Silicon tether-aided coupling metathesis: Application to the synthesis of attenol A

Article abstract of DOI:10.1021/ol0268438

(matrixpresented) A new synthesis of attenol A is described. Key features of this work include a crucial silicon tether-aided coupling metathesis step and the use of iodoetherification as an efficient protection method for 1,5-ene-ols.

Full text of DOI:10.1021/ol0268438

ORGANIC
LETTERS
2002
Vol. 4, No. 23
4105-4108
Silicon Tether-Aided Coupling
Metathesis: Application to the
Synthesis of Attenol A
Pierre Van de Weghe,* Darina Aoun, Jean-Guy Boiteau, and Jacques Eustache*
Laboratoire de Chimie Organique et Bioorganique associe´ au CNRS,
UniVersite´ de Haute-Alsace, Ecole Nationale Supe´rieure de Chimie de Mulhouse, 3,
Rue Alfred Werner, F-68093 Mulhouse Cedex, France
j.eustache@uha.fr
Received September 3, 2002
ABSTRACT
A new synthesis of attenol A is described. Key features of this work include a crucial silicon tether-aided coupling metathesis step and the
use of iodoetherification as an efficient protection method for 1,5-ene-ols.
Attenols A (1) and B have been recently isolated and
characterized1 and then synthesized2 by Uemura. These
compounds, which exhibit moderate cytotoxicity against
P388 cells (IC50 are 24 and 12 µg/mL for attenols A and B,
respectively), only differ in the “ketal region”, attenol A
featuring a [5,4] spiroketal moiety and attenol B containing
a dioxa-bicyclo[3.2.1]octane unit. Attenols are densely
functionalized, asymmetric molecules, and their preparation
poses interesting challenges to synthetic organic chemists,
as nicely illustrated by Uemura et al.2 In the present paper,
we wish to present an alternative approach to attenol A,
which relies on our recently developed metathesis-based
synthesis of spiroketals.3
cyclization of a ketone-diol, itself readily obtained via silicon-
tethered ring-closing metathesis of two fragments.5 Fragment
A (2) was readily prepared from (tert-butyl-diphenyl-
silyloxy)-acetaldehyde according to Oikawa.6 According to
our plans, PG1 was to be removed after assembling the whole
sensitive attenol A skeleton. This led us to select TPS as a
protecting group because of its insensitivity to mild basic or
acidic conditions and its facile cleavage by fluoride ion.
The synthesis of fragment B looked more problematic (and
lengthy) until we realized that it could be derived from a
chiral, C2 symmetrical diol (4), itself obtainable from the
Our strategy is depicted in Scheme 1. After an initial
obvious disconnection between C-5 and C-6,4 the spiroketal
moiety of attenol A can be considered to result from
* Email for P.V.d.W.: p.vandeweghe@uha.fr.
(1) Takada, N.; Suenaga, K.; Yamada, K.; Zheng, S.-Z.; Chen, H.-S.;
Uemura, D. Chem. Lett. 1999, 1025-1026.
(2) (a) Suenaga, K.; Araki, K.; Sengoku, T.; Uemura, D. Org. Lett. 2001,
3, 527-529. (b) Araki, K.; Suenaga, K.; Sengoku, T.; Uemura, D.
Tetrahedron 2002, 58, 1983-1995.
(3) Boiteau, J.-G.; Van de Weghe, P.; Eustache, J. Tetrahedron Lett.
2001, 42, 239-242.
10.1021/ol0268438 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/19/2002

Scheme 1
Scheme 2 a
a (a) CH2dCHCH2CH2MgBr/CuI, THF, -40 °C, 3.5 h, 88%;
(b) PMPCH(OMe)2, CSA (cat.), CH2Cl2, 16 h, 20 °C, 88%; (c)
NaBH3CN, CF3COOH, DMF, 0 °C, 10 h, 76%; (d) NIS, K2CO3,
CH2Cl2, 20 °C, 16 h, 80%; (e) SeO2/TBHP, CH2Cl2, 20 °C, 12 d,
68%.
known diepoxide 3.7 Obviously the key problem in this
approach was the differentiation of the two olefinic double
bonds in monoprotected 4. One of them had to be oxidized
at the allylic position to provide an anchor for the silicon
tether, while the other had to be masked in order not to
interfer with the desired RCM. With respect to the planned
sequence, enantioselectivity of the allylic oxidation step did
not appear to be an issue, as the hydroxyl was to be oxidized
to the corresponding ketone after RCM. The practical
realization of this approach is shown in Scheme 2. Thus,
allylmagnesiumbromide/cuprous iodide opening of diepoxide
3 gave chiral diol 4,8 which was readily converted to ketal
5. Reduction (NaBH3CN, CF3COOH) afforded the corre-
sponding p-methoxybenzyl ether 6.
be protected in a single step by electrophile-induced cyclic
ether formation. Among the various electrophiles we used,
NIS worked best, leading to pyrane derivatives 7a and 7b
in good yield (7a/7b, 7:3).9 Although there are many
examples of halogenoetherification in the literature, we are
aware of only one instance of its use for protection
purposes.10 A matter of concern, in our case, was the
sensitivity of the primary iodide, which had to withstand the
various reaction conditions encountered along the succession
of steps leading to attenol. Optimizing the last reaction of
the sequence, the allylic oxidation of the remaining olefinic
double bond in 7, required extensive experimentation, but
we were rewarded by finally finding the conditions for
reliable conversion of 7 into 8. Although the reaction is slow,
it is very easy to perform and repeatedly affords good yield
of allylic alcohols as a 1:1 mixture of R and S isomers at
the newly formed chiral carbon atom.
The 1,5 relationship between the free hydroxyl and one
of the double bonds in 6 suggested that both functions could
(4) Attenol is numbered as indicated in Scheme 1 (starting from the “right
end” ot the molecule). To have a consistent numbering for all synthetic
intermediates, however, these are numbered starting from the “left end” of
the molecule as shown in Schemes 2 and 3.
(5) For previous examples of silicon-tethered ring-closing metathesis,
see: (a) Evans P. A.; Murthy, V. S. J. Org. Chem. 1998, 63, 6768-6769.
(b) Hoye, T. R.; Promo, M. A. Tetrahedron Lett. 1999, 40, 1429-1432.
(c) Briot, A.; Bujard, M.; Gouverneur, V.; Nolan, S. P.; Mioskowski, C.
Org. Lett. 2000, 2, 1517-1519. (d) Gierash, T. M.; Chytil, M.; Didiuk, M.
T.; Park, J. Y.; Urban, J. J.; Nolan, S. P.; Verdine, G. L. Org. Lett. 2000,
2, 3999-4000. (e) Harrison, B. A.; Verdine, G. L. Org. Lett. 2001, 2, 2157-
2159.
With fragments A and B in hand, we proceeded to the
key coupling/RCM sequence (Scheme 3). Treatment of 2
by dichlorodimethylsilane and addition of the resulting crude
chloro-dimethylsilyl ether to allylic alcohols 8a,b gave the
mixture of silylketals 9 in high yield, which was submitted
to RCM conditions using the molybdenum complex A
(Schrock complex ) [Mo]) as catalyst.
(6) Oikawa, M.; Ueno, T.; Oikawa, H.; Ichihara, A. J. Org. Chem. 1995,
60, 5048-5068.
(7) Rychnovsky, S. D.; Griesgraber, G. Zeller, S.; Skalitzky, D. J. J.
Org. Chem. 1991, 56, 5161-5169.
(8) NMR data and optical rotation of diol 4 were in perfect agreement
with those of ent-4 (Hoffmann, R. W. Colin, K. B.; Schifer, J.; Fleischhauer,
J. J. Chem. Soc., Perkin Trans. 2 1996, 2407-2414).
4106
Org. Lett., Vol. 4, No. 23, 2002

Scheme 3 a
Scheme 4 a
a (a) TBAF (1.2 equiv), THF, 20 °C, 24 h, 80%; (b) Dess-Martin
periodinane, pyridine, CH2Cl2, 20 °C, 2.5 h; (c) (E)-Bu3SnCH2-
CHdCH-CH2CH2OPMB, SnCl4, CH2Cl2, -78 °C, 15 (16(R)) 35%
and 15 (16(S)) 30% (2 steps); (d) BuLi, 3 equiv, -78 °C, 3 h, 60%
(25% 15 recovered); (e) DDQ, CH2Cl2, H2O, 20 °C, 30 min, 60%.
allylic alcohol, reduction of the conjugated double bond, and
oxidative removal of the PMB protective group with
concomitant ketal formation.
Intermediate 12 was converted to attenol A as shown in
Scheme 4.
Removal of the TPS protective group and Dess-Martin
oxidation11 of the resulting primary alcohol produced the
crude sensitive aldehyde 14, which was directly used for the
next step. SnCl4-catalyzed reaction12 with stannyl derivative
18 prepared from the known (E)-5-(4-methoxybenzyloxy)-
pent-2-en-1-ol (17)13 according to Bru¨ckner14 afforded 15
as a ca. 6:4 mixture of 16(R) and 16(S) isomers, which could
be separated by chromatography.
a (a) (i) BuLi, THF, -78 °C, 10 min, then Me2SiCl2 (excess),
-78 f 20 °C, 1 h, (ii) 8a,b, imidazole, THF, 20 °C, 16 h, 92%;
(b) [Mo], benzene, 20 °C, 24 h; (c) TFA, THF, MeOH, 20 °C, 24
h, 22% (11, 2 steps), 30% (8, two steps), 45% (2, 2 steps); (d)
MnO2 (30 equiv), AcOEt, rt, 24 h; (e) (i) H2 Pd/C, AcOEt, rt, 4 h,
(ii) DDQ, CH2Cl2, H2O, 20 °C, 30 min, 72% (3 steps); (f) (i)
pNO2BzCOOH, PPh3, DEAD, -20 °C, 2 h, (ii) NaOH,EtOH, 0 f
20 °C, 2 h, 80% (2 steps).
We observed a partial conversion and the formation of
only two out of four possible isomers of 10. The strong NOE
effect between H11 and H14 showed that both protons in 10
were axially oriented, implying that the RCM products had
the 11(S) configuration as shown in Scheme 2. In contrast
to previous results3 in a similar case, where the different
reactivity of stereoisomers toward RCM could be overcome,
here we were unable to force the reaction to go to completion.
Thus, although the stereochemistry at C11 is irrelevant with
respect to the planned sequence of reactions (as the next step
destroys this asymmetric center), in our case it proved to be
crucial for the success of the metathesis step. This limitation
could be partially overcome as follows: isolation of unre-
acted 9 and quantitative cleavage of the silyl bridge afforded
8a,b as a mixture containing mainly 11(R) 8a,b This was
cleanly converted into a mixture containing mainly 11(S)
8a,b by Mitsunobu reaction (overall yield 80%), which can
be recycled. Cleavage of the silylketal in 10 afforded diol
11 (22% yield from 9), which was converted to the key
intermediate 12 in good (72%) yield, by oxidation of the
These results deserve some comments. Asymmetric δ-m-
ethyl, ꢀ-benzyloxyallylstannanes, in the presence of SnCl4,
are known to react with aldehydes with very high regio- and
stereoselectivity to afford anti-homoallylic alcohols in which
the olefinic double bond is exclusively cis.
According to the mechanism proposed by Thomas et al.,12
the first step of the reaction is a transmetalation by tin(IV)
(11) Smith, A. B., III; Doughty, V.; Sfouggatakis, C.; Bennett, C. S.;
Koyanagi, J.; Yakeudi, M. Org. Lett. 2002, 4, 783-786.
(12) Carey, J. S.; Coulter, T. S.; Thomas, E. J. Tetrahedron Lett. 1993,
34, 3933-3934 and references therein.
(13) Oha, T.; Murai, A. Tetrahedron 1998, 54, 1-20.
(14) Weigand, S.; Bru¨ckner, R. Synthesis 1996, 475-482 and references
therein.
(9) For analytical purposes the sequence 7 f 12 was first performed
using the pure major isomer 7a. On the preparative scale we used the mixture
of diastereoisomers.
(10) Jung, M. E.; Karama, U.; Marquez, R. J. Org. Chem. 1999, 64,
663-665.
Org. Lett., Vol. 4, No. 23, 2002
4107

before one can predict with certainty the outcome of a
particular RCM. We were very pleased that our concerns
regarding the feasibility of using iodoetherification for
simultaneous protection of the hydroxyl and olefinic double
bond in a 1,5-ene-ol proved not to be justified. In fact, the
method perfectly served its purpose: the iodine could be
introduced very early in the synthesis, carried through the
almost complete synthetic sequence, and cleanly removed
toward the end of the synthesis.
Finally, the present work further shows the potential of
silicon tether-aided coupling metathesis for the synthesis of
complex spiroketal-containing systems, which was the main
purpose of this communication. Obviously, for the method
to be competitive from the preparative viewpoint, several
steps (in particular the RCM step) will have to be improved.
Work along these lines is underway in our laboratory.
chloride to give an intermediate believed to react via a six-
membered transition state. The Z configuration is the result
of a complexation of SnCl3 by the OBn group, while the
stereochemistry of the newly created asymmetric center is
imposed solely by the configuration of the carbon atom
bearing the R1 substituent. To the best of our knowledge,
no example of this reaction using an unsubstituted allylstan-
nane (R1 ) H) has been reported so far. In our case, as might
have been expected from Thomas’s proposal, the reaction
showed an excellent “Z preference” but a poor selectivity
when considering the newly formed chiral carbon atom, with
a slight preference for the “anticram” product 16(R) 15.
Deprotection of both the terminal olefinic double bond and
OH-6 was cleanly effected by treatment with butyllithium
at low temperature (with recovery of some starting material).
Finally DDQ removal of the last PMB protecting group
afforded Attenol A.
Acknowledgment. We thank Drs. Didier Le Nouen and
Ste´phane Bourg for help with NMR recording and interpre-
tation.
Supporting Information Available: Selected experi-
mental procedures and 1H and 13C NMR data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0268438
Several features of this synthesis are worth mentioning.
In view of earlier findings in our laboratory using similar
precursors,3 the extreme reluctance of silylketal 11(R) 9 to
ring-cyclize was unexpected.15 In the present case, no change
of solvent or catalyst led to completion of the coupling
reaction. Clearly, more methodological studies are needed
(15) The requirement of adequately substituted precursors for the success
of the RCM reaction, in particular in the case of eight-membered ring
formation, is known: (a) Bourgeois, D.; Pancrazi, A.; Nolan, S. P.; Prunet,
J. J. Organomet. Chem. 2002, 643-644; 247-252. (b) Cui, J.; Evans, P.
A. Abstracts of Papers, 223rd National Meeting of the American Chemical
Society, Orlando, FL; American Chemical Society: Washington, DC, 2002;
ORGN 276. (c) Our work; see ref 3.
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Org. Lett., Vol. 4, No. 23, 2002