A concise stereoselective synthesis of pterosin B

Article abstract of DOI:10.1016/j.tetlet.2018.10.056

Pterosin B is a naturally occurring indanone found in bracken fern (Pteridium aquilinum) that displays a variety of interesting pharmacological properties, but for which few stereoselective syntheses exist. Herein we describe a 7-step stereoselective synthesis of (2R)-pterosin B via 6-bromo-5,7-dimethylindan-1-one whose structure was confirmed by NOE analysis and structure determination by X-ray crystallography. The hydroxyethyl chain was introduced via a Suzuki-Miyaura cross-coupling reaction. The 2-methyl group was introduced stereoselectively by methylation of a SAMP [(S)-1-amino-2-methoxymethyl)pyrrolidine] hydrazone and the chiral auxiliary was removed to produce (2R)-pterosin B. The structure of pterosin B was confirmed by specific rotation and structural determination by X-ray crystallography.

Full text of DOI:10.1016/j.tetlet.2018.10.056

Accepted Manuscript
A concise stereoselective synthesis of Pterosin B
Hannah R. Dexter, Esther Allen, David M. Williams
PII:
S0040-4039(18)31288-7
https://doi.org/10.1016/j.tetlet.2018.10.056
TETL 50366
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
23 August 2018
16 October 2018
24 October 2018
Please cite this article as: Dexter, H.R., Allen, E., Williams, D.M., A concise stereoselective synthesis of Pterosin
B, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.10.056
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A concise stereoselective synthesis of Pterosin B
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Hannah R. Dexter, Esther Allen and David M.
Williams*
Centre for Chemical Biology, Department of Chemistry, Sheffield Institute for Nucleic Acids, University of
Sheffield, S3 7HF, UK
Tetrahedron Letters
journal homepage: www.elsevier.com
A concise stereoselective synthesis of Pterosin B
Hannah R. Dexter , Esther Allen and David M. Williams *
Centre for Chemical Biology, Department of Chemistry, Sheffield Institute for Nucleic Acids, University of Sheffield, S3 7HF, UK.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Pterosin B is a naturally occurring indanone found in bracken fern (Pteridium aquilinum) that
displays a variety of interesting pharmacological properties, but for which few stereoselective
syntheses exist. Herein we describe a 7-step stereoselective synthesis of (2R)-pterosin B via 6-
bromo-5,7-dimethylindan-1-one whose structure was confirmed by NOE analysis and structure
determination by X-ray crystallography. The hydroxyethyl chain was introduced via a Suzuki-
Miyaura cross-coupling reaction. The 2-methyl group was introduced stereoselectively by
methylation of a SAMP [(S)-1-amino-2-methoxymethyl)pyrrolidine] hydrazone and the chiral
auxiliary was removed to produce (2R)-pterosin B. The structure of pterosin B was confirmed by
specific rotation and structural determination by X-ray crystallography.
Available online
Keywords:
Pterosin B
Indanone
Suzuki-Miyaura reaction
SAMP
2009 Elsevier Ltd. All rights reserved.
———
 Corresponding author. Tel.: +44 114-222-9502; fax: +44 114-222-9346; e-mail: d.m.williams@sheffield.ac.uk

1. Introduction
Pterosins are a group of substituted 1-indanones originally characterized following their isolation from the bracken fern Pteridium
aquilinum.1–3 Pterosin B (1) occurs naturally as its (2R) isomer and is a decomposition product of the bracken toxin ptaquiloside (2)
(Fig. 1). Ptaquiloside is a norsesquiterpene glucoside natural product of the illudane type. Under alkaline conditions, ptaquiloside loses
glucose forming an unstable acylfulvene-type compound which subsequently decomposes to form pterosin B.4-6
Figure 1. Structures of pterosin B (1) and ptaquiloside (2).
Pterosin B displays several interesting pharmacological properties, for example in the treatment of diabetes, obesity4,7 and
osteoarthritis.8 Unfortunately, typical concentrations of pterosin B in bracken are very low and most chemical syntheses provide only
the racemic form.9,10 A short stereoselective synthesis of pterosin B is therefore highly desirable.
Recently (2R)-pterosin B has been prepared in 13 steps from 2-(4-bromo-2,6-dimethylphenyl)ethanol.11 A key step in this synthesis
involves an asymmetric intramolecular aldol reaction of compound 3 to produce 4 (syn/anti = 98:2, 85% ee) (Fig. 2). Subsequently,
compound 4 was converted into (2R)-pterosin B in 3 steps. As an alternative, more concise route to (2R)-pterosin B, we envisaged
elaboration of the core indanone structure 5 (Fig. 2), described previously by Sheriden and co-workers12 and describe herein a
stereoselective 7-step synthesis of (2R)-pterosin B and its characterisation by X-ray crystallography.
Figure 2. Synthetic precursors to pterosin B.
2. Results and Discussion
Our initial attempts towards the synthesis of 5, involving the Friedel-Crafts acylation of 2-bromo-1,3-xylene using 3-chloropropionyl
chloride, produced an inseparable mixture of the regioisomers 6a and 6b (Scheme 1). This finding has also been reported by Hsu and
1
co-workers13 in their synthesis of pterosin A. The H NMR spectrum of the mixture revealed a 2.5:1 ratio of products 6a and 6b,
respectively, based on the signals for the aromatic ring protons.
Scheme 1. Friedel-Crafts acylation of 2-bromo-1,3-xylene to produce an inseparable mixture of isomers 6a and 6b.
Heating the mixture of 6a and 6b in concentrated sulfuric acid resulted in cyclisation to produce a mixture containing indanones 5
1
and 7. The H NMR spectrum of the mixture displayed singlets at 7.49 and 7.22 ppm, corresponding to the aromatic protons of the
respective indanones 7 and 5, in agreement with the literature.13 The relative amounts of the two isomers corresponded to that prior to
cyclisation, with 5 being the major product and being produced in a 2.5:1 ratio to 7. After silica column chromatography and
recrystallisation from ethyl acetate, 5 was obtained in 22% yield from bromoxylene. The identity of 5 was further confirmed by both
NOESY NMR (NOEs to H-4 and H-2 were observed upon irradiation of H3) (Fig. 3) and X-ray crystallography14 (ESI Fig. 1).
Me
O
1
O
Figure 3. Structures of indanones 5 and 7 and observed NOE interactions in the H NMR of 5.
Br
Br
Br
A variety of approaches have been used previously for introducing the hydroxyethyl group. McMorris and co-workers15 reacted the
H2
H
Grignard reagent of 22-bromo-1,3-xylene with oxirane. Following acetylation of the hydroxyethyl group, the indanone ring was
consMtreucted using a Friedel Crafts acylation with chloroprOopionyl chloride followed by an acid-catalysed cyclisation.12,15 In contrast,
H3
H3
7
5
H
Farrell and co-workers reported the first example of a Pd-catalysed method in which a 6-bromoindanone was employed in a Heck
4
reaction with vinyl acetate in the synthesis of pterosin Z.16 This cross-coupling reaction gave a 1:1 mixture of E and Z isomers in 29%
yield together with a 6-vinyl indanone by-product. Reduction and de-acetylation afforded the hydroxyethyl side chain. More recently a
Suzuki-Miyaura reaction was used to produce a 6-vinylated indanone precursor of pterosin A. Unfortunately this could not be resolved
from the reduced (6H) by-product. The hydroxyethyl group was obtained following subsequent hydroboration.13
In the synthesis of pterosin B we sought to introduce the hydroxyethyl group directly onto indanone 5 using a Suzuki-Miyaura cross-
coupling with the benzyl-protected trifluoroborate salt 8.17 Thus, cross-coupling of 8 with compound 5 afforded indanone 9 in 54%
yield (Scheme 2).
Scheme 2. Suzuki-Miyaura cross-coupling, and methylation of SAMP hydrazone.
A variety of methods for asymmetric enolate alkylation are available18,19 for achieving selective methylation of 9. These include
well-established procedures using Enders' chiral hydrazone (SAMP/RAMP) methodology20-22 or via chiral N-amino cyclic carbamate
(AAC) hydrazones.23 We elected to use Enders' methodology due to the ready availability of the chiral auxiliary and the expectation that
the methylated diastereomeric hydrazones would be resolvable. To introduce the methyl group with the correct R-configuration,
delivery to the bottom face of the aza-enolate requires the use of SAMP. Thus compound 9 was converted to its corresponding SAMP
hydrazone 10 by heating at reflux with SAMP and PTSA in toluene in the presence of molecular sieves. Methylation of 10 was
achieved by treatment with LDA in THF at -78 °C followed by the addition of iodomethane. This provided 11 as a mixture of
diastereoisomers following silica column chromatography. Although we were unable to separate these two diastereoisomers using silica
chromatography, they could be fully resolved by reversed-phase HPLC (RP-HPLC) using an isocratic elution of water/acetonitrile
(15/85) (ESI, Fig. 2)). Based on HPLC analysis a d.r. of 85:15 in favour of the 2R diastereoisomer (11) was obtained. Following
purification by RP-HPLC, 11 was obtained in 61% yield.
To remove the chiral auxiliary from 11 we investigated using O3 in CH2Cl2 as described previously.24,25 During our initial attempts to
obtain the benzylated indanone 12 (Scheme 3) by ozonolysis, we found that the desired product contained small amounts of a

1
contaminant that was isolated by RP-HPLC. This was subsequently identified by H NMR and mass spectrometry as the benzoylated
O
compound 13. However, by using a low flow o
H
f
-Cozub
o
e
n
®
e
,
, short reaction times and low temperature, oxidation of the benzyl group could
O3, DCM,
BnO
be minimized. Removal of the benzyl group froMmeO12H,b6y8%catalytic hydrogenation using an H-Cube® afforded (2R)-pterosin B as a single
enantiomer in 68% yield following final purification by RP-HPLC.
-78° C, 66%
1
11
We also investigated whether the benzoylated indanone 13 could be successfully converted into pterosin B. Although removal of the
,
12
H
,
e
O
benzoyl group using aqueous ammonia resulted in the expected racemization (as evidenced by chiral phase HPLC, ESI Fig. 3), de-
acylation could be achieved without loss of stereochemistry using an esterase from Bacillus subtilis (ESI Fig. 3).
s
e
a
r
M
O
e
t
q
s
a
e
,
BzO
e
S
n
B
a
x
e
h
%
8
Scheme 3. Completion of the synthesis of (2R)-pterosin B (1).
2
Crystallisation of (R)-pterosin B (1) from a mixture of chloroform and hexane provided a sample with an ee of 100%, identical
13
specific rotation to that described in the literature11 and permitted confirmation of its structure by X-ray crystallography (Fig. 4).26
Figure 4. ORTEP structure of (2R)-pterosin B obtained by X-ray crystallography.19
3. Conclusion
In conclusion we have developed a concise stereoselective
synthesis of the naturally occurring (R)-enantiomer of pterosin B in 7-
steps from commercially available 2-bromo-1,3-xylene. The ready
availability of (R)-pterosin will enable further evaluation of its
biological properties.
4. Acknowledgements
We are very grateful to the Engineering and Physical Sciences
Research Council (EPSRC) UK EP/P010075/1 (DMW, EA) and to
QuantuMDx Ltd. (HRD) for financial support.
5. Supplementary data
Electronic supplementary information (ESI) related to this article containing 1H NMR and 13C NMR spectra for all new compounds,
HPLC data (PDF) and X-ray structures for compounds 1 and 5 (CIF) can be found at xxx
6. References and notes
1.
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Feng-Lin, H. Use of pterosin compounds for treating diabetes and obesity. WO 2010085811 A2, 2010.
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14. Structure for compound 5 deposited at CCDC. Accession number 1851094.
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16. Farrell, R.; Kelleher, F.; Sheridan, H. J. Nat. Prod. 1996, 59, 446-447.
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150-151.
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26. Structure for compound 1 deposited at CCDC. Accession number CCDC 1851093.
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Stereoselective synthesis of natural 2R isomer of pterosin B
Concise 7-step synthesis of natural pterosin B
X-ray structure of pterosin B