ester 14 that was adequately functionalized for introduction
of the butenyl side chain at a later stage in the synthesis. To
that end, reduction of the ester functionality and protection
of the resulting hydroxyl group as the TIPS ether gave diene
15. The synthesis of one of the reactants for the projected
Stille coupling reaction, stannane 16, was then completed
by directed metalation of the diene 15 followed by stan-
nylation with trimethyltin chloride.
Scheme 5
With stannane 16 in hand, our attention turned to the
synthesis of triflate 10, which we felt could be prepared from
the less substituted enolate derivative of cis-2,4-dimethyl
cyclopentanone. To that end, we examined the hydrosilyla-
tion of 3,5-dimethylcyclopentenone 178 under a variety of
conditions. We initially subjected cyclopentenone 17 to tert-
butyldimethylsilane and platinum divinyltetramethyldisi-
loxane complex (Karstedt’s catalyst) according to the
Johnson protocol (70 °C, neat)9 and obtained a disappointing
mixture of cis/trans isomers (2:1). However, the diastereo-
selectivity could be improved by using triethylsilane (6:1)
or dimethylethoxysilane at 0 °C (10:1). The best results were
obtained using a modification of Mori’s conditions10 {HSiMe2-
(OEt), [Rh(OH)(cod)]2, -20 °C} and gave rise to dimeth-
ylethoxysilylenol ether 18 with greater than 20:1 cis/trans
1
selectivity by H NMR spectroscopy (Scheme 4).11,12 This
solid, and its structure and stereochemistry were confirmed
by X-ray crystallography.
Scheme 4
To complete the total synthesis, indoline 21 was oxidized
with MnO2 to give indole 22. Next, the trans-butenyl side
chain was installed using the same protocol reported by
Natsume3a that was successful for the N-phenylsulfonylindole
analogous to carbamate 22, namely, via dehydration of the
benzylic alcohol derived from Grignard addition to aldehyde
22. Finally, removal of the BOC protecting group with
TMSOTf 14 proceeded uneventfully to give (()-cis-trikentrin
B, whose spectra were very similar to the isolated natural
product1 and identical to previously synthesized material.2d,g
enol ether was then directly converted into the desired enol
triflate 10 via a protocol recently reported by Corey and co-
workers.13
The versatility of this particular approach to the trikentrins
was next examined in its straightforward application to the
total synthesis of cis-trikentrin A. Thus, our immediate goal
was the preparation of stannane 24 that now possesses the
eventual C(4) ethyl substituent of trikentrin A (Scheme 6).
To that end, addition of ethyllithium to aldehyde 12 followed
by TPAP/NMO oxidation gave rise to ketone 23. Wittig
olefination followed by stannylation provided stannane 24.
A subsequent Stille coupling of stannane 24 with triflate 10
gave rise to the labile trienecarbamate 25 that decomposed
during several attempts to purify it via column chromatog-
raphy. Accordingly, the crude coupling product was heated
in toluene in order to effect an especially facile electrocyclic
ring closure (30 min, 80 °C) followed by in situ oxidation
with MnO2 to deliver the desired indoline 26. This electro-
cyclic closure is accelerated relative to the triene 19
counterpart presumably because of the placement of the ethyl
substituent, that is, it is not on the terminal carbon of the
triene. Deprotection of the BOC protecting group with
We now directed our attention to the construction of the
central six-membered ring from the two five-membered ring
building blocks. Thus, Stille coupling of stannane 16 with
triflate 10 gave trienecarbamate 19 in good yield (Scheme
5). We were pleased to discover that triene 19 underwent
an electrocyclic closure in refluxing xylenes to afford diene
20 that, in the same pot, could be aromatized with concomi-
tant oxidative desilylation to indoline aldehyde 21 simply
by lowering the reaction temperature to 0 °C and adding
DDQ (2.5 equiv). Moreover, compound 21 was a crystalline
(8) Toder, B. H.; Branca, S. J.; Dieter, R. K.; Smith, A. B., III. Synth.
Commun. 1975, 5, 435.
(9) Johnson, C. R.; Raheja, R. K. J. Org. Chem. 1994, 59, 2287.
(10) Mori, A.; Kato, T. Synlett. 2002, 1167.
(11) The stereochemistry was assigned by hydrolysis to the known2d cis-
2,4-dimethylcyclopentanone
(12) Buchwald and co-workers reported have reported the enantio- and
diastereoselective synthesis of 2,4-dialkylcyclopentanones via analogous silyl
enol ethers that could render this synthesis enantioselective, albeit, with
lower diastereoselectivity, see the following: Jurkauskas, V.; Buchwald,
S. L. J. Am. Chem. Soc. 2002, 124, 2892.
(13) Mi, Y.; Schreiber, J. V.; Corey, E. J. J. Am. Chem. Soc. 2002, 124,
11290.
(14) Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 55, 870.
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