Stereoselective synthesis of 2,6-syn-dimethyl-tetrahydropyran derivatives, important segments of marine polycyclic ethers, by unique insertion of the methyl group

Article abstract of DOI:10.1021/ol9018419

Treatment of 6-methyl-tetrahydropyran derivatives, which have a 1'-mesyioxy group at the C2-side chain, with Me₃AI effected stereoselective Insertion of a methyl group at the C2-position to give 2, 6-syn-dimethyl- tetrahydropyran derivatives. T

Full text of DOI:10.1021/ol9018419

ORGANIC
LETTERS
2009
Vol. 11, No. 21
4814-4817
Stereoselective Synthesis of
2,6-syn-Dimethyl-tetrahydropyran
Derivatives, Important Segments of
Marine Polycyclic Ethers, by Unique
Insertion of the Methyl Group
Michihiro Maemoto, Atsushi Kimishima, and Tadashi Nakata*
Department of Chemistry, Faculty of Science, Tokyo UniVersity of Science, 1-3
Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
nakata@rs.kagu.tus.ac.jp
Received August 8, 2009
ABSTRACT
Treatment of 6-methyl-tetrahydropyran derivatives, which have a 1′-mesyloxy group at the C2-side chain, with Me3Al effected stereoselective
insertion of a methyl group at the C2-position to give 2,6-syn-dimethyl-tetrahydropyran derivatives. This reaction proceeds via removal of the
mesyloxy group, 1,2-hydride shift, and stereoselective insertion of a methyl group into the resulting oxonium ion.
Since the isolation of brevetoxin-B as a red tide toxin, many
marine polycyclic ethers, such as gambierol and maitotoxin,
have been reported.1 They have a unique trans-fused
polycyclic ether ring system and exhibit potent biological
activities, including neurotoxicity, cytotoxicity, and antiviral
activities. Their synthetically challenging structures and
potent bioactivities have attracted the attention of numerous
synthetic organic chemists.2 The marine natural products
often contain cyclic ethers having a C2-methyl group as an
angular methyl group, such as 2-methyl-tetrahydropyran.
Thus, synthetic methods for cyclic ethers including 2-methyl-
tetrahydropyran structures have been extensively investi-
gated.3 Furthermore, 2,6-syn-dimethyl-tetrahydropyran de-
rivatives are also important segments, being present, for
example, in the F-ring of brevetoxin-B, the B-ring of
gambierol, and the W-, Z-, and E′-rings of maitotoxin (Figure
1). However, there are only a few reports on synthetic
methods applicable to 2,6-syn-dimethyl-tetrahydropyran de-
rivatives, that is, 6-endo-cyclization of hydroxy vinyl epoxide
by Nicolaou et al.,3c Claisen rearrangement of allyl enol ether
(1) For reviews on polycyclic ethers, see: (a) Yasumoto, T.; Murata,
M. Chem. ReV. 1993, 93, 1897. (b) Shimizu, Y. Chem. ReV. 1993, 93, 1685.
(c) Murata, M.; Yasumoto, T. Nat. Prod. Rep. 2000, 17, 293. (d) Yasumoto,
T. Chem. Rec. 2001, 1, 228. (e) Deranas, A, H.; Norte, M.; Ferna´ndez, J. J.
Toxicon 2001, 39, 1101.
(3) Selected papers: (a) Nicolaou, K. C.; Prasad, C. V. C.; Hwang, C.-
K.; Duggan, M. E.; Veale, C. A. J. Am. Chem. Soc. 1989, 111, 5321. (b)
Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K. J. Am.
Chem. Soc. 1989, 111, 5330. (c) Nicolaou, K. C.; Nugiel, D. A.;
Couladouros, E.; Hwang, C.-K. Tetrahedron 1990, 46, 4517. (d) Mori, Y.;
Furuta, H.; Takase, T.; Mitsuoka, S.; Furukawa, H. Tetrahedron Lett. 1999,
40, 8019. (e) Rainier, J. D.; Allwein, S. P. J. Org. Chem. 1998, 63, 5310.
(f) Rainier, J. D.; Allwein, S. P.; Cox, J. M. Org. Lett. 2000, 2, 231. (g)
Majumder, U.; Cox, J. M.; Johnson, H. W. B.; Rainier, J. D. Chem.sEur.
J. 2006, 12, 1736. (h) Matsuo, G.; Matsukura, H.; Hori, N.; Nakata, T.
Tetrahedron Lett. 2000, 41, 7673. (i) Suzuki, K.; Matsukura, H.; Matsuo,
G.; Koshino, H.; Nakata, T. Tetrahedron Lett. 2002, 43, 8653. See also
ref 2.
(2) For reviews on synthetic methods and total syntheses, see: (a)
Alvarez, E.; Candenas, M.-L.; Pe´rez, R.; Ravelo, J.; Mart´ın, J. D. Chem.
ReV. 1995, 95, 1953. (b) Fujiwara, K.; Hayashi, N.; Tokiwano, T.; Murai,
A. Heterocycles 1999, 50, 561. (c) Mori, Y. Chem.sEur. J. 1997, 3, 849.
(d) Marmsa¨ter, F. P.; West, F. G. Chem.sEur. J. 2002, 8, 4347. (e) Inoue,
M. Org. Biomol. Chem. 2004, 2, 1811. (f) Fujiwara, K.; Murai, A. Bull.
Chem. Soc. Jpn. 2004, 77, 2129. (g) Sasaki, M.; Fuwa, H. Synlett 2004, 2,
1811. (h) Kadota, I.; Yamamoto, Y. Acc. Chem. Res. 2005, 38, 423. (i)
Inoue, M. Chem. ReV. 2005, 105, 4379. (j) Nakata, T. Chem. ReV. 2005,
105, 4314. (k) Clark, J. S. Chem. Commun. 2006, 3571. (l) Nicolaou, K. C.;
Frederick, M. O.; Aversa, R. J. Angew. Chem., Int. Ed. 2008, 47, 7182.
10.1021/ol9018419 CCC: $40.75
Published on Web 10/07/2009
 2009 American Chemical Society

Figure 1. Structures of brevetoxin B and gambierol and partial structure of maitotoxin.
by Rainier et al.,3g and 6-endo-cyclization of hydroxy epoxy
sulfone by Mori et al.3d Among them, Nicolaou’s method3c
has been frequently used in synthetic studies on marine
polycyclic ethers.2
We have recently developed a stereoselective synthesis
of 2-methyl-tetrahydropyran derivative 2 via unique insertion
of a methyl group by treatment of the mesylate 1 with Me3Al
(Figure 2).4,5 We now report a new synthetic method for
alcohol 3,6 prepared from 2-deoxy-D-ribose (Scheme 1).
Oxidation of 3 with SO3·pyridine afforded aldehyde 4. We
first examined the route via Sharpless asymmetric epoxida-
tion7 to give C1′-R-alcohol 7. The Wittig reaction of 4 with
Ph3P ) CHCO2Et and DIBAH reduction gave allyl alcohol
5 in 70% yield (three steps). The Sharpless epoxidation of 5
using (-)-DET afforded a 2:1 mixture of R- and ꢀ-epoxides,
which was reduced with Red-Al to give the desired R-alcohol
7 in 39% yield (two steps, after separation). To find a more
efficient route to the diol 7, stereoselective allylations were
next examined. Brown’s asymmetric allylation8 of 4 by
treatment with (-)-IPC2B(allyl) at -78 °C afforded the
desired R-alcohol 6 in 82% yield (two steps from 3) with
10:1 diastereomeric ratio. After several attempts, reaction
of 4 with allylTMS in the presence of MgBr2·OEt2 afforded
the desired R-alcohol 6 as a single product in 90% yield
(two steps from 3).9 The alcohol 6 was converted into the
corresponding acetonide 10 by deprotection of TBS and
acetonization to determine the stereochemistry (Figure 4).
Observed NOE and the coupling constant of Ha and Hb (J
) 6.8 Hz) suggested that 10 should have the conformation
10a, which supports the configuration of C1′-R-alcohol 6.
Oxidative cleavage of the olefin 6 with OsO4-NaIO4
followed by NaBH4 reduction in one pot afforded diol 7 in
86% yield. Selective TBS protection of the diol and
mesylation of the secondary alcohol in one pot quantitatively
afforded the required mesylate 8. Treatment of 8 with Me3Al
(3.0 equiv) in n- hexane at 0 °C effected methyl insertion to
give the desired 2,6-syn-dimethyl-tetrahydropyran 9 in 90%
yield. The stereoselectivity was ca. 30:1. The stereostructure
of 9 was confirmed by observed NOE between C2-Me and
C6-Me of the corresponding alcohol 9′.
Figure 2. Insertion reaction of a methyl group.
2,6-syn-dimethyl-tetrahydropyran derivatives, i and ii, by
application of this insertion reaction of a methyl group in
mono- and bicyclic ether ring systems (Figure 3).
Figure 3. 2,6-syn-Dimethyl-tetrahydropyran derivatives.
We next investigated insertion of a methyl group in a
bicyclic ether system. By employing the effective allylation
route shown in Scheme 1, the required mesylate 15 was
First, insertion of a methyl group in a monocyclic ether
system was investigated. The synthesis of the required
6-methyl-tetrahydropyran-1′-mesylate 8, a substrate for inser-
tion of a C2-methyl group, was started with the known
(6) Satoh, M.; Koshino, H.; Nakata, T. Org. Lett. 2008, 10, 1683.
(7) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
(b) Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1–300.
(4) Kimishima, A.; Nakata, T. Tetrahedron Lett. 2008, 49, 6563
.
(5) The same type of reaction using tetrahydrofuran derivatives was
(8) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401.
(9) (a) Keum, G.; Kang, S. B.; Kim, Y.; Lee, E. Org. Lett. 2004, 6,
1895. (b) Keck, G. E.; Boden, E. P. Tetrahedron Lett. 1984, 25, 265.
reported. Donohoe, T. J.; Williams, O.; Churchill, G. H. Angew. Chem.,
Int. Ed. 2008, 47, 2869
.
Org. Lett., Vol. 11, No. 21, 2009
4815

Scheme 1
was also determined based on observed NOE and the
coupling constant of Ha and Hb (J ) 7.0 Hz) of the
corresponding acetonide 17 (Figure 4). Oxidative cleavage
of the olefin 13 with OsO4-NaIO4 followed by NaBH4
reduction in one pot afforded diol 14 in 92% yield. One-pot
TBS protection-mesylation afforded the mesylate 15 in 88%
yield. Upon treatment of 15 with Me3Al (3.0 equiv) in
n-hexane at 0 °C, methyl insertion took place smoothly with
ca. 17:1 stereoselection to give 2,6-syn-dimethyl-tetrahydro-
pyran 16 in 82% yield. The stereostructure of 16 was
confirmed by observed NOE between C2-Me and C6-Me.
Thus, the present methyl insertion reaction was also effective
to give 2,6-syn-dimethyl-tetrahydropyran in a bicyclic ether
system. Stereoselective insertion of the methyl group can
be explained as shown in Figure 5. The reaction would
proceed concertedly via removal of the mesylate, 1,2-hydride
shift, and methyl insertion into the resulting oxonium ion
iii. The methyl group should attack from the R-axial side,
in spite of the steric hindrance of the C6-R-methyl group, to
take a chair-form transition state, providing 2,6-syn-dimethyl-
tetrahydropyran 16.
Figure 4. Observed NOEs of 10 and 17.
obtained (Scheme 2). The reaction started with bicyclic
alcohol 11,10 which was prepared from 2-deoxy-D-ribose.
Oxidation of 11 with SO3·pyridine gave aldehyde 12, which
was treated with allylTMS in the presence of MgBr2·OEt2
to give R-alcohol 13 as a single product in 89% yield (two
steps from 11). The configuration of the C1′-R-alcohol 13
Scheme 2
4816
Org. Lett., Vol. 11, No. 21, 2009

Figure 5. Reaction mechanism of 15 with Me3Al.
In summary, we have developed an efficient and reliable
synthetic method for 2,6-syn-dimethyl-tetrahydropyran de-
rivatives through a unique methyl insertion reaction by
treatment with Me3Al. The present method should be useful
for construction of 2,6-syn-dimethyl-tetrahydropyran seg-
ments as starting materials or key intermediates for the
synthesis of marine polycyclic ethers.
Acknowledgment. This work was financially supported
by a Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science and Technology,
Japan.
Supporting Information Available: Detailed experimen-
tal procedures and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(10) Synthesis of 11, see Supporting Information.
OL9018419
Org. Lett., Vol. 11, No. 21, 2009
4817