Solid-Phase Synthesis and Combinatorial Technologies

2.3 OLIGOSACCHARIDES 83

The synthesis of 2.107 is reported in Fig. 2.34. The first coupling–deacetylation cycle to give resin-bound 2.91 was carried out as above; then this intermediate was coupled with the donor 2.110 (3 eq) and TMSOTf (trimethyl silyl trifluorometan sulfonate) (0.3 eq) at –25 °C using a solvent mixture of dry DCM–dry 1,4-dioxane 1/1 to exploit the 1,2-cis driving anomeric effect of ethereal solvents. After stirring at –25 °C for 1 h the suspension was warmed to rt and the resin washed and dried as described previously to give the resin-bound, protected disaccharide 2.111. This was cleaved using the same reagents and conditions (NBS, DTBP, 4 eq, rt, 90 min) with THF–MeOH as solvent mixture. The pure 1-O-methyl disaccharide 2.107 was prepared from 2.108 in 54% yield after chromatography (Fig. 2.34).

This example should have clearly shown the level of complexity involved in the oligomeric SP synthesis of OSs. If we compare it with the optimized, automated SP protocols commonly used to prepare dipeptides (Section 2.1) or dinucleotides (Section 2.2), it is clear that the protected reagents are more precious and must be prepared, rather than bought; the experimental conditions must be carefully controlled to ensure the desired regioand stereochemical outcome of the reaction; and the cleavage/workup/purification procedures require more attention to preserve the integrity of intermediates and final compounds. Despite all of this, the clear advantages provided by SPS, especially related to simplified work-up/purification of resin-bound compounds compared to solution procedures, make OS SP extremely appealing to obtain large quantities of complex and sensitive oligosaccharides with high yields and purities. We may reasonably expect significant technological improvements to provide the chemist

			Ac
	a	BnO	O
			O
O	SH	BnO
		BnO

	2.108			2.90	S
			BnO	OH	O
	b			O
			BnO
			BnO
				2.91 S
	Ac			O
		Ac			Ac
	O				O Ac
	O		OBn		O	OBn
	c	O		d	O
	BnO		O
	BnO		O		BnO	O
						O
	BnO			2.111	BnO
					BnO
			S
						OMe
				O	2.107

54% from 2.108

a:2.109, TMSOTf, DCM, rt, 1 hr; b: 0.5M NaOMe, DCM/MeOH 10/1, rt, 2 hrs;

c:2.110, TMSOTf, DCM, -25°C to rt, 2 hrs; d: NBS, DTBP, acetone/water 9/1, rt, 90'.

Figure 2.34 SP synthesis of compound 2.107.

84 SOLID-PHASE SYNTHESIS: OLIGOMERIC MOLECULES

with better tools able to provide a large variety of oligosaccharides for the most diverse applications in the future.

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Solid-Phase Synthesis and Combinatorial Technologies. Pierfausto Seneci Copyright © 2000 John Wiley & Sons, Inc.

ISBNs: 0-471-33195-3 (Hardback); 0-471-22039-6 (Electronic)

3Solid-Phase Synthesis: Small Organic Molecules

The high reliability of automated oligomer SPS derives from the capillary optimization of the SP reaction conditions used for the iterative cycles. All the parameters have been thoroughly studied, and improvements such as new coupling agents, new protected building blocks, or new linkers continuously increase the options for the synthetic chemist. The advantages of peptide and ON SPS versus solution-phase synthesis for the same sequence are evident: no need of intermediate purification, complete automation of reaction cycles, fast SP reactions, and negligible loss of material. Examples where significant amounts of pure 10to 100-mers were prepared by SPS are abundant in the literature. The automation of the SP protocols is possible because of the relatively restricted variety of SP reaction conditions used: couplings, deprotections, protections, and cleavage. As an example, the Fmoc protocol for the synthesis of a decapeptide will require from 22 to 23 SP steps: the support of the starting material on SP, 10 Fmoc deprotections, 10 couplings, the final cleavage and deprotection of side chains plus, when necessary, the attachment of a linker onto the support. The couplings and the Fmoc deprotections are identical for each of the 20 steps, so that the classical conditions used in an Fmocprotocol only sporadically require minor adjustments for specific oligomeric sequences. The automation of these steps requires only a few optimized experimental protocols to be repeated in iterative cycles.

The synthesis of nonoligomeric small organic molecules is quite different, and its characteristics do not help an automated transfer onto SP. The whole arsenal of organic reactions can be used to build a molecule, and even a short synthesis may require a few steps with completely different reaction conditions. While each reaction in solution is independent, allowing every intermediate to be purified and submitted to the following reaction conditions without any interference from the previous step, an SPS route requires the support and the linker to be perfectly stable during all the reaction conditions used. A wide variety of different supports and linkers is thus necessary to accomplish the SPS of small organic molecules. For these reasons one or a few common protocols for organic SPS cannot be defined. Instead, a specific study to define an SP-compatible synthetic route and to assess its feasibility must be performed every time. In this chapter the entire process from the selection of a target to its successful SP synthesis, including all of the intermediate steps, will be detailed (Sections 3.1 and 3.2). A scheme showing the important steps in this process is reported in Fig. 3.1. The exploitation of the SP route for a specific target, encompassing the design, assessment, and realization of the SPS of one or more combinatorial libraries (Section 3.3), will also be described. This will represent the introduction to the

91

92 SOLID-PHASE SYNTHESIS: SMALL ORGANIC MOLECULES

TARGET SELECTION

RETROSYNTHESIS

SYNTHESIS VALIDATION

IN SOLUTION

SOLID PHASE SYNTHESIS

DESIGN

SOLID PHASE SYNTHESIS

VALIDATION

OPTIMIZATION OF SPS

REACTION CONDITIONS

EXPLOITATION OF AN SPS ROUTE:

TOWARDS CHEMICAL LIBRARIES

Figure 3.1 Logical scheme to a successful small organic molecule SPS and to related synthetic combinatorial libraries.

following chapters where combinatorial chemistry and combinatorial technologies will be extensively covered.

All of the above-mentioned aspects will also be illustrated through the detailed description of a specific example (1), which spans every phase of a successful SPS and shows its potential to generate synthetic organic libraries (Section 3.4). The same will happen for several other recent examples (Section 3.5) using the analysis model built in Sections 3.1–3.3.

3.1 SMALL ORGANIC MOLECULES ON SOLID PHASE: TARGET SELECTION AND SOLUTION STUDIES

3.1.1 Target Selection and Retrosynthesis

The selection of a small organic molecule as the target for a chemical synthetic route may arise from any potential application for this molecule in any specific field. The selection depends on the requirements of the individual chemical project and cannot be generalized in any way. Once the target is selected, the so-called retrosynthetic