Synthesis of the tricyclic core of aldingenin b by oxidative cyclo ketalization of an alkyne-diol

Article abstract of DOI:10.1021/ol200421s

The preparation and selenium-mediated cyclo-ketalization of an alkyne-diol is described as a model study for the synthesis of aldingenin B. The oxidative cyclization is a simplifying transformation for aldingenin B, as it provides a convenient method for

Full text of DOI:10.1021/ol200421s

ORGANIC
LETTERS
2011
Vol. 13, No. 8
2065–2067
Synthesis of the Tricyclic Core of
Aldingenin B by Oxidative Cyclo-
Ketalization of an Alkyne-Diol
Jingyue Yang, Jumreang Tummatorn, Rimantas Slegeris, Sami F. Tlais, and
Gregory B. Dudley*
Department of Chemistry and Biochemistry, Florida State University, Tallahassee,
Florida 32306-4390, United States
gdudley@chem.fsu.edu
Received February 15, 2011
ABSTRACT
The preparation and selenium-mediated cyclo-ketalization of an alkyne-diol is described as a model study for the synthesis of aldingenin B. The
oxidative cyclization is a simplifying transformation for aldingenin B, as it provides a convenient method for generating the tricylic core of the
natural product from a functionalized cyclohexane.
The aldingenin family1 of bisabolene sesquiterpenes is a
collection of brominated marine natural products2 isolated
from a Brazilian strain of the red alga Laurencia aldingen-
sis. Red algae of the Laurencia genus produce myriad
halogenated secondary metabolites, many of which are
useful as taxonomic markers for species identification.3
It was in this vein that the aldingenins were isolated and
characterized, as part of a taxonomic investigation of the
Figure 1. Aldingenin B and R-bisabolene.
Brazilian species of Laurencia.1
Aldingenin B1b (Figure 1) caught our attention due to its
compact and highly oxygenated tetracyclic structure. As a
target for stereoselective synthesis, it presents challenges
with respect to the controlled oxidation and installation of
complex functionality, especially at C5, into a relatively
simple (bisabolene) carbon framework.
Our retrosynthetic analysis of aldingenin B is presented
in Scheme 1. A late stage bromoetherication is planned for
installation of the C7-C11 oxane ring, leading to the
identification of tricyclic keto-ketal 4 as the core target.
It was tempting retrosynthetically to unravel the keto-
ketal to R-diketone 5, but strategic analysis of 5 prompted
concerns. R-Diketones easily undergo tautomerization to
enols; in the case of R-diketone 5, enolization to give 50
would both compromise C6 stereochemistry and threaten
to promote elimination of the protected C5 alcohol. Note
that keto-ketal 4 cannot tautomerize (Bredt’s rule). There-
fore, we prioritized the goal of installing the C7-C8 keto-
ketal of 4 without producing an intermediate C7-C8
diketone, and our synthetic efforts focused on alkyne 2.
(1) (a) de Carvalho, L. R.; Fujii, M. T.; Roque, N. F.; Kato, M. J.;
Lago, J. H. G. Tetrahedron Lett. 2003, 44, 2637–2640. (b) de Carvalho,
L. R.; Fujii, M. T.; Roque, N. F.; Lago, J. H. G. Phytochemistry 2006,
67, 1331–1335.
(2) (a) Fusetani, N. Drugs from the Sea; Karger Press: Basel, Switzer-
land, 2000. (b) Gribble, G. W. Acc. Chem. Res. 1998, 31, 141–152. (c)
Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1–49. (d) Butler, A.; Carter-
Franklin, J. N. Nat. Prod. Rep. 2004, 21, 180–188.
(3) Fenical, W. J. Phycol. 1975, 11, 245–259.
r
10.1021/ol200421s
2011 American Chemical Society
Published on Web 03/10/2011

to be satisfactory with the acetonide in place (cf. 8 f 9).
Therefore, the protection strategy was altered to feature
TBS ethers (10) in lieu of the acetonide. Reduction of the
methyl ester of 10 and hydroboration/oxidation gave diol
11 as a single diastereomer, in contrast to nonselective
hydroboration leading to acetal 9.
Scheme 1. Retrosynthetic Analysis
The secondary alcohol of diol 11 was converted to a
PMB ether using a standard two-step sequence (11 f 12).7
Primary alcohol 12 was oxidized to the aldehyde with PCC
and then converted to terminal alkyne 14 using the Ohira-
Bestmann reagent (13).8 Finally, methylation of alkyne 14
(n-BuLi; MeI) and desilylation with TBAF completed the
synthesis of alkyne-diol 2.
Oxidative keto-ketalization ofalkynes(Scheme 3) would
be useful in the continued progression of our synthetic
strategy, but such tools are not well developed in organic
synthesis. Oxidation of alkynes to R-diketones (as opposed
to R-keto ketals) can be accomplished with reagents in-
cluding permanganate ion, ozone, and osmium tetroxide,
as well as several transition-metal-catalyzed processes.9
We were interested in potentially coupling one of these
methods with ketal formation, such that cyclization to the
The generation4 and synthetic application5 of complex
alkynes is an ongoing area of interest in the Dudley Lab.
Herein we report the synthesis and cyclo-ketalization of
alkyne-diol 2 as a model study for the synthesis of aldin-
genin B.
The synthesis of alkyne-diol 2 began with the known
Diels-Alder reaction between propiolic acid and isoprene,
which provides cyclohexadienyl acid 6 (Scheme 2).6 After
Scheme 2. Synthesis of Alkyne-Diol 2a
a See Supporting Information for details.
conversion to the methyl ester, regioselective dihydroxyla-
tionof themoreelectron-rich alkene gavediol 7. Diol 7 was
initially protected as an acetonide (8), but downstream in
the synthetic sequence is a hydroboration that proved not
ketal occurs in concert with the alkyne oxidation.
However, these methods generally involve harsh oxidants
with poor functional group tolerance and are best suited
for use on simple alkynes with aryl and/or tert-alkyl
substituents. Specifically, we required a method suitable
for oxidation of dialkylalkynes to R-keto ketals in the
presence of alcohols (Scheme 3).
A thorough scan of the literature revealed a single
example of the type of keto-ketalization envisioned for
the synthesis of aldingenin B. As part of a larger study on
(4) (a) Kamijo, S.; Dudley, G. B. J. Am. Chem. Soc. 2005, 127, 5028–
5029. (b) Kamijo, S.; Dudley, G. B. Org. Lett. 2006, 8, 175–177. (c)
Kamijo, S.; Dudley, G. B. J. Am. Chem. Soc. 2006, 128, 6499–6507. (d)
Tummatorn, J.; Dudley, G. B. J. Am. Chem. Soc. 2008, 130, 5050–5051.
(e) Tummatorn, J.; Dudley, G. B. Org. Lett. 2011, 13, 158–160. (f) Jones,
D. M.; Lisboa, M. P.; Kamijo, S.; Dudley, G. B. J. Org. Chem. 2010, 75,
3260–3267.
(5) (a) Jones, D. M.; Kamijo, S.; Dudley, G. B. Synlett 2006, 936–938.
(b) Jones, D. M.; Dudley, G. B. Synlett 2010, 223–226. (c) Tlais, S. F.;
Dudley, G. B. Org. Lett. 2010, 12, 4698–4701. (d) Jones, D. M.; Dudley,
G. B. Tetrahedron 2010, 60, 4860–4866.
(7) Munakata, R.; Katakai, H.; Ueki, T.; Kurosaka, J.; Takao, K.;
Tadano, K. J. Am. Chem. Soc. 2004, 126, 11254–11267.
(8) (a) Ohira, S. Synth. Commun. 1989, 19, 561–564. (b) Roth, G. J.;
ꢀ
€
€
(6) Frater, G.; Muller, U. Helv. Chim. Acta 1989, 72, 653–658.
Liepold, B.; Muller, S. G.; Bestmann, H. J. Synthesis 2004, 59–62.
2066
Org. Lett., Vol. 13, No. 8, 2011

Scheme 3. Oxidative Keto-Ketalization of Alkynesa
Scheme 4. Oxidative Alkyne-Diol Keto-Ketalization [and Pro-
posed Mechanism] for the Synthesis of Aldingenin Ba
a R, R1, R2 = alkyl groups. Oxidation numbers assigned (red).
selenium-mediated oxidations,10 Tiecco reported the oxi-
dation of 4-octyne to 5,5-dimethoxy-4-octanone using
ammonium peroxydisulfate and diphenyl diselenide in
methanol11 (cf. Scheme 3, R = methyl; R1, R2 = n-propyl,
51% yield). Two features of this reaction were especially
attractive for our purposes: use of methanol as solvent
suggests compatibility with alcohols, and the postulated
mechanism does not involve an intermediate R-diketone.
The mechanism envisioned for the oxidation and diol
cyclization process is outlined in Scheme 4. The first steps
involve coordination of the active selenium oxidant and
cyclohexane ring-flipping into a conformation (I) in which
cyclization is possible. Cyclohexane conformations with
multiple axial substituents are typically disfavored because
of diaxial interactions, but in this case one diaxial interac-
tion is believed to be favorable, leading to bond construc-
tion and formation of vinylselenide intermediate II.
A second oxy-selenenylation would result in seleno-ketal
III, the hydrolysis of which provides keto-ketal 3. In the
event, treatment of alkyne-diol 2 with 1 equiv of diphenyl
diselenide and 2 equiv of ammonium persulfate in aqueous
acetonitrile at 85 °C provided tricylic R-keto ketal 3 in 52%
yield (Scheme 4).
a See Supporting Information for details.
framework. Optimization of this key step remains a work
in progress, but we have concluded that water is a critical
cosolvent (alongside acetonitrile) and 85°C seems to be the
optimal temperature. As we shift our attention to the
natural product, what remains is to construct a more
elaborate analog of alkyne 2, with functionality in place
to facilitate bromoetherification and complete the fourth
and final ring of aldingenin B.
This novel cyclo-ketalization reaction using Tiecco’s
conditions simplifies the synthesis of aldingenin B by
building two new heterocycles into the monocyclic carbon
In summary, we report the first example of an alkyne-
diol oxidative cyclo-ketalization as a model study for the
synthesis of aldingenin B. The selenium-mediated process
delivers the complex tricyclic core of aldingenin B from a
modestly functionalized cyclohexane precursor. Continu-
ing efforts toward the enantioselective synthesis of the
natural product will be reported in due course.
(9) For a general overview with leading references, see: (a) Zibuck, R.
Seebach, D. Helv. Chim. Acta 1988, 71, 237–240. For select recent
examples of alkyne oxidation to R-diketones, see:(b) Ren, W.; Liu, J.;
Chen, L.; Wan, X. Adv. Synth. Catal. 2010, 352, 1424–1428. (c) Ren, W.;
Xia, Y.; Ji, S.-J.; Zhang, Y.; Wan, X.; Zhao, J. Org. Lett. 2009, 11, 1841–
1844. (d) Shine, H. J.; Rangappa, P.; Marx, J. N.; Shelly, D. C.; Ould-
Ely, T.; Whitmire, K. H. J. Org. Chem. 2005, 70, 3877–3883. (e) Zhang,
Y.; Heinsen, M. H.; Kostic, M.; Pagani, G. M.; Riera, T. V.; Perovic, I.;
Hedstrom, L.; Snider, B. B.; Pochapsky, T. C. Bioorg. Med. Chem. 2004,
12, 3847–3856. (f) Mori, Y.; Nogami, K.; Hayashi, H.; Noyori, R. J.
Org. Chem. 2003, 68, 9050–9060. (g) Lai, S.; Lee, D. G. Tetrahedron
2002, 58, 9879–9888. (h) Che, C.-M.; Yu, W.-Y.; Chan, P.-M.; Cheng,
W.-C.; Peng, S.-M.; Lau, K.-C.; Li, W.-K. J. Am. Chem. Soc. 2000, 122,
11380–11392. (i) Xu, G.; Liu, Y.; Sayre, L. M. J. Org. Chem. 1999, 64,
5732–5745.
(10) Introduction and overview: (a) Tiecco, M.; Tingoli, M.; Testa-
ferri, L. Pure Appl. Chem. 1993, 65, 715–722. Recent reports with
leading references:(b) Santoro, S.; Santi, C.; Sabatini, M.; Testaferri, L.;
Tiecco, M. Adv. Synth. Catal. 2008, 350, 2881–2884. (c) Santoro, S.;
Battistelli, B.; Gjoka, B.; Si, C.-W. S.; Testaferri, L.; Tiecco, M.; Santi,
C. Synlett 2010, 1402–1406.
Acknowledgment. This research is supported by a grant
from the National Science Foundation (NSF-CHE
0749918). J.T. was a recipient of the Royal Golden Jubilee
Ph.D. Fellowship (PHD/0239/2547) from the Thailand
Research Fund for study abroad.
Supporting Information Available. Experimental pro-
cedures, characterization data, and copies of NMR spec-
tra. This material is available free of charge via the
Internet at http://pubs.acs.org.
(11) Tiecco, M.; Testaferri, L.; Tingoli, M.; Chianelli, D.; Bartoli, D.
J. Org. Chem. 1991, 56, 4529–4534.
Org. Lett., Vol. 13, No. 8, 2011
2067