The revised structure, total synthesis, and absolute configuration of streptophenazine A

Article abstract of DOI:10.1021/ol202005u

A total synthesis of both diastereomers of the originally proposed structure for streptophenazine A (1) has been achieved. However, both synthetic compounds are different from the natural product. Re-examination of NMR data reported for streptophenazine A

Full text of DOI:10.1021/ol202005u

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5436–5439
The Revised Structure, Total Synthesis,
and Absolute Configuration of
Streptophenazine A
Zhicai Yang,*,† Xiaomin Jin,† Michael Guaciaro,† Bruce F. Molino,† Ursula Mocek,‡
Ricardo Reategui,‡ Joshua Rhea,‡ and Tim Morley§
Medicinal Chemistry Department, AMRI, 26 Corporate Circle, P.O. Box 15098,
Albany, New York 12212-5098, United States, Lead Discovery, AMRI, 22215 26th
Avenue SE, Bothell, Washington 98021, United States, and Aquapharm Biodiscovery
Ltd., European Centre for Marine Biotechnology, Dunstaffnage, Oban, Argyll, PA37
1QA, Scotland, U.K.
zhicai.yang@amriglobal.com
Received July 25, 2011
ABSTRACT
A total synthesis of both diastereomers of the originally proposed structure for streptophenazine A (1) has been achieved. However, both
synthetic compounds are different from the natural product. Re-examination of NMR data reported for streptophenazine A and a concise total
synthesis of both diastereomers of 17 (17a and 17b) led to the structural revision of streptophenazine A to 17b. Asymmetric synthesis of
(ꢀ)-streptophenazine A was also conducted, and its absolute configuration was determined to be 10S,20R.
Phenazine derivatives, such as saphenamycin1 as well as
esmeraldin A and B,2 are a potential source of antibiotics.
Several novel phenazine analogues, streptophenazines
AꢀH (1ꢀ8), have been recently isolated by Mitova and
co-workers from culturesofmarine Streptomyces sp. strain
HB202 (Figure 1), some of which have shown moderate
antibacterial activities.3 The structures of streptophena-
zines AꢀH were elucidated by spectroscopic methods;
however, the stereochemistry of the side chain was not
† AMRI, Medicinal Chemistry.
‡ AMRI, Lead Discovery.
Figure 1. Proposed structures of streptophenazines AꢀH (1ꢀ8).
§ Aquapharm.
(1) (a) Kitahara, M.; Nakamura, H.; Matsuda, Y.; Hamada, M.;
Naganawa, H.; Maeda, K.; Umezawa, H.; Itaka, Y. J. Antibiot. 1982, 35,
determined. We are interested in these novel phenazine
analogues and report herein the first total synthesis, the
1412–1414. (b) Geiger, A.; Keller-Schierlein, W.; Brandl, M.; Zahner, H.
J. Antibiot. 1988, 41, 1542–1551. (c) Laursen, J. B.; Jorgensen, C. G.;
Nielsen, J. Bioorg. Med. Chem. 2003, 11, 723–731.
(2) (a) Keller-Schierlein, W.; Geiger, A.; Zaehner, H.; Brandl, M.
Helv. Chim. Acta 1988, 71, 2058–2070. (b) Van’t Land, C. W.; Mocek,
U.; Floss, H. G. J. Org. Chem. 1993, 58, 6576–6582.
(3) Mitova, M. I.; Lang, G.; Wiese, J.; Imhoff, J. F. J. Nat. Prod.
2008, 71, 824–827.
(4) (a) Rewcastle, G. W.; Denny, W. A.; Baguley, B. C. J. Med. Chem.
1987, 30, 843–851. (b) Petersen, L.; Jensen, K. J.; Nielsen, J. Synthesis
1999, 1763–1766.
r
10.1021/ol202005u
Published on Web 09/29/2011
2011 American Chemical Society

revised structure, and absolute configuration of strepto-
phenazine A.
As shown in Scheme 1, the key step in our synthesis is an
aldol reaction, which couples ester 9 with aldehyde 10 to
generate both diastereomers of 1 in a concise manner.
and 15 were converted to the corresponding methyl esters 9
and 16, which are separable by silica gel chromatography.
Treatment of ester 9 with lithium bis(trimethylsilyl)amide
(LiHMDS), followed by coupling of the resulting enolate
with aldehyde 10,5 afforded a 1:1 mixture of the two
diastereomers (1a and 1b) of the proposed structure of
streptophenazine A. The individual diastereomers 1a and
1b were isolated by semipreparative HPLC on a C18
column.
Scheme 1. Retrosynthetic Analysis
The synthesis of the target 1 started from commercially
available chloride 11 and aniline 12 (Scheme 2). Reaction
of 11 with aniline 12 in the presence of potassium carbo-
nate provided amine 13 in excellent yield. Reductive
cyclization of 13 gave the desired acid 14 and a minor
regioisomer 15 in a ratio of 3:1.4 The mixture of acids 14
Scheme 2. Synthesis of the Proposed Structure 1
Figure 2. 1H and 13C NMR data of synthetic 1a, 1b, and the
naturally occurring streptophenazine A. The revised struc-
ture 17.
The structures of diastereomers 1a and 1b were con-
firmedby HRMS, 1H, 13C, 2D COSY, HSQC, and HMBC
NMR analyses. Unexpectedly, the 1H and 13C NMR data
of both 1a and 1b were different from those reported for
naturally occurring streptophenazine A. In particular, the
1
chemical shifts of H-10 and H-20 in the H NMR spectra
were quite different (Figure 2). For the natural product 1,
the chemical shifts of H-10 and H-20 were reported to be δ
6.15 and δ 3.27, respectively. However, these protons for
synthetic 1a were observed at δ 5.44 and δ 4.41, respec-
tively, and for synthetic 1b the signals were observed at δ
5.47and δ 4.52, respectively. Likewise, significant chemical
shift differences for the corresponding C-10 and C-20 in the
13C NMR spectra were also observed (Figure 2). For the
natural product 1, the chemical shifts for C-10 and C-20
werereported atδ 71.2 and δ 54.7, whereas, in the synthetic
samples, these carbon signals were found at δ 51.9 and δ
75.0 for 1a and at δ 51.2 and δ 73.8 for 1b, respectively.
1
Comparison of the H and 13C NMR data originally
reported for the natural product 1 (i.e., the chemical shifts
for H-10, H-20, C-10, and C-20) with those of the synthetic
(5) Graham, S. M.; Prestwich, G. D. J. Org. Chem. 1994, 59, 2956–
2966.
(6) (a) Nakamura, S.; Yagishita, K.; Umezawa, H. J. Antibiot. 1961,
14, 108–110. (b) Yagishita, K. J. Antibiot. 1960, 13, 83–96.
Org. Lett., Vol. 13, No. 20, 2011
5437

compounds 1a and 1b established that the original struc-
tural assignment for streptophenazine A was incorrect. It
seemed more plausible that the actual structure should be
revised to structure 17 (Figure 2). Based on these results,
we set out to confirm our hypothesis by total synthesis of
the revised structure 17.
are identical with those reported for naturally occurring
streptophenazine A. To confirm the hydroxyl group is
1
located on 10-position, H NMR of 17b was recorded in
CDCl3, in which the hydroxyl was observed at δ 5.07 (d,
J = 10.0 Hz) and the H-10 was observed at δ 5.57 (dd,
J = 10.0, 7.5 Hz). The coupling correlation between the
hydoxyl and H-10 was observed and confirmed by a 2D
COSY NMR experiment8 in CDCl3. Therefore, the ori-
ginally proposed structure for streptophenazine A was
revised to 17, although the stereochemistry of the side
chain was still unknown at that point.
Scheme 3. Synthesis of the Revised Structure 17
Scheme 4. Relative Configuration of (()-17a and (()-17b
The total synthesis of the revised structure 17 employing
an aldol reaction as the key step is shown in Scheme 3.
Utilizing the same strategy from Scheme 2, the known
alcohol 216 was prepared in three steps. Coupling of
chloride 11 with aniline 18 in the presence of potassium
carbonate afforded compound 19 smoothly. Reductive
cyclization of 19 with sodium borohydride and sodium
ethoxide in ethanol provided the desired regioisomer 206
exclusively. Treatment of acid 20 with methyl iodide using
potassium carbonate as base yielded the compound 21, mp
189ꢀ192 °C (lit.6 189 °C). Oxidation of alcohol 21 with
activated manganese(IV) oxide furnished aldehyde 22 in
good yield. Aldol reaction of aldehyde 22 with methyl ester
237 provided two separable diastereomers 17a and 17b in a
ratio of 3:2.
In order to determine the relative configuration of the
side chain of 17a and 17b, both racemic diastereomers were
transformed into cyclic compounds 24a and 24b in two
steps, hydrolysis and cyclization (Scheme 4). As expected,
a significant difference in the proton coupling constant
0
1
J1 -2 between 24a and 24b was observed by H NMR
0
0
0
0
0
(J1 -2 = 2.5 Hz for 24a and J1 -2 = 10.5 Hz for 24b). In 1D
The structures of 17a and 17b were assigned on the basis
of HRMS, 1H, 13C, 2D COSY, HSQC, and HMBC NMR
analyses. Both 1H and 13C NMR data of 17b in CD3OD
(9) The ee values were determined by chiral HPLC analyses on a
chiral column.
(10) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am.
Chem. Soc. 2002, 124, 392–393.
(11) Chavan, S. P.; Pasupathy, K.; Shivasankar, K. Synth. Commun.
2004, 34, 397–404.
(12) Yokokawa, F.; Shioiri, T. J. Org. Chem. 1998, 63, 8638–8639.
(7) Dickschat, J. S.; Helmke, E.; Schulz, S. Chem. Biodiversity 2005,
2, 318–353.
(8) See Supporting Information.
5438
Org. Lett., Vol. 13, No. 20, 2011

NOE studies, a strong NOE between H-10 and H-20 was
recorded for 24a, whereas no NOE between H-10 and H-20
was observed for 24b (Figure 3). The diagnostic NOE
difference between 24a and 24b supported the assignment
of the relative stereochemistry for both compounds and
their precursors (17a and 17b).
Scheme 5. Asymmetric Synthesis of (ꢀ)-17b
Figure 3. Key NOE correlations of (()-24a and (()-24b.
Chiral HPLC resolution of (()-17b was performed on a
chiral column to provide (þ)-17b {[R]20D = þ47.5° (c 1.2,
MeOH, >99% ee9)} and (ꢀ)-17b {[R]20D = ꢀ45.0° (c 1.2,
MeOH, >99% ee9)}. The optical rotation of (ꢀ)-17b is in
agreement with that reported for streptophenazine A in the
literature.3
Asymmetric synthesis of (ꢀ)-17b was conducted utiliz-
ing asymmetric aldol reaction10 as the key step (Scheme 5).
Reaction of acid chloride 2511 with (S)-4-benzyloxazoli-
din-2-one (26) provided 27 smoothly. Asymmetric aldol
reaction of oxazolidinone 27 with aldehyde 22 afforded
exclusively the desired anti-adduct 28. Oxidative hydro-
lysis of 28 with lithium hydroxide in the presence of
hydrogen peroxide,12 followed by treatment of the re-
sulting acid with (trimethylsilyl)diazomethane gave (ꢀ)-17b,
1H, 13C NMR data of (ꢀ)-17b are in agreement with those
of naturally occurring streptophenazine A.3 Therefore, the
absolute configuration of (ꢀ)-17b was determined to be
10S,20R.
configuration of (ꢀ)-streptophenazine A was determined
to be 10S,20R. Utilizing the same strategy described in
Scheme 5, asymmetric synthesis of streptophenazines B
and E has also been carried out.8
Acknowledgment. This research was partially funded
by Aquapharm Biodiscovery Ltd. The authors thank
AMRI analytical department for the collection of IR and
HRMS data and for the determination of ee values.
20
[R]D ꢀ48.4° (c 1.0, CH3OH). The optical rotation and
Supporting Information Available. Asymmetric synthe-
sis of streptophenazines B and E, X-ray crystallographic
data, Experimental procedures, NMR spectra for 1, 9,
13ꢀ17, 19ꢀ22, 27, and 28. This material is available free
of charge via the Internet at http://pubs.acs.org.
In conclusion, we have achieved the first total synthesis
of (ꢀ)-streptophenazine A, leading to the structural revi-
sion of streptophenazine A to structure 17b. The absolute
Org. Lett., Vol. 13, No. 20, 2011
5439