Divergent approach to the polymaxenolide and pinnaic acid cores

Article abstract of DOI:10.1016/j.tet.2011.04.047

The divergent syntheses of the spirocyclic pyran core of polymaxenolide and the spirocyclic piperidine core of pinnaic acid have been achieved. Our divergent approach takes advantage of highly efficient Achmatowicz and aza-Achmatowicz rearrangements to ge

Full text of DOI:10.1016/j.tet.2011.04.047

Tetrahedron 67 (2011) 4988e4994
Contents lists available at ScienceDirect
Tetrahedron
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Divergent approach to the polymaxenolide and pinnaic acid cores
, ,
y
Frank D. Ferrari a, Andrew J. Ledgard b, Rodolfo Marquez a
*
a WestChem, School of Chemistry, University of Glasgow, Glasgow, G12 8QQ, Scotland, UK
b Lilly Research Centre, Erl Wood Manor Windlesham, Surrey, GU20 6PH, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The divergent syntheses of the spirocyclic pyran core of polymaxenolide and the spirocyclic piperidine
core of pinnaic acid have been achieved. Our divergent approach takes advantage of highly efficient
Achmatowicz and aza-Achmatowicz rearrangements to generate the highly functionalised cores, which
are then regioselectively modified.
Received 28 February 2011
Received in revised form 30 March 2011
Accepted 12 April 2011
Available online 20 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Pinnaic acid
Polymaxenolide
Spirocyclic pyrans
Spirocyclic piperidines
1. Introduction
H
H
H
HO
H
Polymaxenolide 1, was isolated in 2004 from the hybrid soft coral
Sinularia maxima x Sinularia polydactyla in the Piti bomb holes in
Guam.1 Polymaxenolide 1 is the product of a mixed biosynthetic
O
HN
O
2
O
H
pathway, and structurally comprises
a
unique hybrid cem-
CO2Me
O
Cl
braneeafricanane joined skeleton through a beautifully defined
spirocyclic pyran from which a large degree of functionality is
appended.
O
HO
OH
O
1
H
H
O
Polymaxenolide 1 is the first example of a hybrid metabolite
from marine origin. From a biological point of view, the mixed
biosynthetic origin of polymaxenolide makes it a very enigmatic
compound. In terrestrial metabolites, 18% of the hybrid species
isolated thus far exhibit different chemical and biological proper-
ties from the parental species.2 This differential behaviour makes
the hybrid compounds important new starting materials for the
development of diversity-orientated synthesis and libraries.
The exciting combination of therapeutic potential, together with
a highly challenging molecular framework makes polymaxenolide
1 a very attractive and interesting synthetic target. However,
despite its potential and attractive structure, no total syntheses of
polymaxenolide have been reported to date (Fig. 1).
N
HO3S
O
O
HN
O
Cl
H
3
H
N
Cl
H
4
HO
OH
Fig. 1. Polymaxenolide 1, Pinnaic acid 2, tauropinnaic acid 3 and halichlorine 4.
Pinnaic acid 2 and tauropinnaic acid 3 were isolated in minute
amounts from the Okinawan bivalve Pinna muricata by Uemura and
co-workers (1 mg and 4 mg were isolated from 10 kg of bivalve,
respectively).3 Biologically, pinnaic acid 2 and tauropinnaic acid 3
have been shown to inhibit cytosolic phospholipase A2 (cPLA2) at
A nitrogenous analogue of the spirocyclic pyran core of poly-
maxenolide 1 is displayed by pinnaic acid 2, tauropinnaic acid 3 and
halichlorine 4.
low micromolar concentrations (200 mM and 90 mM, respectively),
making them promising leads for the treatment of pro-
inflammatory diseases.3b,4
A number of total and formal syntheses of pinnaic acid 2, taur-
opinnaic acid 3 and halichlorine 4 employing widely diverse and
creative synthetic approaches and methodologies have been
* Corresponding author. Tel.: þ44 0141 330 5953; fax: þ44 0141 330 488; e-mail
address: r.marquez@chem.gla.ac.uk (R. Marquez).
y
Ian Sword Lecturer of Organic Chemistry.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.047

F.D. Ferrari et al. / Tetrahedron 67 (2011) 4988e4994
4989
reported.5,6 However, none of the approaches developed are readily
applicable to the synthesis of the spirocyclic pyran core of poly-
maxenolide 1.
The similar structural features present in the spirocyclic cores of
polymaxenolide 1, pinnaic acid 2, tauropinnaic acid 3 and hali-
chlorine 4, however made us to consider the possibility that a di-
vergent synthetic approach could be used to quickly and efficiently
generate both the spirocyclic piperidine and spirocyclic pyran cores
from a common synthetic intermediate (Scheme 1).
Faced with an unreliable approach to the synthesis of the hemi-
aminal intermediate 10, a new strategy to the synthesis of the
spirocyclic core was devised. In our modified approach, the spi-
ropyran 11 and spirocyclic piperidine 12 cores were envisioned as
having originated from the oxidative rearrangement of the cyclic
tertiary furfuryl alcohol 13 and the cyclic tertiary amine 14, re-
spectively. If successful, this approach should provide us with
a rapid and efficient route to the synthesis of the polymaxenolide
and pinnaic acid core structures (Scheme 4).
H
H
H
X
Common
Synthetic
[Ox]
[Ox]
O
HN
O
TsN
O
Intermediate
13 X = OH
14 X = NHTs
H
R
11
12
Scheme 1.
Scheme 4.
2. Results and discussion
This approach was inspired by the work of Couladouros and co-
workers who reported the oxidative rearrangement of a cyclo-
hexylfuryl carbinol 15 to generate the pyranone 17. The analogous
tosylamine 16 however, failed to generate any of the desired aza-
pyranone, yielding instead the spirolactam unit 18 (Scheme 5).10
We previously reported the use of 2,5-disubstituted furan rings
5 to generate pyran units 6 via the highly effective Achmatowicz
rearrangement.7 Significantly, the rearrangement proceeded
cleanly and efficiently to afford the desired lactols 6 in the presence
of various functionalities including olefins without detrimental
effect (Scheme 2).
HO
O
X
mCPBA
65%
O
mCPBA
79%
O
TsN
O
O
O
R
15 X = OH
16 X = NHTs
SiMe3
BF3OEt2
mCPBA
n = 1-4
17
18
R
O
O
n
OH
OH
Scheme 5.
n
5
6
O
O
However, despite this somewhat mixed precedent, we were
confident that through modification of the oxidative rearrange-
ment conditions it would be possible to generate both the pyranone
and azapyranone units whilst avoiding the undesired over-
oxidation. Our initial model studies began with cyclopentanone
19, which was treated with 2-lithiofuran to generate furfuryl al-
cohol 20. As expected, treatment of carbinol 20 under our pre-
viously used Achmatowicz oxidative conditions yielded the desired
lactol 21 in good yield. Boron trifluoride promoted allylation of
lactol 21 with allyltrimethylsilane afforded the polyfunctionalised
[5.4] spirocyclic pyran 22 unit in high yield over the three step
sequence (Scheme 6).
R
H
R
H
Grubbs'
1st Gen.
n = 1-4
O
O
n
n
7
8
Scheme 2.
Lewis-acid promoted allylation of the lactol units yielded the
desired bis-olefins 7 in good yield and more importantly as single
diastereomers. The stereochemistry of the allylation and conse-
quently, that of the newly formed C6 stereocentre was dictated by
that of the C2 carbon in complete consistency with Woerpel’s
model.8 Ring closing metathesis of the bis-alkenes 7 afforded the
desired spirocyclic pyrans 8 as single diastereomers.
Having successfully generated the desired spirocyclic pyrans,
8 it was decided to apply this approach to the synthesis of spi-
rocyclic piperidines. Unfortunately, the aza-Achmatowicz9 rear-
rangement of the furfuryl amine precursors 9 proved to be
extremely temperamental, and highly dependent on the nature of
the C5 furan substituent (i.e., whilst most groups were tolerated
alpha to the furfuryl amine, anything other than a methyl sub-
stituent or an unsubstituted C5 furan position failed to yield any of
the desired hemi-aminals 10) (Scheme 3).
O
O
O
OH
nBuLi
mCPBA
97%
19
20
O
O
SiMe3
BF3Et2O
HO
O
O
54% from 20
21
22
Scheme 6.
O
Epoxidation
Conditions
R
R
R'
NHPG
OH
O
The reaction sequence was then applied successfully to generate
the corresponding [5.3], [5.5], [5.6] and [5.7] spirocyclic pyrans.
Interestingly, all of them proceed in good yield over the entire
synthetic process with the exception of the highly strained [5.3]
spirocyclic unit, which yielded a complex mixture from which the
desired spirocyclic pyran unit was isolated in low yield (Table 1).
NHPG
R'
9
10
R' = H, Me 90-99%
R' = H, Me 0%
Scheme 3.

4990
F.D. Ferrari et al. / Tetrahedron 67 (2011) 4988e4994
Table 1
Synthesis of Spirocyclic Pyrans.
O
O
O
N3
OH
NH2
H2
HN3
76%
TsCl
O
Pd/C
TEA
SiMe3
BF3OEt2
O
O
O
OH mCPBA
HO
97%
68%
36
20
37
O
O
O
O
SiMe3
O
NHTs mCPBA
O
HO
N
BF3OEt2
64% from 38
O
OH
OH
Ts
10%
from 23
HO
HO
39
O
38
23
26
17
27
29
30
31
O
O
i) TsNHNH2
ii) Dibal-H
[(PPh3)CuH]6
85%
O
O
O
O
55%
N
N
O
15
O
Ts
41
Ts
40
63%
from 15
O
O
O
O
EtO2C
CO2Et
N
TsN
Hoveyda-
Grubbs II
48%
Ts
42
43
OH
OH
63%
from 24
HO
HO
Scheme 8.
24
the two steps. Finally, cross metathesis of alkene 42 with ethyl
methacrylate proceeded in reasonable yield to afford the pinnaic
acid core structure 43 as a single E double bond isomer.
In conclusion, we have developed a flexible and divergent
approach to the synthesis of spirocyclic pyrans and spirocyclic pi-
peridines starting from a common cyclic tertiary carbinol precursor.
We believe that this approach is efficient and provides rapid entry
to differentially functionalised spirocyclic structures. Efforts in our
group are focused currently in the application of this methodology
to the total synthesis of polymaxenolide and pinnaic acid.
O
O
O
61%
from 25
O
O
25
28
32
Having successfully generated the desired spirocyclic pyran
cores, the regiospecific modification of the functionality within the
pyran unit was investigated. Thus, selective 1,4-reduction of enone
22 with Stryker’s reagent afforded ketone 33.11 Interestingly, all
other reduction conditions attempted resulted in either the over-
reduction of the enone unit or in the loss of the terminal alkene
unit. Tosylhydrazone mediated reduction of ketone 339a then gave
the fully saturated pyran unit 34, which upon cross metathesis with
ethyl methacrylate yielded the trisubstituted conjugated methyl
ester 35 as a single regio-isomer (Scheme 7).6d
3. Experimental
3.1. General
All reactions were performed in oven-dried glassware under an
inert argon atmosphere unless otherwise stated. Tetrahydrofuran
(THF), diethyl ether and dichloromethane (DCM) were purified
through a Pure Solv 400-5MD solvent purification system (In-
novative Technology, Inc). All reagents were used as received, un-
less otherwise stated. Solvents were evaporated under reduced
pressure at 40 ꢀC using a Buchi Rotavapor.
O
O
i) TsNHNH2
ii) Dibal-H
[(PPh3)CuH]6
84%
O
22
O
33
66%
IR spectra were recorded as thin films on NaCl plates using
a JASCO FT/IR410 Fourier Transform spectrometer. Only significant
absorptions (nmax) are reported in wavenumbers (cmꢁ1). Proton
magnetic resonance spectra (1H NMR) and carbon magnetic reso-
nance spectra (13C NMR) were, respectively, recorded at 400 MHz
and 100 MHz using a Bruker DPX Avance400 instrument. Chemical
CO2Et
EtO2C
O
34
O
2nd Gen
Grubbs' Cat.
83%
35
Scheme 7.
shifts (d) are reported in parts per million (ppm) and are referenced
to the residual solvent peak. The order of citation in parentheses is
(1) number of equivalent nuclei (by integration), (2) multiplicity
(s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet, br¼
broad, dm¼double multiplet), and (3) coupling constant (J) quoted
in hertz to the nearest 0.5 Hz. High resolution mass spectra were
recorded on a JEOL JMS-700 spectrometer by electrospray and
chemical ionisation mass spectrometer operating at a resolution of
15,000 full widths at half height. Flash chromatography was per-
formed using silica gel (Flourochem Scientific Silica Gel 60,
Having demonstrated the ability of cyclic tertiary carbinols to
generate spirocyclic pyrans quickly and efficiently, the synthesis of
the key cyclic tertiary amines was investigated. After much exper-
imentation, we are pleased to report that the treatment of furfuryl
alcohol 20 with hydrazoic acid yielded the desired azide 36, which
was then reduced efficiently in good yield (Scheme 8).10
Tosyl protection of the newly formed tertiary amine yielded the
cyclisation precursor 38, which upon treatment with m-CPBA
afforded the key hemi-aminal 39. Allylation of hemi-aminal 39
under Lewis-acid promoted conditions gave the desired spirocyclic
piperidine 40 in good yield.12 As in the case of the spirocyclic pyran
series, selective 1,4-reduction could be achieved using Stryker’s
reagent to afford piperidone 41. Piperidone deoxygenation then
produced the desired spirocyclic piperidine 42 in good yield over
40e63 m) as the stationary phase. TLC was performed on alumin-
ium sheets pre-coated with silica (Merck Silica Gel 60 F254). The
plates were visualised by the quenching of UV fluorescence
(lmax254 nm) and/or by staining with either anisaldehyde, potas-
sium permanganate, iodine or cerium ammonium molybdate fol-
lowed by heating.

F.D. Ferrari et al. / Tetrahedron 67 (2011) 4988e4994
4991
3.1.1. 1-(Furan-2-yl)cyclopentanol, 20. Cyclopentanone 19 (1.90 g,
22.61 mmol) was added to a stirred suspension of magnesium sul-
fate (13.61 g, 113.05 mmol) in tetrahydrofuran (140 mL) under ar-
gon. The resulting mixture was then allowed to stir at room
temperature for 2 h before being cooled to ꢁ78 ꢀC. In a separate
flask, furan (7.70 g, 113.05 mmol) was added to a ꢁ78 ꢀC solution of
n-BuLi (2.5 M in hexanes, 45 mL,113.05 mmol) and TMEDA (13.14 g,
113.05 mmol) in tetrahydrofuran (100 mL) under argon. The
resulting solution was stirred at ꢁ78 ꢀC for 1 h, and was then
transferred dropwise via cannula into the flask containing the
cyclopentanone/magnesium sulfate mixture in tetrahydrofuran
at ꢁ78 ꢀC. The reaction was then allowed to warm to room tem-
perature overnight before being quenched by the addition of ice
water (100 mL) and extracted with Et2O (3ꢂ75 mL). The combined
organic layers were washed with satd aq NaHCO3 (100 mL), dried
over Na2SO4 and concentrated under vacuum. Purification of the
crude residue by flash column chromatography (silica gel, 1:9
diethyl ether in petroleum ether) afforded 1-(furan-2-yl)cyclo-
pentanol 20 (3.33 g, 97%) as a colourless oil.
1275, 1180, 1073 cmꢁ1; HRMS (CI) observed [MþH]þ 193.1228,
calculated for C12H17O2 193.1229.
3.2. General procedure for the synthesis of alcohols 15, 23e25
Furan (1 equiv) was added to a stirred solution of n-butyllithium
(2.5 M in hexanes, 1.0 equiv) and N,N,N0,N0-tetramethylethylenedi-
amine (1 equiv) in tetrahydrofuran (10 mL) at ꢁ78 ꢀC under argon.
The solution was stirred at ꢁ78 ꢀC under argon for 1 h before being
treated with the cyclic ketone (0.2 equiv). The reaction mixture was
then stirred at ꢁ78 ꢀC for a further 1 h before being quenched with
ice-cold satd aq ammonium chloride (15 mL) and extracted with
diethyl ether (3ꢂ10 mL). The combined organics were dried over
sodium sulfate, filtered and concentrated under vacuum.
3.2.1. 1-(Furan-2-yl)cyclobutanol, 23. Furan (465 mg) was coupled
with cyclobutanone (96 mg) using n-BuLi (2.7 mL) and TMEDA
(794 mg) to afford after purification by flash column chromatog-
raphy (silica gel, elution gradient 10%e20% diethyl ether in petro-
leum) 188 mg (quant.) of alcohol 23 as a colourless oil.
1H NMR (400 MHz; CDCl3) dH: 7.32 (1H, dd, J¼1.8, 0.8 Hz), 6.28
(1H, dd, J¼3.2, 1.8 Hz), 6.18 (1H, dd, J¼3.2, 0.8 Hz), 2.23 (1H, br s),
2.00e2.06 (2H, m), 1.88e1.95 (4H, m), 1.70e1.74 (2H, m); 13C NMR
(100 MHz; CDCl3) dC: 159.4, 141.5, 110.0, 104.1, 79.5, 39.6, 23.6; IR
(thin film) nmax¼3342, 3323, 2966, 1695, 1504, 1450, 1396, 1001,
916, 804, 727, 680 cmꢁ1; HRMS (EI) observed Mþ 152.0834, calcu-
lated for C9H12O2 152.0837.
1H NMR (400 MHz; CDCl3) dH: 7.38 (1H, dd, J¼1.7, 0.6 Hz), 6.33
(1H, dd, J¼3.2, 1.8 Hz), 6.28 (1H, dd, J¼3.2, 0.5 Hz), 2.55 (1H, br s),
2.53e2.46 (2H, m), 1.90e1.81 (2H, m), 1.70e1.58 (2H, m); 13C NMR
(100 MHz; CDCl3) dC: 12.1, 35.6, 72.2, 104.9, 110.0, 142.1, 158.1; IR
(thin film) nmax¼3352, 2989, 2947, 1504, 1423, 1369, 1284, 1249,
1222, 1157, 1130, 1080, 1006, 956, 910, 883, 813, 729, 648 cmꢁ1
;
HRMS (CI) observed [MꢁOH]þ 121.0650, calculated for C8H9O
121.0653.
3.1.2. 7-Hydroxy-6-oxaspiro[4.5]dec-8-en-10-one, 21. A 0 ꢀC solu-
tion of 1-(furan-2-yl)cyclopentanol 20 (120 mg, 0.79 mmol) in
chloroform (2 mL) under argon was treated with the portion-wise
addition of m-chloroperbenzoic acid (77%, 267 mg, 1.2 mmol). The
rate of addition was such that the temperature of the reaction was
not allowed to exceed 10 ꢀC throughout the process. Once the ad-
dition was completed, the reaction was stirred at 0 ꢀC for 30 min,
then for 1.5 h at room temperature. The reaction was quenched
with satd aq NaHCO3 (15 mL) and extracted with chloroform
(3ꢂ10 mL). The organic phase was dried over Na2SO4, filtered and
concentrated under reduced pressure to yield 7-hydroxy-6-oxas-
piro[4.5]dec-8-en-10-one 21 as a colourless oil, which was taken on
to the next step without further purification.
3.2.2. 1-(Furan-2-yl)cyclohexanol, 15. Furan (328 mg) was coupled
with cyclohexanone (95 mg) using n-BuLi (1.9 mL) and TMEDA
(561 mg) to afford after purification by flash column chromatog-
raphy (silica gel, elution gradient 10%e20% diethyl ether in petro-
leum) 154 mg (96%) of alcohol 15 as a colourless oil.
1H NMR (400 MHz; CDCl3) dH: 7.34e7.32 (1H, m), 6.30 (1H, dd,
J¼3.2, 1.8 Hz), 6.19 (1H, d, J¼3.2 Hz), 2.02e1.92 (3H, m), 1.87e1.78
(2H, m), 1.77e1.66 (2H, m), 1.57e1.26 (4H, m); 13C NMR (100 MHz;
CDCl3) dC: 22.2, 25.5, 36.5, 70.0, 104.4, 110.0, 141.3, 160.0; IR (thin
film) nmax¼3407, 2935, 2859, 2360, 2337, 2248, 1501, 1448, 1342,
1259, 1224, 1155, 1057, 1038, 1008, 977, 958, 936, 905, 884,
726 cmꢁ1; HRMS (CI) observed [MꢁOH]þ 149.0963, calculated for
C10H13O 149.0966.
3.1.3. 7-Allyl-6-oxaspiro[4.5]dec-8-en-10-one, 22. A solution of the
crude lactol 21 (96 mg, 0.6 mmol) in dichloromethane (9 mL) was
3.2.3. 1-(Furan-2-yl)cycloheptanol, 24. Furan (289 mg) was coupled
with cycloheptanone (145 mg) using n-BuLi (1.7 mL) and TMEDA
(493 mg) to afford after purification by flash column chromatog-
raphy (silica gel, elution gradient 10%e20% diethyl ether in petro-
leum) 231 mg (99%) of alcohol 24 as a colourless oil.
treated with allyltrimethylsilane (197 mg, 274 mL, 1.8 mmol) under
an argon atmosphere. The resulting mixture was cooled to ꢁ78 ꢀC
and boron trifluoride-diethyl etherate complex (82 mg, 70 mL,
0.6 mmol) was then added. The resulting reaction mixture was
stirred at ꢁ78 ꢀC until completion as indicated by TLC analysis (1 h).
The reaction was then diluted with dichloromethane (15 mL) and
quenched by the slow addition of aq satd ammonium chloride
(25 mL). The phases were separated, and the aqueous layer was
extracted with dichloromethane (3ꢂ15 mL). The combined organic
layers were combined, washed with satd aq NaHCO3 (25 mL), brine
(25 mL), dried over Na2SO4, filtered and concentrated under vac-
uum. Purification of the crude residue by flash column chroma-
tography (silica gel, 9:1 petroleum ether/diethyl ether) afforded the
key 7-allyl-6-oxaspiro[4.5]dec-8-en-10-one 22 (36 mg, 54% over
two steps) as a colourless oil.
1H NMR (400 MHz; CDCl3) dH: 7.35 (1H, appd, J¼1.6 Hz), 6.30
(1H, dd, J¼3.2, 1.8 Hz), 6.19 (1H, br d, J¼3.2 Hz), 2.14 (2H, ddd,
J¼14.5, 9.6, 1.4 Hz), 1.97 (2H, ddd, J¼14.4, 9.0, 1.2 Hz), 1.91 (1H, br s),
1.77e1.41 (8H, m); 13C NMR (100 MHz; CDCl3) dC: 22.1, 29.4, 40.1,
74.1, 104.1, 109.9, 141.5, 160.8; IR (thin film) nmax¼3460, 2924, 2859,
2360, 2341, 1797, 1566, 1504, 1446, 1361, 1222, 1157, 1084, 1014, 883,
806, 732 cmꢁ1; HRMS (CI) observed [MꢁOH]þ 163.1119, calculated
for C11H15O 163.1123.
3.2.4. 1-(Furan-2-yl)cyclooctanol, 25. Furan (465 mg) was coupled
with cyclooctanone (165 mg) using n-BuLi (2.6 mL) and TMEDA
(761 mg) to afford after purification by flash column chromatog-
raphy (silica gel, elution gradient 10%e16% diethyl ether in petro-
leum) 248 mg (98%) of alcohol 25 as a colourless oil.
1H NMR (400 MHz; CDCl3) dH: 6.85 (1H, ddd, J¼10.4, 1.5, 0.4 Hz),
6.02 (1H, dd, J¼10.3, 2.4 Hz), 5.83 (1H, ddt, J¼17.3, 10.3, 6.8 Hz),
5.17e5.15 (1H, m), 5.14e5.09 (1H, m), 4.41 (1H, tt, J¼6.7, 2.0 Hz),
2.49e2.40 (1H, m), 2.40e2.30 (1H, m), 2.14e2.06 (1H, m), 1.82e1.62
(5H, m), 1.53e1.44 (2H, m); 13C NMR (100 MHz; CDCl3) dC: 23.3,
23.9, 31.8, 35.0, 38.2, 67.8, 88.3, 117.1, 125.1, 132.3, 148.7, 198.0; IR
(thin film) nmax¼3080, 2956, 2923, 1727, 1685, 1643, 1466, 1449,
1H NMR (400 MHz; CDCl3) dH: 7.35 (1H, dd, J¼1.8, 0.7 Hz), 6.30
(1H, dd, J¼3.2, 1.8 Hz), 6.20 (1H, dd, J¼3.2, 0.7 Hz), 2.14e2.01 (4H,
m), 1.88 (1H, br s), 1.75e1.59 (5H, m), 1.55e1.41 (5H, m); 13C NMR
(100 MHz; CDCl3) dC: 21.9, 24.6, 28.1, 34.8, 73.8, 104.8, 109.9, 141.5,

4992
F.D. Ferrari et al. / Tetrahedron 67 (2011) 4988e4994
159.9; IR (thin film) nmax¼3398, 2924, 2854, 2360, 2341, 1790, 1504,
1465, 1446, 1361, 1319, 1219, 1157, 1118, 1087, 1018, 991, 925, 883,
848, 794, 732, 682, 667, 644 cmꢁ1; HMRS (CI) observed [MꢁOH]þ
177.1274, calculated for C12H17O 177.1279.
chromatography (silica gel 9:1 hexane/diethyl ether) afforded
2-allyl-1-oxaspiro[5.6]dodec-3-en-5-one, 31 (178 mg, 63% over
two steps) as a colourless oil.
1H NMR (400 MHz; CDCl3) dH: 6.83 (1H, dd, J¼10.3, 1.4 Hz), 5.94
(1H, dd, J¼10.3, 2.4 Hz), 5.88 (1H, ddt, J¼17.2, 10.2, 6.9 Hz),
5.20e5.10 (2H, m), 4.39 (1H, tt, J¼6.9, 1.8 Hz), 2.51e2.42 (1H, m),
2.42e2.33 (1H, m), 2.19e2.10 (1H, m), 2.04e1.94 (1H, m), 1.74e1.48
(10H, m); 13C NMR (100 MHz; CDCl3) dC: 200.2, 149.4, 133.5, 125.0,
118.0, 82.5, 67.8, 39.3, 36.4, 31.7, 29.3, 29.1, 22.1, 21.7; IR (thin film)
nmax¼3078, 2924, 2857, 2702, 2358, 1723, 1683, 1642, 1460, 1444,
1436, 1388, 1335, 1300,1278,1247, 1211,1201, 1164,1148, 1064,1037,
1017, 986, 957, 916, 859, 839, 797, 782, 753, 693 cmꢁ1; HRMS (CI)
observed [MþH]þ 221.1544, calculated for C14H21O2 221.1542.
3.2.5. 6-Allyl-5-oxaspiro[3.5]non-7-en-9-one, 29 via 6-hydroxy-5-
oxaspiro[3.5]non-7-en-9-one, 26. Following the procedure for the
synthesis of lactol 21, a solution of 1-(furan-2-yl)cyclobutanol 23
(189 mg, 1.37 mmol) in chloroform (7 mL) was rearranged using
m-CPBA (354 mg, 2.06 mmol) to afford lactol 26, which was used
without further purification.
Following the procedure for the synthesis of spiropyran 22,
a solution of 6-hydroxy-5-oxaspiro[3.5]non-7-en-9-one in anhy-
drous dichloromethane (3 mL) was treated with allyltrimethylsilane
(469 mg, 4.10 mmol) and boron trifluoride-diethyl etherate
(194 mg, 1.37 mmol). Purification by flash column chromatography
(silica gel 9:1 hexane/diethyl ether) afforded 6-allyl-5-oxaspiro[3.5]
non-7-en-9-one, 29 (24 mg, 10% over two steps) as a colourless oil.
1H NMR (400 MHz; CDCl3) dH: 6.85 (1H, dd, J¼10.2, 1.5 Hz), 6.00
(1H, dd, J¼10.3, 2.4 Hz), 5.86 (1H, ddt, J¼17.2, 10.2, 7.1 Hz),
5.21e5.19 (1H, m), 5.18e5.14 (1H, m), 4.43 (1H, tt, J¼6.6, 1.9 Hz),
2.74e2.65 (1H, m), 2.53e2.44 (1H, m), 2.40 (1H, dd, J¼14.2, 7.1 Hz),
2.37e2.28 (1H, m), 2.13e2.01 (2H, m), 1.93e1.79 (2H, m); 13C NMR
(100 MHz; CDCl3) dC: 197.0, 149.6, 133.0, 125.1, 118.3, 80.8, 69.0,
39.0, 30.0, 29.9, 12.6; IR (thin film) nmax¼3078, 2953, 2848, 2362,
1745, 1687, 1642, 1462, 1446, 1417, 1385, 1337, 1308, 1254, 1206,
1186, 1161, 1093, 1072, 1023, 996, 959, 916, 861, 837, 801, 746,
693 cmꢁ1; HRMS (CI) observed [MþH]þ 179.1067, calculated for
C11H15O2 179.1072.
3.2.8. 2-Allyl-1-oxaspiro[5.7]dodec-3-en-5-one, 32 via 2-hydroxy-1-
oxaspiro[5.7]dodec-3-en-5-one, 28. Following the procedure for the
synthesis of lactol 21, a solution of 1-(furan-2-yl)cyclooctanol 25
(248 mg, 1.28 mmol) in chloroform (10 mL) was rearranged using
m-CPBA (429 mg, 1.92 mmol) to afford lactol 28, which was used
without further purification.
Following the procedure for the synthesis of spiropyran 22,
a solution of 2-hydroxy-1-oxaspiro[5.7]dodec-3-en-5-one 28 in
anhydrous dichloromethane (3 mL) was treated with allyl-
trimethylsilane (438 mg, 3.83 mmol) and boron trifluoride-diethyl
etherate (181 mg, 1.28 mmol). Purification by flash column chro-
matography (silica gel 9:1 hexane/diethyl ether) afforded 2-allyl-1-
oxaspiro[5.7]dodec-3-en-5-one, 32 (182 mg, 61% over two steps) as
a colourless oil.
1H NMR (400 MHz; CDCl3) dH: 6.82 (1H, dd, J¼10.3, 1.4 Hz), 5.94
(1H, dd, J¼10.3, 2.4 Hz), 5.88 (1H, dddd, J¼17.0, 13.8, 7.3, 6.5 Hz),
5.19e5.11 (2H, m), 4.37 (1H, tt, J¼6.6, 1.8 Hz), 2.50e2.42 (1H, m),
2.41e2.33 (1H, m), 2.16e2.09 (1H, m), 1.97e1.89 (1H, m), 1.82e1.45
(12H, m); 13C NMR (100 MHz; CDCl3) dC: 200.1, 149.3, 133.5, 124.9,
117.9, 81.4, 67.8, 39.3, 32.2, 31.6, 28.5, 27.3, 22.6, 20.8, 20.7; IR (thin
film) nmax¼3077, 2967, 2922, 2850, 2355, 1771, 1683, 1642, 1623,
1575, 1539, 1527, 1472, 1444, 1415, 1387, 1369, 1335, 1287, 1264,
1250, 1205, 1163, 1132, 1060, 1048, 1011, 992, 915, 861, 838, 797, 781,
767, 736, 727, 691 cmꢁ1; HRMS (CI) observed [MþH]þ 235.1701,
calculated for C15H23O2 235.1698.
3.2.6. 2-Allyl-1-oxaspiro[5.5]undec-3-en-5-one 30 via 2-hydroxy-1-
oxaspiro[5.5]un-7-en-9-one, 17. Following the procedure for the
synthesis of lactol 21, a solution of 1-(furan-2-yl)cyclohexanol 15
(154 mg, 0.93 mmol) in chloroform (7 mL) was rearranged using
m-CPBA (311 mg, 1.39 mmol) to afford lactol 17, which was used
without further purification.
Following the procedure for the synthesis of spiropyran 22,
a solution of 2-hydroxy-1-oxaspiro[5.5]un-7-en-9-one 17 in anhy-
drous dichloromethane (2 mL) was treated with allyltrimethylsilane
(317 mg, 2.78 mmol) and boron trifluoride-diethyl etherate
(131 mg, 0.93 mmol). Purification by flash column chromatography
(silica gel 9:1 hexane/diethyl ether) afforded 2-allyl-1-oxaspiro[5.5]
undec-3-en-5-one, 30 (120 mg, 63% over two steps) as a colourless
oil.
3.2.9. 7-Allyl-6-oxaspiro[4.5]decan-10-one, 33. A solution of 7-al-
lyl-6-oxaspiro[4.5]dec-8-en-10-one 22 (488 mg, 2.6 mmol) in
a
deoxygenated benzene/water mixture (70 mL:141 mL) was
transferred via cannula to a flask containing (triphenylphosphine)
copper hydride hexamer (1.0 g, 0.51 mmol) under argon. The re-
sultant red/brown suspension was stirred at room temperature
overnight before being opened to the air, and being allowed to stir
for 30 min. The suspension was filtered through Celite, concen-
trated under vacuum, and azeotroped with toluene to remove any
residual benzene. Purification of the crude residue by flash column
chromatography (silica gel, elution gradient 0%e5% ethyl acetate in
hexanes) afforded 7-allyl-6-oxaspiro[4.5]decan-10-one 33 (476 mg,
84%) as a colourless oil.
1H NMR (400 MHz; CDCl3) dH: 6.84 (1H, dd, J¼10.3, 1.4 Hz), 5.97
(1H, dd, J¼10.3, 2.4 Hz), 5.91 (1H, dddd, J¼17.0, 13.9, 7.4, 6.4 Hz),
5.22e5.10 (2H, m), 4.38 (1H, appt, J¼6.7, 1.9 Hz), 2.52e2.35 (2H, m),
2.05e1.88 (2H, m), 1.72e1.44 (6H, m), 1.34e1.20 (2H, m); 13C NMR
(100 MHz; CDCl3) dC: 199.6,149.5,133.6,125.3,118.0, 79.1, 67.5, 39.3,
31.7, 28.4, 25.4, 21.5, 20.6; IR (thin film) nmax¼3076, 2930, 2855,1796,
1771,1683,1642,1462,1450,1443,1434,1386,1360,1336,1285,1264,
1244,1205,1160,1150,1084,1064,1041,1027, 989, 944, 914, 853, 843,
834, 818, 801, 776, 727, 705, 693, 677 cmꢁ1; HRMS (CI) observed
[MþH]þ 207.1389, calculated for C13H19O2 207.1385.
1H NMR (400 MHz; CDCl3) dH: 5.73e5.55 (1H, m), 5.05e4.99
(2H, m), 3.79e3.71 (1H, m), 2.51 (1H, dm, J¼16.1 Hz), 2.41 (1H, dm,
J¼16.1 Hz), 2.34e2.25 (1H, m), 2.22e2.13 (2H, m), 2.01e1.91 (2H,
m), 1.88e1.76 (1H, m), 1.74e1.55 (6H, m); 13C NMR (100 MHz;
CDCl3) dC: 212.3, 134.6, 117.0, 91.6, 70.4, 40.2, 36.7, 36.0, 35.1, 30.5,
24.9, 24.4; IR (thin film) nmax¼3077, 2955, 2870, 2858, 2366, 1714,
1683, 1642, 1444, 1436, 1418, 1355, 1313, 1288, 1271, 1186, 1150,
3.2.7. 2-Allyl-1-oxaspiro[5.6]dodec-3-en-5-one 31 via 2-hydroxy-1-
oxaspiro[5.6]dodec-3-en-5-one, 27. Following the procedure for the
synthesis of lactol 21, a solution of 1-(furan-2-yl)cycloheptanol 24
(231 mg, 1.28 mmol) in chloroform (10 mL) was rearranged using
m-CPBA (355 mg, 2.06 mmol) to afford lactol 27, which was used
without further purification.
Following the procedure for the synthesis of spiropyran 22,
a solution of 2-hydroxy-1-oxaspiro[5.6]dodec-3-en-5-one 27 in
anhydrous dichloromethane (2 mL) was treated with allyl-
trimethylsilane (439 mg, 3.85 mmol) and boron trifluoride-diethyl
etherate (182 mg, 1.28 mmol). Purification by flash column
1078, 1062, 1042, 1019, 995, 971, 914, 803, 754, 705, 640 cmꢁ1
;
HRMS (CI) observed [MþH]þ 195.1387, calculated for C12H19O2
195.1385.
3.2.10. 7-Allyl-6-oxaspiro[4.5]decane, 34. A room temperature solu-
tion of 7-allyl-6-oxaspiro[4.5]decan-10-one 33 (109 mg, 0.56 mmol)

F.D. Ferrari et al. / Tetrahedron 67 (2011) 4988e4994
4993
in absolute ethanol (6 mL) under argon was treated with tosylhy-
drazide(110 mg, 0.59 mmol), andtheresultantsolutionwasstirredfor
18.5 h. The reaction mixture was concentrated under vacuum and the
residue was dissolved in anhydrous dichloromethane (5.4 mL) and
cooled to 0 ꢀC. Diisobutylaluminium hydride (1 M in hexanes, 2 mL,
2.0 mmol) was then added over 15 min and the resultant yellow so-
lution was allowed to warm up to room temperature over1.5 h. The
mixture was diluted with dichloromethane (10 mL), and quenched by
the slow addition of 3 M NaOH soln (15 mL). The organic layer was
separated and the aqueous phase was extracted with diethyl ether
(3ꢂ10 mL). The combined organic layers were dried over sodium
sulfate, filtered and concentrated under vacuum. Flash column chro-
matography of the crude residue (silica gel, petroleum ether) afforded
7-allyl-6-azaspiro[4.5]decane 34 (70.5 mg, 66%) as a colourless oil.
1H NMR (400 MHz; CDCl3) dH: 5.52 (1H, dddd, J¼17.3, 10.2, 7.5,
6.4 Hz), 5.04 (1H, dm, J¼17.2 Hz), 4.99 (1H, dm, J¼10.3 Hz), 3.44
(1H, dtd, J¼11.1, 6.5, 2.1 Hz), 2.24 (1H, dtt, J¼14.2, 6.5, 1.5 Hz), 2.10
(1H, dm, J¼14.1 Hz), 1.92e1.84 (1H, m), 1.76e1.62 (4H, m), 1.61e1.39
(9H, m); 13C NMR (100 MHz; CDCl3) dC: 135.7, 116.1, 83.9, 71.4, 41.6,
41.4, 35.0, 32.7, 31.4, 24.4, 23.3, 21.4; IR (thin film) nmax¼3074, 2956,
2932, 2863, 2847, 2361, 1724, 1641, 1458, 1437, 1371, 1329, 1261,
1215, 1084, 1053, 1016, 997, 911, 863, 817, 803, 722 cmꢁ1; HRMS (CI)
observed [MþH]þ 181.1590, calculated for C12H21O 181.1592.
1500, 1452, 1440, 1330, 1244, 1172, 1153, 1126, 1074, 1041, 1014, 968,
947, 906, 885, 846, 808, 734, 663 cmꢁ1; HRMS (EI) observed
M
þ 177.0906, calculated for C9H11N3O 177.0902.
3.2.13. 1-(Furan-2-yl)cyclopentanamine, 37. A solution of 2-(1-azi-
docyclopentyl)furan 36 (2.0 g, 11.29 mmol) in EtOAc (16 mL) was
treated with 10% Pd/C (200 mg) and placed under a H2 atmosphere.
Hydrogen was bubbled through the solution for 5 min at 10 min
intervals for a total of 1 h. The reaction mixture was then filtered
through Celite and concentrated under vacuum to afford 1-(furan-
2-yl)cyclopentanamine 37 (1.66 g, 97%) as a colourless oil, which
was used without further purification.
1H NMR (400 MHz; CDCl3) dH: 7.31 (1H, dd, J¼1.8, 0.8 Hz), 6.27
(1H, dd, J¼3.2, 1.8 Hz), 6.08 (1H, dd, J¼3.2, 0.7 Hz), 2.08e2.00 (2H,
m), 1.92e1.83 (2H, m), 1.77e1.70 (6H, m); 13C NMR (100 MHz;
CDCl3) dC: 162.3, 141.1, 109.9, 102.8, 60.5, 40.1, 24.0; IR (thin film)
nmax¼2956, 2924, 2870, 2854, 2360, 2330, 1728, 1458, 1377, 1261,
1074, 1014, 800, 738, 704, 699 cmꢁ1
M
; HRMS (EI) observed
þ 151.0991, C9H13NO requires 151.0997.
3.2.14. N-(1-Furan-2-yl)cyclopentyl-4-toluenesulfonamide, 38. A so-
lution of 1-(furan-2-yl)cyclopentanamine 37 (1.66 g, 10.98 mmol) in
anhydrous dichloromethane (25 mL) was treated with triethylamine
(1.93 mL, 13.72 mmol) and cooled to 0 ꢀC. The mixture was then
treated with p-toluenesulfonyl chloride (2.62 g, 13.72 mmol),
allowed to warm up to room temperature and stirred overnight. The
reaction was then diluted with dichloromethane (20 mL) and
washed sequentially with satd aq sodium hydrogen carbonate
(25 mL) and brine (25 mL). The organic layer was separated, dried
over sodium sulfate, filtered and concentrated under vacuum.
Purification by flash column chromatography (silica gel, 20% ethyl
acetate in hexanes) afforded N-(1-furan-2-yl)cyclopentyl-4-tolue-
nesulfonamide 38 (2.29 g, 68%) as a white solid (mp 149 ꢀC).
1H NMR (400 MHz; CDCl3) dH: 7.47 (2H, d, J¼8.3 Hz), 7.10 (2H, d,
J¼8.3 Hz), 6.91 (1H, appdd, J¼1.7, 0.7 Hz), 6.00 (1H, dd, J¼3.3,
1.9 Hz), 5.98 (1H, dd, 3.1, 0.7 Hz), 5.18 (1H, br s), 2.35 (3H, s),
2.23e2.17 (2H, m), 2.10e2.03 (2H, m), 1.82e1.76 (2H, m), 1.62e1.58
(2H, m); 13C NMR (100 MHz; CDCl3) dC: 155.0, 142.4, 141.6, 138.4,
129.2, 127.1, 109.7, 106.8, 64.2, 38.1, 22.4, 21.4; IR (thin film)
nmax¼3254, 2972, 2953, 2918, 2875, 2364, 1915, 1599, 1496, 1460,
1427, 1315, 1290, 1251, 1222, 1153, 1096, 1004, 977, 950, 908, 860,
810, 752, 705, 669 cmꢁ1; HRMS (EI) observed Mþ 305.1085, calcu-
lated for C16H19NO3S 305.1086.
3.2.11. (E)-Ethyl 2-methyl-4-(6-oxaspiro[4.5]decan-7-yl)but-2-enoate,
35. A mixture of 7-allyl-6-oxaspiro[4.5]decane, 34 (100 mg,
0.56 mmol), Grubbs second generation catalyst (13.3 mg, 17 mmol)
and ethyl methacrylate (1.4 mL, 11.2 mmol) was heated to reflux
overnight. The reaction mixture was then concentrated under vac-
uum and the crude residue was purified by flash column chroma-
tography (silica gel, elution gradient 0%e10% diethyl ether in
petroleum ether) to yield (E)-ethyl 2-methyl-4-(6-azaspiro[4.5]
decan-7-yl)but-2-enoate 35 (123 mg, 83%) as a colourless oil.
1H NMR (400 MHz; CDCl3) dH: 6.76 (1H, t, J¼6.9 Hz), 4.25 (2H,
q, J¼6.9 Hz), 3.53e3.41 (1H, m), 2.34e2.18 (2H, m), 1.91e1.83 (1H,
m), 1.80 (3H, br s), 1.26 (3H, t, J¼6.9 Hz), 1.60e1.35 (9H, m),
1.75e1.62 (4H, m); 13C NMR (100 MHz; CDCl3) dC: 168.2, 138.8,
128.9, 84.1, 70.8, 60.4, 41.5, 36.2, 34.8, 32.6, 31.6, 24.3, 23.2, 21.3,
14.3, 12.7; IR (thin film) nmax¼2955, 2931, 2867, 2848, 1708, 1650,
1457, 1439, 1387, 1366, 1329, 1280, 1252, 1233, 1217, 1173, 1143,
1110, 1095, 1082, 1055, 1018, 991, 869, 803, 745 cmꢁ1; HRMS (CI)
observed [MþH]þ 267.1957, calculated for C16H27O3 requires
267.1960.
3.2.12. 2-(1-Azidocyclopentyl)furan, 36. Lukewarm water (4.2 mL)
was added to sodium azide (4.25 g, 65.44 mmol), and the resultant
suspension was stirred for 15 min. Benzene (25 mL) was added,
and the biphasic suspension was cooled to 0 ꢀC. Concentrated
H2SO4 (2.63 mL) was added dropwise, and the mixture was
allowed to stir at 0 ꢀC for 20 min. The organic phase was then
carefully syringed into a dry flask at 0 ꢀC, and 1-(furan-2-yl)
cyclopentanol 20 (600 mg, 3.94 mmol) was added followed by
3.2.15. 7-Hydroxy-6-tosyl-6-azaspiro[4.5]dec-8-en-10-one, 39. A 0 ꢀC
solution of N-(1-furan-2-yl)cyclopentyl-4-toluenesulfonamide, 38
(427 mg, 1.40 mmol) in chloroform (7 mL) was treated with the
dropwise addition of m-chloroperbenzoic acid (ꢃ77%, 470 mg,
2.10 mmol) at a rate such that the temperature did not exceed 10 ꢀC
during the addition. Once addition was completed, the reaction was
allowed to warm to room temperature and stirred until completion
as indicated by TLC analysis (3 h). The solution was diluted with
chloroform (10 mL), washed with 20% aq KI (15 mL), 30% aq Na2S2O3
(15 mL), NaHCO3 (15 mL), water (15 mL) and brine (15 mL) sequen-
tially. The organic phase was dried over Na2SO4, filtered and con-
centrated under vacuum to yield 7-hydroxy-6-tosyl-6-azaspiro[4.5]
dec-8-en-10-one 39 as a yellow foam, which was taken forward
without further purification.
H2SO4 (132 m
L). The resulting mixture was stirred for 5 min at 0 ꢀC
and was then quenched with ice-cold ammonium hydroxide so-
lution (25 mL). For safety reasons, 4 equiv batches of this procedure
were performed simultaneously. The four quenched batches were
combined, and extracted with EtOAc (3ꢂ20 mL). The combined
organic phases were washed with satd aq NH4Cl (25 mL), dried
over Na2SO4 and concentrated under vacuum. Purification of the
crude residue by flash column chromatography (silica gel, hexanes)
afforded 2-(1-azidocyclopentyl)furan 36 (2.11 g, 76%) as a colour-
less oil.
3.2.16. 7-Allyl-6-tosyl-azaspiro[4.5]dec-8-en-10-one, 40. A ꢁ78 ꢀC
solution of hemi-aminal 39, (449 mg, 1.40 mmol) in anhydrous
dichloromethane (7 mL) was treated with allyltrimethylsilane
(319 mg, 2.79 mmol). Boron trifluoride-diethyl etherate (198 mg,
1.40 mmol) was then added and the resulting solution was stirred
at ꢁ78 ꢀC until completion by TLC analysis (45 min). The reaction
mixture was diluted with dichloromethane (10 mL) and washed
1H NMR (400 MHz; CDCl3) dH: 7.39 (1H, dd, J¼1.8, 0.8 Hz), 6.34
(1H, dd, J¼3.2, 1.8 Hz), 6.28 (1H, dd, J¼3.3, 0.7 Hz), 2.14e2.03 (4H,
m), 1.93e1.73 (4H, m); 13C NMR (100 MHz; CDCl3) dC: 155.4, 142.4,
110.1, 106.1, 70.5, 36.6, 23.3; IR (thin film) nmax¼2962, 2875, 2092,

4994
F.D. Ferrari et al. / Tetrahedron 67 (2011) 4988e4994
with cold satd aq ammonium chloride (20 mL). The organic phase
was dried over sodium sulfate, filtered and concentrated under
vacuum. Purification of the crude residue by flash column chro-
matography (silica gel, elution gradient 10%e33% diethyl ether in
petroleum ether) yielded 7-allyl-6-tosyl-azaspiro[4.5]dec-8-en-10-
3.52e3.40 (1H, m), 2.66e2.50 (2H, m), 2.43e2.34 (1H, m), 2.40 (3H,
s), 2.16e1.42 (14H, m); 13C NMR (100 MHz; CDCl3) dC: 142.7, 142.5,
142.4, 141.7, 136.0, 129.7, 129.6, 129.5, 126.6, 126.4, 126.2, 125.8,
117.6, 117.5, 75.5, 69.2, 56.4, 55.1, 40.7, 40.0, 38.5, 36.5, 36.1, 33.8,
27.3, 26.1, 25.2, 25.1, 23.4, 23.2, 22.9, 21.6, 21.5, 20.3; IR (thin film)
nmax¼3510, 3070, 2947, 2877, 1712, 1643, 1597, 1496, 1442, 1411,
one, 40 (311 mg, 64% over two steps) as
a white solid
(mp 89e90 ꢀC).
1311,1234, 1149, 1095, 1003, 964, 902, 810, 763, 702, 663, 601 cmꢁ1
;
1H NMR (400 MHz; CDCl3) dH: 7.56 (2H, d, J¼8.3 Hz), 7.21 (2H, d,
J¼8.3 Hz), 6.85 (1H, dd, J¼4.6, 10.2 Hz), 6.00e5.91 (1H, m), 5.88 (1H,
dd, J¼10.2, 1.8 Hz), 5.22e5.20 (1H, m), 5.19e5.16 (1H, m), 5.11e5.04
(1H, m), 2.82 (1H, dtt, J¼13.4, 6.4, 1.3 Hz), 2.60 (1H, dtm, J¼13.4,
8.1 Hz), 2.37 (3H, s), 2.13e2.02 (3H, m),1.80e1.71 (3H, m),1.44e1.32
(2H, m); 13C NMR (100 MHz; CDCl3) dC: 196.4, 146.2, 143.6, 139.0,
133.9, 129.8, 126.8, 124.8, 118.9, 73.1, 57.3, 42.5, 41.5, 32.2, 23.9, 22.6,
21.6; IR (thin film) nmax¼2957, 2874, 2360, 1681, 1598, 1575, 1495,
1432, 1416, 1377, 1341, 1329, 1307, 1264, 1166, 1089, 1067, 1000, 911,
846, 816, 794, 735, 702, 667, 647 cmꢁ1; HRMS (CI) observed
[MþH]þ 346.1476, calculated for C19H24NO3S 346.1477.
HRMS (CI) observed [MþH2OꢁH]þ 350.1788, calculated for
C19H28NO3S 348.1790.
3.2.19. (E)-Ethyl 2-methyl-4-(6-azaspiro[4.5]decan-7-yl)but-2-enoate,
43. A solution of 7-allyl-6-azaspiro[4.5]decane, 42 (25 mg,
75 mmol) in neat ethyl methacrylate (187 mL, 1.50 mmol) was
treated with HoveydaeGrubbs second generation catalyst (5 mg,
8 mmol) and the resulting mixture was heated to reflux overnight.
Upon completion by TLC analysis, the reaction mixture was con-
centrated under vacuum. Purification of the crude residue by flash
column chromatography (silica gel, elution gradient 20%e50% ethyl
acetate in hexanes) afforded (E)-ethyl 2-methyl-4-(6-azaspiro[4.5]
decan-7-yl)but-2-enoate, 43 (15 mg, 48%) as a yellow oil.
3.2.17. 7-Allyl-6-azaspiro[4.5]decan-10-one, 41. A solution of 7-Al-
lyl-6-azaspiro[4.5]dec-8-en-10-one 40 (300 mg, 1.89 mmol) in
1H NMR (400 MHz; CDCl3) dH: 7.73 (1H, d, J¼8.2 Hz), 7.65 (1.5H,
d, J¼8.4 Hz), 7.25 (2H, d, J¼8.1 Hz), 6.77 (0.4H, t, J¼7.0 Hz), 6.70
(0.6H, t, J¼6.8 Hz), 4.64e4.56 (0.4H, m), 4.37e4.29 (0.6H, m), 4.20
(0.8H, q, J¼7.1 Hz), 4.18 (1.2H, q, J¼7.0 Hz), 3.55e3.44 (1H, m),
2.88e2.59 (2H, m), 2.41 (3H, s), 2.43e2.34 (1.2H, m), 2.26e1.41
(14.8H, m), 1.29 (1.8H, t, J¼7.1 Hz), 1.30 (1.2H, t, J¼7.2 Hz); 13C NMR
(400 MHz; CDCl3) dC: 168.1, 168.0, 142.9, 142.6, 142.4, 141.6, 138.5,
138.4, 130.1, 130.0, 129.8, 129.7, 126.4, 125.9, 75.2, 72.9, 71.7, 69.3,
60.8, 60.7, 56.3, 54.9, 38.8, 36.9, 36.4, 35.1, 34.5, 34.0, 27.3, 26.5,
25.9, 25.2, 23.7, 23.5, 23.1, 21.6, 21.5, 21.2, 14.4 (2C), 13.0, 12.9; IR
(thin film) nmax¼3581, 2947, 2870, 2360, 2252, 1705, 1643, 1597,
1450, 1388, 1373, 1288, 1265, 1211, 1149, 1095, 1018, 972, 910, 810,
732, 663, 601 cmꢁ1; HRMS (FAB) observed [MþH2OꢁH]þ 436.2155,
calculated for C23H34NO5S 436.2158.
a
deoxygenated benzene/water mixture (100 mL:0.2 mL) was
transferred via cannula to a flask containing (triphenylphosphine)
copper hydride hexamer (1.0 g, 0.51 mmol) under argon. The re-
sultant red/brown suspension was stirred at room temperature
overnight before being opened to the air, and being allowed to stir
for 1 h. The suspension was filtered through Celite, concentrated
under vacuum, and azeotroped with toluene to remove any re-
sidual benzene. Purification of the crude residue by flash column
chromatography (silica gel, elution gradient 0%e10% ethyl acetate
in
hexanes)
afforded
7-allyl-6-azaspiro[4.5]decan-10-one
41 (258 mg, 85%) as a white solid (mp 88e90 ꢀC).
1H NMR (400 MHz; CDCl3) dH: 7.74 (2H, d, 8.3 Hz), 7.29 (2H, d,
8.1 Hz), 5.6e5.57 (1H, m), 5.06e5.04 (1H, m), 5.03e5.00 (1H, m),
4.05 (1H, ddt, J¼10.7, 6.3, 4.6 Hz), 2.66 (1H, dt, J¼15.7, 7.4 Hz), 2.50
(1H, ddd, J¼16.9, 9.3, 6.8 Hz), 2.42 (3H, s), 2.41e2.30 (3H, m),
2.20e2.03 (3H, m), 1.98e1.88 (1H, m), 1.86e1.76 (3H, m), 1.74e1.64
(1H, m), 1.57e1.45 (1H, m); 13C NMR (100 MHz; CDCl3) dC: 209.5,
143.4, 139.2, 134.2, 129.8, 127.2, 118.2, 76.5, 53.9, 39.4, 38.2, 36.6,
31.9, 25.5, 24.5, 24.1, 21.6; IR (thin film) nmax¼3070, 2955, 2877,
1712, 1643, 1597, 1442, 1411, 1311, 1234, 1149, 1095, 1003, 964, 902,
810, 763, 671 cmꢁ1; HRMS (CI) observed [MþH]þ 348.1632, calcu-
lated for C19H26NO3S 348.1633.
Acknowledgements
F.D.F. would like to thank the EPSRC and Eli Lilly for a post-
graduate studentship. We are grateful to Dr. Ian Sword, the EPSRC,
and the University of Glasgow for financial support.
References and notes
3.2.18. 7-Allyl-6-azaspiro[4.5]decane, 42. A room temperature solu-
tion of 7-allyl-6-azaspiro[4.5]decan-10-one, 41 (535 mg, 1.54 mmol)
in absolute ethanol (15 mL) was treated with tosylhydrazide (315 mg,
1.69 mmol) and the resultant solution was allowed to stir at room
temperature overnight. The solvent was evaporated under vacuum,
and the crude tosylhydrazone was dissolved in dry dichloromethane
(20 mL) and cooled down to 0 ꢀC. Diisobutylaluminium hydride
(5.4 mL, 1 M in hexanes) was then added dropwise to the solution
over a period of 45 min. The reaction was then stirred at 0 ꢀC until
completion by TLC analysis (2 h). The reaction mixture was diluted
with dichloromethane (20 mL), and quenched by the slowaddition of
15% sodium hydroxide solution (15 mL). The mixture was diluted
with water (10 mL), which resulted in the formation of a biphasic
mixture, which was extracted with diethyl ether (3ꢂ15 mL). The
combined organic layers were dried over sodium sulfate, filtered and
concentrated under reduced pressure. Purification of the crude resi-
due by flash column chromatography (silica gel, 0%e15%e100%
diethyl ether in petroleum ether) afforded 7-allyl-6-azaspiro[4.5]
decane 42 (281 mg, 55%) as a yellow oil.
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1H NMR (400 MHz; CDCl3) dH: 7.73 (1.2H, d, J¼8.3 Hz), 7.65
(1.5H, d, 8.3 Hz), 7.24 (2H, d, J¼8.2 Hz), 5.87e5.71 (1.4H, m),
5.12e5.05 (2H, m), 4.56e4.49 (0.4H, m), 4.32e4.22 (0.6H, m),