Hypervalent iodine(III)-promoted intermolecular C-C coupling of vindoline with β-ketoesters and related substrates

Article abstract of DOI:10.1021/ol400135n

The regioselective intermolecular coupling reaction of vindoline with a wide range of substrates including β-ketoesters, β-diketones, β-ketoaldehydes, β-ketonitriles, malononitriles, and β-cyanoesters provides an opportunity for the synthesis of vinblastine analogues containing deep-seated changes in the upper velbanamine subunit. The transition-metal-free hypervalent iodine(III)-promoted intermolecular sp ³/sp² coupling, representing a special class of selective C-H activation with direct carbon-carbon bond formation, proceeds with generation of a quaternary center capable of incorporation of the vinblastine C16′ methyl ester and functionalized for subsequent divergent heterocycle introduction.

Full text of DOI:10.1021/ol400135n

ORGANIC
LETTERS
2013
Vol. 15, No. 5
1100–1103
Hypervalent Iodine(III)-Promoted
Intermolecular CꢀC Coupling of Vindoline
with β‑Ketoesters and Related Substrates
Travis C. Turner, Kotaro Shibayama, and Dale L. Boger*
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps
Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
boger@scripps.edu
Received January 16, 2013
ABSTRACT
The regioselective intermolecular coupling reaction of vindoline with a wide range of substrates including β-ketoesters, β-diketones,
β-ketoaldehydes, β-ketonitriles, malononitriles, and β-cyanoesters provides an opportunity for the synthesis of vinblastine analogues containing
deep-seated changes in the upper velbanamine subunit. The transition-metal-free hypervalent iodine(III)-promoted intermolecular sp3/sp2 coupling,
representing a special class of selective CꢀH activation with direct carbonꢀcarbon bond formation, proceeds with generation of a quaternary center
capable of incorporation of the vinblastine C160 methyl ester and functionalized for subsequent divergent heterocycle introduction.
A central component in the current synthesis of the
bisindole alkaloids including vinblastine1 has been the
development of methods that permit the generation of
the key C15ꢀC160 bond that links the upper velbanamine
subunit with vindoline by conducting a challenging sp3/sp2
coupling reaction with generation of a quaternary center
(Figure 1). To date and because of their structural com-
plexity, this has largely focused on approaches that permit
the synthesis of the natural products2ꢀ12 with little con-
sideration for the extension of the efforts to key analogues
containing deep-seated changes in the upper velbanamine
subunit.13ꢀ17 In efforts focused on the potential replace-
ment of the velbanamine indole, we became interested in
the development of a coupling reaction with vindoline that
would permit the late stage, divergent18 introduction of
a range of alternative heterocycles. Herein, we report the
development of a powerful and effective intermolecular
coupling reaction of vindoline with substituted acidic
methylene compounds typified by β-ketoesters, enlisting
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130, 420.
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Rayl, T. J.; Hwang, I.; Boger, D. L. J. Am. Chem. Soc. 2009, 131, 4904.
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r
10.1021/ol400135n
Published on Web 02/19/2013
2013 American Chemical Society

hypervalent iodine(III) reagents. Central to the design of
the studies, the coupling substrates permit the incorpora-
tion of the C160 methyl ester as well as functionality
(a ketone) that should permit the late-stage, divergent
heterocycle introduction.
to other potential related cosolvents (TFE, entry 5 vs 7), the
importance of the added base (entry 5 vs 4), and the nature of
the base (entry 5 vs 6).
Figure 1. Structure of vinblastine and vindoline.
With 2-carbomethoxycyclopentanone (2a) and 2-carbo-
methoxycyclohexanone (2b) as model substrates, a range
of oxidants were examined for their ability to promote
their coupling with vindoline (1) including ceric ammo-
nium nitrate(Ce(NH4)2(NO3)6), Mn(OAc)3, VOF3, FeCl3,
or Fe(phen)3(PF6)3 and a full set of alternative Fe(III)
complexes,9,11ꢀ13 CuCl2 and Cu(acac)2, and DDQ in a
range of solvents with a variety of recommended additives,
as well as Koser’s reagent (PhI(OTs)OH). Although small
amounts of coupling were occasionally observed with
the Fe(III)-based reagents,13 only the iodine(III)-based
reagents consistently provided the coupling product in
modest conversions (2a, 33ꢀ29%; 2b, 0%, in 0.05 M in
HFIP,19 25 °C, 5ꢀ10 min). In a survey of readily available
iodine(III)-based reagents including Koser’s reagent
(PhI(OTs)OH), phenyliodine(III) diacetate (PIDA), and
phenyliodine(III) bis(trifluoroacetate) (PIFA) and several
aryl substituted variants, PIFA19 emerged as the most
effective reagent for further optimization studies. With the
more challenging of the two model substrates (2b), the choice
of solvent (1:1 HIPAꢀH2O, 0.05 M) with the inclusion
of H2O and addition of a tertiary amine additive (Et3N,
10 equiv) resulted in effective room temperature coupling to
provide 3b in good yields (Figure 2). Clear from the repre-
sentative optimization efforts summarized in Figure 2 are the
key roles played by the combined elements of the mixed
aqueous solvent system (1:1 HFIPꢀH2O vs HFIP, HFIP
with H2O (5 equiv), or 1:1 HFIPꢀMeOH; entry 5 vs entries
2, 8, or 9), the use of hexafluoroisopropanol (HFIP) relative
Figure 2. Representative initial optimization studies.
In instances where the reaction failed to produce the
coupling product or provided it in more modest conver-
sions, the PIFA electrophilic substitution of vindoline was
observed and provided 4. Efforts to convert 4to the product
3b under a variety of conditions were not successful,
resulting in no reaction with 2b or, on occasion, expectedly
transferring instead the less electron-rich phenyl group
to the substrate 2b. Mechanistically and in line with the
proposals of Kita,19 this suggests the reaction may proceed
by an initial single electron oxidation of vindoline to
generate the corresponding radical cation that either reacts
with the deprotonated β-ketoester nucleophile 2b to pro-
vide 3b after subsequent oxidation of the addition product
radical or competitively recombines with the reagent-
derived radical anion to nonproductively provide 4 (eq 1).
(17) (a) Va, P.;Campbell, E. L.;Robertson, W. M.;Boger, D. L. J. Am.
Chem. Soc. 2010, 132, 8489. (b) Tam, A.; Gotoh, H.; Robertson, W. M.;
Boger, D. L. Bioorg. Med. Chem. Lett. 2010, 20, 6408. (c) Gotoh, H.;
Duncan, K. K.; Robertson, W. M.; Boger, D. L. ACS Med. Chem. Lett.
2011, 2, 948. (d) Leggans, E. K.; Barker, T. J.; Duncan, K. K.; Boger, D. L.
Org. Lett. 2012, 14, 1428. (e) Leggans, E. K.; Duncan, K. K.; Barker, T. J.;
Schleicher, K. D.; Boger, D. L. J. Med. Chem. 2013, 56, 628. (f) Schleicher,
K. D.; Sasaki, Y.; Tam, A.; Kato, D.; Duncan, K. K.; Boger, D. L. J. Med.
Chem. 2013, 56, 483.
(18) Boger, D. L.; Brotherton, C. E. J. Org. Chem. 1984, 49, 4050.
(19) (a) Kita, Y.; Tohma, H.; Hatanaka, K.; Takada, T.; Fujita, S.;
Mitoh, S.; Sakurai, H.; Oka, S. J. Am. Chem. Soc. 1994, 116, 3684.
(b) Arisawa, M.; Ramesh, N. G.; Nakajima, M.; Tohma, H.; Kita, Y.
J. Org. Chem. 2001, 66, 59.
Org. Lett., Vol. 15, No. 5, 2013
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With these parameters defined, the reexamination of
the oxidant (PIFA vs PIDA or Koser’s reagent) and the
amount of reagent employed revealed the superior behav-
ior of PIFA (3 equiv) under these reaction conditions
(Figure 3). Aside from defining a productive stoichiometry
range for the use of PIFA (2ꢀ3 equiv), the studies further
revealed that use of excess PIFA (6 equiv) can result in the
subsequent consumption of the desired product 3b.
Figure 3. Final optimization studies.
With these conditions defined, the scope of the reaction
was examined with a range of substituted acidic methylene
compounds (Figure 4).
A range of substituted β-ketoesters (2aꢀ2d, 2j, and 2m,
but not 2e and 2f), β-diketones(2h, 2i, and2l), β-ketonitriles
(2g, 2k, and 2n), the malononitrile 2p, and the β-cyanoester
2o participated effectively in the coupling reaction to
provide the corresponding products 3 as a mixture of
diastereomers (ca. 1:1), whereas the less acidic dimethyl
methylmalonate 2q did not. It is likely that in HFIP (pKa =
9.3), insufficient amounts of the less acidic substrates such
as 2q are deprotonated (vs solvent) under the reaction
conditions to permit coupling with the vindoline-derived
intermediate radical cation competitive with generation of
4. Even the initially unexpected behavior of 2aꢀf appears
to be related to the relative acidity of the β-ketoesters, which
display a trend correlating precisely with the coupling
capabilities (2a > 2b > 2d > 2c > 2e > 2f),20 with the
pKa cutoff for observation of the coupling reaction
lying between 2c (not 2d) and 2e (Supporting Information
Figure S1). By simply converting the β-ketoester 2f to the
more acidic β-ketonitrile 2g, the substrate now participates
effectively in the coupling reaction. Finally, the coupling
reaction failed to provide identifiable coupling products
if the substrates were unsubstituted (secondary vs tertiary
centers), potentially producing a nonquaternary center.
An additional and special case of coupling substrates
proved to be β-ketoaldehydes (Figure 5). Here, the reaction
Figure 4. Scope of the PIFA-promoted coupling reaction.
Figure 5. β-Ketoaldehyde coupling reaction.
could be conducted best without the addition of Et3N, but
using the sodium enolates directly with PIFA (2ꢀ3 equiv)
in HFIPꢀH2O (25 °C, 0.05 M, 30 min).
In addition to providing access to velbanamine-derived
analogues of vinblastine incorporating alternatives to the
(20) Rhoads, S. J.; Decora, A. W. Tetrahedron 1963, 19, 1645.
1102
Org. Lett., Vol. 15, No. 5, 2013

ketone to provide the indole 513 as a 1:1 mixture of
diastereomers (Scheme 1).
Scheme 1
The intermolecular coupling of a wide range of sub-
strates with vindoline provides an opportunity for the
synthesis of vinblastine analogues with deep-seated
changes in the upper velbanamine subunit, including
those possessing heterocyclic substitutions for the indole.
Notably, the transition-metal-free hypervalent iodine(III)-
promoted intermolecular sp3/sp2 coupling, representing
a special class of selective CꢀH activation with carbonꢀ
carbon bond formation, proceeds with generation of
a quaternary center capable of direct incorporation of
the vinblastine C160 methyl ester and functionalized for
subsequent divergent heterocycle introduction.
Acknowledgment. We gratefully acknowledge the
financial support of the National Institutes of Health
(CA042056, CA115526) and the Skaggs Institute for
Chemical Biology.
key indole, the approach also offers the opportunity to
access those containing the indole as well. Representative
ofsuchopportunities and without optimization, the PIFA-
promoted coupling of 2uor 2v with (ꢀ)-vindoline provided
the coupling products 3u (39%) and 3v (47%) that, upon
reduction tothe saturated aniline (Zn, aqNH4Clꢀacetone,
25 °C, 24 h), undergo condensation with the proximal
Supporting Information Available. Full experimental
details, compound characterizations, and spectra are
provided. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
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