Efficient Synthesis of (-)trans-Kumausyne via Tandem Intramolecular Alkoxycarbonylation-Lactonization

Full text of DOI:10.1021/jo972066r

916
J . Org. Chem. 1998, 63, 916-917
Sch em e 1
Efficien t Syn th esis of (-)-tr a n s-Ku m a u syn e
via Ta n d em In tr a m olecu la r
Alk oxyca r bon yla tion -La cton iza tion
J ohn Boukouvalas,* Genevie`ve Fortier, and
Ioan-Iosif Radu
De´partement de Chimie, Universite´ Laval,
Que´bec G1K 7P4, Canada
Received November 11, 1997
The red algal metabolites trans-kumausyne (1a ) and
deacetylkumausyne (1b),1 by virtue of their unusual all-cis
3-oxygenated-2,5-dialkyltetrahydrofuran core and rich func-
tionality, have been the object of considerable synthetic
effort.2 Overman’s group accomplished the landmark total
synthesis of (()-1a in 18 steps from 2-cyclopentylidenecy-
clopentanone using a novel Prins cyclization-pinacol rear-
rangement for elaborating the tetrahydrofuran (THF) core.3
During the course of our work,4 Sugimura reported an
enantioselective synthesis of 1a from L-arabinose (19 steps,
1.1% overall yield) in which the THF ring is formed by
cyclization of a â-silyl cation.5 More recently, Mart´ın
disclosed a 22-step synthesis of (-)-1b from propargyl alcohol
that employs brominative cyclization as the key step.6
Prompted by these reports, we describe here a considerably
shorter and simpler synthesis of (-)-trans-kumausyne by a
potentially general pathway that we expect to extend in due
course to the preparation of brown algal metabolites (e.g.,
2a -c) that possess a 2S,3S,5R 3-oxygenated-2,5-dialkyltet-
rahydrofuran core.7
of the THF unit (cf. 4 f 3, Scheme 1). Either diastereoiso-
mer of diol 4 (2R,4R or 2R,4S) should be accessible at will
from the same ketone (5) by stereoselective reduction under
the appropriate conditions.9
Our approach began with the selective reduction10 of
dimethyl (R)-malate (6) to the known diol 711,12 (Scheme 2).
Treatment of 7 with 1 equiv of tert-butyldiphenylsilyl
chloride and imidazole in DMF at 0 °C accomplished
selective protection of the primary alcohol group to furnish
813 in 91% yield. Ester 8 was transformed into â-hydroxy
enone 10 by recourse to Weinreb’s method.14 Thus, reaction
of 8 with N,O-dimethylhydroxylamine hydrochloride in the
presence of trimethylaluminum provided the crystalline
N-methoxy-N-methylamide 9 (89%), which on exposure to
vinylmagnesium bromide gave enone 10 in an unoptimized
yield of 53%. This enone was subjected to reduction under
the Evans protocol9 (Me4NHB(OAc)3 in MeCN/AcOH) to
afford the desired anti-diol 11 in 89% yield after silica gel
chromatography. None of the syn-isomer of 11 could be
detected in the 1H NMR spectrum of the crude reduction
product.15
With a supply of diol 11 in hand, the stage was now set
for the crucial alkoxycarbonylation-lactonization. Treat-
ment of 11 with carbon monoxide in the presence of PdCl2
(0.1 equiv), CuCl2 (3 equiv), and AcONa (4 equiv) in AcOH8
afforded uniquely the bicyclic lactone16 12 in a yield of 93%.
Crafting of the lactone ring into the requisite enyne and
hydroxyl appendages was accomplished by DIBAL-H reduc-
tion and subsequent Wittig-olefination with the commer-
cially available [3-(trimethylsilyl)-2-propynyl]triphenylphos-
honium bromide.17 In this manner, pure trans-enyne 13
was obtained in 85% yield after separation from its cis-
isomer (8%) by flash chromatography. Next, 13 was con-
(8) (a) Semmelhack, M. F.; Bodurow, C.; Baum, M. Tetrahedron Lett.
1984, 25, 3171-3174. (b) Tamaru, Y.; Kobayashi, T.; Kawamura, S.; Ochiai,
H.; Hojo, M.; Yoshida, Z. Tetrahedron Lett. 1985, 26, 3207-3210.
(9) Evans, D. A.; Gauchet-Prunet, J . A.; Carreira, E. M.; Charette, A. B.
J . Org. Chem. 1991, 56, 741-750 and references therein.
(10) Saito, S.; Ishikawa, T.; Kuroda, A.; Koga, K.; Moriwake, T. Tetra-
hedron 1992, 48, 4067-4086.
Retrosynthetic analysis dictated by considerations of
atom-economy and stereochemical flexibility suggested that
both 1a and 2a , as well as their congeners, should be
available by a unified strategy based upon tandem intramo-
lecular alkoxycarbonylation-lactonization8 for assemblage
(11) Robinson, R. A.; Clark, J . S.; Holmes, A. B. J . Am. Chem. Soc. 1993,
115, 10400-10401.
(12) Yields refer to chromatographically purified products, characterized
by high-field 1H and 13C NMR. The elemental composition of new compounds
was confirmed by C,H-microanalyses or HRMS.
(1) Suzuki, T.; Koizumi, K.; Suzuki, M.; Kurosawa, E. Chem. Lett. 1983,
1643-1644.
(2) For synthetic studies in this area see: (a) Tonn, C. E.; Palazo´n, J .
M.; Ruiz-Pe´rez, C.; Rodr´ıguez, M. L.; Mart´ın, V. S. Tetrahedron Lett. 1988,
29, 3149-3152. (b) Stuart, J . G.; Nicolas, K. M. Heterocycles 1991, 32, 949-
963. (c) Andrey, O.; Landais, Y. Tetrahedron Lett. 1993, 34, 8435-8438.
(d) Evans, P. A.; Roseman, J . D. Tetrahedron Lett. 1995, 36, 31-35. (e)
Andrey, O.; Glanzmann, C.; Landais, Y.; Parra-Rapado, L. Tetrahedron
1997, 53, 2835-2854.
(13) Banfi, L.; Cascio, G.; Guanti, G.; Manghisi, E.; Narisano, E.; Riva,
R. Tetrahedron 1994, 50, 11967-11982. See also: Wess, G.; Kesseler, K.;
Baader, E.; Bartmann, W.; Beck, G.; Bergmann, A.; J endralla, H.; Bock,
K.; Holtzstein, G.; Kleine, H.; Schnierer, M. Tetrahedron Lett. 1990, 31,
2545-2548.
(14) (a) Levin, J . I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982,
12, 989-993. (b) For an excellent review see: Sibi, M. P. Org. Prep. Proc.
Int. 1993, 25, 15-40.
(3) Brown, M. J .; Harrison, T.; Overman, L. E. J . Am. Chem. Soc. 1991,
113, 5378-5384.
(15) Diol 11 was readily distinguished by NMR from its syn-isomer (R,R);
the latter was prepared by reduction of 10 with NaBH4 in the presence of
Et2BOMe (cf. ref 9).
(16) A substantially longer route to lactone 12 from L-arabinose (12 steps)
and the transformation of 12 into (-)-1a and (-)-1b have been reported by
Sugimura (ref 5).
(4) Presented in parts at the 211th ACS National Meeting, New Orleans,
LA, March 24-28, 1996 (ORGN 434), and the 78th CSC Conference and
Exhibition, Guelph, Ontario, May 28-J une 1, 1995 (OR6: 338).
(5) Osumi, K.; Sugimura, H. Tetrahedron Lett. 1995, 36, 5789-5792.
(6) Mart´ın, T.; Soler, M. A.; Betancort, J . M.; Mart´ın, V. S. J . Org. Chem.
1997, 62, 1570-1571.
(17) Nicolaou, K. C.; Webber, S. E. J . Am. Chem. Soc. 1984, 106, 5734-
5736. See also ref 5.
(7) Barrow, R. A.; Capon, R. J . Aust. J . Chem. 1990, 43, 895-911.
S0022-3263(97)02066-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/30/1998

Communications
J . Org. Chem., Vol. 63, No. 4, 1998 917
Sch em e 2a
a
Key: (a) BH3‚Me2S, NaBH4, THF, rt (87%); (b) TBDPSCl (1 equiv), imidazole, DMF, 0 °C (91%); (c) (MeO)MeNH‚HCl, AlMe3, CH2Cl2, 40 °C
(89%); (d) CH2dCHMgBr, THF, 20 f 50 °C (53%); (e) Me4NHB(OAc)3, MeCN-AcOH, -40 °C (89%); (f) CO, PdCl2 (0.1 equiv), CuCl2 (3 equiv),
AcONa (4 equiv), AcOH, rt (93%); (g) DIBAL-H (1.5 equiv), THF, -78 °C (100%); (h) TMSCtCCH2P+Ph3Br- (2 equiv), t-BuOK, Et2O, rt (85%); (i)
Ac2O, DMAP, pyridine, rt (100%); (j) PhCH2NMe3F‚xH2O, MeCN, 0 f 25 °C (95%); (k) Swern oxidation (96%); (l) (CH2dCH)CH(TMS)Et, BF3‚Et2O,
CH2Cl2, -78 f +25 °C (52%); (m) CBr4, n-Oct3P, toluene, 80 °C (50%).
verted to the acetate 14 in quantitative yield. Removal of
both silyl protecting groups of 14 was best achieved (95%
yield) by using benzyltrimethylammonium fluoride hydrate18
in acetonitrile. Swern oxidation of the resulting alcohol 15
afforded aldehyde 16 with high efficiency. Elaboration of
the trans-1-bromo-3-hexenyl side chain was carried out in
a fashion similar to that described by Overman.3 Thus,
Sakurai reaction of aldehyde 16 with 3-(trimethylsilyl)-1-
pentene3 provided alcohol 17 as the sole isomer in 52% yield.
Treatment of this alcohol with CBr4 and tri-n-octylphosphine
in toluene19 at 80 °C afforded (-)-trans-kumausyne (1a ,
demonstrates the serviceability of the general plan outlined
in Scheme 1 for stereocontrolled construction of 3-oxygenated
2,5-dialkyltetrahydrofurans. In addition, this work serves
to highlight the intrinsic power of tandem intramolecular
alkoxycarbonylation-lactonization for building complexity
rapidly, in atom-economical fashion. Further applications
of this strategy to the synthesis of structurally related
natural products are in progress and will be reported in due
course.
Ack n ow led gm en t. We thank NSERC (Canada) for
financial support and FCAR (Que´bec) for postgraduate
scholarships to G.F. and I.-I.R.
50%), whose optical rotation [[R]26 -2.9° (c 0.11, CHCl3)
D
[lit.1 [R]26 -2.3° (c 0.62, CHCl3)]] and spectral properties
D
(1H and 13C NMR, and IR) were consistent with those
reported in the literature.1,3
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and characterization data for compounds 8-17 and 1a (11
pages).
In summary, we have achieved an exceptionally concise
and efficient synthesis of (-)-trans-kumausyne20 from di-
methyl (R)-malate (13 steps, 6.2% overall yield), which
J O972066R
(18) This reagent proved superior to TBAF for deprotecting 14; for similar
observations see: Paquette, L. A.; Doherty, A. M.; Rayner, C. M. J . Am.
Chem. Soc. 1992, 114, 3910-3926.
(19) (a) Hooz, J .; Gilani, S. S. H. Can. J . Chem. 1968, 46, 86-87. (b)
Tsushima, K.; Murai, A. Tetrahedron Lett. 1992, 33, 4345-4348.
(20) After submission of this manuscript, a 22-step synthesis of (-)-trans-
kumausyne from D-xylose, which employs radical cyclization of a â-alkoxy-
acrylate as the key step, was reported by Lee: Lee, E.; Yoo, S.-K.; Cho,
Y.-S.; Cheon, H.-S,; Chong, Y. H. Tetrahedron Lett. 1997, 38, 7757-7758.