Manganese(III) acetate mediated oxidative radical cyclizations. Toward vicinal all-carbon quaternary stereocenters

Article abstract of DOI:10.1021/ol300625u

Manganese(III) acetate mediated oxidative radical cyclizations have been used to synthesize a range of densely functionalized and sterically congested cyclopentane-lactones. A number of the resulting lactones contain vicinal all-carbon quaternary stereocenters adjacent to a tertiary benzylic stereocenter and are formed with high levels of stereocontrol.

Full text of DOI:10.1021/ol300625u

ORGANIC
LETTERS
2012
Vol. 14, No. 12
2940–2943
Manganese(III) Acetate Mediated
Oxidative Radical Cyclizations. Toward
Vicinal All-Carbon Quaternary
Stereocenters
Angus W.J. Logan,† JeremyS. Parker,‡ Michal S. Hallside,†,§ and JonathanW. Burton*,†
Department of Chemistry, University of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford, OX1 3TA, U.K., and AstraZeneca, Pharmaceutical
Development, Charter Way, Silk Road Business Park, Macclesfield, Cheshire, SK10
2NA, U.K.
jonathan.burton@chem.ox.ac.uk
Received March 12, 2012
ABSTRACT
Manganese(III) acetate mediated oxidative radical cyclizations have been used to synthesize a range of densely functionalized and sterically
congested cyclopentane-lactones. A number of the resulting lactones contain vicinal all-carbon quaternary stereocenters adjacent to a tertiary
benzylic stereocenter and are formed with high levels of stereocontrol.
The direct stereocontrolled installation of all-carbon
quaternary stereocenters adjacent to other stereocenters
remains a considerable challenge in contemporary organic
synthesis.1 Even more challenging is the direct synthesis of
vicinal all-carbon quaternary stereogenic centers.1c,2 In this
regard a number of methods have been developed to directly
synthesize vicinal all-carbon quaternary centers, including
pericyclic reactions, alkylation reactions, photochemical
reactions, and transition metal catalyzed reactions to name
but a few.3,4 Additionally, radical reactions have been
utilized for the direct synthesis of all-carbon quaternary
centers.5 Oxidative radical methods have also been used in
the synthesis of highly congested vicinal stereocenters.5a,h
Previously we have reported the efficient synthesis of
[3.3.0]-bicyclic γ-lactones by the cyclization of terminal
4-pentenyl malonates under the influence of manganese-
(III) acetate and copper(II) triflate.6 Herein we report
an extension of this methodology to the synthesis of bi-
and tricyclic γ-lactones containing adjacent quaternary,
tertiary, tertiary stereocenters; quaternary, quaternary,
tertiary stereocenters; and quaternary, quaternary, qua-
ternary stereocenters.
We envisaged that exposure of a suitably substituted
pentenyl malonate 1 to manganese(III) acetate7 would
generate the corresponding electrophilic C-centered radi-
cal 2, which would undergo 5-exo-trig radical cyclization
to give adduct radical 3 (Scheme 1). The adduct radical
would then undergo further single electron oxidation and
hydrolysis to give the product [3.3.0]-bicyclic γ-lactone 5
potentially via the corresponding carbenium ion 4.8 Thus,
in one step it would be possible toformup tothree adjacent
† University of Oxford.
‡ AstraZeneca.
§ Author to whom correspondence regarding X-ray crystallography should
be addressed.
(1) For recent reviews, see: (a) Corey, E. J.; Guzman-Perez, A.
Angew. Chem., Int. Ed. 1998, 37, 388–401. (b) Douglas, C. J.; Overman,
L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363–5367. (c) Peterson,
E. A.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 11943–
11948. (d) Quaternary Stereocenters: Challenges and Solutions for Or-
ganic Synthesis; Christoffers, J., Baro, A., Eds.; Wiley-VCH: Weinheim,
2005. (e) Trost, B. M.; Jiang, C. Synthesis 2006, 369–396. (f) Denissova, I.;
Barriault, L. Tetrahedron 2003, 59, 10105–10146. (f) Christoffers, J.;
Baro, A. Adv. Synth. Catal. 2005, 347, 1473–1482.
(2) For selected recent reviews which contain synthesis of natural
products with adjacent all-carbon quaternary centers, see: (a) Pihko,
A. J.; Koskinen, A. M. P. Tetrahedron 2005, 61, 8769–8807. (b) Steven,
A.; Overman, L. E. Angew. Chem., Int. Ed. 2007, 46, 5488–5508. (c) Kim,
J.; Movassaghi, M. Chem. Soc. Rev. 2009, 38, 3035–3050. (d) Zuo, Z. W.;
Ma, D. W. Isr. J. Chem. 2011, 51, 434–441.
r
10.1021/ol300625u
Published on Web 06/04/2012
2012 American Chemical Society

stereocenters including, with an appropriately substituted
alkene, vicinal all-carbon quaternary stereocenters.
malonate (E)-6a9 to manganese(III) acetate and copper(II)
triflate10 in acetonitrile (0.1 M) at 80 °C gave rise to the
desired [3.3.0]-bicyclic γ-lactone 7a in 79% yield and 2:1 dr
at the lactone stereocenter (Table 1, entry 1).11 Variation of
the concentration (Table 1, entries 1À6) gave rise to large
changes in both dr and isolated yields, with the optimum
concentration being 0.4 M. Loweringthe temperature gave
an increase in dr, but with a concomitant decrease in yield
(Table 1, entries 7 and 8).
Scheme 1. Proposed Mechanism for Oxidative Radical Cycli-
zation
Table 1. Optimization of the Oxidative Radical Cyclization
Reaction with Malonate 7aa
We began our investigations with the cyclization of the
1,2-disubstituted alkene substrate (E)-6a (Table 1) before
moving to the more challenging trisubstituted and fully
substituted alkene substrates (vide infra). Exposure of the
entry
temp (°C)
concn (M)
yield (%)b
drc
1
2
3
4
5
6
7
8
80
80
80
80
80
80
60
40
0.1
0.2
0.4
0.6
0.8
1.0
0.4
0.4
79
71
84
67
62
55
70
74
2.8:1
3.4:1
4.1:1
5.7:1
5.2:1
3.8:1
6.0:1
7.4:1
(3) For recent selected examples of the one-pot formation of vicinal all
carbon quaternary stereocenters by the following methods, see: Thermal
pericyclic: (a) Lemieux, R. M.; Meyers, A. I. J. Am. Chem. Soc. 1998, 120,
€
5453–5457. (b) Nicolaou, K. C.; Vassilikogiannakis, G.; Magerlein, W.;
Kranich, R. Angew. Chem., Int. Ed. 2001, 40, 2482–2486. (c) Birman, V. B.;
Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 2080–2081. (d) Denmark,
S. E.; Baiazitov, R. Y. Org. Lett. 2005, 7, 5617–5620. (e) George, J.;
Adlington, R. Synlett 2008, 2093–2096. (f) Wu, H.; Xue, F.; Xiao, X.;
Qin, Y. J. Am. Chem. Soc. 2010, 132, 14052–14054. (g) Matsuta, Y.;
Kobari, T.; Kurashima, S.; Kumakura, Y.; Shinada, M.; Higuchi, K.;
Kawasaki, T. Tetrahedron Lett. 2011, 52, 6199–6202. Photochemical: (h)
Crimmins, M. T.; Pace, J. M.; Nantermet, P. G.; Kim-Meade, A. S.;
Thomas, J. B.; Watterson, S. H.; Wagman, A. S. J. Am. Chem. Soc. 1999,
121, 10249–10250. (i) Ng, D.; Yang, Z.; Garcia-Garibay, M. A. Org. Lett.
2004, 6, 645–647. (j) Mortko, C. J.; Garcia-Garibay, M. A. J. Am. Chem.
Soc. 2005, 127, 7994–7995. (k) Mehta, G.; Singh, S. R. Angew. Chem., Int.
Ed. 2006, 45, 953–955. (l) Inoue, M.; Sato, T.; Hirama, M. Angew. Chem.,
Int. Ed. 2006, 45, 4843–4848. (m) Shi, L.; Meyer, K.; Greaney, M. F. Angew.
Chem., Int. Ed. 2010, 49, 9250–9253. Alkylation: (n) Overman, L. E.;
Larrow, J. F.; Stearns, B. A.; Vance, J. M. Angew. Chem., Int. Ed. 2000, 39,
213–215. (o) Overman, L. E.; Peterson, E. A. Tetrahedron 2003, 59, 6905–
6919. (p) Fuchs, J. R.; Funk, R. L. J. Am. Chem. Soc. 2004, 126, 5068–5069.
(q) Clarke, P. A.; Black, R. J. G.; Blake, A. J. Tetrahedron Lett. 2006, 47,
1453–1455. (r) Feldman, K. S.; Nuriye, A. Y. Tetrahedron Lett. 2009, 50,
1914–1916. (s) Couladouros, E. A.; Dakanali, M.; Demadis, K. D.; Vidali,
V. P. Org. Lett. 2009, 11, 4430–4433. (t) Sladojevich, F.; Michaelides, I. N.;
Darses, B. D.; Ward, J. W.; Dixon, D. J. Org. Lett. 2011, 13, 5132–5135.
Transition metal catalyzed: (u) Overman, L. E.; Paone, D. V.; Stearns, B. A.
J. Am. Chem. Soc. 1999, 121, 7702–7703. (v) Chiba, S.; Kitamura, M.;
Narasaka, K. J. Am. Chem. Soc. 2006, 128, 6931–6937. (w) Yang, J.; Wu,
H.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007, 129, 13794–13795. Oxidative:
(x) Ishikawa, H.; Takayama, H.; Aimi, N. Tetrahedron Lett. 2002, 43, 5637–
5639. (y) Snell, R. H.; Woodward, R. L.; Willis, M. C. Angew. Chem., Int.
Ed. 2011, 50, 9116–9119.
a All reactions were carried out with 2 equiv of Mn(OAc)3 2H2O and
3
1 equiv of Cu(OTf)2 in N2-sparged MeCN. b Isolated yield of mixture of
diastereomers. c dr was established from the crude 1H NMR; major
diastereomer shown.
Control reactions demonstrated that both manganese-
(III) acetate and copper(II) triflate were required for efficient
reaction.12 Furthermore, resubmission of diastereomerically
(6) (a) Davies, J. J.; Krulle, T. M.; Burton, J. W. Org. Lett. 2010,
12, 2738–2741. (b) Powell, L. H.; Docherty, P. H.; Hulcoop, D. G.;
Kemmitt, P. D.; Burton, J. W. Chem. Commun. 2008, 2559–2561.
(7) For reviews of manganese(III) acetate in organic synthesis, see:
(a) Snider, B. B. Chem. Rev. 1996, 96, 339–363. (b) Melikyan, G. G. Org.
React. 1997, 49, 427–675. (c) Demir, A. S.; Emrullahoglu, M. Curr. Org.
Synth. 2007, 4, 321–351. Burton, J. W. In Encyclopedia of Radicals in
Chemistry, Biology and Materials; Chatgilialoglu, C., Studer, A., Eds.; John
Wiley & Sons Ltd.: Chichester, U.K., 2012; pp 901À942.
(8) For a review of the mechanisms of manganese(III) acetate mediated
reactions, see: Snider, B. B. Tetrahedron 2009, 65, 10738–10744.
(9) For substrate synthesis see Supporting Information (SI).
(10) For the use of copper(II) triflate in conjunction with manganese-
(III) acetate, see: (a) Toyao, A.; Chikaoka, S.; Takeda, Y.; Tamura, O.;
Muraoka, O.; Tanabe, G.; Ishibashi, H. Tetrahedron Lett. 2001, 42,
1729–1732. (b) Hulcoop, D. G.; Burton, J. W. Chem. Commun. 2005,
4687–4689. (c) Hulcoop, D. G.; Sheldrake, H. M.; Burton, J. W. Org.
Biomol. Chem. 2004, 2, 965–967 and ref 6.
(4) For a recent example of the direct generation of vicinal all-carbon
quaternary centers by reaction of a Grignard reagent with an R-
chlorotosylhydrazone, see: Hatcher, J. M.; Coltart, D. M. J. Am. Chem.
Soc. 2010, 132, 4546–4547.
(11) The cyclization of the diethyl malonate analogue of 6a to give the
lactone corresponding to 7a has previously been reported under various
oxidative radical conditions: with manganese(III) acetate in acetic acid
at 60 °C gives the lactone in 69% yield (10:1 dr) along with 25% of a
benzylic acetate; see: (a) Citterio, A.; Sebastiano, R.; Nicolini, M.
Tetrahedron 1993, 49, 7743–7760. With ferrocenium hexafluoropho-
sphate or copper(II) chloride gives the lactone with up to 28% yield (10:1
dr) along with dimers; see: (b) Jahn, U.; Hartmann, P. Chem. Commun.
1998, 209–210. (c) Jahn, U.; Hartmann, P.; Dix, I.; Jones, P. G. Eur. J.
Org. Chem. 2001, 3333–3355.
(5) (a) Oumar-Mahamat, H.; Moustrou, C.; Surzur, J.-M.; Bertrand,
M. P. J. Org. Chem. 1989, 54, 5684–5688. (b) Journet, M.; Malacria, M.
J. Org. Chem. 1992, 57, 3085–3093. (c) Curran, D. P.; Shen, W.
Tetrahedron 1993, 49, 755–770. (d) Leonetti, J. A.; Gross, T.; Little,
R. D. J. Org. Chem. 1996, 61, 1787–1793. (e) Devin, P.; Fensterbank, L.;
Malacria, M. J. Org. Chem. 1998, 63, 6764–6765. (f) Curran, D. P.;
Sisko, J.; Balog, A.; Sonoda, N.; Nagahara, K.; Ryu, I. J. Chem. Soc.,
Perkin Trans. 1 1998, 1591–1594. (g) Pattenden, G.; Stoker, D. A.;
Thomson, N. M. Org. Biomol. Chem. 2007, 5, 1776–1788. (h) Nicolaou,
K. C.; Gray, D. Angew. Chem., Int. Ed. 2001, 40, 761–763. (i) Kim, J.;
Ashenhurst, J. A.; Movassaghi, M. Science 2009, 324, 238–241. (j)
Movassaghi, M.; Ahmad, O. K.; Lathrop, S. P. J. Am. Chem. Soc.
2011, 133, 13002–13005.
(12) In the absence of copper(II) triflate the yield of 7a was only 28%
(4.2:1 dr). In the absence of manganese(III) acetate substrate decom-
position occurred.
Org. Lett., Vol. 14, No. 12, 2012
2941

pure lactone 7a to the reaction conditions did not lead to
epimerization, indicating that product formation is a kine-
tically controlled process. Cyclization of (Z)-6a gave the γ-
lactone 7a with the same yield and dr as those for (E)-6a in
keeping with the proposed mechanism shown in Scheme 1.
Having developed conditions (Table 1, entry 3) for the
efficient cyclization of 6a we moved to investigate the
cyclization onto a range of substituted styrenes. The results
are summarized in Table 2.9 More electron-rich substrates
gave the γ-lactone products 7 with reduced diastereocontrol
(Table 2, entries 4, 5, and 9), with the most electron-rich
substrate 6h giving an intractable mixture of products in
which the desired γ-lactone was only a minor constituent.
The stereochemistry of the products was established by 1H
NMR NOE experiments on diastereomerically pure cyclo-
pentane-lactones 7a, 7b, and 7i and confirmed by single
crystal X-ray diffraction of cyclopentane-lactone 7i
(Figure 1).13,14 The stereochemistry of the remaining cyclo-
pentane-lactone products, 7cÀ7g and 7j, were established by
Figure 1. 1H NMR NOE data and single crystal X-ray structure
of lactone 7i determined from single crystal diffraction data
(thermal ellipsoids drawn at 50% probability).
Having established an efficient protocol for the synthesis
of [3.3.0]-bicyclic γ-lactones containing adjacent quaternary,
tertiary, tertiary stereocenters we sought to extend this
methodology to the synthesis of products with vicinal all-
carbon quaternary stereocenters.
Pleasingly, on submission to the previously optimized
cyclization conditions, the trisubstituted alkenes 8aÀd9
underwent efficient and highly diastereoselective cycliza-
tion to give the corresponding [3.3.0]-bicyclic γ-lactones
9aÀd containing vicinal all-carbon quaternary stereocen-
ters (Table 3). Importantly, both unsaturation and oxyge-
nation (Table 3, entries 3 and 4) are tolerated in the
cyclization substrate. The high yielding formation of the
γ-lactones 9aÀd is noteworthy given the significantly
reduced rate of 5-exo-trig cyclization onto 2,2-disubsti-
tuted alkenes, compared with monosubstituted alkenes.15
1
analogy, as the H NMR chemical shift of the benzylic
protons of the major and minor isomers fell in characteristic
regions (δH = 5.00À5.40 and 5.80À6.10 ppm respectively).
Table 2. Manganese(III) Acetate Mediated Oxidative Radical
Cyclization of Aryl Substituted Malonates 6bÀ6ja
entry
6, Ar
7, yield (%)b
drc
Table 3. Cyclization of Trisubstituted Pentenyl Malonates
8aÀda
1
2
3
4
5
6
7
8
9
6b, 4-FC6H4
7b, 72
7c, 54
7d, 74
7e, 58
7f, 72
4.1:1
4.8:1
4.2:1
1.5:1
1.3:1
6.0:1
n.d.d
3.4:1
1.9:1
6c, 2-FC6H4
6d, 4-BrC6H4
6e, 4-MeC6H4
6f, 2-MeC6H4
6g, 3-MeOC6H4
6h, 4-MeOC6H4
6i, 3-NO2C6H
6j, 2-naphthyl
7g, 73
7h, n.d.d
7i, 66
entry
8, R
9, yield (%)b
drc
7j, 83
1
2
3
4
8a, Me
9a, 83
9b, 91
9c, 74
9d, 96
8.0:1
10.7:1
11.9:1
10.2:1
a All reactions were carried out with 2 equiv of Mn(OAc)3 2H2O and
3
8b, n-Bu
1equivofCu(OTf)2 in sparged MeCN at 80 °C. b Isolated yield. c dr was estab-
lished from the crude 1H NMR; major diastereomer shown. d Not determined.
8c, CH2CtCH
8d, (CH2)2OTBDPSd
a All reactions were carried out with 2 equiv of Mn(OAc)3 2H2O and
3
(13) Low temperature, single crystal diffraction data were collected
using a Nonius Kappa CCD, reduced using DENZO/SCALEPACK [(a)
Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307À326] and
were solved using SIR92[(b) Altomare, A.; Cascarano, G.; Giacovazzo,
C.; Guagliardi, A.; Burla, M. C.; Polidori, G.; Camalli, M. J. Appl.
Crystallogr. 1994, 27, 435À435]. Refinement was carried out within the
CRYSTALS suite[(c) Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.;
Prout, K.; Watkin, D. J. J. Appl. Crystallogr. 2003, 36, 1487À1487; (d)
Thompson, A. L.; Watkin, D. J. J. Appl. Crystallogr. 2011, 44,
1017À1022] using a Chebychev polynomial weighting scheme [(e)
Carruthers, J. R.; Watkin, D. J. Acta Crystallogr. 1979, A35,
698À699] with the hydrogen atoms treated in the usual fashion[(f)
Cooper, R. I.; Thompson, A. L.; Watkin, D. J. J. Appl. Crystallogr.
2010, 43, 1100À1107]. (g) For full experimental details, see SI (CIF);
crystallographic data (excluding structure factors) have been deposited
with the Cambridge Crystallographic Data Centre (CCDC 879276 and
879277) and can be obtained via http://www.ccdc.cam.ac.uk/data_re-
quest/cif.
1 equiv of Cu(OTf)2 in sparged MeCN at 80 °C. b Isolated yield. c dr was
established from the crude 1H NMR. d TBDPS = tert-butyldiphenylsilyl.
In order to test the limits of steric bulk tolerated on the
alkene moiety, substrates containing an i-Pr or t-Bu group,
8e and 8f respectively,9 were submitted to the optimized
reaction conditions (Table 4). Under these conditions,
substrate 8e underwent competitive 5-exo/6-endo-trig cy-
clization to give the desired γ-lactone 9e (39% as a single
(14) The stereochemistry of the minor diastereomers of lactones 7a
and 7b was assigned on the basis of 1H NMR NOE experiments.
(15) Beckwith, A. L. J. Tetrahedron 1981, 37, 3073–3100.
2942
Org. Lett., Vol. 14, No. 12, 2012

the adduct radical. The fully substituted alkene substrate
119 underwent oxidative radical cyclization to give the
[3.3.0]-bicyclic γ-lactone 12 in 74% yield (Scheme 2). In
this instance, the adduct radical is stabilized by three alkyl
substituents.
Table 4. Cyclization of More Hindered Substrates 8e and 8fa
Scheme 2. Oxidative Radical Cyclization of Malonate 11
entry
8, R
9, yield (%)b
10, yield (%)b
1c
2d
8e, i-Pr
8f, t-Bu
9e, 39
9f, 0
10e, 48
10f, 23
a All reactions were carried out with 2 equiv of Mn(OAc)3 2H2O and
With these results in hand substrate 13,9 which contains
an internal tetrasubstituted alkene, was synthesized. Upon
exposure to the conditions developed above, tricyclic γ-
lactone 14 was formed in good yield as a single diaster-
eomer containing vicinal all-carbon quaternary centers
adjacent to a further quaternary stereocenter (Scheme 3);
the stereochemistry of 14 was assigned on the basis of 1H
NMR NOE experiments.17
3
1 equiv of Cu(OTf)2 in sparged MeCN at 80 °C. b Isolated yield.
c Substrate 8e was a ca. 5:1 mixture of (Z)/(E) geometrical isomers.
d Substrate 8f was 100% (E)-isomer.
diastereomer) and cyclohexene 10e (48%). In contrast, the
t-Bu substituted substrate 8f underwent 6-endo-trig cycli-
zation to give the cyclohexene 10f in 23% yield.16
The stereochemistry of 9e was assigned by 1H NMR NOE
experiments and confirmed by single crystal X-ray analysis,
and the stereochemistry of the remaining γ-lactones 9 was
assigned by analogy with 9e (Figure 2).13 The major diaster-
eomer of the γ-lactones 9 had the opposite configuration at
the benzylic stereocenter compared with the γ-lactones 7,
with the phenyl group positioned on the concave face of the
[3.3.0]-bicyclic system most probably to avoid interaction
with the non-hydrogen bridgehead substituent. The 1H
NMR chemical shifts for the benzylic protons of the
γ-lactones 9 were higher for the major diastereomers com-
pared with the minor diastereomers and followed the same
trend as observed with the γ-lactones 7.
Scheme 3. Oxidative Radical Cyclization of Tetrasubstituted
Alkene 8
In summary, we have developed a robust methodo-
logy for synthesizing highly functionalized and sterically
congested [3.3.0]-bicyclic γ-lactones containing vicinal
all-carbon quaternary stereocenters from simple linear
precursors. Delicate functionalities, such as alkynes and
silyl protecting groups, are tolerated under the reaction
conditions. We are further investigating this oxidative
radical cyclization in the context of natural product
synthesis.
Acknowledgment. We thank the UK PharmaSynth-
esis Network (AstraZeneca, GSK, Novartis, Pfizer)
and the EPSRC for funding this work, and Dr. Amber
Thompson and the Oxford Chemical Crystallography
Service for assistance with X-ray crystallography and
the instrumentation.
Figure 2. 1H NMR NOE data and single crystal X-ray structure
of lactone 9e determined from single crystal diffraction data
(thermal ellipsoids drawn at 50% probability).
It also proved possible to perform cyclizations on sub-
strates which did not contain an aryl group to stabilize
Supporting Information Available. Experimental de-
tails and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(16) A small amount of the dimer formed from two molecules of 8f
and trace amounts of a product with the molecular mass corresponding
to 9f were also detected.
(17) For a related ionic iodocarbocylization and lactonization to give a
compound with adjacent all-carbon quaternary centers, see: Kitagawa, O.;
Inoue, T.; Hirano, K.; Taguchi, T. J. Org. Chem. 1993, 58, 3106–3112.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 12, 2012
2943