Exploring skeletal diversity via ring contraction of glycal-derived scaffolds

Article abstract of DOI:10.1021/ol0618252

(Chemical Equation Presented) Aryl ether C-glycoside scaffolds have been prepared from tri-O-acetyl-D-glucal by C-glycosylation followed by allylic substitution with phenols mediated by Pd(0). The aryl ethers were subjected to either [3,3]-sigmatropic rea

Full text of DOI:10.1021/ol0618252

ORGANIC
LETTERS
2006
Vol. 8, No. 22
5065-5068
Exploring Skeletal Diversity via Ring
Contraction of Glycal-Derived Scaffolds
Adam R. Yeager, Geanna K. Min, John A. Porco, Jr.,* and Scott E. Schaus*
Department of Chemistry, Center for Chemical Methodology and Library DeVelopment
at Boston UniVersity, Life Science and Engineering Building, Boston UniVersity,
24 Cummington Street, Boston, Massachusetts 02215
porco@bu.edu; seschaus@bu.edu
Received July 24, 2006
ABSTRACT
Aryl ether C-glycoside scaffolds have been prepared from tri-O-acetyl-D-glucal by C-glycosylation followed by allylic substitution with phenols
mediated by Pd(0). The aryl ethers were subjected to either [3,3]-sigmatropic rearrangement to produce 3-pyranyl-phenols or Au(III)-mediated
ring contraction to create highly substituted tetrahydrofurans.
The synthesis of focused, chemical libraries provides incen-
tive and inspiration for the discovery of novel chemical
reactions. Glycals are excellent starting scaffolds for library
development due to their rigid structures and inherent
stereochemical diversity. These attributes have previously
been exploited in the synthesis of carbohydrate-based scaf-
folds.1 Recently, diversity-oriented synthesis (DOS)2 has
increasingly emphasized skeletal diversity3 involving the
structural manipulation of scaffolds and synthesis of mol-
ecules with distinct skeletal frameworks.4 However, se-
quences involving rearrangement or fragmentation processes
are highly underdeveloped5 and should continue to receive
attention. Herein, we present a synthetic sequence for the
creation of novel cyclic ethers featuring an unexpected
skeletal modification of a glycal-derived scaffold discovered
during library development.
Our initial plan entailed addition of various carbon
nucleophiles to commercially available tri-O-acetyl-D-glucal
(1) to afford a series of C-glycoside scaffolds 2a-c (Scheme
1). Nucleophilic addition of phenols mediated by Pd(0) to
the resulting allylic alcohol6 would provide allylic ethers
3a-c in a second diversification step. We anticipated that
3a-c would be novel frameworks for skeletal diversification.
For example, [3,3]-sigmatropic rearrangement of the allyl
phenyl ethers may be used to effect positional diversification
of the scaffolds (compounds 4a-c) while unveiling a phenol
for further diversification. Additionally, we serendipitously
(1) For recent examples, see: (a) Kubota, H.; Lim, J.; Depew, K. M.;
Schreiber, S. L. Chem. Biol. 2002, 9, 265. (b) Jain, R.; Kamau, M.; Wang,
C.; Ippolito, R.; Wang, H.; Dulina, R.; Anderson, J.; Gange, D.; Sofia, M.
J. Bioorg. Med. Chem. Lett. 2003, 13, 2185. (c) Hunger, U.; Ohnsmann, J.;
Kunz, H. Angew. Chem., Int. Ed. 2004, 43, 1104. (d) Hotha, S.; Tripathi,
A. J. Comb. Chem. 2005, 7, 968. (e) Moilanen, S. B.; Tan, D. S. Org.
Biomol. Chem. 2005, 3, 798.
(2) (a) Schreiber, S. L. Science 2000, 287, 1964. (b) Hirschmann, R.;
Ducry, L.; Smith, A. B. J. Org. Chem. 2000, 65, 8307. (c) Krueger, E. B.;
Hopkine, T. P.; Keaney, M. T.; Walters, M. A.; Boldi, A. M. J. Comb.
Chem. 2002, 4, 229. (d) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int.
Ed. 2004, 43, 46. (e) Burke, M. D.; Berger, E. M.; Schreiber, S. L. J. Am.
Chem. Soc. 2004, 126, 14095. (f) Kim, Y.; Arai, M. A.; Arai, T.; Lamenzo,
J. O.; Dean, E. F., III.; Patterson, N.; Clemons, P. A.; Schreiber, S. L. J.
Am. Chem. Soc. 2004, 126, 14740. (g) Arya, P.; Joseph, R.; Gan, Z.; Rakic,
B. Chem. Biol. 2005, 12, 163.
(4) For recent reviews, see: (a) Abel, U.; Koch, C.; Speitling, M.;
Hansske, F. G. Curr. Opin. Chem. Biol. 2002, 6, 453. (b) Ortholand, J. Y.;
Ganesan, A. Curr. Opin. Chem. Biol. 2004, 8, 271. (c) Boldi, A. M. Curr.
Opin. Chem. Biol. 2004, 8, 281. (d) Tan, D. S. Comb. Chem. High
Throughput Screening 2004, 7, 631.
(5) For a recent example, see: Kumar, N.; Kiuchi, M.; Tallarico, J. A.;
Schreiber, S. L. Org. Lett. 2005, 7, 2535.
(6) (a) For palladium-mediated phenol addition to allylic carbonates,
see: Toste, F. D.; Trost, B. M. J. Am. Chem. Soc. 1998, 120, 815. (b) For
phenol addition to an O-pseudoglycal system, see: Sinou, D.; Bedjeguelal,
K. Eur. J. Org. Chem. 2000, 4071.
(3) (a) Couladouros, E. A.; Sronglios, A. T. Angew. Chem., Int. Ed. 2002,
41, 3677. (b) Burke, M. D.; Berger, E. M.; Schreiber, S. L. Science 2003,
302, 613. (c) Oguri, H.; Schreiber, S. L. Org. Lett. 2005, 7, 47.
10.1021/ol0618252 CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/27/2006

phenols to produce aryl ethers 3a-c.6 Because the allylic
acetates of 2a-c were unreactive to Pd(0) activation, the
bisacetates were converted to the corresponding biscarbonates
(Scheme 2). Acetate hydrolysis was achieved using a solid-
supported macroporous carbonate resin,13 and the resulting
diols were reprotected as bisethyl carbonates (cf. 8c). We
found that the catalyst system employed by Trost and co-
workers (Pd2(dba)3‚CHCl3 and the Trost ligands)14 provided
optimal yields of the desired aryl ethers. Microwave irradia-
tion (100 °C, 150-300 W) was employed to reduce reaction
times from 12 h (required for thermal reactions) to 15 min.15
Phenols were found to add to the pyran ring both regio-
and stereoselectively, with a net overall retention of config-
uration. The same regio- and stereochemistry was obtained
when either enantiomeric ligand ((R,R)- or (S,S)-Trost
ligands) was employed.16 Interestingly, reactions were unsuc-
cessful when achiral ligands such as diphenylphosphinobu-
tane (dppb) or diphenylphosphinopentane (dppp) were
employed. The regio- and stereochemistry of aryl ether
additions were determined by examination of an X-ray crystal
structure of the p-bromobenzoyl carbonate ester derived from
an allyl C-glycoside.17,18
Scheme 1. Synthetic Plan for Diversification of Glycals
discovered conditions that rearrange scaffolds 3a-c to the
corresponding trisubstituted tetrahydrofurans 5a-c.
In our initial studies, various carbon nucleophiles (allyl,
aryl, and alkynyl) were used to create a diverse set of
C-glycoside scaffolds (2a-c).1a Allyl C-glycoside 2a7 was
formed using Sc(OTf)3-catalyzed addition of allyl trimeth-
ylsilane to glycal 1.8 Pd(II)-mediated addition of arylboronic
acids to glycals provided convenient access to aryl C-
glycosides (2b).9 A series of R-alkynyl C-glycosides (2c)
were synthesized via Sc(OTf)3-catalyzed addition of trim-
ethylsilyl (TMS) alkynes 7 (generated in situ via terminal
alkynes 6)10 to glycal 1 (Scheme 2).11,12
A selection of 12 phenols were evaluated for addition to
a phenyl C-glycoside (8a, R1 ) phenyl) as part of a
preliminary rehearsal screen.19 On the basis of the successful
addition of all the phenols, we next evaluated their addition
to various C-glycosides 8a-c (Figure 1). Diverse phenol
Scheme 2
We next pursued modification of the resulting allylic
alcohol by palladium-mediated nucleophilic addition of
Figure 1. Representative C-glycosides prepared via the Pd-
mediated aryl etherification.
(7) Lewis acid-catalyzed addition of allyltrimethylsilane to glycals: (a)
Danishefsky, S. J.; De Ninno, S.; Lartey, P. J. Am. Chem. Soc. 1987, 109,
2082. (b) Yadav, J. S.; Reddy, B. V. S.; Chand, P. K. Tetrahedron Lett.
2001, 42, 4057. (c) Swamy, N. R.; Srinivasulu, M.; Reddy, T. S.; Goud, T.
V.; Venkateswarlu, Y. J. Carbohydr. Chem. 2004, 23, 435.
(8) Sc(OTf)3-catalyzed Ferrier addition to glycals, see ref 9b and: Ben,
A.; Yamauchi, T.; Matsumoto, T.; Suzuki, K. Synlett 2004, 2, 225.
(9) (a) Ramnauth, J.; Poulin, O.; Rakhit, S.; Maddaford, S. P. Org. Lett.
2001, 3, 2013. (b) Figuera, N.; Forns, P.; Fernandez, J. C.; Fiol, S.;
Fernandez-Forner, D.; Albericia, F. Tetrahedron Lett. 2005, 46, 7271.
(10) Andreev, A. A.; Konshin, V. V.; Komarov, N. V.; Rubin, M.;
Brouwer, C.; Gevorgyan, V. Org. Lett. 2004, 6, 421.
functionality, including halogens (9), ortho substituents (9),
aldehydes (11), nitrogen-containing phenols (10), as well as
(12) For Lewis acids that promote the addition of TMS-alkynes to
glycals, see: (a) Tsukiyama, T.; Isobe, M. Tetrahedron Lett. 1992, 33, 7911.
(b) Isobe, M.; Nishizawa, R.; Hosokawa, S.; Nishikawa, T. Chem. Commun.
1998, 2665. (c) Yadav, J. S.; Reddy, B. V. S.; Raju, A. K.; Rao, C. V.
Tetrahedron Lett. 2002, 43, 5437. (d) Isobe, M.; Phoosaha, W.; Saeeng,
R.; Kira, K.; Yenjai, C. Org. Lett. 2003, 5, 4883. (e) Smitha, G.; Reddy, C.
S. Synthesis 2004, 834.
(11) I2-catalyzed addition of TMS-alkynes to glycals: (a) Yaday, J. S.;
Reddy, B. V. S.; Rao, C. V.; Reddy, M. S. Synthesis 2003, 247. (b) Saeeng,
R.; Sirion, U.; Sahakitpichan, P.; Isobe, M. Tetrahedron Lett. 2003, 44,
6211.
5066
Org. Lett., Vol. 8, No. 22, 2006

coumarins (12), successfully added to aryl, alkynyl, and
allylic C-glycosides.
Methods for skeletal diversification were next examined
using C-glycosides 4a-c (Scheme 3). We first evaluated Eu-
alkynes,21 we evaluated a number of alkynophilic catalysts
and conditions to attempt hydration of alkyne 18. Suprisingly,
gold(III) chloride (AuCl3) promoted partial epimerization to
the corresponding â-C-glycosides (19) rather than alkyne
hydration. Further experimentation revealed that in the
presence of the primary alcohol alkynyl C-glycoside 20 was
transformed into two new, more polar compounds which
were identified as the ring-contracted tetrahydrofurans 21
and 22 (dr ) 8:1, based on isolated yields).
Scheme 3. Europium-Catalyzed Sigmatropic Rearrangement
The ring contraction was not limited to alkynyl glycosides,
as aryl C-glycosides (Scheme 4, compound 23) reacted
similarly to provide tetrahydrofurans 24 and 25 (dr ) 10:1).
The structures of the p-bromobenzoyl ester-protected alkyne
22 (minor product) and aryl 24 (major product) were
confirmed through X-ray crystallographic analysis.18
Other Lewis acids (AuBr3, TfOH, BF3‚OEt2, TMSOTf,
and Sc(OTf)3) also promoted the ring contraction, albeit in
lower conversion and selectivity. Time-dependent 1H NMR
studies of the ring contraction with substrate 23 indicate that
the ratios of tetrahydrofuran diastereomers did not vary
appreciably with time.18 In addition, small amounts of the
R-anomer of 23 (cf. 19, Scheme 4) were also observed by
1H NMR. The relative amounts of the R-pyran anomer did
not change over time indicating that it does not participate
in ring contraction.
(III)-catalyzed Claisen rearrangements of allylic C-glycosides
4a-c.6a The reaction required microwave heating at high
temperatures (200-225 °C). Representative allyl (14) and
aryl (16) C-glycosides underwent [3,3]-sigmatropic rear-
rangement to provide the desired phenols. However, pre-
liminary studies demonstrated that alkynyl C-glycosides such
as 18 (cf. Scheme 4) did not readily undergo rearrangement,
A proposed mechanism for the ring contraction is il-
lustrated in Scheme 5. We propose that AuCl3 promotes
ionization of the doubly activated carbon-oxygen bond of
32 to provide intermediate 33a.22 Ring closure then proceeds
through allylic carbonium ion intermediates 33b or 33c.
Tetrahydrofuran 34, the major product of the reaction, would
be afforded via conformer 33b minimizing A(1,3)-strain23
between the aryl ether and the allylic cation and diaxial
interactions with the pseudodiaxial hydrogen relative to
conformer 33c.
Scheme 4. Reactions of Alkynyl C-Glycosides with AuCl3
(13) Parlow, J. J.; Naing, W.; South, M. S.; Flynn, D. L. Tetrahedron
Lett. 1997, 38, 7959.
(14) See ref 6a. Trost ligand ) (1R,2R)-(+)- or (1S,2S)-(-)-1,2-
diaminocyclohexane-N,N′-bis(2′-diphenylphosphinobenzoyl).
(15) (a) Microwave-accelerated asymmetric allylic alkylations: Trost,
B. M.; Anderson, N. G. J. Am. Chem. Soc. 2002, 124, 14320. (b) Reviews
of microwave-accelerated organic synthesis: Lidstrom, P.; Tierney, J.;
Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225. (c) Kappe, C. O.
Angew. Chem., Int. Ed. 2004, 43, 6250. (d) Leadbeater, N. E.; Pillsbury, S.
J.; Shanahan, E.; Williams, V. A. Tetrahedron 2005, 61, 3565.
(16) For preliminary studies, see: Su, S.; Acquilano, D. E.; Arumu-
gasamy, J.; Beeler, A. B.; Eastwood, E. L.; Giguere, J. R.; Lan, P.; Lei, X.;
Min, G. K.; Yeager, A. R.; Zhou, Y.; Panek, J. S.; Snyder, J. K.; Schaus,
S. E.; Porco, J. A., Jr. Org. Lett. 2005, 7, 2751.
(17) This product may be predicted by the Trost mnemonic using the
(R,R)-(+)-Trost ligand. See ref 6a and: Trost, B. M.; Van Vranken, D. L.;
Bingel, C. J. Am. Chem. Soc. 1992, 114, 9327.
(18) See Supporting Information for details.
(19) For a recent example of rehearsal screening for library synthesis,
see: Beeler, A. B.; Acquilano, D. E.; Su, Q.; Yan, F.; Roth, B. L.; Panek,
J. S.; Porco, J. A., Jr. J. Comb. Chem. 2005, 7, 673.
(20) Recent reviews on gold catalysis: (a) Arcadi, A.; Di Giuseppe, S.
Curr. Org. Chem. 2004, 8, 795. (b) Hoffmann-Roder, A.; Krause, N. Org.
Biomol. Chem. 2005, 3, 387.
(21) Au-catalyzed hydration of alkynes: (a) Mizushima, E.; Sato, K.;
Hayashi, T.; Tanaka, M. Angew. Chem., Int. Ed. 2002, 41, 4563. (b)
Vasudevan, A.; Verzal, M. K. Synlett 2004, 4, 631.
even after prolonged heating with excess Eu(fod)3.
(22) Acid-catalyzed ionization of alkynyl C-glycosides complexed with
Co2(CO)8 has been shown to afford ring-opened products: Tanaka, S.;
Tsukiyama, T.; Isobe, M. Tetrahedron Lett. 1993, 34, 5757.
(23) Johnson, F. Chem. ReV. 1968, 68, 375.
Alternate modifications of the alkynyl C-glycosides with
alkynophilic Lewis acids were thus considered (Scheme 4).20
On the basis of reports of gold-catalyzed hydration of
Org. Lett., Vol. 8, No. 22, 2006
5067

tion, likely due to their inability to support the proposed
allylic carbonium ion intermediate (cf. Scheme 5, 33a). In
addition, electron-rich aryl glycoside substrates (cf. Figure
1, 13) did not undergo clean ring contraction and led to a
variety of other products.
Scheme 5. Proposed Mechanism for the Lewis
Acid-Catalyzed Ring Contraction
The stereochemical diversity of tetrahydrofurans produced
by the ring contraction was addressed using tri-O-acetyl-D-
galactal (Scheme 6). TMS-phenylacetylene added to galactal
Scheme 6. Synthesis of Galactal-Derived Tetrahydrofurans 40
and 41
A series of the C-glycosides 4a-c were subjected to
AuCl3-mediated ring contraction to evaluate the scope of the
reaction. Examples of successful contractions are shown in
Figure 2 with substitutions on both the C-glycoside append-
36 in 75% yield under standard conditions.24 The biscar-
bonate of 37 was found to be unreactive under the previous
Pd(0) conditions that were successful for the glycal system
and was therefore converted to a benzyl ether 39 (via aryl
acetonide 38) for ring contraction. The resulting tetrahydro-
furans 40 and 41 were obtained in 51% overall yield (dr )
2.5:1).18 The diastereoselectivity of this reaction is most likely
controlled by minimization of strain between the benzyl ether
and the newly formed enyne.
In summary, we have demonstrated the utility of aryl ether
C-glycosides for rapid conversion to novel skeletal frame-
works via either [3,3]-sigmatropic rearrangment or Au(III)-
mediated ring contraction to highly substituted tetrahydro-
furans. Further efforts are currently underway to expand the
ring contraction methodology to related reaction types as well
as to evaluate the biological activity of these novel com-
pounds.
Acknowledgment. We thank the National Institutes of
Health (P50 GM067041) for research support. We also thank
CEM Corporation (Matthews, NC) for assistance with
microwave instrumentation, Symyx Technologies, Inc. (Santa
Clara, CA) for assistance with reaction planning software,
Mr. Christopher Singleton (Boston University) for analytical
assistance, and Dr. Emil Lobkovsky (Cornell University) for
X-ray crystal structure analyses.
Figure 2. Au(III)-catalyzed ring contraction of aryl ether C-
glycosides (yield, dr).
age and the aryl ether. Although aryl (26, 27) and alkynyl
(28-30) glycosides underwent ring contraction, the allyl
C-glycosides (cf. 9) were found to be unreactive.
In some cases, significant amounts (26% for 26, 13% for
28) of the tetrahydrofuran (4b,c) â-anomer were recovered.
Incompatible functional groups such as aldehydes (11) and
tertiary anilines (10) resulted in decomposition. Electron-
deficient aryl C-glycosides (31) did not undergo ring contrac-
Supporting Information Available: General information,
selected spectral data, and CIF files. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0618252
(24) For a previous example of TMS-alkyne addition to tri-O-acetal-
D-galactal, see ref 12c.
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Org. Lett., Vol. 8, No. 22, 2006