Total synthesis of (-)-8-O-methyltetrangomycin (MM 47755)

Article abstract of DOI:10.1021/ol060667b

A stereoselective total synthesis of the natural antibiotic (-)-8-O-methyltetrangomycin 1 is reported. The essential steps for this convergent synthesis are the transformation of a geraniol epoxide into a chiral octadiyne derivative, which was converted i

Full text of DOI:10.1021/ol060667b

ORGANIC
LETTERS
2006
Vol. 8, No. 12
2507-2510
Total Synthesis of
)-8-O-Methyltetrangomycin (MM 47755)
(−
Christian Kesenheimer and Ulrich Groth*
Fachbereich Chemie, UniVersita¨t Konstanz, Fach M-720, UniVersita¨tsstrasse 10,
78457 Konstanz, Germany
ulrich.groth@uni-konstanz.de
Received March 17, 2006
ABSTRACT
A stereoselective total synthesis of the natural antibiotic (
synthesis are the transformation of a geraniol epoxide into a chiral octadiyne derivative, which was converted into a triyne. The cobalt-
mediated [2 2] cycloaddition of the triyne led to a benz[a]anthracene system, which was oxidized with Ag(Py)2MnO4 to a benz[a]anthraquinone.
Deprotection with aqueous HF in acetonitrile and photooxidation afforded the desired product ( )-1.
−)-8-O-methyltetrangomycin 1 is reported. The essential steps for this convergent
+2+
−
(-)-8-O-Methyltetrangomycin belongs to the angucyclinone
antibiotics,1 which are mainly isolated from certain strains
of Streptomyces bacteria. The angucyclinones exhibit a broad
range of biological properties such as antiviral, antibacterial,
and antitumor activities, whereby (-)-8-O-methyltetrango-
mycin 1 (or MM 47755) shows mainly activity against gram-
positive organisms such as Bacillus subtilis (MIC: 32
µg/mL).2
Although there are already some familiar methods for the
construction of the stereogenic center at C3 with moderate
to good enantiomeric excess,5,6 we wanted to demonstrate
the fundamental viability of our methodology7 utilizing a
chiral monoprotected diyne as a building block for the
synthesis of angucyclinones.
The stereoselective total synthesis of 1 was successfully
accomplished with an overall yield of 9% over 19 linear steps
Besides its angular benz[a]anthraquinone framework, one
unique feature of (-)-8-O-methyltetrangomycin 1 is its
chiral tertiary hydroxy function at the C3 position in the A
ring, which is also found in other representatives of the
angucyclinone family such as (-)-tetrangomycin 23 and
(-)-rabelomycin 34 (Figure 1).
(1) (a) Rohr, J.; Thiericke, R. Nat. Prod. Rep. 1992, 103-137. (b) Krohn,
K.; Rohr, J. Top. Curr. Chem. 1997, 188, 127-195. (c) Carreno, M. C.;
Urbano, A. Synlett 2005, 1, 1-25.
(2) (a) Shigahara, Y.; Koizumi, Y.; Tamamura, T.; Homma, Y.; Isshiki,
K.; Dobashi, K.; Naganawa, H.; Takeuchi, T. J. Antibiot. 1988, 41, 9, 1260-
1264. (b) Gilpin, M. L.; Balchin, J.; Box, S. J.; Tyler, J. W. J. Antibiot.
1989, 42, 4, 627-628. (c) Grabley, S.; Hammann, P.; Hu¨tter, K.; Kluge,
H.; Thiericke, R.; Wink, J. J. Antibiot. 1991, 44, 6, 670-673.
(3) (a) Dann, M.; Lefemine, D. V.; Barbatschi, F.; Shu, P.; Kunstmann,
M. P.; Mitscher, L. A.; Bohonos, N. Antimicrob. Agents Chemother. 1965,
832-835. (b) Kunstmann, M. P.; Mitscher, L. A. J. Org. Chem. 1966, 31,
2920-2925.
(4) Liu, W.-L.; Parker, W. L.; Slusarchyk, D. S.; Greenwood, G. L.;
Graham, S. F.; Meyers, E. J. Antibiot. 1970, 23, 437-441.
(5) (a) Kim, K.; Boyd, V. A.; Sobti, A.; Sulikowski, G. A. Isr. J. Chem.
1997, 37, 3-22. (b) Boyd, V. A.; Sulikowski, G. A. J. Am. Chem. Soc.
1995, 117, 32, 8472-8473.
(6) (a) Landell, J. S.; Larsen, D. S.; Simpson, J. Tetrahedron Lett. 2003,
44, 5193-5196. (b) Carreno, M. C.; Urbano, A.; Di Vitta, C. Chem.-Eur.
J. 2000, 6, 906-913.
(7) (a) Kalogerakis, A.; Groth, U. Org. Lett. 2003, 5, 843-844. (b)
Kalogerakis, A.; Groth, U. Synlett 2003, 12, 1886-1888.
Figure 1. 3-Hydroxy-angucyclinones.
10.1021/ol060667b CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/16/2006

and an enantiomeric excess of g91%. The stability of the
protected alcohol 19 (Scheme 4) under the conditions of the
cobalt-mediated [2+2+2] cycloaddition was shown by the
racemic synthesis of 1 with 11% overall yield comprising
nine linear steps.
On the basis of previous work of our group,7 we designed
the following retrosynthetic way for 1 which is shown in
Scheme 1.
With the achiral diyne rac-6 in hand, we performed the
total synthesis as shown in Scheme 4 with rac-6 instead of
6 as the starting material. After we had proven that the
expected way to synthesize (()-8-O-methyltetrangomycin
rac-1, in nine steps with an overall yield of 11%, works as
described, we developed an asymmetric synthesis of the
chiral octadiyne 6 as the starting material for an enantiose-
lective approach toward the total synthesis of (-)-1.
The synthesis of 6 (Scheme 3) was started with a Sharpless
epoxidation10 of geraniol 10 giving us the epoxide 11. A
Scheme 1
Scheme 3
The idea was to synthesize (-)-1 via the chiral benz[a]-
anthracene 4 which should be accessible by the cobalt-
mediated [2+2+2] cycloaddition of chiral triyne 5. Triyne
5 should result from the addition of the chiral octadiyne 6
to the substituted benzaldehyde 78 and successive selective
deprotection of both trimethylsilyl groups under basic
conditions.
Our synthesis of the racemic diyne rac-6 (Scheme 2)
started with the addition of 3-(trimethylsilyl)-propargylmag-
reductive ring opening of 11 with Red-Al according to the
protocol of Sharpless et al.11 led us to the chiral diol 12a.
The reductive ring opening was tested under various condi-
tions with Red-Al, LiAlH4,12 and DIBAl-H, whereby it
could be shown that only Red-Al gave the diol 12a without
any loss of optical purity. Interestingly, the reduction of the
epoxide 11 with LiAlH4 led to a significant decrease of the
optical purity down to 57% ee, whereas reduction with
DIBAl-H led to no isolable amounts of the desired diol.
The enantiomeric excess of the diol 12a was determined to
be g91% via chiral GC analysis.13 Protection of the primary
hydroxy function of 12a with benzoyl chloride, protection
of the tertiary alcohol with TBSOTf, and successive saponi-
Scheme 2
nesium-bromide to hex-5-yn-2-one 89 which gave the diynol
rac-9 in 66% yield. The tertiary hydroxy function was
then protected with TBSOTf and 2,6-lutidine as its TBS-
ether rac-6.
(10) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780.
(11) (a) Gao, Y.; Sharpless, K. B. J. Org. Chem. 1988, 53, 4081-4084.
(b) Vitli, S. M. Tetrahedron Lett. 1982, 23 (44), 4541-4544.
(12) Jung, M. E.; MacDougall, J. M. Tetrahedron Lett. 1999, 40, 35,
6339-6342.
(8) For the synthesis of the substrate benzaldehyde 7, see ref 7.
(9) Hex-5-yn-2-one was synthesized according to: Eglington, G.; Whit-
ing, M. C. J. Chem. Soc. 1953, 607, 3052-3059.
(13) See Supporting Information.
2508
Org. Lett., Vol. 8, No. 12, 2006

Scheme 4
Table 1. Ozonolysis of Compound 15 under Various
Conditions
entry
reaction conditions
yield (%) of 16a
1
2
CH2Cl2/MeOH (9:1)
CH2Cl2/MeOH (9:1),
1.5 equiv of KHCO3
CH2Cl2, 2 equiv of HOAc
CH2Cl2
47
30
3
4
5
6
16
66
64-69
85
CH2Cl2, 1 equiv of pyridine
CH2Cl2, 2.5 equiv of pyridine
a The given yields are after workup with dimethyl sulfide and column
chromatography over silica gel.
solvent gave the dimethylacetal with loss of the TMS
protecting group. By adding KHCO3 to the reaction, we
were able to prevent the formation of the acetal, but the
TMS group was still cleaved. Only the addition of 2.5 equiv
of abs pyridine gave the desired aldehyde 16 in an accept-
able yield. Conversion of 16 by the above-mentioned
modified Corey-Fuchs reaction finally gave the chiral
octadiyne 6 with the dibromide 17 as an isolable but unstable
intermediate.
To determine the enantiomeric excess of 6 by chiral GC,
the TBS-protecting group had to be removed. Aqueous
hydrofluoric acid in acetonitrile proved to be the reagent of
choice, leaving the acetylenic TMS-protecting group un-
touched. The enantiomeric purity of 9 was determined by
chiral GC analysis in comparison with the achiral diynol
rac-9 to be >91% ee.18
fication of the benzoate gave the monoprotected diol 12d.
Parikh-Doering oxidation14 was the method of choice for
the oxidation of the primary alcohol 12d to gain access to
aldehyde 13. Oxidizing the primary alcohol 12d with some
classical methods such as PCC and PDC (low or no
observable conversion) or Dess-Martin periodinane (de-
composition, even with additional pyridine to buffer the
acetic acid) failed. 13 was then converted according to a
Corey-Fuchs protocol15 into the dibromide 14. Noteworthy
is that standard Corey-Fuchs conditions did not give the
dibromide 14, and the starting material remained unchanged.
Further experiments showed that the use of triethylamine
was essential for the feasibility of this reaction, as well as
the quality of the tetrabromocarbon.16
Addition of the lithiated diyne 6 to a mixture of the
substituted benzaldehyde 78 and an equivalent borontrifluo-
ride gave the bis-TMS-protected cyclization precursor 18
with 70% yield. Without the use of borontrifluoride, the
addition showed a much lower yield of only 25%. Removal
of the trimethylsilyl groups under basic conditions with
potassium carbonate in methanol led to the TBS-protected
triyne 5. Protection of the secondary hydroxy function with
TBSOTf and 2,6-lutidine gave the triyne 19 which is the
direct precursor for the intramolecular cobalt-mediated
[2+2+2] cycloaddition.19 Cyclization of triyne 19 was
performed under different conditions (see Table 2), but the
Elimination of dibromide 14 with 2 equiv of n-BuLi led
after quenching with TMS-Cl to compound 15.
Ozonolysis17 of the enyne 15 in dichloromethane and
pyridine at -78 °C gave the aldehyde 16, whereby the
classical conditions failed to deliver the expected aldehyde
16 (see Table 1). Ozonolysis with CH2Cl2/MeOH (9:1) as
20
equimolar use of CpCo(C2H4)2 led to the best yields in
(17) For ozonolysis under basic conditions, see: (a) Zheng, W.; DeMattei,
J. A.; Wu, J.-P.; Duan, J. J.-W.; Cook, L. R.; Oinuma, H.; Kishi, Y. J. Am.
Chem. Soc. 1996, 118, 7946-7968. (b) Sugai, T.; Katoh, O.; Ohta, H.
Tetrahedron 1995, 51 (44), 11987-11998. (c) Rosini, G.; Marotta, E.;
Raimondi, A.; Righi, P. Tetrahedron: Asymmetry 1991, 2, 123-138. (d)
Smith, D. B.; Wattos, A. M.; Loughhead, D. G.; Weikert, R. J.; Morgans,
D. J. J. Org. Chem. 1996, 61 (6), 2236-2241.
(14) (a) Parikh, J. R.; Doering, W. von E. J. Am. Chem. Soc. 1967, 89,
5505-5507. (b) Tidwell, T. T. Synthesis 1990, 857-869.
(15) Marshall, J. A.; Sehon, C. A. J. Org. Chem. 1997, 62, 4313-4320.
(16) The CBr4 from Merck Company KG Darmstadt gave the best results.
(18) See Supporting Information.
Org. Lett., Vol. 8, No. 12, 2006
2509

tection of the tertiary alcohol at C3 proved to be difficult:
the usual methods such as TBAF, HF*Pyr, or NH4F failed
completely. Only concentrated aqueous HF in acetonitrile
at elevated temperatures (∼50 °C) showed an efficient
conversion. Finally, regioselective photooxidation24 at C1 of
the completely deprotected tetrahydrobenz[a]anthraquinone
21 in CHCl3 gave (-)-8-O-methyltetrangomycin 1 in 58%
yield.
Table 2. Cobalt-Mediated [2+2+2] Cycloaddition under
Different Reaction Conditions
The structure of 1 was determined by one- and two-
dimensional NMR, mass, and IR spectroscopy. All recorded
data were in accordance with the corresponding published
data. The enantiomeric excess of (-)-8-O-methyltetrango-
mycin 1 was determined to be g91% by comparing its
optical rotation with the data reported earlier.2,6
yield (%)
entry
reaction conditions
of 4a
1
2
3
4
5
6
7
10 mol % of CpCo(CO)2, toluene, reflux, 40 h
20 mol % of CpCo(CO)2, toluene, hν, reflux, 8 h
40 mol % of CpCo(CO)2, toluene, hν, reflux, 4 h
100 mol % of CpCo(CO)2, toluene, hν, reflux, 4 h
20 mol % of CpCo(COD), toluene, hν, rt, 4 h
40 mol % of CpCo(C2H4)2, Et2O, -78 °C to rt, 4 h
100 mol % of CpCo(C2H4)2, Et2O, -78 °C to rt, 4 h
23b
44b
33
64
Acknowledgment. We wish to thank Dr. Barbara Heller,
IfOK Rostock, for her kind supply of the CpCo(COD)
catalyst. Furthermore, the authors are grateful to Merck
Company KG and Wacker Chemie AG for valuable starting
material.
45c
80c
a The given yields are after workup and column chromatography over
silica gel. b The catalyst was added slowly via syringe pump to the starting
material 19 in refluxing toluene (see also ref 22). c Before the workup was
done, 5 drops of acetic acid were added to the solution and stirred at room
temperature for 2 h.
Supporting Information Available: Detailed experi-
mental procedures and full characterization of compounds
1
4-6, 9, 11, 13-21, and 1 are given, as well as H and 13C
comparison with the CpCo(CO)2 and the CpCo(COD)21
catalysts. Application of the recently published syringe pump
technique22 (Table 2, entries 1 and 2) also showed interesting
results, although these results could not match the yields
achieved by the use of equivalent amounts of the “Jonas”
catalyst CpCo(C2H4)2.
NMR spectra for compounds 4, 6, 9, 19-21, and 1. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL060667B
(20) (a) Jonas, K.; Deffense, E.; Habermann, D. Angew. Chem., Int. Ed.
1983, 22 (9), 716-717. For the synthesis of the catalyst, see: (b) Jonas,
K.; Deffense, E.; Habermann, D. Angew. Chem., Int. Suppl. 1983, 22 (S9),
1005-1016. (c) Cammack, J. K.; Jalisatgi, S.; Matzger, A. J.; Negron, A.;
Vollhardt, K. P. C. J. Org. Chem. 1996, 61 (14), 4798-4800. For the
advantage of CpCo(C2H4)2, see also: Groth, U.; Huhn, T.; Kesenheimer,
C.; Kalogerakis, A. Synlett 2005, 11, 1758-1760.
The chiral tetrahydrobenz[a]anthracene 4 was then oxi-
dized with an excess of a 1:2 mixture of Ag(Pyr)2MnO4
and silica gel in dry dichloromethane, which gave the
tetrahydrobenz[a]anthraquinone 20 in 65% yield. The depro-
23
(19) (a) Vollhardt, K. P. C. Acc. Chem. Res. 1977, 10 (1), 1-8. (b)
Vollhardt, K. P. C. Angew. Chem., Int. Ed. 1984, 23 (8), 539-556. (c)
Eichberg, M. J.; Dorta, R. L.; Grotjahn, D. B.; Lamottke, K.; Schmidt, M.;
Vollhardt, K. P. C. J. Am. Chem. Soc. 2001, 123, 9324-9337. (d) Schore,
N. E. Chem. ReV. 1988, 88, 1081-1119. (e) Lautens, M.; Klute, W.; Tam,
W. Chem. ReV. 1996, 96, 49-92. (f) Saito, S.; Yamamoto, Y. Chem. ReV.
2000, 100, 2901-2915. (g) Varela, J. A.; Saa´, C. Chem. ReV. 2003, 103,
3787-3801. (h) Petit, M.; Aubert, C.; Malacria, M. Org. Lett. 2004, 6,
3937-3940.
(21) Heller, B.; Sundermann, B.; Buschmann, H.; Drexler, H.-J.; You,
J.; Holzgrabe, U.; Heller, E.; Oehme, G. J. Org. Chem. 2002, 67, 4414-
4422.
(22) Moser, M.; Sun, X.; Hudlicky, T. Org. Lett. 2005, 7 (25), 5669-
5672.
(23) For the preparation of the oxidant, see: Firouzabadi, H.; Vessal,
B.; Naderi, M. Tetrahedron Lett. 1982, 23 (17), 1847-1850.
(24) Krohn, K.; Ballwanz, F.; Baltus, W. Liebigs. Ann. Chem. 1993, 911-
913.
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Org. Lett., Vol. 8, No. 12, 2006