New chiral pool approach to anthracyclinones. The stereoselective synthesis of idarubicinone

Article abstract of DOI:10.1021/jo026354l

In the present work, a new chiral pool approach has been developed for the synthesis of anthracyclinones. Thus, enone 8, readily available from L-rhamnose, has been converted via addition of 2,5-dimethoxybenzyllithium to the carbonyl group and a series of six reactions into a suitably protected aldehyde 21. The SnCl₄-promoted stereospecific cyclization of the latter afforded enantiopure key intermediate 22. Silylation of benzylic hydroxyl of 21 followed by anodic oxidation and selective hydrolysis gave ketoacetals 25 and 26 to which 3-cyano-1(3H)-isobenzofuranone 27 was annelated. Removal of the isopropylidene group in the resulting 28, subsequent oxidation of the C₁₃ hydroxyl and full deprotection led to idarubicinone (4).

Full text of DOI:10.1021/jo026354l

New Ch ir a l P ool Ap p r oa ch to An th r a cyclin on es.
Th e Ster eoselective Syn th esis of Id a r u bicin on e
Osman Achmatowicz* and Barbara Szechner
Pharmaceutical Research Institute, 8 Rydygiera Str., 01-793 Warsaw, Poland
achosman@ifarm.waw.pl
Received August 26, 2002
In the present work, a new chiral pool approach has been developed for the synthesis of
anthracyclinones. Thus, enone 8, readily available from L-rhamnose, has been converted via addition
of 2,5-dimethoxybenzyllithium to the carbonyl group and a series of six reactions into a suitably
protected aldehyde 21. The SnCl4-promoted stereospecific cyclization of the latter afforded
enantiopure key intermediate 22. Silylation of benzylic hydroxyl of 21 followed by anodic oxidation
and selective hydrolysis gave ketoacetals 25 and 26 to which 3-cyano-1(3H)-isobenzofuranone 27
was annelated. Removal of the isopropylidene group in the resulting 28, subsequent oxidation of
the C13 hydroxyl and full deprotection led to idarubicinone (4).
In tr od u ction
activity than its naturally occurring analogues 1 and 2
and is a registered drug for cancer chemotherapy.7
Originally, idarubicin (3) was obtained by the demethox-
ylation of daunorubicin (2).8 In a search for more efficient
methods for its preparation, a considerable effort was
expanded in total syntheses, which focused on the
synthesis of the corresponding aglycone: idarubicinone
(4).9
Anthracycline antibiotics1 such as doxorubicin (1) and
daunorubicin (2) are among the most potent antitumor
agents, with proven clinical effectiveness against leuke-
mias, lymphomas, breast carcinomas, and sarcomas.2
Their importance in chemotherapy cytostatic activity has
stimulated an ongoing interest in the exploration of this
family of compounds.3
Their cardiotoxicity as well as intrinsic and acquired
resistance4 prompted continued search for analogues with
improved therapeutical properties.5 This has resulted in
the synthesis of many (more then 2000) nonnatural
anthracycline antibiotics, of which only a few reached the
status of a drug used in clinical application. One of them,
idarubicin (3),6 a 4-demethoxy analogue of daunorubicin
(2), exhibits lower toxicity and improved antineoplastic
(1) Brockman, H. Fortsch. Chem. Org. Naturst. 1963, 21, 121.
(2) Weis, R. B.; Savory, G.; Clagget-Carr, K.; Russo, M.; Leyland-
J ones, B. Cancer Chemother. Pharmacol. 1986, 18, 185. Weiss, R. B.
Semin. Oncol. 1992, 19, 670. Lown, J . W. Chem. Soc. Rev. 1993, 165.
Priebe, W. Anthracycline Antibiotics: New Analogues, Method of
Delivery, and Mechanisms of Action; ACS Symposium Series 574;
American Chemical Society: Washington, DC, 1995.
(3) Arcamone, F. The Development of New Antitumor Anthracy-
clines. In Anticancer Agents Based on Natural Products Models;
Cassady, J . M., Doves, J . D., Eds.; Academic Press: New York, 1980;
Vol. 16, pp 1-41. Lown, J . W., Ed. Anthracycline and Anthracenedione-
Based Anticancer Agents; Elsevier: Amsterdam, 1993.
Several methodologies for the synthesis of the aglycone
moiety of the anthracycline antibiotics have been devel-
oped.9,10 Among the strategies for assembling the tetra-
cyclic skeleton of the aglycone, a particularly effective and
(7) Ganzina, F.; Pacciarini, M. A.; Di Pietro, N. New Drugs 1986, 4,
85.
(8) Arcamone, F.; Bernardi, L.; Giardino, P.; Patelli, B.; DiMarco,
A.; Casazza, A. M.; Pratessi, G.; Reggiani, P. Cancer Treat. Rep. 1976,
60, 826.
(4) Beck, W. T. Biochem Pharmacol. 1987, 36, 2879. Keizer, H. G.;
Pinedo, H. M.; Schuurhuis, G. J .; J oenje, H. Pharmacol. Ther. 1990,
47, 219. Raghavan, D.; Koczwara, B,; J avle, M. Eur. J . Cancer 1997,
33, 566.
(5) Priebe, W. Curr. Drug Des. 1995, 1, 73. de Groot, F. M. H.; de
Bart, A. C. W.; Verheijen, J . H.; Scheeren, H. W. J . Med. Chem. 1999,
42, 5277. Kratz, F.; Mu¨ller-Driver, R.; Hofmann, I.; Dreves, J .; Unger,
C. J . Med. Chem. 2000, 43, 1253. Kunnari, T. J .; Ylihonko, K. P. J .;
Klika, K. D.; Ma¨ntsa¨la¨, P. I.; Hakala, J . M. L. J . Org. Chem. 2000, 65,
2851. Faderl, S.; Estrov, Z.; Kantarjian, H. M.; Harris, D.; Van, Q.;
Fokt, I.; Godlewski, C.; Przewloka, T.; Woynarowski, J . M.; Priebe, W.
Anticancer Res. 2000, 20, 1. Garsky, V. M.; Lumma, P. K.; Feng, D.-
M.; Wai, J .; Ramjit, H. G.; Sardana, M. K.; Oliff, A.; J ones, R. E.; DeFeo-
J ones, D.; Freidinger, R. M. J . Med. Chem. 2001, 4216.
(9) Thomas, G. J . Synthesis of Anthracyclines Related to Daunmy-
cin. In Recent Progress in the Chemical Synthesis of Anitbiotics; Lukacs,
G., Ohno, M., Eds.; Springer-Verlag: 1990. Wheeler, D. M. S.; Wheeler,
M. M. Stereoselective Syntheses of Doxorubicin and Related Com-
pounds. In Studies in Natural Products Chemistry; Atta-ur-Rahman,
Ed.; Elsevier: Amsterdam, 1994; Vol. 14, pp 3-46. Ruano, J . L. G.;
Paredes, C. G.; Hamdouchi, C. Tetrahedron: Asymmetry 1999, 10, 2935
and references therein.
(10) Krohn, K.; Ekkundt, V. S. Total Synthesis of Enantiomerically
Pure Anthracyclinones. In Studies in Natural Products Chemistry;
Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1989; Vol. 4, pp 317-
366. Krohn, K. Tetrahedron 1990, 46, 291.
(6) Cabri, W.; Bernardinis, S. D.; Francalanci, F.; Penco, S. J . J .
Chem. Soc., Perkin Trans. 1 1990, 428.
10.1021/jo026354l CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/20/2003
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J . Org. Chem. 2003, 68, 2398-2404

Stereoselective Synthesis of Idarubicinone
SCHEME 1
SCHEME 2
or from the R-side of the pyranoside ring (2,5-dimethoxy-
4-methylphenyllithium). Unexpectedly, in the case of 2,5-
dimethoxybenzyllithium, the reagent required in our
synthetic scheme, 1,4-addition decidedly prevailed over
1,2-addition to the carbonyl group.19 Moreover, the
product of both 1,4- and 1,2-addition resulted from the
R-side attack on the molecule. The tertiary alcohol was
produced not only in small yield but also with a (4R)-
configuration, not suitable for our synthesis.
To alleviate the adverse course of the reaction, i.e., to
eliminate the 1,4-addition of lithium reagent and reverse
its stereochemistry, we decided first to protect the double
bond in enone 8 by introduction of a benzyloxy substitu-
ent R to the C-2 position. Treatment of enone 8 with an
excess of benzyl alcohol in the presence of potassium
carbonate gave ketone 9. The addition should occur on
the face trans to the anomeric substituent.20 The expected
configuration at C-2 of the ketone 9 was consistent with
1H NMR data and was unequivocally confirmed at the
next step of the synthesis by single-crystal X-ray analysis
(vide infra) of its derivative. The introduction of the
benzyloxy substituent at C-2 served yet another pur-
pose: activation of the C-1-C-2 bond for future scission.
Tetr a lin e 22. Reaction of 2,5-dimethoxybenzyllithium,
prepared by the reductive lithiation of 2,5-dimethoxy-
benzyl ethyl ether,21 with ketone 9 in THF-toluene
solution at -70 °C, resulted in a single adduct 10 isolated
in 63% yield1 (Scheme 3).
versatile approach is based on the coupling of its AB and
CD ring segments.11 Since the two stereogenic centers of
an anthracycline are located in ring A, an enantiopure
AB-ring building block with a defined configuration is
required for the synthesis of the chiral target molecule.
Use of this methodology has allowed several syntheses
of daunomycinone and idarubicinone (4) to be accom-
plished. For this purpose, chiral AB fragments have been
obtained by various methods, including resolution of a
racemic precursor, asymmetric synthesis using a chiral
auxiliary or a chiral catalyst, and a chiral pool approach.
In the latter approach, substrates derived from R-amino12
and R-hydroxy acids,13 glycerol-related compounds14 and
sugars15,16 were employed.
In this contribution, we describe the stereoselective
synthesis of (+)-(7S,9S)-idarubicinone (4) using L-rham-
nose as a chiral starting material. Our strategy is
outlined in Scheme 1.
Resu lts a n d Discu ssion
Keton e 9. Di-O-acetylrhamnal (5), obtained from
L-rhamnose or commercial sources, was converted into
the known benzyl glycoside 717 according to the Ferrier
procedure.18 Oxidation of the C-4 hydroxy group in the
latter with pyridinium dichromate gave enone 8 in 67%
overall yield (Scheme 2).
In a previous study, we found that lithium reagents
add to the carbonyl group of an enone, analogous to 8
but with a methyl instead of a benzyl aglycone, either
with low stereoselectivity (butyllithium, benzyllithium)
In the next step, the O-benzyl substituents at C-1 and
C-2 of the alcohol 10 were removed by catalytic hydro-
genation, yielding pyranose 11 and setting the stage for
the oxidative cleavage of the C-1-C-2 bond. Since the
stereochemistry of the newly formed stereogenic center
at C-4 in alcohol 10 (or 11) could not be assigned in a
1
(11) Krohn, K., Building Blocks for the Total Synthesis of Anthra-
cyclinones, Prog. Chem. Org. Nat. Prod. 1989, 55, 1.
straightforward manner from the H NMR spectrum, its
configuration was established by single-crystal X-ray
analysis. To this end, compound 11, which like 10 could
not be induced to crystallize, was reacted with 2,3-
dimethoxypropane in the presence of p-toluenesulfonic
acid. The resulting two-component mixture was sepa-
rated to give a major (55%) product, crystalline 1,2-O-
isopropylidene derivative 12. The minor (14%) product
was identified as the isomeric 1,2-O-isopropylidene de-
rivative 13 with a furanose ring. The latter structural
(12) Krohn, K.; Hamann, I. Liebigs Ann. Chem. 1988, 949.
(13) Krohn, K.; Muller, H. Tetrahedron 1986, 42, 6635. Krohn, K.;
Rieger, H. Liebigs Ann. Chem. 1987, 515. Krohn, K.; Rieger, H.; Broser,
E.; Schiess, P.; Chen, S.; Strubin, T. Liebigs Ann. Chem. 1988, 943.
(14) Watanabe, N.; Ohta, H. Chem. Lett. 1992, 661.
(15) Gupta, R. C.; Harland, P. A.; Stoodley, R. J . Tetrahedron 1984,
40, 4657. Anne, A.; Bennani, F.; Florent, J .-C.; Moiroux, J .; Monneret,
C. Tetrahedron Lett. 1985, 2641. Florent, J .-C.; Gnot, A.; Monneret,
C. Tetrahedron Lett. 1985, 26, 5295. Quereshi, S.; Shaw, G. J . Chem.
Soc., Perkin Trans. 1 1985, 875. Querreshi, S.; Shaw, G.; Burges, G.
J . J . Chem. Soc., Perkin Trans. 1 1985, 1557. Krohn, K.; Broser, F.;
Heins, H. Carbohydr. Res. 1987, 164, 59. Monneret, C.; Florent, J .-C.
Synlett 1994, 305. Monneret, C. Ann. Pharm. Fr. 1997, 55, 5.
(16) Genot, A.; Florent, J .-C.; Monneret, C. J . Org. Chem. 1987, 52,
1057. Genot, A.; Florent, J .-C.; Monneret, C. Tetrahedron Lett. 1989,
30, 711. Dequin, B.; Florent, J .-C.; Monneret, C. J . Org. Chem. 1991,
56, 411.
(19) Achmatowicz, O.; Szechner, B.; Maurin, J . K. Tetrahedron 1997,
53, 6053.
(20) Paulsen, H.; Koebernick, W.; Koebernick, H. Tetrahedron Lett.
1976, 2297. Grynkiewicz, G.; Achmatowicz, O.; Barton´, H. Roczniki
Chem. 1977, 51, 1663. Yunker, M. B.; Plaumann, D. E.; Fraser-Reid,
B. Can. J . Chem. 1977, 55, 4002.
(17) El Khadem, H. S.; Cermak, R. Carbohydr. Res. 1979, 75, 335.
Banaszek, A.; Pakulski, Z.; Zamojski, A. Carbohydr. Res. 1995, 279,
173.
(21) Gilman, H.; Schwebke, G. L. J . Org. Chem. 1962, 27, 4259.
Maercker, A. Angew. Chem., Int. Ed. Engl. 1987, 26, 927.
(18) Ferrier, R. J .; Prasad, N. J . Chem. Soc., C 1969, 575.
J . Org. Chem, Vol. 68, No. 6, 2003 2399

Achmatowicz and Szechner
SCHEME 3 a
SCHEME 4
a
Side products 2,5-dimethoxytoluene and 1,2-bis(2,5-dimethoxy-
phenyl)ethane were identified in this reaction. They were readily
separated from alcohol 10 by silica gel chromatography.
assignment is based on the 1H NMR spectra of furanoside
13 and its oxidation product, ketone 14 (Scheme 3).
methanolysis. Oxidation of 19 with iodoxybenzoic acid
(IBX)22 gave aldehyde 21.
The isopropylidene derivative of dihydroxyaldehyde,
structurally similar to 21 but lacking a methyl group in
the side chain, was readily cyclized16 with high stereo-
selectivity. In our case, the use of isopropylidene as a
protecting group also facilitated cyclization. Treatment
of aldehyde 21 with tin tetrachloride at -70 °C gave a
high yield of bicyclic alcohol 22, as a single isolated
product. The (S)-configuration of the new stereogenic
center, consistent with the rationale advanced by
Monneret,16 as well as the stereochemistry of remaining
chiral centers present in tetraline 22 was firmly estab-
lished by single-crystal X-ray analysis (see Supporting
Information).
Id a r u bicin on e (4). Having in hand the AB building
block of an anthracyclinone with the correct absolute
stereochemistry corresponding to the (7S,9S)-configura-
tion of the target molecule 4, we chose to assemble its
tetracyclic skeleton by the Kraus addition cyclization
method.23 This procedure of CD-segment annelation,
requiring mild conditions to preclude the loss of stereo-
chemical integrity in the chiral AB segment, has been
successfully used before for regiospecific anthracyclinone
syntheses.16,24
Protection of the benzylic hydroxyl group of 23 wih
TBDPS followed by anodic oxidation25 in MeOH solution
of the aromatic ring afforded the resulting bisketal 24,
which was regioselectively hydrolyzed yielding keto-
acetals 25 and 26 in a ratio of approximately 10:1
(Scheme 6). For the synhesis of idarubicinone (4), where
the problem of a substituent at C-4 does not exist,
the presence of the minor regioisomer 26 is of no
consequence. However, it could be easily removed by
chromatography or crystallization.
Recrystallization of compound 12 from ether-hexane
afforded crystals suitable for X-ray analysis (see Sup-
porting Information), which established the (2S,4S)-
configuration and confirmed the expected steric course
of the two additions: benzyl alcohol to the double bond
in enone 8 and 2,5-dimethoxybenzyllithium to the car-
bonyl group in ketone 9. It was gratifying to find that
the stereogenic center at C-4 in 12 (or 11) has the same
configuration as the C-9 center in the idarubicinone (4)
as well as in other anthracyclinones into which it shall
be converted in the course of the synthesis.
Oxidative scission with sodium periodate of the C-1-
C-2 bond in pyranose 11 furnished dihydroxyaldehyde
15, an immediate precursor of the AB fragment of the
target anthracyclinone. However, all our attempts to
carry out cyclization of aldehyde 15 under Friedel-Crafts
reaction conditions resulted in the migration of the formyl
group to the tertiary hydroxyl with concomitant forma-
tion of the stable cyclic hemiacetal 17, instead of forma-
tion of the carbocyclic ring A. An obvious possibility of
suppressing the formation of the hemiacetal 17 was to
use aldehyde 15 with a protected tertiary hydroxy group.
The 4-O-TBDMS derivative of alcohol 10 was converted
as above to silyl ether 16. Unfortunately, all attempts to
cyclize compound 16 failed.
No reaction was observed either at low temperature
(between -70 and -40 °C) in the presence of tin
tetrachloride or on prolonged (>12 h) standing at room
temperature. The use of other Lewis acids (TiCl4, BF3,
AlCl3) led to the decomposition of the starting material.
Since the search for appropriate conditions for the
direct cyclization of aldehyde 15 or 16 did not look
promising, we followed the example of Monneret et
al.16 and switched the protective groups of the tertiary
and secondary hydroxyls from TBDMS and formyl,
respectively, to an isopropylidene group. This could be
achieved only in a stepwise fashion. Reduction of alde-
hyde 15 with sodium borohydride gave triol 18, which
on treatment with 2,3-dimethoxypropane under acidic
conditions yielded isopropylidene derivative 19. Mixed
acetal 20 arising in the reaction as a side product could
be easily converted without isolation into 19 by acidic
The annelation of the 3-cyano-1(3H)-isobenzofuranone
27 to the ketoacetal 25 gave tetracyclic compound 28.
(22) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019.
Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J . Org.
Chem. 1995, 60, 7272.
(23) Kraus, G. A.; Sugimoti, P. G. Tetrahedron Lett. 1978, 2263.
(24) Chenard, B. L.; Dolson, M. G.; Sercel, A. D.; Swenton, J . S. J .
Org. Chem. 1984, 49, 318. Swenton, J . S.; Freskos, J . N.; Morrow, G.
W.; Sercel, A. D. Tetrahedron 1984, 40, 4625. Freskos, J . N.; Morrow,
G. W.; Swenton, J . S. J . Org. Chem. 1985, 50, 805.
(25) Henton, D.; McCreery, R.; Swenton, J . S. J . Org. Chem. 1980,
45, 369.
2400 J . Org. Chem., Vol. 68, No. 6, 2003

Stereoselective Synthesis of Idarubicinone
SCHEME 5
SCHEME 6
Three protecting groups still present in ketone 31 were
removed in two steps according to well-known proce-
dures.24 First, the C-12 methoxy group was cleaved with
the aid of boron trichloride to give 32, and then acetate
and silyl groups were removed by acidic methanolysis.
The order of these reactions could be reversed, but using
boron trichloride cleavage as the last step causes puri-
fication problems due to complexation of idarubicinone
(4) with boron.24 Idarubicinone (4) of high (>99% by
HPLC) purity was obtained in 72.5% yield (calculated on
the annelation product 28).
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points were determined in
capillary tubes and are uncorrected. 1H NMR spectra were
recorded in CDCl3 at 200 MHz using TMS as an internal
reference. IR spectra were recorded for CHCl3 solutions with
an FTIR spectrophotometer. MS and HRMS were obtained by
EI or liquid secondary ionization mass spectrometry (LSIMS).
Chromatography refers to column chromatography on Merck
Kieselgel 60 (230-400 mesh). Thin-layer chromatography was
performed using precoated aluminum plates (Merck Kieselgel
60 F254) and visualized with UV light or acidic molybdate(IV)-
cerium sulfate reagent.
SCHEME 7
Where appropriate, reactions were carried out in oven-dried
glassware (120 °C, 3 h) under an Ar atmosphere. Dry solvents
were prepared using standard procedures.
Ben zyl 4-O-Acetyl-2,3,6-tr id eoxy-r-L-er yth r o-h ex-2-en o-
p yr a n osid e (6). A solution of boron trifluoride etherate (11.5
g, 0.08 mol) in methylene dichloride (25 mL) was added
dropwise to a cooled (5 °C) solution of 3,4-di-O-acetyl-L-
rhamnal (5, 107 g, 0.5 mol) and benzyl alcohol (62.7 g, 60 mL,
0.58 mol) in benzene (500 mL) at a rate such that the
temperature did not exceed 10 °C. After completion of addition,
the reaction mixture was stirred for 1 h at 5-10 °C and then
poured into a saturated solution of sodium bicarbonate (500
mL). The organic layer was washed with water and brine and
dried. After evaporation of the solvent, the residue was
distilled at 118 °C/0.05 Torr to give 116.5 g (88.8%) of product
6 as a pale yellow oil.
Ben zyl 2,3,6-Tr id eoxy-r-L-h ex-2-en op yr a n osid -4-u lose
(8). To a solution of benzyl 4-O-acetyl-2,3,6-trideoxy-R-L-
erythro-hex-2-enopyranoside (6, 44.2 g, 0.17 mol) in methanol
(300 mL) was added a small amount of sodium, and the
solution was left at room temperature for 3 h. It was then
neutralized with a few drops of acetic acid, evaporated to
Selective hydrolysis of isopropylidene group in 28 fol-
lowed by oxidation of the secondary hydroxyl group with
IBX22 gave protected idarubicinone (4). However, better
yields were achieved when, prior to the hydrolysis and
oxidation steps, the phenolic hydroxyl group was pro-
tected as its acetate 29. Then, hydrolysis of the dioxolane
ring and oxidation of triol 30 gave ketone 31 with all the
functional groups of idarubicinone (4) in place (Scheme
7). It should be mentioned that the diol 30 has a
structure, including the defined (13S)-configuration,
identical with that assigned to the aglycon of the metabo-
lite or microbial reduction product of idarubicine (3).26
(26) Cassinelli, G.; Grein, A.; Merli, S.; Penco, S.; Rivola, G.;
Vigevani, A.; Zini, P.; Arcamone, F. Gazz. Chim. Ital. 1984, 114, 1984.
Broadhurst, M. J .; Hassall, C. H.; Thomas, G. J . Tetrahedron Lett.
1984, 25, 6059.
J . Org. Chem, Vol. 68, No. 6, 2003 2401

Achmatowicz and Szechner
dryness, and coevaporated with toluene (2 × 100 mL). The
residue was dissolved in DMF (450 mL) and pyridinium
dichromate (122 g, mol), and powdered 4Å molecular sieves
(40 g) were added; the reaction mixture was stirred overnight,
diluted with ethyl acetate (300 mL), washed thoroughly with
water and then with brine, and dried. After evaporation of the
solvent the residue was distilled at 105-115 °C/0.05 Torr to
give 28.1 g (76.5%) of product 8, which contained (HPLC) 8%
â-anomer.
An analytical sample was chromatographed to give pure 8,
bp 90 °C/0.02 Torr, [R]D +29.16 (c 1, CHCl3). 1H NMR: δ 7.4-
7.3 (m, 5H); 6.83 (dd, J ) 10.2, 3.5 Hz, 1H); 6.09 (d, J ) 10.2
Hz, 1H); 5.28 (bd, J ) 3.5 Hz, 1H); 4.85 (d, J ) 11.7 Hz, 1H);
4.69 (d, J ) 11.9 Hz, 1H); 4.56 (q, J ) 6.8 Hz, 1H); 1.37 (d, J
) 6.8 Hz, 3H). IR: νmax 3028, 1699, 1454, 1026 cm-1. Anal.
Calcd for C13H14O3: C, 71.50; H, 6.50. Found: C, 71.08; H,
6.51. HRMS: calcd for C13H14O3 (M+), 218.094294; found,
218.094166. m/z: 91, 105, 111, 145, 174, 218.
chromatographed to give product 10 (13.5 g, 62.6%) as a thick
yellowish oil. [R]D -66.3 (c 1, CHCl3). H NMR: δ 7.40-7.20
1
(m, 10 H); 6.95 (bs, 1H); 6.77 (bs, 2H); 4.87 (bs, 1H); 4.74 (d,
J ) 11.9 Hz, 1H); 4.50 (d, J ) 12.1 Hz, 1H); 4.49 (s, 2H); 3.94
(q, J ) 6.5 Hz, 1H); 3.92 (s, 1H); 3.77 (2, 3H); 3.74 (s, 3H);
3.52 (m, 1H); 2.81 (dd, J ) 13.4, 1.4 Hz, 1H); 2.57 (d, J ) 13.7,
1H); 1.84 (dd, J ) 15.0, 3.2 Hz, 1H); 1.68 (dm, J ) 15 Hz, 1H);
1.32 (d, J ) 6.4 Hz, 3H). IR: νmax 3500, 1500, 1425, 1124, 1012
cm-1. HRMS: calcd for C29H34O6 (M+), 478.235539; found,
478.235613. m/z 91, 152, 241, 313, 328, 370, 478.
4-C-2,5-Dim eth oxyben zyl-3,6-d id eoxy-r- a n d â-L-r ibo-
Hexop yr a n ose (11). Adduct 10 (12 g, 25 mmol) in 2:1 ethyl
acetate-ethanol (150 mL) was hydrogenated in the presence
of 2 g of 5% Pd/C. After 4 h, the catalyst was filtered off and
washed with ethyl acetate and the solvent evaporated yielding
11 as a thick oil (7.2 g, 96.3%) that existed as a mixture of
anomers R and â in a ratio of approximately 3:2.
r-An om er . 1H NMR (after D2O exchange): δ 6.90-6.60 (m,
3H); 4.63 (bs, 1H); 3.84 (s, 3H); 3.77 (s, 3H); 3.62 (m, 1H); 3.57
(q, J ) 6.4 Hz, 1H); 3.02 (d, J ) 14.1 Hz, 1H); 2.28 (d, J )
14.1 Hz, 1H); 1.82 (dd, J ) 14.8, 3.1 Hz, 1H); 1.52 (dd, J )
14.8, 3.3 Hz, 1H); 1.37 (d, J ) 6.4 Hz, 3H).
Ben zyl 2,3,6-Tr id eoxy-â-L-h ex-2-en op yr a n osid -4-u lose.
1H NMR: δ 7.40-7.30 (m, 5H); 6.91 (dd, J ) 10.3, 2.0 Hz,
1H); 6.13 (dd, J ) 10.3, 1.6 Hz, 1H); 5.40 (m, 1H); 4.95 (d, J )
11.7 Hz, 1H); 4.68 (d, J ) 11.7 Hz, 1H); 4.24 (qd, J ) 7.0, 0.9
Hz, 1H); 1.46 (d, J ) 7.0 Hz, 3H). IR: νmax 3032, 1701, 1454,
â-An om er . 1H NMR (after D2O exchange, partial spec-
trum): δ 5.14 (bs, 1H); 4.09 (q, J ) 6.4 Hz, 1H); 3.05 (d, J )
14.1 Hz, 1H); 2.33 (d, J ) 14.0 Hz, 1H); 1.79 (dd, J ) 14.8, 3.5
Hz, 1H); 1.31 (d, J ) 6.4 Hz, 3H). IR: νmax 3452, 1500, 1460,
1375, 1160, 1059 cm-1
.
Ben zyl 2-O-Ben zyl-3,6-d id eoxy-r-L-th r eo-h exop yr a n -
osid -4-u lose (9). A mixture of unsaturated ketone 8 (28 g,
0.128 mole), benzyl alcohol (100 mL), and anhydrous potas-
sium carbonate (5 g) was stirred at room temperature for 4 h.
The reaction mixture was diluted with ethyl acetate (200 mL),
washed with water until neutral and then with brine, and
dried. After removal of the solvent, the residue was distilled
at reduced pressure to remove unreacted benzyl alcohol and
unsaturated ketone. The residue was bulb-to-bulb distilled at
200 °C/10-3 Torr to give 26.5 g (63.3%) of product 9 containing
7% â-L-erythro isomer.
An analytical sample was chromatographed to give pure 9,
bp 200 °C/10-3 Torr, [R]D -126.3 (c 1, CHCl3). 1H NMR: δ
7.45-7.20 (m, 10 H); 5.03 (bd, J 1,2 ) 2.6 Hz, 1H); 4.83 (d, J )
11.9 Hz, 1H); 4.65 (d, J ) 11.9 Hz, 1H); 4.57 (s, 2H); 4.18 (q,
J ) 6.8 Hz, 1H); 3.91 (ddd, J ) 5.9, 4.4, 2.6 Hz, 1H); 2.81 (dd,
J ) 15.6, 4.4 Hz, 1H); 2.67 (dd, J ) 15.6, 5.9 Hz, 1H); 1.32 (d,
J ) 6.8 Hz, 3H). IR: νmax 3031, 1730, 1074 cm-1. HRMS: calcd
for C20H22O4 (M - Bn), 235.097034; found, 235.097402. m/z:
91, 105, 146, 182, 235.
1045 cm-1
.
4-C-(2,5-Dim et h oxyb en zyl)-1,2-O-isop r op ylid en e-3,6-
d id eoxy-â-L-r ibo-h exop yr a n ose (12). To a solution of com-
pound 11 (500 mg, 1.67 mmol) in acetone (3 mL) and 2,2-
dimethoxypropane (3 mL) was added a small amount of
p-TsOH, and the reaction mixture was left at room tempera-
ture for 20 h. After neutralization with one drop of triethyl-
amine, the solvents were removed on a rotary evaporator, and
the residue was dissolved in ethyl acetate, washed with water
and brine, and dried. Removal of the solvent left an oil that
was flash-chromatographed to give 12 (307 mg, 55%). After
crystallization from ether/hexane, mp ) 120.5-122 °C and [R]D
1
0.54 (c 1, CHCl3). H NMR: δ 6.97-6.64 (m, 3H); 5.10 (bd, J
) 2.0 Hz, 1H); 3.99 (m, 1H); 3.76 (s, 3H); 3.75 (s, 3H); 3.53 (q,
J ) 6.2 Hz, 1H); 3.25 (bd, J ) 1.7 Hz, 1H); 2.76 (dd, J ) 13.6,
1.8 Hz, 1H); 2.53 (d, J ) 13.6 Hz, 1H); 1.94 (dd, J ) 16.0, 2.2
Hz, 1H); 1.79 (dd, J ) 16.1, 3.8 Hz, 1H); 1.59 (s, 3H); 1.32 (d,
J ) 6.3 Hz, 3H); 1.30 (s, 3H). IR: νmax 3540, 1499, 1465, 1161,
1113, 1015 cm-1. HRMS: calcd for C18H26O6 (M+), 338.17294;
found, 338.17460.
Ben zyl 2-O-Ben zyl-3,6-d id eoxy-â-L-er yth r o-h exop yr a n -
1
osid -4-u lose. H NMR: δ 7.40-7.20 (m, 10 H); 4.95 (d, J )
10.9 Hz, 1H); 4.91 (d, J ) 4.0 Hz, 1H); 4.65 (d, J ) 10.9 Hz,
1H); 4.64 (d, J ) 12.1 Hz, 1H); 4.58 (d, J ) 12.1 Hz, 1H); 4.10
(q, J ) 7.0 Hz, 1H); 3.94 (ddd, J ) 5.9, 5.1, 4.2 Hz, 1H); 2.93
(dd, J ) 16.2, 5.0 Hz, 1H); 2.56 (dd, J ) 16.2, 5.9 Hz, 1H);
1.39 (d, J ) 6.9 Hz, 3H).
(3S,4S)-3-(2,5-Dim eth oxyben zyl)-4-for m yloxy-3-h ydr oxy-
p en ta n a l (15). A solution of sodium periodate (8.0 g, 37.4
mmol) in water (100 mL) was added dropwise to a stirred
solution of aldose 11 (7.0 g, 23.5 mmol) in methanol (150 mL).
After complete addition (1 h), the reaction was stirred for an
additional 1 h, and then ethylene glycol (5 mL) was added and
stirring continued for 15 min. The formed precipitate was
filtered off and washed with methanol and the organic phase
concentrated to about 100 mL. The residue was extracted with
ethyl acetate, and the organic layer was washed with water
until neutral and then dried. Evaporation of the solvent gave
aldehyde 15 as an oil (6.5 g) that was used without purification
Ben zyl 2-O-Ben zyl-4-C-2,5-dim eth oxyben zyl-3,6-dideoxy-
r-L-r ibo-h exop yr a n osid e (10). To an energetically stirred
suspension of 3 g of finely cut lithium in THF (30 mL), cooled
to -20 °C, under Ar, was slowly added a solution of 2,5-
dimethoxybenzyl ethyl ether (14.7 g, 75 mmol) in ether (15
mL). After adding ca. 1/4 of the ether solution, an exothermic
reaction started and the rate of addition was adjusted so as
to keep the temperature between -15 and -20 °C. After
completion of the addition (1.5 h), the reaction mixture was
stirred for an additional 1 h at the same temperature, and
then toluene (50 mL) was added and the solution transferred
by double-ended needle to a flask containing toluene (100 mL)
cooled to -70 °C. To this solution was added dropwise ketone
9 (14.7 g, 45 mmol) in toluene (100 mL) over a period of 2 h.
After the addition was finished, the reaction mixture was
stirred for an additional 1 h at -70 °C and then allowed to
warm to -30 °C and poured into saturated ammonium chloride
solution (300 mL). The reaction mixture was washed with
saturated ammonium chloride (2 × 100 mL) and then with
water until neutral and with brine and dried. After removal
of the solvents under reduced pressure, the residue was
1
in the next step. H NMR: δ 9.75 (t, J ) 2.5 Hz, 1H); 8.07 (s,
1H); 6.90-6.60 (m, 3H); 4.97 (qd, J ) 6.4, 0.7 Hz, 1H); 4.17 (s,
1H); 3.81 (s, 3H); 3.75 (s, 23H); 3.06 (d, J ) 13.9 Hz, 1H); 2.88
(d, J ) 13.9 Hz, 1H); 2.59 (dd, J ) 16.0, 2.4 Hz, 1H); 2.49 (dd,
J ) 16.0, 2.6 Hz, 1H); 1.36 (d, J ) 6.4 Hz, 3H). IR: νmax 3482,
2837, 1719, 1500, 1465 cm-1. HRMS: calcd for C15H20O6 (M+),
296.12599; found, 296.12422.
(3S,4S)-3-(2,5-Dim eth oxyben zyl)pen tan e-1,3,4-tr iol (18).
To a solution of sodium borohydride (2 g) in 1:1 water-2-
propanol (40 mL) was added dropwise a solution of aldehyde
15 (6.5 g, 21.9 mmol) in THF (50 mL). After stirring for 1 h,
the reaction mixture was neutralized with acetic acid and
concentrated. The residue was dissolved in ethyl acetate,
washed with water and brine, and dried. Evaporation of the
2402 J . Org. Chem., Vol. 68, No. 6, 2003

Stereoselective Synthesis of Idarubicinone
solvent gave 5.9 g (100%) of triol 18 as a thick oil. The
analytical sample was chromatographed to give pure 18. [R]D
+7.1 (c 1, CHCl3). 1H NMR: δ 6.90-6.75 (m, 3H); 3.82 (s, 3H);
3.76 (s, 3H); 3.81-3.72 (m, 2H); 3.64 (q, J ) 6.4 Hz, 1H); 3.19
(d, J ) 14.1 Hz, 1H); 2.51 (d, J ) 13.9 Hz, 1H); 1.93-1.64 (m,
2H); 1.21 (d, J ) 6.4 Hz, 3H). IR: νmax 3432, 1592, 1500, 1285,
1179, 1117, 1068 cm-1. HRMS: calcd for C14H22O5 (M+),
270.14673; found, 270.14601. m/z: 43, 121, 137, 152, 175, 207,
225, 252, 270.
(3S,4S)-3-(2,5-Dim eth oxyben zyl)-3,4-O-isop r op ylid en e-
p en ta n e-1,3,4-tr iol (19). To a solution of triol 18 (5.5 g, 20.3
mmol) in acetone (25 mL) and dimethoxypropane (10 mL) was
added p-toluenesulfonic acid (50 mg), and the reaction mixture
was stirred for 3 h, evaporated to dryness, and coevaporated
with 100 mL toluene. The residue, consisting of an ap-
proximately 1:1 mixture of 19 and 20, was redissolved in 25:1
acetone-water (40 mL). Pyridinium p-toluenesulfonate (1 g)
was added and the mixture stirred for 2 h. Solvent was
removed under reduced pressure, and the residue was dis-
solved in ethyl acetate and washed with water until neutral,
dried, and evaporated to dryness to give crude 19 (5.7 g, 90%),
which was used in the next step.
3.2 Hz, 1H); 4.14 (d, J ) 8.8 Hz, 1H); 4.08 (q, J ) 6.4 Hz, 1H);
3.86 (s, 3H); 3.78 (s, 3H); 2.98 (dd, J ) 17.6, 1.8 Hz, 1H); 2.46
(d, J ) 17.6 Hz, 1H); 2.13 (ddd, J ) 13.9, 3.3, 2.0 Hz, 1H);
1.95 (dd, J ) 13.7, 5.1 Hz, 1H); 1.41 (s, 3H); 1.39 (s, 3H); 1.26
(d, J ) 6.4 Hz, 3H). IR: νmax 3511, 1602, 1483, 1263, 1099
cm-1. HRMS: calcd for C17H24O5 (M+), 308.16237; found,
308.16243.
(4S,5S,4′S)-4′-ter t-Bu tyldiph en ylsilyloxy-5′,8′-dim eth oxy-
2,2,5-tr im eth ylsp ir o[1,3-d ioxola n e-4,2′-1′,2′,3′,4′-tetr a h y-
d r on a p h th a len e] (23). A solution of bicyclic alcohol 22 (3.1
g, 10 mmol), tert-butyldiphenylsilyl chloride (4.1 g, 15 mmol),
and imidazole (1.5 g, 22 mmol) in DMF (20 mL) was kept, with
stirring, at 70-75 °C (oil bath) for 15 h. After the mixture was
cooled, ethyl acetate was added and the mixture washed
thoroughly with water and brine and dried. Evaporation of
the solvent gave a thick oil that was diluted with ether (10
mL) and left to crystallize. Filtration afforded silyl derivative
23 (4.2 g, 72.4%), mp 109-111 °C, [R]D -2.74 (c 1, CHCl3).
Flash chromatography of the residue gave additionally 0.76 g
(13%) of 23. 1H NMR: δ 7.90-7.80 (m, 2H); 7.50-7.20 (m, 8H);
6.68 (d, J ) 8.92 Hz, 1H); 6.44 (d, J ) 8.79 Hz, 1H); 5.33 (t, J
) 3.57 Hz, 1H); 3.79 (s, 3H); 3.73 (q, J ) 6.2 Hz, 1H); 3.36 (d,
J ) 15.6 Hz, 1H); 3.26 (s, 3H); 2.90 (d, J ) 15.6 Hz, 1H); 2.41
(dd, J ) 14.7, 3.5 Hz, 1H); 1.55 (dd, J ) 14.8, 3.7 Hz, 1H);
1.54 (s, 3H); 1.40 (s, 3H); 0.99 (s, 9H); 0.91 (d, J ) 6.2 Hz,
3H). IR: νmax 2934, 2858, 1489, 1280, 1104 cm-1. HRMS: calcd
for C32H39O5Si (M - CH3) 531.25665; found, 531.25896. Calcd
for C29H33O5Si (M - t-Bu), 489.20972; found, 489.20681.
The analytical samples were obtained by flash chromatog-
raphy of a 1:1 mixture of 19 and 20.
19: [R]D +102.8 (c 1, CHCl3). 1H NMR: δ 7.00 (m, 1 H); 6.80-
6.70 (m, 2H); 4.28 (q, J ) 6.4 Hz, 1H); 3.75 (s, 3H); 3.74 (s,
3H); 3.82-3.47 (m, 2H); 2.96 (d, J ) 13.7 Hz, 1H); 2.55 (J )
13.7 Hz, 1H); 1.80 (ddd, J ) 15.0, 8.2, 4.6 Hz, 1H); 1.59 (ddd,
J ) 15.0, 6.0, 4.2 Hz, 1H); 1.66 (s, 3H); 1.42 (s, 3H); 1.35 (d, J
(4S,5S,4′S)-4′-ter t-Bu tyld ip h en ylsilyloxy-5′,5′,8′,8′-tet-
r a m e t h o x y -2,2,5-t r im e t h y ls p ir o [1,3-d io x o la n e -4,2′-
1′,2′,3′,4′,5′,8′-h exa h yd r on a p h th a len e] (24). A suspension
of silyl derivative 23 (4.2 g, 7.46 mmol) in a solution of KOH
in methanol (1%, 180 mL), cooled to - 5 °C, was oxidized
anodically using a Pt cathode and a Pt-net cylinder as an anode
(0.8-0.95 A, 1.15 V). After 4 h, the electrolysis was terminated,
and the reaction mixture was neutralized with solid CO2 and
evaporated from a cold bath. The resulting oil was dissolved
in methylene chloride, washed with water and brine, and
dried. Removal of the solvent gave tetramethoxy compound
24 (4.3 g, 92.1%) as a thick oil that was used immediately for
) 6.4 Hz, 3H). IR: νmax 3510, 2836, 1590, 1497, 1466 cm-1
.
HRMS: calcd for C17H26O5 (M+), 310.17801; found, 310.17464.
m/z: 59, 101, 151, 159, 205, 235, 295, 310.
(3S,4S)-3-(2,5-Dim eth oxyben zyl)-3,4-O-isop r op ylid en e-
1-O-(1-m et h oxy-1-m et h ylet h yl)-p en t a n e-1,3,4-t r iol (20).
1
[R]D +54.4 (c 1, CHCl3). H NMR: δ 7.05 (m, 1H); 6.80-6.68
(m, 2H); 4.32 (q, J ) 6.2 Hz, 1H); 3.75 (s, 3H); 3.74 (s, 3H);
3.53-3.30 (m, 2H); 3.13 (s, 3H); 2.95 (d, J ) 13.8 Hz, 1H);
2.57 (d, J ) 13.7 Hz); 1.81-1.60 (m, 2H); 1.63 (s, 3H); 1.38 (s,
23H); 1.34 (d, J ) 6.2 Hz, 3H); 1.29 (s, 6H). IR: νmax 1499,
1465, 1380, 1160, 1090 cm-1. HRMS: calcd for C21H34O6 (M+),
382.23554; found, 382.23940.
1
the next step. H NMR: δ 7.85 - 7.25 (m, 10 H); 6.20 (d, J )
10.6 Hz, 1H); 6.12 (d, J ) 10.6 Hz, 1H); 4.78-4.73 (m, 1H);
3.37 (q, J ) 6.41 Hz, 1H); 3.24 (s, 3H); 3.22 (s, 3H); 3.16 (s,
3H); 3.07 (s, 3H); 2.57 (d, J ) 17.2 Hz, 1H); 2.25 (d, J ) 17.6
Hz, 1H); 1.87 (dd, J ) 13.9, 5.7 Hz, 1H); 1.39 (s, 3H); 1.27 (dd,
J ) 14.0, 4.5 Hz, 1H); 1.19 (s, 3H); 1.09 (s, 9H); 1.02 (d, J )
6.2 Hz, 3H).
(3S,4S)-3-(2,5-Dim eth oxyben zyl)-3,4-O-isop r op ylid en e-
3,4-d ih yd r oxyp en ta n a l (21). Alcohol 19 (5.7 g, 18.3 mmol)
and IBX (6.1 g, 22 mmol) in DMSO (35 mL) were stirred for 3
h. Water (50 mL) was added, and the precipitated iodozoben-
zoic acid was filtered off; the filtrate was washed thoroughly
with ether. The ether solution was washed with water until
neutral, dried, and evaporated. The residue was crystallized
from ether-hexane to give aldehyde 21 (4.85 g, 86%), mp
55.5-56.5 °C, [R]D +98.6 (c 1, CHCl3). 1H NMR: δ 9.51 (t, J )
2.5 Hz, 1H); 6.96-6.93 (m, 1H); 6.77-6.74 (m, 2H); 4.15 (q, J
) 6.2 Hz, 1H); 3.76 (s, 3H); 3.72 (s, 3H); 3.03 (d, J ) 13.6 Hz,
1H); 2.56 (d, J ) 13.9 Hz, 1H); 2.52 (dd, J ) 15.9, 1.9 Hz, 1H);
2.39 (dd, J ) 15.9, 2.9 Hz, 1H); 1.66 (s, 3H); 1.40 (d, J ) 6.2
Hz, 3H); 1.35 (s, 3H). IR: νmax 2837, 2746, 1716, 1593, 1500,
1180, 1049 cm-1. HRMS: calcd for C17H24O5 (M+), 308.16238;
found, 308.16058.
(4S,5S,4′S)-4′-ter t-Bu tyldiph en ylsilyloxy-8′,8′-dim eth oxy-
5′-oxo-2,2,5-tr im eth ylspir o[1,3-dioxolan e-4,2′-1′,2′,3′,4′,5′,8′-
h exa h yd r on a p h th a len e] (25). To a solution of tetramethoxy
compound 24 (4.2 g, 6.9 mmol) in acetone (25 mL) was added
aqueous acetic acid (8%, 8 mL), and the mixture was stirred
at rt for 2 h. After neutralization with saturated sodium
bicarbonate solution, acetone was evaporated from a cold bath
and the residue extracted with methylene chloride. The organic
layer was washed with saturated sodium bicarbonate solution,
water, and brine and dried. Removal of solvent gave a ca. 9:1
mixture of 25 and its isomer 26 (3.65 g, 94%). A sample of
this mixture was chromatographed to give as the main product
(4S,5S,4′S)-5′,8′-Dim eth oxy- 4′-h yd r oxy-2,2,5-tr im eth -
ylsp ir o[1,3-d ioxola n e-4,2′-1′,2′,3′,4′-t et r a h yd r on a p h t h a -
len e] (22). A solution of tin tetrachloride (3.31 g, 12.7 mmol)
in methylene chloride (5 mL) was added dropwise to a cooled
(-70 °C) solution of aldehyde 21 (3.9 g, 12.6 mmol) in
methylene chloride (90 mL). Stirring was continued for 1 h,
and then the reaction mixture was poured into a 1.5 M NaOH
solution (100 mL) that was energetically stirred and cooled in
an ice-water bath. The organic phase was separated, washed
with water and brine, and dried. After evaporation of solvent,
the residue was triturated with ether to induce crystallization.
Filtration afforded 22 (3.31 g, 85%). Chromatography of the
mother liquor and crystallization from ether-hexane gave
additionally 0.26 g (6.7%) of 22. Mp 108.5-109.5 °C, [R]D +37.3
1
25: [R]D -4.75 (c 1, CHCl3); H NMR: δ 7.88-7.83 (m, 2H);
7.69-7.64 (m, 2H); 7.42-7.25 (m, 6H); 6.71 (d, J ) 10.4 Hz,
1H); 6.29 (d, J ) 10.4 Hz, 1H); 4.88-4.84 (m, 1H); 3.79 (q, J
) 6.2 Hz, 1H); 3.33 (s, 3H); 3.20 (s, 3H); 2.59 (dd, J ) 18.9,
1.3 Hz, 1H); 2.18 (dd, J ) 19.2, 0.5 Hz, 1H); 1.95 (dm, J )
14.1 Hz, 1H); 1.51 (dd, J ) 14.3, 5.31 Hz, 1H); 1.48 (s, 3H);
1.35 (s, 3H); 1.15 (d, J ) 6.2 Hz, 3H); 1.00 (s, 9H). IR: νmax
3073, 1677, 1651, 1103 cm-1. HRMS: calcd for C32H39O6Si (M+
- CH3), 547.25159; found, 547.24989. Calcd for C29H33O6Si (M+
- C(CH3)3), 505.20456; found, 505.20648.
Min or P r od u ct: (4S,5S,4′S)-4′-ter t-Bu tyld ip h en ylsilyl-
oxy-5′,5′-d im eth oxy-8′-oxo-2,2,5-tr im eth ylsp ir o[1,3-d ioxo-
la n e-4,2′-1′,2′,3′,4′,5′,8′-h exa h yd r on a p h th a len e] (26). [R]D
1
(c 1, CHCl3). H NMR: δ 6.74 (s, 2H); 5.07 (ddd, J ) 8.8, 5.1,
J . Org. Chem, Vol. 68, No. 6, 2003 2403

Achmatowicz and Szechner
+21.1 (c 1, CHCl3); 1H NMR: δ 7.82-7.76 (m, 4H); 7.47-7.31
(m, 6H); 6.73 (d, J ) 10.3 Hz, 1H); 6.43 (d, J ) 10.4 Hz, 1H);
4.83-4.78 (m, 1H); 3.35 (q, J ) 6.2 Hz, 1H); 3.19 (s, 3H); 3.17
(s, 3H); 2.84 (d, J ) 17.4 Hz, 1H); 2.39 (dd, J ) 17.2, 1.5 Hz,
1H); 2.00 (dd, J ) 13.9, 6.4, 1H); 1.39 (s, 3H); 1.33 (dd, J )
13.9, 4.4 Hz, 1H); 1.19 (s, 3H); 1.09 (s, 9H); 0.85 (d, J ) 6.2,
h and then poured into water (50 mL). Precipitated iodosoben-
zoic acid was filtered off and washed thoroughly with tert-butyl
methyl ether. After separation of the water layer, the solution
was extracted with tert-butyl methyl ether. The ethereal
solution was washed with water, 10% sodium bicarbonate,
water, and brine and then dried. Evaporation of the solvent
gave 31 (3.56 g, 87%) as a yellow solid. 1H NMR: δ 8.23-6.82
(m, 14H); 5.48 (bs, 1H); 5.43 (t, J ) 2.9 Hz, 1H); 3.93 (s, 3H);
3.49 (dd, J ) 18.5, 0.9 Hz, 1H); 3.21 (d, J ) 18.5 Hz, 1H); 2.51
(dm, 1H); 2.44 (s, 3H); 2.05 (dd, J ) 14.7, 3.1 Hz, 1H); 1.54 (s,
3H); 0.92 (s, 9H). IR: νmax 3477, 1765, 1715, 1676, 1340, 1114
cm-1. HRMS: calcd for C39H38O8SiNa (M+ + Na), 685.22337;
found, 685.22645.
3H). IR: νmax 3073, 1711, 1673, 1645, 1111 cm-1
.
(7′S,9′S,4S)-7′-ter t-Bu t yld ip h en ylsilyloxy-6′-h yd r oxy-
11′-m e t h oxy-2,2,5-t r im e t h ylsp ir o[1,3-d ioxola n e -4,9′-
7′,8′,9′,10′-tetr ah ydr otetr acen e]-5′,12′-dion e (28). To a cooled
(-15 °C) solution of potassium t-butoxide (970 mg, 8.6 mmol)
in THF (30 mL) was added dropwise a solution of cyano-
phthalide 27 (1.27 g, 8 mmol) in THF (5 mL) followed, after
few minutes, by a solution of monoketals 25 and 26 (3.8 g, 6.7
mmol) in THF (15 mL). The reaction mixture, which turned
black, was stirred at -10 °C for 30 min; then, 10% HCl (40
mL) was added, and the red solution was stirred at room
temperature for 40 min. Most of the THF was evaporated; the
residue was extracted with ethyl acetate, and the organic layer
was washed with water and brine and dried. Evaporation of
solvents furnished product 28 (4.4 g, 98.3%) as a red foam. 1H
NMR: δ 13.09 (s, 1H); 8.29-7.16 (m, 14H);; 5.57 (t, J ) 3.6
Hz, 1H); 3.92 (s, 3H); 3.79 (q, J ) 6.4 Hz, 1H); 3.50 (d, J )
16.1 Hz, 1H); 3.04 (d, J ) 16.1 Hz); 2.37 (dd, J ) 15.0, 3.2 Hz,
1H); 1.58 (dd, J ) 15.0, 3.5 Hz, 1H); 1.57 (s, 3H); 1.42 (s, 3H);
1.04 (s, 9H); 0.95 (d, J ) 6.4 Hz, 3H). IR: νmax 1799, 1668,
1631, 1594, 1359, 1106, 987 cm-1. HRMS: calcd for C40H43O7-
Si (M + H+), 663.27781; found, 663.277776.
(7S,9S,1′S)-6-Acet oxy-9-a cet yl-9,11-d ih yd r oxy-7-(ter t-
bu tyld ip h en ylsilyloxy)-7,8,9,10-tetr a h yd r on a p h th a cen e-
5,12-d ion e (32). Boron trichloride (1 M in CH2Cl2, 20 mL) was
added in one portion to a solution of tetracyclic ketone 31 (2
g, 3 mmol) in methylene chloride (100 mL), cooled to -70 °C,
and the reaction mixture was stirred at that temperature for
1 h. Methanol (30 mL) was added, and after rt was reached,
the solvents were partially removed on a rotary evaporator.
The crystallizing residue was dissolved in ethyl acetate,
washed with water until neutral, and dried. Evaporation left
1
2 g (100%) of 33 as an orange solid. H NMR: δ 13.46 (s, 1H);
8.33-6.98 (m, 14 H); 5.52 (s, 1H); 5.38 (t, J ) 2.9 Hz, 1H);
3.44 (dd, J ) 19.0, 1.3 Hz, 1H); 3.12 (d, J ) 19.0 Hz, 1H); 2.50
(dm, 1H); 2.45 (s, 3H); 2.07 (dd, J ) 15.0, 3.1 Hz, 1H); 1.54 (s,
3H); 0.94 (s, 9H). IR: νmax 3476, 1768, 1717, 1672, 1634, 1595,
1355 cm-1. HRMS: calcd for C38H36O8SiNa (M+ + Na),
671.20772; found, 671. 21026.
(7′S,9′S,4S)-6′-Acet oxy-7′-ter t-b u t yld ip h en ylsilyloxy-
11′-m e t h oxy-2,2,5-t r im e t h ylsp ir o[1,3-d ioxola n e -4,9′-
7′,8′,9′,10′-tetr a h yd r otetr a cen e]-5′,12′-d ion e (29). A solu-
tion of compound 28 (4.2 g, 6.33 mmol) in pyridine (5 mL) and
acetic anhydride (5 mL) with a catalytic amount of DMAP was
kept at 45-50 °C for 3 h and then poured into ice-water. The
organic layer was washed with saturated potassium bicarbon-
ate solution, 10% HCl, water, and brine. After drying and
removal of the solvent, 29 was obtained as a bright yellow solid
Id a r u bicin on e (4). Compound 32 (2 g, 3 mmol) was
dissolved in a solution of hydrogen chloride in methanol (3%,
100 mL) and the mixture left at room temperature for 48 h.
Solid ammonium acetate was added for neutralization, and
the precipitate was filtered off and washed with methanol.
After evaporation to dryness, the residue was extracted with
hot methanol (3 × 20 mL). Crystallization started upon cooling
of the mixture, and after 24 h, the precipitate was filtered,
washed with methanol, and dried, yielding 956 mg (86.5%) of
idarubicinone (4) of 98% purity (HPLC). Enantiomeric homo-
geneity was confirmed by HPLC on a chiral column (Chiralcel
OD-R, 65:35 MeCN/0.5 M HClO4). Trituration of the crude
product with hot methanol (10 mL) gave 4 (940 mg, 98.3%) of
purity >99% (HPLC). 1H NMR: δ 13.52 (s, 1H); 13.23 (s, 1H);
8.35-8.27 (m, 2H); 7.88-7.80 (m, 2H); 5.32-5.26 (m, 1H); 4.59
(s, 1H); 3.86 (d, J ) 5.9 Hz, 1H); 3.18 (dd, J ) 18.9, 2.0 Hz,
1H); 2.94 (d, J 18.9 Hz, 1H); 2.44 (s, 3H); 2.36 (dt, J ) 14.6,
2.1 Hz, 1H); 2.17 (dd, J ) 14.6, 4.6 Hz, 1H).
1
(4.4 g, 98.5%). H NMR: δ 8.23-7.14 (m, 14H); 5.14 (bs, 1H);
3.98 (s, 3H); 3.76 (q, J ) 6.2 Hz, 1H); 3.72 (d, J ) 15.9 Hz,
1H); 3.07 (d, J ) 15.9 Hz, 1H); 2.37 (dd, J ) 15.0, 3.3 Hz, 1H);
1.92 (s, 3H); 1.58 (s, 3H); 1.52 (bd, 1H); 1.42 (s, 3H); 0.99 (s,
9H); 0.93 (d, J ) 6.0 Hz, 3H). IR: νmax 1763, 1674, 1578, 1332,
1097 cm-1. HRMS: calcd for C42H45O8Si (M + H+), 705.28837;
found, 705.28562.
(7S,9S,1′S)-6-Acetoxy-7-(ter t-bu tyld ip h en ylsilyloxy)-9-
h ydr oxy-9-(1′-h ydr oxyeth yl)-11-m eth oxy-7,8,9,10-tetr ah y-
d r otetr a cen e-5,12-d ion e (30). Compound 29 (4.4 g, 6.24
mmol) was dissolved in 80% acetic acid (90 mL) and THF (15
mL), and the reaction mixture was kept at 80 °C for 5 h. After
the mixture was cooled, most of the THF was removed on a
rotary evaporator, and the residue was poured into water (50
mL) and extracted with ethyl acetate. The organic layer was
washed with saturated potassium bicarbonate solution, water,
and brine and dried. Removal of the solvent gave diol 30 as
an orange solid (4.15 g, 100%). 1H NMR: δ 8.23-6.77 (m, 14H);
5.44 (t, J ) 2.9 Hz, 1H); 5.20 (s, 1H); 3.95 (s, 3H); 3.76-3.65
(m, 1H); 3.70 (q, J ) 6.5 Hz, 1H); 3.44 (dd, J ) 19.0, 1.0 Hz,
1H); 2.81 (d, J ) 18.9 Hz, 1H); 2.73 (dm, J ) 14.7 Hz, 1H);
1.76 (dd, J ) 14.7, 3.4 Hz, 1H); 1.46 (s, 3H); 1.33 (d, J ) 6.4
Hz, 3H); 0.89 (s, 9H). IR: νmax 3477, 1763, 1675, 1339, 1113
Ack n ow led gm en t. This research was supported in
part by the Polish State Committee for Scientific
Research (Grant 3T09A 113 13). The authors are
indebted to Professor J anina Karolak-Wojciechowska
and Dr. J an Maurin for X-ray crystallographic analysis.
Su p p or t in g In for m a t ion Ava ila b le: Figure S1 and
Figure S2 showing ORTEP drawings of 12 and 22, respec-
tively, and Tables S1-S15 listing crystallographic details,
fractional coordinates for non-hydrogen and hydrogen atoms,
interatomic bond distances and bond angles, torsion angles,
and anisotropic and isotropic displacement parameters of 12
and 22. This material is available free of charge via the
Internet at http://pubs.acs.org.
cm-1
.
(7S,9S,1′S)-6-Acetoxy-9-a cetyl-9-h yd r oxy-7-(ter t-bu tyl-
d ip h e n ylsilyloxy)-11-m e t h oxy-7,8,9,10-t e t r a h yd r ot e t -
r a cen e-5,12-d ion e (31). To a solution of diol 30 (4.10 g, 6.17
mmol) in DMSO (20 mL) was added IBX (2.8 g, 10 mmol), and
the reaction mixture was stirred at room temperature for 18
J O026354L
2404 J . Org. Chem., Vol. 68, No. 6, 2003