Oxidative radical cyclisations for the synthesis of γ-lactones

Article abstract of DOI:10.1039/b802473a

The use of manganese(III) acetate in combination with copper(II) triflate allows the synthesis of [3.3.0]-bicyclic γ-lactones from 4-pentenylmalonates in excellent yields. The Royal Society of Chemistry.

Full text of DOI:10.1039/b802473a

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Oxidative radical cyclisations for the synthesis of c-lactonesw
Luke H. Powell,ab Paul H. Docherty,ab David G. Hulcoop,a Paul D. Kemmittc and
Jonathan W. Burton*ab
Received (in Cambridge, UK) 13th February 2008, Accepted 31st March 2008
First published as an Advance Article on the web 21st April 2008
DOI: 10.1039/b802473a
The use of manganese(III) acetate in combination with copper(II)
triflate allows the synthesis of [3.3.0]-bicyclic c-lactones from
4-pentenylmalonates in excellent yields.
Substituted cyclopentanes form the core of many biologically
important natural products including the prostaglandins1 and
the brefeldins, and have been used as glycosidase inhibitors,2
as peptidomimetics3,4 and as ligands in catalysis.5 A variety of
Scheme 1 Cyclisation of dimethyl 4-pentenylmalonate.
methodologies have been developed to access these privileged
structures,1,6,7 including diastereoselective radical cyclisations8
most frequently using the ‘tin hydride’ method for radical
generation and termination with its attendant difficulties of
purification and stoichiometric tin waste.9 We became inter-
ested in developing tin-free oxidative radical cyclisations,
mediated by manganese(III), for the synthesis of biologically
active cyclopentane-containing natural products.10
We used dimethyl 4-pentenylmalonate 1 to develop an efficient
procedure for the synthesis of [3.3.0]-bicyclic g-lactones. After
some optimisation we discovered that exposure of the malonate 1
to two equivalents of manganese(III) acetate, and one equivalent
of copper(II) triflate in acetonitrile at reflux delivered the [3.3.0]-
bicyclic g-lactone 2 in excellent yield (Table 1, entry 1).15
Conducting the reaction in deoxygenated solvent (0.2 M in
acetonitrile) is critical for attaining a high yield of the g-lactone 2.
The conditions developed for the efficient formation of 2
readily translated to more complex substrates (Table 1).16,17
Thus, the substituted 4-pentenylmalonate 5 gave the [3.3.0]-
bicyclic g-lactone 6 with good diastereocontrol (dr 413 : 1)18
in 88% yield (Table 1, entry 2). Similarly, exposure of
malonates 7 and 9 to manganese(III) acetate and copper(II)
triflate gave the corresponding [3.3.0]-bicyclic g-lactones 8 and
10 in excellent yields (Table 1, entries 3 and 4).18
Manganese(III) acetate has emerged as a powerful one-
electron oxidant for the generation of electrophilic C-centred
radicals from CH-acidic compounds.11 These educt radicals
readily cyclise to form adduct radicals which undergo a variety
of termination sequences.11 Snider and McCarthy have shown
that the cyclisation of dimethyl 4-pentenylmalonate 1 in the
presence of manganese(III) acetate delivers three different major
products depending on the reaction conditions (Scheme 1).12
Using manganese(III) acetate and copper(II) acetate in acetic
acid gives the [3.3.0]-bicyclic g-lactone 2 in 48% yield along
with the methylenecyclopentane 3 (20%).12–14 Using the same
reagents in DMSO provides the methylenecyclopentane 3 in
53% yield whereas using no copper(II) additive and ethanol as
solvent gives the methylcyclopentane 4 in 40% yield.12
Slight modification of literature conditions12 allowed the
synthesis of methyl and methylenecyclopentanes from the same
Table 1 Synthesis of [3.3.0]-bicyclic g-lactones
[3.3.0]-Bicyclic g-lactones such as 2 are attractive intermediates
for synthesis as they contain adjacent quaternary and tertiary
stereocentres and differentiated oxygen functionality. Herein we
report that exposure of 4-pentenylmalonates to manganese(III)
acetate and copper(II) triflate gives [3.3.0]-bicyclic g-lactones in
excellent yield. This methodology is showcased in the synthesis of
a [5.2.1.01,5]-tricyclo bis-lactone bearing five contiguous stereo-
centres, including adjacent quaternary and tertiary stereocentres,
which we propose to use in the synthesis of a number of
biologically active natural products and analogues.
Entry
Substrate
Product
Yield (%)
1
2
1
5
2
6
92
88
3
7
9
8
92a
a Department of Chemistry, University of Cambridge, Lensfield Road,
Cambridge, UK CB2 1EW
4
10
90a
b Chemistry Research Laboratory, Mansfield Road, Oxford, UK OX1
3TA. E-mail: jonathan.burton@chem.ox.ac.uk; Fax: +44 1865
285002; Tel: +44 1865 285119
c AstraZeneca, Alderley Park, Macclesfield, Cheshire, UK SK10 4TF
w Electronic supplementary information (ESI) available: Experimental
procedures and selected NMR spectra. See DOI: 10.1039/b802473a
a
Combined yield for a 5 : 1 mixture of diastereomers, major dia-
stereomer shown.
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Table 2 Synthesis of methylcyclopentanes
Table 4 Synthesis of bi- and tricyclic g-lactones
Sub-
Entry strate Conditions Product(s) (yield, %)
Entrya Substrate
1
Productb
Yield (%) drc
17
19
21
18 58
2 : 1
1
1
5
Mn(OAc)3,
0.02 M,
EtOH
4 (66)
2
3
20 76
22 57
1.7 : 1
1 : 0
2
Mn(OAc)3,
0.02 M,
EtOH
11 (66)
3
7
9
Mn(OAc)3,
0.02 M,
EtOH
12 (60a)
8 (29)
4
23
25
24 67
26 90
5 : 1
1 : 1
4
Mn(OAc)3,
0.02 M,
EtOH
13 (55a)
10 (29)
5d
a
Combined yield for a ca. 3 : 1 mixture of diastereomers.
a
b
2 equiv. Mn(OAc)3, 1 equiv. Cu(OTf)2. Isolated as a mixture of
diastereomers at the centre marked *, major diastereomer shown.
c
d
Diastereomeric ratio. The crude product was esterified with
substrates (Tables 2 and 3). Under reductive conditions (no
copper(II) additive, 0.02 M in ethanol) the malonate 1 gave the
methylcyclopentane 4 in an improved yield of 66%. Similarly the
methylcyclopentane 11 was synthesised with good diastereocon-
trol (dr 413 : 1) in 66% yield (Table 2, entry 2). The malonates 7
and 9 gave the corresponding methylcyclopentanes 12 and 13 in
60% and 55% yields respectively as ca. 3 : 1 mixtures of
diastereomers; with the corresponding g-lactones 8 and 10
formed as significant by-products.
TMSCHN2 prior to chromatography.
The formation of [3.3.0]-bicyclic g-lactones from 1,2-disub-
stituted alkenes proved possible using our optimised reaction
conditions (Table 4).17 Thus exposure of the linear malonates
17 and 19 to manganese(III) acetate and copper(II) triflate,
under our standard reaction conditions, gave the correspond-
ing g-lactones 18 and 20 (Table 4, entries 1 and 2). Further-
more, cyclisation–lactonisation was possible with cyclic (21)
and trisubstituted (23) alkenes (Table 4, entries 3 and 4). In
order to achieve efficient cyclisation–lactonisation with 1,3-
diene substrates it proved necessary to use the substituted
malonic acid in place of the corresponding dimethyl malonate.
Thus, under our standard conditions the malonic acid 25 gave
the [3.3.0]-bicyclic g-lactone 26 in excellent yield after ester-
ification with TMS-diazomethane (Table 4, entry 5).
Treatment of the malonates with manganese(III) acetate and
copper(II) acetate in DMSO12 gave the methylenecyclopen-
tanes (319 and 14–16) in 50–80% yields (Table 3 entries 1–4).20
Under these conditions the corresponding g-lactones were also
formed as by-products in varying degrees.
Table 3 Synthesis of methylenecyclopentanes
The g-lactone products are densely functionalised small
molecules which should find great utility in synthesis. For
example, the fused bicyclic g-lactone 6 contains three contig-
uous stereocentres, one of which is quaternary, differentiated
Sub-
Entry strate Conditions Product(s) (yield, %)
1
1
Mn(OAc)3,
Cu(OAc)2,
0.2 M,
3 (77)
2 (7)
DMSO
2
5
Mn(OAc)3,
Cu(OAc)2,
0.2 M,
14 (71)
DMSO
3
4
7
9
Mn(OAc)3,
Cu(OAc)2,
0.2 M,
15 (80)
16 (50)
8 (13)
DMSO
Mn(OAc)3,
Cu(OAc)2,
0.2 M,
10 (13)
DMSO
Scheme 2 Conversions of the [3.3.0]-bicyclic g-lactone 6.
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4 T. K. Chakraborty, A. Ghosh, R. Nagaraj, A. R. Sankar and A. C.
Kunwar, Tetrahedron, 2001, 57, 9169.
5 For a list of ligands for asymmetric catalysis including a number of
chiral, non-racemic, cyclopentanes see: Catalytic Asymmetric
Synthesis, ed. I. Ojima, Wiley-VCH, Weinheim, 2000, pp. 801–856.
6 R. J. Ferrier and S. Middleton, Chem. Rev., 1993, 93, 2779.
7 J. Marco-Contelles, C. Alhambra and A. Martinez-Grau, Synlett,
1998, 693.
8 For reviews and books see: B. Giese, B. Kopping, T. Gobel, J.
Dickhaut, G. Thoma, K. J. Kulicke and F. Trach, Org. React.,
1996, 48, 301; T. V. Rajanbabu, Acc. Chem. Res., 1991, 24, 139; D.
P. Curran, N. A. Porter and B. Giese, Stereochemistry of Radical
Reactions, VCH, Weinheim, 1996; J. Marco-Contelles, C. Alham-
bra and A. Martinez-Grau, Synlett, 1998, 693.
Scheme 3 Synthesis of the [3.3.0]-bicyclic g-lactone 34.
9 For an excellent review on tin hydride substitutes and modified tin
reagents/work-ups see: A. Studer and S. Amrein, Synthesis, 2002,
835.
10 For oxidative radical synthesis of cyclopentanes using the ferroce-
nium cation see: U. Jahn, Chem. Commun., 2001, 1600; U. Jahn, P.
Hartmann, I. Dix and P. G. Jones, Eur. J. Org. Chem., 2001, 3333;
U. Jahn, P. Hartmann, I. Dix and P. G. Jones, Eur. J. Org. Chem.,
2002, 718; U. Jahn, P. Hartmann and E. Kaasalainen, Org. Lett.,
2004, 6, 257.
11 For reviews see: B. B. Snider, Chem. Rev., 1996, 96, 339; G. G.
Melikyan, Org. React., 1997, 49, 427.
12 B. B. Snider and B. A. McCarthy, J. Org. Chem., 1993, 58, 6217.
13 Snider and McCarthy studied the oxidative radical cyclisation of
dimethyl 4-pentenylmalonate 1 in a variety of solvents: see ref. 12.
oxygen-based functionality, and is formed under mild condi-
tions. The utility of this g-lactone in synthesis is demonstrated
by the high yielding conversions shown in Scheme 2. The
silicon protecting group is readily removed under standard
conditions to give the primary alcohol 27. Hydrolysis of both
the g-lactone and the methyl ester in 6 followed by re-
lactonisation under acidic conditions gave the malonic-lactone
half acid 28 in excellent yield. The lactone-acid 28 readily
participated in a Curtius rearrangement to give the protected
a-amino acid 31, again in excellent yield. Krapcho decarboxy-
lation of the methyl ester 6 provided the g-lactone 30 which
underwent enolate alkylation to give the benzyl and allyl-
substituted g-lactones 29 with complete diastereocontrol.
Most importantly this methodology has allowed us to
synthesise the [5.2.1.01,5]-tricyclo bis-lactone 33 containing
adjacent quaternary and tertiary stereocentres and differen-
tiated oxygen-based functionality in one step from the
g-lactone 32. Thus, exposure of the g-lactone 3221 to our
standard reaction conditions (manganese(III) acetate and cop-
per(II) triflate in acetonitrile under reflux) delivered the
[5.2.1.01,5]-tricyclo bis-lactone 33 with good diastereocontrol
(dr 410 : 1) which on exposure to methanol gave the [3.3.0]-
bicyclic g-lactone 34 in good yield.17 It is noteworthy that the
lactones 33 and 34 contain five contiguous stereocentres and
that the allylic stereocentre is formed with high diastereocon-
trol. We are synthesising a range of tricyclic and bicyclic
g-lactones such as 33 and 34 which will serve as key inter-
mediates in the synthesis of biologically relevant targets
(Scheme 3).
14 The oxidative cyclisation of dimethyl 4-pentenylmalonate
1
mediated by cerium(IV) ammonium nitrate has been studied. The
use of copper(II) nitrate as additive in AcOH gives the g-lactone 2
in 74% yield, see: E. Baciocchi, A. B. Paolobelli and R. Ruzziconi,
Tetrahedron, 1992, 48, 4617.
15 Based on the pioneering work of Kochi on the oxidation of alkyl
radicals by copper(II) salts (J. K. Kochi, in Free Radicals, ed. J. K.
Kochi, Wiley, New York, 1973, vol. 1, pp. 594–623), we have
reported that the combination of manganese(III) acetate and
copper(II) triflate allows the formation of tethered bicyclic g-
lactones in excellent yields from dimethyl malonates containing a
pendent carboxylic acid: D. G. Hulcoop and J. W. Burton, Chem.
Commun., 2005, 4687. For other references concerning the use of
copper(II) triflate in conjunction with manganese(III) acetate see: A.
Toyao, S. Chikaoka, Y. Takeda, O. Tamura, O. Muraoka, G.
Tanabe and H. Ishibashi, Tetrahedron Lett., 2001, 42, 1729; D. G.
Hulcoop, H. M. Sheldrake and J. W. Burton, Org. Biomol. Chem.,
2004, 2, 965.
16 Cyclisation of the malonyl radical derivedfrom 4-pentenylmalo-
nate 1 gives a E9 : 1 mixture of the corresponding cyclopentyl-
methyl radicals and cyclohexyl radicals: see ref. 12. Analysis of the
crude reaction mixtures from the cyclisations reported in Table 1
shows 490% of the product mixture arises from 5-exo-trig
cyclisation.
17 The stereochemistry of the products was assigned on the basis of
1H NMR NOE experiments.
In summary we have developed an efficient process for the
formation of fused bicyclic g-lactones by the oxidative radical
cyclisation of 4-pentenylmalonates. Application of this metho-
dology to the total synthesis of natural products and biologically
relevant targets is ongoing in our laboratory, in tandem with
efforts to render the above transformations catalytic in metal.
The authors thank the Royal Society (URF to JWB), the
EPSRC (EP/C006054/2) and AstraZeneca for financial support.
18 The stereochemical outcome of these reactions is in accord with the
Beckwith–Houk model for the 5-exo-trig cyclisation of 5-hexenyl
radicals see: A. L. J. Beckwith, Tetrahedron, 1981, 37, 3073; A. L. J.
Beckwith and C. H. Schiesser, Tetrahedron Lett., 1985, 26, 373;
D. C. Spellmeyer and K. N. Houk, J. Org. Chem., 1987, 52, 959.
19 These conditions are the same as those reported by Snider and
McCarthy (ref. 12). We have noticed increased yields of products
arising from oxidative termination with increased substrate con-
centration and increased scale of reaction. The different yields of 3
obtained by Snider and McCarthy (ref. 12) and in this work, may
be due to different reaction scales.
20 For rationalisation of the different product distributions from the
different copper(II) additives see ref. 15. The reason for the solvent
effects is not clear (see ref. 12). Cyclisation of 4-pentenylmalonate 5
with Mn(OAc)3 and Cu(OAc)2 in MeCN gives the lactone 6 and
the methylenecyclopentane 14 in a 1.5 : 1 ratio, whereas the
methylenecyclopentane 14 is the sole product in DMSO. These
results are in accord with Snider and McCarthy’s study (ref. 12).
21 For an example of the use of malonic hemi acids in manganese(III)
mediated reactions see: L. A. Paquette, A. G. Schaefer and J. P.
Springer, Tetrahedron, 1987, 43, 5567.
Notes and references
1 For recent reviews concerning the synthesis of the prostaglandins
see: P. W. Collins and S. W. Djuric, Chem. Rev., 1993, 93, 1533; S.
M. Roberts, M. G. Santoro and E. S. Sickle, J. Chem. Soc., Perkin
Trans. 1, 2002, 1735; S. Das, S. Chandrasekhar, J. S. Yadav and R.
Gree, Chem. Rev., 2007, 107, 3286.
´
2 Carbohydrate Mimics: Concepts and Methods, ed. Y. Chapleur,
Wiley-VCH, Weinheim, 1998.
3 J. P. Schneider and J. W. Kelly, Chem. Rev., 1995, 95, 2169.
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