Connecting Directed Ortho Metalation and Olefin Metathesis Strategies. Benzene-Fused Multiring-Sized Oxygen Heterocycles. First Syntheses of Radulanin A and Helianane

Full text of DOI:10.1021/jo980299s

2808
J . Org. Chem. 1998, 63, 2808-2809
Sch em e 1
Con n ectin g Dir ected Or th o Meta la tion a n d
Olefin Meta th esis Str a tegies. Ben zen e-F u sed
Mu ltir in g-Sized Oxygen Heter ocycles. F ir st
Syn th eses of Ra d u la n in A a n d Helia n a n e
Marijan Stefinovic and Victor Snieckus*
Guelph-Waterloo Center for Graduate Work in Chemistry,
University of Waterloo, Waterloo, Ontario N2L 3G1, Canada
Received February 20, 1998
Despite its profoundly consequential foundation in poly-
mer chemistry,1 the olefin metathesis reaction has only
recently enticed the attention of synthetic organic chemists,
stimulating methodological studies2 and total synthesis
realizations.3 While numerous medium-ring and macro ring
carbocyclic and heterocyclic ring-closing metathesis (RCM)
motifs have been reported,1b,d few benzannulated oxygen
heterocycle constructs have been explored. Herein, we
report the first cases of such RCM processes for various ring
sizes n ) 7-9, 12, and 14, demonstrating the synthetic link
between RCM and the regiospecific directed ortho metalation
(DoM) strategy,4 potentially part of a broader program in
the context of the conceptualization 1 f 2 f 3, and tailor
this combined methodology to the first syntheses of radu-
lanin A (13c) and (()-helianane (18), natural products
isolated from Radula variabilis5 and Haliclona fascigera6
respectively.
Scheme 1 summarizes exploration of ring-size effects on
the RCM of the systematic series 4a -c, prepared by DoM
routes,7 leading to annulated products 5a -c. In consonance
with observations by Grubbs,8 higher yields were observed
for n ) 3 than for n ) 6 and 8 due to greater conformational
restraint in the former system. Attempts to improve yields
by ethylene pretreatment2a were unsuccessful, and refluxing
the reaction mixtures brought only marginal improvement
in yields of 5b and 5c. In contrast, the biaryl systems 6a ,b
underwent cyclization at room temperature without the use
of ethylene to give macrocycle diethers 7a ,b in excellent yield
(Scheme 1). Precursor 8, which exhibits optional RCM
reaction modes, afforded only the benzoxepin 9, indicative
of an entropic preference for seven-membered ring forma-
tion. Grubbs’ ruthenium catalyst was used for all reactions;
Schrock catalyst, in contrast to serving beneficially for a
variety of reported cases,2d was ineffective in these RCM
reactions.
The combined DoM-RCM strategy, 1 f 2 f 3, finds
effective expression in the first total syntheses of a calm-
odulin inhibitor, radulanin A (13c) (Scheme 2), and heli-
anane (18) (Scheme 3). Thus, in the first of these, the readily
constructed 10a 9 was subjected to a DoM-transmetalation-
allylation sequence to give 11a , which upon acid-catalyzed
MOM ether cleavage and O-allylation gave diallylated
(1) (a) Ivin, K.
J Olefin Metathesis and Metathesis Polymerization;
Academic Press: San Diego, 1997. (b) Grubbs, R. J .; Miller, S. J .; Fu, G. C.
Acc. Chem. Res. 1995, 28, 446. (c) Schrock, R. R. Acc. Chem. Res. 1990, 23,
158. (d) Schmalz, H.-G. Angew. Chem., Int. Ed. Engl. 1995, 107, 1981. (e)
Buchmeiser, M. R.; Atzl, N.; Bonn, K. J . Am. Chem. Soc. 1997, 119, 9166.
(d) Review: Blechert, S.; Schuster, M. Angew. Chem., Int. Ed. Engl. 1997,
36, 2036.
(2) (a) Xu, Z.; J ohannes, C. W.; Houri, A. F.; La, D. S.; Cogan, D. A.;
Hofilena, G. E.; Hoveyda, A. H. J . Am. Chem. Soc. 1997, 119, 10302. (b)
Furstner, A.; Langemann, K. J . Am. Chem. Soc. 1997, 119, 9130. (c) Cossy,
J .; Meyer, C. Tetrahedron Lett. 1997, 38, 7861. (d) Grubbs, R. J .; Kirkland,
T. A. J . Org. Chem. 1997, 62, 7310. (e) Snapper, M. L.; Tallarico, J . A.;
Bonitatebus, P. J . J . Am. Chem. Soc. 1997, 119, 7157.
(3) (a) Nicolaou, K. C.; He, Y.; Vourloumis, H.; Vallberg, Z.; Yang, Z.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2554. (b) Danishefsky, S. J .;
Sorensen, E. J .; Balog, A.; Meng, D.; Kamenecka, T.; Bertinato, P.; Su, D.-
S. Angew. Chem., Int. Ed. Engl. 1996, 35, 2801.
(4) Snieckus, V. Chem. Rev. 1990, 90, 879. Snieckus, V. In Chemical
Synthesis Gnosis to Prognosis; Chatgilialoglu, C., Snieckus, V., Eds.; NATO
ASI Series, Series E: Applied Sciences; Kluwer Academic Publishers:
Dordrecht, The Netherlands, 1996; Vol. 320, p 191. For a recent industrial
application, see: Larsen, R. D.; King, A. O.; Chen, C. Y.; Corley E. G.; Foster
B. S.; Roberts, F. E.; Yang, C; Lebermann, D. R.; Reamer, R. A.; Tschaen
R. M.; Verhoeven, T. R.; Rieder P. J .; Lo, Y. S.; Rossano, L. T.; Brookes, S.
A., Meloni, D.; Moore, J . R. Arnett, J . F. J . Org. Chem. 1994, 59, 6391.
(5) Asakawa, Y.; Toyota, M.; Takemoto, T. Phytochemistry 1978, 17, 2005.
(6) Crews, P.; Harrison, B. J . Org. Chem. 1997, 62, 2646.
(9) Compounds 10a and 10b were prepared from commercial 3,5-
dimethoxybenzaldehyde in four steps, 63% and 54% overall yields, respec-
tively, as follows: (1) PPh3CH2Ph/THF; (2) H2/Pd-C; (3) NaSEt/DMF; (4)
for 10a , MOMCl/NaOH(aq)/CH2Cl2/Bu4NHSO4; for 10b, ClCONEt2/K2CO3/
MeCN.
(10) Superchi, S.; Salvadori, P.; Pini, D. J . Organomet. Chem. 1993, 452,
14.
(11) Barghellini, G. Gazz. Chim. Ital. 1906, 36, 337. For use of this
reaction in a similar context, see: Grimm, E. L.; Trimble, L. A. Tetrahedron
Lett. 1994, 35, 6847.
(7) Compounds 4a -c were obtained from 3-methoxyphenol in four steps
as follows: (1) MOMCl/CH2Cl2/NaOH/Bu4NHSO4; (2) s-BuLi/TMEDA/THF
then MgBr2‚Et2O and allyl bromide; (3) HCl (aq)/THF/MeOH; (4) Cs2CO3/
DMF/CH2dCH(CH2)nBr (n ) 3, 6, and 8).
(8) Miller, S. J .; Kim, S.-H.; Chen, Z.-R.; Grubbs, R. H. J . Am. Chem.
Soc. 1995, 117, 2108.
S0022-3263(98)00299-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/11/1998

Communications
J . Org. Chem., Vol. 63, No. 9, 1998 2809
Sch em e 2
Sch em e 3
followed by hydrogenation without intermediate isolation to
give (()-helianane (18) (9 steps, 6% overall yield). Its
identity was established by direct comparison of spectro-
scopic data (NMR, MS) with an authentic sample.6
Multisized benzene-ring annulation processes 4a ,c f 5a ,c
and 6a ,b f 7a ,b by advantageous combination of DoM and
RCM protocols has been demonstrated, and its application
to the synthesis of medium-sized ring natural products has
been achieved. Extensions of the combined methodology to
other directed metalation groups and modern synthetic
processes may be envisaged and are in progress.
product 12a . Upon treatment with 20 mol % of Ru-based
catalyst (0.002 M/CH2Cl2/16 h/25 °C), 12a afforded radulanin
A methyl ether (13a ).5 Since demethylation of 13a was
compromised by the presence of the cyclic allylic ether, the
synthesis of radulanin A (13c) was diverted to an approach
starting with the O-carbamate 10b. Following a sequence
identical to that used for 13a , sequential C- (f 11b) and
O-allylation (f 12b) and RCM reaction afforded benzoxepine
13b. Reduction using LAH completed the synthesis of
radulanin A (13c)5 (11 steps, 14% overall yield). Synthetic
samples of 13c and 13a showed spectroscopic data (NMR)
identical with those reported for the natural product and
its methyl ether, respectively.5
The synthesis of helianane (18), a racemic natural prod-
uct, was initiated from the m-cresol O-carbamate 14, which,
upon regioselective lithiation, transmetalation to the cu-
prate,10 Michael addition, followed by Wittig olefination and
reductive decarbamoylation, furnished the phenol 15 in 52%
overall yield. In an interesting reaction discovered by
Barghellini,11 15 was converted into the gem-dimethyl
carboxylic acid 16. A three-step sequence involving an
ultimate Peterson olefination provided the RCM precursor
17, which was subjected to Ru-mediated conditions as before
Ack n ow led gm en t. We thank Prof. P. Crews for rapid
provision of a sample and spectral data of (+)-helianane
and NSERC Canada for financial support via the Mon-
santo/NSERC Industrial Research Chair and Research
Grant programs. Helpful comments were provided by Bill
Crowe and Marc Snapper. We are grateful to J an Venne
for the provision of high-field NMR spectra.
Su p p or tin g In for m a tion Ava ila ble: Experimental procedure
for the cyclization of 4a to 5a , for the allylation of 10b, for the
synthesis of 15 and 16, characterizations for 4a , 5a , 6a , 7a , 11b,
12b, 13a , 15, and 16, and selected data for synthetic 13c and 18
(7 pages).
J O980299S