 (1H, ddd, J = 12.9, 11.7, 3.9 Hz), 2.37
(1H, m), 2.29 (1H, t, J = 12.9 Hz), 1.99–1.53 (10H, m), 1.61 (3H, s), 1.09 (1H, m);
13C NMR (100 MHz, CDCl3) d149.4 (C), 140.2 (C), 124.0 (CH), 114.0 (CH2), 108.8
(C), 70.6 (C), 65.4 (CH), 64.3 (CH2), 64.1 (CH2), 48.2 (CH), 47.8 (CH), 40.7 (CH2),
38.4 (CH), 34.2 (CH2), 28.1 (CH2), 27.3 (CH2), 27.1 (CH2), 26.5 (CH2), 19.0 (CH3);
MS (Cl) m/z 303 [M+H]+ (base), 302, 285, 241, 99; HRMS (CI) Found m/z
303.1953 [M+H]+, C19H27O3 requires 303.1960.
31. Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc. 1978, 100, 3611–
3613.