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Synthesis of oxygen and nitrogen heterocycles via stabilized carbocations and
ring closing metathesis.
Doodeman, R.
Publication date
2002
Link to publication
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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SYNTHESISS OF OXYGEN E N N I T R O G E N HETEROCYCLES
VIAVIA STABILIZED CARBOCATIONS A N D RING-CLOSING METATHESIS
Thee construction of C-C-bonds is one of the most important reactions in organic synthesis.. A powerful method to make these bonds is the addition of carbon nucleophiles to N-acyliminiumm ions. Already for a long period, there has been significant interest in our groupp for this type of transformation and valuable insight has been gained in inter- and intramolecularr reactions. Together with addition reactions to the related, but somewhat less intensivelyy studied oxycarbenium ions, they form an important access to new, substituted heterocycles.. Another versatile C-C-bond forming reaction, which has attracted widespread attentionn in recent years, is the ring-closing olefin metathesis reaction. Olefin metathesis is a processs in which carbon-carbon double bonds are redistributed in the presence of metal-carbenee complexes. Major advances in catalyst design in the last few years gave access to manyy new applications and transformations. This thesis describes the combination of carbocationicc chemistry and ring-closing metathesis, two versatile methods which offer a powerfull entry into the construction of new, biologically interesting compounds.
Inn Chapter 1, an introduction into the chemistry of N-acyliminium- and oxycarbeniumm ions and into ring-closing metathesis is presented. Chapter 2 describes the synthesiss of several 2-substituted 2H-chromenes. The general strategy is outlined in Scheme 1,, in which the core skeleton is constructed first using ring-closing metathesis (RCM), followedd by introduction of different substituents at the 2-position via an oxycarbenium ion intermediate. . Schemee 1 OR" " Pd(OAc)22 (cat.) dppp,, Et3N MeCN N RR = H, Br, OMe R" = Me, Bn RR = H, Me RCM M OO OR" Lewiss acid CH2C12 2 Nucleophilee R OO Nu
Vinylphenolss 1 were obtained by a standard Wittig reaction from the corresponding commerciallyy available aldehydes or ketones. These phenols were reacted with two
alkoxy-Summary alkoxy-Summary
1,2-propadieness under Pd-catalyzed reaction conditions to arrive at the allylic acetals 2. Benzyloxy-l,2-propadienee (R" = Bn) appeared to react significantly faster and under milder conditionss than methoxy-l,2-propadiene (R" = Me), also resulting in higher yields. These diolefinss were subjected to ring-closing metathesis conditions to yield the chromene core skeletonn 3. In this reaction, the imidazol-2-ylidene-substituted Ru-catalyst proved to be superiorr over the conventional Grubbs' catalyst. Introduction of various nucleophiles at the 2-positionn via the strongly colored and aromatic 1-benzopyrylium ion 4 proceeded uneventfullyy to yield the desired products 5.
Chapterr 3 deals with the synthesis of 4,5-disubstituted frans-fused bicyclic lactams. Startingg from isopropoxylactam 6, which was obtained enantiomerically pure via an enzymaticc route, Michael addition with several derivatives of dimethyl malonate afforded lactamss 7 with complete f raws-selectivity (Scheme 2). Alternatively, the unsaturated substituentt at C-4 could be introduced via a cuprate addition of alkenyllithium species to arrivee at lactams 8 without the two ester groups. Subsequent removal of the acetyl group usingg pyrrolidine afforded the N-acyliminium ion precursors. This time, the N-acyliminium reactionn was used to introduce the second alkene or an acetylenic moiety, in order to be able too perform ring-closing metathesis. Thus, these N,0-acetals were reacted with three different nucleophiles,, i.e. allyltrimethylsilane, allenylmethyltrimethylsilane and allenyltributyltin to affordd diene 9, triene 10 and enyne 15, respectively, all containing the rrans-configuration in thee 5-membered ring.
Schemee 2
O^V'-'O'Pr r
Ac c 6 6 Michaell or cupratee addition C02Me e RR R RCM M 16 6 1)) deacetylation 2)) N-acyliminium ionn chemistry RR R 0 - ^ N N ""O'Pr r Ac c 77 R = C02Me 88 R = H 1)) deacetylation 2)) N-acyliminium ionn chemistry Me02Cxx C02Me H H 15 5 Me02C C 122 R1 = CH7Thee following ene-ene ring-closing metathesis reactions of 9 and 10 furnished the desiredd (raws-fused bicyclic lactams 11 and 12. Interestingly, 7-membered rings were formed 126 6
mostt readily, followed by the 8- and the 12-membered rings. Unfortunately, the synthesis of thee 9- and 10-membered ring could not be accomplished. In addition, the reactions of the substratess with the two ester groups were higher yielding, probably because of the preferred conformationn for ring-closing metathesis. It was also observed that only the least substituted doublee bond of the diene reacted in the metathesis reaction. The same influence of the ring sizee on the ring closure could be seen in the enyne metathesis of 9. The frans-fused 7-memberedd ring bicycle 13 (n = 1) was formed, although the reaction needed three days at 70 °CC to go to completion, but all efforts to obtain the 8- and 10-membered ring failed. Besides, attemptss to form trienes 14 on reaction of the acetylene with the diene failed. Reversal of the positionn of the olefin and acetylene (e.g. 15) had a positive effect on the reaction speed. The trans-fusedd bicyclic lactam 16 (n = 1) was formed much faster than 13 and also the 8-memberedd ring (n = 2) could be isolated.
Inn Chapter 4, the efforts to arrive at bridged azabicyclic systems are described. The initiall approach started with commercially available succinimide 17 and glutarimide 18. Introductionn of the first olefinic moiety via N-alkylation using NaH and alkenyl bromides, partiall reduction of the imide to the ethoxylactam and finally C-alkylation using LHMDS andd alkenyl bromides afforded diolefins 19 (Scheme 3). Unfortunately, all attemps to cyclize thesee compounds failed. Only once, a small amount of compound 20 could be isolated, but thiss result was not reproducible. In addition, the cyclizations of N-alkylated diolefins 22 provedd to be difficult. Only the 13-membered ring bicycle 23 could be obtained in a reproduciblee fashion. Schemee 3 o^=KK x ^ O 00 N u H H 177 n = l 188 n = 2 1) ) 2) ) 3) ) Me02CC C02Me FF wn
O^V'-'O'Pr r
H H 211 n = 1-4,6 N-alkylation n reduction n *~ *~ C-alkylation n N-alkylation n i-v"**-- ^~~OFt 00 N u c x 199 m = 1-3 p = 1-3 MeOzCC C02Meo^V'-oW W
mmk^ k^
222 m = 1,3 j * * 7 \ \ RCM M EtO O M e 02Cx/ C ° 2M e e 0 ^ ^ 23 3V-W W
nn = 6, m = 1Becausee it proved to be difficult to cyclize dienes with one of the alkenes connected to nitrogen,, we turned our attention to ring systems with the nitrogen atom adjacent to the bridgeheadd position. Ethoxylactam 24 was chosen as the starting compound (Scheme 4). Alkylationn using LDA and allyl bromide and protection of the hydroxy functionality
Summary Summary
providedd the N-acyliminium ion precursor 25. This was reacted with BF3-OEt2 and allyltrimethylsilanee to give 26. Reaction of this diene with catalyst C gave cyclizarion to bridgedd bicyclic lactam 27.
Schemee 4
O O
PHH 1) C-alkylation 2)) protection
OAc c Lewiss acid TMS S
OEt t O ^ NN 0 E t M e C N Ph h 24 4 Ph h RCM M toluene e OAc c 25 5 AcO„ „ 44 OAc, P hh 26 cis/cis/ trans 1:4
Finally,, in Chapter 4, the synthesis of azabicyclo[4.x.l]alk-3-enes with a bridging nitrogenn atom is described (Scheme 5). Starting from succinimide 17 and glutarimide 18, the firstt allyl group was introduced in a one-pot procedure. Substitution at nitrogen with a tosyl, ferf-butoxycarbonyll and methoxycarbonyl group, followed by partial reduction of the lactam withh NaBH4 and PFTS in methanol yielded N,0-acetals 28. These were reacted in an N-acyliminiumm ion reaction with different nucleophiles to arrive at diolefins 29 and triolefins 30,, in which the 6-membered ring gave a higher ris/frans-ratio than the corresponding 5-memberedd ring and the methoxycarbonyl group gave a better ratio than the tosyl group. The lastt step was the ring-closing metathesis reaction of the cis-precursors, which afforded the desiredd azabicyclo[4.2.1]non-3-enes 31 and azabicyclo[4.3.1]dec-3-enes 32. In these reactions, thee 6-membered ring gave higher yields than its 5-membered ring counterpart. Structures of typee 31 an 32 are interesting because of their appearance in natural products with important biologicall activity, such as cocaine.
Schemee 5 MgBr r Lewiss acid Nucleophile e 299 R' = H2 300 R' 128 8
