A rapid access to the spiroaminoketal framework

Article abstract of DOI:10.1055/s-2005-872665

A convergent and stereoselective synthesis of 1-oxa-7-azaspiro[5.5]undecane is described. This functional new spiroheterocycle is readily available from acetone N,N-dimethylhydrazone via a double alkylation and subsequent spiroannulation process. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-872665

LETTER
2397
A Rapid Access to the Spiroaminoketal Framework
A
R
apid Access to
h
the
S
piroam
m
inoketa
l
Frameworkatjan Tursun, Bettina Aboab, Anne-Sophie Martin, Marie-Eve Sinibaldi,* Isabelle Canet*
Laboratoire de Synthèse Et Etude de Systèmes à Intérêt Biologique (SEESIB), UMR 6504, Université Blaise Pascal, 63177 Aubière Cedex,
France
Fax +33(4)73407717; E-mail: icanet@chimie.univ-bpclermont.fr; E-mail: sinibald@chimie.univ-bpclermont.fr
Received 16 June 2005
Our synthetic strategy lies in the use of iodides 3 and 4 as
Abstract: A convergent and stereoselective synthesis of 1-oxa-7-
key precursors for the iterative alkylation of acetone N,N-
azaspiro[5.5]undecane is described. This functional new spirohet-
dimethylhydrazone.8b,c,d Upon synthesis of the dissym-
metric ketone 2, cyclization should provide an efficient
erocycle is readily available from acetone N,N-dimethylhydrazone
via a double alkylation and subsequent spiroannulation process.
access to the [5.5]azaoxaspiranic core.
Key words: spiro compounds, alkylations, hydrazones, synthesis,
Synthesis of (S)-3 has been previously reported.8a Prepa-
ration of (S)-4 was accomplished from L-aspartic acid
(Scheme 2). L-Aspartic acid was transformed by classical
procedures into its N-Boc methylester 5 in two steps and
79% yield. The reduction of the carboxylic function of 5,
via its activated ester, led efficiently to 69 (89% yield).
Protection of the resulting alcohol using TBDPSCl in the
presence of imidazole in CH2Cl2 gave, nearly quantita-
tively, the tert-butyldiphenylsilyl ether 7. The ester func-
tion was then reduced by treatment with a 2 M solution of
LiBH4 in THF, resulting in the formation of alcohol 8 in
94% yield. Finally, conversion of 8 into the required io-
dide 410 was cleanly realized by treatment with iodine and
triphenylphosphine/imidazole in toluene at room temper-
ature in 82% yield. Thus (S)-4 was obtained in six steps
and 54% overall yield from L-aspartic acid.
amino acid
Molecules possessing heterocycles fused by a spirocarbon
atom are ubiquitous in nature, with many of them display-
ing interesting biological properties. 1,7-Dioxaspi-
ro[5.5]undecane (6,6-spiroketal) moieties have received
particular attention as they are found in a wide and diverse
series of natural products such as polyether ionophores,
marine alkaloids, or insect pheromones. Approaches for
the elaboration of this ring system have been extensively
reported in the literature.1
On the contrary, synthesis of spiroaminoketals, key inter-
mediates in the preparation of biologically active com-
pounds such as hydantocidin,2 spironucleosides,3
azaspiracid,4 sanglifehrin,5 or solanum alkaloids,6 have
been less explored.7 As part of our continued interest in
the synthesis of homochiral spiroheterocycles of biologi-
cal interest, we wish to report herein an efficient approach
to spiroaminoketal 1 using the spiroannulation methodol-
ogy we have previously reported for the preparation of
spiroketals8a (Scheme 1).
With synthons 3 and 4 in hand, we then began the alkyla-
tion process (Scheme 3). We first used the experimental
protocol developed for the synthesis of spiroketals,8a
namely: initial alkylation of acetone N,N-dimethylhydra-
zone using LDA as base and iodide (S)-3 followed by the
second using BuLi as base and (S)-4. The first step result-
ed in quantitative formation of compound 9, however, and
OH
O
H2N
CO2H
CO2H
NHBoc
CO2Me
a,b
NBoc
c
89%
OR
79%
HO2C
5
1
NHBoc
NHBoc
CO2Me
d
e
O
NHBoc
OPG
O
TBDPSO
CO2Me
HO
quant
94%
O
6
7
2
NHBoc
NHBoc
f
82%
TBDPSO
TBDPSO
OH
I
N
NHBoc
OPG
4
O
8
N
O
+
+
I
I
Scheme 2 Synthesis of iodide 4. Reagents and conditions: a)
SOCl2, MeOH, –10 °C then r.t., 25 min; b) (t-BuOCO)2O, Na2CO3,
dioxane–H2O, r.t.,12 h; c) N-hydroxysuccinimide (1.2 equiv), DCC
(1.2 equiv), CH2Cl2, r.t., 3 h, NaBH4 (1.0 equiv), THF–EtOH (3–1),
0 °C, 15 min; d) TBDPSCl (1.2 equiv), imidazole (1.5 equiv),
CH2Cl2, 0 °C (10 min), r.t. (3 h); e) 2 M LiBH4 (1.5 equiv, THF), 0 °C
(10 min), r.t. (12 h); f) I2 (3.1 equiv), imidazole (2.9 equiv), PPh3 (3.0
equiv), toluene, r.t., 48 h.
3
4
Scheme 1
SYNLETT 2005, No. 15, pp 2397–2399
Advanced online publication: 07.09.2005
DOI: 10.1055/s-2005-872665; Art ID: G16505ST
© Georg Thieme Verlag Stuttgart · New York
1
9
.0
9
.2
0
0
5

2398
A. Tursun et al.
LETTER
in spite of numerous attempts, the second alkylation step The stereochemical course of the acid-catalyzed ring
led to complex mixtures in which the dialkylated product closure of 2 has been investigated by NMR and through
was obtained in very poor yield. This result was certainly molecular modeling of 1a. Conformational analysis14
disappointing but in agreement with those reported by showed that the (2S,6S,8S)-1a (DHf = –240.09 Kcal
others authors. 8b,c,d Indeed, in the literature, alkylation of mol–1) is more stable than its (2S,6R,8S) isomer by 1.4
monosubstituted N,N-dimethylhydrazones was achieved Kcal mol–1 (Figure 1). This results in a 95:5 theoretical
using various experimental conditions depending on the ratio between the isomers, which was consistent with the
nature of the coupled iodide and an extensive work was experimental observation of only one product. Thus, com-
often required. We therefore began a systematic study of pound 1a exhibited a structure stabilized by a double
the experimental conditions for this second step, varying anomeric effect and a weak hydrogen bond between OH
the nature and amount of base, the temperature for the an- and O-1 (calculated distance d = 2.43 Å, valence angle:
ion formation, and the use, in various quantities, of addi- 105 deg). NOESY experiments (Figure 2) confirmed the
tives such as DMPU, HMPA, DABCO, or 18-crown-6.
proposed spirocenter stereochemistry as 6S.
The best results were obtained using BuLi (2.0 equiv), a
reaction temperature of –10 °C, and a reaction time of 1.5
hours; followed by the addition of a mixture of 4 (0.95
equiv) and freshly distilled DMPU (10.0 equiv). In these
conditions, hydrazone 10 was obtained and used without
purification in the hydrolysis step. SiO2/H2O induced
cleavage of 10 furnished ketone 2,11 which was easily
purified and isolated in 42% overall yield from acetone
N,N-dimethylhydrazone (Scheme 3).
N
N
a
O
Figure 1 Calculated structures for (2S,6S,8S)-1a and its isomer
(2S,6R,8S). Hydrogen bond is represented by a blue line.
O
+
I
N
N
O
O
3
9
O
H
2
N
H
O
b
N
NHBoc
OTBDPS
c
O
O
H
8
42%
H
OR
H
N
10
10
H
Boc
O
Figure 2 Selected NOE (red dashed lines) for (2S,6S,8S)-1a.
O
NHBoc
d
O
OTBDPS
quant
2
In summary, we have shown that our double alkylation–
spiroannulation sequence allowed a rapid and stereoselec-
tive access to the spiroaminoketal framework. Functional-
S
S
OH
OH
e
ized 1-oxa-7-azaspiro[5.5]undecanes
1
could be
O
O
90%
efficiently assembled in only five steps and 37% overall
yield, starting from acetone N,N-dimethylhydrazone and
chiral iodides 3 and 4.
NBoc
NBoc
OTBDPS
OH
S
S
1b
1a
Extension of this procedure to spiroaminoketals in the
[4.5]decane and [4.4]nonane series, is in progress in our
laboratory and will be published with full experimental
details in due course.
Scheme 3 Synthesis of spiroaminoketal 1. Reagents and condi-
tions: a) LDA (1.1 equiv), THF, 1 h, –25 °C, (S)-3 (1.0 equiv), 10
min; b) n-BuLi (2.0 equiv), THF, 1.5 h, –10 °C; (S)-4 (0.95 equiv),
DMPU (10.0 equiv), r.t., overnight; c) SiO2/H2O, CH2Cl2, r.t., 48 h;
d) p-TsOH (0.02 equiv), MeOH, 40 °C (2 h), r.t. (12 h); e) TBAF,
THF, r.t., 3 h.
References
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1617.
Finally, acetonide deprotection with concomitant ring clo-
sure was performed by treatment of 2 with a catalytic
amount of p-TsOH in MeOH to afford spiroaminoketal 1a
as the sole product in quantitative yield.12 Treatment of 1a
with TBAF in anhydrous THF for three hours led to the
expected diol 1b13 in 90% yield.
(2) Shiozaki, M. Carbohydr. Res. 2002, 337, 2077; and
references cited therein.
Synlett 2005, No. 15, 2397–2399 © Thieme Stuttgart · New York

LETTER
A Rapid Access to the Spiroaminoketal Framework
2399
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36.4, 52.5, 64.9, 79.0, 127.5, 129.5, 132.6, 135.1, 155.1.
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CHCl3). 1H NMR (400 MHz, CDCl3): d = 1.05 (s, 9 H), 1.33
(s, 3 H), 1.39 (s, 3 H), 1.43 (s, 9 H), 1.40–1.72 (m, 8 H), 2.39
(m, 2 H), 2.42 (t, J = 6.5 Hz, 2 H), 3.49 (t, J = 7.0 Hz, 1 H),
3.57 (dd, J = 9.0, 3.0 Hz, 1 H), 3.65 (m, 2 H), 4.02 (t, J = 7.0
Hz, 1 H), 4.04 (m, 1 H), 4.65 (d, J = 8.5 Hz, 1 H), 7.39 (m, 6
H), 7.62 (m, 4 H). 13C NMR (100 MHz, CDCl3): d = 19.3,
19.9, 20.0, 25.7, 26.8, 26.9, 28.4, 31.2, 32.9, 42.3, 51.4, 65.6,
69.3, 75.7, 79.0, 108.7, 127.7, 129.7, 133.2, 135.5, 155.6,
210.3. HRMS: m/z calcd for C35H53NO6Si [M + Na+]:
634.3540. Found: 634.3549.
(12) Selected data for 1a: foam; [a]D25 –29.2 (c 0.88, CHCl3). 1H
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1.33 (m, 2 H), 1.46 (s, 9 H), 1.46 (m, 1 H), 1.49 (m, 2 H),
1.58 (m, 3 H), 1.74 (m, 3 H), 3.48 (dd, J = 10.0, 4.0 Hz, 1 H),
3.55 (t, J = 6.5 Hz, 1 H), 3.59 (m, 2 H), 3.87 (m, 1 H), 4.08
(m, 1 H), 4.47 (d, J = 9.0 Hz, 1 H, OH), 7.23 (m, 6 H), 7.73
(m, 4 H). 13C NMR (100 MHz, C6D6): d = 17.3, 19.5, 20.1,
27.1, 28.6, 28.7, 32.3, 34.4, 38.0, 52.3, 66.3, 69.0, 74.7, 78.4,
108.8, 128.1, 130.0, 133.9, 136.0, 155.6. HRMS: m/z calcd
for C32H47NO5Si [M + Na+]: 576.3121. Found: 576. 3134.
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1.21 (m, 1 H), 1.35 (m, 2 H), 1.43 (s, 9 H), 1.49 (m, 2 H),
1.56 (m, 3 H), 1.69 (m, 3 H), 2.55 (br s, 1 H, OH), 3.34 (m,
1 H), 3.44 (m, 1 H), 3.56 (m, 2 H), 3.68 (m, 1 H), 4.08 (m, 1
H), 4.60 (d, J = 7.5 Hz, 1 H, OH). 13C NMR (100 MHz,
C6D6): d = 17.3, 20.1, 28.5, 28.6, 31.8, 34.3, 37.8, 53.1, 65.7,
69.0, 74.7, 78.8, 108.8, 156.5. HRMS: m/z calcd for
C16H29NO5 [M + Na+]: 338.1943. Found: 338.1938.
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Synlett 2005, No. 15, 2397–2399 © Thieme Stuttgart · New York