Unexpected effect of an hydroxyl group on π-facial selectivity in the nucleophilic addition to...

4

Click here to load reader

Transcript of Unexpected effect of an hydroxyl group on π-facial selectivity in the nucleophilic addition to...

Page 1: Unexpected effect of an hydroxyl group on π-facial selectivity in the nucleophilic addition to bicyclo[2.2.2]octan-2-ones

Pergamon Tmahedron Lerrers, Vol. 36, No. 52. pp. 9411-9414. 1995

Elsevier Scmce Ltd Printed in Great Britam

mo-4039/95 $9.50+0.00

0040-4039(95)02032-2

Unexpected Effect of an Hydroxyl Group on K-Facial Selectivity in the Nucleophilic Addition to Bicyclo[2.2.2]octan-2-ones

Jean-Franqois Devaux, Pierre Fraisse, Issam Hanna,* and Jean-Yves Lallemand

Laboratoire de SynthCse Organique associC au CNRS, Ecole Polytechnique, F-91 128 Palaiseau, France

Abstract: An unprecedented remote effect of the hydroxyl group on n-facial selectivity

was observed in the addition of Grignnrd reagents to bic~~cio(2.2.2/octan-2-ones. where

nucleophilic attack occuredfrom the sterically more hinderedface.

Vinigrol 1 is an antihypertensive, a platelet aggregation inhibitor’ and a tumor necrosis factor (TNF) antagonist.* Structurally, this compound possesses a unique skeleton involving an eight-membered ring.3 We have recently described the first synthesis of the tricyclic system 2 of this natural product via a key anionic oxy- Cope rearrangement of tricyclic vinyl carbinol 3 which was made from ketone 4.4 In the course of our studies, we observed an intriguing selectivity in the addition of a Grignard reagent to tricyclic hydroxy ketone 4a. Treatement of 4a with vinyl magnesium chloride provided almost exclusively the endo vinyl alcohol 3a (20 : 1

endo: exe). Obviously, in this reaction, addition of the nucleophile occured mostly from the sterically more hindered endo face. This result is interesting in that it presumably reflects the influence of chelation versus steric factors. To gauge further the generality of this observation, we have investigated nucleophilic addition to various tricylic ketones 4.

’ 1 2 3a R=H 4a R=H 3b R=MOM 4b R=MOM 3c R=Me 4c R=Me

Since the conception of Cram’s chelate models, chelation is often invoked to account for the stereochemical outcome of the nucleophilic additions to alkoxy or hydroxy carbonyl compounds. According to this explanation, the intervention of a preorganized complex is followed by nucleophilic addition onto the sterically more accessible K-face .6J

9471

Page 2: Unexpected effect of an hydroxyl group on π-facial selectivity in the nucleophilic addition to bicyclo[2.2.2]octan-2-ones

9472

In order to evaluate the steric effect, addition of Grignard reagents was first carried out on the “naked” ketones ~%7~.tt) (Table, entries l-6). Treatment of 5 with vinylmagnesium chloride in THF led to a mixture of endo and exo isomers in 1:6 ratio. Under the same conditions, addition to the 4a(r epimer 6 proceeded with

completely reversed diastereoselectivity affording a mixture of endo and exo isomers in 5: 1 ratio.’ I”? These expected results may be understood in terms of steric control: in each case the nucleophilic addition occured predominantly from the sterically less hindered face of the ketone i. e. exo for 5 and endo for 6. In contrast, addition of vinylmagnesium bromide to the aromatic ketone 7 occured predominantly from the more hindered face giving a 1.6:l ratio of endo: exo isomers. This observation is in agreement with a previous report by Pudzianowski and coworkers who interpreted the results in the light of a calculation of the electrostatic potential of 7.14

A group of tricyclic ketones containing an oxy-substituent at .5a position was next examined (Table).

Treatment of methoxymethyl ketone 9 with vinyl magnesium chloride in THF afforded the same diastereofacial selectivity as the unsubstituted ketone 5. A higher selectivity was observed by addition of vinyl magnesium bromide to methoxy ketone 10 which gave a 1: 12 ratio of endo:exo isomers (entry 13).

A remarkable inversion of diastereoselectivity was observed with hydroxy ketone 11. Treatment of 11 with excess (3-4 equiv.) vinyl magnesium chloride in THF afforded almost exclusively the endo isomer (entry 17). This diastereoselectivity was also observed, albeit to a lesser extend, with vinylmagnesium bromide. The effect of the solvent was next considered. Although vinyl magnesium chloride in THF gave the highest selectivity. from

synthetic point of view, ethyl ether has been found the solvent of choice. It is worthy of note that addition of E-methyl-3-buten-l-y1 magnesium bromide [(E)-iPr-CH2=CH-MgBrl

to 11 proceeded with the same endo-facial preference of approximately 8:1 (entry 21). The isomers were separated by flash chromatography and the assignment of their stereochemistry was based on the analysis of tH

and t3C NMR spectra and confirmed by their reactivity towards oxy-Cope rearrangement. While the endo isomer rearranged to the tricyclic frame of vinigrol at 80°C in THF for 5h in the presence of KH and 1 S-crown-6. the exo isomer remained unchanged under the same conditions.ts

OH

Figure. Remote effect of the hydroxyl group

In the Figure, a model for the remote effect of the hydroxyl group is offered for consideration. In this rationalization, Grignard reagent first deprotonates the hydroxyl group, and the resulting Mg-alkoxy moiety coordinates with an other equivalent of organomagnesium reagent to deliver the nucleophile to the endo face. In this way, Mg-alkoxy group is acting as a tether for transmitting the chirality from the C-5 to C-2 position.

Although many examples of stereoselective addition to oxy-substituted aldehydes and ketones rationalized by chelation are reported, this result is. to the best of our knowledge, unprecedented.

Page 3: Unexpected effect of an hydroxyl group on π-facial selectivity in the nucleophilic addition to bicyclo[2.2.2]octan-2-ones

9473

Table. Nucleophilic addition to various tricyclic ketones

Entry Ketone Nucleophile iolvent(a’ Ratio Endo / Exe Yield’h’ Ir

I

2

3

4

5

6

I

x Y

IO II

12

13

14

IS

16

17

IX

I9

20

21

8

CH,=CH-M&Cl

CH?=CH-MgBr

CH,=CH-M&I

MeLi”’

MeMgB+<’

CH2=CH-MgBr

CH2=CH-MgCI

MeLi

CH?=CH-Li

MeMgBr

CH,=CH-MgCI

CH2=CH-C&l?

CH?=CH-MgBr

MeLi

MeMgBr

CH,=CH-MgBr

CH,=CH-MgCI

CH2=CH-MgBr

CH,=CH-MgCI

CH,=CH-MgCI

%)-it’,-CH,=CH-MgBl

Endo EXO

I I6

1 I3

5 I I

I / 4.5

3 I I

1.6 / I

I , 2.5

0 / 100

0 / 100

1 , 1.3

I I 6.7

1 I8

I I 12

I 1 4.1

2 i I 13 / ]

20 / I

7 1 I 91 I

6 1 I

8 1 1

THF

THF

,,d”’

nd”’

THF

THF

THF

THF

67

71

80

THF 65

THF

THF

THF

THF

THF

76

nd

86 78

67

THI: X6

THF

THF

THF

THF

Et,0

El?0

duene

THF

70

82

58 (76)“’

64 (X0)“’

73 (c)O)‘”

83 (93)“’

1.5

51

(a) Reactmns were carried out at 0°C. (h) Isolated yield af lash chromatography: (c) D~astereomer ratms based

on ‘H NMR integration on the mlxturc. (d) Preparation of 5 and 6 ir given in Ret. 8. (e) Ref. 14. (11 Yields m

parenthesis include the rccovcrcd material.

Page 4: Unexpected effect of an hydroxyl group on π-facial selectivity in the nucleophilic addition to bicyclo[2.2.2]octan-2-ones

9474

References and Notes

1.

2

3.

4.

5.

6.

I.

8.

9.

10. 11.

12.

13.

14.

15.

a) Ando, T.; Tsurumi, U.; Ohata, N.; Ushida, I.; Hoshida, K. and Okuhara, M. J. Antibiot. 1988, 41, 25-30. b) Ando, T.; Yoshida. K.; Okuhara, M. ibid. 31-35. Norris, D. B.; Depledge, P.; Jackson, A. P.; Xenova, Ltd. International Patent WO 91107953 (Chem. Abstr. 1991, 115, 64776h). Uchida, I.; Ando, T.; Fukami, N.; Yoshida, K.; Hashimoto, M.; Tada, T.; Koda, S. and Morimoto. Y. J. Org. Chem. 1987,52, 5292-5293. Devaux, J. F.; Hanna, I.; Lallemand, J.Y.; Prange, T. J. Org. Ckem. 1993, 58, 2349-2350. Cram, D. J.; Kopecky, K. R. 1. Am. Chem. Sot. 1959,81, 2748-2755. For a review on chelation control in addition reactions, see : Reetz, M. T. Angew. Chem. Int. Ed. Eng1.1984, 23, 556-569. Reetz, M.T. Act. Chem. Rex 1993, 26, 462-468. For selected examples on the effect of oxy-substituents on the stereoselective addition to carbonyl compounds assumed to involve chelation see: a) Chen, X.; Hortelano, E. R.; Eliel, E. L.; Frye, S. V. J. Am. Chem. Sot. 1992,114, 17781784. b) Bloch, R.; Gilbert, L. Tetrahedron Lett. 1987,28. 423-426. c) Hsieh, N. C.; Chiu, C. T.; Chang, N. C. J. Org. Chem. 1989,54, 3820-3823. d) Chang, N. C.; Day, H. M.; Lu, W. F. J. Org. Ckem. 1989, 54, 4083-4088. e) Jung, M. E.; Hudspeth, J. P. J. Am. Ckem. Sot. 1978, ZOO, 4309-4311. f) Fischer, J. C.: Horton, D.; Weckerle, W. Carbokydr. Res. 1977, 59, 459-475.

5 and 6 were prepared from the the known bicyclo[2.2.2]octandione-2,69 by monotriflation (Li(TMS)z, 1.2 equiv, HMPA, PhNTf2, THF) followed by palladium-catalyzed coupling of the resulting enol triflate with vinyltributyltin [Pd(PPh3)4, LiCI, THF, reflux] (71%). Diels-Alder cycloaddition of the resulting diene with phenyl vinyl sulphone and reduction of the crude cycloadduct with excess 6% sodium amalgam afforded 5 and 6 as a 3: 1 inseparable mixture in 69% yield. On the other hand, pure 5 was prepared from alcohol 11 by Barton deoxygenation procedure. Gerlach, H.; Mtiller, W. Angew. Ckem. Int. Ed. E&. 1972, 11, 1030-1031. Almqvist, F.; Eklunnd, L.; Frejd, T. Syntk. Commun. 1993, 23, 1499-1505. All new compounds are fully characterized by their spectroscopic and analytical data

Addition of vinylmagnesium chloride was carried out on the mixture of 5 and 6 and gave rise to a mixture of four allylic alcohols in 84% yield. Separation by flash chromatography provided the 4afi exo (50%) and 4aa endo (21%) isomers in a pure form along with a 2: 1 inseparable mixture (21%) of the 4ap endo and 4aci exo isomers. The stereochemical assignment of the allylic alcohols is supported by spectroscopic data and by their behaviour towards the oxy-Cope rearrangement. In the 1H NMR, the vinyl protons at the terminus of the allylic alcohol moiety of endo isomer appear at higher field (0.1-0.2 ppm) than the corresponding protons of exo isomer. This effect is presumably a consequence of diamagnetic shielding of these protons by the cyclohexenyl double bond. 13 Chemically, endo isomers undergo the oxy-Cope rearrangement whereas exo isomers remain unchanged under the same conditions. a) Martin, S.F.; White, J. B.; Wagner, R. J. Org. Ckem. 1982, $7, 3190-3192 ; b) Paquette. L. A.; Wei, H.; Rogers, R. D. J. Org. Ckem. 1989,54, 2291-2300. Pudzianowski, A. T.; Barrish, J.C.; Spergel, S.H. Tetrahedron L&t. 1992,33, 293-296. Details of this work are beyond the scope of this letter and will be reported in due course.

(Received in France 6 October 1995; accepted 23 October 1995)