Synthetic studies toward ansatrienines: Application of the Evans- Tishchenko reaction to chiral enones

Article abstract of DOI:10.1016/S0957-4166(99)00069-5

Practical syntheses of the C9-C14 sterotriade 5 and the C1-C8 polyene unit 6 in ansatrienine A (mycotriene) (1a), and other ansamycin antibiotics is described. A key step for controlling the configuration of the stereogenic center at C13 involves the stereoselective reduction of enone 10 using the Evans-Tishchenko reaction.

Full text of DOI:10.1016/S0957-4166(99)00069-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 817–820
Synthetic studies toward ansatrienines: application of the
Evans–Tishchenko reaction to chiral enones
Kai-Uwe Schöning,a R. K. Hayashi,b Douglas R. Powell b and Andreas Kirschning a,∗
aInstitut für Organische Chemie, Technische Universität Clausthal, Leibnizstraße 6, D-38678 Clausthal-Zellerfeld, Germany
bDepartment of Chemistry, University of Wisconsin, 1101 University Avenue, Madison, WI 53706, USA
Received 19 January 1999; accepted 24 February 1999
Abstract
Practical syntheses of the C9–C14 sterotriade 5 and the C1–C8 polyene unit 6 in ansatrienine A (mycotriene)
(1a), and other ansamycin antibiotics is described. A key step for controlling the configuration of the stereogenic
center at C13 involves the stereoselective reduction of enone 10 using the Evans–Tishchenko reaction. © 1999
Elsevier Science Ltd. All rights reserved.
The ansamycins comprise a growing class of complex macrolactam antibiotics from microbial
sources.1 They are characterized by a cyclic structure in which an aliphatic ansa chain forms a bridge
between two non-adjacent positions of a cyclic π-system. Many of them exhibit antibacterial, antifungal
or antitumor activity. A subgroup which has seen increasing interest lately is the benzenic ansamycins
with 17 carbons and one nitrogen atom ansa chain.
In 1981, one of the first examples, the ansatrienines 1a and 2a, were isolated from the fermentation
broth of Streptomyces collinus by Zähner, Zeeck and coworkers.2 Independently, the groups of Natori,
∗
Corresponding author.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00069-5

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K.-U. Schöning et al. / Tetrahedron: Asymmetry 10 (1999) 817–820
Sueda and Sasaki3 described identical metabolites from Streptomyces rishiriensis which they named
mycotrienes. Additionally, more potent members were found, namely the trienomycines 3a4 and the
more recently discovered cytotrienes 1b5 as well as the highly active thiazinotrienomycines 4a.6 To date,
only Smith and Panek have reported the total syntheses of mycotrienin and trienomycin7 but this family
of ansamycins still represents a significant challenge to the synthetic chemist.
In this paper we describe practical syntheses of the C1–C8 and C9–C14 units 5 and 6. Methyl ester
78 was the starting point for the synthesis of fragment 5 (Scheme 1). Reduction followed by Lewis acid
mediated allylation of the intermediate aldehyde with 1-trimethylsilyl-2-propene gave rise to a 7.5:1
diastereomeric mixture of homoallyl alcohols which were protected as tert-butyldimethylsilyl (TBS)
ethers 8.9 From this stage, it took five synthetic steps for efficiently preparing allylic alcohol 9. The
sequence was initiated by ozonolysis of the alkenic double bond followed by reductive work-up. At this
stage, the diastereomers were separated by column chromatography. The primary alcohol was protected
as 2-(trimethylsilyl)ethoxymethyl (SEM) ether, which enabled us to remove the benzyl protection. This
was followed by periodinane oxidation10 of the newly formed alcohol. Nucleophilic addition of the
Grignard reagent derived from 2-bromo-1-propene furnished epimeric allyl alcohols 9 in a 2.5:1 ratio.
Scheme 1. Reagents and conditions: (a) dibal-H, CH2Cl2, −78°C, 1 h; (b) TiCl4, −78°C, CH2Cl2, 15 min, then
H2C_CH2CH2SiMe3, 15 min, 71% (for two steps), syn:anti=1:7.5; (c) TBSCl, imidazole, DMF, 35°C, 88%; (d) O3, MeOH,
i
−78°C, then 4–5 equiv. NaBH4, 0°C, 95%; (e) SEMCl, Pr2EtN, CH2Cl2, 40°C, 95%; (f) H2, Pd/C, ethyl acetate, 98%; (g)
Dess–Martin periodinane [lit.10], CH2Cl2, rt; (h) 2-bromo-1-propene, Mg, THF, then aldehyde, 0°C -→ rt, 72% (for two steps);
(i) TBAF, ms 4 Å, THF, 83%; (j) DDQ, C6H6, 60°C, 2d, 82%; (k) SmI2, PhCHO, THF, −10°C, 93%; (l) BzCl, pyr, −10°C -→ rt,
85% (+9% 11); (m) 10 equiv. MgBr2·OEt2, 2.5 equiv. iBuSH, Et2O, rt, 95%
At this stage it was uncertain which isomer prevailed. A Felkin–Ahn based transition state would
preferentially lead to the syn,anti-isomer. However, under chelate-Cram conditions formation of the
opposite anti,anti-stereoisomer would be favoured. Due to the low diastereoselectivity of the addition
process and the stereochemical ambiguity related to the outcome of the reaction, we reckoned that
applying the Evans–Tishchenko reduction11 on β-hydroxy-ketone 10 would selectively furnish the
desired stereotriade. The Evans–Tishchenko reaction requires a solution of SmI2 in THF and the
presence of an aldehyde and results in the directed reduction of a β-hydroxy ketone to afford an anti
diol with selective formation of a monoester.12 For this purpose, alcohols 9 were desilylated to the
corresponding epimeric 1,3-diols which were converted to 10 {[α]D25 +4.2 (c=1.3, CHCl3)} either using
DDQ or triphenylbismuth carbonate13 as selective oxidants, the latter being too expensive for large scale
oxidations. Treatment of 10 with an excess of samarium diiodide and benzaldehyde gave monobenzoate
11 {[α]D24 −15.7 (c=1.27, CHCl3)} as a single diastereomer in excellent yield. The stereochemical result
of this reduction can be rationalized by assuming transition state 13 with all C-substituents occupying
the equatorial positions. Final proof for the desired configurations of the three consecutive stereogenic
centers came from an X-ray structural investigation of dibenzoate 14 (Fig. 1), which was obtained by

K.-U. Schöning et al. / Tetrahedron: Asymmetry 10 (1999) 817–820
819
Figure 1. Thermal ellipsoid plot of 14 (ellipsoids are drawn in a 50% probability level)
benzoylation of the allylic alcohol group followed by removal of the SEM-protection using an alkyl thiol
in the presence of MgBr2 as the only feasable reagent system.14 The resulting alcohol 12 {[α]D +15.4
24
(c=1.18, CHCl3)} is an ideal precursor for fragment 5 and in addition was employed for synthesizing 14
(TPSCl, imidazole, DMF, 50°C, 57%).15
The synthesis of fragment 6 commenced with a regioselective reduction of (S)-dimethyl malate 15
following a known procedure (Scheme 2).16 Simple functional group manipulations led to alcohol 16
20
{[α]D +11.9 (c=1.0, CHCl3)} which was required for the alkenation step. Dess–Martin oxidation10
followed by Horner–Emmons-olefination using phosphonate 18 afforded diene 17 {[α]D20 +18.8 (c=1.0,
CHCl3)} which was converted into the target benzothiazole 6 in two steps which is required for the
coupling of fragments 5 with 6 under Julia-alkenation conditions.17
Scheme 2. Reagents and conditions: (a) BH3 SMe2, NaBH4, THF, rt; (b) TrCl, NEt3, 4-DMAP, DMF, rt, 73%; (c) Ag2O, MeI,
CH2Cl2, ∆, 21d, 76%; (d) LiAlH4, Et2O, 0°C -→ rt, 95%; (e) 4-methoxybenzyl chloride (PMBCl), NaH, DMF, 0°C -→ rt,
97%; (f) Lewatit SP 1080, MeOH/CHCl3, (7:1), 3–4d, 65%, (+12% starting trityl ether); (g) Dess–Martin periodinane [lit.10],
CH2Cl2, rt, 1.5 h; (h) 18, NaHMDS, THF, −70°C -→ −40°C, then addition of aldehyde, 67% (for two steps); (i) dibal-H, CH2Cl2,
−70°C -→ rt, 81%; (j) PPh3, DEAD, 2-mercapto-benzothiazole, THF, 32%; (k) H2O2, Mo7O24(NH4)6·4H2O, EtOH, rt, 24 h,
85%
In summary, we developed highly stereoselective syntheses of the C1–C8 and C9–C14 units 6 (11
steps; 6.8% overall yield) and 5 (13 steps; 20% overall yield) of most members of the benzenic
ansamycins. The Evans–Tishchenko reduction was efficiently applied for controlling the stereochemistry
at C13.

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K.-U. Schöning et al. / Tetrahedron: Asymmetry 10 (1999) 817–820
Acknowledgements
We thank the Fonds der Chemischen Industrie and the National Science Foundation (grant CHE-
9310428) for financial support. Donation of chemicals from E. Merck AG (Darmstadt) is gratefully
acknowledged.
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