4674
J . Org. Chem. 1987,52, 4674-4681
Stereoselectivity of Intramolecular Nitrile Oxide Cycloadditions to 2and E Chiral Alkenes’ Rita Annunziata, Mauro Cinquini, Franco Cozzi,* Cesare Gennari,* and Laura Raimondi Centro CNR and Dipartmento di Chimica Organica e Industriale dell’llniversitd, I-20133 Milano, Italy
Received March 26, 1987
Intramolecular nitrile oxide cycloaddition (INOC) reactions on chiral alkenes were studied in order to evaluate the influence of the double bond configuration on the stereochemical outcome of the process. Oximes 11-16 were prepared, starting from aldehydes 1-4, via Wittig reaction, isomerization of the double bond for the E derivatives, Swern oxidation, and reaction with hydroxylamine. Treatment of oximes 11-16 with sodium hypochlorite gave the nitrile oxides, which were trapped in situ by intramolecular cycloaddition to give the corresponding isoxazolines 17-22 as mixtures of diastereoisomers (Table I). From (2)-alkenyl oximes C-4/C-5 syn products and from (E)-alkenyloximes C-4/C-5 anti products were obtained, while the relative stereochemistry at C-5/C-5‘of the predominant isomers was found to be anti in all cases. The assignment of relative stereochemistry was based on ‘Hand 13C NMR spectroscopic evidence and on chemical correlations. With Houk‘s approach, MM2 calculations were performed to evaluate the relative energies of the transition structures. The CNO-ethylene fragment was frozen in the ab initio HCNO-ethylene transition structure model geometry, and the substituents were fully optimized by MM2. With the (2)-alkenes,the “small”group of the allylic stereocenter prefers the inside position, the “medium”the anti, and the “large” the outside, with respect to the forming C-0 bond, and the factors controlling the stereoselectivity are mainly steric. On the contrary, with the (E)-alkenesthe “medium” group will be inside, the “large” anti, and the “small”outside. In the case of allyl ethers this model is mainly ruled by electronic factors. Quite good stereoselectivities were achieved in the INOC reactions using the allyl ethers derived from glyceraldehyde. A rationale for this result has been proposed. The versatility of 4,5-dihydroisoxazoles (A2-isoxazolines) for the stereocontrolled synthesis of various classes of highly functionalized molecules, such as @-hydroxyketones and acids, y-amino alcohols, sugars and amino sugars, and complex heterocycles is well recognizeda2 A2-Isoxazolines are generally synthesized via the cycloaddition of nitrile oxides to olefin^,^ a reaction known to proceed stereo~pecifically.~Attempts to simultaneously control relative and absolute stereochemistry by the use of chiral nitrile oxides5 have met with limited success so far. On the other hand, cycloadditions to chiral alkenes have been more successful and have received a great deal of attention.2a-cs6 Indeed, chiral allyl ethers derived from 3-buten-2-01 and 3-buten-1,2-diol were s h ~ w n ’to~ undergo ~ nitrile oxide cycloadditions with diastereoselections ranging from 2:l up to 91. While a variation of the alkoxy group seems to have only negligible effects,’~~ an increase of the bulkiness of the alkyl group bound t o the allylic stereocenter substantially enhances the stereoselectivity.8 Non-heteroatom-substituted chiral alkenesg have generally been found (1) A preliminary report of this work has been published Annunziata, Chem. Commun. R.; Cinquini, M.; Cozzi, F.; Raimondi, L. J. Chem. SOC., 1987, 529. (2) (a) Kozikowski, A. P. Acc. Chem. Res. 1984,17,410. (b) Jager, V.; MOller, I.; Schohe, R.; Frey, M.; Ehrler, R.; Hiifele, B.; Schroter, D. Lect. Heterocycl. Chem. 1986,9,79. (c) Jgger, V.; MSlller, I. Tetrahedron 1985, 41, 3519. (d) Curran, D. P. J.Am. Chem. SOC.1983, 105, 5826. (3) Grundmann, C.; Grbanger, P. The Nitrile Oxides; Springer Verlag: Berlin, 1971. Caramella, P.; Grunanger, P. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley-Interscience: New York, 1984; Vol. 1, pp 291-392. (4) Houk, K. N.; Firestone, R. A.; Munchausen, L. L.; Mueller, P. H.; Arison, B. H.; Garcia, L. A. J. Am. Chem. SOC.1985, 107, 7227. (5) (a) Kozikowski, A. P.; Kitagawa, Y.; Springer, J. P. J. Chem. Soc., Chem. Commun. 1983, 1460. (b) Larsen, K. E.; Torssell, K. B. G. Tetrahedron 1984,40 2985. (6) For an alternative a proach to the synthesis of enantio- and diastereoisomerically pure A P-isoxazolines, see: Cinquini, M.; Cozzi, F.; Gilardi, A. J. Chem. SOC.,Chem. Commun.1984, 551. Annunziata, R.; Cinquini, M.; Cozzi, F.; Gilardi, A.; Restelli, A. J. Chem. SOC.,Perkin Trans. 1 1985, 2289. (7) Kozikowski, A. P.; Ghosh, A. K. J. Org. Chem. 1984, 49, 2762. (8) Houk, K. N.; Moses, S. R.; Wu, Y.-D.; Rondan, N. G.; Jager, V.; Schohe, R.; Fronczek, F. R. J. Am. Chem. SOC.1984,106, 3880. (9) Houk, K. N.; Duh, H.-Y.;Wu, Y.-D.; Moses, S. R. J. A m . Chem. SOC.1986, 108, 2754.
to be less selective.lOJ1 Independently of the nature of the substituents, all these cycloadditions gave C-5/C-5’ anti12 isomers as major products (see below for isoxazoline numbering). In order to rationalize the results of the cycloaddition on chiral allyl ethers Kozikowski proposed a Felkin-type transition structure where the nitrile oxide attacks the olefin in an anti fashion with respect to the alkoxy group. Houk and Jager, on the basis of theoretical studies, suggested8 that the attack occurs anti to the alkyl group, while the allylic ether adopts an inside position (“inside alkoxy effect”). In a recent extension of this model to chiral alkenesg Houk proposed that the major product of a nitrile oxide cycloaddition arises from a transition structure featuring the “large” group in the anti and the “medium” group in the inside position, respectively. Despite this impressive amount of research, the influence of double bond configuration on the stereochemical outcome of the cycloaddition reaction has been studied only t o a very limited probably because of the poor regioselectivity observed for the cycloaddition to unsymmetrical disubstituted alkenes. As reported in a preliminary account of this work’ we thought that an intramolecular nitrile oxide cycloaddition (INOC) reaction,13forced to occur in a regiochemical defined fashion, would allow the evaluation of the effect of alkene geometry on the stereochemistry of the process. In this paper we wish to report our experimental results in this area, together with theoretical investigations (MM2) of the cycloaddition transition structures, in order to shed new light on the stereoselectivity of the intramolecular nitrile oxide cycloadditions to chiral alkenes. (10)For an example of a nitrile oxide cycloaddition on a sifcon-substituted chiral alkene, see: Curran, D. P.;Kim, B. H. Synthesis 1986,312. (11) For a cycloaddition on a nitrogen-substituted olefin that occurs with good stereoselectivity, see: Kozikowski, A. P.; Chen, X.-M. Tetrahedron Lett. 1985, 26, 4047. (12) Masamune, S.; Ali, S. A.; Snitman, D. L.; Garvey, D. S. Angezu. Chem., Int. Ed. Engl. 1980, 19, 557. (13) INOC reactions of (E)-and (2)-alkenes featuring an allylic stereocenter within the carbon chain connecting dipole and dipolarophile have been reported Kozikowski, A. P.; Chen, Y. Y. Tetrahedron Lett. 1982, 23, 2081.
0022-3263/87/1952-4674$01.50/0 0 1987 American Chemical Society
J. Org. Chem., Vol. 52, No. 21, 1987 4675
Intramolecular Nitrile Oxide Cycloadditions Scheme I'
-
Scheme I1
Ph-0
a or b 2-11,
2-15
H 1-4
0-N
0-N
178. 21.3
1 7 b , 21b
Ph-? E-11,
E-15
--
~
0 -N
2
5-10
1
E
5-10
0-N
17C , 21 C
d,e 2-12,
2 - 1 3 , 2-16
-
17d
RO
RO
R O q C H s ) n
I C H J ,
+
0- N
0-N
l s a , 19a,22a
2
11-16
1, 5, 11: 2, 6, 12: 3, 7, 13: 4, 8, 14: 9, 15: 10, 16:
E
11-16
E- 1 2 , E- 13
R1 = OCHzPh, R2 = Me; n = 2 R2 = OCHzPh, R1 = CHZOCH2Ph; n = 2 Rz,R1 = OC(CHZ),OCHz; n = 2 R1= i-Pr, Rz = Me; n = 2 Rl = OCH2Ph, R2 = Me; n = 1 R2,Ri = OC(CH2)50CHz, n = 1
'Reagents:
(a) Ph3P+(CHz)sCHz0H,Br-, n-BuLi, THF; (b) Ph3P+(CHJ4CH20H,Br-, n-BuLi, THF; (c) PhSH, AIBN, benzene; (d) DMSO, (C0C1)2, CH2Cl2;(e) NH20H.HC1, Py. Table I. Synthesis of 4,5-Dihydroisoxazoles 17-22 from Oximes 11-16 diastereoisomeric oximes products yield, % ratios' 62 8020b (z)-ll 17a,b (E)-11 17c,d 70 6040 72 83:17b (2)-12 18a,b (E)-12 18c,d 87 77:23 63 8614b 6913 19a,b (E)-13 m,a 84 8614b 57 6634 (014 20a,b (E)-14 20c,d 56 6634 57 75:2fib (a-15 21a,b (E)-15 21c,d 26 58:42 58 81:1gb (a-16 22a,b (E)-16 22c,d 43 78:22b
'As determined by 'H and 13C NMR spectroscopy. products can be separated by flash chromatography.
Isomeric
Results and Discussion The synthetic route to the desired cycloadduct precursors is reported in Scheme 1.l 2 alcohols 6-10 were prepared from (S)-0-benzyllactaldehyde (l), (R)-0,O-dibenzylglyceraldehyde (2),(R)-0,O-cyclohexylideneglyceraldehyde (3), and (R,S)-2,3-dimethylbutanal(4) by Wittig reaction with the corresponding (w-(hydroxyalky1)triphenylphosphonium bromide.14 From (2)-5-10 the E isomers were obtained by reaction with thiophenol in refluxing benzene in the presence of azoisobutyronitrile (AIBN). Conversion of the alcohols to the oximes 11-16 was readily achieved by Swern oxidation and subsequent reaction with hydroxylamine hydrochloride in pyridine. Treatment of a dichloromethane solution of 11-16 with sodium hypochlorite gave the nitrile oxides which were (14) Schlosser,M.; Trong, H. B.; Schaub, B. Tetrahedron Lett. 1985,
26, 311.
,
E-16
-
lab,l9b,?2b
RO
RO R
O
II H ' s l n
W
+
m*Hs)n
0-N
0-N
lSC, 1 9 c , 2 2 c
2-14
-
E-14
i.Pr
21d
l a d , 19d, 2 2 d
-
i-Pr
0-N
0-N
20a,b
20C,d
17: n = 2 18: R = CH2Ph; n = 2 19: R = C(CH,),; n = 2
21: n = 1 . 22: R = C(CH2)5; n = 1
trapped in situ by intramolecular cycloaddition to give the corresponding isoxazolines 17-22 as mixtures of diastereoisomers (Scheme 11). Chemical yields and diastereoisomeric ratios are collected in Table I. In several cases the products could be separated by flash chromatography, thus affording isomerically pure compounds. In the synthesis of cycloadducts yields were generally good for cyclohexane forming reactions (17-20,n = 2), while slightly decreased for the cyclopentane forming ones (21-22,n = l),probably as the result of the difficulty for dipole and dipolarophile to reach the geometry required by the transition state.*J5J6Isomer ratios were determined by high-field 13C and 'H NMR spectroscopy. The cycloaddition reaction retains the stereochemistry of the alkene:3,4thus from (2)-alkenyl oximes C-4/C-5 syn and from (E)-alkenyl oximes C-4/C-5 anti products were obtained, respectively. The assignment of the relative stereochemistry a t C-5/C-5' was based on NMR spectroscopic evidence and chemical correlations. The relevant NMR data for compounds 17-22 are collected in Table 11. Comparison with the literature data7J7J8for related substrates was possible only for 17, (15) In order to have a homogeneous set of data no attempt to improve chemical yields of cycloadditions of (E)-15 and (E)-16 by changing reaction conditions was made. (16) INOC reactions leading to isoxazolines with the same structure as 21 and 22 but featuring a sulfur atom instead of a CH2group (Scheme 11) from the corresponding nitro sulfides occurred only upon overnight refluxing in benzene. Annunziata, R.; Cinquini, M.; Cozzi, F.; Dondio, G.; Raimondi, L. Tetrahedron 1987,43, 2369. (17) J e e r , V.; Schohe, R. Tetrahedron 1984, 40, 2199. (18) Annunziata, R.; Cinquini, M.; Cozzi, F.; Raimondi, L.; Restelli,A. Helu. Chin. Acta 1985, 68, 1217.
4676
J. Org. Chem., Vol. 52,No. 21,1987 Table 11. Relevant
*
Annunziata et al.
and 'H NMR Data of 4,5-Dihydroisoxazoles 17-22 (CH2)"
c 4'
0-N
compd 17a 17b 17c 17d 18a 18b 18c
18d 19a 19b 19c 19d 20a 20b 20c
20d 21a 21b 21c 21d 22a 22b 22c 22d
c-4 50.6 50.1 49.6 49.5 50.7 49.7 49.7 49.7 50.7 49.3 52.1 49.9 51.0 51.5 51.4 51.9 57.5 56.7 55.8 56.8 57.8 56.7 58.5 56.2
13C NMR, b c-5 c-5' 83.5 73.6 84.7 73.9 89.1 74.9 88.1 74.8 79.4 77.2 80.5 77.5 85.6 78.0 85.8 77.9 81.6 72.8 74.9 80.6 85.7 76.5 85.1 75.3 38.4 84.0 84.2 37.5 42.9 88.1 43.1 88.8 83.9 73.3 73.8 84.9 91.4 73.7 91.1 74.9 82.3 71.7 81.1 75.0 87.7 76.1 75.0 87.3
c-4' 16.9 17.3 16.9 15.0 70.5 70.2 70.1 70.1 67.7 65.7 67.0 64.9 30.2 27.7 28.4 29.4 16.4 16.4 17.9 16.6 67.5 65.3 67.2 65.2
19,21, and 22. For the products derived from (R)-0,Ocyclohexylideneglyceraldehyde (4) (i.e., 19 and 22) on passing from major (19a,c, 22a,c) to minor (19b,d,22b,d) isomers, a decrease of the chemical shift values of C-4, (2-5, and C-4' and an increase of the chemic4 shift values of HC-5 and HC-5' were constantly observed. In addition a common trend was found for the HC-5/HC-5' coupling constants, which were always larger for the major than for the minor p r o d u c t ~ . ~ JOn ~ ' this ~ basis the C-5/C-5' anti relative configuration was firmly assigned to predominant isomers of the INOC reaction of (2)-and (E)-alkenyl oximes 13 and 16. For the products derived from (S)-0benzyllactaldehyde (1) (i.e., 17 and 21) comparison with the literature7 was possible only for 'H NMR data. In particular the only reliablelg feature was found to be the trend of the chemical shift value for HC-5 that always increases on passing from anti (major) 17a,c,21a,c to syn (minor) 17b,d, 21b,d isomers. The attribution of the stereochemistry to (R)-0,O-dibenzylglyceraldehyde derived isoxazolines 18 was not possible on the basis of NMR spectroscopy. The reasonable assumption that also in this case the INOC reactions of both (2)and (E)-12are anti selective was confirmed by chemical correlation of 19c with 18c (Scheme 111). As a further proof of the anti diastereoselectivity shared by these cycloadditions, compound 19a was converted into the enantiomer of 17a by the reaction sequence outlined in Scheme 111. Finally the stereoselectivity of an INOC reaction dictated by a non-heteroatom-substituted allylic stereocenter was investigated. Both (2)-and (E)-alkenyl oximes 14 gave a 2:l mixture of cycloadducts. The relative configuration a t C-5/C-5' of the prevailing isomers 20a and 20c was tentatively assigned by extension to these cycloadditions of the anti diastereoselectivity observed by Houk in intermolecular reactions of p-nitrobenzonitrile oxide with (19) The HC-5/HC-5' coupling values proved to be misleading (see Table I1 and ref. 16) and led us to incorrect attribution of the relative stereochemistry to 17c,d.'
'H NMR, 6 HC-5 HC-5' 4.34 3.70 3.67 4.40 3.77 4.02 4.16 3.74 3.76 4.61 3.66 4.66 3.85 4.25 3.73 4.25 4.10 4.37 4.14 4.44 4.06 3.96 4.30 4.18 1.63 4.28 1.75 4.11 3.96 4.00 3.60 4.36 3.56 4.45 3.88 4.16 3.82 4.26 4.01 4.38 4.07 4.45 4.28 4.13 4.41 4.30
J, Hz HC-4/HC-5 10.8 10.3 8.7 9.1 10.0 10.0 8.5 9.8 10.4 11.0 8.0 9.0 10.0 10.0 9.3 9.5 11.0 10.7 11.3 11.9 10.0 10.0 10.0
11.0
HC-5/HC-5' 8.4 6.0 4.8 6.0 8.5 3.8 4.8 4.9 8.6 5.0 8.0 5.5 7.7 10.0 8.8 6.6 8.0 6.6 4.5 6.9 10.0 4.5 8.0 5.8
Scheme 111" 19 a
13
24
ant-
178
19C
"Reagents: (a) AcOH, HzO; (b) TosC1, Et3N, CH2C12;(c) NaBH4, DMSO; (d) NaH, catalytic Bu4N+I-, PhCH2Br, THF.
3,4-dimethyl-l-pentene and related alkene^.^ Molecular mechanics calculations of the transition structures of these reactions supported this assignment (see the following section). In the case of chiral allyl ethers intramolecular cycloadditions of (2)-alkenyl oximes occur with a better diastereoselection than that observed for the corresponding E derivatives. This difference is particularly noticeable in the case of lactaldehyde derived products (Table I), the cycloadditionof (2)-11 and (2)-15 giving diastereoisomeric ratios which are even higher than those observed in comparable intermolecular case^.^^^ The stereoselectivity of the INOC reaction of glyceraldehyde derived oximes is less influenced by the double bond geometry and is very similar to that reported in intermolecular reaction^.^" Transition Structure Models. As the sense and the extent of diastereoselection of the INOC reactions of
J. Org. Chem., Vol. 52,No.21, 1987 4677
Intramolecular Nitrile Oxide Cycloadditions
Table 111. Relative Energies of the Transition Structures of the Intramolecular Nitrile Oxide Cycloaddition relative energies, kcal/mol entry 1 2 3 4 5
6
olefin geometry Z Z
z
E E E
R
R’
H H H (CH2)4 (CHd4 (CHd,
(CH2)4 (CH2)4 (CHZ), H H H
L Me CHzO i-Pr i-Pr Me CHzO
M OMe OCMez Me Me OMe OCMe2
O.Ob
anti B 0.9
O.Oc O.Od
1.9 1.3
0.5 1.2 0.7
0.0‘ 0.d 0.38
A
C 4.1 3.2 3.6 3.0 2.3 1.3
A’ 1.2 0.2 0.2 0.1 0.0 0.0
SYn B’ 1.4 1.9 1.8
2.1 0.6 0.2
anti/syn calcda exptl 84/16 80/20 58/42 86/14 60/40 66/34 60/40 66/34 60/40 86/14
C’ 4.7 4.7 3.8 1.9 1.3 1.1
products
17a/17b 19a/19b 20a/20b 20c/20d 17c/17d 19c/19d
a Stereoselectivity predictions come from calculations of a Boltzmann distribution including all six low-energy conformations. Stereoview 1, Chart I. eStereoview 2, Chart 1. dStereoview 3, Chart I. ‘Stereoview 4, Chart I. fstereoview 5, Chart I. 8Stereoview 6, Chart I.
Chart I
stereoview 2 (Table 111, entry 2, conformer A)
stereoview 1 (Table 111, entry 1, conformer A)
Y
q
