Iron(II)-mediated fragmentation of unsaturated hydroperoxy acetals: A rapid synthetic route to 13-membered macrolides

Article abstract of DOI:10.1039/a801802b

Treatment of (1-hydroperoxy)cyclohexyloxyethyl acrylate with either iron(II) sulfate or iron(II) sulfate/copper(II) chloride affords novel 13-membered macrolides via tandem radical scission-cyclisation reactions.

Full text of DOI:10.1039/a801802b

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Iron(ii)-mediated fragmentation of unsaturated hydroperoxy acetals: a rapid
synthetic route to 13-membered macrolides
Kevin J. McCullough,*a† Yuji Motomura,b Araki Masuyamab and Masatomo Nojima*b
a Department of Chemistry, Heriot-Watt University, Edinburgh, UK EH14 4AS
b Department of Materials Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
Treatment of (1-hydroperoxy)cyclohexyloxyethyl acrylate
OOH
O
O
O
R
R
FeII
with either iron(II) sulfate or iron(II) sulfate/copper(II)
chloride affords novel 13-membered macrolides via tandem
radical scission-cyclisation reactions.
O
O
O
O
4
5
The development of synthetic strategies to macrocyclic com-
pounds has attracted considerable attention because many of
them are naturally occurring and several possess important
biological properties.1,2 In this respect, intramolecular radical
addition to a,b-unsaturated ketones has been found to provide
convenient access to a variety of macrocycles.3 This method is
generally based on the intramolecular cyclisation of the long-
chain unsaturated radicals generated by the reaction of the
corresponding iodo enones and their homologues with tri-
butyltin hydride.4 We report herein that the iron(ii)-mediated
fragmentation of the readily prepared 1-(hydroperoxy)-
cycloalkyloxyethyl acrylates provides an alternative approach
to the synthesis of novel macrolides.5,6
R
CuCl2
O
R
O
R
O
Cl
O
O
O
O
O
O
O
O
O
8
7
6
a R = H
b R = Me
CuCl2
O
Cl
O
9a
The key to our approach is the ease of preparation of the
desired intermediate unsaturated hydroperoxy acetals 4. Thus,
treatment of a solution of vinyl ether 1 and unsaturated alcohol
3 (3 equiv.) in CH2Cl2 with ozone (1 equiv.) at 270 °C resulted
in the selective ozonolysis of the electron rich vinyl ether 1 to
give carbonyl oxide 2 which was subsequently captured by 3
affording the corresponding hydroperoxide 4 in moderate yield
(3a, 27%; 3b, 40%) (Scheme 1).7 Subsequent treatment of a
solution of the hydroperoxide 4a in MeCN with a solution of
iron(ii) sulfate (1 equiv.) and copper(ii) chloride (3 equiv.) in
water at room temperature gave the macrolide 8a (49%) and the
acyclic diketone 9a (17%) (Scheme 2).‡ Compound 8a was
shown to be the structurally novel 13-membered bislactone by
X-ray crystallographic analysis (Fig. 1).§ From hydroperoxide
3b, the corresponding chloro-substituted macrolide 8b was
obtained in 35% yield, along with the unidentified acyclic
products.¶
Scheme 2
In the absence of copper(ii) chloride, the reaction of the
hydroperoxide 4a with iron(ii) sulfate (2 equiv.) yielded three
new crystalline products: the monomeric bislactone 10a (18%)
and two dimeric isomers 11a (Scheme 3). X-Ray crystallo-
graphic analysis of the higher melting dimer (mp 168 °C; 25%)
demonstrated unambiguously that this was the meso-isomer
(Fig. 2).∑ Thus, the other dimeric isomer 11a (mp
140.5–141.5 °C; 25%) was assigned as the dl form. From the
hydroperoxide 4b, the monocyclic macrolide 10b was obtained
in 25% yield along with unidentified acyclic products. Since the
corresponding dimeric compounds were not observed in
significant quantities, it appears that the sterically more
hindered radical 7b does not undergo dimerisation as readily as
7a.
These results indicate that the acyclic radical 6, generated by
sequential fragmentation of the O–O bond to give oxy radical 5
followed by b-scission of the cyclohexylidene ring, had
undergone a very efficient intramolecular cyclisation to give 7,
which in turn reacted with copper(ii) chloride to provide the
chlorinated macrolide 8.8
O3
+
O
OMe
O–
R
1
2
O
HO
O
3a,b
OOH
R
O
O
O
4a R = H
b R = Me
Fig. 1 The molecular structure of macrolide 8a as determined by X-ray
crystallography (ORTEP, 50% probability ellipsoids for non-hydrogen
atoms) (ref. 10)
Scheme 1
Chem. Commun., 1998
1173

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dilution techniques (0.01–0.05 m). Moreover, the mode of
termination can be controlled by the judicious choice of reaction
conditions.
This work was supported in part by a Grant-in Aid for
Scientific Research on Priority Areas (09270212) from the
Ministry of Education, Science, Culture and Sports of Japan.
We thank the British Council (Tokyo) for the award of travel
grant to K. J. McC., M. N. and A. M.
R
O
R
O
O
O
O
O
O
O
6
7
(i) FeII
(ii) H +
7
R = H
O
O
O
O
Notes and References
R
O
† E-mail: k.j.mccullough@hw.ac.uk
‡ All new compounds gave satisfactory microanalytical and spectroscopic
data.
O
O
O
O
O
O
O
a R = H
§ Crystal data for 8a: C11H17ClO4, M = 248.70, colourless needles,
monoclinic, space group P21/c (No. 14), a = 15.1404 (12), b = 5.0426 (4),
b R = Me
11a
10
c = 16.1490 (11) Å, b = 100.550 (5)°, U = 1212.12 (2) Å3, Z = 4, Dc
=
Scheme 3
1.363 g cm23, F(000) = 528, m(Mo-Ka) = 0.312 cm21. The intensity data
were collected on a Siemens P4 diffractometer at 160 (2) K using graphite
monochromated Mo-Ka radiation (l = 0.710693 Å). The structure was
solved by direct methods and refined by full-matrix least-squares methods
on F2 using anisotropic temperature factors for the non-hydrogen atoms
(SHELXTL10). At convergence, the discrepancy indices R1 and wR2 were
0.032 [for 1942 data with Fo > 4s(Fo)] and 0.0878 (all 2111 unique data)
respectively. The final difference Fourier map contained no feature greater
than ±0.31 e Å23
.
¶ Since the separation of 8b from other acyclic products was difficult, the
reaction mixture was ozonised further to break down the latter. Thus, 8b
could be cleanly isolated by column chromatography on silica gel.
∑ Crystal data for 11a (higher mp dimer): C22H34O8, M
= 426.49,
¯
colourless prisms, triclinic, space group P1 (No. 2), a = 5.0600 (10), b =
8.512 (2), c = 13.090 (2) Å, a = 88.800 (10), b = 83.78 (2), g = 77.010
(10)°, U = 546.1 (2) Å3, Z = 1 (molecule on an inversion centre), T =
160(2) K, Dc = 1.297 g cm23, F(000) = 230, m(Mo-Ka) = 0.098 cm21
.
The final discrepancy indices R1 and wR2 were 0.0341 [for 1595 data with
Fo > 4s(Fo)] and 0.0883 (all 1907 unique data) respectively. The final
Fig. 2 The molecular structure of the dimeric macrolide 11a as determined
by X-ray crystallography (ORTEP, 50% probability ellipsoids for non-
hydrogen atoms) (ref. 10)
difference Fourier map contained no feature greater than ±0.20 e Å23
CCDC 182/842.
.
The iron(ii) catalysed decomposition of the methyl-substi-
tuted hydroperoxide 12 results in the formation of the
monomeric chloromacrolide 15 as the sole isolable product
(54%, a mixture of two isomers in the ratio ca. 2:1). Thus,
intermediate 13 had undergone a selective b-scission of the
cyclohexylidene ring via the more highly substituted radical 14
as outlined in Scheme 4. Similar selectivity has been observed
previously in the thermal rearrangements of a-substituted
1,2,4-trioxanes.9
1 K. C. Nicolaou, Tetrahedron, 1977, 33, 683; C. J. Roxburgh,
Tetrahedron, 1995, 51, 9676.
2 For some recent examples see: M. P. Doyle, C. S. Peterson, M. N.
Protopopova, A. B. Marnett, D. L. Parker, Jr., D. G. Ene and V. Lynch,
J. Am. Chem. Soc., 1997, 119, 8826; D. Meng, P. Bertinato, A. Balog,
D.-S. Su, T. Kamenecka, E. J. Sorense and S. J. Danishefski, J. Am.
Chem. Soc., 1997, 119, 10 073; A. B. Smith, III and G. R. Ott, J. Am.
Chem. Soc., 1996, 118, 13 095.
3 C. Thebtaranonth and Y. Thebtaranonth, in Cyclization Reactions, CRC
Press, Boca Raton, 1994.
In summary, the readily available unsaturated hydroperoxy
acetals such as 4 offer considerable potential as precursors of
novel macrolides. The fragmentation-cyclisation reactions take
place under relatively mild conditions and do not require high
4 N. A. Porter, B. Lacher, V. H.-T. Chang and D. R. Magnin, J. Am. Chem.
Soc., 1989, 111, 8309; S. A. Hitchock and G. Pattenden, Tetrahedron
Lett., 1990, 31, 3641; J. E. Baldwin, R. M. Adlington, M. B. Mitchell
and J. Robertson, Tetrahedron, 1991, 47, 5901; I. Ryu, K. Nagahara, S.
Tsunoi and N. Sonoda, Synlett, 1994, 643; A. L. J. Beckwith, K. Drok,
B. Maillard,M. Degueol-Castaing and A. Philippon, Chem. Commun.,
1997, 499.
5 For the metal ion promoted ring-opening of a-siloxy-, a-hydroxy- and
a-alkoxy-substituted cycloalkyl hydroperoxides, see: I. Saito, R.
Nagata, K. Yuba and T. Matuura, Tetrahedrol Lett., 1983 24, 4439 and
references cited therein.
6 S. L. Schreiber, B. Hulin and W.-F. Liew, Tetrahedron, 1986, 42, 2945
and references cited therein.
7 Y. Ushigoe, Y. Torao, A. Masuyama and M. Nojima, J. Org. Chem.,
1997, 62, 4949.
8 J. K. Kochi, in Free Radicals, ed. J. K. Kochi, Wiley, New York, 1973,
vol. 1, ch. 11.
9 A. Haq, B. Kerr and K. J. McCullough, J. Chem. Soc., Chem. Commun.,
1993, 1076.
FeSO4
OOH
O
O
O
in MeCN–H2O
O
O
O
O
O
O
O
O
12
13
O
O
O
O
10 SHELXTL/PC (Ver. 5.03), G. M. Sheldrick, Siemens Analytical X-ray
Instruments Inc., Madison, WI, USA.
Cl
15
14
Scheme 4
Received in Liverpool, UK, 4th March 1998; 8/01802B
1174
Chem. Commun., 1998