[81925-09-9]  · C12H20O2  · [(2S)-(2a,3aa,4a,7a,7aa)]-2,3,3a,4,5,6,7,7a-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-ol  · (MW 196.32) (enantiomer)

[108031-75-0] (2S) acetal dimer (1)

[87248-50-8]  · C24H38O3  · [(2S)-(2a,3aa,4a,7a,7aa)]-2,3,3a,4,5,6,7,7a-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-ol Acetal Dimer  · (MW 374.62) (enantiomeric acetal dimer)


(useful for resolving racemic alcohols via formation of diastereomeric acetals,1 and also for determining the absolute configuration of certain types of chiral alcohols2)

Alternate Name: MBF-OH.

Physical Data: monomeric lactol: bp 120 °C/0.005 mmHg, [a]20D + 100° (c, 11.24, THF); acetal dimer: mp 150-151 °C, [a]21 + 199.1° (c, 2.25, THF).

Solubility: monomeric lactol: sol ether, CHCl3, THF; acetal dimer: sol CHCl3, THF, hot petroleum ether.

Form Supplied in: the acetal dimer, and its enantiomer, are available as the neat solids.

Analysis of Reagent Purity: NMR,3 mp.

Preparative Methods: the [(2S)-(2a,3aa,4a,7a,7aa)]-isomer is prepared from (+)-camphor,3a and the (2R)-enantiomer from (-)-borneol via oxidation to (-)-camphor.3b

Purification: the monomeric lactols can be purified by distillation, and the acetal dimers by recrystallization from petroleum ether.

Handling, Storage, and Precautions: no reported instability or toxicity.

Resolving Agent for Chiral Alcohols.

The title lactol reagent (known as the Noe reagent) has been used mainly for resolving racemic alcohols through formation of diastereomeric, separable acetals.1 From each alcohol enantiomer, a single diastereomer of the product acetal is formed with high selectivity. Separation of the diastereomeric derivatives by chromatography or crystallization, followed by mild methanolysis, gives the resolved alcohol in good yield and high enantiomeric purity. If an excess of the racemic alcohol is employed, enantiomer-selective acetal formation results in one of the product diastereomers being produced in excess, which increases the yield of pure diastereomer obtained (eq 1).4

The commercially available acetal dimer (1), and the enantiomeric dimer, can also be used as reagents instead of the lactols.1 As an alternative to the (2R)-enantiomer of the endo-lactol, one can use the exo-lactol (2), or the corresponding acetal dimer.5 Compound (2) is prepared from (+)-camphor, as is the (2S)-enantiomer of the endo-lactol, but the two reagents show opposite sense of enantiomer selectivity in acetal formation.

Using these reagents, resolutions of various types of racemic alcohols, including alkylarylcarbinols,1 alkylthienylcarbinols,6 cyanohydrins,1,7 a-hydroxyalkynes,2b and a-hydroxyphosphonates,8 and also of a thiol1 and an amine,1 have been performed.

An alternative procedure has been reported for the resolution of alcohols through separation of diastereomeric O-methylmandelates;9 a drawback of this approach is that partial racemization of the mandelic acid derivative sometimes occurs during the esterification. In contrast, the Noe reagents are configurationally stable; also, complete separation of the derived diastereomeric acetals can usually be achieved, which gives access to enantiomerically pure alcohols when the selectivity of the acetal formation is low. An additional advantage of the title reagents is that the derived acetal can be used as an ordinary hydroxyl-protecting group in subsequent synthetic operations, with a reactivity similar to a THP group.7,10 Of other alternative methods for resolution of racemic alcohols, kinetic resolutions by enzyme-catalyzed transformations often give very high selectivities.11

Determination of Absolute Configuration for Chiral Alcohols.

Using NMR data for the derived acetals, in combination with the known sense of enantiomer selectivity for the Noe reagent used, one can also determine the absolute configuration of the starting alcohol.2 Gas chromatography data can be used as well.2c This method for determining absolute configuration should be a useful complement to the more commonly used methods based on NMR analysis of Mosher esters12 or O-methylmandelates.9

1. Noe, C. R. CB 1982, 115, 1591.
2. (a) Noe, C. R.; Knollmüller, M.; Wagner, E.; Völlenkle, H. CB 1985, 118, 1733. (b) Noe, C. R.; Knollmüller, M.; Oberhauser, B.; Steinbauer, G.; Wagner, E. CB 1986, 119, 729. (c) Schönauer, K. J.; Walter, P.; Noe, C. R. M 1986, 117, 127.
3. (a) Noe, C. R. CB 1982, 115, 1576. (b) Noe, C. R.; Knollmüller, M.; Göstl, G.; Oberhauser, B.; Völlenkle, H. AG(E) 1987, 26, 442.
4. Knollmüller, M.; Noe, C. R.; Steinbauer, G.; Dungler, K. S 1986, 501.
5. Noe, C. R.; Knollmüller, M.; Steinbauer, G.; Jangg, E.; Völlenkle, H. CB 1988, 121, 1231.
6. Noe, C. R.; Knollmüller, M.; Dungler, K.; Miculka, C.; Gärtner, P. M 1991, 122, 705.
7. Noe, C. R.; Knollmüller, M.; Göstl, G.; Gärtner, P. M 1991, 122, 283.
8. Hammerschmidt, F.; Völlenkle, H. LA 1989, 577.
9. Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.; Balkovec, J. M. JOC 1986, 51, 2370.
10. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis 2nd ed.; Wiley: New York, 1991; pp 37-38.
11. (a) Santaniello, E.; Ferraboschi, P.; Grisenti, P.; Manzocchi, A. CRV 1992, 92, 1071. (b) Frykman, H.; &OOuml;hrner, N.; Norin, T.; Hult, K. TL 1993, 34, 1367.
12. (a) Dale, J. A.; Mosher, H. S. JACS 1973, 95, 512. (b) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. JACS 1991, 113, 4092.

Tobias Rein

The Royal Institute of Technology, Stockholm, Sweden

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