Asymmetric Organocatalysis in Drug DevelopmentâHighlights of

Subscriber access provided by UNIV OF DURHAM

Asymmetric Organocatalysis in Drug Development – Highlights of Recent Patent Literature David L Hughes Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00096 • Publication Date (Web): 19 Apr 2018 Downloaded from http://pubs.acs.org on April 19, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 36 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

Organic Process Research & Development

Asymmetric Organocatalysis in Drug Development – Highlights of Recent Patent Literature David L. Hughes Cidara Therapeutics, Inc., 6310 Nancy Ridge Dr., Suite 101, San Diego, California 92121, United States E-mail of corresponding author: [email protected]

1 ACS Paragon Plus Environment

Organic Process Research & Development 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

Page 2 of 36

GRAPHICAL ABSTRACT:

ABSTRACT: Enantioselective organocatalytic reactions published in the recent patent literature are highlighted in this review and include inter- and intramolecular phase transfer conjugate additions catalyzed by quaternized Cinchona alkaloids, a Diels-Alder reaction catalyzed by oxazaborolidine complexes, asymmetric Betti reactions, the Lonza synthesis of L-carnitine, and several CBS-reductions. KEY WORDS: organocatalysis, Cinchona alkaloids, phase transfer catalysis, asymmetric synthesis, oxazaborolidine, CBS-reduction


Page 3 of 36 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 current article continues a series of thematic reviews intended to highlight noteworthy chemistry from recent patents and patent applications that has not been published in journal articles.1 While patents generally provide minimal details and offer limited or no discussion of the results, nonetheless, patents often describe practical chemistry carried out on highly functionalized molecules of pharmaceutical interest. The patent literature thus often bridges the gap between methodology papers, which generally describe chemistry on simple substrates, and total synthesis papers, which tackle highly complex targets but often with reaction conditions that would not be practical on larger scale.

This review is focused on routes to approved drugs and drug candidates in development that employ an asymmetric organocatalysis step, published in the patent literature during years 2015 to early 2018.

Organocatalysis, broadly defined as the use of organic molecules of low-

molecular weight as reaction catalysts, has emerged in recent years as an effective and scalable enantioselective methodology, often providing complementary scope relative to metal-based catalysis and biocatalysis.2 The major modes of catalysis include hydrogen-bonding, ion pairing, Lewis acid-base interaction, and Bronsted acid-base pairing. Two broad reviews of applications of enantioselective organocatalysis in the pharmaceutical industry have been published, primarily focused on peer-reviewed journal publications.3

1. Asymmetric Phase Transfer Catalysis in the Preparation of Isoxazolines Afoxolaner, fluralaner, sarolaner, and lotailaner are isoxazoline insecticides that are approved veterinary drugs to control fleas and ticks in companion animals.4 The syntheses of this class of drugs and drug candidates rely on asymmetric phase transfer chemistry (PTC) to install the 3 ACS Paragon Plus Environment


Page 4 of 36

quaternary asymmetric center of the isooxazoline moiety. PTC is thought to introduce asymmetry via both ion-pairing and hydrogen-bonding effects. As noted in the review on phase transfer catalysis by Tan and Yasuda,5 a patent application from Nissan Chemical Industries in 2009 described the first asymmetric synthesis of isoxazolines using an intramolecular asymmetric conjugate addition catalyzed by Cinchona alkaloid catalysts, which provided the isooxazoline 2 in 95% yield and 78% ee using the anthracenyl catalyst 3 (Scheme 1).6 The double bond geometry in the starting material 1 did not appear to impact the enantioselectivity of the reaction, as comparative examples using 3:1 and 1:2 E/Z ratios afforded product having the same ee (54%) using 4-trifluoromethylbenzyl)dihydroquinidinium bromide as catalyst.

Scheme 1. Nissan Asymmetric Isoxazoline Synthesis

Br

OMe N OH

Br CF3

Me

N 3 (2%)

Br

50% aq. NH2OH, -15 oC Cl

Cl

1 (E/Z = 3:1)

CF3

Me

O

N O

NaOH, H2O, ClCH2CH2Cl 95%

2 (78% ee)

Cl

Cl

In a follow up publication in 2010, Matoba and co-workers suggested the reaction does not proceed via the oxime intermediate 6, since no cyclization of isolated oxime 6 occurred under


Page 5 of 36 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


phase transfer conditions and since cyclization would have to occur via the unfavorable 5-endotrig pathway.7 Instead they suggested the reaction proceeds via initial conjugate addition of hydroxylamine, which affords an intermediate that can then cyclize by the favored 5-exo-trig pathway (Scheme 2). The purported conjugate intermediate 7a, could not be isolated, and may be present only at low concentration due to the equilibrium with the more favored 7b arising from nucleophilic addition of the nitrogen. Scheme 2. Pathways for Isoxazoline Formation Ph F3C

O

Ph

NH2OH HCl Ph

EtOH, reflux

5

OH No cyclization

F3C

Ph 6

NH2 O O

50% aq, NH2OH catalyst CHCl3, CsOH -10 to -30 oC

N

Ph F3C

O Ph

Ph 8

7a

Ph OH F3C

N

Ph F3C

NHOH

Ph 7b

As reported in the Tan review,5 additional patent applications on the use of asymmetric PTC for the syntheses of isoxazolines were published by Nissan, Syngenta, and Zoetis in 2011 to 2013, with ee’s improved to >90% in several cases. Below, we highlight additional patent applications that have published in 2016 and 2017 describing new catalysts and applications for this transformation.



Page 6 of 36

A 2017 patent application from Merial describes the synthesis of (S)-afoxolaner using various substituted aryl quininium catalysts (Scheme 3, Table 1).8

Scheme 3. Enantioselective Synthesis of (S)-Afoxolaner Catalyzed by Substituted Quaterinized Quininium Salts

Table 1. Survey of Catalysts for Formation of (S)-Afoxolaner Entry

R1

R2

R3

R4

R5

ee (%)

1

H

H

OBn

OBn

OBn

83 (99)a

2

H

3

H

H

H

H

H

8

4

H

H

OPMB

OPMB

OPMB

80

5

H

H

OEt

OEt

OEt

80

6

H

H

OMe

OMe

OMe

80

7

H

OMe

OMe

OMe

H

74

8

H

O-i-Pr

O-i-Pr

O-i-Pr

H

60

anthracenyl

24


Page 7 of 36 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


9

allyl

H

OEt

OEt

OEt

0

10

H

Br

OEt

OEt

OEt

40

11

H

Cl

OEt

OEt

OEt

38

12

H

H

H

29

13

H

H

H

vinyl

H

7

14

H

H

H

NO2

H

9

15

allyl

H

OMe

OMe

OMe

0

a

-OCH2O-

After crystallization

A wide variation in enantioselectivity was observed, depending on the substitution pattern on the benzyl ring, as summarized below. A similar sensitivity of the enantioselectivity to the benzyl substituents was reported in the original asymmetric phase transfer publication by Dolling.9 1. The unsubstituted benzyl catalyst afforded only a slight 8% ee (entry 3). 2. The 3,4,5-tri-benzyloxy catalyst afforded the optimum enantioselectivity with an ee of 83%. The ee could be upgraded to 99% via crystallization from toluene with an overall isolated yield of 52% (entry 1). 3. The tri-ethoxy, tri-methoxy, and tri-OPMB analogs (entries 4 - 6) gave similar but slightly lower ee’s (80%) vs the tri-benzyloxy catalyst. 4. The 2,3,4-substitution pattern resulted in lower ee’s of 60-74% (entries 7 and 8), while the 2,3,4,5-substitution pattern (entries 10 and 11) gave much lower ee’s (38-40%), suggesting the ortho-substituent was impacting ion-pairing or hydrogen-bonding necessary for a tight binding to the substrate.



Page 8 of 36

5. The anthracenylmethyl analog (entry 2), which afforded a 78% ee with the Nissan substrate 1 (Scheme 1), only provided an ee of 24% with substrate 9. 6. No enantioselectivity was observed for catalysts in which the -OH group was replaced with O-allyl (entries 9 and 15), suggesting the hydroxyl group plays an important role in enantioselectivity via hydrogen bonding in the transition state, similar to the original report from Dolling in 1984.9

Two patent applications from Syngenta describe formation of oxazolines using dimeric Cinchona catalysts (Scheme 4).10 Dimeric catalysts, formed by linking the monomeric species via a xylenyl moiety, have been well-studied,11 but the Syngenta patents describe novel dimers linked via tetra-fluoro (10a, 10b) and tetra-chloro-xylenyl (10c) groups. A chemical yield of 86% was achieved with a 90:10 dr at the newly formed chiral center using the tetra-fluoro catalyst 10a. The product has another chiral center remote from the reaction site that partially epimerizes (up to 7%) when the phase transfer reaction was carried out at room temperature. Optimum conditions that resulted in only 1% epimerization were 2.5% of the tetrafluoro catalyst 10a, KOH, 50% aq. NH2OH, -10 oC, and dichloromethane as solvent. Scheme 4. Syngenta Isoxazoline Formation using Dimeric Catalysts


Page 9 of 36 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


2. Asymmetric Intermolecular Phase-Transfer Michael Additions A. Intermolecular Michael Additions to Create One Chiral Center Syngenta has been granted a patent for asymmetric Michael additions with cyanide and nitromethane using substrates similar to those described above for the formation of isoxazolines.12 For the Michael reaction with cyanide as nucleophile, anthrylmethyl quininium catalyst 3 (chloride counterion, 15 mol%) in toluene at 60 oC, with KCN (1.0 equiv) and acetone cyanohydrin (3.0 equiv) as the cyanide sources, afforded product 14 in 68% yield and with 90% 9 ACS Paragon Plus Environment


Page 10 of 36

ee (Scheme 5). Anhydrous conditions were used and no additional base was added. Use of 2,3,4,5,6-pentafluorophenyl)methyl quininium catalyst (20 %) afforded 66% yield and an 88% ee. For the Michael reaction with nitromethane, the reaction was carried out in neat nitromethane using 10 mole % of non-quaternized thiourea catalyst 16 at 50 oC for 2.5 days to afford a 77% yield of 15 with 97.4% ee (Scheme 5). Again no water or base was used for the reaction.

Scheme 5. Enantioselective Intermolecular Michael Addition to Generate Quaternary Carbon Center


Page 11 of 36 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


B. Intermolecular Michael Additions to Create Two Chiral Centers Entresto is a fixed-dose combination of sacubitril, a neprilysin (NEP) inhibitor, and valsartan, an angiotensin II receptor blocker, indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure.13 The final form of the API is a 1:1 co-crystal of the sodium salts of sacubitril and valsartan.14

Figure 1. Structures of Sacubitril and Valsartan

Sacubitril contains two chiral centers (Figure 1). Two previous approaches to installing the chiral centers have been disclosed by Novartis in the patent literature, both relying on the chiral pool for one center and substrate control to introduce the second (Scheme 6).15,16 In the first approach, the first chiral center was derived from the unnatural amino acid, D-tyrosine. The second center was introduced via hydrogenation of enoate 17, generating product 18 with 80:20 dr. Upgrade of the dr was achieved via subsequent crystallization.15 In the second approach, methylation of lactam 19 afforded 20 with selectivity of 83:17 to 92:8 in the eleven reported examples using the pivaloyl protecting group.16 Other protecting groups provided lower dr’s. The 11 ACS Paragon Plus Environment


Page 12 of 36

optimum conditions were use of KHMDS as base, dimethyl sulfate as methylating agent in toluene solution at -10 oC, affording 20 having 92:8 dr.

Scheme 6. Initial Approaches for Installation of 1,3-Stereochemistry of Sacubitril

A recent patent from Novartis describes two organocatalytic approaches to sacubitril to install both stereocenters simultaneously.17 In the first approach, propionaldehyde was reacted with the nitrovinyl Michael acceptor 21 with the diphenyl proline catalyst 22. While the chemical yield of product 23 was excellent (96%), only slight selectivity for the desired diastereomer (2R,4S) was realized (33%) (Scheme 7). In the second approach, the nitro compound 24 served as the nucleophile in the reaction with methacrolein, catalyzed by thiourea catalyst 25. This approach provided improved selectivity of 59% for the desired diastereomer, but was still modest (Scheme 8) and no details were provided on whether the dr could be improved via crystallization. While many other catalysts were noted 12 ACS Paragon Plus Environment

Page 13 of 36 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


in the patent specification, no other examples were provided. If improved diastereoselectivity could be realized, this approach would provide a much shorter manufacturing route to sacubitril.

Scheme 7. First Organocatalytic Approach to Sacubitril

Scheme 8. Second Organocatalytic Approach to Sacubitril

3. Organocatalytic Diels-Alder Reaction A patent application from Gilead describes an organocatalytic Diels-Alder reaction to synthesize an intermediate for an HCV inhibitor.18 The initial Medicinal Chemistry route used a chiral 13 ACS Paragon Plus Environment


Page 14 of 36

auxiliary approach to introduce the desired stereochemistry. The catalytic asymmetric DielsAlder approach was developed as a second generation process using the Corey oxazaborolidine catalyst 27 (Scheme 9), which introduces asymmetry via Lewis acid-base interactions. The catalyst loading was reduced to 6%, compared to 20% levels generally reported in the original publications.19 The chemistry is described in substantial detail on a multi-kilogram scale. The catalyst was prepared by treating (S)-diphenylprolinol (6.25 mol % relative to substrate 26) with tri-otolylboroxine (2.13 mol %) in toluene (3.3 volumes relative to 26) at room temperature, then concentrated to 0.8 volumes of toluene. The contents were cooled to 0 oC, then triflimide (5%) in CH2Cl2 was added, followed by 2,2,2-trifluoroethyl acrylate (26) (1.0 equiv). Isoprene (2.0 equiv) was added over 4 h, maintaining the temperature at 0 oC, affording cyclohexene product 28. When the reaction was complete (no time provided), the contents were concentrated to remove most of the CH2Cl2, then THF was added and the reaction mixture warmed to 40 oC. Lithium hydroxide in water was added over 1 h to cleave the trifluoroethyl ester. After a series of concentrations and solvent switches, morpholine was added in CH2Cl2/n-heptane to crystallize 29 as a morpholinium salt with 98.3% ee (no yield provided).

Scheme 9. Enantioselective Organocatalytic Diels-Alder Process


Page 15 of 36 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


4. Enantioselective Betti Reaction The 3-component reaction of aldehydes, primary aromatic amines and phenols to produce αaminobenzylphenols is known as the Betti reaction, named for Italian chemist Mario Betti who first reported the reaction in 1901.20 Over the past decade a number of groups have reported asymmetric variants of the reaction, generally employing a pre-formed imine that is often protected as a sulfonamide.21 A patent application from Avidin describes an enantioselective Betti reaction using quinidine and quinine to selectively form each product enantiomer.22 The catalysts were used at nearly a stoichiometric level (50 -70 mol %). While no information was provided on reduced catalyst loading, the high loading suggests the uncatalyzed reaction to generate racemic product might well be competitive.



Page 16 of 36

The most detailed example was described on an 11.5 g scale of 8-hydroxyquinoline (1.0 equiv) (Scheme 10). The reaction was carried out with formic acid (0.8 equiv), pyrimidine 30 (2.5 equiv) and 4-trifluoromethylbenzaldehyde (3.7 equiv) in the presence of quinine (0.7 equiv) for 6 days at 73 oC in acetonitrile. After work up, silica gel chromatography and crystallization from 2-PrOH, the product 31 was obtained in 41% yield with 96% chemical purity and 99+% ee. It was not noted if any ee upgrade occurred as a result of the crystallization step. Scheme 10. Enantioselective Betti Reaction with 8-Hydroxyquinoline

A wide range of substituted benzaldehydes, 8-hydroxyquinolines, and aminopyridine substrates was studied, as presented in Chart 1. Of the 32 examples reported, the ee’s of the isolated products were 99% in all cases except one.

Chart 1. Substrate Scope for 3-Component Asymmetric Betti Reaction


Page 17 of 36 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


For enantioselective organocatalytic Betti reactions, two proposals have been advanced in the literature to explain the observed selectivity, neither providing much evidence for their proposals. Tanazawa and co-workers suggested formation of an ion-pair between the catalyst and the phenol reactant, creating a chiral species which then reacts enantioselectively with the imine.21c Using cupreine-derived catalysts (similar to quinine and quinidine except with 6-OH instead of 6-OMe group), Chauhan and Chimni proposed that asymmetry was created via bifunctional catalysis with the 6-OH group of the catalyst hydrogen-bonding to the imine nitrogen and the quinuclidine nitrogen helping to deprotonate the phenolic OH.21a In the current examples using quinine and quinuclidine, it seems unlikely that dual activation of both the imine and phenol can occur via a single catalyst since the hydroxyl group and quinuclidine groups are in close proximity in these catalysts. Since 8-hydroxyquinoline contains both a hydrogen bond donor (-OH) and acceptor (quinoline N), the catalyst may hydrogen bond to the nucleophile to create an asymmetric complex and direct attack on one face of the imine (Figure 2). It would be interesting to determine if similar enantioselectivity could be obtained with 1-naphthols as substrate, which lack the quinoline nitrogen handle.



Page 18 of 36

Figure 2. Two-Point Hydrogen Bonding of 8-Hydroxyquinoline with Quinidine to Form an Asymmetric Complex

5. Synthesis of L-Carnitine via Organocatalytic [2+2]-Cycloaddition L-Carnitine plays a key role in human metabolism by facilitating the transport of fatty acids across the mitochondrial membrane in heart and muscle tissue, where oxidation occurs to produce energy. L-Carnitine is available via diet, primarily from red meat, and is also synthesized in vivo in the liver from lysine and methionine.23 L-Carnitine is approved in the U.S. for carnitine deficiency and is often used to treat patients undergoing hemodialysis. L-Carnitine is also available as a nutritional supplement and is suggested to be beneficial in treating a number of disorders such as myocardial injury and nervous system degenerative diseases. The original commercial route to L-carnitine developed by Lonza involved a racemic synthesis coupled with a resolution using L-tartaric acid (Scheme 11).24 Reaction of epichlorohydrin with trimethylamine afforded racemic chlorohydrin 32 which was resolved with L-tartaric acid. The chloride was displaced with cyanide to generate nitrile 33, which was then hydrolyzed to Lcarnitine. 18 ACS Paragon Plus Environment

Page 19 of 36 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


Scheme 11. First Commercial Synthesis of L-Carnitine

A second generation biocatalytic asymmetric route to L-carnitine was also developed at Lonza, starting from butyrolactone (Scheme 12).25 In the first step, butyrolactone was opened with HCl/EtOH followed by displacement of the resulting chloride with trimethylamine and ester hydrolysis to produce γ-butryobetaine (34). The fermentation was then carried out to install the hydroxyl group enantioselectively via the intermediate unsaturated acid 35. Scheme 12. Second GenerationAsymmetric Synthesis of L-Carnitine

Recent patent applications from Lonza describe a third generation route to L-carnitine involving an enantioselective organocatalytic [2+2]-cycloaddition step that leverages Lonza’s in-house 19 ACS Paragon Plus Environment


Page 20 of 36

production of ketene (Scheme 13).26 Press releases from Lonza, which refer to a new route starting from acetic acid (from which ketene is derived), suggests this third generation route may have been commercialized by Lonza.27

Scheme 13. Organocatalytic Route to L-Carnitine

A summary of seven experiments is presented in Table 2 for the enantioselective [2+2]cycloaddition of chloroacetaldehyde and ketene to generate beta-lactone 36. In a representative example, ketene was bubbled into a solution of chloroacetaldehyde, LiBF4 (75 mM), and Otrimethylsilylquinine (10 mol %) in acetonitrile/dichloromethane at -30 oC. The reaction was followed using in-line IR at a wavenumber of 1832 cm-1, diagnostic for the beta-lactone product 36. The reaction was quenched with aqueous bicarbonate solution, then the organic layer was separated and evaporated to dryness. Four experiments (entries 1-4) gave ee’s ranging from 6281%. In another set of experiments (entries 5-7), the bis-sulfonamide ligand 37 was used. The catalysts 38a and 38b were generated in situ from the bis-sulfonamide ligand 37 and either AlMe3 or


Page 21 of 36 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


AlEt3 in dichloromethane solution (Scheme 14).28 In the three experiments provided, AlMe3 complex 38b afforded the best enantioselectivity (87-94%) although conversions were a modest 34-45%.

Scheme 14. Preparation of Bis-Sulfonamide-Aluminum Catalyst Bn

Bn i-Pr

i-Pr

i-Pr

i-Pr

AlR3

HN

NH

SO2CF3

F3CO2S

CH2Cl2

N F3CO2S

Al R

N SO2CF3

38a R = Et 38b R = Me

37

Table 2. Summary of Enantioselective [2,2]-Cycloaddition Experiments with TMS-Quinine and Sulfonamide-Al catalysts 38a and 38b Entry Catalyst (loading) Reaction Conditions 1

TMSQ (10%)

CH2Cl2/MeCN, -30 oC,

Conversion ee (%) 81%

81%

--

--

32%

62%

--

76%

LiBF4 (0.075M) 2

TMSQ (10%)

CH2Cl2/THF, -50 oC, LiClO4 (0.075M)

3

TMSQ (10%)

CH2Cl2/THF, -30 oC, LiClO4 (0.075M)

4

TMSQ (10%)

CH2Cl2/MeCN, -30 oC, LiClO4 (0.075M), i-Pr2NEt



5

Ligand 37 (5%),

Page 22 of 36

-40 oC, CH2Cl2

62%

54%

-40 oC, CH2Cl2

34%

87%

-78oC, CH2Cl2

45%

94%

AlEt3 (7.5%) 6

Ligand 37 (5%), AlMe3 (7.5%)

7

Ligand 37 (5%), AlMe3 (7.5%)

In the second step, the lactone 36 was reacted with trimethylamine in an aqueous solution of NaOH at 0 oC for one hour followed by room temperature for one 1 hour, resulting in lactone ring opening and chloride displacement in a single step (Scheme 13). According to the patent specification, this step required considerable development to achieve a high yield with minimal side reactions. The best conditions involved mixing trimethylamine and NaOH in water, then either adding that solution to the substrate, or the reverse addition, at 0 oC, followed by warming to room temperature after one hour. Sequential addition of NaOH or trimethylamine resulted in more by-products such as 4-hydroxycrotonic acid. Work up consisted of desalting the aqueous solution via membrane-based electrodialysis, then concentration of the resulting stream to a solid by rotary evaporation. Crystallization was carried out by dissolution in EtOH at 65 oC, cooling to 37 oC, seeding, then addition of acetone over a 2 h period, followed by cooling to 10 oC, to afford L-carnitine in 88% yield across the crystallization step with 99% chemical purity and 99.6% ee. While the reported yields and conversions are modest, additional development may have been carried out that is not reported in the patents. In addition, even if the yield is modest, the route is


Page 23 of 36 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


only two steps from very simple starting materials, much shorter than the original chemical route, and avoids the complex fermentation involved in the second generation route.

6. Enantioselective Oxazaborolidine-Catalyzed Ketone Reductions First reported by Corey and Itsuno and their co-workers,29 oxazaborolidine-catalyzed asymmetric ketone reductions have proven to be versatile reactions that have been widely used by industrial chemists over the past 25 years.30 The catalysts are commonly referred to as “CBS,” for the three authors from the first paper from the Corey group (Corey, Bakshi, and Shibata). The active reducing agent is a complex of the oxazaborolidine and BH3 (39), which can be isolated as a crystalline solid (Scheme 15).31a,b The first large scale application was reported by Merck process chemists in 1991 for the preparation of the carbonic anhydrase inhibitor MK-0417.31c,d Other published industrial applications up to 2011 have been reviewed previously.3a Scheme 15. Formation of Active Oxazaborolidine Reducing Agent

A summary of examples from the patent literature from years 2016 and 2017 is provided in Table 3. The most common application of this reaction has been for the preparation of prostaglandin analogs (entries 1-7, 11, 12, 14), where remarkable selectivity (either enantioselectivity or diastereoselectivity) has been achieved in many cases where the two substituents on either side of the ketone are quite similar electronically and sterically. 23 ACS Paragon Plus Environment


Page 24 of 36

(R)- and (S)-methyl CBS-oxazaborolidine are available as neat liquids and as 1.0 M solutions in toluene and are the predominate catalysts used for asymmetric reductions in Table 3. (R)- and (S)-2-butyl CBS-oxazaborolidine are also available as 1.0M solutions in toluene (example 3). The most common co-reducing agent is borane-dimethyl sulfide (8 of the 15 entries) which is available as a neat liquid and also as 2.0M solutions in toluene and THF, which are common solvents for the asymmetric reductions. The other reducing agents include borane-THF, catechol borane, and borane-diethylaniline. Temperatures for the reaction range from -50 oC to room temperature. Other reducible functional groups, including esters, amides, nitro groups, double and triple bonds, are compatible with the conditions. The reduction can also take place in the presence of an alcohol (entry 3), but this particular reaction required 3 equiv of the oxazaboroline vs 2 equiv when the alcohol was protected as a TBS group (entry 2). Table 3. CBS-Catalyzed Asymmetric Reductions Entry Conditions 1

Product

R-2-Me-CBS (0.33 equiv),

Ref 32

catechol-borane (1.5 equiv), THF-toluene, -10 o

C, 55% yield, 92% de

(98% after crystallization) 2

R-2-Me-CBS (2 equiv),

33

BH3-SMe2, toluene, -30 o

C, 87% yield


Page 25 of 36 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


3

33

R-2-Bu-CBS (3 equiv), catechol-borane, toluene, 10 oC, 77% yield

4

R-2-Me-CBS, BH3-SMe2,

34

THF-toluene, -30 oC, 100% yield

5


34

BH3-SMe2 (2.7 equiv), THF-toluene, -40 oC, 94% yield

6

R-2-Me-CBS, BH3-SMe2

34

(4.0 equiv), THF-toluene 40 oC, 95% yield

7


35

BH3-SMe2(4.0 equiv), THF-toluene, -50 oC, 96.6% de



8

S-2-Me-CBS, BH3-SMe2,

Page 26 of 36

36

toluene and THF or CH2Cl2, 98-99% ee

9

R-2-Me-CBS, BH3-

37

PhNEt2, CH2Cl2-THF, -10 o

C, 88% yield, >97% ee

10

R-2-Me-CBS, BH3-SMe2,

38

CH2Cl2, 0 oC, 20 h, 97% ee

11

R-2-Me-CBS, BH3-

39

THF,THF-toluene, -70 oC, 85% yield

12

R-2-Me-CBS, BH3-

39

THF,THF-toluene, -70 oC, 79% yield


Page 27 of 36 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


13

R-2-Me-CBS, BH3-

40

THF,THF, -20 oC, single diastereomer at hydroxyl center

14

R-2-Me-CBS, BH3-

41

Me2S,THF-toluene, Room temp

15

R-2-Me-CBS, catechol-

42

borane, CH2Cl2, room temp, 99:1 dr

Summary Novel and expedient asymmetric organocatalytic methodologies have emerged in recent years that are often complementary in scope to metal-based catalysis and biocatalysis. Organocatalysis offers several potential advantages over other asymmetric methodologies, such as avoidance of



Page 28 of 36

precious metals, use of mild conditions, and access to a large pool of inexpensive chiral natural product catalysts that are non-toxic and insensitive to moisture and oxygen. Despite these potential advantages, application in industry has so far been relatively limited. A true understanding of the slow uptake would require a deeper analysis, but some possible reasons may include the following: 1) While cheap natural products such as amino acids may be available as catalyst sources, some of the most effective organocatalysts are complex to prepare and expensive, and often must be used at high loadings. 2) Some organocatalytic reactions have limited scope such that the catalyst must be tuned for a specific substrate. Many published methodologies from academic labs include only simple substrates and translation to highly functionalized molecules of pharmaceutical interest may not be straightforward. 3) A lag time exists between academic discovery and industry uptake. Process chemistry in the pharmaceutical industry has been focused in the past decade on implementing metalbased catalysis and biocatalysis. Bandwidth constraints has likely limited a similar emphasis on organocatalysis. Organocatalysis is a rapidly growing field and its use in the hands of industrial chemists is likely to expand as the scope, reliability, and catalyst availability continue to grow. As the examples provided in this short review have shown, organocatalysis can provide practical and efficient routes to molecules of pharmaceutical interest. References


Page 29 of 36 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


(1) Previous publication in this series. Hughes, D. Applications of Flow Chemistry in Drug Development – Highlights of Recent Patent Literature, Org. Process Res. Dev. 2018, 22, 13-20. (2) (a) Berkessel, A.; Gröger, H. Asymmetric Organocatalysis: From Biomimetic Concepts to Applications in Asymmetric Synthesis; Wiley-VCH: Weinheim, Germany, 2005. (b) Dalko, P. I. Ed. Enantioselective Organocatalysis: Reactions and Experimental Procedures; WileyVCH: Weinheim, 2007. (c) Doyle, A. G.; Jacobsen, E. N. Small-Molecule H-Bond Donors in Asymmetric Catalysis, Chem. Rev. 2007, 107, 5713. (d) List, B. Asymmetric Organocatalysis; Springer: New York, 2009. (e) Pellissier, H. Recent Developments in Asymmetric Organocatalysis; RSC Publishing: Cambridge, U.K., 2012. (f) Dalko, P. I. Comprehensive Enantioselective Organocatalysis, Vols. 1−3; Wiley-VCH: Weinheim, Germany, 2013.

(3) (a) Bulger, P. G. Industrial Applications of Organocatalysis, in Comprehensive Chirality, Vol. 9; Carreira, E. M., Yamamoto, H., Eds.; Elsevier: Amsterdam, 2012, Chapter 10. (b) Xu, F. Organocatalysis for Asymmetric Synthesis: From Lab To Factory, in Sustainable Catalysis: Challenges and Practices for the Pharmaceutical and Fine Chemical Industries, (eds. Dunn, P.; Krische, M. J.; Williams, M. T.), John Wiley and Sons, Hoboken, NJ, 2013, 317-337.

(4) Casida, J. E. Golden Age of RyR and GABA-R Diamide and Isoxazoline Insecticides: Common Genesis, Serendipity, Surprises, Selectivity, and Safety, Chem. Res. Toxicol. 2015, 28, 560-566.

(5) Tan, J.; Yasuda, N. Contemporary Asymmetric Phase Transfer Catalysis: Large-Scale Industrial Applications, Org. Process Res. Dev. 2015, 19, 1731−1746.



Page 30 of 36

(6) Matoba, K. Method for Catalytic Asymmetric Synthesis of Optically Active Isoxazoline Compound. PCT Int. Patent Application, WO 2009063910, May 22, 2009. (7) Matoba, K.; Kawai, H.; Furukawa, T.; Kusada, A.; Tokunaga, E.; Nakamura, S.; Shiro, M. Shibata, N. Enantioselective Synthesis of Trifluoromethyl-Substituted 2-Isoxazolines: Asymmetric Hydroxylamine/Enone Cascade Reaction, Angew. Chem. Int. Ed. 2010, 49, 57625766. (8) Yang, C.; Le Hir de Fallois, L. P.; Meng, C. Q.; Long, A.; De Vries, R. J. G.; Baillon, B.; Lafont, S.; de Saint Michel, M. G.; Kozlovic, S. Process for the Preparation of Isoxazoline Compounds. U.S. Patent Application 2017/0311601 A1, Nov 2, 2017. (9) Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. Efficient Catalytic Asymmetric Alkylations. 1. Enantioselective Synthesis of (+)-Indacrinone via Chiral Phase-transfer Catalysis, J. Am. Chem. Soc. 1984, 106, 446-447. (10) (a) Smejkal, T.; Smits, H. Process for the Preparation of Optically Active Isoxazoline Compounds. U.S. Patent Application 2017/0217953, Aug 3, 2017. (b) Smejkal, T.; Smits, H. Process for the Preparation of Optically Active Isoxazoline Compounds. U.S. Patent 9,815,829, Nov 14, 2017. (11) Review of dimeric and trimeric Cinchona-based catalysts using o, m, and p-xylene and mesitylene as linkers: Przemysław J. Boratyński, P. J. Dimeric Cinchona Alkaloids, Mol. Diversity 2015, 19, 385-422. (12) El Qacemi, M.; Smits, H.; Cassayre, J. Y.; Mulholland, N. P.; Renold, P.; Godineau, E.; Pitterna, T. Process for the Preparation of Dihydropyrrole Derivatives. U.S. Patent Application 2016/0073631 A1, March 17, 2016.


Page 31 of 36 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


(13) https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207620Orig1s000lbl.pdf; accessed Mar 23, 2018. (14) (a) Feng, L.; Karpinski, P. H.; Sutton, P.; Liu, Y.; Hook, D. F.; Hu, B.; Blacklock, T. J.; Fanwick, P. E.; Prashad, M.; Godtfredsen, S.; Ziltener, C. LCZ696: A Dual-acting Sodium Supramolecular Complex, Tetrahedron Lett. 2012, 53, 275-276. (b) Feng, L.; Godtfredsen, S. E.; Hu, B.; Liu, Y.; Karpinski, P.; Sutton, P. A.; Prashad, M.; Girgis, M. J.; Blacklock, T. J. Compounds Containing S-N-Valeryl-N-{[2’-(1H-tetrazole-5-yl)-biphenyl-4-yl-4-(3-carboxyproprionylamino)-2-methyl-pentanoic Acid Ethyl Ester Moieties and Cations. U.S. Patent 8,877,938 B2, Nov 4, 2014. (15) Ksander. G. Biaryl Substituted 4-Amino-butyric Acid Amides. U.S. Patent 5,217,996, Jun 8, 1993. (16) Hook, D.; Ruch, T.; Riss, B.; Wietfeld, B.; Sedelmeier, G.; Napp, M.; Banziger, M.; Hawker, S.; Ciszewski, L.; Waykole, L. M. Process for Preparing 5-Biphenyl-4-amino-2-methyl Pentanoic Acid. Int. Patent Application WO 2008083967, Jul 17, 2008. (17) Martin, L.; Mandrelli, F.; Venturoni, F. Process and Intermediates for the Preparation of NEP Inhibitors. U.S. Patent Application 2018/0022690 A1, Jan 25, 2018. (18) Watkins, W. J.; Liu, Q. Synthesis of an Antiviral Compound. U.S. Patent 8,927,741 B2, Jan 6, 2015. (19) (a) Original publication: Ryu, D. H.; Lee, T. W.; Corey, E. J. Broad-Spectrum Enantioselective Diels−Alder Catalysis by Chiral, Cationic Oxazaborolidines, J. Am. Chem. Soc. 2002, 124, 99929993. (b) Use of triflimide as the acid catalyst: Ryu, D. H.; Corey, E. J. Triflimide Activation of a Chiral Oxazaborolidine Leads to a More General Catalytic System for Enantioselective Diels−Alder Addition, J. Am. Chem. Soc. 2003, 125, 6388-6390. (c) Use of trifluoroethyl acrylate



Page 32 of 36

to improve enantioselectivity: Ryu, D. H.; Kim, K. H.; Sim, J. Y.; Corey, E. J. Catalytic Enantioselective Diels–Alder Reactions of Furans and 1,1,1-Trifluoroethyl Acrylate, Tetrahedron Lett. 2007, 48, 5735-5737. (d) Review: Murkhejee, S.; Corey, E. J. Enantioselective Synthesis Based on Catalysis by Chiral Oxazaborolidinium Cations, Aldrichimica Acta 2010, 43 (2), 49-59. (20) (a) Betti, M. Reazione Generale di Condensazione fra β-Naftolo, Aldeidi e Amine. Gazz. Chim. Ital. 1901, 31, 377-393. (b) Betti, M. β-Naphthol Phenylaminomethane, Org. Synth. 1929, 9, 60. (21) (a) Chauhan, P.; Chimni, S. S. Asymmetric Organocatalytic Aza‐Friedel–Crafts Reaction of Naphthols with N‐Sulfonyl Imines, Eur. J Org. Chem. 2011, 1636-1640. (b) Zhou, D.; Huang, Z.; Yu, X.; Wang, Y.; Li, J.; Wang, W.; Xie, H. A Quinine-Squaramide Catalyzed Enantioselective Aza-Friedel–Crafts Reaction of Cyclic Trifluoromethyl Ketimines with Naphthols and Electron-Rich Phenols, Org. Lett. 2015, 17, 5554-5557. (c) Takizawa, S.; Sako, M.; Aboseid, M. A.; Kishi, K.; Wathsala, H. D. P.; Hirata, S.; Murai, K.; Fujioka, H.; Sasai, H. Enantio- and Diastereoselective Betti/aza-Michael Sequence: Single Operated Preparation of Chiral 1,3-Disubstituted Isoindolines, Org. Lett. 2017, 19, 5426-5429, and references found therein. (22) Puskas, L.; Kanizsai, I.; Pillot, T.; Gyuris, M.; Szabo, A.; Takacs, F.; Hackler, L. Enantiomers of 8-Hydroxyquinoline Derivatives and the Synthesis Thereof. U.S. Patent Application 2017/0197936 A1, Jul 13, 2017. (23) Rebouche, C. J. Carnitine Function and Requirements During the Life Cycle, The FASEB Journal 1992, 6, 3379-3386. (24) (a) Hardt, P.; Stravs, A.; Brig, R. B.; Abgottspon, P. Process for the Production of GammaBuryobetaine. U.S. Patent 5,087,745, Feb 11, 1992. (b) Voeffray, R.; Perlberger, J.-C.; Tenud,


Page 33 of 36 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


L.; Gosteli, J. L‐Carnitine. Novel Synthesis and Determination of the Optical Purity, Helv. Chim. Acta. 1987, 70, 2058-2064. (25) (a) Kulla, H. G. Enzymatic Hydroxylations in Industrial Application, Chimia 1991, 45, 81-85. (b) Meyer, H.-P., Robins, K.T. Large Scale Bioprocess for the Production of Optically Pure LCarnitine, Monatsh. Chem. 2005, 136, 1269-1277. (26) (a) Hanselmann, P.; Klegraf, E. Process for the Production of Carnitine from Beta-Lactones. U.S. Patent Application 2015/0126775 A1, May 7, 2015. (b) Hanselmann, P.; Klegraf, E. Process for the Production of Carnitine from Beta-Lactones. U.S. Patent 9,394,238 B2, Jul 19, 2016. (c) Hanselmann, P.; Klegraf, E.; Elzner, S.; Quittmann, W.; Fischer, D. F. Process for the Production of Carnitine by Cycloaddition. U.S. Patent 8,563,752 B2, Oct 22, 2013. (d) Hanselmann, P.; Klegraf, E.; Elzner, S.; Quittmann, W.; Fischer, D. F. Process for the Production of Carnitine by Cycloaddition. U.S. Patent Application 2012/002227 A1, Jan 26, 2012. (27) (a) file:///C:/Users/dhughes/Downloads/140327_Carniking_News_Release_Next_Generation%20(3) .pdf; accessed, Mar 1, 2018. (b) http://www.feedstuffs.com/story-lonzas-nextgenerationcarnitine-process-52-111433; accessed, Mar 1, 2018. (28) Kull, T.; Peters, R. Practical Enantioselective Synthesis of β‐Lactones Catalyzed by Aluminum Bissulfonamide Complexes, Adv. Synth. Catal. 2007, 349, 1647–1652. (29) (a) Itsuno, S.; Ito, K.; Hirao, A.; Nakahama, S. Asymmetric Reduction of Aromatic Ketones with the Reagent Prepared from (S)-(–)-2-Amino-3-methyl-1,1-diphenylbutan-1-ol and Borane, J. Chem. Soc., Chem Commun. 1983, 469-470. (b) Itsuno, S.; Hirao, A.; Nakahama, S.; Yamazaki, N. Asymmetric Synthesis using Chirally Modified Borohydrides. Part 1.



Page 34 of 36

Enantioselective Reduction of Aromatic Ketones with the Reagent Prepared from Borane and (S)-Valinol J. Chem. Soc., Perkin Trans. 1 1983, 1673-1676. (c) Itsuno, S.; Nakano, M.; Ito, K. Asymmetric Synthesis using Chirally Modified Borohydrides. Part 4. Enantio-selective Reduction of Ketones and Oxime Ethers with the Reagent Prepared from Borane and Polymersupported (S)-(–)-2-amino-3-(p-hydroxyphenyl)-1,1-diphenylpropan-1-ol, J. Chem. Soc., Perkin Trans. 1. 1985, 2615-2619. (d) Corey, E. J.; Baksi, R. K.; Shibata, S. Highly Enantioselective Borane Reduction of Ketones Catalyzed by Chiral Oxazaborolidines. Mechanism and Synthetic Implications, J. Am. Chem. Soc. 1987, 109, 5551–5553. (e) Itsuno, S.; Sakurai, Y.; Ito, K.; Hirao, A.; Nakahama, S. Catalytic Behavior of Optically Active Amino Alcohol–Borane Complex in the Enantioselective Reduction of Acetophenone Oxime O-Alkyl Ethers, Bull. Chem. Soc. Jap. 1987, 60, 395–396. (30) Reviews: (a) reference 3a. (b) Corey, E. J.; Helal, C. J. Reduction of Carbonyl Compounds with Chiral Oxazaborolidine Catalysts: A New Paradigm for Enantioselective Catalysis and a Powerful New Synthetic Method, Angew. Chem. Int. Ed. 1998, 37, 1986–2010. (b) Itsuno, S. Enantioselective Reduction of Ketones, Org. Reactions 1998, 52, 395–576. (c) Burkhardt, E. R.; Matos, K. Boron Reagents in Process Chemistry: Excellent Tools for Selective Reductions, Chem. Rev. 2006, 106, 2617–2650. (31) (a) Mathre, D. J.; Jones, T. K.; Xavier, L. C.; Blacklock, T. J.; Reamer, R. A.; Mohan, J. J.; Jones, E. T. T.; Hoogsteen, K.; Baum, M. W.; Grabowski, E. J. J. A Practical Enantioselective Synthesis of α,α-Diaryl-2-pyrrolidinemethanol. Preparation and Chemistry of the Corresponding Oxazaborolidines, J. Org. Chem. 1991, 56, 751-762. (b) Mathre, D. J.; Thompson, A. S.; Douglas, A. W.; Hoogsteen, K.; Carroll, J. D.; Corley, E. G.; Grabowski, E. J. J. A Practical Process for the Preparation of Tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-


Page 35 of 36 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


c][1,3,2]oxazaborole-borane. A highly Enantioselective Stoichiometric and Catalytic Reducing Agent, J. Org. Chem. 1993, 58, 2880-2888. (c) Jones, T. K.; Mohan, J. J.; Xavier, L. C.; Blacklock, T. J.; Mathre, D. J.; Sohar, P.; Jones, E. T. T.; Reamer, R. A.; Roberts, F. E.; Grabowski, E. J. J. J. An Asymmetric Synthesis of MK-0417. Observations on Oxazaborolidine-catalyzed Reductions, Org. Chem. 1991, 56, 763–769. (d) King, A. O.; Mathre, D. J.; Tschaen, D. M.; Shinkai, I. The Practical Enantioselective Reduction of Prochiral Ketones, in Reductions in Organic Synthesis. ACS Symposium Series, Vol 641, (Abdel-Magid, A. F., ed), Washington, D.C.: American Chemical Society, 1996, Chapter 6, 98-111. (32) Kardos, Z.; Kiss, T.; Laszlofi, I.; Hortobagyi, I.; Bischof, Z.; Bodis, A. M.; Havasi, G. Process for the Preparation of Travoprost. U.S. Patent Application 2016/0137621 A1, May 19, 2016. (33) Batra, H.; Tuladhar, S. M.; Tummala, S. H.; Penmasta, R.; Walsh, D. A. Methods for Producing Beraprost and its Derivatives. U.S. Patent Application 2017/0166545 A1, Jun 15, 2017. Sharma, V.; Batra, H.; Tuladhar, S. Method of Producing Beraprost. U.S. Patent 9,611,243 B2, Apr 4, 2017. (34) Juhasz, I.; Hortobagyi, I.; Altsach, T.; Laszlofl, I.; Nagyne Borko, A.; Rozsumberszki, I.; Havasi, G.; Kardos, Z.; Buzder-Lantos, P. Process for the Preparation of Treprostinil. U.S. Patent Application 2017/0313643 A1, Nov 2, 2017. (35) Hering, K. W.; Chambournier, G.; Endres, G. W.; Krell II, T. J.; Mahmoud, H. M. Methodsof Synthesizing a Protacyclin Analog. U.S. Patent Application 2017/0297995 A1, Oct 19, 2017. (36) Bhirud, S. B.; Bhushan, K. H.; Zhope, S. S.; Ghadigaonkar, S. G.; Singh, F.; Deshmukh, S. A.; Chand, P. Process for the Preparation of Luliconazole. U.S. Patent Application 2017/0362212 A1, Dec 21, 2017.



Page 36 of 36

(37) Reddy, G. P.; Sanku, V. A Process for Preparing Olodaterol and Intermediates Thereof. U.S. 2017/0260149 A1, Sep 14, 2017. (38) Nozulak, J.; Kalkman, H.; Benzisoxazoles. U.S. Patent Application 2017/0129878 A1, May 11, 2017. (39) Yiannikouros, G. P.; Gamage, C. P.; Arefyev, D. V. Novel Synthesis Routes for Prostaglandins and Prostaglandin Intermediates Using Metathesis. U.S. Patent Application 2016/0237056 A1, Aug 18, 2016. (40) Zheng, G.; Want, Y.; Feng, S. Synthetic Intermediate of Maxacalcitol, Preparation Method Therefor and Use Thereof. U.S. Patent Application 2016/0237030 A1, Aug 18, 2016. (41) Kambe, T.; Maruyama, T.; Yamane, S.; Nakayama, S.; Tani, K. Bicyclic Compound and Use Thereof for Medical Purposes. U.S. Patent Application 2016/0287551 A1, Oct 6, 2016. (42) Barrett, S. D.; Ciske, F. L.; Colombo, J. M.; Endress, G. W.; Germaln, B. D.; Komilov, A.; Uzieblo, A.; Owen, T. A.; O’Malley, J. P. Difluorolactam Compositions for EP4-Mediated Osteo Related Diseases and Conditions. U.S. Patent Application 2017/0260173 A1, Sep 14, 2017.


Asymmetric Organocatalysis in Drug DevelopmentâHighlights of

Recommend Documents

Asymmetric Organocatalysis in Drug DevelopmentâHighlights of