Synthesis of spiroacetal enol ethers by oxidative activation of furan derivatives

Article abstract of DOI:10.1021/ol802138t

(Chemical Equation Presented) Activation of furan by electron transfer combines with the radical stabilizing effect of the alkynyl substituent (R = Ph, MeC=C-) to achieve site-selective cation formation. A tethered hydroxy group acts as a probe of this site-selectivity to produce the ring system present in spirocyclic natural products found in Artemisia and Chrysanthemum species. cis-Dihydroxylation proceeds with high anti-stereoselectivity with respect to the tetrahydropyranyl ring oxygen.

Full text of DOI:10.1021/ol802138t

ORGANIC
LETTERS
2008
Vol. 10, No. 23
5445-5448
Synthesis of Spiroacetal Enol Ethers by
Oxidative Activation of Furan
Derivatives
Jeremy Robertson* and Se´bastien Naud
Department of Chemistry, Chemistry Research Laboratory, UniVersity of Oxford,
Mansfield Road, Oxford OX1 3TA, U.K.
jeremy.robertson@chem.ox.ac.uk
Received September 12, 2008
ABSTRACT
Activation of furan by electron transfer combines with the radical stabilizing effect of the alkynyl substituent (R ) Ph, MeCt C-) to achieve
site-selective cation formation. A tethered hydroxy group acts as a probe of this site-selectivity to produce the ring system present in spirocyclic
natural products found in Artemisia and Chrysanthemum species. cis-Dihydroxylation proceeds with high anti-stereoselectivity with respect
to the tetrahydropyranyl ring oxygen.
Furan can be easily incorporated into synthetic intermediates
and subsequently converted into a variety of heterocycles
and other structural units, usually by oxidation.1 For example,
the Achmatowicz reaction2 and its aza-counterpart3 result
in the conversion of R-hydroxymethyl- and R-aminomethyl
furans into hydroxypyrones and hydroxypyridones, respec-
tively, by interception of an ene-dione intermediate by the
appended hydroxy or amino nucleophile. We4 and others5
have shown that, under conditions similar to those used for
the Achmatowicz reaction, substrates bearing more remote
nucleophiles are converted into spirocyclic products that have
wide application in natural product synthesis.
Treatment of furan derivatives with oxidizing agents that
induce overall loss of hydride, such as 2,3-dichloro-5,6-
dicyanobenzo-1,4-quinone (DDQ),6 can initiate nucleophilic
attack R to the ring and return an intact furan derivative.7 In
the early stages of this process, rapid charge-transfer complex
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10.1021/ol802138t CCC: $40.75
Published on Web 11/06/2008
2008 American Chemical Society

formation precedes reversible electron transfer to the reagent
and the resulting delocalized radical-cation 1 (Scheme 1) is
in these natural products, we set out to establish whether
such functionality could direct the course of oxidation
toward spirocyclization.
A model substrate (12, Scheme 2) was prepared from 2-(4-
tert-butyldimethylsilanyloxy)butylfuran (10),11 and a range
Scheme 1. 4-Hydroxybutyl Group as a Probe of Regioselective
Proton Abstraction from a Furan-Centered Radical Cation
Scheme 2. Preparation and Cyclization of a Model Substrate
of oxidants was screened for the spirocyclization. Of these,12
only DDQ resulted in an acceptable reaction; reproducible
results, applicable on a reasonable scale, were achieved with
addition of 2.2 equiv13 of DDQ to a solution of the substrate
at -95 °C followed by warming to -78 °C. The formation
of over-oxidation products was minimized by performing an
inverse quench of the cold reaction mixture into dilute
aqueous sodium thiosulfate solution. Under these conditions
the spiroacetal 1314 was isolated in acceptable yield, typically
as a ca. 6:1 ratio of Z/E diastereomers. Treatment of the
separated diastereomers with a catalytic quantity of cam-
phorsulfonic acid (CSA) in CDCl3 led to their equilibration,
the Z/E ratio stabilizing after a few days at ca. 2.5:1.
then activated toward overall loss of H• (by sequential
H+ and electron transfers) to generate cations 2 or 3.8 In
principle, the preferred site of deprotonation, which
dictates the regiochemistry of cation formation, could be
probed by a nucleophile present in either R1 or R2; for
example, if R2 ) (CH2)3OH, two cyclization products 4
or 5 could result. Reported cases of this type of oxidative
cyclization afford products of the second type (e.g., 5)7a
but if R1 can stabilize an adjacent radical more effectively
than R2 then deprotonation from its R-position should
ensue, generating spirocyclic products preferentially. This
paper presents a realization of this predicted pathway and
provides preliminary results for its application in natural
product synthesis.
(8) (a) Ho¨fler, C.; Ru¨chardt, C. Liebigs Ann. Recl. 1996, 183–188. (b)
Baciocchi, E.; Giacco, T. D.; Elisei, F.; Lanzalunga, O. J. Am. Chem. Soc.
1998, 120, 11800–11801. (c) Yamamoto, S.; Sakurai, T.; Yingjin, L.;
Sueishi, Y. Phys. Chem. Chem. Phys. 1999, 1, 833–837. (d) Fukuzumi, S.;
Ohkubo, K.; Tokuda, Y.; Suenobu, T. J. Am. Chem. Soc. 2000, 122, 4286–
4294. (e) Wurche, F.; Sicking, W.; Sustmann, R.; Kla¨rner, F.-G.; Ru¨chardt,
C. Chem.sEur. J. 2004, 10, 2707–2721.
Spirocycle 4 bears close structural resemblance to a group
of natural products (examples, Figure 1) that occur widely
(9) Key papers: (a) Bohlmann, F.; Herbst, P.; Arndt, C.; Scho¨nowsky,
H.; Gleinig, H. Chem. Ber. 1961, 94, 3193–3216. (b) Bohlmann, F.; Herbst,
P.; Dohrmann, I. Chem. Ber. 1963, 96, 226–236. (c) Bohlmann, F.; Jastrow,
H.; Ertinghausen, G.; Kramer, D. Chem. Ber. 1964, 97, 801–808. (d)
Bohlmann, F.; Arndt, C.; Bornowski, H.; Kleine, K.-M.; Herbst, P. Chem.
Ber. 1964, 97, 1179–1192. (e) Bohlmann, F.; Diedrich, B.; Gordon, W.;
Fangha¨nel, L.; Schneider, J. Tetrahedron Lett. 1965, 1385–1388. (f)
Bohlmann, F.; Fangha¨nel, L.; Kleine, K.-M.; Kramer, H.-D.; Mo¨nch, H.;
Schuber, J. Chem. Ber. 1965, 98, 2596–2604. (g) Bohlmann, F.; Kramer,
H.-D.; Ertingshausen, G. Chem. Ber. 1965, 98, 2605–2607.
(10) (a) Gao, Y.; Wu, W.-L.; Ye, B.; Zhou, R.; Wu, Y.-L. Tetrahedron
Lett. 1996, 37, 893–896. (b) Gao, Y.; Wu, W.-L.; Wu, Y.-L.; Ye, B.; Zhou,
R. Tetrahedron 1998, 54, 12523–12538. (c) Toshima, H.; Aramaki, H.;
Ichihara, A. Tetrahedron Lett. 1999, 40, 3587–3590. (d) Miyakoshi, N.;
Mukai, C. Org. Lett. 2003, 5, 2335–2338. (e) Miyakoshi, N.; Aburano, D.;
Mukai, C. J. Org. Chem. 2005, 70, 6045–6052. (f) Wensley, A. M.; Hardy,
A. O.; Gonsalves, K. M.; Koviach, J. L Tetrahedron Lett. 2007, 48, 2431–
2434. See also ref 9c, e, f.
Figure 1. Representative bis(acetylene) enol ether spiroacetals from
Artemisia and Chrysanthemum species.
(11) Sun, M.; Deng, Y.; Batyreva, E.; Sha, W.; Salomon, R. G. J. Org.
Chem. 2002, 67, 3575–3584.
in Artemisia and Chrysanthemum species and for which
antifeedant, antifungal, and tumor growth inhibitory
activities have been reported. Following Bohlmann’s
extensive investigations,9 over 30 examples have now been
characterized, and some have been synthesized.10 Because
the penta-1,3-diynyl side chain is a characteristic feature
(12) E.g., ferrocenium hexafluorophosphate, iron(III) nitrate, tetracya-
noethylene, bis(acetoxy)iodobenzene, bis(trifluoroacetoxy)iodobenzene, ce-
rium(IV) ammonium nitrate.
(13) As the reaction progresses, the forming DDQH- consumes DDQ
to form DDQH• + DDQ•-, the DDQH• disproportionating to DDQH2
+
DDQ; overall, 1.5 equiv of DDQ is theoretically required: 2 substr + 3
DDQ f 2 substr+ + 2 DDQ•- + DDQH2.8c
5446
Org. Lett., Vol. 10, No. 23, 2008

Application of this method to the synthesis of natural
product 7 (“homo-tonghaosu”) (Figure 1) required access to
a hexa-2,4-diynyl electrophile for the furan alkylation. Our
method for the synthesis of this side chain was based on
Tykwinski’s protocol for oligo(acetylene) synthesis.15 Com-
mercially available alkynone 14 (Scheme 3) was converted
kinetic isomer distribution was converted into a ca. 1:1 ratio
upon exposure to catalytic CSA, as before.
During our work on the synthesis of the lituarines, we
reported that conjugate additions to certain spiroacetal
butenolides proceed with high anti-stereoselectivity with
respect to the tetrahydropyranyl (THP) oxygen (A, Figure
2).4,19 Conversely, in conjugate additions of lithium amides
Scheme 3. Synthesis of E- and Z-Homo-tonghaosu (7)
Figure 2. Stereochemical control in conjugate addition to spirocetal-
butenolides (A) and -alkylidene dihydrofurans (B) and the question
of diastereoselective dihydroxylation of spirocycles 7 and 13 (C).
to analogous enol ethers, a high syn-stereoselectivity was
reported (B), the authors attributing this to chelation con-
trol.20 Although dihydroxylation is expected to be regiose-
lective for the endocyclic alkene in these systems9a (C), the
sense and level of stereocontrol imparted by the THP oxygen
is not known. Knowledge of this aspect would allow us to
complete a synthesis of diacetate cis-Z-9 (Figure 1) isolated
from Chrysanthemum boreale,21 and determine the relative
stereochemistry at its spiro center.
For the dihydroxylation of spirocycle Z-13, the combina-
tion of OsO4 and TMEDA in dichloromethane at low-
temperature22 gave complete conversion to essentially one
stereoisomer of an osmate complex (cis-Z-22, Scheme 4) that
could be isolated in 81% yield. Although this complex could
not be crystallized, its stereochemistry was inferred by X-ray
analysis of the derived diacetate (cis-Z-21) which revealed
that dihydroxylation had proceeded from the face opposite
to the THP oxygen.23 Application of the same conditions to
bis(acetylene) variant Z-7 was also successful, and the
diacetate cis-Z-9 could also be crystallized for X-ray
confirmation of the anti-disposition of the acetoxy groups
relative to the THP oxygen (Figure 3).24
into gem-dibromide 15 and the TMS group removed to
provide the Fritsch-Buttenberg-Wiechell substrate 16.
Lithiation, rearrangement, and alkylation in situ with paraform-
aldehyde gave alcohol 1716 which was converted into
bromide 1817 without complication.
Alkylation of furan derivative 10 with this electrophile
was somewhat low yielding, and dimer 20 was also pro-
duced;18 however, while this step remains unoptimized,
sufficient material was prepared after desilylation to assess
the DDQ oxidation. With this substrate (19), the formation
of products of over-oxidation was more problematic but
maintaining the reaction mixture at -95 °C gave a very clean
reaction, and a 90% yield of spirocyclic product 7 was
obtained based on a 39% conversion of starting material.
Again, the Z- isomer predominated (Z/E ratio, ca. 5:1). This
We found significant chemical shift deviations between
1
our H NMR data (for cis-Z-9) and those reported for the
natural product.25 Furthermore, the coupling constants
(19) Robertson, J.; Dallimore, J. W. P. Org. Lett. 2005, 7, 5007–5010
.
(20) (a) Yin, B.-L.; Hu, T.-S.; Wu, Y.-L. Tetrahedron Lett. 2004, 45,
2017–2021. (b) Yin, B.-L.; Li, C.; Xu, H.-H.; Hu, T.-S.; Wu, Y.-L. Chin.
J. Chem. 2006, 24, 240–246.
(21) Matsuo, A.; Uchio, Y.; Nakayama, M.; Hayashi, S. Tetrahedron
Lett. 1974, 1885–1888.
(14) Chen, L.; Xu, H.-H.; Yin, B.-L.; Xiao, C.; Hu, T.-S.; Wu, Y.-L. J.
Agric. Food Chem. 2004, 52, 6719–6723.
(22) Donohoe, T. J.; Moore, P. R.; Waring, M. J.; Newcombe, N. J.
Tetrahedron Lett. 1997, 38, 5027–5030.
(15) Luu, T.; Morisaki, Y.; Cunningham, N.; Tykwinski, R. R. J. Org.
Chem. 2007, 72, 9622–9629.
(23) The influence of allylic alkoxy groups on the stereoselectivity of
alkene dihydroxylation is reviewed in: Cha, J. K.; Kim, N.-S. Chem. ReV.
1995, 95, 1761–1795.
(16) First preparation: Armitage, J. B.; Cook, C. L.; Entwistle, N.; Jones,
E. R. H.; Whiting, M. C J. Chem. Soc. 1952, 1998–2005.
(17) Bohlmann, F.; Seyberlich, A. Chem. Ber. 1965, 98, 3015–3019.
(18) In the 1H NMR spectrum of the crude product, the components
10, 19-OTBS, and 20 were present in a ratio of 50:40:10.
(24) CCDC 697832 and 697833 contain crystallographic data for this
paper (for compounds cis-Z-9 and cis-Z-21, respectively). These can be
obtained free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
Org. Lett., Vol. 10, No. 23, 2008
5447

cis assignment in the original report. While we cannot rule
out the possibility that the natural product is the spiro-
diastereomer of our cis-Z-9, it is more likely to be the trans
isomer.27 Indeed, the corresponding coupling constant re-
ported28 for trans-E-9 is 7.5 Hz and a trans-1,2-dioxygen-
ation pattern would also be expected on the basis of a
biosynthetic epoxide ring-opening.
Scheme 4
. Regio- and Stereoselective Dihydroxylation of
Acetylenic Spiroacetal Enol Ethers 13 and 7.
It remains, of course, to establish the correct identity of
the natural product by independent synthesis. We will
describe our efforts toward that end in a full account of this
work, along with the DDQ-mediated reactions of furans
bearing a variety of non-acetylenic conjugating substituents,
and molecular modeling studies that shed light on the
stereochemical aspects of our results. In closing, we note
that substituent-controlled oxidative activation processes of
this type should not be limited to furan derivatives and
broader applications are envisaged.
Acknowledgment. We thank the EU (MEIF CT2006-
039126 to SN) for financial support, Andrew Tyrrell,
University of Oxford, for X-ray analysis of compounds cis-
Z-9 and cis-Z-21, and Drs. Tim Claridge and Barbara Odell,
University of Oxford, for supporting NMR studies.
Supporting Information Available: Experimental details
1
and copies of H and 13C NMR spectra for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL802138T
(25) In the following listings, significant deviations are evident in the
marked (*) resonances. Reported data for cis-Z-9:21 1H NMR (CCl4)
1.50-1.90 (6 H, m), 1.97 (3 H, d, J 1.0 Hz), 2.08 and 2.10 (2 × 3 H, 2 ×
s), 3.73 (2 H, t, J 5.0 Hz), 4.99* (1 H, d, J 7.5 Hz), 5.03* (1 H, dq, J 2.0,
1.0 Hz), 6.07* (1 H, dd, J 7.5, 2.0 Hz). Data for cis-Z-9: 1H NMR (500
MHz, CCl4) 1.45-1.70 and 1.84-2.00 (6 H, 2 × m), 1.90, 1.93 and 1.98
(3 × 3 H, 3 × s), 3.63-3.69 and 3.81-3.88 (2 × 1 H, 2 × m), 4.42* (1
H, app. s), 4.98* (1 H, d, J 4.7 Hz), 5.82* (1 H, poorly resolved dd, J 4.7,
1.8 Hz).
(26) For a discussion of the magnitude of geminal 1H-1H coupling
constants in cyclopentanes, see: Constantino, M. G.; da Silva, G. V. J.
Tetrahedron 1998, 54, 11363–11374.
Figure 3. ORTEP diagram of diacetate cis-Z-9.
(27) I.e., one of the two trans-Z-9 isomers that differ in the configuration
at the spiro center. The Z-stereochemical assignment for the side chain enol
ether in the natural product was secured21 by conversion of the diacetate
into the corresponding alkene (i.e., Z-7) and comparison of data with those
from an authentic sample.
between the CH(OAc) protons in both cis-Z-21 and cis-Z-9
are 4.8 ( 0.2 Hz (in C6D6, CDCl3 and CCl4), whereas the
value reported21 for the natural product is 7.5 Hz (in CCl4).
This is significant because this value26 led to the authors’
(28) (a) Marco, J. A.; Sanz, J. F.; Jakupovic, J.; Huneck, S. Tetrahedron
1990, 46, 6931–6938. (b) Wurz, G.; Hofer, O.; Sanz-Cervera, J. F.; Marco,
J. A. Liebigs. Ann. Chem. 1993, 99–101.
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