A new method for the stereoselective construction of angular methyl group of fuzed cyclic ethers

Article abstract of DOI:10.1016/j.tetlet.2010.05.109

A convenient method for the stereoselective construction of angular methyl group of fuzed cyclic ethers is described. Reactions of mixed thioacetals with Me₂Zn/Zn(OTf)₂ afforded the corresponding methylated products in good yields. Various protective groups such as MOM ether, benzylidene acetal, TBS ether, and pivaloyl group were stable under the reaction conditions.

Full text of DOI:10.1016/j.tetlet.2010.05.109

Tetrahedron Letters 51 (2010) 3960–3961
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new method for the stereoselective construction of angular methyl group
of fuzed cyclic ethers
*
Isao Kadota , Takayuki Kishi, Yuka Fujisawa, Yuji Yamagami, Hiroyoshi Takamura
Department of Chemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushimanaka, Kitaku, Okayama 700-8530, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient method for the stereoselective construction of angular methyl group of fuzed cyclic ethers
is described. Reactions of mixed thioacetals with Me2Zn/Zn(OTf)2 afforded the corresponding methylated
products in good yields. Various protective groups such as MOM ether, benzylidene acetal, TBS ether, and
pivaloyl group were stable under the reaction conditions.
Received 22 April 2010
Revised 19 May 2010
Accepted 24 May 2010
Available online 27 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Marine polycyclic ethers
Fuzed cyclic ethers
Angular methyl group
Mixed thioacetals
In recent years there has been an explosion of interest in biolog-
ically active natural products of marine origin.1 Due to their struc-
tural novelty and toxicity, these compounds are particularly
attractive targets for synthetic chemists.2 In the synthesis of poly-
cyclic ethers, the insertion of angular methyl groups as well as the
construction of the fuzed ring system is an important task.
Recently, we have achieved a total synthesis of brevenal.3 The
synthesis included the insertion of an angular methyl group to 1
(Scheme 1). According to the reported procedure, the mixed thi-
oacetal 1 was oxidized with mCPBA, and the resulting sulfoxide
or sulfone 2 was treated with Me3Al in one-pot.4 Although the de-
sired product 3 was obtained in a reasonable yield, the formation
of significant amount of unidentified by-products was observed.
Furthermore, the reproducibility of this reaction was not satisfac-
tory in large-scale experiments, presumably, because of the low
stability of the intermediate 2. After several attempts, we found
that the reaction of 1 with Me2Zn/Zn(OTf)2 afforded 3, directly, in
quantitative yield.5 The reaction conditions did not affect the
MOM protection of 1. This result prompted us to investigate the
generality of this reaction. In this Letter, we wish to report a new
Scheme 1.
* Corresponding author. Tel./fax: +81 86 251 7836.
E-mail address: kadota-i@cc.okayama-u.ac.jp (I. Kadota).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.109

I. Kadota et al. / Tetrahedron Letters 51 (2010) 3960–3961
3961
Zn(OTf)2 gave the mixed thioacetal 5 in 85% yield.4b The reaction
of 5 with Me2Zn/Zn(OTf)2 proceeded smoothly to furnish the bicy-
clic ether 6 as a single stereoisomer in 93% yield.6 The stereochem-
istry of
6
was determined by 1H NMR analysis and NOE
experiments as shown in Figure 1.
On the basis of the results described above, we next examined
the reaction of substrates 7–11 having various ring system and
protective groups.7 The results are summarized in Table 1. The
reaction of 7 gave the corresponding 6-7 ring ether 12 in 93% yield
(entry 1). The benzylidene acetal was stable under the reaction
conditions. Similarly, the mixed thioacetal 8 was converted to
the 6-6-7 ring system 13 in 81% yield (entry 2). On the other hand,
the reaction of 8 under the reported procedure, mCPBA oxidation
followed by treatment with Me3Al,4 gave a complex mixture. For-
mation of 13 was not observed. The substrate 9 having primary and
secondary TBS ethers could be used for the reaction (entry 3). The
product 14 was obtained in 93% yield. The reaction conditions did
not affect the pivaloyl (Piv) group of 10. The product 15 was ob-
tained in 88% yield (entry 4). Furthermore, the methodology was
successfully applied to the reaction of 11 to provide the 6-8-7 ring
ether 16 in 88% yield, although prolonged reaction time was re-
quired (entry 5).
In conclusion, we have demonstrated a simple and convenient
method for the insertion of angular methyl group to fuzed cyclic
ethers via the reaction of mixed thioacetals with Me2Zn/Zn(OTf)2.
Various protective groups such as MOM ether, benzylidene acetal,
TBS ether, and pivaloyl group can survive under the reaction con-
ditions. We anticipate that the present method will be useful in
the total synthesis of polycyclic ethers and other natural products.
Scheme 2.
Figure 1. Observed NOEs are shown by arrows.
Table 1
Reactions of mixed thioacetalsa
Entry Substrate
Product
Yieldb
(%)
1
2
3
93
81
93
Acknowledgment
This work was financially supported by the Grant-in-Aid for Sci-
entific Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
References and notes
1. For reviews, see: (a) Yasumoto, T.; Murata, M. Chem. Rev. 1993, 93, 1897–1909;
(b) Scheuer, P. J. Tetrahedron 1994, 50, 3–18; (c) Murata, M.; Yasumoto, T. Nat.
Prod. Rep. 2000, 17, 293–314; (d) Yasumoto, T. Chem. Rec. 2001, 1, 228–242.
2. For recent reviews of the total synthesis of polycyclic ethers, see: (a) Marmsäter,
F. P.; West, F. G. Chem. Eur. J. 2002, 8, 4346–4353; (b) Evans, P. A.; Delouvrie, B.
Curr. Opin. Drug Discovery Rev. 2002, 5, 986–999; (c) Inoue, M. Org. Biomol. Chem.
2004, 2, 1811–1817; (d) Nakata, T. Chem. Rev. 2005, 105, 4314–4347; (e) Inoue,
M. Chem. Rev. 2005, 105, 4379–4405.
3. Takamura, H.; Kikuchi, S.; Nakamura, Y.; Yamagami, Y.; Kishi, T.; Kadota, I.;
Yamamoto, Y. Org. Lett. 2009, 11, 2531–2534.
4. (a) Nicolaou, K. C.; Prasad, C. V. C.; Hwang, C.-K.; Duggan, M. E.; Veale, C. A. J. Am.
Chem. Soc. 1989, 111, 5321–5330; Also see: (b) Fuwa, H.; Sasaki, M.; Tachibana,
K. Tetrahedron Lett. 2000, 41, 8371–8375.
4
88
88
5c
5. For the reaction of hemiacetals with Me2Zn/BF3ÁOEt2, see: Tomooka, K.;
Matsuzawa, K.; Suzuki, K.; Tsuchihashi, G. Tetrahedron Lett. 1987, 28, 6339–
6342.
6. Experimental procedure is as follows: To a mixture of 5 (57 mg, 0.28 mmol) in
CH2Cl2 (2.7 mL) at 0 °C were added Me2Zn (1.4 mL, 1.0 M in hexane, 1.4 mmol)
and Zn(OTf)2 (200 mg, 0.56 mmol). After stirring the reaction mixture for 5 h at
the same temperature, the reaction was quenched with a 1:1 mixture of MeOH/
Et3N. The mixture was filtered through a Celite pad with ether as an eluent, and
the filtrate was concentrated. The residue was purified by column
chromatography to give 6 (41 mg, 93%): 1H NMR (400 MHz, CDCl3) d 4.00–
3.92 (m, 1H), 3.76 (ddd, J = 11.5, 11.5, 2.5 Hz, 1H), 3.75–3.70 (m, 1H), 3.36 (ddd,
J = 12.4, 11.2, 2.2 Hz, 1H), 3.21–3.19 (m, 1H), 2.04–1.66 (m, 5H), 1.45–1.23 (m,
3H), 1.16 (s, 3H).
a
Reactions were carried out with Me2Zn (5 equiv) and Zn(OTf)2 (2 equiv) in
CH2Cl2 at O °C for 0.5–3 h.
b
Isolated yield.
c
The reaction was carried in ClCH2CH2Cl at 80 °C for 54 h.
method for the stereoselective construction of angular methyl
group of fuzed cyclic ethers.
In an initial experiment, the synthesis of a 6-6 ring system was
examined (Scheme 2). Treatment of the hemiacetal 4 with EtSH/
7. The substrates 7–10 were prepared from the corresponding hemiacetals by the
same procedure described in the Scheme 2. The mixed thioacetal 11 was
synthesized from a hydroxy dithioacetal by using the Nicolaou’s protocol, see
Ref. 4a.