Total synthesis of the rubrolone aglycon

Article abstract of DOI:10.1021/ja002997b

A total synthesis of the rubrolone aglycon is detailed and is based on two key Diels-Alder reactions. The AB ring system incorporating a tetrasubstituted pyridine was assembled, enlisting the rare 4π participation of an O-alkyl α,β-unsaturated oxime in an

Full text of DOI:10.1021/ja002997b

J. Am. Chem. Soc. 2000, 122, 12169-12173
12169
Total Synthesis of the Rubrolone Aglycon
Dale L. Boger,* Satoshi Ichikawa, and Hongjian Jiang
Contribution from the Department of Chemistry and The Skaggs Institute for Chemical Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
ReceiVed August 11, 2000
Abstract: A total synthesis of the rubrolone aglycon is detailed and is based on two key Diels-Alder reactions.
The AB ring system incorporating a tetrasubstituted pyridine was assembled, enlisting the rare 4π participation
of an O-alkyl R,â-unsaturated oxime in an intramolecular [4 + 2] cycloaddition reaction (70%). The C-ring
oxygenated tropolone was introduced through a room-temperature, exo selective [4 + 2] cycloaddition of a
cyclopropenone ketal (97%) followed by in situ generation of a norcaradiene and room-temperature electrocyclic
rearrangement to a cycloheptatrienone ketal appropriately substituted for hydrolysis directly to a 2,4-
dihydroxycycloheptatrienone.
Rubrolone (1),1 a red tropoloalkaloid isolated from Strepto-
myces enchinoruber, was identified in a single-crystal X-ray
structure determination and shown to possess the unique
azuleno[2,3-c]pyridine-2,5,13-trione aglycon 2 characteristic of
a class of structurally related agents (Figure 1).2,3 To date, only
a single total synthesis of the rubrolone aglycon has been
reported4 despite this unique structure. As part of the exploration
of the Diels-Alder reactions of azadienes5-11 and the thermal
cycloaddition reactions of cyclopropenone ketals,12-19 their
respective potential for introduction of the AB and C rings of
rubrolone have been examined.3b,20 Herein we describe the
Figure 1.
(1) Schuep, W.; Blount, J. F.; Williams, T. H.; Stempel, A. J. Antibiot.
1978, 31, 1226.
realization of a total synthesis, based on these two unusual
Diels-Alder reactions, of the rubrolone aglycon 2. Key to the
approach was the implementation of a rare 4π participation of
an O-alkyl R,â-unsaturated oxime in an intramolecular Diels-
Alder reaction for construction of the tetrasubstituted pyridine
with assemblage of the AB ring system (Scheme 1, 11 f 12)
and the Diels-Alder reaction of the cyclopropenone ketal 17
with the highly oxygenated diene 16 as a prelude to C-ring
tropolone introduction. Conversion of the [4 + 2] cycloadduct
18 to the norcaradiene 29, in situ low-temperature electrocyclic
rearrangement to a cycloheptatrienone ketal and tautomerization
was anticipated to provide a fully oxygenated precursor to the
rubrolone aglycon 2. Inherent in the design of the tropolone
annulation was the incorporation of three oxygen substituents
in the diene-dienophile reaction partners, permitting the direct
preparation of a 2,4-dihydroxycycloheptatrienone in a process
complementary to those we have detailed in total syntheses of
grandirubrine/imerubrine and colchicine based on the [4 + 2]
and [3 + 4] cycloaddition reactions of cyclopropenone ketals,
respectively.12-15
(2) Palleroni, N. J.; Reichelt, K. E.; Mueller, D.; Epps, R.; Tabenkin,
B.; Bull, D. N.; Schuep, W.; Berger, J. J. Antibiot. 1978, 31, 1218.
(3) AB ring system: (a) Kelly, T. R.; Liu, H. J. Am. Chem. Soc. 1985,
107, 4998. (b) Boger, D. L.; Zhu, Y. Tetrahedron Lett. 1991, 32, 7643.
(4) Aglycon total synthesis: Kelly, T. R.; Echavarren, A.; Whiting, A.;
Weibel, F. R.; Miki, Y. Tetrahedron Lett. 1986, 27, 6049.
(5) Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology in
Organic Synthesis; Academic Press: San Diego, 1987. Boger, D. L.
Tetrahedron 1983, 39, 2869. Boger, D. L. Chemtracts: Org. Chem. 1996,
9, 149.
(6) Boger, D. L.; Corbett, W. L.; Curran, T. T.; Kasper, A. M. J. Am.
Chem. Soc. 1991, 113, 1713 and references therein. Boger, D. L.; Curran,
T. T. J. Org. Chem. 1990, 55, 5439. Boger, D. L.; Corbett, W. L.; Wiggins,
J. M. J. Org. Chem. 1990, 55, 2999.
(7) Hwang, Y. C.; Fowler, F. W. J. Org. Chem. 1985, 50, 2719.
(8) Ito, Y.; Nakajo, E.; Saegusa, T. Synth. Commun. 1986, 16, 1073.
(9) Serckx-Poncin, B.; Herbain-Frisque, A.-M.; Ghosez, L. Tetrahedron
Lett. 1982, 23, 3261. For reports of the failure of R,â-unsaturated oximes
and their derivatives to act as 4π components in [4 + 2] cycloaddition
reactions, see ref 5, 6, and references therein.
(10) Ihara, M.; Kirihara, T.; Kawaguchi, A.; Fukumoto, K.; Kametani,
T. Tetrahedron Lett. 1984, 24, 4541.
(11) Teng, M.; Fowler, F. W. J. Org. Chem. 1990, 55, 5646.
(12) Boger, D. L.; Brotherton-Pleiss, C. E. In AdVances in Cycloaddition
Chemistry; Curran, D. P., Ed.; JAI Press: Greenwich, CT.; Vol. 2, pp 147-
219.
(13) Boger, D. L.; Brotherton, C. E. J. Am. Chem. Soc. 1986, 108, 6695.
(14) Boger, D. L.; Brotherton, C. E. Tetrahedron 1986, 42, 2777.
(15) Colchicine: Boger, D. L.; Brotherton, C. E. J. Am. Chem. Soc. 1986,
108, 6713. Boger, D. L.; Brotherton, C. E. J. Org. Chem. 1985, 50, 3425.
Grandirubrine and imerubrine: Boger, D. L.; Takahashi, K. J. Am. Chem.
Soc. 1995, 117, 12452.
Synthesis of the Rubrolone AB Ring System: 4π Partici-
pation of an O-Alkyl r,â-Unsaturated Oxime in an Intramo-
lecular Diels-Alder Reaction. The AB ring system 12 was
prepared by an approach we previously disclosed3b (Scheme
2). Condensation of aldehyde 321 with 1-lithio-1-pentyne
provided 4 (90%). Protection of the secondary alcohol as the
(16) Boger, D. L.; Wysocki, R. J., Jr. J. Org. Chem. 1989, 54, 714.
(17) Boger, D. L.; Brotherton, C. E. J. Am. Chem. Soc. 1984, 106, 805.
(18) Boger, D. L.; Brotherton, C. E. Tetrahedron Lett. 1984, 25, 5611.
(19) Boger, D. L.; Brotherton, C. E.; Georg, G. I. Tetrahedron Lett. 1984,
25, 5615.
(20) Model rubrolone ABC ring system: Boger, D. L.; Zhu, Y. J. Org.
Chem. 1994, 59, 3453.
(21) Nicolaou, K. C.; Prasad, C. V. C.; Hwang, C.-K.; Duggran, M. E.;
Veale, C. A. J. Am. Chem. Soc. 1989, 111, 5321.
10.1021/ja002997b CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/28/2000

12170 J. Am. Chem. Soc., Vol. 122, No. 49, 2000
Boger et al.
Scheme 1
Scheme 2
Table 1
temperature time yield 12
substrate
R
solvent
(°C)
(h)
(%)
11a
11a
11b
11b
11b
11b
Me triisopropylbenzene 185
Me triisopropylbenzene 175
24 53
36 70
72 no reaction
18 54
36 70
48 58
Bn toluene
110-140
Bn triisopropylbenzene 180
Bn triisopropylbenzene 185
Bn triisopropylbenzene 185
of the initial cycloadduct to the corresponding pyridine was
found to occur under the reaction conditions to provide 12
directly in 70% yield. Precedent for this Diels-Alder reaction
may be found in the use of R,â-unsaturated N,N-dimethylhy-
drazones in intermolecular9 and intramolecular22 [4 + 2]
cycloaddition reactions, even though the general reported failure
of R,â-unsaturated oxime cycloadditions suggested that their
use may not prove viable.9 Since our initial disclosure,3b
additional examples of such reactions have been disclosed.23,24
Thus, the observation that the O-alkyl R,â-unsaturated oximes
11 participate as effective 4π components of an intramolecular
Diels-Alder reaction with an electron-deficient dienophile
indicate that the introduction of an alkoxy electron-donating
substituent (OR) on the nitrogen atom of the inherently electron-
deficient 1-aza-1,3-butadiene system, like the dimethylamino
group of the unsaturated dimethylhydrazones (NMe2), may be
THP ether 5 (DHP, PPTS, CH2Cl2, 99%) followed by removal
of the OTBS ether (Bu4NF, THF, 99%) and PDC oxidation of
the primary alcohol 6 (77%) provided aldehyde 7. Treatment
of 7 with dimethyl (2-oxopropyl)phosphonate provided the key
intermediate 8 in 96% yield. Condensation of 8 with O-methyl
hydroxylamine hydrochloride (pyridine, 96%) followed by
removal of the THP-protecting group of 9a (Amberlyst, MeOH,
96%) provided 10a. Subsequent Swern oxidation of 10a afforded
11a (86%), which provided the initial O-alkyl R,â-unsaturated
oxime for study. Similarly, treatment of 8 with O-benzyl
hydroxylamine hydrochloride provided 9b (96%). Removal of
the THP-protecting group of 9b (99%) followed by Swern
oxidation of 10b (95%) provided 11b, an additional oxime for
study.
Table 1 summarizes representative results obtained from a
study of the intramolecular [4 + 2] cycloaddition of 11. No
reaction was found to occur at temperatures lower than 140 °C,
and a productive rate of reaction was observed at 170-200 °C
(triisopropylbenzene, bp 233-236 °C). The elimination of
methanol (11a) or benzyl alcohol (11b) with formal oxidation
sufficient to promote its participation in a normal, HOMOdiene
-
controlled Diels-Alder reaction.
Synthesis of the Rubrolone Aglycon: [4 + 2] Cycloaddi-
tion of a Cyclopropenone Ketal. In a prior study, we
demonstrated that the 1,4-addition of 2-bromoinden-1-one with
(22) Dolle, R. E.; Armstrong, W. P.; Shaw, A. N.; Novelli, R.
Tetrahedron Lett. 1988, 29, 6349.
(23) Kusurkar, R. S.; Bhosale, D. K. Tetrahedron Lett. 1991, 32, 3199.
Snyder, S.; Vosburg, D. A.; Jarvis, M. G.; Markgraf, J. H. Tetrahedron
2000, 56, 5329.
(24) Vijn, J. R.; Arts, J. H.; Green, R.; Castelijns, A. M. Synthesis 1994,
13, 573. Behforouz, M.; Gu, Z.; Stelzer, L. S.; Ahmadian, M.; Haddad, J.;
Scherschel, J. A. Tetrahedron Lett. 1997, 38, 2211.

Synthesis of the Rubrolone Aglycon
J. Am. Chem. Soc., Vol. 122, No. 49, 2000 12171
Scheme 3
Figure 2.
coupling of 14 with 1526 cleanly provided the diene 16 in superb
yield upon treatment with (Ph3P)4Pd (DMF-THF 1:4, 95%). No
coupling product was observed when Pd(II) catalysts such as
bis(benzonitrile)palladium dichloride were used, and a mixture
of DMF-THF (1:4) as solvent gave 16 in high yield while the
use of DMF or THF individually resulted in decreased yields.
The key Diels-Alder reaction of 16 with the cyclopropenone
ketal 1728 was conducted at room temperature and was complete
within 45 min, providing the single cycloadduct 18 in 97% yield.
The success of this rapid and unusually effective [4 + 2]
cycloaddition reaction may be attributed to the combined use
of a reactive electron-rich diene and the strained dienophile 17.
The [4 + 2] cycloaddition reaction provided a single diastere-
omer, which could be purified by simple crystallization from
EtOAc/hexanes. Single-crystal X-ray structure analysis29 re-
vealed that 18 was the anticipated cycloadduct shown in
Supporting Information Figure 1a derived from exclusive
cycloaddition through the less sterically encumbered exo
transition state14,15 (Figure 2).
Treatment of 18 with NBS-MeOH provided 19 in 80% yield
as a single diastereomer, the structure of which was established
by single-crystal X-ray structure analysis.29 The stereochemical
outcome indicates that the initial reaction of 18 with NBS
proceeded selectively on the less hindered face (Supporting
Information Figure 1b). Selective deprotection of dimethyl ketal
was accomplished by brief treatment with aqueous TFA (CH2-
Cl2, quant.) to give ketone 20. Elimination of HBr from 20 was
effected by mild treatment with DBU, and was followed by
acid-catalyzed hydrolysis of the mixed ketal (90% aqueous TFA,
CH2Cl2, 72% for two steps) to provide 21. In light of the number
of potentially competitive reactions, this transformation pro-
ceeded smoothly and cleanly to 21. Base treatment of the
corresponding bromohydrin, derived from the reaction of the
[4 + 2] cycloadduct 18 with NBS-H2O, failed to give the
analogous elimination product and resulted instead in the
formation of the remarkable and stable epoxide 25 (Scheme 4)
the higher-order cyanocuprate25 prepared from 2-lithio-1,4-
dioxene was followed by the elimination of HBr to provide the
corresponding diene which could serve as a suitably function-
alized substrate for a Diels-Alder approach to rubrolone C-ring
introduction.20 However, all attempts to extend this approach
to the preparation of 16 from 12 failed to afford the desired
diene. Nonetheless, the diene 16 was obtained by Stille coupling
of 14 with 15 which is formally equivalent to such a conjugate
addition. Thus, C6 hydroxylation of 12 with PhI(OAc)227 (KOH,
MeOH), under conditions that provide the corresponding
R-hydroxy dimethyl ketal in a reaction that first generates the
R-iodoso intermediate and is followed by the formation of the
alkoxy epoxide and ring opening of the epoxide with a MeOH
trap, followed by elimination of water ((CF3CO)2O, Et3N, 65%)
gave 13, Scheme 3.
Bromination of 13 (Br2, CH2Cl2) and subsequent elimination
of HBr (t-BuOK, DMF, 91% for two steps) selectively afforded
14 which is derived from an E2 elimination with removal of
the most acidic and sterically most accessible hydrogen. Stille
(28) Isaka, M.; Ejiri, S.; Nakamura, E. Tetrahedron 1992, 48, 2045.
(29) The author has deposited the atomic coordinates for these structures
with the Cambridge Crystallographic Data Centre, and these are allocated
the deposition numbers (18: CCDC 147871, 25: CCDC 147872, 19: CCDC
147873). The coordinates may be obtained upon request from the Director,
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2
1 EZ, UK.
(25) Blanchot-Courtois, V.; Hanna, I. Tetrahedron Lett. 1992, 33, 8087.
(26) Blanchot-Courtois, V.; Fetizon, M.; Hanna, I. Synthesis 1990, 9,
755.
(27) Moriarty, R. M.; Hu, H.; Gupta, S. C. Tetrahedron Lett. 1981, 22,
1283.

12172 J. Am. Chem. Soc., Vol. 122, No. 49, 2000
Boger et al.
(35 mL) was stirred under Ar at 185 °C for 36 h. The reaction mixture
was purified directly by column chromatography (SiO2, 2 × 30 cm,
30% EtOAc-hexane) to give 1231 (132 mg, 70%) as white needles:
mp 56-57 °C (EtOAc-hexane).
Scheme 4
5,5-Dimethoxy-2-methyl-4-propyl-5H-cyclopenta[c]pyridine (13).
A solution of 12 (1.30 g, 6.87 mmol) in MeOH (70 mL) was treated
with KOH (3.85 g, 68.7 mmol) and PhI(OAc)2 (4.43 g, 13.7 mmol),
and the reaction mixture was stirred at 0 °C for 3 h. The reaction mixture
was diluted with Et2O (500 mL), and the mixture was washed with
saturated aqueous NaCl (300 mL), dried (Na2SO4), filtered, and
concentrated in vacuo. The residue was taken up in CH2Cl2 (70 mL)
and treated with trifluoroacetic anhydride (1.94 mL, 13.7 mmol) and
Et3N (4.77 mL, 34.4 mmol), and the reaction mixture was stirred at 25
°C for 24 h. The reaction mixture was diluted with CH2Cl2 (200 mL),
and the organic phase was washed with saturated aqueous NaHCO3
(200 mL) and saturated aqueous NaCl (100 mL), dried (Na2SO4),
filtered, and concentrated in vacuo. Flash chromatography (SiO2, 5 ×
15 cm, 1% Et3N and 20% EtOAc-hexane) afforded 1331 (1.04 g, 65%)
as a light tan syrup.
Scheme 5
7-Bromo-5,5-dimethoxy-2-methyl-4-propyl-5H-cyclopenta[c]pyr-
idine (14). A solution of 13 (60 mg, 0.25 mmol) in CH2Cl2 (2.5 mL)
was treated with Br2 (79 mg, 0.5 mmol), and the reaction mixture was
stirred at 0 °C for 2 h. The volatiles were removed in vacuo. The residue
in DMF (2.5 mL) was treated with t-BuOK (1.0 M solution in THF,
0.75 mL, 0.75 mmol), and the reaction mixture was stirred at 0 °C for
2 h. The reaction mixture was diluted with EtOAc (10 mL), and the
organic phase was washed with H2O (10 mL) and saturated aqueous
NaCl (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo.
Flash chromatography (SiO2, 1 × 6 cm, 1% Et3N and 20% EtOAc-
hexane) afforded 1431 (71 mg, 91%) as a light tan syrup.
7-(1,4-Dioxen-2-yl)-5,5-dimethoxy-2-methyl-4-propyl-5H-cyclo-
penta[c]pyridine (16). A solution of 14 (53 mg, 0.17 mmol) and 1526
(76 mg, 0.20 mmol) in DMF-THF (1:4, 1.7 mL) was treated with
(Ph3P)4Pd (209 mg, 0.19 mmol), and the reaction mixture was stirred
at 50 °C for 2 h. The reaction mixture was diluted with EtOAc (20
mL), and the mixture was washed with H2O (20 mL) and saturated
aqueous NaCl (10 mL), dried (Na2SO4), filtered, and concentrated in
vacuo. Flash chromatography (SiO2, 1 × 8 cm, 1% Et3N and 20%
EtOAc-hexane) afforded 1631 (51 mg, 95%) as a light tan syrup.
Cycloadduct 18. Compound 16 (350 mg, 1.10 mmol) was treated
with 1728 (403 mg, 2.88 mmol) at 25 °C for 45 min. Crystallization of
the mixture from EtOAc-hexane afforded 1831 (420 mg, 84%) as
colorless prisms. The filtrate was concentrated in vacuo, and flash
chromatography of the mother liquors (SiO2, 1 × 5 cm, 1% Et3N and
33% EtOAc-hexane) afforded additional 18 (66 mg, 13%; 97% total)
as a white solid: mp 164-166 °C (EtOAc-hexane).
Compound 19. A solution of 18 (280 mg, 0.61 mmol) in MeOH-
THF (1:1, 5 mL) was treated with NBS (163 mg, 0.92 mmol), and the
reaction mixture was stirred at 0 °C for 10 min before aqueous Na2S2O3
and saturated aqueous NaHCO3 (50 mL) were added. The reaction
mixture was extracted with EtOAc (3 × 50 mL), and the organic layers
were washed with saturated aqueous NaCl (30 mL), dried (Na2SO4),
filtered, and concentrated in vacuo. Crystallization of the residue from
EtOAc-hexane afforded 1931 (280 mg, 80%) as colorless prisms: mp
153-155 °C (EtOAc-hexane).
whose structure was established by X-ray analysis29 (Supporting
Information Figure 1c). Although not extensively investigated,
treatment of either 19 or 25 with base under various conditions
(t-BuOK, KOH, or DBU) gave no evidence of desired elimina-
tion product. Thus, ketone activation for elimination of HBr
from 20 was required, and the subsequent formation of the
cycloheptatrienone derivative 21 is derived from a reaction
sequence that proceeds by mixed ketal hydrolysis (26 f 27),
enolization with norcaradiene generation (28 f 29), electro-
cyclic rearrangement to the cycloheptatrienone ketal (29 f 30),
and tautomerization to 21 (Scheme 5).
Subjection of 21 to hydrolysis (LiOH, THF-MeOH-H2O
3:1:1, 99%) led to clean monodeprotection with selective
generation of 22. The remaining 2-hydroxyethyl ether of 22
could not be removed by either vigorous acid or base-catalyzed
hydrolysis and was removed in a two-step sequence involving
conversion of the alcohol to the primary bromide 23 (TMSBr,
MeCN, 99%)30 followed by reductive cleavage of the 2-bromo-
ethyl ether (Zn, NH4Cl, EtOH). Under these conditions, the
benzylic ketone is also reduced, leading to the generation of
24. Without purification or optimization, this crude alcohol was
oxidized (NBS, DMSO) to provide 2 in 48% yield (two steps
from 23) completing the preparation of the rubrolone aglycon.
Compound 20. A solution of 19 (100 mg, 0.17 mmol) in 20 mL of
CH2Cl2 was treated with 90% aqueous TFA (500 µL), and the reaction
mixture was stirred at 25 °C for 10 min before saturated aqueous
NaHCO3 (30 mL) was added. The mixture was extracted with CH2Cl2
(50 mL), and the organic layer was washed with saturated aqueous
NaCl (30 mL), dried (Na2SO4), filtered, and concentrated in vacuo to
afford 2031 (88 mg, quantative) as a colorless oil which was used without
further purification.
2-[(2,2-Dimethyl-3-hydroxypropyl)oxy]-5,13-dioxo-9-methyl-11-
propyl-4-[(2-hydroxyethyl)oxy]azuleno[2,3-c]pyridine (21). A solu-
tion of 20 (88 mg, 0.17 mmol) in 2 mL of CH2Cl2 was treated with
DBU (31 µL, 2.0 mmol), and the reaction mixture was stirred at 0 °C
for 10 min. The mixture was diluted with CH2Cl2 (20 mL), and the
Experimental Section
2-Methyl-5-oxo-4-propyl-6,7-dihydro-5H-cyclopenta[c]pyridine
(12). A solution of 11a31 (298 mg, 1.58 mmol) in triisopropylbenzene
(30) Treatment of 24 with NBS and PPh3 gave only a trace of 25, whereas
NBS/PBu3 effectively provided 25 although it was difficult to isolate free
of reaction byproducts. Bates, H. A.; Farina, J.; Tong, M. J. Org. Chem.
1986, 51, 2637.
(31) Full details of the preparation and characterization of 4-11 and
full characterization data for 12-14, 16, 18-23, and 2 are provided in the
Supporting Information.

Synthesis of the Rubrolone Aglycon
J. Am. Chem. Soc., Vol. 122, No. 49, 2000 12173
organic layer was washed with saturated aqueous NaCl (10 mL), dried
(Na2SO4), filtered, and concentrated in vacuo. A solution of the residue
in 2 mL of CH2Cl2 was treated with 90% aqueous TFA (200 µL), and
the reaction mixture was stirred at 25 °C for 1 h before addition of
saturated aqueous NaHCO3 (30 mL). The mixture was extracted with
CHCl3 (30 mL), and the organic layer was washed with saturated
aqueous NaCl (10 mL), dried (Na2SO4), filtered, and concentrated in
vacuo. Flash chromatography (SiO2, 1 × 4 cm, 2% MeOH-CHCl3)
afforded 2131 (52 mg, 72%) as a yellow powder.
mg, 49.6 µmol), and the reaction mixture was stirred at 60 °C for 3 h.
The reaction mixture was filtered, and the filtrate was concentrated in
vacuo. A solution of the residue containing 24 in 0.5 mL of DMSO
was treated with NBS (5.5 mg, 24.5 µmol), and the reaction mixture
was stirred at 25 °C for 1 h before H2O was added. The reaction mixture
was concentrated in vacuo. Flash chromatography (reverse phase, 1 ×
4 cm, 20% H2O-MeOH) afforded 231 (0.7 mg, 48%) as an orange
solid identical in all respects with properties reported for authentic
material. 4
5,13-Dioxo-2-hydroxy-9-methyl-11-propyl-4-[(2-hydroxyethyl)-
oxy]azuleno[2,3-c]pyridine (22). A suspension of 21 (21.3 mg, 0.05
mmol) in 2 mL of THF-MeOH-H2O(3:1:1) was treated with LiOH‚
H2O (10.5 mg, 0.25 mmol), and the reaction mixture was stirred at 50
°C for 2 h. The mixture was cooled to 0 °C, and the THF was removed
under a stream of N2. The yellow precipitate was collected by filtration
to afford 2231 (17.0 mg, 99%) as a yellow powder.
Acknowledgment. We gratefully acknowledge the financial
support of the National Institute of Health (CA42056), the
Skaggs Institute for Chemical Biology, and the Japan Society
for Promotion of Sciences (S.I.). We also thank Yan Zhu who
was responsible for the development of the route to 12.
5,13-Dioxo-2-hydroxy-9-methyl-11-propyl-4-[(2-bromoethyl)oxy]-
azuleno[2,3-c]pyridine (23). A suspension of 22 (4.0 mg, 0.012 mmol)
in 2 mL of CH3CN was treated with TMSBr (23 µL, 0.18 mmol), and
the reaction mixture was warmed at reflux for 3 h. The mixture was
cooled and washed with hexane (3 × 4 mL), and the CH3CN layer
was concentrated in vacuo to afforded 2331 (4.9 mg, quantitative) as a
yellow solid sufficiently pure to use directly in the next reaction.
Rubrolone Aglycon (2). A solution of 23 (2.0 mg, 4.9 µmol) in 1
mL of EtOH was treated with Zn (3.2 mg, 49.6 µmol) and NH4Cl (2.7
Supporting Information Available: Full experimental
details and characterization for 4-11 and full characterization
data for 12-14, 16, 18-23 and 2, and Supporting Information
Figure 1a-c (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
JA002997B