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Synthesis 2008(18): 2841-2867  
DOI: 10.1055/s-2008-1067241
REVIEW
© Georg Thieme Verlag Stuttgart ˙ New York

Chiral Bispidines

Matthias Breuning*, Melanie Steiner
Institute of Organic Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany
Fax: +49(931)8884755; e-Mail: breuning@chemie.uni-wuerzburg.de;
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Publication History

Received 12 March 2008
Publication Date:
04 September 2008 (online)

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Abstract

Chiral bispidines are characterized by a modified 3,7-diazabicyclo[3.3.1]nonane framework. Their structural diversity is broad, reaching from simple bicyclic derivatives with chiral substituents at the nitrogen atoms to sophisticated tetracyclic ones like (-)-sparteine. This review focuses on the stereoselective preparation of chiral bispidines and on their applications in selected asymmetric transformations, thus showing the tremendous progress achieved in both areas over the last 15 years.

1 Introduction

2 Synthesis of Chiral Bispidines

2.1 Classification

2.2 Simple Bispidines with Chiral Substituents at the Nitrogen Atoms

2.3 Chiral Bicyclic Bispidines

2.4 Chiral Tricyclic Bispidines

2.5 Chiral Tetracyclic Bispidines

3 Bispidines in Enantioselective Deprotonation Reactions

3.1 N-Boc-Pyrrolidine

3.1.1 Mechanism

3.1.2 Evaluation of Chiral Diamines

3.2 N-Boc-N-PMP-Benzylamine

3.3 Comparison of (-)-Sparteine with Tricyclic Bispidines

4 Bispidine Transition-Metal Complexes in Asymmetric Synthesis

4.1 Oxidative Kinetic Resolutions

4.2 Enantioselective Additions of Diethylzinc

4.3 Other Applications

5 Concluding Remarks

Key words

chiral bispidines - asymmetric synthesis - bicyclic compounds - chiral auxiliaries - (-)-sparteine

6

To the best of our knowledge, the technical procedure for the isolation of (-)-sparteine (5) is not published. All literature available refers to the original isolation procedures (refs. 5a,b), which delivers 5 from Cytisus scoparius in 0.03 mass%.

8

According to a Beilstein search, Nov. 2007.

9

For a discussion of early applications of (-)-sparteine (5) in asymmetric synthesis, see ref. 42a.

17

It should be noted that most of the allyllithium compounds known are configurationally labile at -78 ˚C; see, inter alia, refs. 42a,b,f.

41

(-)-Sparteine (5) is commercially available, as the free base or as the sulfate pentahydrate, from, for example, Sigma-Aldrich, ABCR, Acros, and TCI.

51

Bispidines with chiral side chains prepared for pharma-ceutical purposes are not included.

59

For the preparation of ent-52a, see ref. 61.

88

The C 2-symmetric epimer of (-)-sparteine (5) with two exo-annelated piperidine rings, (-)-β-isosparteine, also known as l-spartalupine and pusilline, has not been used as a chiral auxiliary in asymmetric synthesis until now.

94

Although of no synthetic importance, (-)-sparteine (5) can be obtained analogously from rac-lupanine (rac-147) by resolution with l-CSA and reduction.9³

100

The cyclization of 141 to 142 or ent-142 was later improved to 68% yield by changing the solvent from EtOH to DMF, see Scheme  [²7] and ref. 85. Adaptation of this protocol would raise the overall yield from 9% to 14%.

101

For a comparison of 8 vs. 5, see refs. 4 and 45.

121

The high configurational stability of α-lithio N-Boc-pyrrolidine is also obvious from the following experiment: (S)-tributylstannyl N-Boc-pyrrolidine (96% ee), subjected to a tin-lithium exchange using s-BuLi or s-BuLi-TMEDA, gives, after electrophilic trapping with TMSCl, 12 in 93% ee (15% yield) or 74% ee (36% yield), respectively; see ref. 15.

125

The original experiment by Lesma et al.48 was performed with 134 leading to 12.

126

Deprotonation of 11 with 1.3 equivalents of 8-s-BuLi and 1.3 equivalents of 5-s-BuLi gave, after trapping with TMSCl, ent-12 in 80% ee, thus indicating that 8 is about ten times more reactive than 5, see ref. 29.

127

It should be noted that diminished enantioselectivities in reactions with low conversions might be a consequence of competing deprotonation processes with low stereocontrol that are mediated by other unknown diamine-RLi adducts, which are not of importance if the ‘correct’ diamine-RLi adduct possesses a decent reactivity.

128

The original experiment by Kozlowski et al.64 was performed with 78 leading to ent-12.

129

Breuning, M.; Steiner, M. unpublished results.

130

In should be mentioned that the formation of prelithiation complexes between the ligand 131e, s-BuLi, and other substrates is very probable, since 131e gives acceptable to good yields and enantioselectivities in the deprotonation of the O-alkyl carbamate 179 and the phosphine boranes 17, 181, and 182 (see Section 3.3).

131

Amongst others, the Li+ complexes of the following diamines have been used: 5, ent-8, 78, ent-134, 148 (see Figure  [³] ), ent-36, ent-53, ent-64 (see Figure  [5] ), 166, 175, 176a, 176c, and ent-176b (see Figure  [7] ).

139

Enantioselective deprotonations of O-alkyl carbamates were widely investigated by Hoppe and co-workers; see refs. 11a-d,f and 124.

140

For quantum chemical calculations on the deprotonation of O-alkyl carbamates, see the end of Section 3.1.1 and ref. 124.

144

For the use of other electrophiles, see, inter alia, refs. 12 and 13.