Skeletal diversity via cationic rearrangements of substituted dihydropyrans

Article abstract of DOI:10.1021/ol101144k

(Figure Presented) Substituted dihydropyrans, easily accessed from a commercially available glycal, undergo acid-catalyzed rearrangement to provide highly functionalized isochroman and dioxabicyclooctane scaffolds.

Full text of DOI:10.1021/ol101144k

ORGANIC
LETTERS
2010
Vol. 12, No. 14
3222-3225
Skeletal Diversity via Cationic
Rearrangements of Substituted
Dihydropyrans
Matthew R. Medeiros, Radha S. Narayan, Nolan T. McDougal, Scott E. Schaus,*
and John A. Porco, Jr.*
Department of Chemistry, Center for Chemical Methodology and Library DeVelopment
(CMLD-BU), Boston UniVersity, 590 Commonwealth AVenue,
Boston, Massachusetts 02215
porco@bu.edu; seschaus@bu.edu
Received May 20, 2010
ABSTRACT
Substituted dihydropyrans, easily accessed from a commercially available glycal, undergo acid-catalyzed rearrangement to provide highly
functionalized isochroman and dioxabicyclooctane scaffolds.
Diversity-oriented synthesis (DOS) has proven to be an
exceptional strategy for exploring chemical space.1 Synthetic
approaches employing the principles of DOS address varia-
tions in three aspects of molecular structure: skeleton,
substitution, and stereochemistry.2 Following the tenets of
DOS, controlled skeletal rearrangement processes offer rapid
access to diverse, stereochemically rich frameworks.3 As a
method to access skeletal diversity, we recently reported the
rearrangement of stereochemically well-defined dihydropy-
rans derived from glycals such as 1 to afford highly
substituted tetrahydrofurans (Scheme 1).4 In this transforma-
tion, dihydropyrans (2) underwent Au(III)-mediated ioniza-
tion at the anomeric C-O bond to form an allylic carbocation
intermediate (3) which was trapped by the C6 hydroxyl
generating tetrahydrofurans 4. We sought to exploit this
reactivity by incorporating nucleophiles at different positions
of the precursor pyrans (5).5 We anticipated that this design
(3) (a) Schreiber, S. L.; Burke, M. D. Angew. Chem., Int. Ed. 2004, 43,
46. (b) Kesavan, S.; Panek, J. S.; Porco, J. A., Jr. Org. Lett. 2007, 9, 5203.
(c) Su, S.; Porco, J. A., Jr. Org. Lett. 2007, 9, 4983. (d) Garcia-Cuadrado,
D.; Barluenga, S.; Winssinger, N. Chem. Commun. 2008, 4619. (e) Aguilar-
Moncayo, M.; Ortiz-Mellet, C.; Garcia-Fernandez, J. M.; Garcia-Moreno,
M. I. J. Org. Chem. 2009, 74, 3595.
(1) Select reviews: (a) Liao, Y.; Hu, V.; Wu, J.; Zhu, Q.; Donovan, M.;
Fathi, R.; Yang, Z. Curr. Med. Chem. 2003, 10, 2285. (b) Reayi, A.; Arya,
P. Curr. Opin. Chem Biol. 2005, 9, 240. (c) Thomas, G. L.; Wyatt, E. E.;
Spring, D. R. Curr. Opin. Drug DiscoVery DeV. 2006, 9, 700. (d) Grabowski,
K.; Baringhaus, K.-H.; Schneider, G. Nat. Prod. Rep. 2008, 25, 892. (e)
Cordier, C.; Morton, D.; Murrison, S.; Nelson, A.; O’Leary-Steele, C. Nat.
Prod. Rep 2008, 25, 719. (f) Nielsen, T. E.; Schreiber, S. L. Angew. Chem.
Intl. Ed. 2008, 47, 48.
(4) Yeager, A. R.; Min, G. K.; Porco, J. A., Jr.; Schaus, S. E. Org. Lett.
2006, 8, 5065.
(5) For selected applications of glycals in synthesis, see the following.
Heck reaction: (a) Bedjeguelal, K.; Bolitt, V.; Sinou, D. Synlett 1999, 6,
762. Pauson-Khand reaction: (b) Kubota, H.; Lim, J.; Depew, K. M.;
Schreiber, S. L. Chem. Biol. 2002, 9, 265. Radical reactions: (c) Fraser-
Reid, B.; Lo´pez, J. C. Curr. Org. Chem. 2009, 13, 532.
(2) (a) Schreiber, S. L. Science 2000, 287, 1964. (b) Schreiber, S. L.
Chem. Eng. News 2003, 302, 613. (c) Tan, D. S. Chem. Biol. 2007, 2, 483.
(d) Spandl, R. J.; Bender, A.; Spring, D. R. Org. Biomol. Chem. 2008, 6,
1149. (e) Shaw, J. T. Nat. Prod. Rep. 2009, 26, 11.
10.1021/ol101144k  2010 American Chemical Society
Published on Web 06/15/2010

glucal (1) using ((4-(tert-butyl)phenyl)-ethynyl)trimethylsi-
lane was employed to access an alkynyl dihydropyran (cf.
Table 2, entry 12).5
Scheme 1. Skeletal Diversification Strategies Based on
Rearrangement of Substituted Dihydropyrans
Dihydropyran 11a was selected to investigate the trapping
of proposed carbocation intermediate 3 (Scheme 2b) using
Lewis acid catalysis.8 A preliminary screen revealed that
scandium(III) triflate was the optimal Lewis acid for this
transformation.9 Indeed, exposure of 11a to 100 mol %
Sc(OTf)3 in CH2Cl2 provided the isochroman regioisomers
12 and 13 (5.5:1) in 95% combined yield.
Encouraged by this result, we set out to decrease catalyst
loading (Table 1). Reducing the amount of Sc(OTf)3 to 25
Table 1. Optimization of Catalytic Reaction Conditionsa
might allow rapid access to a series of diverse skeletons (e.g.,
6 and 7) by changing the nature of the substituents at C1,
C4, and C6 in the dihydropyran substrates. Herein, we
demonstrate the realization of this concept employing
terminating groups at C4 that dictate various reaction
pathways involving Friedel-Crafts and cation-olefin cy-
clizations.
We initially focused our efforts on development of a
general synthesis of the appropriate dihydropyran substrates
containing benzyl or allyl ethers at C4. D-Glucal-derived diol
84 was converted to substrates 10a-d and 11a-e in a
straightforward manner (Scheme 2a). An aryl ether (cf. Table
entry
x
solvent/additive (equiv)
% yield; 12:13b
1
2
3
4
5
6
7
8
9
25 CH2Cl2/none
20 MeNO2/none
10 MeNO2/Bu4NPF6 (2)
2
20 MeNO2/Bu4NPF6 (0.2)
0
0
20 MeNO2/Bu4NPF6 (0.2)/DTBMP (1)
20 MeNO2/Bu4NPF6 (0.2)/3 Å MS
72; 5:1c
94; 3.7:1
97; 3.3:1d
85; 2.8:1
93; 3.6:1d
e
MeNO2/Bu4NPF6 (2)
MeNO2/Bu4NPF6 (2)
MeNO2/TfOH (0.2)
87; 2.5:1d
e
e
a All reactions conducted at 0 °C to rt for 2 h unless otherwise noted.
b Isolated yield and ratios. c rt, 17 h. d Time ) 30 min. e No reaction.
DTBMP ) 2,6-di-tert-butyl-4-methylpyridine.
Scheme 2. (a) General Synthesis of Dihydropyran Substrates
and (b) Initial Attempt at Pyran Rearrangement
mol % in CH2Cl2 resulted in a longer reaction time and low
yields of 12/13 (entry 1). Substituting CH3NO2 for CH2Cl2,
the former a cation-stabilizing and Lewis acid-activating
solvent,10 enabled use of 20 mol % catalyst while maintaining
the reaction rate (entry 2). A desire to further improve the
catalytic efficiency of the reaction led us to evaluate Bu4NPF6
as additive (entries 3-5). Organic salts having noncoordi-
nating anions have been shown to activate Lewis acid
catalysts.11 Conducting the rearrangement in the presence
of Bu4NPF6 increased the rate of the reaction. As a control,
conducting the reaction in the absence of Sc(OTf)3 resulted
in recovery of 11a (entry 6).
Triflic acid (TfOH) has been shown to be an active catalyst
in reactions employing metal triflates.12 Accordingly, use of
TfOH (20 mol %) provided a slightly lower yield and ratio
of 12 and 13 in comparison to Sc(OTf)3 (entry 7). Further-
more, inclusion of 2,6-di-tert-butyl-4-methylpyridine (DT-
BMP) as an acid scavenger completely inhibited the
reaction (entry 8). Addition of 3 Å molecular sieves to
the reaction to eliminate adventitious water also resulted
in the recovery of 11a (entry 9). Taken together, our
2, entry 11) was synthesized via allylic alkylation of 3,4-
dimethoxyphenol with the corresponding allylic carbonate
using Pd2(dba)3 and (S,S)-DACH phenyl Trost ligand under
microwave conditions.6,7 Ferrier reaction of tri-O-acetyl-D-
(6) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1998, 120, 815
.
(7) See Supporting Information for complete experimental details.
Org. Lett., Vol. 12, No. 14, 2010
3223

Functional group compatibility at C6 was first examined.
Notably, in the case of substrates containing a competing
nucleophile at C6, Friedel-Crafts alkylation was observed
as the preferred pathway (80-95% yield, entries 1, 2, and
5). Dihydropyrans containing either acetate or bromide
functionality at C6 also rearranged efficiently (entries 3 and
4). Within the C4 benzyl ether series, electron-rich deriva-
tives produced the corresponding isochromans effectively
(entries 6 and 7). On the other hand, 3-bromobenzyl ether
substrate 10d afforded the ring contraction product 28 in low
yield (entry 8). Epimerization at C1 of the corresponding
methyl ether derivative 11b (entry 9) provided support for
our proposed mechanism. The neutral benzyl ether substrate
11c regained Friedel-Crafts alkylation reactivity producing
a 2:1 mixture of trans:cis substituted isochromans in 78%
yield (entry 10). Although moderately successful, rearrange-
ment of C4 aryl ether 32 provided the distinct dihydroben-
zofuran scaffold 33 (entry 11). Finally, the C1-alkynyl
dihydropyran substrate 34 (entry 12) rearranged in good yield
to afford isochroman enyne 35.
Scheme 3
.
Proposed Mechanism of the Dihydropyran
Rearrangement
results strongly suggest involvement of TfOH as a viable
catalyst for the rearrangement.
A possible mechanism for the dihydropyran rearrangement
is illustrated in Scheme 3. We propose initial Sc(OTf)3- or
TfOH-promoted ionization of the anomeric C-O bond to
afford a highly stabilized allyl cation similar to our previously
reported Au(III)-catalyzed process.4 Subsequent Friedel-Crafts
alkylation13 likely proceeds through a chair-like transition
state (14) in which both the hydroxymethyl ether and styryl
substituents are oriented equatorially. This reactive conformer
would lead to the observed trans stereochemistry of the
newly formed pyran ring of products 12 and 13.
To investigate alternative reaction pathways accessible via
the allylic cation, other π-terminating substituents at C4 were
examined (Scheme 4). By replacing the benzyl group at C4
with an allyl group, we hoped to observe a sequential process
where an initial cation-olefin cyclization14 would provide a
tertiary carbocation that could undergo further transforma-
We next explored the substrate scope of the Friedel-Crafts
reaction employing 20 mol % Sc(OTf)3 and 20 mol %
Bu4NPF6 in CH3NO2 as standard conditions (Table 2).
Table 2. Dihydropyran Rearrangements Resulting from Friedel-Crafts Alkylationa
a Conditions: Sc(OTf)3 (20 mol %), Bu4NPF6 (20 mol %), CH3NO2, 0 °C to rt, 30 min. b Isolated yield and ratio.
3224
Org. Lett., Vol. 12, No. 14, 2010

analysis of a crystalline 2,4-dinitrophenylhydrazone deriva-
tive.7 In this case, the tertiary carbocation 39 apparently
undergoes a 1,2-hydride shift (migration of the appropriately
aligned H1 provides the major diastereomer observed)
resulting in formation of an oxocarbenium ion, which is
trapped by the metal alkoxide leading to 40.
Scheme 4
.
Rearrangements of Substituted Allyl Ethers and
Mechanistic Rationale
In summary, we have demonstrated divergent rearrange-
ments of glycal-derived dihydropyrans to afford a series of
structurally distinct frameworks. Isochroman skeletons were
obtained by Friedel-Crafts trapping of allylic cations gener-
ated from the acid-catalyzed opening of a dihydropyran.
Dioxabicyclo[2.2.2]- and dioxabicyclo[3.2.1]octanes have
been accessed in a process involving nucleophilic attack on
the cation generated from olefin cyclizations. Expansion of
the rearrangement chemistry to cascade processes, as well
as library synthesis applications, is currently underway and
will be reported in future publications.
Acknowledgment. We gratefully acknowledge the NIGMS
CMLD initiative (P50-GM067041) for financial support and
the National Science Foundation for the purchase of the
Waters high resolution mass spectrometer (CHE-0443618)
used in this work. We also thank Dr. Paul Ralifo (Boston
University) for NMR assistance and Dr. Jeff Bacon (Boston
University) for X-ray crystallographic analysis.
tions. Under the optimized conditions, R-styrenyl ether 11d
afforded the dioxabicyclo[2.2.2]-octane 38 in 63% yield.
Presumably, this reaction proceeds through trapping of the
stabilized tertiary carbocation, arising from a cation-olefin
cyclization, by the newly formed secondary metal-alkoxide
(37). Interestingly, rearrangement of the related 2-methallyl
ether substrate 11e resulted in formation of an unexpected
product which was characterized as the dioxabicyclo[3.2.1]-
octane 40. The structure of 40 was confirmed by X-ray
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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