Synthesis of angucyclines. 8. Biomimetic-type synthesis of rabelomycin, tetrangomycin, and related ring B aromatic angucyclinones

Article abstract of DOI:10.1021/jo9622587

The angucyclinones with aromatic ring B (1a-c and 2a-c) are prepared in a biomimetic-type synthesis by two successive aldol cyclizations starting from the substituted naphthoquinones 12a-c. In both cyclization steps the C-H acidity of the potential nucleophilic centers determines the mode of cyclization under kinetically controlled conditions. The tetrahydroanthraquinones 13a-c/14a-c are hydroxylated at C-4 to the phenolic anthraquinones 16a-c upon treatment with excess NMO.

Full text of DOI:10.1021/jo9622587

2350
J . Org. Chem. 1997, 62, 2350-2356
Syn th esis of An gu cyclin es. 8. Biom im etic-Typ e Syn th esis of
Ra belom ycin , Tetr a n gom ycin , a n d Rela ted Rin g B Ar om a tic
An gu cyclin on es
Karsten Krohn,* Norbert Bo¨ker, Ulrich Flo¨rke, and Christian Freund
Universita¨t-GH-Paderborn, FB Chemie und Chemietechnik, Warburger Str. 100,
33098 Paderborn, Germany
Received December 3, 1996X
The angucyclinones with aromatic ring B (1a -c and 2a -c) are prepared in a biomimetic-type
synthesis by two successive aldol cyclizations starting from the substituted naphthoquinones 12a -
c. In both cyclization steps the C-H acidity of the potential nucleophilic centers determines the
mode of cyclization under kinetically controlled conditions. The tetrahydroanthraquinones 13a -
c/14a -c are hydroxylated at C-4 to the phenolic anthraquinones 16a -c upon treatment with excess
NMO.
Sch em e 1
In tr od u ction
The angucyclines are a relatively new group of anti-
biotics with a broad spectrum of biological activities
comprising antitumor, enzyme inhibitory, antiviral, and
antifungal effects.1 In recent years, considerable effort
has been made in their total synthesis, notably of the
aglycon part, including several C-glycosides.2 In most
cases, the angularly condensed benzo[a]anthraquinone
skeleton was constructed by a Diels-Alder reaction.2
Yamaguchi et al.3 used a “biomimetic type” approach in
the synthesis of (-)-urdamycinone B (the antipode of the
natural product) employing their previously established
route of successive condensation of â-diketo or â-keto
ester dianions.4
We now describe a different biomimetic synthesis of
the ring B aromatic angucyclinones 1a -c and 2a -c that
is based on the sequential attachment of two ketide
fragments (“top” and “bottom” chains) on a [1,4]naph-
thoquinone core as shown in Scheme 1. This attachment
on the ortho-positions of a six-membered nucleus restricts
the many possible unwanted aldol condensations of open
chain polyketides5 to two cyclization modes designated
as “linear” and “angular” according to the position of the
side chaines leading finally to linearly or angularly
condensed tetracycles (see below).
During or after the folding and condensation of the
decaketide A (reviews2,6-8), a number of enzymatic modi-
fications (mostly reductions and oxidations) are required
to obtain the final natural products as indicated in
Scheme 1. We introduced several simplifications in the
precursor B as compared to A designed for the chemical
biomimetic-type synthesis of angucyclinones: omission
of the ester group in the top chain and of the carbonyl
group on the quasi-benzylic position in the bottom chain
as well as protection of one of the two carbonyl groups.
These changes are closely connected with the question
of linear versus angular condensation to anthracyclines
or angucyclines, respectively. Previously, we observed
that the presence of the quasi benzylic carbonyl group
in the bottom chain led to the linearly arranged aklanonic
acid, the biosynthetic precursor of the anthracyclines.9
We assumed that modification of the nucleophilicity by
omitting the benzylic carbonyl group might lead to the
angular condensation products (vide infra). Thus, a
major objective of the present study is to investigate the
factors that control the cyclization mode of oligoketides
such as B in the chemical synthesis of 1a -c and 2a -c.
* To whom correspondence should be addressed. Tel.: int + 5251-
602172. Fax: int + 5251-603245. E-mail: KK@CHEMIE.UNI-pader-
born.DE.
Resu lts a n d Discu ssion
X Abstract published in Advance ACS Abstracts, March 15, 1997.
(1) Rohr, J .; Thiericke, R. Nat. Prod. Rep. 1992, 9, 103-137.
(2) Krohn, K.; Rohr, J . Top. Curr. Chem. 1997, 118, 127-195.
(3) Yamaguchi, M.; Okuma, T.; Horiguchi, A.; Ikeura, C.; Minami,
T. J . Org. Chem. 1992, 57, 1647-1649.
The attachment of the two side chains outlined in
Scheme 2 was previously tested with model naphtho-
quinones (e.g., X ) H in 3c).10 The starting materials
for this investigation were readily accessible from known
compounds. Thus, 2-bromo-3-(bromomethyl)juglone (3a )
was prepared by acidic saponification of the correspond-
ing acetate 3d obtained by NBS-bromination of 5-acetoxy-
(4) Yamaguchi, M.; Hasebe, K.; Higashi, H.; Uchida, M.; Irie, A.;
Minami, T. J . Org. Chem. 1990, 55, 1611-1623.
(5) Harris, T. M.; Harris, C. M.; Hindley, K. B. Fortschr. Chem. Org.
Naturstoff. 1974, 31, 217-282.
(6) Simpson, T. J . Nat. Prod. Rep. 1987, 4, 339.
(7) O’Hagan, D. The Polyketide Metabolites; Ellis Horwood: Chich-
ester, 1991.
(9) Krohn, K.; Scha¨fer, G. Liebigs Ann. 1996, 265-270.
(10) Krohn, K.; Bo¨ker, N. J . Prakt. Chem. 1997, 339, 114-120.
(8) O’Hagan, D. Nat. Prod. Rep. 1995, 12, 1-32.
S0022-3263(96)02258-X CCC: $14.00 © 1997 American Chemical Society

Synthesis of Angucyclines
Sch em e 2a
J . Org. Chem., Vol. 62, No. 8, 1997 2351
scheme envisioned a cleavage of the double bond in the
top side chain to yield the corresponding ketones. Ozo-
nolysis of 7c showed that the quinoid double bond was
also effected to some extent, and therefore, the Lemieux-
J ohnson18 procedure (OsO4/NaIO4) was used to cleave the
olefin.
A surprising result was obtained when this method
was first applied to the keto ester 7c. The expected
ketone could not be isolated but immediately cyclized to
the linearly condensed tricyclic â-hydroxy ester 8. This
cyclization already occurred under the very mild and
essentially neutral conditions of the J ohnson-Lemieux
reaction. It demonstrated the high reactivity of oli-
goketides if centers of high nucleophilicity and electro-
philicity are opposed to each other in favorable six-
membered transition states. It also confirmed our initial
assumption to reduce the nucleophilicity of C-2′ by
omitting the neighboring quasi-benzylic keto group to
prevent a linear cyclization mode. The â-hydroxy ester
8 could be demethoxycarbonylated by treatment with bis-
(n-tributyltin) oxide19 to afford small amounts of 9 (23%)
and the major aromatization product 10 (53%). This
anthraquinone is the decarboxylation product of a 4,6-
dideoxyaklanonic acid derivative, an interesting precur-
sor for dideoxy anthracycline antibiotics.20-22
To probe the possible angular cyclization, the ester
group in 7a -c had to be removed. Bis(n-tributyltin)
oxide, introduced by Mata and Mascaretti19 for mild
decarboxylations, was the ideal reagent for this purpose
because the naphthoquinones 7a -c were unstable under
prolonged treatment with base. By use of this tin reagent
the olefinic ketones 11a -c were isolated in 65, 78, and
83% yield. Treatment of the olefins 11a -c with the
Lemieux-J ohnson reagent18 then afforded the ketones
12a -c as stable materials (78, 77, and 81% yield).
The crucial first cyclization experiment was then
performed using potassium carbonate in 2-propanol as
the mild base. In accordance with our reasoning, the
doubly activated and highly nucleophilic position at C-1′′
added to the carbonyl group at C-3′ to form diastereo-
meric mixtures 13a -c/14a -c of cyclization products (66,
86, and 68% yield). Protection of the second carbonyl
group as a ketal in the bottom side chain was also
required for this first aldol cyclization. Enolate formation
under basic conditions in a 1,3-diketo bottom side chain
would significantly reduce the electrophilicity of the C-3′
carbonyl group and thus prevent addition of C-1′′ to C-3′
or give rise to mixtures of aldol condensation products.
A low selectivity in the formation of the diastereomeric
acyclic â-hydroxy ketones 13a -c and 14a -c was ob-
served (a , 1.4:1; b, 2.4:1; c, 2.4:1). A separation could be
achieved in the case of 13b/14b and 13c/14c by crystal-
lization of one isomer. A straightforward assignment of
the configuration was not possible on the basis of the
NMR spectra because of the absence of a proton on C-2.
Fortunately, crystals of good quality for X-ray structure
determination of one isomer were obtained, showing that
this crystalline isomer can be assigned the Z-configura-
a
Key: (a) base, -20 °C, 0.5 h (5a , 78%; 5b, 88%; 5c, 86%); (b)
Pd(PPh3)4/CuBr, dioxane, reflux, 7-9 h (7a , 78%; 7b, 78%; 7c,
92%); (c) OsO4, NaIO4 (8, 52%); (d) (nBu3Sn)2O, reflux (9, 23%;
10, 53%).
2-bromo-3-methyl[1,4]naphthoquinone,11 obtained from
1,5-diacetoxynaphthalene by NBS bromination12 and by
radical iron-mediated methylation with DMSO.11 The
corresponding methyl ether 3b was synthesized by
saponification of 3d to 3e followed by methylation to 3f
and NBS bromination. Finally, the dibromide 3c (R )
H) leading to the not naturally occurring angucyclines
1c and 2c was obtained by NBS-bromination of the
known 2-bromo-3-methyl-[1,4]naphthoquinone.13
The two bromine atoms in 3a -c have different chemi-
cal reactivity that is exploited in the regiospecific attach-
ment of the two different ketide side chains. The bromine
in the quasi-benzylic position is easily displaced in a SN2
reaction by the anion of the â-keto ester 414 to yield the
corresponding alkylation products 5a -c in 78, 88, and
86% yield, respectively. The vinylic bromine at C-2 of
3a -c has the important function of protecting the
electrophilic site at C-2 from unwanted Michael addition
of the stabilized anion of 4. The attachment of the second
“top” side chain was investigated in an earlier study.10
The best procedure proved to be a two-step sequence
making use of the vinylic bromine atom at C-2 of 3a -c
in a palladium-catalyzed Stille reaction15-17 with the
allylstannane 6 to afford the bisalkylated naphthoqui-
nones 7a -c (78, 76, and 92% yield).10 The synthetic
(11) Wurm, G.; Geres, U. Arch. Pharm. (Weinheim) 1984, 317, 606-
609.
(12) Grunwell, J . R.; Heinzman, S. W. Tetrahedron Lett. 1980, 21,
4305-4308.
(18) Pappo, R.; Allen, D. S., J r.; Lemieux, R. U.; J ohnson, W. S. J .
Org. Chem. 1956, 21, 478.
(13) Adams, R.; Geissman, T. A.; Baker, B. R. J . Am. Chem. Soc.
1941, 63, 528.
(19) Mata, E. G.; Mascaretti, O. A. Tetrahedron Lett. 1988, 29,
6893-6896.
(14) Krohn, K.; Bo¨ker, N.; Gauhier, A.; Scha¨fer G.; Werner, F. J .
Prakt. Chem. 1996, 338, 349-354.
(20) Wagner, C.; Eckardt, K.; Schumann, G.; Ihn, W.; Tresselt, D.
J . Antibiot. 1984, 37, 691-692.
(15) Stille, J . K. Angew. Chem. 1986, 98, 504-519.
(16) Echavarren, A. M.; Tamayo, N.; Ca´rdenas, D. J . J . Org. Chem.
1994, 59, 6075-6083.
(21) Eckardt, K.; Tresselt, D.; Schumann, G.; Ihn, W.; Wagner, C.
J . Antibiot. 1985, 38, 1034-1039.
(17) Tamayo, N.; Echavarren, A. M.; Paredes, M. C. J . Org. Chem.
1991, 56, 6488-6491.
(22) Krohn, K.; Roemer, E.; Top, M.; Wagner, C. Angew. Chem., Int.
Ed. Engl. 1993, 32, 1151-1152.

2352 J . Org. Chem., Vol. 62, No. 8, 1997
Krohn et al.
Sch em e 3a
tion 13c (Figure 1 in the Supporting Information shows
the molecular structure of 13c). Interestingly, a second
independent molecule in the asymmetric unit shows a
different conformation by 180° rotation about the C11-
C17 bond (not shown). By comparing the integrals in
the NMR spectra of the diastereomeric mixtures 13a -
c/14a -c it could be shown that the major products
including the two crystalline isomers 13b and 13c have
the Z-configuration.
The primary cyclization products 13a -c/14a -c are
possible precursors for the large group of biologically
active angucyclines that are not aromatic in ring B. In
the present study we focused our interest on the synthe-
sis of the simpler aromatic representatives related to
tetrangomycin (1a ) and rabelomycin (2a ). Thus, the next
steps in the synthesis would be â-elimination of the
hydroxy group followed by dehydrogenation to an-
thraquinone derivatives such as 15a -c. However, the
â-hydroxy ketones 13a -c/14a -c were surprisingly stable
and resisted the usual procedures for â-elimination, and
no definite products could be isolated under a great
variety of reaction conditions. An explanation could be
that deprotonation at C-1 required for E2 elimination is
disfavored because the negatively charged oxygen of the
planar enolate would electronically and sterically interact
with the angular quinone carbonyl group.
Therefore, we checked if the initial dehydrogenation
with N-methylmorpholine N-oxide (NMO), a reagent
introduced by Sulikowski et al.23 into angucycline chem-
istry, would enhance water elimination and aromatiza-
tion. This was in fact the case, and the desired aro-
matization products 15a -c could be isolated in good
yields (91, 84, and 76%) using a moderate excess of NMO.
However, to our surprise and delight addition of a larger
excess of NMO introduced a phenolic hydroxy group and
16a -c were the major reaction products (54, 72, and 73%
yield). Kim and Sulikowski23 postulated a tautomeric
quinone methide as a Michael acceptor of the nucleophilic
NMO-oxygen as the initial step in the reaction sequence.
However, reductive elimination with concomitant aro-
matization was observed in their examples, whereas the
oxygenation at C-4 in our case required a second oxida-
tion step (perhaps at C-1) to introduce a new phenolic
hydroxy group at C-4. This step necessarily must occur
at the stage of some intermediates prior to aromatization
to 15a -c because the anthraquinones 15a -c are per-
fectly inert to NMO-treatment. For synthetic purposes,
the unexpected hydroxylation step was very welcome.
The tetrangomycin series 15a -c as well as the rabelo-
mycins 16a -c could be prepared selectively by appropri-
ate choice of the reaction conditions.
a
Key: (a) (nBu3Sn)2O, toluene, 80 °C, 24 h (11a , 65%; 11b, 78%;
11c, 83%); (b) OsO4/NaIO4, dioxane, 20 °C (12a , 78%; 12b, 77%;
12c, 81%); (c) K2CO3/2-PrOH, 20 °C, 4 h (13a /14a , 66%; 13b/14b,
86%; 13c/14c, 68%); (d) 1,2 equiv of NMO, CH2Cl2, 40 °C (15a ,
91%; 15b, 84%; 15c, 76%); (d) 14 equiv of NMO, CH2Cl2, 40 °C
(16a , 54%; 16b, 72%; 16c, 73%); (e) SiO2, H2SO4/CH2Cl2 (17a , 96%;
17b, 94%; 17c, 92%; 18a , 78%; 18b, 93%; 18c, 91%); (f) 0.2 N KOH,
MeOH (1a , 90%; 1b, 83%; 1c, 70%; 2a , 92%; 2b, 88%; 2c, 67%).
agreement with the related experiment of Yamaguchi et
al.3 Our expectation was fulfilled, and all of the four
racemic natural products tetrangomycin (1a ),25,26 8-O-
methyltetrangomycin (1b)27 (MM 47755),28 rabelomycin
(2a ),29 and 8-O-methylrabelomycin (2b)27 as well as the
not naturally occuring 8-deoxyproducts 1c and 2c were
isolated in good to excellent yields (67-92%). Traces of
the fully aromatized benzo[a]anthracene quinones related
to tetrangulol30 were also detected by TLC.
Exp er im en ta l Section
The final steps of the reaction sequence leading to
1a -c and 2a -c required the deprotection of the ketal.
When the heterogeneous system silica gel/sulfuric acid/
dichloromethane24 was used, the diketones 17a -c and
18a -c were obtained in 78-96% yield. Again, two modes
of cyclization are theoretically possible by base treatment
of the diketones 17a -c and 18a -c. We expected that
anion formation at the acetyl side chain at C-1, acidified
by conjugation to the anthraquinoid system, would be the
initial step under the mild basic kinetically controlled
conditions (0.2 N KOH in methanol at -20 °C) in
For instrumentation and general procedures see ref 31.
5-Acetoxy-2-br om o-3-(br om om eth yl)-[1,4]n a p h th oqu i-
n on e (3d ). A solution of 5-acetoxy-2-bromo-3-methyl-[1,4]-
(25) Kunstmann, M. P.; Mitscher, L. A. J . Org. Chem. 1966, 31,
2920-2925.
(26) Dann, M.; Lefemine, D. V.; Barbatschi, F.; Shu, P.; Kuntsmann,
M. P.; Mitscher, L. A.; Bohonos, N. Antimicrob. Agents Chemother.
1965, 832-835.
(27) Shigihara, Y.; Koizumi, Y.; Tamamura, T.; Homma, Y.; Isshiki,
K.; Dobashi, K.; Naganawa, H.; Takeuchi, T. J . Antibiot. 1988, 41,
1260-1264.
(28) Gilpin, M. L.; Balchin, J .; Box, S. J .; Tyler, J . W. J . Antibiot.
1989, 42, 627-628.
(23) Kim, K.; Sulikowski; G. A. Angew. Chem., Int. Ed. Engl. 1995,
34, 2396-2398.
(24) Huet, F.; Lechevallier, A.; Pellet, M.; Conia, J . M. Synthesis
1978, 63-65.
(29) Liu, W.-C.; Parker, W. L.; Slusarchyk, D. S.; Greenwood, G. L.;
Graham, S. F.; Meyers, E. J . Antibiot. 1979, 23, 437-441.
(30) Brown, P. M.; Thomson, R. H. J . Chem. Soc., Perkin Trans. 1
1976, 997-1000.

Synthesis of Angucyclines
J . Org. Chem., Vol. 62, No. 8, 1997 2353
naphthoquinone (prepared from 1,5-diacetoxynaphthalene by
NBS bromination12 followed by radical methylation11) (3.0 g,
9.71 mmol), NBS (2.08 g, 11.65 mmol), and AIBN (100 mg,
0.61 mmol) in acetic acid anhydride (40 mL) was heated for
1.5 h to 90 °C (TLC control). The reaction mixture was then
poured onto ice (ca. 250 g), and the precipitate was filtered
off, washed with water, and dissolved in dichloromethane. The
solution was dried (Na2SO4) and filtered, and the solvent was
removed under reduced pressure until crystallization began,
which was completed by addition of diethyl ether to afford 3d
(3.2 g, 85%) as yellow needles: mp 182 °C; IR (KBr) 1768
(CdO, ester), 1676 (CdO, quinone), 1662 (CdO, quinone),
1604, 1588 (arom C)C) cm-1; UV (methanol) λmax (lg ꢀ) 206
none11 (2.0 g, 6.5 mmol) and 4-toluenesulfonic acid (325 mg,
2.0 mmol) in methanol (130 mL) was refluxed for 3 h under
argon. The solvent was removed under reduced pressure and
the residue redissolved in CH2Cl2 (50 mL), washed with a
saturated aqueous solution of NaHCO3, dried (Na2SO4), and
evaporated at reduced pressure. The residue was purified by
filtration over a batch of silica gel (CH2Cl2) and crystallized
from petroleum ether to yield 3e (1.65 g, 96%), mp 139 °C; IR
(KBr) 1671 (quinone CdO) cm-1; UV (methanol) λmax (lg ꢀ) 214
1
nm (4.33), 243 (3.77), 285 (4.01), 427 (3.57); H NMR (CDCl3,
3
4
300 MHz) δ 2.39 (s, 3 H, CH3), 7.28 (dd, J ) 7.8 Hz, J ) 0.9
3
3
Hz, 1 H, 6-H), 7.61 (dd, J ) 7.8 Hz, 1 H, 7-H), 7.71 (dd, J )
7.8 Hz, J ) 0.9 Hz, 1 H, 8-H), 11.93 (s, 1 H, OH); 13C NMR
4
1
nm (4.18), 246 (3.70), 278 (3.85), 344 (3.20); H NMR (CDCl3,
(CDCl3, 75 MHz) δ 17.23 (q, CH3), 114.41 (s, C-4a), 120.56 (d,
C-6), 124.73 (d, C-8), 131.17 (s, C-8a), 136.33 (d, C-7), 139.84
(s, C-2), 148.31 (s, C-3), 161.82 (s, C-5), 176.33 (s, C-1), 187.03
300 MHz) δ 2.47 (s, 3 H, CH3CO2), 4.56 (s, 2 H, CH2Br), 7.43
(d, 3J ) 7.9 Hz, 1 H, 6-H), 7.78 (dd, 3J ) 7.9 Hz, 1 H, 7-H),
3
8.14 (d, J ) 7.9 Hz, 1 H, 8-H); 13C NMR (CDCl3, 75 MHz) δ
(s, C-4); MS (EI) m/z 266 (86)/268 (86) [M+], 187 (100) [M+
-
21.08 (q, CH3CO2), 25.47 (t, CH2Br), 122.81 (s, C-4a), 126.28
(d, C-6), 130.56 (d, C-8), 132.73 (s, C-8a), 135.16 (d, C-7), 139.61
(s, C-2), 147.13 (s, C-3), 150.24 (s, C-5), 169.20 (s, CH3CO2),
176.90 (s, C-4), 177.97 (s, C-1); MS (EI/75 °C) m/z 390 (1.3)/
388 (2.5)/386 (1.2) [M+], 348 (50)/346 (100)/344 (54) [M+ + 1 -
CH3CO], 268 (20)/267 (20)/266 (20)/265 (20) [M+ + 1 - CH3-
CO - Br], 43 (46) [CH3CO+]. Anal. Calcd for C13H8O4Br2: C,
40.24; H, 2.08. Found: C, 40.14; H, 2.11.
Br]. Anal. Calcd for C11H7O3Br: C, 49.47; H, 2.64. Found:
C, 49.36; H, 2.72.
2-Br om o-3-m eth yl-5-m eth oxy-[1,4]n aph th oqu in on e (3f).
A solution of 3e (200 mg, 750 µmol) and methyl iodide (215
mg, 1.5 mmol) in dry acetone (12 mL) was treated with Ag2O
(465 mg, 2 mmol), and the suspension was stirred for 24 h at
20 °C. The solvent was removed under reduced pressure, the
residue suspended in CH2Cl2 (5 mL) filtered, and the filtrate
purified by flash chromatography on silica gel to afford 3f (197
mg, 93%) as yellow needles: mp 139.5 °C (petroleum ether);
IR (KBr) 2925 (CH), 1674 (quinone CO), 1655 (quinone CO),
1650, 1586 (arom CdC) cm-1; UV (methanol) λmax (lg ꢀ) 211
2-Br om o-3-(br om om eth yl)-5-h yd r oxy-[1,4]n a p h th oqu i-
n on e (3a ). A solution of acetic ester 3d (7.0 g, 18.0 mmol)
and 4-toluenesulfonic acid (3.5 g, 18.4 mmol) in methanol (145
mL) was heated for 2.5 h under reflux (TLC control). The
reaction mixture was cooled to 20 °C, and the precipitate was
filtered off to afford after recrystallization from CH2Cl2/Et2O
3a (4.12 g, 66%) as orange red needles. The mother liquors
were evaporated to dryness at reduced pressure, dissolved in
CH2Cl2, washed with a saturated aqueous solution of sodium
hydrogen carbonate (50 mL) and water (50 mL), and dried
(Na2SO4). The solution was then chromatographed on silica
gel (CH2Cl2) to yield from the less polar fraction additional 3a
(1.12 g, total yield 5.24 g, 84%), mp 125 °C. From the polar
fraction 0.59 g (11%) of 2-bromo-5-hydroxy-3-(methoxymethyl)-
[1,4]naphthoquinone were obtained in the form of light orange
needles: mp 108 °C; IR (KBr) 3051 (ArH), 2987 (CH), 2929
(CH), 1674 (CdO, quinone), 1637 (CdO, quinone), 1589 (CdC),
1570 (CdC), 1449 (CH) cm-1; UV (methanol) λmax (lg ꢀ) 218
1
nm (4.35), 245 (3.92), 279 (4.00), 399 (3.49); H NMR (CDCl3,
3
300 MHz) δ 2.37 (s, 3 H, CH3), 4.02 (s, 3 H, OCH3), 7.31 (d, J
3
) 8.1 Hz, 1 H, 6-H), 7.67 (dd, J ) 8.1 Hz, 1 H, 7-H), 7.82 (d,
3J ) 8.1 Hz, 1 H, 8-H); 13C NMR (CDCl3, 75 MHz) δ 18.16 (q,
CH3), 56.45 (q, OCH3), 118.03 (d, C-6), 119.28 (s, C-4a), 120.27
(d, C-8), 133.32 (s, C-8a), 134.89 (d, C-7), 136.11 (s, C-2), 150.22
(s, C-3), 159.91 (s, C-5), 176.49 (s, C-4), 177.88 (s, C-1); MS
(EI/80 °C) m/z 280 (92)/282 (92) [M+], 201 (100) [M+ - Br].
Anal. Calcd for C12H9O3Br: C, 51.27; H, 3.23. Found: C,
51.38; H, 3.39.
2-Br om o-3-(br om om eth yl)-5-m eth oxy-[1,4]n aph th oqu i-
n on e (3b). A solution of 3f (500 mg, 1.78 mmol) was
brominated as described for 3d with NBS (380 mg, 2.14 mmol)
and AIBN (18 mg, 0.1 mmol) in acetic acid anhydride (7 mL)
(3 h under argon) to yield 3b (560 mg, 88%): mp 193 °C; IR
(KBr) 1675 (quinone CO), 1655 (quinone CO), 1604, 1584 (arom
CdC) cm-1; UV (methanol) λmax (lg ꢀ) 215 nm (4.34), 243 (3.90),
281 (3.94), 405 (3.44); 1H NMR (CDCl3, 300 MHz) δ 4.04 (s, 3
H, OCH3), 4.61 (s, 2 H, CH2Br), 7.36 (d, 3J ) 8.0 Hz, 1 H, 6-H),
7.71 (dd, 3J ) 8.0 Hz, 1 H, 7-H), 7.83 (d, 3J ) 8.0 Hz, 1 H,
8-H); 13C NMR (CDCl3, 75 MHz) δ 25.97 (t, CH2Br), 56.62 (q,
OCH3), 118.53 (d, C-6), 118.78 (s, C-4a), 120.53 (d, C-8), 133.17
(s, C-8a), 135.42 (d, C-7), 138.13 (s, C-2), 147.58 (s, C-3), 160.33
(s, C-5), 177.82 (s, C-4), 178.26 (s, C-1); MS (EI/80 °C) m/z 362
(10)/360 (20)/358 (10) [M+], 280 (100)/278 (88) [M+ - Br], 253
(18), 251 (18), 200 (22) [M+ - 2 Br]. Anal. Calcd for C12H8O3-
Br2: C, 40.04; H, 2.24. Found: C, 39.91; H, 2.40.
2-[(3-Br om o-8-h yd r oxy-1,4-d ioxo-1,4-d ih yd r on a p h th a -
len -2-yl)m eth yl]-4-(2-m eth yl-1,3-d ioxola n -2-yl)-3-oxobu -
ta n oic Acid Meth yl Ester (5a ). A solution of dibromide 3a
(2.00 g, 5.78 mmol) in dry THF (50 mL) was cooled under
nitrogen to -20 °C (solution A). In a second vessel the sodium
salt of â-keto ester 4 (2.34 g, 11.58 mmol) was prepared under
nitrogen in dry THF (30 mL) by addition of NaH (278 mg,
11.58 mmol) (solution B). Solution B was then added dropwise
at -20 °C via a Teflon tube to solution A, and the resulting
mixture was stirred for ca. 30 min at -20 °C (TLC control).
The reaction was then quenched by addition of a mixture of 1
N HCl (15 mL) and saturated aqueous NH4Cl, and the mixture
was extracted with Et2O (3 × each 50 mL). The combined
organic phases were washed successively with NH4Cl solution
(100 mL) and brine (50 mL), dried (Na2SO4), and filtered, and
the solvent was removed under reduced pressure. The residue
slowly crystallized (2 d) from a mixture of CH2Cl2 (ca. 2-3
mL) and Et2O (ca. 2 mL) to yield 5a (2.11 g, 78%) as an orange
solid: mp 100 °C; IR (KBr) 3187 (OH), 2985 (CH), 2897 (CH),
1744 (CdO, ester), 1718 (CdO, ketone), 1671 (CdO, quinone),
1
nm (4.50), 289 (4.09), 432 (3.64); H NMR (200 MHz, CDCl3)
δ 4.61 (s, 2 H, CH2Br), 7.33 (dd, 4J ) 1.4 Hz, 3J ) 8.2 Hz, 1 H,
3
4
6-H), 7.66 (dd, J ) 7.5, 8.2 Hz, 1 H, 7-H), 7.75 (dd, J ) 1.4
Hz, J ) 7.5 Hz, 1 H, 8-H), 11.80 (s, 1 H, OH); 13C NMR (50
3
MHz, CDCl3) δ 25.30 (t, CH2Br), 114.62 (s, C-4a), 121.47 (d,
C-6), 125.75 (d, C-8), 131.35 (s, C-8a), 137.24 (d, C-7), 142.21
(s, C-2), 146.64 (s, C-3), 162.48 (s, C-5), 177.12 (s, C-1, C-4),
185.02 (s, C-1, C-4); MS (EI/55 °C) m/z 348 (50), 346 (100),
344 (50) [M+], 267 (24), 239 (54), 237 (54), 186 (52) [M+ - 2 ×
Br], 158 (32), 130 (24), 102 (28). Anal. Calcd for C11H6O3Br2:
C, 38.19; H, 1.75. Found: C, 38.33; H, 1.65.
Da ta for 2-br om o-5-h yd r oxy-3-(m eth oxym eth yl)-[1,4]-
n a p h th oqu in on e: IR (KBr) 2938 (CH), 1680 (CdO, quinone),
1640 (CdO, quinone), 1598 (CdC), 1592 (CdC), 1572 (CdC),
1473, 1454 (CH), 1439, 1393, 1369, 1348, 1267 (CO), 1232 (CO)
cm-1; UV (methanol) λmax (lg ꢀ) 215 nm (4.57), 286 (4.18), 325
1
(2.99), 430 (3.76); H NMR (200 MHz, CDCl3) δ 3.50 (s, 3 H,
4
3
OMe), 4.66 (s, 2 H, CH2OMe), 7.31 (dd, J ) 1.4 Hz, J ) 8.2
3
Hz, 1 H, 6-H), 7.64 (dd, J ) 7.5, 8.1 Hz, 1 H, 7-H), 7.73 (dd,
4J ) 1.3 Hz, 3J ) 7.5 Hz, 1 H, 8-H), 11.91 (s, 1 H, OH); 13C
NMR (50 MHz, CDCl3) δ 59.90 (q, OMe), 68.35 (t, CH2O),
115.10 (s, C-4a), 121.20 (d, C-6), 125.60 (d, C-8), 131.35 (s,
C-8a), 136.91 (d, C-7), 143.70 (s, C-2), 145.70 (s, C-3), 162.32
(s, C-5), 177.50 (s, C-1), 186.57 (s, C-4); MS (EI/60 °C) m/z 298/
296 (100) [M+], 283/281 (93) [M+ - CH3], 255 (18), 253 (22),
237 (8), 217 (8), 202 (8), 187 (8), 174 (16), 173 (45), 157 (7),
145 (14), 130 (6), 102 (9), 89 (8), 63 (10), 45 (3). Anal. Calcd
for C12H9O4Br: C, 48.51; H, 1.36. Found: C, 48.38; H, 1.49.
2-Br om o-5-h ydr oxy-3-m eth yl-[1,4]n aph th oqu in on e (3e).
A solution of 5-acetoxy-2-bromo-3-methyl-[1,4]naphthoqui-
(31) Krohn, K.; Bo¨rner, G. J . Org. Chem. 1994, 6063-6068.

2354 J . Org. Chem., Vol. 62, No. 8, 1997
Krohn et al.
1639 (CdO, quinone), 1589 (CdC), 1572 (CdC), 1455 (CH)
cm-1; UV (methanol) λmax (lg ꢀ) 215 nm (4.60), 287 (4.19), 428
(t, C-2′), 53.49 (q, ester-OCH3), 65.05 (t, OCH2CH2O), 65.14
(t, OCH2CH2O), 65.86 (s, C-2), 72.29 (s, C-3), 108.50 (s,
dioxolane-OCO), 126.70 (d, C-5, C-8), 126.75 (d, C-5, C-8),
132.38 (s, C-8a, C-10a), 132.51 (s, C-8a, C-10a), 134.03 (d, C-6,
C-7), 134.06 (d, C-6, C-7), 141.23 (s, C-9a, C-4a), 142.28 (s,
C-9a, C-4a), 172.81 (s, ester CO), 184.17 (s, C-9, C-10), 184.22
(s, C-9, C-10), 201.76 (s, C-1′); MS (EI/100 °C) m/z 428 (0.3)
[M+], 413 (0.9) [M+ - CH3], 381 (0.2) [M+ - 1 - (CH3, OCH3)],
368 (0.2) [M+ - 1 - CO2CH3], 87 (100) [CH3C(OCH2CH2O)+].
Anal. Calcd for C23H24O8: C, 64.48; H, 5.65. Found: C, 64.34;
H, 5.51.
Rea ction of 8 w ith Bis(tr ibu tyltin ) Oxid e. A solution
of 8 (80 mg, 0.19 mmol) was treated with bis(tributyltin) oxide
(225 mg, 377 mmol) in toluene (2 mL) as described for 11a
(see below) for 10 h. The products were separated by thin layer
chromatography on silica gel (petroleum ether/AcOEt: 2/1) to
afford the anthraquinone 10 (35 mg, 53%), mp 143 °C, from
the less polar fraction and compound 9 (16 mg, 23%), mp 139
°C, from the polar fraction.
Da ta for 2-m eth yl-3-[(2-m eth yl-1,3-d ioxola n -2-yl)a cet-
yl]a n th r a qu in on e (10): IR (KBr) 2925 (CH), 1718 (aliph CO),
1702, 1676 (aliph CO) cm-1; UV (methanol) λmax (lg ꢀ) 208 nm
(4.72), 252 (4.79), 262 (4.81); 1H NMR (CDCl3, 200 MHz) δ 1.50
(s, 3 H, dioxolane-CH3), 2.64 (s, 3 H, C-2 CH3), 3.38 (s, 2 H,
2′-H), 3.89-3.97 (m, 4 H, OCH2CH2O), 7.78-7.87 (m, 2 H, 6-H,
7-H), 8.16 (s, 1 H, 1-H, 4-H), 8.28-8.35 (m, 2 H, 5-H, 8-H),
8.52 (s, 1 H, 1-H, 4-H); 13C NMR (CDCl3, 50 MHz) δ 21.68 (q,
C-2 CH3), 25.31 (q, dioxolane-CH3), 51.08 (t, C-2′), 65.11 (t,
OCH2CH2O), 108.68 (s, dioxolane-OCO), 127.72 (d, C-5, C-8),
127.80 (2 × d, C-1, C-4, C-5, C-8), 130.68 (d, C-1, C-4), 131.50
(s, C-4a, C-8a, C-9a, C-10a), 133.94 (2 × s, C-4a, C-8a, C-9a,
C-10a), 134.45 (s, C-4a, C-8a, C-9a, C-10a), 134.71 (d, C-6, C-7),
134.78 (d, C-6, C-7), 144.15 (s, C-2, C-3), 145.06 (s, C-2, C-3),
182.85 (s, C-9, C-10), 183.15 (s, C-9, C-10), 200.78 (s, C-1′).
Data for 2-h ydr oxy-2-m eth yl-3-[(2-m eth yl-1,3-dioxolan -
2-yl)a cetyl]-1,2,3,4-tetr a h yd r oa n th r a qu in on e (9): IR (KBr)
3441 (OH), 2961 (CH), 2930 (CH), 1674 (quinone CO), 1591
(arom CdC), 1335 cm-1; UV (methanol) λmax (lg ꢀ) 215 nm
(3.98), 260 (4.17), 332 (3.26); 1H NMR (CDCl3, 200 MHz) δ 1.27
(s, 3 H, dioxolane-CH3), 1.44 (s, 3 H, C-2 CH3), 2.59-3.20 (m,
5 H, 1-H, 2′-H, 3-H, 4-H), 3.59-3.65 (m, 1 H, 1-H, 2′-H, 3-H),
3.75-3.80 (m, 1 H, 1-H, 2′-H, 3-H), 3.99 (s, 4 H, OCH2CH2O),
7.67-7.75 (m, 2 H, 6-H, 7-H), 8.03-8.12 (m, 2 H, 5-H, 8-H);
13C NMR (CDCl3, 50 MHz) δ 24.26 (q, dioxolane-CH3), 25.02
(q, C-2 CH3), 25.68 (t, C-1, C-4), 38.96 (t, C-1, C-4), 53.09 (t,
C-2′), 54.99 (d, C-3), 65.05 (t, OCH2CH2O), 65.08 (t, OCH2-
CH2O), 70.99 (s, C-2), 108.76 (s, dioxolane-OCO), 126.70 (d,
C-5, C-8), 126.74 (d, C-5, C-8), 132.41 (s, C-8a, C-10a), 132.56
(s, C-8a, C-10a), 134.04 (d, C-6 and C-7), 142.11 (s, C-4a, C-9a),
142.90 (s, C-4a, C-9a), 184.58 (s, C-9 and C-10), 209.38 (s, C-1′);
MS (EI/70 °C) m/z 336 (0.5) [M+ - (H2O, CH4)], 335 (2.5) [M+
- 1 - (H2O, CH4)], 250 (6) {M+ - 1 - [H2O, CH3C(OCH2-
CH2O)CH2]}, 249 (23), 221 (6), 193 (11), 139 (3), 115 (2), 87
(100) [CH3C(OCH2CH2O)+], 43 (22).
1
(3.78); H NMR (200 MHz, CDCl3) δ 1.36 (s, 3 H, dioxolane-
CH3), AB-system (δA ) 2.82, δB ) 3.05, 2J ) 13.6 Hz, 2 H,
4-H), 3.43 (m, 2 H, quinone-CH2), 3.70 (s, 3 H, OMe), 3.92 (s,
4 H, OCH2CH2O), 4.18 (t, 1 H, 2-H), 7.29 (d, 1 H, 7′-H), 7.59-
7.74 (m, 2 H, 6′-H and 5′-H), 11.90 (s, 1 H, OH); 13C NMR (50
MHz, CDCl3) δ 24.75 (q, dioxolane-CH3), 29.71 (t, quinone-
CH2), 51.35 (t, C-4), 53.24 (q, OMe), 57.18 (d, C-2), 64.89, 65.14
(2 × t, OCH2CH2O), 108.30 (s, dioxolane-OCO), 114.71 (s,
C-8a′), 121.17 (d, C-7′), 125.31 (d, C-5′), 131.39 (s, C-4a′), 136.91
(d, C-6′), 141.45 (s, C-3′), 149.04 (s, C-2′), 162.26 (s, C-8′),
169.45 (s, C-1), 177.11 (s, C-1′, C-4′), 187.06 (s, C-1′, C-4′),
200.42 (s, C-3); MS (EI/120 °C) m/z 453/451 (1) [M+ - CH3],
335/333 (3), 279 (2), 241 (1), 239 (2), 237 (2), 227 (2), 200 (1),
199 (6), 186 (1), 171 (3), 170 (1), 129 (2), 113 (6), 89 (2), 87
(100) [CH3C(OCH2CH2O)+], 59 (2). Anal. Calcd for C20H19O8-
Br: C, 51.41; H, 4.10. Found: C, 51.27; H, 4.24.
2-[8-Hyd r oxy-3-(2-m et h yla llyl)-1,4-d ioxo-1,4-d ih yd r o-
n a p h th a len -2-ylm eth yl]-4-(2-m eth yl-1,3-d ioxola n -2-yl)-3-
oxobu ta n oic Acid Meth yl Ester (7a ). A solution of keto
ester 5a (1.0 g, 2.14 mmol) in dry 1,4-dioxane (20 mL) was
treated under argon with Pd(PPh3)4 (140 mg, 0.12 mmol), CuBr
(110 mg, 0.77 mmol), and tributyl(2-methylallyl)stannane32 (6)
(830 mg, 2.40 mmol) (compare with ref 10). The mixture was
refluxed for ca. 7 h (TLC control), and the solvent was removed
under reduced pressure at 40 °C. The residue was redissolved
in CH2Cl2 (ca. 1-2 mL) and purified by column chromatog-
raphy on silica gel (elution with petroleum ether and then with
a 2:1 mixture of petroleum ether/AcOEt) to yield 7a (740 mg,
78%) as an orange oil: IR (KBr) 2954 (CH), 2926 (CH), 2855
(CH), 1743 (CdO, ester), 1719 (CdO, ketone), 1655 (CdO,
quinone), 1637 (CdO, quinone) cm-1; UV (methanol) λmax (lg
1
ꢀ) 214 nm (4.49), 273 (4.11), 349 (3.74); H NMR (200 MHz,
CDCl3) δ 1.30 (s, 3H, dioxolane-CH3), 1.83 (s, 3 H, 2′′-CH3),
AB-system (δA ) 2.82, δB ) 3.03, 2J ) 13.4 Hz, 2 H, 4-H), 3.13
(d, 2 H, quinone-CH2), 3.48 (s, 2 H, 1′′-H), 3.71 (s, 3 H, OMe),
3.83-3.99 (m, 4 H, OCH2CH2O), 4.24 (t, 1 H, 2-H), 4.51, 4.77
(2 × s, 2 H, 3′′-H), 7.19-7.27 (m, 1 H, 7′-H), 7.55-7.63 (m, 2
H, 5′-H and 6′-H), 12.05 (s, 1 H, OH); 13C NMR (50 MHz,
CDCl3) δ 24.01, 24.62 (2 × q, dioxolane-CH3 and C-2′′-CH3),
25.82 (t, quinone-CH2), 34.13 (t, C-1′′), 51.73 (t, C-4), 53.11 (d,
C-2), 58.29 (q, OMe), 64.84, 65.02 (2 × t, OCH2CH2O), 108.29
(s, dioxolane-OCO), 111.78 (t, C-2′′-CH2), 115.77 (s, C-8a′),
119.72 (d, C-7′), 124.29 (d, C-5′), 132.43 (s, C-4a′), 136.65 (d,
C-6′), 142.66 (s, C-3′), 145.08 (s, C-2′′), 148.44 (s, C-2′), 161.62
(s, C-8′), 169.59 (s, C-1), 183.38 (s, C-1′, C-4′), 190.37 (s, C-1′,
C-4′), 201.49 (s, C-3); MS (EI/95 °C) m/z 442 (4) [M+], 356 (6)
[M+ - CH3C(OCH2CH2O) + 1], 279 (12), 241 (15) [M+
-
CH3C(OCH2CH2O)CH2COCHCO2CH3], 240 (38), 225 (8), 167
(15), 149 (46), 113 (4), 97 (4), 87 (100) [CH3C(OCH2CH2O)+],
71 (11), 57 (15). Anal. Calcd for C24H26O8: C, 65.15; H, 5.92.
Found: C, 65.01; H, 6.07.
3-H yd r oxy-3-m et h yl-2-[(2-m et h yl-1,3-d ioxola n -2-yl)-
a cet yl]-9,10-d ioxo-1,2,3,4,9,10-h exa h yd r oa n t h r a cen e-2-
ca r boxylic Acid Meth yl Ester (8). The Lemieux-J ohnson18
reaction was carried out with 7c (400 mg, 0.94 mmol) as
described for 11a (see below) using OsO4 solution (2.3 mL, 2
× 10-2 M in 2-methyl-2-propanol) and NaIO4 (2 × each 220
mg, 1 mmol) in dioxane (28 mL) and water (28 mL) (24 h) to
yield after thin layer chromatography on silica gel (petroleum
ether/AcOEt: 2/1) 8 (210 mg, 52%) as a yellow solid: mp 148
°C; IR (KBr) 3470 (OH), 2990 (CH), 2886 (CH), 1750 (ester
CO), 1713 (aliph CO), 1661 (quinone CO), 1653 (quinone CO),
1636, 1591 (arom CdC) cm-1; UV (methanol) λmax (lg ꢀ) 204
5-Hydr oxy-2-(2-m eth ylallyl)-3-[4-(2-m eth yl-1,3-dioxolan -
2-yl)-3-oxobu tyl]-[1,4]n a p h th oqu in on e (11a ). A solution
of keto ester 7a (450 mg, 1.02 mmol) and bis(tributyltin) oxide
(1.83 g, 3.06 mmol) in dry toluene (6 mL) was stirred under
argon for 30 h at 80 °C (TLC control). The mixture was diluted
with Et2O (30 mL) and stirred for 1 min after addition of 0.1
N HCl (50 mL). The phases were separated, the aqueous
phase was extracted with Et2O (3 × each 25 mL), dried (Na2-
SO4), and filtered, and the solvent was removed at reduced
pressure. The residue was dissolved in CH2Cl2 (ca. 1 mL) and
purified by column chromatography on silica gel (elution first
with petroleum ether and then with petroleum ether/AcOEt
2/1) to afford 11a (254 mg, 65%) as an orange oil: IR (KBr)
3438 (OH), 2925 (CH), 1718 (CdO, ketone), 1655 (CdO,
quinone), 1635 (CdO, quinone) cm-1; UV (methanol) λmax (lg
1
nm (4.17), 245 (4.26), 269 (4.13); H NMR (CDCl3, 200 MHz)
δ 1.33 (s, 3 H, dioxolane-CH3), 1.45 (s, 3 H, C-3 CH3), 2.87-
3.12 (m, 2 H, 1-H, 4-H), AB-system [δA ) 2.94 (d), δB ) 3.06
(d), (2J ) 16.1 Hz, 2 H, 2′-H)], 3.22-3.46 (m, 2 H, 1-H, 4-H),
3.77 (s, 3 H, OCH3), 3.85 (s, 1 H, OH), 3.90 (s, 4 H, OCH2-
CH2O), 7.67-7.75 (m, 2 H, 6-H, 7-H), 8.03-8.11 (m, 2 H, 5-H,
8-H); 13C NMR (CDCl3, 50 MHz) δ 24.97 (q, dioxolane-CH3),
25.31 (q, C-3 CH3), 28.92 (t, C-1, C-4), 37.77 (t, C-1, C-4), 50.00
1
ꢀ) 214 nm (4.44), 275 (3.99), 349 (3.62), 383 (3.49); H NMR
(200 MHz, CDCl3) δ 1.40 (s, 3 H, dioxolane-CH3), 1.81 (s, 3 H,
C-2′-CH3), 2.69-2.90 (m, 6 H, 1′′-H, 2′′-H, and 4′′-H), 3.39 (s,
2 H, 1′-H), 3.95 (s, 4 H, OCH2CH2O), 4.54, 4.78 (2 × s, 2 H,
3′-H), 7.18-7.27 (m, 1 H, 6-H), 7.54-7.64 (m, 2 H, 7-H and
8-H), 12.14 (s, 1 H, OH); 13C NMR (50 MHz, CDCl3) δ 21.64 (t,
C-1′′), 23.84, 24.90 (2 × q, dioxolane-CH3 and C-2′-CH3), 34.35
(32) Naruta, Y.; Nishigaichi, Y.; Maruyama, K. Chem. Lett. 1986,
1857-1860.

Synthesis of Angucyclines
J . Org. Chem., Vol. 62, No. 8, 1997 2355
(t, C-1′), 43.21 (t, C-2′′), 52.14 (t, C-4′′), 65.04 (t, OCH2CH2O),
108.00 (s, dioxolane-OCO), 111.88 (t, C-3′), 115.49 (s, C-4a),
119.62 (d, C-6), 124.26 (d, C-8), 132.75 (s, C-8a), 136.56 (d,
C-7), 142.75 (s, C-2), 146.91 (s, C-2′), 147.76 (C-3), 161.67 (s,
C-5), 184.09 (s, C-1, C-4), 190.58 (s, C-1, C-4), 206.19 (s, C-3′′);
MS (EI/80 °C) m/z 384 (3) [M+], 366 (1), 356 (1), 298 (15) [M+
- H3CC(OCH2CH2O) + 1], 282 (14) [M+ - H3CC(OCH2CH2O)
- CH3], 255 (3), 241 (11) [M+ - H3CC(OCH2CH2O)CH2-
COCH2], 240 (24), 239 (5), 225 (8), 149 (10), 97 (6), 87 (100)
[H3CC(OCH2CH2O)+], 71 (7), 57 (8), 43 (13).
(s, C-5), 183.93, 184.51 (s, C-9, C-10), 190.23 (s, C-9, C-10),
207.77, 208.73 (s, C-1′); MS (EI/100 °C) m/z 386 (1) [M+], 371
(1) [M+ - CH3], 353 (1), 344 (2), 326 (2) [M+ - COCH3 - OH],
311 (2) [M+ - COCH3 - OH - CH3], 300 (1), 282 (1), 243 (10),
242 (26) [M+ - COCH3 - CH3C(OCH2CH2O)CH2], 241 (6), 214
(8), 213 (4), 139 (2), 121 (5), 88 (5), 87 (100) [CH3C(OCH2-
CH2O)+], 59 (2), 43 (22) [COCH3+]. Anal. Calcd for C21H22O7:
C, 65.28; H, 5.74. Found: C, 64.96; H, 5.57.
1-Acetyl-5-h ydr oxy-2-[(2-m eth yl-1,3-dioxolan -2-yl)m eth -
yl]a n th r a qu in on e (15a ). 13a /14a (120 mg, 0.31 mmol) was
treated with a solution of NMO monohydrate in CH2Cl2 (4.5
mL, 10.3 mg/ml, 1.1 equiv). After 20 min at 40 °C, 0.3 equiv
of NMO monohydrate was added, and the volume of the
solution was reduced to ca. 0.5 mL. The mixture was stirred
until the starting material was converted (TLC control, ca. 40
min). The solution was diluted with CH2Cl2 (30 mL) and then
successively washed with cold 0.2 N HCl (2 × each 20 mL)
and water (25 mL), dried (Na2SO4), and filtered. The solvent
was removed under reduced pressure, and the residue was
purified by column chromatography on silica gel (CH2Cl2) to
yield 15a (104 mg, 91%) as yellow crystals: mp 140 °C; IR
(KBr) 3449 (OH), 2986 (CH), 2937 (CH), 2885 (CH), 1688
(CdO, aryl), 1669 (CdO, quinone), 1636 (CdO, quinone), 1619
(CdC), 1573 (CdC), 1561 (CdC) cm-1; UV (methanol) λmax (lg
5-Hydr oxy-3-[4-(2-m eth yl-1,3-dioxolan -2-yl)-3-oxobu tyl]-
2-(2-oxop r op yl)-[1,4]n a p h th oqu in on e (12a ). A solution of
olefin 11a (200 mg, 0.52 mmol) and NaIO4 (123 mg, 0.58 mmol)
in 1,4-dioxane (60 mL) and water (50 mL) was treated with a
solution of OsO4 (0.1 mL of a 0.13 M solution in water) until
the starting material was completely converted (ca. 5 h, TLC
control). Additional NaIO4 (139 mg, 0.65 mmol) was added,
and the mixture was stirred again (5 h, TLC control). The
mixture was poured into water and extracted with Et2O (5 ×
each 50 mL), the combined organic phases were dried (Na2-
SO4) and filtered, and the solvent was removed under reduced
pressure at 40 °C. The residue was purified by column
chromatography on silica gel (petroleum ether/AcOEt 1/1) to
afford 12a (157 mg, 78%) as yellow crystals: mp 72 °C; IR
(KBr) 2978 (CH), 2884 (CH), 1709 (CdO, ketone), 1655 (CdO,
1
ꢀ) 218 nm (4.29), 260 (4.38), 343 (3.34), 407 (3.67); H NMR
quinone), 1638 (CdO, quinone), 1616 (CdC), 1578 (CdC) cm-1
;
(200 MHz, CDCl3) δ 1.37 (s, 3 H, dioxolane-CH3), 2.62 (s, 3 H,
2
2′-H), AB-system (δA ) 2.97 (d), δB ) 3.18 (d), J ) 13.7 Hz, 2
UV (methanol) λmax (lg ꢀ) 214 nm (4.43), 250 (4.00), 272 (3.98),
420 (3.61); 1H NMR (200 MHz, CDCl3) δ 1.39 (s, 3 H, dioxolane-
CH3), 2.35 (s, 3 H, 3′′-H), 2.75 (s, 2 H, 4′-H), 2.80 (s, 4 H, 1′-H
and 2′-H), 3.92 (s, 2 H, 1′′-H), 4.01 (s, 4 H, OCH2CH2O), 7.21-
7.28 (m, 1 H, 6-H), 7.57-7.59 (m, 2 H, 7-H and 8-H), 12.08 (s,
1 H, OH); 13C NMR (50 MHz, CDCl3) δ 21.83 (t, C-1′), 24.88
(q, dioxolane-CH3), 30.87 (q, C-3′′), 42.09, 43.24 (2 × t, C-2′
and C-1′′), 52.06 (t, C-4′), 65.02 (t, OCH2CH2O), 108.20 (s,
dioxolane-OCO), 115.47 (s, C-4a), 119.60 (d, C-6), 124.52 (d,
C-8), 132.15 (s, C-8a), 136.66 (d, C-7), 143.06, 148.54 (2 × s,
C-2 and C-3), 161.77 (s, C-5), 183.92 (s, C-1, C-4), 190.25 (s,
C-1, C-4), 204.26 (s, C-2′′), 206.56 (s, C-3′); MS (EI/90 °C) m/z
H, 1′′-H), 3.59-3.68 (m, 2 H, OCH2CH2O), 3.88-3.97 (m, 2 H,
OCH2CH2O), 7.32 (dd, 4J ) 1.4 Hz, 3J ) 8.2 Hz, 1 H, 6-H),
3
4
3
7.67 (dd, J ) 7.6, 8.1 Hz, 1 H, 7-H), 7.77 (dd, J ) 1.4 Hz, J
) 7.5 Hz, 1 H, 8-H), 7.97 (d, 3J ) 8.1 Hz, 1 H, 3-H), 8.27 (d, 3J
) 8.1 Hz, 1 H, 4-H), 12.49 (s, 1 H, OH); 13C NMR (50 MHz,
CDCl3) δ 23.11 (q, dioxolane-CH3), 32.47 (q, C-2′), 41.44 (t,
C-1′′), 65.23 (t, OCH2CH2O), 109.64 (s, dioxolane-OCO), 116.07
(s, C-10a), 120.32 (d, C-6), 125.00 (d, C-7), 126.91 (d, C-3),
130.70 (s, C-8a), 132.41, 133.46 (2 × s, C-4a and C-9a), 137.35
(s, C-8), 138.54 (d, C-4), 140.76 (s, C-2), 145.04 (s, C-1), 162.81
(s, C-5), 183.16 (s, C-9, C-10), 188.40 (s, C-9, C-10), 206.19 (s,
C-1′); MS (EI/90 °C) m/z 366 (<1) [M+], 351 (1) [M+ - CH3],
306 (2), 279 (1), 264 (1), 152 (3), 151 (2), 139 (1), 111 (1), 88
(6), 87 (100) [CH3C(OCH2CH2O)+], 84 (1), 57 (2), 49 (2), 43 (20)
[CH3CO+]. Anal. Calcd for C21H18O6: C, 68.85; H, 4.95.
Found: C, 68.62; H, 4.80.
386 (<1) [M+], 371 (2) [M+ - CH3], 300 (1), 285 (2) [M+
-
CH3C(OCH2CH2O)CH2COCH2], 243 (10), 215 (6), 214 (12), 213
(2), 181 (3), 129 (1), 88 (5), 87 (100) [CH3C(OCH2CH2O)+], 69
(3), 43 (17). Anal. Calcd for C21H22O7: C, 65.28; H, 5.74.
Found: C, 65.38; H, 5.91.
1-Acet yl-4,5-d ih yd r oxy-2-[(2-m et h yl-1,3-d ioxola n e-2-
yl)m eth yl]a n th r a qu in on e (16a ). A solution of 13a /14a (43
mg, 0.11 mmol) in CH2Cl2 (2.5 mL) was treated with NMO
monohydrate (17 mg, 126 mmol). The reaction mixture was
stirred for 39 h at 20 °C. During this time an additional 2
equiv of NMO monohydrate was added. Workup as described
above gave 16a (23 mg, 54%) as a yellow, unseparable solid of
15a /16a : 1H NMR (200 MHz, CDCl3) δ 1.38 (s, 3 H, dioxolane-
CH3), 2.56 (s, 3 H, 2′-H), 2.88-3.14 (m, 2 H, 1′′-H), 3.60-3.92
(Z)- a n d (E)-1-Acetyl-2,5-d ih yd r oxy-2-(2-m eth yl-1,3-d i-
oxolan -2-ylm eth yl)-1,2,3,4-tetr ah ydr oan th r aqu in on e (13a/
14a ). A solution of diketone 12a (100 mg, 0.26 mmol) in dry
2-propanol (12 mL) was treated with freshly dried K2CO3 (334
mg, 2.42 mmol), and the mixture was stirred for 3 h at 20 °C
(TLC control). The suspension was filtered, and the filtrate
was poured onto a mixture of water (50 mL) and CH2Cl2 (50
mL). The phases were separated, the aqueous phase was
extracted with CH2Cl2 (3 × each 50 mL), and the combined
organic phases were successively washed with aqueous NH4-
Cl solution (150 mL) and water (100 mL), dried (Na2SO4), and
filtered. The solvent was removed under reduced pressure at
30 °C, and the residue was purified by column chromatography
on silica gel (petroleum ether/AcOEt 1/1) to yield 13a /14a (66
mg, 66%) as an unseparable 1.4:1 mixture of diastereoisomers
as yellow crystals: mp 130 °C; IR (KBr) 3475 (OH), 2976 (CH),
2941 (CH), 2887 (CH), 1709 (CdO, ketone), 1659 (CdO,
4
3
(m, 4 H, OCH2CH2O), 7.30 (dd, J ) 1.3 Hz, J ) 8.1 Hz, 1 H,
6-H), 7.49 (s, 1 H, 3-H), 7.63-7.79 (m, 2 H, 7-H and 8-H), 11.97
(s, 1 H, OH), 12.16 (s, 1 H, OH); 13C NMR (50 MHz, CDCl3) δ
25.53 (q, dioxolane-CH3), 32.42 (q, C-2′), 41.37 (t, C-1′′), 65.26
(t, OCH2CH2O), 109.58 (s, dioxolane-OCO), 114.50, 115.85 (2
× s, C-4a and C-10a), 120.77 (d, C-6), 125.29 (d, C-7), 128.26
(d, C-3), 130.33 (s, C-8a), 133.46 (s, C-9a), 137.85 (d, C-8),
140.77 (s, C-2), 144.27 (s, C-1), 162.11, 162.77 (2 × s, C-5 and
C-4), 182.61 (s, C-9, C-10), 193.01 (s, C-9, C-10), 205.72 (s, C-1′).
1-Acetyl-5-h ydr oxy-2-(2-oxopr opyl)an th r aqu in on e (17a).
A suspension of silica gel (1 g) in CH2Cl2 (4 mL) was treated
with H2SO4 (15% in H2O, 100 mg, 0.17 mmol) and stirred for
ca. 15 min. The anthraquinone ketal 15a (30 mg, 0.08 mmol)
was added, and the mixture was stirred until the starting
material was converted (overnight, TLC control). The suspen-
sion was filtered, the silica gel washed with CH2Cl2, and the
organic solution evaporated under reduced pressure. The
residue was purified by chromatography on silica gel (CH2-
Cl2) and crystallized from CH2Cl2/Et2O to afford 17a (25.3 mg,
96%) as yellow crystals: mp 198 °C; IR (KBr) 3416 (OH), 3081
(CH), 1716 (CdO, aliph ketone), 1691 (CdO, arom ketone),
quinone), 1637 (CdO, quinone), 1614 (CdC), 1577 (CdC) cm-1
;
UV (methanol) λmax (lg ꢀ) 213 nm (4.53), 248 (4.06), 273 (4.06),
332 (3.05), 420 (3.72); 1H NMR (200 MHz, CDCl3) δ 1.29, 1.36
(s, 3 H, dioxolane-CH3), AB-system (δA ) 1.79-1.91, δB
)
2.08-2.21, m, 2 H, 3-H), 1.99-2.05 (m, 2 H, 1′′-H), 2.50, 2.54
(s, 3 H, 3′-H), AB-system (δA ) 2.60-2.80, δB ) 2.85-3.10, m,
2 H, 4-H), 3.97-4.20 (m, 4 H, OCH2CH2O), 4.44 (s, 1 H, 1-H),
4.58, 4.62, (s, 1 H, C-2-OH), 7.17-7.25 (m, 1 H, 6-H), 7.51-
7.57 (m, 2 H, 7-H and 8-H), 12.07, 12.08 (s, 1 H, chel OH); 13
C
NMR (50 MHz, CDCl3) δ 20.63, 22.90 (t, C-4), 25.81, 26.01 (q,
dioxolane-CH3), 29.28, 29.92 (t, C-3), 33.49, 34.18 (q, C-2′),
44.26 (t, C-1′′), 55.36, 57.18 (d, C-1′′), 64.00, 64.10, 64.16, 64.23
(4 × t, OCH2CH2O), 71.53, 73.05 (s, C-2), 111.28, 111.41 (s,
C-2′′), 115.30 (s, C-10a), 119.32, 119.42 (d, C-6), 124.50, 124.64
(d, C-7), 132.28, 132.37 (s, C-8a), 136.43, 136.54 (d, C-8),
143.04, 143.54 (s, C-9a), 145.70, 146.59 (s, C-4a), 161.71, 161.80
1671 (CdO, quinone), 1638 (CdO, quinone), 1578 (CdC) cm-1
;
UV (methanol) λmax (lg ꢀ) 215 nm (4.48), 259 (4.53), 344 (3.49),
1
407 (3.84); H NMR (200 MHz, CDCl3) δ 2.27 (s, 3 H, 3′′-H),

2356 J . Org. Chem., Vol. 62, No. 8, 1997
Krohn et al.
2.49 (s, 3 H, 2′-H), 3.86 (s, 2 H, 1′′-H), 7.33 (dd, 4J ) 1.3 Hz, 3J
3,8-Dih yd r oxy-3-m et h yl-3,4-d ih yd r o-2H -b en zo[a ]a n -
th r a cen e-1,7,12-tr ion e (Tetr a n gom ycin ) (1a ). A solution
of dione 17a (10 mg, 0.031 mmol) in KOH (0.2 N in methanol,
14 mL) was stirred at -20 °C under argon for ca. 6.5 h (TLC
control). The mixture was neutralized by addition of HCl (0.1
N, 30 mL) and extracted with CH2Cl2 (3 × each 20 mL). The
organic phase was dried (Na2SO4), filtered, and purified by thin
layer chromatography on silica gel to afford racemic tetrango-
mycin (1a ) (9 mg, 90%) as yellow crystals, mp 182 °C (mp 182-
184 °C for natural tetrangomycin, ref 25) and 184-186 °C for
racemic tetrangomycin, ref 33). All relevant data of the
synthetic material were identical with those published for the
natural product.25 In addition to tetrangomycin, 1 mg (10%)
of tetrangulol25 was isolated.
3
) 8.1 Hz, 1 H, 6-H), 7.64 (d, J ) 8.0 Hz, 1 H, 3-H), 7.68 (dd,
4
3
3J ) 7.6, 8.0 Hz, 1 H, 7-H), 7.70 (dd, J ) 1.2 Hz, J ) 7.5 Hz,
3
1 H, 8-H), 8.34 (d, J ) 8.0 Hz, 1 H, 4-H), 12.46 (s, 1 H, OH);
13C NMR (50 MHz, CDCl3) δ 30.56 (q, C-3′′), 31.98 (q, C-2′),
47.50 (t, C-1′′), 116.03 (s, C-10a), 120.41 (d, C-6), 125.28 (d,
C-7), 127.97 (d, C-3), 131.08 (s, C-8a), 132.92, 133.27 (2 × s,
C-4a and C-9a), 137.46 (d, C-8), 137.65 (d, C-4), 137.94 (s, C-2),
143.98 (s, C-1), 162.95 (s, C-5), 183.03 (s, C-9, C-10), 188.02
(s, C-9, C-10), 204.30 (s, C-2′′), 205.53 (s, C-1′); MS (EI/130
°C) m/z 322 (11) [M+], 307 (14) [M+ - CH3], 281 (18), 280 (100)
[M+ - CH3CO + 1], 265 (44), 224 (4), 152 (8), 116 (2), 43 (17)
[CH3CO+]. Anal. Calcd for C19H14O5: C, 70.80; H, 4.38.
Found: C, 70.67; H, 4.21.
1-Ace t yl-4,5-d ih yd r oxy-2-(2-oxop r op yl)a n t h r a q u i-
n on e (18a ). A mixture of the ketals 15a /16a (15 mg, contain-
ing 11.5 mg of 16a (NMR), 0.03 mmol) was cleaved as
described for 17a to yield after thin layer chromatography on
silica gel 18a (8 mg, 78%) as yellow crystals: mp 212 °C; IR
(KBr) 3416 (OH), 2925 (CH), 2854 (CH), 1716 (CdO, aliph
ketone), 1694 (CdO, arom ketone), 1669 (CdO, quinone), 1655
(CdO, quinone), 1600 (CdC), 1561 (CdC) cm-1; UV (methanol)
Ra belom ycin (2a ). The diketone 18a (18.5 mg, 55 mmol)
was cyclized as described for 1a to yield racemic rabelomycin
2a (16 mg, 92%), mp 185 °C (mp 188-189 °C for natural
rabelomycin29). All relevant data of the synthetic material
were identical with those published for the natural product.29
Ack n ow led gm en t. We thank the Deutsche For-
schungsgemeinschaft for financial support.
1
λmax (lg ꢀ) 207 nm (4.27), 228 (4.43), 259 (4.28), 433 (3.87); H
NMR (200 MHz, CDCl3) δ 2.27 (s, 3 H, 3′′-H), 2.43 (s, 3 H,
2′-H), 3.80 (br s, 2 H, 1′′-H), 7.14 (s, 1 H, 2-H), 7.33 (dd, 1 H,
6-H), 7.63-7.80 (m, 2 H, 7-H and 8-H), 11.95 (s, 1 H, OH),
12.22 (s, 1 H, OH); 13C NMR (50 MHz, CDCl3) δ 30.60 (q, C-3′′),
31.93 (q, C-2′), 47.74 (t, C-1′′), 114.88, 115.80 (2 × s, C-4a and
C-10a), 120.89 (d, C-6), 125.59 (d, C-7), 127.61 (d, C-3), 131.00
(s, C-8a), 133.30 (s, C-9a), 137.26 (s, C-2), 138.00 (d, C-8),
141.38 (s, C-1), 162.81, 162.92 (2 × s, C-5 and C-4), 182.57 (s,
C-9, C-10), 192.92 (s, C-9, C-10), 204.09 (s, C-2′′), 205.29 (s,
C-1′); MS (EI/125 °C) m/z 338 (28) [M+], 323 (66) [M+ - CH3],
297 (20), 296 (100) [M+ - CH3CO+ + 1], 281 (76) [M+ - CH3-
COCH2+], 280 (54), 268 (33), 265 (18), 252 (11), 152 (6), 139
(9), 115 (2), 87 (6), 63 (2), 49 (2), 43 (32) [CH3CO+]. Anal. Calcd
for C19H14O6: C, 67.45; H, 4.17. Found: C, 67.18; H, 3.98.
Su p p or tin g In for m a tion Ava ila ble: Detailed experi-
mental procedures and spectral data for compounds 1b-18b
and 1c-18c including information on the X-ray structure
determination of 13c (21 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
J O9622587
(33) Krohn, K.; Khanbabaee, K. Liebigs Ann. Chem. 1994, 1109-
1112.