Catalytic asymmetric synthesis of halenaquinone and halenaquinol

Full text of DOI:10.1021/jo960773z

4876
J . Org. Chem. 1996, 61, 4876-4877
Ch a r t 1. Str u ctu r e of 1 a n d 2
Ca ta lytic Asym m etr ic Syn th esis of
Ha len a qu in on e a n d Ha len a qu in ol
Akihiko Kojima, Toshiyasu Takemoto,
Mikiko Sodeoka, and Masakatsu Shibasaki*
Faculty of Pharmaceutical Sciences, University of Tokyo,
Hongo, Bunkyo-ku, Tokyo 113, J apan
Sch em e 1. Ca ta lytic Asym m etr ic Syn th esis of 10a
Received April 29, 1996
Halenaquinone (1) and halenaquinol (2), which have
a benzylic quaternary carbon center, have been isolated
from a variety of sea sponges (Chart 1).1 These marine
natural products have been shown to possess antibiotic,
cardiotonic, and protein tyrosine kinase inhibitory activ-
ity.2 To date, only Harada and co-workers have suc-
ceeded in the total synthesis of 1 and 2 starting from
optically pure Wieland-Miescher ketone.3 We report
here the catalytic asymmetric synthesis of 1 and 2
starting from commercially available 6,7-dimethoxy-1-
tetralone (3).4,5 This synthesis features the first use of a
cascade Suzuki cross-coupling and an asymmetric Heck
reaction as well as the one-pot construction of a penta-
cyclic ring system from a tricyclic ring system.
The catalytic asymmetric synthesis of the tricyclic key
intermediate 10, which has a benzylic quaternary carbon
center, was achieved through three different routes
(Scheme 1). The dihydroxynaphthalene derivative 4 was
synthesized from 3 in 58% overall yield (five steps) as
shown in Scheme 1, and was first converted to the
ditriflate 5 (99%). To the best of our knowledge, there
has been no previous example of a cascade Suzuki cross-
coupling6 and an asymmetric Heck reaction.7 However,
we considered that this quite challenging process could
be possible under suitable reaction conditions to give
optically active 10 in a single step. Therefore, alkylbo-
rane 12 was prepared,8 and after many attempts, we
were very pleased to find that treatment of 5 with 129
(1.1 equiv), Pd(OAc)2 (20 mol %), (S)-BINAP10 (40 mol
%), and K2CO3 (6 equiv) in THF (0.063 M) at 60 °C for
42 h gave 10 with 85% ee in 20% yield.11 The enantio-
meric excess of 10 was determined by DAICEL CHIRAL-
CEL OD (hexane:2-propanol, 9:1) using 15 readily de-
rived from 10. The absolute configuration of 10 was
unequivocally determined from the successful conversion
of 10 to natural halenaquinone and halenaquinol. Al-
a
Reaction conditions: (a) (1) BBr3 (2.1 equiv), CH2Cl2, -78 °C
to rt, (2) BnBr (2.0 equiv), K2CO3, n-Bu4NI, DMF, 60 °C, (3) CrO3
(5 equiv), AcOH-H2O, 0 °C to rt, (4) KHMDS (3 equiv), THF, -78
°C, then MeI (6 equiv), -78 °C to rt, (5) H2 (1 atm), Pd-C, AcOEt,
rt (five steps, 58%); (b) Tf2O (3 equiv), pyridine, CH2Cl2, -78 °C
to rt (99%); (c) 12 (1.1 equiv), Pd(OAc)2 (20 mol %), (S)-BINAP (40
mol %), K2CO3, THF, 60 °C (85% ee, 20%); (d) (1) TBDMSCl (1.1
equiv), Et3N, CH2Cl2, 0 °C, (2) Tf2O (1.3 equiv), Et3N, CH2Cl2,
-78 °C to rt (two steps, 85%); (e) CH2dCHCH2MgBr (5 equiv),
PdCl2(dppf)‚CH2Cl2 (9 mol %), Et2O, -78 °C to rt (quant); (f)
(1) 9-BBN (2.1 equiv), THF, 0 °C to rt, (2) 11 (1.5 equiv),
PdCl2(dppf)‚CH2Cl2 (5 mol %), K3PO4‚nH2O, THF, 50 °C (90%);
(g) 12 (1.3 equiv), PdCl2(dppf)‚CH2Cl2 (10 mol %), K2CO3, THF,
50 °C (61%); (h) (1) n-Bu4NF (1.0 equiv), THF, 0 °C, (2) Tf2O (1.3
equiv), Et3N, CH2Cl2, -78 °C to rt (two steps, 69%); (i) Pd(OAc)2
(10 mol %), (S)-BINAP (20 mol %), K2CO3, THF, 60 °C (87% ee,
78%).
though the chemical yield is still unsatisfactory, this is
the first example of a cascade Suzuki cross-coupling and
(1) Roll, D. M.; Scheuer, P. J .; Matsumoto, G. K.; Clardy, J . J . Am.
Chem. Soc. 1983, 105, 6177. Kobayashi, M.; Shimizu, N.; Kyogoku,
Y.; Kitagawa, I. Chem. Pharm. Bull. 1985, 33, 1305. Kobayashi, M.;
Shimizu, N.; Kitagawa, I.; Kyogoku, Y.; Harada, N.; Uda, H. Tetrahe-
dron Lett. 1985, 26, 3833. Nakamura, H.; Kobayashi, J .; Kobayashi,
M.; Ohizumi, Y.; Hirata, Y. Chem. Lett. 1985, 713. Schmits, F. J .; Bloor,
S. J . Org. Chem. 1988, 53, 3922.
(8) Compounds 11-13 were prepared as follows ((I) Cochrane, J .
S.; Hanson, J . R. J . Chem. Soc., Perkin Trans. 1 1972, 3, 361. (II)
Kruithof, K. J . H.; Schmits, R. F.; Klumpp, G. W. Tetrahedron 1983,
39, 3073).
(2) Ikegami, S.; Kitagawa, I.; Takayama, S.; Makihara, R.; Koba-
yashi, M.; Miyashiro, S. J P 03173881, 1991. Lee, R. H.; Slate, D. L.;
Moretti, R.; Alvi, K. A.; Crews, P. Biochem. Biophys. Res. Commun.
1992, 184, 765. Alvi, K. A.; Diaz, M. C.; Crews, P.; Slate, D. L.; Lee, R.
H.; Moretti, R. J . Org. Chem. 1992, 57, 6604.
(3) Harada, N.; Sugioka, T.; Ando, Y.; Uda, H.; Kuriki, T. J . Am.
Chem. Soc. 1988, 110, 8483.
(4) Purchased from Aldrich Chemical Co., Inc.
(5) For a synthetic approach to 1 and 2 using a Heck reaction, see:
Cristofoli, W. A.; Keay, B. A. Synlett 1994, 625.
(6) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(7) Shibasaki, M.; Sodeoka, M. J . Synth. Org. Chem. J pn. 1994, 52,
956. Ashimori, A.; Matsuura, T.; Overman, L. E.; Poon, D. J . J . Org.
Chem. 1993, 58, 6969. Ozawa, F.; Kubo, A.; Matsumoto, Y.; Hayashi,
T.; Nishioka, E.; Yanagi, K.; Moriguchi, K. Organometallics 1993, 12,
4188. Sakamoto, T.; Kondo, Y.; Yamanaka, H. Tetrahedron Lett. 1992,
33, 6845. Tietze, L. F.; Schimpf, R. Angew. Chem., Int. Ed. Engl. 1994,
33, 1089. Sakuraba, S.; Awano, K.; Achiwa, K. Synlett 1994, 291.
Moinet, C.; Fiaud, J .-C. Tetrahedron Lett. 1995, 36, 2051.
(9) For the use of (Z)-trisubstituted olefins, see: Takemoto, T.;
Sodeoka, M.; Sasai, H.; Shibasaki, M. J . Am. Chem. Soc. 1993, 115,
8477.
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S0022-3263(96)00773-6 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 15, 1996 4877
Sch em e 2. Syn th esis of 1 a n d 2 fr om 10a
an asymmetric Heck reaction. Alternatively, the benzylic
quaternary carbon 10 was also constructed through a
multistep sequence of reactions. 4 was converted to the
silyl ether, which underwent trifluoromethanesulfony-
lation to give 6 in 85% overall yield. The Pd(0)-catalyzed
cross-coupling reaction gave 7 in a quantitative yield,
which underwent hydroboration followed by a Suzuki
cross-coupling reaction using 118 to give 8 (90%). Silyl
ether 8 was also constructed by a Suzuki cross-coupling
reaction using 6 and trialkylborane 12 (61%). 8 was then
converted to the requisite triflate 9 (69%) for an asym-
metric Heck reaction in a two-step sequence of reactions.
Treatment of 9 with Pd(OAc)2 (10 mol %), (S)-BINAP (20
mol %), and K2CO3 (3 equiv) in THF at 60 °C for 22 h
gave 10 with 87% ee in 78% yield.
Having developed a catalytic asymmetric synthesis for
the key intermediate 10, which has a benzylic quaternary
carbon center, we then examined the conversion of 10 to
natural halenaquinone and halenaquinol (Scheme 2). We
expected that the alkenyl iodide 21 would be a reasonable
synthetic intermediate for constructing the pentacyclic
ring system in a one-pot reaction.12 Therefore, 10 was
first converted to alcohol 14 in a two-step sequence of
reactions (93%). Transformation of 14 to the triflate
followed by reaction with the acyl anion equivalent 138
and then 2% NaF gave ketone 16 (68% yield). After
protection of the carbonyl functionality as an acetal
(98%), and of the ethynyl functionality with a triisopro-
pylsilyl group (98%), 17 underwent benzylic oxidation to
give 18 (96%). Exposure of 18 to O2 (1 atm) in the
presence of KO-t-Bu (5 equiv) in tert-butyl alcohol gave
enol 19 (79%). Treatment of 19 with NaI (10 equiv) and
CuSO4‚5H2O (10 equiv) in aqueous methanol gave the
requisite alkenyl iodide 20 quite efficiently (97%),13 and
exposure of 20 to p-toluenesulfonic acid in aqueous
acetone furnished 21 (98%). We were very pleased to find
that reaction of 21 with Pd2(dba)3‚CHCl3 (0.28 molar
equiv) and K2CO3 (5 equiv) in DMF at room temperature
for 8 h gave the desired pentacycle 22 in a single step
(72%). The pentacyclic intermediate 22 was subjected
to desilylation, which gave 23 in 83% yield: [R]23D +123.7
(c 0.335, CH2Cl2, 87% ee). Finally, Harada’s synthetic
a
Reaction conditions: (a) (1) n-Bu4NF (2 equiv), AcOH (3
equiv), THF, 0 °C to rt, (2) NaBH4 (5 equiv), MeOH, 0 °C to rt
(two steps, 93%); (b) 4-nitrobenzoyl chloride (1.1 equiv), Et3N,
4-(dimethylamino)pyridine, CH2Cl2, 0 °C to rt (96%); (c) (1) Tf2O
(1.2 equiv), pyridine, CH2Cl2, -78 °C to rt, (2) LDA/13 (1.5 equiv),
THF, -78 °C, then 2% NaF (two steps, 68%); (d) (1) HO(CH2)3OH
(10 equiv), TsOH‚H2O, benzene, reflux (98%), (2) n-BuLi (2 equiv),
THF, -78 to -50 °C, then TIPSCl (2 equiv), -78 °C to rt (98%);
(e) DDQ (3 equiv), CH2Cl2, H2O, rt (96%); (f) O2 (1 atm), KO-t-Bu
(5 equiv), t-BuOH, 35 °C (79%); (g) NaI (10 equiv), CuSO4‚5H2O
(10 equiv), MeOH, H2O, rt (97%); (h) TsOH‚H2O, acetone, H2O,
60 °C (98%); (i) Pd2(dba)3‚CHCl3 (0.28 equiv), K2CO3, DMF (0.003
M), rt (72%); (j) n-Bu4NF (16 equiv), AcOH (24 equiv), THF, MeCN,
60 °C (83%); (k) CAN (5 equiv), MeOH, H2O, 0 °C (45%); (l)
Na2S2O4 (20 equiv), acetone, H2O, 0 °C (quant).
intermediate 233 was readily converted to halenaquinone
(1) and halenaquinol (2).
In conclusion, we have developed a catalytic asym-
metric synthesis of 1 and 2 (87% ee) that incorporates
the first example of a cascade Suzuki cross-coupling-
asymmetric Heck reaction as well as a single-step process
promoted by Pd(0) for constructing a pentacyclic ring
system from a tricyclic ring system.
(11) The byproducts are iii and iv.
Su p p or tin g In for m a tion Ava ila ble: Details of the prepa-
ration and characterization of 1, 2, 5, 6, 8-10, 14, 16, and
18-23 (29 pages).
(12) The related reaction for the synthesis of indole and furan
skeletons has been previously reported. See: Larock, R. C.; Yum, E.
K.; Doty, M. J .; Sham, K. K. C. J . Org. Chem. 1995, 60, 3270.
(13) Starostin, E. K.; Mazurchik, A. A.; Ignatenko, A. V.; Nikishin,
G. I. Synthesis 1992, 917.
J O960773Z