Direct substitution of arylalkynyl carbinols provides access to diverse terminal acetylene building blocks

Article abstract of DOI:10.1021/acs.orglett.6b03438

To develop next generation antifolates for the treatment of trimethoprim-resistant bacteria, synthetic methods were needed to prepare a diverse array of 3-aryl-propynes with various substitutions at the propargyl position. A direct route was sought whereb

Full text of DOI:10.1021/acs.orglett.6b03438

Letter
pubs.acs.org/OrgLett
Direct Substitution of Arylalkynyl Carbinols Provides Access to
Diverse Terminal Acetylene Building Blocks
Narendran G-Dayanandan,†,§ Eric W. Scocchera,†,§ Santosh Keshipeddy,† Heather F. Jones,†
Amy C. Anderson,† and Dennis L. Wright*,†,‡
†Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269, United States
‡Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269, United States
S
* Supporting Information
ABSTRACT: To develop next generation antifolates for the treatment of
trimethoprim-resistant bacteria, synthetic methods were needed to prepare a diverse
array of 3-aryl-propynes with various substitutions at the propargyl position. A direct
route was sought whereby nucleophilic addition of acetylene to aryl carboxaldehydes
would be followed by reduction or substitution of the resulting propargyl alcohol.
The direct reduction, methylation, and dimethylation of these readily available
alcohols provide efficient access to this uncommon functional array. In addition, an
unusual silane exchange reaction was observed in the reduction of the propargylic
alcohols.
analogs to target a variety of organisms6 that are either naturally
he incorporation of alkyne functionality in screening
1
2
3
Tlibraries, biological probes, and therapeutic agents is insensitive or have evolved resistance to the clinically used
agent. These antimicrobial agents exert their effects by
inhibiting dihydrofolate reductase (DHFR), depleting the
organism of thymidine and other metabolites essential for
replication. Our efforts employing a structure-based approach
has led to a series of propargyl-linked antifolates (PLAs)
(Scheme 1, eq 1) characterized by the insertion of a propargylic
linker6a between the diaminopyrimidine A ring and a
hydrophobic B-ring in place of the simple methylene spacer
found in TMP. The acetylenic linker offers unique advantages,
as it projects the B-ring deeper into a large hydrophobic cavity
in the enzyme while the small, linear projection of the alkyne
allows it to pass through a narrow channel in the reductase.
In developing this class of inhibitors, the importance of
propargyl substitution has shown itself to be critical with
unsubstituted, monomethylated, and dimethylated derivatives
showing strong effects on organism-specific potency,6c,7−9
selectivity over the human enzyme,10 metabolic stability,11a
and its influence over the cofactor binding.11b Various
propargyl substituents to determine structure−activity relation-
ship are required to probe the hydrophobic pocket of the
enzyme.
becoming increasingly prevalent, owing to the relative ease of
their incorporation into complex molecules through cross-
coupling chemistry,4 participation in biocompatible azide
“click” cycloadditions,5 and distinct topological features. Over
the past several years, we have been pursuing the development
of next-generation trimethoprim (TMP) (Scheme 1, eq 1)
Scheme 1. Antibacterial Antifolates and Synthetic Route to
Propargyl Linked Antifolates
We had previously developed12 a route (Scheme 1, eq 2) to
the acetylenic component of PLAs based on stepwise Wittig
homologation of biaryl aldehydes 1 or methyl ketones 2 to
produce the unsubstituted and monomethylated intermediates
Received: November 17, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03438
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
3 and 4 respectively; the dimethyl congener 5 is prepared by a
subsequent enolate alkylation. Condensation of the homo-
logated aldehydes with the Ohira−Bestmann13 reagent delivers
the terminal alkyne building blocks 6−8, followed by
Sonogashira coupling with the diaminopyrimidine A ring.
The limitations of the above route include (1) repetitive
homologation required from ketone and aldehyde starting
material to generate CH3 and H substitution respectively, at the
propargyl position; (2) use of toxic mercury acetate salts for
hydrolysis; (3) use of expensive Ohira−Bestmann reagent; and
(4) formation of isomeric allene byproducts during Ohira−
Bestmann homologation, leading to lower yields of terminal
alkyne. We have been interested in developing an alternative
route to these terminal acetylene building blocks that would
allow access to the different propargyl-substitution variants
from a common starting material. We envisioned that the new
route (Scheme 1, eq 3) would begin with nucleophilic acetylide
addition to biaryl aldehydes 1, obtained by Suzuki coupling, to
produce propargylic alcohols 9. Divergence from 9 via
substitution of the propargyl alcohol would generate the
unbranched, monomethyl, and dimethyl derivatives 6−8. The
direct substitution of these types of systems has been poorly
studied and are often complicated by the formation of allene
products. Moreover, the frequent presence of basic heterocycles
in the inhibitors could also limit the ability to effect such direct
substitution reactions. Herein, we describe an efficient series of
propargylic substitution reactions compatible with the
functionality in these inhibitors that can be used to generate
a homologous series of propargylic variants from a common
starting material.
Table 1. Product Distribution Using Alternative Silanes
a
silane
alkyne distribution
b
triethylsilane
1:0.4:0.3
triisopropylsilane
1:0.4:0.8
1:0.5:0.4
1:0.1:0
1:0:0
triphenylsilane
1,1,3,3-tetramethyldisiloxane (1 equiv)
polymethylhydrosiloxane
a
b
Ratios obtained by NMR. Ratios of TMS alkyne/free alkyne/silyl
exchanged alkyne.
a
Scheme 2. Deoxygenation of Propargyl Alcohols
Several commercially or readily available m-bromo-
benzaldehydes were directly converted to a variety of
heterobiaryl aldehydes 9a−j by Suzuki cross-coupling with a
suitable boronic acid. The aryl propargyl alcohols 10a−k were
prepared by nucleophilic addition of trimethylsilylacetylene to
the aryl aldehyde. Initial studies focused on the direct reductive
deoxygenation of the highly activated carbinol to produce the
unsubstituted building blocks. Although there are examples of
this type of process on secondary alcohols14 and internal
alkynes,15 there are far fewer studies involving such highly
activated systems with the alcohol flanked by both an acetylenic
and aryl substituent. Nitrogenous heteroaromatics and silyl
protected terminal alkynes also possess uncommon function-
ality in the reported examples. After a variety of conditions
were screened, it was observed that treatment of the alcohols
with an excess of boron trifluoride etherate and triethylsilane
led to the reduced methylene derivatives, as an unexpected
mixture of TMS-, TES-, and desilylated terminal acetylenes
(Table 1). Other Lewis acids including aluminum chloride,
indium chloride, and zinc bromide also facilitated deoxygena-
tion leading to a mixture of silyl- and terminal alkyne products.
The reaction was compatible with several different nitrogenous
heterocycles (Scheme 2), with the exception of pyrimidine
(11f, 11h), where there was competitive reduction of the
heterocycle itself. Surprisingly, a simple aromatic alkynol 10k
underwent extensive decomposition with no deoxygenated
product formation. This result suggested that the basic
heteroaromatic ring found in most of the substrates (10a−j)
may be playing an active role in facilitating the reduction
reaction. Support for this participation was observed as the
addition of exogenous pyridine to substrate 10k resulted in a
45% yield of the deoxygenated product 11k.
a
Increase in yield after addition of exogenous pyridine.
In order to process the mixture of deoxygenated products,
the crude reaction mixture was subjected to a mild deprotection
involving either a silver/cyanide mediated16a hydrolysis or a less
toxic equimolar mixture16b of n-Bu4NF and CH3COOH that
was utilized to convert all species to the desired terminal
alkyne. In addition to the potential participatory role of the
heterocyclic moiety, the exchange of the silyl groups during the
reduction stood out as an unusual observation. There is no
precedent, to our knowledge, for the silyl exchange reaction
that occurs in the reduction process. We investigated whether
alteration of the silyl hydride reagent would impact the silyl
exchange process using a representative substrate 10a (Table
1).
Using five different silanes, it was possible to show that the
environment of the reducing agent impacted the distribution
between the three products. Increasing steric bulk on the silane
from triethyl to triisopropyl to triphenylsilyl, had little impact
on the overall product distribution. However, we were pleased
to see that the use of hydrosiloxanes gave almost exclusively the
TMS-protected derivatives. It is interesting to note that
desilylation likely proceeded prior to product formation as
exposure of a TMS-protected product 11g to the reaction
conditions did not lead to silyl exchange or deprotection
(Scheme 3, eq 1). A plausible mechanistic pathway that
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DOI: 10.1021/acs.orglett.6b03438
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Letter
a
Scheme 3. Plausible Mechanistic Routes to Deoxygenated
Products
Scheme 4. Alkylation
accounts for both the silane exchange as well as a stabilization
role for the N-heteroaromatic (N-Het) substituent was
conceived (Scheme 3, eq 2). Rapid ionization of the activated
alcohol 14 leads to the stabilized cation 15 that can conceivably
suffer three different fates, direct reduction leading to the TMS-
derivative 16, reversible capture by the nucleophilic N-
heteroaromatic to give iminium ion 17, or, in the absence of
this stabilization, decomposition of the cation as seen with
substrate 10k. The fluoride ion liberated in the ionization step
could effect a subsequent desilylation reaction leading to
zwitterionic species 18 which upon loss of the N-hetero-
aromatic would generate an allenyl carbene such as 19. Rapid
reduction of the carbene with a silyl hydride would produce the
acetylide 20 that upon workup would deliver the unprotected
alkyne 21. Alternatively, formation of a silicate-like complex 22
followed by a hydride migration could lead to the product
containing the terminal silyl group 23 derived from the
reducing agent. The formation of neutral allenyl silane
byproduct from complex 22 was not observed. The steric
environment and reactivity of the silane would be a factor in the
relative preponderance of the deprotected/exchanged materials,
as rapid reduction of the initial carbocation would limit these
other products.
With the success of the direct reduction of the intermediate
alcohols, our attention turned to alkylation reactions of the
putative carbocation intermediate 15 (Scheme 3, eq 2). Herein,
we show that treatment of the secondary alcohols with
dimethylzinc17 in the presence of titanium tetrachloride led
to direct formation of the methyl branched systems in good
overall yields (Scheme 4). Addition to the pendant heterocycles
or formation of allenic products were observed only in trace
amounts. But with substrate 12b lacking an electron-donating
group at the ortho and para position of the aromatic ring,
allenyl byproduct formation appeared to be competitive. This
compliments other methods for installing propargyl methyl
groups such as cuprate displacement18a and Negishi cou-
pling.18b Likewise, it was relatively straightforward to prepare
the gem-dimethyl congener from the propargylic alcohols by
initial oxidation to the ynone and subsequent introduction of
a
Inseparable mixture of allene and alkyne.
methyl groups and final desilylation. Again, addition to the
alkyne carbons or allene formation was not observed under
these reaction conditions.
In summary, these methods allow for ready access to a series
of 3-aryl propynes with both unsubstituted and branched
propargylic carbons. Additional stabilization of the putative aryl
substituted propargyl cation by suitably placed donor groups on
the aromatic ring improves the overall efficiency of the reaction.
These direct substitution reactions were sufficiently mild to
allow the incorporation of the wide range of nitrogenous
heterocycles in the substrate. In addition, there is evidence that
the basic heterocycle plays a role in the facility of the reduction
process, an effect that can be mimicked by the addition of
exogenous pyridine to the reaction. These direct methods
provide for the preparation of the series of differentially
substituted 3-aryl propynes from propargyl alcohols by direct
reduction or substitution of the readily ionized hydroxyl group.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03438.
Experimental procedures and full characterization data
for all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dennis.wright@uconn.edu.
C
DOI: 10.1021/acs.orglett.6b03438
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Organic Letters
ORCID
Letter
(c) Gevorgyan, V.; Rubin, M.; Benson, S.; Liu, J.; Yamamoto, Y. J. Org.
Chem. 2000, 65, 6179.
Narendran G-Dayanandan: 0000-0002-8922-4339
Dennis L. Wright: 0000-0003-4634-3351
Author Contributions
§N.G.-D. and E.W.S. contributed equally to this work
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the support of NIH AI104841 and
NIH AI11957 to A.C.A. and D.L.W.
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DOI: 10.1021/acs.orglett.6b03438
Org. Lett. XXXX, XXX, XXX−XXX