A novel sulfoxide-directed route to enantiopure tetrahydrofurans: Application to the expedient formal synthesis of (+)-trans-kumausyne and (+)- kumausallene

Full text of DOI:10.1021/jo9816414

9612
J . Org. Chem. 1998, 63, 9612-9613
Sch em e 1
A Novel Su lfoxid e-Dir ected Rou te to
En a n tiop u r e Tetr a h yd r ofu r a n s: Ap p lica tion
to th e Exp ed ien t F or m a l Syn th esis of
(+)-tr a n s-Ku m a u syn e a n d (+)-Ku m a u sa llen e1,†
Roberto Ferna´ndez de la Pradilla,*,‡ Carlos Montero,‡
J ulia´n Priego,‡ and Luis Alfonso Mart´ınez-Cruz§
Instituto de Qu´ımica Orga´nica, CSIC, J uan de la Cierva, 3,
E-28006 Madrid, Spain, and Departamento de Cristalograf´ıa,
Instituto de Qu´ımica-F´ısica Rocasolano, CSIC, Serrano 119,
E-28006 Madrid, Spain
Received August 14, 1998
In previous reports from this laboratory, the nucleophilic
epoxidation of simple vinyl sulfoxides has been documented
as a general and efficient route to enantiopure sulfinyl and
sulfonyl oxiranes,2 versatile synthetic intermediates.3 Fur-
thermore, the epoxidation of vinyl sulfoxides bearing oxy-
genated substituents at allylic positions was found to be
primarily directed by the chiral sulfur atom.4 Seeking to
apply our methodology to the synthesis of carbohydrate
derivatives, the nucleophilic epoxidation of hydroxy dienyl
sulfoxides A (Scheme 1) was explored with the expectation
that oxiranes B should be amenable to straightforward
manipulations to produce carbohydrates.5 The 1,4 conjugate
addition pathway was perceived as a potential hurdle to our
approach,6 which in the unlikely event of selectively produc-
ing oxiranes C could be of synthetic relevance as a simple
route to tetrahydrofurans.7 Herein, we describe a novel stra-
tegy for the expedient preparation of enantiopure highly sub-
stituted tetrahydrofurans D, which presumably takes place
by sequential remote nucleophilic epoxidation of dienes A,
ring closure of vinyl oxiranes C, and further nucleophilic
epoxidation in a single synthetic operation. In addition, this
methodology has been successfully applied to the enantio-
selective formal synthesis of (+)-trans-kumausyne and (+)-
kumausallene.
Sch em e 2
The initial stage of our investigation was carried out on
readily available dienols 2a and 3a (Scheme 2), prepared
by lithiation of the mixture of dienes 1,8,9 trapping with
acrolein, and chromatographic separation. Dienol 2a proved
* To whom correspondence should be addressed. Phone: 34-(91)-562-
2900 ext 210. Fax: 34-(91)-564-4853. E-mail: RIF@CC.CSIC.ES.
† Taken in part from the M.S. Thesis of J .P. and Ph.D. Thesis of C.M.
‡ Instituto de Qu´ımica Orga´nica.
to be very unreactive to the standard nucleophilic epoxida-
tion protocol and under forcing conditions led to intractable
mixtures of products that were not investigated in detail.
In sharp contrast, diastereomeric dienol 3a reacted with
KOO-t-Bu to afford a low yield (ca. 10%) of a product 5a for
which a detailed NMR analysis suggested a tetrahydrofuran
structure D (Scheme 1). This assignment, as well as the
relative and absolute configuration of 5a , was subsequently
confirmed by an X-ray diffraction analysis of the p-nitroben-
zoate ester of 5a .
After considerable experimentation, a 48% yield of a sep-
arable 83:17 mixture of sulfoxide 5a and sulfone 6a , as prac-
tically single isomers, was obtained by carefully monitoring
the reaction parameters (temperature, time, stoichiometry,
etc.),10 and the structure of sulfone 6a was secured by inde-
pendent oxidation of the known 5a (MMPP, MeOH, 71%) to
6a . To gain insight on the reaction pathway of this remark-
able process, the isolation of the proposed reaction interme-
diates C (Scheme 1) and dihydrofuran 4a (Scheme 2) was
attempted. Under optimal reaction conditions and at short
reaction times (10 min), a small amount of an intermediate
§ Instituto de Qu´ımica-F´ısica Rocasolano.
(1) Presented in part at the 12th International Conference on Organic
Synthesis (ICOS-12), Venice, Italy, J une 28-J uly 2, 1998.
(2) Ferna´ndez de la Pradilla, R.; Castro, S.; Manzano, P.; Mart´ın-Ortega,
M.; Priego, J .; Viso, A.; Rodr´ıguez, A.; Fonseca, I. J . Org. Chem. 1998, 63,
4954-4966.
(3) For reviews, see: (a) Satoh, T.; Yamakawa, K. Synlett 1992, 455-
468. (b) Satoh, T. Chem. Rev. 1996, 96, 3303-3325.
(4) Ferna´ndez de la Pradilla, R.; Manzano, P.; Priego, J .; Viso, A.;
Mart´ınez-Ripoll, M.; Rodr´ıguez, A. Tetrahedron Lett. 1996, 37, 6793-6796.
(5) For a review on the synthesis of carbohydrate derivatives from acyclic
precursors, see: Ager, D. J .; East, M. B. Tetrahedron 1993, 49, 5683-5765.
(6) For 1,4-additions of lithiated protected cyanohydrins to a dienyl
sulfoxide, see: (a) Guillet, E.; J ulia, S. Tetrahedron Lett. 1978, 37, 1155-
1158. (b) Guillet, E.; J ulia, S. Synth. Commun. 1981, 11, 697-708. (c)
Guillet, E.; J ulia, S. Synth. Commun. 1981, 11, 709-722.
(7) For
a review see: Harmange, J .-C.; Figade`re, B. Tetrahedron:
Asymmetry 1993, 4, 1711-1754.
(8) Prepared in one step by the method of Craig. Craig, D.; Daniels, K.;
MacKenzie, A. R. Tetrahedron 1993, 49, 11263-11304. Lithiation of Z vinyl
sulfoxides yields E lithio derivatives; there are conflicting reports on the
configurational stability at sulfur in this process; see: (a) Posner, G. H. In
Asymmetric Reactions and Processes in Chemistry; Eliel, E. L., Otsuka, S.,
Eds.; ACS Symposium Series No. 185; Washington, DC, 1982; p 142. (b)
Fawcett, J .; House, S.; J enkins, P. R.; Lawrence, N. J .; Russell, D. R. J .
Chem. Soc., Perkin Trans. 1 1993, 67-73.
(9) All new products have been fully characterized. See the Supporting
Information.
(10) The reaction conditions should be strictly controlled to avoid a larger
degree of overoxidation of sulfoxide 5a to sulfone 6a in the reaction medium.
10.1021/jo9816414 CCC: $15.00 © 1998 American Chemical Society
Published on Web 12/01/1998

Communications
J . Org. Chem., Vol. 63, No. 26, 1998 9613
Sch em e 3
Smooth protection of the primary alcohol of 5a as a
TBDPS ether, subsequent oxirane cleavage and concurrent
carbonyl reduction by treatment with (PhSe)2 in the presence
of a large excess of NaBH4 led to alcohol 11 (Scheme 3) as a
separable 87:13 mixture of epimers at C-4.17 Next, 11 was
transformed into the desired lactol 10 by a regiocontrolled
Wacker protocol in good yield.18 A subsequent Wittig reac-
tion (Ph3PdCHCO2Me) gave unsaturated ester 13 as an 83:
17 mixture of isomers that was cyclized with catalytic
NaOMe/MeOH and deprotected in good overall yield with
n-Bu4NF/AcOH to produce 9 (6:1 mixture of epimers at C-2).
Our synthetic lactol 10 and ester 9 had spectral features
identical to those reported in the literature.14e,15a Since the
enantiomers of 1014b,e and (()-915a have been transformed
into the natural products, 7 and 8, respectively, this ap-
proach constitutes a formal synthesis of the kumausynes and
kumausallene.
In conclusion, we have developed an extremely concise and
unified formal synthesis of enantiopure kumausynes and
kumausallene. The key step of this novel entry to the
tetrahydrofuran core is likely to be an unprecedented highly
stereoselective remote nucleophilic epoxidation of the sulfi-
nyl diene moiety. We are currently studying the scope of this
remarkable process as well as additional applications of the
methodology to the synthesis of natural products.
Ack n ow led gm en t. This research was supported by
DGICYT (AGF98-0805-CO2-02 and PB96-0822). We thank
the CAM for a doctoral fellowship to C.M. We are grateful
to Professor B. Rodr´ıguez and Dr. J . C. Lo´pez (IQO, CSIC)
for encouragement and support. We warmly thank Dr. A.
Viso (UCM, Madrid) for many fruitful discussions and
constant encouragement.
of general structure C (ca. 7%) was isolated; alternatively,
with 0.8 equiv of KOO-t-Bu at 4 °C for 18 h, a 35:35:5:25
mixture of 3a , 5a , 6a , and the elusive dihydrofuran 4a (ca.
10% isolated yield) was obtained. The epoxidation of 4a
under standard conditions produced 5a smoothly. These
findings support a highly stereoselective reaction pathway
in which an unprecedented remote nucleophilic epoxidation
is followed by a 5-exo-trig cyclization and further epoxidation
to afford sulfinyl tetrahydrofuran 5a , which is partially
oxidized to sulfone 6a in the reaction medium.11
To explore the scope of the methodology, the reactions
between 2b, 2c, 3b, and 3c and KOO-t-Bu were examined
with results very similar to those described above, and
sulfinyl tetrahydrofurans 5b and 5c were obtained in fair
yields considering the complexity of the process (Scheme 2).12
Next, the transformation of the “unreactive” diastereomer
2c into 3c was briefly examined with acceptable results via
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and spectroscopic data for all new compounds and X-ray
diffraction analysis data for the p-nitrobenzoate of 5a (24 pages).
J O9816414
(14) For previous syntheses of trans-kumausyne, see: (a) Brown, M. J .;
Harrison, T.; Overman, L. E. J . Am. Chem. Soc. 1991, 113, 5378-5384.
First total synthesis of (()-7 in 18 steps from 2-cyclopentylidenecyclopen-
tanone. An optically enriched intermediate (84% ee) was prepared in just
one additional step using (S)-O-methylprolinol as chiral controller. (b)
Osumi, K.; Sugimura, H. Tetrahedron Lett. 1995, 36, 5789-5792. First
enantioselective synthesis of of (-)-7 in 18 steps from L-arabinose; 12 steps
are required to lactol 10, our key synthetic intermediate. (c) Mart´ın, T.;
Soler, M. A.; Betancort, J . M.; Mart´ın, V. S. J . Org. Chem. 1997, 62, 1570-
1571. Total synthesis of (+)-trans-deacetylkumausyne in 22 steps from
propargyl alcohol. (d) Lee, E.; Yoo, S.-K.; Cho, Y.-S.; Cheon, H.-S.; Chong,
Y. H. Tetrahedron Lett. 1997, 38, 7557-7558. Total synthesis of (-)-7 in
22 steps from D-xylose. (e) When this work was in progress Boukouvalas
reported an improved synthesis of (-)-7 in 13 steps: Boukouvalas, J .;
Fortier, G.; Radu, I.-I. J . Org. Chem. 1998, 62, 9916-917. This approach
produces lactol 10 in seven steps from dimethyl (R)-malate.
(15) Previous syntheses of kumausallene. (a) Grese, T.; Hutchinson, K.;
Overman, L. E. J . Org. Chem. 1993, 58, 2468-2477. First total synthesis
of (()-8 in 21 steps from 2-cyclopentylidenecyclopentanone. Ester 9 was
prepared in eight steps. (b) More recently, Lee has published an enantio-
selective synthesis of intermediate 9 in 16 steps from (-)-diethyl D-tartrate;
see: Lee, E.; Yoo, S.-K.; Choo, H.; Song, H. Y. Tetrahedron Lett. 1998 39,
317-318.
a
Mitsunobu protocol (DIAD, Ph3P, PhCO2H, toluene;
NaOMe, MeOH, 59%, two steps).13
At this stage of the project, an application of the meth-
odology was pursued, and we focused our attention on the
red algal metabolites (-)-trans-kumausyne, 7, and (-)-
kumausallene, 8 (Scheme 3), which possess a 2,5-cis-disub-
stituted tetrahydrofuran core. On the basis of previous
syntheses of these marine products,14,15 lactol 10 was
envisioned as an appropriate precursor for both target
molecules, but since our efforts had begun with (-)-menthyl
sulfinate, the unnatural enantiomers would be derived from
this research.16
(11) Under these conditions a sulfonyl diene related to 3a gave a more
complex mixture of inseparable sulfonyl tetrahydrofurans (62:29:9) in which
6a was the major component. This demonstrates that the sulfinyl func-
tionality plays a crucial role in the observed stereocontrol.
(12) It should be pointed out that phenyl-substituted tetrahydrofuran
5c was produced with diminished selectivity (74:14:12).
(16) The enantiomeric (1S,2R,5S)-(+)-menthyl (R)-p-toluenesulfinate is
commercially available.
(17) Satoh, T.; Kaneko, Y.; Izawa, T.; Yamakawa, K. Bull. Chem. Soc.
J pn. 1985, 58, 1983-1990.
(18) Mereyala, H. B.; Gadikota, R.; Krishnan, R. J . Chem. Soc., Perkin
Trans. 1 1997, 3567-3571.
(13) Hughes, D. L. Org. React. 1992, 42, 335-669.