A novel spiroketalization reaction of 1,7-dihydroxyhepta-2,5-diyn-4-ones

Article abstract of DOI:10.1039/b200215a

Symmetrical halogented spiroketals were synthesized by the reaction of optically active 1,7 dihydroxyhepta-2,5-diyn-4-ones with hydrogen halide in AcOH. Spiroketals in yields of 62-97% was obtained by the dihydroxydiynones. The optical purity was determin

Full text of DOI:10.1039/b200215a

View Article Online / Journal Homepage / Table of Contents for this issue
A novel spiroketalization reaction of 1,7-dihydroxyhepta-
2,5-diyn-4-ones
Koichi Tanaka* and Naoyuki Harada
1
Department of Applied Chemistry, Faculty of Engineering, Ehime University, Matsuyama,
Ehime 790-8577, Japan. E-mail: tanaka@en3.ehime-u.ac.jp
Received (in Cambridge, UK) 8th January 2002, Accepted 7th February 2002
First published as an Advance Article on the web 18th February 2002
Table 1 Yields and melting points of halogenated spiroketals (4)
Treatment of 1,7-dihydroxyhepta-2,5-diyn-4-ones with
hydrogen halide in AcOH gave halogenated spiroketals in
good yield.
Spiroketal
Yield (%)
Mp/ЊC
4a (X = Cl)
4a (X = Br)
4a (X = I)
4b (X = Cl)
4b (X = Br)
4b (X = I)
4c (X = Cl)
4c (X = Br)
4c (X = I)
4d (X = Cl)
4d (X = Br)
4d (X = I)
4e (X = Cl)
4e (X = Br)
4e (X = I)
4f (X = Cl)
4f (X = Br)
4f (X = I)
4g (X = Cl)
4g (X = Br)
4g (X = I)
85
72
68
73
63
77
62
63
62
72
97
64
78
63
64
75
85
82
81
84
77
168–171
152–155
198–202
219–225
226–230
280–283
268–274
293–297
267–273
115–116
135–138
109–112
84–87
Introduction
Spiroketals are found in a wide variety of biologically active
natural products, including insect pheromones, steroidal
saponins, marine macrolides, and microbial metabolites.1 The
development of new methods for the synthesis of spiroketals
has thus attracted much attention in recent years. During our
studies on the synthesis of benzocyclobutene derivatives via
thermal cyclization of diallenes,2 we found unexpectedly that
1,7-dihydroxyhepta-2,5-diyn-4-ones (3) can be smoothly con-
verted into halogenated spiroketals (4) by simple treatment
with aq. hydrogen halides in AcOH. Optically active halogen-
ated spiroketals (4) were also obtained by the reaction of
optically active 1,7-dihydroxyhepta-2,5-diyn-4-ones (3) without
any racemization.
99–103
128–131
Oil
Oil
Oil
Oil
Oil
Oil
Results and discussion
1,7-Dihydroxyhepta-2,5-diyn-4-ones (3) were prepared by
active MnO2 oxidation of the corresponding hepta-2,5-diyne-
1,4,7-triol (2) obtained by Grignard reaction of the dimag-
nesium salt of propargyl alcohol (prop-2-yn-1-ol, 1) to ethyl
formate in ether–benzene. Treatment of 3a with conc. HCl in
AcOH at 0 ЊC for 1 h gave the 3,8-dichloro-2,2,7,7-tetraphenyl-
1,6-dioxaspiro[4.4]nona-3,8-diene (4a, X = Cl) in 85% yield.
Similar treatment of 3a with HBr and HI afforded the corre-
sponding dibromo- (4a, X = Br) and diiodospiroketals (4a,
X = I) in 72 and 68% yields, respectively. Dihydroxydiynones
(3b–3g) also gave the corresponding spiroketals (4b–4g) in
yields of 62–97% (Table 1).
A plausible mechanism for this spiroketalization reaction
probably involves the allene intermediate (5) formed by HX
addition to 3 (Scheme 1). Intramolecular cyclization of the
OH group of 5 gives 6 which again reacts with another HX to
give allene (7). Finally, cyclization of the OH of 7 leads to
dihalospiroketal (4).
Interestingly, spiroketalization of optically active 1,7-di-
hydroxy-1,7-bis(o-chlorophenyl)-1,7-diphenylhepta-2,5-diyn-4-
one (3h) with aq. HX in AcOH was found to produce optically
active spiroketals (4h) without any racemization. In a typical
experiment a mixture of (S,S)-(Ϫ)-3h (0.1 g, 0.20 mmol)
prepared from optically pure propargyl alcohol (1h),3 and 47%
aq. HBr (0.2 ml) in AcOH (10 ml) was stirred at 0 ЊC for 1 h.
A crystalline powder formed which was filtered, washed with
water and dried to give (R,R)-(ϩ)-4h (X = Br) (0.09 g, 70%
yield) as colorless prisms (mp 285–288 ЊC, [α]D ϩ386Њ (c 1.2,
CHCl3). The optical purity was determined by chiral HPLC
(Chiralcel OD, Daicel). Similarly (S,S)-(Ϫ)-4h (X = Br) of
100% ee was obtained by the reaction of (R,R)-(ϩ)-3h with
aq. HBr in AcOH (Table 2). Similar treatment of (Ϫ)-3h with
HCl and HI in AcOH gave the corresponding optically pure
dichloro- and diiodospiroketals (ϩ)-4h (X = Cl) and (ϩ)-4h
Scheme 1
DOI: 10.1039/b200215a
J. Chem. Soc., Perkin Trans. 1, 2002, 713–714
This journal is © The Royal Society of Chemistry 2002
713

View Article Online
Table 2 Optically active halogenated spiroketals (4h)
by the reaction of 1,7-dihydroxyhepta-2,5-diyn-4-ones (3) with
HX in AcOH. Further studies directed at broadening the scope
of this spiroketalization protocol are now under way.
Spiroketal
Yield (%)
Mp/ЊC
[α]D/Њa
Ee (%)b
(ϩ)-4h (X = Cl)
(ϩ)-4h (X = Br)
(ϩ)-4h (X = I)
(Ϫ)-4h (X = Cl)
(Ϫ)-4h (X = Br)
(Ϫ)-4h (X = I)
68
70
68
77
62
69
284–286
285–288
277–284
284–286
285–288
284–286
ϩ392
ϩ386
ϩ368
ϩ394
ϩ387
ϩ362
100
100
100
100
100
100
Experimental
Typical procedure for the spiroketalization of 3a to 4a
When a mixture of 3a (0.20 g, 0.45 mmol) and conc. HCl
(0.4 ml) in AcOH (20 ml) was stirred at 0 ЊC for 1 h, a crystalline
powder was formed. The crude product was filtered, washed
with water and dried to give 4a (0.19 g, 85% yield). Recrystal-
lization of the crude product from AcOEt gave pure 4a as
a Measured in CHCl3. b Optical purity was determined by HPLC
(Chiralcel OD, Daicel).
colorless prisms (mp 168–171 ЊC). IR (ν/cmϪ1) 1627 (C᎐C);
᎐
λmax/nm (CHCl3) 241 (ε/dm3 molϪ1 cmϪ1, 700), 253 (ε 670), 259
1
(ε 840), 265 (ε 700); H-NMR (300 MHz, CDCl3) δ 7.50–7.21
(m, 20 H), 5.96 (s, 2 H); 13C-NMR (75 MHz, CDCl3) δ 94.0,
117.3, 124.8, 127.7, 127.8, 128.0, 128.2, 140.8, 140.9, 141.1.
Anal. Calcd for C31H22O2Cl2: C, 74.85; H, 4.46. Found: C,
74.88; H, 4.54%.
Typical procedure for the spiroketalization of (S,S)-(؊)-3h to
(R,R)-(؉)-4h (X ؍ Br)
When a mixture of (S,S)-(Ϫ)-3h (0.10 g, 0.20 mmol) and conc.
HBr (0.2 ml) in AcOH (10 ml) was stirred at 0 ЊC for 1 h, a
crystalline powder was formed. The crude product was filtered,
washed with water and dried to give (R,R)-(ϩ)-4h (X = Br)
(0.09 g, 70% yield). Recrystallization of the crude product from
AcOEt gave pure (R,R)-(ϩ)-4h (X = Br) as colorless prisms
(mp 285–288 ЊC). IR (ν/cmϪ1) 1610 (C᎐C); λmax/nm (CHCl3) 243
᎐
(ε/dm3 molϪ1 cmϪ1, 16900), 255 (ε 7370), 261 (ε 9290), 267
(ε 9050), 276 (ε 4740); 1H-NMR (300 MHz, CDCl3) δ 7.73–7.07
(m, 18 H), 6.44 (s, 2 H); 13C-NMR (75 MHz, CDCl3) δ 93.7,
118.3, 126.1, 127.8, 129.2, 129.4, 130.0, 131.2, 133.0, 134.2,
138.3, 140.1. Anal. Calcd for C31H20O2Br2Cl2: C, 56.83; H, 3.08.
Found: C, 56.85; H, 3.16%.
Acknowledgements
The authors thank Bruker Japan Co., Ltd. for the X-ray crystal
structure analysis of (S,S)-(Ϫ)-4h (X = Br).
(X = I), respectively. Optically pure spiroketals (Ϫ)-4h (X = Cl)
and (Ϫ)-4h (X = I) were also prepared by the reaction of (ϩ)-3h
with HCl and HI in AcOH, respectively. The absolute configur-
ation of the optically active spiroketal (S,S)-(Ϫ)-4h (X = Br)
was determined by X-ray crystal structure analysis4 (Fig. 1).
References
1 F. Rerron and K. F. Albizati, Chem. Rev., 1989, 89, 1617; M. T.
Fletcher and W. Kitching, Chem. Rev., 1995, 95, 789; I. Paterson,
D. J. Wallace and R. M. Oballa, Tetrahedron Lett., 1998, 39, 8545;
H. Zhang, M. T. Fletcher, K. Dettner, W. Francke and W. Kitching,
Tetrahedron Lett., 1999, 40, 7851; I. E. Marko, Tetrahedron Lett,
2000, 41, 4383; A. N. Cuzzupe, C. A. Hutton, M. J. Lilly, R. K. Mann,
M. A. Rizzacasa and S. C. Zammit, Org. Lett., 2000, 2, 191;
M. Uchiyama, M. Oka, S. Harai and A. Ohta, Tetrahedron Lett.,
2001, 42, 1931; D. C. Craig, G. L. Edwards and D. J. Sinclair, Tetra-
hedron, 2001, 57, 563; P. Hayes, M. T. Fletcher, C. J. Moore and
W. Kitching, J. Org. Chem., 2001, 66, 2530.
2 F. Toda, K. Tanaka, I. Sano and T. Isozaki, Angew. Chem., Int. Ed.
Engl., 1994, 33, 1757; F. Toda, K. Tanaka, M. Watanabe, K. Tamura,
I. Miyahara, T. Nakai and K. Hirotsu, J. Org. Chem., 1999, 64,
3102; K. Tanaka, N. Takamoto, Y. Tezuka, M. Kato and F. Toda,
Tetrahedron, 2001, 57, 3761.
3 F. Toda, K. Tanaka, H. Ueda and T. Oshima, J. Chem. Soc., Chem.
Commun., 1983, 743; F. Toda, K. Tanaka, H. Ueda and T. Oshima,
Isr. J. Chem., 1985, 25, 338.
4 Crystal data for (S,S)-(Ϫ)-4h (X = Br): C31H20Br2Cl2O2, M = 655.19,
orthorhombic, a = 12.0964(14), b = 13.5239(15), c = 16.1906(19) Å,
α = 90Њ, β = 90Њ, γ = 90Њ, V = 2648.6(5) Å3, T = 100 K, space group
P212121, Z = 4, µ(Mo-Kα) = 3.291 mmϪ1, 22651 reflections measured,
8166 unique (Rint = 0.0223) which were used in all calculations. Final
R indices [I > 2σ(I )]: R1 = 0.0215, wR2 = 0.0327. CCDC reference
number 177772. See http://www.rsc.org/suppdata/p1/b2/b200215a for
crystallographic files in .cif or other electronic format.
Fig. 1 X-Ray crystal structure of (S,S)-(Ϫ)-4h (X = Br).
Conclusion
In conclusion, we have developed a simple and efficient
synthesis of symmetrical halogenated spiroketals in good yields
714
J. Chem. Soc., Perkin Trans. 1, 2002, 713–714