Mild reductive opening of aryl pyranosides promoted by scandium(III) triflate

Article abstract of DOI:10.1021/ja067234o

An efficient method for the nucleophilic ring opening of stereochemically well-defined aryl pyranosides is described. The reaction effects a formal deoxygenation of the benzylic position to provide useful, enantioenriched building blocks. To illustrate th

Full text of DOI:10.1021/ja067234o

Published on Web 12/14/2006
Mild Reductive Opening of Aryl Pyranosides Promoted by Scandium(III)
Triflate
Hua-Li Qin, Jason T. Lowe, and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and Library DeVelopment, Metcalf Center for
Science and Engineering, Boston UniVersity, 590 Commonwealth AVenue, Boston, Massachusetts 02215
Received October 13, 2006; E-mail: panek@bu.edu
Scheme 1. Reductive Opening of Aryl Pyranoside
Scandium(III) complexes have increasingly found use as pro-
moters in a variety of organic transformations.1 While the majority
of available methods draw upon the ability of scandium to activate
CdX π-bonds toward nucleophilic additions, more recent studies
have shown that scandium complexes may also activate C-X
σ-bonds.2 Though still underdeveloped, this mode of activation
holds considerable potential in chemical synthesis.
Table 1. Reduction Promoted by Sc(OTf)3
Recent efforts in our laboratories have focused on the design
and development of a range of chiral organosilane reagents for the
synthesis of functionalized pyrans through a stereoselective [4+2]-
annulation.3 Herein, we report a mild and efficient reductive opening
of aryl pyranosides obtained from our annulation methodology,
using scandium(III) triflate in the presence of a hydride source
(Et3SiH). The reaction results in the efficient reduction of the
benzylic C-O σ-bond with formation of a stereochemically well-
defined acyclic system (Scheme 1).
Historically, the opening of cyclic ethers has relied on hydro-
genation employing high pressure, temperature, or strong acids,
limiting the reaction scope.4 Dissolving metal reduction has also
been employed with some degree of success,5 and conditions
utilizing trialkylsilanes have also been described. However, strong
acidic conditions6 or activated substrates7 are typically needed to
achieve conversion.
entrya
promotor
equiv
equiv Et3SiH
time
isolated yield (%)b
1
2
3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
1
2
2
2
20
20
2
5
5
24 h
24 h
24 h
24 h
61
88
67
88
80
4
5c
0.25
100 min
a Reactions were run in DCM at 25 °C for 24 h unless otherwise noted.
b All yields are based on isolated product after purification by chromatog-
raphy. c Reaction was irradiated under microwave conditions (DCM, 300
W, 70 PSI, 100 °C).
Table 2. Scope of Sc(OTf)3 Promoted Ring-Opening Reaction
Accordingly, a range of Lewis acids were screened in the
presence of Et3SiH with the hope of providing acyclic substrates.8
This survey identified Sc(OTf)3 as the only reliable promoter, giving
the desired acyclic congener in moderate yields (Table 1, entry 1).
Increasing the catalyst loading to 2 equiv gave excellent yields of
the desired acyclic product after 24 h (entry 2). Decreasing the
amounts of triethylsilane slowed the reaction rate and lowered the
yield (entry 3). Finally, it was found that 2 equiv of scandium triflate
and 5 equiv of triethylsilane gave the best results under ambient
conditions (entry 4). Microwave irradiation was also considered to
expedite the reaction. A significant reduction in reaction time (24
h to 100 min) with minimal loss of chemical yield was achieved
(entry 5). In addition, the quantities of Sc(OTf)3 for the reaction
could be lowered to substoichiometric amounts.
To determine functional group compatibility, a series of aryl
pyranosides were subjected to both room temperature and micro-
wave ring-opening conditions (Table 2). Aromatic nitro groups
(entry 3) and basic nitrogens (entry 4) were tolerated. Aromatic
halogens, which may be lost under normal hydrogenation, remained
intact (entries 5 and 8). Aromatic and aliphatic methyl ethers toler-
ated the reduction (entries, 3, 5, 8-10, and 12); however, TBS
ethers are cleaved under the described conditions to give the acyclic
product as its triol (entry 10). No stereochemical dependency was
observed in either the 2,6-trans or cis-tetrahydropyran giving
excellent yields of the opened form (entries 1-8 trans, 9-12 cis).
The methodology was also extended to 1-aryl deoxyribose (entry
11) and aryl C-glycosides (entry 12) to give highly oxygenated
acyclic products.
a All yields are based on isolated product after purification by chroma-
tography. b Reactions were run in DCM using 5 equiv of Et3SiH in the
presence of Sc(OTf)3 (2.0 equiv) at 25 °C. c Reactions were run in DCM
using Sc(OTf)3 (0.25-2 equiv) and 5 equiv of silane at 300 W, 70 PSI,
and 100 °C.
Having optimized the reductive opening of a number of aryl
pyranosides using Et3SiH, other nucleophiles were evaluated to
widen the scope of the reaction (Table 3). We were pleased to find
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J. AM. CHEM. SOC. 2007, 129, 38-39
10.1021/ja067234o CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Ring-Opening Utilizing Carbon and Nitrogen
Nucleophiles
Scheme 2. C11-C21 Fragments of Reblastatin and
Geldanamycin
a Reagents and conditions: (a) ArCHO, TfOH, DCM, -78 °C, 8a Ar′
) 63% 2,6-trans/cis ) 3:1, 8b Ar′′ ) 87% 2,6-trans/cis ) 20:1. (b) (i)
BH3‚SMe2, H2O2, THF; (ii) Me3OBF4, DCM; (iii) LiBH4, Et2O, three steps,
9a Ar′ ) 68%, dr ) 4:1, 9b Ar′′ ) 56%, dr ) 3:1. (c) Sc(OTf)3, Et3SiH,
DCM, 10a Ar′ ) 84%, 10b Ar′′ ) 63%.
a All yields are based on isolated product after purification by chroma-
tography and dr determined by 1H NMR. b Reactions were irradiated under
microwave conditions (DCM, 300 W, 70 PSI, 100 °C).
ing to note that the benzyl ether of 10b was preserved under the
described conditions.
In conclusion, an efficient method for the nucleophilic ring
opening of stereochemically well-defined aryl pyranosides is
presented. The reaction effects a formal deoxygenation of the
benzylic position to provide useful, enantioenriched, building
blocks. Future work will include further determination of the
reaction scope and application of the present methodology in natural
product synthesis.
Acknowledgment. This work was supported by NIH Grant
CA56304. J.S.P. is grateful to Dr. Fredrik Lake and Dr. Andreas
Heutling as well as Professors Jonathan Lee (Boston Univ.) and
Gwilherm Evano (Univ. of Versailles) for helpful discussions.
Figure 1. Related ansamycin antibiotics.
that both nitrogen and carbon-based nucleophiles9 participated in
the opening to give substitution on the benzylic position (entries
1-3). For example, 1a in the presence of allylsilane provided allyl
derivative 3a in 80% yield (entry 1). Utilizing trimethylsilyl azide
gave 3b in similar yields and selectivity (entry 2). Finally, TMSCN
provided 3c in lower yield but at a useful level of selectivity (entry
3). Initial experiments utilizing the described reaction conditions
gave acyclic products with moderate levels of selectivity (dr ) 1.4-
4:1) and provided the basis for the introduction of useful functional
groups at the benzylic carbon.10
Our immediate plan is to use this methodology in the synthesis
of geldanamycin 4, a potent inhibitor of heat-shock protein 90 (HSP
90). HSP 90 has been of great interest since the discovery of the
ATPase binding regions’ role in cancer and protein maintenance.11
Many inhibitors of HSP 90 are currently known, of which the
ansamycins antibiotics have received notable attention not only for
their potential role in cancer treatment but also for their synthetically
challenging molecular architecture.12
Supporting Information Available: Experimental details and
selected spectral data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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