Consecutive reactions with sulfoximines: Straightforward synthesis of substituted 5,5-spiroketals

Article abstract of DOI:10.1055/s-0030-1260039

An efficient synthesis of 5,5-spiroketals (i.e., 1,6-dioxa-spiro[4.4]nonane derivatives) is described from 2-(sulfonimidoyl-methylene)tetrahydrofurans involving a consecutive epoxide opening/oxa-Michael spiroketalization sequence. This methodology was applied to the very direct synthesis of chalcogran, a beetle pheromone. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0030-1260039

PAPER
2085
Consecutive Reactions with Sulfoximines: Straightforward Synthesis of
Substituted 5,5-Spiroketals
S
ynthesis of Subst
e
itute
d
5,5-S
l
piroke
l
tals aisamy Sridharan, Nikolay Vologdin, Marie-Alice Virolleaud, Damien Bonne, Cyril Bressy, Gaëlle Chouraqui,
Laurent Commeiras, Jean-Luc Parrain, Yoann Coquerel, Jean Rodriguez*
Aix-Marseille Université, Institut des Sciences Moléculaires de Marseille, iSm2 – UMR CNRS 6263, Centre Saint Jérôme, Service 531,
13397 Marseille Cedex 20, France
Fax +33(4)91289187; E-mail: jean.rodriguez@univ-cezanne.fr
Received 24 February 2011; revised 8 April 2011
able, the access to the spiroketalization precursor(s) usu-
Abstract: An efficient synthesis of 5,5-spiroketals (i.e., 1,6-dioxa-
ally requires several steps.
spiro[4.4]nonane derivatives) is described from 2-(sulfonimidoyl-
methylene)tetrahydrofurans involving
a consecutive epoxide
An important focus for contemporary organic synthesis is
economy.11 Indeed, the efficiency of a synthetic sequence
is more than ever determined by issues of brevity and sus-
tainability, as witnessed by the tremendous efforts cur-
rently directed at the development of multiple bond-
forming12 and catalytic chemical processes.13 The effi-
ciency of a chemical synthesis can be measured by param-
eters such as selectivity and overall yield. Moreover, raw
material, time, human resources and energy requirements,
as well as the toxicity and hazard of the chemicals, and the
protocols are also involved. Thus, it is now recognized
that the step count is one of the most important criteria
when evaluating the efficiency of a synthesis.
opening/oxa-Michael spiroketalization sequence. This methodolo-
gy was applied to the very direct synthesis of chalcogran, a beetle
pheromone.
Key words: sulfoximine, 5,5-spiroketals, consecutive reaction,
chalcogran
Spiroketals are structural subunits found in many biologi-
cally active natural products originated from a variety of
sources including marine, vegetal, insect, or bacterial
sources.1 These molecules display a broad range of bio-
logical activities such as antibiotic,2 antifungal,3 anti-
HIV,4 or could find applications in cancer therapy.5 The
spiroketal moiety is often the primary pharmacophore in
these molecules, and in some cases, simplified analogues
retaining essentially the spiroketal moiety have shown
comparable biological activity with the natural products.6
Because of their pharmaceutical interest, spiroketals have
become popular synthetic targets and a variety of methods
are now available to access these useful compounds. The
most common strategy relies on the cyclization of a linear
a,w-dihydroxy ketone or a synthetic equivalent,7 and tran-
sition-metal-catalyzed spiroketalizations of unsaturated
a,w-diols were also described.8 Other useful strategies in-
volve the iodoetherification of ene ketals9 or a hetero-
Diels–Alder cycloaddition between an a,b-unsaturated
carbonyl compound and an a-methylene tetrahydropyran
or -furan.10 Although these methods are effective and reli-
In connection with our continuous interest in the develop-
ment of novel multiple bond-forming transformations,14
we recently reported the chemo- and regioselective syn-
thesis of 2-(sulfonimidoylmethylene)tetrahydrofurans 2
by a consecutive acylation/SN reaction of sulfoximines 1
with a,w-halo esters (Scheme 1).15 The use of chiral sulf-
oximines in asymmetric synthesis is well established,16
and changing the nature of the substituent on the nitrogen
atom can easily modify their steric and electronic demand.
In addition these chiral auxiliaries can be removed, recy-
cled or even exploited in further transformations. We re-
port herein an efficient transformation of compounds 2
into 5,5-spiroketals (i.e., 1,6-dioxaspiro[4.4]nonane de-
rivatives) in a single operation, and its application to the
synthesis of chalcogran, a beetle pheromone.
R2
n-BuLi (2 equiv), –20 °C, 30 min;
O
R2
MeO2C
Cl
R2
LiO
O
S
NR1
O
O
O
O
Li
S
O
α-lithiation
4
–80 to –40 °C, 1.5 h;
O
NR1
Ph
Me
NR1
Ph
NR1
S
aq 5% NaOH, r.t., 1 h
(ref. 15)
O
S
O
Ph
S
NR1
O
Ph
Ph
1a: R1 = Me
1b: R1 = Boc
1c: R1 = Piv
2a: 86%, E/Z = 52:48
2b: 67%, E/Z = 37:63
2c: 64%, E/Z = 21:79
2d: 70%, E/Z = 35:65
2e: 64%, E/Z = 37:63
6
3
5
1d: R1 = neopentyl
1e: R1 = Alloc
Scheme 1
SYNTHESIS 2011, No. 13, pp 2085–2090
x
x.
x
x
.
2
0
1
1
Advanced online publication: 11.05.2011
DOI: 10.1055/s-0030-1260039; Art ID: N21911SS
© Georg Thieme Verlag Stuttgart · New York

2086
V. Sridharan et al.
PAPER
We surmised that compounds 2 could be transformed into sequence12 could also be viable. Indeed, after in situ gen-
5,5-spiroketals 6 in a single operation via a domino ep- eration of the lithium alcoholate 5aa (R1 = R2 = Me) from
oxide ring opening/oxa-Michael spiroketalization se- 2a, addition of HMPA (hexamethylphosphoramide) pro-
quence involving successively the lithiated olefin 3 and moted the desired spiroketalization in good yield, thus al-
the lithium alcoholate 5 (Scheme 1). It should be noted lowing the synthesis of 6aa directly from 2a by a
that related stepwise strategies have been explored from consecutive reaction. As in the two-step protocol, the sul-
a-lithiated vinyl sulfones.17,18
fonimidoyl group was cleaved to yield 8a as the same
mixture of diastereomers, but the consecutive protocol
was found to be more efficient (Scheme 2).
In order to validate this strategy, the diastereomeric mix-
ture of (E)- and (Z)-N-methyl-2-(sulfonimidoylmethyl-
ene)tetrahydrofuran (2a) was first treated with The scope and limits of this spiroketalization reaction
methyllithium at low temperature to produce mainly the were examined by changing the nature of the substituents
lithiated intermediate (E)-3a (R1 = Me).15b Subsequent on both the oxirane and the sulfinimidoyl group. The re-
addition of 2-methyloxirane (4a; R2 = Me) led to the open- sults are summarized in Table 1. The consecutive reaction
ing of the epoxide; however, the resulting alcoholate did proved to be very general affording the 5,5-spiroketal
not undergo the expected spiroketalization, and following products 6 in good yields, and functionalized substituents
hydrolysis, the alcohol 7aa was instead isolated in good could be introduced via the epoxide 4 (Table 1, entries 7
yield (Scheme 2). Surprisingly, the use of various Lewis and 9). It seems that in every case a fraction of the product
acids (BF3·OEt2, Et2AlCl, InCl3)19 resulted in lower yields 8 decomposed during the removal of the sulfonimidoyl
of product and/or decomposition of the starting material. group and/or during the purification by flash chromatog-
Prolonged reaction time and/or elevation of the reaction raphy on silica gel as evidenced by the systematically
temperature did not allow the expected domino spiroket- lower yields of spiroketal 8 compared to sulfinamide 9.
alization. Alternatively, the desired intramolecular oxa- The configuration of the double bond in substrate 2a had
Michael cyclization could be achieved by treatment of no significant impact on the reaction outcome (compare
7aa with sodium hydride at room temperature and afford- entries 1 and 2, see ref 15b) as well as the nature of the ni-
ed the targeted 5,5-spiroketal 6aa in good yield, but as an trogen substituent R (compare entries 3, 4 and 5, 6). Un-
inseparable mixture of at least four diastereomers fortunately, the diastereomeric ratio of the sulfonimidoyl-
(Scheme 2). In a separate experiment, a single diastereo- free 5,5-spiroketals 8 was very close to 1:1 in all cases, ex-
mer of 7aa was subjected to the same conditions to pro- cept for 8a and 8f (dr = 2:1). Actually, the lack of diaste-
vide 6aa as a 1:1 mixture of two diastereomers in similar reoselectivity observed in this approach to 5,5-spiroketals
yield, showing some degree of diastereoselectivity in the is a common feature to many syntheses of such systems.
oxa-Michael cyclization step (2 diastereomers obtained, Indeed, it is well known that 5,6- and 6,6-spiroketals can
from 4 possible). In order to facilitate analysis, the chiral equilibrate due to an anomeric effect combined with the
sulfonimidoyl group was reductively cleaved from 6aa (4 minimization of steric interactions. However, in the case
diastereomers) with aluminum/mercury amalgam to af- of 5,5-spiroketals, the anomeric effect is severely dimin-
ford the 5,5-spiroketal 8a (dr = 2:1) in 58% yield with the ished due to the lack of well-defined axial and equatorial
corresponding sulfinamide 9a.
positions. Although the stereoselective formation of 5,5-
spiroketals has been described in few examples,20 epimers
at the spiranic carbon atom typically equilibrate to nearly
Having shown the feasibility of each individual step, we
had yet to demonstrate that a domino or consecutive
1. MeLi (1 equiv), –80 °C, THF, 30 min;
O
2.
–80 °C to –24 °C over 1.5 h,
then –24 °C for 48 h
HO
O
O
4a
NMe
S
NMe
S
83%
O
O
Ph
Ph
2a
7aa: dr = 1:1
NaH, THF
r.t., 24 h
90%
1. MeLi (1 equiv), –80 °C, THF, 30 min;
O
2.
–80 °C to –24 °C over 1.5 h,
then –24 °C for 48 h;
4a
O
O
O
Al/Hg
O
S
O
O
THF–H2O
3. HMPA (2 equiv), r.t., 24 h
+
Ph
NHMe
58%
84%
S
NMe
8a: dr = 2:1
9a
Ph
6aa (4 diastereomers)
Scheme 2 Stepwise and consecutive synthesis of 5,5-spiroketal 6aa
Synthesis 2011, No. 13, 2085–2090 © Thieme Stuttgart · New York

PAPER
Synthesis of Substituted 5,5-Spiroketals
2087
Table 1 Consecutive Reaction for the Synthesis of 5,5-Spiroketals 6 and 8a
Entry
Substrate
Epoxide 4
Yield of 6 (%)b
6aa: 84 (75)
6aa: 72
Yield of 8 (%)c
8a: 58 (84)
8a: 55 (84)
8b: 69 (85)
8b: 70 (81)
8c: 72 (83)
8c: 69 (79)
8d: 85 (86)d
8e: 50 (69)
8f: 85 (86)
1
2
3
4
5
6
7
8
9
2a (E/Z = 52:48)
(Z)-2a
4a: R2 = Me
4a: R2 = Me
4b: R2 = Et
2a (E/Z = 52:48)
2b (E/Z = 37:63)
2a (E/Z = 52:48)
2b (E/Z = 37:63)
2a (E/Z = 52:48)
2a (E/Z = 52:48)
2a (E/Z = 52:48)
6ab: 85 (81)
6bb: 71
4b: R2 = Et
4c: R2 = n-Bu
4c: R2 = n-Bu
4d: R2 = CH2OPh
4e: R2 = Ph
6ac: 80
6bc: 75
6ad: 61
6ae: 68
4f: R2 = but-3-enyl
6af: 79 (70)
a All reactions were performed under the conditions described in Scheme 2.
b Yields of the consecutive reaction determined by isolation of the mixture of diastereomers after flash chromatography on silica gel. The yields
in brackets are for the two-step sequence via 7 (when determined).
c Compounds 8 were obtained as nearly 1:1 mixtures of two diastereomers, except for 8a and 8f (dr = 2:1). The yields have been determined
based on isolated product after flash chromatography on silica gel. The yields for 9a (or 9b for entries 4 and 6) are in parentheses.
d Product 8d was contaminated by an unknown impurity (ca. 10%, see Supporting Information).
on a Bruker Avance 300 spectrometer in CDCl3 and chemical shifts
(d) are given in ppm relative to the residual nondeutered solvent sig-
nal for 1H NMR (CHCl3: 7.26 ppm), and relative to the deutered sol-
vent signal for 13C NMR (CDCl3: 77.0 ppm); coupling constants (J)
are in hertz, and the classical abbreviations are used to describe the
signal multiplicity. Mass spectra were recorded on a Bruker Esquire
6000 spectrometer equipped with an electrospray ionization source
and an ion trap detector. High-resolution mass spectra were ob-
tained from the Spectropole (http://www.spectropole.u-3mrs.fr/).
Melting points were determined with a Büchi Melting-point B-450
apparatus and were not corrected. FTIR spectra were recorded on a
PerkinElmer 1600 spectrometer.
1:1 mixtures in these systems, especially for lightly sub-
stituted compounds.21 Overall, the above methodology al-
lows a straightforward and efficient synthetic access to
5,5-spiroketals 6 from sulfoximines 1 in only two steps,
each step being a consecutive reaction. It is worth to note
that the present approach to 2-substituted-1,6-dioxa-
spiro[4.4]nonane derivatives 8 has allowed one of the
most direct synthesis of ( )-chalcogran (8b), the principal
component of the aggregation pheromone of the bark bee-
tle Pityogenes chalcographus (L.), a pest of the Norway
spruce.22
5,5-Spiroketals 6 via 7; General Procedure
In conclusion, we have developed a simple and rapid
methodology for the synthesis of substituted 5,5-spiroket-
als based on two successive anionic consecutive reactions
from sulfoximines 1. Indeed, a consecutive acylation/SN2
reaction allowed the synthesis of a variety of 2-(sulfon-
imidoylmethylene)tetrahydrofurans 2, which in turn were
the substrates of a consecutive epoxide ring opening/oxa-
Michael reaction affording 5,5-spiroketals 6. However,
and as it is the case in most alternative syntheses of 5,5-
spiroketal moities, the stereochemistry of the spiro carbon
atom could not be controlled. The methodology was ap-
plied to the synthesis of ( )-chalcogran (8b), a naturally
occurring pheromone.
To a stirred solution of 2 (3 mmol) in THF (18 mL) under an argon
atmosphere at –80 °C was added an ethereal solution of MeLi (3
mmol) and the stirring was continued for 30 min. Epoxide 4 (4.5 to
6 mmol) was then added and the temperature was gradually in-
creased (over 1.5 h) to –24 °C and kept at this temperature for 48 h.
The reaction mixture was then hydrolyzed with sat. aq NH4Cl (20
mL), and the organic layer was separated. The aqueous layer was
extracted with Et2O (2 × 15 mL), and the combined organic layers
were washed with brine (10 mL), dried (MgSO4), filtered, and con-
centrated to give the crude product. The crude product was purified
by flash chromatography on silica gel eluting with EtOAc (60%) in
PE to give 7 as an inseparable mixture of two diastereomers. [The
two diastereomers of 7aa were partially separated (90% diastereo-
meric purity)]. To a stirred suspension of NaH (1.2 mmol) in THF
(6 mL) under an argon atmosphere was added a solution of 7 (1
mmol) in THF (6 mL) at r.t. The stirring was continued for 24 h, the
reaction mixture was then hydrolyzed with sat. aq NH4Cl (20 mL),
and the organic layer was separated. The aqueous medium was ex-
tracted with Et2O (2 × 20 mL), and the combined organic layers
were washed with brine (20 mL), dried (MgSO4), filtered, and con-
centrated to give the crude product. The crude product was purified
by flash chromatography on silica gel eluting with EtOAc (30%) in
PE to give 6 as an inseparable mixture of four isomers.
All reagents were obtained from commercial sources and used as
supplied unless otherwise stated. HMPA was dried over CaH2 and
distilled under an argon atmosphere. Anhydrous Et2O, THF, and
CH2Cl2 were obtained from a solvent purification system. Petro-
leum ether (PE) refers to the fraction boiling in the range 40–60 °C.
The reactions were monitored by TLC, which were performed on
Merck 60 F254 plates. Flash chromatography was performed with
Macherey-Nagel 70–230 mesh silica gel. NMR data were recorded
Synthesis 2011, No. 13, 2085–2090 © Thieme Stuttgart · New York

2088
V. Sridharan et al.
PAPER
From 7aa (90% diastereomeric purity), 6aa was obtained as a mix-
ture of two isomers, which were separated (90% diastereomeric pu-
rity).
(m, 1 H), 2.62 (s, 3 H), 3.83–3.94 (m, 3 H), 4.07–4.16 (m, 1 H),
7.48–7.54 (m, 3 H), 7.76–7.79 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 21.3, 24.3, 29.2, 33.9, 34.6, 66.2,
68.3, 71.0, 112.7, 128.7, 130.4, 132.6, 136.8.
HRMS (ESI+): m/z calcd for C15H22NO3S [M + H]+: 296.1315;
found: 296.1318.
5,5-Spiroketals 6 by the Consecutive Reaction; General Proce-
dure
To a stirred solution of 2 (1 mmol) in THF (6 mL) at –80 °C under
an argon atmosphere was added an ethereal solution of MeLi (1
mmol) and the stirring was continued for 30 min. Epoxide 4 (2
mmol) was then added and the temperature was gradually increased
(over 1.5 h) to –24 °C and kept at this temperature for 48 h. The
mixture was then allowed to warm to r.t.; HMPA (2 mmol) was then
added and the stirring was continued for 24 h. The reaction mixture
was then hydrolyzed with sat. aq NH4Cl (30 mL), and the organic
layer was separated. The aqueous medium was extracted with Et2O
(2 × 30 mL), and the combined organic layers were washed with
brine (20 mL), dried (MgSO4), filtered, and concentrated to give the
crude product. The crude product was purified by flash chromatog-
raphy on silica gel eluting with EtOAc (30%) in PE to give 6 as an
inseparable mixture of four isomers identical to the mixture ob-
tained by the two-step protocol.
5,5-Spiroketals 8; General Procedure
Al/Hg amalgam was prepared by adding small pieces of Al foil (1.0
g) to a solution of HgCl2 (1.0 g) in H2O (50 mL). The mixture was
stirred for 1 min and filtered. The resulting material was washed
rapidly with H2O (20 mL) and THF (20 mL), and then added to a
stirred solution of 6 (1.3 mmol) in 7:1 THF–H2O (40 mL). The stir-
ring was continued for 2 h whereupon the mixture was filtered
through Celite, and the filtrate was extracted with CH2Cl2 (2 × 40
mL). The combined organic layers were washed once with a small
amount of H2O, dried (MgSO4), filtered, and concentrated to give
the crude product. The crude product was purified by flash chroma-
tography on silica gel eluting with increasing amounts of EtOAc (10
→ 50%) in PE to give the spiroketal 8 as a mixture of two diastere-
omers followed by the sulfinamide 9.
7aa (1st eluted diastereomer)
Viscous liquid.
IR (neat): 2985, 1615, 1434, 1226, 1141 cm–1.
Compounds 8a,21a,b 8b,23 and 8f21b exhibited physical and spectro-
scopic properties identical with previously reported data, except for
optical rotations where applicable.
1H NMR (300 MHz, CDCl3): d = 1.20 (d, J = 6.2 Hz, 3 H), 1.97–
2.19 (m, 2 H), 2.25–2.33 (m, 1 H), 2.56–2.64 (m, 1 H), 2.67 (s, 3 H),
2.92–3.03 (m, 1 H), 3.28–3.39 (m, 1 H), 3.89–3.95 (m, 1 H), 4.11–
4.23 (m, 2 H), 6.40 (br s, 1 H), 7.51–7.57 (m, 3 H), 7.80–7.84 (m, 2
H).
13C NMR (75 MHz, CDCl3): d = 24.0, 24.5, 28.9, 29.7, 37.2, 67.1,
71.6, 109.6, 128.5, 129.2, 132.1, 140.2, 169.8.
8c
Liquid; dr = 1:1.
IR (neat): 2933, 2853, 1447, 1333, 1144, 1010 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.83–0.88 (m, 6 H), 1.19–1.75 (m,
14 H), 1.82–2.12 (m, 14 H), 3.78–4.09 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 13.9, 22.6, 22.7, 24.3, 24.5, 27.9,
28.1, 30.0, 30.8, 34.6, 34.8, 35.1, 35.3, 35.7, 36.9, 66.6, 66.8, 78.1,
80.0, 114.2, 114.4.
HRMS (ESI+): m/z calcd for C11H21O2 [M + H]+: 185.1536; found:
185.1535.
HRMS (ESI+): m/z calcd for C15H22NO3S [M + H]+: 296.1315;
found: 296.1314.
7aa (2nd eluted diastereomer)
Viscous liquid.
IR (neat): 2994, 1615, 1435, 1227, 1140 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.17 (d, J = 6.2 Hz, 3 H), 1.94–
2.11 (m, 3 H), 2.62 (s, 3 H), 2.69–2.85 (m, 2 H), 3.14–3.25 (m, 1 H),
3.92–3.42 (m, 1 H), 4.09–4.22 (m, 2 H), 5.93 (br s, 1 H), 7.48–7.59
(m, 3 H), 7.84–7.88 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 23.1, 24.5, 28.8, 29.5, 35.6, 66.8,
71.5, 109.2, 128.4, 129.0 (2 C), 131.9 (2 C), 140.6, 169.9.
HRMS (ESI+): m/z calcd for C15H22NO3S [M + H]+: 296.1315;
found: 296.1313.
8d
Liquid (ca. 90% purity); dr = 1:1.
IR (neat): 2931, 1446, 1328, 1139, 1012 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.81–2.32 (m, 16 H), 3.83–4.15
(m, 8 H), 4.43–4.53 (m, 2 H), 6.93–6.98 (m, 6 H), 7.26–7.32 (m, 4
H).
13C NMR (75 MHz, CDCl3): d = 24.3, 24.5, 27.1, 27.8, 34.2, 34.3,
34.6, 35.0, 66.8, 67.1, 70.1, 72.1, 76.1, 114.5, 115.0, 115.3, 120.6,
120.7, 129.2, 129.3, 158.8, 158.9.
HRMS (ESI+): m/z calcd for C14H19O3 [M + H]+: 235.1329; found:
235.1330.
6aa (1st eluted major diastereomer)
Viscous liquid.
IR (neat): 2953, 2861, 1435, 1243, 1137 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.27 (d, J = 6.3 Hz, 3 H), 1.77–
1.85 (m, 1 H), 1.97–2.34 (m, 4 H), 2.60–2.64 (m, 1 H), 2.68 (s, 3 H),
3.69–4.10 (m, 4 H), 7.53–7.60 (m, 3 H), 7.83–7.86 (m, 2 H).
8e
Liquid; dr = 1:1.
IR (neat): 2925, 1482, 1335, 1148, 1011 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.86–2.39 (m, 16 H), 3.93–4.16
(m, 4 H), 5.00–5.17 (m, 2 H), 7.24–7.30 (m, 3 H), 7.33–7.38 (m, 5
H), 7.43–7.46 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 19.7, 24.5, 29.2, 32.6, 36.4, 66.5,
71.1, 71.4, 113.2, 129.2, 129.6, 132.8, 138.3.
13C NMR (75 MHz, CDCl3): d = 24.4, 24.6, 33.7, 34.7, 34.8, 35.0,
35.1, 36.3, 67.0, 67.1, 79.5, 82.1, 114.9, 115.2, 125.7, 126.2, 127.1,
127.2, 128.2, 128.3, 143.0, 143.7.
HRMS (ESI+): m/z calcd for C13H17O2 [M + H]+: 205.1223; found:
205.1205.
HRMS (ESI+): m/z calcd for C15H22NO3S [M + H]+: 296.1315;
found: 296.1317.
6aa (2nd eluted major diastereomer)
Viscous liquid.
IR (neat): 2850, 2847, 1435, 1235, 1136 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.12 (d, J = 6.3 Hz, 3 H), 1.19–
1.27 (m, 1 H), 1.70–1.77 (m, 1 H), 1.98–2.05 (m, 3 H), 2.40–2.50
Synthesis 2011, No. 13, 2085–2090 © Thieme Stuttgart · New York

PAPER
Synthesis of Substituted 5,5-Spiroketals
2089
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are the 1H and 13C NMR spectra of 8b and all new compounds.
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Synthesis 1990, 1013.
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de Brabander, J. K. Org. Lett. 2006, 8, 4907. (c) Zhang, Y.;
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Acknowledgment
The Agence Nationale pour la Recherche (A.N.R. 07-BLAN-0269),
the C.N.R.S., and the Université Paul Cézanne (UMR 6263) are
gratefully acknowledged for financial support.
(9) Fujioka, H.; Nakahara, K.; Hirose, H.; Hirano, K.; Oki, T.;
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(10) Rizzacasa, M. A.; Pollex, A. Org. Biomol. Chem. 2009, 7,
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