Published on Web 04/21/2005
One-Pot Regio- and Stereoselective Cyclization of 1,2,n-Triols
Tao Zheng, Radha S. Narayan, Jennifer M. Schomaker, and Babak Borhan*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
Received November 19, 2004; E-mail: borhan@cem.msu.edu
Table 1. One-Pot Cyclization of trans-1,4,5-Decanetriol with
Various Acid Promoters
Substituted tetrahydrofurans and tetrahydropyrans represent
versatile synthetic building blocks in a variety of natural products,
such as polyether antibiotics and annonaceous acetogenins.1,2 The
Lewis acid-catalyzed intramolecular ring-opening of epoxides by
alcohols is one of the most popular methods to construct cyclic
ethers in an efficient and stereocontrolled manner.3,4 Although the
necessary epoxide substrates can be delivered with a variety of well-
established methods, including the Sharpless asymmetric epoxida-
tion5 and the Jacobsen-Katsuki6 and Shi epoxidations,7 the struc-
tural requirements of the parent olefin can limit synthetic strategy.
Compared to asymmetric epoxidations, the well-defined Sharp-
less asymmetric dihydroxylation is less limited in its choice of
substrates. Since its inception,8 substantial progress has been attained
in the development of ligands for the SAD that generate high levels
of enantioselectivity from unfunctionalized olefins of various sub-
stitution patterns.9 However, to utilize the chirality induced by the
Sharpless asymmetric dihydroxylation in intramolecular cyclizations
to generate cyclic ethers, the diol often needs to be converted to
an epoxide or reactive equivalent,10,11 such as a cyclic sulfate.12-14
Noteworthy is the method developed by Kolb and Sharpless in
which vicinal diols are converted to their corresponding epoxides
via the use of a cyclic ortho ester.15 However, these conversions
are often multistep and/or intolerant of certain functional groups.
We have effectively addressed these shortcomings by the develop-
ment of a mild, convenient, one-pot method to access cyclic ethers
directly from 1,2,n-triols via the intermediacy of a cyclic ortho ester.
As depicted in the scheme in Table 1, the overall strategy depends
on the in situ generation of an ortho ester (3) via transortho esterifi-
cation of trimethyl orthoacetate with a 1,2-diol (1a). The subsequent
ionization of the intermediate ortho ester with a Lewis acid leads
to a reactive acetoxonium species (4), which upon intramolecular
displacement with the pendant hydroxyl yields the cyclized ether
(2a). A short list of Lewis acids screened to effect the cyclization
employing trans-decane-1,4,5-triol 1a is provided in Table 1. We
were pleased to find that after treatment of 1a with 1.2 equiv of
trimethyl orthoacetate and a catalytic amount of PPTS (0.1 equiv)
in dichloromethane, followed by addition of 0.1 equiv of BF3‚Et2O,
the cyclization proceeded to deliver product 2a as a single
diastereomer in excellent yield (entry 5). Other Lewis acids screened
also delivered the desired 2a, albeit in lower yields (Table 1).
A variety of 1,2,n-triols were synthesized and subjected to the
one-pot cyclization reaction (Table 2). The following details are
noteworthy: (1) The substitution pattern of the nucleophilic hy-
droxyl did not affect the efficiency and stereoselectivity of the reac-
tion. Substrates with a primary, secondary, or tertiary hydroxyl
group all afforded good yields of the desired product (entries 1-7,
Table 2). An exception was the use of a tertiary cyclic alcohol to
generate a spiro compound, which was unsuccessful (data not shown).
Moving the nucleophilic alcohol one carbon away from the pro-
spiro center (entry 9) again resulted in successful generation of the
cyclic ether. (2) Comparable results were obtained for syn and anti
vicinal diols (entries 1 and 2). (3) Bicyclic structures can be obtained
(entries 8-11). It is noteworthy that triol 1j yielded the six-member
entry
LA
equiv
time
temp
% yielda
1
2
3
4
5
AcCl
AlMe3
TMSCl
TMSOTf
BF3‚Et2O
1.2
1.0
1.2
1.2
0.1
5 min
12 h
1 h
5 min
1 h
0 °C
rt
0 °C
0 °C
0 °C
0
12
72
91
99
a Yields are based on GC analysis.
ring product 2j instead of the expected tetrahydrofuran. This is most
likely due to the reversibility in the ring-opening of the anticipated
five-member ring product afforded by the presence of the aryl group
that eventually leads to the production of the more thermodynami-
cally stable six-member ring. (4) Partially deacetylated products
were observed along with the desired product in some cases (entries
6, 11, and 15), possibly as a result of transesterification of the acetate
with the methanol generated during the course of the reaction.
The aromatic substituted 1,2,5-triol 1l gave mixtures of the tetra-
hydrofuran 2l and tetrahydropyran 5l products. Presumably, the
stability of the intermediate carbocation allows nucleophilic attack
at the benzylic position (forming a six-member ring) to compete
with the expected 5-exo process leading to the five-member ring
product. Evidence for this supposition was obtained via the one-
pot cyclization of triols 1n and 1o, which contain electron-donating
and electron-withdrawing aromatic groups, respectively. As antici-
pated, the p-methoxyaryl group in 1n led to the formation of
tetrahydropyran products 2n and 5n, exclusively, in contrast to the
reaction of 1o, which yielded only tetrahydrofuran 2o. The forma-
tion of the epimeric 2n also points to the stable carbocationic nature
of the intermediate; in fact, treatment of a pure sample of 2n or 5n
with BF3‚Et2O gave isomerization to a mixture of 2n and 5n in a
similar ratio observed for cyclization of 1n. Interestingly, cyclization
of triol 1m (epimer of 1l) yielded the six-member ring product 2m,
exclusively. A possible explanation is illustrated in Scheme 1. The
phenyl group in the anti triol 1l is axially juxtaposed in the putative
transition state. Presumably, the increased steric repulsion coun-
terbalances the greater carbocation stability at the benzylic position
and thus leads to two pathways yielding a mixture of five- and
six-member ring products. On the other hand, the syn triol 1m
would have its aryl group situated equatorially in the transition state,
therefore, enjoying both steric relief and electronic stability, which
results in the formation of only the six-member ring product.
Five- and six-member cyclic ethers were also produced from
1,2,4- and 1,2,6-triols in good yields using our one-pot process
9
6946
J. AM. CHEM. SOC. 2005, 127, 6946-6947
10.1021/ja043002i CCC: $30.25 © 2005 American Chemical Society
Zheng, Tao
