Newer Strategies for the Synthesis of Mono-and Bicyclic Oxygen Heterocycles

A dissertation submitted to the Indian Institute of Technology Guwahati in partial fulfillment of the requirements. I hereby declare that the matter embodied in this thesis entitled “Newer Strategies for the Synthesis of Mono- and Bicyclic Oxygen Heterocycles” is the result of research carried out by me at the Department of Chemistry, Indian Institute of Technology Guwahati, India under the supervision of Prof. I am forwarding his dissertation entitled “Newer Strategies for the Synthesis of Mono- and Bicyclic Oxygen Heterocycles” which is being submitted for the Ph.D.

The first chapter provides a brief introduction to mono- and bicyclic oxygen heterocycles and oxonium-ene cyclization reactions. In the second chapter, a new synthesis of oxabicyclo[3.3.1]nonanone via the (3,5)-oxonium-ene reaction is described. The third chapter describes the synthesis of oxabicyclo[3.3.1]nonenes and substituted tetrahydropyrananes via the (3,5)-oxonium-ene reaction.

In the fourth chapter there is a description about the stereoselective synthesis of 6-oxabicyclo[3.2.1]octene via (3,5)-oxonium-one reaction. The sixth chapter describes the diastereoselective synthesis of substituted dihydropyrans via oxonium-ene cyclization reaction.

Introduction to Mono- and Bicyclic Oxygen Heterocycles

Introduction to Mono- and Bicyclic Oxygen Heterocycles 01

General Approaches for the synthesis of Dihydro- and Tetrahydropyrans 03

Hetero Diels-Alder Reaction 03
Manipulation of Carbohydrates 10
Intramolecular Michael Reaction 12
Prins Cyclization 14

General Approaches for the Synthesis of Oxabicyclic Compounds 20

Method for the Synthesis of Oxabicyclo[3.3.1]nonanone 20
Method for the Synthesis of Oxabicyclo[3.3.1]nonene 20

Oxonium-Ene Reaction 21

A Novel Synthesis of Oxabicyclo[3.3.1]nonanone via

Importance and Applications 29

An Overview of Relevant Synthetic Methods 29

Present Work 30

Experimental Section 36

Instrumentation and Characterization 36
General Procedure for the Synthesis of Oxabicyclic

Spectral Data 40

Selected Spectra of Oxabicyclo[3.3.1]nonanone 46

The Crystal Parameters of Compond 9i 52

Synthesis of Oxabicyclo[3.3.1]nonenes and Substituted

Present Work 56

Spectral Data 66

Selected Spectra of Oxabicyclo[3.3.1]nonenes and Substituted

Stereoselective Synthesis of 6-Oxabicyclo[3.2.1]octene via

Present Work 88

General Procedure for the Synthesis of Oxabicyclic 94

Spectral Data 98

Selected Spectra of 6-Oxabicyclo[3.2.1]octenes 104

The Crystal Parameters of Compond 24d 110

Synthesis of 2,3,5,6-Tetrasubstituted Tetrahydropyrans

Present Work 116

General Procedure for the Synthesis of α-Alkyl-β-keto esters 124
General Procedure for the Synthesis of Ethyl 2-(1-
General Procedure for the Synthesis of 2,3,5,6-Tetrasubstituted

Spectral Data 128

Selected Spectra of 2,3,5,6-Tetrasubstituted Tetrahydropyrans 148

Crystal Parameters 155

Diastereoselective Synthesis of Substituted Dihydropyrans

Importance and Applications 159

Dihydropyrans are important intermediates for the synthesis of biologically active natural products such as ambruticin, phorboxazoles, levcasandrolide, kendomycin, neopeltolide, clavisolides and diospongins.1 The 4-methyl substituted dihydropyran unit is present in the macrolide natural products laulimalide and okadaic acid (Figure 6.1. 1) .2 The olefinic functionality of dihydropyrans can be manipulated to synthesize polysubstituted tetrahydropyrans.3 Substituted dihydropyrans are also used as flavoring or flavoring in food and other products.4.

An Overview of Relevant Synthetic Methods 159

Hinkle and co-workers reported a tandem silyl-Prins reaction between δ-triethyl-silyloxyvinyltrimethylsilanes and a variety of aldehydes to yield cis-2,6-disubstituted dihydropyrans (DHPs) using 5 mol% BiBr3 in CH2Cl2 (Scheme The diastereoselectivities in the crude products were significantly affected by aldehyde substitution with electron-rich aldehydes, yielding 2-3:1 (cis:trans) and neutral (or electron-poor) aldehydes, yielding dr ≥ 19:1 (cis:trans). have reported a stereoselective synthesis of cis-2,6-disubstituted dihydropyrans (DHPs) via stannyl-Prins cyclization. The reaction of vinylstannans 4 with aldehydes in the presence of trimethylsilyltrifluoromethanesulfonate (TMSOTf) afforded cis-2,6-disubstituted dihydropyrans 5 in good yields with excellent stereoselectivity (scheme Although the dihydropyrans are obtained in the racemic form, but the use.

These spirocyclic compounds are prepared by the reaction of homoallylic alcohols 9 with isatin ketals 10 in the presence of trimethylsilyl trifluoromethanesulfonate (Scheme 6.2.1.4).7. Loh and co-workers reported the synthesis of 2,6-trans dihydropyrans from the reaction of allene alcohols and aldehydes in the presence of an indium salt catalyst in good yields.8 However, good diastereoselectivity was achieved using bulk silicon-substituted allene alcohols. under the same condition (scheme 6.2.1.5). The reason for the high trans diastereoselectivity is the result of the anomeric effect as well as the stabilization of the δ+ lone pairs of the oxo-carbenium intermediate with the ester group.8.

Saikia and co-workers reported the synthesis of 4-aryl-5,6-dihydro-2H-pyrans from the reaction of carbonyl compounds or epoxides with homopropargyl alcohol and arenes TH. Schmidt and co-workers reported a highly diastereoselective route to enantiomerically pure dihydropyrans.11 The synthetic concept is based on the use of R-hydroxyketones that are conveniently obtained in enantiomerically pure form, a highly diastereoselective vinylation that relies on efficient chelate control and a ring closing olefin metathesis step (Scheme 6.2.2.2).

Present Work 163

Ethyl 3-alkyl-3-hydroxy-5-methylhex-5-enoate 25 was synthesized from β-keto ester A and 3-bromo-2-methylpropene as shown below.13 Reaction of β-keto ester A with 3 -bromo -2-methylpropene in the presence of metallic Zn and SnCl2.2H2O in THF gives alcohol 25 in 80-82% yields (Scheme 6.3.2). To determine the optimal reaction conditions, the reaction of benzaldehyde 26a and ethyl 3-hydroxy-3,5-dimethylhex-5-enoate 25a with different amounts of different Lewis acids was studied by varying the solvents. The reaction was found to proceed smoothly with one equivalent of boron trifluoride etherate in dry CH2Cl2, giving 68% of the desired product, while only 10 mol% of trimethylsilyl trifluoromethanesulfonate produced 78% of the same product in the same solvent.

Therefore, TMSOTf in dry CH2Cl2 was considered the best combination for this reaction and the extent of the reaction was investigated using different types of aliphatic and aromatic aldehydes (Table 6.3.2). Aromatic aldehydes having electron-donating groups on the aromatic ring gave higher yields compared to electron-withdrawing groups on the ring. This may be due to the better stability conferred on the oxocarbenium ion 29 (Scheme 6.3.3) by aliphatic and aromatic aldehydes having electron-donating groups on the aromatic ring, which in turn is attacked by the double bond in order effective.

On the other hand, aromatic aldehydes having electron-withdrawing groups in the ring destabilize the oxocarbenium ion 29. The presence of a strong NOE between the H6 and C-2 methyl protons of 27a clearly indicates that they are cis to each other (Figure 6.3. 1 ). Lewis acid activates aldehyde 26 for nucleophilic attack by alcohol 25 to give acetal 28, which upon decomposition forms oxocarbenium ion 29.

This is because, under Lewis acid conditions, epoxides rearrange to the aldehyde equivalent.14 Here, monosubstituted terminal epoxides (point a) fail to give substituted dihydropyran, whereas the 2,2-disubstituted and styrene oxides give the corresponding products in good to moderate yields. This is attributed to the lower stability of carbocation 32, obtained from monosubstituted epoxides, compared to 2,2-disubstituted epoxides and styrene oxides, where carbocation 32 is better stabilized due to tertiary and benzylic centers, respectively.14a. The epoxide 30 in the presence of Lewis acid rearranges to aldehyde equivalent 33, which after nucleophilic attack by alcohol 25 gives acetal 34.

Acetal 34 cleaves to give oxocarbenium ion 35, which after oxonium-ene cyclization reaction affords the final product 31. In summary, we have developed a simple and efficient methodology for the synthesis of substituted dihydropyrans in good yields. The presence of methylene ester functionality at the C-2 position of the dihydropyran ring will increase its synthetic applicability as the ester group can be further converted into other groups.

Figure 6.3.1. NOE diagram of compound 27a

Experimental Section 171

General Procedure for the Synthesis of Ethyl 3-alkyl-
General Procedure for the Synthesis of Substituted

The course of the reaction was monitored by TLC with ethyl acetate and hexane (1:24) as eluent. The organic layer was dried (Na 2 SO 4 ) and evaporated to give the crude product, which was purified by flash column chromatography on silica gel to give 27a (214 mg, 78%) as a colorless oil. The course of the reaction was monitored by TLC with ethyl acetate and hexane as eluent.

The organic layer was dried (Na 2 SO 4 ) and evaporated to leave the crude product which was purified by short column chromatography over silica gel to afford the title compounds. The progress of the reaction was monitored by TLC with ethyl acetate and hexane (1:49) as eluents. Na 2 SO 4 ) and evaporated to leave the crude product which was purified by flash column chromatography over silica gel to give 31b (163 mg, 68%) as a colorless oil.

Spectral Data 175

Selected Spectra of Substituted Dihydropyrans 182