Accepted Manuscript Polymer Supported Synthesis of a Natural Product-Inspired Oxepane Library Sudipta Basu, Herbert Waldmann PII: DOI: Reference:

S0968-0896(14)00388-5 http://dx.doi.org/10.1016/j.bmc.2014.05.039 BMC 11600

To appear in:

Bioorganic & Medicinal Chemistry

Received Date: Revised Date: Accepted Date:

25 March 2014 14 May 2014 16 May 2014

Please cite this article as: Basu, S., Waldmann, H., Polymer Supported Synthesis of a Natural Product-Inspired Oxepane Library, Bioorganic & Medicinal Chemistry (2014), doi: http://dx.doi.org/10.1016/j.bmc.2014.05.039

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Polymer Supported Synthesis of a Natural Product-Inspired Oxepane Library Sudipta Basu and Herbert Waldmann*

* Prof. Dr. H. Waldmann, Dr. Sudipta Basu Max-Planck-Institut für molekulare Physiologie, Otto-Hahn Strasse 11, 44227 Dortmund (Germany) and Technische Universität Dortmund, Fachbereich Chemische Biologie, Otto-Hahn-Str. 6, 44227 Dortmund, Germany Fax: (+49) 321-133-2499 E-mail: [email protected]

Abstract Natural product inspired compound collections are prevalidated due to the evolutionary selection of the natural product scaffolds. Their synthesis requires the development of novel strategies amenable to formats suitable for library build-up. We describe a method for the synthesis of an oxepane library inspired by the core structure of oxepane natural products endowed with multiple bioactivities. Core aspects of the strategy are the establishment of a one-pot method employing different immobilized scavengers, the employment of an enyne ring closing reaction and diversification by means of different transformations, e. g. cycloadditions and cross-metathesis reactions. In total, a collection of 115 oxepanes was obtained in 5-6-step reaction sequences.

1

Introduction Biologically active natural products are a source of inspiration for the development of compound libraries based on prevalidated scaffolds.1,2 In this context, the canonical solution synthesis of compound libraries using solid supported reagents and scavengers is a powerful technique for chemical biology and medicinal chemistry research. 2 The oxepane scaffold occurs widely in natural products with a broad range of interesting biological activities (Figure 1). For instance, the Heliannual family contains benzoxepane systems having allelopathic and phytotoxic activities,3 the sodwanone family, isolated from marine organisms, contains dimeric keto oxepane scaffolds and shows activity against human tumor cell lines.4 The halogenated marine toxins regioloxepane A and isolaurepinnacin are representative memberes of the Laurencia-derived C15 acetogenins containing α, α’-disubstituted oxepane rings.5 (+)-Zoapatanol is one of the numerous diterpenoid oxepanes isolated from leaves of the Mexican plant Montanoa tomentosa.6 Tea prepared from extracts of the leaves has long been used as a contraceptive in ancient time and recent studies indicate that zoapatanol metabolites might be responsible for the antifertility activity.7 Due to the manifold biological activities of these compounds, their underlying structural architectures may be regarded as biologically pre-validated and as promising guiding scaffolds for natural product inspired compound library development. In developing the concept of Biology Oriented Synthesis (BIOS)8, we have devised synthesis methods that give efficient access to natural product inspired compound collections.9 Among these, the oxepane scaffold had attracted our attention as well.9e

2

O HO HO

HO

H

O

O H

OH O

O

OH

OH Heliannuol C

Heliannuol B

Sodwanone S

Allelopathic and Phytotoxic

Active aginst Human Tumor Cell Lines

OR1 HO R

O

Br

O R = (CH3)2C=CHCH2- , R1 = H, Zoapatanol Antifertility activity

H

O

H

Cl

Br

(+)-Regioloxepane A

H

O

H

Cl

Isolaurepinnacin

Marine Toxin

R = (CH3)2CHC(CH3)=CH-, R1 = H, Montanol R = (CH3)2C(OH)CH=CH-, R1 = Ac, Tomentol R = H2C=C(CH3)CH(CH3)CH2-, R1 = H, Tomentanol

Figure 1: Natural products having different biological activities containing oxepane scaffold.

Here we report in full detail the development of a practical and efficient polymersupported solution phase parallel synthetic route to a compound library focused on the highly substituted oxepane scaffold. The key step of the method includes a ring-closing enyne metathesis reaction.10

Results and discussion The retrosynthetic analysis of the oxepane library 1 is shown in the Scheme 1. It was planned to access the oxepane core 1 by ring-closing enyne metathesis from the open chain precursors 2 as key transformation. The open chain enyne precursors 2, homoallyl alcohols, can be obtained from the aldehydes 3, in diastereomerically pure form using the asymmetric Brown allylation. Aldehydes 3 could be generated from the esters 4 by controlled reduction. Intermediates 4 can be synthesized from the easily available building blocks 5 and 6, which are the starting points of the synthetic route.

3

Ring-closing enyne metathesis

HO

Asymmetric Brown Allylation

HO

2

3

R

O 1

R

R

R1

3

R R1

O

O O

H

2

R3 R1

R2

3

2

Reduction

O Br

O R3 5

+

O

Coupling

HO R2

R1

O

6

O 2 R3 R1 R

4

Scheme 1: Retrosynthetic analysis of focused oxepane core 1.

Strategy for the synthesis of oxepane library 1 Keeping the retro-synthetic blue print in mind, the synthesis commenced by coupling of the substituted propargyl alcohols 6 and the substituted α-bromo ethyl acetates 5 (Scheme 2). When the alcohols 6 were deprotonated using sodium hydride as base in THF at 0 oC and coupled with 5, the ethers 4 were formed in 70-80 % yield depending on the building blocks 5 and 6 used.11 The ethers 4 were purified by means of silica gel chromatography. The ethyl ester in 4 was reduced in a controlled manner using diisobutyl aluminiumhydride (DIBAL-H) in diethyl ether at -78 oC for 20 minutes to afford the aldehydes 3. Application of THF or CH2Cl2 for this reduction proved to be unsuitable because in those solvents a 1:1 mixture of the desired aldehydes 3 and over reduced alcohols were formed. The over reduced alcohols were removed by chromatography. All attempts to oxidize the alcohols to the desired aldehydes 3 were unsuccessful due to decomposition. The aldehydes 3 were then allylated using Brown’s asymmetric allylation procedure.12 The chiral allyl borane reagent was prepared in situ by treating either (+)- or (-)- B-chlorodiisopinocampheylborane (DIPCl) and allyl magnesium chloride at -78 oC to room temperature. When either of (+)- or (-)- diisopinocampheylallyl borane (Ipc2Ballyl) reagents was treated with aldehydes 3 in THF at -78 oC, the homoallyl alcohols 2 were formed stereoselectively. As soon as the reaction was complete (determined by

4

TLC), the excess allylmagnesium chloride was scavenged using polystyrene supported sulfonic acid resin 7 or the cation exchange sulfonic acid resin DOWEX® 50WX8-200 (8).13 The resin was filtered and the crude products 2 were obtained after evaporating the solvent. The diastereomeric excess was determined by means of 1H NMR spectroscopy of the crude products. With aldehyde 3a (R1 = n-pentyl, R2 = H, R3 = H) and using (+)DIPCl, the expected homoallyl alcohol 2a was obtained in 8:1 diastereomeric ratio (syn:anti = 8:1). Under the same conditions (-) –DIPCl yielded the other diastereomer in only 2.5:1 diastereomeric ratio (anti:syn = 2.5:1). It was assumed at this point that the Brown asymmetric allylation proceeded with the expected stereoselectivity as predicted by Brown et al12 and confirmed later by the nOe measurements of a particular member of the oxepane library (Figure 2). Thus, use of the chiral allylborane formed from (+) DIPCl is a “matched” case and from (-)-DIPCl is a “mismatched” case for aldehyde 3a. It was also observed that the polymer bound sulfonic acid resin 7 gave better results than the DOWEX® 50WX8-200 cation exchange resin 8. Impurities in the commercially available resin 8 contaminated the product mixture and had to be removed by chromatography before proceeding to the next reactions. But in the case of polymer bound sulfonic acid resin 7, the impurities were negligible and the product was sufficiently pure to proceed for the next reactions. The following reactions were carried out using the isomeric mixtures of the homoallyl alcohols without any further purification.

5

O

NaH, THF, 0 o C to rt, 10h, 70-80%

HO R2

1

R

O 3

O

6

O DIBAL-H, Et2O, -78 oC

O R R 4

Br

O

1

R2

2 R R1 R 3 3a = R1 = -(CH2)4CH3, R2 = -H, R3 = -H

20 min

3

3 5 R

O 4

R N C O 18

or

Cl 19

R4

MgCl

THF, -78 oC to rt 4h

9 1. CDI, CH2Cl2, 10h

R

5

R X

O

2

O

CH2Cl2, reflux, 18h or

2. K2CO3, THF: DMF (4:1) R5R4NH (17), rt, 5h HO

R O R3

2

R

then 7 or 8 rt, 4h

R1

O

3

R

Y

O

OH O R3 R1 2

10 CH2Cl2, Reflux, 3h-18h

R1

1

12: X = -CH213: X = -NHO

OH (d.r. = 8:1)

Toluene, 70 oC, 3h-10h 15% to 50% after 5 or 6 steps

1

2b = R = -(CH2)4CH3, R2 = -H, R3 = -H OH (d.r. = 2.5:1)

PCy3

R4 X R5

O

Y

SO3 H

H

O O R3

Ru

Cl

8

PCy3 9

PCy3 Cl

R2 O

Cl

DOWEX 50WX8-200

7

H

R1

Cl

15: X = -CH216: X = -NH-

Ru

R2

2a = R1 = -(CH2)4CH3, R2 = -H, R3 = -H

then 11, rt, 10h

20

O H

then 7 or 8 rt, 5h

(+) DIPCl or (-) DIPCl

Py, THF, rt, 6h then 14, rt, 6h

4

O

H

PPh2 Ph

N PPh2

PCy3

NH2 14

11

10

Oxepane Library 1 NH2

5a: R3 = -H 5b: R3 = CH3 5c: R3 =

CH3

NH2

NH2

O n NH2

HN

Y

O

Z

20 n n = 5 (17g) Z = CH2 (17j) Y = NH (20a) O n = 1 (17e) n = 10 (17h) Z = O (17k) R = -H (17a) 6a: R1 = -(CH2)4CH3, O n = 2 (17f) n = 11 (17i) Z = N-4-FPh (17l) Y = NPh (20b) 2 R = 3-Cl (17b) Y = O (20c) R = -H R = 3-F (17c) 17d NCO NCO 6b: R1 = R2 = -(CH2)5O CO2Me 6c: R1 = R2 = -CH3 R COCl 1 2 n 6d: R = R = -H R COCl n = 8 (19h) COCl COCl n = 12 (19i) CO2Me R = -H (19a) 18a R = -H (18b) O R = 4-OMe (19b) R = 4-Cl (18c) 20e R = 2-F (19c) R = 2,4- di-OMe (18d) 20d R = 4-Me (19d) 19g R = 3,4- di-Cl (19e) 19f R

Scheme 2. Synthesis of Oxepane Library 1.

6

The crude enyne precursors 2 were then subjected to the decisive enyne metathesis reaction. When intermediates 2 were treated with polymer supported 1st generation Grubbs catalyst 914 (loading = 0.11 mmol/g, 2 x 40 mol%) in refluxing CH2Cl2, the oxepanes 1 were formed. After the reaction was complete (monitored by TLC), the resin was filtered and the solvent was evaporated to obtain the colorless crude products 1. In this reaction the catalyst loading is too low (0.11 mmol/g) for the synthesis of an entire library. So an alternative method was implemented to scavenge the ruthenium. Precursors 2 were treated with 1st generation Grubbs catalyst 10 (20 mol%) in refluxing CH2Cl2. As soon as the reaction was complete (monitored by TLC), the resin 1115 (20 equiv. relative to the metal catalyst used) was added to scavenge the ruthenium. After filtration through a silica gel pad the solvent was evaporated to furnish the colorless crude products 1. The strategy to scavenge ruthenium from the metathesis reaction developed by Breinbauer et. al.15 turned out to be efficient and inexpensive for library generation. The oxepanes 1 were formed in the same diastereomeric ratio already displayed the precursors 2 which indicates that the configuration of the enyne precursor 2 was translated into the cyclic product 1 after the ring-closing enyne metathesis. The diastereomeric excess was determined by means of 1H NMR spectroscopy of the crude products. At this point, the oxepane scaffold was ready for diversification to generate a fully functionalized oxepane library 1. The free alcohol in 1 was functionalized as ester and carbamate. Hence oxepane 1 was treated with different commercially available carboxylic acids (3 equiv. relative to the alcohol 1) in CH2Cl2 using either dicyclohexylcarbodiimide (DCC) or its solid supported analogue, N-cyclohexyl-carbodiimide, N’methyl polystyrene, dimethylamino pyridine (DMAP) as catalyst,16 but esters 12 were not formed. As more reactive coupling partners, acid chlorides were then chosen. When alcohol 1 was treated with commercially available acid chlorides 19 (3 equiv relative to the alcohol 1) in THF in the presence of pyridine as base, the esters 12 were formed. The same reaction conditions were used to synthesize the carbamates 13 from alcohol 1 using different commercially available isocyanates 18 (3 equiv relative to the alcohol).17 In both cases excess acid chlorides and isocyanates were scavenged from the reaction mixture using aminomethylated polystyrene scavenger 14 (6 equiv. relative to the acid chlorides and 3 equiv relative to the isocyanate). Esters or carbamates were not formed in

7

the presence of polymer-supported pyridine as base. Excellent reactivity was observed using aromatic isocyanates (e.g. naphthyl 18a and phenyl isocyanate 18b), but a sluggish reaction was experienced in case of 2,4-dimethoxy phenyl isocyanate 18d. Tertiary-butyl isocyanate and tertiary-butyl isothiocyanate were unreactive under these reaction conditions. In case of ester formation, aliphatic acid chlorides (19f-i) are more reactive than the aromatic acid chlorides (19a-e). Among the aromatic acid chlorides, the orthosubstituted acid chloride 19c showed lower reactivity due to steric hindrence. Electron donating substituents on the aromatic ring (19b and 19d) reduced reactivity whereas electron withdrawing substituents (19e) led to higher reactivity. To introduce higher diversity in the oxepane library a two step carbamate synthesis protocol was implemented. To this end, alcohol 1 was treated with 1,1’carbonyldiimidazole (CDI) in CH2Cl2 to obtain a imidazolyl carbamate intermediate which was immediately heated in a sealed tube at 40 oC with commercially available primary amines in CH2Cl2, using triethylamine and catalytic amounts of DMAP. The carbamates 13 were formed after 48h.18 As this reaction appeared to be sluggish, a stronger base (K2CO3) was used with different primary and secondary amines 17 in THF:DMF (4:1) at room temperature for 5h (determined by TLC). The excess potassium carbonate and amines were scavenged by polymer-supported sulfonic acid resin 7 or 8. After filtration of the resin and evaporation of the solvent the crude carbamates 13 were obtained. In this scavenging technique again the sulfonic acid resin 7 was preferable over 8 because of the described impurity problem. This two step protocol appeared to be suitable because a wide range of primary and secondary amines can be used. All primary and secondary amines showed similar reactivity in this reaction. It was noted that the secondary amines (17j-l) are slightly less reactive than the primary amines (17a-i) because of steric hindrance. For diversification of the crude diene esters 12 and carbamates 13 were treated separately with different dienophiles 20 in toluene at 70 oC to afford the fully substituted oxepanes 15 and 16 respectively in 15-50% overall yield after 5 steps (for 15) or 6 steps (for 16). The products were isolated by column chromatography as single isomers (entries 11-14, 21-30, 32, 34, 35, 39, 40, 42, 44-46, 49-51, 56-58, 62-64, 66, 67, 74-76 in Table 1) as well as the inseparable mixtures of two isomers (entries 1-10, 15-20, 31, 33, 36-38, 41,

8

43, 47, 48, 52-55, 59-61, 65, 68-73 in Table 1) . The isomeric ratios of the oxepanes were determined by means of 1H NMR spectroscopy (see the Supporting Information). All oxepanes prepared as shown in Scheme 2 are given in Table 1. Among the different commercially available dienophiles used, the maleimide (20a), Nphenyl maleimide (20b) and maleic anhydride (20c) reacted very fast and the reactions were complete within 3h of heating in toluene. But in the case of p-benzoquinone (20d) and dimethyl acetylene dicarboxylate (20e), the reactions were sluggish (complete after 10h of heating). Using p-benzoquinone (20d) as dienophile, the hydroquinone product was obtained after purification, which suggests that the initial Diels-Alder adduct was aromatized in the reaction condition.

9

Table 1. Oxepane Library 1. Y

H

H

H

R4 3

R

Entry 1.

R1 -(CH2)5-

R2 -(CH2)5-

O

R2 R1

R3 -H

R4

Y H

N O

2.

-(CH2)5-

-(CH2)5-

H

H N

-H

H

O

H

-(CH2)5-

-(CH2)5-

-H

Ph

H N

H

O

H

-(CH2)5-

-(CH2)5-

H

Cl

-H

O

O O

N Ph

O

4.

COOH

N Ph

5 O

3.

COOH

O

O

HN

H

Yielda 34 % (after 6 steps) d.r. = 4:1 32% (after 6 steps) d.r. = 8:1 40% (after 6 steps) d.r. = 7.5:1

O COOH COOH

15% (after 6 steps) d.r. = 5:1

O

5.

-(CH2)5-

-(CH2)5-

-H

H N

O

N Ph

O

6.

-(CH2)5-

-(CH2)5-

H

O

-H

H

O H N

7.

-(CH2)5-

-(CH2)5-

-H

O N

10

H

O

H

O

O O

O O N Ph

O O

O

N Ph H

O

32% (after 6 steps) d.r. = 8:1 32% (after 6 steps) d.r. = 8:1 34% (after 6 steps) d.r. = 8:1

8.

-(CH2)5-

-(CH2)5-

Cl

-H

H

O N Ph

HN

O H O

9.

-(CH2)5-

-(CH2)5-

-H

Ph

H N

H

O O

10.

-(CH2)5-

-(CH2)5-

H N

-H

H H

O

5 O H

11.

-CH3

-CH3

-H

O

H

N

-CH3

-CH3

-H

H

-CH3

-H

Ph

COOH COOH COOH O

O O

O H

H N

H

O

O O

H

14.

-CH3

Cl

-H

15% (after 6 steps) d.r. = 7:1 30% (after 6 steps)

22% (after 6 steps)

20% (after 6 steps)

NH

O

-CH3

20% (after 6 steps) d.r. = 4:1

NH

O

-CH3

COOH

NH H

N

13.

O

O O

12.

32% (after 6 steps) d.r. = 6:1

H

O O

16% (after 6 steps)

NH HN

O H

O

H

O

O

15.

-CH3

-CH3

H N

-H

O

NH

5 O H

16.

-(CH2)5-

-(CH2)5-

-H

Ph

H N

H

O

H

17.

-CH3

-CH3

Cl

-H

O O N Ph

O H

O

O H O

11

29% (after 6 steps) d.r. = 3:1

O

NH HN

31% (after 6 steps) d.r. = 3:1

O

22% (after 6 steps) d.r. = 4:1

18.

-CH3

-CH3

-H

H

O N

O

NH

O

19.

-CH3

-CH3

H

-H

H N

O

-CH3

-CH3

H

O

-H

H

O H N

-CH3

-CH3

H N

-H

H

H

O O

H

22.

-H

-H

-H

H N

O

-H

-H

H

H N

-H

H

O

H

-H

-H

-H

H

O O

N

-H

-H

H N

-H

H H

O

H

(CH2)4CH3

-H

-H

H

O N

O

(CH2)4CH3

-H

H

F

-H

16% (after 6 steps)

COOH O

O O

O O

O O

O O

O OH

O

HN O

12

COOH

20% (after 6 steps)

26% (after 6 steps)

30% (after 6 steps)

20% (after 6 steps)

16% (after 6 steps)

NH

O

27.

O

NH

5 O

26.

30% (after 6 steps) d.r. = 3:1

NH

O

25.

15% (after 6 steps) d.r. = 3.8:1

NH

O

24.

15% (after 6 steps) d.r. = 3:2

NH

O

23.

O O NH

O O

21.

O O NH

O

20.

O

OH

15% (after 6 steps)

28.

(CH2)4CH3

-H

O

-H

H

O H N

(CH2)4CH3

-H

H N

-H

16% (after 6 steps)

NH

O

H

O

29.

O

O

OH

O

15% (after 6 steps)

5 O OH

30.

(CH2)4CH3

-H

OH

Cl

-H

HN

O OH

O

31.

(CH2)4CH3

-H

H N

-H

H

O

H

(CH2)4CH3

-H

Cl

-H

HN

(CH2)4CH3

-H

20% (after 6 steps)

OH

Cl

-H

O OH

16% (after 6 steps) d.r. = 25:1

O O

33.

O NH

O

32.

15% (after 6 steps)

H

HN

O

H

COOH COOH

15% (after 6 steps) d.r. = 3:2

O

34.

(CH2)4CH3

-H

F

-H

H

HN

O

H

COOH

20% (after 6 steps)

COOH

O

35.

(CH2)4CH3

-H

H N

-H

O

H

H

36.

(CH2)4CH3

-H

Ph

H N

O

H

O H

13

23% (after 6 steps)

NH

10 O

-H

O

O

COOH COOH

41% (after 6 steps) d.r. = 3:2

37.

-CH3

-CH3

-H

F

H

COOH

N N

O

H

COOH

25% (after 6 steps) d.r. = 6:1

O

38.

(CH2)4CH3

-H

H N

-H

H

O

O NH

5 O H

39.

(CH2)4CH3

-H

H N

-H

H

O

O O

H

(CH2)4CH3

-H

H N

-H

H

O

O O

H

(CH2)4CH3

-H

O

-H

24% (after 6 steps)

NH

11 O

41.

31% (after 6 steps)

NH

O

40.

29% (after 6 steps) d.r. = 2.6:1

H

O H N

O

H

O COOH COOH

15% (after 6 steps) d.r. = 4:1

O

42.

(CH2)4CH3

-H

-H

H N

O

(CH2)4CH3

-H

H

Cl

-H

O OH

Cl O O

44.

(CH2)4CH3

-H

H N

-H

20% (after 6 steps)

NH

O

43.

O

O

OH OH

30% (after 5 steps) d.r. = 4:1

20% (after 5 steps)

O

45.

(CH2)4CH3

-H

12

-H

O

OH O O O

O

O

14

44% (after 5 steps)

46.

(CH2)4CH3

-H

CH 3

OH

H

O N Ph

H

47.

(CH2)4CH3

-H

O O

O

HN

(CH2)4CH3

-H

CH 3

O

49.

(CH2)4CH3

-H

H

H N

O O

O

32% (after 5 steps) d.r. = 8:1

O

O

48.

O

O

CH 3

70% (after 5 steps)

CH 3

O N Ph

H H

O O N Ph

O

HN

H

50% (after 5 steps) d.r. = 8:1 60% (after 5 steps)

O

O

50.

(CH2)4CH3

-H

O

CH3

O

O O

O

51.

(CH2)4CH3

-H

O OH

Cl

-H Cl

26% (after 5 steps)

60% (after 5 steps)

O O

52.

(CH2)4CH3

-H

OH H

F

-H

COOH

O

53.

(CH2)4CH3

-H

O 12 O

-H

H H

O

54.

(CH2)4CH3

-H

H H

Cl

-H Cl

O

H

COOH COOH COOH

COOH COOH

21% (after 6 steps) d.r. = 8:1 25% (after 6 steps) d.r. = 9:1 24% (after 6 steps) d.r. = 6.5:1

O

55.

(CH2)4CH3

-H

H

-H

COOH

O O

15

H

COOH

20% (after 6 steps) d.r. = 6:1

56.

(CH2)4CH3

-H

12

-H

O

O

O O

O

57.

(CH2)4CH3

-H

O O

-H HN

O O

O

(CH2)4CH3

-H

O

-H O

O O

O

59.

(CH2)4CH3

-H

O O

-H O

O O

O

60.

(CH2)4CH3

-H

16% (after 5 steps)

O

O

58.

28% (after 5 steps)

O O

-H O

O O

O

32% (after 5 steps)

25% (after 5 steps) d.r. = 4:1

25% (after 5 steps) d.r. = 8:1

O

61.

(CH2)4CH3

-H

H N

-H

O O

Cl

62.

(CH2)4CH3

-H

H

H

H N

-H

O

H

H

(CH2)4CH3

-H

COOH O N Ph

O

63.

COOH

-H

H

O O N Ph

HN

O

H

26% (after 6 steps) d.r. = 6:1 32% (after 5 steps)

30% (after 5 steps)

O

O

64.

(CH2)4CH3

-H

OH

O

-H

O O OH

16

17% (after 5 steps)

65.

(CH2)4CH3

-H

OH

CH3

H

O N Ph

H

66.

(CH2)4CH3

-H

OH

CH3

H

O O N Ph

H

67.

(CH2)4CH3

-H

12

-H

70% (after 4 steps)

O

OH

O

60% (after 4 steps) d.r. = 8:1

23% (after 5 steps)

O OH

68.

(CH2)4CH3

-H

-H

OH

H

O N Ph

H

69.

(CH2)4CH3

-H

OH

CH3

H

O O N Ph

H

70.

(CH2)4CH3

-H

50% (after 4 steps)

O

O

OH

CH3

65% (after 4 steps) d.r. = 20:1

O O

55% (after 4 steps) d.r. = 2.8:1

O

71.

(CH2)4CH3

-H

H N

-H

H

O

5 O

72.

-CH3

-CH3

H N

-H

10

73.

-(CH2)5-

-(CH2)5-

-H

O O

H H

O N

-H

-H

H N

-H

H

O

H

COOH COOH COOH COOH

O NH

O H

17

COOH

O O

74.

H H

COOH

O

27% (after 6 steps) d.r. = 4:1 20% (after 6 steps) d.r. = 6:1 10% (after 6 steps) d.r. = 4:1 25% (after 6 steps)

-H

75.

-H

-H

F

H N

O

H

O

(CH2)4CH3

-H

28% (after 6 steps)

NH

N

76.

O

O OH

-H O

20% (after 5 steps)

O

77.

(CH2)4CH3

-H

-H

OH H O

F

NH

N N

O O

a

Isolated yield after column chromatography, d.r. = diastereomeric ratio.

18

H

O

22% (after 6 steps)

The Diels-Alder adduct with electron withdrawing dienophiles 20 was formed with endoselectivity. The relative stereochemistry of one of the library members was determined by nOe experiments as shown in Figure 2.

nOe H N

O

O O

H HN

O O

6 7

O

O

11 H H 10 H 9 5 4 8 2 3

HN

O

H

nOe

H

H

H 5 4 11 9 6 O 3 10 7 2 8 O O H O H N 1 H

O

1 H

O

nOe endo-product

endo-product

Figure 2. nOe study of a oxepane library member.

In this nOe experiment protons H2, H4 and H6 were irradiated in their resonance frequency and the signal enhancements observed are shown in Table 2. Table 2. nOe irradiation and intensity of the protons.

Irradiation at

Signal enhancements of protons

H6

H4 (5.0%), H5 (3.0 %)

H4

H6 (6.0%), H11 (3.0%), H5 (3.0%)

H2

H8 (4.0%), H7 (2.0%)

From the nOe experiment it was evident that the Brown asymmetric allylation proceeded with the expected stereochemistry. The Diels-Alder reaction also proceeded with endoselectivity. Based on this experiment the configuration of the other library members was assigned by analogy. In the Diels-Alder reaction the diene can react through four possible transition states (a, b, c, d, Scheme 3) with the dienophile. When the Diels-Alder reaction proceeds through exo-transition state d, the dienophile approaches from the less sterically hindered and more favorable face of the diene, giving rise to the exo-adduct D. When the

19

dienophile approaches from the face occupied by the bulky n-pentyl group, steric hindrance renders the exo-transition state c less favorable. O H

R HN

Y

O H R HN

H

O O

O H

H

O

O

Y

O

O

H N R

O

O

H O

b endo-TS less favorable TS

H a endo-TS more favorable TS O

R HN

O H

O

O

O

H

O H N R

OO

O

Y

R HN

O O

O

O

O

Y H

c exo-TS less favorable TS

Y

H H

O

H

O

H

O

H

H N R

O

Y

O H

H

Y

H

H

O

H

O

H

H N R

O O

H

H

O

H

Y O

H

A endo-product

endo-product

O

O

H

O

B

Y

O d exo-TS more favorable TS

O H

H

O H

R HN

H

O O

C exo-product

O

O

Y

H H H

D exo-product

Scheme 3. Endo-transition state for the Diels-Alder reaction.

20

In transition state b the dienophile approaches from the side occupied by the bulky pentyl group, encountering a steric hindrance and hence making b a less favorable transition state. In transition state a, the dienophile approaches from the face opposite to the bulky n-pentyl group. Thus, transition state a is less sterically hindered and more favorable giving rise to the desired product A. The nOe study described above rules out the possibility of the exo-transition states (c and d) and also the more sterically hindered transition state b. Hence the only product A was obtained from this Diels-Alder reaction through the more favorable endo-transition state a. Interestingly, we did not detect any thermodynamically stable exo-product (D) through transition state d. We anticipate that kinetically controlled endo-product (A) formation was more favorable as the oxepane diene is not electronically rich leading to slow reaction kinetics even at 70 oC for 10h.19

Synthesis of oxepane library 2 by cross metathesis Further diversification was achieved by cross metathesis including the diene group embedded in 1(Scheme 4). Diene 1 was refluxed in CH2Cl2 with methyl acrylate in the presence of either 2nd generation Grubbs catalyst 2120a (15 mol%) or 2nd generation Hoveyda-Grubbs catalyst 2220b (20 mol%) for 18 h. When the reaction was complete (determined by TLC), the ruthenium scavenger resin 11 was added. O Ha

O O

HO R3

O 1

R4

O

19

4 Cl or R N C O 18 THF, Py, rt, 6h

O HO

R2 21 or 22 R1 CH Cl , reflux, 18h 2 2

R3

O

R2 H R1

then 14

b

R5 or 1. CDI, CH2Cl2, rt, 10h 2. K2CO3, THF:DMF (4:1) R5R4NH (17), rt, 5h then 7, rt, 6h 25% to 75% after 5 or 6 steps

23

then 11 rt,10h

N

R4 X

N

N

N

Cl Ru Cl O

Cl Ru Ph Cl PCy3 21

22

Scheme 4. Synthesis of the oxepane library 2.

21

O

Ha

O

O

2H

O R3

O

R R1

b

24: X = -CH225: X = -NHOxepane Library 2

In this cross metathesis strategy it was realized that the 2nd generation Grubbs catalyst 21 showed higher reactivity than the 2nd generation Hoveyda-Grubbs catalyst 22. The free alcohol was functionalized to give esters 24 and carbamates 25 in 47%-57% (after 5 steps) and 25%-75% (after 5 or 6 steps) isolated overall yield respectively. In the products 24 and 25, the newly formed olefin after the cross metathesis reaction was Econfigured exclusively as was evident from the coupling constant (JHa-Hb = 16.0 Hz, (see also the Supporting Information) between Ha and Hb in the 1H NMR spectrum. The oxepanes synthesized by means of this procedure are shown in Table 3.

22

Table 3. Oxepane library 2.

R3 R4 R2

O

Entry 1.

R1 -CH3

R2 -CH3

R1

R3 -H

R4

Yielda 40% (after 5 steps)

F N N

O O

2.

-CH3

-CH3

H N

-H

25% (after 5 steps)

O

5 O

3.

-CH3

-CH3

-H N

O

29% (after 5 steps)

O

40% (after 5 steps)

O

4.

-CH3

-CH3

-H

O N O

5.

-CH3

-CH3

H N

-H

O

45% (after 5 steps)

O

35% (after 6 steps)

O

6.

-CH3

-CH3

O

H N O

7.

-CH3

-CH3

O

O

36% (after 6 steps)

O N

O

O O

8.

-CH3

-CH3

F

O O

38% (after 6 steps) N N

O O

9.

-CH3

-CH3

H N

O O

23

O O

35% (after 6 steps)

10.

-CH3

-CH3

O

H N O

11.

-CH3

-CH3

5 O

O N

O

12.

(CH2)4CH3

-H

(CH2)4CH3

-H

30% (after 6 steps)

O

O 12 O

O O

13.

35% (after 6 steps)

O

47% (after 5 steps)

O O

O

30% (after 5 steps)

O

14.

(CH2)4CH3

-H

H N

O O

(CH2)4CH3

-H

H N

O O

16.

(CH2)4CH3

-H

75% (after 5 steps)

O

Cl

15.

O

47% (after 5 steps)

O O

O

40% (after 5 steps)

O

HN

O O

(CH2)4CH3

-H

-H

OH

18.

(CH2)4CH3

-H

-H

OH

19.

(CH2)4CH3

-H

-H

17.

Cl Cl O

20.

(CH2)4CH3

-H

O H N

-H

O

Cl

21.

(CH2)4CH3

-H

-H

O

H N

O O

22.

(CH2)4CH3

-H

O

OH O

a

Isolated yield after column chromatography, d.r. = diastereomeric ratio.

24

60% (after 3 steps) d.r. = 8:1 60% (after 3 steps) d.r. = 2.5:1 57% (after 4 steps) d.r. = 8:1

65% (after 4 steps) d.r. = 8:1 40% (after 4 steps) d.r. = 8:1 45% (after 4 steps)

Synthesis of keto oxepanes The Sodwanones are a family of marine natural products displaying activity against different human cancer cell lines (Figure 3).5

O H

O

O OH

O

H

O OH

O

H

O

O Sodwanone G

O H

O

H

O

O OH Sodwanone A

O

O

HO O H

O

Sodwanone H

OH Sodwanone S

Figure 3. Few representatives of Sodwanone family natural products

The Sodwanone family contains the keto oxepane scaffold. Inspired by this marine natural product family and its anti cancer activity, a small keto oxepane collection was synthesized. Aldehydes 26 were treated with allylmagnesium chloride in THF at 0 oC to room temperature for 2h to obtain the enyne metathesis precursors 27 as a 1:1 mixture of two inseparable isomers after scavenging the excess allylmagnesium chloride with the polymer supported sulfonic acid resin 7 (Scheme 5). These crude enyne metathesis precursors were treated with 1st generation Grubbs catalyst 10 in refluxing CH2Cl2 for 18h. When the reaction was complete (monitored by TLC), the ruthenium metal was scavenged using the metal chelating resin 11. After filtering the resin and removal of solvent, a 1:1 mixture of colorless crude oxepanes 28 was obtained. The crude alcohols 28 were then oxidized to the ketones 29 using pyridinium chlorochromate (PCC) in CH2Cl2 at room temperature for 10h. After total consumption of the starting alcohols 28 (monitored by TLC), the reaction mixtures were filtered through a Celite pad to remove the chromium metal from the reaction mixture.

25

O

MgCl

O

H

R1 R

THF, 0 oC to rt, 2h

2

O

HO

R1 27

then 7, rt, 6h

26

10 CH2Cl2, reflux, 18h R

HO

then 11, rt, 10h

2

O

R2 R1

28

PCC, CH2Cl2, rt, 10h

R3

O O

O

Y

H

H

H

R3O-NH2. HCl 31 R3 = Me (31a) R3 = Bn (31b)

N

O H

O

Y

H H

O

R 1

R 32 Oxepane Library 4

EtOH: H2O (2:1) rt, 10h 10%-15% overall yield (after 6 steps)

O 30

Y

O

20

O 2

O

R

2

1

R

O

Toluene, 70 oC, 3h-10h 10%-25%overall yield (after 5 steps)

O

R2 R1

29

Oxepane Library 3

Scheme 5. Synthesis of keto-oxepane library 3 and oxime library 4.

After the keto oxepane scaffold was formed the diene moiety of 29 was functionalized by means of Diels-Alder reactions. When crude 29 was treated with different commercially available dienenophiles 20 in the minimum volume of toluene necessary at 70 oC for 3h to 10h (depending on the dienophile used) the crude adducts 30 were formed. The crude products 30 were purified by silica gel chromatography to obtain pure keto oxepanes in 10% to 25% overall yield after 5 steps for the major isomer. In this case also, it was assumed that the endo-adduct had been formed based on the nOe study described above. The isomeric ratios of the individual keto oxepanes were determined by means of 1H NMR spectroscopy and are shown in the Supporting Information and Table 4. Crude 30 were further treated with either O-methyl hydroxylamine hydrochloride salt (31a) or O-benzyl hydroxylamine hydrochloride salt (31b) in ethanol:water (2:1) mixture at room temperature for 10h.21 After the reaction was complete (monitored by TLC) the solvent was evaporated and the crude 32 were purified by preparative thin layer chromatography (PTLC) to afford the pure oximes in 10% to 15% overall yield after 6 steps. O-Benzylhydroxyl amine (31b) gave better yields than O-methylhydroxyl amine (31a). The structures, yields and isomeric ratios of the oximes are shown in Table 4.

26

Table 4. Oxepane libraries with keto-/and oxime functional groups.

Y H

H

H X R2 R1

O

Entry 1.

R1 (CH2)4CH3

R2 -H

X O

Y O O O

Yield 30%a (after 5 steps)

O

2.

(CH2)4CH3

-H

O

O

H

25%a (after 5 steps)

O H

3.

(CH2)4CH3

-H

O

H

O O N Ph

H

4.

-(CH2)5-

-(CH2)5-

OBn N

H

N Ph H

5.

-(CH2)5-

-(CH2)5-

OBn N

O O

H

25%a (after 5 steps)

10%b (after 6 steps)

O

O

12%b (after 6 steps)

NH H

6.

-(CH2)5-

-(CH2)5-

O

H

O O

15%a (after 5 steps)

NH H

7.

-(CH2)5-

-(CH2)5-

O

H

O O N Ph

H

27

O

10%a (after 5 steps)

8.

-(CH2)5-

-(CH2)5-

O

O

O O

9.

-(CH2)5-

-(CH2)5-

OMe N

10.

-CH3

-CH3

O

O OH

15%a (after 5 steps)

10%b (after 6 steps) d.r. = 8:1

OH H

O N Ph

H

11.

-CH3

-CH3

O

H

12%a (after 5 steps)

O

O

15%a (after 5 steps)

NH H

12.

-CH3

-CH3

OBn N

H

O O

15%b (after 6 steps)

NH H

13.

-CH3

-CH3

OBn N

H

N Ph H

14.

(CH2)4CH3

-H

OBn N

H

(CH2)4CH3

16.

-(CH2)5-

-H

O

-(CH2)5-

OMe N

O O N Ph

H

15.

O O

13%b (after 6 steps) d.r. = 4.3:1 10%b (after 6 steps) d.r. = 20:1

O

OH

14%a (after 5 steps)

OH H

H a

COOH COOH

10%b (after 6 steps) d.r. = 6:1

Isolated yield after column chromatography, bIsolated yield after preparative thin layer

chromatography (PTLC), d.r. = diastereomeric ratio

28

Synthesis of diacids Further diversification on the oxepane scaffold was achieved after the Diels-Alder reaction with maleic anhydride (20c) and hydrolysis of the formed anhydride to diacids 34 (Scheme 6). The dienes 33 were treated with maleic anhydride (20c) in toluene at 70 oC for 3h. As soon as the dienes 33 were totally consumed (monitored by TLC), the solvent was evaporated and the crude products were dissolved in a solution of 20% water in THF and stirred at room temperature for 10h.

1.

3

R X

O O

O

O

O 20c

toluene, 70 oC, 3h O 33

R2 R1

2. 20% H2O in THF, rt, 10h 20%-25% after 6 steps

X = -NH, -NR4, -CH2

COOH H

HOOC H

R3 X

H

O O

O 34

R2 R1

Scheme 6: Synthesis of diacid.

The solvent was evaporated by coevaporation with excess ethanol and purified by silica gel chromatography to obtain the diacids 34 in 20% to 25% yield after 6 steps.22 The diacids were formed as inseparable mixtures of two isomers determined by means of 1H NMR spectroscopy. The structures, yields and diastereomeric ratios of the diacids are shown in Table 1 and in the Supporting Information.

Summary and Conclusion A collection of 77 fully functionalized oxepanes (library 1) has been synthesized by means of the synthetic strategy shown in Scheme 2. The ring-closing enyne metathesis reaction was used as the key step to synthesize the oxepane scaffold 1. Diversity on the oxepane scaffold was generated by reacting isocyanates 18 and acid chlorides 19 with alcohols to generate carbamates and esters respectively. In addition, carbamates were synthesized by a two step procedure using carbonyl diimidazole and different primary and secondary amines 17. The diene moiety was functionalized by Diels-Alder cycloaddition to yield fused seven-six membered bicyclic systems. A collection of 22

29

diene oxepanes (library 2) has been synthesized by means of a cross metathesis reaction followed by diversification of alcohols 23 to esters 24 and carbamates 25 (Scheme 4). A small collection of 16 compounds (library 3 and library 4) was synthesized using PCC oxidation of secondary alcohols 28 to ketones 29 and functionalization to oximes 32 after Diels-Alder reaction (Scheme 5). A total of 115 oxepane molecules have been obtained by solution phase parallel synthesis using polymer-supported reagents and scavengers.

Among the substituted propargyl alcohol building blocks 6, all propargyl alcohols gave moderate to good yields except propargyl alcohol (6d) itself. It was noted that the propargyl alcohol is difficult to handle due to its volatility and that is reflected in the low yields of the oxepane molecules using this building block. Bromo ethyl acetate (5a) showed the best reactivity and yields than the other two building blocks among the substituted α-bromo ethyl acetates (5b and 5c). Among the isocyanate building blocks 18, the 2,4-dimethoxyphenyl isocyante (18d) showed the lowest reactivity and yield due to its electron donating substituents as well as the bulky ortho-substituent. The naphthyl(18a) and phenyl isocyante (18b) showed moderate reactivity. The best reactivity was observed with p-chlorophenyl isocyanate (18c) due to the electron withdrawing chlorine. It was noted that the aliphatic acid chlorides (19f-i) are more reactive than the aromatic acid chlorides (19a-e). Among the aromatic acid chlorides 2-fluorobenzoyl chloride (19c) and 3,4-dichlorobenzoyl chloride (19e) are most reactive due to their electron withdrawing character. On the other hand p-methoxy- (19b) and p-methylbenzoyl chlorides (19d) are least reactive due to their electron donating substituents. It was observed that all primary and secondary amines 17 showed similar reactivity. It was experienced that among the dienophiles N-phenyl maleimide (20b), maleimide (20a) and maleic anhydride (20c) showed the best reactivity, whereas p-benzoquinone (20d) and diemthyl acetylene diacarboxylate (20e) are not particularly reactive. Our results demonstrate that the solution phase synthesis of the oxepane collection using solid-supported scavengers is very practical and allows to synthesize a diversely functionalized oxepanes in an efficient manner.

30

Acknowledgments This research was financially supported by the International Max-Planck Research School in Chemical Biology (IMPRS-CB) and the Max-Planck Society.

References and notes 1.

(a) Breinbauer, R.; Vetter, I.; Waldmann, H. Angew. Chem. Int. Ed. 2002, 41, 2878; (b) Kumar, K.; Waldmann, H. Angew. Chem. Int. Ed. 2009, 2009 48, 3224; (c) Kaiser, M.; Wetzel, S,; Kumar, K.; Waldmann, H. Cell. Mol. Life Sci. 2008, 2008 65, 1186.

2.

Ley, S. V.; Baxendale, I. R. Nature Reviews Drug Discovery 2002, 1, 573 and the references therein.

3.

Macías, F. A.; Molinillo, J. M. G.; Varela, R. M.; Torres, A. J. Org. Chem. 1994, 59, 8261.

4.

(a) Bon, C. F.–L.; Berrué, F.; Thomas, O. P.; Reyes, F.; Amade, P. J. Nat. Prod. 2005, 68, 1284; (b) Rudi, A.; Goldberg, I.; Stein, Z.; Kashman, Y. J. Nat. Prod. 1995, 58, 1702.

5.

Guella, G.; Mancini, I.; Chiasera, G.; Pietra, F. Helv. Chim. Acta 1992, 75, 310.

6.

Levine, S. D.; Adams, R. E.; Chen, R.; Cotter, M. L.; Hirsch, A. F.; Kane, V. V.; Kanijoa, R. M.; Shaw, C. J.; Wachter, M. P.; Chin, E.; Huetteman, R.; Ostrowski, P.; Mateos, J. L.; Noriega, L.; Guzmán, A.; Mijarez, A. Tovar, L. J. Am. Chem. Soc. 1979, 101, 3404.

7.

(a) Marcelle, G. B.; Bunyapraphatsara, N.; Cordell, G. A.; Fong, H. S.; Nicolaou, K. C.; Zipkin, R. E. J. Nat. Prod. 1985, 48, 739; (b) Kanojia, R. M.; Chin, E.; Smith, C.; Chen. R.; Rowand, D.; Levine, S. D.; Wachter, M. P.; Adams, R. E.; Hahn, D. W. J. Med. Chem. 1985, 28, 796.

8.

(a) Wetzel, S.; Bon, R. S.; Kumar, K.; Waldmann, H. Angew. Chem. Int. Ed. 2011, 50, 10800; (b) Bon, R. S.; Waldmann, H. Acc. Chem. Res. 2010, 43, 1103.

9.

(a) Nören-Müller, A.; Reis-Correa, I.; Prinz, H.; Rosenbaum, C.; Saxena, K.; Schwalbe, H. J.; Vestweber, D., Cagna, G.; Schunk, S.; Schwarz, O.; Schiewe, H.; Waldmann, H. Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 10606; (b) Nören-

31

Müller, A.; Wilk, W.; Saxena, K.; Schwalbe, H.; Kaiser, M.; Waldmann, H. Angew. Chem. Int. Ed. 2008, 47, 5973; (c) Waldmann, H.; Khedkar, V.; Dückert, H.; Schürmann, M.; Oppel, I. M.; Kumar, K. Angew. Chem. Int. Ed. 2008, 47, 6869; (d) Antonchick, A. P.; Gerding-Reimers, C.; Catarinella, M.; Schurmann, M.; Preut, H.; Ziegler, S.; Rauh, D.; Waldmann, H. Nat. Chem. 2010, 2, 735; (e) Basu, S.; Ellinger, B.; Rizzo, S.; Deraeve, C.; Schurmann, M.; Preut, H.; Arndt, H. D.; Waldmann, H.; Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 6805; (f) Dueckert, H.; Pries, V.; Khedkar, V.; Menninger, S.; Bruss, H.; Bird, A. W.; Maliga, Z.; Brockmeyer, A.; Janning, P.; Hyman, A.; Grimme, S.; Schurmann, M.; Preut, H.; Hubel, K.; Ziegler, S.; Kumar, K.; Waldmann, H. Nat. Chem. Biol. 2012, 8, 179; (g) Potowski, M.; Bauer, J. O.; Strohmann, C.; Antonchick, A. P.; Waldmann, H. Angew. Chem. Int. Ed. 2012, 51, 9512; (h) Potowski, M.; Schurmann, M.; Preut, H.; Antonchick, A. P.; Waldmann, H. Nat. Chem. Biol. 2012, 8, 428-430.; (i) Over, B.; Wetzel, S.; Grütter, C.; Nakai, Y.; Renner, S.; Rauh, D.; Waldmann, H. Nat. Chem. 2013, 5, 21; (j) Dakas, P.-Y.; Parga, J. A.; Höing, S.; Schöler, H. R.; Sterneckert, J.; Kumar, K.; Waldmann, H.; Angew. Chem. Int. Ed. 2013, 52, 9576; (k) Voigt, T.; Gerding-Reimers, C.; Tuyen, T. N. T.; Bergmann, S.; Lachance, H.; Scholermann, B.; Brockmeyer, A.; Janning, P.; Ziegler, S.; Waldmann, H. Angew. Chem. Int. Ed. 2013, 52, 410; (l) Antonchick, A. P.; López-Tosco, S.; Parga, J.; Sievers, S.; Schürmann, M.; Preut, H.; Höing, S.; Schöler, H. R.; Sterneckert, J.; Rauh, D.; Waldmann, H. Chem. Biol. 2013, 20, 500; (m) Potowski, M.; Antonchick, A. P.; Waldmann, H. Chem. Commun. 2013, 49, 7800; (n) Takayama, H.; Jia, Z.-J.; Kremer, L.; Bauer, J. O.: Strohmann, C.; Ziegler, S.; Antonchick, A.; Waldmann, H. Angew. Chem. Int. Ed. 2013, 52, 12404; (o) Narajan, R.; Bauer, J. O.; Strohmann, C.; Antonchick, A.; Waldmann, H. Angew. Chem. Int. Ed. 2013, 52, 12892; (p) Eschenbrenner-Lux, V.; Kuechler, P.; Ziegler, S.; Kumar, K.; Waldmann, H. Angew. Chem. Int. Ed. 2014, 53, 2134. 10.

(a) Moreno-Mañas, M.; Pleixats, R.; Santamaria, A. Synlett. 2001, 1784; (b) Majumdar, K. C.; Rahaman, H.; Muhuri, S.; Roy, B. Synlett. 2006, 466.

11.

Crimmins, M. T.; DeBaillie, A. C. Org. Lett. 2003, 5, 3009.

12.

Jadav, P. K.; Bhat, K. S.; Perumal, T.; Brown, H. C. J. Org. Chem. 1986, 51, 432.

32

13.

Storer, R. I.; Takemoto, T.; Jackson, P. S.; Brown, D. S.; Baxendale, I. R.; Ley, S. V. Chem. Eur. J. 2004, 10, 2529.

14.

Ahmed, M.; Barrett, A. G. M.; Braddock, D. C.; Cramp, S. M.; Procopiou, R. A. Tetrahedron Lett. 1999, 40, 8657.

15.

Westhus, M.; Gonthier, E.; Brohm, D.; Breinbauer, R. Tetrahedron Lett. 2004, 45, 3141.

16.

(a) Chadha, N. K.; Batcho, A. D.; Tang, P. C.; Courtney, L. F.; Cook, C. M.; Wovkulich, P. M.; Uskoković, M. R. J. Org. Chem. 1991, 56, 4714. (b) Cano, M.; Ladlow, M.; Balasubramanian, S. J. Org. Chem. 2002, 67, 129. 17. Harding, W. W.; Tidgewell, K.; Byrd, N.; Cobb, H.; Dersch, C. M.; Butelman, E. R.; Rothman, R. B.; Prisinzano, T. E. J. Med. Chem. 2005, 48, 4765.

18.

Smith, A. B. III; Rucker, P. V.; Brouard, I.; Freeze, B. S.; Xia, S.; Horwitz, S. B. Org. Lett. 2005, 7, 5199.

19.

Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem. Int. Ed. 2002, 41, 1668-1698.

20.

(a) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 3782. (b) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168.

21.

(a) Kulkarni, B. A.; Roth, G. P.; Lobkovsky, E.; Porco, J. A., Jr. J. Comb. Chem. 2002, 4, 56-72. (b) Pelish, H. E.; Westwood, N. J.; Feng, Y.; Kirchhausen, T.; Shair, M. D. J. Am. Chem. Soc. 2001, 123, 6740.

22.

Boger, D. L.; Tarby, C. M.; Myers, P. L.; Caporale, L. H. J. Am. Chem. Soc. 1996, 118, 2109.

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