Stereoselective Synthesis of (E)-α,β-dehydroamino acid esters

Article abstract of DOI:10.1002/ejoc.201300112

Dehydroamino acid (Dhaa) is recognized as a useful tool or substrate for amino acid and peptide research. Although the stereoselective synthesis of the thermodynamically more stable Z-Dhaa has been well examined and established, the stereoselective synthesis of E-Dhaa has still remained to be a challenging synthetic task. In this paper, a stereoselective synthesis of E-Dhaa esters using a new (α-diphenylphosphono)glycine is described. The characteristic aspects of the new method are summarized as follows: (i) metal additives play an important role in the promotion of E-stereoselectivities. (ii) the use of NaI was effected for the synthesis of E-Dhaas bearing an aryl substituent and an amino functionality, (iii) MgBr₂·OEt₂ and ZnCl ₂ contributed to improve the E-stereoselective synthesis of E-Dhaas bearing an alkyl substituent and an oxygen functionality, (iv) various protecting and functional groups were compatible under the reaction conditions, and (v) N-Cbz, Boc, and acyl-α-(diphenylphosphono)glycines were served for the stereoselective olefination reaction to provide the corresponding E-Dhaas. A variety of (E)-dehydroamino acid esters were stereoselectively synthesized by using (diphenylphosphono)glycinate. The stereoselectivity was influenced by metal additives. Various (E)-dehydroamino acid esters were prepared by the condensation reaction of the new phosphonates with easily available aldehydes by choosing the appropriate reaction conditions.

Full text of DOI:10.1002/ejoc.201300112

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300112
Stereoselective Synthesis of (E)-α,β-Dehydroamino Acid Esters
Yoko Yasuno,[a] Makoto Hamada,[a] Takeshi Yamada,[a] Tetsuro Shinada,*[a] and
Yasufumi Ohfune*[a]
Keywords: Amino acids / Olefination / Aldehydes / Metal additive effects
Dehydroamino acid (Dhaa) is recognized as a useful tool or
substrate for amino acid and peptide research. Although the
stereoselective synthesis of the thermodynamically more
stable Z-Dhaa has been well examined and established, the
stereoselective synthesis of E-Dhaa has still remained to be
a challenging synthetic task. In this paper, a stereoselective
ties. (ii) the use of NaI was effected for the synthesis of E-
Dhaas bearing an aryl substituent and an amino function-
ality, (iii) MgBr2·OEt2 and ZnCl2 contributed to improve the
E-stereoselective synthesis of E-Dhaas bearing an alkyl sub-
stituent and an oxygen functionality, (iv) various protecting
and functional groups were compatible under the reaction
synthesis of E-Dhaa esters using a new (α-diphenylphos- conditions, and (v) N-Cbz, Boc, and acyl-α-(diphenylphos-
phono)glycine is described. The characteristic aspects of the
new method are summarized as follows: (i) metal additives
play an important role in the promotion of E-stereoselectivi-
phono)glycines were served for the stereoselective ole-
fination reaction to provide the corresponding E-Dhaas.
Introduction
α,β-Dehydro amino acids (Dhaas) are often recognized
as constituents of biologically active natural peptides[1] and
are widely used as starting materials for the synthesis of
natural and non-natural α-amino acids by catalytic asym-
metric hydrogenation reactions[2,3] and C–C bond-forming
reactions involving 1,4-addition reactions, cyclopropan-
ation reactions, [3+2] cycloaddition reactions, and the
Diels–Alder reaction.[1–4] It has been reported that the in-
troduction of Dhaas into peptides contributes to an en-
hancement in biological activity and chemical stability
towards enzymes such as peptidases.[5]
Dhaas are conformationally restricted non-proteinogenic
amino acid analogues in which the sp3 carbon atoms at the
α- and β-positions of the α-amino acids are replaced with
sp2 carbon atoms. Two geometrical isomers, (E)-1 and (Z)-
2, are available when a substituent is present at the β-posi-
tion of α,β-dehydroalanine (Figure 1). The presence of these
stereoisomers offers opportunities for comparative bio-
logical and chemical studies by using these stereoisomers
in the research of amino acids and peptides. However, the
potency has not fully tested because of the lack of practi-
cally useful synthetic methods for (E)-1.
Figure 1. Stereoselective synthesis of (E)- and (Z)-Dhaa esters 1
and 2 by using 3 and 4.
Much synthetic effort has been devoted to the synthesis
of Dhaas as a result of their potential utilities. The Erlen-
meyer reaction[5] and the Schmidt method, both of which
involve the use of (dialkylphosphono)glycinate,[1g,6] are
known to be representative methods to access various
Dhaas. However, these established methods provide ther-
modynamically more stable (Z)-2 as the major stereoiso-
mer. In contrast, example of the stereoselective synthesis of
(E)-1 are relatively limited. Previously, the syntheses of (E)-
1 have been achieved by stereospecific β-elimination reac-
tions of β-hydroxy-, thio-, and seleno-α-amino acid deriva-
tives and by cross-coupling reactions involving β-halo
Dhaas.[1,7] These methods require one of the stereoisomers
of the synthetic precursors that are usually prepared in a
[a] Graduate School of Science Osaka City University,
3-3-138 Sugimoto, Sumiyoshi, Osaka 558-8585, Japan
Fax: +81-6-6605-3153
E-mail: shinada@sci.osaka-cu.ac.jp
ohfune@sci.osaka-cu.ac.jp
Homepage: http://www.sci.osaka-cu.ac.jp/chem/henkan/
index_e.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300112.
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Stereoselective Synthesis of (E)-α,β-Dehydroamino Acid Esters
multistep sequence. In this context, the straightforward and suppressed under the DBU/NaI conditions, the E/Z ratio
efficient synthesis of a variety of (E)-1 still remains an im- was moderate (E/Z = 50:50; Table 1, entry 10). Similarly,
portant synthetic subject in this research field.
the olefination reaction of acetoaldehyde (6i) gave a 1:1
Ando et al. developed an efficient Horner–Wadsworth– mixture of (E)-1i/(Z)-2i (Table 1, entry 11). Aldehydes 6j
Emmons (HWE) reagent [(PhO)2P(=O)CH2CO2R, R = and 6k bearing oxygen functionalities at the adjacent posi-
alkyl] for the stereoselective synthesis of (Z)-α,β-unsatu- tion underwent smooth olefination to give (E)-1j and (E)-
rated esters.[8] Inspired by the elegant synthetic results, we 1k, respectively, in high yield. However, these selectivities
became intrigued by the idea of using (diphenylphos- were moderate to good (up to 81:19; Table 1, entries 12 and
phono)glycinate (3), in which the –P(=O)(OMe)2 moiety of 13). To improve the moderate E selectivities, we re-exam-
Schmidt reagent 4[1a] is replaced with a –P(=O)(OPh)2 ined the reaction conditions by using 6g as a model sub-
group. It was anticipated that preferential Z selectivity strate (Table 2). After extensive experimentation, we found
could be promoted by the introduction of Ando’s reagent. that the E stereoselectivity was dramatically influenced by
Along this line, we prepared 3 for the first time and ex- metal additives. Among them, the use of DBU/
plored its synthetic utility in the total synthesis of a struc- MgBr2·OEt2/THF resulted in a significant improvement in
turally complex unnatural amino acid natural product, kai- the E stereoselectivity [(E)-1g/(Z)-2g = 87:13; Table 2, en-
tocephalin.[9] New reagent 3 allowed the stereoselective for- try 5]. In sharp contrast, (Z)-2g was formed without any
mation of the (E)-Dhaa (E/Z = Ͼ95:5) from the highly metal additive [(E)-1g/(Z)-2g = 4:96; Table 2, entry 1). The
functionalized aldehyde having the right half moiety of kai- use of KI or LiCl in the olefination reaction gave (Z)-2g as
tocephalin. We believed that the use of 3 could be extended the major product (Table 2, entries 3 and 4). Although the
to the synthesis of a variety of Dhaa esters of type (E)-1 use of ZnCl2 contributed to improve the E selectivity (80:20;
as a result of its synthetic advantages, including its high E Table 2, entry 6), the product yield and E selectivity were
selectivity, its simplistic utilization, and its compatibility not reproducible in this model substrate.
with several functional groups. In this communication, we
describe the potential utility of 3, which holds promise for
the synthesis of a variety of Dhaa esters of type (E)-1, as
well as intriguing metal additive effects that play a key role
in the promotion of the E stereoselectivity.
Table 1. Stereoselective synthesis of (E)-Dhaa esters 1a–j by using
5.
Results and Discussion
We reported that benzaldehyde (6a) underwent the (E)-
stereoselective Dhaa synthesis with 5[9] under Ando’s ole-
fination conditions [NaH/NaI[10] or 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU)/NaI;[8c] Table 1, entry 1]. We initially
examined the scope of the reaction conditions by using al-
dehydes 6a–k. Aromatic aldehydes 6b and 6c bearing a m-
nitro and p-methoxy group, respectively, as well as 2-pyr-
idinecarbaldehyde (6d) were converted into (E)-1b, (E)-1c,
and (E)-1d, respectively, in
a stereoselective manner
(Table 1, entries 2–4).[11] N-Boc-prolinal (6e) was trans-
formed in to (E)-1e with high E selectivity in 82% yield
(Table 1, entry 5). Aldehyde 6f derived from serine gave (E)-
1f in low yield (29%; Table 1, entry 6). Instead, lactam 7
was obtained as the major product in 66% yield. These re-
sults indicate that an intramolecular cyclization between the
ester and the carbamate groups, which are in close proxim-
ity, occurred after the E selective olefination. To circumvent
the competitive cyclization reaction, milder reaction condi-
tions (DBU/NaI) were attempted. Under these conditions,
(E)-1f was selectively obtained in 74% (E/Z = 92:8; Table 1,
entry 7). In contrast to the results described above, aliphatic
aldehydes 6g–i resulted in poor to moderate E selectivities
(up to 72:28; Table 1, entries 8–11). 3-Phenylpropanal (6g)
gave a 72:28 mixture of (E)-1g/(Z)-2g in 93% yield (Table 1,
entry 8). Olefination of 6h gave a 69:31 mixture of (E)-1h/
(Z)-2h (15%), in addition to acetal 8 (26%; Table 1, en-
Entry
Substrate
Conditions
Yield [%]
(E)-1/(Z)-2[d]
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
NaH, NaI
NaH, NaI
NaH, NaI
NaH, NaI
NaH, NaI
NaH, NaI
DBU, NaI
NaH, NaI
NaH, NaI
DBU, NaI
NaH, NaI
NaH, NaI
NaH, NaI
93
100
70
97:3
97:3
96:4
90:10
92:8
92:8
75
82
29[a]
74[b]
93
6f
92:8
6g
6h
6h
6i
72:28
69:31
50:50
52:48
67:33
81:19
9
15[c]
77
10
11
12
13
100
81
82
6j
6k
[a] Byproduct 7 formed in 66% yield. [b] Byproduct 7 formed in
21% yield. [c] Byproduct 8 formed in 26% yield. [d] Determined by
try 9). Although the formation of undesired acetal 8 was 1H NMR spectroscopy (300 MHz, CDCl3 or C6D6).[11]
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Y. Yasuno, M. Hamada, T. Yamada, T. Shinada, Y. Ohfune
SHORT COMMUNICATION
Table 2. Additive effects for the olefination of 6g.
hyde (6a) and prolinal (6e) smoothly underwent the ole-
fination reaction under the DBU/MgBr2·OEt2 conditions.
However, these E selectivities were moderate in comparison
to those of the NaH/NaI conditions [1a: DBU/
MgBr2·OEt2, 74:26 vs. NaH/NaI, 97:3; 1e: DBU/
MgBr2·OEt2, 58:42 vs. NaH/NaI, 92:8]. (4) Functional
groups such as acetonide, Boc, and unsaturated ester are
compatible under the reaction conditions. These results,
coupled with our previous observations in the total synthe-
sis of kaitocephalin by using 5, proved the potential func-
tional group compatibility of this reaction.
We next turned our attention to N-acetyl 11 and N-Boc
13 for direct access to (E)-N-Boc and N-acyl Dhaas
(Scheme 2). We thought that 11 and 13 could be prepared
in a manner similar to the conversion of N-Cbz Schmidt
reagent 4 to the corresponding Boc or N-acyl reagents.[6a]
However, removal of the Cbz group of 5 gave a complex
mixture in the absence or presence of an acylating reagent.
The unexpected decomposition may have arisen from the
elimination of –P(=O)(OPh)2 from 9 as a result of the elec-
tronically more stable nature of –P(=O)(OPh)2 than
–P(=O)(OMe)2.
Entry Additive
Temp.
[°C]
Yield
[%]
(E)-1g/(Z)-2g[a]
1
2
3
4
5
6
none
NaI
KI
LiCl
MgBr2·OEt2
ZnCl2
(2.0 equiv.)
r.t.
–78 to 0
–78
–78
r.t.
97
93
84
59
4:96
72:28
Ͻ5:Ͼ95
16:84
87:13
99
r.t.
27–62[b]
66:34 to
80:20[b]
1
[a] Determined by H NMR spectroscopy. [b] Not reproducible.
The MgBr2·OEt2/DBU and ZnCl2/DBU conditions were
successfully applied to aliphatic aldehydes 6h–k (Scheme 1).
These results are summarized as follows: (1) The moderate
to low E selectivity for 1h–k in Table 1 was improved under
the MgBr2·OEt2/DBU conditions. (2) The DBU/ZnCl2 con-
ditions are more effective than the DBU/MgBr2·OEt2 con-
ditions for the syntheses of (E)-1j and (E)-1k [(E)-1j/ZnCl2,
90:10 (92%) vs. MgBr2·OEt2, 73:27 (97%); (E)-1k/ZnCl2,
88:12 (93%) vs. MgBr2·OEt2, 89:11 (37%)]. (3) Benzalde-
Scheme 2. Hydrogenation of 5 without HCl.
To circumvent the above obstacle, we attempted to trap
the resulting free amine as an ammonium salt in situ to sup-
press the undesired elimination reaction (Scheme 3). As ex-
pected, the hydrogenation reaction of 5 in the presence of
HCl gave stable HCl salt 10. Although treatment of 10 with
Et3N gave a complex mixture, we found reaction conditions
enabling the synthesis of N-acetyl derivative 11. Treatment
of 10 with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
(EDCI) in the presence of 4-(dimethylamino)pyridine
(DMAP, 0.5 equiv.) furnished N-acetyl derivative 11 (60%
from 5).[12] In contrast, the installation of the Boc group
to 5 under the same reaction conditions was unsuccessful.
Alternatively, we developed a new method by the initial in-
troduction of the Boc group to 5 by using Boc2O in the
Scheme 1. Stereoselective synthesis of (E)-1.
Scheme 3. Synthesis of N-Ac 11 and N-Boc 13.
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Stereoselective Synthesis of (E)-α,β-Dehydroamino Acid Esters
presence of DMAP (76%) followed by the removal of the
Cbz group under the hydrogenation conditions to give 13
in 97% yield.
The olefination reaction of benzaldehyde (6a) with N-
Boc 13 under the NaH/NaI conditions gave (E)-14 in a
highly stereoselective manner (Scheme 4). The reaction with
6g in the presence of MgBr2·OEt2 afforded (E)-16 as the
major stereoisomer (89:11). Switching to N-Ac derivatives
11 provided (E)-15 and 17 in good yields. However, these
selectivities were lower than those of N-Cbz 5 and N-Boc
13. These results indicate that the carbamate moiety is
superior to the acyl group in promoting E selectivity.
Scheme 4. HWE olefination with N-Ac 11 and N-Boc 13.
To gain some insight into the reaction mechanism, ole-
fination of 6g with HWE reagents 18, 19, and 20 was at-
tempted in the absence and in the presence of MgBr2·OEt2
(Scheme 5). In the absence of MgBr2·OEt2, 6g was treated
with Schmidt reagent 18 to give (Z)-2g in a highly stereose-
lective manner [E/Z = 4:96; Scheme 5, Eq. (1)]. Although
the selectivity was moderate, treatment of 6g with 18 under
the DBU/MgBr2·OEt2 conditions gave a 45:55 mixture of
(E)-1g/(Z)-2g. These results corroborate the promoting ef-
fects of MgBr2·OEt2 in the olefination reaction of not only
new phosphonate 5 but also Schmidt reagent 18. Ando re-
ported that the reaction of 19 and n-C7H15CHO with DBU/
NaI preferentially produced (Z)-olefin 21 [E/Z = 8:92;
Scheme 5. Olefination reaction under the MgBr2·OEt2/DBU condi-
tions.
chain can be converted into the desired products under
MgBr2·OEt2/DBU conditions. ZnCl2/DBU efficiently pro-
motes the olefination of the aldehydes bearing an oxygen
functionality. Although the full mechanistic details of the
present HWE olefination remain unclear, synergistic effects
of –NHP, –P(=O)(OPh)2, and the metal additive play an
important role in the E-stereoselective olefination. The use
of 5, 11, and related acylating reagents permits access to a
wide variety of (E)-1 and offers the opportunity for bio-
logical and chemical studies that have, up to this point, re-
mained unexplored in the realm of amino acids and pept-
ides.
Scheme 5,
Eq. (2)].[8c]
Interestingly,
switching
to
MgBr2·OEt2 provided (E)-22 as the major isomer [E/Z =
86:14; Scheme 5, Eq. (3)]. Olefination with 20[8f] in which
the –NHCbz group of 5 is substituted with a methyl group
resulted in the predominant formation of (E)-22 [E/Z =
81:19; Scheme 5, Eq. (4)]. These results suggest that syner-
gistic effects of the N-Ac, N-Boc, or N-Cbz group, Experimental Section
MgBr2·OEt2 or NaI, or –P(=O)(OPh)2 play an important
role in the stereoselective formation of (E)-1 by using new
phosphonates 5, 11, and 13.
Typical Procedure for the Preparation of (E)-1 under DBU/
MgBr2·OEt2 Conditions: To a solution of 5 (100 mg, 0.2 mmol) and
MgBr2·OEt2 (52 mg, 0.2 mmol) in THF (2 mL) was added DBU
(30 μL, 0.2 mmol) at 0 °C under an atmosphere of argon. The mix-
ture was stirred for 30 min at 0 °C. Aldehyde 6 (0.2 mmol) in THF
(2 mL) was added to the mixture. The mixture was stirred for 17 h
at room temperature, and then quenched with satd. NH4Cl (5 mL)
and extracted with EtOAc (3ϫ 15 mL). The combined organic lay-
ers were washed with brine, dried with MgSO4, and filtered. The
filtrate was concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel to afford
Conclusions
In summary, we have established a stereoselective syn-
thetic method to access a wide variety of Dhaa esters of
type (E)-1 by olefination of phosphonates 5, 11, and 13 with
commercially available and easily prepared aldehydes by
choosing three reaction conditions that are currently used (E)-1.
as standard protocols. The NaH/NaI and DBU/NaI sys-
tems are effective for aromatic aldehydes and aldehydes de-
Supporting Information (see footnote on the first page of this arti-
cle): General procedures, experimental data, and 1H NMR and 13
C
rived from amino acids. Aldehydes bearing an alkyl side NMR spectral data.
Eur. J. Org. Chem. 2013, 1884–1888
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Y. Yasuno, M. Hamada, T. Yamada, T. Shinada, Y. Ohfune
SHORT COMMUNICATION
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Acknowledgments
This work was financially supported by the Yamada Science Foun-
dation (Scientific Research of Innovative Areas, Chemical Biology
of Natural Products), the Ministry of Education, Culture, Sports,
Science and Technology (MEXT) (grant number 23102009) and
supported in part by the Japan Society for the Promotion of Sci-
ence (KAKENHI) (grant number 23228001).
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Received: January 21, 2013
Published Online: February 25, 2013
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Eur. J. Org. Chem. 2013, 1884–1888