Asymmetric Synthesis of the α-d-Galactosyl Ceramide KRN7000 via an Organocatalytic Aldol Reaction as Key Step

Abstract

The asymmetric synthesis of the antitumor and immunostimulatory α-d-galactosyl ceramide KRN7000 using a (R)-proline-catalyzed enantioselective aldol reaction as key step is described. The title compound is synthesized in thirteen linear steps with excellent stereoselectivity (de >98%, ee = 95%) employing the commercially available substrates 1-pentadecanal, 2,2-dimethyl-1,3-dioxan-5-one, hexacosanoic acid, and d-galactose.

Through the cooperation between Japan’s Kirin Brewery and the University of the Ryukyus, several compounds with related chemical structures called agelasphins (AGLs) were isolated from the naturally occurring Okinawan­ marine sponge Agelas mauritianus in 1993. [¹] After screening their biological activities using several assay systems, KRN7000 (also called AGL-582 or α-GalCer) displayed the most potent immunostimulatory and antitumor activities. [²] This α-galactosylceramide is able to activate NKT-cells (natural killer cells) via interaction with CD1d, a glycoprotein expressed on the surface of the antigen-presenting cells. [³] After activation, the NKT cells produce large numbers of cytokines, which are responsible for the in vitro and in vivo antitumor activities. [4] Additionally, the cytokines provide protection against various autoimmune diseases [5] such as type I diabetes, [6] and are efficient­ against hepatitis B, [7] bacterial infections such as tuberculosis [8] as well as malaria. [9]

The structure of KRN7000 (1) consists of a ceramide unit with a non-polar aliphatic ‘tail’, a polar amidoalcohol ‘head’ and galactose, which are linked via an α-glycosidic bond. The substituents of the ceramide unit, the length of its aliphatic chains as well as the sugar type and its configuration, all play an important role in the antitumor activity. [¹0]

With the aim of understanding the relationship between the chemical structure and bioactivity in order to create more effective drugs, a variety of synthetic approaches to KRN7000 [¹¹] and its analogues [¹²-²0] have been reported.

Accordingly, we were interested in developing a straightforward and efficient asymmetric synthesis of this important class of immunostimulatory compounds that allows the option of introducing flexible modifications into the structure to access analogues.

Retrosynthetically, we envisaged the preparation of the α-galactosyl ceramide (1) using four building blocks, namely, the relatively inexpensive, commercially available d-galactose (A), the hexacosanoic acid (B), along with the easily prepared 1-pentadecanal (C) and the dioxanone D (Scheme  [¹] ).

The route to KRN7000 consists of an organocatalytic aldol reaction followed by reductive amination of the keto group to generate three of the required stereocenters; N-acylation and stereoselective glycosylation complete the synthesis. As the first stereogenic step, we employed a highly diastereo- and enantioselective proline-catalyzed aldol reaction developed in our research group as a key step (Scheme  [²] ). [²¹] The precursor aldol adduct 2 could be obtained on a multigram scale in 59% yield with virtually complete anti-diastereoselectivity (de >98%) and an enantiomeric excess of 95%.

To commence the synthesis of the KRN7000 target, the TBS-protected syn-1,3-azido alcohol 3 was prepared from the aldol product 2 — obtained from dioxanone D [²²] and 1-pentadecanal (C) [²³] using the diastereo- and enantioselective (R)-proline-catalyzed aldol reaction [²4] — in four steps in an overall yield of 67%. [²5] The four steps involved TBS-protection of the alcohol, diastereoselective reduction with L-Selectride, conversion of the resulting alcohol into a mesylate, and an S_N2 displacement with sodium azide in the presence of 18-crown-6, which took place with virtually complete inversion of configuration (de >98% by NMR and GC analyses).

At this point we decided to attach the sugar moiety before attempting the N-acylation, because the solubility of the corresponding amide, which bears a polar head and two long aliphatic chains, turned out to be low in organic solvents and the resulting poor yields meant that such a sequence of steps in the synthesis of KRN7000 could not be completed in a satisfactory manner.

After simultaneous deprotection of the three hydroxy groups using Dowex exchange resin, the triol azide 4 was protected once again with TBSOTf. The strategic advantage of this route (Scheme  [³] ) is the increased solubility of azido-phytosphingosine 4 compared to the corresponding amide and, as a result, virtually quantitative conversion into the triple silyl protected azide 5. Removal of the primary silyl protecting group was accomplished in a regio­selective manner by employing a known literature procedure. [¹¹b] [¹7b] The trichloroacetimidate 10 was generated from the commercially available 2,3,4,6-tetra-O-benzyl-d-galactopyranose according to a procedure previously described by Schmidt et al. [²6] Stereoselective glycosylation of 6 with the galactosyl donor 10 was then achieved in the presence of boron trifluoride etherate at -20˚C, giving the α-galactoside 7 as the major anomer (^¹H NMR) in good yield (65%). The conversion of azide 7 into the corresponding primary amine was effected by a Staudinger reduction [²7] using trimethylphosphine (1 M solution in THF). The amine was used directly without purification­ in the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and hydroxybenzotria­zole hydrate (HOBt)-mediated acylation reaction, employing the commercially available cerotinic acid (B).

Following a procedure reported by Kim et al., [¹¹e] the resulting fully protected a-GalCer 8 was treated with TBAF in THF to give benzyl-protected KRN7000 9 in 96% yield. To complete the synthesis, compound 9 was subjected to a debenzylation reaction by catalytic hydrogenation [H₂/Pd(OH)₂/C]. Purification of the crude product could not be accomplished by conventional chromatographic methods; however, we were able to purify the crude solid by employing reversed-phase C18 silica gel (MeOH-THF-CHCl₃, 18:1:1). After purification, KRN7000 (1) could be obtained with a yield of 89%.

In summary, we have developed an efficient asymmetric synthesis of the α-d-galactosyl ceramide KRN7000 by using an organocatalytic aldol reaction as key step in excellent diastereo- and enantiomeric excesses (de >98%, ee = 95%). The title compound was obtained in thirteen steps starting from four, readily available building blocks. This method allows access to both enantiomers of KRN7000, depending on whether (R)- or (S)-proline is used as catalyst. Furthermore, the prochiral ketone function of 2 can be easily converted into the epimeric amino group. [²¹] Theoretically, by using derivates of A, B and C, access to distinct analogues of KRN7000 for pharmaceutical studies via this route should be possible.

All solvents were dried by conventional methods. Starting materials and reagents were purchased from commercial suppliers and used without further purification. THF and Et₂O were freshly distilled from SOLVONA^® (a sodium doped material) under argon. CH₂Cl₂ was freshly distilled from CaH₂ under argon. Preparative column chromatography was performed using silica gel 60, particle size 0.040-0.063 mm (230-240 mesh, flash) or reversed-phase octadecylsilicate (POLYGOPREP 60-50 mesh, C18-RP). Analytical TLC was carried out by employing silica gel 60 F₂₅₄ plates from Merck, Darmstadt. Visualization of the developed chromatograms was achieved by staining with phosphomolybdic acid solution in EtOH and anisaldehyde. Optical rotation values were measured with a Perkin-Elmer P241 polarimeter. Microanalyses were obtained with a Vario EL element analyzer. Mass spectra were acquired with a Finnigan SSQ7000 spectrometer (CI 100 eV; EI 70 eV). HRMS data were recorded with a Finnigan MAT95 spectrometer (EI) or a Thermo Fisher Scientific OrbitrapXL (ESI) instrument. IR spectra were measured with a Perkin-Elmer FT-IR 1760 or a Spectrum 100 spectrophotometer. ^¹H and ^¹³C NMR spectra were recorded with Varian Mercury 300, Gemini 300 or Inova 400 spectrometers with TMS as the internal standard.

(2 S ,3 S ,4 R )-2-Azido-1,3,4-octadecanetriol (4)

DOWEX 50WX2 (2 g) was added to a solution of 3 (1.00 g, 2.01 mmol) in MeOH (15 mL) and THF (2 mL) and the mixture was heated at reflux for 3 h. After filtration of the resin, the solvent was removed under reduced pressure. Purification by flash chromatography (silica gel; CH₂Cl₂-MeOH, 3:1) afforded the azido triol 4.

Yield: 0.63 g (91%); colorless solid; mp 92 ˚C; de >98% (NMR analysis); [α]_D ^²0 +10.9 (c 0.5, MeOH).

IR (CHCl₃): 3293, 2916, 2848, 2097, 1463, 1253, 1066, 1011, 880, 720, 669 cm^-¹.

^¹H NMR (400 MHz, CD₃OD): δ = 0.87 (t, J = 6.9 Hz, 3 H, CH₃, H-18), 1.26 (m, 24 H, 12 × CH₂, H6-17), 1.51-1.67 (m, 2 H, CH₂, H-5), 3.50 (m, 2 H, H-3, H-4), 3.57 (ddd, J _1b-2 = 3.6 Hz, J _2-3 = 7.8 Hz, J _1a-2 = 11.2 Hz, 1 H, H-2), 3.73 (dd, J _1a-1b = 14.9 Hz, J _1a-2 = 11.5 Hz, 1 H, H-1a), 3.89 (dd, J _1a-1b = 14.9 Hz, J _1b-2 = 3.3 Hz, 1 H, H-1b).

^¹³C NMR (100 MHz, CD₃OD): δ = 13.1 (CH₃), 22.4, 25.4, 29.1, 29.4, 31.7, 32.5 (13 × CH₂), 61.1 (C-1), 65.3 (C-2), 71.4, 74.6 (C-3/C-4).

ESI-MS: m/z = 344 [M + H]⁺, 366 [M + Na]⁺, 709 [2M + Na]⁺.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₈H₃₇N₃O₃Na: 366.2727; found: 366.2726.

(2 S ,3 S ,4 R )-2-Azido-1,3,4-tri- tert -buthyldimethylsilyloxy-1,3,4-octadecanetriol (5)

Compound 4 (0.50 g, 2.12 mmol) was dissolved in CH₂Cl₂ (30 mL) and THF (6 mL) and cooled to 0 ˚C. Under argon, sequentially, 2,6-lutidine (2.9 mL, 25.4 mmol) and TBSOTf (3.9 mL, 17.0 mmol) were added dropwise via syringe. After 2 h, the reaction mixture was warmed to r.t. and stirred for an additional 14 h then quenched with sat. NaHCO₃ (20 mL). The aqueous phase was extracted with CH₂Cl₂ (3 × 40 mL), the combined organic layers were dried over MgSO₄, and the solvent was removed under reduced pressure. Purification by flash chromatography on silica gel (Et₂O-pentane, 3:1) provided the TBS-protected azido triol 5.

Yield: 1.43 g (98%); colorless oil; de >98% (NMR); [α]_D ^²² +4.3 (c 2.3, CHCl₃).

IR (CHCl₃): 2954, 2856, 2099, 1468, 1255, 1072, 836, 778, 670 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 0.01, 0.02, 0.03, 0.07, 0.08, 0.09 (6 × s, 18 H, 6 × CH₃Si), 0.87 (t, J = 7.1 Hz, 3 H, H-18), 0.87-0.89 (m, 27 H, 3 × t-BuSi), 1.27 (m, 24 H, 12 × CH₂, H6-17), 1.40-1.56 (m, 2 H, CH₂, H-5), 3.59 (m, 2 H, H-3, H-4), 3.59-3.75 (m, 2 H, H-1a, H-2), 3.99 (dd, J = 11.8, 1.9 Hz, 1 H, H-1b).

^¹³C NMR (75 MHz, CDCl₃): δ = -5.4, -4.7, -4.4, -4.1, -3.9, -2.9 (6 × CH₃Si), 14.1 (C-18), 18.1, 18.2, 18.3 (3 × C-Si), 22.7, 25.3, 25.7, 25.8, 26.02, 26.06, 29.4, 29.6, 29.7, 29.9, 31.9, 32.8, 64.1 (C-1), 65.3 (C-2), 74.6, 75.8 (C-3, C-4).

ESI-MS: m/z (%) = 658 (37) [M⁺ - N₂], 687 (100) [M + H]⁺, 709 (45) [M + Na]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₆H₈₀N₃O₃Si₃: 686.5502; found: 686.5503.

(2 S ,3 S ,4 R )-2-Azido-3,4-bis- tert -butyldimethylsilyloxy-1-octa­decaneol (6)

To a stirred solution of 5 (1.20 g, 1.75 mmol) in THF (40 mL) aq TFA (10%, 13 mL) was added dropwise at -20 ˚C. The reaction temperature was gradually raised to 0˚C with stirring over 4 h. The reaction was quenched with aq NaOH (15%, 15 mL) and the reaction mixture was extracted with Et₂O (10 mL). The combined organic layers were washed with H₂O (10 mL), sat. aq NaHCO₃ (10 mL) and brine (10 mL), dried with MgSO₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (pentane-EtOAc, 9:1) to give 6.

Yield: 0.85 g (85%); colorless oil; de >98% (NMR); [α]_D ^²¹ -3.6 (c 1.5, CHCl₃).

IR (CHCl₃): 3346, 2991, 2891, 2167, 1235, 1054, 797, 774, 658 cm^-¹.

^¹H NMR (400 MHz, CDCl₃): δ = 0.09 (s, 6 H, 2 × CH₃Si), 0.12 (s, 6 H, 2 × CH₃Si), 0.87 (t, J = 6.6 Hz, 3 H, H-18), 0.91 (s, 18 H, 2 × t-BuSi), 1.26 (m, 24 H, 12 × CH₂), 1.50-1.63 (m, 2 H, H-5), 2.60 (br s, 1 H, OH), 3.70 (m, 2 H, H-3, H-4), 3.75 (m, 1 H, H-2), 3.90 (m, 2 H, H-1a, H-1b).

^¹³C NMR (100 MHz, CDCl₃: δ = -4.8, -4.5, -4.1, -4.0 (4 × CH₃Si), 14.1 (C-18), 18.1, 18.2 (2 × C-Si), 22.7, 25.5, 26.0 (6 × C-CH₃), 29.4, 29.6, 29.7, 29.8, 31.9, 33.7 (13 × CH₂), 62.1 (C-1), 64.8 (C-2), 75.4 (C-4), 76.0 (C-3).

ESI-MS: m/z (%) = 572 (100) [M + H]⁺, 594 (66) [M +Na]⁺, 610 (10) [M⁺ +K].

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₆₆N₃O₃Si₂: 572.4637; found: 572.4634.

(2 S ,3 S ,4 R )-2-Azido-3,4-bis- tert -butyldimethylsilyloxy-1-(2,3,4,6-tetra- O -benzyl-α- d -galactopyranosyl)octadecane (7)

Compound 10 (1.00 g, 1.46 mmol), which was prepared as described previously,^¹¹e and azidoshingosine 6 (417 mg, 0.73 mmol) were dissolved in Et₂O (13 mL) and THF (3 mL). Freshly dried 4Å molecular sieves (400 mg) were added and the reaction mixture was cooled to -20 ˚C under an argon atmosphere. BF₃˙OEt₂ (140 mL, 1.5 equiv) was added and the reaction mixture was stirred at -20 ˚C. After 18 h, the reaction mixture was diluted with EtOAc (35 mL) followed by filtration. The organic solution was washed with aq NaHCO₃ (15 mL) and brine (10 mL), dried with MgSO₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel; pentane-EtOAc, 9:1).

Yield: 519 mg (65%); colorless oil; de >98% (NMR), [α]_D ^²¹ +20.8 (c 1.3, CHCl₃).

IR (CHCl₃): 2921, 2877, 2109, 1644, 1541, 1464, 1365, 1239, 1109, 777 cm^-¹.

^¹H NMR (400 MHz, CDCl₃): δ = 0.06, 0.08, 0.09, 0.10 (4 × s, 12 H, CH₃Si), 0.88 (t, J = 5.8 Hz, 3 H, H-18), 0.87 (s, 9 H, t-BuSi), 0.89 (s, 9 H, t-BuSi), 1.26 (m, 24 H, 12 × CH₂), 1.42-1.62 (m, 2 H, H-5), 3.54 (m, 2 H, CH₂, H-6′), 3.62 (m, 1 H, CH, H-4), 3.72-3.93 (m, 6 H, H-1a, 3, 2′, 3′, 4′, 5′), 3.98-4.14 (m, 2 H, H-1b, H-2), 4.4 (d, J = 10.7 Hz, 1 H, PhCH ₂), 4.52 (d, J = 11.3 Hz, 1 H, PhCH ₂), 4.61 (d, J = 11.8 Hz, 1 H, PhCH ₂), 4.72 (d, J = 4.1 Hz, 1 H, H-1′), 4.76 (d, J = 10.9 Hz, 1 H, PhCH ₂), 4.90 (d, J = 11.3 Hz, 1 H, PhCH ₂), 4.91 (d, J = 11.5 Hz, 1 H, PhCH ₂), 4.97 (d, J = 11.5 Hz, 2 H, PhCH ₂), 7.24-7.39 (m, 20 H, Ar-H).

^¹³C NMR (100 MHz, CDCl₃): δ = -4.79 to -4.04 (6 × CH₃Si), 14.1 (C-18), 18.1, 18.2 (2 × C-Si), 22.6, 25.3, 25.98, 25.99, 29.3, 29.53, 29.58, 29.6, 29.7 (alkyl CH₂), 31.8 (CH₂, C-5), 33.0 (CH₂, C-16), 60.3 (CH, C-2), 63.4 (CH₂, C-6′), 68.3, 68.8, 69.2 (3 × CH, C-3′, 4′, 5′), 69.5 (CH₂, C-1), 70.4, 72.61, 72.64, 72.8, 73.2, 73.3, 73.4, 74.3, 74.6, 74.8, 75.1, 75.7, 75.8 (PhCH ₂), 78.5 (CH, C-3), 79.3 (CH, C-4), 81.9 (CH, C-2′), 103.6 (CH, H-1′), 127.2-128.2 (CH, Ar), 137.6-138.5 (C, Ar).

ESI-MS: m/z (%) = 1111 (100) [M⁺ + 17], 1116 (39) [M⁺ + Na].

HRMS (ESI): m/z [M + Na]⁺ calcd for C₆₄H₉₉N₃O₈Si₂Na: 1116.6862; found: 1116.6842.

(2 S ,3 S ,4 R )-3,4-Bis- tert -butyldimethylsilyloxy-2-hexacosanoyl­amino-1-(2,3,4,6-tetra- O -benzyl-α- d -galactopyranosyl)octadecane (8)

Azide 7 (300 mg, 0.274 mmol) was dissolved in THF (6 mL) and cooled to 0 ˚C. Me₃P (1.37 mL, 1.0 M in THF, 1.37 mmol) was added to the solution and the reaction was stirred for 45 min at 0 ˚C and for 3 h at r.t.. After complete conversion of the starting material (reaction monitored by TLC), aq NaOH (1 M, 2.5 mL) was added and the mixture was stirred for 1.5 h. EtOAc (10 mL) was then added to the solution and the organic layers were washed with H₂O (3 × 5 mL), brine (3 mL) and dried over MgSO₄. Evaporation of the solvent afforded the crude amine as a yellow oil, which was used for the next step without purification.

To a suspension of hexacosanoic acid B (326 mg, 0.822 mmol) in DMF (20 mL) and CH₂Cl₂ (55 mL) was added EDCI (185 mg, 0.82 mmol) and HOBt (130 mg, 0.82 mmol) at 0 ˚C. After the mixture was stirred 45 min at r.t., a solution of the crude amine prepared as described above and DIPEA (0.35 mL) in CH₂Cl₂ (30 mL) were added. The mixture was stirred at r.t. for 24 h, then diluted with EtOAc-Et₂O (4:1, 30 mL) and washed with sat. aq NaHCO₃ (35 mL), aq HCl (1 M, 35 mL) and brine (25 mL). The organic layers were dried over MgSO₄ and the solvent was removed under reduced pressure. Purification by flash chromatography (silica gel; hexane-EtOAc, 4:1) afforded the desired product 8.

Yield: 194 mg (49% over 2 steps); colorless oil; de >98% (NMR); [α]_D ^²0 +11.2 (c 1.0, CHCl₃) {Lit. [¹¹b] [α]_D ^²4 +15.4 (c 1.0, CHCl₃); Lit. [¹¹e] [α]_D ^¹7 +9.5 (c 0.6, CHCl₃)}.

IR (CHCl₃): 3437, 2922, 2852, 1671, 1463, 1253, 1101, 1028, 835, 757 cm^-¹.

The NMR data are in good agreement with those reported in literature. [¹¹b] [e]

^¹H NMR (400 MHz, CDCl₃): δ = 0.02, 0.04, 0.06, 0.09 (4 × s, 12 H, CH₃Si), 0.85-0.90 (m, 6 H, CH₃, H-18, 26′), 0.87 (s, 9 H, t-BuSi), 0.89 (s, 9 H, t-BuSi), 1.26 (m, 66 H, 33 × CH₂), 1.44-1.68 (m, 6 H, H-5, 6, 3′), 1.94 (t, J = 7.9 Hz, 2 H, H-2′), 3.53 (m, 2 H, CH₂, H-6′′), 3.61 (m, 1 H, CH, H-4), 3.77-3.98 (m, 6 H, H-1a, 3, 2′′, 3′′, 4′′, 5′′), 4.03 (dd, J = 10.3, 3.6 Hz, 1 H, H-1b), 4.10 (m, 1 H, H-2), 4.36 (d, J = 12.1 Hz, 1 H, PhCH ₂), 4.55 (d, J = 11.3 Hz, 1 H, PhCH ₂), 4.58 (d, J = 11.8 Hz, 1 H, PhCH ₂), 4.65 (d, J = 12.1 Hz, 1 H, PhCH ₂), 4.68 (d, J = 3.3 Hz, 1 H, H-1′′), 4.74 (d, J = 11.3 Hz, 1 H, PhCH ₂), 4.80 (d, J = 11.8 Hz, 1 H, PhCH ₂), 4.91 (d, J = 11.5 Hz, 1 H, PhCH ₂), 4.97 (d, J = 11.5 Hz, 1 H, PhCH ₂), 5.92 (d, J = 7.1 Hz, 1 H, N-H), 7.23-7.38 (m, 20 H, Ar-H).

^¹³C NMR (100 MHz, CDCl₃): δ = -5.14, -4.70, -3.96, -3.81 (4 × CH₃Si), 14.3 (C-18, C-26′), 18.3, 18.5 (2 × C-Si), 22.8, 24.0, 25.7, 26.1, 26.3, 29.40, 29.49, 29.56, 29.61, 29.69, 29.74, 29.83 (alkyl CH₂), 30.1, 32.0, 33.1, 36.9, 51.1, 68.31, 69.01, 69.75, 72.8, 72.9, 73.49, 74.55, 74.86, 75.0, 75.3, 75.6, 78.7, 79.6, 82.1, 85.1, 103.9 (CH, H-1′′), 127.3-128.4 (CH, Ar), 137.7-138.8 (C, Ar), 172.8 (NH-CO).

ESI-MS: m/z (%) = 1447 (100) [M]⁺, 1469 (19) [M +Na]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₉₀H₁₅₂NO₉Si₂: 1447.1000; found: 1447.1012.

(2 S ,3 S ,4 R )-2-Hexacosanoylamino-1-(2,3,4,6-tetra- O -benzyl-α- d -galactopyranosyl)octadecane-3,4-diol (9)

Following the procedure of Kim et al., [¹¹e] a solution of 8 (150 mg, 0.103 mmol) in THF (10 mL) was cooled to 0 ˚C and TBAF (4.41 mL, 1.0 M solution in THF, 4 equiv) was added dropwise. After the mixture was stirred at r.t. for 3 h, H₂O (30 mL) was added and an the mixture was extracted with Et₂O (3 × 30 mL). The combined organic layers were washed with brine (20 mL) and dried with MgSO₄. Evaporation of the solvent followed by column chromatography (silica gel; hexane-EtOAc, 3:1) of the crude product afforded 9.

Yield: 121 mg (96%); colorless solid; mp 79 ˚C (Lit. [¹¹b] [e] 70.5-71.5 ˚C); de >98% (NMR); [α]_D ^²¹ +30.8 (c 1.5, CHCl₃) {Lit. [¹¹b] [α]_D ^²5 +33.3 (c 1.0, CHCl₃); Lit. [¹¹e] [α]_D ^¹6 +27.6 (c 2.1, CHCl₃)}.

IR (KBr): 3457, 3350, 2955, 2849, 1648, 1631, 1532, 1489, 1174, 1048, 716, 698, 659 cm^-¹.

The NMR data are in good agreement with those reported in literature. [¹¹b] [e]

^¹H NMR (300 MHz, CDCl₃): δ = 0.88 (m, 6 H, H-18, 26′), 1.26 (m, 66 H, 33 × CH₂), 1.38-1.68 (m, 6 H, H-3′, 5, 6), 2.22 (s, 1 H, OH), 2.35 (s, 1 H, OH), 2.38 (t, J = 7.42 Hz, 2 H, H-2′), 3.44-3.58 (m, 3 H, H-4, 6′′), 3.98-4.06 (m, 6 H, H-1a, 3, 2′′, 3′′, 4′′, 5′′), 4.02 (dd, J = 3.8, 10.9 Hz, 1 H, H-1b), 4.14 (m, 1 H, H-2), 4.28-4.95 (m, 9 H, H-1′′, PhCH ₂), 6.40 (d, J = 8.1 Hz, 1 H, NH), 7.20-7.39 (m, 20 H, Ar-H).

^¹³C NMR (75 MHz, CDCl₃): δ = 14.0 (C-18, C-26′), 22.6, 25.6, 25.9, 29.1, 29.3, 29.6, 31.8, 32.6, 36.4, 50.8, 68.8, 70.5, 72.8, 72.9, 73.3, 73.5, 74.6, 74.7, 75.3, 76.6, 76.9, 77.4, 79.1, 99.1 (CH, H-1′′), 127.5-128.3 (CH, Ar), 137.2-138.1 (C, Ar), 173.9 (NH-CO).

ESI-MS: m/z (%) = 1219 (3) [M + H]⁺, 1069 (100), 867 (10), 467 (13), 120 (20).

HRMS (ESI): m/z [M + H]⁺ calcd for C₇₈H₁₂₄NO₉: 1218.9270; found: 1218.9273.

KRN7000 [(2 S ,3 S ,4 R )-1-(α- d -Galactopyranosyl)-2-hexacosanoylamminooctadecane-3,4-diol; 1]

To a solution of 9 (80 mg, 0.065 mmol) in CHCl₃ (1 mL) and EtOH (4 mL) were added Pd(OH)₂/C (20% wt, 320 mg). The reaction mixture was stirred for 24 h under an atmosphere of H₂ at r.t., then filtered through a short pad of Celite and washed with CHCl₃-MeOH (1:1, 25 mL). The combined filtrate and washings were concentrated in vacuo and the residual solid was triturated with hexane-EtOAc (1:1, 4 mL). Purification by flash chromatography using reversed-phase C-18 silica gel (MeOH-THF-CHCl₃, 18:1:1) afforded the title compound 1.

Yield: 49 mg (89%); colorless solid; mp 185 ˚C (Lit. [¹¹b] 189.5-190.0 ˚C); de >98% (NMR); ee = 95%; [α]_D ^²0 +39.8 (c 0.2, pyridine) {Lit. [¹¹b] [α]_D ^²³ +42.2 (c 0.54, pyridine); Lit. [¹¹a] [α]_D ^²³ +43.6 (c 1.0, pyridine)}.

IR (KBr): 3425, 2922, 2851, 1631, 1605, 1532, 1483, 1163, 1247, 1058, 748 cm^-¹.

^¹H NMR (400 MHz, pyridine-d ₅): δ = 0.88 (t, J = 6.6 Hz, 6 H, H-18, 26′), 1.20-1.46 (m, 66 H, 33 × CH₂), 1.63-1.69 (m, 1 H, H-6a), 1.78-1.86 (m, 2 H, H-3′), 1.89-1.96 (m, 2 H, H-5a, 6b), 2.24-2.30 (m, 1 H, H-5b), 2.51 (t, J = 7.4 Hz, 2 H, H-2′), 4.00-4.10 (m, 2 H, H-3, 4), 4.18 (m, 3 H, H-1a, 6′′), 4.26 (m, 2 H, H-4′′, 5′′), 4.56 (m, 1 H, H-3′′), 4.64-4.72 (m, 2 H, H-1b, 2′′), 5.27 (m, 1 H, H-2), 5.60 (d, J = 3.3 Hz, 1 H, H-1′′), 6.50 (br s, 6 H, OH), 8.65 (d, J = 8.5 Hz, 1 H, N-H).

^¹³C NMR (100 MHz, pyridine-d ₅): δ = 14.3 (C-18, C-26′), 22.9, 25.7, 26.2, 29.5, 29.7, 29.9, 30.3, 32.1, 33.2, 33.5, 36.8, 52.2, 62.4, 66.6, 70.1, 70.7, 72.5, 72.6, 76.9, 101.2 (CH, H-1′′), 173.2 (NH-CO).

ESI-MS: m/z = 858 [M + H]⁺, 880 [M + Na]⁺, 896 [M + K]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₅₀H₁₀₀NO₉: 858.7392; found: 858.7394.

Acknowledgment

This work was supported by the Fonds der Chemischen Industrie and the Deutsche Forschungsgemeinschaft (Schwerpunktprogramm 1179 Organokatalyse). We thank the companies Bayer AG, BASF AG, Wacker Chemie and the former Degussa AG for the donation of chemicals.

References

• 1a Natori T. Koezuka Y. Higa T. Tetrahedron Lett.  1993,  34:  5591 
  Search in Google Scholar
• 1b Natori T. Morita M. Akimoto K. Koezuka Y. Tetrahedron  1994,  50:  2771 
  Search in Google Scholar
• 2a Morita M. Kazuhiro M. Akimoto K. Natori T. Sakai T. Sawa E. Yamaji K. Koezuka Y. Kobayashi E. Fukushima H. J. Med. Chem.  1995,  38:  2176 
  Search in Google Scholar
• 2b Motoki K. Kobayashi E. Uchida T. Fukushima H. Koezuka Y. Bioorg. Med. Chem. Lett.  1995,  5:  705 
  Search in Google Scholar
• 2c Koezuka Y. Kazuhiro M. Sakai T. Takenori N. Recent Res. Dev. Cancer  1999,  1:  341 
  Search in Google Scholar
• 3a Kawano T. Cui J. Koezuka Y. Toura I. Kaneko Y. Motoki K. Ueno H. Nakagawa R. Sato H. Kondo E. Koseki H. Taniguchi M. Science  1997,  278:  1626 
  Search in Google Scholar
• 3b Yamaguchi Y. Motoki K. Ueno H. Maeda K. Kobayashi E. Inoue H. Fukushima H. Koezuka Y. Oncology Res.  1996,  8:  399 
  Search in Google Scholar
• 3c Hénon E. Dauchez M. Haudrechy A. Banchet A. Tetrahedron  2008,  64:  9480 
  Search in Google Scholar
• 4 Kobayashi E. Motoki K. Uchida T. Fukushima H. Koezuka Y. Oncology Res.  1995,  7:  529 
  PubMedSearch in Google Scholar
• 5a Van Kaer L. Nat. Rev. Immunol.  2005,  5:  31 
  Search in Google Scholar
• 5b Van Kaer L. Immunol. Cell Biol.  2004,  82:  315 
  Search in Google Scholar
• 6a Duarte N. Stenström M. Campino S. Bergman ML. Lundholm M. Holmberg D. Cardell SL. J. Immunol.  2004,  173:  3112 
  Search in Google Scholar
• 6b Hong S. Wilson MT. Serizawa I. Wu L. Singh N. Naidenko OV. Miura T. Haba T. Scherer DC. Wei J. Kronenberg M. Koezuka Y. Van Kaer L. Nature Med.  2001,  7:  1052 
  Search in Google Scholar
• 6c Falcone M. Facciotti F. Ghidoli N. Monti P. Olivieri S. Zaccagnino L. Bonifacio E. Casorati G. Sanvito F. Sarvetnick N. J. Immunol.  2004,  172:  5908 
  Search in Google Scholar
• 7a Kakimi K. Guidotti LG. Koezuka Y. Chisari FV. J. Exp. Med.  2000,  192:  921 
  Search in Google Scholar
• 7b Baron JL. Gardiner L. Nishimura S. Shinkai K. Locksley R. Ganem D. Immunity  2002,  16:  583 
  Search in Google Scholar
• 8 Chackerian A. Alt J. Perera V. Behar SM. Infect. Immun.  2002,  70:  6302 
  CrossrefSearch in Google Scholar
• 9a Hansen DS. Siomos M. Koning-Ward T. Buckingham L. Crabb BS. Schofield L. Eur. J. Immunol.  2003,  33:  2588 
  Search in Google Scholar
• 9b Gonzalez-Aseguinolaza G. Van Kaer L. Bergmann CC. Wilson JM. Schmieg J. Kronenberg M. Nakayama T. Taniguchi M. Koezuka Y. Tsuji M. J. Exp. Med.  2002,  195:  617 
  Search in Google Scholar
• 10 Kobayashi E. Motoki K. Yamaguchi Y. Uchida T. Fukushima H. Koezuka Y. Bioorg. Med. Chem. Lett.  1996,  4:  615 
  CrossrefSearch in Google Scholar
• For selected examples, see:
• 11a Morita M. Natori T. Akimoto K. Osawa T. Fukushima H. Koezuka Y. Bioorg. Med. Chem. Lett.  1995,  5:  699 
  Search in Google Scholar
• 11b Takikawa H. Muto S. Mori K. Tetrahedron  1998,  54:  3141 
  Search in Google Scholar
• 11c Figueroa-Pérez S. Schmidt RR. Carbohydr. Res.  2000,  328:  95 
  Search in Google Scholar
• 11d Plettenburg O. Bodmer-Narkevitch V. Wong C. J. Org. Chem.  2002,  67:  4559 
  Search in Google Scholar
• 11e Kim S. Song S. Lee T. Jung S. Kim D. Synthesis  2004,  847 
• 11f Xia C. Yao Q. Schümann J. Rossy E. Chen W. Zhu L. Zhang W. Libero GD. Wang PG. Bioorg. Med. Chem. Lett.  2006,  16:  2195 
  Search in Google Scholar
• 11g Michieletti M. Bracci A. Compostella F. De Libero G. Mori L. Fallarini S. Lombardi G. Panza L. J. Org. Chem.  2008,  73:  9192 
  Search in Google Scholar
• 11h Park J. Lee JH. Ghosh SC. Bricard G. Venkataswamy M. Porcelli SA. Chung S. Bioorg. Med. Chem. Lett.  2008,  18:  3906 
  Search in Google Scholar
• 11i Boututeira O. Morales-Serna JA. Diaz Y. Matheu MI. Castillón S. Eur. J. Org. Chem.  2008,  1851 
• 11j Morales-Serna JA. Boututeira O. Diaz Y. Matheu MI. Castillón S. Carbohydr. Res.  2007,  342:  1595 
  Search in Google Scholar
• 11k Veerapen N. Brigl M. Garg S. Cerundolo V. Cox LR. Brenner MB. Besra GS. Bioorg. Med. Chem. Lett.  2009,  19:  4288 
  Search in Google Scholar
• 12 For β-GalCer, see: Rai AN. Basu A. J. Org. Chem.  2005,  70:  8228 
  CrossrefSearch in Google Scholar
• For α-C-glycoside analogues, see:
• 13a Yang G. Schmieg J. Tsuji M. Franck RW. Angew. Chem. Int. Ed.  2004,  43:  3818 ; Angew. Chem. 2004, 116, 3906
  Search in Google Scholar
• 13b Wipf P. Pierce JG. Org. Lett.  2006,  8:  3375 
  Search in Google Scholar
• 13c Pu J. Franck RW. Tetrahedron  2008,  64:  8618 
  Search in Google Scholar
• For β-C-glycoside analogues, see:
• 14a Chaulagain MR. Postema MHD. Valeriote F. Pietraszkewicz H. Tetrahedron Lett.  2004,  45:  7791 
  Search in Google Scholar
• 14b Postema MHD. Piper JL. Betts RL. Synlett  2005,  1345 
• For α-S-glycoside analogues, see:
• 15a Dere RT. Zhu X. Org. Lett.  2008,  10:  4641 
  Search in Google Scholar
• 15b Blauvelt ML. Khalili M. Jaung W. Paulsen J. Anderson AC. Wilson SB. Howell AR. Bioorg. Med. Chem. Lett.  2008,  18:  6374 
  Search in Google Scholar
• 15c Rajan R. Mathew T. Buffa R. Bornancin F. Cavallari M. Nussbaumer P. De Libero G. Vasella A. Helv. Chim. Acta  2009,  92:  918 
  Search in Google Scholar
• Truncated analogues:
• 16a Fan GT. Pan Y. Lu KC. Cheng YP. Lin WC. Lin S. Lin CH. Wong CH. Fang JM. Lin CC. Tetrahedron  2005,  61:  1855 
  Search in Google Scholar
• 16b Tsujimoto T. Ito Y. Tetrahedron Lett.  2007,  48:  5513 
  Search in Google Scholar
• Sphinganine analogues:
• 16c Ndonye RM. Izmirian DP. Dunn MF. Yu KOA. Porcelli SA. Khurana A. Kronenberg M. Richardson SK. Howell AR. J. Org. Chem.  2005,  70:  10260 
  Search in Google Scholar
• 16d Lacône V. Hunault J. Pipelier M. Blot V. Lecourt T. Rocher J. Turcot-Dubois AL. Marionneau S. Douillard JY. Clément M. Le Pendu J. Bonneville M. Micouin L. Dubreuil D. J. Med. Chem.  2009,  52:  4960 
  Search in Google Scholar
• 16e Du W. Gervay-Hague J. Org. Lett.  2005,  7:  2063 
  Search in Google Scholar
• For BODIPY α-GalCer, see:
• 17a Vo-Hoang Y. Micouin L. Ronet C. Gachelin G. Bonin M. ChemBioChem  2003,  4:  27 
  Search in Google Scholar
• RCAI derivatives, see:
• 17b Tashiro T. Hongo N. Nakagawa R. Seino K. Watarai H. Ishii Y. Tanaguchi M. Mori K. Bioorg. Med. Chem.  2008,  16:  8896 
  Search in Google Scholar
• 17c Tashiro T. Nakagawa R. Inoue S. Shiozaki M. Watarai H. Taniguchi M. Mori K. Tetrahedron Lett.  2008,  49:  6827 
  Search in Google Scholar
• 17d Tashiro T. Nakagawa R. Hirokawa T. Inoue S. Watarai H. Taniguchi M. Mori K. Tetrahedron Lett.  2007,  48:  3343 
  Search in Google Scholar
• For iGb3 derivatives, see:
• 18a Kimura A. Imamura A. Ando H. Ishida H. Kiso M. Synlett  2006,  2379 
• 18b

  See also ref. 11f.
• 18c For tritiated analogues: Risseeuw MDP. Berkers CR. Ploegh HL. Ovaa H. Tetrahedron Lett.  2006,  47:  3677 
  Search in Google Scholar
• 18d For biotinylated derivatives, see: Sakai T. Naidenko OV. Iijima H. Kronenberg M. Koezuka Y. J. Med. Chem.  1999,  42:  1836 
  Search in Google Scholar
• 18e For NBD-derivatives, see: Sakai T. Ehara H. Koezuka Y. Org. Lett.  1999,  1:  359 
  Search in Google Scholar
• For fluoro analogues, see:
• 19a Leung L. Tomassi C. Van Beneden K. Decruy T. Trappeniers M. Elewaut D. Gao Y. Elliott T. Al-Shamkhani A. Ottensmeier C. Werner JM. Williams A. Van Calenbergh S. Linclau B. ChemMedChem  2009,  4:  329 
  Search in Google Scholar
• 19b Leung L. Tomassi C. Van Beneden K. Decruy T. Elewaut D. Elliott T. Al-Shamkhani A. Ottensmeier C. Van Calenbergh S. Werner J. Williams T. Linclau B. Org. Lett.  2008,  10:  4433 
  Search in Google Scholar
• 19c For triazole analogues, see: Lee T. Cho M. Ko S. Youn H. Baek D. Cho W. Kang C. Kim S. J. Med. Chem.  2007,  50:  585 
  Search in Google Scholar
• GalCer related compounds:
• 20a Matto P. Modica E. Franchini L. Facciotti F. Mori L. De Libero G. Lombardi G. Fallarini S. Panza L. Compostella F. Ronchetti F. J. Org. Chem.  2007,  72:  7757 
  Search in Google Scholar
• 20b Stallforth P. Adibekian A. Seeberger PH. Org. Lett.  2008,  10:  1573 
  Search in Google Scholar
• 20c Park JJ. Lee JH. Seo KC. Bricard G. Venkataswamy MM. Porcelli SA. Chung SK. Bioorg. Med. Chem. Lett.  2010,  20:  814 
  Search in Google Scholar
• 20d For carbocyclic analogues, see: Yu SH. Park JJ. Chung SK. Tetrahedron: Asymmetry  2006,  17:  3030 
  Search in Google Scholar
• 21 Enders D. Paleček J. Grondal C. Chem. Commun.  2006,  655 
  Crossref
• 2,2-Dimethyl-1,3-dioxan-5-one was prepared in two steps from tris(hydroxymethyl)aminomethane hydrochloride, see:
• 22a Review: Enders D. Voith M. Lenzen A. Angew. Chem.Int. Ed.  2005,  44:  1304 ; Angew. Chem. 2005, 117, 1330
  Search in Google Scholar
• 22b Enders D. Voith M. Ince SJ. Synthesis  2002,  1775 
• 22c Enders D. Whitehouse DL. Runsink J. Chem. Eur. J.  1995,  1:  382 
  Search in Google Scholar
• 23 1-Pentadecanal was prepared in one step from 1-penta-decanol using IBX, see: More JD. Finney NS. Org. Lett.  2002,  4:  3001 
  CrossrefSearch in Google Scholar
• 24a Enders D. Grondal C. Angew. Chem. Int. Ed.  2005,  44:  1210 ; Angew. Chem. 2005, 117, 1235
  Search in Google Scholar
• 24b Enders D. Grondal C. Vrettou M. Raabe G. Angew. Chem. Int. Ed.  2005,  44:  4079 ; Angew. Chem. 2005, 117, 4147
  Search in Google Scholar
• 24c Westermann B. Neuhaus C. Angew. Chem. Int. Ed.  2005,  44:  4077 ; Angew. Chem. 2005, 117, 4145
  Search in Google Scholar
• 24d Suri JT. Ramachary DB. Barbas CF. Org. Lett.  2005,  7:  1383 
  Search in Google Scholar
• 24e Ibrahem I. Córdova A. Tetrahedron Lett.  2005,  46:  3363 
  Search in Google Scholar
• 24f Grondal C. Enders D. Tetrahedron  2006,  62:  329 
  Search in Google Scholar
• 24g Enders D. Vrettou M. Synthesis  2006,  2155 
• 24h Enders D. Grondal C. Vrettou M. Synthesis  2006,  3597 
• 24i Grondal C. Enders D. Synlett  2006,  3507 
• 24j Enders D. Chow S. Eur. J. Org. Chem.  2006,  4578 
• 24k Suri JT. Mitsumori S. Albertshofer K. Tanaka F. Barbas CF. J. Org. Chem.  2006,  71:  3822 
  Search in Google Scholar
• 24l Ibrahem I. Zou W. Casas J. Sundén H. Córdova A. Tetrahedron  2006,  62:  357 
  Search in Google Scholar
• 24m Ibrahem I. Zou W. Xu Y. Córdova A. Adv. Synth. Catal.  2006,  348:  211 
  Search in Google Scholar
• 24n Majewski M. Niewczas I. Palyam N. Synlett  2006,  2387 
• 24o Grondal C. Enders D. Adv. Synth. Catal.  2007,  349:  694 
  Search in Google Scholar
• 25 Enders D. Terteryan V. Paleček J. Synthesis  2008,  2278 
  Thieme Connect
• 26a Schmidt RR. Michel J. Angew. Chem. Int. Ed. Engl.  1980,  19:  731 
  Search in Google Scholar
• 26b Schmidt RR. Michel J. Roos M. Liebigs Ann. Chem.  1984,  1343 
• 26c Schmidt RR. Angew. Chem., Int. Ed. Engl.  1986,  25:  212 ; Angew. Chem.; 1986, 98: 213
  Search in Google Scholar
• 27 Xing GW. Wu D. Poles MA. Horowitz A. Tsuji M. Ho DD. Wong CH. Bioorg. Med. Chem.  2005,  13:  2907 
  CrossrefSearch in Google Scholar

References

• 1a Natori T. Koezuka Y. Higa T. Tetrahedron Lett.  1993,  34:  5591 
  Search in Google Scholar
• 1b Natori T. Morita M. Akimoto K. Koezuka Y. Tetrahedron  1994,  50:  2771 
  Search in Google Scholar
• 2a Morita M. Kazuhiro M. Akimoto K. Natori T. Sakai T. Sawa E. Yamaji K. Koezuka Y. Kobayashi E. Fukushima H. J. Med. Chem.  1995,  38:  2176 
  Search in Google Scholar
• 2b Motoki K. Kobayashi E. Uchida T. Fukushima H. Koezuka Y. Bioorg. Med. Chem. Lett.  1995,  5:  705 
  Search in Google Scholar
• 2c Koezuka Y. Kazuhiro M. Sakai T. Takenori N. Recent Res. Dev. Cancer  1999,  1:  341 
  Search in Google Scholar
• 3a Kawano T. Cui J. Koezuka Y. Toura I. Kaneko Y. Motoki K. Ueno H. Nakagawa R. Sato H. Kondo E. Koseki H. Taniguchi M. Science  1997,  278:  1626 
  Search in Google Scholar
• 3b Yamaguchi Y. Motoki K. Ueno H. Maeda K. Kobayashi E. Inoue H. Fukushima H. Koezuka Y. Oncology Res.  1996,  8:  399 
  Search in Google Scholar
• 3c Hénon E. Dauchez M. Haudrechy A. Banchet A. Tetrahedron  2008,  64:  9480 
  Search in Google Scholar
• 4 Kobayashi E. Motoki K. Uchida T. Fukushima H. Koezuka Y. Oncology Res.  1995,  7:  529 
  PubMedSearch in Google Scholar
• 5a Van Kaer L. Nat. Rev. Immunol.  2005,  5:  31 
  Search in Google Scholar
• 5b Van Kaer L. Immunol. Cell Biol.  2004,  82:  315 
  Search in Google Scholar
• 6a Duarte N. Stenström M. Campino S. Bergman ML. Lundholm M. Holmberg D. Cardell SL. J. Immunol.  2004,  173:  3112 
  Search in Google Scholar
• 6b Hong S. Wilson MT. Serizawa I. Wu L. Singh N. Naidenko OV. Miura T. Haba T. Scherer DC. Wei J. Kronenberg M. Koezuka Y. Van Kaer L. Nature Med.  2001,  7:  1052 
  Search in Google Scholar
• 6c Falcone M. Facciotti F. Ghidoli N. Monti P. Olivieri S. Zaccagnino L. Bonifacio E. Casorati G. Sanvito F. Sarvetnick N. J. Immunol.  2004,  172:  5908 
  Search in Google Scholar
• 7a Kakimi K. Guidotti LG. Koezuka Y. Chisari FV. J. Exp. Med.  2000,  192:  921 
  Search in Google Scholar
• 7b Baron JL. Gardiner L. Nishimura S. Shinkai K. Locksley R. Ganem D. Immunity  2002,  16:  583 
  Search in Google Scholar
• 8 Chackerian A. Alt J. Perera V. Behar SM. Infect. Immun.  2002,  70:  6302 
  CrossrefSearch in Google Scholar
• 9a Hansen DS. Siomos M. Koning-Ward T. Buckingham L. Crabb BS. Schofield L. Eur. J. Immunol.  2003,  33:  2588 
  Search in Google Scholar
• 9b Gonzalez-Aseguinolaza G. Van Kaer L. Bergmann CC. Wilson JM. Schmieg J. Kronenberg M. Nakayama T. Taniguchi M. Koezuka Y. Tsuji M. J. Exp. Med.  2002,  195:  617 
  Search in Google Scholar
• 10 Kobayashi E. Motoki K. Yamaguchi Y. Uchida T. Fukushima H. Koezuka Y. Bioorg. Med. Chem. Lett.  1996,  4:  615 
  CrossrefSearch in Google Scholar
• For selected examples, see:
• 11a Morita M. Natori T. Akimoto K. Osawa T. Fukushima H. Koezuka Y. Bioorg. Med. Chem. Lett.  1995,  5:  699 
  Search in Google Scholar
• 11b Takikawa H. Muto S. Mori K. Tetrahedron  1998,  54:  3141 
  Search in Google Scholar
• 11c Figueroa-Pérez S. Schmidt RR. Carbohydr. Res.  2000,  328:  95 
  Search in Google Scholar
• 11d Plettenburg O. Bodmer-Narkevitch V. Wong C. J. Org. Chem.  2002,  67:  4559 
  Search in Google Scholar
• 11e Kim S. Song S. Lee T. Jung S. Kim D. Synthesis  2004,  847 
• 11f Xia C. Yao Q. Schümann J. Rossy E. Chen W. Zhu L. Zhang W. Libero GD. Wang PG. Bioorg. Med. Chem. Lett.  2006,  16:  2195 
  Search in Google Scholar
• 11g Michieletti M. Bracci A. Compostella F. De Libero G. Mori L. Fallarini S. Lombardi G. Panza L. J. Org. Chem.  2008,  73:  9192 
  Search in Google Scholar
• 11h Park J. Lee JH. Ghosh SC. Bricard G. Venkataswamy M. Porcelli SA. Chung S. Bioorg. Med. Chem. Lett.  2008,  18:  3906 
  Search in Google Scholar
• 11i Boututeira O. Morales-Serna JA. Diaz Y. Matheu MI. Castillón S. Eur. J. Org. Chem.  2008,  1851 
• 11j Morales-Serna JA. Boututeira O. Diaz Y. Matheu MI. Castillón S. Carbohydr. Res.  2007,  342:  1595 
  Search in Google Scholar
• 11k Veerapen N. Brigl M. Garg S. Cerundolo V. Cox LR. Brenner MB. Besra GS. Bioorg. Med. Chem. Lett.  2009,  19:  4288 
  Search in Google Scholar
• 12 For β-GalCer, see: Rai AN. Basu A. J. Org. Chem.  2005,  70:  8228 
  CrossrefSearch in Google Scholar
• For α-C-glycoside analogues, see:
• 13a Yang G. Schmieg J. Tsuji M. Franck RW. Angew. Chem. Int. Ed.  2004,  43:  3818 ; Angew. Chem. 2004, 116, 3906
  Search in Google Scholar
• 13b Wipf P. Pierce JG. Org. Lett.  2006,  8:  3375 
  Search in Google Scholar
• 13c Pu J. Franck RW. Tetrahedron  2008,  64:  8618 
  Search in Google Scholar
• For β-C-glycoside analogues, see:
• 14a Chaulagain MR. Postema MHD. Valeriote F. Pietraszkewicz H. Tetrahedron Lett.  2004,  45:  7791 
  Search in Google Scholar
• 14b Postema MHD. Piper JL. Betts RL. Synlett  2005,  1345 
• For α-S-glycoside analogues, see:
• 15a Dere RT. Zhu X. Org. Lett.  2008,  10:  4641 
  Search in Google Scholar
• 15b Blauvelt ML. Khalili M. Jaung W. Paulsen J. Anderson AC. Wilson SB. Howell AR. Bioorg. Med. Chem. Lett.  2008,  18:  6374 
  Search in Google Scholar
• 15c Rajan R. Mathew T. Buffa R. Bornancin F. Cavallari M. Nussbaumer P. De Libero G. Vasella A. Helv. Chim. Acta  2009,  92:  918 
  Search in Google Scholar
• Truncated analogues:
• 16a Fan GT. Pan Y. Lu KC. Cheng YP. Lin WC. Lin S. Lin CH. Wong CH. Fang JM. Lin CC. Tetrahedron  2005,  61:  1855 
  Search in Google Scholar
• 16b Tsujimoto T. Ito Y. Tetrahedron Lett.  2007,  48:  5513 
  Search in Google Scholar
• Sphinganine analogues:
• 16c Ndonye RM. Izmirian DP. Dunn MF. Yu KOA. Porcelli SA. Khurana A. Kronenberg M. Richardson SK. Howell AR. J. Org. Chem.  2005,  70:  10260 
  Search in Google Scholar
• 16d Lacône V. Hunault J. Pipelier M. Blot V. Lecourt T. Rocher J. Turcot-Dubois AL. Marionneau S. Douillard JY. Clément M. Le Pendu J. Bonneville M. Micouin L. Dubreuil D. J. Med. Chem.  2009,  52:  4960 
  Search in Google Scholar
• 16e Du W. Gervay-Hague J. Org. Lett.  2005,  7:  2063 
  Search in Google Scholar
• For BODIPY α-GalCer, see:
• 17a Vo-Hoang Y. Micouin L. Ronet C. Gachelin G. Bonin M. ChemBioChem  2003,  4:  27 
  Search in Google Scholar
• RCAI derivatives, see:
• 17b Tashiro T. Hongo N. Nakagawa R. Seino K. Watarai H. Ishii Y. Tanaguchi M. Mori K. Bioorg. Med. Chem.  2008,  16:  8896 
  Search in Google Scholar
• 17c Tashiro T. Nakagawa R. Inoue S. Shiozaki M. Watarai H. Taniguchi M. Mori K. Tetrahedron Lett.  2008,  49:  6827 
  Search in Google Scholar
• 17d Tashiro T. Nakagawa R. Hirokawa T. Inoue S. Watarai H. Taniguchi M. Mori K. Tetrahedron Lett.  2007,  48:  3343 
  Search in Google Scholar
• For iGb3 derivatives, see:
• 18a Kimura A. Imamura A. Ando H. Ishida H. Kiso M. Synlett  2006,  2379 
• 18b

  See also ref. 11f.
• 18c For tritiated analogues: Risseeuw MDP. Berkers CR. Ploegh HL. Ovaa H. Tetrahedron Lett.  2006,  47:  3677 
  Search in Google Scholar
• 18d For biotinylated derivatives, see: Sakai T. Naidenko OV. Iijima H. Kronenberg M. Koezuka Y. J. Med. Chem.  1999,  42:  1836 
  Search in Google Scholar
• 18e For NBD-derivatives, see: Sakai T. Ehara H. Koezuka Y. Org. Lett.  1999,  1:  359 
  Search in Google Scholar
• For fluoro analogues, see:
• 19a Leung L. Tomassi C. Van Beneden K. Decruy T. Trappeniers M. Elewaut D. Gao Y. Elliott T. Al-Shamkhani A. Ottensmeier C. Werner JM. Williams A. Van Calenbergh S. Linclau B. ChemMedChem  2009,  4:  329 
  Search in Google Scholar
• 19b Leung L. Tomassi C. Van Beneden K. Decruy T. Elewaut D. Elliott T. Al-Shamkhani A. Ottensmeier C. Van Calenbergh S. Werner J. Williams T. Linclau B. Org. Lett.  2008,  10:  4433 
  Search in Google Scholar
• 19c For triazole analogues, see: Lee T. Cho M. Ko S. Youn H. Baek D. Cho W. Kang C. Kim S. J. Med. Chem.  2007,  50:  585 
  Search in Google Scholar
• GalCer related compounds:
• 20a Matto P. Modica E. Franchini L. Facciotti F. Mori L. De Libero G. Lombardi G. Fallarini S. Panza L. Compostella F. Ronchetti F. J. Org. Chem.  2007,  72:  7757 
  Search in Google Scholar
• 20b Stallforth P. Adibekian A. Seeberger PH. Org. Lett.  2008,  10:  1573 
  Search in Google Scholar
• 20c Park JJ. Lee JH. Seo KC. Bricard G. Venkataswamy MM. Porcelli SA. Chung SK. Bioorg. Med. Chem. Lett.  2010,  20:  814 
  Search in Google Scholar
• 20d For carbocyclic analogues, see: Yu SH. Park JJ. Chung SK. Tetrahedron: Asymmetry  2006,  17:  3030 
  Search in Google Scholar
• 21 Enders D. Paleček J. Grondal C. Chem. Commun.  2006,  655 
  Crossref
• 2,2-Dimethyl-1,3-dioxan-5-one was prepared in two steps from tris(hydroxymethyl)aminomethane hydrochloride, see:
• 22a Review: Enders D. Voith M. Lenzen A. Angew. Chem.Int. Ed.  2005,  44:  1304 ; Angew. Chem. 2005, 117, 1330
  Search in Google Scholar
• 22b Enders D. Voith M. Ince SJ. Synthesis  2002,  1775 
• 22c Enders D. Whitehouse DL. Runsink J. Chem. Eur. J.  1995,  1:  382 
  Search in Google Scholar
• 23 1-Pentadecanal was prepared in one step from 1-penta-decanol using IBX, see: More JD. Finney NS. Org. Lett.  2002,  4:  3001 
  CrossrefSearch in Google Scholar
• 24a Enders D. Grondal C. Angew. Chem. Int. Ed.  2005,  44:  1210 ; Angew. Chem. 2005, 117, 1235
  Search in Google Scholar
• 24b Enders D. Grondal C. Vrettou M. Raabe G. Angew. Chem. Int. Ed.  2005,  44:  4079 ; Angew. Chem. 2005, 117, 4147
  Search in Google Scholar
• 24c Westermann B. Neuhaus C. Angew. Chem. Int. Ed.  2005,  44:  4077 ; Angew. Chem. 2005, 117, 4145
  Search in Google Scholar
• 24d Suri JT. Ramachary DB. Barbas CF. Org. Lett.  2005,  7:  1383 
  Search in Google Scholar
• 24e Ibrahem I. Córdova A. Tetrahedron Lett.  2005,  46:  3363 
  Search in Google Scholar
• 24f Grondal C. Enders D. Tetrahedron  2006,  62:  329 
  Search in Google Scholar
• 24g Enders D. Vrettou M. Synthesis  2006,  2155 
• 24h Enders D. Grondal C. Vrettou M. Synthesis  2006,  3597 
• 24i Grondal C. Enders D. Synlett  2006,  3507 
• 24j Enders D. Chow S. Eur. J. Org. Chem.  2006,  4578 
• 24k Suri JT. Mitsumori S. Albertshofer K. Tanaka F. Barbas CF. J. Org. Chem.  2006,  71:  3822 
  Search in Google Scholar
• 24l Ibrahem I. Zou W. Casas J. Sundén H. Córdova A. Tetrahedron  2006,  62:  357 
  Search in Google Scholar
• 24m Ibrahem I. Zou W. Xu Y. Córdova A. Adv. Synth. Catal.  2006,  348:  211 
  Search in Google Scholar
• 24n Majewski M. Niewczas I. Palyam N. Synlett  2006,  2387 
• 24o Grondal C. Enders D. Adv. Synth. Catal.  2007,  349:  694 
  Search in Google Scholar
• 25 Enders D. Terteryan V. Paleček J. Synthesis  2008,  2278 
  Thieme Connect
• 26a Schmidt RR. Michel J. Angew. Chem. Int. Ed. Engl.  1980,  19:  731 
  Search in Google Scholar
• 26b Schmidt RR. Michel J. Roos M. Liebigs Ann. Chem.  1984,  1343 
• 26c Schmidt RR. Angew. Chem., Int. Ed. Engl.  1986,  25:  212 ; Angew. Chem.; 1986, 98: 213
  Search in Google Scholar
• 27 Xing GW. Wu D. Poles MA. Horowitz A. Tsuji M. Ho DD. Wong CH. Bioorg. Med. Chem.  2005,  13:  2907 
  CrossrefSearch in Google Scholar