Diastereoselective SmI2-mediated cyclisation of δ-oxo-α,β-unsaturated esters to cyclopropanols

Article abstract of DOI:10.1016/S0040-4039(02)02437-1

In the presence of samarium diiodide and a proton source, δ-oxo-γ,γ-disubstituted-α,β-unsaturated esters readily cyclise with complete diastereocontrol to give anti-cyclopropanol products.

Full text of DOI:10.1016/S0040-4039(02)02437-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9517–9520
Diastereoselective SmI2-mediated cyclisation of
d-oxo-a,b-unsaturated esters to cyclopropanols
He´le`ne Villar and Franc¸ois Guibe´*
Institut de Chimie Mole´culaire et des Mate´riaux d’Orsay, Laboratoire de Catalyse Mole´culaire, ESA-8075 Baˆt. 420,
Universite´ Paris-Sud, 91405 Orsay, France
Received 24 September 2002; revised 24 October 2002; accepted 29 October 2002
Abstract—In the presence of samarium diiodide and a proton source, d-oxo-g,g-disubstituted-a,b-unsaturated esters readily cyclise
with complete diastereocontrol to give anti-cyclopropanol products. © 2002 Elsevier Science Ltd. All rights reserved.
We recently reported that d-iodo and d-bromo-a,b-
unsaturated esters readily cyclise to cyclopropane com-
pounds in the presence of samarium diiodide and a
proton source.1 We present here an extension of this
cyclisation reaction to the obtention of cyclopropanols
starting from g,g-disubstituted d-oxo a,b-unsaturated
esters (Fig. 1).
with trimethylaluminum7 and alcohol oxidation with
pyridinium dichromate.
The cyclisation reactions were carried out in THF at
0°C with 2 equiv. of SmI2 and 3 equiv. of t-BuOH as
the proton source. Our results are summarized in Table
1. The relative stereochemistry of the cyclopropanols
1
was determined by H NMR and deduced from values
Unsaturated aldehydes 1a and 1b were prepared in four
steps (Scheme 1) that included the preparation of mor-
pholino-enamines 4a,b from isobutyraldehyde2 or
cyclohexane–carboxaldehyde, their condensation with
2-chloro-1,3-dithiane,3 Horner–Emmons olefination
with benzyl diethoxyphosphonoacetate and unmasking
of the aldehyde by cleavage of the thioacetal function
through acid catalysed hydrolysis4 or treatment with
methyl iodide/collidine in acetone/water.5 Unsaturated
aldehyde 2 with Z-configuration of the double bond
was prepared in a similar manner except that the
olefination reaction was conducted with benzyl ditri-
fluoroethoxy–phosphonoacetate.6 Unsaturated methyl-
ketone 3 was prepared from tiglic aldehyde 7 (Scheme
2) via Horner–Emmons olefination, monoepoxidation
of diene-ester 8, ring opening of unsaturated epoxide 9
of coupling constants and from NOE studies.8,9
All reactions, which were repeated several times, pro-
ceed efficiently and with complete anti-selectivity, irre-
spective of the E or Z configuration of the double bond
in starting olefins (entries 1, 2 and 3). Some alcohol
resulting from direct reduction of the carbonyl group
without cyclisation was also sometimes observed.
Attempts to separate them from the cyclised adducts by
chromatography were unsuccessful.
At the present time, we have no clear-cut explanation
for the observed stereoselectivity. We tentatively pro-
pose the following one. A likely mechanism for the
present cyclisation, akin to that already proposed for
Figure 1.
Keywords: samarium and compounds; radical reactions; cyclisation; cyclopropanols.
* Corresponding author. Tel.: +33-01-69-15-52-59; fax: +33-01-69-15-46-80; e-mail: fraguibe@icmo.u-psud.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02437-1

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H. Villar, F. Guibe´ / Tetrahedron Letters 43 (2002) 9517–9520
Scheme 1. Reagents and conditions: (i) 2-chloro-1,3-dithiane, 0°C, Et2O/THF; (ii) (EtO)2P(O)CH2CO2Bn, NaH, THF, 0°C, then
reflux 5 h; (iii) HgO, BF3OEt2, 15% aqueous THF; (iv) s-collidine, MeI, acetone/H2O (v/v 4:1).
Scheme 2. Reagents and conditions: (i) (EtO)2P(O)CH2CO2Bn, NaH, THF, 0°C, then reflux 5 h; MCPBA 1.5 equiv., CHCl3, rt;
(iii) Me3Al/H2O, DCM, −35°C; (iv): PDC, DCM, molecular sieves, rt.
Table 1.
Entry
Substrate
Double bond configuration
R%
R, R
Cyclopropanol yielda (%)
1
1a
1a
2
1b
3
E
E
Z
E
E
H
H
H
H
Me, Me
Me, Me
Me, Me
(CH2)5
87 (11b)
90 (11)
60 (11)
60 (12b)
81 (13b)
2c
3
4
5
Me
Me, Me
a Isolated yields.
b NMR data: see notes 8 and 9.
c The reaction was run in the presence of HMPA (8 equiv.).
cyclisation of d-halo-a,b-unsaturated esters, is repre-
sented in Fig. 2. Monoelectronic reduction of the alde-
hydic or ketonic carbonyl group leads, probably in a
reversible manner,10 to ketyl intermediate 14 which
adds intramolecularly to the double-bond in a 3-exo-
trig process. Due to strain energy associated with the
cyclopropyl group, such a process is quite unfavorable,
but a further easy reduction by a second molecule of
SmI2 of the a-carbalkoxy-substituted cyclopropyl-
carbinyl radical 15 to enolate 16 would drive the overall
reaction towards cyclisation. Radical 3-exo-trig cyclisa-
tion are known to be reversible.11 At the present time,
however, it is hardly possible to decide whether under
our reaction conditions, equilibration between the open
and cyclised form does take place (which implies that
reopening of cyclised radical is faster than its reduction
to 16) or not. In the latter case, the stereochemistry of
the reaction is determined at the cyclisation step and
may be explained by a strong preference for a trans
relationship (as represented in A, Fig. 3) of the ketyl
oxygen and the double bond over the cis one in the
transition state. Such preference, due to stereoelectronic
factors,12 has ample precedents in the literature and has
been observed in particular in the samarium iodide-
mediated cyclisation of d-ethylenic ketones to cyclopen-
tanols,13
of
h-oxo-a,b-unsaturated
esters
to
cyclohexanols14 and o-oxo-a,b-unsaturated esters to
cyclobutanols.15,16
If on the contrary a rapid equilibration between uncy-
clised and cyclised radical occurs before reduction to
enolate,17 application of the Curtin–Hammet principle
would suggest to link the observed stereoselectivity to
the comparative easiness with which the cis and trans
radical species C and D are reduced to enolates. The
development of strong repulsive electrostatic interac-
tions in the transition state in the case of the cis isomer
could explain why the reduction of this species is much
disfavored.
Finally, it should also be recalled that other mechanistic
pathways, involving ionic cyclisation, albeit less likely,
may nevertheless be considered such as addition of
ketone dianion (or its monoprotonated form)18 or to
the double bond or, contrarily, addition of the dianion
from the a,b-unsaturated ester to the carbonyl
group.1a,19

H. Villar, F. Guibe´ / Tetrahedron Letters 43 (2002) 9517–9520
9519
Figure 2.
Figure 3.
Examples can be found in the literature in which the
geometry of the double bond dramatically influences
the stereochemical outcome of samarium induced ketyl
olefin cyclisation.20 Cyclisation of compound 2 with a
Z-geometry of the double bond was studied in the
expectation that it could bring about a reversal of
diastereoselectivity. Indeed, a possible chelation of
samarium by the ketyl oxygen atom and the ester
function could now favor a syn transition state as
represented in B (Fig. 3). In the event, in this case too,
only the anti product was obtained. Thus, either
chelated transition state B remains disfavored com-
pared to the trans one or the stereochemistry is not
determined at the cyclisation step.
extracted with Et2O and the combined organic extracts
were washed with saturated sodium thiosulfate, dried
over MgSO4, concentrated in vacuo and purified by
chromatography (silica gel, cyclohexane/AcOEt (80/
20)). Colourless oils were obtained in all cases.
Acknowledgements
We thank Drs. J.-P. Baltaze and C. Aroulanda for
performing the NOE studies.
References
In summary, we have shown that cyclopropanols can
be obtained by samarium diiodide-mediated cyclisation
of d-oxo-a,b-unsaturated esters. This reaction, contrary
to the corresponding cyclisation of d-halo-unsaturated
esters, displays high stereocontrol, leading exclusively
to anti cyclopropanols. The extension of this reaction to
more complex substrates and towards the obtention of
highly functionalised cyclopropanols is currently under
investigation.
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Experimental procedure
The reactions were carried out in Schlenk tubes in dried
and degassed THF and under an argon atmosphere.
7. Miyazawa, M.; Ishibashi, N.; Ohnuma, S.; Miyashita, M.
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A solution of 1.3 mmol of t-BuOH and 0.43 mmol of
carbonyl compound in 1 mL of THF was added drop-
wise at 0°C to 8.6 mL of a 0.1 M solution of SmI2 in
THF. After complete addition, the reaction mixture
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quenched by addition of water. The aqueous layer was
8. 1H NMR (250 MHz, CDCl3); 11: l 7.45–7.25 (m, 5H);
5.12 (s, 2H); 2.95 (d, J=3 Hz); 2.45–2.25 (two dd, ABX
system, JAB=17 Hz, JAX=JBX=7 Hz, 2H); 1.8 (very
broad s, 1H); 1.15 (s, 3H); 0.93 (s, 1H); 0.92–0.82 (m,
1H); 12: l 7.45–7.25 (m, 5H); 5.12 (s, 2H); 2.99 (d, J=3.5

9520
H. Villar, F. Guibe´ / Tetrahedron Letters 43 (2002) 9517–9520
14. Kito, M.; Sakai, T.; Yamda, K.; Matsuda, F.; Shira-
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5H); 5.11 (s, 2H); 2.27 (J=7.5 Hz, 2H); 1.26 (s, 3H); 1.18
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9. Important NOE interactions for gem-dimethylsubstituted
cyclopropanols:
17. This appears to be the case for simple a-carbalkoxy
cyclopropylmethyl radical (i.e. without oxygen atom
attached to the ring). Indeed we have found1b that the
cyclisation of enantiopure g-monosubstituted d-iodo-a,b-
unsaturated esters is accompanied by extensive racemisa-
tion at the g centre.
18. Molander, G. A. In Organic Reactions; Reductions with
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sation of g-d-unsaturated carbonyl compounds to
cyclobutanols, a reversal of stereochemistry from anti to
syn, was observed on going from aldehydes to methyl
ketones16d and has been interpreted as a result of a
change in mechanism from addition of the ketyl radical
anion to the enoate moiety to addition of the dianion
from the enoate moiety to carbonyl function. However,
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trig cyclisations and in our case, the anti selectivity is
maintained with the ketonic substrate.
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11. We are not aware of any kinetic or thermodynamic data
in the literature pertaining to the interconversion of radi-
cals species 14 and 15 or, more generally, to the intercon-
version of b,g-ethylenic ketyl radicals and their
corresponding cyclised forms. On the other hand, kinetics
data are available for ring closing-ring opening of but-3-
enyl radicals and the corresponding cyclopropylcarbinyl
radicals, including those bearing a carbalkoxysubstituents
on the ethylenic bond. Even in this latter case, the
equilibrium constant is still in favor of the uncyclised
species (kc/k-c=ca. 50, see Ref. 1a, note 10 and references
cited therein).
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