A flexible route to new spirodioxanes, oxathianes, and morpholines

Article abstract of DOI:10.1016/j.tet.2009.03.044

This work describes a modular efficient route to 10-aza-4-thia-, 10-aza-4-oxa-, and 10-oxa-4-thia-1,7-dioxaspiro[5.5]undecanes. The synthetic pathway relies upon the iterative nucleophilic substitution of 1,3-dichloropropan-2-one O-benzyloxime by solketal

Full text of DOI:10.1016/j.tet.2009.03.044

Tetrahedron 65 (2009) 4182–4189
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A flexible route to new spirodioxanes, oxathianes, and morpholines
*
*
`
Marlene Goubert, Isabelle Canet , Marie-Eve Sinibaldi
Clermont Universite´, Universite´ Blaise Pascal, CNRS UMR 6504, SEESIB 63177 Aubie`re Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
This work describes a modular efficient route to 10-aza-4-thia-, 10-aza-4-oxa-, and 10-oxa-4-thia-1,7-
dioxaspiro[5.5]undecanes. The synthetic pathway relies upon the iterative nucleophilic substitution of
1,3-dichloropropan-2-one O-benzyloxime by solketal derivatives. The oxime key-intermediates, sub-
mitted to an acidic deprotection–spiroacetalization process, afforded these original spiroketal com-
pounds in three steps, few purifications, and very good yields.
Received 6 February 2009
Received in revised form 13 March 2009
Accepted 16 March 2009
Available online 26 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Indeed, and to our knowledge, only two syntheses of 1,7-diox-
aspiro[5.5]undecanes incorporating heteroatoms at the C-4 and C-
Spiroketals are found as crucial substructures in a wide variety
of natural compounds of diverse origins.1 Due to their broad
spectrum of biological activities, these moieties have therefore
attracted considerable synthetic interest leading to numerous
strategies, which have been described and reviewed.1a,1d,2
Recently, it has been recognized that for spiroketal-containing
drug compounds, the incorporation of a heteroatom at the C-4
position in one cycle of the spiranic core led to an enhancement of
their activity. Thus, a series of new spiroketal derivatives possessing
a nitrogen atom were evaluated as tachykinin antagonists; these
spiromorpholino compounds showed a high affinity and excellent
CNS penetration.3 By the same way, preparation of aza-4 or thia-5
analogues of the GM3 ganglioside lactone led to useful compounds
that revealed hydrolytically stable immunogens. Lastly, the modi-
fication of the functionality of the tonghaosu skeleton afforded new
substrates showing obvious antifeedant activity.6
10 positions were reported (Scheme 1). The first one rested on the
use of a
D
-fructose unit as chiral source.8a,b The authors employed
a step-by-step nucleophilic substitution by chloroethanol followed
by an oxidative fructose-ring opening to prepare the key in-
termediate 1, from which the 10-thia- or the 10-aza-1,4,7-triox-
aspiro[5.5]undecanes 2 and 3 were elaborated, once again, through
nucleophilic displacements. The targeted spiroketals were thus
isolated as sole isomers, in seven steps from fructose in 19% and 33%
overall yields, respectively. This approach has not been extended to
substituted derivatives, probably because of the choice of the
starting material.
The secondmethod8c consisted of theregioselectiveringopening
of the 2,2-dimethyl-4-[(oxiran-2-ylmethoxy)methyl]-1,3-dioxolane
(obtained from solketal and epichlorohydrin) by the (2,2-dimethyl-
1,3-dioxolan-4-yl)methanamine, leading to the key alcohol 4.
The main approach for the synthesis of spiroketal units involves
(i) elaboration of a key acyclic keto-diol or its equivalent7 via in-
termolecular C–C bond formations followed by (ii) an intra-
molecular acid-catalyzed dehydrative ketalization. In this
approach, the control of the stereochemistry of the anomeric
center is usually based on the relative stabilities of the different
isomers in the spiroketalization process: when maximum
anomeric effects and minimum steric interactions are conjugated,
a thermodynamically most favored isomer is formed as the almost
sole product. However, although this strategy has been largely
reported for the synthesis of numerous spiroketal skeletons, it has
been rarely used for the elaboration of diheteroatom-containing
spiroketals.
OH
O
O
OH
O
O
O
OH
O
O
X
HO
OH
OH
O
2 X = S
1
OH
3 X = NH
O
O
O
O
O
OH
O
NHBn
O
O
O
OH
O
Bn
O
O
N
O
OH
4
N
5
Ph
* Corresponding authors. Tel.: þ33 473407875; fax: þ33 473407717.
E-mail addresses: isabelle.canet@univ-bpclermont.fr (I. Canet), m-eve.sini-
baldi-troin@univ-bpclermont.fr (M.-E. Sinibaldi).
O
Scheme 1.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.044

M. Goubert et al. / Tetrahedron 65 (2009) 4182–4189
4183
BnO
X
OBn
Cl
X
X
OH
OH
N
O
O
O
O
N
O
(a)
O
O
O
O
OH
X
+
O
O
or (b)
(S)-9a
(S)-11a
Y
Y
7a X = O, Y = H;H
7b X = S, Y = H;H
7c X = NBn, Y = H;H
7d X = NH, Y = O
6a X = O
6b X = S
6c X = NH
OBn
Cl
BnO
N
N
N
O
O
O
(c)
(d)
O
O
SH
O
O
S
Cl
Cl
+
+
O
BnO
(R)-9b
(R)-11b
8
N
O
HN
O
+
Cl
O
Cl
XH
O
OH
OBn
Cl
O
8
9a X = O
9b X = S
Boc
N
NH2
HN
OH
10
(S)-9c
(S)-11c
O
Scheme 3. Reagents and conditions: (a) KH (2 equiv), THF, 20 ꢀC, 30%; (b) KOH
(1 equiv), 18-C-6 (0.5 equiv), toluene, 70 ꢀC, 40–60%; (c) NaH (2 equiv), THF, 20 ꢀC, 64%;
(d) two steps, 28% overall yield.10
Scheme 2.
Finally, oxidation and acid-catalyzed deprotection–spiroketaliza-
tion conduced to the 10-aza-1,4,7-trioxaspiro[5.5]undecane
(seven steps, 22% overall yield) but only after modification of the
nitrogen protective group. The use of an oxidation step in this
synthetic scheme disfavored the direct introduction of a sulfur atom
at C-4.
led to the expected chlorides 11a and 11b in 30% and 64% yields,
respectively, accompanied with only 5–10% of the corresponding
undesired bi-adduct 7a or 7b. Unreacted starting materials 9a and
9b could be recycled from flash column chromatography. In the
case of 11a, better yieldsd even if more wavering, from 40% to 60%
yielddwere obtained using a similar procedure as that previously
described for the synthesis of 4-hydroxymethyl-1,3-dioxolane
ethers:11 namely, treatment of solketal by potassium hydroxide in
toluene at 70 ꢀC followed by the slow addition of an excess
(1.5 equiv) of oxime 8 (Scheme 3).
5
For our part, we have recently demonstrated9 that the synthesis
of ‘symmetrical’ new 1,4,7,10-tetraoxaspiro[5.5]undecane 6a and
4,10-dithia-1,7-dioxaspiro[5.5]undecane 6b could be efficiently
achieved through a one-step acid-catalyzed deprotection–spiro-
ketalization from the elaborated key oximes 7a,b; these latter being
readily synthesized by a one-step double substitution of 1,3-
dichloropropan-2-one O-benzyloxime 8 by solketal 9a or its thiol
derivative 9b (Scheme 2). Disappointingly, this synthetic pathway
revealed ineffective to elaborate the biologically interesting 4,10-
aza-1,7-dioxaspiro[5.5]undecane framework 6c and led to the 3-
aza-6,8-dioxabicyclo[3.2.1]octan-2-one 10 in place of the spiranic
system (Scheme 2). With oxime 7c, the presence of amine functions
made critical the final spirocyclization and gave numerous by-
products.10
Nevertheless, and even if spirobismorpholines could not be
obtained, we pursued the study of this strategy to elaborate this
time ‘dissymmetrical’ spiroketals possessing different hetero-
atoms in C-4 and C-10 positions. In this paper, we would like to
present our results toward the successful syntheses of three
families of original compounds owning a 2,8-dihydroxymethyl-
4-thia-1,7,10-trioxaspiro[5.5]undecane, a 2,8-dihydroxymethyl-
10-aza-4-thia-1,7-dioxaspiro[5.5]undecane, and a 2,8-dihydroxy-
methyl-10-aza-1,4,7-trioxaspiro[5.5]undecane skeleton.
Compound 11a appeared as a mixture of Z and E isomers in a 1/1
ratio determined from the 1H NMR spectrum, whereas compound
11b was a mixture of the two isomers in a 3/2 ratio in favor of the Z
one.12
Concerning the synthesis of ‘aza-monooximes’, our exploratory
work in this area10 has shown that nitrogen atoms implied in amine
function (i.e., oxime 7c, Scheme 2) hindered the final spiroketali-
zation carried out under acidic conditions. Furthermore, the ex-
tensive study toward aza-substitution of oxime 8 allowed us to
prepare the monochlorooxime 11c10 issued from 8 and the Boc-
derivative of 9c in a correct yield of 33% (Scheme 3). Consequently,
this kind substrate had also been considered for the synthesis of
new ‘dissymmetrical’ 4-aza-1,7-dioxaspiro[5.5]undecanes.
With the mono-substituted chlorooximes 11a–c in hands, we
engaged them in spiroketal synthesis. Considering our previous
results in the symmetrical series, we first explored the access
to 2,8-dihydroxymethyl-4-thia-1,7,10-trioxaspiro[5.5]undecane 13.
This was realized according to two parallel pathways using both 11a
and 11b as key building blocks (Scheme 4). Thus, conversion of
11a,b to the required oxime 12 was achieved using KH in tetrahy-
drofuran at 20 ꢀC, and gave, after purification, oxime 12 in 86% yield
2. Results and discussion
The crucial point for the elaboration of these spiroketals was the
efficient control of the monosubstitution of 1,3-dichloropropan-2-
one O-benzyloxime 8 by solketal derivatives 9.
BnO
O
BnO
X
In the conditions used for oxa- and thia-series 6a,bdalkali hy-
drides treatmentdmono-substituted oximes were detected during
the TLC monitoring as the first product of the reaction but usually
very fast accompanied with the disubstituted compounds.9 We
therefore undertook a study of the best operating conditions in
terms of base, concentration ratio, solvent, and temperature to
obtain oximes 11a,b from 8 and 9a,b and avoid the more favored
double substitution. In all cases, reactions were TLC-monitored and
quenched at the appearance of disubstituted oximes 7. From alkali
hydrides, best results were obtained by carrying out the reaction in
tetrahydrofuran (1 mmol of 8/3 mL of solvent) at 20 ꢀC, with an
addition of 1 equiv of alcohol 9a or freshly prepared thiol 9b on
a mixture of oxime 8 and 2 equiv of alkali hydride. These conditions
O
N
N
O
O
(a)
O
O
O
Cl
S
11a X = O
11b X = S
12
OH
cycle B
O
S
OH
OH
8
9
(b)
O
O
O
6
O
2
OH
cycle A
11
O
S
3
5
13
13a
Scheme 4. Reagents and conditions: (a) KH, THF, 7b or 7a, 20 ꢀC (86% from 11a, 54%
from 11b); (b) AmberlystÒ 15, (CH2O)n, acetone/H2O (10:1),
, 48 h, 79%.
D

4184
M. Goubert et al. / Tetrahedron 65 (2009) 4182–4189
Table 1
NMR data for ‘symmetrical’ and ‘dissymmetrical’ spirobisdioxanes 6a,9 spirobisoxathianes 6b,9 and spirodioxane–oxathiane 13a (recorded at 400 MHz, measured in CD3OD)
OH
OH
OH
8
8
9
8
9
9
O
O
O
S
6
O
O
O
6
2
2
6
2
OH
OH
OH
11
11
11
O
O
O
S
S
3
5
3
5
3
5
(6S)-6b
(6S)-6a
13a
dH, J in Hz
4.03, dtd, 11.0, 5.0, 3.0
3.37, t, 11.0; 3.80, dd, 11.0, 3.0
3.24, d, 11.5; 3.55, d, 11.5
dC
dH, J in Hz
4.06, dddd, 11.0, 6.0, 5.0, 2.0
2.37, dt, 13.0, 2.0; 2.57, dd, 13.0, 11.0
2.31, dd, 13.5, 1.5; 2.68, d, 13.5
dC
dH, J in Hz
3.97, dt, 11.5, 5.0
2.37, d, 11.5; 2.54, t, 11.5
dC
2
3
5
6
8
9
70.2
68.8
69.6
93.0
70.2
68.8
69.6
62.9
62.9
72.0
27.5
31.0
92.3
70.4
68.7
72.9
65.9
62.8
72.4
27.8
35.2
91.9
72.4
27.8
35.2
65.9
65.9
2.40, d, 13.5; 2.76, d, 13.5
4.03, dtd, 11.0, 5.0, 3.0
3.37, t, 11.0; 3.80, dd, 11.0, 3.0
3.24, d, 11.5; 3.55, d, 11.5
3.51, dd, 12.0, 5.0; 3.55, dd, 12.0, 5.0
3.51, dd, 12.0, 5.0; 3.55, dd, 12.0, 5.0
4.02, dtd, 11.0, 5.0, 2.5
3.41, t, 11.0; 3.84, dd, 11.5, 2.5
3.34, d, 11.5; 3.62, d, 11.5
3.49, dd, 11.5, 5.0; 3.56, dd, 11.5, 6.0
3.57, dd, 12.0, 5.0; 3.60, dd, 12.0, 5.0
3.97, dt, 11.5, 5.0
2.37, d, 11.5; 2.54, t, 11.5
2.40, d, 13.5; 2.76, d, 13.5
3.48, dd, 11.5, 5.0; 3.56, dd, 11.5, 5.0
3.48, dd, 11.5, 5.0; 3.56, dd, 11.5, 5.0
11
CH2OH
CH2OH
(from 11a and 7b) and 54% yield (from 11b and 7a), respectively.
Compound 12 appeared as a mixture of Z and E isomers (3/2 ratio
determined on 1H NMR spectrum) easily identified by the chemical
At this stage of the work, the examination of the more doubtful
synthesis of aza-spiroketals remained unsolved. We began our in-
vestigation starting from the monochlorooxime 11c, from which
oxa- and thia-compounds could be envisioned. Substitution of 11c
by the thio-solketal 9b was efficiently accomplished using KH in
THF and furnished 14 in 81% yield (Scheme 5). The assignment of all
signals in the 1H and 13C NMR spectra was in this case complicated
by the existence of rotamers due to the carbamate group, together
with the presence of the two Z and E isomers.
Treatment of 14 in our classical acidic medium afforded after 4 h
at reflux the tetraol 15 as the sole product of the reaction. Pursuing
the heating, we observed the disappearance of 14 (TLC monitoring)
accompanied by the formation of numerous side-products lacking
the Boc group in their skeleton (checked by 1H NMR spectrum). At
ambient temperature and even after 4 days, the oxime function of
15 remained unchanged.
At this stage, the reactivity of the Boc group under our acid-
heating conditions, together with the trouble to obtain in good
yields aza-protected chlorooximes 11,10 prompted us to investigate
the synthesis of spiromorpholines from the monochlorooximes
11a,b, testing their reactivity toward amine 9c (Scheme 6).
Oximes 11a,b were heated in boiling methanol during 8 h in the
presence of 3 equiv of amine 9c. Under these conditions, only
monosubstitution was observed, leading to oxime 16 in 61% yield as
a mixture of E/Z isomers (5/3 ratio determined on the 1H NMR
spectrum) and oxime 17 in 67% yield as a 1/3 mixture of E/Z iso-
mers. Compounds 16 and 17 were then treated by freshly distilled
benzoylchloride in presence of NEt3 and DMAP in dichloromethane
to furnish the attempted amides 18 and 19 in 90% and 95% yields,
respectively. The final deprotection–spiroketalization step was
then carried out as usual, through the addition of
shift of the methylene group in the
a position of the benzyloxime
function.12 Lastly, oxime 12 was heated under reflux for 2 days in an
acetone/water solution in the presence of AmberlystÒ 15. In this
case and as in 4,10-dithia-1,7-dioxaspiro[5.5]undecane series, the
addition of 10 equiv of paraformaldehyde was necessary to achieve
efficiently the ketone deprotection and promote the spiroketali-
zation (Scheme 4). Spiroketal 13 was thus obtained in 79% yield as
a mixture of two inseparable isomers 13a/13b in a 19/1 ratio as
determined on the quantitative 13C NMR spectrum.
This result was in agreement with those observed in the
symmetrical series.9 Indeed, in our spirocyclisation acid-cata-
lyzed conditions, dioxa-spiroketal 6a (Scheme 1) was isolated as
a sole isomer, possessing a C2 symmetry with a double anomeric
effect, having two cycles in a chair conformation and the
hydroxymethyl groups in an equatorial position. Conversely, we
observed for dithia-spiroketal 6b a loss of stereoselectivity due to
the presence of the less electron-withdrawing sulfur atom. Thus,
starting from enantiopure solketal 9a, we isolated a mixture of
two C-6 epimers.
The major isomer 13a could be isolated and characterized after
a classical TBDPS-protection/deprotection sequence. Its 13C NMR
spectrum comprised nine peaks with a spiranic carbon detected at
92.3 ppm (see Table 1). In the 1H NMR spectrum, H-2 (
d
¼4.06 ppm)
and H-8 (
d
¼4.02 ppm) exhibited vicinal coupling constants 3J with
H-3 and H-9 of 11.0 and 2.0 Hz, 11.0 and 2.5 Hz, respectively. Thus,
13a adopted a chair conformation for its two cycles with H-2 and H-
8 in an axial position. Moreover, structural data for 13a fitted with
those of (6S)-2,8-dihydroxymethyl-4,10-dithia-1,7-dioxaspiro[5.5]-
undecane 6b for its A cycle and (6S)-2,8-dihydroxymethyl-1,4,7,10-
tetraoxaspiro[5.5]undecane 6a for its B cycle (see Table 1): for
instance, C-3 was found at 27.5 ppm and C-9 at 68.7 ppm. The
values of the chemical shifts of C-2 and C-8 in 13a, are also similar
to those observed in the symmetrical series. Because of the oxa-
thiane–dioxane sequence, the chemical shifts of C-5 and C-11 were
slightly modified and were observed, now, at 31.0 ppm and
72.9 ppm, respectively. Their corresponding hydrogens were
shielded for H-5 and deshielded for H-11.
OBn
N
O
O
(a)
Boc
N
+
O
O
SH
Cl
(R)-9b
(S)-11c
BnO
S
(b)
N
O
O
Boc
N
O
O
From all these data, and as the configuration of C-2 and C-8 was
governed by that of starting materials 9a and 9b, isomer 13a
adopted necessarily a structure stabilized by a double anomeric
effect and equatorial positions for its substituents, with a (2R,6S,8R)
configuration. Starting from 1,3-dichloropropan-2-one, this spi-
ranic oxathiane–dioxane system was obtained in four steps, and
28–34% range overall yield depending of the order of introduction
of oxa- and thia-synthons 9a,b.
(R, S)-14
BnO
OH
N
OH
(c)
Boc
numerous products
HO
S
N
OH
(R, S)-15
Scheme 5. Reagents and conditions: (a) KH, THF, 81%; (b) AmberlystÒ 15, acetone/H2O
(10:1), , 4 h, 33%; (c)
D
D.

M. Goubert et al. / Tetrahedron 65 (2009) 4182–4189
4185
BnO
X
systems based on the association of dioxane–oxathiane, dioxane–
morpholine, and oxathiane–morpholine cores. Finally, this work
completed and generalized our previous study in the ‘symmetrical’
series, namely spirobisdioxane and spirobisoxathiane systems.
BnO
X
N
N
O
O
O
R
N
(a)
O
O
O
Cl
(S)-11a X = O
(R)-11b X = S
(S, S)-16 X = O, R = H
(R, S)-17 X = S, R = H
(b)
4. Experimental section
(S, S)-18 X = O, R = COPh
(R, S)-19 X = S, R = COPh
4.1. General experimental methods
OH
2
X
OH
OH
8
9
Infrared spectra were recorded on a Perkin–Elmer 881 in-
strument. 1H NMR (400 MHz) and 13C NMR (100 MHz) were
(c)
O
O
O
6
HN
2
OH
recorded with a BRUKER AC 400 spectrometer. Chemical shifts (
d
11
RN
O
X
8
values) are expressed in parts per million (ppm), coupling con-
stants (J) are expressed in hertz, and multiplicities are mentioned
as follows: s (singlet), d (doublet), t (triplet), q (quartet), Q
(quintet), m (multiplet). NMR spectra were recorded in CDCl3,
CD3OD or DMSO-d6, using the solvent signals as reference. Mass
spectra were recorded with a Hewlett Packard 5989B instrument
and high resolution mass spectra (HRMS) were performed with
a Q-TOF micromass. Chromatography was performed using silica
gel 60 (230–400 mesh) and thin layer chromatography (TLC) was
performed on silica gel 60PF254 plates (20ꢁ20 cm). Compounds
3
5
(R, S)-20 X = O, R = COPh
(R, S)-21 X = S, R = COPh
(2R,6S,8S)-22a X = O
(2R,6S,8S)-23a X = S
(d)
(R, S)-22 X = O, R = H
(R, S)-23 X = S, R = H
Scheme 6. Reagents and conditions: (a) MeOH,
D
, 9c, 8 h, 61% from 11a, 67% from 11b;
(b) PhCOCl, NEt3, DMAP, CH2Cl2, 0 ꢀC, 90% from 16, 95% from 17; (c) AmberlystÒ 15,
(CH2O)n, acetone/H2O (10:1),
quantitative.
D, 61% from 18, 65% from 19; (d) LiAlH4, THF, nearly
paraformaldehyde to regenerate the keto-function. The targeted
spiromorpholinoketals 20 and 21 were obtained in 61% and 65%
yields, respectively. No other derivatives were detected in the crude
reaction mixture.
were identified using UV fluorescence (
l
¼254 nm) and/or stain-
ing with a 5% phosphomolybdic acid solution in ethanol follow-
ing by heating. Commercially reagents (Aldrich, Acros, Lancaster)
were used as received without additional purification. Tetrahy-
drofuran (THF) was distilled from potassium/benzophenone
while dichloromethane (CH2Cl2) was dried over calcium hydride
prior to use.
Finally, compounds 20 and 21 were obtained from 1,3-dichloro-
propan-2-one in five steps in 17% and 26% overall yields, re-
spectively. Full structural characterization of 20 and 21 could not be
achieved at ambient temperature, as 1H spectra were typical of
coalescence phenomena and 13C NMR spectra revealed mixtures of
4.2. Synthesis
13
spiranic compounds. From C NMR spectrum recorded at 70 ꢀC,
each compound, 20 and 21, appeared clearly as a mixture of two
inseparable isomers. The attribution of 13C chemical shifts of the
major and minor ones could be realized at this stage and, in the case
of 20, spectroscopic data were correlated with those already pub-
lished in the literature.8c
To overcome the problem of coalescence and determine without
ambiguity the structure of each major isomer of 20 and 21, we re-
duced their amide function. The full cleavage of the amido group
was efficiently accomplished using a large excess of LiAlH4 in THF,13
furnishing the spiromorpholines 22 and 23 as, once again, a mix-
ture of inseparable isomers in a 4/1 ratio for 22 and 9/1 ratio for 23.
Finally, major compounds could be isolated and characterized
through their derivatization as silylether derivatives (TBDPS-pro-
tection/Bu4NF deprotection).
Spiranic carbons of major isomers 22a and 23a were detected at
91.6 ppm (22a) and 90.9 ppm (23a). These values were once again
in agreement with those observed for (6S)-spiro[5.5]undecane se-
ries. The C-3 and C-9 appeared at 67.2 ppm (22a)–66.2 ppm (23a)
and 46.1 ppm (22a and 23a), respectively. Major isomers adopted
a chair conformation for the two cycles as evidenced by (i) H-9ax
and H-3ax that were detected as triplets with 2J¼3J¼12.0 Hz, and (ii)
H-9eq and H-3eq resonating either as broad doublets (2J¼12.0 Hz) or
dedoubled doublet (2J¼12.0 Hz, 3J¼2.5 Hz). From all spectroscopic
data, we assumed that majors isomers were the (2R,6S,8S)-22a and
the (2R,6S,8S)-23a.
4.2.1. (2E)- and (2Z)-1-Chloro-3-{[(4S)-2,2-dimethyl-1,3-dioxolan-
4-yl]methoxy}propanone O-benzyloxime (11a)
Method A. To a solution of oxime 8 (2.11 g, 9.1 mmol) and KH
(2.44 g, 18.2 mmol) in THF (3 mL) was added (S)-9a (1.21 g,
9.1 mmol) and the resulting mixture was stirred until disubstituted
compound was detected on TLC. The reaction was stopped by ad-
dition of a saturated solution of NH4Cl. After extraction with ethyl
acetate, the crude solution was concentrated in vacuo and purified
by flash chromatography using (19:1/7:3) cyclohexane/ethyl ac-
etate as eluent to give pure 11a as a colorless liquid (0.90 g, 30%).
Method B. To a solution of (S)-9a (0.330 g, 2.5 mmol) in toluene
(10 mL) were added KOH (0.165 g, 2.5 mmol) and 18-crown-6
(0.330 g, 1.25 mmol). The resulting mixture was heated at 70 ꢀC for
1 h before addition, at 70 ꢀC and over a period of 1 h, of a solution of
oxime 8 (0.580 g, 2.5 mmol) in toluene (5 mL). At the appearance of
disubstituted compound, reaction is stopped by addition of water.
The resulting mixture is concentrated in vacuo and layers were
separated. After extraction of the aqueous one by ethyl acetate, the
combined organic layers are dried and concentrated. A final puri-
fication by flash chromatography using (4:1/1:1) cyclohexane/
ethyl acetate as eluent furnished pure 11a in a 40–60% yield.
Compound 11a: IR nmax (neat, cmꢂ1) 1600 (C]N), 1250–1040 (C–
O); 1H NMR (CDCl3)
d/ppm 7.40–7.30 (m, 10H, H–Ar, E and Z), 5.17 (s,
2H, CH2Ph, Z), 5.11 (s, 2H, CH2Ph, E), 4.48 (d, J¼15.0 Hz, 1H, O–CH2–
C], E), 4.44 (d, J¼15.0 Hz, 1H, O–CH2–C], E), 4.27 (Q, J¼6.0 Hz, 1H,
CH–O, E), 4.26 (m, 1H, CH–O, Z), 4.23 (d, J¼11.5 Hz, 1H, CH2Cl, E),
4.21 (d, J¼11.5 Hz, 1H, CH2Cl, E), 4.21 (m, 2H, O–CH2–C], Z), 4.20
(m, 1H, CH2Cl, Z), 4.19 (d, J¼11.5 Hz, 1H, CH2Cl, Z), 4.05 (t, J¼7.0 Hz,
1H, CH2–O, E), 4.03 (t, J¼6.5 Hz, 1H, CH2–O, Z), 3.77 (dd, J¼8.0,
6.5 Hz, 1H, CH2–O, E), 3.70 (dd, J¼8.0, 6.5 Hz, 1H, CH2–O, Z), 3.55
(dd, J¼10.0, 5.5 Hz, 1H, CHO–CH2O, E), 3.50 (dd, J¼10.0, 5.0 Hz, 1H,
CHO–CH2O, E), 3.49 (dd, J¼10.0, 5.5 Hz, 1H, CHO–CH2O, Z), 3.44 (dd,
J¼10.0, 5.0 Hz, 1H, CHO–CH2O, Z), 1.42 (s, 6H, Me, E and Z), 1.36
3. Conclusion
To summarize, we have developed an original and efficient
pathway to new 1,7-dioxaspiro[5.5]undecanes incorporating in
their skeleton two different heteroatoms in positions 4 and 10.
Starting from commercially available (S)-solketal and 1,3-dichloro-
propan-2-one, we have shown that, in few steps and with good
overall yields, we were able to elaborate in a modular way, spiranic
(s, 6H, Me, E and Z); 13C NMR (CDCl3)
d/ppm 154.9 (C]N, E), 152.4

4186
M. Goubert et al. / Tetrahedron 65 (2009) 4182–4189
(C]N, Z), 137.1 (C–Ar, Z), 137.0 (C–Ar, E), 128.4 (C–Ar, Z and E), 128.1
(C–Ar, Z), 128.0 (C–Ar, E), 127.9 (C–Ar, Z and E), 109.5 (C–(CH3)2, E),
109.4 (C–(CH3)2, Z), 76.7 (CH2Ph, E), 76.5 (CH2Ph, Z), 74.4 (CH–O, E),
74.3 (CH–O, Z), 72.3 (CHO–CH2O, E), 71.3 (CHO–CH2O, Z), 69.3 (O–
CH2–C], Z), 66.5 (CH2–O, E and Z), 63.9 (O–CH2–C], E), 41.1 (CH2Cl,
E), 32.7 (CH2Cl, Z), 26.7 (CH3, E), 26.6 (CH3, Z), 25.3 (CH3, Z and E).
Anal. Calcd for C16H22ClNO4: C, 58.62; H, 6.76; Cl, 10.82; N, 4.27.
Found C, 58.57; H, 6.79; Cl, 10.72; N, 4.25.
J¼8.5 and 6.5 Hz, 1H, O–CH2–CHO, E), 3.68 (dd, J¼8.5 and 6.5 Hz,
1H, O–CH2–CHO, Z), 3.59 (dd, J¼8.5 and 6.5 Hz, 2H, O–CH2–CHO, E
and Z), 3.53 (dd, J¼10.0 and 5.5 Hz, 1H, CHO–CH2–O–CH2–, E), 3.48
(d, J¼13.5 Hz, 1H, S–CH2–C]N, Z), 3.48 (dd, J¼10.0 and 5.5 Hz, 1H,
CH2–OCH2C]N, E), 3.47 (dd, J¼10.0 and 6.0 Hz,1H, CH2–OCH2C]N,
Z), 3.46 (d, J¼13.5 Hz, 1H, S–CH2–C]N, Z), 3.42 (dd, J¼10.0 and
5.0 Hz, 1H, CH2–OCH2C]N, Z), 3.34 (d, J¼13.5 Hz, 1H, S–CH2–C]N,
E), 3.30 (d, J¼13.5 Hz, 1H, S–CH2–C]N, E), 2.68 (dd, J¼13.5 and
6.0 Hz, 1H, S–CH2–CHO, Z), 2.62 (dd, J¼13.5 and 6.0 Hz, 1H, S–CH2–
CHO, E), 2.55 (dd, J¼13.5 and 6.5 Hz, 1H, S–CH2–CHO, Z), 2.49 (dd,
J¼13.5 and 6.5 Hz, 1H, S–CH2–CHO, E), 1.41 (s, 9H, Me), 1.40 (s, 3H,
Me), 1.35 (s, 6H, Me), 1.34 (s, 3H, Me), 1.32 (s, 3H, Me); 13C NMR
4.2.2. (2E)- and (2Z)-1-Chloro-3-({[(4R)-2,2-dimethyl-1,3-
dioxolan-4-yl]methyl}thio)propanone O-benzyloxime (11b)
To a solution of oxime 8 (0.254 g, 1.1 mmol) and NaH (0.090 g,
2.2 mmol) in THF (3 mL) was added (R)-9b (0.200 g, 1.1 mmol) and
the resulting mixture was stirred until disubstituted compound
was detected on TLC. The reaction was stopped by addition of
a saturated solution of NH4Cl (2 mL). After extraction with ethyl
acetate, the crude solution was concentrated in vacuo and purified
by flash chromatography using (19:1/4:1) cyclohexane/ethyl ac-
etate as eluent to give pure 11b as a colorless oil (0.255 g, 64%). IR
(CDCl3) d/ppm 155.9 (C]N, E), 154.6 (C]N, Z), 137.6 (C–Ar, E), 137.1
(C–Ar, Z), 128.4 (C–Ar, Z and E), 128.3 (C–Ar, Z), 128.2 (C–Ar, Z), 128.0
(C–Ar, E), 127.9 (C–Ar, E), 109.5 (C–(CH3)2, Z),109.4 (C–(CH3)2, E),
76.2 (CH2Ph Z), 76.1 (CH2Ph, E), 74.9 (CH–O, E), 74.8 (CH–O, Z), 74.5
(CH–O, Z), 74.4 (CH–O, E), 72.2 (CHO–CH2O, E), 71.2 (CHO–CH2O, Z),
69.4 (O–CH2–C]N, Z), 68.8 (O–CH2–CHO, E), 68.6 (O–CH2–CHO, Z),
66.5 (O–CH2–CHO, Z and E), 64.5 (O–CH2–C]N, E), 35.2 (S–CH2–
CHO, Z), 34.1 (S–CH2–CHO, E), 31.2 (N]C–CH2–S, E), 26.9 (CH3, Z
and E), 26.7 (CH3, Z and E), 25.6 (CH3, Z and E), 25.4 (CH3, E), 25.3
(CH3, Z), 24.5 (N]C–CH2–S, Z). Anal. Calcd for C22H33NO6S: C, 60.11;
H, 7.57; N, 3.1. Found: C, 60.21; H, 7.51; N, 3.29.
nmax (neat, cmꢂ1) 1618 (C]N),1250–1040 (C–O); 1H NMR (CDCl3)
d/
ppm 7.38–7.30 (m, 10H, H–Ar, E and Z), 5.14 (s, 2H, CH2Ph, Z), 5.11 (s,
2H, CH2Ph, E), 4.37 (s, 2H, CH2Cl, Z), 4.29 (d, J¼11.5 Hz, 1H, CH2Cl, E),
4.26 (d, J¼11.5 Hz, 1H, CH2Cl, E), 4.19 (Q, J¼6.0 Hz, 1H, CH–O, E), 4.17
(Q, J¼6.0 Hz, 1H, CH–O, Z), 3.99 (dd, J¼8.5, 6.0 Hz, 1H, CH2–O, Z),
3.95 (dd, J¼8.5, 6.0 Hz,1H, CH2–O, E), 3.60 (d, J¼13.5 Hz,1H, S–CH2–
C], E), 3.55 (d, J¼13.5 Hz, 1H, S–CH2–C], E), 3.59 (dd, J¼8.5,
J¼6.0 Hz, 1H, CH2–O, E), 3.57 (dd, J¼8.5, 6.0 Hz, 1H, CH2–O, Z), 3.40
(d, J¼14.0 Hz, 1H, S–CH2–C], Z), 3.37 (d, J¼14.0 Hz, 1H, S–CH2–C],
Z), 2.63 (dd, J¼13.5, 6.0 Hz,1H, CH–CH2S, E), 2.56 (dd, J¼13.5, 6.5 Hz,
1H, CH–CH2S, Z), 2.52 (dd, J¼13.5, 6.5 Hz, 1H, CH–CH2S, E), 2.45 (dd,
J¼13.5, 6.0 Hz,1H, CH–CH2S, Z),1.41 (s, 3H, Me, Z),1.40 (s, 3H, Me, E),
4.2.4. 2,8-Dihydroxymethyl-4-thia-1,7,10-trioxaspiro-
[5.5]undecane (13)
A solution of (S,R)-12 (0.500 g, 1.14 mmol) in 10 mL of a mixture
(10:1, v/v) of acetone/water, AmberlystÒ15 (0.250 g), and para-
formaldehyde (0.034 g, 1.14 mmol) was heated under reflux for
48 h. After cooling, the mixture was filtered on a CeliteÒ pad. The
residue was purified by column chromatography on silica gel using
gradient (1:0/49:1) ethyl acetate/methanol as eluent, which gave
1.34 (s, 3H, Me, Z), 1.32 (s, 3H, Me, E); 13C NMR (CDCl3)
d/ppm 153.4
(C]N, E), 152.0 (C]N, Z), 137.3 (C–Ar, Z), 136.7 (C–Ar, E), 128.4 (C–
Ar, Z and E), 128.1 (C–Ar, E), 128.0 (C–Ar, Z), 127.9 (C–Ar, Z and E),
109.5 (C–(CH3)2, Z and E), 76.6 (CH2Ph, E), 76.4 (CH2Ph, Z), 74.9 (CH–
O, Z), 74.8 (CH–O, E), 68.6 (CH2–O, Z), 68.5 (CH2–O, E), 42.5 (CH2Cl,
E), 35.1 (CHO–CH2S, E), 34.0 (CHO–CH2S, Z), 33.7 (CH2Cl, Z), 32.9 (S–
CH2–C], Z), 26.9 (CH3, Z and E), 25.5 (CH3, Z), 25.4 (CH3, E), 24.4 (S–
CH2–C], E); HRMS (ESI): calculated for C16H22ClNO3Na [MþNa]þ
366.0907, found 366.0892.
a 19:1 mixture of isomers 13 (0.185 g, 79%). IR nmax (neat, cmꢂ1
)
3400 (O–H); 13C NMR (CD3OD)
d/ppm 107.0–92.3 (C-6), 75.6–72.9
(C-11), 75.9–72.0 (C-2), 72.1–70.4 (C-8), 74.4–68.7 (C-9), 65.9 (C-
12), 64.3–62.8 (C-13), 32.2–31.0 (C-5), 29.8–27.5 (C-3).
Major compound: (2R,6S,8R)-13a: 1H NMR (CDCl3)
d/ppm 4.06
(dddd, J2ax3ax¼11.0 Hz, J2ax12a¼6.0 Hz, J2ax12b¼5.0 Hz, J2ax3eq¼2.0 Hz,
1H, H-2ax), 4.02 (dtd, J8ax9ax¼11.0 Hz, J8ax13¼5.0 Hz, J8ax9eq¼2.5 Hz, 1H,
H-8ax), 3.84 (dd, J9eq9ax¼11.5 Hz, J9eq8ax¼2.5 Hz, 1H, H-9eq), 3.62 (d,
J11eq11ax¼11.5 Hz, 1H, H-11eq), 3.60 (dd, J13a13b¼12.0 Hz, J13a8¼5.0 Hz,
1H, H-13a), 3.57 (dd, J13b13a¼12.0 Hz, J13b8¼6.0 Hz,1H, H-13b), 3.56 (dd,
J12a12b¼11.5 Hz, J12a2¼6.0 Hz, 1H, H-12a), 3.49 (dd, J12b12a¼11.5 Hz,
J12b2¼5.0 Hz,1H, H-12b), 3.41(t, J9ax9eq¼J9ax8ax¼11.0 Hz,1H, H-9ax), 3.34
(d, J11ax11eq¼11.5 Hz, 1H, H-11ax), 2.68 (d, J5ax5eq¼13.5 Hz, 1H, H-5ax),
2.57 (dd, J3ax3eq¼13.0 Hz, J3ax2ax¼11.0 Hz, 1H, H-3ax), 2.37 (dt,
J3eq3ax¼13.0 Hz, J3eq2ax¼J3eq5eq¼2.0 Hz, 1H, H-3eq), 2.31 (dd,
4.2.3. (2Z)- and (2E)-1-{[(4S)-2,2-Dimethyl-1,3-dioxolan-4-
yl]methoxy}-3-({[(4R)-2,2-dimethyl-1,3-dioxolan-4-
yl]methyl}thio)propanone O-benzyloxime (12)
To a pre-washed KH (1.35 g, 10.4 mmol) solution in THF (10 mL)
was added, under argon, thiol (R)-9b (0.850 mg, 5.7 mmol) in THF
(10 mL) followed after 15 min by a solution of 11a (1.70 g,
5.2 mmol) in THF (20 mL). After the completion of the reaction
(disappearance of 11a), water was added and the resulting solution
was extracted with dichloromethane. The organic layer was con-
centrated in vacuo and purified by flash chromatography using
(9:1) cyclohexane/ethyl acetate to give 12 (2.0 g, 86%) as a colorless
oil of a mixture of Z and E isomers.
J5eq5ax¼13.5 Hz, J5eq3eq¼1.5 Hz, 1H, H-5eq); 13C NMR(CDCl3)
d/ppm 92.3
(C-6), 72.9 (C-11), 72.0 (C-2), 70.4 (C-8), 68.7 (C-9), 65.9 (C-12), 62.8 (C-
13), 31.0 (C-5), 27.5 (C-3); HRMS (ESI): calculated for C9H16O5NaS
[MþNa]þ 259.0616, found 259.0620.
4.2.5. tert-Butyl {[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}(3-
{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}thio)-{2-
[(benzyloxy)imino]propyl}carbamate (14)
The same protocol applied to 11b (0.200 g, 0.58 mmol) and (S)-
solketal 9a (0.092 mg, 0.70 mmol) using KH (0.155 g, 1.16 mmol)
gave, after purification, 12 (0.138 g, 54%).
To a suspension of KH (0.125 g, 0.92 mmol) in mineral oil, was
added, under argon, a solution of (S)-11c (0.200 g, 0.46 mmol) in
THF (3 mL), followed, after 30 min, by a solution of thiol (R)-9b
(0.082 mg, 0.55 mmol) in THF (1 mL). The reaction was monitored
by TLC. After adjunction of water, the mixture was extracted with
dichloromethane (3ꢁ10 mL) and the organic extracts combined
before being dried (MgSO4), filtered, and then the solvent was re-
moved using a rotary evaporator. The residue was purified by flash
chromatography on silica gel using (1:0/4:1) cyclohexane/ethyl
acetate as an eluent to give 14 as a mixture of two rotamers
(0.200 g, 81%, colorless oil). IR nmax (neat, cmꢂ1) 1697 (C]O), 1250–
Compound 12: IR nmax (neat, cmꢂ1) 1600 (C]N), 1250–1050 (C–
O); 1H NMR (CDCl3)
d/ppm 7.40–7.25 (m, 10H, H–Ar, E and Z), 5.09
(s, 2H, CH2Ph, Z), 5.06 (s, 2H, CH2Ph, E), 4.46 (d, J¼15.0 Hz, 1H, O–
CH2–C]N, E), 4.43 (d, J¼15.0 Hz, 1H, O–CH2–C]N, E), 4.25 (Q,
J¼6.0 Hz, 1H, CH–O, E), 4.24 (Q, J¼6.0 Hz, 1H, CH–O, Z), 4.20 (Q,
J¼6.5 Hz, 1H, CH–O, Z), 4.20 (d, J¼12.0 Hz, 1H, O–CH2–C]N, Z), 4.18
(Q, J¼6.0 Hz, 1H, CH–O, E), 4.17 (d, J¼12.0 Hz, 1H, O–CH2–C]N, Z),
4.03 (dd, J¼8.5 and 6.5 Hz, 1H, O–CH2–CHO, E), 4.02 (dd, J¼8.5 and
6.5 Hz, 1H, O–CH2–CHO, Z), 4.00 (dd, J¼8.5 and 6.0 Hz, 1H, O–CH2–
CHO, E), 3.95 (dd, J¼8.5 and 6.0 Hz, 1H, O–CH2–CHO, Z), 3.74 (dd,

M. Goubert et al. / Tetrahedron 65 (2009) 4182–4189
4187
1060 (C–O); 1H NMR (CDCl3)
d
/ppm 7.36–7.27 (m, 10H, H–Ar), 5.08
NHCH2CH–CH2O, E and Z), 3.58 (d, 2J¼15.0 Hz, 1H, CH2NH, E), 3.57
(d, 2J¼15.0 Hz, 1H, CH2NH, E), 3.53–3.40 (m, 6H, CH2–O–CH2C]N, E
and Z, ]C–CH2NH, Z), 2.72–2.62 (m, 4H, NH–CH2, Z and E), 1.91 (br
s, 2H, NH, E and Z), 1.40 and1.38 (s, 12H, Me, Z and E), 1.34 and 1.33
(s, 2H, CH2Ph), 5.06 (s, 2H, CH2Ph), 4.41–4.28 (m, 4H, CH2S), 4.21 (m,
2H, CHO–CH2N), 4.17 (Q, J¼6.5 Hz, 2H, SCH2–CHO), 3.98 (dd,
2J¼8.5 Hz, 3J¼6.0 Hz, 2H, CH2O), 4.02–3.95 (m, 2H, CH2O), 3.59 (dd,
2J¼8.5 Hz, 3J¼6.5 Hz, 2H, CH2O), 3.56 (dd, 2J¼8.5 Hz, 3J¼6.5 Hz, 2H,
CH2O), 3.45–3.25 (m, 4H, O–CH–CH2N), 3.22 (s, 2H, NCH2), 3.18 (s,
2H, NCH2), 2.58 (dd, 2J¼13.5 Hz, 3J¼6.0 Hz, 2H, SCH2), 2.46 (dd,
2J¼13.5 Hz, 3J¼6.5 Hz, 2H, SCH2), 1.44 (s, 9H, t-Bu), 1.42 (s, 6H, Me),
1.41 (s, 6H, Me), 1.39 (s, 9H, t-Bu), 1.34 (s, 6H, Me), 1.33 (s, 6H, Me);
(s, 12H, Me, Z and E); 13C NMR (CDCl3)
d/ppm 156.9 (C]N, Z), 156.6
(C]N, E), 137.6 (C–Ar, Z), 137.5 (C–Ar, E), 128.3 (C–Ar, Z and E), 128.0
(C–Ar, Z and E), 127.8 (C–Ar, Z and E), 109.4 (C–(CH3)2, Z and E), 109.0
(C–(CH3)2, Z and E), 76.0 (CH2Ph, Z and E), 75.3 (NHCH2CHO, Z), 75.1
(NHCH2CHO, E), 74.4 (CHOCH2O, E), 74.3 (CHOCH2O, Z), 72.3
(CHOCH2O, Z), 71.2 (CHOCH2O, E), 70.6 (O–CH2–C]N, E), 67.5
(NHCH2CHOCH2, Z), 67.4 (NHCH2CHOCH2, E), 66.6 (OHCH2CHOCH2,
E), 66.5 (OHCH2CHOCH2, Z), 66.3 (OCH2C]N, Z), 52.2 (NH–CH2–
CHO, E), 51.5 (NH–CH2–CHO, Z), 49.1 (N]C–CH2–NH, Z), 44.9
(N]C–CH2–NH, E), 26.9 (CH3, Z), 26.8 (CH3, E), 26.8 (CH3, Z and E),
25.4 (CH3, Z and E), 25.3 (CH3, Z and E); HRMS (ESI): calculated for
C22H35N2O6 [MþH]þ 423.2495, found 423.2497.
13C NMR (CDCl3)
d/ppm 155.5 (CO2t-Bu), 155.4 (CO2t-Bu), 155.0
(C]N), 137.7 (C–Ar), 128.3 (C–Ar), 128.1 (C–Ar), 127.8 (C–Ar), 109.5
(C–(CH3)2), 109.3 (C–(CH3)2), 80.7 (C–(CH3)3), 80.5 (C–(CH3)3), 76.2
(CH2Ph), 76.1 (CH2Ph), 75.1 (CHO), 74.9 (CHO), 68.7 (CH2O), 67.2
(CH2O), 67.1 (CH2O), 51.0 (CH2N), 50.7 (CH2N), 44.1 (NCH2), 44.0
(NCH2), 34.0 (SCH2), 33.8 (SCH2), 32.6 (CH2S), 32.0 (CH2S), 28.3 (t-
Bu), 26.9 (CH3), 26.8 (CH3), 25.6 (CH3), 25.5 (CH3); HRMS (ESI):
calculated for C27H42N2O7NaS [MþNa]þ 561.2610, found 561.2603.
4.2.8. (2E)- and (2Z)-1-({[(4S)-2,2-Dimethyl-1,3-dioxolan-4-
yl]methyl}amino)-3-({[(4R)-2,2-dimethyl-1,3-dioxolan-4-
4.2.6. tert-Butyl [(2S)-2,3-dihydroxypropyl]3-{[(2R)-2,3-
dihydroxypropyl]thio}-{2-[(benzyloxy)imino]propyl}carbamate (15)
To a solution of (S,R)-14 (0.050 g, 0.093 mmol) in a mixture of
yl]methyl}thio)propanone O-benzyloxime (17)
To a solution of (R)-11b (0.150 g, 0.44 mmol) in 1 mL of anhy-
drous methanol was added a solution of amine (S)-9c (0.172 g;
1.31 mmol) in methanol (0.5 mL). The resulting mixture was stirred
under reflux for 8 h. The solution was then concentrated in vacuo
and a saturated aqueous solution of NaHCO3 (7 mL) followed by
dichloromethane (15 mL) was introduced. After extraction, the or-
ganic layer was dried (MgSO4) and concentrated. The crude product
was then purified by flash chromatography using (1:1/7:3) ethyl
acetate/cyclohexane as eluent to give pure 17 as a yellow oil
(0.128 mg; 67%). Compound 17 appeared as a mixture of Z and E
isomers. IR nmax (neat, cmꢂ1) 3341 (N–H), 1624 (C]N), 1250–1050
acetone/water (10:1 (v:v), 600 m
L) was added AmberlystÒ 15
(0.023 g). After stirring at reflux for 4 h, the solution was filtered on
a CeliteÒ pad and concentrated. The residue was purified by flash
chromatography on silica gel using ethyl acetate as eluent to give
pure (S, R)-15 (0.014 g, 33%) as a colorless oil. 1H NMR (CDCl3) two
isomers E (min) and Z (maj) d/ppm 7.38–7.26 (m, 10H, H–Ar, Z and
E), 5.08 (s, 2H, CH2Ph, E), 5.07 (s, 2H, CH2Ph, Z), 4.42 (d, J¼16.0 Hz,
1H, CH2S, Z), 4.30–4.15 (m, 3H, CH2S, Z and E), 3.82 (m, 2H, CHO–
CH2N, Z and E), 3.73 (Q, J¼6.0 Hz, 1H, CHO–CH2S, Z), 3.68 (Q,
J¼5.5 Hz, 1H, CHO–CH2S, E), 3.54–3.41 (m, 10H, CH2O, Z and E, CH2N
and NCH2), 3.37–3.30 (m, 3H, CH2N and NCH2), 3.28–3.10 (m, 3H,
CH2N and NCH2), 2.67 (m, 1H, SCH2, E), 2.56 (m, 1H, SCH2, E), 2.56
(dd, 2J¼14.0 Hz, 3J¼7.0 Hz, 1H, SCH2, Z), 2.44 (dd, 2J¼14.0 Hz,
(C–O); 1H NMR (CDCl3)
d/ppm 7.36–7.27 (m, 10H, H–Ar, Z and E),
5.08 (s, 4H, CH2Ph, Z and E), 4.24–4.14 (m, 4H, CHO, Z and E), 4.00
(dd, 2J¼8.0 Hz, 3J¼6.5 Hz, 1H, NCH2CHCH2O, Z), 4.02–3.96 (m, 2H,
3J¼7.0 Hz, 1H, SCH2, Z); 13C NMR (CD3OD)
d/ppm 157.0 and 156.8
NCH2CHCH2O,
E
and SCH2CHCH2O, E), 3.95 (dd, 2J¼8.5 Hz,
(CO2t-Bu, Z), 155.6 (C]N, Z), 155.4 (C]N, E), 153.8 and 153.7 (CO2t-
Bu, E),139.3 (C–Ar, E),139.1 (C–Ar, Z),129.4 (C–Ar, Z and E),129.2 (C–
Ar, Z),129.1 (C–Ar, E), 128.9 (C–Ar, Z and E), 81.8 and 81.7 (C–(CH3)3),
77.2 (CH2Ph, E), 77.1 (CH2Ph, Z), 72.3 (SCH2–CHO, Z), 72.2 (SCH2–
CHO, E), 71.8 and 71.7 (NCH2–CHO), 66.1 (SCH2CH–CH2O, E), 66.0
(SCH2CH–CH2O, Z), 65.4 (NCH2CH–CH2O, E), 65.1 (NCH2CH–CH2O,
Z), 53.2 (NCH2CH–CH2O, E), 52.4 (NCH2CH–CH2O, Z), 51.1 and 50.8
(N]CCH2S), 46.2 and 45.8 (N]CCH2S), 36.9 and 36.7 (SCH2–CHO,
E), 35.5 and 35.3 (N]CCH2N, Z), 33.5 and 33.1 (N]CH2, Z), 28.7
(CH3), 26.6 and 26.2 (CH3).
3J¼6.0 Hz, 1H, SCH2CHCH2O, Z), 3.67–3.55 (m, 6H, SCH2CHCH2O (Z
and E), NCH2CHCH2O (Z and E), N]CCH2N, E), 3.48 (s, 2H,
N]CCH2N, Z), 3.46 (s, 2H, N]CCH2N, Z), 3.32 (d, 2J¼13.5 Hz, 1H,
SCH2C]N, E), 3.29 (d, 2J¼13.5 Hz, 1H, SCH2C]N, E), 2.70 (dd,
2J¼13.5 Hz, 3J¼6.5 Hz, 1H, OCHCH2S, Z), 2.67 (d, 3J¼6.0 Hz, 4H,
NHCH2CHO, E and Z), 2.59 (dd, 2J¼13.5 Hz, 3J¼6.5 Hz, 1H, OCHCH2S,
E), 2.56 (dd, 2J¼13.5 Hz, 3J¼6.5 Hz, 1H, OCHCH2S, Z), 2.47 (dd,
2J¼13.5 Hz, 3J¼6.5 Hz, 1H, OCHCH2S, E), 1.64 (br s, 2H, NH, E and Z),
1.41 (s, 6H, Me, E and Z), 1.40 (s, 6H, Me, E and Z), 1.34 (s, 6H, Me, E
and Z), 1.32 (s, 6H, Me, E and Z); 13C NMR (CDCl3)
d/ppm 156.5
(C]N, E), 155.8 (C]N, Z), 137.7 (C–Ar, E), 137.4 (C–Ar, Z), 128.3 (C–
Ar, Z and E), 128.0 (C–Ar, Z and E), 127.9 (C–Ar, Z), 127.8 (C–Ar, E),
109.4 (C–(CH3)2, Z and E), 109.1 (C–(CH3)2, Z and E), 76.0 (CH2Ph, Z
and E), 75.2 (NHCH2–CHO, Z), 75.1 (NHCH2–CHO, E), 74.8 (SCH2–
CHO, Z and E), 68.6 (SCH2CHCH2O, Z and E), 67.4 (NHCH2CHCH2O,
Z), 67.3 (NHCH2CHCH2O, E), 52.1 (NH–CH2–CHO, E), 51.5 (NH–CH2–
CHO, Z), 50.2 (N]C–CH2, Z), 45.0 (N]C–CH2, E), 35.2 (S–CH2–CHO,
Z), 33.8 (S–CH2–CHO, E), 33.2 (S–CH2–C]N, E), 26.9 (CH3, E), 26.8
(CH3, Z), 25.6 (CH3, E), 25.4 (CH3, Z), 25.5 (CH3, Z and E), 25.3 (S–
CH2–C]N, Z); HRMS (ESI): calculated for C22H35N2O5S [MþH]þ
439.2267, found 439.2251.
4.2.7. (2E)- and (2Z)-1-({[(4S)-2,2-Dimethyl-1,3-dioxolan-4-
yl]methyl}amino)-3-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-
yl]methoxy}propanone O-benzyloxime (16)
To a solution of (S)-11a (0.166 g; 0.51 mmol) in anhydrous
methanol (1.5 mL) was added a solution of amine (S)-9c (0.200 g;
1.53 mmol) in methanol (0.5 mL). The resulting mixture was heated
at reflux for 4 h. The solvent was then concentrated and a saturated
aqueous NaHCO3 (10 mL) solution was added. The mixture was
extracted with dichloromethane (3ꢁ10 mL), dried (MgSO4), and
concentrated in vacuo. The crude product was purified by flash
chromatography using (7:3) ethyl acetate/cyclohexane as eluent to
give 16 as a yellow oil (0.132 g, 61%). IR nmax (neat, cmꢂ1) 3345 (N–
4.2.9. N-{[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methyl}-N-3-
{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-2-
{[(benzyloxy)imino]propyl}benzamide (18)
H), 1590 (C]N), 1255–1050 (C–O); 1H NMR (CDCl3)
d/ppm 7.35–
7.26 (m, 10H, H–Ar, E and Z), 5.09 (s, 2H, CH2Ph, E), 5.06 (s, 2H,
CH2Ph, Z), 4.43 (d, 2J¼15.5 Hz, 1H, O–CH2–C]N, Z), 4.40 (d,
2J¼15.5 Hz, 1H, O–CH2–C]N, Z), 4.27–4.15 (m, 4H, H–CHO, E and Z),
4.14 (d, 2J¼12.0 Hz, 1H, O–CH2–C]N, E), 4.12 (d, 2J¼12.0 Hz, 1H, O–
CH2–C]N, E), 4.05–3.96 (m, 4H, CHO–CH2O, Z and E), 3.72 (dd,
2J0¼8.0 Hz, 3J¼6.5 Hz, 1H, O–CH2–CHO, Z), 3.67 (dd, 2J¼8.5 Hz,
3J¼6.5 Hz, 1H, O–CH2–CHO, E), 3.62 (dd, 2J¼8.0 Hz, 3J¼7.0 Hz, 2H,
To (S,S)-16 (0.317 g, 0.75 mmol) in anhydrous dichloromethane
(8 mL) were added at 0 ꢀC and under argon, triethylamine (155
m
L,
1.13 mmol) and 4-dimethylaminopyridine (0.018 mg, 0.15 mmol).
After 15 min, benzoylchloride (105 L, 0.90 mmol) was added
m
dropwise to the reaction mixture. The solution was quenched with
H2O after 2 h and the mixture was extracted with dichloromethane.

4188
M. Goubert et al. / Tetrahedron 65 (2009) 4182–4189
The combined organic extracts were dried over MgSO4, filtered, and
concentrated in vacuo. The crude product was purified by silica gel
chromatography using (3:2) cyclohexane/ethyl acetate as eluant to
give 18 as a colorless oil (0.355 g, 90%). Compound 18 is made of
a mixture of the two isomers Z and E. IR nmax (neat, cmꢂ1) 1635
52.2–50.7–50.3–48.6–46.4–45.1–44.9–43.4 (C-9 and C-11); HRMS
(ESI): calculated for C16H21NO6Na [MþNa]þ 346.1267, found
346.1261.
4.2.12. (2R,8S)-2,8-Dihydroxymethyl-10-benzoyl-10-aza-4-thia-
1,7-dioxaspiro[5.5]undecane (21)
(C]O), 1260–1000 (C–O); 1H NMR (CDCl3)
d/ppm 7.40–7.20 (m,
10H, H–Ar), 5.16–5.00 (m, 2H, CH2Ph), 4.69–3.75 (m, 8H, CHO,
A solution of oxime (R,S)-19 (0.112 g, 0.20 mmol) in 2 mL of
CH2O, O–CH2–C]), 3.75–3.15 (m, 6H, CHO–CH2–O, N–CH2–CHO,
a
10:1 (v/v) mixture of acetone/water with AmberlystÒ15
]C–CH2–N), 1.40–1.20 (m, 12H, Me); 13C NMR (CDCl3)
d
/ppm 172.6
(0.050 g) and 2 mmol of paraformaldehyde was heated under
reflux for 2 days. After cooling and filtration on a CeliteÒ pad, the
solvent was evaporated in vacuo and the crude mixture purified
by silica gel chromatography using (1:0/49:1) ethyl acetate/
MeOH as eluent to give 21 as a white syrup (0.045 g, 65%). IR nmax
(neat, cmꢂ1) 3394 (O–H), 1618 (C]O), 1047 (C–O); 13C NMR
(C], E and Z), 153.8 (NCO, E and Z), 137.7 (C–Ar–Bn, E and Z), 136.2
(C–Ar, Z), 135.8 (C–Ar, E), 129.5 (C–Ar, E), 129.3 (C–Ar, Z), 128.3 (C–
Ar–Bn, E and Z), 128.2 (C–Ar, E and Z), 128.0 (C–Ar–Bn, E and Z),
127.0 (C–Ar–Bn, E and Z), 126.4 (C–Ar, E and Z), 109.4 (C–(CH3)2, Z),
109.1 (C–(CH3)2, E), 76.4 (CH2–Ph, Z), 76.2 (CH2–Ph, E), 75.1 (NCH2–
CHO, Z), 74.4 (NCH2–CHO, E), 74.2 (OCH2–CHO, E and Z), 72.5 (CHO–
CH2–O, E), 72.0 (CHO–CH2–O, Z), 67.4–66.9–66.6–66.3–65.8–65.5
(CH2–O, O–CH2–C], E and Z), 51.8 (N–CH2–CHO, E), 50.3 (N–CH2–
CHO, Z), 48.1 (]C–CH2–N, Z), 44.6 (]C–CH2–N, E), 26.8–26.7–26.6–
25.4–25.3 (CH3, E and Z); HRMS (ESI): calculated for C29H38N2O7Na
[MþNa]þ 549.2577, found 549.2572.
(DMSO-d6, 293 K) d/ppm 170.1–169.4 (N–CO), 135.7 (C–Ar), 129.4
(C–Ar), 128.4–128.2 (C–Ar), 127.3–126.6 (C–Ar), 91.6–91.2 (C-6),
70.3–70.2 (C-2), 68.7 (C-8), 63.9–63.8–61.9–61.5 (C-12 and C-13),
54.1–48.5–43.5 (C-9 and C-11), 30.8–30.5 (C-5), 26.6 (C-3); HRMS
(ESI): calculated for C16H21NO5NaS [MþNa]þ 362.1038, found
362.1021.
4.2.10. N-{[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methyl}-N-[3-
({[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-thio)-2-
[(benzyloxy)imino]propyl]benzamide (19)
Compound 17 (0.350 g; 0.80 mmol) was dissolved in anhy-
drous dichloromethane (8 mL) at 0 ꢀC and under argon. Triethyl-
4.2.13. 2,8-Dihydroxymethyl-10-benzoyl-10-aza-1,4,7-
trioxaspiro[5.5]undecane (22)
To a solution of spiroketal 20 (0.056 g, 0.17 mmol) in THF
(1 mL) was added at 0 ꢀC and under argon, a 1.0 M solution of
LiAlH4 in THF (693 mL, 0.68 mmol). After 3 h, the reaction is
amine (170
m
L, 1.20 mmol) and 4-dimethylaminopyridine (0.020 g,
L,
quenched by adjunction of water and the residue filtered over
MgSO4. The solvent was eliminated to give nearly quantitatively
a crude and inseparable mixture of isomers 22, in a 4:1 ratio as
0.16 mmol) were added followed by benzoylchloride (110
m
0.96 mmol). The mixture was stirred at 0 ꢀC for 2 h whereupon the
reaction was stopped by addition of water, extracted with ethyl
acetate, and dried (MgSO4). After evaporation of the solvent, the
crude product was purified by flash chromatography using (7:3)
cyclohexane/ethyl acetate as eluent to give pure 19 (0.412 mg,
95%) as a colorless oil. IR nmax (neat, cmꢂ1) 1638 (C]O), 1260–
determined from 13C NMR. 13C NMR (CDCl3)
d/ppm 105.9–91.6 (C-
6), 75.0–70.0 (C-8), 72.6–70.0 (C-5), 70.6–69.0 (C-2), 68.4–67.2
(C-3), 63.7–63.4 (CH2OH), 62.5–62.0 (CH2OH), 49.9–49.1 (C-11),
47.9–46.1 (C-9).
Major isomer: (2R,6S,8S)-22a: 1H NMR (CDCl3)
d/ppm 4.06 (m,
1060 (C–O); 1H NMR (CDCl3)
(s, 2H, CH2Ph), 4.67–3.74 (m, 6H, CHO, CH2O), 3.73–3.00 (m, 6H,
d
/ppm 7.40–7.26 (m, 10H, H–Ar), 5.09
1H, H-2), 3.90 (m, 1H, H-8), 3.60–3.48 (m, 4H, CH2OH), 3.74 (dd,
J3eq3ax¼11.0 Hz, J3eq2ax¼2.5 Hz, 1H, H-3eq), 3.60 (d, 2J¼11.5 Hz, 1H,
H-5), 3.33 (t, J3ax3eq¼J3ax2ax¼11.0 Hz, 1H, H-3ax), 3.26 (d, 2J¼11.5 Hz,
1H, H-5), 3.13 (br d, 1H, NH), 2.83 (br d, J9eq9ax¼12.0 Hz, 1H, H-9eq),
2.73 (d, 2J¼13.0 Hz, 1H, H-11), 2.57 (t, J9ax9eq¼J9ax8ax¼12.0 Hz, 1H,
N–CH2–CHO, S–CH2–C]N and N]C–CH2N), 2.82–2.20 (m, 2H,
CHO–CH2–S), 1.45–1.20 (m, 12H, Me); 13C NMR (CDCl3)
d/ppm
172.5 (C]N, E), 172.4 (C]N, Z), 152.1 (C]O, E and Z), 137.3 (COC–
Ar, E and Z), 135.9 (COC–Ar, Z), 135.7 (COC–Ar, E), 129.6 (COC–Ar, E),
129.4 (COC–Ar, Z), 128.6, 128.3, 128.2, 128.1, 128.0, 127.9, 127.0 and
126.5 (C–Ar, E and Z), 109.4 (C–(CH3)2, Z), 109.2 (C–(CH3)2, E), 76.4
(CH2Ph, E), 76.3 (CH2Ph, Z), 74.9, 74.8 and 74.6 (CHO, E and Z), 68.6
(CH2–CHOCH2S, E), 68.5 (CH2–CHOCH2S, Z), 67.2 (CH2–CHOCH2N,
Z), 66.8 (CH2–CHOCH2N, E), 51.6 (N–CH2–CHO, Z), 47.9 (N]CCH2,
Z), 46.1 (N–CH2–CHO, E), 42.6 (N]CCH2, E), 35.5 (CHO–CH2S, E),
34.7 (CHO–CH2S, Z), 34.1 and 33.4 (S–CH2–C]N, E), 26.8 (CH3, E
and Z), 26.0 (S–CH2–C]N, Z), 25.4 (CH3, E and Z); HRMS (ESI):
calculated for C29H38N2O6NaS [MþNa]þ 565.2348, found
565.2374.
H-9ax), 2.52 (d, 2J¼13.0 Hz, 1H, H-11); 13C NMR (CDCl3)
d/ppm 91.6
(C-6), 70.0 (C-8), 70.0 (C-5), 69.0 (C-2), 67.2 (C-3), 63.4 (CH2OH),
62.0 (CH2OH), 49.1 (C-11), 46.1 (C-9); HRMS (ESI): calculated for
C9H18NO5 [MþH]þ 220.1185, found 220.1175.
4.2.14. 2,8-Dihydroxymethyl-10-benzoyl-10-aza-4-thia-1,7-
dioxaspiro[5.5]undecane (23)
To a solution of spiroketal 21 (0.060 g, 0.18 mmol) in THF
(1 mL) was added at 0 ꢀC and under argon, a 1.0 M solution of
LiAlH4 in THF (710 mL, 0.72 mmol). After 3 h, the reaction is
quenched by adjunction of water and the residue filtered over
MgSO4. The solvent was eliminated to give nearly quantitatively
a crude and inseparable mixture of isomers 23, in a 9:1 ratio
4.2.11. (2R,8S)-2,8-Dihydroxymethyl-10-benzoyl-10-aza-1,4,7-
trioxaspiro[5.5]undecane (20)
(determined from 13C NMR). 13C NMR (CDCl3)
d
/ppm 99.9–90.9 (C-
6), 71.4–70.8 (C-2), 70.8–70.2 (C-8), 68.8–63.3 (CH2OH), 65.2–65.2
(CH2OH), 53.0–51.6 (C-11), 47.7–46.1 (C-9), 37.0 –32.0 (C-5),
36.6 –26.2 (C-3).
Major isomer: (2R,6S,8S)-23a: 1H NMR (CDCl3)
A solution of (S,S)-18 (0.150 g, 0.28 mmol) in 2.8 mL of a 10:1
(v/v) mixture of acetone/water and AmberlystÒ 15 (0.070 g) was
*
heated for
2
days under reflux with 2.8 mmol of para-
*
formaldehyde. After cooling and filtration on a CeliteÒ pad, the
solvent was evaporated in vacuo and the crude mixture was
purified by flash chromatography using (49:1) ethyl acetate/
MeOH as eluent to give a mixture of isomers 20 as a colorless oil
(0.056 g, 61%). IR nmax (neat, cmꢂ1) 3400 (O–H), 1618 (C]O), 1051
d/ppm 4.04 (m,
1H, H-2), 3.89 (m, 1H, H-8), 3.58–3.45 (m, 4H, CH2OH), 2.81 (br d,
J9eq9ax¼12.0 Hz, 1H, H-9eq), 2.79 (d, 2J¼13.0 Hz, 1H, H-11), 2.67 (d,
2J¼13.5 Hz, 1H, H-5), 2.57 (d, 2J¼13.0 Hz, 1H, H-11), 2.51 (t,
J9ax9eq¼J9ax8ax¼12.0 Hz, 1H, H-9ax), 2.48 (t, J3ax3eq¼J3ax2ax¼12.0 Hz,
1H, H-3ax), 2.29 (d, 2J¼13.5 Hz, 1H, H-5), 2.18 (br d, J3eq3ax¼13.0 Hz,
(C–O); 13C NMR (DMSO-d6, 293 K)
d/ppm 170.6–170.4–170.0–
169.6 (C–Ar), 136.7–135.3 (C–Ar), 129.7–129.4 (C–Ar), 128.4–128.2
(C–Ar), 127.3–127.0–126.8 (C–Ar), 92.1–91.6 (C-6), 73.4–73.2–
71.9–69.0–67.8–67.4 (C-3 and C-5), 72.8–72.4–70.5–70.3–68.6
(C-2 and C-8), 63.0–62.9–62.8–61.9–61.6–61.0 (C-12 and C-13),
1H, H-3eq); 13C NMR (CDCl3)
d/ppm 90.9 (C-6), 70.8 (C-2), 70.2 (C-
8), 65.2 (CH2OH), 63.3 (CH2OH), 53.0 (C-11), 46.1 (C-9), 32.0 (C-5),
26.2 (C-3); HRMS (ESI): calculated for C9H18NO4S [MþH]þ
236.0957, found 236.0946.

M. Goubert et al. / Tetrahedron 65 (2009) 4182–4189
4189
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Synthesis 1995, 627–629.
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