Diastereoselective reductive ring expansion of spiroketal dihydropyranones to cis -fused bicyclic ethers

Article abstract of DOI:10.1021/ol302813e

A novel double cascade synthetic strategy was developed for the diastereoselective syntheses of cis-fused bicyclic ethers, featuring cascade Achmatowicz rearrangement/spiroketalization and cascade spiroketal reduction/oxa-Michael cyclization. Especially, the chemo-, regio-, and diastereoselective reduction of densely functionalized spiroketal dihydropyranones, followed by oxa-Michael cyclization in a one-pot fashion, was achieved.

Full text of DOI:10.1021/ol302813e

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Diastereoselective Reductive
Ring Expansion of Spiroketal
Dihydropyranones to cis-Fused
Bicyclic Ethers
Liangyu Zhu, Liyan Song, and Rongbiao Tong*
Department of Chemistry, The Hong Kong University of Science and Technology,
Clear Water Bay, Kowloon, Hong Kong, China
rtong@ust.hk
Received October 12, 2012
ABSTRACT
A novel double cascade synthetic strategy was developed for the diastereoselective syntheses of cis-fused bicyclic ethers, featuring cascade
Achmatowicz rearrangement/spiroketalization and cascade spiroketal reduction/oxa-Michael cyclization. Especially, the chemo-, regio-, and
diastereoselective reduction of densely functionalized spiroketal dihydropyranones, followed by oxa-Michael cyclization in a one-pot fashion, was
achieved.
Achmatowicz Rearrangement (AR),1 an oxidative re-
arrangement process of substituted furfuryl alcohol to
pyranone acetals, has found wide application in organic
synthesis,2 particularly in the Targeted Oriented Synthesis
(TOS) of natural products where the pyranone acetals
derived from AR have been utilized as building blocks to
construct substituted tetrahydropyrans, spiroketals, and
Oxa-bridged bicycles (Scheme 1).3 For example, DeShong3b
et al. used the AR to build the 2,9-dioxabicyclononane
core structure of tirandamycin A; Wender3d developed a
strategy exploiting [5 þ 2] cycloaddition3a of an AR adduct
for the total synthesis of phorbol; and Nicolaou3e and
Phillips3f,g employed AR to make highly functionalized
tetrahydropyrans as the building blocks for maitotoxin and
norhalichondrin B, respectively. Recently, Schreiber4 et al.
took advantage of the skeletal transformations of AR and
developed a diversity-oriented synthesis (DOS) strategy to
provide ∼1260 more complex and diverse products. Never-
theless, the fundamental transformations based on AR
adducts are still very limited5 (Scheme 1): reductive etherifi-
cation, cyclo- and/or spiroketalization, [5 þ 2] cycloaddition,
and a few others (glycosylation).2 Apparently, the synthetic
utilities of these densely functionalized dihydropyranones
are underdeveloped, and some new reaction patterns should
be further uncovered. In the course of our studies directed
toward exploration of new reactivity patterns of AR adducts
(1) Achmatowicz, O., Jr.; Bukowski, P.; Szechner, B.; Zwierzchowska,
Z.; Zamojski, A. Tetrahedron 1971, 27, 1973.
(2) For a review, see: (a) Harris, J. M.; Li, M.; Scott, J. G.;
O’Doherty, G. A. In Strategies and Tactics in Organic Synthesis;
Harmata, M., Ed.; Elsevier: 2004; Vol. 5, pp 221ꢀ253. For selected
applications, see: (b) Al-Tel, T. H.; Semreen, M. H.; Voelter, W. Org.
Biomol. Chem. 2010, 8, 5375. (c) DeShong, P.; Waltermire, R. E.;
Ammon, H. L. J. Am. Chem. Soc. 1988, 110, 1901. (d) Haukaas,
M. H.; O’Doherty, G. A. Org. Lett. 2001, 3, 3899. (e) Arrayas, R. G.;
Liebeskind, L. S. J. Am. Chem. Soc. 2003, 125, 9026. (f) Cassidy, M. P.;
Padwa, A. Org. Lett. 2004, 6, 4029. (g) Leverett, C. A.; Cassidy, M. P.;
Padwa, A. J. Org. Chem. 2006, 71, 8591. (h) Guo, H.; O’Doherty, G. A.
Org. Lett. 2006, 8, 1609. (i) Herrmann, A. T.; Martinez, S. R.; Zakarian,
A. Org. Lett. 2011, 13, 3636.
(3) For a review, see: (a) Pellissier, H. Adv. Synth. Catal. 2011, 353,
189. For selected papers, see: (b) DeShong, P.; Ramesh, S.; Elango, V.;
Perez, J. J. J. Am. Chem. Soc. 1985, 107, 5219. (c) Snider, B. B.; Wu, X.;
Nakamura, S.; Hashimoto, S. Org. Lett. 2007, 9, 873. (d) Wender, P. A.;
Rice, K. D.; Schnute, M. E. J. Am. Chem. Soc. 1997, 119, 7897. (e)
Nicolaou, K. C.; Baker, T. M.; Nakamura, T. J. Am. Chem. Soc. 2011,
133, 220. (f) Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips,
A. J. Angew. Chem., Int. Ed. 2009, 48, 2346. (g) Henderson, J. A.;
Jackson, K. L.; Phillips, A. J. Org. Lett. 2007, 9, 5299.
(4) Burke, M. D.; Berger, E. M.; Schreiber, S. L. J. Am. Chem. Soc.
2004, 126, 14095.
(5) Only 81 hits from Scifinder database for “Achmatowicz” key-
word search (Sept, 2012).
r
10.1021/ol302813e
XXXX American Chemical Society

which involved cascade spiroketal reduction/oxa-Michael
cyclization, leading to diastereoselective formation of cis-
fused bicyclic ethers. Interestingly, the cis-fused bicyclic
pyrans were thought to be an “abnormal” unit in maito-
toxin6 and halichondrins7 (Scheme 2) and only a few
synthetic methods have been exclusively developed.8 The
double cascade processes described here, therefore, would
provide a concise route to diastereoselective synthesis of cis-
fused cyclic ethers present in halichondrins and other (non-)
natural products.
Scheme 1. Representative Transformations of Achmatowicz
Rearrangement Adducts
Our studies started with finding appropriate conditions
for chemo-, regio- and diastereoselective reduction of
spiroketal in the presence of enone. However, there is no
precedence that documented this type of selective reduc-
tion. Given the facts that ketones or enones are readily
reduced by conventional hydrides such as LiAlH4ꢀAlCl3
or diisobutylaluminium hydride (DIBAL-H) that were
used for spiroketal reduction,8 we devoted our efforts on
screening a variety of combinations of Lewis (or Brønsted)
acids and silanes.9 As shown in Table 1, Kishi reduction10
(entries 1 and 3), a widely used reduction protocol for AR
adducts to prepare the cis-disubstituted pyrans,3eꢀg un-
fortunately, gave only a trace amount of the desired
product (3) after 48 h at rt. Amberlyst-15 and triethylsilane
(TES) (entry 2) led sluggishly to saturation of the olefin.
The TMSOTf-TES and FeCl3-TES (entries 4 and 6) did
not result in the ring opening at ꢀ78 °C while decomposi-
tion was observed at elevated temperatures. Interestingly,
Scheme 2. Synthetic Plan for Exploration of Spiroketal
Dihydropyranone
Table 1. Lewis AcidꢀSilane Reduction of Spiroketala
and potential applications in the total synthesis of natural
products, we observed spontaneous spiroketalization of AR
adducts tethered to tert-butyldimethylsilyl ether (TBSO, 1)
(Scheme 2). In order to make full use of these easily
accessible, densely functionalized spiroketal dihydro-
pyranones,2b we set forth to explore their reactivity and thus
expand the syntheic utilities of AR adducts. Herein, we
disclose our findings on an unprecedented reductive ring
expansion of spiroketal dihydropyranone derived from AR,
Lewis acid
(equiv)
silane
temp
time conv yield
entry
(equiv)
(°C)
(h) (%)a (3, %)b
1
2
3
4
5
6
7
8
9c
TFA (10)
A-15 (2)
TES (5)
ꢀ78f25 72
48
100
40
0
TES (1.2) 25
<5
<10
<5
0
BF3-Et2O (1.2) TES (1.2) ꢀ78f25 48
TMSOTf (1.2) TES (1.2) ꢀ78f25 24
20
10
Sc(OTf)3 (1.2) TES (1.5) ꢀ78f25
2
80
FeCl3 (1.2)
SnCl4 (1.2)
TiCl4 (1.2)
TiCl4 (1.2)
TES (1.2) ꢀ78f25 24
<5
0
TES (1.2) ꢀ78f25
DPS (1.2) ꢀ78
TES (1.2) ꢀ78
TES (2.5) ꢀ78
1
1
1
1
100
100
100
100
27
50
65
35
(6) (a) Murata, M.; Yasumoto, T. Nat. Prod. Rep. 2000, 17, 293. (b)
Sasaki, M.; Matsumori, N.; Muruyama, T.; Nonomura, T.; Murata, M.;
Tachibana, K.; Yasumoto, T. Angew. Chem., Int. Ed. Engl. 1996, 35,
1672. (c) Nonomura, T.; Sasaki, M.; Matsumori, N.; Murata, M.;
Tachibana, K.; Yasumoto, T. Angew. Chem., Int. Ed. Engl. 1996, 35,
1675.
(7) (a) Uemura, D.; Takahashi, K.; Yamamoto, T.; Katayama, C.;
Tanaka, J.; Okumura, Y.; Hirata, Y. J. Am. Chem. Soc. 1985, 107, 4796.
(b) Hirata, Y.; Uemura, D. Pure Appl. Chem. 1986, 58, 701.
(8) (a) Fearnley, S. P.; Lory, P. Org. Lett. 2007, 9, 3507. (b)
Leeuwenburgh, M. A.; Overkleeft, H. S.; van der Marel, G. A.; van
Boom, J. H. Synlett 1997, 1263. (c) Leeuwenburgh, M. A.; Kulker, C.;
Duynstee, H. I.; Overkleeft, H. S.; van der Marel, G. A.; van Boom, J. H.
Tetrahedron 1999, 55, 8253. (d) Kozikowski, A. P.; Lee, J. J. Org. Chem.
1990, 55, 863. (e) Martin, V. S.; Palazon, J. M. Tetrahedron Lett. 1992,
33, 2399. (f) Lee, E.; Park, C. M.; Yun, J. S. J. Am. Chem. Soc. 1995, 117,
8017. (g) Takemoto, Y.; Furuse, S.; Hayase, H.; Echigo, T.; Iwata, C.;
Tanaka, T.; Ibuka, T. Chem. Commun. 1999, 2515. (h) Sarang, P.;
Bhalerao, P.; Mobin, S. M. Synlett 2011, 386.
10d TiCl4 (1.2)
a Reaction progress was monitored by TLC. b Isolated yields. 4 A
molecular sieves or 2,6-di-tert-butyl-4-methylpyridine was added, but
did not improve the yield significantly. d The side products derived from
conjugated reduction. TFA: trifluoroacetic acid. TMSOTf: trimethylsilyl
trifluoromethanesulfonate. A-15:Amberlyst-15. TES:triethylsilane. DPS:
diphenylsilane.
c
˚
(9) (a) Mori, I.; Ishihara, K.; Flippin, L. A.; Nozaki, K.; Yamamoto,
H.; Bartlett, P. A.; Heathcock, C. H. J. Org. Chem. 1990, 55, 6107. (b)
Denmark, S. E.; Almstead, N. G. J. Am. Chem. Soc. 1991, 113, 8089.
(10) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
4976.
B
Org. Lett., Vol. XX, No. XX, XXXX

Sc(OTf)3-TES (entry 5) cleanly promoted both reductive
ring opening of the spiroketal and conjugated reduction,
leading to only γ-hydroxytetrahydropyran-3-one (30)
in 70% yield. Fortunately, SnCl4-TES was found for the
first time to deliver the desired bicyclic ether product in
27% yield (entry 7), along with some side products due
to saturation of olefin and/or reduction of the ketone.
Further experimentation revealed that the reductive
ring expansion proceeded smoothly with TiCl4-TES to
give the bicyclic ether as a single diastereomer in 65% yield
(entry 9), through chemo-, regio-, and diastereoselective
reduction of spiroketal dihydropyranone followed by oxa-
Michael cyclization. Note that 2.5 equiv of triethylsilane
with TiCl4 (1.2 equiv) led to partial reduction of bicyclic
ketone to the corresponding alcohol (entry 10).
Table 2. Cascade AchmatowiczꢀSpiroketalization and Cascade
Spiroketal Reduction-Oxa-Michael Cyclization
Having identified the optimal conditions for the cascade
reductive ring expansion of spiroketal dihydropyranone to
cis-fused bicyclic ethers, we set out to examine the scope
of substrates for both cascade processes: Achmatowicz/
spiroketalization and spiroketal reduction/oxa-Michael
cyclization (Table 2). A series of substituted furfuryl diols
(1aꢀj) were prepared by following modified literature
methods.11 Pleasingly, the first stage cascade reactions,
Achmatowicz/spiroketalization proceeded smoothly for
almost all substrates to afford the spiroketal pyranones
(2aꢀ2i) in good to excellent yields (54ꢀ93%) with good
diastereoselectivity due to anomeric effects. Notably,
Achmatowicz adducts tethered to γ-secondary (R2
=
Me) or γ-tertiary (R2 = Me2) alcohols (entries 3 and 4)
could also efficiently cyclize to form spiroketals. Although
the [6,6] spiroketal dihydropyranone was not generated
spontaneously during the AR, subjection of the crude AR
adduct to Amberlyst-15 in CH2Cl2 gave the desired pro-
duct 2j with excellent yields (entry 10). Most importantly,
we first demonstrated that the allyl, alkenyl, and phenyl
substituted furfuryl alcohols (entries 6ꢀ8) are competent
substrates for AR in good yields. For the second stage
cascade reactions, reductive ring expansion proceeded
smoothly with most substrates (even a diastereomeric
mixture), except 2d, to afford the corresponding bicyclic
ethers in an exclusive cis-fused fashion in moderate togood
yields (32%ꢀ65%). The relative stereochemistry of 3a
was established by nuclear Overhauser enhancement
(NOE) experiments.11 As shown in Table 2, the unsuccess-
ful reductive ring expansion of 2d (entry 4) suggested the
bulky group at tetrahydrofuran could prevent the reduc-
tion of spiroketal, while the substituents on pyranone
have less effects on the reductive ring expansion (entries
1 and 2). Noteworthy is that when R1 was an allyl (entry 6),
alkenyl (entry 8), or tert-butyldiphenylsilyl ether group
(entry 9), reductiveringexpansionproduced bicyclic ethers
with the functional groups at the positions (3f, 3h and 3i)
that could be further elaborated for fusion of (an)other
ring(s). It was also noted that the reductive ring-opening
intermediate of [6,6]-spiroketal pyranone 2j (entry 10)
undergoes slow 7-exo-trig oxa-Michael cyclization, which
a Isolated yields of cascade Achmatowicz-spiroketalization. b Isolated
yield of spiroketal reduction/oxa-Michael cyclization. c Diastereomeric
ratio was determined by 1H NMR of crude mixture. d Decomposition
was observed. mCPBA: 3-chloroperbenzoic acid. NBS: N-bromo-
succinimide.
could be accelerated by addition of Amberlyst-15 to
provide 3j in 35% combined yields.
Next, we were interested in the stereochemical outcomes
and possible mechanisms of the reductive ring expansion.
As outlined in Scheme 3, there are two possible pathways
leading to bicyclic ethers but with different stereochemis-
try. If the Lewis acid coordinates with carbonyl (path b),
ring expansion (4bf5b) might occur stereospecifically to
generate an oxonium ion, followed by hydride reduction,
to provide 3a0 with a 2,5-anti configuration. On the other
(11) For details, see Supporting Information.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Stereochemical Outcomes on Reductive Ring
Expansion of Spiroketal Dihydropyranonea
Scheme 4. Kishi Reductive Cyclization of Dihydropyranones
Acetal and Hydroxy Ketonea
a Isolated yield.
a Conditions: (a) TFA (5 equiv), Et3SiH (5 equiv), CH2Cl2, ꢀ40 °C,
90%; (b) TBAF (1.2 equiv), THF, rt, 81%; (c) Amberlyst-15, MeOH/
CH2Cl2, rt, 83%. mCPBA: 3-chloroperbenzoic acid. NBS: N-bromo-
succinimide.
cyclization to give the single diastereomer 3a with the
exclusive syn-cis configuration.
In order to utilize the ketone functional group that
resulted from the AR, Kishi reduction was carried out
for simple substrate 8a (Scheme 4). To our delight, trans-
fused [6,6]-bicyclic ether 9a was obtained as the only major
product in 65% yield. This comprises the first double Kishi
reduction for Achmatowicz adducts with simultaneous
removal ofthe silyl group. Analogously, [6,7]-bicyclicether
9b was achieved in 50% yield. Remarkably, the bicyclic
ketone 8c obtained from our double cascades could be
efficiently transformed into the desired [6,6,6]-tricyclic
ether 9c in 80% yield with a cis-anti-trans configuration.11
In summary, we have developed a novel double cascade
synthetic strategy for the diastereoselective syntheses of
cis-fused bicyclic ethers through Achmatowicz/spiroketa-
lization and spiroketal reduction/oxa-Michael cyclization.
Significantly, we have achieved the chemo-, regio-, and
diastereoselective reduction of the highly functionalized
spiroketal dihydropyranone and subsequent oxa-Michael
cyclization, which expands the current fundamental trans-
formations of Achmatowicz adducts. Further exploration
of Achmatowicz rearrangement adducts for natural pro-
duct synthesis is ongoing in our laboratory.
hand, when reductive opening of spiroketals12 (2f4af5a)
via oxonium 4a takes place first to afford the enone
tethered to an alkyl alcohol, intramolecular oxa-Michael
cyclization13 of 5a would follow to give cis-fused bicyclic
ether 3a with a 2,5,6-syn-cis configuration (path a). The
high 2,6-syn diastereoselectivity of reduction in path a has
been well established due to the conformation in which iPr
sits at the equatorial position and the planaroxacarbenium
was attacked by hydride from the axial position.14 In
view of the all syn stereochemical outcomes obtained in
Table 2, weproposedthe reductive ring expansion operates
via cascade spiroketal reduction/oxa-Michael cyclization
(path a). In fact, a diastereomeric mixture of spiroketal
pyranones (cf. 2a and 2e) may be employed for the
reductive ringexpansion and a single diastereomer product
(3a and 3e, respectively) could be obtained. To further
support this mechanistic speculation, we performed a
careful Kishi reduction of dihydropyranone acetal 6 to
produce intermediate pyranone 7 (5a in path a), which
was subjected to intramolecular oxa-Michael cyclization
under both acidic and basic conditions. Remarkably, both
Amberlyst-15 in CH2Cl2/MeOH and TBAF in THF effi-
ciently promoted the cascade desilylation/oxa-Michael
Acknowledgment. This research was supported by start-
up funding from The Hong Kong University of Science and
Technology and Direct Allocation Grant (DAG12CS03)
from the Research Grant Council of Hong Kong.
(12) For selected papers, see: (a) Pettit, G. R.; Albert, A. H.; Brown,
P. J. Am. Chem. Soc. 1972, 94, 8095. (b) Mori, A.; Ishihara, K.;
Yamamoto, H. Tetrahedron Lett. 1986, 27, 987. (c) Ishihara, K.; Mori,
A.; Yamamoto, H. Tetrahedron Lett. 1987, 28, 6613. (d) Oikawa, H.;
Oikawa, M.; Ichihara, A.; Kobayashi, K.; Uramoto, M. Tetrahedron
Lett. 1993, 34, 5303. (e) Oikawa, M.; Oikawa, H.; Ichihara, A. Tetra-
hedron 1995, 51, 6237.
Supporting Information Available. Detailedexperiments
1
and H and 13C NMR of new compounds. This material
isavailable free of chargevia the Internetat http://pubs.acs.
org.
€
(13) For reviews, see: (a) Brase, S.; Nising, C. F. Chem. Soc. Rev.
€
2008, 37, 1218. (b) Brase, S.; Nising, C. F. Chem. Soc. Rev. 2012, 41, 988.
(14) Um, J. M.; Houk, K. N.; Phillips, A. J. Org. Lett. 2008, 10,
3769.
The authors declare no competing financial interest.
D
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