1221
J. Org. Chem. 1993,58, 1221-1227
Regiochemical Control of the Ring Opening of 1,2-Epoxides by Means of Chelating Processes. 5.' Synthesis and Reactions of Some 2,3-Epoxy-l-alkanolDerivatives Marco Chini,t Paolo Crotti,'*+Lee A. Flippin,'.$ Cristina Gardelli,t Elena Giovani,? Franco Macchia,+and Mauro Pineschit Dipartimento di Chimica Bioorganica, Universitb di Pisa, Via Bonanno 33, 56126 &a, Italy, and Institute of Organic Chemistry, Syntex Discovery Research, 3401 Hillview, Palo Alto, California 94303 Received July 13, 1992
In order to study the effect of a remote polar functionality on the regiochemistry of the ring opening of aliphatic epoxides, the synthesis and some nucleophilic additions (methanolysis, azidolysis, and aminolysis) of suitable 2,3-epoxy-l-alkanol derivatives (epoxides t r a n s - l a 4 and cis-2) were carried out. The C-3 selectivity commonly observed when nonchelating ring opening conditions are used is lower than when the epoxides are allowed to react in the presence of metal ions (Li+,Mg2+,Zn2+) due to the probable intervention of bidentate-chelated intermediates in the latter case, and in some instances an almost complete C-3 regioselection is obtained. Under identical conditions involving chelation control, trans epoxide la shows higher C-3 selectivity than cis isomer 2. A free hydroxyl functionality is not necessary in order to observe chelation-controlledregioselectivity in the epoxides that we examined. The stereo- and regiocontrolled addition of suitable nucleophiles to 1,2-epoxides can in theory be helpful for the stereoselective synthesis of complex polyfunctional molecules. Whereas the stereoselectivity of the ring opening of 1,2-epoxides is usually completely anti12p3 regioselectivity control is not always simple, especially in the case of l,2-disubstituted examples. In previously described works, the introduction of a polar heterofunctionality (OR) in the 8-position of a conformationally semirigid cycloaliphaticoxirane system turned out to be efficaciousin directing the regiochemistry of the addition process by allowing the elective use of either metal-assisted chelating or nonchelating reaction condit i o n ~ .Regiochemical ~ control was achieved in epoxide ring-opening reactions with several nucleophiles (CH3-,48 H-$b CH30H,4b C1-,4b amines," N3-," P h C W a ) . However, when the ring opening of aliphatic @-alkoxyoxiranes was examined, we found that the regioselectivity was significantly affected by chelating procedures only in the m e of organometallic additions in nonpolar ~olvents,~ other reaction conditionssuch as CH30H/CH3O-M+being essentially unselective.6 Important results obtained by Sharpless et al. on 2,3epoxy-1-alkanol derivatives were indicative of chelative regioselection control in these systems by means of Ti(IV).718 The data were taken from several reactions (with Universit.4 di Pisa. Svntex Discoverv Research. (1fPrecedingpap;r in this series: Chini, M.; Crotti, P.; Flippin, L. A,; Gardelli, C.; Macchia, F. J. Org. Chem. 1992,57, 1713. (2) Buchanan, J. G.;Sable, H. 2.In Selective Organic Transformution; Thyagarajan, B. S., Ed.;Wiley Interscience: New York, 1972; Vol. 1, p + f
I.
(3) Barili, P. L.; Bellucci, G.; Macchia, B.; Macchia, F.; Parmigiani, G. Gazz. Chim. Ital. 1971,101,300.
(4) (a) Chini, M.; Crotti, P.; Flippin, L. A.; Macchia, F. Tetrahedron Lett. 1989,?, 6563; (b) J. Org. Chem. 1990,55,4265. (c) Zbid. 1991,56, 7043. (d) Chini, M.; Crotti, P.;Favero, L.; Macchia, F. Tetrahedron Lett. 1991, 32, 6617. (5) Flippin, L. A,; Brown, P. A.; Jalali-Araghi, K. J . Org. Chem. 1989, 54,3588. (6) Unpublished results from thew laboratories. (7) Caron, M.; Sharpleas, K. B. J. Org. Chem. 198S, 50,1560. See also: Martin, V. S.; Ode, J. M.; Palazon, J. M.; Solei, M. A. Tetrahedron: Asymmetry 1992, 3, 573.
0022-326319311958-1221$04.00/0
the exception of methanolysis),but the method appeared to be fully operative only when a free alcoholic function was p r e ~ e n t .Consequently, ~~~ we have studied the ringopening reactions (methanolysis, azidolysis, and aminolysis) of epoxy benzyl ethers la: IC, Id, and 2 as well as epoxy alcohol lb.8*9
2
Id
1c
Rseults Epoxides la and 2 were prepared by m-chloroperoxybenzoic acid (m-CPBA) oxidation of the benzyl ethers 4 and 6 obtained by benzylation of the commercially available alcohols 3 and 6, respectively. The direct epoxidation of 3 with m-CPBA yielded the epoxide lb.8 The synthesis of the epoxides ICand Id was accomplished by oxidation of benzyl ethers 1ICand 1Id with m-CPBA. In this case, the necessary unsaturated trans alcohols 100 and 10d were obtained by DIBAL reduction of the corresponding esters 9c1O*and 9d.Iob Esters 9c and 9d were selectively synthesized by reaction of the aldehydes 70 and 7d, respectively, with the stabilized Wittig reagent obtained from 8 in a nonpolar solvent" (Scheme I).9 (8) Caron, M.; Carlier, P. R.; Sharpleas, K. B. J. Org. Chem. 1988,53, 5185. (9) All the structures depicted in the formulae and in Schemes 1-111 represent one enantiomeric series of the racemic mixtures used in this study. (10) (a) Mataui, S. Bull. Chem. SOC.Jpn 1984,57,426. (b) Andrwkiewicz, R.; Silverman, R. B. Synthesis 1989, 953. (11) (a) Cadogan, J. I. G. Organophosphorus Reagents in Organic Synthesis; Academic Preas: New York, 1979. (b) Bestmann, H. J. Pure Appl. Chem. 1979,51,515.
Q
1993 American Chemical Society
Chini et al.
1222 J. Org. Chem., Vol. 58, No.5, 1993 Scheme I la,b
-OR
3, R=H 4, R=Bn
-
-OR-
2
5. R=H 6, R=Bn
R-CHO
+
OE1 I EO-P-CH,COOEl
II 0
Ha
-$&+
increase in the C-3 selectivity was found when metal ion catalytic ring opening conditions were used (Table I). In the case of tert-butyl-substituted epoxide Id,the very high steric crowding at C-3 emphatically disfavored nucleophilic attack on that carbon under all conditions tried (entries 28-34, Table I); however, the metal ioncatalyzed methanolysis and azidolysis of epoxide Id showed a significant increase in the amount of C-3 attack (entries 30 and 32, Table I). Interestingly, the LiC104catalyzed aminolysis of Id occurred in good yield (entry 34, Table I), although the regiochemistry of attack was exclusivelyon the C-2 carbon; this result is in contrast to an uncatalyzed aminolysis attempt that failed completely (entry 33, Table I).
Discussion Hd
Hd
11
10
The results of ring openingof epoxides la-dand 2under a variety of reaction conditions are summarized in Tables I and 11. The determination of relative amounts of the regioisomericC-2- (12a-dand 16)and C-3-typeproducts12 (13a-dand 17) was accomplished by combined GC and 1HNMR analysis of the acetylatedcrude reaction products that contained correspondingmixtures of 14a-d and 15ad, from trans epoxides la-d, and 18 and 19, from cis epoxide 2 (SchemeII).9 The acetylationstep was necessary in order both to improve the separation of the pairs of regioisomers in GC analysis and to clarify the signals of protons H, and/or Hd in the lH NMR spectra of the products. These proton signals have been unequivocally assigned by double resonanceexperiments, irradiating the quite distinct signal of the proton a to the acetyl group.l3 As expected on the basis of Sharpless' results obtained with epoxy alcohol lb,8a prevalence of nucleophilic attack on C-3 was observed in the reactions of trans epoxy ether la carried out under nonchelating conditions (H+/MeOH and MeONa/MeOH for methanolysis, NaN3/NH&1 for azidolysis, and NHEt2/EtOH for aminolysis, Table I). However, when epoxide la was allowed to react in the presence of metal ions (Li+, Mg2+,Zn2+),an increase of C-3 nucleophilic attack was observed in all the reactions studied. This increase appeared to be largely dependent on the type and amount of the metal ion (Table I). In some cases (entries 9 and 11, Table I) a complete or practically complete C-3 regioselection was obtained. Analogous behavior was observed for the reactions of cis epoxide 2 (see Table 111, although the effectivenessof the metal ion in favoring C-3 selectivity was lower than in the case of the corresponding trans epoxide la. Our results from trans epoxy alcohol 1b ring openings (Table I) further confirm a metal ion-dependent selectivity for C-3 attack. The reactions of the cyclohexyl-substitutedepoxide IC under nonchelatingconditionswere less C-3selectivethan la,probably as a consequence of the larger steric hindrance present on the C-3 oxirane carbon of IC; however, an (12) TheC-2- andC-3-typeproductnomenclaturereferstotheattacking site of the nucleophile (Le.,at the C-2 or C-3 oxirane carbon of both la-d and 2) in accordance with the numbering scheme shown in Schemes I1 and 111. (13) Jackman, L. M.; Sternhell, S. Application of Nuclear Magnetic Resonance Spectroscopy to Organic Chemistry, 2nd ed.; Pergamon Press: London, 1969; p 151.
The above results indicate that metal salts affect the regiochemistry of somering-opening reactions (azidolysis, methanolysis, and aminolysis) of l-alkoxy-2,3-epoxyalkanes (epoxides l a 4 and 2). An increase in C-3 nucleophilic attack is generally observed in the metal saltcatalyzed reactions that, in the case of epoxide la,can lead to practically complete C-3 regioselection (entries 9 and 11, Table I). This effect is probably due to the intervention of bidentate-chelated structures of type 2014 (from trans epoxides la-d) and 21 (from cis epoxide 2) (Scheme111)in which the metal cation is coordinated both to the oxirane and to the alkoxideoxygen. These bidentate structures (20and 21) are similar to the ones suggested for the methylating ring opening of l-alkoxy-2,3-epoxyalkanes15 and for the Ti(1V)-mediated azidolysis of 2,3epo~y-l-alkanols.~J The increase in C-3selectivity (route a, Scheme 111) in the ring opening of epoxides l a 4 and 2 through intermediates 20 and 21,respectively, may be rationalized by invoking stereoelectronic factors similar to those implicated in the chelation-controlledring opening of 3,4-epoxy-l-dkanol derivative^.^ The lower efficiency of metal ions in promoting the C-3 selectivity of the cis epoxide 2 compared with that observed in the reactions of the corresponding trans isomer la can be rationalized on the basis of the incursion of two new eclipsing interactions (between M and a methylene group) in the formation of the chelate intermediate 21 from the cis epoxide 2;5only one of these repulsive interactions is necessarily present in the formation of the similar intermediate 20 from the trans epoxide la. Moreover, the formation of the conformationally restricted chelate structure 21 from the cis isomer 2 may cause an increase in strain between the C-1 and C-4 methylene groups (Scheme 111). A comparison of the reaction of trans epoxides la, IC, and Id indicates that an increase in the steric hindrance at C-3 results in a general decrease in C-3 selectivity, as expected.8 However, when metal salt-catalyzed reaction conditions are used in methanolysis and azidolysis, an increase in C-3 selectivity occurs. The only exception is the metal salt-catalyzed aminolysis of Id with NHEh, in which only the C-2-type product is observed (entry 34, Table I). Evidently in this case, where the nonchelating aminolysis conditions (NHEtdEtOH, refluxing) failed even after several days' heating, the strong catalytic effect (14) For the sake of simplicity, only the generic structure 20 is shown in Scheme 111, valid for all trans epoxides l a 4 (15) Pfaltz, A.; Mattenberger, A. Angew. Chem. Suppl. 1982,161.
J. Org. Chem., Vol. 58, No. 5, 1993 1223
Control of the Ring Opening of 1,2-Epoxides
Table I. Redoselectivity (%) of the Ring-Opening Reactions of Trans Epoxides l a 4 C-2-type productb
C-3-type productb
5 L
entry 1
2 3 4 5 6 7 8 9 10 11
12 13 14 15 16
17 18 19 20 21 22 23 24 25 26 27
epoxide
la la la la la la la la la la la la la la lb lb lb lb lb lb IC IC
IC IC IC IC
IC
reagents MeOH/H+ MeONa MeOH/LiC104 MeOH/Mg(C104)2 NaNdNHdCl NaN3/LiClO4
react. condnsa (OC) A (rt) B (60) C (60) C (80)
D (80) E (80) F (80) G (80) H (80) NaN3/Mg(C104)~ E (80) N ~ N ~ / Z ~ ( O S O ~ C F ~ ) Z E (80) NaN3/NaC104 E (80) NHEB I (80) NHEtdLiC104 J (rt) MeOH/H+ A (rt) C (80) MeOH/LiClO4 D (80) NaNS/NH&l F (80) NaNdLiC104 NHEtZ 1 (80) J (80) NHEtdLiC104 MeOH/H+ A (rt) MeONa B (80) c (80) MeOH/LiC104 D (80) NaNs/NH&l F (80) NaNs/LiC104 NHEt2 1 (80) J (80) NHEtz/LiC104
react. time (h)
R1
O
R
I
2
O * 1R ,2
OH
X
1 18
19
81d
2w
24 24
11' 8'
18
13e 6e 5' 4e 3e 6' 2e
80d 89 92d 871 94f 95, 9(V 97f 94f 981
18 18 18 18 18
18 10 days
no reaction
18
1%
24
99v
