An entry to 1,6-dioxaspiro[4.6]undecanes and 1,7-dioxaspiro[5.6]dodecanes

Article abstract of DOI:10.1016/j.tetlet.2010.06.003

Ketones 11a-c obtained by iterative alkylation of acetone N,N-dimethylhydrazone with iodides 6 and 8a,b or epoxide 9 followed by SiO₂/H₂O-induced cleavage of the hydrazone were quantitatively transformed into 1,6-dioxaspiro[4.6]undec

Full text of DOI:10.1016/j.tetlet.2010.06.003

Tetrahedron Letters 51 (2010) 4147–4149
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Tetrahedron Letters
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An entry to 1,6-dioxaspiro[4.6]undecanes and 1,7-dioxaspiro[5.6]dodecanes
c
Anthony Ollivier a, Marie-Eve Sinibaldi a,b, , Loïc Toupet , Mounir Traïkia a,b, Isabelle Canet a,b,
*
*
a Clermont Université, Université Blaise Pascal, Laboratoire SEESIB, BP 10448, F-63000 Clermont-ferrand, France
b CNRS, UMR 6504, SEESIB, F-63177 Aubiere, France
c Groupe Matière Condensée et Matériaux, Université Rennes 1, Avenue du Général Leclerc, F-35042 Rennes, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Ketones 11a–c obtained by iterative alkylation of acetone N,N-dimethylhydrazone with iodides 6 and
8a,b or epoxide 9 followed by SiO2/H2O-induced cleavage of the hydrazone were quantitatively trans-
formed into 1,6-dioxaspiro[4.6]undecanes 12a,c and 1,7-dioxaspiro[5.6]dodecanes 12b using Yb(OTf)3
in CH3CN.
Received 29 April 2010
Revised 31 May 2010
Accepted 1 June 2010
Available online 8 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Spiroketal
Cyclization
Hydrazone
Alkylation
Spiroketalsformthecommonstructuralpartofmanybiologically
active, naturally occurring products issued from various sources
including insects, plants, fungi, and marine organisms.1 The mainly
encounteredstructuralvariations relatetothesizeofthetwospiran-
ic cycles (spiro[4.4], spiro[4.5], and spiro[5.5] systems) and the pres-
ence or not of alkyl or alkoxy substituents on the spirocyclic
skeleton. Becauseof theirwide range of biological activities, spiroke-
talshaveseenasustainedinterestinthedevelopmentof methodsfor
their preparation—mainly for 1,7-spiro[5.5]undecane and 1,6-
spiro[4.5]decane systems—and numerous strategies have been re-
ported and reviewed.2 An interesting but rarer structural variation
is exhibited by seven-membered ring spiroketals which could be
formed stereoselectively but often in moderate yields.3
We investigated these last years’ short routes to spiroketals and
analogues. Our general strategy led to the elaboration of linear key-
ketones of type 1–3, obtained by iterative substitution of conve-
niently protected acetone,4 followed by a one-step deprotection—
spiroketalization cascade. Thus, in spiro[5.5] series, we described
the efficient synthesis of dihydroxymethyl-substituted 1,7-dioxa-
spiro[5.5]undecane 25 and demonstrated the facility in incorporat-
ing supplementary heteroatoms in the two cycles, starting from
acetone O-benzyloxime.6 In spiro[4.5] series, we evaluated our
strategy through the elaboration of 1,6-dioxaspiro[4.5]decane.5
Exposure of ketone intermediate 3 to acidic conditions led to a
mixture of the targeted [4.5]-spiroketal, as the anomeric 4a and
non-anomeric 4b forms, but and contrarily to spiro[5.5] series,
accompanied with the 1,7-dioxaspiro[5.5]undecane 5—resulting
from a double attack of primary alcohol functions on the keto
group (Scheme 1).
To further evaluate the scope of this sequence, we decided to
extend it to the preparation of 1,6-dioxaspiro[4.6]undecane and
1,7-dioxaspiro[5.6]dodecane systems. Herein are disclosed details
of our investigations in this area. In this course, we chose to pre-
pare the spiro precursors 11 (Scheme 2).
O
N
O
O
N
O
O
I
O
O
1
OH
H+
quant.
O
O
OH
O
2
O
N
N
O
O
O
I
O
O
O
3
O
I
OH
+
OH
OH
H+
O
O
O
O
O
O
+
OH
OH
OH
4b
9%
5
4a
3:2
84%
* Corresponding authors. Tel.: +33 473 405 284, +33 473 407 875; fax: +33 473
407 717.
E-mail addresses: M-Eve.Sinibaldi-troin@univ-bpclermont.fr (M.-E. Sinibaldi),
isabelle.canet@univ-bpclermont.fr (I. Canet).
Scheme 1. Synthesis of 1,7-dioxaspiro[5.5]undecanes and 1,6-dioxaspiro[4.5]-
decanes.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.003

4148
A. Ollivier et al. / Tetrahedron Letters 51 (2010) 4147–4149
N
N
N
N
O
NBoc
NBoc
iii), iv), v)
vi)
i), ii)
OR1
R2
O
O
( )n
7
10a R1 = TBDPS, R2 = H, n = 1
10b R1 = TBDPS, R2 = H, n = 2
11c R1 = H, R2 = CH2OTBDPS, n = 1 43%
44%
55%
NBoc
O
O
OTBDPS
OTBDPS
( )n
I
I
6
8a n = 1
8b n = 2
9
NHBoc
NHBoc O
O
NBoc
vii)
O
O
R2
O
HO
OH
OH
R2
( )n
( )n
( )n
R
12a n = 1, R2 = H, quant.
12b n = 2, R2 = H, quant.
11a R2 = H, n = 1 93%
11b R2 = H, n = 2 86%
12c n = 1, R2 = CH2OTBDPS, 90%
11c R2 = CH2OTBDPS, n = 1
Scheme 2. (i) n-BuLi, THF, À10 °C; (ii) 6, THF, quant.; (iii) LDA, À78 °C, THF; (iv) 8a, 8b or 9, À20 °C, 12 h; (v) SiO2/H2O, CH2Cl2, 20 °C, 48 h, (vi) for 10a,b, TBAF, THF, 20 °C,
quant.; (vii) Yb(OTf)3, CH3CN, 20 °C, 24 h.
Thus, treatment of the lithiated acetone N,N-dimethylhydraz-
NH2.HCl
CO2H
NHBoc
CO2Me
i), ii), iii), iv)
v), vi), vii)
one by iodide 6 (see Scheme 3 for an access to 6 by an adaptation
of the reported synthesis7 of this substrate) led quantitatively (1H
NMR of the crude) to hydrazone intermediate 7. Compound 7 sub-
mitted to basic treatment (LDA) underwent a second alkylation
step with the known iodides 8a,b8 furnishing the disubstituted
hydrazones that delivered after their selective SiO2/H2O induced
cleavage, ketones 10a and 10b in 44% and 55% yields, respectively
(three steps, one final purification). Subsequent removal of the silyl
ether protecting group of 10a,b was then classically accomplished
using TBAF in THF and afforded the key hydroxy-ketones 11a and
HO
HO2C
L-aspartic-acid
NBoc
O
I
(S)-6
Scheme 3. Synthesis of iodide (S)-6. (i) SOCl2, À10 °C, MeOH, 91%; (ii) Boc2O,
Na2CO3, dioxane/H2O, 20 °C, 12 h, 89%; (iii) N-hydroxysuccinimide, DCC, CH2Cl2,
20 °C, 12 h; (iv) NaBH4, THF/EtOH (3/1), 0 °C, 15 min, 89% in two steps; (v) DMPE, p-
TsOH, CH2Cl2, 20 °C, 87%; (vi) LiAlH4, THF, 0 °C then 20 °C, 12 h, quant.; (vii) I2,
imidazole, PPh3, Et2O/CH3CN (3/2), 20 °C, 48 h, 95%.
Table 1
13C and 1H NMR data for 12a and 12b isomers (CDCl3)
O
O
O
14 O
O
14 O
12
12
16
15
16
15
15
15
13
13
9 HN
9 HN
13 O
13 O
HN
9
HN
9
14
14
10
10
8
8
10
11
7
10
11
7
8
11
12
8
11
12
(5R,8S)-12a
(5S,8S)-12a
(6R,9S)-12b
(6S,9S)-12b
O
5 O
2
O
5 O
2
O
O
2
O
4
4
5
5
6
6
3
O
3
3
2
4
4
3
dH, J in Hz
dC
dH, J in Hz
dC
dH, J in Hz
dC
dH, J in Hz
dC
2
3
4
5
3.63, td (8.0, 5.0)
3.66, br t (7.5)
1.41, m
1.71, m
1.22, m
66.8
3.67, td (8.0, 6.0)
3.77, td (8.0, 6.5)
1.46, m
1.80, m
1.29, m
66.9
3.42, dd (11.0, 5.0)
3.53, td (12.0, 2.5)
1.14, m
1.33, qt (13.0, 4.0)
1.21, m
1.64, qt (13.5, 3.5)
1.02, td (13.0, 4.0)
1.44, m
61.0
3.49, dd (10.0, 4.0)
3.66, m
1.20, m
1.39, m
1.33, m
1.85, m
1.12, m
1.71, m
61.1
24.9
38.1
24.7
38.2
25.7
19.2
25.8
19.2
35.4
99.6
1.66, m
1.89, m
110.5
110.1
35.2
6
7
100.0
3.37, dt (12.5, 2.5)
3.68, dd (13.0, 1.0)
3.85, dq (8.0, 2.0)
64.0
49.7
35.7
19.2
38.6
3.45, dd (12.0, 10.0)
3.60, br d (12.0)
3.91, m
65.4
51.1
36.1
20.5
38.1
8
3.32, dt (12.5, 2.5)
3.60, d (12.5)
3.88, m
62.9
49.7
35.9
18.1
41.7
3.37, td (11.0, 5.0)
3.62, m
3.87, m
64.2
51.0
36.5
19.6
41.2
9
1.11, m
1.93, br d (13.5)
1.14, m
0.90, dt (11.0, 10.5)
1.65, m
1.21, m
1.37, m
1.65, m
10
11
12
1.10, m
1.92, br d (13.0)
1.10, m
1.21, m
1.53, d (11.0)
1.59, m
0.74, m
1.68, m
1.22, m
1.23, m
1.63, dt (14.5, 7.5)
1.77, dd (14.5, 11.0)
5.38, d (8.0)
1.85, m
4.20, br s
1.68, m
13
14
15
16
155.1
78.6
28.6
155.0
78.5
28.5
5.41, d (8.5)
4.07, br s
155.1
78.6
28.6
155.0
78.6
28.5
1.47, s
1.43, s
1.47, s
1.45, s

A. Ollivier et al. / Tetrahedron Letters 51 (2010) 4147–4149
4149
Table 2
13C and 1H NMR data for 12c isomers
O
O
12
HN
HN
O
O
9
8
10
11
7
(2S,5S,8S)-12c
(2S,5R,8S)-12c
O
O
O
4
5
O
2
3
OTBDPS
OTBDPS
13
dH, J in Hz
dC
dH, J in Hz
dC
2
3
4.18, dq (8.0, 4.5)
1.68, m
78.9
26.9
4.21, q (6.5)
1.67, m
80.5
27.8
2.01, ddt (14.5, 11.5, 8.5)
1.51, dt (11.0, 8.0)
1.91, m
4
38.0
1.16, m
1.69, m
38.2
5
7
110.8
65.5
110.5
63.7
3.60, m
3.47, dd (11.5, 10.0)
3.91, m
3.11, br d (12.5)
3.53, d (13.0)
3.81, m
8
9
51.31
36.2
49.6
35.6
1.66, m
1.08, m
0.95, m
1.23, m
1.40, m
1.70, m
1.91, br d (13.5)
1.19, m
10
11
20.4
38.3
19.2
38.5
1.60, dd (15.0, 7.5)
1.76, dd (15.0, 11.5)
5.29, d (8.5)
3.53, dd (10.0, 5.5)
3.78, dd (10.0, 6.5)
1.46, s
1.91, m
12
13
4.26, br d (8.0)
3.68, dd (10.5, 4.0)
3.58, dd (10.5, 4.5)
1.43, s
66.7
68.7
N-Boc
155.0, 78.6, 28.5
19.6, 27.1
155.0, 78.5, 28.6
Si-tBu
1.15, s
1.17, s
47% yield) as a 1/1 separable mixture of the two spiranic epimers.
Our approach allowed the introduction of substitutions on the b
and
c positions relative to the spiranic center, using simple iodides
or epoxide precursors. Extension to the synthesis of others spiroke-
tals will be reported in due course.
References and notes
1. (a) Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617; (b) Jacobs, M. F.;
Kitching, W. Curr. Org. Chem. 1998, 2, 395; (c) Francke, W.; Schröder, W. Curr.
Org. Chem. 1999, 3, 407; (d) Francke, W.; Kitching, W. Curr. Org. Chem. 2001, 5,
233.
2. (a) Faul, M. M.; Huff, B. E. Chem. Rev. 2000, 100, 2407; (b) Mead, K. T.; Brewer, B.
N. Curr. Org. Chem. 2003, 7, 227; (c) Aho, J. E.; Pihko, P. M.; Rissa, T. K. Chem. Rev.
2005, 105, 4406.
3. For recent examples of synthesis of these systems, see: (a) Aponick, A.; Li, C. Y.;
Palmes, J. A. Org. Lett. 2009, 11, 121; (b) Selvaratnam, S.; Ho, J. H. H.; Huelatt, P.
B.; Messerle, B. A.; Chai, C. L. L. Tetrahedron Lett. 2009, 50, 1125; (c) Liu, G.;
Wurst, J. M.; Tan, D. S. Org. Lett. 2009, 11, 3670; (d) Aponick, A.; Li, C.-Y.;
Palmes, J. A. Org. Lett. 2009, 11, 121; (e) de Greef, M.; Zard, S. Z. Org. Lett. 2007,
9, 1773; (f) Moilanen, S. B.; Potuzak, J. S.; Tan, D. S. J. Am. Chem. Soc. 2006, 128,
1792; (g) Doubsky, J.; Streinz, L.; Saman, D.; Zednik, J.; Koutek, B. Org. Lett.
2004, 6, 4909; (h) Ghosh, S. K.; Hsung, R. P.; Wang, J. Tetrahedron Lett. 2004, 45,
5505; (i) Bez, G.; Bezbarua, M. S.; Saikia, A. K.; Barua, N. C. Synthesis 2000, 537;
(j) Nakamura, K.; Kitayama, T.; Inoue, Y.; Ohno, A. Tetrahedron 1990, 46, 7471.
4. For a review of the use of N,N-dialkylhydrazones in organic synthesis see: (a)
Lazny, R.; Nodzewska, A. Chem. Rev. 2010, 110, 1366; For some recent
applications in spiroketals synthesis see: (b) Dias, L. C.; de Oliveira, L. G. Org.
Lett. 2004, 6, 2587; (c) Panek, J. S.; Jain, N. F. J. Org. Chem. 2001, 66, 2747.
5. Tursun, A.; Canet, I.; Aboab, B.; Sinibaldi, M.-E. Tetrahedron Lett. 2005, 46, 2291.
6. Goubert, M.; Canet, I.; Sinibaldi, M.-E. Eur. J. Org. Chem. 2006, 4805.
7. Kadota, I.; Saya, S.; Yamamoto, Y. Heterocycles 1997, 46, 335.
8. Compounds 7a,b were prepared from their monosilylated alcohol (Mac Dougal,
P. G.; Rico, J. G.; Oh, Y.-I.; Condon, B. D. J. Org. Chem. 1986, 51, 3388).
Spectroscopic data were in accordance with those reported by Paquette, L. A.;
Doherty, A. M.; Rayner, C. M. J. Am. Chem. Soc. 1992, 114, 3910 for 8a, by
Dawson, I. M.; Gregory, J. A.; Herbert, R. B.; Sammes, P. G. J. Chem. Soc. Perkin
Trans. 1 1988, 2585 for 8b.
9. (a) Nicolaou, K. C.; He, Y.; Vourloumis, D.; Valberg, H.; Roschangar, F.; Sarabia,
F.; Ninkovic, S.; Yang, Z.; Trujilla, J. I. J. Am. Chem. Soc. 1997, 34, 7960; For ring
opening of epoxide by N,N-dimethylhydrazones see: (b) Evans, D. A.; Bender, S.
L.; Morris, J. J. Am. Chem. Soc. 1988, 110, 2506.
Figure 1. ORTEP of 12b.
11b in good yields. In a same manner, the attack of the anion of
hydrazone 7 on epoxide 99 permitted its ring opening, leading di-
rectly to the keto-diol 11c in 43% yield.
Finally, p-TsOH/MeOH mediated deprotection-spirocyclization
of 11a,b,c afforded, as the sole cleanly isolated derivatives, 1,6-
dioxaspiro[4.6]undecanes 12a,c and 1,7-dioxaspiro[5.6]dodecane
12b (Scheme 2). In an attempt to increase the formation of these
spirocyclic compounds, we modified the nature of the acid. Treat-
ment of 11 by HCl/methanol or AmberlystÒ 15 led unfortunately to
degradation of the reaction mixture. Conversely, the use of
Yb(OTf)3 in CH3CN revealed efficient3d and gave nearly quantita-
tively and exclusively the spirocyclic epimers 12 in a 1/1 ratio.
These diastereomers could be cleanly separated on neutral alu-
mina and fully characterized (Tables 1 and 2). Furthermore, in the
spiro[5.6] series, if the (6R,9S)-isomer of 12b occurred as an oil, its
(6S,9S) epimer could be obtained as a fine white powder easily
recrystallized from ethanol. Its structure and the relative stereo-
chemistry of the spiranic center were then confirmed by an X-
ray crystallographic analysis as shown as ORTEP plot in Figure 1.10
In summary, we demonstrated here the efficiency of our strat-
egy to prepare in a few steps and good yields the 1,6-dioxaspi-
ro[4.6]undecanes 12a,c (five steps, 41% yield for 12a; four steps,
39% yield for 12c) and 1,7-dioxaspiro[5.6]dodecane 12c (five steps,
10. The crystal structure has been deposited at the Cambridge Crystallographic
Data Centre and allocated the deposition number CCDC 720349.