Quaternary β2,2-Amino Acids: Catalytic Asymmetric Synthesis and Incorporation into Peptides by Fmoc-Based Solid-Phase Peptide Synthesis

Article abstract of DOI:10.1002/anie.201711143

β-Amino acid incorporation has emerged as a promising approach to enhance the stability of parent peptides and to improve their biological activity. Owing to the lack of reliable access to β^2,2-amino acids in a setting suitable for peptide synthesis, most contemporary research efforts focus on the use of β³- and certain β^2,3-amino acids. Herein, we report the catalytic asymmetric synthesis of β^2,2-amino acids and their incorporation into peptides by Fmoc-based solid-phase peptide synthesis (Fmoc-SPPS). A quaternary carbon center was constructed by the palladium-catalyzed decarboxylative allylation of 4-substituted isoxazolidin-5-ones. The N?O bond in the products not only acts as a traceless protecting group for β-amino acids but also undergoes amide formation with α-ketoacids derived from Fmoc-protected α-amino acids, thus providing expeditious access to α-β^2,2-dipeptides ready for Fmoc-SPPS.

Full text of DOI:10.1002/anie.201711143

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Quaternary β2,2-Amino Acids: Catalytic Asymmetric Synthesis
and Incorporation into Peptides by Fmoc-Based Solid Phase
Peptide Synthesis
Authors: Jin-Sheng Yu, Hidetoshi Noda, and Masakatsu Shibasaki
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201711143
Angew. Chem. 10.1002/ange.201711143
Link to VoR: http://dx.doi.org/10.1002/anie.201711143
http://dx.doi.org/10.1002/ange.201711143

Angewandte Chemie International Edition
10.1002/anie.201711143
COMMUNICATION
2
,2
Quaternary β -Amino Acids: Catalytic Asymmetric Synthesis
and Incorporation into Peptides by Fmoc-Based Solid Phase
Peptide Synthesis
Jin-Sheng Yu, Hidetoshi Noda* and Masakatsu Shibasaki*
Abstract: β-Amino acid incorporation has emerged as a promising
available routes to these classes of β-amino acids.
approach to enhance the stability of parent peptides and to improve
2
,2
their biological activity. Owing to the lack of reliable access to β
amino acids in setting suitable for peptide synthesis, most
contemporary research efforts focus on the use of β - and certain
-
a
3
2
,3
β
-amino acids. Herein, we report a catalytic asymmetric synthesis
2
,2
of β -amino acids and their incorporation into peptides by Fmoc-
based solid phase peptide synthesis (Fmoc-SPPS). Construction of
a
quaternary carbon is accomplished by Pd-catalyzed
decarboxylative allylation of 4-substituted isoxazolidin-5-ones. The
N–O bond in the products not only acts as a traceless protecting
group for β-amino acids but also undergoes amide formation with α-
ketoacids derived from Fmoc-protected α-amino acids, providing
2
,2
expeditious access to α-β -dipeptides ready for Fmoc-SPPS.
Figure 1. Structural classifications of α- and β-amino acids.
In 2009, Seebach elegantly summarized the synthetic
The highly organized structure of proteins is closely linked with
their functions. Identification of artificial molecules that form well
defined three-dimensional structures has opened up the avenue
for designing new functional molecules beyond what nature can
2
challenges associated with the preparation of β -amino acids
[
10
]
suitable for peptide synthesis,
and the situation has not
2
,2
changed since then. The enantioselective synthesis of β
-
[
1]
amino acids faces even more difficulties. Most known methods
create. Among various foldamers, oligomers of homologated β-
resort to chiral auxiliaries to construct the all-carbon quaternary
amino acids stand out as the most investigated class of
11
[
]
[
2
]
stereocenter.
Nevertheless several catalytic asymmetric
unnatural foldamers.
established the incorporation of β-amino acids as one of the
Extensive research efforts have
approaches have been reported, including the conjugate
addition of carbon nucleophiles to α-substituted-β-
nitroacrylates and the addition of α-substituted-α-
cyanoacetates to carbon electrophiles.
[
3,4]
most successful approaches in peptidomimetics.
12
]
[
The extra carbon atom in β-amino acids restricts the
conformation of the resulting peptide, inducing the formation of
more rigid secondary structures than those found in α-
13
]
[
Despite the
2
,2
tremendous efforts directed at β -amino acid synthesis by
[
5]
asymmetric catalysis, the number of available approaches
peptides. β-Amino acids are structurally classified according to
3
remains limited, and most of them are not readily translated to
their substituent position, with substituent at the β-carbon for β -
14
[
]
2
peptide synthesis.
In this Communication, we describe
amino acids, α-carbon for β -amino acids, both α- and β-carbon
2
,2
2
,3
catalytic asymmetric synthesis of β -amino acids and their
for β -amino acids, and so on (Figure 1). Almost all substitution
patterns have been demonstrated to induce the formation of
certain higher order structures. For instance, the seminal work of
incorporation into peptides by a combination of decarboxylative
[
15
]
amide formation with α-ketoacids
and Fmoc-based solid
2
,2
phase peptide synthesis (Fmoc-SPPS).
From the outset, we sought to adopt a unified strategy that
Seebach revealed that achiral
formation of reverse turned structures featuring 10-membered
β -amino acids cause the
2
,2
[
6 ]
would provide a variety of quaternary β -amino acids from a
single intermediate. Given the prospective transformations of C–
C double bonds, we set compound 1 as the target structure
hydrogen bonding rings.
structures in biological settings, it would be valuable to study
Given the importance of turned
[
7]
2
,2
the effect of chirality in β -amino acids on peptide conformation
2
[
8]
(Scheme 1a). α-Quaternerization of racemic β -amino acids
or to incorporate them into α/β-mixed peptides. So far, most
studies and applications employing β-amino acids have dealt
appears to be the most straightforward route to 1. In such an
approach, however, the low acidity of the α-protons can hamper
the generation of the corresponding carboxylate-type enolate by
a catalytic amount of Brønsted base. Geometric control of the
resulting α,α-disubstituted enolate would also complicate the
3
2,3
2
with β - and certain β -amino acids, neglecting their β - and
2
,2
[ 9 ]
β
-counterparts.
This apathy partly reflects the lack of
stereoselective synthesis. Substituted isoxazolidin-5-ones have
[*]
Dr. J.-S. Yu, Dr. H. Noda, Prof. Dr. M. Shibasaki
Institute of Microbial Chemistry (BIKAKEN), Tokyo
[16]
often been utilized as β-amino acid precursors,
e.g., in the
2
,2,3
synthesis of β -amino acids by chiral auxiliary based alkylation
3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
[
17]
E-mail: hnoda@bikaken.or.jp; mshibasa@bikaken.or.jp
(Scheme 1b).
bond formation of racemic isoxazolidin-5-ones for the synthesis
Nevertheless, the catalytic asymmetric C–C
Supporting information for this article is given via a link at the end of
the document.
2
,2
[18]
of quaternary β -amino acids has not been reported.
Recent
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Angewandte Chemie International Edition
10.1002/anie.201711143
COMMUNICATION
[
a]
Table 1. Optimization of reaction conditions
.
contributions from Stoltz, Tunge, Trost, and others have
demonstrated that Pd-catalyzed decarboxylative asymmetric
O
O
O
1
0 mol% [Pd]
1
2 mol% Ligand
[
19,20]
allylation of carbonyl compounds
is a reliable means to
O
O
O
THF, Temp, 24 h
N
N
construct a quaternary carbon at the α-position, making this
Boc
Boc
[
21]
= 2-naphthyl-CH2
5a
rac-4a
approach particularly suitable for our goal.
With this in mind,
2
we selected 4-substituted isoxazolidin-5-ones as β -amino acid
surrogates, and embarked on the development of
decarboxylative asymmetric allylation of 3 (Scheme 1c).
[b]
[c]
Entry
[Pd]
Ligand
Temp
(°C)
Yield
Ee
(10 mol%)
(12 mol%)
(%)
(%)
1
2
3
4
5
Pd
Pd
Pd
Pd
2
2
2
2
(dba)
(dba)
(dba)
(dba)
3
3
3
3
L1
L2
L3
L4
L4
L4
L4
25
25
95
96
10
65
75
78
79
6
10
25
–52
85
25
Pd(dba)
Pd(dba)
2
25
85
[
d]
6
2
–20
–20
92
[
d,e]
7
Pd(dmdba)
2
93
O
O
O
O
O
O
PPh2
PPh2 Ph2P
NH HN
O
O
N
NH HN
PPh2 Ph2P
O
PPh2 Ph2P
L1
L2
(S)-tBu-Phox
L3
L4
(
R)-Segphos
(S,S)-DACH-Naphthyl Trost
(S,S)-ANDEN-Ph Trost
1
Scheme 1. Reaction design, precedents, and current approach.
[a] 0.05 mmol scale at 0.05 M. [b] Determined by H NMR analysis. [c]
Determined with normal phase HPLC on a chiral support. [d] The reaction time
equaled 48 h. [e] 0.1 mmol scale at 0.025 M. Isolated yield is reported. dba =
dibenzylideneacetone, dmdba = 3,5,3’,5’-dimethoxydibenzylideneacetone.
The optimization study for the decarboxylative allylation of
4
a was summarized in Table 1. Whereas most evaluated chiral
2
ligands exhibited low to moderate selectivity, commercial (S,S)-
ANDEN-Ph Trost ligand L4 performed exceptionally well,
product 5f or 5i can be considered as analogues of β -tyrosine
2
or β -tryptophane, respectively. Furthermore,
a
pyrene-
affording 5a in 85% ee with fair reactivity (entries 1–4). Pd(dba)
was found to present a slightly higher reactivity while preserving
selectivity (entry 5). Although the origin of Pd(dba) superiority to
Pd (dba) is not clear, the larger amount of dba ligand in the
former precatalyst may stabilize an active Pd complex in the
2
containing substrate was also efficiently allylated (entry 11). The
2
,2
generated β -amino acids are potential reporter molecules due
to the fluorescent nature of the pyrene ring. A substituted alkenyl
chain and a simple alkyl group were both tolerated, providing the
products in good selectivities (entries 12–13). The scalability of
the current protocol was ascertained by synthesizing 1.18 g of
5a in 95% ee (Eq 1). The absolute configuration of 5c at the
carbonyl α-carbon was determined as S by X-ray diffraction
(Figure S1); the stereochemistry of other products was assigned
by analogy.
2
2
3
[
22]
catalytic cycle, preventing its decomposition.
Lowering the
reaction temperature to –20 °C further improved the
enantioselectivity albeit with prolonged reaction time (entry 6).
The removal of residual dba ligand from the product proved to
be challenging. Fortunately Pd precatalyst containing 3,5,3’,5’-
dimethoxydibenzylideneacetone (dmdba) showed reactivity and
O
O
O
10 mol% Pd(dmdba)2
2
selectivity comparable to those obtained in the case of Pd(dba) ,
12 mol% L4
O
O
O
(Eq. 1)
with the dmdba ligand readily separated from the product by
standard silica gel column chromatography (entry 7).
THF, –20 °C
2-naphthyl-CH2
N
N
Boc
Boc
=
rac-4a
.5 mmol
5a
With the optimized conditions in hand, a series of substrates
were subjected to catalytic asymmetric allylation (Table 2).
Similar reactivities and selectivities were observed for 2-
naphthylmethyl and benzyl substituted compounds (entries 1–2).
A broad range of substituted benzyl groups also proved to be
suitable for this transformation; the electronic nature and the
position of substituents on the phenyl ring barely affect the
reaction outcome. Both electron-withdrawing (entries 3–4) and
3
1.18 g (91% yield)
95% ee
electron-donating
groups
(entries
5–6)
afforded
the
corresponding products with the same level of selectivity. The
positional isomers of 5c also produced the desired compounds
with similarly high efficiency (entries 7–8). Potentially detrimental
heteroaromatics were also tolerated (entries 9–10). The allylated
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Angewandte Chemie International Edition
10.1002/anie.201711143
COMMUNICATION
[
a]
Table 2. Substrate scope of catalytic asymmetric allylation
.
O
a) TFA
b) Pd/C, H2
O
O
O
1
0 mol% Pd(dmdba)2
O
H N
OH
92% yield
2
12 mol% L4
N
O
O
O
THF, –20 °C
5
a
Boc
6
9
O
N
N
=
2-naphthyl-CH2
tBuO C
Boc
Substituent
2-naphthyl-CH
Boc
Ee (%)
e) Grubbs 2nd
tBu acrylate
f) Pd/C, H2
2
rac-4
5
Entry
Product
Yield (%)
82
c) Zn, AcOH
d) BnBr or 12
R = Bn
81% yield
BocHN
OH
1
2
3
4
5
6
7
8
9
2
5a
5b
5c
5d
5e
5f
94
92
93
93
92
92
94
90
94
90
91
94
92
O
C
6
H
5
-CH
-CH
-CH
2
89
OH
4-Cl-C
4-Br-C
4-MeO-C
4-tBuO-C
6
H
4
2
80
g) BH •THF; NaBO
3
3
BocHN
OR
R = Bn
1% yield
6
H
4
2
91
7
BocHN
OBn
O
1
0
O
6
H
4
-CH
2
88
R = Bn: 7 (91% yield)
R = tBu: 8 (92% yield)
6
H
4
-CH
2
85
HO C
2
OtBu
h) OsO ; NaIO
4
4
i) PCC; LiOH
iPr
iPr
3-Cl-C
2-Cl-C
6
6
H
H
4
4
-CH
-CH
2
2
5g
5h
5i
96
N
H
N
BocHN
OtBu
R = tBu
77% yield
1
2
1
1
O
94
2
,2
Scheme 2. Transformations to various quaternary β -amino acids.
N-Boc-3-indolyl-CH
3-thienyl-CH
1-pyrenyl-CH
2
89
Br
1
1
1
1
0
1
2
3
2
5j
76
O
2
5k
5l
92
FmocHN
OH
O
O
(E)-Ph-CH=CH-CH
2
81
13
H
N
OH
tBuOH/H O
2
FmocHN
O
2
5 °C
Me
5m
58
O
O
1
5d (90% yield)
NH•TFA
4d•TFA
4-Br-C H -CH
2
[
a] 0.2 mmol scale at 0.025 M. Isolated yields are reported. Ee was
1) X-phos Pd G2 2) Ru(bpz) (PF )
3
6 2
1
K PO
17, p-toluidine
determined with normal phase HPLC on a chiral support.
3
4
=
16
blue LED
58% yield
6
4
99% yield
The allylated products in Table 2 were readily converted to
2
,2
OMe
AcO
AcO
various protected β -amino acids (Scheme 2). After removing
the Boc group, treatment of the crude amine with Pd/C under a
hydrogen atmosphere reduced the double bond in the side chain
concomitant with N–O bond cleavage, producing 6 in excellent
yield. Switching the reductive conditions allowed for selective
cleavage of the N–O bond without disturbing the olefin moiety,
which was followed by the esterification of thus obtained
carboxylic acid to furnish 7 or 8. Cross metathesis provides a
convenient means to elongate the side chain with varying
functionality; thus treatment with the Grubbs 2nd generation
catalyst and tert-butyl acrylate smoothly extended the side chain.
Subsequent reduction of the alkene moiety afforded 9. Standard
oxidative functionalizations of the terminal double bond also
O
OAc
OMe AcO
AcO
3
O
OAc
3
O
O
AcO
AcO
S
Bpin
SH
16
17
H
N
OH
O
FmocHN
O
1
8
2
,2
Scheme 3. Synthesis of hybrid α-β -dipeptide 15d and its functionalization.
The hydroxylamine moiety in the products also acts as a
springboard for further transformations. Removing the Boc group
makes the O-acyl hydroxylamines suitable for the α-ketoacid-
hydroxylamine (KAHA) ligation developed by Bode and
3
proved effective. Hydroboration with BH •THF produced primary
alcohol 10 after oxidative workup. Carboxylic acid 11 was
provided by first cleaving the terminal double bond to unveil an
aldehyde, which was intramolecularly captured by the
carbamate nitrogen to give the corresponding aminal. PCC
oxidation to lactam and subsequent ring opening under aqueous
basic conditions gave 11. These transformations demonstrated
that the allyl group in the products is a useful handle for the
[
23]
coworkers.
The crude mixture of TFA salt of 14d was treated
with α-ketoacid 13 derived from Fmoc-L-leucine to furnish Fmoc-
2
,2
protected α-β -dipeptide 15d (Scheme 3). The 2nd generation
[
24]
Buchwald palladacycle ligated with X-phos ligand
smoothly
promoted the Suzuki–Miyaura reaction of 15d with PEGylated
arylboronate 16 even in the presence of the base-sensitive
Fmoc group. The terminal olefin in the functionalized dipeptide
underwent a thiol-ene reaction with glycosyl thiol 17 under the
2
,2
synthesis of various quaternary β -amino acids.
[
25]
influence of a photoredox catalyst.
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Angewandte Chemie International Edition
10.1002/anie.201711143
COMMUNICATION
Disorders for financial support. The authors are grateful to Dr.
Ryuichi Sawa, Ms. Yumiko Kubota, and Dr. Kiyoko Iijima for
assistance with NMR analysis and Dr. Tomoyuki Kimura for
assistance with X-ray crystallography.
1
3
H
N
tBuOH/H O
OH
2
1
4a•TFA
FmocHN
2
5 °C
O
1
O
=
2-naphthyl-CH2
5a
9
2% yield
dr 97:3
Keywords: Amino acids • Asymmetric catalysis • Peptides
recryst.
62% yield
dr >99:1
[
1]
a) S. Hecht, I. Huc, Foldamers: structure, properties, and applications,
Wiley-VCH, Weinheim, 2007; b) D. J. Hill, M. J. Mio, R. B. Prince, T. S.
Hughes, J. S. Moore, Chem. Rev. 2001, 101, 3893; c) R.
Gopalakrishnan, A. I. Frolov, L. Knerr, W. J. Drury III, E. Valeur, J. Med.
Chem. 2016, 59, 9599.
Rink amide
resin
Fmoc-SPPS
Ph
O
O
O
H
H
H
N
[2]
[3]
a) R. P. Cheng, S. H. Gellman, W. F. DeGrado, Chem. Rev. 2001, 101,
3219; b) D. Seebach, J. Gardiner, Acc. Chem. Res. 2008, 41, 1366.
a) E. A. Porter, X. Wang, H. S. Lee, B. Weisblum, S. H. Gellman,
Nature 2000, 404, 565; b) Y. Imamura, N. Watanabe, N. Umezawa, T.
Iwatsubo, N. Kato, T. Tomita, T. Higuchi, J. Am. Chem. Soc. 2009, 131,
7353; c) L. M. Johnson, S. Barrick, M. V. Hager, A. McFedries, E. A.
Homan, M. E. Rabaglia, M. P. Keller, A. D. Attie, A. Saghatelian, A.
Bisello, S. H. Gellman, J. Am. Chem. Soc. 2014, 136, 12848.
a) J. X. Qiu, E. J. Petersson, E. E. Matthews, A. Schepartz, J. Am.
Chem. Soc. 2006, 128, 11338; b) G. A. Lengyel, W. S. Horne, J. Am.
Chem. Soc. 2012, 134, 15906; c) C. Mayer, M. M. Müller, S. H.
Gellman, D. Hilvert, D. Angew. Chem. Int. Ed. 2014, 53, 6978; Angew.
Chem. 2014, 126, 7098.
N
N
NH2
O
N
N
N
H
H
H
O
O
O
hybrid α/β2,2 peptide 19
1% yield from resin
4
2
,2
Scheme 4. Synthesis of hybrid α/β peptide by Fmoc-SPPS.
2
,2
Fmoc-protected α-β -dipeptides 15 appeared amenable to
Fmoc-SPPS. Regarding stereochemistry, peptide chemistry
standards exceed those of asymmetric catalysis, requiring
substrates possessing at least >99:1 stereochemical integrity.
Despite the somewhat lower selectivity obtained herein, the
crystalline nature of Fmoc-protected dipeptides can compensate
[4]
[5]
[6]
[7]
Y.-D. Wu, W. Han, D.-P. Wang, Y. Gao, Y.-L. Zhao, Acc. Chem. Res.
2
008, 41, 1418.
for this drawback; a single recrystallization from hexane/Et
2
O
D. Seebach, S. Abele, T. Sifferlen, M. Hänggi, S. Gruner, P. Seiler,
Helv. Chim. Acta 1998, 81, 2218.
allowed for removal of the minor diastereomer, rendering
[
26]
dipeptide 15a ready for Fmoc-SPPS (Scheme 4).
Since the
J. D. A. Tyndall, B. Pfeiffer, G. Abbenante, D. P. Fairlie, Chem. Rev.
2005, 105, 793.
growing number of applications is found in hybrid α/β
[
27]
2,2
peptides,
the facile synthesis of diastereomerically pure α-
-dipeptides would be advantageous. In contrast to other
geminally substituted amino acids —α,α-disubstituted α-amino
[8]
Examples of β -amino acids bearing a heteroatom at the α-carbon.
2
,2
β
Oxygen: a) G. V. M. Sharma, K. Rajender, G. Sridhar, P. S. Reddy, M.
Kanakaraju, Carbohydr. Res. 2014, 388, 8; b) F. Rodríguez, F. Corzana,
A. Avenoza, J. H. Busto, J. M. Peregrina, M. M. Zurbano, Curr. Topics
Med. Chem. 2014, 14, 1225. Nitrogen: c) L. Mata, A. Avenoza, J. H.
Busto, F. Corzana, J. M. Peregrina, Chem. Eur. J. 2012, 18, 15822; d)
N. Mazo, I. García-González, C. D. Navo, F. Corzana, G. Jiménez-
Osés, A. Avenoza, J. H. Busto, J. M. Peregrina, Org. Lett. 2015, 17,
5804. Sulfur: e) I. García-González, L. Mata, F. Corzana, G. Jiménez-
Osés, A. Avenoza, J. H. Busto, J. M. Peregrina, Chem. Eur. J. 2015, 21,
1156.
3
,3
acids and β -amino acids, both of which often need to be
[
11]
coupled under special conditions — 15 is sufficiently reactive
under the standard Fmoc-SPPS conditions. Thus dipeptide 15a
was incorporated into the middle of the peptide sequence on a
[
28]
Rink-amide resin,
followed by cleavage from the polymer
support and HPLC purifications to provide analytically pure
peptide 19 in good overall yield. Functionalizations of the
[
29]
[9]
For selected recent examples, see: a) T. Fujino, Y. Goto, H. Suga, H.
Murakami, J. Am. Chem. Soc. 2016, 138, 1962; b) D. F. Kreitler, D. E.
Mortenson, K. T. Forest, S. H. Gellman, J. Am. Chem. Soc. 2016, 138,
terminal olefin in the resulting peptide would also be feasible.
In summary, we have documented a new entry for the
2
,2
catalytic asymmetric synthesis of quaternary β -amino acids. A
proficient chiral catalyst system comprising Pd(dmdba) and a
6
498.
2
[10] D. Seebach, A. K. Beck, S. Capone, G. Deniau, U. Grošelj, E. Zass,
Synthesis 2009, 1.
Trost ligand promotes the decarboxylative allylation of 4-
substituted isoxazolin-5-ones in a stereoselective fashion. The
allylated products are converted to a range of the otherwise
[11] S. Abele, D. Seebach, Eur. J. Org. Chem. 2000, 1.
[12] Aldehydes: a) R. Kastl, H. Wennemers, Angew. Chem. Int. Ed. 2013,
52, 7228; Angew. Chem. 2013, 125, 7369. Indoles: b) J.-Q. Weng, Q.-
M. Deng, L. Wu, K. Xu, H. Wu, R.-R. Liu, J.-R. Gao, Y.-X. Jia, Org. Lett.
2014, 16, 776; c) K. Mori, M. Wakazawa, T. Akiyama, Chem. Sci. 2014,
2
,2
inaccessible β -amino acids. Moreover, the N–O bond in the
products participates in the KAHA ligation with α-ketoacids,
2
,2
affording expeditious access to Fmoc-protected α-β -dipeptides.
5
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up mixed α/β peptides, showcasing the potential of the current
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JPMJCR12YO), and JSPS KAKENHI Grant Number
JP16K18856. J.-S.Y. is a JSPS International Research Fellow.
H.N. thanks the Astellas Foundation for Research on Metabolic
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1
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COMMUNICATION
Jin-Sheng Yu, Hidetoshi Noda,* and
Masakatsu Shibasaki*
Page No. – Page No.
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Quaternary β -Amino Acids:
Catalytic Asymmetric Synthesis and
Incorporation into Peptides by Fmoc-
Based Solid Phase Peptide Synthesis
2
,2
Catalytic asymmetric synthesis of β -amino acids and their incorporation into
hybrid α/β peptides are described.
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