Facile synthesis of L-3,4-didehydrovaline constituting an antibiotic, phomopsin A

Article abstract of DOI:10.1055/s-2000-6382

A convenient synthesis of δ,γ-unsaturated valine (L-3,4- didehydrovaline), an important constituent of an antibiotic phomopsin A, was achieved from H-D-Ser-OH through a seven-step conversion in 31percent overall yield.

Full text of DOI:10.1055/s-2000-6382

634
SHORT PAPER
Facile Synthesis of L-3,4-Didehydrovaline Constituting an Antibiotic,
Phomopsin A
Yasuchika Yonezawa, Kanetaka Shimizu, Kwan-sik Yoon, Chung-gi Shin*
Laboratory of Organic Chemistry, Faculty of Technology, Kanagawa University, Rokkakubashi, Kanagawa-ku, Yokohama 221-8686,
Japan
Fax +81(45)4917915
Received 16 June 1999; revised 20 September 1999
dependent groups,12-14 although the racemic form has
Abstract: A convenient synthesis of b,g-unsaturated valine (L-3,4-
been resolved only by using hogacylase.15 Here, we wish
to report the facile syntheses of (S)- and (R)-H-3-DVal-
OH•HCl (8a and 8b) from D- and L-H-Ser-OH, respec-
tively, in seven steps (Scheme).
didehydrovaline), an important constituent of an antibiotic phomop-
sin A, was achieved from H-D-Ser-OH through a seven-step con-
version in 31% overall yield.
Key words: didehydrovaline, deprotection, Jones’ oxidation,
b-elimination, Grignard reaction, amino acids
MeO
BocN
O
DMP/PTS
CH2Cl2
Antibiotic phomopsin A (1),1,2 isolated from the culture of
Phomopsis leptostromifomis, has a unique hexapeptide
consisting of two parts. The natural product 1 features a
very interesting main cyclodidehydrotripeptide called
Fragment A and linear didehydrotripeptide called Frag-
ment B as the exocyclic substructure, as illustrated in the
Figure.
Boc-
D
-Ser-OMe
75%
O
2a
3a
OH
MeMgI
Et2O
MsCl/Et3N
CH2Cl2
BocN
BocN
Cl
quant.
O
76%
O
Fragment A
OH
4a
5a
HO
O
Fragment B
Jones oxid.
74%
acetone
O
N
MeHN
HN
Jones oxid.
acetone
H
N
HN
70% AcOH
33%
O
COOH
COOH
O
O
N
H
OH
69%
O
BocHN
BocHN
COOH
6a
7a
Figure Structure of Phomopsin A (1).
3M-HCl
/EtOH
92%
The above-mentioned Fragment A is entirely constituted
of unusual a-amino acid moieties, 2-amino-3-methylbut-
3-enoic acid [(S)-3,4-didehydrovaline, H-L-3-DVal-OH)]
(9a), (2S,3S)-hydroxyisoleucine, and (2S,3S)-3-hydroxy-
2-(N-methyl)tyrosine derivatives. Recently, besides the
novel syntheses3,4 of (E)-2,3-didehydroaspartic acid
(DAsp), (E)-2,3-didehydroisoleucine (DIle) and 3,4-dide-
hydroproline (DPro) constructing the Fragment B, we
have already reported briefly the syntheses of a variety of
the related didehydrooligopeptides as well.5,6 At present,
the synthesis of each moiety of the cyclopeptide segment
has been carried out; in particular, the convenient synthe-
sis of 9 is thought to be very essential. Furthermore, inter-
estingly, the b,g-unsaturated a-amino acids, including 9,
have potent biological activity,7 both as enzyme
inhibitors8-10 and as antibiotics.11 So far, the synthesis of
9 has been already reported in racemic form by three in-
H2N
COOH
HCl.H2N
COOH
9a
8a
Jones oxid.
acetone
OH
4a
66%
BocHN
COOH
10a
Scheme
Synthesis 2000, No. 5, 634–636 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
Facile Synthesis of L-3,4-Didehydrovaline Constituting an Antibiotic, Phomopsin A
635
NaHCO3 solution (3 × 50 mL), brine (3 × 50 mL), and then dried
(Na2SO4). Concentration in vacuo gave a crude oil, which was dis-
tilled in vacuo to give 3a as a colorless oil; yield: 16.5 g (76%); bp
111-113 °C/4 Torr; [a]D25 +54.5 (c =1.0, CHCl3). {Lit.16 bp 101-
102 °C/2 Torr; [a]D +53 (c =1.5, CHCl3)}.
First of all, N-tert-butoxycarbonyl (Boc)-D-Ser-OMe
(2a), derived by the protection of H-Ser-OMe with di-tert-
butyl dicarbonate (Boc2O), was further protected with
2,2-dimethoxypropane (DMP) to give methyl (4R)-3-
Boc-2,2-dimethyl-1,3-oxazolidine-4-carboxylate (3a).16
Subsequently, Grignard reaction of 3a with MeMgI in di-
ethyl ether at 0 °C proceeded smoothly to give (4S)-4-(1-
hydroxy-1-methylethyl)-3-Boc-2,2-dimethyl-1,3-oxazo-
lidine (4a) almost quantitatively. Then, b-elimination of
4a with methanesulfonyl chloride (MsCl) in the presence
of Et3N in CH2Cl2 at -10 °C gave (4S)-4-(1-methylethe-
nyl)-3-Boc-2,2-dimethyl-1,3-oxazolidine (5a), the iso-
propylidene (Ip) group of which was deprotected with
70% AcOH to give the corresponding 2-aminobutenol de-
rivative 6a. Subsequent Jones’ oxidation of 6a was per-
formed to give (2S)-2-(N-Boc)amino-3-methylbut-3-
enoic acid (Boc-L-3-DVal-OH) (7a) in 69% yield. How-
ever, unfortunately, the yield of 6a from 5a was found to
be markedly low (33%). Accordingly, an alternative di-
rect synthetic method from 5a to 7a was tried successful-
ly. Namely, in this case, the simultaneous deprotection
and oxidation of 5a using excess Jones’ reagent in acetone
was carried out to give the expected 7a in 74% yield. The
Boc group of 7a was deprotected with 3 M HCl to give 8a
in 92% yield, as shown in the Scheme. Quite similarly, the
synthesis of 8b has been also successful from H-L-Ser-OH
(2b). The melting points and the specific rotations of 8a
and 8b were identical to those of the authentic samples de-
rived by the resolution of the racemic form.15 Further-
more, the aqueous solution of both hydrochlorides have
been readily neutralized to pH 6 with 1 M LiOH to give
the expected 9a and 9b, respectively.15
3b (from L-Ser)
[a]D25 -55.5 (c =1.0, CHCl3) (from L-Ser).
(4S) and (4R)-4-(1-Hydroxy-1-methyethyl)-3-(tert-butoxycar-
bonyl)-2,2-dimethyl-1,3-oxazolidines (4a and 4b)
To a stirred suspension of Grignard reagent [prepared from Mg (5.6
g, 230.0 mmol) and MeI (16.8 mL, 270 mmol) in Et2O (200 mL)]
was added dropwise a solution of 3 (10.0 g, 38.6 mmol) in Et2O
(30 mL) at 0 °C. After stirring for 30 min at 0 °C, to the resulting
solution was added dropwise an aq sat. NH4Cl (100 mL). The mix-
ture was extracted with EtOAc (3 × 100 mL). The combined ex-
tracts were washed with brine (2 × 50 mL) and dried (Na2SO4).
Concentration in vacuo gave a residue, which was purified on a sil-
ica gel column using a mixture of hexane and EtOAc (3:1, v/v) to
give 4 as colorless crystals, which were recrystallized from a mix-
ture of EtOAc and hexane to give 4 as colorless needles; yield: 10.3
g (quant.); mp 36-37 °C; [a]D25 +23.0 (c =1.0, MeOH).
IR (KBr): n = 3412, 2974, 2938, 2880, 1698, 1668 cm-1.
1H NMR ((CDCl3/TMS): d = 1.18 (s, 3 H, CH3), 1.19 (s, 3 H, CH3),
1.51[(s, 12 H, Boc(CH3)3, Ip(CH3)], 1.60 [s, 3 H, Ip(CH3)], 3.78 (m,
1 H, 5-H ), 4.00 (m, 2 H, 4-H), 5.30 (br s, 1 H, OH).
Anal. Calcd for C13H25NO4: C, 60.32; H, 10.04; N, 5.21. Found: C,
60.21; H, 9.73; N, 5.40.
4b (from L-Ser)
mp 36-37 °C; [a]D25 -22.5 (c =1.0, MeOH).
(4S) and (4R)-4-(1-Methylethenyl)-3-(tert-butoxycarbonyl)-2,2-
dimethyl-1,3-oxazolidines (5a and 5b)
To a stirred solution of 4 (1.96 g, 7.33 mmol) in CH2Cl2 (20 mL)
were added MsCl (2.8 mL, 36.6 mmol) and Et3N (10.3 mL,
73.2 mmol) at -10 °C. After stirring at r.t. for 1 h, the mixture was
poured into Et2O (100 mL) and H2O (60 mL). The organic layer was
washed with aq 1 M 10% citric acid (3 × 50 mL), aq sat. NaHCO3
solution (3 × 50 mL), brine (3 × 50 mL), and then dried (Na2SO4).
Concentration in vacuo gave a residue, which was purified on a sil-
ica gel column using a mixture of hexane and EtOAc (8:1, v/v) to
give 5 as a colorless syrup; yield: 1.35 g (76%); [a]D25 +16.8 (c =1.2,
MeOH).
In addition, convenient synthesis of L-2-(N-Boc)-3-hy-
droxyvaline (10), which is an important and unusual a-
amino acid constituent of a macrocyclic antibiotic, berni-
namycin A,17 was achieved by oxidation of 4a with Jones'
reagent in acetone at 0 °C.
In conclusion, the facile and convenient syntheses of L-,
D-3-DVal-OH and 3-hydroxy-Val-OH were accomplished
by simple reactions using readily accessible D- and L-H-
Ser-OH, respectively. In particular, simultaneous depro-
tection and oxidation of 5 and 4 with Jones' reagent to 7
and 10, respectively, was found to be very effective.
IR (KBr): n = 2980, 2932, 2872, 1704, 1660 cm-1.
1H NMR (CDCl3/TMS): d = 1.41 [s, 3 H, Ip(CH3)], 1.51 [s, 9 H,
Boc(CH3)3], 1.66 [s, 3 H, Ip(CH3)], 1.73 (s, 3 H, CH3), 3.74 (dd, 1
H, J = 5.9, 8.8 Hz, 5-Ha), 4.07 (dd, 1 H, J = 7.3, 8.8 Hz, 5-Hb), 4.33
(dd, 1 H, J = 5.9, 7.3 Hz, 4-H), 4.85 (br s, 1 H, vinyl-Ha), 4.90 (br
s, 1 H, vinyl-Hb).
Melting points were determined with Yamato Mp-21 melting points
apparatus, and are uncorrected. The IR spectra were recorded on a
1
Hitachi 270-30 spectrometer in KBr. The H NMR spectra were
Anal. Calcd for C13H23NO3: C, 64.70; H, 9.61; N, 5.80. Found: C,
64.43; H, 9.41; N, 5.55.
measured with a JEOL EX 270 spectrometer in CDCl3 solution with
TMS as the internal standard. The specific rotations were measured
in a 0.5 dm tube using a JASCO DIP-4 polarimeter in MeOH (Japan
Spectroscopic Co., Ltd.).
5b (from L-Ser)
[a]D25 -15.5 (c =1.2, MeOH).
Methyl (4R) and (4S)-3-tert-Butoxycarbonyl-2,2-dimethyl-1,3-
oxazolidine-4-carboxylates (3a and 3b)
(2S)-2-(N-tert-Butoxycarbonyl)amino-3-methylbut-3-enol (6a)
A solution of 5a (570mg, 2.36 mmol) in 70% AcOH (4 mL) was
stirred at r.t. for 24 h. The mixture was concentrated in vacuo to give
a residue, which was purified on a silica gel column using a mixture
of hexane and EtOAc (5:1-2:1, v/v) to give 6a as colorless crystals;
yield: 157 mg (33%); mp 54-55 °C; [a]D25 -10.5 (c = 1.0, MeOH).
To a stirred solution of Boc-D-Ser-OMe (2, 17.9 g, 81.5 mmol) in
CH2Cl2 (100 mL) were added DMP (50 mL, 410 mmol) and p-tol-
uenesulfonic acid monohydrate (1.6 g, 8.2 mmol) at 0 °C. After stir-
ring at r.t. for 12 h, the mixture was poured into aq sat NaHCO3
solution (100 mL) and then the resulting solution was extracted with
Et2O (3 × 60 mL). The organic layer was washed with aq satd
IR (KBr): n = 3376, 2980, 2938, 2878, 1692, 1653, 1524 cm-1.
Synthesis 2000, No. 5, 634–636 ISSN 0039-7881 © Thieme Stuttgart · New York

636
Y. Yonezawa et al.
SHORT PAPER
1H NMR (CDCl3/TMS): d = 1.45 [s, 9 H, Boc(CH3)3], 1.79 (s, 3 H,
CH3), 2.52 (br s, 1 H, OH), 3.68 (m, 2 H, 1-H), 4.10 (m, 1 H, 2-H),
4.97 (s, 1 H, vinyl-Ha), 5.00 (s, 1 H, vinyl-Hb), 5.12 (br s, 1 H, NH).
(2S) and (2R)-2-(N-tert-Butoxycarbonyl)amino-3-hydroxy-3-
methylbutanoic Acids (10a and 10b)
To a stirred solution of 4a (3.3 g, 13.0 mmol) in acetone (100 mL)
was added Jones’ reagent (7.3 mL, 19.5 mmol) at 0 °C. After stir-
ring for 1.5 h, Celite (2 g) and isopropyl alcohol (30 mL) were add-
ed to the mixture. The precipitate deposited was filtered off and the
filtrate was adjusted to pH 8 with aq NaHCO3 solution and then con-
centrated in vacuo. The aqueous layer was washed with Et2O (2 ×
50 mL) and acidified to pH 3 with citric acid. The resulting solution
was extracted with EtOAc (3 × 50 mL) and the combined extracts
were washed with brine (2 × 50 mL), and then dried (Na2SO4). Con-
centration in vacuo gave colorless crystals. Recrystallization from a
mixture of hexane and EtOAc gave 10 as colorless needles; yield:
1.85 g (66%); mp 164-165.5 °C; [a]D29 -7.0 (c = 1.0, MeOH).
Anal. Calcd for C10H19NO3: C, 59.67; H, 9.52; N, 6.96. Found: C,
59.45; H, 9.46; N, 6.73.
(2S) and (2R)-2-(N-tert-Butoxycarbonyl)amino-3-methylbut-3-
enoic Acids (7a and 7b)
To a stirred solution of 5 (1.28 g, 5.23 mmol) in acetone (13 mL)
was added Jones’ reagent (4.0 ml, 10.7 mmol) at 0 °C. After stirring
at r.t. for 12 h, Celite (1.0 g) and isopropyl alcohol (5.0 mL) were
added to the mixture. The precipitate deposited was filtered off and
the filtrate was adjusted to pH 9 with aq NaHCO3 solution and then
concentrated in vacuo. The aqueous layer was washed with Et2O
(2 × 20 mL) and acidified to pH 3 with citric acid. The resulting so-
lution was extracted with EtOAc (3 × 20 mL) and the combined ex-
tracts were washed with brine (2 × 30 mL), and then dried (Na2SO4).
Concentration in vacuo gave colorless crystals. Recrystallization
from hexane gave 7 as colorless needles; yield: 843 mg (74%).
IR (KBr): n = 3304, 2968, 2110, 1587 cm-1.
1H NMR (DMSO-d6): d = 1.18 (s, 3 H, CH3), 1.19 (s, 3 H, CH3),
3.97 (d, 1 H, J = 8.8 Hz, 2-H), 5.05 (s, 2 H, Cbz's CH2), 7.17 (br d,
1 H, J = 8.8 Hz , NH), 7.36 (s, 5 H, C6H5), 12.50 (br s, 1 H, CO2H).
Anal. Calcd for C13H17NO5•0.5 H2O: C, 56.51; H, 6.20; N, 5.07.
Found: C, 56.47; H, 5.88; N, 4.64.
(2S)-7a
mp 60-66 °C; [a]D25 +56.2 (c = 1.0, MeOH).
IR (KBr): n = 3448, 2980, 1715, 1704, 1660, 1503 cm-1.
1H NMR (CDCl3/TMS): d = 1.43 [s, H, Boc(CH3)3], 1.82 (s, 3 H,
CH3), 4.59, 4.80 (2 br s, 1 H, 2-H), 5.04 (br s, 1 H, vinyl-Ha), 5.12
(br s, 1 H, vinyl-Ha), 5.31, 7.38 (2 br s, 1 H, NH), 8.20 (br s, 1 H,
CO2H).
1H NMR (CDCl3/TMS, 65°C): d = 1.44 [s, H, Boc(CH3)3], 1.82 (s,
3 H, CH3), 4.72 (d, 1 H, J = 7.0 Hz, 2-H), 5.07 (d, 1 H, J = 5.5 Hz,
vinyl-Ha), 5.08 (d, 1 H, J = 5.5 Hz, vinyl-Hb), 5.57 (br d, 1 H, J =
7.0 Hz, NH), 7.40 (br s, 1 H, CO2H).
References
(1) Payne, A.L. Appl. Envivon. Macrobiol. 1983, 45, 389.
(2) Culvenor, C. C. J.; Edger, J. A.; Mackay, M. J. Tetrahedron
1989, 45, 2351.
(3) Shin, C.; Obara, T.; Yonezawa, Y. Bull. Chem. Soc. Jpn. 1988,
61, 3265.
(4) Shin, C.; Takahashi, N.; Yonezawa, Y. Chem. Pharm. Bull.
1990, 38, 2020.
(5) Shin, C.; Ikeda, T.; Morita, S.; Yonezawa, Y. Agric. Biol.
Chem. 1984, 49, 2243
(6) Shin, C.; Yonezawa, Y.; Ikeda, T. Bull. Chem. Soc. Jpn. 1986,
59, 3573.
(7) Rando, R. Acc. Chem. Rec. 1975, 8, 281.
(8) Giovanelli, I.; Owenes, L.D.; Mudd, S.H. Biochim. Biophys.
Acta 1971, 227, 671.
Anal. Calcd for C10H17NO4: C, 55.80; H, 7.96; N, 6.51. Found: C,
55.75; H, 8.20; N, 6.27.
(2R)-7b (from L-Ser)
mp 60-66 °C; [a]D25 -56.2 (c = 1.0, MeOH).
Owenes, L.D.; Thompson, J. F.; Pitcher, R. G.; Williams, T. J.
Chem. Soc., Chem. Commun. 1972, 714
(9) Rando, D. Nature 1974, 250, 586.
(10) Rando, D. Biochemistry 1974, 13, 3859.
(11) Scannell, J. P.; Preuss, D. L.; Demney T. C.; Sello, L. H.;
Williams, T.; Stempel, A. J. Antibiot. 1972, 25, 122.
Sahm, U.; Knoblock, G.; Wagner, F. J. Antibiot. 1973, 26,
389.
(12) Nunomi, K.; Suzuki, M; Yoneda, K. J. Chem. Soc., Perkin
Trans.1 1979, 2224.
(13) Heinzer, F.; Bellus, D. Helv. Chem. Acta 1981, 64, 2279.
(14) Grout, D. H. G.; Lutstorf, M.; Mougan, P. J. Tetrahedron
1983, 39, 3457.
(2S) and (2R)-2-Amino-3-methylbut-3-enoic Acid Hydrochlo-
rides (8a and 8b)
To a stirred solution of 7 (110 mg, 0.51 mmol) in EtOH (500 mL)
was added 3 M HCl (200 mL) at 0 °C. After stirring at r.t. for 30 min,
the solution was concentrated and the residue dried in vacuo at 60°C
to give a solid. Recrystallization from a mixture of EtOH and Et2O
to gave 8 as colorless needles; yield: 73 mg (92%).
(2S)-8a
26
mp 203-206 °C (dec.); [a]D +114.5 (c = 1.0, H2O). {Lit.15 mp
201-204°C (dec.); [a]D +113 (c = 3.64, H2O)}.
IR (KBr): n = 3432, 1636, 1508, 1404, 1338, 1261 cm-1.
1H NMR (D2O, 25°C): d = 1.68 (s, 3 H, CH3), 4.18 (s, 1 H, 2-H),
5.99 (s, 1 H, vinyl-Ha), 5.13 (s, 1 H, vinyl-Hb),
(15) Baldwin, J. E.; Haber, S.B.; Hoskins, C.; Kruse, L. I. J.
Org.Chem. 1977, 42, 1239.
(16) Garner, P.; Park, M. J. Org. Chem. 1987, 52, 2361.
(17) Liesch, J. M.; Rinehart, K. L. J. Am. Chem. Soc. 1977, 99,
1645.
Anal. Calcd for C5H10NO2Cl: C, 39.57; H, 6.60; N, 9.23; Found: C,
39.75; H, 6.32; N, 9.05.
(2R)-8b (from L-Ser)
Abe, H.; Kushida, K.; Shiobara, Y.; Kodama, M. Tetrahedron
Lett. 1988, 28, 1404.
26
mp 202-205 °C (dec.); [a]D -113.6 (c = 1.0, H2O). {Lit.15 mp
202-205 °C (dec.); [a]D27 -112 (c = 3.44, H2O)}.
Article Identifier:
1437-210X,E;2000,0,05,0634,0636,ftx,en;F03699SS.pdf
Synthesis 2000, No. 5, 634–636 ISSN 0039-7881 © Thieme Stuttgart · New York