Eu(OTf)3-Catalyzed highly regioselective nucleophilic ring opening of 2,3-epoxy alcohols: An efficient entry to 3-substituted 1,2-diol derivatives

Article abstract of DOI:10.1021/ol502264y

In our study of the total synthesis of (+)-irciniastatin A, we found a need to develop a method that enables a C3-selective nucleophilic ring opening of 2,3-epoxy alcohol by MeOH, by which we found that the use of combined catalytic amounts of Eu(OTf)₃ and 2,6-di-tert-butyl-4-methylpyridine (DTBMP) enables the intended transformation to obtain 3-methoxy-1,2-diol efficiently. Promising features of a protocol that effects a highly regioselective nucleophilic ring opening of 2,3- and 3,4-epoxy alcohols using various nucleophiles including alcohols, thiols, and unprotected amines are described.

Full text of DOI:10.1021/ol502264y

Letter
pubs.acs.org/OrgLett
Eu(OTf)3‑Catalyzed Highly Regioselective Nucleophilic Ring Opening
of 2,3-Epoxy Alcohols: An Efficient Entry to 3‑Substituted 1,2-Diol
Derivatives
Shun-ichiro Uesugi, Tsubasa Watanabe, Takamichi Imaizumi, Masatoshi Shibuya, Naoki Kanoh,
and Yoshiharu Iwabuchi*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Sendai 980-8578, Japan
S
* Supporting Information
ABSTRACT: In our study of the total synthesis of
(+)-irciniastatin A, we found a need to develop a method
that enables a C3-selective nucleophilic ring opening of
2,3-epoxy alcohol by MeOH, by which we found that the use
of combined catalytic amounts of Eu(OTf)3 and 2,6-di-tert-
butyl-4-methylpyridine (DTBMP) enables the intended trans-
formation to obtain 3-methoxy-1,2-diol efficiently. Promising features of a protocol that effects a highly regioselective
nucleophilic ring opening of 2,3- and 3,4-epoxy alcohols using various nucleophiles including alcohols, thiols, and unprotected
amines are described.
strategy employing the asymmetric epoxidation of allylic
We therefore developed an efficient and catalytic protocol to
effect the C3-selective epoxide opening of 2,3-epoxy alcohol
using various nucleophiles. Herein, we report a protocol for
Eu(OTf)3-catalyzed regioselective nucleophilic ring opening of
diverse 2,3-epoxy alcohols and their derivatives using alcohols,
thiols, and amines. This reagent system is also applicable to the
C4-selective epoxide opening of 3,4-epoxy alcohols.
A
alcohols1 followed by the stereoselective modification of an
epoxide product2 provides chemists with a reliable latitude for the
design and synthesis of optically active compounds with multiple
stereogenic centers. The Ti(O-i-Pr)4-mediated nucleophilic ring
opening of the glycidol (2,3-epoxyl alcohol) unit, developed by
Sharpless and co-workers, provides many applications for
realizing a regio- and diastereocontrolled introduction of various
substituents including ethers, esters, amino groups, chalcogens,
and halogens at position C3.3 Some other conditions have also
been reported over the past decades.4−6 However, we have
recently realized that there is still room for developing effective
conditions for this kind of transformation. For example, in our
efforts to realize the total synthesis of (+)-irciniastatin A,7 we were
unable to achieve a C3 epoxide opening of 2,3-epoxy alcohol by
MeOH using the preexisting protocols (Figure 1). In addition,
First, we screened Lewis acid conditions that led to the
C3-selective ring opening of 2,3-epoxy alcohol 1 with MeOH
(Table 1). The treatment of 1 with BF3·OEt2 in MeOH at 0 °C
yielded the desired 1,2-diol 2 and the undesired 1,3-diol 5 in
a 1:1 ratio, indicating that the stereoelectronic requirements for
epoxide opening at C2 and C3 are essentially identical (entry 1).
The Sharpless conditions3 using Ti(O-i-Pr)4 gave an inseparable
3:1 mixture of 2 and 5 in 54% yield after refluxing in MeOH for
5 days (entry 2).9 The unexpectedly slow reaction would be due
tothe formation of Ti(OMe)4 orTi(OMe)n(O-i-Pr)4−n in MeOH,
as indicated by the formation of a white precipitate in the reaction
mixture. The Crotti conditions4 using LiClO4 resulted in low
conversion even after 3 days (entries 3 and 4). In contrast, a
promising reactivity was observed in the case of using 1.2 equiv of
Yb(OTf)3, although the selectivity was moderate (3:1, entry 5).10
We assumed that the generation of the undesired isomer (C2-Nu
isomer) 5 was caused by TfOH, which was generated in small
amounts from Yb(OTf)3 during the reaction. Considering this
hypothesis, several bases for scavenging TfOH were examined,
and the addition of 1.0 equiv of 2,6-di-tert-butyl-4-methylpyridine
(DTBMP) was found to improve the regioselectivity (>20:1,
entry 6). We then sought for the optimal catalytic conditions.
Decreasing the amount of Yb(OTf)3 to 30 mol % required an
Figure 1. Outline of our synthesis of (+)-irciniastatin A.
literature survey revealed that most of the reported methods
require stoichiometric amounts of Lewis acids to achieve
regioselective ring opening, and thus, an effective catalytic
method is desired.8
Received: June 25, 2014
© XXXX American Chemical Society
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Organic Letters
Letter
Table 1. Optimization of Regioselective Ring-Opening
Reaction of Epoxy Alcohol 1
Table 3. Regioselective Ring-Opening Reactions of Epoxy
Alcohol Derivatives with MeOH
a
b
Combined yields of the isolated C3 and C2 regioisomers. All ratios
1
were determined by H spectroscopy.
Table 2. Regioselective Ring-Opening Reactions of 2,3-Epoxy
Alcohol Derivatives with MeOH
a
b
20 mol % Eu(OTf)3/DTBMP was used. 10 mol % Eu(OTf)3/
c
DTBMP was used. 5 mol % Eu(OTf)3/DTBMP was used.
d
e
f
Selectivity of C4/C3 regioisomer. No reaction. Not determined.
a
Not determined.
Encouraged by the high reactivity and regioselectivity of
the Eu(OTf)3-catalyzed, DTBMP-assisted epoxide ring opening
reaction with MeOH, we examined the compatibility of this
catalytic system using protected 2,3-epoxy-1-hexanols 6b−f
(Table 2). Fortunately, methyl-, MOM-, and PMB-protected
substrates gave the corresponding C3-methoxylated pro-
ducts as the sole detectable products.11 However, TBS- and
Ac-protected substrates resulted in the detachment of the
increase in the reaction temperature to reflux for completion
and reduced the regioselectivity (8.3:1, entry 7). Further
screening of lanthanoid triflates eventually led to the identifica-
tion of Eu(OTf)3 as the ideal catalyst for this particular substrate
(entries 8−11).
B
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Letter
Table 4. Ring-Opening Reactions with Various Alcohol/Thiol
Nucleophiles
Table 5. Ring-Opening Reactions with Various Amine
Nucleophiles
a
b
20 mol % Eu(OTf)3/DTBMP was used. 5 mol % Eu(OTf)3/
c
DTBMP was used. 5 equiv of NuH was added. (Toluene was used as
the solvent.)
protecting group together with nucleophilic ring opening
(entries 5 and 6).
Next, we explored the scope and limitations of the catalytic
system using various epoxy alcohols (Table 3). cis-2,3-Epoxy
alcohol 9a gave the corresponding C3 adduct 10a with sufficient
regioselectivity of 12:1. Interestingly, the PMB-protected cis-
epoxide 9b showed higher regioselectivity (entry 2). Importantly,
this method was also found to be applicable to the trisubstituted
epoxides 9c and 9d to provide the corresponding C3-methoxylated
products 10c and 10d, respectively (entries 3 and 4). The sub-
strate 9e with an alkyne moiety provided moderate C3 selectivity
(entry 5). Note that the catalytic system could be used for the
C4-selective opening of 3,4-epoxy alcohols: 3,4-epoxy-1-alcohols 9f
and 9g, respectively, gave 10f and 10g in good yields with sufficient
C4 regioselectivities (entries 6 and 7). Various cyclic substrates
were found to undergo a C3-selective nucleophilic ring opening
with high regioselectivity (entries 9−12). Cyclic cis-epoxy alcohols
gave the corresponding C3 adducts, whereas anti-epoxy alcohol 9m
was recovered unreacted (entry 13).
After screening the reaction with MeOH, we became interested
in the regioselective epoxide ring opening reaction using other
nucleophiles. We thus explored the scope of the reaction using
other solvents (Table 4). We confirmed that various alcohols
attack at the C3 position with high regioselectivity (entries 1−5).
In addition, thiol nucleophiles can also be used with high
regioselectivity (entries 6 and 7). It should be stressed that these
nucleophiles can be applied not only as solvents but also as
reagents at several equivalents.
a
b
20 mol % Eu(OTf)3 was used. 10 mol % Eu(OTf)3 was used in
c
toluene (0.5 M). The ratio was determined after Boc protection.
d
The ratio was determined after acetylation.
nucleophile were successfully employed to achieve excellent
yields and regioselectivities, even at room temperature (entries
1−4). Note that the addition of DTBMP is not necessary
in the case of amine nucleophiles.12 Moreover, the use of some
aliphatic amines as nucleophiles resulted in the formation
of the corresponding 3-amino-1,2-diols with good selectivity
(entries 5−7). These results strongly indicate that this method
can be applied to the synthesis of nitrogen-containing natural
products.
In summary, we have developed a highly stereo- and
regioselective ring-opening reaction of epoxy alcohols and their
derivatives using catalytic amounts of Eu(OTf)3 and DTBMP.
This method has the following advantages: (1) excellent regio-
selectivities are achieved with various epoxides, including
unprotected and protected 2,3-epoxy alcohols, 3,4-epoxy alcohols,
and cyclic epoxy alcohols; (2) various O-, S-, and N-nucleophiles
can be used; (3) the reaction conditions are not sensitive to water
or air; (4) the reaction is induced using commercially available
europium salt. The present protocol can therefore be widely
applied to the synthesis of complex molecules with continuous
stereocenters.
Furthermore, we found that various amines can be used as
nucleophiles for the system (Table 5). Some types of aniline
C
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Letter
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: y-iwabuchi@m.tohoku.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partly supported by the Ministry of Education,
Culture, Sports, Science and Technology, Japan (MEXT)
Platform for Drug Discovery, Informatics, and Structural Life
Science, and a Grant-in-Aid for Scientific Research on Innovative
Areas “Advanced Molecular Transformations by Organocatalysis.”
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