Synthesis of oxygen and nitrogen heterocycles via stabilized carbocations and ring closing metathesis. - CHAPTER 1 INTRODUCTION

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Synthesis of oxygen and nitrogen heterocycles via stabilized carbocations and

ring closing metathesis.

Doodeman, R.

Publication date

2002

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Citation for published version (APA):

Doodeman, R. (2002). Synthesis of oxygen and nitrogen heterocycles via stabilized

carbocations and ring closing metathesis.

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I N T R O D U C T I O N N

1.11 Carbocations stabilized by o x y g e n and nitrogen

1.1.11 O x y c a r b e n i u m a n d i m i n i u m ion chemistry

Amongg the most important reactions in organic chemistry is the C-C bond forming reaction.. One way to achieve this transformation is the addition of a carbon nucleophile to a carbocation.. Well-known carbocations are heteroatom-stabilized carbenium ions, which are powerfull precursors for alkylation at the oc-position of heteroatoms. From these types of cations,, the oxycarbenium ion 1 and the iminium ion 2 are the most widely used and studied oness (Scheme 1.1). The oxycarbenium ion 1 is considerably more reactive than iminium ion 2 becausee of the greater electronegativity of oxygen compared to nitrogen.

Schemee 1.1 R2 2

o o

ft ft

yy

-

' - ' + N R

Thee most frequently used precursors to generate oxycarbenium ions are 0,0-acetals. Uponn treatment with either a Lewis or a protic acid, this highly reactive intermediate is formed,, which can undergo nucleophilic attack of 7t-nucleophiles such as alkenes, alkynes, aromaticc rings and enol derivatives in an inter- or intramolecular fashion. In intermolecular reactions,, oxycarbenium ions are highly suitable for the stereoselective introduction of a substituent.. For example, reaction of 5-substituted tetrahydropyran acetal 3 with BF3-OEt2 affordedd oxycarbenium ion 4 in which the methyl group adopts a pseudo-equatorial position (eqq 1.1). The incoming allyl group reacts predominantly from the bottom side to arrive at 1,4-disubstitutedd pyran 5 as a 94:6 mixture of ris/frans-isomers.1 The cf's-selectivity can be explainedd by the preference for an antiperiplanar pseudo-axial attack of the nucleophile throughh a chairlike transition state.2

"OAc c

Xj Xj

L£s s

yy yy

Inn the case of 6-substituted dihydropyran 6, the introduction of several nucleophiles alsoo proceeded in a highly stereoselective fashion.3 Treatment with BF3'OEt2 resulted in

allylicc oxycarbenium intermediate 7, which in the presence of allyltrimethylsilane reacted to thee 2,6-disubstituted dihydropyran 8 in a yield of 65% and excellent frans-selectivity (eq 1.2).

Me02CC O OMe 6 6 MeO,CC O SiMe3 3 (1.2) ) Me02CC O "'^ 8 8 65%% cis:trans 0:100 0

Thee same methods of preparation and reactivity can be applied for the formation and additionn reactions of iminium ion 2. This is the reactive intermediate in the Mannich reaction44 and has been frequently applied in the synthesis of pharmaceutical products.5 This nitrogen-stabilizedd carbocation is often prepared in situ via condensation of an aldehyde or ketonee with an amine and allows the introduction of several activated nucleophiles.

1.1.22 N - A c y l i m i n i u m ion chemistry6

Inn comparison with the iminium ion, the presence of an electron-withdrawing carbonyll group on the nitrogen enhances the electrophilicity and consequently the reactivity dramatically.. These so-called N-acyliminium ions (10) -also called amidoalkylating reagents-aree almost always generated in situ because of their limited stability and high reactivity. Theree are several ways to generate acyliminium ions. These include protonation of N-acyliminess and protonation of enamides or enecarbamates, but by far the most widely used methodd to generate these intermediates is by Lewis or protic acid-mediated heterolysis of acetal-likee structures of type 9 (eq 1.3). In most cases, the leaving group X is a hydroxy, alkoxy,, acyloxy or halogen substituent. The equilibrium in which the N-acyliminium ion is involvedd is usually favored by acidic catalysts; the subsequent reaction with the nucleophile iss an irreversible process and leads to the desired addition product.

xx Ri O

XX = OH, OR, OCOR,, Hal

Lewiss acid or

proticc acid Rii O

N ^ R44 -i -i R3 3 10 0 R-,, O i i R3 3 N-acyliminiumm ion (1.3) )

Thiss methodology usually requires mild reaction conditions, in which only a low concentrationn of the reactive intermediate is present. Due to their high electrophilicity N-acyliminiumm ions show reactivity to a wider range of nucleophiles than iminium ions.

Off the several synthetic routes leading to cyclic forms of acetal precursors 9, two approachess are particularly attractive. The first is the selective hydride reduction of one of 2 2

thee carbonyl groups of a cyclic imide with NaBLL or DIBALH. This transformation marked thee beginning of the expansion of N-acyliminium ion chemistry in the last 30 years.7

Treatmentt of the obtained precursors with an appropriate acid leads to an endocyclic iminiumm ion with the N-acyl group in the ring (eq 1.4) or outside the ring (eq 1.5).

0

^

^ uu i^H£!i^ HcrV^o ^ _ 4 >

RR R R

O ^ N '' reduction H O ^ V ^ _ ^ N ' :

O ^ RR O ^ R O ^ R

Thee second approach to N-acyliminium ion precursors is the electrochemical oxidationn of amides (or lactams) of type 11 and decarboxylation of N-acylated a-amino acids (viz.(viz. 13, eq 1.6). Anodic a-oxidation of lactams 11 in ethanol leads to the a-ethoxylated lactamss 12. Since the pioneering work of Shono,8 this method has been applied frequently in thee synthesis of biologically interesting compounds.9 The same types of precursors can be obtainedd by decarboxylative oxidation of a-N-acylamino acids 13. Both electrochemical processess can be applied to cyclic and linear precursors and probably proceed via the intermediacyy of an N-acyliminium ion, which is captured by a solvent molecule.810

R'' R" R' R" R' R"

NN EtOH t t u N E t O H M U U l- N

RR R R

111 12 13

1.1.33 Intermolecular N-acyliminium ion reactions

Ass the N-acyliminium ion itself is planar, the stereoselectivity has to arise from chiralityy in the substrate, the Lewis acid or the nucleophile. The stereochemical aspects of the intermolecularr N-acyliminium ion reaction of 4-hydroxy-substituted pyrrolidin-2-ones have beenn investigated by Speckamp11 and Scolastico.12 Reaction of 14 with a Lewis acid generates thee N-acyliminium ion 15, which was reacted with allyltrimethylsilane to arrive at olefinic pyrrolidin-2-oness 16 (eq 1.7). These additions proceeded with moderate frans-preference (up too 1:3 ris:trans-ratio) in the case of an acetyl-acyliminium ion, whereas the TBS and O-benzyll derivatives gave reversal of diastereoselectivity (up to 4:1 ris:frans-ratio). In these reactions,, the nature of the Lewis acid and the type of nucleophile did not have a significant influencee on the stereochemical outcome.13 The reason for this difference in selectivity can be explainedd by the ability of the acetoxy group to bridge to the adjacent cationic center, thus favoringg fraws-addition, whereas the ris-selectivity of the TBS or benzyl group can be

rationalizedd through the stabilization of the emerging a*-orbital by interaction with the adjacentt and antiperiplanar OcH-bond.14

-PR R RR = Ac RR = TBS Lewiss acid

NN

'

Inn the synthesis of 2,5-disubstituted pyrrolidines, the nature of the N-acyliminium ion intermediatee also plays an important role in the stereochemical outcome. The observed diastereoselectivityy of the nucleophilic attack of allyltrimethylsilane on bicyclic iminium ion 17,, which led preferentially to the frans-stereoisomer 18,15 is opposite to that obtained from monocyclicc iminium ion 19, which gave predominantly the a's-isomer 2016 (Scheme 1.2). The mainn difference between these substrates is the geometry around the nitrogen atom.17 In the casee of 17, the bicyclic iminium ion is distorted from planarity because of the two five-memberedd fused rings. The steric effects due to its concave shape can explain the facial selectivity.. The monocyclic iminium ion 19 almost shows no distortion from planarity. Duringg the approach trans to the C-2-methyl ester, the N-acyl group is pushed towards the methyll ester, thereby increasing the steric hindrance between the two methoxycarbonyl groups.. Conversely, ris-approach pushes the N-acyl group away from the methyl ester, whichh causes relief of steric hindrance. Therefore, the ris-isomer was predominantly formed inn the reaction of 19 with allyltrimethylsilane.

Schemee 1.2 O O O O 17 7 SiMe-, , N N P P P P ^ + ^ C P2M e e CP2Me e 188 19 cis:transcis:trans 4:96 SiMe3 3 v ^ x .N/ ^ * C P2M e e C02Me e 20 0 cis:transcis:trans 80:20 1.1.44 I n t r a m o l e c u l a r N - a c y l i m i n i u m ion reactions

Intramolecularr acyliminium ion cyclization is a powerful tool to construct N-heterocyclicc ring systems. As has been elegantly shown in our group, both bridged azabicyclicc ring systems and fused bicyclic azaheterocycles could be synthesized (Scheme 1.3).. An example of the former one is the novel iodide-promoted allene N-acyliminium ion cyclizationn of lactam 21 (eq l).1 8 Subjection to formic acid in the presence of an excess of Nal ledd to the formation of vinyl iodide 22 as the main product in 42% yield and the 4 4

c o r r e s p o n d i n gg k e t o n e 23 as a b y p r o d u c t in 34% yield. A n e x a m p l e of t h e latter o n e is t h e tertiaryy N - a c y l i m i n i u m ion cyclization of bicyclic e n a m i d e 24. By s t i r r i n g 24 in formic acid, N - a c y l i m i n i u mm i o n 25 w a s f o r m e d w h i c h r e a c t e d i n t r a m o l e c u l a r l y to a r r i v e at tricyclic s t r u c t u r ee 26 i n 92% yield as a single ris-diastereomer after t r e a t m e n t w i t h N H b / M e O H (eq 2).w w Schemee 1.3 P h - > / ^ O E> > 21 1 855 C 1)) HCOzH, rt »--2)) NH3, MeOH (1) ) (2) ) 266 92%

AA r e c e n t d e v e l o p m e n t is t h e a p p l i c a t i o n of this cationic r e a c t i o n o n solid s u p p o r t . Originallyy r e p o r t e d b y Wipf a n d C u n n i n g h a m ,2 0 _{t h e d e v e l o p m e n t a n d a p p l i c a t i o n of N}

-a c y l i m i n i u mm ion c h e m i s t r y o n solid p h -a s e w -a s extensively s t u d i e d b y V e e r m -a n -a n d M e e s t e r inn o u r g r o u p .2 1 Schemee 1.4 O O

*-*-V--

6 6

AA typical e x a m p l e is s h o w n i n S c h e m e 1.4. Resin 27 w a s p r e p a r e d i n a few s t e p s f r o m t h ee Merrifield resin. A d d i t i o n of B F3O E t2 i n d u c e d cyclization to N O - a c e t a l 28, w h i c h in situ

f o r m e dd t h e N - a c y l i m i n i u m ion t h a t w a s t r a p p e d w i t h a l l y l t r i m e t h y l s i l a n e t o a r r i v e at t h e

resinn bound functionalized pyrrolidines 29. Cleavage of the carbamate functionality using a 1.00 M solution of NaOMe in THF/MeOH afforded pyrrolidines 30.18b Via this reaction sequence,, several nucleophiles could be introduced to arrive at differently substituted pyrrolidiness in moderate to good yields.

Neww pathways for the preparation and cyclization of N-acyliminium ion precursors havee also been studied and applied as the key step in the total synthesis of natural products. Forr example, the group of Nagasaka22 reported a formal total synthesis of cephalotaxine 36 usingg sequential N-acyliminium ion reactions (Scheme 1.5). Starting from enamide 31, which wass synthesized in four steps from 4-pentyn-l-ol, generation of the acyliminium ion precursorr 32 was accomplished by oxidation with dimethyldioxirane (DMD) in the presence off MeOH. Subsequent cyclization of the unstable methoxylactam using BF3-OEt2 in CH2CI2 affordedd pyrroloisoquinoline 33 in excellent yield as a diastereomeric mixture (2:1). Ring-expansionn to a seven-membered ring via an acyliminium ion, followed by some functional groupp transformations gave enamide 34, which again could be used as an N-acyliminium ion precursor.. This time, the cyclization of 34 was achieved on exposure to TiCU in the presence off AcOH in CH2CI2 and proceeded smoothly via a tertiary acyliminium ion to arrive at the pentacyclicc P-ketoester 35 in 97% as a 1:4.3 diastereomer mixture of the cis- and frans-fused pyrrolobenzazepinee ring system.

355 cephalotaxine 36

ReagentsReagents and conditions: (a) DMD (excess), MeOH, -78 to -30 °C; (b) BFrOEt2, CH2CI2, -45 to 0 °C; (c)

TiCl4,, AcOH-CH2Cl2 (1:10), rt.

Inn another example, Padwa et al.23 _{described the total synthesis of jamtine using a}

thionium/N-acyliminiumm ion cascade, developed in their group.24 Heating a sample of enamidee 37 in camphorsulfonic acid led to the desired tricyclic core of jamtine in excellent yieldd (Scheme 1.6). The major diastereomer 39 was the result of a 4n-Nazarov type electrocyclization,, which directed the ring closure of the a-acylthiocarbenium ion to generate 6 6

thee N-acyliminium ion 38. Subsequent cyclization involved attack of the aromatic moiety on thee less hindered side of the acyliminium ion, affording tetrahydroisoquinoline 39 in 88% yield. . Schemee 1.6 MeO O

rn. .

N-Acyliminiumm ion chemistry is only one of several methodologies to construct this typee of indolizidine ring system with the lactam nitrogen at the ring-fusion position (39, 42). Anotherr strategy is the use of ring-closing metathesis as the key cyclization step. An illustrativee example is the synthesis of (3-, y- and 5-lactams, as described by Holmes and coworkerss (eq 1.8).25 Ring-closing metathesis of diolefin 41, which was obtained via an N-acyliminiumm ion reaction of lactam 40 with allyltrimethylsilane, using catalyst C in CH2CI2 affordedd lactams 42 in good yields.26

BF3OEt2 2 ^ r \ ^ , S i M e3 3

c i

4

C y 3 3

Fromm the latter example, it is clear that the combination of cationic chemistry and ring-closingg metathesis provides a powerful and efficient pathway to hetero(bi)cyclic systems.. Because this combination is used throughout this thesis, a brief survey of olefin metathesiss will be given here.

1.22 Olefin metathesis

1.2.11 I n t r o d u c t i o n

Afterr the discovery by Ziegler that transition metal catalysts can promote polymerizationn of olefins, it was found that they can also effect the mutual alkylidene exchangee reaction of olefins or 'olefin metathesis'. Currently, we understand this transformationn as a metal-catalyzed redistribution of carbon-carbon double bonds (Scheme 1.7).. The term metathesis is a composite of the Greek words meta (change) and tithemi (place).

Schemee 1.7 R ii R? R33 R4 catalyst t Ri i R3 3 R2 2 R4 4

Somee important types of olefin metathesis reactions are depicted in Scheme 1.8. The shownn examples include ring-closing metathesis (RCM), ring-opening metathesis (ROM), ring-openingg metathesis polymerization (ROMP), acyclic diene metathesis polymerization (ADMET)) and cross-metathesis (CM or XMET). Through these reactions, olefin metathesis makess unsaturated cyclic and linear molecules available that are difficult or impossible to synthesizee using different methods. Because the major part of this thesis deals with ring-closingg metathesis, this part of the introduction will be focused on this type of transformation.27 7 Schemee 1.8 CM M -C2H4 4 R1 1 1.2.22 M e c h a n i s m

AA lot of effort has been put in the elucidation of the reaction mechanism in order to understandd catalyst activity and to synthesize better and more active catalysts. Ultimately, thee mechanism developed by Chauvin28 was found to be most consistent with the experimentall evidence and is still generally accepted today (Scheme 1.9).

Schemee 1.9

H,C C

H,C' '

CH,=CH H

Itt consists of a sequence of formal [2+2] cycloadditions/cycloreversions involving alkenes (433 and 47), metal carbenes (45 and 48) and metallacyclobutane intermediates (44 and 46). Becausee all the steps of the catalytic cycle are reversible, it is necessary to shift the equilibriumm in one direction in order to make metathesis productive. In the case of ring-closingg metathesis of a diene, the process is entropically driven because RCM provides two products,, starting from one substrate molecule. If one of them is volatile (ethene), the equilibriumm shifts to one side and the desired cycloalkene will be formed predominantly.

1.2.33 Mo-based catalysts

Thee first catalysts to become widely used were the tetracoordinated alkylidene speciess of the general formula (NAr)(OR')2M=CHR (M = Mo, W), developed by the group of Schrock.299 The most active catalyst is catalyst A, shown in Chart 1. This catalyst exhibits very highh activity to cyclize internal and terminal alkenes as well as sterically demanding and electron-poorr substrates.

Chartt 1

Thiss catalyst has been the only catalyst for a long time that allowed the formation of tetrasubstitutedd olefins 50 from diolefin 49 (Scheme 1.10)30 (only recently, Ru-based catalysts weree discovered which allow the synthesis of these products as well, see; Section 1.2.4). An additionall advantage is its tolerance towards some functional groups that inhibit Ru-based catalystss (see: Section 1.2.4), such as sulfur-containing precursors.

Schemee 1.10 EE E catalyst t 49 9 A A C C D D E E 93% % 0% % 40% % 31% % EE E

Anotherr advantage of this metathesis catalyst is that the alkoxides in the [Mo] system cann be readily exchanged to adjust their reactivity. Because of this feature, it is relatively simplee to synthesize a chiral catalyst to perform catalytic asymmetric ring-closing metathesis. Thee field in which the asymmetric olefin metathesis can have the largest impact is the desymmetrizationn of achiral molecules, as illustrated in eq 1.9. Treatment of achiral triene 51 withh 2 mol% of chiral catalyst B led within 5 minutes at room temperature to the formation off (R)-52 in 93% chemical yield and in 99% enantiomeric excess.31 In this way, readily accessiblee achiral substrates are rapidly transformed into optically enriched molecules that aree difficult to make via other methodologies.

catalystt B (2 mol%) noo solvent, rt catalystt F (5 mol%), Nall (1 equiv) THF,rt t O O (R)-52 2 93%% cy 99%% ee 82%% conv. 90%% ee (1.9) )

However,, these Mo-catalysts are limited by the high oxophilicity of the metal center andd therefore are very sensitive toward oxygen and moisture. Another disadvantage of these earlyy metal catalysts is the poor functional group tolerance, which reduces the number of substratess substantially.

1.2.44 R u - b a s e d catalysts

Thee development of ruthenium carbene complex C (Chart 2) by Grubbs and coworkers322 meant a breakthrough in olefin metathesis. This catalyst proved to be a highly activee (pre)catalyst for all types of alkene metathesis. Although its activity is lower than that 10 0

off molybdenum alkylidene A (no formation of tetrasubstituted olefin 50, Scheme 1.10), its tolerancee towards a wide range of functional groups such as alcohols, acids, aldehydes, acetals,, amines, amides etc,33 together with its stability against oxygen, water and minor impuritiess in the solvent renders it much more practical. These properties are particularly usefull for their use in natural product synthesis, in which often many functional groups are present.344 This catalyst has its highest activity in chlorinated solvents, so that in most cases, dichloromethanee or -ethane is used.

Inn order to increase the lifetime and reactivity of the reactive intermediates, the ligandd on the ruthenium atom should be more basic and more sterically demanding than PCy3.. Ligands that meet these criteria are the N-heterocyclic carbenes (NHC),35 _{which were}

firstt described as metal-carbene complexes by Wanzlick.36 The most widely used catalysts containingg this type of ligand are the Nolan catalyst D37 with an unsaturated mesityl-substitutedd N-heterocyclic carbene and the 2nd generation Grubbs' catalyst E,38 which has a saturatedd backbone (Chart 2). They combine the resistance towards oxygen and moisture andd the functional group tolerance of the parent Grubbs' catalyst C with the reactivity of Schrock'ss molybdenum alkylidene complex A. In addition, they show an exceptional thermal stabilityy and superior reactivity at elevated temperatures. For example, these Ru-based catalystss are able to perform RCM of sterically demanding dienes to form tetrasubstituted olefins,, albeit in lower yields (Scheme 1.4). The reactivity of D and E is greater in toluene thann in chlorinated solvents. This can be attributed to competing interactions of the N-mesityll group with the aromatic solvent, which reduces the stabilizing effect of the intramolecularr 7i-re-stacking with the benzylidene moiety and therefore provides greater conformationall freedom, which results in higher activity.39

Chartt 2

c,^

CI//X X

r r

cr r

W W

NMess ArNt ^NAr

PCy33 Ph w ' PCy3 Ph Cl*^^ ' Arr = o-isopropylphenyl DD E F

Thee introduction of the NHC-ligands in olefin metathesis also provides a new entryy into asymmetric RCM. Up to now, only one report concerning enantioselective ruthenium-catalyzedd RCM has appeared in literature. Grubbs40 synthesized enantiomerically puree catalyst F that contains a chiral N-heterocyclic carbene. This catalyst was tested in the desymmetrizationn of substrate 51 (eq 1.9) and it was found that in the presence of Nal, which exchangedd the chloride ligands for an iodide, high enantioselectivity (90% ee) and high conversionn were achieved. The enantioselectivity proved to be neither solvent, nor temperaturee dependent. The activity and stability of catalyst F was found to be similar to thatt of catalyst E. Because of the ease of handling and its functional group tolerance, these

enantiopuree Ru-based catalysts may well expand the use of enantioselective olefin metathesiss in the near future.

Withh all of these metathesis catalysts available, ring-closing metathesis has become a powerfull tool to synthesize ring systems of almost every possible ring size. It should be mentioned,, however, that despite its enormous potential, not all substrates are suitable precursors.. For example, formation of 8-10-membered rings might be problematic because of thee entropically unfavorable ring size. For some substrates this problem is not as serious, namelyy in cases where the substrate is forced in a favorable conformation for ring closure (preorientationn of the alkene functional groups).27b

1.33 General aspects

1.3.11 (£)/(Z)-ratio

Especiallyy in the construction of macrocyclic carbo- and heterocycles, another drawbackk of RCM shows up. The formed cycloalkenes are usually mixtures of (E)- and (Z)-isomers.. The ratio of these isomers can neither be controlled nor properly predicted, because thee selectivity changes with ring size and position of the olefin, but usually the (E)-isomer is beingg favored. Recently, NHC-containing metathesis catalysts were shown to be particularly (E)-selective,, because of isomerization of the ring-closed product to the thermodynamic ring closuree product.41 An illustrative example is the synthesis of the macrolide core of salicylihalamidee (eq 1.10). Macrocyclic ring closure of dienes 53 with catalyst D led to macrocycless 54 with a completely different stereochemical outcome, depending on the protectivee group on the phenolic alcohol.42 The free alcohol gave selectively the (Z)-isomer, whereass a MOM or methyl group gave predominantly the (E)-isomer. Thus far, only macrocyclicc (Z)-alkenes could be synthesized in a selective and predictable manner. This was achievedd via a protocol developed by Fiirstner, comprising alkyne metathesis, followed by Lindlarr reduction.43 OPMBB r~OPMB R £ : Z „ O M O MM . , . _ y^^y<r/ \,,-OMOM catalystt D 54 4 H H TBS S Me e MOM M 0 0 40 0 66 6 68 8 100 0 60 0 34 4 32 2 (1.10) ) 1.3.22 E n y n e metathesis

Onee type of ring-closing metathesis, which has received much less attention than dienee metathesis, is alkene-alkyne (enyne) metathesis. This process formally implies the

formationn of a new carbon-carbon double bond between the triple and the double bond to givee the cyclized product 56 and the migration of the alkylidene part of the alkene 55 (C-R2) ontoo the alkyne carbon, to form a diene moiety (Scheme l.ll).4 4 This reaction can be performedd with all catalysts described above. It is relevant to note that this catalytic process hass a more favorable atom economy than diene metathesis because no olefin is expelled.

Schemee 1.11

55 5

catalyst t

56 6

Inn contrast with RCM, the mechanism of this transformation is not yet completely clear.. Methylidene ruthenium-carbene complex 62 should react first with the alkyne from enynee 57 to form ruthenacyclobutene 58 via a [2+2] cycloaddition reaction (Scheme 1.12).45

ViaVia a [2+2] cycloreversion reaction it is converted into vinylcarbene complex 59, which reacts intramolecularlyy to give ruthenacyclobutane 60. Subsequent bond fission gives cyclized dienee 61 and methylidene ruthenium complex 62, which propagates the catalytic cycle. On thee other hand, when 62 reacts first with the olefin moiety of enyne 57, a similar catalytic cyclee would occur and the same final product would be obtained.46

Schemee 1.12 H,C C [M]=CH2 2 62 2 HoC C 59 9 13 3

1.44 Purpose and outline of the investigation

Thee main goal of this investigation is to combine heteroatom-stabilized carbocation chemistryy and ring-closing metathesis to develop general synthetic methodology to construct bicyclicc heterocycles.

Chapterr 2 describes the synthesis of various 2-substituted chromenes, in which first thee core skeleton is constructed using RCM, followed by variation of the substituents at the 2-positionn via oxycarbenium ion chemistry.

Chapterr 3 deals with the synthesis of frans-fused bicyclic lactams, which were obtainedd via RCM of 4,5-frans-disubstituted pyrrolidin-2-ones. Introduction of several differentt olefinic groups on the pyrrolidin-2-ones was accomplished by N-acyliminium ion chemistry. .

Inn the final chapter of this thesis, Chapter 4, research directed at the synthesis of bridgedd bicyclic lactams with the nitrogen at the bridgehead position is described. In addition,, the preparation of homotropene structures with the nitrogen at the bridging positionn is investigated. First, N-acyliminium ion chemistry was used to introduce the alkene functionalities,, followed by a RCM reaction of the resulting dienes and trienes.

1.55 References

ii Romero, J. A. C ; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2000,122,168.

22

For stereoelectronic aspects of the addition reaction, see: Deslongchamps, P. Stereoelectronic EffectsEffects in Organic Chemistry; Pergamon: New York, 1983, 209.

33

Rutjes, F. P. J. T.; Kooistra, T. M.; Hiemstra, H.; Schoemaker, H. E. Synlett 1998,192.

44

For a recent review, see: Arend, M.; Westermann, B.; Risch, N. Angew. Chem. Int. Ed. 1998, 37,37,1045. 1045.

55

(a) Traxler, P.; Trinks, U.; Buchdunger, E.; Mett, H.; Meyer, T.; Muller, M.; Regenass, U.; Rösel,, J.; Lydon, N. ƒ. Med. Chem. 1995, 38, 2441; (b) Overman, L. E.; Ricca, D. J. in

ComprehensiveComprehensive Organic Synthesis, Trost, B. M.; Fleming, I.; Heathcock, C. H. Eds.; Pergamon: Oxford,, 1991 Vol. 2, p. 1007.

66

For reviews on N-acyliminium ion chemistry, see: (a) Speckamp, W. N.; Hiemstra, H.

TetrahedronTetrahedron 1985, 41, 4367; (b) Hiemstra, H.; Speckamp, W. N. in The Alkaloids, Brossi, A. Ed.; Academic:: Oxford, 1988; Vol. 32, pp 271-339; (c) Hiemstra, H.; Speckamp, W. N. in

ComprehensiveComprehensive Organic Synthesis, Trost B. M.; Fleming, I. Eds.; Pergamon: Oxford, 1991; Vol. 2, p.. 1047-1082; (c) de Koning, H.; Moolenaar, M. J.; Hiemstra, H.; Speckamp, W. N. in Bioactive

Naturall Products (part A); Studies in Natural Products Chemistry, Atta-ur-Rahman, Ed.; Elsevier:: Amsterdam, 1993; Vol. 13, p p 473-518; (d) de Koning, H.; Speckamp, W. N. in

Houben-Weyl,Houben-Weyl, Methods in Organic Chemistry, Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann,, E. Eds.; Thieme: Stuttgart, 1995; Vol. E21b, p p 1953-2009; (e) Speckamp, W. N.;

Moolenaar,, M. J. Tetrahedron 2000,56, 3817.

77 Hubert, J. C ; Speckamp, W. N.; Huisman, H. O. Tetrahedron Lett. 1972, 13,4493.

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