A flexible, stereoselective approach to the decorated cis-hydrindane skeleton: Synthesis of the proposed structure of faurinone

Article abstract of DOI:10.1002/chem.200800930

A flexible, stereoselective approach to the cis-hydrindane motif found in a number of biologically active natural products that utilizes highly diastereoselective SmI₂-mediated cyclizations of aldehyde and halide substrates was demonstrated. Aldehydes were prepared to investigate the stereoselectivity of the proposed SmI₂-mediated construction of the cis-hydrindane system. Treatment of aldehydes with SmI₂ in THF and tBuOH resulted in successful cyclization and construction of three contiguous stereocenters. This cyclization proceeds through reduction of the aldehyde and addition of the resulting ketyl-radical anion to the alkene through anti-transition structure to give samarium (III) enolates. It was observed that SmI₂-mediated halide-alkene cyclizations provide an easy alternative for the synthesis of less oxygenated targets.

Full text of DOI:10.1002/chem.200800930

DOI: 10.1002/chem.200800930
A Flexible, Stereoselective Approach to the Decorated cis-Hydrindane
Skeleton: Synthesis of the ProposedStructure of Faurinone
[a]
Thomas J. K. Findley,[a] DavidSucunza, Laura C. Miller,[a] DavidT. Davies, [b] and
DavidJ. Procter* [a]
Since its introduction to the synthetic community by
Kagan, the one-electron reducing agent samarium(II) iodide
(SmI2) has found widespread use in organic synthesis.[1] The
reagent has been used to mediate many processes ranging
from functional group interconversions to complex carbon-
carbon bond-forming sequences.[1] Cyclisation reactions are
among the most useful transformations mediated by SmI2
and these have proved to be valuable tools for natural prod-
uct synthesis.[1k] The intramolecular addition of radicals, gen-
erated from aldehydes and halides, to alkenes, are among
the most common classes of cyclisation mediated by the re-
Figure 1. Selected natural products containing a substituted cis-hydrin-
dane core.
agent.[1]
The hydrindane skeleton is found in a multitude of bio-
logically active natural products. We wished to develop a
stereoselective approach to the cis-hydrindane skeleton 1
that would allow stereocontrolled installation of substituents
around the bicyclic structure.[2] A flexible approach to 1
would facilitate approaches to a number of natural products,
many of which display important biological activity
(Figure 1). The sesquiterpene glycosides, dendronobiloside
A and B, display immunomodulatory activity,[3] and are
closely related to faurinone 2.[4] Pleuromutilin 3 has an in-
hibitory effect against the bacteria Staphylococcus aureous
and is known to prevent bacterial protein synthesis.[5] Bak-
kenolides, such as 4, display a variety of biological activities
including selective cytotoxicity.[6] Here we report a flexible
approach to the substituted cis-hydrindane skeleton that ex-
ploits diastereoselective conjugate additions to b-substituted
cyclohexenones in conjunction with highly diastereoselective
SmI2-mediated cyclisations of aldehyde and halide sub-
strates. We have applied the approach in the first synthesis
of the proposed structure of rac-faurinone.
We envisaged constructing the quaternary stereocentre in
1 by conjugate addition to substituted b-alkyl cyclohexe-
nones. Prior to our work, little was known about the efficacy
and diastereoselectivity of such additions.[7] Aldehydes or
halides 5 would therefore be accessible from enones 7 via
intermediates 6. We believed that substrates 5 would under-
go highly stereoselective cyclisations on treatment with
SmI2. The flexible approach would provide expedient access
to the cores of a number of natural products (Scheme 1).
Aldehydes 13 and 14 were prepared to investigate the dia-
stereoselectivity of the proposed SmI2-mediated construc-
tion of the cis-hydrindane system. Grignard addition to 8[8]
according to the procedure of Tietze et al.,[9] and protection
[a]T. J. K. Findley, Dr. D. Sucunza, L. C. Miller, Dr. D. J. Procter
School of Chemistry
The University of Manchester
Oxford Road, M13 9PL (UK)
Fax : (+44)161-275-4939
E-mail: david.j.procter@manchester.ac.uk
[b]Dr. D. T. Davies
GlaxoSmithKline
Gunnelswood Road, Stevenage, SG1 2NY (UK)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200800930.
Scheme 1. General approach to the cis-hydrindane skeleton (PG=pro-
tecting group, X=H or OEt).
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Chem. Eur. J. 2008, 14, 6862 – 6865

COMMUNICATION
of the primary hydroxy group gave 9 (Scheme 2). Subse-
quent dimethylation of enone 9 gave 10. Treatment of
enones 9 and 10 with dimethylcuprate and trapping of the
resultant enolates with Cominsꢁ reagent[10] gave enol triflates
Scheme 3. Diastereroselective samarium(II)-mediated cyclisations.
Scheme 2. General route to cyclisation substrates (Cominsꢁ reagent=
N-(5-chloro-2-pyridyl)triflimide).
11 and 12, respectively. Palladium-catalysed methoxycarbo-
nylation, deprotection, and oxidation then gave 13 and 14 in
excellent overall yield (Scheme 2).
Pleasingly, treatment of 13 and 14 with SmI2 in THF and
tBuOH resulted in successful cyclisation and concomitant
construction of three contiguous stereocentres. Products 15
and 16 were obtained in high yield and with high diastereo-
1
selectivity (d.r., >10:1 by H NMR spectroscopy, a- to the
ester). Strikingly, 13 underwent cyclisation to give 15 as the
syn, syn-diastereoisomer, whereas cyclisation of 14 gave 16
as the syn, anti-diastereoisomer. The stereochemistry of the
products was confirmed by conversion of 15 and 16 to the
corresponding 1-naphthyl carbamates and subsequent X-ray
crystallographic analysis.[11] The SmI2-mediated cyclisation
proceeds via reduction of the aldehyde and addition of the
resulting ketyl-radical anion to the alkene through anti-tran-
Scheme 4. Diastereoselective route to cyclisation substrates.
19 and 21 were then converted to cyclisation substrates 20
and 22 using the straightforward sequence outlined in
Scheme 2.
sition structure 17 to give samarium
A
An alkyl iodide cyclisation substrate 23 was also prepared
from an intermediate, protected alcohol in three steps (HF,
pyridine, MeCN; MsCl, NEt3, CH2Cl2; NaI, acetone; 74%
over 3 steps). Treatment of 20 and 22 with SmI2 in THF and
tBuOH resulted in successful cyclisation, and products 24
and 25 were obtained in high yield with excellent diastereo-
control, again being observed in the cyclisation (d.r., >10:1
Protonation of the enolate in these systems typically
occurs selectively from the a-face (vide infra). In the cyclisa-
tion of 13 (R=H), a-protonation occurs to give 15, howev-
er, reaction of 14 (R=Me) gives rise to a samarium(III)
T
enolate in which protonation from the a-face is blocked by
an axial methyl group, and quenching from the b-face
occurs to give 16 (Scheme 3).
1
by H NMR spectroscopy). The stereochemistry of 24 was
The general route can be adapted to access cis-hydrindane
frameworks decorated with five stereocentres (Schemes 4
and 5). The formation of enol triflate 19 illustrates the utility
of the cuprate addition for the stereocontrolled construction
of the quaternary stereocentre and the introduction of
groups other than methyl. Enol triflate 21 was prepared by
methylation of enol ether 8, Grignard addition, protection,
and methylcuprate addition–enolate trapping. Enol triflates
confirmed by X-ray crystallography on a related product,[11]
while the stereochemistry of 25 was confirmed by NOE
studies. Iodide 23 also underwent highly diastereoselective
1
cyclisation (d.r., >5:1 by H NMR spectroscopy) on treat-
ment with SmI2-HMPA[13] to give 26. SmI2-mediated halide-
alkene cyclisations provide a convenient alternative for the
synthesis of less-oxygenated targets (Scheme 5). Cyclisation
products 24 and 25 possess the substitution patterns found
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D. J. Procter et al.
Scheme 7. Diastereoselective samarium(II)-mediated cyclisations in an
approach to the proposed structure of faurinone.
Scheme 5. Diastereoselective samarium(II)-mediated cyclisations.
in the cis-hydrindane cores of pleuromutilin 3 and bakkeno-
lide III 4, respectively (see Figure 1)
We have exploited the approach in a concise synthesis of
the proposed structure of faurinone (2), a sesquiterpene
ketone isolated from Valeriana officinalis (Figure 1).[4] The
TMS enol ether derived from 4-isopropylcyclohexanone un-
derwent Saegusa oxidation[14] to give 4-isopropylcyclohexe-
none.[15] Grignard addition and oxidative rearrangement of
the resultant tertiary alcohol with pyridinium chlorochro-
mate (PCC) then gave enone 27. Highly diastereoselective
organocopper addition, enolate trapping, carbonylation and
acetal deprotection gave cyclisation substrate 28 (d.r.,
>20:1) (Scheme 6).
Scheme 8. Completing an approach to the proposed structure of fauri-
As expected, cyclisation of aldehyde 28 with SmI2 pro-
ceeded with excellent stereocontrol to give 29 as a single
none (TCDI=1,1’-thiocarbonyldiimidazole).
the stability of the cyclic, bis-
hemi-ketal accounts for the
smooth monoaddition of meth-
yllithium to each carbonyl
group. Conversion of 33 to the
thioimidazolide and radical de-
oxygenation completes the
first synthesis of the proposed
structure of faurinone 2[16]
(Scheme 8).
We have developed a flexi-
ble, stereoselective approach[17]
Scheme 6. Preparation of the cyclisation substrate in an approach to the proposed structure of faurinone.
to the cis-hydrindane motif
found in a number of biologi-
1
diastereoisomer by H NMR spectroscopy. The stereochemi-
cal outcome of the cyclisation was confirmed by conversion
of 29 to the corresponding 1-naphthyl carbamate and X-ray
crystallographic analysis.[11] Alkyl iodide 30 was prepared
from 28 (NaBH4, THF-MeOH, RT, then I2, Ph3P, imidazole,
CH2Cl2, RT; 58% for two steps) and underwent smooth cyc-
lisation on treatment with SmI2-HMPA[13] to give 31 as a
cally active natural products that utilizes highly diastereose-
lective SmI2-mediated cyclisations of aldehyde and halide
substrates. The strategy has been exploited in the first syn-
thesis of the proposed structure of faurinone, a sesquiter-
pene ketone isolated from Valeriana officinalis.
single
diastereoisomer
by
1H NMR
spectroscopy
(Scheme 7).
Acknowledgements
Our approach to faurinone continued with the epimerisa-
tion of 29 and formation of the bis-lactone 32. The structure
of 32 was confirmed by X-ray crystallography.[11] Reaction
of 32 with methyllithium gave 33 in good yield. We believe
We thank the University of Manchester (studentship, T.J.K.F.), Glaxo-
SmithKline (CASE award, L.C.M.) and the EPSRC and EU (D.S.) for
funding.
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Stereoselective Approach to the cis-Hydrindane Skeleton
COMMUNICATION
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Keywords: hydrindane
samarium · total synthesis
· natural products · radicals ·
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Received: May 15, 2008
Published online: July 4, 2008
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