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DOI: 10.1055/s-0034-1379027
A New Deprotection Procedure of MTM Ether
Publication History
Received: 10 July 2014
Accepted after revision: 05 August 2014
Publication Date:
15 September 2014 (online)
Abstract
A new deprotection procedure of methylthiomethyl (MTM) ether, a protective group for the hydroxy group, was developed. MTM was oxidized with MCPBA or Oxone, and the resulting sulfoxide was treated under conditions of the Pummerer rearrangement, to give acetoxy sulfide and/or acetoxy acetal. Alkaline hydrolysis of the products provided the unprotected alcohols in good yields. Details of the reactions using several different substrates are described.
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Methylthiomethyl (MTM) ether, introduced by E. J. Corey in 1975,[1] has been employed as an important protective group for the hydroxy group.[2] [3] Since the stability of MTM ether under acidic conditions as well as specific conditions for its removal are different from those for other acetal protective groups such as MOM, MEM, BOM, etc., MTM has played an important role in the syntheses of complex natural products.[4] In the course of our synthesis of chiriquitoxin, a densely functionalized natural product, we encountered a problem regarding deprotection of the MTM group of intermediate 1 (Scheme [1]).[5] Unfortunately, preceding conditions, such as AgNO3 or HgCl2 in aqueous organic solvents,[1] did not give the corresponding alcohol 2. When deprotection of MTM of compound 1 was attempted, we frequently observed the formation of methylene acetal 4; for example, when 1 was treated with TBSOTf in the presence of 2,6-lutidine, a cyclic methylene acetal 4 was obtained as a sole product.[6] This result indicates that oxonium ion intermediate 3 was generated from the MTM ether in the presence of the Lewis acid and was intercepted with the internal hydroxy group to form the acetal 4, a dead-end product in the synthesis of such a highly functionalized natural product. Since most of the literature conditions for deprotection of MTM ether utilize the same oxonium ion intermediates, we explored a new procedure of the deprotection that avoids the oxonium ion intermediate.
In the event, we developed a new deprotection procedure of MTM that enabled us to achieve the first total synthesis of chiriquitoxin (Scheme [2]); the MTM of an intermediate 5 was oxidized with MCPBA to the corresponding sulfoxide. A subsequent Pummerer reaction with trifluoroacetic anhydride (TFAA) in the presence of 2,6-lutidine provided acetoxy sulfide 6, which was hydrolyzed with aqueous ammonia to furnish 7 in an acceptable yield. Throughout this procedure, we considered that oxonium ion intermediates would not be generated according to a proposed reaction mechanism (vide infra). We disclose herein the full details of model experiments of the new deprotection that we have carried out prior to the total synthesis of chiriquitoxin and the substrate scope of this procedure.
We initially expected the mechanism of the Pummerer rearrangement of sulfoxide A prepared from a MTM ether as shown in Scheme [3].[7] Acetylation of the sulfoxide oxygen is followed by deprotonation from the α-carbons of the sulfoxide to give two possible acyl sulfonium ions C and D, which are trapped with acetate to give E and F, respectively. Alkaline hydrolysis of both intermediates provides the same alcohol G. The oxonium ion intermediates would not be involved in the series of reactions.
To prove the utility of this procedure, model experiments were carried out by using pinene-derived compound 8,[8] which contains a 1,2-diol structure similar to that of the intermediates of chiriquitoxin synthesis (Scheme [4]). MTM of 8 was oxidized with MCPBA (96%), and the resulting sulfoxide 9 was treated with Ac2O and NaOAc at 80 °C, a typical condition of the Pummerer rearrangement, to give an inseparable ca. 1:4.6 mixture of acetoxy sulfide 10a and acetoxy acetal 10b, an unexpected product.[9] Under the conditions, the other acetoxy sulfide corresponding to F (Scheme [3]) was not detected at all. Upon treatment of the mixture with K2CO3 in methanol, the desired diol 12 was obtained in 90% yield from 9. The Pummerer reaction of 9 with TFAA in the presence of 2,6-lutidine underwent at lower temperature (0 °C) to give an ca. 1:5 mixture of 11a and 11b as unstable products.[10] Subsequent hydrolysis with aqueous ammonia provided the diol 12 in 85% yield from 9. The cyclic methylene acetal 13 was not detected under these two procedures.[11] We therefore established the new deprotection procedure of MTM through the corresponding sulfoxide.
As acetoxy acetal 10b and 11b, the unexpected products, were obtained under the conditions of the Pummerer reaction, we must assume that oxonium ion H was generated via B from sulfoxide A by elimination of methylsulfenyl acetate (Scheme [5]).[12] [13] Another possibility, that oxonium ion H might be generated from acetoxy sulfide E, was excluded by the following experiment: when a ca.18:82 mixture of 10a and 10b was exposed to the same conditions of the Pummerer reaction, a change in the product ratio was not observed. These experiments using 8 revealed that the two mechanisms of the deprotection operated under the Pummerer conditions to give diol 12. With these results in mind, we investigated deprotection of the intermediate 5 of chiriquitoxin as shown in Scheme [1]. Fortunately, the sulfoxide of MTM of 5 underwent the Pummerer reaction to give trifluoroacetoxy sulfide 6 without formation of a trifluoroacetoxy acetal in this specific case, probably due to steric hindrance around the sulfoxide moiety.
The successful deprotection of MTM of the highly functionalized compound 5 already indicates the highly compatible nature of this procedure to many functional groups such as Boc, TBS, TIPS, internal acetal, imine, and lactone. We further examined the tolerance of this deprotection procedure for other functional groups by using substrates as shown in Table [1].[14] Oxidation of MTM of the substrates containing alkene (vinyl and trisubstituted alkene) were carried out by MCPBA at –78 °C in high yields. Oxone could also be used for oxidation of the same substrates in comparable yields (Table [1], entry 1). Results of the attempted Pummerer reaction using TFAA and 2,6-lutidine in CH2Cl2 at 0 °C and subsequent hydrolysis with aqueous ammonia are shown in Table [1]. MTM groups of all the substrates were successfully removed by the procedures in good yields. Interestingly, 1H NMR analysis of the crude products obtained under the Pummerer conditions indicated that the structures of the products were all the corresponding trifluoroacetoxy acetal (R = CH2OTFA) except 17a.[15] The reaction of compound 17a yielded a mixture of the corresponding trifluoroacetoxy acetal 17b (R = CH2OTFA) and trifluoroacetate 17c (R = TFA). It is noteworthy that the reaction of sulfoxide 19 obtained by the oxidation of 18 gave sulfenate ester 20 [16] [17] as a major product after treatment with the Pummerer conditions followed by alkaline hydrolysis with aqueous ammonia (Scheme [6]). However, prolonged treatment (overnight) of the mixture with aqueous ammonia yielded phenol 21 in a moderate yield. Alternatively, when Ph3P was added after the treatment with aqueous ammonia, phenol 21 was obtained in quantitative yield from sulfoxide 19.
a Isolated yield.
b Reaction conditions: MCPBA in CH2Cl2 at –78 °C.
c Reaction conditions: TFAA, 2,6-lutidine in CH2Cl2; aq NH3 in MeOH.
d Reaction conditions: Oxone, NaHCO3 in aq THF at 0 °C.
In summary, we have developed new deprotection procedure of MTM ethers through the corresponding sulfoxides. Although products formed under the Pummerer conditions depend on the substrate, the procedure was found to be compatible with a wide range of functional groups, including TBS, TIPS, Boc, Cbz, Bn, MOM, acetonide, lactone, trichloroacetamide, alkene, and TMS-acetylene. The new conditions thus should expand the usefulness of the MTM protective group in the synthesis of densely functionalized natural products.
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Acknowledgement
This work was supported by a Grants-in-Aid on Innovative Areas ‘Chemical Biology of Natural Products’[18] from MEXT, the Sumitomo Foundation, the Daiichi Sankyo Foundation of Life Science, the Yamada Science Foundation, and a SUNBOR GRANT from the Suntory Institute for Bioorganic Research.
Supporting Information
- for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/products/ejournals/journal/
10.1055/s-00000083.
- Supporting Information
-
References and Notes
- 1 Corey EJ, Bock MG. Tetrahedron Lett. 1975; 16: 3269
- 2a Kocienski PJ In Protective Groups . Thieme; Stuttgart: 2004. 3rd ed, 320-323
- 2b Wuts PG. M, Greene TW In Greene’s Protective Groups in Organic Synthesis . Wiley; New York: 2007: 38-41
- 3a Yamada K, Kato K, Nagase H, Hirata Y. Tetrahedron Lett. 1976; 17: 65
- 3b Pojer PM, Angyal SJ. Aust. J. Chem. 1978; 31: 1031
- 3c Suzuki K, Inanaga J, Yamaguchi M. Tetrahedron Lett. 1979; 20: 1277
- 3d Medine JM, Salomon M, Kyler KS. Tetrahedron Lett. 1988; 29: 3773
- 4a Corey EJ, Wollenberg RH, Williams DR. Tetrahedron Lett. 1977; 18: 2243
- 4b Corey EJ, Hua DH, Pan B.-C, Seitz SP. J. Am. Chem. Soc. 1982; 104: 6818
- 4c Keck GE, Boden E, Wiley MR. J. Org. Chem. 1989; 54: 896
- 4d Niwa H, Miyachi Y, Okamoto O, Uosaki Y, Kuroda A, Ishiwata H, Yamada K. Tetrahedron 1992; 48: 393
- 4e Kigoshi H, Suenaga K, Mutou T, Ishigaki T, Atsumi T, Ishiwata H, Sakakura A, Ogawa T, Ojika M, Yamada K. J. Org. Chem. 1996; 61: 5326
- 5 Adachi M, Imazu T, Sakakibara R, Satake Y, Isobe M, Nishikawa T. Chem. Eur. J. 2014; 20: 1247
- 6 The similar cyclic methylene acetal formation in deprotection of MTM was reported: Wachter MP, Adams RE. Synth. Commun. 1980; 10: 111
- 7a DeLucchi O, Miotti U, Modena G In Organic Reactions . Paquette LA. John Wiley; New York: 1991. Chap. 3, 157-184
- 7b Grieson DS, Husson HP. In Comprehensive Organic Synthesis . Vol. 6. Trost BM. Pargamon; Oxford: 1991: 909-947
- 7c Bur SK, Padwa A. Chem. Rev. 2004; 104: 2401
- 8 The model compound 8 was prepared from d-pinene through diol 12 in two steps. For details, see the Supporting Information.
- 9 1H NMR Data of Acetoxy Sulfide 10a and Acetoxy Acetal 10b (ca. 1:4.6 Inseparable Mixture) 1H NMR (300 MHz, CDCl3): δ = 0.96 (3 H, s, CH3), 1.26 (3 H, s, CH3), 1.40–1.52 (1 H, m), 1.80–1.98 (5 H, m), 2.02 (3 H, s, CH3 of Ac), 2.08 (3 H, s, CH3 of Ac), 2.13–2.24 (2 H, m), 4.12 (0.18 H, d, J = 12 Hz, CCHA HBOAc of acetoxy sulfide), 4.14 (1.64 H, s, CCH2OAc of acetoxy acetal), 4.22 (0.18 H, d, J = 12 Hz, CCHA HB OAc of acetoxy sulfide), 4.50 (0.18 H, d, J = 10 Hz, OCHA HBS), 4.64 (0.18 H, d, J = 10 Hz, OCHA HB S), 5.22 (0.82 H, d, J = 7 Hz, OCHA HBOAc), 5.24 (0.36 H, s, SCH2OAc), 5.35 (0.82 H, d, J = 7 Hz, OCHA HB OAc).
- 10 1H NMR spectra of the crude products of the Pummerer reaction indicated the presence of cyclic methylene acetal 13, which might be formed from 11a and/or 11b during the workup (concentration). Therefore, the reaction mixture was directly poured into an aq ammonia, resulting in exclusive formation of 12. For details, see the Supporting Information.
- 11 TLC analysis indicated that the primary alcohol of 9 was first acetylated and then acetylation of the sulfoxide occurred to a mixture of the product 10a and 10b.
- 12a Kahne D, Walker S, Cheng Y, Van Engen D. J. Am. Chem. Soc. 1989; 111: 6881
- 12b Tanaka H, Chino A, Takahashi T. Tetrahedron Lett. 2012; 53: 2493
- 13 As it turned out later, the similar reactions giving acetoxy sulfides from the sulfoxides of MTM were reported: Antonsen Q, Benneche T, Undheim K. Acta Chem. Scand., Ser. B 1988; 42: 515
- 14 For details regarding preparation of the substrates, see the Supporting Information.
- 15 1H NMR Data of the Trifluoroacetoxy Acetal Derived from 16 1H NMR (300 MHz, CDCl3): δ = 0.19 (9 H, s, CH3 of TMS), 0.83 (3 H, s, CH3), 0.84–2.42 (18 H, m), 1.02 (3 H, s, CH3), 3.37 (3 H, s, CH 3OCH2O), 5.26 (1 H, br d, J = 5 Hz, C=CH), 5.76 (1 H, d, J = 6 Hz, OCHA HBOTFA), 5.84 (1 H, d, J = 6 Hz, OCHA HB OTFA).
- 16 The structure of 21 was identified by analysis of NMR and MS spectra. For details, see the Supporting Information.
- 17 The mechanism of formation for 20 is unclear.
- 18 Ueda M. Chem. Lett. 2012; 41: 658
For examples, see:
For reviews of Pummerer rearrangement, see:
The related reactions involving oxonium intermediates generated from the sulfoxides of S,O-thioacetals with Tf2O or TFAA, and subsequent transformation were reported. For examples, see:
-
References and Notes
- 1 Corey EJ, Bock MG. Tetrahedron Lett. 1975; 16: 3269
- 2a Kocienski PJ In Protective Groups . Thieme; Stuttgart: 2004. 3rd ed, 320-323
- 2b Wuts PG. M, Greene TW In Greene’s Protective Groups in Organic Synthesis . Wiley; New York: 2007: 38-41
- 3a Yamada K, Kato K, Nagase H, Hirata Y. Tetrahedron Lett. 1976; 17: 65
- 3b Pojer PM, Angyal SJ. Aust. J. Chem. 1978; 31: 1031
- 3c Suzuki K, Inanaga J, Yamaguchi M. Tetrahedron Lett. 1979; 20: 1277
- 3d Medine JM, Salomon M, Kyler KS. Tetrahedron Lett. 1988; 29: 3773
- 4a Corey EJ, Wollenberg RH, Williams DR. Tetrahedron Lett. 1977; 18: 2243
- 4b Corey EJ, Hua DH, Pan B.-C, Seitz SP. J. Am. Chem. Soc. 1982; 104: 6818
- 4c Keck GE, Boden E, Wiley MR. J. Org. Chem. 1989; 54: 896
- 4d Niwa H, Miyachi Y, Okamoto O, Uosaki Y, Kuroda A, Ishiwata H, Yamada K. Tetrahedron 1992; 48: 393
- 4e Kigoshi H, Suenaga K, Mutou T, Ishigaki T, Atsumi T, Ishiwata H, Sakakura A, Ogawa T, Ojika M, Yamada K. J. Org. Chem. 1996; 61: 5326
- 5 Adachi M, Imazu T, Sakakibara R, Satake Y, Isobe M, Nishikawa T. Chem. Eur. J. 2014; 20: 1247
- 6 The similar cyclic methylene acetal formation in deprotection of MTM was reported: Wachter MP, Adams RE. Synth. Commun. 1980; 10: 111
- 7a DeLucchi O, Miotti U, Modena G In Organic Reactions . Paquette LA. John Wiley; New York: 1991. Chap. 3, 157-184
- 7b Grieson DS, Husson HP. In Comprehensive Organic Synthesis . Vol. 6. Trost BM. Pargamon; Oxford: 1991: 909-947
- 7c Bur SK, Padwa A. Chem. Rev. 2004; 104: 2401
- 8 The model compound 8 was prepared from d-pinene through diol 12 in two steps. For details, see the Supporting Information.
- 9 1H NMR Data of Acetoxy Sulfide 10a and Acetoxy Acetal 10b (ca. 1:4.6 Inseparable Mixture) 1H NMR (300 MHz, CDCl3): δ = 0.96 (3 H, s, CH3), 1.26 (3 H, s, CH3), 1.40–1.52 (1 H, m), 1.80–1.98 (5 H, m), 2.02 (3 H, s, CH3 of Ac), 2.08 (3 H, s, CH3 of Ac), 2.13–2.24 (2 H, m), 4.12 (0.18 H, d, J = 12 Hz, CCHA HBOAc of acetoxy sulfide), 4.14 (1.64 H, s, CCH2OAc of acetoxy acetal), 4.22 (0.18 H, d, J = 12 Hz, CCHA HB OAc of acetoxy sulfide), 4.50 (0.18 H, d, J = 10 Hz, OCHA HBS), 4.64 (0.18 H, d, J = 10 Hz, OCHA HB S), 5.22 (0.82 H, d, J = 7 Hz, OCHA HBOAc), 5.24 (0.36 H, s, SCH2OAc), 5.35 (0.82 H, d, J = 7 Hz, OCHA HB OAc).
- 10 1H NMR spectra of the crude products of the Pummerer reaction indicated the presence of cyclic methylene acetal 13, which might be formed from 11a and/or 11b during the workup (concentration). Therefore, the reaction mixture was directly poured into an aq ammonia, resulting in exclusive formation of 12. For details, see the Supporting Information.
- 11 TLC analysis indicated that the primary alcohol of 9 was first acetylated and then acetylation of the sulfoxide occurred to a mixture of the product 10a and 10b.
- 12a Kahne D, Walker S, Cheng Y, Van Engen D. J. Am. Chem. Soc. 1989; 111: 6881
- 12b Tanaka H, Chino A, Takahashi T. Tetrahedron Lett. 2012; 53: 2493
- 13 As it turned out later, the similar reactions giving acetoxy sulfides from the sulfoxides of MTM were reported: Antonsen Q, Benneche T, Undheim K. Acta Chem. Scand., Ser. B 1988; 42: 515
- 14 For details regarding preparation of the substrates, see the Supporting Information.
- 15 1H NMR Data of the Trifluoroacetoxy Acetal Derived from 16 1H NMR (300 MHz, CDCl3): δ = 0.19 (9 H, s, CH3 of TMS), 0.83 (3 H, s, CH3), 0.84–2.42 (18 H, m), 1.02 (3 H, s, CH3), 3.37 (3 H, s, CH 3OCH2O), 5.26 (1 H, br d, J = 5 Hz, C=CH), 5.76 (1 H, d, J = 6 Hz, OCHA HBOTFA), 5.84 (1 H, d, J = 6 Hz, OCHA HB OTFA).
- 16 The structure of 21 was identified by analysis of NMR and MS spectra. For details, see the Supporting Information.
- 17 The mechanism of formation for 20 is unclear.
- 18 Ueda M. Chem. Lett. 2012; 41: 658
For examples, see:
For reviews of Pummerer rearrangement, see:
The related reactions involving oxonium intermediates generated from the sulfoxides of S,O-thioacetals with Tf2O or TFAA, and subsequent transformation were reported. For examples, see:
