An Efficient Synthesis of 3,3′-Bipiperidines Using an ROM/RCM Metathesis Sequence: Extension to Oxygenated Analogues

ss-2014-z0181-op.fm, 7/31/14 Imprimatur:

PAPER ▌A

paper

An Efficient Synthesis of 3,3′-Bipiperidines Using an ROM/RCM Metathesis Sequence: Extension to Oxygenated Analogues

3,3′-Bipiperidines

Esma Maougal,

Sylvain Dalençon,

Morwenna S. M. Pearson-Long,

Monique Mathé-Allainmat,

Jacques Lebreton,*

Stéphanie Legoupy*

a Université de Nantes, CNRS, Laboratoire CEISAM-UMR 6230, Faculté des Sciences et des Techniques, 2 rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France

E-mail: jacques.lebreton@univ-nantes.fr

b Université du Maine, IMMM, UMR 6283 CNRS, Avenue O. Messiaen, 72085 Le Mans cedex 9, France

c Université d’Angers, Laboratoire MOLTECH-Anjou, UMR 6200 CNRS-, 2, Bd Lavoisier, 49045 Angers cedex, France Fax +33(2)51125562; E-mail: stephanie.legoupy@univ-angers.fr

Received: 14.03.2014; Accepted after revision: 18.07.2014 Dedicated to the memory of Dr. Hans Greuter

Abstract: A short and efficient diastereoselective synthesis of 3,3′- bipiperidine and 3,3′-bis(1,2,3,6-tetrahydropyridine) was accom- plished using a tandem ring-opening metathesis/ring-closing me- tathesis (ROM/RCM) sequence as a key step. This strategy has been extended to the synthesis of the oxygenated analogues.

Key words: heterocyclics, alkaloids, metathesis, piperidines, cy- clobutene

The piperidine motif is contained in a huge number of both natural alkaloids and synthetic compounds, which exhibit a wide range of biological activities, as well as in marketed drugs.

Development of highly efficient strate- gies to prepare piperidine derivatives has been extensively investigated for the past two decades.

Surprisingly, preparation of the dipiperidine scaffold has attracted less attention. The most popular representation of this class of compounds, the heterocyclic diamine, 2,2′-bipiperidine (1), was first prepared by Blau in 1889 (Figure 1).

Due to the presence of two stereogenic centers, compound

present as three isomers, meso (R,S) and a pair of racemic forms (R,R) and (S,S). For the preparation of 2,2′-bipiper- idine (1) essentially two methods have been used, either reduction of the 2,2′-bipyridine

or photodimerization of piperidine,

leading in both cases to a mixture of diaste- reoisomers. In general, after separation of the two diaste- reoisomers by recrystallization, optically pure 2,2′- bipiperidines are obtained via resolution with chiral aux- iliary methods.

In contrast, to the best of our knowledge, there is only a limited number of reports focusing on the preparation of 3,3′-bipiperidine (2).

In this paper, we disclose a short, direct, and efficient synthesis of 3,3′-bipiperidine (2) starting from the diol 7

as illustrated in the retrosynthetic Scheme 1. Moreover, our synthetic route permits the preparation of 3,3′-bis(1,2,3,6-tetrahydropyridine) (3), which could be regarded as a valuable intermediate high-

lighting our strategy.

In addition, our strategy provided access to structurally bicyclic oxygenated analogues 4 and

Figure 1 2,2′-Bipiperidine (1) and target heterocyclic compounds 2–

5

Scheme 1 Retrosynthesis of the target heterocyclic compounds 2–5

N N H H

N

N

H

H N

N

H

H

1 2 3

O

O

O

O

4 5

O O

O OH OH

O O

O

O N

N

N

N Boc

Boc

H

H

ROM/RCM

2 3

6

7

8 9

4 C C 5

C C

C C C C

SYNTHESIS2014, 46, 000A–000E Advanced online publication:0039-78811437-210X

DOI: 10.1055/s-0034-1378663; Art ID: SS-2014-z0181-OP

© Georg Thieme Verlag Stuttgart · New York

B E. Maougal et al. PAPER

We envisioned a fast and reliable strategy to reach our

four target molecules starting from the easily available diol

with LiAlH

. From this diol 7, the corresponding bis-pro- tected allyl derivative 8 and 9 could be prepared by using standard procedures. A tandem ring-opening metathesis (ROM)/ring-closing metathesis (RCM) sequence was planned as a key step of our work. Over the past few de- cades, olefin metathesis has proven to be one of the most powerful tools for the rapid construction of complex het- erocycles.

In addition, a ruthenium-catalyzed tandem metathesis sequence offers a unique opportunity to pre- pare efficiently original heterocyclic compounds, as building blocks for more elaborated structures,

in few steps from readily available simple olefinic substrates.

The success of this metathesis cascade in our plan results from the release of the ring-strain during the ROM reac- tion of the cyclobutene ring acting as the driving force.

Also in this context, it is important to point out that ROM/RCM reaction sequence to prepare the 2,2′-bis(di- hydropyran) from the cis- or trans-4,5-bis(allyloxy)cyclo- hexene failed; only the 6,8-fused bicyclic RCM reaction adducts were isolated.

A close result was also mentioned in the literature with cis-N,N′-bis(tosyl)-4,5-diallylamino- cyclohexene.

Our synthesis began with the diol 7, which was obtained by simple reduction of anhydride 6

with LiAlH

as pre- viously described.

According to the literature,

the diol 7 was successively subjected to dimesylation and to nucle- ophilic displacement with sodium azide to give the corre- sponding diazide, which was then reduced with LiAlH

. The resulting diamine was finally protected as its bis(N,N′-Boc) derivative to provide the intermediate

(Scheme 2). This four-step sequence could be carried out on a multi-gram scale to afford the intermediate 10 in 45%

overall yield from 7. At this point, the full characterization of all the following synthetic intermediates by NMR spec- troscopy was hampered by the presence of rotamers about the

spectroscopy to complete assignments on these bis-Boc intermediates 8, 10, and 11 failed. The N-allylation of 10 was achieved by treatment with an excess of allyl bromide in the presence of NaH to furnish the key metathesis pre- cursor 8 in 85% yield. With 8 in hand, it was now possible to investigate the key ROM/RCM reaction. Pleasingly, the treatment of the diene 8 in the presence of a catalytic amount of second-generation Grubbs catalyst in dichloro- methane for 3 days at room temperature cleanly provided the desired adduct 11 in 60% yield after silica gel chroma- tography. Towards our first objective, removal of the Boc groups was achieved by treatment of 11 with an excess of trifluoroacetic acid in dichloromethane providing the de- sired unsaturated bis-heterocycle

salt in 90% yield. To prepare the saturated derivative

the key intermediate 11 was first hydrogenated upon treat- ment with a catalytic amount of Pd/C in ethanol under one atmosphere of hydrogen followed by cleavage of the Boc protecting groups as previously described, to furnish the

saturated bis-heterocycle

50% yield for the two steps (Scheme 2).

Scheme 2 Reagents and conditions: (i) see ref. 8 (ii) allyl bromide, NaH, r.t., DMF, 85%; (iii) Grubbs II catalyst, CH₂Cl₂, r.t., 60%; (iv) TFA, CH₂Cl₂, r.t., for 3 90%, for 2 77%; (v) H₂, 10% Pd/C, r.t., EtOH, 70%.

Having synthesized the two first target molecules 2 and 3, our attention turned to decreasing the number of steps of this synthesis. It was then envisaged that the key metathe- sis substrates 12 or 13 could be directly obtained from the diol

Mitsunobu conditions according to literature precedent, to install the allylamine moiety.

Unfortunately, all attempts failed as neither conversion nor decomposition was ob- served.

Scheme 3 Reagents and conditions: (i) 1,1′-(azodicarbonyl)dipiper- idine (ADDP) or diisopropyl azodicarboxylate (DIAD), Ph₃P, 14 or 15, THF or toluene.

Encouraged by our results in the synthesis of 3,3′-bipiper- idines 2 and 3, we extended this strategy to the oxygenat- ed series as outlined in Scheme 4. To the best of our knowledge no work has been published on the synthesis of compounds 4 and 5, only their corresponding racemic 2,2′-bis(tetrahydropyran)

and 5,5-bis(6-oxacyclohex- 2-ene)

analogues have been described. Both primary alcohol functions in 7 were alkylated as their correspond- ing allyl ethers by using standard conditions to furnish 9 in 40% yield. Then, this bis(allyl ether) was subjected to the ROM/RCM reaction in the same conditions as previ- ously described for 8 to give the desired 3,3′-bis(dihydro-

OH i OH

NHBoc NHBoc

ii N iii

N Boc

Boc

N

N Boc

Boc

N

N H

H

N

N H

H iv

v, iv 10

7 8

11

3·2TFA

2·2TFA 45%

7 OH i OH

N N R R

12 R = CF3CO 13 R = Ts

14 R = CF3CO 15 R = Ts

N R H

PAPER 3,3′-Bipiperidines C

pyran) (5) in 76% yield. This later compound was

subsequently hydrogenated under classical conditions, as already reported for intermediate

bis(pyran) 4 in 75% yield. It should be noted that the mod- est yields obtained in this series are mainly due to the vol- atility of these compounds.

Scheme 4 Reagents and conditions: (i) allyl bromide, NaH, 0 °C to r.t., THF, 40%; (ii) Grubbs II catalyst, CH₂Cl₂, r.t., 76%; (iii) H₂, 10%

Pd/C, r.t., EtOH, 75%.

In conclusion, to the best of our knowledge, the prepara- tion of 3 and 2 are not described in the literature and this present work has provided an efficient access to these ni- trogen heterocycles from intermediate

eight steps, respectively. Also, this strategy has been ex- tended to the preparation of the oxygenated analogues

and 5.

All solvents used were reagent grade. Petroleum ether (PE) refers to the fraction boiling at ????–???? °C. TLC was performed on silica gel coated aluminum sheets (Kieselgel 60 F₂₅₄, Merck) and visual- ized by UV radiation (λ = 254 nm), or a vanillin or molybdate solu- tion. Flash column chromatography was performed on silica gel 60 ACC 40–63 μm (SDS-Carlo Erba). NMR spectra were recorded on a Bruker AC300 (300 MHz for ¹H), on a Bruker 400 (400 MHz for

1H) or on a Bruker 500 (500 MHz for ¹H) at r.t., on samples dis- solved in an appropriate deuterated solvent. Used references were Me₄Si for ¹H, deuterated solvent signal for ¹³C. Chemical shifts (δ) are expressed in parts per million (ppm), and coupling constants (J) in hertz (Hz). Low-resolution mass spectra (MS) were recorded in CEISAM laboratory on a Thermo-Finnigan DSQII quadripolar at 70 eV (CI with NH₃ gas). High-resolution mass spectrometry (HRMS in Da unit) analyses were recorded on a LC-Q-TOF (Syn- apt-G2 HDMS, Waters) in IRS-UN center (Mass Spectrometry plat- form, Nantes) or a LTQ-Orbitrap ThermoFisher Scientific in Oniris center (LABERCA laboratory, Nantes) or a MALDI-TOF-TOF ap- paratus (Autoflex III from Bruker) in INRA center (BIBS platform, Nantes).

The compounds 7¹⁴ and 10^8a have been described previously.

cis-3,4-Bis(tert-butoxycarbonylaminomethyl)(allylcarba- mate)cyclobut-1-ene (8)

To a solution of compound 10 (250 mg, 0.80 mmol, 1 equiv) in an- hydrous DMF (14 mL) was added portionwise NaH (60% in miner- al oil, 160 mg, 4 mmol, 5 equiv), at 0 °C and the reaction mixture was stirred at the same temperature for 15 min. Allyl bromide (2.78 mL, 16 mmol, 20 equiv) was added and the mixture stirred at r.t. for 12 h. After evaporation of the solvent, the residue was dissolved in CH₂Cl₂ (34 mL) and washed successively with H₂O (3 × ?? mL) and brine (3 × ?? mL). The organic layer was dried (Na₂SO₄) and the solvents were removed in vacuo.The crude product was purified

by column chromatography on silica gel (PE–EtOAc, 100:0 to 93:7) to give 8 as a brown oil; yield: 210 mg (85%).

1H NMR (300 MHz, CDCl₃): δ = 6.18 (s, 2 H, CH=CH), 5.77 (m, 2 H, 2 × CH₂CH=CH₂), 5.13 (m, 4 H, 2 × CH₂CH=CH₂), 3.80–3.60 (br s, 4 H, 2 × NCH₂CH=CH₂), 3.55–3.13 (m, 6 H, 2 × CHCH₂NBoc and 2 × CHCH₂NBoc), 1.45 [s, 18 H, 2 × C(CH₃)].

13C NMR (75 MHz, CDCl₃): δ = 155.4 (C=O), 139.4, 139.3, 139.2, 139.0 (rotamers, CH=CH), 134.1 (CH₂CH=CH₂), 116.2, 115.9 (ro- tamers, CH₂CH=CH₂), 79.6 [C(CH₃)₃], 49.9, 49.4 (rotamers, CH₂NBoc), 47.2 and 44.1 (rotamers, CHCH₂NBoc), 28.4 [C(CH₃)₃].

MS (MALDI-DHB-PEG 400): m/z= 415 [M + Na]⁺.

HRMS (MALDI-DHB-PEG 400): m/z [M + Na]⁺ calcd for C₂₂H₃₆N₂O₄ + Na: 415.2567; found: 415.2570.

Di-tert-butyl 2,2′,3,3′-Tetrahydro[3,3′-bipyridine]- 1,1′(6H,6′H)-dicarboxylate (11)

To a solution of compound 8 (260 mg, 0.66 mmol, 1 equiv) in an- hydrous CH₂Cl₂ (36 mL) was added Grubbs II catalyst (28 mg, 0.033 mmol, 0.15 equiv) in three portions and the solution was stirred at r.t. for 3 days, until TLC (PE–EtOAc, 90:10) indicated no remaining starting material. The solvent was removed in vacuo to give the crude product, which was purified by column chromatog- raphy on a silica gel column (PE–EtOAc, 99:1 to 90:10) to give 11 as a colorless oil; yield: 140 mg (60%).

1H NMR (300 MHz, CDCl₃): δ = 5.90 (br d, 1 H, CH=CH), 5.72 (br s, 1 H, CH=CH), 3.85–3.79 (m, 4 H, 2 × CH₂NBoc) 3.58–3.27 (m, 4 H, 2 × CH₂NBoc), 2.16 (m, 2 H, 2 × CHCH₂), 1.45 [s, 18 H, 2 × C(CH₃)₃].

13C NMR (125 MHz, CDCl₃): δ = 154.97 (C=O), 128.01, 127.78 (rotamers, CH=CH), 125.59, 125.01 (rotamers, CH=CH), 79.63 [C(CH₃)₃], 43.90 and 43.24 (rotamers, CH₂NBoc) 37.90 and 37.63 (rotamers, CHCH₂NBoc), 28.46 [C(CH₃)₃].

MS (MALDI): m/z= 387 [M + Na]⁺.

HRMS (MALDI-DHB-PEG 400): m/z [M + Na]⁺ calcd for C₂₀H₃₂N₂O₄ + Na: 387.2254; found: 387.2249.

3,3′-Bipiperidine Trifluoroacetic Salt (2·2 CF₃CO₂H) N-Boc-3,3′-bipiperidine

Compound 11 (510 mg, 1.40 mmol, 1 equiv) was reduced in the presence of Pd/C (10%, 100 mg) in EtOH (30 mL) under H₂ atmo- sphere. The reaction mixture was stirred at r.t. for 2 h. The mixture was filtered on Celite and the filtrate was concentrated in vacuo to give the desired product as a white solid; yield: 400 mg (77%).

13C NMR (125 MHz, C₆D₆): δ = 154.66 (C=O), 78.77 [C(CH₃)₃], 47.82–47.76 (rotamers CH₂NBoc), 44.87–44.82 (rotamers CH₂NBoc), 38.55 (CHCH₂), 30.16 (CH₂CH₂), 28.6 [C(CH₃)₃], 25.2 (CH₂CH₂).

HRMS (MALDI-DHB-PEG 400): m/z [M + Na]⁺ calcd for C₂₀H₃₆N₂O₄ + Na: 391.2567; found: 391.2567.

2·2 CF₃CO₂H

To a solution of this N-Boc-bipiperidine (100 mg, 0.27 mmol) in an- hydrous CH₂Cl₂ was added TFA (805 mg, 7.06 mmol, 26 equiv) at 0 °C. The solution was stirred at this temperature for 15 min and then for 2 h at r.t., until TLC (PE–EtOAc, 90:10) indicated no re- maining starting material. The mixture was diluted with toluene (??

mL) and then solvents were removed in vacuo to give the salt 2·2 CF₃CO₂H as a brown solid; yield: 80 mg (75%).

1H NMR (400 MHz, MeOD): δ = 3.41 (d, J= 12.3 Hz, 2 H, 2 × CHCHH′NH), 3.35 (dd, J= 12.1, 2.7 Hz, 2 H, 2 × CH₂CHH′NH), 2.89 (td, J= 12.1, 4 Hz, 2 H, 2 × CH₂CHH′NH), 2.77 (t, J= 12.Hz, 2 H, 2 × CHCHH′NH), 1.94 (m, 4 H, 2 × CH₂CHH′CH and 2 × CH₂CHH′CH₂), 1.73 (m, 4 H,

7 OH i OH

O O

O

O

ii O

O

iii 9

5 4

D E. Maougal et al. PAPER

2 × CHCH₂ and 2 × CH₂CHH′CH₂), 1.31 (m, 2 H, 2 × CH₂CHH′CH).

13C NMR (100 MHz, MeOD): δ = 47.61 (CH₂NH), 45.30 (CH₂NH), 37.87 (CH), 26.72 (CH₂CH₂), 23.37 (CH₂CH₂).

MS (CI⁺): m/z= 169 [M + H]⁺.

HRMS (CI⁺): m/z [M + H]⁺ calcd for C₁₀H₂₁N₂: 169.1699; found:

169.1699.

1,1′,2,2′,3,3′,6,6′-Octahydro-3,3′-bipyridine Trifluoroacetic Salt (3·2 CF₃CO₂H)

To a solution of compound 11 (220 mg, 0.060 mmol, 1 equiv) in an- hydrous CH₂Cl₂ (2 mL) was added TFA (1.79 g, 15.71 mmol, 26 equiv) at 0 °C. The solution was stirred at this temperature for 15 min and then for 2 h at r.t. until TLC (PE–EtOAc, 90:10) indicated no remaining starting material. The reaction was diluted with tolu- ene (?? mL) and the solvents were removed in vacuo to give the salt 3·2 CF₃CO₂H as a yellow oil; yield: 150 mg (90%).

1H NMR (400 MHz, MeOD): δ = 5.98 (m, 2 H, 2 × CH=CHCH₂NH), 5.88 (d, J= 12 Hz, 2 H, 2 × CHCH=CH), 3.68 (AB system, 4 H, 2 × CH=CHCH₂NH), 3.54 (dd, J= 12, 4 Hz, 2 H, 2 × CHCHH′NH), 3.01 (dd, J= 12 Hz, 2 H, 2 × CHCHH′NH), 2.87 (m, 2 H, 2 × CHCH₂NH).

13C NMR (100 MHz, MeOD): δ = 127.91 (CH=CH), 124.29 (CH=CH), 43.71 (CHCH₂NH), 43.04 (CH=CHCH₂NH), 35.56 (CHCH₂NH).

MS (CI⁺): m/z= 165 [M + H]⁺.

HRMS (ESI⁺): m/z [M + H]⁺ calcd for C₁₀H₁₇N₂: 165.1386; found:

165.1379.

cis-3,4-Bis(allyloxymethyl)cyclobut-1-ene (9)

To a solution of diol 7 (1 g, 8.77 mmol, 1 equiv) in anhydrous THF (28 mL), was added portionwise NaH (60% in mineral oil, 1.75 g, 43.85 mmol, 5 equiv) at 0 °C and the solution was stirred at this temperature for 15 min. Allyl bromide (3.78 mL, 43.85 mmol, 5 equiv) was added and the solution was stirred at r.t. for 24 h. After evaporation of the solvent, the residue was dissolved in CH₂Cl₂ (68 mL) and washed successively with H₂O (3 × ?? mL) and brine (3 ×

?? mL). The organic layer was dried (Na₂SO₄) and the solvents were removed in vacuo to give the crude product, which was puri- fied by column chromatography on silica gel (PE–EtOAc, 99:1 to 90:10). The desired product 9 was obtained as a colorless oil; yield:

660 mg (40%).

1H NMR (300 MHz, CDCl₃): δ = 6.19 (s, 2 H, CH=CH), 5.91 (m, 2 H, 2 × CH₂CH=CH₂), 5.27 (dd, J= 17.6, 1.8 Hz, 2 H, 2 × CH₂CH=CHH′), 5.17 (dd, J= 10.5, 1.5 Hz, 2 H, 2 × CH₂CH = CHH′), 3.97 (dt, J= 5.4, 1.2 Hz, 4 H, 2 × CH₂CH=CH₂), 3.56 (m, 4 H, 2 × CH₂OAllyl), 3.21 (m, 2 H, CHCH₂OAllyl).

13C NMR (100 MHz, CDCl₃): δ = 138.56 (CH=CH), 135.0 (CH₂CH=CH₂), 116.81 (OCH₂CH=CH₂), 72.05 (OCH₂CH=CH₂), 70.37 (CH₂OAllyl), 45.51 (CHCH).

MS (CI⁺): m/z= 195 [M + H]⁺.

HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₁₂H₁₈O₂ + Na: 217.1199;

found: 217.1191.

3,3′,6,6′-Tetrahydro-2H,2′H-3,3′-bipyran (5)

The title compound was prepared according to the procedure de- scribed for compound 11, starting from the cyclobutene derivative 9 (660 mg, 3.40 mmol) in the presence of Grubbs II catalyst (146 mg, 0.17 mmol). Flash chromatography on a silica gel column (PE–

EtOAc, 95:5 to 90:10) afforded 5 as a brown oil; yield: 420 mg (76%).

1H NMR (300 MHz, CDCl₃): δ = 5.80 (s, 4 H, 2 × CH=CH), 4.09 (d, J= 2.2 Hz, 4 H, 2 × CH=CHCH₂O), 3.85 (AB part of ABX sys- tem, J_AB= 11.1 Hz and J_AX= 4.5 Hz, 2 H, 2 × OCHH′CH), 3.65

(AB part of ABX system, J_AB= 11.1 and J_BX= 5.7 Hz, 2 H, 2 × OCHH′CH), 2.32 (X part of ABX system, m, 2 H, 2 × CHCH₂O).

13C NMR (75 MHz, CDCl₃): δ = 127.41 (CH=CH), 126.52 (CH=CH), 67.07 (CH₂O), 65.47 (CH₂O), 37.14 (CHCH₂).

MS (CI⁺): m/z= 167 [M + H]⁺.

HRMS (CI⁺): m/z [M + H]⁺ calcd for C₁₀H₁₅O₂: 167.1067; found:

167.1064.

Octahydro-2H,2′H-3,3'-bipyran (4)

The title compound was prepared according to the procedure de- scribed for compound 2, starting from the unsaturated bicyclic de- rivative 5 (140 mg, 0.84 mmol) in the presence of Pd/C as the catalyst (10%, 28 mg). Flash chromatography on a silica gel column (PE–EtOAc, 90:10) afforded 4 as a brown oil; yield: 106 mg (74%).

1H NMR (400 MHz, CDCl₃): δ = 3.91 (dd, J= 11.2, 2.0 Hz, 2 H, 2 × CHCHH′O), 3.85 (m,2 H, 2 × CH₂CHH′O), 3.33 (m, 2 H, 2 × CH₂CHH′O), 3.14 (m, 2 H, 2 × CHCHH′O), 1.81 (m, 2 H, 2 × CH₂CHH′CH), 1.57 (m, 4 H, CH₂-CH₂CH₂), 1.41 (m, 2 H, 2 × CHCH₂O), 1.22 (m, 2 H, 2 × CH₂CHH′CH).

13C NMR (100 MHz, CDCl₃): δ = 71.29 (CH₂O), 68.41 (CH₂O), 37.87 (CHCH₂), 27.22 (CH₂CH₂), 25.75 (CH₂CH₂).

HRMS (CI⁺): m/z [M + H]⁺ calcd for C₁₀H₁₉O₂ [M + H]⁺: 171.1380;

found: 171.1381.

Acknowledgment

The authors are deeply indebted to the Ministère de l’Enseignement Supérieur et de la Recherche, the Centre National de la Recherche Scientifique (CNRS), the Université de Nantes, the Université du Maine, and the Université d’Angers for their constant support. E.M.

wishes to acknowledge the Algerian Government for a Ph.D. grant (Programme National Exceptionnel). The authors would like to thank Dr. Samuel Golten for fruitful discussions and comments.

Supporting Information

10.1055/s-00000084.Supporting InformationSupporting Information

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OH OH

N N Boc

Boc

N

N H

H 8 steps

graphic abstract