Synthesis of the ABCD fragment of gymnocin-B

Article abstract of DOI:10.1016/j.tetlet.2019.151261

A convergent synthesis of the ABCD fragment of gymnocin-B was accomplished. The tetracyclic ether ring system was synthesized by the construction of the BC ring system via the oxiranyl anion alkylation and ring expansion reaction, followed by the formation of the five-membered A-ring via a stereoselective radical cyclization reaction of a neopentyl-type iodide.

Full text of DOI:10.1016/j.tetlet.2019.151261

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Synthesis of the ABCD fragment of gymnocin-B
Takeo Sakai, Kohei Hata, Yuki Kitamura, Renji Ishibashi, Yuji Mori
PII:
S0040-4039(19)31041-X
https://doi.org/10.1016/j.tetlet.2019.151261
TETL 151261
DOI:
Reference:
Tetrahedron Letters
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13 September 2019
5 October 2019
10 October 2019
Please cite this article as: Sakai, T., Hata, K., Kitamura, Y., Ishibashi, R., Mori, Y., Synthesis of the ABCD fragment
of gymnocin-B, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151261
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Corresponding author. E-mail address: sakait@meijo-u.ac.jp (T. Sakai); mori@meijo-
u.ac.jp (Y. Mori).
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1
Tetrahedron Letters
journal homepage: www.elsevier.com
Synthesis of the ABCD fragment of gymnocin-B
Takeo Sakai*, Kohei Hata, Yuki Kitamura, Renji Ishibashi, Yuji Mori1
Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
A convergent synthesis of the ABCD fragment of gymnocin-B was accomplished. The
tetracyclic ether ring system was synthesized by the construction of the BC ring system via the
oxiranyl anion alkylation and ring expansion reaction, followed by the formation of the five-
membered A-ring via a stereoselective radical cyclization reaction of a neopentyl-type iodide.
Received in revised form
Accepted
Available online
Keywords:
2019 Elsevier Ltd. All rights reserved.
Marine natural product
Gymnocin-B
Polycyclic ether
Oxiranyl anion
Ladder-shaped polyethers are marine natural products characterized by trans-fused cyclic ether skeletons and potent
bioactivities.[1],[2] Gymnocin-B is a pentadecacyclic ether produced by the red-tide dinoflagellate Karenia mikimotoi,[3] and it shows
potent cytotoxicity against mouse leukemia cells P388 (IC50 1.7 M). The first total synthesis of gymnocin-B was recently
accomplished by Sittihan and Jamison,[4] and a synthetic study on the NO ring system was reported earlier by Tsukano and Sasaki.[5]
We have also described a convergent synthesis of the GHIJKL fragment[6] based on the oxiranyl anion strategy.[7] As a continuation
of our studies on the synthesis of gymnocin-B, we report herein a convergent synthesis of the ABCD fragment of gymnocin-B.
Figure 1. Structures of gymnocin-A and gymnocin-B.
The ABC system of gymnocin-B is largely similar to that of gymnocin-A, and it includes a five-seven-six membered ring with a 2-
methyl-2-butenal side chain on ring A (Figure 1). The difference between the two gymnocins is the presence of an angular methyl group

2
Tetrahedron
at the AB bridgehead in gymnocin-B, while the AB bridgehead of gymnocin-A is unsubstituted. Thus, the construction of the ABC
system of gymnocin-B is more challenging, because of the difficulty in introducing a methyl group at the bridgehead position.
Retrosynthesis of the ABCD fragment was performed based on the reported synthesis of the ABC system of gymnocin-A.[8] Synthesis
of the A-ring moiety of the ABCD fragment 1 was planned by radical cyclization from alkyl iodide 2, which would be prepared from
BCD diol 3.[9] This conversion is the key feature of our approach because it involves transformation from a neopentyl-type alcohol to
an iodide. The BC ring system of 3 would be formed from coupling product 4, which could be obtained by the nucleophilic substitution
of oxiranyl anion 6 with alkyl triflate 5 bearing the methyl group.
Scheme 1. Retrosynthetic analysis of the ABCD fragment of gymnocin-B.
Scheme 2. Synthesis of neopentyl-type iodide 11 and radical cyclization.
We began our study by using model diol 8 for the A-ring construction (Scheme 2). Diol 8 was prepared from known compound 70 in
two steps by silylene protection and removal of the benzylidene acetal group. The primary alcohol in 8 was selectively tosylated to
afford 9, and the remaining secondary alcohol in 9 was subjected to oxa-Michael reaction using ethyl propiolate to afford unsaturated
ester 10. Conversion of alkyl tosylate 10 to iodide 11 did not proceed at all upon heating with NaI and 18-crown-6 in acetone at reflux
temperature. Fortunately, the reaction was promoted with KI at 120 °C in DMSO to give the desired iodide 11 in good yield, without
the significant formation of any byproduct. Radical cyclization0 of iodide 11 using triethylborane provided bicyclic product 12 in good
yield as a single diastereomer.[10]

3
Scheme 3. Synthesis of alkyl triflate 5 and epoxy sulfone 6.
We next focused on the preparation of the requisite alkyl triflate 5 (Scheme 3(a)). Tertiary alcohol 13[11] was protected with TMS
triflate to give 14, which was subjected to hydrogenation using Pd/C (type NX catalyst) for removal of the benzylidene acetal
group.[12] The obtained diol 15 was protected with a di-tert-butyl silylene group to form a 1,3,2-dioxasilinane ring, and demasking of
the TMS and TBS groups afforded diol 16. TMS protection of the tertiary alcohol in 15 was necessary because a five-membered 1,3,2-
dioxasilolane ring was exclusively formed during the di-tert-butylsilylene protection of the corresponding 1,2,3-triol. Diol 16 was
subjected to one-pot triflation and TMS protection to provide alkyl triflate 5. Epoxy sulfone 6 was synthesized from known bicyclic
ester 17[13] (Scheme 3(b)), which upon diethylisopropylsilyl (DEIPS) protection[14] and DIBALH reduction provided aldehyde 18.
Horner–Wadsworth–Emmons reaction of 18 under Masamune–Roush conditions provided vinyl sulfone 19, which was oxidized into
epoxy sulfone 6 using t-BuOOH and t-BuOK.

4
Tetrahedron
Scheme 4. Synthesis of BCD diol 3.
Having prepared alkyl triflate 5 and epoxy sulfone 6, we next carried out oxiranyl anion coupling to give the corresponding product
4 in good yield (Scheme 4). Although 6 was an 81:19 mixture of - and -epoxides, the major -epoxide reacted preferentially to
provide the coupling product as a single diastereomer. The TMS group of 4 was selectively removed to give epoxy alcohol 20, which
was then treated with MgBr2·OEt2 and LiBr to afford bromoketone 21. Williamson-type etherification from tertiary alcohol 21
proceeded smoothly when using aqueous NaOH in the presence of 18-crown-6,[15] and the obtained six-membered ketone 22 was
subjected to ring expansion to furnish seven-membered ketone 23.[16] Silyl enol ether formation, followed by oxidation with OsO4,
Error! Bookmark not defined.
provided -hydroxy ketone 24.0h,
Treatment of 24 with p-toluenesulfonic acid and trimethyl orthoformate
facilitated simultaneous DEIPS group removal, methyl acetalization, and deprotection of the benzylidene acetal moiety to afford
trihydroxy acetal 25. Global protection of the hydroxy groups with benzyl bromide gave tribenzyl ether 26. BCD diol 3 was obtained
after reductive etherification of the methyl acetal,[17] followed by deprotection of the di-tert-butylsilylene group.

5
Scheme 6. Synthesis of ABCD fragment 1.
The final step was the construction of the A ring in BCD diol 3 (Scheme 6). The primary alcohol of 3 was selectively tosylated to
give hydroxy tosylate 28, which was converted into unsaturated ester 29 by an oxa-Michael reaction. Transformation of 29 into iodide 2
was achieved under the reaction conditions outlined in Scheme 2. Thus, heating with potassium iodide in DMSO gave iodide 2, and
subsequent radical cyclization afforded tetracyclic ester 30 in high yield.0, Error! Bookmark not defined. The ester was reduced to an alcohol, and
global deprotection of the benzyl groups afforded tetraol 31. The 1,3-diol moiety was protected as an acetonide to give 32, and the
remaining dihydroxy groups in 32 were protected with benzyl groups to give 33. Finally, deprotection of the acetonide provided ABCD
fragment 1, which could be readily subjected to the next oxiranyl anion coupling with a right-side fragment.
In conclusion, we have synthesized the ABCD fragment of gymnocin-B from alkyl triflate 5 and epoxy sulfone 6 using the oxiranyl
anion strategy. The five-memberd A ring was constructed by a conversion from the neopentyl-type alcohol to the iodide followed by the
stereoselective radical cyclization reaction. The synthesis has been accomplished in 28 steps from known diol 7. Further synthetic study
of gymnocin-B is ongoing in our laboratory.
Acknowledgments
This research was partially supported by Grant-in-Aids for Scientific Research (C) (16K08182 and 19K06983) from the Japan
Society for the Promotion of Science (JSPS) and the Science Research Promotion Fund from the Promotion and Mutual Aid
Corporation for Private Schools of Japan. We are grateful to Ms. Atsuko Kawai and Ms. Arisa Toyoda for the preliminary experiments
in this study.

6
Tetrahedron
Supplementary Material
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References and notes
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References

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