Solid-Phase Synthesis and Combinatorial Technologies

3.4 AN EXAMPLE: SOLID-PHASE SYNTHESIS OF 1H-[2]PYRINDINONES 103

			O		O
	COOH		O Wang	b,c	O Wang
	a	HN			HN
HN			Fmoc
	Fmoc				Ts
3.15				3.17
		3.16
	O			O
d	O	Wang	e	O	Wang
	N		O	N
	Ts
				Ts
	3.12			H	f
				3.13a,b

O

a)2,6-dichlorobenzoyl chloride, pyridine, Wang resin, DMF, rt, 22 hrs;

b)20% piperidine in DMF/DCM 1/1, rt, 20'; c) TsCl, TEA, DCM, rt, 7 hrs;

d)allyl bromide, Cs2CO3, DMF, rt, 16 hrs;

e)Co2(CO)8, DCM, rt, 2 hrs, then N-methylmorpholine-N-oxide, DCM, rt, 2 hrs;

f)TFA/DCM 1/1, rt, 1 hr, then off-bead characterization: 84% yield (3.14a,b from 3.12) and 74% yield (3.23 from 3.21);

g)propargyl bromide, Cs2CO3, DMF, rt, 20 hrs.

O

OH

N

Ts

H

3.14a,b

HN

3.18

g

Figure 3.9

		O		O
COOH		O Wang	b,c	O Wang
a	HN			HN
		Fmoc
Fmoc				Ts
			3.20
	3.19
O			O
			H
O	Wang	e	O	Wang
N		O	N
Ts
			Ts
3.21			3.22	f
				O
				H
				OH
				O
				N
				Ts

3.23

Solid-phase synthesis of two functionalized 1H-[2]pyrindinones 3.14a,b and 3.23.

increase the number of compounds available from this SPS, but significant efforts to improve the reaction yields would be necessary.

The substitution of allyl bromide as the alkylating reagent in the functionalization of 3.17 (Fig. 3.10, point 2) was investigated using 2- and 3-substituted allyl bromides (Fig. 3.12). The former gave modest results in the SP cyclization, while the latter

104 SOLID-PHASE SYNTHESIS: SMALL ORGANIC MOLECULES

			O		O
	COOH		O Wang		O Wang
HN		HN			HN
	Fmoc		Fmoc	3.17	Ts
3.15
		3.16			ArSO2Cl
					1
	O			O 6
			5
	O	Wang		O Wang
			O
	N			N
	Ts		3
				Ts
	R2			H
R1	X			3.13a,b	O
		3.12
	2
					OH
					O
					N
					Ts
					H

3.14a,b

Figure 3.10 Combinatorial exploitation of successful SPS strategy: options 1–6.

O		O
				O
O Wang	a	O Wang	+ Ar	b
				S
HN		NH2		Cl
				O
Fmoc

3.16

	O
	O Wang		O
	HN O	O	OH
	S		N O
	Ar
	O		S
		H	Ar
			O
	a) 20% piperidine, DMF/DCM 1/1;	Cl
			and
	b) TEA, DCM.	Ar =

NO2

Figure 3.11 Diversification of sulfonyl chlorides (option 1): arenesulfonyl N-substituted 1H-[2]pyrindinones.

3.4 AN EXAMPLE: SOLID-PHASE SYNTHESIS OF 1H-[2]PYRINDINONES 105

	O				O
	O Wang	+ R1	R2	a	O Wang
				X
	HN				N
					Ts
3.17	Ts
					R2
				R1
			O
	O		OH	a) Cs2CO3, DMF
		N

Ts

R1 R2

R1 = Ph, R2 = H

R1 = H, R2 = Me

Figure 3.12 Diversification of allyl bromides (option 2): alkylor aryl-C-substituted 1H- [2]pyrindinones.

compound produced only traces of the expected cyclic scaffold. Although the reaction conditions could potentially be optimized to give better yields, this may require significant efforts and does not seem a suitable modification for the exploitation of the SPS strategy with respect to library generation.

When the advanced resin-bound intermediate 3.12 was reacted with an aryl iodide prior to cyclization (point 3, Fig. 3.10), an aryl group was inserted in the original scaffold. A number of examples showed reasonable to good yields of cleaved 1H- [2]pyrindinones could be obtained by inserting various aryl groups (Fig. 3.13).

O			O
O	Wang	a	O Wang
N		Ar	N
Ts			Ts
3.12
	Ar	O
O		OH	a) (PPh3)2PdCl2, CuI, ArI, TEA, DCM, rt, 18 hrs.
		N
		Ts
		H
	Cl	OMe	MeOOC
Ar =	,	,	and

Figure 3.13 Addition of aryl iodides (option 3): aryl substituted 1H-[2]pyrindinones.

106 SOLID-PHASE SYNTHESIS: SMALL ORGANIC MOLECULES

Therefore, the introduction of selected representatives from the many commercially available aryl iodides should make it possible to generate a population of analogues with good yields. This modification is thus suitable for combinatorial library generation (see the next chapters for the detailed description of these processes).

The final resin-bound scaffold contains two functional groups, ketone and carboxylic acid, amenable to chemical decoration. The ketone (Fig. 3.10, point 5), after reduction of the double bond to give the saturated scaffold 3.24a,b (Fig. 3.10, point 4), was reductively aminated and capped with an acyl chloride or with an isocyanate (Fig. 3.14). Final cleavage from the resin produced diastereomeric decorated scaffolds with good yields opening a route to prepare a set of ketone-modified analogues of the original scaffold. Finally, an amino acid could be inserted between the Wang linker and the carboxylic function (Fig. 3.10, point 6) to produce, after cleavage, a high yield of a diastereomeric carboxyamide (Fig. 3.15) as a representative of another decorated family of analogues.

	O				O
					H
O	O	Wang	a			O	Wang
	N		O		N
	Ts				Ts
	H				H
	3.13a,b				3.24a,b
	H	O				H	O
b	R1	O	Wang	c	R1		O Wang
	N	N			N		N
	H			R2
	H	Ts				H	Ts
					O
							O
	a) [(PPh3)CuH]6, toluene, rt, 24 hrs;				R1		OH
					N		N
b) R1NH2, NaBH(OAc)3, AcOH, DCM, rt, 24 hrs;				R2
c) R2 reagent, TEA, DMAP, DCM, rt, 4 hrs.						H	Ts
					O

R1 = Me, benzyl

Cl

R2 = Me, Ph,

N

H

Figure 3.14 Reduction of endocyclic double bond and decoration of 1H-[2]pyrindinones on keto group (options 4 and 5).

3.5	SOLID-PHASE SYNTHETIC STRATEGIES: SELECTED EXAMPLES 107
O		Ts
H			O
N	O Wang	N
Fmoc		a, b	H
			N
R			O Wang
		O	R

O		R	O	R
	N	OH		OH
O		+ O		N
	H		N	H
N		O		O
Ts			Ts
H			H

a)25% piperidine in DMF/DCM, rt, 15';

b)3.11, HOBt, WSC, DMF, rt, 16 hrs.

Figure 3.15 Decoration of 1H-[2]pyrindinones on the carboxylic group (option 6).

3.5 SOLID-PHASE SYNTHETIC STRATEGIES: SELECTED EXAMPLES

3.5.1 General Considerations

A full coverage and an adequate referencing of the most significant and recent SP efforts by leading academic and industrial groups would require a whole book to be accurate; the reader is referred to several updated reviews (12–18) and to a book (19) to navigate through this fascinating synthetic world at the interphase.

In this Section four examples are covered following the arrangement of an ideal process for the development of a successful solid-phase synthetic strategy as described in Sections 3.1–3.3. The rationale of the project and the structure of the synthetic target are presented and discussed first, followed by the design of a synthetic route in solution and by its validation; the design and assessment of a related SP route complete the process. Both assessments are critically examined and alternative options are presented; the choice of supports, linkers, reagents, solvents, concentration, temperature and reaction time is analyzed as much as possible; key experimental observations from the authors are discussed, while additional details can be found in the original paper. Each example shares the thoroughness used in the design and the assessment of a SP synthetic scheme, and also the sound project rationale to which the SPS is related; each project is inspired by completely different purposes and this is reflected by the diverse strategies used, hopefully providing the reader with a small but significant sampling of high quality, complex and challenging SPS. For each example the exploitation of the successful SPS scheme for combinatorial library synthesis is covered at the end, but is also an inspiring criterion throughout the whole example.

108 SOLID-PHASE SYNTHESIS: SMALL ORGANIC MOLECULES

3.5.2 SPS of 2,2-Dimethylbicyclo[3.3.1]nonan-9-ones (20)

Rationale of the project:

•The 2,2-dimethylbicyclo[3.3.1]nonan-9-one scaffold exemplified by structure 3.25 (Fig. 3.16) is the core structural motif of several natural products (e.g. 3.26 and 3.27, Fig. 3.16) with, among others, strong neurotrophic properties;

•Synthetic analogues containing the 2,2-dimethylbicyclo[3.3.1]nonan-9-one scaffold should likely possess relevant biological activities;

•The assembly of an efficient and versatile synthesis of a tricyclic nucleus with two quaternary bridgehead carbon atoms is a great challenge, although previous reports could provide assistance (21, 22);

•The structure of 3.25 looks suited for the introduction of decorating functions in various positions to create a combinatorial library based on a natural rigid scaffold;

•The full combinatorial exploitation of 3.25 requires an assessed SP synthetic method to build and decorate the scaffold for SP library generation;

•This approach may represent a novel application for recently reported multipurpose selenium-based SP linkers (21).

Target selection and synthetic strategy in solution: Compound 3.25 contains a condensed lactone and a selenium-based substituent; appropriate transformations of the two groups should give access to diverse tricyclic compounds. A more radical decoration of the nucleus (3.28, Fig. 3.17) could reasonably be conceived to fully exploit the bicyclo[3.3.1]nonan-9-one nucleus. Literature search found a related approach (22) where a similar, less congested tricyclic nucleus 3.29 was prepared by selenium-

O

O

O

Se

O

3.25

OH

	O	O
O		HO
O		OO
O
	3.26	3.27

Figure 3.16.

3.5 SOLID-PHASE SYNTHETIC STRATEGIES: SELECTED EXAMPLES 109

	O
R2	R1
		Se
		R7
R	O	R6
4		R5
R3

3.25R1, R2 = -CH2COO-; R3, R4 = H; R5 = i-Pr; R6, R7 = Me

3.28R1-R7 = alkyls, alkoxy, aryls, condensed cycles

Figure 3.17.

promoted, acid-catalyzed intramolecular C-endocyclization of an olefin onto a P-dicarbonyl system (Fig. 3.18).

The authors tried to validate this route for congested tricycles using the easily accessible β-ketoester 3.30 (Fig. 3.19), but the conversion of kinetically favored O-cyclized 3.31 into the desired 3.32 did not happen even forcing the reaction conditions. An elegant solution was found by masking the β-ketoester function of 3.30 as the acetate 3.33, thus preventing O-cyclization; C-cyclization took place in extremely mild conditions, simultaneously releasing the acetate function and giving 3.32 in high yields and purities (Fig. 3.19).

The same strategy was applied for the synthesis in solution of 3.25 (Fig. 3.20). The suitable protected β-ketoester 3.35 was easily prepared according to published procedures (23, 24) with moderate yields. Selenium-mediated endocyclization to 3.25 proceeded rather cleanly at higher temperatures but only up to 40% conversion of 3.35; any attempt to increase the conversion by further increasing the temperature or the reaction time only decomposed the starting material. The reported assessment in solution was considered satisfactory, and the authors moved to SP studies.

		Se
		O	kinetically
			preferred
			COOMe
	b
OH
COOMe	a	c
	c	O
			Se
a: N-PhSePhthalimide, rt; b: SnCl4 (cat.),		O	thermodynamically
			preferred
DCM, 5', rt; c: SnCl4 (stoich.), DCM, 17 hrs, rt.		OMe

3.29

Figure 3.18.

110 SOLID-PHASE SYNTHESIS: SMALL ORGANIC MOLECULES

O				Se
		OH
COOEt	a	COOEt	b	O
		3.30		COOEt
		d	c	3.31
				c
		OAc		O
		COOEt	e	Se
				O
		3.33		OEt
				3.32
		64% for a,d
				94%

a:LDA, prenyl bromide, 1 hr, -78°C to 0°C; rt; b: N-PhSePhthalimide, SnCl4 (cat.), DCM, 0°C;

c:SnCl4 (stoich.), DCM, 17 hrs, rt, or harsher conditions; d: Ac2O, DMAP, 30', 80°C;

e:N-PhSePhthalimide, SnCl4 (stoich.), DCM, 5', -78°C.

Figure 3.19.

	O
		O			OH
	a-c	d,e		HOOC
		EtOOC
O
		O		HO
		3.34
					O
					O
f,g	O	OAc	O	k	O
		h-j				Se
	O	O			O
	O	O			3.25
		3.35
					40% conversion,
		41% from 3.34			80% yield

a: 1-Br-3-MeButene, Cu, KOH, H2O, 2 hrs, rt; b: 6N HCl, pH 4; c: BrCH2COOEt, DBU, LiI, THF, 24 hrs, 65°C; d: LiAlH(Ot-Bu)3, THF, 2.5 hrs, 0°C; e: LiOH, THF/H2O 4/1, 30', rt; f: DCC, DMAP, DCM,

30', rt; g: PDC, celite, DCM, 6 hrs, rt; h: LHDMS, HMPA, THF, 30', -78°C; i: i-PrCOCN, 15', -78°C, then 15', 0°C; j: Ac2O, DMAP, 30', 80°C; k: N-PhSePhthalimide, SnCl4 (stoich.), DCM, 15', -23°C.

Figure 3.20.

3.5 SOLID-PHASE SYNTHETIC STRATEGIES: SELECTED EXAMPLES 111

SP synthetic strategy to analogues of 3.25 and chemical assessment: Nicolaou et al. (21) recently reported the use of PS-supported selenium reagents 3.36 and 3.37 (Fig. 3.2 1). A simple reasoning prompted to substitute N-phenyl selenium phthalimide with 3.36 in the scheme to 3.25 (Fig. 3.21); unfortunately even an extensive scan of experimental conditions could not support any trace of tricyclic 3.38. The reaction with supported bromide 3.37, though, worked extremely well and the final, assessed protocol (Fig. 3.21) gave 3.38 with an 81% loading using an excess of dissolved reagents at –23 °C for 20 min. The higher conversion (81% versus 40% in solution) should have derived from the excess of 3.35 which probably drove the reaction to completion even with the decomposition of some starting material.

Cleavage of 3.38 was attempted with an oxidation-elimination double protocol (steps c,d, Fig. 3.21) which proved to be extremely efficient in releasing pure 3.39 with 91% yield. The use of supported Se reagents ensured higher conversions and cleaner workup procedures than their counterparts in solution; additional advantages provided by SPS for this project are reported below.

Exploitation of the synthetic route in solution to 3.25: The diversification of the 2,2-dimethylbicyclo[3.3.1]nonan-9-one scaffold using the same synthetic route, as intended by general structure 3.28 (Fig. 3.17), was done by preparing 16 tricyclic analogues. Their general structures (3.44–3.59) and their synthesis from the appropriate β-ketoesters (3.40a–d, 3.41a–d, 3.42a,b, 3.43a–f) are reported in Fig. 3.22; yields

			O	Se
	P	Se	P
				Br
		N
		O	3.37
	3.36
			O
			O
	OAc	O	a
			O
			Se

O

b

O

O

P

	3.35	(3 eqs.)	3.38
	O
		O
c,d	O

a: 3.36, any experimental protocol; b: 3.37, SnCl4 (3 eqs.), DCM, 20', -23°C; c: H2O2, THF, 2 hrs, 0°C; d: CCl4, 10', 80°C.

O

3.39

Figure 3.21.

112 SOLID-PHASE SYNTHESIS: SMALL ORGANIC MOLECULES

and reaction conditions are also provided. Most of the introduced substituents gave the expected products with good yields and purities; the only exception was represented by substituted allyl chains (3.43a–f) which seem very stringent for the prenyl radical to prevent O-cyclization and orient towards C-cyclization (Fig. 3.22).

			O
			O
	OAc	O	O
		a, b or c
			Se
	O	R5	O
	O		R5
	3.40a-d		3.44 R5 = OMe (a, 95%)
			3.45 R5 = Me (a, 93%)
	O		3.46 R5 = Ph (b, 85%)
OAc O	O		3.47 R5 = CH=CMe2 (c, 62%)
OMe	O	Se
	a, b or c
		COOMe
R4
	R3	R
R
3		4
3.41a-d	3.48 R3 = CH, R4 = H (c, 90%)

3.49R3 = CH, R4 = 5-OMe (b, 78%)

3.50R3 = CH, R4 = 6-OMe (a, 89%)

3.51R3 = N, R4 = 6-OMe (c, 21%)

			OAc O					O
			OMe						Se
		Me		a or b		R2
		R2						O
								OMe
			3.42a,b				3.52 R2 = H (a, 98%)
							3.53 R2 = 6-OMe (b, 95%)
	R6					O		R	Se
		R8 OAc O						6
R							Se	R7
7			c				R6	R	O
			OMe	O			R	+	8
									COOEt
						R 8
						OEt	7
		3.43a-f				3.54	R6, R7 and R8 = H (0% + 90%)
						3.55	R6, R8 = H, R7 = Me (45% + 41%)
						3.56	R8 = H, R7, R6 = Me (94% + 0%)
						3.57	R8 = Me, R7, R6 = H (0% + 64%)
						3.58	R6, R8 = Me, R7 = H (0% + 89%)
						3.59	R6, R7, R8 = Me (0% + 86%)

a: N-PhSephthalimide, SnCl4, DCM, -23°C, 5 min; b: as a, 10 min; c: as a, 15 min.

Figure 3.22.