Sonogashira coupling of 2-iodo-2-cycloalkenones: Synthesis of (+)- and (-)-harveynone and (-)-tricholomenyn A

Full text of DOI:10.1021/jo962295y

1582
J . Org. Chem. 1997, 62, 1582-1583
Ch a r t 1
Son oga sh ir a Cou p lin g of
2-Iod o-2-cycloa lk en on es: Syn th esis of (+)-
a n d (-)-Ha r veyn on e a n d
(-)-Tr ich olom en yn A
Michael W. Miller1 and Carl R. J ohnson*
Department of Chemistry, Wayne State University,
Detroit, Michigan 48202-3489
Received December 10, 1996
Our laboratory has been involved with the production
of enantiopure, densely functionalized, bioactive targets.2
Our strategy has involved the tandem use of biocatalysis
as a method for the introduction of absolute stereochem-
istry3 and transition metal catalysis as a tool for the
elaboration of the enantiopure intermediates.4 Recently,
we initiated a program along these lines utilizing p-
benzoquinone as a starting material and the bioactive,
epoxyquinol natural products as targets. This prelimi-
nary study resulted in the first synthesis of enantiomeri-
cally pure (+)- and (-)-bromoxone (Chart 1).5a We have
directed our attention toward the epoxyquinol natural
products containing an acetylenic side chain at the
2-position, typified by (+)-harveynone and (-)-tricholom-
enyn A (Chart 1). (+)-Harveynone was isolated from
Pestalotiopsis theae and was shown to be a phytotoxin.6a
Its enantiomer, (-)-harveynone, was isolated from Cur-
vularia harveyi and was found to possess antitumor
activity (inhibitor of spindle formation).6b,c More recently,
(-)-tricholomenyn A was isolated from Tricholoma acer-
bum and was reported to display antimitotic activity.6d
Near the completion of our studies, Kamikubo and
Ogasawara described the synthesis of (-)-tricholomenyn
A7a and Taylor and co-workers reported the synthesis of
(()-harveynone.7b In these studies, both Ogasawara7a
and Taylor7b utilized a Stille coupling of a tin acetylide
with a 2-iodo-2-cyclohexenone. Both reported that at-
tempted Sonogashira coupling between the functionalized
2-iodo-2-cyclohexenone and the appropriate terminal
acetylene failed to give the desired coupled product. In
light of these reports, we describe below our entry into
this class of epoxyquinol natural products utilizing as a
key step a Sonogashira coupling of a 2-iodo-2-cycloalk-
enone with a terminal acetylene (Scheme 1).8
Sch em e 1
Our first objective was to find optimal conditions for
the Sonogashira coupling of a 2-iodo-2-cycloalkenone with
a terminal acetylene.9 The optimal conditions were found
to be the presence of PdCl2(PPh3)2, CuI, and diisopropyl-
amine in THF at 0 °C (Table 1). The reaction was found
to be complete within 25-45 min under these conditions.
Five-, six-, and seven-membered ring 2-iodo-2-cycloalk-
enones gave good yields of the desired coupled product
(74-97%). Oxygenated functionality did not affect the
efficiency of the reaction (i.e., 5-8).
At this stage, we utilized technology we had developed
in our bromoxone study (Scheme 2).5a The dibromide (+)-
9, obtained in two steps from an enzymatically resolved
diol, was converted into the allylic alcohol (+)-10 in 81%
yield (Zn/refluxing MeOH). The allylic alcohol (+)-10 was
oxidized (PCC) to the enone (+)-11 in 82% yield. Iodi-
nation of the enone (+)-11 (I2/pyridine/CCl4) furnished
the iodoenone (+)-12 in 77% yield.10,11 Lastly, deprotec-
tion of the TBS ether (+)-12 was accomplished utilizing
DeShong’s protocol (H2SiF6/CH3CN)12 which provided the
alcohol (+)-iodoxone (13) in 86% yield ([R]D +96.1 (c 0.95,
acetone). In an analogous fashion, (-)-9 was converted
into (-)-iodoxone [(-)-13] ([R]D -94.3 (c 0.70, acetone);13
(+)- and (-)-iodoxone (13) were found to be g99% ee by
chiral HPLC analysis.14
(1) Current address: Schering-Plough Research Institute, Kenil-
worth, NJ 07033.
(8) Taylor7b examined a range of successful Sonagashira couplings
with isomeric 3-iodo-2-cyclohexenones. The epoxyquinol products are
very base sensitive, and in our hands it was found necessary to
carefully remove all traces of amine promoters by extraction with cold
aqueous 1 M HCl. Experimental details are not available in ref 7a,b;
it is possible that their failures are attributable to workup conditions.
The Sonogashira coupling reactions we examined proceeded faster with
diisopropylamine than with triethylamine.
(2) J ohnson, C. R.; Adams, J . P.; Bis, S. J .; DeJ ong, R. L.; Golebio-
wski, A.; Medich, J . R.; Penning, T. D.; Senanayake, C. H.; Steensma,
D. H.; Van Zandt, M. C. Pure Appl. Chem. 1992, 64, 1115.
(3) Enzymatic asymmetrization: J ohnson, C. R.; Harikrishnan, L.
S.; Golebiowski, A. Tetrahedron Lett. 1994, 35, 7735. Enzymatic
resolution: J ohnson, C. R.; Sakaguchi, H. Synlett 1992, 813. Sundram,
H.; Golebiowski, A.; J ohnson, C. R. Tetrahedron Lett. 1994, 35, 6975.
(4) Suzuki coupling of a 2-iodo-2-cyclopentenone: (a) J ohnson, C.
R.; Braun, M. P. J . Am. Chem. Soc. 1993, 115, 11014. Stille coupling
of 2-iodo-2-cycloalkenones: (b) J ohnson, C. R.; Adams, J . P.; Braun,
M. P.; Senanayake, C. B. W. Tetrahedron Lett. 1992, 33, 919.
(5) (a) J ohnson, C. R.; Miller, M. W. J . Org. Chem. 1995, 60, 6674.
For a synthesis of (()-bromoxone see: (b) Gautier, E. C. L.; Lewis, N.
J .; McKillop, A.; Taylor, R. J . K. Tetrahedron Lett. 1994, 35, 8759.
(6) (a) Nagata, T.; Ando, Y.; Hirota, A. Biosci. Biotech. Biochem.
1992, 56, 810. (b) Kawazi, K.; Kobayashi, A.; Oe, K. J P 03 41,075, 1991;
Chem. Abstr. 1991, 115, 181517k. (c) Kobayashi, A.; Ooe, K.; Yata, S.;
Kawazu, K. Symposium of Papers, the 31st Symposium on the
Chemistry of Natural Products, Nagoya, October 1989, pp 388-395.
(d) Garlaschelli, L.; Magistrali, E.; Vidari, G.; Zuffardi, O. Tetrahedron
Lett. 1995, 36, 5633.
(9) For one example of a successful Sonogashira coupling between
2-bromo-2-cycloalkenone (2-bromo-2-cyclopentenone/THF/60 °C)
a
see: Buszek, K. R.; J eong, Y. Synth. Commun. 1994, 24, 2461. For a
recent review of the Sonogashira reaction see: Rossi, R.; Carpita, A.;
Bellina, F. Org. Prep. Proc. 1995, 27, 129.
(10) Kamikubo and Ogasawara utilized the enantiomeric enones (-)-
11 and (-)-12 in their synthesis of tricholomenyn A.7a Their synthesis
of the enone (-)-11 is quite different from ours.
(11) For R-iodination of enones see: J ohnson, C. R.; Adams, J . P.;
Braun, M. P.; Senanayake, C. B. W.; Wovkulich, P. M.; Uskokovic, M.
R. Tetrahedron Lett. 1992, 33, 917.
(12) Pilcher, A. S.; Hill, D. K.; Shimshock, S. J .; Waltermire, R. E.;
DeShong, P. J . Org. Chem. 1992, 57, 2492.
(13) These are interesting analogues of the natural product (+)-
bromoxone (ref 5). For a synthesis of (()-13 see ref 7b.
(14) Chiralcel OB: elution with i-PrOH/hexanes (15/85); 0.5 mL/
min; 260 nm; 20 min (+)-13; 33 min (-)-13.
(7) (a) Kamikubo, T.; Ogasawara, K. J . Chem. Soc., Chem. Commun.
1996, 1679. (b) Graham, A. E.; McKerrecher, D.; Huw Davies, D.;
Taylor, R. J . K. Tetrahedron Lett. 1996, 37, 7445.
S0022-3263(96)02295-5 CCC: $14.00 © 1997 American Chemical Society

Communications
Ta ble 1. Son oga sh ir a Cou p lin g w ith
J . Org. Chem., Vol. 62, No. 6, 1997 1583
Sch em e 4
2-Iod ocycloa lk en on es
from (-)-9.6b,c Furthermore, (+) and (-)-harveynone
were found to be g99% ee by chiral HPLC analysis.15
For the synthesis of (-)-tricholomenyn A, the side
chain 19 was assembled (Scheme 4).7a The commercially
available ketone, 6-methyl-5-hepten-2-one (16), was con-
verted into the vinyl triflate 17 using Comins’ triflimide
in 73% yield.16 The vinyl triflate 17 was converted into
the TMS enyne 18 in 88% yield (Sonogashira coupling).
The TMS group in 18 was removed (K2CO3/MeOH),
which gave the volatile enyne 19 in 81% yield. The iodo
enone (-)-12 and enyne 19 gave, after Sonogashira
coupling (PdCl2(PPh3)2/CuI/i-Pr2NH), the functionalized
enone (-)-20 in 54% yield. The TBS ether was removed
in (-)-20 under the standard conditions (H2SiF6/CH3CN)
to furnish the allylic alcohol (-)-21 in 79% yield. Lastly,
conversion of the alcohol (-)-21 into (-)-tricholomenyn
A (22) proceeded in 92% yield (DCC/AcOH). The data
for synthetic (-)-tricholomenyn A (22) agreed well with
that reported for natural (-)-22.6d The synthetic (-)-
tricholomenyn A was shown to be g99% ee by chiral
HPLC analysis.17 Thus, the synthesis of (-)-tricholo-
menyn A (22) and (+)- and (-)-harveynone (15) from
intermediates of known, absolute stereochemistry have
further corroborated their assignment.6a,d,7a
Sch em e 2
Sch em e 3
Ack n ow led gm en t. This work was supported by a
grant from the National Science Foundation (CHE-
9223011) and by an NIH postdoctoral fellowship (GM
16706) to M.W.M.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures, compound characterization data including chiral
HPLC data, and H and 13C NMR spectra of compounds 1-8,
1
The TBS ether (+)-12 and 2-methyl-1-buten-3-yne were
subjected to Sonogashira coupling (PdCl2(PPh3)2/CuI/i-
Pr2NH) to provide enyne (+)-14 in 52% yield (Scheme
3). The TBS ether (+)-14 was deprotected (H2SiF6/CH3-
CN), which furnished (+)-harveynone (15) in 81% yield.
The data for synthetic (+)-15 correspond well with those
reported for natural (+)-15.6a In an analogous fashion,
(-)-harveynone ([R]D -208 (c 0.45, MeOH)) was prepared
10-15, and 17-22 (51 pages).
J O962295Y
(15) Chiralcel OB: elution with i-PrOH/hexanes (5/95); 0.5 mL/min;
260 nm; 39 min (-)-15 min; 47 min (+)-15.
(16) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
(17) Chiralcel OB: elution with i-PrOH/hexanes (5/95); 0.5 mL/min;
260 nm; 23 min (-)-22 min; 40 min (+)-22.