Synthesis of novel macrocyclic derivatives with a sucrose scaffold by the RCM approach

Accepted Manuscript Synthesis of novel macrocyclic derivatives with a sucrose scaffold by the RCM approach Katarzyna Łęczycka, Sławomir Jarosz PII:

S0040-4020(15)30146-0

DOI:

10.1016/j.tet.2015.10.046

Reference:

TET 27218

To appear in:

Tetrahedron

Received Date: 5 July 2015 Revised Date:

2 October 2015

Accepted Date: 16 October 2015

Please cite this article as: Łęczycka K, Jarosz S, Synthesis of novel macrocyclic derivatives with a sucrose scaffold by the RCM approach, Tetrahedron (2015), doi: 10.1016/j.tet.2015.10.046. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Synthesis of novel macrocyclic derivatives with a sucrose scaffold by the RCM approach

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Katarzyna Łęczycka and Sławomir Jarosz* Institute of Organic Chemistry, Polish Academy of Sciences Kasprzaka 44/52, 01-224 Warsaw, Poland [email protected]

Abstract

1’2,3,3’4,4’-Hexa-O-benzylsucrose was esterified at both terminal positions with an

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unsaturated acid derived from D-glucose. Cyclization of the resulting di-olefin under the RCM conditions afforded the corresponding 21-membered macrocyclic unsaturated di-ester. The

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same sequence of reactions performed for 6,6’-diamino-6,6’-dideoxy-1’2,3,3’4,4’-hexa-Obenzylsucrose gave a 21-membered macrocyclic unsaturated di-amide. The cyclization in both cases was highly selective and provided a cyclic olefin with the E-geometry exclusively. Dihydroxylation of the olefin provided only one diol with relative configuration is consistent

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with the Kishi’s rule. The absolute configuration was determined by CD spectroscopy. Keywords: sucrose, ring-closing metathesis, macrocycles, dihydroxylation Introduction

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Metal-catalyzed olefin metathesis is one of the most powerful tools for the creation of the carbon-carbon bond in modern synthetic chemistry.1 This methodology allows the

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preparation, often in large scale, of a variety of complex fine chemicals including natural products. It has also found an application in materials chemistry and chemical biology.1b Most of the catalysts applied in such transformations are commercially available and can be used without special precautions. The synthesis of macrocyclic compounds with a sucrose scaffold is one of the main research areas in our laboratory.2 Our strategy is based on the connection of the terminal positions of appropriately protected sucrose via a -X-CH2CH2-Y- unit (X and Y = O, NR). Representative 1

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examples of such compounds, some of which possess interesting complexing properties, are shown in Figure 1. We have also started to explore more complex sucrose macrocycles which contain the amide type units (Fig. 1),3 as it is known that macrocyclic di-lactams can

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selectively complex chiral anions.4

Figure 1. Examples of sucrose-based crown- and aza-crown ether analogs and di-lactams.

In this paper we present the synthesis of a new type of sucrose macrocycle, in which the terminal positions: C6 and C6’ are connected via a highly functionalized long carbon bridge

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(1 in Fig. 2).

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Figure 2. New type of sucrose macrocycles.

Results and Discussion

The synthesis of our target, schematically depicted as 1, can be initiated either from known 1',2,3,3',4,4'-hexa-O-benzylsucrose5 (2a) or 6,6’-dideoxy-6,6’-diamino-1',2,3,3',4,4'-hexa-Obenzylsucrose (2b). It can be realized via two routes: 1) direct reaction of compounds 2 with long-chain alditols (or their derivatives; route a, Scheme 1) or 2) a stepwise sequence 2

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involving conversion of 2 into di-olefin 3 by reaction with relatively short unsaturated

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fragments, followed by cyclization under the RCM conditions (route b, Scheme 1).

Scheme 1. Synthetic plan towards a new type of sucrose macrocycles.

Although we have access to the selectively protected C12-alditol (e.g. 46) with the terminal positions unprotected, this route is not convenient, since only the C2-symmetrical alditols can

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react in a selective manner. We have decided, therefore, to carry out the synthesis following route b which should be more convenient and simpler, and may allow the preparation of different derivatives just by simple changing the olefins attached to the glucose and/or

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fructose ‘end’ of the sucrose starting material.

Planning the synthesis, we required a good method for the efficient preparation of both

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starting materials: diol 2a and di-amine 2b. Diol 2a has been usually prepared in our laboratory by deprotection of di-tritylated derivative 5 (route a in Scheme 2); however, this procedure is challenging, since the glycosidic bond in sucrose is very labile in acidic media and the yield of the diol is only moderate.5

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Scheme 2. Synthesis of hexa-O-benzylsucrose and hexa-O-benzyl-6,6'-diaminosucrose.

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An alternative route to 2a can be realized from known7 di-chlorosucrose 5 (route b); it is, however, rather capricious, since benzylation of 5, realized in strongly basic media, is often accompanied by elimination of HCl and – moreover – regeneration of the hydroxyl functions at the C6 and C6’ positions may be also demanding.8

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We now report an alternative preparation of 2a, by selective removal of the trityl protecting groups in 7 using a heterogeneous, silica-supported sodium hydrogen sulfate (NaHSO4/SiO2) catalyst.9 The yield of 2a was higher (60% vs 52%) than in our original procedure (acetic acid

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in toluene, 2 h, reflux)5 and the process is much easier to control (see Experimental). Diamine 2b was prepared by reduction of known10 azide 6 with LiAlH4 (see Scheme 2 and

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Experimental).

We first decided to prepare the “symmetrical” derivative of type 3, i.e. to place the same unsaturated unit at the C6 (glucose) and C6’ (fructose) terminal positions of our sucrose building block.

The required olefinic unit was prepared by a reductive dehalogenation (commonly known as the Vasella reaction11) of iodosugar 8 which was prepared by the standard methodology from methyl α-D-glucopyranoside (Scheme 3).12 4

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Scheme 3. Preparation of the olefinic unit 8.

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The esterification of unsaturated acid 9 with diol 2a, under the conditions introduced by Steglich,13 afforded di-ester 3a in 83% yield. The analogous reaction of 9 with di-amine 2b

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gave di-amide 3b also in good yield 75% (see Scheme 4).

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Scheme 4. Preparation of unsaturated sucrose di-ester 3a and di-amide 3b and their cyclization under RCM conditions. Ring-closing metathesis macrocyclisation can be very demanding,14 especially for highly oxygenated long-chain di-olefins.6 The control of stereochemistry of the resulting olefin is

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also problematic. A variety of factors can determine the stereochemical outcome and general strategies leading to either Z- or E-configured products remain a significant challenge.15 Our

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primary efforts were focused, therefore, on the construction of the desired macrocyclic skeleton rather than the geometry of the newly created double bond. We initiated our studies by investigating the cyclization of di-ester 3a. The Grubbs’ catalysts (either I or II generation) were ineffective. We therefore tested other commercially available catalysts (A-G; see Fig. 3) in the RCM reaction leading to 10a.

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Figure 3. Catalysts used in the RCM reaction.

The results of the optimization of this cyclization process are summarized in Table 1. On the

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basis of our results, the Hoveyda-Grubbs' II catalyst (G) was chosen as the best one. It is characterized by low sensitivity to air and moisture, as well as the tolerance to a variety of common organic functional groups.16

Table 1 Optimization of the RCM reaction (c= 6 x 10-3 mol L-1) of 3a and 3b. catalyst

solvent

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

A A B B C D E F G G G G G G G G

CH2Cl2 toluene toluene toluene toluene toluene toluene toluene toluene toluene perfluorobenzene perfluorotoluene toluene toluene perfluorobenzene perfluorotoluene

time (h)

temp.

MW

24 24 15 10 10 10 10 10 48 48 46 49 8 8 8 8

rt. 40 °C 50 °C 80 °C 60 °C 70 °C 70 °C 70 °C 60 °C 100 °C 70 °C 95 °C 60 °C 70 °C 70 °C 70°C

+ + + +

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entry

Isolated yield (%) diester (10a) diamide (10b) 36 15 50 45 43 40 60 50 74 69 83 79 83 76 84 80

In the RCM reaction of 3a with the Hoveyda-Grubbs’ II catalyst (toluene, 60 °C, 48 h; entry 9 Table 1) the corresponding cyclization product was not observed; the starting material remained unchanged. At higher temperature (100 °C; entry 10 in Table 1) 50% of the olefin 6

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was formed. Cyclization performed in perfluorotoluene was more effective than in toluene and provided 10a in 60% yield at 95 °C (entry 12 in Table 1). As discussed by Grela in his recent paper “The use of fluorinated aromatic hydrocarbons (FAH) as solvents for olefin

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metathesis reactions catalysed by standard commercially available ruthenium precatalysts allows substantially higher yields of the desired products especially in the case of demanding polyfunctional molecules”.17

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The yields were even higher under microwave irradiation and reached 84% at 70 °C (entry 16 in Table 1). Moreover, because the reaction time under MW irradiation was significantly

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shorter (8 h vs 48 h without MW), we required less catalyst (15 mol %), since significant decomposition of the catalyst is observed only upon prolonged reaction times at high temperatures. Cyclization of 3a or 3b under MW conditions should be performed below 90 °C, since significant decomposition of the starting material was noted above this temperature. Reaction of diol 3a gave olefin 10a as the single E-isomer; the configuration was proven by

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the 1H NMR spectra in which a large coupling constant between the olefinic protons was observed (J = 15.6; see Scheme 4). The same optimization of the reaction conditions was applied to the cyclization of di-amide 3b (see Table 1) and we were able to obtain di-amide

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10b in 80% yield, again as a single E-isomer (J = 16.0 Hz; Scheme 4).

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To accomplish the synthesis of our target, the macrocyclic derivatives 10a and 10b were subjected to syn-dihydroxylation according to the standard procedure [OsO4 (cat.), NMO, THF-tert.-BuOH-H2O].18 Reaction of the olefin 10a under these conditions did not provide the expected diol(s); only a product of hydrolysis i.e. sucrose diol 2a, was isolated from the post-reaction mixture. This may result from the high sensitivity of the ester linkage to base, even as mild as N-methylmorpholine, which is liberated during the oxidation process.

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Dihydroxylation of the double bond in di-amide 10b was more successful; we isolated only one diol to which structure 11 was assigned. This assignment can be predicted by Kishi’s rule, according to which the attack of osmium tetraoxide takes place from the side opposite the

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hydroxyl (alkoxyl) function(s) in the close vicinity of the double bond.19 In the case of 10b, both methoxyl groups flanking the double bond act in the same direction; the highly selective

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formation of diol 11 can, therefore, be expected (Scheme 5).

Scheme 5. Complelety diastereoselective syn-dihydroxylation of the double bond in 10b.

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Final proof of the structure of this diol was provided by circular dichroism spectroscopy (CD). It is well established that CD spectroscopy using the in situ dimolybdenum methodology, provides hard proof of the absolute configuration of the optically pure vic-diols with the

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relative threo-configuration.20 Recently, based on this method, we were able to propose

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structure 13 to the oxidation product of olefin 12 (Figure 4).21

Figure 4. Assignment of the absolute configuration of diol 13.

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A positive Cotton effect was observed in the CD spectrum of the complex of diol 11 with Mo2(OAc)4 (Figure 5) which is the same, as observed for diol 13; thus the arrangement of

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both hydroxyl groups in 11 is the same as in 13 (see Figure 6).

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Figure 5. CD spectrum of in situ-formed chiral complex of 11 with dimolybdenum tetraacetate recorded in DMSO.

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OH

HO

HO

OH

HO

13

11

OH

OH

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Figure 6. The arrangement of the diol grouping in 1321 and diol 11.

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CONCLUSION

The synthesis of macrocyclic derivatives with a sucrose scaffold having the terminal positions connected with a long polyhydroxylated carbon bridge is presented. The strategy of the preparation of such derivatives was realized by placing the relatively short unsaturated unit via an ester or amide linkage at both sucrose ‘ends’ (C6 and C6’) and cyclization of such precursors by the RCM approach. This process gave the single E-isomers; conducting the 9

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cyclization under the microwave irradiation the cyclic olefins in high yields. The resulting olefin derived from a di-amide was highly selectively syn-dihydroxylated providing the diol, configuration of which was consistent with Kishi’s rule. Its absolute configuration was

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assigned by CD spectroscopy. The methodology presented in this paper may open a convenient route to a new class of sucrose macrocycles in which the terminal positions (C6 and C6’) are connected with a long

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polyhydroxylated carbon bridge.

General methods

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Experimental

All reported NMR spectra were recorded with a Varian AM-600 (600 MHz 1H, 150 MHz 13C) or with a Varian AM-400 (400 MHz 1H, 100 MHz

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C) for solutions in CDCl3 at room

temperature. Chemical shifts (δ) are reported in ppm relative to TMS (δ 0.00) for 1H and 13

C. All significant resonances (carbon skeleton) were

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residual chloroform (δ 77.0) for

assigned by COSY (1H-1H), HSQC (1H-13C) and HMBC (1H-13C) correlations. IR spectra (CH2Cl2 film or KBr disc) were recorded with a JASCO FT/IR 6200. Mass spectra were

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recorded with a ESI/MS Mariner (PetSeptive Biosystem) mass spectrometer. Optical rotations were measured with a Jasco P 2000 apparatus in CHCl3 using sodium light (c = 0.3) at room

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temperature. Elemental analyses were obtained with a Perkin–Elmer 2400 CHN analyzer. The ECD spectra were acquired at room temperature in DMSO (for UV-spectroscopy, Fluka) on a Jasco J-715 spectropolarimeter. Microwave synthesizer: Discover SP. 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. The solvents were degassed by bubbling with argon for 10 min. Organic solutions were dried over anhydrous MgSO4 and concentrated under reduced pressure. Flash chromatography was performed on 10

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Grace Resolv or Grace Reveleris cartridges, using a Grace Reveleris X2 system (UV and ELSD detection). Analytical and preparative TLC were performed on Silica Gel 60 F254

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(Merck).

Preparation of 2(R),3(S),4(R)-2,3,4-trimethoxy-5-ene-hexanoic acid (9). To a solution of iodosugar 712 (500 mg, 1.44 mmol) in a THF-water mixture (9:1 v/v; 15 mL) activated zinc

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dust* (10 equiv.) was added, and the reaction mixture was stirred under reflux until all of the starting material disappeared (~1 h, TLC monitoring in: hexane-EtOAc, 2:1). The mixture

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was filtered through a Celite pad to remove solid inorganic material and the filtrate was concentrated under reduced pressure. The residue was dissolved in acetone (15 mL) to which Jones’ reagent (1.5 mL of a 1.25 M solution) was added, the mixture was stirred at rt. for 2 h, filtered, concentrated, and partitioned between EtOAc (20 mL) and brine (10 mL). The organic layer was separated, washed with water (10 mL), dried, and the crude acid 9 (250 mg,

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85% yield, colorless oil) was used in the next step without further purification. 1H NMR (400 MHz) δ 5.77 (ddd, J = 16.4, 11.2, 8.0 Hz, 1H), 5.39 – 5.31 (m, 2H), 3.92 (d, J = 3.3 Hz, 1H), 3.88 (dd, J = 7.5, 6.9 Hz, 1H), 3.59 (dd, J = 6.4, 3.3 Hz, 1H) 3.53 (s, 3H), 3.45 (s, 3H), 3.32 13

C NMR (100 MHz) δ 174.83, 134.78, 119.98, 83.91, 83.66, 80.28, 61.19, 59.44,

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(s, 3H);

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57.04. ESI-MS: m/z Calcd for C9H16O5 [M+Na]+ 227.0895; found: 227.0900 [M+Na]+.

Improved procedure for the preparation of 1’,2,3,3’,4,4’-hexa-O-benzylsucrose (2a). Trityl ether 75 (1g, 0.73 mmol) was dissolved in a CH2Cl2-MeOH mixture (10:1 v/v; 11 mL) and the solution was stirred at room temperature for 5 min. NaHSO4 (1.5 g) embedded on silica (1.5 g) was added and the mixture was stirred at rt. until TLC (hexane–AcOEt, 9:1)

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Zinc activation: Zinc dust was stirred in a 1 M aqueous HCl soln. (0.5 mL/1.0 mmol of zinc) for 1 min, then filtered, and used directly in the reaction.

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indicated disappearance of the starting material (ca 20 h). Then it was filtered and the residue was purified by flash chromatography (hexane–AcOEt, 9:1) to afford diol 2a (colorless oil;

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385 mg, 60 %) identical in all respect with the material prepared independently.5

Preparation of 6,6’-diamino-6,6’-dideoxy-1’,2,3,3’,4,4’-hexa-O-benzylsucrose (2b). To a cooled (0 °C) and stirred solution of azide 610 (4.66 g, 5 mmol) in dry THF (70 mL), LiAlH4

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(0.45 g, 12 mmol) was added in small portions over 5 min. The mixture was warmed to room temperature and stirring was continued for 2 h. After cooling in an ice bath, the reaction was

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quenched by the addition of sat. aq. Na2SO4 and Celite. It was then filtered through a Celite pad, the layers were separated, and the aqueous phase extracted with EtOAc (3 x 30 mL). The combined organic solutions were washed with brine (20 mL), dried, and concentrated under reduced pressure to afford di-amine 2b (3.78 g, 86 %) as a colorless oil. [α]D = +45; 1H NMR (400 MHz) δ 7.36 – 7.19 (m, 30H), 5.57 (d, J = 3.6 Hz, 1H), 4.88 (dd, J = 15.0, 11.0 Hz, 2H),

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4.80 – 4.36 (m, 9H), 4.14 – 3.83 (m, 4H), 3.78 – 3.65 (m, 3H), 3.56 – 3.30 (m, 3H), 3.02 – 2.76 (m, 2H), 2.67 (dd, J = 13.6, 5.6 Hz, 2H); 13C NMR (100 MHz) δ 138.79, 138.31, 138.27, 138.25, 138.07, 137.82, 128.45 - 127.54, 104.27, 90.33, 84.15, 82.00, 81.84, 80.10, 78.34,

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75.48, 74.80, 73.46, 72.79, 72.74, 72.44, 72.07, 71.12, 62.62, 44.71, 42.6; IR (film) νmax 3375, 3030, 2918, 2867, 1584, 1454, 1089, 1072, 1028, 736, 698 cm-1; ESI-MS: m/z Calcd for

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C54H60N2O9 [M+Na]+ 903.4197; found: 903.4156 [M+Na]+. Synthesis of di-ester 3a. To a stirred solution of acid 9 (0.81g, 3.97 mmol) in dry CH2Cl2 (6 mL), diol 2a (0.87 g, 0.99 mmol) was added followed by DCC (4.95 mL of 1 M solution in CH2Cl2; 4.95 mmol) and DMAP (60 mg, 0.50 mmol). The mixture was stirred for 1 h at room temperature, filtered, and the filter cake was washed with dry CH2Cl2 (10 mL). The filtrates were combined, concentrated under reduced pressure and the residue was purified by column chromatography (hexane–EtOAc, 4:1) to afford 3a (1.03 g, 83%) as colorless oil. [α]D = +33; 12

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H NMR (600 MHz) δ 7.36 – 7.19 (m, 30H), 5.75 – 5.66 (m, 2H), 5.62 (d, J = 3.5 Hz, 1H),

5.36 – 5.27 (m, 4H), 4.93 (d, J = 10.9 Hz, 1H), 4.87 (d, J = 10.9 Hz, 1H), 4.90 – 4.74 (m, 3H), 4.77 (d, J = 10.9 Hz, 1H), 4.68 – 4.47 (m, 7H), 4.47 – 4.37 (m, 3H), 4.32 (dd, J = 11.7, 3.6

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Hz, 1H), 4.24 (s, 2H), 4.19 – 4.11 (m, 2H), 4.10 – 3.93 (m, 2H), 3.86 – 3.75 (m, 3H), 3.69 (d, J = 11.0 Hz, 2H), 3.57 – 3.45 (m, 3H), 3.45 (s, 3H), 3.42 (s, 3H), 3.35 (s, 3H), 3.29 (s, 3H), 3.27 (s, 6H); 13C NMR (150 MHz) δ 170.45, 170.22, 138.65, 138.14, 138.10, 137.85, 137.76,

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137.70, 134.84, 134.83, 128.40 - 127.56, 119.36, 119.23, 105.06, 90.00, 83.97, 83.90, 83.87, 83.63 (double intensity), 83.61, 82.55, 81.73, 80.42, 80.35, 79.85, 78.50, 75.59, 74.93, 73.40, 73.00, 72.64, 72.53, 70.92, 69.06, 66.06, 63.00, 60.84, 60.79, 58.96, 58.81, 56.83, 56.81; IR

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(film) νmax 2928, 1758, 1736, 1454, 1094, 738, 699 cm-1; ESI-MS: calcd for C72H86O19 [M+Na]+ 1277.5661; found: 1277.5643 [M+Na]+; anal. calcd for C72H86O19: C, 68.88; H, 6.90; found: C, 68.74; H, 6.83.

Synthesis of di-amide 3b. To a stirred solution of acid 9 (0.69 g, 3.38 mmol) in dry CH2Cl2

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(7.2 mL), di-amine 2b (1 g, 1.13 mmol) was added followed by DCC (5.65 mL of 1 M solution in CH2Cl2; 5.65 mmol) and DMAP (69 mg, 0.56 mmol). The mixture was stirred for 1 h at room temperature, filtered, and the filter cake was washed with dry CH2Cl2 (10 mL).

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The filtrates were combined, concentrated under reduced pressure and the residue was purified by column chromatography (hexane–EtOAc, 1:1) to afford 3b (1.06 g, 75%) as

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colorless oil. [α]D = +31; 1H NMR (600 MHz) δ 7.42 – 7.16 (m, 30H), 7.04 (dd, J = 7.5, 4.3 Hz, 1H), 6.86 (dd, J = 9.5, 2.2 Hz, 1H), 5.81 – 5.66 (m, 2H), 5.56 (d, J = 3.4 Hz, 1H), 5.38 – 5.25 (m, 3H), 4.94 – 4.86 (m, 2H), 4.80 – 4.75 (m, 2H), 4.74 – 4.65 (m, 2H), 4.66 – 4.56 (m, 3H), 4.56 – 4.44 (m, 4H), 4.38 (t, J = 8.8 Hz, 3H), 4.26 – 4.16 (m, 2H), 4.13 – 3.81 (m, 6H), 3.83 – 3.72 (m, 3H), 3.72 – 3.63 (m, 3H), 3.56 (s, 3H), 3.54 – 3.45 (m, 2H), 3.39 (s, 3H), 3.38 (s, 3H), 3.31 (s, 3H), 3.29 (s, 3H), 3.26 (s, 3H);

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C NMR (150 MHz) δ 170.87, 170.71,

139.02, 138.53, 138.17, 138.01, 137.76, 137.75, 135.07, 135.02, 128.51 - 127.16, 119.60, 13

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119.42, 105.30, 90.68, 84.54, 84.26, 83.86, 83.69, 83.65, 83.26, 82.47, 82.12, 81.68, 79.90, 79.80, 77.58, 75.08, 75.07, 73.40, 72.93, 72.75, 72.28, 70.83, 69.91, 61.26, 61.18, 59.59, 59.21, 56.82, 56.62, 42.63, 38.34; IR (film) νmax 3425, 2932, 1676, 1526, 1092, 737, 699 cm-1;

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ESI-MS: calcd for C72H88N2O17 [M+Na]+ 1275.5981; found: 1275.5973 [M+Na]+.

General procedure for RCM reaction. To a solution of the corresponding diene (3a or 3b; 0.02 mmol) in degassed, anhydrous solvent (3.3 mL which makes the concentration ca. 6 x

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10-3 mol L-1), the catalyst (A-G; 10 mol %) was added, and the mixture was stirred and

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heated. The progress of the reaction was monitored by TLC (hexane–AcOEt, 1:1 for 3a or hexane–AcOEt, 1:3 for 3b); the precise conditions of the process are shown in Table 1. For prolonged reaction times additional portions of the catalyst were required.

General procedure for the RCM reaction induced with microwaves. Experiments were

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carried out in 20 mL closed microwave glass process vials. A solution of the corresponding diene 3a or 3b (25 mg; 0.02 mmol) and Hoveyda-Grubbs-II catalyst (1.3 mg, 0.002 mmol, 10 mol %) in toluene (3.3 mL; c = 6 x 10-3 mol L-1 degassed, anhydrous) was stirred and

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irradiated for 5 h at 70°C. Another portion of the catalyst (0.6 mg, 0.001 mmol, 5 mol %) was added and the reaction was continued for another 3 h.

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Olefin 10a. This compound was obtained from 3a and purified by preparative TLC (benzeneEt2O, 1:3) to afford 10a (20.5 mg, 84%) as a white amorphous foam. [α]D = +68; 1H NMR (600 MHz) δ 7.53 – 7.08 (m, 30H), 6.03 (d, J = 3.6 Hz, 1H), 5.87 (dd, J = 15.6, 5.8 Hz, 1H), 5.61 (dd, J = 15.4, 6.2 Hz, 1H), 4.93 (d, J = 10.9 Hz, 1H), 4.82 (d, J = 10.5 Hz, 1H), 4.74 (t, J = 10.8 Hz, 2H), 4.67 – 4.42 (m, 4H), 4.34 – 4.23 (m, 3H), 4.19 – 4.01 (m, 3H), 3.97 – 3.73 (m, 7H), 3.73 – 3.39 (m, 10H), 3.53 (s, 3H), 3.51 (s, 3H), 3.35 (s, 3H), 3.34 (s, 3H), 3.30 (s, 3H), 3.24 (s, 3H);

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C NMR (150 MHz) δ 170.55, 169.68, 138.85, 138.36, 138.04, 137.73, 14

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137.67, 137.24, 129.82, 129.71, 128.52 - 127.33, 103.96, 88.06, 83.06, 82.89, 82.36 (double intensity), 81.96, 81.23, 81.22, 80.62, 80.43, 78.98, 77.21, 76.49, 75.58, 75.08, 73.72, 73.53, 73.07, 72.94, 71.94, 69.36, 62.90, 62.58, 60.90, 60.73, 58.95, 58.50, 57.47, 57.36; IR (KBr)

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νmax 3088, 3063, 3031, 1744, 1093 cm-1; ESI-MS: calcd for C70H82O19 [M+Na]+ 1249.5348; found: 1249.5360 [M+Na]+; anal. calcd for C70H82O19 ·H2O: C, 67.51; H, 6.80; found: C, 67.96; H, 6.87.

Olefin 10b. This compound was obtained from 3b and purified by preparative TLC (acetone-

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CH2Cl2, 1:5) to afford 10b (19.7 mg, 80%) as a colorless oil; [α]D = +70; 1H NMR (600 MHz)

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δ 7.36 – 7.18 (m, 30H), 7.16 (s, 1H), 6.64 (s, 1H), 5.60 – 5.57 (m, 2H), 5.52 (d, J = 3.2 Hz, 1H), 4.97 – 4.33 (m, 17H), 4.21 – 3.44 (m, 14H). 3.48 (s, 3H), 3.42 (s, 3H), 3.35 (s, 3H), 3.34 (s, 3H), 3.33 (s, 3H), 3.24 (s, 3H);

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C NMR (150 MHz) δ 170.68, 170.62, 138.61, 138.59,

138.14, 137.90, 137.89, 137.86, 131.60, 131.37, 128.38 - 127.51, 105.01, 90.29, 83.71, 83.04, 82.27, 81.77, 81.57, 81.38, 81.13, 81.01, 79.81, 79.51, 79.22, 79.21, 75.26, 74.93, 73.37,

TE D

72.88, 72.87, 72.75, 72.15, 70.27, 60.08, 60.04, 58.85, 58.24, 56.96, 56.94, 40.93, 39.77; IR (film) νmax 3418, 3375, 1680, 1524, 1092, 699 cm-1; ESI-MS: calcd for C70H84N2O17 [M+Na]+ 1247.5668; found: 1247.5647 [M+Na]+; anal. calcd for C70H84N2O17 ·H2O: C, 67.62; H, 6.97;

EP

N, 2.25; found: C, 67.26; H, 6.96; N, 2.28.

AC C

syn-Dihydroxylation of cyclic olefin 10b with OsO4. To a solution of compound 10b (55 mg, 0.045 mmol) in THF-tert.-BuOH-H2O (1 mL, 0.1 mL, 0.02 mL), NMO (6.3 mg, 0.054 mmol) was added followed by OsO4 (0.1 mL of a ~ 2.5% solution in tert.-butyl alcohol) and the mixture was stirred at rt. until TLC indicated the disappearance of the starting material and formation of a new, more polar product (TLC monitoring in hexane–AcOEt, 1:4). Then MeOH (1 mL) and sat. aq. NaHSO3 (0.5 mL) were added and the mixture was stirred for 15 min at rt. and then filtered through Celite. The layers were separated, and the aqueous phase 15

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extracted with EtOAc (3 x 5 mL). The combined organic solutions were washed with brine (3 mL), dried, concentrated under reduced pressure and the product was purified by preparative TLC (CH2Cl2-MeOH, 10:1) to afford diol 11 (29 mg, 52%) as a white amorphous powder.

RI PT

[α]D = +35; ESI-MS: calcd for C70H86N2O19 [M+Na]+ 1281.5722; found: 1281.5736 [M+Na]+; anal. calcd for C70H86N2O19·H2O: C, 65.81; H, 6.94; N, 2.19; found: C, 65.97; H, 7.03; N, 2.23.

SC

Compound 11 was characterized as its diacetate:1H NMR (600 MHz) δ 7.38 – 7.13 (m, 31H), 6.72 (s, 1H), 5.57 (dd, J = 5.2, 3.4 Hz, 1H), 5.47 (d, J = 3.7 Hz, 1H), 4.88 (d, J = 11.0 Hz,

M AN U

1H), 4.84 (d, J = 10.7 Hz, 1H), 4.80 – 4.67 (m, 3H), 4.66 – 4.56 (m, 4H), 4.46 (dd, J = 11.9, 3.2 Hz, 3H), 4.39 (d, J = 12.0 Hz, 2H), 4.33 (d, J = 4.9 Hz, 1H), 4.24 (s, 1H), 4.20 – 4.14 (m, 2H), 4.05 – 3.93 (m, 2H), 3.88 (d, J = 6.7 Hz, 1H), 3.79 – 3.62 (m, 6H), 3.60 – 3.53 (m, 2H), 3.48 – 3.45 (m, 3H), 3.49 (s, 3H), 3.45 (s, 3H), 3.44 (s, 3H), 3.41 (s, 3H), 3.35 (s, 3H), 3.24 (s, 3H), 2.14 (s, 3H), 2.09 (s, 3H);

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C NMR (150 MHz) δ 170.84, 170.11 (double intensity),

TE D

169.95, 138.52, 138.32, 138.19, 137.96, 137.88, 137.71, 128.50 - 127.45, 106.38, 89.98, 84.57, 83.34, 81.83, 81.72, 81.58, 81.56, 80.71, 79.81 (double intensity), 78.85, 75.60, 74.77, 73.34, 72.79, 72.76, 72.60, 72.14, 71.02, 69.22, 69.14, 69.13, 68.19, 60.82, 60.47 (double

EP

intensity), 59.37, 59.09, 58.45, 43.01, 38.91, 21.07, 21.01.

syn-Dihydroxylation of olefin 10a. To a solution of 10a (63 mg, 0.051mmol) in THF-tert.-

AC C

BuOH-H2O (1 mL, 0.1 mL, 0.02 mL), NMO (7.2 mg, 0.061 mmol) was added followed by OsO4 (0.1 mL of a ~ 2.5% solution in tert.-butyl alcohol) and the mixture was stirred at rt. until TLC indicated the disappearance of the starting material (TLC monitoring in hexane– AcOEt, 1:2). Then MeOH (1 mL) and sat. aq. NaHSO3 (0.5 mL) were added and the mixture was stirred for 15 min at rt. and then filtered through Celite. The layers were separated and the aqueous phase extracted with AcOEt (3 x 5 mL). The combined organic solutions were 16

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washed with brine (3 mL), dried, concentrated under reduced pressure and the product was purified by preparative TLC (CH2Cl2-MeOH,10:1); only the diol 2a (resulted from hydrolysis of the macrocycle) was isolated (35 mg, 78%).

RI PT

Acknowledgement The support. from the Grant of National Science Centre UMO-2012/05/B/ST5/00377 is acknowledged.

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References

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1. (a) Connon, S. J.; Blechert., S. Angew. Chem. Int. Ed. 2003, 42, 1900-1923; (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. Engl. 2005, 44, 4490-4527; (c) Grubbs, R. H. Tetrahedron, 2004, 60, 7117– 7140; (d) Samojłowicz, C.; Bieniek, M.; Grela, K. Chem. Rev. 2009, 109, 3708-3742; (e) Grela K. ‘Olefin Metathesis: Theory and Practice’ Wiley 2014, ISBN: 978-1-118-20794-9. 2. (a) Potopnyk, M. A.; Jarosz, S. Eur. J. Org. Chem. 2013, 23, 5117–5126; (b) Jarosz, S.; Potopnyk, M. A.; Kowalski, M. Carbohydrate Chemistry-Chemical and Biological Approaches, RSC publication, 2014, 40, 236256; (c) Potopnyk, M. A.; Jarosz, S. Adv. Carbohydr. Chem. Biochem. 2014, 71, 227-295. 3. Potopnyk, M. A.; Cmoch, P.; Jarosz, S. Org. Lett. 2012, 14, 4258-4261. 4. Szumna, A.; Jurczak, J. Eur. J. Org. Chem. 2001,4031-4039.

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6. Osuch-Kwiatkowska, A.; Jarosz, S. Tetrahedron: Asymmetry, 2013, 24, 468-473.

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7. Whistler, R. L.; Anisuzzaman, A. K. M. Methods Carbohydr. Chem. 1980, 8, 227–231. 8. Jarosz, S.; Listkowski, A. J. Carbohydr. Chem. 2003, 22, 753-763. 9. Das, B.; Mahender, G.; Kumar, V. S.; Chowdhury N. Tetrahedron Lett., 2004, 45, 6709–6711. 10. Garndnig, G.; Legler, G.; Stütz, A. E. Carbohydr. Res. 1996, 287, 49–57. 11. (a) Bernet, B.; Vasella, A. Helv. Chim. Acta, 1979, 62, 1990–2016; Bernet, B.; (b)Vasella, A. Helv. Chim. Acta, 1979, 62, 2400–2410.

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12. Trimnell, D.; Doane, M. W.; Russell, C. R. Carbohydr. Res. 1972 , 22, 351-358. 13. Neises, B.; Steglich, W. Angew. Chem. Int. Ed. 1978, 17, 522-524. 14. Miller, S. J.; Kim, S.; Chen, Z.; Grubbs, R. H. J. Am. Chem. Soc. 1995, 117, 2108-2109.

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15. Wang, Y.; Jimenez, M.; Hansen, A. S.; Raiber, E.; Schreiber S. L.; Young, D. W. J. Am. Chem. Soc. 2011, 133, 9196-9199. 16. Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29. 17. Samojłowicz, C.; Bieniek, M.; Pazio, A.; Makal, A.; Woźniak, K.; Poater, A.; Cavallo, L.; Wójcik, J.; Zdanowski, K.; Grela, K. Chem. Eur. J. 2011, 17, 12981-12993. 18. (a) Van Rheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 1973–1976; (b) Jarosz, S. Carbohydr. Res. 1988, 183, 209-215; (c) Jarosz, S.; Skóra, S.; Kościołowska, I. Carbohydr. Res. 2003, 338, 407-413; (d) Jarosz, S. Carbohydr. Res. 1992, 224, 73–81. 19. Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron 1984, 40, 2247–2255. 20. (a) Frelek, J.; Pakulski, Z.; Zamojski, A. Tetrahedron: Asymmetry, 1996, 7, 1363-1372; (b) Frelek, J.; Ikekawa, N.; Takatsutu, S.; Snatzke, G. Chirality, 1997, 9, 578-582; (c) Frelek, J.; Klimek, A.; Ruśkowska, P. Curr. Org. Chem., 2003, 7, 1081-1104.

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21. Pakulski, Z.; Gajda, N.; Jawiczuk, M.; Frelek, J.; Cmoch, P.; Jarosz, S. Beilstein J. Org. Chem., 2014, 10, 1246-1254.

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