Syntheses and absolute stereochemistries of UPA0043 and UPA0044, cytotoxic antibiotics having a p-quinone-methide structure

Article abstract of DOI:10.1021/ol016960n

(Formula Presented) The first syntheses of new antibiotics UPA0043 and UPA0044 were accomplished starting from commercially available 18β-glycyrrhetinic acid and vanillin. The present syntheses involve the coupling of a sesquiterpenoid aldehyde and an ary

Full text of DOI:10.1021/ol016960n

ORGANIC
LETTERS
2001
Vol. 3, No. 26
4291-4294
Syntheses and Absolute
Stereochemistries of UPA0043 and
UPA0044, Cytotoxic Antibiotics Having a
p-Quinone-methide Structure
Ken-ichi Takao,† Tomoko Sasaki,† Tomohito Kozaki,† Yumiko Yanagisawa,†
,†
Kin-ichi Tadano,* Akira Kawashima,‡ and Hideki Shinonaga‡
Department of Applied Chemistry, Keio UniVersity, Hiyoshi, Kohoku-ku,
Yokohama 223-8522, Japan, and Medicinal Research Laboratories,
Taisho Pharmaceutical Co., Ltd., 1-403, Yoshino-cho, Saitama 330-8530, Japan
tadano@applc.keio.ac.jp
Received October 26, 2001
ABSTRACT
The first syntheses of new antibiotics UPA0043 and UPA0044 were accomplished starting from commercially available 18â-glycyrrhetinic acid
and vanillin. The present syntheses involve the coupling of a sesquiterpenoid aldehyde and an aryllithium, the stereoselective formation of
a p-quinone-methide system, and regioselective intramolecular cyclization via an epoxy ring opening.
UPA0043 (1) and UPA0044 (2) (Figure 1), which exhibit
significant cytotoxic and antifungal activities, were isolated
from the culture broth of a fungus by the Taisho research
group.1 Their gross structures and relative stereochemistries
were determined by spectroscopic means; the absolute
configurations were not determined. Structurally related
natural products, such as puupehenone (3)2 and its ana-
logues,3 were also discovered from marine sponges. Most
of this family exhibits a variety of biological activities.2,3
These compounds 1-3 have a common p-quinone-methide
system that is thought to be responsible for their biological
activities.4 As a result of their unique structures and biological
properties, this class of compounds has attracted considerable
attention among several research groups studying synthet-
ics.5,6 We report herein the enantiospecific syntheses of
UPA0043 (1) and UPA0044 (2), thereby establishing their
absolute stereochemistries.
(3) (a) Amade, P.; Chevelot, L.; Perzanowski, H. P.; Scheuer, P. J. HelV.
Chim. Acta 1983, 66, 1672-1675. (b) Hamann, M. T.; Scheuer, P. J.
Tetrahedron Lett. 1991, 32, 5671-5672. (c) Hamann, M. T.; Scheuer, P.
J.; Kelly-Borges, M. J. Org. Chem. 1993, 58, 6565-6569. (d) Nasu, S. S.;
Yeung, B. K. S.; Hamann, M. T.; Scheuer, P. J.; Kelly-Borges, M.; Goins,
K. J. Org. Chem. 1995, 60, 7290-7292. (e) Bourguet-Kondracki, M.-L.;
Debitus, C.; Guyot, M. Tetrahedron Lett. 1996, 37, 3861-3864. (f)
Bourguet-Kondracki, M.-L.; Lacombe, F.; Guyot, M. J. Nat. Prod. 1999,
62, 1304-1305. (g) El Sayed, K. A.; Bartyzel, P.; Shen, X.; Perry, T. L.;
Zjawiony, J. K.; Hamann, M. T. Tetrahedron 2000, 56, 949-953.
(4) Zjawiony, J. K.; Bartyzel, P.; Hamann, M. T. J. Nat. Prod. 1998,
61, 1502-1508 and references therein.
† Keio University.
‡ Taisho Pharmaceutical Co., Ltd.
(1) Shinonaga, H.; Obuchi, T.; Kawashima, A. Unpublished results.
(2) (a) Ravi, B. N.; Perzanowski, H. P.; Ross, R. A.; Erdman, T. R.;
Scheuer, P. J.; Finer, J.; Clardy, J. Pure Appl. Chem. 1979, 51, 1893-
1900. (b) Urban, S.; Capon, R. J. J. Nat. Prod. 1996, 59, 900-901.
(5) (a) The total synthesis of 3 in racemic form: Trammell, G. L.
Tetrahedron Lett. 1978, 1525-1528. (b) The total synthesis of 3 in optically
active form: Barrero, A. F.; Alvarez-Manzaneda, E. J.; Chahboun, R.
Tetrahedron Lett. 1997, 38, 2325-2328.
10.1021/ol016960n CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/01/2001

at the angular carbon of the B/C ring.6c The advanced
synthetic intermediate A would be obtained by the elimina-
tion of an acetoxy group in B, forming the p-quinone-methide
system. We envisioned the intermediate B to be divided into
two segments, a drimane-type sesquiterpenoid C and an
aromatic derivative D.
The synthesis of the sesquiterpenoid segment 8 (P ) TBS
in C) began with commercially available 18â-glycyrrhetinic
acid (4), the aglycone of glycyrrhizic acid occurring in
licorice root (Scheme 2). According to Falck’s report, the
Scheme 2a
Figure 1. Structures of UPA0043, UPA0044, and puupehenone.
Unlike 3, the target compounds 1 and 2 possess an angular
hydroxy group at the B/C ring juncture. Thus, previously
reported synthetic approaches to 35 could not be applied to
the synthesis of 1 or 2. Our retrosynthetic analysis for 1 and
2 is shown in Scheme 1. We anticipated that the cyclization
a Reagents and conditions: (a) NaOMe, MeOH, 25% for 10 steps
from 4; (b) TBSOTf, pyridine, 0 °C, 86%; (c) Dibal-H, toluene,
-78 °C, 70% for 8 and 22% for 9; (d) Dess-Martin periodinane,
DMSO, 88%.
Scheme 1
triterpene 4 was degraded to a mixture of the known A/B
ring-derived compound 5 and D/E ring-derived products.7
Without separation, the mixture was treated with sodium
methoxide to provide 6,8 which was isolated in its pure form
by chromatography on silica gel. After silylation of 6, the
resulting tert-butyldimethylsilyl (TBS) ether 7 was reduced
with diisobutylaluminum hydride (Dibal-H) in toluene to give
aldehyde 8 (70%) and alcohol 9 (22%).9 Dess-Martin
oxidation10 of 9 afforded additional 8.
The aromatic segment 14 (P ) Bn, P′ ) TBS in D) was
synthesized using a well-established reaction sequence
(Scheme 3). A trisubstituted benzaldehyde 11, efficiently
prepared from vanillin (10) by a known procedure,11
underwent Baeyer-Villiger oxidation with m-chloroper-
(7) Manna, S.; Yadagiri, P.; Falck, J. R. J. Chem. Soc., Chem. Commun.
1987, 1324-1325.
(8) All new compounds were fully characterized by spectroscopic means
[1H (270 or 300 MHz in CDCl3) and 13C (68 or 75 MHz in CDCl3) NMR,
IR] and gave satisfactory HRMS. Yields refer to homogeneous samples
purified by chromatography on silica gel.
(9) When 7 was reduced with Dibal-H in CH2Cl2 instead of toluene, the
epoxy ring opening was observed in some extent.
(10) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-
7287.
of epoxy alcohol A would proceed regioselectively to
construct the tetracyclic skeleton, installing a hydroxy group
(6) Syntheses of analogues of 3: (a) Arjona, O.; Garranzo, M.; Mahugo,
J.; Maroto, E.; Plumet, J.; Sa´ez, B. Tetrahedron Lett. 1997, 38, 7249-
7252. (b) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Herrador, M. M.;
Valdivia, M. V.; Chahboun, R. Tetrahedron Lett. 1998, 39, 2425-2428.
(c) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Chahboun, R.; Corte´s, M.;
Armstrong, V. Tetrahedron 1999, 55, 15181-15208. (d) Maiti, S.; Sengupta,
S.; Giri, C.; Achari, B.; Banerjee, A. K. Tetrahedron Lett. 2001, 42, 2389-
2391.
(11) (a) Sinhababu, A. K.; Borchardt, R. T. Synth. Commun. 1983, 13,
677-683. (b) Sinhababu, A. K.; Ghosh, A. K.; Borchardt, R. T. J. Med.
Chem. 1985, 28, 1273-1279.
4292
Org. Lett., Vol. 3, No. 26, 2001

Scheme 3a
Scheme 4a
a Reagents and conditions: (a) mCPBA, CH2Cl2; (b) Et3N,
MeOH, 93% for 2 steps; (c) TBSCl, imidazole, DMF, 93%; (d)
NBS, SiO2, CH2Cl2, 85%.
benzoic acid (mCPBA), and methanolysis of the resulting
formate gave a trisubstituted phenol 12. The phenolic
hydroxy group in 12 was protected as a silyl ether to provide
13, which was subjected to regioselective bromination with
N-bromosuccinimide (NBS) affording 14. The brominated
position in 14 was secured on the basis of NOE experiment.
With the upper and lower segments in hand, the coupling
of 8 and 14 was examined (Scheme 4). Thus, the bromide
14 was treated with tert-butyllithium in Et2O at -78 °C, and
the resulting aryllithium 15 was reacted with the aldehyde
8. The reaction proceeded smoothly at -78 °C, and separable
coupling products 16a (48%) and 16b (15%) were obtained.12
Acetylation of the major product 16a in the presence of
4-(dimethylamino)pyridine (DMAP) gave diacetate 17a as
a result of concomitant conversion of the phenolic silyl ether
into an acetyl ester. Desilylation of 17a followed by
introduction of an acetyl group in the A ring of 18a afforded
triacetate 19a. The benzyl protecting groups in 19a were
a Reagents and conditions: (a) 14, t-BuLi, Et2O, -78 °C, then
8, Et2O, -78 °C, 48% for 16a and 15% for 16b; (b) Ac2O, DMAP,
pyridine, 95%; (c) aq HF, MeCN, 84%; (d) Ac2O, pyridine, 92%;
(e) H2, Pd on C, MeOH, quant; (f) NaHCO3, MeOH, 1 h, 51% for
21 and 14% for 2; (g) same as (f), 33%; (h) NaHCO3, MeOH, 4 h,
46%.
(12) Deprotection of the phenolic silyl ether of 16b afforded the 6-endo
cyclization product i via an epoxy ring opening, which underwent a
concerted pinacol rearrangement under acetylation conditions. The structure
of the resulting rearrangement product ii determined the stereochemistry
of the benzylic hydroxy group in 16b.
removed by hydrogenolysis to give a catechol derivative 20a.
Brief exposure of 20a to sodium bicarbonate in methanol
underwent elimination of the benzylic acetoxy group. As a
result, the p-quinone-methide system was constructed to
provide the desired 21. The Z-geometrical structure of 21
was established on the basis of the NOE experiment.13 Under
these conditions, the target compound UPA0044 (2) was also
produced as a minor product. Accordingly, 21 was separately
treated under the same conditions. Additional 2 was produced
as a result of deacetylation of the aromatic acetate and
subsequent regioselective (6-endo) cyclization. The minor
coupling product 16b was transformed into 20b in an overall
yield of 68% by the same reaction sequence used for the
conversion of 16a to 20a. Prolonged treatment of 20b with
sodium bicarbonate gave 2 directly. The spectroscopic data
(13) As shown in Scheme 4, significant signal enhancement (17%) of
the methide proton was observed when the methyl group at C-3 was
irradiated.
Org. Lett., Vol. 3, No. 26, 2001
4293

Next, we conducted the synthesis of UPA0043 (1)
(Scheme 5). The esterification of 18a with 3-methylcrotonyl
chloride under phase-transfer catalyzed conditions14 pro-
ceeded smoothly, giving 22a.15 Deprotection of the benzyl
groups in 22a by hydrogen-transfer conditions provided 23a
with the R,â-unsaturated ester moiety intact. The treatment
of 23a with sodium bicarbonate in ethanol produced a
p-quinone-methide 24 and UPA0043 (1). Additional 1 was
obtained from 24 under basic conditions, although the yield
was less efficient. The minor coupling-product-derived 18b
was also transformed into 1 in a similar fashion in an overall
yield of 11%. Synthetic 1 was identical to an authentic
sample of natural 1 in all respects, including the optical
Scheme 5a
rotation {[R]27 +232 (c 0.21, MeOH) for synthetic, [R]D
D
+241 (c 1.0, MeOH) for natural}.
In conclusion, we have achieved the syntheses of UPA0043
(1) and UPA0044 (2) in natural enantiomeric form starting
from 18â-glycyrrhetinic acid (4) and vanillin (10). These
syntheses established the absolute stereochemistries of 1 and
2.
Supporting Information Available: Experimental pro-
cedures and spectroscopic characterization (1H and 13C NMR,
IR, and HRMS) of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
a Reagents and conditions: (a) 3-methylcrotonyl chloride, Na2CO3,
BnN+Et3Cl- (cat.), CCl4, reflux, 89%; (b) Pd on C, cyclohexene/
EtOH (1:2), reflux, 98%; (c) NaHCO3, EtOH, 4 h, 54% for 24 and
14% for 1; (d) Et3N, MeOH, 24 h, 30% for 1 and 23% for recovered
24.
OL016960N
(IR, 1H and 13C NMR, MS) of synthetic 2 were well matched
with those of natural 2. The optical rotation of synthetic 2
{[R]26D +235 (c 0.18, MeOH); for natural [R]D +234 (c 1.0,
MeOH)} established the absolute stereochemistry of natural
2 as depicted.
(14) Szeja, W. Synthesis 1980, 402-403.
(15) Under the standard esterification conditions (3-methylcrotonic acid,
WSC‚HCl, DMAP, Et3N, CH2Cl2; 3-methylcrotonyl chloride, pyridine), the
double-bond isomerization of the 3-methylcrotonyl moiety occurred and
the â,γ-unsaturated ester was introduced: Ozeki, T.; Kusaka, M. Bull. Chem.
Soc. Jpn. 1967, 40, 2686-2688.
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