Synthesis of high enantiopurity N-protected α-amino ketones by thiol ester-organostannane cross-coupling using pH-neutral conditions

Article abstract of DOI:10.1021/ol8018456

(Chemical Equation Presented) An efficient synthesis of high enantiopurity N-protected α-amino ketones is described. Complementing other studies using boronic acids and thiol esters, this Cu(I) diphenylphosphinate (CuDPP)-mediated, palladium-catalyzed cou

Full text of DOI:10.1021/ol8018456

ORGANIC
LETTERS
2008
Vol. 10, No. 19
4375-4378
Synthesis of High Enantiopurity
N-Protected r-Amino Ketones by Thiol
Ester-Organostannane Cross-Coupling
Using pH-Neutral Conditions
Hao Li, Hao Yang,† and Lanny S. Liebeskind*
Department of Chemistry, Emory UniVersity, 1515 Dickey DriVe, Atlanta, Georgia 30322
chemLL1@emory.edu
Received August 8, 2008
ABSTRACT
An efficient synthesis of high enantiopurity N-protected r-amino ketones is described. Complementing other studies using boronic acids and
thiol esters, this Cu(I) diphenylphosphinate (CuDPP)-mediated, palladium-catalyzed coupling of r-amino thiol esters with aryl, heteroaryl, allyl,
and alkenyl organostannanes gives N-protected r-amino ketones in high yields with high enantiopurity (in almost all cases) under mild and
pH-neutral reaction conditions. The viability of π-deficient heteroarylstannanes is an advantage of this reaction compared to the related
boronic acid system.
Peptidic ketones and their derived R-ketoheterocycles rep-
resent significant functionalities for the development of
molecular therapeutics.1 Potent enzyme inhibitors based on
the peptidic R-ketoheterocycle motif have been found for a
large number of enzymes.1b
Many different approaches for the synthesis of R-amino
ketones and aldehydes are known, with recent studies
focusing on the construction of enantiopure R-amino ketones
starting from naturally occurring amino acids.2 Among these
newer protocols, the use of organozinc reagents by Fuku-
yama/Tokuyama2c and Rovis2p provides improved functional
group compatibility relative to organolithium and organo-
magnesium reagents, but none of the known reactions take
place under nonbasic (non-epimerizing) conditions, nor are
they adequately functional group selective to be broadly
general.
peptidic ketone synthesis. However, known constructions of
ketones by the reaction of boronic acids with various acid
equivalents such as anhydrides,3 esters,4 acid fluorides,2p and
acid chlorides5 are not suitable for use with functionally
complex molecules because either the carboxyl equivalent
functional groups are too reactive or the reactions take place
under conditions that are inappropriate for racemization
sensitive substrates or products.
To address this issue, a pH-neutral, room temperature,
desulfitative synthesis of peptidyl ketones from thiol esters
and boronic acids using palladium catalysts and stoichio-
metric CuI carboxylate cofactors was recently described.6 The
reaction occurs at or near ambient temperature and has
proven valuable for the synthesis of racemization sensitive
peptidyl ketones.7 As a follow-up to that first study, we
describe herein a highly effective and general variant of that
chemistry in which organostannanes rather than boronic acids
are the reaction partners. Although organostannanes have not
previously been used as reaction partners for thiol esters,
vinylstannanes have been coupled with acid chlorides derived
from N-protected R-amino acids.8 Compared to the related
boronic acid system, the new organostannane-peptidic thiol
In contrast to the use of RLi, RMgX, and RZnX-based
protocols, the metal-catalyzed reaction of COOH-equivalent
functionalities with boronic acids offers the potential for a
fully general and functional group compatible approach to
† Current address: Abbott Laboratories, GPRD, Process R&D, R450-
NCR13-323A, 1401 Sheridan Road, North Chicago, IL, 60064.
10.1021/ol8018456 CCC: $40.75
Published on Web 08/30/2008
2008 American Chemical Society

ester coupling provides an efficient reaction using only 1.1
equiv of the stannane coupling partner, and significantly,
π-deficient heteroaromatic peptidyl ketones can be prepared
(which are important in drug design1b).
CuDPP was dictated by earlier published studies comparing
copper(I) thiophene-2-carboxylate (CuTC) with CuDPP in
the desulfitative coupling of thiol esters with organostan-
nanes.9 A brief study revealed that optimum yields of L-Z-
Phe-2-thienyl were obtained using 2.5 mol % of Pd2(dba)3
with 20 mol % of freshly distilled P(OEt)3 as the supporting
ligand. The probe reactions proceeded well using THF or
THF/hexanes mixtures as the reaction solvent. THF/hexanes
mixtures were previously demonstrated to prevent undesired
Cu-catalyzed side reactions like protodestannylation and
oxidative homocoupling by minimizing the effective con-
centration of copper(I) carboxylate in solution.9
This new reaction was initially probed by exposure of the
prototypical substrates L-Z-Phe-S-p-tolyl and 2-thienyl-tri-
n-butylstannane to 2.2 equiv of the Cu(I) cofactor, copper(I)
diphenylphosphinate (CuDPP),9 in the presence of various
palladium catalysts and supporting ligands. The choice of
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The scope and limitations of the desulfitative coupling of
peptidic thiol esters and organostannanes were then explored.
Results are depicted in Table 1. Freshly distilled P(OEt)3 is
essential for an efficient coupling, in which case a near
stoichiometric quantity of CuDPP (1.2 equiv) is sufficient
for most reactions, although 2.2 equiv of CuDPP delivered
incrementally higher yields in some cases (entry 1: 98% vs
93%; entry 17: 80% vs 70%; entry 20: 92% vs 86%; entry
27: 84% vs 80%). Electron-rich heteroarylstannanes reacted
efficiently in 1:2 THF/hexanes at or slightly above room
temperature (entries 1-4, 15, 17-20, 22, 24-30). Vinyl
(entry 5), allyl (entry 6), and Z-1-propenyl (entry 14)
stannanes reacted to give acceptable to good yields of
corresponding peptidyl ketone products, the latter stannane
with complete retention of the double bond stereochemistry.
A variety of arylstannanes (entries 7-10, 13, 23) reacted
well in the cross-coupling, although a solvent switch to DMF
at 50 °C was required for acceptable reaction rates and
product yields in five of the six entries.
The results in Table 1 demonstrate that a diverse range of
amino acid thiol esters can couple efficiently with orga-
nostannanes. Those reactants derived from nonpolar N-
protected amino acids included Phe, Leu, Pro, Trp, and Met
(entries 1-21). Polar N-protected amino acids studied
included Ser, Tyr, Gln, His, Glu, Lys, and Arg (entries
22-29). Unprotected indole (entries 18 and 19), thioether
(entries 20 and 21), alcohol (entry 22), phenol (entry 24),
and amide (entry 25) functional groups were well-tolerated
using this pH-neutral reaction. In addition, protected imida-
zole, carboxylic acid, amine, and guanidine functional groups
did not interfere in the transformation (entries 26-29).
Although disulfides are known to be cleaved by CuI and
couple with boronic acids to produce thioethers,10 the bisthiol
ester derived from N-protected cystine reacted with 2-thienyl-
tri-n-butylstannane to cleanly give the bisketonic product
without cleaving the disulfide bond (entry 30). Given the
chemical sensitivity of the disulfide linkage, this example
shows the high chemoselectivity of the cross-coupling toward
the C-S bond of thiol esters.
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Table 1. Peptidyl Ketones from Thiol Esters and Organostannanes
a Isolated yield. b ee determined by HPLC chiral OD, OJ, or AS reversed phase column using racemic mixtures as standards. c 35 °C, 1:2 THF/hexanes,
2 h. d 50 °C, DMF, 1 h. e 50 °C, THF, 1 h. f 50 °C, 1:2 THF/hexanes, 2 h. g 23 °C, THF, 1 h. h 2-Thienyl-tri-n-butylstannane (2.2 equiv), CuOP(O)Ph2 (2.4
equiv), Pd2(dba)3 (5 mol %), P(OEt)3 (40 mol %), 23 °C, THF, 3 h.
The enantiopurity of the N-protected R-amino ketones was
investigated in a number of cases. No racemization was found
in most of the cases investigated. Serine, however, is known
to easily racemize during peptide coupling,11 and the serine-
derived coupling system did show slight racemization. Using
Boc-protected L-serine (in place of Cbz protection used for
the other amino acids), the thiol ester reactant L-Boc-Ser-
S-p-tolyl can be obtained in high enantiopurity after recrys-
tallization from CH2Cl2/hexanes (ee >99%). However, when
coupled with 2-thienyl-tri-n-butylstannane, a 3% ee loss was
observed during silica gel chromatographic purification (entry
22). The slight racemization can be inhibited by using the
O-protected variant O-TBS-L-Boc-Ser-S-p-tolyl; upon cou-
pling with 2-methoxy-3-(tri-n-butylstannyl)pyridine, the enan-
tiopure R-amino ketone was delivered in excellent yield after
the silica gel column purification (entry 23).
For the other examples assayed for enantiopurity, only
those reaction systems using π-deficient heteroarylstannanes
as coupling partners showed any tendency toward racem-
ization. Relevant examples from Table 1 are gathered for
comparison in Figure 1. The peptidyl ketone products from
reactions using 2-(tri-n-butylstannyl)thiazole and 2-(tri-n-
butylstannyl)pyridine were obtained with significant to
complete racemization. However, the racemization is not a
function of the reaction conditions used; rather, it appears
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1998, 39, 8529–8532.
Org. Lett., Vol. 10, No. 19, 2008
4377

In summary, a synthesis of high enantiopurity N-protected
R-amino ketones has been developed using thiol esters
derived from 13 amino acids and a variety of organostan-
nanes. Structurally diverse N-protected R-amino ketones were
prepared in good yields with high ee. Advantages of this
new reaction compared to the related system that uses boronic
acids as coupling partners6 are the use of only 1.1 equiv of
the organostannane reactant to complete the coupling reaction
and the viability of π-deficient heteroarylstannanes, which
are far superior to the corresponding boronic acids in overall
coupling reactivity. Racemization was problematic only when
some electron-deficient heteroarylstannanes were used. This
mild, pH-neutral method possesses high functional group
compatibility and could be very useful for constructing more
complex molecular systems.
Figure 1. Structural features influencing racemization.
to be inherent to the structure of the products. A purified
sample of the 2-pyridyl R-amino ketone L-Z-Phe-2-pyridyl
racemized slowly in solution (24 h, ee from 37% to 31%)
even in the absence of CuDPP. Not surprisingly, it is those
π-deficient heteroaryl peptidyl ketones that possess func-
tionality similar to 1,2-diketones (2-pyridyl, 2-thiazolyl) that
are inherently prone to racemization, presumably via facile
enol-keto equilibration. Note, in contrast, that the isomeric
3-pyridyl peptidyl ketones L-Z-Phe-3-pyridyl and L-Z-Phe-
2-methoxy-3-pyridyl were significantly less prone to race-
mization: 3-(tri-n-butylstannyl)pyridine gave the desired
R-amino ketone in 94% ee (crude 99% ee), while 3-(tri-n-
butylstannyl)-2-methoxypyridine provided the peptidyl ke-
tone in 99% ee.
Acknowledgment. Dedicated to our new Emory col-
league, Professor Huw M. L. Davies. The National Institutes
of General Medical Sciences, DHHS, supported this inves-
tigation through grant No. GM066153. Dr. Gary Allred of
Synthonix provided the CuDPP and many of the organostan-
nanes used in our studies.
Supporting Information Available: Experimental pro-
cedures, synthesis, and characterization of all new com-
pounds and scanned spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
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