Divergent and Stereoselective Synthesis of β-Silyl-α-Amino Acids through Palladium-Catalyzed Intermolecular Silylation of Unactivated Primary and Secondary C?H Bonds

Article abstract of DOI:10.1002/anie.201607766

A general and practical Pd^II-catalyzed intermolecular silylation of primary and secondary C?H bonds of α-amino acids and simple aliphatic acids is reported. This method provides divergent and stereoselective access to a variety of optical pure

Full text of DOI:10.1002/anie.201607766

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201607766
German Edition: DOI: 10.1002/ange.201607766
Silylation
Divergent and Stereoselective Synthesis of b-Silyl-a-Amino Acids
through Palladium-Catalyzed Intermolecular Silylation of Unactivated
À
Primary and Secondary C H Bonds
Yue-Jin Liu, Yan-Hua Liu, Zhuo-Zhuo Zhang, Sheng-Yi Yan, Kai Chen, and Bing-Feng Shi*
Abstract: A general and practical PdII-catalyzed intermolec-
À
ular silylation of primary and secondary C H bonds of a-
amino acids and simple aliphatic acids is reported. This
method provides divergent and stereoselective access to
a variety of optical pure b-silyl-a-amino acids, which are
useful for genetic technologies and proteomics. It can also be
readily performed on a gram scale and the auxiliary can be
easily removed with retention of configuration. The synthetic
importance of this method is further demonstrated by the late-
stage functionalization of biological small molecules, such as
(À)-santonin and b-cholic acid. Moreover, several key pallada-
cycles were successfully isolated and characterized to elucidate
3
À
the mechanism of this b C(sp )-H silylation process.
Amino acids, specifically a-amino acids (a-AAs), are the
building blocks of bioactive peptides, peptidomimetics, and
proteins.[1] The incorporation of silicon into a-amino acids can
have a dramatic influence on the stability, solubility, lip-
ophilicity, and pharmacokinetic properties.[2] For example, b-
trimethylsilyl alanine (TMS-Ala) plays an important role in
peptidomimetic strategies as a bioisostere for phenylala-
nine.[3] Cetrorelix is a synthetic decapeptide with gonadotro-
pin-releasing hormone (GnRH) antagonistic activity. Its
silicon analogue, in which the tyrosine in position 5 is
replaced with TMS-Ala, was found to lower both testosterone
and luteinizing hormone levels longer than the carbon
analogue (Scheme 1a).[3b] Since the first preparation of
racemic b-silyl-a-AAs by Birkofer and Ritter through clas-
sical a-alkylation of a glycine anion equivalent,[4] the explo-
ration of efficient methods for the chemical synthesis of chiral
b-silyl-a-AAs has received much attention.[5] Asymmetric a-
alkylation of chiral glycine equivalents and amination of b-
silyl propionic acid derivatives induced by chiral auxiliaries
have been investigated (Scheme 1b).[5] A series of chiral
auxiliaries, such as Seebachꢀs auxiliary,[5a] Myerꢀs auxiliary,[5b]
Schçllkopfꢀs auxiliary[3b] and Evansꢀ auxiliary,[5c] have been
employed for this purpose. Although these elegant methods
have been successfully applied in the synthesis of certain b-
Scheme 1. The importance of b-silyl-a-amino acids and their asymmet-
ric synthesis.
silyl-a-AAs, there are still some limitations, such as narrow
substrate scope with limited diversity, the requirement for
multiple steps, the use of expensive chiral auxiliaries and
silicon reagents, and harsh reaction conditions with strong
bases. Therefore, new methods to prepare chiral b-silyl-a-
AAs that are efficient, practical, and divergent are in high
demand.
À
Recently, transition-metal-catalyzed C H silylation has
emerged as a promising strategy for broadening the diversity
of silicon-containing compounds.[6] However, catalytic silyla-
3
À
tion of aliphatic C(sp ) H bonds is rather rare, mostly due to
the fact that bulky silyl groups are reluctant to transfer to
catalytic metal centers.[7–11] So far, most of the established
3
[*] Y.-J. Liu, Y.-H. Liu, Z.-Z. Zhang, S.-Y. Yan, Prof. Dr. B.-F. Shi
Department of Chemistry, Zhejiang University
Hangzhou 310027 (China)
À
methods for C(sp ) H silylation have been limited to intra-
molecular examples [8] or those involving activated C(sp ) H
3
À
bonds.[9,10] The intermolecular silylation of unactivated C-
E-mail: bfshi@zju.edu.cn
Homepage: http://mypage.zju.edu.cn/en/bfshi/
3
[10a,11]
À
(sp ) H bonds is even more challenging.
Ir-[10a] and Ru-
catalyzed[11a] silylation of unactivated primary C H bonds
assisted by a nonremovable pyridine auxiliary has been
reported. The pioneering work of Kanai and co-workers
demonstrated that Pd-catalyzed silylation of purely aliphatic
À
K. Chen
Division of Chemistry and Chemical Engineering
California Institute of Technology, Pasadena, California 91125 (USA)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201607766.
À
C H bonds can be achieved with the assistance of bidentate
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auxiliary. However, the reaction proceeded with low effi-
ciency (17–39% yield) and narrow scope.[11b] Herein, we
report a Pd-catalyzed stereoselective synthesis of chiral b-
silyl-a-AAs through intermolecular silylation of unactivated
À
primary and secondary C H bonds with the assistance of an
8-aminoquinoline (AQ) auxiliary (Scheme 1b).[12,13] This
method enables the divergent and gram-scale synthesis of
various chiral b-silyl-a-AAs with excellent diastereoselectiv-
ity and complete retention of configuration. The late-stage
silylation of natural products such as (À)-santonin and b-
cholic acid further showcases the importance of this method.
Given the applicability of chiral TMS-Ala, we began this
study by examining the feasibility of Pd-catalyzed silylation of
alanine derivative 1, which bears an AQ auxiliary. This
auxiliary was first introduced by Daugulis[12,13] and has been
À
proven to be highly efficient in the Pd-catalyzed C H
functionalization of a-AAs.[14–16] After extensive screening
of the reaction conditions (see Tables S1,S2 in the Supporting
Information for details), we were delighted to find that TMS-
Ala 1a could be obtained in 81% yield without racemization
(98% ee) under the following conditions (Conditions A):
Pd(OAc)2 (10 mol%), N-Boc-Val-OH (20 mol%), hexame-
thyldisilane (5.0 equiv), and Ag2CO3 (2.0 equiv) in tBuOH
under air at 1258C for 12 h. The use of N-Boc-Val-OH was
found to be crucial for the efficiency of the reaction.[17]
Additionally, the reaction could be scaled up to 3 mmol,
and chiral TMS-Ala derivative 1a was prepared in 80% yield
(1.0 gram, Scheme 2). Notably, the auxiliary could be
removed by treatment with BF3·Et2O in MeOH, leading to
b-l-TMS-alanine methyl ester 1aa in 65% yield without
racemization (99% ee).[14b,15]
À
Scheme 3. Pd-catalyzed silylation of secondary C H bonds. [a] Condi-
tions B: 2 (0.1 mmol), Pd(OAc)2 (15 mol%), hexamethyldisiliane (5.0
equiv), Ag2CO3 (0.5 equiv), DMBQ (1.5 equiv) in 1.0 mL 1,4-dioxane at
1258C under air for 12 h. Yields of isolated product are shown.
isolated yield. [b] 1408C. DMBQ=2,6-dimethoxy-1,4-benzoquinone.
jected to Conditions B (Scheme 3, 3a–3j). A wide variety of
functional groups, including methoxy (3b, 3h and 3j),
acetamino (3c and 3i), chloro (3 f), and trifluoromethyl (3g)
groups, were well tolerated. It is worth noting that the
silylation of arylalanine derivatives proceeded with uniformly
high stereoselectivity (3a–3j, d.r. > 20:1), regardless of the
electronic properties on the phenyl ring. The relative and
absolute stereochemistry of 3e was unambiguously deter-
mined by X-ray analysis.[19] The trans orientation of the newly
introduced trimethylsilyl and the N-phthaloyl group was
consistent with previous reports and isolated palladacycles
(Scheme S2, Int-B).[14,15c] Importantly, the silylation method
Scheme 2. Gram-scale synthesis of chiral TMS-Ala through Pd-cata-
À
lyzed primary C H silyation, and removal of theauxiliary.
Encouraged by this promising result, we next focused on
À
À
the exploration of direct silylation of secondary C H bonds to
also worked with an aliphatic secondary C H bond, albeit in
prepare an array of more complicated chiral b-silyl-a-AAs.
N-Phthaloyl phenylalanine derivative 2a, which was obtained
through a Pd-catalyzed monoarylation of alanine 1 established
by our group,[15a] was chosen as the model substrate. After
screening various additives that are commonly used in
a modest yield (3k, 43%) and with relatively low diastereo-
selectivity (d.r. = 3:1). This is likely a result of the reduced
degree of steric repulsion between the methyl group and the
N-phthaloyl group in the palladacycle intermediate. Notably,
the a-amino butyric acid derivative 2k was prepared through
b-methylation of alanine 1 by using our established meth-
od.[15b] Therefore, this method also showcases the preparation
[18]
À
promoting C H functionalization (Table S3),
we found
that b-Silylated product 3a could be obtained in 71% yield
À
under the optimized conditions (Conditions B): Pd(OAc)2
of chiral b-silyl-a-AAs through a two-step C H functional-
ization sequence.
(15 mol%),
hexamethyldisilane
(5.0 equiv),
Ag2CO3
(0.5 equiv), DMBQ (1.5 equiv) in tBuOH under air at
1258C for 12 h. Importantly, the chiral b-TMS-phenylalanine
product 3a was obtained with excellent diastereoselectivity
(d.r. > 20:1) without racemization (Scheme 3, 98% ee).
With the reliable silylation procedure in hand, a series of
l-arylalanine derivatives (2a–2j) that were synthesized
through monoarylation of l-alanine derivative 1 were sub-
2-Aryl propionic acids (2-APAs) are common motifs in
drug molecules, including ibuprofen, naproxen, flurbiprofen.
À
Direct C H silylation could provide a potentially useful
modification of this class of biologically useful molecules. We
thus tested a number of 2-APA derivatives with modified
conditions (Conditions C): Pd(OAc)2 (10 mol%), s-BINA-
PO2H (30 mol%), hexamethyldisilane (5.0 equiv), NaHCO3
2
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(2.0 equiv), LiOAc (0.5 equiv) and Ag2CO3 (2.0 equiv) in
toluene under air at 1258C for 12 h (Tables S4–S8) and
Based on the unusual observation that silylation of 5a
3
À
exclusively takes place at b-C(sp ) H bonds rather than g-
2
À
discovered that the silylation selectively occurred at the b-
C(sp ) H bonds in the same molecule, we were eager to gain
3
À
methyl C(sp ) H bonds (Scheme 4). Substrates bearing both
further insight into the origin of the site selectivity
(Scheme 5). We anticipated that palladacycle intermediates,
Scheme 5. Experimental investigations of the origin of the site selectiv-
À
ity in the C H silylation of 2-APA.
if attainable, could directly offer evidence for the site
selectivity. Unfortunately, the reaction of 5a with stoichio-
metric Pd(OAc)2 under the standard reaction conditions
failed to give any isolable intermediates. We postulated that
the introduction of a strong neutral ligand might stabilize the
resulting palladacycle.[20] Consistent with this hypothesis, we
found that the reaction of 5a with 1 equivalent of Pd(OAc)2 in
the presence of 2 equivalents of 2,4,6-collidine in toluene at
508C afforded the six-membered palladacycle Int-D in 62%
À
Scheme 4. Pd-catalyzed silylation of primary C H bonds. [a] Condi-
2
À
yield through g-C(sp ) H bond activation (Scheme 5). When
tions C: 5 (0.1 mmol), Pd(OAc)2 (10 mol%), hexamethyldisiliane (5.0
equiv), s-BINA-PO2H (30 mol%), Ag2CO3 (2.0 equiv), NaHCO3 (2.0
equiv), LiOAc (0.5 equiv) in 1.0 mL toluene at 1258C under air for 12
h. Yields of isolated product are shown; the yields in parentheses are
for recovered carboxamides 5.
the reaction was performed at 1258C, the five-membered
palladacycle Int-C was isolated in 41% yield, together with
13% of Int-D. Interestingly, when a solution of Int-D in
toluene was heated at 1258C, it was transformed into Int-C in
15% yield, with 52% recovered 5a (Scheme 5).
To further understand the reaction mechanism, we sought
to ascertain whether Int-C or Int-D is the active intermediate
in the silylation reaction. Stoichiometric reactions of Int-C
and Int-D with hexamethyldisilane under Conditions C were
electron-donating and electron-withdrawing substituents at
different positions reacted smoothly, providing the silylated
products in moderate to good yields (6b–6l).
The compatibility of this method with 2-alkylpropana-
mides was investigated next (Scheme 4, 6m–6v). Generally,
amides derived from aliphatic carboxylic acids gave the
conducted. Int-C successfully gave product 6a in 46% yield.
2
À
However, Int-D failed to afford g-C(sp ) H silylation product
6ab and solely gave 6a in 51% yield (Scheme S3). According
to these experimental results, we are able to draw the
following conclusions: 1) the formation of six-membered
desired b-silylation products in moderate to good yields. The
3
À
potential of this C(sp ) H silylation was further demonstrated
by the late-stage modification of amides 5u and 5v, which are
derived from (À)-santonin and b-cholic acid respectively.
Finally, b-TMS-Phe 3a was easily transformed into its
methyl ester 4a in 62% yield with retention of configuration
(Scheme S1a, 97% ee).[14b,15] The auxiliary in 6a can be
removed in good yield through a two-step sequence (Sche-
me S1b).[14d]
palladacycle Int-D is kinetically favored, while Int-C is
2
À
thermodynamically more stable; 2) the C(sp ) H activation
3
À
step is reversible; 3) the b-C(sp ) H silylation is favored over
the g-C(sp ) H silylation, which can be explained by Curtin–
2
À
Hammett principle.
In summary, we have developed a general and practical
PdII-catalyzed intermolecular silylation of primary and sec-
À
To understand the process of formation of the b-silyl-a-
amino acids, palladacycles Int-A[19] and Int-B[15c] were pre-
pared, and the structure of Int-A was unambiguously
confirmed by X-ray analysis (Scheme S2).[19] We found that
both Int-A and Int-B react with hexamethyldisilane stoichio-
metrically to give the silylation products 1a and 3a, respec-
tively. Catalytic reactions also suggested that these pallada-
ondary C H bonds of a-amino acids and aliphatic acids by
employing an 8-aminoquinoline auxiliary. This method allows
stereoselective access to a series of chiral b-silyl-a-AAs.
Moreover, this method can be scaled up to the gram scale and
used for the late-stage functionalization of biological small
molecules. Several key intermediates have been successfully
isolated to elucidate the mechanism of this b-C(sp ) H
silylation process. We anticipate that this method may offer
3
À
À
cycles are viable intermediates for primary and secondary C
H silylation (Scheme S2).
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Acknowledgements
Financial support from the National Basic Research Program
of China (2015CB856600) and the NSFC (21572201,
21422206) is gratefully acknowledged.
Keywords: amino acids · asymmetric transformations ·
À
chiral auxiliaries · C H activation · silylation
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Received: August 11, 2016
Revised: September 10, 2016
Published online: && &&, &&&&
4
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Communications
Silylation
Y.-J. Liu, Y.-H. Liu, Z.-Z. Zhang, S.-Y. Yan,
K. Chen, B.-F. Shi*
&&&& — &&&&
Good to Si you: A general and practical
optical pure b-silyl-a-amino acids. Fur-
Divergent and Stereoselective Synthesis
of b-Silyl-a-Amino Acids through
Palladium-Catalyzed Intermolecular
Silylation of Unactivated Primary and
PdII-catalyzed intermolecular silylation of
thermore, the late-stage functionalization
of biological small molecules such as
(À)-santonin and b-cholic acid is dem-
onstrated.
À
primary and secondary C H bonds of a-
amino acids and simple aliphatic acids is
reported. This method provides divergent
and stereoselective access to a variety of
À
Secondary C H Bonds
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!