Stereoselective Total Synthesis of the Non-Contiguous
Polyketide Natural Product (–)-Dolabriferol
and Srihari Pabbaraja*
Abstract: The stereoselective total synthesis of the non-contig-
uous polypropionate dolabriferol has been accomplished in 17
steps, by an approach that is both divergent and convergent.
The key reactions involved are enantioselective cross-aldol cou-
pling, aldol dimerisation of propionaldehyde, Sharpless asym-
Investigation of biological and pharmacological properties of
the secondary metabolites isolated from marine natural sources
has been a subject of great importance. The polyketide natural
products attract significant attention due to their remarkable
biological and pharmacological activities, such as antibiotic,
antifungal, anticancer, anti-inflammatory, immunosuppressant
In 1996, Gavagnin et al. isolated dolabriferol (1, Figure 1)
from the skin of the anaspidean mollusc Dolabrifera dolabrifera,
a tropical sea hare.
This compound is assumed to protect the
shell-less mollusc from predators, but its biological properties
have not been fully explored. In 2012 the structurally related
molecules dolabriferol B (2) and C (3) were also isolated from
Structurally, these natural products are each made up of two
polypropionate subunits joined through an unusual acyclic es-
ter linkage. This is also a key skeleton of other similar natural
products, such as baconipyrones A–D
(4–7) and siserrone A
(8, Figure 1). Dolabriferol B has a similar skeleton to dolabriferol
but possesses an ethyl moiety in place of the isopropyl moiety
at C18. Dolabriferol C has an extended polyketide chain in the
acid fragment. Although the structure of dolabriferol was
established by extensive NMR experiments and X-ray analysis,
its absolute configuration was only determined after its total
synthesis by Vogel et al.
The unusual ester linkage and the
stereochemistry present in dolabriferols make it an attractive
[a] Department of Organic Synthesis and Process Chemistry
CSIR-Indian Institute of Chemical Technology,
Tarnaka, Hyderabad - 500007, Telangana, India
[b] Academy of Scientific and Innovative Research (AcSIR), Anusandhan
2-Rafi Marg, New Delhi 110001, India
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201701748.
Eur. J. Org. Chem. 2018, 1230–1240
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
metric epoxidation, regioselective epoxide opening and Yama-
guchi esterification. The effects of the protecting groups on the
alcohol substrate on differential reactivity in Yamaguchi esterifi-
cation were noteworthy.
Figure 1. Polyketide/polypropionate natural products.
synthetic target, and several contributions have provided exten-
sive precedent in this regard.
Although it is believed that
the unusual connectivity might originate from a biosynthetic
its production through a mild base- or acid-catalysed
retro-Claisen rearrangement was not ruled out, because the re-
arrangement would proceed by an energetically favourable
this was further supported by its total synthesis by
means of a retro-Claisen approach.
Vogel et al.
the first total synthesis of (–)-dolabriferol by use of Paterson's
esterification protocol, in which a polyketide alicyclic alcohol
was coupled with a polyketide acid. Attempts to couple hemi-
acetal and acid fragments were unsuccessful. However, through
the use of the enol acetate, the steric bulk of the alcohol frag-
ment was reduced, which gave a promising result for esterifica-
tion. Goodman et al.
utilised Evan's aldol approach and retro-
Claisen rearrangement as the key steps for the total synthesis