Efficient synthesis of hydrocarbon-bridged diaminodiacids through nickel-catalyzed reductive cross-coupling

Article abstract of DOI:10.1016/j.tetlet.2017.09.006

Solid-phase incorporation of pre-prepared diaminodiacids has been established as an efficient strategy for the chemical synthesis of peptide disulfide bond mimics. Hydrocarbon-bridged diaminodiacids represent one important category of diaminodiacids but they remain difficult to synthesize. In the present work, we reported the use of newly-developed nickel catalyzed reductive cross-coupling reaction to efficiently synthesize diaminodiacids with hydrocarbon bridges. Through optimization of the reaction conditions, the yield of the hydrocarbon bridge formation reached about 50%, even when the reaction was scaled up to the gram level. Subsequently, using our recently developed Dmab/ivDde protecting group system, we obtained a new hydrocarbon-bridged diaminodiacid that are suitable for metal-free deprotection conditions. We demonstrated the utility of this Dmab/ivDde protected hydrocarbon-bridged diaminodiacid in the synthesis of a disulfide surrogate of oxytocin.

Full text of DOI:10.1016/j.tetlet.2017.09.006

Accepted Manuscript
Efficient synthesis of hydrocarbon-bridged diaminodiacids through nickel-cat-
alyzed reductive cross-coupling
Tao Wang, Yi-Fu Kong, Yang Xu, Jian Fan, Hua-Jian Xu, Donald Bierer, Jun
Wang, Jing Shi, Yi-Ming Li
PII:
S0040-4039(17)31111-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.09.006
TETL 49276
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 July 2017
28 August 2017
4 September 2017
Please cite this article as: Wang, T., Kong, Y-F., Xu, Y., Fan, J., Xu, H-J., Bierer, D., Wang, J., Shi, J., Li, Y-M.,
Efficient synthesis of hydrocarbon-bridged diaminodiacids through nickel-catalyzed reductive cross-coupling,
Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.09.006
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Tao Wang, Yi-Fu Kong, Yang Xu, Jian Fan, Hua-Jian Xu, Donald Bierer, Jun Wang*, Jing Shi*, Yi-Ming Li*

1
Tetrahedron Letters
journal homepage: www.els evier.com
Efficient synthesis of hydrocarbon-bridged diaminodiacids through nickel-catalyzed
reductive cross-coupling
Tao Wang a,1, Yi-Fu Kong a,1,Yang Xu b, Jian Fan b, Hua-Jian Xu a, Donald Bierer c, Jun Wang a,*, Jing Shi b,*, Yi-Ming Li a,*
a School of Biological and Medical Engineering, Hefei University of Technology, Hefei 230009, PR China
b Department of Chemistry, University of Science and Technology of China, Hefei 230026, PR China
c Bayer AG, Department of Medicinal Chemistry, Aprather Weg 18A, 42096 Wuppertal, Germany
*Corresponding authors at: School of Biological and Medical Engineering, Hefei University of Technology, Hefei 230009, P.R. China (J. Wang and Y. M. Li) or Department of
Chemistry, University of Science and Technology of China, Hefei 230026, P.R. China (J. Shi).
E-mail addresses: wangjun-08@126.com (J. Wang), shijing@ustc.edu.cn (J. Shi), ymli@hfut.edn.cn (Y. M. Li).
1 These authors contributed equally to this work.
ARTICLE INFO
ABSTRACT
Article history:
Received
Solid-phase incorporation of pre-prepared diaminodiacids has been established as an efficient
strategy for the chemical synthesis of peptide disulfide bond mimics. Hydrocarbon-bridged
diaminodiacids represent one important category of diaminodiacids but they remain difficult to
synthesize. In the present work, we reported the use of newly-developed nickel catalyzed
reductive cross-coupling reaction to efficiently synthesize diaminodiacids with hydrocarbon
bridges. Through optimization of the reaction conditions, the yield of the hydrocarbon bridge
formation reached about 50%, even when the reaction was scaled up to the gram level.
Subsequently, using our recently developed Dmab/ivDde protecting group system, we obtained a
new hydrocarbon-bridged diaminodiacid that are suitable for metal-free deprotection conditions.
We demonstrated the utility of this Dmab/ivDde protected hydrocarbon-bridged diaminodiacid in
the synthesis of a disulfide surrogate of oxytocin.
Received in revised form
Accepted
Available online
Keywords:
Diaminodiacids
Hydrocarbon bridge
Nickel-catalyzed reductive coupling
Peptide
Disulfide
(Fmoc-SPPS). Since all the cyclization steps can be carried out
by condensation of the amino group and the carboxylic acid in
1. Introduction
Conformationally rigidified peptidic macrocycles have been
demonstrated to exhibit good metabolic stability, high
bioactivity, and target selectivity in recent studies.1 The favorable
features enable these compounds to become highly promising
molecules for diagnostic and therapeutic applications.2 Many of
such peptidic macrocycles contain one or multiple disulfide
bridges, which are important to their thermal and metabolic
stability, as well as conformational stability.3 However, the
disulfide bonds in these cyclic peptides are potentially unstable
under reductive conditions or in the presence of disulfide
isomerases.4 Therefore, the development of stable peptide
containing disulfide bond mimic has attracted considerable
interest. Various strategies have been developed to stabilize
peptide disulfide bond, using structures including thioether5,
lactam6 as well as triazole bridges7. The different bridge types
provide structural diversity of disulfide bond surrogates for
tuning of bioactivity.
the polypeptide, it is possible to obtain a disulfide-substituted
polypeptide directly on the resin. Till now, four pairs of
orthogonal protecting group for diaminodiacids were developed,
including allyl/allyloxycarbonyl (Alloc), p-nitrobenzyl (pNb)
/pnitrobenzyloxycarbonyl (pNz), benzyl (Bn)/benzyloxycarbonyl
(Cbz) and 4-(N-[1-(4,4-dimethyl-2,6-dioxocyclo-hexylidene)-3-
methylbutyl]amino)benzyl (Dmab)/1-(4,4-dimethyl-2,6-dioxo-
cyclohex-1-ylidene)-3-methylbutyl (ivDde) protecting group.8d
In previous reports, diaminodiacids were equipped with two
types of thioether bridges and a hydrocarbon bridge (Scheme
1).8a The different chain types make a flexible synthetic route for
generating disulfide bond surrogates with different structures.
However, although the thioether-bridged diaminodiacids can be
readily prepared, the synthesis of diaminodiacids with
hydrocarbon bridges is rather challenging. This type of bridge
was previously prepared by electrochemical oxidation
decarboxylation of two glutamate segments using Kolbe
electrolysis.9 Unfortunately, this method suffered from relatively
low yield (15%) of the bridge formation step, in addition to the
need for specific operating conditions and technical equipment.8a
Therefore, it is necessary to develop a more convenient and
efficient strategy for the synthesis of hydrocarbon bridged
diaminodiacids.
Unlike the post-chain-assembly side-chain cyclization
approaches such as azide-alkyne cycloaddition, an alternative
strategy is the use of diaminodiacids to replace disulfide bonds in
cyclic peptides.8 In this strategy, pre-prepared diaminodiacids are
used to replace disulfide bonds during conventional 9-
fluorenylmethoxycarbonyl-based solid phase peptide synthesis

2
Tetrahedron Letters
primary halides. Moreover, the feed ratio of two different alkyl
halides was only 1:1.5, indicating good atomic economy of the
reaction. Therefore, we set out to test whether this reaction
system is suitable for cross-coupling of two ortho-protected
homoserine bromides. We first tested this reaction according to
the optimal conditions reported by Gong group (Table 1, Entry
2). Thin layer chromatography (TLC) monitoring indicated that
the starting material 1 was completely consumed when reaction
was carried out for about 4 hours. Then, the desired coupling
product 3 was obtained in 41% yield. In order to save the starting
material homoserine bromides, we next optimize the cross-
coupling reaction to find a balance between the feed ratio and the
reaction yield. Specifically, we first screened different ratios of
Boc/tBu homoserine bromide, B2(Pin)2 and LiOMe and found
that the highest yield (56%) was obtained by using 1.5
equivalents of bromide 2, 2.2 equivalents of B2(Pin)2 and 2.5
equivalents of LiOMe (Table 1, Entry 3). To our delight, the
reaction yield still reached 52% when only 1 equivalent of
bromide 2 was used. Moreover, the yield of compound 3 was
slightly reduced to 48% when the reaction was carried out on
gram scale (6 mmol) (Table 1, Entry 6). Collectively, compared
to the previous electrolytic approach, nickel-catalyzed cross-
coupling enabled the production of hydrocarbon-bridged
diaminodiacid with high efficiency and operational simplicity.
Scheme 1. a) Diaminodiacids with three chain types of bridge; b)
General strategy for diaminodiacid-based SPPS.
In the present work, we report the use of nickel catalyzed
reductive cross-coupling10 to synthesize hydrocarbon-bridged
diaminodiacids with high efficiency. After careful optimization
of the reaction conditions, the yield for the construction of
hydrocarbon bridges reached 52%. Even when the reaction was
expanded to the gram level, the yield was still as high as 48%.
The hydrocarbon-bridged diaminodiacid synthesized here is
protected by the Dmab/ivDde pair, enabling the use of metal-free
deprotection conditions. By using our new diaminodiacid as a
building block in SPPS, we demonstrated that a hydrocarbon-
bond-containing analogue of oxytocin could be synthesized in a
facile and efficient manner.
Table 1. Screening the reaction conditions
2. Results and discussion
We design to synthesize the hydrocarbon bridge by linking
benzyl (Bn)/Cbz protected homoserine bromides11 and tert-butyl
(tBu)/tert-butoxycarbonyl
(Boc)
protected
homoserine
bromides12. Thus our study began with the synthesis of two
orthogonal protected homoserine bromides. According to the
synthetic route shown in Scheme 2, we successfully obtained the
Cbz/Bn protected homoserine bromide and Boc/tBu protected
homoserine bromide in 29% and 32% yields respectively. With
the two bromides in hands, we initially tested the nickel-
catalyzed cross-coupling method using zinc powder as reductant,
which was reported by Gong and co-workers in 2011.13 Although
we were able to obtain diaminodiacids 3 on 0.2 mmol scale with
a 30% yield, the yield of product was reduced to 10% in a gram
scale reaction which might due to the uncertain surface state of
zinc powder as a heterogeneous reductant.
Scheme 2. The synthesis of homoserine bromides
To solve the problem, we turned to a recently developed
method by Gong group in which bis(pinacolato)diboron
(B2(Pin)2) was used as reductant regent.10 This interesting
reductant was reported to efficiently promote the nickel-
catalyzed cross-coupling of inactive alkyl halides, especially for
Scheme 3. The synthetic route of Dmab/ivDde-protected carbon-
bridged diaminodiacids

3
After the hydrocarbon bridge was successfully constructed, we
next changed the protecting groups of diaminodiacid 3 to make it
suitable for use in Fmoc-SPPS. Recently, we developed the
Dmab/ivDde protecting group pair that can be easily removed by
mild hydrazinolysis during solid-phase synthesis,8d we intended
to obtain the first hydrocarbon-bridged diaminodiacid protected
by Dmab/ivDde group (Scheme 3). To this end, the Cbz/Bn of 3
was cleaved with Pd/C in H2 to yield compound 4. The amino
group of 4 was coupled with ivDde-OH to yield compound 5.
Then the esterification was carried out by using dicyclimide
(DCC) as condensation reagent between the ivDde-protected
amino acid 5 and Dmab-OH. After the Boc/tBu was cleaved with
TFA, the product could be reacted with Fmoc-OSu to yield the
final desired diaminodiacid 7 (17 % for overall yield).
the analogue containing a hydrocarbon bridge has not been
obtained. In this context, the disulfide-replaced analogue of
oxytocin nonapeptide was synthesized by using Dmab/ivDde
protected hydrocarbon-bridged diaminodiacid for the first time.
The synthesis of oxytocin analogue was carried out by using
the rink amide AM resin. After the resin was swelled, a linear
tripeptide was assembled onto the resin by using HCTU (5-
chloro-1-[bis(dimethylamino)methylene]-1H
benzotriazolium-
oxide hexafluorophosphate) as the coupling reagent. Diamino-
diacid 7 was coupled to the resin by using PyAop (3-hydroxy-
3H-1,2,3-triazolo[pyridinato-O]tri-1-pyrrolidinyl-phosphonium
heaxfluorophosphate) as condensation reagents.17 Then, the other
four amino acids (i.e. Aln, Gln, Ile, Tyr) were coupled to the
resin by using HCTU. The Dmab-OH and ivDde-OH groups
were removed through treatment with 2% NH2NH2 and the Fmoc
protecting group of the peptide chain was also removed by 2-
methylpiperidine (20% 2-methylpiperidine in DMF for 8-10
min). Next, the PyAop and NMM (N-methylmorpholine) were
added to promote cyclization between the acid group of the
diaminodiacid and the terminal amino group of the growing
peptide chain.18 Finally, the cleavage cocktail reagent,
TFA/phenol/water/Tips (88:5:5:2 v/v/v/v) were subsequently
added to react for 3 hours, and then the final product crude
oxytocin analogue 11 was obtained by precipitation (Scheme 4).
The crude peptide 11 was analyzed by reverse-phase high
performance liquid chromatography (HPLC) and mass
spectrometry (MS). The results in Figure 1 indicate relative high
purity and correct Molecular Weight (MW) of the product (Fig.
1a-b). We can obtain the purified oxytocin analogue 11 in a good
yield after routine HPLC purification (Fig. 1a, overall yield = 20
%). In order to confirm the secondary structure of oxytocin
analogue, we tested analogue 11 by circular dichroism
spectrometer (CD). The CD spectrum showed a negative peak at
196 nm and a positive band at 220-230 nm (Fig. 1c). These
observations were consistent with the structure of the reported
native oxytocin, indicating correct folding of the synthetic
analogue.8d
Scheme 4. Synthetic route for oxytocin analogue 11 on solid support
using diaminodiacid 7
With hydrocarbon-bridged diaminodiacid 7 in hands, we next
focused on determining the feasibility and efficiency of the
diaminodiacid for the chemical synthesis of peptide containing
disulfide bond mimic. The hypothalamic neuropeptide oxytocin
was chosen as the synthetic target for this purpose. Oxytocin
contains 9 amino acid residues and has a pair of intramolecular
disulfide bond between the cysteine residues at positions 1 and 6.
14 It is a multifunctional peptide hormone and the in vivo receptor
of oxytocin belongs to the G protein-coupled receptor family.
Recently, oxytocin was found to play a crucial role in milk-
ejection reflex and uterine contractility.15 Some studies revealed
that oxytocin receptor is important for many reproductive and
social behaviors.16 Nonetheless, most of oxytocin used in
previous studies is in its natural form; thus we consider that it
remain necessary to explore whether the use of disulfide bonds
mimic analogues of oxytocin would have different effects. To
this end, we have successfully synthesized oxytocin analogue by
using the thioether-bridged diaminodiacids previously, whereas
Fig 1. a) HPLC traces of crude and purified oxytocin analogue; b)
ESI-QTOF-MS spectrum of oxytocin analogue 11, Calcd: 970.6,
Found: 971.6. c) CD spectra of oxytocin analogue in water.
3. Conclusions
In summary, we have developed a facile and efficient method

4
Tetrahedron Letters
for the preparation of hydrocarbon-bridged diaminodiacid.
Shigenaga, A.; Otaka, A. Tetrahedron 2015, 71, 4183. c) Zhou, P.; Liu,
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Taking advantage of nickel-catalyzed reductive cross-coupling
reaction, the hydrocarbon bridge could be synthesized smoothly
with a 48% yield on gram scale, which presents advantages on
the synthetic efficiency and operation simplicity over previous
electrolysis method. By using our recently developed
Dmab/ivDde protecting group system, we obtained a new
hydrocarbon-bridged diaminodiacid with metal-free deprotection
conditions. Subsequently, we also demonstrated that the oxytocin
disulfide bond mimic 11 containing a hydrocarbon bridge can be
obtained in good efficiency via the diaminodiacid-based strategy.
We envisage that the Dmab/ivDde-protected hydrocarbon-
bridged diaminodiacid would serve as a valuable complement to
the growing arsenal of diamonodiacids, which provide a flexible
approach for generating peptide disulfide bond mimics with
structural diversity.
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5
Highlights
1. Hydrocarbon-bridged diaminodiacids have been
developed via nickel catalyzed reductive cross-
coupling reaction.
2. New diaminodiacids was protected by Dmab/ivDde
protecting group.
3. a hydrocarbon-bond-containing analogue of oxytocin
was synthesized.
4. newly-developed nickel catalyzed reductive cross-
coupling reaction