A new strategy for the reiterative synthesis of trans-fused tetrahydropyrans via alkylation of oxiranyl anion and 6-endo cyclization

Full text of DOI:10.1021/ja961454s

8158
J. Am. Chem. Soc. 1996, 118, 8158-8159
Scheme 1
A New Strategy for the Reiterative Synthesis of
trans-Fused Tetrahydropyrans Wia Alkylation of
Oxiranyl Anion and 6-endo Cyclization
Yuji Mori,* Keisuke Yaegashi, and Hiroshi Furukawa
Faculty of Pharmacy, Meijo UniVersity
150 Yagotoyama, Tempaku, Nagoya 468, Japan
ReceiVed May 2, 1996
One of the most characteristic and interesting classes of
marine toxins produced by dinoflagellates is the polycyclic
ethers which show strong biological activities by interacting with
the cation channels of cellular membranes.1 trans-Fused
tetrahydropyran rings are the most frequently encountered cyclic
units and form a rigid backbone of this class of toxins. The
synthesis of such a ring system (I) by Baldwin’s rule2
-disfavored 6-endo mode of cyclization of II is receiving
attention3 since such cyclization is considered to be a key step
in the biosynthesis of polycyclic ethers.4 Furthermore, in a
proposal for the biosynthesis of brevetoxin B, it has been
suggested that the hypothetical building block of tetrahydropyran
rings may be a C3 unit derived from a succinate or its
equivalent.5 This suggestion inspired us to attempt to mimic
nature by using the coupling reaction of a C3 oxiranyl anion
III followed by 6-endo cyclization in a reiterative manner to
construct a polycyclic framework (Scheme 1).
Although epoxides are widely recognized as extremely useful
electrophiles,6 the reaction of an epoxide as a nucleophile, i.e.,
oxiranyl anion, is less common. Several methods for generating
oxiranyl anions have been reported: desilylation of epoxy
silanes with fluoride,7 desulfinylation of epoxy sulfoxides,8
transmetalation of trialkylstannyl-substituted epoxides,9 and
deprotonation of epoxides having an anion-stabilizing group
such as sulfonyl,10 silyl,11 and unsaturated functional groups.12
Scheme 2a
a (a) t-BuOOH, n-BuLi, THF, -20 °C, 4 h; (b) TsOH, MeOH, 40
°C, 2 h; (c) NaIO4, MeOH-H2O, 15 min; (d) NaBH4, MeOH, -20
°C, 0.5 h; (e) TBDPSCl, imidazole, DMF, 1.5 h.
These pioneering studies demonstrated that oxiranyl anions can
be generated only at low temperature and that they react with
very reactive electrophiles such as aldehydes, ketones, and
chlorotrimethylsilanes. However, alkylation of oxiranyl anions
has scarcely been studied.10,11a We recently found that alkyl
triflates are reactive enough to couple with the anions.13 In
this communication, we report a new strategy for the synthesis
of trans-fused tetrahydropyran systems using epoxy sulfone 1a
as the source of the C3 oxiranyl anion III.
The synthesis of the key building block 1a was initiated with
the Peterson olefination between (R)-O-pentylideneglyceralde-
hyde and trimethylsilylmethyl phenyl sulfone14 to provide
Z-vinyl sulfone 2 along with the E-isomer (1:1 ratio) (Scheme
2). Epoxidation of 2 with lithium tert-butylperoxide proceeded
with only 4:1 selectivity.10a,15 In an attempt to enhance even
further this selectivity, the diphenylmethylene ketal 3 was
utilized in the reaction. One of the phenyl groups was expected
to increase the steric bulk of the R-side of the molecule.16 The
epoxidation led to a higher ratio (12:1) of 4 to its isomer (78%
total yield). Deprotection and recrystallization gave optically
pure diol, which was treated with NaIO4 to give 5 in 75% overall
yield. Reduction and protection of the resulting alcohol as a
silyl ether afforded epoxy sulfone 1a.
(1) For reviews, see: (a) Yasumoto, T.; Murata, M. Chem. ReV. 1993,
93, 1897-1909. (b) Marine Toxins: Origin, Structure and Molecular
Pharmacology; Hall, S., Strichartz, G., Eds.; ACS Symposium Series 418;
American Chemical Society: Washington, DC, 1990.
(2) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734-736.
(3) (a) Nicolaou, K. C.; Duggan, M. E.; Hwang, C.-K.; Somers, P. K. J.
Chem. Soc., Chem. Commun. 1985, 1359-1362. (b) Nicolaou, K. C.; Prasad,
C. V. C.; Somers, P. K.; Hwang, C.-K. J. Am. Chem. Soc. 1989, 111, 5330-
5334. (c) Suzuki, T.; Sato, O.; Hirama, M. Tetrahedron Lett. 1990, 31,
4747-4750. (d) Mukai, C.; Ikeda, Y.; Sugimoto, Y.; Hanaoka, M.
Tetrahedron Lett. 1994, 35, 2179-2182. (e) Mukai, C.; Sugimoto, Y.;
Hanaoka, M. Tetrahedron Lett. 1994, 35, 2183-2186. (f) Janda, K. D.;
Shevlin, C. G.; Lerner, R. A. Science 1993, 259, 490-493. (g) Na, J.; Houk,
K. N.; Shevlin, C. G.; Janda, K. D.; Lerner, R. A. J. Am. Chem. Soc. 1993,
115, 8453-8454. For a review of the synthesis of trans-fused polycyclic
ethers, see: Alvarez, E.; Candenas, M.-L.; Pe´rez, R.; Ravelo, J. L.; Martin,
J. D. Chem. ReV. 1995, 95, 1953-1980.
(4) Shimizu, Y. Chem. ReV. 1993, 93, 1685-1698 and references cited
therein.
The synthesis of the trans-fused tetrahydropyran system began
from 617 (Scheme 3). Regioselective activation and protection
of two hydroxyl groups were carried out by a one-pot process.
Treatment of a solution of 6 and 2,6-lutidine in methylene
chloride with triflic anhydride (-78 °C, 30 min) followed by
(5) (a) Chou, H. N.; Shimizu, Y. J. Am. Chem. Soc. 1987, 109, 2184-
2185. (b) Lee, M. S.; Repeta, D. S.; Nakanishi, K.; Zagorski, M. G. J. Am.
Chem. Soc. 1986, 108, 7855-7856. (c) Nakanishi, K. Toxicon 1985, 23,
473-479.
(6) (a) Rao, A. S.; Paknikar, S. K.; Kirtane, J. G. Tetrahedron 1983, 39,
2323-2367. (b) Crandall, J. K.; Apparu, M. Org. React. 1983, 29, 345-
443. (c) Smith, J. G. Synthesis 1984, 624-656.
(7) Dubuffet, T.; Sauveˆtre, R.; Normant, J. F. Tetrahedron Lett. 1988,
29, 5923-5924.
(12) (a) Eisch, J. J.; Galle, J. E. J. Org. Chem. 1990, 55, 4835-4840.
(b) Grandjean, D.; Pale, P.; Chuche, J. Tetrahedron: Asymmetry 1993, 4,
1991-1994.
(13) Mori, Y.; Yaegashi, K.; Iwase, K.; Yamamori, Y.; Furukawa, H.
Tetrahedron Lett. 1996, 37, 2605-2608.
(14) Craig, D.; Ley, S. V.; Simpkins, N. S.; Whitham, G. H.; Prior, M.
J. J. Chem. Soc., Perkin Trans. 1 1985, 1949-1952.
(15) Briggs, A. D.; Jackson, R. F. W.; Clegg, W.; Elsegood, R. J.; Kelly,
J.; Brown, P. A. Tetrahedron Lett. 1994, 35, 6945-6948.
(16) (a) Kozikowski, A. P.; Ghosh, A. K. J. Org. Chem. 1984, 49, 2762-
2772. (b) Bru¨ckner, R.; Priepke, H. Angew. Chem., Int. Ed. Engl. 1988,
27, 278-280.
(17) Nicolaou, K. C.; Hwang, C.-K.; Marron, B. E.; DeFrees, S. A.;
Couladouros, E. A.; Abe, Y.; Carroll, P. J.; Snyder, J. P. J. Am. Chem.
Soc. 1990, 112, 3040-3054.
(8) (a) Satoh, T.; Kaneko, Y.; Yamakawa, K. Bull. Chem. Soc. Jpn. 1986,
59, 2463-2470. (b) Satoh, T.; Kaneko, Y.; Yamakawa, K. Tetrahedron
Lett. 1986, 27, 2379-2382. (c) Satoh, T.; Horiguchi, K. Tetrahedron Lett.
1995, 36, 8235-8238.
(9) (a) Molander, G. A.; Mautner, K. J. Org. Chem. 1989, 54, 4042-
4050. (b) Lohse, P.; Loner, H.; Acklin, P.; Sternfeld, F.; Pfaltz, A.
Tetrahedron Lett. 1991, 32, 615-618.
(10) (a) Ashwell, M.; Clegg, W.; Jackson, R. F. W. J. Chem. Soc., Perkin
Trans. 1 1991, 897-908. (b) Dunn, S. F. C.; Jackson, R. F. W. J. Chem.
Soc., Perkin Trans. 1 1992, 2863-2870.
(11) (a) Eisch, J. J.; Galle, J. E. J. Am. Chem. Soc. 1976, 98, 4646-
4648. (b) Murthi, K. K.; Salomon, R. G. Tetrahedron Lett. 1994, 35, 517-
520.
S0002-7863(96)01454-0 CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 34, 1996 8159
Scheme 3a
a (a) (CF3SO2)2O, 2,6-lutidine, CH2Cl2, -78 °C, 30 min, then TBSOTf, -78 to 0 °C, 30 min; (b) 1a, n-BuLi, THF, DMPU, -100 °C, 30 min;
(c) p-TsOH‚H2O, CHCl3, 55 °C, 6 h; (d) NaBH4, MeOH-CH2Cl2, -78 °C, 2 h; (e) n-Bu4NF, THF, rt, 1 h.
tert-butyldimethylsilyl triflate (-78 to 0 °C) gave 7 in 93%
yield. The coupling reaction of 1b and 7 is a major hurdle in
our strategy, because a sulfone-stabilized cis-oxiranyl anion is
very unstable and partially isomerizes to a trans-isomer even
at -105 °C.10a This crucial C-C bond formation was smoothly
performed by employing the following procedure: a mixture
of epoxy sulfone 1a (1.7 equiv) and triflate 7 (1 equiv) in THF
was treated with n-butyllithium (1.7 equiv) at -100 to -90 °C
for 30 min to afford 8 in 90% yield with a trace amount of
isomer epimeric at the sulfone-bearing center. This procedure
effectively minimizes the decomposition of the unstable oxiranyl
anion.13
desilylation provided diol 11, from which point the original steps
can be repeated.
The second cycle of the five-step operation afforded the
tricyclic diol 16 in 52% overall yield from 11. The second key
coupling reaction of 12 with the oxiranyl anion 1b and
subsequent endo mode of cyclization proceeded uneventfully.
The selectivity of the hydride reduction of 14 was 96% ds. Since
16 contains two hydroxyl groups, the sequence reported here
was reiterated to construct the tetracyclic all-trans-fused frame-
work 20 in 54% overall yield. The diastereomeric ratio of the
final reduction was 97:3.
Theoretically, epoxide 8 (R ) H) could suffer ring closure
Via a 5-exo or 6-endo mode of cyclization leading to a
tetrahydofuran or a tetrahydropyran system, respectively, but
the presence of a sulfonyl group would be expected to favor
the endo mode pathway due to its electron-withdrawing ability.18
This idea is complementary to that of the π-orbital-assisted
cyclizations.3a-e Indeed, 6-endo cyclization of 8 was effected
by heating with p-toluenesulfonic acid monohydrate in chloro-
form, thus furnishing the bicyclic system 9 in 80% yield with
complete regio- and stereoselectivity; the stereochemistry was
confirmed by NOE studies. Reduction of 9 with NaBH4 gave
the desired alcohol 10 in 92% yield and 94% ds. Successive
The reported processes represent a highly effective method
for the construction of trans-fused tetrahydropyran ring systems.
The advantages of using the sulfone-stabilized oxiranyl anion
are 3-fold: efficiency of the C-C bond formation, control of
the 6-endo mode of cyclization, and facilitation of the secondary
hydroxyl regeneration. Applications of the present methodology
to the synthesis of marine polycyclic ethers are in progress.
Supporting Information Available: Typical experimental proce-
dures and characterization data for 1a and 7-20 as well as NMR spectra
(1H, COSY, and DIFNOE) of 9, 11, 17, and 19 (26 pages). See any
current masthead page for ordering and Internet access instructions.
(18) For similar cyclization reactions, see: Satoh, T.; Iwamoto, K.;
Sugimoto, A.; Yamakawa, K. Bull Chem. Soc. Jpn. 1988, 61, 2109-2115.
JA961454S