Synthetic and computational studies of acyl radical cyclizations with β-alkoxyacrylates: Formal synthesis of (±)-longianone

Article abstract of DOI:10.1071/CH10462

An investigation into the cyclization of acyl radicals with mono- and disubstituted β-alkoxyacrylates is described. Ether-tethered acyl radicals, generated directly from the corresponding aldehyde, undergo cyclization to form dioxaspiro heterocyclic syste

Full text of DOI:10.1071/CH10462

RESEARCH FRONT
Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2011, 64, 409–415
Synthetic and Computational Studies of Acyl Radical
Cyclizations with b-Alkoxyacrylates: Formal Synthesis
of (6)-Longianone-
A B
,
A B
,
Heather M. Aitken,
Carl H. Schiesser,
A B C
, ,
and Christopher D. Donner
A
School of Chemistry, The University of Melbourne, Vic. 3010, Australia.
Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne,
Vic. 3010, Australia.
B
C
Corresponding author. Email: cdonner@unimelb.edu.au
An investigation into the cyclization of acyl radicals with mono- and disubstituted b-alkoxyacrylates is described.
Ether-tethered acyl radicals, generated directly from the corresponding aldehyde, undergo cyclization to form dioxa-
spiro heterocyclic systems including 1,7-dioxaspiro[4,4]nonane-4,8-dione and 1,8-dioxaspiro[5,4]decane-5,9-dione. This
strategy is applied to a concise formal synthesis of the fungal metabolite longianone. Density functional theory
calculations provide insight into the chemistry of the acyl radicals in this study.
Manuscript received: 17 December 2010.
Manuscript accepted: 15 February 2011.
Introduction
CO2Me
R
O
Among the variety of functional groups used as radical pre-
cursors, the straightforward synthetic accessibility of aldehydes
makes such substrates convenient and versatile precursors for
radical reactions. Commonly, reductive conditions using either
tributyltin hydride[1] or samarium(II) iodide[2] are applied to
precursors such as 1 (Scheme 1), resulting in ketyl radical for-
mation and subsequent cyclization to generate cyclic secondary
alcohols, e.g. 2, in which two new asymmetric centres are cre-
ated. Such a cyclization strategy has seen regular application in
natural products synthesis,[3] particularly in the preparation of
polycyclic ethers. Examples of ketyl radical cyclizations with
b-disubstituted acrylates (e.g. 1, R ¼ H) are somewhat less
common, but in such cases a quaternary asymmetric centre can
be generated.[4]
H
O
n
1 (n ꢀ 1–3)
Ketyl
radical
Acyl
radical
conjugate
addition
conjugate
addition
CO2Me
CO2Me
H
R
O
O
R
HO
O
Unlike the formation and subsequent cyclization of ketyl
radicals generated from aldehydes, the direct generation of acyl
radicals from aldehydes is far less common. More typically,
the generation of acyl radicals is achieved either via thio- or
selenoester precursors, by carbonylation of alkyl radicals, or
through fragmentation processes.[5] The usual tin-mediated
conditions associated with selenoesters and the necessary
high-pressure conditions used in carbonylation procedures are
seen as drawbacks to the widespread application of these
conditions. Few practical examples of the direct generation of
acyl radicals from aldehydes and their subsequent addition or
cyclization have been reported. This is in part due to the
existence of unfavourable polar effects in the transition state
for H-atom transfer. However, the use of polarity-reversal
n
n
3
2
Scheme 1. Radical cyclization strategies towards cyclic ethers from
aldehyde precursors.
catalysis can overcome this hurdle.[6] Tsujimoto and
coworkers reported the intermolecular addition of acyl radicals
to electron-deficient alkenes in the presence of benzoyl peroxide
as radical initiator and using N-hydroxyphthalimide (NHPI)
as a polarity-reversal catalyst.[7] Yoshikai and coworkers
have described an intramolecular hydroacylation process using
tert-dodecanethiol as catalyst and 2,20-azobis(isobutyronitrile)
yDedicated to the memory of Athel Beckwith, an inspirational scientist, teacher and mentor.
Ó CSIRO 2011
10.1071/CH10462
0004-9425/11/040409

RESEARCH FRONT
410
H. M. Aitken, C. H. Schiesser, and C. D. Donner
O
O
O
(AIBN) (or 1,10-azobis(cyclohexanecarbonitrile) (ABCN))
initiation.[8] Although carbocyclic structures have been pre-
pared in this way, the formation of heterocyclic compounds
under such conditions does not appear to have been reported.
Wehaveanongoing interest indevelopinganunderstandingof
the fundamental reactivity of acyl and related radicals and their
application to synthesis,[9] especially as these radicals can often
‘masquerade’ as electrophiles.[10] One of us recently reported
the application of aldehyde-containing substrates as radical pre-
cursors in cyclization reactions with b-alkoxyacrylates.[11] In a
continuation of these investigations, we sought to explore the
possibility of direct acyl radical formation from aldehyde pre-
cursors and their subsequent cyclization to generate novel hetero-
cycles. Specifically, we planned to use b-disubstituted acrylates
(e.g. 1, R¼ H) that would, on cyclization, give functionalized
tetrahydrofuran-3-one products, e.g. 3 (n ¼ 1) that may be further
transformed to dioxaspirocyclic systems.
O
O
CO2R
OPG
A
B
O
O
O
O
O
n
n
m
m
6
Longianone 4
5
CO2R
CO2R
OPG
O
ꢁ
PGO
OH
H
O
n
m
n
OPG
m
8
9
7
Scheme 2. Retrosynthetic analysis of spirocyclic systems 5. PG ¼
protecting group.
CO2Me
(a)
PMBO
OH
PMBO
O
Results and Discussion
10
11
12
Dioxaspirocyclic systems, of varying ring sizes, are present in
several naturally occurring structure classes.[12] The simplest
example is longianone 4, a fungal metabolite from Xylaria
longiana,[13] which we considered an ideal target to demonstrate
the feasibility, or otherwise, of using acyl radical cyclizations
for the preparation of spirocycles. The proposed general syn-
thetic strategy towards spirocycles, e.g. longianone 4, is shown
in Scheme 2. Thus, the intermediate b-disubstituted acrylate 7
may undergo acyl radical generation and cyclization to form the
2,2-disubstituted furan 6, while subsequent deprotection of the
primary alcohol and lactonization to form the B-ring completes
the spirocyclic framework in 5. The cyclization substrate 7
should be available from the precursor alcohol 9 and acetylene 8,
with the choice of chain lengths (n, m ¼ 1, 2) dictating the
ultimate size of the spirocyclic ring system in 5. Dioxaspirocycle
5 (n ¼ m ¼ 1) has been prepared as a precursor to longianone 4 in
both previous syntheses of this metabolite, with final conversion
to 4 being achieved either by an a-selenation–oxidation–
elimination sequence[14] or by direct oxidation using stabilized
2-iodoxybenzoic acid (IBX).[15]
(b)
CO2Me
CO2Me
O
(c)
H
O
HO
O
13
(d)
O
CO2Me
O
14
Scheme 3. Reagents and conditions: (a) methyl propiolate, PMe3 (1 M in
THF, 0.2 equiv.), CH2Cl2, 08C, 45 min (98%); (b) DDQ, CH2Cl2, H2O, 08C,
3 h (75%); (c) PhI(OAc)2, TEMPO, CH2Cl2, 4 h (72%); (d) tert-dodeca-
nethiol (0.3 equiv.), ABCN (0.3 equiv.), toluene, reflux, 18 h. PMB ¼ para-
methoxybenzyl.
Before attempting the acyl radical cyclization using hindered
substrates such as 7, we sought to investigate whether simpler
b-alkoxyacrylates would undergo the expected cyclization with
acyl radicals generated directly from aldehydes under the
reported conditions.[7,8] The aldehyde 13 (Scheme 3), a potential
acyl radical precursor, was prepared from the monoprotected
diol 10 by first reacting with methyl propiolate in the presence
of trimethylphosphine[16] to form the (E)-b-alkoxyacrylate 11,
which was then deprotected and subsequently oxidized to the
aldehyde 13 (53% yield over three steps). First, applying
conditions developed by Ishii (benzoyl peroxide/NHPI/toluene,
808C)[7] led to aldehyde 13 being recovered essentially
unchanged.
Turning to Tomioka’s methodology,[8] the aldehyde 13 was
heated in toluene with ABCN initiation and using tert-dodeca-
nethiol as the polarity-reversal catalyst. A complex mixture of
products was recovered from the reaction, with the expected
cyclized product 14 being a minor component of the mixture. It
may be concluded that the low yields of heterocycle 14 result
from the more electron-rich nature of the acrylate substrate 13,
which may lead to polymerization. Additionally, thiyl radicals
are known to add to olefins,[17] a process that is more favourable
for electron-rich double bonds. Aware of the possibility of
competitive decarbonylation occurring, the anticipated product
formed from such a process (enol-ether 38, vide infra) was
prepared. However, spectroscopic comparison of the enol-ether
38 with the product mixture formed from reaction of 13
(Scheme 3) indicated that enol-ether 38 was not present.
Undeterred by the modest success in achieving direct acyl
radical formation and cyclization using aldehyde 13, we pursued
a b-disubstituted system as an acyl radical precursor. Initially
targeting the bis-furanone spirocyclic system that leads to
longianone 4, the aldehyde intermediate 18 was prepared from
acetylene 15 (Scheme 4). Thus, conjugate addition of mono-
protected 1,3-propanediol with acetylene 15, followed by depro-
tection and oxidation gave the aldehyde substrate 18. Treating
aldehyde 18 under the thiol-mediated radical cyclization con-
ditions gave a less complex product mixture than obtained
previously for the monosubstituted substrate. The sole product
isolated from the reaction was shown to be the tetrahydrofuran-
3-one 19, formed from successful acyl radical cyclization.
Characteristic signals in the 1H NMR spectrum of 19 included
two pairs of doublets at d 2.57 and 2.71 (J 16.5 Hz) and d 3.58
and 3.70 (J 10.1 Hz) from the exocyclic methylene groups.
The success in forming the cyclized product 19 from the

RESEARCH FRONT
Studies of Acyl Radical Cyclizations
411
CO2Me
CO2Me
CO2Me
CO2Me
OTBS
(a)
(a)
PMBO
O
OTBS
OTBS
PMBO
O
22
OTBS
21
16
(b)
15
(b)
CO2Me
CO2Me
OTBS
O
(c)
CO2Me
OTBS
CO2Me
O
HO
O
OTBS
H
O
(c)
OTBS
23
24
HO
O
H
O
O
18
(d)
(d)
17
O
O
O
CO2Me
O
CO2Me
(e)
OTBS
O
ꢁ
O
CO2Me
OTBS
Ref.
[14] or [15]
O
O
OTBS
O
O
(e)
4
27
25
26
O
O
(e)
20
19
HO
O
O
Scheme 4. Reagents and conditions: (a) 10, PMe3 (1 M in THF,
0.25 equiv.), CH2Cl2, 08C to rt, 2 h (91%); (b) DDQ, CH2Cl2, H2O, 08C,
3 h (98%); (c) PhI(OAc)2, TEMPO, CH2Cl2, 4 h (70%); (d) tert-dodeca-
nethiol (0.3 equiv.), ABCN (0.3 equiv.), toluene, reflux, 15 h (28%);
(e) 10-CSA, CHCl3, MeOH, 2 days (61%). TBS ¼ tert-butyldimethylsilyl,
PMB ¼ para-methoxybenzyl.
O
O
O
O
CO2Me
28
29
Scheme 5. Reagents and conditions: (a) 10, PMe3 (1 M in THF,
0.25 equiv.), CH2Cl2, 08C to room temperature (rt), 2 h (84% (E)-isomer,
6% (Z)-isomer); (b) DDQ, CH2Cl2, H2O, 08C, 2 h (95%); (c) PhI(OAc)2,
TEMPO, CH2Cl2, 2 h (77%); (d) tert-dodecanethiol (0.3 equiv.), ABCN
(0.6 equiv.), toluene, reflux, 21 h (25, 42%; 26, 36%); (e) 10-CSA,
CHCl3, MeOH, 20 h (71%). TBS ¼ tert-butyldimethylsilyl, PMB ¼ para-
methoxybenzyl.
b-disubstituted acrylate 18 is consistent with our earlier propo-
sals that the sulfur radical may be reacting directly with the
less-hindered double bond in 13 (Scheme 3) in preference to
hydrogen abstraction from the aldehyde group, or that polymer-
ization of 13 may be occurring.
Treatment of 19 with camphorsulfonic acid (CSA) in
methanol/chloroform leads to removal of the silyl group and
lactonization to give the dioxaspirononane 20 (dihydrolongia-
none). The structure of 20 could be confirmed by spectroscopic
comparison (1H and 13C NMR) with the same product derived
from hydrogenation of naturally occurring longianone 4.[13]
Preparation of dihydrolongianone 20, which has previously
been converted to longianone 4,[14,15] completes a formal
synthesis of this natural product. Notably, in the originally
reported synthesis of longianone 4 by Steel,[14] the spiro system
was formed by cyclization of a vinyl radical generated from a
terminal acetylene using Bu3SnH, with subsequent ozonolysis
of the resultant exocyclic methylene group giving 20. The
reported intention of applying an acyl radical cyclization using
a selenoester precursor was not able to be realised owing to the
instability of the proposed intermediates. Thus, the direct for-
mation of acyl radicals from aldehydes, as demonstrated in
the present work, may serve as an alternative methodology in
situations where the formation of selenoesters, or other acyl
radical precursors, is not viable.
As an extension of this acyl radical cyclization procedure,
we sought to prepare dioxaspiro systems of varying ring sizes.
It was expected that heterocycle 27 (Scheme 5), having an
expanded lactone ring, could be prepared from the homologous
acetylene 21. Hetero-Michael addition of alcohol 10 with
acetylene 21 gave the (E)-acrylate 22, which was then depro-
tected and oxidized to generate the cyclization precursor 24 in
61% yield over the three steps. Applying the radical cyclization
conditions under polarity-reversal catalysis led to the isolation
of two products in a combined yield of 78%. The first product
was identified as the expected tetrahydrofuranone 26 resulting
1
from acyl radical cyclization. The H NMR spectrum of 26
included a pair of doublets at d 2.72 and 2.82 (J 16.4 Hz) from
the isolated methylene group while the remaining eight methy-
lene protons gave clearly resolved multiplets between d 1.70
and 4.28. The second product from this reaction, isolated in 42%
yield, was the enol-ether 25. This product clearly derives from
decarbonylation and subsequent reduction of the acyl radical
generated from 24. Confirmation of the identity of 25 was
achieved by spectroscopic analysis and comparison with an
authentic sample prepared directly from acetylene 21 and
ethanol (Scheme 7). The formation of 25 is somewhat surprising
given that the corresponding decarbonylated product that would
be formed from aldehyde 18 (Scheme 4) was not observed. This
was confirmed by preparing an authentic sample of the enol-
ether 39 (Scheme 7) to show, by spectroscopic comparison, that
it was not part of the crude reaction mixture formed from the
radical cyclization reaction of aldehyde 18. Exposure of silyl
ether 26 to acid, however, failed to form the dioxaspiro system
27. Instead, the novel propellane 29 was isolated in 71% yield.
Presumably the product 29 is formed by trapping of the inter-
mediate acetal 28 formed after deprotection of the primary
alcohol in 26.[18]
As a final demonstration of the application of this strategy,
the isomeric system 36 (Scheme 6) was prepared. Thus,
disubstituted acrylate 30 was prepared from acetylene 15
and monoprotected 1,4-butanediol. Removal of the para-
methoxybenzyl (PMB) group and subsequent oxidation of the

RESEARCH FRONT
412
H. M. Aitken, C. H. Schiesser, and C. D. Donner
CO2Me
CO2Me
CO2Me
OTBS
CO2Me
(a)
(a)
38
PMBO
O
O
H
OTBS
30
37
15
(b)
CO2Me
CO2Me
OTBS
CO2Me
CO2Me
39 R ꢀ Et
34 R ꢀ Pr
(c)
(b)
HO
H
OTBS
O
O
OTBS
R
O
O
32
31
OTBS
15
(d)
CO2Me
CO2Me
O
CO2Me
CO2Me
CO2Me
OTBS
(c)
ꢁ
25
OTBS
ꢁ
OTBS
O
O
O
O
OTBS
OTBS
33
34
35
21
(e)
Scheme 7. Reagents and conditions: (a) EtOH, PMe3 (1 M in THF,
0.2 equiv.), CH2Cl2, 08C, 1 h (94%); (b) EtOH or n-PrOH, PMe3 (1 M in
THF, 0.5 equiv.), CH2Cl2, 08C to room temperature (rt), 1.5 h (83% for 39,
84% for 34); (c) EtOH, PMe3 (1 M in THF, 0.7 equiv.), CH2Cl2, 08C to rt, 5 h
(86%). TBS ¼ tert-butyldimethylsilyl.
O
O
O
O
36
O
R
R
ΔE‡1
ΔE‡4
O
Scheme 6. Reagents and conditions: (a) 4-(4-methoxybenzyloxy)butan-
1-ol, PMe3 (1 M in THF, 0.25 equiv.), CH2Cl2, 08C to room temperature (rt),
1 h (87%); (b) DDQ, CH2Cl2, H2O, 08C, 2 h (96%); (c) PhI(OAc)2, TEMPO,
CH2Cl2, 3 h (97%); (d) tert-dodecanethiol (0.3 equiv.), ABCN (0.8 equiv.),
toluene, reflux, 42 h (33, 32%; 34, 26%; 35, 19%); (e) 10-CSA, CHCl3,
O
n
O
n
41
40
ΔE‡5
ΔE‡2
CO
MeOH,
2
days (75%). TBS ¼ tert-butyldimethylsilyl, PMB ¼ para-
R
R
methoxybenzyl.
ΔE‡3
n
O
ΔE‡6
n ꢀ 2
O
43
42
primary alcohol 31 gave the aldehyde 32 (81% yield over three
steps). Given that the previously described acyl radical cycliza-
tion of aldehyde 24, which involves a 5-exo process, was prone
to competitive decarbonylation, it was expected that the 6-exo
cyclization of aldehyde 32 might be less successful. However,
treating the aldehyde 32 under similar radical reaction condi-
tions to those used previously led to formation of the pyran 33 in
32% yield, only marginally lower than the 36% yield obtained
from the 5-exo cyclization of aldehyde 24. The decarbonylated
product 34 was also isolated from the reaction mixture (26%
yield) and its structure confirmed by comparison with an
authentic sample prepared directly from conjugate addition of
propanol with acetylene 15 (Scheme 7). A third product was
identified as the tetrahydrofuran 35 (19% yield) that is formed
via 5-exo cyclization of the primary radical generated after
decarbonylation of 32. Finally, exposure of 33 to CSA catalyzed
desilylation and formation of the g-lactone ring and completed
the 6,5 dioxaspiro system 36.
In order to provide further insight into this chemistry, we
sought recourse to computational techniques. To that end, the
cyclization and decarbonylation chemistries of the acyl radicals
40 (Scheme 8) were investigated using ab initio and density
functional theory (DFT) techniques as described below. Radical
40 can undergo intramolecular homolytic addition chemistry to
afford the ketone 41, or it can decarbonylate via an a-scission
process to afford 42, which, depending on chain length, can
ΔE‡1
ΔE‡2
ΔE‡3
ΔE‡4
ΔE‡5
ΔE‡6
n
R
1
1
2
2
H
61.6
52.3
68.8
57.5
78.3
76.2
75.3
73.3
–
97.5
95.5
25.7
26.4
26.5
25.7
–
CO2Me
H
–
–
50.7
43.3
107.4
105.9
106.5
116.1
CO2Me
kJ molꢂ1 (BHandHLYP/6ꢂ311ꢁꢁG(d,p)).
Scheme 8.
undergo further cyclization to afford the tetrahydrofuranylalkyl
radical 43.
Searching of the relevant potential energy surfaces located
structures 40–43, and these proved to correspond to minima on
the respective potential energy surface (Scheme 8). Transition
states for the cyclization of radicals 40 are displayed in Fig. 1,
and transition states for the decarbonylation of 40 leading to 42,
and those for subsequent cyclization to 43 are not shown;
however, full geometric details are available in the Accessory
Publication. Energy barriers calculated at the BHandHLYP/
6–311þþG(d,p) level of theory are listed in Scheme 8. Data
obtained at other levels of theory are provided in the Accessory
Publication, together with the Gaussian Archive entries for all
optimized structures in this study.

RESEARCH FRONT
Studies of Acyl Radical Cyclizations
413
O
CO2Me
OTMS
CO2Me
67.7 kJ molꢂ1
OTMS
O
O
O
48
49
Scheme 9.
2.163 Å
2.194 Å
be significantly exothermic, while the decarbonylation reactions
are predicted to be endothermic by ,50 kJ molꢀ1
.
Unfortunately, no kinetic data are available for either the
cyclization or decarbonylation reactions of the ‘parent’ radicals
40 (R ¼ H); however, it is instructive to compare the decarbo-
nylation data with those obtained for the decarbonylation of
the propanoyl radical, which was determined to lose carbon
monoxide with an activation energy of ,62 kJ molꢀ1 in the gas
phase.[20] Clearly, our calculated energy barriers for decarbo-
nylation are slightly overestimated; however, we believe that
they are nevertheless instructive from a qualitative perspective.
In order to provide an explanation for the products observed
when aldehyde 32 was subjected to the standard reaction
conditions, we next turned our attention to the chemistry of
the analogous silylated acyl radical 48 (Scheme 9). The inclu-
sion of the silylated substituent on the alkene serves to
significantly raise the energy barrier for ring-closure to 67.7 kJ
molꢀ1 at the same level of theory as employed previously. When
compared with the barrier for decarbonylation (73.3 kJ molꢀ1),
it is clear that decarbonylation is now competitive with cycliza-
tion; these calculations are consistent with the experimental
observations for the ring-closure of aldehyde 32. In this case,
one might expect that in the absence of a trapping agent (e.g.
Bu3SnH), rapid 5-exo cyclization of the decarbonylated radical
will lead to the tetrahydrofuran (35).
44
45
2.175 Å
2.184 Å
46
47
Fig. 1. BHandHLYP/6–311þþG(d,p) optimized geometries of the transi-
tion states 44–47 involved in the cyclization of acyl radicals 40.
Conclusions
Fig. 1 reveals that the transition states 44–47 adopt similar
chair-like conformations to those of the parent 5-hexenyl and
6-heptenyl radicals,[19] with key separations of between 2.16
We have thus demonstrated that acyl radicals, formed directly
from the corresponding aldehyde, undergo cyclization to
b-disubstituted acrylates under polarity-reversal catalysis. The
formation of 2,2-disubstituted tetrahydrofuranones and tetra-
hydropyranones has been achieved, with moderate yields for the
acyl radical cyclization of these hindered systems resulting from
a competitive decarbonylation pathway being available. This
strategy has given access to a range of dioxaspiro systems and
been successfully applied to a formal synthesis of longianone 4.
The convenient preparation of aldehyde precursors and the
simple and benign reaction conditions employed in this acyl
radical cyclization should allow this procedure to be of wider
applicability. Further studies in this area are currently in
progress.
˚
and 2.19 A at the BHandHLYP/6–311þþG(d,p) level of theory.
Not unexpectedly, BHandHLYP/6–311þþG(d,p) calcu-
lated energy barriers (DEz1) (Scheme 8) reveal that the cycliza-
tion reactions of radicals 40 to form five-membered radicals
41 (n ¼ 1) are favoured over their six-membered counterparts
(n ¼ 2) by ,5–7 kJ molꢀ1; values for DEz1 of 61.6 and
52.3 kJ molꢀ1 are calculated for the former radicals, with values
of 68.8 and 57.5 kJ molꢀ1 calculated for the analogous six-
membered ring-forming reactions. As expected, the chemistry
of the esters (R ¼ CO2Me) is also calculated to proceed more
readily than that of the corresponding parent system (R ¼ H),
consistent with acyl radicals reacting as nucleophilic radicals
towards alkenes.[9c]
Experimental
All decarbonylation reactions are calculated to proceed with
very similar barriers (DEz2) of ,73–78 kJ molꢀ1. In the case of
40 (n ¼ 1, R ¼ CO2Me) cyclization is calculated to be strongly
preferred (by more than 20 kJ molꢀ1) over decarbonylation and
this is consistent with experimental observations. For 40 (n ¼ 2,
R ¼ H), cyclization and decarbonylation are calculated to take
place with barriers that are within ,6 kJ molꢀ1 of each other,
whereas the corresponding ester (n ¼ 2, R ¼ CO2Me) is pre-
dicted to ring-close with a barrier (DEz1) within ,15 kJ molꢀ1 of
the barrier (DEz2) for decarbonylation. As evident in the data
provided in Scheme 8, all cyclization reactions are calculated to
Representative Synthetic Procedure: Synthesis
of Dihydrolongianone 20
(E)-Methyl 4-(tert-Butyldimethylsilyloxy)-3-(3-(4-
methoxybenzyloxy)propoxy)but-2-enoate 16
To a solution of alcohol 10 (2.33 g, 11.9 mmol) and tri-
methylphosphine (1 M in THF, 3.6 mL) in dichloromethane
(60 mL) at 08C was added acetylene 15 (3.25 g, 14.2 mmol) in
dichloromethane (20 mL) dropwise over 20 min. The solution
was allowed to warm to ambient temperature over 30 min and
stirred for a further 1 h. Saturated NH4Cl (75 mL) was added,

RESEARCH FRONT
414
H. M. Aitken, C. H. Schiesser, and C. D. Donner
and the mixture extracted with ethyl acetate (3 ꢁ 50 mL) and
the combined organic layers were washed with brine (50 mL),
dried (MgSO4) and concentrated under vacuum. Flash column
chromatography (ethyl acetate/petrol 1:9) gave the (E)-acrylate
16 (4.57 g, 91%) as a colourless oil.
m/z (high-resolution electrospray ionization (HR-MS ESI)
MS) 425.2349. C22H37O6Si [M þ H]þ requires 425.2354, dH
(CDCl3, 500 MHz) 0.07 (6H, s), 0.90 (9H, s), 2.03 (2H, m), 3.58
(2H, t, J 6.1), 3.67 (3H, s), 3.80 (3H, s), 3.89 (2H, t, J 6.3), 4.42
(2H, s), 4.80 (2H, s), 5.01 (1H, s), 6.87 (2H, d, J 8.8), 7.24 (2H, d,
J 8.8). dC (CDCl3, 125 MHz) ꢀ5.3 (CH3), 18.4 (C), 25.8 (CH3),
29.1 (CH2), 50.8, 55.2 (CH3), 60.5, 65.5, 66.1, 72.7 (CH2), 91.0,
113.8, 129.2 (CH), 130.3, 159.2, 167.5, 172.3 (C). nmax/cmꢀ1
2930, 1713, 1627, 1613, 1513, 1247, 1142, 1092, 1048. GC-MS
(retention time, Rt 38.25 min) m/z 424.3 ([M]þ, 1%), 367.2 (16),
121.1 (100).
flushed with argon for 30 min. The solution was then heated at
reflux for 15 h. After removal of the solvent under vacuum, flash
column chromatography (ethyl acetate/petrol 1:4) gave tetra-
hydrofuranone 19 (210 mg, 28%) as a colourless oil.
m/z (HR-MS ESI) 303.1621. C14H27O5Si [M þ H]þ requires
303.1622. dH (CDCl3, 500 MHz) 0.02 (3H, s), 0.04 (3H, s), 0.86
(9H, s), 2.50 (1H, ddd, J 18.1, 8.7 and 5.6), 2.57 (1H, d, J 16.5),
2.71 (1H, d, J 16.5), 2.79 (1H, ddd, J 18.1, 9.2 and 7.0), 3.58 (1H,
d, J 10.1), 3.65 (3H, s), 3.70 (1H, d, J 10.1), 4.31 (1H, m), 4.34
(1H, m). dC (CDCl3, 125 MHz) ꢀ5.8, ꢀ5.6 (CH3), 18.1 (C), 25.7
(CH3), 36.6, 38.5 (CH2), 51.9 (CH3), 65.1, 68.0 (CH2), 82.3,
170.2, 216.1 (C). nmax/cmꢀ1 2930, 1741, 1254, 1135, 1078.
GC-MS (Rt 20.49 min) m/z 287.1 ([M – 15]þ, 1%), 271.1 (30),
245.1 (81), 227.1 (31), 215.1 (34), 171.0 (100), 153.0 (31), 129.0
(66), 89.0 (69), 73.1 (56), 59.0 (23).
1,7-Dioxaspiro[4,4]nonane-4,8-dione
(E)-Methyl 4-(tert-Butyldimethylsilyloxy)-
3-(3-hydroxypropoxy)but-2-enoate 17
(Dihydrolongianone) 20
To the silyl ether 19 (200 mg, 0.69 mmol) in chloroform (5 mL)
and methanol (3 mL) was added 10-CSA (113 mg, 0.49 mmol),
and the mixture was stirred at ambient temperature for 24 h.
After removal of the solvent under vacuum, the remaining
residue was resuspended in chloroform (5 mL) and stirring
was continued for 21 h. Saturated NaHCO3 (10 mL) was added
and the mixture was extracted with chloroform (3 ꢁ 5 mL), the
combined organic layers dried (MgSO4) and concentrated under
vacuum. Flash column chromatography (ethyl acetate/petrol
1:1) gave dihydrolongianone 20 (63 mg, 61%) as a colourless
oil.
To a solution of PMB ether 16 (4.30 g, 10.1 mmol) in a
mixture of dichloromethane/water (20:1, 105 mL) cooled to 08C
was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
(3.00 g, 13.2 mmol) and the solution was stirred rapidly for 3 h.
Saturated NaHCO3 (100 mL) was added and the mixture was
extracted with chloroform (3 ꢁ 20 mL). The combined organic
layers were washed with saturated NaHCO3 (30 mL), dried
(MgSO4) and concentrated under vacuum. Flash column chro-
matography (ethyl acetate/petrol 1:4) gave the alcohol 17
(3.01 g, 98%) as a colourless oil.
m/z (HR-MS ESI) 305.1779. C14H29O5Si [M þ H]þ requires
305.1779. dH (CDCl3, 500 MHz) 0.10 (6H, s), 0.91 (9H, s), 2.01
(2H, m), 3.67 (3H, s), 3.82 (2H, t, J 5.6), 3.97 (2H, t, J 5.9), 4.83
(2H, s), 5.04 (1H, s). dC (CDCl3, 125 MHz) ꢀ5.4 (CH3), 18.4
(C), 25.9 (CH3), 31.2 (CH2), 50.9 (CH3), 60.5, 60.6, 67.1 (CH2),
91.1 (CH), 167.4, 171.9 (C). nmax/cmꢀ1 3459, 2930, 1714, 1626,
1143, 1048. GC-MS (Rt 24.12 min) m/z 304.1 ([M]þ, 1%), 247.1
(93), 215.1 (39), 189.1 (61), 157.0 (100), 129.0 (37), 89.1 (23),
75.1 (48), 73.1 (29).
m/z (HR-MS ESI) 157.0495. C7H9O4 [M þ H]þ requires
157.0495. dH (CDCl3, 500 MHz) 2.63 (1H, dd, J 17.9 and 0.9),
2.64 (2H, m), 2.79 (1H, d, J 17.9), 4.22 (1H, m), 4.27 (1H, m),
4.31 (1H, d, J 10.1), 4.34 (1H, dd, J 10.1 and 0.9). dC (CDCl3,
125 MHz) 35.8, 37.6, 63.2, 74.2 (CH2), 84.2, 173.1, 211.9 (C).
n
max/cmꢀ1 2927, 1777, 1754, 1158, 1029, 1012. GC-MS
(Rt 12.35 min) m/z 156.1 ([M]þ, 7%), 126.0 (84), 100.0 (26),
98.0 (100).
The spectroscopic data (1H and 13C NMR) for 20 are in
accord with reported data.[13,15]
(E)-Methyl 4-(tert-Butyldimethylsilyloxy)-
3-(3-oxopropoxy)but-2-enoate 18
Computational Methods
To a solution of alcohol 17 (550 mg, 1.81 mmol) in CH2Cl2
(4 mL) was added PhI(OAc)2 (698 mg, 2.17 mmol) and (2,2,6,6-
tetramethyl-piperidin-1-yl)oxyl (TEMPO) (28 mg, 0.18 mmol)
and the mixture was stirred at ambient temperature for 4 h. After
removal of the solvent under vacuum, the remaining residue was
purified by flash column chromatography (ethyl acetate/petrol
1:4) to give aldehyde 18 (380 mg, 70%) as a colourless oil.
m/z (HR-MS ESI) 303.1622. C14H27O5Si [M þ H]þ requires
303.1622. dH (CDCl3, 500 MHz) 0.06 (6H, s), 0.89 (9H, s), 2.90
(2H, td, J 6.1 and 1.2), 3.68 (3H, s), 4.13 (2H, t, J 6.1), 4.80
(2H, s), 5.06 (1H, s), 9.82 (1H, t, J 1.2). dC (CDCl3, 125 MHz)
ꢀ5.3 (CH3), 18.3 (C), 25.8 (CH3), 42.4 (CH2), 51.0 (CH3), 60.3,
61.9 (CH2), 91.8 (CH), 167.1, 171.7 (C), 198.9 (CH). nmax/cmꢀ1
2930, 1714, 1628, 1142, 1104, 1049. GC-MS (Rt 22.88 min)
m/z 302.1 ([M]þ, 1%), 245.1 (63), 189.1 (50), 157.0 (38), 129.0
(100), 89.1 (42), 75.1 (28), 73.1 (36).
Ab initio and DFT calculations were carried using the Gaussian
03 program.[21] Geometry optimizations were performed with
standard gradient techniques at HF and BHandHLYP levels
of theory, using restricted and unrestricted methods for closed-
and open-shell systems, respectively. All ground and transition
states were verified by vibrational frequency analysis. Opti-
mized geometries and energies for all transition structures in this
study (Gaussian Archive entries) are available in the Accessory
Publication.
Accessory Publication
General experimental details, full experimental procedures,
spectroscopic data for compounds 11–13, 22–26, 29–36 and
38, 39, and Gaussian Archive entries for all ab initio and DFT
optimized structures in this work are available from the
Journal’s website.
Methyl 2-(2-((tert-Butyldimethylsilyloxy)methyl)-3-oxo-
tetrahydrofuran-2-yl)acetate 19
Acknowledgements
Financial support from the Australian Research Council through the Centres
of Excellence program is gratefully acknowledged. Computing support
through the School of Chemistry High-Performance Computing Facility is
also gratefully acknowledged.
A solution of aldehyde 18 (750 mg, 2.48 mmol), tert-
dodecanethiol (175 mL, 0.74 mmol) and 1,10-azobis(cyclo-
hexanecarbonitrile) (182 mg, 0.74 mmol) in toluene (5 mL) was

RESEARCH FRONT
Studies of Acyl Radical Cyclizations
415
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