Total Synthesis of Phenanthroquinolizidine Alkaloids Using a Building

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Total Synthesis of Phenanthroquinolizidine Alkaloids Using a Building Block Strategy Young-In Jo, and Cheol-Hong Cheon J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01768 • Publication Date (Web): 26 Aug 2019 Downloaded from pubs.acs.org on August 26, 2019

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The Journal of Organic Chemistry

Total Synthesis of Phenanthroquinolizidine Alkaloids Using a Building Block Strategy Young-In Jo and Cheol-Hong Cheon* Department of Chemistry, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea, Phone: +82-2-3290-3147; Fax: +82-2-3290-3121 * Corresponding author. E-mail: [email protected] OMe MeO

Me N

B

Br

1

B(OH)2

O

O

O O

+

X

p-

Y

m-

R

MeO

quinolizidine f ormation

N

A

OMe

MeO

MeO oxidative electrocyclization

R1

R1

N

MeO

concise

and

general

N

MeO R2

OH

R2

Abstract:

OMe iterative Suzuki-Miyaura coupling

strategy

R2

for

the

total

synthesis

of

the

phenanthroquinolizidine alkaloids has been developed. An iterative Suzuki–Miyaura coupling reaction between the requisite aryl boronic acid, 2-bromo-4,5-dimethoxyphenyl Nmethyliminodiacetate (MIDA) boronate derived from boronic acid, and a suitable bromopyridine substrate bearing a homopropargyl alcohol at the 2-position generated the desired ortho-aza-terphenyl compounds. Hydrogenation of the triple bond followed by treatment

with

methanesulfonyl

chloride

afforded

their

corresponding

tetrahydroquinolizinium ion intermediates, which were subsequently reacted with NaBH4 to provide the desired hexahydroquinolizine products. A final oxidative electrocyclization reaction gave the target phenanthroquinolizidine natural products. This synthetic approach only requires the use of three chromatographic separations throughout the entire synthesis.

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Introduction Phenanthroizidine alkaloids (phenanthroindolizidine and phenanthroquinolizidine alkaloids) possess pentacyclic structures in which a phenanthrene ring is fused to an indolizidine or quinolizidine ring, respectively (Figure 1).1 Since these natural products display interesting biological properties including anticancer and antiamoebic activities, they have been considered target molecules of impotance from both synthetic and medicinal chemists.2 Consequently, numerous synthetic strategies have been developed to further investigate their biological activities.3,4 However, although these two classes of natural products have structurally similar pentacyclic skeletons, only a few synthetic strategies that are applicable to the total syntheses of both types of the natural products have been reported.5 In addition, a considerable number of the synthetic approaches have been developed for the synthesis of the phenanthroindolizidine alkaloids,3 while far less have been developed for the preparation of the phenanthroquinolizidines,4 even though they are known to display more promising biological activities than the phenanthroindolizidines.6 Therefore, it is still highly desirable to develop an efficient strategy applicable to the total synthesis of both the phenanthroizidine alkaloids to fully investigate the structure-activity relationships (SAR) of these natural products.


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a) The genaral structures of the phenanthroindolizidine and phenanthroquinolizidine alkaloids 2

2 n(OR)

3 4

A

1 14

B m(OR)

5

D

n(OR)

13a 13

N

E

8

6

4

A

1 15

B

12

9 10 11

C

3

m(OR)

5

D

14

14a

N

E

13 12

9 10 11

C 8

6 7

7

Phenanthroindolizidine

Phenanthroquinolizidine

b) Examples of the phenanthroquinolizidine alkaloids OMe

OMe

MeO

MeO

N

N MeO

MeO

OMe Cryptopleurine (1)

7-Methoxycryptopleurine (2)

OMe

OMe

MeO

MeO N N

MeO MeO

MeO

5-Methoxycryptopleurine (3)

Boehmeriasin A (4)

Figure 1. (a) The general structures of the phenanthroizidine alkaloids, and (b) some examples of the phenanthroquinolizidine alkaloids.

Phenanthroizidine

alkaloids

possess

distinguishable

structural

features;

phenanthroindolizidines possess an indolizidine ring, while the phenanthroquinolizidines contain a quinolizidine scaffold. Furthermore, a different number of methoxy groups are found at different positions around the phenanthrene moiety in the members of these families of natural products, which makes the development of a general synthetic strategy applicable to their total synthesis very challenging. Despite the apparent structural diversity of these natural products, we noticed the structural similarity present in these two families of natural products. As demonstrated in Figure 1b, many of these natural products possess a 1,2methoxy group in the A-ring of the phenanthrene ring, although they possess the nitrogen atom at the different position in the quinolizidine moiety.



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Considering the structural similarity of these natural products, our group very recently developed a general building block strategy to access the phenanthroindolizidine alkaloids.7,8 An iterative Suzuki–Miyaura reaction9 of the requisite aryl boronic acid bearing a methoxy group(s) at a suitable position with the MIDA boronate10-12 of 2-bromo-4,5-dimethoxyphenyl boronic acid afforded the corresponding biphenyl MIDA boronates, which were subjected to a second Suzuki–Miyaura reaction with a suitable bromopyridine derivative bearing a propargyl alcohol at the 2-position to provide the desired ortho-aza-terphenyl products. Subsequent saturation of the triple bond into a single bond followed by reaction with methanesulfonyl (mesyl, Ms) chloride allowed the formation of the 5-membered E-ring. Treatment of the resulting

dihydroindolizinium

salts

with

NaBH4

provided

the

corresponding

hexahydroindolizine compounds. The final vanadium-catalyzed oxidative electrocyclization reaction would provide the desired phenanthroindolizidine natural products. Considering the structural similarity between the phenanthroizidine natural products, we expected that the phenanthroquinolizidine alkaloids could be synthesized via a similar building block strategy. Herein, we disclose the development of a general strategy for the total synthesis of the phenanthroquinolizidine alkaloids using a building block approach. It should be noted that all the phenanthroquinolizidine alkaloids could be prepared using this synthetic approach and only required the use of three chromatographic separations throughout the entire synthesis. Furthermore, this building block strategy offers a highly generalized synthetic protocol to access a range of phenanthroizidine alkaloids.

Results and Discussion Although we have successfully demonstrated the advantages of the building block strategy in our previous total synthesis of the phenanthroindolizidine alkaloids,7 we used pyridyl building blocks bearing a propargyl alcohol at the 2-position. After construction of the


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ortho-aza-terphenyl building blocks, the triple bond was reduced to a single bond, which may decrease the efficiency of the overall building block strategy. Thus, we envisaged that the overall efficiency of the building block strategy used for the total synthesis of the phenanthroquinolizidines could be further improved using pyridyl building blocks whose side chain was saturated instead of their triple bond analogues. With this in mind, our retrosynthetic analysis of the phenanthroquinolizidine alkaloids is depicted in Scheme 1. We envisaged that the phenanthroquinolizidines could be obtained from hexahydroquinolizine 5 via the formation of ring B using an oxidative electrocyclization reaction.13 Hexahydroquinolizine 5 would be accessible from ortho-aza-terphenyl 6 via the 6membered

E-ring

formation

followed

by

partial

reduction

of

the

resulting

tetrahydroquinolizinium salt.14 The ortho-aza-terphenyl compound 6 was expected to be synthesized via an iterative Suzuki–Miyaura coupling reaction of three simple building blocks: Aryl boronic acid 7,15 2-bromo-4,5-dimethoxyphenyl MIDA boronate 8,16,17 and a pyridyl bromide 9 bearing a 4-hydroxybutyl moiety at the 2-position. OMe

OMe

MeO A B

R1

oxidative electrocyclization

14a

D

N

E

MeO

R1

10

C MeO

R2 Cryptopleurine (1) : R1 = R2 = H 7-Methoxycryptopleurine (2) : R1 = H, R2 = OMe 5-Methoxycryptopleurine (3) : R1 = OMe, R2 = H Boehmeriasin A (4)a : R1 = R2 = H

N

MeO

5

R2

E-ring formtion; partial reduction of D-ring

OMe MeO

8

R

1

B(OH)2

MeO R2

7

Br

+

iterative Suzuki-Miyaura coupling

Me N B O O

OMe MeO

O O

X

p-

Y

m-

R1

N OH

MeO

N OH

9a X = Br, Y = H 9b X = H, Y = Br


R

2

6


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Scheme 1. Retrosynthetic Analysis of Phenanthroquinolizidine Alkaloids. a Boehmeriasin A (4) contains an isomeric quinolizidine structure, where a nitrogen atom is located at the 14aposition and a carbon atom at the 10-position, and can be synthesized from meta-pyridyl bromide 9b instead of its para-analogue 9a.

With this retrosynthetic analysis in mind, we first focused our attention toward the preparation of the requisite pyridyl bromide substrates 9 (Scheme 2). A regioselective Sonogashira coupling reaction of dibromopyridines 10a and 10b with 3-butyn-1-ol provided coupling products 11a and 11b in 79 and 91% yield, respectively.18 Reduction of the triple bond in 11a via hydrogenation over PtO2 afforded the corresponding saturated pyridine derivative 9a in 41% yield; concomitant debromination reaction occurred under these reaction conditions leading to the debrominated product 13 in 14% yield along with its partially reduced analogue 12 in 18% yield.

Y

3-butyn-1-ol Pd(PPh3)2Cl2, CuI

Br

X

X

TEA, 0 oC to rt

N

Y

10a X = Br, Y = H 10b X = H, Y = Br

Br

OH N

11a X = Br, Y = H (79%) 11b X = H, Y = Br (91%)

H2, PtO2 MeOH, rt

Br

Br +

N OH

11a

OH N

9a (41%)

+

N OH 12 (18%)

N OH 13 (14%)

Scheme 2. Synthesis of Pyridine Building Blocks

Without further optimization of the reaction conditions to improve the yield of 9a, we investigated the total synthesis of crytopleurine (1) using pyridyl bromide 9a as a building block (Scheme 3). The Suzuki–Miyaura coupling reaction between boronic acid 7a and


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MIDA boronate 8 under anhydrous conditions provided the corresponding biphenyl MIDA boronate 14a. Addition of pyridyl bromide 9a and water to the above reaction mixture promoted a second Suzuki–Miyaura coupling reaction with the resulting biphenyl MIDA boronate 14a under slow release conditions to afford ortho-aza-terphenyl compound 6a in 67% yield over two steps. Treatment of compound 6a with mesyl chloride afforded tetrahydroquinolizinium salt 15a via an intramolecular SN2 reaction of the activated alcohol and the nitrogen atom in the pyridine ring. Without isolation, compound 15a was treated with sodium borohydride to afford hexahydroquinolizine 5a in 85% yield over two steps. Finally, cryptopleurine (1) was synthesized using a vanadium-catalyzed oxidative electrocyclization reaction of 5a in 82% yield. OMe MeO

B(OH)2

Me N B O O

Br 8

OMe MeO

Me N B O O

O O

Pd(OAc)2, XPhos, K3PO4 dioxane, 75 oC

MeO

O MeO

7a

14a

Br

OMe

OMe MeO

MeO

N OH

9a

O

MsCl, TEA

N

o

H2O, 75 C

OH

MeO

Cl

CH2Cl2 0 oC to rt

N MeO

6a 67% over two steps

15a not isolated

OMe

OMe

MeO

MeO

NaBH4

VOF3, TFAA, TFA N

MeOH, rt MeO

CH2Cl2/EtOAc -78 oC to -10 oC


N MeO Cryptopleurine (1) 82%

Scheme 3. Our First Approach toward the Total Synthesis of Cryptopleurine (1)



Although this total synthesis of cryptopleurine (1) was completed using a much simpler synthetic approach compared to our previous synthesis of the phenanthroindolizidine alkaloids using a similar strategy,7 the preparation of pyridyl bromide 9a, one of the key building blocks, was problematic. Despite numerous efforts to increase the yield of 9a, the concomitant formation of 13 could not be avoided; the debromination reaction was found to occur at the same rate as the reduction of the triple bond. Thus, we decided to modify our synthetic strategy towards these natural products. Similar to our previous phenanthroindolizidine synthesis,7 we used pyridyl bromide 11a bearing a homopropargyl alcohol as the building block instead of pyridyl bromide 9a, and re-investigated the total synthesis of cryptopleurine (1) using our building block strategy (Scheme 4). The Suzuki–Miyaura reaction of 7a and 8 under anhydrous conditions followed by the second Suzuki–Miyaura coupling reaction with pyridyl bromide 11a under aqueous basic conditions afforded ortho-aza-terphenyl compound 16a. Without isolating compound 16a, the crude mixture was directly used in the hydrogenation reaction and gave compound 6a in 62% yield over three steps. From intermediate 6a, cryptopleurine (1) was synthesized using the same synthetic route shown in Scheme 3 in a similar yield. Although the first synthetic approach (shown in Scheme 3) may be regarded as a better building block strategy, the second approach shown in Scheme 4 provides cryptopleurine (1) in a significantly improved yield. Therefore, we decided to use this approach to the synthesis of the other phenanthroquinolizidine alkaloids.


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OMe MeO

B(OH)2

Br

Me N B O O

8

OMe MeO

Me N B O O

O O


MeO

O O

MeO

7a

14a OMe MeO

Br

OH N

OH

11a

N

o

H2O, 75 C MeO

H2, Pd/C CH2Cl2/MeOH rt

16a not isolated

OMe

OMe

MeO

MeO Cl

MsCl, TEA N OH

MeO

NaBH4

N

CH2Cl2 0 oC to rt

MeOH, rt

MeO

6a 62% over three steps

15a not isolated

OMe

OMe

MeO

MeO VOF3, TFAA, TFA N


MeO

N MeO


Cryptopleurine (1) 82%

Scheme 4. Our Second Synthetic Approach towards the Total Synthesis of Cryptopleurine (1).

Subsequently, we attempted to apply this strategy to the syntheses of 7methoxycryptopleurine (2) and 5-methoxycryptopleurine (3) (Scheme 5). The first coupling reaction of boronic acids 7b and 7c with MIDA boronate 8 under anhydrous conditions provided biphenyl MIDA boronates 14b and 14c, respectively. Pyridyl bromide 11a and water were added to the above reaction mixtures containing 14b and 14c to promote the second Suzuki–Miyaura reaction affording the desired ortho-aza-terphenyl compounds 16b



and 16c. Without isolation, the triple bonds in ortho-aza-terphenyl 16b and 16c were reduced into a single bond by the hydrogenation to provide their saturated analogues 6b and 6c in 55 and 15%19 yield over three steps, respectively. Treatment of 6b and 6c with mesyl chloride afforded tetrahydroquinolizinium salts 15b and 15c, which were reduced with NaBH4 to give 5b and 5c in 31 and 56% yields together with their unexpected regioisomers 17b (51%) and 17c (27%), respectively.20 The final oxidative electrocyclization reaction of 5b and 5c gave 7methoxycryptopleurine (2) and 5-methoxycryptopleurine (3) in 78 and 53% yield, respectively. Furthermore, regioisomers 17b and 17c were also subjected to the vanadiumcatalyzed oxidative cyclization reaction and gave 7-methoxyisocryptopleurine (18) and 5methoxyisocryptopleurine (19) in 84 and 69% yield, respectively.


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OMe MeO

R1

B(OH)2

MeO R2

Br 8

OMe

Me N B O O

MeO

O Pd(OAc)2, XPhos, K3PO4 dioxane, 75 oC

R1

O

11a

H2O, 75 oC

O R2 14b R1 = H, R2 = OMe 14c R1 = OMe, R2 = H

OMe

OMe

MeO

MeO H2, Pd/C

OH 1

N

MsCl, TEA R1

CH2Cl2/MeOH rt

MeO

N OH

MeO

OMe

OMe

MeO

OMe

MeO Cl N

MeO R2 15b R1 = H, R2 = OMe 15c R1 = OMe, R2 = H not isolated

CH2Cl2 0 oC to rt

R2 6b R1 = H, R2 = OMe, 55% 6c R1 = OMe, R2 = H, 15%

R2 16b R1 = H, R2 = OMe 16c R1 = OMe, R2 = H not isolated

R1

OH N

MeO

7b R1 = H, R2 = OMe 7c R1 = OMe, R2 = H

R

Br

Me N B O O

O

MeO

NaBH4 R1

MeOH, rt

N

+

R1

N

MeO

MeO



VOF3, TFAA, TFA CH2Cl2/EtOAc -78 oC, to -10 oC

same as shown left

OMe

OMe

MeO

R1

MeO

N

MeO R2 7-Methoxycryptopleurine (2) R1 = H, R2 = OMe, 78% 5-Methoxycryptopleurine (3) R1 = OMe, R2 = H, 53%

R1

N

MeO R2 7-Methoxyisocryptopleurine (18) R1 = H, R2 = OMe, 84% 5-Methoxyisocryptopleurine (19) R1 = OMe, R2 = H, 69%

Scheme 5. The Total Syntheses of 7-Methoxycryptopleurine (2), 5-Methoxycryptopleurine (3), 7-Methoxyisocryptopleurine (18) and 5-Methoxyisocryptopleurine (19).



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With the successful application of this strategy to the total synthesis of the phenanthroquinolizidine alkaloids, we attempted to prepare boehmeriasin A (4), which has an isomeric quinolizidine structure (Scheme 6). A Suzuki-Miyaura reaction of boronic acid 7a with MIDA boronate 8 under anhydrous conditions and a second Suzuki-Miyaura reaction with pyridyl bromide 11b afforded the desired ortho-aza-terphenyl compound 16d, in which the triple bond was saturated by the hydrogenation in the presence of a palladium catalyst to give ortho-aza-terphenyl 6d in 67% yield over three steps. Treatment of the alcohol in 6d with mesyl chloride afforded tetrahydroquinolizinium salt 15d via a spontaneous intramolecular SN2 reaction. Without isolation, 15d was treated with NaBH4 to give hexahydroquinololizine 5d in 82% yield. Boehmeriasin A (4) was obtained in 73% yield via the vanadium-catalyzed oxidative electrocyclization reaction of 5d.

OMe MeO

B(OH)2

Br 8

Me N B O O

Br

OH O

7a

9b

H2, Pd/C

H2O, 75 oC

CH2Cl2/MeOH rt

O


MeO

N

OMe MeO

OH N

MsCl, TEA

NaBH4

CH2Cl2, 0 oC to rt

MeOH, rt

MeO 6d 67% over three steps OMe

OMe

MeO

MeO VOF3, TFAA, TFA

N


MeO

N

MeO

5d 82% over two steps


Boehmeriasin A (4) 73%

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Scheme 6. The Total Synthesis of Boehmeriasin A (4).

Conclusions A building block strategy for the synthesis of the phenanthroquinolizidine alkaloids has been developed. An iterative Suzuki–Miyaura reaction of the requisite aryl boronic acids with an MIDA boronate obtained from 2-bromo-4,5-dimethoxyphenylboronic acid under anhydrous conditions afforded the corresponding biphenyl MIDA boronate compounds, which were directly subjected to a second Suzuki–Miyaura reaction with a pyridyl bromide substrate bearing a homopropargyl alcohol at the 2-position under aqueous basic conditions to afford the desired ortho-aza-terphenyl compounds. Hydrogenation of the triple bond followed by

treatment

with

methanesulfonyl

chloride

provided

their

corresponding

tetrahydroquinolizinium salts, which were reduced to afford the desired hexahydroquinolizine products. Formation of the remaining 6-membered B-ring via an oxidative electrocyclization provided the target phenanthroquinolizidine alkaloids. It should be noted that all the phenanthroquinolizidine alkaloids could be prepared using this synthetic approach and only required the use of three chromatographic separations throughout the entire synthesis. Furthermore, this building block strategy offers a highly generalized synthetic protocol to access a range of phenanthroizidine alkaloids. The development of an asymmetric approach to these natural products and further application of this building block strategy to the total synthesis of other biologically important natural products are currently underway in our laboratory and will be reported in due course.

Experimental Section



General Information. All reactions were carried out in oven- or flame-dried glassware unless stated otherwise. All reactions were magnetically stirred and monitored using analytical thin layer chromatography (TLC) using pre-coated silica gel glass plates (0.25 mm) and an F254 indicator unless stated otherwise. Visualization was accomplished using UV light (254 nm). Flash column chromatography was carried out on silica gel 60 (230–400 mesh). All yields refer to chromatographically and spectroscopically pure compounds, unless stated otherwise. All commercially available reagents and solvents were used without further purification. Boronic acids 7 and dibromopyridines 10 were purchased from commercial suppliers and used without further purification. 2-Bromo-4,5-dimethoxyphenyl boronic acid MIDA boronate 8 was prepared according to a literature procedure.16 1H NMR and 13C NMR spectra were recorded at 500 MHz and 125 MHz spectrometers, respectively. Tetramethylsilane (δ: 0.0 ppm) and CDCl3 (δH: 7.26 ppm, δC: 77.16 ppm) were used as internal standards for 1H and

13C

NMR spectra, respectively. The 1H NMR spectra were

reported as follows: δ (position of proton, multiplicity, coupling constant J, number of protons). The multiplicities are indicated by s (singlet), d (doublet), t (triplet), q (quartet), p (quintet), h (septet), m (multiplet), and br (broad). High resolution mass spectra (HRMS) were recorded on a quadrupole time-of-flight mass spectrometer (QTOF-MS) in electrospray ionization (ESI) mode as an ionization method.

Synthesis of pyridyl bromide derivatives 11 A solution of dibromopyidine 10 (10 mmol), 3-butyn-1-ol (0.76 mL, 10 mmol), Pd(PPh3)2Cl2 (0.21 g, 0.30 mmol), and copper(I) iodide (57 mg, 0.30 mmol) in 20 mL of triethylamine was stirred at 0 C under a nitrogen atmosphere. The reaction mixture was warmed to room temperature and stirred for 2 h. Water was added to the reaction mixture to quench the reaction and the resulting mixture was extracted with dichloromethane. The organic layers


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were combined, dried over MgSO4, and concentrated in vacuo. The crude mixture was purified by flash column chromatography on silica gel to provide the desired product 11.

4-(4-Bromopyridin-2-yl)but-3-yn-1-ol (11a) Compound 11a was obtained as a brown solid (1.8 g, 79%) after purification by column chromatography on silica using a mixture of ethyl acetate and hexanes (1:3) as the eluent. 1H NMR (500 MHz, CDCl3, ppm): δ 8.34 (d, J = 5.2 Hz, 1H), 7.56 (d, J = 1.5 Hz, 1H), 7.38 (dd, J = 5.5, 1.8 Hz, 1H), 3.86 (q, J = 6.3 Hz, 2H), 2.81 (t, J = 6.4 Hz, 1H), 2.72 (t, J = 6.3 Hz, 2H). 13C

NMR (125 MHz, CDCl3, ppm): δ 150.4, 144.5, 132.9, 130.2, 126.2, 89.5, 80.8, 60.8, 23.9.

HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C9H8BrNONa 247.9687; Found 247.9689.

4-(5-Bromopyridin-2-yl)but-3-yn-1-ol (11b) Compound 11b was obtained as a brown solid (2.1 g, 91%) after purification by column chromatography on silica using a mixture of ethyl acetate and hexanes (1:3) as the eluent. 1H NMR (500 MHz, CDCl3, ppm): δ 8.59 (s, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 3.85 (q, J = 6.1 Hz, 2H), 2.66 - 2.76 (m, 2H).

13C

NMR (125 MHz, CDCl3, ppm): δ

151.1, 141.8, 139.0, 128.0, 120.0, 89.1, 81.1, 60.8, 24.0. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C9H8BrNONa 247.9687; Found 247.9688.

Synthesis of 4-(4-Bromopyridin-2-yl)butan-1-ol (9a) To a solution of 11a (0.23 g, 1.0 mmol) in methanol (10 mL) was added Pt2O (23 mg). The mixture was then stirred at room temperature under a hydrogen atmosphere and monitored by TLC. After 30 min, the reaction mixture was filtered through celite to remove the undissolved solid. The filtrate was concentrated and purified by flash column chromatography on silica gel to afford desired compound 9a, along with compounds 12 and 13.



4-(4-Bromopyridin-2-yl)butan-1-ol (9a) Compound 9a was obtained as yellow oil (94 mg, 41%) after purification by column chromatography on silica using ethyl acetate as the eluent. 1H NMR (500 MHz, CDCl3, ppm): δ 8.32 (d, J = 5.5 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H), 7.29 (dd, J = 5.5, 1.8 Hz, 1H), 3.67 (t, J = 6.4 Hz, 2H), 2.81 (t, J = 7.6 Hz, 2H), 1.82 (p, J = 7.6 Hz, 2H) 1.59 - 1.67 (m, 2H). 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 163.7, 150.0, 133.3, 126.4, 124.6, 62.5, 37.5, 32.2, 25.8. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C9H12BrNONa 252.0000; Found 252.0003.

(Z)-4-(4-Bromopyridin-2-yl)but-3-en-1-ol (12) Compound 12 was obtained as yellow oil (41 mg, 18%) after purification by column chromatography on silica using ethyl acetate as the eluent. 1H NMR (500 MHz, CDCl3, ppm): δ 8.32 (d, J = 5.5 Hz, 1H) 7.40 (d, J = 1.7 Hz, 1H), 7.36 (dd, J = 5.5, 1.7 Hz, 1H), 6.59 (d, J = 11.6 Hz, 1H), 6.11 (dt, J = 11.6, 8.7 Hz, 1H), 5.44 (br, 1H), 3.86 (t, J = 5.7 Hz, 2H), 2.72 (dt, J = 8.7, 5.4 Hz, 2H). 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 156.4, 148.9, 136.2, 133.8, 129.5, 127.4, 125.5, 61.9, 31.4. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C9H10BrNONa 249.9843; Found 249.9844.

4-(Pyridin-2-yl)butan-1-ol (13) Compound 13 was obtained as yellow oil (21 mg, 14%) after purification by column chromatography on silica using ethyl acetate as the eluent. Spectroscopic data matched with those reported in the literature.21 1H NMR (500 MHz, CDCl3, ppm): δ 8.49 (d, J = 4.6 Hz, 1H), 7.58 (td, J = 7.6, 1.5 Hz, 1H), 7.15 (d, J = 7.9 Hz, 1H), 7.10 (dd, J = 6.9, 5.3 Hz, 1H), 3.67 (t, J = 6.4 Hz, 2H), 2.83 (t, J = 7.6 Hz, 2H), 1.83 (p, J = 7.6 Hz, 2H), 1.60 - 1.67 (m, 2H).


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Synthesis of 4-(4-(3',4,5-trimethoxy-[1,1'-biphenyl]-2-yl)pyridin-2-yl)butan-1-ol (6a) In a one-neck round bottom flask were placed 7a (0.46 g, 2.4 mmol), 8 (0.74 g, 2.0 mmol), Pd(OAc)2 (45 mg, 0.20 mol), SPhos (0.16 g, 0.40 mmol), and K3PO4 (1.3 g, 6.0 mmol) under an argon atmosphere. To the flask was added 10 mL of 1,4-dioxane and the reaction mixture was heated to 75 C in an oil bath and monitored by TLC. After 3 h, 9a (0.55 g, 2.4 mmol) and water (4.0 mL) were directly added to the reaction mixture and the reaction mixture was further stirred at 75 C in an oil bath for an additional 3 h. The reaction mixture was cooled to room temperature, quenched with water (20 mL), and extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The mixture was purified by flash column chromatography on silica gel (ethyl acetate:methanol = 20:1) to afford compound 6a as a white solid (0.53 g, 67%). 1H NMR (500 MHz, CDCl3, ppm): δ 8.33 (d, J = 4.9 Hz, 1H), 7.14 (t, J = 7.9 Hz, 1H), 6.92 - 6.97 (m, 2H), 6.89 (s, 1H), 6.86 (s, 1H), 6.73 - 6.78 (m, 1H), 6.71 (d, J = 7.3 Hz, 1H), 6.61 (s, 1H), 3.94 (s, 3H), 3.93 (s, 3H), 3.62 (s, 3H), 3.59 (t, J = 6.4 Hz, 2H), 3.00 (br, 1H), 2.67 (t, J = 7.3 Hz, 2H), 1.63 (p, J = 7.5 Hz, 2H), 1.43 - 1.50 (m, 2H).

13C{1H}

NMR (125 MHz, CDCl3, ppm): δ

161.5, 159.2, 149.9, 149.1, 148.7, 148.6, 142.2, 133.4, 130.2, 129.3, 124.3, 122.4, 122.1, 115.6, 113.7, 113.0, 112.5, 62.3, 56.2, 56.2, 55.2, 37.4, 32.0, 25.9. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C24H27NO4Na 416.1838; Found 416.1840.

Synthesis of ortho-aza-terphenyl compound 6 In a one-neck round bottom flask were placed boronic acid 7 (2.4 mmol), MIDA boronate 8 (0.74 g, 2.0 mmol), Pd(OAc)2 (45 mg, 0.20 mol), SPhos (0.16 g, 0.40 mmol), and K3PO4 (1.3 g, 6.0 mmol) under an argon atmosphere. To the mixture was added 10 mL of 1,4-dioxane and the resulting reaction mixture was heated to 75 C in an oil bath and monitored by TLC. After 3 h, pyridyl bromide 11 (0.54 g, 2.4 mmol) and water (4.0 mL) were added to the



reaction mixture and the resulting mixture was further stirred at 75 C in an oil bath for an additional 3 h. After 3 h, the reaction mixture was cooled to room temperature, quenched with water (20 mL), and extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to provide the crude product, ortho-aza-terphenyl 16. The crude product was re-dissolved in a mixture of methanol and dichloromethane (2:1, 20 mL), and Pd/C (80 mg) was added to the resulting solution. The resulting mixture was stirred at room temperature under a hydrogen atmosphere and monitored by TLC. After completion of reaction, the mixture was filtered through celite to remove the insoluble solid. The filtrate was concentrated in vacuo and purified by flash column chromatography on silica gel to afford compound 6.

4-(4-(3',4,5-trimethoxy-[1,1'-biphenyl]-2-yl)pyridin-2-yl)butan-1-ol (6a) Compound 6a was obtained as a white solid (0.49 g, 62%) after purification by column chromatography on silica using a mixture of ethyl acetate and methanol (20:1) as the eluent. The spectroscopic data obtained for 6a were in good agreement with those obtained from the reaction performed using 9a.

4-(4-(3',4,4',5-Tetramethoxy-[1,1'-biphenyl]-2-yl)pyridin-2-yl)butan-1-ol (6b) Compound 6b was obtained as a white solid (0.47 g, 55%) after purification by column chromatography on silica using a mixture of ethyl acetate and methanol (20:1) as the eluent. 1H

NMR (500 MHz, CDCl3, ppm): δ 8.35 (d, J = 4.9 Hz, 1H), 6.95 (dd, J = 1.2, 4.9 Hz, 1H),

6.93 (s, 1H), 6.88 (s, 1H), 6.84 (s, 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.74 (dd, J = 1.8, 8.2 Hz, 1H), 6.53 - 6.46 (m, 1H), 3.93 (s, 3H), 3.93 (s, 3H), 3.84 (s, 3H), 3.63 - 3.53 (m, 5H), 2.67 (t, J = 7.3 Hz, 2H), 1.62 (td, J = 7.4, 14.9 Hz, 2H), 1.49 - 1.40 (m, 2H). 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 161.5, 150.2, 149.1, 148.7, 148.4, 148.4, 148.0, 133.4, 133.3, 130.2, 124.3,


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122.2, 122.0, 113.6, 113.0, 111.1, 62.3, 56.3, 56.2, 56.0, 55.7, 37.5, 32.0, 26.0. HRMS (ESITOF) m/z: [M + Na]+ Calcd for C25H29NO5Na 446.1943; Found 446.1946.

4-(4-(2',3',4,5-tetramethoxy-[1,1'-biphenyl]-2-yl)pyridin-2-yl)butan-1-ol (6c) Compound 6c was obtained as a white solid (0.13 g, 15%) after purification by column chromatography on silica using a mixture of ethyl acetate and methanol (20:1) as the eluent. 1H

NMR (500 MHz, CDCl3, ppm): δ 8.32 (d, J = 4.9 Hz, 1H), 6.97 - 6.90 (m, 5H), 6.84 (d, J

= 7.9 Hz, 1H), 6.64 (d, J = 7.6 Hz, 1H), 3.96 (s, 3H), 3.91 (s, 3H), 3.82 (s, 3H), 3.60 (t, J = 6.4 Hz, 2H), 3.49 (s, 3H), 2.69 (t, J = 7.3 Hz, 2H), 1.65 (p, J = 7.3 Hz, 2H), 1.47 (p, J = 6.9 Hz, 2H). 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 161.3, 152.9, 149.9, 148.7, 148.7, 148.6, 146.7, 135.0, 131.2, 129.6, 124.0, 123.6, 123.6, 121.7, 114.3, 112.5, 111.8, 62.6, 60.4, 56.2, 56.2, 56.0, 37.5, 32.0, 25.9. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C25H29NO5Na 446.1943; Found 446.1947.

4-(5-(3',4,5-trimethoxy-[1,1'-biphenyl]-2-yl)pyridin-2-yl)butan-1-ol (6d) Compound 6d was obtained as a white solid (0.53 g, 67%) after purification by column chromatography on silica using a mixture of ethyl acetate and methanol (20:1) as the eluent. 1H

NMR (500 MHz, CDCl3, ppm): δ 8.33 (d, J = 1.8 Hz, 1H), 7.28 (dd, J = 2.4, 7.9 Hz, 1H),

7.12 (t, J = 7.9 Hz, 1H), 6.96 (d, J = 7.9 Hz, 1H), 6.94 (s, 1H), 6.89 (s, 1H), 6.73 (dd, J = 2.0, 8.1 Hz, 1H), 6.69 (d, J = 7.3 Hz, 1H), 6.65 - 6.61 (m, 1H), 3.92 (s, 3H), 3.93 (s, 3H), 3.66 3.60 (m, 5H), 3.03 (br, 1H), 2.77 (t, J = 7.5 Hz, 2H), 1.78 (p, J = 7.5 Hz, 2H), 1.63 - 1.55 (m, 2H).

13C{1H}

NMR (125 MHz, CDCl3, ppm): δ 159.7, 159.3, 149.5, 148.7, 148.6, 142.3,

137.7, 134.5, 133.4, 129.2, 129.1, 122.6, 122.0, 115.7, 113.7, 113.4, 112.4, 62.2, 56.2, 56.1, 55.2, 37.1, 32.1, 25.9. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C24H27NO4Na 416.1838; Found 416.1841.



Synthesis of hexahydroquinolizine compound 5 To a solution of 6 (1.0 mmol) in dichloromethane (10 mL) were added MsCl (0.15 mL, 2.0 mmol) and TEA (0.41 mL, 3.0 mmol) at room temperature, and the resulting mixture was stirred for 2 h. The reaction mixture was concentrated in vacuo to give the crude product. Recrystallization of the crude product from a mixture of dichloromethane and ethyl acetate gave tetrahydroquinolizinium salt 15, which was used in the next step. To a solution of 15 in methanol was added NaBH4 (0.15 g, 4.0 mmol) and the resulting reaction mixture was stirred at room temperature and monitored by TLC. After 30 min, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel to provide compound 5.

8-(3',4,5-trimethoxy-[1,1'-biphenyl]-2-yl)-1,3,4,6,9,9a-hexahydro-2H-quinolizine (5a) Compound 5a was obtained as a yellow solid (0.32 g, 85%) after purification by column chromatography on silica using a mixture of dichloromethane and methanol (10:1) as the eluent. 1H NMR (500 MHz, CDCl3, ppm): δ 7.27 (t, J = 7.9 Hz, 1H), 7.01 - 6.94 (m, 2H), 6.87 - 6.79 (m, 3H), 5.66 (br, 1H), 3.89 (s, 6H), 3.83 (s, 3H), 3.40 (d, J = 14.6 Hz, 1H), 3.00 (d, J = 10.1 Hz, 1H), 2.85 (br, 1H), 2.10 - 1.90 (m, 3H), 1.83 - 1.59 (m, 5H), 1.51 (s, 1H), 1.18 (s, 1H).

13C{1H}

NMR (125 MHz, CDCl3, ppm): δ 159.4, 148.1, 148.0, 143.2, 137.6,

133.8, 132.0, 129.2, 121.6, 114.5, 113.3, 113.0, 112.4, 57.7, 56.2, 56.1, 55.7, 55.4, 55.1, 33.0, 29.8, 25.7, 24.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C24H30NO3 380.2225; Found 380.2224.


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Compound 5b was obtained as a yellow solid (0.13 g, 31%) along with its regioisomer 17b (0.23 g, 56%) after purification by column chromatography on silica using a mixture of dichloromethane and methanol (10:1) as the eluent.

8-(3',4,4',5-tetramethoxy-[1,1'-biphenyl]-2-yl)-1,3,4,6,9,9a-hexahydro-2H-quinolizine (5b) Compound 5b was obtained as a yellow solid (0.13 g, 31%). 1H NMR (500 MHz, CDCl3, ppm): δ 7.00 - 6.97 (m, 1H), 6.95 (dd, J = 1.8, 8.2 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.82 (s, 1H), 6.80 (s, 1H), 5.69 (d, J = 4.3 Hz, 1H), 3.92 (s, 3H), 3.89 (d, J = 3.1 Hz, 9H), 3.40 (dd, J = 4.1, 16.6 Hz, 1H), 2.99 (d, J = 11.0 Hz, 1H), 2.81 (d, J = 16.8 Hz, 1H), 2.06 - 1.87 (m, 3H), 1.81 - 1.56 (m, 5H), 1.49 (d, J = 12.5 Hz, 1H), 1.16 - 1.11 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 148.4, 148.0, 147.9, 147.9, 138.0, 134.6, 133.8, 131.8, 121.1, 113.3, 113.2, 112.4, 111.1, 57.9, 56.2, 56.1, 56.0, 56.0, 55.3, 37.2, 33.1, 25.8, 24.1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C25H31NO4Na 432.2151; Found 432.2150.

8-(3',4,4',5-tetramethoxy-[1,1'-biphenyl]-2-yl)-1,3,4,6,7,9a-hexahydro-2H-quinolizine (17b) Compound 17b was obtained as a yellow solid (0.23 g, 56%). 1H NMR (500 MHz, CDCl3, ppm): δ 6.98 (d, J = 1.8 Hz, 1H), 6.94 (dd, J = 1.8, 8.2 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.82 (s, 1H), 6.79 (s, 1H), 5.41 (s, 1H), 3.91 (s, 3H), 3.89 (s, 3H), 3.89 (s, 3H), 3.89 (s, 3H), 2.84 (d, J = 11.0 Hz, 1H), 2.70 (dd, J = 5.8, 11.0 Hz, 1H), 2.52 (br, 1H), 2.42 - 2.32 (m, 1H), 2.24 2.09 (m, 2H), 1.81 - 1.73 (m, 2H), 1.71 - 1.60 (m, 3H), 1.39 - 1.32 (m, 2H). 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 148.4, 148.0, 148.0, 147.9, 137.9, 134.7, 133.9, 132.0, 129.7, 121.1, 113.3, 113.0, 112.6, 111.0, 62.1, 56.2, 56.0, 52.9, 32.1, 30.0, 25.8, 24.9. HRMS (ESITOF) m/z: [M + Na]+ Calcd for C25H31NO4Na 432.2151; Found 432.2154.



Compound 5c was obtained as a yellow solid (0.21 g, 51%) along with its regioisomer 17c (0.11 g, 27%) after purification by column chromatography on silica using a mixture of dichloromethane and methanol (10:1) as the eluent.

8-(2',3',4,5-tetramethoxy-[1,1'-biphenyl]-2-yl)-1,3,4,6,9,9a-hexahydro-2H-quinolizine (5c) Compound 5c was obtained as a yellow solid (0.21 g, 51%). 1H NMR (500 MHz, CDCl3, ppm): δ 7.01 (t, J = 7.9, 1H), 6.87 (d, J = 7.9, 1H), 6.86 (s, 1H), 6.82 (d, J = 7.9, 1H), 6.82 (s, 1H), 5.50 (br, 1H), 3.89 (s, 6H), 3.85 (s, 3H), 3.58 (s, 3H), 3.53 (d, J = 16.2 Hz, 1H), 3.19 (br, 1H), 2.80 (br, 1H), 2.04 - 2.28 (m, 4H), 1.80 - 1.95 (m, 2H), 1.73 (br, 1H), 1.42 (br, 1H). 13C{1H}

NMR (125 MHz, CDCl3, ppm): δ 150.7, 148.8, 147.9, 146.4, 126.6, 125.9, 123.7,

123.4, 119.0, 112.2, 109.3, 103.6, 60.4, 60.2, 56.6, 55.9, 55.3, 54.4, 34.1, 31.4, 21.8. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C25H32NO4 410.2331; Found 410.2333.

8-(2',3',4,5-tetramethoxy-[1,1'-biphenyl]-2-yl)-1,3,4,6,7,9a-hexahydro-2H-quinolizine (17c) Compound 17c was obtained as a yellow solid (0.11 g, 27%). 1H NMR (500 MHz, CDCl3, ppm): δ 7.01 (t, J = 7.9 Hz, 1H), 6.79 - 6.91 (m, 4H), 5.54 (br, 1H), 3.90 (s, 6H), 3.85 (s, 3H), 3.58 (s, 3H), 3.15 (br, 1H), 2.76 (br, 1H), 1.82 - 2.25 (m, 7H), 1.74 (br, 1H), 1.45 (br, 1H). 13C{1H}

NMR (125 MHz, CDCl3, ppm): δ 152.9, 148.1, 147.4, 146.8, 136.0, 128.7, 125.3,

123.9, 123.4, 113.8, 112.1, 111.3, 60.6, 56.1, 56.0, 54.1, 31.1, 30.4, 21.3. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C25H32NO4 410.2331; Found 410.2334.

7-(3',4,5-trimethoxy-[1,1'-biphenyl]-2-yl)-1,3,4,6,9,9a-hexahydro-2H-quinolizine (5d) Compound 5d was obtained as a yellow solid (0.31 g, 82%) after purification by column chromatography on silica using a mixture of dichloromethane and methanol (10:1) as the eluent. 1H NMR (500 MHz, CDCl3, ppm): δ 7.26 (t, J = 7.9 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H),


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6.95 - 6.92 (m, 1H), 6.86 - 6.83 (m, 1H), 6.82 (s, 1H), 6.80 (s, 1H), 5.60 (br, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.82 (s, 3H), 3.14 (d, J = 16.2 Hz, 1H), 2.84 (d, J = 11.3 Hz, 1H), 2.55 (d, J = 15.0 Hz, 1H), 2.08 (br, 2H), 2.03 (br, 1H), 1.93 - 1.82 (m, 1H), 1.70 (br, 2H), 1.61 (br, 2H), 1.29 - 1.23 (m, 2H).

13C{1H}

NMR (125 MHz, CDCl3, ppm): δ 159.1, 147.9, 147.7, 143.1,

135.8, 132.5, 132.3, 128.9, 124.5, 121.7, 114.7, 113.0, 112.6, 112.2, 58.0, 56.7, 55.9, 55.4, 55.2, 32.9, 29.6, 25.4, 24.0. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C24H29NO3Na 402.2045; Found 402.2049.

Synthesis of the phenanthroquinolizidine alkaloids Preparation of the VOF3 solution: To a solution of VOF3 (1.0 g, 8.0 mmol) in anhydrous dichloromethane (20 mL) and anhydrous ethyl acetate (10 mL) were added trifluoroacetic acid (TFA, 1.0 mL, 13 mmol) and trifluoroacetic anhydride (TFAA, 4 drops) under a nitrogen atmosphere and the resulting mixture was stirred at room temperature. A solution of 5 (0.50 mmol) and TFAA (2 drops) in anhydrous dichloromethane (100 mL) was stirred at –78 C under a nitrogen atmosphere. The freshly prepared VOF3 solution (4.9 mL, 1.3 mmol) was added to this solution over 10 min. After 1 h, the reaction mixture was warmed to –10 C and stirred for an additional 1 h. 50 mL of 10% NaOH solution was added to the reaction mixture and the resulting mixture was stirred vigorously at room temperature for 1 h. The mixture was extracted with dichloromethane, the organic layers combined, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash silica gel column chromatography using a 10:1 mixture of dichloromethane and methanol as the eluent to provide the corresponding phenanthroquinolizidine alkaloid.

Cryptopleurine (1)



Cryptopleurine (1) was obtained as a yellow solid (0.15 g, 82%) after purification by column chromatography on silica using a mixture of dichloromethane and methanol (10:1) as the eluent. The spectroscopic data obtained for 1 were in accordance with those reported in the literature.5c 1H NMR (500 MHz, CDCl3, ppm): δ 7.94 - 7.87 (m, 2H), 7.80 (d, J = 8.9 Hz, 1H), 7.19 (dd, J = 2.3, 9.0 Hz, 1H), 4.46 (d, J = 15.6 Hz, 1H), 4.10 (s, 3H), 4.06 (s, 3H), 4.01 (s, 3H), 3.64 (d, J = 15.3 Hz, 1H), 3.29 (d, J = 11.0 Hz, 1H), 3.10 (dd, J = 2.7, 16.2 Hz, 1H), 2.94 - 2.86 (m, 1H), 2.42 (br, 1H), 2.31 (dt, J = 3.7, 11.1 Hz, 1H), 2.04 (d, J = 12.8 Hz, 1H), 1.89 (d, J = 12.2 Hz, 1H), 1.84 - 1.76 (m, 2H), 1.59 - 1.52 (m, 1H), 1.49 - 1.43 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 157.6, 149.5, 148.5, 130.3, 126.6, 125.7, 124.6, 124.3, 123.8, 123.6, 115.0, 104.9, 104.0, 57.7, 56.3, 56.2, 56.1, 55.7, 34.8, 33.9, 26.0, 24.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C24H28NO3 378.2069; Found 378.2067.

7-Methoxycryptopleurine (2) 7-Methoxycryptopleurine (2) was obtained as a yellow solid (0.16 g, 78%) after purification by column chromatography on silica using a mixture of dichloromethane and methanol (10:1) as the eluent. The spectroscopic data obtained for 2 were in accordance with those reported in the literature.5c 1H NMR (500 MHz, CDCl3, ppm): δ 7.84 (s, 1H), 7.83 (s, 1H), 7.27 (s, 1H), 7.14 (s, 1H), 4.40 (d, J = 15.0 Hz, 1H), 4.11 (s, 6H), 4.06 (s, 3H), 4.05 (s, 3H), 3.64 (d, J = 15.0 Hz, 1H), 3.32 (d, J = 10.7 Hz, 1H), 3.14 (d, J = 13.4 Hz, 1H), 2.98 - 2.89 (m, 1H), 2.44 (br, 1H), 2.37 - 2.32 (m, 1H), 2.06 (d, J = 11.9 Hz, 1H), 1.91 (br, 1H), 1.82 (br, 2H), 1.57 (d, J = 13.1 Hz, 1H), 1.51 - 1.44 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 148.9, 148.7, 148.5, 125.4, 124.1, 123.7, 123.5, 104.0, 103.7, 103.6, 103.2, 57.7, 56.3, 56.2, 56.1, 56.1, 34.9, 33.8, 26.0, 24.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C25H30NO4 408.2175; Found 408.2176.


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5-Methoxycryptopleurine (3) 5-Methoxycryptopleurine (3) was obtained as a yellow solid (0.11 g, 53%) after purification by column chromatography on silica using a mixture of dichloromethane and methanol (10:1) as the eluent. 1H NMR (500 MHz, CDCl3, ppm): δ 9.30 (s, 1H), 7.81 (d, J = 8.9 Hz, 1H), 7.30 (s, 1H), 7.20 (d, J = 8.9, 1H), 4.63 (d, J = 14.7 Hz, 1H), 4.12 (s, 6H), 4.06 (s, 3H), 4.05 (s, 3H), 3.68 (d, J = 14.3 Hz, 1H), 3.49 (t, J = 7.9 Hz, 1H), 3.38 (dd, J = 15.9, 2.4 Hz, 1H), 2.87 2.97 (m, 1H), 2.43 - 2.56 (m, 2H), 2.22 - 2.30 (m, 1H), 2.05 (dd, J = 11.6, 8.6 Hz, 1H), 1.89 1.98 (m, 1H), 1.74 - 1.83 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 148.9, 148.7, 126.5, 126.0, 124.5, 123.8, 123.6, 104.1, 103.6, 103.5, 103.3, 60.4, 56.2, 56.0, 55.3, 54.2, 34.0, 31.4, 21.8. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C25H29NO4Na 430.1994; Found 430.1997.

Boehmeriasin A (4) Boehmeriasin A (4) was obtained as a yellow solid (0.14 g, 73%) after purification by column chromatography on silica using a mixture of dichloromethane and methanol (10:1) as the eluent. The spectroscopic data obtained for 1 were in accordance with those reported in the literature.5c 1H NMR (500 MHz, CDCl3, ppm): δ 7.92 - 7.86 (m, 3H), 7.20 (dd, J = 2.4, 8.9 Hz, 1H), 7.11 (s, 1H), 4.34 (d, J = 15.3 Hz, 1H), 4.09 (s, 3H), 4.04 (s, 3H), 4.00 (s, 3H), 3.57 (d, J = 15.0 Hz, 1H), 3.29 (d, J = 11.0 Hz, 1H), 3.16 (dd, J = 3.1, 16.5 Hz, 1H), 2.93 (dd, J = 10.7, 16.2 Hz, 1H), 2.41 - 2.34 (m, 1H), 2.34 - 2.27 (m, 1H), 2.01 (d, J = 11.3 Hz, 1H), 1.88 (d, J = 12.2 Hz, 1H), 1.84 - 1.75 (m, 2H), 1.57 - 1.50 (m, 1H), 1.47 - 1.41 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 157.7, 149.5, 148.3, 130.4, 126.0, 125.3, 125.1, 125.1, 124.2, 123.4, 114.9, 104.7, 104.1, 103.1, 57.6, 56.4, 56.2, 56.1, 56.1, 55.6, 34.6, 33.7, 26.0, 24.4. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C24H28NO3 378.2069; Found 378.2066.



7-Methoxyisocryptopleurine (18) 7-Methoxyisocryptopleurine (18) was obtained as a yellow solid (0.17 g, 84%) after purification by column chromatography on silica using a mixture of dichloromethane and methanol (10:1) as the eluent. 1H NMR (500 MHz, CDCl3, ppm): δ 7.82 (s, 1H), 7.81 (s, 1H), 7.32 (s, 1H), 7.24 (s, 1H), 4.28 (d, J = 10.7 Hz, 1H), 4.11 (s, 6H), 4.04 (s, 3H), 4.04 (s, 3H), 3.44 (t, J = 11.7 Hz, 1H), 3.33 - 3.11 (m, 4H), 2.91 (td, J = 5.0, 10.7 Hz, 1H), 2.21 (d, J = 13.4 Hz, 1H), 1.97 (d, J = 11.9 Hz, 1H), 1.90 - 1.82 (m, 1H), 1.78 (d, J = 12.5 Hz, 1H), 1.72 1.64 (m, 1H), 1.54 (d, J = 12.5 Hz, 1H).

13C{1H}

NMR (125 MHz, CDCl3, ppm): δ 157.7,

149.5, 148.3, 130.4, 126.0, 125.3, 125.1, 125.1, 124.2, 123.4, 114.9, 104.7, 104.1, 103.1, 57.6, 56.4, 56.2, 56.1, 56.1, 55.6, 34.6, 33.7, 26.0, 24.4. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C25H30NO4 408.2175; Found 408.2177.

5-Methoxyisocryptopleurine (19) 5-Methoxyisocryptopleurine (19) was obtained as a yellow solid (0.14 g, 69%) after purification by column chromatography on silica using a mixture of dichloromethane and methanol (10:1) as the eluent. 1H NMR (500 MHz, CDCl3, ppm): δ 9.33 (s, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.33 (s, 1H), 7.29 (d, J = 9.2 Hz, 1H), 4.67 (d, J = 15.0 Hz, 1H), 4.07 (s, 6H), 4.04 (s, 3H), 3.92 (s, 3H), 3.69 (d, J = 14.7 Hz, 1H), 3.44 - 3.50 (m, 1H), 3.34 (dd, J = 15.7, 2.3 Hz, 1H), 2.88 - 2.97 (m, 1H), 2.43 - 2.54 (m, 2H), 2.21 - 2.29 (m, 1H), 2.00 - 2.08 (m, 1H), 1.88 - 1.98 (m, 1H), 1.75 - 1.84 (m, 1H).

13C{1H}

NMR (125 MHz, CDCl3, ppm): δ 150.7,

148.8, 147.9, 146.4, 126.6, 125.9, 123.7, 123.4, 119.0, 112.2, 109.3, 103.6, 60.4, 60.2, 56.6, 55.9, 55.3, 54.4, 34.1, 31.4, 21.8. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C25H30NO4 C25H29NO4Na 430.1994; Found 430.1995.

Associated Content


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Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 1H

and 13C NMR spectra for all compounds (PDF)

Author Information Corresponding Author * E-mail: [email protected] (C.-H.C.). ORCID Cheol-Hong Cheon: 0000-0002-6738-6193 Young-In Jo: 0000-0002-1734-9941 Notes The authors declare no competing financial interest.

Acknowledgements This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korean Government (NRF-2018R1D1A1A02086110 and NRF-2014-011165, Center for New Directions in Organic Synthesis).

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Total Synthesis of Phenanthroquinolizidine Alkaloids Using a Building

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