Crystallization-Induced Dynamic Resolution toward the Synthesis of (S)-7-Amino-5H,7H-dibenzo[b,d]-azepin-6-one: An Important Scaffold for γ-Secretase Inhibitors

Article abstract of DOI:10.1021/acs.oprd.6b00207

An enantioselective synthesis of (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one (S-1) is described. The key step in the sequence involved crystallization-induced dynamic resolution (CIDR) of compound 7 using Boc-d-phenylalanine as a chiral resolving agent and

Full text of DOI:10.1021/acs.oprd.6b00207

Subscriber access provided by CORNELL UNIVERSITY LIBRARY
Full Paper
Crystallization-induced Dynamic Resolution towards the
Synthesis of (S)-7-Amino-5H,7H-dibenzo[b,d] -azepin-6-
one: An Important Scaffold for #-Secretase Inhibitors
Sukhen Karmakar, Vijay Byri, Ashvinikumar V Gavai,
Richard Rampulla, Arvind Mathur, and ANURADHA GUPTA
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00207 • Publication Date (Web): 28 Sep 2016
Downloaded from http://pubs.acs.org on September 28, 2016
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 free 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 accessible to all
readers and 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.
Organic Process Research & Development 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 14
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Crystallizationꢀinduced Dynamic Resolution
towards the Synthesis of (S)ꢀ7ꢀAminoꢀ5H,7Hꢀ
dibenzo[b,d] ꢀazepinꢀ6ꢀone: An Important Scaffold
for γꢀSecretase Inhibitors
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
Sukhen Karmakar,† Vijay Byri,† Ashvinikumar V. Gavai,‡ Richard Rampulla,‡ Arvind Mathur, ‡
and Anuradha Gupta*†
† Department of Discovery Synthesis, Biocon BristolꢀMyers Squibb Research Centre, Biocon
Park, Bommasandra IV phase, Jigani Link Road, Bengaluru – 560099, India
‡BristolꢀMyers Squibb Company, P.O Box 4000, Princeton, New Jersey 08543ꢀ4000, United
States
ACS Paragon Plus Environment
1

Organic Process Research & Development
Page 2 of 14
1
2
3
4
5
Graphic for TOC Only
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
ACS Paragon Plus Environment
2

Page 3 of 14
Organic Process Research & Development
1
2
3
4
ABSTRACT
5
6
7
An enantioselective synthesis of (S)ꢀ7ꢀaminoꢀ5H,7Hꢀdibenzo[b,d]azepinꢀ6ꢀone (S-1) is
8
9
described. Key step in the sequence involved crystallizationꢀinduced dynamic resolution (CIDR)
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
of compound 7 using BocꢀDꢀphenylalanine as a chiral resolving agent and 3,5ꢀ
dichlorosalicylaldehyde as a racemization catalyst to afford S-1 in 81% overall yield with 98.5%
enantiomeric excess.
KEYWORDS
Alzheimer’s disease, Notch inhibitors, DKR, CIDR, 3,5ꢀdichloro salicylaldehyde, BocꢀDꢀ
Phenylalanine, Dibenzoazepenone
ACS Paragon Plus Environment
3

Organic Process Research & Development
Page 4 of 14
1
2
3
4
INTRODUCTION
5
6
7
8
Alzheimer’s disease (AD) 1, 2 is characterized by the formation of abnormal and characteristic
deposits of amyloidꢀβ (Aβ) peptides in the brain. It has been established that βꢀ and γ–secretase
enzymes cause sequential proteolysis of the amyloidꢀprecursor protein (APP) to generate
amyloidꢀβꢀpeptides. The amyloid cascade hypothesis of Alzheimer’s disease postulates a
causative role to the accumulation of these amyloidꢀβꢀpeptides in brain tissue.3 In mouse models,
small molecule inhibitors of the γꢀsecretase enzyme have been shown to suppress the production
of amyloidꢀβꢀpeptides inꢀvivo and inhibit deposition of amyloid peptides in the brain. γꢀ
Secretase inhibitors are also being developed as anticancer agents owing to their ability to
modulate the Notch signaling pathway.4 Several γꢀsecretase inhibitors have been described
based on (S)ꢀ7ꢀaminoꢀ5H,7H dibenzo[b,d]azepinꢀ6ꢀone (S-1) as the core structure.5 The
essential level of potency and drugꢀlike properties are then conferred by attaching a sideꢀchain to
the amino group and an optional substituent on the nitrogen of the central lactam ring.6
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
Figure 1: (S)ꢀ7ꢀaminoꢀ5H,7H dibenzo[b,d]azepinꢀ6ꢀone (S-1)
The reported syntheses of S-1 and its analogs rely on enantiomer separation via chiral HPLC6a or
chromatography of derived diastereoisomers.7 Resolution of the Nꢀmethylated lactam of 1 has
been reported by crystallization with diꢀpꢀtoluylꢀD
ꢀtartaric acid monohydrate.8 HoffmanꢀEmery
et al reported an improved synthesis of S-1 based on a selective crystallization of epimeric
menthyl carbamates followed by simultaneous cleavage of the carbamate and the lactam
ACS Paragon Plus Environment
4

Page 5 of 14
Organic Process Research & Development
1
2
protecting groups.9 The undesired menthyl carbamate was epimerized by treatment with LDA to
improve the overall yield of S-1. Although this methodology is attractive in terms of the overall
yield, it is not preferred since it employs the expensive menthyl chloroformate and requires
additional synthetic steps for protection and removal of the chiral auxiliary group. As part of our
γ–secretase inhibitor program, we required compound S-1 in large quantity to synthesize a
developmental candidate for toxicology studies. We sought an efficient, scalable and cost
effective synthesis of enantiopure Sꢀ1 by applying crystallizationꢀinduced dynamic resolution
(CIDR).10 CIDR is a process that has the potential to afford a quantitative yield of the chiral
product from a racemic starting material through inꢀsitu epimerization, resolution and
crystallization with a chiral resolving agent.
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
RESULTS AND DISCUSSION
Several approaches have been reported for the preparation of dibenzoazepinone core 4.11ꢀ13 We
decided to follow the palladiumꢀcatalyzed coupling of 2ꢀbromoaniline (1) with 2ꢀ
iodophenylacetonitrile (2) as shown in Scheme 1 due to the availability and inexpensive nature
of both starting materials.
Oneꢀpot palladium acetate catalyzed borylationꢀSuzuki coupling (BSC) reaction between 2ꢀ
bromoaniline (1) and 2ꢀiodophenylacetonitrile (2) provided 2,2’ꢀdisubstituted biphenyl 3.11
Cyclization of 3 to the lactam 4 was promoted by aqueous potassium hydroxide at 60 °C to
provide dibenzoazepinone core 4 in 62% yield over two steps. Two methods have been reported
for the Nꢀalkylation of the lactam and the introduction of the amino group in the alpha position
of the carbonyl group, 8 one route applied a sequence of iodination, substitution by azide,
reduction, and then lactam alkylation, the other route commenced with alkylation of the lactam
followed by nitrosation at C(7), and reduction. We followed the latter as it seemed a safer
ACS Paragon Plus Environment
5

Organic Process Research & Development
Page 6 of 14
1
2
3
4
5
6
7
8
9
alternative. Accordingly, compound 4 was subjected to sodium hydride and pꢀmethoxy benzyl
chloride in DMFa to afford 5 in 80 % yields. Compound 5 was treated with isoꢀamyl nitrite and
KHMDS in anhydrous THF followed by hydrogenation of the resulting Nꢀhydroxyl imineꢀ
derivative 6 to furnish racemic 2ꢀamino dibenzoazepinone 7 in 50 % yield over two steps
(Scheme 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
Scheme 1: Synthesis of racemic N-PMB protected amino dibenzoazepinone
With a scalable method to prepare the racemic intermediate 7 in hand, we were intrigued by the
possibility of simultaneously racemizing the undesired enantiomer of 7 during the resolution
process (a dynamic resolution), thus converting all of the racemate to the desired enantiomer.
Initially, we attempted classical crystallization with various chiral acids in different solvent
system combinations as the first step towards 7 establishing the proposed CIDR but we did not
have any success (See Table 1). Our results were largely in accordance with reported results by
aThe combination of DMF and NaH is not advisable for larger scale operations but due to lack of
other suitable scalable method the reagent was used without any safety issue for the scales we
handled following the guidance provided in the literature.15
ACS Paragon Plus Environment
6

Page 7 of 14
Organic Process Research & Development
1
2
3
4
Table 1: Screening of rac-7b
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
Vial Chiral Acids
S1
ꢀ
S2
ꢀ
S3
ꢀ
S4
ꢀ
S5
ꢀ
S6
T
ꢀ
S7
ꢀ
S8
ꢀ
1
2
Dꢀ(−)ꢀTartaric acid
(+)ꢀO,O′ꢀDiꢀpꢀtoluoylꢀDꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
T
tartaric acid
3
4
BocꢀDꢀPheꢀOH
ꢀ
ꢀ
LS
ꢀ
ꢀ
LS
T
(1R)ꢀ(−)ꢀ10ꢀCamphorsulfonic
T
-
-
-
-
-
-
-
acid
5
6
BocꢀDꢀPhgꢀOH
O
ꢀ
T
ꢀ
O
ꢀ
-
-
-
-
-
(S)ꢀ(−)ꢀ2ꢀPyrrolidoneꢀ5ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
carboxylic acid
7
(R)ꢀ(ꢀ)ꢀMandelic acid
-
-
-
-
-
-
-
-
bFollowing solvents were selected for rac-7 S1 = Acetonitrile; S2 = Ethyl acetate , S3 = 1,2ꢀ
Dichloroethane; S4= Methanol, S5 = THF ; S6 = nꢀBuOH; S7 = Toluene S8 = MTBE. The
classical resolution screening of amine rac-7 was performed in parallel manner in vials utilizing
commercially available chiral acid and solvent (S1 – S8). Each vial solvent concentration was
maintained 30ꢀ 40 mg /ml with equamolar ratio of resolving acid and racemate. The vials were
heated until clear solution obtained and left overnight under closed system. T = Vial solution
was found Turbid, O = vial contained an oil, LS = Vial contained little amount solid. Blank
Cells = vials found either clear solution or only chiral acid separated out as solid.
ACS Paragon Plus Environment
7

Organic Process Research & Development
Page 8 of 14
1
2
HoffmanꢀEmery et al.9 Further, it was decided to remove the PMB group attached to the amide
nitrogen before attempting a classical resolution or CIDR. Accordingly, compound 7 was
heated at 80 °C with a mixture of trifluoromethanesulfonic acid and trifluroacetic acid to afford
solid compound rac-1.
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 2: Deprotection of p-methoxybenzyl group
After examining numerous chiral acids and solvent combinations for resolution of rac-1, (see
Table – 2) we were delighted to find that Bocꢀ
crystals as a single enantiomer in solvents such as dichloroethane, toluene, ethyl acetate and
acetonitrile. Initially, the resolution was performed in acetonitrile with addition of Bocꢀ ꢀPheꢀ
DꢀPheꢀOH proved to be optimal to provide pure
D
OH at room temperature to afford desired crystalline salt 8 in 43% yields and 99.5% ee (by chiral
HPLC) and the undesired Rꢀisomer remained in the solution. Subsequently, based on previous
reported work with similar structural motifs, 14 few aromatic aldehydes (salicylaldehyde,
benzaldehyde, 2ꢀchlorobenzaldehyde and 3,5ꢀdichlorosalicylaldehyde were screen as
racemization catalysts under refluxing condition with different solvent (dichloroethane, toluene,
ethyl acetate, acetonitrile or chloroform) and traces of water. We were delighted to find that
3,5ꢀdichlorosalicylaldehyde was optimal catalyst for the racemization of the undesired
enantiomer. Solvents like toluene, dichloroethane, chloroform or acetonitrile were found to be
effective at their respective reflux temperatures and suitable to achieve DKR process. Based on
literature precedence, 10(d) traces of water were found to be critical for racemization. In the
ACS Paragon Plus Environment
8

Page 9 of 14
Organic Process Research & Development
1
2
3
4
Table – 2 screening of rac-1c
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
Vial Acids
S1
ꢀ
S2
T
ꢀ
S3
ꢀ
S4
ꢀ
S5
ꢀ
S6
ꢀ
S7
ꢀ
1
2
Dꢀ(−)ꢀTartaric acid
(+)ꢀDiꢀpꢀtoluoylꢀ
D
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
tartaric Acid
S
3
Boc-
D
-Phe-OH
S
-
S
-
S
-
O
-
O
-
T
-
4
(1R)ꢀ(−)ꢀ10ꢀ
Camphorsulfonic acid
Bocꢀ ꢀPhgꢀOH
5
6
D
LS
LS
T
T
O
O
O
O
T
T
LS
LS
-
(S)ꢀ(−)ꢀ2ꢀPyrrolidoneꢀ
T
5ꢀcarboxylic acid
7
(R)ꢀ(ꢀ)ꢀMandelic acid
T
-
-
-
-
-
-
cThese solvents were selected for racꢀ1 S1 = Acetonitrile; S2 = Ethyl acetate , S3 = 1,2ꢀ
Dichloroethane; S4= Methanol, S5 = THF ; S6 = nꢀBuOH; S7 = Toluene. The classical
resolution screening of amine rac-1 was performed in parallel manner
commercially available chiral acid and solvent (S1 – S7). Each vial solvent concentration was
maintained 30ꢀ 40 mg /ml with equimolar ratio of resolving acid and racemate. The vials were
heated until clear solution obtained and left overnight under closed system. T = Vial solution
was found Turbid, S = Vial contained large amount of solid materials that was free flowing, O =
vial contained an oil, LS = Vial contained little amount solid. Blank Cells = vials found either
clear solution or only chiral acid separated out as solid.
in vials utilizing
ACS Paragon Plus Environment
9

Organic Process Research & Development
Page 10 of 14
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: Resolution of amino dibenzoazepinone
absence of water, no racemization was seen to take place. The best results were found with
toluene as the solvent, which gave the shortest reaction time and highest ee (> 99 % ee).
Thus, oneꢀpot resolutionꢀracemization of racꢀ1 was achieved using 3,5ꢀdichlorosalicylaldehyde
(2 mol %), water (1.5ꢀ2.0 mole %), and BocꢀDꢀPheꢀOH in toluene under heating for 12 h to
provide the resolved salt 8 in 82 % yield and 99.4% ee. The salt 8 was characterized by NMR
analysis and confirmed to have an optical purity of 99.4% ee via chiral HPLC analysis. The
conversion of the salt 8 to free base (S)ꢀ1 was accomplished by addition of aqueous solution of
sodium hydroxide to the salt, followed by extraction with methylene chloride and vacuum
concentration. Compound (S)-1 was characterized by NMR, LCMS and chemical purity and
optical purity were found to be 97 % and 99 % (ee) respectively. The overall yield of the free
amine (S)-1 from rac-1 was 80 %.
CONCLUSION
In conclusion, we have developed a novel, scalable and economically viable synthesis of
optically pure (S)-1 through dynamic kinetic resolution using BocꢀDꢀPheꢀOH as a chiral
resolving agent and 3, 5ꢀdichlorosalicylaldehyde as a racemization agent. Efforts to develop
DKR with other amino dibenzo[b,d] azepinꢀ6ꢀone cores are ongoing.
ACS Paragon Plus Environment
10

Page 11 of 14
Organic Process Research & Development
1
2
3
4
EXPERIMENTAL SECTION
5
6
7
8
(7S)-6-Oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-aminium (R)-2-(tert-
butoxycarbonylamino)-3-phenylpropanoate (8). To a dry RB flask was charged racemic 7ꢀ
aminoꢀ5Hꢀdibenzo[b,d]azepinꢀ6(7H)ꢀone (6.0 g, 26.8 mmol) (rac-1), 3,5ꢀ
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
dichlorosalicylaldehyde (0.256 g, 1.338 mmol), toluene (120 mL), BocꢀDꢀphenylalanine (7.10 g,
26.8 mmol), followed by water (0.222 g, 12.31 mmol) and heated to 100 ºC overnight. The
progress of the reaction was monitored by chiral HPLC (Initially, two peaks was observed at
4.87 min and 8.43 min corresponding to R and S isomer of 1 respectively and on completion of
DKR the peak corresponding to Rꢀisomer disappeared and only peak at 8.43 found along with
peak of BocꢀDꢀPheꢀOH). The obtained thick slurry was filtered, washed with toluene and dried
1
under vacuum to obtain the salt 8 (10.7 g) as a white solid. H NMR (400 MHz, DMSOꢀd6) δ
1.32 (s, 9H), 2.83 (dd, J=14.06, 10.54 Hz, 1H), 3.02 (dd, J=14.05, 4.52 Hz, 1H), 4.00ꢀ4.09 (m,
1H), 4.12 (s, 1H), 7.00 (br. s., 1H), 7.15ꢀ7.33 (m, 7H), 7.37ꢀ7.56 (m, 4H), 7.61ꢀ7.73 (m, 2H),
10.22 (s, 1H); LCMS(EI) for C28H31N3O5, (M+H)+ calcd.489.2; found, 490.2.
(S)-7-Amino-5H—dibenzo[b,d]azepin-6(7H)-one (S-1). The above salt 8 (10.7 g) was basified
with using 50% aqueous NaOH solution (100 mL) and extracted with DCM (2 × 200 mL). The
combined organic layers were washed with water (75 mL), brine solution (75 mL), dried over
Na2SO4, and concentrated in vacuum to obtain compound (Sꢀ1) (4.8 g, 80 % yield) as white
foam, chiral purity: > 99.0 % ee.
Absolute configuration was assigned by comparing chiral HPLC (SFC method) retention time of
the sample prepared by DKR method and literature9 known sample under above conditions (Coꢀ
1
injection). [α]25 ꢀ203 (C = 1.0 MeOH) H NMR (400 MHz, DMSOꢀd6) δ 1.34 (s, 2H), 4.10
D
(s, 1H), 7.12 (s, 1H), 7.21 (dd, J = 8.03, 1.00 Hz, 1H), 7.26ꢀ7.34 (m, 1H), 7.43 (ddd, J = 5.65,
ACS Paragon Plus Environment
11

Organic Process Research & Development
Page 12 of 14
1
2
3
4
4.14, 1.76 Hz, 2H), 7.45ꢀ7.56 (m, 2H), 7.65 (dd, J = 7.78, 1.25 Hz, 1H), 7.70 (d, J = 8.03 Hz,
5
6
1H); LCMS(EI) for C14H12N2O, (M+H)+ calcd.224.1; found, 225.2.
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
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: anuradha.gupta@syngeneintl.com.
ACKNOWLEDGMENT
Authors are thankful to Discovery Analytical Department, Biocon BristolꢀMyers Squibb
Research Centre (BBRC), Bangalore (India) for Analytical support.
SUPPORTING INFORMATION
Supporting Information contains experimental and analytical data for the intermediates 3, 4, 5, 6
and 7 and the analytical data for the compounds 8 and S-1
ACS Paragon Plus Environment
12

Page 13 of 14
Organic Process Research & Development
1
2
3
4
REFERENCES
5
6
7
(1) Selkoe, D. J. Physiol. Rev. 2001, 81, 741.
8
9
(2) Price, D. L.; Sisodia, S. S. Annu. Rev. Neurosci. 1998, 21, 479.
(3) Beher, D.; Graham, S. L. Exp. Opin. Investig. Drugs 2005, 14, 1385.
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) Gavai, A. V.; Quesnelle, C.; Norris, D.; Han, W.ꢀC.; Gill, P.; Shan, W.; Balog, A.;
Chen, K.; Tebben, A.; Rampulla, R.; Wu, D.ꢀR.; Zhang, Y.; Mathur, A.; White, R.;
Rose, A.; Wang, H.; Yang, Z.; Ranasinghe, A.; D’Arienzo, C.; Guarino, V.; Xiao, L.;
Su, C.; Everlof, G.; Arora, V.; Shen, D. R.; Cvijic, M. E.; Menard, K.; Wen, M. ꢀL.;
Meredith, J.; Trainor, G.; Lombardo, L. J.; Olson, R.; Baran, P. S.; Hunt, J. T.; Vite, G.
D.; Fischer, B. S.; Westhouse, R. A.; Lee, F. Y. ACS Med. Chem. Lett. 2015, 6, 523.
(5) (a) Wu, J. T.; Tung, J. S.; Thorsett, E. D.; Pleiss, M. A.; Nissen, J. S.; Neitz, J.;
Latimer, L. H.; John, V.; Freedman, S.; Britton, T. C.; Audia, J. E.; Reel, J. K.; Mabry,
T. E.; Dressman, B. A.; Cwi, C. L.; Droste, J. J.; Henry, S. S.; McDaniel, S. L.; Scott,
W. L.; Stucky, R. D.; Porter, W. PCT Int. Appl., WO1998028268 A2. (b) Audia, J. E.;
Hyslop, P. A.; Nissen, J. S.; Thompson, R. C.; Tung, J. S.; Tanner, L. I. PCT Int. Appl.
WO200019210 A2. (c) Gavai, A. V. PCT Int. Appl. WO2014047370 A1.
(6) (a) Flohr, A.; Galley, G.; JakobꢀRoetne, R.; Kitas, E.; Peters, J.ꢀW.; Wostl, W. PCT Int.
Appl. WO2005023772. (b) Audia, J. E.; Dressman, B. A.; Shi, Q. PCT US6528505
B1.
(7) Fauq, A. H.; Simpson, K.; Maharvi, G. M.; Giolde, T.; Das, P. Bioorg. Med. Chem.
Lett. 2007, 17, 6392.
ACS Paragon Plus Environment
13

Organic Process Research & Development
Page 14 of 14
1
2
3
4
5
6
(8) Audia, J. E.; Porter, W. J.; Scott, W. L.; Stack, D. R.; Thompson, R. C. PCT Int. Appl.
WO200134571.
7
8
9
(9) HoffmannꢀEmery, F.; JakobꢀRoetne, R.; Flohr, A.; Bliss, F.; Reents, R. Tetrahedron
Lett. 2009, 50, 6380.
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
(10) (a) Pellissier, H. Tetrahedron. 2011, 67, 3769ꢀ 3802. (b) Anderson, N. Org. Process
Res. Dev. 2005, 9, 800ꢀ813. (c) Stock, H. T.; Turner, N. J. Tetrahedron Lett. 1996, 37,
6575. (d) Armstrong, J.D.; Eng, K. K.; Keller, J. L.; Purick, R. M.; Hartner, F. W.;
Choi, W. B.; Askin, D.; Volante, R. P. Tetrahedron Lett. 1994, 35, 3239.
(11) Baudoin, O.; Cesario, M.; Guénard, D.; Guéritte, F. J. Org. Chem. 2002, 67, 1199.
(12) (a) Wiesner, K.; Valenta, Z.; Manson, A. J.; Stonner, F. W. J. Am. Chem. Soc. 1955,
77, 675. (b) Brown, R. F. C.; Butcher, M. Tetrahedron Lett. 1971, 12, 667.
(13) Fuwa, H.; Okamura, Y.; Morohashi, Y.; Tomita, T.; Iwatsubo, T.; Kan, T.;
Fukuyama, T.; Natsugari, H. Tetrahedron Lett. 2004, 45, 2323.
(14) Reider, P. J.; Davis, P.; Hughes, D. L.; Grabowski, E. J. J. J. Org. Chem. 1987, 52,
955 and references therein.
(15) Ishii, Y.; Fujimoto, R.; Mikami, M.; Murakami, S.; Miki, Y.; Furukawa, Y. Org.
Process Res. Dev. 2007, 11, 609.
ACS Paragon Plus Environment
14