Total synthesis of (±)-O-methyl PD 116740

Article abstract of DOI:10.1021/ol026104r

(matrix presented) Condensation of the phthalide sulfide with an ortho-quinone monoketal was employed as a key step in the first total synthesis of a derivative of (±)-PD 116740.

Full text of DOI:10.1021/ol026104r

ORGANIC
LETTERS
2002
Vol. 4, No. 13
2237-2239
Total Synthesis of (±)-O-Methyl PD
116740
Frank M. Hauser,* Warren A. Dorsch, and Dipakranjan Mal
Department of Chemistry, State UniVersity of New York at Albany,
Albany, New York 12222
FH473@mail.albany.edu
Received April 30, 2002
ABSTRACT
Condensation of the phthalide sulfide with an ortho-quinone monoketal was employed as a key step in the first total synthesis of a derivative
of (±)-PD 116740.
PD 1167401 (1a) and TAN 10842 (1b) are the only
angucyclines that have been isolated with 5,6-dihydroxyl-
ation. Since these, as well as other angucyclines, exhibit
significant anticancer activity, there has been strong interest
in their total synthesis.3 To date, only two approaches to
angucyclines with C5,C6-dihydroxylation have been re-
ported, and both were model studies.4,5
Our planned approach, shown in Scheme 1, was based on
the expectation6 that condensation of the phthalide sulfone
Scheme 1
(1) Wilton, J. H.; Cheny, D. C.; Hoakson, G. C.; Cun-heng, H.; Clardy,
J. J. Org. Chem. 1985, 50, 3936.
(2) JP 009 263, 1990; JP 2 289 532, 1990; Chem. Abstr. 1991, 115,
47759n.
(3) For a review, see: Krohn, K.; Rohr, J. Top. Curr. Chem. 1997, 188,
127-195.
(4) Larsen, D. S.; O’Shea, M. D. J. Org. Chem. 1996, 61, 5681.
(5) Mal, D.; Roy, H. N.; Hazra, N. K.; Adhikari, S. Tetrahedron, 1997,
53, 2177.
(6) Hauser, F. M.; Rhee, R. P. J. Org. Chem. 1978, 43, 178. For use of
this reaction in natural product syntheses, see: Hauser, F. M.; Mal, D. J.
Am. Chem. Soc. 1984, 106, 1098. Hauser, F. M.; Prasanna, S. Tetrahedron
1984, 40, 4711. Hauser, F. M.; Chakrapani, S.; Ellenberger, W. P. J. Org.
Chem. 1991, 56, 5248. Hauser, F. M.; Tommasi, R. A. J. Org. Chem. 1991,
56, 5758. Hauser, F. M.; Yin, H. Org. Lett. 2000, 2, 1045.
2 with the ortho-quinone ketal 3 would provide an overall
convergent route to the functionalized benz[a]anthracene 4,
with direct introduction of oxygenation at the C5 and C6
positions. There was a concern that the condensation would
instead furnish 5, through base-catalyzed elimination of
methanol (vide supra).5 Nevertheless, we were optimistic that
we could overcome this anticipated difficulty.
The route that was employed to prepare the needed ortho-
quinone ketal 3 is shown in Scheme 2 and exploits
10.1021/ol026104r CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/07/2002

acetate,10 we needed a method for regiospecific conversion
of 11 to the unsubstituted naphthol 12. Ultimately, we were
able to accomplish this transformation in a regiospecific
manner11 through reaction of the anion of dimethyl methyl-
phosphonate with the benzopyranone 11.12,13 The resultant
naphthol 12 was methylated with K2CO3 and (CH3O)2SO2
to afford the methyl ether 13 (75% from 11). Hydrogenolysis
of 13 followed by oxidation of the resultant phenol with
PhI(OAc)2 in MeOH14 afforded the ortho-quinone ketal 3
(67% from 13).
Scheme 2a
Attempted condensation of the anion of sulfone 2 with
ortho-quinone ketal 3 failed to give any product (Scheme
3). It was unclear whether the reaction failure was due either
to a steric effect from interaction of the phenyl-sulfonyl group
in 2 and the methoxy group in 3 during the condensation or
the possibility that the sulfone anion was insufficiently
nucleophilic to add to the enone fragment in 3. In an attempt
Scheme 3a
a Reagents and conditions: (a) CuSO4, K2S2O8, CH3CN/H2O.
(b) NaClO2, H2NSO3H, 2:1 H2O/THF; 90% from 6. (c) LDA,
dimethyl carbonate, from -78 °C to rt; 86%. (d) py, Ac2O, ether.
(e) NaOH, ∆. (f) H+, Ac2O, EtOAc; 70% from 9. (g) BBr3, CH2Cl2,
from -78 °C to rt, 24 h; 82%. (h) BnBr, K2CO3, acetone; 92%. (i)
CH3P(O)(OCH3)2, n-BuLi, THF, from -78 °C to rt. (j) (CH3O)2SO2,
K2CO3, acetone; 75% from 11. (k) Pd/C, H2, MeOH/EtOAc; 96%.
(l) PhI(OAc)2 (2.2 equiv), MeOH, from 0 °C to rt; 70%.
methodology previously developed by us for selective
transformation of benzenoid systems and our development
of a new procedure for regiospecific conversion of iso-
benzopyranones to 1-naphthols. A protocol we previously
reported7 was employed to regiospecifically convert the
commercially available anisole 6 to the ortho-toluic acid 8.
Copper-catalyzed persulfate oxidation of the anisole 6
afforded the aldehyde 7, which was oxidized with NaClO2
to the acid 8. Another procedure, also developed by us,8 was
used to convert the ortho-toluic acid 8 to the homophthalic
acid 9. Thus, treatment of 8 with 2 equiv of n-BuLi afforded
the dianion intermediate, which was quenched with dimethyl
carbonate. Subsequent workup resulted in in situ hydrolysis
to the homophthalic acid 9 (86% yield). Sequential treatment
of 9 with Ac2O and pyridine, hydrolysis with decarboxyl-
ation, and then cyclization of the keto carboxylic acid
intermediate with Ac2O and catalytic HClO4 afforded the
benzopyranone 10 (70% overall yield).
At this point, it was necessary to prepare for eventual
selective deprotection of the phenolic group and a change
in protective groups was needed. Demethylation of 10 with
BBr3 followed by benzylation (BnBr and K2CO3) of the
resultant phenol furnished the benzyl ether 11 (75% from
10).
Although we have previously shown that benzopyranones
can be converted to 1-hydroxy-2-carboxy-naphthoates through
reaction either with the Reformatsky reagent derived from
ethyl bromoacetate9 or more conveniently with lithio-ethyl
a Reagents and conditions: (a) tBuOLi, THF, -78 °C; 72%. (b)
(CH3O)2SO2, K2CO3, acetone; 91%. (c) NBS, CCl4, hν, ∆; 48%.
(d) NaOAc, DMF; 87%. (e) TFA, CHCl3/H2O; 92%. (f) NaBH4,
EtOH, from 0 °C to rt; 98%. (g) Ac2O, Py, DMAP (cat.), CH2Cl2;
90%. (h) CAN, CH3CN/H2O, 0 °C; 74%.
(7) Hauser, F. M.; Ellenberger, S. R. Synthesis 1987, 723.
(8) Hauser, F. M.; Rhee, R. P. Synthesis 1977, 245.
(9) Hauser, F. M.; Rhee, R. P. J. Am. Chem. Soc. 1977, 99, 4533.
2238
Org. Lett., Vol. 4, No. 13, 2002

to evaluate these factors, reaction of the anion of the sulfide
14 with the ortho-quinone monoketal 3 was explored.
Condensation of the anion of the sulfide 14 with 3 cleanly
afforded a new product. The presence of only three methoxyl
and cis-diols 18 (98%). The diastereoisomeric mixture of
diols 18 was only slightly soluble in most solvents. While it
was possible to recrystallize the mixture from polar solvents,
there did not seem to be significant separation of the isomers.
In an effort to improve the solubility, the mixture was
acetylated with Ac2O and pyridine to afford 19. Although
we were now able to chromatograph the material, the isomers
were still not cleanly separable by silica chromatography.
Nevertheless, we were able to obtain a pure sample of the
major product and establish through 1H NMR spectroscopy
that it was the trans-diacetate. The observed coupling
constant for the H5 and H6 protons was 3.3 Hz, which is
consistent with trans stereochemistry. Oxidation of 19 with
CAN afforded the methyl ether acetate derivative 20 of PD
116740 and the cis isomer 21, which were chromatographi-
cally separable.
1
absorptions in the H NMR spectrum and the presence of
quinone absorptions in the IR spectrum established that the
new product was not the desired hydroquinone 4 but was
instead the quinone 5. We suspected that 5 was formed from
4 during acid (HCl) neutralization of the reaction and did
not arise through base-catalyzed elimination of methanol,
as has been previously suggested.5 This hypothesis was
straightforwardly validated. When the reaction was quenched
with acetic acid, exclusive formation of 4 was achieved in
72% yield. A further indication that 4 was stable to base
was the fact that upon methylation with K2CO3 and
(CH3O)2SO2, the methyl ether 15 was exclusively produced
in 91% yield.
In summary, we have accomplished the first total synthesis
of a derivative of PD 116740. The developed route demon-
strates that condensation of phthalide sulfides with ortho-
quinone monoketals not only provides an expedient approach
to benz[a]anthracene natural products but also results in
direct introduction of 5,6-dihydroxylation. Furthermore, we
have shown that benzopyranones can be regiospecifically
converted to 1-naphthols through reaction with the anion of
dimethyl methylphosphonate. We believe that this approach
is generally applicable to other polycyclic aromatic natural
products with this substitution pattern. In the following paper,
we demonstrate its use to prepare an analogue of the
benanomicin/pradimicin aglycone.
Bromination of 15 with NBS afforded the bromomethyl
intermediate (48%),15 which was reacted with NaOAc in
DMF to afford the acetoxymethyl compound 16 (87%). Brief
treatment of 16 with TFA in CHCl3/H2O gave the ortho-
quinone 17 (98%). The excellent procedure reported by
Harvey et al.,16 for conversion of ortho-quinones to diols
through reaction with NaBH4 in the presence of air, was
employed to convert 17 to a roughly 3:1 mixture of trans-
(10) Hauser, F. M.; Pogany, S. J. Heterocycl. Chem. 1978, 15, 1535.
(11) Reaction of 11 with methyllithium, followed by intramolecular aldol
reaction, gave regioisomeric naphthol products.
(12) This is a general reaction of benzopyranones, and this work will be
published shortly.
(13) For the similar conversion of enol lactones to unsaturated enones
see: Herrick, C. A.; Boehme, E.; Edwards, J. A.; Fried, J. H. J. Am. Chem.
Soc. 1968, 90, 5926.
(14) Mallik, U.K.; Mallik, A. K. Ind. J. Chem. 1991, 30B, 611.
(15) The modest yield here is due to cleavage of the acetal by in situ-
generated HBr. Undoubtedly, the yield could be improved by addition of a
base.
Acknowledgment. This work was generously supported
by the National Cancer Institute of the National Institutes
of Health (CA 18141).
(16) Zhang, J.; Dai, W.; Harvey, R. G. J. Org. Chem. 1998, 63, 8125.
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