Stereocontrolled synthesis of α-amino-α′-alkoxy ketones by a copper-catalyzed cross-coupling of peptidic thiol esters and α-alkoxyalkylstannanes

Article abstract of DOI:10.1021/ol201330j

A stereocontrolled synthesis of α-amino-α′-alkoxy ketones is described. This pH-neutral copper(I) thiophene-2-carboxylate (CuTC)-catalyzed cross-coupling of amino acid thiol esters and chiral nonracemic α-alkoxyalkylstannanes gives α-amino-α′-alkoxy keton

Full text of DOI:10.1021/ol201330j

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3682–3685
Stereocontrolled Synthesis of r-
Amino-r0-alkoxy Ketones by a Copper-
Catalyzed Cross-Coupling of Peptidic
Thiol Esters and r-Alkoxyalkylstannanes
Hao Li,† Anyu He,‡ John R. Falck,‡ and Lanny S. Liebeskind*,†
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta,
Georgia 30322, United States, and Departments of Biochemistry and Pharmacology,
University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas,
Texas 75390, United States
chemLL1@emory.edu
Received May 17, 2011
ABSTRACT
A stereocontrolled synthesis of R-amino-R0-alkoxy ketones is described. This pH-neutral copper(I) thiophene-2-carboxylate (CuTC)-catalyzed
cross-coupling of amino acid thiol esters and chiral nonracemic R-alkoxyalkylstannanes gives R-amino-R0-alkoxy ketones in good to excellent
yields with complete retention of configuration at the R-amino- and R-alkoxy-substituted stereocenters.
Enantioenriched R-alkoxy ketones are common moi-
eties found in natural products and biologically active
compounds. They are also useful building blocks in or-
ganic synthesis.1 The construction of enantioenriched
R-alkoxy ketones is known,2 with recent studies3 focusing
on asymmetric benzoin condensations4 and the asym-
metric R-hydroxylation of ketones5 or tin enolates6 using
chiral nonracemic catalysts. Complementary synthetic
approaches to R-alkoxy ketones were developed in which
the sp3 carbon of an R-alkoxyalkylstannane is transferred
to an acyl chloride via Stille-type cross-couplings using
either Pd/Cu cocatalysts7 or Cu-only catalysts.7c,8 These
reactions proceed with ca. 98% retention of stereo-
chemistry at the R-carbon center of enantioenriched
R-alkoxyalkylstannanes.7b,c
† Emory University.
‡ University of Texas Southwestern Medical Center.
(1) (a) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew.
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Ed. Engl. 1984, 23, 556–569.
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r
10.1021/ol201330j
Published on Web 06/15/2011
2011 American Chemical Society

The value of the acid halide based Stille cross-coupling
notwithstanding, thiol esters offer much greater functional
group compatibility as cross-coupling partners compared
toacidhalides. Theyhavebeen shown to participate inpH-
neutral, Pd-catalyzed, Cu(I) carboxylate mediated cou-
plings with a wide variety of aromatic, heteroaromatic,
allylic, and alkenyl boronic acids9 and organostannanes.10
The Pd-catalyzed, Cu(I) carboxylate mediated reaction
conditions are sufficiently mild that even racemization-
sensitive peptidic thiol esters engage in efficient, racemiza-
tion-free desulfitative couplings with a similar range of
boron and tin reagents.11 Peptidic ketones can also be
preparedinhigh enantiopurityfromthesamesubstratesby
two novel, Cu-only catalyzed reaction systems, one using
an aerobic recycle pathway12 and the other an anaerobic
pathway that mimics the release of Cu from the metal-
lothionein family of proteins.13
Of the different solvents screened, dioxane proved opti-
mum, minimizing loss of the stannane 2 via an O-to-S
rearrangement.16 A variety of different copper sources
were effective precatalysts (CuTC, CuCl, CuOAc, CuI,
CuCN, Cu(OAc)2, and CuCl2). Among those precatalysts
investigated CuTc produced slightly higher isolated yields
of the ketone products and was chosen for subsequent
studies. In the absence of a copper catalyst no ketone
product was formed; both the thiol ester and R-alkoxyalk-
ylstannanes were recovered.
Table 1. Optimization Studies
The pH-neutral reaction conditions of the desulfitative
coupling of thiol esters with boron and tin reagents should
allow the racemization-free coupling of thiol esters with
transfer agents that bear stereogenic transferrable carbon
centers, but no studies have yet appeared in the literature.
Two indirectly relevant examples are the coupling of ethyl
chlorothioformate with an R-alkoxyalkylstannane in which
the CꢀCl bond was selectively cleaved,7c and Movassaghi’s
stoichiometric CuTC-mediated coupling of a thiol ester with
various aminomethyl stannane reagents as part of the total
synthesis of the agelastatin alkaloids.14 To address this
synthetic opportunity, we describe herein the palladium-
free, copper(I) thiophene-2-carboxylate (CuTC)-catalyzed
desulfitative cross-coupling of R-aminoacidthiolesterswith
Falck’s enantioenriched R-alkoxyalkylstannanes7c,15 for the
straightforward stereocontrolled synthesis of R-amino-R0-
alkoxy ketones.
Effective reaction parameters were determined by ex-
ploring the cross-coupling of R-amino acid thiol esters
derived from L-phenylalanine with racemic pyrrolidi-
nylthionocarbamoyl (PTC)-protected R-alkoxyalkylstan-
nane 27c holding constant the catalyst (20 mol % CuTC)
and the reaction temperature and time (100 °C for 20 h).
Results are depicted in Table 1. In dioxane as solvent the
isolated yield of the desired ketone increased as the elec-
trophilicity of the L-phenylalanine thiol ester was increased
from L-Boc-Phe-SEt, 1a (entry 1, 0%), to L-Boc-Phe-SPh, 1b
(entry 2, 43%), to L-Boc-Phe-S-p-NO2Ph, 1c (entry 3, 81%).
entry
R
solvent
dioxane
yield (%)a
1
2
3
4
5
6
Et (1a)
0
43
81
61
48
52
Ph (1b)
“”
p-NO2Ph (1c)
“”
“”
“”
“”
toluene
1,2-dichloroethane
DMF
a Isolated yield.
The desulfitative coupling reaction conditions used in
this study are specific to the PTC-protected R-alkoxyalk-
ylstannanes. Thus, in contrast to other desulfitative cross-
couplings developed previously in our laboratory,9,10
neither a test case sp2-hydridized boronic acid (p-methox-
yphenylboronic acid) nor an sp2-hydridized organostannane
(2-tri-n-butylstannylthiophene) participated in desulfitative
coupling with thiol ester 1c under the copper-catalyzed
conditions used herein. The special effectiveness of the
PTC-protected R-alkoxyalkylstannanes as reaction partners
under these Cu-only reaction conditions is likely a function
of the Cu-ligating ability of the PTC group.7c Substrate
precoordination to Cu seems to play a critical role in all
Cu-only catalyzed desulfitative couplings of thiol esters with
boronic acids and organostannanes seen to date. Thus Cu-
ligating functional groups attached to the thiol ester,12,13,17
or to the organostannane in this current case as well as in
Movassaghi’s synthesis,14 probably stabilize the in situ
generated organocopper intermediate and/or increase the
coupling reaction rate through the proximate orientation of
both reaction partners around the Cu.
(9) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122, 11260–
11261.
(10) Wittenberg, R.; Srogl, J.; Egi, M.; Liebeskind, L. S. Org. Lett.
2003, 5, 3033–3035.
(11) (a) Yang, H.; Li, H.; Wittenberg, R.; Egi, M.; Huang, W.;
Liebeskind, L. S. J. Am. Chem. Soc. 2007, 129, 1132–1140. (b) Yang,
H.; Liebeskind, L. S. Org. Lett. 2007, 9, 2993–2995. (c) Li, H.; Yang, H.;
Liebeskind, L. S. Org. Lett. 2008, 10, 4375–4378.
(12) Liebeskind, L. S.; Yang, H.; Li, H. Angew. Chem., Int. Ed. 2009,
48, 1417–1421.
The scope of this desulfitative coupling of R-amino acid
thiol esters and enantioenriched R-alkoxyalkylstannes was
explored using the optimum reaction conditions. Results
(13) Zhang, Z.; Lindale, M. G.; Liebeskind, L. S. J. Am. Chem. Soc.
2011, 133, 6403–6410.
(14) Movassaghi, M.; Siegel, D. S.; Han, S. Chem. Sci. 2010, 1
561–566.
(15) (a) He, A.; Falck, J. R. Angew. Chem., Int. Ed. 2008, 120, 6688–
6691. (b) Mohapatra, S.; Bandyopadhyay, A.; Barma, D. K.; Capdevila,
J. H.; Falck, J. R. Org. Lett. 2003, 5, 4759–4762.
(16) Falck, J. R.; Patel, P. K.; Bandyopadhyay, A. J. Am. Chem. Soc.
2007, 129, 790–793. Correction: J. Am. Chem. Soc. 2008, 130, 2372.
(17) Villalobos, J. M.; Srogl, J.; Liebeskind, L. S. J. Am. Chem. Soc.
2007, 129, 15734–15735.
Org. Lett., Vol. 13, No. 14, 2011
3683

its enantiomer 5d (er 28:1, entry 7) participated in efficient
reactions. The cyclohexyl-substituted stannane 5b (er 99:1)
also provided good yields of ketone products (entries 2, 5,
8, 10, and 13). The R,β-dialkoxystannane 5c (entries 3, 6,
and 14), which is prone to β-elimination,15b,16 reacted
smoothly with R-amino acid thiol esters to generate the
corresponding trialkoxyketones in modest yields, while the
more robust R-alkoxy-β-aminostannane 5e (entries 11 and 15)
produced R-alkoxy-β-amino ketones in excellent yields.
Generally, a 20 mol % CuTC catalyst loading was appro-
priate, although a 5 mol % catalyst loading afforded the
ketone products with slightly higher yields in some cases
(entry 1: 92% vs 81%; entry 12: 89% vs 87%).
Table 2. Thiol Ester and Enantioenriched R-Alkoxyalkylstan-
nane Cross-Coupling
A variety of N-protected R-amino acid thiol esters derived
from naturally occurring R-amino acids such as L-Phe
(entries 1ꢀ3), L-Ala (entries 4ꢀ6), L-Met (entries 7 and 8),
L-Glu (entries 9ꢀ11), and L-Trp (entries 12ꢀ15) also couple
with R-alkoxyalkylstannes. Thus, carbamate, ester, free
indole, thiol ether, and acetal functional groups were well-
tolerated using this pH-neutral cross-coupling reaction.
No stereocenterepimerizationwas observed inthe cross-
couplings using the enantioenriched stannanes 5a (er 58:1)
and 5b (er 99:1). Control experiments using racemic R-
amino acid thiol esters also confirmed that no epimeriza-
tion occurred at the R-amino centers.
To determine the absolute stereochemistry at the trans-
ferring stereocenter in this R-amino acid thiol ester/R-
alkoxyalkylstannane coupling, FelkinꢀAhn selective18 re-
duction of R-amino-R0-alkoxy ketone 6aa with L-selectride
followed by deprotection of the thionocarbamate group19
afforded the syn,syn-aminodiol 7 (Scheme 1), which matches
characteristic spectroscopic data of the enantiomer of a
known compound prepared by Pedersen and co-workers.20
This result demonstrated that the cross-coupling proceeded
with retention of stereochemistry at the newly formed
stereocenters of the R-amino-R0-alkoxy ketones.
Scheme 1. Confirmation of Stereochemistry
A reasonable mechanistic pathway for the CuTC-cata-
lyzed cross-coupling of R-amino acid thiol esters and
a Isolated yield. b dr determined by 1H NMR and confirmed by
HPLC chiral OJ reversed phase column using racemic mixtures derived
from racemic R-alkoxystannanes as standards. c 5 mol % CuTC, diox-
ane, 100 °C, 20 h. d 20 mol % CuTC, dioxane, 100 °C, 20 h. e (S)-O-3-
Phenyl-1-(tri-n-butylstannyl)propyl pyrrolidine-1-carbothioate (er 58:1)
was used. f (S)-O-Cyclohexyl(tributylstannyl)methyl pyrrolidine-1-car-
bothioate (er 99:1) was used. g (R)-O-3-Phenyl-1-(tri-n-butylstannyl)-
propyl pyrrolidine-1-carbothioate (er 28:1) was used.
(18) Hoffman, R. V.; Maslouh, N.; Cervantes-Lee, F. J. Org. Chem.
2002, 67, 1045–1056.
(19) Barma, D. K.; Bandyopadhyay, A.; Capdevila, J. H.; Falck,
J. R. Org. Lett. 2003, 5, 4755–4757.
(20) Konradi, A. W.; Kemp, S. J.; Pedersen, S. F. J. Am. Chem. Soc.
1994, 116, 1316–1323.
(21) (a) Still, W. C.; Sreekumar, C. J. Am. Chem. Soc. 1980, 102,
1201–1202. (b) Sawyer, J. S.; Kucerovy, A.; Macdonald, T. L.; McGar-
vey, G. J. J. Am. Chem. Soc. 1988, 110, 842–853. (c) Linderman, R. J.;
Ghannam, A.; Badejo, I. J. Org. Chem. 1991, 56, 5213–5216. (d) Hoppe,
D.; Hense, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 2282–2316. (e)
Smyj, R. P.; Chong, J. M. Org. Lett. 2001, 3, 2903–2906. (f) Monje, P.;
Paleo, M. R.; Garca-Ro, L.; Sardina, F. J. J. Org. Chem. 2008, 73, 7394–
7397.
are summarized in Table 2. The enantioenriched PTC-
protected stannane 5a (er 58:1, entries 1, 4, 9, and 12) and
3684
Org. Lett., Vol. 13, No. 14, 2011

enantioenriched R-alkoxyalkylstannanes is proposed in
Figure 1. Similar to the known tin-to-lithium transm-
etalation,21 tin-to-copper transmetalation with retention
of configuration is precedented.7c,8b,8c In the case at hand,
tin-to-copper transmetalation will generate an organocop-
per intermediate presumed to be stabilized by coordination
to the internal thionocarbamate pendant. Reaction of this
putative organocopper nucleophile with the electrophilic
thiol ester would afford the desired enantioenriched R-
amino-R0-alkoxy ketone and a copper thiolate, the latter
of which typically terminates the catalytic cycle. The current
reaction system is therefore of significant mechanistic inter-
est because all prior Cu-based desulfitative coupling systems
that are catalytic in Cu required a reaction design element
that would scavenge the strongly bonding thiolate thereby
liberating the Cu to reenter the catalytic cycle. The current
reaction system requires only catalytic Cu and proceeds
without a “second cycle” designed into the catalysis to retain
an active form of Cu.13
This unprecedented Cu-catalyzed desulfitative coupling is
undoubtedly driven by formation of the thermodynamically
strong tinꢀsulfur bond that facilitates an in situ transmetala-
tion between the catalytically unreactive Cu(I) thiolate and
the in situ generated n-Bu3SnOCO(2-thienyl) to regenerate
the catalytically active CuTC and the thermodynamically
stable end product, n-Bu3SnSR (the SnꢀS bond dissocia-
tion energy is 274 kJ molꢀ1 23). This assumption was sup-
ported by the observed formation of Bu3SnS-p-NO2Ph
in a ca. 1:1 ratio to the desired ketone products.
The overall reaction is a delicately balanced process,
since the buildup of Bu3SnS-p-NO2Ph during the process
also inhibits the catalyzed cross-coupling, presumably by
ligatingtoCu andfillingavailablecoordinationsites. Thus,
the rate of cross-coupling was significantly retarded upon
addition of 1.2 equiv of n-Bu3Sn-p-NO2Ph to a reaction
mixture comprised of thiol ester L-Boc-Phe-S-p-NO2Ph
(1c), stannane 2, and 20 mol % CuTC. Under identical
reaction conditions a lower ketone yield was observed in the
presence of the added n-Bu3SnS-p-NO2Ph than in the
standard process (48% vs 81%). Since control experiments
demonstrated that the ketone forming step can take place at
room temperature, the higher reaction temperature used
here is required to overcome the inhibition and drive the
reaction to completion in a reasonable time period
Figure 1. Proposed mechanism.
In summary, a highly efficient R-amino-R0-alkoxy ke-
tone synthesis has been developed that proceeds via a
copper-catalyzed transfer of secondary alkoxyalkyl
groups from enantioenriched R-alkoxyalkylstannanes
to R-amino acid thiol esters. This new coupling takes
place with good efficiency and with complete retention
of configuration at the R-carbon center of the enantioen-
riched R-alkoxyalkylstannanes. When coupled with
stereodefined reduction of the ketone, this method pro-
vides a facile stereocontrolled construction of acyclic
molecules bearing contiguous heteroatom substituted
stereocenters.
tion energy is 464 kJ mol
;
ꢀ1 22 the CuꢀS bond dissocia-
Acknowledgment. The National Institutes of General
Medical Sciences, DHHS, supported this investigation
through Grant Nos. GM066153and GM031278. Dr. Gary
Allred of Synthonix provided the CuTC 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.
(22) Colin, R.; Drowart, J. J. Chem. Phys. 1962, 37, 1120–1125.
(23) Smoes, S.; Mandy, F.; Vander Auwera-Mahieu, A.; Drowart, J.
Bull. Soc. Chim. Belg. 1972, 81, 45–56.
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