Tetrafibricin: Synthesis of the C1-C13, C15-C25, and C27-C40 fragments

Article abstract of DOI:10.1021/ol048862i

(Chemical Equation Presented) A sequence of chemoselective cross-metathesis reactions and enantioselective allyltitanations of aldehydes has been used to prepare the C1-C13, C15-C26, and C27-C40 fragments of tetrafibricin.

Full text of DOI:10.1021/ol048862i

ORGANIC
LETTERS
2004
Vol. 6, No. 20
3469-3472
Tetrafibricin: Synthesis of the C1
−C13,
C15 C25, and C27 C40 Fragments
−
−
Samir BouzBouz* and Janine Cossy*
Laboratoire de Chimie Organique associe´ au CNRS, ESPCI, 10 rue Vauquelin,
75231 Paris Cedex 05, France
samir.bouzbouz@espci.fr; janine.cossy@espci.fr
Received June 16, 2004
ABSTRACT
A sequence of chemoselective cross-metathesis reactions and enantioselective allyltitanations of aldehydes has been used to prepare the
C1 C13, C15 C26, and C27 C40 fragments of tetrafibricin.
−
−
−
The 1,2-, 1,3-, and 1,5-diol units, as well as polyene units,
are present in a great number of natural products possessing
interesting biological properties. Among these, tetrafibricin,
a polyoxygenated polyene, was isolated in 1993 from
Streptomyces neyagawaensis NR0577,1 and its structure was
fully established in 2003.2 Tetrafibricin exhibits potent
inhibition on platelet aggregation through the blockage of
the GPIIb/IIIa receptor on the platelet surface.3,4 Compared
to other fibrinogen receptor antagonists, tetrafibricin is
unique, as its structure lacks any peptidic sequence.5 Tetra-
fibricin bears an extended chain of polyalcohols, in particular,
1,3-diols and hexa-1,5-dien-3-ols, as well as a functionalized
tetraene. Recently, we have shown that optically active 1,3-
syn- and 1,3-anti-diols of type C can be obtained from
optically active homoallylic alcohols of type A via non-
protected â-hydroxy-aldehydes of type B by utilizing an
enantioselective allyltitanation.6
Furthermore, from homoallylic alcohol of type A, we were
able to obtain the optically active hexa-1,5-dien-3-ols of type
E with good stereo-, diastereo-, and enantioselectivity via
R,â-unsaturated aldehydes of type D using a cross-metathesis
Scheme 1
(1) Kamiyama, T.; Umino, T.; Fujisaki, N.; Fujimori, K.; Satoh, T.;
Yamashita, Y.; Ohshima, S.; Watanabe, J.; Yokose, K. J. Antibiot. 1993,
46, 1039.
(2) Kobayashi, Y.; Czechtizky, W.; Kishi, Y. Org. Lett. 2003, 4, 93.
(3) Satoh, T.; Yamashita, Y.; Kamiyama, T.; Watanabe, J.; Steiner, B.;
Hadvary, B.; Arisawa, M. Thromb. Res. 1993, 72, 389.
(4) Satoh, T.; Yamashita, Y.; Kamiyama, T.; Arisawa, M. Thromb. Res.
1993, 72, 401.
(5) Alig, A.; Edenhofer, A.; Hadvary, P.; Hurzelel, M.; Knopp, D.;
Muller, M.; Steiner, B.; Trzeciak, A.; Weller, T. J. Med. Chem. 1992, 35,
4393.
(6) BouzBouz, S.; Cossy, J. Org. Lett. 2000, 2, 501.
10.1021/ol048862i CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/10/2004

Scheme 2
reaction (CM) followed by an enantioselective allyltitanation.
greater than 95%. In the aim of introducing the C34-C35
double bond, compound 2 was treated with acrolein (3 equiv)
in the presence of Hoveyda’s catalyst II11 (5 mol %, CH2Cl2,
25 °C, 4 h) and the unsaturated hydroxy aldehyde 3 was
produced in 81% yield with an E/Z ratio greater than 20/1.
After protection of the hydroxy group in 3 as a methoxy-
methyl ether (MOMCl, i-Pr2NEt, CH2Cl2, 25 °C, 91% yield)
the resulting protected unsaturated hydroxy aldehyde 4 was
treated with the allyltitanium (R,R)-I to introduce the
hydroxyl group at C33, and compound 5 was produced in
86% yield (dr ) 95/5). As the CM has to be chemoselective
to introduce the C30-C31 (E)-double bond, the hydroxy
group at C33 was protected by a sterically hindered protect-
ing group. Thus, 5 was transformed into the tert-butyldi-
phenylsilyl ether 6 (imidazole, CH2Cl2, 25 °C, 1 h, 88%
yield), which was then treated with acrolein (3 equiv) in the
presence of II (5 mol %, CH2Cl2, 25 °C, 24 h), and the
corresponding unsaturated aldehyde 7 was obtained in 53%
yield. The third stereogenic center present in the C27-C40
fragment of tetrafibricin was introduced by addition of the
(R,R)-I complex to aldehyde 7 (ether, -78 °C). The
unsaturated triol 8 was isolated in 85% yield, and the
resulting hydroxy group at C16 was protected as a tert-
butyldiphenylsilyl ether (TBDPSCl, imidazole, CH2Cl2,
25 °C, 2 h) to lead to 9 in 89% yield. This compound
corresponds to the C27-C40 fragment of tetrafibricin.
The synthesis of the C15-C25 fragment of tetrafibricin,
which possesses three stereogenic centers and an (E)-double
bond, was thought possible from the protected aldehyde 10
by using the (R,R)-I complex to control the stereogenic
We have also demonstrated that electronic and/or chelating
effects7 (R ) Ac) as well as steric effects8 (R ) Sit-BuPh2,
Sit-BuMe2) induced chemoselective CM reactions when
protected 1,5-diols of type F were treated with an activated
olefin in the presence of catalyst II (Scheme 1).
The enantioselective allyltitanation and chemoselective
CM reactions were envisaged to enable the construction of
the C27-C40 and C15-C25 fragments of tetrafibricin from
the protected amino aldehyde 1 and the hydroxy aldehyde
10, respectively. Furthermore, as tetraenes can be obtained
by dehydration of 1,5-diols via their corresponding acetates
under basic conditions, the same allyltitanation/cross-
metathesis sequence was considered for preparation of the
C1-C13 fragment of tetrafibricin from aldehyde 17, which
can be prepared from (S)-methyl hydroxyl propionate9
(Scheme 2). The control of all the stereogenic centers in the
C1-C13, C15-C25, and C27-C40 fragments could be
achieved by treatment of aldehydes with the highly face-
selective allyltitanium complexes (R,R)-I and (S,S)-I.10 The
synthesis of the C27-C40 fragment was accomplished by
action of the allyltitanium complex (R,R)-I on the N-Boc
amino-aldehyde 1 to control the stereogenic centers at C29,
C33, and C37 and by using cross-metathesis reactions to
control the (E)-double bonds at C30-C31 and C34-35
(Scheme 3). When N-Boc amino aldehyde 1 was treated with
the allyltitanium complex (R,R)-I (ether, -78 °C), the
homoallylic alcohol 2 was isolated in 83% yield with an ee
(7) BouzBouz, S.; Cossy, J. Org. Lett. 2001, 2, 1451.
(8) BouzBouz, S.; Simmons, R.; Cossy, J. Org. Lett. 2004, accepted.
(9) Konno, K.; Fujishima, T. J. Chem. Med. 2000, 43, 4247.
(10) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, J.; Rothe-Streit, P.;
Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114, 2321.
(11) Hoveyda, A. H.; Gillingham, D. G.; Van Veldhuizen, J. J.; Kataoka,
O.; Garber, S. B.; Kingsbury J. S.; Harrity J. P. A. Org. Biomol. Chem.
2004, 2, 8.
3470
Org. Lett., Vol. 6, No. 20, 2004

Scheme 3a
a Reagents and conditions: (a) (R,R)-I, ether, -78 °C, 83%; (b) acrolein (3 equiv), 5 mol % II, CH2Cl2, 25 °C, 81%; (c) MOMCl,
i-Pr2NEt, CH2Cl2, 25 °C, 91%; (d) (R,R)-I, ether, -78 °C, 86%; (e) TBDPSCl, imidazole, CH2Cl2, 25 °C, 88%; (f) Acrolein (3 equiv),
5 mol % II, CH2Cl2, 25 °C, 24 h, 53%; (g) (R,R)-I, ether, -78 °C, 85%; (h) TBDPSCl, imidazole, CH2Cl2, 25 °C, 89%.
centers and by using a chemoselective CM to control the
(E)-double bond. Aldehyde 10 was transformed to the
homoallylic alcohol 11 by using the allyltitanium complex
(S,S)-I (ether, -78 °C, 85% yield, ee ) 95%), the stereogenic
center of which corresponds to the C23 stereogenic center
in tetrafibricin. To introduce the C20-C21 (E)-double bond,
the homoallylic 11 was treated with acrolein (3 equiv) in
the presence of the ruthenium complex II (5 mol %) in
CH2Cl2 at 25 °C to afford the aldehyde 12 in 87% yield. As
the C17 and C19 stereogenic centers have a 1,3-relationship,
they can be introduced by using an allyltitanation/oxidation/
allyltitanation sequence. Thus, the unsaturated aldehyde 12
was treated with the (R,R)-I (ether, -78 °C) resulting in the
homoallylic alcohol 13 in 84% yield. The choice of a
hindered protecting group for the hydroxy group is of
significant importance, as it will protect the disubstituted
double bond at C20-C21 during the oxidation of the terminal
olefin.12 Thus, the homoallylic alcohol 13 was subjected to
TBDPSCl (imidazole, CH2Cl2, 25 °C) and transformed into
the silyl ether 14 in 77% yield. Compound 14 was then
selectively oxidized to the corresponding aldehyde (OsO4,
NMO then NaIO4, THF/H2O) which was not purified but
directly subjected to the allyltitanation [(R,R)-I, -78 °C,
ether] to produce the homoallylic alcohol 15 with an overall
yield of 75%. After protection of the secondary alcohol
(TBSOTf, 2,6-lutidine) and selective deprotection of the
primary alcohol, the C15-C25 fragment of tetrafibricin,
compound 16, was obtained in 59% yield (Scheme 4).
The C1-C13 fragment of tetrafibricin contains the tetraene
unit and stereogenic centers at C11 and C12. It should be
obtained by dehydration of an unsaturated diacetate ester of
type G (EWG ) CO2Et) which can be generated from
compound of type F using a chemoselective cross-metathesis
reaction (Scheme 1).
The synthesis of the C1-C13 fragment originated with
aldehyde 17, the stereogenic center of which corresponds to
the C12 center present in tetrafibricin. Aldehyde 17 was
subjected to the (R,R)-I titanium complex (ether, -78 °C)
Scheme 4a
a Reagents and conditions: (a) (S,S)-I, ether, -78 °C, 85%. (b) Acrolein (3 equiv), 5 mol % II, CH2Cl2, 25 °C, 87%. (c) (R,R)-I, ether,
-78 °C, 84%. (d) TBDPSCl, imidazole, CH2Cl2, 25 °C, 77%. (e) (i) OsO4, NMO, NaIO4, acetone/H2O, 25 °C; (ii) 24 h, (R,R)-I, ether,
-78 °C, 75% for the two steps. (f) (i) TBSOTf, 2,6-lutidine, CH2Cl2, -78 °C; (ii) NH4F, MeOH, 60 °C, 59% for the two steps.
Org. Lett., Vol. 6, No. 20, 2004
3471

Scheme 5a
a Reagents and conditions: (a) (R,R)-I, ether, -78 °C, 87%. (b) TBSOTf, 2,6-lutidine, CH2Cl2, -78 °C, 90%. (c) (i) O3, CH2Cl2,
-78 °C, Me2S, 25 °C; (ii) allylMgCl, THF, -40 °C, 70% for the two steps. (d) Acrolein (3 equiv), 5 mol % II, CH2Cl2, 25 °C, 82%. (e)
AllylSnBu3, CH2Cl2, -78 °C, 76%. (f) Ac2O, pyridine, DMAP, 25 °C, 86%. (g) Ethyl acrylate (3 equiv), 5 mol % II, CH2Cl2, 25 °C, 78%.
(h) DBU, THF, 25 °C, 36 h, 79%. (i) NH4F, MeOH, 60 °C, 70%.
and transformed into the homoallylic alcohol 18 in 87% yield
(de ) 95%). After protection of the hydroxy group as a tert-
butyldimethylsilyl ether (TBSOTf, 2,6-luditine, CH2Cl2,
-78 °C, yield ) 90%), the resulting compound 19 was
ozonolyzed (O3, CH2Cl2, -78 °C, Me2S) to produce the
corresponding aldehyde, which was directly treated with
allylmagnesium chloride (THF, -40 °C) to produce two
inseparable homoallylic alcohols 20 (dr ) 1/1) with an
overall yield of 70% from 19. A CM reaction between the
mixture of homoallylic alcohols 20 and acrolein in the
presence of catalyst II (5 mol %, CH2Cl2, 25 °C) afforded
aldehyde 21 in 82% yield, which was allylated with tri-n-
butylstannane in the presence of BF3‚OEt2 (CH2Cl2,
-78 °C).13 The tetraol 22 was isolated in 76% yield as a
mixture of stereoisomers. To complete the synthesis of the
C1-C13 fragment from 22, a chemoselective CM reaction
as well as a deoxygenation were necessary. As allylic acetates
can be eliminated under basic conditions14 to produce dienes
and as we have shown previously that a chemoselective CM
can take place with hexa-1,5-dien-3-acetates, compound 23
was transformed into the corresponding diacetate 24 (Ac2O,
pyridine, DMAP, 25 °C) in 86% yield. The introduction of
an unsaturated ester group, precursor of the carboxylic
functionality at C1, was achieved by treatment of 24 with
ethyl acrylate under the CM conditions [ethyl acrylate (3
equiv), II (5 mol %), CH2Cl2, 25 °C, 16 h]. The unsaturated
ester 24 was isolated in 78% yield. After treatment of 25
with DBU in THF at 25 °C for 36 h, the desired tetraene 26
was obtained in 79% yield with good stereoselectivity (E/Z
) 10/1). A selective cleavage of the primary silyl ether in
compound 25 by using NH4F in refluxing methanol gave
compound 26 in 70%. This compound corresponds to the
C1-C13 fragment of tetrafibricin.
The extreme versatility of the cross-metathesis reaction/
allylmetallation of aldehydes has allowed the synthesis of
the C1-C13, C15-C25, and C27-C40 fragments of tetra-
fibricin via the formation of hexa-1,5-dien-3-ols. The syn-
thesis of homoallylic 1,5-diols could represent a biomimetic
method of obtaining polyenes. The complete synthesis of
tetrafibricin will be reported in due course.
Acknowledgment. We thank Dr. R. A. Fisher (Materia,
Inc.) and Prof. A. H. Hoveyda for generous gifts of catalyst
II.
Supporting Information Available: 1H NMR and 13C
NMR spectrum for compounds 3, 5, 7, 9, 12, 15, 16, and
24-26. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) Andrus, M. B.; Lepore, S. D.; Sclafani, J. A. Tetrahedron Lett. 1997,
38, 4043.
(13) Marshall, J. A.; Jablonowski, J. A.; Welmaker, G. S. J. Org. Chem.
1996, 61, 2904.
(14) Hudlicky, T.; Frazier, J. O.; Seoane, G.; Tiedje, M. J. Am. Chem.
Soc. 1986, 108, 3755.
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