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Synthesis 2009(14): 2423-2429  
DOI: 10.1055/s-0029-1216835
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Rhodium Carbenoid Induced [1,2]-Migration in an l-Lyxo-Configured α-Diazo β-Keto Ester: Synthesis of a New Griseolic Acid Analogue

Namdeo N. Bhujbal, K. S. Ajish Kumar, Dilip D. Dhavale*
Department of Chemistry, Garware Research Centre, University of Pune, Pune 411007, India
Fax: +91(20)25691728 ; e-Mail: ddd@chem.unipune.ernet.in;

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Publication History

Received 10 February 2009
Publication Date:
19 May 2009 (online)

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Abstract

An appropriately substituted α-diazo β-keto ester, prepared from d-glucose, on treatment with a catalytic amount of dirhodium tetraacetate gave a strained 1,5-dioxabicyclo[3.3.0]octane ring system with concomitant diastereoselective formation of a quaternary carbon substituted with both an ethoxycarbonyl group and a 2-ethoxy-2-oxoethyl group; the product is a key intermediate in the synthesis of a new griseolic acid analogue.

Key words

carbenoids - carbohydrates - carboxylic acids - diazo compounds - oxygen heterocycles

Griseolic acids are a group of bicyclic adenine-base nucleosides isolated from culture broths of Streptomyces griseoaurantiacus SANK 63479. [¹] On the basis of spectroscopic and crystallographic studies, griseolic acids A and B have been assigned the structures 1a and 1b, respectively, which contain an endo-cyclic double bond at the ring junction. Griseolic acid C (1c) has been shown to be a saturated form of griseolic acid B with a d-ribo configuration (Figure  [¹] ).

Figure 1 Griseolic acid bicyclic nucleosides

Griseolic acids act as strong competitive inhibitors of cyclic guanosine monophosphate phosphodiesterase and as templates in the search for more selective inhibitors in antihypertensive­ agents. [²] Some structural analogues of griseolic acids are more active and selective than the natural compounds. [²] [³]

Attempts at total syntheses of griseolic acid and its analogues have been hampered by stereochemical and structural complications. These include problems in the formation of the strained 1,5-dioxabicyclo[3.3.0]octane ring system, difficulties in the diastereoselective formation of the quaternary C-6′ atom carrying both alkoxycarbonyl and 2-alkoxy-2-oxoethyl substituents, problems in the introduction of the adenine nucleoside in the β-position, and difficulties arising from the presence of a reactive vinyl ether group at C-4′. Despite these problems, a few strategies are known for the synthesis of griseolic acid and its structural analogues; these involve either modification of an existing natural product or the use of d-glucose as a substrate. [4] Tulshian and co-workers reported a total synthesis of griseolic acid A and its derivatives from d-glucose, in which the dioxabicyclo ring with the alk­oxy­carbonyl group was initially constructed and the two-carbon acid unit (the 2-alkoxy-2-oxoethyl group) was added by means of carbanion chemistry. [5] Knapp and co-workers reported a one-pot, π-face-dependent, radical cyclization that gives the oxabicyclo ring with the necessary substituents on the quaternary carbon. [6] As a part of our studies on rhodium carbenoid chemistry, [7] we reported a dirhodium tetraacetate-catalyzed reaction of a d-xylo α-diazo β-keto ester A to give the key intermediate B in which the formation of the oxabicyclo ring skeleton and the generation of the quaternary carbon with the required stereochemistry (6′R) occurred simultaneously through α-facial [1,2]-migration of the 2-ethoxy-2-oxoethyl group, thereby providing access to the griseolic acid analogue 1d (Scheme   [¹] ). [8]

Scheme 1 Synthesis of the griseolic acid analogue 1d

As an extension of this method, we investigated the reaction of dirhodium tetraacetate with an l-lyxo-configured α-diazo β-keto ester to give the 1,5-dioxabicyclic ring system. We hypothesized that the oxonium ylide-mediated [1,2]-migration of the 2-ethoxy-2-oxoethyl group might provide control of the stereochemistry at the quaternary carbon (C-6), and that the product could be elaborated to give the target molecule. By this method, we prepared a griseolic acid B analogue 1e (Figure  [¹] ), and we studied the mechanism of the rhodium carbenoid chemistry that was involved in the synthesis.

d-Glucose was converted into the enol acetate 2 (Scheme  [²] ) as reported earlier. [9] Hydrogenation of 2 over 10% palladium/carbon at balloon pressure and 40 ˚C gave 1,2:5,6-di-O-isopropylidene-3-O-acetyl-α-d-gulofuranose (3a) in 86% yield. [¹0] Treatment of 3a with sodium methoxide in methanol led to a complex mixture of products, whereas treatment with lithium aluminum hydride in tetrahydrofuran at 0 ˚C gave the deacetylated product 3b in 96% yield. In the next step, 3b was treated with ethyl bromoacetate in the presence of sodium hydride in tetrahydrofuran to give the ester 3c as a white solid. Regioselective deprotection of the 5,6-isopropylidene functionality in 3c by treatment with 20% trifluoroacetic acid in dichloromethane added slowly over six hours at 15 ˚C gave the corresponding diol; this underwent oxidative cleavage with sodium metaperiodate to give the aldehyde ester 4 in 53% yield over the two steps. [¹¹] Treatment of aldehyde ester 4 with ethyl diazoacetate (EDA) in the presence of catalytic amount of boron trifluoride diethyl etherate gave the β-keto ester 5, [¹²] which on treatment with mesyl azide and triethylamine gave the 3-O-(2-ethoxy-2-oxoethyl) α-diazo β-keto ester 6. In a key step, the reaction of diazo compound 6 in the presence of a catalytic amount of dirhodium tetracetate in refluxing benzene gave the bicyclic ketone 7. The IR spectrum of the crude product showed bands at 1784 and 1741 cm-¹, indicating the presence of the five-membered ring ketone and the ester carbonyl group, respectively. The ¹H NMR spectrum was, however, found to be complex, and therefore the assignment of the structure was made after the subsequent step. [¹³] Ketone 7 was treated with sodium borohydride in methanol to give bicyclic C-5α hydroxy compound 8 as the sole isolable product in 54% yield. [¹4] The structure of 8, the stereochemistry at C-6, and the nature of the rhodium carbenoid reaction were determined by means of ¹H NMR spectroscopy and decoupling experiments. The two doublets at δ = 2.48 and 3.04 with J 7a,7b = 14.5 Hz were assigned to the methylene protons of the 2-ethoxy-2-oxoeth­yl group. The H-5 proton appeared as a doublet at δ = 4.07 (J 5,4 = 6.8 Hz), the high coupling constant in the furan ring showed a cis relative stereochemistry with H-4. In the precursor l-lyxo diazo compound 6, the initial β-oriented cis-stereochemistry of H-2, H-3 and H-4, and the observed cis-stereochemistry of H-4 and H-5, ensure that H-5 has a β-orientation in 8. In one-dimensional (1D) NOESY experiments (Scheme   [²] ), irradiation of one of the C-7 methylene­ protons at δ = 2.48 showed a nuclear Overhauser effect (NOE) with H-3, H-4, and H-5, whereas, irradiation of other methylene proton at δ = 3.04 showed a NOE with H-5, demonstrating the syn-relationship of the C-7 methylene protons with the protons of the sugar ring. In addition, one of the methyl protons of the 1,2-O-isopropylidene group appeared at δ = 1.67 as a result of the diamagnetic anisotropic deshielding effect of the α-oriented carboxylate functionality. On the basis of this spectroscopic analysis, the alcohol was assigned the structure 8, and therefore the rhodium carbenoid reaction product has the bicyclic ketone structure 7 with an (S)-absolute configuration at the quaternary carbon atom C-6.

Scheme 2 Synthesis of the griseolic acid analogue 1e

A plausible mechanism for the formation of the bicyclic keto product 7 by the dirhodium tetraacetate catalyzed reaction of diazo compound 6 could involve the initial generation of the rhodium carbenoid species A (Scheme  [³] ), which accepts a lone pair of electrons from the oxygen atom to form an oxonium ylide B. During the reaction, the 2-ethoxy-2-oxoethyl group migrates from the oxygen to the rhodium atom via the four-centered oxabicyclo[3.2.0]heptane transition state C to give the transition state D. Subsequently, cleavage of the Rh-CH2COOEt bond followed by concerted formation of a new carbon-carbon bond between C-6 and the 2-ethoxy-2-oxoethyl group, and cleavage of the Rh-C-6 bond with loss of dirhodium tetraacetate, in a three-membered transition state E, gives the 1,5-dioxabicyclo[3.3.0]octane ring skeleton and the quaternary carbon (C-6) with the requisite ethoxycarbonyl and 2-ethoxy-2-oxoethyl functionalities with an (S)-absolute configuration at C-6.

Scheme 3 A mechanism for the formation of the bicyclic ketone intermediate 7

Note that in the d-xylo α-diazo-β-keto ester A, both the substituents at C-3 and C-4 are β-oriented and that the [1,2]-migration of the 2-ethoxy-2-oxoethyl group from the oxygen atom to C-6 takes place from the α-face opposite the substituents to give B (Scheme  [¹] ). Similarly, in case of the l-lyxo diazo compound 6, [1,2]-migration of the 2-ethoxy-2-oxoethyl functionality occurs from the β-face, the side opposite the two α-substituents at C-3 and C-4. This observation support the view that in the rhodium carbenoid species C, the vacant orbital at C-6 and the lone pair of the oxygen atom are parallel to one another (as shown in C′) and lie in the same plane. The electron-deficient carbon atom C-6 therefore accepts the oxygen lone pair of electrons from the same side as that in which the substituents are oriented to give the oxonium ylide D, thereby dictating that the RhLn at C-6 occupies the opposite face, which subsequently determines the orientation of the migrating group.

During the preparation of the target molecule, the alcohol 8 was acetylated with acetic anhydride in pyridine to give the monoacetyl derivative 9, [¹5] which on acetolysis with acetic acid/acetic anhydride in the presence of a catalytic amount of sulfuric acid at room temperature gave the triacetate 10 as an anomeric mixture in 78% yield. [¹6] Subsequently, Vorbrüggen glycosylation [¹7] of the anomeric mixture 10 with 6N,N 9-bis(trimethylsilyl)-6N-benzoyladenine in the presence of tert-butyl(dimethyl)silyl triflate in refluxing acetonitrile gave nucleoside 11 in 70% yield. In the ¹H NMR spectrum, the presence of signals for the aromatic region and two singlets at δ = 8.19 and 8.74 corresponding to the adenine protons confirmed the formation of 11.

In the final step, 11 was deprotected with sodium hydroxide in aqueous ethanol for 48 h at 30 ˚C and the product was purified by column chromatography to give the griseolic acid analogue 1e as an amorphous white solid. The ¹H and ¹³C NMR spectra and the analytical data confirmed the structure of this compound as 1e.

In conclusion, we showed that the dirhodium tetraacetate-catalyzed reaction of the l-lyxo 3-O-carbethoxymethylene α-diazo-β-keto ester 6 is highly stereoselective and stereospecific and gives the bicyclic keto product 7 exclusively through migration of the 2-ethoxy-2-oxoethyl group from the β-face opposite the C-3 and C-4 substituents. The keto product 7 was elaborated the give the previously unknown griseolic acid analogue 1e.

Melting points were recorded with the Thomas Hoover capillary melting point apparatus and are uncorrected. FT-IR spectra were recorded on a Shimadzu 8400 as thin films or KBr pellets. ¹H (300 MHz) and ¹³C (75 MHz) NMR spectra were recorded on a Varian Mercury 300 with CDCl3 or D2O as the solvent and TMS as an internal standard. The assignments of signals were confirmed by decoupling experiments. Elemental analyses were carried out on a Thermo Electron Corp. Flash EA-1112 series analyzer. Optical rotations were measured using a Jasco P-1020 polarimeter at 25 ˚C. TLC was performed on precoated plates (0.25 mm, silica gel 60 F254). Column chromatography was carried out on silica gel (100-200 mesh). All reactions were carried out in oven-dried glassware under dry N2. MeOH, pyridine, and THF were purified and dried before use. Distilled hexane and EtOAc were used for column chromatography. 10% Pd/C and Rh2(OAc)4 were purchased from Aldrich and/or Fluka. In general, the reactions were quenched with H2O and worked up by washing the combined organic layers with H2O and brine, drying (Na2SO4), and evaporating the solvent under reduced pressure.

1,2:5,6-Di- O -isopropylidene-3- O -acetyl-α- d -gulofuranose (3a)

A soln of enol acetate 2 (10.0 g, 33.33 mmol) and 10% Pd/C (200 mg) in anhyd EtOH (30 mL) at 30 ˚C was hydrogenated at 20 psi for 3 h. The mixture was filtered through Celite and purified by column chromatography [hexane-EtOAc (9.5:0.5)] to give 3a as a white solid; yield: 8.7 g (86%); mp 74 ˚C; R f  = 0.36 [hexane-EtOAc (8:2)]; [α]D +60.0 (c 0.10, CHCl3).

IR (KBr): 1733, 1248 cm-¹.

¹Η NMR (300 MHz, CDCl3): δ = 1.35 (s, 3 H, CH3), 1.39 (s, 3 H, CH3), 1.45 (s, 3 H, CH3), 1.59 (s, 3 H, CH3), 2.13 (s, 3 H, COCH3), 4.07 (t, J = 6.8 Hz, 1 H, H-6a), 4.10 (dd, J = 8.8 and 6.3 Hz, 1 H, H-4), 4.62 (dt, J = 8.8 and 6.8 Hz, 2 H, H-5, H-6b), 4.80 (dd, J = 5.4 and 4.1 Hz, 1 H, H-2), 5.06 (dd, J = 6.3 and 5.4 Hz, 1 H, H-3), 5.81 (d, J = 4.1 Hz, 1 H, H-1).

¹³C NMR (75 MHz, CDCl3): δ = 20.4 (COCH3), 25.1 (CH3), 26.5 (CH3), 26.6 (CH3), 26.7 (CH3), 66.1 (C-6), 71.5 (C-5), 74.9 (C-4), 78.3 (C-2), 81.0 (C-3), 104.7 (C-1), 108.9 (OCO), 114.0 (OCO), 169.1 (COCH3).

Anal. Calcd for C14H22O7: C, 55.62; H, 7.33. Found: C, 55.69; H, 7.27.

1,2:5,6-Di- O -isopropylidene-α- d -gulofuranose (3b)

A soln of acetylgulofuranose 3a (8.00 g, 26.05 mmol) in THF (25 mL) was added dropwise to a slurry of LiAlH4 (2.54 g, 66.32 mmol) in anhyd THF (10 mL) at 0 ˚C. The mixture was stirred at r.t. for 2 h then neutralized with a mixture of sat. aq NH4Cl (4 mL) and EtOAc (20 mL), filtered, concentrated, and purified by column chromatography [hexane-EtOAc (8:2)] to give the gulofuranose 3b as a white solid; yield: 6.49 g (96%); mp 103 ˚C; R f  = 0.30 [hexane-EtOAc (5:5)]; [α]D +6.3 (c 0.94, CHCl3).

IR (KBr): 3340 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 1.38 (s, 3 H, CH3), 1.43 (s, 3 H, CH3), 1.45 (s, 3 H, CH3), 1.63 (s, 3 H, CH3), 2.67 (br s, 1 H, OH, D2O exch.), 3.72 (dd, J = 8.6 and 7.3 Hz, 1 H, H-4), 3.89 (dd, J = 7.3 and 6.1 Hz, 1 H, H-3), 4.22 (ddd, J = 13.1, 8.5, and 6.7 Hz, 2 H, H-6), 4.48 (dt, J = 8.5 and 6.7 Hz, 1 H, H-5), 4.66 (dd, J = 6.1 and 4.1 Hz, 1 H, H-2), 5.79 (d, J = 4.1 Hz, 1 H, H-1).

¹³C NMR (75 MHz, CDCl3): δ = 25.2 (CH3), 26.7 (CH3), 27.2 (CH3), 27.3 (CH3), 66.3 (C-6), 69.6 (C-3), 75.5 (C-5), 79.8 (C-2), 84.2 (C-4), 105.2 (C-1), 109.1 (OCO), 114.9 (OCO).

Anal. Calcd for C12H20O6: C, 55.37; H, 7.74. Found: C, 55.48; H, 7.64.

3- O -(2-Ethoxy-2-oxoethyl)-1,2:5,6-di- O -isopropylidene-α- d -gulofuranose (3c)

A soln of protected d-gulofuranose 3b (6.00 g, 23 mmol) in THF (20 mL) was added dropwise to a slurry of 60% NaH (1.38 g, 34.50 mmol) in anhyd THF at 0 ˚C, and the mixture was stirred well for 5 min. BrCH2CO2Et (3 mL, 27.72 mmol) and TBAI (0.270 g, 0.72 mmol) were added sequentially to the mixture, which was stirred for 10 min, allowed to warm to r.t., stirred for 6 h, and then concentrated. The residue was extracted with CHCl3 (3 × 25 mL), concentrated, and purified by column chromatography [hexane-EtOAc (9.5:0.5)] to give the O-alkylated product 3c as a white solid; yield: 7.18 g (90%); mp 84 ˚C; R f = 0.64 [hexane-EtOAc = (8:2)]; [α]D +43.3 (c 3.74, CHCl3).

IR (KBr): 1745, 1215 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 1.29 (t, J = 6.8 Hz, 3 H, OCH2CH 3), 1.36 (s, 6 H, 2 × CH3), 1.44 (s, 3 H, CH3), 1.58 (s, 3 H, CH3), 3.70 (dd, J = 8.8 and 7.1 Hz, 1 H, H-4), 4.04-4.31 (m, 7 H, 2 × H-6, H-3, OCH 2CH3, OCH 2CO), 4.60-4.65 (m, 2 H, H-5, H-2), 5.77 (d, J = 3.8 Hz, 1 H, H-1).

¹³C NMR (75 MHz, CDCl3): δ = 14.1 (OCH2 CH3), 25.1 (CH3), 26.5 (CH3), 26.6 (CH3), 26.7 (CH3), 61.1 (OCH2CH3), 66.7 (C-6), 67.4 (C-5), 75.1 (C-3), 78.2 (C-4, OCH2CO), 78.3 (C-2), 104.7 (C-1), 108.3 (OCO), 114.0 (OCO), 169.3 (COCH2CH3).

Anal. Calcd for C16H26O8: C, 55.48; H, 7.57. Found: C, 55.28; H, 7.33.

(5 R )-3- O -(2-Ethoxy-2-oxoethyl)-4,5- O -isopropylidene- l - arabino -pentodialdo-5,2-furanose (4)

A mixture of TFA and H2O (2:8; 15 mL) was added dropwise over 6 h to a chilled soln of ester 3c (7.00 g, 20 mmol) in anhyd CH2Cl2 (30 mL) at 0 ˚C. The mixture was neutralized by using basic resin, filtered, concentrated, and purified by column chromatography [(hexane-EtOAc (1:1)] to yield the corresponding 5,6-deprotected diol; yield: 4.2 g (68%). A soln of this diol (4.0 g, 13 mmol) in acetone-H2O (3:1; 30 mL) was treated with NaIO4 (3.35 g, 15.78 mmol) at 0 ˚C, and stirred for 30 min at 15 ˚C. Excess NaIO4 was decomposed with ethylene glycol (0.8 mL) and the mixture was concentrated and extracted with CHCl3 (3 × 25 mL). The combined organic layers were concentrated and purified by column chromatography [hexane-EtOAc (9:1)] to give the aldehyde 4 as a thick liquid; yield 3.12 g (2 steps, 53%); R f  = 0.60 [hexane-EtOAc (6:4)]; [α]D -23.3 (c 1.8, CHCl3).

IR (neat): 2374, 1743 cm-¹.

¹H NMR (300 MHz, CDCl3): 1.27 (t, J = 7.1 Hz, 3 H, OCH2CH 3), 1.35 (s, 3 H, CH3), 1.58 (s, 3 H, CH3), 4.23 (q, 2 H, J = 7.1 Hz, COOCH 2CH3), 4.28 (s, 2 H, OCH 2COOEt), 4.47 (dd, J = 8.2 and 1.9 Hz, 1 H, H-4), 4.53 (dd, J = 8.2 and 4.1 Hz, 1 H, H-3), 4.75 (dd, J = 4.1 and 3.5 Hz, 1 H, H-2), 5.84 (d, J = 3.5 Hz, 1 H, H-1), 9.89 (d, J = 1.9 Hz, 1 H, HCO).

¹³C NMR (75 MHz, CDCl3): δ = 14.0 (COCH2 CH3), 25.8 (CH3), 26.1 (CH3), 61.1 (OCH2CH3), 67.9 (OCH2CO), 77.3 (C-3), 81.1 (C-4), 81.7 (C-2), 104.8 (C-1), 114.1 (OCO), 169.5 (COCH3), 199.7 (CHO).

Anal. Calcd for C12H18O7: C, 52.55; H, 6.62. Found: C, 51.99; H, 6.83.

Ethyl 6-Deoxy-3- O -(2-ethoxy-2-oxoethyl)-1,2- O -isopropylidene-β- l - lyxo -hept-5-ulosefuranuronate (5)

A soln of BF3˙OEt2 (0.77 g, 5 mmol) in anhyd CH2Cl2 (5 mL) was added dropwise, with controlled evolution of N2, to a soln of aldehyde 4 (3.00 g, 10.92 mmol) and ethyl diazoacetate (1.86 g, 16.38 mmol) in anhyd CH2Cl2 (40 mL) at 0 ˚C under N2. The mixture was stirred at 0 ˚C for 2 h and then the reaction was quenched with sat. aq NaHCO3. The mixture was extracted with CHCl3 (3 × 50 mL) and the combined organic layers were dried (Na2SO4) and purified by column chromatography [hexane-EtOAc (9:1)] to give β-keto ester 5 as a thick liquid; yield: 2.75 g (70%); R f  = 0.57 [hexane-EtOAc (6:4)]; [α]D -25.1 (c 2.1, CHCl3).

IR (neat): 1743, 1733, 1719 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 1.24 (t, J = 7.1 Hz, 3 H, CH3), 1.27 (t, J = 7.1 Hz, 3 H, CH3), 1.36 (s, 3 H, CH3), 1.57 (s, 3 H, CH3), 3.78 (ABq, J = 16.3 Hz, 2 H, CCH2COOEt), 4.12-4.31 (m, 6 H, 2 × OCH2CH3, OCH2CO), 4.41 (dd, J = 7.2, 4.9 Hz, 1 H, H-3), 4.67 (d, J = 7.2 Hz, 1 H, H-4), 4.72 (dd, J = 4.9, 4.1 Hz, 1 H, H-2), 5.77 (d, J = 4.1 Hz, 1 H, H-1).

¹³C NMR (75 MHz, CDCl3): δ = 14.1 (OCH2CH3), 14.2 (OCH2CH3), 25.9 (CH3), 26.9 (CH3), 47.2 (CH2COOEt), 61.1 (OCH2), 67.8 (OCH2), 77.3 (OCH2), 78.8 (C3), 79.0 (C2), 83.3 (C4), 105.1 (C1), 115.3 (OCO), 167.2 (COOEt), 169.5 (COOEt), 198.9 (CO).

The ¹H and ¹³C NMR spectra show additional signals of less than 10% as a result of the presence of the enol form.

Anal. Calcd for C16H24O9: C, 53.33; H, 6.71. Found: C, 53.49; H, 6.54.

Ethyl 6-Diazo-6-deoxy-3- O -(2-ethoxy-2-oxoethyl)-1,2- O -isopropylidene-β-l- lyxo -hept-5-ulosefuranuronate (6)

Et3N (1.1 mL, 10.2 mmol) and MsN2 (0.70 mL, 6.1 mmol) were added sequentially to a soln of β-keto ester 5 (2.00 g, 5.55 mmol) in anhyd MeCN (50 mL) at 15 ˚C. The mixture was stirred for 2 h then neutralized with 2 M aq NaOH, concentrated, and extracted with CHCl3 (3 × 20 mL). The combined organic layers were dried (Na2SO4), concentrated, and purified by column chromatography [hexane-EtOAc (9:1)] to give the diazo compound 6 as a thick liquid; yield: 1.80 g (85%); R f = 0.60 (hexane-EtOAc (4:6)]; [α]D -45.1 (c 1.9, CHCl3).

IR (neat): 2143, 1749, 1728, 1657 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 1.27 (t, J = 7.1 Hz, 3 H, OCH2CH 3), 1.32 (t, J = 7.1 Hz, 3 H, OCH2CH 3), 1.39 (s, 3 H, CH3), 1.66 (s, 3 H, CH3), 4.12-4.24 (m, 3 H, OCH2CH3, H-3), 4.25-4.37 (m, 4H, H-4, OCH 2CH3, CCH2COOEt), 4.80 (t, J = 3.6 Hz, 1 H, H-2), 5.34 (d, J = 8.5 Hz, 1 H, CCH2COOEt), 5.8 (d, J = 3.6 Hz, 1 H, H-1).

¹³C NMR (75 MHz, CDCl3): 14.2 (OCH2CH 3), 14.3 (OCH2CH 3), 26.8 (CH3), 27.1 (CH3), 61.0 (CCH2CO), 61.8 (C = N), 68.2 (2 × OCH2CH3), 78.3 (C-3), 78.6 (C-2), 80.6 (C-4), 104.3 (C-1), 113.8 (OCO), 160.0 (COOCH2CH3), 170.0 (COOCH2CH3), 187.4 (CO).

Anal. Calcd for C16H22O9N2: C, 49.73; H, 5.74. Found: C, 49.96; H, 5.56.

Ethyl 3,6-Anhydro-6-(ethoxycarbonyl)-1,2- O -isopropylidene-α- d - gulo -hept-5-ulosefuranuronate (7)

Rh2(OAc)4 (20 mg, 0.09 mmol) was added to a soln of diazo compound 6 (1.60 g, 4.15 mmol) in refluxing anhyd benzene (25 mL), The mixture was refluxed for 15 min, cooled, and loaded directly onto a silica gel column. Elution with hexane-EtOAc (9:1) gave the bicyclic ketone 7 as a thick liquid (0.99 g, 67%); R f = 0.56 [hexane-EtOAc (6:4)]; [α]D +40.1 (c 1.9, CHCl3).

IR (neat): 1784, 1741, 1726, 1213 cm-¹.

The ¹Η and ¹³C NMR (CDCl3) were too complex to interpret; however, we assume that the compound is mixed with its keto-enol tautomer in a 4:1 ratio.

Anal. Calcd for C16H22O9: C, 53.63; H, 6.19; Found: C, 53.93; H, 6.31.

Ethyl 3,6-Anhydro-7-deoxy-6-(ethoxycarbonyl)-1,2- O -isopropylidene-l- glycero -β-l- manno -octofuranuronate (8)

NaBH4 (0.120 g, 3.30 mmol) was added in three portions over 30 min to a soln of ketone 7 (0.99 g, 2.76 mmol) in MeOH (20 mL) at 0 ˚C. The mixture was stirred for 2 h, neutralized with sat. aq NH4Cl (2 mL), and extracted with CHCl3 (3 × 15 mL). The combined organic layers were dried (Na2SO4) and concentrated to afford a thick liquid that was purified by column chromatography [hexane-EtOAc (3:1)] to give alcohol 8; yield: 0.50 g (54%); R f = 0.50 [hexane-EtOAc (3:7)]; [α]D -28.8 (c 2.29, CHCl3).

IR (neat): 3600-3200 (br), 1761, 1738 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 1.22 (t, J = 6.9 Hz, 3 H, OCH2CH 3), 1.32 (t, J = 7.0 Hz, 3 H, OCH2CH 3), 1.38 (s, 3 H, CH3), 1.73 (s, 3 H, CH3), 2.48 (d, J = 14.5 Hz, 1 H, CCH 2COOEt), 3.40 (d, J = 14.5 Hz, 1 H, CCH 2COOEt), 3.72 (d, J = 9.0 Hz, 1 H, OH, D2O exch.),4.07 (d, J = 6.8Hz, 1 H, H-5), 4.08-4.17 (m, 2 H, OCH2CH3), 4.20-4.42 (m, 2 H, OCH 2CH3), 4.62-4.71 (m, 2 H, H-2, H-3), 5.08-5.18 (m, 1 H, H-4), 5.96 (d, J = 3.5 Hz, 1 H, H-1).

¹³C NMR (75 MHz, CDCl3): δ = 14.0 (OCH2CH3), 14.1 (OCH2CH3), 25.5 (CH3), 26.6 (CH3), 39.2 (CCH2COOEt), 61.1 (OCH2CH3), 61.5 (OCH2CH3), 74.5 (C-3), 78.8 (C-4), 79.3 (C-2), 86.3 (C-6), 92.5 (C-5), 108.4 (C-1), 114.1 (OCO), 168.0 (COOEt), 168.1 (COOEt).

Anal. Calcd for C16H24O9: C, 53.33; H, 6.71; Found: C, 53.55; H, 6.42.

Ethyl 5- O -Acetyl-3,6-anhydro-7-deoxy-6-(ethoxycarbonyl)-1,2- O -isopropylidene-l- glycero -β-l- manno -octofuranuronate (9)

Ac2O (1.26 mL, 13.8 mmol) and DMAP (8 mg, 0.07 mmol) were added to a soln of bicyclic alcohol 8 (0.500 g, 1.38 mmol) in pyridine (2.00 mL, 26.38 mmol) at 0 ˚C, and the mixture was stirred at 30 ˚C for 48 h. Excess Ac2O and pyridine were removed under vacuum, and the residue was purified by column chromatography [hexane-EtOAc (9:1)] to give the acetylated product 9; yield: 0.470 g (89%); R f = 0.45 [hexane-EtOAc (65:35)]; [α]D +68.9 (c 4.9, CHCl3).

IR (neat): 1770, 1735 cm-¹.

¹Η NMR (300 MHz, CDCl3): δ = 1.18 (t, J = 6.6 Hz, 3 H, OCH2CH 3), 1.28 (t, J = 6.6 Hz, 3 H, OCH2CH 3), 1.32 (s, 3 H, CH3), 1.66 (s, 3 H, CH3), 2.03 (s, 3 H, COCH3) 2.63 (d, J = 14.8 Hz, 1 H, CCH 2COOEt), 3.02 (d, J = 14.8 Hz, 1 H, CCH 2COOEt), 4.02-4.13 (m, 2 H, OCH 2CH3), 4.16-4.32 (m, 2 H, OCH 2CH3), 4.60-4.79 (m, 2 H, H-2, H-3), 4.96-5.03 (m, 1 H, H-4), 5.16 (d, J = 6.0 Hz, 1 H, H-5), 5.84 (d, J = 2.4 Hz, 1 H, H-1).

¹³C NMR (75 MHz, CDCl3): δ = 13.9 (OCH2CH3), 14.2 (OCH2CH3), 20.7 (COCH3), 26.1 (CH3), 27.1 (CH3), 40.3 (CCH2COOEt), 61.0 (OCH2CH3), 61.4 (OCH2CH3), 75.6 (C-3), 79.3 (C-4), 80.5 (C-2), 84.2 (C-5), 89.4 (C(COOEt)(CH2COOEt)(CO)O), 109.3 (C-1), 115.1 (OCO), 167.5 (COOEt), 167.7 (COOEt), 169.3 (COCH3).

Anal. Calcd for C18H26O10: C, 53.73; H, 6.51; Found: C, 53.55; H, 6.47.

Ethyl 1,2,5-Tri- O -acetyl-3,6-anhydro-7-deoxy-6-(ethoxycarbonyl)-l- glycero -α- and -β-l- manno -octofuranuronate (10)

A mixture of HOAc and Ac2O (1:1.5; 20 mL) and H2SO4 (0.01 mL) were added to a stirred soln of acetyl compound 9 (0.44 g, 0.001 mmol) in CH2Cl2 (25 mL) at 0 ˚C, and the mixture was allowed to warm to r.t. then stirred for 7 h. The organic layer, on workup and evaporation of solvent, gave an anomeric mixture of products, column chromatography [hexane-EtOAc (8:2)] of which initially gave the β-anomer of 10 as a thick oil; yield: 0.23 g (59%); R f  = 0.48 [hexane-EtOAc (6:4)]; [α]D -111.3 (c 0.7, CHCl3).

IR (neat): 1745 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 1.23 (t, J = 7.1 Hz, 3 H, OCH2CH 3), 1.34 (t, J = 7.1 Hz, 3 H, OCH2CH 3), 2.08 (s, 3 H, COCH3), 2.11 (s, 3 H, COCH3), 2.16 (s, 3 H, COCH3), 2.88 (d, J = 16.5 Hz, 1 H, CCH 2COOEt), 2.96 (d, J = 16.5 Hz, 1 H, CCH 2COOCH2CH3), 4.11 (q, J = 7.1 Hz, 2 H, COOCH2CH3), 4.19-4.34 (m, 2 H, OCH 2CH3), 4.98 (t, J = 4.6 Hz, 1 H, H-3), 5.03-5.09 (m, 2 H, H-2, H-4), 5.57 (d, J = 5.0 Hz, 1 H, H-5), 6.35 (d, J = 3.85 Hz, 1 H, H-1).

¹³C NMR (75 MHz, CDCl3): δ = 13.99 (OCH2 CH3), 14.05 (OCH2 CH3), 20.4 (COCH3), 20.5 (COCH3), 21.0 (COCH3), 41.2 (CCH2COOEt), 60.7 (OCH2CH3), 61.6 (OCH2CH3), 76.6 (C-3), 77.3 (C-4), 79.7 (C-5) 82.0 (C-2), 86.3 (C-6), 100.0 (C-1), 168.4 (COOEt), 168.8 (COOEt), 169.1 (COCH3), 169.4 (COCH3), 169.8 (COCH3).

Anal. Calcd for C19H26O12: C, 51.12 H, 5.87; Found: C, 51.67 H, 5.68.

Further elution gave a mixture of anomers. The anomeric mixture was used in the next reaction.

N -Benzoyl-9-[2,5-di- O -acetyl-3,6-anhydro-7-deoxy-6-(ethoxycarbonyl)-8-ethyl-l- glycero -β-l- manno -octofuranosyluronosyl]adenine (11)

6N,N 9-Bis(trimethylsilyl)-6N-benzoyladenine (0.13 mg, 0.34 mmol) and t-BuSiMe2O2SCF3 (0.05 mL) were added sequentially to a stirred soln of triacetate 10 (0.100 g, 0.23 mmol) in MeCN (5 mL), and the mixture was refluxed for 3 h. EtOAc (25 mL) was added, and the organic layer was washed with cold 10% aq NaHCO3 then concentrated. The crude product was purified by column chromatography [hexane-EtOAc (5:5)] to give 11 as a thick liquid; yield: 0.098 g (70%); R f  = 0.35 [hexane-EtOAc (3:7)]; [α]D -86.3 (c 0.36, CHCl3).

IR (neat): 3315 (br), 1745, 1705 cm-¹.

¹NMR (300 MHz, CDCl3): δ = 1.27 (3 H, t, J = 7.1 Hz, OCH2CH 3), 1.35 (3 H, t, J = 7.1 Hz, OCH2CH 3), 2.03 (s, 3 H, CH3), 2.06 (s, 3 H, CH3), 3.10 (ABq, J = 16.7 Hz, 2 H, CCH 2COOEt), 4.15 (q, J = 7.1 Hz, 2 H, COOCH 2CH3), 4.19-4.34 (qd, J = 7.1 and 2.6 Hz, 2 H, OCH 2CH3), 5.20 (t, J = 4.4 Hz, 1 H, H-3), 5.4 (t, J = 4.1, Hz, 1 H, H-4), 5.78 (d, J = 4.6 Hz, 1 H, H-5), 6.06 (dd, J = 6.8 and 4.4 Hz, 1 H, H-2), 6.59 (d, J = 6.8 Hz, 1 H, H-1), 7.48-7.61 (m, 3 H, Ar-H), 8.04 (d, J = 7.4 Hz, 2 H, Ar-H), 8.19 (s, 1 H, Ad-H), 8.74 (s, 1 H, Ad-H), 9.05 (br s, 1 H, NH, D2O exch.).

¹³C NMR (75 MHz, CDCl3): δ = 14.2 (OCH2CH3), 14.3 (OCH2CH3), 20.60 (COCH3), 26.63 (COCH3), 41.4 (OCH2COOEt), 60.9 (OCH2CH3), 61.9 (OCH2CH3), 77.2 (C-6), 77.7, 80.5 (C-3/C-4), 82.7, 85.3 (C-2/(C-5), 87.8 (C-1), 123.5, 127.8, 128.7, 132.7, 133.2, 142.4, 149.4, 151.5, 152.4 (Ar-C), 164.5, 169.1, 169.2, 169.5, 170.0 (ester and amide carbonyls).

Anal. Calcd for C29H31N5O11: C, 55.68; H, 4.99; Found: C, 55.81; H, 4.72.

9-(3,6-Anhydro-6-carboxy-7-deoxy-l- glycero -β-l- manno -octofuranuronosyl)adenine (Griseolic Acid Analogue; 1e)

A soln of 11 (0.090 g, 0.23 mmol) in EtOH-H2O (7:3; 2 mL) and NaOH (46 mg, 1.15 mmol) was stirred at r.t. for 24 h, then neutralized with 1 M HCl. The volume of the mixture was then reduced by a half through evaporation at reduced pressure. The soln was loaded on a column and eluted with EtOH-H2O (8:2). Evaporation of the solvent gave a semisolid that was repeatedly washed with CHCl3 (3 × 2 mL) to give solid 1e; yield: 35 mg (64%); R f  = 0.375 [EtOH-HOAc (9:1)]; mp 248-251 ˚C; [α]D -8.56 (c, 0.733, H2O).

IR (KBr): 3600-2800 br, 1726, 1692 br cm-¹.

¹H NMR (300 MHz, D2O): δ = 2.70 (d, J = 15.6 Hz, 1 H, CCH2COOH), 3.15 (d, J = 15.6 Hz, 1 H, CCH2COOH), 4.45 (d, J = 3.3 Hz, 1 H, H-5), 4.92 (br s, 1 H, H-3), 5.1 (br s, 2 H, H-4, H-2), 6.05 (br s, 1 H, H-1), 8.00 (br s, 1 H, Ad-H), 8.20 (br s, 1 H, Ad-H).

¹³C NMR (75 MHz, D2O): δ = 44.2 (CCH2COOH), 76.4 (C-6), 78.0, 80.0, 85 7, 87.0 (C-2, C-3, C-4, C-5), 90.1 (C-1), 116.3, 140.7, 148.4, 153.1, 156.1 (Ad-C), 179.0, 179.2 (2 × COOH).

Anal. Calcd for C14H15N5O8: C, 44.08; H, 3.96. Found: C, 44.29; H, 3.78.

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

Acknowledgment

We are grateful to Prof. M. S. Wadia for helpful discussion. We thank DST, New Delhi for the financial support (Grant No. SR/S1/OC-21/2005). N.N.B. thanks the UGC, New Delhi for a teacher fellowship.

11

Selective hydrolysis of the 5,6-O-isopropylidene group in 3c was possible probably because of the α-orientation of the 5,6-diol in the furanose ring; transfer of a proton from the protonated oxygen at the C-6 carbon to the C-1 acetonide facilitates the 1,2-acetonide deprotection competitively. Attempts with various other acidic reagents, such as 10% H2SO4, CuCl2˙2H2O, 30% HClO4, or acidic resin (Indion 140), failed to give good yields.

13

The unstable nature of compound 7 precluded further characterization. At this stage, attempts were made to convert the keto compound 7 into one with an olefinic functionality at the ring junction. Thus, attempts at the reaction of 7 by using the Shapiro protocol (SO2Cl2 and POCl3) led to a complex mixture. Attempts to activate the hydroxyl functionality by using mesyl chloride and subsequent treatment with base under reflux were also unsuccessful.

14

Our attempts to isolate the other diastereomer (C-5β-OH) in a pure form were unsuccessful.

15

In the ¹H NMR spectrum of 9, the C-5 appeared at δ = 5. 5 as a doublet (J 5,4 = 5.00 Hz). In 1D NOSEY irradiation, one of the C-7 methylene protons at δ = 2.48 showed a NOE with H-3, H-4, H-5, indicating a syn-relationship between the
-CCH2COOEt group and the sugar ring protons, and confirming our earlier assignment.

16

The ¹H NMR spectrum of 10 shows the presence of an anomeric mixture in the ratio 1:15 in favor of the β-anomer.

11

Selective hydrolysis of the 5,6-O-isopropylidene group in 3c was possible probably because of the α-orientation of the 5,6-diol in the furanose ring; transfer of a proton from the protonated oxygen at the C-6 carbon to the C-1 acetonide facilitates the 1,2-acetonide deprotection competitively. Attempts with various other acidic reagents, such as 10% H2SO4, CuCl2˙2H2O, 30% HClO4, or acidic resin (Indion 140), failed to give good yields.

13

The unstable nature of compound 7 precluded further characterization. At this stage, attempts were made to convert the keto compound 7 into one with an olefinic functionality at the ring junction. Thus, attempts at the reaction of 7 by using the Shapiro protocol (SO2Cl2 and POCl3) led to a complex mixture. Attempts to activate the hydroxyl functionality by using mesyl chloride and subsequent treatment with base under reflux were also unsuccessful.

14

Our attempts to isolate the other diastereomer (C-5β-OH) in a pure form were unsuccessful.

15

In the ¹H NMR spectrum of 9, the C-5 appeared at δ = 5. 5 as a doublet (J 5,4 = 5.00 Hz). In 1D NOSEY irradiation, one of the C-7 methylene protons at δ = 2.48 showed a NOE with H-3, H-4, H-5, indicating a syn-relationship between the
-CCH2COOEt group and the sugar ring protons, and confirming our earlier assignment.

16

The ¹H NMR spectrum of 10 shows the presence of an anomeric mixture in the ratio 1:15 in favor of the β-anomer.

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Figure 1 Griseolic acid bicyclic nucleosides

Scheme 1 Synthesis of the griseolic acid analogue 1d

Scheme 2 Synthesis of the griseolic acid analogue 1e

Scheme 3 A mechanism for the formation of the bicyclic ketone intermediate 7