Angewandte
Communications
Chemie
Asymmetric Synthesis
Short Enantioselective Total Synthesis of Tatanan A and 3-epi-
Tatanan A Using Assembly-Line Synthesis
Abstract: Short and highly stereoselective total syntheses of the
sesquilignan natural product tatanan A and its C3 epimer are
described. An assembly-line synthesis approach, using iterative
lithiation–borylation reactions, was applied to install the three
contiguous stereocenters with high enantio- and diastereose-
lectivity. One of the stereocenters was installed using a config-
urationally labile lithiated primary benzyl benzoate, resulting
in high levels of substrate-controlled (undesired) diastereose-
lectivity. However, reversal of selectivity was achieved by using
a novel diastereoselective Matteson homologation. Stereospe-
cific alkynylation of a hindered secondary benzylic boronic
ester enabled completion of the synthesis in a total of eight
steps.
I
terative strategies are highly attractive for the synthesis of
complex molecules,[1] particularly when minimal or no func-
tional-group manipulations between chain-extension steps
are required.[2,3] Iterative aldol reactions provide one such
strategy,[3] but if the target molecule is devoid of appropriate
functional-group handles, alternative methodologies are
required. We recently reported an iterative strategy for the
homologation of boronic esters that notably does not require
any functional-group manipulations between chain-extension
steps.[4,5] The process involves the repeated addition of chiral
lithiated carbamates or triisopropylbenzoate (TIB) esters and
leads to carbon chains bearing multiple contiguous methyl-
substituted stereogenic centers (Figure 1A). This approach
enabled the generation of extended chains of vicinal stereo-
centers (up to 10) with complete control over the relative and
absolute stereochemistry and applications to complex natural
products have also been reported.[6]
The power of iterative homologation of boronic esters lies
in its versatility since other alkyl groups can be easily
incorporated simply by varying the groups on the lithiated
benzoate reagent. In extending the reach of this method, we
sought to introduce aryl substituents as this would enable
access to an even broader array of targets, for example
tatanan A (1) and iryantherin K (2) (Figure 1B).[7,8] We
Figure 1. A) Iterative homologation of boronic esters. B) Natural prod-
ucts with alkyl- and aryl-substituted carbon chains. C) Use of primary
benzyl benzoates in homologation of boronic esters.
targeted the sesquilignan tatanan A (1) as this structurally
unique molecule had been reported to display potent
glucokinase-activating properties, thereby having implica-
tions for the development of antihyperglycemic drugs,
although its bioactivity has since been questioned by Zakar-
ian, who also reported its first synthesis.[9] The synthesis of
such a molecule would require homologation with a mixture
of alkyl- and aryl-substituted lithiated benzoates. Whilst
alkyl-substituted lithiated benzoates were known to be
effective in assembly-line synthesis, little was known about
the aryl-substituted lithiated benzoates.[10,11] Such species
present additional challenges in that, unlike the alkyl-
substituted lithiated benzoates, they are configurationally
[*] Dr. A. Noble, Dr. S. Roesner, Prof. Dr. V. K. Aggarwal
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS8 1TS (UK)
E-mail: v.aggarwal@bristol.ac.uk
Supporting information and the ORCID identification number(s) for
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!