Recent applications of olefin metathesis to combinatorial chemistry

Recent applications of olefin metathesis to combinatorial chemistry Anthony D Piscopio
and John E Robinson Olefin metathesis has emerged as a versatile technology for the synthesis of combinatorial libraries with regard to both scaffold creation and embellishment. The incessant pursuit of ‘next-generation’ catalysts continues to raise the bar in terms of efficiency, functional group tolerability, diminished reaction times and temperatures and has helped foster both diversityoriented and target-directed efforts. This report summarizes recent contributions in the area of olefin cross-metathesis and ring-closing metathesis as applied to combinatorial and parallel synthesis. These examples include generation of dimeric benzo[b]furans as novel probes for protein–protein interaction, a cross-metathesis approach to ‘traceless linkers’ for azide-containing sugars, stereo-diversified synthesis of 1,4- and 1,5-enediols, a novel mannitol derived combinatorial scaffold, parallel synthesis strategies for aza-sugars, as well as the synthesis of dehydro-Freidinger lactams. Addresses Array BioPharma Inc., Process Chemistry Division, 3200 Walnut Street, Boulder, Colorado 80301, USA
e-mail: [email protected]

Current Opinion in Chemical Biology 2004, 8:245–254 This review comes from a themed issue on Combinatorial chemistry Edited by A Ganesan and Anthony D Piscopio Available online 6th May 2004 1367-5931/$ – see front matter ß 2004 Elsevier Ltd. All rights reserved. DOI 10.1016/j.cbpa.2004.04.001 Abbreviations CM cross-metathesis MOR mu opioid receptor RCM ring-closing metathesis

homologation of alkylidene functionality between olefins, mediated by transition-metal carbene complexes. Herein, the most recent reports (spanning the past 12 months) concerning the application of olefin CM and RCM to combinatorial library and parallel synthesis are discussed [6,7–9,10,11].

Applications of cross-metathesis Generation of benzo[b]furan dimers

The concept of employing homodimeric compounds [12] to enhance ligand-binding affinity [13] and ultimately shed light on enzymatic and cellular processes has generated considerable interest in the drug discovery arena [14,15]. Inspired by recent work from the Schreiber laboratories [16] that exploits the use of site–site interactions on solid support, Liao et al. developed a general CM strategy for the synthesis of substituted benzo[b]furan [17] homodimers. This interesting chemoptype was specifically chosen for its ubiquity in nature, broad range of biological activities and synthetic accessibility. Previously, Nicolaou and coworkers reported the solid-phase synthesis of benzofurans in a split pool fashion [18] resulting in the production of libraries of significant complexity and diversity. As shown in Figure 2, immobilized, aromatic building blocks, available from the corresponding iodides via a Sonogashira coupling, are converted to their respective benzofuran monomers 10 through a carbonylative annulation process. The immobilized monomers are then subjected to olefin CM using Grubbs’ first-generation catalyst 6 (Figure 1) to afford the corresponding crosslinked polystyrene beads. The homo-dimers 11 are then cleaved from the resin, affording the benzofurans 12 with average yields and purities of 70–80%; in most cases, E isomers predominated. This technology provides access to a wide range of structurally diverse dimeric benzofuranoid congeners suitable for biological screening.

Introduction

Stereodiversified synthesis of 1,4-enediols

The desire to synthesize both structurally related and functionally diverse collections of compounds to enhance understanding of biological activity [1], generate novel lead series [2] and optimize leads [3], has led to an increase in the application of transition-metal-catalyzed reactions in combinatorial and parallel synthesis [4]. Among these methods, olefin metathesis has emerged as one of the most widely adopted, primarily because of catalyst efficiency, accessibility and functional group compatibility [5]. As shown in Figure 1, both ring-closing metathesis (RCM) and cross-metathesis (CM) reactions can be defined as the

For the most part, diversity-oriented combinatorial synthesis has centered around the functionalization of cyclic scaffolds [19,20]. Recently, Verdine and co-workers reported a complimentary strategy for the construction of acyclic, 1,4-enediol arrays [21] to investigate the relationship between stereochemistry and mu opioid receptor (MOR) affinity in these systems [22,23]. This approach derives precedence form earlier work involving the synthesis and evaluation of related 1,5-enediols using the potent and selective MOR peptide agonist endomorphin-2 as the structural lead [24,25] (Figure 3).

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Current Opinion in Chemical Biology 2004, 8:245–254

246 Combinatorial chemistry

Figure 1

( )n R1

R1

R3 Catalyst

X

1

( )n

R2

R2 R3 X 2

Ring closing metathesis

R2

R1

R4

R3

3

Catalyst

R3

R1

4

R4

R1 5b

5a

R3

R2 5c

R4

R2 5d

Cross-metathesis

Cl Cl

PCy3 Ru Ph

PCy3

Mes N N Mes Mes N Cl Ru Cl Ph PCy3

N Mes Cl

Br

N Ru Cl N

Ph

Br 6

7

8 Current Opinion in Chemical Biology

General depiction of ring-closing/cross-metathesis reactions and ruthenium based catalysts 6–8. Mes, mesitylene (1,3,5-trimethylbenzyl).

To conduct a full biological evaluation, 16 stereoisomers of 17 were constructed via a modular approach using the building blocks shown 14(a–d)/15(a–d). The corresponding building blocks, in turn, were prepared in enantiomerically pure form using a straightforward sequence [21]. A general CM procedure was developed wherein slow addition (syringe pump) of 14 to a twofold excess of 15 produced 16aa in useful quantities (51–81%). CM products were then converted to their respective free acids and coupled to phenylalanine Rink amide AM resin. After washing and cleavage from resin, exhaustive deprotection followed by reverse phase HPLC purification cleanly afforded the desired stereoisomers. While each showed varying degrees of affinity for MOR, the (S,S,R,S)-17aa isomer had the highest affinity, with a Ki value of 14 nM. Interestingly, absolute stereochemistry in this case was not conserved relative to endomorphin-2, suggesting that the observed binding affinity was a result of the combined impact of multiple stereocenters on the ligand–receptor interaction. This strategy is noteworthy in that it is one of the first general methods aimed at stereo-diversification through CM of highly functionalized (a-substituted) allyl-containing moieties.

construction [26]. Subsequently, controlled release of the immobilized products from solid support in a nondestructive manner is of seminal importance to the overall paradigm. The desire to access azide-containing sugars [27,28] using a solid phase technique led Seeberger and co-workers [29] to consider a CM strategy based on the anticipated compatibility of the required catalysts with organo azides. To evaluate the efficacy of various combinations of metathesis catalysts and cofactors, a solution-phase model study was conducted using the monobenzyl octenediol derivative 18 (Figure 4) as a resin/linker surrogate. After identifying appropriate CM conditions, the method was successfully extrapolated to solid phase. For example, non-azide, mono-azide and bis-azide substrates were all efficiently cleaved under mild conditions and in good overall yield using catalyst 8 in the presence of 1-pentene. Interestingly, use of the highly active catalyst 8 and 1-pentene was critical, as alternate catalyst/cofactor combinations were less effective.

Cross-metathesis release of azide-containing sugars from solid support

The use of naturally occurring compounds as scaffolds in combinatorial synthesis, including peptides [30], steroids [31] and carbohydrates [32], has received considerable attention. Though carbohydrates have been widely used for this purpose, an unfortunate shortcoming is the

Solid-phase automated synthesis utilizing suitably protected monosaccharide building blocks has significantly accelerated the process of complex oligosaccharide Current Opinion in Chemical Biology 2004, 8:245–254

Applications of ring-closing metathesis Use of a mannitol-derived oxacycle as a combinatorial scaffold

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Recent applications of olefin metathesis to combinatorial chemistry Piscopio and Robinson 247

Figure 2

i Pr X Si O i Pr

CO, Pd(PPh 3)2Cl2-dppp CsOAc, DMF, 45 oC ( )4 HO 48 h

R1

X = CH2, (CH2)2CONR3 R3 = -(CH2)2OH, OH

OAc 9

OMe O

i

Pr

O ( )4

Si X O i Pr

R1 O

10 OMe iPr

6 CH2Cl2 40 oC

OMe

Si O iPr X

O R1 O

O

11

O

O

( )4 ( )4 R1

HF/Py 5% in THF TMSOMe 0.5 h

i

Pr X Si O i Pr

O OMe

O O

R2

O

R2

O O O

R1 12

R1

O

O

R1 = Ph, trityl, 4-MeOPh, 3-MeOPh 4-nBuPh, Tol, -(CH 2)3CN R2 = OH, -CH2CONHR3 75-80% Current Opinion in Chemical Biology

Synthesis of structurally diverse dimeric benzofuran congeners from immobilized aromatic building blocks. DMF, dimethyl formamide; dppp, 1,3-(bisdiphenylphosphine) propane; py, pyridine, TMSO, trimethylsilyloxy; Tol, toluene.

propensity for these highly functionalized molecules to adopt multiple conformations depending on the nature and spatial orientation of appended substituents. Conversely, fused bicyclic carbohydrate mimics typically have fewer accessible conformations allowing appended groups to be projected along pre-defined vectors [33]. Recently, Timmer et al. reported an interesting strategy for the construction and use of fused mannitol-derived oxacycles as combinatorial library scaffolds. As envisaged by the authors, maximum utility would require www.sciencedirect.com

an easily modifiable core containing an unsaturated tether/allyl ether combination to leverage an RCM/resin release manifold [34,35]. As shown in Figure 5, D-(þ)mannitol 28 was readily converted to the activated acetonide 29 via a known 3-step sequence [36]. Subsequent functionalization gave the key carboxylic acid intermediate 33, which was coupled to Rink-amide resin. Silyl group deprotection provided the corresponding alcohol, which served as the first diversity point; phosphine-mediated azide reduction (to give the corresponding amine) provided the second diversity handle. After functionalization was achieved, the immobilized Current Opinion in Chemical Biology 2004, 8:245–254

248 Combinatorial chemistry

Figure 3

HO

HO O N

+

H 3N O

N H H 13a

OH

O

H N

2 +H N 3

NH2

8

*

* * OH O

*

O

H N

O NH2

17

Endomorphin-2

t-BuO OH

SBn

BocHN

OH O (R,S)-15a

(S,S)-14a

t-BuO

Cat. 7 DCM, 40oC 53%

OH BocHN

SBn

t-BuO

OH O (R,R)-15b

(S,R)-14b OH t-BuO

SBn

BocHN OH O

OH

SBn

(S,S,R,S)-16aa

BocHN

OH O (S,R)-15c

(R,R)-14c t-BuO

HO OH BocHN

OH +H

H N

3N

OH O

(R,S)-14d

O NH2

SBn OH O (S,S)-15d

(S,S,R,S)-17aa Current Opinion in Chemical Biology

Synthesis of stereo-diverse 1,4-enediols. Asterisks denote stereocenters. Boc, N-tert-butoxycarbonyl; DCM, dichloromethane.

dienes were exposed to Grubbs’ catalyst 7. The ensuing RCM reaction delivered, as expected based on solutionphase experiments, the desired conformationally constrained bicyclic analogs. This concise strategy was applied to the synthesis of a small library of pyranofurans both validating its utility and adding to the growing list of motifs available through the simultaneous RCM/resin cleavage manifold [34,35,37]. Parallel divergent synthesis of polyhydroxylated nitrogen heterocycles

The synthesis of polyhydroxylated piperdines has attracted significant attention [38] based on the broad Current Opinion in Chemical Biology 2004, 8:245–254

potential applicability of azasugars over a wide therapeutic range [39–42]. Additionally, the recent isolation of three new biologically active fagomine isomers 40–42 (Figure 6) [43] prompted the development of a general strategy for their synthesis [44]. For example, fagomine-1 39 was identified as a selective a-glucosidase/ b-galactosidase [45] inhibitor and antihyperglycemic [46], whereas the non-naturally occurring fagomine isomer 42 was found to possess lysosomal a-galactosidase inhibitory activity in Fabry lymphoblasts [47]. Motivated by these interesting biological properties, Takahata and co-workers developed a parallel, divergent www.sciencedirect.com

Recent applications of olefin metathesis to combinatorial chemistry Piscopio and Robinson 249

Figure 4

OBn

HO 18a

O

O

OAc

OAc TMSOTf

O

DCM, -20 oC BnO BnO OAc

HO 18b

8, 1-pentene O

DCM, 0oC, 10h

OBn

20

88% (2 steps)

O

21

HN

O

O

OAc

OAc TMSOTf

O

DCM, -20 oC BnO BnO OAc

23

O

BnO BnO

O N3

8, 1-pentene O

DCM, 0oC, 10h

N3

82% (2 steps)

O N3 OBn

TMSOTf

O

o

DCM, -20 C

AcO

N3 OBn O 25

N3

( )n

24

N3

N3 OBn 8, 1-pentene

O

N3 26

O AcO

O

CCl3

O

18b

O

BnO BnO

HN

22

HO

( )n

CCl3

OBn

19

18b

O

OBn

O

BnO BnO

HO

O

BnO BnO

o

DCM, 0 C, 10h 85% (2 steps)

O AcO

O

N3

( )n

27

CCl3

HN Current Opinion in Chemical Biology

A cross-metathesis strategy for the synthesis of azide-containing sugars. DCM, dichloromethane; TMSOTf, trimethylsilyl trifluoromethanesulfonate.

strategy for the rapid synthesis of hydroxypiperidines starting from a common, unsaturated piperidine derivative 47 which in turn, was readily available via RCM of the corresponding diene 46 (Figure 6) [48]. Stereodivergence was achieved through a random epoxidation event, followed by both acid and base promoted hydrolyses to give the corresponding isomeric diols; stereorandom dihydroxylation delivered two additional isomeric congeners. www.sciencedirect.com

Freidinger lactams: b-turn mimetics The in vivo modulation of protein–protein interactions remains at the forefront of the pharmaceutical industry [49]. While several biologically active proteins have been commercialized, the general applicability of proteins as therapeutics has been mired due to their poor physiochemical properties, lack of cellular permeability, rapid clearance and degradation, antigenicity and systemic toxicology. Protein Current Opinion in Chemical Biology 2004, 8:245–254

250 Combinatorial chemistry

Figure 5

O R

O

RCM

R

( )n

( )n

O

HO HO HO

O

OTs

OTs

O O

OH OH OH

3 Steps

HO

O

ii. TDDPSCl

O

21%

85% (2

28

O

i. NaN 3, TBAI HO

steps)

O

29

30 i. TFA ii. Trityl-Cl iii. Allyl bromide

O N3

OH N3

( )9 i. Dess-Martin

O

OH

TBDPSO

33

O

80% (2

72% (3

steps)

TBDPSO

TBDPSO

O 31

i. TBAF (89%) ii. BOPCl, DiPEA O

O

Steps)

O 32

Cat. 7 DCM, reflux 99% (2 steps) N3

O

TiPSH, TFA

ii. BrPh 3(CH2)10COOH TBDPSO

OTr

N3

O

NH2

H

N3

H O

O

H N

( )9

N3

( )9

HO

34

O

H N O

R1-NCO, TEA, 16h

36 O

O

O O

35

HN R1 i. Me 3P, THF; H 2O ii. R 2-C(O)Cl, DiPEA, 16h

O R2

O

O NH O

R2

H

O H O O HN 38 R1

( )9

NH O

Cat. 7 DCM, reflux 16

H N

O

O

h

O HN R1

37

Current Opinion in Chemical Biology

The construction of fused mannitol-derived oxacycles for use as novel combinatorial scaffolds. BOPCl, bis(2-oxo-3-oxazolidinyl) phosphinic chloride; DiPEA, diisopropylethyl amine; TBAF, tetrabutylammonium fluoride; TBAI, tetrabutylammonium iodide; TBDPS, tertbutyl(diphenyl) silane; TBDPSCl, tertbutyl(diphenyl)silyl chloride; TEA, triethylamine; TFA, trifluoroacetic acid; TiPSH, triisopropyl silane.

Current Opinion in Chemical Biology 2004, 8:245–254

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Recent applications of olefin metathesis to combinatorial chemistry Piscopio and Robinson 251

Figure 6

N H

OH

39

N H

OH OH

OH

OH N Boc OTBDPS 47

OH

OH

OH

N H

OH

40

OH N H

OH

41

OH

42

CHO O

NBoc

Ph3P+CH3INaN(TMS)2, THF 63%

43

NHBoc OTBDPS

i. TsOH-MeOH O

NBoc

ii. TBDPSCl, DMAP

45

72%

44

i. TFA ii. 4-bromo-1-butene iii. (Boc) 2O O

O Oxone +

N Boc OTBDPS 49 60%

N Boc OTBDPS 48 30%

Grubbs' catalyst X

CF3COCH3, NaHCO3 Na2-EDTA, MeCN

H2SO4 dioxane, H 2O

H2SO4 dioxane, H 2O

KOH dioxane, H 2O

OH

OH

OH

OH N H 41

OH

39 75%

OH

33% + 1 (44%)

N H

N Boc 50

OH

OH

41 82% + 1 (17%)

OH i. OsO 4, TMEDA ii. 35% HCl

OH OH

N H

N Boc OTBDPS 46

97%

97%

i. K 2OsO4, NMO ii. 10% HCl

OH

OH

CH2Cl2

N Boc OTBDPS 47 TBAF

N H

60%

OH OH

N H

OH

42

42

87%

56%

OH

OH N H

OH

40 30% Current Opinion in Chemical Biology

A parallel divergent strategy for the synthesis of poly-hydroxylated piperdine derivatives. DMAP, 4-(Dimethylamino)-pyridine; EDTA, ethylenediamine tetraacetic acid; TBDPSCl, Tertbutyl(diphenyl)silyl chloride; TMEDA, N,N,N0 ,N0 -tetramethylethylenediamine.

secondary structural motifs, b-turns in particular, have been identified to play critical roles in molecular recognition and thus represent an opportunity for evaluating protein function through the use of relatively low molecular weight b-turn mimetics. This provided the impetus for the development of a high speed, solid-phase strategy [50] for the synthesis of Freidinger lactams, as shown in Figure 7. This diversity-oriented two-step resin capture/RCM release strategy allowed rapid access the desired products in good overall yields and purity. www.sciencedirect.com

More recently, Gmeiner and co-workers [51] extended the RCM approach to a series of medium-sized Freidinger-type lactams as shown in Figure 8. In addition, the authors demonstrated the ability of these compounds to potentially stabilize b-turns as evidenced through FT-IR and NMR studies.

Conclusion Ruthenium-carbene-catalyzed olefin metathesis has emerged as a versatile technology for combinatorial and parallel synthesis in solution and on solid-phase. Current Opinion in Chemical Biology 2004, 8:245–254

252 Combinatorial chemistry

Figure 7

O O

H

NC

tBuO

O NHt-Boc

i-Pr

HN

Ph

O Me O NH2

Me

H N

51 HO2C

N

NHt-Boc

52

Me OtBu

N H

i-Pr

O

O Cat. 6 1,2-Dichloroethane, 80oC

O

O NH3+ TFA -

HN

O Me O N i-Pr

NHt-Boc HN

TFA, CH 2Cl2 Me OH

N H

O Me O

RT, 16h N

55% Overall

i-Pr

O

Me N H

OtBu O

53

54

Current Opinion in Chemical Biology

High speed, solid-phase strategy for the synthesis of Freidinger lactams.

Figure 8

R2 n( )

NMM, ClCO2iBu

OH

BocHN

or DCC, HOBT, DIEA

O

n(

)

) N

BocHN O

59

Cat. 6 or 7

R2 CO2R1

n(

n(

) ( )n N

CO2R1

BocHN O

R 60

R

61 R2

N

CO2R1

BocHN O

R

R = R2 = H, R1 = Et R = R1 = Me, R2 = H R = H, R1 = Et, R2 = Me

N BocHN O

R

R = H = H, R1 = Et R = R1 = Me

O N OR1

BocHN

70% 60%

O 86%

68% 42% 89%

O

O OEt

BocHN

N

OEt

O 8% Current Opinion in Chemical Biology

RCM approach to a series of medium-ring Freidinger lactams. DIEA, Diisopropylethyl amine; HOBT, 1-hydroxybenzotriazole hydrate; NMM, N-methyl morpholine. Current Opinion in Chemical Biology 2004, 8:245–254

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Recent applications of olefin metathesis to combinatorial chemistry Piscopio and Robinson 253

Incremental improvements in catalyst effectiveness have rendered compounds that were once considered too complex for synthesis in a library format readily accessible. New constructs, however, will be needed to overcome current limitations regarding catalyst loading, stability, E,Z selectivity and compatibility.

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