A biosynthesis-inspired approach to over twenty diverse natural product-like scaffolds

Article abstract of DOI:10.1039/c6cc04662b

A synthetic approach to diverse scaffolds was developed that was inspired by diterpene biosynthesis. Initial scaffolds, generated using Diels-Alder reactions of furyl-functionalised amines, were transformed into alternative scaffolds using cleavage, ring expansion, annulation and rearrangement reactions. In total, 25 diverse scaffolds were prepared that were shown to have high natural product-likeness.

Full text of DOI:10.1039/c6cc04662b

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A biosynthesis-inspired approach to over twenty
diverse natural product-like scaffolds†
Cite this:DOI: 10.1039/c6cc04662b
James D. Firth,a Philip G. E. Craven,a Matthew Lilburn,a Axel Pahl,b
Stephen P. Marsden*a and Adam Nelson*ac
Received 3rd June 2016,
Accepted 13th July 2016
DOI: 10.1039/c6cc04662b
www.rsc.org/chemcomm
A synthetic approach to diverse scaffolds was developed that (Panel A); subsequent enzyme- (e.g. class I diTC) catalysed reactions
was inspired by diterpene biosynthesis. Initial scaffolds, generated then yield the final diterpene scaffolds. Inspired by this two-stage
using Diels–Alder reactions of furyl-functionalised amines, were synthesis of natural product scaffolds,10 we envisaged that a range
transformed into alternative scaffolds using cleavage, ring expan- of initial scaffolds might be analogously prepared11 by reacting
sion, annulation and rearrangement reactions. In total, 25 diverse furyl-substituted amines with maleic anhydride (Panel B).
scaffolds were prepared that were shown to have high natural The initial scaffolds would then be transformed into product
product-likeness.
scaffolds using a suite of cleavage, ring expansion, annulation
and rearrangement reactions. Thus, analogously to diterpene
The exploration of biologically-relevant chemical space is an biosynthesis, sp2-rich starting materials would be transformed
enduring challenge in both medicinal chemistry and chemical into diverse, sp3-rich polycyclic scaffolds.
biology. Natural products arise through the evolution of bio-
To start with, a range of substituted furyl-substituted amines
synthetic pathways driven by functional benefit to the host (ESI†) was reacted with maleic anhydride to give the corres-
organism,1 In biology-oriented synthesis,2 this pre-validated ponding cycloadducts 2a–k in moderate to excellent yield
relevance3 is exploited in the design of productive small mole- (Scheme 2). For example, DMB-protected (2-furyl)-amine 1 yielded
cules informed by the frameworks of natural products.4 The the tricyclic adduct 2a in 90% yield as a single diastereomer.
structural features of natural products are highly distinctive, Whilst syntheses of similar g-lactams are known,11 we were
and may be captured in a natural product-likeness score.5 In delighted that the synthesis of the related12 d-lactams 2b and 2c
particular, a high fraction of sp3-hybridised carbons6 (Fsp3) is was also efficient. Substitution of the 4-11c or 5-11b position of
an attractive feature because it correlates strongly with the the furan ring was well tolerated (- 2d and 2e respectively).
successful translation of clinical candidates.7 Indeed, about a Substitution a to nitrogen11d,e was also tolerated but the
third of small molecule drugs approved between 1981–2010 diastereoselectivity was poor: however, after esterification, the
were inspired by natural products.8
We envisaged a synthetic approach to diverse natural product- readily separated.
diastereomeric cycloadducts (2f/epi-2f and 2g/epi-2f) could be
like scaffolds that was broadly inspired by diterpene biosynthesis
The fusion of addition rings to the furyl-substituted amine
(Scheme 1).9 The bi- and polycyclic scaffolds of labdanes and starting material was possible in several contexts. For example, the
clerodanes are formed in two steps by diterpene synthases (diTCs). tetracyclic scaffolds 2h and 2i were obtained in 90% and 70% yield
Class II diTCs catalyse the initial cyclisation of geranylgeranyl respectively (the latter notably as a single diastereomer). In the
diphosphate (GGPP) to give bicyclic diphosphate intermediates case of 7-(2-furyl)-1,4-diazepane, esterification and hydrogenation
(to prevent retro-cycloaddition) gave the diastereomeric tetracyclic
scaffolds 2j and epi-2j in 44% and 17% yield respectively. The
reaction of a 2-(2-furyl)-pyrrolidine was, however, more proble-
a School of Chemistry, University of Leeds, Leeds LS2 9JT, UK.
E-mail: a.s.nelson@leeds.ac.uk, s.p.marsden@leeds.ac.uk
b Max Planck Institute of Molecular Physiology, Otto-Hahn Strasse 11, 44227
matic: reaction with maleic anhydride gave an open-chain
adduct which underwent (reversible) cycloaddition only after
esterification. After subsequent hydrogenation of the thermo-
dynamic mixture of products, the scaffold 2k was obtained
in 48% overall yield. The relative configuration of the cyclo-
adducts 2f, epi-2f, epi-2g 2j, epi-2j and 2k was determined by X-ray
crystallography (Fig. 2 and ESI†).
Dortmund, Germany
c Astbury Centre for Structural Molecular Biology, University of Leeds,
Leeds LS2 9JT, UK
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterisation data, computational analyses and crystallographic data
in CIF or other electronic forms. CCDC 1478957–1478963. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c6cc04662b
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Scheme 1 Pathways to natural products and natural product-like scaffolds. Panel A: class II diTCs catalyse the cyclisation of GGPP into alternative initial scaffolds
(e.g. CPP); diterpene scaffolds are formed in subsequent enzyme- (e.g. class I diTC) catalysed reactions. Panel B: envisaged synthetic strategy in which the generation
of alternative initial scaffolds would be followed by formation of natural product-like scaffolds. CPP, copalyl diphosphate. Sug and Sug’ denote glycosyl groups.
We established a suite of methods to transform the cycloadducts
into a wide range of molecular scaffolds (Scheme 3). Initially, we
focused on reactions that would cleave (and hence simplify) the
initial scaffold (Panel A). Cleavage of the dihydrofuran ring of 3
(from 2a; ESI†) was possible by dihydroxylation of the alkene and
treatment with periodate: subsequent reaction with sodium
borohydride gave the fused bicyclic scaffold 4 in 75% yield.
Crucially, the approach was effective with other initial scaffolds,
to give the related bi- and tricyclic scaffolds 5–8; remarkably, the
scaffold 6 was obtained as a single diastereomer, albeit in only
20% yield due to a difficult purification.
Next, we focused on formal ring expansions of the initial
scaffolds (Panel B).11f After dihydroxylation and oxidative cleavage
of 3 and 2c, it was possible to intercept the resulting dialdehydes:
thus, treatment with benzylamine and sodium triacetoxyboro-
hydride gave the ring-expanded analogues 9 and 10 in 82% and
62% yield respectively.
Annulation allowed access to more structurally complex
scaffolds (Panel C). For example, Boc-deprotection of 2e, followed
by TBTU-mediated g-lactamisation, gave the tetracyclic scaffold 11
in 87% yield. In addition, Boc-deprotection of 8, and concomitant
esterification, was followed by treatment with CDI to give the
spirocyclic scaffold 12 in 97% yield.
We harnessed alkene metathesis to induce rearrangement of
initial scaffolds (Panel D).13 Treatment of the diene 2f with
5 mol% Hoveyda–Grubbs second generation catalyst in TBME
gave the tricyclic scaffold 13 in 31% yield. In a similar vein, the
dienes 2g and epi-2g were converted into the related tricycles 14
and epi-14. The relative configuration of epi-14 was determined
by X-ray crystallography.
Finally, we employed functional group interconversions to modify
the substitution of two scaffolds (Scheme 4). These transformations
may be considered analogous to steps (e.g. hydroxylation; esterifica-
tion) that tailor the substitution of diterpene scaffolds. Esterification
of 2a, followed by hydrogenation and LiAlH4 reduction, gave the
hydroxymethyl-substituted scaffold 15. Mitsunobu reaction of
Scheme 2 Synthesis of alternative initial scaffolds. Panel A: synthesis of
an exemplar initial scaffold. Panel B: additional initial scaffolds prepared.
a
Deviations from standard conditions: then conc. HCl(aq), EtOH, 78 1C;
b
c
then H2, 10% Pd/C, EtOH; MeCN, rt then HCl, MeOH.
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Scheme 4 Tailoring of natural product-like scaffolds. Methods: (A) HCl,
EtOH; (B) H2, Pd/C; (C) LiAlH4; (D) NH4 HCO2, Pd/C; (E) DPPA, BnOH;
(F) PhB(OH)2, K3PO4, 5 mol% Pd(PPh3)4.
The diversity of the scaffolds was assessed by constructing a
hierarchical scaffold tree (Fig. 1).17 Twenty one different frame-
works are represented at the graph-node-bond level, which are
related hierarchically to seven parent (monocyclic) frameworks.
There is significant scaffold diversity at each level of hierarchy,
meaning that the scaffolds are not simply closely related
derivatives.
We determined natural product-likeness scores5 for both the
25 (deprotected) scaffolds prepared, and for a range of their
derivatives (Fig. 2). A virtual library of 11 223 decorated com-
pounds was enumerated using our open-access tool, LLAMA,18
by combining the 25 (deprotected) scaffolds with up to two typical
medicinal chemistry capping groups (ESI†). To assess comple-
mentarity to existing collections, natural product-likeness
scores were compared with those of 278 365 compounds from
Scheme 3 Generation of diverse natural product-like scaffolds. Panel A:
by ring Cleavage. Panel B: by ring expansion. Panel C: by annulation. Panel
D: by rearrangement. HG-II, Hoveyda–Grubbs second generation catalyst.
15 with N-Boc ethyl oxamate (16) as nucleophile, followed by
hydrolytic work up,14 gave the orthogonally-protected diamine
17 in 72% yield. Alternatively, transfer hydrogenation of 2a,
followed by Curtius rearrangement in the presence of benzyl
alcohol, gave the related Cbz-protected scaffold 18 in 67% yield.
Finally, esterification of 2d, Suzuki reaction with phenyl boronic
acid, and hydrogenation gave the scaffold 19 as a single diastereo-
isomer (46% yield over 3 steps).
In total, 25 scaffolds were prepared using our biosynthesis-
inspired approach (ESI†). The scaffolds were highly novel: the
Murcko framework15 of only two deprotected scaffolds were
substructures in a 2% sample of the ZINC database.16
Fig. 1 Hierarchical scaffold tree. The twenty one frameworks (red) at the
graph-node-bond level are related hierarchically to bicyclic (black) and
parent (monocyclic; blue) frameworks.
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Notes and references
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We acknowledge support from the Innovative Medicines
Initiative Joint Undertaking under grant number 115489,
resources of which are composed of financial contribution
from the European Union’s Seventh Framework Programme
(F97/2008-2013), EFPIA companies’ in kind contribution for
scaffold synthesis and Dr Chris Pask for X-Ray crystallography.
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2016