10-Dicyclohexylsulfonamidoisoborneol1

(1S)-exo; R = cyclohexyl

[96303-88-7]  · C22H39NO3S  · 10-Dicyclohexylsulfonamidoisoborneol  · (MW 397.69) (1S)-exo; R = isopropyl

[89156-11-6]  · C16H31NO3S  · 10-Diisopropylsulfonamidoisoborneol  · (MW 317.55)

(chiral auxiliary: enoate derivatives undergo stereoselective Diels-Alder2,3 and 1,3-dipolar3 cycloadditions and 1,4-cuprate additions;4 enol ether derivatives undergo stereoselective [2 + 2] cycloadditions with dichloroketene;5 ester enolate derivatives participate in stereoselective imine condensation,6 alkylation,4a aldolization,7 acetoxylation,8 halogenation,9 and amination10 reactions)

Physical Data: R = cyclohexyl: mp (from hexane) 163-164 °C; [a]21D -25.7 (c = 0.76, EtOH). R = isopropyl: mp (from hexane) 102-103 °C; [a]21D -34.4 (c = 4.74, EtOH).

Form Supplied in: white crystalline solids.

Preparative Methods: crystalline, enantiomerically pure 10-diisopropyl- and 10-dicyclohexylsulfonamidoisoborneol auxiliaries are readily prepared from the appropriate enantiomer of 10-Camphorsulfonyl Chloride by successive amidation and exo selective reduction (eq 1).2

Simple acyl derivatives are prepared in good yields from carboxylic acids using Mukaiyama's 2-Chloro-1-methylpyridinium Iodide coupling reagent2 or from carboxylic acid chlorides using Silver(I) Cyanide.9a The former method is also suitable for the preparation of enoyl derivatives, although a Horner-Wadsworth-Emmons reaction has also been employed for this purpose.4b The cis-propenyl enol ether derivative of 10-diisopropylsulfonamidoisoborneol was prepared by base-promoted isomerization of the corresponding allyl ether (the preparation of which was not described).5

Handling, Storage, and Precautions: these reagents are stable indefinitely at ambient temperature in sealed containers.

Introduction.

The 10-dialkylsulfonamidoisoborneol auxiliaries exert a powerful topological bias over the p-facial reactivity of enoate, enol ether, and ester enolate derivatives in a wide range of asymmetric transformations. However, the subsequently developed 10,2-Camphorsultam chiral auxiliary outperforms these auxiliaries both in terms of stereoinduction and ease of nondestructive cleavage for most applications. Consequently, only transformations for which the 10-dialkylsulfonamidoisoborneol auxiliaries are particularly advantageous, or for which the analogous transformations of the 10,2-camphorsultam have not been reported, are described here. It should be noted, however, that the origin of the stereoinduction provided by these two camphor-derived auxiliaries is fundamentally different;1 hence key references for all transformations are provided above.

Reactions of Enoate, Enol Ether, and Acyl Derivatives.

1,4-Organocopper Addition (Alkene to b-Functionalized Product).4

Tri-n-butylphosphine-stabilized organocopper reagents add in a conjugate fashion to trans-enoate derivatives of the 10-dicyclohexylsulfonamidoisoborneol auxiliary from the less hindered C(a)-si p-face with excellent selectivity (eq 2) (Table 1). This type of reaction has formed the basis of several natural product syntheses.4

[2 + 2] Dichloroketene Addition (Enol Ether to b-Alkoxy-a-dichlorocyclobutanone).5

Of six different chiral auxiliaries screened for their ability to control stereochemistry in the reaction of dichloroketene with derived cis-propenyl enol ethers, the 10-diisopropylsulfonamidoisoborneol auxiliary was the best. Thus, following ring expansion of the initially formed cyclobutanone (4) with Diazomethane-Chromium(II) Perchlorate, a-chloro-g-methylcyclopentenone was isolated in ~60% yield and 80% ee [C(a)-si face attack of the ketene] (eq 3). The auxiliary was also recovered in unspecified yield.

Imine Condensation (Acyl Species to b-Lactam).6

Lithium enolates of acyl 10-diisopropylsulfonamidoisoborneols condense with N-aryl aldimines to give cis-disubstituted b-lactams with 56-92% ee, accompanied by 2.5-9% of their trans isomers (in undetermined ee) (eq 4) (the key step in a synthesis of the carbapenem antibiotic (+)-PS-5). Menthol was found to be a less efficient auxiliary for this application.6

a-Acetoxylation and a-Halogenation (Acyl Species to a-Acetoxy or a-Halo Acyl Product).8,9

a-Acetoxylations of O-silyl enol ether derivatives of acyl 10-dicyclohexylsulfonamidoisoborneols with Lead(IV) Acetate proceed in high yield with excellent p-facial stereocontrol (95-100% de, with C(a)-re topicity).8 Mechanistically related a-halogenations with N-halosuccinimides also proceed smoothly to afford a-halo acyl products in 76-96% de, but with C(a)-si topicity.9 The observed topicities are consistent with initial attack of the electrophilic species from the less hindered C(a)-si face to give transient plumbonium/bromonium/chloronium ions. The plumbonium intermediates undergo SN2-type attack by acetate at the b-position, whereas the bromonium/chloronium intermediates fragment with retention at C(b).9a The stereofacial influence of the auxiliary overrides any preexisting b-stereocenter. Hence, consecutive alkylcopper conjugate addition, then a-acetoxylation or a-bromination, allows the concise and stereocontrolled formation of two contiguous stereocenters. a-Acetoxy ester derivative (6) formed in this way is a precursor to a key intermediate for the synthesis of the elm bark beetle pheromone (eq 5), and a-bromo ester derivative (7) was converted via azide displacement, trans- esterification, and hydrogenolysis into L-allo-isoleucine (eq 6).9b a-Halo esters are also useful precursors of enantiomerically pure epoxides.9a

a-Amination (Acyl Species to a-Amino Acyl Product).10

Although asymmetric bromination and stereospecific azide displacement of O-silyl enol ethers of acyl 10-dicyclohexylsulfonamidoisoborneols (as described above) is a generally applicable route to optically active a-amino acids,9b a complementary and more direct approach to this important class of compounds is via electrophilic amination of these same compounds using Di-t-butyl Azodicarboxylate (DBAD). The initially formed a-(di-N-Boc-hydrazido)amino acid derivatives (8) (eq 7) may be efficiently converted to the corresponding a-amino acid hydrochlorides by successive deacylation, hydrogenolysis, transesterification, and hydrolysis. This reaction sequence has been shown to be efficient for the preparation of a wide range of a-amino acids in excellent enantiomeric purity10 and compares favorably with closely related methods using alternative auxiliaries.11

Nondestructive Auxiliary Cleavage.

The hindered ester linkage present in acyl derivatives of 10-dialkylsulfonamidoisoborneols is less readily cleaved than the corresponding sulfonamidic linkage of N-acyl-10,2-camphorsultam derivatives. However, it can be hydrolyzed and the auxiliary recovered intact under basic conditions using Potassium Hydroxide7 or Potassium Carbonate8 in MeOH, Sodium Hydroxide in aq EtOH,4a or Lithium Hydroxide in aq THF. Elevated temperatures are required to achieve acceptable reaction rates for all but the latter procedure which, although sluggish at ambient temperature, was employed for unmasking sensitive aldol products.7 Nonbasic transesterification using Ti(OBn)4/BnOH affords benzyl esters which may be subject to hydrogenolysis to give the corresponding carboxylic acids.9b Alternatively, transesterification with Ti(OEt)4/EtOH10b may be followed by hydrolysis under acidic conditions.10

Primary alcohols can be obtained by hydride reduction using either Lithium Aluminum Hydride in ether2,8 or Ca(BH4)2 in THF,9a and this latter reagent is compatible with halogen functionality. A dimethyl tertiary alcohol was obtained by addition of 2 equiv of methyllithium in ether.4b

Related Reagents.

a-Methyltoluene-2,a-sultam.


1. Oppolzer, W. T 1987, 43, 1969.
2. Oppolzer, W.; Chapuis, C.; Bernardinelli, G. TL 1984, 25, 5885.
3. Curran, D. P.; Kim, B. H.; Piyasena, H. P.; Loncharich, R. J.; Houk, K. N. JOC 1987, 52, 2137.
4. (a) Oppolzer, W.; Dudfield, P.; Stevenson, T.; Godel, T. HCA 1985, 68, 212. (b) Oppolzer, W.; Moretti, R.; Bernardinelli, G. TL 1986, 27, 4713.
5. Greene, A. E.; Charbonnier, F. TL 1985, 26, 5525.
6. Hart, D. J.; Lee, C.-S.; Pirkle, W. H.; Hyon, M. H.; Tsipouras, A. JACS 1986, 108, 6054.
7. Oppolzer, W.; Marco-Contelles, J. HCA 1986, 69, 1699.
8. Oppolzer, W.; Dudfield, P. HCA 1985, 68, 216.
9. (a) Oppolzer, W.; Dudfield, P. TL 1985, 26, 5037. (b) Oppolzer, W.; Pedrosa, R.; Moretti, R. TL 1986, 27, 831.
10. (a) Oppolzer, W. In Chirality in Drug Design and Synthesis, Academic: New York, 1990. (b) Oppolzer, W.; Moretti, R. HCA 1986, 69, 1923. (c) Oppolzer, W.; Moretti, R. T 1988, 44, 5541.
11. (a) Gennari, C.; Colombo, L.; Bertolini, G. JACS 1986, 108, 6394. (b) Evans, D. A.; Britton, T. C.; Dorow, R. L.; Dellaria, J. F. JACS 1986, 108, 6395. (c) Evans, D. A.; Britton, T. C.; Dorow, R. L.; Dellaria, J. F. T 1988, 44, 5525. (d) Trimble, L. A.; Vederas, J. C. JACS 1986, 108, 6397.

Alan C. Spivey

University of Cambridge, UK



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