HETEROCYCLES

Communication | Special issue | Vol. 80, No. 2, 2010, pp. 805-810
Received, 30th July, 2009, Accepted, 4th September, 2009, Published online, 9th September, 2009.
DOI: 10.3987/COM-09-S(S)87

■ Methyl Insertion Reactions of Tetrahydropyrans Having a C1’-Mesyloxy Group on the C2-Side Chain with Trimethylaluminum

Keigo Nakamura, Atsushi Kimishima, and Tadashi Nakata*

Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka 1-3, Shinjuku-ku, Tokyo 162-8601, Japan

Abstract

Methyl insertion reactions of tetrahydropyrans having a C1’-mesyloxy group on the C2-side chain, mediated by trimethylaluminum, were investigated. Removal of the mesyloxy group, 1,2-hydride shift and/or ring-expansion, and methyl insertion took place concertedly, depending on the stereostructure of the substrate, to give 2-methylated tetrahydropyran and/or 2- or 3-methylated oxepane.

Since brevetoxin B was isolated as a red tide toxin, many marine polycyclic ethers have been reported.1 They have a unique trans-fused polycyclic ether ring system and exhibit potent biological activities, such as neurotoxicity, cytotoxicity, and antiviral and antifungal activities. The marine natural products often contain cyclic ethers having a C2-methyl group as an angular methyl group, such as 2-methyl-tetrahydropyran. In connection with synthetic studies on marine polycyclic ethers, we have recently developed a new synthetic method for 2,3-trans-2-methyl-tetrahydropyran-3-ol and oxepan-3-ol derivatives through a unique methyl insertion reaction of cyclic ethers (1) having mesylate on the C2-side chain.2,3 Thus, upon treatment of cyclic ethers (1) having a C1’-mesyloxy (OMs) group with trimethylaluminum (Me3Al), methyl insertion took place to give the C2-methylated compound (2) as the sole product (Figure 1). The present reaction is considered to take place concertedly via removal of the mesyloxy group, 1,2-hydride shift, and methyl insertion into the resulting oxonium ion.
We now report further studies on the present reaction using the four possible stereoisomers of 2-(1’-mesyloxy)ethyl-5-hexyl-tetrahydropyrans (3–6) (Figure 2).4,5

First, the reactions of two stereoisomers (3 and 4) having 1’,2-syn-configuration with Me3Al were examined in n-hexane at 0 °C (Scheme 1).6 Upon treatment of 1’,2-syn-2,6-syn-tetrahydropyran (3) with 1.1 equiv of Me3Al for 20 min, methyl insertion took place stereoselectively to give 2,6-syn-2-methyl-tetrahydropyran7 (7) in 71% yield (Scheme 1). The same reaction using 1.5 equiv of Me3Al afforded 7 in 73% yield within 10 min. On the other hand, reaction of the 1’,2-syn-2,6-anti-isomer (4) with 1.1 equiv of Me3Al also stereoselectively afforded the same product (7) in 57% yield, along with recovered starting material (4, 22%). The reaction of 4 using 1.5 equiv of Me3Al increased the yield to give 7 as the sole product in 84% yield.

The present methyl insertion reactions of 3 and 4 with Me3Al can be explained as follows (Figure 3). Treatment of 3 and 4 with Me3Al concertedly effected removal of the mesyloxy group and 1,2-hydride shift through the conformers (3-i and 4-i),8 respectively, which have an antiperiplanar relationship between C2-H and C1’-OMs, to produce the same oxonium ion intermediate (A). Then, the methyl group would attack from the β-axial side into this oxonium ion (A) to take a chair-form transition state, giving 2,6-syn-2- methyl-tetrahydropyran (7).

Next, the reactions of the other stereoisomers (5 and 6), having 1’,2-anti-configuration, were examined (Scheme 2). Reaction of 1’,2-anti-2,6-syn-5 with 1.1 equiv of Me3Al for 20 min resulted only in recovery of the starting material (5) in 92% yield. But, treatment with 1.5 equiv of Me3Al for 4 h afforded 2,6-syn-2-methyl-tetrahydropyran (7) (65%) and ring-expanded 2,7-anti-2,3-trans-2,3-dimethyl-oxepane9 (8) (29%). Furthermore, the reaction using 2.0 equiv of Me3Al afforded 7 (80%) and 8 (13%). Reaction of 1’,2-anti-2,6-anti-6 with 1.1 equiv of Me3Al for 20 min also resulted in recovery of the starting material

(6) in 87% yield. The reaction using 1.5 equiv of Me3Al gave three products, i.e., 2,6-syn-2-methyl- tetrahydropyran (7) (18%), 2,7-syn-2,3-trans-2,3-dimethyl-oxepane10,11 (9) (11%), and 2,7-anti-2,3-cis- 2,3- dimethyl-oxepane10,11 (10) (13%), along with recovered 6 (35%). Use of 4.0 equiv of Me3Al resulted in completion of the reaction within 10 min to give 7 (33%), 9 (19%), and 10 (21%).
In order to examine the reaction mechanism for 5 and 6, we employed C1’-deuterated compounds (d-5 and d-6), which were prepared from the corresponding alcohols by oxidation with TPAP-NMO, followed by NaBD4 reduction. Reaction of the C1’-deuterated 1’,2-anti-2,6-syn-tetrahyropyran (d-5) with Me3Al afforded C1’-deuterated 2,6-syn-2-methyl-tetrahydropyran (d-7) and C3-deuterated 2,7-anti-2,3-trans- 2,3-dimethyl-oxepane (d-8). Thus, the reaction would proceed as shown in Figure 4. The C1’-deuterated 2-methyl-tetrahydropyran (d-7) would be produced through the conformer (d-5-i) via methyl insertion into the resulting oxonium ion (d-A). From the conformer (d-5-ii), removal of the mesyloxy group, antiperiplanar C2-C3 bond migration, and methyl insertion into the oxonium ion (d-B) would take place from the β-side to give the C3-deuterated 2-methylated oxepane (d-8).

Next, reaction of the C1’-deuterated 2,6-anti-1’,2-anti-tetrahydropyran (d-6) with Me3Al produced C1’-deuterated 2-methyl-tetrahydropyran (d-7), C2-deuterated 2,7-syn-2,3-trans-2,3-dimethyl-oxepane (d-9a), and C3-deuterated 2,7-syn-2,3-trans- and 2,7-anti-2,3-cis-2,3-dimethyl-oxepanes (d-9b and d-10). The ratio of d-9a and d-9b was ca. 91:9. The 2-methylated tetrahydropyran (d-7) would also be produced via methyl insertion into the oxonium ion (d-A) through the conformer (d-6-i).12 Ring-expanded C2-deuterated 3-methylated oxepane (d-9a) should be produced through the conformer (d-6-ii), which has an antiperiplanar relationship between the C1’-MsO group and C2-O bond, via methyl insertion at the C3-position into the oxonium ion (d-C). The other C3-deuterated 2-methylated products (d-9b and d-10) would be produced through the conformer (d-6-iii) via methyl insertion at the C2-position into the oxonium ion (d-D) from the α-side and β-side, respectively. Thus, it was found that 2,7-syn-2,3-trans-oxepane (9) in Scheme 2 was produced via two routes through transition states corresponding to d-C and d-D.
In conclusion, the reactions of 2-(1’-mesyloxy)ethyl-5-hexyl-tetrahydropyrans with Me3Al proceed via removal of the mesyloxy group, 1,2-hydride shift and/or ring-expansion, and methyl insertion, depending on the stereostructure of the substrate, to give 2-methylated tetrahydropyran and/or 2- or 3-methylated oxepane.

ACKNOWLEDGEMENTS
This work was financially supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

References

1. For reviews on polycyclic ethers, see: (a) T. Yasumoto and M. Murata, Chem. Rev., 1993, 93, 1897; CrossRef (b) Y. Shimizu, Chem. Rev., 1993, 93, 1685; CrossRef (c) M. Murata and T. Yasumoto, Nat. Prod. Rep., 2000, 17, 293; CrossRef (d) T. Yasumoto, Chem. Rec., 2001, 1, 228; CrossRef (e) A. H. Deranas, M. Norte, and J. J. Fernández, Toxicon, 2001, 39, 1101. CrossRef
2. A. Kimishima and T. Nakata, Tetrahedron Lett., 2008, 49, 6563. CrossRef
3. The same type of reaction using tetrahydrofuran derivatives was reported. T. J. Donohoe, O. Williams, and D. H. Churchill, Angew. Chem. Int. Ed., 2008, 47, 2869. CrossRef
4. We have already reported the rearrangement reaction of the same stereoisomers (3-6) with zinc acetate; K. Nagasawa, N. Hori, H. Koshino, and T. Nakata, Heterocycles, 1999, 50, 919. CrossRef
5. Only one enantiomer of the racemate is drawn for the sake of simplicity.
6. A typical procedure for methyl-insertion reaction: To a solution of 3 (74.0 mg, 0.25 mmol) in n-hexane (1.5 mL) was added Me3Al (1.08 M solution in n-hexane, 250 μL, 0.27 mmol) at 0 °C under argon atmosphere. After stirring at 0 °C for 20 min, the mixture was quenched with sat. NaHCO3 solution and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (Silica gel 60N, n-hexane:EtOAc= 100:1) to give 7 (37.8 mg; 71 % yield) as a colorless oil.
7. Data for 7: 1H NMR (400 MHz, CDCl3) δ 3.46 (m, 1H), 1.67-1.60 (m, 2H), 1.57–1.49 (m, 2H), 1.47-1.25 (m, 13H), 1.11 (s, 3H), 1.10–1.00 (m, 1H), 0.89 (t, J = 7.5 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 73.3, 69.9, 37.4, 37.0, 34.4, 31.94, 31.89, 29.4, 25.5, 22.6, 20.0, 19.2, 14.1, 7.6. HRMS (EI) calcd for C14H28ONa [M+Na+] 212.2140, found 212.2144.
8. The coupling constants (J2,3-syn = 3.3 Hz and J2,3-anti = 9.9 Hz) and ROE observation between C2-H and methylene protons of the C6-hexyl group in 4 suggested that 4 would mainly take the conformation having an equatorial C2-side chain, although 4 is a mixture of ring-flipped conformers.4.
9. Data for 8: 1H NMR (400 MHz, CDCl3) δ 3.53 (m, 1H), 3.35 (dq, J = 9.1, 6.3 Hz, 1H), 1.78–1.67 (m, 2H), 1.57–1.54 (m, 2H), 1.49–1.34 (m, 6H), 1.32–1.24 (m, 7H), 1.15 (d, J = 6.3 Hz, 3H), 0.88 (t, J = 7.0 Hz, H), 0.85 (t, J = 6.6 Hz, 3H). 13C NMR (100 MHz, ) δ 76.3, 73.5. 42.3, 36.8, 36.23, 36.15, 31.9, 29.4, 27.4, 26.4, 22.6, 20.4, 19.9, 14.1. HRMS (EI) calcd for C14H28ONa [M+Na+] 212.2140, found 212.2144.
10. Yields of 9 and 10 were calculated from the 1H NMR analysis, because the products could not be isolated.
11. Selected 1H-NMR data (600 MHz, CDCl3): for 9 d 3.37 (m, 1H), 3.04 (dq, J = 9.5, 6.4 Hz, 1H), 1.10 (d, J = 6.4 Hz, 3H), 0. 84 (d, J = 6.8 Hz, 3H); for 10 δ 3.80 (dd, J = 6.8, 6.4 Hz, 1H), 3.60 (m, 1H), 1.20 (d, J = 6.4 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H). HRMS (EI) calcd for C14H28ONa [M+Na+] 212.2140, found 212.2137.
12. The observed ROEs between the C1’- and C6-H2, and C2-H and methylene protons of the C6-hexyl group in 6 support the presence of ring-flipped conformers.4