Atropo-enantioselective reduction of configurationally unstable biaryl lactones with BINAL-H1

Article abstract of DOI:10.1016/S0957-4166(98)00503-5

The atropo-enantioselective reduction of configurationally unstable biaryl lactones with BINAL-H yields axially chiral biaryl alcohols in high enantiomeric ratios of up to 94:6 (er >99.5:0.5 after one crystallization step). Within this two-step reduction

Full text of DOI:10.1016/S0957-4166(98)00503-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 385–390
Atropo-enantioselective reduction of configurationally unstable
biaryl lactones with BINAL-H1
Gerhard Bringmann ∗ and Matthias Breuning
Institut für Organische Chemie, Universität Würzburg, Am Hubland, D-97074 Würzburg, Germany
Received 26 November 1998; accepted 15 December 1998
Abstract
The atropo-enantioselective reduction of configurationally unstable biaryl lactones with BINAL-H yields axially
chiral biaryl alcohols in high enantiomeric ratios of up to 94:6 (er >99.5:0.5 after one crystallization step). Within
this two-step reduction process the stereochemically deciding step is the first attack on the lactones and not the
reduction of the likewise configurationally unstable biaryl lactol/hydroxy aldehyde intermediates, as evident from
the non-stereoselective reduction of the latter under the same conditions. © 1999 Elsevier Science Ltd. All rights
reserved.
1. Introduction
Given the increasing importance of axially chiral biaryls both for biologically active natural products
and useful reagents for asymmetric synthesis, the availability of efficient and reliable methods for the
regio- and stereocontrolled biaryl coupling is an urgent demand.2 A versatile novel solution to this
problem is offered by the ‘biaryl lactone concept’ (Scheme 1).3,4 Configurationally unstable model biaryl
lactones like 2, which are easily built up by PdII-catalyzed intramolecular coupling of the esters 1,5 can
be ring-opened to axially chiral biaryls by reduction (e.g. to 4-A),6–8 alcoholysis,3,4,9,10 or aminolysis3,4,9
in good to excellent optical and chemical yields. This useful principle has been applied successfully to
the synthesis of numerous biaryl natural products11,12 and chiral auxiliaries.13
The key step in this process is the dynamic kinetic resolution of the helically distorted and thus
chiral, but rapidly interconverting lactones 2-Az2-B.†3 Particularly high enantiomeric ratios (er) of
up to 98.5:1.5 have been obtained in the CBS-reduction of 2 with borane activated by Corey’s14
oxazaborolidine 3, giving the diols 4-A in high enantiomeric purities.6,8 In an early screening for H-
nucleophiles for the asymmetric ring cleavage of the lactones 2, Noyori’s BINAL-H15 initially seemed
∗
†
Corresponding author. Tel: +49-931-888-5323; fax: +49-931-888-4755; e-mail: bringman@chemie.uni-wuerzburg.de
In order to avoid different M/P-descriptors for stereochemically analogous biaryls that just differ by the residue R, a
substituent-invariant A/B-denotion (A=P for R=Me and A=M for R=OMe and vice versa for B) is used in this paper instead.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00503-5

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G. Bringmann, M. Breuning / Tetrahedron: Asymmetry 10 (1999) 385–390
Scheme 1. Synthesis and atropo-selective ring opening of the configurationally unstable lactones 2
to be inferior to other reagents.7 Nonetheless, in view of the excellent results with other nucleophiles
meanwhile achieved3,12,13 and the sometimes low isolated yields in the application of the CBS-reduction
to alkaloid syntheses,12 we have looked at the BINAL-H reductions more closely. We now report on
the efficient atropo-enantioselective BINAL-H reduction of 2 and on new mechanistic aspects of the
introduction of the stereochemical information within this intriguing ring opening process.
2. Results and discussion
2.1. Atropo-enantioselective BINAL-H reduction of the biaryl lactones 2
The stereoselective reductions of 2a and 2b with BINAL-H (5) were performed in THF giving the
alcohols 4a-B and 4b-B respectively, as the main enantiomers (Scheme 2 and Table 1). This nicely
complements the tendency of the L-proline derived oxazaborolidines 3 to deliver 4-A6,8 — which now
can likewise be attained by reduction of 2 with ent-5. For the dimethyl lactone 2b, the good B:A ratio of
86:14, as achieved at 20°C (entry 1), was further improved by lowering the reaction temperature to −35°C
(er 89:11, entry 2). The best asymmetric induction (er 94:6) was attained with the dimethoxy compound
2a (entry 3). For both alcohols 4a and 4b, the isolated chemical yields (91% and 94%, respectively) were
high.
Scheme 2. Atropo-enantioselective reductions of the lactones 2 with BINAL-H (5)
The enantiomerically enriched alcohols 4-B can be easily transformed into virtually enantiopure
material (er >99.5:0.5), by fractionated crystallization6,8 from petroleum ether:diethyl ether. Thus, within
the lactone concept, the BINAL-H reductions of 2 open a worthy new access to axially chiral biaryl
alcohols 4. Additionally, either by changing the chiral reductant [oxazaborolidine 3/BH36,8 vs BINAL-H
(5)], or by varying its configuration (e.g. 5 vs ent-5), both enantiomers of 4 are easily accessible from
the same lactone precursor 2 — an efficient atropo-enantiodivergent reaction principle. The application

G. Bringmann, M. Breuning / Tetrahedron: Asymmetry 10 (1999) 385–390
387
Table 1
Stereocontrolled ring cleavage of 2 with BINAL-H (5)
of this stereocontrolled BINAL-H reduction to the atropisomer-selective synthesis of axially chiral biaryl
natural products is currently under investigation.
2.2. On the stereochemically deciding step of the BINAL-H reduction
The atropo-enantioselective reduction of lactones 2 involves two reductive steps. As for other ste-
reocontrolled ring cleavage reactions, in particular with O- and N-nucleophiles,3,4,9,10 and as suggested
by quantum chemical calculations,16,17 it is assumed that — in the sense of a dynamic kinetic resolu-
tion — the chiral hydride transfer reagent attacks 2-B exclusively, i.e. only one of the two interconver-
ting helimeric forms 2-Az2-B (for a simplified reaction course, see Scheme 3). This presumably16,17
axial attack should give rise to the initial formation of the lactolate 6-B only. If 6-B bursts open
immediately, it should specifically give 7-B, whose further reduction (and hydrolysis) would lead to
4-B, with full conservation of the chirality information at the axis. There is, however, the risk of a
significant loss of that stereoinformation (the ‘stereochemical leakage’3,4,8) by the experimentally8,18,19
and quantumchemically17,20 known configurational instability of lactols of type 6-B8 (and related
compounds18,19): like the lactones 2 themselves,3–5 the lactols are bridged biaryls with low atropo-
isomerization barriers. If interconversion 6-Bz6-A occurs faster than ring cleavage and further reduction
to 4-B, then the high asymmetric inductions actually attained must result from a preferential reduction of
7-B over 7-A, again in the sense of a dynamic kinetic resolution, but at the level of the second reduction
step.

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Scheme 3. Two possible stereochemical courses of the atropo-enantioselective reduction of 2; metallated intermediates
formulated as anionic, for reasons of clarity
For differentiating between these two stereochemical courses, the configurationally unstable racemic
hydroxy aldehydes 8a and 8b18 (i.e. the ‘non-anionic’ analogs of 7) were reduced with BINAL-H (5)
(Scheme 4) under the same conditions as the lactones 2 (cf. Scheme 2). It is feasible that through
initial deprotonation of 8 by 5,‡ intermediate species originate that are similar (if not identical) to the
postulated intermediates 6-A/Bz7-A/B of the lactone reduction (cf. Scheme 3). In addition, even if the
reduction process should be more rapid than the deprotonation, the hydroxy aldehydes (8) themselves
should display closely related (also still non-deprotonated) model substrates for 7. In both cases, for 8a
and 8b, the reduction led to the fully racemic alcohols 4-A/4-B, clearly showing that racemic 8a and
8b do not constitute substrates for a dynamic kinetic resolution. This provides strong evidence that the
asymmetric induction in the atropo-selective BINAL-H reduction of biaryl lactones 2 is achieved in the
first, not in the second reduction step, without a significant loss of stereochemical information at the level
of the intermediates 6 and 7.
Scheme 4. Reduction of the configurationally unstable hydroxy aldehydes 8 with BINAL-H (5)
Configurationally unstable biaryl lactones of type 2 can thus be reduced highly atropo-
enantioselectively to give the virtually enantiopure axially chiral biaryl alcohols 4, further assisted
by a simple crystallization step. Apparently the stereochemically deciding step is the first hydride
transfer, which, out of the equilibrium of rapidly interconverting helimeric lactone enantiomers 2-
Az2-B, reduces only 2-B, in the sense of a dynamic kinetic resolution, and allows conservation of
‡
This deprotonation would also explain the low conversion (11%) obtained in the reduction of 8b with only 1.0 equiv. of 5.

G. Bringmann, M. Breuning / Tetrahedron: Asymmetry 10 (1999) 385–390
389
this stereochemical information into the target molecule, despite the configurational instability of the
lactolate and hydroxy aldehyde intermediates.
3. Experimental section
HPLC analyses were carried out with a combination of a Waters M 510 pump, a Chiralcel OD-H
column (Daicel Chem. Ind. Ltd., 4.6×250 mm), and an ERC-7215 UV-detector. LiAlH4 and M-BINOL
were purchased from Aldrich; THF was freshly distilled from potassium. All reactions were performed
in dry glassware under an argon atmosphere using the Schlenk tube technique.
3.1. General procedure for the BINAL-H reductions and enantiomer analysis of the alcohols 4
A solution of 4.4 equiv. of M-BINOL in THF (5 ml/mmol M-BINOL) was slowly added to 4.0 equiv.
of LiAlH4 (1.0 M in THF) at room temp. After 30 min of stirring, 4.4 equiv. of ethanol were added and
stirring was continued for additional 30 min. If a large quantity of material precipitated, the suspension
had to be discarded and the preparation was started from the beginning.15 The freshly prepared BINAL-
H solution was cooled to −35°C and 1.0 equiv. of the biaryl compound were added. After 12 h the
reaction mixture was carefully hydrolyzed with water (20 ml/mmol biaryl), slightly acidified with 2
N HCl, and extracted with diethyl ether (3×20 ml/mmol biaryl). The combined organic layers were
dried over MgSO4 and the solvent was removed in vacuo. Chromatographic purification gave the crude
alcohols 4, the spectroscopic data of which were identical to those of material previously obtained.8,21
The enantiomer analysis of the biaryl alcohols 4a and 4b was done by HPLC on a chiral phase (Chiralcel
OD-H, UV-detection at 280 nm, flow rate 1.0 ml/min): 4a (eluent n-hexane:2-propanol, 92:8): tR=20 min
(4a-A), tR=23 min (4a-B); 4b (eluent n-hexane:2-propanol, 95:5): tR=16 min (4b-A), tR=22 min (4b-B).
The absolute configurations were assigned according to the literature.8
3.2. Preparative ring opening of 2a
According to the general procedure, 123 mg (400 µmol) of 2a were reduced. Purification of the crude
product by column chromatography on silica gel (petroleum ether:diethyl ether, 1:1) gave the alcohol 4a-
B (113 mg, 364 µmol, 91%, er 94:6). Crystallization of 4a-B from petroleum ether:diethyl ether resulted
in virtually enantiopure (er >99.5:0.5) colorless crystals of 4a-B (95.6 mg, 308 µmol, 77%).
3.3. Preparative ring opening of 2b
According to the general procedure, 2b (110 mg, 400 µmol) was reduced and the crude product
purified by column chromatography on silica gel (petroleum ether:diethyl ether, 2:1). The alcohol 4b-
B (105 mg, 377 µmol, 94%, er 89:11) was obtained as a colorless oil. Crystallization of 4b-B from
petroleum ether:diethyl ether gave virtually enantiopure (er >99.5:0.5) colorless crystals of 4b-B (77.9
mg, 280 µmol, 70%).

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G. Bringmann, M. Breuning / Tetrahedron: Asymmetry 10 (1999) 385–390
3.4. Reduction of the hydroxy aldehydes 8
The hydroxy aldehydes 8a and 8b (50 µmol each) were reduced according to the general procedure
until conversions were quantitative. The resulting alcohols 4 were purified by TLC on silica gel
(petroleum ether:diethyl ether. 2:1). In both cases no enantiomeric excesses were detected by HPLC.
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft (SFB 347 ‘Selektive Reaktionen
Metall-aktivierter Moleküle’) and by the Fonds der Chemischen Industrie (graduate research fellowship
to M. B. and financial support).
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