Stereoselective construction of cyclic ethers using a tandem two-component etherification: Elucidation of the role of bismuth tribromide

Article abstract of DOI:10.1021/ja036439j

The stereodivergent construction of cyclic ethers remains an important area of synthetic interest, particularly given the ubiquity of C-glycoside derivatives in natural and unnatural pharmacologically important agents. This work describes a series of intr

Full text of DOI:10.1021/ja036439j

Published on Web 08/27/2003
Stereoselective Construction of Cyclic Ethers Using a Tandem
Two-Component Etherification: Elucidation of the Role of Bismuth
Tribromide
P. Andrew Evans,* Jian Cui, Santosh J. Gharpure, and Robert J. Hinkle*,†
Department of Chemistry, Indiana UniVersity, Bloomington, Indiana 47405
Received May 30, 2003; E-mail: paevans@indiana.edu
Scheme 1
The stereodivergent construction of cyclic ethers remains an
important area of synthetic interest, particularly given the ubiquity
of C-glycoside derivatives in natural and unnatural pharmacologi-
cally important agents.1 Bismuth(III) halides are inexpensive and
environmentally benign reagents, which have been utilized as mild
Lewis acid catalysts for an array of synthetic transformations.2,3
Herein, we describe a series of stereoselective intramolecular
etherification reactions of δ-trialkylsilyloxy aldehydes and ketones
1, using catalytic bismuth tribromide and various trialkylsilyl
nucleophiles for the construction of cis- and trans-2,6-di- and
trisubstituted tetrahydropyrans 2 (eq 1).4
Table 1. Elucidation of the Role of BiBr3 in the Two-Component
The mechanistic hypothesis, outlined in Scheme 1, describes the
basis of the two-component etherification reaction. Since bismuth-
(III) trihalides are known to readily undergo hydrolysis to afford
bismuth oxyhalides and the requisite Brønsted acid,2,5 we anticipated
that the latter would promote the formation of ii, which should
then undergo in situ desilylation to afford the lactol iii.6 Acid-
catalyzed dehydration of iii could then lead to the formation of the
oxocarbenium ion iv and facilitate axial nucleophilic attack to
furnish the cyclic ether v.7 The potential advantage of this approach
over that involving a Lewis acid is the unusual chemoselectivity,
which will provide a powerful tool for the construction of cyclic
ethers. This selectivity is presumably the result of the low reactivity
of the protonated carbonyl, which requires addition of the pendant
triorganosilyloxy group to afford the more reactive oxocarbenium
ion.8 Moreover, the acid concentration is modulated using the
hydrolysis of the triorganosilyl halide, making it an exceedingly
mild and convenient method.
Preliminary studies demonstrated that the nature of the bismuth-
(III) halide was inconsequential in terms of both efficiency and
selectivity (Cl ∼ Br ∼ I). In light of this fact we elected to utilize
the less expensive BiBr3. Interestingly, while the selectivity was
unaffected by the nature of the triorganosilyl ether, the efficiency
of the reaction was found to be directly related to the rate of
protodesilylation (TMS ∼ TES > TBS . TIPS).9 Additional studies
using pendant triethylsilyl ethers then focused on providing evidence
for the proposed hypothesis outlined in Scheme 1. Initial studies
examined the proposal that BiBr3 or triethylsilyl bromide provided
a source of HBr, which then functions as the catalyst (Table 1,
entries 1, 5, and 7). Consistent with this hypothesis, the addition
of water to BiBr3 did not prove detrimental to the reaction and
further supports the notion that the BiBr3 is not acting as a Lewis
acid (entry 2). Moreover, the addition of activated molecular sieves
Etherification Reaction (eq 1, 1a, R ) Et; R1 ) Bn; R2 ) H; Nu )
CH2CHdCH2)
entry
catalysta
mol %
additive
ratio of 2a:3ae,f
(%) yieldg
1
2
3
4
5
6
7
8
9
BiBr3
"
"
"
HBr
"
TESBr
"
"
10
-
H2Ob
g99:1
g99:1
NA
NA
g99:1
NA
g99:1
NA
g99:1
NA
99
92
0
0
34
0
"
"
20
"
"
"
4Å sievesc
DTBMPd
-
4Å sievesc
-
32
0
4Å sievesc
BrBidOd
-
"
"
91h
0
10
BrBidO
a All reactions were carried out on a 0.1 mmol reaction scale in CH3CN
at room temperature using 3 equiv of allyltrimethylsilane. b 10 equiv based
on BiBr3. c Molecular sieves were activated at 150 °C under high vacuum.
d 20 mol % based on 1a. e Ratios of diastereoisomers were determined by
capillary GLC analysis. f The cis-diastereoisomer 3a was prepared from the
ketone Via a reductive etherification reaction. g GLC yields. h The addition
of 4Å molecular sieves to this reaction also led to no observable reaction.
to each of these reagents, to sequester HBr and water, gave none
of the desired product (entries 3, 6, and 8).10 This idea was further
supported by the addition of 2,6-di-tert-butyl-4-methylpyridine
(DTBMP), which neutralizes the hydrogen bromide and leads to
no observable reaction (entry 4). The relatively poor catalytic
activity of HBr and triethylsilyl bromide (entries 5 and 7) prompted
additional studies to determine the potential role of bismuth in the
reaction. Interestingly, the addition of an equimolar amount of
BrBidO appears to reconstitute the catalytic activity (entries 7 and
10 Vs 9).11 Further investigations are underway to determine the
precise role of the BrBidO.
Table 2 outlines the scope of the two-component etherification
reaction in terms of various nucleophiles. This study demonstrated
that δ-triethylsilyloxy-substituted aldehydes and ketones serve as
substrates for the etherification reaction. Interestingly, while the
two-component coupling reactions with carbon nucleophiles fur-
† Sabbatical Leave from the Department of Chemistry, College of William and
Mary, P.O. Box 8795, Williamsburg, VA 23187-8795.
9
11456
J. AM. CHEM. SOC. 2003, 125, 11456-11457
10.1021/ja036439j CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of the Tandem Two-Component Etherification
Reactions (eq 1; 1, R ) Et; R1 ) Bn)a
synthetic utility of this protocol is highlighted in the ability to
construct adjacent tertiary ethers in a highly stereoselective manner
and the sequential two-component cross-coupling followed by
reductive etherification process for the expiditious synthesis of
nonadjacent tetrahydropyrans. These methods will undoubtedly be
widely applicable to target-directed synthesis.
2
c
f
entry
1; R )
R Si-Nub
cyclic ether 2/3 Nu )
ds ) 2:3
yield (%)
3
1
2
3
4
5
6
7
8
H
Me
H
Me
H
Me
2H
Me
A
A
B
B
C
C
D
D
-CH2CHdCH2
a
b
c
d
e
f
g99:1d
g19:1
g19:1e
g19:1e
g19:1
g19:1
g19:1
g99:1d
90
88
80
72
73
80
85
95
"
-CHdCdCH2
"
Acknowledgment. We sincerely thank the National Institutes
of Health (GM58877) for generous financial support and the College
of William and Mary for funding a Faculty Research Assignment
(R.J.H.). 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 both a Camille Dreyfus Teacher-Scholar Award (P.A.E.)
and a Henry Dreyfus Teacher-Scholar Award (R.J.H.).
-CH2C(O)CH3
"
-H
"
g
h
a All reactions were carried out on a 0.2-0.3 mmol reaction scale in
CH3CN at room temperature using 5-10 mol % BiBr3 and 1.2-3.0 equiv.
of R3Si-Nu. b A ) Me3SiCH2CHdCH2; B ) Me3SiCH2CtCH; C )
CH2dC(OSiMe3)CH3; D ) Et3SiH. c Ratios of diastereoisomers were
determined by 400 MHz 1H NMR on the crude reaction mixture unless
otherwise indicated. d Determined by capillary GLC. e Contaminated with
5-10% of the propargylated derivative. f Isolated yields.
Supporting Information Available: Experimental procedures,
X-ray analysis of the p-nitrobenzoate derivative of 5, and spectral data
for 1a-c, 2a-h, 4-5, and 7-9. This material is available free of charge
via the Internet at http://pubs.acs.org.
nished the trans-diastereoisomer (entries 1-6),12 the reductive
coupling furnished the cis-diastereoisomer consistent with axial
addition of the nucleophile (entries 7 and 8).13,14
References
(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) Matano, Y.; Ikegami, T. In Organobismuth Chemistry; Suzuki, H., Matano,
Y., Eds.; Elsevier: New York, 2001; Chapter 2, pp 21-245.
(3) For a recent review on the uses of Bi(III) compounds in organic synthesis,
see: Leonard, N. M.; Wieland, L. C.; Mohan, R. S. Tetrahedron 2002,
58, 8373.
(4) (a) Komatsu, N.; Uda. M.; Suzuki, H.; Takahashi, T.; Domae, T.; Wada,
M Tetrahedron Lett. 1997, 38, 7215. (b) Komatsu, N.; Ishida, J.-Y.;
Suzuki, H. Tetrahedron Lett. 1997, 38, 7219.
(5) For an example of protodesilylation of alkyl triorganosilyl ethers using
bismuth bromide, see: Bajwa, J. S.; Vivelo, J.; Slade, J.; Repic, O.;
Blacklock, T. Tetrahedron Lett. 2000, 41, 6021.
(6) For an example of using silyl ethers as masked hydroxyl groups, see:
Angle, S. R.; El-Said, N. A. J. Am. Chem. Soc. 1999, 121, 10211.
(7) For 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.
(8) For the comparison of the kinetics of allylation of oxocarbenium ions
and aldehyde Lewis acid complexes, see: Mayr, H.; Gorath, G. J. Am.
Chem. Soc. 1995, 117, 7862.
We envisioned that the stereoselective construction of adjacent
tertiary ethers would prove challenging and thereby highlight the
synthetic utility of the tandem two-component etherification reaction
(eq 2). Treatment of the triethylsilyl ether 4 with BiBr3 and excess
allyltrimethylsilane at room temperature furnished the bicyclic
tetrahydropyran derivatives 5/6 in 77-81% yield, with excellent
diastereoselectivity favoring 5.15,16 The ability to accomplish the
selective formation of this bis-tertiary ether from the cis-ring fusion
is particularly interesting given there are potentially two conformers
of the oxocarbenium ion. Indeed, the stereochemical outcome is
consistent with the Woerpel model,14 which predicts the 4-alkoxy
substituent will adopt a pseudoaxial orientation in the transition
state, thereby favoring the trans-addition of the allylsilane.
(9) Schelhaas, M.; Waldmann, H. Angew. Chem., Int. Ed. Engl. 1996, 35,
2056.
(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, 46, 3979.
(11) The structure of bismuth oxybromide, isolated from the hydrolysis of
bismuth bromide, was confirmed Via X-ray powder diffraction.
(12) RepresentatiVe Experimental Procedure for the Two-Component AllylatiVe
Etherification: 6-Phenyl-5-(triethylsilyloxy)hexanal 1a (57.0 mg, 0.186
mmol) was dissolved in acetonitrile (2.0 mL) and stirred at room
temperature. Bismuth tribromide (8.9 mg, 0.020 mmol) prepared as a
solution in acetonitrile at 1 mg/10 µL was added via syringe directly
followed by the rapid addition of allyltrimethylsilane (90 µL, 0.56 mmol).
The reaction mixture was stirred at room temperature for ca. 16 h (tlc
control). The solvent was removed in Vacuo to afford the crude oil.
Purification by flash chromatography (5% ethyl acetate/hexanes) furnished
2a (34.6 mg, 90%) as a colorless oil (ds g 99:1 by GLC).
(13) An alternative mechanistic proposal suggests that triethylsilyl bromide is
formed from triethylsilane and bismuth tribromide and behaves as the
Lewis acid catalyst, see: Bajwa, J. S.; Jiang, X.; Slade, J.; Prasad. K.;
Repic, O.; Blacklock, T. J. Tetrahedron Lett. 2002, 43, 6709.
(14) 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.
(15) In the more demanding reactions outlined in eqs 2 and 3, use of
stoichiometric BiBr3 improved the overall efficiency. This trend is
presumably a function of the ease of desilylation of the tertiary alcohol
(eq 2) and increased rate of the initial intermolecular reaction in the
sequential sequence (eq 3).
(16) The stereochemistry of 5 was established through X-ray crystallographic
analysis of the p-nitrobenzoate derivative formed through reductive
ozonolysis and esterification of the intermediary alcohol.
Encouraged by the preliminary results in Table 2, we also
examined the feasibility of a sequential two-component reaction
that involved an intermolecular addition followed by an intramo-
lecular reductive etherification as outlined in eq 3.15,17 Treatment
of the aldehyde 7 with excess trimethylsilyl enol ether 8 installs
the trans-2,6-disubstituted tetrahydropyran, which upon addition
of triethylsilane facilitates the reductive etherification to afford the
bis-tetrahydropyran 9 in 73% yield with excellent diastereoselec-
tivity (by GLC, eq 3). Hence, this cross-coupling reaction provides
a one-step method for the installation of nonadjacent tetrahydro-
pyran rings having complementary stereochemistry.
In conclusion, we have developed a tandem two-component
etherification reaction for the stereoselective construction of cis-
and trans-2,6-di- and trisubstituted tetrahydropyran rings in which
excellent selectivity could be obtained for either stereoisomer
through the judicious choice of the nucleophile and substrate. This
work also provides compelling evidence for hydrogen bromide and
bismuth oxybromide to be responsible for the catalysis. The
(17) For a related tandem Mukaiyama aldol-Prins cyclization cascade reaction,
see: Kopecky, D. J.; Rychnovsky, S. D. J. Am. Chem. Soc. 2001, 123,
8420.
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