A short and versatile route to chiral spiroketal skeletons

Article abstract of DOI:10.1016/j.tetlet.2005.02.009

Different chiral spiroketal skeletons are obtained, in a versatile manner, by iterative alkylations of acetone N,N-dimethylhydrazone with iodides 2 followed by a one-pot deprotection/spirocyclization sequence. This methodology has been applied successfull

Full text of DOI:10.1016/j.tetlet.2005.02.009

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2291–2294
A short and versatile route to chiral spiroketal skeletons
Ahmatjan Tursun, Isabelle Canet,* Bettina Aboab and Marie-Eve Sinibaldi*
` `
Laboratoire de Synthese Et Etude de Systemes a Interet Biologique (SEESIB), UMR CNRS 6504,
Universite BlaisePascal, 63177 Aubiere Cedex, France
`
´ ˆ
´
`
Received 16 December 2004; revised 27 January 2005; accepted 1 February 2005
Abstract—Different chiral spiroketal skeletons are obtained, in a versatile manner, by iterative alkylations of acetone N,N-dimeth-
ylhydrazone with iodides 2 followed by a one-pot deprotection/spirocyclization sequence. This methodology has been applied suc-
cessfully to the synthesis of 1,7-dioxaspiro[5.5]undecane and 1,6-dioxaspiro[4.5]decane systems.
Ó 2005 Elsevier Ltd. All rights reserved.
The 1,7-dioxaspiro[5.5]undecane and the 1,6-dioxa-
spiro[4.5]decane systems are important subunits of nat-
ural products from various sources, including insects,
microbes, plants, fungi and marine organisms.1 In par-
ticular, these moieties occur in a large number of biologi-
cally active compounds such as polyether ionophores,
insect pheromones and antibiotic macrolides. They have
also been employed as scaffold in the synthesis of con-
formationally restrained glycomimetics.2
As a part of our research programme is devoted to the
synthesis of novel antimitotic spiroketal derivatives, we
focused our attention on the epidermal growth factor
inhibitors reveromycins A and B.3 In contrast with other
natural antitumour compounds bearing a spiroketal
framework in their skeleton (i.e., spongistatin) these
products show a more simplified structure while main-
taining interesting activity. Additionally, it was recently
reported that poorly substituted spiroketals exhibit bio-
logical effects such as tubulin modulation4 (Spiket P)
and cytotoxicity against tumour cell lines5 (Fig. 1).
Therefore, in order to prepare analogues (modulations
of sizes and substituents) of spiroketal units, we devel-
oped a short and versatile synthesis of frameworks 1.
The key step of our approach is based upon an acidic
spirocyclization of a chiral diketalketone 4 obtained in
three steps from N,N-dimethylhydrazones and isopropyl-
idene iodides 2 (Scheme 1).
To check the validity of our approach, we first addressed
the synthesis of unsubstituted spiroketals 1 (Scheme 1,
R = H).
First part of our work was devoted to the preparation of
synthons 2a and 2b. Iodide 2a was synthesized from
L-malic acid using an improved sequence (Scheme 2),
inspired from the procedure previously described by
Mori and Watanabe.6 Thus, 2a was obtained in six
steps in 47% overall yield. Compound 2b was prepared
in two steps from commercially available (S)-solketal.7
Figure 1.
Keywords: Spiroketals; Stereoselective synthesis; Hydrazone; Isoprop-
ylidene iodides.
*
Corresponding authors. Tel.: +33 473 407 875; fax: +33 473 407
017; e-mail addresses: icanet@chimie.univ-bpclermont.fr; sinibald@
chimie.univ-bpclermont.fr
Alkylation of the lithiated acetone N,N-dimethylhydraz-
one8 with (S)-iodide 2a provided, nearly quantitatively,
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.009

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A. Tursun et al. / Tetrahedron Letters 46 (2005) 2291–2294
1b and 1c were obtained, in 84% yield, as an inseparable
mixture of isomers (3/2 ratio determined from quantita-
tive 13C NMR spectrum). This mixture was then treated
with TBDPSCl in DMF in the presence of imidazole,
furnishing silylated derivatives 1e and 1f, which could
be separated by flash chromatography. Transformation
Scheme 1.
the monoalkylated hydrazone 3, which was immediately
used in the next step without further purification. A sec-
ond alkylation using either iodide (S)-2a, or (R)-2b led,
after SiO2-induced cleavage9 of the hydrazone function,
to the appropriate ketones 4a,b10 in 43% and 64% over-
all yield, respectively (Scheme 3).
Deprotection of the two acetal groups concomitant with
spirocyclization was achieved by simple treatment of
4a,b with AmberlystÒ 15 in MeOH at room temperature
during 48 h (Scheme 3).
In this way, the (2S,6S,8S)-1a isomer10 was efficiently
obtained from 4a as the sole product. The absolute con-
figuration at the central spirocarbon of 1a is controlled
by steric and anomeric effects11 whereas the configura-
tions of the carbons bearing the side chains resulted
from the configuration of the iodide precursor 2a.
Finally, compound 1a is obtained, without racemiza-
tion, from L-malic acid in 10 steps and 15% overall yield.
Our methodology is therefore competitive with that re-
ported by Uckun et al.4a (10 steps, 8.6% yield) or
Chattopadhyay and co-workers4d (eight steps, 15.5%
yield).
In the case of compound 4b the acidic tandem deprotec-
tion/cyclization reaction provided, as expected,12
a
mixture of 1,7-dioxaspiro[5.5]undecane 1b (Scheme 3,
pathway a) and 1,6-dioxaspiro[4.5]decanes 1c and 1d
(Scheme 3, pathway b), in 93% yield. Although com-
pound 1d13 could be isolated in 9% yield, compounds
Scheme 3.
Scheme 2.

A. Tursun et al. / Tetrahedron Letters 46 (2005) 2291–2294
2293
ily available starting materials. By this route, 1a, 1b, 1c
and 1d were obtained, from iodides 2a and 2b, in 32%
(four steps), 29% (six steps), 14% (six steps) and 6%
(six steps) overall yield, respectively. Furthermore, as
the enantiomers of the starting materials are readily
available, this approach is also applicable to the synthe-
sis of the antipode spiroketals.
Application of this methodology to the synthesis of
substituted spiroketals from modified iodide derivatives
2 is actually in progress in our laboratory. In addition,
the antitumoural activity of all synthesized spiroketals
will be evaluated in due course.
Figure 2. Calculated structures for (2S,5R,7S)- and (2S,5S,7S)-1,6-
dioxaspiro[4.5]decanes. Hydrogen bonds are represented by a line.
of compounds 1e and 1f to the corresponding alcohols
1b13 and 1c13 was achieved by a classical method using
Bu4NF in THF (Scheme 3).
References and notes
For the same reasons as 1a, the configuration of com-
pound 1b is (3S,6S,8S) as confirmed by the equatorial
position of the hydroxyl group at C3 (H3 gave a triplet
of triplet, J = 10.0 and 4.5 Hz).14 We assumed that by
taking into account the factors that determine the ste-
reochemistry of 1a the major isomer 1c has configura-
tion (2S,5S,7S). In order to confirm this hypothesis,
we compared the experimental data to those obtained
by molecular modeling (Fig. 2).15
1. (a) Vaillancourt, V.; Pratt, N. E.; Perron, F.; Albizali, K.
F. In The Total Synthesis of Natural Products; John Wiley
& Sons: New York, 1992; Vol. 8; (b) Perron, F.; Albizati,
K. F. Chem. Rev. 1989, 89, 1617–1661; (c) Mead, K. T.;
Brewer, B. N. Curr. Org. Chem. 2003, 7, 227–256.
2. Bell, W.; Block, M. H.; Cook, C.; Grant, J. A.; Timms, D.
J. Chem. Soc., Perkin Trans. 1 1997, 18, 2789–2801.
3. (a) El Sous, M.; Ganame, D.; Tregloan, P. A.; Rizzacasa,
M. A. Org. Lett. 2004, 6, 3001–3004; (b) Shimizu, T.;
Usui, T.; Machida, K.; Furuya, K.; Osada, H.; Nakata, T.
Bioorg. Med. Chem. Lett. 2002, 12, 3363–3366; (c)
Tanaka, Y.; Ishikawa, F.; Osada, H.; Imajoh-Ohmi, S.;
Uchida, T.; Kakiuchi, T. J. Antibiot. 2002, 55, 904–913;
(d) Cuzzuppe, A. N.; Hutton, C. A.; Lilly, M. J.; Mann, R.
K.; McRae, K. J.; Zammit, S. C.; Rizzacasa, M. A. J. Org.
Chem. 2001, 66, 2382–2393.
4. (a) Synthesis of spiroketal, named Spiket P by Uckun
et al., was pioneered in our laboratory by Jeminet et al.
Uckun, F. M.; Mao, C.; Vassilev, A. O.; Huang, H.; Jan,
S.-T. Bioorg. Med. Chem. Lett. 2000, 10, 541–545; (b)
Huang, H.; Mao, C.; Jan, S.-T.; Uckun, F. M. Tetrahe-
dron Lett. 2000, 41, 1699–1702; (c) Sauret, S.; Cuer, A.;
Gourcy, J.-G.; Jeminet, G. Tetrahedron: Asymmetry 1995,
6, 1995–2000; (d) Sharma, A.; Iyer, P.; Gamre, S.;
Chattopadhyay, S. Synthesis 2004, 1037–1040.
5. (a) Mitsuhashi, S.; Shima, H.; Kawamura, T.; Kikuchi,
K.; Oikawa, M.; Ichihara, A.; Oikawa, H. Bioorg. Med.
Chem. Lett. 1999, 9, 2007–2012; (b) Kikuchi, K.; Shima,
H.; Mitsuhashi, S.; Suzuki, M.; Oikawa, H. Drugs Future
2000, 25, 501–507.
The isomer I of (2S,5R,7S) configuration (highest energy,
DH0f ¼ À189:57 kcal molÀ1) presented a structure in
which the lost of one anomeric effect is counterbalanced
by an intercyclic hydrogen bond (calculated distance be-
˚
tween OH and O6: 1.82 A). The isomer II of (2S,5S,7S)
configuration, is the more stable isomer (DH0f ¼
À193:42 kcal molÀ1) exhibiting the attempted double
anomeric structure (Fig. 2). In this isomer, the existence
of an 1,3-diaxial relationship between H7, H9ax and O1
should lead to a deshielded position of the resonances
for these two hydrogens. Both calculated structures were
in close agreement with the experimental NMR data13
as illustrated by (i) the chemical shifts observed for
H7 and H9 (1c: dH7 = 3.91 ppm, dH9ax = 1.82 ppm,
d
H9eq = 1.70 ppm; 1d: dH7 = 3.70 ppm, dH9 = 1.52 and
1.31 ppm) supporting a trans-configured tetrahydropy-
ran ring for 1c, (ii) the calculated and measured scalar
coupling constants (Table 1).
6. Selected data for compound 2a: 1H NMR (400 MHz,
CDCl3): d 4.18 (tdd, 1H, J = 6.0, 7.5, 4.5 Hz), 4.08 (dd,
1H, J = 8.0, 6.0 Hz), 3.57 (dd, 1H, J = 8.0, 6.0 Hz), 3.27
(ddd, 1H, J = 10.0, 5.5, 8.0 Hz), 3.22 (dt, 1H, J = 10.0,
7.5 Hz), 2.10 (tdd, 1H, J = 7.5, 14.0, 5.5 Hz), 2.03 (tdd,
1H, J = 8.0, 14.0, 4.5 Hz), 1.41 (3H, s), 1.35 (3H, s); 13C
NMR (100 MHz, CDCl3): d 109.1, 75.6, 68.6, 37.8, 26.9,
In summary, we have developed an efficient and stereo-
selective approach to 1,7-dioxaspiro[5.5]undecane and
to 1,6-dioxaspiro[4.5]decane ligands 1a,b,c,d from read-
25
25
25.5, 1.2; ½aꢀD À23.8 (c 2.1, CHCl3) lit. ½aꢀD À22.3 (c 2.12,
CHCl3) Mori, K.; Watanabe, H. Tetrahedron Lett. 1986,
42, 295–304.
Table 1. Selected calculated and observed scalar coupling constants
for 1c and 1d
Calculated Calculated Observed
J (Hz)
7. Kawakami, Y.; Asai, T.; Umeyama, K.; Yamashita, Y.
J. Org. Chem. 1982, 47, 3581–3585.
8. (a) Enders, D.; Dahmen, W.; Dederichs, E.; Gatzweiler,
W.; Weuster, P. Synthesis 1990, 1013–1019; (b) Crimmins,
M. T.; Rafferty, S. W. Tetrahedon Lett. 1996, 37, 5649–
5652.
9. Under the used experimental conditions (Kotsuki, H.;
Miyazaki, I.; Kadota, M. O. J. Chem. Soc., Perkin Trans.
1 1990, 429–430), no deprotection of the cyclic ketals was
detected.
dihedral
angle (deg)
J (Hz)
Isomer I (1d)
H2–H3a 1.7
H2–H3b 120.4
9.6
4.7
8.0
2.5
Isomer II (1c) H2–H3a 6.7
H2–H3b 125.2
H7–H8a 172.3
9.5
5.5
8.0
5.0
12.2
3.9
12.0
3.0
H7–H8b
55.1

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A. Tursun et al. / Tetrahedron Letters 46 (2005) 2291–2294
10. Compounds 4a, 4b and 1 were characterized by 1H and
13C NMR measurements and mass spectra. In the case of
1a comparison with an authentical sample of our
laboratory was also realized. All the data of 1a were in
good agreement with the proposed structure 1a: 1H
NMR (400 MHz, CDCl3): d 3.74 (dddd, 2H, J = 11.5,
7.0, 3.0, 2.5 Hz), 3.60 (dd, 2H, J = 11.0, 3.0 Hz), 3.50 (dd,
2H, J = 11.0, 7.0 Hz), 2.20 (2H, OH), 1.89 (qt, 2H,
J = 13.0, 4.5 Hz), 1.62 (m, 4H), 1.50 (md, 2H,
J = 13.0 Hz), 1.41 (td, 2H, J = 13.0, 4.5 Hz), 1.30 (tdd,
2H, J = 13.0, 11.5, 4.0 Hz); 13C NMR (100 MHz,
CDCl3): d 96.3 (C6), 70.0 (C2 and C8), 66.5 (CH2OH),
35.5 (C5 and C11), 26.6 (C3 and C9), 18.5 (C4 and C10);
6.5, 3.0 Hz), 3.73 (dd, 1H, J = 11.5, 3.0 Hz), 3.58 (dd, 1H,
J = 11.5, 3.0 Hz), 3.52 (dd, 1H, J = 11.5, 6.0 Hz), 3.48 (dd,
1H, J = 11.5, 6.5 Hz), 2.3 (br s, 2H, OH), 2.1 (m, 1H), 1.96
(m, 1H), 1.82 (qt, 1H, J = 13.0, 4.0 Hz), 1.70 (m, 5H), 1.50
(dq, 1H, J = 13.0, 3.0 Hz), 1.32 (qd, 1H, J = 13.0, 3.5 Hz);
13C NMR (100 MHz, CDCl3): d 106.6 (C5), 78.2 (C2),
71.0 (C7), 66.0 (CH2OH), 64.7 (CH2OH), 37.7 (C10), 32.9
(C4), 26.2 (C8), 25.3 (C3), 19.6 (C9); IR (film) 3335, 2941,
25
1150, 1380, 1222, 1042; ½aꢀD +70.87 (c 1.38, CHCl3).
Compound 1d: 1H NMR (400 MHz, CDCl3): d 4.36 (tt,
1H, J = 8.0, 2.5 Hz), 3.84 (dd, 1H, J = 12.0, 2.5 Hz), 3.70
(m, 1H), 3.65 (br s, 2H, OH), 3.62 (m, 2H), 3.48 (dd, 1H,
J = 12.0, 8.0 Hz), 2.4 (m, 1H), 2.1 (m, 1H), 1.90 (m, 2H),
25
½aꢀD +70.0 (c 0.46, CHCl3). For (2R,6R,8R)-Spi-
1.74 (m, 1H), 1.62 (m, 2H), 1.52 (m, 2H), 1.31 (m, 1H); 13
C
22
ket P4a ½aꢀD À59.4 (c 0.7, CHCl3).
NMR (100 MHz, CDCl3): d 107.6 (C5), 81.2 (C7), 75.6
(C2), 66.3 (CH2OH), 64.0 (CH2OH), 34.0 (C4), 33.3 (C6),
11. Deslongchamps, P. Stereoelectronic Effects in Organic
Chemistry; Pergamon: New York, 1983; Chapter 2.
12. Mori, K.; Watanabe, H.; Yanagi, K.; Minobe, M.
Tetrahedron 1985, 41, 3663–3672.
25
26.2 (C3), 24.2 (C8), 21.1 (C9); ½aꢀD +18.84 (c 0.34,
CHCl3).
14. Baker, R.; Herbert, R. H. J. Chem. Soc., Perkin Trans. 1
1987, 1123–1127.
13. Compound 1b: 1H NMR (400 MHz, C6D6): d 4.1 (br s,
2H, OH), 3.76 (ddd, 1H, J = 10.0, 4.5, 2.0 Hz), 3.71 (m,
1H), 3.66 (tt, 1H, J = 10.0, 4.5 Hz), 3.57 (t, 1H,
J = 10.0 Hz), 3.51 (dd, 1H, J = 11.5, 6.5 Hz), 3.48 (dd,
1H, J = 11.5, 4.0 Hz), 2.0 (m, 1H), 1.88 (qt, 1H, J = 13.0,
4.0 Hz), 1.77 (m, 1H), 1.65 (dt, 1H, J = 13.0, 3.5 Hz), 1.46
(d, 1H, J = 13 Hz), 1.37 (m, 1H), 1.37 (td, 1H, J = 13.0,
4.0 Hz), 1.22 (m, 2H), 1.05 (qd, 1H, J = 12.5, 4.0 Hz); 13C
NMR (100 MHz, C6D6): d 95.0 (C6), 71.0 (C2), 66.4
(CH2OH), 66.3 (C9), 64.8 (C8), 35.2 (C11), 34.6 (C5), 28.3
(C10), 26.8 (C3), 19.0 (C4); IR (film) 3401, 2944, 1660,
15. Conformational analysis was performed using Monte-
Carlo multiple method (Chang, G.; Wayne, C.; Guida, W.
C.; Still, W. C. J. Am. Chem. Soc. 1989, 111, 4379–4386)
with MM3 force field (Allinger, N. L.; Yuh, Y. H.; Lii, J.
H. J. Am. Chem. Soc. 1989, 111, 8551–8566) of Macro-
model 7.0 program (Macromodel 7.0, Shroedinger Inc.,
1500 SW First Ave., Suite 1180, Portland, OR 97201,
USA). Then quantum semi-empirical calculations SAM1
(Dewar, M. J. S.; Lie, C.; Yu, J. Tetrahedron 1993, 49,
5003–5038) on both isomers global minima geometries
found previously were carried out using AMPAC 7.0
program (Ampac7.0, Ó 2000 Semichen, 7128 Summit,
Shawnee, KS 66216, USA).
25
1446, 1377, 1227, 1177, 1054, 1018; ½aꢀD +76.43 (c 1.26,
CHCl3). Compound 1c: 1H NMR (400 MHz, CDCl3): d
4.21 (dtd, 1H, J = 8.0, 5.5, 3.0 Hz), 3.91 (ddt, 1H, J = 11.5,