Unexpected Cyclization During the Mitsunobu Reaction of D-Talose

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Unexpected Cyclization During the Mitsunobu Reaction of D-Talose Derivatives letter

Huei-Lin Chuang,1 R. C. Sawant,1 Shun-Yuan Luo* Mitsunobu Reaction of D-Talose Derivatives

Department of Chemistry, National Chung Hsing University, Taichung 402, Taiwan Fax +886(4)22862547; E-mail: [email protected] Received: 26.12.2012; Accepted after revision: 18.01.2013

to achieve inversion of stereochemistry in product 7 by generating side products 8 and 9.

Abstract: A D-talose derivative underwent unexpected cyclization during a Mitsunobu reaction. A plausible pathway for the reaction involves an attack of the nucleophilic azide on the benzyl ring by intramolecular cyclization with loss of the benzyl group. These newly formed, unexpected compounds may be used in the synthesis of derivatives of C-nucleosides.

Albeck et al. reported an unexpected rearrangement of sugar derivatives during Mitsunobu epimerization.4a Several protective groups are stable under Mitsunobu reaction conditions; the benzyl group is relatively more susceptible to the Mitsunobu conditions.4b However, a number of unexpected rearrangements and migrations have been documented in the literature.5a–e Recently, Kulkarni et al.5f examined debenzylative cyclization. In addition to these studies, the rearrangements and cyclizations have been documented extensively in related literature.6 We focused on the development of simple methodologies for the synthesis of tetrahydroxy-LCB (long-chain base) 11, which is a component of natural cerebroside (10, Figure 1) and has considerable biological activity.7 A few studies have addressed the synthesis of tetrahydroxy-LCB.8 However, these studies examined the tetrahydroxy-LCB synthesis using acetonide-protected D-galactose. Albeck et al. reported4a the formation of unexpected products from Dglucose, D-mannose, and D-galactose. To the best of our knowledge, the unexpected products from D-talose have not been reported in previous studies. Therefore, this is the first study to address unexpected cyclization of Dtalose derivatives under Mitsunobu conditions.

Key words: Mitsunobu reaction, tetrahydroxy-LCB, D-talose, nucleosides, cyclization

In the past few decades, the Mitsunobu reaction2 has attracted considerable attention because of its broad application in C–O, C–S, C–N, and C–C bond formation with excellent stereochemical inversion.3 The mild reaction conditions offer inversion of primary and secondary alcohols to various functional groups. Azido or phthalimido nucleophiles can be installed on the alcohol starting material followed by reduction to form the desired amines. For clarity the general mechanistic pathway4a for the Mitsunobu reaction is shown in Scheme 1. Initially, the nucleophilic attack of triphenylphosphine (1) on 2 forms a betaine intermediate 3a and 3b deprotonates the alcohol 4a to form alkoxide 4b. This alkoxide 4b attacks the electron-deficient Ph3P to obtain intermediate 5. Finally, nucleophile 6 attacks from the conflicting side of the alcohol O RO

O N N

O

O OR

RO

2

N Ph3P

N

N

RO

Ph3P

O R1

3a

Ph3P

H+

OR

OH 1

R2 4a

N

RO

OR

H+

R2

2

R

8

Nu R1

O

O

4b

O PPh3

H N

Ph3P

O

R1

H N

7 RO

5

O

O

R2

O

OR

3b

R1

– H+

H N

N H

OR O

9

Nu– 6

Scheme 1 The Mitsunobu reaction mechanism

SYNLETT 2013, 24, 0522–0526 Advanced online publication: 29.01.201309 36-521 41437-2 096 DOI: 10.1055/s-0032-1318196; Art ID: ST-2012-W1103-L © Georg Thieme Verlag Stuttgart · New York Synthesis 2000, No. X, x–xx

ISSN 0039-7881

© Thieme Stuttgart · New York

is a copy of the author's personal reprint l

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l This

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Mitsunobu Reaction of D-Talose Derivatives

523

O HN OH OH

OH O

HO HO

O HO OH

OH natural cerebroside (10)

NH2

OH

HO OH

OH tetrahydroxy-LCB (11)

Figure 1 Structures of natural cerebroside (10) and (2S,3S,4R,5R,6Z)-2-amino-1,3,4,5-tetrahydroxyoctadecene (tetrahydroxy-LCB, 11)

We prepared acetonide-protected D-galactose9 as the starting material from the literature procedure. The synthesis began with a simple TBDPS-group10 protection of primary alcohol 12, which provided compound 13 in good yield (Scheme 2). The epimerization of compound 13 exposed a number of failures; for example, a triflation11a reaction in the presence of pyridine produced an intermediate triflation compound, whereas the SN2 reaction with H2O formed another compound that showed a higher polarity spot on the TLC plate than the starting material. A similar triflation reaction followed by epimerization11b with NaNO2 in the presence of HMPA resulted in several spots by TLC; therefore, we were unO

OH O

O

O

OTBDPS O STol HO 13

a

STol

O

HO 12

O

c

OTBDPS OBn O

O

able to obtain the expected product. Moreover, epimerizing compound 13 using PCC11c oxidation and NaBH4 reduction resulted in the formation of a trace amount of the product. Conversely, Swern oxidation11c of compound 13 followed by NaBH4 reduction also produced a trace amount of the product. Finally, the Dess–Martin periodinane reaction11d using 1.22 equivalents of Dess–Martin reagent followed by NaBH4 reduction generated 20% of the product. The stepwise increase in the amount of the Dess– Martin reagent from 1.22 to 2.42 equivalents increased the yield of product 14 considerably to 89%. The use of the relatively costly Dess–Martin reagent provides an excellent yield.

O

d STol

O b

OTBDPS OH O

O

STol 14

OTBDPS OBn O

O

e OH

15

16

O

O O

observed

RO

C11H23

g BnO N3

O 17 R = TBDPS 18 R = Tr

19 R = TBDPS 20 R = Tr

+

O

f

C11H23

RO

BnO HO

RO

C11H23 O O expected


Scheme 2 Preparation of compounds 19 and 20. Reagents and conditions: (a) TBDPSCl, imidazole, CH2Cl2, r.t., 84%; (b) (1) Dess–Martin periodinane, CH2Cl2, r.t.; (2) NaBH4, MeOH, r.t., 89% in 2 steps; (c) BnBr, NaH, DMF, r.t., 90%; (d) NBS, acetone–H2O, 0 °C, 95%; (e) LHMDS, C12H25PPh3Br, THF, –30 °C to 0 °C, 89% (cis/trans = 3.5:1); (f) (1) TBAF, THF, r.t., 93%; (2) TrCl, Et3N, DMAP, r.t., 76%; (g) Ph3P, DIAD, DPPA, THF, 0 °C to r.t., 19: 64%; 20: 66%. © Georg Thieme Verlag Stuttgart · New York

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The benzylation of compound 14 in the presence of sodium hydride in DMF produced fully protected compound 15. The thiocresol at the anomeric carbon was hydrolyzed using NBS in acetone–water at 0 °C which resulted in an excellent yield of compound 16. Wittig reaction of 16 in the presence of NaH12a and n-BuLi12b did not proceed, whereas, in the presence of KOt-Bu a trace amount of the product was formed. Furthermore, the use of LiHMDS12c in anhydrous tetrahydrofuran at 0 °C formed an expected product in a 43% cis/trans mixture of compounds. Therefore, the reaction flask was stirred at –30 °C to 0 °C and generated the expected compound 17 in 89% yield in a 3.5:1 ratio (cis/trans). This mixture of compounds was separated using column chromatography to obtain the major cis compound 17 in 70% yield.

H O

O H O

TrO

H

C11H23 H

H H

20

Figure 2 NOESY data for cyclic olefin 20

TBAF in THF, followed by tritylation in the presence of trityl chloride in pyridine at room temperature. Subsequently, compound 18 was subjected to the Mitsunobu conditions.13 The debenzylative cyclized product 20 evidently indicated no effect of the bulky group at the primary carbon. A detailed analysis of the newly formed compounds revealed the formation of the debenzylative cyclized product (β-L-ribofuranose). These cyclized compounds 19 and 20 can serve as valuable intermediates in the synthesis of C-nucleosides and related analogues.15 The overall yield of compounds 19 and 20 were 28% and 29%, respectively.

To resemble the expected stereochemistry in tetrahydroxy-LCB at the C2 position, we tried to introduce an azido group at the C2 position with inversion of configuration using the Mitsunobu reaction. However, when alcohol 17 was subjected to the Mitsunobu conditions,13 and the reaction was stirred at room temperature overnight, a colorless liquid as the crude product was obtained, which was purified using silica gel chromatography to produce colorless oil 19. The 1H NMR analysis of the product indicated that the benzyl protons have disappeared. Furthermore, olefinic protons moved upfield, indicating that the group adjacent to the olefin may have changed. The MS data showed an m/z peak at 615 corresponding to the [M + Na+] peak of the debenzylated compound. The 1H NMR and 13C NMR spectra did not show benzylic aromatic protons and carbons. Furthermore, the IR spectra showed no azido stretching vibration.

The 1H–1H COSY analysis permitted the assignment of the H1–H5 and side-chain protons. A NOESY spectrum of 20 (Figure 2) confirmed the correlation between the H2 proton and the olefin proton, and the correlation between the H1 and H4 weak-proton interaction confirmed the structure of compound 20. This study led to the proposal of a suitable mechanism based on previously reported mechanisms.4a When olefin 17 or 18 was subjected to the Mitsunobu reagents,14 we expected the formation of the common, cyclic oxonium intermediate 24 through intramolecular attack of the C14 benzylic oxygen on the C17 carbon bearing the activated alcohol, through intermediate 23.

The TBDPS bulky group at the primary carbon may drive the reaction to debenzylative cyclization. However, we performed a similar reaction with another bulky trityl group on the primary alcohol in adduct 17. Compound 18 was prepared by hydrolysis of the TBDPS group using OR

BnO HO

O C11H23

RO O

Nu A Bn

O

O+

OBn O PPh3

O

B

14

O

O 23 H23C11

17 R = TBDPS

RO H23C11 24

18 R = Tr

starting material path B

cyclization path A

O O

O

C

O

OR OBn OH

Nu OBn

O H23C11


OR O

O C11H23

RO

rearrangement path C

25

26

H23C11

Scheme 3 Plausible mechanisms for the formation of the rearrangement products 19 and 20 during the Mitsunobu reaction on 17 and 18 Synlett 2013, 24, 522–526

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Mitsunobu Reaction of D-Talose Derivatives

The nucleophile diphenylphosporyl azide (DPPA) attacks the common intermediate 24 in three manners. First, nucleophilic azide can attack the benzyl-ring substituent to yield the cyclized products 19 and 20 (path A, Scheme 3). Second, a nucleophilic attack on the C17 carbon forms the corresponding ester and after solvolysis the starting material is obtained (path B, Scheme 3). Finally, a similar attack occurs on the C14 carbon to obtain the rearranged product 26 with inversion of configuration (path C, Scheme 3). In addition, the approach in path A (Scheme 3) is more favorable for talose derivative 17 because only a cyclized product without the formation of other rearranged products was obtained, which may be attributed to the inhibition of the formation of oxyphosoponium ion 5 by steric hindrance caused by the neighboring acetonide.

Rev. 2009, 109, 2551. (b) Mitsunobu, O. Synthesis 1981, 1. (c) Hughes, D. L. Org. React. 1992, 42, 336. (a) Persky, R.; Albeck, A. J. Org. Chem. 2000, 65, 3775. (b) Wuts, P. G.; Green, T. W. Greene’s Protective Groups in Organic Synthesis; John Wiley and Sons: Hoboken, NJ, 2007. (a) Dinsmore, C. J.; Mercer, S. P. Org. Lett. 2004, 6, 2885. (b) Hadfield, P. S.; Galt, R. H. B.; Sawyer, Y.; Layland, N. J.; Page, M. I. J. Chem. Soc., Perkin Trans. 1 1997, 503. (c) Banfi, L.; Basso, A.; Guanti, G.; Lecinska, P.; Riva, R. Mol. Diversity 2008, 12, 187. (d) Perali, R. S.; Mandava, S.; Chunduri, V. R. Tetrahedron Lett. 2011, 52, 3045. (e) Marsac, Y.; Nourry, A.; Legoupy, S.; Pipelier, M.; Dubreuil, D.; Huet, F. Tetrahedron Lett. 2004, 45, 6461. (f) Thota, V. N.; Gervay-Hague, J.; Kulkarni, S. S. Org. Biomol. Chem. 2012, 10, 8132. (a) Martin, R.; Yang, F.; Xie, F. Tetrahedron Lett. 1995, 36, 47. (b) Gray, G. R.; Hartman, F. C.; Barker, R. J. Org. Chem. 1965, 30, 2020. (c) Brimacombe, J. S.; Ching, O. A. Carbohydr. Res. 1967, 5, 239. (d) Ermert, P.; Vasella, A. Helv. Chim. Acta 1991, 74, 2043. (e) Mootoo, D. R.; FraserReid, B. J. Chem. Soc., Chem. Commun. 1986, 1570. (f) Yang, B.-H.; Jiang, J.-Q.; Ma, K.; Wu, H.-M. Tetrahedron Lett. 1995, 36, 2831. (g) Reddy, L. V. R.; Roy, A. D.; Roy, R.; Shaw, A. K. Chem. Commun. 2006, 3444. (h) Dehmlow, H.; Mulzer, J.; Seilz, C.; Strecker, A. R.; Kohlmann, A. Tetrahedron Lett. 1992, 33, 3607. (i) Cribiù, R.; Cumpstey, I. Chem. Commun. 2008, 1246. (j) Rychnovsky, S. D.; Bartlett, P. A. J. Am. Chem. Soc. 1981, 103, 3963. (k) Nicotra, F.; Panza, L.; Ronchetti, F.; Russo, G.; Toma, L. Carbohydr. Res. 1987, 171, 49. Luca, G. D.; Zilic, J.; Cateni, F. Helv. Chim. Acta 2007, 90, 282. (a) Li, Y.-L.; Wu, Y.-L. Tetrahedron Lett. 1995, 36, 3875. (b) Yoda, H.; Oguchi, T.; Takabe, K. Tetrahedron: Asymmetry 1996, 7, 2113. (c) Luo, S. Y.; Kulkarni, S. S.; Chou, C. H.; Liao, W. M.; Hung, S. C. J. Org. Chem. 2006, 71, 1226. (d) Rathore, K.; Sridhar, B.; Raghavan, S. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2011, 50, 559. (e) Kawamoto, M.; Niwa, Y.; Schimizu, M. Chem. Commun. 1999, 1151. Marinier, A.; Martel, A.; Bachand, C.; Plamondon, S.; Turmel, B.; Daris, J. P.; Banville, J.; Lapointe, P.; Ouellet, C.; Dextraze, P. Bioorg. Med. Chem. 2001, 9, 1395. Huang, C.-M.; Liu, R.-S.; Wu, T.-S.; Cheng, W.-C. Tetrahedron Lett. 2008, 49, 2895. (a) Xiao, H.; Wang, G.; Wang, P.; Li, Y. Chin. J. Chem. 2012, 28, 1229. (b) Lee, J.-C. Chang S.-W.; Liao, C.-C.; Chi, F.-C.; Chen, C.-S.; Wen, Y.-S.; Wang, C.-C.; Kulkarni, S. S.; Puranik, R.; Liu, Y.-H.; Hung, S.-C. Chem. Eur. J. 2004, 10, 399. (c) Lowary, T. L.; Eichler, E.; Bundle, D. R. Can. J. Chem. 2002, 80, 1112. (d) Granier, T.; Vasella, A. Helv. Chim. Acta 1998, 81, 865. (a) Kim, I. S.; Kim, S. J.; Lee, J. K.; Li, Q. R.; Jung, Y. H. Carbohydr. Res. 2007, 342, 1502. (b) Dondoni, A.; Formaglio, P.; Marra, A.; Massi, A. Tetrahedron 2001, 57, 7719. (c) Lin, C.-C.; Fan, G.-T.; Fang, J.-M. Tetrahedron Lett. 2003, 44, 5281. Procedure for the Synthesis of Compound 19 To a solution of olefin 17 (104 mg, 0.15 mmol) and Ph3P (116 mg, 0.47 mmol) in anhyd THF (1 mL) was stirred at 0 °C. Diisopropyl azodicarboxylate (87 μL, 0.44 mmol) and diphenyl phosphoryl azide (102 μL, 0.44 mmol) were slowly added to the reaction mixture at 0 °C. The reaction mixture was stirred at r.t. overnight. The solvent was evaporated and the colorless oil 19 (57 mg, 0.096 mmol, 64%) was obtained by column chromatography.

(4)

(5)

(6)

Besides, the nucleophilicity of the C14 benzyloxy group is susceptible enough to promote the cyclization reaction rather than the rearrangement. Moreover, the steric hindrance of the neighboring acetonide inhibited the intermolecular attack of the azide nucleophile to the C17 carbon of the intermediate 23; therefore the reaction favored the intramolecular attack of the C14 benzyloxy group to form intermediate 24. Moreover, the acetonide of 24 also blocked the azide nucleophile from favoring pathway B and C. In conclusion, D-talose derivatives exhibit unexpected activity during Mitsunobu reaction. Bulky groups on the primary alcohol do not affect the driving force of the Mitsunobu reaction and promote cyclization. However, Albeck et al. indicated that D-glucose, D-mannose, and Dgalactose sugars undergo rearrangement. Further studies will extend D-talose derivatives to these sugars for unexpected cyclization without the formation of other rearranged products. These debenzylative cyclized products may serve as intermediate compounds for the synthesis of derivatives of C-nucleosides with potential applications in the synthesis of natural products.

Acknowledgment The author thanks the National Science Council in Taiwan (NSC992113-M-005-013-MY2 and NSC101-2113-M-005-006-MY2) and National Chung Hsing University for financial support. R.C.S. acknowledges the receipt of a doctoral fellowship from National Chung Hsing University.

Supporting Information for this article is available online at

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(9) (10) (11)

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http://www.thieme-connect.com/ejournals/toc/synlett.SupmInforgiSta

References and Notes (1) Huei-Lin Chuang and R. C. Sawant contributed equally to this work. (2) (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380. (b) Mitsunobu, O.; Yamada, M.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1967, 40, 935. (3) For reviews, see: (a) Kumara Swamy, K. C. K.; Bhuvan Kumar, N. N.; Balaraman, E.; Pavan Kumar, K. V. P. Chem.


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Analytical Data for Compound 19 1 H NMR (400 MHz, CDCl3): δ = 7.71–7.67 (m, 4 H, ArH), 7.45–7.26 (m, 6 H, ArH), 5.63–5.60 (m, 1 H, CH=CH), 5.45–5.40 (m, 1 H, CH=CH), 4.74 (dd, J = 6.4, 3.2 Hz, 1 H, H-3), 4.68–4.64 (m, 1 H, H-1), 4.37 (t, J = 4.8 Hz, 1 H, H-2), 4.10 (td, J = 7.2, 4.0 Hz, 1 H, H-4), 3.77 (d, J = 3.6 Hz, 1 H, H-5), 2.17–2.11 (m, 2 H, CH2), 1.57 (s, 3 H, CH3), 1.40–1.38 (m, 2 H, CH2), 1.35 (s, 3 H, CH3), 1.31–1.26 (m, 16 H, CH2), 1.06 (m, 9 H, CH3), 0.90–0.86 (m, 3 H, CH3). 13C NMR (150 MHz, CDCl3): δ = 135.7 (2 × CH), 135.6 (2 × CH), 134.7 (CH), 133.3 (C), 133.1 (C), 129.71 (CH), 129.66 (CH), 127.72 (CH), 127.69 (2 × CH), 127.65 (2 × CH), 113.8 (C), 85.9 (CH), 84.0 (CH), 82.3 (CH), 80.5 (CH), 64.2 (CH2), 31.9 (CH2), 29.69 (CH2), 29.66 (CH2), 29.64 (CH2), 29.61 (CH2), 29.5 (CH2), 29.4 (CH2), 29.3 (CH2), 28.0 (CH2), 27.6 (CH3), 26.8 (3 × CH3), 25.6 (CH3), 22.7 (CH2), 19.3 (C), 14.1 (CH3). (14) Orsato, A.; Barbagallo, E.; Costa, B.; Olivieri, S.; De Gioia, L.; Nicotra, F.; La Ferla, B. Eur. J. Org. Chem. 2011, 5012. (15) (a) Kim, G.; Kim, H.-S. Tetrahedron Lett. 2000, 41, 225. (b) Radha, Krishna. P.; Lavanya, B.; Ilangovan, A.; Sharma,

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