P.-P. Guo, K. Ding / Tetrahedron Letters 56 (2015) 4096–4100
4097
OSO2C4F9
tolerated in the methodology to offer trifluoroacetate ester 9 in
OH
moderate yield. The reaction with water as nucleophile took
DBU, C4F9SO2F
toluene,0°C
place and directly offered 17-
low yield.
a-hydroxyl product 10, albeit in
BzO
96%
BzO
We next examined the substrate scope (Table 3). The pure sul-
fonyl esters were separated and reacted with nucleophiles accord-
ing to the procedure described above. All 17b-hydroxy steroids
performed well in both the sulfonylation and substitution steps.
The unstable enol ethers could be incorporated owing to the mild
reaction condition (entry 3). Notably, although a stoichiometric
amount of fluoride salt formed during the sulfonylation, silyl-pro-
tected substrate was insusceptible (entry 4). The non-steroid sub-
strate derived from Hajos–Parrish ketone was tolerated, affording
product 21 in high yield (entry 5). However, the sulfonic esters
of Wieland–Miescher ketone, 3-hydroxy steroid, and 11-hydroxy
steroid were found to be very unstable (entries 6–8), thereby
resulting in deoxyfluorination and elimination side reaction9 prior
to the separation.
5
4
Scheme 1. Preparation of perfluoroalkylsulfonyl ester.
filtration through a short silica gel column to offer pure ester 5 in
high yield (Scheme 1).7
With the perfluoroalkylsulfonyl ester 5 in hand, we turned our
attention to the subsequent inversion reaction. Recently Shi
reported the tunable complex of organic base and carboxyl acid
was highly efficient nucleophiles for the SN2 substitution of
mesyl
ester.5a
As
expected,
the
reaction
rate
of
perfluoroalkylsulfonyl ester was dramatically faster than that of
mesyl ester (0.5 h vs 9 h, Table 1, entry 1), albeit with
significant amount of
rearrangement and elimination
The method was proved to be reliable for large-scale prepara-
byproducts. When more base was used, the byproducts were
decreased at the expense of partial hydrolysis of product (entry
2). Further study indicated that the low temperature
suppressed the deprotection (entries 3–6). Notably, the reaction
performed well even at room temperature (entry 6). The
solvent effect was then investigated, and toluene, THF, and
ethyl acetate was revealed to be the best solvent of choice
(entries 7–12). The amount of acid and base can be reduced
without a significant decrease of yield and rate (entries 13–15).
However, attempts to replace DBU with Et3N or inorganic bases
were unsuccessful (entries 16–18).
Encouraged by the initial findings, we set out to explore the
nucleophile scope (Table 2). Acetic acid and benzoic acid as
nucleophiles gave desired products in good yield. Formic acid,
an unusual nucleophile, smoothly provided desired ester 8 in
good yield (entry 3). Surprisingly, trifluoroacetic acid was
tion of valuable 17a-hydroxy steroids (Scheme 2). The conven-
tional synthesis of 17b-estradiol 3-benzoate 10 from
commercially available 4 was laborious because the attempts to
obtain benzoate ester 10 from acetate ester 6 in one step were
unsuccessful.10 The substitution of sulfonic ester 22 with HCOOH
or CF3COOH as nucleophiles led to low yield (<30%). With perfluo-
roalkylsulfonyl fluoride as activating agent, alcohol 4 was con-
verted into 17a-formate 8 on multigram scale, and subsequent
selective deprotection produced 17-
a-estradiol 3-benzoate 10 (3
steps, 75% yield).
In summary, our study demonstrates that perfluoroalkylsul-
fonyl fluoride is an efficient hydroxyl activating agent for SN2-type
substitution. Notably, the procedure is rapid and can be carried out
under mild condition with broad scope of nucleophiles. Further
efforts to expand this strategy to other interesting substrates are
underway in our laboratory.
Table 1
Optimization of reaction condition
OAc
OSO2C4F9
DBU, AcOH
OAc
HO
BzO
BzO
10
6
6x
Entrya
Nucleophile (equiv)
Solvent
Temp (°C)
Time (h)
Yieldb,c (%)
1
2
3
4
5
6
7
8
9
10
11
12
13d
14
15
16
17
18
DBU–AcOH(3:6)
DBU–AcOH(6:6)
DBU–AcOH(6:6)
DBU–AcOH(6:6)
DBU–AcOH(6:6)
DBU–AcOH(6:6)
DBU–AcOH(6:6)
DBU–AcOH(6:6)
DBU–AcOH(6:6)
DBU–AcOH(6:6)
DBU–AcOH(6:6)
DBU–AcOH(6:6)
DBU–AcOH(4:4)
DBU–AcOH(3:3)
DBU–AcOH(2:2)
Et3N–AcOH(4:4)
NaOAc(4)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
100
100
80
60
40
25
40
40
40
40
40
40
40
40
40
40
40
40
0.5
0.5
0.5
0.5
0.5
2
0.5
0.5
1
0.5
0.5
5
0.5
1
60
66(13)
75(6)
85
84
84
81
80
72
70
62
31
83
83
79
30
2
9
EA
CH2Cl2
Acetone
MeCN
DMSO
Toluene
Toluene
Toluene
Toluene
DMSO
2.5
11
0.5
0.5
KOAc(4)
DMSO
a
b
c
Substrate (0.05 mmol), solvent (0.5 mL).
NMR yield.
Yield of byproduct 6x in brackets. EA = ethyl acetate.
d
Optimized reaction condition.