The first total synthesis of a tetracyclic antibiotic, (-)-tetrodecamycin

Article abstract of DOI:10.1016/j.tetlet.2006.03.078

(-)-Tetrodecamycin (1) has been synthesized from optically active butenolide through stereoselective SmI₂-mediated pinacol cyclization and newly developed deoxygenation.

Full text of DOI:10.1016/j.tetlet.2006.03.078

Tetrahedron Letters 47 (2006) 3595–3598
The first total synthesis of a tetracyclic antibiotic,
(ꢀ)-tetrodecamycin
Kuniaki Tatsuta,* Yasuaki Suzuki, Akiho Furuyama and Hiroshi Ikegami
Department of Applied Chemistry, School of Science and Engineering, Waseda University, 3-4-1 Ohkubo,
Shinjuku-ku, Tokyo 169-8555, Japan
Received 6 February 2006; revised 2 March 2006; accepted 5 March 2006
Abstract—(ꢀ)-Tetrodecamycin (1) has been synthesized from optically active butenolide through stereoselective SmI2-mediated
pinacol cyclization and newly developed deoxygenation.
Ó 2006 Elsevier Ltd. All rights reserved.
(ꢀ)-Tetrodecamycin (1) has been isolated from the cul-
ture broth of Streptomyces sp. MJ885-mF8 to show
antimicrobial activities especially against Pasteurella
piscicida, which is well known as the causative bacteria
of pseudotuberculosis in cultured fishes.1 The structure
is distinguished by a tetronic acid-containing 6-6-7-5-
membered tetracyclic core, the one cyclohexane ring of
which is fully and diversely substituted.2 Moreover, the
quaternary carbons are located at C7 and C13.3 The
imposing structure and potential medicinal importance
of this molecule have attracted a great deal of attention
from other researchers since the disclosure of the
structure,4–6 although the total synthesis has not been
reported yet.
The synthesis was initiated with the stereoselective
conversion of the optically active butenolide 2 into the
2,3-dimethyl derivative 3 in three steps by our reported
procedures (Scheme 2).9–11 Reaction of the lithiated 3
with cyclohexanone was followed by dehydration to
stereoselectively give the quaternary product 412 as
expected from our previous synthesis.10 The structure
was confirmed by X-ray crystallographic analysis.13
Hydride reduction of 4 to the diol was successively
followed by selective O-benzylation and silylation to
give 6.
Regioselective oxidation of 6 with SeO2 gave the a,b-
unsaturated ketone 7 as a single product in 86% yield.14
The 1,4-reduction of 7 was achieved by a couple of
NaBH4 and NiCl2Æ6H2O15 to give a diastereomeric
mixture of 8 and 9 in 77% and 15%, respectively,
although the undesired 9 was recycled by epimerization
to the desired 8 in alkaline MeOH. The structure of 8
was also determined by the X-ray analysis.13
Herein, we report the first total synthesis of (ꢀ)-tetro-
decamycin (1).
From the retrosynthetic perspective, we envisioned that
the 6-6-7-membered tricyclic core 17 would be accessible
from the aldehyde 16 by a Baylis–Hillman-type reaction
(Scheme 1).7 In another critical step, we planned an effi-
cient construction of 16 through the formation of the
cis-diol by the SmI2-mediated pinacol cyclization of
the keto-aldehyde 10,8 which would be stereospecifically
derived from our reported lactone 39–11 through the
unsaturated ketone 7 by reaction with cyclohexanone
followed by reductive opening of the lactone ring.
De-O-tritylation of 8 and subsequent PCC oxidation
gave the keto-aldehyde 10. This was submitted to
SmI2-mediated cyclization in question to stereoselec-
tively give the requisite cis-diol 11 as a single product
resulting from the most stable transition state of the
chelation-controlled reaction.8 The configuration was
confirmed by the X-ray analysis of the following aceton-
ide 12.13 Michael addition of 12 to diethyl acetylenedi-
carboxylate gave a mixture of 13 and 14 in 75% and
15% yield, respectively, the stereochemistry of which
was defined by the NMR studies,12 especially by the
chemical shifts of the olefin protons.16
*
Corresponding author. Tel./fax: +81 3 3200 3203; e-mail: tatsuta@
waseda.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.078

3596
K. Tatsuta et al. / Tetrahedron Letters 47 (2006) 3595–3598
O
O
17
Me
H
O
6
Me
Me
CO2Et
CO2Et
CHO
Me
H
H
1
16
15
Me
O
Me
O
4
7
18
8
CO2Et
3
13
CO2Et
14
O
O
5
O
HO
O
H
O
OH
O
17
16
(–)-Tetrodecamycin (1)
Me
Me
O
OBn
Me
OBn
H
Me
Me
TrO
O
O
O
OTBS
OTBS
Me
OTr
O
10
7
3
Scheme 1.
Me
OH
Me
TrO
HO
Me
TrO
d, e
g, h
a-c
f
O
O
O
O
O
O
OH
Me
Me
OTr
Me
2
3
4
5
Me
H
Me
H
Me
Me
OBn
Me
OBn
Me
OBn
Me
OBn
Me
j
i
+
O
O
OTBS
OTBS
O
OTBS
OTBS
OTr
OTr
OTr
OTr
6
7
8
9
k
Me
OBn
Me
H
Me
Me
SmI2
OTBS
OH
7
7
l, m
n
O
o, p
BnO
BnO
OTBS
OH
8
8
8
O
13
14
Me
O
OTBS
Me
H
H
H
O
10
11
Me
Me
H
Me
H
OBn
Me
OBn
Me
OBn
Me
CO2Et
H
q
7
8
CO2Et
+
13
H
CO2Et
14
O
OH
O
O
O
O
O
O
CO2Et
H
O
12
13
14
Scheme 2. Reagents and conditions: (a) TrCl, NH4NO3/DMF, rt, 16 h; (b) MeMgBr, CuBrÆSMe2, TMSCl, HMPA/THF, ꢀ78 °C to ꢀ50 °C, 20 min;
(c) MeI, LDA/THF, ꢀ78 °C, 20 min, 81% in three steps; (d) cyclohexanone, LDA/THF, ꢀ78 °C, 10 min; (e) SOCl2/Py, 0 °C, 1 h, 91% in two steps;
(f) LiBH4/THF, 65 °C, 38 h; (g) BnBr, K2CO3, 18-crown-6-ether/MeCN, 50 °C, 8 h; (h) TBSCl, DBU/MeCN, 65 °C, 20 h, 88% in three steps; (i)
SeO2/aq dioxane, 90 °C, 17 h, 86%; (j) NaBH4, NiCl2Æ6H2O/MeOH–CH2Cl2, 0 °C, 10 min, 8: 77%, 9: 15%; (k) KOH/MeOH, 60 °C, 2 h, 60%; (l)
Et2AlCl/CH2Cl2, ꢀ78 °C to 0 °C, 0.5 h; (m) PCC, Al2O3/CH2Cl2, rt, 6 h; (n) SmI2, t-BuOH/THF, ꢀ78 °C, 0.5 h, 73% in three steps; (o) 2-
methoxypropene, PPTS/CH2Cl2, rt, 8 h; (p) TBAF/THF, 50 °C, 15 h, 71% in two steps; (q) diethyl acetylenedicarboxylate, KH/ClCH2CH2Cl, 75 °C,
6 h, 13: 75%, 14: 15%.
Reductive de-O-benzylation of the desired olefin 13 gave
the alcohol 15, which was oxidized to aldehyde 16
(Scheme 3). After some experimentation, treatment of
16 with NaHMDS constructed smoothly the seven-
membered ring to afford a 5:1 diastereomeric mixture
of the alcohols,7 which was oxidized to a single product
17 as expected.
The stage was now set for further elaboration to
tetrodecamycin.
In the diester 17, the C2 ester is anticipated to be less
reactive than the C3 ester for saponification because of
the tautomerization with the ring oxygen atom. In the
event, 17 was selectively hydrolyzed to the mono-acid

K. Tatsuta et al. / Tetrahedron Letters 47 (2006) 3595–3598
3597
Me
Me
Me
OBn
Me
OH
Me
CHO
Me
H
H
H
CO2Et
CO2Et
CO2Et
a
b
c, d
CO2Et
CO2Et
CO2Et
O
O
O
O
O
O
H
H
H
O
O
O
13
15
16
O
O
O
Me
Me
Me
2
3
CO2Et
CO2Et
CO2Et
OH
CO2Et
SEt
H
H
H
Me
O
Me
O
Me
O
e
f
g
O
O
O
O
O
O
O
O
17
18
19
O
O
O
O
O
O
Me
Me
Me
H
H
H
Me
O
Me
O
O
Me
O
h
PPh3
H+
O
O
OH
Br
O
O
O
O
O
O
20
O
O
O
17
Me
H
O
O
O
O
6
Me
Me
H
H
1
16
Me
Me
O
Me
O
O
4
O
i
j
7
18
8
3
13
14
O
15
5
HO
O
HO
OH
O
OH
21
22
(–)-Tetrodecamycin (1)
Scheme 3. Reagents and conditions: (a) H2, Pd–C/EtOH, rt, 2 h; (b) PCC, Al2O3/CH2Cl2, rt, 6 h, 88% in two steps; (c) NaHMDS/THF, ꢀ78 °C,
10 min; (d) IBX/PhMe–DMSO, rt, 3 h, 81% in two steps; (e) Na2CO3/aq THF, rt, 15 h, 91%; (f) EtSH, WSCIÆHCl, Py/CH2Cl2, rt, 1 h, 74%; (g)
Et3SiH, Lindlar cat./acetone, rt, 0.5 h, 80%; (h) CBr4, PPh3/CH2Cl2, rt, 0.5 h, 75%; (i) 70% aq TFA, 50 °C, 10 h, 85%; (j) CH2@N+Me2Iꢀ, i-Pr2NEt/
1,4-dioxane, rt, 12 h, then MeI, rt, 11 h, 63%.
18. The acid 18 was transformed to the thioester 19,
which was reduced by Et3SiH to the aldehyde with con-
comitant cyclization to the diastereomeric acetal 20.17
The formation of lactone 21 was then tested from 18
or 20 under a variety of conditions, and finally the best
result was realized from 20 by our newly developed pro-
cedures. Deoxygenation of the acetal 20 was effected in
one operation using CBr4 and PPh3 to furnish lactone
21 by bromination18 followed by debromination with
PPh3 and subsequent protonation.19
Culture, Sports, Science and Technology (MEXT) for
the financial supports of our program.
References and notes
1. (a) Tsuchida, T.; Sawa, R.; Iinuma, H.; Nishida, C.;
Kinoshita, N.; Takahashi, Y.; Naganawa, H.; Sawa, T.;
Hamada, M.; Takeuchi, T. J. Antibiot. 1994, 47, 386–388;
(b) Tsuchida, T.; Iinuma, H.; Nishida, C.; Kinoshita, N.;
Sawa, T.; Hamada, M.; Takeuchi, T. J. Antibiot. 1995, 48,
1104–1109.
We then turned our attention to the introduction of the
exo-methylene group onto the tetronic acid moiety.
Deacetonation of 21 afforded diol 22, which, upon
treatment with Eschenmoser’s reagent,20 underwent
introduction of an exo-methylene group to give
(ꢀ)-tetrodecamycin (1). This was identical in all respects
with the natural product,21 completing the first total
synthesis to establish the absolute structure.
2. Tsuchida, T.; Iinuma, H.; Sawa, R.; Takahashi, Y.;
Nakamura, H.; Nakamura, K. T.; Sawa, T.; Naganawa,
H.; Takeuchi, T. J. Antibiot. 1995, 48, 1110–1114.
3. The carbon-numbering protocol parallels conveniently
that of the natural product 1.1a,2
4. Tsuchida, T.; Iinuma, H.; Nakamura, K. T.; Nakamura,
H.; Sawa, T.; Hamada, M.; Takeuchi, T. J. Antibiot. 1995,
48, 1330–1335.
5. (a) Paintner, F. F.; Allmendinger, L.; Bauschke, G.; Berns,
C.; Heisig, P. Bioorg. Med. Chem. 2003, 11, 2823–2833; (b)
Paintner, F. F.; Bauschke, G.; Polborn, K. Tetrahedron
Lett. 2003, 44, 2549–2552; (c) Paintner, F. F.; Allmen-
dinger, L.; Bauschke, G.; Polborn, K. Synlett 2002, 1308–
1312.
6. (a) Warrington, J. M.; Barriault, L. Org. Lett. 2005, 7,
4589–4592; (b) Barriault, L.; Denissova, I. Org. Lett. 2002,
4, 1371–1374.
Acknowledgements
We are grateful to the 21COE ‘Center for Practical
Nano-Chemistry’, the Consolidated Research Institute
for Advanced Science and Medical Care, a Grant-in-
Aid for Scientific Research (A), and Scientific Research
on Priority Areas 16073220 from Ministry of Education,
7. Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev.
2003, 103, 811–891.

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K. Tatsuta et al. / Tetrahedron Letters 47 (2006) 3595–3598
8. Matsuda, F. J. Synth. Org. Chem., Jpn. 1995, 53, 987–998.
9. Tatsuta, K.; Hosokawa, S. Chem. Rev. 2005, 105, 4707–
4729.
18-Me), 6.10 (1H, s, H-2). Compound 16: d 0.99 (3H, d,
J = 7.0, H-18), 4.11 (1H, d, J = 2.5, H-14), 4.15 (1H, dd,
J = 2.5 and 1.5, H-15), 5.39 (1H, s, H-2), 9.42 (1H, s, H-6).
Compound 19: d 1.07 (3H, d, J = 7.5, H-18), 2.90 (1H, dq,
J = 13.0 and 7.0, –SCH2–), 2.92 (1H, dq, J = 13.0 and 7.0,
–SCH2–), 4.20 (1H, d, J = 2.5, H-14), 4.31 (1H, dq,
J = 10.5 and 7.0, –OCH2–), 4.33 (1H, dq, J = 10.5 and 7.0,
–OCH2–), 4.51 (1H, dd, J = 2.5 and 0.5, H-15). Com-
pound 20 (diastereomeric mixture): d 1.00 (3H, d, J = 6.5,
H-18), 1.03 (3H, d, J = 6.5, H-18), 5.77–5.85 (2H, br, OH-
10. Tatsuta, K.; Yasuda, S.; Kurihara, K.; Tanabe, K.; Shinei,
R.; Okonogi, T. Tetrahedron Lett. 1997, 38, 1439–1442.
11. Tatsuta, K.; Narazaki, F.; Kashiki, N.; Yamamoto, J.;
Nakano, S. J. Antibiot. 2003, 56, 584–590.
12. 1H NMR (600 MHz: d, ppm from TMS, and J in Hz)
spectra were in CDCl3 solution, unless otherwise stated.
26
Selected data; Tetrodecamycin (1): ½aꢁD ꢀ6.0 (c 0.42,
21
MeOH). d 1.01 (3H, d, J = 7.5, H-18), 1.12 (1H, ddddd,
J = 13.0, 13.0, 13.0, 3.0 and 3.0, H-10), 1.25 (3H, s, H-17),
1.22–1.29 (1H, m, H-12), 1.34 (1H, dd, J = 12.5 and 4.0,
H-8), 1.42 (1H, ddddd, J = 13.0, 13.0, 13.0, 3.0 and 3.0,
H-11), 1.48–1.53 (1H, m, H-9), 1.54–1.65 (2H, m, H-90 and
H-110), 1.76–1.83 (1H, m, H-100), 2.07 (1H, s, OH-13),
2.09 (1H, ddd, J = 14.0, 5.0 and 2.5, H-120), 2.65 (1H, dq,
J = 3.0 and 7.5, H-16), 3.17 (1H, d, J = 6.5, OH-14), 3.62
(1H, d, J = 6.5, H-14), 4.81 (1H, dd, J = 3.0 and 0.5, H-
15), 5.27 (1H, d, J = 2.5, H-5), 5.37 (1H, d, J = 2.5, H-50).
4), 5.90 (1H, s, H-4), 5.95 (1H, s, H-4). Compound 22: ½aꢁD
+97 (c 0.43, MeOH). (acetone-d6): d 0.96 (3H, d, J = 7.0,
H-18), 3.70 (1H, d, J = 6.5, H-14), 4.63 (1H, d, J = 16.0,
H-4), 4.66 (1H, d, J = 16.0, H-40), 4.80 (1H, d, J = 3.0, H-
15), 5.02 (1H, d, J = 6.5, OH-14).
13. Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication numbers CCDC 290461 for 4, CCDC
288233 for 8, and CCDC 288691 for 12. Copies of the data
can be obtained, free charge, on application to CCDC, 12
Union Road, Cambridge, CB2 1EZ, UK [fax: +44-0-1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk].
14. Arigoni, D.; Vasella, A.; Sharpless, K. B.; Jensen, H. P.
J. Am. Chem. Soc. 1973, 95, 7917–7919.
15. Satoh, T.; Nanba, K.; Suzuki, S. Chem. Pharm. Bull. 1971,
19, 817–820.
16. Pascual, C.; Meier, J.; Simon, W. Helv. Chim. Acta 1966,
49, 164–168.
17. Fukuyama, T.; Lin, S.-C.; Li, L. J. Am. Chem. Soc. 1990,
112, 7050–7051.
18. Jones, L. A.; Sumner, C. E., Jr.; Franzus, B.; Huang, T.
T.-S.; Snyder, E. I. J. Org. Chem. 1978, 43, 2821–
2827.
19. Borowitz, I. J.; Kirby, K. C., Jr.; Virkhaus, R. J. Org.
Chem. 1966, 31, 4031–4037.
Compound
4
[needles from i-PrOH, mp 154 °C
24
(decomp.)]: ½aꢁD +12 (c 1.53, CHCl3). d 0.73 (3H, d,
J = 6.5, H-18), 1.19 (3H, s, H-17), 2.65 (1H, dq, J = 10.0
and 6.5, H-16), 4.08 (1H, ddd, J = 10.0, 4.0 and 3.0,
H-15), 5.62–5.68 (1H, m, H-9). Compound 8 (prisms from
MeOH, mp 115 °C): ½aꢁ2D3 +3.6 (c 0.82, CHCl3). d 0.70 (3H,
d, J = 7.5, H-18), 2.51 (1H, dd, J = 12.0 and 4.0, H-8),
4.08 (1H, ddd, J = 8.0, 2.5 and 1.5, H-15). Compound 10:
d 1.05 (3H, d, J = 7.5, H-18), 2.06 (1H, ddd, J = 12.5, 6.0
and 3.0, H-12), 2.37 (1H, ddd, J = 12.5, 12.5 and 6.0,
H-120), 2.82 (1H, dd, J = 12.5 and 4.0, H-8), 3.95 (1H, dd,
J = 3.5 and 3.0, H-15), 9.43 (1H, d, J = 3.0, H-14).
28
Compound 12 (needles from EtOAc, mp 135 °C): ½aꢁD
+26 (c 1.57, MeOH). d 1.10 (3H, d, J = 6.5, H-18), 1.43
(3H, s, IP-Me), 1.45 (3H, s, IP-Me), 1.90 (1H, dd, J = 12.0
and 3.0, H-8), 3.45–3.51 (1H, m, H-15), 3.89 (1H, d,
J = 2.5, H-14). Compound 13: d 0.92 (3H, d, J = 7.0, H-
18), 3.22 (2H, s, H-6), 4.15 (2H, q, J = 7.0, –OCH2–), 4.31
(1H, dq, J = 10.5 and 7.0, –OCH2–), 4.33 (1H, dq,
J = 10.5 and 7.0, –OCH2–), 4.39–4.46 (1H, m, H-15),
5.23 (1H, s, H-2). Compound 14: d 1.01 (3H, d, J = 7.0,
20. Takano, S.; Inomata, K.; Samizu, K.; Tomita, S.; Yanase,
M.; Suzuki, M.; Iwabuchi, Y.; Sugihara, T.; Ogasawara,
K. Chem. Lett. 1989, 1283–1284.
21. An authentic sample of (ꢀ)-tetrodecamycin was kindly
provided by Dr. Tomio Takeuchi, Inst. Microb. Chem.