Chiral 6-phenyl-2,3-bismethylenemethoxycarbonyl-[1,4]-dioxane as a designer synthon for an efficient and short synthesis of optically pure 2,6-dioxabicyclo[3.3.0]octane-3,7-dione

Article abstract of DOI:10.1016/j.tetlet.2005.11.116

Chiral 6-phenyl-2,3-bismethylenemethoxycarbonyl-[1,4]-dioxane, synthesized by the PET cyclization of 8, has been used as a designer synthon for an efficient and short synthesis of optically pure 2,6-dioxabicyclo[3.3.0]octane-3, 7-dione.

Full text of DOI:10.1016/j.tetlet.2005.11.116

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 701–703
Chiral 6-phenyl-2,3-bismethylenemethoxycarbonyl-[1,4]-dioxane as
a designer synthon for an efficient and short synthesis of
optically pure 2,6-dioxabicyclo[3.3.0]octane-3,7-dione
Ganesh Pandey,* Amrut L. Gaikwad and Smita R. Gadre
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411008, India
Received 15 August 2005; revised 16 November 2005; accepted 23 November 2005
Available online 9 December 2005
Abstract—Chiral 6-phenyl-2,3-bismethylenemethoxycarbonyl-[1,4]-dioxane, synthesized by the PET cyclization of 8, has been used
as a designer synthon for an efficient and short synthesis of optically pure 2,6-dioxabicyclo[3.3.0]octane-3,7-dione.
Ó 2005 Elsevier Ltd. All rights reserved.
H
2,6-Dioxabicyclo[3.3.0]octane-3,7-dione (bis-lactone, 1)
O
Iodolactonization
HO2C
has been shown to be a useful intermediate in the syn-
thesis of some important biologically active compounds
such as eldanolide,1 the Geisman–Weiss lactone,2 pros-
taglandin analogs,3 trans-laurediols,4 8,9-epoxyeicosatri-
enoic acid5 and enantiomerically pure butenolides.6
However, in spite of the significant utility of 1, it was
surprising to note that only two strategies exist for its
synthesis. Hizuka et al.,1 have synthesized 1 in racemic
form by the iodo lactonization of trans-3-hexenedioic
acid (2) and its synthesis in the optically pure form
was achieved by catalytic asymmetric reduction,6 using
RuCl2[(S)-BINAP](p-cymene) as the catalyst, of 3,4-
dioxohexanedioate (3) to give 4 followed by cyclization.
O
O
CO2H
O
H
1
2
Cyclization H+
HO
Cat. asymm.
reduction
O
O
CO2Me
CO2Me
CO2Me
CO2Me
HO
3
4
Scheme 1.
H
H
Ph
O
O
O
CO2Me
CO2Me
O
O
However, the yield of 1 in the latter approach is poor
due to the formation of other un-utilizable diastereoiso-
mers of 4 (Scheme 1). Considering the importance of 1
in the synthesis of several important classes of com-
pounds, we envisaged optically pure 6-phenyl-2,3-bis-
O
H
H
1
5
O
Ph
methylenemethoxycarbonyl-[1,4]-dioxane (5) as
a
O
OMe
OMe
O
possible precursor for its synthesis. The design of 5
was based on its stable but equally labile 1,4-dioxane
moiety, which is suitable for an easy transformation to
1 with the aid of a Lewis acid as shown in Scheme 2.
O
Scheme 2.
egy, developed in our group7,8 between two activated
olefins through a photoinduced electron transfer (PET)
cycle as shown in Figure 1.
We envisioned the synthesis of 1 utilizing a novel trans-
1,2-stereoselective carbon–carbon bond formation strat-
In this letter, we report our success in synthesizing
diastereomerically pure 5 and its conversion to optically
active 1.
Keywords: Chiral dioxan; Bis-lactone; Photoinduced electron transfer.
*
Corresponding author. Tel.: +91 20 25902324; fax: +91 20
25893153; e-mail: gp.pandey@ncl.res.in
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.116

702
G. Pandey et al. / Tetrahedron Letters 47 (2006) 701–703
hν
EWG
EWG
1
_12 A
HA
DCA
1
_2 HA + _2 H
+
DMN
EWG
EWG
H2A (or HA )
DCA
DMN
-
H2A = Ascorbic acid, HA = Ascorbate anion, A = Dehydroascorbic acid
DCA = 9,10-Dicyanoanthracene, DMN = 1,5-Dimethoxynaphthalene
Figure 1.
Compound 5 was characterized by 1H NMR, 13C NMR
and mass spectrometry.11 Since, H-2, H-3 and one of the
H-4 protons appeared together between d 3.80 and 4.10
Ph
OH
Ph
O
O
Ph
O
OH
OH
a
b
CO2Me
CO2Me
OH
1
6
7
8
(3H, multiplets) in the H NMR spectrum, the stereo-
chemical assignment of this compound by 2D NMR
spectroscopy proved difficult. Furthermore, our attempt
to obtain single crystals for X-ray diffraction of the cor-
responding diacid also failed due to its poor crystalline
nature (crystals were found twinned). Therefore, we
decided to establish the absolute stereochemistry by
transforming 5 to a known compound and comparing
its optical rotation values. In this context, 5 was first
transformed to 9 by LAH reduction followed by protec-
Scheme 3. Reagents and conditions: (a) LAH, dry THF, reflux, 8 h,
86%; (b) methyl propiolate, NMM, dry DCM, rt, 6 h, 78%.
We began the synthesis of optically pure (S)-5 by synthe-
sizing precursor 8 in 78% yield by the reaction of 7 with
methyl propiolate in the presence of N-methylmorpho-
line (NMM).9 Compound 7 was obtained in 86% yield
by the LAH reduction of commercially available (S)-
(+)-mandelic acid (Scheme 3).
tion of the primary alcohols as –OTBS ethers. Subject-
22
ing 9 to Na/liq. NH3 reduction gave 10 (½aꢀ ꢁ24.5, c
0.24, MeOH) in quantitative yield along withDthe forma-
tion of styrene (Scheme 5). Comparison of the optical
rotation value of 10 with the same substrate prepared
from L-(ꢁ)-tartaric acid confirmed the absolute stereo-
chemistry of 5 as 6(S)-phenyl-2,3-(R,R)-bismethylene-
methoxycarbonyl-[1,4]-dioxane.
PET activation of 8 involved irradiation (k = 405 nm) of
a
solution of
8
(1.96 mmol) containing DMN
(0.29 mmol), DCA (0.59 mmol) and ascorbic acid
(5.09 mmol) in 700 mL of solvent [DMF/i-PrOH/H2O
(88:10:2)] in a specially designed photoreactor consisting
of three chambers. The first and outermost chamber
contained the irradiation solution and the second one
was charged with CuSO4Æ5H2O/NH3 filter solution.10
A 450 W Hanovia medium pressure mercury lamp was
housed in a water-cooled jacketed chamber, which was
immersed into the second chamber. The whole photore-
actor was constructed of Pyrex glass. The i-PrOH func-
tioned as the hydrogen donor. All the light (k = 405 nm)
under this experimental set up was absorbed by DCA
only. Before irradiation, the solution was deoxygenated
by bubbling argon for 2 h and a slow stream of argon
was continued throughout the entire duration of the
irradiation. After acceptable consumption of the start-
ing material (92%, monitored by GC), irradiation was
discontinued. Work-up and purification of the crude
Although, the use of 5 for the synthesis of a C2 symmet-
ric 1,2-disubstituted 1,2-diol was not projected origi-
nally, this result indicated that the above strategy
could also be used for the synthesis of enantiomerically
pure C2 symmetric 1,2-disubstituted 1,2-diols as this
structural unit is part of various biologically active nat-
ural products12 and useful auxiliaries for asymmetric
synthesis.13 Therefore, the development of a stereoselec-
O
HO
HO
a
CH2OTBS
CH2OTBS
CH2OTBS
CH2OTBS
+
Ph
O
10
9
photolysate through silica gel column chromatography
22
e
gave 5 (½aꢀD EtOH, +60.83, c 2.05, CHCl3) in 88% yield
(Scheme 4).
HO
O
O
O
CH2OTBS
CH2OTBS
CH2OTBS
CH2OTBS
H
e
Ph
O
O
Ph
O
O
PET
CO2Me
CO2Me
CO2Me
CO2Me
HO
O
CH2OTBS
CH2OTBS
(405 nm)
H
8
5
Scheme 5. Reagents and conditions: (a) Na, liq. NH3, dry THF,
ꢁ78 °C, 20 min, quantitative.
Scheme 4.

G. Pandey et al. / Tetrahedron Letters 47 (2006) 701–703
703
H
Acknowledgements
H
Ph
Br
Ph
O
O
O
BBr3
DCM
CO2Me
CO2Me
+
O
O
We are thankful to Manas Kumar Ghorai for initiating
this work.
O
Br
H
H
5
11
1
Scheme 6.
References and notes
1. Hizuka, M.; Hayashi, N.; Kamashita, T.; Suemune, H.;
Sakai, K. Chem. Pharm. Bull. 1988, 36, 1550.
2. Tanaka, M.; Murakami, T.; Suemune, H.; Sakai, K.
Heterocycles 1992, 33, 697.
3. Hizuka, M.; Fang, C.; Suemune, H.; Sakai, K. Chem.
Pharm. Bull. 1989, 37, 1185.
tive synthesis of C2 symmetric 1,2-disubstituted 1,2-diols
has been an important subject in organic chemistry.
These compounds have been prepared by the stereo-
selective addition of a nucleophile to a carbonyl function-
ality bearing a chiral a-alkoxy group,14 nucleophilic
opening of a chiral epoxide15 and by asymmetric dihydr-
oxylation16 of trans-olefins. However, the enantiomeric
excess recorded has ranged from poor to good.
4. Anorbe, B.; Martin, V. S.; Palazone, J. M.; Trujillo, J. M.
Tetrahedron Lett. 1986, 27, 4991.
5. (a) Moustakis, C. A.; Viala, J.; Capdevila, J.; Falk, J. R. J.
Am. Chem. Soc. 1985, 107, 5283; (b) Mosset, F.; Yadagiri,
P.; Lumin, S.; Capdevila, J.; Falck, J. R. Tetrahedron Lett.
1986, 27, 6035; (c) Ennis, M. D.; Base, M. E. Tetrahedron
Lett. 1986, 27, 6031.
6. Kiegiel, J.; Nowacki, J.; Tarnowska, A.; Stachurska, M.;
Jurczak, J. Tetrahedron Lett. 2000, 41, 4003.
7. Pandey, G.; Hajra, S.; Ghorai, M. K.; Ravikumar, K. J.
Am. Chem. Soc. 1997, 119, 8777.
Since both forms of optically active 6 are cheaply avail-
able, we also synthesized (R)-5 and transformed it to the
22
corresponding D-(+)-10 (½aꢀD +23.8, c 0.24, MeOH) by
following similar sequences from (R)-6 as described ear-
lier for (S)-6.
Next, we examined the cleavage of 5 in order to obtain 1
in optically pure form. Towards this end, substrate 5
(0.33 mmol) dissolved in dry dichloromethane (5 mL)
was cooled to ꢁ78 °C and treated with BBr3
(0.79 mmol). After 30 min, the temperature was raised
to ꢁ20 °C and the reaction was allowed to stir for 1 h.
After additional stirring for 2 h at 0 °C, the solution
was poured into a beaker containing ice-cold water.
Extraction with DCM followed by concentration
produced a gummy residue. Washing of the residue
with petroleum ether several times removed all of the
by-product 11 and crystallization of the remaining
8. Pandey, G.; Ghorai, M. K.; Hajra, S. Tetrahedron Lett.
1998, 39, 1831.
9. Winterfeldt, E.; Preuss, H. Chem. Ber. 1966, 99, 450.
10. Calvert, J. G.; Pitts, J. N. Photochemistry; Wiley: New
York, 1966; p 736.
11. 1H NMR (CDCl3, 200 MHz) d: 2.66 (4H, m), 3.59 (6H, s),
3.62 (2H, m) 4.01–3.80 (2H, m), 4.65 (1H, dd, J = 1.53,
3.80 Hz), 7.45–7.30 (5H, m). 13C NMR (CDCl3, 50 MHz)
d: 37.2, 37.5, 52.1, 72.5, 75.5, 76.0, 77.6, 126.2, 128.0,
128.5, 138.0, 170.6. MS m/z: 308 (M+, 1), 246
(M+ꢁC2H6O2, 1), 235 (M+ꢁC3H5O2, 1), 203 (3), 188
(8), 156 (15), 140 (8), 129 (16), 104 (100), 91 (18), 77 (21),
59 (35).
12. Ko, S. Y. Tetrahedron Lett. 1994, 35, 3601.
13. (a) Alexakis, A.; Mangeney, P. Tetrahedron: Asymmetry
1990, 1, 477; (b) Gharibi, A.; Alexakis, A.; Normant, J. F.
Tetrahedron Lett. 1984, 25, 3083.
14. Still, W. C.; McDonald, J. H., III. Tetrahedron Lett. 1980,
21, 1031.
15. Sharpless, K. B. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 7, pp 389–436.
16. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483.
residue with acetone–petroleum ether mixture produced
22
1
[yield, 98%, mp 132–133 °C, ½aꢀD +124.48 (c
19
0.21, H2O), literature6 mp 132 °C, ½aꢀD +143 (c
1.0, H2O)] (Scheme 6).
In summary, we have shown the utility of designer syn-
thon 5 in the synthesis of optically active bis-lactone 1
and C2 symmetric 1,2-disubstituted 1,2-diols. Further
application of 5 in the synthesis of a prostaglandin pre-
cursor is in progress and will be reported in due course.