Stereoselective synthesis of the C(1)-C(19) fragment of tetrafibricin

Article abstract of DOI:10.1021/ol0629869

A stereoselective synthesis of the C(1)-C(19) fragment of tetrafibricin has been accomplished via a highly diastereoselective double allylboration reaction of 6-8 and an iodonium ion promoted urethane cyclization for the installation of the C(15) alkoxy f

Full text of DOI:10.1021/ol0629869

ORGANIC
LETTERS
2007
Vol. 9, No. 3
533-536
Stereoselective Synthesis of the
C(1) C(19) Fragment of Tetrafibricin
−
Ricardo Lira and William R. Roush*
Departments of Chemistry and Biochemistry, Scripps Florida, Jupiter, Florida 33458
roush@scripps.edu
Received December 10, 2006
ABSTRACT
A stereoselective synthesis of the C(1)−C(19) fragment of tetrafibricin has been accomplished via a highly diastereoselective double allylboration
reaction of 6 8 and an iodonium ion promoted urethane cyclization for the installation of the C(15) alkoxy function in 3.
−
Tetrafibricin is a polyoxygenated fibrinogen receptor inhibitor
that was isolated in 1993 from the culture broth of Strep-
tomyces neyagawaensis NR0577.1 Fibrinogen binding to the
glycoprotein GPIIb/IIIa complex on the platelet surface plays
a crucial role in platelet aggregation.2 The ability of
tetrafibricin to block fibrinogen from binding to its glyco-
protein receptor makes it a viable target for the potential
therapeutic intervention of arterial thrombotic diseases such
as coronary occlusion.3,4 Kishi and co-workers recently
assigned the stereochemistry of tetrafibricin (1) through the
use of an NMR database method, supplemented by data
obtained from NMR measurements in chiral solvents.5 The
interesting biological properties and challenging structure,
which includes 11 stereocenters of which 10 are secondary
hydroxyls arrayed as 1,3- and 1,5-diols, render tetrafibricin
an excellent target for synthetic study. Development of an
efficient, convergent synthesis of tetrafibricin (1) will
facilitate structure-activity relationship studies designed to
probe its biological properties. To our knowledge, only Cossy
has disclosed efforts toward the total synthesis of tetrafibri-
cin.6 We report herein our initial synthetic studies on 1,
culminating in an efficient synthesis of the C(1)-C(19)
fragment 3 via application of the double allylboration
methodology developed in our laboratory.7
Our retrosynthetic analysis of tetrafibricin is outlined in
Figure 1. We envisaged that tetrafibricin can be assembled
from a late-stage double allylboration sequence involving
the coupling of the functionalized aldehydes 2 and 3 with
bifunctional allylborane 4.7 It is expected that this reaction
will provide the C(19)-C(23) anti-1,5-diol unit of 1 with
an embedded trans-olefin in a single step. Aldehyde 3 would
be assembled in turn from cyclic carbonate 5 through a
(1) Kamiyama, T.; Umino, T.; Fujisaki, N.; Satoh, T.; Yamashita, Y.;
Ohshima, S.; Watanabe, J.; Yokose, K. J. Antibiot. 1993, 46, 1039.
(2) Kamiyama, T.; Itezono, Y.; Umino, T.; Satoh, T.; Nakayama, N.;
Yokose, K. J. Antibiot. 1993, 46, 1047.
(3) Satoh, T.; Kouns, W. C.; Yamashita, Y.; Kamiyama, T.; Steiner, B.
Biochem. Biophys. Res. Commun. 1994, 204, 325.
(4) Satoh, T.; Yamashita, Y.; Kamiyama, T.; Arisawa, M. Thromb. Res.
1993, 72, 401.
(5) Kobayashi, Y.; Czechtizky, W.; Kishi, Y. Org. Lett. 2003, 5, 93.
(6) BouzBouz, S.; Cossy, J. Org. Lett. 2004, 6, 3469.
(7) Flamme, E. M.; Roush W. R. J. Am. Chem. Soc. 2002, 124,
13644.
10.1021/ol0629869 CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/12/2007

Figure 1. Tetrafibricin retrosynthetic analysis.
Horner-Wadsworth-Emmons olefination sequence, fol-
lowed by oxidation of the C(13) and C(19) alcohols. Further
analysis of carbonate 5 suggests it can be accessed via a
three-component coupling of aldehydes 68 and 79 with
bifunctional allylborane 8, followed by installation of
C(15)-OH.
alcohol of the diol corresponding to 12. Therefore, it proved
advantageous to synthesize 12 via an interrupted, three-pot
double allylboration sequence to differentiate the secondary
C(17) and C(13) alcohols.11 Thus, treatment of aldehyde 79
The synthesis of the C(1)-C(19) fragment 3 commenced
with the construction of benzyl carbamate 13 (Scheme 1).
Scheme 2. Synthesis of Aldehyde 16
Scheme 1. Synthesis of Benzyl Carbamate 13
with the in situ generated bifunctional (E)-allylborane
87 [derived from the hydroboration of allene 97 with
(dIpc)2BH],12 followed by quenching with water, afforded
â-hydroxy allylboronate 10 in 82% isolated yield.13 The
resultant allylic alcohol was protected by treatment with
TBSOTf and 2,6-lutidine to afford allylboronate 11 in 89%
yield. Treatment of 11 with 1.1 equiv of aldehyde 68 at 23
°C for 96 h proceeded in a matched fashion and provided
homoallyl alcohol 12 in 73% yield as a 16:1 mixture of
Intially, we pursued the synthesis of alcohol 12 via a one-
pot double allylboration sequence followed by selective
protection of the C(17) allylic alcohol.10 However, we were
only able to achieve ca. 2:1 selectivity in protecting the allylic
(10) (a) Flamme, E. M.; Roush, W. R. Beilstein J. Org. Chem. 2005, 1,
7. (b) Hicks, J. D.; Flamme, E. M.; Roush, W. R. Org. Lett. 2005, 7, 5509.
(11) Flamme, E. M.; Roush, W. R. Org. Lett. 2005, 7, 1411.
(12) Brown, H. C.; Singaram, B. J. Org. Chem. 1984, 49, 945.
(13) The absolute stereochemistry of C(17)-OH of 10 was assigned by
Mosher ester analysis of an analogue of 13; see Supporting Information
for details.
(8) Prepared as reported for the synthesis of ent-6: Anderson, O. P.;
Barrett, A. G. M.; Edmunds, J. M.; Hachiya, S.-I.; Hendrix, J. A.; Horita,
K.; Malecha, J. W.; Parkinson, C. J.; VanSickle, A. Can. J. Chem. 2001,
79, 1562.
(9) Holmes, A. B.; Hughes, A. B.; Smithe, A. L. J. Chem. Soc., Perkin
Trans. 1 1993, 633.
534
Org. Lett., Vol. 9, No. 3, 2007

diastereomers.14 The homoallyl alcohol was then treated with
benzyl isocyanate in toluene at 115 °C to provide key benzyl
carbamate 13 in 85% yield.
Attention was next focused on the diastereoselective
installation of the C(15)-â alkoxy group of fragment 3 via
an iodonium ion promoted urethane cyclization. Initial
attempts to effect this cyclization by treatment of 13 with
iodine monochloride in CH2Cl2 at -78 °C15 afforded a
mixture of the desired iodo carbonate 14 along with an
inseparable furan side product 15 (Table 1, entry 1). This
carbamate 13 with a preformed pyridine-ICl complex in
CH2Cl2 at -78 °C and warming to 23 °C provided a small
amount of the targeted iodo carbonate 14 (17%, entry 2);
however, more importantly, formation of the furan side
product was completely suppressed. This observation prompted
an investigation of NIS as the iodine source due to its stability
and ease of handling. Gratifyingly, treatment of benzyl
carbamate 13 in CHCl3 at 23 °C with NIS (added portion-
wise) effected a clean cyclization which provided carbonate
14 as the sole product in 70% yield and >20:1 diastereo-
1
selectivity as judged by H NMR analysis.16
Deiodination of 14 by treatment with Et3B and n-Bu3SnH
generated desired intermediate 5 in 88% yield.17 To verify
the C(13)-C(15) syn stereochemistry, intermediate 5 was
converted to acetonide analogue 17 via a two-step sequence.18
13C NMR analysis of the acetonide according to the Rych-
novsky method18 confirmed the presence of a syn-1,3-diol
relationship (see Supporting Information for details). Depro-
tection of the primary DMPM group of 5 with DDQ followed
by Dess-Martin oxidation19 yielded sensitive aldehyde 16,
the substrate for the subsequent Horner-Wadsworth-
Emmons olefination with phosphonate 20.
Table 1. Installation of the C(15) Oxygen by an Iodonium Ion
Promoted Urethane Cyclization
Horner-Wadsworth-Emmons reagent 20 was synthesized
starting with the MnO2 oxidation of the known alcohol 1820
(Scheme 3). Subjection of the derived aldehyde to a Horner-
Wadsworth-Emmons21 olefination with triethyl phospho-
noacetate afforded intermediate 19 in 70% yield. Deprotec-
tion of 19 by treatment with TBAF, followed by conversion
of the allylic alcohol to the corresponding allylic bromide
by treatment with PBr3 and pyridine, and then treatment of
the allylic bromide with P(OEt)3 in refluxing toluene yielded
the phosphonate coupling partner 20 in 76% yield over three
steps.22 Gratifyingly, treatment of 20 with LHMDS followed
by addition of a solution of aldehyde 16 at -78 °C with
warming to 0 °C provided intermediate 21 in 77% yield.23
yield of
14 (%)
entry
conditions
13/14/15a
1
2
3
ICl/CH2Cl2, -78 °C
ICl-Pyr/CH2Cl2, -78 to 23 °C
NIS/CHCl3, 0-23 °C
0:80:20
50:20:0
0:100:0
17
70
a
1
Ratio determined by H NMR analysis.
side product arises from a 5-exo-type cyclization with
concomitant deprotection of the TBDPS ether. We antici-
pated that use of a pyridine-ICl complex would slow the
rate of the competing furan formation by moderating the
reactivity of the iodonium ion. Accordingly, treatment of
Tetraenoate 21 contains all the carbon atoms of the
C(1)-C(19) fragment 3 of tetrafibricin; all that remained to
Scheme 3. Completion of the Synthesis of the C(1)-C(19) Fragment 3 of Tetrafibricin
Org. Lett., Vol. 9, No. 3, 2007
535

access keto-aldehyde 3 was to adjust the oxidation state of
the C(13) and C(19) alcohols. This was achieved by cleavage
of the cyclic carbonate in 21, followed by a selective
silylation of the less-hindered C(15)-OH, which provided
22 with 10:1 regioselectivity. The crucial and selective
deprotection of the C(19) TBDPS ether was accomplished
in 55% yield by using TAS-F in a DMF-AcOH solvent
mixture.24 Finally, oxidation of the C(13)-C(19) diol with
the Dess-Martin reagent19 provided the fully elaborated
C(1)-C(19) fragment 3 of tetrafibricin.
In summary, we have accomplished an efficient and
highly diastereoselective synthesis of 3 corresponding to the
C(1)-C(19) fragment of tetrafibricin. This synthesis proceeds
in 13 steps from aldehyde 7. The highlights of this synthesis
include the highly diastereoselective interrupted double
allylboration sequence used to prepare intermediate 12, the
diastereoselective iodonium ion promoted urethane cycliza-
tion of 13 for the installation of the syn-C(15) alkoxy group
in 14, and a Horner-Wadsworth-Emmons olefination of
16 for introduction of the tetraenoate moiety. Further progress
toward the completion of the total synthesis of tetrafibricin
will be reported in due course.
(14) The absolute stereochemistry of C(13)-OH of 12 was assigned by
1H NMR analysis of the corresponding Mosher esters; see Supporting
Information for details.
(15) Duan, J. J.-W.; Smith, A. B., III. J. Org. Chem. 1993, 58, 3703.
(16) These conditions have previously been employed for the cyclization
of allylic trichloroacetimidates: Bongini, A.; Cardillo, G.; Orena, M.; Sandri,
S.; Tomasini, C. J. Org. Chem. 1986, 51, 4905.
Acknowledgment. This work was supported by the
National Institutes of Health (GM 38436).
(17) Miura, K.; Ichinose, Y.; Nozaki, K.; Fugami, K.; Oshima, K.;
Utimoto, K. Bull. Chem. Soc. Jpn. 1989, 62, 143.
Supporting Information Available: Experimental pro-
cedures and tabulated spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I. Acc. Chem.
Res. 1998, 31, 9.
(19) Dess, P. B.; Martin, J. C. J. Am. Chem. Soc. 1978, 100, 300.
(20) Berube, G.; Deslongchamps, P. Can. J. Chem. 1990, 68, 404.
(21) (a) Horner, L.; Hoffmann, H.; Wippel, H. G. Chem. Ber. 1958, 91,
61. (b) Wadsworth, W. S.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83,
1733. (c) Wadsworth, W. S. Org. React. 1977, 25, 1.
(22) Mori, Y.; Asai, M.; Kawade, J.-I.; Furukawa, H. Tetrahedron 1995,
51, 5315.
OL0629869
(24) Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler, S. R.; Coffey,
(23) Roush, W. R. J. Am. Chem. Soc. 1980, 102, 1390.
D. S.; Roush, W. R. J. Org. Chem. 1998, 63, 6436.
536
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