Diastereoselective synthesis of 1,2-O-isopropylidene-1,6-dioxaspiro[4,4]nonane applying the methodology of generation of radical cations under non-oxidizing conditions

Article abstract of DOI:10.1016/S0040-4039(03)00817-7

We report the stereoselective synthesis of an optically pure spiroketal via an intramolecular tandem hydrogen abstraction reaction promoted by an alkoxy radical. Expanding the use of alkene radical cation under non-oxidizing conditions in the synthetic sc

Full text of DOI:10.1016/S0040-4039(03)00817-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3919–3921
Diastereoselective synthesis of
1,2-O-isopropylidene-1,6-dioxaspiro[4,4]nonane applying the
methodology of generation of radical cations under
non-oxidizing conditions
Fernando Sartillo-Piscil,a,* Mo´nica Vargas,a Cecilia Anaya de Parrodib and Leticia Quinteroa,*
aCentro de Investigacio´n de la Facultad de Ciencias Qu´ımicas, Beneme´rita Universidad Auto´noma de Puebla, 72570 Puebla,
Mexico
bDepartamento de Qu´ımica y Biolog´ıa, Universidad de las Americas-Puebla, 72820, Santa Catarina Ma´rtir, Puebla, Mexico
Received 13 March 2003; revised 27 March 2003; accepted 27 March 2003
This manuscript is dedicated to the memory of our friend, Adelina Gonza´lez
Abstract—We report the stereoselective synthesis of an optically pure spiroketal via an intramolecular tandem hydrogen
abstraction reaction promoted by an alkoxy radical. Expanding the use of alkene radical cation under non-oxidizing conditions
in the synthetic scenario. © 2003 Elsevier Science Ltd. All rights reserved.
The generation of radical cations from b-(phos-
phatoxy)alkyl and b-(acetoxy)alkyl radicals under non-
oxidizing conditions has been widely studied.1 The
importance of this finding not only has enormous
implications on the understanding of the DNA degra-
dation by anti-cancer agents such as bleomycin and
enedyine agents,2 but, on the synthesis of various hete-
rocycles.3 In this regard, Crich et al., have developed
new access for the construction of tetrahydrofuran,3a,b
pyrrolizidine,3c indolizidine3d,e and spiroacetal nucleus.3f
Although, spiroacetal nucleus3f were synthesized for
mechanistic purposes, yields were very low after purifi-
cation. Thus, we decided to apply this methodology for
the construction of a spiroketal nucleus. These nucleus
are present in many molecular structures, and some
exhibit pheromonal activity (Scheme 1).4
A convenient alkoxy radical precursor was the N-
alkoxyphthalimide 4. So, the synthesis of compound 4,
was started with a ‘one pot’ hydrolysis–oxidation and
Wittig olefination of the 1:2,5:6-di-O-isopropylidene-a-
D
-glucose 5a to give the corresponding a,b-unsaturated
ester 6a followed by a reduction reaction to afford 7.
The reduction of the double bond and carbonyl group
of 6a was performed first, with H2/Pd(OH)2, then with
Scheme 1. 2-Ethyl-1,6-dioxaspiro[4,4]nonane (1 and 2). Prin-
cipal aggregation pheromone of Pityogenes chalcographus.
Our strategy was based on the tandem hydrogen
abstraction cyclization sequence, promoted by an
alkoxy radical (A).3a Radical (A) abstracted the hydro-
gen atom at C%4 position, and the alkyl radical formed
(B) rapidly expelled the phosphate group affording (C).
Then, the enol ether radical cation (C) was trapped by
the hydroxy group, and finally, the reduction reaction
afforded the expected spiroketal 3 (Scheme 2).
Scheme 2. Tandem hydrogen abstraction cyclization
* Corresponding authors. Tel.: +52 2222 454293; fax: +52 2222
454293; e-mail: fsarpis@siu.buap.mx; lquinter@siu.buap.mx
sequence.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00817-7

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F. Sartillo-Piscil et al. / Tetrahedron Letters 44 (2003) 3919–3921
LiAlH4.5 Diol 7 was converted regioselectively to the
primary N-alkoxyphthalimide 8 in good yield using the
Mitsunobu protocol.6 Finally, 8 was phosphorylated
with diethylchlorophosphate in the presence of DMAP
yielding the alkoxy radical precursor 4 (see Scheme 3).
Scheme 4. AlCl3-catalyzed spiroisomerization of 3.
The accessibility of the sequential hydrolysis–oxidation
and Wittig olefination transformation of 5a to the
corresponding a,b-unsaturated ester 6a in one pot
prompted us to test this protocol to other 1:2,5:6-di-O-
isopropylidene-a-
-glucose derivatives 5b–d.7 The selec-
D
tivity of the double bond formation was modest and
low, as previously some authors have reported when
stabilized ylides and protected or unprotected a-
alkoxyaldehydes are used8 (see Table 1).
Figure 2. Intermediate ion pair model for the nucleophilic
addition of the alkoxy radical A to the radical cation.
Tin hydride-mediated cleavage of the N-alkoxyphthal-
imide 4 was carried out using the Kim’s3a,9 protocol.
Compound 4 was refluxed in benzene. Then, a solution
of Ph3SnH, and a catalytic amount of AIBN in benzene
were added dropwise. The analysis of the reaction
1
mixture by H NMR showed the presence of only two
products in a ratio 10:1 (based on the anomeric hydro-
gen), 13C NMR spectrum showed only one ketalic
carbon at 115.6 ppm. The major product corresponded
to the expected spiroketal 310 (in a 75% yield).
Scheme 3. Reagents and conditions: (a) i. 1.3 equiv. H5IO6/
AcOEt; ii. 2.3 equiv. Ph3PꢀCHCOOMe/THF (one pot) (86%);
(b) i. H2/Pd(OH)2/AcOEt; ii. LiAlH4/THF/rt (one pot) (88%);
(c) N-hydroxyphthalimide/Ph3P/DEAD/THF/rt/15 h (76%);
(d) EtO2POCl/DMAP/CH2Cl2/rt/24 h (72%).
The stereochemistry of the spiroketal 3 was deducted
by 2D NOESY experiments. The main cross-peak inter-
actions are shown in Figure 1.
Unfortunately, after several attempts, we could not
isolate the minor product. Nevertheless, we looked
forward to prove that the minor product was not the
diastereoisomeric spiroketal 3%. So, we prepared 3%
adding a catalytic amount of AlCl3 into the NMR tube
containing spiroketal 3 in CDCl3. The mixture was
analyzed by 13C NMR, and the 13C NMR spectrum
showed two ketalic carbons at 115.6 and 116.1 ppm
(Scheme 4).
Table 1. Sequential hydrolysis–oxidation–Wittig olefination
(SHOWO)a
Entry
Compound
R
Product
E/Z
Yield
Thus, the regioselectivity and stereoselectivity outcome
depend on two important factors. First, the remarkable
favored [1,5] hydrogen abstraction over [1,6] hydrogen
abstraction, due to the well-known entropic factors.
Second, the contact ion pair and memory effects
recently introduced by Crich and Ranganathan (see
Fig. 2).3e
1b
2
3
5a
5b
5c
5d
H-
Me-
Bn-
6a
6b
6c
6d
4/1.0c
1/1.4
1/1.5
1/3.0
86
83
81
80
4
MsO-
a Yields were obtained after purification in column chromatographic
and E/Z ratios were determined by 1H NMR.
b 2.5 equivalents of ylide were added.
In conclusion, a novel protocol for dehomologation
and transformation of 1:2,5:6-di-O-isopropylidene-a-D-
c Z olefin was obtained as an a,b-lactone.
glucose and some derivatives to the corresponding a,b-
unsaturated esters (in one pot) was described. Besides,
the introduction of a new way of generation of C%4
b-(phosphatoxy)alkyl radical was discussed. Finally, a
novel method for the synthesis of spiroketals is
described. In this regard, the applications of this
methodology for the synthesis of optically pure spiroke-
tals with pheromonal activity are currently underway
and will be reported in due course.
Figure 1. Representative NOESY interactions observed for
the spiroketal 3.

F. Sartillo-Piscil et al. / Tetrahedron Letters 44 (2003) 3919–3921
3921
Acknowledgements
4H), 3.66 (m, 2H), 4.0 (s, 1H), 4.14 (t, 1H, J=6.6 Hz),
4.16 (a, 1H), 4.5 (d, 1H, J=3.6 Hz), 5.8 (d, 1H, J=3.6
Hz); 13C NMR (100 MHz, CDCl3) l 24.2, 26.1, 26.6,
28.5, 62.3, 75.0, 80.7, 82.2, 85.3, 104.2, 111.4.
Authors thank CONACYT for financial support (Pro-
ject No. 35102-E) and the referees for their nice
suggestions.
6. Mitsunobu, O. Synthesis 1981, 1.
7. General protocol for the SHOWO: A solution of 5a–d
(0.8 mmol) and periodic acid (0.9 mmol) in 15 mL of dry
ethyl acetate was allowed to stir for 3 h, then filtration,
and evaporation under reduce pressure afforded a color-
less syrup which immediately was dissolved in 5 mL of
dry THF and added to the freshly prepared ylide (1.9
mmol of phosphonium salt and 1.2 mL of n-BuLi, 1.6 M
(1.9 mmol) dissolved in 30 mL of dry THF at 0°C were
stirred for 30 min). The reaction mixture was allowed to
react overnight, quenched with H2O and extracted with
ethyl acetate and the residue was purified by flash
chromatography.
8. (a) Harcken, C.; Martin, S. F. Org. Lett. 2001, 3, 3591–
3593; (b) Valverde, S.; Martin-Lomas, M.; Herradon, B.;
Garcia-Ochoa, S. Tetrahedron 1987, 43, 1895–1901; (c)
Corey, E. J.; Goto, G. Tetrahedron Lett. 1980, 21, 3463–
3466.
References
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P.; Sibi, M., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2,
pp. 188–206; (b) Huang, X. Ph.D. Dissertation, Univer-
sity of Illinois at Chicago, 2000.
2. Pogozelski, W. K.; Tullius, T. D. Chem. Rev. 1998, 98,
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5. Protocol for the double bond and carbonyl groups reduc-
tion of the 5a ‘in one pot’: A solution of 5a (803 mg, 3.28
mmol) and palladium hydroxide, 20% wt (100 mg) in 20
mL of dry ethyl acetate was allowed to stir for 4 h under
an hydrogen atmosphere. Then, solid catalyst was filtered
and the organic phase was evaporated under reduced
pressure. The colorless syrup obtained was dissolved in
20 mL of dry THF, LAH was added (377 mg, 9.9 mmol)
at 0°C and the reaction mixture was allowed to stir for 2
h. The reaction was quenched by the slow addition of a
mixture of H2O and THF (1:1). Finally, the reaction
mixture was dried with Na2SO4 and evaporated under
9. Kim, S.; Lee, T. A.; Song, Y. Synlett 1998, 471–472.
10. To a solution of 4 (100 mg, 0.2 mmol) in 40 mL of dried
and degased benzene at 80°C was added dropwise
Ph3SnH (91 g, 2.6 mmol) and AIBN (8 mg) dissolved in
40 mL of dried and degased benzene. The reaction mix-
ture was allowed to stir for 2 h before evaporating under
reduced pressure. The residue was purified by column
chromatography through silica gel (petroleum ether–ethyl
acetate–triethylamine, 80:10:1) giving 3 as colorless oil
1
(30 mg, 75%). [h]D=+32.2 (c 1, CHCl3); H NMR (400
MHz, CDCl3) l 1.34 (s, 3H), 1.54 (s, 3H), 1.94 (m, 2H),
2.17 (m, 2H), 2.31 (m, 1H), 2.38 (dd, 1H, J=14.4, 5.8
Hz), 3.86 (m, 1H), 3.97 (m, 1H), 4.78 (ddd, 1H, J=5.8,
4.0, 1.8 Hz), 5.81 (d, 1H, J=4.0); 13C NMR (100 MHz,
CDCl3) l 24.5, 26.7, 27.5, 37.2, 41.3, 67.8, 80.1, 104.6,
112.2, 115.8. Anal calcd for C10H16O4: C, 59.98; H, 8.05.
Found C, 60.23; H, 8.21%.
1
reduced pressure to give 6a (0.63 g, 88%). H NMR (400
MHz, CDCl3) l 1.31 (s, 3H), 1.49 (s, 3H), 1.52–1.8 (m,