Total Synthesis of Angucyclines. XVII. First Synthesis of Antibiotic 100-1, a Deoxydisaccharide Angucycline Antibiotic of the Urdamycinone B-Type

Article abstract of DOI:10.1081/CAR-120026460

Two routes to the deoxydisaccharide angucycline antibiotic 100-1 (3) are described. Key steps comprise the regioselective oxidation/bromination of the 1,5-diacetoxy-olivose C-saccharide 7 to the bromoquinone 8. Diels-Alder reaction of the bromoquinone wit

Full text of DOI:10.1081/CAR-120026460

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Total Synthesis of Angucyclines. XVII. First Synthesis
of Antibiotic 100‐1, a Deoxydisaccharide Angucycline
Antibiotic of the Urdamycinone B‐Type
Karsten Krohn a , Attila Agocs a & Christiane Bäuerlein a
a Department of Chemistry , University of Paderborn , Warburger Str. 100, 33098, Paderborn,
Germany
Published online: 23 Feb 2007.
To cite this article: Karsten Krohn , Attila Agocs & Christiane Bäuerlein (2003) Total Synthesis of Angucyclines. XVII.
First Synthesis of Antibiotic 100‐1, a Deoxydisaccharide Angucycline Antibiotic of the Urdamycinone B‐Type , Journal of
Carbohydrate Chemistry, 22:7-8, 579-592, DOI: 10.1081/CAR-120026460
To link to this article: http://dx.doi.org/10.1081/CAR-120026460
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JOURNAL OF CARBOHYDRATE CHEMISTRY
Vol. 22, Nos. 7 & 8, pp. 579–592, 2003
Total Synthesis of Angucyclines. XVII. First Synthesis of
Antibiotic 100-1, a Deoxydisaccharide Angucycline
Antibiotic of the Urdamycinone B-Typey
*
Karsten Krohn, Attila Agocs, and Christiane Ba¨uerlein
Department of Chemistry, University of Paderborn, Paderborn, Germany
ABSTRACT
Two routes to the deoxydisaccharide angucycline antibiotic 100-1 (3) are described.
Key steps comprise the regioselective oxidation/bromination of the 1,5-diacetoxy-
olivose C-saccharide 7 to the bromoquinone 8. Diels–Alder reaction of the bromo-
quinone with the diene 9 followed by HBr elimination afforded the urdamycinone B
precursor 11 as a diastereomeric mixture. Selective protection as the TBDMS ether 13,
acetylation and deprotection of the silyl ether afforded the alcohol 15 which was
selectively glycosylated to the a-rhamnal glycoside 17 in 72% yield (at 70% con-
version) using benzoyl rhamnal (16) as the glycoside donor and scandium triflate as the
promotor. The silyl group at C-3 of the aglycone was then transformed into a hydroxyl
group. Zemple´n deacylation and photooxidation of the benzylic position at C-1 then
converted the two diastereoisomers into the natural product 3 and the C-3 diaste-
reoisomer 20. At this stage the diastereomers 3 and 20 were separated. Alternatively
and more easily, the diastereomers were separated at the stage of the urdamycinone B
analogues 21a and 21b, followed by a similar reaction sequence to the natural
disaccharide 3.
Key Words: Deoxydisaccharides; Angucycline antibiotics; C-glycosides; Scandium
triflate.
yThis paper is dedicated to Prof. Ge´rard Descotes on the occasion of his 70th birthday.
*
Correspondence: Karsten Krohn, Department of Chemistry, University of Paderborn, Warburger
Str. 100, 33098, Paderborn, Germany; E-mail: kk@chemie.uni-paderborn.de.
579
DOI: 10.1081/CAR-120026460
0732-8303 (Print); 1532-2327 (Online)
www.dekker.com
Copyright D 2003 by Marcel Dekker, Inc.

580
Krohn, Agocs, and Ba¨uerlein
INTRODUCTION
The angucycline antibiotics are a large group of glycosidic natural products with
benzo[a]anthraquinone as the aglycone skeleton (reviews, see Refs. [1–3]). Typical
representatives are the urdamycins[4–6] with some of their structures shown in Figure 1.
The comparatively simple benzo[a]anthraquinone skeleton was the first angucyclinone
isolated from microbial sources and named tetrangomycin.[7,8] Since the D-olivose is
attached C-glycosidically to the quinone skeleton, the true aglycone has to be named
urdamycinone B (2). This name is derived from the trisaccharide urdamycin B (4), first
isolated by Rohr and Zeeck et al.[4,5] A disaccharide, antibiotic 100-1 (3), was isolated
during studies on the biosynthesis of the urdamycin family from a mutant strain.[9]
Remarkably, the sequence of sugars present in urdamycin B (4) is representative for
most other related angucycline antibiotics with quite different aglycones.[1,2] Thus,
D-olivose is b-C-glycosidically linked at C-9 of the benzo[a]anthraquinone, followed by
an a-O-glycosidically attached L-rhodinose and then again by D-olivose as a b-O-
glycoside. Accordingly, work on the glycosides, which contain the simple tetra-
ngomycin as polyketide derived core, has model character for the entire group of
angucycline antibiotics. Apart from the remarkable syntheses of the trisaccharide
fragment of the antibiotic PI-080[10] and the hexasaccharide fragment of landomycin
A[11] by the Sulikowski group, only three syntheses of angucycline antibiotics are
known with the sugars attached to the benzo[a]anthraquinones (reviews on deoxyo-
ligosaccharide synthesis, see Refs. [12,13]). In the first biomimetic-type synthesis of
ent-urdamycinone B by Yamaguchi et al.[14] the phenolic precursor was constructed
around the deoxysugar. In contrast the C-glycoside was prepared in a Lewis acid-
promoted reaction of electron rich phenols with deoxysugars in the groups of Suli-
kowski[15] and Toshima.[16] This method of C-glycoside construction using phenols,
and probably involving O-C-glycoside rearrangement, was pioneered by work of
Suzuki et al.[17–19] Toshima et al. extended this method even to unprotected sugars,[20,21]
Figure 1. Structures of urdamycinones from wild strains and blocked mutants. (From Ref. [9].)

Synthesis of Angucyclines. XVII
581
while the very simple protocol of Andrews and Larsen relied on corresponding anomeric
acetates of 2-deoxy sugars.[22]
RESULTS AND DISCUSSION
We now disclose two routes to the first total synthesis of the disaccharide, antibiotic
100-1 (3), based on the earlier model studies on the stereoselective disaccharide de-
oxysugar synthesis performed on naphthol models[23] and on the tetrangomycin synthesis
that relied on a Diels–Alder reaction to construct the benzo[a]anthraquinone skeleton.[24]
A direct electrophilic substitution of potential C-glycosyl donors with the electron-
deficient naphthoquinones is not possible. Therefore, C-glycoside formation according
to an electrophilic mechanism is usually performed with the corresponding eletron-rich
hydroquinones or naphthols. However, to avoid the somewhat tedious preparation of
the selectively protected juglone hydroquinones and the formation of possible
regioisomers with less protected oligophenolic nucleophiles, we decided to start with
the symmetrical 1,5-dihydroxynaphthalene, related to the first step of the Toshima
urdamycinone B synthesis.[16] Thus, D-olivose acetate (5)[25] was reacted with a 1.6
fold excess of 1,5-dihydroxynaphthalene (6) and boron trifluoride etherate according to
the procedure of Andersen and Larsen[22] (Scheme 1). The intermediate mono-C-
glycoside was directly acetylated to afford the tetraacetate 7 as colorless crystals in
43% yield over the two steps. Photooxidation in the presence of oxygen of the
corresponding bisphenol was performed by the group of Toshima to afford a mixture of
the regioisomeric related juglone derivative in a 57:13 ratio on a small scale.[16] We
anticipated that NBS bromination of 7 might selectively attack the less substituted
benzene ring. Gratifyingly, our reasoning proved to be correct and the bromoquinone
8 was isolated in 86% yield in a multi-gram scale with no trace of a regioisomeric
quinone detected. This reaction can be considered a breakthrough in this and all related
Diels–Alder based approaches to the angucycline glycosides. The procedure is more
simple than the NBS oxidation of a corresponding selectively acetylated monophenol
reported by Sulikowski[15] and has a number of advantages over the reported photo-
oxidation:[16] 1) only one regioisomer is formed and no chromatographic separation is
required, 2) it can be conducted on a large scale, 3) the bromine atom on the quinone
double bond directs the regiochemistry of the subsequent Diels–Alder reactions, 4) the
presence of the bromine atom also facilitates the HBr elimination of the intermediate
Diels–Alder adduct to afford the desired benzo[a]anthraquinone.
The subsequent Diels–Alder reaction of the bromoquinone 8 with the readily
available known diene 9[24,26,27] afforded the primary Diels–Alder adduct 10 with
complete regioselectivity. This was in agreement with our experience that the less
hindered site of dienes always adds to the sterically less hindered site of halogenated
naphthoquinones such as 8. This steric effect even dominates opposite electronic effects
of the halogen atom. In the next step, as anticipated, elimination of hydrogen bromide
was easily effected by treatment of bromide 10 with K2CO3 in methanol to yield the
anthraquinone 11 in 76% yield over the two steps. The Diels–Alder products derived
from the reaction of the enantiomerically pure C-glycoside 8 with the racemic diene 9
were a ca. 1:1 mixture of diastereoisomers that were chromatographically not separable.

582
Krohn, Agocs, and Ba¨uerlein
Scheme 1. a) 1. CH3CN, BF3 Et2O; 2. Ac2O/py (43%). b) NBS, H2O/CH3CN, 86%. c) Toluene,
6 h at 70°C. d) K2CO3, methanol (76%, 2 steps). e) HBF4 ꢀ Et2O (60%). f) TBDMSCl/imidazole,
DMF. g) Ac2O/py. h) HF/CH3CN (76% yield for the 3 steps). i) Sc(OTf)3/CH2Cl2 (72% yield at
70% conversion). j) NaOMe/MeOH, (87%). k) THF/MeOH, KHCO3, KF, H2O2. l) O2/hn, methanol
(each 3 and 20 17% over 2 steps).
The dimethylphenylsilyl group served as a placeholder to avoid possible
elimination of the tertiary hydroxyl group at C-3.[24,28] Its replacement by a hydroxyl
group (with retention of stereochemistry) is usually performed in two steps: 1) proto-
desilylation by cleavage of the phenyl–silicon bond replacing the phenyl group by a
fluoride, and 2) oxidative replacement of the dimethylfluorosilyl group by a hydro-
xyl group.[29] This strategy was applied previously in a number of angucyclinone

Synthesis of Angucyclines. XVII
583
syntheses[16,24] (review, see Ref. [2]). In the first of these two steps, the fluoride 12 was
obtained upon treatment of silane 11 with HBF4 Et2O in 60% yield.
The stage was now set to perform the selective disaccharide synthesis making use
of the experience gained in our previous model studies with the bicyclic naphthol
derivatives.[23] We applied a very easy and high yielding three step protection strategy.
First, the slightly less hindered 3-OH of the olivose residue in 12 was selectively
protected as the TBDMS ether 13, as also performed by Suzuki et al. in the synthesis of
antibiotic C-104.[30] The alcohol 13 was then acetylated to the diacetate 14, thus
protecting also the free chelated phenolic hydroxyl group. The silyl ether was then
cleaved by treatment with HF/CH3CN to afford the diacetate 15 with a free hydroxyl
group at C-4 in 76% yield over the three steps. In the previous model studies, we
employed scandium triflate for the first time in an a-selective O-glycoside synthesis.[23]
According to that procedure, the alcohol 15 was treated with the L-rhodinal benzoate
(16)[23] and scandium triflate to yield the a-O-gylcoside 17 selectively in 72% yield at
70% conversion as a yellow resin in addition to recovered starting C-glycoside 15.
Zemple´n deacylation using sodium methoxide in methanol then afforded the depro-
tected disaccharide 18.
It has to be remembered that up to the present stage of the synthesis, all the
mono- and disaccharides with nonpolar methyl and silyl groups at C-3 were
diastereoisomeric mixtures that were not separable by chromatography. Differentiation
was only possible by replacing the hydrophobic silyl group with a polar hydroxyl
group. This oxidative desilylation was performed according to the procedure of Chan
and Nwe[29] by treating the silyl fluoride 18 with hydrogen peroxide in the presence
of KF and KHCO3. The crude mixture of the alcohols 19a,b was then exposed to
sunlight in methanol solution as described earlier by our group for C-1 oxidation of
angucyclinones.[24,31] It was important to perform the photooxidation in the last step
to avoid facile b-elimination of the C-3 tertiary hydroxyl group during glycosidation
or deprotection steps. The products could now be separated by repeated TLC chro-
matography on silica gel. The less polar compound was identical in all respects to a
sample kindly provided by Prof. J. Rohr, whereas the polar component was assigned
the structure of the diastereoisomer 20.
However, the separation of the isomers 3 and 20 proved to be rather difficult due
to small differences in Rf. Earlier in the synthesis, we observed that the corresponding
monosaccharides related to urdamycinone B were more easily separable. Thus, the
diastereomeric mixture of the silyl fluorides 11 was oxidatively desilylated. Column
chromatography on silica gel of the crude product with a gradient elution (CH2Cl2/
MeOH 95:5–93:7) afforded the diastereomer 21a corresponding to the natural
configuration (23%) and the non-natural isomer 21b (21%), both as faint yellow
resins (Scheme 2). The less polar fraction was irradiated with sunlight to afford
urdamycinone B (2), identical in all data to the natural product.[4,5,16]
The natural isomer 21a was then transformed via 22 and 23 into the diacetate 24,
employing the three step protection procedure described for 12 (67%). The mono-
alcohol 24 was then glycosylated using L-rhodinal benzoate 16 and scandium triflate as
promotor in analogy to the conversion of 15 into 17 to afford the disaccharide 25 (85%
yield at 77% conversion) as a yellow resin and the starting monoglycoside 24. Zemple´n
deacylation gave the pure diastereoisomer 19a that was photooxidized to antibiotic 100-
1 (3) as described above. Interestingly, the formation of the monoacetate 26 was

584
Krohn, Agocs, and Ba¨uerlein
Scheme 2. a) THF/MeOH, KHCO3, KF, H2O2 (60%), TLC separation. b–d) Steps f–h of Scheme
1 (67% for three steps). e) Sc(OTf)3/CH2Cl2 (85% yield at 77% conversion). f) NaOMe/MeOH
g) O2/hn, methanol.
observed depending on the duration of the Zemple´n saponification procedure. This
compound would be ideally suited for further attachment of deoxysugars, for instance
employing the selective a-glycoside synthesis using 2-deoxyglycosyl phosphates as
proposed by Hashimoto[32] and recently employed by Sulikowski et al.[33]
In summary, the regioselective NBS bromination of the tetraacetate 7 allowed the
large-scale preparation of the quinoid D-olivose-C-glycoside 8. The aglycone was
constructed by Diels–Alder reaction and the stereoselective a-L-rhodinose-O-glycoside
by using monoalcohol 15 and L-benzoylrhodinal (16) and scandium triflate as the
promotor. The separation of the diastereomers was more easily performed with the
mono-C-glycoside 21a/21b than with the disaccharides 3/20.
EXPERIMENTAL
General remarks and instrumentation. Silica gel 60 F254 coated plates from
Merck AG Darmstadt were used for TLC. Spots were detected by UV light (l = 254
and 366 nm), spraying and heating with 8% ethanolic sulfuric acid or the ce-
rium(IV)molybdato phosphoric acid reagent (Merck AG). Preparative LC was
performed using silica gel plates (1 mm) from Macherey and Nagel. Melting points
were recorded with a Gallenkamp Melting Point apparatus (uncorrected); IR spectra:
NICOLET 510 P; optical rotations: Perkin–Elmer polarimeter 241 (589 nm); elemental
analyses: Perkin–Elmer Elementar Analysator 240; mass spectra: FINNEGAN MAT
8200 and FISON MD 800, relative intensities in brackets; NMR spectra: Bruker ARX
200 (200/50 MHz) and Bruker AMX 300 (300/75 MHz) spectrometer.

Synthesis of Angucyclines. XVII
585
1,5-Diacetoxy-2-(3,4-di-O-acetyl-2,6-dideoxy- -D-arabino-hexopyranosyl)-naph-
thalene (7). A solution of 1,5-dihydroxynaphthalene 5 (2.6 g, 16.3 mmol) and
D-olivose triacetate (6) (2.7 g, 10.1 mmol) in dry acetonitrile (60 mL) was treated
dropwise at 0°C under argon with a solution of BF3 OEt2 (2.7 mL) in acetonitrile (10
mL). After 40 min (TLC monitoring), the reaction was quenched by addition of dry
pyridine (20 mL) and acetic anhydride (9.8 mL, 100 mmol) and the solution was kept
overnight at room temperature. The reaction mixture was then diluted with ethyl acetate
(200 mL), washed with water (3 ꢁ 20 mL), 1 M HCl (15 mL) and saturated aqueous
NaHCO3 (2 ꢁ 10 mL). The organic phase was dried (Na2SO4), filtered, concentrated
at reduced pressure and the residue purified by column chromatography on silica gel
(hexane: ethyl acetate 6:4) to afford the C-glycoside 7 as a white foam (1.95 g, 43%).
Crystallization from diethyl ether/pentane afforded colorless needles, mp 186–187°C.
20
1
[a]D = 12.8 (c 0.53, CH2Cl2). H NMR: d = 1.28 (d, J5’,6’ = 6.1 Hz, 3H, 6’-H), 1.61–
2.78 (m, 2H, 2’-Hax, 2’-Hequ), 2.03, 2.09, 2.22, 2.46 (4s, 12H, OAc), 3.60–3.84 (m, 1H,
5’-H), 4.74 (d, J1’,2’ax = 10.5 Hz, 1H, 1’-H), 4.88 (pt, J = 9.4 Hz, 1H, 4’-H), 5.09–5.25
(m, 1H, 3’-H), 7.20–7.31, 7.48–7.60, 7.68–7.73, 7.80–7.91 (4m, 5H, aromatic). 13C
NMR: d = 18.4 (C-6’), 21.0, 21.3 (OAc), 37.6 (C-2’), 72.5, 72.9, 75.0 (C-1’, C-3’, C-4’,
C-5’), 119.3, 119.9, 120.4, 124.8, 126.9 (5 aromatic), 128.0, 128.6, 130.2, 143.6, 147.2
(5 aromatic), 169.5, 169.6, 170.6, 170.8 (4 OAc). MS (70 eV): m/z = 458.5.
Anal. Calcd for C24H26O9: C, 62.88; H, 5.72. Found: C, 62.80; H, 5.78.
5-Acetoxy-6-(3,4-di-O-acetyl-2,6-dideoxy- -D-arabino-hexopyranosyl)-2-bromo-
[1,4]naphthoquinone (8). A solution of NBS (1.5 g, 18 mmol) in a mixture of
water (50 mL) and acetic acid (25 mL) was heated to 55–60°C. A warm solution of
3 (1.1 g, 2.4 mmol) in acetic acid (25 mL) was then added dropwise to the NBS
solution within 15 min at 60°C. After 45 min, the suspension was poured into ice–
water (300 mL) and the mixture was extracted with CH2Cl2 (3 ꢁ 180 mL). The
organic phase was washed with saturated aqueous NaHCO3 (2 ꢁ 100 mL), water
(150 mL), dried (Na2SO4), filtered, and concentrated at reduced pressure. The residue
was purified by filtration through a short column of silica gel (hexane: ethyl acetate
6:4) to afford the bromoquinone 8 (1.05 g, 86%) as a yellow foam. 1H NMR:
d = 1.28 (d, J5’,6’ = 6.2 Hz, 3H, 6’-H), 1.55–1.79 (m, 1H, 2’a-H), 2.02, 2.08, (2s, 6H,
OAc), 2.44–2.59 (m, 1 H, 2’b-H), 2.47 (s, 3 H, OAc), 3.62–3.73 (m, 1H, 5’-H), 4.78
(m, 1H, 1’-H), 4.88 (pt, J = 9.4 Hz, J = 9.6 Hz, 1H, 4’-H), 5.05–5.18 (m, 1H, 3’-H),
7.36 (s, 1H, 3-H), 7.98, 8.14 (2d, J7,8 = 8.1 Hz, 7-H, 8-H). 13C NMR: d = 18.4 (C-
6’), 21.29, 21.48 (OAc), 37.65 (C-2’), 72.03, 72.22, 74.46, 75.07 (C-1’, C-3’, C-4’, C-
5’), 123.1 (C-8a), 126.8 (C-8), 132.0 (C-4a), 132.9 (C-7), 138.9 (C-2), 141.9 (C-3),
142.2, 146.6 (C-5, C-6), 169.4, 170.6, 170.9 (OAc), 177.7, 181.4 (C-1, C-4). (70
eV): m/z = 509.3 (M+).
Anal. Calcd for C22H21BrO9: C, 51.88; H, 4.16. Found: C, 51.75; H, 4.06.
Cycloadduct 10 and Anthraquinone 11. A solution of diene 9 (750 mg, 1.75
mmol) and bromoquinone 8 (900 mg, 1.75 mmol) in dry toluene (5 mL) was kept at
70°C for 6 h. After evaporation of the solvent, the labile orange-brown adduct was used
without purification for the next step. A small sample was purified by column
1
chromatography on silica gel (1% MeOH/CH2Cl2). H NMR of 10: d = 0.32, 0.33, 0.34
(3s, 6H, SiMe2), 0.78 (s, 3H, Me), 0.94–1.20 (m, 1H), 1.28 (d, J5’,6’ = 6.1 Hz, 3H, 6’-

586
Krohn, Agocs, and Ba¨uerlein
H), 1.63–1.76 (m, 3H), 1.92–2.08 (m, 2H), 2.02, 2.08 (2s, OAc), 2.34–2.64 (m, 3H),
2.44 (m, OAc), 2.73–2.78 (m, 1H, 12b-H), 3.56–3.67 (m, 2H, 6a-H, 5’-H), 4.67–4.72
(m, 1H, 1’-H), 4.85 (t, J = 9.5 Hz, 1H, 4’-H), 5.06–5.19 (m, 1H, 3’-H), 7.32–7.35 (m,
3H, Ph), 7.43–7.53 (m, 2H, Ph), 7.90–8.01 (m, 1H, 10-H or 11-H), 8.05–8.10 (m, 1H,
10-H or 11-H).
Silyl fluoride 12. A solution of the crude Diels–Alder adduct in dry methanol
(30 mL) was treated with K2CO3 (6.0 g) and the suspension was stirred overnight.
After filtration and solvent evaporation, the residue was dissolved in CH2Cl2 (200 mL)
and washed with brine (2 ꢁ 10 mL). The organic phase was dried (Na2SO4), filtered,
concentrated at reduced pressure and the residue purified by column chromatography
on silica gel (4% MeOH/CH2Cl2) to afford an orange solid 11 (755 mg, 76%). The
spectral data were in agreement with those published by Toshima et al.[16] 13C NMR:
d = ꢂ6.0, ꢂ5.9 (SiMe2), 18.6 (C-6’), 18.9 (C-3), 19.6, 19.6 (Me), 25.2 (C-1), 29.8 (C-
2’), 38.7 (C-2), 40.3 (C-4), 71.6, 73.5, 76.4, 78.4 (C-1’, C-3’, C-4’, C-5’), 115.4, 119.7,
125.0, 128.0, 129.5, 131.2, 133.1, 133.6, 134.2, 134.9, 135.7, 136.5, 137.0, 141.7,
146.1, 151.4 (aromatic), 185.2, 189.6 (C-7, C-12).
Anal. Calcd for C33H36O6Si: C, 71.19; H, 6.52. Found: C, 71.50; H, 6.58.
Fluoride 12. A solution of the silane 11 (750 mg, 1.3 mmol) in dichloromethane
was treated with HBF4 Et2O as described in the literature[16,24,28] to afford the fluoride
12 (390 mg, 60%). The spectral data were identical to those reported.[16] 13C NMR:
d = ꢂ 4.3, ꢂ 4.0–4.04, ꢂ 3.7 (SiMe2), 18.6, 19.5, 19.6 (Me, C-6’), 19.9 (C-3), 25.3,
29.5, 38.6, 39.9 (C-1, C-2, C-4, C-2’), 71.6, 73.5, 76.4, 78.4 (C-1’, C-3’, C-4’, C-5’),
115.4, 119.7, 125.3, 125.8, 129.5, 131.3, 133.3, 133.6, 134.2, 135.6, 136.6, 137.5,
141.4, 145.3 (aromatic), 158.4 (OAc), 185.2, 189.5 (C-7, C-12).
Anal. Calcd for C27H31FO6Si: C, 65.04; H, 6.27. Found: C, 65.27; H, 6.23.
TBDMS–Ether 13. A solution of the C-glycoside 12 (350 mg, 0.7 mmol),
imidazole (250 mg, 3.5 mmol) and TBDMSCl (270 mg, 2 mmol) in dry DMF (2.5 mL)
was kept under argon for 3 h at room temperature. The reaction mixture was then
poured into water (50 mL) and extracted with diethyl ether (3 ꢁ 50 mL). The
combined organic phase was washed with water (10 mL), dried (Na2SO4), filtered, and
concentrated at reduced pressure. The crude silyl ether 13 was used in the next
1
reaction. H NMR for 13: d = 0.11, 0.15 (2s, 6H, TBDMS), 0.22 (d, JF,SiMe = 8.1 Hz,
3H, SiMe), 0.26 (d, JF,SiMe = 7.9 Hz, 3H, SiMe), 0.90 (s, 9H, C(CH3)3), 1.03 (s, 3H,
Me), 1.41 (d, J5’,6’ = 6.0 Hz, 3H, 6’-H), 1.56–1.92 (m, 3H, 2-H, 2’-Hax), 2.33–2.42 (m,
2H, 2’-Hequ, OH), 2.62 (d, Jgem = 17.4 Hz, 1H, 4-Ha), 3.10 (d, Jgem = 17.4 Hz, 1H, 4-
Hb), 3.17–3.24 (m, 1 H, 4’-H), 3.43–3.46 (m, 2H, 1-H), 3.51–3.64 (m, 1H, 3’-H),
3.75–3.87 (m, 1H, 5’-H), 4.92 (d, J1’,2’ax = 10.8 Hz, 1H, 1’-H), 7.48 (d, J = 8.0 Hz,
1H), 7.74 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 7.9 Hz, 1H), 8.16 (d, J = 7.9 Hz, 1H), 12.92
(s, 1H, OH).
Diacetate 14. A solution of the monosilyl ether 13 in dry pyridine (15 mL) was
treated with Ac2O (1 mL) and stirred overnight at 20°C. The reaction mixture was
diluted with ethyl acetate (100 mL) and washed with 1 M HCl (2 ꢁ 10 mL) followed by
saturated aqueous NaHCO3 (2 ꢁ 10 mL). The organic phase was dried (Na2SO4),

Synthesis of Angucyclines. XVII
587
filtered, concentrated at reduced pressure and the residue 14 was used without purifi-
cation in the next step. 1H NMR for 14: d = 0.10 (s, 6H, TBDMS), 0.21 (d, JF,SiMe = 8.1
Hz, 3H, SiMe), 0.25 (d, JF,SiMe = 8.0 Hz, 3H, SiMe), 0.85 (s, 9H, C(CH3)3), 1.02 (s, 3H,
Me), 1.29 (d, J5’,6’ = 6.2 Hz, 3H, 6’-H), 1.60–1.92 (m, 3H, 2-H, 2’-Hax), 2.11 (s, 3H,
OAc), 2.22–2.37 (m, 1H, 2’-Hequ), 2.51 (s, 3H, OAc), 2.60 (d, Jgem = 17.0 Hz, 1H, 4-
Ha), 3.08 (d, Jgem = 17.0 Hz, 1H, 4-Hb), 3.41–3.44 (m, 2H, 1-H), 3.52–3.64, 4.20–4.24
(2m, 2H, 3’-H, 5’-H), 4.64–4.79 (m, 2H, 1’-H, 4’-H), 7.46 (d, J = 8.0 Hz, 1H), 7.99 (d,
J = 8.2 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 8.20 (d, J = 8.2 Hz, 1H).
Alcohol 15. Hydrogen fluoride (0.2 mL, 40% in water) was added to the solution
of TBDMS ether 14 in CH3CN (7 mL). After stirring for 5 h at 20°C (TLC
monitoring), the reaction was quenched by addition of saturated aqueous NaHCO3 (10
mL) and extracted with diethyl ether (3 ꢁ 50 mL). The organic phase was dried
(Na2SO4), filtered, concentrated at reduced pressure and the residue purified by column
chromatography on silica gel (3% MeOH/CH2Cl2) to afford 15 (310 mg, 76%) as an
1
orange resin. H NMR: d = 0.21 (d, JF,SiMe = 8.1 Hz, 3H, SiMe), 0.25 (d, JF,SiMe = 8.0
Hz, 3H, SiMe), 1.02 (s, 3H, Me), 1.29 (d, J5’,6’ = 6.2 Hz, 3H, 6’-H), 1.56–1.96 (m, 3H,
2-H, 2’-Hax), 2.16 (s, 3H, OAc), 2.25–2.63 (m, 2H, 4-Ha, 2’-Hequ), 2.51 (s, 3H, OAc),
3.07 (d, Jgem = 17.3 Hz, 1H, 4-Hb), 3.40–3.43 (m, 2H, 1-H), 3.57–3.73, 3.83–3.96
(2m, 2H, 3’-H, 5’-H), 4.56–4.71 (m, 2H, 1’-H, 4’-H), 7.46 (d, J = 8.0 Hz, 1H), 7.57 (d,
J = 8.2 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 8.20 (d, J = 8.2 Hz, 1H). 13C NMR:
d = ꢂ4.3, ꢂ4.0, ꢂ3.7 (SiMe2), 18.5, 19.5 (Me, C-6’), 20.0 (C-3), 21.5, 21.7 (OAc),
25.0, 29.5, 38.4, 41.1 (C-1, C-2, C-4, C-2’), 71.9, 72.3, 74.6, 79.1 (C-1’, C-3’, C-4’, C-
5’), 124.1, 125.6, 126.2, 130.5, 132.6, 134.6, 135.8, 135.4, 140.6, 140.9, 144.1, 146.2
(aromatic), 169.6. 172.3 (OAc), 182.9, 185.1 (C-7, C-12).
Anal. Calcd for C31H35FO8Si: C, 63.90; H, 6.05. Found: C, 64.02; H, 6.13.
Disaccharide 17. A solution of C-glycoside 15 (150 mg, 0.25 mmol) and 4-O-
benzoyl-L-rhodinal (16)[23] (80 mg, 0.38 mmol) in dry CH2Cl2 (3 mL) was treated at
0°C with Sc(OTf)3 (10 mg, 0.02 mmol) and the mixture was stirred for 1 h. The
reaction was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with
CH2Cl2 (2 ꢁ 50 mL). The organic phase was dried (Na2SO4), filtered, concentrated at
reduced pressure and the residue purified by column chromatography on silica gel (1%
MeOH/CH2Cl2) to yield the disaccharide 17 (104 mg, 52% yield; 72% at 70%
1
conversion) as a yellow resin, and the starting material, C-glycoside 15 (45 mg). H
NMR: d = 0.25 (d, JF,SiMe = 8.0 Hz, 3H, SiMe), 0.29 (d, JF,SiMe = 8.0 Hz, 3H, SiMe),
1.06 (s, 3H, Me), 1.25–1.34 (m, 6H, 6’-H, 6@-H), 1.52–2.11 (m, 7H), 2.17 (s, 3H, OAc),
2.34–2.50 (m, 1H), 2.57 (s, 3H, OAc), 2.57–2.68 (m, 1H, 4-Ha), 3.11 (d, Jgem = 17.1
Hz, 1H, 4-Hb), 3.35–3.49 (m, 2H, 1-H), 3.64–3.72 (m, 1H, 3’-H), 4.01–4.17 (m, 2H,
5’-H, 5@-H), 4.72–4.74 (m, 1H, 4@-H), 4.91 (dd, J = 9.4 Hz, 1H, 1’-H), 5.01 (s, 2H, 4’-
H, 1@-H), 7.46–7.61 (m, 5 H), 8.00–8.16 (m, 3H), 8.24 (d, J = 8.2 Hz, 1H). 13C NMR:
d = ꢂ4.3, ꢂ4.0, ꢂ3.7 (SiMe2), 17.7 (C-6@), 18.5 (C-6’), 19.5 (CH3), 20.0 (C-3), 21.5,
21.8 (OAc), 23.3, 24.7, 25.4, 29.5, 37.4, 38.4 (C-1, C-2, C-4, C-2’, C-2@, C-3@), 65.9,
70.2, 72.2, 73.2, 75.1, 75.7, (C-1’, C-3’, C-4’, C-5’, C-4@, C-5@), 93.3 (C-1@), 124.1,
125.7, 126.2, 128.9, 130.1, 130.5, 130.7, 132.8, 133.5, 134.6, 135.8, 136.4, 140.6, 141.0,
144.2, 146.1 (aromatic), 166.5, 170.4 (OAc), 182.9, 185.1 (C-7, C-12).
Anal. Calcd for C44H49FO11Si: C, 65.98; H, 6.17. Found: C, 66.08; H, 6.12.

588
Krohn, Agocs, and Ba¨uerlein
Disaccharide 18. A solution of disaccharide 17 (50 mg, 0.06 mmol) in dry
methanol (5 mL) was treated with NaOMe (1 mL, 1 M in methanol) and kept for 20
h at 20°C. The solvent was removed under reduced pressure, the residue redissolved in
diethyl ether (30 mL) and the solution washed with 2% HCl (10 mL) and then brine
(10 mL). The organic phase was dried (Na2SO4), filtered, concentrated at reduced
pressure and the residue purified by column chromatography on silica gel (3% MeOH/
1
CH2Cl2) to afford the deacylated disaccharide 18 (33 mg, 87%) as a yellow solid. H
NMR: d = 0.16 (m, 6 H, SiMe2), 1.01 (s, 3H, Me), 1.29 and 1.40 (2d, 6H, 6’-H, 6@-H),
1.5–2.2 (m, 7H), 2.40–2.70 (m, 2H), 3.0–3.3 (m, 2H, 4-Ha, 4-Hb), 3.35–3.49 (m, 2H,
1-H), 3.65–3.80 (m, 3H, 3’-H, 5’-H, 5@-H), 4.20 and 4.42 (2m, 2H, 4’-H, 4@-H), 4.94 (d,
1H, J = 9.8 Hz, 1’-H), 5.06 (s, 1H, 1@-H), 7.52 (d, 1H, J = 8.1 Hz), 7.78 (d, 1H, J = 7.8
Hz), 7.92 (d, 1H, J = 7.8 Hz), 8.18 (d, 1H, J = 8.1 Hz), 12.96 (s, 1H, OH). 13C NMR:
d = ꢂ5.40, ꢂ5.25 (SiMe2), 17.5 (C-6@), 18.8 (C-6’), 19.4 (CH3), 20.1 (C-3), 24.6, 25.1,
25.9, 29.5, 37.9, 38.9 (C-1, C-2, C-4, C-2’, C-2@, C-3@), 67.6, 68.0, 70.9, 71.5, 76.5,
81.6 (C-1’, C-3’, C-4’, C-5’, C-4@, C-5@), 97.9 (C-1@), 115.4, 119.8, 125.1, 132.2, 133.7,
135.7, 136.7, 141.8, 146.1, 158.4 (aromatic) 185.1, 189.7 (C-7, C-12).
Anal. Calcd for C33H41FO8Si: C, 64.68; H, 6.74. Found: C, 64.52; H, 6.71.
Alcohol 19. From 18: A solution of the fluoride 18 (25 mg, 0.04 mmol) in a 1:1
mixture of THF and methanol (3 mL) was treated with KHCO3 (150 mg, 1.5 mmol),
KF (90 mg, 1.5 mmol) and hydrogen peroxide (0.3 mL, 35% in water, 2.7 mmol).[29]
The suspension was stirred for 24 h at room temperature and then quenched by addition
of aqueous saturated Na2S2O3 (5 mL) and extracted with ether (2 ꢁ 20 mL). The
organic phase was dried (Na2SO4), filtered, concentrated at reduced pressure and the
polar yellow product was used directly in the next reaction (photooxidation).
From 25: A solution of the disaccharide 25 (100 mg, 0.14 mmol) in dry methanol
(8 mL) was deacylated as described for 18 to yield 19 (52 mg, 70%) as a yellow resin.
1
MS: m/z = 552.0 (M+). H NMR for 19: d = 1.25 and 1.43 (2d, 6H, 6’-H, 6@-H), 1.51
(s, 3H, Me), 1.6–2.3 (m, 7H), 2.40–2.70 (m, 2H), 3.25 (m, 2H, 4-Ha, 4-Hb), 3.4–3.6
(m, 2H, 1-H), 3.65–3.90 (m, 3H, 3’-H, 5’-H, 5@-H), 4.15 and 4.45 (2m, 2H, 4’-H, 4@-H),
4.95 (d, 1H, J = 9.6 Hz, 1’-H), 5.07 (s, 1H, 1@-H), 7.52 (d, 1H, J = 8 Hz), 7.79 (d, 1H,
J = 8 Hz), 7.93 (d, 1H, J = 8 Hz), 8.22 (d, 1H, J = 8 Hz), 12.95 (s, 1H, OH).
Anal. Calcd for C31H36O9: C, 67.38; H, 6.57. Found: C, 67.46; H, 6.62.
Antibiotic 100-1 (3) and the diastereomer 20. A solution of the crude disac-
charide 19 from the oxidative desilylation reaction described above, in methanol (15
mL), was exposed to sunshine for 2 days, using NMR tubes as the reaction vessels.
After evaporation of the solvent, the reaction mixture was separated by preparative
TLC on silica (CH2Cl2/Et2O/MeOH 80:20:3) to give antibiotic 100-1 (3) (3.5 mg, 17%)
from the less polar fraction and 20 (3.5 mg, 17%) from the polar fraction, both yellow
solids. The less polar compound was identical in all respects with a sample kindly
provided by Prof. J. Rohr.[32]
NMR data of 3: 1H NMR: d = 1.25 and 1.38 (2d, 6H, 6’-H, 6@-H), 1.51 (s, 3H,
Me), 1.2–1.9 (m, 5H, 3’-H, 2@-H, 3@-H), 2.55 (m, 1H, 3’-H), 3.0–3.4 (m, 5H, 4-H, 2-H,
5’-H), 3.5–3.8 (m, 2H, 6’-H, 4@-H), 4.0 (m, 1H, 4’-H), 4.23 (m, 1H, 5@-H), 4.92 (d, 1H,
1’-H, J = 10.2 Hz), 5.04 (s, 1H, 1@-H), 7.60 (d, 1H, J = 8 Hz), 7.74 (d, 1H, J = 8 Hz),

Synthesis of Angucyclines. XVII
589
7.95 (d, 1H, J = 8 Hz), 8.36 (d, 1H, J = 8 Hz), 12.72 (s, 1H, OH). 13C NMR: d = 17.5
(C-6@), 18.8 (C-6’), 24.5, 26.2, 30.2, 38.1, 44.7, 54.4 (Me, C-2, C-4, C-2’, C-2@, C-3@),
67.6, 68.0, 71.4, 72.8, 76.7, 77.4 (C-1’, C-3’, C-4’, C-5’, C-4@, C-5@), 97.9 (C-1@), 116.0,
120.1, 129.8, 134.1, 134.3, 135.3, 137.0, 137.7, 150.2, 158.7 (aromatic) 183.6, 189.2
(C-7, C-12), 196.5 (C-1).
NMR data for diastereoisomer 20: 1H NMR: d = 1.25 and 1.38 (2d, 6H, 6’-H,
6@-H), 1.51 (s, 3H, Me), 1.2–1.9 (m, 5H, 3’-H, 2@-H, 3@-H), 2.55 (m, 1H, 3’-H), 3.0–
3.4 (m, 5H, 4-H, 2-H, 5’-H), 3.5–3.8 (m, 2H, 6’-H, 4@-H), 4.0 (m, 1H, 4’-H), 4.23 (m,
1H, 5@-H), 4.92 (d, 1H, 1’-H, J = 10.2 Hz), 5.04 (s, 1H, 1@-H), 7.60 (d, 1H, J = 8 Hz),
7.74 (d, 1H, J = 8 Hz), 7.95 (d, 1H, J = 8 Hz), 8.36 (d, 1H, J = 8 Hz), 12.72 (s, 1H,
OH). 13C NMR: d = 17.5 (C-6@), 18.8 (C-6’), 24.6, 26.4, 30.3, 38.1, 44.8, 54.2 (Me, C-
2, C-4, C-2’, C-2@, C-3@), 67.5, 68.1, 71.4, 72.9, 76.7, 77.5 (C-1’, C-3’, C-4’, C-5’, C-4@,
C-5@), 97.8 (C-1@), 116.2, 120.2, 129.8, 134.1, 134.3, 135.5, 137.0, 137.7, 150.2, 158.8
(aromatic) 183.4, 189.1 (C-7, C-12), 196.4 (C-1).
Alcohols 21a and 21b. The diastereomeric mixture of the silyl fluorides 11 (850
mg, 1.7 mmol) was oxidatively desilylated as described by Chan and Nwe[29] and
applied by Toshima et al. to urdamycinone B.[16] Column chromatography on silica gel
of the crude product with polarity gradient elution (CH2Cl2/MeOH 95:5–93:7) afforded
the diastereomer 21a corresponding to the natural configuration (170 mg, 23%) and the
non-natural isomer 21b (160 mg, 21%), both as yellow solids. For spectral data see
Ref. [16].
21a: MS: m/z = 438.2 (M+).
Anal. Calcd for C25H26O7: C, 68.48; H, 5.98. Found: C, 68.28; H, 6.02.
21b: MS: m/z = 438.2 (M+).
Anal. Calcd for C25H26O7: C, 68.48; H, 5.98. Found: C, 68.34; H, 6.05.
Diacetate 24. The natural isomer 21a (170 mg, 0.37 mmol) was transformed via
22 and 23 into the diacetate 24 employing the three step protection procedure described
for 12. After column chromatography (4% MeOH/CH2Cl2), 24 (130 mg, 67% for three
1
steps) was obtained as a yellow resin. MS: m/z = 522.1 (M+). H NMR: d = 1.32 (d,
J5’,6’ = 6.1 Hz, 3H, 6’-H), 1.41 (s, 3H, Me), 1.6–2.0 (m, 3H, 2-H, 2’-Hax), 2.2 (s, 3H,
OAc), 2.2–2.6 (m, 2H, 4-Ha, 2’-Hequ), 2.54 (s, 3H, OAc), 3.07 (d, Jgem = 17.3 Hz,
1H,), 3.4–3.7 (m, 4H, 1-H, 3’-H, 4-Hb), 3.9 (m, 1H, 5’-H), 4.5–4.8 (m, 2H, 1’-H, 4’-H),
7.46 (d, J = 8.0 Hz, 1H), 8.0 (d, J = 8.2 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 8.21 (d,
J = 8.2 Hz, 1H). 13C NMR: d = 18.5 (C-6’), 21.5, 21.7 (OAc), 29.1 (Me) 26.9, 36.1,
42.2, 45.1 (C-1, C-2, C-4, C-2’), 59.3 (C-3) 71.8, 72.26, 74.64, 79.1 (C-1’, C-3’, C-4’,
C-5’), 124.0, 125.9, 126.2, 129.4, 130.6, 134.7, 135.7, 136.0, 139.6, 140.9, 143.7, 146.2
(aromatic), 169.6, 172.4 (OAc), 182.8, 185.0 (C-7, C-12).
Anal. Calcd for C29H30O9: C, 66.66; H, 5.79. Found: C, 66.58; H 5.84.
Disaccharide 25. A solution of C-glycoside 24 (110 mg, 0.23 mmol) and 4-O-
benzoyl-L-rhodinal (16) (90 mg, 0.41 mmol) in dry CH2Cl2 (5 mL) was treated at 0°C
with Sc(OTf)3 (8 mg, 0.02 mmol). The mixture was stirred for 1 h and the reaction was
then quenched by addition of aqueous saturated NaHCO3 (50 mL) and extracted with
CH2Cl2 (2 ꢁ 50 mL). Column chromatography on silica gel (2% MeOH/CH2Cl2) gave

590
Krohn, Agocs, and Ba¨uerlein
the disaccharide 25 (102 mg, 60% yield, 85% at 77% conversion) as a yellow resin and
the monoglycoside 24. (25 mg). Data of 25: MS: m/z = 741 (M + H+). 1H NMR:
d = 1.2–1.3 (m, 6H, 6’-H, 6@-H), 1.42 (s, 3H, Me), 1.5–2.1 (m, 7H), 2.17 (s, 3H, OAc),
2.35–2.5 (m, 1H), 2.54 (s, 3H, OAc), 3.07 (d, Jgem = 17.3 Hz, 1H,), 3.4–3.75 (m, 4H,
1-H, 3’-H, 4-H), 4.0–4.25 (m, 2H, 5’-H, 5@-H) 4.72–4.74 (m, 1H, 4@-H), 4.88 (dd,
J = 9.4 Hz, 1H, 1’-H), 5.08 (s, 2H, 4’-H, 1@-H), 7.46–7.6 (m, 5H), 8.00–8.16 (m, 3H),
8.24 (d, J = 8.2 Hz, 1H). 13C NMR: d = 17.7 (C-6@) 18.5 (C-6’), 21.5, 21.7 (OAc), 29.7
(Me) 23.3, 24.7, 26.9, 36.2, 37.4, 45.2 (C-1, C-2, C-4, C-2’, C-2@, C-3@), 54.1 (C-3)
65.9, 70.2, 71.8, 72.2, 73.2, 75.1, 75.7 (C-1’, C-3’, C-4’, C-5’, C-4@, C-5@), 93.3 (C-1@)
124.1, 125.9, 126.2, 128.8, 130.1, 130.6, 133.5, 134.7, 135.7, 136.4, 139.7, 141.0,
143.7, 147.0 (aromatic), 166.5, 170.4 (OAc), 182.8, 185.0 (C-7, C-12), 203.6 (C O).
Anal. Calcd for C42H44O12: C 68.10, H 5.99; Found C: 68.15, H 5.93.
ACKNOWLEDGMENT
We thank Prof. Dr. J. Rohr, University of Kentucky, USA, for a sample of
authentic antibiotic 100-1.
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Received January 21, 2003
Accepted May 9, 2003