Concise entry to chiral 5-(4-Hydroxybutyl)-2(5 H)-furanone via HTIB-mediated novel oxidative fragmentation: Formal total synthesis of (+)-dubiusamine A

Article abstract of DOI:10.1021/ol4005239

The concise synthesis of 5-(4-hydroxybutyl)-2(5H)furanone has been accomplished from 9-oxabicyclo[4.2.1]non-7-en-1-ol on the basis of HTIB [PhI(OH)OTs, a.k.a. Koser's reagent]-mediated novel oxidative fragmentation. Chiral (-)-(R)-5-(4-hydroxy-butyl)-2(5H

Full text of DOI:10.1021/ol4005239

ORGANIC
LETTERS
2013
Vol. 15, No. 7
1788–1790
Concise Entry to Chiral
5‑(4-Hydroxybutyl)-2(5H)‑furanone
via HTIB-Mediated Novel Oxidative
Fragmentation: Formal Total Synthesis
of (þ)-Dubiusamine A
Muneo Kawasumi and Yoshiharu Iwabuchi*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku University, Aobayama, Sendai 980-8578
y-iwabuchi@m.tohoku.ac.jp
Received February 25, 2013
ABSTRACT
The concise synthesis of 5-(4-hydroxybutyl)-2(5H)furanone has been accomplished from 9-oxabicyclo[4.2.1]non-7-en-1-ol on the basis of HTIB
[PhI(OH)OTs, a.k.a. Koser’s reagent]-mediated novel oxidative fragmentation. Chiral (ꢀ)-(R)-5-(4-hydroxy-butyl)-2(5H)-furanone (>99% ee) was
used for the formal total synthesis of (þ)-dubiusamine A (1).
The fertile nature of hypervalent iodine reagents has
continuously spurred the sustainable development of syn-
thetic organic chemistry.1,2 We have recently reported a
concise entry to both enantiomers of 8-oxabicyclo[3.2.1]-
oct-3-en-2-one (3) via the HTIB [PhI(OH)OTs,3 a.k.a.
Koser’s reagent]-mediated, novel intramolecular oxidative
etherification of 4-hydroxy-cyclohept-2-enone (2),4 which
features the direct R0(C7)-functionalization5 of 2 (Scheme 1).
During our effort toward expanding the synthetic scope
ofthe HTIB-mediated oxidative etherificationreaction, we
encountered the unexpected fragmentation of 9-oxabicyclo-
[4.2.1]non-7-en-1-ol (4b), which is a substantial tautomer of
4-hydroxycyclooct-2-enone (4a),6 to give 5-(4-hydroxy-
butyl)-2(5H)-furanone (5). Herein, we disclose a concise
entry to highly enantiomerically enriched 5-(4-hydroxybutyl)-
2(5H)-furanone (5) based on a sequential organocatalytic
asymmetric Toste-Kornblum-DeLaMare rearrangement6
(1) For leading books, see: (a) Wirth, T., Ed. Hypervalent Iodine
Chemistry: Modern Developments in Organic Synthesis; Topics in Current
Chemistry Series 224; Springer: Berlin, 2003. (b) Varvoglis, A. Hypervalent
Iodine in Organic Synthesis; Academic Press: San Diego, 1997.
(2) For leading reviews, see: (a) Zhdankin, V. V.; Stang, P. J. Chem.
Rev. 2008, 108, 5299. (b) Zhdankin, V. V.; Stang, P. Chem. Rev. 2002,
102, 2523. (c) Wirth, T. Angew. Chem., Int. Ed. 2005, 44, 3656. (d) Silva,
L. F., Jr.; Oloff, B. Nat. Prod. Rep. 2011, 28, 1722.
(3) (a) Moriary, R. M.; Vaid, R. K.; Koser, G. F. Synlett 1990, 365.
(b) Koser, G. F. Aldrichimica 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.
(4) Kawasumi, M.; Kanoh, N.; Iwabuchi, Y. Org. Lett. 2011, 13,
3620.
(5) Merritt, E. A.; Olofsson, B. Synthesis 2011, 517.
(6) Staben, S. T.; Linghu, X.; Toste, F. D. J. Am. Chem. Soc. 2006,
128, 12658.
(7) Tan, M. A.; Kitajima, M.; Kogure, N.; Nonato, M. G.; Takayama,
H. Tetrahedron 2010, 66, 3353.
(8) (a) Nonato, M. G.; Takayama, H.; Garson, M. J. Chapter 4 in The
Alkaloids; Cordell, G. A., Ed.; Academic: New York, 2008; Vol. 66, 215. (b)
Lim. T. K. Edible Medicinal and Non-Medicinal Plants: Vol. 4, Fruits;
Springer: Netherlands, 2012.
r
10.1021/ol4005239
Published on Web 03/26/2013
2013 American Chemical Society

and HTIB-mediated oxidative fragmentation. We also
demonstrate the synthetic use of 5 by transforming it into
(þ)-dubiusamine A (1), which was isolated from the crude
base of Pandanus dubius,7 a congener of a medicinally
relevant tropical plant of the family Pandanaceae.8
At the outset, we envisioned that 9-oxa-bicyclo[3.3.1]-
non-3-en-2-one (6) could be obtained from 4-hydroxy-
cyclooct-2-enone (4a)9 by employing HTIB-mediated, intra-
molecular oxidative etherification (Scheme 1). The attempt
was carried out using racemic 4,10 and unfortunately, the
attempted intramolecular oxidative etherification using
HTIB/NaOAc4 gave not even a trace amount of 6; instead,
5-(4-hydroxybutyl)-2(5H)-furanone (5) was obtained with
modest yields (Scheme 1, Table 1, entries 1ꢀ3). The cause
of the unexpected reaction is considered to be the reluc-
tance of 4b to tautomerize to 4a, where HTIB reacts with
4b at the hemiacetalic OH moiety to give the covalent
intermediate B, from which oxidative fragmentation11
occurred and the concomitant hydrolysis furnished the
butenolide 5 (Scheme 2).12
Scheme 2. Plausible Reaction Pathway for Oxidative Etherification
the synthesis of γ-lactone-containing natural products13,14
(Figure 1), we then focused on identifying optimal condi-
tions for oxidative fragmentation.
Scheme 1. Oxidative Fragmentation
Figure 1. Natural products featuring γ-lactone moiety.
After the set of examinations summarized in Table 1, we
found that the presence of NaH2PO4 2H2O significantly
improved the productivity of the reaction: treatment of 4a
with 1.5 equiv of HTIB in the presence of 1.4 equiv of
Prompted by the novel mode of the reaction as well as
the potential use of the butenolide 5 as a building block for
3
(9) 1H NMR indicated that 4-hydroxycyclooct-2-enone (4a) exists as
a tautomeric mixture with 9-oxabicyclo[4.2.1]non-7-en-1-ol (4b) in a
1:24 ratio in CDCl3 at rt.
(10) Racemic 4 was prepared in one-pot reaction from cis,cis-1,3-
cyclooctadiene in 95% yield via photooxygenation (O2 bubbling, 5 mol%
tetraphenylprophyrin, 100 W tungsten lamp) and the following treatment
with 2 equiv of Et3N.
(11) Selected examples of oxidative ring fragmentation; (a) HgO/I2:
Suginome, H.; Yamada, S. J. Org. Chem. 1985, 50, 2489. Tetrahedron
1987, 43, 3371. Pb(OAc)4/I2: (b) Fuhrer, H.; Lorenc, L.; Pavlovic, V.;
Rihs, G.; Rist, G.; Kalvoda, J.; Mihailovic, M. Lj. Helv. Chim. Acta
NaH2PO4 2H2O in MeCN at 50 °C afforded 5 with 54%
yield (entry 10).
3
Having identified reliable conditions for conducting
HTIB-mediated oxidative fragmentation to give 5, we
embarked on the formal total synthesis of (þ)-dubius-
amine A (1) to demonstrate the synthetic use of the reaction.
The requisite starting material, namely, (1S,6R)-9-
oxabicyclo[4.2.1]non-7-en-1-ol (ꢀ)-4b, was prepared via one-
pot synthesis with 92% yield and >99% ee15 starting from
1981, 64, 703. IBDA/I2: (c) Freire, R.; Marrero, J. J.; Rodrıguez, M. S.;
´
ꢀ
Suarez, E. Tetrahedron Lett. 1986, 27, 383. Iodosyl-benzene/I2: (d)
ꢀ
Arrmas, P.; Francisco, C. G.; Suarez, E. Tetrahedron Lett. 1993, 34,
7331. FeSO4/Cu(OAc)2: (e) Schreiber, S. L. J. Am. Chem. Soc. 1980, 102,
6163. Pb(OAc)4 with γ-hydroxyalkylstannanes: (f) Nakatani, K.; Isoe,
S. Tetrahedron Lett. 1984, 25, 5335. Mn(OAc)3/Cu(OAc)2: (g) Heiba,
E. I.; Dessau, R. M. J. Am. Chem. Soc. 1971, 93, 524. Pb(OAc)4/
Cu(OAc)2: (h) Rigby, J. H.; Psyn, A.; Warshakoon, N. Tetrahedron
Lett. 2001, 42, 2047.
(12) According to a reviewer’s comment, we examined the use of
other iodine(III) reagents for this transformation. PhI(OAc)2 resulted in
no reaction after 24 h at 50 °C either in the presence or absense of
NaH2PO4. PhI(OCOCF3)2 caused gradual decomposition of 4b to give
intractable polar byproducts under the same reaction conditions.
(13) (a) Bandichhor, R.; Nosse, B.; Reiser, O. Top. Curr. Chem. 2005,
243, 43. (b) Kitson, R. R. A.; Millemaggi, A.; Taylor, R. J. K. Angew.
Chem., Int. Ed. 2009, 48, 9426.
(14) For recent synthesis of chiral butenolides, see: (a) Devalankar,
D. A.; Chouthaiwale, P. V.; Sudalai, A. Tetrahedron; Asymmetry 2012,
23, 240. (b) Wu, Y.; Singh, R. P.; Li, D. J. Am. Chem. Soc. 2011, 133,
ꢀ
12458. (c) Mao, B.; Geurts, K.; Fananas-Mastral, M.; van Zijl, A. W.;
Fletcher, S. P.; Minnaard, A. J.; Feringa, B. L. Org. Lett. 2011, 13, 948.
(15) The enantiomeric purity of the butenolide (ꢀ)-5 was determined
after benzoylation. See Supporting Information.
Org. Lett., Vol. 15, No. 7, 2013
1789

Table 1. Optimization of Oxidative Fragmentation
Scheme 3. Application to the Formal Synthesis of (þ)-1
yield (%)
entry
additive
AcONa
5
7
1a,b
2
trace
29
0
0
3
AcONa
AcOK
26
0
4c
5
28
4
LiOH H2O
34
0
3
6
KH2PO4
KaHPO4
KHSO4
29
nd.
nd.
nd.
0
7
30
8
36
9
NazHPO4
45
10
NaH2PO4 2H2O
54
0
3
a Reaction was carried out at rt. b Reaction Time was 24 h. c 12 was
obtained with 6% yield.
cis,cis-1,3-cyclooctadiene, through sequential photooxygena-
tion to give the prochiral endoperoxide 13 and deMeQAc (14)-
catalyzed Toste-Kornblum-DeLaMare rearrangement.6
Upon treatment with 1.5 equiv of HTIB in the presence
of 1.4 equiv of NaH2PO4 2H2O in warm MeCN for 0.5 h,
3
(ꢀ)-4b furnished (ꢀ)-5 with 54% yield without the loss of
enantiomeric integrity. Prior to the introduction of a C-2
methyl group, the butenolide moiety of (ꢀ)-5 was hydro-
genated and the primary hydroxyl group was masked as
the TBS ether. The treatment of 15 with LHMDS and MeI
allowed the diastereoselective R-methylation of the lactone
ring to give 16 with a 10:1 (anti/syn) ratio. After the re-
moval of the TBS group from 16 using camphorsulfonic
acid in MeOH at 0 °C, the resultant alcohol 17 was sub-
jected to the Mitsunobu reaction employing 2-nitrobenzene-
sulfonamide,16 PPh3, and DIAD in THF/toluene to give 18
in 79% yield, which was again subjected to the Mitsunobu
reaction with alcohol 17 to give the nosyl16-protected
symmetrical amide 19. The treatment of 19 with K2CO3
and PhSH in MeCN-DMF affected the deprotection of the
nosyl group. After carefully purifying the crude product using
silica gel chromatography, diastereomerically pure (þ)-1 was
obtained, Scheme 3. All the spectral data and the specific
rotation of (þ)-1were in good agreement with those reported
by Takayama et al.,7 which clearly determined the stereo-
chemical course of the HTIB-mediated reaction of (ꢀ)-4b.
In summary, the concise enantioselective synthesis of 5-(4-
hydroxybutyl)-2(5H)-furanone (5) has been accomplished
via the HTIB-mediated oxidative fragmentation of 9-oxa-
bicyclo[4.2.1]non-7-en-1-ol (4b), which represents the fur-
ther potential of hypervalent iodine reagents for organic
synthesis. The synthetic use of (ꢀ)-5 was demonstrated by a
formal total synthesis of dubiusamine A (1). Since a chiral
catalyst that leads to the asymmetric Toste-Kornblum-
DeLaMare reaction of (þ)-4b (>99% ee) has been
established,6 the present work will allow the realization
of a concise entry to both enantiomers of 5.
Acknowledgment. This work was partly supported by a
Grant-in-Aid for Scientific Research on Innovative Areas
“Advanced Molecular Transformations by Organocata-
lysis” from the Ministry of Education, Culture, Sports,
Science and Technology, Japan, and by a Grant-in Aid for
the Research Fellowship for Young Scientists (M.K)
(234661) from Japan Society for the Promotion of Science.
Supporting Information Available. Experimental pro-
cedures and spectroscopic and analytical data for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(16) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353.
The authors declare no competing financial interest.
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