A Highly Regio- and Chemoselective Reductive

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Deprotection of N-Boc protective group is often observed in the presence of Lewis acids,1,17 however under the reaction conditions, N-Boc protecting group is ...

LETTER

647

A Highly Regio- and Chemoselective Reductive Cleavage of Benzylidene Acetals with EtAlCl2–Et3SiH ReductiveCleavageofBenzyliden AcetalswithEtAlC2–Et3SiH Vijayakrishnan Balakumar, Appu Aravind, Sundarababu Baskaran* Department of Chemistry, Indian Institute of Technology Madras, Chennai 600 036, India Fax +91(44)22570545; E-mail: [email protected] Received 5 December 2003

Abstract: A highly regio- and chemoselective reductive cleavage of benzylidene acetals derived from 1,2- and 1,3-diols was achieved under mild conditions using EtAlCl2–Et3SiH reagent system in good to excellent yields. Labile protecting groups such as N-Boc, NCbz and -OTBDMS are found to be stable under the reaction conditions. Key words: regioselectivity, chemoselectivity, reductive cleavage, benzylidene acetal, EtAlCl2, Et3SiH

Protection and deprotection of hydroxy group play a prominent role in organic synthesis, especially compounds containing more than one hydroxy group.1 Benzylidene acetal is a widely used protecting group, due to its tolerance to a wide variety of reagents as well as deprotection under mild conditions. The reductive cleavage of benzylidene acetal is an important transformation as it leads to synthetically useful mono-protected diols. The reductive cleavage of benzylidene acetal to form primary or secondary alcohols was achieved using various reducing agents. These include LiAlH4–AlCl3,2 DIBAL-H,3 NaBH3CN–HCl,4 CF3COOH–Et3SiH,5 BF3·OEt2–Et3SiH6 and others.7 However, many of these methods suffer from one or more drawbacks such as excessive use of hydride source, incongruity with other functional groups and moderate yield. Interestingly, alkyl aluminum halides offer many advantages over conventional Lewis acids such as BF3, AlCl3, TiCl4 and InCl3. Alkyl aluminum halides minimize the hydrolysis of the acid sensitive functional groups, as they would not allow the formation of any protic acid by virtue of their inherent ability to scavenge the adventitious protons.8 It has been used effectively to catalyze the intramolecular Diels–Alder reactions,9 Ene reactions,10 Sakurai reactions11 and [2+2] cycloaddition reactions.12 Furthermore, EtAlCl2 in combination with Et3SiH has been used for the reductive elimination of allylic acetates13 and deoxygenation of benzylic alcohols.14 Recently, we observed a highly stereoselective opening of epoxide–azides with EtAlCl2, leading to azabicyclic compounds.15 In this communication, we report a highly regio- and chemoselective reductive cleavage of benzylidene acetal using EtAlCl2 as a Lewis acid in combination with Et3SiH.

SYNLETT 2004, No. 4, pp 0647–065009.03204 Advanced online publication: 10.02.2004 DOI: 10.1055/s-2004-817752; Art ID: G34203ST © Georg Thieme Verlag Stuttgart · New York

To explore the feasibility of the EtAlCl2–Et3SiH reagent system in the regioselective reductive cleavage of benzylidene acetal, the dioxolane A derived from styrene diol was chosen as a model substrate (Scheme 1). A detailed study was carried out using different Lewis acids and the results are shown in Table 1. Interestingly, EtAlCl2 was found to be an excellent Lewis acid to bring about this transformation in a highly regioselective manner and in good yield. The formation of the primary alcohol can be rationalized by the steric hindrance of the phenyl group, which directs the coordination of the Lewis acid to the dioxolane ring oxygen from the less hindered side. Ph O

O

Lewis Acid Et3SiH, CH2Cl2

Ph A

Ph

OH OBn B

Ph

OBn

+ OH C

Scheme 1

The regio- and chemoselective reductive cleavage of benzylidene acetals bearing different functional groups were studied with EtAlCl2–Et3SiH and the results are summarized in Table 2. Benzylidene acetal, prepared from 2,2dimethyl-1,3-propane diol (entry 1), furnished the corresponding mono benzylated product in excellent yield in a shorter reaction time. Deprotection of N-Boc protective group is often observed in the presence of Lewis acids,1,17 however under the reaction conditions, N-Boc protecting group is found to be stable (entries 3–6). Moreover sensitive functional groups like N-Cbz, -OTBDMS, -OMs and -OAc are also found to be compatible under the reaction conditions (entries 2, 5, 6, 7, 9, 11 and 12). A high degree of chemoselectivity was observed in the case of benzylidene acetal 17, where the dioxane ring underwent a smooth reductive cleavage in preference to the oxazolidine ring. Under similar reaction conditions benzylidene acetal derived from (2R,4R)-pentanediol and diethyl-L-tartarate (entries 8 and 10) furnished the corresponding mono benzylated products in good yields with high optical purity.18 The synthetic utility of this methodology was further exemplified in carbohydrate chemistry. 4,6-Di-O-benzylidene acetal derivative of glucose 21 was smoothly reduced to the corresponding 6-O-Bn ether 22 in excellent yield, demonstrating the complete regioselectivity of the reaction. In the case of 4,6-di-O-benzylidene acetal derivative of mannose 23, 6-O-Bn ether 24 was

648 Table 1

LETTER

V. Balakumar et al. Regioselective Reductive Cleavage of Benzylidene Acetal A with Various Lewis Acids

Entry

Lewis Acida

Temperature (°C)

Time (h)

% Yieldb (Conversion) Ratio (B/C)c

1

BF3·OEt2

–78

1

12 (40)d

6.5:1

d

1.5:1

2

CF3COOH

0–25

4

19 (70)

3

CF3SO3H

–78

1

38 (48)

7.5:1

4

EtAlCl2

–78

0.5

77 (100)

10.1:1

5

TiCl4

–78

0.5

77 (100)

2.4:1

d

6.0:1

6

InCl3

0–25

5

10 (58)

7

DIBAL-He

0

4

70 (80)

1.6:1

a

1.1 equiv of Lewis acid and 1.2 equiv of Et3SiH were used. Isolated yield. c Based on NMR spectra of the purified product. d Major process is acetal hydrolysis. e See ref.16 b

observed as a major product. The formation of the 6-O-Bn ether in the case of glucose and mannose (entries 11 and 12) is presumably due to chelation control.19 Interestingly, chemo- and regioselective reductive cleavage of isopropylidene acetals was also realized in very good yields under the reaction conditions (entries 13 and 14).

the products in excellent yields under very mild conditions. Labile protecting groups such as N-Cbz, N-Boc and -OTBDMS and sensitive functional groups such as -OMs and -OAc are found to be stable under the reaction conditions. We believe this mild and efficient transformation will find wide applications in organic synthesis.20

In summary, we have developed a highly regio- and chemoselective reductive cleavage of benzylidene acetals with EtAlCl2–Et 3SiH. This reagent system furnished Table 2 Entry 1

Regio- and Chemoselective Reductive Cleavage of Benzylidene Acetals with EtAlCl2–Et3SiH Substrate H 3C

O

Equiv of EtAlCl2a

Time (min)

Productb

Yield (%)c

1.1

30

H 3C

OH

H 3C

OBn

89

Ph H 3C

O

1

2 H3C

O

H 3C

OH

Ph O

R-HN

2 3

BocHN

OBn

R-HN

3 R = Cbz 5 R = Boc

2.2 2.2

30 30

O

4 R = Cbz 6 R = Boc

78 76

BocHN

OH

RO

OBn

Ph RO

4 5 6

O

7R=H 9 R = Ac 11 R = TBDMS

7

O MsO

2.2 3.1 3.1

30 45 45

2.2

30

8R=H 10 R = Ac 12 R = TBDMS

80 78 85

OBn

86

MsO

Ph

OH

O

13

14

8

1.1

Ph O

30

OH

O

16 15

Synlett 2004, No. 4, 647–650

© Thieme Stuttgart · New York

OBn

70

LETTER Table 2

649

Reductive Cleavage of Benzylidene Acetals with EtAlCl2–Et3SiH

Regio- and Chemoselective Reductive Cleavage of Benzylidene Acetals with EtAlCl2–Et3SiH (continued)

Entry

Substrate

9

O

O

Equiv of EtAlCl2a

Time (min)

2.2

30

Productb

N

O

Ph

Cbz

OBn

18 3.1

O O

30

OEt

O

86

O HO

OEt

Ph

OEt OEt

BnO

O

O

19

20

Ph

O O AcO

4.1

O AcO

30

BnO HO AcO

81

O AcO

OAc

21 12

N Cbz

17 10

11

98d

OH

O

Ph Ph

Yield (%)c

OAc

22

Ph

4.1

OAc O

O O AcO

30

91e

OAc O

BnO HO AcO

OAc

OAc

24

23 13

3.1

O O

30

OEt OEt

O

85

O HO

OEt OEt

PriO O

O

25

26

14

1.1

30

O O

OH

HO

OH

PriO

PriO

28a

27

OH

79f

HO

28b

a

1.2 equiv of Et3SiH was used in all the cases. All the products were characterized by IR, 1H and 13C NMR spectroscopy. c Yield of isolated product. d 6:4 diastereomeric mixture. e 6-O-Benzylated and 4-O-benzylated in 7:1 ratio. f 28a and 28b in 8:1 ratio. b

Acknowledgment We thank CSIR and DST, New Delhi for the financial support. AA (SRF) thanks CSIR, New Delhi for a fellowship.

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(5) Deninno, M. P.; Etienne, J. B.; Duplantier, K. C. Tetrahedron Lett. 1995, 36, 669. (6) Debenham, S. D.; Toone, E. J. Tetrahedron: Asymmetry 2000, 11, 385. (7) (a) Samuelsson, B.; Johanasson, R. J. Chem. Soc., Perkin Trans. 1 1984, 2371. (b) Guindon, Y.; Girard, Y.; Berthiaume, S.; Gorys, V.; Lemieux, R.; Yoakim, C. Can. J. Chem. 1990, 68, 897. (c) Chan, T.-H.; Jiang, L. Tetrahedron Lett. 1998, 39, 355. (d) Chandrasekar, S.; Reddy, Y. R.; Reddy, C. R. Chem. Lett. 1998, 1273. (e) Sakagami, M.; Hamana, H. Tetrahedron Lett. 2000, 41, 5547. (f) Wang, C.-C.; Luo, S.-Y.; Shie, C.-R.; Hung, S.-C. Org. Lett. 2002, 4, 847. (g) Morelli, C. F.; Fornili, A.; Sironi, M.; Duri, L.; Speranza, G.; Manittoa, P. Tetrahedron: Asymmetry 2002, 13, 2609. (h) Oikawa, M.; Liu, W.-C.; Nakai, Y.; Koshida, S.; Fukase, K.; Kusumoto, S. Synlett 1996, 1179. (i) Seiki, S.; Kuroda, A.; Tanaka, K.; Kimura, R. Synlett 1996, 231. (8) Snider, B. B. Acc. Chem. Res. 1980, 13, 426. (9) (a) Smith, A. B.; Hale, K. J.; Laasko, L. M.; Chen, K.; Riera, A. Tetrahedron Lett. 1989, 30, 6963. (b) Oppolzer, W.; Dupuis, D. Tetrahedron Lett. 1985, 26, 5437.

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V. Balakumar et al.

(10) (a) Snider, B. B.; Rodini, D. J.; Conn, R. S. E.; Sealfon, S. J. Am. Chem. Soc. 1979, 101, 5283. (b) Snider, B. B.; Phillips, G. B. J. Org. Chem. 1983, 48, 3685. (11) (a) Majetich, G.; Behnke, M.; Hull, K. J. Org. Chem. 1985, 50, 3615. (b) Majetich, G.; Khetani, V. Tetrahedron Lett. 1990, 31, 2243. (c) Schinzer, D. Synthesis 1988, 263. (12) (a) Snider, B. B.; Spindell, D. K. J. Org. Chem. 1980, 45, 5017. (b) Snider, B. B.; Ron, E. J. Org. Chem. 1986, 51, 3643. (13) Schreiber, S. L.; Kelly, S. E.; Porco, J. A. Jr.; Sammakia, T.; Suh, E. M. J. Am. Chem. Soc. 1988, 110, 6210. (14) Guanti, G.; Riva, R. Tetrahedron Lett. 1995, 36, 3933. (15) Reddy, P. G.; Varghese, B.; Baskaran, S. Org. Lett. 2003, 5, 583. (16) Gautier, D. R. Jr.; Szumigala, R. H. Jr.; Armstrong, J. D.; Volante, R. P. Tetrahedron Lett. 2001, 42, 7011. (17) Herdeis, C.; Kelm, B. Tetrahedron 2003, 59, 217. (18) Compound 16 (see ref. 3c): [a]D25 = –53.6 (c = 1.14, CHCl3). Compound 20 (see ref. 4b): [a]D25 = +72.8 (c = 1.35, CHCl3) (19) (a) For a review on chelation and non-chelation controlled reactions see: Reetz, M. T. Angew. Chem. Int. Ed. Engl. 1984, 23, 556. (b) Corcoran, R. C. Tetrahedron Lett. 1990, 31, 2101. (c) Zheng, B.-Z.; Yamauchi, M.; Dei, H.; Kusaka, S.; Matsui, K.; Yonemitsu, O. Tetrahedron Lett. 2000, 41, 6441.

Synlett 2004, No. 4, 647–650

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LETTER (20) Representative Experimental Procedure of Compound 14: To a stirred solution of benzylidene acetal 13 (103 mg, 0.40 mmol) in anhyd CH2Cl2 (5 mL) was added Et3SiH (56 mg, 0.48 mmol). The reaction mixture was cooled to –78 °C, treated with EtAlCl2 (0.49 mL of 1.8 M solution in toluene, 0.88 mmol) dropwise, and the resultant mixture was stirred at –78 °C for 30 min. After completion of the reaction, as indicated by TLC, the reaction mixture was quenched with sat. solution of NaHCO3 (10 mL) and extracted with CH2Cl2 (3 × 10 mL). The combined organic extracts were dried over anhyd Na2SO4, filtered and concentrated under reduced pressure to yield the crude compound, which was purified by column chromatography on silica gel (gradient elution with 50–60% EtOAc in hexane) to afford pure compound 14 (89 mg, 86% yield) as a colorless liquid. IR (neat): 3504, 3040, 2944, 1452, 1340, 1171, 1104, 972, 924, 803, 736, 697 cm–1. 1H NMR (400 MHz, CDCl3): d = 2.70 (br s, 1 H), 3.08 (s, 3 H), 3.87–3.69 (m, 5 H), 4.83 (d, J = 12.2 Hz, 1 H), 4.89 (d, J = 12.2 Hz, 1 H), 7.39–7.28 (m, 5 H). 13C NMR (100 MHz, CDCl3): d = 38.4, 62.3, 69.2, 73.6, 127.8, 128.1, 128.4, 137.3.

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