syn-dihydroxylation in the synthesis of bicyclic iminosugars

Tetrahedron: Asymmetry 26 (2015) 29–34

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Ruthenium-catalyzed one-pot ring-closing metathesis/syndihydroxylation in the synthesis of bicyclic iminosugars Michał Malik a,⇑, Magdalena Ceborska b, Grzegorz Witkowski a, Sławomir Jarosz a,⇑ a b

Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland

a r t i c l e

i n f o

Article history: Received 14 October 2014 Accepted 19 November 2014

a b s t r a c t Novel polyhydroxylated derivatives of quinolizidine and decahydropyrido[1,2-a]azepine were prepared starting from a common oxazolidinone. The bicyclic cores were prepared by a ruthenium-catalyzed ring-closing metathesis, followed by re-use of the catalyst in the subsequent syn-dihydroxylation in a one-pot procedure. Ó 2014 Elsevier Ltd. All rights reserved.

1. Introduction The syn-dihydroxylation is usually performed using an osmium-based reagent.1 However, their reliability goes hand in hand with serious drawbacks such as high price and high toxicity. Over the last decade, several protocols have been developed, in which good results were also obtained with osmium-free species,2 most notably the in situ synthesized RuO4. Although its most commonly used precursor RuCl3 is relatively inexpensive, stable and non-toxic, ruthenium tetroxide itself is very reactive and lacks selectivity. Therefore, in order to reduce the formation of side products, great care must be taken to choose the proper reaction conditions.3 For instance, Plietker et al. proved that the addition of a Lewis or Brønsted acid is beneficial and renders the transformation much more predictable.4 Since the olefin metathesis most commonly uses Ru catalysts, one-pot procedures were developed, in which the formation of a new double bond via a metathesis reaction is followed by the oxidation of the catalyst to RuO4, which in turn oxidizes the resulting olefin into a syn-diol.5 In this convenient approach, the expensive transition metal (ruthenium) is reused. However, despite this obvious advantage, the transformation remains rarely used in total syntheses. In one of our preceding papers, we have shown its application in the synthesis of iminosugars (Scheme 1).6 These compounds belong to a vast group of carbohydrate analogues that bear a nitrogen atom in the ring(s).7 In general, iminosugars are known for interesting biological properties, for example, for their inhibitory activity against certain glycosidases.8 A variety of the ⇑ Corresponding authors. Fax: +48 22 632 66 81. E-mail addresses: [email protected] (M. Malik), slawomir.jarosz@icho. edu.pl (S. Jarosz). http://dx.doi.org/10.1016/j.tetasy.2014.11.013 0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

synthetic routes to this class of compounds have been elaborated on over the last years.9 However, taking into account their promising biological activity, the development of new synthetic approaches leading to iminosugars is still needed. Herein, we report the application of the Ru-catalyzed one-pot ring-closing metathesis/syn-dihydroxylation to the synthesis of novel imino sugars. The ‘classical’, osmium-based approach to the problem is also shown for the sake of comparison. 2. Results and discussion Our synthetic route started from D-xylose derived oxazolidinone 1 (Scheme 2), a versatile intermediate which has already been used in the total synthesis of ()-castanospermine.10 After methanolysis, which afforded aminoalcohol 2, the N-acryloyl derivative 3a was obtained, along with considerable amounts (26%) of diacryloyl derivative 3b as a by-product. Subsequent ring-closing meta thesis (Scheme 3) of 3a with Grubbs-II cat. (5 mol %) furnished bicyclic product 4 in excellent yield. In the following step, the osmium-mediated (5 mol % OsO4) syn-dihydroxylation yielded 5 as the sole diastereoisomer. 2D-NOESY experiment indicated that the newly formed hydroxyl groups were in an anti-relationship to the already existing one (no interactions between: H-9a and H-2, H-9a and H-3, H-1 and H-3). This observation is in accordance with Kishi’s empirical rule.11 We envisaged that 3a could also be obtained directly from 1 by reaction with a vinyl anion equivalent. Although oxazolidinones are commonly employed as chiral auxiliaries12 or act as masked amino alcohols in total syntheses,13 reports on their reactivity with carbon nucleophiles, such as Grignard reagents or alkyllithiums, are very limited.14 Nonetheless, we attempted to open the oxazolidinone ring in 1 with vinyl magnesium bromide. Various conditions were

30

M. Malik et al. / Tetrahedron: Asymmetry 26 (2015) 29–34 Grubbs II, TFA toluene/DCM 70 °C, 4 h evaporation N

BnO

OH

OH

N

then NaIO 4, CeCl3 .7H 2O AcOEt/MeCN/H 2O 0°C, 1 h

OBn

OH OH

BnO

OBn

OBn

N

+

H

H BnO

OBn

OBn 13%

Ref. 6 Grubbs II, toluene 50 °C, 4 h evaporation

O

OH

then NaIO 4, CeCl3 7H 2O AcOEt/MeCN/H 2O 0°C, 1 h

BnO

56%

OH

O

.

N

OBn

OBn

OH N

OBn

OH N

+

H BnO

OBn

O

H BnO

OBn

OBn OBn

31%

43%

Scheme 1. Previous application of a one-pot RCM/syn-dihydroxylation to the synthesis of iminosugars.

tested (numerous solvents and broad temperature range), but the desired compound was not formed. It turned out, however, that the reaction with allylmagnesium bromide proceeded smoothly, and afforded compound 6 in very good yield (Scheme 4).

O O N

7 steps D-xylose

H Ref. 6, 10

BnO

OBn OBn

3a

1

vinyl-MgBr O

HO

KOH, MeOH 75 °C, 12 h, 85%

O

H N H

Ref. 10

BnO

O

N H BnO

OBn

allyl-MgBr, THF

N

-78 °C, 40 min, 84%

OBn 2

BnO

OBn

OBn OBn

1 O

OH H

OBn

6

O O

acryloyl chloride DCM

N

N OH

Et3 N, 0 °C, 15 min

BnO

O

O

H

+

OBn

H BnO OBn

3a (57%)

3b (26%)

H OH

50 °C, 6h, 83%

OBn

OBn

N

Grubbs-II, toluene BnO

OBn OBn 7

Scheme 2. Synthesis of N-acryloyl derivative 3a.

7

7'

H

H

OH

8

O OsO4 , NMO O

O N OH

THF/t-BuOH/H 2O rt, 24 h, 76% N

Grubbs-II, toluene

H BnO

OBn

H 50 °C, 0.5 h 97%

BnO

OH

OBn

3a

OsO 4, NMO THF/t-BuOH/H 2O 0 °C, 6 h, 89%

N

9a

BnO

OH

OBn OBn

BnO

OBn OBn

Scheme 4. ‘Classical’ osmium-based approach to syn-dihydroxylation of olefin 7.

1

H

H OH

4

OH

2

OH

10

8

OH 3

N 10a

OBn

OBn

O

9

5

Scheme 3. ‘Classical’ osmium-based approach to syn-dihydroxylation of olefin 4.

In the subsequent steps, ring-closing metathesis with Grubbs-II catalyst (5 mol %) was performed on 6, followed by osmium-mediated (5 mol % OsO4) syn-dihydroxylation, which finally provided triol 8 as a single diastereoisomer. In order to elucidate the relative stereochemistry, we assigned the positions of the H-7 and H-70 protons in this product (strong interaction between the H-7 and H-10a in 2D-NOESY). Although in the 7-membered ring the J values were not as diagnostic as in the 6-membered, we can assume that two large (13.2 and 11.8 Hz) coupling constants observed for the

M. Malik et al. / Tetrahedron: Asymmetry 26 (2015) 29–34

H-7 signal indicate the anti-relationship between the H-7 and H-8. Again, Kishi’s rule was obeyed. We next turned our attention to the application of the one-pot RCM/syn-dihydroxylation with the re-use of the ruthenium catalyst to the synthesis of triols 6 and 8. Once the RCM was finished, the solvent was removed and the Plietker’s conditions (MeCN/ AcOEt/H2O, NaIO4, CeCl37H2O) were used.4b However, this methodology failed when applied to derivatives 3a and 6; complicated mixtures of products were formed in both cases. Therefore, we decided to mask the hydroxyl groups as acetates. First, compound 3a was acetylated (Scheme 5) and the resulting derivative 9 was subjected to metathesis (5 mol % of Grubbs-II), after which Plietker’s conditions were applied. After changing the solvent system to MeCN/AcOEt/H2O, the Ru catalyst was oxidized with NaIO4 and CeCl37H2O (20 mol %) to RuO4, which in turn effectively oxidized the newly created double bond (20 min at 0 °C) to provide diol 10 as a single diastereoisomer in good yield. Similar to 5, no NOE interactions were observed between the H-2 and H-9a, H-3 and H-9a, H-1 and H-3 signals.

Ac 2O, DMAP

N OH

DCM/py, rt, 24 h 90%

H BnO

OBn

N

OAc

3. Conclusion

H BnO

OBn

In conclusion we have shown that the Ru-catalyzed one-pot RCM/syn-dihydroxylation can be successfully applied to the synthesis of densely substituted polyhydroxylated bicyclic compounds. The transformations presented proceed with very high diastereoselectivities. Until now, the standard approach consisted in the following two-step procedure: RCM followed by osmiummediated dihydroxylation and was used often in the synthesis of iminosugars.15 The approach proposed herein is both faster and more economic, whereas the overall yields are similar. The necessity of using highly toxic OsO4 is eliminated.

OBn

OBn 3a

9 OH

Grubbs-II, toluene 50 °C, 2 h; evaporation then NaIO 4, CeCl3 .7H 2O MeCN/AcOEt/H 2O 0 °C, 20 min, 75%

O

3

N

Grubbs-II catalyst (10 mol %) ensured its full conversion. Next, the solvent was changed to MeCN/AcOEt/H2O and NaIO4, along with CeCl37H2O (20 mol %), were added, resulting in the formation of diol 12 (1 h at 0 °C). 2D-NOESY experiments allowed us to assign the stereochemical relationship between the H-7 and H-70 protons in 12 (interaction between H-7 and H-10a). As in the case of 8 we can assume that the two large (13.3 and 11.7 Hz) coupling constants observed on the H-7 signal indicate the anti-relationship between H-7 and H-8. This assumption was fully confirmed by the X-ray analysis of diol 12 (Fig. 1).

Figure 1. X-ray structure of diol 12; hydrogen atoms removed for the sake of clarity.

O

O

31

OH

2

9a

1

OAc

H BnO

OBn OBn 10

Scheme 5. Application of the one-pot RCM/syn-dihydroxylation to the synthesis of diol 10.

4. Experimental 4.1. General

The preparation of a bicyclic derivative with a larger ring, alternative to the one reported already in Scheme 4, was initiated from compound 6. Again, the free hydroxyl group was acetylated to give 11 (Scheme 6), which was then subjected to the RCM reaction. This acetate reacted sluggishly and only a relatively high loading of

O

O Ac 2O, DMAP N

OH H

BnO

OBn OBn

N

DCM/py, rt, 24 h 92%

OAc H

BnO

OBn OBn

6

11

7'

H

7

H Grubbs-II, toluene 60 °C, 4 h; evaporation

8

N then NaIO 4, CeCl3 .7H2 O MeCN/AcOEt/H 2O 0 °C, 1 h, 66%

OH 9

O 10a

OH

10

H OAc BnO

NMR spectra were recorded with a Varian AM-600 (600 MHz H, 150 MHz 13C) or with a Varian AM-400 (400 MHz 1H, 100 MHz 13C) at room temperature. Chemical shifts (d) are reported in ppm relative to TMS (d 0.00) for 1H and residual chloroform (d 77.0) for 13C. All significant resonances (carbon skeleton) were assigned by COSY (1H-1H), HSQC (1H-13C), and HMBC (1H-13C) correlations. Relative stereochemistry was assigned based on 2DNOESY experiments. Mass spectra were recorded with a MALDISynapt G2-S HDMS, melting points were measured with an SRS OptiMelt and are uncorrected. Optical rotations were measured in CH2Cl2 or MeOH with a Jasco P 1020 apparatus using sodium light (c = 1, T = 23 °C); elemental analyses were performed with an Elementar vario ELIII. Reagents were purchased from Sigma– Aldrich, Alfa Aesar or ABCR, and used without further purification. Dry solvents were purchased from Sigma–Aldrich and used as obtained. Organic solutions were dried over anhydrous MgSO4 and concentrated under reduced pressure. Flash chromatography was performed on Grace Resolv or Grace Reveleris cartridges, using a Grace Reveleris X2 system (UV and ELSD detection). Analytical and preparative TLC was performed on Silica Gel 60 F254 (Merck). 1

OBn OBn 12

Scheme 6. Application of the one-pot RCM/syn-dihydroxylation to the synthesis of diol 12.

4.1.1. 1-{(2S,3S,4S,5R)-3,4,5-Tribenzyloxy-2-[(1R)-1-hydroxyprop2-en-1-yl]piperidin-1-yl}prop-2-en-1-one 3a This reaction was performed under an argon atmosphere. To a stirred solution of 2 (217 mg, 0.47 mmol) in dry DCM (3.7 mL),

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M. Malik et al. / Tetrahedron: Asymmetry 26 (2015) 29–34

dry triethylamine (0.1 mL) was added. The solution was cooled to 0 °C and a freshly prepared solution of acryloyl chloride (ca. 0.5 M, 1.0 mL, 1.05 equiv) was added dropwise. Once the addition was complete, toluene (2 mL) was added and the solution was concentrated. The residue was purified by chromatography (flash chromatography, linear gradient: 100% hexanes to 100% ethyl acetate) to yield 3a (137 mg, 57%) as a colorless oil and the diacryloyl derivative 3b (70 mg, 26%) as a colorless oil. 3a: HRMS: found: m/ z = 536.2416; calcd for C32H35NO5Na ([M+Na]+): 536.2413. Anal.: found: C, 74.82; H, 6.90; N, 2.64%; calcd C, 74.83; H, 6.87; N, 2.73%. [a]23 D = +16.1 (c 1, DCM); Rf = 0.3 (hexanes/ethyl acetate 2:3). 1H NMR and 13C NMR spectra indicate, that this compound exists as a mixture of rotamers. 3b: LRMS: m/z = 590.3 ([M+Na]+). Anal.: found: C, 74.04; H, 6.57; N, 2.48%; calcd C, 74.05; H, 6.57; N, 2.47%. [a]23 D = +2.3 (c 1, DCM); Rf = 0.8 (hexanes/ethyl acetate 2:3). 4.1.2. (1R,7R,8S,9S,9aS)-1-Hydroxy-7,8,9-tribenzyloxy-1,6,7,8,9,9ahexahydro-4H-quinolizin-4-one 4 This reaction was performed under an argon atmosphere. To a solution of 3a (49 mg, 0.096 mmol) in dry toluene (1 mL), Grubbs-II cat. (4 mg, 5 mol %) was added and the mixture was heated to 50 °C. After 30 min, the solvent was evaporated and the residue was purified by chromatography (preparative TLC, 1 mm, DCM/MeOH 15:1) to yield 4 (45 mg, 97%) as a pale brown solid. LRMS: m/z = 508.4 ([M+Na]+). Anal. : found: C, 74.04; H, 6.40; N, 2.70%; calcd C, 74.21; H, 6.43; N, 2.88%. [a]23 D = 111.7 (c 1, DCM); mp = 135–138 °C; Rf = 0.5 (DCM/methanol 20:1). 1H NMR (600 MHz, CDCl3) d: 7.32 (m, arom.), 6.74 (dd, 1H, J = 9.7, 5.7 Hz, H-2), 6.02 (d, 1H, J = 9.7 Hz, H-3), 4.94, 4.89, 4.78, 4.75, 4.70, 4.60 (6  d, 6H, J = 11.0–11.6 Hz, OCH2Ph), 4.36 (ddd, 1H, J = 9.4, 5.6, 3.8 Hz, H-1), 4.19 (dd, 1H, J = 13.6, 4.0 Hz, H-6), 4.03 (dd, 1H, J = 10.4, 8.4 Hz, H-9), 3.73 (dd, 1H, J = 8.4, 6.6 Hz, H-8), 3.63 (ddd, 1H, J = 8.6, 6.6, 4.1 Hz, H-7), 3.43 (dd, 1H, J = 10.4, 3.7 Hz, H-9a), 3.24 (dd, 1H, J = 13.6, 8.6 Hz, H-60 ), 2.21 ppm (d, 1H, J = 9.4 Hz, –OH). 13C NMR (150 MHz, CDCl3) d: 164.6 (C-4), 139.4 (C-2), 138.13, 138.10, 137.7 (3  quat. benzyl), 128.6–127.8 (arom.), 126.5 (C-3), 85.2 (C-8), 76.6 (C-9), 75.8 (C-7), 74.9, 74.2, 71.9 (3  OCH2Ph), 60.8 (C-1), 59.6 (C-9a), 42.1 ppm (C-6). 4.1.3. (1S,2R,3R,7R,8S,9S,9aR)-1,2,3-Trihydroxy-7,8,9-tribenzyloxyoctahydro-4H-quinolizin-4-one 5 To a stirred solution of 4 (35 mg, 0.072 mmol) in THF (0.7 mL), H2O (50 lL) and anhydrous NMO (17 mg) were added and the solution was cooled to 0 °C. Next, OsO4 (35 lL, 5 mol %, 0.1 M in t-BuOH) was added. The mixture was vigorously stirred at 0 °C for 6 h. Then, satd. aq. Na2SO3 (2 mL) and H2O (2 mL) were added and the mixture was stirred for 10 min. After extraction with ethyl acetate (3  20 mL), the combined organic layers were dried and the solvent was evaporated to give a white solid. Triol 5 was dissolved in hot ethyl acetate and precipitated with hexanes to give 33 mg (89%) of the pure product. HRMS: found: m/z = 542.2167; calcd for C30H33NO7Na ([M+Na]+): 542.2155. [a]23 D = 0.4 (c 1, MeOH); mp = 177–179 °C; Rf = 0.3 (DCM/methanol 20:1). 1H NMR (600 MHz, CD3OD/CDCl3, 2:1) d: 7.31 (m, arom.), 4.98 (d, 1H, J = 11.0 Hz, OCH2Ph), 4.94 (d, 1H, J = 10.7 Hz, OCH2Ph), 4.79 (m, 4H, H-6, OCH2Ph), 4.67 (d, 1H, J = 11.4 Hz, OCH2Ph), 4.48 (d, 1H, J = 2.9 Hz, H-3), 4.32 (m, 1H, H-1), 4.22 (dd, 1H, J = 4.7, 3.1 Hz, H-2), 3.91 (dd, 1H, J = 10.3, 9.3 Hz, H-9), 3.65 (t, 1H, J = 9.1 Hz, H-8), 3.55 (dd, 1H, J = 10.4, 3.5 Hz, H-9a), 3.49 (ddd, 1H, J = 10.9, 9.2, 5.0 Hz, H-7), 2.53 ppm (m, 1H, H-60 ). 13C NMR (150 MHz, CD3OD/CDCl3, 2:1) d: 172.2 (C-4), 138.1, 138.0, 137.4 (3  quat. benzyl), 127.8–127.0 (arom.), 85.9 (C-8), 76.4 (C-7), 76.1 (C-9), 75.0, 74.4, 72.1 (3  OCH2Ph), 70.4 (C-2), 67.0 (C-3), 64.6 (C-1), 59.2 (C-9a), 43.2 ppm (C-6).

4.1.4. 1-{(2S,3S,4S,5R)-3,4,5-Trihydroxy-2-[(1R)-1-hydroxyprop2-en-1-yl]piperidin-1-yl}but-3-en-1-one 6 This reaction was performed under an argon atmosphere. To a stirred and cooled to 78 °C solution of 1 (147 mg, 0.30 mmol) in dry THF (1.5 mL), allylmagnesium bromide (0.9 mL, 1 M in diethyl ether, 3 equiv) was added via a syringe pump (10 min). After an additional 30 min at 78 °C, sat. aq. NH4Cl (10 mL) was added, followed by water (10 mL) and ethyl acetate (30 mL). The layers were separated and the aqueous one was washed with ethyl acetate (2  15 mL). The combined organic solutions were dried, concentrated, and the residue was purified by chromatography (flash chromatography, linear gradient: 100% hexanes to 100% ethyl acetate) to yield 6 (135 mg, 84%) as a colorless oil. Anal.: found: C, 75.11; H, 7.21; N, 2.49%; calcd C, 75.12; H, 7.07; N, 2.65%. 1 [a]23 D = +0.9 (c 1, DCM); Rf = 0.4 (hexanes/ethyl acetate 1:1). H NMR and 13C NMR spectra indicate, that this compound exists as a mixture of rotamers. 4.1.5. (1S,2S,3R,10R,10aS)-1,2,3-Tribenzyloxy-10-hydroxy-1,3,4,7,10,10a-hexahydropyrido[1,2-a]azepin-6(2H)-one 7 This reaction was performed under an argon atmosphere. To a stirred solution of 6 (61 mg, 0.12 mmol) in dry toluene (1.2 mL), Grubbs-II catalyst (5 mg, 5 mol %) was added and the mixture was kept at 50 °C for 6 h, after which it was cooled to ambient temperature, concentrated, and the residue was purified by chromatography (preparative TLC, 1 mm, DCM/MeOH 15:1) to yield 7 (45 mg, 83%) as a pale brown solid (amorphous). HRMS: found: m/z = 522.2256; calcd for C31H33NO5Na ([M+Na]+): 522.2256. [a]23 D = 45.7 (c 1, DCM); Rf = 0.2 (hexanes/ethyl acetate 2:3). 1H NMR (600 MHz; CDCl3) d: 7.31 (m, arom.), 5.80 (ddd, 1H, J = 11.3, 4.7, 3.1 Hz, H-9), 5.74 (m, 1H, H-8), 4.99 (d, 1H, J = 11.0 Hz, OCH2Ph), 4.68 (m, 5H, H-4, OCH2Ph), 4.42 (d, 1H, J = 11.4 Hz, OCH2Ph), 4.29 (m, 1H, H-10), 4.10 (t, 1H, J = 9.3 Hz, H-1), 3.84 (m, 1H, H-3), 3.80 (dd, 1H, J = 9.3, 3.5 Hz, H-2), 3.76 (d, 1H, J = 9.0 Hz, H-10a), 3.36 (ddd, 1H, J = 16.3, 5.4, 2.6 Hz, H-7), 3.16 (dd, 1H, J = 14.5, 3.2 Hz, H-40 ), 2.93 (dd, 1H, J = 16.6, 8.9 Hz, H-70 ), 2.59 ppm (d, 1H, J = 9.0 Hz, –OH). 13C NMR (600 MHz; CDCl3) d: 172.3 (C-6), 137.97, 137.96, 137.6 (3  quat. benzyl), 131.0 (C-9), 128.5–127.7 (arom.), 123.7 (C-8), 84.9 (C-2), 79.8 (C-3), 75.2 (C-1), 75.0, 72.7, 70.5 (3  OCH2Ph), 66.1 (C-10), 60.0 (C-10a), 40.0 (C-4), 35.8 ppm (C-7). 4.1.6. (1S,2S,3R,10S,10aS)-1,2,3-Tribenzyloxy-8,9,10-trihydroxyoctahydropyrido[1,2-a]azepin-6(2H)-one 8 To a stirred solution of 7 (36 mg, 0.072 mmol) in THF (0.7 mL), H2O (50 lL), and anhydrous NMO (17 mg) were added. Subsequently, OsO4 (35 lL, 5 mol %, 0.1 M in t-BuOH) was added. The mixture was stirred vigorously at room temperature for 24 h. Next, Na2SO3 (2 mL, satd. aq.) and H2O (2 mL) were added and the mixture was stirred for 10 min. After extraction with ethyl acetate (2  20 mL), the combined organic layers were dried and concentrated to give a white solid, which was dissolved in hot ethyl acetate and precipitated with hexanes to give triol 8 (29 mg; 76%) as a pure compound (white solid). HRMS: found: m/z = 556.2303; calcd for C31H35NO7Na ([M+Na]+): 556.2311. [a]23 D = 18.1 (c 1, MeOH); mp = decomp. (>100 °C); Rf = 0.4 (DCM/MeOH 10:1). 1H NMR (600 MHz, CD3OD/CDCl3, 5:1) d: 7.30 (m, arom.), 4.97 (d, 1H, J = 11.1 Hz, OCH2Ph), 4.66 (m, 5H, OCH2Ph, H-4), 4.42 (d, 1H, J = 11.3 Hz, OCH2Ph), 4.01 (m, 1H, H-8), 4.00 (m, 1H, H-10), 3.98 (m, 1H, H-10a), 3.94 (m, 1H, H-9), 3.86 (t, 1H, J = 9.6 Hz, H-1), 3.83 (m, 1H, H-3), 3.71 (dd, 1H, J = 9.7 Hz, 3.5 Hz, H-2), 3.36 (dd, 1H, J = 13.2, 11.8 Hz, H-7), 3.07 (dd, 1H, J = 14.8, 3.3 Hz, H-40 ), 2.26 ppm (m, 1H, H-70 ). 13C NMR (150 MHz, CD3OD/CDCl3, 5:1) d: 171.9 (C-6), 137.5, 137.3, 137.0 (3  quat. benzyl), 127.5–126.7

M. Malik et al. / Tetrahedron: Asymmetry 26 (2015) 29–34

(arom.), 84.1 (C-2), 79.1 (C-3), 75.2 (C-1), 73.8 (OCH2Ph), 72.7 (C-9), 71.9, 69.4 (2  OCH2Ph), 69.2 (C-10), 64.3 (C-8), 54.7 (C-10a), 39.1 (C-4), 37.5 ppm (C-7). 4.1.7. (1R)-1-[(2R,3S,4S,5R)-1-acryloyl-3,4,5-tribenzyl oxypiperidin-2-yl]prop-2-en-1-yl acetate 9 To a stirred solution of 3a (62 mg, 0.12 mmol) in dichloromethane (1 mL), pyridine (0.1 mL) was added, followed by acetic anhydride (0.1 mL) and DMAP (1 mg, 5 mol %). The resulting mixture was stirred at room temperature for 24 h, concentrated, and the residue was purified by chromatography (flash chromatography, linear gradient: 100% hexanes to 100% ethyl acetate) to yield 9 (60 mg, 90%) as a colorless oil. HRMS: found: m/z = 578.2518; calcd for C34H37NO6Na ([M+Na]+): 578.2519. [a]23 D = 6.4 (c 1, DCM); Rf = 0.3 (hexanes/ethyl acetate 2:1). 1H NMR and 13C NMR spectra indicate, that this compound exists as a mixture of rotamers. 4.1.8. (1S,7R,8S,9S,9aR)-2,3-Dihydroxy-7,8,9-tribenzyloxy-4-oxooctahydro-2H-quinolizin-1-yl acetate 10 To a stirred solution of 9 (60 mg, 0.11 mmol) in dry toluene (1.1 mL), Grubbs-II catalyst (4.5 mg, 5 mol %) was added and the mixture was kept at 50 °C for 2 h. Next, it was cooled to room temperature, the solvent was evaporated, and the residue was dissolved in AcOEt (0.5 mL) and MeCN (0.5 mL). The resulting mixture was cooled to 0 °C. Simultaneously, in a separate vial, NaIO4 (75 mg, 3.1 equiv) and CeCl37H2O (8 mg, 20 mol %) were suspended in water (0.1 mL) and the mixture was heated at 50 °C until it turned yellow (1 min), after which MeCN (0.2 mL) was added; the yellow suspension was cooled to 0 °C and added in one portion to a solution of the RCM product. The mixture was stirred vigorously for 20 min at 0 °C. Next, pulverized MgSO4 (250 mg) and Na2SO3 (400 mg) were added and stirring was continued for 30 min. After this time, the mixture was filtered through a pad of Celite, which was then repeatedly washed with ethyl acetate. The solvent was evaporated and the residue was purified by chromatography (preparative TLC, 1 mm, DCM/MeOH 15:1) to yield 10 (46 mg, 75%) as an off-white solid. HRMS: found: m/z = 584.2263; calcd for C32H35NO8Na ([M+Na]+): 584.2260. Anal.: found: C, 68.12; H, 6.11; N, 2.43%; calcd C, 68.44; H, 6.28; N, 2.49%. [a]23 D = +1.0 (c 1, DCM); mp = 140–142 °C; Rf = 0.5 (DCM/methanol 20:1). 1H NMR (600 MHz, CDCl3) d: 7.30 (arom.), 5.61 (dd, 1H, J = 4.4, 3.7 Hz, H-1), 5.03 (d, 1H, J = 10.8 Hz, OCH2Ph), 4.95 (d, 1H, J = 10.2 Hz, OCH2Ph), 4.77 (m, 3H, OCH2Ph, H-6), 4.68 (d, 1H, J = 11.5 Hz, OCH2Ph), 4.39 (m, 1H, H-2), 4.34 (d, 1H, J = 10.2 Hz, OCH2Ph), 4.19 (d, 1H, J = 2.8 Hz, H-3), 3.77 (dd, 1H, J = 9.8, 3.5 Hz, H-9a), 3.73 (br s, 1H, –OH) 3.66 (m, 2H, H-8, H-9), 3.52 (ddd, 1H, J = 10.9, 8.8, 5.1 Hz, H-7), 2.83 (br s, 1H, –OH), 2.59 (dd, 1H, J = 12.8, 11.2 Hz, H-60 ), 2.08 ppm (s, 3H, CH3C(O)O–).13C NMR (150 MHz, CDCl3) d: 171.8 (C-4), 169.0 (CH3C(O)O–), 138.2, 137.7, 137.4 (3  quat. benzyl), 128.5–127.8 (arom.), 86.3 (C-8), 76.8 (C-7), 76.0 (C-9), 75.7, 75.2, 72.7 (3  OCH2Ph), 67.4 (C-3), 66.8 (C-1), 66.6 (C-2), 58.1 (C-9a), 44.0 (C-6), 20.9 ppm (CH3C(O)O–). 4.1.9. (1R)-1-[(2R,3S,4S,5R)-1-(But-3-enoyl)-3,4,5-triben zyloxypiperidin-2-yl]prop-2-en-1-yl acetate 11 To a stirred solution of 6 (95 mg, 0.18 mmol) in dichloromethane (1.5 mL), pyridine (0.2 mL) was added, followed by acetic anhydride (0.2 mL) and DMAP (1 mg, 5 mol %). The resulting mixture was stirred at room temperature for 24 h. Next, the solvent was evaporated and the residue was purified by chromatography (flash chromatography, linear gradient: 100% hexanes to 100% ethyl acetate) to yield 11 (94 mg, 92%) as a colorless oil. HRMS: found: m/z = 592.2674; calcd for C35H39NO6Na ([M+Na]+): 592.2675. [a]23 D = 6.3 (c 1, DCM); Rf = 0.4 (hexanes/ethyl acetate 2:1). 1H NMR and 13C NMR spectra indicate, that this compound exists as a mixture of rotamers.

33

4.1.10. (1S,2S,3R,10S,10aR)-1,2,3-Tribenzyloxy-8,9-dihydroxy-6oxodecahydropyrido[1,2-a]azepin-10-yl acetate 12 To a stirred solution of 11 (51 mg, 0.09 mmol) in dry toluene (2 mL), Grubbs-II catalyst (7 mg, 10 mol %) was added. The reaction was carried out at 60 °C for 4 h, after which the solvent was evaporated and the residue was dissolved in AcOEt (0.5 mL) and MeCN (0.5 mL). The resulting mixture was cooled to 0 °C. Simultaneously, in a separate vial, NaIO4 (60 mg, 3.1 equiv) and CeCl37H2O (7 mg, 20 mol %) were suspended in water (0.1 mL) and the mixture was heated gently at 50 °C until it turned yellow (1 min), after which MeCN (0.2 mL) was added; the yellow suspension was cooled to 0 °C and added in one portion to the solution of RCM product. The mixture was stirred vigorously for 1 h at 0 °C, after which pulverized MgSO4 (250 mg) and Na2SO3 (400 mg) were added and the stirring was continued for 30 min. After this time, the mixture was filtered through a pad of Celite, which was then repeatedly washed with ethyl acetate. The solvent was evaporated and the residue was purified by chromatography (prep. TLC, 1 mm, DCM/MeOH 15:1) to yield 12 (34 mg, 66%) as an off-white solid. HRMS: found: m/z = 598.2415; calcd for C33H37NO8Na ([M+Na]+): 598.2417. Anal.: found: C, 68.86; H, 6.36; N, 2.37%; calcd C, 68.85; H, 6.48; N, 2.43%. [a]23 D = 11.3 (c 1, DCM); Rf = 0.3 (DCM/methanol 20:1); mp = decomp. (>100 °C). 1H NMR (600 MHz, CDCl3) d: 7.30 (m, arom.), 5.30 (d, 1H, J = 4.5 Hz, H-10), 4.89 (d, 1H, J = 10.9 Hz, OCH2Ph), 4.71 (d, 1H, J = 11.7 Hz, OCH2Ph), 4.62 (m, 4H, OCH2Ph, H-4), 4.43 (d, 1H, J = 11.7 Hz, OCH2Ph), 4.15 (d, 1H, J = 9.0 Hz, H-10a), 4.02 (br s, 1H, H-9), 3.96 (d, 1H, J = 11.5 Hz, H-8), 3.75 (m, 2H, H-2, H-3), 3.54 (t, 1H, J = 8.8 Hz, H-1), 3.31 (dd, 1H, J = 13.3, 11.7 Hz, H-7), 2.98 (dd, 1H, J = 14.6, 3.1 Hz, H-40 ), 2.42 (d, 1H, J = 13.5 Hz, H-70 ), 1.98 ppm (s, 3H, CH3C(O)O–). 13C NMR (150 MHz, CDCl3) d: 171.3, 169.9 (C-6, CH3C(O)O–), 137.74, 137.71, 137.4 (3  quat. benzyl), 128.4–127.8 (arom.), 84.6 (C-2), 78.9 (C-3), 75.8 (C-1), 74.6, 72.8 (2  OCH2Ph), 71.0 (C-10), 70.5 (C-9), 70.3 (OCH2Ph), 65.6 (C-8), 53.8 (C-10a), 39.4 (C-4), 38.7(C-7), 20.8 ppm (CH3C(O)O–). X-ray analysis of 12: Colorless crystal of approximate dimensions 0.30  0.05  0.02 was used. Diffraction data were collected at 100 K using SuperNova Agilent diffractometer using CuKna radi0 ation (k = 1.54184 Å A). The data were processed with CrysAlisPro. Structure was solved by direct methods and refined using SHELXL-97. Non-hydrogen atoms were refined with anisotropic thermal displacement parameters. All hydrogen atoms were placed in geometric positions and treated as riding with C–H = 0.95 Å. Formula: C33H37NO8, monoclinic, space group P21, a = 12.7147(5) Å, b = 8.9634(3) Å, c = 13.4711(6) Å, V = 1447.9(1) Å3, b = 109.423(5), Z = 2, Final Goof = 1.04, R = 0.06 [I >2s(I)], wR = 0.15 [R = 0.07, wR = 0.16 for all data]. CCDC number 1020185. Acknowledgments Financial support from the Grant: POIG.01.01.02-14-102/09 (part-financed by the European Union within the European Regional Development Fund) is acknowledged. References 1. (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483; (b) Sundermeier, U.; Döbler, C.; Beller, M. Recent Developments in the Osmium-Catalyzed Dihydroxylation of Olefins. In Modern Oxidation Methods; Bäckvall, J.-E., Ed.; Wiley-VCH: Weinheim, 2005. 2. For a review, see: Bataille, C. J. R.; Donohoe, T. J. Chem. Soc. Rev. 2011, 40, 114. 3. (a) Shing, T. K.; Tam, E. K. W.; Tai, V. W.-F.; Chung, I. H. F.; Jiang, Q. Chem. Eur. J. 1996, 2, 50; (b) Shing, T. K.; Tam, E. K. W. Tetrahedron Lett. 1999, 40, 2179; For a review, see: (c) Piccialli, V. Molecules 2014, 19, 6534. 4. (a) Plietker, B.; Niggemann, M. Org. Lett. 2003, 5, 3353; (b) Plietker, B.; Niggemann, M. J. Org. Chem. 2005, 70, 2402; (c) Fürstner, A.; Wuchrer, M. Chem. Eur. J. 2006, 12, 76. 5. (a) Scholte, A. A.; An, M. H.; Snapper, M. L. Org. Lett. 2006, 8, 4759; (b) Beligny, S.; Eibauer, S.; Maechling, S.; Blechert, S. Angew. Chem., Int. Ed. 2006, 45, 1900; (c) Neisius, N. M.; Plietker, B. J. Org. Chem. 2008, 73, 3218.

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