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Synthesis 2013; 45(13): 1863-1869
DOI: 10.1055/s-0033-1338706
paper
© Georg Thieme Verlag Stuttgart · New York

Synthesis of (+)-Febrifugine and a Formal Synthesis of (+)-Halofuginone Employing an Organocatalytic Direct Vinylogous Aldol Reaction

Sunil V. Pansare*
Department of Chemistry, Memorial University, St. John’s, NL, A1B 3X7, Canada   Fax: +91(709)8643702   Email: spansare@mun.ca
,
Eldho K. Paul
Department of Chemistry, Memorial University, St. John’s, NL, A1B 3X7, Canada   Fax: +91(709)8643702   Email: spansare@mun.ca
› Author Affiliations
Further Information

Publication History

Received: 19 February 2013

Accepted after revision: 14 April 2013

Publication Date:
08 May 2013 (online)

 
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Dedicated to Professor Scott E. Denmark on the occasion of his 60th birthday

Abstract

The enantioselective organocatalytic direct vinylogous aldol reaction of γ-crotonolactone and a suitable aldehyde was utilized in the synthesis of a functionalized γ-butenolide. The γ-butenolide (aldol product) was stereoselectively converted into a 5-aminoalkyl butyrolactone, which isomerized to the key 2,3-disubstituted piperidinone, a common intermediate to (+)-febrifugine and (+)-halofuginone.


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Key words

asymmetric catalysis - aldol reaction - stereoselective synthesis - piperidines - total synthesis

The prevalence of malaria in tropical regions and the need for new medicines to combat malaria have resulted in a persistent, and often challenging, search for new antimalarial agents.[1] In this context, febrifugine (1, Figure [1]) and halofuginone (2) have attracted considerable interest due to their pronounced antimalarial activity.[2] In solution, febrifugine (1) is gradually converted to isofebrifugine (3) which is less potent, but exhibits antimalarial activity similar to febrifugine.[2d] The asymmetric synthesis of febrifugine[3] continues to be actively investigated and the reported syntheses often showcase new methodology for stereoselective construction of the 2,3-disubstituted piperidine ring in the targets. Only two asymmetric syntheses of halofuginone[3a] [4] are reported. Febrifugine and halofuginone also have numerous other applications, which have contributed to a continued interest in these alkaloids. Notably, in addition to its antimalarial properties, halofuginone is used as an antiprotozoal agent in poultry[5] and also as an antiangiogenic agent.[6] It has been approved for the treatment of scleroderma and is active against estrogen-deficient osteoporosis in mice.[7] Recently, the molecular mechanism of action of febrifugine and halofuginone in mice has been determined.[8] These studies have highlighted the importance of structural analogues of febrifugine in the treatment of multiple sclerosis, scleroderma, and rheumatoid arthritis. Hence, an important consideration in devising a synthesis of the title compounds is the flexibility of the approach for making analogues of febrifugine.

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Figure 1 (+)-Febrifugine (1), (+)-halofuginone (2) and isofebrifugine (3)

Accordingly, we decided to develop a synthesis of febrifugine (1) that would proceed through a precursor that could also be converted into halofuginone and, potentially, other heteroaryl-linked piperidines by simple coupling with a suitable heterocycle. Retrosynthetically, the common precursor to 1 or 2 is a suitably protected piperidinyl bromoketone[3j] such as A (Scheme [1]), which derives from the functionalized piperidinone B. The piperidinone B can be obtained by isomerization[9] of an aminoalkyl lactone such as C. Ultimately, C derives from the functionalized butenolide D, which leads us to the organocatalytic direct vinylogous aldol reaction[10] of crotonolactone and an appropriate aldehyde. The vinylogous aldol reaction[11] directly sets the absolute stereochemistry at C-3 in the piperidine ring of the target. The stereochemistry at C-2 is indirectly controlled by the aldol reaction and is achieved by manipulation of the secondary alcohol stereocenter in the aldol adduct (Scheme [1]).

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Scheme 1

Our investigations began with the synthesis of 6 (Scheme [2]). Initially, the direct vinylogous aldol reaction of commercially available γ-crotonolactone and the aldehyde 4 [12] was examined in the presence of selected cyclohexanediamine, stilbenediamine, and cinchonidine derived thioureas[13] (5a, 5b, 5c) and cyclohexanediamine and stilbenediamine derived squaramides[14] (5d and 5e, Figure [2]).

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Scheme 2
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Figure 2 Selected aminothiourea and aminosquaramide catalysts

Table 1 Optimization of the Vinylogous Aldol Reaction of Crotonolactone and Aldehyde 4

Entrya

Cat.b

Solvent

Time (h)

Yield (%)

drc (anti/syn)

eed (%) anti

 1

5a

CH2Cl2

 24

59

1.1:1

–55

 2

5a

toluene

 24

68

1:1

–18

 3

5a

EtOAc

 24

31

1.1:1

–58

 4

5a

DMF

 24

12

1:1

–30

 5

5a

CH2Cl2

144e

 8

4.2:1

–62

 6

5b

CH2Cl2

144

 2

–

–61

 7

5b

EtOAc

144

 0

–

–

 8

5b

toluene

144

 0

–

–

 9

5c

CH2Cl2

 48

13

1.5:1

–74

10

5d

CH2Cl2

 48

31

1.9:1

–90

11

5d

CH2Cl2

144e

16

2.2:1

–93

12

5d

EtOAc

 48

20

1.6:1

–88

13

5d

toluene

 48

39

1.5:1

–88

14

5e

EtOAc

120

18

2.4:1

 95

15

5e

CH2Cl2

192

74

8:1

 91

16

5e

toluene

120

27

2.9:1

 90

a Crotonolactone used: 2 equiv.

b Catalyst: 20 mol%.

c Based on 1H NMR of crude products.

d Based on chiral HPLC analysis; negative ee values indicate formation of the enantiomer of 6.

e Reaction at 0 °C.

Orienting experiments with the catalyst 5a suggested dichloromethane as a solvent for further studies based on the yield and enantiomeric excess of 6 (Table [1], entries 1–4). Although lowering the temperature (0 °C), increased the diastereoselectivity and enantiomeric excess for 6, the reaction was prohibitively slow (Table [1], entry 5, 8% yield of 6). The stilbenediamine-derived aminothiourea 5b was ineffective as a catalyst and provided only a trace of 6 in dichloromethane (entries 6–8). Catalyst 5c provided 6 in low yield and moderate enantiomeric excess (entry 9). Reactions with the aminosquaramide catalysts 5d and 5e were slower, but provided 6 with higher enantiomeric excess (entries 10–16) than the aminothiourea catalysts 5a–c. For catalyst 5d, the use of dichloromethane as the solvent provided the highest enantiomeric excess (entries 10–12), but the yield and diastereostelectivity for 6 remained low. Further studies with the aminosquaramide catalyst 5e [14a] in ethyl acetate provided 6 with good enantiomeric excess (entry 14, 95%) but low diastereoselectivity and yield. In comparison, the reaction with 5e was synthetically more useful when dichloromethane was used as the solvent (entries 14–16). Thus the direct vinylogous aldol reaction of γ-crotonolactone with the aldehyde 4 using 5e as the catalyst provided the butenolide 6 in good yield and diastereoselectivity (entry 15, 74%, anti/syn = 8:1) and excellent enantiomeric excess (er = 19:1 for the anti-diastereomer) when the reaction was conducted in dichloromethane[15] (Scheme [2]). Following the planned synthetic strategy (Scheme [1]), it may be noted that the 2,3-trans substitution in the target piperidine can be obtained only from the anti-diastereomer of the corresponding amino butyrolactone (Scheme [1, ] C). Since our approach to this amino lactone would involve an invertive amination of the precursor alcohol, a switch of the aldol product stereochemistry from the anti- to the syn-isomer is required. For this, 6 was first hydrogenated and then Mitsunobu inversion of the secondary alcohol was examined under a variety of conditions. These attempts invariably lead to complex mixtures and hence an alternate strategy for alcohol inversion became necessary. Accordingly, the alcohol was first oxidized to provide the ketolactone 7. Reduction of 7 with K-Selectride® gave syn-8 (70%) with good diastereoselectivity (syn/anti = 16:1, presumably via the Felkin–Anh mode,[16] Scheme [2]).[17]

The lactone 8 was readily converted into the azido lactone 9 (mesylation and azidation with inversion) with the required anti stereochemistry (anti/syn = 16:1). Reduction of the azide (H2, Pd/C) generated a mixture of the corresponding amino butyrolactone and the required piperidone 10, obtained from the intramolecular N-acylation of the amino lactone. Notably, hydrogenation of 9 in the presence K2CO3 significantly facilitated this rearrangement to directly provide 10 (80% from 8) without any residual amino lactone. Reduction of the lactam in 10 provided the corresponding piperidine, which was isolated as a single diastereomer, presumably due to enrichment of the trans-isomer during the reduction and isolation. N-Protection of the piperidine provided 11, which was benzylated to provide the key intermediate 12 (71% from 10, Scheme [3]).

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Scheme 3

With the piperidine 12 in hand, the final steps of the synthesis were initiated (Scheme [4]). The ketone in 12 was unmasked by treatment of the ketal with iodine in acetone to provide 13. Comparison of the spectral data of 13 with reported values[3a] [i] confirmed the trans orientation of the substituents on the piperidine ring. This also confirms the initial stereochemical assignments for 6. Bromination of the ketone in 13 was achieved by the procedure reported by Honda (TMSOTf, DBU then NBS)[3i] and the crude bromoketone was reacted with 4-hydrazoquinazoline to provide the protected febrifugine derivative 14. Deprotection of 14 (aq 6 M HCl) and subsequent neutralization provided (+)-febrifugine (1) ([α]D 23 +17.7 (c 0.6, EtOH) {Lit.[3a] [α]D 25 +14.6 (c 1.0, EtOH), 86% ee}.

Zoom Image
Scheme 4

In conclusion, a stereoselective synthesis of (+)-febrifugine (1, 14 steps, 6.8% overall yield) was achieved by employing an organocatalytic asymmetric direct vinylogous aldol reaction of γ-crotonolactone and the isomerization of a 2-aminoalkyl furanone to the 2,3-disubstituted piperidine core of the target as the key steps. Since the bromoketone obtained from 13 can be converted into (+)-halofuginone by coupling with 7-bromo-6-chloro-4-hydroxyquinazoline,[3a] the present study also constitutes a formal synthesis of (+)-halofuginone.

All commercially available reagents were used without purification. All reactions requiring anhyd conditions were performed under an atmosphere of dry N2 using oven-dried glassware. CH2Cl2 and THF were distilled from CaH2 and sodium/benzophenone, respectively. Commercial precoated silica gel plates were used for TLC. Silica gel for column chromatography was 230–400 mesh. All melting points are uncorrected. Optical rotations were measured at the sodium D line on a digital polarimeter at r.t.


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(S)-5-[(R)-1-Hydroxy-2-(2-methyl-1,3-dioxolan-2-yl)ethyl]furan-2(5H)-one (6)

A mixture of the catalyst 5e (20 mol%, 1.17 g), the aldehyde 4 (1.4 g, 10.75 mmol), and 2-(5H)-furanone (1.5 mL, 21.5 mmol) in CH2Cl2 (10 mL) was stirred for 192 h at r.t. The mixture was diluted with EtOAc (100 mL), filtered, and the filtrate was concentrated. The residue was purified by flash chromatography (CH2Cl2–EtOAc­, 10:1) to provide 1.73 g (74%) of 6 as a pale yellow solid (anti/syn = 8:1 as determined by 1H NMR analysis of the crude product); Rf = 0.30 (EtOAc–hexanes, 4:1); ee: 90% (anti).

HPLC: Chiralpak AS-H, hexanes–propan-2-ol (92:8), 210 nm, anti-6: t R = 42.4 min (minor), 76.7 min (major); syn-6: t R = 57.9 min (major), 83.1 min (minor). In repeated runs anti-6 was obtained in 89–93% ee.

IR (neat): 3467, 2988, 2889, 1795, 1748, 1378, 1163, 1104, 1034, 826 cm–1.

1H NMR (500 MHz, CDCl3): δ (anti) = 7.67–7.66 (dd, J = 5.8, 1.5 Hz, 1 H), 6.18–6.17 (dd, J = 5.8, 1.9 Hz, 1 H), 4.86–4.84 (dt, J = 7.0, 1.7 Hz, 1 H), 4.04–3.99 (m, 4 H), 3.90–3.86 (ddd, J = 10.1, 7.0, 2.0 Hz, 1 H), 3.83 (s, 1 H), 2.19–2.16 (dd, J = 14.6, 1.9 Hz, 1 H), 1.95–1.89 (m, 1 H), 1.37 (s, 3 H); δ (syn) = 7.53–7.51 (dd, J = 5.7, 1.5 Hz, 1 H), 6.19 (part of dd, 1 H), 5.04–5.02 (m, 1 H), 4.28–4.25 (m, 1 H).

13C NMR (75 MHz, CDCl3): δ (anti) = 172.8, 154.9, 122.1, 110.0, 85.2, 69.6, 64.7, 64.3, 41.4, 24.1; δ (syn) = 172.9, 153.8, 122.7, 109.8, 84.9, 67.4, 64.8, 64.3, 40.1, 24.0.

MS (APCI, +): m/z = 215.1 (M + 1).

HRMS (CI): m/z (M + H) calcd for C10H15O5: 215.0919; found: 215.0915.


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(S)-5-[(S)-1-Hydroxy-2-(2-methyl-1,3-dioxolan-2-yl)ethyl]dihydrofuran-2(3H)-one (7)

Pd/C (10%, 340 mg) was added to a stirred solution of 6 (1.7 g, 7.93 mmol) in MeOH (80 mL). The mixture was stirred for 16 h at r.t. under a balloon filled with H2 and then filtered through a pad of Celite. The filter cake was washed with MeOH (2 × 30 mL) and the combined filtrates were concentrated under reduced pressure to provide 1.7 g (99%) of (S)-dihydro-5-[(R)-1-hydroxy-2-(2-methyl-1,3-dioxolan-2-yl)ethyl]furan-2(3H)-one as a white solid (anti/syn = 8:1); Rf = 0.30 (EtOAc–hexanes, 3:2).This was pure (1H NMR) and was directly used in the next step.


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(S)-Dihydro-5-[(R)-1-hydroxy-2-(2-methyl-1,3-dioxolan-2-yl)ethyl]furan-2(3H)-one

IR (neat): 3500, 2985, 2892, 1770, 1658, 1567, 1549, 1459, 1377, 1278, 1190, 1171, 1119, 1027, 996 cm–1.

1H NMR (500 MHz, CDCl3): δ (anti) = 4.37–4.32 (m, 1 H), 4.06–3.99 (m, 5 H), 3.58 (br s, 1 H), 2.62–2.57 (ddd, J = 17.8, 9.4, 6.4 Hz, 1 H), 2.53–2.48 (m, 1 H), 2.28–2.23 (m, 1 H), 2.04–1.98 (dd, J = 14.6, 2.0 Hz, 1 H), 1.83–1.78 (dd, J = 14.6, 10.0 Hz, 1 H), 1.38 (s, 3 H); δ (syn) = 4.43–4.40 (m, 1 H), 2.68–2.64 (m, 1 H), 2.46–2.45 (m, 1 H), 2.11–2.04 (dd, J = 14.9, 10.5 Hz, 1 H), 1.88–1.85 (dd, J = 14.8, 1.8 Hz, 1 H), 1.37 (s, 3 H).

13C NMR (75 MHz, CDCl3): δ (anti) = 177.2, 110.0, 82.3, 69.1, 64.8, 64.3, 40.9, 28.3, 24.2, 22.8; δ (syn) = 177.9, 109.9, 82.4, 69.8, 68.5, 64.8, 40.8, 28.3, 24.0, 23.9.

MS (APCI, +): m/z = 217.1 (M + 1).

HRMS (CI): m/z (M + H) calcd for C10H17O5: 217.1076; found: 217.1072.

To a solution of the above alcohol (900 mg, 4.16 mmol) in CH2Cl2 (30 mL) was added Dess–Martin periodinane (3.53 g, 8.32 mmol) and the mixture was stirred at r.t. for 16 h. Sat. aq NaHCO3 (30 mL) was added, the organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2 × 30 mL). The combined organic layers were washed with brine (30 mL), dried (Na2SO4), and concentrated. The residue was purified by flash chromatography (hexanes–EtOAc, 1:1) to provide 714 mg (80%) of 7 as a pale yellow liquid; Rf = 0.30 (EtOAc–hexanes, 1:1); [α]D 23 +18.8 (c 0.92, CHCl3).


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7

IR (neat): 2996, 2893, 1769, 1718, 1373, 1252, 1153, 1043, 995, 947, 874 cm–1.

1H NMR (500 MHz, CDCl3): δ = 4.91–4.88 (m, 1 H), 3.99–3.95 (m, 4 H), 3.09 (d, J = 13.4 Hz, 1 H), 2.88 (d, J = 13.4 Hz, 1 H), 2.55–2.45 (m, 3 H), 2.38–2.33 (m, 1 H), 1.44 (s, 3 H).

13C NMR (75 MHz, CDCl3): δ = 205.0, 176.3, 108.0, 82.2, 64.8, 64.7, 47.5, 27.3, 24.7, 24.2.

MS (APCI, +): m/z = 215.1 (M + 1).

HRMS (CI): m/z calcd for C10H14O5: 214.0841; found: 214.0808.


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(S)-5-[(S)-1-Hydroxy-2-(2-methyl-1,3-dioxolan-2-yl)ethyl)furan-2(5H)-one (8)

K-Selectride® (1.0 M soln in THF, 2.8 mL, 2.8 mmol) was added to a stirred solution of the ketone 7 (400 mg, 1.86 mmol) in THF (2 mL) at –78 °C and the mixture was stirred at –78 °C for 1 h. Sat. aq NH4Cl (15 mL) was added followed by EtOAc (20 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were dried (Na2SO4), and concentrated. The residue was purified by flash chromatography (hexanes–EtOAc, 1:1) to provide 283 mg (70%) of 8 as a colorless liquid (syn/anti = 16:1); Rf = 0.30 (EtOAc–hexanes, 3:2).

IR (neat): 3498, 2986, 2960, 2933, 2890, 1765, 1378, 1260, 1167, 1110, 1038, 913, 845 cm–1.

1H NMR (500 MHz, CDCl3): δ (syn) = 4.44–4.39 (m, 1 H), 4.02–4.01 (m, 4 H), 4.00–3.95 (m, 1 H), 3.57 (br s, 1 H), 2.74–2.63 (m, 1 H), 2.50–2.39 (m, 1 H), 2.31–2.25 (m, 2 H), 2.15–2.02 (m, 1 H), 1.89–1.84 (dd, J = 14.8, 1.8 Hz, 1 H), 1.38 (s, 3 H); δ (anti) = 4.43–4.40 (m, 1 H), 2.68–2.64 (m, 1 H), 1.88–1.85 (dd, J = 14.6, 2.0 Hz, 1 H), 1.37 (s, 3 H).

13C NMR (75 MHz, CDCl3): δ (syn) = 177.9, 109.9, 82.4, 69.8, 64.8, 64.3, 40.8, 28.3, 24.1, 23.9; δ (anti) = 177.2, 110.0, 82.2, 69.1, 64.8, 40.9, 28.3, 24.2, 22.8.

MS (APCI, +): m/z = 217.1 (M + 1).

HRMS (CI): m/z (M + H) calcd for C10H17O5: 217.1076; found: 217.1072.


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(S)-5-[(R)-1-Azido-2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-dihydrofuran-2(3H)-one (9)

To a solution of 8 (600 mg, 2.77 mmol) in CH2Cl2 (10 mL) at 0 °C under N2 was added Et3N (463 μL, 3.32 mmol) followed by MsCl (259 μL, 3.32 mmol). The mixture was stirred for 1 h at 0 °C and H2O (20 mL) was added at 0 °C. The mixture was extracted with CH2Cl2 (2 × 20 mL). The combined organic layers were dried (Na2SO4) and concentrated to provide 810 mg (99%) of the mesylate as a yellow oil. This was used immediately in the next step without purification. NaN3 (822 mg, 12.6 mmol) was added to a solution of the crude mesylate (744 mg, 2.53 mmol) in DMF (8 mL) and the mixture was stirred at 80 °C for 96 h under N2. The mixture was cooled to r.t. and EtOAc (30 mL) was added followed by H2O (30 mL). The resulting biphase was separated and the aqueous layer was extracted with EtOAc (2 × 30 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated to provide 610 mg (quant) of 9 as a yellow oil (anti/syn = 16:1). This was pure (1H NMR) and was directly used in the next step. An analytical sample (anti/syn = 25:1) was obtained by flash column chromatography on silica gel (hexanes–EtOAc, 7:3); Rf = 0.50 (EtOAc–hexanes, 3:2).

IR (neat): 2987, 2959, 2923, 2852, 2108, 1772, 1462, 1378, 1255, 1186, 1144, 1029, 948 cm–1.

1H NMR (500 MHz, CDCl3): δ (anti) = 4.56–4.52 (m, 1 H), 4.04–3.96 (m, 4 H), 3.94–3.91 (m, 1 H), 2.66–2.60 (ddd, J = 17.9, 10.2, 5.5 Hz, 1 H), 2.55–2.48 (m, 1 H), 2.27–2.19 (m, 1 H), 2.15–2.07 (m, 1 H), 1.96–1.91 (dd, J = 14.9, 7.3 Hz, 1 H), 1.90–1.86 (dd, J = 14.9, 4.5 Hz, 1 H), 1.37 (s, 3 H); δ (syn) = 4.60–4.57 (m, 1 H), 3.58–3.54 (m, 1 H), 1.39 (s, 3 H).

13C NMR (75 MHz, CDCl3): δ (anti) = 176.5, 108.1, 80.9, 64.7, 64.5, 60.5, 39.3, 28.2, 24.3, 22.2; δ (syn) = 176.4, 108.2, 81.8, 64.64, 64.61, 60.5, 39.2, 28.1, 24.5, 22.4.

MS (CI, +): m/z = 242.1 (M + 1).

HRMS (APCI, +): m/z calcd (M + H) for C10H16N3O4: 242.1141; found: 242.1145.


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(5S,6R)-5-Hydroxy-6-[(2-methyl-1,3-dioxolan-2-yl)methyl]piperidin-2-one (10)

To a stirred solution of the azide 9 (281 mg, 1.16 mmol) in MeOH (5 mL) at r.t. was added K2CO3 (56 mg, 20%) followed by 10% Pd/C (56 mg). The mixture was stirred for 16 h at r.t. under a balloon filled with H2 and then filtered through a pad of Celite. The filter cake was washed with MeOH (2 × 20 mL) and the combined filtrates were concentrated under reduced pressure to provide a yellow gum. This was purified by flash chromatography on silica gel (CH2Cl2–MeOH, 19:1) to provide 200 mg (80%) of 10 as a white solid (trans/cis = 17:1). The overall yield of 10 (from 8) is 80%; Rf = 0.25 (CH2Cl2–MeOH, 4:1).

IR (neat): 3352, 3229, 1633, 1464, 1420, 1384, 1255, 1215, 1173, 1129, 1064, 1029, 988, 947, 902, 855 cm–1.

1H NMR (500 MHz, CDCl3): δ (trans) = 6.63 (br s, 1 H), 4.01–3.97 (m, 4 H), 3.56 (br t, J = 9.5 Hz, 1 H), 3.43–3.39 (m, 1 H), 2.86 (br s, 1 H), 2.52–2.46 (ddd, J = 18.0, 6.2, 3.4 Hz, 1 H), 2.41–2.34 (ddd, J = 17.9, 11.4, 6.4 Hz, 1 H), 2.33–2.30 (dd, J = 14.5, 2.1 Hz, 1 H), 2.08–2.03 (m, 1 H), 1.89–1.83 (m, 1 H), 1.75–1.70 (dd, J = 14.5, 9.8 Hz, 1 H), 1.35 (s, 3 H); δ (cis) = 6.47 (s, 1 H), 3.67–3.64 (m, 1 H), 2.01–1.99 (m, 1 H).

13C NMR (75 MHz, CDCl3): δ (trans) = 170.9, 109.7, 68.9, 64.7, 64.3, 55.5, 41.8, 29.1, 29.0, 24.0; δ (cis) = 171.5, 109.4, 65.7, 64.6, 53.1, 40.5, 27.6, 25.8, 24.2.

MS (APCI, +): m/z = 216.1 (M + 1).

HRMS (CI): m/z (M + H) calcd for C10H18NO4: 216.1236; found: 216.1235.


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Benzyl (2R,3S)-3-Hydroxy-2-[(2-methyl-1,3-dioxolan-2-yl)methyl]piperidine-1-carboxylate (11)

To a stirred suspension of LiAlH4 (101 mg, 2.66 mmol) in THF (5 mL) was added 10 (190 mg, 0.88 mmol) dissolved in THF (5 mL) and the mixture was heated to reflux for 24 h. The mixture was cooled to 0 °C, H2O (0.5 mL) was added slowly, and the mixture was stirred for 20 min at r.t. Na2SO4 (1 g) was added to the mixture and it was stirred for 10 min. The mixture was then filtered through a pad of Celite. The filter cake was washed with EtOAc (3 × 20 mL) and the combined filtrates were concentrated under reduced pressure to provide 160 mg (90%) of (2R,3S)-2-[(2-methyl-1,3-dioxolan-2-yl)methyl]piperidin-3-ol as a white solid; mp 108–111 °C; Rf  = 0.30 (CH2Cl2–MeOH, 4:1). This was exclusively the trans-dia­stereomer (500 MHz 1H NMR) and was used in the next step without purification.


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(2R,3S)-2-[(2-Methyl-1,3-dioxolan-2-yl)methyl]piperidin-3-ol

IR (neat): 3316, 3122, 2928, 2862, 2824, 1439, 1374, 1252, 1117, 1086, 1036, 958 cm–1.

1H NMR (500 MHz, CDCl3): δ = 4.01–3.96 (m, 4 H), 3.22–3.18 (ddd, J = 13.1, 8.7, 4.4 Hz, 1 H), 2.96–2.92 (m, 1 H), 2.56–2.53 (td, J = 11.8, 2.7 Hz, 1 H), 2.52–2.46 (ddd, J = 11.0, 7.3, 3.7 Hz, 1 H), 2.24–2.21 (dd, J = 14.8, 3.7 Hz, 1 H), 2.09–2.04 (m, 1 H), 1.74–1.69 (dd, J = 14.8, 7.2 Hz, 1 H), 1.68–1.66 (m, 1 H), 1.54–1.50 (m, 1 H), 1.38 (s, 3 H), 1.35–1.27 (m, 1 H).

13C NMR (75 MHz, CDCl3): δ = 110.1, 72.2, 64.6, 64.4, 59.9, 46.1, 42.2, 34.2, 25.4, 24.1.

MS (APCI, +): m/z = 202.1 (M + 1).

HRMS (CI): m/z (M – H) calcd for C10H18NO3: 200.1287; found: 200.1287. m/z (M + H) calcd for C10H20NO3: 202.1443; found: 202.1444.

To a solution of the above amino alcohol (160 mg, 0.79 mmol) in CH2Cl2 (10 mL) were added benzyl chloroformate (113 μL, 0.79 mmol), and Et3N (133 μL, 0.95 mmol) at 0 °C. The solution was stirred at r.t. for 16 h, H2O (10 mL) was added and the resulting mixture was extracted with CH2Cl2 (2 × 20 mL). The combined organic layers were dried (Na2SO4) and concentrated. Purification of the residue by flash chromatography on silica gel (hexanes–EtOAc, 2:3) provided 243 mg (91%) of 11 as a colorless oil; Rf = 0.30 (EtOAc­–hexanes, 3:2); [α]D 23 –20.9 (c 0.38, CHCl3).


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11

IR (neat): 3467, 2940, 2880, 1672, 1428, 1352, 1257, 1153, 1117, 1077, 1033, 983 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.38–7.28 (m, 5 H), 5.15 (s, 2 H), 4.49 (br s, 1 H), 4.07 (br s, 1 H), 3.90–3.88 (br m, 5 H), 2.89 (br m, 1 H), 1.98–1.83 (m, 2 H), 1.82–1.77 (dd, J = 14.6, 6.1 Hz, 1 H), 1.74–1.68 (m, 3 H), 1.45–1.35 (br m, 1 H), 1.32 (br s, 3 H).

13C NMR (75 MHz, CDCl3): δ = 156.3, 136.9, 128.4, 127.9, 127.8, 109.0, 68.2, 67.2, 64.54, 64.50, 54.0, 39.1, 38.2, 25.7, 23.9, 19.1.

MS (APCI, +): m/z = 336.2 (M + 1).

HRMS (CI): m/z (M + H) calcd for C18H26NO5: 336.1811; found: 336.1813.


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Benzyl (2R,3S)-3-(Benzyloxy)-2-[(2-methyl-1,3-dioxolan-2-yl)methyl]piperidine-1-carboxylate (12)

To a solution of the carbamate 11 (80 mg, 0.24 mmol) in THF (3 mL) under N2 at r.t. was added KH (30% dispersion in mineral oil, 32 mg, 0.24 mmol) followed by benzyl bromide (29 μL, 0.24 mmol) at r.t. The mixture was stirred at r.t. for 2 h, cooled to 0 °C, and H2O (5 mL) was added. The resulting mixture was extracted with EtOAc­ (2 × 10 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on silica gel (hexanes–EtOAc, 1:1) to give 87 mg (86%) of 12 as a colorless oil; Rf = 0.60 (EtOAc–hexanes, 1:1); [α]D 23 –12.4 (c 0.48, CHCl3).

IR (neat): 2930, 2881, 1692, 1423, 1351, 1255, 1200, 1157, 1090, 1045, 1025, 946 cm–1.

1H NMR (500 MHz, CDCl3): δ (major rotamer) = 7.34–7.24 (m, 10 H), 5.11–5.07 (AB system, J = 12.4 Hz, 2 H), 4.69 (t, J = 5.6 Hz, 1 H), 4.54 (d, J = 12.2 Hz, 1 H), 4.43 (d, J = 12.2 Hz, 1 H), 4.18–4.15 (dd, J = 13.5, 3.5 Hz, 1 H), 3.91–3.82 (m, 3 H), 3.74–3.72 (m, 1 H), 3.50–3.46 (m, 1 H), 2.88–2.82 (td, J = 13.5, 2.9 Hz, 1 H), 2.04–1.82 (m, 3 H), 1.78–1.73 (m, 1 H), 1.70–1.62 (m, 2 H), 1.25 (s, 3 H); δ (minor rotamer) = 5.19–5.14 (AB system, J = 12.6 Hz, 2 H), 4.88 (t, J = 5.8 Hz, 1 H), 4.73 (d, J = 12.0 Hz, 1 H), 4.47 (d, J = 12.0 Hz, 1 H), 4.07–4.04 (dd, J = 13.4, 3.4 Hz, 1 H), 3.54–3.52 (m, 1 H), 2.92–2.89 (td, J = 13.6, 2.8 Hz, 1 H), 1.36 (s, 3 H).

13C NMR (75 MHz, CDCl3): δ (major rotamer) = 155.9, 138.9, 137.0, 128.3, 128.2 (2 C), 127.9, 127.7, 127.1, 109.1, 74.5, 69.8, 67.1, 64.5, 64.4, 49.8, 39.1, 38.4, 24.1, 24.0, 19.6; δ (minor rotamer) = 155.7, 137.3, 128.4, 127.7, 127.6, 127.3, 109.2, 75.7, 70.1, 66.8, 64.6, 64.4, 48.9, 39.2, 38.0, 24.6, 24.0, 19.9.

MS (APCI, +): m/z = 426.2 (M + 1).

HRMS (CI): m/z (M + H) calcd for C25H32NO5: 426.2280; found: 426.2284.


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Benzyl (2R,3S)-3-(Benzyloxy)-2-(2-oxopropyl)piperidine-1-carboxylate (13)

To a solution of 12 (64 mg, 0.15 mmol) in acetone (2 mL) was added a solution of I2 (1.0 mg, 7.8 × 10–2 mmol, 5 mol%) in acetone (1 mL) at r.t. The solution was stirred at r.t. for 30 min and then concentrated. The residue was dissolved in CH2Cl2 (10 mL) and aq 5% Na2S2O3 (5 mL) was added. The biphase was stirred vigorously for a few minutes and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (2 × 10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel (hexanes–EtOAc, 7:3) to provide 48 mg (84%) of 13 as a colorless oil; Rf = 0.25 (hexanes–EtOAc, 7:3); [α]D 23 –29.2 (c 1.0, CHCl3) {Lit.[3a] [α]D 25 –26.8 (c 1.0, CHCl3) with 86% ee[3a]}.

IR (neat): 2943, 2866, 1689, 1422, 1355, 1254, 1200, 1132, 1050, 959, 737, 697 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.32–7.25 (m, 10 H), 5.15–5.09 (AB system, J = 12.5 Hz, 2 H), 5.01 (br s, 1 H), 4.65 (br s, 1 H), 4.51 (d, J = 12.0 Hz, 1 H), 4.13 (br s, 1 H), 3.44 (br s, 1 H), 2.84 (br s, 1 H), 2.69–2.58 (m, 2 H), 2.11 (br s, 3 H), 1.94–1.85 (m, 2 H), 1.65–1.59 (m, 1 H), 1.40 (br d, J = 11.8 Hz, 1 H).

13C NMR (75 MHz, CDCl3): δ = 205.9, 155.9, 138.6, 136.8, 128.4, 128.3, 127.9, 127.8, 127.5, 127.4, 73.3, 70.2, 67.2, 49.7, 43.7, 39.5, 30.0, 24.4, 19.5.

HRMS (CI): m/z (M + H) calcd for C23H28NO4: 382.2018; found: 382.2021.

The 1H NMR and 13C NMR data are in agreement with reported data­.[3a] [i] See the Supporting Information for a detailed comparison.


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(2R,3S)-3-Benzyloxy-2-[2-oxoquinazolin-3(4H)-yl)propyl]piperidine-1-carbamic Acid Benzyl Ester (14)

Bromination[3i] of 13 and coupling of the bromide with 4-hydroxyquinazoline according to the literature procedure[3g] provided 14 (47%) as a colorless liquid; Rf = 0.30 (EtOAc); [α]D 23 –24.8 (c 1.7, CHCl3) {Lit.[3m] [α]D 25 –22.0 (c 1.0, CHCl3)}.

IR (neat): 1726, 1674, 1610, 1424, 1358, 1257, 1085, 1049, 910 cm–1.

1H NMR (500 MHz, CDCl3): δ = 8.28–8.26 (dd, J = 8.0, 1.5 Hz, 1 H), 7.92 (br s, 1 H), 7.79–7.73 (m, 2 H), 7.52–7.49 (m, 1 H), 7.32–7.26 (m, 10 H), 5.18–5.15 (d, J = 12.4 Hz, 1 H), 5.11–5.09 (d, J = 12.4 Hz, 1 H), 5.01–4.98 (m, 1 H), 4.94 (br s, 1 H), 4.65–4.63 (m, 1 H), 4.54–4.52 (br d, J = 11.9 Hz, 1 H), 4.06 (br s, 1 H), 3.52 (br s, 1 H), 2.97 (br s, 1 H), 2.88–2.83 (dd, J = 14.7, 8.7 Hz, 1 H), 2.80–2.76 (br dd, J = 14.7, 6.1 Hz, 1 H), 1.94–1.88 (br m, 2 H), 1.75 (br s, 1 H), 1.70–1.63 (m, 1 H), 1.45–1.43 (app br d, J = 12.5 Hz, 1 H).

13C NMR (75 MHz, CDCl3): δ = 200.0, 160.9, 156.2, 148.2, 146.5, 138.3, 136.5, 134.5, 128.5, 128.4, 128.0, 127.8, 127.7, 127.6, 127.5, 127.3, 126.7, 121.8, 73.7, 70.4, 67.4, 53.9, 50.6, 41.0, 39.6, 24.3, 19.4.

MS (APCI, +): m/z = 526.2 (M + 1).

HRMS (EI+): m/z (M + H) calcd for C31H31N3O5: 525.2264; found: 525.2285.

Spectroscopic data (IR, 1H NMR, 13C NMR) and optical rotation for 14 are in agreement with the reported data.[3a] [m]


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3-{3-[(2R,3S)-3-Hydroxypiperidin-2-yl]-2-oxopropyl}quinazolin-4(3H)-one [(+)-Febrifugine, 1]

Acid hydrolysis of 14 and purification of the crude product according to the literature procedure[3a] provided (+)-1 (75%); amorphous white solid; mp 133–136 °C; (Lit.[3a] mp 135–138 °C); Rf = 0.20 (CH2Cl2–MeOH–Et3N, 9.00:0.95:0.05); [α]D 23 +17.7 (c 0.6, EtOH) {Lit.[3a] [α]D 25 +14.6 (c 1.0, EtOH)}.

IR (neat): 3306, 3052, 2926, 2851, 2687, 1726, 1669, 1607, 1468, 1361, 1325, 1078, 997 cm–1.

1H NMR (300 MHz, CDCl3): δ = 8.27 (d, J = 7.9 Hz, 1 H), 7.91 (s, 1 H), 7.78–7.71 (m, 2 H), 7.54–7.48 (m, 1 H), 4.93–4.80 (AB system, J = 17.5 Hz, 2 H), 3.30–3.26 (m, 1 H), 3.11 (dd, J = 16.0, 4.5 Hz, 1 H), 2.96 (d, J = 11.9 Hz, 1 H), 2.88–2.87 (m, 1 H), 2.64 (dd, J = 16.1, 7.5 Hz, 1 H), 2.58 (dt, J = 12.2, 3.0 Hz, 1 H), 2.22 (br s, 2 H), 2.10–2.06 (m, 1 H), 1.74–1.70 (m, 1 H), 1.53–1.47 (m, 1 H), 1.38–1.30 (m, 1 H).

13C NMR (75 MHz, CDCl3): δ = 202.7, 161.0, 148.2, 146.4, 134.5, 127.6, 127.4, 126.8, 121.8, 72.2, 60.2, 54.9, 46.0, 44.0, 34.5, 25.6.

The 1H NMR and 13C NMR data are in agreement with the reported data.[3a] [i] See the Supporting Information for a detailed comparison.


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Acknowledgment

Financial support from the Natural Sciences and Engineering Research Council of Canada and the Canada Foundation for Innovation is gratefully acknowledged.

Supporting Information

    for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synthesis.
  • Supporting Information


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Figure 1 (+)-Febrifugine (1), (+)-halofuginone (2) and isofebrifugine (3)
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Scheme 1
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Scheme 2
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Figure 2 Selected aminothiourea and aminosquaramide catalysts
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Scheme 3
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Scheme 4