HETEROCYCLES

Short Paper | Special issue | Vol. 88, No. 2, 2014, pp. 1553-1563
Received, 5th July, 2013, Accepted, 13th September, 2013, Published online, 24th September, 2013.
DOI: 10.3987/COM-13-S(S)85

■ Yb(OTf)3-Mediated Ring Opening of Functionalized Cyclopentane Epoxides with Aniline: Aspects of Regiochemistry and Stereochemistry

Stephen Hanessian* and Changwei Mu

Department of Chemistry, University of Montreal, C.P. 6128, Succ. Centre-ville, Montréal, Québec H3C 3J7, Canada

Abstract

The ring-opening reaction of cyclopentan-1-ol 2,3-epoxides bearing alkoxy and hydroxyl groups with aniline was studied in the presence of Yb(OTf)3 in refluxing toluene. The syn- and anti- relationship of the alkoxy group has an influence on the regioselectivity of attack affording aniline adducts at the secondary or tertiary position.

The antibiotic pactamycin1 isolated in 1961 from a fermentation broth of Streptomyces pactum var.pactum, is a unique member of a handful of naturally occurring aminocyclopentitols2 (Figure 1). It exhibits activity against bacterial and also as a cytotoxic agent against cancer cell lines.3 Among the several functional groups and unusual patterns of substitution is the presence of a 3-acetyl aniline moiety at C-3. A key reaction in our total synthesis of pactamycin4 was the introduction of a 3-isopropenyl aniline through the highly regioselective ring opening of an epoxide spanning a secondary and a tertiary carbon center mediated by Yb(OTf)3 (Scheme 1).5 The same type of reaction allowed us to prepare a number of substituted aniline analogs of de-6-methylsalicylyl pactamycin and to study their biological activities (Figure 1).6
Intrigued by the exclusive formation of the aniline corresponding to ring opening at the secondary carbon atom as hoped for, we initiated a study of the ring- opening of stereoisomeric model cyclopentan-1-ol 2,3-epoxides with aniline in the presence of Yb(OTf)3 as a Lewis acid.7

In this paper, we report on the influence of the orientation of a vicinal alkoxy or alcohol group relative to the epoxide function in Yb(OTf)3-mediated ring opening reactions with aniline using a model 3-hydroxymethylcyclopentan-1-ol 2,3-epoxide derivative, to stimulate the partial structure of the epoxide intermediate shown in Scheme 1.


Reaction of the anti-oriented benzyl ether 1 with aniline in the presence of 30 mol% Yb(OTf)3 in refluxing toluene led to the aniline adducts 2 and 3 in 10% and 75% yields respectively. In contrast, identical conditions with the syn-oriented benzyl ether 4, afforded 5 and 6 in 13% and 80% yields respectively in a much shorter reaction time. Confirmation of the structure of the major products 3 and 6 was established through single crystal X-ray structure determination of the corresponding di-p-bromobenzoate ester 7, and mono-p-bromobenzoate ester 8, respectively.

The corresponding OTBS and O-methyl ethers were studied next. Thus, treatment of the anti-oriented OTBS ether 9 with the same condition as shown in Scheme 2, led to the aniline adducts 10 and 11 (Scheme 3). However, the presumed 10 was obtained as a mixture of products in 3.5% only. The major isomer 11 was obtained in 63% yield. The analogous O-methyl ether 12 afforded 13 and 14, also favoring ring-opening at the tertiary carbon atom.

As observed in the syn-oriented O-benzyl series, the corresponding OTBS and O-methyl ethers 15 and 16 led to major ring-opening products corresponding to attack at the secondary epoxide carbon atom to give aniline adducts 19 and 20 respectively.

Finally, treatment of the anti-oriented cyclopentanol epoxide 21 under the same conditions afforded the major product 23 after 15 h at reflux (Scheme 4). A small amount of a mixture of isomeric anilines 22 presumably resulting from a Payne rearrangement prior to ring opening was not investigated further.

The syn-oriented epoxide 24 reacted within 5 h to give 25 and 26 as aniline adducts in 16% and 53% yields respectively. Correlation of structures was possible by treatment with TBAF in the case of 23 and 26, which gave the same products derived from the hydrogenation of 3 and 6 respectively, followed by removal of the silyl protecting group to give 27 and 28 (Scheme 5).

As seen in the preceding reactions, the anti-oriented epoxides harboring the vicinal alkoxy or hydroxyl groups consistently led to ring-opening at the tertiary carbon atom of the corresponding epoxide. On the other hand, the syn-oriented epoxides with regard to the alkoxy group led to the corresponding aniline adducts resulting from attack at the secondary carbon atom. It is noteworthy that reaction times were considerably shorter in the syn-oriented epoxides. A plausible rationale for these results may be given by considering a combination of coordination effects and conformational bias.5 Thus, in the case of the anti-oriented epoxides A, a monodentate chelated Yb3+ coordination will render the tertiary carbon atom more susceptible to attack to release a 1,3-syn- interaction of the two ether sunstituents, in addition to stabilization of the developing positive charge in the transition state by an inductive effect of the hydroxymethyl substituent. It is of interest that in spite of the steric effects of the alkoxy and bulky O-silylated hydroxymethyl groups, attack is favored at the tertiary carbon center in an SN2-like process, allowing for a better overlap of the nucleophilic aniline with the σ* orbital of the C-O bond as it begins break.
In contrast, the syn-oriented epoxide B can engage in a bidentate coordination which activates the secondary carbon atom of the epoxide toward attack, in addition to a more favorable trajectory of approach of the nucleophilic aniline (Figure 2).

In conclusion, we have shown that a vicinal polar ether or hydroxyl group can dramatically influence the direction of ring opening of 2,3-epoxides in model cyclopentan-1-ols bearing a bulky hydroxymethyl substituent. It is also interesting that no ring opening was observed at the tertiary C-4 site in the case of the more densely functionalized pactamycin intermediate (Scheme 1). This would have necessitated a major change in synthetic strategy. Further studies in the synthesis of related substituted aniline derivatives of hydroxycycloalkane epoxides are in progress and will be reported in due course.

ACKNOWLEDGEMENT
We are grateful to NSERC and to Pharmaron for financial assistance, C.M thanks Pharmaron for a sabbatical leave. We thank Benoit Deschênes-Simard and Robert D. Giacometti for X-ray crystallographic analyses.

EXPERIMENTAL
General procedure for epoxide ring opening reactions:

The stirred solution of epoxide (1 equiv.), aniline (5.8 equiv.) and Yb(OTf)3 (0.3 equiv.) in toluene (0.28 mmol/mL) was heated to 110 °C for several hours with TLC monitoring. The reaction mixture was then concentrated in vacuum, and the residue was purified by flash column chromatography to give the corresponding aniline adducts.

(1R,2R,3R)-3-(Benzyloxy)-1-((tert-butyldiphenylsilyloxy)methyl)-2-(phenylamino)cyclopentanol (2) and (1R,2R,5R)-5-(Benzyloxy)-2-((tert-butyldiphenylsilyloxy)methyl)-2-(phenylamino)cyclopentanol (3).

Prepared according to the general procedure. From 504 mg (1.1 mmol) of epoxide 1, after 11 h reaction, were obtained product 2 (64 mg, 10.5%) as a sticky solid, and product 3 (435 mg, 72%) as a light yellow solid.

For compound 2:

HRMS, (ESI-POS-DI.m), [M+H]+, C35H42NO3Si, Calc. m/z: 552.29285, found m/z: 552.29425; [M+Na]+, C35H41NNaO3Si, Calc. m/z: 574.27479, found m/z: 574.27487.
1H NMR (CDCl3, 400 MHz): δ 7.59-7.65 (m, 4H), 7.17-7.43 (m, 11H), 7.10-7.14 (m, 2H), 6.65-6.74 (m, 3H), 4.38 (d,d, J 1= 11.6 Hz, J 2=11.6 Hz, 2H), 4.40 (b, 1H), 4.20-4.21 (m, 1H), 3.79 (d,d, J1 = 10 Hz, J2= 10.4 Hz, 2H), 3.81 (d, J= 5.2 Hz, 1H), 3.01 (s, 1H), 2.00-2.09 (m, 1H), 1.87-1.95 (m, 1H), 1.64-1.75 (m, 2H), 1.07 (s, 9H).

For compound 3:

HRMS, (ESI-POS-DI.m), [M+H]+, C35H42NO3Si, Calc. m/z: 552.29285, found m/z: 552.29438; [M+Na]+, C35H41NNaO3Si, Calc. m/z: 574.27479, found m/z: 574.27491.
1H NMR (CDCl3, 400 MHz): δ 7.49-7.62 (m, 4H), 7.28-7.49 (m, 11H), 7.09-7.13 (m, 2H), 6.61-6.77 (m, 3H), 4.70 (d,d, J 1= 12.4 Hz, J 2=12 Hz, 2H), 4.25 (d, J= 6.0 Hz, 1H), 3.93-3.98 (m, 1H), 3.93 (d,d, J1 = 10.8 Hz, J2= 10.4 Hz, 2H), 1.88-2.06 (m, 3H), 1.72-1.79 (m, 1H), 1.05 (s, 9H).

(1S,2S,5R)-5-(Benzyloxy)-2-((tert-butyldiphenylsilyloxy)methyl)-2-(phenylamino)cyclopentanol (5) and (1S,2S,3R)-3-(Benzyloxy)-1-((tert-butyldiphenylsilyloxy)methyl)-2-(phenylamino)cyclopentanol (6).

Prepared according to the general procedure. From 503 mg (1.1 mmol) of epoxide 4, after 3 h reaction, were obtained product 5 (70 mg, 11.5%) as a light yellow solid and product 6 (480 mg, 80%) as a sticky solid.

For compound 5:

HRMS, (ESI-POS-DI.m), [M+H]+, C35H42NO3Si, Calc. m/z: 552.29285, found m/z: 552.29468; [M+Na]+, C35H41NNaO3Si, Calc. m/z: 574.27479, found m/z: 574.27573.
1H NMR (CDCl3, 400 MHz): δ 7.45-7.48 (m, 4H), 7.19-7.37 (m, 11H), 7.13-7.17 (m, 2H), 6.73-6.81 (m, 3H), 4.61 (d,d, J 1= 11.6 Hz, J 2=11.6 Hz, 2H), 4.21-4.24 (m, 1H), 4.15-4.19 (m, 1H), 4.13 (b, 1H), 3.98 (d,d, J1 = 10.4 Hz, J2= 10.4 Hz, 2H), 3.23 (d, J= 6 Hz, 1H), 1.97-2.13 (m, 2H), 1.76-1.87 (m, 2H), 0.97 (s, 9H).

For compound 6:

HRMS, (ESI-POS-DI.m), [M+H]+, C35H42NO3Si, Calc. m/z: 552.29285, found m/z: 552.29477; [M+Na]+, C35H41NNaO3Si, Calc. m/z: 574.27479, found m/z: 574.276.
1H NMR (CDCl3, 400 MHz): δ 7.63-7.66 (m, 4H), 7.29-7.46 (m, 11H), 7.12-7.16 (m, 2H), 6.62-6.72 (m, 3H), 4.58 (d,d, J 1= 12 Hz, J 2= 12 Hz, 2H), 4.40 (b, 1H), 3.83-3.87 (m, 2H), 3.73 (d,d, J1 = 10.4 Hz, J2= 10.4 Hz, 2H), 2.98 (b, 1H), 1.88-2.13 (m, 4H), 1.09 (s, 9H).

(1R,2R,3R)-1-((tert-Butyldiphenylsilyloxy)methyl)-3-methoxy-2-(phenylamino)cyclopentanol (13) and (1R,2R,5R)-2-((tert-Butyldiphenylsilyloxy)methyl)-5-methoxy-2-(phenylamino)cyclopentanol (14).

Prepared according to the general procedure. From 170 mg (0.44 mmol) of epoxide 12, after 8 h reaction, were obtained product 13 (23.3 mg, 11%) as a light yellow sticky solid and product 14 (146.5 mg, 68.5%) as a white solid.

For compound 13:

HRMS, (ESI-POS-DI.m), [M+H]+, C29H38NO3Si, Calc. m/z: 476.26155, found m/z: 476.26284; [M+Na]+, C29H37NNaO3Si, Calc. m/z: 498.24349, found m/z: 498.24343.
1H NMR (CDCl3, 400 MHz): δ 7.60-7.65 (m, 4H), 7.30-7.44 (m, 6H), 7.10-7.14 (m, 2H), 6.65-6.76 (m, 3H), 4.31 (b, 1H), 3.97-3.98 (m, 1H), 3.75 (d,d, J1 = 10 Hz, J2 =10.4 Hz, 2H), 3.78 (d, J= 5.6 Hz, 1H), 3.21 (s, 3H), 2.96 (s, 1H), 1.95-2.05 (m, 1H), 1.83-1.91 (m, 1H), 1.61-1.78 (m, 2H), 1.08 (s, 9H).

For compound 14:

HRMS, (ESI-POS-DI.m), [M+H]+, C29H38NO3Si, Calc. m/z: 476.26155, found m/z: 476.2629; [M+Na]+, C29H37NNaO3Si, Calc. m/z: 498.24349, found m/z: 498.24349.
1H NMR (CDCl3, 400 MHz): δ 7.62-7.63 (m, 2H), 7.26-7.47 (m, 8H), 7.08-7.12 (m, 2H), 6.59-6.76 (m, 3H), 4.08-4.13 (m, 3H), 3.69-3.79 (m, 3H), 3.44 (s, 3H), 1.96-2.05 (m, 2H), 1.85-1.93 (m, 1H), 1.60-1.69 (m, 1H), 1.05 (s, 9H).

(1S,2S,5R)-2-((tert-Butyldiphenylsilyloxy)methyl)-5-methoxy-2-(phenylamino)cyclopentanol (18) and (1S,2S,3R)-1-((tert-Butyldiphenylsilyloxy)methyl)-3-methoxy-2-(phenylamino)cyclopentanol (20).

Prepared according to the general procedure. From 153 mg (0.40 mmol) of epoxide 16, after 3 h reaction, were obtained product 18 (25.5 mg, 13.4%) as a light yellow solid and product 20 (145 mg, 76%) as a light yellow sticky solid.

For compound 18:

HRMS, (ESI-POS-DI.m), [M+H]+, C29H38NO3Si, Calc. m/z: 476.26155, found m/z: 476.26313; [M+Na]+, C29H37NNaO3Si, Calc. m/z: 498.24349, found m/z: 498.24396.
1H NMR (CDCl3, 400 MHz): δ 7.43-7.53 (m, 4H), 7.22-7.39 (m, 6H), 7.13-7.17 (m, 2H), 6.72-6.81 (m, 3H), 4.20-4.23 (m, 1H), 4.15 (b, 1H), 3.92-3.96 (m, 1H), 3.98 (d,d, J 1= 10 Hz, J 2=10.4 Hz, 2H), 3.41 (s, 3H), 3.31 (d, J= 6 Hz, 1H), 1.95-2.07 (m, 2H), 1.74-1.82 (m, 2H), 0.99 (s, 9H).

For compound 20:

HRMS, (ESI-POS-DI.m), [M+H]+, C29H38NO3Si, Calc. m/z: 476.26155, found m/z: 476.26302; [M+Na]+, C29H37NNaO3Si, Calc. m/z: 498.24349, found m/z: 498.24437.
1H NMR (CDCl3, 400 MHz): δ 7.65-7.68 (m, 4H), 7.36-7.46 (m, 6H), 7.15-7.19 (m, 2H), 6.68-6.73 (m, 3H), 4.45 (d, J= 5.6 Hz, 1H), 3.67-3.80 (m, 4H), 3.39 (s, 3H), 2.99 (s, 1H), 2.02-2.16 (m, 2H), 1.82-1.96 (m, 2H), 1.13 (s, 9H).

(1R,2R,3R)-3-(tert-Butyldimethylsilyloxy)-1-((tert-butyldiphenylsilyloxy) methyl)-2-(phenylamino)-cyclopentanol (10) and (1R,2R,5R)-5-(tert-Butyldimethylsilyloxy)-2-((tert-butyldiphenylsilyloxy)methyl)-2-(phenylamino)cyclopentanol (11).

Prepared according to the general procedure. From 227.5 mg (0.47 mmol) of epoxide 9, after 11 h reaction, were obtained product 10 (9.4 mg, 3.5%, mixture, containing a unknown impurity, [M+1]=582) as a light yellow sticky solid and product 11 (171 mg, 63%) as a colorless sticky solid.

For compound 11:

HRMS, (ESI-POS-DI.m), [M+H]+, C34H50NO3Si2, Calc. m/z: 576.33237, found m/z: 576.33362; [M+Na]+, C34H49NNaO3Si2, Calc. m/z: 598.31432, found m/z: 598.31507.
1H NMR (CDCl3, 400 MHz) δ 7.65-7.67 (m, 2H), 7.53-7.55 (m, 2H), 7.30-7.50 (m, 8H), 7.09-7.13 (m, 2H), 6.59-6.75 (m, 3H), 3.96 (d,d, J1 = 10.4 Hz, J 2= 10.4 Hz, 2H), 4.12-4.18 (m, 1H), 4.03 (m, 1H), 3.73 (b, 1H), 1.96-2.00 (m, 3H), 1.65-1.71 (m, 1H), 1.09 (s, 9H), 0.96 (s, 9H), 0.17 (s, 3H), 0.14 (s, 3H).

(1S,2S,5R)-5-(tert-Butyldimethylsilyloxy)-2-((tert-butyldiphenylsilyloxy) methyl)-2-(phenylamino)-cyclopentanol (17) and (1S,2S,3R)-3-(tert-Butyldimethylsilyloxy)-1-((tert-butyldiphenylsilyloxy)methyl)-2-(phenylamino)cyclopentanol (19).

Prepared according to the general procedure. From 156.5 mg (0.32 mmol) of epoxide 15, after 11 h reaction, were obtained product 17 (28 mg, 15%) as a white solid and product 19 (116.5 mg, 62.4%) as a light yellow sticky solid.

For compound 17:

HRMS, (ESI-POS-DI.m), [M+H]+, C34H50NO3Si2, Calc. m/z: 576.33237, found m/z: 576.33318; [M+Na]+, C34H49NNaO3Si2, Calc. m/z: 598.31432, found m/z: 598.31389.
1H NMR (CDCl3, 400 MHz) δ 7.51-7.53 (m, 2H), 7.15-7.39 (m, 10H), 6.79-6.84 (m, 3H), 4.36-4.40 (m, 1H), 4.14-4.16 (m, 1H), 3.90 (d,d, J1 = 10.4 Hz, J 2= 10.4 Hz, 2H), 2.86 (d, J = 6 Hz, 1H), 2.18-2.63 (m, 1H), 1.95-2.05 (m, 1H), 1.64-1.78 (m, 2H), 0.98 (s, 9H), 0.88 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H).

For compound 19:

HRMS, (ESI-POS-DI.m), [M+H]+, C34H50NO3Si2, Calc. m/z: 576.33237, found m/z: 576.33324; [M+Na]+, C34H49NNaO3Si2, Calc. m/z: 598.31432, found m/z: 598.31467.
1H NMR (CDCl3, 400 MHz) δ 7.68-7.70 (m, 4H), 7.39-7.48 (m, 6H), 7.16-7.19 (m, 2H), 6.65-6.73 (m, 3H), 4.72 (d, J = 5.6 Hz, 1H), 4.14-4.17 (m, 1H), 3.71-3.74 (m, 1H), 3.77 (d,d, J1 = 10 Hz, J 2= 10.4 Hz, 2H), 3.35 (s, 1H), 2.20-2.27 (m, 1H), 2.05-2.12 (m, 1H), 1.82-1.91 (m, 2H), 1.16 (s, 9H), 0.91 (s, 9H), 0.10 (s, 6H).

(1R,2R,3R)-1-((tert-Butyldiphenylsilyloxy)methyl)-2-(phenylamino) cyclopentane-1,3-diol (22) and (1R,2R,3R)-3-((tert-Butyldiphenylsilyloxy) methyl)-3-(phenylamino)cyclopentane-1,2-diol (23).

Prepared according to the general procedure. From 143.7 mg (0.39 mmol) of epoxide 21, after 15 h reaction, were obtained product 22 (25.5 mg, 14.2%, as a mixture of A and B) as a light yellow sticky solid and product 23 (97.6 mg, 55.5%) as a light yellow sticky solid.

For compound 22:
Compound A:

HRMS, (ESI-POS-DI.m), [M*]+, C28H35NO3Si, Calc. m/z: 461.23807, found m/z: 461.23746; [M+H]+, C28H36NO3Si, Calc. m/z: 462.2459, found m/z: 462.24707.
1H NMR (CDCl3, 400 MHz): δ 7.65-7.68 (m, 4H), 7.37-7.46 (m, 6H), 7.15-7.19 (m, 2H), 6.71-6.76 (m, 3H), 4.37-4.39 (m, 1H), 3.82 (d,d, J1 = 10.4 Hz, J2 = 10.4 Hz, 2H), 3.78 (d, J = 4.8 Hz, 1H), 2.71 (b, 1H), 2.11-2.15 (m, 1H), 1.90-1.98 (m, 1H), 1.68-1.79 (m, 2H), 1.12 (s, 9H).

Compound B:

HRMS, (ESI-POS-DI.m), [M*]+, C28H35NO3Si, Calc. m/z: 461.23807, found m/z: 461.23827; [M+H]+, C28H36NO3Si, Calc. m/z: 462.2459, found m/z: 462.24729.
1H NMR (CDCl3, 400 MHz): δ 7.65-7.67 (m, 4H), 7.39-7.48 (m, 6H), 7.19-7.23 (m, 2H), 6.76-6.82 (m, 3H), 3.98 (s, 1H), 3.80 (d,d, J1 = 10.4 Hz, J2 = 10.4 Hz, 2H), 3.72 (m, 1H), 2.42 (b, 1H), 2.17-2.27 (m, 1H), 1.60-1.80 (m, 3H), 1.08 (s, 9H).

For compound 23:

HRMS, (ESI-POS-DI.m), [M+H]+, C28H36NO3Si, Calc. m/z: 462.2459, found m/z: 462.24726; [M+Na]+, C28H35NNaO3Si, Calc. m/z: 484.22784, found m/z: 484.22865.
1H NMR (CDCl3, 400 MHz): δ 7.61-7.63 (m, 2H), 7.26-7.48 (m, 8H), 7.13-7.17 (m, 2H), 6.69-6.86 (m, 3H), 4.08-4.13 (m, 1H), 4.05 (d, J = 5.2 Hz, 1H), 3.86 (d,d, J1 = 10.4 Hz, J2 = 10.8 Hz, 2H), 3.62 (b, 2H), 1.96-2.17 (m, 2H), 1.72-1.82 (m, 2H), 1.07 (s, 9H).

(1R,2S,3S)-3-((tert-Butyldiphenylsilyloxy)methyl)-3-(phenylamino)cyclopentane-1,2-diol (25) and (1S,2S,3R)-1-((tert-Butyldiphenylsilyloxy)methyl)-2-(phenylamino)cyclopentane-1,3-diol (26).

Prepared according to the general procedure. From 133 mg (0.36 mmol) of epoxide 24, after 5 h reaction, were obtained a mixture of product 25 and 26 (115 mg, 69% estimated by NMR) as a light yellow sticky solid. Products can be separated and get exact yield after removing the TBDPS group.
HRMS, (ESI-POS-DI.m), [M+H]+, C28H36NO3Si, Calc. m/z: 462.2459, found m/z: 462.24688; [M+Na]+, C28H35NNaO3Si, Calc. m/z: 484.22784, found m/z: 484.22859.
1H NMR (CDCl3, 400 MHz): δ 7.62-7.68 (m, 4H), 7.29-7.50 (m, 6H), 7.10-7.20 (m, 2H), 6.60-6.78 (m, 3H), 3.68-4.26 (m, 4H), 2.99 (b, 2H), 1.81-2.19 (m, 4H), 1.08, 1.11 (s, 9H).

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