Stereoselective metal-free synthesis of β-amino thioesters with tertiary and quaternary stereogenic centers

Article abstract of DOI:10.1002/anie.201310532

β-Amino thioesters are important natural building blocks for the synthesis of numerous bioactive molecules. An organocatalyzed Mannich reaction was developed which provides direct and highly stereoselective access to acyclic β²- and β^2,3,3-amino thioesters with adjacent tertiary and quaternary stereocenters. Mechanistic studies showed that the stereochemical course of the reaction can be controlled by the choice of the substrates. The β-amino thioesters were further functionalized by, for example, stereoselective decarboxylation to access β^2,3- frameworks. In addition, the value of the β-amino thioesters was shown in coupling-reagent-free peptide synthesis.

Full text of DOI:10.1002/anie.201310532

Angewandte
Chemie
DOI: 10.1002/anie.201310532
b-Amino Acids
Stereoselective Metal-Free Synthesis of b-Amino Thioesters with
Tertiary and Quaternary Stereogenic Centers**
Annette Bahlinger, Sven P. Fritz, and Helma Wennemers*
Dedicated to the MPI fꢀr Kohlenforschung on the occasion of its centenary
Abstract: b-Amino thioesters are important natural
building blocks for the synthesis of numerous bioac-
tive molecules. An organocatalyzed Mannich reaction
was developed which provides direct and highly
stereoselective access to acyclic b2- and b2,3,3-amino
thioesters with adjacent tertiary and quaternary ste-
reocenters. Mechanistic studies showed that the stereo-
chemical course of the reaction can be controlled by
the choice of the substrates. The b-amino thioesters
were further functionalized by, for example, stereose-
lective decarboxylation to access b2,3-frameworks. In
addition, the value of the b-amino thioesters was
shown in coupling-reagent-free peptide synthesis.
Scheme 1. Monothiomalonates (MTMs) as thioester enolate equivalents.
b-Amino thioesters are used by nature in the
biosynthesis of a multitude of biologically active
compounds.[1] As activated derivatives of b-amino acids, they
are also attractive building blocks in organic synthesis and
foldamer research.[2] Their use has, however, been limited
since effective stereoselective syntheses are still rare.[3–6]
Particularly interesting but, because of steric restraints, very
challenging and not yet achieved, is the stereoselective
synthesis of b-amino thioesters bearing an all-carbon quater-
nary stereogenic center.[7]
approaches were introduced by the research groups of
Barbas and Coltart, and utilize activated electron-poor
thioesters or soft enolization, respectively.[4,5] All of these
advances allow for the stereoselective synthesis of b-amino
thioesters bearing tertiary stereogenic centers; however, high
catalyst loadings of ꢀ 10 mol% and long reaction times of
days are common.[3–6] In addition, none of these methods
enabled the synthesis of b-amino thioesters with quaternary
stereogenic centers.
Recently, our research group introduced monothiomalo-
nates (MTMs) as thioester enolate equivalents.[11] These
MAHT analogues bear an easily removable protecting
group on the ester moiety, which provides for controlled
nucleophilic reactivity and with the decarboxylation occur-
ring only upon removal of the protecting group. Previous
studies showed that MTMs allow for highly stereoselective
1,4-addition reactions with nitroolefins in the presence of
catalytic amounts of cinchona alkaloid urea derivatives
(Scheme 1, top).[11,12] Encouraged by these findings, we
became interested whether MTMs could also be used for
the synthesis of b-amino thioesters, by using imines as
electrophiles (Scheme 1, bottom).
Herein we present highly stereoselective syntheses of b-
amino thioesters that proceed under mild organocatalytic
conditions. Even acyclic b2,2,3-amino thioesters, bearing an all-
carbon quaternary stereogenic center adjacent to a tertiary
stereocenter, formed in excellent yields and stereoselectivi-
ties. Furthermore, we show the synthetic value of the b-amino
thioesters in coupling-reagent-free peptide synthesis.
We started with addition reactions of unsubstituted
MTMs (R1 = H, Scheme 1) to imines using conditions that
had been found to be optimal for the previously examined
Catalytic asymmetric transformations of thioester enolate
equivalents with imines are an attractive, direct way to
generate b-amino thioesters.[3–6] However, the formation of
thioester enolates under mild conditions is challenging
because of the low acidity of the a-protons paired with the
reactivity of thioesters towards nucleophiles.[8,9] Nature’s
thioester enolate equivalents, malonic acid half thioesters
(MAHTs), have been used in organocatalytic decarboxylative
Mannich reactions.[3,4] MAHTs are, however, prone
À
to decarboxylate without
a
concomitant C C bond
formation.[3,4,10] Mild, non-decarboxylative organocatalytic
[*] Dr. A. Bahlinger,[+] Dr. S. P. Fritz,[+] Prof. H. Wennemers
ETH Zꢀrich, Laboratorium fꢀr Organische Chemie, D-CHAB
Wolfgang Pauli-Strasse 10, 8093 Zꢀrich (Switzerland)
E-mail: Helma.Wennemers@org.chem.ethz.ch
Homepage: http://www.wennemers.ethz.ch
[+] These authors contributed equally to this work.
[**] S.P.F. thanks the German Research Foundation for a fellowship
(FR3418/1-1). We thank the Swiss National Science Foundation and
Bachem for support and are grateful to the University of Basel,
where parts of this research were carried out.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310532.
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Encouraged by these results, we next explored whether
this method would also allow for the significantly more
challenging reactions between a-substituted MTMs and
imines to yield b-amino thioesters with a quaternary stereo-
genic center (Scheme 1, bottom). We therefore treated a-
methyl-substituted MTM 1b (R1 = Me) with Cbz-protected
imine 2a (R2 = Ph) under the developed conditions and were
delighted to observe the formation of the desired Mannich
product. Further optimization of the reaction parameters (see
the Supporting Information) led to the formation of b-amino
thioester 4a in > 95% yield with excellent diastereoselectivity
(> 20:1) and enantioselectivity (99% ee) in the presence of
5 mol% epiquinine-urea B.[13]
The substrate scope proved to be broad with respect to
variations in both the imine 2 and the a-substituent of the
MTM (Scheme 3). Mannich products 4a–o were obtained in
high yields, with excellent enantioselectivities of 90–99% ee
and high diastereoselectivities of typically about 20:1 or
greater. Even aromatic imines bearing substituents in the
Scheme 2. Scope of Mannich reactions with unsubstituted MTM 1a.
Yields of isolated products; reactions were performed on a 0.2 mmol
scale; ee values were determined by HPLC on a chiral stationary phase.
[a] 5 mol% catalyst was used. [b] Determined after Boc (re)protection
of the initially resulting free amine.
addition reactions with nitroolefins.[11] Cinchona alkaloid
(thio)urea derivatives were, therefore, used as catalysts and
MTM 1a bearing a p-methoxyphenyl (PMP) thioester and
a p-methoxybenzyl (PMB) oxoester group was used as the
substrate. Variations in the catalyst, the nature of the
protecting group (PG) of the imine, as well as other reaction
parameters such as the solvent, stoichiometry, concentration,
and catalyst loading showed that conditions similar to those
used for reactions with nitroolefins are also ideal for reactions
with Cbz- or Boc-protected imines (Cbz = carboxybenzyl,
Boc = tert-butyloxycarbonyl) as electrophiles (see the Sup-
porting Information for optimization and screening details).
This versatility demonstrates that the reactivity of MTMs
towards variations in the electrophile is general and robust. A
large variety of different Cbz-protected imines 2 reacted
readily with MTM 1a in CH2Cl2 within 4 h at À788C in the
presence of only 1 mol% of epidihydroquinine-urea A
(Scheme 2). The desired b-amino thioesters 3a–j were
obtained in high yields and excellent enantioselectivities
after removal of the PMB protecting group with trifluoro-
acetic acid (TFA) and base-induced decarboxylation. In
comparison to previously reported methods for the synthesis
of such b-amino thioesters,[3–6] the low catalyst loading of
1 mol%, the short reaction times, as well as the excellent
enantioselectivities for a broad substrate range stand out.
Scheme 3. Scope of Mannich reactions with a-substituted MTMs 1b–e.
Yields of isolated products; reactions were performed on a 0.2 mmol scale;
d.r. values were determined by 1H NMR spectroscopy; ee values were
determined by HPLC on a chiral stationary phase. [a] Reaction was
performed at 08C. [b] 10 mol% catalyst, 08C, and 48 h were used.
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plausible transition state, therefore, involves coordina-
tion of the MTM to the urea moiety of the catalyst,[16]
with the flexible benzyl ester on the same side as the 3,5-
di(trifluoromethyl)phenyl group of the catalyst, and
addition of the MTM enolate from the Si face in the case
of 1b (X = O, Y = S) to the Re face of the imine
(Scheme 4b, left). This orientation is likely favored by
stabilization through a hydrogen bond between the
quinuclidine moiety and the carbamate protecting
group. An alternative Re-Re face approach is less
likely due to unfavorable steric interactions (Scheme
4b, right).
We then set out to evaluate the synthetic value of
the b-amino thioesters and started by investigating the
decarboxylation of representative examples of products
4. Removal of the PMB protecting group using TFA
followed by base-induced decarboxylation proceeded
with good to excellent diastereoselectivities, thereby
leading to syn-b2,3-amino thioesters 5e/g/h/m/
n (Scheme 5). It is noteworthy that this method provides
products with higher selectivity than a direct decarbox-
ylative approach using MAHTs and with opposite
relative configuration (syn instead of anti).[3b,17] Further-
more, we found that Cbz cleavage is possible, despite
the presence of a sulfur moiety, which sometimes
impedes metal-catalyzed hydrogenations.[18] Acidolysis
of 5e with TFA, by using thioanisole as a nucleophilic
promoter, led to the formation of 6e in good yield and high
purity (Scheme 5).
Finally, we explored the value of b-amino thioesters for
peptide synthesis. Whereas thioesters are commonly used in
nature and also for ligating two peptide or protein fragments
by native chemical or Staudinger ligation, they are seldom
used in peptide synthesis, since their formation is often
difficult.[1,19,20] The incorporation of b-amino acids into
a peptide by solution- or solid-phase peptide synthesis
(SPPS) can be cumbersome and is generally achieved by the
use of coupling reagents.[21] Despite their widespread use,
coupling reagents are not atom-efficient and syntheses can be
Scheme 4. a) Substrate-controlled diastereoselectivity and crystal structures
of 4e and 4e’. b) Proposed transition state.
ortho position and aliphatic imines (2d, 2 f, and 2k), which are
difficult substrates, gave diastereoselectivities of at least 3:1
and enantioselectivities of 99, 96, and 90% ee, respectively.
MTMs bearing ethyl, benzyl, allyl, or propargyl substituents
at the a-position were also tolerated well and the addition
products 4l–4o were obtained in high yields, with diastereo-
selectivities of 6:1–20:1 and enantioselectivities of 97–
99% ee. Thus, in all of these addition reactions a remarkably
high level of stereochemical differentiation between the two
ester moieties of the MTM occurred. Current limitations are
MTMs with larger a-substituents, such as Ph or iPr as well as
N-Boc-protected imines that did not react in the sterically
challenging reaction with a-substituted MTMs or did so only
sluggishly. The relative and absolute stereochemistry of the
major Mannich products was unambiguously assigned by
crystal structures of b-amino thioesters 3e and 4e (Schemes 2
and 4a).[14]
Next we investigated the reason for the high level of
differentiation between the oxo- and thioester moieties in the
stereochemical course of the reaction. Towards this goal we
prepared a “reversed” MTM 1b’, with a benzyl thioester
(SBn) and a phenyl oxoester (OPMP), and allowed it to react
under the same conditions as before with Cbz-protected
imine 2e (Scheme 4a). This reaction provided the diastereo-
isomeric addition product 4e’ with opposite stereochemistry
to 4e at the carbon atom bearing the ester moieties, as
revealed by crystal-structure analysis (Scheme 4a). 4e’ was
also obtained in high yield and stereoselectivity, thus demon-
strating that diastereomeric products can be easily obtained
with the same catalyst by changing the MTM substrate. The
result also shows that it is not the oxo or thio moiety but the
nature of the ester (flexible benzyl versus rigid phenyl)[15] that
determines the stereochemical outcome of the reaction. A
Scheme 5. Decarboxylation of b-amino thioesters 4. a) TFA/CH2Cl2
(1:1), 5 min; b) 10% Et3N/CH2Cl2, 3 min; c) MeSPh in TFA, 3 h.
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complicated when, for example, purification is difficult or side
reactions occur. The presented b-amino thioesters are, there-
fore, attractive for enabling the incorporation of b-amino
acids into peptides without coupling reagents.
To explore the value of the b-amino thioesters for
coupling-reagent-free amidation reactions we initially treated
3a with benzylamine (2 equiv) at room temperature and
obtained the desired amide 7 in 97% yield (Scheme 6a). Even
sterically hindered b2,2,3-amino thioester 4a was transformed
to amide 8 under the same conditions in good yield
(Scheme 6a). Transformations with less-reactive amines,
Scheme 7. Solid-phase peptide synthesis (SPPS) with b-amino thio-
esters. a) 20% piperidine/DMF; b) Boc-b3Phe-SPMP (3k), iPr2NEt,
pyridine, 1 h MW at 758C, then 15 h at RT; c) 50% TFA/CH2Cl2;
d) Boc-Gly-OH; HCTU, iPr2NEt, DMF; e) 10% Et3N/MeOH; f) HCl in
Et2O (2m). Fmoc=fluorenylmethoxycarbonyl, HCTU=N,N,N’,N’-tetra-
methyl-O-(6-chloro-1H-benzotriazol-1-yl)uronium hexafluorophosphate.
Scheme 6. Coupling-reagent-free amidation reactions. MW=micro-
waves.
Experimental Section
Synthesis of Cbz-protected b2,2,3-amino thioesters 4a–o: The imines
were prepared from the appropriate a-amido sulfone: An aqueous
solution of Na2CO3 (10%, saturated with NaCl, 1 mL per mmol of a-
amido sulfone) was added to a suspension of a-amido sulfone
(1 equiv) in CH2Cl2 (0.1m). The mixture was vigorously stirred for
15 h at room temperature. The phases were separated and the
aqueous phase was extracted with CH2Cl2 (2 ꢀ 2.5 mL per mmol of
sulfone). The combined organic phases were washed with brine, dried
with MgSO4, filtered, and concentrated in vacuo. The resulting freshly
prepared imine was then dissolved in dry CH2Cl2 (0.1m), and MTM
(1.4 equiv) was added. The reaction mixture was cooled to the
temperature stated, and then the catalyst (5 mol%) added. The
reaction mixture was stirred at the specified temperature for 18 h,
followed by removal of all the volatiles at reduced pressure and
purification by flash column chromatography on silica, using a mixture
of CH2Cl2/methanol or EtOAc/n-pentane as eluents.
such as the amino acid phenylalanine (Phe), were more
difficult. Only traces of amide 9 were observed in the reaction
of two equivalents of b3-amino thioester 3a in CH2Cl2 at room
temperature. The use of pyridine as a solvent under micro-
wave conditions significantly accelerated the reaction, and
a,b-dipeptide 9 was isolated in 87% yield (Scheme 6b).
To our delight these coupling-reagent-free conditions
were also applicable for SPPS with b3-amino thioesters. N-
Boc-protected b3-amino thioester 3k was readily incorpo-
rated into a,b-peptides 10 and 11, which were isolated in 71%
and 62% yields, respectively, by a simple precipitation
without the need for purification by column chromatography
(Scheme 7).
Received: December 4, 2013
Revised: January 30, 2014
Published online: March 18, 2014
In summary we have developed a mild organocatalytic
method for the synthesis of b-amino thioesters through
Mannich reactions of MTMs. Not only b3- but also b2,2,3
-
amino thioesters, which contain an acyclic all-carbon quater-
nary stereogenic center adjacent to a tertiary stereocenter,
were for the first time obtained in excellent yields and
remarkably high stereoselectivities. Mechanistic studies pro-
vided insight into the high stereochemical differentiation
between the two ester moieties within the MTMs and showed
that the stereochemistry can be controlled by the choice of the
substrate. The functional groups within the b-amino thioesters
were found to be orthogonal and can be selectively modified
to provide, for example, access to syn-b2,3-amino thioesters in
high yields and stereoselectivities. Furthermore, we showed
the synthetic value of b-amino thioesters as building blocks
for coupling-reagent-free peptide synthesis. We are currently
extending the scope of MTMs as thioester enolate equivalents
and are performing further mechanistic studies.
Keywords: b-amino acid · cinchona alkaloids · organocatalysis ·
peptide coupling · thioesters
.
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