Asymmetric synthesis and absolute configuration of streptophenazine G

Article abstract of DOI:10.1021/jo202642a

The asymmetric synthesis of the antibacterial natural product, streptophenazine G, has been achieved by employing asymmetric alkylation and asymmetric aldol reactions using chiral oxazolidinones as the key steps. The originally proposed structure for streptophenazine G has been revised, and its absolute configuration has been determined to be 1′S,2′R,6′S. The asymmetric total synthesis of 6′-epi-streptophenazine G is also described.

Full text of DOI:10.1021/jo202642a

Article
pubs.acs.org/joc
Asymmetric Synthesis and Absolute Configuration of
Streptophenazine G
Zhicai Yang,* Xiaomin Jin, Michael Guaciaro, and Bruce F. Molino
Medicinal Chemistry Department, AMRI, 26 Corporate Circle, P.O. Box 15098, Albany, New York 12212-5098, United States
S
* Supporting Information
ABSTRACT: The asymmetric synthesis of the antibacterial
natural product, streptophenazine G, has been achieved by
employing asymmetric alkylation and asymmetric aldol reactions
using chiral oxazolidinones as the key steps. The originally
proposed structure for streptophenazine G has been revised, and
its absolute configuration has been determined to be 1′S,2′R,6′S.
The asymmetric total synthesis of 6′-epi-streptophenazine G is also
described.
(Figure 1), and further studies on streptophenazines B and E
have demonstrated that their absolute configurations are the
same as streptophenazine A.3 We assume that the structure of
streptophenazine G should also be revised to 1′-hydroxy-2′-
carboxylate and that it possesses 1′S,2′R stereochemistry on the
side chain as well. Thus, the true structure of streptophenazine
G is either 4 or 5 (Figure 2).
INTRODUCTION
■
Phenazine derivatives are a potential source of antibiotics.1
Several novel phenazine analogues, streptophenazines A−H,
have been recently isolated from cultures of marine
Streptomyces sp. strain HB202, some of which have shown
moderate antibacterial activities.2 In the streptophenazine
family, streptophenazine G (1) is a unique member that
possesses three stereogenic centers on the side chain (Figure
1). The structure of streptophenazine G was elucidated by
Figure 2. Structure of streptophenazine G (4 or 5).
As shown in Schemes 1 and 2, the well-developed
methodology of Evans was employed to establish the
stereochemistry for the 6′-position on the side chain.4
Treatment of (R)-4-benzyloxazolidin-2-one [(R)-6] with n-
butyllithium followed by reaction with acid chloride 7 provided
oxazolidinone 8 in good yield. Deprotonation of 8 with sodium
bis(trimethylsilylamide) followed by highly diastereoselective
alkylation of the resulting chiral imide enolate with iodo-
methane afforded the desired compound 9 in good yield.5
Reduction of 9 with lithium borohydride produced the
corresponding alcohol. Because of its low boiling point,
however, the isolated yield of the alcohol was low. By treatment
of the crude alcohol with tosyl chloride in the presence of
pyridine, the tosylate 10 was isolated in 80% overall yield from
9. Reaction of 10 with sodium iodide in acetonitrile yielded
iodide 11 smoothly. Reaction of 11 with triphenylphosphine
Figure 1. Structures of streptophenazines A and G.
spectroscopic methods. However, its stereochemistry was not
determined. Our interest in these novel phenazine analogues
has led to the structural revision for streptophenazine A (3).3
We report herein the first synthesis and absolute stereo-
chemistry of streptophenazine G.
RESULTS AND DISCUSSION
Our recent efforts on streptophenazine chemistry have led to
the structural revision for streptophenazine A from 2 to 3
■
Received: December 21, 2011
Published: March 21, 2012
© 2012 American Chemical Society
3191
dx.doi.org/10.1021/jo202642a | J. Org. Chem. 2012, 77, 3191−3196

The Journal of Organic Chemistry
Article
Scheme 1. Synthesis of Acid 16
Scheme 2. Asymmetric Synthesis of 4
provided the phosphonium salt 12 in 86% yield. Wittig reaction
of the ylide that was generated from 12 using n-butyllithium as
base with the commercially available aldehyde 13 gave a
mixture of (E) and (Z)-olefins 14 (E/Z = 4:1).6 The mixture
was smoothly transformed into 15 by hydrogenation with
palladium on carbon. Hydrolysis of ester 15 with lithium
hydroxide afforded the corresponding acid (R)-16 in good
yield.
one as the chiral auxiliary (Scheme 3). The commercially
available alcohol 2110 was converted to acid (S)-16 with
NaClO and NaClO2 in the presence of 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO).11 Treatment of acid (S)-16 with
oxalyl chloride provided acid chloride (S)-17. Reaction of (S)-
17 with the lithium salt that was generated from (S)-6 and n-
butyllithium afforded oxazolidinone 22 in good yield.
Asymmetric aldol reaction of oxazolidinone 22 with aldehyde
19 afforded exclusively the desired anti-adduct 23. Hydrolysis
of 23 with lithium hydroxide in the presence of hydrogen
peroxide, followed by treatment of the resulting acid with
Conversion of acid (R)-16 to 4 is depicted in Scheme 2. Acid
(R)-16 was transformed into the corresponding acid chloride
(R)-17, and subsequent coupling of (R)-17 with the lithium salt
of (S)-4-benzyloxazolidin-2-one [(S)-6] provided oxazolidi-
none 18 in 74% overall yield from (R)-16. Asymmetric aldol
reaction of 18 with aldehyde 193 afforded exclusively the
desired anti-adduct 20.7 Hydrolysis of 20 with lithium
hydroxide in the presence of hydrogen peroxide,8 followed by
treatment of the resulting acid with (trimethylsilyl)-
diazomethane gave compound 4. The structure of 4 was
(trimethylsilyl)diazomethane gave 5, [α]20 −44.6 (c 1.5,
D
MeOH). The structure of 5 was assigned on the basis of
HRMS, 1H, 13C, 2D COSY, HSQC, and HMBC NMR studies.
The spectroscopic data of compound 5 are consistent with the
naturally occurring (−)-streptophenazine G,9,12 and its physical
properties are in agreement with those reported in the
literature.3 Therefore, the originally proposed structure for
(−)-streptophenazine G was revised to 5, and its absolute
stereochemistry was determined to be 1′S,2′R,6′S.
1
confirmed by HRMS, H, 13C, 2D COSY, HSQC, and HMBC
1
NMR studies. However, the data of H and 13C NMR of
compound 4 are slightly different from those reported for
naturally occurring streptophenazine G.10 For example, the
signal of the methylene group at 4′-position on the side chain of
CONCLUSIONS
■
In conclusion, we accomplished the first asymmetric synthesis
of (−)-streptophenazines G by utilizing asymmetric aldol
reaction developed by Evans and co-workers8 as the key step.
The originally proposed structure for streptophenazine G was
revised to be 5, and its absolute stereochemistry was
determined to be 1′S,2′R,6′S. In the meantime, the asymmetric
total synthesis of 6′-epi-streptophenazine G (4) was also
1
the natural product was recorded at δ 1.22 in the H NMR
spectrum, whereas the signals for those protons were found at δ
1
1.27 and δ 1.15, respectively in the H NMR spectrum of
compound 4.9 The results compelled us to synthesize isomer 5.
Utilizing the same strategy from Scheme 2, asymmetric
synthesis of 5 was conducted using (S)-4-benzyloxazolidin-2-
3192
dx.doi.org/10.1021/jo202642a | J. Org. Chem. 2012, 77, 3191−3196

The Journal of Organic Chemistry
Article
(R)-4-Benzyl-3-butyryloxazolidin-2-one (8). A mixture of
oxazolidinone (R)-6 (5.00 g, 28.2 mmol) and THF (100 mL) was
cooled to −78 °C, and n-butyllithium in hexanes (2.5 M, 11.0 mL, 27.5
mmol) was added. The mixture was stirred at −78 °C for 10 min, and
acid chloride 7 (2.50 g, 23.5 mmol) was added. After being stirred at
−78 °C for 30 min, the cooling bath was removed, and the reaction
was allowed to warm to room temperature. Then saturated aqueous
ammonium chloride (100 mL) was added, and the resulting mixture
was extracted with ethyl acetate (2 × 200 mL). The combined extracts
were dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue obtained was purified by chromatog-
raphy on silica gel (0−50% ethyl acetate/hexanes) to give compound 8
Scheme 3. Asymmetric Synthesis of 5
(4.55 g, 78%) as a colorless oil: [α]20 −57.5 (c 0.8, CHCl3) [lit.13
D
[α]20D −57.1 (c 1.14, CHCl3)]; 1H NMR (500 MHz, CDCl3) δ 7.35−
7.32 (m, 2H), 7.29−7.26 (m, 1H), 7.22−7.20 (m, 2H), 4.69−4.65 (m,
1H), 4.22−4.15 (m, 2H), 3.30 (dd, J = 13.0, 3.5 Hz, 1H), 2.99−2.85
(m, 2H), 2.77 (dd, J = 13.5, 10.0 Hz, 1H), 1.77−1.70 (m, 2H), 1.01 (t,
J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 173.2, 153.5, 135.4,
129.4 (2C), 129.0 (2C), 127.3, 66.2, 55.1, 38.0, 37.4, 17.7, 13.7;
HRMS (ESI) calcd for C14H18NO3 [M + H]+ 248.1287, found
248.1287.
(R)-4-Benzyl-3-((R)-2-methylbutanoyl)oxazolidin-2-one (9).
A mixture of 8 (4.00 g, 16.2 mmol) and anhydrous THF (25 mL)
was cooled to −78 °C, and NaHMDS in THF (1.0 M, 24.3 mL, 24.3
mmol) was added dropwise. After the mixture was stirred at −78 °C
for 1 h, a solution of iodomethane (11.5 g, 81.0 mmol) in anhydrous
THF (25 mL) was added. The reaction mixture was stirred at −78 °C
for 5 h and then quenched with acetic acid (5 mL). The resulting
mixture was then partitioned between water (50 mL) and ethyl acetate
(50 mL). The organic phase was separated, and the aqueous phase was
extracted with ethyl acetate (50 mL). The combined extracts were
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue obtained was purified by chromatog-
raphy on silica gel (0−40% ethyl acetate/hexanes) to give compound 9
1
(3.40 g, 80%) as a colorless oil: [α]20 −124.7 (c 0.4, MeOH); H
D
NMR (500 MHz, CDCl3) 7.35−7.32 (m, 2H), 7.29−7.26 (m, 1H),
7.22−7.21 (m, 2H), 4.70−4.66 (m, 1H), 4.22−4.15 (m, 2H), 3.64 (m,
1H), 3.27 (dd, J = 13.0, 3.0 Hz, 1H), 2.77 (dd, J = 13.5, 9.5 Hz, 1H),
1.80−1.75 (m, 1H), 1.50−1.45 (m, 1H), 1.22 (d, J = 6.5 Hz, 3H), 0.93
(t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 177.2, 153.1,
135.4, 129.5 (2C), 128.9 (2C), 127.3, 66.0, 55.4, 39.2, 37.9, 26.4, 16.9,
11.7; HRMS (ESI) calcd for C15H20NO3 [M + H]+ 262.1443, found
262.1437.
(R)-2-Methylbutyl 4-Methylbenzenesulfonate (10).14 To a
mixture of 9 (2.37 g, 9.08 mmol), methanol (0.05 mL), and THF (40
mL) at 0 °C was added lithium borohydride (593 mg, 27.2 mmol).
After the mixture was stirred at room temperature for 3 h, the reaction
was quenched with saturated aqueous Rochelle salt solution (5 mL).
The mixture obtained was diluted with methylene chloride (80 mL)
and dried over anhydrous Na2SO4. The drying agent was removed by
filtration, and the filtrate was cooled to 0 °C. p-Toluenesulfonyl
chloride (17.3 g, 90.8 mmol) was added, followed by pyridine (14.4 g,
182 mmol). After the mixture was stirred at 0 °C for 10 h, water (100
mL) was added, and the resulting mixture was extracted with
methylene chloride (3 × 50 mL). The combined extracts were washed
with saturated aqueous sodium bicarbonate (300 mL) and water (100
mL) and dried over anhydrous Na2SO4. The drying agent was then
removed by filtration, and the filtrate was concentrated under reduced
pressure. The residue obtained was purified by chromatography on
achieved by employing both asymmetric alkylation and
asymmetric aldol reactions using (R) or (S)-4-benzyloxazoli-
din-2-one as chiral auxiliaries.
EXPERIMENTAL SECTION
■
General Experimental Methods. Unless otherwise noted,
reagents and solvents were used as received from commercial
suppliers. Melting points were not corrected. Optical rotations were
measured at room temperature. 1H and 13C NMR spectra were
recorded at 300 and 75 MHz or 500 and 125 MHz, respectively.
Spectra are given in ppm (δ), and coupling constants, J, are reported in
hertz. Tetramethylsilane was used as an internal standard for proton
spectra, and the solvent peak was used as the reference peak for carbon
spectra. Mass spectra were obtained on an electrospray ionization
(ESI) mass spectrometer. High-resolution mass spectrometry
(HRMS) was performed in ESI a positive or negative mode.
Chromatography was performed on a silica gel column. Chiral
HPLC analyses were obtained using a Chiralcel OJ-H column (250 ×
4.6 mm) with PDA detection at 20 nm. Chromatography was
performed using a Combi-Flash Companion on a silica gel column.
silica gel (0−10% ethyl acetate/hexanes) to give compound 10 (1.77 g,
1
80%) as a colorless oil: [α]20 −4.1 (c 1.1, pentane); H NMR (500
D
MHz, CDCl3) δ 7.79 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0, 2H), 3.88
(dd, J = 9.0, 5.5 Hz, 1H), 3.82 (dd, J = 9.0, 6.5 Hz, 1H), 2.45 (s, 3H),
1.74−1.68 (m, 1H), 1.43−1.35 (m, 1H), 1.19−1.10 (m, 1H), 0.86 (d, J
= 7.0 Hz, 3H), 0.83 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 144.6, 133.2, 129.8 (2C), 127.9 (2C), 74.8, 34.4, 25.4, 21.6, 16.0,
11.0; HRMS (ESI) calcd for C12H19O3S [M + H]+ 243.1055, found
243.1048.
(R)-1-Iodo-2-methylbutane (11). A mixture of 10 (500 mg, 2.07
mmol), sodium iodide (1.55 g, 10.3 mmol), and DMF (10 mL) was
3193
dx.doi.org/10.1021/jo202642a | J. Org. Chem. 2012, 77, 3191−3196

The Journal of Organic Chemistry
Article
heated at 60 °C for 2 h. Water (20 mL) was added, and the resulting
mixture was extracted with pentane (3 × 30 mL). The combined
extracts were dried over anhydrous Na2SO4, filtered, and concentrated
by distillation under atmospheric pressure to give compound 11 (346
Hz, 2H), 1.73−1.66 (m, 2H), 1.38−1.28 (m, 5H), 1.15−1.11 (m, 2H),
0.87−0.84 (m, 6H). A mixture of oxazolidinone (S)-6 (627 mg, 3.54
mmol) and THF (10 mL) was cooled to −78 °C, and n-butyllithium
in hexanes (2.5 M, 1.42 mL, 3.54 mmol) was added. The mixture was
stirred at −78 °C for 10 min, and acid chloride (R)-17 (313 mg, 1.77
mmol) was added. After the mixture was stirred at −78 °C for 30 min,
the cooling bath was removed, and the reaction mixture was allowed to
warm to room temperature. Then saturated aqueous ammonium
chloride (10 mL) was added, and the resulting mixture was extracted
with ethyl acetate (2 × 20 mL). The combined extracts were dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue obtained was purified by chromatography on
mg, 84%) as a colorless oil: [α]20D −4.8 (c 1.0, pentane) [lit.15 [α]20
D
−5.32 (c 4.87, pentane)]; 1H NMR (500 MHz, CDCl3) δ 3.23 (dd, J =
10.0, 5.0 Hz, 1H), 3.18 (dd, J = 9.5, 6.0 Hz, 1H), 1.45−1.37 (m, 2H),
1.29−1.25 (m, 1H), 0.98 (d, J = 6.5 Hz, 3H), 0.89 (t, J = 7.5 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 36.4, 29.2, 20.2, 17.4, 11.3.
(R)-(2-Methylbutyl)triphenylphosphonium Iodide (12).16
A
mixture of 11 (1.45 g, 7.31 mmol), triphenylphosphine (2.88 g, 11.0
mmol), and toluene (15 mL) was heated at 105 °C for 48 h. The
reaction mixture was then cooled to room temperature and filtered.
The filter cake was washed with tert-butylmethyl ether (15 mL) and
dried at room temperature for 16 h to give compound 12 (3.36 g,
silica gel (0−50% ethyl acetate/hexanes) to give compound 18 (416
1
mg, 74%) as a colorless oil: [α]20 +71.1 (c 1.1, MeOH); H NMR
D
(500 MHz, CDCl3) δ 7.35−7.32 (m, 2H), 7.29−7.27 (m, 1H), 7.22−
7.20 (m, 2H), 4.69−4.66 (m, 1H), 4.22−4.15 (m, 2H), 3.30 (dd, J =
13.5, 3.5 Hz, 1H), 3.00−2.88 (m, 2H), 2.77 (dd, J = 13.5, 9.5 Hz, 1H),
1.71−1.65 (m, 2H), 1.41−1.31 (m, 5H), 1.17−1.12 (m, 2H), 0.88−
0.85 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 173.5, 153.5, 135.4,
129.4 (2C), 129.0 (2C), 127.4, 66.2, 55.2, 38.0, 36.3, 35.6, 34.3, 29.5,
26.7, 24.6, 19.2, 11.4; HRMS (ESI) calcd for C19H28NO3 [M + H]+
318.2069, found 318.2072.
86%) as a white solid: mp 155−156 °C; [α]20 −9.3 (c 0.6, MeOH);
D
1H NMR (500 MHz, CD3OD) δ 7.90−7.83 (m, 9H), 7.77−7.73 (m,
6H), 3.43−3.29 (m, 2H), 1.94−1.89 (m, 1H), 1.44−1.32 (m, 2H),
0.91 (d, J = 6.5 Hz, 3H), 0.84 (d, J = 7.5 Hz, 3H).
(R)-Methyl 6-Methyloctanoate (15). A mixture of 12 (1.50 g,
3.26 mmol) and THF (10 mL) was cooled to 0 °C, and n-butyllithium
in hexanes (2.5M, 1.30 mL, 3.26 mmol) was added. After the mixture
was stirred at 0 °C for 20 min, a solution of methyl 4-oxobutanoate
(13, 522 mg, 4.50 mmol) in THF (1 mL) was added. The reaction
mixture was stirred at 0 °C for 30 min, saturated aqueous ammonium
chloride (5 mL) was added, and the resulting mixture was extracted
with pentane (3 × 30 mL). The combined extracts were dried over
anhydrous Na2SO4, filtered, and concentrated under atmospheric
pressure. The residue obtained was purified by chromatography on
silica gel (0−50% methylene chloride/pentane) to give compound 14
Methyl 6-((1S,2R,6R)-2-((S)-4-Benzyl-2-oxooxazolidine-3-car-
bonyl)-1-hydroxy-6-methyloctyl)phenazine-1-carboxylate
(20). A mixture of 18 (179 mg, 0.56 mmol), anhydrous magnesium
chloride (72 mg, 0.75 mmol), triethylamine (114 mg, 1.13 mmol), and
ethyl acetate (5 mL) was stirred at room temperature for 10 min.
Aldehyde 19 (100 mg, 0.376 mmol) was added, followed by
chlorotrimethylsilane (82 mg, 0.75 mmol). The mixture was stirred
at room temperature overnight, and saturated aqueous ammonium
chloride (3 mL) was added to quench the reaction. The resulting
mixture was extracted with ethyl acetate (2 × 10 mL), and the
combined extracts were dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The residue obtained was
redissolved in methanol (10 mL), and TFA (0.2 mL) was added. After
the mixture was stirred at room temperature for 10 min, saturated
aqueous NaHCO3 (0.2 mL) was added. Then the mixture was
concentrated under reduced pressure, and the residue obtained was
purified by chromatography on silica gel (0−50% ethyl acetate/
hexanes) to give compound 20 (170 mg, 77%) as a yellow solid: mp
1
(554 mg) as a colorless oil and a mixture of (E) and (Z)-isomers: H
NMR (500 MHz, CDCl3) δ 5.34−5.26 (m, 1H), 5.17 (t, J = 10.5 Hz,
1H), 3.67 (s, 3H), 2.39−2.30 (m, 5H), 1.36−1.17 (m, 2H), 0.93 (d, J
= 6.5 Hz, 3H), 0.84 (t, J = 7.5 Hz, 3H). A mixture of 14 (554 mg, 3.26
mmol), ethyl acetate (10 mL) and 10% palladium on carbon (50%
wet, 100 mg dry weight) was stirred under hydrogen (1 atm) at room
temperature for 6 h. After this time, the catalyst was removed by
filtration through a pad of Celite 521 and the filter cake was washed
with methylene chloride (400 mL). The filtrate was concentrated
under reduced pressure to afford 15 (397 mg, 71%) as a colorless oil:
51−52 °C; [α]20 −29.3 (c 0.9, MeOH); 1H NMR (500 MHz,
1
[α]20 −3.9 (c 0.9, CDCl3); H NMR (500 MHz, CDCl3) δ 3.67 (s,
D
D
CDCl3) δ 8.53 (dd, J = 8.5, 1.5 Hz, 1H), 8.30−8.26 (m, 2H), 7.88 (dd,
J = 9.0, 7.0 Hz, 1H), 7.85−7.79 (m, 2H), 7.34−7.24 (m, 5H), 5.56−
5.45 (m, 2H), 5.20−5.18 (m, 1H), 4.78−4.75 (m, 1H), 4.18−4.14 (m,
2H), 4.12 (s, 3H), 3.39 (dd, J = 13.5, 3.0 Hz, 1H), 2.73 (dd, J = 13.5,
9.5 Hz, 1H), 1.74−1.72 (m, 1H), 1.26−1.06 (m, 6H), 1.01−0.94 (m,
2H), 0.73 (t, J = 7.5 Hz, 3H), 0.69 (t, J = 6.5 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 176.9, 167.0, 153.3, 144.0, 141.3, 141.1, 141.0, 138.9,
135.5, 133.8, 132.6, 131.1, 130.4, 130.3, 129.8, 129.5 (2C), 129.4,
128.9 (2C), 127.3, 77.2, 65.8, 55.8, 52.7, 49.0, 37.8, 36.3, 34.1, 30.8,
29.1, 24.5, 19.2, 11.2; HRMS (ESI) calcd for C34H38N3O6 [M + H]+
584.2761, found 584.2745.
3H), 2.31 (t, J = 8.0 Hz, 2H), 1.63−1.57 (m, 2H), 1.35−1.26 (m, 5H),
1.14−1.09 (m, 2H), 0.85 (t, J = 7.0 Hz, 3H), 0.84 (d, J = 6.5 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 174.3, 51.4, 36.2, 34.2 (2C), 29.4,
26.7, 25.3, 19.1, 11.4; HRMS (ESI) calcd for C10H21O2 [M + H]+
173.1542, found 173.1550.
(R)-6-Methyloctanoic Acid [(R)-16]. A mixture of 15 (455 mg,
2.65 mmol), lithium hydroxide (636 mg, 26.5 mmol), ethanol (20
mL), water (10 mL), and THF (5 mL) was stirred at room
temperature for 4 h. The organic solvent was removed under reduced
pressure, and the residue obtained was extracted with tert-butylmethyl
ether (5 mL). The aqueous phase was then acidified to pH 0 with 2 N
HCl, and the mixture was extracted with methylene chloride (3 × 10
mL). The combined extracts were dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The residue
obtained was dried under vacuum at room temperature to give
compound (R)-16 (284 mg, 79%) as a colorless oil: [α]20D −5.7 (c 0.8,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 10.80 (br s, 1H), 2.36 (t, J =
7.5 Hz, 2H), 1.66−1.59 (m, 2H), 1.37−1.29 (m, 5H), 1.14−1.10 (m,
2H), 0.87−0.84 (m, 6H); 13C NMR (125 MHz, CD3OD) δ 179.2,
36.2, 34.2, 33.9, 29.4, 26.6, 25.0, 19.1, 11.4; HRMS (ESI) calcd for
C9H19O2 [M + H]+ 159.1385, found 159.1388.
((S)-4-Benzyl-3-((R)-6-methyloctanoyl)oxazolidin-2-one (18).
A mixture of acid (R)-16 (280 mg, 1.77 mmol), DMF (7 mg, 0.09
mmol), and methylene chloride (5 mL) was cooled to 0 °C, and oxalyl
chloride (247 mg, 1.95 mmol) was added. The mixture was stirred at
room temperature for 2 h. The resulting mixture was concentrated
under reduced pressure, and the residue obtained was dried under
vacuum at room temperature for 3 h to give compound (R)-17 (313
mg) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 2.89 (t, J = 7.5
(−)-6′-epi-Streptophenazine G (4). A mixture of 20 (140 mg,
0.240 mmol) and THF (4 mL) was cooled to 0 °C. Hydrogen
peroxide (30 wt % in water, 82 mg, 2.40 mmol) was added, followed
by a solution of lithium hydroxide (29 mg, 1.20 mmol) in water (1
mL). After the mixture was stirred at 0 °C for 7 h, a saturated aqueous
solution of NaHSO3 (2 mL) was added, and the mixture was stirred at
room temperature overnight. The mixture was diluted with 1 M
KH2PO4 (3 mL) and extracted with ethyl acetate (2 × 10 mL). The
combined extracts were dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The resulting acid was
redissolved in methanol (4 mL) and cooled to 0 °C. (Trimethylsilyl)-
diazomethane in hexanes (2.0 M, 2.40 mL, 4.80 mmol) was added.
The mixture was stirred at 0 °C for 1 h and then concentrated. The
residue obtained was purified by chromatography on silica gel (0−50%
ethyl acetate/hexanes) to give compound 4 (65 mg, 61%) as a yellow
1
solid: mp 72−73 °C; [α]20 −59.0 (c 0.4, MeOH); H NMR (500
D
MHz, CD3OD) δ 8.43 (dd, J = 8.5, 1.5 Hz, 1H), 8.27 (dd, J = 6.5, 1.0
Hz, 1H), 8.25 (dd, J = 8.5, 1.5 Hz, 1H), 8.03−7.94 (m, 3H), 6.16 (d, J
3194
dx.doi.org/10.1021/jo202642a | J. Org. Chem. 2012, 77, 3191−3196

The Journal of Organic Chemistry
Article
= 7.5 Hz, 1H), 4.08 (s, 3H), 3.63 (s, 3H), 3.28−3.24 (m, 1H), 1.70−
1.64 (m, 1H), 1.30−1.10 (m, 6H), 1.01−0.91 (m, 2H), 0.74−0.70 (m,
6H); 13C NMR (125 MHz, CD3OD) δ 176.7, 168.8, 144.6, 143.0,
142.8, 142.7, 141.7, 134.6, 133.5, 132.6, 132.4, 130.7, 130.3, 130.0,
71.1, 54.8, 53.2, 52.0, 37.3, 35.4, 30.6, 30.2, 25.9, 19.5, 11.6; HRMS
(ESI) calcd for C25H31N2O5 [M + H]+ 439.2233, found 439.2228.
(S)-6-Methyloctanoic Acid [(S)-16]. To a mixture of alcohol 21
(400 mg, 2.77 mmol), TEMPO (43 mg, 0.277 mmol), aqueous
NaH2PO4 (0.67 M, 15 mL), and acetonitrile (15 mL) were added
bleach (6.15 wt % in water, 1.5 mL) and a solution of NaClO2 (501
mg, 5.54 mmol) in water (1 mL). The mixture was stirred at room
temperature for 16 h, and a saturated aqueous solution of Na2S2O3 (10
mL) was added. The resulting mixture was extracted with ethyl acetate
(2 × 20 mL), and the combined extracts were washed with 1 N HCl
(5 mL), dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The residue obtained was dried under vacuum
hexanes) to give compound 23 (153 mg, 70%) as a yellow solid: mp
52−53 °C; [α]20 −23.1 (c 0.8, MeOH); 1H NMR (500 MHz,
D
CDCl3) δ 8.53 (dd, J = 9.0, 1.5 Hz, 1H), 8.30−8.26 (m, 2H), 7.88 (dd,
J = 8.5, 7.0 Hz, 1H), 7.85−7.79 (m, 2H), 7.34−7.25 (m, 5H), 5.55−
5.47 (m, 2H), 5.21−5.17 (m, 1H), 4.78−4.75 (m, 1H), 4.19−4.13 (m,
2H), 4.12 (s, 3H), 3.39 (dd, J = 13.5, 3.0 Hz, 1H), 2.74 (dd, J = 13.5,
9.5 Hz, 1H), 1.77−1.71 (m, 1H), 1.20−1.05 (m, 6H), 1.02−0.95 (m,
1H), 0.91−0.86 (m, 1H), 0.72−0.68 (m, 6H); 13C NMR (125 MHz,
CDCl3) δ 176.9, 167.0, 153.3, 144.0, 141.3, 141.1, 141.0, 138.9, 135.5,
133.8, 132.6, 131.1, 130.4, 130.3, 129.8, 129.5 (2C), 129.4, 128.9 (2C),
127.3, 77.3, 65.8, 55.8, 52.7, 49.0, 37.8, 36.3, 34.1, 30.7, 29.5, 24.5,
19.0, 11.3; HRMS (ESI) calcd for C34H38N3O6 [M + H]+ 584.2761,
found 584.2757.
(−)-Streptophenazine G (5). A mixture of 23 (123 mg, 0.211
mmol) and THF (4 mL) was cooled to 0 °C. Hydrogen peroxide (30
wt % in water, 72 mg, 2.11 mmol) was added, followed by a solution of
lithium hydroxide (25 mg, 1.05 mmol) in water (1 mL). After the
mixture was stirred at 0 °C for 7 h, a solution of saturated aqueous
NaHSO3 (2 mL) was added, and the mixture was stirred at room
temperature overnight. The mixture was diluted with 1 M KH2PO4 (3
mL) and extracted with ethyl acetate (2 × 10 mL). The combined
extracts were dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The resulting acid was redissolved in
methanol (4 mL) and cooled to 0 °C. (Trimethylsilyl)diazomethane
in hexanes (2.0 M, 2.11 mL, 4.22 mmol) was added. The mixture was
stirred at 0 °C for 1 h and then concentrated. The residue obtained
was purified by chromatography on silica gel (0−50% ethyl acetate/
at room temperature for 16 h to give compound (S)-16 (432 mg, 98%
1
yield) as a colorless oil: [α]20 +7.9 (c 0.9, CHCl3); H NMR (500
D
MHz, CDCl3) δ 10.30 (br s, 1H), 2.36 (t, J = 7.5 Hz, 2H), 1.65−1.60
(m, 2H), 1.37−1.29 (m, 5H), 1.14−1.10 (m, 2H), 0.87−0.84 (m, 6H);
13C NMR (125 MHz, CDCl3) δ 179.4, 36.2, 34.2, 34.0, 29.4, 26.6,
25.0, 19.1, 11.4; HRMS (ESI) calcd for C9H17O2 [M − H]− 157.1229,
found 157.1225.
(S)-4-Benzyl-3-((S)-6-methyloctanoyl)oxazolidin-2-one (22).
A mixture of acid (S)-16 (420 mg, 2.66 mmol), DMF (10 mg,
0.133) and methylene chloride (10 mL) was cooled to 0 °C, and oxalyl
chloride (371 mg, 2.92 mmol) was added dropwise. The mixture was
stirred at room temperature for 2 h. The resulting mixture was
concentrated under reduced pressure, and the residue obtained was
dried under vacuum at room temperature for 3 h to give compound
hexanes) to give 5 (54 mg, 58%) as a yellow solid: mp 75−76 °C;
1
[α]20 −44.6 (c 1.5, MeOH); H NMR (500 MHz, CD3OD) δ 8.45
D
(dd, J = 9.0, 1.5 Hz, 1H), 8.28 (dd, J = 6.5, 1.0 Hz, 1H), 8.26 (dd, J =
8.5, 1.5 Hz, 1H), 8.03−7.95 (m, 3H), 6.15 (d, J = 7.5 Hz, 1H), 4.08 (s,
3H), 3.63 (s, 3H), 3.29−3.24 (m, 1H), 1.71−1.66 (m, 1H), 1.29−1.09
(m, 6H), 1.02−0.92 (m, 2H), 0.74−0.71 (m, 6H); 13C NMR (125
MHz, CD3OD) δ 176.7, 168.7, 144.6, 143.0, 142.7, 142.6, 141.7, 134.6,
133.5, 132.5, 132.4, 130.7, 130.3, 130.1, 71.2, 54.8, 53.2, 52.0, 37.2,
35.3, 30.6, 30.5, 25.8, 19.3, 11.7; HRMS (ESI) calcd for C25H31N2O5
[M + H]+ 439.2233, found 439.2234.
1
(S)-17 (468 mg) as a colorless oil: H NMR (500 MHz, CDCl3) δ
2.89 (t, J = 7.5 Hz, 2H), 1.73−1.67 (m, 2H), 1.40−1.28 (m, 5H),
1.16−1.11 (m, 2H), 0.87−0.84 (m, 6H). A mixture of (S)-6 (706 mg,
3.99 mmol) and THF (10 mL) was cooled to −78 °C, and n-
butyllithium in hexanes (2.5 M, 1.60 mL, 3.99 mmol) was added. The
mixture was stirred at −78 °C for 10 min, and (S)-17 (468 mg, 2.66
mmol) was added. After being stirred at −78 °C for 30 min, the
cooling bath was removed, and the reaction mixture was allowed to
warm to room temperature. Then saturated aqueous ammonium
chloride (10 mL) was added, and the resulting mixture was extracted
with ethyl acetate (2 × 10 mL). The combined extracts were dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue obtained was purified by chromatography on
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR data of compounds 4 and 5 and NMR
spectra for compounds 4, 5, 8−12, 14−16, 18, 20, 22, and 23.
This material is available free of charge via the Internet at
http://pubs.acs.org.
silica gel (0−50% ethyl acetate/hexanes) to give compound 22 (567
1
mg, 67%) as a colorless oil: [α]20 +90.1 (c 0.6, MeOH); H NMR
D
(500 MHz, CDCl3) δ 7.35−7.32 (m, 2H), 7.29−7.27 (m, 1H), 7.22−
7.20 (m, 2H), 4.69−4.65 (m, 1H), 4.21−4.15 (m, 2H), 3.30 (dd, J =
13.5, 3.5 Hz, 1H), 3.01−2.87 (m, 2H), 2.77 (dd, J = 13.5, 9.5 Hz, 1H),
1.68 (quant, J = 7.0 Hz, 2H), 1.42−1.31 (m, 5H), 1.17−1.13 (m, 2H),
0.88−0.85 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 173.5, 153.5,
135.4, 129.4 (2C), 129.0 (2C), 127.4, 66.2, 55.2, 38.0, 36.3, 35.6, 34.3,
29.5, 26.7, 24.6, 19.2, 11.4; HRMS (ESI) calcd for C19H28NO3 [M +
H]+ 318.2069, found 318.2077.
AUTHOR INFORMATION
■
Corresponding Author
*Tel: (518) 512-2133. Fax: (518) 512-2079. E-mail: zhicai.
yang@amriglobal.com.
Notes
The authors declare no competing financial interest.
Methyl 6-((1S,2R,6S)-2-((S)-4-Benzyl-2-oxooxazolidine-3-car-
bonyl)-1-hydroxy-6-methyloctyl)phenazine-1-carboxylate
(23). A mixture of 22 (179 mg, 0.56 mmol), anhydrous magnesium
chloride (72 mg, 0.75 mmol), triethylamine (114 mg, 1.13 mmol), and
ethyl acetate (5 mL) was stirred at room temperature for 10 min.
Aldehyde 19 (100 mg, 0.376 mmol) was added, followed by
chlorotrimethylsilane (82 mg, 0.75 mmol). The mixture was stirred
at room temperature overnight, and saturated aqueous ammonium
chloride (3 mL) was added to quench the reaction. The resulting
mixture was extracted with ethyl acetate (2 × 10 mL), and the
combined extracts were dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The residue obtained was
redissolved in methanol (10 mL), and TFA (0.2 mL) was added. After
the mixture was stirred at room temperature for 10 min, saturated
aqueous NaHCO3 (0.2 mL) was added. Then the mixture was
concentrated under reduced pressure, and the residue obtained was
purified by chromatography on silica gel (0−50% ethyl acetate/
ACKNOWLEDGMENTS
■
We thank the AMRI PQS Department for the collection of
HRMS data.
REFERENCES
■
(1) (a) Kitahara, M.; Nakamura, H.; Matsuda, Y.; Hamada, M.;
Naganawa, H.; Maeda, K.; Umezawa, H.; Itaka, Y. J. Antibiot. 1982, 35,
1412−1414. (b) Geiger, A.; Keller-Schierlein, W.; Brandl, M.; Zahner,
H. J. Antibiot. 1988, 41, 1542−1551. (c) Keller-Schierlein, W.; Geiger,
A.; Zaehner, H.; Brandl, M. Helv. Chim. Acta 1988, 71, 2058−2070.
(2) Mitova, M. I.; Lang, G.; Wiese, J.; Imhoff, J. F. J. Nat. Prod. 2008,
71, 824−827.
(3) Yang, Z.; Jin, X.; Guaciaro, M.; Molino, B. F.; Mocek, U.;
Reategui, R.; Rhea, J.; Morley, T. Org. Lett. 2011, 13, 5436−5439.
3195
dx.doi.org/10.1021/jo202642a | J. Org. Chem. 2012, 77, 3191−3196

The Journal of Organic Chemistry
Article
(4) (a) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc.
1988, 110, 1238−1256. (b) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J.
Am. Chem. Soc. 1982, 104, 1737−1739.
(5) The alkylation reaction provided two diastereomers in a ratio of
93:7 in favor of the desired isomer 9. The minor diastereomer was
removed by chromatography on a silica gel column.
1
(6) The E/Z ratio was determined by H NMR analysis.
(7) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am.
Chem. Soc. 2002, 124, 392−393.
(8) Yokokawa, F.; Shioiri, T. J. Org. Chem. 1998, 63, 8638−8639.
(9) See Table 1 in the Supporting Information.
(10) The optical purity of the commercially available alcohol 21 is
98.0% ee.
(11) Zanka, A. Chem. Pharm. Bull. 2003, 51, 888−889.
(12) Only one 7′-H at δ 1.01 was reported for naturally occurring
streptophenazine G, and another 7′-H at δ 1.15 was not described in
the Supporting Information of ref 2. We have located the second 7′-H
at δ 1.15 by 2D HSQC NMR studies (see the Supporting
Information).
(13) Wullschleger, C. W.; Gertsch, J.; Altmann, K. Org. Lett. 2010,
12, 1120−1123.
(14) (a) Mori, K. Tetrahetron 2009, 65, 3900−3909. (b) Mori, K.;
Tashiro, T.; Zhao, B.; Suckling, D. M.; El-Sayed, A. M. Tetrahetron
2010, 66, 2642−2653.
(15) Akasaka, K.; Tamogami, S.; Beeman, R.; Mori, K. Tetrahedron
2011, 67, 201−209.
(16) Suzuki, T. Agric. Biol. Chem. 1981, 45, 1357−1363.
3196
dx.doi.org/10.1021/jo202642a | J. Org. Chem. 2012, 77, 3191−3196