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Proposed Mechanism for the Enantioselective Alkynylation of an Aryltrifluoromethyl Ketone, Key Step in the Synthesis of Efavirenz Gareth John Griffiths, and Aleksander Warm Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00058 • Publication Date (Web): 15 Mar 2016 Downloaded from http://pubs.acs.org on March 16, 2016

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Organic Process Research & Development

1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Proposed Mechanism for the Enantioselective Alkynylation of an Aryltrifluoromethyl Ketone, Key Step in the Synthesis of Efavirenz Gareth J. Griffiths and Aleksander Warm*

Lonza AG, Walliser Werke, CH-3930 Visp, Switzerland.

[email protected]

ACS Paragon Plus Environment


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TABLE OF CONTENTS GRAPHIC


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ABSTRACT: The rationalization of observations made during optimization of the zinc-mediated enantioselective addition of cyclopropylacetylene (2) to ketoaniline 8 in the presence of (1R,2S)-1-Phenyl-2-(pyrrolidin-1-yl)propan-1-ol (3) to afford amino alcohol 11 has enabled us to propose a mechanism for this transformation. The proposed mechanism has been used as the basis for development of a spreadsheet-based mass-balance simulation, which has proved useful in predicting the effects of stoichiometry changes and in process troubleshooting.

KEYWORDS: Efavirenz, enantioselective, alkynylation, organozinc, catalysis.



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INTRODUCTION Efavirenz (1) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV) type 1, and the enantioselective addition of cyclopropylacetylene (CPA, 2) to aryltrifluoromethyl ketones mediated by (1R,2S)-1-Phenyl-2-(pyrrolidin-1-yl)propan-1-ol (PNE, 3) has been the key step in syntheses of 1 run at industrial scale.

One such synthesis reported by Merck scientists involved the addition of lithium cyclopropylacetylide (4) to ketone 5 in the presence of the lithium salt 6 to give alcohol 7 in 96 – 98% enantiomeric excess after aqueous acidic work-up (Scheme 1).1 The results of detailed mechanistic studies of this reaction using 6Li and 13C NMR spectroscopy, ReactIR and semiempirical (MNDO) computational studies supported a stereochemical model based upon 1,2-addition via a C2 symmetric 2:2 mixed tetramer formed from 4, 6 and THF.2 Scheme 1. Enantioselective addition of 4 to 5 mediated by 6.1-2


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Other Merck scientists later pointed out disadvantages associated with the synthesis of 1 via 7, namely the requirement for the use of 2.2 equivalents of both 4 and 6, and the necessity for additional steps to insert and remove the PMB protecting group used, and they reported a more direct route via

zinc-mediated enantioselective addition of 2 to

ketoaniline 8 in the presence of 3, 2,2,2-trifluoroethanol (TFE, 9) and methylmagnesium chloride (MeMgCl, 10), followed by aqueous acidic work-up to afford amino alcohol 11.3-4

An autocatalytic version of this reaction was subsequently reported by Carreira et al,5 and a catalytic version has also been patented.6-8 The Merck authors pointed out the importance of the presence of the unprotected NH2 group adjacent to the carbonyl group in 8,9 and proposed a mechanism (Scheme 2) in which complex 12 converts to dimer 13 and thence to monomer 14, from which the alkyne unit was expected to undergo rapid addition to 8 resulting in formation of 15.4



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Scheme 2. Proposed mechanism for the formation of 15.4 _ Me ClMg+ O

Ph

N

F3CH2CO

Zn O

Zn

O Zn

N

Ph

N

Ph 12

Me 13 Me Slow CF3 Cl

O

CF3

Cl

OMgCl NH2

CF3CH2OMgCl

NH2 8 O

Fast

Zn N

15 Ph 14

Me

Rationalization of the results of our own investigations of this enantioselective alkynylation has enabled us to propose an alternative mechanism, which is more in accordance with reaction features not taken into account earlier.


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RESULTS AND DISCUSSION Features of the reaction The standard reaction for conversion of 8 to 11 involves addition of diethyl zinc (ZnEt2, DEZ) in toluene to a solution of amino alcohol 3 and alcohol 9 in THF, followed by sequential addition of solutions of acetylene 2 in toluene, Grignard 10 in THF, and ketoaniline 8 in THF (3-9-DEZ-2-10-8). Reaction conversion and enantioselectivity can be monitored by HPLC analysis (after quench of the sample in aqueous citric acid) using a chiral column. The results discussed below are restricted almost exclusively to our investigation of the reaction which uses approximately stoichiometric quantities of reagents, but it should be noted that recent publications have shown that the use of substoichiometric reagent quantities can also be effective.5-8 Our initial assumption was that the reaction would require very accurate charging of solutions containing approximately equimolar amounts of 3, 9, DEZ, 2, 10 and 8, and we were concerned that lack of process robustness might mean that a combination of even minor variation of the reagent quantities charged, solution assay determination errors, and effects caused by the variability of other reaction parameters might lead to low conversion and/or enantioselectivity. The main goal of our work was therefore to establish parameter ranges which would reproducibly afford the conversion and enantioselectivity required (both ≥ 98.0%), and this optimization was achieved using a combination of multivariate (Design of Experiments, DoE) and a large number of monovariate (single parameter adjustment) experiments. The results of the DoE work provided the information (including reagent-charging accuracy and precision requirements) required to define the process and the equipment to be used. Further scrutiny of the mass of experimental data revealed some results which could not be readily interpreted, and this led us to try to rationalize



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these data in terms of a mechanistic proposal and, based on this, to develop a model which might help to predict the outcome (conversion and enantioselectivity) of the reaction as a function of planned or unplanned variations of stoichiometry. The DoE results had indicated that non-stoichiometric reaction parameters (temperature, concentrations, solvent ratios, addition times, etc) could be varied within the ranges investigated with rather limited impact on the course of the reaction, and only variation of stoichiometry and the resulting mechanistic implications will be discussed in detail here. Among the observed features of the reaction were the following: 1. High sensitivity of the reaction to stoichiometry parameters. This observation was a conclusion from the DoE work mentioned above. In addition, the desired conversion and enantioselectivity could be obtained with stoichiometry settings well outside the proven acceptable ranges of the standard (optimized) settings under conditions in which several stoichiometry parameter settings had been changed simultaneously and in some fortuitous way. 2. Influence of the amount of amino alcohol 3 on enantioselectivity and conversion. As already reported,3-4 the use of 2 equivalents of amino alcohol 3 without any alcohol 9 gave reasonably good enantioselectivity (e.p. 96%) but only 50% conversion of 8 to 11. 3. Sequence of addition of DEZ, 3 and 9. It had already been reported4 that that DEZ, 3 and 9 can be charged in any order without any significant influence on reaction enantioselectivity or conversion. We found the single exception to be the sequence 9-DEZ-3, which gave 3 – 5% lower enantioselectivity. 4. Alternative sequence of addition of acetylene 2 and Grignard 10. Reversal of the order of addition of 10 and 2 described above (i.e. use of the sequence 39-DEZ-10-2-8) might be expected to lead to formation of a complex analogous to 134


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(Scheme 2), but containing CH3 (in place of 2) bound to Zn, and, in the presence of excess 10, to the formation of uncomplexed 16. This could lead to formation of alcohol 17 and/or a drop in the enantioselectivity of the alkynylation. It was found, however, that this addition sequence can be used without any adverse effect on enantioselectivity and without formation of alcohol 17.

5. Influence of excess Grignard 10. It was observed that addition of excess (up to 1.3 eq) Grignard 10 led to a drop in enantioselectivity but, once again, not to formation of alcohol 17 as a by-product. 6. Pattern of gas evolution. The proposed4 intermediacy of complex 12 (Scheme 2) would mean that evolution of 2 molar equivalents of ethane (from DEZ) and 1 molar equivalent of methane (from 10) should occur prior to addition of 8. Our studies (Figure 1) indicated that only 1.5 molar equivalents of ethane are evolved during the mixing of 3, 9, and DEZ. Addition of 10 leads to the expected evolution of 1 molar equivalent of methane, and the remaining 0.5 molar equivalents of ethane are evolved only during and after the addition of 8. The identity of the evolved gases was confirmed by GC-MS, and 1H NMR monitoring demonstrated that there was almost no accumulation of dissolved ethane or methane in the reaction solution during the addition sequence.



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Figure 1. Evolution of ethane and methane during the conversion of 8 to 11.

7. Sequence of adding acetylene 2 and ketoaniline 8. The alternative addition sequence 3-9-DEZ-10-8-2, i.e. charging acetylene 2 at the end of the sequence, gave identical conversion and very slightly improved enantioselectivity compared to the standard reaction. Replacement of acetylene 2 by the acetylenic Grignard reagent

16

(sequence

3-9-DEZ-8-10-16)

resulted

in

dramatically

reduced

enantioselectivity (63% e.p.) 8. The employment of sub-stoichiometric amounts of the reagents DEZ and 3 resulted in slower reaction, but conversion of 8 to 11 was higher than expected. These results suggested at least some participation of a catalytic mechanism. Additional mechanistic information was gathered by monitoring the progress of the reaction using HPLC and reaction calorimetry.


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HPLC analysis of samples taken during or shortly after completion of the addition of 8 typically showed, in addition to starting material and product, the presence of four peaks as shown in Figure 2.

Figure 2. HPLC monitoring of the conversion of 8 to 11 on ChiralPak AD, 250 x 4.6 mm, with detection at 260 nm. The chromatogram shows ketoaniline 8 (4.73’, relative retention time (RRT) 1.00), bridged dimer 18 (4.95’, RRT 1.05 and 5.36’, RRT 1.13), amino alcohol 11 (7.58’, RRT 1.60), and dimer 19 (10.21’, RRT 2.16 and 12.25’, RRT 2.59). The peak at 3.28’ is toluene; the shoulder on the peak at 12.25’ is the enantiomer of 11.

The two peaks at RRT 1.05 (usually visible as a shoulder on the peak assigned to 8) and RRT 1.13 were of low intensity, and did not disappear during prolonged reaction. Higher and approximately equal levels of the two peaks at RRT 2.16 and RRT 2.59 were present during and shortly after the addition of 8, but these two peaks disappeared as conversion of 8 to product 11 progressed. HPLC monitoring of reactions of 8 with bases such as nbutyllithium (BuLi), 10 or 16 also showed the presence of these four peaks, and it was suspected that they might be dimers of 8 (MW = 223). The impurity responsible for the peaks at RRT 1.05 and RRT 1.13 was isolated and identified as racemic 18 (MW = 428). LC-MS of a solution of the more transient impurity (RRT 2.16 and 2.59) indicated a



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molecular weight of 446, but this compound could not be isolated by chromatography. The 1

H and

13

C NMR spectra (measured at 0°C) of the solution resulting from addition of BuLi

(4.1 mmol) in hexane to a solution of 8 (8.6 mmol) in THF-d8 at -5°C indicated rather clean formation of racemic dimer 19 (M = Li) as a single diastereomer (relative stereochemistry not assigned). Our interpretation of these results (Scheme 3) is that 8 can react with base to form 19, which can either be converted to 18 or collapse to reform 8 on work-up. Formation of racemic 19 (M = MgCl) was also observed in additional control experiments in which 8 was treated with either 10 (some formation of racemic 17 was also observed) or 16 (some unselective conversion of 8 to a mixture of 11 and its enantiomer was also observed). It is noteworthy that reaction of PMB-protected ketone 5 with BuLi under similar conditions did not lead to any dimerization of 5 as monitored using 1H NMR spectroscopy, and it was mentioned earlier that the enantioselectivity of the alkynylation with the PMBprotected ketone 5 was significantly lower than that with 8.3-4 Scheme 3. Base-promoted dimerization of ketoaniline 8

The results of a reaction calorimetry experiment to monitor the conversion of 8 to 11 are illustrated in Figures 3 and 4. Figure 3 shows the heat flow and gas evolution data; the latter correspond to those discussed above (reaction feature # 6). The IR profiles of selected frequencies measured throughout the experiment are shown in Figure 4. Our


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interpretation of the data was that the appearance and disappearance of the absorption at 1317 cm-1 are related to the formation and decay of the dimer 19 or of a related transient intermediate, and that the slightly delayed formation of alcohol 11, presumably as the chloromagnesium alkoxide 15 or a related zinc-alkoxide precursor, is shown by the progress of the absorption at 1252 cm-1. The absorption at 1346 cm-1 is believed to indicate binding of trifluoroethanolate with Zn, and its decay and reappearance suggest the rearrangement of a zinc complex which enables conversion of 8 to 15 accompanied by breaking and reforming of the Zn-OCH2CF3 bond. Most conspicuous is, however, the C=O stretch of 8 (1625 cm-1) which decays, reappears, and fades away with concomitant increase in the intensity of the 1252 cm-1 absorption. Heat flow [W](violet), off-gas stream [rel](light blue), Reaction mass [rel](green) 35

Diethylzinc addition

30

Addition of ketoaniline 8

25 20 15 CPA and MeMgCladdition

10 5 0 50

100

150

200

250

300

350

400

450

500

Time [min]

Figure 3. Reaction calorimetry of the conversion of 8 to 11: Heat- and off-gas-flow data.



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IR-Profile [rel]: 1625(red), 1346(violet), 1317(blue), 1252(green), 2124(black) 1

0.8

0.6

0.4

0.2

0

50

100

150

200

250 300 Time [min]

350

400

450

500

Figure 4. Reaction calorimetry of the conversion of 8 to 11: IR monitoring. The selected frequencies are tentatively interpreted as follows: 1252 cm-1 (green) Zn-O-C stretch of a zinc-alkoxide analogue of 15; 1317 cm-1 (dark blue) Zn-O-C stretch of dimer 19 or a related transient intermediate; 1346 cm-1 (violet) absorption related to CF3CH2O-Zn; 1625 cm-1 (red) C=O (ketoaniline 8) stretch; 2142 cm-1 (black) CΞC (2) stretch.

Proposed reaction mechanism In order to account for the reaction features summarized above, we propose a reaction mechanism which differs significantly from that suggested earlier.4 Our current understanding leads us to suppose that the course of events in a reaction involving approximately equimolar quantities of amino alcohol 3, DEZ, alcohol 9, acetylene 2, Grignard 10 and ketoaniline 8 is as shown in Schemes 4 – 11 and summarized below. Reaction of DEZ with 3 results in formation of the dimeric zinc complex 20, which still contains two Zn-Et elements, and this is accompanied by the evolution of 1 mol C2H6 per mol DEZ (Scheme 4).


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Scheme 4. Reaction of 3 with DEZ to give complex 20

Reaction of 20 with 9 leads to formation of 21 accompanied by the evolution of 0.5 mol C2H6 per mol DEZ. 50% of the added 9 is bound within 21, the remaining 50% does not react (Scheme 5). Acetylene 2 is added, but does not react. Scheme 5. Reaction of complex 20 with alcohol 9 to give complex 21

Addition of Grignard 10 leads to its reaction with the remaining 9 to give 22 and with 50% of the acetylene 2 added to give acetylenic Grignard 16, resulting in the evolution of 1 mol CH4 per mol 10 (Scheme 6). Scheme 6. Addition and reaction of Grignard 10



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Addition of ketoaniline 8 results in its dimerization to 19 via deprotonation by Grignard 16, with the result that none of the acetylene 2 added is now in its deprotonated form (Scheme 7). Scheme 7. Dimerisation of 8 with formation of 19

19 and 21 react via displacement of trifluoroethanolate 22 to form 23, and either 19 or the related 23 are suspected to give rise to the IR absorption at 1317 cm-1 (see above). Formation of 23 is followed by deprotonation of the aromatic NH2 group and rearrangement (with evolution of the remaining 0.5 mol C2H6 per mol DEZ) to form complex 24 (Scheme 8). All the 9 added is now present as 22, which means that no 9 is bound to Zn, and this is assumed to be a possible explanation for the disappearance of the IR absorption at 1346 cm-1 (see above). Scheme 8. Reaction of dimer 19 with complex 21


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Collapse of 24 to monomeric complex 26, which is envisaged to proceed via 25 (Scheme 9), is accompanied by temporary reappearance of the C=O absorption of 8 at 1625 cm-1 as observed in the IR profile (see above). Scheme 9. Collapse of 24 to monomeric complex 26

The system does not now contain a base strong enough to deprotonate acetylene 2, and it is proposed that 2 could react with 26 to form 28 via a transition state such as 27 (Scheme 10). Reaction of 28 with 22 could lead to formation of 15, the chloromagnesium salt of the desired alcohol 11, and zinc complex 29; this last transformation is a prerequisite for operation of the catalytic process (see below) but it would not be absolutely necessary in the stoichiometric process. Scheme 10. Reaction of 26 with acetylene 2



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Any strong base still present could deprotonate acetylene 2, and we postulate a possible alternative pathway (Scheme 11), which involves addition of Grignard 16 to 26 to form 31 via transition state 30, and which is significantly less enantioselective than the addition via 27 (Scheme 10). This proposal could explain reaction features # 5 and # 7 above, i.e. that both deprotonation of acetylene 2 by excess Grignard 10 present in the system (feature # 5), and the addition of Grignard 16 instead of acetylene 2 (feature # 7), were shown to lead to lower enantioselectivity but not to formation of alcohol 17. Intermediate 31 could collapse to alcohol 11 on aqueous acidic work-up, or reaction with 22 might lead to formation of 32, an alternative precursor of 11. Scheme 11. Reaction of 26 with Grignard 16

Ph Me

Ph

O

16 26

ClMg

N

O

Zn

ClMg+

Me

CF3

O Zn

N HN

O CF3

HN

30 31

Cl

Cl

Me

Cl

Ph F3C

OMgCl

N

22

OMgCl

NH ClMg

CF3

+

O Zn O

29

32 F3 C

The possible participation of a catalytic process was mentioned above (reaction feature # 8), and it is possible that this could be initiated by extrusion of chloromagnesium salt 15 from 28 and formation (via dimerization of 29) of complex 33 as shown in Scheme 12. 33, which has a structure analogous to that of 20 (Scheme 4), could react with dimer 19 (formed from 8 and 10 as shown in Scheme 3) and Grignard 10 to form complex 25, which ACS Paragon Plus Environment

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could convert to 15 via 26 and 28 as shown for the stoichiometric process (Scheme 10). A mechanism of this type can be used to explain that the employment of sub-stoichiometric amounts of DEZ and amino alcohol 3 resulted in higher conversion than that expected on the basis of a purely stoichiometric process, and a catalytic process based on these ideas was subsequently developed.6-8 Scheme 12. Possible mechanism with sub-stoichiometric DEZ and 3 Cl Me

OMgCl 2

Ph NH2

15

CF3

N O Zn

2 OMgCl

O

29 F3C

2 F3 C

22

F3 C

O

Ph

Me

Me Ph

N

O

Zn

Zn

O

O

Ph

O

33

CF3

Zn 2

Me

O

N

Cl

N

28 19 + CH3MgCl

NH2

CF3

10 CH4 + 2 22

Ph N O

CF3

2 2

Ph

O

Me

N

Cl

O Zn

2

Me

N H

Me O

Zn Zn

O N H

26

Cl F3 C


N H 25

O CF3

N Ph Cl


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The mechanism proposed for the stoichiometric process (Schemes 4 – 11) allows rationalization of the observed reaction features # 1 – 8. Feature # 2, i.e. that replacement of alcohol 9 by additional amino alcohol 3 leads to 50% conversion and slightly lower enantioselectivity (96% e.p.), could be explained by operation of the mechanism shown in Scheme 13, which assumes that 19 and 34 (formed by reaction of DEZ with excess 3) can react to give 35, and that the latter can rearrange to 37 (possibly in equilibrium with 36) by a mechanism analogous to that proposed for formation of complex 24 (Scheme 8). Complex 37 could then fragment with extrusion of the inactive zinc complex 38, chloromagnesium salt 39 (which can dimerise), and monomeric complex 26, which can undergo highly enantioselective reaction with acetylene 2 as discussed above and shown in Scheme 10. The resulting complex 28 could react with 40 (instead of the 22 present in the standard process) to give 15 and 38. The outcome of this sequence of reactions is 50% conversion of 8 to 15 and 100% conversion of DEZ to the inactive complex 38, which renders any further conversion of 8 (now present in its dimeric form 19) impossible. It should be noted that the measured enantioselectivity (96% e.p.) of this reaction, in which 9 is replaced by additional 3, is slightly lower than that of the standard reaction (98.5% e.p.), even though both are thought to involve reaction of 2 with 26 (see Schemes 10 and 13). Scheme 13. Possible mechanism with 2 eq 3 and without 9


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Ph N

Zn

O Me

ClMg+

Me N

O

N

Ph

Ph

O

Me

N Ph

34 ClMgO H N

Cl

Ph CF3

Cl

O

O F3 C

-C2H6

O H N

Me

CF3

Me

O

O

N

+

Cl

N Zn

O

Cl

F3C

H2N 19

H2 N 35 ClMg+

ClMg+ N

N

Ph

Ph N

Me

Zn

O

Ph

O

Ph

O

O OH N

Cl

N

CF3

Zn

O

Cl Cl F3C

O Zn

Me

N

Ph

Cl

O

+ O

Ph

O

Cl

O Zn

+

N H

N

Me

NHMgCl

26

39

38 (inactive)

Cl

CF3

CF3 Me

N

Ph

N H

37

36 Ph

O CF3

H N

N H

F3C

N O

O Zn

O Ph

N Me

Me

2 Dimer of 8 (50%)

Ph Me

Me

Cl

OMgCl N

40

Ph N

Cl

OMgCl

38 (inactive) + NH2

Zn O

CF3 15 (50%)


NH2

CF3

O 28


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Development and application of a predictive mechanistic model As described above, we envisage the conversion of 8 to 15 (Scheme 2) to involve a sequence of discrete reaction steps, and we were intrigued by the possibility of developing a reaction model, which might be used to predict and understand the effects of stoichiometry variations, and which might thus be useful for optimization purposes. Our efforts in this direction have led to the development of a spreadsheet-based mass-balance simulation, in which the reaction matrix composition resulting from a reagent addition or a reaction is calculated by application of the steps in the mechanistic proposals (Schemes 4 – 13) described above. The sequence of the reactions, which the raw materials and hypothetical complexes undergo, is predicted on the basis of their acidic or basic strength, their ability to act as ligands or chelating agents, and the reaction rates observed in selected experiments. The calculations in the simulation are based primarily on the stoichiometric mechanism (Schemes 4 – 11), which was deemed to be the most rapid and enantioselective. In many cases (depending on the reagent ratios chosen), this mechanism does not lead to full conversion in the 1st cycle of reactions, and any remaining reagents or intermediates are processed further in repeated stoichiometric and catalytic cycles resulting in a final matrix, which, in its current form, consists of 88 discrete steps. The principle is illustrated by consideration of the 1st stoichiometric process cycle involving 16 steps as shown in Figure 5, which can be explained as follows: - The reaction stoichiometry (molar quantities of DEZ, acetylene 2, amino alcohol 3, alcohol 9, Grignard 10 and ketoaniline 8) is entered in the “Variables” box.


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- The enantioselectivities of each of the 3 reactions10 which lead to formation of the purported transition states 27 and 30 are entered in the “Settings” box. - The species charged or formed in the sequence of reactions shown in Schemes 4 - 13 are listed on the left of the spreadsheet in order of their addition or formation. - Conditions # 1 and 2 are quick tests. The simulation is not designed to deal with unreacted DEZ, and condition # 1 is a test to ensure that no unreacted DEZ remains after the addition of 3, i.e. that each Zn atom is bound to 3. Condition # 2 is a calculation of the difference between the number of molar equivalents of base (DEZ and Grignard 10) and acid (3, 9, and 8); a negative number (excess acid) leads to prediction of low conversion with high enantioselectivity, a high positive number (excess base) results in a prediction of low enantioselectivity with high conversion. - The predicted results (conversion and enantiomeric purity) are calculated and appear in the “Results” box. The basis of the matrix composition calculations is illustrated by consideration of the initial steps with the “Variables” (stoichiometry) settings shown in Figure 5. Step # 1. DEZ (1.18 mol) reacts with 3 (1.38 mol) as shown in eq 1. ZnEt2 (1.18 mol) + 3 (1.38 mol) → ZnEt(PNE)*ZnEt(PNE) (20) (0.59 mol) + 3 (0.20 mol) + EtH↑ (1.18 mol)

(1)

Step # 2. Remaining 3 reacts with 20 as shown in eq 2. ZnEt(PNE)*ZnEt(PNE) (20) (0.59 mol) + 3 (0.20 mol) → Zn(PNE)2*ZnEt(PNE) (34) (0.20 mol) + ZnEt(PNE)*ZnEt(PNE) (20) (0.39 mol) + EtH↑ (0.20 mol)

(2)

Step # 3. 9 (0.94 mol) reacts with remaining 20 to form 21 as shown in eq 3. ZnEt(PNE)*ZnEt(PNE) (20) (0.39 mol) + 9 (0.94 mol) → Zn(PNE)TFE*ZnEt(PNE) (21) (0.39 mol) + 9 (0.55 mol) + EtH↑ (0.39 mol)

(3)



Page 24 of 31

24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The calculations are continued with the addition of acetylene 2 (1.20 mol) in step # 4, the sequence of reactions (steps # 5 – 8) initiated by the addition of Grignard 10 (0.96 mol), and the subsequent sequence of reactions leading to the formation of 0.80 mol of the monomeric complex 26 (steps # 9 – 13). The majority (0.78 mol) of 26 is formed by the collapse of complex 25, but the stoichiometry chosen in this example means that a small amount (0.02 mol) of 37 is formed, which can also collapse to 26. Step # 14 leads to formation of the product precursor 28 via reaction of 2 with 26 (formed from 25) with 98.5% enantioselectivity (Scheme 10). Step # 15 leads to formation of the product precursor 28 via reaction of acetylene 2 with 26 (formed from 37) with 96% enantioselectivity (Scheme 13). Step # 16 would lead to formation of 28 with lower (63%) enantioselectivity via 30 (see the acetylide addition in Scheme 11), but the stoichiometry (“Variables”) settings chosen (no excess of base) ensure that 16 has already been completely consumed in step # 9. The results of the 1st stoichiometric cycle are thus 80.0% conversion with 98.4% enantioselectivity, but the presence of 0.18 mol ketoaniline 8, 0.40 mol acetylene 2, 0.18 mol 34, and 0.94 mol 22, the weak base required to bring about dimerization of 8 to 19, ensure that further conversion of 8 will occur in subsequent cycles (not shown in Figure 5). A 2nd example (Figure 6) shows how different stoichiometry settings (especially higher 10) can lead to incomplete consumption of acetylide 16 in step # 9. This leads to lower enantioselectivity due to the contribution of the less selective reaction of 26 with 16 (step # 16 in Figure 6, see also Scheme 11).


Page 25 of 31


Stoichiometric Process cycle # 1

step #

8-Zn-PNE 26 (from 24/25) reacts with CPA 2 to 10-ZnPNE complex 28


8-Zn-PNE 26 reacts with CPAMgCl 22 to 10-Zn-MgClPNE complex 31

9

10

11

12

13

14

15

16

Stoichiometric Process Cycle # 1

process process

8

(8-Zn-MgCl-PNE2)*(8-Zn-PNE)-complex 36/37 collapses to monomeric complex 8-Zn-PNE 26, inactive 38 and ketoaniline salt 39

7

(8-Zn-PNE)2-complex 24/25 collapses to monomeric complex 8-Zn-PNE 26

6

remaining 8-dimer (8-OMgCl*2-NH2) 19 reacts with Zn(PNE)2*ZnEt(PNE) 34 to (8-Zn-MgCl-PNE2)*(8-ZnPNE)-complex 36/37

remaining MeMgCl reacts with CPA 2 (order of decreasing acidity for steps 5, 6, 7)

5

8-dimer (2-OMgCl*2-NH2) 19 reacts with Zn(PNE)TFE*ZnEt(PNE) 20 to (2-Zn-PNE)2-complex 24/25

remaining MeMgCl reacts with PNE 3

4

19

MeMgCl (10) reacts with TFE (9)

3

remaining 8 reacts with CPAMgCl 16 (order of decreasing basicity) to form 8-dimer (8-OMgCl*2-NH2)

CPA 2 does not react or bind

2

19

TFE binds to remaining ZnEt(PNE)*ZnEt(PNE) 13 to form Zn(PNE)TFE*ZnEt(PNE) 20

1

8 reacts with MeMgCl to form 8-dimer (2-OMgCl*2-NH2)

remaining PNE (3) binds to ZnEt(PNE)*ZnEt(PNE) 19 to form Zn(PNE)2*ZnEt(PNE) 34

step#

2DEZ react with 2PNE (3) to ZnEt(PNE)*ZnEt(PNE) 20

D

ES C RI P

TI O N

25 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48

species

1

ZnEt(PNE)*ZnEt(PNE) 20

2

Zn(PNE)2*ZnEt(PNE) 34

3

Zn(PNE)TFE*ZnEt(PNE) 21

3

TFE 9

1

PNE 3

1

EtH

4

CPA 2

5

TFEMgCl 22

6

PNEMgCl 40

7

CPAMgCl 16

5

MeMgCl 10

5

MeH

0.59

0.39 0.20

0.20 1.18

0.00 1.38

Variables PNE (3) ZnEt2 TFE (9) CPA (2) MeMgCl (10) Ketoaniline 8

0.00 0.20 0.39 0.55 0.00 1.77

Input 1.38 1.18 0.94 1.20 0.96 1.00 Input

mol mol mol mol mol mol

8

Ketoaniline 8

8

8-OMgCl*2-NH2 (Dimer 19)

Settings

10

(8-Zn-PNE)2 24/25

enantioselectivity step 14

98.5 %

11

(8-Zn-MgCl-PNE2)*(2-Zn-PNE) 36/37


96.0 %


63.0 %

12

8-Zn-PNE 26 (from 24/25)

13

8-Zn-PNE 26 (from 36/37)

13

Zn(PNE)2 38

13

8-MgCl 39

14

(S)-11-Zn-PNE 22 (from 24/25 =>26)

14

(R)-11-Zn-PNE 28 (from 24/25 =>26)

15

(S)-11-Zn-PNE 22 (from 36/37 =>26)

15

(R)-11-Zn-PNE 28 (from 36/37 =>26)

16

(S) -11-Zn-MgCl-PNE 31

16

(R) -11-Zn-MgCl-PNE 31

0.00 0.20 0.39 0.55 0.00 1.77

0.00 0.20 0.39 0.00 0.00 1.77

0.00 0.20 0.39 0.00 0.00 1.77

0.00 0.20 0.39 0.00 0.00 1.77

0.00 0.20 0.39 0.00 0.00 1.77

0.00 0.20 0.39 0.00 0.00 1.77

0.00 0.20 0.00 0.00 0.00 2.16

0.00 0.18 0.00 0.00 0.00 2.18

0.00 0.18 0.00 0.00 0.00 2.18

0.00 0.18 0.00 0.00 0.00 2.18

0.00 0.18 0.00 0.00 0.00 2.18

0.00 0.18 0.00 0.00 0.00 2.18

0.00 0.18 0.00 0.00 0.00 2.18

1.20

1.20

1.20

0.79

0.79

1.20

1.20

1.20

1.20

1.20

0.42

0.40

0.40

0.55

0.55 0.00

0.41 0.55

0.41 0.55

0.55 0.00 0.41 0.00 0.96

0.55 0.00 0.41 0.00 0.96

0.55 0.00 0.00 0.00 0.96

0.94 0.00 0.00 0.00 0.96

0.94 0.00 0.00 0.00 0.96

0.94 0.00 0.00 0.00 0.96

0.94 0.00 0.00 0.00 0.96

0.94 0.00 0.00 0.00 0.96

0.94 0.00 0.00 0.00 0.96

0.94 0.00 0.00 0.00 0.96

1.00 0.00

0.18 0.41

0.18 0.02 0.39

0.18 0.00 0.39 0.02

0.18 0.00 0.00 0.02

0.18 0.00 0.00 0.00

0.18 0.00 0.00 0.00

0.18 0.00 0.00 0.00

0.18 0.00 0.00 0.00

0.78

0.78 0.02 0.02 0.02

0.00 0.02 0.02 0.02

0.00 0.00 0.02 0.02

0.00 0.00 0.02 0.02

0.77 0.01

0.77 0.01 0.019 0.001

0.77 0.01 0.019 0.001 0.00 0.00

Condition 1 : 2ZnEt 2 > PNE > ZnEt 2 PNE 1.38 Quick-Test OK Condition 2 : 2*ZnEt 2 +MeMgCl > PNE+TFE+ 8 acids (PNE, TFE, 8) 3.32 bases (2*ZnEt2+MeMgCl) 3.32 excess base 0.00 Quick-Test e.p.OK, conv.OK Results conversion 80.0 % enantiomeric purity 98.4 %

Figure 5. Predictive model for the conversion of 8 to 15. Example 1.



Page 26 of 31

Stoichiometric Process cycle # 1

step #



8-Zn-PNE 26 reacts with CPAMgCl 22 to 10-Zn-MgClPNE complex 31

9

10

11

12

13

14

15

16

Stoichiometric Process Cycle # 1

process process

8

(8-Zn-MgCl-PNE2)*(8-Zn-PNE)-complex 36/37 collapses to monomeric complex 8-Zn-PNE 26, inactive 38 and ketoaniline salt 39

7

(8-Zn-PNE)2-complex 24/25 collapses to monomeric complex 8-Zn-PNE 26

6

remaining 8-dimer (8-OMgCl*2-NH2) 19 reacts with Zn(PNE)2*ZnEt(PNE) 34 to (8-Zn-MgCl-PNE2)*(8-ZnPNE)-complex 36/37

remaining MeMgCl reacts with CPA 2 (order of decreasing acidity for steps 5, 6, 7)

5

8-dimer (2-OMgCl*2-NH2) 19 reacts with Zn(PNE)TFE*ZnEt(PNE) 20 to (2-Zn-PNE)2-complex 24/25

remaining MeMgCl reacts with PNE 3

4

19

MeMgCl (10) reacts with TFE (9)

3

remaining 8 reacts with CPAMgCl 16 (order of decreasing basicity) to form 8-dimer (8-OMgCl*2-NH2)

CPA 2 does not react or bind

2

19

TFE binds to remaining ZnEt(PNE)*ZnEt(PNE) 13 to form Zn(PNE)TFE*ZnEt(PNE) 20

1

8 reacts with MeMgCl to form 8-dimer (2-OMgCl*2-NH2)

remaining PNE (3) binds to ZnEt(PNE)*ZnEt(PNE) 19 to form Zn(PNE)2*ZnEt(PNE) 34

step#

2DEZ react with 2PNE (3) to ZnEt(PNE)*ZnEt(PNE) 20

D

ES C RI P

TI O N

26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48

species

1

ZnEt(PNE)*ZnEt(PNE) 20

2

Zn(PNE)2*ZnEt(PNE) 34

3

Zn(PNE)TFE*ZnEt(PNE) 21

3

TFE 9

1

PNE 3

1

EtH

4

CPA 2

5

TFEMgCl 22

6

PNEMgCl 40

7

CPAMgCl 16

5

MeMgCl 10

5

MeH

0.59

0.52 0.07

0.07 1.18

0.00 1.25

Variables PNE (3) ZnEt2 TFE (9) CPA (2) MeMgCl (10) Ketoaniline 8

0.00 0.07 0.52 0.42 0.00 1.77

Input 1.25 1.18 0.94 1.20 1.30 1.00 Input

mol mol mol mol mol mol

8

Ketoaniline 8

8

8-OMgCl*2-NH2 (Dimer 19)

Settings

10

(8-Zn-PNE)2 24/25


98.5 %

11

(8-Zn-MgCl-PNE2)*(2-Zn-PNE) 36/37


96.0 %


63.0 %

12

8-Zn-PNE 26 (from 24/25)

13

8-Zn-PNE 26 (from 36/37)

13

Zn(PNE)2 38

13

8-MgCl 39

14

(S)-11-Zn-PNE 22 (from 24/25 =>26)

14

(R)-11-Zn-PNE 28 (from 24/25 =>26)

15

(S)-11-Zn-PNE 22 (from 36/37 =>26)

15

(R)-11-Zn-PNE 28 (from 36/37 =>26)

16

(S) -11-Zn-MgCl-PNE 31

16

(R) -11-Zn-MgCl-PNE 31

0.00 0.07 0.52 0.42 0.00 1.77

0.00 0.07 0.52 0.00 0.00 1.77

0.00 0.07 0.52 0.00 0.00 1.77

0.00 0.07 0.52 0.00 0.00 1.77

0.00 0.07 0.52 0.00 0.00 1.77

0.00 0.07 0.52 0.00 0.00 1.77

0.00 0.07 0.02 0.00 0.00 2.27

0.00 0.07 0.02 0.00 0.00 2.27

0.00 0.07 0.02 0.00 0.00 2.27

0.00 0.07 0.02 0.00 0.00 2.27

0.00 0.07 0.02 0.00 0.00 2.27

0.00 0.07 0.02 0.00 0.00 2.27

0.00 0.07 0.02 0.00 0.00 2.27

1.20

1.20

1.20

0.32

0.32

0.82

0.82

0.82

0.82

0.82

0.00

0.00

0.00

0.42

0.42 0.00

0.88 0.42

0.88 0.42

0.42 0.00 0.88 0.00 1.30

0.42 0.00 0.88 0.00 1.30

0.42 0.00 0.38 0.00 1.30

0.92 0.00 0.38 0.00 1.30

0.92 0.00 0.38 0.00 1.30

0.92 0.00 0.38 0.00 1.30

0.92 0.00 0.38 0.00 1.30

0.92 0.00 0.38 0.00 1.30

0.92 0.00 0.38 0.00 1.30

0.92 0.00 0.20 0.00 1.30

1.00 0.00

0.00 0.50

0.00 0.00 0.50

0.00 0.00 0.50 0.00

0.00 0.00 0.00 0.00

0.00 0.00 0.00 0.00

0.00 0.00 0.00 0.00

0.00 0.00 0.00 0.00

0.00 0.00 0.00 0.00

1.00

1.00 0.00 0.00 0.00

0.18 0.00 0.00 0.00

0.18 0.00 0.00 0.00

0.00 0.00 0.00 0.00

0.81 0.01

0.81 0.01 0.000 0.000

0.81 0.01 0.000 0.000 0.11 0.07

Condition 1 : 2ZnEt 2 > PNE > ZnEt 2 PNE 1.25 Quick-Test OK Condition 2 : 2*ZnEt 2 +MeMgCl > PNE+TFE+ 8 acids (PNE, TFE, 8) 3.19 bases (2*ZnEt2+MeMgCl) 3.66 excess base 0.47 Quick-Test e.p.low, conv. OK Results conversion 100.0 % enantiomeric purity 92.1 %

Figure 6. Predictive model for the conversion of 8 to 15. Example 2.


Page 27 of 31


27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

A single stoichiometry parameter can be varied within defined ranges, which can be as wide as several % of the target setting, provided that all the other stoichiometry parameters

are

kept

constant.

The

stoichiometry

parameters

are,

however,

interdependent, and simultaneous variation of several parameters within their defined ranges can lead to lower conversion and/or enantioselectivity, if the requirements of the proposed mechanism (as defined in the mass balance simulation shown in Figure 5) are infringed. On the other hand, fortuitous variation of several parameters outside their defined ranges can give satisfactory results (see reaction feature # 1 above), provided that the requirements of the proposed mechanism are not infringed. An extension of the simulation was necessary to allow definition of the narrower ranges, which allow simultaneous variation of more than one stoichiometry parameter, and which correspond to allowable errors in reagent charging and/or assay measurement. If each of the 6 stoichiometry parameters can vary by ± ∆, the number of possible combinations is 26 = 64, and this was taken into account in the simulation by defining the half-ranges (∆) as independent variables. The simulation was therefore extended to include 64 sets of calculations for each set of stoichiometry parameters (“Variables”), with the final result being the mean of all 64 results. The maximal allowable value of the range (2∆) for each reagent at the stoichiometry settings chosen can be found by minimizing (ideally to zero) the number of combinations in which conversion and/or e.p. are ≤ 98.0%, and we were not surprised to discover that some ranges must be as narrow as ± 1% to ensure a successful reaction outcome. Consideration of the results of more than 100 batches at laboratory, pilot and manufacturing scale, showed that the simulation gave satisfactory agreement between predicted and observed values of conversion and enantioselectivity in most cases. It



Page 28 of 31

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should be mentioned that these batches had not been designed for model verification purposes, that parameters other than stoichiometry had often been varied, and that the simulation does not take these other parameters into account. The proposed mechanism and the resulting model suggest that there is not just a single setting of reagent ratios which lead to optimal conversion and enantioselectivity, but rather a variety of stoichiometries which fulfill the mechanistic requirements and lead to good results, and the results of many experiments confirmed this. The model does have limitations, one of which is that equimolar stoichiometry settings (1.00 mol of each reagent) predict ideal results (100% for conversion and 98.5% for enantioselectivity), whereas our experimental work showed that molar excesses of some reagents are required to achieve high conversion and enantioselectivity. We suspect that this is due to formation of complexes other than 20 (possibly containing more 9 and less 3) during the initial mixing of DEZ with 3 and 9, which might lead to slower and less enantioselective reaction; in this connection it was noted earlier that the sequence of addition 9-DEZ-3 led to lower enantioselectivity (reaction feature # 3). In spite of these limitations, the simulation algorithm was found to be a useful instrument to predict the reaction outcome from sets of stoichiometric parameters (and their ranges), and for optimization and fine-tuning. The model was also especially useful in troubleshooting; in case of a problem (low yield or conversion) related to stoichiometry, a variety of possible scenarios could be tested as part of the problem-solving process. CONCLUSIONS Consideration of reaction features observed during multivariate and monovariate experiments to investigate the enantioselective addition of acetylene 2 to ketoaniline 8 has allowed us to propose a reaction mechanism which is envisaged to consist of a series of


Page 29 of 31


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discrete reaction steps. The postulated mechanism was used as the basis for development of a simulation model, which has helped to rationalize measured conversion, enantioselectivity and reaction rate data as a function of raw material ratios. The numerical values for enantioselectivity and conversion calculated on the basis of the proposed mechanism were found to give good agreement with most of the experimental data acquired. The model proved to be very useful for optimization, fine-tuning and troubleshooting of the enantioselective alkynylation reaction in spite of the assumptions and simplifications made during its development.

4. EXPERIMENTAL SECTION Lithium

(2-amino-5-chlorophenyl)-chloro-bis-trifluoromethyl-1,4-dihydro-2H-

benzo[d][1,3]oxazin-4-olate (19, M = Li) as a solution in THF-d8. A solution of 8 (2.00 g, 8.9 mmol) in THF-d8 (8.3 g) was cooled to 5°C before addition of n-BuLi (1.6 M in hexane, 4.3 mmol) over 20 minutes at 5°C. The pale yellow solution was stirred briefly before removal of a sample for NMR (1H and 13C) analysis at 0°C (see supporting information). 2-(2-Amino-5-chlorophenyl)-1,1,1-trifluoropropan-2-ol

(17)

and

2,8-Dichloro-6,12-

bis(trifluoromethyl)-5,6,11,12-tetrahydro-6,12-oxodibenzo[b,f]-1,5-diazocine (18) To a stirred solution of 8 (22.0 g, 100 mmol) in THF (45 mL) was added CH3MgCl (10, 3.0 M solution in THF, 35.1 g, 104.2 mmol) over 30 minutes at 18 – 24°C. To the dark red solution was added aqueous citric acid (1.0 M aqueous solution, 100 mmol) and EtOAc (100 mL). The layers were separated, and the organic layer was dried (MgSO4) and filtered. A portion of the solution was evaporated in vacuo, and the resulting oil (7.5 g) was chromatographed on Kieselgel 60 (14% EtOAc in hexane) to give 18 (2.50 g) as a yellow solid, Rf = 0.33 (14% EtOAc in hexane). An analytical sample of 18 was prepared by



Page 30 of 31

30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

recrystallization from iPrOH/H2O to give an off-white solid: mp 222°C; 1H NMR (400 MHz, DMSO-d6) δ: 6.89 (d, J = 9.3 Hz, 2H), 7.30 (m, 4H), 8.19 (s, 2H);

13

C NMR (125 MHz,

DMSO-d6) δ: 82.0 (q, J = 32 Hz), 119.1, 120.1, 122.5 (q, J = 284 Hz), 123.3, 124.2 (q, J = 2 Hz), 130.3, 140.4; 19F NMR (376 MHz, DMSO-d6) δ: -78.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H9Cl2F6N2O 428.991; Found 428.9996. The structure assignment of 18 is supported by an X-ray crystallographic structure determination (see supporting information). Further elution gave 8 (1.55 g) as a yellow solid, Rf = 0.17 (14% EtOAc in hexane). Further elution with 25% EtOAc in hexane gave 17 as a yellow solid, Rf = 0.07 (14% EtOAc in hexane). An analytical sample of 17 was prepared by sublimation at 62°C/4 mbar to give a pale yellow solid: mp 71°C; 1H NMR (400 MHz, DMSO-d6) δ: 1.73 (s, 3H), 5.70 (s, 2H), 6.67 (d, J = 8.3 Hz, 1H), 7.01 (s, 1H), 7.05 (m, 2H);

13

C NMR (125 MHz, DMSO-d6) δ:

22.7, 75.7 (q, J = 29 Hz), 118.3, 118.4, 121.3, 126.4 (q, J = 288 Hz), 127.7, 128.7, 147.3; 19

F NMR (376 MHz, DMSO-d6) δ: -79.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for

C9H10ClF3NO 240.0398; Found 240.0384.

Acknowledgements We thank our Lonza colleagues Dr. Michael Hauck (NMR spectroscopy), Dr. Silvan Eichenberger (HRMS), Dr. Stéphane Dubuis (reaction calorimetry and DoE discussions). We thank Dr. Markus Neuburger of the University of Basel for determination of the X-ray structure of compound 18.


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Supporting Information Spectral data for compounds 17, 18 and 19 (M = Li). X-ray structure determination of compound 18.

REFERENCES (1) Thompson, A. S.; Corley, E. G.; Huntington, M. F.; Grabowski, E.J.J. Tetrahedron Lett. 1995, 36, 8937. (2) Thompson, A.; Corley, E. G.; Huntington, M. F.; Grabowski, E.J.J.; Remenar, J. F.; Collum, D. B. J. Am. Chem. Soc. 1998, 120, 2028. (3) Tan, L.; Chen, C.-y.; Tillyer, R. D.; Grabowski, E. J. J.; Reider, P.J. Angew. Chem., Int. Ed. 1999, 38, 711 – 713. (4) Chen, C.-y.; Tan, L. Enantiomer 1999, 4, 599 – 608. (5) Chinkov, N.; Warm, A.; Carreira, E. M. Angew. Chem., Int. Ed. 2011, 50, 2957 – 2961. (6) Brenner, M.; Carreira, E. M.; Chinkov, N.; Lorenzi, M.; Warm, A.; Zimmermann, L. WO 2012048884, 2012. (7) Brenner, M.; Carreira, E. M.; Chinkov, N.; Lorenzi, M.; Warm, A.; Zimmermann, L. WO 2012048886, 2012. (8) Brenner, M.; Carreira, E. M.; Chinkov, N.; Lorenzi, M.; Warm, A.; Zimmermann, L. WO 2012048887, 2012. (9) The enantioselectivity of the reaction with the PMB-protected ketone 5 was significantly lower than that with 8.3-4 (10) Reaction of 2 with 26 in Scheme 10 (98.5% enantioselectivity), reaction of 2 with 26 in Scheme 13 (96.0% enantioselectivity), reaction of 16 with 26 in Scheme 11 (63.0% enantioselectivity).


Proposed Mechanism for the Enantioselective ... - ACS Publications

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