Studies towards the synthesis of medermycin via d?tz benzannulation

Article abstract of DOI:10.1002/chir.22383

The C-arylglycosides are available in enantiomerically pure form via the D?tz benzannulation reaction between Fischer alkenyl chromium carbene complexes and alkynes; it also could be converted to a precursor of medermycin by O-carbamate directed ipso bromination and nitrile substitution in good overall yields. Chirality 27:18-22, 2015.

Full text of DOI:10.1002/chir.22383

CHIRALITY (2014)
Studies Towards the Synthesis of Medermycin via Dötz
Benzannulation
CHUNRONG QU,1 ERQING TANG,1,2 RICHARD LOEPPKY,2,† ZIXIN DENG,1 SHON R. PULLEY,2 AND XUECHUAN HONG1,2
*
1Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, and Wuhan University School of
Pharmaceutical Sciences, Wuhan, China
2Department of Chemistry, University of Missouri-Columbia, Columbia, Missouri, USA
ABSTRACT
The C-arylglycosides are available in enantiomerically pure form via the Dötz
benzannulation reaction between Fischer alkenyl chromium carbene complexes and alkynes; it
also could be converted to a precursor of medermycin by O-carbamate directed ipso bromination
and nitrile substitution in good overall yields. Chirality 00:000–000, 2014. © 2014 Wiley Periodicals, Inc.
KEY WORDS: Streptomyces sp; Dötz benzannulation; C-arylglycoside; Fischer carbene
complex; ipso bromination
measured and transferred by gas-tight syringes and added to the reaction
INTRODUCTION
flask through rubber septa. Moisture-sensitive and hygroscopic solid
compounds were transferred under a nitrogen atmosphere in a glove
bag. The reaction mixture was concentrated by using a rotary evaporator
attached to a water aspirator. Residual solvents were usually removed un-
der reduced pressure using a vacuum pump. Analytical thin-layer chro-
matography (TLC) was performed on glass-backed silica gel plates with
an F254 indicator. Compounds were visualized under a UV lamp or
by developing in iodine, vanillin, phosphomolybdic acid solution or
with a potassium permanganate solution followed by heating on a
hotplate to ~350 °C. Flash chromatography was performed on
230–400 mesh silica gel with technical grade solvents which were dis-
tilled prior to use. 1H NMR spectra were recorded on a Brüker
(Billerica, MA) AMX-250, Brüker AMX-300, Brüker AMX-500 at
250, 300, or 500 MHz, respectively, as CDCl3 solutions with
tetramethylsilane (δ = 0 ppm) as the internal standard. 13C spectra
were obtained on the same instruments at 62.5, 75, or 125 MHz, re-
spectively, with CDCl3 (δ = 77 ppm) as the internal reference. Chem-
ical shifts are reported in parts per million (ppm). Multiplicities are
The C-arylglycosides are carbohydrate derivatives whose
anomeric centers are directly bonded to a mono- or polycyclic
aromatic moiety through a carbon–carbon bond.1 The C-C bond
in C-arylglycosides is stable to acid hydrolysis, which makes
C-arylglycosides much more stable than O-arylglycosides. Up
to now, more than 20 naturally occurring C-arylglycosides have
been isolated.2 Such compounds exhibit a diversity of biological
activities including antitumor, antibacterial, and antifungal prop-
erties.3–5 Their importance in medicinal chemistry and limited
availability have brought enormous attention to their synthesis
in the recent past.6,7
Medermycin (1) (Fig. 1) is a unique member of the
pyranonaphthoquinone family of antibiotics containing a
β-C-glycoside linkage to an aminosugar, D-angolosamine,
which was first isolated from Streptomyces sp. by Takano
et al. in 1976.8 Biological evaluation of medermycin showed
that it has strong activity against Gram-positive organisms
including many species of Staphylococcus and Bacillus.9
Medermycin can also inhibit human leukemia K-562 cells
and platelet aggregation,9 making it of interest as a leading
target for synthesis. Since its reported isolation, several an-
alog syntheses10–15 and one total synthesis16 of medermycin
have appeared in the literature.
reported as
s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), dd (doublet of doublet), etc. Infrared spectra were re-
corded on a Thermo Nicolet NEXUX 670 FT-IR spectrometer as
neat liquids with NaCl cells. Melting points were determined using
a
Fisher-Johns Hot Stage melting point apparatus and were
uncorrected. Optical rotations were measured on a Jasco DIP-370
digital polarimeter.
We have successfully developed a new methodology for the
synthesis of C-arylglycosides via a Dötz benzannulation reac-
tion.17,18 The reaction of C-alkyne glycoside 2 with vinyl TMS
carbene complex afforded C-arylglycoside 4 in 56% yield
(Scheme 1). The results showed that regioselective oxidation
for the larger group of an unsymmetrical alkyne ortho to
the phenolic hydroxyl group is consistent with the orien-
tation of the naturally occurring C-arylglycosides such as
medermycin. We applied this Dötz benzannulation strat-
egy, formally a [3 + 2 + 1] cycloaddition, to the total syn-
theses of (S, S)-isodityrosine19 and shikonin.20
In an effort to expand the scope of this process, we decided
to explore the synthesis of medermycin using our methodol-
ogy to construct the core ring of the C-arylglycoside of
the target. A retrosynthesis based on this approach is
shown in Scheme 2.
Preparation of aryl bromide 15e. To a solution of 9e (380 mg,
0.59 mmol) in 12 mL distilled DMF, NBS (350 mg, 1.97 mmol) was
added. The solution was stirred for 12 h. Then the reaction mixture
was put on the vacuum to remove DMF and purified via flash chro-
matography (10% EtOAc/Hexane) which gave 288 mg (75%) of the
aryl bromide 15e. [α]20 = À2.63; 1H NMR (300 MHz, CDCl3):
D
Contract grant sponsor: National Natural Science Foundation of China; Con-
tract grant numbers: 81373254 and 21390402
Contract grant sponsor: National Institutes of Health (SP), NIGMS; Contract
grant number: GM59350-01
Contract grant sponsor: National Science and Technology Major Project of the
Ministry of Science and Technology of China; Contract grant number:
2012ZX10004801-003-011
Contract grant sponsor: Key Project of Chinese Ministry of Education; Con-
tract grant number: 313040
*Correspondence to: Xuechuan Hong, Key Laboratory of Combinatorial Bio-
synthesis and Drug Discovery (Wuhan University), Ministry of Education,
and Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071,
China. E-mail: xhy78@whu.edu.cn
Dedicated to the memory of Professor Richard Loeppky. Deceased April 21, 2012.
Received for publication 3 April 2014; Accepted 4 August 2014
DOI: 10.1002/chir.22383
MATERIALS AND METHODS
All air- and moisture-sensitive reactions were carried out in flame-dried
glassware under a nitrogen atmosphere. Reactive liquid compounds were
Published online in Wiley Online Library
(wileyonlinelibrary.com).
© 2014 Wiley Periodicals, Inc.

QU ET AL.
(d, J= 11.1 Hz, 1H), 3.82 (m, 4H), 3.50-3.38 (m, 5H), 3.21-3.19 (m, 1H),
2.42 (d, J = 12.0 Hz, 1H), 1.31-1.22 (m, 1H), 0.91-0.88 (m, 18H), 0.12-0.1
(m, 12H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 153.0, 152.3, 147.7,
137.8, 121.4, 115.7, 112.9, 105.2, 78.2, 77.2, 74.6, 71.3, 55.8, 42.5, 42.1,
41.1, 26.2, 26.1, 19.0, 18.3, 18.0, 14.1, 13.2, –-2.8, –3.0, –4.0, –4.3 ppm.
IR (neat): 2947, 2861, 2236, 1736, 1400, 1123. HRMS: m/z calc’d for
C
31H54N2O6Si2Li, [M+ Li]+ 613.3680, found 613.3673.
Preparation of phenol 8. O-Carbamate protected aryl nitrile 21 (45 mg)
was dissolved in 8 mL of EtOH and then 40 mg of NaOH was added. The so-
lution was heated to reflux and stirred for 14 h. After the solution was cooled,
the solvent was evaporated. Then water (5 mL) was added and CH2Cl2 (5 mL)
was added to the residue and separated. The water layer was extracted with
another three portions of CH2Cl2, and the organic layer was combined and
dried with MgSO4 and then concentrated. Flash chromatography gave
Fig. 1. Structure of medermycin.
δ = 7.29 (s, 3H), 7.00 (s, 1H), 4.63 (d, J = 11.2 Hz, 2H), 3.79 (s, 3H),
3.73-3.48 (m, 1H), 3.48-3.34 (m, 5H), 3.20 (t, J = 3.1 Hz, 1H), 2.30
(dd, J = 12.9 Hz, 1H), 1.46-1.84 (m, 10H), 0.91-0.89 (m, 18H), 0.12-
0.07 (m, 12H) ppm. 13C NMR (75 MHz, CDCl3): δ = 153.3, 152.9,
142.6, 131.2, 121.3, 114.5, 114.4, 78.3, 77.1, 74.7, 71.2, 55.7, 42.2, 41.8,
41.4, 26.2, 26.0, 19.0, 18.2, 18.0, 14.1, 13.2, -2.8, -3.0, –4.0, –4.3 ppm.
IR (neat): 2945, 2841, 2337, 1770, 1543, 1482, 1102. HRMS: m/z calc’d
for C30H54NO6Si729BrLi, [M + Li]+ 666.2833, found 666.2862.
1
25 mg of the desired product 8 (67%). H NMR (300 MHz, CDCl3): δ =7.13
(s, 1H), 6.85 (s, 1H), 4.66 (d, J= 11.0 Hz, 1H), 3.78-3.73 (m, 4H), 3.42-3.37
(s, 1H), 3.18 (t, J=8.4Hz, 1H), 2.32 (dd, J= 12.8, 7.1 Hz, 1H), 1.37-1.23 (m,
4H), 0.91-0.89 (m, 18H), 0.12-0.08 (m, 12H) ppm. 13C NMR (62.5 MHz, CDCl3)
: δ = 152.9, 149.3, 138.8, 114.6, 112.4, 97.2, 78.3, 77.2, 74.6, 71.2, 55.8, 41.2, 26.2,
26.0, 19.0, 18.3, 18.0, –2.7, –3.0, –4.0, –4.3 ppm. HRMS: m/z calc’d for
C26H44NO5Si-2, [M-H]- 506.2764, found 506.2784.
Preparation of o-carbamate protected aryl nitrile 21. Compound
15e (50 mg, 0.76 mmol) was dissolved in 5 mL distilled DMF. Then
16 mg CuCN was added. The solution was heated to 160 °C and kept
at that temperature for 12 h. After the solution was cooled, the reac-
tion mixture was poured into water and extracted with CH2Cl2
(3 × 10 mL). The organic layer was dried with MgSO4, Flash chroma-
Preparation of deoxygenated nitrile 22. A solution of phenol 8
(13 mg, 0.04mmol) in 1 mL CH2Cl2 at 0 °C was treated with pyridine
(10 μL) and the solution was stirred for 15min, after which was added
Tf2O (30 μL). The reaction was monitored by TLC and completed after half
an hour, at which time it was poured into sat. NaHCO3 (5 mL) and extracted
with CH2Cl2 (3× 5 mL). The organic layer was combined and dried with
MgSO4, then concentrated. Flash chromatography gave 11mg of the de-
sired triflate (66.9% yield). To a solution of the triflate (10 mg, 0.0156mmol)
tography gave 45 mg of the desired product 21 (98%). [α]20 = 7.32;
D
1H NMR (500 MHz, CDCl3): δ = 7.41 (s, 1H), 6.99 (s, 1H), 4.68
Scheme 1. C-Arylglycosides via a benzannulation mediated by Fischer chromium carbene complexes.
Scheme 2. Retrosynthesis of medermycin.
Chirality DOI 10.1002/chir

SYNTHESIS OF MEDERMYCIN VIA DÖTZ BENZANNULATION
Scheme 3. Synthesis of C-arylglycoside 9a.
in 1 mL DMF was added Pd(OAc)2 (3.5mg, 0.016 mmol), dppf (8.8mg,
Preparation of aryl carboxylic acid 7. To a solution of deoxygen-
ated nitrile 22 (49.6 mg, 0.101 mmol), 1 M DIBAL-H solution in hex-
ane (400 μL, 0.4 mmol) was added at the temperature of –70 °C. It
was then allowed to warm up slowly to room temperature for 2 h
and stirred for another 12 h. NH4Cl solution (2 mL) was added and
the reaction mixture was stirred for another 2 h. Then the reaction
mixture was extracted with CH2Cl2 (3 × 5 mL). The organic layer
was combined and dried with MgSO4, and then concentrated to give
the crude aldehyde. The crude aldehyde was taken up in 10 mL of a
1:1 solution of CH3CN and t-BuOH and 40 drops of 2-methyl-2-butene
was added. To this solution, 50 mg of NaH2PO4 and 40 mg of NaClO2
in 2 mL of water were added. The mixture was vigorously stirred for
20 min at room temperature and then extracted with EtOAc (15 mL)
three times. The organic layer was dried by MgSO4 and
concentrated. Flash chromatography gave 42 mg of the desired acid
0.016 mmol), TEA (15 μL, 0.106 mmol), HCO2H (3.0 μL, 0.091 mmol). Then
the solution was warmed to 70°C and stirred for 0.5 h. Filtration through
SiO2 to remove baseline material gave 7 mg (91%) of the desired deoxy-
genated nitrile 22. [α]20 = 27.06. 1H NMR (250 MHz, CDCl3): δ =7.57
D
(d, J= 7.8 Hz, 1H), 7.28 (dd, J= 7.9, 1.4 Hz, 1H), 7.05 (d, J= 1.4 Hz, 1H), 4.47
(d, J= 12.5 Hz, 1H), 3.84 (s, 1H), 3.82-3.74 (m, 1H), 3.50-3.34 (m, 1H), 3.2
(t, J= 8.38 Hz, 1H), 2.13 (ddd, J= 13.0, 6.0, 3.0 Hz, 1H),1.37-1.30 (m, 1H), 1.32
(d, J= 6.2 Hz, 3H), 0.92-0.90 (m, 18H), 0.13-0.08 (m, 12H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 156.2, 137.3, 127.6, 119.8, 113.8, 112.1, 79.1, 75.5,
72.1, 56.3, 42.1, 27.1, 26.9, 19.9, 19.1, 10.9, –1.9, –2.2, –3.1, –3.4. IR (neat):
2966, 2907, 2861, 2242, 1729, 1584, 1477, 1400, 1255, 1104 ppm. HRMS: m/z
calc’d for C26H47NO4Si2H, [M + H]+ 492.2965, found 492.2979.
7 (82% yield). [α]20 = 28.7. 1H NMR (300 MHz, CDCl3): δ = 7.74 (d,
D
TABLE 1. Ipso Bromination of compound 9
J = 7.9, 1.5 Hz, 1H), 7.59-7.55 (m, 2H), 4.75 (d, J = 12.5 Hz, 1H), 3.88
(s, 3H), 3.50-3.35 (m, 1H), 3.22 (t, J = 8.3 Hz, 1H), 2.40-2.29 (m,
1H),1.40-1.20 (m, 4H), 0.92-0.90 (m, 18H), 0.13-0.08 (m, 12H) ppm.
13C NMR (75 MHz, CDCl3): δ = 171.0, 136.9, 128.7, 125.9, 123.0,
111.1, 78.4, 77.2, 74.7, 71.5, 55.3, 41.4, 26.2, 26.0, 19.1, 18.3, 18.0,
–2.8, –3.0, –4.0, –4.3 ppm. IR (neat): 3421, 2967, 2866, 1693, 1584,
1466, 1116. HRMS: m/z calc’d for C26H48O6Si2, [M-H]- 511.2911,
found 511.2887.
Entry
Aryl TMS (9)
R1
R2
Bromide(15)
Yield (%)
1
2
3
4
9a
9b
9c
9d
OBn
H
H
Me
Me
Ac
15a
15b
15c
15d
12
Trace
40
OH
Ac
31
Scheme 4. Ipso Bromination of compound 9e.
Chirality DOI 10.1002/chir

QU ET AL.
Scheme 5. Explanation of the regioselectivity.
RESULTS AND DISCUSSION
synthesis started with 3, 4, 6-O-acetyl D-glucal 11.
Nicolaou’s method was employed to synthesize the D-
rhamnal 12 in three steps in 45% overall yield.21 The D-
rhamnal 12 is protected by TBS group under standard
conditions. Then PCC oxidation gives lactone 13. Addition
of the Grignard acetylide to lactone and the subsequent
reductive deoxygenation and selective desilylation under
phase transfer conditions gave the desired the C-alkyne
glycoside 14 in 70% yield in stereocontrol. With the desired
C-alkyne glycoside 14 in hand, the Dötz benzannulation
reaction proceeded under standard conditions to give the
chromium arene complex, which was air-oxidized to the de-
sired free phenol. The standard Williamson conditions
(NaH, MeI) successfully methylated the phenol to give the
C-arylglycoside 9a in 65% yield.
The C-arylglycoside 9a (R1 = OBn, R2 = Me) needed for
this process was prepared as shown in Scheme 3. The
Scheme 6. “Metallo-Fries” attempt of 2-lithio-phenol derivatives.
Scheme 7. Final steps for the synthesis of core intermediate 7.
Chirality DOI 10.1002/chir

SYNTHESIS OF MEDERMYCIN VIA DÖTZ BENZANNULATION
The next challenge involved the ipso halogenation of the
Central Universities (CQ) and Innovation Seed Fund of Wuhan
University School of Medicine (XH).
TMS-group in compound 9. Bromination of 9a and deoxygen-
ated aryl TMS 9b using NBS in DMF gave the desired aryl
bromide product 15a and 15b in 12% yield and a trace amount,
respectively (Table 1, entries 1–2). The major product isolated
is the electrophilic bromination product without the de-
silylation. When the acetyl group was chosen as the protective
group for the phenol to decrease the ortho directing effect of
OR2 group the best yield was improved to 40% (Table 1, entries
3–4). A possible way to improve the yields of ipso bromination is
to increase the directing ability of the R1 group of compound 9
to compete with methoxy group. Possibly, H, OH, and OBn are
not very strong ortho directing groups, which is responsible for
the low yield.22 Thus, the O-carbamate was chosen as the
protecting group for the hydroxyl group meta to the sugar.
Fortunately, bromination of O-carbomate protected aryl
TMS compound 9e with NBS (3.0 equiv.) in 12 h resulted
in the formation of the expected aryl bromide 15e in 75%
yield (Scheme 4).
SUPPORTING INFORMATION
Additional supporting information may be found in the
online version of this article at the publisher’s web-site.
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the National Institutes of Health (SP), NIGMS Grant
GM59350-01, the University of Missouri, Monsanto, the Na-
tional Science and Technology Major Project of the Ministry
of Science and Technology of China No. 2012ZX10004801-
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Chirality DOI 10.1002/chir