Asymmetric total synthesis of (-)-saframycin A from l-tyrosine

Article abstract of DOI:10.1021/jo200758r

The asymmetric total synthesis of (-)-saframycin A, a natural antitumor product of the tetrahydroisoquinoline antitumor antibiotics family, has been accomplished by employing l-tyrosine as the starting chiral building block in 24 steps for the longest lin

Full text of DOI:10.1021/jo200758r

ARTICLE
pubs.acs.org/joc
Asymmetric Total Synthesis of (ꢀ)-Saframycin A from L-Tyrosine
Wenfang Dong, Wei Liu, Xiangwei Liao, Baohe Guan, Shizhi Chen, and Zhanzhu Liu*
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical
College and Chinese Academy of Medical Sciences, Beijing 100050, P. R. China
S Supporting Information
b
ABSTRACT:
The asymmetric total synthesis of (ꢀ)-saframycin A, a natural antitumor product of the tetrahydroisoquinoline antitumor
antibiotics family, has been accomplished by employing L-tyrosine as the starting chiral building block in 24 steps for the longest
linear sequence in an overall yield of 9.7%. The key steps in the synthesis involve stereoselective intermolecular and intramolecular
PictetꢀSpengler reactions, which induced the correct stereochemistry at C-1 and C-11, respectively. The selective protec-
tionꢀdeprotection protocol of an amino group in the two-step transformation from intermediate 10 to 12 and a hydroxyl group in
the first two steps resulted in both high selectivity and efficiency of the synthetic route.
’ INTRODUCTION
reaction of compound 10. Compound 10 could be synthesized
through the coupling of N-Cbz-protected 1,2,3,4-tetrahydroiso-
quinoline moiety 5 and N-Boc protected amino acid moiety 6,
both of which could be prepared through several steps from the
same starting material L-tyrosine.
(ꢀ)-Saframycin A is a member of the tetrahydroisoquinoline
antitumor antibiotics that were isolated from Streptomyces laven-
dulae 314 in 1977 by Arai et al.1ꢀ3 Members of this family of
alkaloids have shown potent antitumor activities, such as Et-743,
which has been launched in Europe for treating soft tissue
sarcoma,4 and its analogue Zalypsis, which has been under phase
II clinical trials for treating Ewing’s sarcoma5,6 (Figure 1). As a
typical member of this family of natural products, (ꢀ)-saframy-
cin A has a characteristic pentacyclic skeleton and remarkable
antitumor activity. So far, one racemic and two asymmetric total
syntheses have been reported.7ꢀ11
Our group has established a novel biomimetic strategy for
the stereocontrolled synthesis of the tetrahydroisoquinoline
alkaloids employing L-dopa or L-tyrosine as the starting chiral
building block. A series of simplified analogues have been
synthesized from L-dopa,12,13 and (ꢀ)-renieramycin G and its
derivatives have been synthesized from L-tyrosine in our lab.14ꢀ16
As a continuation of the total synthesis research on the tetra-
hydroisoquinoline antitumor antibiotics, we report herein a
biomimetic total synthesis of (ꢀ)-saframycin A from L-tyrosine.
Following the strategy of our previous studies on bistetrahy-
droisoquinoline alkaloids, we obtained amino acid moiety 6 from
commercially available L-tyrosine methyl ester in 12 steps in an
overall yield of 36%.14 On the other hand, the amino alcohol
intermediate 2 and N-Cbz-protected amino acetaldehyde 3 were
coupled in acetic acid through the stereospecific intermolecular
PictetꢀSpengler reaction to afford compound 4 in 86% yield
(Scheme 2).15 In this reaction, the use of bromine to protect the
position para to the hydroxyl group was avoided to improve the
synthetic efficiency. The regioselectivity and stereoselectivity for
the conversion of 2 to 4 were found to be affected by the
temperature and the addition speed of aldehyde 3. Keeping a
slow addition speed and the temperature at 0 °C, the 1,3-cis-
stereoisomer could be obtained dominantly through the highly
regioselective and diastereoselective ortho cyclization on the
benzene ring. Strong NOE correlations between Me- and H-5
indicated that a correct cyclization occurred at the ortho site of
the phenolic hydroxyl group. Additionally, obvious NOE corre-
lations between H-1 and H-3 confirmed a cis relationship
between these two protons (Figure 2). Silylation of compound
’ RESULTS AND DISCUSSION
The retrosynthetic analysis of (ꢀ)-saframycin A is shown in
Scheme 1. We envisioned that (ꢀ)-saframycin A (1) could be
obtained by the oxidation of the phenolic hydroxyl groups of
compound 17. Next, the pentacyclic skeleton could be constru-
cted through the stereospecific intramolecular PictetꢀSpengler
Received: April 12, 2011
Published: May 25, 2011
r
2011 American Chemical Society
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already established intramolecular PictetꢀSpengler reaction
conditions by our group, super acid TfOH (trifluoromethanesul-
fonic acid) was chosen to realize the PictetꢀSpengler cyclization
reaction. However, several attempts using various proportions of
TfOH in CH2Cl2 were not successful, and only N-deprotected
10 was obtained. Finally, pure TfOH was used to treat compound
10 at room temperature for two hours to successfully give the
expected pentacyclic intermediate 11 in 83% yield. Noticeably,
the N-Boc and N-Cbz protecting groups were removed simulta-
neously in this reaction. Next, the primary amine group of com-
pound 12. Reductive methylation of compound 12 with HCHO
afforded compound 13 (Scheme 3).
With intermediate 13 in hand, we completed the final stage of
the synthesis of (ꢀ)-saframycin A in five steps. First, removal of
the bromine atom by catalytic hydrogenolysis afforded com-
pound 14. Then the lactam ring of compound 14 was reduced
with LiAlH4 at low temperature in THF for two hours to afford
the corresponding hemiaminal intermediate, which was then
cyanided with KCN in acidified THF/H2O to give amino nitrile
15.22 The N-Boc protecting group of compound 15 was removed
in high yield via treatment with TFA. Then deprotected com-
pound 16 was coupled with pyruvic acid to afford pyruvamide
17.23 Oxidation of compound 17 with air in the presence of
catalyst salcomine afforded (ꢀ)-saframycin A as the final target
1
product (Scheme 4).24 The H NMR, 13C NMR, and HRMS
Figure 1. Structures of tetrahydroisoquinoline alkaloids.
spectra and the specific optical rotation of the synthetic product 1
were consistent with those reported for natural saframycin A.1,2,11
Scheme 1. Retrosynthetic Analysis of (ꢀ)-Saframycin A
’ CONCLUSIONS
(ꢀ)-Saframycin A has been successfully synthesized as a single
enantiomer in 24 steps for the longest linear sequence from L-
tyrosine methyl ester in an overall yield of 9.7%. In the key step of
the synthesis of 1,2,3,4-tetrahydroisoquinoline 5, we avoided
introducing the bromine atom at the para site of the phenolic
hydroxyl group and realized the highly regioselective and stereo-
selective cyclization through the careful control of the tempera-
ture and the addition speed of the aldehyde. The key pentacyclic
intermediate 11 was constructed through the intramolecular
PictetꢀSpengler reaction with pure TfOH as both the solvent
and catalyst. Following a selective protectionꢀdeprotection
protocol, we finally obtained (ꢀ)-saframycin A which is identical
with the natural product. Among the five chiral centers, C-3 and
C-13 came from L-tyrosine; C-1 and C-11 were induced through
the intermolecular and intramolecular PictetꢀSpengler reaction;
and C-21 was induced in the substitution reaction. In the future
studies, the present route with L-tyrosine as the starting chiral
building block will be employed to synthesize the derivatives of
(ꢀ)-saframycin A and other related tetrahydroisoquinoline
antitumor antibiotics.
4 with TBSCl afforded O-TBS-protected 1,2,3,4-tetrahydroiso-
quinoline fragment 5.17
’ EXPERIMENTAL SECTION
1,2,3,4-Tetrahydroisoquinoline 5 and amino acid 6 were
coupled through the catalysis of BOPCl to give the amide
intermediate 7.18 Then the TBS-ether derivative 7 was selectively
deprotected with HCOOH to afford the primary alcohol com-
pound 8.19 Oxidation of compound 8 with DessꢀMartin period-
inane afforded the corresponding hemiaminal 9.20 Complete
removal of the two phenolic TBS groups of compound 9 with
TBAF afforded compound 10. Having obtained the deprotected
hemiaminal 10, we investigated its stereoselective conversion to
the pentacyclic skeleton intermediate 11.14,21 On the basis of the
Benzyl((1R,3S)-8-hydroxy-3-(hydroxymethyl)-7-methoxy-
6-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methylcarba-
mate (4). To a stirred solution of compound 2 (6.90 g, 32.70 mmol),
acetic acid (4.98 mL, 81.75 mmol), and 4 Å molecular sieves (5.00 g) in
CH2Cl2ꢀCF3CH2OH (7:1, v/v, 180 mL) was added aldehyde 3 (0.6 M in
CH2Cl2, 60 mL) dropwise at 0 °C under argon, and then the mixture was
stirred for 10 h at this temperature. The reaction mixture was filtered and
concentrated under reduced pressure to give the crude product. Purifica-
tion by column chromatography (CH2Cl2/MeOH = 100:3) afforded
the tetrahydroisoquinoline product 4 (10.8 g, 86%) as a white solid.
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Scheme 2. Synthesis of Compounds 5 and 6
Scheme 4. Synthesis of (ꢀ)-Saframycin A
Figure 2. NOE correlations of compound 4.
Scheme 3. Synthesis of Compound 13
Benzyl((1R,3S)-8-(tert-butyldimethylsilyloxy)-3-((tert-bu-
tyldimethylsilyloxy)methyl)-7-methoxy-6-methyl-1,2,3,4-
tetrahydroisoquinolin-1-yl)methylcarbamate (5). To a solu-
tion of compound 4 (5.00 g, 12.95 mmol) in DMF (15 mL) was added
imidazole (7.78 g, 113.96 mmol) and TBSCl (8.60 g, 56.98 mmol), and
then the mixture was stirred at room temperature under argon for 48 h.
After dilution with EtOAc (150 mL), the mixture was washed with water
(70 mL ꢁ 3) and brine (70 mL), dried over anhydrous Na2SO4, and
concentrated under reduced pressure to give the crude product. Purifica-
tion by column chromatography (PET/EtOAc = 10:1) afforded the TBS-
protected product 5 (7.25 g, 91%) as a yellow oil. 1H NMR (300 MHz,
CDCl3) δ 7.36ꢀ7.28 (m, 5H), 6.54 (s, 1H), 5.08ꢀ5.00 (m, 2H), 4.43 (s,
1H), 3.68 (d, J = 9.9 Hz, 1H), 3.64 (d, J = 9.9 Hz, 1H), 3.59 (s, 3H),
3.60ꢀ3.54 (m, 2H), 2.92ꢀ2.82 (m, 1H), 2.46ꢀ2.41 (m, 2H), 2.21 (s,
3H), 0.97 (s, 9H), 0.91 (s, 9H), 0.26 (s, 3H), 0.09 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 156.6, 147.8, 145.8, 136.8, 132.7, 129.9, 128.4 (2C),
127.9 (2C), 125.6, 124.4, 123.8, 67.3, 66.8, 66.3, 60.0, 54.0, 52.8, 45.4,
32.8, 26.1 (2C), 25.9 (2C), 25.6, 18.6, 18.4, 15.8, ꢀ3.6, ꢀ3.7, ꢀ4.3, ꢀ5.3;
HRMS calcd for C33H55N2O5 Si2 [M þ H]þ 615.3649, found 615.3645.
Compound 7. To an ice-cooled solution of compound 5 (8.90 g,
14.50 mmol) in CH2Cl2 (200 mL) were added Et3N (5.20 mL, 37.70
20
1
Mp = 157ꢀ159 °C; [R]D = ꢀ137 (c 0.10, CH2Cl2); H NMR (600
MHz, DMSO-d6) δ 8.69 (s, 1H), 7.36ꢀ7.29 (m, 5H), 6.91 (t, J = 5.4 Hz,
1H), 6.37 (s, 1H), 4.99 (d, J = 12.6 Hz, 2H), 4.61 (t, J = 5.4 Hz, 1H), 4.20
(d, J = 6.0 Hz, 1H), 3.74ꢀ3.71 (m, 1H), 3.59 (s, 3H), 3.42ꢀ3.39 (m, 1H),
3.34ꢀ3.30 (m, 1H), 3.06ꢀ3.01 (m, 1H), 2.69ꢀ2.68 (m, 1H), 2.42 (dd, J =
14.4, 1.8 Hz, 1H), 2.25 (dd, J = 14.4, 10.8 Hz, 1H), 2.14 (s, 3H); 13C NMR
(100 MHz, DMSO-d6) δ 156.3, 146.6, 143.9, 137.3, 132.5, 128.3 (3C),
128.0, 127.6 (2C), 121.7, 120.8, 65.4, 65.0, 59.9, 54.1, 52.2, 45.9, 32.8, 15.4;
HRMS calcd for C21H27N2O5 [M þ H]þ 387.1919, found 387.1920.
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mmol), compound 6 (9.74 g, 18.85 mmol), and BOPCl (4.80 g, 18.85
mmol) in portions, and then the mixture was stirred at room
temperature for 72 h. The reaction was quenched with 2 N aq. HCl,
and the organic phase was separated and washed with brine, dried over
anhydrous Na2SO4, and concentrated under reduced pressure to give
the crude product. Purification by column chromatography (PET/
EtOAc = 20:1) afforded the amide derivative 7 (14.23 g, 88%) as a
white solid. Mp = 62ꢀ64 °C; [R]D = þ10 (c 0.10, CH2Cl2); H
NMR (300 MHz, CDCl3) δ 7.31ꢀ7.29 (m, 5H), 6.58 (s, 1H), 6.55 (s,
1H), 5.99 (m, 1H), 5.89 (br s, 1H), 5.06 (s, 2H), 4.37 (m, 1H),
3.86ꢀ3.74 (m, 2H), 3.73 (m, 1H), 3.71 (m, 1H), 3.63 (s, 3H), 3.62 (s,
3H), 3.24ꢀ3.14 (m, 1H), 3.00ꢀ2.90 (m, 1H), 2.90ꢀ2.80 (m, 1H),
2.78ꢀ2.70 (m, 1H), 2.70ꢀ2.62 (m, 1H), 2.35 (s, 1H), 2.27 (s, 3H),
2.22 (s, 3H), 1.29 (s, 9H), 1.02 (s, 9H), 0.98 (s, 9H), 0.84 (s, 9H), 0.28
(s, 3H), 0.17 (s, 3H), 0.16 (s, 3H), 0.14 (s, 3H), 0.05 (s, 3H), 0.03 (s,
3H); 13C NMR (150 MHz, CDCl3) δ 174.0, 156.2, 154.6, 149.1,
148.1, 147.5, 145.1, 137.1, 132.8, 131.6, 131.1, 128.3 (2C), 127.8,
127.7 (2C), 127.6, 124.2, 123.3, 121.9, 119.2, 79.1, 68.0, 66.1, 65.4,
60.0, 52.9, 52.3, 50.6, 48.8, 45.6, 41.0, 28.8, 28.2 (3C), 26.1 (3C), 25.9
(3C), 25.6 (3C), 18.6, 18.2, 18.1, 16.9, 15.8, ꢀ3.8, ꢀ4.3, ꢀ4.6, ꢀ5.5,
ꢀ5.6; HRMS calcd for C55H89BrN3O10 Si3 [M þ H]þ 1114.5033,
found 1114.4994.
Compound 10. To an ice-cooled solution of compound 9 (1.90 g,
1.91 mmol) in THF (40 mL) was added TBAF (1.0 M in THF,
5.73 mL), and then the mixture was stirred at 0 °C for 1 h. The reaction
was quenched with saturated aq. NH4Cl and extracted with EtOAc
(40 mL ꢁ 3). The combined organic phase was washed with brine, dried
over anhydrous Na2SO4, and concentrated under reduced pressure to
give the crude product. Purification by column chromatography (PET/
EtOAc = 1:1) afforded the deprotected product 10 (1.45 g, 99%) as a
white solid. Mp = 84ꢀ86 °C; [R]D20 = ꢀ85 (c 0.10, CH2Cl2); 1H NMR
(300 MHz, DMSO-d6) δ 9.22 (s, 1H), 9.02 (s, 1H), 7.30ꢀ7.16 (m, 5H),
6.88 (s, 1H), 6.76 (s, 1H), 6.52 (s, 1H), 5.74 (s, 1H), 5.64 (s, 1H), 4.88
(s, 2H), 4.66 (d, J = 9.0 Hz, 1H), 3.63 (s, 3H), 3.58 (s, 3H), 3.57ꢀ3.40
(m, 4H), 3.11ꢀ3.03 (m, 2H), 2.89 (t, J = 13.2 Hz, 1H), 2.68 (d, J = 13.2
Hz, 1H), 2.26 (s, 3H), 2.17 (s, 3H), 0.98 (s, 9H); 13C NMR (150 MHz,
DMSO-d6) δ 167.2, 156.1, 152.2, 148.7, 146.2, 145.1, 144.4, 137.1,
133.7, 131.2, 130.6, 129.3, 128.2 (2C), 127.6, 127.4 (2C), 119.8, 119.4,
118.0, 116.5, 79.0, 73.8, 65.2, 59.8, 59.7, 58.0, 54.9, 48.9, 44.2, 42.2, 30.8,
27.7, 27.3, 16.6, 15.5, 14.0; HRMS calcd for C37H44BrN3O10Na [M þ
Na]þ 792.2102, found 792.2071.
20
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Compound 11. A mixture of compound 10 (1.02 g, 1.33 mmol) in
TfOH (10 mL) was stirred at room temperature under argon for 2 h, and
then the mixture was basified with saturated aq. NaHCO3 and extracted
with EtOAc (40 mL ꢁ 3). The combined organic phase was washed with
brine, dried over anhydrous Na2SO4, and concentrated under reduced
pressure to give the crude product. Purification by column chromatog-
raphy (CH2Cl2/MeOH = 100:2) afforded the pentacyclic product 11
Compound 8. A mixture of compound 7 (8.60 g, 7.73 mmol) in
THFꢀHCOOHꢀH2O (6:3:1, 130 mL) was stirred at room tempera-
ture for 10 h, and then the mixture was concentrated under reduced
pressure. The residue was dissolved in EtOAc, washed with saturated aq.
NaHCO3 and brine, dried over anhydrous Na2SO4, and concentrated
under reduced pressure to give the crude product. Purification by
column chromatography (PET/EtOAc = 8:1) afforded selectively
deprotected product 8 (7.11 g, 92%) as a white solid. Mp =
20
(568 mg, 83%) as a white solid. Mp = 183ꢀ185 °C; [R]D = ꢀ47
(c 0.10, CH2Cl2); 1H NMR (300 MHz, DMSO-d6) δ 6.46 (s, 1H), 5.23
(d, J = 6.6 Hz, 1H), 4.39 (d, J = 3.0 Hz, 1H), 3.83 (d, J = 12.9 Hz, 1H),
3.74 (s, 1H), 3.64 (s, 3H), 3.61 (s, 3H), 2.96 (d, J = 13.2 Hz, 1H), 2.80
(s, 2H), 2.66 (dd, J = 11.4, 3.0 Hz, 1H), 2.27 (s, 3H), 2.13 (s, 3H), 2.08
(d, J = 13.8 Hz, 1H), 1.95 (dd, J = 11.4, 9.6 Hz, 1H); 13C NMR (100
MHz, DMSO-d6) δ 170.3, 147.5, 146.0, 145.9, 144.5, 130.5, 130.0,
129.7, 129.1, 122.3, 122.2, 119.7, 116.0, 61.1, 60.4, 59.4, 53.4, 51.2, 48.4,
46.6, 36.1, 31.9, 16.5, 15.6; HRMS calcd for C24H29BrN3O5 [M þ H]þ
518.1285, found 518.1274.
20
1
78ꢀ80 °C; [R]D = þ21 (c 0.10, CH2Cl2); H NMR (300 MHz,
DMSO-d6) δ 7.33ꢀ7.14 (m, 5H), 6.87 (s, 1H), 6.63 (s, 1H), 6.30 (s,
1H), 5.92 (s, 1H), 4.99 (d, J = 12.6 Hz, 1H), 4.92 (d, J = 12.6 Hz, 1H),
4.74ꢀ4.72 (m, 1H), 4.26 (s, 1H), 3.67 (s, 1H), 3.66ꢀ3.56 (m, 1H), 3.56
(s, 3H), 3.55 (s, 3H), 2.98ꢀ2.95 (m, 1H), 2.86ꢀ2.81 (m, 1H),
2.74ꢀ2.62 (m, 3H), 2.28ꢀ2.20 (m, 2H), 2.20 (s, 3H), 2.15 (s, 3H),
1.24 (s, 9H), 0.94 (s, 18H), 0.22 (s, 3H), 0.12 (s, 9H); 13C NMR (150
MHz, DMSO-d6) δ 173.3, 155.6, 155.3, 148.4, 147.3, 146.9, 144.4,
137.2, 132.3, 131.9, 131.6, 130.2, 128.2 (2C), 127.5 (2C), 127.3 (2C),
123.3, 121.8, 118.2, 78.0, 65.1, 63.9, 59.7, 52.3, 50.8, 48.1, 44.5, 38.1,
28.5, 28.0 (2C), 27.9, 27.6, 26.0 (3C), 25.5 (3C), 18.3, 17.9, 16.7, 15.5,
ꢀ3.8, ꢀ4.4, ꢀ4.7, ꢀ4.8; HRMS calcd for C49H75BrN3O10Si2 [M þ
H]þ 1000.4169, found 1000.4182.
Compound 12. To a solution of compound 11 (568 mg, 1.10
mmol) and Et3N (0.38 mL, 2.75 mmol) in CH2Cl2 (60 mL) was added
Boc2O (1.0 M in CH2Cl2, 11 mL) dropwise at 0 °C, and then the
mixture was stirred at room temperature for 4.5 h. The reaction mixture
was washed with brine, dried over anhydrous Na2SO4, and concentrated
under reduced pressure to give the crude product. Purification by
column chromatography (CH2Cl2/MeOH = 100:1) afforded the
N-protected product 12 (616 mg, 91%) as a white solid. Mp =
Compound 9. To a solution of compound 8 (4.30 g, 4.30 mmol) in
CH2Cl2 (100 mL) was added DessꢀMartin periodinane (3.20 g, 7.52
mmol) and NaHCO3 (5.00 g, 60.20 mmol), and then the mixture was
stirred at room temperature for 2 h. The mixture was washed with
saturated aq. NaHCO3 and brine, dried over anhydrous Na2SO4, and
concentrated under reduced pressure to give the crude product.
Purification by column chromatography (PET/EtOAc = 10:1) afforded
the hemiaminal product 9 (4.01 g, 94%) as a white solid. Mp =
20
1
127ꢀ129 °C; [R]D = ꢀ74 (c 0.10, CH2Cl2); H NMR (300 MHz,
DMSO-d6) δ 8.93 (br s, 2H), 6.46 (s, 1H), 5.52 (s, 1H), 5.50 (s, 1H),
4.39 (s, 1H), 3.81ꢀ3.73 (m, 1H), 3.73 (s, 1H), 3.62 (s, 3H), 3.59 (s,
3H), 3.31 (br s, 1H), 3.26 (s, 1H), 2.97 (d, J = 13.2 Hz, 1H), 2.90ꢀ2.82
(m, 3H), 2.27 (s, 3H), 2.25 (d, J = 13.2 Hz, 1H), 2.15 (s, 3H), 1.15 (s,
6H), 0.94 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 170.6, 154.8,
146.3, 146.0, 144.5, 144.4, 132.4, 129.9, 129.8, 129.3, 122.1, 119.9, 119.1,
116.0, 77.4, 61.4, 60.4, 59.8, 53.3, 48.3, 47.4, 44.0, 36.1, 31.8, 27.9 (2C),
27.3, 16.5, 15.4; HRMS calcd for C29H37BrN3O7 [M þ H]þ 618.1809,
found 618.1795.
20
1
112ꢀ114 °C; [R]D = ꢀ75 (c 0.10, CH2Cl2); H NMR (300 MHz,
DMSO-d6) δ 7.28ꢀ7.19 (m, 5H), 6.97 (s, 1H), 6.70 (s, 1H), 6.68 (s,
1H), 5.74ꢀ5.73 (m, 2H), 4.91 (d, J = 12.3 Hz, 1H), 4.84 (d, J = 12.3 Hz,
1H), 4.68 (dd, J = 10.8, 3.6 Hz, 1H), 3.64 (s, 3H), 3.55 (s, 3H),
3.52ꢀ3.47 (m, 2H), 3.42ꢀ3.31 (m, 3H), 3.15 (t, J = 13.2 Hz, 1H),
2.96ꢀ2.86 (m, 1H), 2.74 (d, J = 13.2 Hz, 1H), 2.28 (s, 3H), 2.17 (s, 3H),
2.07 (s, 9H), 1.00ꢀ0.93 (m, 18H), 0.21ꢀ0.08 (m, 12H); 13C NMR
(150 MHz, DMSO-d6) δ 167.3, 156.0, 152.1, 148.1, 147.6, 146.9, 144.6,
137.0, 133.7, 131.2, 130.0, 128.2 (2C), 127.6, 127.4 (2C), 123.8, 122.8,
122.0, 119.4, 79.2, 73.5, 65.2, 59.7, 59.5, 57.9, 54.6, 49.2, 44.4, 42.5, 27.4
(3C), 25.9 (3C), 25.5 (3C), 18.3, 17.9, 16.7, 15.7, ꢀ4.0, ꢀ4.6, ꢀ4.7,
ꢀ4.8; HRMS calcd for C49H76BrN4O10Si2 [M þ NH4]þ 1015.4278,
found 1015.4235.
Compound 13. To a solution of compound 12 (507 mg, 0.82
mmol) in CH3OH (40 mL) were added HCHO (37%, 4.40 mL),
NaBH3CN (520 mg, 8.2 mmol), and acetic acid (7.9 mL), and then the
mixture was stirred at room temperature for 2 h. The mixture was
concentrated under reduced pressure and then dissolved in EtOAc,
washed with saturated aq. NaHCO3 and brine, dried over anhydrous
Na2SO4, and concentrated under reduced pressure to give the crude
product. Purification by column chromatography (CH2Cl2/MeOH =
100:1) afforded methylated product 13 (516 mg, 99%) as a white solid.
20
1
Mp = 132ꢀ134 °C; [R]D = ꢀ72 (c 0.10, CH2Cl2); H NMR (300
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MHz, DMSO-d6) δ 9.34 (s, 1H), 8.99 (s, 1H), 6.46 (s, 1H), 5.52 (s, 1H),
5.47 (t, J = 5.1 Hz, 1H), 4.27 (d, J = 2.4 Hz, 1H), 3.84 (d, J = 11.7 Hz,
1H), 3.64 (s, 3H), 3.57 (s, 3H), 3.57ꢀ3.54 (m, 1H), 2.99ꢀ2.87 (m, 3H),
2.70 (s, 1H), 2.64 (s, 1H), 2.29 (s, 6H), 2.16 (s, 3H), 2.29ꢀ2.22 (m,
1H), 1.15 (s, 6H), 0.95 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ
170.2, 154.8, 147.0, 146.3, 144.6, 144.4, 132.3, 130.0, 129.3, 128.8, 119.9,
119.4, 119.0, 115.8, 77.4, 60.4, 59.8, 59.2, 58.2, 54.9, 54.6, 47.8, 43.6,
31.3, 30.6, 27.9 (2C), 27.3, 16.5, 15.4; HRMS calcd for C30H39BrN3O7
[M þ H]þ 632.1966, found 632.1971.
J = 15.0, 2.1 Hz, 1H), 2.58 (dd, J = 13.5, 5.4 Hz, 1H), 2.47 (d, J = 18.0 Hz,
1H), 2.32 (s, 3H), 2.23 (s, 3H), 2.21 (s, 3H), 2.06 (dd, J = 15.0, 12.3 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 146.6, 145.9, 144.4, 142.7, 131.7,
130.8, 129.1, 128.7, 120.8(2C), 119.5, 118.2, 116.9, 60.7, 60.4, 60.3, 59.1,
56.6, 55.4, 45.5, 41.8, 32.1, 29.7, 25.8, 15.7, 15.6; HRMS calcd for
C26H33N4O4 [M þ H]þ 465.2496, found 465.2508.
Compound 17. To a solution of compound 16 (40 mg, 0.086
mmol) in CH2Cl2 (5 mL) were added pyruvic acid (10.5 mg, 0.129
mmol), DMAP (10.5 mg, 0.086 mmol), and EDC (25.2 mg, 0.129
mmol), and then the mixture was stirred at room temperature for 10 h.
The mixture was diluted with CH2Cl2, washed with saturated aq.
NaHCO3 and brine, dried over anhydrous Na2SO4, and concentrated
under reduced pressure to give the crude product. Purification by
column chromatography (PET/EtOAc = 1:1) afforded pyruvamide 17
(37 mg, 80%) as a white solid. Mp = 100ꢀ102 °C; [R]D20 = þ4 (c 0.10,
CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 6.46 (s, 1H), 6.44 (s, 1H),
6.40 (br s, 1H), 5.82 (s, 1H), 5.70 (s, 1H), 4.20 (br s, 1H), 4.09 (s, 1H),
4.01 (d, J = 1.8 Hz, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 3.58ꢀ3.49 (m, 1H),
3.45ꢀ3.38 (m, 1H), 3.35 (d, J = 7.8 Hz, 1H), 3.30ꢀ3.29 (m, 1H), 3.02
(dd, J = 18.3, 8.1 Hz, 1H), 2.78 (d, J = 17.7 Hz, 1H), 2.44 (d, J = 17.7 Hz,
1H), 2.30 (s, 3H), 2.24 (s, 3H), 2.23 (s, 3H), 2.22 (s, 3H), 2.10 (dd, J =
16.2, 11.4 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 196.1, 159.9, 146.6,
144.9, 143.6, 129.3, 121.3 (2C), 120.9 (2C), 117.6, 60.8, 59.9, 56.7, 56.6,
55.4, 41.6, 41.3, 31.8, 29.7, 25.5, 24.4, 22.7, 15.9, 15.7; HRMS calcd for
C29H35N4O6 [M þ H]þ 535.2551, found 535.2555.
Compound 14. To a solution of compound 13 (426 mg, 0.68
mmol) in CH3OH (40 mL) were added Pd(OH)2 (moist, Pd content
20%, 340 mg) and acetic acid (40 drops); then the mixture was
hydrogenated in a Parr apparatus (50 psi H2) for 10 h at room
temperature. The reaction mixture was filtered and concentrated under
reduced pressure. The residue was dissolved in EtOAc (50 mL), washed
with saturated aq. NaHCO3 and brine, dried over anhydrous Na2SO4,
and concentrated under reduced pressure to give the crude product.
Purification by column chromatography (PET/EtOAc = 1:2) afforded
hydrogenation product 14 (349 mg, 93%) as a white solid. Mp =
167ꢀ169 °C; [R]D20 = ꢀ263 (c 0.10, CH2Cl2); 1H NMR (300 MHz,
DMSO-d6) δ 8.96 (s, 1H), 8.91 (s, 1H), 6.45 (s, 2H), 5.50 (t, J = 5.4 Hz,
1H), 5.32 (s, 1H), 4.18 (s, 1H), 3.83 (d, J = 12.6 Hz, 1H), 3.62 (s, 3H),
3.60 (s, 3H), 3.50 (d, J = 6.0 Hz, 1H), 3.10 (dd, J = 17.1, 6.6 Hz, 1H),
2.96ꢀ2.86 (m, 2H), 2.63 (s, 1H), 2.57 (s, 1H), 2.31 (s, 3H), 2.31ꢀ2.25
(m, 1H), 2.17 (s, 3H), 2.16 (s, 3H), 1.17 (s, 6H), 0.95 (s, 3H); 13C NMR
(100 MHz, DMSO-d6) δ 170.6, 154.7, 147.3, 146.3, 144.3, 143.9, 132.4,
129.4, 129.3, 128.7, 120.6, 119.9, 119.2, 117.2, 77.4, 59.9, 59.8, 59.2, 58.3,
54.9, 54.6, 47.4, 43.8, 31.4, 28.1, 27.9 (2C), 27.3, 15.6, 15.4; HRMS calcd
for C30H40N3O7 [MþH]þ 554.2861, found 554.2871.
(ꢀ)-Saframycin A (1). To a solution of compound 17 (12 mg,
0.022 mmol) in CH3CN (2 mL) were added salcomine (7.5 mg, 0.022
mmol) at room temperature, and the dark suspension was stirred in air
for 2 h. The mixture was purified by column chromatography (PET/
EtOAc = 1:1) and pTLC (PET/EtOAc = 1:1) to give (ꢀ)-saframycin A
Compound 15. To a stirred solution of compound 14 (94 mg, 0.17
mmol) in THF (15 mL) was added LiAlH4 (32 mg, 0.84 mmol)
at ꢀ17 °C under argon, and then the mixture was stirred for 2 h at
room temperature. The reaction was cooled to ꢀ17 °C, which was
followed by careful addition of KCN (88.40 mg, 1.36 mmol) in 2.7 mL of
H2O and acetic acid (0.2 mL, 3.40 mmol). The mixture was stirred for 10
h at room temperature. The reaction was then quenched by saturated aq.
NaHCO3 and extracted with EtOAc (15 mL ꢁ 3). The combined
organic phase was washed with brine, dried over anhydrous Na2SO4, and
concentrated under reduced pressure to give the crude product.
Purification by column chromatography (CH2Cl2/MeOH = 100:1)
afforded cyanided product 15 (79 mg, 82%) as a white solid. Mp =
20
(10.6 mg, 87%) as a yellow solid. Mp = 120ꢀ122 °C; [R]D = ꢀ98
(c 0.10, CH2Cl2); [R]D20 = þ18 (c 0.10, MeOH); 1H NMR (600 MHz,
CDCl3) δ 6.67 (br dd, J = 8.1, 4.2 Hz, 1H), 4.06 (br d, J = 0.6 Hz, 1H),
4.03 (s, 3H), 4.02 (s, 3H), 3.99 (d, J = 2.4 Hz, 1H), 3.97 (m, 1H), 3.73
(ddd, J = 13.8, 9.0, 1.5 Hz, 1H), 3.43 (br d, J = 7.2 Hz, 1H), 3.26 (dt, J =
14.4, 4.2 Hz, 1H), 3.13 (dt, J = 11.4, 3.0 Hz, 1H), 2.88 (dd, J = 18.0, 3.0
Hz, 1H), 2.82 (dd, J = 21.0, 7.8 Hz, 1H), 2.31 (s, 3H), 2.26 (s, 3H), 2.24
(d, J = 21.0 Hz, 1H), 1.99 (s, 3H), 1.92 (s, 3H), 1.28 (ddd, J = 18.0, 11.4,
3.0 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 196.7, 186.6, 185.3, 182.4,
180.8, 160.1, 155.9, 155.6, 141.5, 141.2, 135.5 (2C), 129.2, 128.3, 116.6,
61.1, 60.9, 58.2, 56.2, 54.4, 54.1, 53.9, 41.6, 40.6, 25.0, 24.3, 21.5, 8.7
(2C); HRMS calcd for C29H31N4O8 [M þ H]þ 563.2136, found
563.2148.
20
1
90ꢀ92 °C; [R]D = þ29 (c 0.10, CH2Cl2); H NMR (600 MHz,
DMSO-d6) δ 8.78 (s, 1H), 8.57 (s, 1H), 6.35 (s, 1H), 6.26 (s, 1H), 4.53
(s, 1H), 4.32 (s, 1H), 3.98 (s, 1H), 3.86 (s, 1H), 3.58 (s, 3H), 3.55 (s,
3H), 3.23 (d, J = 7.2 Hz, 1H), 3.19 (t, J = 9.0 Hz, 1H), 2.99 (d, J = 12.0
Hz, 1H), 2.92 (dd, J = 18.0, 8.4 Hz, 1H), 2.89 (d, J = 7.2 Hz, 1H), 2.66 (d,
J = 12.0 Hz, 1H), 2.44 (d, J = 18.0 Hz, 1H), 2.40 (dd, J = 16.2, 8.4 Hz,
1H), 2.16 (s, 3H), 2.14 (s, 3H), 2.09 (s, 3H), 1.10 (s, 9H); 13C NMR
(150 MHz, DMSO-d6) δ 177.8, 154.9, 147.3, 145.9, 143.8, 143.3, 131.4,
130.4, 128.6, 128.4, 119.4 (2C), 118.9, 117.6, 77.2, 68.2, 65.7, 59.9, 59.4,
56.8, 56.1, 54.5, 43.4, 41.2, 31.4, 27.9, 27.4, 24.9, 21.7, 15.6, 15.4; HRMS
calcd for C31H41N4O6 [M þ H]þ 565.3021, found 565.3027.
’ ASSOCIATED CONTENT
S
Supporting Information. Full experimental details and
b
copies of NMR spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Compound 16. A mixture of compound 15 (60 mg, 0.106 mmol)
in TFA (1 mL) was stirred at room temperature for 1 h, and then the
mixture was basified with saturated aq. NaHCO3 and extracted with
EtOAc (15 mL ꢁ 3). The combined organic phase was washed with
brine, dried over anhydrous Na2SO4, and concentrated under reduced
pressure to give the crude product. Purification by column chromatog-
raphy (CH2Cl2/MeOH = 30:1) afforded deprotected product 16 (44
mg, 90%) as a white solid. Mp = 140ꢀ142 °C; [R]D20 = þ40 (c 0.10,
CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 6.45 (s, 1H), 6.39 (s, 1H),
4.72 (s, 2H), 4.10 (br s, 1H), 4.01 (s, 1H), 3.98 (d, J = 2.1 Hz, 1H), 3.75
(s, 3H), 3.72 (s, 3H), 3.34 (d, J = 7.8 Hz, 1H), 3.30 (d, J = 12.0 Hz, 1H),
3.06 (dd, J = 18.0, 8.1 Hz, 1H), 2.84 (dd, J = 13.5, 1.8 Hz, 1H), 2.75 (dd,
Corresponding Author
liuzhanzhu@imm.ac.cn
’ ACKNOWLEDGMENT
We thank Beijng Natural Sciences Foundation (NO.7092069),
Specialized Research Fund for the Doctoral Program of Higher
Education (NO.200800230030), and the National Science &
Technology Major Project “Key New Drug Creation and Man-
ufacturing Program” China (Number: 2009ZX09301-003-10-1)
for financial support.
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