3-Hydroxyisoborneol1

(1; R1 = neopentyl, R2 = H) (1R,exo,exo)

[85695-96-1]  · C15H28O2  · 3-Hydroxyisoborneol 2-Neopentyl Ether  · (MW 240.43) (2; R1 = neopentyl, R2 = H) (1S,exo,exo)

[85718-76-9]  · C15H28O2  · 3-Hydroxyisoborneol  · (MW 240.43) (3; R1 = H, R2 = neopentyl) (1R,exo,exo)

[85695-92-7]  · C15H28O2  · 3-Hydroxyisoborneol  · (MW 240.43) (4; R1 = benzyl, R2 = H) (1R,exo,exo)

[104154-98-5]  · C17H24O2  · 3-Hydroxyisoborneol 2-Benzyl Ether  · (MW 260.41) (5; R1 = H, R2 = benzyl) (1R,exo,exo)

[73440-88-7]  · C17H24O2  · 3-Hydroxyisoborneol  · (MW 260.41) (6; R1 = Ph2CH, R2 = H) (1R,exo,exo)

[85695-93-8]  · C23H28O2  · 3-Hydroxyisoborneol 2-Benzhydryl Ether  · (MW 336.51) (7; R1 = 1-naphthylmethyl, R2 = H) (1R,exo,exo)

[85695-95-0]  · C21H26O2  · 3-Hydroxyisoborneol 1-Naphthylmethyl Ether  · (MW 310.47) (8; R1 = 2-naphthylmethyl, R2 = H) (1R,exo,exo)

[85695-94-9]  · C21H26O2  · 3-Hydroxyisoborneol 2-Naphthylmethyl Ether  · (MW 310.47)

(chiral auxiliary; acrylate2 and acyl nitroso3 derivatives undergo stereoselective [4 + 2] cycloadditions; enoate derivatives undergo stereoselective 1,4-conjugate additions of organocopper reagents;4 enol ether derivatives undergo stereoselective Pauson-Khand cyclizations,5 [4 + 2]6 and [2 + 2]7 cycloadditions; alkynyl ether derivatives undergo stereoselective Pauson-Khand cyclizations5)

Alternate Name: 1,7,7-trimethylbicyclo[2.2.1]heptane-2,3-diol.

Physical Data: (1) mp 4-5 °C; [a]25D (EtOH) -42.4° (c = 1.40). (2) mp 4-5 °C; [a]25D (EtOH) +42.6° (c = 2.52). (3) oil; [a]25D (EtOH) -18.8° (c = 1.08). (4) oil; bp 130 °C/0.05 mmHg; [a]25D (CHCl3) -36.1° (c = 1.44). (5) mp 43 °C; [a]25D (EtOH) +0.4° (c = 4.99). (6) mp 57 °C; [a]25D (EtOH) -107.6° (c = 1.70). (7) mp 69-70 °C; [a]25D (EtOH) -79.2° (c = 0.90). (8) mp 70-71 °C; [a]25D (EtOH) -61.5° (c = 0.57).

Preparative Methods: the 3-hydroxyisoborneol derivatives are readily prepared from (+)- or (-)-camphor. The preparation of the 2-neopentyl ether derivative (1) is representative (eq 1).2b Analogous alkylation with different electrophiles allows for easy variation of the shielding moiety.2c,8 The corresponding 3-substituted derivatives have been prepared from either 3-hydroxyisoborneol after separation of the regioisomeric mixture or from 3-exo-hydroxycamphor regioselectively after reduction with Lithium Tri-s-butylborohydride (L-Selectride).2c,9

Handling, Storage, and Precautions: these auxiliaries vary from oils to white crystalline solids depending on the ether substituent and are stable indefinitely at ambient temperatures in sealed containers.

Introduction.

The abundance of (+)-camphor in the chiral pool provided Oppolzer with an excellent framework to develop a chiral auxiliary which provides high levels of stereoselectivity in a wide range of reaction classes. The 3-hydroxyisoborneol skeleton provides two derivatizable positions at C-2 and C-3 of the molecule which are in close proximity to each other. By appending a reactive functionality to one and a sterically shielding appendage to the other, high stereodirecting ability can be envisioned. Likewise by reversing the roles of C-2 and C-3 it is possible to tune the auxiliary to fit the reaction parameters and desired product configuration. These characteristics have provided a means for p-facial differentiation to acrylates, enol ethers, and alkynyl ethers.

Preparation of Derivatives.

Enoate derivatives are prepared from the corresponding chiral alcohol by treatment with acryloyl chloride in the presence of Triethylamine and catalytic 4-Dimethylaminopyridine or the appropriate carboxylic acid chloride and Silver(I) Cyanide.2b Alkynyl ethers are readily available from the potassium alkoxide by treating with Trichloroethylene, in situ dechlorination with n-Butyllithium, and electrophilic trapping.10 Trapping the intermediate anion with a proton source or Iodomethane followed by Lindlar reduction of the alkynyl ether affords the corresponding vinyl and 1-(Z)-propenyl ether, respectively, while reduction of the alkynyl ether with Lithium Aluminum Hydride affords the 1-(E)-propenyl ether.

[4 + 2] Cycloadditions of Acrylate Derivatives.2

Acrylate derivatives undergo highly stereoselective Diels-Alder cycloadditions with 1,3-dienes when promoted by a Lewis acid, Dichlorotitanium Diisopropoxide or Titanium(IV) Chloride (eq 2). With the latter, care must be taken to avoid acid mediated cleavage of the auxiliary ether linkage. Generally, 2-substituted auxiliaries (10) show higher facial and endo selectivity than the corresponding 3-substituted analogs. This has been rationalized by a buttressing effect caused by the C-10 methyl forcing the ether side chain into close proximity to the acrylate. Of the range of shielding moieties examined, the neopentyl ether was shown to provide the highest selectivity. The stereochemical outcome can be explained by assuming that the acrylate adopts an s-trans conformation on coordination of the Lewis acid11 and that the diene approaches from the face opposite the neopentyl ether. It should be noted that the analogous cycloadditions with crotonate derivatives give ve ry poor yields (<7%).2b Similar highly stereoselective Diels-Alder cycloadditions have also been reported for fumarate and allenic ester derivatives.12

[4 + 2] Cycloadditions of Enol Ether Derivatives.6

Asymmetric, inverse electron demand Diels-Alder reactions between nitroalkenes and alcohol (1)-derived vinyl and 1-(E)- and 1-(Z)-propenyl ethers have been reported to proceed with high stereoselectivity (eq 3). The resulting cycloadducts undergo an intramolecular [3 + 2] cycloaddition at rt to afford nitroso acetals which, after hydrogenolytic cleavage, provide tricyclic a-hydroxy lactams in high enantiomeric excess. The auxiliary alcohol can be recovered in 86-92% yield. The overall sense of asymmetric induction is dependent on the Lewis acid promoter employed, either Ti(O-i-Pr)2Cl2 or Methylaluminum Bis(2,6-diphenylphenoxide) (MAPh).6b This has been rationalized by a switch from a highly endo selective cycloaddition with Ti(O-i-Pr)2Cl2 to a highly exo selective cyclization with MAPh. When promoted by Ti(O-i-Pr)2Cl2 the corresponding 1-(E)-propenyl ether shows exclusive endo selectivity and 99% facial selectivity; however, facial selectivity for the 1-(Z)-propenyl ether is only 50%.

[4 + 2] Cycloadditions of Acyl Nitroso Derivatives.3

In situ formation of the acyl nitroso derivative by oxidation of the hydroxy carbamic acid under Swern-Moffat conditions in the presence of a functionalized diene affords the corresponding cycloadduct in 94% yield and 96% diastereomeric excess (eq 4). The resulting cycloadduct can be further elaborated to prepare optically active functionalized amino alcohols.

1,4-Conjugate Additions of Enoate Derivatives.4

Boron trifluoride-mediated conjugate additions of organocopper reagents to (E)-enoates derived from auxiliary (1) proceed with high stereoselectivity, affording optically active carboxylic acids after saponification (eq 5). The organocopper reagent is formed by addition of an alkyllithium reagent to Copper(I) Iodide, Tri-n-butylphosphine, and Boron Trifluoride Etherate in equimolar amounts, where Bu3P is believed to stabilize the reagent. The overall sense of asymmetric induction can be controlled by changing either the order of substituent introduction (R1 and R2) or the configuration of the auxiliary. The stereochemical course of the reaction has been rationalized by assuming that the enoate exists in an s-trans conformation and the organocopper reagent approaches from the face opposite to the neopentyl ether. Conjugate additions of this type have been applied to the total synthesis of several natural products.

Pauson-Khand Bicyclization.5

Alkynyl and enol ether derivatives have been studied in the cobalt mediated intramolecular Pauson-Khand reaction and found to provide high diastereoselectivity, superior to previous work with the auxiliary 2-phenylcyclohexanol.13 The 3-substituted auxiliary alcohol (3) provides higher selectivity than the 2-substituted analog. Also, the alkynyl ether derivatives exhibit higher reactivity and selectivity than the corresponding enol ether derivatives (eq 6).

Photochemical [2 + 2] Cycloadditions.7

Photochemical [2 + 2] cycloadditions between alkenes and chiral phenylglyoxylate derivatives of 3-hydroxyisoborneol show minimal diastereoselectivity (16% de).14 Better results are obtained in [2 + 2] cycloadditions between chiral enol ethers and Dichloroketene (eq 7). After ring expansion and expulsion of the auxiliary (Diazomethane, Chromium(II) Perchlorate), chiral a-chlorocyclopentenones are obtained in 60% yield. The observed diastereoselectivity is believed to arise from the enol ether s-trans conformation and approach of the ketene to the face opposite to the neopentyl ether.

Nondestructive Auxiliary Cleavage.

The high stability of the ether linkage to the shielding moiety generally allows for a very high recovery of the auxiliary alcohol. For acyl derivatives, primary alcohols can be obtained by LiAlH42b or AlH315 reduction. Hydrolysis of the auxiliary under basic conditions providing the carboxylic acid has been accomplished with NaOH in aq. ethanol,3 NaOH in methanol,4b or KOH in ethanol.16 Intramolecular transesterification has been applied using KO-t-Bu in THF.17 Enol ethers derived from Pauson-Khand cyclizations of alkynyl ether derivatives can be readily cleaved to the corresponding ketone and recovered auxiliary by catalytic HCl in methanol.5

Related Reagents.

10,2-Camphorsultam; 10-Dicyclohexylsulfonamidoisoborneol; (S)-Ethyl Lactate; a-Methyltoluene-2,a-sultam; (R)-Pantolactone.


1. Oppolzer, W. T 1987, 43, 1969.
2. (a) Oppolzer, W. AG(E) 1984, 23, 876. (b) Oppolzer, W.; Chapuis, C.; Dupuis, D.; Guo, M. HCA 1985, 68, 2100. (c) Oppolzer, W.; Chapuis, C.; Dao, G. M.; Reichlin, D.; Godel, T. TL 1982, 23, 4781.
3. Martin, S. F.; Hartmann, M.; Josey, J. A. TL 1992, 33, 3583.
4. (a) Rossiter, B. E.; Swingle, N. M. CRV 1992, 92, 771. (b) Oppolzer, W.; Moretti, R.; Godel, T.; Meunier, A.; Löher, H. TL 1983, 24, 4971.
5. Verdaguer, X.; Moyano, A.; Pericàs, M. A.; Riera, A.; Greene, A. E.; Piniella, J. F.; Alvarez-Larena, A. JOM 1992, 433, 305.
6. (a) Denmark, S. E.; Senanayake, C. B. W.; Ho G.-H. T 1990, 46, 4857. (b) Denmark, S. E.; Schnute, M. E.; Senanayake, C. B. W. JOC 1993, 58, 1859.
7. Greene, A. E.; Charbonnier, F. TL 1985, 26, 5525.
8. Herzog, H.; Scharf, H.-D. S 1986, 788.
9. (a) Oppolzer, W.; Kurth, M.; Reichlin, D.; Chapuis, C.; Mohnhaupt, M.; Moffatt, F. HCA 1981, 64, 2802. (b) Sasaki, S.; Kawasaki, M.; Koga, K. CPB 1985, 33, 4247.
10. Moyano, A.; Charbonnier, F.; Greene, A. E. JOC 1987, 52, 2919.
11. Loncharich, R. J.; Schwartz, T. R.; Houk, K. N. JACS 1987, 109, 14.
12. (a) Helmchen, G.; Schmieres, R. AG(E) 1981, 20, 205. (b) Oppolzer, W.; Chapuis, C. TL 1985, 24, 4665.
13. Castro, J.; Sörensen, H.; Riera, A.; Morin, C.; Moyano, A.; Pericàs, M. A.; Greene, A. E. JACS 1990, 112, 9388.
14. Herzog, H.; Koch, H.; Scharf, H.-D.; Runsink, J. T 1986, 42, 3547.
15. Oppolzer, W.; Pitteloud, R.; Bernardinelli, G.; Baettig, K. TL 1983, 24, 4975.
16. Cativiela, C.; López, P.; Mayoral, J. A. TA 1991, 2, 449.
17. Remiszewski, S. W.; Yang, J.; Weinreb, S. M. TL 1986, 27, 1853.

Mark E. Schnute

Stanford University, CA, USA



Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.