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Synthesis 2014; 46(23): 3268-3272
DOI: 10.1055/s-0034-1378663
paper
© Georg Thieme Verlag Stuttgart · New York

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

Esma Maougal
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   Email: jacques.lebreton@univ-nantes.fr
,
Sylvain Dalençon
b   Université du Maine, IMMM, UMR 6283 CNRS, Avenue O. Messiaen, 72085 Le Mans cedex 9, France
,
Morwenna S. M. Pearson-Long
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   Email: jacques.lebreton@univ-nantes.fr
b   Université du Maine, IMMM, UMR 6283 CNRS, Avenue O. Messiaen, 72085 Le Mans cedex 9, France
,
Monique Mathé-Allainmat
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   Email: jacques.lebreton@univ-nantes.fr
,
Jacques Lebreton*
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   Email: jacques.lebreton@univ-nantes.fr
,
Stéphanie Legoupy*
c   Université d’Angers, Laboratoire MOLTECH-Anjou, UMR 6200 CNRS-, 2, Bd Lavoisier, 49045 Angers cedex, France   Fax: +33(2)51125562   Email: stephanie.legoupy@univ-angers.fr
› Author Affiliations
Further Information

Publication History

Received: 14 March 2014

Accepted after revision: 18 July 2014

Publication Date:
28 August 2014 (online)

 
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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 accomplished using a tandem ring-opening metathesis/ring-closing metathesis (ROM/RCM) sequence as a key step. This strategy has been extended to the synthesis of the oxygenated analogues.


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Key words

heterocyclics - alkaloids - metathesis - piperidines - cyclobutene

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.[1] Development of highly efficient strategies to prepare piperidine derivatives has been extensively investigated for the past two decades.[2] 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]).[3] Due to the presence of two stereogenic centers, compound 1 is present as three isomers, meso (R,S) and a pair of racemic forms (R,R) and (S,S). For the preparation of 2,2′-bipiperidine (1) essentially two methods have been used, either reduction of the 2,2′-bipyridine[4] or photodimerization of piperidine,[5] leading in both cases to a mixture of diastereoisomers. In general, after separation of the two diastereoisomers by recrystallization, optically pure 2,2′-bipiperidines are obtained via resolution with chiral auxiliary methods.[5d] [6]

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).[7] In this paper, we disclose a short, direct, and efficient synthesis of 3,3′-bipiperidine (2) starting from the diol 7 [8] 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 highlighting our strategy.[9] In addition, our strategy provided access to structurally bicyclic oxygenated analogues 4 and 5, as outlined in retrosynthetic Scheme [1].

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Figure 1 2,2′-Bipiperidine (1) and target heterocyclic compounds 2–5
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Scheme 1 Retrosynthesis of the target heterocyclic compounds 2–5

We envisioned a fast and reliable strategy to reach our four target molecules starting from the easily available diol 7, prepared by simple treatment of the anhydride 6 with LiAlH4. From this diol 7, the corresponding bis-protected 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 decades, olefin metathesis has proven to be one of the most powerful tools for the rapid construction of complex heterocycles.[9] In addition, a ruthenium-catalyzed tandem metathesis sequence offers a unique opportunity to prepare efficiently original heterocyclic compounds, as building blocks for more elaborated structures,[10] 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 reaction of the cyclobutene ring acting as the driving force.[11] Also in this context, it is important to point out that ROM/RCM reaction sequence to prepare the 2,2′-bis(dihydropyran) from the cis- or trans-4,5-bis(allyloxy)cyclohexene failed; only the 6,8-fused bicyclic RCM reaction adducts were isolated.[12] A close result was also mentioned in the literature with cis-N,N′-bis(tosyl)-4,5-diallylaminocyclohexene.[13]

Our synthesis began with the diol 7, which was obtained by simple reduction of anhydride 6 [14] with LiAlH4 as previously described.[8] According to the literature,[8a] the diol 7 was successively subjected to dimesylation and to nucleophilic displacement with sodium azide to give the corresponding diazide, which was then reduced with LiAlH4. The resulting diamine was finally protected as its bis(N,N′-Boc) derivative to provide the intermediate 10 (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 spectroscopy was hampered by the presence of rotamers about the N-Boc bond. The use of variable temperature NMR 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 precursor 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 dichloromethane for 3 days at room temperature cleanly provided the desired adduct 11 in 60% yield after silica gel chromatography. 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 desired unsaturated bis-heterocycle 3 as its trifluoroacetate salt in 90% yield. To prepare the saturated derivative 2, the key intermediate 11 was first hydrogenated upon treatment 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 2 as its trifluoroacetate salt in 50% yield for the two steps (Scheme [2]).

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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 metathesis substrates 12 or 13 could be directly obtained from the diol 7 (see Scheme [3]) by treatment with 14 or 15 under Mitsunobu conditions according to literature precedent, to install the allylamine moiety.[15] Unfortunately, all attempts failed as neither conversion nor decomposition was observed.

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

Encouraged by our results in the synthesis of 3,3′-bipiperidines 2 and 3, we extended this strategy to the oxygenated 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)[5a] [b] and 5,5-bis(6-oxacyclohex-2-ene)[11b,e,16] analogues have been described. Both primary alcohol functions in 7 were alkylated as their corresponding 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 previously described for 8 to give the desired 3,3′-bis(dihydropyran) (5) in 76% yield. This later compound was subsequently hydrogenated under classical conditions, as already reported for intermediate 11, to provide the bis(pyran) 4 in 75% yield. It should be noted that the modest yields obtained in this series are mainly due to the volatility of these compounds.

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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 preparation of 3 and 2 are not described in the literature and this present work has provided an efficient access to these nitrogen heterocycles from intermediate 7 in seven and eight steps, respectively. Also, this strategy has been extended to the preparation of the oxygenated analogues 4 and 5.

All solvents used were reagent grade. Petroleum ether (PE) refers to the fraction boiling at 40–60 °C. TLC was performed on silica gel coated aluminum sheets (Kieselgel 60 F254, Merck) and visualized by UV radiation (λ = 254 nm), or a vanillin or molybdate solution. 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 dissolved 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 (Synapt-G2 HDMS, Waters) in IRS-UN center (Mass Spectrometry platform, Nantes) or a LTQ-Orbitrap ThermoFisher Scientific in Oniris center (LABERCA laboratory, Nantes) or a MALDI-TOF-TOF apparatus (Autoflex III from Bruker) in INRA center (BIBS platform, Nantes).

The compounds 7 [14] and 10 [8a] have been described previously.


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

To a solution of compound 10 (250 mg, 0.80 mmol, 1 equiv) in anhydrous DMF (14 mL) was added portionwise NaH (60% in mineral 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 × 15 mL) and brine (3 × 15 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=CH 2), 3.80–3.60 (br s, 4 H, 2 × NCH 2CH=CH2), 3.55–3.13 (m, 6 H, 2 × CHCH2NBoc and 2 × CHCH 2NBoc), 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 (CH2 CH=CH2), 116.2, 115.9 (rotamers, 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.


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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 anhydrous 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 chromatography 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 × CH 2NBoc) 3.58–3.27 (m, 4 H, 2 × CH 2NBoc), 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.


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


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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 atmosphere. 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.


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2·2 CF3CO2H

To a solution of this N-Boc-bipiperidine (100 mg, 0.27 mmol) in anhydrous 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 remaining starting material. The mixture was diluted with toluene (11 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, 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 (CH2 CH2).

MS (CI+): m/z = 169 [M + H]+.

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


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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 anhydrous 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 toluene (17 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=CHCH 2NH), 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.


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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 × 10 mL) and brine (3 × 15 mL). The organic layer was dried (Na2SO4) and the solvents were removed in vacuo to give the crude product, which was purified 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 × CH 2CH=CH2), 3.56 (m, 4 H, 2 × CH 2OAllyl), 3.21 (m, 2 H, CHCH2OAllyl).

13C NMR (100 MHz, CDCl3): δ = 138.56 (CH=CH), 135.0 (CH2 CH=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.


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

The title compound was prepared according to the procedure described 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=CHCH 2O), 3.85 (AB part of ABX system, 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.


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Octahydro-2H,2′H-3,3'-bipyran (4)

The title compound was prepared according to the procedure described for compound 2, starting from the unsaturated bicyclic derivative 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-CH 2CH2), 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 (CH2 CH2).

HRMS (CI+): m/z [M + H]+ calcd for C10H19O2 [M + H]+: 171.1380; found: 171.1381.


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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

    for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/products/ejournals/journal/ 10.1055/s-00000084.
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Zoom Image
Figure 1 2,2′-Bipiperidine (1) and target heterocyclic compounds 2–5
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Scheme 1 Retrosynthesis of the target heterocyclic compounds 2–5
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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%.
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Scheme 3 Reagents and conditions: (i) 1,1′-(azodicarbonyl)dipiperidine (ADDP) or diisopropyl azodicarboxylate (DIAD), Ph3P, 14 or 15, THF or toluene.
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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%.