Facile access to α,β-dehydroalanine and α,β-dehydroamino butyric acid derivatives from DL-serines and threonines

Article abstract of DOI:10.1080/00397911.2016.1149194

ABSTRACT: Not only α,β-dehydroamino acids are important constituents for a number of bioactive peptides in nature, but also they are important building blocks for a variety of synthetic amino acids in organic synthesis. Methods to prepare dehydroamino aci

Full text of DOI:10.1080/00397911.2016.1149194

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Facile access to α,β-dehydroalanine and α,β-
dehydroamino butyric acid derivatives from DL-
serines and threonines
Yong-Qing Yang, Meng-Chen Ji, Zheng Lu, Mao Jiang, Wei-Wei Huang & Xue-
Zhi He
To cite this article: Yong-Qing Yang, Meng-Chen Ji, Zheng Lu, Mao Jiang, Wei-Wei Huang
& Xue-Zhi He (2016): Facile access to α,β-dehydroalanine and α,β-dehydroamino butyric
acid derivatives from DL-serines and threonines, Synthetic Communications, DOI:
10.1080/00397911.2016.1149194
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1149194
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Date: 17 June 2016, At: 23:41

SYNTHETIC COMMUNICATIONS®
http://dx.doi.org/10.1080/00397911.2016.1149194
Facile access to α,β-dehydroalanine and α,β-dehydroamino
butyric acid derivatives from DL-serines and threonines
Yong-Qing Yang, Meng-Chen Ji, Zheng Lu, Mao Jiang, Wei-Wei Huang, and Xue-Zhi He
School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu, China
ABSTRACT
ARTICLE HISTORY
Received 12 January 2016
Not only α,β-dehydroamino acids are important constituents for a
number of bioactive peptides in nature, but also they are important
building blocks for a variety of synthetic amino acids in organic
synthesis. Methods to prepare dehydroamino acids have been
reported extensively in the literature; however, efficient and
convenient protocols are still required. Here we have developed a
convenient method to prepare dehydroalanine (ΔAla) and dehydro-
amino butyric acid (ΔAbu) derivatives derived from DL-serines and
DL-threonines, respectively. 4-Toluenesulfonyl chloride (TsCl) and
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were employed in this
procedure, which carried out activation of hydroxyl group and
β-elimination in one pot. Because it is convenient and easy to handle,
this method will attract the attention of synthetic chemists.
KEYWORDS
Dehydroamino acids; one
pot; serine; threonine
GRAPHICAL ABSTRACT
Introduction
α,β-Dehydroamino acids (ΔAAs) are important components of many bioactive peptides[1]
and are very useful precursors for synthetic amino acids[2] in organic chemistry. Their
preparation procedures are common in the literature.[3] One main type of ΔAAs is
α,β-dehydroalanine (ΔAla), which is derived from serine and cystein biosynthetically, via
activation of β-hydroxyl or thiol group and posterior β-elimination. There are mainly
two approaches to prepare ΔAAs from β-hydroxyl-amino acid derivatives. One is a
two-step procedure, which is mild and high yielding. Under mild conditions, the hydroxyl
group was converted to a leaving group, and then β-elimination occurred under basic
conditions.[3c,3d,3j,3l,3o,3q] Chandrasekaran and coworkers have reported that O-Cbz serine
derivatives could be converted to ΔAla in the presence of K2CO3 or tetrabutylammonium
fluoride (TBAF) in good yield.[3n,3o] However, the protection of hydroxyl group has to be
CONTACT Zheng Lu
lz@ujs.edu.cn
School of Pharmacy, Jiangsu University, No. 301 Xuefu Road, Zhenjiang,
212013 China.
Supplemental data (Full experimental detail, IR, 1H NMR, and EI-MS data) can be accessed on publisher’s website
© 2016 Taylor & Francis

2
Y.-Q. YANG ET AL.
carried out at À 50 °C for several hours.[3o] The other one is a one-pot procedure, and
reagents such as PhNTf2/Et3N,[3f] Boc2O/dimethylaminopyridine (DMAP),[3i,3p]
,
ClCOCHCl2/Et3N[3g] and SOCl2/1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)[3j] were
employed. Depending on the configuration of β-hydroxyamino esters (2o or 3o OH),
Wandless and coworkers have reported that SOCl2/DBU can selectively transform them
to E or Z isomers via cyclic sulfamidites in good to excellent yield.[3j] However, the harsh
reaction conditions limit its application, because the solvent, dichloromethane (DCM),
has to be distilled beforehand and the reaction temperature has to be kept low, initially
at À 78 °C and then raised to 0 °C. In terms of cost, convenience, and efficiency, new
methods to prepare ΔAAs are still required. Here we describe a mild way to prepare dehy-
droalanine derivatives, starting from DL-serines in one pot. It is efficient and easy, and its
application has been expanded to preparation of dehydroamino butyric acid (ΔAbu)
derivatives with high regioselectivity.
Results and discussion
Our story starts from preparation of methyl 2-((tert-butoxycarbonyl)amino) -3-(tosyloxy)
propanoate (1) (Fig. 1). It could be prepared from DL-serine under low temperature with
pyridine[4] or a combination of triethylamine and trimethylamine hydrochlorate[5] as the
base. This shows that sulfonylation of β-OH of serine is a subtle way.
For N-Boc-DL-serine-O-Me (2), we have employed TsCl as tosylating agent and triethy-
lamine (Et3N) as base at r.t., and the reaction ends up as a complex mixture. To our
surprise, the major product was not 1 but N-Boc-dehydroalanine (ΔAla)-O-Me (3). This
means that the major side reaction is β-elimination. This one-pot transformation to
dehydroamino acid from amino acid derivatives aroused our interest. Experiments have
been carried out to find out the optimal condition to obtain 3 from 2 (Table 1).
We started the investigation with DCM as the solvent. We found that with 1 equivalent
of TsCl and triethylamine, in the presence of 10% DMAP, a small amount of dehydroa-
mino acid was formed after 24 h with most of the substrate intact. Increasing the tosylating
agent, the base, and the catalyst resulted in marked raise of the yield (entries 1–5). The
highest yield in DCM is 80%, with 2 equivalents of TsCl, 5 equivalents of TEA, and 20%
of DMAP. The effect of solvents was studied too. Among the commonly used solvents
we tested, acetonitrile is the best (entries 5–10). Then we made an effort to study different
organic bases. Tributylamine (pKa (H2O) 10.89[6]) shared not only the structure but also
the yield with triethylamine (pKa (H2O)10.65,[6] pKa (CH3CN) 18.82[7]). When pyridine
was used, only 5% of product was isolated; we attributed this to its low basicity (pKa
(CH3CN) 12.53[7] vs. 17.95[7] of DMAP). The strongest base we tested was DBU (pKa
(CH3CN) 24.34[7]), and it gave the best result: the highest yield accompanied by reduced
reaction time. As this reaction is a dehydration reaction, we thought that water could retard
Figure 1. Methyl 2-((tert-butoxycarbonyl)amino)-3-(tosyloxy)propanoate (1).

SYNTHETIC COMMUNICATIONS®
3
Table 1. Optimization of conditions for preparation of N-Boc-ΔAla-O-Me (3) from N-Boc-DL-
Ser-O-Me (2).
Entrya
TsCl (eq.)
DMAP (eq.)
Base (eq.)
Solvent
Time (h)
Yieldb (%)
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
2
2
0.1
0.1
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
Et3N (1)
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (5)
Et3N (5)
Et3N (5)
Et3N (5)
Et3N (5)
Et3N (5)
Et3N (5)
Bu3N (5)
NMM (5)
DIPEA (5)
Py (5)
DCM
DCM
DCM
DCM
DCM
THF
24
24
24
24
4
3
2
10
41
45
80
53
66
85
0
3
4
5
6
4
7
DMF
ACN
4
8
4
9
DMSO
Toluene
DCE
4
10
11
12
13
14
15
16
17
4
59
80
80
42
84
5
4
ACN
4
ACN
10
10
10
1
ACN
ACN
DBU (5)
DBU (5)
ACN
85
94
ACNc
1
aReaction temperature is 25 °C.
bIsolated yield.
cMS (4 Å) was added.
the desired reaction. A molecular sieve was added to eliminate trace amount of water in the
reaction mixture, and finally we were gratified to see the yield come up to 94%.
With this optimal condition in hand, we set out to explore its application scope
(Table 2). First, protection groups on amino and carboxylic acid affect the yield of the reac-
tion (entries 3, 4, 5, and 6). Second, reaction of DL-threonines is more sluggish and has
poorer yield compared to reaction of DL-serines (entries 3 versus 7, 6 versus 8), impeded
by the steric hindrance upon SN2 reaction in stage 1. Third, dehydration of both
N-Boc-DL-Thr-O-Me and N-Boc-DL-Thr-O-Me gives all Z-isomers, which means that
the β-elimination is highly regioselective (1H NMR data of entries 7 and 8 are identical
to reported data[3o]).
To expand the scope of this reaction, the application to preparing dehydropeptide has
been studied (Scheme 1). Under this condition, (�)-N-Boc-Phe-ΔAla-O-Me (9) could
be obtained from N-Boc-L-Phe-L-Ser-O-Me (11) in excellent yield (88%). However, the
chiral center of neighboring amino acid (phenylalanine) became racemized. For
N-Boc-L-Phe-L-Thr-OMe (12), (�)-N-Boc-Phe-ΔAbu-OMe was obtained in 45%. It is
likely that chiral center in the peptide is susceptible to basic conditions; with excessive base
in the reaction system, the racemization occurred inevitably.
In summary, a convenient method to prepare α,β-dehydroalanine (or α,β-dehydroamino
butyric acid) derivatives in one pot has been developed. All the reagents are easily
accessible, and the procedure is easy to handle. Starting from DL-serine or threonine
derivatives, the reaction could be completed in 1 h, with yields up to 94%. OH (1o) on
DL-serine derivatives was eliminated faster than OH (2o) on DL-threonine derivatives.
In the meanwhile, elimination on threonine derivatives gives only the Z-isomers.

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Y.-Q. YANG ET AL.
Table 2. Exploration of scope of dehydration.
aConditions: TsCl (2.0 eq), DMAP (0.2 eq), and MS (4 Å, 40 mg/mmol) were added to starting material in acetonitrile (0.2 M) at
rt, followed by slow addition of DBU (5.0 eq).
bIsolated yield.
Application to dehydrodipeptide has also been carried out, with moderate to excellent yield
but with racemization, so the method can only be employed to prepare racemic
dehydropeptide.
Experimental
All reagents were purchased from commercial sources and were used without further
treatment. 1H (400 MHz) and 13C NMR (100 MHz) were recorded on a Bruker 400
spectrometer. Infrared (IR) spectra were recorded on a JASCO FTIR spectrophotometer.
Electron ionization–mass spectrometry (EI-MS) was acquired on an Agilent Technologies
5973 N instrument.
General procedure for preparation of dehydroamino acid (or dehydrodipeptide)
4-Toluenesulfonic chloride (TsCl) (2.0 eq) and 4-dimethylamino pyridine (DMAP) (0.2 eq)
were added sequentially to the solution of N-Boc-DL-Ser-OMe (1.0 eq) in acetonitrile (0.2 M,
containing MS (Molecular Sieve) (4 Å), 40 mg/mmol) at r.t., and 1,8-diazobicyclo[5.4.0]
Scheme 1. Preparation of dehydrodipeptide from dipeptide.

SYNTHETIC COMMUNICATIONS®
5
undec-7-ene (DBU) (5.0 eq) was added dropwisely to the solution, whose color darkened
during the addition. The reaction was monitored by thin-layer chromatography (TLC).
When starting material was consumed, the MS was filtered off and the solution was diluted
with ethyl acetate and washed with saturated citric acid, water, and then brine. The organic
phase was dried over anhydrous sodium sulfate. The crude product was obtained after
concentration under reduced pressure, which was purified through flash chromatography.
Compound 3[3o]
1
N-Boc-ΔAla-O-Me, yield 94%, colorless oil. H NMR (400 MHz, CDCl3) δ 7.01 (br s, 1H),
6.16 (s, 1H), 5.73 (d, J ¼ 1.6 Hz, 1H), 3.83 (s, 3H), 1.48 (s, 9H). FT-IR (film) vmax 3421,
2957, 2921, 1719, 1511, 1327, 1159 cmÀ 1. EI-MS m/z (%) 201 (Mþ, 3.31), 57 (100), 41
(25.5), 59 (21.5), 145 (13.5), 101 (12.3), 43 (11.3), 55 (11), 56 (10.4).
Funding
The research is supported by Jiangsu University (No. 14JDG018, 10JDG042) and the Priority
Academic Program Development of Jiangsu Higher Education Institutions.
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