Ruthenium Carbenoids as Catalysts for Olefin Metathesis of ω-Alkenyl Glycosides

[2]

ruthenium carbenoids as catalysts for olefin metathesis

17

Turbidimetric Analysis Equivalent amounts of the compounds (corresponding to 9.1
mol of monosaccharide residue) are delivered separately into microtiter wells. The lectin from Canavalia ensiformis, concanavalin A (Con A; SigmaAldrich, st. Louis, MO) (80
l of a stock solution of 1.0 mg in 100 ml of phosphate-buffered saline [PBS]), is delivered via a microsyringe in each well. PBS solution is added to each well so that the total volume in each well is 120
l. The blank consists of a solution of 80
l of Con A solution and 40
l of PBS. The optical density (OD) at 490 nm is monitored for 2 h at room temperature. Each test is done in triplicate. The turbidity is measured on a Dynatech MR (Burlington, MA) 600 microplate reader at regular time intervals.

[2]

Ruthenium Carbenoids as Catalysts for Olefin Metathesis of !-Alkenyl Glycosides

By Romyr Dominique, Sanjoy K. Das, Bingcan Liu, Joe Nahra, Brad Schmor, Zhonghong Gan, and Rene´ Roy Introduction

Olefin metathesis is a powerful synthetic process that translates, in its most simplified version, into the combination of two alkenes to generate a new double bond between the reacting partners with the evolution of ethylene gas when dealing with terminal alkenes.1–3 The procedure can lead to self- and cross-metathesis, to ring-closing (RCM), and to ringopening metathesis polymerization (ROMP) (Scheme 1). The most widely used catalysts for this process are transition metal carbenoids 1–3. Although Schrock’s molybdenum catalyst 1 is also efficient, it requires more stringent operating conditions and, consequently, Grubbs’s ruthenium catalysts 2 and 3 are used more often, particularly in carbohydrate chemistry where functional group tolerance plays a critical factor.4 Moreover, the most recent, air-stable, and more versatile carbenoid 3 has been shown to provide access to better chemo- and stereoselective transformations.

1

R. R. Schrock, Acc. Chem. Res. 12, 98 (1979). R. H. Grubbs and S. Chang, Tetrahedron 54, 4413 (1998). 3 A. Fu¨rstner, Angew. Chem. Int. Ed. 39, 3012 (2000). 4 R. Roy and S. K. Das, Chem. Commun. 519 (2000). 2

METHODS IN ENZYMOLOGY, VOL. 362

Copyright 2003, Elsevier (USA). All rights reserved. 0076-6879/03 $35.00

18

[2]

preparative methods O

O

O

+

Self-metathesis

O O

O

[Mt] =

+

R

R O

Cross-metathesis

O RCM

O

O

[Mt] = iPr N (F3C)2MeCO (F3C)2MeCO

Mo

iPr Ph

Cl Cl Me Me

Schrock’s Molybdenum Catalyst 1

PCy3 Ru

N Ph

PCy3

Cl

N Ru

Ph

Cl PCy3

Grubbs’ Ruthenium Catalyst 2

3

Scheme 1. General olefin metathesis processes using transition metal carbenoid species. Mt, Metal.

Carbohydrate derivatives with allyl ethers as well as with O- and Clinked allyl glycosides have been known for a long time and several of these derivatives are well-established precursors in synthetic carbohydrate chemistry. Obviously, olefin metathesis in its various forms represents a particularly appealing chemical process for the design of small carbohydrate clusters (e.g., dimers), glycomimetics, conformationally restrained oligosaccharides, and perhaps, more importantly, functionalized aglycones with pendant functionalities suitable for further neoglycoconjugate syntheses. We report here some of the above-cited applications in which the terminal alkene groups have been introduced in key positions around the ring. Olefin Self-Metathesis

Olefin self-metathesis of O- or C-linked allyl, pentenyl, and vinyl glycosides is a straightforward process leading to homodimers having either trans or cis geometries (Scheme 2, compounds 4–21; Table I5–9). 5

Z. Gan and R. Roy, Tetrahedron 56, 1423 (2000). S. K. Das, R. Dominique, C. Smith, J. Nahra, and R. Roy, Carbohydr. Lett. 3, 361 (1999). 7 R. Dominique, B. Liu, S. K. Das, and R. Roy, Synthesis 862 (2000). 8 R. Roy, R. Dominique, and S. K. Das, J. Org. Chem. 64, 5408 (1999). 9 B. Liu, S. K. Das, and R. Roy, Org. Lett. 4, 2723 (2002). 6

[2]

19

ruthenium carbenoids as catalysts for olefin metathesis OBn O

BnO BnO BnO

OBn

OBn O

BnO BnO BnO

OBn

13

OBn O

OBn O

BnO BnO BnO

OBn

O

OBn

14

5

n

6 n=1 7 n=3 O

O

OH

OH O

HO HO HO

O

O

OBn

BnO

OH O

HO HO HO

OBn

O

4 BnO BnO BnO

OBn

OH OH

n O

O n

15 n = 1 16 n = 3

O

O O

OH

O

O

O O

O

O

O

O ( ) n

( ) n

n 8 n=1 9 n=3 BnO BnO BnO

17 n = 1 18 n = 3 BnO BnO BnO

O

OBn

O

O

O

AcO AcO AcO

O

NHAc

OBn OBn

O

O AcHN

NHAc

OAc Me

O

OAc Me AcO

O OAc 12

OAc OAc Me

O

AcO OAc

Scheme 2

OAc OAc

O OAc

20

11

OBn

O

BnO

19

10 O

O

O

OBn AcO AcO AcO

O

O

OAc 21

20

[2]

preparative methods TABLE I Olefin Self-Metathesis of Alkenyl O- and C-Glycopyranosidesa

Entry

Alkene

Product

Reaction conditions

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

4 5 6 6 7 7 8 9 10 10 10 11 12 24 26 27 28 32 34

13 14 15 15 16 16 17 18 19 19 19 20 21 25 29 30 31 33 35

CH2Cl2,
CH2Cl2,
CH2Cl2:CH3OH (3:1)b
CH2Cl2:CH3OH (3:1), 40 b CH2Cl2:CH3OH (3:1)
CH2Cl2:CH3OH (3:1), 40 CH2Cl2,
CH2Cl2,
CH2Cl2b CH2Cl2,

ClCH2CH2Cl, 70 CH2Cl2,
CH2Cl2,
CH2Cl2,
CH2Cl2,
CH2Cl2,
CH2Cl2,
CH2Cl2,
CH2Cl2,


Reaction time (h)

Yield (%)

E/Z ratio

8 8 8 18 8 16

83 70 60 34 67 42 85 85 NR 8 24 66 95 91 82 88 26 37 78

1:1 1.4:1 1.7:1 1.4:1 1.3:1 1.1:1 5:1 5:1 — 100:0 100:0 5:2 3:1 100:0 7:1 3:1 2.5:1 100:0 1.7:1

24 16 16 8 8 4 6 2 24 24 2

Abbreviation: NR, Not recorded. a From Refs. 5–9. b At room temperature.

Unfortunately, separation of the two stereoisomers is sometimes difficult and requires high-performance liquid chromatography (HPLC) separation. Alternatively, hydrogenation of the double bonds generates single aliphatic spacers that are otherwise generally obtained in much lower yields and anomeric stereoselectivities when double glycosidation reactions are utilized with the corresponding diols. As can be seen from dimerization of vinyl glycoside 10 (Table I, entries 9–11), steric factors may drastically reduce the overall efficacy of the reaction with, however, increased stereoselectivity. Interestingly, even with catalyst 2, the olefin metathesis reaction allows for a wide range of functional group tolerance. Even unprotected allyl glycosides 6 and 7 afford the desired products 15 and 16, albeit in lower yields, when the reactions are performed under refluxing conditions. In this latter case, performing the reaction at room temperature has a beneficial effect on the yield (compare entries 5 and 6 in Table I). The usual

[2]

ruthenium carbenoids as catalysts for olefin metathesis

21

acetates, benzyl ethers, and acetal protecting groups are all compatible with the reaction conditions. The olefin self-metathesis is not restricted to aliphatic alkenes, because even styryl (Table I, entries 14 and 18) and allylbenzene derivatives (Table I, entry 19) provide good to moderate yields of the corresponding glycosyl stilbene analogs 25, 33, and 35, respectively (Scheme 3, compounds 22–35). para-Vinylphenyl-O-glycosides such as 24 and 32 are readily accessible under phase transfer catalysis (PTC). The synthesis of the sialic acid-containing dimers is also noteworthy (see compounds 29, 30, 33, and 35 in Scheme 3). More important is the finding that S-allyl glycoside 28 also provides the expected dimer 31 (26%; Table I, entry 17). The lower yield in this case may be attributed to reduction of the catalyst turnover, because the remaining starting material 28 can be recovered intact and reentered into the catalytic cycle with fresh catalyst. The -pentenyl sialoside 27 (Table I, entry 16) affords a better yield of dimer 30 than the corresponding allyl sialoside 26 (entry 15), although with a decrease in E/Z stereoselectivity due to steric decompression (3:1 for 30 versus 7:1 for 29). Once deprotected, some of the above-described homodimers represent useful bivalent ligands for protein cross-linking studies. Olefin Cross-Metathesis

Olefin cross-metathesis is conceptually more complicated than selfmetathesis simply because each of the intervening partners can, in principle, participate in the catalytic process leading to each homodimer, together with the desired cross-products. Two easy solutions to this problem have been undertaken. In the most simple cases, a slight excess of one of the olefins can be used. This protocol is favored when one of the alkenes is commercially available or is readily accessible. A conceptually different approach can be used in which one of the reacting alkenes can be anchored to a solid phase, thus preventing self-metathesis of the immobilized alkene from occurring. With the advent of the more reactive and more selective ruthenium alkylidene catalyst 3, somewhat ‘‘controlled’’ cross-metathesis reactions are possible. The usually random [2 þ 2] cycloadditions/cycloreversions catalytic cycles involving alkenes, carbenes, and metallo-cyclobutane intermediates can be partly controlled with catalyst 3, which has been shown to be more chemoselective toward electron-poor olefins. For instance, allyl chloride (Table II, entries 1–3; Scheme 4, compounds 36–50) and tert-butyl acrylate (Table II, entries 6 and 7) are unreactive with the original Grubbs’s catalyst 2, although they have been found to react efficiently with catalyst 3. It also appears that the new ruthenium catalyst 3 is slightly better

22

AcO

AcO

OAc

OAc

1M Na2CO3 TBAHS, EtOAc

O AcO

O

O

AcO AcO 22

Br

AcO

HO

24 3

23

CH2Cl2, ∆, 4 h, 91%

OAc AcO O

OAc O AcO

AcO

25

AcO

CO2Me

OAc O

AcHN

X

AcO

OAc

O

AcO

AcO

O

preparative methods

AcO

AcO

2 CH2Cl2, ∆

AcO

O

AcHN AcO

OAc

CO2Me

OAc

X

X MeO2C

26 X = OCH2

29 X = OCH2

27 X = O(CH2)3

30 X = O(CH2)3

28 X = SCH2

31 X = SCH2

NHAc O AcO

OAc OAc

Scheme 3. (continued)

[2]

[2]

OAc

AcO

CO2Me O

O

AcHN

2

AcO 32

O

AcHN

CH2Cl2, ∆ 37%

O

AcHN

CO2Me

2

O

CH2Cl2, ∆

CO2Me

OAc O

O

AcO

OAc

78%

AcO

AcO

33

AcHN OAc

O

MeO2C

AcO

AcO

NHAc

O O

AcO

AcO

AcO

OAc

CO2Me

OAc

AcO

O 35 MeO2C

34

Scheme 3

NHAc

O AcO

OAc OAc

OAc OAc

ruthenium carbenoids as catalysts for olefin metathesis

AcO

AcO

23

24

[2]

preparative methods BnO

OBn

BnO

OBn

O O

BnO BnO

37

3

AcO

O

OAc O

O

AcO

O

AcO

Cl

AcO

Cl

AcO

3, CH2Cl2, ∆

38 a 39 b

40 a 41 b

AcO

OAc O

AcO

OAc O

2 CH2Cl2, 12h, ∆

AcO

AcO

43

44

N

3

AcO

O

RO

ClCH2CH2Cl ∆, o. n.

Boc 12

46

RO

47 R = Bn 48 R = Ac

OR O

O

OtBu

RO RO

AcO

Boc

OAc

OAc

45

O

OR

O

Me

N

OAc

OAc

NHCbz

AcO

NHCbz

42

Me

Cl

BnO

OAc

AcO

O

BnO

CH2Cl2, ∆, o.n. 36

AcO

O

Cl

CH2Cl2, ∆, 12 h

OtBu

RO RO O

3 49 R = Bn 50 R = Ac

Scheme 4

at overcoming steric hindrance problems because N-Boc-2-vinylpyrrolidine (compound 45; Table II, entry 5) reacts smoothly to provide cross-product 46 (64%) containing the fucoside residue (12) whereas catalyst 2 fails to afford the desired cross-metathesis.

[2]

25

ruthenium carbenoids as catalysts for olefin metathesis

TABLE II Olefin Cross-Metathesis of Alkenyl O- and C-Glycopyranosides with Catalyst 3

Entry Compound 1 2 3 4 5 6 7 8 9 10

36 38 39 42 12 47 48 51 42 42 a

Alkene CH2 CH2 CH2 CH2 45 CH2 CH2 8 54 56

== == == ==

CHCH2Cl CHCH2Cl CHCH2Cl CHCH2NHCbz

== CHC(O)Ot-Bu == CHC(O)Ot-Bu

Product

Reaction conditions

37 40 41 44 46 49 50 52a 55 57

CH2Cl2,
CH2Cl2,
CH2Cl2,
CH2Cl2,
ClCH2CH2Cl,
CH2Cl2,
CH2Cl2,
CH2Cl2,
CH2Cl2,
CH2Cl2,


Time Yield E/Z (h) (%) ratio 6 6 6 12 16 12 12 13 6 6

75 65 55 45a 64b 74 91 48a 75a 67

>20:1 17:1 15:1 >20:1 3.3:1 95:5 97:3 5:1 100:0 4:1

Catalyst 2 is used. Homodimer 21 (22%) is also formed. No trace of 45 homodimer is detected.

b

More complex reactions can also be undertaken by cross-metathesis. Scheme 5 (compounds 51–57) illustrates the double cross-metathesis reactions between diene 51 and allyl mannoside 8 (4 equivalents), using catalyst 2. The reaction proceeds smoothly to provide tetramer 52a (fully protected intermediate) in 48% yield. In this particular case, the reaction conditions must be fine-tuned because both the homodimer of 8 (17) and the competitive ring-closing metathesis (RCM) product 53 are inevitably formed during the process (Scheme 5). The cross-metathesis reaction has also been extended to C-linked glycoside-containing aryl functionalities (55, 50%; E/Z, 100:0) using 4-acetoxystyrene 54 and to the synthesis of pseudodisaccharide as seen with the coupling of C-allyl galactoside 42 and 6-O-allyl isopropylidene galactoside 56, which affords cross-dimer 57 in 67% yield (E/Z, 4:1) (entries 9 and 10, Table II). Typical Procedures

Reagents Catalyst 2 [Cl2Ru(PCy3)2 CHPh; bis(tricyclohexylphosphine)benzylideneruthenium(IV)dichloride, Grubbs’s catalyst] and catalyst 3 [Cl2Ru(PCy3)(=CHPh)(IMes2); tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene]benzylidene]ruthenium(IV) dichloride] are obtained from Strem Chemicals (Newburyport, MA).

26

[2]

preparative methods

O

O O O

O

1. Catalyst 2, 8 O

O O

O

O

51

OH OH O O

O O

OH OH

O

O

O

O O O

OH OH

O OH

O

O

O

O

O O OH

OH

O

O

HO HO HO

O

O

O

HO HO HO

48% 52a (5/1; E/Z) 2. H2, Pd/C 3. 60% HOAc, 45⬚C

O

O O

O O

O

OH 53

52 AcO

OAc O

AcO

AcO

AcO 54

OAc

42

AcO

2 CH2Cl2, ∆

OAc O

55

AcO AcO O O

O O

O O

O O

O O O

56

O

57

Scheme 5

These reagents are best conserved in dry boxes under a nitrogen atmosphere at room temperature. O-Allyl glycosides are prepared by standard procedures using allyl alcohol and a Lewis acid.10,11 C-Allyl glycosides are synthesized from peracetylated or perbenzylated sugars, allyl trimethylsilane, and a Lewis acid12–15 or by the lactone procedure of Lewis et al.16 10

J. Gigg, R. Gigg, S. Payne, and R. Conant, Carbohydr. Res. 141, 91 (1985). B. Fraser Reid, U. E. Udolong, Z. Wu, H. Otosson, J. R. Meritt, C. S. Rao, and R. Madsen, Synlett 927 (1992). 12 A. P. Kozikowski and K. L. Sorgi, Tetrahedron Lett. 2281 (1982). 13 A. Giannis and K. Sandhoff, Tetrahedron Lett. 1479 (1985). 14 D. Horton and T. Miyake, Carbohydr. Res. 184, 221 (1988). 15 A. Hosomi, Y. Sakata, and H. Sakurai, Carbohydr. Res. 171, 223 (1987). 16 M. D. Lewis, J. K. Cha, and Y. Kishi, J. Am. Chem. Soc. 104, 4976 (1982). 11

[2]

ruthenium carbenoids as catalysts for olefin metathesis

27

Self-Metathesis (E,Z)-1,4-Di-C-(2,3,4,6-tetra-O-benzyl--d-mannopyranosyl)but-2-ene (13). To a solution of 3-(2,3,4,6-tetra-O-benzyl--d-mannopyranosyl)propene (4)15 (200 mg, 0.355 mmol) in CH2Cl2 (3 ml) and under nitrogen atmosphere is added ruthenium catalyst 2 (15 mg, 10 mol%). The purple reaction mixture is heated under reflux and the solution turns black over 1 h. The reaction mixture is stirred at this temperature for another 5 h. The solution is then concentrated under reduced pressure and the residue is purified by silica gel column chromatography using ethyl acetate–hexane (1:2, v/v) as eluent to give syrupy compound 1317 (162 mg, 83%) as a cis/ trans mixture. 1H nuclear magnetic resonance (NMR) (500 MHz, CDCl3):  (ppm) 7.35–7.19 (m, 40 H, aromatic), 5.46 (t, 2H, J ¼ 4.4 Hz, H-20 cis), 5.37 (t, 2H, J ¼ 3.8 Hz, H-20 trans), 4.72–4.49 (m, 16H, 4 CH2Ph), 4.02 (m, 2H, H-1), 3.88 (t, 2H, J ¼ 6.7 Hz, H-4 trans), 3.87 (t, 2H, J ¼ 6.7 Hz, H-4 cis), 3.82–3.70 (m, 8H, H-3, H-5, H-6a, H-6b), 3.62 (dd, 2H, J ¼ 3.3 and 4.6 Hz, H-20 trans), 3.61 (dd, 2H, J ¼ 3.1 and 4.5 Hz, H-20 cis), 2.30 (m, 4H, H-10 cis), 2.30–2.10 (m, 4H, H-10 trans); 13C NMR (125 MHz):  (ppm) 138.5–127.4 (aromatic), 75.2 (C-3), 74.9 (C-2), 74.9 (C-4), 73.8, 73.3, 71.5, 71.5 (CH2Ph), 73.6 (C-5), 72.1 (C-1), 69.2 (C-6), 33.4 (C-10 trans), and 28.4 (C-10 cis): Analysis: calculated for C72H76O10: C 78.51, H 6.95: Found: C 78.17, H 7.00. Cross-Metathesis N-(tert-Butoxycarbonyl)-2(S)-[3-(2,3,4-tri-O-acetyl--l-fucopyranosyl)] propen-1-ylpyrrolidine (46). 3-(2,3,4-Tri-O-acetyl--L-fucopyranosyl)propene (12)18 (51.4 mg, 164
mol) along with (S)-N-(tert-butoxycarbonyl)-2-vinylpyrrolidine (45)19 (64.5 mg, 327
mol, 2.0 equivalents) are dissolved in 1.4 ml of dry 1,2-dichloroethane, under a nitrogen atmosphere. Catalyst 3 (6.9 mg, 5 mol%) is then added to the solution, which is stirred for 30 min at room temperature, and then brought to reflux for 16 h. The solution is then evaporated, and the residue is chromatographed on a silica gel column [hexane–ethyl acetate, 3:1 (v/v)] to give the cis isomer (46Z) (11.9 mg, 15%) and the trans isomer (46E) (39.0 mg, 49%) as thick oils with a brown color, which can be removed by chromatographing a second 17

R. Dominique and R. Roy, Tetrahedron Lett. 43, 395 (2002). T. Uchiyama, T. J. Woltering, W. Wong, C.-C. Lin, T. Kajimoto, M. Takebayashi, G. WetzSchmidt, T. Asakura, M. Noda, and C.-H. Wong, Bioorg. Med. Chem. 4, 1149 (1996). 19 Compound 45 was made from (l)-prolinal and triphenylmethylidenephosphorane under conventional Wittig conditions. The physical data of 45 compared well with those published in: C. Serino, N. Stehle, Y. S. Park, S. Florio, and P. Beak, J. Org. Chem. 64, 1160 (1999). 18

28

preparative methods

[2]

time. The samples are stable, showing no decomposition over several months at room temperature. The expected homodimer 21 is also obtained in 22% yield and no pyrrolidine homodimer of 45 is detected. Thin-layer chromatography (TLC) (1:1 hexane–ethyl acetate): Rf: 0.67 (3), 0.62 (45), 0.53 (12), 0.32 (46Z), 0.28 (46E). Trans-N-(tert-Butoxycarbonyl)-2(S)-[3-(2,3,4-tri-O-acetyl--L-fucopyranosyl)]propen-1-ylpyrrolidine (46E). 1H NMR (500 MHz, CDCl3):  (ppm) 5.38 (2H, m, C¼CH  2), 5.27 (1H, dd, J1,2 ¼ 10.0 Hz, J2,3 ¼ 5.6 Hz, H-2), 5.24 (1H, dd, J3,4 ¼ 3.4 Hz, J4,5 ¼ 2.0 Hz, H-4), 5.17 (1H, dd, J2,3 ¼ 10.0 Hz, J3,4 ¼ 3.4 Hz, H-3), 4.25 (1H, m, 2-pyrrolidine-H), 4.18 (1H, m, H-1), 3.93 (1H, dq, J5,6 ¼ 6.4 Hz, J4,5 ¼ 1.8 Hz, H-6), 3.33 (2H, dd, J ¼ 3.7, 7.0, 5-pyrrolidine-H), 2.47 (1H, m, H-10 ), 2.17 (1H, m, H-10 ), 2.12, 2.03, 1.98 (3  3H, s, COCH3), 1.95 (1H, m, 3-pyrrolidine-H), 1.80 (2H, m, 4-pyrrolidine-H), 1.64 (1H, m, 3-pyrrolidine-H), 1.41 (9H, s, tert-butylH), 1.10 (3H, d, J ¼ 6.4 Hz, H-6). 13C NMR (125 MHz):  (ppm) 170.5, 170.1, 169.9 (3  CO), 154.5 (NCO), 133.6, 124.8 (C¼C  2), 79.0 [C(CH3)3], 72.2 (C-1), 70.7 (C-4), 68.6 (C-2), 68.3 (C-3), 65.6 (C-5), 58.2, (2pyrrolidine), 46.2 (5-pyrrolidine), 32.0 (3-pyrrolidine), 29.7 (4-pyrrolidine), 28.8 (C-10 ), 28.5 [C-(CH3)3], 20.8, 20.7, 20.6, (COCH3) 15.9 (C-6). MS: (þFAB-HRMS, m/z): (C24H38NO9þ) calculated: 484.2547: Found: 484.2559. Comments

Some of the homodimers described in this chapter show improved binding affinities with plant lectins in comparison with their corresponding monomers. For instance, the fully hydrogenated derivative of the -mannoside 13 shows Ka values of 5.3  104 M1 and 10.6  104 M1 with concanavalin A and Dioclea grandiflora lectins, respectively (methyl--mannoside, 1.2  104 M1).20 There is also strong evidence that these simple dimers form cross-linked lattices with tetrameric lectins.

20

T. K. Dam, R. Roy, S. K. Das, S. Oscarson, and C. F. Brewer, J. Biol. Chem. 275, 14223 (2000).