Ketyl radical cyclization of β-disubstituted acrylates: Formal syntheses of (+)-secosyrin 1 and longianone and the total synthesis of (+)-4-epi-secosyrin 1

Article abstract of DOI:10.1021/ol4001894

A novel approach to the synthesis of a series of 1,7-dioxaspirononanes that applies a ketyl radical cyclization strategy is described. Radical cyclization of the β-disubstituted acrylate 23, prepared in five steps from (R)-1,2-isopropylideneglycerol, gives both 2,3-syn- and 2,3-anti-furan products. The densely functionalized furan heterocycles are used to complete a concise formal synthesis of secosyrin 1, a metabolite of Pseudomonas syringae, and the total synthesis of 4-epi-secosyrin 1.

Full text of DOI:10.1021/ol4001894

ORGANIC
LETTERS
2013
Vol. 15, No. 6
1258–1261
Ketyl Radical Cyclization of
β‑Disubstituted Acrylates: Formal
Syntheses of (þ)-Secosyrin 1 and
Longianone and the Total Synthesis
of (þ)-4-epi-Secosyrin 1
Christopher D. Donner*
Australian Research Council Centre of Excellence for Free Radical Chemistry and
Biotechnology, School of Chemistry and Bio21 Molecular Science and Biotechnology
Institute, The University of Melbourne, Victoria, 3010, Australia
cdonner@unimelb.edu.au
Received January 22, 2013
ABSTRACT
A novel approach to the synthesis of a series of 1,7-dioxaspirononanes that applies a ketyl radical cyclization strategy is described. Radical
cyclization of the β-disubstituted acrylate 23, prepared in five steps from (R)-1,2-isopropylideneglycerol, gives both 2,3-syn- and 2,3-anti-furan
products. The densely functionalized furan heterocycles are used to complete a concise formal synthesis of secosyrin 1, a metabolite of
Pseudomonas syringae, and the total synthesis of 4-epi-secosyrin 1.
Naturally occurring spirocyclic ethers are widespread in
naturehavingbeenisolatedfrom a variety ofsources. Most
common among the dioxaspiro group are spiroketal-type
ring systems1 that can be readily prepared, at least from
a conceptual standpoint, by dehydration of a keto-diol
precursor. The preparation of dioxaspiro systems in which
onlyone or neitherofthe oxygens isdirectly attachedtothe
spiro center requires the development and application of
less well-defined synthetic strategies.2
Of the various nonketal dioxaspiro compounds that are
known to occur naturally,3 1,7-dioxaspiro[4.4]nonanes
such as 1ꢀ4 and 7ꢀ8 (Figure 1A) represent a small group
of compounds that have been isolated from bacterial and
fungal sources. The syringolides 1 (1) and 2 (2), secosyrins
1 (3) and 2 (4), and syributins 1 (5) and 2 (6) were first
isolated from the plant pathogen Pseudomonas syringae,4
whereas sphydrofuran (7) was isolated from strains of
Actinomycetes5 and longianone (8) was isolated from the
fungus Xylaria longiana.6 The syringolides 1/2 have the
most significant bioactivity of this group, being elicitors
of a hypersensitive defense response in infected soy
bean plants resistant to Pseudomonas syringae. It has been
proposed that biosynthetically the secosyrins 3/4 are
derived from syringolides 1/2 by a reverse Claisen reaction,
with a subsequent retro-Michael reaction and 1,3-acyl
migration forming the syributins 5/6.4b
The synthesis of 3 and 4 has been the subject of some
interest.7 A number of synthetic strategies used to date for
(1) (a) Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617–1661. (b)
Aho, J. E.; Pihko, P. M.; Rissa, T. K. Chem. Rev. 2005, 105, 4406–4440.
(2) Rosenberg, S.; Leino, R. Synthesis 2009, 2651–2673.
(3) Alonso, F.; Foubelo, F.; Yus, M. Curr. Chem. Biol. 2007, 1, 317–
346.
(4) (a) Midland, S. L.; Keen, N. T.; Sims, J. J.; Midland, M. M.;
Stayton, M. M.; Burton, V.; Smith, M. J.; Mazzola, E. P.; Graham, K. J.;
Clardy, J. J. Org. Chem. 1993, 58, 2940–2945. (b) Midland, S. L.; Keen,
N. T.; Sims, J. J. J. Org. Chem. 1995, 60, 1118–1119.
(5) (a) Umezawa, S.; Usui, T.; Umezawa, H.; Tsuchiya, T.; Takeuchi,
T.; Hamada, M. J. Antibiot. 1971, 24, 85–92. (b) Usui, T.; Umezawa, S.;
Tsuchiya, T.; Naganawa, H.; Takeuchi, T.; Umezawa, H. J. Antibiot.
1971, 24, 93–106.
(6) Edwards, R. L.; Maitland, D. J.; Oliver, C. L.; Pacey, M. S.;
Shields, L.; Whalley, A. J. S. J. Chem. Soc., Perkin Trans. 1 1999, 715–
719.
r
10.1021/ol4001894
Published on Web 03/01/2013
2013 American Chemical Society

Samarium(II) iodide has become the reagent of choice for
the formation of ketyl radicals;10 however, use of SmI2
commonly leads to a preference for the formation of anti-
products upon cyclization with acrylate acceptors. This
reagent may therefore not enable us to directly access the
required syn-arrangement of alcohol and acetate substitu-
ents flanking the C4ꢀC5 bond in A. Use of tributyltin
hydride to generate ketyl radicals typically results in the
formation of mixtures of diastereomers,11 with the addi-
tion of Lewis acids also allowing anti-selectivity to be
achieved.12 However, wehavedemonstratedcasesinwhich
the use of tributyltin hydride can lead to preferential
formation ofsyn-isomers from β-alkoxyacrylate systems.13
Despite the extensive use of ketyl radical cycliza-
tions with acrylate acceptors,10,14 the use of hindered
β-disubstituted acrylate systems as ketyl radical acceptors
appears to have been used on limited occasions.15 To
explore the proposed cyclization we first prepared the
aldehyde substrate 13 (Scheme 1), anticipating that this
model system would also give us access to longianone (8).
Aldehyde 13 was obtained in three steps (64% yield) from
alcohol 9 and acetylene 10, the (E)-configuration being
formed exclusively upon conjugate addition of 9 with 10
in the presence of PMe3.16 Heating a solution of 13 with
tributyltin hydride (1.3 equiv) and AIBN (0.2 equiv) led
to the formation of two products that were identified as the
syn-14 and anti-15 substituted furans that were isolated
in 34% and 38% yields, respectively, the less polar syn-
product having undergone lactonization in situ.17 Orga-
notin byproducts from the reaction mixture were removed
efficiently by filtration through a short column of 10%
KF-silica prior to further chromatographic purification.18
The anti-product 15 was then converted to dihydrolongia-
none (17)6,19 by oxidation of the secondary alcohol using
Swern conditions to form ketone 16 followed by deprotec-
tion of the primary alcohol using DDQ and acid-catalyzed
lactonization (56% yield, three steps).20 Dihydrolongia-
none has previously been converted to 8 by oxidation using
Figure 1. (A) Naturally occurring 1,7-dioxaspiro[4.4]nonanes
and cometabolites. (B) Retrosynthesis of dioxaspirononanes
using a “conventional” intramolecular hetero-Michael addition
strategy and ketyl radical cyclization strategy.
the synthesis of dioxaspirononanes take advantage of the
nucleophilic behavior of a tetheredprimaryalcohol suchas
B (Figure 1B) that can undergo an intramolecular hetero-
Michael addition (IHMA) to form the CꢀO bond of the
spiro center in spirocycle A,7b,fꢀh,8 in a reverse manner
to that which is proposed to occur biosynthetically. We
identified a less intuitive disconnection of the secosyrin
dioxaspiro framework A that would involve a ketyl radical
cyclization of substrate C to form the C4ꢀC5 bond. This
strategy would allow formation of the adjacent C4
(secondary alcohol) and C5 (spiro) stereocenters in a single
step. With the existing C3 asymmetric center expected to
impart favorable diastereocontrol during formation of the
C5 center,9 the ability to control the relative stereochem-
istry between the C4 and C5 centers is of importance.
(11) Enholm, E. J.; Prasad, G. TetrahedronLett. 1989, 30, 4939–4942.
(12) Enholm, E. J.; Allais, F.; Bareyt, S. Tetrahedron: Asymmetry
2003, 14, 2871–2874.
(13) Donner, C. D. Synthesis 2010, 415–420.
(14) For a review, see: (a) Srikanth, G. S. C.; Castle, S. L. Tetrahedron
2005, 61, 10377–10441. Selected examples involving β-alkoxyacrylates
include: (b) Kerrigan, N. J.; Upadhyay, T.; Procter, D. J. Tetrahedron
Lett. 2004, 45, 9087–9090. (c) Takahashi, S.; Kubota, A.; Nakata, T.
Org. Lett. 2003, 5, 1353–1356. (d) Matsuo, G.; Kadohama, H.; Nakata,
T. Chem. Lett. 2002, 148–149.
(15) (a) Suzuki, K.; Matsukura, H.; Matsuo, G.; Koshino, H.;
Nakata, T. Tetrahedron Lett. 2002, 43, 8653–8655. (b) Enholm, E. J.;
Burroff, J. A. Tetrahedron 1997, 53, 13583–13602. (c) Kang, H.-Y.; Koh,
H. Y.; Chang, M. H.; Hwang, J.-T.; Shim, S. C. Bull. Korean Chem. Soc.
1994, 15, 710–712. (d) Enholm, E. J.; Satici, H.; Trivellas, A. J. Org.
Chem. 1989, 54, 5841–5843.
(7) (a) Mukai, C.; Moharram, S. M.; Hanaoka, M. Tetrahedron Lett.
1997, 38, 2511–2512. (b) Yu, P.; Yang, Y.; Zhang, Z. Y.; Mak, T. C. W.;
Wong, H. N. C. J. Org. Chem. 1997, 62, 6359–6366. (c) Mukai, C.;
Moharram, S. M.; Azukizawa, S.; Hanaoka, M. J. Org. Chem. 1997, 62,
8095–8103. (d) Carda, M.; Castillo, E.; Rodrıguez, S.; Falomir, E.;
´
(16) Inanaga, J.; Baba, Y.; Hanamoto, T. Chem. Lett. 1993, 22, 241–
244.
Marco, J. A. Tetrahedron Lett. 1998, 39, 8895–8896. (e) Donohoe, T. J.;
Fisher, J. W.; Edwards, P. J. Org. Lett. 2004, 6, 465–467. (f) Koumbis,
A. E.; Varvogli, A.-A. C. Synlett 2006, 3340–3342. (g) Gautam, D.; Rao,
B. V. Tetrahedron Lett. 2009, 50, 1693–1695. (h) Varvogli, A.-A. C.;
Karagiannis, I. N.; Koumbis, A. E. Tetrahedron 2009, 65, 1048–1058.
(8) (a) Lykakis, I. N.; Zaravinos, I.-P.; Raptis, C.; Stratakis, M.
J. Org. Chem. 2009, 74, 6339–6342. (b) Perali, R. S.; Kalapati, S.
Tetrahedron 2012, 68, 3725–3728.
(17) Whilst use of SmI2 has not been attempted, reaction of 13 with
(TMS)3SiH/AIBN led to complete recovery of the starting aldehyde.
(18) Harrowven, D. C.; Guy, I. L. Chem. Commun. 2004, 1968–1969.
(19) Aitken, H. M.; Schiesser, C. H.; Donner, C. D. Aust. J. Chem.
2011, 64, 409–415.
(20) The spectroscopic data for 17 were identical to material we had
prepared previously via an acyl radical cyclization (ref 19) and also to the
data reported for dihydrolongianone 17 formed by reduction of the
natural product longianone 8 (ref 6).
(9) Beckwith, A. L. J. Tetrahedron 1981, 37, 3073–3100.
(10) Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. Rev. 2004,
104, 3371–3403.
Org. Lett., Vol. 15, No. 6, 2013
1259

IBX;8 thus, preparation of 17 constitutes a formal synthe-
sis of 8.
Scheme 2. Formal Synthesis of Secosyrin 1 (3)
Scheme 1. Formal Synthesis of Longianone (8)
Having established the viability of using a ketyl radical
cyclization approach for the synthesis of dioxaspiro
systems, albeit without apparent diastereoselectivity, we
continued with our plans for the synthesis of secosyrin 1
(3) using a similar strategy. Toward this end, the asym-
metric protected triol 18 underwent addition to acetylene
10 to deliver the β-disubstituted acrylate 19 in 91% yield,
exclusively as the E-isomer (Scheme 2). Protecting group
interconversion involving firstthe removal ofthe acetonide
(HCl/MeOH) to give the 1,2-diol 20, bis-silylation using
TBSOTf, and finally selective silyl group removal (CSA/
CH2Cl2/MeOH) gave the primary alcohol 22 in 74% yield
over the three steps. Oxidation of 22 using Swern condi-
tions then delivered the (R)-configured aldehyde substrate
23 in preparation for cyclization.
Subjecting aldehyde 23 to O-stannyl ketyl radical form-
ing conditions (Bu3SnH/AIBN) led to the isolation of the
syn- and anti-cyclized products 24 and 25, respectively,
having a combined yield of 58%. The stereochemical
assignment for the anti-product 25 could be made con-
fidently by acetylation of the secondary alcohol to give 28,
the product showing clear NOE correlations between the
C3 methine proton and both the C4 methine proton and
R-methylene protons (Scheme 2). The stereochemistry of
the syn-product 24 was also confirmed by NOE analysis.
Stereochemical control during formation of the quaternary
centers in 24 and 25 may be explained by invoking a
chairlike transition state for the radical cyclization.9,21
The bis-silyl ether 27 has previously been converted over
five steps to secosyrin 1 (3);7g thus, a straightforward
exchange of the PMB protecting group in 24 for a TBS
group delivers 27 (77%, two steps) and completes a concise
formal synthesis of 3. The spectroscopic data for the bis-
silyl ether 27 obtained in this manner,21 including specific
rotation, are in complete agreement with the material
prepared by Rao over 12 steps from D-mannitol.7g,22
In addition to the formation of cyclized products 24 and
25 from the ketyl radical cyclization reaction of aldehyde
23, reduction of aldehyde 23 also took place to form
alcohol 22. Isolation of the alcohol 22 was unexpected
given the simpler aldehyde 13 described above (Scheme 1)
showed no evidence of competitive reduction taking place
under similar conditions. With the expectation that for-
mation of thealcohol22results from H-atom transfer from
Bu3SnH to the intermediate ketyl radical, with the rate of
sucha process being competitive withcyclization, the effect
of tin hydride concentration was examined. However, little
change in the product ratio was observed across a 10-fold
concentration range.21
In an attempt to obtain evidence that directly identifies
the source of hydrogen that leads to formation of alcohol
22 we resorted to deuterium-labeling experiments. Reac-
tion of 23 with Bu3SnD/AIBN led to the isolation of three
products (Scheme 3). Analysis by both 1H and 13C NMR
spectroscopy showed that the syn-product 24-d contained
(22) Dr. B. V. Rao, Indian Institute of Chemical Technology, is
thanked for providing the complete spectroscopic data for compound
27, including specific rotation, not reported in the original publication
(ref 7g).
(21) See Supporting Information.
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Org. Lett., Vol. 15, No. 6, 2013

proton and the C9 methylene protons, confirming both
the location of the acyl group and absolute configuration
of the final product, 4-epi-secosyrin 1 (32).
Scheme 3. Deuterium Incorporation into 24 and 25
Scheme 4. Completion of the Synthesis of 4-epi-Secosyrin 1 (32)
deuterium at the R-methylene or benzylic ether position
in near equal amounts, while the anti-product 25-d was
deuterated almost exclusively at the benzylic ether posi-
tion. Incorporation of deuterium at the benzylic position is
likely to occur after initial cyclization, and a subsequent
1,5-hydrogen atom transfer takes place. Such a process
closely resembles reported tandem radical reactions that
have been used to prepare all-carbon spirocycles from
similar β-disubstituted acrylate systems.15b However, the
product of most interest from the radical cyclization,
alcohol 22, showed no incorporation of deuterium as
determined by 1H and 13C NMR spectroscopy and high-
resolution mass measurement. While not entirely efficient,
it should be recognized that the alcohol 22that results from
this competing side reaction can simply be oxidized to
regenerate aldehyde 23, a notable advantage in the use
of aldehydes as radical precursors, in comparison to alkyl
halides, when competitive reduction of the substrate
occurs.
In summary, the formal syntheses of both (þ)-secosyrin
1 (3) and longianone (8) have been achieved by applying
a ketyl radical cyclization of β-disubstituted acrylate
precursors. While the diastereoselectivity exhibited upon
cyclization of model aldehyde 13 was not significant, the
further functionalized substrate 23 exhibited a preference
for the formation of the 2,3-anti-substituted furan 25.
Additionally, we have recognized this as an opportunity
to access analogues of the naturally occurring compounds
and thus completed a synthesis of (þ)-4-epi-secosyrin 1 (32).
Acknowledgment. Financial support from the Australian
Research Council through the Centres of Excellence pro-
gram is gratefully acknowledged. Professor Carl Schiesser,
The University of Melbourne, is acknowledged for useful
discussions.
The isolation of anti-furan 25 from the cyclization of
aldehyde 23 gave us the opportunity to prepare a novel
analogue of the secosyrins. Thus, acylation of 25 with
hexanoyl chloride provided 29 in 71% yield (Scheme 4).
Deprotection of the primary alcohol in 29 using DDQ gave
30, which upon exposure to acid formed the dioxaspiro
system 31 in 76% yield over the two steps. Finally,
desilylation of 31 using TBAF gave alcohol 32 having
Supporting Information Available. Experimental pro-
1
cedures and H and 13C NMR spectra for compounds
9ꢀ17 and 19ꢀ32. This material is available free of charge
via the Internet at http://pubs.acs.org.
26
[R]D þ27.3 (c 0.14, CHCl3). NOE analysis of 32 showed
a clear correlation between the deshielded C4 methine
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 6, 2013
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