Diastereoselective SmI2-mediated cascade radical cyclisations of methylenecyclopropane derivatives - A synthesis of paeonilactone B

Article abstract of DOI:10.1039/a804297g

The SmI₂-mediated cascade reaction of methylenecyclopropyl ketone 9 proceeds with high diastereoselectivity, which is critically dependent on the presence of HMPA, and provides a short route to paeonilactone B.

Full text of DOI:10.1039/a804297g

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Diastereoselective SmI2-mediated cascade radical cyclisations of
methylenecyclopropane derivatives—a synthesis of paeonilactone B
Raymond J. Boffey,a Marco Santagostino,a William G. Whittinghamb and Jeremy D. Kilburn*a†
a Department of Chemistry, University of Southampton, Southampton, UK SO17 1BJ
b Zeneca Agrochemicals, Jealott’s Hill Research Station, Bracknell, Berkshire, UK RG42 6ET
The SmI2-mediated cascade reaction of methylenecyclopro-
O
O
i, ii
pyl ketone 9 proceeds with high diastereoselectivity, which is
O
O
critically dependent on the presence of HMPA, and provides
a short route to paeonilactone B.
+
H
H
OH
7
OH
8
Cascade radical cyclisation reactions have proved to be very
popular as a synthetic strategy as they allow the construction of
1:1 mixture, overall yield 65%
several C–C bonds in one step and can provide elegant synthetic
routes to complex polycyclic compounds and natural products.1
Tandem reactions, initiated in particular by the versatile
lanthanide reagent SmI2, have also been a focus of recent
attention.2 We now report that SmI2-promoted cascade cyclisa-
tions of methylenecyclopropyl ketone derivatives lead to
bicyclic products in good yield and with excellent diaster-
eoselectivity. This approach provides a short synthetic route to
(±)-paeonilactone B 1, one of several structurally related
monoterpenes isolated from paeony roots,3 all of which feature
a highly oxygenated cyclohexane nucleus.4
A retrosynthetic analysis of paeonilactone B (Scheme 1)
suggested that the cis-fused bicyclic methylenecyclohexane 2
could be prepared by a 5-exo cyclisation of methylenecyclo-
hexyl radical 3 onto a pendant alkyne, and 3 could, in turn, arise
from cyclisation of ketyl radical 5 onto a methylenecyclopro-
pane unit with subsequent ‘endo’ ring opening of 4.5 Whether
such a sequence would prove to be diastereoselective and
provide the correct relative stereochemistry of the tertiary
alcohol required for the natural product remained to be tested by
experiment.
iii–v
O
O
O
O
O
O
+
CHO
H
H
6
9
99%
10 99%
Scheme 2 Reagents and conditions: i, BuLi, THF, 278 °C; ii, compound 6;
iii, NaH, DMPU, THF; iv, HC°CCH2Br; v, TsOH, acetone, H2O
Treatment of ketone 9 with SmI2, under standard conditions9
(slow addition of 9 to 2.2 equiv. SmI2, ButOH, HMPA, THF,
0 °C) gave the desired bicyclic products as a readily separable
mixture of diastereoisomers, 11 and 12, in 57 and 6% isolated
1
yields respectively (ratio 11:12 = 10: 1 by analysis of the H
NMR spectrum of the crude reaction mixture) (Table 1). In
contrast, treatment of diastereoisomeric ketone 10 with SmI2,
under identical conditions, gave the bicyclic product 12 in 73%
isolated yield, and only a trace of the diastereoisomer 11 (ratio
12:11 > 30: 1).
In order to rationalise the observed diastereoselectivity we
repeated the cyclisations under identical conditions, but replac-
ing HMPA with the less effective chelator DMPU.10 These
cyclisation reactions gave the bicyclic products with reduced
overall yields and required a larger excess of SmI2 ( ~ 6 equiv.)
for consumption of starting material.2b Notably, for the
cyclisation of 9, the diastereoselectivity was reduced (ratio
11:12 = 1.5 : 1), whereas for the cyclisation of 10 the
Addition of lithiated methylenecyclopropane to aldehyde 6,6
produced the desired alcohols as a readily separable mixture of
diastereoisomers 7 and 8 (Scheme 2).7 The relative ster-
eochemistry for the two diastereoisomers was established by
X-ray crystallographic structure analysis of the p-nitrobenzoate
ester derived from alcohol 8.8 Alkylation of the alcohols gave
the corresponding prop-2-ynyl ethers, and subsequent ketal
deprotection provided the two diastereomeric cyclisation pre-
cursors, 9 and 10 respectively, in essentially quantitative
yield.
Table 1 Reaction of 9 or 10 with different additives
O
O–
HO
HO
HO
HO
SmI2, ButOH, addditive
THF, 0 °C
9 or 10
+
•
O
O
O
O
12
O
11
2
3
O
1 Paeonilactone B
•
Starting material
Additive
Yield (%)
11:12
O–
O
O–
•
9
9
9
10
10
10
HMPA
DMPU
—
HMPA
DMPU
—
63
40
~ 20
79
62
0
10:1
1.5:1
1:1.3
< 1:30
< 1:30
—
OH
O
O
6
5
4
Scheme 1
Chem. Commun., 1998
1875

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O
H
H
Et3SiO
HO
OSmIIILn
CH3
RO
RO
SmI2
i, ii
•
•
H
H
HA
CH3
HA
OSmIIILn
O
O
9
O
O
14
16
13
15
11
17 45%
O
LnSmIII
O
H
H
H
H3C
H
iii–v
SmI2
•
•
O
O
LnSmIII
O
H3C
OR
OR
O
HO
Et3SiO
O
10
SPh
Scheme 3
vi, vii
O
O
diastereoselectivity was seemingly unaffected (ratio 12:11 >
30 : 1). In the absence of either DMPU or HMPA the cyclisation
was, as expected, a poor reaction. Thus 9 gave an overall yield
of ~ 20% of 11 and 12, but with a reversal of stereoselectivity
(ratio 11:12 = 1 : 1.3), while cyclisation of 10 yielded none of
the desired bicyclic compounds.
1
96%
O
18 43% O
Scheme 4 Reagents and conditions: i, Et3SiOTf, Et3N, CH2Cl2, 0 °C; ii,
CrO3, pyridine, CH2Cl2, room temp.; iii, PhSH, Et3N, MeOH; iv, O3,
MeOH, 278 °C; v, Me2S; vi, CCl4, reflux; vii, HF·pyridine, THF
ether was successfully achieved using pyridine·HF,15 to give
(±)-paeonilactone B, whose structure was confirmed by com-
parison of its NMR and IR spectroscopic data to those reported
previously for the natural paeonilactone.3
We thank the EPSRC and Zeneca Agrochemicals for a CASE
award (R. J. B.) and the EC for a TMR Fellowship (ERBCH-
BICT930286) (M. S.). We also thank Ms J. Street (South-
ampton University) and Mr M. Kipps (Zeneca Agrochemicals)
for assistance with NMR studies.
The selectivity for the cyclisation of 9 in favour of 11, in
which the tertiary alcohol and ether oxygen are cis in the
bicyclic product, might be the consequence of chelation control
from the weakly basic prop-2-ynylic ether oxygen to the
samarium(III) bound to the ketyl radical. However, the decrease
in selectivity for the cyclisation of 9 as HMPA is replaced by the
weaker chelator DMPU, and reversal of selectivity when neither
is present, effectively rules out this possibility. It seems
probable that the first step of the cyclisation of 9, which
effectively sets the relative stereochemistry of the product,
proceeds through a chair-like transition state, allowing the prop-
2-ynyl ether substitutent to adopt a pseudo-equatorial position
(Scheme 3). As a consequence of the bond angles of the
methylenecyclopropyl group, the alkene appears to be essen-
tially staggered between the ketyl radical oxygen and the ketyl
methyl group. Thus the preference for conformer 13 over 14
may largely result from the preference for the bulky OS-
mIII(HMPA)n moiety to also adopt a pseudo-equatorial position
and avoid a 1,3-diaxial interaction with HA. Replacement of
HMPA with DMPU may effectively reduce the steric bulk of
the OSmIIILn moiety,10 leading to a lower selectivity for
conformer 13. In the absence of either HMPA or DMPU the
ketyl methyl becomes sterically dominant, leading to a reversal
in selectivity.
In contrast, the first step of the cyclisation of 10 may well
proceed through a boat-like transition state, since a chair-like
transition state would force the prop-2-ynyl ether substituent
into a severely hindered axial orientation. In the boat-like
transition state the alkene now appears to be largely eclipsed
with either the ketyl methyl group (15) or the ketyl radical
oxygen (16). Conformer 15 may now be preferred over 16 since
it alleviates the electronic repulsion between the ketyl oxygen
functionality and the alkene p-system,11 and this preference is
unaffected by replacing HMPA with DMPU.
Completion of the synthesis of paeonilactone B firstly
required protection of the tertiary allylic alcohol as the
triethylsilyl ether,12 followed by oxidation of the allyl ether to
the desired a-methylene lactone 17 using CrO3 and pyridine
(Scheme 4).13 The selective oxidation of the ostensibly more
electrophilic cyclohexyl alkene of 17 proved to be impossible
with both alkenes reacting rapidly with ozone at 2110 °C in
EtOH in almost quantitative yield. Even more frustratingly,
treatment of 17 with OsO4 led to dihydroxylation of just the the
a-methylene lactone, presumably due to steric congestion
around the cyclohexyl alkene. Instead, base-mediated Michael
addition of PhSH to 17 gave the thioether which was then
successfully ozonolysed to give the desired ketone, with
concomitant oxidation of the thioether to the corresponding
sulfoxide 18. Thermal elimination of phenylsulfenic acid14 then
reinstalled the a-methylene lactone and deprotection of the silyl
Notes and References
† E-mail: jdk1@soton.ac.uk
1 M. Malacria, Chem. Rev., 1996, 96, 289.
2 (a) For a review on SmI2-initiated tandem reactions, see: G. A.
Molander and C. R. Harris, Tetrahedron, 1998, 54, 3321. Surprisingly
few cascade radical process initiated by SmI2 have been reported. Two
notable examples are: (b) T. L. Fevig, R. L. Elliott and D. P. Curran,
J. Am. Chem. Soc., 1988, 110, 5064; (c) R. A. Batey, J. D. Harling and
W. B. Motherwell, Tetrahedron, 1996, 52, 11 421.
3 T. Hayashi, T. Shinbo, M. Shimizu, M. Arisawa, N. Morita, M. Kimura,
S. Matsuda and T. Kikuchi, Tetrahedron Lett., 1985, 26, 3699.
4 For previous syntheses of paeonilactones see: M. Rönn, P. G. Andersson
and J.-E. Bäckval, Acta Chem. Scand., 1998, 52, 524; S. Hatakeyama,
M. Kawamura, Y. Mukugi and H. Irie, Tetrahedron Lett., 1995, 36, 267
and references cited therein.
5 For previous studies on cyclisations of methylenecyclopropylalkyl
radicals see: C. Destabel, J. D. Kilburn and J. Knight, Tetrahedron,
1994, 38, 11 267; M. Santagostino and J. D. Kilburn, Tetrahedron Lett.,
1995, 36, 1365 and references cited therein.
6 T. Oishi, M. Nagai and Y. Ban, Tetrahedron Lett., 1968, 491.
7 All compounds were characterised by 1H and 13C NMR and IR
spectroscopy, and by HRMS or microanalysis.
8 We thank Dr M. Webster, University of Southampton, for carrying out
the X-ray crystallographic analysis. Details will be published else-
where.
9 G. A. Molander and J. A. McKie, J. Org. Chem., 1995, 60, 872.
10 For a study on the effects of HMPA and DMPU as additives in SmI2-
mediated cyclisations of unactivated olefinic ketones, see: G. A.
Molander and J. A. McKie, J. Org. Chem., 1992, 57, 3132. See also ref.
2b.
11 Electronic repulsion between the ketyl oxygen functionality and the
alkene p-system is generally accepted as being a major factor
determining stereoselectivity in SmI2-mediated cyclisations of un-
activated olefinic ketones: see refs. 10 and 2(b).
12 C. H. Heathcock, S. D. Young, J. P. Hagen, R. Pilli and U. Badertscher,
J. Org. Chem., 1985, 50, 2095.
13 T. J. Brocksom, R. B. dos Santos, N. A. Varanda and U. Brocksom,
Synth. Commun., 1988, 18, 1403.
14 D. J. Cram and C. A. Kingsbury, J. Am. Chem. Soc., 1960, 82, 1810.
15 D. Boschelli, T. Takemasa, Y. Nishitani and S. Masamune, Tetrahedron
Lett., 1985, 26, 5239.
Received in Glasgow, UK, 8th June 1998; 8/04297G
1876
Chem. Commun., 1998