Biomimetic-type synthesis of the racemic non-aromatic angucyclinones of the SF 2315 and SS 228Y types

Article abstract of DOI:10.1002/(SICI)1099-0690(200004)2000:8<1627::AID-EJOC1627>3.0.CO;2-A

The biomimetic-type aldol reaction of the tricyclic (E)-configured precursors 6a/b gave the racemic nonaromatic angucycline derivatives 11-13 of the SF 2315 and SS 288Y types. Chelate controlled conditions in the cyclization of 6b led to the regioisomeric product 10.

Full text of DOI:10.1002/(SICI)1099-0690(200004)2000:8<1627::AID-EJOC1627>3.0.CO;2-A

FULL PAPER
Total Synthesis of Angucyclines, 12[°]
Biomimetic-Type Synthesis of the Racemic Non-Aromatic Angucyclinones of
the SF 2315 and SS 228Y Types
[
a]
[a]
[a]
[a]
Karsten Krohn,* Ulrich Flörke, Christian Freund, and Nasir Hayat
Dedicated to Prof. Wolf Walter on the occasion of his 80th birthday
Keywords: Angucyclines / Biomimetic type synthesis / Aldol reaction / Polyketides / Chelate control
The biomimetic-type aldol reaction of the tricyclic (E)-config-
Chelate controlled conditions in the cyclization of 6b led to
ured precursors 6a/b gave the racemic nonaromatic angucyc- the regioisomeric product 10.
line derivatives 11–13 of the SF 2315 and SS 288Y types.
Introduction
report on an alternative approach, in which the substitution
pattern originally generated by the biosynthetic pathway is
The class of the angularly condensed angucyclines with constructed in only two successive base-catalyzed aldol re-
the benz[a]anthracenequinone skeleton has grown to more actions of an appropriate oligoketide precursor.
than 250 structurally defined representatives.[1,2] They ex-
hibit a variety of interesting biological activities, such as
[
3–5]
[6–8]
[9,10]
antibacterial,
antifungal,
antitumor,
and vincris-
platelet aggrega-
activity as endothelin receptor antag-
[11]
Results and Discussion
tine-cytotoxicity potentiating activity,
tion inhibition,
and inhibition of prolyl,
amine hydrolases.
[
12,13]
[
14]
[15]
[16]
onists,
tyrosine,
or dop-
The starting materials 4a/b and 5a/b (natural pattern a:
[
17]
The biological activity is most often
R ϭ OH, nonnatural pattern b: R ϭ H) were prepared as
linked (with the exception of antitumor and weak antibac-
terial activity) to a nonaromatic ring B and one or more
glycosidic connections to deoxy sugars. One or two hy-
droxyl groups are located at the angular positions con-
[26]
described previously
by an aldol reaction of the open-
chain diketone 3 yielding the diastereoisomeric mixtures 4a/
a and 4b/5b (both ratios ca. 1:1.8 by NMR spectroscopy)
5
in 88 and 94% yield, respectively. In the preceding commun-
[18,19]
necting the rings A and B, named SF 2315-type,
[ex-
[26]
ication, only the synthesis of the ring B aromatic angucy-
[18]
[20,21]
ample SF 2315 A (1), Scheme 1]
or SS 228Y-type,
clines was reported and separation of the (E)- and (Z)-iso-
mers 4 and 5 was not required for that purpose. By contrast,
the stereochemistry of the vicinal side chains played a major
role in the construction of nonaromatic derivatives and the
stereoisomers had to be separated. The chromatographic
separation of the stereoisomers 4 and 5 could be achieved
at the stage of the ketals 4/5 but was carried out more con-
veniently with the corresponding diketones 6/7. The best
method for ketal cleavage proved to be the procedure of
Huet et al.[ using dilute sulfuric acid adsorbed on silica
gel in dichloromethane to yield the mixture of 6/7 almost
quantitatively starting from 4/5. Separation of the diketones
by preparative TLC chromatography on silica gel afforded
the pure (E)-stereoisomers 6a and 6b and the (Z) isomers
example WP 3688–2 (2)][ (for review see ref. ).
22]
[1]
[
27]
Scheme 1. Examples of angucyclines of the SF 2315 and SS 288Y
types
In previous studies the stereocontrolled assembly of the
[
23]
SF 2315B ring system was reported by Sulikowski et al.
7
a and 7b. The unambiguous assignment by NMR spectro-
and our group[
24,25]
using Diels–Alder reactions. We now
scopy proved to be difficult in view of the absence of relev-
ant protons at the stereogenic centers, for application of the
Karplus rules, or NOE effects. Fortunately, single crystal X-
ray analysis of the more polar compound revealed the (Z)-
stereochemistry of 7a as shown in Figure 1.
[
°]
Part 11: K. Krohn, C. Bäuerlein, J. Carbohydr. Chem. 1999,
18, 807–831.
[
a]
Fachbereich Chemie und Chemietechnik,
University of Paderborn,
Warburger Strasse 100, D-33098 Paderborn, Germany
Fax: (internat.) ϩ 49-5251/603-245
The stage was now set to study the cyclization by mild-
base-catalyzed aldol reaction. Preliminary studies at room
E-mail: kk@chemie.uni-paderborn.de
Eur. J. Org. Chem. 2000, 1627Ϫ1632

WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0408Ϫ1627 $ 17.50ϩ.50/0
1627

K. Krohn, U. Flörke, C. Freund, N. Hayat
FULL PAPER
Figure 1. The structure of the (Z)-isomer 7a in the crystal
and a very slow conversion was observed above –25 °C in
0
.2  methanolic KOH. This yielded only the aromatic
angucyclines 8-deoxytetrangomycin (8b) and 8-deoxy-
tetrangulol (9b), identical with samples from previous bio-
mimetic[ and Diels–Alder reactions (Scheme 2).
26]
[28]
Disappointingly, no trace of the more interesting nonaro-
matic cyclization products could be detected. The low react-
ivity and the total absence of hydroaromatic intermediates
suggested that water elimination preceded the aldol reac-
tion. How can this behavior be explained? From model con-
siderations, the steric requirements of the transition states
leading to a trans-decalin system should be comparable to
those leading to the cis-decalin arrangement of rings A and
B. However, there are electronic effects to rationalize the
high activation energy for cyclization of 7b to nonaromatic
cyclization products. The ketide side chains necessarily have
to assume a bisequatorial configuration for six-membered
ring formation. Consequently, the negatively charged oxy-
gen of the enolate of the C-1 acetyl group has to approach
the oxygen carbonyl of the naphthoquinone for formation
of the regioisomers of type 8 or 9 which were isolated in
the reaction. Presumably, this electrostatic repulsion pre-
vents cyclization to hydroaromatic products, and side reac-
tions such as base-catalyzed water elimination can take
place. Remarkably, to the best of our knowledge, in nature
there are no known angucyclines with a trans fusion of
rings A and B.[
Scheme 2. Starting materials for aldol cyclizations and reaction of
the (Z)-isomer 7b
29]
temperature of either isomer 6 or 7 always led to decom-
In the next series, the influence of catalytic amounts of
position, or complete aromatization to benzo[a]anthraqui- base on the (E)-isomers 6a/b with cis-alkyl chains at C-1
nones by twofold water elimination. We therefore decided and C-2 was studied. In the previous experiment with the
to test the reaction at much lower temperatures (–25 to (Z)-isomer 7b, chelate-breaking alkaline methanolic condi-
–
60 °C). The reaction of the (Z)-isomer 7b, with two trans- tions were employed. To study the influence of the reaction
configured ketide chains attached to C-1 and C-2, was conditions on the regio- and stereochemical outcome, we
studied first. Virtually no reaction occurred below –35 °C now employed chelate-controlled conditions (LiH in THF).
1628
Eur. J. Org. Chem. 2000, 1627Ϫ1632

Total Synthesis of Angucyclines, 12
FULL PAPER
catalyzed aromatization to 9b, a rapid and infallible test for
formation of benz[a]anthracenequinone with a phenolic hy-
droxyl group at C-1 [cyclization mode (a) in 6]. The prefer-
ence of cyclization mode (b) under the chelation-controlled
conditions can be rationalized by a modified Zimmerman-
Traxler transition state A, in which an optimal chelation of
the lithium cation with three oxygens is possible (Scheme 3).
Finally, the most promising cyclization experiments were
performed with the (E)-isomers 6a and 6b under chelate-
breaking conditions at –45 to –55 °C in 0.2  methanolic
KOH. The slow emergence of a polar cyclization product
in the reaction of 6b could be observed by TLC. At longer
reaction times (ca. 2 days), the previously observed aroma-
tization products 8-deoxytetrangomycin 8b (30%) and trace
amounts of 8-deoxytetrangulol 9b were also isolated in ad-
dition to the major nonaromatic product 11b (63%) (at 48%
conversion). Again, the elucidation of the relative config-
uration at the two quaternary centers at C-3 and C-4a of
1
1b was difficult by NMR methods. However, it was pos-
sible to achieve an X-ray single crystal analysis proving the
trans arrangement of the respective hydroxyl groups of 11b
as shown in Figure 2.
A similar base-catalyzed aldol reaction at –55 °C was per-
formed with the diketone 6a (R ϭ OH) leading to products
with the natural substitution pattern. Interestingly, in this
experiment, two additional polar cyclization products were
formed. Again, the most polar constituent corresponded to
the trans-diol 11a (24%) as verified by comparison of the
NMR spectra of 11b which was almost identical in the rel-
Scheme 3. Cyclization of 6a/b under chelate-breaking and chelate-
controlled conditions
Surprisingly, the regioisomer 10 resulting from cyclization evant parts. Essential parts of the data of 11a were also very
mode (b) in 6b was isolated as the major product (55%) in similar to those of the natural product 2, isolated by Gould
addition to minor amounts (13%) of the 8-deoxytetrango- and Cheng in 1993 from Streptomyces phaeochromogenes
mycin 8b. It was not possible to elucidate the relative config- WP 3688.[ The racemic synthetic material 11a can thus
uration of 10 by analysis of the NMR spectra. However, be named 4a-deoxy WP 3688–2 and it is also related to SF
there was no doubt about the configuration of the re- 2315 A (1), the product of water elimination from 11a. In
gioisomer 10, which was in agreement with the NMR spec- the biosynthesis, the hydroxyl group at C-12a present in WP
troscopic data. In addition, the structure was confirmed by 3688–2 does not originate from the common 1,3-oxygen
chemical evidence. This regioisomer failed to undergo acid- pattern of the polyketide precursors. The oxygen is intro-
22]
Figure 2. The structure of the trans-diol 11b in the crystal
Eur. J. Org. Chem. 2000, 1627Ϫ1632
1629

K. Krohn, U. Flörke, C. Freund, N. Hayat
FULL PAPER
duced by later oxygenation with atmospheric oxygen as es- or C-10a), 119.46, 124.70 (2 ϫ d, C-6 and C-7), 132.18 (s, C-8a or
tablished by the elegant work of Rohr et al.[
30]
C-10a), 136.06 (d, C-8), 142.95, 146.62 (2 ϫ s, C-4a and C-9a),
Although
1
1
61.82 (d, C-5), 184.76, 189.98 (2 ϫ s, C-9 and C-10), 208.14 (s, C-
Ј), 210.89 (s, C-2ЈЈ).
1
1a or its 5,6-desaturation product is postulated as one of
the early intermediates in the biosynthesis of the largest
group of nonaromatic angucyclines, it has not yet been isol- (Z)-1-Acetyl-2,5-dihydroxy-2-(2-oxopropyl)-1,2,3,4-tetrahydro-
ated from natural sources.
anthraquinone (7a): UV (CH
Cl ): λmax (lg ε) ϭ 425 nm (3.63), 304
The cis-diol structure 12 (8.5%) was assigned to the se- (3.24), 273 (4.03), 256 (3.97). Ϫ IR (KBr): ν
2
2
–
1
˜
ϭ 3454 cm (OH),
941 (CH), 2916 (CH), 2850 (CH), 1712 and 1695 (CϭO), 1658
and 1633 (CϭO), 1608, 1458, 1350, 1287, 1178, 1137, 954, 779,
07. – H NMR (200 MHz, CDCl
or 4-H), 2.02Ϫ2.10 (m, 1 H, 3-H or 4-H), 2.20 (s, 3 H, 3ЈЈ-H),
.30Ϫ2.49 (m, 1 H, 3-H or 4-H), 2.48 (s, 3 H, 2Ј-H), AB-system:
ϭ 2.62 (d), δ ϭ 2.74 (d), J ϭ 18.0 Hz, 2 H, 1ЈЈ-H), 2.94Ϫ3.04
m, 1 H, 3-H or 4-H), 4.17 (s, 1 H, 1-H), 4.50 (s, 1 H, OH),
.21Ϫ7.28 (m, 1 H, 6-H), 7.54Ϫ7.62 (m, 2 H, 7-H and 8-H), 12.00
2
cond most polar product as deduced from the NMR spec-
tra, the HRMS spectrum, and the chemical transformation
to tetrangomycin 8a and tetrangulol 9a. The cis-diol 12 was
very unstable relative to the trans isomer 11a. A solution of
1
7
3
): δ ϭ 1.68Ϫ1.96 (m, 1 H, 3-H
2
1
2 in CDCl decomposed by water elimination on standing
3
[δ
A
B
for a few hours. This elimination product was also formed
in the alkaline reaction mixture as the third most polar
(
7
1
3
compound. On standing in solution, it was further trans- (s, 1 H, chel. OH). Ϫ C NMR (50 MHz, CDCl ): δ ϭ 21.92,
3
formed by dehydrogenation to the natural product tetra- 29.03 (2 ϫ t, C-3 and C-4), 32.25, 33.70 (2 ϫ q, C-2Ј and C-3ЈЈ),
ngomycin 8a, isolated in 9% yield from the aldol reaction 49.85 (t, C-1ЈЈ), 55.04 (d, C-1), 115.60 (s, C-10a), 119.60, 124.85
(
1
(
2 ϫ d, C-6 and C-7), 132.09 (s, C-8a), 136.75 (d, C-8), 143.18,
45.47 (2 ϫ s, C-4a and C-9a), 161.86 (s, C-5), 183.85, 189.84
2 ϫ s, C-9 and C-10), 207.23, 210.70 (2 ϫ s, C-1Ј and C-2ЈЈ). Ϫ
mixture. Several possible olefinic structures, but most plaus-
ibly 1 and 13, can be postulated as being formed by loss of
one molecule of water from 12. An assignment in favor of
ϩ
ϩ
MS (EI, 159 °C): m/z (%) ϭ 342 (6) [M ], 300 (8) [M ϩ 1 –
1
3 could be made unambiguously by the absence of the
ϩ
COCH
3 (100) [C
found C 64.78, H 4.19.
3
], 282 (73) [M ϩ 1 – COCH
3
– H
2
O], 240 (58), 225 (23)
proton at C-12b and the presence of two new quaternary
carbons C-4a and C-12b in the NMR spectra. The isolation
of the intermediate 13 from natural sources has not yet been
reported. The instability of the cis isomer 12 when com-
pared to the trans isomer 11a can perhaps be explained by
the enhanced leaving-group capability of 4a-OH in 12 by
chelation with the neighboring hydroxyl group at C-3.
In conclusion, a biomimetic-type aldol reaction of 6a/b,
ϩ
4
H O ]. Ϫ C19H O (342.35): calcd. C 66.66, H 5.30;
2 3 18 6
X-ray Structure Analysis of 7a:[32]
0
a ϭ 6.925(1), b ϭ 8.066(1), c ϭ 14.922(2) A, α ϭ 88.58(2), β ϭ
8
cm , µ ϭ 0.10 mm , F(000) ϭ 360. Data collection was performed
on a Siemens P4 diffractometer using graphite monochromated
19 18 6
C H O , crystal size
.22 ϫ 0.28 ϫ 0.47 mm, M
r
ϭ 342.3, triclinic, space group P1(bar),
˚
˚
3
8.56(1), γ ϭ 85.44(2)°, V ϭ 830.4(2) A , Z ϭ 2, Dcalcd. ϭ 1.369 g
–3
–1
with cis orientated side chains at C-1 and C-2, with meth- Mo-K radiation, ω-scan, 5 Ͻ 2Θ Ͻ 50°; –8 Յ h Յ 1, –9 Յ k Յ
α
anolic KOH at low temperature led, for the first time, to 9, –17 Յ l Յ 17, 3720 reflections collected, 2928 unique reflections,
the isolation of nonaromatic angucycline derivatives 11–13
of the SF 2315 and SS 288Y types. Under chelate controlled
conditions the regioisomeric cyclization product 10 was
formed.
Rint ϭ 0.022, LP correction. Structure solved by direct and conven-
tional Fourier synthesis, full-matrix least-squares refinement based
2
on F and 231 parameters, all but H-atoms refined anisotropically,
H-atoms refined with riding model. Refinement converged at R1 ϭ
0
.054, wR2 (all data) ϭ 0.134, Goof ϭ 1.018, min/max height in
˚
–3
final ∆F map –0.16/0.17 eA , max(δ/σ) ϭ 0.001. Programs used:
SHELXTL.[
33]
Experimental Section
Cleavage of the Ketals 4b/5b: A mixture of 4b/5b[26] (200 mg,
0.54 mmol) was treated as described for 6a/7a to afford the nonpo-
lar (E)-isomer 6b (59.5 mg, 34%) m.p. 177.5 °C and the polar (Z)-
isomer 7b (108.5 mg, 62%) m.p. 154 °C as yellow solids.
For general methods and instrumentation see ref.[31]
Cleavage of the Ketals 4a/5a: A suspension of silica gel (800 mg) in
CH
2 2 2 4
Cl (9 mL) was treated with 15% aqueous H SO (80 mg) and
[26]
stirred for ca. 15 min. A mixture of 4a/5a
(208 mg, 0.54 mmol) (1R*,2S*)-1-Acetyl-2-hydroxy-2-(2-oxopropyl)-1,2,3,4-tetrahydro-
1
was then added, the suspension was stirred for 4 h at 20 °C (TLC
anthraquinone (6b): H NMR (200 MHz, CDCl ): δ ϭ 1.79Ϫ1.99
3
monitoring), filtered, and the filtrate washed with water (10 mL).
(m, 2 H, 3-H), 2.25 (s, 3 H, 3ЈЈ-H), 2.49 (s, 3 H, 2Ј-H), 2.69Ϫ2.84
The organic phase was dried (Na
under reduced pressure. The residue was separated by preparative
TLC chromatography on silica gel (CH Cl /MeOH, 100:1) to af-
ford the nonpolar (E)-isomer 6a (20 mg, 34%) m.p. 158Ϫ160 °C (2 ϫ t, C-3 and C-4), 31.95, 33.26 (2 ϫ q, C-2Ј and C-3ЈЈ), 49.90 (t,
2
4
SO ) and the solvent removed
(m, 4 H, 4-H and 1ЈЈ-H), 4.34 (s, 1 H, 1-H or OH), 4.43 (s, 1 H,
1-H or OH), 7.67Ϫ7.72 (m, 2 H, 6-H and 7-H), 7.98Ϫ8.10 (m, 2
1
3
2
2
3
H, 5-H and 8-H). Ϫ C NMR (50 MHz, CDCl ): δ ϭ 20.61, 29.54
and the polar (Z)-isomer 7a (36 mg, 60%) m.p. 160Ϫ162 °C as
yellow solids.
C-1ЈЈ), 56.72 (d, C-1), 70.83 (s, C-2), 126.68, 126.79 (2 ϫ d, C-5
and C-8), 132.18, 132.41 (2 ϫ s, C-8a and C-10a), 134.02, 134.19
(
1
2 ϫ d, C-6 and C-7), 141.90, 146.19 (2 ϫ s, C-4a and C-9a),
84.76, 185.15 (2 ϫ s, C-9 and C-10), 208.53 (s, C-1Ј), 211.00 (s,
C-2ЈЈ).
(
E)-1-Acetyl-2,5-dihydroxy-2-(2-oxopropyl)-1,2,3,4-tetrahydro-
1
anthraquinone (6a): H NMR (200 MHz, CDCl
(
(
3
): δ ϭ 1.91Ϫ1.95
m, 2 H, 3-H), 2.29 (s, 3 H, 3ЈЈ-H), 2.51 (s, 3 H, 2Ј-H), 2.72Ϫ2.87
m, 4 H, 4-H and 1ЈЈ-H), 4.36 (s, 1 H, 1-H or OH), 4.42 (s, 1 H, (1R*,2R*)-1-Acetyl-2-hydroxy-2-(2-oxopropyl)-1,2,3,4-tetrahydro-
1
1
-H or OH), 7.24Ϫ7.25 (m, 1 H, 6-H), 7.58Ϫ7.61 (m, 2 H, 7-H
anthraquinone (7b): H NMR (200 MHz, CDCl
): δ ϭ [δ ϭ 1.78Ϫ1.84 (m), δ ϭ 2.02Ϫ2.14 (m), 2 H, 3-H], 2.20 (s, 3 H,
0.04, 29.27 (2 ϫ t, C-3 and C-4), 31.90, 33.23 (2 ϫ q, C-2Ј and C- 3ЈЈ-H), AB-system: [δ ϭ 2.34Ϫ2.44 (m), δ ϭ 2.93Ϫ3.05 (m), 2
ЈЈ), 49.97 (t, C-1ЈЈ), 56.66 (d, C-1), 70.66 (s, C-2), 115.30 (s, C-8a H, 4-H], 2.50 (s, 3 H, 2Ј-H), AB-system: [δ ϭ 2.63 (d), δ ϭ 2.75
3
): δ ϭ AB-system:
13
and 8-H), 12.01 (s, chel. OH). Ϫ C NMR (50 MHz, CDCl
2
3
3
A
B
A
B
A
B
1630
Eur. J. Org. Chem. 2000, 1627Ϫ1632

Total Synthesis of Angucyclines, 12
FULL PAPER
ϩ
2
ϩ
(
d), J ϭ 17.8 Hz, 2 H, 1ЈЈ-H], 4.19 (s, 1 H, 1-H), 4.51 (s, 1 H, OH), 225 (19), 43 (22) [C
2
H
3
O ], 18 (32) [H
2 18 6
O ]. Ϫ HRMS (C19H O ):
7
.68Ϫ7.75 (m, 2 H, 6-H and 7-H), 7.97Ϫ8.09 (m, 2 H, 5-H and 8-
calcd. 342.1103; found 342.1097.
13
H). Ϫ C NMR (50 MHz, CDCl
and C-4), 32.26, 33.72 (2 ϫ q, C-2Ј and C-3ЈЈ), 49.86 (t, C-1ЈЈ),
5
1
7
9
3
): δ ϭ 22.46, 29.10 (2 ϫ t, C-3
3,8-Dihydroxy-3-methyl-3,4,5,6-tetrahydro-2H-benz[a]anthracene-
1,7,12-trione (13): m.p. 187 (dec.). Ϫ UV (CH Cl ): λmax (lg ε) ϭ
4
21 nm (3.15), 300 (3.26), 233 (3.69). Ϫ IR (KBr): ν˜ ϭ 3420 cm
2
2
4.97 (d, C-1), 72.17 (s, C-2), 126.77 (2 ϫ d, C-5 and C-8), 132.12,
32.36 (2 ϫ s, C-8a and C-10a), 134.18, 134.34 (2 ϫ d, C-6 and C-
), 142.05, 145.55 (2 ϫ s, C-4a and C-9a), 184.63, 184.73 (2 ϫ s, C-
and C-10), 207.54 (s, C-1Ј), 210.83 (s, C-2ЈЈ).
Ϫ1
(
(
2
2
OH), 2960 (C–H), 2924 (C–H), 1729 (CϭO), 1673 (CϭO), 1655
1
CϭO). Ϫ H NMR (200 MHz, CDCl
3
): δ ϭ 1.29 (s, 3 H, CH
.45Ϫ3.54 (m, 2 H, 5-H or 6-H), 2.73Ϫ3.92 (m, 2 H, 5-H or 6-H),
.82 (s, 2 H, 2-H or 4-H), 2.85 (s, 2 H, 2-H or 4-H), 3.62 (s, C-3-
3
),
Cyclization of the (E)-Isomer 6a: To a solution of KOH in dry meth-
anol (0.2 , 30 mL) was added the dione 6a (30 mg, 0.077 mmol)
under argon at –55 °C and the mixture was stirred for ca. 72 h at
this temperature (TLC monitoring). The mixture was then acidified
by addition of 1  HCl (8 mL) and a saturated aqueous solution
OH), 7.23Ϫ7.26 (m, 1 H, 9-H), 7.60Ϫ7.63 (m, 2 H, 10-H and 11-
1
3
H), 12.03 (s, 1 H, C-8-OH). Ϫ C NMR (50 MHz, CDCl
8.71 (t, C-6), 29.24 (t, C-5), 29.35 (q, CH ), 45.46 (t, C-4), 52.20
t, C-2), 71.49 (s, C-3), 114.89 (s, C-7a), 119.08 (d, C-9), 123.44 (d,
C-10), 129.78 (s, C-11a and 6a), 132.94 (s, C-8a), 136.06 (d, C-11),
3
): δ ϭ
1
(
3
of NH
with CH
with water (15 mL), dried (Na
der reduced pressure. The residue was separated by preparative
TLC on silica gel (1 mm, (CH Cl /MeOH, 100:3) to afford the
starting material 6a (10.5 mg, 35%), the trans-diol 11a (5.1 mg,
4%), the cis-diol 12 (1.8 mg, 8.5%), the olefin 13 (5.1 mg, 25.5%),
tetrangomycin (8a) (1.8 mg, 9%) and tetrangulol (9a) (0.5 mg, Cyclization of the (E)-Isomer 6b: The dione 6b (25 mg, 0.077 mmol)
4
Cl (35 mL). The aqueous phase was extracted three times
Cl (15 mL), the combined organic phases were washed
SO ) and the solvent removed un-
1
4
41.27, 141.70 (2 ϫ s, C-12a and C-12b), 160.00, 160.90, (2 ϫ s, C-
a and C-8), 182.12, 188.40 (2 ϫ s, C-7 and C-12), 193.34 (s, C-1).
2
2
2
4
ϩ
ϩ
Ϫ MS (EI, 188 °C): m/z (%) ϭ 324 (12) [M ], 306 (60) [M
Ϫ
ϩ
2 2 2 3
H O], 266 (100) [M Ϫ H O ϩ 3 Ϫ C H O], 264 (20), 237 (18),
2
2
ϩ
ϩ
2
25 (19), 43 (7) [C
2 3 2 16 5
H O ], 18 (18) [H O ]. Ϫ HRMS (C19H O ):
calcd. 324.0997; found 324.0995.
2
2
.6%).
was treated for ca. 90 h at –40 to –50 °C with 0.2  methanolic
KOH, as described above for 6a, to afford the starting material
(
3S*,4aS*,12bR*)-3,4,4a,5,6,12b-Hexahydro-3,4a,8-trihydroxy-3-
(
13.1 mg, 52%), the diol 11b (7.5 mg, 63%) m.p. 201 °C (dec.), 8-
methyl-2H-benz[a]anthracene-1,7,12-trione (11a): m.p. 210 °C
[26]
deoxytetrangomycin (8b) (3.4 mg, 30%) m.p. 214 °C and 8-deoxy-
tetrangulol (9b) (0.5 mg, 2.6%).[ Compounds 8b and 9b were
also formed by similar treatment of 7b at –25 °C.
(dec.). – UV (CH
2 2
Cl ): λmax (lg ε) ϭ 422 nm (3.71), 271 (4.13), 250
26]
Ϫ1
(
4.04). Ϫ IR (KBr): ν˜ ϭ 3494 cm (OH), 3408 (OH), 2962 (CH),
1
2
925 (CH), 1708 (CϭO), 1640 and 1633 (CϭO), 1612. Ϫ H NMR
(
200 MHz, [D ]acetone): δ ϭ 1.28 (s, 3 H, CH ), 1.54Ϫ1.65 (m, 1
6
3
(3S*,4aS*,12bR*)-3,4,4a,5,6,12b-Hexahydro-3,4a-dihydroxy-3-
H, 5-H), 2.04Ϫ2.15 (m, 2 H, 2-H or 5-H), 2.19Ϫ2.37 (m, 2 H, 4- methyl-2H-benz[a]anthracene-1,7,12-trione (11b): IR (KBr): ν˜ ϭ
Ϫ1
H), 2.47Ϫ2.57 (m, 2 H, 2-H or 6-H), 2.77Ϫ2.84 (m, 1 H, 6-H), 3492 cm (OH), 3411 (OH), 2960 (C–H), 2930 (C–H), 1702 (Cϭ
3
.71 (s, 1 H, C-3-OH), 3.89 (s, 1 H, 12b-H), 4.03 (s, 1 H, C-4a-
O), 1661 (CϭO), 1644 (CϭO), 1589 (CϭC). Ϫ UV (methanol):
1
OH), 7.13Ϫ7.17 (dd, J ϭ 7.2 Hz, J ϭ 1.1 Hz, 1 H, 9-H), 7.41Ϫ7.44
λ
max (lg ε) ϭ 270 nm (3.52), 331 (2.74). Ϫ H NMR (600 MHz,
m, J ϭ 7.2 Hz, 1 H, 10-H), 8.31 (m, J ϭ 7.6 Hz, 1 H, 11-H), 11.99 [D ]acetone): δ ϭ 1.42 (s, 3 H, CH ), AB-system: [δ ϭ 1.72 (m),
s, 1 H, C-8-OH). Ϫ 13C NMR (75 MHz, [D
]acetone): δ ϭ 20.45
ϭ 2.24 (m), 2 H, 5-H], AB-system: [δ ϭ 2.22 (dd), δ
t, C-6), 31.25 (t, C-5), 31.53 (q, CH
), 51.87 (t, C-4), 54.00 (t, C- (d), J ϭ 14.1 Hz, J ϭ 2.5 Hz, 2 H, 4-H], AB-system: [δ
(
(
(
2
7
6
3
A
δ
B
A
B
ϭ 2.44
ϭ 2.37
6
2
4
3
A
2
4
), 56.28 (d, C-12b), 71.53 (s, C-3), 72.07 (s, C-4a), 115.28 (s, C-
B
(dd), δ ϭ 2.94 (d), J ϭ 12.8 Hz, J ϭ 2.5 Hz, 2 H, 2-H],
a), 118.87 (d, C-9), 123.77, (d, C-10), 132.75 (s, C-11a), 136.71 (d, 2.59Ϫ2.74 (m, 2 H, 6-H), 3.77 (s, 1 H, C-3-OH), 4.04 (s, 1 H, 12b-
C-11), 142.68, 145.34 (2 ϫ s, C-12a and C-6a), 161.41 (s, C-8), H), 4.08 (s, 1 H, C-4a-OH), 7.77Ϫ7.86 (m, 2 H, 9-H and 10-H),
1
3
1
2
83.28, 190.40 (2 ϫ s, C-12 and C-7), 204.69 (s, C-1). Ϫ MS (EI,
7.98Ϫ8.11 (m, 2 H, 8-H and 11-H). Ϫ C NMR (75 MHz, [D
O], 307 (10) tone): δ ϭ 21.45 (t, C-6), 31.09 (t, C-5), 32.04 (q, CH ), 52.52 (t,
O ], 18 C-4), 54.52 (t, C-2), 56.74 (d, C-12b), 72.00 (s, C-3), 72.60 (s, C-
6
]ace-
ϩ
ϩ
40 °C): m/z (%) ϭ 343 (15) [M ], 324 (15) [M Ϫ H
2
3
ϩ
ϩ
[M
Ϫ 2 H
2
O], 265 (20) 240 (100), 225 (19), 43 (22) [C
2
H
3
ϩ
(9) [H
2
O ].
Ϫ
HRMS (C19
H
18
O
6
): calcd. 342.1103; found
4a), 126.69, 126.76 (2 ϫ d, C-8 and C-11), 134.09 (2 ϫ s, C-7a and
C-11a), 134.42 (2 ϫ d, C-9 and C-10), 141.76 (s, C-12a), 145.83 (s,
C-6a), 184.48 (s, C-12), 185.00 (s, C-7), 205.19 (s, C-1). Ϫ MS (DCI
3
42.1097.
(
3R*,4aS*,12bR*)-3,4,4a,5,6,12b-Hexahydro-3,4a,8-trihydroxy-3-
methyl-2H-benz[a]anthracene-1,7,12-trione (12): m.p. 150Ϫ152. –
UV (CH Cl ): λmax (lg ε) ϭ 422 nm (3.62), 273 (4.04), 250 (3.99).
Ϫ IR (KBr): ν˜ ϭ 3475 cm (OH), 3441 (OH), 2950 (CH), 2929
CH), 1708 (CϭO), 1666 (CϭO), 1645 (CϭO), 1462, 1366, 1300,
ϩ
ϩ
negative, NH
Ϫ H
3
, 8 mA/s): m/z (%) ϭ 326 (100) [M ], 308 (37) [M
O], 290 (23) [M Ϫ 2H O]. Ϫ HRMS (C19H O ): calcd.
2 18 5
ϩ
2
2
2
3
26.11542; found 326.11571.
Ϫ1
X-ray Structure Analysis of 11b:[32]
ϭ 326.3, monoclinic, space group P2
n, a ϭ 5.7780(4), b ϭ 19.885(6), c ϭ 13.319(6) A, β ϭ 100.37(3)°,
V ϭ 1505.8(1) A , Z ϭ 4, Dcalcd. ϭ 1.439 g cm , µ ϭ 0.10 mm ,
F(000) ϭ 688. Data collection as before, 4 Ͻ 2Θ Ͻ 50°, –6 Յ h Յ
, –23 Յ k Յ 0, –15 Յ l Յ 15, 2876 reflections collected, 2622
unique reflections, Rint ϭ 0.053, LP correction. Structure solved by
direct and conventional Fourier synthesis, full-matrix least-squares
19 18 5
C H O , crystal size
(
1
1
0.06 ϫ 0.07 ϫ 0.58 mm, M
r
1
/
270, 1237, 1195, 1141, 762. Ϫ H NMR (200 MHz, [D
6
]acetone):
˚
–3
δ ϭ 1.13 (s, 3 H, CH ), 1.65Ϫ1.83 (m, 2 H, 4-H), 1.97Ϫ2.00 (s, 1
3
˚
3
–1
H, 2-H), 2.13Ϫ2.38 (m, 2 H, 5-H or 6-H), 2.60Ϫ2.66 (m, 2 H, 5-
H or 6-H), 2.40 (s, 1 H, 2-H), 3.71 (s, 1 H, 12b-H), 4.45 (s, 1 H,
C-3-OH), 4.58 (s, 1 H, C-4a-OH), 7.13Ϫ7.17 (dd, J ϭ 8.4 Hz, 1 H,
0
9
8
-H), 7.38Ϫ7.42 (m, J ϭ 7.5 Hz, 1 H, 10-H), 7.55Ϫ7.63 (m, J ϭ
.2 Hz, 1 H, 11-H), 11.90 (s, 1 H, C-8-OH). Ϫ 13C NMR (75 MHz,
2
refinement based on F and 220 parameters, all but H-atoms re-
[D
6
]acetone): δ ϭ 21.58 (t, C-6), 30.55 (q, CH
3
), 33.53 (t, C-5),
7.42 (t, C-4), 53.60 (t, C-2), 57.96 (d, C-12b), 73.59, 73.84 (2 ϫ s,
C-3 and C-4a), 115.28 (s, C-7a), 119.21 (d, C-9), 124.27 (d, C-10),
fined anisotropically, H-atoms at calculated positions refined with
riding model. Refinement converged at R1 ϭ 0.069, wR2 (all
data) ϭ 0.175, Goof ϭ 1.002, min/max height in final ∆F map
4
1
6
(
33.60 (s, C-11a), 136.71 (d, C-11), 142.84 (s, C-12a), 145.89 (s, C-
˚
–3
[33]
–
0.23/0.23 eA , max(δ/σ) ϭ 0.001. Programs as before.
a), 161.80 (s, C-8), 183.36, 184.41 (2 ϫ s, C-12 and C-7), 206.67
ϩ
s, C-1). Ϫ MS (EI, 200 °C): m/z (%) ϭ 343 (12) [M ], 324 (60) (1RS,4aS*,12bS*)-1,4a-Dihydroxy-1-methyl-1,4,4a,5,6,12b-hexa-
ϩ ϩ
[M
Ϫ H
2
O], 306 (100) [M Ϫ 2H
2
O], 265 (30), 264 (77), 240 (90), hydro-2H-benz[a]anthracene-3,7,12-trione (10): The (E)-isomer 6b
Eur. J. Org. Chem. 2000, 1627Ϫ1632
1631

K. Krohn, U. Flörke, C. Freund, N. Hayat
FULL PAPER
Matsuda, T. Sawa, H. Naganawa, M. Hamada, T. Takeuchi,
H. Umezawa, J. Antibiot. 1985, 38, 1171–1180.
10]
was added under argon at Ϫ25 °C to a suspension of LiH (4 mg,
0
.50 mmol) in dry THF (10 mL). The mixture was stirred for 4 days
at Ϫ25 °C (TLC monitoring) and was then acidified by addition of
 HCl (6 mL) and saturated NH Cl solution (5 mL). The aque-
ous phase was extracted with CH Cl (3 ϫ 20 mL), washed with
water (10 mL), dried (Na SO ), and the solvent removed under re-
duced pressure. Chromatographic separation by TLC (1 mm, silica
gel) (CH Cl /MeOH, 100:5) afforded the starting material 6b
3 mg, 16%), 9b (2 mg, 13%) and 10 (9 mg, 55%) as a yellow solid,
[
R. R. Rasmussen, M. E. Nuss, M. H. Scherr, S. L. Mueller, J.
B. McAlpine, J. Antibiot. 1986, 39, 1515–1526.
[11]
1
4
M. Oka, H. Kamel, Y Hamagishi, K. Tomita, T. Miyaki, M.
Konishi, T. Oki, J. Antibiot. 1990, 43, 967–976.
A. Kawashima, Y. Kishimura, M. Tamai, K. Hanada, Chem.
Pharm. Bull. 1987, 37, 3429–3431.
2
2
[
[
12]
13]
2
4
S. Omura, A. Nakagawa, N. Fukamachi, S. Miura, Y. Takah-
ashi, K. Komiyama, B. Kobayashi, J. Antibiot. 1988, 41, 812–
2
2
(
8
13.
Ϫ1
[14]
m.p. 211 °C (dec.). Ϫ IR (KBr): ν˜ ϭ 3444 cm (OH), 3384 (OH),
S. Miyata, N. Ohhata, H. Mural, Y. Masui, M. Ezaki, S. Tak-
ase, M. Nishikawa, S. Kiyoto, M. Okuhara, M. Kohsaka, J.
Antibiot. 1992, 45, 1029–1040.
15]
2
1
966 (C–H), 2925 (C–H), 1699 (CϭO), 1659 (CϭO), 1643 (CϭO),
626 (CϭC), 1592 (CϭC). Ϫ UV (methanol): λmax (lg ε) ϭ 237 nm
[
K. Ohta, E. Mizuta, H. Okazaki, T. Kishi, Chem. Pharm. Bull.
1
(3.09), 270 (3.66), 329 (2.89). Ϫ H NMR (200 MHz, [D
6
]acetone):
), 2.30Ϫ2.55 (m,
), 2.64Ϫ2.66 (m, 2 H, 6-H), 2.85Ϫ2.99
), 3.74 (s, 1 H, 12b-H), 3.84 (s, 1 H, OH),
1984, 32, 4350–4359.
δ ϭ 1.18 (s, 3 H, CH
3
3
), 1.62Ϫ1.64 (m, 1 H, 5-H
a
[16]
S. Ayukawa, T. Takeuchi, M. Sezaki, T. Hara, H. Umezawa, T.
Nagatsu, J. Antibiot. 1968, 21, 350–353.
H, 2-H
a
, 4-H
a
and 5-H
and 4-H
b
[
[
17]
18]
(m, 2 H, 2-H
b
b
T. Nagatsu, S. Ayukawa, H. Umezawa, J. Antibiot. 1968, 21,
3
54–357.
4
.04 (br s, 1 H, OH), 7.80Ϫ7.84 (m, 2 H, 9-H and 10-H), 8.04Ϫ8.07
13
T. Sasaki, J. Yoshida, M. Itoh, S. Gomi, T. Shomura, M. Se-
zaki, J. Antibiot. 1988, 41, 835–842.
T. Sasaki, S. Gomi, M. Sezaki, Y. Takeuchi, Y. Kodoma, K.
Kawamura, J. Antibiot. 1988, 41, 843–848.
T. Kitahara, H. Naganawa, T. Okazaki, Y. Okami, H. Umez-
awa, J. Antibiot. 1975, 28, 280–285.
N. Imamura, K. Kakinuma, N. Ikekawa, H. Tanaka, S. Omura,
J. Antibiot. 1982, 35, 602–608.
S. J. Gold, X. C. Cheng, J. Org. Chem. 1994, 59, 400.
K. Kim, Y. Guo, G. A. Sulikowski, J. Org. Chem. 1995, 60,
6866–6871.
(
m, 2 H, 8-H and 11-H). Ϫ C NMR (50 MHz, CDCl
]MeOH, 9:1): δ ϭ 21.44 (t, C-6), 29.59 (t, C-5), 31.17 (q, CH
7.58 (d, C-12b), 55.03, 55.56 (2 ϫ t, C-2 and C-4), 72.29, 73.83
3
/
[D
4
3
),
[19]
4
[
[
20]
21]
(
2 ϫ s, C-1 and C-4a), 126.03, 126.29 (2 ϫ d, C-8 and C-11),
32.03, 132.15 (2 ϫ s, C-7a and C-11a), 133.38, 133.45 (2 ϫ d, C-9
and C-10), 141.54, 147.78 (2 ϫ s, C-6a and C-12a), 184.60, 185.36
2 ϫ s, C-7 and C-12), 208.28 (s, C-3). Ϫ MS (DCI negative, NH
1
(
8
3
,
[22]
[23]
ϩ
mA/s): m/z (%) ϭ 326 (100) [M ], 268 (Ͻ1), 226 (Ͻ1), 147 (Ͻ1).
Ϫ HRMS (C19 ): calcd. 326.11542; found 326.11603.
18 5
H O
[
[
[
24]
25]
26]
R. Faust, B. Göbelt, J. Prakt. Chem. 1998, 340, 90–93.
K. Krohn, J. Micheel, Tetrahedron 1998, 54, 4827–4838.
K. Krohn, N. Böker, U. Flörke, C. Freund, J. Org. Chem. 1997,
Acknowledgments
We thank the Deutsche Forschungsgemeinschaft and the Fonds der
Chemischen Industrie for financial support and Prof. J. Rohr for
helpful advice about the angucycline structures.
6
2, 2350–2356.
[
[
[
27]
28]
29]
F. Huet, A. Lechevallier, M. Pellet, J. M. Conia, Synthesis 1978,
3–65.
K. Krohn, K. Khanbabaee, Liebigs Ann. Chem. 1994, 1109–
112.
6
1
J. Rohr, personal communication.
G. Udvarnoki, T. Henkel, R. Machinek, J. Rohr, J. Org. Chem.
1992, 57, 1274–1276.
[
[
[
1]
2]
3]
[30]
J. Rohr, R. Thiericke, Nat. Prod. Rep. 1992, 9, 103–137.
K. Krohn, J. Rohr, Top. Curr. Chem. 1997, 188, 128–195.
T. Nagasawa, H. Fukao, H. Irie, H. Yamada, J. Antibiot. 1984,
[
[
31]
32]
K. Krohn, A. Michel, U. Flörke, H.-J. Aust, S. Draeger, B.
Schulz, Liebigs Ann. Chem. 1994, 1093–1097.
Crystallographic data (excluding structure factors) for the
structures reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication nos. CCDC-137358 for 7a and CCDC-137359
for 11b. Copies of the data can be obtained free of charge
on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [Fax: (internat.) ϩ 44-1223/336-033; E-mail:
deposit@ccdc.cam.ac.uk].
41, 693–699.
[
[
4]
5]
R. W. Rickards, J.-P. Wu, J. Antibiot. 1984, 38, 513–515.
R. Sawa, N. Matsuda, T. Uchida, T. Ikeda, T. Sawa, H. Na-
ganawa, M. Hamada, T. Takeuchi, J. Antibiot. 1991, 44, 396–
402.
[
6]
Y. Sawada, K. I. Numata, T. Murakami, H. Tanimichi, S. Yam-
amoto, T. Oki, J. Antibiot. 1990, 43, 715–721.
S. F. Queener, J. Med. Chem. 1995, 38, 4739–4759.
[
[
7]
8]
[33]
T. Oki, M. Kakushima, M. Hirano, A. Takahashi, A. Ohta, S.
SHELXTL NT, Ver. 5.10, Bruker Analytical X-ray Systems,
Masuyoshi, M. Hatori, H. Kamei, J. Antibiot. 1992, 45,
Madison, Wisconsin, USA.
1512–1517.
Received November 23, 1999
[
9]
T. Uchida, M. Imoto, Y. Watanabe, K. Miura, T. Dobashi, N.
[O99646]
1632
Eur. J. Org. Chem. 2000, 1627Ϫ1632