Concise entry to both enantiomers of 8-oxabicyclo[3.2.1]oct-3-en-2-one based on novel oxidative etherification: Formal synthesis of (+)-sundiversifolide

Article abstract of DOI:10.1021/ol201273b

Both enantiomers of 8-oxabicyclo[3.2.1]oct-3-en-2-one (6) have been synthesized from 4-hydroxycyclohept-2-enone (3) on the basis of a novel oxidative cyclo-etherification using PhI(OH)OTs (Koser's reagent). (-)-(1S,5R)-8-Oxabicyclo[3.2.1]oct-3-en-2-one [(

Full text of DOI:10.1021/ol201273b

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3620–3623
Concise Entry to Both Enantiomers of
8-Oxabicyclo[3.2.1]oct-3-en-2-one Based
on Novel Oxidative Etherification: Formal
Synthesis of (þ)-Sundiversifolide
Muneo Kawasumi, Naoki Kanoh, and Yoshiharu Iwabuchi*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku University, Aobayama, Sendai 980-8578, Japan
iwabuchi@mail.pharm.tohoku.ac.jp
Received May 12, 2011
ABSTRACT
Both enantiomers of 8-oxabicyclo[3.2.1]oct-3-en-2-one (6) have been synthesized from 4-hydroxycyclohept-2-enone (3) on the basis of a novel
oxidative cyclo-etherification using PhI(OH)OTs (Koser’s reagent). (ꢀ)-(1S,5R)-8-Oxabicyclo[3.2.1]oct-3-en-2-one [(ꢀ)-6, 95% ee] was
expeditiously transformed to (þ)-sundiversifolide (1).
The diastereoselective functionalization of a cycloheptane
derivative often poses challenges to synthetic chemists owing
to the inherent conformational uncertainties. To address this
issue, the structural motif of 8-oxabicyclo[3.2.1]octanes1 with
definite stereoelectronic basis has often served as a useful
platform for the manipulation of cycloheptane derivatives.2
Current methods of securing an 8-oxabicyclo[3.2.1]
octane skeleton rely predominantly on [4 þ 3]-3 or [5 þ 2]-
type4 cycloaddition reactions: Unfortunately, they typi-
cally require many steps in the elaboration of the sub-
strates, particularly in the case of enantioselective
synthesis. We envisioned that 8-oxabicyclo[3.2.1]oct-3-
en-2-one (6)5 would be accessible from 4-hydroxycyclo-
hept-2-enone (3) via an oxidative transformation.
In this paper, we disclose a concise entry to both enantio-
mers of 8-oxabicyclo[3.2.1]oct-3-en-2-one (6), featuring
PhI(OH)OTs6 (Koser’s reagent)-mediated, intramolecular
oxidative etherification7 of 4-hydroxycyclohept-2-enone
(3). We also demonstrate its use by converting (ꢀ)-6 to
(þ)-sundiversifolide (1), which was isolated from the
(1) For reviews, see: (a) Hartung, I. V.; Hoffmann, H. M. R. Angew.
Chem., Int. Ed. 2004, 43, 1934. (b) Harmata, M. Adv. Synth. Catal. 2006,
348, 2297.
(2) For reviews, see: (a) Battiste, M. A.; Pelphrey, P. M.; Wright,
D. L. Chem.;Eur. J. 2006, 12, 3438. (b) Harmata, M. Chem. Commun.
2010, 8886.
(3) For selected examples, see: (a) Orugunty, R. S.; Wright, D. L.;
Battiste, M. A.; Abboud, K. A. Org. Lett. 2002, 4, 1997. (b) Pelphrey,
P. M.; Abboud, K. A.; Wright, D. L. J. Org. Chem. 2004, 69, 6931. (c)
Chung, W. K.; Lam, S. K.; Lo, B.; Liu, L. L.; Wong, W.-T.; Chiu, P. J.
Am. Chem. Soc. 2009, 131, 4556.
(4) For selected examples, see: (a) Hendrickson, J. B.; Farina, J. S.
J. Org. Chem. 1980, 45, 3359. (b) Hendrickson, J. B.; Farina, J. S. J. Org.
Chem. 1980, 45, 3361. (c) Sammes, P. G.; Street, L, J. J. Chem. Soc.,
Chem Commun. 1982, 1056. (d) Wender, P. A.; Mascarenas, J. L.
Tetrahedron Lett. 1992, 33, 2115. (e) Padwa, A.; Weingarten, M. D.
Chem. Rev. 1996, 96, 223. (f) Ali, M. A.; Bhogal, N.; Findlay, J. B. C.;
Fishwick, C. W. G. J. Med. Chem. 2005, 48, 5655. (g) Snider, B. B.;
Grabowski, J. F. Tetrahedron Lett. 2005, 46, 823. (h) Snider, B. B.;
Grabowski, J. F. Tetrahedron 2006, 62, 5171. (i) Snider, B. B.; Wu, X. X.;
Nakamura, S.; Hashimoto, S. Org. Lett. 2007, 9, 873. (j) Garnier, E. C.;
Liebeskind, L. S. J. Am. Chem. Soc. 2008, 130, 7449. (k) Shimada, N.;
Hanari, T.; Kurosaki, Y.; Takeda, K.; Anada, M.; Nambu, H.; Shiro,
M.; Hashimoto, S. J. Org. Chem. 2010, 75, 6039.
(5) For a previous synthesis of 6, see: Fattori, D.; Henry, S.; Vogel, P.
Tetrahedron 1993, 49, 1649.
(6) (a) Moriarty, R. M.; Vaid, R. K.; Koser, G. F. Synlett 1990, 365.
(b) Koser, G. F. Aldrichim. Acta 2001, 34, 89. (c) Nabana, T.; Togo, H.
J. Org. Chem. 2002, 67, 4362. (d) Ueno, M.; Nabana, T.; Togo, H. J. Org.
Chem. 2003, 68, 6424. (e) Yamamoto, Y.; Togo, H. Synlett 2006, 798. (f)
Yamamoto, Y.; Kawano, Y.; Toy, P. H.; Togo, H. Tetrahedron 2007, 63,
4680. (g) Akiike, J.; Yamamoto, Y.; Togo, H. Synlett 2007, 2168.
(7) For similar oxidative etherification induced by hypervalent indine
compounds, see: (a) Fan, R.; Sun, Y.; Ye, Y. Org. Lett. 2009, 11, 5174.
(b) Ye, Y.; Wang, L.; Fan, R. J. Org. Chem. 2010, 75, 1760. (c) Uyanik,
M.; Okamoto, H.; Yasui, T.; Ishihara, K. Science 2010, 328, 1376.
r
10.1021/ol201273b
Published on Web 06/09/2011
2011 American Chemical Society

exudate of germinating sunflowers (Helianthus annuus L.) as
a species-selective allelopathic substance.8,9
PhI(OH)OTs6 in warm MeCN, 6 was obtained in 36%
yield accompanied by the enedione 7 in 8% yield (Table 1,
entry 1). Attempts using other hypervalent iodine reagents,
including 2-iodoxybenzoic acid (IBX), DessꢀMartin per-
iodinane (DMP), and PhI(OAc)2,7a resulted in a simple
oxidation of the allylic alcohol moiety to give 7 (data not
shown). Changing the solvent to 1,1,1,3,3,3-hexafluoro-2-
propanol (HFIP) and DMF among others or increasing
and/or decreasing the reaction temperature did not im-
prove the yield (entries 3ꢀ8). The dilution of the reaction
was found to be beneficial: the optimal reaction was
performed at 0.1 M to obtain a yield of 44% (entry 9).
We were delighted to find that the addition of NaOAc
brought about marked improvement: the treatment of
(þ)-3 (95% ee) with 1.5 equiv of PhI(OH)OTs in the
presence of 1.4 equiv of NaOAc in MeCN at 50 °C,
followed by addition of SiO2 to the mixture, afforded
(ꢀ)-6 in 65% yield, the enantiomeric purity of which was
preserved throughout the reaction.11 Intriguingly, the
addition of KOAc or CsOAc stopped the formation of
(ꢀ)-6; instead, 7 was obtained chemoselectively (entries 11
and 12).
The preparation of the chiral starting material 3 (95%
ee) was facilitated by cooperative asymmetric organo- and
enzymatic catalysis (Scheme 1). Thus, the prochiral endo-
peroxide 2, prepared in situ by the photooxygenation of 1,3-
cycloheptadiene, was subjected to the chiral amine-catalyzed
KornblumꢀDeLaMare rearrangement10 using 5 mol % of
deMeQDAc (4) or deMeQAc (5), developed by Toste and
co-workers,10e to give the (S)-(ꢀ)-4-hydroxy-cyclohept-2-
enone (ꢀ)-3 in 90% yield with 88% ee or (þ)-3 in 91% yield
with 86% ee, respectively. On treatment of (ꢀ)-3 (88% ee)
with vinyl acetate in the presence of lipase PS in THF, (ꢀ)-3
(95% ee) was obtained in 83% yield. Meanwhile, (þ)-3(95%
ee) was obtained from (þ)-3 (86% ee) in 71% yield, via
acetylation and subsequent lipase-PS-catalyzed hydrolysis of
acetate in phosphate bufferꢀacetone (9:1).11
Scheme 1. Preparation of Both Enantiomers of 3
Table 1. Optimization of the Oxidative Cycloetherification
yielda
entry
solvent
additive
6b
7
1
MeCN
HFIP
36
9
8
2
3
1
3
DMF
29
28
11
26
28
28
44
65
0
4
DMSO
THF
5
5
1
The projected oxidative etherification of 3 to give
8-oxabicyclo[3.2.1]oct-3-en-2-one (6) was an unprece-
dented reaction, but a clue was found by screening hyper-
valent iodine reagents.7 Thus, upon treatment of 3 with
6
benzene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
4
7b
0
8c
6
9d
4
10d,e,f
11d,f
12d,f,g
NaOAc (1.4 equiv)
KOAc (1.4 equiv)
CsOAc(1.4 equiv)
3
32
61
(8) Isolation: Ohno, S.; Tomita-Yokotani, K.; Kosemura, S.; Node,
M.; Suzuki, T.; Amano, M.; Yasui, K.; Goto, T.; Yamamura, S.;
Hasegawa, K. Phytochemistry 2001, 56, 577.
0
a The ratio or products was determine by 1H NMR spectrometry.
b The reaction was carried out at 0 °C. c The reaction was carried out at
80 °C. d Concentration of the reaction was 0.1 M. e After the oxidative
reaction, SiO2 was added to crude mixture. f 1.5 equiv of Koser’s reagent
was used . g The reaction time was 24 h.
(9) For total synthesis of sundiversifolide, see the following refer-
ences. (þ)-Form: (a) Yokoe, H.; Sasaki, H.; Yoshimura, T.; Shindo, M.;
Yoshida, M.; Shishido, K. Org. Lett. 2007, 9, 969. (()-Form:(b)
Hashimoto, T.; Tashiro, T.; Sasaki, M.; Takikawa, H. Biosci. Biotecnol.
Biochem 2007, 71, 2046. (þ)- and (ꢀ)-forms: (c) Ohtsuki, K.; Matsuo,
K.; Yoshikawa, T.; Moriya, C.; Tomita-Yokotani, K.; Shishido, K.;
Shindo, M. Org. Lett. 2008, 10, 1247. (d) Shishido, K. Heterocycles 2009,
78, 873. (e) Matsuo, K.; Ohtsuki, K.; Yoshikawa, T.; Shishido, K.;
Yokotani-Tomita, K.; Shindo, M. Tetrahedron 2010, 66, 8407.
(10) (a) Kornblum, N.; DeLaMare, H. E. J. Am. Chem. Soc. 1951, 73,
880. (b) Hagenbuch, J. P.; Vogel, P. J. Chem. Soc., Chem. Commun.
1980, 1062. For mechanistic studies, see: (c) Kelly, D. R.; Bansal, H.;
Morgan, J. J. G. Tetrahedron Lett. 2002, 43, 9331. (d) Mete, E.;
Altundas, R.; Secen, H.; Balci, M. Turk. J. Chem. 2003, 27, 145. (e)
Staben, S. T.; Linghu, X.; Toste, F. D. J. Am. Chem. Soc. 2006, 128,
12658.
Plausible pathways of the PhI(OH)OTs-mediated oxi-
dative etherification of (þ)-3 are outlined in Scheme 2. The
enol form of 3 would react with a hypervalent iodine
reagent to form intermediate A in preference to form B.12
Then, an intramolecular SN2 displacement by the hydroxy
group should proceed to give (ꢀ)-6 (path a), or an
(11) For the gram-scale preparation of both enantiomers of 6, see the
Supporting Information.
(12) For additional discussion, see the Supporting Information.
Org. Lett., Vol. 13, No. 14, 2011
3621

intermolecular SN2 displacement by a tosylate might pre-
cede to give the R-tosyloxyenone 8, which collapses to give
(ꢀ)-6 as above (path b). The reason why the oxidation of
allylic alcohol by the addition of KOAc and CsOAc
chemoselectively proceeded is under scrutiny.
which was considered to be furnished via the oxy-Michael
addition of 15. After various attempts, the best conditions
identified were the use of p-TsOH in 1,4-dioxane at 50 °C.
Sequential hydrogenation, DIBAL-H reduction, and acetali-
zation with p-TsOHinMeOHprovidedthealcohol18, which
was efficiently oxidized with the aid of a catalytic amount of
1-methyl-2-azaadamantane N-oxyl (1-Me-AZADO)15 in the
presence of PhI(OAc)2 to give known ketone 199a in 93%
yield. Compound 9 was conveniently converted to 1 in
accordance with a previously reported procedure.9a It is
interesting to note that previous enantioselective syntheses
of 1 employed annulations of the advanced linear precursors
for the construction of the cycloheptane motif of 1,9a,c show-
ing a clear contrast to our substrate-controlled approach.
Scheme 2. Plausible Reaction Pathway for the Oxidative
Etherification
Scheme 3. Application to the Formal Total Synthesis of 1
To demonstrate the use of 6, we embarked on the formal
total synthesis of the (þ)-sundiversifolide (1).8,9 As shown
in Scheme 3, the synthesis commenced with the 1,4-addi-
tion of the cuprate reagent derived from methylmagnesium
bromide and CuI onto (ꢀ)-6 to furnish 9 as a single
isomer13 in good yield. The treatment of 9 with L-Selec-
tride allowed the stereocontrolled reduction to give the
desired β-alcohol 10 quantitatively.14 The next focus of our
endeavor was the installation of γ-lactone to form the
8-oxabicyclo[5.3.0]decane skeleton of the target molecule.
Tothisend, the alcohol10was treated withdiketene togive
11, which was subjected to Regitz diazo-transfer reaction15
to give the diazo ester 12. We attempted the CꢀH insertion
of12undervariousconditions, butthedesired productwas
only obtained in a disappointing yield. After considerable
experimentation, it was found that the adoption of the
protocol of Bolm et al.,16 introducing a TMS group at the
R-position of the diazo group, was crucial for the desired
CꢀH insertion to be successful. As such, upon treatment
with a catalytic amount of Rh2(OAc)4 in boiling 1,2-
dichloroethane, 13 furnished 14 as a single isomer in
80% yield, the stereochemistry of which was confirmed
from NOESY correlations. With the bicyclic skeleton in
hand, we attempted the selectivecleavageof the oxo-bridge
in 14. Treatment with TBAF gave not only 15 but also 16,
In summary, we have developed a novel entry for both
enantiomers of 8-oxabicyclo[3.2.1]oct-3-en-2-one (6)
based on PhI(OH)OTs (Koser’s reagent)-mediated, intra-
molecular oxidative etherification of 4-hydroxycyclohept-
2-enone (3). The synthetic versatility of 6 as a chiral
building block was demonstrated by its conversion to
allelopathic bisnorsesquiterpene (þ)-sundiversifolide (1).
Further studies for expanding the synthetic scope of the
novel oxidative etherification are underway.
(13) Reaction of 4-triethylsiloxy-cyclophet-2-enone with MeMgBr/
CuI gave the 1,4-adduct as a single diastereomer, but the NaBH4
reduction of which resulted in 1:1 diastereomeric alcohols, indicating
an advantage of the oxa-bridged structure of 6.
(14) NaBH4-mediated reduction of 9 gave the R-alcohol selectively.
(15) Regitz, M. Synthesis 1972, 351.
(16) Bolm, C.; Saladin, S.; Kasyan, A. Org. Lett. 2002, 4, 4631.
3622
Org. Lett., Vol. 13, No. 14, 2011

Acknowledgment. We thank Prof. Kozo Shishido of
the University of Tokushima for providing us with
the spectral data of the synthetic intermediate of
sundiversifolide.
Supporting Information Available. Full experimental
and characterization details for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 14, 2011
3623