A Stereoselective Anti-Aldol Route to (3R,3aS,6aR)-Hexahydrofuro[2,3-b] furan-3-ol: A Key Ligand for a New Generation of HIV Protease Inhibitors

Abstract

A stereoselective synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol, an important high affinity P₂-ligand, in high enantiomeric excess (>99%) is reported. The synthesis features an ester-derived titanium enolate based highly stereoselective anti-aldol reaction as the key step.

The AIDS epidemic has become one of the most serious medical problems of our time.¹ The highly active antiret-roviral therapy (HAART) with HIV protease inhibitors and reverse transcriptase inhibitors continues to be a major treatment option.² However, more effective HAART with new generation inhibitors is in critical need to combat drug-resistant HIV and reduce serious drug side effects.³ As part of our continuing studies aimed at developing novel inhibitors to combat drug resistance, we have designed and synthesized a series of nonpeptidyl HIV protease inhibitors that are exceedingly potent both against wild-type and resistant viruses.⁴ One of these inhibitors (1, K_i = 16 pM, and ID₅₀ = 3 nM, Figure 1) has been under advanced clinical development.^4,5 It was recently approved by the U.S. Food and Drug Administration for treatment of drug-resistant HIV. This inhibitor incorporates a very important structure-based designed and stereochemically defined bis-tetrahydrofuran (bis-THF) derived urethane as the P₂-ligand. This ligand is designed to hydrogen bond with the backbone of HIV-1 protease. The significance of this ligand particularly for withstanding potency against drug-resistant HIV is now well documented.⁴ Inhibitor 2, which also incorporates the same bis-THF ligand, is currently undergoing phase II clinical trials.⁷

Figure 1.

Structure of inhibitors 1 and 2

The bis-THF ligand has also been utilized in the design and synthesis of a number of other very potent HIV-1 protease inhibitors. Our initial synthesis of optically active bis-THF involved (3R)-diethyl malate as the key starting material.^8a This route provided optically pure bis-THF ligand but the overall process was not very efficient. Subsequently, we developed an efficient racemic synthesis of bis-THF ligand followed by a lipase-catalyzed enzymatic resolution to provide quantities of optically active bis-THF ligand.^8b We have also investigated a stereoselective photochemical addition of 1,3-dioxolane to a chiral furan-one derivative which was prepared by a lipase-catalyzed enzymatic resolution as the key step.^8c Both these procedures provided access to quantities of optically active bis-THF ligand alcohol. However, optical purity was in the range of 92–96% ee. Recently, Quaedflieg and co-workers have reported the synthesis of this ligand utilizing a diastereoselective Michael addition as the key step.⁹ For our continued interest in optically pure bis-THF ligand, we have investigated the feasibility of ester-derived titanium enolate based anti-aldol reaction to prepare bis-THF ligand in high optical purity. Herein, we report a stereo-controlled synthesis of bis-THF utilizing an ester-derived titanium enolate based anti-aldol reaction as the key step. The overall route is amenable to quantities of bis-THF ligand in high optical purity.

As shown in Scheme 1, our plan was to carry out an acid-catalyzed cyclization of intermediate 4 to provide the desired (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (3). A logical precursor to intermediate 4 would be the anti-aldol product 5. Thus, asymmetric anti-aldol reaction would provide a convenient access to two key stereocenters of bis-THF enantioselectively. For stereoselective generation of this anti-aldol, we elected to utilize an ester-derived titanium enolate-mediated asymmetric anti-aldol reaction developed in our laboratory.¹⁰ For stereoselective generation of anti-aldol product 5, we planned to utilize readily available optically pure amino-indanol derived chiral auxiliary. Accordingly, acylation of commercially available (1S,2R)-1-tosylamido-2-indanol (6) with pent-4-enoic acid in the presence of EDC and DMAP furnished ester 7 in nearly quantitative yield (Scheme 2).¹¹ Exposure of ester 7 to TiCl₄ (1.2 equiv) and N,N-diisopropyl-ethylamine (3.8 equiv) in CH₂Cl₂ at 0 °C generated the corresponding titanium enolate. Treatment of the resulting enolate with TiCl₄ (1 equiv) pre-complexed cinnamal-dehyde (2 equiv) at −78 °C furnished anti-aldol product 8 and its diastereomer in 60% yield as a 8:2 diastereomeric mixture. In order to improve the diastereomeric ratio and yield we examined a number of other reaction conditions. As shown in Table 1, we examined the additive effect especially with MeCN and NMP as additives. Both of these additives showed good improvement in diastereoselectivity and yield. However, diastereomeric excess of these aldol reactions appeared to be very sensitive to small changes in the Lewis acid stoichiometry. The use of one equivalent of TiCl₄ and two equivalents of TMEDA provided reproducible results with good diastereomeric excess but the observed yield was not satisfactory (Table 1, entry 4). Subsequently we investigated the effect of one equivalent of TiCl₄ and two equivalents of DIPEA on anti-aldol diastereoselectivity (Table 1, entry 5).

Scheme 1.

Anti-aldol strategy to bis-THF ligand

Scheme 2.

Synthesis of bis-THF ligand

Table 1.

Aldol Reaction with Cinnamaldehyde

Entry	Additivea	Yield (%)	Anti/Syn
1	none	60	80:20
2	MeCN	60	96:4
3	NMP	55	90:10
4	TMEDA	30	96:4
5	DIPEA	70	96:4

^aOne equiv of TiCl₄ and 2 equiv of additive.

These conditions have provided the best result. The titanium enolate was generated as described above. In a separate flask, cinnamaldehyde was pre-complexed with one equivalent of TiCl₄ and two equivalents of DIPEA at −78 °C. This enolate was added dropwise to the above pre-complexed cinnamaldehyde at −78 °C for 30 min. The mixture was stirred for 3.5 h at −78 °C and then quenched by saturated aqueous NH₄Cl solution. This protocol consistently provided excellent diastereoselectivity and good yield.

To convert the aldol product 8 to bis-THF 3, the hydroxyl group was first protected as the THP ether 9. LiAH₄ reduction of 9 afforded the alcohol 10 in excellent yield. The chiral auxiliary 6 was also recovered in near-quantitative yield. Swern oxidation of 10 gave the corresponding aldehyde which was protected as methyl acetal 11 in 89% yield in a two-step sequence. Ozonolysis of 11 followed by reduction with dimethyl sulfide and NaBH₄ provided the corresponding diol. Exposure of the resulting diol to aqueous HCl effected deprotection of THP group and acid-catalyzed cyclization to the desired bis-THF alcohol 3. The optical purity of bis-THF alcohol was determined to be >99% by Mosher ester analysis.^12,13

In conclusion, a stereoselective synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (3), an important P2-ligand for TMC-114 and GW0385 has been achieved. The key step involves a diastereoselective ester-derived Ti-enolate based anti-aldol reaction utilizing to-sylamidoindanol as the chiral auxiliary. This anti-aldol route provides an easy access to bis-THF 3 in high optical purity (>99% ee).

Anhydrous solvents were obtained as follows: CH₂Cl₂, distillation over CaH₂; THF, distillation from sodium/benzophenone under N₂. Flash chromatography was performed using 230–400 mesh silica gel under low pressure of 5–10 psi. TLC was performed on silica gel 60F 254 plates. All melting points are uncorrected. ¹H NMR and ¹³C NMR spectra were recorded on Bruker 300 MHz and Varian 300 MHz instruments. IR spectra were recorded on a ATI Mattson Genesis series FT-IR spectrometer. Optical rotation was measured using a PerkinElmer 241 spectropolarimeter with a sodium lamp (589 nm). Mass spectra were recorded on a Finnigan Mat 90 mass spectrometer.

(1S,2R)-1-(Tosylamino)-2,3-dihydro-1H-inden-2-ylpent-4-enoate (7)

To a solution of N-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-4-methylbenzenesulfonamide (6; 6.85 g, 22.6 mmol) in CH₂Cl₂ (100 mL) were added EDCI (4.32 g, 22.6 mmol), pent-4-enoic acid (2.26 g, 22.6 mmol) and DMAP (2.76 g, 22.6 mmol) and stirred for 3 h. The mixture was quenched with H₂O and the organic layer was washed with aq sat. NaHCO₃ solution. The aqueous layer was extracted with CH₂Cl₂ (2 ×) and the combined organic layers were dried (Na₂SO₄), filtered and then concentrated in vacuo. Flash column chromatography of the crude product over silica gel (R_f 0.27, 25% EtOAc in hexanes) afforded product 7 (8.6 g, 99%) as a white solid; mp 120–121 °C.

IR (neat): 3283, 1738 cm⁻¹.

¹H NMR (300 MHz, CDCl₃): δ = 7.80 (d, J = 8.4 Hz, 2 H), 7.17–7.27 (m, 6 H), 5.76 (m, 1 H), 5.18 (m, 2 H), 4.98 (m, 3 H), 3.06–3.13 (dd, J = 17.1 Hz, 1 H), 2.90 (d, J = 17.1 Hz, 1 H), 2.46 (s, 3 H), 2.27 (m, 4 H).

¹³C NMR (75 MHz, CDCl₃): δ = 171.9, 143.9, 139.7, 138.6, 137.8, 136.4, 129.9, 128.7, 127.4, 127.0, 125.0, 124.3, 115.8, 74.9, 59.5, 37.5, 33.2, 28.6, 21.6.

HRMS-ESI: m/z [M + Na]⁺ calcd for C₂₁H₂₃NO₄S + Na: 408.1246; found: 408.1256.

(2S)-(1S,2R)-1-(Tosylamino)-2,3-dihydro-1H-inden-2-yl-2-[(S,E)-1-hydroxy-3-phenylallyl]pent-4-enoate (8)

To a stirred solution of 7 (7.89 g, 20.5 mmol) in CH₂Cl₂ (210 mL) at 0 °C was added a 1.8 M solution of TiCl₄ (13.8 mL, 24.8 mmol) under N₂ and the resulting solution was stirred for an additional 5 min. To this solution was added N,N-diisopropylethylamine (13.9 mL, 79.7 mmol) dropwise. The mixture was allowed to warm to 23 °C and stirred for 2 h. To a separate flask charged with cinnam-aldehyde (5.30 mL, 42 mmol) and CH₂Cl₂ (320 mL) at −78 °C was added a 1.8 M solution of TiCl₄ (11.5 mL, 20.7 mmol) dropwise. After stirring for 5 min at the same temperature, N,N-diisopropyl-ethylamine (7.3 mL, 41.9 mmol) was added dropwise and mixture was stirred for further 5 min. After this period, the above titanium enolate solution was added to cinnamaldehyde solution dropwise via an insulated cannula over 30 min. The mixture was stirred at −78 °C for 3.5 h and quenched by addition of aq NH₄Cl. The resulting mixture was allowed to warm to 23 °C and the layers were separated. The aqueous layer was extracted with CH₂Cl₂ (2 ×). The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated to afford the crude aldol product. Silica gel chro-matography (15% and then 20% EtOAc-hexanes; (R_f 0.13, 20% EtOAc in hexanes) yielded diastereomerically pure anti-aldol product 8 (7.43 g, 70%) as a gummy solid; [α]²³_D −18.3 (c = 1.26, CHCl₃).

IR (neat): 3477, 3283, 1738, 1232 cm⁻¹.

¹H NMR (CDCl₃, 300 MHz): δ = 7.78 (d, J = 8.5 Hz, 2 H), 7.35 (m, 1 H), 7.15–7.30 (m, 10 H), 7.04 (m, 1 H), 6.48 (d, J = 16 Hz, 1 H), 6.38 (d, J = 9.5 Hz, 1 H), 6.08 (dd, J = 7, 16 Hz, 1 H), 5.50–5.70 (m, 1 H), 5.34 (t, J = 5 Hz, 1 H), 4.98 (dd, J = 10.5, 18 Hz, 2 H), 4. 80 (dd, J = 5, 9.5 Hz, 1 H), 4.25 (t, J = 7.5 Hz, 1 H), 2.98 (dd, J = 5, 17 Hz, 1 H), 2.80 (d, J = 17 Hz, 1 H), 2.60 (m, 1 H), 2.38 (s, 3 H), 2.14−2.25 (m, 2 H).

¹³C NMR (CDCl₃, 75 MHz): δ = 171.7, 143.5, 140.2, 138.4, 137.6, 135.9, 134.3, 133.3, 129.7, 128.6, 128.5, 128.4, 128.2, 127.4, 127.2, 126.7, 124.8, 124.5, 117.7, 75.1, 73.6, 59.6, 51.9, 37.4, 33.5, 21.6.

LRMS-ESI: m/z [M − H]⁻ calcd for C₃₀H₃₀NO₅S: 516; found: 516.

Anal. Calcd for C₃₀H₃₀NO₅S: C, 69.61; H, 6.04; N, 2.71. Found: C, 69.47; H, 6.19; N, 2.55.

(2S)-(1S,2R)-1-(Tosylamino)-2,3-dihydro-1H-inden-2-yl-2-[(S,E)-3-phenyl-1-(tetrahydro-2H-pyran-2-yloxy)allyl]pent-4-enoate (9)

To an ice cold (0 °C) solution of anti-aldol product 8 (8.52 g, 16.5 mmol) and pyridinium p-toluenesulfonate (0.41 g, 1.65 mmol) in CH₂Cl₂ (150 mL) was added 3,4-dihydro-2H-pyran (4.50 mL, 49.4 mmol) dropwise and stirred for 5 min. The mixture was stirred for 3 h while allowing it to warm up to 23 °C. The reaction was quenched by the addition of brine and the aqueous layer was extracted with CH₂Cl₂ (2 ×). The combined organic layers were dried (Na₂SO₄) and filtered. Removal of solvent under reduced pressure followed by purification by flash column chromatography using 25% EtOAc-hexanes afforded compound 9 (9.18 g, 92%, mixture of diastereomers) as a colorless gum in 92% yield.

IR (neat): 2942, 1737 cm⁻¹.

¹H NMR (300 MHz, CDCl₃): δ (polar diastereomer) = 7.85 (d, J = 8.4 Hz, 2 H), 7.17–7.45 (m, 11 H), 6.66 (d, J = 10.2 Hz, 1 H), 6.53 (d, J = 16.2 Hz, 1 H), 5.84 (dd, J = 8.7, 15.6 Hz, 1 H), 5.57–5.65 (m, 1 H), 5.33 (t, J = 4.5 Hz, 1 H), 4.91–5.02 (m, 3 H), 4.44 (t, J = 5.1 Hz, 1 H), 4.37 (t, J = 9.3 Hz, 1 H), 3.93 (br d, J = 10.8 Hz, 1 H), 3.34 (t, J = 9.3 Hz, 1 H), 3.01 (dd, J = 4.2, 17.1 Hz, 1 H), 2.84 (br d, J = 17.1 Hz, 1 H), 2.59–2.66 (m, 1 H), 2.43 (s, 3 H), 2.04–2.30 (m, 2 H), 1.74–1.78 (m, 2 H), 1.60–1.61 (m, 2 H), 1.40–1.44 (m, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 172.3, 143.2, 140.6, 138.5, 138.4, 138.2, 135.8, 134.2, 129.6 128.6, 128.2, 128.1, 127.1, 126.6, 126.2, 124.7, 124.0, 117.5, 97.1, 76.8, 75.3, 64.9, 59.7, 50.9, 37.6, 33.9, 30.6, 24.5, 21.5, 21.2.

Anal. Calcd for C₃₅H₃₇NO₆S: C, 69.86; H, 6.53; N, 2.33. Found: C, 69.77; H, 6.57; N, 2.20.

(2R,3S,E)-2-Allyl-5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)pent-4-en-1-ol (10)

To a solution of compound 9 (9.12 g, 15.2 mmol) in THF (140 mL) at 0 °C was added LiAlH₄ (1.12 g, 29.5 mmol) in three portions and the mixture was stirred first at 0 °C for 10 min and then at 23 °C for 1 h. The reaction was quenched by aq sat. potassium sodium tartrate solution. The aqueous layer was extracted with CH₂Cl₂ (2 ×) and EtOAc (2 ×). The combined organic layers were dried (Na₂SO₄), filtered and concentrated under reduced pressure. Flash chromatography of the crude compound using EtOAc–hexanes (1:2) afforded product 10 (4.46 g, 99%) as a colorless oil (R_f 0.47, 40% EtOAc in hexanes). N-Tosylamidoindanol 6 was recovered quantitatively (4.47 g).

IR (neat): 3455, 2939, 1116 cm⁻¹.

¹H NMR (300 MHz, CDCl3): δ (polar diastereomer) = 7.22–7.40 (m, 5 H), 6.56 (d, J = 16.2 Hz, 1 H), 6.30 (dd, J = 8.4, 15.9 Hz, 1 H), 5.70–5.90 (m, 1 H), 5.01–5.13 (m, 2 H), 4.79 (d, J = 2.7 Hz, 1 H), 4.28 (t, J = 8.4 Hz, 1 H), 3.93 (dd, J = 2.7, 11.1 Hz, 2 H), 3.66 (dd, J = 5.1, 11.4 Hz, 1 H), 3.49–3.57 (m, 1 H), 2.53 (br s, 1 H), 2.30 (m, 1 H), 2.12 (m, 1 H), 1.40–1.91 (m, 7 H).

¹³C NMR (75 MHz, CDCl₃): δ = 136.9, 136.7, 134.5, 129.1, 128.4, 127.0, 117.0, 96.6, 79.8, 64.0, 62.8, 45.3, 33.0, 31.2, 25.7, 20.7.

2-[(3S,4S,E)-4-(Dimethoxymethyl)-1-phenylhepta-1,6-dien-3-yloxy]tetrahydro-2H-pyran (11)

To a solution of oxalyl chloride (2.61 mL, 29.9 mmol) in CH₂Cl₂ (170 mL) at −78 °C, was added DMSO (3.18 mL, 44.8 mmol) drop-wise. The mixture was stirred for 15 min and a solution of alcohol 10 (4.25 g, 14 mmol) in CH₂Cl₂ (20 mL) was added via a syringe. The mixture was stirred for 30 min and Et₃N (12.5 mL, 89.4 mmol) was added. The reaction was quenched with brine after 1 h. The aqueous layer was extracted with CH₂Cl₂ (2 ×). The combined organic layers were dried (Na₂SO₄), filtered and concentrated under reduced pressure. Flash column chromatography (R_f 0.30, 0.25 for THP diastereomers; 20% EtOAc in hexanes) afforded the corresponding aldehyde (3.80 g, 90%) as a colorless oil.

Precursor Aldehyde

IR (neat): 2941, 1727 cm⁻¹.

¹H NMR (300 MHz, CDCl₃): δ (polar diastereomer) = 9.65 (d, J = 3.3 Hz, 1 H), 7.05–7.30 (m, 5 H), 6.50 (d, J = 15.9 Hz, 1 H), 6.13 (dd, J = 8.4, 15.9 Hz, 1 H), 5.60 (m, 1 H), 4.89–4.98 (m, 2 H), 4.61 (t, J = 2.7 Hz, 1 H), 4.47 (t, J = 8.1 Hz, 1 H), 3.70 (m, 1 H), 3.26 (m, 1 H), 2.56 (m, 1 H), 2.14–2.33 (m, 2 H), 1.30–1.75 (m, 6 H).

¹³C NMR (75 MHz, CDCl₃): δ = 203.9, 136.3, 135.7, 134.9, 129.0, 128.6, 127.0, 126.6, 117.7, 94.8, 76.0, 62.5, 56.3, 31.1, 30.8, 25.8, 19.4.

To a stirred solution of the above aldehyde (3.12 g, 10.4 mmol) in trimethyl orthoformate (34 mL) at 0 °C, were added anhydrous MeOH (0.84 mL, 20.8 mmol) and camphorsulfonic acid (0.24 g, 1.04 mmol). The resulting mixture was stirred for 1 h at 0 °C and quenched with aq sat. NaHCO₃ solution (30 mL). The aqueous layer was carefully extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were dried (Na₂SO₄, filtered and concentrated. The crude product was purified by flash column chromatography (R_f 0.31, 0.25 for THP diastereomers, 25% EtOAc in hexanes) using a mixture (1:70) of Et₂O and CH₂Cl₂ as the eluent to afford acetal 11 (3.57 g, 99%) as colorless liquid.

11

¹H NMR (300 MHz, CDCl₃): δ (polar diastereomer) = 7.22–7.40 (m, 5 H), 6.54 (d, J = 15.6 Hz, 1 H), 6.12 (dd, J = 7.2, 15.9 Hz, 1 H), 5.90–5.99 (m, 1 H), 4.97 (dd, J = 9.3, 17.1 Hz, 1 H), 4.70 (d, J = 3.3 Hz, 1 H), 4.42–4.47 (m, 2 H), 3.86–3.93 (m, 1 H), 3.50–3.54 (m, 1 H), 3.39 (s, 6 H), 2.26–2.30 (m, 2 H), 2.13–2.19 (m, 1 H), 1.55–1.85 (m, 6 H).

¹³C NMR (75 MHz, CDCl₃): δ = 138.4, 138.6, 133.0, 128.4, 128.0, 127.5, 126.4, 114.9, 105.4, 94.9, 75.7, 62.1, 54.3, 53.8, 46.0, 30.7, 30.2, 25.5, 19.4.

HRMS-EI: m/z [M + Na]⁺ calcd for C₂₁H₃₀O₄ + Na: 369.2036; found: 369.2034.

(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol (3)

Compound 11 (2.8 g, 8.08 mmol) was dissolved in CH₂Cl₂ (210 mL) and the clear solution was cooled to −78 °C. A stream of ozone (generated by PCI ozone generator) was bubbled through the solution at −78 °C until the solution turned light blue (~50 min). Excess of ozone was displaced by bubbling argon through the mixture at −78 °C until the blue color disappeared (~30 min). Me₂S (4.0 mL, 54.5 mmol) was then added to the solution and the mixture was stirred for 1 h and then warmed up to 0 °C. MeOH (50 mL) and NaBH₄ (1.40 g, 37 mmol) were added respectively to the mixture and stirring was continued for further 2 h. After this period, the mixture was allowed to warm up to 23 °C. The mixture was concentrated under reduced pressure and the residue was dissolved in aq THF. The mixture was cooled to 0 °C and aq 6 M HCl was added until pH 2. The mixture was stirred for 3 days and then solid NaHCO₃ was added. The mixture was stirred for 30 min and filtered and concentrated under reduced pressure. Purification of compound by flash column chromatography using EtOAc in hexanes (1:1) afforded the bis-THF 3 as a colorless oil (0.63 g, 60% in 3 steps); R_f 0.31(75% EtOAc in hexane); [α]_D²³ −12.2, (c = 2.4, MeOH).

¹H NMR (300 MHz, CDCl₃): δ = 5.48 (d, J = 5 Hz, 1 H), 4.21 (dd, J = 6.5, 14.2 Hz, 1 H), 3.65–3.85 (m, 4 H), 3.38 (t, J = 7.5 Hz, 1 H), 2.65 (dd, J = 6.5, 9 Hz, 1 H), 2.11 (m, 1 H), 1.60–1.74 (m, 1 H).

¹³C NMR (CHCl₃, 75 MHz): δ = 109.5, 73.1, 71.1, 69.9, 46.6, 24.8.

HRMS-EI: m/z [M + H]⁺ calcd for C₆H₁₀O₃: 131.0709; found: 131.0710.