C(21)-C(40) of tetrafibricin via metal catalysis: Beyond stoichiometric chiral reagents, auxiliaries, and premetalated nucleophiles

Article abstract of DOI:10.1021/ol200735r

Chemical equations presented. The C(21)-C(40) fragment of fibrinogen receptor inhibitor tetrafibricin was prepared in 12 steps from propane diol (longest linear sequence). In this approach, 6 C-C bonds are formed via asymmetric iridium catalyzed transfer

Full text of DOI:10.1021/ol200735r

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2484–2487
C(21)ÀC(40) of Tetrafibricin via Metal
Catalysis: Beyond Stoichiometric Chiral
Reagents, Auxiliaries, and Premetalated
Nucleophiles
Esa T. T. Kumpulainen, Byungsoo Kang, and Michael J. Krische*
University of Texas at Austin, Department of Chemistry and Biochemistry, Austin,
Texas 78712, United States
mkrische@mail.utexas.edu
Received March 18, 2011
ABSTRACT
The C(21)ÀC(40) fragment of fibrinogen receptor inhibitor tetrafibricin was prepared in 12 steps from propane diol (longest linear sequence).
In this approach, 6 C;C bonds are formed via asymmetric iridium catalyzed transfer hydrogenative carbonyl allylation and 2 CdC bonds are
formed via Grubbs olefin cross-metathesis.
In the course of exploring CÀC bond forming hydro-
genations beyond alkene hydroformylation, we have iden-
tified a broad new class of catalytic CÀC couplings in
which alcohol dehydrogenation triggers reductive gene-
ration of nucleophiles from π-unsaturated reactants.1 Un-
der transfer hydrogenation conditions employing isopro-
panol as a hydrogen source, the reductive coupling of
π-unsaturated reactants to aldehydes and activated ke-
tones is achieved. Of greater interest, primary alcohols can
serve dually as hydrogen donors and aldehyde precursors,
enabling carbonyl addition directly from the alcohol
oxidation level.2 Such CÀC bond forming transfer hydro-
genations merge oxidation and construction events, by-
passing discrete oxidation and use of stoichiometric
organometallic reagents. Accordingly, applications of this
methodology in target oriented synthesis have begun to
emerge.3
(1) For selected reviews on CÀC bond forming hydrogenation and
transfer hydrogenation, see: (a) Patman, R. L.; Bower, J. F.; Kim, I. S.;
Krische, M. J. Aldrichimica Acta 2008, 41, 95. (b) Bower, J. F.; Kim, I. S.;
Patman, R. L.; Krische, M. J. Angew. Chem., Int. Ed. 2009, 48, 34. (c)
Han, S. B.; Kim, I. S.; Krische, M. J. Chem. Commun. 2009, 7278. (d)
Bower, J. F.; Krische, M. J. Top. Organomet. Chem. 2011, 43, 107.
(2) In related “hydrogen auto-transfer” or “borrowing hydrogen”
processes, alcohol dehydrogenation and nucleophile generation occur
independently. Hence, conventional preactivated nucleophiles are re-
quired. Such processes deliver products of formal alcohol substitution
rather than carbonyl addition. For selected reviews, see: (a) Guillena, G.;
In this account, a concise synthesis of the C(21)ÀC(40)
substructure of tetrafibricin is disclosed employing alcohol-
mediated carbonyl allylations developed in our labora-
tory.4 Tetrafibricin is a fibrinogen receptor inhibitor that
(3) For applications in total synthesis, see: (a) Lu, Y.; Krische, M. J.
Org. Lett. 2009, 11, 3108. (b) Harsh, P; O’Doherty, G. A. Tetrahedron
2009, 65, 5051. (c) Sawant, P.; Maier, M. E. Tetrahedron 2010, 66, 9738.
(d) Han, S. B.; Hassan, A.; Kim, I.-S.; Krische, M. J. J. Am. Chem. Soc.
2010, 132, 15559.
(4) (a) Kim, I. S.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2008,
130, 6340. (b) Kim, I. S.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc.
2008, 130, 14891. (c) Lu, Y.; Kim, I. S.; Hassan, A.; Del Valle, D. J.;
Krische, M. J. Angew. Chem., Int. Ed. 2009, 48, 5018. (d) Hassan, A.; Lu,
Y.; Krische, M. J. Org. Lett. 2009, 11, 3112.
ꢀ
Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2007, 46, 2358. (b)
Hamid, M. H. S. A.; Slatford, P. A.; Williams, J. M. J. Adv. Synth. Catal.
2007, 349, 1555. (c) Nixon, T. D.; Whittlesey, M. K.; Williams, J. M. J.
Dalton Trans. 2009, 753. (d) Dobereiner, G. E.; Crabtree, R. H. Chem.
ꢀ
Rev. 2010, 110, 681. (e) Guillena, G.; Ramon, D. J.; Yus, M. Chem. Rev.
2010, 110, 1611. (f) Related dehydrogenative couplings of amines also
require pre-activated nucleophiles; see: Li, C.-J. Acc. Chem. Res. 2009,
42, 335.
r
10.1021/ol200735r
Published on Web 04/06/2011
2011 American Chemical Society

Scheme 1. Retrosynthetic Analysis of the Fibrinogen Receptor Inhibitor Tetrafibricin
embodies a unique array of functionality, including alter-
nating 1,3-diol and 1,5-ene-diol substructures, a tetraenoic
acid moiety, and a primary amine.5 Although biosyntheti-
cally related to oxo-polyene macrolide antibiotics such as
lienomycin,6 tetrafibricin lacks a macrocyclic structure and
is inactive against Bacillus subtilis and Escherichia coli.
Additionally, the structure of tetrafibricin deviates from
all other naturally occurring fibrinogen receptor antago-
nists. Tetrafibricin is of interest as a tool to study fibrinogen
binding as well as platelet aggregation and as a potential
therapeutic agent for treatment of arterial thrombotic
disease.7 The total synthesis of tetrafibricin remains an un-
requited challenge, which, if met, would enable further
investigations into its biological properties. Toward this
end Cossy,8 Roush,9 Curran,10 and Friestad11 report syn-
theses of various tetrafibricin fragments.
We envisioned a convergent approach to tetrafibricin
involving the union of fragment A C(21)ÀC(40) and
fragment B C(1)ÀC(20) via JuliaÀKocienski olefination.
As demonstrated in this account, the C(21)ÀC(40) frag-
ment A can itself be prepared through cross-metathesis of
homoallylic ether 6 and allylic alcohol 14 (Scheme 1).
Synthesis of the C(31)ÀC(40) fragment 6 begins with the
enantioselective iridium catalyzed allylation ofcommercial
N-Boc-4-aminobutan-1-ol 1 to provide the homoallylic
alcohol 2. For reactions performed on a large scale (20
mmol), the cyclometalated iridium C,O-benzoate catalyst
modified by (S)-BINAP, designated (S)-I, was generated
in situ. The desired homoallylic alcohol 2 was produced in
68% isolated yield and 92% enantiomeric excess. Notably,
(S)-I exhibits excellent chromatographic stability and can
be recovered from the reaction in 91% yield. Recovered
(S)-I may be recycled in a second round of allylation to
provide homoallylic alcohol 2 in comparable yield and
with equally high levels of enantioselectivity. The ability to
recyclethecatalyst, alongwiththe abilitytobypass discrete
alcohol oxidation, enhances the cost-effectiveness of this
allylation methodology (Scheme 2).
Scheme 2. Enantioselective Allylation of N-Boc-4-aminobutan-
1-ol 1 with Recovery of the Iridium Catalyst
(5) For isolation and stereochemical assignment, see: (a) Kamiyama,
T.; Umino, T.; Fujisaki, N.; Satoh, T.; Yamashita, Y.; Ohshima, S.;
Watanabe, J.; Yokose, K. J. Antibiot. 1993, 46, 1039. (b) Kamiyama, T.;
Itezono, Y.; Umino, T.; Satoh, T.; Nakayama, N.; Yokose, K. J.
Antibiot. 1993, 46, 1047. (c) Kobayashi, Y.; Czechtizky, W.; Kishi, Y.
Org. Lett. 2003, 5, 93.
(6) Pawlak, J.; Nakanishi, K.; Iwashita, T.; Borowski, E. J. Org.
Chem. 1987, 52, 2896.
Exposure of homoallylic alcohol 2 to acrolein in the
presence of the second generation Grubbs catalyst pro-
vides the product of cross-metathesis 3 in 83% yield. The
δ-hydroxy enal 3 was converted to the tert-butyldimethyl-
silyl ether 4 in 52% yield, which was subjected to iridium
catalyzed carbonyl allylation to furnish the homoallyllic
alcohol 5 in 83% yield as a 30:1 mixture of diastereomers,
as determined by chiral stationary phase HPLC analysis.
Here, the cyclometalated iridium C,O-benzoate catalyst
modified by (S)-Cl,MeO-BIPHEP, designated (S)-II, was
generated in situ and no attempt at catalyst recovery was
(7) (a) Satoh, T.; Yamashita, Y.; Kamiyama, T.; Arisawa, M.
Thromb. Res. 1993, 72, 401. (b) Satoh, T.; Yamashita, Y.; Kamiyama,
T.; Arisawa, M. Thromb. Res. 1993, 72, 401. (c) Satoh, T.δ; Kouns,
W. C.; Yamashita, Y.; Kamiyama, T.; Steiner, B. Biochem. J. 1994, 301,
785. (d) Satoh, T.; Kouns, W. C.; Yamashita, Y.; Kamiyama, T.; Steiner,
B. Biochem. Biophys. Res. Commun. 1994, 204, 325.
(8) BouzBouz, S.; Cossy, J. Org. Lett. 2004, 6, 3469.
(9) (a) Lira, R.; Roush, W. R. Org. Lett. 2007, 9, 533. (b) Kister, J.;
Nuhant, P.; Lira, R.; Sorg, A.; Roush, W. R. Org. Lett. 2011, 13, 1868.
(10) (a) Gudipati, V.; BajPai, R.; Curran, D. P. Collect. Czech. Chem.
2009, 74, 774. (b) Zhang, K.; Gudipati, V.; Curran, D. P. Synlett 2010,
667. (c) Gudipati, V.; Curran, D. P. Tetrahedron Lett. 2011, 52, 2254.
(11) Friestad, G. K.; Sreenilayam, G. Org. Lett. 2010, 12, 5016.
Org. Lett., Vol. 13, No. 9, 2011
2485

Scheme 3. Conversion of Homoallylic Alcohol 2 to 1,5-Ene-
diol 6
Scheme 4. Conversion of 1,3-Propanediol to 1,3-Polyol 14
made. Finally, homoallyllic alcohol 5 was converted to
the bis(tert-butyldimethylsilyl ether) 6 in 94% yield
(Scheme 3).
Scheme 5. Cross-Metathesis To Form the C(21)ÀC(40) Frag-
With the C(31)ÀC(40) fragment 6 in hand, preparation
of the C(21)ÀC(30) fragment 14 was undertaken. The
synthesis of fragment 14 begins with the conversion of 1,
3-propanediol to 1,3-polyol 7, which is performed via
iterative two-directional carbonyl allylation from the diol
oxidation level in accordance with our published pro-
cedure.4c Conversion of 7 to the bis(tert-butyldiphenylsilyl
ether) 8 is followed by ozonolysis of the terminal olefins to
provide the C2-symmetric polyol 9 in good overall yield.
Differentiation of the homotopic diol termini of 9 is accom-
plished through pivaloylation to form the mono-pivalic ester
10 as a component of a statistical mixture. However, the
product of bis(pivaloylation) 11 could be recycled by treat-
ment with DIBAL. Finally, Grieco’s two-step method for
primary alcohol dehydration12 followed by removal of the
tert-butyldiphenylsilyl ethers provides the C(21)ÀC(30)
fragment 14 in ten steps from 1,3-propanediol (Scheme 4)
Guided by studies of the cross-metathesis of related
polyketide fragments,13 it was found that exposure of
fragments 6 and 14 to the second generation HoveydaÀ
Grubbs catalyst delivered the product of cross-metathesis
15 in 58% yield with complete (E)-selectivity, as determined
by 1H NMR. The free hydroxyl moieties of compound 15
were converted to the corresponding tert-butyldimethylsilyl
ment of Tetrafibricin
ethers to give the fully protected C(21)ÀC(40) fragment of
tetrafibricin 16 in 12 linear steps from propane diol and in
only 17 total steps (Scheme 5).14
In summary, we report an approach to the C(21)ÀC(40)
fragment of tetrafibricin that extends beyond classical
strategies involving use of chiral auxiliaries, stoichiometric
chiral reagents, and premetalated nucleophiles. Notably,
all CÀC bonds formed in the longest linear sequence are
made via metal catalysis: 6 CÀC bonds formed via transfer
hydrogenative coupling and 2 CÀC bonds formed via
(12) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41,
1485.
(13) (a) BouzBouz, S.; Simmons, R.; Cossy, J. Org. Lett. 2004, 6,
3465. (b) Nyavanandi, V. K.; Nadipalli, P.; Nanduri, S.; Naidu, A.;
Iqbal, J. Tetrahedron Lett. 2007, 48, 6905 and ref 3d.
(14) As described in ref 10c the C(21)ÀC(40) fragment of tetrafibricin
was produced in 14 linear steps and 34 total steps from a commercial
chiral building block derived from malic acid. Also, as described in ref
9b, a synthesis of the C(23)ÀC(40) was recently disclosed.
(15) “The ideal synthesis creates a complex skeleton...in a sequence
only of successive construction reactions involving no intermediary
refunctionalizations, and leading directly to the structure of the target,
not only its skeleton but also its correctly placed functionality.”
Hendrickson, J. B. J. Am. Chem. Soc. 1975, 97, 5784.
2486
Org. Lett., Vol. 13, No. 9, 2011

cross-metatheses. In keeping with longstanding ideals of
synthetic efficiency,15 this approach circumvents additional
manipulations associated with the use of non-native directing
groups to mediate bond construction and merges redox-
construction events to further enhance step economy.
(RO1-GM093905), and the Center for Green Chemistry
and Catalysis for partial support of this research. E.T.T.K.
is a fellow of the Magnus Ehrnrooth Foundation.
Supporting Information Available. 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.
Acknowledgment. Acknowledgment is made to the
Robert A. Welch Foundation (F-0038), the NIH-NIGMS
Org. Lett., Vol. 13, No. 9, 2011
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