Synthetic studies on the thiostrepton family of peptide antibiotics: Synthesis of the tetrasubstituted dehydropiperidine and piperidine cores

Article abstract of DOI:10.1016/S0040-4039(01)02090-1

The tetrasubstituted dehydropiperidine and piperidine cores of the thiostrepton family of peptide antibiotics were synthesized which featured the coupling between the azomethine ylide and the enantiopure sulfinimine, and the subsequent stereoselective reduction of the six-membered imine.

Full text of DOI:10.1016/S0040-4039(01)02090-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 105–110
Synthetic studies on the thiostrepton family of peptide
antibiotics: synthesis of the tetrasubstituted dehydropiperidine
and piperidine cores
Syuhei 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 12 October 2001; revised 29 October 2001; accepted 2 November 2001
Abstract—The tetrasubstituted dehydropiperidine and piperidine cores of the thiostrepton family of peptide antibiotics were
synthesized which featured the coupling between the azomethine ylide and the enantiopure sulfinimine, and the subsequent
stereoselective reduction of the six-membered imine. © 2001 Elsevier Science Ltd. All rights reserved.
In 1955, thiostrepton was isolated from the culture
broth of Streptomyces azureus by the Squibb group.1 Its
structure was elucidated by chemical degradation stud-
ies,2 X-ray crystallographic analysis,3 and NMR stud-
ies.4 Other structurally related antibiotics, the
siomycins,5 the thiopeptins,6 and Sch 18640,7 were also
isolated. The characteristic structure of this thiostrep-
ton family of peptide antibiotics is the bicyclic structure
containing a tetrasubstituted dehydropiperidine and/or
piperidine moiety, a tetrasubstituted dihydroquinoline
moiety, four thiazole moieties, a thiazoline moiety,
dehydroamino acid moieties, and a dihydroxyisoleucine
moiety (Fig. 1). Because of these complex structural
features, synthetic studies on the thiostrepton family of
antibiotics have scarcely been attempted.8 Most efforts
have focused on the syntheses of the much simpler
thiopeptide antibiotics.9,10 These antibiotics show high
activities against Gram-positive bacteria and mycobac-
teria.1,5,6,a,b In this letter, we describe the enantioselec-
tive synthesis of the tetrasubstituted dehydropiperidine
and piperidine cores, 1 and 2, of the thiostrepton family
of antibiotics.
dehydrogenation.11 The precursor 3 of 2 would be
obtained from the six-membered imine derivative 4 by
stereoselective reduction. It is likely that the six-mem-
bered imine derivative 4 exists in the equilibrium mix-
ture of the five-membered imine derivative 6a via the
intermediate 5a. We anticipated that the six-membered
imine 4 in this equilibrium mixture would be preferen-
tially reduced due to steric hindrance around the imine
function in the five-membered imine 6a. It is expected
that this stereoselective reduction would be realized by
considering the stereoelectronic effect shown in Scheme
1. In order to synthesize the equilibrium mixture of
4–6a, we selected the coupling reaction between the
azomethine ylide derived from 7 and the chiral sulfin-
imine 8 or 9, followed by desulfinylation. This coupling
reaction may proceed via the 1,3-dipolar cyclo-
addition12 (giving 5b) or the 1,2-addition reaction (giv-
ing 6b). There is a precedent for the 1,3-dipolar
cycloaddition between the azomethine ylides derived
from the N-benzylidene a-aminoesters and the chiral
sulfinimines.13,14 The stereochemical outcome described
in the literature13a matches our demand when sulfin-
imine 8 is used. On the other hand, when this reaction
proceeds via the 1,2-addition reaction, it is possible to
control the C6 stereochemistry in 6b by employing
sulfinimine 8 or its epimer 9;15 however, the C5 stereo-
chemistry in 6b is unpredictable.
The retrosynthetic analysis is shown in Scheme 1. The
tetrasubstituted dehydropiperidine core 1 would be
derived from the tetrasubstituted piperidine core 2 by
Keywords: thiostrepton; piperidines; sulfinimines; stereoselective
reduction.
* Corresponding author. Present address: Plant Science Center,
RIKEN, Laboratory for Biochemical Resources, 2-1 Hirosawa,
Wako, Saitama 351-0198, Japan. Tel.: +81-48-467-5893; fax: +81-
48-467-5407; e-mail: kimikoh@postman.riken.go.jp
One of the key segments, 2,5-dithiazolyl-1,2-dehydropy-
rrolidine 7,16 was prepared from the known pyrrolidine
dicarboxylic acid derivatives (Schemes 2 and 3).17 cis-1-
Boc-2,5-dicarbethoxypyrrolidine 1017 (Scheme 2) was
hydrolyzed to the acid, which was converted into the
0040-4039/02/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02090-1

106
S. Higashibayashi et al. / Tetrahedron Letters 43 (2002) 105–110
O
O
S
R5
S
H
N
O
N
H
N
H
H
N
H
N
R4
R3
CO2Et
O
O
N
S
S
S
N
N
H
NH
N
H
N
H
H
O
HN
OH
O
H
O
H
N
H
N
R2
H
O
N
O
N
NHBoc
S
N
OH
H
O
H
H
H
NH
S
S
H
N
N
NH
N
H
O
O
EtO2C
H
H
R1
NH
NH
S
HN
O
H
O
H
S
1
("a" series of thiopeptin
and Sch 18640)
HO
BocN
N
H
N
O
N
S
(thiostrepton, siomycins,
and "b" series of thiopeptin)
H
H
O
HO
CO2Et
H
S
OH
Thiostrepton: R1 = O, R2 = CH2CH3, R3 = CH3, R4 = H, R5
H
O
H
N
H
N
O
=
N
NHBoc
S
N
H
NH2
NH
H
O
H
N
N
O
EtO2C
H
N
Siomycin A: R1 = O, R2 = CH3, R3 = R4 = CH2, R5
=
S
N
H
NH2
(dehydroalanine)
H
O
O
2
BocN
O
H
N
O
Thiopeptin Ba / Bb: R1 = S, R2 =CH3, R3 = CH3, R4 = H, R5
=
N
H
OH
O
O
H
N
Sch 18640: R1 = S, R2 =CH2CH3, R3 = CH3, R4 = H, R5
=
N
H
NH2
O
Figure 1.
H
H
H
O
O
NHBoc
NHBoc
O
NH2
NHBoc
EtO2C
HN
HN
H
2
H
S
S
N
S
S
N
S
N
S
N
OH
5
N
6
N
N
NH
1
NH
EtO2C
EtO2C
CO2Et
CO2Et
CO2Et
H
H
H
S
N
H
S
N
H
S
N
H
1
2
3
BocN
O
BocN
O
HN
O
O
O
O
NH2
S
N
S
N
2
R2
R1
R2
R1
N
H
5
6
1,3-dipolar
cycloaddition
N
N
NR
EtO2C
CO2Et
1
R3
R3
5a: R = H
5b: S(O)p-Tol
7
4
+
H
O
S
R2
1,2-addition reaction
N
R3
R2
2
N
p-Tol
R1
R1
O
R3
6
5
N
1
S
4
NH2
N
H
S
N
p-Tol
H
NHR
or
8
6a: R = H
6b: S(O)p-Tol
9
HN
O
O
Scheme 1.

S. Higashibayashi et al. / Tetrahedron Letters 43 (2002) 105–110
107
1) 1M aq NaOH,
H2O:MeOH:dioxane =
2:1:1, rt, 2 h
2) ClCO2Et, Et3N, THF,
rt, 1 h
DIBAL reduction of 16 followed by oxidation with
chemical manganese dioxide (CMD)20 afforded alde-
hyde 17 in 73% yield. Condensation of 17 (1 equiv.) in
THF with the Davis sulfinamide21 18 (1 equiv.) or 19 (1
equiv.) in the presence of LiClO4 (8 equiv.) and Et3N (8
equiv.) provided sulfinimine 8 or 9, respectively.22 Each
solution of these sulfinimines was directly used in the
subsequent coupling. First, based on the results
described in the literature,13a dehydropyrrolidine 7 and
sulfinimine 8 were selected for the coupling partners.
However, this coupling proceeded via the 1,2-addition
reaction (not the 1,3-dipolar cycloaddition); further-
more, the following transformation of the coupling
product 20 led to the diastereomer of 21 (vide infra)
having the opposite configurations at the C2, C5, and
C6 positions.23 Therefore, sulfinimine 9 was next chosen
as the coupling partner. To the above-mentioned solu-
tion was added 7 at −25°C. After 1 day, the addition
product 6b and its diastereomer24 were obtained in 71
CO2Et
CSNH2
EtO2C
H2NSC
N
N
3) NH3, rt, 10 min
4) Lawesson reagent,
dioxane, 90 ˚C, 1.5 h
33% (4 steps)
Boc
10
Boc
11
ethyl bromopyruvate,
EtOH, reflux, 2 h
S
+
N
S
S
S
N
N
H
N
N
R
H
13 (R = CO2Et)
N
R
R
R
12 (R = CO2Et)
61%
17%
t-BuOCl, THF, -78 ˚C, 20 min,
then Et3N, rt, 4 h
95%
1
and 17% yields, respectively. The H NMR signal of
S
S
N
NHSO (l 5.79, J=8.7 Hz) in 6b supported the five-
membered imine structure; however, the C5 and C6
configurations could not be determined at this stage.
N
N
EtO2C
CO2Et
7
Scheme 2.
With the addition product 6b in hand, we turned our
attention to the final stage (Scheme 5). After desulfinyl-
ation of 6b with TFA in EtOH, the obtained mixture of
4–6a was subjected to reduction with NaBH3CN in
AcOH/EtOH to afford piperidine 3 in 52% yield as the
sole reduction product. Subsequent protection of the
oxazoline amine in 3 with Boc2O followed by condensa-
1) 1M aq NaOH,
H2O:MeOH:dioxane =
2:1:1, rt, 3 h
2) ClCO2Et, Et3N, THF,
rt, 1.5 h
CO2Et
CSNH2
EtO2C
H2NSC
N
N
3) NH3, rt, 10 min
4) Lawesson reagent,
dioxane, 90 ˚C, 1.5 h
Boc
14
Boc
15 (19%, 4 steps)
+ 11 (16%, 4 steps)
CO2Et
CHO
1) DIBAL, toluene,
-78 ˚C to rt, 1.5 h
ethyl bromopyruvate,
EtOH, reflux, 2 h
HO
H
N
N
S
S
ref. 9d
H
H
H
2) CMD, EtOAc:
CH2Cl2 = 1:1,
rt, 20 h
H2N
CO2H
HN
O
HN
O
12
+
13
L-threonine
O
O
32%
32%
73%
t-BuOCl, THF, -78 ˚C, 20 min,
then Et3N, rt, 4 h
76%
16
17
O
7
S
N
p-Tol
Scheme 3.
N
7
N
H
S
O
S
NH
O
8
H
S
mixed anhydride; and into this solution, gaseous NH3
was introduced. The resulting amide was treated with
Lawesson reagent,18 giving thioamide 11 in 33% overall
yield. Treatment of 11 with ethyl bromopyruvate9d in
EtOH afforded 12 and its trans-isomer 13 in 61 and
17% yields, respectively. Treatment of 12 with t-
BuOCl19 in THF followed by triethylamine provided 7
in 95% yield. In addition, trans-1-Boc-2,5-dicarb-
ethoxypyrrolidine 1417 (Scheme 3) was also transformed
to 7 by the same procedure as described in the cis-
series. From thioamide 15, obtained from 14 in 19%
yield together with the 16% yield of the cis-isomer 11, a
comparable yield (each 32%) of 12 and 13 was obtained
and then 13 was converted into 7 in 76% yield.
H2N
p-Tol
20
HN
p-Tol
18
O
S
S
LiClO4, Et3N,
THF, rt, 5 h
O
5
N
N
N
6
EtO2C
CO2Et
NH
H
S
O
17
S
N
H
p-Tol
HN
O
O
S
6b
O
O
S
H2N
p-Tol
N
p-Tol
19
N
H
LiClO4, Et3N,
THF, rt, 5 h
S
9
7
HN
O
-25 ˚C, 1 d
71%
O
Synthesis of another key segment, the chiral sulfinimine
8 or 9, and its connection with 7 began with the known
16,9d which was prepared from
L
-threonine (Scheme 4).
Scheme 4.

108
S. Higashibayashi et al. / Tetrahedron Letters 43 (2002) 105–110
S
N
S
N
NaBH3CN,
AcOH, EtOH,
NH2
NH2
H
N
TFA, EtOH,
CO2Et
EtO2C
NH
H
N
rt, 1 h
S
O
N
NH
rt, 2 h
52%
S
N
H
H
NH2
H
p-Tol
H
6a
4
3
HN
O
6b
O
1) Boc2O, cat DMAP, Et3N, THF, 0 ˚C, 1 h, 84%
2) CIP, HOAt, (i-Pr)2NEt, CH2Cl2, rt, 1 d, 93%
H
O
NHBoc
OH
H
H
H
t-BuOCl, THF, -78 ˚C,
0.5 h, then cat DMAP, Et3N,
rt, 5 h, 95%
O
O
O
1) LiOH, H2O:MeOH:
dioxane = 2:1:1,
rt, 2 h
NHBoc
N
NHBoc
NH2
2
HN
HN
H
HN
S
H
S
N
S
S
N
S
N
S
N
5
2
5
N
6
2) 1M HCl:
HO2C
N
6
NH
1
NH
1
EtO2C
EtO2C
CO2Et
CO2Et
CO2H
dioxane
= 2:1, rt, 1 h
76%
H
H
H
S
N
H
S
N
H
S
N
R
H
H2N
1
2
21 (HCl salt)
BocN
O
BocN
O
H
O
O
HO
H
H
H
H
NOE:
H4ax
H4ax
NH
HBMC:
NOE:
H
H2 : 4%
H6 : 7%
H3ax : 2%
H
H4ax
H2 : 6%
H6 : 9%
2
2
4
4
3
3
R1
R1 H4ax
R2
R2
6
N
H
6
N
H
5
5
R3
R3
H
H
2
21
BocAlaHN
AlaHN
from H6 to C2
Scheme 5.
tion with Boc-Ala-OH using 2-chloro-1,3-dimethylimi-
dazolidium hexafluorophosphate (CIP)25 and 1-
hydroxy-7-azabenzotriazole (HOAt) afforded piperidine
226 in 78% yield. The HMBC spectrum of 2 (from H6
to C2) supported the piperidine skeleton and the NOE
experiments of 2 supported the relative configurations
of the piperidine ring. The absolute structure of 2 was
confirmed by its transformation to 21, which was a
degradation product from natural thiopeptin Ba.27,28
Finally, dehydrogenation of 2 with t-BuOCl19 and tri-
ethylamine gave dehydropiperidine 129 in 95% yield.
of Education, Culture, Sports, Science and Technology,
Japan.
References
1. (a) Pagano, J. F.; Weinstein, M. J.; Stout, H. A.;
Donovick, R. Antibiot. Ann. 1955–1956, 554–559; (b)
Vandeputte, J.; Dutcher, J. D. Antibiot. Ann. 1955–1956,
560–561; (c) Steinberg, B. A.; Jambor, W. P.; Suydam, L.
O. Antibiot. Ann. 1955–1956, 562–565.
2. (a) Kenner, G. W.; Sheppard, R. C.; Stehr, C. E. Tetra-
hedron Lett. 1960, 23–26; (b) Cross, D. F. W.; Kenner, G.
W.; Sheppard, R. C.; Stehr, C. E. J. Chem. Soc. 1963,
2143–2150; (c) 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;
(d) Barton, M. A.; Kenner, G. W.; Sheppard, R. C. J.
Chem Soc. (C) 1966, 2115–2119; (e) Bodanszky, M.;
Scozzie, J. A.; Muramatsu, I. J. Antibiot. 1970, 23, 9–12.
3. Anderson, B.; Hodgkin, D. C.; Viswamitra, M. A. Nature
1970, 225, 233–235.
In summary, we have synthesized, for the first time, the
tetrasubstituted dehydropiperidine and piperidine cores,
1 and 2, of the thiostrepton family of antibiotics via the
coupling reaction of the azomethine ylide derived from
7 and the chiral sulfinimine 9, followed by stereoselec-
tive reduction of the six-membered imine function. We
believe that the synthetic route described herein is a
convergent and unique one. Synthetic studies of other
portions in the thiostrepton family of antibiotics are
now in progress.
4. (a) Tori, K.; Tokura, K.; Okabe, K.; Ebata, M.; Otsuka,
H.; Lukacs, G. Tetrahedron Lett. 1976, 185–188; (b)
Olesker, A.; Valente, L.; Barata, L.; Lukacs, G.; Hull, W.
E.; Tori, K.; Tokura, K.; Okabe, K.; Ebata, M.; Otsuka,
H. J. Chem. Soc., Chem. Commun. 1978, 577–578; (c)
Tori, K.; Tokura, K.; Yoshimura, Y.; Okabe, K.; Otsuka,
H.; Inagaki, F.; Miyazawa, T. J. Antibiot. 1979, 32,
1072–1077; (d) Tori, K.; Tokura, K.; Yoshimura, Y.;
Acknowledgements
This research was supported by a Grant-in Aid for
Scientific Research on Priority Areas (A) ‘Exploitation
of Multi-Element Cyclic Molecules’ from the Ministry

S. Higashibayashi et al. / Tetrahedron Letters 43 (2002) 105–110
109
12. Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.;
Linden, A.; Coss´ıo, F. P. J. Am. Chem. Soc. 2000, 122,
6078–6092 and references cited therein.
13. (a) Viso, A.; Ferna´ndez de la Pradilla, R.; Guerrero-Stra-
chan, C.; Alonso, M.; Mart´ınez-Ripoll, M.; Andre´, I. J.
Org. Chem. 1997, 62, 2316–2317; (b) Viso, A.; Ferna´ndez
de la Pradilla, R.; Garc´ıa, A.; Alonso, M.; Guerrero-Stra-
chan, C.; Fonseca, I. Synlett 1999, 1543–1546.
Terui, Y.; Okabe, K.; Otsuka, H.; Matsushita, K.; Ina-
gaki, F.; Miyazawa, T. J. Antibiot. 1981, 34, 124–129; (e)
Hensens, O. D.; Albers-Scho¨nberg, G.; Anderson, B. F.
J. Antibiot. 1983, 36, 799–813; (f) Hensens, O. D.; Albers-
Scho¨nberg, G. J. Antibiot. 1983, 36, 814–831; (g)
Hensens, O. D.; Albers-Scho¨nberg, G. J. Antibiot. 1983,
36, 832–845; (h) Mocek, U.; Beale, J. M.; Floss, H. G. J.
Antibiot. 1989, 42, 1649–1652.
14. There is also a precedent for the 1,3-dipolar cycloaddition
between the azomethine ylide derived from 2,5-dicar-
bethoxy-1,2-dehydropyrrolidine and N-methylmaleimide,
see: Husinec, S.; Milovanovic, L.; Savic, V. J. Serb.
Chem. Soc. 1996, 61, 523–528.
5. (a) Nishimura, H.; Okamoto, S.; Mayama, M.; Ohtsuka,
H.; Nakajima, K.; Tawara, K.; Shimohira, M.; Shi-
maoka, N. J. Antibiot., Ser. A 1961, 14, 255–263; (b)
Ebata, M.; Miyazaki, K.; Otsuka, H. J. Antibiot. 1969,
22, 364–368; (c) Tokura, K.; Tori, K.; Yoshimura, Y.;
Okabe, K.; Otsuka, H.; Matsushita, K.; Inagaki, F.;
Miyazawa, T. J. Antibiot. 1980, 33, 1563–1567. See also
Refs 4a,b,c,d.
6. (a) Miyairi, N.; Miyoshi, T.; Aoki, H.; Kohsaka, M.;
Ikushima, H.; Kunugita, K.; Sakai, H.; Imanaka, H. J.
Antibiot. 1970, 23, 113–119; (b) Miyairi, N.; Miyoshi, T.;
Aoki, H.; Kohsaka, M.; Ikushima, H.; Kunugita, K.;
Sakai, H.; Imanaka, H. Antimicrob. Ag. Chemother. 1972,
1, 192–196; (c) Muramatsu, I.; Hikawa, E.; Hagitani, A.;
Miyairi, N. J. Antibiot. 1972, 25, 537–538; (d) Mura-
matsu, I.; Motoki, Y.; Aoyama, M.; Suzuki, H. J.
Antibiot. 1977, 30, 383–387; (e) Hensens, O. D.; Albers–
Scho¨nberg, G. Tetrahedron Lett. 1978, 3649–3652; (f)
Motoki, Y.; Muramatsu, I. Pept. Chem. 1979, 13–18 See
also Refs 4c,d,f,g.
7. Puar, M. S.; Ganguly, A. K.; Afonso, A.; Brambilla, R.;
Mangiaracina, P.; Sarre, O.; MacFarlane, R. D. J. Am.
Chem. Soc. 1981, 103, 5231–5233.
8. Only one report on the synthesis of the N-protected
2-(1-amino)propenyl-thiazoline-4-carboxylate derivative
(a small moiety of siomycin A and thiopeptin Ba), see:
Shin, C.-g.; Ito, A.; Okumura, K.; Nakamura, Y. Chem.
Lett. 1995, 45–46.
9. Examples of syntheses of micrococcins, see: (a) Kelly, T.
R.; Jagoe, C. T.; Gu, Z. Tetrahedron Lett. 1991, 32,
4263–4266; (b) Nakamura, Y.; Shin, C.-g.; Umemura, K.;
Yoshimura, J. Chem. Lett. 1992, 1005–1008; (c) Oku-
mura, K.; Shigekuni, M.; Nakamura, Y.; Shin, C.-g.
Chem. Lett. 1996, 1025–1026; (d) Ciufolini, M. A.; Shen,
Y. C. J. Org. Chem. 1997, 62, 3804–3805; (e) Shin, C.-g.;
Okumura, K.; Shigekuni, M.; Nakamura, Y. Chem. Lett.
1998, 139–140; (f) Okumura, K.; Ito, A.; Yoshioka, D.;
Shin, C.-g. Heterocycles 1998, 48, 1319–1324; (g) Oku-
mura, K.; Nakamura, Y.; Shin, C.-g. Bull. Chem. Soc.
Jpn. 1999, 72, 1561–1569; (h) Okumura, K.; Suzuki, T.;
Nakamura, Y.; Shin, C.-g. Bull. Chem. Soc. Jpn. 1999,
72, 2483–2490; (i) Ciufolini, M. A.; Shen, Y.-C. Org.
Lett. 1999, 1, 1843–1846.
15. Davis, F. A.; Zhou, P.; Chen, B.-C. Chem. Soc. Rev.
1998, 27, 13–18.
16. Satisfactory analytical data (NMR and IR spectra, ele-
mental analyses and/or HRMS, optical rotations) were
obtained for all new compounds.
17. Kemp, D. S.; Curran, T. P. J. Org. Chem. 1988, 53,
5729–5731.
18. Thomsen, I.; Clausen, K.; Scheibye, S.; Lawesson, S.-O.
In Organic Syntheses; Freeman, J. P., Ed.; John Wiley &
Sons: New York, 1990; Collect Vol. 7, pp. 372–375.
19. (a) Bachmann, W. E.; Cava, M. P.; Dreiding, A. S. J.
Am. Chem. Soc. 1954, 76, 5554–5555; (b) Scully, F. E. Jr.;
Davis, R. C. J. Org. Chem. 1978, 43, 1467–1468.
20. Aoyama, T.; Sonoda, N.; Yamauchi, M.; Toriyama, K.;
Anzai, M.; Ando, A.; Shioiri, T. Synlett 1998, 35–36.
21. Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Reddy, G.
V.; Portonovo, P. S.; Zhang, H.; Fanelli, D.; Reddy, R.
T.; Zhou, P.; Carroll, P. J. J. Org. Chem. 1997, 62,
2555–2563.
22. In our case, the mixture of LiClO4–Et3N,12 which was
very effective for the subsequent one-pot coupling, was
convenient for this condensation. For other dehydration
reagents, see; (a) Liu, G.; Cogan, D. A.; Ellman, J. A. J.
Am. Chem. Soc. 1997, 119, 9913–9914; (b) Liu, G.;
Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A.
J. Org. Chem. 1999, 64, 1278–1284; (c) Davis, F. A.;
Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D. L.;
Zhang, H. J. Org. Chem. 1999, 64, 1403–1406.
23. The details will be described in a full account.
24. The stereochemistry of this diastereomer has not yet been
determined.
25. (a) Akaji, K.; Kuriyama, N.; Kiso, Y. Tetrahedron Lett.
1994, 35, 3315–3318; (b) Akaji, K.; Kuriyama, N.; Kiso,
Y. J. Org. Chem. 1996, 61, 3350–3357.
26. Compound 2: [h]3D0 +20.9 (c 1.00, MeOH); IR (CHCl3):
1820, 1795, 1720, 1500, 1370, 1325, 1100, 1070, and 1045
cm−1 1H NMR (CDCl3, 300 MHz): l 8.54 (1H, br s),
.
8.12 (1H, s), 7.84 (1H, s), 6.89 (1H, s), 5.45 (1H, d, J=6.0
Hz), 5.17 (1H, d, J=2.7 Hz), 5.03 (1H, dq, J=2.7 and
6.3 Hz), 4.59 (1H, s), 4.46 (1H, dd, J=2.7 and 10.1 Hz),
4.41 (2H, q, J=7.2 Hz), 4.40 (2H, q, J=7.2 Hz), 4.16
(1H, dq, J=6.0 and 6.6 Hz), 3.51 (1H, ddd, J=3.0, 3.0,
and 14.1 Hz), 2.72 (1H, ddd, J=3.6, 14.1, and 14.1 Hz),
2.24 (1H, dddd, J=2.7, 3.0, 3.6, and 18.0 Hz), 2.01 (1H,
dddd, J=3.0, 10.1, 14.1, and 18.0 Hz), 1.61 (3H, d,
J=6.3 Hz), 1.46 (9H, s), 1.45 (3H, d, J=6.6 Hz), 1.39
(6H, t, J=7.2 Hz), 1.30 (9H, s). 13C NMR (CDCl3, 75
MHz): l 174.9, 173.3, 173.0, 167.4, 161.4, 161.3, 155.3,
152.8, 151.3, 148.8, 146.8, 127.3, 127.1, 119.7, 85.4, 79.7,
75.8, 64.9, 61.5, 61.4, 61.3, 61.2, 58.0, 51.4, 30.7, 28.2,
10. An example of the synthesis of promothiocin A, see: (a)
Moody, C. J.; Bagley, M. C. Chem. Commun. 1998,
2049–2050; (b) Bagley, M. C.; Bashford, K. E.; Hesketh,
C. L.; Moody, C. J. J. Am. Chem. Soc. 2000, 122,
3301–3313.
11. The C2-hydrogen in 2 is more acidic than the C6-hydro-
gen, see: (a) Meyers, A. I.; Knaus, G. N. J. Am. Chem.
Soc. 1973, 95, 3408–3410; (b) Knaus, G.; Meyers, A. I. J.
Org. Chem. 1974, 39, 1189–1192; (c) Knaus, G.; Meyers,
A. I. J. Org. Chem. 1974, 39, 1192–1195. The numbering
system depicted in Scheme 1 is employed for convenience.

110
S. Higashibayashi et al. / Tetrahedron Letters 43 (2002) 105–110
28.1, 27.8, 27.4, 20.4, 18.7, 14.3. HRMS (FAB+) calcd for
C37H50N7O11S3 (M+H)+: 864.2731. Found: 864.2726.
MHz): l 8.64 (1H, s), 8.49 (1H, s), 7.59 (1H, s), 5.45 (1H,
s), 5.37 (1H, br d, J=16.5 Hz), 4.94 (1H, d, J=6.9 Hz),
4.50 (1H, q, J=6.9 Hz),), 4.38 (1H, dq, J=6.6 and 6.9
Hz), 3.44 (1H, br d, J=14.7 Hz), 2.94 (1H, br dd,
J=12.6 and 14.7 Hz), 2.79 (1H, br d, J=12.6 Hz), 2.47
(1H, br ddd, 12.6, 12.6, and 16.5 Hz), 1.77 (3H, d, J=6.9
Hz), 1.32 (3H, d, J=6.6 Hz) [lit.28 1H NMR (D2O, 100
MHz): l 8.61 (1H, s), 8.46 (1H, s), 7.59 (1H, s), 5.48 (1H,
s), 5.40 (1H), 5.0–4.7 (1H), 4.52 (1H, q, J=8 Hz), 4.40
(1H, dq, J=6.5 and 6.5 Hz), 3.6–3.3 (1H), 3.2–2.2 (3H),
1.77 (3H, d, J=8 Hz), 1.30 (3H, d, J=6.5 Hz)]. 13C
NMR (D2O, 75 MHz): l 172.3, 171.5, 166.4, 166.2 165.2,
164.9, 147.5, 147.2, 146.2, 132.5, 132.1, 126.5, 68.9, 62.6,
62.2, 58.4, 58.3, 51.3, 32.1, 26.3, 20.1, 18.1 [lit.28 13C
NMR (D2O, 25 MHz): l 172.3, 171.4, 166.4, 165.8 165.2,
164.8, 147.4, 147.1, 146.0, 132.6, 132.1, 126.6, 68.9, 62.6,
62.2, 58.4, 58.4, 51.4, 32.2, 26.2, 20.2, 18.2].
27. According to Ref. 6f, the authors have isolated two
degradation products, IIA and IIB, from thiopeptin Ba as
the piperidine residue. Compound IIA, the epimer of
compound IIB at the C2 position in the piperidine ring,
was formed from IIB as an artifact under their degrada-
tion conditions. Therefore, compound IIB was the intact
piperidine residue. Unfortunately, they could not analyze
the coupling constant J2,3 of compound IIB because the
C2 proton signal overlapped with the C6 proton signal at
the 100 MHz NMR spectrometer (see Ref. 28). Instead,
judging from the coupling constant (J2,3=3.5 and 12.0
1
Hz) in the H NMR spectrum of compound IIA together
with X-ray analysis of thiostrepton,3 they proposed that
compound IIA was 21 and hence the C2 configuration of
the piperidine ring in natural thiopeptin Ba was S. On the
other hand, according to Ref. 4f, the authors proposed
the C2 configuration of the piperidine ring in thiopeptin
Ba to be R judging from the coupling constant (J2,3=3.5
28. Motoki, Y. Ph.D. Thesis, Department of Chemistry,
College of Science, Rikkyo University, 1980.
29. Compound 1: [h]D30 +23.3 (c 1.00, CHCl3). IR (CHCl3):
1820, 1720, 1500, 1370, 1330, 1160, 1100, 1070, and 1045
1
and 10.0 Hz) in the H NMR spectrum of thiopeptin A1a
(thiopeptin A1a is methyl ester of thiopeptin Ba at the
terminal position in R5 depicted in Fig. 1). These two
arguments conflicted. Therefore, we did NOE experi-
ments for both 2 and synthetic 21 that are shown in
Scheme 5 and unambiguously determined the C2, C5,
and C6 relative configurations. Additionally, the absolute
configuration of the piperidine ring in synthetic 21 was
confirmed by comparison of its optical rotation with that
of the compound IIB described in Refs. 6f and 28.
Compound 21: [h]D30 +45.6 (c 1.02, 1 M HCl) [lit.6f,28 [h]2D6
+44.7 (c 1.02, 1 M HCl)]. UV (1 M HCl) umax 239 nm
(m 19500) [lit.6f,28 UV (1 M HCl) umax 240 nm (m 16900)].
IR (KBr): 1685, 1580, and 1380 cm−1 [lit.6f,28 IR (KBr):
1690, 1580, 1480, and 1370 cm−1]. 1H NMR (D2O, 300
cm−1 1H NMR (CDCl3, 300 MHz): l 8.43 (1H, br s),
.
8.19 (1H, s), 7.91 (1H, s), 7.00 (1H, s), 5.43 (1H, br s),
5.30–5.12 (3H, m), 4.51–4.34 (4H, m), 3.99 (1H, dq,
J=5.7 and 7.2 Hz), 3.63 (1H, ddd, J=0.0, 5.4 and 13.8
Hz), 3.46–3.31 (1H, m), 3.12–2.92 (1H, m), 2.80 (1H,
ddd, J=6.0, 13.2, and 13.8 Hz), 1.61 (3H, d, J=6.3 Hz),
1.50 (9H, s), 1.47–1.35 (6H, m), 1.35 (3H, d, J=7.2 Hz),
1.21 (9H, s). 13C NMR (CDCl3, 75 MHz): l 175.2, 173.7,
168.9, 167.6, 163.6, 161.2, 161.1, 155.2, 153.2, 150.5,
148.6, 147.9, 147.0, 130.0, 127.3, 120.0, 85.2, 79.6, 74.9,
66.7, 61.6, 61.4, 61.3, 59.8, 51.9, 27.9, 27.8, 26.9, 24.5,
20.5, 17.9, 14.2, 14.2. HRMS (FAB+) calcd for
C37H48N7O11S3 (M+H)+: 862.2574. Found: 862.2573.
.