COMMUNICATION
Synthesis of a versatile multifunctional building block for the construction of
polyketide natural products containing ethyl side-chains†
Daniel Keck and Stefan Bra¨se*
Received 25th July 2006, Accepted 18th August 2006
First published as an Advance Article on the web 30th August 2006
DOI: 10.1039/b610702h
The synthesis of a multifunctional building block for poly-
ketide construction and several subsequent reactions are
presented.
Polyketides are a major class of natural products that are
biosynthetically produced by sequential linkage of malonyl-
CoA subunits. Some life forms of mainly marine origin also
incorporate butyryl units in the form of ethylmalonyl-CoA into
the growing chains, which leads to ethyl side-groups in the natural
product.1 Thus, stereoselective syntheses of building blocks for the
Scheme 2 Reagents and conditions: (i) a) (c-Hex)2BCl (1.5 equiv.), NEt3
construction of pharmacologically interesting compounds such as
(1.8 equiv.), Et2O, −78 ◦C, then 0 ◦C, 2 h; b) formaldehyde (4.0 equiv.),
−78 ◦C, 2 h, then −26 ◦C, 14 h; c) H2O2, MeOH–pH7 buffer, 90%, dr =
19 : 1.
concanamycin A (1),2 salinomycin,3 lasalocid A4 and others are
highly significant. In this manuscript, we report the synthesis of
a multifunctional building block for the synthesis of compounds
such as 1 (Scheme 1).
Scheme 1 Core structure of concanamycin A (1) and multifunctional
building block 2.
Our synthetic efforts started from commercially available methyl
(R)-3-hydroxy-2-methylpropionate (3), which was transformed to
ketone 4 utilising a strategy originally developed by Paterson.5
This intermediate was then reacted with gaseous formaldehyde in
an anti-selective aldol reaction6 using a commercially available
hexane solution of chlorodicyclohexylborane. Upon oxidative
workup using hydrogen peroxide in MeOH, we were able to obtain
multifunctional building block 2 in an overall yield of 90% with a
diastereoselectivity of 19 : 1 in favour of the anti isomer (Scheme 2).
This useful building block can easily be transformed to
the corresponding triols. The stereochemistry of the newly
formed alcohol function can be controlled by variation of the
order of protecting group manipulations and reduction steps
(Scheme 3). Direct chelation-controlled reduction of 2 using
sodium triacetoxyborohydride7 leads to clean reduction in a
Scheme
3
Reagents and conditions: (i) NaBH(OAc)3 (3.0 equiv.),
THF–AcOH, 0 ◦C, 18 h, 90%, dr = 9 : 1; (ii) TIPSCl (1.1 equiv.), imidazole
(2.5 equiv.), DMAP (cat.), CH2Cl2, rt, 22 h, 99%; (iii), H2, 10% Pd/C,
MeOH, rt, 4 h, 99%; (iv) repeat of step (i), 72%, dr = 9 : 1.
yield of 90% with a 9 : 1 diastereoselectivity in favour of the
diastereomer with a syn relationship between the alcohol and
ethyl groups. When 2 is first protected as a TIPS-derivative
under standard conditions, debenzylated and then subjected to
reduction, isomer 8, with an anti relationship between the alcohol
and ethyl groups, can be obtained in a yield of 72%. Thus, alcohols
with opposite stereochemistry at C-3 can be synthesized using
a similar methodology in comparable yields and stereoisomeric
purities.
To emphasize the utility of our approach, we developed two
routes that could be useful in the application of these building
blocks to the synthesis of complex natural products. As the Wittig
reaction is a useful approach for fragment union, we transformed
alcohol 8 using the sequence detailed in Scheme 4. We were able to
obtain Wittig salt 10 in a overall yield of 47% starting from 8 using
University of Karlsruhe (TH), Institute of Organic Chemistry, Fritz-Haber-
Weg 6, 76131, Karlsruhe, Germany. E-mail: braese@ioc.uka.de; Fax: +49
721 608 8581; Tel: +49 721 608 2903
† Electronic supplementary information (ESI) available: Experimental
procedures and spectroscopic data for selected compounds. See DOI:
10.1039/b610702h
3574 | Org. Biomol. Chem., 2006, 4, 3574–3575
This journal is
The Royal Society of Chemistry 2006
©
Keck, Daniel
