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Development of a Robust Process for the Preparation of High-Quality 4-Methylenepiperidine Hydrochloride Fuqiang Zhu, Haji Akber Aisa, Jian Zhang, Tianwen Hu, Changliang Sun, Yang He, Yuanchao Xie, and Jingshan Shen Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00350 • Publication Date (Web): 19 Dec 2017 Downloaded from http://pubs.acs.org on December 19, 2017

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Organic Process Research & Development

Development of a Robust Process for the Preparation of High-Quality 4-Methylenepiperidine Hydrochloride Fuqiang Zhu,†, ⊥ Haji A. Aisa,*,† Jian Zhang,§ Tianwen Hu,§ Changliang Sun,§ Yang He,‡ Yuanchao Xie,‡ and Jingshan Shen*,‡ †Key Laboratory of Plant Resources and Chemistry in Arid Regions, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, South Beijing Road 40-1, Urumqi, Xinjiang 830011, P. R China. ⊥University of Chinese Academy of Sciences，No.19A Yuquan Road, Beijing 100049, P. R China. ‡CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R China. §Topharman Shanghai Co., Ltd., Building 1, No.388 Jialilue Road, Zhangjiang Hitech Park, Shanghai 201209, P. R China.

ABSTRACT An efficient route for the preparation of 4-methylenepiperidine hydrochloride 1 was designed and then a process feasible for large-scale production was developed with a total yield of 83.5% at a purity of 99.9%. Keywords: 4-methylenepiperidine hydrochloride, Efinaconazole, N-benzylpiperidinone

and ethyl chloroformate.

INTRODUCTION Efinaconazole is a novel triazole antifungal administered as a 10% topical solution

1

ACS Paragon Plus Environment

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

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for the treatment of mild to moderate onychomycosis (trade name Jublia (R), marketed in 2014) developed by Valeant Pharmaceuticals International.1,

2

It is

currently the most effective topical anti-fungal drug acting by inhibiting ergosterol biosynthesis,3 and is predicted to have broad market prospects in the near future. Retrosynthetic

analysis

shows

that

efinaconazole

is

constructed

from

4-methylenepiperidine hydrochloride 1 and epoxytriazole 2 (Figure 1). Since the 4-methylenepiperidine moiety is introduced to the efinaconazole structure in the final step, the impurity profile of 1 will impact significantly on the quality of the final API. Thus, development of a reliable, robust and cost-effective process for the preparation of 4-methylenepiperidine hydrochloride 1 is critical for the commercial production of efinaconazole. Figure 1. Structure of Efinaconazole and its Two Key Intermediates

Several approaches of the synthesis of 4-methylenepiperidine hydrochloride 1 have been reported.4-8 Started from N-benzyl piperidinone 3 or N-Boc piperidinone 6, Mimura and Cooper

4, 5

reported the preparation of hydrochloride 1 involving

formation of the methylene unit by Wittig reaction (Scheme 1 and Scheme 2). However, the use of n-BuLi and column chromatography are not desirable for industrial production. More importantly, when we repeated these procedures, two undesired impurities (1A and 1B) were detected and could not be completely removed 2


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by normal purification. This fact revealed that the terminal methylene structure was unstable and prone to generate related impurities in an acidic environment. Naito et al. reported another route for the synthesis of 1 starting from ethyl isonipecotate 8 (Scheme 3).6-8 The terminal methylene unit was constructed by elimination reaction of the chloromethyl piperidine 11 in the presence of t-BuOK. This route consisted of a linear sequence of six steps and the overall yield was only 35%. Attolini et al. adopted a similar route using Boc as protection group to prepare 4-methylenepiperidine hydrochloride 1(Scheme 4).9

Scheme 1. Mimura’s Approach for the Synthesis of 4-Methylenepiperidine Hydrochloride

Scheme 2. Cooper’s Approach for the Synthesis of 4-Methylenepiperidine Hydrochloride

Scheme

3.

Naito

and

Mimura’s

Approach

4-Methylenepiperidine Hydrochloride 1 3


for

the

Synthesis

of


COOC2H5

N H

CH2OH

COOC2H5

CH2Cl

BzCl,Py

NaBH4

SOCl2

toluene

dioxane, MeOH

DCM

8

N Bz

t-BuOK N Bz 11

DMF

N Bz 12

hydrochloric acid

KOH, ethylene glycol

76%, 5 steps

N Bz 10

9

Page 4 of 18

46%

·HCl

N H

N H 1

13

Scheme 4. Attolini’s Approach for the Synthesis of 4-Methylenepiperidine Hydrochloride 1

Herein we report the development of a reliable and robust process, which is suitable to produce high quality 4-methylenepiperidine hydrochloride 1 in large quantities. RESULTS AND DISCUSSION Through literature search and market survey, the commercially available N-benzylpiperidinone 3 was considered to be the ideal starting material for the synthesis of 4-methylenepiperidine hydrochloride 1. The potential synthetic routes for hydrochloride 1 from N-benzylpiperidinone 3 are shown in Scheme 5. It was particularly noted that the free base of 4-methylenepiperidine 13 was prepared before 4


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the formation of hydrochloride in all routes considering its instability in an acid environment. 4-Methylenepiperidine 13 was produced from the common key amide intermediate 20, which could be prepared by three synthetic routes. In route A, the methylene unit was first constructed and then N-benzyl was removed by appropriate chloroformate reagent to give key intermediate 20. In both route B and C, N-benzyl was first removed, and the difference between them was the conditions of removing benzyl group. It was considered that the one-step method of using chloroformate in route C was far more easier than hydrogenation and followed acylation reactions in route B. Preliminary experiments confirmed that the reactions in route A and C gave similar results, but the work-up procedure of Wittig reaction step in route A was greatly easier than that in route C by employing simple acid-base switching. Thus, route A was adopted for process development of 4-methylenepiperidine hydrochloride 1 and depicted in more detail in Scheme 6. Scheme 5. Possible Routes for the Synthesis of 4-Methylenepiperidine Hydrochloride 1

Scheme 6. Established Route for the Synthesis of 4-Methylenepiperidine 5



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Hydrochloride 1

Reagents and conditions: (a) CH3P(Ph)3+Br-, t-BuONa, toluene, 20-30 oC; (b) ClCO2Et, Na2CO3, toluene, 55-60 oC; (c) ethylene glycol, NaOH; (d) 20% HCl/EtOH, isopropyl acetate. 83.5% over four steps.

For the Wittig reaction between N-benzylpiperidinone 3 and methyltriphenylphosphonium bromide, hazardous n-BuLi was successfully replaced by t-BuONa. This reaction proceeded well with t-BuONa in THF or toluene at 0-10 °C. After work-up, the methylene intermediate 4 was obtained as a pale yellow liquid in 95% yield. As a switch from t-BuONa to t-BuOK did not provide any advantage (Table 1, entry 1-4), detail reaction parameters of toluene / t-BuONa system were further optimized. Raising reaction temperature to 20-30 oC did not decrease the yield and selectivity. The optimal amounts of methyltriphenylphosphonium bromide and t-BuONa were both 1.1 equiv (entry 5-7). Table 1 Screening Results of Wittig Reaction Parameters of 3a entry

solvent

base (equiv)

MeP(Ph)3+Br-

temp (oC)

6b (area %)

（equiv） 1

THF

t-BuOK (1.5)

1.5

0-10

98.6

2

THF

t-BuONa (1.5)

1.5

0-10

98.3

3

toluene

t-BuOK (1.5)

1.5

0-10

98.2

6


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a

4

toluene

t-BuONa (1.5)

1.5

0-10

98.4

5

toluene

t-BuONa (1.1)

1.1

0-10

98.6

6

toluene

t-BuONa (1.05)

1.05

0-10

96.5

7

toluene

t-BuONa (1.1)

1.1

20-30

98.7

Conditions: 3 (500 mg scale), magnetic stirring. All reagents were charged followed

by a nitrogen purge. b Determined by HPLC

The stability of intermediate 4 in an acidic environment was studied in order to take appropriate work-up procedure. The results revealed that the impurities with structures similar to 1A and 1B were obviously observed when pH was lower than 1.0 even at -10 oC. The level of these impurities was reduced to less than 0.15% (calculated by area of chromatography) when pH was higher than 3.0 at 5-10 o C and the quality of the final product was unaffected. Upon completion of the Wittig reaction monitored by HPLC, the reaction mixture was quenched with water and 6N hydrochloric acid at 5-10 o C. The separated organic layer containing triphenylphosphine oxide was discarded, and the methylene intermediate 4 was left in the aqueous phase as its hydrochloride form. Then the aqueous phase was basified to pH = 9.5~10 by 20% NaOH solution and methylene intermediate 4 was extracted back into the organic phase with toluene. This solution of methylene intermediate 4 in toluene was directly used in the subsequent N-debenzylation reaction. N-Dealkylation of tertiary amines via acylation using cloroformate has been well 7



Page 8 of 18

reported and demonstrated many applications in organic synthesis,10-13 as well as synthesis of Noromorphine and Loratadine.14,

15

The preferred reagent was ethyl

chloroformate, the most widely used reagent in this field. Fortunately, the methylene intermediate 4 was smoothly transformed to amide 21 with ethyl chloroformate in the presence of catalytic quantity sodium carbonate (entry 1, Table 2).16 Then, the reaction temperature, time and the equivalent of ethyl chloroformate were fully investigated. As shown in Table 2, the optimal temperature range was 55-60oC. Lower temperature obviously decreased the yield (entry 4), while higher temperature caused more impurities (entry 3). The optimal equivalent of ethyl chloroformate was found to be 1.1 equiv as lower equivalent led to incomplete conversion of methylene intermediate 4 (entry 2). This N-debenzylation reaction generated an equivalent of benzyl chloride, which could be collected and purified as a raw material. Table 2 Optimization Results of the N-Debenzylation Reaction entry

a

temp (oC)

conversion b,c

15c,d

(%)

(area %)

1.5

99.7

92.5

85-90

8

93

83.6

0.1

85-90

3

99.6

95.7

1.1

0.1

35-40

10

82.3

81.5

1.1

0.1

55-60

4

99.7

97.8

ClCO2Et

Na2CO3

(equiv)

(equiv)

1

2.5

0.1

85-90

2

1.02

0.1

3

1.1

4 5

time (h)

Conditions: 4 (10g scale), magnetic stirring. All reagents were charged followed by a

nitrogen purge. b Conversion was calculated from the HPLC area. 8


c

Detected by HPLC.

d

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The amount of benzyl chloride generated in this reaction mixture was not calculated.

While the methylene intermediate 4 was consumed to less than 0.5% (monitored by HPLC), water was charged to quench reaction and wash off the inorganic salts. Then the separated organic phase was concentrated in vacuum to remove most of toluene and a mixture of benzyl chloride and amide 21 was obtained. Because the boiling point of benzyl chloride is 35 oC lower than amide 21 under reduced pressure (2.6 kPa), the two could be separated by fractional distillation in vacuum. The benzyl chloride was successfully distilled off and collected under reduced pressure (2.7 kPa) at 95-110 °C while the amide 21 remained in the vessel. Experimental result confirmed that the remaining amide 21 could be directly used in the following hydrolysis reaction without extra purification procedure. Normal hydrolysis conditions, such as NaOH/EtOH-H2O, KOH/EtOH and KOH/2-propanol only gave poor to moderate conversion of the amide 21 (table 3, entry 1-4). But this reaction proceeded completely in ethylene glycol at 115 °C (entry 6), which indicated the reaction temperature was the key parameter. Increasing the reaction temperature not only achieved higher conversion, but also shortened the reaction time (entry 5 and 6). The quantity of NaOH could not be less than 3.0 equiv, otherwise it led to incomplete conversion even if the reaction time was extended to 18 hours (entry 7). After the completion of hydrolysis reaction, the mixture of free base of 4-methylenepiperidine 13 and by-product ethanol were distilled and collected from the reaction mixture under reduced pressure (20 kPa). Based on the GC analysis result, the collected mixture consisted of 71% 4-methylenepiperidine, 25% ethanol, 2% 9



Page 10 of 18

ethylene glycol as well as several unknown impurities. Table 3. Screening Results of Hydrolysis Reaction of 21 a

a

entry

base (equiv.)

solvent

temp (oC)

time (h)

conversion b,c (%)

1

NaOH (3.0)

70% EtOH-H2O

80

20

26.3

2

NaOH (6.0)

70% EtOH-H2O

80

20

81.6

3

KOH (3.0)

EtOH

80

20

83.5

4

KOH (3.0)

2-propanol

85

20

86.7

5

NaOH (3.0)

Ethylene glycol

95

15

94.8

6

NaOH (3.0)

Ethylene glycol

115

6

100

7

NaOH (2.5)

Ethylene glycol

115

18

96.3

Conditions: 21 (500mg scale), magnetic stirring. All reagents were charged followed by nitrogen

purge. b Conversion was determined from the HPLC area

Treatment of the above obtained crude 4-methylenepiperidine 13 with 20% HCl/EtOH only afforded a small amount of precipitated solid but two liquid phases were formed. Then water content of the different batches of material was determined to be 5-7 % by Karl Fischer method. It was thought that this water was derived from the reaction of ethylene glycol with NaOH. Therefore, water in the distillate needs to be removed before proceeding with the hydrochloride salt formation. Calcium oxide, as one of the most popular dehydrating reagents applied in alkaline environments, was carefully tested. But water content was only decreased to 2-3% from 5-7% even when increasing the amount of calcium oxide and raising 10


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dehydration temperature. Then azeotropic distillation was ready to be used to remove water. Due to the low boiling point of 4-Methylenepiperidine 13 (bp: 130−135 °C, measured value), its hydrochloride had to be formed prior to azeotropic distillation. The pH was adjusted to 6.0 ~ 6.2 using 20% HCl/EtOH monitored by a pH meter. In order to prevent the formation of related impurities 1A and 1B shown in Scheme 1, it must be ensured that no excess acid was charged. The water content was successfully reduced to 0.35% using ethanol as co-zeotropic solvent and no other impurity was formed. After the required water content was met (< 0.5%), isopropyl acetate was charged with stirring and crystals of 4-methylenepiperidine hydrochloride 1 gradually precipitated. The precipitated solid was filtered, rinsed by a solution of isopropyl acetate and ethanol (10/1, v/v) and dried in vacuum to give the final product 4-methylenepiperidine hydrochloride 1 in a total yield of 83.5% with a purity of 99.9%. In addition to the above discussed route, another route, starting from N-methylpiperidinone 22, was also investigated (Scheme 7). N-Methylpiperidinone 22 is a readily available starting material of Loratadine15 and has better atom economy than N-benzylpiperidinone 3. The first step Wittig reaction proceeded well using similar condition with preparation of compound 4. After acid-base switching work-up, N-methyl-4-methylenepiperidine 23 was obtained as a solution in toluene. However, in the subsequent N-demethylation step, 20-30% compound 23 remained even if 3 equiv of ethyl chloroformate were employed. 11



Scheme 7. Route of Amide 21 from N-Methylpiperidinone 22.

Owing to the incomplete N-demethylation of compound 23, then demethylation of N-Methylpiperidinone 22 was attempted (Scheme 8). Using 2.5 equiv of ethyl chloroformate realized complete N-demethylation, but unfortunately a ring opened impurity 25 with a level of 15-20% was detected. It is likely that this was formed via elimination of the resulting quaternary ammonium chloride. A previous research reported that the yield of a similar ring opened product reached 40-50% in the presence of Hünig’s base.17 Although the current results (Scheme 7 and 8) were unsatisfactory, the protocol was still regarded to be of great potential and will continue to be studied. Scheme 8. Alternative Route of amide 21 from N-Methylpiperidinone 22.

CONCLUSION In summary, we have developed a robust process to prepare 4-methylenepiperidine hydrochloride 1, starting from N-benzylpiperidinone 3 in four steps and an overall yield of 83.5%. This process was successfully transferred to the pilot plant and was utilized to manufacture more than 100 kg of 1 with >99.9 % purity (as determined by 12


Page 12 of 18

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HPLC). EXPERIMENTAL SECTION General Procedures. All reactions were performed under a nitrogen atmosphere using anhydrous techniques unless otherwise noted. All commercially available material and solvents were used directly without further purification. 1H NMR (400 MHz) and

13

C NMR (100 MHz) were recorded on a Bruker spectrometer with TMS

as internal standard. The mass spectra were determined on a THERMO LTQ (ESI) or Agilent 5973 MSD (EI) spectrometer. HPLC method of 4-methylenepiperidine hydrochloride 1: YMC Pack Pro C18 (3 µm，4.6 mm × 250 mm); flowing rate = 1.0 mL/min; 30 °C; gradient elution from 95:5 A/B to 20:80 A/B over 30 min, where A = H2O/acetonitrile/HClO4 = 95:5:0.2 and B = acetonitrile/H2O = 85:15; UV detection at 210 nm. N-Benzyl-4-methylenepiperidine (6) To a 10 L four-necked flask was charged toluene (3.2 L), sodium t-butoxide (448 g, 4.66 mol) and methyltriphenylphosphonium bromide (1736 g, 4.86 mol). After stirring for 2h, N-benzylpiperidinone 3 (802g, 4.24 mol) was added at 20-30 °C within 3h. The resulting mixture was stirred at the same temperature for 1h and monitored by HPLC. Upon completion, the mixture was quenched with water (2.4 L) and stirred for 0.5 h. The resulting phases were separated and aqueous phase was discarded. To the organic layer was added 0.8kg water, then the pH was adjusted to 3-4 using 6N hydrochloric acid leaving product 4 into the aqueous phase at 0-5 o C. The aqueous phase was extracted with 1.5L toluene again and the combined organic layer containing triphenylphosphine oxide was separated and discarded. The aqueous phase was basified until pH = 9 ~ 10 using 20% sodium hydroxide solution. Then 13



olefin 4 was extracted with 2 L toluene and this extract was used directly in the next step. For characterization, an aliquot of an equivalent solution obtained in the laboratory was evaporated and purified by flash chromatography on silica-gel (n-heptane / EtOAc = 12:1) to give intermediate 4 as colorless oil after evaporation of solvents. 1H NMR (400 MHz, d6-DMSO) δ 7.21-7.32 (m, 5H), 4.64 (s, 2H), 3.46 (s, 2H), 2.49 (t, J = 4.0 Hz, 4H), 2.29 (t, J = 4.0 Hz, 4H); 13C NMR (100 MHz, d6-DMSO) δ 146.13, 138.50, 128.65, 128.08, 126.80, 107.87, 61.84, 54.26, 34.08. ESI-MS (m/z): 188.26 [M + H] +. Ethyl 4-methylenepiperidine-1-carboxylate (21) To a 10 L four-necked flask was charged 4 as a solution in toluene from the previous step and sodium carbonate (44.5 g, 0.42 mol). Ethyl chloroformate (504 g, 4.64 mol) was dropped under stirring while maintaining the internal temp below 60 °C. The mixture was then stirred for another 6 h at 50~60 °C. Upon completion, 0.5 kg water was charged and resulting aqueous phase was discarded. The separated organic layer was concentrated to remove most of toluene under reduced pressure (25-30 kPa) at 55-60 °C. Then benzyl chloride was distilled and collected under reduced pressure (2.7 kPa) at 95-110 °C. The crude amide 21 remained in the vessel as yellow oil (Caution: Benzyl chloride should be handled under good protection as it is hazardous as well as irritating to eyes and skin). . For characterization, an aliquot of an equivalent solution obtained in the laboratory was evaporated and purified by flash chromatography on silica-gel (n-heptane / EtOAc 12:1) to give 21 as colorless oil after evaporation of solvents. 1H NMR (400 MHz, d6-DMSO) δ 4.76 (s, 2H), 4.03 (q, J = 8.0 Hz, 2H), 3.37 (t, J = 8.0 Hz, 4H), 2.12 (t, J = 8.0 Hz, 4H), 1.18 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, 14


Page 14 of 18

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d6-DMSO) δ 154.47, 144.83, 109.37, 60.69, 44.81, 33.85, 14.54. ESI-MS (m/z): 170.15 [M + H] +. 4-methylenepiperidine hydrochloride (1) To a 5 L three-necked flask was charged ethylene glycol (1.2 kg) and NaOH (504 g, 12.6 mol). The reaction mixture was then heated to 90-100 °C. Crude amide 21 from the previous step was added during 1 hour with stirring at 90-100 °C. Then the resulting mixture was stirred at 110-120 °C for 6-8 h until complete conversion monitored by HPLC. The mixture was cooled 30-40 °C and the distillation was started at this temperature range under reduced pressure (20 kPa). The distillation was stopped

until the

temperature

reached

95-100

°C.

The

collected

crude

4-methylenepiperidine 13(608 g) was used directly in the next step. To a 3 L three-necked flask was charged ethanol (500 g) and the above crude 4-methylenepiperidine 13. Then 20% HCl/EtOH (768 g) was added below 20 °C to make pH = 6.0-6.2. Then co-azeotropic distillation with ethanol was conducted until water content was below 0.5%. Then isopropyl acetate (1.5 kg) was added and the resulting slurry was held for 2 h at 0~5 °C. The precipitated solid was filtered and rinsed with a solution of isopropyl acetate and ethanol (10/1, v/v, 300 g). The wet cake was dried in vacuum at 35~40 °C for 10 hours to yield 472.8 g 4-methylenepiperidine hydrochloride 1 (83.5% total yield, 99.9% HPLC purity). 1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 2H), 4.83 (s, 2H), 3.02 (q, J = 8.0 Hz, 4H), 2.58 (t, J = 8.0 Hz, 4H); 13C NMR (100 MHz, DMSO-d6) δ 141.07, 111.03, 44.13, 30.22. EI-MS (m/z): 97.

15



Page 16 of 18

Associated Content Experimental details and spectroscopic data for the compounds described in this paper. This material is available free of charge via the Internet at http://pubs.acs.org. Corresponding Author *

Address:

Tel:

+86-0991-3835679.

Fax:

+86-0991-3835679.

E-mail:

+86-21-20231000-2407.

E-mail:

[email protected]. *

Address:

Tel:

+86-21-2023100-2407.

Fax:

[email protected] NOTES The authors declare no competing financial interest. ACKNOWLEDGMENTS The authors wish to thank Topharman Shandong Ltd. for their helpful scale-up support. REFERENCES (1) Patel, T.; Dhillon, S. Efinaconazole: First Global Approval. Drugs. 2013, 73, 1977–1983. (2) http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/203567s000lbl.pdf (3) Tatsumi, Y.; Nagashima, M.; Shibanushi, T.; Iwata, A.; Kangawa, Y.; Inui, F.; Jo Siu, W. J.; Pillai, R.; Nishiyama, Y. Antimicrob. Agents Chemother. 2013, 57, 2405-2409. (4) Mimura, M.; Hayashida, M.; Nomiyama, K.; Ikegami, S.; Iida, Y.; Tamura, M.; Hiyama, Y.; Qhishi, Y. Chem. Pharm. Bull. 1993, 41, 1971-1986. 16


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(5) Cooper, J.; Duan, M.; Grimes, R.; Kazmierski, W.; Tallant, Matthew. U.S. Patent. 20100196321, 2010. (6) Ogura, H.; Kobayashi, H.; Nagai, K.; Nishida, T.; Naito, T.; Tatsumi, Y.; Yokoo, M.; Arika, T. Chem. Pharm. Bull. 1999, 47, 1417-1425. (7) Naito, T. WO Patent. 9711939, 1997. (8) Mimura, M.; Watanabe, M.; Ishiyama, N.; Yamada, T. U.S. Patent. 20130150586, 2013. (9) Emanuele, A.; Elisabeth, R.; Davide, R. E.P. Patent. 3091007, 2016. (10) Cooley, J. H.; Evain, E. J. Synthesis. 1989. 1-7. And references cited therein. (11) Časar, Z.; Mesar, T. Org. Process Res. Dev. 2015, 19, 378−385 (12) Fan, X.; Zhang, H. S.; Chen, Li.; Long, Y. Q. Eur. J. Med. Chem. 2010, 45, 2827–2840. (13) Truong, P. M.; Hassan, S. A.; Lee, Y-S.; Kopajtic, T. A.; Katz, J. L.; Chadderdon, A. M.; Traynor, J. R.; Deschamps, J. R.; Jacobson, A. E.; Rice, K. C. Bioorganic & Medicinal Chemistry. 2017, 25, 2406–2422. (14) Montzka, T. A.; Matiskella, J. D.; Partyka, R. A. Tetrahedron Lett. 1974, 14, 1325-1327. (15) Villani, F. J.; Wong, J. K. U.S. Patent 4659716, 1987. (16) He, P.; Sun, H.; Jian, X-X.; Chen, Q. H.; Chen, D. L.; Liu, G. T.; Wang, F. P. J Asian Nat Prod Res, 2012 , 14, 6, 564 - 576. (17) Lévy, J.; Laronze, J. Y.; Sapi, J. Tetrahedron Lett. 1988, 29, 3303-3306.

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