The C2 selective nucleophilic substitution reactions of 2,3-epoxy alcohols mediated by trialkyl borates: The first endo-mode epoxide-opening reaction through an intramolecular metal chelate

Article abstract of DOI:10.1021/ol034455f

(Matrix presented) Highly efficient C2 selective substitution reactions of 2,3-epoxy alcohols with nucleophiles were developed by using NaN ₃-(CH₃O)₃B, NaSPh-(CH₃O) ₃B, or NaCN-(C₂H₅

Full text of DOI:10.1021/ol034455f

ORGANIC
LETTERS
2003
Vol. 5, No. 10
1789-1791
The C2 Selective Nucleophilic
Substitution Reactions of 2,3-Epoxy
Alcohols Mediated by Trialkyl Borates:
The First endo-Mode Epoxide-Opening
Reaction through an Intramolecular
Metal Chelate
Minoru Sasaki, Keiji Tanino, Atsushi Hirai, and Masaaki Miyashita*
DiVision of Chemistry, Graduate School of Science, Hokkaido UniVersity,
Sapporo 060-0810, Japan
miyasita@sci.hokudai,ac.jp
Received March 15, 2003
ABSTRACT
Highly efficient C2 selective substitution reactions of 2,3-epoxy alcohols with nucleophiles were developed by using NaN −(CH O)3B, NaSPh−
3
3
(CH O)3B, or NaCN−(C H O)3B system. The reaction proceeds through novel endo-mode epoxide opening of an intramolecular boron chelate,
3
2 5
which was suggested from both experimental and quantum mechanic studies.
Since the discovery of the Katsuki-Sharpless asymmetric
epoxidation in 1980,1 reactions of 2,3-epoxy alcohols with
various nucleophiles2 have been extensively studied in the
context with the chiral synthesis of biologically important
natural compounds. The utility of this type of reaction is
dependent on its regioselectivity, and the C3 selective
substitution reactions via an intramolecular metal chelate
(Figure 1, path a) have been widely used in organic
synthesis.3-5 On the contrary, it has been known that the C2
selective substitution reaction of a 2,3-epoxy alcohol is
extremely difficult, despite its synthetic importance,6 although
a few particular cases with use of steric and/or electronic
bias have been reported.7
(1) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974-
5976. (b) Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1-299.
(2) (a) Caron, M.; Sharpless, K. B. J. Org. Chem. 1985, 50, 1560-1563.
(b) Hanson, R. M. Chem. ReV. 1991, 91, 437-475.
Figure 1. The pathways of the reactions of a 2,3-epoxy alcohol
with nucleophiles.
(3) For C3 selective reactions with azide ion equivalents. (a) Maruoka,
K.; Sano, H.; Yamomoto, H. Chem. Lett. 1985, 599-602. (b) Onaka, M.;
Sugita, K.; Izumi, Y. Chem. Lett. 1986, 1327-1328. (c) Caron, M.; Carlier,
P. R.; Sharpless, K. B. J. Org. Chem. 1988, 53, 5187-5189. (d) Benedetti,
F.; Berit, F.; Norbedo, S. Tetrahedron Lett. 1998, 39, 7971-7974. (e)
Martin, R.; Islas, G.; Moyano, A.; Pericas, M. A.; Riera, A. Tetrahedron.
2001, 57, 6367-6374. See also ref 2.
Recently, we have reported that the combined use of NaN3
and PhB(OH)2 effected the C2 azide substitution reaction
of a trans-2,3-epoxy alcohol,8 which was originally designed
10.1021/ol034455f CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/17/2003

by assuming an intramolecular ate complex (Figure 1, path
b), the same as the reactions of an epoxy alcohol with Red-
Al9 or organocopper reagents.6a-d The synthetic potential of
the reaction prompted us to investigate the boron-induced
substitution reaction in detail. We now report the new
findings that the boron-mediated substitution reaction of 2,3-
epoxy alcohols proceeds via an intramolecular boron chelate
through an unprecedented endo-mode epoxide opening with
extremely high C2 selectivity (Figure 1, path c).
The exceptionally high C2 selectivity exhibited by the
(CH3O)3B-NaN3 system led us to examine the scope of the
boron-mediated substitution reaction (Tables 2 and 3). The
reactions of trans-epoxy alcohols 2 and 3 with NaN3, NaSPh,
or NaCN produced the corresponding C2 substitution
products with extremely high regioselectivity (>92:8) and
chemical yields, respectively (Table 2, entries 1-6).
Initially, the reactions of trans-2,3-epoxy-1-hexanol (1)
with several reagents were examined to compare the regi-
oselectivity (Table 1).
Table 2. Substitution Reactions of trans-Epoxy Alcohols
entry
epoxide (R)
X
C2:C3
yield,d
%
Table 1. Substitution Reaction of trans-2,3-Epoxyhexanol
1a
2b
3c
4a
5b
6c
7b
8c
2 (BnOCH2)
N3
92:8
95:5
92:8
92:8
95:5
93:7
85:15
84:16
96
97
96
99
98
89
97
83
SPh
CN
N3
SPh
CN
SPh
CN
3 (TBSOCH2)
1 (nPr)
entry
reagents
X
C2:C3
yield,e %
1a
2b
3c
4d
NaN3, (CH3O)3B
NaN3,NH4Cl
Ti(OiPr)2(N3)2
Me2CuLi
N3
N3
N3
Me
82:18
15:85
3:97
97
95
88
93
a With 2 equiv of NaN3 and 1.5 equiv of (CH3O)3B at 50 °C. b With 1.5
41:59
c
equiv of NaSPh and 1.3 equiv of (CH3O)3B at room temperature. With
a The reaction was carried out in DMF at 50 °C. b Reference 2.
c Reference 3c. d The reaction was carried out in ether at -30 °C.
e Combined isolated yield.
4 equiv of NaCN and 3 equiv of (C2H5O)3B at 70 °C. d Combined isolated
yield.
Similarly, the trans-epoxy alcohol 1 having no particular
oxygen function on the side chain produced the C2-
substitution products predominantly (Table 2, entries 7 and
8). These results unambiguously demonstrate that the boron-
mediated substitution reaction of trans-epoxy alcohols gener-
ally occurs at the C2 position with high regioselectivity,
whereas the reactions of cis-epoxy analogues were far more
sluggish and resulted in decreased regioselectivity (Table 3).
Use of a new combination (CH3O)3B-NaN3 instead of
the previous system (PhB(OH)2-NaN3) was found to
enhance both the reaction rate and the regioselectivity, and
an 82:18 mixture of the azido diols was obtained in
quantitative yield (entry 1). The remarkable C2 selectivity
of the boron-mediated substitution reaction is apparent in
comparison with that of conventional azide substitution
reactions3 (entries 2 and 3). It should be noted that even the
reaction of 1 with the Gilman reagent, which would involve
an ate complex intermediate (Figure 1, path b), does not
proceed regioselectively (entry 4).
Table 3. Substitution Reactions of cis-Epoxy Alcohols.
(4) For a C3 selective reaction with a thiolate ion equivalent: Onaka,
M.; Sugita, K.; Takeuti, H.; Izumi, Y. J. Chem. Soc., Chem. Commun. 1988,
1173-1174. See also ref 2.
(5) For C3 selective reactions with carbon nucleophiles. (a) Suzuki, T.;
Saimoto, H.; Tomioka, H.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1982,
23, 3597-3600. (b) Roush, W. R.; Adam, M. A.; Peseckis, S. M.
Tetrahedron Lett. 1983, 24, 1377-1380. (c) Takatsuto, S.; Yazawa, N.;
Ishiguro, M.; Morisaki, M.; Ikekawa, N. J. Chem. Soc., Perkin Trans. 1
1984, 139-146.
entry
epoxide (R)
X
C2:C3
yield,c %
1a
2b
3a
4b
4 (BnOCH2)
N3
SPh
N3
73:27
76:24
31:69
48:52
96
90
89
85
5 (nPr)
SPh
(6) For C2 selective reactions with carbon nucleophiles. (a) Johnson,
M. R.; Nakata, T.; Kishi, Y. Tetrahedron Lett. 1979, 20, 4343-4346. (b)
Tius, M. A.; Fauq, A. H. J. Org. Chem. 1983, 48, 4131-4132. (c) Chong,
J. M.; Cyr, D. R.; Mar, E. K. Tetrahedron Lett. 1987, 28, 5009-5012. (d)
Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135-631. (e) Sasaki,
M.; Tanino, K.; Miyashita, M. Org. Lett. 2001, 3, 1765-1767.
(7) (a) Behrens, C. H.; Sharpless, K. B. J. Org. Chem. 1985, 50, 5696-
5704. (b) Chakraborty, T. K.; Reddy, G. V. Tetrahedron Lett. 1991, 32,
679-682.
a With 3 equiv of NaN3 and 3.5 equiv of (CH3O)3B at 50 °C. b With 1.5
equiv of NaSPh and 1.3 equiv of (CH3O)3B at room temperature.
c Combined isolated yield.
In turn, we focused on the mechanism of the present
boron-induced substitution reactions. Contrary to our as-
sumption involving the ate complex intermediate (Figure 2,
B), the transition structures proposed by calculation strongly
suggested the intermediary of an intramolecular boron chelate
(C).
(8) Hayakawa, H.; Okada, N.; Miyazawa, M.; Miyashita, M. Tetrahedron
Lett. 1999, 40, 4589-4592.
(9) (a) Ma, P.; Martin, V, S.; Masamune, S.; Sharpless, K. B.; Viti, S,
M. J. Org. Chem. 1982, 47, 1378-1380. (b) Finan, J. M.; Kishi, Y.
Tetrahedron Lett. 1982, 23, 2719-2722. (c) Viti, S. M. Tetrahedron Lett.
1982, 23, 4541-4544.
1790
Org. Lett., Vol. 5, No. 10, 2003

contrary, if the reaction proceeds under chelation control
(path c), syn-6 would react faster than anti-6 with higher
selectivity because of severe steric hindrance between the
methyl and a nucleophile in the latter.
Indeed, the reaction of anti-6 with Me2CuLi gave the C2
substitution product predominantly (Table 4, entry 2), while
Table 4. Substitution Reactions of syn-6 and anti-6
entry
epoxide
reagents
Me2CuLi
Me2CuLi
NaN3, (CH3O)3B
NaN3, (CH3O)3B
X
C2:C3
yield,c %
1a
2a
3b
4b
syn-6
anti-6
syn-6
anti-6
Me
Me
N3
N3
50:50
79:21
89:11
46:54
76
83
92
30d
a The reaction was carried out in ether at -30 °C. b The reaction was
carried out in DMF at 50 °C. c Combined isolated yield of the isomers.
d Ca. 70% of anti-6 was recovered.
Figure 2. Optimized transition structures of boron-mediated
substitution reactions of trans-2,3-epoxybutanol and azide ion.10
Bond lengths are shown in Å. Energies relative to C are shown in
brackets.
syn-6 afforded a 1:1 mixture of regioisomers in lower yield.
These outcomes are consistent with the reaction mechanism
involving an ate complex intermediate. On the other hand,
the reaction of syn-6 with (CH3O)3B-NaN3 produced the
C2 substitution product with high regioselectivity and
chemical yield (entry 3), whereas the reaction of anti-6 under
the same conditions resulted in the formation of an almost
equal amount of regioisomers in poor yield (entry 4). These
results clearly demonstrate that the boron-induced substitution
reaction of epoxy alcohols does proceed via a novel endo-
mode epoxide opening of an intramolecular boron chelate
(path c).
Since this type of substitution reaction has never been
reported, we designed two epoxy alcohols syn-6 and anti-6
as probes to discriminate between the two reaction mecha-
nisms (Figure 3). In the case of the reaction involving an
In conclusion, we have realized the first C2 selective
substitution reactions of epoxy alcohols with nucleophiles
which proceed through novel endo-mode epoxide opening
of intramolecular boron chelates with extremely high selec-
tivity. The boron-induced substitution reaction of epoxy
alcohols should provide a powerful methodology in organic
synthesis, including natural product synthesis.
Acknowledgment. Financial support from the Ministry
of Education, Science, Sports and Culture of Japan through
a Grant-in-Aid for Scientific Research (A) (No. 12304042),
a Grant-in-Aid for Scientific Research on Priority Areas (A)
Exploitation of Multi-Element Cyclic Molecules (No.
13029003), and a Grant-in-Aid for Spraut Research (No.
14654138).
Figure 3. A probe to discriminate between the two reaction
mechanisms.
Supporting Information Available: Spectroscopic data,
experimental details, and Cartesian coordinates of transition
structures A-C at the B3LYP/6-31G*//HF/3-21G level. This
material is available free of charge via the Internet at
http://pubs.acs.org.
ate complex intermediate (path b), syn-6 would exhibit lower
reactivity and selectivity than anti-6 owing to steric repulsion
between the methyl group and the epoxide ring. On the
(10) Calculations were performed with the GAUSSIAN 98 program at
the B3LYP/6-31G*//HF/3-21G level. For details, see the Supporting
Information.
OL034455F
Org. Lett., Vol. 5, No. 10, 2003
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