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Synlett 2012(6): 913-916  
DOI: 10.1055/s-0031-1290614
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Concise Synthetic Approach to (+)-Valienamine Starting from Garner’s Aldehyde

Bing Zhoua,, Zhi Luoa,, Sui Linb, Yuanchao Li*a
a Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Road Zu Chong Zhi, Zhangjiang Hi-Tech Park,Shanghai 201203, P. R. of China
Fax: +86(21)50807288; e-Mail: ycli@mail.shcnc.ac.cn;
b Fujian Institute of Medical Sciences, Fuzhou 350001, P. R. of China

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Publication History

Received 15 December 2011
Publication Date:
15 March 2012 (online)

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Abstract

A synthesis of (+)-valienamine was achieved starting from Garner’s aldehyde in ten steps and 23% overall yield. A unique feature of the synthetic route is that an acyclic precursor was constructed, using diastereoselective antireductive coupling reaction of alkyne and Garner’s aldehyde as the key step, which was then cyclized in an intramolecular aldol reaction to form the valienamine skeleton.

Key words

(+)-valienamine - Garner’s aldehyde - diastereoselective - hydrozirconation-transmetalation - intramolecular aldol reaction

Valienamine (1) is an α-glucosidase inhibitor [²] that was isolated from the microbial degradation of validoxyl­amine A (2) with Pseudomonas denitrificans, [³] Flavobacterium saccharophilum, [4] or from the NBS cleavage of validoxylamine A or its derivatives (Figure  [¹] ). [5] Moreover, valienamine (1) is also an essential core unit in many kinds of pseudo-oligosaccharidic α-d-glucosidase inhibitors. [6] In view of these desirable properties, a considerable amount of effort [7-¹0] has been put into the enantiospecific syntheses of valienamine, among which most reported total syntheses employ cyclitol quebrachitol, [7] d-glucose derivatives, [8] or (-)-quinic acid [9] as the chiral building block. However, such strategies are often limited by the use of relatively expensive chiral building blocks and/or the need for lengthy protecting-group manipulation. In some other methods the cyclohexene skeleton of 1 was constructed through Diels-Alder reaction or ring-closing metathesis of an acyclic diene. [¹0] In this letter, we report a novel synthetic approach that leads from a construction of an acyclic precursor and its cyclization at a later stage to form the valienamine skeleton.

Figure 1

We reasoned that 1 can be obtained by Luche reduction of aldehyde group and removing ethoxymethyl and Boc protecting group in 3 (Scheme  [¹] ). Disconnection via intramolecular aldol condensation led to the acyclic precursor 4. The requisite precursor 4 can in turn be synthesized from the monoprotected tetraol 5, the product of a diastereoselective dihydroxylation of 6. We envisioned that the highly functionalized key intermediate 6 could be obtained by reductive coupling of Garner’s aldehyde 7 [¹¹] and protected 3-butyn-1-ol 8, which is commercially available. Compounds 7 and 8 can also be synthesized from readily available starting materials l-serine and 3-butyn-1-ol, respectively.

Scheme 1 Retrosynthetic analysis of 1

Generally, the design of addition of nucleophiles to α-chrial aldehyde 7 could be based on models of either chelation-control transition state [¹²] or Felkin-Anh transition state, [¹³] which would lead to syn or anti addition. Some methodologies for alkyne addition of Garner’s aldehyde have been previously investigated, [¹4] and Herold [¹4a] and co-workers further investigated the effect of additives and found that the anti selectivity increased in the presence of HMPA, a cation-complexing agent. However, this type of alkyne-addition method requires an additional step, that is, reduction of the triple bond to an E-olefin. In the search for a complementary method for producing the anti diastereomer we turned to vinylzinc nucleophiles, generated conveniently from an alkyne such as 8 by a hydrozirconation-transmetalation sequence, [¹5] which have been reported to add to Garner’s aldehydes with high anti diastereoselectivity in the presence of ZnBr2. [¹6] Herein we further show the utility of this reaction.

As depicted in Scheme  [²] , treatment of 8 with zirconocene hydrochloride [¹5] in THF, followed by addition of Garner’s aldehyde 7 and ZnBr2 delivered the desired allylic alcohol 6 [¹7] in good yield (84%) with virtually complete diastereocontrol (anti/syn > 15:1). The ratio of anti/syn was determined by HPLC analysis. Similar results regarding the diastereoselectivity have been published by Murakami et al. [¹6] Dihydroxylation of allylic alcohol using osmium tetroxide with TMEDA [¹8] produced the syn,syn-triol 5 in an acceptable 73% yield with a small amount of syn,anti diastereomer (15%). The diastereoselectivity was good (syn/anti = 4.5:1˜5:1), and the unwanted syn,anti diastereomer could be separated by column chromatography at this point. When AD-mix-β was used, the product obtained was a 2:1 mixture of the diastereomeric triols, with the desired syn,syn diastereomer as the major product. With all the stereocenters in place, we set out to prepare for the cyclization. Exposure of triol 5 to EOMCl gave compound 9 in 93% yield. The ¹³C NMR spectra of compound 9 was complex due to the presence of the Boc protecting group, which resulted in a number of rotational isomers at 23 ˚C. Selective deprotection of TBS ethers by exposure of 9 to TsOH in MeOH, followed by removal of the N,O-acetonide with CuCl2 in MeCN provided diol 10 in 90% yield for the two steps.

Scheme 2 Synthesis of valienamine (1) from Garner’s aldehyde

In order to execute the planned aldol-type cyclization, the terminal dihydroxy group needed to be oxidized to the level of aldehyde. A protocol involving Dess-Martin periodinane oxidation was found to be superior to other conditions, and the desired dialdehyde 4, without further purification, was directly converted to the six-membered ring structure 3 through an intramolecular aldol condensation reaction under mild conditions [¹9] (cat. TsOH, piperidine, r.t., 2 h), followed by β-elimination of the formed hydroxyl group with MsCl and Et3N. Attempt at other intramolecular aldol condensation cyclization conditions [²0] failed to give our desired compound 3. Thus, the intramolecular aldol-type cyclization provided the valienamine skeleton. Controlled reduction of enal 3 with NaBH4 in methanol solution containing cerium chloride, followed by removal of the EOM ether and Boc in TFA-CH2Cl2 provided (+)-valienamine (1), which was characterized as its pentaacetate 11 [²¹] (68%). Comparison of the physical properties to those recorded confirms its identity. [9b] This synthesis, based on a diastereoselective anti-reductive coupling reaction of alkyne and chiral aldehyde followed by intramolecular aldol-type cyclization, requires ten steps from readily available Garner’s aldehyde 7 to give (+)-valienamine in 23.0% overall yield.

In conclusion, a synthesis of (+)-valienamine was achieved starting from Garner’s aldehyde and well-established, highly efficient reactions were employed in this synthesis. A unique feature of the synthetic route is that an acyclic precursor was constructed, which was then cyclized in an intramolecular aldol reaction to form the (+)-valienamine skeleton.

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

Acknowledgment

This work was supported by National Science & Technology Major Project ‘Key New Drug Creation and Manufacturing Program’, ­P. R. of China (2009ZX09102-026).

17

Procedure for the Synthesis of 6
To an ice-cooled stirred suspension of Cp2Zr(H)Cl (5.05 g, 19.6 mmol) in THF (50 mL) under argon protection was added tert-butyl(but-3-ynyloxy)dimethylsilane (3.61 g, 19.6 mmol), the mixture was stirred at r.t. for 1 h, and then cooled to 0 ˚C. To the resulting orange solution was added aldehyde 7 (2.25g, 9.8 mmol) in THF (35 mL) followed by ZnBr2 (552 mg, 2.45 mmol, dried under vacuum for 1 h before use), and the mixture was stirred for 24 h at r.t. The mixture was diluted with EtOAc (100 mL) and aq potassium sodium
(+)-tartrate (5.7 g, 19.6 mmol), and stirred for 10 min. The resulting suspension was filtered off and washed thoroughly with EtOAc (100 mL). The combined filtrate was transferred into a separatory funnel and successively washed with H2O and brine. The aqueous phase was extracted with EtOAc (2 × 200 mL), and the combined organic layers were dried over anhyd Na2SO4. The mixture was concentrated and purified by silica gel chromatography to afford 6 (3.625 g, 84%) as a colorless oil: [α] D ²0 -27.0 (c 1.2, CHCl3). ¹H NMR (300 MHz, CDCl3): δ = 5.72 (m, 1 H), 5.49 (dd, J = 15.0, 6.0 Hz, 1 H), 4.02 (m, 4 H), 3.61 (t, J = 6.0, 2 H), 2.26 (m, 2 H), 1.48 (s, 15 H), 0.86 (s, 9 H), 0.01 (s, 6 H). ¹³C NMR (100 MHz, CDCl3): δ = 153.8, 130.6, 128.7, 94.1, 80.7, 73.6, 64.7, 62.7, 61.9, 35.9, 28.2, 28.2, 28.2, 26.3, 25.8, 25.8, 25.8, 24.5, 18.1, -5.4, -5.4. IR (film): 3454, 2931, 2858, 1699, 1473, 1387, 1255, 1174, 1097, 837, 775 cm-¹. MS (EI): m/z (%) = 415 (0.04)[M+], 100 (64.29), 57 (100.00). HRMS (EI): m/z calcd for C21H41NSiO5 [M+]: 415.2754; found: 415.2765.

21

Procedure for the Synthesis of 11
To a suspension of 3 (40 mg, 0.09 mmol) and CeCl3˙7H2O (52 mg, 0.135 mmol) in MeOH (3 mL) was added NaBH4 (4 mg, 0.1 mmol) at 0 ˚C. The mixture was stirred for 15 min, and the solvent was removed under reduced pressure. Then, H2O (3 mL) was added to the residue, which was then extracted with EtOAc (3 × 6 mL). The organic layer was washed with H2O (3 mL) and brine (3 mL), dried (Na2SO4), filtered, and and the solvent was removed under reduced pressure to give the colorless oil, which was directly dissolved in CH2Cl2 (4 mL), and TFA (2 mL) was added. The mixture was stirred for 4 h at 0 ˚C. Then, the solvent was removed in vacuum to give the crude product 1, which was dissolved in pyridine (2 mL) and Ac2O (1 mL) containing a catalytic amount of DMAP. The mixture was stirred at r.t. for 24 h. The reaction mixture was diluted with EtOAc (10 mL) and washed with sat. NaHCO3 (10 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, and filtered. Concentration of the filtrate followed by chromatography gave pentaacetate 11 (23 mg, 68% over 3 steps) as a white solid; mp 91-93 ˚C; [α]D ²0 +20.0 (c 0.075, CHCl3). ¹H NMR (400 MHz, CDCl3): δ = 2.02 (s, 6 H), 2.06 (s, 3 H), 2.07 (s, 6 H), 4.39 and 4.64 (ABq, J = 13.2 Hz, 2 H), 5.02-5.11 (m, 2 H), 5.36 (br d, J = 6.8 Hz, 1 H), 5.45 (dd, J = 10.0, 6.4 Hz, 1 H), 5.70 (br d, J = 8.4 Hz, 1 H), 5.89 (dd, J = 5.2, 1.2 Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 20.7, 20.8, 20.8, 20.8, 23.3, 44.9, 62.9, 68.5, 69.0, 71.2, 126.1, 134.3, 169.9, 170.0, 170.2, 170.3, 170.4. IR (film): 3363, 3269, 2924, 2850, 1743, 1649, 1556, 1469, 1371, 1223, 1024 cm-¹. MS (EI): m/z (%) = 385 (0.67) [M+], 326 (100.00), 223 (57.20), 164 (68.60). HRMS (EI): m/z calcd for C17H23NO9 [M+]: 385.1373; found: 385.1370.

17

Procedure for the Synthesis of 6
To an ice-cooled stirred suspension of Cp2Zr(H)Cl (5.05 g, 19.6 mmol) in THF (50 mL) under argon protection was added tert-butyl(but-3-ynyloxy)dimethylsilane (3.61 g, 19.6 mmol), the mixture was stirred at r.t. for 1 h, and then cooled to 0 ˚C. To the resulting orange solution was added aldehyde 7 (2.25g, 9.8 mmol) in THF (35 mL) followed by ZnBr2 (552 mg, 2.45 mmol, dried under vacuum for 1 h before use), and the mixture was stirred for 24 h at r.t. The mixture was diluted with EtOAc (100 mL) and aq potassium sodium
(+)-tartrate (5.7 g, 19.6 mmol), and stirred for 10 min. The resulting suspension was filtered off and washed thoroughly with EtOAc (100 mL). The combined filtrate was transferred into a separatory funnel and successively washed with H2O and brine. The aqueous phase was extracted with EtOAc (2 × 200 mL), and the combined organic layers were dried over anhyd Na2SO4. The mixture was concentrated and purified by silica gel chromatography to afford 6 (3.625 g, 84%) as a colorless oil: [α] D ²0 -27.0 (c 1.2, CHCl3). ¹H NMR (300 MHz, CDCl3): δ = 5.72 (m, 1 H), 5.49 (dd, J = 15.0, 6.0 Hz, 1 H), 4.02 (m, 4 H), 3.61 (t, J = 6.0, 2 H), 2.26 (m, 2 H), 1.48 (s, 15 H), 0.86 (s, 9 H), 0.01 (s, 6 H). ¹³C NMR (100 MHz, CDCl3): δ = 153.8, 130.6, 128.7, 94.1, 80.7, 73.6, 64.7, 62.7, 61.9, 35.9, 28.2, 28.2, 28.2, 26.3, 25.8, 25.8, 25.8, 24.5, 18.1, -5.4, -5.4. IR (film): 3454, 2931, 2858, 1699, 1473, 1387, 1255, 1174, 1097, 837, 775 cm-¹. MS (EI): m/z (%) = 415 (0.04)[M+], 100 (64.29), 57 (100.00). HRMS (EI): m/z calcd for C21H41NSiO5 [M+]: 415.2754; found: 415.2765.

21

Procedure for the Synthesis of 11
To a suspension of 3 (40 mg, 0.09 mmol) and CeCl3˙7H2O (52 mg, 0.135 mmol) in MeOH (3 mL) was added NaBH4 (4 mg, 0.1 mmol) at 0 ˚C. The mixture was stirred for 15 min, and the solvent was removed under reduced pressure. Then, H2O (3 mL) was added to the residue, which was then extracted with EtOAc (3 × 6 mL). The organic layer was washed with H2O (3 mL) and brine (3 mL), dried (Na2SO4), filtered, and and the solvent was removed under reduced pressure to give the colorless oil, which was directly dissolved in CH2Cl2 (4 mL), and TFA (2 mL) was added. The mixture was stirred for 4 h at 0 ˚C. Then, the solvent was removed in vacuum to give the crude product 1, which was dissolved in pyridine (2 mL) and Ac2O (1 mL) containing a catalytic amount of DMAP. The mixture was stirred at r.t. for 24 h. The reaction mixture was diluted with EtOAc (10 mL) and washed with sat. NaHCO3 (10 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, and filtered. Concentration of the filtrate followed by chromatography gave pentaacetate 11 (23 mg, 68% over 3 steps) as a white solid; mp 91-93 ˚C; [α]D ²0 +20.0 (c 0.075, CHCl3). ¹H NMR (400 MHz, CDCl3): δ = 2.02 (s, 6 H), 2.06 (s, 3 H), 2.07 (s, 6 H), 4.39 and 4.64 (ABq, J = 13.2 Hz, 2 H), 5.02-5.11 (m, 2 H), 5.36 (br d, J = 6.8 Hz, 1 H), 5.45 (dd, J = 10.0, 6.4 Hz, 1 H), 5.70 (br d, J = 8.4 Hz, 1 H), 5.89 (dd, J = 5.2, 1.2 Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 20.7, 20.8, 20.8, 20.8, 23.3, 44.9, 62.9, 68.5, 69.0, 71.2, 126.1, 134.3, 169.9, 170.0, 170.2, 170.3, 170.4. IR (film): 3363, 3269, 2924, 2850, 1743, 1649, 1556, 1469, 1371, 1223, 1024 cm-¹. MS (EI): m/z (%) = 385 (0.67) [M+], 326 (100.00), 223 (57.20), 164 (68.60). HRMS (EI): m/z calcd for C17H23NO9 [M+]: 385.1373; found: 385.1370.

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Figure 1

Scheme 1 Retrosynthetic analysis of 1

Scheme 2 Synthesis of valienamine (1) from Garner’s aldehyde