Highly stereoselective and efficient synthesis of the dopa analogue in pepticinnamin E via enantioselective hydrogenation of dehydroamino acids

Article abstract of DOI:10.3906/kim-0904-14

An efficient and new method was developed to prepare the dopa analogue 11 in natural pepticinnamin via catalytic hydrogenation of dehydroamino acids (DDAA) with a good yield and ee. Product 11 is a key intermediate towards the total synthesis of pepticinnamin E and its analogues. TUeBITAK.

Full text of DOI:10.3906/kim-0904-14

Turk J Chem
34 (2010) , 181 – 186.
¨
˙
c
ꢀ TUBITAK
doi:10.3906/kim-0904-14
Highly stereoselective and efficient synthesis of the dopa
analogue in pepticinnamin E via enantioselective
hydrogenation of dehydroamino acids
Dequn SUN
Marine College, Shandong University at Weihai, Weihai 264209, P. R. CHINA
e-mail: dequn.sun@sdu.edu.cn
Received 13.04.2009
An efficient and new method was developed to prepare the dopa analogue 11 in natural pepticinnamin
via catalytic hydrogenation of dehydroamino acids (DDAA) with a good yield and ee. Product 11 is a key
intermediate towards the total synthesis of pepticinnamin E and its analogues.
Key Words: Synthesis; dopa analogue; enantioselective hydrogenation; dehydroamino acid.
Introduction
Pepticinnamin E1 (Figure) is a major product of the pepticinnamins, which are isolated from the culture of
Streptomyces sp. OH-4652. It was identified as a depsipeptide having an O − Z -pentenylcinnamin acid and a
novel dopa analogue, whose configuration has been determined as S by the Waldmann group using the Scho¨llkopf
method.2 Pepticinnamin E shows rather potent inhibitory activity against farnesyl protein transferase (FPTase)
with an IC50 of 0.3 μM and is the first competitive inhibitor derived from a natural product. Our interest
in the exploitation of a new methodology to synthesise naturally bioactive peptides containing non-ribosomal
amino acids led us to initiate the synthesis of pepticinnamin E (1). Emphasis was placed on preparing both
dopa analogue 2 and O − Z -pentenylcinnamin acid.3 This study reports the enantioselective synthesis of the
precursor of the dopa analogue 2, which would be suitable for the total synthesis of pepticinnamin E and its
analogues.
181

Highly stereoselective and efficient synthesis of the dopa..., D. SUN
OMe
HO
OCH3
Cl
HO
Cl
O
Me
N
O
O
O
H
N
N
Me
O
NH
O
O
HN
OH
HN
Me
O
2
OH
1
Figure. Structures of pepticinnamin E (1) and the dopa analogue 2.
Experimental section
General. Melting points were determined with an Electrothermol digital melting point apparatus, and were
uncorrected. Optical rotation was recorded on a Perkin-Elmer Model 341 polarimeter, at the sodium D line.
Elemental analysis was undertaken on a Carlo-1106 model automatic instrument. Infrared spectra (IR) were
run on a Nicolet MX-1 and Nicolet-560 MAGNA. 1 H-NMR and spectra were run either on a Bruker-200 and
Bruker-300 or on a Varian-400. 13 C-NMR was given by a Bruker-200. MS-EI mass spectra were obtained on a
VG 7070E.
2-Chloro-3-hydroxy-4-methoxybenzaldehyde (6): A solution of compound 5 (9.35 g, 61.0 mmol) in
freshly distilled CH2 Cl2 (260 mL) was bubbled into gas Cl2 until the yellow colour disappeared. After stirring
at RT for 1 h, the white solid was collected by filtration and washed with warm CH2 Cl2 to give compound 6,
8.0 g, yield 71%, mp 207∼208 ◦ C. FT-IR (KBr): 3209, 3199, 1662, 1590, 1490, 1286, 1248, 1213, 1030, 810,
670 cm−1
.
1 H-NMR (200 MHz, DMSO-d6)δ = 10.3 (s, 1H, CHO), 7.57 (d, J = 8.0 Hz, 1H, Ar-H), 6.90 (d,
J = 8 Hz, 1H, Ar-H), 3.98 (s, 3H, OCH3); MS-EI (m/z): 187 (M+), peak of isotope for Cl: 185/187 = 3:1,
187/189 = 3:1. Anal. Calcul. for C8 H7 ClO3 : C 51.49, H 3.78, Found: C 51.41, H 3.83.
2-Chloro-3-acetyloxy-4-methoxybenzaldehyde (7): To a solution of compound 6 (1.94 g, 10.4
mmol) in dry pyridine (25 mL) was added dropwise the acetyl chloride (0.75 mL, 10.5 mmol) at 0 ◦ C. After
stirring at RT for another 2 h, the reaction solution was diluted with ethyl acetate, and then washed with cold
1N H2 SO4 and water (until pH 7). The organic layer was dried over anhydrous MgSO4 , and concentrated to
give a crude product, which was purified by flash column chromatography on silica gel (with petr./ethyl acetate
6:1, 4:1 as eluent) to obtain white solid 7, 2.12 g, yield 89.1%, mp 64∼65 ◦ C. FT-IR (KBr): 3082, 3012, 2883,
1778, 1685, 1594, 1496, 1435, 1370, 1298, 1256, 1190, 1167, 1037, 891, 818 cm−1 1 H-NMR (200 MHz, CDCl3)δ
.
= 10.32 (s, 1H, CHO), 7.88 (d, J = 8.8 Hz, 1H, Ar-H), 7.0 (d, J = 8.8 Hz, 1H, Ar-H), 3.93 (s, 3H, OCH3),
2.41 (s, 3H, COCH3). Anal. Calcul. for C10 H9 ClO4 : C 52.53, H 3.97, Found: C 52.47, H 4.02
(Z)-Methyl3-(3-acetyloxy-2-chloro-4-methoxyphenyl-2-(tert-butyloxycarbonyl) acrylate (8):
To a solution of methyl N -protected-2-(diethoxycarbonyl)phosphinyl)-glycinate (2.2 mmol) in dry CH2 Cl2 (6
mL) was added DBU (0.3 mL, 2.2 mmol) at 0 ◦ C; after 1 min, the solution of compound 7 (2.0 mmol) in dry
CH2 Cl2 (6 mL) was added. After stirring at 0 ◦ C for another 2 h, the reaction solution was diluted with 40
182

Highly stereoselective and efficient synthesis of the dopa..., D. SUN
mL of ethyl acetate and then washed with cold 1 N H2 SO4 (5 mL). The organic layer was dried over anhydrous
Na2 SO4 , and concentrated to give a crude product, which was purified by column chromatography on silica gel
(with petr./ethyl acetate as eluent) to obtain white solid 8, 0.78 g, yield 98%, mp 126-127 ◦ C. FT-IR (KBr):
3526, 3349, 2980, 2949, 1782, 1720, 1642, 1601, 1494, 1440, 1371, 1337, 1302, 1247, 1174, 1034, 880, 772 cm−1
;
1 H-NMR (200 MHz, CDCl3)δ = 7.56 (d, J = 8.91 Hz, Ar-H), 7.35 (s, 1H, = CH), 6.88 (d, J = 8.91 Hz, Ar-H),
6.17 (bs, 1H, NH), 3.87 (s, 3H, ArOCH3), 3.86 (s, 3H, COOMe), 2.38 (s, 3H, COMe), 1.41 (s, 9H, Boc). MS-EI
(m/z): 399 (M+); Anal. Calcul. for C18 H22 ClNO7 : C 54.52, H 5.57, N 3.46. Found: C 54.34, H 5.51, N 3.51.
(S)-N-tert-butyloxycarbonyl-(3-acetyloxy-2-chloro-4-methoxy)-phenylalanine methyl ester
(9): To a solution of DIPAMP (2.7 mg, 0.0059 mmol) in 1.5 mL of absolute acetone (deoxygenation before
use) was added [Rh(COD)BF4 (2.4 mg, 0.0059 mmol) under Ar2 . After stirring at RT for 1 h, this catalyst
with a concentration of 0.0004 mmol/0.1 mL was prepared and used in subsequent procedure right away. To
a solution of compound 8 (0.70 g, 1.75 mmol) in absolute acetone (26 mL) (deoxygenation before use) was
added the catalyst prepared in the above procedure. The reaction solution was hydrogenated under 1 atm
for 42 h at RT. Active carbon was then added by stirring. After 30 min, the solid was filtered off through
a Celite pad and the filtrate was concentrated to give a crude product, 0.70 g, with a 90.6% ee value and S
configuration (determined by chiralpak OD, Hexane:iPrOH/90:10, rate: 1 mL/min). The crude product was
twice recrystallised from ethyl acetate and hexane to give a white needle solid 9, 0.62 g with >99% ee value
and 89.1% yield, mp 108∼109 ◦ C. [α]D28 +18 (c 0.35, CH2 Cl2). FT-IR (KBr): 3368, 2980, 2942, 1774, 1753,
1686, 1606, 1514, 1441, 1370, 1286, 1207, 1171, 1042 cm−1 1 H-NMR (400 MHz, CDCl3)δ = 7.06 (d, J = 8.4
.
Hz, 1H, Ar-H), 6.82 (d, J = 8.4 Hz, 1H, Ar-H), 5.06 (bs, 1H, NH), 4.56 (m, 1H, CH), 3.82 (s, 3H, OCH3), 3.68
(s, 3H, COOCH3), 3.25-3.11 (m, 2H, β-CH2), 2.37 (s, 3H, COCH3), 1.37 (s, 9H, Boc). MS-EI (m/z): 401
(M+); Anal. Calcul. for C18 H24 ClNO7 : C 53.80, H 6.03, N 3.49. Found: C 53.88, H 5.96, N 3.45.
(S)-N-tert-butyloxycarbonyl-(3-benzyloxy-2-chloro-4-methoxy)-phenylalanine methyl ester
(10): To a solution of compound 9 (0.10 g, 0.25 mmol) in CH3 OH (6 mL) and distilled water (2 mL) was
added dropwise saturated NaHCO3 (2 mL). The reaction solution was stirred at RT for 3 h and acidified to
pH 3∼4 at 0◦ C, and then extracted with ethyl acetate 4 times. The combined ethyl acetate layer was washed
with brine and dried over anhydrous MgSO4 , and then concentrated to give a slight yellow slurry, which was
dissolved in freshly distilled DMF (5 mL) at once. The powdered anhydrous K2 CO3 (86 mg, 0.63 mmol) was
added, followed by addition of BnBr (36.0 μL, 0.30 mmol) at 0 ◦ C. After stirring at RT for 3 h under N2 , cold
water was added and extracted with ethyl acetate 4 times. The combined organic layer was then washed in cold
1 N KHSO4 and brine and dried over anhydrous MgSO4 , and concentrated to give a slight slurry, which was
purified by column chromatography on silica gel (with hexane/ethyl acetate as an eluent) to obtain compound
102a as a slight yellow slurry, 63 mg, (23 mg of compound 9 was recovered), yield 73.7% for 2 steps (based on
transformed starting material). [α]2D8 +17.2 (c 0.25, CH2 Cl2). 1 H-NMR (400 MHz, CDCl3)δ (main rotamer)
= 7.45 (m, 2H, Ar-H), 7.29 (m, 3H, Ar-H), 6.84 (d, J = 8.0 Hz, 1H, Ar-H), 6.71 (d, J = 8.0 Hz, 1H, Ar-H), 4.95
(s, 2H, OCH2 Ph), 4.52 (m, 1H, α-CH), 3.77 (s, 3H, OCH3), 3.63 (s, 3H, COOCH3), 3.16 (dd, 2J = 13.6 Hz,
3J = 6 Hz, 1H, β-CH2), 3.01 (dd, 2J = 13.6 Hz, 3J = 6 Hz, 1H, β-CH2), 1.33 (s, 9H, Boc). MS-EI (m/z):
449 (M+). Anal. Calcul. for C23 H28 ClNO6 : C 61.40, H 6.27, N 3.11. Found: C 61.37, H 3.18, N 3.20.
(S)-N-tert-butyloxycarbonyl-N-methyl-(3-benzyloxy-2-chloro-4-methoxy)-phenylalanine
methyl ester (11): To a solution of compound 10 (0.10 g, 0.22 mmol) in THF (2.5 mL) was added a solution
183

Highly stereoselective and efficient synthesis of the dopa..., D. SUN
of LiOH.H2 O (25.0 mg) in water (0.5 mL) at 0 ◦ C. After stirring at RT for 3 h, cold water was added and
acidified to pH 3∼4 with 0.1 N HCl, and then extracted with ethyl acetate 4 times. The combined organic
layer was washed with brine and dried over anhydrous Na2 SO4 , and concentrated to give a slight slurry, which
was purified by column chromatography (petr./ethyl acetate: 3:1, 1:1, 1:2 as an eluent) to obtain the acid 81
mg (0.186 mmol), which was used for next N -methylation directly. The acid was dissolved in 4.5 mL of dry
THF. To this solution was added NaH (22.4 mg, 0.56 mmol), followed by MeI (46 μL, 0.75 mmol) at 0 ◦ C The
reaction suspension was then stirred at 27 ◦ C for 16 h. Cold water was added and acidified to pH 3∼4 with
0.1 N HCl, and then extracted with ethyl acetate 4 times. The combined organic layer was washed with brine
and dried over anhydrous MgSO4 , and concentrated to give a crude product, which was purified by column
chromatography on a silica gel (with petr./ethyl acetate: 3:1, 1:1, 1:2 as an eluent) to obtain a colourless oil
112a 50 mg, yield 50%. [α]D20 -85.9 (c 0.11, CH2 Cl2). FT-IR (Neat): 3010, 2984, 2936, 2851, 1739, 1705,
1487, 1444, 1374, 1245, 1947, 758 cm−1 1 H-NMR (200 MHz, CDCl3)δ (main rotamer) = 7.54 (m, 2H, Ar-H),
.
7.34 (m, 3H, Ar-H), 6.88 (d, 1H, J = 8.6 Hz, Ar-H), 6.77 (d, J = 8.6 Hz, 1H, Ar-H), 5.05 (s, 2H, OCH2 Ph),
4.63 (m, 2H, α-CH, COOH), 3.86 (s, 3H, OCH3), 3.51-3.07 (m, 2H, β-CH2), 2.70 (s, 3H, NCH3), 1.43 (s, 9H,
Boc). MS-EI (m/z): 449 (M+). Anal. Calcul. for C23 H28 ClNO6 : C 61.40, H 6.27, N 3.11. Found: C 61.31,
H 6.35, N 3.17.
Results and discussion
Many methods have been published for the preparation of enantiomerically pure dopa analogues, such as the
improved synthesis of selectively protected L-dopa derivatives from L-tyrosine,4 the traditional Sch¨ollkopf
method for chiral amino acids, and enantioselective catalysis with chiral auxiliaries.5 We also wanted to obtain
the dopa analogue 2 fromL-tyrosine. As shown in the retro-synthetic route a (Scheme 1), compound 3 was
obtained conveniently from L-tyrosine through acetylation, hydroxylation, and methylation under the Coggins
condition.6 Unfortunately, the final chlorination of compound 3 was unsuccessful, maybe because of the steric
hindrance effect. Even when Cbz was firstly removed before chlorination, and the undesired compound 4 was
obtained.
OH
HO
OMe
HO
OMe
O
OMe
HO
Cl
OMe
a
Cl
OH
H
OMe
Cbz
OMe
Cbz
OMe
H2N
N
N
N
H
O
CH3 O
CH3 O
O
H
OH
L-Tyr.
N
4
3
CH3 O
b
2
BnO
Cl
OMe
HO
Cl
OMe
HO
OMe
Boc
OMe
H
H
N
O
O
CH3 O
Scheme 1. Retro-synthesis of the dopa analogue.
184

Highly stereoselective and efficient synthesis of the dopa..., D. SUN
Another method (according to retro-synthetic route b; Scheme 1) was then developed with the aim of
obtaining the target compound via enantioselective catalytic hydrogenation of the chlorinated dehydroamino
acid by employing a chiral catalyst such as DIPAMP.7
Chlorination of isovanillin gave compound 6, and protection of the OH group by acetylation afforded
aldehyde 7, which was coupled with N -protected-2-(diethoxycarbonyl)phosphinyl)glycine ester8,9 by using
DBU as a base under the Horner–Emmons condensation condition8 to afford DDAA 8. Subsequently, 8
has been hydrogenated using the chiral catalyst DIPAMP to give 9 with 100% conversion and 90.6% ee. In
particular, this step can be conducted on a large scale with good ee. After recrystallisation, compound 9 was
obtained in enantiopure form (>99% ee, Scheme 2).
OMe
OMe
OMe
AcCl/Py
OH
OH
Cl
OAc
Cl
0~25
oC, 2 h
Cl2 (gas)/CH2Cl2
71%
89.1%
CHO
CHO
CHO
7
5
6
1) [(S,R)-DIPAMP-Rh(COD)]BF4
acetone, 1 atm H2, 25 oC, 42 h
90.6%ee
OMe
O
NHBoc
OAc
(EtO2C)2P CHCO2Me
Cl
NHBoc
COOMe
DBU/CH2Cl2
Z/E = 100
2) recryst., >99%ee, 89% yield
98%
8
OMe
OBn
OMe
OAc
1) Sat.NaHCO3
CH3OH/H2O (3:1)
Cl
Cl
2) BnBr/K2CO3, DMF
91% (2 steps)
COOMe
COOMe
NHBoc
10
NHBoc
9
OMe
OBn
1) LiOH.H2O, THF
Cl
COOH
2) MeI/NaH,THF
50% (2 steps)
Me NBoc
11
Scheme 2. Asymmetric synthesis of the dopa analogue 11.
Since the acetyl group was unstable under strong basic conditions (such as LiOH and NaH), it was
selectively removed by treatment of 9 with a saturated solution of NaHCO3 in MeOH/H2 O (Scheme 2)
without removing the Me group;10 then the OH group was protected by benzylation to give the closely related
known compound 10.2a Subsequently, under the Bnoiton condition,6 10 has been transformed into the known
compound 11.2a
185

Highly stereoselective and efficient synthesis of the dopa..., D. SUN
Conclusion
A new synthetic route was developed to prepare the dopa analogue by employing the methodology of asymmetric
catalytic hydrogenation of dehydroamino acids. Such a method is of practical use for the total synthesis of
pepticinnamin E and its analogues.
Acknowledgements
We are grateful for the financial support from the National Science Fund of China (No. 29602008 and 20025205).
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186

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