Biomimetic-type synthesis of halogenated tetrahydrofurans from Laurencia. Total synthesis of trans-(+)-deacetylkumausyne

Full text of DOI:10.1021/jo962135m

1570
J . Org. Chem. 1997, 62, 1570-1571
Biom im etic-Typ e Syn th esis of Ha logen a ted
Tetr a h yd r ofu r a n s fr om La u r en cia . Tota l
Syn th esis of tr a n s-(+)-Dea cetylk u m a u syn e
Toma´s Mart´ın, Marcos A. Soler,
J uan M. Betancort, and Victor S. Mart´ın*
Instituto Universitario de Bio-Orga´nica “Antonio Gonza´lez”,
Universidad de La Laguna, Carretera de La Esperanza, 2,
38206 La Laguna, Tenerife, Spain
Received November 15, 1996
An important group of marine natural products are a
series of nonterpenoid C15-metabolites generically named
lauroxanes that are derived from fatty acid metabolism
(acetogenins).1 The structural diversity of this kind of
molecule is very wide, but all have in common the
presence of polysubstituted cyclic ethers with a defined
stereochemistry in the substituents and ring size chang-
ing from five to nine members (Figure 1). Such cyclic
ethers are considered to be biogenetically originated from
laurediols through electrophilic cyclizations usually in-
duced by bromonium ion.1
Many compounds of this class contain a tetrahydrofu-
ran ring usually with a syn-stereochemistry in the alkyl
substituents close to the oxygen atom of the cycle.1
Substances of this class are trans-(-)-kumauseine (1) and
trans-(+)-deacetylkumausine (2) isolated from Laurencia
nipponica Yamada.2 To the best of our knowledge, until
now only two syntheses of kumauseine (1) have been
reported: in one case in racemic form, reported by
Overman et al.,3 and the other in enantiomeric form,
reported by Osumi et al.4 In our group, synthetic studies
directed to the enantiomeric synthesis of this compound
have also been carried out, mainly directed toward the
stereocontrolled synthesis of the substituted tetrahydro-
furan by intramolecular cyclization of hydroxyalkenes
induced by a bromonium ion.5 Unfortunately, we were
unable to extend our methodology to the final natural
products mainly because the difficulties encountered to
construct the carbon framework.6
F igu r e 1.
Sch em e 1
Sch em e 2
As pointed out above, we have considered an approach
to the synthesis of exo-bromotetrahydrofurans by a
procedure that is formally similar to that considered as
the responsible of the biogenetic origin of this kind of
structural unit.5 On the other hand, we have also
performed the total enantiomeric synthesis of laurediols,
which are assumed to be the biogenetic precursors of the
whole series of compounds.7 Our synthesis of such
precursors was performed in a lineal manner and was
not considered as optimal to scale the final products to
perform electrophilic cyclization studies. In this paper,
we report a different approach to (+)-deacetylkumausine,
as an example of a compound of this class, based on the
retrosynthetic analysis, outlined in Scheme 1, in which
we tried to solve both problems discussed above: con-
vergence in the synthesis of the hydroxyalkene precursors
with the possibility of scaling up the amount of final
product obtained and stereochemical control in the
synthesis of the cyclic ether with facilities to build the
whole molecule.
(1) (a) Moore, R. E. In Marine Natural Products; Scheuer, P. J ., Ed.;
Academic Press: New York, 1978; Vol. 1, pp 43-121. (b) Erickson, K.
L. In Marine Natural Products; Scheuer, P. J ., Ed.; Academic Press:
New York, 1983; Vol. V, pp 131-257. (c) Faulkner, D. J . Nat. Prod.
Rep. 1984, 1, 251; (d) 1986, 3, 1; (e) 1987, 4, 539; (f) 1988, 5, 613; (g)
1990, 7, 269; (h) 1991, 8, 97; (i) 1992, 9, 323; (j) 1993, 10, 497; (k)
1994, 11, 355; (l) 1995, 12, 223.
(2) Suzuki, T.; Koizumi, K.; Suzuki, M.; Kurosawa, E. Chem. Lett.
1983, 1643.
(3) Brown, M. J .; Harrison, T.; Overman, L. E. J . Am. Chem. Soc.
1991, 113, 5378.
(4) Osumi, K.; Sugimura, H. Tetrahedron Lett. 1995, 36, 5789.
(5) Tonn, C. E.; Palazo´n, J . M.; Ruiz-Pe´rez, C.; Rodr´ıguez, M. L.;
Mart´ın, V. S. Tetrahedron Lett. 1988, 29, 3149.
(6) An˜orbe, B.; Mart´ın, V. S. Unpublished results.
(7) An˜orbe, B.; Mart´ın, V. S.; Palazo´n, J . M.; Trujillo, J . M.
Tetrahedron Lett. 1986, 27, 4991.
Our synthesis of 2 started from the silyl-protected
threo-1,2-epoxy-3-alcohol 7 easily available from the
known enyne 38 (Scheme 2). In this procedure, especially
remarkable is the new method to obtain the threo-epoxy
alcohol from the diolbenzoate 5 by intramolecular dis-
placement of the secondary mesylate group with the
(8) Taber, D. F.; You, K. J . Org. Chem. 1995, 60, 139.
S0022-3263(96)02135-4 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 6, 1997 1571
Sch em e 3
Sch em e 4
primary alkoxide. This method is actually an alternative
to that previously reported from our laboratory.9
The silyl epoxy ether 7 was used as the central
fragment to homologate the chain in both directions.
Thus, the double bond was cleaved with ozone under
reductive conditions and the resulting aldehyde submit-
ted to the corresponding Wittig reaction yielding the
diene 8 with excellent stereocontrol (Scheme 3). On the
other hand, the terminal epoxide was opened with the
lithium salt of protected propargylic alcohol yielding the
lineal chain 9 in which all hydroxy groups are chemically
differentiated, being suitable to perform the cyclization
reaction.10 Thus, 9 was treated in CH2Cl2 with 2,4,4,6-
tetrabromo-2,5-cyclohexadienone (TBCD) as source of
Br+,11 yielding, after the cleavage of the THP group, the
1:1 mixture of the tetrahydrofurans 10 and 11.12
Although the stereochemistry of 10 is concordant with
that present in the natural products, we considered the
possibility of improving the stereoselection in the cycliza-
tion reaction, basically performing this step with a
precursor in which the stereochemistry in the silyl-
protected carbinol was changed. Thus, 13 was obtained
by a similar sequence of reactions through the erythro-
epoxy ether 12 (Scheme 4). In this case, gratifyingly, the
desired syn-2,5-disubstituted tetrahydrofuran 15 was
obtained in a ratio of 5:1.
Sch em e 5
ported procedure7 using Corey’s methodology (Scheme
5).13 Finally, the inversion of configuration of the second-
ary carbinol by a consecutive sequence of oxidation and
reduction reactions afforded (+)-deacetylkumausine (2)
[R]25 ) +6.5 (c 0.8, CHCl3) [lit.4 [R]20 ) +6.5 (c 1.08,
D
D
CHCl3)].
In summary, we have described a convergent and
stereocontrolled synthesis of a halogenated tetrahydro-
furan natural product in which the key step is a bromo-
nium ion-induced cyclization of a suitable hydroxy alk-
ene; this type of reaction is considered as the biogenetic
origin of Laurencia halogenated cyclic lipids. Application
of this methodology to other halogenated tetrahydro-
furans is in progress and will be published elsewhere.
Ack n ow led gm en t. This research was supported by
the DGICYT (PB92-0489, PB95-0751), the Human
Capital and Mobility Program (ERBCHRXCT93-0288)
of the European Community, and the Consejer´ıa de
Educacio´n, Cultura y Deportes del Gobierno de Canar-
ias. J .M.B. thanks the M.E.C. and T.M. the Gobierno
Auto´nomo de Canarias for a fellowship.
The one-carbon homologation to the trans-enyne 16
was performed in accordance with our previously re-
(9) Palazo´n, J . M.; An˜orbe, B.; Mart´ın, V. S. Tetrahedron Lett. 1986,
27, 4987.
(10) Yamaguchi, M.; Hirao, I. J . Chem. Soc., Chem. Commun. 1984,
202.
Su p p or tin g In for m a tion Ava ila ble: Copies of NMR
spectra of compounds 2, 10, 11, and 13-16 and experimental
details for the synthesis of 13-15 (15 pages).
(11) For the use of other reagents to promote the cyclization of
hydroxyalkene to exo-bromotetrahydrofurans, see: Harding, K. E.,
Tiner, T. H. In Comprehensive Organic Synthesis; Trost, B. M., et al.,
Eds.; Pergamon Press: New York, 1991; Vol. 4, pp 363-421.
(12) The use of highly polar solvents such us THF:HMPTA yielded
a poorer stereoselection of 10 relative to 11 (1:2). See ref 5.
J O962135M
(13) Corey, E. J .; Ruden, R. A. Tetrahedron Lett. 1973, 1495.