Synthetic studies on the dienophile unit of methyl isosartortuoate. Part 1: Assembly of the acyclic precursor

Article abstract of DOI:10.1016/S0040-4039(02)02608-4

A strategically functionalized compound, as the acyclic precursor of the dienophile unit of methyl isosartortuoate has been synthesized, and its stereochemistry was also assigned.

Full text of DOI:10.1016/S0040-4039(02)02608-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 485–488
Synthetic studies on the dienophile unit of methyl
isosartortuoate. Part 1: Assembly of the acyclic precursor
Zhangyong Hong, Xinchao Chen and Xingxiang Xu*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
Received 26 September 2002; revised 7 November 2002; accepted 15 November 2002
Abstract—A strategically functionalized compound, as the acyclic precursor of the dienophile unit of methyl isosartortuoate has
been synthesized, and its stereochemistry was also assigned. © 2002 Elsevier Science Ltd. All rights reserved.
Methyl isosartortuoate 1 is the first tetracyclic tetra-
terpenoid exhibiting a novel molecular architecture,
isolated from the marine Sarcophyton tortuosum tixier-
durivanlt by Su et al.1a A preliminary bioassay proved
that compounds of this type displayed inhibitory effects
novelties and the potential bioactivities as well as the
interesting biogenetic possibility prompted us to initiate
a synthetic project3 towards methyl isosartortuoate 1
and methyl sartortuoate 2.1a,c In this and the following
letter4 we wish to report our results of the research on
the synthesis of dienophile 5, which is the common
dienophile unit of compounds 1 and 2.
1c
against mice S180 and cytotoxic activity towards KB
cells,2a but the scarcity of the material made further
studies difficult. It has been hypothesized1,2 that a plau-
sible biogenesis would involve the generation of the
cyclohexene ring by a Diels–Alder reaction of two
cembrenoids (e.g. 3 and 4, Fig. 1). The structural
Our initial attempts for the elaboration of 5 were based
on an intramolecular Wittig–Horner macrocyclization
strategy, which has been successfully employed in the
syntheses of 14-membered carbocycles.5 However, such
a cyclization of 6 proved unsuccessful.3a Thus, we
changed the plan and temporarily removed the car-
bonyl of ketone 5 from the ring. The resultant sim-
plified compound 7 was expected to provide higher
feasibility and more tactical flexibility in the macrocy-
clization. Further retrosynthesis is shown in Figure 2.
According to the new synthetic strategy, we prepared
the sulfone segment 9 as shown in Scheme 1. Optically
active epoxide 126 was derived from 11 by Sharpless
asymmetric epoxidation with 95% ee. Initial attempts at
the nucleophilic epoxy opening reaction of 12 with
isopropylmagnesium bromide catalyzed by CuI gave
complicated mixtures. To the best of our knowledge, no
direct opening of hydroxy epoxides with isopropylmag-
nesium bromide has been reported,7 so various reaction
conditions were tried. We found that, to ensure an
acceptable selectivity and yield, it was crucial to control
the temperature of forming the CuI catalyzed Grignard
reagent. When it was formed in advance at around
−50°C, and the whole reaction was also conducted at
low temperature (−78°C), C-2 to C-3 selectivity was
improved to 2.5:1 and the diol 13 was obtained in 65%
Figure 1. Structures of methyl isosartortuoate 1, methyl sar-
tortuoate 2 and their biogenetic precursors 3 and 4.
Keywords: methyl isosartortuoate; precusor of the dienophile unit.
* Corresponding author. Fax: +86-21-64166128; e-mail: xuxx@
pub.sioc.ac.cn
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02608-4

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Z. Hong et al. / Tetrahedron Letters 44 (2003) 485–488
reaction proceeded smoothly and fast (it was essentially
complete after 1 h at rt), and the desired benzyl ether 9
was obtained in 85% yield. It seems that complex
factors caused by deprotonation of the sulfone9 and
deprotection of the TBDPS ether10 were suppressed
under the latter reaction conditions.
The synthesis of the other segment, the (2S,6R)-
dimethyl substituted aldehyde 10, could be accom-
plished by coupling sulfone 19 with iodide 20 prepared
from (S)-(+)-citronellol11 (Scheme 2). Fragment 19 was
obtained from methyl (R)-(−)-3-hydroxyisobutyrate in
four steps in 80% overall yield. Coupling of the sulfone
19 with iodide 20 proceeded smoothly to afford 21,
which was desulfonated to give compound 22. Previous
exploration suggested that the conversion of the double
bond of 22 in advance into an acetal group would be
beneficial for subsequent transformations, for example,
the formation and a-bromination of the ester (see the
next letter).4 The exposure of compound 22 to ozone
followed by a workup with Me2S/p-TsOH/CH(OMe)3
gave acetal 23 in one pot in 80% yield. Oxidation of 23
afforded the required aldehyde 10.
With segments 9 and 10 in hand, their coupling was
carried out by treatment of the sulfone anion of 9 with
aldehyde 10 in THF at −78°C (Scheme 3). Unfortu-
nately, the yield was only 40%, and no improvement
was achieved by addition of a Lewis acid.12 It is
assumed that the coupling process was sluggish because
of steric hindrance, and the aldehyde was being lost by
enolization. Based on this idea, the assumed side reac-
tion was minimized when a pre-cooled and highly
diluted solution of aldehyde 10 (0.07 M in THF) was
added slowly to the sulfone anion solution, and indeed
compound 24 was obtained in up to 88% yield. After
oxidation, desulfonation and reduction, the separable
hydroxy epimers 26a and 26b13 were obtained in a ratio
of 1:1.
Figure 2. Retrosynthesis of dienophile 5.
Scheme 1. Reagents and conditions: (a)
D-(−)-DIPT,
i
i
,
Ti(O Pr)4, TBHP, 4 A MS, −20°C, 90%, 95% ee; (b) PrMgBr,
0.1 equiv. CuI, THF, −50°C, 1.5 h, then epoxide 11, −78°C 1
h, 65%; (c) (PhS)2, Bu3P, Py, 80%; (d) MCPBA, CH2Cl2, 75%;
(e) Pd/C, MeOH, 97%; (f) TBDPSCl, NEt3, DMAP, CH2Cl2,
92%; (g) BnBr, THF, Bu4NI, NaH, 85%.
yield. Next, the primary hydroxyl group of 13 was
converted selectively to the sulfone group by treatment
8
with (PhS)2-PBu3 followed by oxidation with mCPBA.
For the protection of the secondary hydroxy group, the
benzyl ether was considered to be the most suitable for
subsequent transformations after a preliminary screen-
ing. So 15 was converted to 16 through debenzylation
and silylation. However, benzylation of compound 16
proceeded only after some difficulty. It is noteworthy
that this reaction depended on the solvent used. Protec-
tion with NaH/BnBr/DMF gave a very complicated
mixture. When NaH/BnBr/THF/Bu4NI was used, the
Scheme 2. Reagents and conditions: (a) DHP, PPTS, CH2Cl2;
(b) LiAlH4, Et2O, 95% for two steps; (c) (i) (PhS)2, Bu3P,
THF, 93%; (ii) MCPBA, CH2Cl2, NaHCO3, 83%; (d) BuLi,
THF, 90%; (e) Na(Hg), CH3OH, THF, 84%; (f) O3, MeOH,
CH2Cl2, −78°C; then Me2S, PTSA, CH(OMe)3, 80%; (g)
Swern oxid., 90%.

Z. Hong et al. / Tetrahedron Letters 44 (2003) 485–488
487
Scheme 3. Reagents and conditions: (a) 9, BuLi, THF, −78°C,
then aldehyde 10, 88%; (b) Dess–Martin periodinane, pyri-
dine, CH2Cl2; (c) lithium naphthanilide, THF, −78°C, 69%
for two steps; (d) LiAlH4, ether, 98%.
Scheme 5. Reagents and conditions: (a) NaH, BnBr, Bu4NI,
THF, DMF, 50°C, 80%; (b) Bu4NF, THF, 92%; (c) (i) Swern
oxid.; (ii) I2, KOH, MeOH, 0°C, 85% for two steps.
NOE correlation between 9-H and 12-H, suggesting
that the THF ring was trans. This assignment was also
confirmed by the presence of strong NOE correlations
between 9-H and 10-H (b), 9-H and 11-H, and between
10-H (b) and 11-H. The stereochemistry of compounds
29 and 26b were finally assigned shown in Scheme 4.
When the secondary hydroxyl group of 26 (26a or 26b)
was protected as its benzyl ether (Scheme 5), an inter-
esting solvent effect was again noticed. The reaction of
26 with NaH/BnBr/DMF was still very complex. On
treating 26 with NaH/BnBr/Bu4NI/THF, no reaction
took place even after refluxing for 10 h. Interestingly,
we found that the addition of DMF played a role in
controlling both the yield and the rate of the reaction.
The combination of NaH/BnBr/Bu4NI/THF and a
small amount of DMF increased the yield of 30 to 80%.
Finally a three-step procedure involving desilylation,
Swern oxidation, and oxidation with I2/KOH/MeOH16
afforded directly the desired ester 3117 (Scheme 5).
In summary, a strategically chiral precursor 31 for
carbocyclization to the dienophile unit of methyl isosar-
tortuoate 1 has been prepared. Further manipulation of
31 to 5 is reported in the following letter.4
Scheme 4. Reagents and conditions: (a) MsCl, Et3N, CH2Cl2,
rt 30 min, 80%; (b) MsCl, Et3N, CH2Cl2, rt 2 days, 85%; (c)
Bu4NF, THF; (d) Ac2O, DMAP, Et3N, CH2Cl2, rt.
Acknowledgements
In theory both epimers 26a and 26b could be used as
intermediates, but they exhibited quite different reac-
tion properties in the following transformations (see the
next letter4). So the C-9 configuration was determined
as shown in Scheme 4. Treatment of compound 26b
with NEt3/MsCl/CH2Cl2 at rt for 30 min afforded the
mesylate 27 in 80% yield. However, with the reaction
time increased, a THF-ring containing product 28 was
formed as a byproduct.14 Further increasing the reac-
tion time to 2 days at rt led to an improved 85% yield
of 28. In order to distinguish proton signals in its
NMR, the TBDPS ether of 28 was converted into the
acetate 29.15 The 2D NOESY spectra of 29 showed no
This work was supported by the Chinese Academy of
Sciences and the National Natural Science Foundation
of China.
References
1. Su, J.-Y.; Long, K.-H.; Peng, T.-S.; He, C.-H.; Clardy, J.
J. Am. Chem. Soc. 1986, 108, 177. For methyl sartotuoate
2, see: (b) Su, J.-Y.; Long, K.-H.; Peng, T.-S.; Zheng,
Q.-T.; Lin, X.-Y. Acta Chimica Sinica 1985, 43, 796; (c)
Su, J.-Y.; Long, K.-H.; Peng, T.-S.; Zeng, L.-M.; Zheng,
Q.-T.; Lin, X.-Y. Sci. Sin. Ser. B 1988, 31, 1172.

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Z. Hong et al. / Tetrahedron Letters 44 (2003) 485–488
NMR (300 MHz, CDCl3) l 7.68 (m, 4H), 7.30ꢀ7.40 (m,
2. For other related compounds, see: (a) Kusumi, T.; Igari,
11H), 4.63, 4.43 (AB system, 2H, J=12.0 Hz, CH2Ph),
4.36 (t, 1H, J=6.3 Hz, acetal H), 3.71 (m, 3H, CHO,
CH2OTBDPS), 3.34 (s, 6H, 2CH3O), 3.34 (m, 1H, CHO),
1.86 (m, 2H), 1.55ꢀ1.70 (m, 8H), 1.45ꢀ1.08 (m, 10H),
1.08 (s, 9H, 3CH3), 0.89 (m, 9H, 3CH3), 0.75 (d, 3H, 6.3
Hz, CH3). Anal. calcd for C45H70O5Si: C, 75.16; H, 9.81.
Found: C, 75.50; H, 9.61%. For 26b: [h]2D0=−9.7 (c 1.20,
M.; Ishitsuka, M. O.; Itezono, Y.; Nakayama, N.; Kak-
isawa, H. J. Org. Chem. 1990, 55, 6286; (b) Leone, P. A.;
Bowden, B. F.; Carrol, A. R.; Coll, J. C.; Meehan, G. V.
J. Nat. Prod. 1993, 56, 521.
3. For our group’s previous works on this project, see: (a)
Chen, X.-C.; Fan, C.-F.; Xu, X.-X. Chin. J. Chem. 2000,
18, 717; (b) Gao, Y.; Nan, F.-J.; Xu, X.-X. Tetrahedron
Lett. 2000, 41, 4811; (c) Liao, X.-B.; Xu, X.-X. Tetra-
hedron Lett. 2000, 41, 4641.
4. Hong, Z.-Y.; Xu, X.-X. Tetrahedron Lett. 2003, 44, 489.
5. (a) Tius, M. A.; Fauq, A. H. J. Am. Chem. Soc. 1986,
108, 1035; (b) Tius, M. A.; Fauq, A. H. J. Am. Chem.
Soc. 1986, 108, 6389.
CHCl3); IR (film) 3453, 2955, 2932, 1112, 1067 cm−1
;
ESI-MS (m/z, %) 741.6 (M+Na+, 40.0); 1H NMR (300
MHz, CDCl3) l 7.67 (m, 4H, ArH), 7.42 (m, 6H, ArH),
7.34 (m, 5H, ArH), 4.63, 4.40 (AB system, 2H, J=11.1
Hz, CH2Ph), 4.33 (t, 1H, J=6.0 Hz, acetal H), 3.68 (t,
2H, J=6.3 Hz, CH2OTBDPS), 3.52 (m, 3H, 2CHO,
OH), 3.31 (s, 6H, 2CH3O), 1.92 (m, 1H), 1.78 (m, 2H),
1.10ꢀ1.60 (m, 19H), 1.06 (s, 9H, 3CH3), 0.86 (m, 12H,
4CH3). Anal. calcd for C45H70O5Si: C, 75.16; H, 9.81.
Found: C, 74.95; H, 9.60%.
6. (a) James, F.; Yoshito, K. Tetrahedron Lett. 1982, 23,
2719; (b) Dominique, K.; Michelle, P. Tetrahedron Lett.
1993, 34, 2757.
7. (a) Tius, M. A.; Fauq, A. H. J. Org. Chem. 1983, 52,
4131; (b) Chong, J. M.; Cyr, D. R.; Mar, E. K. Tetra-
hedron Lett. 1987, 28, 5009; (c) Johnson, M. R.; Nakata,
T.; Kishi, Y. Tetrahedron Lett. 1979, 20, 4343.
8. Nakagawa, I.; Hata, T. Tetrahedron Lett. 1975, 16, 1409.
9. In some solvents sulfone groups are able to be deproto-
nated by NaH at rt, see: (a) Hales, N. J.; Paquette, L. A.
J. Org. Chem. 1979, 44, 4603; (b) Laduree, P. D.; Rioult,
P.; Vialle, J. Bull. Soc. Chim. Fr. 1973, 2, 637.
10. Sometimes TBDPS silyl ethers are unstable under
strongly basic conditions, see: (a) Shekhani, M. S.; Khan,
K. M.; Mahmood, K.; Shah, P. M.; Malik, S. Tetra-
hedron Lett. 1990, 31, 1669; (b) Nelson, T. D.; Crouch,
R. D. Synthesis 1996, 1031.
14. (a) Persky, R.; Albeck, A. J. Org. Chem. 2000, 65, 3775;
(b) Yang, B.-H.; Jiang, J.-Q.; Ma, K.; Wu, H. Tetra-
hedron Lett. 1995, 36, 2831.
15. By combination of 2D NOESY (600 MHz) and 2D
COESY (400 MHz), the chemical shifts (l=ppm) of
compound 28 was assigned as following: 15-H (4.10, 2H),
14-H (1.82), 14-H (1.70), 12-H (3.65), 11-H (1.57), 10-H
(b) (1.95), 10-H (a) (1.25), 9-H (3.57).
16. Yamada, S.; Morizono, D.; Yamamoto, K. Tetrahedron
Lett. 1992, 33, 4329.
17. Physical and spectroscopic data for 31: [h]2D0=+48.3 (c
0.50, CHCl3); IR (film) 2955, 1740, 1455, 1368, 1069, 698
cm−1; ESI-MS (m/z, %) 616.6 (M+NH4+, 100.0), 621.6
1
(M+Na+, 55.0); H NMR (300 MHz, CDCl3) l 7.30 (m,
11. Gordon, L.; Christine, G. Synth. Commun. 1990, 20,
1473.
10H, ArH), 4.58, 4.38 (AB system, 2H, J=12 Hz,
CH2Ph), 4.36 (m, 3H, CH2Ph, acetal H), 3.60 (s, 3H,
OCH3), 3.37 (m, 2H), 3.31 (s, 6H, 2CH3O), 2.32 (m, 2H,
CH2CO2Me), 1.87 (m, 4H), 1.73 (m, 1H), 1.60–1.05 (m,
13H), 0.95 (d, 3H, J=7.0 Hz, CH3), 0.90 (m, 9H, 3CH3).
Anal. calcd for C37H58O6: C, 74.21; H, 9.76. Found C,
74.24; H, 9.64%.
12. Achmatowicz, B.; Baranowska, E.; Daniewski, A. R.;
Pankowski, J.; Wicha, J. Tetrahedron 1988, 44, 4989.
13. Physical and spectroscopic data. For 26a: [h]2D0=−32.1 (c
0.85, CHCl3); IR (film) 3460, 2956, 1464, 1429, 1112,
1
1067 cm−1; ESI-MS (m/z, %) 741.6 (M+Na+, 100.0); H