Intramolecular iodoetherification of ene or diene ketals: Facile synthesis of spiroketals

Article abstract of DOI:10.1039/c0cc03933k

A novel and rapid approach to chiral mono- or di-substituted spiroketals based on remote asymmetric induction by intramolecular iodoetherification of ene or diene ketals has been developed. This strategy concisely offers 5,5- and 5,6-spiroketals including

Full text of DOI:10.1039/c0cc03933k

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Intramolecular iodoetherification of ene or diene ketals: facile synthesis
of spiroketalsw
Hiromichi Fujioka,* Kenji Nakahara, Hideki Hirose, Kie Hirano, Tomohiro Oki and
Yasuyuki Kitaz
Received 17th September 2010, Accepted 27th October 2010
DOI: 10.1039/c0cc03933k
A novel and rapid approach to chiral mono- or di-substituted
spiroketals based on remote asymmetric induction by intra-
molecular iodoetherification of ene or diene ketals has been
developed. This strategy concisely offers 5,5- and 5,6-spiroketals
including the natural insect pheromone of the wasp.
Spiroketals are the basic structural units of natural products
isolated from insects, microbes, plants, fungi and marine
organisms.1 In particular, five- and six-membered rings are
Scheme 1 Working hypothesis.
frequently found in a large number of biologically active
compounds. Therefore, spiroketal synthesis has attracted
much attention in the area of organic chemistry. The most
common approach for the construction of spiroketals is the
acid-catalyzed cyclization of functionalized dihydroxyketone
precursors or their equivalents.2 This method involves multi-step
sequences to synthesize the starting dihydroxyketones,
especially, the chiral ones. Much more elegant methods have
been developed to construct the spiroketals based on organo-
metallic reactions.3 However, some methods were not suitable
for the asymmetric spiroketal synthesis because many reaction
steps were required to obtain the optically-active cyclization
precursors bearing one or more stereogenic centers and the
substituent variations on the spiroketals were limited. Due to
the wide occurrence of spiroketal frameworks with asymmetric
centers adjacent to the oxygen atoms in nature, the development
of alternative methodology has been strongly desired. We now
report a novel and rapid approach for the asymmetric synthesis
of spiroketals by intramolecular iodoetherification of ene or
diene ketals.
materials. Our synthetic strategy is shown in Scheme 1.
The chiral ketals from the chiral diol, (R,R)-hydrobenzoin,5
would react with electrophile (I+ source) and lead to the
compounds having newly formed stereogenic centers. These
compounds would be directly converted into five- or six-
membered spiroketals, which contain one or two stereogenic
centers adjacent to the oxygen atoms.
To investigate the iodoetherification of chiral ketals, we
studied the reactivity of the ene ketal 1a bearing the hydroxyl
group under various reaction conditions (Table 1). First, we
examined the effect of electrophiles (I+ source) in CH3CN as
the solvent at rt (entries 1–3). Among the electrophiles,
bis(2,4,6-collidine)iodonium hexafluorophosphate (I(coll)2PF6)6
was the most effective reagent to give 2a with a good diastereo-
selectivity (entry 3). Increased selectivity was observed at low
temperature (ꢀ40 to 0 1C) (entry 4). Using CH2Cl2 as a
solvent instead of CH3CN did not have
a significant
influence on the result (entry 5). The reaction was performed
at 0.3 M to give the best result in 90% yield and 4.3 : 1 dr
(entry 6). The reaction would proceed as follows. Initially,
As a part of our ongoing research for asymmetric synthesis
using acetals, we have developed an intramolecular
haloetherification of C2-symmetric ene or diene acetals from
aldehydes and its application to natural product synthesis.4
This reaction proceeds via the reactive chiral oxonium ion
intermediates, followed by the stereoselective attack of the
nucleophiles such as water or alcohols. We then considered
that this methodology was applicable to chiral spiroketal
synthesis using ene or diene ketals from ketones as starting
Table 1 Optimization
Entry I+ source
Temperature Time
Yielda (%) drb
1
2
I2
NIS
rt
rt
1.5 h
2 h
ndc
58
—
2 : 1
Graduate School of Pharmaceutical Sciences, Osaka University,
1-6 Yamada-oka, Suita, Osaka, 565-0871, Japan.
E-mail: fujioka@phs.osaka-u.ac.jp; Fax: +81 668798229;
Tel: +81 668798225
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data for the product compounds.
CCDC 766288. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c0cc03933k
3
I(coll)2PF6 rt
30 min 84
3.4 : 1
4.3 : 1
3.5 : 1
4.3 : 1
4
I(coll)2PF6 ꢀ40 to 0 1C
I(coll)2PF6 ꢀ78 to 0 1C
I(coll)2PF6 ꢀ40 to 0 1C
2 h
2 h
2 h
84
88
90
5d
6e
a
b
Total isolated yield of two isomers. Diastereomeric ratio (dr) of the
c
major isomer (2a) and the other isomer. 2a was not detected.
d
e
CH2Cl2 was used as a solvent instead of CH3CN. Reaction was
performed at 0.3 M.
z Present address: College of Pharmaceutical Sciences, Ritsumeikan
University, 1-1-1, Nojihigashi, Kusatsu, Shiga, 525-8577, Japan.
c
This journal is The Royal Society of Chemistry 2011
1060 Chem. Commun., 2011, 47, 1060–1062

View Article Online
Table 2 Iodoetherification of ene ketals 1b–da
Entry
Ene ketal (1)
Product (2)
Yieldb (%)
1
61
2
59c
71
Scheme 3 Double iodoetherification of diene ketal 5.
re-cyclization sequences. Our synthetic route requires fewer
steps compared to the previous reports.
3
The spiroketal subunits contained two stereogenic centers
adjacent to the oxygen atoms also widely present in many
natural products.1 In general, these spiroketals have been
synthesized through the coupling of two optically active
segments. Our group already has developed the novel double
intramolecular iodoetherification of diene acetals.4f,g We then
chose the chiral diene ketals as a substrate assuming that the
spiroketals bearing two asymmetric centers were concisely
obtained. As expected, the treatment of the diene ketal 5 with
I(coll)2PF6 in the presence of H2O as a nucleophile and
NaHCO3 in CH3CN at ꢀ40 to 0 1C, afforded 6 in 55% yield
(Scheme 3). This reaction proceeded via the oxonium ion
intermediate B and then nucleophilic attack by H2O gave the
hemiketal intermediate C. Usually, hemiketal structures were
easily converted to the hydroxy ketones due to their unstability.
However, in this reaction, another olefin is situated at the proper
position and the second intramolecular iodoetherification
smoothly occurred. Although the product 6 had two iodomethyl
functions, the regioselective nucleophilic substitution of iodine
atoms has been achieved (Scheme 4). Substitution of 6 with
NaCN in THF–DMF (1 : 1) gave 7 in 66% yield.
a
Reactions were performed using I(coll)2PF6 (1.5 equiv.) in CH3CN
b
(0.3 M) at ꢀ40 to 0 1C for 2 h. Isolated yield of the major isomer.
c
Diastereomeric mixture at the spiro carbon.
iodoetherification occurred between the oxygen atom of the
acetal and the olefin to generate the intermediate A. The
resulting oxonium ion would give 2a by the intramolecular
nucleophilic attack of the hydroxyl group.
Under the optimized conditions, we conducted the
iodoetherification of the alcohol 1b, and the carboxylic acids
1c and 1d (Table 2). The alcohol 1b was converted into
the corresponding spiroketal 2b in good yield (entry 1).
Iodoetherification of the carboxylic acids 1c and 1d smoothly
produced the corresponding spirolactones 2c and 2d,
respectively (entries 2 and 3). The stereochemistries of the
products 2a–d were determined by NOE analysis.7
Compounds 2a–d were useful synthetic precursors for the
naturally occurring five- and six-membered spiroketals or
spirolactones by the removal of the chiral auxiliary unit.
Previous studies revealed that the hydroxyethyl units were
eliminated from the parent 2-hydroxyethyl ethers using cerium
ammonium nitrate (CAN) under mild conditions.8 We then
applied our strategy for the synthesis of the pheromone of the
wasp Paravespula vulgaris (Scheme 2).9–11 2a was subjected to
radical conditions in water12 to deliver 3 in 83% yield. The
treatment of 3 with CAN in CH3CN–H2O (1 : 1) directly
afforded the desired pheromone 4 (3 : 2 diastereomeric
mixture at the spiro carbon) in 70% yield through the ring
opening of the spiroketal,13 removal of the chiral auxiliary and
Compounds 6 and 7 were easily converted into the 5,5-
spiroketals 8a and 8b having two chiral centers (Scheme 5).
In particular, the spiroketal 8b has two versatile substituents.
Therefore, they would be suitable precursors for further
chemical transformations into substituted spiroketals. The
stereochemistry of 6 was determined by NOE analysis and
the measurement of the optical rotations of 8a and 8b.7
Double iodoetherification of the chiral ketal 9 having an
unsymmetric diene was next examined (Scheme 6). Exposure
of the diene ketal 9 to the same conditions in Scheme 3
Scheme 4 Regioselective nucleophilic substitution of 6.
Scheme 2 Synthesis of the pheromone of the wasp Paravespula
vulgaris 4. VA-061
=
2,20-azobis[2-(2-imidazolin-2-yl)propane];
EPHP = 1-ethylpiperidine hypophosphite.
Scheme 5 One-pot conversion into spiroketals.
Chem. Commun., 2011, 47, 1060–1062 1061
c
This journal is The Royal Society of Chemistry 2011

View Article Online
3 For recent examples, see: (a) B. Liu and J. K. De Brabander,
Org. Lett., 2006, 8, 4907; (b) B. D. Sherry, L. Maus,
B. N. Laforteza and F. D. Toste, J. Am. Chem. Soc., 2006, 128,
8132; (c) M. Lejkowski, P. Banerjee, J. Runsink and H.-J. Gais,
Org. Lett., 2008, 10, 2713; (d) L.-Z. Dai and M. Shi, Chem.–Eur. J.,
2008, 14, 7011; (e) A. Aponick, C.-Y. Li and J. A. Palmes,
Scheme 6 Double iodoetherification of diene ketal 9 and subsequent
Org. Lett., 2009, 11, 121; (f) J. Barluenga, A. Mendoza, F. Rodrı
and F. J. Fananas, Angew. Chem., Int. Ed., 2009, 48, 1644.
´
´
guez
spiroketal synthesis.
4 (a) H. Fujioka, H. Kitagawa, Y. Nagatomi and Y. Kita, J. Org.
Chem., 1996, 61, 7309; (b) H. Fujioka, N. Kotoku, Y. Sawama,
H. Kitagawa, Y. Ohba, T.-L. Wang, Y. Nagatomi and Y. Kita,
Chem. Pharm. Bull., 2005, 53, 952; (c) H. Fujioka, Y. Sawama,
N. Kotoku, T. Ohnaka, T. Okitsu, N. Murata, O. Kubo, R. Li and
Y. Kita, Chem.–Eur. J., 2007, 13, 10225; (d) H. Fujioka, Y. Ohba,
K. Nakahara, M. Takatsuji, K. Murai, M. Ito and Y. Kita,
Org. Lett., 2007, 9, 5605; (e) H. Fujioka, K. Nakahara, T. Oki,
K. Hirano, T. Hayashi and Y. Kita, Tetrahedron Lett., 2010, 51,
1945; (f) H. Fujioka, Y. Ohba, H. Hirose, K. Murai and Y. Kita,
Angew. Chem., Int. Ed., 2005, 44, 734; (g) H. Fujioka, Y. Ohba,
H. Hirose, K. Nakahara, K. Murai and Y. Kita, Tetrahedron,
2008, 64, 4233.
5 Z.-M. Wang and K. B. Sharpless, J. Org. Chem., 1994, 59,
8302.
Fig. 1 ORTEP drawing of compound 12.
6 F. Homsi, S. Robin and G. Rousseau, Org. Synth., 2000, 77,
206.
7 Details are shown in ESIw.
8 (a) H. Fujioka, Y. Ohba, H. Hirose, K. Murai and Y. Kita,
Org. Lett., 2005, 7, 3303; (b) H. Fujioka, H. Hirose, Y.
Ohba, K. Murai, K. Nakahara and Y. Kita, Tetrahedron, 2007,
63, 625.
afforded the spiroketal 10. CAN treatment of 10 directly gave
the 5,6-spiroketal 11 in 68% yield. The absolute configuration
of 10 was determined by X-ray analysis of the dimethyl
derivative 12w obtained from 10 by the radical-mediated
deiodination (Fig. 1).7
9 W. Francke, G. Hindorf and W. Reith, Angew. Chem., Int. Ed.
Engl., 1978, 17, 862.
In conclusion, we have developed a novel and rapid
approach to chiral mono- and di-substituted spiroketals.
Our method needs only the chiral diol, hydrobenzoin, as the
chiral source, and asymmetric centers can be generated in one
operation. The iodine atom in the products can be further
functionalized. Since five- or six-membered spiroketal subunits
are found in many biologically active natural products, this
method is very valuable for their syntheses. A detailed
mechanistic study and application to complex natural
products are currently underway.
10 For racemic synthesis, see: (a) C. Phillips, R. Jacobson,
B. Abrahams, H. J. Williams and L. R. Smith, J. Org. Chem.,
1980, 45, 1920; (b) S. V. Ley and B. Lygo, Tetrahedron Lett., 1982,
23, 4625; (c) G. Rosini, R. Ballini and E. Marotta, Tetrahedron,
1989, 45, 5935.
11 For asymmetric synthesis, see: (a) E. Hungerbuhler, R. Naef,
¨
D. Wasmuth and D. Seebach, Helv. Chim. Acta, 1980, 63, 1960;
(b) K. Mori and H. Watanabe, Tetrahedron Lett., 1984, 25,
6025; (c) K. Mori, H. Watanabe, K. Yanagi and M. Minobe,
Tetrahedron, 1985, 41, 3663; (d) S. V. Ley, B. Lygo and
A. Wonnacott, Tetrahedron Lett., 1985, 26, 535; (e) S. V. Ley,
B. Lygo, F. Sternfeld and A. Wonnacott, Tetrahedron, 1986, 42,
4333; (f) C. Iwata, Y. Moritani, K. Sugiyama, M. Fujita and
T. Imanishi, Tetrahedron Lett., 1987, 28, 2255; (g) C. Iwata,
Y. Moritani, K. Sugiyama, H. Izaki, T. Kuroki and T. Imanishi,
Chem. Pharm. Bull., 1988, 36, 4785; (h) I. I. Cubero, M. T. P.
Lopez-Espinosa and N. Kari, Carbohydr. Res., 1995, 268, 187;
(i) P. H. G. Zarbin, A. R. M. De Oliveira and C. E. Delay,
Tetrahedron Lett., 2003, 44, 6849.
This work was supported by Grant-in-Aid for Scientific
Research (A) and (B), and Grant-in-Aid for Scientific
Research for Exploratory Research from Japan Society for
the Promotion of Science and by Grant-in-Aid for Scientific
Research on Priority Areas (17035047) from the Ministry of
Education, Culture, Sports, Science, and Technology, Japan.
12 (a) Y. Kita, H. Nambu, N. G. Ramesh, G. Anilkumar and
M. Matsugi, Org. Lett., 2001, 3, 1157; (b) H. Nambu,
G. Anilkumar, M. Matsugi and Y. Kita, Tetrahedron, 2003, 59,
77; (c) H. Nambu, A. H. Alinejad, K. Hata, H. Fujioka and
Y. Kita, Tetrahedron Lett., 2004, 45, 8927.
13 For deprotection of acetals by CAN, see: N. Maulide,
J.-C. Vanherck, A. Gautier and I. E. Marko, Acc. Chem. Res.,
´
2007, 40, 381.
Notes and references
1 (a) F. Perron and K. F. Albizati, Chem. Rev., 1989, 89, 1617;
(b) M. T. Fletcher and W. Kitching, Chem. Rev., 1995, 95, 789;
(c) M. A. Brimble and D. P. Furkert, Curr. Org. Chem., 2003, 7,
1461; (d) J. E. Aho, P. M. Pihko and T. K. Rissa, Chem. Rev., 2005,
105, 4406.
2 K. T. Mead and B. N. Brewer, Curr. Org. Chem., 2003, 7, 227.
c
This journal is The Royal Society of Chemistry 2011
1062 Chem. Commun., 2011, 47, 1060–1062