Synthesis of a CGRP Receptor Antagonist via an Asymmetric Synthesis of 3-Fluoro-4-aminopiperidine

Article abstract of DOI:10.1021/acs.joc.9b00569

A practical and efficient enantioselective synthesis of the calcitonin gene-related peptide receptor antagonist 1 has been developed. The key structural component of the active pharmaceutical ingredient is a syn-1,2-amino-fluoropiperidine 4. Two approaches were developed to synthesize this important pharmacophore. Initially, Ru-catalyzed asymmetric hydrogenation of fluoride-substituted enamide 8 enabled the synthesis of sufficient quantities of compound 1 to support early preclinical studies. Subsequently, a novel, cost-effective route to this intermediate was developed utilizing a dynamic kinetic asymmetric transamination of ketone 9. This synthesis also features a robust Ullmann coupling to install a bis-aryl ether using a soluble Cu(I) catalyst. Finally, an enzymatic desymmetrization of meso-diester 7 was exploited for the construction of the γ-lactam moiety in 1.

Full text of DOI:10.1021/acs.joc.9b00569

Subscriber access provided by BUFFALO STATE
Article
Synthesis of a CGRP Receptor Antagonist via a
Asymmetric Synthesis of 3-Fluoro-4-aminopiperidine
Carmela Molinaro, Eric M. Phillips, Bangping Xiang, Erika M. Milczek, Michael Shevlin,
Jaume Balsells, Scott Ceglia, Jiahui Chen, Lu Chen, Qinghao Chen, Zhongbo Fei,
Scott Hoerrner, Ji Qi, Manuel de Lera Ruiz, Lushi Tan, Baoqiang Wan, and Jingjun Yin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00569 • Publication Date (Web): 24 May 2019
Downloaded from http://pubs.acs.org on May 24, 2019
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
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Synthesis of a CGRP Receptor Antagonist via a
Asymmetric Synthesis of 3-Fluoro-4-
aminopiperidine
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
Carmela Molinaro, ‡ Eric M. Phillips,* ‡ Bangping Xiang,*‡ Erika Milczek, ‡ Michael Shevlin, ‡
Jaume Balsells,† Scott Ceglia, ‡ Jiahui Chen, ± Lu Chen, ± Qinghao Chen, ‡ Zhongbo Fei, ‡ Scott
Hoerrner, ‡ Ji Qi, ± Manuel de Lera Ruiz,† Lushi Tan, ‡ Baoqiang Wan,± Jingjun Yin, ‡
‡Process Research & Development, Merck & Co., Inc., 126 E. Lincoln Avenue, Rahway, New
Jersey 07065, United States
†Process Research & Development, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA
19486, United States
± STA Pharmaceutical R&D Co., Ltd, 90 Delin Road, Waigaoqiao Free Trade Zone, Shanghai
200131
eric.phillips@merck.com, bangping_xiang@merck.com
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 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
ABSTRACT: A practical and efficient enantioselective synthesis of the CGRP receptor antagonist
1 has been developed. The key structural component of the API is a syn-1,2-amino-
fluoropiperidine 4. Two approaches were developed to synthesize this important pharmacophore.
Initially, Ru-catalyzed asymmetric hydrogenation of fluoride-substituted enamide 8 enabled the
synthesis of sufficient quantities of compound 1 to support early preclinical studies. Subsequently,
a novel, cost-effective route to this intermediate was developed utilizing a dynamic kinetic
asymmetric transamination of ketone 9. This synthesis also features a robust Ullmann coupling to
install a bis-aryl ether using a soluble Cu(I) catalyst. Finally, an enzymatic desymmetrization of
meso-diester 7 was exploited for the construction of the -lactam moiety in 1.
KEYWORDS: 3-Fluoro-4-aminopiperidine, Asymmetric Hydrogenation, Dynamic Kinetic
Asymmetric Transamination, Ullmann Coupling, Enzymatic Enantioselective Hydrolysis, CGRP
Receptor
2
ACS Paragon Plus Environment

Page 3 of 36
The Journal of Organic Chemistry
1
2
3
4
Introduction
5
6
7
8
Migraine is a debilitating neurovascular disease that causes severe headaches often accompanied
with nausea and vomiting in nearly 12% of adults worldwide.1 The main course of treatment for
migraine has relied on the triptan class of 5-HT1B/1D receptor agonists.2 Unfortunately, patients
treated with these agents are frequently plagued by vasoconstrictive effects, and those with
cardiovascular issues can be precluded from usage.3 Calcitonin gene-related peptide (CGRP) is
also believed to have a role in migraines; its mechanism of action avoids the vasoconstrictor off-
target effect of triptans and should therefore offer a significant advantage over triptans.4,5 As part
of our discovery CGRP program, compound 1 was identified as a potent CGRP receptor antagonist
and was selected as a preclinical candidate (Scheme 1).
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 1. Retrosynthetic Plan for CGRP Receptor Antagonist 1
We describe herein a robust, scalable and enantioselective synthesis of 1. The molecule can be
disconnected into three fragments of similar complexity: aryl bromide 2, tetrasubstituted arene 3,
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 36
1
2
3
4
5
6
7
8
9
and chiral aminofluoropiperidine 4 (Scheme 1). The key structural component of the molecule,
syn-1,2-amino-fluoropiperidine 4, is prepared through two novel strategies: (1) asymmetric
hydrogenation of fluoroenamide 8, and (2) a novel and sustainable enzymatic dynamic
asymmetric-transamination of ketone 9. Enantioenriched -lactam 6 was obtained through an
enzyme-catalyzed desymmetrization of di-ester 7. An Ullmann coupling using a soluble Cu(I)
catalyst forms the key bis-aryl ether functionality between compounds 2 and 3 and, finally, an
amide coupling completes the synthesis of 1.
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
Results and Discussion
Synthesis of piperidine 4 (Asymmetric Hydrogenation Route). Asymmetric hydrogenation
has proven to be a highly robust and successful strategy for the construction of tertiary
stereocenters bearing an amine functionality.6 The vicinal syn functionality of piperidine 4
rendered an asymmetric hydrogenation approach particularly attractive. Additionally, this method
would allow us to employ a fluorine-containing starting material, obviating the need for a
potentially problematic stereoselective fluorination.7-8 Our success and rich experience in this field
led us to believe we could quickly identify and develop reliable hydrogenation conditions.9
Following the work of Stump et al.,10 we began by acylating pyridine 10 with benzoyl chloride
(Scheme 2). Pyridinium formation with benzyl bromide was followed with regioselective NaBH4-
mediated reduction to yield the key hydrogenation substrate, enamide 8.11
With substrate 8 in hand, we examined the desired asymmetric hydrogenation in the presence of
rhodium, ruthenium, and iridium catalysts formed from combination of 192 commercially
available chiral phosphines and the corresponding metal precursors.12 While iridium catalysts gave
4
ACS Paragon Plus Environment

Page 5 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
primarily reduction of both the olefin and the fluoride to form des-fluoro by-product 14, rhodium
and ruthenium complexes catalyzed significant conversions to the desired product 12 in up to 97%
ee (see supporting information). However, the reactions that were highly enantioselective also
produced more of the des-fluoro piperidine 14. Since the formation of by-product 14, which proved
difficult to separate from the desired product, was minimized in the presence of ruthenium, we
decided to focus our attention to the optimization of ruthenium--based systems.
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 catalyst formed from (COD)Ru(Me-allyl)2 and MeO-BIPHEP ligand13 (A108-1) initially
provided the product in the best yield and ee in THF (entries 1-5). Reduction of the catalyst loading
from 10% to 3% increased the ee from 79 to 86% while maintaining high conversion (entry 6);
however, the presence of stoichiometric HBF4ꞏOEt2 was required to avoid catalyst poisoning by
the substrate,14 but led to significant polymerization of the solvent and problematic isolation of the
product. While the reaction in the alternative solvent, 2-Me-THF, did not undergo acid-catalyzed
polymerization, mixtures of compound 12 and HBF4 in 2-Me-THF formed gummy solids that
proved difficult to stir. Addition of MeOH (10 v%) was sufficient to solubilize the reaction
mixture and provided similar results to THF (entry 6 vs 7). During reaction optimization, it was
observed that reactions would frequently stall with 1-10% remaining starting material 8, and an
additional catalyst charge was required to achieve complete conversion. We hypothesized that free
fluoride liberated during the formation of by-product 14 was a potential catalyst poison. This was
confirmed in an experiment where addition of 10 mol % TBAF resulted in a 3-fold decrease of
reaction conversion.15 A number of additives were screened at 1 mol % Ru-catalyst loading in an
attempt to sequester any free fluoride, with Ti(OiPr)4 providing significant enhancement in
reactivity (entries 18-19).16 Under optimized conditions of 1.1 equivalents HBF4ꞏOEt2 and 2
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 36
1
2
3
4
5
6
equiv. Ti(OiPr)4, complete conversion was obtained at 1 mol % catalyst loading (entry 10), giving
97% of compound 12 (86% ee) and only 3% of by-product 14.
7
8
9
With the optimal hydrogenation conditions in hand, we completed the synthesis of the amine
side chain (Scheme 2). Following an optical purity upgrade (from 86% ee to 99.8% ee) via
preparative supercritical fluid chromatography (SFC), we utilized Pd-catalyzed hydrogenolysis to
remove the benzyl protecting group of compound 12. The secondary amine was successfully
prepared using 5 mol % Pd/C under 45 psi H2 atmosphere. Subsequent reductive amination
furnished piperidine 13 in 70% yield over two steps. Lastly, hydrolysis of the benzamide moiety
was accomplished with HCl in 87% yield to provide the bis HCl salt of compound 4 in 28% yield
over 5 steps. Even though the asymmetric hydrogenation protocol provided quick entry to the
optically active piperidine side chain and allowed us to support preclinical studies, several
challenges still remained.
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 2. Synthesis of Piperidine 4 via Asymmetric Hydrogenation Route
Table 1a. Top Screening Results and Optimization of Asymmetric Hydrogenation of 8.
6
ACS Paragon Plus Environment

Page 7 of 36
The Journal of Organic Chemistry
1
2
3
(COD)Ru(Me-allyl)2 (xx mol %)
4
5
MeO
MeO
PR2
PR2
6
R = 2-furyl
7
8
9
NHBz
NHBz
NHBz
N
A108-1 (1.05 (xx) mol %)
HBF4·OEt2 (2 (xx) mol %)
F
F
+
1 equiv HBF4·OEt2
H2 (500 psi)
40 °C
N
N
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
8
12
14
Ph
Ph
Ph
Ratio
8 : 12 : 14
Ru
(mol %)
25
(% ee)
Entry
Solvent
Conc
1
2
3
4
5
10
10
10
10
10
MeOH
TFE
DCE
EtOAc
THF
0.02
0.02
0.02
0.02
0.02
61 36
7 87
0 95
3
6
5
60
12
43
83
79
1 82 17
1 94
5
6
7
8
3
3
1
1
1
THF
0.2
0.2
0.2
0.2
0.2
1 96
1 97
26 72
15 82
0 97
3
2
2
3
3
86
88
85
86
86
2-MeTHFb
2-MeTHFb
2-MeTHFb
2-MeTHFb
9c
10d
Conditions: a) (COD)Ru(Me-allyl)2 / A108-1 / HBF4·OEt2 (1 :
1.05 : 2), 1 equiv HBF4·OEt2, 500 psi H2, 40 °C. b) 10% v/v
MeOH added. c) 0.2 equiv Ti(OiPr)4 added. d) 2 equiv
Ti(OiPr)4 added and 1.1 equiv HBF4·OEt2 used.
Synthesis of piperidine 4 (Dynamic Asymmetric Transamination Route).
With an eye towards increased sustainability of our processes, we wished to reduce the use of
heavy transition metals in our long term routes. To this end, we envisioned utilizing biocatalytic
technology. Specifically, an enzyme-catalyzed dynamic asymmetric-transamination (DA-TA)
process of -fluoropiperidinone was identified (Scheme 3). Transaminations of ketones are well-
established,17,18 but no example involving -fluoroketones has been reported. The labile, fluorine-
bearing α-position would potentially allow us to simultaneously set the two desired stereocenters
in one step. Building upon our internal experience with Vernakalant,18f we envisioned that we
could access enantio- and diastereoenriched 4 through a similar approach. In addition to
minimizing heavy metal usage, this route potentially offered other benefits including higher
enantioselectivity and minimization of by-product 14 which was difficult to remove through
recrystallization and column chromatography.
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 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 3. Proposed Dynamic Kinetic Transamination
The initial DA-TA screening was performed with commercially available Codexis Inc.
transaminases using pyridoxal 5′-phosphate (PLP) as the cofactor and isopropylamine as the
nitrogen source.19 The screening of the panel was carried out under previously established
conditions for dynamic kinetic resolution-transaminations at pH 10.5 to promote epimerization of
the starting material. We were pleased to find that the initial results confirmed the feasibility of a
dynamic kinetic reaction for this substrate and delivered high selectivity. All the enzymes tested
enabled access to the syn-isomer with the (R)-configuration at the amine center (Table 2). We
explored both immobilized and lyophilized enzymes and the most promising enzyme was Codexis
ATA-303 (entries 1 and 2).20 Since the immobilized version of the enzyme gave the product in
lower d.r., we decided to pursue the optimization of this reaction with lyophilized enzyme. In this
first example, 79% ee was obtained with 16:1 d.r. We maximized the efficiency of the reaction by
increasing the substrate loading to 100 g/L and optimized the enzyme loading to 2 wt% while still
maintaining high d.r. 19:1 and improving the enantiomeric excess from 74% ee to 94% ee. (entries
2-4).
8
ACS Paragon Plus Environment

Page 9 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
Table 2a : Optimization of the Dynamic Kinetic Asymmetric Transamination of 9.
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 major by-products of this reaction were the de-fluorination products 17 and 18 which form
with the decrease in the pH of the reaction mixture over time. Minimization of 17 and 18 was
achieved by controlling and maintaining high pH (>9.5) of the mixture during the course of the
reaction (entries 6-7) with a borate buffer. Furthermore, any reversibility from 15 to 9 was
addressed by continuously feeding isopropylamine into the reaction and removing acetone from
the reaction mixture with a sweep of nitrogen or a slight vacuum, collectively leading to an increase
in conversion to the desired product (Scheme ).
Using this dynamic kinetic transamination, the piperidine 4 was prepared in 4 steps from the
enzymatic product 15 (Scheme 4). Benzoylation, followed by TFA-mediated Boc deprotection
provided 20 in 86% yield over 2 steps. At this point, several chiral acids were screened in order to
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 36
1
2
3
4
5
6
7
8
9
upgrade the enantioselectivity and diastereoselectivity of compound 20. D-dibenzoyltartaric acid
was selected for further development since it allowed for an ee upgrade from 92 to 96% ee and
removed ~3.5% of the undesired diastereomer. At this stage, the overall recovery after 2
crystallizations was 86% and the purity was >97% by HPLC. Reductive amination with tetrahydro-
4-H-pyran-4-one and NaBH(OAc)3 provided 13 in 87% yield, 99% ee and 93% purity. A second
chiral acid screen was explored at this stage to try to further improve the purity profile and
diastereoselectivity of 13. It was found that L-dibenzoyltartaric acid in a mixture of acetone and
THF (1:1 ratio) removed 1.7% of the undesired diastereomer with minimal loss of product to the
mother liquors. After a salting break, compound 13 was isolated in 95% yield, 99.3% ee and 98.4%
purity with ~1 % of the undesired diastereomer remaining. Finally, HCl-mediated deprotection of
13 provided 4 as the HCl salt in 95% yield.
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 4. Synthesis of Piperidine 4 through Dynamic Asymmetric-Transaminase Approach
Synthesis of lactam 6. -Substituted lactam 6 was prepared in 5 steps by desymmetrization of
commercially available di-ester 7 as shown in Scheme 5Scheme . Following the protocol of
10
ACS Paragon Plus Environment

Page 11 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Silverman,21 the initial enantioselective hydrolysis of dimethyl 3-methylglutarate (7) to the
corresponding acid 21 was possible using pig liver esterase (PLE) with strict control of the pH of
the reaction mixture at pH 7. This allowed for a reproducible and scalable process providing 96%
yield and 89% ee of the desired (S)-acid 21. A modified Curtius rearrangement with the use of
diphenylphosphoryl azide (DPPA)22 in hot BnOH, followed by hydrolysis, provided the CBz-
protected intermediate 23 in 62% yield, 89% ee and 83% purity by HPLC analysis for the 2 steps.
Enantiomeric purity upgrade of intermediate 23 was achieved by crystallization of its quinine salt
in acetonitrile yielding 99% ee in 82% yield.23 Finally, lactam formation via the corresponding
acid chloride, followed by hydrogenolysis, provided chiral lactam 6 in 77% yield, 99% ee and 96%
purity.24
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 5. Synthesis of Lactam 6
Synthesis of Phenol 3. The preparation of phenol 3 is presented in Scheme . The central arene
core of 3 was synthesized by alkylation of methyl 2-fluoro-5-hydroxy-4-methylbenzoate (25) with
iodomethane followed by radical bromination with AIBN/NBS. Approximately 25% over-
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 36
1
2
3
4
5
6
7
8
9
bromination product was observed in the reaction mixture; this impurity was reduced to the desired
product by adding diethylphosphite following the consumption of starting material,25 producing
benzyl bromide 26 in 88% yield and 98% purity over two steps. Reaction of lactam 6 with
electrophile 26 in the presence of KHMDS produced the desired alkylated product in 84% yield.
Finally, AlCl3-mediated deprotection of the methyl ether yielded compound 3 in 85% without any
observable hydrolysis of the methyl ester.
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 6. Synthesis of Phenol 3
Synthesis of Aryl Bromide 2. The pyridazine side chain 2 was constructed via a pyrrolidine-
promoted aldol reaction between isopropyl methyl ketone 27 and ethyl 2-oxoacetate to form the
corresponding secondary alcohol. After aqueous work-up, addition of hydrazine hydrate and
heating the reaction mixture produced pyridazine 28 in 51% yield over two steps after
recrystallization from a toluene:n-heptane mixture (Scheme ). Subsequent aryl bromide formation
i
was accomplished with POBr3 in CH3CN. Salt formation with HBr in PrOAc/CH3CN (6:1)
allowed for isolation of bromopyridazine 29 in 75% yield with a significant purity upgrade from
90% to 98%.
Our first attempt to affect a Suzuki coupling began by subjecting bromide 29 to boronic acid
3026 in the presence of (dppf)PdCl2 in THF. While we successfully synthesized 2 in 81% yield, a
12
ACS Paragon Plus Environment

Page 13 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
significant amount of impurity 32 was produced (table 3, entry 1). To obviate this challenge we
surveyed different solvents. Performing the reaction in toluene increased the yield to 92% while
limiting the dehalogenated side product (entry 2). Switching to CH3CN yielded 2 in 95% yield
while producing only 2% of impurity 32 (entry 3). We were able to limit the formation of 32 to
0.7% while maintaining a 97% assay yield27 by using boronic ester 3128 instead as the coupling
partner (entry 4). Following recrystallization from water/CH3CN, compound 2 was isolated in 87%
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
yield and 98.5% purity.
Br
O
Br
O
a, b
c
d
NH
N
N
N
Me
Me
27
N
N
Me
28
29
Me Me
2
Me Me
Me Me
Conditions : a) ethyl 2-oxoacetate, pyrrolidine, AcOH,
toluene, 48 oC. b) NH2NH2-H2O, AcOH, 52 oC, 51%.
c) POBr3, CH3CN, 82 oC, 75%. d) boronate ester 31,
CH3CN/H2O, K3PO4, (dppf)PdCl2, 50 oC, 87%.
Scheme 7. Synthesis of Aryl Bromide 2
Table 3a. Preparation of 2 through Suzuki Coupling
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 36
1
2
3
4
Bis Aryl Ether Synthesis
5
6
7
8
The synthesis of diaryl ethers has received much attention in the last two decades.29 We
envisioned that diaryl ether 33 could be obtained through a similar C-O coupling approach between
arene 3 and aryl bromide 2 (Figure 1). We started our screen with palladium-based catalyst
systems.30 Although the reactions proceeded to ~50% conversion at 5 mol % Pd (90% conversion
at 10 mol % Pd), the high catalyst loadings required for this system would have made the process
prohibitively expensive on scale (see supporting information). Also, isolation of diaryl ether 33
was challenging due to the presence of numerous impurities generated in these reactions.
Given our lack of success with Pd systems, we turned our attention to copper-based systems.31
Among the copper sources tested,32 CuI was selected due to its efficiency, low cost, and
availability. Arylations conducted in acetonitrile were cleaner and higher yielding than those
conducted in other solvents,33 and cesium carbonate was found to be the most efficient base.34,35
A set of 24 amine and ketone ligands was examined for the arylation of phenol 3 with bromide 2.
The reaction performance was reported as the ratio of product against biphenyl as the internal
standard (Pdt:IS ratio). Only the 1,3-diketone ligands 2-acetylcyclohexanone (AcHXn, L1) and
2,2,6,6-tetramethylheptane-3,5-dione (TMHD, L2),36 as well as trans-N,N’-dimethylcyclohexane-
1,2-diamine gave more than 10% conversion to product. Arylation of the diamine ligand led us to
focus on the diketone ligands for further optimization.
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 order to further improve the solubility of the copper catalyst and reaction rates, NaI and
tetrabutylammonium iodide (Bu4NI)37 were added to the reaction mixtures. The best conversion
and yield were obtained (89%) when using 10 mol % of CuI, 10 mol % Bu4NI, 25 mol % TMHD
and 3 equiv of Cs2CO3 at 60 oC in CH3CN. It is noteworthy that these conditions minimized the
formation of by-products 35 and 36, resulting from the diarylation of adventitious water by two
14
ACS Paragon Plus Environment

Page 15 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
equivalents of bromide 2 and de-bromination of bromide 2 , respectively. The superior reaction
profiles of the optimized conditions enabled the downstream processing of biaryl ether ester 2
without further purity upgrade. Saponification of the crude reaction mixture with LiOH, followed
by crystallization of the dicyclohexylamine salt in THF/MTBE (1:1) provided product 34 in 78%
isolated yield for 2 steps and 95% purity (Scheme 8).
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
Finally, after salt breaking with 1 M HCl, amide coupling between acid 34 and amine 4 afforded
the final product 1 (Scheme 8). While HATU-mediated coupling yielded product in >85%, the
side products generated under these reaction conditions rendered the isolation of 1 in >97% purity
by crystallization challenging. Alternatively, use of EDC/HOAt, without an exogenous base,
afforded compound 1 in 80% yield and 98.5% purity after recrystallization from a EtOAc:heptanes
mixture.
Figure 1. Ullmann Coupling Optimization
10
8
Pdt:IS 6
4
ratio
2
0
10 mol % CuI
25 mol % L1
NaI
10 mol % CuI
25 mol % L1
Bu4NI
20 mol % CuI
50 mol % L2
N/A
5 mol % CuI
12.5 mol % L2
Bu4NI
10 mol % CuI
25 mol % L2
NaI
10 mol % CuI
25 mol % L2
Bu4NI
conditions
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 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 8. Endgame to CGRP Receptor antagonist 1
Conclusion
In summary, an efficient, asymmetric synthesis of 1 has been demonstrated. The overall route
illustrates the positive impact chemo- and biocatalysis can have in enabling preclinical and early
clinical synthesis of pharmaceutical drug candidates. Development of a robust C-O coupling using
a diketone ligand enabled formation of the penultimate intermediate 34. A first-generation
asymmetric hydrogenation approach was undertaken for the preclinical delivery of piperidine 4.
Fluoride liberated during the reaction was discovered to be a catalyst poison. As a result, Ti(OiPr)4
was employed as a fluoride sequestration reagent which enabled full conversion during the
hydrogenation. Moderate enantioselectivities and high catalyst loadings provided impetus to
develop a more robust and sustainable synthesis of the amine side chain. In this vein, a novel
dynamic kinetic resolution was developed using a transaminase. We were able to directly and
simultaneously install the amine- and fluorine-bearing stereocenters. Additionally, a key
biocatalytic approach was undertaken and realized to provide lactam 6. The lactam was prepared
beginning with an enzymatic desymmetrization, subsequent Curtius rearrangement and ring
closure provided 6. Finally, a straightforward amide coupling provided final product 1. Eliminating
16
ACS Paragon Plus Environment

Page 17 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
the use of a heavy-metal mediated-asymmetric hydrogenation and SFC optical upgrades has made
this route attractive for a more sustainable and long term supply.
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
Experimental Section
Reactions were carried out under an atmosphere of dry nitrogen unless otherwise stated. Reagents
and solvents were used as received from commercial sources. 1H NMR spectra were recorded on
a 300, 400 or 500 MHz spectrometer. Chemical shifts are reported in ppm from tetramethylsilane
with the solvent resonance as the internal standard (dmso-d6: δ 2.49, chloroform-d: δ 7.24). Data
are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
br = broad, m = multiplet), integration and coupling constants (Hz). 13C NMR spectra were
recorded on a 75, 100 or 125 MHz spectrometer with complete proton decoupling. Chemical shifts
are reported in ppm from tetramethylsilane with the solvent as the internal reference (dmso-d6: δ
19
39.5, chloroform-d: δ 77.0). F NMR spectra were recorded on 282 or 375 MHz spectrometer
with complete proton decoupling. Chemical shifts are reported in ppm with α,α,α-trifluorotoluene
added as an internal reference (δ – 67).
(R)-5-Methoxy-3-methyl-5-oxopentanoic acid (21): To a reactor was charged K3PO4ꞏ3H2O
(56.1 kg) and water (112 kg). The contents were mixed at room temperature for 30 minutes. 35%
HCl (9.1 kg) was added dropwise until the pH of the mixture was 7.0. The reaction mixture was
cooled to 10-12 °C. PLE (1.39 kg) was charged and the contents stirred for 30 minutes. 7 (14.1
kg) was charged to the mixture followed by MeOH (14 kg). The contents were mixed 24 hours.
Following consumption of 7, 35% HCl (20 kg) was added dropwise over 1 hour until the pH of
the mixture was pH = 2.0 and then heated to 15-20 °C. Water (42 kg) was added, followed by IPAc
(140 kg) and IPA (14 kg). The phases were cut. The aqueous layer was back extracted with IPAc
(2 x 70 kg). The combined organic layers were washed with 1N HCl (29 kg) and concentrated to
an approximate volume of 42 L. The solvent was switched to only IPAc via distillation with a final
volume of ~22 L. The desired product 21 was isolated as a 38.2 wt% IPAc solution (32.5 kg,
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 36
1
2
3
4
5
95.8%). Analytical data for 10:38 1H NMR (400 MHz, CDCl3) δ 3.67 (m, 3 H), 2.36 (m, 5 H), 1.03
(m, 3 H). []D25: -1.60 (c 10.02, DMSO).
6
7
8
9
Methyl (S)-4-(((benzyloxy)carbonyl)amino)-3-methylbutanoate (22): To a reactor was charged
21 (3.62 kg, 85.7 wt% in IPAc, 1.0 equiv) followed by Et3N (2.16 kg), BnOH (2.10 kg) and toluene
(8.0 kg). The mixture was heated to 75-80 °C. DPPA (5.86 kg) was added over 4 hours while
maintaining the temperature. The contents were mixed for 1 hour and the mixture cooled to ~20
°C. 7% aqueous NaHCO3 (16 kg) was added, the layers mixed and separated. The aqueous layer
back extracted twice with Toluene (26.8 kg total). The combined organic layers were washed with
water (31 kg) and concentrated. The desired product 22 was isolated as a 46.9 wt% Toluene
solution (7.8 kg, 71.3%). Analytical data for 22: 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 5 H), 5.10
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
(s, 2 H), 3.67 (m, 3 H), 3.16 (m, 3 H), 2.19 (m, 2 H), 0.98 (m, 3 H); C{1H} NMR (100 MHz,
CDCl3) δ 173.2, 156.7, 136.6, 128.4, 128.3, 128.1, 128.0, 127.8, 66.5, 51.5, 46.4, 38.7, 31.1, 17.6;
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C14H20NO4 266.1314; Found: 266.1393. []D25: + 0.90
(c 12.27, DMSO).
(S)-4-(((Benzyloxy)carbonyl)amino)-3-methylbutanoic acid (23): To a reactor was charged 22
(3.66 kg, 46.9 wt% in toluene, 1 equiv) followed by 2M LiOH (2.78 kg). The contents were mixed
at room temperature for 16 hours. Following the consumption of 22, the layers were separated.
The aqueous layer was back extracted 3 times with MTBE (25.5 kg total). Discard the organic
layers. Acidify the aqueous layer with 5M HCl (15 kg) to pH 1-2 and extract with EtOAc (14.8
kg). Cut the layers and wash the organic layer twice with brine (21.5 kg total). Concentrate the
organic layer to ~8 L and solvent switched to ACN via distillation to a final volume of ~35 mL.
The desired product 23 was isolated as a 57.1 wt% CH3CN solution (5.1 kg, 85%).
Ee upgrade (Quinine salt formation/salt break): To a reactor was charged quinine (17 kg, 1.4
equiv) followed by CH3CN (600 kg) and the contents were mixed for 1 hour until the solution was
clear. 23 was added (9.1 kg, 63.9 wt% in CH3CN, 0.49 equiv) at 55-65 °C. Seeds were added (42
g) and the mixture stirred for 1 hour. Remaining 23 (9.59 kg, 63.9 wt% in CH3CN, 0.51 equiv)
was added dropwise over 1.5 hours. The contents were mixed at 55-65 °C for 1.5 hours and then
cooled to 15-30 °C and stirred for an additional 4 hours. The solids were collected by filtration and
washed three times with CH3CN (180 kg total). To a reactor at 25 °C was charged the cake (37.4
Kg) and CH2Cl2 (150 kg). 1N HCl (98 kg) was added in portion over 1 hour and adjusted to pH
18
ACS Paragon Plus Environment

Page 19 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1. The mixture was stirred for 2 hours and the layers separated. The aqueous layer was back
extracted with CH2Cl2 (72 kg). The combined organic layers were washed twice with water (141
kg total). The solution is distilled to a final volume of 40 L. The desired product was isolated as a
15.6 wt% solution (9.75 kg, 82%, 98.7% ee). Analytical data for 23: 1H NMR (400 MHz, CDCl3)
δ 7.36 (m, 5 H), 5.11 (m, 2 H), 3.17 (m, 2 H), 2.25 (m, 3 H), 1.02 (br d, J = 6.4 Hz, 3 H); 13C{1H}
NMR (100 MHz, CDCl3) δ 178.0, 156.9, 136.5, 128.6, 66.9, 46.3, 38.8, 31.0, 17.7; HRMS (ESI-
TOF) m/z: [M+H]+ calcd for C13H18NO4 252.1158; Found 252.1235; HRMS (ESI-TOF) m/z:
[M+Na]+ calcd for C13H17NNaO4 274.1158; Found: 274.1055. []D25= -3.46 (c 10.10, CHCl3).
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
Benzyl (S)-4-methyl-2-oxopyrrolidine-1-carboxylate (24): To a reactor was charged 23 (62.6
kg, 15.6 wt%) followed by CH2Cl2 (15 kg). (COCl)2 (8.0 kg) was added dropwise at 30 °C over 5
hours. The content were mixed at that temperature for 1-2 hours. Following consumption of 23
water (200 mL) was added dropwise over 3 hours to quench the reaction. The phases were cut.
The organic layer was washed three times with ater (90 kg total). The pH of the organic layer was
adjusted to 6-7 with 7% aqueous NaHCO3 (0.6 kg). The organic layer was washed twice with
water (60 kg total). The organic layer was distilled to a final volume of ~10 L. The desired product
was isolated as a 49 wt% solution in CH2Cl2 (17.45 kg, 94%). Analytical data for 24 : 1H NMR
(400 MHz, CDCl3) δ 7.38 (m, 5 H), 5.28 (s, 2 H), 5.11 (s, 1 H), 3.95 (dd, J = 10.8, 7.5 Hz, 1 H),
3.36 (dd, J = 10.5, 7.0 Hz, 1 H), 2.41 (m, 3 H), 1.15 (d, J = 6.8 Hz, 2 H); 13C{1H} NMR (100 MHz,
CDCl3) δ 176.8, 173.9, 151.4, 135.3, 128.4, 128.2, 68.0, 53.4, 40.9, 31.0, 25.9, 18.9; HRMS (ESI-
TOF) m/z: [M+Na]+ calcd for C13H15NNaO3 256.0944; Found: 256.0948. []D 25= + 1.60 (c 10.01,
DMSO).
(S)-4-Methylpyrrolidin-2-one (6): To a reactor was charged 24 (17.4 kg, 49 wt% in CH2Cl2, 1
equiv) followed by wet 10 wt% Pd/C (0.5 kg) and CH2Cl2 (119 kg). Purge the system with N2 (3x)
and H2 (3x). The reaction mixture was stirred at 25 °C at 0.30 Mpa for 8-24 hours. Following
consumption of 24 the mixture was filtered and rinsed with CH2Cl2 (35 kg). The solution was
concentrated to ~9 L and solvent switched to THF. The desired product 6 was isolated as a 26.3
wt% solution in THF (2.96 kg, 83%, 98.6% ee). Analytical data for 6:39 1H NMR (400 MHz,
CDCl3) δ 6.14 (br s, 1 H), 3.51 (t, J = 8.4 Hz, 1 H), 2.97 (dd, J = 9.3, 6.3 Hz, 1 H), 2.47 (m, 2 H),
1.98 (m, 1 H), 1.15 (d, J = 6.4 Hz, 3 H). []D: -24.11 (c 0.16, CHCl3).
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 36
1
2
3
4
5
6
7
8
9
Methyl 4-(bromomethyl)-2-fluoro-5-methoxybenzoate (26): To a reactor was charged DMF
(55.0 kg), methyl 2-fluoro-5-hydroxy-4-methylbenzoate (25) (5.8 kg, 31.5 mol), and K2CO3 (9.9
kg, 2.3 equiv). The contents were mixed at room temperature for 30 minutes. Iodomethane (1.20
kg, 1.6 equiv) was added. The contents were mixed for 12 hours. Following consumption of 14,
AcOH (2.0 kg, 0.3 equiv) was added at 10 °C over 30 minutes and then mixed for 7 h. Water (90
kg) was added over 1 h while maintaining the temperature between 10 and 15 °C. IPAc (54 kg)
was then added. The phases were cut. The organics were washed with water (3 x 30 kg). The
organics were then concentrated to an approximate volume of 30 L. IPAc (35 kg) was then charged
to the reactor followed by AIBN (0.9 kg, 19 mol %) and NBS (10.8 kg, 2.07 equiv) in portions at
70 °C of 12 h. The contents were mixed for 3 h at 70 °C. Upon consumption of the intermediate,
the contents were cooled to room temperature and IPAc (28 kg) was added to the reactor followed
by 7% aqueous NaHCO3 (58 kg). The phases were separated and the organics were washed with
water (2 x 80 kg). The solution was then distilled to an approximate volume of 52 L. Diethyl
phosphite (4.0 kg, 0.7 equiv) was added followed by N,N-diisopropylethylamine (2.1 kg, 0.3
equiv). The contents were mixed for 10 hours. IPAc (40 kg) was added to the reactor followed by
water (58 kg). The phases were separated and the organics were washed with water (58 kg). The
solvent was switched to THF via distillation with a final volume of approximately 25 L. The
desired product 26 was isolated as a 28 wt% THF solution (7.6 kg, 94%). Analytical data for 26:
1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 5.8 Hz, 1 H), 6.93 (d, J = 11.0 Hz, 1 H), 3.93 (s, 3 H),
3.86 (s, 3 H), 2.25 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.6 (d, J = 4.2 Hz), 155.8 (d, J
= 254.0 Hz), 152.9 (d, J = 2.4 Hz), 132.7 (d , J = 8.0 Hz), 119.0 (d, J = 25.3 Hz), 118.5 (d, J = 11.4
Hz), 113.1 (d, J = 1.0 Hz), 56.2, 52.4, 26.4; HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C10H1179BrFO3 276.9870; Found 276.9873; HRMS: HRMS (ESI-TOF) m/z: [M+H] calcd for
C10H1181BrFO3 278.9850; Found 276.9856.
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
To a reactor was charged lactam 6 (2.25 kg, 26 wt% solution in THF, 1.1 equiv) followed by THF
(7.8 kg). The internal temperature was adjusted to a temperature range of -15 to -5 °C. KHMDS
(5.8 kg, 1.2 equiv) was added over 2 hours while maintaining the temperature below -5 °C. The
contents were mixed for 1 h. Alkyl bromide 15 (1.53 kg, 6.8 mol) was added as a solution in THF
(5.4 kg) over 2 h so as to maintain the temperature of the reaction between -15 and -5 °C. The
contents were mixed for 1 h. Upon consumption of 15, 20 wt% aqueous NH4Cl (5.63 kg) was
charged to the reactor over 30 minutes followed by water (7.5 kg) and EtOAc (13.5 kg). The
20
ACS Paragon Plus Environment

Page 21 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
contents were mixed for 30 minutes at a temperature range of 20 to 30 °C. The phases were settled
and separated. To the organic phase was charged water (5.0 kg) and the pH of the mixture was
adjusted to ~5 with 1 M HCl. The phases were separated. The organic layer was washed with water
(10.5 kg). The aqueous layer was back extracted with EtOAc (6.8 kg). The solvent was switched
to heptanes via distillation to a total volume of ~6 L causing crystallization of the desired product.
n-Heptane (8.4 kg) was added and the contents were mixed for 18 h. The solids were collected by
vacuum filtration and the washed with n-heptane (2 kg). The solids were dried in a vacuum oven
at 40 °C for 20 h to yield 37 (1.34 kg, 84%). The material was used as is in the next step.
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
Methyl (S)-2-fluoro-5-hydroxy-4-((4-methyl-2-oxopyrrolidin-1-yl)methyl)benzoate (3): To a
reactor was charged 37 (6.6 kg, 22.4 mol) and CH2Cl2 (204 kg). The contents were mixed at 25 °C
for 30 min. AlCl3 (15.1 kg, 5.1 equiv) was charged in portions over 3 h while maintaining the
internal temperature between 20 and 30 °C. Upon consumption of 37, the temperature was adjusted
to ~ 0 °C and 2N HCl (70 kg) was added. The phases were settled and separated. The aqueous
layer was back extracted with CH2Cl2 (56 kg). The combined organics were washed with 10 wt%
aqueous NaCl (25.3 kg). The aqueous layer was back extracted with CH2Cl2 (67 kg). The combined
were organics were then concentrated to ~60 L. The solution was filtered. The solvent of the filtrate
was switched to MTBE via distillation with a final volume of ~60 L. The internal temperature was
adjusted to a temperature range of 50 to 60 °C and the contents were mixed for approximately 2
h. The temperature was adjusted to 20 to 30 °C and n-heptane (69 kg) was added over 3 h. The
contents were mixed for 2 h and the solids were collected by vacuum filtration. The solids were
washed with a 1:1 MTBE:n-heptane solution (2.0 kg) followed by n-heptane (6.4 kg). The solids
were then dried in a vacuum oven at 40 °C for 10 h to yield 3 (5.4 kg, 85%). Analytical data for 3:
1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1 H), 7.49 (d, J = 6.3 Hz, 1 H), 6.88 (d, J = 10.3 Hz, 1 H),
4.31 (d, J = 2.5 Hz, 2 H), 3.92 (s, 3 H), 3.62 (t, J = 8.7 Hz, 1 H), 3.08 (dd, J = 9.5, 6.0 Hz, 1 H),
13
2.58 (m, 2 H), 2.10 (dd, J = 16.8, 6.5 Hz, 1 H), 1.12 (d, J = 6.5 Hz, 3 H); C{1H} NMR (100
MHz, CDCl3) δ 176.6, 164.3, 154.8 (d, J = 252.1 Hz), 151.4 (d, J = 2.5 Hz), 128.2 (d, J = 7.1 Hz),
119.9, 118.9 (d, J = 11.1 Hz), 117.9 (d, J = 24.2 Hz), 55.2, 52.3, 43.0, 38.7, 26.6, 19.7; HRMS
(ESI-TOF) m/z: [M+Na]+ calcd for C14H16FNNaO4 304.0956; Found: 304.0957. []D25 = +3.7 (c
12.3, DMSO, er = >99.5:0.5).
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 36
1
2
3
4
5
6
7
8
9
6-Isopropylpyridazin-3(2H)-one (28): To a reactor was charged toluene (32 kg) and 3-methyl-2-
butanone (8.0 kg, 93 mol). The temperature was adjusted to 20 °C. To a separate reactor was
charged pyrrolidine (6.6 kg, 1 equiv) was added. The contents were adjusted to a temperature of 0
°C and AcOH (3.3 kg, 0.6 equiv) was added while maintaining the temperature between 0 and 30
°C. The temperature was adjusted to 20 °C and mixed for 1 h. The pyrrolidine/AcOH mixture was
then charged to the 3-methyl-2-butanone solution over 2 h while maintaining the temperature
between 20 and 25 °C. The reactor that contained the pyrrolidine/AcOH solution was washed with
toluene (8 kg) and the resulting solution was charged to the reaction solution. The contents of the
reactor were then adjusted to a temperature range of 43 to 58 °C and mixed for 2 h. Glyoxylate
ethyl ester (50 wt% toluene solution, 26.6 kg, 1.4 equiv) was added over 11 h. The contents were
mixed at 43 to 48 °C for 14 h. Upon consumption of 3-methyl-2-butanone, the reaction was cooled
to 20 °C. 25 wt% Aqueous NaCl (54 kg) was added and the contents were mixed for 30 minutes.
The phases were settled and separated. The aq. layer was back extracted with toluene (3 x 63 kg).
The combined organics were concentrated to an approximate volume of 50 L. Hydrazine hydrate
(6.96 kg, 2.3 equiv) was added to a separate reactor and cooled to 0 °C under N2 atmosphere.
AcOH (16.7 kg, 3.0 equiv) was added to the hydrazine hydrate while maintaining the temperature
below 30 °C. The contents were mixed for 1 h at 20 °C. The hydrazine/AcOH solution was then
added to the reaction mixture over 1 h. The contents were then heated to ~ 50 °C and mixed for 10
h. Upon consumption of the aldol intermediate, the reaction was cooled to 20 °C. The solution was
then washed with 25 wt% aqueous NaCl (54 kg). The aqueous layer was back extracted with a
mixed solvent solution of 3.2 wt% CH3CN in EtOAc (2 x 70 kg). The combined organics were
then concentrated to an approximate volume of 60 L. The solution was then switched to toluene
until CH3CN and EtOAc were undetectable and AcOH was present at 3.4%. Tolune (233 kg) was
added to the reactor followed by Ecosorb C-941 (4.0 kg). The contents were mixed for 2 h. The
solution was then filtered and the cake was washed with toluene (32 kg). The filtrate was
concentrated to an approximate volume of 25 L. n-Heptane (12 kg) was added over 3 h. The
contents were mixed for ~3 h at 20 °C. The solids were then collected by vacuum filtration and
the cake was washed with a 1:1 v/v solution of n-heptane/toluene (2 x 12 kg). The solids were then
dried under vacuum at 40 °C for 20 h to yield 28 (5.6 kg, 44%). Analytical data for 28: 1H NMR
(400 MHz, CDCl3) δ 12.53 (br s, 1 H), 7.22 (d, J = 9.6 Hz, 1 H), 6.94 (d, J = 9.2 Hz, 1 H), 2.90
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
(hept, J = 6.8 Hz, 1 H), 1.22 (d, J = 7.2 Hz, 6 H); C{1H} NMR (100 MHz, CDCl3) δ 162.4,
22
ACS Paragon Plus Environment

Page 23 of 36
The Journal of Organic Chemistry
1
2
3
4
153.4 132.6, 130.0, 33.3, 21.3; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C7H10N2O 139.0871;
5
6
Found 139.0865.
7
8
9
3-Bromo-6-isopropylpyridazine (29): To a reactor was charged CH3CN (170 kg), 28 (5.5 kg,
39.8 mol), and POBr3 (22.8 kg, 2.0 equiv). The temperature was adjusted to 25 °C and the contents
were mixed for 30 min. The contents were then heated at 80 °C for 13 h. Upon consumption of 28,
the temperature was adjusted to 20 °C. The solution was then concentrated to an approximate
volume of 100 L. The solvent was then switched via distillation to IPAc. 10% Aqueous NaOH
(116 kg) was added at 10 °C to bring the pH of the solution 10. 20 wt% Aqueous Na2SO4 (39 kg)
was charged to the reactor followed by MTBE (81 kg) and celite (11 kg). The contents were mixed
at 20 °C for 30 minutes and filtered. The cake was washed with MTBE (2 x 15 kg). The phases
were settled and separated. The organic layer was wasehd with 20 wt% Na2SO4 (3 x 110 kg). The
organics were then concentrated to ~100 L and the solvent was switched to IPAc via distillation.
IPAc (44 kg) was then charged to the reactor followed by Ecosorb C-941 (1.7 kg) and the contents
were mixed for 3 h. The solution was filtered and the cake was washed with IPAc (3 x 13 kg). The
filtrate was concentrated to approximately 150 L and CH3CN (21.6 kg) was added. HBr (33%
acetic acid solution, 10.4 kg) was added over 2 h while maintaining the temperature between 18
and 24 °C. The contents were mixed for 5 h. The solids were then collected by vacuum filtration
and washed with IPAc (22 kg). The solids were charged to a reactor followed by IPAc (195 kg).
The pH was adjusted to 9 with 7 wt% NaHCO3 (123 kg). The phases were then settled and
separated. The organics were washed with 20 wt% Na2SO4 (3 x 85 kg). The organic layer was then
concentrated to ~100 L. IPAc (56 kg) and CH3CN (22 kg) were added to the reactor. HBr (33%
acetic acid solution, 10.4 kg) was added over 2 h at 20 C. The contents were mixed for 5 h and the
solution was filtered. The cake was washed with IPAc (22 kg). The solids were then charged to a
reactor followed by IPAc (195 kg) and 7 wt% aqueous NaHCO3 (123 kg). The phases were settled
and separated. The organics were washed with 20 wt% aqueous Na2SO4 (3 x 85 kg). The solvent
was then switched to EtOAc via distillation and the solution was filtered. The filtrate was
concentrated to ~30 L and the solvent was switched to CH3CN via distillation to yield 29 (5.5 kg,
22 wt% CH3CN solution, 68%). Analytical data for 29: 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J
= 8.8 Hz, 1 H), 7.24 (d, J = 8.8 Hz, 1 H), 3.28 (hept, J = 7.2 Hz, 1 H), 1.34 (d, J = 7.2 Hz, 6 H);
13C{1H} NMR (100 MHz, CDCl3) δ 167.9, 146.2, 131.7, 127.0, 34.3, 22.2; HRMS (ESI-TOF) m/z:
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
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 36
1
2
3
4
[M+H]+ calcd for C7H1079BrN2 201.0027; Found 201.0027; m/z (M+H+) calcd for C7H1081BrN2:,
5
6
203.0007; Found 203.0006.
7
8
9
3-(4-Bromophenyl)-6-isopropylpyridazine (2): To a reactor was charged 29 (5.3 kg, 22 wt%
CH3CN solution, 26.4 mol), boronic ester 31 (5.7 kg, 0.77 equiv), CH3CN (11 kg), and a solution
of K3PO4 (14.7 kg, 2.6 equiv) in water (26.5 kg). The mixture was sparged with argon for 1.5 h.
PdCl2(dppf) (742 g, 3.8 mol %) was then added followed by sparging with argon for 30 minutes.
The mixture was heated at 50 °C for 8 h. Upon consumption of boronic ester 20, the mixturew as
cooled to room temperature and EtOAc (95 kg) and water (27 kg) were added. The phases were
cut and the organic layer was washed with 10 wt% aqueous Na2SO4 (2 x 60 kg). CH3CN was
removed from the organic solution by continuous distillation with EtOAc with a final volume of
approximately 20 L. EtOAc (53 kg) and Ecosorb C-941 (1.6 kg) were added. The contents were
mixed for 3 h. The mixture was filtered and the cake was washed with EtOAc (2 x 18 kg). The
solution was concentrated to 30 L. The solvent was switched to CH3CN via distillation. Water (34
kg) was added dropwise over 3 h. The slurry was aged for 4 h at room temperature and the solids
were collected by filtration. The cake was washed with a 3:1 v/v H2O:CH3CN solution (43 kg).
The solids were collected and dried in a vacuum oven at 45 °C for 6 h to yield 2 (4.6 kg, 82%).
Analytical data for 2: 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.8 Hz, 2 H), 7.76 (d, J = 8.8
Hz, 1 H), 7.64 (d, J = 8.4 Hz, 2 H), 7.40 (d, J = 8.8 Hz, 1 H), 3.35 (hept, J = 6.8 Hz, 1 H), 1.42
(d, J = 7.2 Hz, 6 H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.1, 156.4, 135.4, 132.1, 128.3, 125.1,
124.3, 123.8, 34.6, 22.3; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C13H1379BrN2: 277.0340;
Found: 277.0477. m/z calcd for C13H1381BrN2 279.0320; Found: 279.0457.
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
N-(3-Fluoropyridin-4-yl)benzamide (38): To a three neck round bottom flask equipped wih
overhead stirrer was charged 3-fluoropyridin-4-amine (130 g, 1.16 mol), THF (875 mL), and Et3N
(245 g, 2.09 equiv). The internal temperature was adjusted to 3 °C. Benzoyl chloride (156 mL,
1.16 equiv) was dissolved in THF (225 mL) and added dropwise to the pyridine solution while
maintaining the temperature of the solution to less than 15 °C. After 4 h, the material filtered and
the cake washed with THF (1 L) and EtOAc (2 L). The solution was then concentrated. The solids
were transferred to a 4-neck round bottom flask equipped with overhead stirrer, reflux condenser,
and addition funnel. The solids were diluted with EtOAc (800 mL) and the internal temperature
was adjusted to 65 °C. Hexanes (350 mL) was added and the solution was removed from the heat.
24
ACS Paragon Plus Environment

Page 25 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
As the mixture cooled, hexanes (350 mL) was added over 1 h. After reaching room temperature,
the slurry was cooled to 0 °C and aged for 2 h. The solids were collected by vacuum filtration and
the cake was washed with hexanes (500 mL). The solids were dried under N2 sweep to yield 38 as
off white, slightly brown needles (186 g, 74%). The material was used as is in the next step.
Analytical data matched previously reported.
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-Benzamido-1-benzyl-3-fluoropyridin-1-ium bromide (11): To a four neck round bottom flask
equipped wih overhead stirrer and reflux condenser was charged N-(3-fluoropyridin-4-
yl)benzamide (180 g, 833 mmol) and toluene (1.4 L). Benzyl bromide (139 mL, 1.4 equiv) was
added and the internal temperature was adjusted to 90 °C with a heating mantle. As the reaction
progresses a thick slurry is produced. After aging for 20 h, the solution was cooled to rt and MTBE
(1 L) was added. The solids were collected by vacuum filtration and the cake was washed with
MTBE (1.5 L). The solids were dried under N2 sweep to yield pyridinium 11 as a white solid (305
g, 95%). Analytical data for 11: 1H NMR (300 mHz, DMSOd6)  11.47 (s, 1H), 9.73 (dd, J = 6.0,
1.2 Hz, 1H), 9.08 (dd, J = 7.0, 1.0 Hz, 1H), 8.77 (t, J = 7.3 Hz, 1H), 8.01-7.98 (m, 2H), 7.74-7.41
(m, 8H), 5.87 (s, 2H); 13C{1H} NMR (75 MHz, DMSOd6) 167.2, 150.1 (d, J = 253.7 Hz), 142.3,
142.3, 142.1, 142.0, 134.3, 133.8, 133.3, 132.5, 19.3, 129.1, 128.8, 128.8, 128.5, 118.16, 118.14,
61.9; 19F NMR (376 MHz, CDCl3) δ -133.43; HRMS (ESI-TOF) m/z: [M] calcd for C19H16FN2O
307.1241; Found: 307.1251.
N-(1-benzyl-5-fluoro-1,2,3,6-tetrahydropyridin-4-yl)benzamide (8): To a 5 L reactor with
overhead stirrer was charged pyridium 11 (295 g, 763 mmol) and MeOH (2.28 L). The internal
temperature was adjusted to 0 °C and NaBH4 was added in portions over 30 minutes to maintain
the temperature below 9 °C. The reaction was aged for 30 minutes. Saturated aqueous NH4Cl (1
L) was added the mixture was aged for 1 h at 0 °C. Saturated aqueous NaHCO3 was then added
the mixture was aged for an additional hour. The mixture was warmed to room temperature and
the methanol was removed under vacuum. The aqueous layer was then extracted with EtOAc (2
L). The phases were cut and the aqueous layer was back extracted with EtOAc (500 mL). The
combined organics were washed wth water (400 mL) and brine (500 mL). The organics were dried
over Na2SO4 and filtered through 750 g of SiO2. The SiO2 was washed with EtOAc (1.5 L). The
solutoin was concentrated and then purified by column chromatography in three portions using 1.5
kg SiO2 pre-packed columns with a gradient of 10 to 100% EtOAc in heptanes. The fractions
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 36
1
2
3
4
5
6
7
8
9
containing product were combined and concentrated to yield 8 as a light yellow solid in >95%
purity (220 g, 93%). Analytical data for 8: 1H NMR (400 MHz, CDCl3)  7.78 (d, J = 5.4 Hz, 2H),
7.54-7.26 (m, 9H), 3.68 (s, 2H), 3.18 (s, 2H), 2.92-2.90 (m, 2H), 2.72 (t, J = 4.2 Hz, 2H); 13C{1H}
NMR (100 MHz, CDCl3)  165.4, 145.0 (d, J = 251.0 Hz), 137.6, 134.5, 131.9, 129.0, 128.7,
128.4, 127.4, 127.1, 114.0 (d, J = 5.0 Hz), 61.9, 51.1, 50.7, 49.6, 25.7;19F NMR (376 MHz, CDCl3)
δ -128.61; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C19H19FN2O 311.1559, Found: 311.1570.
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
N-((3S,4R)-1-Benzyl-3-fluoropiperidin-4-yl)benzamide (12): Catalyst solution : In a glove box,
SL-A108-1 (5.26 g, 3.15 mol %), (COD)Ru(Me-allyl)2 (2.95 g, 3 mol %) and CH2Cl2 (37 mL)
were charged in a visually clean 250 ml round bottom flask. After mixing for 15 minutes, HBF4-
OEt2 (3.25 mL) and CH2Cl2 (30 mL) were added.
To a 2 L, visually clean bottle was charged enamide 8 (95.5 g, 308 mmol), 2-MeTHF (700 mL),
and MeOH (117 mL). The contents were mixed until solids dissolved. HBF4ꞏOEt2 (57.8 g, 1.16
equiv) and Ti(OiPr)4 (175 g, 2 equiv) were added. The solution was combined with 23 mL of
catalyst solution in an autoclave and purged with N2 three times. The reaction mixture was then
purged with H2 gas three times and pressurized with H2 (500 psi). The contents were adjusted to
40 °C and mixed for 72 h. The mixture was then concentrated to approximately 500 mL and diluted
with EtOAc (1.5 L) in a 5 L reactor equipped with overhead stirrer. Potassium glycolate (322 mL,
5 M, 5 equiv) and K2CO3 (579 mL, 10 wt%) were added and the contents were mixed for 2 h. The
phases were settled and separated. The aqueous layer was back extracted with EtOAc (2 x 1 L).
The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was
purified by column chromatography on a 1.5 kg SiO2 pre-packed column with an eluent gradient
of 5-30% EtOAc in CH2Cl2. The fractions containing product were combined and concentrated.
The residue was further purified by Prep-SFC (Column: IA 5x25 cm 5um, Mobile Phase: 25%
EtOH/CO2, Flow Rate: 250 mL/min, Oven Temp: 35 °C). The desired compound 12 (67 g, 70%)
was obtained as a white solid in >97% purity. Analytical data for 12: 1H NMR (300 MHz, CDCl3)
 7.76 (d, J = 9.0 Hz, 2H), 7.53-7.25 (m, 8H), 6.42 (d, J = 8.7 Hz, 1H), 4.75 (d, J = 49.5 Hz, 1H),
4.26-4.15 (m, 1H), 3.61 (dd, J = 18.0, 13.2 Hz, 2H), 3.28-3.21 (m, 1H), 2.95 (dd, J = 11.5, 1.9 Hz,
1H), 2.38-2.17 (m, 2H), 1.99-1.83 (m, 2H); 13C{1H} NMR (75 MHz, CDCl3)  166.9, 137.6, 134.2,
131.7, 129.0, 128.6, 128.3, 127.2, 127.0, 88.7 (d, J = 176.2 Hz), 87.5, 62.7, 55.6 (d, J = 18.6 Hz)
26
ACS Paragon Plus Environment

Page 27 of 36
The Journal of Organic Chemistry
1
2
3
4
5
, 51.5, 48.7 (d, J = 18.1 Hz), 27.1; 19F NMR (282 MHz, CDCl3) δ -201.19; HRMS (ESI-TOF) m/z:
25
[M+H]+ calcd for C19H21FN2O 313.1716; Found 313.1722; []D = -56.2 (c 0.5, MeOH).
6
7
8
9
N-((3S,4R)-3-Fluoro-1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)benzamide (13): To a 2 L
vessel was charged 12 (47 g, 151 mmol) in MeOH (940 mL) and 5% Pd/C (39 g). The vessel was
purged with H2 three times. H2 was then charged to a pressure of 45 psi and the temperature was
adjusted to 35 °C. After 6 h, the starting material was consumed and the reaction mixture was
filtered through a small pad of celite. The cake was washed with CH2Cl2 (200 mL) and the filtrate
was concentrated to dryness and used without further purification.
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
To a 1 L round bottom flask equipped with overhead stirrer and internal temperature probe was
charged crude piperidine (26.7 g, 120 mmol) and CH2Cl2 (400 mL). Tetrahydro-4H-pyran-4-one
(13.2 g, 1.1 equiv) was then added. NaHB(OAc)3 (31.0 g, 1.22 equiv) was added portion wise over
30 minutes to ensure the reaction did not exceed 27 °C. The reaction mixture was aged overnight
at a temperature range of 21 °C to 26 °C. Upon consumption of the piperidine starting material, 5
wt% aqueous K2CO3 was added. An additional 8.8 g of K2CO3 was added to bring the pH of the
aqueous layer to 10. The layers were separated. The organic phase was dried over MgSO4, filtered,
and concentrated. The solids were dissolved in CH2Cl2 and purified by column chromatography
on a 750 g SiO2 column with 0% to 17% MeOH in CH2Cl2 as an eluent. The fractions containing
product were combined and concentrated to yield 13 as a white solid in 98% purity (32.4 g, 70%).
Characterization of 13 is described below.
tert-Butyl (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylate (15):
The two following solutions were prepared in advance of running the reaction:
Solution 1 (0.8 M sodium borate containing 1 M isopropylamine at final pH of 10.5): Sodium
tetraborate decahydrate (7.6 g) was dissolved in deionized water (100 mL) at room temperature.
The pH of the solution was ~ 9.5. To this solution was added neat isopropylamine (4.25 mL)
bringing buffer to 0.5 M isopropylamine. The pH was >11.0. The pH of the solution was adjusted
to pH 10.5 using concentrated HCl. The solution cooled to room temperature and was readjusted
pH to 10.5. Let the buffer cool to RT and checked pH before dissolving PLP and enzyme.
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 36
1
2
3
4
Solution 2 (8.0 M aqueous isopropylamine was prepared for pH control): Isopropylamine (68 mL)
5
6
was dissolved in deionized water (32 mL).
7
8
9
To a reactor was added pyridoxal-5-phosphate (30 mg, 13.81 mmol) and ATA-303 (60 mg, 2.000
µmol) in 0.8 M sodium borate and 1 M isopropylamine at a final pH of pH 10.5 (24 ml) at room
temperature. The solids slowly went into solution with gentle overhead stirring and the solution
turned bright yellow. The solution was not heated while the enzyme dissolved. After the enzyme
went into solution, the stirring was increased. In a small vial, 9 (3 g, 13.81 mmol) was dissolved
in DMSO (6 ml). This solution was then added dropwise to the yellow enzyme solution at room
temperature over 7 minutes while heating and maintaining the solution at 45 °C. The pH was
adjusted to pH 10.5 using 8 M isopropylamine. The reaction stirred overnight and a pH control
was used to maintain pH 10.5 by adding 8.0 M isopropylamine. The reaction vessel was placed
under vacuum to remove the iPrNH2. MeTHF (30 mL) was added to the reaction followed by 10%
brine (20 mL) and methanol (10 mL). The phases were separated and the aqueous layer was back
extracted with MeTHF (15 mL). The combined organic layers were concentrated. The desired
product was isolated as an orange oil (7.52 g, 66%, 15:1 dr, 96% ee). Analytical data for 15 : 1H
NMR (300 MHz, CDCl3) δ 4.57 (d, J = 47.7 Hz, 1H), 4.31-4.06 (m, 2H), 3.09-2.83 (m, 3H), 1.83
(s, 2H), 1.69-1.67 (m, 2H), 1.50 (s, 9H); 13C{1H} NMR (100 MHz, DMSOd6) δ 154.7, 90.6 (d, J
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
19
= 174.8 Hz), 79.2, 50.4 (d, J = 19.5 Hz), 29.9, 28.5; F NMR (376 MHz, CDCl3) δ -205.73, -
206.00; HRMS (ESI-TOF) m/z: [M+H-Boc+H] calcd for C10H19FN2O2 119.0987; Found
25
119.0996; []D = + 26.4 (c 0.5, MeOH).
tert-Butyl (3S,4R)-4-benzamido-3-fluoropiperidine-1-carboxylate (19): In a 3-necked round-
bottom flask, was charged 15 (1.15 g, 5.27 mmol), 2-MeTHF (11 ml), and Et3N (0.90 g, 8.9 mmol).
The reaction mixture was cooled to ~ 5 °C, and stirred at that temperature for ~30 min. BzCl was
added dropwise and then the mixture was stirred at ~25 °C for 15 h. The resulting solution was
washed twice with 10% aqueous critic acid, aqueous NaHCO3 and brine. The organic layer was
dried over anhydrous magnesium sulfate and concentrated under vacuum. The desired product was
1
isolated as a 60 wt% solution in 2-MeTHF (1.6 g, 83%). Analytical data for 19: H NMR (400
MHz, CDCl3) δ 7.77 (d, J = 7.2 Hz, 2H), 7.54-7.42 (m, 3H), 6.42 (s, 1H), 4.76 (d, J = 48.8 Hz,
1H), 4.68-4.11 (m, 3H), 3.04-2.84 (m, 2H), 1.86-1.81 (m, 2H), 1.47(s, 9H); 13C{1H} NMR (100
MHz, CDCl3) δ 166.9, 155.1, 133.9, 131.8, 130.0, 128.6, 127.0, 87.7 (d, J = 177.2 Hz), 80.2, 48.9
28
ACS Paragon Plus Environment

Page 29 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
(d, J = 18.6 Hz), 28.3, 28.3, 26.3; 19F NMR (282 MHz, CDCl3) δ -204.41; HRMS (ESI-TOF) m/z:
25
[M+H-Boc+H] calcd for C17H23FN2O3 223.1249; Found: 223.1250; []D = +60.4 (c 0.46,
MeOH).
8
9
N-((3S,4R)-3-Fluoropiperidin-4-yl)benzamide (20): To a 3-necked round-bottom flask, was
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
o
charged TFA (10 ml). 19 (1.45 g, 4.5 mmol) was added in portions at ~25 C. The mixture was
stirred at room temperature for 3 h. The reaction mixture was poured into H2O (10 mL) and
aqueous NaHCO3 was then added dropwise until pH = 8 to 9. Then, CH2Cl2 was added and the
mixture back extracted ten times. The combined organic were dried over Na2SO4, concentrated
under vacuum to afford 20 (1.0 g, 100%).
Ee upgrade (D-benzoyl tartaric acid salt formation/salt break): To a 3-necked round-bottom flask,
was charged 20 and EtOH (10 mL) at room temperature. A solution of solution D-dibenzoyl
tartaric acid (1.6 g) in EtOH (10 ml) was added dropwise via cannula over 10 minutes. The reaction
o
mixture was stirred at 25 C for 5 h and filtered to obtain the salt. In a round-bottom flask, was
charged 7% aqueous NaHCO3 (23 mL) and CH2Cl2 (45 mL), followed by the wet cake. The
mixture was stirred at ~25 oC for 2 h. The phases were cut and the aqueous layer back extracted
three times with CH2Cl2. The combined organic layers were dried over anhydrous magnesium
sulfate and concentrated under reduced pressure to afford 20 as a white solid (0.8 g, 80 % yield).
Analytical data for 20 : 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.2 Hz, 2H), 7.53-7.42 (m, 3H),
6.45 (d, J = 8.0 Hz, 1H), 4.71 (d, J = 50.4 Hz, 1H), 4.38-4.17 (m, 1H), 3.39-3.22 (m, 1H), 3.17-
3.12 (m, 1H), 2.92-2.70 (m, 2H), 1.88-1.84 (m, 1H), 1.72-1.67 (m, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 166.7, 134.2, 131.7, 128.6, 126.9, 88.8 (d, J = 171.4 Hz), 49.3 (d, J = 20.5 Hz), 48.8 (d,
J = 18.4 Hz), 44.8, 28.6; 19F NMR (376 MHz, CDCl3) δ -204.99; HRMS (ESI-TOF) m/z: [M+H]+
calcd for C12H15FN2O 223.1246; Found: 223.1250. []D25 = +71.8 (c 0.5, MeOH).
N-((3S,4R)-3-Fluoro-1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)benzamide (13) : To a 3-
necked round-bottom flask was charged 20 (0.62 g, 2.79 mmol), tetrahydro-4H-pyran-4-one (559
mg, 2 equiv), and NaBH(OAc)3 (1.06 g, 1.8 equiv) in CH2Cl2 (6.2 ml). The reaction mixture was
stirred at room temperature for 18 h. 5% aqueous Na2CO3 was the added drop-wise until pH 8.
The aqueous layer was extracted with CH2Cl2 (8 mL×3). The combined organic layers were dried
over anhydrous Na2SO4 and concentrated under reduced pressure. The solid obtained was slurried
29
ACS Paragon Plus Environment