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Asymmetric syntheses of 2,5-dideoxy-2,5-imino-d -glucitol [(+)-DGDP] and 1,2,5-trideoxy-1-amino-2,5-imino-d -glucitol [(+)-ADGDP]
Tetrahedron 70 (2014) 3601e3607
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Asymmetric syntheses of 2,5-dideoxy-2,5-imino-D-glucitol [(þ)-DGDP] and 1,2,5-trideoxy-1-amino-2,5-imino-D-glucitol [(þ)-ADGDP] Stephen G. Davies *, Aude L.A. Figuccia, Ai M. Fletcher, Paul M. Roberts, James E. Thomson Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
a r t i c l e i n f o
a b s t r a c t
Article history: Received 31 January 2014 Accepted 31 March 2014 Available online 5 April 2014
The asymmetric syntheses of 2,5-dideoxy-2,5-imino-D-glucitol [(þ)-DGDP] and 1,2,5-trideoxy-1-amino2,5-imino-D-glucitol [(þ)-ADGDP] were achieved via the ring-closing iodoamination of an enantiopure bishomoallylic amine, followed by functionalisation of the resultant iodomethyl substituted pyrrolidine. In the case of (þ)-DGDP, formation of the corresponding aziridinium ion followed by regioselective ringopening with H2O gave the desired hydroxymethyl substituted pyrrolidine as a single diastereoisomer (>99:1 dr), with subsequent deprotection giving (þ)-DGDP in good yield. Whereas in the case of (þ)-ADGDP, displacement of iodide with NaN3 proved to be optimal, giving (þ)-ADGDP in good yield after reduction and deprotection. Ó 2014 Elsevier Ltd. All rights reserved.
Keywords: (þ)-DGDP (þ)-ADGDP Pyrrolidine alkaloids Asymmetric synthesis
1. Introduction Many polyhydroxylated pyrrolidines occur within Nature. Given the potent and specific inhibitory activity toward carbohydrate processing enzymes that many members of this class of compounds display, polyhydroxylated pyrrolidines have been the targets of numerous synthetic endeavours,1 and have been documented as highly promising candidates for the development of new therapeutic agents for the treatment of disorders such as diabetes, cancer and viral infections (e.g., HIV).2 For example, 2,5-dideoxy-2,5imino-D-mannitol [(þ)-DMDP] 1, 2,5-dideoxy-2,5-iminogalactitol (DGADP) 2 and 2,5-dideoxy-2,5-imino-D-glucitol [(þ)-DGDP] 3 are known inhibitors of several galactosidase and glucosidase enzymes.3,4 Furthermore, the synthetic 1-deoxy-1-amino-analogue of DMDP [(þ)-ADMDP] 4, and N(1)-substituted derivatives, have also been shown to display significantly enhanced selectivity and potency toward the inhibition of glucosidases.5 Most syntheses of compounds such as (þ)-DGDP 3 concern the elaboration of readily available carbohydrate precursors;6,7 in contrast, relatively few asymmetric syntheses of (þ)-DGDP 3 have been reported (Fig. 1).8 Herein we report asymmetric syntheses of both (þ)-DGDP 3 and its 1-deoxy-1-amino-analogue 1,2,5-trideoxy-1-amino-2,5-imino-Dglucitol [(þ)-ADGDP], employing a ring-closing iodoamination
* Corresponding author. Tel.: þ44 (0)1865 275695; fax: þ44 (0)1865 275633; e-mail address: [email protected] (S.G. Davies). 0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2014.03.100
Fig. 1. Biologically active polyhydroxylated pyrrolidines 1e4.
reaction, followed by functionalisation of the resultant iodomethyl substituted pyrrolidine. As part of our ongoing research programme concerning the asymmetric syntheses of enantiopure pyrrolidines,9 piperidines,10 and related natural products,11 we have recently reported the asymmetric syntheses of ()-1-deoxymannojirimycin 14 and its diastereoisomer (þ)-1-deoxyallonojirimycin.12 Our synthetic strategy for the construction of the piperidine ring relied on the ring-closing iodoamination of an enantiopure bishomoallylic amine such as 9, which proceeds with concomitant N-debenzylation, followed by ring-expansion of the resultant C(2)-iodomethyl
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substituted pyrrolidine 10. Bishomoallylic amine 9 was prepared in five steps from a,b-unsaturated ester 5: conjugate addition of lithium (R)-N-benzyl-N-(a-methylbenzyl)amide to 5,13 followed by in situ oxidation of the intermediate lithium (Z)-b-amino enolate14 with ()-camphorsulfonyloxaziridine [()-CSO] gave a-hydroxy-bamino ester 6 in >99:1 dr;13 subsequent O-benzyl protection, reduction of the ester moiety within 7, oxidation of the resultant alcohol 8, and reaction with vinylmagnesium bromide gave 9, which was isolated as a single diastereoisomer (>99:1 dr). Treatment of 9 with I2 and NaHCO3 in MeCN gave C(5)-iodomethyl substituted pyrrolidine 10, which could then be converted into carbonate 12 via the intermediacy of aziridinium ion 11, following intramolecular ring-opening of the aziridinium intermediate by a carbonate group tethered at the C(4)-position.15 However, it was found that under optimised conditions a superior yield of carbonate 12 could be obtained directly from 9. In this case, subsequent O-silyl deprotection of 12, methanolysis, and hydrogenolysis of 13 gave ()-1deoxymannojirimycin 14, which was isolated in good yield as a single diastereoisomer (Scheme 1).
2. Results and discussion We envisaged that repetition of the protocol for the generation of aziridinium ion 11, followed by treatment of 11 with dioxane/H2O (i.e., omitting the addition of NaHCO3) would produce pyrrolidine 15 preferentially, as a result of ring-opening with H2O at the least hindered C(6)-position within aziridinium ion 11. Thus, treatment of 10 with AgBF4 in CH2Cl2 gave quantitative conversion to aziridinium ion 11, which was then treated with a 3:1 mixture of dioxane and H2O, which produced a 90:10 mixture of pyrrolidine 15 and the known piperidine 16,12 respectively. The relative configuration within pyrrolidine 15 was initially assigned on the basis that substitution occurs with overall retention of configuration, and this assignment was subsequently confirmed unambiguously via single crystal X-ray diffraction analysis of a derivative. O-Silyl deprotection of the mixture of 15 and 16, followed by peracetylation of the mixture of 17 and 18 facilitated the isolation of both 19 and 20 in 65 and 4% yield (from 10), respectively, as single diastereoisomers (>99:1 dr) in each case (Scheme 2).
Scheme 2.
Scheme 1.
Transesterification of pyrrolidine 19 upon treatment with K2CO3 in MeOH was followed by conversion to the corresponding hydrochloride salt 21, which was isolated in quantitative yield and >99:1 dr. The relative configuration within 21 was assigned unambiguously by single crystal X-ray diffraction analysis;16 furthermore, the determination of a Flack x parameter17 of 0.057(13) for the crystal structure of 21$H2O allowed the assigned absolute
S.G. Davies et al. / Tetrahedron 70 (2014) 3601e3607
(2R,3R,4R,5S)-configuration within 21 to be confirmed unambiguously (Fig. 2), thereby also confirming the assigned configurations within 15, 17 and 19. Subsequent hydrogenolytic N- and Odebenzylation of 21 upon treatment with Pearlman’s catalyst [Pd(OH)2/C] under an atmosphere of H2 (5 atm) gave hydrochloride salt 22 in quantitative yield and >99:1 dr. Further purification of this sample by ion exchange chromatography on Dowex 50WX8 (Hþ form) resin gave (þ)-DGDP 3 in quantitative yield as a single diastereoisomer (Scheme 3). The melting point, specific rotation, and 1H and 13C NMR spectroscopic data for 3 were in excellent agreement with literature values18 for both the natural product and synthetic samples {mp 124e127 C; lit.3c for sample isolated from the natural source mp 127e130 C; lit.8 mp 139e141 C; lit.6 mp 3c 136e138 C; [a]20 D þ22.2 (c 0.5, H2O); lit. for sample isolated from the natural source [a]D þ26.1 (c 0.84, H2O); lit.7k [a]28 D þ22.7 (c 0.14, H2O); lit.18a [a]22 D þ24.1 (c 1.0, H2O)}.
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Attempts to effect ring-opening of aziridinium ion 11 with nitrogen-centred nucleophiles (e.g., azide, ammonia, etc.) were not efficacious, although when 9 was subjected to our standard ringclosing iodoamination protocol (i.e., treatment with I2 and NaHCO3 in MeCN),9b,c,d followed by immediate treatment of the crude reaction mixture with NaN3 in DMF, a 49:10:41 mixture of the corresponding pyrrolidine 23, piperidine 24,19 and returned starting material 9, respectively, was produced; chromatographic purification of this mixture gave azide 23 in 23% isolated yield. O-Silyl deprotection of 23 was then achieved upon treatment of 23 with HF$pyridine, giving 25 in quantitative yield and >99:1 dr. Tandem hydrogenolysis/reduction of 25 upon treatment with Pearlman’s catalyst [Pd(OH)2/C] under a hydrogen atmosphere (5 atm) gave (þ)-ADGDP, which was isolated as the corresponding dihydrochloride salt 26 in quantitative yield and >99:1 dr (Scheme 4). The spectroscopic data for 26 were also consistent with literature values {mp>170 C; lit.7p mp >150 C; [a]20 D þ33.2 (c 0.6, H2O); lit.7p [a]25 D þ43 (c 1.43, H2O)}.
Scheme 3.
Scheme 4.
3. Conclusion In conclusion, the ring-closing iodoamination of an enantiopure bishomoallylic amine provided an enantiopure pyrrolidine scaffold. Subsequent elaboration of the iodomethyl substituted pyrrolidine by either formation of the corresponding aziridinium ion followed by regioselective ring-opening with H2O, or direct displacement with NaN3 gave (þ)-DGDP and (þ)-ADGDP, respectively, in good yield after reduction/deprotection. 4. Experimental 4.1. General experimental
Fig. 2. X-ray crystal structure of (2R,3R,4R,5S)-21$H2O (H2O and selected H atoms are omitted for clarity).
All reactions involving organometallic or other moisture sensitive reagents were carried out under a nitrogen or argon atmosphere using standard vacuum line techniques and glassware that
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was flame dried and cooled under nitrogen before use. Solvents were dried according to the procedure outlined by Grubbs and coworkers.20 Water was purified by an ElixÒ UVe10 system. BuLi was purchased as a solution in hexanes and titrated against diphenylacetic acid before use. All other reagents were used as supplied without prior purification. Organic layers were dried over MgSO4. Thin layer chromatography was performed on aluminium plates coated with 60 F254 silica. Plates were visualised using UV light (254 nm), iodine, 1% aq KMnO4, or 10% ethanolic phosphomolybdic acid. Flash column chromatography was performed on Kieselgel 60 silica. Melting points are uncorrected. Optical rotations were recorded in a water-jacketed 10 cm cell. Specific rotations are reported in 101 deg cm2 g1 and concentrations in g/100 mL. IR spectra were recorded using an ATR module. Selected characteristic peaks are reported in cm1. NMR spectra were recorded in the deuterated solvent stated. Spectra were recorded at rt. The field was locked by external referencing to the relevant deuteron resonance. 1He1H COSY, 1He13C HSQC, and 1He13C HMBC analyses were used to establish atom connectivity. Accurate mass measurements were run on a TOF spectrometer internally calibrated with polyalanine. 4.2. (R,R,R,R)-N(1)-Benzyl-2-[(triisopropylsilyloxy)methyl]-3benzyloxy-4-hydroxy-5-(iodomethyl)pyrrolidine 10 I2 (518 mg, 2.04 mmol) and NaHCO3 (171 mg, 2.04 mmol) were added to a stirred solution of 912 (400 mg, 0.68 mmol, >99:1 dr) in MeCN (20 mL) at rt, and the resultant mixture was stirred at rt for 16 h. The reaction mixture was diluted with Et2O (50 mL) and washed with satd aq Na2S2O3 (50 mL), then dried and concentrated in vacuo to give a 50:50 mixture of 10 and N-(a-methylbenzyl)acetamide. Purification via flash column chromatography (eluent 30e40 C petrol/EtOAc, 50:1) gave 10 as a yellow oil (83 mg, 20%, >99:1 dr);12 [a]20 D þ50.7 (c 1.0, CHCl3); dH (400 MHz, CDCl3) 0.95e1.04 (21H, m, Si(CHMe2)3), 3.11 (1H, dd, J 8.9, 3.1, CHAHBI), 3.19 (1H, m, C(2)H), 3.22e3.28 (1H, m, C(2)CHAHB), 3.30 (1H, d, J 8.9, CHAHBI), 3.40 (1H, app dt, J 11.1, 3.1, C(5)H), 3.48 (1H, d, J 10.4, C(2)CHAHB), 3.68 (1H, d, J 14.0, NCHAHBPh), 3.86 (1H, app s, C(3)H), 3.95e4.02 (2H, m, NCHAHBPh, OH), 4.23 (1H, dd, J 11.1, 3.2, C(4)H), 4.53 (1H, d, J 12.0, OCHAHBPh), 4.66 (1H, d, J 12.0, OCHAHBPh), 7.22e7.40 (10H, m, Ph). 4.3. (1S,2R,3R,4R,5S)-N(1)-Benzyl-2-[(triisopropylsilyloxy)methyl]-3-benzyloxy-4-hydroxy-1-azabicyclo[3.1.0]hexanium tetrafluoroborate 11 AgBF4 (58 mg, 0.30 mmol) was added to a stirred solution of 102 (150 mg, 0.25 mmol, >99:1 dr) in CH2Cl2 (4 mL) at rt, and the resultant mixture was allowed to stir at rt for 1 h. The reaction mixture was then filtered through CeliteÒ (eluent CH2Cl2) and concentrated in vacuo to give 11 as an orange oil (138 mg, quant, >99:1 dr);2 [a]20 D þ0.6 (c 0.4, CHCl3); dH (400 MHz, CD2Cl2) 0.94e1.24 (21H, m, Si(CHMe2)3), 3.09 (1H, dd, J 8.0, 4.5, C(6)HA), 3.56 (1H, dd, J 6.3, 4.5, C(6)HB), 3.76e3.86 (2H, m, C(2)H, C(3)H), 3.98e4.04 (2H, m, C(2)CHAHB, OH), 4.07e4.20 (2H, m, C(2)CHAHB, C(5)H), 4.42 (1H, d, J 13.1, NCHAHBPh), 4.54 (1H, d, J 11.6, OCHAHBPh), 4.77 (1H, d, J 13.1, NCHAHBPh), 4.82 (1H, d, J 11.6, OCHAHBPh), 4.83e4.88 (1H, m, C(4)H), 7.28e7.58 (10H, m, Ph). 4.4. (2R,3R,4R,5S)-N(1)-Benzyl-2,5-bis(acetoxymethyl)-3benzyloxy-4-acetoxypyrrolidine 19 and (R,R,R,R)-N(1)-benzyl2-(acetoxymethyl)-3-benzyloxy-4,5-diacetoxypiperidine 20 Step 1: A solution of 11 (138 mg, 0.25 mmol, >99:1 dr) in dioxane/H2O (3:1, 4 mL) was allowed to stir at rt for 16 h. The reaction
mixture was then diluted with Et2O (15 mL) and washed with 2.0 M aq KOH (15 mL), then dried and concentrated in vacuo to give a 90:10 mixture of 15 and 16 (124 mg), respectively. Data for mixture: nmax (ATR) 3406 (OeH), 2942, 2866 (CeH); m/z (ESIþ) 500 ([MþH]þ, 100%); HRMS (ESIþ) C29H46NO4Siþ ([MþH]þ) requires 500.3191; found 500.3166. Data for 15: dH (400 MHz, CDCl3) 0.90e1.08 (21H, m, Si(CHMe2)3), 3.00 (1H, app q, J 3.4, C(2)H), 3.11e3.16 (1H, m, C(5)H), 3.51 (1H, app t, J 4.4, C(2)CH2), 3.57 (2H, dd, J 11.6, 4.8, C(5)CHAHB), 3.70 (1H, dd, J 11.6, 1.6, C(5)CHAHB), 3.77 (1H, d, J 13.7, NCHAHBPh), 3.82e3.87 (2H, m, C(3)H, NCHAHBPh), 4.18e4.25 (1H, m, C(4)H), 4.52 (1H, d, J 11.7, OCHAHBPh), 4.64 (1H, d, J 11.7, OCHAHBPh), 7.18e7.31 (10H, m, Ph); dC (100 MHz, CDCl3) 11.8 (Si(CHMe2)3), 18.0 (Si(CHMe2)3), 58.2 (NCH2Ph), 60.0 (C(5)CH2), 63.8 (C(2)CH2), 66.7 (C(5)), 70.4 (C(2)), 71.5 (OCH2Ph), 76.8 (C(4)), 85.4 (C(3)), 127.6, 127.6, 128.4, 128.5, 128.5, 129.0 (o,m,p-Ph), 138.2 (2i-Ph). Data for 16: dH (400 MHz, CDCl3) 1.02e1.14 (21H, m, Si(CHMe2)3), 2.24 (1H, d, J 12.4, C(6)HA), 2.38e2.47 (1H, m, C(2)H), 2.92 (1H, dd, J 12.4, 4.6, C(6)HB), 3.36 (1H, d, J 13.3, NCHAHBPh), 3.57 (1H, app t, J 8.1, C(3)H), 3.65 (1H, dd, J 8.1, 3.3, C(4)H), 3.72e3.80 (1H, m, C(5)H), 4.03 (1H, dd, J 11.1, 4.0, C(2)CHAHB), 4.22 (1H, dd, J 11.1, 1.8, C(2)CHAHB), 4.43 (1H, d, J 13.3, NCHAHBPh), 4.65 (1H, d, J 11.4, OCHAHBPh), 5.03 (1H, d, J 11.4, OCHAHBPh), 7.26e7.40 (10H, m, Ph); dC (100 MHz, CDCl3) 12.0 (Si(CHMe2)3), 18.1 (Si(CHMe2)3), 54.1 (C(6)), 57.2 (NCH2Ph), 61.9 (C(2)CH2), 66.6 (C(2)), 67.9 (C(5)), 74.3 (OCH2Ph), 75.8 (C(4)), 78.6 (C(3)), 127.2, 127.6, 127.9, 128.4, 128.5, 129.0 (o,m,p-Ph), 138.5 (2i-Ph). Step 2: HF$pyridine (70% in pyridine, 0.19 mL, 7.50 mmol) was added dropwise to a stirred solution of the 90:10 mixture of 15 and 16 (124 mg), respectively, in THF (4 mL) at 0 C. The resultant mixture was allowed to warm to rt and was stirred at rt for 16 h. The reaction mixture was then cooled to 0 C and satd aq NaHCO3 (0.5 mL) was added carefully. The resultant mixture was concentrated in vacuo and the residue was partitioned between H2O (10 mL) and CHCl3/iPrOH (3:1, 10 mL). The aqueous layer was extracted with CHCl3/iPrOH (3:1, 25 mL) and the combined organic extracts were then concentrated in vacuo. The residue was dissolved in CHCl3 (10 mL) and the resultant solution was washed with satd aq NaHCO3 (10 mL), then dried and concentrated in vacuo to give a 90:10 mixture of 17 and 18 (85 mg), respectively. Data for mixture: nmax (ATR) 3368 (OeH), 2926 (CeH); m/z (ESIþ) 344 ([MþH]þ, 100%); HRMS (ESIþ) C20 H26 NO4 þ ([MþH]þ) requires 344.1856; found 344.1846. Data for 17: dH (400 MHz, CDCl3) 3.02e3.06 (1H, m, C(2)H), 3.15e3.19 (1H, m, C(5)H), 3.39 (1H, dd, J 11.3, 3.5, C(2)CHAHB), 3.54 (1H, dd, J 11.3, 1.6, C(2)CHAHB), 3.70 (1H, dd, J 11.8, 4.6, C(5)CHAHB), 3.77e3.84 (3H, m, C(3)H, C(5)CHAHB, NCHAHBPh), 3.88 (1H, d, J 13.4, NCHAHBPh), 4.29 (1H, dd, J 5.4, 2.5, C(4)H), 4.59 (1H, d, J 12.0, OCHAHBPh), 4.69 (1H, d, J 12.0, OCHAHBPh), 7.25e7.39 (10H, m, Ph); dC (100 MHz, CDCl3) 57.8 (NCH2Ph), 60.7 (C(5)CH2), 61.5 (C(2)CH2), 66.6 (C(5)), 69.6 (C(2)), 71.8 (OCH2Ph), 76.6 (C(4)), 86.2 (C(3)), 127.6, 127.6, 127.8, 128.5, 128.7, 128.8 (o,m,p-Ph), 138.0, 138.7 (i-Ph). Data for 18: dH (400 MHz, CDCl3) 2.29e2.34 (2H, m, C(2)H, C(6)HA), 3.04 (1H, dd, J 12.6, 3.8, C(6)HB), 3.39 (1H, d, J 13.2, NCHAHBPh), 3.60 (1H, dd, J 8.7, 3.3, C(4)H), 3.77 (1H, app t, J 8.7, C(3)H), 3.85 (1H, br s, C(5)H), 3.93 (1H, dd, J 12.0, 1.6, C(2)CHAHB), 4.03 (1H, dd, J 12.0, 2.7, C(2)CHAHB), 4.14 (1H, d, J 13.2, NCHAHBPh), 4.78 (1H, d, J 11.3, OCHAHBPh), 4.93 (1H, d, J 11.3, OCHAHBPh), 7.26e7.42 (10H, m, Ph); dC (100 MHz, CDCl3) 54.8 (C(6)), 57.0 (NCH2Ph), 58.3 (C(2)CH2), 65.7 (C(2)), 67.8 (C(5)), 75.0 (OCH2Ph), 75.2 (C(4)), 77.2 (C(3)), 127.5, 128.0, 128.1, 128.6, 128.7, 128.8 (o,m,p-Ph), 137.7, 138.3 (i-Ph). Step 3: Ac2O (0.24 mL, 2.50 mmol) and DMAP (6 mg, 0.05 mmol) were added to a stirred solution of the 90:10 mixture of 17 and 18 (85 mg), respectively, in pyridine (4 mL) at 0 C. The resultant mixture was allowed to warm to rt and was stirred at rt for 16 h. The reaction mixture was then diluted with H2O (15 mL) and EtOAc (15 mL), and the aqueous layer was extracted with EtOAc (25 mL).
S.G. Davies et al. / Tetrahedron 70 (2014) 3601e3607
The combined organic extracts were washed with brine (20 mL), then dried and concentrated in vacuo. Purification via flash column chromatography (eluent 30e40 C petrol/acetone, 9:1) gave 19 as a yellow oil (76 mg, 65%, >99:1 dr); [a]20 D þ50.8 (c 1.0, CHCl3); nmax (ATR) 1741 (C]O); dH (400 MHz, CDCl3) 1.87 (3H, s, COMe), 1.99 (3H, s, COMe), 2.08 (3H, s, COMe), 3.16 (1H, ddd, J 8.2, 5.6, 2.1, C(2)H), 3.51 (1H, app dt, J 7.6, 5.2, C(5)H), 3.67e3.73 (2H, m, C(3)H, C(2)CHAHB), 3.86 (1H, d, J 13.9, NCHAHBPh), 3.93e4.01 (2H, m, C(2)CHAHB, NCHAHBPh), 4.03e4.14 (2H, m, C(5)CH2), 4.58 (1H, d, J 12.1, OCHAHBPh), 4.68 (1H, d, J 12.1, OCHAHBPh), 5.30 (1H, dd, J 5.2, 1.6, C(4)H), 7.25e7.38 (10H, m, Ph); dC (100 MHz, CDCl3) 20.7, 20.8, 21.0 (COMe), 59.1 (NCH2Ph), 62.4 (C(5)CH2), 63.4 (C(5)), 64.5 (C(2)CH2), 68.0 (C(2)), 71.4 (OCH2Ph), 76.1 (C(4)), 86.3 (C(3)), 127.4, 127.7, 127.8, 128.4, 128.4, 128.8 (o,m,p-Ph), 137.7, 138.6 (i-Ph), 170.2, 170.6, 170.6 (COMe); m/z (ESIþ) 492 ([MþNa]þ, 100%); HRMS (ESIþ) C26 H31 NNaO7 þ ([MþNa]þ) requires 492.1993; found 492.1983. Further elution gave 20 as a yellow oil (5 mg, 4%, >99:1 dr); [a]20 D þ1.5 (c 0.4, CHCl3); nmax (ATR) 1740 (C]O); dH (400 MHz, CDCl3) 2.03 (3H, s, COMe), 2.05 (3H, s, COMe), 2.09 (3H, s, COMe), 2.50 (1H, dd, J 13.1, 2.7, C(6)HA), 2.81e2.85 (1H, m, C(2)H), 3.00 (1H, dd, J 13.1, 6.0, C(6)HB), 3.58 (1H, d, J 13.9, NCHAHBPh), 3.85 (1H, app t, J 7.0, C(3)H), 4.08 (1H, d, J 13.9, NCHAHBPh), 4.37 (1H, dd, J 12.3, 4.7, C(2)CHAHB), 4.51 (1H, dd, J 12.3, 3.8, C(2)CHAHB), 4.62 (1H, d, J 11.3, OCHAHBPh), 4.73 (1H, d, J 11.3, OCHAHBPh), 5.13 (1H, dd, J 7.0, 3.5, C(4)H), 5.28 (1H, ddd, J 6.0, 3.5, 2.7, C(5)H), 7.24e4.38 (10H, m, Ph); dC (100 MHz, CDCl3) 20.9, 21.0 (3COMe), 49.9 (C(6)), 57.2 (NCH2Ph), 60.9 (C(2)CH2), 61.8 (C(2)), 66.9 (C(5)), 73.2 (C(4)), 74.0 (OCH2Ph), 74.8 (C(3)), 127.2, 127.7, 127.8, 128.3, 128.5, 128.5 (o,m,pPh), 137.8, 138.4 (i-Ph), 170.0, 170.2, 170.7 (COMe); m/z (ESIþ) 470 ([MþH]þ, 100%); HRMS (ESIþ) C26 H31 NNaO7 þ ([MþNa]þ) requires 492.1993; found 492.1981. 4.5. (2R,3R,4R,5S)-N(1)-Benzyl-2,5-bis(hydroxymethyl)-3benzyloxy-4-hydroxypyrrolidine hydrochloride 21 Step 1: K2CO3 (54 mg, 0.39 mmol) was added to a stirred solution of 19 (61 mg, 0.13 mmol, >99:1 dr) in MeOH (4 mL) at rt and the resultant mixture was allowed to stir at rt for 16 h. The reaction mixture was then concentrated in vacuo and the residue was partitioned between H2O (15 mL) and CHCl3/iPrOH (3:1, 15 mL). The aqueous layer was extracted with CHCl3/iPrOH (3:1, 25 mL) and the combined organic extracts were then dried and concentrated in vacuo to give 17 as a yellow oil (55 mg, quant, >99:1 dr); [a]20 D þ11.9 (c 1.0, CHCl3). Step 2: HCl (2.0 M in Et2O, 1 mL) was added to a stirred solution of 17 (55 mg, >99:1 dr) in Et2O (4 mL) and the resultant mixture was stirred at rt for 10 min. The reaction mixture was then concentrated in vacuo to give 21 as a yellow solid (49 mg, quant, >99:1 dr); mp 64e66 C; [a]20 D þ18.3 (c 1.0, CHCl3); nmax (ATR) 3307 (OeH), 2929 (CeH); dH (400 MHz, CDCl3) 3.74e3.87 (4H, m, C(2)H, C(3)H, C(5)H, C(5)CHAHB), 4.09e4.17 (2H, m, C(5)CHAHB, NCHAHBPh), 4.32 (1H, d, J 13.1, NCHAHBPh), 4.43e4.49 (3H, m, C(4)H, C(2)CHAHB, OCHAHBPh), 4.54 (1H, d, J 12.0, OCHAHBPh), 4.72 (1H, d, J 13.1, C(2)CHAHB), 4.74 (1H, br s, OH), 5.16 (1H, br s, OH), 5.46 (1H, d, J 4.7, OH), 7.12e7.16 (2H, m, Ph), 7.31e7.38 (3H, m, Ph), 7.44e7.49 (3H, m, Ph), 7.60e7.64 (2H, m, Ph); dC (100 MHz, CDCl3) 57.7 (NCH2Ph), 60.1 (C(5)CH2), 61.1 (C(2)CH2), 70.7 (C(2)), 71.9 (OCH2Ph), 73.9 (C(4)), 74.1 (C(5)), 83.4 (C(3)), 127.5, 128.3, 128.6, 129.4, 130.5, 132.1 (o,m,p-Ph), 136.4 (2i-Ph); m/z (ESIþ) 344 ([MþH]þ, 100%); HRMS (ESIþ) C20 H26 NO4 þ ([MþH]þ) requires 344.1856; found 344.1851. 4.6. 2,5-Dideoxy-2,5-imino-D-glucitol [(D)-DGDP] 3 Pd(OH)2/C (22 mg, 20% w/w) was added to a stirred solution of 21 (44 mg, 0.13 mmol, >99:1 dr) in degassed MeOH (4 mL) and the
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resultant suspension was stirred at rt for 48 h under an atmosphere of H2 (5 atm). HCl (2.0 M in Et2O, 1 mL) was then added and the resultant suspension was stirred for 5 min before being filtered through CeliteÒ (eluent MeOH), and concentrated in vacuo to give 22. Purification via ion exchange chromatography on Dowex 50WX8 resin (hydrogen form, 100e200 mesh, eluent H2O) gave 3 as a white solid (21 mg, quant, >99:1 dr); mp 124e127 C; {lit.3c for sample isolated from the natural source mp 127e130 C; lit.8 mp 20 139e141 C; lit.6 mp 136e138 C}; [a]20 D þ22.2 (c 0.5, H2O); [a]D þ14.4 (c 0.5, MeOH); {lit.3 for sample isolated from the natural 18a source [a]D þ26.1 (c 0.84, H2O); lit.7k [a]28 D þ22.7 (c 0.14, H2O); lit. [a]22 þ24.1 (c 1.0, H O)}; n (ATR) 3300 (OeH), 2926 (CeH); dH D 2 max (400 MHz, D2O) 2.99 (1H, app q, J 5.2, C(2)H), 3.30 (1H, app q, J 5.5, C(5)H), 3.60e3.67 (2H, m, C(2)CHAHB, C(5)CHAHB), 3.70e3.78 (2H, m, C(2)CHAHB, C(5)CHAHB), 3.84 (1H, dd, J 5.2, 2.8, C(3)H), 4.08 (1H, dd, J 5.5, 2.8, C(4)H); dC (100 MHz, D2O) 59.9 (C(5)CH2), 60.8 (C(5)), 62.1 (C(2)CH2), 64.8 (C(2)), 77.2 (C(4)), 78.9 (C(3)); m/z (ESIþ) 164 ([MþH]þ, 100%); HRMS (ESIþ) C6 H14 NO4 þ ([MþH]þ) requires 164.0917; found 164.0913.
4.7. (2R,3R,4R,5S)-N(1)-Benzyl-2-[(triisopropylsilyloxy)methyl]-3-benzyloxy-4-hydroxy-5-(azidomethyl)pyrrolidine 23 Step 1: I2 (453 mg, 1.79 mmol) and NaHCO3 (150 mg, 1.79 mmol) were added to a stirred solution of 912 (350 mg, 0.60 mmol, >99:1 dr) in MeCN (20 mL) at rt, and the resultant mixture was stirred at rt for 16 h. The reaction mixture was diluted with Et2O (50 mL) and washed with satd aq Na2S2O3 (50 mL), then dried and concentrated in vacuo to give a 50:50 mixture of 10 and N-(a-methylbenzyl)acetamide (397 mg). Step 2: NaN3 (193 mg, 2.98 mmol) was added to a stirred solution of the residue of 10 and N-(a-methylbenzyl)acetamide (50:50, 397 mg) in DMF (15 mL). The resultant mixture was heated at 80 C for 16 h before being allowed to cool to rt. The reaction mixture was then diluted with H2O (50 mL) and EtOAc (50 mL), and the aqueous layer was extracted with EtOAc (220 mL). The combined organic extracts were washed with brine/H2O (1:1, 550 mL), then dried and concentrated in vacuo to give an 49:10:41 mixture of 23, 24 and 9, respectively. Purification via flash column chromatography (eluent 30e40 C petrol/EtOAc, 50:1) gave 23 as a pale yellow oil (72 mg, 23%, >99:1 dr); [a]20 D þ46.8 (c 1.0, CHCl3); nmax (ATR) 3406 (OeH), 2942, 2866 (CeH), 2100 (N3); dH (400 MHz, CDCl3) 0.97e1.04 (21H, m, Si(CHMe2)3), 3.05 (1H, br s, C(2)H), 3.16e3.22 (1H, m, C(5)H), 3.25e3.30 (2H, m, C(5)CHAHB, C(2)CHAHB), 3.50 (1H, dd, J 10.1, 2.5, C(2)CHAHB), 3.63 (1H, dd, J 11.8, 8.7, C(5)CHAHB), 3.71 (1H, d, J 14.2, NCHAHBPh), 3.85 (1H, app s, C(3)H), 3.96e4.02 (2H, m, NCHAHBPh, OH), 4.11 (1H, dd, J 11.0, 3.8, C(4)H), 4.53 (1H, d, J 12.0, OCHAHBPh), 4.64 (1H, d, J 12.0, OCHAHBPh), 7.23e7.38 (10H, m, Ph); dC (100 MHz, CDCl3) 11.8 (Si(CHMe2)3), 17.9 (Si(CHMe2)3), 50.3 (C(5)CH2), 59.0 (NCH2Ph), 64.6 (C(2)CH2), 67.3 (C(5)), 71.3 (OCH2Ph), 72.7 (C(2)), 73.5 (C(4)), 85.4 (C(3)), 127.2, 127.6, 127.7, 128.3, 128.4, 128.8 (o,m,p-Ph), 138.0, 139.6 (i-Ph); m/z (ESIþ) 525 ([MþH]þ, 100%); HRMS (ESIþ) C29H45N4O3Siþ ([MþH]þ) requires 525.3255; found 525.3248. Data for 24: dH (400 MHz, CDCl3) 0.89e1.12 (21H, m, Si(CHMe2)3), 2.47 (1H, dd, J 12.6, 3.5, C(6)HA), 2.68e2.74 (1H, m, C(2)H), 3.11 (1H, dd, J 12.6, 7.4, C(6)HB), 3.60 (1H, d, J 13.9, NCHAHBPh), 3.68 (1H, t, J 5.7, C(3)H), 3.78 (1H, app dt, J 7.4, 3.5, C(5)H), 3.88 (1H, dd, J 10.7, 4.7, C(2)CHAHB), 3.92e3.98 (1H, m, C(4)H), 4.15 (1H, dd, J 10.7, 3.5, C(2)CHAHB), 4.28 (1H, d, J 13.9, NCHAHBPh), 4.64 (1H, d, J 11.4, OCHAHBPh), 4.72 (1H, d, J 11.4, OCHAHBPh), 7.21e7.40 (10H, m, Ph); dC (100 MHz, CDCl3) 11.9 (Si(CHMe2)3), 18.0 (Si(CHMe2)3), 49.2 (C(6)), 58.0 (C(5)), 58.5 (NCH2Ph), 63.0 (C(2)CH2), 63.7 (C(2)), 72.2 (C(4)), 73.4 (OCH2Ph), 78.7 (C(3)), 127.0, 127.6, 128.3, 128.5, 128.6, 128.8, 129.0 (o,m,p-Ph), 138.2, 139.1 (i-Ph).
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4.8. (2R,3R,4R,5S)-N(1)-Benzyl-2-(hydroxymethyl)-3benzyloxy-4-hydroxy-5-(azidomethyl)pyrrolidine 25 HF$pyridine (70% in pyridine, 0.06 mL, 2.40 mmol) was added dropwise to a stirred solution of 23 (42 mg, 0.080 mmol, >99:1 dr) in THF (2 mL) at 0 C, and the resultant mixture was allowed to warm to rt and was stirred at rt for 16 h. The reaction mixture was cooled to 0 C and satd aq NaHCO3 (0.5 mL) was then carefully added. The resultant mixture was concentrated in vacuo and the residue was partitioned between H2O (5 mL) and CHCl3/iPrOH (3:1, 5 mL). The aqueous layer was extracted with CHCl3/iPrOH (3:1, 25 mL) and the combined organic extracts were then concentrated in vacuo. The residue was dissolved in CHCl3 (10 mL), and the resultant solution was washed with satd aq NaHCO3 (10 mL), then dried and concentrated in vacuo. Purification via flash column chromatography (eluent CHCl3/MeOH, 50:1) gave 25 as a yellow oil (29 mg, quant, >99:1 dr); [a]20 D þ41.5 (c 1.0, CHCl3); nmax (ATR) 3381 (OeH), 2927 (CeH), 2100 (N3); dH (400 MHz, CDCl3) 3.02e3.04 (1H, m, C(2)H), 3.17 (1H, dd, J 11.3, 3.5, C(2)CHAHB), 3.26 (1H, dt, J 7.6, 4.7, C(5)CHAHB), 3.34 (1H, app dd, J 12.3, 4.7, C(5)H), 3.45 (1H, app d, J 11.3, C(2)CHAHB), 3.51 (1H, dd, J 12.3, 7.6, C(5)CHAHB), 3.74 (1H, d, J 13.6, NCHAHBPh), 3.83 (1H, app t, J 2.5, C(3)H), 3.92 (1H, d, J 13.6, NCHAHBPh), 4.17 (1H, br s, C(4)H), 4.58 (1H, d, J 12.0, OCHAHBPh), 4.68 (1H, d, J 12.0, OCHAHBPh), 7.27e7.40 (10H, m, Ph); dC (100 MHz, CDCl3) 50.4 (C(5)CH2), 58.5 (NCH2Ph), 61.5 (C(2)CH2), 66.4 (C(5)), 70.6 (C(2)), 71.8 (OCH2Ph), 74.2 (C(4)), 86.5 (C(3)), 127.6, 127.7, 127.9, 128.5, 128.7, 128.7 (o,m,p-Ph), 137.9, 138.8 (i-Ph); m/z (ESIþ) 369 ([MþH]þ, 100%); HRMS (ESIþ) C20 H25 N4 O3 þ ([MþH]þ) requires 369.1921; found 369.1924. 4.9. 1,2,5-Trideoxy-1-amino-2,5-imino-D-glucitol dihydrochloride [(D)-ADGDP$2HCl] 26 Pd(OH)2/C (14 mg) and HCl (2.0 M in Et2O, 0.5 mL) were added to a stirred solution of 25 (27 mg, 0.07 mmol, >99:1 dr) in degassed MeOH (2 mL), and the resultant suspension was stirred at rt for 48 h under an atmosphere of H2 (5 atm). The resultant suspension was filtered through CeliteÒ (eluent MeOH) and the filtrate was concentrated in vacuo. Purification via ion exchange chromatography on Dowex-50WX8 resin (hydrogen form, 100e200 mesh, eluent H2O) gave (þ)-ADGDP as a colourless oil. HCl (2.0 M in Et2O, 1 mL) was added to a stirred solution of (þ)-ADGDP in Et2O (2 mL) and the resultant mixture was stirred at rt for 10 min then concentrated in vacuo to give 26 as pale yellow glassy solid (16 mg, quant, >99:1 9 dr); mp >170 C; {lit.7p mp >150 C}; [a]20 D þ33.2 (c 0.6, H2O); {lit. [a]25 þ43 (c 1.43, H O)}; n (ATR) 3300 (OeH), 3300 (NeH); d D 2 max H (400 MHz, D2O) 3.46 (1H, dd, J 13.9, 6.0, C(1)HA), 3.58 (1H, dd, J 13.9, 7.0, C(1)HB), 3.64e3.68 (1H, m, C(5)H), 3.81 (1H, dd, J 12.1, 9.0, C(6)HA), 3.94 (1H, dd, J 12.1, 4.7, C(6)HB), 4.05 (1H, app td, J 6.5, 3.6, C(2)H), 4.08e4.11 (1H, m, C(4)H), 4.29e4.32 (1H, m, C(3)H); dC (100 MHz, D2O) 35.4 (C(1)), 58.7 (C(2)), 59.3 (C(6)), 68.3 (C(5)), 74.5 (C(3)), 75.6 (C(4)); m/z (ESIþ) 163 ([MþH]þ, 100%); HRMS (ESIþ) C6 H15 N2 O3 þ ([MþH]þ) requires 163.1077; found 163.1073. 4.10. X-ray crystal structure determination for 21$H2O Data were collected using an Oxford Diffraction SuperNova diffractometer with graphite monochromated Cu-Ka radiation, using standard procedures at 150 K. The structures were solved by direct methods (SIR92); all non-hydrogen atoms were refined with anisotropic thermal parameters. Hydrogen atoms were added at idealised positions. The structure was refined using CRYSTALS.21 X-ray crystal structure data for 21$H2O [C20H28ClNO5]: M¼397.90, monoclinic, space group P21, a¼16.4392(3) A, b¼7.4924(2) A, c¼16.8150(4) A, b¼93.3685(19) , V¼2067.51(8) A3, Z¼4, m¼1.886 mm1, colourless plate, crystal
dimensions¼0.120.220.25 mm. A total of 8578 unique reflections were measured for 43.0s(I)], with Flack enantiopole¼0.057(13).17 Supplementary data Supplementary data associated with this article can be found in the online version, at http://dx.doi.org/10.1016/j.tet.2014.03.100. References and notes 1. For example, see: (a) Blanco, O.; Pato, C.; Ruiz, M.; Ojea, V. Org. Biomol. Chem. 2009, 7, 2310; (b) Tsou, E.-L.; Yeh, Y.-T.; Liang, P.-H.; Cheng, W.-C. Tetrahedron 2009, 65, 93. 2. (a) Dwek, R. A.; Butters, T. D.; Platt, F. M.; Zitzmann, N. Nat. Rev. Drug Discovery 2002, 1, 65; (b) Iminosugars. From Synthesis to Therapeutic Applications; Compain, P., Martin, O. R., Eds.; Wiley & Sons: Chichester, UK, 2007. 3. (a) Liu, K. K. C.; Kajimoto, T.; Chen, L.; Zhong, Z.; Ichikawa, Y.; Wong, C.-H. J. Org. Chem. 1991, 56, 6280; (b) Wang, Y. F.; Takaoka, Y.; Wong, C.-H. Angew. Chem., Int. Ed. Engl. 1994, 33, 1242; (c) Asano, N.; Yamauchi, T.; Kagamifuchi, K.; Shimizu, N.; Takahashi, S.; Takatsuka, H.; Ikeda, K.; Kizu, H.; Chuakul, W.; Kettawan, A.; Okamoto, T. J. Nat. Prod. 2005, 68, 1238; (d) Liang, P. H.; Cheng, W. C.; Lee, Y. L.; Yu, H. P.; Wu, Y. T.; Lin, Y. L.; Wong, C. H. ChemBioChem 2006, 7, 165. 4. N-Substituted derivatives have also shown potential as therapeutic agents; for example, see: (a) Liu, J.; Numa, M. M. D.; Liu, H.; Huang, S.-J.; Sears, P.; Shikhman, A. R.; Wong, C.-H. J. Org. Chem. 2004, 69, 6273; (b) Yu, Z.; Sawkar, A. R.; Whalen, L. J.; Wong, C.-H.; Kelly, J. W. J. Med. Chem. 2007, 50, 94. 5. Wrodnigg, T. M.; Diness, F.; Gruber, C.; Hausler, H.; Lundt, I.; Rupitz, K.; Steiner, € tz, A. E.; Tarling, C. A.; Withers, S. G.; Wolfler, H. Bioorg. Med. Chem. A. J.; Stu 2004, 12, 3485. 6. Blanco, O.; Pato, C.; Ruiz, M.; Ojea, V. Org. Biomol. Chem. 2008, 6, 3967. 7. For example, see: (a) Legler, G.; Korth, A.; Berger, A.; Ekhart, C.; Gradnig, G.; € tz, A. E. Carbohydr. Res. 1993, 250, 67; (b) Baxter, E. W.; Reitz, A. B. J. Org. Stu Chem. 1994, 59, 3175; (c) Lee, R. E.; Smith, M. D.; Nash, R. J.; Griffiths, R. C.; McNeil, M.; Grewal, R. K.; Yan, W.; Besra, G. S.; Brennan, P. J.; Fleet, G. W. J. Tetrahedron Lett. 1997, 38, 6733; (d) Long, D. D.; Frederiksen, S. M.; Marquess, D. G.; Lane, A. L.; Watkin, D. J.; Winkler, D. A.; Fleet, G. W. J. Tetrahedron Lett. 1998, 39, 6091; (e) Fechter, M. H.; Stutz, A. E. Carbohydr. Res. 1999, 319, 55; (f) Dondoni, A.; Giovannini, P. P.; Perrone, D. J. Org. Chem. 2002, 67, 7203; (g) Singh, S.; Han, H. Tetrahedron Lett. 2004, 45, 6349; (h) Gautier-Lefebvre, I.; Behr, J.-B.; Guillerm, G.; Muzard, M. Eur. J. Med. Chem. 2005, 40, 1255; (i) García-Moreno, ndez, J. M. Org. Lett. 2006, 8, 297; M. I.; Aguilar, M.; Ortiz Mellet, C.; García Ferna (j) Izquierdo, I.; Plaza, M. T.; Rodríguez, M.; Tamayo, J. A.; Martos, A. Tetrahedron 2006, 62, 2693; (k) Kumar, V.; Ramesh, N. G. Tetrahedron 2006, 62, 1877; (l) nez, V. Tetrahedron 2007, 63, 1440; (m) Doyagu € ez, E. Izquierdo, I.; Plaza, M. T.; Ya nchez, F.; Fern G.; Calderon, F.; Sa andez-Mayoralas, A. J. Org. Chem. 2007, 72, 9353; (n) Vyavahare, V. P.; Chattopadhyay, S.; Puranik, V. G.; Dhavale, D. D. Synlett 2007, 559; (o) Malle, B. M.; Lundt, I.; Wrodnigg, T. M. Org. Biomol. Chem. 2008, 6, 1779; (p) Merino, P.; Delso, I.; Tejero, T.; Cardona, F.; Marradi, M.; Faggi, E.; Parmeggiani, C.; Goti, A. Eur. J. Org. Chem. 2008, 2929; (q) Ayers, B. J.; Ngo, N.; Jenkinson, S. F.; Martínez, R. F.; Shimada, Y.; Adachi, I.; Weymouth-Wilson, A. C.; Kato, A.; Fleet, G. W. J. J. Org. Chem. 2012, 77, 7777. 8. For an alternative asymmetric synthesis of (þ)-DGDP 3, see: Donohoe, T. J.; Cheeseman, M. D.; O’Riordan, T. J. C.; Kershaw, J. A. Org. Biomol. Chem. 2008, 6, 3896. 9. (a) Davies, S. G.; Garner, A. C.; Goddard, E. C.; Kruchinin, D.; Roberts, P. M.; Smith, A. D.; Rodríguez-Solla, H.; Thomson, J. E.; Toms, S. M. Org. Biomol. Chem. 2007, 5, 1961; (b) Davies, S. G.; Nicholson, R. L.; Price, P. D.; Roberts, P. M.; Russell, A. J.; Savory, E. D.; Smith, A. D.; Thomson, J. E. Tetrahedron: Asymmetry 2009, 20, 758; (c) Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E.; West, C. J. Tetrahedron Lett. 2011, 52, 6477; (d) Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E.; West, C. J. Tetrahedron 2012, 68, 4302; (e) Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E.; Yin, J. Org. Lett. 2012, 14, 218; (f) Davies, S. G.; Foster, E. M.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. Tetrahedron 2013, 69, 8680. 10. (a) Davies, S. G.; Hughes, D. G.; Price, P. D.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E.; Williams, O. M. H. Synlett 2010, 567; (b) Bagal, S. K.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Scott, P. M.; Thomson, J. E. J. Org. Chem. 2010, 75, 8133; (c) Davies, S. G.; Fletcher, A. M.; Hughes, D. G.; Lee, J. A.; Price, P. D.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E.; Williams, O. M. H. Tetrahedron 2011, 67, 9975; (d) Davies, S. G.; Huckvale, R.; Lorkin, T. J. A.; Roberts, P. M.; Thomson, J. E. Tetrahedron: Asymmetry 2011, 22, 1591; (e) Bagal, S. K.; Davies, S. G.; Fletcher, A. M.; Lee, J. A.; Roberts, P. M.; Scott, P. M.; Thomson, J. E. Tetrahedron Lett. 2011, 52, 2216; (f) Davies, S. G.; Fletcher, A. M.; Lee, J. A.; Roberts, P. M.; Russell, A. J.; Taylor, R. J.; Thomson, A. D.; Thomson, J. E. Org. Lett. 2012, 14, 1672; (g) Davies, S. G.; Huckvale, R.; Lee, J. A.; Lorkin, T. J. A.; Roberts, P. M.; Thomson, J. E. Tetrahedron 2012, 68, 3263. 11. (a) Bentley, S. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. Org. Lett. 2011, 13, 2544; (b) Csatayov a, K.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Russell, A. J.; Thomson, J. E.; Wilson, D. L. Org. Lett. 2011, 13, 2606; (c) Brock, E. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. Org. Lett. 2011, 13, 1594; (d) Brock, E. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. Org. Lett. 2012, 14,
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e, C.; Roberts, P. M.; Thomson, J. E.; 4278; (e) Davies, S. G.; Fletcher, A. M.; Lebe Yin, J. Tetrahedron 2013, 69, 1369; (f) Davies, S. G.; Fletcher, A. M.; Lee, J. A.; Lorkin, T. J. A.; Roberts, P. M.; Thomson, J. E. Org. Lett. 2013, 15, 2050; (g) Brock, E. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. Org. Biomol. Chem. 2013, 11, 3187; (h) Davies, S. G.; Fletcher, A. M.; Lee, J. A.; Lorkin, T. J. A.; Roberts, P. M.; Thomson, J. E. Tetrahedron 2013, 69, 9779. Davies, S. G.; Figuccia, A. L. A.; Fletcher, A. M.; Roberts, P. M.; Thomson, J. E. Org. Lett. 2013, 15, 2042. Abraham, E.; Davies, S. G.; Millican, N. L.; Nicholson, R. L.; Roberts, P. M.; Smith, A. D. Org. Biomol. Chem. 2008, 6, 1655. Davies, S. G.; Foster, E. M.; McIntosh, C. R.; Roberts, P. M.; Rosser, T. E.; Smith, A. D.; Thomson, J. E. Tetrahedron: Asymmetry 2011, 22, 1035. For examples of studies concerning the regioselective ring-opening of aziridinium intermediates, see: (a) Graham, M. A.; Wadsworth, A. H.; ThorntonPett, M.; Rayner, C. M. Chem. Commun. 2001, 966; (b) Ori, M.; Toda, N.; Takami, K.; Tago, K.; Kogen, H. Tetrahedron 2005, 61, 2075; (c) D’hooghe, M.; Van Speybroeck, V.; Waroquier, M.; De Kimpe, N. Chem. Commun. 2006, 1554; (d) Metro, T. X.; Pardo, D. G.; Cossy, J. J. Org. Chem. 2007, 72, 6556; (e) Jarvis, S. B.; Charette, A. B. Org. Lett. 2011, 13, 3830; (f) Chuang, T. H.; Sharpless, K. B. Org.
16.
17.
18.
19. 20. 21.
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Lett. 2000, 2, 3555; (g) Ortiz, G. X., Jr.; Kang, B.; Wang, Q. J. Org. Chem. 2014, 79, tro, T.-X.; Duthion, B.; Gomez Pardo, D.; Cossy, J. 571; For a review, see: (h) Me Chem. Soc. Rev. 2010, 39, 89. Crystallographic data (excluding structure factors) for compound 21 have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 982801. (a) Flack, H. D. Acta Crystallogr., Sect. A 1983, 39, 876; (b) Flack, H. D.; Bernardinelli, G. Acta Crystallogr., Sect. A 1999, 55, 908; (c) Flack, H. D.; Bernardinelli, G. J. Appl. Crystallogr. 2000, 33, 1143. For example, see: (a) Kim, I.-S.; Kim, S.-J.; Lee, J. K.; Li, Q.-R.; Jung, Y.-H. Carbohydr. Res. 2007, 342, 1502; (b) Minami, Y.; Kuriyama, C.; Ikeda, K.; Kato, A.; Takebayashi, K.; Adachi, I.; Fleet, G. W. J.; Kettawan, A.; Okamoto, T.; Asano, N. Bioorg. Med. Chem. 2008, 16, 2734. See also Refs. 1b,3c,6,7g,7k and 8. The relative configuration within 24 was established by 1H NMR NOE analysis. Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics 1996, 15, 1518. Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, C. K.; Watkin, D. J. J. Appl. Crystallogr. 2003, 36, 1487.
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Asymmetric syntheses of 2,5-dideoxy-2,5-imino-D-glucitol [(þ)-DGDP] and 1,2,5-trideoxy-1-amino-2,5-imino-D-glucitol [(þ)-ADGDP] Stephen G. Davies *, Aude L.A. Figuccia, Ai M. Fletcher, Paul M. Roberts, James E. Thomson Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
a r t i c l e i n f o
a b s t r a c t
Article history: Received 31 January 2014 Accepted 31 March 2014 Available online 5 April 2014
The asymmetric syntheses of 2,5-dideoxy-2,5-imino-D-glucitol [(þ)-DGDP] and 1,2,5-trideoxy-1-amino2,5-imino-D-glucitol [(þ)-ADGDP] were achieved via the ring-closing iodoamination of an enantiopure bishomoallylic amine, followed by functionalisation of the resultant iodomethyl substituted pyrrolidine. In the case of (þ)-DGDP, formation of the corresponding aziridinium ion followed by regioselective ringopening with H2O gave the desired hydroxymethyl substituted pyrrolidine as a single diastereoisomer (>99:1 dr), with subsequent deprotection giving (þ)-DGDP in good yield. Whereas in the case of (þ)-ADGDP, displacement of iodide with NaN3 proved to be optimal, giving (þ)-ADGDP in good yield after reduction and deprotection. Ó 2014 Elsevier Ltd. All rights reserved.
Keywords: (þ)-DGDP (þ)-ADGDP Pyrrolidine alkaloids Asymmetric synthesis
1. Introduction Many polyhydroxylated pyrrolidines occur within Nature. Given the potent and specific inhibitory activity toward carbohydrate processing enzymes that many members of this class of compounds display, polyhydroxylated pyrrolidines have been the targets of numerous synthetic endeavours,1 and have been documented as highly promising candidates for the development of new therapeutic agents for the treatment of disorders such as diabetes, cancer and viral infections (e.g., HIV).2 For example, 2,5-dideoxy-2,5imino-D-mannitol [(þ)-DMDP] 1, 2,5-dideoxy-2,5-iminogalactitol (DGADP) 2 and 2,5-dideoxy-2,5-imino-D-glucitol [(þ)-DGDP] 3 are known inhibitors of several galactosidase and glucosidase enzymes.3,4 Furthermore, the synthetic 1-deoxy-1-amino-analogue of DMDP [(þ)-ADMDP] 4, and N(1)-substituted derivatives, have also been shown to display significantly enhanced selectivity and potency toward the inhibition of glucosidases.5 Most syntheses of compounds such as (þ)-DGDP 3 concern the elaboration of readily available carbohydrate precursors;6,7 in contrast, relatively few asymmetric syntheses of (þ)-DGDP 3 have been reported (Fig. 1).8 Herein we report asymmetric syntheses of both (þ)-DGDP 3 and its 1-deoxy-1-amino-analogue 1,2,5-trideoxy-1-amino-2,5-imino-Dglucitol [(þ)-ADGDP], employing a ring-closing iodoamination
* Corresponding author. Tel.: þ44 (0)1865 275695; fax: þ44 (0)1865 275633; e-mail address: [email protected] (S.G. Davies). 0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2014.03.100
Fig. 1. Biologically active polyhydroxylated pyrrolidines 1e4.
reaction, followed by functionalisation of the resultant iodomethyl substituted pyrrolidine. As part of our ongoing research programme concerning the asymmetric syntheses of enantiopure pyrrolidines,9 piperidines,10 and related natural products,11 we have recently reported the asymmetric syntheses of ()-1-deoxymannojirimycin 14 and its diastereoisomer (þ)-1-deoxyallonojirimycin.12 Our synthetic strategy for the construction of the piperidine ring relied on the ring-closing iodoamination of an enantiopure bishomoallylic amine such as 9, which proceeds with concomitant N-debenzylation, followed by ring-expansion of the resultant C(2)-iodomethyl
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substituted pyrrolidine 10. Bishomoallylic amine 9 was prepared in five steps from a,b-unsaturated ester 5: conjugate addition of lithium (R)-N-benzyl-N-(a-methylbenzyl)amide to 5,13 followed by in situ oxidation of the intermediate lithium (Z)-b-amino enolate14 with ()-camphorsulfonyloxaziridine [()-CSO] gave a-hydroxy-bamino ester 6 in >99:1 dr;13 subsequent O-benzyl protection, reduction of the ester moiety within 7, oxidation of the resultant alcohol 8, and reaction with vinylmagnesium bromide gave 9, which was isolated as a single diastereoisomer (>99:1 dr). Treatment of 9 with I2 and NaHCO3 in MeCN gave C(5)-iodomethyl substituted pyrrolidine 10, which could then be converted into carbonate 12 via the intermediacy of aziridinium ion 11, following intramolecular ring-opening of the aziridinium intermediate by a carbonate group tethered at the C(4)-position.15 However, it was found that under optimised conditions a superior yield of carbonate 12 could be obtained directly from 9. In this case, subsequent O-silyl deprotection of 12, methanolysis, and hydrogenolysis of 13 gave ()-1deoxymannojirimycin 14, which was isolated in good yield as a single diastereoisomer (Scheme 1).
2. Results and discussion We envisaged that repetition of the protocol for the generation of aziridinium ion 11, followed by treatment of 11 with dioxane/H2O (i.e., omitting the addition of NaHCO3) would produce pyrrolidine 15 preferentially, as a result of ring-opening with H2O at the least hindered C(6)-position within aziridinium ion 11. Thus, treatment of 10 with AgBF4 in CH2Cl2 gave quantitative conversion to aziridinium ion 11, which was then treated with a 3:1 mixture of dioxane and H2O, which produced a 90:10 mixture of pyrrolidine 15 and the known piperidine 16,12 respectively. The relative configuration within pyrrolidine 15 was initially assigned on the basis that substitution occurs with overall retention of configuration, and this assignment was subsequently confirmed unambiguously via single crystal X-ray diffraction analysis of a derivative. O-Silyl deprotection of the mixture of 15 and 16, followed by peracetylation of the mixture of 17 and 18 facilitated the isolation of both 19 and 20 in 65 and 4% yield (from 10), respectively, as single diastereoisomers (>99:1 dr) in each case (Scheme 2).
Scheme 2.
Scheme 1.
Transesterification of pyrrolidine 19 upon treatment with K2CO3 in MeOH was followed by conversion to the corresponding hydrochloride salt 21, which was isolated in quantitative yield and >99:1 dr. The relative configuration within 21 was assigned unambiguously by single crystal X-ray diffraction analysis;16 furthermore, the determination of a Flack x parameter17 of 0.057(13) for the crystal structure of 21$H2O allowed the assigned absolute
S.G. Davies et al. / Tetrahedron 70 (2014) 3601e3607
(2R,3R,4R,5S)-configuration within 21 to be confirmed unambiguously (Fig. 2), thereby also confirming the assigned configurations within 15, 17 and 19. Subsequent hydrogenolytic N- and Odebenzylation of 21 upon treatment with Pearlman’s catalyst [Pd(OH)2/C] under an atmosphere of H2 (5 atm) gave hydrochloride salt 22 in quantitative yield and >99:1 dr. Further purification of this sample by ion exchange chromatography on Dowex 50WX8 (Hþ form) resin gave (þ)-DGDP 3 in quantitative yield as a single diastereoisomer (Scheme 3). The melting point, specific rotation, and 1H and 13C NMR spectroscopic data for 3 were in excellent agreement with literature values18 for both the natural product and synthetic samples {mp 124e127 C; lit.3c for sample isolated from the natural source mp 127e130 C; lit.8 mp 139e141 C; lit.6 mp 3c 136e138 C; [a]20 D þ22.2 (c 0.5, H2O); lit. for sample isolated from the natural source [a]D þ26.1 (c 0.84, H2O); lit.7k [a]28 D þ22.7 (c 0.14, H2O); lit.18a [a]22 D þ24.1 (c 1.0, H2O)}.
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Attempts to effect ring-opening of aziridinium ion 11 with nitrogen-centred nucleophiles (e.g., azide, ammonia, etc.) were not efficacious, although when 9 was subjected to our standard ringclosing iodoamination protocol (i.e., treatment with I2 and NaHCO3 in MeCN),9b,c,d followed by immediate treatment of the crude reaction mixture with NaN3 in DMF, a 49:10:41 mixture of the corresponding pyrrolidine 23, piperidine 24,19 and returned starting material 9, respectively, was produced; chromatographic purification of this mixture gave azide 23 in 23% isolated yield. O-Silyl deprotection of 23 was then achieved upon treatment of 23 with HF$pyridine, giving 25 in quantitative yield and >99:1 dr. Tandem hydrogenolysis/reduction of 25 upon treatment with Pearlman’s catalyst [Pd(OH)2/C] under a hydrogen atmosphere (5 atm) gave (þ)-ADGDP, which was isolated as the corresponding dihydrochloride salt 26 in quantitative yield and >99:1 dr (Scheme 4). The spectroscopic data for 26 were also consistent with literature values {mp>170 C; lit.7p mp >150 C; [a]20 D þ33.2 (c 0.6, H2O); lit.7p [a]25 D þ43 (c 1.43, H2O)}.
Scheme 3.
Scheme 4.
3. Conclusion In conclusion, the ring-closing iodoamination of an enantiopure bishomoallylic amine provided an enantiopure pyrrolidine scaffold. Subsequent elaboration of the iodomethyl substituted pyrrolidine by either formation of the corresponding aziridinium ion followed by regioselective ring-opening with H2O, or direct displacement with NaN3 gave (þ)-DGDP and (þ)-ADGDP, respectively, in good yield after reduction/deprotection. 4. Experimental 4.1. General experimental
Fig. 2. X-ray crystal structure of (2R,3R,4R,5S)-21$H2O (H2O and selected H atoms are omitted for clarity).
All reactions involving organometallic or other moisture sensitive reagents were carried out under a nitrogen or argon atmosphere using standard vacuum line techniques and glassware that
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was flame dried and cooled under nitrogen before use. Solvents were dried according to the procedure outlined by Grubbs and coworkers.20 Water was purified by an ElixÒ UVe10 system. BuLi was purchased as a solution in hexanes and titrated against diphenylacetic acid before use. All other reagents were used as supplied without prior purification. Organic layers were dried over MgSO4. Thin layer chromatography was performed on aluminium plates coated with 60 F254 silica. Plates were visualised using UV light (254 nm), iodine, 1% aq KMnO4, or 10% ethanolic phosphomolybdic acid. Flash column chromatography was performed on Kieselgel 60 silica. Melting points are uncorrected. Optical rotations were recorded in a water-jacketed 10 cm cell. Specific rotations are reported in 101 deg cm2 g1 and concentrations in g/100 mL. IR spectra were recorded using an ATR module. Selected characteristic peaks are reported in cm1. NMR spectra were recorded in the deuterated solvent stated. Spectra were recorded at rt. The field was locked by external referencing to the relevant deuteron resonance. 1He1H COSY, 1He13C HSQC, and 1He13C HMBC analyses were used to establish atom connectivity. Accurate mass measurements were run on a TOF spectrometer internally calibrated with polyalanine. 4.2. (R,R,R,R)-N(1)-Benzyl-2-[(triisopropylsilyloxy)methyl]-3benzyloxy-4-hydroxy-5-(iodomethyl)pyrrolidine 10 I2 (518 mg, 2.04 mmol) and NaHCO3 (171 mg, 2.04 mmol) were added to a stirred solution of 912 (400 mg, 0.68 mmol, >99:1 dr) in MeCN (20 mL) at rt, and the resultant mixture was stirred at rt for 16 h. The reaction mixture was diluted with Et2O (50 mL) and washed with satd aq Na2S2O3 (50 mL), then dried and concentrated in vacuo to give a 50:50 mixture of 10 and N-(a-methylbenzyl)acetamide. Purification via flash column chromatography (eluent 30e40 C petrol/EtOAc, 50:1) gave 10 as a yellow oil (83 mg, 20%, >99:1 dr);12 [a]20 D þ50.7 (c 1.0, CHCl3); dH (400 MHz, CDCl3) 0.95e1.04 (21H, m, Si(CHMe2)3), 3.11 (1H, dd, J 8.9, 3.1, CHAHBI), 3.19 (1H, m, C(2)H), 3.22e3.28 (1H, m, C(2)CHAHB), 3.30 (1H, d, J 8.9, CHAHBI), 3.40 (1H, app dt, J 11.1, 3.1, C(5)H), 3.48 (1H, d, J 10.4, C(2)CHAHB), 3.68 (1H, d, J 14.0, NCHAHBPh), 3.86 (1H, app s, C(3)H), 3.95e4.02 (2H, m, NCHAHBPh, OH), 4.23 (1H, dd, J 11.1, 3.2, C(4)H), 4.53 (1H, d, J 12.0, OCHAHBPh), 4.66 (1H, d, J 12.0, OCHAHBPh), 7.22e7.40 (10H, m, Ph). 4.3. (1S,2R,3R,4R,5S)-N(1)-Benzyl-2-[(triisopropylsilyloxy)methyl]-3-benzyloxy-4-hydroxy-1-azabicyclo[3.1.0]hexanium tetrafluoroborate 11 AgBF4 (58 mg, 0.30 mmol) was added to a stirred solution of 102 (150 mg, 0.25 mmol, >99:1 dr) in CH2Cl2 (4 mL) at rt, and the resultant mixture was allowed to stir at rt for 1 h. The reaction mixture was then filtered through CeliteÒ (eluent CH2Cl2) and concentrated in vacuo to give 11 as an orange oil (138 mg, quant, >99:1 dr);2 [a]20 D þ0.6 (c 0.4, CHCl3); dH (400 MHz, CD2Cl2) 0.94e1.24 (21H, m, Si(CHMe2)3), 3.09 (1H, dd, J 8.0, 4.5, C(6)HA), 3.56 (1H, dd, J 6.3, 4.5, C(6)HB), 3.76e3.86 (2H, m, C(2)H, C(3)H), 3.98e4.04 (2H, m, C(2)CHAHB, OH), 4.07e4.20 (2H, m, C(2)CHAHB, C(5)H), 4.42 (1H, d, J 13.1, NCHAHBPh), 4.54 (1H, d, J 11.6, OCHAHBPh), 4.77 (1H, d, J 13.1, NCHAHBPh), 4.82 (1H, d, J 11.6, OCHAHBPh), 4.83e4.88 (1H, m, C(4)H), 7.28e7.58 (10H, m, Ph). 4.4. (2R,3R,4R,5S)-N(1)-Benzyl-2,5-bis(acetoxymethyl)-3benzyloxy-4-acetoxypyrrolidine 19 and (R,R,R,R)-N(1)-benzyl2-(acetoxymethyl)-3-benzyloxy-4,5-diacetoxypiperidine 20 Step 1: A solution of 11 (138 mg, 0.25 mmol, >99:1 dr) in dioxane/H2O (3:1, 4 mL) was allowed to stir at rt for 16 h. The reaction
mixture was then diluted with Et2O (15 mL) and washed with 2.0 M aq KOH (15 mL), then dried and concentrated in vacuo to give a 90:10 mixture of 15 and 16 (124 mg), respectively. Data for mixture: nmax (ATR) 3406 (OeH), 2942, 2866 (CeH); m/z (ESIþ) 500 ([MþH]þ, 100%); HRMS (ESIþ) C29H46NO4Siþ ([MþH]þ) requires 500.3191; found 500.3166. Data for 15: dH (400 MHz, CDCl3) 0.90e1.08 (21H, m, Si(CHMe2)3), 3.00 (1H, app q, J 3.4, C(2)H), 3.11e3.16 (1H, m, C(5)H), 3.51 (1H, app t, J 4.4, C(2)CH2), 3.57 (2H, dd, J 11.6, 4.8, C(5)CHAHB), 3.70 (1H, dd, J 11.6, 1.6, C(5)CHAHB), 3.77 (1H, d, J 13.7, NCHAHBPh), 3.82e3.87 (2H, m, C(3)H, NCHAHBPh), 4.18e4.25 (1H, m, C(4)H), 4.52 (1H, d, J 11.7, OCHAHBPh), 4.64 (1H, d, J 11.7, OCHAHBPh), 7.18e7.31 (10H, m, Ph); dC (100 MHz, CDCl3) 11.8 (Si(CHMe2)3), 18.0 (Si(CHMe2)3), 58.2 (NCH2Ph), 60.0 (C(5)CH2), 63.8 (C(2)CH2), 66.7 (C(5)), 70.4 (C(2)), 71.5 (OCH2Ph), 76.8 (C(4)), 85.4 (C(3)), 127.6, 127.6, 128.4, 128.5, 128.5, 129.0 (o,m,p-Ph), 138.2 (2i-Ph). Data for 16: dH (400 MHz, CDCl3) 1.02e1.14 (21H, m, Si(CHMe2)3), 2.24 (1H, d, J 12.4, C(6)HA), 2.38e2.47 (1H, m, C(2)H), 2.92 (1H, dd, J 12.4, 4.6, C(6)HB), 3.36 (1H, d, J 13.3, NCHAHBPh), 3.57 (1H, app t, J 8.1, C(3)H), 3.65 (1H, dd, J 8.1, 3.3, C(4)H), 3.72e3.80 (1H, m, C(5)H), 4.03 (1H, dd, J 11.1, 4.0, C(2)CHAHB), 4.22 (1H, dd, J 11.1, 1.8, C(2)CHAHB), 4.43 (1H, d, J 13.3, NCHAHBPh), 4.65 (1H, d, J 11.4, OCHAHBPh), 5.03 (1H, d, J 11.4, OCHAHBPh), 7.26e7.40 (10H, m, Ph); dC (100 MHz, CDCl3) 12.0 (Si(CHMe2)3), 18.1 (Si(CHMe2)3), 54.1 (C(6)), 57.2 (NCH2Ph), 61.9 (C(2)CH2), 66.6 (C(2)), 67.9 (C(5)), 74.3 (OCH2Ph), 75.8 (C(4)), 78.6 (C(3)), 127.2, 127.6, 127.9, 128.4, 128.5, 129.0 (o,m,p-Ph), 138.5 (2i-Ph). Step 2: HF$pyridine (70% in pyridine, 0.19 mL, 7.50 mmol) was added dropwise to a stirred solution of the 90:10 mixture of 15 and 16 (124 mg), respectively, in THF (4 mL) at 0 C. The resultant mixture was allowed to warm to rt and was stirred at rt for 16 h. The reaction mixture was then cooled to 0 C and satd aq NaHCO3 (0.5 mL) was added carefully. The resultant mixture was concentrated in vacuo and the residue was partitioned between H2O (10 mL) and CHCl3/iPrOH (3:1, 10 mL). The aqueous layer was extracted with CHCl3/iPrOH (3:1, 25 mL) and the combined organic extracts were then concentrated in vacuo. The residue was dissolved in CHCl3 (10 mL) and the resultant solution was washed with satd aq NaHCO3 (10 mL), then dried and concentrated in vacuo to give a 90:10 mixture of 17 and 18 (85 mg), respectively. Data for mixture: nmax (ATR) 3368 (OeH), 2926 (CeH); m/z (ESIþ) 344 ([MþH]þ, 100%); HRMS (ESIþ) C20 H26 NO4 þ ([MþH]þ) requires 344.1856; found 344.1846. Data for 17: dH (400 MHz, CDCl3) 3.02e3.06 (1H, m, C(2)H), 3.15e3.19 (1H, m, C(5)H), 3.39 (1H, dd, J 11.3, 3.5, C(2)CHAHB), 3.54 (1H, dd, J 11.3, 1.6, C(2)CHAHB), 3.70 (1H, dd, J 11.8, 4.6, C(5)CHAHB), 3.77e3.84 (3H, m, C(3)H, C(5)CHAHB, NCHAHBPh), 3.88 (1H, d, J 13.4, NCHAHBPh), 4.29 (1H, dd, J 5.4, 2.5, C(4)H), 4.59 (1H, d, J 12.0, OCHAHBPh), 4.69 (1H, d, J 12.0, OCHAHBPh), 7.25e7.39 (10H, m, Ph); dC (100 MHz, CDCl3) 57.8 (NCH2Ph), 60.7 (C(5)CH2), 61.5 (C(2)CH2), 66.6 (C(5)), 69.6 (C(2)), 71.8 (OCH2Ph), 76.6 (C(4)), 86.2 (C(3)), 127.6, 127.6, 127.8, 128.5, 128.7, 128.8 (o,m,p-Ph), 138.0, 138.7 (i-Ph). Data for 18: dH (400 MHz, CDCl3) 2.29e2.34 (2H, m, C(2)H, C(6)HA), 3.04 (1H, dd, J 12.6, 3.8, C(6)HB), 3.39 (1H, d, J 13.2, NCHAHBPh), 3.60 (1H, dd, J 8.7, 3.3, C(4)H), 3.77 (1H, app t, J 8.7, C(3)H), 3.85 (1H, br s, C(5)H), 3.93 (1H, dd, J 12.0, 1.6, C(2)CHAHB), 4.03 (1H, dd, J 12.0, 2.7, C(2)CHAHB), 4.14 (1H, d, J 13.2, NCHAHBPh), 4.78 (1H, d, J 11.3, OCHAHBPh), 4.93 (1H, d, J 11.3, OCHAHBPh), 7.26e7.42 (10H, m, Ph); dC (100 MHz, CDCl3) 54.8 (C(6)), 57.0 (NCH2Ph), 58.3 (C(2)CH2), 65.7 (C(2)), 67.8 (C(5)), 75.0 (OCH2Ph), 75.2 (C(4)), 77.2 (C(3)), 127.5, 128.0, 128.1, 128.6, 128.7, 128.8 (o,m,p-Ph), 137.7, 138.3 (i-Ph). Step 3: Ac2O (0.24 mL, 2.50 mmol) and DMAP (6 mg, 0.05 mmol) were added to a stirred solution of the 90:10 mixture of 17 and 18 (85 mg), respectively, in pyridine (4 mL) at 0 C. The resultant mixture was allowed to warm to rt and was stirred at rt for 16 h. The reaction mixture was then diluted with H2O (15 mL) and EtOAc (15 mL), and the aqueous layer was extracted with EtOAc (25 mL).
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The combined organic extracts were washed with brine (20 mL), then dried and concentrated in vacuo. Purification via flash column chromatography (eluent 30e40 C petrol/acetone, 9:1) gave 19 as a yellow oil (76 mg, 65%, >99:1 dr); [a]20 D þ50.8 (c 1.0, CHCl3); nmax (ATR) 1741 (C]O); dH (400 MHz, CDCl3) 1.87 (3H, s, COMe), 1.99 (3H, s, COMe), 2.08 (3H, s, COMe), 3.16 (1H, ddd, J 8.2, 5.6, 2.1, C(2)H), 3.51 (1H, app dt, J 7.6, 5.2, C(5)H), 3.67e3.73 (2H, m, C(3)H, C(2)CHAHB), 3.86 (1H, d, J 13.9, NCHAHBPh), 3.93e4.01 (2H, m, C(2)CHAHB, NCHAHBPh), 4.03e4.14 (2H, m, C(5)CH2), 4.58 (1H, d, J 12.1, OCHAHBPh), 4.68 (1H, d, J 12.1, OCHAHBPh), 5.30 (1H, dd, J 5.2, 1.6, C(4)H), 7.25e7.38 (10H, m, Ph); dC (100 MHz, CDCl3) 20.7, 20.8, 21.0 (COMe), 59.1 (NCH2Ph), 62.4 (C(5)CH2), 63.4 (C(5)), 64.5 (C(2)CH2), 68.0 (C(2)), 71.4 (OCH2Ph), 76.1 (C(4)), 86.3 (C(3)), 127.4, 127.7, 127.8, 128.4, 128.4, 128.8 (o,m,p-Ph), 137.7, 138.6 (i-Ph), 170.2, 170.6, 170.6 (COMe); m/z (ESIþ) 492 ([MþNa]þ, 100%); HRMS (ESIþ) C26 H31 NNaO7 þ ([MþNa]þ) requires 492.1993; found 492.1983. Further elution gave 20 as a yellow oil (5 mg, 4%, >99:1 dr); [a]20 D þ1.5 (c 0.4, CHCl3); nmax (ATR) 1740 (C]O); dH (400 MHz, CDCl3) 2.03 (3H, s, COMe), 2.05 (3H, s, COMe), 2.09 (3H, s, COMe), 2.50 (1H, dd, J 13.1, 2.7, C(6)HA), 2.81e2.85 (1H, m, C(2)H), 3.00 (1H, dd, J 13.1, 6.0, C(6)HB), 3.58 (1H, d, J 13.9, NCHAHBPh), 3.85 (1H, app t, J 7.0, C(3)H), 4.08 (1H, d, J 13.9, NCHAHBPh), 4.37 (1H, dd, J 12.3, 4.7, C(2)CHAHB), 4.51 (1H, dd, J 12.3, 3.8, C(2)CHAHB), 4.62 (1H, d, J 11.3, OCHAHBPh), 4.73 (1H, d, J 11.3, OCHAHBPh), 5.13 (1H, dd, J 7.0, 3.5, C(4)H), 5.28 (1H, ddd, J 6.0, 3.5, 2.7, C(5)H), 7.24e4.38 (10H, m, Ph); dC (100 MHz, CDCl3) 20.9, 21.0 (3COMe), 49.9 (C(6)), 57.2 (NCH2Ph), 60.9 (C(2)CH2), 61.8 (C(2)), 66.9 (C(5)), 73.2 (C(4)), 74.0 (OCH2Ph), 74.8 (C(3)), 127.2, 127.7, 127.8, 128.3, 128.5, 128.5 (o,m,pPh), 137.8, 138.4 (i-Ph), 170.0, 170.2, 170.7 (COMe); m/z (ESIþ) 470 ([MþH]þ, 100%); HRMS (ESIþ) C26 H31 NNaO7 þ ([MþNa]þ) requires 492.1993; found 492.1981. 4.5. (2R,3R,4R,5S)-N(1)-Benzyl-2,5-bis(hydroxymethyl)-3benzyloxy-4-hydroxypyrrolidine hydrochloride 21 Step 1: K2CO3 (54 mg, 0.39 mmol) was added to a stirred solution of 19 (61 mg, 0.13 mmol, >99:1 dr) in MeOH (4 mL) at rt and the resultant mixture was allowed to stir at rt for 16 h. The reaction mixture was then concentrated in vacuo and the residue was partitioned between H2O (15 mL) and CHCl3/iPrOH (3:1, 15 mL). The aqueous layer was extracted with CHCl3/iPrOH (3:1, 25 mL) and the combined organic extracts were then dried and concentrated in vacuo to give 17 as a yellow oil (55 mg, quant, >99:1 dr); [a]20 D þ11.9 (c 1.0, CHCl3). Step 2: HCl (2.0 M in Et2O, 1 mL) was added to a stirred solution of 17 (55 mg, >99:1 dr) in Et2O (4 mL) and the resultant mixture was stirred at rt for 10 min. The reaction mixture was then concentrated in vacuo to give 21 as a yellow solid (49 mg, quant, >99:1 dr); mp 64e66 C; [a]20 D þ18.3 (c 1.0, CHCl3); nmax (ATR) 3307 (OeH), 2929 (CeH); dH (400 MHz, CDCl3) 3.74e3.87 (4H, m, C(2)H, C(3)H, C(5)H, C(5)CHAHB), 4.09e4.17 (2H, m, C(5)CHAHB, NCHAHBPh), 4.32 (1H, d, J 13.1, NCHAHBPh), 4.43e4.49 (3H, m, C(4)H, C(2)CHAHB, OCHAHBPh), 4.54 (1H, d, J 12.0, OCHAHBPh), 4.72 (1H, d, J 13.1, C(2)CHAHB), 4.74 (1H, br s, OH), 5.16 (1H, br s, OH), 5.46 (1H, d, J 4.7, OH), 7.12e7.16 (2H, m, Ph), 7.31e7.38 (3H, m, Ph), 7.44e7.49 (3H, m, Ph), 7.60e7.64 (2H, m, Ph); dC (100 MHz, CDCl3) 57.7 (NCH2Ph), 60.1 (C(5)CH2), 61.1 (C(2)CH2), 70.7 (C(2)), 71.9 (OCH2Ph), 73.9 (C(4)), 74.1 (C(5)), 83.4 (C(3)), 127.5, 128.3, 128.6, 129.4, 130.5, 132.1 (o,m,p-Ph), 136.4 (2i-Ph); m/z (ESIþ) 344 ([MþH]þ, 100%); HRMS (ESIþ) C20 H26 NO4 þ ([MþH]þ) requires 344.1856; found 344.1851. 4.6. 2,5-Dideoxy-2,5-imino-D-glucitol [(D)-DGDP] 3 Pd(OH)2/C (22 mg, 20% w/w) was added to a stirred solution of 21 (44 mg, 0.13 mmol, >99:1 dr) in degassed MeOH (4 mL) and the
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resultant suspension was stirred at rt for 48 h under an atmosphere of H2 (5 atm). HCl (2.0 M in Et2O, 1 mL) was then added and the resultant suspension was stirred for 5 min before being filtered through CeliteÒ (eluent MeOH), and concentrated in vacuo to give 22. Purification via ion exchange chromatography on Dowex 50WX8 resin (hydrogen form, 100e200 mesh, eluent H2O) gave 3 as a white solid (21 mg, quant, >99:1 dr); mp 124e127 C; {lit.3c for sample isolated from the natural source mp 127e130 C; lit.8 mp 20 139e141 C; lit.6 mp 136e138 C}; [a]20 D þ22.2 (c 0.5, H2O); [a]D þ14.4 (c 0.5, MeOH); {lit.3 for sample isolated from the natural 18a source [a]D þ26.1 (c 0.84, H2O); lit.7k [a]28 D þ22.7 (c 0.14, H2O); lit. [a]22 þ24.1 (c 1.0, H O)}; n (ATR) 3300 (OeH), 2926 (CeH); dH D 2 max (400 MHz, D2O) 2.99 (1H, app q, J 5.2, C(2)H), 3.30 (1H, app q, J 5.5, C(5)H), 3.60e3.67 (2H, m, C(2)CHAHB, C(5)CHAHB), 3.70e3.78 (2H, m, C(2)CHAHB, C(5)CHAHB), 3.84 (1H, dd, J 5.2, 2.8, C(3)H), 4.08 (1H, dd, J 5.5, 2.8, C(4)H); dC (100 MHz, D2O) 59.9 (C(5)CH2), 60.8 (C(5)), 62.1 (C(2)CH2), 64.8 (C(2)), 77.2 (C(4)), 78.9 (C(3)); m/z (ESIþ) 164 ([MþH]þ, 100%); HRMS (ESIþ) C6 H14 NO4 þ ([MþH]þ) requires 164.0917; found 164.0913.
4.7. (2R,3R,4R,5S)-N(1)-Benzyl-2-[(triisopropylsilyloxy)methyl]-3-benzyloxy-4-hydroxy-5-(azidomethyl)pyrrolidine 23 Step 1: I2 (453 mg, 1.79 mmol) and NaHCO3 (150 mg, 1.79 mmol) were added to a stirred solution of 912 (350 mg, 0.60 mmol, >99:1 dr) in MeCN (20 mL) at rt, and the resultant mixture was stirred at rt for 16 h. The reaction mixture was diluted with Et2O (50 mL) and washed with satd aq Na2S2O3 (50 mL), then dried and concentrated in vacuo to give a 50:50 mixture of 10 and N-(a-methylbenzyl)acetamide (397 mg). Step 2: NaN3 (193 mg, 2.98 mmol) was added to a stirred solution of the residue of 10 and N-(a-methylbenzyl)acetamide (50:50, 397 mg) in DMF (15 mL). The resultant mixture was heated at 80 C for 16 h before being allowed to cool to rt. The reaction mixture was then diluted with H2O (50 mL) and EtOAc (50 mL), and the aqueous layer was extracted with EtOAc (220 mL). The combined organic extracts were washed with brine/H2O (1:1, 550 mL), then dried and concentrated in vacuo to give an 49:10:41 mixture of 23, 24 and 9, respectively. Purification via flash column chromatography (eluent 30e40 C petrol/EtOAc, 50:1) gave 23 as a pale yellow oil (72 mg, 23%, >99:1 dr); [a]20 D þ46.8 (c 1.0, CHCl3); nmax (ATR) 3406 (OeH), 2942, 2866 (CeH), 2100 (N3); dH (400 MHz, CDCl3) 0.97e1.04 (21H, m, Si(CHMe2)3), 3.05 (1H, br s, C(2)H), 3.16e3.22 (1H, m, C(5)H), 3.25e3.30 (2H, m, C(5)CHAHB, C(2)CHAHB), 3.50 (1H, dd, J 10.1, 2.5, C(2)CHAHB), 3.63 (1H, dd, J 11.8, 8.7, C(5)CHAHB), 3.71 (1H, d, J 14.2, NCHAHBPh), 3.85 (1H, app s, C(3)H), 3.96e4.02 (2H, m, NCHAHBPh, OH), 4.11 (1H, dd, J 11.0, 3.8, C(4)H), 4.53 (1H, d, J 12.0, OCHAHBPh), 4.64 (1H, d, J 12.0, OCHAHBPh), 7.23e7.38 (10H, m, Ph); dC (100 MHz, CDCl3) 11.8 (Si(CHMe2)3), 17.9 (Si(CHMe2)3), 50.3 (C(5)CH2), 59.0 (NCH2Ph), 64.6 (C(2)CH2), 67.3 (C(5)), 71.3 (OCH2Ph), 72.7 (C(2)), 73.5 (C(4)), 85.4 (C(3)), 127.2, 127.6, 127.7, 128.3, 128.4, 128.8 (o,m,p-Ph), 138.0, 139.6 (i-Ph); m/z (ESIþ) 525 ([MþH]þ, 100%); HRMS (ESIþ) C29H45N4O3Siþ ([MþH]þ) requires 525.3255; found 525.3248. Data for 24: dH (400 MHz, CDCl3) 0.89e1.12 (21H, m, Si(CHMe2)3), 2.47 (1H, dd, J 12.6, 3.5, C(6)HA), 2.68e2.74 (1H, m, C(2)H), 3.11 (1H, dd, J 12.6, 7.4, C(6)HB), 3.60 (1H, d, J 13.9, NCHAHBPh), 3.68 (1H, t, J 5.7, C(3)H), 3.78 (1H, app dt, J 7.4, 3.5, C(5)H), 3.88 (1H, dd, J 10.7, 4.7, C(2)CHAHB), 3.92e3.98 (1H, m, C(4)H), 4.15 (1H, dd, J 10.7, 3.5, C(2)CHAHB), 4.28 (1H, d, J 13.9, NCHAHBPh), 4.64 (1H, d, J 11.4, OCHAHBPh), 4.72 (1H, d, J 11.4, OCHAHBPh), 7.21e7.40 (10H, m, Ph); dC (100 MHz, CDCl3) 11.9 (Si(CHMe2)3), 18.0 (Si(CHMe2)3), 49.2 (C(6)), 58.0 (C(5)), 58.5 (NCH2Ph), 63.0 (C(2)CH2), 63.7 (C(2)), 72.2 (C(4)), 73.4 (OCH2Ph), 78.7 (C(3)), 127.0, 127.6, 128.3, 128.5, 128.6, 128.8, 129.0 (o,m,p-Ph), 138.2, 139.1 (i-Ph).
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4.8. (2R,3R,4R,5S)-N(1)-Benzyl-2-(hydroxymethyl)-3benzyloxy-4-hydroxy-5-(azidomethyl)pyrrolidine 25 HF$pyridine (70% in pyridine, 0.06 mL, 2.40 mmol) was added dropwise to a stirred solution of 23 (42 mg, 0.080 mmol, >99:1 dr) in THF (2 mL) at 0 C, and the resultant mixture was allowed to warm to rt and was stirred at rt for 16 h. The reaction mixture was cooled to 0 C and satd aq NaHCO3 (0.5 mL) was then carefully added. The resultant mixture was concentrated in vacuo and the residue was partitioned between H2O (5 mL) and CHCl3/iPrOH (3:1, 5 mL). The aqueous layer was extracted with CHCl3/iPrOH (3:1, 25 mL) and the combined organic extracts were then concentrated in vacuo. The residue was dissolved in CHCl3 (10 mL), and the resultant solution was washed with satd aq NaHCO3 (10 mL), then dried and concentrated in vacuo. Purification via flash column chromatography (eluent CHCl3/MeOH, 50:1) gave 25 as a yellow oil (29 mg, quant, >99:1 dr); [a]20 D þ41.5 (c 1.0, CHCl3); nmax (ATR) 3381 (OeH), 2927 (CeH), 2100 (N3); dH (400 MHz, CDCl3) 3.02e3.04 (1H, m, C(2)H), 3.17 (1H, dd, J 11.3, 3.5, C(2)CHAHB), 3.26 (1H, dt, J 7.6, 4.7, C(5)CHAHB), 3.34 (1H, app dd, J 12.3, 4.7, C(5)H), 3.45 (1H, app d, J 11.3, C(2)CHAHB), 3.51 (1H, dd, J 12.3, 7.6, C(5)CHAHB), 3.74 (1H, d, J 13.6, NCHAHBPh), 3.83 (1H, app t, J 2.5, C(3)H), 3.92 (1H, d, J 13.6, NCHAHBPh), 4.17 (1H, br s, C(4)H), 4.58 (1H, d, J 12.0, OCHAHBPh), 4.68 (1H, d, J 12.0, OCHAHBPh), 7.27e7.40 (10H, m, Ph); dC (100 MHz, CDCl3) 50.4 (C(5)CH2), 58.5 (NCH2Ph), 61.5 (C(2)CH2), 66.4 (C(5)), 70.6 (C(2)), 71.8 (OCH2Ph), 74.2 (C(4)), 86.5 (C(3)), 127.6, 127.7, 127.9, 128.5, 128.7, 128.7 (o,m,p-Ph), 137.9, 138.8 (i-Ph); m/z (ESIþ) 369 ([MþH]þ, 100%); HRMS (ESIþ) C20 H25 N4 O3 þ ([MþH]þ) requires 369.1921; found 369.1924. 4.9. 1,2,5-Trideoxy-1-amino-2,5-imino-D-glucitol dihydrochloride [(D)-ADGDP$2HCl] 26 Pd(OH)2/C (14 mg) and HCl (2.0 M in Et2O, 0.5 mL) were added to a stirred solution of 25 (27 mg, 0.07 mmol, >99:1 dr) in degassed MeOH (2 mL), and the resultant suspension was stirred at rt for 48 h under an atmosphere of H2 (5 atm). The resultant suspension was filtered through CeliteÒ (eluent MeOH) and the filtrate was concentrated in vacuo. Purification via ion exchange chromatography on Dowex-50WX8 resin (hydrogen form, 100e200 mesh, eluent H2O) gave (þ)-ADGDP as a colourless oil. HCl (2.0 M in Et2O, 1 mL) was added to a stirred solution of (þ)-ADGDP in Et2O (2 mL) and the resultant mixture was stirred at rt for 10 min then concentrated in vacuo to give 26 as pale yellow glassy solid (16 mg, quant, >99:1 9 dr); mp >170 C; {lit.7p mp >150 C}; [a]20 D þ33.2 (c 0.6, H2O); {lit. [a]25 þ43 (c 1.43, H O)}; n (ATR) 3300 (OeH), 3300 (NeH); d D 2 max H (400 MHz, D2O) 3.46 (1H, dd, J 13.9, 6.0, C(1)HA), 3.58 (1H, dd, J 13.9, 7.0, C(1)HB), 3.64e3.68 (1H, m, C(5)H), 3.81 (1H, dd, J 12.1, 9.0, C(6)HA), 3.94 (1H, dd, J 12.1, 4.7, C(6)HB), 4.05 (1H, app td, J 6.5, 3.6, C(2)H), 4.08e4.11 (1H, m, C(4)H), 4.29e4.32 (1H, m, C(3)H); dC (100 MHz, D2O) 35.4 (C(1)), 58.7 (C(2)), 59.3 (C(6)), 68.3 (C(5)), 74.5 (C(3)), 75.6 (C(4)); m/z (ESIþ) 163 ([MþH]þ, 100%); HRMS (ESIþ) C6 H15 N2 O3 þ ([MþH]þ) requires 163.1077; found 163.1073. 4.10. X-ray crystal structure determination for 21$H2O Data were collected using an Oxford Diffraction SuperNova diffractometer with graphite monochromated Cu-Ka radiation, using standard procedures at 150 K. The structures were solved by direct methods (SIR92); all non-hydrogen atoms were refined with anisotropic thermal parameters. Hydrogen atoms were added at idealised positions. The structure was refined using CRYSTALS.21 X-ray crystal structure data for 21$H2O [C20H28ClNO5]: M¼397.90, monoclinic, space group P21, a¼16.4392(3) A, b¼7.4924(2) A, c¼16.8150(4) A, b¼93.3685(19) , V¼2067.51(8) A3, Z¼4, m¼1.886 mm1, colourless plate, crystal
dimensions¼0.120.220.25 mm. A total of 8578 unique reflections were measured for 4
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12. 13. 14. 15.
e, C.; Roberts, P. M.; Thomson, J. E.; 4278; (e) Davies, S. G.; Fletcher, A. M.; Lebe Yin, J. Tetrahedron 2013, 69, 1369; (f) Davies, S. G.; Fletcher, A. M.; Lee, J. A.; Lorkin, T. J. A.; Roberts, P. M.; Thomson, J. E. Org. Lett. 2013, 15, 2050; (g) Brock, E. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. Org. Biomol. Chem. 2013, 11, 3187; (h) Davies, S. G.; Fletcher, A. M.; Lee, J. A.; Lorkin, T. J. A.; Roberts, P. M.; Thomson, J. E. Tetrahedron 2013, 69, 9779. Davies, S. G.; Figuccia, A. L. A.; Fletcher, A. M.; Roberts, P. M.; Thomson, J. E. Org. Lett. 2013, 15, 2042. Abraham, E.; Davies, S. G.; Millican, N. L.; Nicholson, R. L.; Roberts, P. M.; Smith, A. D. Org. Biomol. Chem. 2008, 6, 1655. Davies, S. G.; Foster, E. M.; McIntosh, C. R.; Roberts, P. M.; Rosser, T. E.; Smith, A. D.; Thomson, J. E. Tetrahedron: Asymmetry 2011, 22, 1035. For examples of studies concerning the regioselective ring-opening of aziridinium intermediates, see: (a) Graham, M. A.; Wadsworth, A. H.; ThorntonPett, M.; Rayner, C. M. Chem. Commun. 2001, 966; (b) Ori, M.; Toda, N.; Takami, K.; Tago, K.; Kogen, H. Tetrahedron 2005, 61, 2075; (c) D’hooghe, M.; Van Speybroeck, V.; Waroquier, M.; De Kimpe, N. Chem. Commun. 2006, 1554; (d) Metro, T. X.; Pardo, D. G.; Cossy, J. J. Org. Chem. 2007, 72, 6556; (e) Jarvis, S. B.; Charette, A. B. Org. Lett. 2011, 13, 3830; (f) Chuang, T. H.; Sharpless, K. B. Org.
16.
17.
18.
19. 20. 21.
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Lett. 2000, 2, 3555; (g) Ortiz, G. X., Jr.; Kang, B.; Wang, Q. J. Org. Chem. 2014, 79, tro, T.-X.; Duthion, B.; Gomez Pardo, D.; Cossy, J. 571; For a review, see: (h) Me Chem. Soc. Rev. 2010, 39, 89. Crystallographic data (excluding structure factors) for compound 21 have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 982801. (a) Flack, H. D. Acta Crystallogr., Sect. A 1983, 39, 876; (b) Flack, H. D.; Bernardinelli, G. Acta Crystallogr., Sect. A 1999, 55, 908; (c) Flack, H. D.; Bernardinelli, G. J. Appl. Crystallogr. 2000, 33, 1143. For example, see: (a) Kim, I.-S.; Kim, S.-J.; Lee, J. K.; Li, Q.-R.; Jung, Y.-H. Carbohydr. Res. 2007, 342, 1502; (b) Minami, Y.; Kuriyama, C.; Ikeda, K.; Kato, A.; Takebayashi, K.; Adachi, I.; Fleet, G. W. J.; Kettawan, A.; Okamoto, T.; Asano, N. Bioorg. Med. Chem. 2008, 16, 2734. See also Refs. 1b,3c,6,7g,7k and 8. The relative configuration within 24 was established by 1H NMR NOE analysis. Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics 1996, 15, 1518. Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, C. K.; Watkin, D. J. J. Appl. Crystallogr. 2003, 36, 1487.