Synthesis of spirocyclic γ-lactones by cascade Beckwith-Dowd ring expansion/cyclization

Article abstract of DOI:10.1021/ol301386k

A range of spirocyclic γ-lactones have been prepared exploiting a Beckwith-Dowd ring expansion cascade involving 1-, 3-, 4-, and 5-carbon expansion of cyclopentanone and cyclohexanone followed by 5-exo-trig or 5-exo-dig cyclization. This radical cascade reaction can be achieved with various substrates to provide a broad range of γ-lactones spirofused to 6- to 10-membered cycloalkanones.

Full text of DOI:10.1021/ol301386k

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3412–3415
Synthesis of Spirocyclic γ-Lactones
by Cascade BeckwithÀDowd Ring
Expansion/Cyclization
Judith Hierold and David W. Lupton*
School of Chemistry, Monash University, Clayton 3800, Victoria, Australia
david.lupton@monash.edu
Received May 19, 2012
ABSTRACT
A range of spirocyclic γ-lactones have been prepared exploiting a BeckwithÀDowd ring expansion cascade involving 1-, 3-, 4-, and 5-carbon
expansion of cyclopentanone and cyclohexanone followed by 5-exo-trig or 5-exo-dig cyclization. This radical cascade reaction can be achieved
with various substrates to provide a broad range of γ-lactones spirofused to 6- to 10-membered cycloalkanones.
Spirocyclic lactones and derived structures are prevalent
motifs in medicinal and natural product chemistry
(Scheme 1).1,2 The structural rigidity imparted by spirofu-
sion, in association with the latent functionality of the
lactone, is postulated as the source of medicinal activity.3
Due to the prevalence of this motif, a range of synthetic
approaches to spirocyclic lactones have been developed.4
As part of a program on the assembly of spirocyclic
oxygen-containing heterocycles,5 we envisaged a novel
approach to spirocyclic γ-lactones exploiting a cascade
ring expansion cyclization sequence (Scheme 2). Such a
strategy would potentially be modular and thereby allow
flexible assembly of a range of complex γ-lactones.
To realize this approach we intended to exploit BeckwithÀ
Dowd ring expansion6,7 followed by 5-exo radical cycliza-
tion. Despite the well-established utility of the BeckwithÀ
Dowd ring expansion,8,9 its application in radical cascades
Scheme 1. Representative Spirolactones and Derivatives
(2) For a recent review on sesquiterpene γ-lactone natural products
as anticancer agents, see: (a) Ghantous, A.; Gali-Muhtasib, H.; Vuorela,
H.; Saliba, N. A.; Darwiche, N. Drug Discov. Today 2010, 15, 668. For a
review on parthenolide, see: (b) Mathema, V. B.; Koh, Y.-S.; Thakuri,
€€
B. C.; Sillanpaa, M. Inflammation 2011, 35, 560. For drug design using
spirocyclic γ-lactones, see: (c) Reddy, D. M.; Qazi, N. A.; Sawant, S. D.;
Bandey, A. H.; Srinivas, J.; Shankar, M.; Singh, S. K.; Verma, M.;
Chashoo, G.; Saxena, A.; Mondhe, D.; Saxena, A. K.; Taneja, S. C.;
Qazi, G. N.; Kumar, H. M. S. Eur. J. Med. Chem. 2011, 46, 3210.
(3) Bouhlel, A.; Curti, C.; Bertrand, M. P.; Vanelle, P. Tetrahedron
Lett. 2012, 68, 3596 and references therein.
(4) For reviews on the synthesis of spirofused compounds, see: (a)
Sannigrahi, M. Tetrahedron 1999, 55, 9007. (b) Pradham, R.; Patra, M.;
Behera, A. K.; Mishra, B. K.; Behera, R. K. Tetrahedron 2006, 62, 779.
(5) (a) Ngatimin, M.; Frey, R.; Andrews, C.; Lupton, D. W.; Hutt,
O. E. Chem. Commun. 2011, 47, 11778. (b) Ngatimin, M.; Gartshore,
C. J.; Kindler, J.; Naidhu, S.; Lupton, D. W. Tetrahedron Lett. 2009,
50, 6008.
(6) (a) Beckwith, A. L. J.; O’Shea, D. M.; Gerba, S.; Westwood, S. W.
J. Chem. Soc., Chem. Commun. 1987, 666. (b) Beckwith, A. L. J.; O’Shea,
D. M.; Westwood, S. W. J. Am. Chem. Soc. 1988, 110, 2565.
(1) For representative natural products bearing spirocyclic γ-
ꢀ
lactones and derivatives, see: (a) Brocksom, T. J.; Coelho, F.; Depres,
J.-P.; Greene, A. E.; Freire de Lima, M. E.; Hamelin, O.; Hartmann, B.;
Kanazawa, A. M.; Wang, Y. J. Am. Chem. Soc. 2002, 124, 15313.
(b) Bunyapaiboonsri, T.; Yoiprommarat, S.; Intereya, K.; Rachtawee,
P.; Hywel-Jones, N. L.; Isaka, M. J. Nat. Prod. 2009, 72, 756. (c) Lane,
J. F.; Koch, W. T.; Leed, N. S.; Gorin, G. J. Am. Chem. Soc. 1952, 74,
3211. (d) Yamada, K.; Takada, S.; Nakamura, S.; Hirata, Y. Tetrahe-
dron 1968, 24, 199.
r
10.1021/ol301386k
Published on Web 06/19/2012
2012 American Chemical Society

has received little attention. Boger has reported single carbon
ring expansion followed by cyclization to provide fused
bicyclic cyclopentenes,10 while Curran has developed a re-
lated approach, although this was plagued by premature
hydrogen atom transfer (HAT).11 Finally, Crimmins has
exploited β-scission followed by BeckwithÀDowd ring
expansion in an elegant synthesis of (()-lubiminol.12 Be-
yond these examples, we are unaware of any studies using
BeckwithÀDowd ring expansion in radical cascades.13
5-Exo-trig cyclizations to form γ-lactones are known to be
slow in comparison to the hexenyl variant,16 with studies
by Curran demonstrating that increased temperature fa-
vors cyclization.17 Thus, the initiator was changed to
ACCN, and the reaction conducted in toluene heated to
reflux. Using these conditions the desired product 3a now
formed in an improved 16% yield, although the Beck-
withÀDowd product 4a still dominated (Table 1, entry 2).
Addition of the reducing agent over 12 h improved the
yield (Table 1, entry 3), while the higher boiling chloro-
benzene provided 3a in 72% isolated yield (Table 1, entry 4).
Scheme 2. Reaction Design
Table 1. Optimization of Reaction Conditions
reducing
agent
ratioa
3a:4a:5a 3ab
yield
entry
1
conditions
We postulated that the synthesis of γ-lactones should be
well suited to a BeckwithÀDowd ring-expansion cascade.
The rigidity imparted by the ester linkage within β-keto-
ester 1 should impede the undesired 1,5-HAT of intermedi-
ate 2 (Scheme 2), while providing a useful linkage for
substrate synthesis.14,15 Herein, we report initial studies
on this topic.
Reaction discovery commenced by subjecting β-keto-
ester 1a to the conditions reported by Dowd for ring
expansion.7 Along with the noncyclized material 4a and
the reductively dehalogenated product 5a, 3% of the
desired lactone 3a could be isolated (Table 1, entry 1).
10 mol % AIBN, 10 mM
C6H6, 85 °C
Bu3SnH
Bu3SnH
Bu3SnHc
1:19:9
1:2:1
5:3:0
5:1:0
3:2:0
5:1:0
1:0:0
3%
2
3
4
5
6
7
10 mol % ACCN, 10 mM
16%
53%
72%
58%
51%
85%
C6H5CH3, 115 °C
10 mol % ACCN, 10 mM
C6H5CH3, 115 °C
10 mol % ACCN, 10 mM Bu3SnHc
ClC6H5, 135 °C
10 mol % ACVA, 10 mM
Bu3SnHc
Bu3SnHc
ClC6H5, 135 °C
10 mol % ACCN, 10 mM
xylenes, 150 °C
10 mol % ACCN, 10 mM (TMS)3SiHc
C6H5CH3, 115 °C
a Determined from isolated yields of the components. b Isolated yield
of a 1:1 diastereomeric and racemic mixture. c Addition of reducing
agent by syringe pump over 12 h, then 4 additional hours at reflux.
(7) (a) Dowd, P.; Choi, S.-C. J. Am. Chem. Soc. 1987, 109, 3493. For
related rearrangements of three and four carbons, see: (b) Dowd, P.;
Choi, S.-C. J. Am. Chem. Soc. 1987, 109, 6548.
(8) For a review, see: Dowd, P.; Zhang, W. Chem. Rev. 1993, 93, 2091.
(9) For computational studies, see: (a) Wilsey, S.; Dowd, P.; Houk,
K. N. J. Org. Chem. 1999, 64, 8801. (b) Ardura, D.; Sordo, T. L. J. Org.
Chem. 2005, 70, 9417.
(10) Boger, D. L.; Mathvink, R. J. J. Org. Chem. 1990, 55, 5542.
(11) Wang, C.; Gu, X.; Yu, M. S.; Curran, D. P. Tetrahedron 1998,
54, 8355.
(12) Crimmins, M. T.; Wang, Z.; McKerlie, L. A. J. Am. Chem. Soc.
1998, 120, 1747.
(13) For elegant examples of ring-expansion cascades, see: (a) Oh,
Neither changing the radical initiator to ACVA (Table 1,
entry 5) nor conducting the reaction at further elevated
temperatures (Table 1, entry 6) improved the transforma-
tion. In contrast exploiting (TMS)3SiH as the reducing
agent18,19 allowed the reaction to be achieved at lower
temperatures, in excellent yield, and with none of the
BeckwithÀDowd product 4a (Table 1, entry 7).
H.-S.; Lee, H. I.; Cha, J. K. Org. Lett. 2002, 4, 3707. (b) Rodrıguez, J. R.;
´
~
Castedo, L.; Mascarenas, J. L. Org. Lett. 2001, 3, 1181. (c) Sangostino,
M.; Kilburn, J. D. Tetrahedron Lett. 1995, 36, 1365. (d) Hollingworth,
G. J.; Pattenden, G.; Schulz, D. J. Aust. J. Chem. 1995, 48, 381.
(e) Ellwood, C. W.; Pattenden, G. Tetrahedron Lett. 1991, 32, 1591.
For selected radical ring expansions, see: (f) Bacque, E.; Pautrat, F.;
Zard, S. Z. Org. Lett. 2003, 3, 325. (g) Lange, G. L.; Gottardo, C.;
Merica, A. J. Org. Chem. 1999, 64, 6738. (h) Toyota, M.; Wada, T.;
Fukumoto, K.; Ihara, M. J. Am. Chem. Soc. 1998, 120, 4916.
(16) Forkineticsofradicalcyclization to yieldγ-lactones, see: Beckwith,
A. L. J.; Glover, S. A. Aust. J. Chem. 1987, 40, 157 and therein.
(17) For examples, see: (a) Curran, D. P.; Tamine, J. J. Org. Chem.
1991, 56, 2746. (b) Sibi, M.; Ji, J. J. Am. Chem. Soc. 1996, 118, 3063.
(c) Musa, O. M.; Choi, S.-Y.; Horner, J. H.; Newcomb, M. J. Org. Chem.
1998, 63, 786. For the role of temperature in cascades, see: (d) Takasu,
K.; Kuroyanagi, J.-I.; Katsumata, A.; Ihara, M. Tetrahedron Lett. 1999,
40, 6277. (e) Takasu, K.; Maiti, S.; Katsumata, A.; Ihara, M. Tetra-
hedron Lett. 2001, 42, 2157.
(14) For the use of related materials in synthesis, see: (a) Hierold, J.;
Hsia, T.; Lupton, D. W. Org. Biomol. Chem. 2011, 9, 783. (b) Hierold, J.;
Gray-Weale, A.; Lupton, D. W. Chem. Commun. 2010, 46, 6789.
(15) For a review on β-ketoester haloalkylation, see: Roman, B. I.;
De Kimpe, N.; Stevens, C. V. Chem. Rev. 2010, 110, 5914.
Org. Lett., Vol. 14, No. 13, 2012
3413

Having identified conditions for the ring-expansion
spirocyclization, the flexibility of this cascade was investi-
gated. Initially the nature of the radical precursor was
examined by changing the iodide within 1a to the bromide
(i.e., 1b). While the reaction remained successful, in this
case the forcing conditions (Method B: Table 1, entry 4)
were required to bring about ring expansion/cyclization
(Table 2, entry 1c). The substitution pattern and electronic
nature of the olefin were examined, initially with an
electron-rich cinnamate side chain, i.e. 1c, which cyclized
using the standard conditions (Method A) to provide
γ-lactone 3c in 90% yield (Table 2, entry 2). Similarly
β-dimethyl allyl ester 1d provided product 3d in good yield,
demonstrating the viability of termination by reduction of
a tertiary alkyl radical (Table 2, entry 3). When the related
β-diphenyl allyl ester 1e was subjected to identical condi-
tions none of the expected γ-lactone 3e was observed, with
only the ring-expansion product formed. While cyclization
should provide a highly stable radical intermediate, pre-
sumably the bulk of the diphenyl group makes cyclization
kinetically unfavorable. By exploiting the more forcing
conditions (Method B) this cyclization could be achieved
providing 3e with good conversion (Table 2, entry 4).
The degree of unsaturation in the side chain was inves-
tigated using alkynes 1fÀh. When phenyl acetylene 1f was
subjected to Method B, γ-lactone 3f formed as a single
diastereoisomer20 ingood yield (Table 2, entry 5). Similarly
both TMS acetylenes containing an iodide (i.e., 1g) and
those containing a bromide (i.e., 1h) reacted smoothly to
provide γ-lactone 3g in excellent yields (Table 2, entry 6).
The TMS olefin 3gwas targeted as derivatization of related
materials is known to provide access to a range of synthe-
tically useful intermediates.21
Table 2. Scope of the Ring Expansion/Cyclization with Variable
Esters
Finally, the allyl group within 1a was replaced by a
homoallyl (i.e., 1i), thereby providing a substrate capable
of BeckwithÀDowd ring expansion followed by 6-exo-trig
or 7-endo-trig cyclization. Under the described conditions
(Method B) the BeckwithÀDowd product dominated,
although the product of 7-endo-trig cyclization, i.e., 3i,
was also isolated in modest yield (Table 2, entry 7).22
(18) For a review on the use of (TMS)3SiH, see: (a) Chatgilialoglu, C.;
Lalevee, J. Molecules 2012, 17, 527. For application in the BeckwithÀ
Dowd ring expansion, see: (b) Sugi, M.; Togo, H. Tetrahedron 2002, 58,
3171.
(19) For other reducing agents viable for BeckwithÀDowd rearran-
gements, see: (a) Studer, A.; Amrein, S.; Schleth, F.; Schulte, T.; Walton,
J. C. J. Am. Chem. Soc. 2003, 125, 5726. (b) Studer, A.; Amrein, S.
Angew. Chem., Int. Ed. 2000, 39, 3080. For a review on non-tin
reductants in radical chemistry, see: (c) Studer, A.; Amrein, S. Synthesis
2002, 835. For a recent report on the use of chloroform as a hydrogen
donor in radical reactions, see: (d) Ko, E. J.; Savage, G. P.; Williams,
C. M.; Tsanaktsidis, J. Org. Lett. 2011, 13, 1944 and references therein
for other non-tin reducing agents.
a Except as noted isolated as a 1:1 diastereoisomeric and racemic
mixture. b Isolated yield. c Conversion as judged by 1H NMR. d Isolated
yield of single diastereoisomer.
(20) Olefin geometry of olefins 3f and 3g assigned by NOE analysis
of 3g.
Studies then moved to access γ-lactones spirofused to
larger cycloalkanones (Table 3), compounds potentially
challenging to prepare in a concise fashion.23 To access
these structures using cascade ring-expansion cyclization
either larger cycloalkanones can be exploited as substrates
or expansion by more than one-carbon can be conducted;
both strategies were examined. Thus, cyclohexanone 1j
(21) For the derivatization of related olefins, see: Trost, B. M.;
Machacek, M. R.; Faulk, B. D. J. Am. Chem. Soc. 2006, 128, 6745.
(22) For recent studies exploiting 7-endo cyclization in synthesis and
discussions on factors affecting this selectivity, see: (a) Yokoe, H.;
Mitsuhashi, C.; Matsuoka, Y.; Yoshimura, T.; Yoshida, M.; Shishido,
K. J. Am. Chem. Soc. 2011, 133, 8854. (b) Alcaide, B.; Almendros, P.;
Martınez del Campo, T. Angew. Chem., Int. Ed. 2007, 46, 6684 and
´
references therein.
3414
Org. Lett., Vol. 14, No. 13, 2012

excellent 73% yield (Table 3, entry 2). The analogous four-
carbon expansion provided a 27% yield of cyclononane 3l
(Table 2, entry 3), with the major product arising from
reductive dehalogenation. Similar yields were obtained
when expanding cyclopentanone 1m by five carbons to
give γ-lactone 3m (Table 2, entry 4) and expanding cyclo-
hexanone 1n by four carbons to give the isomeric 3n
(Table 2, entry 5). While these later examples only pro-
ceeded in modest yield, the significant structural complex-
ity generated offsets the limited yield. In addition, Dowd
observed similar outcomes, when performing expansions
to form larger ring systems.24
Table 3. Scope of the Ring Expansion/Cyclization with Variable
Expansion
The BeckwithÀDowd ring expansion remains a highly
useful reaction to access unusual cycloalkanones from
commonly available β-ketoesters. Our studies demonstrate
that by the inclusion of allyl or propargyl ester side chains
ring-expansion triggered cascades can be achieved. In a
number of cases the rate of cyclization can allow premature
reduction. However this can be addressed, through the use
of higher boiling solvents in association with Bu3SnH rather
than (TMS)3SiH. Using these strategies, a range of complex
spirocyclic γ-lactones have been assembled that should
serve as useful intermediates in complex target synthesis.12,25
In addition, application of the BeckwithÀDowd ring ex-
pansion, in association with other radical cyclization pro-
cesses, should provide an avenue for the discovery of other
important transformations in chemical synthesis.
Acknowledgment. We dedicate this paper to the fond
memory of Professor Athelstan L. J. Beckwith (Research
School of Chemistry, ANU) and acknowledge early con-
tributions by Tina Hsia (Monash University) and the
financial support of the ARC (Future Fellowship and
Discovery programs) and the Monash Research Accel-
erator Program.
a Where applicable isolated as a 1:1 diastereoisomers and racemic
mixture. b Isolated yield. c Conversion as judged by 1H NMR. d Isolated
yield of a single diastereoisomer.
Supporting Information Available. Experimental proce-
dures, characterization of all new compounds, and copies
of 1H and 13C NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
when subjected to one-carbon ring expansion using Meth-
od B provided cycloheptanone 3j in 53% yield (Table 3,
entry 1). Cyclooctanones could be prepared by three-
carbon ring expansion/cyclization of cyclopentanones; this
was demonstrated with 1k providing γ-lactone 3k in an
(24) Three-carbon expansion of cyclopentanones proceeds in up to
69% yield. Four-carbon expansion of cyclopentanones proceeds in up to
36% yield; for more details see ref 7b.
(25) For examples of the application of the BeckwithÀDowd ring
expansion in total synthesis, see: (a) Mehta, G.; Krishnamurthy, N.;
Rao Karra, S. J. Am. Chem. Soc. 1991, 113, 5765. (b) Banwell, M. G.;
Cameron, J. M. Tetrahedron Lett. 1996, 37, 525. For related ring
expansions in total synthesis, see: (c) Heim, R.; Wiedemann, S.;
Williams, C. M.; Bernhardt, P. V. Org. Lett. 2005, 7, 1327. (d) Tilly,
D. P.; Williams, C. M.; Bernhardt, P. V. Org. Lett. 2005, 7, 5155.
(23) For reviews on synthetic approaches to medium to large rings,
see: (a) Yet, L. Chem. Rev. 2000, 100, 2963. (b) Mehta, G.; Singh, V.
Chem. Rev. 1999, 99, 881. For anionic ring expansions, and a discussion
of methods to access medium sized rings, see: (c) Lavoisier-Gallo, T.;
Charonnet, E.; Rodriguez, J. J. Org. Chem. 1998, 63, 900.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
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