Versatile synthesis of bicyclo[9.3.1]pentadecatriene for new bicyclic taxoids

Article abstract of DOI:10.1055/s-1998-1683

A common carbon skeleton bicyclo[9.3.1]pentadecatriene of taxachitrienes was synthesized in its des-methyl form in short steps. The key step was Nicholas-Hosomi type reaction in the acidic cyclization between ene-yne biscobalthexacarbonyl complex electrophile with allyltrimethylsilane nucleophile. Decomplexation of the biscobalthexacarbonyl was achieved with a tin hydride and NBS in 1,4-cyclohexadiene solvent.

Full text of DOI:10.1055/s-1998-1683

April 1998
SYNLETT
373
Versatile Synthesis of Bicyclo[9.3.1]pentadecatriene for New Bicyclic Taxoids
Satoshi Shibuya and Minoru Isobe*
Laboratory of Organic Chemistry, School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan
Fax +81-52-789-4111
Received 22 January 1998
Abstract: A common carbon skeleton bicyclo[9.3.1]pentadecatriene of
taxachitrienes was synthesized in its des-methyl form in short steps. The
key step was Nicholas-Hosomi type reaction in the acidic cyclization
between ene-yne biscobalthexacarbonyl complex electrophile with
One of the routes via intermediate 6 is summarized in Scheme 2. An
ene-yne coupling between the vinyl iodide 8 and acetylene 9 was
facilitated by palladium as catalyst under Sonogashira condition to give
11. Addition of biscobaltoctacarbonyl to this conjugate yne-diene
provided deep red color complex 12 which was further treated with
6
allyltrimethylsilane
nucleophile.
Decomplexation
of
the
biscobalthexacarbonyl was achieved with a tin hydride and NBS in 1,4-
cyclohexadiene solvent.
BF ·OEt for coupling with the third building block 10 under Nicholas
3 2
7,8,
effect and Hosomi-Sakurai condition.
The final cyclization of the
acetylene-ketone 6 with basic condition showed only 9 % yield at best
as an extremely poor result. This result suggested a thermodynamic
limitation of the intramolecular yne-one addition reaction for the 12-
membered ring cyclization.
Drug development toward antitumor agents has been continued as an
activity of organic synthesis. Recently several new bicyclic taxoids
diterpenoids (1, 2 and 3 ) were found from the needles of Taxus
chinensis, or Taxus canadensis, respectively. These have been proposed
as the biogenetic precursor for taxanes. We became interested in the
1
2
synthesis of this class of compounds (1,
2
and 3) having
bicyclo[9.3.1]pentadecatriene. It has
a similarity of the carbon
3
framework with taxol (4) to which five total syntheses have been
4
achieved. All of these compounds possess the same A ring having gem-
dimethylcyclohexene, but the former bicyclic compounds have the
double bond with less strain energy at the bridge head position because
of fused ring with 12 membered ring rather than the 8 membered ring in
taxol. This paper deals with a versatile synthesis of a common
framework bicyclo[9.3.1]pentadecatriene of 1, 2 and 3.
Scheme 2
Retrosynthesis of the target framework 5 (des-methyl at the olefinic
position of A ring) is summarized in Scheme 1. Disconnection of the C-
C bonds at the 3 positions (a, b and c) should lead us two routes for 3
components coupling strategy, to which we decided first to connect
bond a. Two alternative coupling orders at b or c should give two
possible synthetic intermediates 6 and 7, respectively. In these cases an
acetylene biscobalthexacarbonyl complex is to be involved for putting
the reaction centers as close as possible to each other (Fig 1, in Scheme
3). All of the 3 building blocks (8, 9 and 10) were synthesized from
We have examined an alternative b route of cyclization through
intermediate 7 (equivalent to 15 in Scheme 3). Intermolecular addition
of the magnesium acetylide of 10 to the ketone 11 afforded the adduct
14. The tert-propargylic alcohol was protected as TBS ether, and one of
the two acetylene groups was selectively converted into the
corresponding biscobalthexacarbonyl complex under the usual way to
9
provide 15.
5
commercially available compounds in a few steps, respectively.
Scheme 1
Scheme 3

374
LETTERS
SYNLETT
Marquess, D. G.; McGrane, P. L.; Meng, W.; Natchus, M. G.; Shuker,
A. J.; Sutton, J. C.; Taylor, R. E. J. Am. Chem. Soc. 1997, 119, 2757-
2758. (e) Mukaiyama, T.; Shiina, I.; Iwadare, H.; Sakoh, H.; Tani, Y.;
Hasegawa, M.; Saitoh, K. Proc. Japan Acad. 1997, 73, Ser. B, 95-100.
The cyclization reaction of 15 was the most crucial step in this
synthesis; thus, simple addition of Lewis acid in dichloromethane as
solvent provided very poor yield of 17. A variety of possible conditions
for this cyclization were examined; e.g. usage of a resin (Amberlyst
15E) having strong protonic acid nature and diluted conditions afforded
the cyclized product 17 in 58 % yield, but poor reproducibility. Finally
(5) Preparation of starting material
8, 9 and 10:
(a) A-ring 8 was synthesized from mono ketal of 2,2-dimethyl 1,3-
cyclohexadione in 4 steps.
we found that careful addition of BF •OEt into a 0.001M solution of
3
2
10
16 in dichloromethane at -78 °C and then warmed to 0 °C for 40 min
11
afforded 17 in 43 % yield with reproducibility. Decomplexation of the
product 17 was achieved by heating its solution containing n-Bu SnH
3
12
and a catalytic amount of NBS in 1,4-cyclohexadiene at 39 °C for 2 h.
13
The product 18 as isolated in 40-45% yield.
(i) H2NNHTs / MeOH, 87 %; (ii) n-BuLi, n-Bu3SnCl / THF-TMEDA
(5:1); (iii) I2 / Et2O, 77 % in 2 steps; (iv) 3N HCl-THF (1:1), 97 %.
(b) Allylic alcohol 9 was synthesized from metyhl vinyl ketone in 4
steps.
(i) Me3Si-≡-Li / THF, 31 %; (ii) K2CO3 / MeOH; (iii) 10 % H2SO4; (iv)
TBSCl, imidazole / DMF, 53 % in 3 steps.
(c) Terminal acetylene 10 was synthesized from 2,3-dibromopropene in
3 steps.
As a summary we examined two cyclization reactions for the desmethyl
carbon framework of taxachitrienes, and only one of the two routes
exhibited
a reasonable result in the 12-membered cyclization.
Decomplexation of the biscobalthexacarbonyl was achieved under new
condition to provide the tetra-ene-yne bicyclo[9.3.1]pentadecatriene.
Overall reaction from 8 to 18 was 13 % in 8 steps.
(i) Me3SiLi, CuI / HMPA, 42 %; (ii) Me3Si-≡-H, Pd(OAc)2, Ph3P, CuI,
n-BuNH2 / THF, 95 %; (iii) K2CO3 / MeOH, 93 %.
Acknowledgement This research was financially supported by a Grant-
In-Aids for Scientific Research from the Ministry of Education,
Science, Sports and Culture and by JSPS-RFTF. S. S. is grateful to JSPS
for a Research Fellowships for Young Scientists. Special thanks are due
to Mr. S. Kitamura in Nagoya University for the measurement of
elemental analysis and high resolution mass spectra.
(6) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467-
4470.
(7) (a) Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207-214., and references
cited therein. (b) Schreiber, S. L.; Sammakia, T.; Crowe, W. E. J. Am.
Chem. Soc. 1986, 108, 3128-3130. (c) Nakamura, T.; Matsui, T.;
Tanino, K.; Kuwajima, I.
. , , 3032-3033.
J. Org. Chem 1997 62
(d) Hosomi, S. Acc. Chem. Res. 1988, 21, 200-206.
(8) Our laboratory reported polyether syntheses using acetylene
biscobalthexacarbonyl as key intermediates. (a) Isobe, M.; Yenjai, C.;
Tanaka, S. Synlett, 1994, 916-918. (b) Hosokawa, S.; Isobe, M. Synlett,
1995, 1178-1179. (c) Hosokawa, S.; Isobe, M. Synlett, 1996, 351-352.
(d) Isobe, M.; Hosokawa, S.; Kira, K. Chem. Lett. 1996, 473-474.
References and Notes
(1) (a) Fang, W.-S.; Fang, Q.-C.; Liang, X.-T.; Lu, Y.; Zheng, Q.-T.
Tetrahedron 1995, 51, 8483-8490. (b) Fang, W.-S.; Fang, Q.-C.; Liang,
X.-T. Planta Med., 1996, 62, 567-569.
(2) (a) Zamir, L. O.; Zhou, Z. H.; Caron, G.; Nedea, M. E.; Sauriol, F.;
Mamer, O. J. Chem. Soc., Chem. Commun. 1995, 529-530.
(b) Boulanger, Y.; Khiat, A.; Zhou, Z.-H.; Caron, G.; Zamir, L. O.
Tetrahedron 1996, 52, 8957-8968.
(9) When a methyl group was present on the olefin of the 6-membered ring,
the cobalt complex did not form at this position.
(10) Precursor 16 was synthesized from TBS ether of 14 in 3 steps.
(i) Amberlyst 15E / MeOH, 83 %; (ii) Ac2O, pyridine, 93 %;
(iii) Co2(CO)8 / CH2Cl2, quant.
(3) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail, A. T.
J. Am. Chem. Soc. 1971, 93, 2325-2327.
(11) Hosokawa, S.; Isobe, M. Tetrahedron Lett. submitted for publication.
(4) (a) Holton, R. A.; Somoza, C.; Kim, H.-B.; Liang, F.; Biediger, R. J.;
Boatman, P. D.; Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H.;
Suzuki, Y.; Tao, C.; Vu, P.; Gentile, L. N.; Liu, J. H. J. Am. Chem. Soc.
1994, 116, 1597-1598. Holton, R. A.; Kim, H.-B.; Sozoma, C.; Liang,
F.; Biediger, R. J.; Boatman, P. D.; Shindo, M.; Smith, C. C.; Kim, S.;
Nadizadeh, H.; Suzuki, Y.; Tao, C.; Vu, P.; Gentile, L. N.; Liu, J. H.
ibid. 1994, 116, 1599-1600. (b) Nicolaou, K. C.; Yang, Z.; Liu, J. J.;
Ueno, H.; Nantermet, P. G.; Guy, R. K.; Claiborne, C. F.; Renaud, J.;
Couladouros, E. A.; Paulvannan, K.; Sorensen, E. J. Nature, 1994, 367,
630-634. (c) Masters, J. J.; Link, J. T.; Snyder, L. B.; Young, W. B.;
Danishefsky, S. J. Angew. Chem. Int. Ed. Engl. 1995, 34, 1723-1726.
(d) Wender, P. A.; Badham, N. F.; Conway, S. P.; Floreancig, P. E.;
Glass, T. E.; Gränicher, C.; Houze, J. B.; Jänichen, J.; Lee, D.;
Marquess, D. G.; McGrane, P. L.; Meng, W.; Mucciaro, T. P.;
Mühlebach, M.; Natchus, M. G.; Paulsen, H.; Rawlins, D. B.; Satkofsky,
J.; Shuker, A. J.; Sutton, J. C.; Taylor, R. E.; Tomooka, K. J. Am. Chem.
Soc. 1997, 119, 2755-2756. Wender, P. A.; Badham, N. F.; Conway, S.
P.; Floreancig, P. E.; Glass, T. E.; Houze, J. B.; Krauss, N. E.; Lee, D.;
(12) In previous report (ref.11), we used a large excess of n-Bu3SnH (10-12
equiv.) in benzene solvent at 65 °C for 2 h. NBS promoted this
decomplexation, which was effective to reduce the amount of n-Bu3SnH
and to lower the reaction temperature. We used 3 equiv. of n-Bu3SnH
and 0.2 equiv. of NBS.
(13) Compound 18: IR (KBr, film) νmax 2956, 2929, 2856, 1249 cm-1 1H
.
NMR (CDCl3, 400 MHz) δ 0.20 (3H, s, SiCH3), 0.22 (3H, s, SiCH3),
0.90 (9H, s, SiC(CH3)3), 1.11 (3H, s, C(CH3)2), 1.16 (3H, s, C(CH3)2),
1.64 (3H, d, J = 1.5 Hz, C(CH3)=CH), 1.71-1.79 (1H, m, CH2), 2.01-
2.18 (3H, m, CH2), 2.21-2.40 (4H, m, CH2 ×2), 5.19 (1H, d, J = 2.1 Hz,
C=CHH), 5.20 (1H, tq, J = 6.5, 1.5 Hz, C(CH3)=CH), 5.23 (1H, d, J =
2.1 Hz, C=CHH), 5.78 (1H, d, J = 11.5 Hz, CH=C-CH=CH), 5.83-5.93
(2H, m, CH=C-CH=CH). 13C NMR (CDCl3, 100 MHz) δ -3.1, -2.9,
17.0, 18.3, 21.9, 24.3, 24.8, 25.8, 29.8, 32.3, 38.4, 43.5, 74.2, 86.2, 93.4,
120.1, 122.5, 127.8, 128.9, 131.2, 132.4, 134.4, 142.0. MS (EI) m/z 382
(M+), 367 (M-15). HRMS (EI) calcd for C25H38OSi: 382.2692, found
382.2712.