Synthetic studies on thiostrepton family of peptide antibiotics: Synthesis of the dihydroquinoline portion of thiostrepton, the siomycins, and the thiopeptins

Article abstract of DOI:10.1016/j.tetlet.2005.07.121

Synthesis of the dihydroquinoline portion of thiostrepton, the siomycins, and the thiopeptins, members of the thiostrepton family of peptide antibiotics, has been achieved featuring the one-pot olefination via the Matsumura- Boekelheide rearrangement "using trifluoromethanesulfonic anhydride and triethylamine" and the stereoselective addition reaction controlled by the stereocenter of the peri-position.

Full text of DOI:10.1016/j.tetlet.2005.07.121

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6417–6422
Synthetic studies on thiostrepton family of peptide
antibiotics: synthesis of the dihydroquinoline portion of
thiostrepton, the siomycins, and the thiopeptins
Tomonori Mori, Yukiko Satouchi, Hiraku Tohmiya, Shuhei Higashibayashi,ꢀ
Kimiko Hashimoto*,ꢁ and Masaya Nakata*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku,
Yokohama 223-8522, Japan
Received 5 July 2005; revised 21 July 2005; accepted 25 July 2005
Abstract—Synthesis of the dihydroquinoline portion of thiostrepton, the siomycins, and the thiopeptins, members of the thiostrep-
ton family of peptide antibiotics, has been achieved featuring the one-pot olefination via the Matsumura–Boekelheide rearrange-
ment ‘‘using trifluoromethanesulfonic anhydride and triethylamine’’ and the stereoselective addition reaction controlled by the
stereocenter of the peri-position.
ꢀ 2005 Elsevier Ltd. All rights reserved.
We have recently reported the synthesis of the dehydro-
piperidine,1 dihydroquinoline,2 and pentapeptide3 seg-
ments (1, 2, and 3, respectively) of the thiostrepton
family of peptide antibiotics (Fig. 1).4–6 Compound 2
having the hydroxymethyl group is, however, the di-
hydroquinoline portion of only siomycin D1. In this
letter, we report the synthesis of the hydroxyethyl-bear-
ing dihydroquinoline segment 4 of the more popular
thiostrepton family of peptide antibiotics (e.g., thio-
strepton, siomycins A and C, and thiopeptin A1b,
Fig. 1) via two different synthetic routes for the con-
struction of the asymmetric center attached by the
methyl group: the stereoselective addition of the methyl
group to the aldehyde function and the stereoselective
reduction of the methyl ketone function. In addition,
we developed a one-pot procedure using trifluoro-
methanesulfonic anhydride (Tf2O) and triethylamine to
introduce the olefin function into the C7–C8 position
of the 5,6,7,8-tetrahydroquinoline derivative via the
Matsumura–Boekelheide rearrangement. In the follow-
ing letter,7 we report the synthesis of the siomycin cyclic
core portion containing the dehydropiperidine, dihydro-
quinoline (i.e., 4), L-valine, and masked dehydroalanine
(i.e., b-phenylselenoalanine) segments.
We have previously synthesized the dihydroquinoline
segment 2 of siomycin D1 from 5,6,7,8-tetrahydroquino-
line (5) featuring the modified Reissert–Henze reaction
(5!6), the radical heteroaromatic substitution reaction
(6!7), the Boekelheide rearrangement (7!8), and the
Jacobsen asymmetric epoxidation (8!9) as the key steps
(Scheme 1).2 The intermediate aldehyde 9 (91% ee) was
the starting substance for our first route. After a variety
of unsuccessful experiments, the best conditions so far to
introduce the methyl group to aldehyde 9 were as fol-
lows (Scheme 2). MeMgBr/Et2O (1.1 equiv, 3 M) was
added at ꢀ78 ꢁC to a solution of 9 (1.0 equiv) and
HMPA (1.1 equiv) in toluene. After 0.5 h at ꢀ78 ꢁC,
the desired addition product 10 was obtained in 48%
yield together with the undesired stereoisomer 11
(15%) and the recovered 9 (20%). The configuration of
the newly formed chiral center in 10 was determined
by the transformation of 10 into the quinoline derivative
12,8 which was identical to the degradation product
derived from thiostrepton9 and siomycin A.10 The configu-
ration at the C5 position in 9 plays a key role in the
Keywords: Thiostrepton; Siomycins; Dihydroquinoline; Matsumura–
Boekelheide rearrangement; Stereoselective addition.
*
Corresponding authors. Tel.: +81 45 566 1577; fax: +81 45 566 1551
(M.N.); tel.: +81 75 595 4673; fax: +81 75 595 4763 (K.H.); e-mail
addresses: kimikoh@mb.kyoto-phu.ac.jp; msynktxa@applc.keio.ac.jp
ꢀ Present address: Research Center for Molecular-Scale Nanoscience,
Institute for Molecular Science, Okazaki 444-8787, Japan.
ꢁ Present address: Kyoto Pharmaceutical University, 1 Shichono-cho,
Misasagi, Yamashina-ku, Kyoto 607-8412, Japan.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.121

6418
T. Mori et al. / Tetrahedron Letters 46 (2005) 6417–6422
O
O
O
H
OEt
S
N
N
H
R6
N
O
S
O
H
N
N
O
NHBoc
O
O
S
R3
R2
N
H
N
H
O
N
N
H
S
N
N
H
MeO
O
N
H
H
N
O
HN
OH
O
H
H
N
H
R1
H
O
N
OEt
S
OH
O
H
H
O
NH
H
S
HO
2
H
1
N
NH
H
H
BocN
O
O
H
R5
N
NH
HN
O
S
R4
H
O
NTeoc
H
HO
H
N
H
HN
O
N
S
O
O
N
OEt
N
H
H
O
S
t-BuO
O
HO
H
OH
H
N
N
S
TBSO
4
Thiostrepton: R1 = CH2CH3, R2 = CH3, R3 = H, R4 = CH3, R5 = O, R6 = NH2
H
H
H
O
Siomycin A: R1 = CH3, R2 = R3 = CH2 (dehydroalanine), R4 = CH3, R5 = O, R6 = NH2
Siomycin C: R1 = CH3, R2 = R3 = CH2 (dehydroalanine), R4 = CH3, R5 = O, R6 = OMe
Siomycin D1: R1 = CH3, R2 = R3 = CH2 (dehydroalanine), R4 = H, R5 = O, R6 = NH2
Thiopeptin A1b: R1 = CH3, R2 = CH3, R3 = H, R4 = CH3, R5 = S, R6 = OMe
TESO
H
OTES
3
Teoc = 2-(trimethylsilyl)ethoxycarbonyl
TES = triethylsilyl
Figure 1.
O
O
the modified
Reissert-Henze
reaction
O
O
O
N
N
N
N
a
MeO
MeO
MeO
5
CHO Br
9 (91% ee)
Br
5
6
HO
H
10
radical heteroaromatic
substitution
b,c,d
+
O
O
O
OMe
N
O
N
N
O
MeO
MeO
N
MeO
MeO
the Boekelheide
rearrangement
MeO
O
MeO
O
H Br
HO
H
HO
8
7
12
11
asymmetric
epoxidation
Scheme 2. Synthesis of 10. Reagents and conditions: (a) 3 M MeMg-
Br/Et2O (1.1 equiv), HMPA (1.1 equiv), toluene, ꢀ78 ꢁC, 0.5 h, 48%
of 10, 15% of 11, 20% of 9; (b) DBU (3.0 equiv), THF, rt, 1 h; (c) 1 M
aq HCl, rt, 6 h; (d) CH2N2, MeOH, rt, 1 h, 83% (three steps).
HMPA = hexamethylphosphoric triamide, DBU = 1,8-diazabicyclo-
[5.4.0]undec-7-ene.
O
O
N
N
2 steps
MeO
MeO
CHO Br
HO
9 (91% ee)
2
yield (Scheme 3), which was oxidized to N-oxide 14 with
MCPBA in 88% yield. According to our reported proce-
dure,2 N-oxide 14 was next subjected to the Boekelheide
rearrangement12 with trifluoroacetic anhydride (TFAA)
followed by hydrolysis of the resulting trifluoroacetate
15 in one pot with sodium methoxide to afford 16 in
52% yield. We expected that under the non-protic condi-
tions, the olefin function would be directly introduced
into the C7–C8 position. It was found that the one-pot
treatment of 15 with DBU (3 equiv) at rt for 20 min
afforded the elimination product 17 albeit in low yield
(22%, see the figure of Table 1). Therefore, we antici-
pated that using Tf2O instead of TFAA in the Matsu-
mura–Boekelheide rearrangement would more efficiently
afford the elimination product 17.13,14 The relevant
Scheme 1. Synthesis of the dihydroquinoline segment 2 of siomycin
D1.
stereoselectivity of this reaction, the details of which will
be discussed later. Although the hydroxyethyl-bearing
dihydroquinoline substructure was secured at this stage,
the synthetic route from 5 to 10 was lengthy and the
total yield was not satisfactory. Therefore, we investi-
gated a new route including the stereoselective reduction
of the methyl ketone function.
Instead of hydroxymethylation (6!7, Scheme 1),
methyl ester 6 was acetylated under the radical hetero-
aromatic substitution conditions11 to afford 13 in 84%

T. Mori et al. / Tetrahedron Letters 46 (2005) 6417–6422
6419
O
O
our knowledge, this is the first example using Tf2O in
the Matsumura–Boekelheide rearrangement.15
N
N
a
MeO
MeO
Although the reaction mechanism for the accompanied
deoxygenation remains to be solved,16 that for the
olefination using Tf2O and a base via the Matsumura–
Boekelheide rearrangement seems to be probable as
depicted in Scheme 4. In the case of the Boekelheide
rearrangement using TFAA,12 the first step is the triflu-
oroacetylation of N-oxide A (=14) to give B. The triflu-
oroacetate anion abstracts the proton to give the
unstable intermediate C, which undergoes rearrange-
ment to give D (=15); then the base hydrolysis of D
finally affords alcohol E (=16). For the Tf2O case,
N-oxide A is sulfonylated to give F, which is a stable
trifluoromethanesulfonyloxy salt.14 The base abstracts
the proton to give the unstable intermediate G, which
undergoes rearrangement to give H; finally, the b-elimi-
nation of H affords olefin I (=17).
6
O
13
b
O
O
OR
O
N
N
c
MeO
MeO
O
O
15: R = COCF3
16: R = H
14
d
Scheme 3. Synthesis of 16. Reagents and conditions: (a) MeCHO,
H2O, TFA (1.0 equiv), FeSO4Æ7H2O (0.1 equiv), aq H2O2 (2.0 equiv),
0 ꢁC to rt, 3 h, 84%; (b) MCPBA (2.0 equiv), CH2Cl2, 0 ꢁC to rt, 6 h,
88%; (c) TFAA (1.2 equiv), THF, rt, 40 min; (d) NaOMe (2.0 equiv),
MeOH, rt, 20 min, 52% (two steps). MCPBA = 3-chloroperoxybenzoic
acid.
Asymmetric epoxidation of 17 with Jacobsenꢂs reagent
1817 afforded epoxide 19 (75% ee)18 in 54% yield to-
gether with an 18% yield of the quinoline derivative 20
(Scheme 5). The absolute configuration of 19 was deter-
mined in the next stage. Bromination of 19 with NBS in
CCl4 afforded 21 in 56% yield together with a 6% yield
of its diastereomer. The absolute configuration of 21
(and hence 19) was confirmed by X-ray crystallographic
analysis (Fig. 2).19 After many unsuccessful reduction
experiments using DIBAL, LiBH(s-Bu)3, and BH3ÆTHF,
we found that the treatment of 21 with NaBH4 in
MeOH at ꢀ78 ꢁC for 19 h afforded the desired reduction
product 10 and its stereoisomer 11 in 81% and 11%
yields, respectively.
experimental data along this line are shown in Table 1.
The treatment of 14 in CH2Cl2 with Tf2O and the con-
secutive addition of 2,6-lutidine or diisopropylethyl-
amine (DIPEA) expectedly afforded the elimination
product 17 (entries 1 and 2). Interestingly but unexpect-
edly, deoxygenation of N-oxide 14 to 13 accompanied
this reaction. Fortunately, we found that dilution of
DIPEA in CH2Cl2 raised the ratio of 17:13 from 3.8:1
to 5.6:1 (entries 2 and 3). Triethylamine was found to
be a more suitable base; the ratio was improved to
10:1 (entry 4). Finally, the best result was obtained by
the slow addition of a 0.45 M CH2Cl2 solution of tri-
ethylamine to a solution of 14 and Tf2O in CH2Cl2,
giving only 17 in 98% yield (entry 6). To the best of
The stereoselectivity observed in the addition reactions
to aldehyde 9 and methyl ketone 21 may be interpreted
as follows (Scheme 6). Aldehyde 9, coordinated with the
Table 1. One-pot olefination of 14 via the Matsumura–Boekelheide rearrangement
O
O
N
O
O
N
N
MeO
MeO
MeO
+
CH2Cl2
O
O
O
14
17
13
Entry
1
Conditions
Tf2O (1.2 equiv) was added at 0 ꢁC,
Yield (%)a of 17+13
Ratiob of 17:13
63
2.8:1
then 2,6-lutidine (5.0 equiv) was added at 0 ꢁC, then rt, 4 h
Tf2O (1.2 equiv) was added at 0 ꢁC,
then DIPEA (5.0 equiv) was added at 0 ꢁC, then rt, 4 h
Tf2O (1.2 equiv) was added at 0 ꢁC, then 2 M DIPEA (5.0 equiv)/CH2Cl2
was added at 0 ꢁC during 10 min, then rt, 5 h
Tf2O (1.2 equiv) was added at 0 ꢁC, then 2 M Et3N (5.0 equiv)/CH2Cl2
was added at 0 ꢁC during 10 min, then rt, 5 h
Tf2O (1.2 equiv) was added at 0 ꢁC, then 0.45 M Et3N (5.0 equiv)/CH2Cl2
was added at 0 ꢁC during 0.5 h, then rt, 5 h
Tf2O (1.2 equiv) was added at 0 ꢁC, then 0.45 M Et3N (5.0 equiv)/CH2Cl2
was added at 0 ꢁC during 1 h, then rt, 5 h
2
3
4
5
6
54
66
58
74
98
3.8:1
5.6:1
10:1
17 only
17 only
a Isolated yield (17+13) after silica-gel column chromatography.
b The ratio of 17:13 was based on 1H NMR analysis of the isolated products.

6420
T. Mori et al. / Tetrahedron Letters 46 (2005) 6417–6422
CF3
CF3
CF3
O
N
O
O
N
O
O
N
O
OH
H
O2CCF3
R1
R1
R1
R1
N
Base
hydrolysis
(CF3CO)2O
R2
R2
R2
R2
O
N
R1
B
C
D (= 15)
E (= 16)
O3SCF3
O
O
O
R2
A (= 14)
CF3
CF3
O
F3C
S
S
S
O
N
O
H
O
O
N
O
(CF3SO2)O
Base
R1
R1
N
R1
N
R1
Base
R1 = CO2Me, R2 = Ac
β elimination
–
R2
R2
R2
R2
F
G
H
I (= 17)
Scheme 4. Mechanisms for the Boekelheide rearrangement and one-pot olefination via the Matsumura–Boekelheide rearrangement.
O
O
Conformation of 9
O
O
O
N
N
a
O
O
MeO
MeO
N
N
MeO
MeO
O
O
H
H
Br
Br
17
19
b
O
M
H
H
O
M
J
K
CO2Me
N O
O
Br
M
O
O
N
H
MeO
H5
H
H
Me
5
J
Br
O
Conformation of 21
21
O
O
O
O
N
N
MeO
c
MeO
O
O
O
O
H
N
N
11
N
H
Br
Br
MeO
MeO
Me
O
O
Me
+
L
M
H
Br
H Br
O
CO2Me
N O
CO2Me
N O
HO
H
HO
Me
Br
Br
10
Me
H5
O
H
H
H5
H
H
N
O
O
H
H
Scheme 6. Plausible explanation for stereoselectivity in the reactions of
9 with MeMgBr and 21 with NaBH4.
N
N
MeO
Mn
Cl
t-Bu
O
O
t-Bu
O
t-Bu
t-Bu
20
18
the aldehyde plane to avoid the bromine atom, affording
the major isomer 10.20 In contrast, the carbonyl and
pyridine planes of methyl ketone 21 seem to be twisted
to avoid the steric repulsion found in the conformations
L and M. Among the two conformations N and O, the
former would be preferable to the latter from the view
point of dipole–dipole interaction.21 The hydride attack
seems to occur from the re-face of the carbonyl plane,
affording the major isomer 10.
Scheme 5. New synthesis of 10. Reagents and conditions: (a) 18
(0.05 equiv), 4-phenylpyridine N-oxide (0.5 equiv), PhIO (2.0 equiv),
CH3CN, ꢀ10 ꢁC, 12 h, 54% of 19 (75% ee), 18% of 20; (b) NBS
(1.1 equiv), AIBN (0.1 equiv), CCl4, 140 W sun lamp, 60 ꢁC, 4 h, 56%,
6% of the diastereomer of 21; (c) NaBH4 (4.0 molar amounts), MeOH,
ꢀ78 ꢁC, 19 h, 81% of 10, 11% of 11. NBS = N-bromosuccinimide,
AIBN = 2,20-azobisisobutyronitrile.
metal species under the stated reaction conditions, seems
to prefer the conformation depicted as J rather than the
conformation K because of steric crowding. The attack
of a methyl anion seems to occur from the si-face of
Comparing these two routes aimed at the preparation of
10, the first one consists of the 15 steps from 5 to 10 in a
1.8% overall yield and the second one in 10 steps in a
14% overall yield. Therefore, through the second route,

T. Mori et al. / Tetrahedron Letters 46 (2005) 6417–6422
6421
Acknowledgements
We thank Drs. Takashiro Akitsu and Masaru Yao
(Keio University) for X-ray crystallographic analysis.
This research was partially supported by a Grant-in-
Aid for the 21st Century COE program ꢃKEIO Life
Conjugate Chemistryꢂ from the Ministry of Education,
Culture, Sports, Science and Technology, Japan and a
Grant-in-Aid for Scientific Research on Priority Areas
(A) ꢃExploitation of Multi-Element Cyclic Moleculesꢂ
from the Ministry of Education, Culture, Sports, Sci-
ence and Technology, Japan.
Figure 2. X-ray crystal structure of 21.
References and notes
1. Higashibayashi, S.; Hashimoto, K.; Nakata, M. Tetra-
hedron Lett. 2002, 43, 105–110.
O
O
N
O
O
2. Higashibayashi, S.; Mori, T.; Shinko, K.; Hashimoto, K.;
Nakata, M. Heterocycles 2002, 57, 111–122.
3. Higashibayashi, S.; Kohno, M.; Goto, T.; Suzuki, K.;
Mori, T.; Hashimoto, K.; Nakata, M. Tetrahedron Lett.
2004, 45, 3707–3712.
N
a,b
MeO
MeO
Br
HO
H
TBSO
H
4. The thiostrepton family of peptide antibiotics, see Refs. 1
and 2.
10
22
5. Synthetic studies on the thiostrepton family of peptide
antibiotics, see: (a) Shin, C.; Ito, A.; Okumura, K.;
Nakamura, Y. Chem. Lett. 1995, 45–46; (b) Nicolaou,
c,d
O
O
´
K. C.; Safina, B. S.; Funke, C.; Zak, M.; Zecri, F. J.
N
t-BuO
Angew. Chem., Int. Ed. 2002, 41, 1937–1940; (c) Nicolaou,
K. C.; Nevalainen, M.; Safina, B. S.; Zak, M.; Bulat, S.
Angew. Chem., Int. Ed. 2002, 41, 1941–1945; (d) Nicolaou,
K. C.; Nevalainen, M.; Zak, M.; Bulat, S.; Bella, M.;
Safina, B. S. Angew. Chem., Int. Ed. 2003, 42, 3418–3424;
(e) Nicolaou, K. C.; Safina, B. S.; Zak, M.; Estrada, A. A.;
Lee, S. H. Angew. Chem., Int. Ed. 2004, 43, 5087–5092; (f)
Nicolaou, K. C.; Zak, M.; Safina, B. S.; Lee, S. H.;
Estrada, A. A. Angew. Chem., Int. Ed. 2004, 43, 5092–
5097.
TBSO
H
4
Scheme 7. Synthesis of the dihydroquinoline segment 4. Reagents and
conditions: (a) TBSOTf (1.2 equiv), 2,6-lutidine (2.0 equiv), CH2Cl2,
0 ꢁC, 0.5 h, 82%; (b) DBU (3.5 equiv), THF, rt, 1h, 95%; (c) TMSOK
(1.0 equiv), Et2O, 0 ꢁC, 0.5 h; (d) Boc2O (2.0 equiv), DMAP (0.3 equiv),
t-BuOH, rt, 3 h, 86% (two steps). TBS = tert-butyldimethylsilyl,
TMS = trimethylsilyl, Boc = tert-butoxycarbonyl, DMAP = 4-(di-
methylamino)pyridine.
6. Recently, a total synthesis of thiostrepton has appeared;
see Refs. 5e and 5f.
7. Mori, T.; Tohmiya, H.; Satouchi, Y.; Higashibayashi, S.;
Hashimoto, K.; Nakata, M, see following letter, Tetra-
hedron Lett. 2005, 46, doi:10.1016/j.tetlet.2005.07.122.
28
20
8. ½aꢁD ꢀ76.3 (c 1.00, EtOH) [lit.9 ½aꢁD ꢀ78 (c 1.6,
we could obtain sufficient amounts of the hydroxyethyl-
bearing dihydroquinoline substructure.
20
EtOH), lit.10 ½aꢁD ꢀ79 (c 1, EtOH)].
9. Bodanszky, M.; Fried, J.; Sheehan, J. T.; Williams, N. J.;
Alicino, J.; Cohen, A. I.; Keeler, B. T.; Birkhimer, C. A.
J. Am. Chem. Soc. 1964, 86, 2478–2490.
After silylation (82%) of 10, the resulting silyl ether was
subjected to dehydrobromination with DBU to afford
22 in 95% yield (Scheme 7). Methyl ester 22 was trans-
formed into the desired dihydroquinoline segment 4 by
deprotection with TMSOK22 followed by re-esterifica-
tion with Boc2O23 in 86% yield.
10. Ebata, M.; Miyazaki, K.; Otsuka, H. J. Antibiot. 1969, 22,
423–433.
11. Priestley, N. D.; Smith, T. M.; Shipley, P. R.; Floss, H. G.
Bioorg. Med. Chem. 1996, 4, 1135–1147.
12. (a) Kobayashi, G.; Furukawa, S. Pharm. Bull. 1953, 1,
347–349; (b) Boekelheide, V.; Linn, W. J. J. Am. Chem.
Soc. 1954, 76, 1286–1291; (c) Koenig, T. J. Am. Chem.
Soc. 1966, 88, 4045–4049; (d) Korytnyk, W.; Srivastava, S.
C.; Angelino, N.; Potti, P. G. G.; Paul, B. J. Med. Chem.
1973, 16, 1096–1101; (e) Konno, K.; Hashimoto, K.;
Shirahama, H.; Matsumoto, T. Heterocycles 1986, 24,
2169–2172; (f) Fontenas, C.; Bejan, E.; Haddou, H. A.;
Balavoine, G. G. A. Synth. Commun. 1995, 25, 629–
633.
In summary, we have synthesized the dihydroquinoline
segment 4 of thiostrepton, the siomycins, and the thio-
peptins. The key reactions are the one-pot olefination
via the Matsumura–Boekelheide rearrangement using
Tf2O and triethylamine and the stereoselective addition
reaction controlled by the stereocenter of the peri-posi-
tion. In the following letter,7 we will describe the synthe-
sis of the siomycin cyclic core portion containing the
dehydropiperidine, dihydroquinoline (i.e., 4), L-valine,
and masked dehydroalanine (i.e., b-phenylselenoala-
nine) segments.
13. It has been reported that 2-picoline N-oxide was trans-
formed with tosyl chloride into 2-chloromethylpyridine
via 2-tosyloxymethylpyridine, see: Matsumura, E. Nippon
Kagaku Kaishi 1953, 74, 363–364.

6422
T. Mori et al. / Tetrahedron Letters 46 (2005) 6417–6422
14. It has been reported that pyridine and picoline N-oxides
reacted with Tf2O to give N-sulfonyloxy triflate salts, see:
Chen, Z.-C.; Stang, P. J. Tetrahedron Lett. 1984, 25, 3923–
3926.
15. It has been reported that the reaction of Tf2O with 2,6-
dimethyl- and 2,4,6-trimethylpyridine produced com-
pounds in which a methyl hydrogen was replaced by
either a trifluoromethyl or a [(trifluoromethyl)sulfinyl]oxy
group, see: Binkley, R. W.; Ambrose, M. G. J. Org. Chem.
1983, 48, 1776–1777.
16. The mechanism for deoxygenation of pyridine N-oxides
with alkanesulfonyl chlorides and triethylamine has been
reported, see: (a) Morimoto, Y.; Kurihara, H.; Yokoe, C.;
Kinoshita, T. Chem. Lett. 1998, 829–830; (b) Morimoto,
Y.; Kurihara, H.; Kinoshita, T. Chem. Commun. 2000,
189–190; (c) Morimoto, Y.; Kurihara, H.; Shoji, T.;
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18. The enantiomeric excess was not optimized. It was
determined by chiral HPLC analysis (Daicel Chiralcel
OD column, 4.6 · 250 mm, 90:10 hexane–IPA; 1 mL/min,
254 nm, t = 20.6 min; enantiomer of 19, t = 30.8 min).
19. Recrystallization of 21 from 1:3 dioxane–hexane twice
afforded crystals suitable for X-ray crystallographic analy-
sis. Crystallographic data for 21 have been deposited
with the Cambridge Crystallographic Data Centre with
number 279853.
20. The fact that the compound 10 derived from 9 was
identical with that derived from methyl ketone 21
confirmed the structure of
determined.
9 which had not been
21. This argument is supported from X-ray crystallographic
analysis of 21 (Fig. 2).
22. Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25,
5831–5834.
23. Takeda, K.; Akiyama, A.; Nakamura, H.; Takizawa, S.;
Mizuno, Y.; Takayanagi, H.; Harigaya, Y. Synthesis 1994,
1063–1066.