Total synthesis of (-)-MY 336a from L-tyrosine

Article abstract of DOI:10.1002/jhet.248

(Chemical Equation Presented) Using L-tyrosine as a chiral starting material, we developed an efficient synthetic route to (-)-MY 336a. A key step in the sequence is a highly regio- and diastereoselective intermolecular Pictet-Spengler cyclization reaction between amino alcohol and benzyloxyacetaldehyde.

Full text of DOI:10.1002/jhet.248

50
Total Synthesis of (–)-MY 336a from L-Tyrosine
Vol 47
Xiang Wei Liao, Wen Fang Dong, Wei Liu, Bao He Guan,
and Zhan Zhu Liu*
Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine,
Ministry of Education, Institute of Materia Medica, Chinese Academy of Medical Sciences and
Peking Union Medical College, Beijing 100050, People’s Republic of China
*E-mail: liuzhanzhu@imm.ac.cn
Received May 11, 2009
DOI 10.1002/jhet.248
Published online 21 December 2009 in Wiley InterScience (www.interscience.wiley.com).
Using L-tyrosine as a chiral starting material, we developed an efficient synthetic route to (–)-MY
336a. A key step in the sequence is a highly regio- and diastereoselective intermolecular Pictet-Spengler
cyclization reaction between amino alcohol and benzyloxyacetaldehyde.
J. Heterocyclic Chem., 47, 50 (2010).
INTRODUCTION
ditions to prepare compound 7 (Scheme 1) [7]. Com-
pound 4 was conveniently prepared from L-tyrosine in
four steps [7a]: Reduction of compound 4 by catalytic
hydrogenation to give compound 5; Formylation of 5
with MeOCHCl2 in CH2Cl2 at room temperature in the
presence of TiCl4 to afford aldehyde 6; Baeyer-Villiger
oxidation of 6 using MCPBA in chloroform at room
temperature and the subsequent hydrolysis of the result-
ing formate to give phenol 7. Next, compound 7 was
reduced to the corresponding alcohol 8 by LiBH4 in
91% yield. The N-acetyl group was removed with 6N aq
HCl in CH3OH to give the amino alcohol 9 in 87%
yield. The highly regio- and diastereoselective Pictet-
Spengler cyclization reaction between amino alcohol 9
and benzyloxyacetaldehyde at 0ꢀC provided the 1,3-cis-
tetrahydroisoquinoline 10 in 64% yield and 11 in 20%
yield, respectively [8]. Initially, we removed the N-ace-
tyl group of compoud 7 to get a phenylalanine methyl
ester. However, the Pictet-Spengler cyclization reaction
between phenylalanine methyl ester and benzyloxyace-
taldehyde to construct the tetrahydrosioquinoline frag-
ment met with low yield and poor diastereoselectivity
and was ultimately abandoned [5,8a]. Finally, the O-
benzyl group of tetrahydroisoquinoline 10 was removed
by catalytic hydrogenation to give the expected product
(–)-MY 336a in 86% yield.
MY 336a was isolated in 1986 from the culture broth of
Streptomyces gabonae KY2234 (ATCC 15282) and was
characterized as a b-adrenergic receptor antagonist with
high affinities toward b1- and b2-adrenergic receptors [1]
(Fig. 1). Although the relative stereochemistry of MY
336a was determined by an X-ray study of its tetra-acetyl
derivative, there has been no report on the elucidation of
its absolute stereochemistry so far [2]. Kaufman reported
the total synthesis of the racemic MY 336a and its epimer,
which used Jackson’s isoquinoline synthesis as the key
reaction [3]. To date, there has been no report on the total
synthesis of its optically pure isomer except an attempt to
an enantioselective synthesis of MY336a [4].
In the course of our study of the total synthesis of (–)-
Renieramycin G and (–)-Lemonomycin, we take (–)-MY
336a as a key precursor for the construction of the AB
ring system of (–)-Renieramycin G and (–)-Lemonomycin.
Our group had previously reported the construction of the
AB ring system of ecteinascidin-saframycin alkaloids by
the Pictect-Spengler cyclization between the L-DOPA
derivatives and benzyloxyacetaldehyde in which the 1,3-
cis-diastereoisomer was the main product [5]. Herein, we
report an efficient total synthesis of (–)-MY 336a on the
basis of this methodology.
The stereochemistry of compound 1 was verified on
the basis of its NOE spectroscopy. Obvious NOE
enhancement was observed between 1-H and 3-H; thus
a cis-1,3-diaxial relationship was confirmed. The ortho-
relationship between 5-H and 6-Me was confirmed by
the observed NOE enhancement between them.
RESULTS AND DISCUSSION
Various methods to synthesize the highly functional-
ized L-tyrosine derivatives have been reported [6], and
we followed an existing procedure under modified con-
C
V
2009 HeteroCorporation

January 2010
Total Synthesis of (–)-MY 336a from L-Tyrosine
51
Figure 1. Structures of (–)-MY 336a and related tetrahydroisoquinoline alkaloids.
methyl methyl ether (16 mL, 0.18 mol, 1.3 equiv) in CH2Cl2
(250 ml) with stirring under 0ꢀC. The cooling bath was
removed, and the mixture was stirred for a further 3 h, and
then poured into ice-water (400 mL). The phases were sepa-
rated, and the aqueous phase was extracted with CH2Cl2 (200
mL 2ꢁ). The combined organic phase was washed with brine,
dried over Na2SO4, and concentrated by rotary evaporation.
The residue was purified by column chromatography (25% n-
hexane in EtOAc) to provide compound 6 (37.7 g, 92%) as a
white solid. [a]D20: þ102.5 (c 1.0, CHCl3). HRMS calcd. for
In summary, we have developed a new efficient route
to synthesize (–)-MY 336a using L-tyrosine as a chiral
starting material, which can be used to elucidate the
absolute stereochemistry of natural MY 336a. Further
study on the synthesis of Renieramycin G and Lemono-
mycin based on the methodology is ongoing in our
laboratory.
EXPERIMENTAL
1
C15H20NO5(MþHþ) 294.1341, found 294.1339. H NMR (300
1
General. H NMR spectra were recorded at 600 MHz or
MHz, CDCl3): d 10.33 (s, 1 H), 7.41 (d, J ¼ 2.1 Hz, 1 H),
7.22 (d, J ¼ 2.1 Hz, 1 H), 6.09 (d, J ¼ 7.5 Hz, 1 H), 4.88 (m,
1 H), 3.88 (s, 3 H), 3.75 (s, 3 H), 3.17 (dd, J ¼ 13.8, 5.4 Hz,
1 H), 3.06 (dd, J ¼ 13.8, 6.0 Hz, 1 H), 2.31 (s, 3 H), 1.99 (s,
3 H). 13C NMR (75 MHz, CDCl3): d 190.0, 171.8, 169.4,
160.8, 138.3, 132.5, 132.1, 128.9, 126.6, 63.1, 53.0, 52.4, 37.0,
23.0, 15.5.
300 MHz spectrometer at 24 ꢀC in the indicated solvent and
are reported in ppm relative to tetramethylsilane and refer-
enced internally to the residually protonated solvent. 13C NMR
spectra were recorded at 150 or 75 MHz spectrometer at 24ꢀC
in the solvent indicated and are reported in ppm relative to tet-
ramethylsilane and referenced internally to the residually pro-
tonated solvent. HRMS were carried out by Agilent LC/MSD
TOF. Optical rotations were measured on a PerkinElmer Polar-
imeter 341LC using 10 cm cells and the sodium D line (589
nm) at 20ꢀC and concentration indicated. All reagents were
obtained from commercial suppliers unless otherwise stated.
(S)-Methyl-2-acetamido-3-(4-methoxy-3-methylphenyl)pro-
panoate (5). To a solution of compound 4 (48 g, 0. 17 mol) in
MeOH (750 mL) at room temperature was added 1N aq. HCl
(40 mL) and 10% Pd-C (moist, 30 g), and the mixture was
hydrogenated in a Parr apparatus (50 psi H2) for 4 h. The reac-
tion mixture was filtered through celite, washed with MeOH,
and concentrated under vacuum. The residue was dissolved in
EtOAc (500 mL) and was then washed with saturated aq.
NaHCO3. The phases were separated, and the aqueous phase
was extracted with EtOAc (200 mL 2ꢁ). The combined or-
ganic phase was washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was puri-
fied by column chromatography (CHCl3) to afford compound
5 (38 g, 83%) as a clear oil. [a]D20: þ103.6 (c 1.0, CHCl3).
HRMS calcd. for C14H20NO4(MþHþ) 266.1392, found
266.1390. 1H NMR (300 MHz, CDCl3): d 6.89 (m, 2 H),
6.74 (d, J ¼ 8.1 Hz, 1 H), 6.00 (d, J ¼ 7.5 Hz, 1 H), 4.85
(m, 1 H), 3.79 (s, 3 H), 3.72 (s, 3 H), 3.08 (m, 2 H), 2.17 (s,
3 H), 1.98 (s, 3 H). 13C NMR (75 MHz, CDCl3): d 172.2,
169.5, 156.8, 131.4, 127.3, 127.1, 126.6, 109.8, 55.1, 53.2, 52.1,
36.8, 23.0, 16.1.
(S)-methyl-2-acetamido-3-(3-hydroxy-4-me-thoxy-5-meth-
ylphenyl)propanoate (7). To an ice cold solution of com-
pound 6 (15.0 g, 51.2 mmol) in CHCl3 (300 mL) was added
MCPBA (26.5 g, 153.6 mmol). The mixture was stirred vigo-
rously at room temperature for 6 h and then washed sequentially
with 10% Na2S2O3, saturated aqueous NaHCO3, brine, and dried
over Na2SO4. The solution was concentrated, and the residue
was dissolved in MeOH (150 mL). Then concentrated HCl
(12 N, 1.28 mL, 15.3 mmol, 0.3 equiv) was added at 0ꢀC. The
solution was then stirred for 10 h at room temperature and then
concentrated by rotary evaporation. The residue was purified by
column chromatography (2% CH3OH in CHCl3) to provide com-
pound 7 (13.2 g, 91%) as a yellow oil. [a]D20: þ91.5 (c 0.5,
CHCl3). HRMS calcd. for C14H20NO5(MþHþ) 282.1345, found
282.1341.1H NMR (300 MHz, CDCl3): d 6.54 (d, J ¼ 1.5 Hz,
1 H), 6.42 (d, J ¼ 1.2 Hz, 1 H), 6.14 (d, J ¼ 7.5 Hz, 1 H), 4.83
(dd, J ¼ 12.9, 5.7 Hz, 1 H), 3.77 (s, 3 H), 3.75 (s, 3 H), 2.97 (m,
2 H), 2.24 (s, 3 H), 2.00 (s, 3 H). 13C NMR (75 MHz, CDCl3): d
172.1, 170.0, 148.9, 144.5, 131.9, 130.9, 122.9, 114.2, 60.3,
53.1, 52.2, 37.1, 22.9, 15.7.
(S)-5-(2-Amino-3-hydroxypropyl)-2-meth-oxy-3-methyl-
phenol (9). To a solution of compound 7 (5.0 g, 13.9 mmol)
in THF (25 mL) was added LiBH4 (0.39 g, 18.1 mmol, 1.3
equiv) in portions at 0ꢀC. Then, the mixture was stirred for
18 h at room temperature and quenched slowly with saturated
aqueous NH4Cl (60 mL) and extracted with EtOAc (80 mL
3ꢁ). The organic layer was washed with brine (100 mL), dried
over Na2SO4, and concentrated by rotary evaporation. The res-
idue was purified by column chromatography (EtOAc) to pro-
vide 8 (4.2 g, 91%) as a white solid.
(S)-Methyl-2-acetamido-3-(3-formyl-4-methoxy-5-methyl-
phenyl)propanoate(6). Titanium chloride (58 mL, 0.42 mol, 3
equiv) in CH2Cl2 (150 mL ) was added dropwise over 1 h to a
solution of compound 5 (37 g, 0.14 mol) and a,a-dichloro-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

52
X. W. Liao, W. F. Dong, W. Liu, B. H. Guan, and Z. Z. Liu
Vol 47
Scheme 1. Reagents and conditions: (a) H2 (50 psi), 10% Pd-C, 1N aq. HCl, CH3OH, 4 h, 83%; (b) MeOCHCl2, TiCl4, CH2Cl2, r.t., 4 h, 92%; (c)
MCPBA, CHCl3, r.t., 6 h; (d) 12N HCl, CH3OH, 10 h, 91% for two steps; (ꢀe) LiBH4, THF, r.t., 24 h, 91%; (f) 6N aq. HCl, CH3OH, reflux, 10 h,
˚
87% ; (g) BnOCH2CHO, 4 A molecular sieves, CH2Cl2/CF3CH2OH¼7:1, 0 C, 8 h, compound 10 in 64% yield, compound 11 in 20% yield; (h)
H2(50 psi), Pd(OH)2, CH3OH, 12 h, 86%.
To a solution of 8 (3.4 g, 10.2 mmol) in CH3OH (60 mL)
was added 6 N aq. HCl (11 mL), and then, the mixture was
refluxed in an oil bath (80ꢀC) for 6 h. The reaction solution
was removed by rotary evaporation, and the residue was dis-
solved in CH3OH. The solution was basified with NEt3 and
purified directly by column chromatography (SiO2 treated with
NEt3, 5% CH3OH in CHCl3; then 10% CH3OH in CHCl3) to
provide 9 (2.6 g, 87%) as a white solid. [a]2D0: ꢂ7.4 (c 0.5,
CH3OH). HRMS calcd. for C11H18NO3(MþHþ) 212.1281,
8.65 (s, 1 H), 7.32 (m, 5 H ), 6.37 (s, 1 H), 4.71(t, J ¼ 5.1 Hz,
1 H), 4.52 (d, J ¼ 12.0 Hz, 1 H), 4.46 (d, J ¼ 12.0 Hz, 1 H),
4.31 (brd, J ¼ 6.0 Hz, 1 H), 4.13 (dd, J ¼ 8.7, 2.7 Hz,1 H),
3.59 (s, 3 H), 3.46 (m, 1 H), 3.43 (d, J ¼ 8.7 Hz, 1 H ), 3.34
(m, 1 H), 3.33 (s, 1H), 2.68(m, 1 H), 2.42 (dd, J ¼ 14.7, 2.4
Hz, 1 H), 2.28(dd, J ¼ 14.7, 10.8 Hz, 1 H), 2.14(s, 3 H). 13C
NMR (75 MHz, DMSO-d6): d 146.7, 143.8, 138.7, 132.6, 128.1,
128.0, 127.3, 127.2, 120.9, 73.8, 72.0, 65.2, 59.9, 53.9, 53.0,
33.0, 15.3. Compound 11: 1H NMR (300 MHz, DMSO-d6): d
8.94 (s, 1 H), 7.35 (m, 5 H ), 6.40 (s, 1 H), 4.77(t, J ¼ 2.4 Hz,
1 H), 4.59 (d, J ¼ 12.3 Hz, 1 H), 4.53 (d, J ¼ 12.3 Hz, 1 H),
4.09 (dd, J ¼ 9.9, 2.7 Hz, 1 H), 3.60 (s, 3 H), 3.50 (d, J ¼ 9.9,
5.4 Hz, 1 H), 3.47(d, J ¼ 12.9 Hz, 1 H), 3.28(dd, J ¼ 8.4, 2.7
Hz, 1 H), 3.22(m, 1 H), 3.10 (m, 1 H), 2.74(s, 1 H), 2.44 (dd,
J ¼ 15.9, 3.9 Hz, 1 H), 2.17(dd, J ¼ 15.9, 10.8 Hz, 1 H),
2.03(s, 3 H). 13C NMR (75 MHz, DMSO-d6): d 148.1, 143.9,
138.6, 130.4, 128.2, 127.8, 127.5, 127.3, 125.8, 124.4, 114.2,
71.9, 68.8, 65.7, 59.3, 53.0, 47.5, 31.3, 11.2.
(–)-MY 336a (1). To a solution of compound 10 (230 mg,
0.67 mmol ) in MeOH (4 mL) at room temperature was added
Pd(OH)2 (moist, Pd content 20%, 50 mg), and the mixture was
hydrogenated in a Parr apparatus (50 psi H2) for 10 h. The reac-
tion mixture was filtered through celite, washed with MeOH,
and concentrated under vacuum. The pale yellow residue was
purified by column chromatograph (SiO2 treated with triethyl-
amine, 5% MeOH in CHCl3) to afford compound 1 (147 mg,
86%) as a yellow solid. [a]2D0: ꢂ97.3 (c 0.5, CH3OH). HRMS
calcd. for C13H20NO4(MþHþ) 254.1387, found 254.1421 1H
NMR (600 MHz, DMSO- d6): d 8.65 (s, 1 H), 6.34 (s, 1 H), 4.66
(s, 1 H), 4.10 (t, J ¼ 4.2 Hz, 1 H), 3.90 (dd, J ¼ 10.2, 4.2 Hz,
1 H, 1-CH2OH,), 3.59(s, 3 H, 7-OMe), 3.43 (dd, J ¼ 10.8, 4.8
1
found 212.1313. H NMR (300 MHz, CD3COD): d 6.78 (d, J
¼ 2.1 Hz, 1H), 6.73 (d, J ¼ 1.8 Hz, 1H), 3.90 (s, 3 H), 3.85
(dd, J ¼ 11.7 Hz, 3.9 Hz, 1H), 3.67 (dd, J ¼ 11.7 Hz, 6.6Hz,
1H), 3.52 (m, 1H), 2.92 (m, 2 H), 2.40 (s, 3 H). 13C NMR
(75MHz, CD3COD): d 151.4, 146.5, 133.1, 133.0, 123.4,
116.0, 61.9, 60.4, 55.8, 36.3, 15.9.
(1R,3S)-1-(Benzyloxymethyl)-3-(hydroxyl-methyl)-7-methoxy-
6-methyl-1,2,3,4-tetra-hydroisoquinolin-8-ol (10) and (1R,3S)1-
(benzyloxymethyl)-3-(hydroxyl-methyl)-7-methoxy-8-methyl-1,2,
3,4-tetra-hydroisoquinolin-6-ol (11). To a solution of 9 (0.60 g,
2.84 mmol), acetic acid (0.43 g, 0.42 mL, 7.5 mmol, 2.5 equiv)
˚
and the 4 A molecular sieves (0.5 g) in dichloromethane and
2,2,2-trifluoroethanol (7:1, v/v, 12 mL), a solution of benzylox-
yacetaldehyde (0.47 g, 3.1 mmol, 1.1 equiv) in dichloromethane
was added slowly via syringe over 1 h at 0ꢀC. After being
stirred at 0ꢀC for 8 h, the reaction mixture was diluted with
dichloromethane and filtered. The filtrate was concentrated under
reduced pressure, and the residue was purified by flash column
chromatography (2% MeOH in chloroform) to afford 10 (0.63 g,
64%) and 11 (0.19 g, 20%) as white solid. Compound 10: [a]2D0:
ꢂ115.2 (c 0.5, CH3OH). HRMS calcd. for C20H26NO4(MþHþ)
344.1856, found 344.1885. 1H NMR (300 MHz, DMSO-d6): d
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2010
Total Synthesis of (–)-MY 336a from L-Tyrosine
53
[2] Hirayama, N.; Iida, T.; Shirahata, K. Acta Crystaallogr Sect
C 1990, 46, 86.
Hz, 1H, 3-CH2OH), 3.36 (dd, J ¼ 10.2, 6.6 Hz, 1H, 1-CH2OH),
3.32 (dd, J ¼ 10.8, 6.6 Hz, 1 H, 3-CH2OH), 2.68 (m, 1 H, 3-H),
2.41 (dd, J ¼ 15.0, 2.4 Hz, 1 H, 4-Heq), 2.24 (dd, J ¼ 14.4, 11.4
Hz, 1 H, 4-Hax), 2.11(s, 3 H, 6-Me). 13C NMR (75MHz, DMSO-
d6): d 146.8, 143.9, 132.4, 127.8, 121.9, 120.9, 65.3, 64.8, 59.7,
54.9, 53.9, 33.0, 15.3.
[3] (a) Kaufman, T. S. J Chem Soc Perkin Trans 1 1993, 4,
403; (b) Kaufman, T. S. J Chem Soc Perkin Trans 1 1996, 20, 2497.
[4] Kaufman, T. S. Tetrahedron Lett 1996, 37, 5329.
[5] (a) Wang, Y.; Liu, Z. Z.; Chen, S. Z.; Liang, X. T. Chin Chem
Lett 2004, 15, 505; (b) Tang, Y. F.; Liu, Z. Z.; Chen, S. Z. Tetrahedron
Lett 2003, 44, 7091; (c) Liu, Z. Z.; Wang, Y.; Tang, Y. F.; Chen, S. Z.;
Chen, X. G.; Li, H. Y. Bioorg Med Chem Lett 2006, 16, 1282.
[6] (a) Schmidt, E. W.; Nelson, J. T.; Fillmore, J. P. Tetrahe-
dron Lett 2004, 45, 3921; (b) Jin, W.; Williams, R. M. Tetrahedron
Lett 2003, 44, 4635; (c) Paolis, M. D.; Chen, X. C.; Zhu, J. P. Synlett
2004, 4, 729.
Acknowledgments. The Authors thank the National Natural Sci-
ence Foundation of China (No. 30672518) and Specialized
Research Fund for the Doctoral Program of Higher Education
(No. 20060023025) for financial support.
[7] (a) Arnold, Z. S. Polish J Chem 1985, 59, 837; (b) Jow, C.
K. Ph.D. Dissertation, W. M. Rice University, Texas, 1995.
[8] (a) Kwon, S.; Myers, A. G. J Am Chem Soc 2005, 127,
16796; (b) Chen, J.; Chen, X.; Zhu, J. J Am Chem Soc 2006, 128, 87.
REFERENCES AND NOTES
[1] Kase, H.; Fujita, H.; Nakamura, J.; Hashizumi, K.; Goto, J.;
Kubo, K.; Shito, K. J Antibiot 1986, 39, 354.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet