10.1002/asia.202100383
Chemistry - An Asian Journal
COMMUNICATION
(Scheme 3). The single-electron reduction of 7h utilizing SmI2 in
the presence of H2O and triethylamine gave the desired equatorial
alcohol eq-11 (57%) as a major diastereomer, along with the axial
alcohol ax-11 (43%).[16] Compound ax-11 was returned to 7h by
Dess-Martin periodinane (DMP) oxidation and re-submitted to the
SmI2-mediated reduction.[17] After methoxymethyl (MOM) acetal
protection of the hydroxyl group in eq-11, piperidine 12 was
oxidized by ruthenium tetroxide, giving lactam 13.[18] After
reducing the lactam carbonyl moiety in 13 using
diisobutylaluminum hydride (DIBALH), the resulting aldehyde was
treated under acidic conditions, giving ene-carbamate 14 in
quantitative yield. The allylation of 14 with allyltrimethylsilane and
trifluoroacetic acid (TFA) afforded allylpiperidine 15 in dr 75:25.[19]
The two diastereomers were easily separated by silica gel column
chromatography.
Scheme 4. Total synthesis of histrionicotoxin alkaloids.
synthesis of HTX-235A. Application of the methodology to other
HTX analogues and natural products is under investigation in our
laboratory.
Experimental Section
Experimental procedures, spectroscopic data, copies of 1H- and 13C-NMR
spectra, and crystallographic data are available in the SI.
Acknowledgements
This work was financially supported by the Astellas Foundation,
the JGC-S Scholarship Foundation (Nikki Saneyoshi Scholarship),
and JSPS KAKENHI Grant Number JP19K05461.
Keywords: alkaloids • cyclization • diastereoselectivity • spiro
compounds • total synthesis
Scheme 3. Synthesis of allylpiperidine 15
[1]
a) Y. Zheng, C. M. Tice, S. B. Singh, Bioorg. Med. Chem. Lett. 2014, 24,
3673–3682; b) L. K. Smith, I. R. Baxendale, Org. Biomol. Chem. 2015,
13, 9907–9933.
Scheme 4 outlines the synthesis of HTX-235A (2) from
synthesized 15. The tert-butyldiphenylsilyl group in 15 was
deprotected with tetrabutylammonium fluoride (TBAF), yielding
alcohol 16. After constructing a vinylic group by Nishizawa-Grieco
elimination,[7e,20] the methoxycarbonyl group was removed by the
diethylenetriamine-mediated cleavage reaction reported by
Ohshima et al.[21] The deprotection of the MOM group provided
the natural product 2. The 1H- and 13C-NMR data for synthetic 2
were consistent with those of the previously synthesized authentic
sample.[7e] Tokuyama et al. have reported that compound 2 can
be transformed to HTX-283A (1);[7e] therefore, this synthesis also
means the formal one of 1.
In conclusion, we have developed a novel methodology for the
direct one-step synthesis of the 1-azaspiro[5.5]undecane
skeleton common to histrionicotoxin alkaloids from linear
substrates bearing an N-methoxycarbonyl group. The key
reaction proceeds via our Hg(OTf)2-catalyzed cycloisomerization.
The utility of the methodology was demonstrated by the total
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[3]
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For a review, see: a) A. Sinclair, R. A. Stockman, Nat. Prod. Rep. 2007,
24, 298−326; For asymmetric total syntheses of HTX-283A, see: b) G.
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racemic total syntheses of HTX-283A, see: f) A. C. Carey, M. Aratani, Y.
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