Formation of dissymmetric eight-membered silalketals by ring-closing metathesis and their conversion to spiroketals

Article abstract of DOI:10.1016/S0040-4039(00)01929-8

Eight-membered unsymmetrical silalketals are formed by RCM of mixed allyl/homoallyl silalketals. They are crucial intermediates in a short synthetic sequence to spiroketals illustrated in this paper by the synthesis of the C₂₈-C₃₈ po

Full text of DOI:10.1016/S0040-4039(00)01929-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 239–242
Formation of dissymmetric eight-membered silalketals by
ring-closing metathesis and their conversion to spiroketals
Jean-Guy Boiteau, Pierre Van de Weghe and Jacques Eustache*
Laboratoire de Synthe`se Organique et Chimie Microbienne associe´ au CNRS. Universite´ de Haute-Alsace,
Ecole Nationale Supe´rieure de Chimie de Mulhouse, 3, Rue Alfred Werner, F-68093 Mulhouse Cedex, France
Received 30 August 2000; accepted 30 October 2000
Abstract—Eight-membered unsymmetrical silalketals are formed by RCM of mixed allyl/homoallyl silalketals. They are crucial
intermediates in a short synthetic sequence to spiroketals illustrated in this paper by the synthesis of the C28–C38 portion of
okadaic acid. © 2000 Elsevier Science Ltd. All rights reserved.
Recent reports indicate that synthetic molecules con-
taining the spiro [5.5] ketal system (commonly found in
a number of naturally occurring substances), may ex-
hibit interesting pharmacological activities.1,2 To fully
assess the potential of these molecules, the synthesis of
series of analogs and the development of structure–
activity relationships will be required. The most widely
used strategy for spiroketal preparation involves an
acid-catalyzed cyclization of dihydroxyketones (spiro-
ketalization) as a key step. Although the spiroketaliza-
tion itself is a very facile process, access to the dihydrox-
yketone precursor is not always easy, in particular for
complex molecules.3 We wanted to develop an alterna-
tive strategy in which two fully functionalized fragments
would be first assembled, the resulting adducts being
converted to dihydroxyketones then to the correspond-
ing spiroketals in a few simple steps. Obviously, for such
an approach to be successful, the reaction conditions for
the coupling and subsequent steps must be compatible
with most functional groups. For some time, we have
been interested in applications of the ring-closing
metathesis (RCM) reaction in total synthesis. The main
advantages of RCM are its wide applicability and its
remarkable tolerance to functional groups. The use of
temporary tethers in conjunction with RCM renders the
method even more versatile and may be used for the
stereoselective coupling of olefins. This led us to envis-
age the approach shown in Fig. 1, in which the key step
is the RCM of a mixed allyl/homoallyl silalketal. The
preparation of (mostly) symmetrical seven-membered4–7
and a few 10- or 11-membered6 cyclic silalketals by
RCM and their conversion to diols has been described
but, to the best of our knowledge, the method has not
yet been applied to eight-membered silalketals despite
the potential usefulness of these intermediates. For
example the presence of an exclusively cis double bond
and of two differentiated (allylic/homoallylic) hydroxyl
groups should allow a range of selective transforma-
tions. In this communication, we describe the prepara-
tion of dissymmetric eight-membered silalketals by
RCM and show that they can readily be converted to
spiroketals.8 To illustrate our strategy we have chosen
to prepare by this method the known C28–C38 spiroke-
tal moiety of okadaic acid (8: Scheme 1).9
Figure 1.
* Corresponding author. Fax: 33 (0)3 89 336860; e-mail: j.eustache@univ-mulhouse.fr
0040-4039/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01929-8

240
J. -G. Boiteau et al. / Tetrahedron Letters 42 (2001) 239–242
The starting compounds (1 and 3) were readily ob-
tained following literature procedures. Thus, the chiral
homoallylic alcohol 1 was prepared by diastereoselec-
tive addition of crotyl tributyl stannane,10,11 to (S)-3-
[(tert-butyldiphenylsilyl)oxy]-2-methylpropanal,12 and
the racemic monosilylated ene-diol 3 was prepared as
described previously.13 The two precursors 1 and 3 were
linked through a dimethylsilyl bridge as indicated in
Scheme 1, to provide the bis-alkoxysilane 4 as a 1:1
mixture of diastereoisomers. This mixture was submit-
ted to two sets of RCM conditions, using ‘Grubbs’
catalysts’ 9 and 10.
(C7) in 5a on the basis of nOe data: a strong (20%)
positive nOe effect between H4 and H7 clearly indicated
that both protons were axially oriented (Fig. 2), point-
ing towards structure 5a.
To further confirm that diastereoselective differentia-
tion had indeed taken place, the silyl bridge in unre-
acted 4 was cleaved and the optical rotation of
recovered 3 was measured; the positive value observed
implies that the RCM reaction occurred stereoselec-
tively.14
In contrast, using the recently described complex 10,15
we were pleased to observe a smooth and complete
RCM leading to a 1:1 mixture of diastereoisomers 5a
and 5b which was directly converted by brief acidic
treatment to the corresponding mixture of diols 6 (65%
over two steps).16 6a and 6b could be easily separated
by chromatography but, from a synthetic viewpoint, it
is more convenient to use the mixture 6.
Until now, attempts to directly effect the conversion
6“7 using a variety of transition metal-induced allylic
alcohol/ketone isomerization failed. We then turned to
the short sequence shown in Scheme 1 in which the
crude ketone 7 (a mixture of ketone and hemiketal) was
obtained by sequential selective oxidation of the allylic
The outcome of the RCM reaction using catalyst 9 was
interesting as only a single cyclized product (5a) was
formed (as evidenced by NMR) while recovered unre-
acted 4 was strongly enriched in one isomer. We tenta-
tively attribute the S configuration at the allylic center
Scheme 1. Reagents and conditions: (a) BuLi, Me2SiCl2, THF, −78°C, 10 min; (b) 3, imidazole, THF, 20°C, 16 h, 92% (for steps
(a) and (b)); (c) 9 (0.25 equiv.), benzene, reflux, 48 h, 46%; (d) 10 (0.1 equiv.), benzene, reflux, 48 h; (e) CF3COOH (0.2 equiv.),
THF/MeOH, 20°C, 3 h, 65% (for steps (d) and (e)); (f) (i) MnO2 (70 equiv.), CH2Cl2/ethyl acetate, 20°C, 24 h, (ii) H2, Pd/C; (g)
(i) NBu4F, THF, (ii) CF3COOH, toluene, 20°C, 60% (for steps (f) and (g)).
Figure 2. nOe effects in 5a and 5b.

J. -G. Boiteau et al. / Tetrahedron Letters 42 (2001) 239–242
241
hydroxyl group in 6 using MnO2, followed by catalytic
hydrogenation. Removal of the silyl protecting groups
with tetrabutylammonium fluoride and classical tri-
fluoroacetic acid-induced spiroketalization gave 8 as a
single isomer, in agreement with earlier findings.9,17 The
conversion 6“8 was effected in 60% overall yield,
without purification of intermediates.
11. Marshall, J. A.; Pavlovich, M. R. J. Org. Chem. 1998, 63,
4381–4384.
12. Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem.
Soc. 1990, 112, 6339–6348.
13. Lopez-Tucanda, P. L.; Jones, K.; Brownbridge, P. Tetra-
hedron Lett. 1991, 32, 2261–2264.
14. The monoprotected diol 3 has been described only in the
racemic form, the [h]D value of recovered 3 in our
experiment cannot be used to support our structural
assignment for 5. However, the positive optical rotation
indicates that diastereoselectivity had occurred.
15. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org.
Lett. 1999, 1, 953–956.
16. For analytical purposes, the two isomers 5a and 5b were
separated by chromatography and the nOe effects be-
tween H4 and H7 determined: whereas a strong (+20%)
nOe effect was observed for 5a, no significant signal
enhancement was seen for 5b.
In conclusion, we have described a short and simple
RCM-based sequence for the preparation of spiro[5.5]
ketals. The mild reaction conditions used and the facile
preparation of the precursors suggest that this new
approach should be widely applicable. This work and
additional functionalization possibilities of the eight-
membered silalketals intermediates are under study in
our laboratory.
Acknowledgements
17. Experimental details:
RCM of diene 5: To a solution of diene 5 (175 mg, 0.22
mmol) in benzene (3 mL) was added tricyclohexylphos-
phine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-
2-ylidene][benzylidine] ruthenium(IV) dichloride (10, 10
mg, 11 mmol, 5 mol%). The resulting mixture was
refluxed for 48 h. The solvents were removed in vacuo
and the residue was filtered over a short pad of silica gel
(5% ethyl acetate in cyclohexane) to removed the metallic
residues. The oil thus obtained was dissolved in THF/
MeOH (2/1), trifluoroacetic acid (5 mL, 20 mol%) was
added, and the solution was stirred for 3 h at room
temperature. Flash chromatography over silica gel (15%
ethyl acetate in cyclohexane) provided the desired diols
6a (48 mg) and 6b (52 mg). Overall yield: 65% over two
steps.
We thank Drs. Didier Le Nouen and Ste´phane Bourg
for help with NMR recording and interpretation.
References
1. Mitsuhashi, S.; Shima, H.; Kawamura, T.; Kikuchi, K.;
Oikawa, M.; Ichihara, A.; Oikawa, H. Bioorg. Med.
Chem. Lett. 1999, 7, 2007–2012.
2. Uckun, F. M.; Mao, C.; Vassilev, A. O.; Huang, H; Jan,
S.-T. Bioorg. Med. Chem. Lett. 2000, 10, 541–545.
3. For a review on the chemistry of spiroketals, see: Perron,
F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617–1661. The
dihydroxyketone precursor is almost always obtained by
addition of an organometallic reagent onto various nucle-
ophiles (ketone, lactone, …) which implies severe restric-
tions with regard to functional groups present in the
fragments to be coupled.
4. Evans, P. A.; Murthy, V. S. J. Org. Chem. 1998, 63,
6768–6769. The conversion of a seven-membered silylke-
tal into altritol is described in this paper.
5. Hoye, T. H.; Promo, M. A. Tetrahedron Lett. 1999, 40,
1429–1432.
6a: [h]2D0= −7.7 (c 1.3, CHCl3); anal. calcd: C, 74.8; H,
8.6; found: C, 74.65; H, 8.6.
1H NMR (CDCl3, 250 MHz): 7.69–7.66 (m, 8H, ArH);
7.48–7.34 (m, 12H, ArH); 5.37 (dd, J=8.9, 10.9, 1H,
CHꢀCHCHCH2); 5.23 (t, J=10.8, 1H, CHꢀCHCH-
CH2); 4.39 (m, 1H, MeCHCHOH); 3.81–3.62 (m, 5H,
TPSOCH2, TPSOCH2 and HOCHCHMe); 3.01 (broad s,
1H, OH); 2.70 (m, 1H, MeCHCHꢀCH); 1.81 (m, 2H,
SiOCH2CHMe and OH); 1.63–1.33 (m, 6H, (CH2)3);
1.07 (2s, 18H, tBuSi); 1.07 (d, 3H, CH3); 0.97 (d, J=7,
3H, CH3).
6. Lobbel, M.; Ko¨ll, P. Tetrahedron: Asymmetry 2000, 11,
393–396.
13C NMR (CDCl3, 62.9 MHz): 135.7, 135.6, 134.4, 132.7,
129.9, 129.5, 127.8, 127.6, 77.8, 69.8, 67.7, 63.8, 37.3,
36.5, 36.4, 32.5, 26.9, 21.8, 19.2, 18.2, 9.8.
7. Briot, A.; Bujard, M.; Gouverneur, V.; Nolan, S. P.;
Mioskowski, C. Org. Lett. 2000, 2, 1517–1519.
8. To the best of our knowledge, RCM has been used in
two instances for the preparation of spiroketals. Concep-
tually, however, the approaches are entirely different: (a)
Van Hooft, P. A. V.; Leeuwenburgh, M. A.; Overkleeft,
H. S.; Van der Marel, G. A.; Van Boeckel, C. A. A.; Van
Boom, J. Tetrahedron Lett. 1998, 39, 6061–6064. (b)
Bassindale, M. J.; Hamley, P.; Leitner, A.; Harrity, J. P.
A. Tetrahedron Lett. 1999, 40, 3247–3250
6b [h]2D0= −1.2 (c 0.8, CHCl3); anal. calcd: C, 74.8; H,
8.6; found: C, 74.03; H, 8.58.
1H NMR (CDCl3, 250 MHz): 7.67–7.64 (m, 8H, ArH);
7.47–7.33 (m, 12H, ArH); 5.35 (t, J=9.9, 1H,
CHꢀCHCH-CH2); 5.22 (t, J=10.6, 1H, CHꢀCHCH-
CH2); 4.40 (m, 1H, MeCHCHOH); 3.77–3.59 (m, 5H,
TPSOCH2, TPSOCH2 and HOCHCHMe); 2.85 (broad s,
1H, OH); 2.67 (m, 1H, MeCHCHꢀCH); 1.70–1.32 (m,
8H, (CH2)3, SiOCH2CHMe and OH)); 1.13 (d, J=6.5,
3H, CH3); 1.07 and 1.03 (2s, 18H, tBuSi); 0.88 (d, J=7,
3H, CH3).
9. Urbanek, R. A.; Sabes, S. F.; Forsyth, C. J. J. Am.
Chem. Soc. 1998, 120, 2523–2533. Spiroketals are often
constituted of thermodynamic mixtures of isomers. The
C28–C38 spiroketal moiety of okadaic acid has been
13C NMR (CDCl3, 62.9 MHz): 135.7, 135.6, 134.9, 132.3,
129.9, 129.5, 127.8, 127.6, 77.8, 69.5, 67.9, 63.7, 37.3,
36.8, 36.3, 32.6, 26.9, 21.7, 19.2, 18.6, 9.4.
reported to exist as a single isomer.
10. Keck, G. E.; Abbott, D. E. Tetrahedron Lett. 1984, 25,
1883–1886.

242
J. -G. Boiteau et al. / Tetrahedron Letters 42 (2001) 239–242
Conversion 6“8: To a solution of a 1:1 mixture of diols
cally dried (10 mL toluene) in presence of trifluoroacetic
acid (20 mL, 0.26 mmol). The solvents were evaporated
and the residue was chromatographed over silica gel
(50% ethyl acetate in cyclohexane) to provide the desired
spiroketal 8 (11 mg, 48 mmol) in 60% yield. 8: [h]2D0= +
67 (c 0.75, CHCl3). Reported: [h]2D0= +69 (c 1.55,
CHCl3).
6a and 6b (60 mg, 83 mmol) in dichloromethane/ethyl
acetate 8/2 (2 mL) was added activated manganese diox-
ide (390 mg, 4.5 mmol). The resulting suspension was
stirred for 12 h with occasional sonication whereupon
more manganese dioxide was added (150 mg, 1.7 mmol)
and the suspension was stirred for an additional 12 h
(NMR control showed 75% conversion). The suspension
was filtered and concentrated in vacuo and the resulting
oil directly dissolved in methanol/THF 9:1 and hydro-
genated for 4 h using Pd/C (10 mol%); after removal of
the catalyst and solvents, the residue was dissolved in
THF (5 mL) and a solution of tetrabutylammonium
fluoride (1 M in THF, 180 mL, 0.18 mmol) was added.
The reaction mixture was stirred overnight, the solvents
were removed in vacuo and the residue was azeotropi-
1H NMR (CDCl3, 400 MHz): 3.68 (m, 1H); 3.65 (dd,
J=4, 10.4, 1H); 3.57 (m, 1H); 3.56 (dd, J=2, 10, 1H);
3.48 (dd, J=6.4, 10.8, 1H); 2.05 (dddd, J=4.6, 4.6,
13.8, 13.8, 1H); 1.90–1.75 (m, 3H); 1.69–1.34 (m, 8H),
1.13 (d, J=6.8, 3H); 0.95 (d, J=7, 3H).
13C NMR (CDCl3, 100 MHz): 72.6, 64.8, 60.4, 37.5,
35.8, 30.3, 28.0, 26.5, 25.4, 18.7, 14.4, 11.4. Reported:
(CDCl3, 125 MHz): 95.7, 72.6, 64.9, 60.4, 37.6, 35.9,
30.3, 28.1, 26.4, 25.4, 18.7, 14.4, 11.4.
.
.