Stereocontrolled preparation of the C1-C14 polyene fragment of benzenic ansamycin antibiotics ansatrienin A and B

Article abstract of DOI:10.1055/s-1999-2888

A practical synthesis of the C1-C14 polyene unit 5 in ansatrienin A (mycotrien l), 1a, and other ansamycin antibiotics is described which involves elaboration of the chiral unsaturated aldehyde 6 and phosphonate 7, followed by coupling of the building blocks by Horner-Emmons-olefination and Duthaler's aldolation. The synthesis of 6 successfully applies two consecutive Evans-aldol reactions for constructing the carbon backbone.

Full text of DOI:10.1055/s-1999-2888

1624
LETTER
Stereocontrolled Preparation of the C1-C14 Polyene Fragment of Benzenic
Ansamycin Antibiotics Ansatrienin A and B
Kai-Uwe Schöning, Rüdiger Wittenberg, Andreas Kirschning*
Institut für Organische Chemie der Technischen Universität Clausthal, Leibnizstraße 6, D-38678 Clausthal-Zellerfeld, Germany
Fax 5323-72 2858; E-mail: andreas.kirschning@tu-clausthal.de
Received 1 July 1999
Dedicated to Professor Axel Zeeck on the occasion of his 60th birthday
Typical structural features for all these natural products
Abstract: A practical synthesis of the C1-C14 polyene unit 5 in an-
are a stereotriad from C-13 to C-11,7 an all trans triene
satrienin A (mycotrien I), 1a, and other ansamycin antibiotics is de-
unit as well as a trisubstituted (Z)-alkene. As this ansa
bridge is identical for all derivatives listed, the develop-
scribed which involves elaboration of the chiral unsaturated
aldehyde 6 and phosphonate 7, followed by coupling of the building
blocks by Horner-Emmons-olefination and Duthaler´s aldolation. ment of a short and highly efficient synthesis represents
The synthesis of 6 successfully applies two consecutive Evans-aldol
reactions for constructing the carbon backbone.
the entrance for all members, including those that were
discovered recently. To date, only the groups of Smith and
Key words: Evans-aldolation, Horner-Emmons olefination, macro-
lactam antibiotic
Panek have reported the total syntheses of mycotrienin
and trienomycin.8 In both cases the aromatic portion was
introduced at an earlier stage and ring closure was
achieved in the triene unit.
The ansamycins are an important class of complex macro-
lactam antibiotics from microbial sources.1 Typically they
consist of a cyclic structure in which an aliphatic ansa
chain forms a bridge between two non-adjacent positions
of a cyclic p-system. Many of the ansamycins exhibit an-
tibacterial, antifungal or antitumor activity. E. g., rifamy-
cin, the most prominent example of ansamycin
antibiotics, is in clinical use and is one of the most potent
drugs against tuberculosis. One ansamycin subgroup, has
seen increasing interest lately. They are benzenic mem-
bers with a 17 carbons and one nitrogen atom containing
ansa chain. In 1981, the first examples, the ansatrienins A
and B 1a and 2a, were isolated from the fermentation
broth of Streptomyces collinus by Zähner, Zeeck and co-
workers.2 Independently, the groups of Natori, Sueda and
Sasaki3 described identical metabolites from Streptomy-
ces rishirensis which they named mycotrienins I and II.
Additionally, more potent members were found, namely
the trienomycins 3a4 and the recently discovered cyto-
triens 1b5 as well as the highly active thiazinotrienomy-
cins 4a.6
Scheme 1
In this paper9 we describe a practical synthesis of the C1-
C14 unit 5 which is uniformly present in benzenic ansa-
mycin antibiotics 1 - 4. We decided to assemble fragment
5 from aldehyde 6 and phosphonate 7 and acetate 8
(Scheme 1). For the preparation of the stereotriad in 6, we
developed an efficient aldol-based strategy utilizing
Evans oxazolidinones as chiral auxiliaries.10,11 Thus, the
boron enolate derived from acylated oxazolidinone deriv-
ative 9 reacted with methacrolein to afford the (2´R, 3´R)-
adduct 10 as a single isomer. Transamidation and silyla-
tion generated the Weinreb amide 11 which was reduced
to the corresponding aldehyde 12.12
Compound 12 then served as the aldehyde component in
the aldol reaction with the boron enolate generated from
(4S)-3-(methylthioacetyl)-4-benzyl-1,3-oxazolidin-2-one
14.13 The coupling reaction led to the b-hydroxy amide 13
in a >20:1 diastereomeric ratio. The methylthio substitu-
Synlett 1999, No. 10, 1624–1626 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
C1-C14 Polyene Fragment of Benzenic Ansamycin Antibiotics Ansatrienin A and B
1625
Reagents and Conditions:
a) Bu2BOTf, Et3N, CH2Cl2, -78 °C, CH2 = C(CH3)CHO, 87%; b) Me-
t
ONHMe∑HCl, AlMe3, THF, -20 °CÆ rt; c) BuMe2SiCl, imidazole,
Reagents and Conditions:
DMF, 50 °C, 79% (for two steps); d) 1.15 eq. DIBALH, CH2Cl2, -
78 °C; e) 14, Bu2BOTf, iPr2EtN, CH2Cl2, -78 °C, then addition of 12,
-78 °CÆ rt, 66% (for two steps); f) TBSOTf, 2,6-lutidine, CH2Cl2,
50 °C, 12h, 95%; g) Raney-Ni, THFabs, D, 1.5h. 90%; h) BnSH, nBu-
Li, THF, 0 °C, then addition to oxazolidinone, 20 min, 85%; i) 1.25
eq. DIBALH, CH2Cl2, -78 °C, 90% crude.
a) Br2, MeOH, -40 °C, 39%; b) 6% H3PO4, 100 °C, 1h; c)
(EtO)2P(O)CH2CO2Et, NaH, THF, -10 °C, 83% (for two steps); d)
HOAc, H2O, NaOAc, 100 °C, 2.5h; e) NaBH4, EtOH, 87% (for two
steps); f) PBr3, Et2O, D, 1h; g) P(OEt)3, 120 °C,1h, 82% (for two
steps); h) 4 eq. 7, 3 eq. LiHMDS, THF, -78 °CÆ rt, 1h, -78 °C, then
6, -70 °CÆ rt, 77%; i) 2 eq. DIBALH, CH2Cl2, -78 °C; j) MnO2 (90%
crude for two steps); k) 8, LDA, -78 °C, then addition of 22, -30 °C,
then addition of aldehyde at -78 °C, 69%; l) MeI, Ag2O, 72%.
Scheme 2
Scheme 3
ent induced the desired configuration in the b-position
with high stereoselectivity. Silylation followed by reduc-
tive removal of the methylthio group with Raney-Ni under reaction afforded the elongated product in 69% isolated
anhydrous conditions14 and subsequent cleavage of the yield with high stereoselectivity. The other diastereoiso-
1
oxazolidinone ring, using lithiated benzyl mercaptan af- mer was not formed, as judged from the H NMR spec-
forded thiolester 15 in satisfactory yield.15 It should be trum.21 Finally, the target C1-C14 fragment 5 was
noted that all other attempts to transamidate, reduce or hy- obtained after methylation of the alcohol at C-3 under
drolyse the amide group met with total failure. Finally, neutral conditions using MeI/Ag2O.
DIBALH promoted reduction of the thiolester group in 15
provided the aldehyde 6 in 9 steps and about 28% overall
yield.
Work is now in progress to synthesise the top aromatic
portions and to link it to 5 and hence achieve the total syn-
theses of the benzenic ansamycin antibiotics 1a and 4a.
The second building block, phosphonate 7, required for
olefination with aldehyde 6 was readily prepared from fu-
Acknowledgement
ran 16 (Scheme 3). According to Makin and Telegina16
We thank the Fonds der Chemischen Industrie and the Bayer AG
(Germany) for financial support.
oxidative cleavage with bromine in methanol led to the
acid labile tetramethoxybutene 17 which was selectively
transformed into aldehyde 18.17 Horner-Emmons olefina-
tion afforded diene 19 which was converted into phospho-
nate 7 in four straightforward steps,18 starting with acetal
hydrolysis and reduction of the intermediate aldehyde to
the corresponding alcohol, followed by bromination to
give 20 and subsequently phosphonation under Michae-
lis-Arbuzov conditions. The Horner-Emmons-olefination
between phosphonate 7 and aldehyde 6 was accomplished
in the presence of lithium hexamethyldisilazide in THF at
-78 °C, and gave rise to triene 21 (all-trans/other diastere-
omers 10:1).19 A two-step reduction/oxidation sequence
led to the corresponding aldehyde which was subjected to
Duthaler´s aldolation conditions.20 The asymmetric aldol
References and Notes
(1) Lancini, G., in Biotechnology, Rehm, H.-J., Reed, G., ed.,
VCH Verlagsgesellschaft, Weinheim 1986, 433-463.
(2) (a) Weber, W., Zähner, H., Damberg, M., Russ, P., Zeeck, A.,
Zbl. Bakt. Hyg., I. Abt. Orig. C2 1981, 122-139. (b) Damberg,
M., Russ, P., Zeeck, A., Tetrahedron Lett. 1982, 23, 59-62.
–
(3) (a) Sugita, M., Furihata, K., Seto, H., Otake, N., Sasaki, T.,
Agric. Biol. Chem. 1982, 46, 1111-1113. (b) Sugita, M.,
–
Sasaki, T., Furihata, K., Seto, H., Otake, N., J. Antibiot. 1982,
35, 1467-1473. (c) Sugita, M., Natori, Y., Sueda, N., Furihata,
–
K., Seto, H., Otake, N., J. Antibiot. 1982, 35, 1474-1479.
(d) Sugita, M., Hiramato, S., Ando, C., Sasaki, T., Furihata,
–
K., Seto, H., Otake, N., J. Antibiot. 1985, 38, 799-802.
Synlett 1999, No. 10, 1624–1626 ISSN 0936-5214 © Thieme Stuttgart · New York

1626
K.-U. Schöning et al.
LETTER
(4) (a) Umezawa, I., Funayama, S., Okada, K., Iwasaki, K., Satoh,
J., Masuda, K., Komiyama, K., J. Antibiot. 1985, 38, 699-705.
(b) Funayama, S., Okada, K., Komiyama, K., Umezawa, I., J.
Antibiot. 1985, 38, 1107-1109. (c) Funayama, S., Okada, K.,
Iwasaki, K., Komiyama, K., Umezawa, I., J. Antibiot. 1985,
Huisman, H. O., Rec. Trav. Chim. Pays-Bas 1973, 92, 683-
688.
(19) All compounds showed satisfactory spectroscopic data as well
as microanalytical and/or mass spectrometry data.
Diastereomeric ratios were established by 1H NMR. Selected
physical and spectroscopic data for compounds 21 and 5: 21:
colourless oil; 1H NMR (200 MHz, CDCl3) δ:7.28 (1H, dd,
J = 15.0, 11.2, 6-H), 6.50 (1H, dd, J = 14.8, 10.4, 4-H), 6.19
(1H, dd, J = 14.8, 11.2, 5-H), 6.09 (1H, dd, J = 15.0, 10.4, 3-
H), 5.85 (1H, ddd, J = 15.0, 6.8, 6.8, 7-H), 5.84 (1H, d,
J = 15.0, 2-H), 4.85 (1H, m, 13-HA), 4.81 (1H, m, 13-HB),
4.20 (2H, q, J = 7.0, OCH2CH3), 3.76 (1H, d, J = 6.0, 11-H),
3.53 (1H, m, 9-H), 2.15 (2H br t, J = 6.8, 8- HA, 8-HB), 1.79
(1H, m, 10-H), 1.69 (3H, s, 12-CH3), 1.29 (3H, t, J = 7.0,
OCH2CH3), 0.94 (3H, d, J = 6.8, 10-CH3), 0.89, 0.86 (18H, 2s,
38, 1677-1681. (d) Nomoto, H., Katsumata, S., Takahashi, K.,
–
Funayama, S., Komiyama, K., Umezawa, I., Omura, S. J., J.
Antibiot. 1989, 42, 479-481.
(5) Zhang, H.-P., Kakeya, H., Osada, H., Tetrahedron Lett. 1997,
38, 1789-1792.
(6) The thiazinotrienomycins inhibit the growth of HeLa-cells in
concentrations between 1.5 to 200 ng/ml: Hosokawa, N.,
Naganawa, H., Iinuma, H., Hamada, M., Takeuchi, T., J.
Antibiot. 1995, 48, 471-478.
(7) The absolute configuration of the stereotriad was determined
by Smith, A. B., Wood, J. L., Wong, W., Gould, A. E., Rizzo,
C. J., J. Am. Chem. Soc. 1990, 112, 7425-7426.
(8) (a) Smith, A. B., Wood, J. L., Wong, W., Gould, A. E., Rizzo,
C. J., Barbosa, J., Komiyama, K., Omura, S., J. Am. Chem.
Soc. 1996, 118, 8308-8315. (b) Masse, C. E., Yang, M.,
Solomon, J., Panek, J. S., J. Am. Chem. Soc. 1998, 120, 4123-
4134.
(9) For an alternate synthetic approach see: Schöning, K.-U.;
Hayashi, R. K.; Powell, D. R.; Kirschning, A., Tetrahedron
Asymm. 1999, 10, 817-820.
(10) Devant, M., Radunz, H.-E. in Stereoselective Synthesis,
Houben Weyl - Methods of Organic Chemistry, G. Helmchen,
R. W. Hoffmann, J. Mulzer, E. Schaumann, Eds., E 21, Vol 2,
Georg Thieme Verlag, Stuttgart, New York 1996, p 1151-
1334.
(11) Heathcock, C. H., in Modern Synthetic Methods, Scheffold,
R., Ed., Verlag Helvetica Chimica Acta, Basel 1992, 1-102.
(12) Aldehyde 12 has also been prepared similarly by Smith and
coworkers.8a
(13) Evans, D. A., Gage, J. R., Leighton, J. L., J. Am. Chem. Soc.
1992, 114, 9434-9453.
2 tBu), 0.04, 0.01, -0.01 and -0.05 (12H, 4s, 2 SiMe2); 13
C
NMR (50 MHz, CDCl3) δ:167.2 (CO2Et), 146.5 (C-12),
144.8, 141.0, 138.5, 131.5, 127.9, 120.1 (C-2 - C-7), 112.8 (C-
13), 79.5 (C-11), 72.5 (C-9), 60.2 (OCH2CH3), 43.5 (C-10),
35.2 (C-8), 25.8 (2 x tBu), 18.2, 18.0 (2 x tBu), 16.7 (12-CH3),
14.3 (OCH2CH3), 10.0 (10-CH3), -4.3, -4.5, -4.6, -5.0
(2 x SiMe2). 5: colourless oil; [a]24D = -23.2 (c 0.77, CHCl3);
IR (cm-1) n: 2956(s), 2930(s), 2858(s), 1732(m), 1463(m),
1368(m), 1254(s), 1055(s), 836(s); 1H NMR (400 MHz,
CDCl3) δ:6.28-5.92 (m, 4H, 5-H, 6-H, 7-H, 8-H), 5.67 (1H, m,
9-H), 5.48 (1H, dd, J = 15.0, 8.0, 4-H), 4.84 (1H, m, 15-HA),
4.81 (1H, m, 15-HB), 4.01 (1H, ddd, J = 8.0, 7.6, 6.1, 3-H),
3.77 (1H, d, J = 9.0, 13-H), 3.51 (1H, m, 11-H), 3.27 (3H, s,
OCH3), 2.54 (1H, dd, J = 14.8, 7.6, 2-HA), 2.63 (1H, dd,
J = 14.8, 6.1, 2-HB), 2.10 (2H br t, J = 6.6, 10-H), 1.78 (1H, m,
12-H), 1.70 (3H, br s, 14-CH3), 1.43 (9H, s, OtBu), 0.93 (3H,
d, J = 6.8, 12-CH3), 0.88, 0.86 (18H, 2s, 2x tBu), 0.04, 0.0, -
0.02 -0.04 (12H, 4s, 2 x SiMe2); 13C NMR (100 MHz, CDCl3)
δ:170.1 (C-1), 146.5 (C-15), 134.1, 134.0, 133.5, 131.8,
131.1, 129.4 (C-4 - C-9), 112.7 (C-14), 80.6 (OtBu), 79.5 (C-
3), 78.9 (C-13), 72.7 (C-11), 56.4 (OCH3), 43.5 (C-12), 42.4
(C-2), 35.0 (C-10), 28.1 (OtBu), 25.8 (2 x SitBu), 18.2, 18.0
(2x SitBu), 16.7 (14-CH3), 10.0 (12-CH3), -4.3, -4.5, -4.6 and
-5.0 (2 x SiMe2).
(14) Tietze, L. F., Hartfiel, U., Hübsch, T., Voß, E., Bogdanowicz-
Szwed K., Wichmann, J., Liebigs. Ann. 1991, 275-281.
(15) (a) Evans, D. A., Black, W. C., J. Am. Chem. Soc. 1992, 114,
2260-2262. (b) Damon, R. E., Coppola, G. M., Tetrahedron
Lett. 1990, 31, 2849-2852.
(16) Makin, S. K., Telegina, N. I., Gen. Chem. USSR 1962, 32,
1082.
(17) Yanovskaya, L. A., Rudenko, B. A., Kucherov, V. F.,
Stepanova, R. N., Kogan, G. A., Bull. Acad. Sci. USSR, Div.
Chem. Si. 1962, 2093-2099.
(20) Duthaler, R. O.; Herold, P.; Lottenbach, W.; Oertle, K.;
Riediker, M.; Angew. Chem. 1989, 101, 490-491; Angew.
Chem. Int. Ed. Engl. 1989, 28, 495-496.
(21) The assignment of the configuration is based on the known
preference for the Duthaler method.
(18) (a) de Koning, H.; Subramanian-Erhart; K. E. C.; Huisman, H.
O., Synth. Commun. 1973, 3, 25. (b) de Koning, H.; Mallo, G.
N.; Springer-Fidder, A.; Subramanian-Erhart; K. E. C.;
Article Identifier:
1437-2096,E;1999,0,10,1624,1626,ftx,en;G17599ST.pdf
Synlett 1999, No. 10, 1624–1626 ISSN 0936-5214 © Thieme Stuttgart · New York