1,4-Dithiothreitol mediated cleavage of the acetal and ketal type of diol protecting groups

Yan Liu a, Jing Zeng a, Jiuchang Sun a, Lei Cai a, Yueqi Zhao a, Jing Fang a, Bo Hu a, Penghua Shu a, Lingkui Meng a and Qian Wan *ab
aHubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei 430030, China. E-mail: wanqian@hust.edu.cn
bInstitute of Brain Research, Huazhong University of Science and Technology, China

Received 7th March 2018 , Accepted 26th March 2018

First published on 27th March 2018


The use of 1,4-dithiothreitol (DTT) as an acetal or ketal exchange reagent and camphorsulfonic acid (CSA) as a catalyst permitted the efficient removal of benzylidene acetal and isopropylidene ketal protecting groups under mild conditions. A variety of acetal and ketal protected carbohydrates were deprotected with this method in 78–98% yields. In addition, terminal isopropylidene ketal or benzylidene acetal was selectively cleaved in the presence of internal isopropylidene ketal. Moreover, it was found that an unusual seven-membered 1,3-dithiepane was formed during the deprotection of benzylidene acetal with DTT.


Introduction

1,2- and 1,3-diols are frequently protected as acetal or ketal forms in organic synthesis especially in carbohydrate chemistry.1 It has been found that acetal and ketal protecting groups are able to influence the reactivity and selectivity of the glycosylation reactions due to the formed fused 5- or 6-membered rings.2 For example, the 4,6-benzylidene protecting group governed the 1,2-cis selectivity in Crich β-mannosylation reaction.3 Acetal and ketal protecting groups are normally stable under basic conditions and they are often cleaved under hydrogenation conditions4 or by hydrolysis with protic or Lewis acids.5 However, most of these methods are associated with several disadvantages, such as relatively harsh conditions, long reaction time, incompatibility with many functional groups and formation of unwanted byproducts. To overcome these problems, several new methods with mild and green reaction conditions have been reported. For instance, Ye6 and Hayashi7 applied silica gel supported NaHSO4 or NaHSO4·H2O to cleave benzylidene acetals; Baskaran reported that phosphomolybdic acid supported on silica gel efficiently cleaved benzylidene acetals.8 Majumdar9 developed an imidazole based protic ionic liquid catalyst to deprotect acetals and ketals; most recently, Wang10 employed photochemical conditions to remove a photolabile benzylidene-type acetal group.

We recently focused on the synthesis of a series of naturally occurring phenylethanoid glycosides based on the interrupted Pummerer reaction mediated glycosylation strategy.11 However, during the synthesis of leonuriside B,12 we encountered difficulty in the removal of the 4,6-benzylidene group of compound 1.11c Traditionally used acidic conditions such as AcOH–H2O or TsOH·H2O resulted in low yields due to the slow transformation rate and the partial cleavage of the aglycone. After screening of several conditions, this deprotection was finally achieved with 86% yield with modified Williams’ conditions13 reported by Danishefsky et al.14 The protocol involved camphorsulfonic acid (CSA) as a catalyst and 1,2-ethanedithiol as a ketal exchange reagent.11c Despite the successful removal of the protecting group, the requirement of a large excess of odorous thiol and high reaction temperature prompted us to further optimize the reaction conditions to provide a practical method for the complete removal of the ketal and acetal type of diol protecting groups (Scheme 1).


image file: c8qo00247a-s1.tif
Scheme 1 Attempts to cleave benzylidene acetal during the synthesis of leonuriside B. Conditions: AcOH–H2O (9[thin space (1/6-em)]:[thin space (1/6-em)]1), 90 °C, 10 h, 50%. p-TsOH·H2O (0.3 equiv.), MeOH, 50 °C, 5 h, 30%. (CH2SH)2 (10.0 equiv.), CSA (0.1 equiv.), CHCl3, reflux, 12 h, 86%.

Results and discussion

Initially, the deprotection of 4,6-O-benzylidene glucopyranoside (3a) was selected as a model reaction. The treatment of compound 3a with 0.1 equiv. of CSA in MeOH at room temperature furnished 68% yield of deprotected product 4a in combination with 30% of the recovered starting material after 1.5 h (Table 1, entry 1). Then 2.0 equiv. of ethylene glycol (II) was introduced into the reaction system, unfortunately, no apparent improvement was observed (Table 1, entry 2). The replacement of ethylene glycol with 1,2-ethanedithiol (III) dramatically increased the yield to 90% (entry 3). However, the unpleasant odor of 1,2-ethanedithiol prompted us to further search for its surrogate. We recently found that odorless DL-1,4-dithiothreitol (DTT, I) was an efficient trans-thioesterification reagent in a selective anomeric S-deacetylation reaction for the synthesis of glycosyl thiols.15 This observation stimulated us to use DTT as an acetal exchange reagent in this deprotection reaction. As expected, the reaction with 2.0 equiv. of DTT in MeOH resulted in 4a in 92% yield (entry 4). The reaction carried out in CH2Cl2 produced comparable results even on a gram scale (entry 5). Reducing the amount of DTT to 1.2 equiv. slightly affected the yield and required a much longer reaction time (entry 6). CH3CN was also a good solvent for this deprotection reaction (entry 7). However, other solvents such as THF, toluene, ethyl acetate, ethanol and DMF were less efficient (entries 8–12). It is worth noting that other acid catalysts such as p-TsOH and acidic resin Amberlyst 15 also performed perfectly to remove the protecting groups (entries 13 and 14).
Table 1 Optimization of reaction conditions

image file: c8qo00247a-u1.tif

Entry Additive (2.0 equiv.) Solvent Time (h) Yielda
a Isolated yield. b Yield of gram scale is given in parentheses. c 1.2 equiv. of DTT. d 0.1 equiv. of p-TsOH·H2O used instead of CSA. e 5 wt% of Amberlyst 15 resin used instead of CSA. CSA: (+)-camphor-10-sulfonic acid; p-TsOH: p-toluenesulfonic acid monohydrate.
1 MeOH 1.5 68%
2 Ethylene glycol (II) MeOH 1.5 70%
3 1,2-Ethanedithiol (III) MeOH 1.5 90%
4 DTT (I) MeOH 1.5 92%
5 DTT (I) CH2Cl2 2.5 94% (92%)b
6c DTT (I) CH2Cl2 12 87%
7 DTT (I) MeCN 2.0 90%
8 DTT (I) THF 24 45%
9 DTT (I) Toluene 24 50%
10 DTT (I) EtOAc 24 65%
11 DTT (I) EtOH 24 77%
12 DTT (I) DMF 24 Trace
13d DTT (I) CH2Cl2 2.5 95%
14e DTT (I) MeCN 2.5 94%


With these optimized reaction conditions in hand, we next turned our attention to examining the applicability of this protocol. As depicted in Table 2, 4,6-benzylidene acetals of both glucose (3b–c) and galactose (3h) were readily removed without affecting the other protecting groups. The acid sensitive PMB group was able to survive under the reaction conditions (3d). Phenylethanoid glycosides 3e and 3f reacted smoothly which implied the further applicability of this protocol in complex phenylethanoid glycoside synthesis. The deprotection of (4-methoxy)benzylidene groups (3g, 3i) occurred equally well as that of 4,6-benzylidene groups. Notably, the 2,3-benzylidene acetal protecting group of rhamnose (3i) was removed smoothly without touching the anomeric 2-(2-propylthio)benzyl (PTB) group. The benzylidene group of disaccharide 3j containing a sensitive 2-deoxysugar moiety was deprotected in excellent yield.

Table 2 Cleavage of benzylidene acetal with DTT and CSA

image file: c8qo00247a-u2.tif

Entry Substrate Product Yielda
a Isolated yield. b MeOH was used as a reaction solvent. PTB: 2-(2-propylthio)benzyl.
1 image file: c8qo00247a-u3.tif image file: c8qo00247a-u4.tif 95% (98%)b
2 image file: c8qo00247a-u5.tif image file: c8qo00247a-u6.tif 93%
3 image file: c8qo00247a-u7.tif image file: c8qo00247a-u8.tif 83%
4 image file: c8qo00247a-u9.tif image file: c8qo00247a-u10.tif 86%
5 image file: c8qo00247a-u11.tif image file: c8qo00247a-u12.tif 93%
6 image file: c8qo00247a-u13.tif image file: c8qo00247a-u14.tif 87%
7 image file: c8qo00247a-u15.tif image file: c8qo00247a-u16.tif 96%
8 image file: c8qo00247a-u17.tif image file: c8qo00247a-u18.tif 96%
9 image file: c8qo00247a-u19.tif image file: c8qo00247a-u20.tif 95%


Encouraged by these results, we further considered to expand the method to the removal of the isopropylidene ketal protecting group (Table 3). However, compared to those of the benzylidene acetals the deprotection reactions of isopropylidene ketals proceeded slower under the optimized conditions. Increasing the solvent concentration speeded up the reaction which furnished the desired products in good yields (4k, 4i). It should be noted that a part of the TBS group in 3m was slowly removed under the reaction conditions with extended reaction time, which resulted in lower yield.

Table 3 Cleavage of isopropylidene ketal with DTT and CSA

image file: c8qo00247a-u21.tif

Entry Substrate Product Time Yield
1 image file: c8qo00247a-u22.tif image file: c8qo00247a-u23.tif 6 h 93%
2 image file: c8qo00247a-u24.tif image file: c8qo00247a-u25.tif 15 h 95%
3 image file: c8qo00247a-u26.tif image file: c8qo00247a-u27.tif 10 h 75%


The reaction rate difference between the removal of acetal and ketal protecting groups prompted us to apply this protocol to selectively deprotect the benzylidene acetal in the presence of ketal functionalities. It was found that the spiroketal moiety of diosgenin aglycone was kept intact under the current reaction conditions (Scheme 2, 4n). In addition, the selective deprotection of benzylidene acetal of 3o in the presence of isopropylidene ketal proceeded smoothly to furnish the desired product 4o in excellent yield under the above conditions. Furthermore, this protocol was also sufficiently lenient to allow the selective unravelling of the terminal isopropylidene ketal moiety of compound 3p (Scheme 2).


image file: c8qo00247a-s2.tif
Scheme 2 Chemoselective cleavage of ketal and acetal protecting groups. Conditions: DTT (2.0 equiv.), CSA (0.1 equiv.), DCM, rt. for a specified reaction time.

This protocol was then applied to benzylidene acetal deprotection reaction in the synthesis of naturally occurring phenylethanoid glycosides. Subjecting 5a, which is the protected precursor of natural product decaffeoyl acteoside,16 to the standard reaction conditions furnished 6a in 90% yield, albeit the requirement of 30 h to accomplish the reaction. Interestingly, increasing the amount of CSA to 1.0 equiv. produced 6a in almost quantitative yield in 10 h. Unlike the aforementioned deprotection reaction for leonuriside B synthesis, the cleavage of the aglycone was not observed even in the presence of such a high dosage of CSA. This protocol was further applied to the complete deprotection of the benzylidene acetal group and the isopropylidene ketal group of a tetrasaccharide 5b which is a synthetic intermediate of resin glycoside tricolorin A.17 The presence of three deoxysugar moieties (2 rhamnoses and 1 fucose), two β-glycosidic bonds as well as the macrolactone ring in compound 5b makes the deprotection reaction very challenging. Nevertheless, by the utilization of 4.0 equiv. of DTT and 1.0 equiv. of CSA, the goal was perfectly achieved which offered 6b in 90% yield, highlighting the extensive applicability of the DTT mediated deprotection reactions (Scheme 3).


image file: c8qo00247a-s3.tif
Scheme 3 Cleavage of benzylidene acetals in natural product synthesis.

During the deprotection reaction of benzylidene acetals, it was found that DTT was transformed to a cyclic product 7 with an unusual seven-membered ring (Scheme 4a). The structure of compound 7 was confirmed by X-ray crystal analysis (Fig. 1).18 The formation of this unusual 1,3-dithiepane possibly resulted from the higher nucleophilicity of thiol atoms. Nevertheless, the isolation of this 1,3-dithiepane compound 7 clearly indicated that DTT played the role of an acetal exchange reagent in the deprotection reactions. Interestingly, it was observed that the DTT mediated cleavage of the benzylidene acetal proceeded faster than that of other thiols including 1,2-ethanedithiol, 1,3-propanedithiol, 1,4-butanedithiol, 2-mercaptoethanol, etc.19 The isolation of a large amount of 1,3-dithiepane 7 in competition reactions between DTT and 1,2-ethanedithiol (III) or 1,3-propanedithiol (IV) further revealed the higher reaction rate of DTT mediated deprotection reactions (Scheme 4b and c).20 These observations evidently demonstrated the advantages of the DTT mediated deprotection reaction: less odour and higher efficiency.


image file: c8qo00247a-s4.tif
Scheme 4 (a) Formation of 1,3-dithiepane 7; (b) competition reaction with 1,2-ethanedithiol; (c) competition reaction with 1,3-propanedithiol.

image file: c8qo00247a-f1.tif
Fig. 1 X-ray ORTEP drawing of compound 7.

Conclusion

In conclusion, we have introduced a practical and efficient method for the complete removal of the acetal and ketal type of diol protecting groups with Brønsted acids such as CSA and p-TsOH as catalysts and DTT as the acetal/ketal exchange reagent. This protocol has remarkable advantages compared with the conventional methods in view of its operational simplicity, mild conditions and compatibility with other functional groups. We believe that this new method will find wide applications in carbohydrate chemistry and synthetic organic transformations.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

Financial support from the National Natural Science Foundation of China (21672077, 21761132014, 21772050), the State Key Laboratory of Bio-organic and Natural Products Chemistry (SKLBNPC13425), the Natural Science Funds of Hubei Province for Distinguished Young Scholars (2015CFA035), Wuhan Creative Talent Development Fund, “Thousand Talents Program” Young Investigator Award, and Huazhong University of Science and Technology is greatly appreciated. We also thank Prof. Xing Lu, and Dr Lipiao Bao and Mr Wangqiang Shen (HUST) for X-ray testing and analysis.

Notes and references

  1. (a) P. G. M. Wuts and T. W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 4th edn, 2007 Search PubMed ; (b) P. J. Kocienski, Protecting Groups, Georg Thieme Verlag, Stuttgart, 3rd edn, 2005 Search PubMed .
  2. S. Aubry, K. Sasaki, I. Sharma and D. Crich, Top. Curr. Chem., 2011, 301, 141 CrossRef CAS PubMed .
  3. (a) D. Crich and S. Sun, J. Org. Chem., 1996, 61, 4506 CrossRef CAS PubMed ; (b) D. Crich and S. Sun, J. Org. Chem., 1997, 62, 1198 CrossRef CAS .
  4. (a) S. Peat and L. F. Wiggins, J. Chem. Soc., 1938, 1088 RSC ; (b) A. B. Smith and K. J. Hale, Tetrahedron Lett., 1989, 30, 1037 CrossRef CAS ; (c) M. Mori, S. Tejima and T. Niwa, Chem. Pharm. Bull., 1986, 34, 4037 CrossRef CAS .
  5. (a) R. M. Hann, N. K. Richtmyer, H. W. Diehl and C. S. Hudson, J. Am. Chem. Soc., 1950, 72, 561 CrossRef CAS ; (b) M. Smith, D. H. Rammler, I. H. Goldberg and H. G. Khorana, J. Am. Chem. Soc., 1962, 84, 430 CrossRef CAS ; (c) T. G. Bonner, E. J. Bourne and S. McNally, J. Chem. Soc., 1960, 2929 RSC ; (d) W. A. Szarek, A. Zamojski, K. N. Tiwari and E. R. Ison, Tetrahedron Lett., 1986, 27, 3827 CrossRef CAS ; (e) M. H. Park, R. Takeda and K. Nakanishi, Tetrahedron Lett., 1987, 28, 3823 CrossRef CAS ; (f) B. Capon, W. G. Overend and M. Sobell, Tetrahedron, 1961, 16, 106 CrossRef CAS ; (g) A. Procopio, R. Dalpozzo, A. D. Nino, L. Maiuolo, M. Nardi and G. Romeo, Org. Biomol. Chem., 2005, 3, 4129 RSC ; (h) J. Xia and Y. Hui, Synth. Commun., 1996, 26, 881 CrossRef CAS ; (i) T. Nishio, Y. Miyake, K. Kubota, M. Yamai, S. Miki, T. Ito and T. Oku, Carbohydr. Res., 1996, 280, 357 CrossRef CAS ; (j) K. C. Nicolaou, Y. Li, K. C. Fylaktakidou, H. J. Mitchell, H. Wei and B. Weyershausen, Angew. Chem., Int. Ed., 2001, 40, 3849 CrossRef CAS ; (k) G. Barone, E. Bedini, A. Iadonisi, E. Manzo and M. Parrilli, Synlett, 2002, 1645 CAS ; (l) F. Pfrengle, V. Dekaris, L. Schefzig, R. Zimmer and H. U. Reissig, Synlett, 2008, 2965 CAS ; (m) J. S. Yadav, P. N. Lakshmi, S. J. Harshavardhan and B. V. S. Reddy, Synlett, 2007, 1945 CrossRef CAS ; (n) M. Yan, Y. Chen, H. Wu, C. Lin, C. Chen and C. Lin, J. Org. Chem., 2007, 72, 299 CrossRef CAS PubMed .
  6. Y. Niu, N. Wang, X. Cao and X. Ye, Synlett, 2007, 2116 CAS .
  7. K. Michigami, M. Terauchi and M. Hayashi, Synthesis, 2013, 1519 CAS .
  8. P. S. Kumar, G. D. K. Kumar and S. Baskaran, Eur. J. Org. Chem., 2008, 6063 CrossRef CAS .
  9. S. Majumdar, M. Chakraborty, D. K. Maiti, S. Chowdhury and J. Hossain, RSC Adv., 2014, 4, 16497 RSC .
  10. (a) X. Ding, D. A. Devalankar and P. Wang, Org. Lett., 2016, 18, 5396 CrossRef CAS PubMed ; (b) P. Wang, Y. Wang, H. Hu, C. Spencer, X. Liang and L. Pan, J. Org. Chem., 2008, 73, 6152 CrossRef CAS PubMed .
  11. (a) P. Shu, X. Xiao, Y. Zhao, Y. Xu, W. Yao, J. Tao, H. Wang, G. Yao, Z. Lu, J. Zeng and Q. Wan, Angew. Chem., Int. Ed., 2015, 54, 14432 CrossRef CAS PubMed ; (b) P. Shu, W. Yao, X. Xiao, J. Sun, X. Zhao, Y. Zhao, Y. Xu, J. Tao, G. Yao, J. Zeng and Q. Wan, Org. Chem. Front., 2016, 3, 177 RSC ; (c) X. Xiao, Y. Zhao, P. Shu, X. Zhao, Y. Liu, J. Sun, Q. Zhang, J. Zeng and Q. Wan, J. Am. Chem. Soc., 2016, 138, 13402 CrossRef CAS PubMed ; (d) J. Zeng, G. Sun, W. Yao, Y. Zhu, R. Wang, L. Cai, K. Liu, Q. Zhang, X. Liu and Q. Wan, Angew. Chem., Int. Ed., 2017, 56, 5227 CrossRef CAS PubMed ; (e) Y. Xu, Q. Zhang, Y. Xiao, P. Wu, W. Chen, Z. Song, X. Xiao, L. Meng, J. Zeng and Q. Wan, Tetrahedron Lett., 2017, 58, 2381 CrossRef CAS .
  12. (a) K. Sugaya, F. Hashimoto, M. Ono, Y. Ito, C. Masuoka and T. Nohara, Food Sci. Technol. Int., 1998, 4, 278 CAS ; (b) Y. Li, Z. Chen, Z. Feng, Y. Yang, J. Jiang and P. Zhang, Carbohydr. Res., 2012, 348, 42 CrossRef CAS PubMed .
  13. D. R. Williams and S. Y. Sit, J. Am. Chem. Soc., 1984, 106, 2949 CrossRef CAS .
  14. Z. Hua, D. A. Carcache, Y. Tian, Y. Li and S. J. Danishefsky, J. Org. Chem., 2005, 70, 9849 CrossRef CAS PubMed .
  15. P. Shu, J. Zeng, J. Tao, Y. Zhao, G. Yao and Q. Wan, Green Chem., 2015, 17, 2545 RSC .
  16. (a) J. F. W. Burger, E. V. Brandt and D. Ferreira, Phytochemistry, 1987, 26, 1453 CrossRef CAS ; (b) A. Argyropoulou, P. Samara, O. Tsitsilonis and H. Skaltsa, Phytother. Res., 2012, 26, 1800 CrossRef CAS PubMed .
  17. (a) S.-F. Lu, Q. O'Yang, Z.-W. Guo, B. Yu and Y.-Z. Hui, Angew. Chem., Int. Ed. Engl., 1997, 36, 2344 CrossRef CAS ; (b) S.-F. Lu, Q. O'Yang, Z.-W. Guo, B. Yu and Y.-Z. Hui, J. Org. Chem., 1997, 62, 8400 CrossRef CAS PubMed ; (c) D. P. Larson and C. H. Heathcock, J. Org. Chem., 1997, 62, 8406 CrossRef CAS PubMed .
  18. CCDC 1584138 for compound 7 contains the supplementary crystallographic data for this paper.
  19. For details, see the ESI..
  20. The exchange reaction between compound 8 and DTT to form 7 under acid conditions was not observed.

Footnotes

Electronic supplementary information (ESI) available: Experimental procedures and compound characterization data. CCDC 1584138. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c8qo00247a
These authors contributed equally to this work.

This journal is © the Partner Organisations 2018