Synthesis and Characterization of Some α,β-Didehydroamino Acid Derivatives

Article abstract of DOI:10.1081/SCC-120027714

A mild Horner-Wadsworth-Emmons reaction is described. Treatment 4-substituted cyclohexanones with trimethyl 1-(N-benzyloxycarbonyl) phosphonoacetate afforded the corresponding α,β-didehydroamino acid derivatives.

Full text of DOI:10.1081/SCC-120027714

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Synthesis and Characterization of Some
α,β‐Didehydroamino Acid Derivatives
Guifa Su a b , Chengxue Pan b , Hengshan Wang b & Longmei Zeng a
a College of Chemistry & Chemical Engineering , Zhongshan University , Canton, P.R.
China
b College of Chemistry & Chemical Engineering , Guangxi Normal University , 15 Yucai
Rd., Guilin, 541004, P.R. China
Published online: 16 Aug 2006.
To cite this article: Guifa Su , Chengxue Pan , Hengshan Wang & Longmei Zeng (2004) Synthesis and Characterization of
Some α,β‐Didehydroamino Acid Derivatives, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 34:4, 665-671, DOI: 10.1081/SCC-120027714
To link to this article: http://dx.doi.org/10.1081/SCC-120027714
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 4, pp. 665–671, 2004
Synthesis and Characterization of Some
a,b-Didehydroamino Acid Derivatives
2
2
Guifa Su,1,2, Chengxue Pan, Hengshan Wang,
*
and Longmei Zeng1
1College of Chemistry & Chemical Engineering, Zhongshan University,
Canton, P.R. China
2College of Chemistry & Chemical Engineering, Guangxi Normal
University, Guilin, P.R. China
ABSTRACT
A mild Horner–Wadsworth–Emmons reaction is described. Treatment
4-substituted cyclohexanones with trimethyl 1-(N-benzyloxycarbonyl)
phosphonoacetate afforded the corresponding a,b-didehydroamino acid
derivatives.
Key Words: HWE olefination; Substituted cyclohexanones; Trimethyl
1-(N-benzyloxycarbonyl)phosphonoacetate; DBU; a,b-Didehydroamino
acid.
*
Correspondence: Guifa Su, College of Chemistry & Chemical Engineering, Guangxi
Normal University, 15 Yucai Rd., Guilin 541004, P.R. China; Fax: 86-773-5833630;
E-mail: su_gf@sina.com.
665
DOI: 10.1081/SCC-120027714
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Su et al.
The introduction of an a,b-didehydroamino acid (DDAA) residue into a
peptide sequence causes a significant limitation of possible side chain
orientations and strongly induces folded conformations. a,b-Didehydroamino
acid have been used as structural modifications in the design of model peptides
with well-defined structures.[1–6]
A straightforward synthesis of DDAA derivatives is the Horner–
Wadsworth–Emmons olefination of aldehydes with N-acyl-2-dialkoxyphos-
phorylglycine esters in aprotic solvents and in the presence of strong bases.
The typical method is condensation in CH2Cl2 at 2708C with addition of
potassium tert-butoxide, but ketones do not react.[7,8]
From 1984, some researchers used tertiary amine bases such as diisopro-
pylethylamine (DIPEA),[9] 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),[9,10]
tetramethylguanidine (TMG),[10] and triethylamine,[11] to generate the
phosphinate carbanion, which then was treated with carbonyl compounds,
typically aldehydes (1 : 1 ratio methyl ketones were unreactive under these
conditions[11]). The mild reaction conditions permit the substrates that race-
mize easily or are base-sensitive to remain unaffected. Schmidt and coworkers
used excess ketone as solvent, DBU as base and realized the condensation of
2-butanone, cyclohexanone and acetone with trimethyl 1-(N-alkoxycar-
bonyl)phosphonoacetate.[10]
Here we wish to report the Horner–Wadsworth–Emmons olefinations of
several 4-substituted cyclohexanones 1 with trimethyl 1-(N-benzyloxycar-
bonyl)phosphono-acetate 2 in the presence of a tertiary amine such as DBU or
TMG (Sch. 1 and Table 1). All a,b-didehydroamino acid derivatives 3 are
new compounds.
t
Scheme 1. R ¼ a: Me; b: Ph; c: Bu; d: 22OCH2CH2CH2O22; e: EtOOC.
From Table 1 we could conclude:
1. Reactivity of 4-substituted cyclohexanone: 1e –1d . 1a . 1b . 1c,
the reactivity is a function of the steric hindrances of the substituent.
2. The molar ratio between substituted cyclohexanone and trimethyl 1-
(N-benzyloxy-carbonyl)phosphonoacetate affected the formation of
DDAA. Excess ketone facilitates the olefination and increases the
yield (Entry 1–2, 5–7).

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667
Table 1. Synthesis of 3a–3e.
Time Yield
(%)
Entry
R
Base
1/2 Solvent Temperature
(h)
1
2
Me
Me
DBU
DBU
DBU
TMG
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
1/1 CH2Cl2
1.4/1 CH2Cl2
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
87
46
46
93
72
72
31
71
77
85
85
77
134
25
52
50
44
56
64
75
67
68
83
86
42
60
3
Me
Me
1.4/1
1.4/1
THF
THF
4
5
Me
Me
2/1 CH2Cl2
3/1 CH2Cl2
4/1 CH2Cl2
4/1 CH3CN
4/1 CH2Cl2
4/1 CH2Cl2
4/1 CH2Cl2
4/1 CH2Cl2
4/1 CH2Cl2
6
7
Me
Me
8
9
Ph
10
11
12
13
OCH2CH2O
EtOOC
tBu
tBu
3. DBU was a better base than TMG and CH2Cl2 was a better solvent
than THF (Entry 2–4).
So, the optimal reaction conditions are: solvent CH2Cl2; base DBU; molar
ratio 1/2 ¼ 4/1; reaction temperature room temperature; reaction time about
3 days.
In conclusion, the presented mild olefination procedure provides a
convenient alternative to traditional Horner–Wadsworth–Emmons tech-
niques,[7,8] especially with base-sensitive substrates.
EXPERIMENTAL SECTION
General Considerations
All reactions with air- or moisture-sensitive reactions were carried out in
oven- or flamed-dried glassware under a positive pressure of dry Ar. Liquid
reagents and solvents were purified by distillation shortly before use according
to literature. Thin layer chromatography (TLC) was carried out using Merck
Kieselgel 60 F254 precoated, glass backed plates. The plates were visualized
using ultraviolet light (254 nm), anisaldehyde solution or iodine as
appropriate. Flash column chromatography was carried out using Merck 60

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Su et al.
silica gel (70–240 mm). IR spectra were recorded in Mattson Genesis FT IR
Spectrophotometer, NMR spectra were recorded in Bruker-ARX300 or Varian
Unity-300 apparatus (13C: 75 MHz). M.p. were determined in Gallenkamp
apparatus (uncorrected).
Synthesis of 3: General Procedure
To a solution of trimethyl 1-(N-benzyloxycarbonyl)phosphonoacetate 2
(332 mg, 1 mmol) in the appropriate solvent was added base dropwise. 10 min
later, the respective carbonyl compound 1 was added. The reaction times are
listed in Table 1. The reaction solution was then diluted with AcOEt (20 mL),
washed with 1N of H2SO4 (5 mL), dried over MgSO4, filtered and
concentrated in vacuo. The crude product was purified by column chroma-
tography on silica gel (3a, 3b: eluent: hexane/AcOEt ¼ 7/1, then 6/1. 3c:
eluent: hexane/AcOEt ¼ 4/1. 3d: eluent: hexane/AcOEt ¼ 3/1. 3e: eluent:
hexane/AcOEt ¼ 4/1, then 2/1).
3a: White solid, M.p. 90–918C, Rf 0.25 (hexane/ethyl acetate 4/1, v/v),
IR (nujol, v, cm21): 3303 (N–H), 1717 (C55O), 1693 (amide), 1645 (C55C),
1516, 751, 698 (Ar). 1H NMR (CDCl3, d, ppm): 7.4–7.2 (m, 5H, C6H5), 5.84
(s, 1H, NH), 5.14 (s, 2H, OCH2), 3.70 (s, 3H, OCH3), 3.39 (br d, J ¼ 14.1 Hz,
1H, eqatorial 2- or 6-H), 2.68 (br d, J ¼ 14.1 Hz, 1H, eqatorial 2- or 6-H), 2.2–
1.7 (m, 4H, eqatorial 3,5-H and axial 2,6-H), 1.7–1.5 (m, 1H, 4-H), 1.2–1.1
(m, 2H, axial 3,5-H), 0.91 (d, J ¼ 6.6 Hz, CH3). 13C NMR (CDCl3, d, ppm):
165.55 (–CO2Me), 155.02 (–NH–CO2–), 151.33 (cyclohexyl C1), 136.51
(Cbz C1), 128.49, 128.49, 128.11, 128.07, 128.07 (phenyl, C2–C6), 118.72
(55C–CO2Me), 67.19 (–OCH2Ph), 51.57 (–OCH3), 35.75, 35.35 (cyclohexyl
C2, C6), 32.08 (cyclohexyl C4), 30.63, 29.72 (cyclohexyl C3, C5), 21.35
(CH3). Anal. calcd. for C18H23NO4 (317.38): C, 68.12; H, 7.30; N, 4.41.
Found: C, 68.26; H, 7.21; N, 4.38.
3b: White solid, M.p. 145–1488C, Rf 0.18 (hexane/ethyl acetate 4/1,
v/v), IR (nujol, v, cm21): 3321 (N–H), 1706 (C55O), 1634 (C55C), 1510,
746, 694 (Ar). 1H NMR (CDCl3, d, ppm): 7.4–7.1 (m, 10H, 2 C6H5), 5.89 (s,
1H, NH), 5.14 (s, 2H, OCH2), 3.71 (s, 3H, OCH3), 3.7–3.5 (m, 1H, Ph–CH),
2.9–2.7 (m, 2H, eqatorial 2,6-H), 2.2–2.0 (m, 4H, eqatorial 3,5-H and axial
2,6-H), 1.7–1.5 (m, 2H, axial 3,5-H). 13C NMR (CDCl3, d, ppm): 165.51
(–CO2Me), 155.03 (–NH–CO2–), 150.27 (cyclohexyl C1), 145.95 (–Ph,
C1), 136.45 (Cbz, C1), 128.54, 128.54, 128.45, 128.45, 128.20, 128.13,
128.13, 126.82, 126.82, 126.24 (10C, C2-C6 in phenyl and Cbz), 119.17
(55C–CO2Me), 67.32 (–OCH2Ph), 51.71 (–OCH3), 44.05 (Ph-CH, cyclo-
hexyl C4), 34.81, 34.45 (cyclohexyl C2, C6), 31.20, 30.28 (cyclohexyl C3,

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669
C5). Anal. calcd. for C23H25NO4 (379.45): C, 72.80; H, 6.64; N, 3.69. Found:
C, 72.89; H, 6.58; N, 3.63.
3c: White solid, M.p. 122–1238C, Rf 0.26 (hexane/ethyl acetate 4/1,
v/v), IR (nujol, v, cm 21): 3309 (N–H), 1725, 1710 (C55O), 1648 (C55C),
1515, 750, 700 (Ar). 1H NMR (CDCl3, d, ppm): 7.4–7.3 (M, 5H, C6H5), 5.79
(s, 1H, NH), 5.13 (s, 2H, OCH2), 3.69 (s, 3H, OCH3), 3.50 (br d, J ¼ 13.5 Hz,
1H, eqatorial 2- or 6-H), 2.75 (br d, J ¼ 13.5 Hz, 1H, eqatorial 2- or 6-H), 2.0–
t
1.8 (m, 4H, eqatorial 3,5-H and axial 2,6-H), 1.3–1.0 (m, 3H, Bu-CH and
axial 3,5-H), 0.84 (s, 9H, C(CH3)3). 13C NMR (CDCl3, d, ppm): 165.57
(–CO2Me), 155.04 (–NH–CO2–), 150.93 (cyclohexyl C1), 136.47 (phenyl
C1), 128.52, 128.52, 128.12, 128.08, 128.08 (5C, phenyl C2-C6), 118.90
(55C–CO2Me), 67.23 (–OCH2Ph), 51.65 (–OCH3), 47.90 (cyclohexyl C4),
32.93, 31.81 (cyclohexyl C2, C6), 30.72 (C(CH3)3), 28.72, 28.39 (cyclohexyl
C3, C5), 27.53 (C(CH3)3). Anal. calcd. for C21H29NO4 (359.46): C, 70.17;
H, 8.13; N, 3.90. Found: C, 70.02; H, 8.19; N, 3.93.
3d: Orange solid, M.p. 88–908C, Rf 0.25 (hexane/ethyl acetate 2/1,
v/v), IR (nujol, v, cm21): 3336 (N–H), 1720 (C55O), 1692 (amide), 1502,
756, 700 (Ar). 1H NMR (CDCl3, d, ppm): 7.34 (s, 5H, C6H5), 5.88 (s, 1H, NH),
5.14 (s, 2H, OCH2Ph), 3.96 (s, 4H, OCH2CH2O), 3.70 (s, 3H, OCH3), 2.9 (m,
2H, eqatorial 2,6-H), 2.5 (m, 2H, eqatorial 3,5-H), 1.8 (m, 4H, axial 2,6-H and
axial 3,5-H). 13C NMR (CDCl3, d, ppm): 165.32 (–CO2Me), 154.93 (–NH–
CO2–), 148.78 (cyclohexyl C1), 136.43 (phenyl C1), 128.53, 128.53, 128.19,
128.12, 128.12 (phenyl 5C, C2-C6), 119.62 (55C–CO2Me), 108.08
(cyclohexyl C4), 67.31 (–OCH2Ph), 64.45, 64.45 (–OCH2CH2O), 51.72
(–OCH3), 35.10, 34.75 (cyclohexyl C2, C6), 28.16, 26.99 (cyclohexyl C3,
C5). Anal. calcd. for C19H23NO6 (361.39): C, 63.15; H, 6.41; N, 3.88. Found:
C, 63.04; H, 6.48; N, 3.91.
3e: Pale yellow solid, M.p. 77–798C, Rf 0.16 (hexane/ethyl acetate 4/1,
v/v), IR (nujol, v, cm21): 3291 (N–H), 1725 (C55O), 1693 (amide), 1511,
743, 693 (Ar). 1H NMR (CDCl3, d, ppm): 7.4–7.2 (m, 5H, C6H5), 5.84 (s, 1H,
NH), 5.12 (s, 2H, OCH2Ph), 4.12 (q, 2H, J ¼ 7.2 Hz, OCH2Me), 3.67 (s, 3H,
OCH3), 3.4–3.2 (m, 1H, eqatorial 2- or 6-H), 2.7–2.2 (m, 3H, eqatorial 2- or
6-H, eqatorial 3,5-H), 2.1–1.9 (m, 3H, axial 2,6-H and EtO2C-CH), 1.8–1.6
(m, 2H, axial 3,5-H), 1.23 (t, J ¼ 7.2 Hz, 3H, OCH2CH3). 13C NMR (CDCl3,
d, ppm): 174.65 (–CO2Et), 165.31 (–CO2Me), 154.92 (–NHCO2–), 149.36
(cyclohexyl C1), 136.40 (phenyl C1), 128.52, 128.52, 128.18, 128.10, 128.10
(phenyl 5C, C2-C6), 119.51 (55C-CO2Me), 67.30 (–OCH2Ph), 60.29
(–CO2CH2Me), 51.70 (–OCH3), 42.10 (cyclohexyl C4), 29.50, 29.33
(cyclohexyl C2, C6), 28.85, 28.59 (cyclohexyl C3, C5), 14.18 (CH3CH2O-).
Anal. calcd. for C20H25NO6 (375.42): C, 63.99; H, 6.71; N, 3.73. Found: C,
64.07; H, 6.65; N, 3.77.

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ACKNOWLEDGMENTS
Financial support from the Foundation of Educational Bureau of the
Guangxi Zhuang Autonomous Region, People’s Republic of China and the
International Cooperation Agency of Spain are gratefully acknowledged.
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Received in the USA August 14, 2003

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