Construction of bicyclic systems containing an oxygen bridge by isomerization of cyclic epoxy alcohols

Accepted Manuscript Construction of bicyclic systems containing an oxygen bridge by isomerization of cyclic epoxy alcohols Masaru Iwakura, Hiroshi Tokura, Keiji Tanino PII: DOI: Reference:

S0040-4039(17)30194-6 http://dx.doi.org/10.1016/j.tetlet.2017.02.023 TETL 48634

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Tetrahedron Letters

Received Date: Revised Date: Accepted Date:

16 January 2017 7 February 2017 9 February 2017

Please cite this article as: Iwakura, M., Tokura, H., Tanino, K., Construction of bicyclic systems containing an oxygen bridge by isomerization of cyclic epoxy alcohols, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/ j.tetlet.2017.02.023

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Construction of bicyclic systems containing an oxygen bridge by isomerization of cyclic epoxy alcohols

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Masaru Iwakura, Hiroshi Tokura, Keiji Tanino

R1

LiI O

HO

EtCN R2

R1

I

R1

OLi

R2

O

HO R2

OH

1

Tetrahedron Letters

Construction of bicyclic systems containing an oxygen bridge by isomerization of cyclic epoxy alcohols Masaru Iwakura,a Hiroshi Tokura,b and Keiji Tanino b a b

Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo 060-0810, Japan Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan

A RT I C L E I N F O

A BS T RA C T

Article history: Received Received in revised form Accepted Available online

A novel method for constructing a 7-oxabicyclo[2.2.1]heptane skeleton was developed. The substrates, namely cis-3,4-epoxy-1-cyclohexanol derivatives, were prepared from the corresponding 3-cyclohexen-1-ol derivatives via a stereoselective epoxidation reaction using a vanadium catalyst. Upon heating with lithium iodide in propionitrile, the cis-epoxy alcohol was transformed into the 7-oxabicyclo[2.2.1]heptane derivative in high yield. The reaction proceeds through formation of a lithium alkoxide bearing an iodohydrin moiety, followed by an intramolecular SN2 reaction.

Keywords: Epoxide Cyclic ether Iodohydrin SN2 reaction Isomerization

———  Corresponding author. E-mail address: [email protected] (K. Tanino).

2017 Elsevier Ltd. All rights reserved .

2

Tetrahedron

A number of natural products possess the 7oxabicyclo[2.2.1]heptane skeleton, and therefore the development of efficient methods for constructing this bicyclic system is important in synthetic organic chemistry. 1,2 To date, several approaches have been reported, such as the Diels-Alder reaction of furan derivatives and dienophiles,3 intramolecular haloetherification reactions,4 or intramolecular O-alkylation reactions of cyclohexanol derivatives.5 In our previous study on the total synthesis of glycinoeclepin A, a 7oxabicyclo[2.2.1]heptane skeleton, corresponding to the A ring moiety, was synthesized by the cyclization of an iodohydrin. 5d This type of intramolecular SN2 reaction requires the use of a substrate (such as compound 1 in Scheme 1) in which the hydroxy group and the leaving group are arranged trans to one another. We therefore became intrigued with the possibility of converting epoxy alcohol trans-2 to bicyclic alcohol trans-3, as no successful example of this type of intramolecular SN2 reaction has been reported in the literature.6 We herein report that the cis-epoxy alcohol cis-2 is superior to the corresponding trans-epoxy alcohol trans-2 as a precursor of the bicyclic system, as cis-2 is readily transformed into bicyclic alcohol cis-3 under specific reaction conditions.

Initially, we attempted generation of the corresponding metal alkoxide to induce the intramolecular SN2 reaction by treatment of the trans-epoxy alcohol 4b with a base, such as NaH or BuLi. However, in all cases, only 4b was recovered, even following reflux in THF. The low reactivity of the metal alkoxides could be attributable to the poor overlap between the lone pair of the alkoxide oxygen and the anti-bonding orbital of the C(4)O(epoxide) bond. These results led us to focus on the use of the cis-epoxy alcohol 4a as a substrate for the cyclization reaction, as shown in Scheme 3. Thus, treatment of epoxide 4a with a suitable metal halide (MX) would give the metal alkoxide halohydrins 8 or 8’, both of which are in equilibrium with the substrate. These alkoxides would also be in equilibrium with alkoxides 9 or 9’, respectively. While the former may undergo the intramolecular SN2 reaction to afford the desired 7-oxabicyclo[2.2.1]heptane derivative 10a, a similar cyclization reaction of alkoxide 9’ would be problematic due to the highly strained nature of the oxetane skeleton. X

BnO

X

BnO

BnO O

HO

OM

MO

8

OH

OH 9

10a

MX 4a MX BnO

OM

BnO

OH

BnO

OH O

HO

X 8'

MO

X 9'

Scheme 3. Metal halide-mediated cyclization reaction of the cis-epoxy alcohol Scheme 1. Construction of the oxabicyclo[2.2.1]heptane skeleton from cyclohexanol

With a view to reducing the volatility of the substrates and products, epoxides 4a and 4b, each possessing a benzyloxy group, were synthesized from cis-diol 57 as shown in Scheme 2. The vanadium catalyzed oxidation of alkenol 7,8 which was prepared via DIBAH reduction of benzylidene acetal 6, afforded the cis-epoxy alcohol 4a as a single stereoisomer. Preparation of the cis-epoxy alcohol 4a was achieved in fewer steps than preparation of the corresponding trans-isomer 4b, which was prepared through the Mitsunobu reaction of 4a. PhCH(OMe)2 TsOH•H2O

HO HO

O O

DMF 5

CH2Cl2

HO

6

TBHP VO(OEt)3

BnO

CH2Cl2

HO

88% from 5

BnO

DIBAH

Ph

O 4a

7

1) 4-NO2C6H4CO2H PPh3, DIAD BnO THF 2) LiOH THF-H2O

Efforts to establish suitable reaction conditions for the transformation of epoxide 4a into bicyclic alcohol 10a are outlined in Table 1. Treatment of 4a with sodium iodide in acetone failed to induce any reaction even at an elevated temperature (80 °C, entry 1). However, heating with magnesium iodide in THF led to the quantitative formation of iodohydrins 11 and 11’ (entry 2).9 Further optimization showed that lithium iodide was the reagent of choice, giving rise to the desired compound 10a in high yields (entries 3-5). Reactions in both THF (entry 3) and propionitrile (entry 5) gave satisfactory results (>90% yield), while the use of acetonitrile resulted in partial recovery of the epoxy alcohol (entry 4). In contrast, reaction using an excess of lithium bromide, which showed lower reactivity than lithium iodide, gave 10a in 80% yield (entry 6).

O

HO

15% from 4a

Scheme 2. Stereoselective synthesis of epoxy alcohols

Table 1. Optimization of reaction conditions a

4b

3 BnO

BnO MX

O HO

O

4a

10a 10ab (%)

MX (equiv.)

solvent

1

NaI (3)

acetone

2c

MgI2 (3)

entry

OH

solvent 80 °C, 5 h

4ab (%)

0

85 0

THF

0

3

LiI

(1)

THF

94

0

4

LiI

(1)

MeCN

73

20

LiI

(1)

EtCN

96 (87d)

0

LiBr (3)

EtCN

80

0

5 6

X

BnO

BnO

OH

+ HO

OH 11

X

HO 11'

a

Reaction conditions: A solution of 4a (0.1 mmol), MX (1-3 equiv.) in the indicated solvent (1.0 mL) was stirred for 5 h at 80 °C. bYields were determined by 1H NMR spectroscopy using (CHCl2)2 as the internal standard. c A mixture of iodohydrins 11 and 11’ was obtained in quantitative yield. d Isolated yield.

Subsequently, the optimized reaction conditions were applied to the transformation of various epoxy cyclohexanols (Table 2). As expected, epoxy alcohol 4c, bearing no additional substituents, afforded the desired bicyclic alcohol 10c in poor yield (22%, from 1H, entry 1), likely due to both the high volatility of 10c and the formation of 2-cyclohexen-1-one via isomerization of the epoxide moiety. Epoxide 4d, a silylated analogue of substrate 4a, underwent a smooth transformation into bicyclic alcohol 10d. In addition, the corresponding epimer 4e gave the desired products in high yield (entries 2 and 3). Furthermore, with a prolonged reaction time, tertiary alcohol 4f afforded alcohol 10f, bearing a methyl group at the bridgehead position, in excellent yield (entry 4). However, the corresponding epimer 4g exhibited lower reactivity, giving alcohol 10g in moderate yield after 3 d reaction (entry 5). Disappointingly, tri-substituted epoxide 4h failed to undergo the desired transformation (entry 6), resulting in the formation of a complex mixture containing iodohydrins and allyl alcohols.

4

Tetrahedron Table 2. Cyclization reactions of epoxy cyclohexanols a R1 O

HO 4

O

1

O

EtCN 90 °C, time

substrate

entry

R1

LiI (3 equiv.)

R3

R2

10

time (h)

product

24

O

4c

10c O

O

5

HO

1) DMP CH2Cl2

17

96

10d

RO

O CN 19

RO

3d

5

O 4e

10e

Bn

R CN

THF

CN

59% from 17

CN

18

R = Ph(CH2)3

79

O

O

NaBH4

R

2) CH2(CN)2 NH 4OAc EtOH

OH 4d

OH

OLi

OH

OLi

Bn O

HO

O

24 Me

Me 4f

R

97

LiI

R

I CN

OH 10f

Bn

CN

O

72

Me 4g

CN

OH 10g

LiI

I

I

CN

Bn

Bn 6

O 4h

21

0

O

OH 10h Me

Me

CN

21

18

56

O Me

R

I C NLi CN

20

Bn

HO

HO

(22c)

RO

2d

5

yieldb (%)

OH

RO

4

OH R3

R2

HO

HO

The successful cyclization of epoxide 17 prompted us to develop a C-C bond forming reaction based on a similar principle (Scheme 5). Thus, epoxy alcohol 17 was converted to epoxy nitrile 18 through a Knoevenagel condensation of the corresponding aldehyde with malononitrile, followed by conjugate reduction of the resulting nitrile 19. We therefore envisioned that treatment of epoxy nitrile 18 with lithium iodide would lead to the intramolecular SN2 reaction of anionic intermediate 20, giving rise to bicyclic compound 21.

R

R

OLi CN CN

20'

OH C NLi CN

R

CN

OLi

21'

a

Reaction conditions: A solution of 4 (0.1 mmol) and LiI (0.3 mmol) in EtCN (1.0 mL) was stirred at 90 °C for the indicated time. bIsolated yield. cYields were determined by 1H NMR spectroscopy using (CHCl2)2 as the internal standard. dR=tert-butyldiphenylsilyl group.

The cyclization reaction of other classes of epoxy alcohols was then investigated (Scheme 4). Upon heating with lithium iodide in propionitrile, the seven-membered epoxy alcohol 12, prepared from the corresponding cycloalkene 13,10 underwent a transformation into 8oxabicyclo[3.2.1]octane derivative 14 in almost quantitative yield. Furthermore, the 6-oxabicyclo-[3.2.1]octane derivative 15 was also synthesized from cyclohexene 16,11 which bears an acyclic alcohol moiety.

BnO

BnO

TBHP VO(OEt)3 CH2Cl2

HO

O

HO 12

Upon heating with lithium iodide in propionitrile, epoxy nitrile 18 gave a mixture of two highly polar compounds. This mixture was treated with aqueous acetic acid to afford tricyclic lactones 22 and 23 in 51% and 29% yield, respectively (Table 3, entry 1).12 In this reaction, the malononitrile moiety acted as a nucleophile in the intramolecular SN2 reaction. Epoxy nitrile 18, however, exhibited lower regioselectivity than epoxy alcohol 17. In addition, the alkoxides (21 and 21’ in Scheme 5) underwent a spontaneous intramolecular addition reaction with the proximate cyano group. It is noteworthy that the tricyclic skeleton of lactone 22 is found as a substructure in many naturally occurring compounds.13

BnO

Table 3. Cyclization reactions of epoxy nitrile 18 a

O

75%

13

LiI (3 equiv.)

Scheme 5. Synthesis of epoxy nitrile 18 as a new cyclization precursor

EtCN 90 °C, 13 h

OH

14

98%

LiX (3 equiv.) 18

TBHP VO(OEt)3 R

CH2Cl2 OH

82%11

16

O R OH 17

LiI (3 equiv.) EtCN 90 °C, 5 h

solvent 80°C, time

OH

CN AcOH

O R

+

H2 O

R

O 22

CN

R = Ph(CH2)3

R

97%

R = Ph(CH2)3

Scheme 4. Synthesis of oxabicyclo[3.2.1]octanes

O 15

22b (%)

23b (%)

5

51

29

entry

LiX

solvent

time (h)

1

LiI

EtCN

2

LiI

THF

5

38

39

3

LiBr

EtCN

5

67 (56c)

14 (10c)

4

LiCl

EtCN

57

0

0

O O

23

5 a

A solution of 18 (0.1 mmol), LiX (0.3 mmol) in the indicated solvent (1.0 mL) was used. bYields were determined by 1H NMR spectroscopy using (CHCl2)2 as the internal standard. cIsolated yield

A number of factors were found to affect the regioselectivity of the intramolecular SN2 reaction. Reaction in THF resulted in lower regioselectivity (entry 2), while the use of lithium bromide rather than lithium iodide increased the regioselectivity (entry 3). Finally, lithium chloride had no apparent effect on the cyclization reaction (entry 4). In summary, we have developed a novel efficient method for the synthesis of 7-oxabicyclo[2.2.1]heptane derivatives. The substrates, namely cis-3,4-epoxy-1-cyclohexanol derivatives, were prepared from the corresponding 3-cyclohexen-1-ol derivatives via a stereoselective epoxidation reaction using a vanadium catalyst. Upon heating with lithium iodide in propionitrile, the cis-epoxy alcohol was transformed into the desired 7-oxabicyclo[2.2.1]heptane derivative in high yield. The reaction proceeds through formation of a lithium alkoxide bearing an iodohydrin moiety, followed by an intramolecular SN2 reaction. Other types of bicyclic ethers can also be synthesized by adopting this methodology, and the intramolecular C-C bond formation using an epoxy nitrile shows promise for application in the total synthesis of natural products.

Acknowledgments This work was supported in part by a Grant-in-Aid for Scientific Research on Innovative Areas (Project No. 2707: Middle Molecular Strategy), and a Grant-in-Aid for Scientific Research (B) (15H03806) from the Ministry of Education, Culture, Sports, Science and Technology, Japan. This research was also supported by grants from the Project of the Bio-oriented Technology Research Advancement Institution, NARO (the special scheme project on advanced research and development for next-generation technology). We would like to thank Editage for English language editing.

Supplementary data Supplementary data (experimental procedures and characterization data) associated with this article can be found, in the online version, at ~

References and notes 1.

2. 3.

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4.

5.

6.

7. 8. 9. 10. 11.

12.

13.

1976, 41, 104. (c) Mukaiyama, T.; Iwasawa, N. Chem. Lett. 1981, 10, 29. (d) Sneden, A. T. Synlett 1993, 313. (e) Tanino, K.; Takahashi, M.; Tomata, Y.; Tokura, H.; Uehara, T.; Narabu, T.; Miyashita, M. Nature Chem. 2011, 3, 484. (a) Murai, A.; Tanimoto, N.; Sakamoto, N.; Masamune, T. J. Am. Chem. Soc. 1988, 110, 1985. (b) Mori, K.; Watanabe, H. Pure Appl. Chem. 1989, 61, 543. (c) Watanabe, H.; Mori, K. J. Chem. Soc., Perkin Trans. 1, 1991, 2919. (d) Yajima, A.; Saitou, F.; Sekimoto, M.; Maetoko, S.; Nukada, T.; Yabuta, G. Tetarahedron 2005, 61, 9164. (a) Kato, T.; Kondo, H.; Kitano, Y.; Hata, G.; Takagi, Y. Chem. Lett. 1980, 9, 757. (b) Aziz, M.; Rouessac, F. Tetrahedron Lett. 1987, 28, 2579. (c) Demnitz, F. W.; Philippini, C.; Raphael, R. A. J. Org. Chem. 1995, 60, 5114. (d) Shiina, Y.; Tomata, Y.; Miyashita, M.; Tanino, K. Chem. Lett. 2010, 39, 835. There are a few reports on the SN1-type reactions of epoxy alcohols under acidic conditions: (a) Yamano, Y.; Ito, M. Chem. Pharm. Bull. 2004, 52, 780. (b) Yamano, Y.; Ito, M.; Wada, A. Org. Biomol. Chem. 2008, 6, 3421. (c) Barton, A. F. M.; Dell, B.; Knight, A. R. J. Agric. Food Chem. 2010, 58, 10147. Donohoe, T. J.; Mitchell, L.; Waring, M. J.; Helliwell, M.; Bell, A.; Newcombe, N. J. Org. Biomol. Chem. 2003, 1, 2173. Nicolaou, K. C.; Harrison, S. T. Angew. Chem. Int. Ed. 2006, 45, 3256. Karikomi, M.; Watanabe, S.; Kimura, Y.; Uyehara, T. Tetrahedron Lett. 2002, 43, 1495. Lautens, M.; Rovis, T. J. Am. Chem. Soc. 1997, 119, 11090. Cyclohexene 16 was synthesized from commercially available methyl 4-cyclohexenecarboxylate via alkylation with 1-bromo-3phenylpropane followed by LAH reduction. Epoxy alcohol 17 was obtained in 82% yield for three steps from methyl 4cyclohexenecarboxylate (see the Supporting Information). The structures of 22 and 23 were established based on the 2D NMR spectrum involving COSY, HMQC, HMBC, and NOESY (see the Supporting Information). Maldonado, E. M.; Salamanca, E.; Giménez, A.; Saavedra, G.; Sterner, O. Phytochemistry Lett. 2014, 10, 281.

6

Tetrahedron

A new synthetic method of 7oxabicyclo[2.2.1]heptane derivatives is described. The operation, heating epoxy cyclohexanols with LiI in propionitrile, is very simple. The methodology was also applicable to a carboncarbon bond forming reaction.