Selective Synthesis of Cyclooctanoids by Radical Cyclization of Seven-Membered Lactones: Neutron Diffraction Study of the Stereoselective Deuteration of a Chiral Organosamarium Intermediate

Article abstract of DOI:10.1002/anie.201606792

Seven-membered lactones undergo selective SmI₂–H₂O-promoted radical cyclization to form substituted cyclooctanols. The products arise from an exo-mode of cyclization rather than the usual endo-attack employed in the few radical syntheses of cyclooctanes. The process is terminated by the quenching of a chiral benzylic samarium. A labeling experiment and neutron diffraction study have been used for the first time to probe the configuration and highly diastereoselective deuteration of a chiral organosamarium intermediate.

Full text of DOI:10.1002/anie.201606792

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International Edition: DOI: 10.1002/anie.201606792
German Edition: DOI: 10.1002/ange.201606792
Radical Cyclization
Selective Synthesis of Cyclooctanoids by Radical Cyclization of Seven-
Membered Lactones: Neutron Diffraction Study of the Stereoselective
Deuteration of a Chiral Organosamarium Intermediate
Xavier Just-Baringo, Jemma Clark, Matthias J. Gutmann, and David J. Procter*
Abstract: Seven-membered lactones undergo selective SmI2–
H2O-promoted radical cyclization to form substituted cyclo-
octanols. The products arise from an exo-mode of cyclization
rather than the usual endo-attack employed in the few radical
syntheses of cyclooctanes. The process is terminated by the
quenching of a chiral benzylic samarium. A labeling experi-
ment and neutron diffraction study have been used for the first
time to probe the configuration and highly diastereoselective
deuteration of a chiral organosamarium intermediate.
M
apping new routes to challenging molecular architectures
is a major driving force in the development of synthetic
chemistry.[1] Cyclooctanes are found in important natural
products and pharmaceuticals and present a fascinating
synthetic challenge due to their high ring strain and trans-
annular interactions.[2,3] The race towards the total synthesis
of paclitaxel (Taxol)[4] spurred particular interest in the motif
and the construction of cyclooctanes has become a fertile field
(Scheme 1).[5–11] Among these methods, radical cyclization
approaches are scarce and have relied mainly on radicals
generated from halides,[12] ketones[13,14] and aldehydes[15] and
8-endo cyclization modes (Scheme 2A).[16]
Scheme 2. A) 8-Endo cyclizations dominate cyclooctane synthesis
under radical conditions. B) A proposed 5-exo radical cyclization
approach to cyclooctanes and the challenges involved.
Samarium diiodide (Kaganꢀs reagent, SmI2)[17,18] is per-
haps the most versatile reductive electron transfer (ET)
reagent and has been used extensively for carbon–carbon
bond forming reactions.[19] We recently expanded the scope of
SmI2-mediated reactions by introducing activation modes
involving the reduction of carboxylic acid derivatives using
SmI2–H2O.[20] The acyl-type radicals now accessible have been
exploited in new functional group transformations and highly
selective radical cyclizations involving carbon–carbon bond
formation.[20–24] In the case of lactones, ET from SmII to the
carbonyl gives rise to radical anions (cf. I in Scheme 2) that
are stabilized by hyperconjugation with the adjacent oxygens
and by H2O.[20,21a–e] Very recently, we demonstrated that ET to
all lactones using SmI2–H2O is reversible and this back ET
typically impedes productive reductive transformations.[21d]
However, new opportunities for carbon–carbon bond forma-
tion arise if the transient radical anions can be trapped by
a suitably placed radical acceptor.
Scheme 1. Natural products containing cyclooctane rings.
[*] Dr. X. Just-Baringo, J. Clark, Prof. Dr. D. J. Procter
School of Chemistry, University of Manchester
Manchester, M13 9PL (UK)
E-mail: david.j.procter@manchester.ac.uk
Here we describe a synthesis of substituted cyclooctanes
that exploits the first radical cyclizations of seven-membered
lactones, which can be easily accessed by Baeyer–Villiger
oxidation of cyclohexanones. The process involves ET to the
lactone 1, and generation of radical anion I, followed by
Dr. M. J. Gutmann
ISIS Facility, Rutherford Appleton Laboratory
Chilton, Didcot, Oxfordshire, OX11 0QX (UK)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201606792.
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Table 1: Cyclooctanoid synthesis by 5-exo-trig radical cyclization of
trapping of the radical by the tethered alkene. Crucially,
potential issues involving back ET to SmIII, radical fragmen-
tation, and radical reduction are overcome. In situ reduction
of the hemiketal intermediate 3 delivers 1,4-cyclooctandiols 2
(Scheme 2B). The 5-exo-trig radical cyclization of lactones
stands in sharp contrast to most radical approaches to
cyclooctanes that involve 8-endo attack (Scheme 2B).[3b]
Furthermore, we report the use of a labeling experiment
and a neutron diffraction study to probe for the first time the
configuration and highly diastereoselective quenching of
a chiral organosamarium.
seven-membered lactones with SmI2–H2O.[a]
The feasibility of the transformation was first assessed
using lactone 1a (R1 = Me; R2 = Ph; R3 = H) (Table 1). As
expected, no reaction was observed when 1a was treated with
SmI2 in THF (2-fold excess) and only upon addition of H2O
was conversion observed. After optimization of the amount of
H2O additive employed, 1,4-cyclooctandiol 2a was obtained
in good isolated yield. Oxidation of the crude diol 2a with
Dess–Martin periodinane facilitated assessment of the dia-
stereoselectivity and stereochemical course of the radical
cyclization by simplifying the diastereoisomeric mixture and
providing crystalline product 3a in 74% overall, isolated
yield. 7-Methyl substituted lactones 1b–h (R1 = Me), bearing
aryl-substituted alkene tethers with various groups in all
positions of the aromatic moiety, underwent efficient cycliza-
tion to give the corresponding hemiketals 3b–h in good to
excellent yields (62–93%, 2 steps) and with good diastereo-
selectivities (75:25 to 89:11 d.r.). Variation of the substituent
in position 7 of the lactone proved possible. For example,
benzyl substituted hemiketals 3l,m (R1 = Bn) were obtained
in good to excellent isolated yield and with good diastereo-
control. Halogen substituents were compatible with the
cyclization conditions (formation of 3b, 3c, 3d, 3e, 3m, 2o)
and serve as handles for further functionalization of the
products. The trifluoromethyl group also proved stable to the
reducing conditions and cyclooctane 3c was obtained in
excellent overall isolated yield. X-ray crystallographic anal-
ysis of 3a–d revealed the syn selectivity of the cyclization.[25]
Terminal alkenes could also be employed to intercept the
radical anion intermediate, however, in the absence of an aryl
substituent on the alkene, radical cyclization was less efficient
and cyclooctanes 3i and 3k were obtained in low overall yield
and with lower diastereoselectivity. The cyclization proved
surprisingly tolerant of steric hindrance: lactone 1j, bearing
gem-disubstitution a to the lactone carbonyl, underwent
efficient radical cyclization upon treatment with SmI2–H2O.
In this particular case, the product obtained in good overall
yield after oxidation was the hydroxyketone 3j rather than
the corresponding hemiketal.
[a] Conditions: SmI2 (8 equiv, 2-fold excess), THF, H2O (800 equiv),
room temperature. Isolated yields for 2 steps. Diastereoselectivities were
determined from H NMR spectra of crude product mixtures.
1
Lactones 1n and 1o lacking an alkyl substituent at the 7
position of the ring (R1 = H) also underwent cyclization to
give 1,4-cyclooctandiols 2n and 2o in moderate yield. This
observation likely results from the lower relative stability of
the required reactive conformation in which the alkene tether
adopts a pseudo-axial conformation (Scheme 3). The absence
of an alkyl substituent in position 7 of the lactone ring favors
a pseudo-equatorial conformation of the tether, disfavoring
its interaction with the radical anion.
Scheme 3. The impact of lactone conformation on the efficiency of
radical cyclization.
2
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The relative configuration of the products is consistent
intermediate IV is formed[29] and the more stable anti-IV
with an anti attack of the radical anion intermediate on the
tethered alkene (conformation IIb) involving a product-like
transition state, followed by a second ET and subsequent
protonation (or deuteration, see below) (Scheme 4). The
diastereomer is quenched selectively with retention of con-
figuration at carbon to generate samarium alkoxide V. Finally,
deuteration of samarium(III) alkoxide V delivers d-3a.[30] To
our knowledge this is the first time that the configuration of
a diastereoselectively deuterated product has been confirmed
using neutron diffraction.[31]
In conclusion, radical exo-cyclization of unsaturated
seven-membered lactones, triggered by single ET to the
carbonyl group by SmI2–H2O, generates cyclooctanes typi-
cally in good yield and high diastereoselectivity. Neutron
diffraction has been used to probe, for the first time, the
stereochemical course of the selective deuteration of a chiral
organosamarium intermediate.
Acknowledgements
We thank the EPSRC (Established Career Fellowship to
D.J.P. and Postdoctoral Fellowship to X.J.-B.).
Scheme 4. Proposed mechanism and rationale for the origin of diaste-
reoselectivity in the radical cyclization.
Keywords: cyclization · cyclooctanes · neutron diffraction ·
radicals · samarium diiodide
observed selectivity likely results from minimization of
electrostatic interactions and steric clashes between the
alkene and the radical anion intermediate, thus favoring IIb
over IIa.[26] Subsequent ET to III and protonation of IV gives
rise to hemiketal 3a, which is then reduced further.
Interestingly, carrying out the cyclization of 1a with SmI2–
D2O gave d-3a with high diastereoselectivity at the benzylic
position (> 90:10 d.r.). To gain further insight into the
mechanism of the radical cyclization and the nature of the
organosamarium intermediate IV,[27] formed upon reduction
of radical III, we determined the relative configuration of the
deuterated product d-3a using neutron diffraction
(Scheme 5).[28] Based on the analysis of a crystalline sample
of d-3a, we propose that a chelated, chiral organosamarium
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Received: July 13, 2016
Published online: && &&, &&&&
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Communications
Radical Cyclization
X. Just-Baringo, J. Clark, M. J. Gutmann,
D. J. Procter*
&&&& — &&&&
Selective Synthesis of Cyclooctanoids by
Radical Cyclization of Seven-Membered
Lactones: Neutron Diffraction Study of
the Stereoselective Deuteration of
Seven-membered lactones undergo
selective SmI2–H2O-promoted radical
cyclization to form substituted cyclo-
octanols. The products arise from an exo-
mode of cyclization rather than the usual
endo-attack. A labeling experiment and
neutron diffraction study have been used
for the first time to probe the configu-
ration and highly diastereoselective
deuteration of a chiral organosamarium
intermediate.
a Chiral Organosamarium Intermediate
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