First enantioselective total synthesis of the angucyclinone-type antibiotic YM-181741

Article abstract of DOI:10.1055/s-2007-973863

A simple and efficient strategy for angucyclinone antibiotics is described with the disclosure of first total synthesis of YM-181741. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-973863

LETTER
977
First Enantioselective Total Synthesis of the Angucyclinone-Type Antibiotic
YM-181741
Synthesis of
A
ngu
r
cyclinon
i
e-Type
s
Antibioti
h
c
Y
M-18174
n
1
a P. Kaliappan,* Velayutham Ravikumar
Department of Chemistry, Indian Institute of Technology-Bombay, Powai, Mumbai 400076, India
Fax +91(22)25723480; E-mail: kpk@chem.iitb.ac.in
Received 19 December 2006
Dedicated to Professor E. Peter Kündig on the occasion of his 60th birthday
highly efficient first enantioselective total synthesis of
Abstract: A simple and efficient strategy for angucyclinone anti-
biotics is described with the disclosure of first total synthesis of
YM-181741.
YM 181741 in 22% overall yield, a notable feature of this
approach is the generation of the requisite diene for Diels–
Alder reaction through intramolecular enyne metathesis.6
Key words: Grubbs’ catalyst, enyne metathesis, Diels–Alder reac-
tion, quinones, angucyclinone antibiotic
O
O
O
O
R
OH
Peptic ulcer is one of the common problems in the world
and it is estimated that about half of the old population
suffers from this. Initially it was believed that lifestyle,
stress and spicy food were responsible for peptic ulcer.
However, recent studies have shown that it is being main-
ly caused by Helicobacter pylori (H. pylori) bacterial
infection1 and other factors like smoking, excessive alco-
hol consumption, stress, regular use of pain relievers ag-
gravate this problem. A two-pronged approach, to kill the
bacteria and reduce the acid level in the stomach, has been
successfully used to treat this problem. It has also been
observed that destruction of this bacterium decreases the
recurrence rate in peptic ulcer patients. Broad-spectrum
antibiotics like amoxicillin and clarithromycin have been
normally used to kill this bacterium with reasonable
success. Nevertheless, these antibiotics cause several side
effects like diarrhea or build up of drug resistance, which
necessitated the need for the development of new drugs
for the selective treatment of peptic ulcer.2
OH
O
OH
O
tetrangomycin (3)
R = OH: YM 181741 (1)
R = H: ochromycinone (2)
Figure 1 A few examples of angucyclinones
Our retrosynthetic analysis of compound 1 is depicted in
Scheme 1. Not surprisingly, our thought was to utilize a
Diels–Alder reaction between the diene 5 and bromo-
quinone 4.7 We envisaged that the requisite diene 5 could
be formed by an intramolecular enyne metathesis of 6.
Enyne 6 could then be traced back to N-acyloxazolidinone
7 and propargyl bromide 8, which could be coupled via an
asymmetric enolate alkylation.
O
OR
Br
+
Recently, Taniguchi et al. reported the isolation of a new
angucycline antibiotic YM 181741 (1, Figure 1), which
shows selective activity against Helicobacter pylori, with
a MIC value of 0.2 mg/mL.3 This new angucyclinone
antibiotic is structurally similar to another anthraquinone
antibiotic ochromycinone (2).4 Apart from its angular
benz[a]anthraquinone moiety, another interesting feature
of YM 181741 is the presence of CH2OH group at C-3
position in the A-ring, and it appears that it could be an
isomer of tetrangomycin (3). Though the related angu-
cyclinones are well studied and synthesized,5 total synthe-
sis of 1 has not been achieved so far. In view of the
importance of its significant biological properties, cou-
pled with its intriguing molecular architecture, we became
interested in the synthesis of YM 181741 and its simpler
analogues. In this communication, we report a new,
YM 181741
5
OAc
O
4
O
OR
Br
Aux
+
8
7
6
Scheme 1 Retrosynthesis of YM 181741
The synthesis of diene 5 (Scheme 2) began with the
preparation of known 118 from hexenoic acid 9 using a
modified protocol.9 Then, the key asymmetric enolate
alkylation was successfully accomplished by treating with
n-BuLi in the presence of HMPA10 followed by quench-
ing with propargyl bromide to afford the enyne 12 in
greater than 95% de, which was confirmed by HPLC.11
SYNLETT 2007, No. 6, pp 0977–0979
0
3.
0
4.
2
0
0
7
Advanced online publication: 26.03.2007
DOI: 10.1055/s-2007-973863; Art ID: G37706ST
© Georg Thieme Verlag Stuttgart · New York

978
K. P. Kaliappan, V. Ravikumar
LETTER
After chromatographic purification, it was possible to
obtain 12 as a single diastereomer.
O
O
OTBS
Br
H
OTBS
other
regioisomer
The chiral auxiliary was then reductively removed by
LiBH4 to afford the primary alcohol 13 which was subse-
quently protected as its TBS ether 14. When this enyne
was subjected to metathesis reaction conditions under an
ethylene atmosphere12 with Grubbs’ second-generation
catalyst 16, the required diene 15 was obtained in excel-
lent yield.13
a
+
b
OAc
15
17
O
O
O
OTBS
O
OTBS
c
O
O
O
OH
OH
O
19
a
18
O
N
O
HN
Bn
O
HO
O
O
O
OH
Bn
11
10
9
d
synthetic: [α]25D +27.2 (c 0.367, CHCl3)
O
O
[α]25D +29.6 (c 0.15, CHCl3)
natural:
d
c
OH
b
O
N
OH
YM 181741
Bn
13
Scheme 3 Synthesis of YM 181741. Reagents and conditions: a) 4,
toluene, 80 °C, 12 h; b) K2CO3, MeOH, 71% for two steps; c) hn, O2,
benzene, 79% (based on 88% conversion); d) TBAF, THF, r.t., 2 h,
68%.
12
MesN
NMes
OTBS
OTBS
e
Cl
Cl
Ru
14
Ph
PCy3
Acknowledgment
15
16
Authors acknowledge DST, New Delhi for financial support and
SAIF, IIT Bombay for providing spectral facilities. V.R.K. thanks
CSIR, New Delhi for a fellowship.
Scheme 2 Synthesis of diene. Reagents and conditions: a) PivCl,
Et3N, 5-hexenoic acid, THF then LiCl, 10, –10 °C to r.t., 12 h, 96%;
b) n-BuLi, THF, HMPA, propargyl bromide, –78 °C, 20 h, 89%;
c) LiBH4, Et2O, 0 °C, 2 h, 82%; d) TBSCl, imidazole, CH2Cl2, 0 °C,
1 h, 92%; e) ethylene, G-II (16), toluene, 80 °C, 12 h, 88%.
References and Notes
(1) (a) Peterson, W. L. N. Engl. J. Med. 1991, 324, 1043.
(b) Van der Hults, R. W. M.; Rauws, E. A. J.; Koycu, B.;
Keller, J. J.; Bruno, M. J.; Tussen, J. G. P.; Tytgat, G. N. J.
Gastroenterology 1997, 113, 1082.
(2) (a) Domizio, P.; Farthing, M. J. G. Aliment. Pharmacol.
Ther. 1995, 9, 205. (b) Megraud, F. Brit. Med. Bull. 1998,
54, 207.
(3) Taniguchi, M.; Nagai, K.; Watanabe, M.; Niimura, N.;
Suzuki, K.-I.; Tanaka, A. J. Antibiot. 2002, 55, 30.
(4) Bowie, J. H.; Johnson, W. Tetrahedron Lett. 1967, 34, 1449.
(5) (a) Rohr, J.; Thiericke, R. Nat. Prod. Rep. 1992, 9, 103.
(b) Carreño, M. C.; Urbano, A. Synlett 2005, 1.
With the diene 15 in hand, we then investigated its Diels–
Alder reaction with the appropriate quinone (Scheme 3).
Treatment of diene 15 with 5-acetoxy-2-bromo-1,4-naph-
thaquinone (4)14 at 80 °C in toluene afforded the cyclo-
adduct 17 which was immediately subjected to
aromatization reaction with K2CO3 in MeOH to provide
an inseparable mixture of 18 and its regioisomer in 9:1
ratio as confirmed by 1H NMR spectrum.
Subsequent photochemical oxidation (Hg lamp, 125 W,
Philips India) of 18 yielded the ketone 19 in 79% yield
(based on 88% conversion)15 and at this stage we were
able to separate this isomer after column chromatography.
Finally, removal of the TBS group with TBAF afforded
the natural product YM 181741 (1) in 68% yield.
(6) For sequential enyne metathesis and Diels–Alder reaction
with quinones as well as other dienophiles, see:
(a) Kaliappan, K. P.; Ravikumar, V. Org. Biomol. Chem.
2005, 848. (b) Dolhem, F.; Lievre, C.; Demailly, G. Eur. J.
Org. Chem. 2003, 2336. (c) Yang, Y.-K.; Tae, J. Synlett
2003, 2017. (d) Guo, H.; Madhushaw, R. J.; Shen, F.-M.;
Liu, R.-S. Tetrahedron 2002, 58, 5627. (e) Moreno-Mañas,
M.; Pleixats, R.; Santamaria, A. Synlett 2001, 1784.
(f) Kotha, S.; Sreenivasachary, N.; Brahmachary, E. Eur. J.
Org. Chem. 2001, 787. (g) Bentz, D.; Laschat, S. Synthesis
2000, 1766.
The spectral data of the synthesized product matched
those reported, in all aspects, thus confirming the first
total synthesis of YM 181741.16
In summary, a short and first enantioselective total syn-
thesis of YM 181741 in 22% overall yield is described
here. This strategy could be easily extended to synthesize
diverse analogues of this natural product as well as all
related angucyclinone antibiotics.
(7) For selected examples of utility of Diels–Alder reaction in
the synthesis of angucyclinone, see: (a) Krohn, K.; Sohrab,
M. H.; Flörke, U. Tetrahedron: Asymmetry 2004, 15, 713.
(b) Landells, J. S.; Larsen, D. S.; Simpson, J. Tetrahedron
Lett. 2003, 44, 5193. (c) Krohn, K.; Michael, J.; Zukowski,
M. Tetrahedron 2000, 56, 4753. (d) Matsuo, G.; Miki, Y.;
Synlett 2007, No. 6, 977–979 © Thieme Stuttgart · New York

LETTER
Nakata, M.; Matsumura, S.; Toshima, K. J. Org. Chem.
Synthesis of Angucyclinone-Type Antibiotic YM-181741
979
MHz, CDCl3): d = 12.55 (1 H, s), 8.14 (1 H, d, J = 8.4 Hz),
7.72 (1 H, dd, J = 7.6, 1.2 Hz), 7.64 (1 H, t, J = 7.8 Hz), 7.50
(1 H, d, J = 7.6 Hz), 7.24 (1 H, dd, J = 8.4, 1.2 Hz), 3.68–
3.29 (2 H, m), 3.28–3.20 (1 H, m), 3.00 (1 H, dd, J = 17.2,
2.8 Hz), 2.67 (1 H, dd, J = 17.2, 10.8 Hz), 2.09–2.0 (2 H, m),
1.47–1.25 (1 H, m), 3.05–2.81 (2 H, m), 0.92 (9 H, s), 0.07
(6 H, s). 13C NMR (100 MHz, CDCl3): d = 188.8, 161.9,
146.2, 141.7, 136.6, 136.5, 135.1, 135.0, 132.8, 131.2,
124.8, 123.1, 119.4, 115.7, 67.5, 35.7, 34.5, 28.9, 26.1, 18.5,
–5.1, –5.2; HRMS (EI): m/z calcd for C25H31O4Si: 423.1992;
found: 423.1981.
1999, 64, 7101. (e) Carreño, M. C.; Urbano, A.; Fischer, J.
Angew. Chem., Int. Ed. Engl. 1997, 36, 1621. (f) Matsuo,
G.; Miki, Y.; Nakata, M.; Matsumura, S.; Toshima, K.
Chem. Commun. 1996, 225. (g) Kim, K.; Sulikowski, G. A.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2396. (h) Datta, S.
C.; Franck, R. W.; Triphaty, R.; Quigley, G. J.; Huang, L.;
Chen, S.; Sihaed, A. J. Am. Chem. Soc. 1990, 112, 8472.
(i) Carreño, M. C.; Somoza, A.; Ribagorda, M.; Urbano, A.
Chem. Eur. J. 2007, 23, 879.
(8) Ghosh, A. K.; Gong, G. J. Org. Chem. 2006, 71, 1085.
(9) Hu, X.; Nguyen, K. T.; Verlinde, C. L. M. J.; Hol, W. G. J.;
Pei, D. J. Med. Chem. 2003, 46, 3771.
(10) Pettigrew, J. D.; Wilson, P. D. Org. Lett. 2006, 8, 1427.
(11) HPLC conditions: YMC Pack Pro-C18, 4.6 × 250 mm,
eluents H2O–MeCN (10:90), flow 1.0 mL/min, UV detector
at 254 nm; tR = 2.928 min.
(12) Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998,
63, 6082.
(13) For reviews on enyne metathesis, see: (a) Mori, M. Top.
Organomet. Chem. 1998, 1, 133. (b) Poulsen, C. S.;
Madsen, R. Synthesis 2003, 1. (c) Diver, S. T.; Giessert, J.
Chem. Rev. 2004, 104, 1317.
(14) Heinzman, S. W.; Grunwell, J. R. Tetrahedron Lett. 1980,
21, 4305.
(15) (a) Krohn, K.; Ballwanz, F.; Baltus, W. Liebigs Ann. Chem.
1993, 911. (b) Motoyoshiya, J.; Masue, Y.; Iwayama, G.;
Yoshioka, S.; Nishii, Y.; Aoyama, H. Synthesis 2004, 2099.
(16) Spectral Data for Selected Compounds
20
Ketone 19: Rf = 0.33 (EtOAc–PE, 1:9); mp 91–93 °C; [a]D
+56.5 (c 0.52, CHCl3). IR (KBr): 3425, 2927, 1706, 1672,
1592, 1457, 1363, 1284, 1099 cm–1. 1H NMR (300 MHz,
CDCl3): d = 12.30 (1 H, s), 8.30 (1 H, d, J = 7.8 Hz), 7.69 (1
H, dd, J = 5.4, 1.8 Hz), 7.65 (1 H, d, J = 7.8 Hz), 7.58 (1 H,
d, J = 8.1 Hz), 7.28 (1 H, dd, J = 8.1, 2.1 Hz), 3.71 (1 H, dd,
J = 9.9, 5.1 Hz), 3.62 (1 H, dd, J = 10.2, 6.3 Hz), 3.05–2.81
(2 H, m), 2.73 (2 H, dd, J = 16.2, 10.8 Hz), 2.56–2.49 (1 H,
m), 0.91 (9 H, s), 0.07 (6 H, s). 13C NMR (100 MHz, CDCl3):
d = 199.3, 187.6, 183.0, 162.2, 150.4, 137.2, 136.9, 135.8,
135.1, 133.5, 133.4, 129.1, 123.8, 119.8, 115.5, 66.2, 42.3,
38.0, 33.0, 26.0, 18.4, –5.3. HRMS (EI): m/z calcd for
C25H29O5Si: 437.1784; found: 437.1779.
Natural product YM 181741 (1): 68% yield (0.05 g); Rf = 0.3
(EtOAc–PE, 6:4); mp 192 °C; [a]D25 +27.2 (c 0.367, CHCl3).
IR (KBr): 3433, 2927, 1702, 1671, 1588, 1453, 1362, 1276,
1588, 1453, 1362, 1276, 1215 cm–1. UV (MeOH): lmax (e) =
276, 402 nm. 1H NMR (400 MHz, CDCl3): d = 12.30 (1 H,
s), 8.30 (1 H, d, J = 7.6 Hz), 7.68 (1 H, dd, J = 7.6, 2.4 Hz),
7.65 (1 H, d, J = 7.2 Hz), 7.58 (1 H, d, J = 8 Hz), 7.28 (1 H,
dd, J = 8.0, 2.4 Hz), 3.77 (1 H, dd, J = 10.4, 4.8 Hz), 3.70 (1
H, dd, J = 7.2, 10.4 Hz), 3.10 (1 H, dd, J = 16.8, 4.8 Hz),
3.03 (1 H, dd, J = 16, 6.4 Hz), 2.85 (1 H, dd, J = 16.4, 10.4
Hz), 2.69 (1 H, dd, J = 16.0, 10.4 Hz), 2.61–2.54 (1 H, m),
1.86 (1 H, br s). 13C NMR (100 MHz, CDCl3): d = 198.8,
187.4, 182.9, 162.0, 149.8, 137.0, 136.7, 135.6, 134.9,
133.5, 133.2, 129.1, 123.8, 119.6, 115.4, 65.8, 42.0, 37.6,
32.7. HRMS (EI): m/z calcd for C19H15O5: 323.0919; found:
323.0910.
Diene 15: Rf = 0.9 (EtOAc–PE, 3:7); [a]D20 +99.1 (c 1.35,
CHCl3). IR (neat): 3454, 2930, 1655, 1465, 1257, 1104
cm–1. 1H NMR (400 MHz, CDCl3): d = 6.37 (2 H, dd,
J = 17.6, 10.8 Hz), 5.75 (1 H, br s), 5.07 (1 H, d, J = 17.7
Hz), 4.9 (1 H, d, J = 10.8 Hz), 3.59–3.49 (2 H, m), 2.30–2.18
(2 H, m), 2.30–2.18 (1 H, m), 1.80–1.76 (2 H, m), 1.29–1.20
(1 H, m), 0.89 (9 H, s), 0.06 (6 H, s). 13C NMR (75 MHz,
CDCl3): d = 140.0, 135.3, 129.6, 109.8, 67.9, 36.3, 26.9,
26.0, 25.3, 18.4, –5.4, –5.3.
Compound 18: Rf = 0.4 (EtOAc–PE, 1:19); mp 86–88 °C;
[a]D20 +130.0 (c 0.9, CHCl3). IR (KBr): 3444, 2896, 2930,
1667, 1634, 1454, 1284, 1256, 1107 cm–1. 1H NMR (300
Synlett 2007, No. 6, 977–979 © Thieme Stuttgart · New York

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