Stereoselective Construction of cis-2,6-Disubstituted Tetrahydropyrans via the Reductive Etherification of δ-Trialkylsilyloxy Substituted Ketones: Total Synthesis of (-)-Centrolobine

Article abstract of DOI:10.1021/ol035438t

(Matrix presented). The stereoselective intramolecular reductive etherification of δ-trialkylsilyloxy substituted ketones with catalytic bismuth tribromide and trielhylsilane provides a convenient method for the construction of cis-2,6-disubstituted tetra

Full text of DOI:10.1021/ol035438t

ORGANIC
LETTERS
2003
Vol. 5, No. 21
3883-3885
Stereoselective Construction of
cis-2,6-Disubstituted Tetrahydropyrans
via the Reductive Etherification of
δ-Trialkylsilyloxy Substituted Ketones:
Total Synthesis of (−)-Centrolobine
P. Andrew Evans,* Jian Cui, and Santosh J. Gharpure
Department of Chemistry, 800 East Kirkwood AVenue, Indiana UniVersity,
Bloomington, Indiana 47405
paeVans@indiana.edu
Received July 30, 2003
ABSTRACT
The stereoselective intramolecular reductive etherification of δ-trialkylsilyloxy substituted ketones with catalytic bismuth tribromide and
triethylsilane provides a convenient method for the construction of cis-2,6-disubstituted tetrahydropyrans. This method was highlighted in the
key step of an expeditious total synthesis of the antibiotic, (−)-centrolobine.
The stereoselective construction of cyclic ethers remains a
topical area of synthetic interest, particularly with respect
to C-glycosides that are ubiquitous in biologically important
natural products.1 This may be attributed to their diverse and
significant biological activity and the challenges associated
with the design of stereochemically flexible approaches that
provide access to either diastereoisomer. We have recently
developed a two-component etherification reaction for the
diastereoselective construction of cis- and trans-2,6-di- and
trisubstituted tetrahydropyrans in excellent yield.2,3 These
studies provided compelling evidence for hydrogen bromide
and bismuth oxybromide, derived from the in situ hydrolysis
of bismuth tribromide, to be responsible for the catalysis.4,5
Herein, we now describe the extension of the intramo-
lecular reductive etherification process using a series of tert-
butylsilyloxy ketones 1 to highlight this strategy for the
stereoselective construction of cis-2,6-disubstituted tetrahy-
dropyrans 2 (Scheme 1). This work also provides additional
support for Brønsted acid rather than Lewis acid catalysis,
and highlights this transformation in an expeditious total
synthesis of the antibiotic (-)-centrolobine (4).6
Recent studies by Bajwa and co-workers implicated
triethylsilyl bromide as the Lewis acid catalyst in a series of
intermolecular reductive etherification reactions with catalytic
bismuth tribromide and triethylsilane.7,8 We have demon-
strated that the two-component etherification is catalyzed by
hydrogen bromide and bismuth oxybromide, derived from
(1) For a review on recent advances in the stereoselective construction
of C-Glycosides, see: Du, Y.; Linhardt, R. J.; Vlahov, I. R. Tetrahedron
1998, 54, 9913 and pertinent references therein.
(2) Evans, P. A.; Cui, J.; Gharpure, S. J.; Hinkle, R. J. J. Am. Chem.
Soc. 2003, 125, 11456.
(3) For closely related approaches to the formation of C-glycosides
involving nucleophilic addition to oxocarbenium ions, see: (a) Lewis, M.
D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 4976. (b) Sassaman,
M. B.; Prakash, G. K. S.; Olah, G. A. Tetrahedron 1988, 44, 3771. (c)
Homma, K.; Mukaiyama, T. Chem. Lett. 1989, 259 and pertinent references
therein.
(4) Matano, Y.; Ikegami, T. In Organobismuth Chemistry; Suzuki, H.,
Matano, Y., Eds.; Elsevier: New York, 2001; Chapter 2, pp 21-245.
(5) For a recent review on the uses of bismuth compounds in organic
synthesis, see: Leonard, N. M.; Wieland, L. C.; Mohan, R. S. Tetrahedron
2002, 58, 8373.
(6) (a) De Albuquerque, I. L.; Galeffi, C.; Casinovi, C. G.; Marini-Bettolo,
G. B. Gazz. Chim. Ital. 1964, 94, 287. (b) Alcantara, A. F. de C.; Souza,
M. R.; Pilo´-Veloso, D. Fitoterapia 2000, 71, 613.
(7) Komatsu, N.; Ishida, J.-Y.; Suzuki, H. Tetrahedron Lett. 1997, 38,
7219.
10.1021/ol035438t CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/20/2003

Scheme 1. General Strategy for the Stereoselective
Construction of cis-2,6-Disubstituted Tetrahydropyrans with an
Intramolecular Reductive Etherification
the hydrolysis of bismuth tribromide.2 This subtle difference
in catalyst and similarity in the reagents prompted the
reinvestigation of the reductive etherification to determine
which of these species was responsible for the catalysis.
The combination of bismuth tribromide and triethylsilane
is known to generate elemental bismuth, hydrogen bromide,
and triethylsilyl bromide.8 Preliminary studies focused on
the hypothesis that bismuth tribromide and triethylsilyl
bromide provide an in situ source of hydrogen bromide,
which then functions as the active Brønsted acid catalyst
(Table 1, entries 1, 4, and 7). The addition of activated
Figure 1. Proposed catalytic cycle for the reductive etherification
with bismuth trihalides and trialkylsilanes.
These experimental findings prompted the mechanistic
revision of the original catalytic cycle proposed by Bajwa
and co-workers, as outlined in Figure 1. The Brønsted acid
formed through the reduction of bismuth trihalide is clearly
not effectively buffered by the acetonitrile.8 Protodesilylation
of the δ-trialkylsilyloxy substituted ketone i catalyzed by
the Brønsted acid should afford the hemiketal iii. Acid-
catalyzed dehydration of iii should afford the intermediary
oxocarbenium ion iv, which will be reduced to afford the
cis-2,6-disubstituted tetrahydropyran v. The Brønsted acid
can then be recycled through the hydrolysis of the trialkylsilyl
halide, with the water derived from the dehydration of the
hemiketal completing the catalytic cycle.
Table 1. Elucidation of the Role of Bismuth Tribromide in the
Intramolecular Reductive Etherification Reaction (Scheme 1; 1a,
R1 ) PhCH2, R2 ) Ph)a
entry catalyst
additive
mol % ratio of 2a :3a e yield (%)f
1
2
3
4
5
6
7
8
9
BiBr3
"
"
-
5
"
"
15d
"
"
15d
"
"
g99:1
NA
NA
g99:1
NA
NA
g99:1
NA
NA
97
0
0
99
0
0
99
0
0
4Å Sievesb
DTBMPc
-
TESBr9
"
4Å Sievesb
DTBMPc
-
4Å Sievesb
DTBMPc
"
HBr
"
"
Table 2. Scope of the Diastereoselective Intramolecular
Reductive Etherification Reactions (Scheme 1; R1 ) PhCH2)a
a All the reductive etherification reactions were carried on a 0.1 mmol
reaction scale in acetonitrile at room temperature with 1.2 equiv of
triethylsilane. b Molecular sieves were activated at 150 °C under high
vacuum. c 20 mol % based on 1a. d Assuming bismuth tribromide can yield
up to 3 equiv of hydrogen bromide and/or triethylsilyl bromide. e Ratios of
diastereoisomers were determined by GLC on the crude reaction mixtures.
f GLC yields.
tert-butylsilyloxy
ratio of
2:3b,c
entry
ketone, R2
)
1
yield (%)d
1
2
3
4
5
6
7
8
9
Ph
Me
a
b
c
d
e
f
g
h
i
g99:1
g99:1
g99:1
g99:1
g99:1
g99:1
g99:1
g99:1
g99:1
97
90
95
96
95
97e
82f
93
91
iPr
(CH2)6Br
molecular sieves to each of these reagents, which should
sequester only the HBr and water, completely suppresses the
reaction (entries 2, 5, and 8).10 Moreover, the addition of
2,6-di-tert-butyl-4-methylpyridine (DTBMP), which should
neutralize any hydrogen bromide, leads to analogous results
(entries 3, 6, and 9).2 Hence, the reductive etherification
reactions are consistent with Brønsted acid rather than Lewis
acid catalysis.11,12
CH2CHdCH2
CH2CO2Et
CH2OH
CH2OBz
CH2OBn
a All the reductive etherification reactions were carried on a 0.2 mmol
reaction scale in acetonitrile at room temperature with 5 mol % of BiBr3
and 1.2 equiv of triethylsilane. b Ratios of regioisomers were determined
by GLC. c The stereochemical assignment was made with use of an NOE
in each case. d Isolated yields. e 10 mol % of BiBr3 and 2.0 equiv of
triethylsilane. f 20 mol % of BiBr3 and 2.0 equiv of triethylsilane.
(8) For an alternative mechanistic proposal that suggests the triethylsilyl
bromide formed from triethylsilane and bismuth tribromide behaves as a
Lewis acid catalyst, see: Bajwa, J. S.; Jiang, X.; Slade, J.; Prasad. K.; Repic,
O.; Blacklock, T. J. Tetrahedron Lett. 2002, 43, 6709.
(9) The addition of water (100 mol %) afforded the cyclic ether 2 in
quantitative yield and with excellent selectivity (entry 4). This further
supports the notion that triethylsilyl bromide is not the active catalyst.
(10) For an example of using molecular sieves to scavenge hydrogen
chloride, see: Weinstock, L. M.; Karady, S.; Roberts, F. E.; Hoinowski,
A. M.; Brenner, G. S.; Lee, T. B. K.; Lumma, W. C.; Sletzinger, M.
Tetrahedron Lett. 1975, 16, 3979.
Table 2 summarizes the scope of the intramolecular
reductive etherification. The δ-tert-butyldimethylsilyloxy
ketones 1a-i furnished the cis-2,6-disubstituted tetrahydro-
(11) Interestingly, the nature of the triorganosilyloxy protecting group
is inconsequential in terms of the overall reaction efficiency and selectivity
(TES ∼ TBS ∼ TIPS).
3884
Org. Lett., Vol. 5, No. 21, 2003

pyrans 2a-i in 82-97% yield with excellent diastereose-
lectivity (Scheme 1).13 Interestingly, the reaction is remark-
ably tolerant to a wide array of substituents. For example
aryl-, R-branched alkyl-, alkyl halide-, and alkene-containing
substituents (entries 1-5), â-keto esters (entry 6), and hy-
droxymethyl derivatives (entries 7-9) are suitable substrates.
then subjected to cross-metathesis by using the second-
generation Grubbs’ catalyst, to afford the corresponding R,â-
unsaturated ketone.17 Selective hydrogenation of the alkene
with Wilkinson’s catalyst furnished the aryl ketone 7 in 74%
yield from 6. Treatment of the δ-triethylsilyloxy aryl ketone
7 with bismuth tribromide and triethylsilane at room tem-
perature, followed by in situ removal of the tert-butyldim-
ethylsilyl group afforded (-)-centrolobine (4) in 93% yield,
with excellent diastereoselectivity. Synthetic (-)-centrolobine
(4) was identical in all respects with the reported spectral
data for the natural substance (1H/13C NMR and IR),
Scheme 2. Retrosynthetic Analysis for (-)-Centrolobine;
Potential Reductive Etherification Reactions
including optical rotation [R]22 -90.3 (c ) 0.88, CHCl3)
D
{lit.6b [R]D -92.2 (c ) 1, CHCl3)}. Overall, this total
synthesis was accomplished in 5 steps from aldehyde 5, in
53% overall yield, making it the most efficient route
developed to date.
The alternative approach to (-)-centrolobine (4) involved
the reductive coupling of a benzylic triethylsilyl ether ii
(Scheme 2; Route B). Treatment of the ketone 8, which was
prepared in 4 steps by using an analogous reaction sequence,
with bismuth tribromide and triethylsilane furnished none
of the desired product. This observation is presumably the
result of the solvolysis of the activated benzylic triethylsilyl
ether and/or alcohol formed through protodesilylation.
(-)-Centrolobine A (4) is an antibiotic that was isolated
from the heartwood of Centrolobium robustum and from the
stem of Brosimum potabile in the amazon rain forest.6
Solladie and Rychnovsky have recently completed indepen-
dent enantioselective total syntheses of this agent, and thereby
determined its absolute configuration.14 We envisioned that
the reductive etherification using bismuth tribromide and
triethylsilane would provide an expeditious route to this
agent, as outlined in Scheme 2.
Scheme 4. Attempted Reductive Etherification with the
Benzylic Triethylsilyl Ether 8
Scheme 3. Stereoselective Synthesis of (-)-Centrolobine with
an Intramolecular Reductive Etherification
In conclusion, we have demonstrated that the intramo-
lecular reductive etherification using bismuth tribromide and
triethylsilane provides a versatile route for 2,6-disubstituted
tetrahydropyrans. These studies also provide additional
support for the notion that the hydrolysis of bismuth
tribromide leads to the generation of hydrogen bromide,
which functions as a Brønsted acid catalyst. Finally, this
methodology was highlighted in an expeditious total syn-
thesis of the antibiotic, (-)-centrolobine.
Acknowledgment. We sincerely thank the National
Institutes of Health (GM58877) for generous financial
support. We also thank Johnson and Johnson for a Focused
GiVing Award, and Pfizer Pharmaceuticals for the CreatiVity
in Organic Chemistry Award. The Camille and Henry
Dreyfus Foundation is thanked for a Camille Dreyfus
Teacher-Scholar Award (P.A.E.).
The initial approach to (-)-centrolobine (4) involved the
examination of the reductive etherification of an aryl ketone
i (Scheme 2; Route A). Enantioselective allylation of
aldehyde 5,15 and protection of the resulting secondary
alcohol (95% ee), furnished the triethysilyl ether 6 in 77%
overall yield, as detailed in Scheme 3.16 The alkene 6 was
(12) For an example of protodesilylation of alkyl triorganosilyl ethers
with bismuth bromide, see: Bajwa, J. S.; Vivelo, J.; Slade, J.; Repic, O.;
Blacklock, T. Tetrahedron Lett. 2000, 41, 6021.
(13) For a discussion of substituent effects on the stereochemical outcome
of additions to tetrahydropyran-derived oxocarbenium ions, see: Romero,
J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2000, 122, 168.
(14) (a) Colobert, F.; Des Mazery, R.; Solladie, G.; Carreno, M. C. Org.
Lett. 2000, 4, 1723. (b) Marumoto, S.; Jaber, J. J.; Vitale, J. P.; Rychnovsky,
S. D. Org. Lett. 2002, 4, 3919.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL035438T
(15) Jones, G. B.; Heaton, S. B. Tetrahedron: Asymmetry 1993, 4, 261.
(16) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993,
115, 8467.
(17) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am.
Chem. Soc. 2000, 122, 3783. For a recent review on olefin cross-metathesis,
see: Connon, S. J.; Blechert, S. Angew. Chem. Int. Ed. 2003, 42, 1900.
Org. Lett., Vol. 5, No. 21, 2003
3885