Efficient and Stereoselective Syntheses of ... - ACS Publications

Full Paper

Efficient and Stereoselective Syntheses of Isomerically pure 4-Aminotetrahydro- 2H-thiopyran 1-Oxide Derivatives Ryo Mizojiri, Kazuaki Takami, Tatsuya Ito, Hiroyuki Maeda, Mitsuhisa Yamano, and Tetsuji Kawamoto Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 07 Jun 2017 Downloaded from http://pubs.acs.org on June 7, 2017

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 28

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

Efficient and Stereoselective Syntheses of Isomerically Pure 4-Aminotetrahydro- 2H-thiopyran 1-Oxide Derivatives Ryo Mizojiri,a,* Kazuaki Takami,a Tatsuya Ito,b Hiroyuki Maeda,b Mitsuhisa Yamano,b and Tetsuji Kawamoto a,* a

Research, Takeda Pharmaceutical Company Ltd., Fujisawa, Kanagawa 251-8555, Japan

b

Pharmaceutical Sciences, Takeda Pharmaceutical Company Ltd., Yodogawa-ku, Osaka 532-

8686, Japan

ACS Paragon Plus Environment

1


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

Page 2 of 28

Table of Contents


2

Page 3 of 28

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


KEYWORDS 4-Aminotetrahydro-2H-thiopyran 1-oxide derivatives, Stereoselective oxidation, Hydrogen chloride catalyzed isomerization, Large-scale synthesis

ABSTRACT

Efficient and stereoselective syntheses of isomerically pure 4-aminotetrahydro-2H-thiopyran 1oxide

derivatives

have

successfully

been

achieved.

Isomerically

pure

(4-

nitrophenyl)sulfonyltetrahydro-2H-thiopyran 1-oxides were identified by X-ray crystallographic analyses and thus isomerically pure sulfoxide derivatives were characterized by means of 1H NMR.

Oxidation reaction of tert-butyl (4-nitrophenyl)sulfonyl(tetrahydro-2H-thiopyran-4-

yl)carbamate with Oxone® has been found to provide predominance of steric approach control to afford its trans sulfoxide with high efficiency and selectivity. From the obtained trans sulfoxide derivatives, cis sulfoxide derivatives were synthesized conveniently by means of a hydrogen chloride catalyzed isomerization.

1. Introduction Sulfoxides1 have many chemical and industrial uses and they have also attracted considerable attention because of their significant biological and pharmacological importance. Because the stereochemistry of the sulfur atom of a sulfoxide molecule significantly affects their biological activities2 is well-established, the need for stereoselective synthesis of sulfoxides3 has become increasingly more relevant.


3


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 4 of 28

4-Aminotetrahydro-2H-thiopyran 1-oxide is one of the popular six-membered ring sulfoxides4 components which appears in many biologically active compounds.5 Although each isomer is anticipated to exhibit different biological and pharmacological activities,5f there have been few examples of the direct preparation of isomerically pure sulfoxides for their evaluation. In many cases the sulfoxides are prepared through separation of a mixture of isomeric sulfoxides by an HPLC5f which would not be a suitable or practical synthesis of the requisite quantity of drug candidates required for further evaluation and development. The stereochemical outcome of the oxidation of tetrahydro-2H-thiopyran derivatives substituted at C(4) position by different oxidizing reagents and substituents has been welldescribed.6–8 Johnson6 reported formation of predominantly axial sulfoxides of tetrahydro-2Hthiopyran 1-oxide bearing hydrocarbon substituents and also an almost pure equatorial sulfoxide. Klein7 demonstrated the stereoselective preparation of isomerically pure 4-hydroxytrahydro-2Hthiopyran 1-oxides. However, stereoselective synthesis of isomerically pure 4-aminotetrahydro2H-thiopyran 1-oxide derivatives has not been reported. In the present paper, we describe identification of each isomer of 4-aminotetrahydro-2Hthiopyran 1-oxide derivatives by means of an X-ray crystallographic analyses, their characterization by 1H NMR, and their practical and stereoselective syntheses as useful building blocks for research and development of drugs as well as industrial uses.

2. Results and Discussion 2.1 Preparation and identification of isomeric 4-aminotetrahydro-2H-thiopyran 1-oxide derivatives


4

Page 5 of 28

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


Considering steric effects of the protected amino group at C(4) position of 1 on stereoselective oxidation and convenience in practical syntheses, Boc and Ns protecting groups were selected for 1 and 2a–2c for the investigation of the stereoselective oxidation into isomeric sulfoxides. Treatment of 2a–2c with NaIO4 in aqueous MeCN gave corresponding mixtures of isomeric sulfoxides trans-3 and cis-4 in 39–77% yield.

Among the obtained isomeric sulfoxides,

purification of trans-Ns,Boc-3c and cis-Ns,Boc-4c has been found to be possible easily by column chromatography on silica gel. From trans-Ns,Boc-3c and cis-Ns,Boc-4c obtained, compounds trans-Ns-3a, trans-Boc-3b, trans-3d, cis-Ns-4a, cis-Boc-4b, and cis-4d were prepared as single sulfoxide isomers without isomerization (Scheme 1): Treatment of trans-Ns,Boc-3c and cis-Ns,Boc-4c with K2CO3 in MeOH afforded trans-Ns-3a and cis-Ns-4a, and with mercaptoacetic acid in the presence of lithium hydroxide in DMSO or DMF gave trans-Boc-3b and cis-Boc-4b. Compounds trans-3d and cis-4d were synthesized from trans-Ns-3a and cis-Ns-4a by the treatment with mercaptoacetic acid in the presence of lithium hydroxide in DMSO and from trans-Boc-3b and cis-Boc-4b by the treatment with TFA. X-ray crystallographic analyses of trans-Ns-3a and cisNs-4a confirmed their structure to be the trans- and cis-sulfoxide, respectively (Figure 1).

Scheme 1. Synthesis of isomerically pure 4-aminotetrahydro-2H-thiopyran 1-oxide derivatives trans-3 and cis-4


5


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 6 of 28

Reagents and conditions: a) NsCl, Et3N, THF, rt, 2 h, 78%; b) Boc2O, Et3N, THF, rt, 16 h, 81%; c) Boc2O, DMAP, Et3N, MeCN, rt, 2 h, 93%; d) NaIO4, water, AcOH, rt, 2–16 h, 39–77%; e) column chromatography on silica gel, trans-Ns,Boc-3c: 57%, cis-Ns,Boc-4c: 20%; f) K2CO3, MeOH, 60 °C, 2 h, 73–84%; g) mercaptoacetic acid, LiOH, DMSO or DMF, rt, 2–16 h, 68–72%; h) TFA, rt, 1 h, quant.

It is interesting to note that in the solid state the isomerically pure sulfoxides trans-Ns-3a and cis-Ns-4a adopt chair-shaped six-membered ring confirmations with an oxygen atom of sulfoxide occupying axial positions. Considering from distance between the two functional groups,9 formation of intermolecular hydrogen bonding would be suggested which could affect their conformations in the crystal lattice of trans-Ns-3a and cis-Ns-4a.

Figure 1.

ORTEP of trans-Ns-3a and cis-Ns-4a, thermal ellipsoids are drawn at 50%

probability.10


6

Page 7 of 28

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


2.2 Characterization of isomeric 4-aminotetrahydro-2H-thiopyran 1-oxide derivatives Next, isomerically pure sulfoxides trans-3 and cis-4 were characterized by means of 1H NMR (Table 1). It has been found that chemical shifts for Hb and He in trans-3a–d are lower than those in cis-4a–d suggesting that chemical shifts of Hb and He might be characteristic of each sulfoxide isomer and useful for determination of stereochemistry of 4-aminotetrahydro-2Hthiopyran 1-oxide derivatives. Also, NMR spectra for β-axial protons (Hc) of trans-3a–d and cis-4a–d appear lower field than β-equatorial ones (Hd) which suggest that the sulfoxide groups of trans-3 and cis-4 adopt axial configuration.

7,11–13

Furthermore, NOESY experiments revealed significant correlation

between Hc and He and that between Hc and Hf in cis-Ns-4a suggesting the sulfonamide groups of trans-Ns-3a and cis-Ns-4a occupy axial and equatorial position respectively.

Table 1. Characterization of isomeric 4-aminotetrahydro-2H-thiopyran 1-oxide derivatives by means of 1H NMR 11


7


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 8 of 28

Ha

Hb

Hc

Hd

He

trans-Ns-3aa

2.60–2.72

3.03

2.01–2.16

1.47–1.66

3.43–3.51

cis-Ns-4aa

2.60–2.73

2.84

2.02–2.17

1.62

3.32–3.38

2.65

3.06

2.04–2.21

1.48–1.60

3.57

2.67–2.74

2.86

1.90–2.06

1.68

3.40–3.48

trans-Ns,Boc-3ca

2.87

3.37

2.43–2.48

2.10

4.39

cis-Ns,Boc-4ca

2.99

2.99

2.85–2.93

1.80

4.29

2.68–2.81

3.13–3.23

2.16–2.29

1.60–1.76

3.27–3.35

2.73

2.90–3.01

2.06–2.24

1.84–2.00

3.21

trans-Boc-3ba cis-Boc-4ba

trans-3d-MsOHb cis-4d-HClb a

400 MHz in DMSO at 298 K. b300 MHz in DMSO at 298 K.

2.3 Investigation for stereoselective synthesis of isomerically pure 4-aminotetrahydro-2Hthiopyran 1-oxide derivatives. To develop a practical and stereoselective synthesis of isomerically pure 4-aminotetrahydro2H-thiopyran 1-oxide derivatives, oxidation reactions of 1 and 2a–c with various oxidizing reagents were investigated. The stereoselectivities of the oxidation reactions were determined by HPLC or 1H NMR (Table 2). In the oxidation reactions of 1, Ns-2a and Boc-2b with aqueous NaIO4 corresponding cis-4 were obtained as major products (Runs 1–3) similarly to the results with other 4-substituted tetrahydro-2H-thiopyran reported by Johnson.6 In contrast to the results, it is interesting to note


8

Page 9 of 28

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


that Ns,Boc-2c has been found to yield trans-Ns,Boc-3c as a major product (Runs 4 and 5) under the same reaction conditions, suggesting that the tert-butyl-N-(2-nitrophenylsulfonyl)carbamate group of Ns,Boc-2c might provide predominance of steric approach control in the formation of sulfoxides.6a As it is well studied that most peroxide oxidants provide a predominance of the trans 4substituted tetrahydro-2H-thiopyran-1-oxides,6 aqueous H2O2, MMPP, CHPO, and Oxone® were employed to investigate oxidation reactions of Ns,Boc-2c with expectation of formation of transNs,Boc-3c with higher stereoselectivity (Runs 6-9 in Table 2). Although aqueous H2O2, MMPP and CHPO afforded trans-Ns,Boc-3c in insufficient yield and/or selectivity, Oxone® has been found to give rise to trans-Ns,Boc-3c in excellent yield and selectivity. Furthermore, similar selectivity and yield of trans-Ns,Boc-3c have been found to be reproduced even in scaled-up experiments of the reaction (Run 9 in Table 2) up to in ca. 70 mol scale.

Table 2. Oxidation reactions of 4-aminotetrahydro-2H-thiopyran derivatives (2)a

Reaction Run

Products

Reagent

Solvents

Conv. (%)b

Ratio (trans3/cis-4)b

1

1

NaIO4

MeOH, H2O (2/1)

100c

15/85c,d

2

Ns-2a

NaIO4

MeOH, H2O (2/1)

100c

40/60c


9


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 10 of 28

3

Boc-2b

NaIO4

MeOH, H2O (2/1)

100c

38/62c

4

Ns,Boc-2c

NaIO4 (1.0 eq)

MeOH, H2O (2/1)

92

59/41

5

Ns,Boc-2c

NaIO4 (1.1 eq)

MeCN, H2O (5/3)

98

70/30

6

Ns,Boc-2c

33% H2O2 (1.1 eq)

MeCN

28

61/39

7

Ns,Boc-2c

MMPP (1.1 eq)

MeCN, H2O (5/3)

31

65/35

8

Ns,Boc-2c

CHPO (1.1 eq)

MeCN, H2O (5/3)

3

93/7

9e

Ns,Boc-2c

Oxone® (0.55 eq)

MeCN, H2O (5/2)

97e

92/8

a

[Substrate] = 0.15 (M), [Reagent] = 0.22 (M), at room temperature for 16 h. bDetermined by HPLC. cDetermined by 1H NMR. dRatio of trans-3d and cis-4d (trans-3d/cis-4d). eAt 0 °C for 2 h.

2.4. Practical and stereoselective synthesis of isomerically pure 4-aminotetrahydro-2Hthiopyran 1-oxide derivatives Isolation of isomerically pure trans-Ns,Boc-3c was achieved by recrystallization of the reaction mixture (Run 9 in Table 2) from acetonitrile and water in 81–90% yield (trans-Ns,Boc3c/cis-Ns,Boc-4c = 98/2–99/1) without the need of purification by column chromatography. Thus, efficient and stereoselective syntheses of trans-Ns-3a, trans-Boc-3b, and trans-3d via trans-Ns,Boc-3c have successfully been achieved according to the method shown in Scheme 1. On the other hand, preparation of cis-4 from the mixture of isomeric sulfoxides shown in Runs 1–4 in Table 2 resulted in low yield or insufficient separation of cis-4 from trans-3.

Table 3. Hydrogen chloride catalyzed isomerization of 4-aminotetrahydro-2H-thiopyran 1-oxide derivativesa


10

Page 11 of 28

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


Substrate Run

Product Ratio

Yield

Ratio

(trans-3/cis-4)b

(%)

(trans-3/cis-4)b

1

trans-Ns,Boc-3c

>95/95/ 95% using elemental analysis or analytical HPLC. Purity data were collected by HPLC with NQAD (Nano Quality Analyte Detector) or Corona CAD (Charged Aerosol Detector). The column was an L-column 2 ODS (30 x 2.1 mm I.D., CERI, Japan) or a Capcell Pak C18AQ (50 mm x 3.0 mm I.D., Shiseido,


14

Page 15 of 28

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


Japan) with a temperature of 50 °C and a flow rate of 0.5 ml/min. Mobile phases A and B under a neutral condition were a mixture of 50 mmol/L ammonium acetate, water and acetonitrile (1/8/1, v/v/v) and a mixture of 50 mmol/L ammonium acetate and MeCN (1/9, v/v), respectively. The ratio of mobile phase B was increased linearly from 5% to 95% over 3 min, 95% over the next 1 min. Reagents and solvents were obtained from commercial sources and used without further purification. Reaction progress was determined by thin layer chromatography (TLC) analysis on Merck Kieselgel 60 F254 plates or Fuji Silysia NH plates.

Chromatographic

purification was carried out on silica gel columns ((Inject column and Universal column, YAMAZEN Co.) or on Purif-Pack (Si or NH, Shoko Scientific Co., Ltd.)). All commercially available solvents and reagents were used without further purification. Yields were not optimized.

2-Nitro-N-(tetrahydro-2H-thiopyran-4-yl)benzenesulfonamide (Ns-2a)

To a stirred

suspension of tetrahydro-2H-thiopyran-4-amine hydrochloride (1) (100 g, 650 mmol) and Et3N (227 mL, 1.63 mol) in THF (500 mL) was added 2-nitrobenzenesulfonyl chloride (147 g, 664 mmol) in THF (500 mL). After stirring at room temperature for 2 h, the mixture was extracted with AcOEt (1000 mL) and water (500 mL). The organic layer was washed with saturated brine (250 ml), dried over MgSO4 and concentrated under reduced pressure. To the residue was added IPE (500 mL) and evaporated. To the residue was added IPE (500 mL) and the mixture was concentrated to half volume under reduced pressure. The deposited solid was collected by filtration and dried under reduced pressure to afford Ns-2a (153 g, 78 %) as a beige crystalline solid.


15


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

Page 16 of 28

H NMR (300 MHz, CDCl3) δ 1.60–1.79 (2H, m), 2.05–2.16 (2H, m), 2.57–2.68 (4H, m),

3.30–3.52 (1H, m), 5.30 (1H, d, J = 7.8 Hz), 7.70–7.81 (2H, m), 7.84–7.92 (1H, m), 8.14–8.21 (1H, m).

13

C NMR (75 MHz, CDCl3) δ 27.24, 34.86, 52.82, 125.51, 130.56, 133.06, 133.68,

134.91, 147.82. LCMS m/z calcd for C11H14N2O4S2: 302.04, found 303.0 [M+H]. Anal. Calcd for C11H14N2O4S2: C, 43.69; H, 4.67; N, 9.26. Found: C, 43.71; H, 4.67; N, 9.14. Mp. 135–137 °C.

tert-Butyl (tetrahydro-2H-thiopyran-4-yl)carbamate (Boc-2b) A mixture of 1 (2 g, 13 mmol), (BOC)2O (4.5 mL, 19.5 mmol) and Et3N (5.4 mL, 39 mmol) in THF (20 mL) was stirred at room temperature for 16 h. The mixture was extracted with AcOEt (20 mL) and water (20 mL). The organic layer was washed with saturated brine (20 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was crystallized from EtOH and water to afford Boc-2b (2.3 g, 81 %) as a beige crystalline solid. 1

H NMR (300 MHz, CDCl3) δ 1.44 (9H, s), 1.48–1.55 (2H, m), 2.15–2.32 (2H, m), 2.55–2.80

(4H, m), 3.45 (1H, d, J = 8.2 Hz), 4.46 (1H, brs).

13

C NMR (75 MHz, CDCl3) δ 27.86, 28.40,

34.56, 48.87, 79.43, 154.95. LCMS m/z calcd for C10H19NO2S: 217.11, found 118.2 [M+HBoc]. Anal. Calcd for C10H19NO2S: C, 55.27; H, 8.81; N, 6.45. Found: C, 55.23; H, 8.73; N, 6.51. Mp. 139–141 °C.

tert-Butyl [(2-nitrophenyl)sulfonyl]tetrahydro-2H-thiopyran-4-ylcarbamate (Ns,Boc-2c). To a stirred solution of 2a (153 g, 507 mmol), DMAP (6.2 g, 50.8 mmol) and Et3N (81 mL, 584


16

Page 17 of 28

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


mmol) in MeCN (600 mL) was added (BOC)2O (135 mL, 584 mmol) in MeCN (150 mL) over 30 min. The reaction mixture was stirred at room temperature for 2 h. To the reaction mixture, water (650 mL) was added dropwise and the mixture was stirred at room temperature for 1 h, the precipitated solid was collected by filtration and dried under reduced pressure to afford Ns,Boc2c (190 g, 93 %) as a beige crystalline solid. 1

H NMR (300 MHz, CDCl3) δ 1.41 (9H, s), 2.26 (2H, dd, J = 12.7, 3.0 Hz), 2.50 (2H, qd, J =

12.3, 3.3 Hz), 2.65–2.77 (2H, m), 2.81–3.00 (2H, m), 4.11 (1H, tt, J = 11.8, 3.3 Hz), 7.68–7.85 (3H, m), 8.27–8.42 (1H, m).

13

C NMR (75 MHz, CDCl3) δ 27.95, 29.78, 32.96, 59.20, 85.28,

124.40, 131.91, 133.26, 134.02, 134.20, 147.60, 150.43. LCMS m/z calcd for C16H22N2O6S2: 402.09, found 303.0 [M+H-Boc]. Anal. Calcd for C16H22N2O6S2: C, 47.75; H, 5.51; N, 6.96. Found: C, 47.78; H, 5.45; N, 6.75. Mp. 144–146 °C.

General

procedure

for

oxidation

reactions

of

4-aminotetrahydro-2H-thiopyran

derivatives (2) (Table 3) The mixture of 2 (4.6 mmol) and NaIO4 (1.1 g, 5.1 mmol) in MeOH (20 mL) and water (10 mL) was stirred at room temperature for 16 h. The mixture was extracted with AcOEt (40 mL) and water (20 mL). The organic layer was washed with saturated brine (20 mL), dried over MgSO4 and concentrated under reduced pressure. Conversion and ratio of the corresponding trans-3 and cis-4 were determined by HPLC or 1H NMR. HPLC conditions: CAPCELLPAK MG II, 0.05 M K2HPO4/MeCN = 4/6, 220 nm, 1mL/min, 25 °C. CAPCELLPAK MG II, 0.05 M AcONH4/MeCN = 6/4, 220 nm, 1mL/min, 25 °C.


17


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 18 of 28

trans-tert-Butyl[(2-nitrophenyl)sulfonyl]-1-oxidotetrahydro-2H-thiopyran-4-ylcarbamate (trans-Ns,Boc-3c)

and

cis-tert-Butyl[(2-nitrophenyl)sulfonyl]-1-oxidotetrahydro-2H-

thiopyran-4-ylcarbamate (cis-Ns,Boc-4c) Method A (Purification by column chromatography): To a stirred solution of Ns,boc-2c (5.24 g, 13 mmol) in AcOH (50 mL) was added 30% aqueous H2O2 solution (1.3 mL, 13 mmol) and the reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and the residue was extracted with AcOEt (200 mL) and water (100 mL). The organic layer was washed with saturated brine (50 mL), dried over MgSO4 and concentrated under reduced pressure (trans-Ns,Boc-3c/cis-Ns,Boc-4c = 70/30). The residue was purified by column chromatography (silica gel, eluent: 10/90 to 50/50 AcOEt/hexanes) to afford transNs,Boc-3c (3.4 g, 62%) as a more polar compound and cis-Ns,Boc-4c (878 mg, 16%) as a less polar compound.

Method B (Purification by crystallization): To a stirred mixture of Ns,Boc-2c (95 g, 236 mmol) in MeCN (760 mL) was added Oxone® (80 g, 130 mmol) in water (380 mL) at 0–10 °C. After stirring at 0–10 °C for 2 h, 5% aqueous NaHCO3 solution (950 mL) was added at 0–10 °C. To the reaction solution, was added water (180 mL) at 0–10 °C and the mixture was stirred at 0– 10 °C for 1 h. Then, to the mixture additional water (1710 mL) was added at 0–10 °C and the mixture was stirred at 0–10 °C for 2 h. The precipitated solid was collected by filtration, washed with water/MeCN (7/1) and dried under reduced pressure to afford trans-Ns,Boc-3c (87 g, transNs,Boc-3c/cis-Ns,Boc-4c = 92/8) as a beige amorphous solid. The solid was recrystallized from


18

Page 19 of 28

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


MeCN (450 mL) and water (1800 mL) to afford trans-Ns,Boc-3c (80 g, 81 %, trans-Ns,Boc3c/cis-Ns,Boc-4c = 99.02/0.98) as a white crystalline solid.

Method C (Large-scale synthesis): The solution of Oxone® (24.7 kg, 40.2 mol) in water (117.7 kg) was added to the mixture of Ns,boc-2c (29.4 kg, 73.01 mol) and MeCN (231.2 kg) at 0–10 °C over 30 min and the mixture was stirred at 0–10 °C for 2 h. 5% aqueous NaHCO3 solution (302 kg) was added dropwise at 0–10 °C. Water (58.8 kg) was added at 0–10 °C and the mixture was stirred at 0–10 °C for 1 h. Water (529.6 kg) was added at 0–10 °C and the mixture was stirred at 0–10 °C for 2 h. The resulting crystals were collected by filtration and washed with water/MeCN (490.4 kg/77.1 kg), and dried under reduced pressure (50 °C) to give crude trans-Ns,Boc-3c (27.52 kg, 90%, HPLC area 97.0%) as a white crystalline powder. HPLC conditions: CAPCELLPAK MG II (4.6 mm ɸ × 150 mm), 0.05 M K2HPO4/MeCN = 4/6, 220 nm, 1 mL/min, 25 °C. trans/cis = 98.17/1.83; HPLC conditions: CAPCELLPAK MG II (4.6 mm ɸ × 150 mm), 0.05 M AcONH4/MeCN = 6/4, 220 nm, 1 mL/min, 25 °C. trans-Ns,Boc-3c: 1H NMR (400 MHz, DMSO-d6) δ 1.22 (9H, s), 2.10 (2H, d, J = 13.2 Hz), 2.43–2.48 (2H, m), 2.87 (2H, t, J = 12.4 Hz), 3.37 (2H, d, J = 10.7 Hz), 4.39 (1H, t, J = 11.7 Hz), 7.90–8.02 (2H, m), 8.09 (1H, d, J = 7.5 Hz), 8.14 (1H, d, J = 7.8 Hz).

13

C NMR (75 MHz,

CDCl3) δ 26.59, 27.85, 51.59, 56.75, 77.28, 86.10, 124.67, 132.13, 133.14, 133.84, 134.42, 147.44, 149.87. LCMS m/z calcd for C16H22N2O7S2: 418.09, found 419.1 [M+H]. Anal. Calcd for C16H22N2O7S2: C, 45.92; H, 5.30; N, 6.69. Found: C, 45.84; H, 5.45; N, 6.64. Mp. 176–178 °C.


19


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 20 of 28

cis-Ns,Boc-4c: 1H NMR (400 MHz, DMSO-d6) δ 1.29 (9H, s), 1.80 (2H, d, J = 10.0 Hz), 2.85– 2.93 (2H, m), 2.99 (4H, t, J = 11.8 Hz), 4.29 (1H, t, J = 11.4 Hz), 7.92–8.01 (2H, m), 8.05–8.11 (1H, m), 8.18 (1H, d, J = 9.0 Hz).

13

C NMR (75 MHz, CDCl3) δ 20.90, 28.00, 46.99, 56.95,

77.28, 85.89, 124.43, 132.07, 133.83, 134.03, 134.28, 147.66, 150.29.

LCMS m/z calcd for

C16H22N2O7S2: 418.09, found 419.1 [M+H]. Anal. Calcd for C16H22N2O7S2: C, 45.92; H, 5.30; N, 6.69. Found: C, 45.56; H, 5.43; N, 6.63. Mp. 150–152 °C.

trans-2-Nitro-N-(1-oxidotetrahydro-2H-thiopyran-4-yl)benzenesulfonamide (trans-Ns-3a). The mixture of trans-Ns,Boc-3c (1 g, 2.4 mmol) and K2CO3 (0.66 g, 4.8 mmol) in MeOH (10 mL) was stirred at 60 °C for 2 h. After cooling to room temperature, 0.5 M aqueous HCl solution (20 mL) was added dropwise to the mixture. After stirring at room temperature for 1 h and at 0 °C for 1 h, the precipitated solid was collected by filtration and dried under reduced pressure to afford trans-Ns-3a (636 mg, 84 %, trans-Ns-3a/cis-Ns-4a = 99/1) as a white crystalline solid. 1

H NMR (400 MHz, DMSO-d6) δ 1.47–1.66 (2H, m), 2.01–2.16 (2H, m), 2.60–2.72 (2H, m),

3.03 (2H, t, J = 10.9 Hz), 3.43–3.51 (1H, m), 7.82–7.91 (2H, m), 7.92–8.00 (1H, m), 8.02–8.09 (1H, m), 8.34 (1H, brs).

13

C NMR (75 MHz, CDCl3) δ 23.26, 27.95, 43.20, 49.03, 77.23,

125.69, 131.19, 133.11, 133.32, 134.09. LCMS m/z calcd for C11H14N2O5S2: 318.03, found 319.0 [M+H]. Anal. Calcd for C11H14N2O5S2: C, 41.50; H, 4.43; N, 8.80. Found: C, 41.67; H, 4.68; N, 8.57. Mp. 220–222 °C.


20

Page 21 of 28

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


trans-tert-Butyl (1-oxidotetrahydro-2H-thiopyran-4-yl)carbamate (trans-Boc-3b)

To a

stirred solution of trans-Ns,Boc-3c (80 g, 191 mmol) and mercaptoacetic acid (41 mL, 574 mmol) in DMSO (400 mL) was added lithium hydroxide monohydrate (48 g, 1147 mmol). The mixture was stirred at room temperature for 2 h. The mixture was extracted with AcOEt (800 mL) and saturated aqueous NaHCO3 solution (800 mL). The aqueous layer was extracted with AcOEt (400 mL) and the organic layer was washed with saturated brine (400 mL). To the organic layer activated carbon and Na2SO4 were added and the mixture was stirred at room temperature for 30 min. After filtration, the mixture was concentrated under reduced pressure. IPE (500 mL) was added and the mixture was concentrated under reduced pressure. To the resulting residue, IPE (500 mL) was added and the precipitated solid was collected by filtration and dried under reduced pressure to afford trans-Boc-3b (30 g, 68 %) as a beige crystalline solid. 1

H NMR (400 MHz, DMSO-d6) δ 1.38 (9H, s), 1.48–1.60 (2H, m), 2.04–2.21 (2H, m), 2.65

(2H, t, J = 9.9 Hz), 3.06 (2H, t, J = 10.6 Hz), 3.57 (1H, brs), 6.98 (1H, brs).

13

C NMR (75 MHz,

CDCl3) δ 25.82, 28.38, 46.56, 47.08, 77.29, 79.91, 155.22. LCMS m/z calcd for C10H19NO3S: 233.11, found 234.1 [M+H]. Anal. Calcd for C10H19NO3S: C, 51.48; H, 8.21; N, 6.00. Found: C, 51.41; H, 8.25; N, 5.78. Mp.160–162 °C.

trans-4-Aminotetrahydro-2H-thiopyran 1-oxide methanesulfonate (trans-3d-MsOH): Compound trans-Boc-3b (30 g, 129 mmol) was added portionwise to TFA (60 mL) with stirring at room temperature.

After stirring at room temperature for 30 min, the mixture was

concentrated under reduced pressure. The residue was azeotropically distilled with AcOEt twice. The residue was dissolved in DMSO (100 mL) and AcOEt (100 mL). To the mixture was added


21


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 22 of 28

MsOH (16.7 mL, 257 mmol) dropwise. After stirring at room temperature for 30 min, the precipitated solid was collected by filtration, washed with AcOEt (50 mL) and dried under reduced pressure to give crude amorphous solid. Crystallization form EtOH (200 mL) and water (20 mL) afforded trans-3d-MsOH (20 g, 68 %) as a white crystalline solid. 1

H NMR (300 MHz, DMSO-d6) δ 1.60–1.76 (2H, m), 2.16–2.29 (2H, m), 2.31 (3H, s), 2.68–

2.81 (2H, m), 3.13–3.23 (2H, m), 3.27–3.35 (1H, m), 7.86 (3H, brs).

13

C NMR (75 MHz, D2O) δ

24.98, 38.51, 46.18, 46.84. LCMS m/z calcd for C5H11NOS: 133.06, found 134.1 [M+H]. Anal. Calcd for C6H15NO4S2: C, 31.43; H, 6.59; N, 6.11. Found: C, 31.62; H, 6.48; N, 6.19. Mp. 214– 216 °C.

General

procedure

for

a

hydrogen

chloride

catalyzed

isomerization

of

4-

aminotetrahydro-2H-thiopyran 1-oxide derivatives (Table 3). The mixture of trans-3 (2.4 mmol) and 2 M methanolic HCl solution (10 mL, 20 mmol) was stirred at 60 °C for 16 h. The mixture was extracted with AcOEt (30 mL) and water (20 mL). The organic layer was washed with saturated brine (20 mL), dried over MgSO4 and concentrated under reduced pressure. Conversion and ratio of the corresponding trans-3 and cis-4 were determined by 1H NMR.

cis-2-Nitro-N-(1-oxidotetrahydro-2H-thiopyran-4-yl)benzenesulfonamide (cis-Ns-4a). To a stirred mixture of cis-Ns,Boc-4c (1 g, 2.4 mmol) in methanol (10 mL) was added K2CO3 (0.66 g, 4.8 mmol). The reaction mixture was stirred at 60 °C for 2 h and cooled to 0 °C (trans-


22

Page 23 of 28

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


Ns-3a/cis-Ns-4a = 1/99). 1 M aqueous HCl solution (10 mL) was added to the mixture to afford precipitate and the resulting mixture was stirred at 0 °C for 1 h. The obtained precipitate was collected by filtration, washed with 25% aqueous methanol solution (5 mL) and dried under reduced pressure to afford cis-Ns-4a (545 mg, 73%, trans-Ns-3a/cis-Ns-4a = 1/99) as a white crystalline solid. 1

H NMR (400 MHz, DMSO-d6) δ 1.62 (2H, d, J = 11.4 Hz), 2.20–2.17 (2H, m), 2.60–2.73

(2H, m), 2.84 (2H, d, J = 13.2 Hz), 3.32–3.38 (1H, m), 7.82–7.91 (2H, m), 7.93–7.99 (1H, m), 8.01–8.09 (1H, m), 8.40 (1H, brs). 125.59, 130.24, 133.03, 133.75.

13

C NMR (75 MHz, CDCl3) δ 23.26, 45.35, 51.43, 77.24,

LCMS m/z calcd for C11H14N2O5S2: 318.03, found 319.0

[M+H]. Anal. Calcd for C11H14N2O5S2: C, 41.50; H, 4.43; N, 8.80. Found: C, 41.56; H, 4.59; N, 8.84. Mp. 230–232 °C.

cis-tert-Butyl 1-oxidotetrahydro-2H-thiopyran-4-ylcarbamate (cis-Boc-4b). To a stirred suspension of cis-Ns,Boc-4c (10 g, 23.9 mmol) and 2 M aqueous lithium hydroxide solution (47.8 mL, 95.6 mmol) in DMF (70 mL) was added mercaptoacetic acid (3.4 mL, 47.8 mmol). After stirring at room temperature for 16 h, the mixture was extracted with AcOEt (300 mL). The organic layer was washed with saturated brine (100 mL), dried over MgSO4 and concentrated under reduced pressure. The precipitated solid was collected by filtration, washed with IPE, and then dried under reduced pressure to afford cis-Boc-4b (4 g, 72 %) as a light yellow crystalline solid. 1

H NMR (400 MHz, DMSO-d6) δ 1.38 (9H, s), 1.68 (2H, d, J = 11.0 Hz), 1.90–2.06 (2H, m),

2.67–2.74 (2H, m), 2.86 (2H, d, J = 13.1 Hz), 3.40–3.48 (1H, m), 7.00 (1H, brs).

13

C NMR (75


23


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 24 of 28

MHz, CDCl3) δ 22.71, 28.38, 45.59, 47.43, 79.70, 155.04. LCMS m/z calcd for C10H19NO3S: 233.11, found 234.1 [M+H]. Anal. Calcd for C10H19NO3S: C, 51.48; H, 8.21; N, 6.00. Found: C, 51.44; H,8.12; N, 5.92. Mp.201–203 °C.

cis-4-Aminotetrahydro-2H-thiopyran 1-oxide hydrochloride (cis-4d-HCl): The mixture of trans-Boc-3b (50 g, 214 mmol) and 2 M HCl EtOH solution (300 mL, 600 mmol) was stirred at room temperature for 16 h. The precipitated solid was collected by filtration and washed with EtOH (50 mL). The wet cake was crystallized from 10% aqueous DMSO (300 mL) and AcOEt (300 mL) to afford cis-4d-HCl (22.5 g, 62 %) as a white crystalline solid. 1

H NMR (400 MHz, DMSO-d6) δ 1.81–2.00 (2H, m), 2.06–2.24 (2H, m), 2.73 (2H, td, J =

13.6, 3.2 Hz), 2.90–3.01 (2H, m), 3.21 (1H, brs), 8.19 (3H, brs).

13

C NMR (75 MHz, D2O) δ

19.80, 42.94, 47.34. LCMS m/z calcd for C5H11NOS: 133.06, found 134.1 [M+H]. Anal. Calcd for C5H12NClOS: C, 35.39; H, 7.13; N, 8.26. Found: C, 35.28; H, 6.87; N, 8.26. Mp. 230–232 °C.

Author Information Corresponding Authors *Phone: +81-466-32-1058. E-mail: [email protected] *Phone: +81-466-32-1193. E-mail: [email protected] Notes


24

Page 25 of 28

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 authors declare no competing financial interest.

Acknowledgment We sincerely appreciate Etsuo Kotani, Shin-ichi Masada and Dr. Toshiki Murata for useful discussion during this work. We are grateful to Mr. Daisaku Yoshida of Hamari Chemical Industries, Ltd. for his helpful discussion in the scaled-up synthesis of trans-Ns-3a; Dr. Yuichiro Kondo, Teppei Otsuda, Noritaka Kuroda and Dr. Toru Yamano for their help in HPLC analyses of trans-3 and cis-4; Keiko Higashikawa and Mitsuyoshi Nishitani for their support in X-ray crystallographic analyses of 3a and 4a.

Abbreviation Used Boc; tert-Butoxycarbonyl, CHPO; Cumene Hydroperoxide, IPE; diisopropylether, MMPP; Magnesium Monoperoxyphthalate, MsOH; Methanesulfonic Acid, NOESY; Nuclear Overhauser Effect Spectroscopy, Ns; 2-Nitrobenzenesulfonyl, TFA; Trifluoroacetic Acid.

Supporting Information 1

H and 13C NMR spectra for all compounds, 2D-NMR spectra for trans-Ns-3a and cis-Ns-4a,

and Crystal date for trans-Ns-3a and cis-Ns-4a are displayed in Supplementary Material.


25


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

Page 26 of 28

References and Notes 1.

Kalir A.; Kalir H. H. In The chemistry of sulphur-containing functional groups; Patai, S. Rappoport Z, Eds.; J. Wiley & Sons: New York, 1993; pp. 957–973.

2.

For biological importance of nonracemic sulfoxides: (a) for Esomeprazole. Cotton, H.; Elebring, T.; Larsson, M.; Li, L.; Sörensen, H.; von Unge,S. Tetrahedron Asymm. 2000, 11, 3819–3825. (b) for armodaﬁnil. Osorio-Lozada, A.; Prisinzano, T.; Olivo, H. F. Tetrahedron Asymm. 2004, 15, 3811–3815. (c) for OPC-29030. Matsugi, M.; Fukuda, N.; Muguruma, Y.; Yamaguchi, T.; Minami-kawa, J.; Otsuka, S. Tetrahedron 2001, 57, 2739– 2744. (d) for aprikalim. Brown, T. J.; Chapman, R. F.; Cook, D. C.; Hart, T. W.; McLay, I. M.; Jordan, R.; Mason, J. S.; Palfreyman, M. N.; Walsh, R. J. A.; Withnall, M. T.; Aloup, J.-C.; Cavero, I.; Farge, D.; James, C.; Mondot, S. J. Med. Chem. 1992, 35, 3613–3624. (e) ustiloxins A & B. Hutton, C. A.; White, J. M. Tetrahedron Lett. 1997, 38, 1643–1646.

3.

For review of enantioselective synthesis of sulfoxides: Wojaczyńska. E.; Wojaczyński, J. Chem. Rev. 2010, 110, 4303–4356.

4.

Ingall, A. H. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R.; Rees, C. W., Eds. Pergamon Press, Oxford, 1984; Vol. 3, Prat 2B, pp. 885–942.

5.

as anti HIV agent. Orlemans, Everardus O. M.; Haynes, Barton F.; Ferrari, G.; Haystead, T.; Kwiek, Jesse J. U.S. Pat. Appl. Publ. US 20160143884 A1. 2016. (b) as PAK1 inhibitors. Crawford, James J.; Drobnick, J.; Gazzard, Lewis J.; Lee, W.; Ndubaku, C.; Rudolph, J. PCT Int. Appl. WO2015011252, A1. 2015. (c) as neutrophil elastase inhibitor. Gnamm, C.; Oost, T.; Peters, S.; Rudolf, K. U.S. Pat. Appl. Publ. US20140249129, A1. 2014. (d) as serotonin 4 receptor agonist. Ikeda, J.; Nakamura, T.; Otaka, H. PCT Int.


26

Page 27 of 28

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


Appl. WO2014092104, A1. 2014. (e) as JAK inhibitors. Bergeron, P.; Bodil Van Niel, M.; Dragovich, P.; Hurley, C.; Kulagowski, J.; Labadie, S.; McLean, Neville J.; Mendonca, R.; Pulk, R.; Zak, M. PCT Int. Appl. WO2013007765, A1. 2013. (f) as melanin-concentrating hormone receptor antagonists. Murata, T.; Takami, K.; Kamaura, M.; Okawa, T. PCT Int. Appl. WO2009123194, A1. 2009. 6.

Johnson, C. R.; McCants, Jr. D. J. Am. Chem. Soc. 1965, 87, 1109–1114, (b) Johnson, C. R. J. Am. Chem. Soc. 1963, 85, 1020–1021, (c) Johnson, C. R.; McCants, Jr. D. J. Am. Chem. Soc. 1964, 86, 2935–2936.

7.

Klein, J.; Stollar, H. Tetrahedron 1974, 30, 2541–2548.

8.

Fatiadi, A. J. Synthesis 1974, 229–272.

9.

Distance between NH of sulfonamide and O of sulfoxide in crystals of trans-Ns-3a and cis-Ns-4a are 2.926 Å and 2.733 Å respectively suggesting formation of intermolecular hydrogen bonding between them.

10. Crystal date for trans-Ns-3a and cis-Ns-4a are displayed in Supplementary Material. 11. Foster, A. B.; Inch, T. D.; Qadir, M. H.; Webber, J. M. Chem. Commun. 1968, 1086– 1089. 12. Hutchinson, B. J.; Andersen, K. K. Katritzky, A. R. J. Am. Chem. Soc. 1969, 91, 3839– 3844. 13. Klein, J.; Stollar, H. J. Am. Chem. Soc. 1973, 95, 7437–7444.


27


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

Page 28 of 28

14. Mislow, K.; Simmons, T.; Melillo, J. T.; Ternay, Jr. A. L. J. Am. Chem. Soc. 1964, 86, 1452–1453.


28

Efficient and Stereoselective Syntheses of ... - ACS Publications

Recommend Documents