Chelation-Assisted Substrate-Controlled Asymmetric Lithiation-Allylboration of Chiral Carbamate 1,2,4-Butanetriol Acetonide

The lithiation of 2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl diisopropylcarbamate (1) is achieved freely by sec-butyllithium in diethylether with high lk-diastereoselectivity: the bicyclic chelate complexes 3a and 3b are reacted with electrophiles to form optically active precursors 4a and 4b with >95% diastereoselectivity. In addition, tertiary diamines can undergo an external complexation in contest with the internal oxygen ligand, leading to improved stereoselectivities. The further reactions of lithiated carbamates with trans alkenyl-9-BBN derivatives after 1,2 metallate rearrangements, gave the key intermediate α-substituted allylic boranes 7. Subsequent allylboration of aldehydes gave (Z)-anti-homoallylic alcohols 8 in good yield and excellent d.r.


Introduction
Hoppe and co-workers investigated the lithiation of carbamates derived from non-racemic chiral primary alcohols generating organolithium intermediates which undergo electrophile-dependent stereodivergent substitution that often have remarkable configurational stability [1][2][3][4].This stability is due to dipole stabilization and intramolecular chelation of the lithium counterion by the carbamoyl group [5].The importance of carbamate group, in the enhancement of the kinetic acidity of α-protons and the stabilization of lithio derivatives by chelation through one of the oxygen lone-pairs has been recognized by many research groups [1].It has been shown that the sterically congested 1,2,4-butanetriol acetonide carbamate could be lithiated by s-BuLi/TMEDA in diethylether to form an α-lithiated species [1,2], whilst in the presence of the chiral diamine (−)-sparteine, pro-S H deprotonates preferably and the configurationally stable lithiated complexes are subsequently trapped with different electrophiles with retention of configuration [6].Generally, it has been considered that the remote donor substituents or groups, such as acetonide group, could also interfere in lithiation [7,8].

Chemistry
Two procedures were adopted for the deprotonation of the carbamate 1, one in the presence of external ligands (procedure A) and another with no external ligands involved (procedure B) (Scheme 1).Although very similar results were obtained as per Hoppe [3], but products more bench stable (no isomerization occured even at longer time and elevated temperatures), and reactions are quicker, and give high yields and good d.r.This shows that the expulsion of an unhindered carbamate leaving group (OCb) could be quicker than that of a bulky carbamate (OCby).The protocol involved the Chelation-Directed-Asymmetric-Lithiation (CDAL) of 1,2,4-butanetriol acetonide by the drop-wise addition of sBuLi in Et2O or sBuLi in Et2O/additative chelating ligands e.g., N,N,N,N-tetramethylethylenediamine (TMEDA), (−)-sparteine or (+)-sparteine surrogate.An effective substrate-inherent chiral induction was exploited with acetonide-type carbamate 1.Here we report on the generation of chiral synthetic equivalents for the 1,2,4-trihydroxybutanide ion 1a, showing the stereo-directing influence of the protected 3-hydroxy group.Furthermore the conformational strain of the dioxalane ring is noteworthy for attaining good diastereoselectivities.

Scheme 1. Chelation-directed lithiation/ES of carbamate 1.
The relative rate for the deprotonation of the diastereotopic protons (pro-S or pro-R) reflects the rate-ratio in the presence of chiral inductor (diamine additives).The configurationally stable chiral ion pairs or lithio-intermediate 2a originates preferably when we used (−)-sparteine as an external chiral bi-dentate ligand, following the abstraction of the pro-S proton.Subsequent trapping of this configured complex 2a with different electrophiles (with retention of configuration) would then furnish 4a in good yield and high d.r.(Table 1).Indeed, the opposite diastereomer 4b to (−)-sparteine can be effectively achieved through the appropriate choice of chiral diamines employed ((−)-sparteine, or (+)-sparteine surrogate) [21][22][23] (procedure A), whilst the racemic mixture with 1:1 ratio of the diastereomeric complexes 2a and 2b arises with sec-butyllithium/TMEDA.Interestingly, the diastereomeric ratio in 4a and 4b adequately increased to 98:2 when the lithiation was done without the addition of any external chelating diamine (procedure B).
From these results, it is clearly indicated that the intra-and intermolecular complexation involved an almost similar rate in the kinetically controlled deprotonation of the diastereotopic HS and HR protons in the carbamate ester.If no external bidentate ligands are linked to it then the β-oxygen atom acts mainly as a ligand to the lithium cation providing the bicyclic chelate complexes 3a or 3b, where two neighboring five-membered rings are trans-annulated to the central ring, in contrast to the intermediates 2a or 2b which are stabilized through intermolecular complexation with an external bidenate ligand e.g., TMEDA or (−)-sparteine or (+)-sparteine surrogate.It is noteworthy that chiral induction [24] arises in the deprotonation step due to the presence of a good donor substituent next to a stereogenic C atom in the γ-or δ-position and therefore high substrate-controlled diastereoselectivities can be easily achieved.A bicyclic chelate complex of the type 3a is generated in the presence of (−)-sparteine, even if the specific stereochemistry of the bis-chelate complexes like 2a, 2b or 3a, 3b is doubtful.It is likely that a seven-or eight-membered ring might form due to the fixing of the more effective coordinating carbonyl group of the γ-or δ-carbamoyloxy residue.In addition, Et2O coordinates in monodentate fashion and hence the more favorable exo-position of the electrophile determines the transition state.It is believed that the formation of the anti-annulated tricyclic chelate complex 3a is highly selective despite the fact that the lithiation step is kinetically controlled, whilst, in the presence of external ligands e.g., (−)-sparteine, due to the mismatched pair situation; the connection towards the abstraction of the pro-S proton is further enhanced, because in this case 3b is no longer evident in the reaction mixture.The 2,2-dimethyl-substituted 1,3-dioxolane ring in the carbamate 1 is simply a weak ligand for lithiation, and as with sparteine, it is expelled by TMEDA.As Table 1 shows, diastereoselectivity is reduced under these conditions and is reversed by means of (+)-sparteine surrogate due to preference for the pro-R proton [25].Furthermore the normal deprotonation pathway relates to the presence of a bidentate complexing ligand where intramolecular complexation is not concerned.Also the ion pair 3a reacts efficiently with electrophiles and consequently the substrate generates a valuable synthetic equivalent to the (S)-1,3,4-trihydroxybutanide 1a [26,27].
No isomerization of the labile α-substituted allylic borane 7 during the 1,2-metalate rearrangement was observed.This could be achieved by simply adding the aldehyde to the ate-complex 6 at low temperature after 1,2-metalate and rearrangement would occur upon warming to give the allyl borane 7 which would subsequently undergo allylation to give 8 before isomerization could occur.This protocol was found to be successful with a range of representative trans-vinylboranes 5a and 5b, carbamate 1, and aldehydes (Table 2).In all cases, good diastereomeric ratios with moderate yields were observed.
Table 2. Synthesis of anti-(Z)-homoallylic alcohols through the lithiation/allylboration method.The high selectivity originates from the closed 6-membered chair transition-state structures involved in minimizing non-bonded steric interactions [19,41], which can be rationalized by the increased steric hindrance in the transition-state structure TS2 compared to TS1 [42].Severe steric hindrance between the 9-BBN ring and R 1 would push the α-carbon substituent into a pseudo-axial position resulting in the anti-diastereoisomer and (Z)-alkene geometry [43][44][45][46].It is interesting to note that external complexation of tertiary diamines can compete with the internal oxygen ligand, furnishing stereoselectivities with good diastereoselectivities in the desired compounds.

General Information
All air-and water-sensitive reactions were carried out in oven-dried (180 °C) glassware and under an Air atmosphere using standard Schlenk techniques.Anhydrous solvents were prepared using a Grubbs-type anhydrous solvent drying columns. 1 H-and 13 C-Nuclear Magnetic Resonance (NMR) spectra were acquired at various field strengths as indicated, and were referenced to CHCl3 (7.27 and 77.0 ppm for 1 H and 13 C, respectively) or TMS (0.00 ppm for 1 H and 13 C). 1 H-and 13 C-NMRspectra are shown in the Supplementary Materials. 11B-NMR spectra were recorded with complete proton decoupling using BF3•Et2O (0.00 ppm) as an external standard.Assignment of signals in 1 H-and 13 C-spectra was performed using 1 H-1 H COSY, DEPT, HMQC and HMBC, where appropriate.Low-and high-resolution mass spectra were recorded using Electron Impact (EI), Chemical Ionization (CI) or Electron-Spray Ionization (ESI) techniques.For CI, methane or NH4OAc/MeOH were used.Analytical TLC: aluminum backed plates pre-coated (0.25 mm) with Silica Gel 60 F254 (Merck Millipore, Darmstadt, Germany).Compounds were visualized by exposure to UV-light or by staining with 5% solution of (NH4)2Mo7O24 .4H2O in EtOH followed by heating.Flash chromatography was carried out using Merck silica Gel 60, 0.040-0.063mm particle size.Melting points were determined with a Boetius hot stage apparatus and were not corrected.All IR data were obtained on a Perkin-Elmer Spectrum One FT-IR spectrometer (Perkin-Elmer, Boston, MA, USA).N,N,N,N-Tetramethylethylenediamine (TMEDA) was purchased from Sigma-Aldrich (Gillingham, UK) and (−)-sparteine was purchased from Aldrich (5 years back from Gillingham, UK).(+)-sparteine surrogate was synthesized from commercially available (−)-cytisine [21].Both were distilled under reduced pressure over CaH2 prior to use.9-((E)-Prop-1-enyl)-9-borabicyclo[3.3.1]nonane(9-BBN) as dimer was purchased from Aldrich.sBuLi (1.3 M solution in cyclohexane/hexanes, 92:8) was purchased from Sigma-Aldrich.

(R)-3-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-hydroxy-1-phenylpropan-2-yl Diisopropylcarbamate (4a-I)
To a solution of carbamate(0.208mg, 0.75 mmol) in Et2O (5 mL) at -78 °C was added sBuLi (1.3 M in cyclohexane, 0.84 mL, 1.05 mmol,) drop-wise.This mixture was then stirred at -78 °C for 5 h followed by addition of benzaldehyde (2.00 mL, 2.00 mmol).The reaction was stirred for 2h and then warmed to r.t. and stirred for 12h.The reaction mixture was then cooled to 0 °C and a solution of 2 N HCl (10 mL) was added drop-wise.The layers were separated and the aqueous layer was extracted with Et2O (3 × 15 mL).The combined organic layers were dried over MgSO4 and concentrated in vacuo.The crude product with four pairs of diastereomers was purified by flash chromatography (SiO2, 10% EtOAc/petroleum ether) to give the major diastrereomeric product 4a-I (196 mg, 84%, d.r.= 98:2) as a colourless oil.Here the stereochemical identity for a carbon bearing the hydroxyl group shown with squiggly line is unspecified.This might be due to the possible attack of the lithiated intermediate on faces of benzadehyde.Secondly, in the 1 H-NMR spectrum, the proton coupling at this position is not clear hence it is given as a multiplet.Spectral data matched those reported in the literature [3].Rf = 0.40 (10% EtOAc in petroleum ether); IRνmax (neat)/cm − To a solution of carbamate (0.208 mg, 0.75 mmol) in Et2O (5 mL) at -78 °C was added sBuLi (1.3 M in cyclohexane, 0.84 mL, 1.05 mmol,) drop-wise.This mixture was then stirred at -78 °C for 5 h followed by addition of benzophenone (1.75 mL, 2.00 mmol).The reaction was stirred for 4h and then warmed to r.t. and stirred for 12 h.The reaction mixture was then cooled to 0 °C and a solution of 2 N HCl (10 mL) was added drop-wise.The layers were separated and the aqueous layer was extracted with Et2O (3 × 15 mL).The combined organic layers were dried over MgSO4 and concentrated in vacuo.The crude product with 4 diastereomers was purified by flash chromatography (SiO2, 10% EtOAc/petroleum ether) to give the major diastereomeric product 4a-III (170 mg, 84%, d.r.= 98:2) as a colourless oil.Spectral data matched those reported in the literature [3].Rf = 0.35 (10% EtOAc in petroleum ether); IRνmax (neat)/cm −1 3432, 2890, 1690, 1438, 1060;