Asymmetric alcohol C-H allylation and syn -Crotylation: C9-C20 of tetrafibricin

Article abstract of DOI:10.1021/ol403566w

The C9-C20 segment of the fibrinogen receptor inhibitor tetrafibricin was prepared in 10 steps (longest linear sequence). Ruthenium catalyzed enantioselective syn-crotylation is used to construct C9-C13. Iridium catalyzed asymmetric alcohol C-H allylation

Full text of DOI:10.1021/ol403566w

Letter
pubs.acs.org/OrgLett
Asymmetric Alcohol C−H Allylation and syn-Crotylation: C9−C20 of
Tetrafibricin
Takahiko Itoh, T. Patrick Montgomery, Antonio Recio, III, and Michael J. Krische*
University of Texas at Austin, Department of Chemistry and Biochemistry, Austin, Texas 78712, United States
S
* Supporting Information
ABSTRACT: The C9−C20 segment of the fibrinogen receptor
inhibitor tetrafibricin was prepared in 10 steps (longest linear
sequence). Ruthenium catalyzed enantioselective syn-crotylation is
used to construct C9−C13. Iridium catalyzed asymmetric alcohol
C−H allylation of a commercial malic acid derived alcohol is used
to construct C14−C20. Recovery and recycling of the iridium
catalyst is described.
etrafibricin1 is a potent fibrinogen receptor inhibitor
isolated from Streptomyces neyagawaensis NR0577 that
accomplished through ruthenium catalyzed hydrohydroxyalky-
lation of 2-silyl-butadiene 2 with the monoprotected 1,3-
propane diol 1. A modification of our previously reported
conditions,15a which involves use of the catalyst generated from
RuHCl(CO)(PPh3)3 and (R)-DM-SEGPHOS in the presence
of substoichiometric sodium sulfate, provided the desired
product of diene hydrohydroxyalkylation 3 in 75% yield with
excellent control of syn-diastereo- and enantioselectivity (92%
ee, 18:1 dr). Adduct 3 was converted to the p-methoxy
benzylidene acetal in 87% yield upon DDQ oxidation.16 Finally,
exposure of the alkenyl silane to pyridinium bromide
perbromide gave the crude dibromide 5, which was treated
with sodium methoxide to furnish the alkenyl bromide 6
(Scheme 2).17
T
functions by blocking GPIIb/IIIa receptors on the platelet
surface, thus inhibiting platelet aggregation.2,3 While biosyn-
thetically related to the oxo-polyene macrolide antibiotic
lienomycin,4 tetrafibricin is acyclic and inactive against Bacillus
subtilis and Escherichia coli. Further, the structure of
tetrafibricin, which includes alternating 1,3-diol and 1,5-ene-
diol motifs, represents a significant departure from all known
fibrinogen receptor antagonists. Tetrafibricin has garnered
interest with regard to the study of fibrinogen binding, platelet
aggregation, and as a treatment for arterial thrombosis,3,5 which
in turn has evoked interest in its preparation via total synthesis.
Despite efforts reported from the laboratories of Cossy,6
Curran,7 Friestad,8 Roush,9 and the present author,10 including
syntheses of a protected derivative of the natural product by
Curran7d and of N-acetyl dihydrotetrafibricin methyl ester by
Roush,9c the total synthesis of tetrafibricin remains an unmet
challenge.
Synthesis of the C14−C20 epoxide 13 began with the
asymmetric iridium catalyzed alcohol C−H allylation14 of the
commercially available chiral alcohol 7 derived from (S)-malic
acid. Using the cyclometalated iridium catalyst “(S)-I”
generated in situ from [Ir(cod)Cl]2, 4-chloro-3-nitrobenzoic
acid, allyl acetate, and (S)-BINAP, the desired homoallylic
alcohol 8 was obtained in 69% isolated yield as a single
Using catalytic C−C bond-forming processes that occur
through the addition, transfer, or removal of hydrogen,11 total
syntheses of 6-deoxyerythronolide B,12a bryostatin 7,12b
trienomycins A and F,12c cyanolide A,12d and roxaticin12e
were completed in our laboratory. Due to the redox economy13
of the methods underlying their construction, the aforemen-
tioned syntheses represent the most concise routes to any
member of their respective natural product families.11d Inspired
by the unanswered synthetic challenges posed by tetrafibricin, a
12 step route to the C21−C40 segment was devised using
iridium catalyzed alcohol C−H allylation developed in our
laboratory.10,14 Here, we report a 10 step synthesis of the C9−
C20 substructure of tetrafibricin featuring enantioselective
methods for ruthenium catalyzed alcohol C−H syn-crotyla-
tion15 and iridium catalyzed alcohol C−H allylation.14
1
diastereomer as determined by H NMR of the crude reaction
product. As previously noted,18 cyclometalated iridium catalysts
of this type are remarkably stable to conventional silica gel flash
chromatography. Given evidence that the carbonyl addition is
turnover limiting,14b the chromatographically stable π-allyl
complex “(S)-I” is a potential catalyst resting state. In accord
with this interpretation, “(S)-I” can be recovered from the
reaction mixture and recycled to provide homoallylic alcohol 8
in 53% yield with equally high levels of diastereoselectivity. No
further erosion in yield or selectivity was observed upon further
iterations of recovery and recycling. Catalyst recovery and
recycling, along with the ability to bypass discrete alcohol-to-
The C9−C20 substructure of tetrafibricin was envisioned to
arise through the reductive coupling of bromide 6 to epoxide
13 (Scheme 1). Synthesis of bromide 6 was readily
Received: December 9, 2013
Published: January 14, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
Scheme 1. Retrosynthetic Analysis of the Fibrinogen Receptor Inhibitor Tetrafibricin
excellent levels of site-selectivity to provide mono-benzyl ether
mono-Boc-carbonate 11. Modified Bartlett halocyclization of
the Boc-carbonate20 followed by treatment of the crude mixture
with K2CO3 in methanol delivered the epoxy diol 12 in 48%
yield as an 8:1 mixture of diastereomers. Protection of the diol
as the acetonide provides the requisite epoxide 13 (Scheme 4).
Scheme 2. Synthesis of Alkenyl Bromide 6 via Ruthenium
Catalyzed Hydrohydroxyalkylation of Diene 2
a
Scheme 4. Conversion of Homoallylic Alcohol 8 to Epoxide
a
13
a
Yields are of material isolated by silica gel chromatography. (R)-DM-
SEGPHOS: (R)-(+)-5,5-bis(diphenylphosphino)-4,4-bi-1,3-benzo-
dioxole. See Supporting Information for further details.
aldehyde redox reactions, renders our asymmetric allylation
protocol more cost-effective (Scheme 3).
To complete the synthesis of epoxide 13, homoallylic alcohol
8 was converted to the tert-butyl carbonate 9, which was
subjected to conditions for acid catalyzed methanolysis to
furnish diol 10. Primary benzyl protection of diol 10 using
Taylor’s diphenylborinic acid catalyst19 was achieved with
a
Yields are of material isolated by silica gel chromatography. See
Supporting Information for further details.
Scheme 3. Catalyst Recovery and Recycling in the
Asymmetric Alcohol C−H Allylation of 7
a
To form the C9−C20 substructure of tetrafibricin, the
cuprate derived from alkenyl bromide 6 was reacted with
epoxide 13.21,22 Initially, it was desired to use the commercially
available lithium 2-thienyl(cyano)cuprate solution to form the
higher order mixed organocuprate reagent,21b,22b so as to limit
the stoichiometry of alkenyl bromide 6 used in the trans-
formation. However, this method failed to deliver serviceable
quantities of adduct 14. In contrast, using cuprous iodide as the
copper source with 2 equiv of alkenyl bromide, the product of
epoxide opening was obtained in good yield, based on 13.21a,22a
Silyl protection of alcohol 14, followed by ozonolysis of olefin
15, delivered the C9−C20 fragment of tetrafibricin in 10 linear
steps from the commercial malic acid derivative 7 and in 15
total steps (Scheme 5).
In summary, we report a synthetic route to the C9−C20
substructure of tetrafibricin using ruthenium catalyzed
enantioselective syn-crotylation to construct C9−C13 and
iridium catalyzed asymmetric alcohol C−H allylation to
construct C14−C20. This synthetic exercise led to the
observation that the cyclometalated iridium complex used in
the C−H allylation of primary alcohols may be recovered and
recycled. The ability to perform multiple rounds of catalyst
recovery and recycling, along with the ability to engage alcohols
directly as partners for catalytic C−C coupling in the absence of
a
Yields are of material isolated by silica gel chromatography. The third
and higher cycles provided yields ranging between 50 and 60%. See
Supporting Information for further details.
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Organic Letters
Letter
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Scheme 5. Reductive Coupling of Alkenyl Bromide 6 and
Epoxide 13 To Form the C9−C20 Substructure of
a
Tetrafibricin
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a
Yields are of material isolated by silica gel chromatography. See
Supporting Information for further details.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Spectral data for all new compounds (1H NMR, 13C NMR, IR,
HRMS). This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: mkrische@mail.utexas.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(16) Oikawa, Y.; Nishi, T.; Yonemitsu, O. Tetrahedron Lett. 1983, 24,
4037.
■
Acknowledgment is made to the Robert A. Welch Foundation
(F-0038), the NIH-NIGMS (RO1-GM093905), and the
Center for Green Chemistry and Catalysis for partial support
of this research. Dr. Taichiro Touge and Dr. Hideo Shimizu of
Takasago are thanked for the generous donation of SEGPHOS
ligands.
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NOTE ADDED AFTER ASAP PUBLICATION
■
An updated version was reposted January 14, 2014 which
includes reference 11d. On January 15, 2014 and error in
Scheme 3 was corrected.
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