34
REVIEW 187 The Oxa-Pictet–Spengler Cyclization: Synthesis of Isochromans and Related Pyran-Type Heterocycles The Oxa-Pictet–Spengler Cyclization Enrique L. Larghi, Teodoro S. Kaufman* Instituto de Química Orgánica de Síntesis (IQUIOS, CONICET-UNR) and Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, (S2002LRK) Rosario, República Argentina Fax +54(341)4370477; E-mail: [email protected] Received 29 June 2005; revised 22 August 2005 SYNTHESIS 2006, No. 2, pp 0187–0220xx.xx.2005 Advanced online publication: 21.12.2005 DOI: 10.1055/s-2005-918502; Art ID: E14105SS © Georg Thieme Verlag Stuttgart · New York Abstract: Compounds bearing the isochroman ring system are found in natural and synthetic products of interest. The oxa-Pictet– Spengler condensation is a valuable tool for the preparation of polysubstituted isochromans and related oxygen-bearing heterocy- cles. The different stagings of the oxa-Pictet–Spengler reaction, as well as the scope and limitations of this transformation, are dis- cussed. 1 Introduction 2 Intermolecular Oxa-Pictet–Spengler Condensation 2.1 Synthesis of 1-Substituted Isochromans 2.2 Synthesis of 1,1-Disubstituted Isochromans 2.3 Diastereoselective Synthesis of 1,3-Disubstituted Isochro- mans 2.4 Synthesis of 3-Substituted Isochromans 2.5 Synthesis of C-4 Substituted Isochroman Derivatives 3 Intramolecular Oxa-Pictet–Spengler Cyclizations 3.1 Synthesis of 1-Substituted Isochromans 3.2 Diastereoselective Synthesis of 1,3-Disubstituted Isochro- mans 3.3 Synthesis of 1,3,4-Trisubstituted Isochromans 4 The Oxa-Pictet–Spengler Condensation in the Absence of Acid Catalysts 5 Naturally Occurring Oxa-Pictet–Spengler Cyclizations 6 Oxa-Pictet–Spengler Reactions towards Optically Active Compounds 7 Synthesis of Heterocycles other than Isochroman Deriva- tives 8 Conclusions Key words: oxa-Pictet–Spengler, cyclization, isochromans, natural products, chemical synthesis 1 Introduction The isochroman template is present in structures of drugs (medicines, agrochemicals, etc.) and drug candidates, as well as among natural products. Compound 1, found in the leaves of Tectaria subtrifilla 1 and stephaoxocanine (2), obtained from Stephania cepharantha 2 are selected examples of isochromans of vegetal origin (Figure 1) . In addition, DMHI (3a), a plant growth regulator isolated from Penicillium steckii of terrestrial and marine origin, 3 the anticoccidial isochroman 3b, originally found in a hy- brid strain of Penicillium citreo-vitride, later in Penicilli- um sp. FO-2295 and recently in Penicillium expansum, 4 glucoside B (4), an aphid insect pigment derivative 5 and bioxanthracene 5, 6 a promising antimalarial agent, consti- tute examples of natural isochromans obtained from in- sects and microorganisms. Furthermore, the synthetic isochroman galaxolide (6) 7 and the tricyclic etodolac (7), 8 bearing the related pyra- no[3,4-b]indole ring, are isochromans with commercial importance in the cosmetics and drug industries. Figure 1 Isochromans can also be found among synthetic investi- gational drugs, such as the series of compounds related to 8 (Figure 2), which have been recently described as herbi- cides. 9 There are also families of natural and synthetic products akin to the isochromans bearing a more oxidized hetero- cyclic ring. These include isochroman-3-ols 10a,b and the related isochroman-3-ones, such as the antibiotic cytosporone D (9) which is an example of the phenylace- R 3 O OH Me Me OH HO GlcO O OMe MeO N OH H O Me 4 5 2 R 2 O OR 4 O 6 Me Me Me Me Me Me N O H Me CO 2 H Me 7 O Me HO HO 1 Me Me O OH Me Me OH MeO MeO O OH Me Me OH MeO MeO R 1 3a R 1 = R 4 = H, R 2 = R 3 = Me 3b R 1 = R 4 = Me, R 2 = R 3 = H

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  • REVIEW 187

    The Oxa-Pictet–Spengler Cyclization: Synthesis of Isochromans and Related Pyran-Type HeterocyclesThe Oxa-Pictet–Spengler CyclizationEnrique L. Larghi, Teodoro S. Kaufman*Instituto de Química Orgánica de Síntesis (IQUIOS, CONICET-UNR) and Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, (S2002LRK) Rosario, República ArgentinaFax +54(341)4370477; E-mail: [email protected] 29 June 2005; revised 22 August 2005

    SYNTHESIS 2006, No. 2, pp 0187–0220xx.xx.2005Advanced online publication: 21.12.2005DOI: 10.1055/s-2005-918502; Art ID: E14105SS© Georg Thieme Verlag Stuttgart · New York

    Abstract: Compounds bearing the isochroman ring system arefound in natural and synthetic products of interest. The oxa-Pictet–Spengler condensation is a valuable tool for the preparation ofpolysubstituted isochromans and related oxygen-bearing heterocy-cles. The different stagings of the oxa-Pictet–Spengler reaction, aswell as the scope and limitations of this transformation, are dis-cussed.

    1 Introduction2 Intermolecular Oxa-Pictet–Spengler Condensation2.1 Synthesis of 1-Substituted Isochromans2.2 Synthesis of 1,1-Disubstituted Isochromans2.3 Diastereoselective Synthesis of 1,3-Disubstituted Isochro-

    mans2.4 Synthesis of 3-Substituted Isochromans2.5 Synthesis of C-4 Substituted Isochroman Derivatives3 Intramolecular Oxa-Pictet–Spengler Cyclizations3.1 Synthesis of 1-Substituted Isochromans3.2 Diastereoselective Synthesis of 1,3-Disubstituted Isochro-

    mans3.3 Synthesis of 1,3,4-Trisubstituted Isochromans4 The Oxa-Pictet–Spengler Condensation in the Absence of

    Acid Catalysts5 Naturally Occurring Oxa-Pictet–Spengler Cyclizations6 Oxa-Pictet–Spengler Reactions towards Optically Active

    Compounds7 Synthesis of Heterocycles other than Isochroman Deriva-

    tives8 Conclusions

    Key words: oxa-Pictet–Spengler, cyclization, isochromans, naturalproducts, chemical synthesis

    1 Introduction

    The isochroman template is present in structures of drugs(medicines, agrochemicals, etc.) and drug candidates, aswell as among natural products. Compound 1, found inthe leaves of Tectaria subtrifilla1 and stephaoxocanine(2), obtained from Stephania cepharantha2 are selectedexamples of isochromans of vegetal origin (Figure 1) .

    In addition, DMHI (3a), a plant growth regulator isolatedfrom Penicillium steckii of terrestrial and marine origin,3

    the anticoccidial isochroman 3b, originally found in a hy-brid strain of Penicillium citreo-vitride, later in Penicilli-um sp. FO-2295 and recently in Penicillium expansum,4

    glucoside B (4), an aphid insect pigment derivative5 andbioxanthracene 5,6 a promising antimalarial agent, consti-tute examples of natural isochromans obtained from in-sects and microorganisms.

    Furthermore, the synthetic isochroman galaxolide (6)7

    and the tricyclic etodolac (7),8 bearing the related pyra-no[3,4-b]indole ring, are isochromans with commercialimportance in the cosmetics and drug industries.

    Figure 1

    Isochromans can also be found among synthetic investi-gational drugs, such as the series of compounds related to8 (Figure 2), which have been recently described as herbi-cides.9

    There are also families of natural and synthetic productsakin to the isochromans bearing a more oxidized hetero-cyclic ring. These include isochroman-3-ols10a,b and therelated isochroman-3-ones, such as the antibioticcytosporone D (9) which is an example of the phenylace-

    R3

    O

    OH

    Me

    MeOH

    HO

    GlcO

    O

    OMe

    MeO

    N

    OH

    HO

    Me

    4

    5

    2

    R2O

    OR4

    O

    6

    MeMe

    MeMe

    Me

    Me

    NO

    HMe CO2HMe

    7

    O

    Me

    HO

    HO

    1

    MeMe

    O

    OH

    Me

    MeOH

    MeO

    MeO

    O

    OH

    Me

    MeOH

    MeO

    MeO

    R1

    3a R1 = R4 = H, R2 = R3 = Me3b R1 = R4 = Me, R2 = R3 = H

  • 188 E. L. Larghi, T. S. Kaufman REVIEW

    Synthesis 2006, No. 2, 187–220 © Thieme Stuttgart · New York

    tic acid lactone derivatives of rare occurrence in nature10c

    and relatively scarce among synthetic compounds.10d

    The isochroman-1-ols, which include important naturalproducts such as the topoisomerase II inhibitor CJ-12,37311a (10a) and the structurally similar antitumor andamiloid aggregation inhibitor 10b isolated from Penicilli-um simplicissimum FERM BP-6357,11b constitute anothergroup, while the related tetrahydroisocoumarins such asthe inhibitor of pollen development 6-hydroxymellein(11)12 are members of a third family of products bearingisochroman rings.

    Figure 2

    Isochroman derivatives are structural analogues of tet-rahydroisoquinolines and have been repeatedly recog-nized as such.13 This analogy has been exploited andseveral studies report on the use of isochromans as start-ing materials or intermediates for the synthesis of isoquin-oline derivatives14 and vice versa,15 as well as for thepreparation of other nitrogen-bearing heterocycles.16

    Moreover, naturally occurring isochroman derivativeshave been isolated and described as precursors ofisoquinolines17 and isochroman analogues of isoquinolinealkaloids have also been synthesized.18

    Contrasting with the relative scarcity of isochromans innature, the 1-substituted tetrahydroisoquinolines and 1-substituted b-carbolines are among the most abundantclasses of natural products. This is the result of the meta-bolic systems present in many plants, which biosynthesizethese compounds by complex enzymatic processes.19

    Emulating nature, Pictet and Spengler devised a syntheticprotocol which was initially employed towards the elabo-ration of tetrahydroisoquinolines,20 but which later dem-onstrated to be useful for accessing b-carbolines.21 In its simplest form, this reaction consists in the cyclocon-densation of a b-phenethylamine with a carbonyl com-pound under acidic conditions, to give a Schiff base whichis protonated in situ generating an iminium salt; in turn,this undergoes an intramolecular electrophilic aromatic

    Enrique L. Larghi wasborn in Rosario (Santa Fe,Argentina). He received hisBS in Chemistry in 1997from the National Universi-ty of Rosario (Argentina).He immediately started re-search work at the Univer-

    sidade Federal de SantaMaría (Brazil) where he re-ceived his MSc in 1999(with Dr. Claudio C. Silvei-ra) and his PhD in chemistryin 2003 (with Dr. AdemirFarias Morel). After a shortexperience in the Argentine

    pharmaceutical industry, hejoined Dr. Kaufman’s groupas a postdoctoral researchfellow. His areas of researchare organometallic chemis-try and synthesis of hetero-cyclic natural products.

    Teodoro S. Kaufman wasborn near Moises Ville(Santa Fe, Argentina). Hegraduated as Biochemist(1982) and Pharmacist(1985) from the NationalUniversity of Rosario (Ar-gentina). He received hisPhD in organic chemistryfrom the same university(1987), working with Pro-fessor Edmundo A. Rúvedaon the synthesis ofgeochemically interestingterpenoids. From 1987 to1989, he was a postdoctoral

    fellow in the laboratory ofProfessor Robert D. Sindel-ar at The University of Mis-sissippi, working on thedesign and synthesis of ana-logues of the naturally oc-curring complementinhibitor K-76. In 1990, hereturned to Argentina wherehe became Assistant Re-search Scientist of the Ar-gentine National ResearchCouncil (CONICET) andAssistant Professor at theNational University of Ro-sario. He is now Associate

    Professor, and Sub-Directorof IQUIOS, the Institute ofSynthetic Organic Chemis-try (Rosario, Argentina),where he heads a small re-search group as IndependentResearch Scientist ofCONICET. His areas of re-search are synthetic meth-odology, asymmetricsynthesis and natural prod-ucts synthesis. The work inhis laboratory has been sup-ported by ANPCyT,CONICET, Fundación An-torchas, IFS and TWAS.

    Biographical Sketches

    O

    (CH2)nCH3

    OH

    HO2C

    HO

    OH

    10a n = 610b n = 4

    11

    8

    O

    OH

    HO

    O

    Me

    O

    Me

    OEt

    F

    F

    O

    O

    HO

    OH

    HO

    Me

    9

  • REVIEW The Oxa-Pictet–Spengler Cyclization 189

    Synthesis 2006, No. 2, 187–220 © Thieme Stuttgart · New York

    substitution reminiscent of a Friedel–Crafts-type cycliza-tion. The Pictet–Spengler condensation is currently an ex-cellent and extensively exploited tool for the synthesis ofisoquinolines, b-carbolines and other nitrogen-bearingheterocycles.

    The oxygen version of the Pictet–Spengler reaction wastermed the ‘oxa-Pictet–Spengler reaction’ for the firsttime by Wünsch and Zott in 1992.22 In this reaction, acompound such as a 2-arylethanol reacts with an aldehydeor a ketone, as such or in masked form, to give an aromaticcompound with a newly formed pyranic ring. In the caseof 2-phenylethanols, 3,4-dihydro-1H-benzo[c]pyranic(isochromanic) structures are formed.

    Because of their comparative scarcity, isochromans andrelated heterocycles are a relatively little-studied class ofcompounds and thus it is not surprising that the oxa-Pict-et–Spengler condensation has received less attention thanits nitrogen counterpart; however, this protocol consti-tutes a very important strategy for the synthesis of iso-chromans and other oxygenated heterocycles.

    Interestingly, the analogy between isoquinolines (12) andisochromans (13) can be extended to b-carbolines (14)and 1,3,4,9-tetrahydropyrano[3,4-b]indoles (15) and oth-er heterocycles, as shown in Figure 3; this offers the pos-sibility of employing the oxa-Pictet–Spengler cyclizationfor the synthesis of different heterocycles.

    Figure 3

    The oxa-Pictet–Spengler reaction seems to be relativelynew; however, as this review will show, the use of this re-action for the preparation of isochromans is of long dateand the transformation has been carried out under differ-ent names. The reaction has been classified in the litera-ture as a special case of either the Friedel–Craftsalkylation, the Prins cyclization or the Mukaiyama reac-tion, among others.

    It was found that activated substrates need moderatelymild conditions;23 the reaction has been described as tak-ing place in the absence of added acid catalyst and it isknown that sometimes only a weak promoter such as acarboxylic acid is sufficient. However, the literaturerecords many examples in which the cyclization was ac-complished under more difficult operative conditions,such as by the use of typical Lewis or Brönsted acids ascatalysts, and several articles record the use of high reac-tion temperatures or prolonged reaction times.

    The ease with which some activated b-phenethyl alcoholsundergo the oxa-Pictet–Spengler cyclization inducedGuiso to suppose that not all of the isolated isochromansmay be truly natural products.24,25 Among the artifacts,compound 1 isolated from the leaves of Tectaria subtrifil-la by an acetone extraction procedure1a may be a likely ex-ample, in view of the abundance of the hydroxytyrosol26

    precursor in this plant.27

    The chemistry of isochromans has been partially reviewedin short articles dating 15 years or more, covering theirpreparation, chemical properties and some selected appli-cations.28

    No recent reviews are available, however, despite thatseveral important improvements, as well as new, moregeneral and powerful methodologies have been described,aiming towards the synthesis of isochromans.

    In this review, we provide an overview of the oxa-Pictet–Spengler reaction as a key synthetic tool towards the iso-chroman and related ring systems, including its applica-tion for the preparation of optically active compounds.However, the use of the so-synthesized oxa-heterocyclesfor the elaboration of more complex targets is not alwaysfully covered.

    2 Intermolecular Oxa-Pictet–Spengler Condensation

    The oxa-Pictet–Spengler reaction has been implementedintermolecularly by reaction of b-arylethanols and alde-hydes, ketones or their surrogates. Depending on the na-ture of the starting b-arylethanol and carbonylcomponents, this condensation has been used to provide1-substituted (aldehydes) and 1,1-substituted (ketones)derivatives, as well as polysubstituted compounds withfunctionalization on C-3 and C-4. In the latter cases, thepossibility of diastereoselective synthesis, particularly by1,3-induction, has been observed and recorded.

    2.1 Synthesis of 1-Substituted Isochromans

    Campaigne informed that reaction of 3,4-dimethoxyphen-ethyl alcohol with aminoacetal in dioxane under hydro-chloric acid catalysis gave 82% of the corresponding 1-aminomethylisochroman 16a.29

    Later, in an analogous fashion, the group of Macchia elab-orated isochromans 16–19 as conformationally restrictedanalogues of the sympathomimetic catecholamines(Figure 4).30 The syntheses were carried out by employingpartial modifications of the protocols previously used byKumar and co-workers in their preparation of 19a.30c

    More recently, the group of Guiso effected changes to theoxa-Pictet–Spengler reaction,24 and proposed that theirmodified version could be generalized to obtain 1-benzyl-isochromans as oxygenated analogues of benzyltetrahy-droisoquinoline alkaloids such as coclaurine (20).

    NH

    O

    NN

    H

    NO

    H

    H1

    2

    345

    6

    78

    1

    2

    345

    6

    78

    1

    2

    345

    6

    78

    1

    2

    345

    6

    78

    12 14

    1513

  • 190 E. L. Larghi, T. S. Kaufman REVIEW

    Synthesis 2006, No. 2, 187–220 © Thieme Stuttgart · New York

    Figure 4

    In order to test this hypothesis, Guiso and co-workers pre-pared several oxygenated analogues of 1-alkyl- and 1-phenyltetrahydroisoquinolines by the oxa-Pictet–Spen-gler protocol (Scheme 1).25 This included 6,7-demeth-yloxacoclaurine (21), which was synthesized bycondensation of 4-hydroxyphenylethanal (22), an oxida-tion product of tyrosol (23), and hydroxytyrosol (24). In-terestingly, this transformation occurred in 80% yield,without the need for protecting groups.

    Scheme 1

    According to these authors, the reaction has a three-stepmechanism (Scheme 2) in which the first step consists ofthe acid-catalyzed formation of the hemiacetal 25 formedby condensation of the hydroxyethyl derivative 26 with analdehyde or a ketone (27). This is followed by water loss,which provides the reactive intermediates 28a,b that final-ly undergo intramolecular electrophilic aromatic substitu-tion, in the activated position para to the hydroxyl group(29), furnishing the isochroman 30.

    In these activated systems, the group of Guiso24,25 foundthat aldehydes react faster than ketones and that aromaticaldehydes gave higher yields than their aliphatic counter-parts. This is probably because, for the aromatic alde-hydes, the positive charge present in the reactionintermediate may give a resonance on the aromatic ring,thus increasing the stability of the intermediate cation;31

    alternatively, this can be explained as a consequence ofthe fact that these aldehydes cannot undergo enolization.

    Scheme 2

    Observation of the outcome of the reaction with differentcarbonyl components was also indicative that the waterelimination step is of fundamental importance to thecourse of the reaction and the product yield.

    In order to demonstrate the key role of the water elimina-tion stage in the proposed mechanism, this group carriedout reactions with and without dehydrating agents(Table 1). They found that the presence of a dehydratingagent was fundamental for achieving high yields; this ef-fect was more pronounced in cyclizations involving ali-phatic aldehydes.

    In their stereocontrolled total synthesis of deoxyfrenoly-cin 31, a natural product isolated from Streptomycesroseofulvus, Xu and co-workers32 prepared the heterocy-clic ring of this pyranonaphthoquinone antibiotic bymeans of an oxa-Pictet–Spengler reaction, as shown inScheme 3.

    The required alcoholic precursor 32 was elaborated by ahighly regioselective benzannulation of chromium car-bene complex 33 with terminal acetylene 34,33 availablein turn from 3-buten-1-ol (35) via its protected derivative36, by ring opening of epoxide 37 with lihium acetylide(38) into alcohol 39.34

    Williamson methylation of the resulting 32 to the 1,4,5-trimethoxynaphthalene 4035 and deprotection of the alco-holic function (41) expedited the way to the oxa-Pictet–Spengler condensation to 42 which was carried out withformaldehyde dimethyl acetal under BF3·Et2O assis-tance.36

    DDQ-induced oxidative coupling with allyl triphenylstan-nane stereospecifically gave the 1,3-trans-substituted al-lyl naphthopyran 43.37 This outcome was a distinctivecharacteristic of the synthesis, since previous approachesfurnished the 1,3-cis-derivative.38

    HOO

    HO

    NHR

    O

    HO

    NHR

    OH

    18a R = H18b R = i-Pr

    19a R = H19b R = i-Pr

    MeOO

    MeO

    NHR16a R = H16b R = i-Pr

    O

    MeO

    NHR

    OMe

    17a R = H17b R = i-Pr

    O

    HO

    HO

    HO

    NH

    HO

    HO

    HO

    CHO

    OH

    HO

    HO

    HO

    +

    HOOH

    PCC

    2322

    21 20

    24

    R1 R2

    O

    R1 R2

    +O H

    OH

    OR3H+

    +OH

    R1

    R2OH

    R3O

    +O

    R3O

    R1 R2

    O

    R3O

    R1 R2

    O

    R3O

    R1 R2+

    O

    R3O

    R2H R1

    +

    27

    2528a

    28b 29 30

    26

    ..

  • REVIEW The Oxa-Pictet–Spengler Cyclization 191

    Synthesis 2006, No. 2, 187–220 © Thieme Stuttgart · New York

    Table 1 Synthesis of 7-Hydroxyisochroman Derivatives by the Oxa-Pictet–Spengler Condensation

    Entry R1 Carbonyl Compound Yield (%) R2 R3

    Protocol Aa Protocol Bb Protocol Cc

    1 OH Pentanal 80 60 50 H n-Bu

    2 OH 3-OH-C6H4-CHO 98 90 80 H 3-OH-C6H4-

    3 OH 4-MeO-C6H4-CHO 98 90 80 H 4-MeO-C6H4-

    4 OH Benzaldehyde 95 80 60 H Ph

    5 OH Isovaleraldehyde 90 73 62 H 2-Bu

    6 OH Propanal 95 80 72 H Et

    7 OH Nonanal 95 90 75 H n-Oct

    8 H Pentanal 80 H n-Bu

    9 H Piperonal 98 H 3¢,4¢-OCH2O-C6H4-

    10 H 4-Cl-C6H4-CHO 95 H 4-Cl-C6H4-

    11 H 4-MeO2C-C6H4-CHO 90 H 4-MeO2C-C6H4-

    12 OH 4-HO-C6H4-CH2CHO 80 75 60 H 4-OH-C6H4-CH2-

    13 OH Acetone 95 80 63 Me Me

    a Protocol A: MeOH, activated MS, TsOH (cat.), 4 °C, 24–48 h. b Protocol B: MeOH, anhydrous Na2SO4, TsOH (cat.), 4 °C, 24–48 h. c Protocol C: MeOH, TsOH (cat.), 4 °C, 24–48 h.

    HO

    R1OH

    HO

    R1O

    R2 R3R2 R3

    O+

    Reaction conditions

    Scheme 3

    OROBn

    O OBn

    OR

    35 R = H36 R = Bn

    BnBr, NaOH, Et3N, hexane, reflux, 5h

    (98%)

    37

    MCPBA, CH2Cl2,r.t., 24 h

    (91%)

    HLi

    H2N(CH2)2NH2, DMSO, r.t., 40 min

    (91%)

    39 R = H34 R = Ac

    AcCl, Ac2O, pyridine, CH2Cl2, r.t. (91%)

    OR1

    OMe OMe

    OR

    32 R = H, R1 = Ac40 R = Me, R1 = Ac41 R = Me, R1 = H

    THF, 60 °C, 15 h(74%)

    MeI, K2CO3, acetone, reflux, 3 h (81%)

    K2CO3, MeOH, H2O, r.t., 6 h (85%)

    O

    OMe OMe

    OMe CH2(OMe)2, BF3⋅Et2O, Et2O, r.t.

    (85%) OBnOBnO

    OMe OMe

    OMe

    OBn

    Ph3SnCH2CH=CH2,DDQ, CH2Cl2,

    r.t., 2 h

    (94%)

    43 42

    O

    OMe OMe

    OMe

    OH

    Me

    44

    O

    OMe O

    O

    Me

    45 R = H 46 R = Me

    O

    OH O

    O

    Me

    47 R = Me 31 R = H

    H2, 10% Pd/C, EtOH, r.t.,

    2 days

    (77%)

    CrO3, Me2CO, AcOH, H2O,r.t., 40 min

    MeOH, H2SO4, r.t., 12 h (43%, 2 steps)

    KOH, MeOH, r.t., 3 h (97%)

    BBr3, CH2Cl2, –78 °C → 0 °C

    CO2R CO2R

    33

    OMe

    Cr(CO)5MeO38

  • 192 E. L. Larghi, T. S. Kaufman REVIEW

    Synthesis 2006, No. 2, 187–220 © Thieme Stuttgart · New York

    The synthesis was completed with functional group trans-formations on the side chains (43 → 44 and 45 → 46) andon the aromatic moiety (44 → 45 and 46 → 47). These in-cluded double bond catalytic hydrogenation, the simulta-neous oxidation of the primary alcohol to a carboxylicacid and of the central benzene ring to the correspondingquinone with CrO3 in acetic acid,

    39 and the boron tribro-mide assisted demethylation of the remaining methylether. Final saponification of the methyl ester in 46 fur-nished the natural product 31.

    An interesting oxa-Pictet–Spengler cyclization leading to1-alkylisochromans was disclosed by Jung and co-work-ers.40a In this case (Scheme 4), starting b-phenethyl alco-hol was protected as a silyl ether (48) and the TMSIadduct of acetaldehyde (49) was employed as a maskedcarbonyl component.

    Scheme 4

    This process seems to entail a first step that consists in thecomplexation or association of the iodo derivative and thesilyl ether moiety originally tethered to the aromatic ring,with concomitant loss of TMSI (50 → 51), because nopara-substituted products, the typical Friedel–Crafts by-products, were observed.

    Next, loss of trimethylsilyloxy anion to form hexamethyl-disiloxane and subsequent nucleophilic attack by iodide to52 would furnish iodo intermediate 53, capable of cycliz-ing to the final isochroman 54. However, since the reac-tion occurs with formation of HI, which is a Brönsted acidand useful catalyst, it is likely that the mechanistic picturemay be more complex.

    2.2 Synthesis of 1,1-Disubstituted Isochromans

    The use of ketones in place of aldehydes gives rise to 1,1-disubstituted oxacycles. In addition to the example pro-vided by Guiso (Table 1, entry 13), a few others have beenrecorded. 1,1-Dialkylisochroman derivatives 55 havebeen synthesized from 3,4-methylenedioxy b-phenethyl

    alcohol and described as non-steroidal antiinflammatoryagents.41

    Among other 1,1-disubstituted pyran-type heterocycleswith the same activity, etodolac (7)42 and pemedolac(56)43 have prominent importance (Figure 5). These areclinically effective as antiinflammatories, with the activi-ty related to the presence of the dihydropyran acetic sub-unit. Interestingly, conformational changes in the oxygenring, such as those produced by the introduction of thebenzyl moiety in pemedolac, have been observed. Thesechanges have an effect on the biological activity.44

    Figure 5

    In addition, compound 57 and analogues have been pre-pared by Moltzen and co-workers, employing the oxa-Pic-tet–Spengler reaction of b-phenethyl alcohol withpiperidin-4-one.45 This Danish team demonstrated that 57has subnanomolar affinity and preference for the brain s2binding sites (IC50 = 0.9 nM). The s ligands have poten-tial as therapeutic agents for the treatment of psychosis.

    Using safrole (58) as starting material, Da Silva and Bar-reiro were able to synthesize the 1,1-disubstituted isoch-roman derivatives 59 and 60 (Scheme 5),46 which relate tothe pyran-type antiinflammatories but have some confor-mational restrictions.47

    Thus, safrole (58) was reductively ozonolyzed and the re-sulting aldehyde was further reduced to b-phenethyl alco-hol 61.48 When submitted to boron trifluoride assistedcyclization with b-ketoesters 62a and 62b,49 tricycliccompounds 63 and 64 were obtained, respectively. Inturn, these were hydrolyzed to the corresponding acidswith hydroalcoholic potassium hydroxide.50

    Interestingly, the reaction did not proceed under p-tolue-nesulfonic acid assistance, which is a useful reagent forthe acyclic congeners, and BF3·Et2O was chosen after asystematic promoter search.51

    Products were obtained as diastereomeric mixtures, withprevalence (9:1) of one diastereomer. The observed dia-stereoselectivity was ascribed (Scheme 6) to a preferentialattack of the regioactivated pro-C-6 position of the meth-ylenedioxy phenyl group to the oxonium intermediate

    OTMS

    I

    OTMS

    Me

    O+

    Me

    TMS

    OTMS

    I–

    CHCl3, 50 °C, 2 h

    O:

    Me OTMS

    – TMSI

    O+

    Me

    O

    MeI

    O

    Me

    +TMSI or HI – HI

    – TMSO–

    (50%)

    MeCHO + TMSI

    CHCl3, 25 °C, 30 min

    49

    5051

    52 53 54

    48

    N(S)(S) O

    (R)(R)

    R

    Me CO2H

    7 R = H, R1 = Et, Etodolac56 R = Bn, R1= H, Pemedolac

    O

    O O CO2H

    R

    55a R = H55b R = Me

    R1

    O

    N

    57

    N F

    H

  • REVIEW The Oxa-Pictet–Spengler Cyclization 193

    Synthesis 2006, No. 2, 187–220 © Thieme Stuttgart · New York

    through its less-hindered face (65), opposite to the meth-oxycarbonyl moiety.

    In agreement with the proposed hypothesis on the activityof these compounds, they showed poor antiinflammatoryactivity but powerful analgesic properties,52 with the fivemembered ring analogue being the most potent.

    2.3 Diastereoselective Synthesis of 1,3-Disubsti-tuted Isochromans

    The group of Jung40a disclosed that the self-condensationof the TMSI adduct of phenylacetaldehyde (66) gave thedibenzocyclooctadiene derivative 67 (Scheme 7), pre-

    sumably through a mechanism similar to that shown inScheme 4.

    Here, displacement of iodide from one molecule of 66 bythe oxygen atom of a second molecule of 66 led to the si-lylated oxonium iodide 68, which upon loss of trimethyl-silyl iodide afforded the iodo acetal 69. In turn, thiscompound was converted into the iodo ether 70 by eitherof two pathways: (a) initial oxa-Pictet–Spengler cycliza-tion with loss of hydrogen iodide to give the acetal 71which is then converted into the iodo ether 70 by hydro-gen iodide or TMSI; or (b) initial conversion of the acetalfunction to the symmetrical diiodo ether 72 followed bythe oxa-Pictet–Spengler cyclization to 70.

    The iodo ether 70 is then transformed into 67 by a secondintramolecular oxa-Pictet–Spengler condensation. Ether67 was transformed into dibenzo[a,e]cycloocta-1,5-dien-3-one 73 through a reductive ring opening by sodium inliquid ammonia, followed by oxidation of the resulting al-cohol. Ketone 73 is a useful starting material for com-pounds with antiinflammatory or psychotropic activity.40b

    Wünsch and Zott22,53a reported that the condensation ofseveral optically active phenyllactic acids 74 with benzal-dehyde and butyraldehyde under acid catalysis gave mix-

    Scheme 5

    O

    O

    O

    O OH

    O

    O O(S)(S)

    (R)(R)CO2Me

    O

    O O(S)(S)

    (R)(R)CO2H

    O

    O O(S)(S)

    (R)(R)CO2Me

    O

    O O(S)(S)

    (R)(R)CO2H

    1. O3, AcOH, Zn2. NaBH4, MeOH, 0 °C

    BF3⋅Et2O, THF(79%)

    MeO2CO

    CO2MeO

    KOH, MeOH–H2Oreflux

    KOH, MeOH–H2O,reflux

    (96%)

    (96%) (96%)

    63

    61

    5960

    64

    58

    62b62a

    BF3⋅Et2O, THF

    (83%)

    Scheme 6

    O

    O O(S)(S)

    (R)(R)CO2Me

    O

    O O(S)(S)

    (S)(S)CO2Me

    Path a Path b

    (SR/RS)-63 (SS/RR)-63

    65

    O+

    O

    OR2

    R1

    R1 = CO2Me, R2 = H

    R1 = H, R2 = CO2Me

    6

    6

    Scheme 7

    OTMSI

    OTMS

    I

    OTMS

    O+TMS

    I

    OTMS

    O

    II–

    I

    O:

    I

    O

    I

    OTMS

    O O

    – TMSI

    Path a

    Path b

    – IH

    TMSI or HI

    – HI

    TMSI or HI – HI

    O

    6869 72

    73

    66 71 70

    67

    1. Na/NH3, AcOH, Et2O (81%)2. CrO3, pyridine (85%)

    ..

    a

    a

    b

    b

    66

  • 194 E. L. Larghi, T. S. Kaufman REVIEW

    Synthesis 2006, No. 2, 187–220 © Thieme Stuttgart · New York

    tures of 1,3-cis- and 1,3-trans-disubstituted isochromans75, with the cis diastereomers being favored (Table 2).

    A similar observation was recently made by Chinese in-vestigators.53b Compounds 76 were occasionally isolatedas side products of these transformations. In addition, spi-rocyclic compounds related to 75 were obtained in fair-to-good yields when ketones were employed as the carbonylcomponents.

    D1 dopaminergic agonists with 1,3-disubstituted isochro-man skeletons are among the few D1 agonists known todate. Dopamine receptors have been divided into severalclasses on the basis of their pharmacological differences,and selective dopaminergic agents show promise for thetreatment of extended conditions such as Parkinson’s dis-ease, and as probes to better understand the role of thesereceptors.54

    Michaelidis and co-workers55 reported the synthesis of 3-cyclohexylisochroman derivatives 77, 78 and 79 follow-ing the synthetic route shown in Scheme 8. Lateral metal-lation of phenolic ether 80, followed by reaction withcyclohexane carboxaldehyde gave the required b-phen-ethyl alcohol 81, which was cyclocondensed in an oxa-Pictet–Spengler reaction either with N-formyl aminoace-tal 82a to furnish 83, or with bromoacetal 82b to give 84.

    The former 1,3-cis-disubstituted isochroman was thensubmitted to formyl-group reduction and hydrobromicacid assisted demethylation, providing compound 77,while the second heterocycle was transformed into the pri-mary amine 85 by nucleophilic substitution with lithiumazide and reduction of the resulting azide 86. After de-methylation to phenol 87, alkylation of the amino groupfurnished the final compounds 78 and 79.

    A slight variation of this strategy led to the preparation of3-phenyl derivative 88. To this end, benzylic bromide 89was reacted with the lithium species 90 to furnish thioket-al 91, which was oxidatively deprotected to unveil ketone

    92, and further reduced to b-phenethyl alcohol 93. Cy-clization of the latter with bromoacetal 82b to 1,3-cis iso-chroman 94, followed by transformation of the bromideinto the corresponding amine 95 by way of azide 96, and

    Table 2 Synthesis of 1,3-Disubstituted Isochromans Employing the Oxa-Pictet–Spengler Condensation Protocol

    Entry R R1 R2 R3 Conditions cis/trans Yield (%)

    1 H H Ph H HCl, ZnCl2, r.t., 12 h 90:10 67

    2 OH Me Ph H HCl, MeOH, r.t., 14h 61:39 71

    3 OH Me Pr H TsOH, CHCl3, 66 h 58:42 48

    4 OH Me –H2C-(CH2)3CH2– TsOH, CHCl3, 3 h – 85

    5 OH Me –(CH2)2NMe(CH2)2– TsOH, Cl(CH2)2Cl, 48 h – 57

    6 OH Me –(CH2)2NAc(CH2)2– TsOH, Cl(CH2)2Cl, 16 h – 32

    7 OMe Me –(CH2)2NMe(CH2)2– HCl, dioxane, r.t., 48 h – 27

    OH(R)(R)

    CO2R1R

    RO

    (S)(S)CO2R1R

    R

    +

    74 75

    O(S)(S)

    R

    R

    76

    O

    O

    Reaction conditions

    R3 R2 R3R2

    Scheme 8

    OMe

    Me Me

    OMe

    Me

    OH

    OMe

    Me

    O

    OMe

    Me

    O

    R

    OH

    Me

    O

    NR1R2⋅HX

    OH

    Me

    O

    NHMe⋅HBr

    80 81

    83

    77

    CHO

    1. n-BuLi, THF

    2.

    NHCHO

    87 R1 = R2 = H, X = Br78 R1 = R2 = Me, X = Cl79 R1 = H, R2 = n-Pr, X = Cl

    1. LiAlH4, THF, reflux, 12 h2. 48% HBr, reflux, 2 h

    NHCHO

    OMeMeO

    BF3⋅Et2O, Et2O, 0 °C, 2 d (55%)

    Br

    OMeMeO

    (48%)

    LiN3, DMF, 80 °C, 1.5 h (51%)

    LiAlH4, Et2O, 0 °C (90%)

    48% HBr, AcOH, reflux, 2 h

    (94%)

    H2CO, NaCNBH3, r.t., 2 d (57%)

    1. MeCH2COCl, Et2O, NaOH2. LiAlH4, THF,

    reflux, 5 h (24%)

    (65%)

    82a

    BF3⋅Et2O,CH2Cl2,–50 °C → 0 °C, 7 h (91%)82b

    84 R = Br 86 R = N3 85 R = NH2

  • REVIEW The Oxa-Pictet–Spengler Cyclization 195

    Synthesis 2006, No. 2, 187–220 © Thieme Stuttgart · New York

    final catalytic debenzylation culminated in 88 to completethe synthetic sequence, shown in Scheme 9.

    These compounds made it possible to deduce that a prima-ry amine was the best functional group for inducing thetested activity, and that the 3-phenyl analogues are morepotent than their 3-cyclohexyl congeners. It was also con-cluded that the 6-methoxy substitution decreases the bind-ing affinity, while a 6-methyl functionalization exhibits alack of selectivity, with increased affinity towards 5-HT1Aand 5-HT1C receptors.

    More recently, Unterhalt and Heppert56 reported the syn-thesis of 3¢-phenyl-1¢-isochromanyl-2-ethylamines relat-ed to fluoxetine by oxa-Pictet–Spengler condensation of1,2-diphenylethanols with 3-chloropropanal diethylacetalunder BF3·Et2O assistance and nucleophilic displacementof the resulting chlorides with amines. The affinities of thesynthetic compounds towards the 5-HT2A receptor and theserotonin transporter were tested, and the authors synthe-sized 1-aryl analogues as well.

    Scheme 9

    While these oxa-Pictet–Spengler cyclizations selectivelyprovided the 1,3-cis diastereomers, during their study ofprospective antitumor agents, Grasso and co-workers57 re-cently reported the oxa-Pictet–Spengler synthesis of the1,3-trans-disubstituted isochroman derivative 97 from al-cohol 98 (Scheme 10).58

    Interestingly, however, the amine 99, prepared by catalyt-ic hydrogenation of 97, did not pass the National CancerInstitute (U.S.A.) criteria for activity in the primary assay.

    2.4 Synthesis of 3-Substituted Isochromans

    During the synthesis of the ochratoxins A and B (100),metabolites of the toxicogenic strains of the fungus As-pergillus ochraceus Wilh,59 Steyn and Holzapfel60 pre-pared 3-methylisochroman derivatives 101–104 from 3-bromophenol (105). Thus, the starting phenol was protect-ed as a THP ether (106), and after preparation of the cor-responding Grignard reagent, it was reacted withpropylene oxide, furnishing b-phenethyl alcohol deriva-tive 107 in good yield (Scheme 11).

    Acid deprotection to 108, followed by chlorination ac-cording to Campbell,61 gave monochloride 109 anddichloride 110, among other nuclearly mono- and di-chlo-rinated compounds. Williamson etherification furnishedmethyl ethers 111 and 112, and upon reaction with theMOMCl–ZnCl2 reagent, dihalogenated heterocycle 112gave isochroman 101; analogously, 102 was obtainedquantitatively from 111 after treatment with MOMCl un-der ZnCl2 catalysis at room temperature.

    However, prolonged heating of 111 under reflux yieldedchloromethyl derivative 103, which was hydrolyzed to al-cohol 104 and then selectively dechlorinated with Raneynickel under basic conditions to afford 113. In turn, thiswas oxidized to carboxylic acid 114, and demethylated byacid treatment, furnishing salicylic acid derivative 115,which is analogous to the isochroman accessed by hydro-lysis of natural ochratoxin B (100).

    From chiral 115, obtained by hydrolysis of the naturalproduct, ochratoxin B (100) was reconstructed in 26%yield by reaction of the related acyl azide and L-phenyl-alanine.

    The procedure of Singh62 is very useful for the synthesisof simple 3-alkylisochromans (116 → 117); however, at-tempts to employ this strategy for accessing 3-phenyl or3-vinyl derivatives met with failure, with the benzylic(118) and allylic (119, 120) chlorides being the major re-action products (Scheme 12).63

    Interestingly, Rama64 disclosed that 1,3-dimethyl-6,8-dimethoxyisochroman, as well as 1-methyl-, 1-ethyl-, 1-

    OBn

    MeO

    OBn

    MeO

    OBn

    MeO

    O

    OBn

    MeO

    O

    R

    OR

    MeO

    O

    NH2

    OBn

    MeO

    OH

    8991

    9293

    Br

    OMeMeO

    (82%)

    BrS S

    Li PhS S

    NaBH4, EtOH, 12 h, r.t.

    NCS, AgNO3, MeCN–H2O, 45 min

    –78 °C, 1 h, THF(100%)

    (38%)

    BF3⋅Et2O, CH2Cl2,–50 °C → 0 °C, 7 h (91%)

    95 R = Bn88 R = H

    10% Pd/C, H2, 24 h, MeOH (66%)

    94 R = Br 96 R = N3

    LiN3, DMF, 80 °C, 1.5 h (51%)

    LiAlH4, Et2O, 0 °C

    (90%)

    90

    82b

    Scheme 10

    O

    O

    Me

    OH

    O

    O

    Me

    O

    4-NO2-C6H4-CHO, HCl, dioxane, reflux, 1 h

    (94%)

    NO2O

    O

    Me

    O

    NH2

    10% Pd/C, MeOH, r.t., 4 h

    (68%)

    98

    97

    99

  • 196 E. L. Larghi, T. S. Kaufman REVIEW

    Synthesis 2006, No. 2, 187–220 © Thieme Stuttgart · New York

    propyl- and 1-isopropyl-6,8-dimethoxyisochromans,were prepared in 80–85% yield from the corresponding3,5-dimethoxyphenyl alkanols 121a and 121b in ni-tromethane under BF3·Et2O catalysis, without dimeriza-tion.

    However, under the same conditions, bis(isochroman)ssuch as 122a–c were isolated (Scheme 13) when the prep-aration of 6,8-dimethoxyisochroman derivatives was at-tempted from the corresponding b-phenethyl alcohols121a–c with formaldehyde or formaldehyde diethyl acetalas the carbonyl component.

    A report by Bird and co-workers65 confirmed some ofthese observations, indicating that when 3,5-dimethoxy-b-phenyl alkanols were submitted to condensation eitherwith dimethoxymethane and boron trifluoride or with

    formaldehyde and hydrochloric acid, in addition to the ex-pected oxa-Pictet–Spengler condensation, a side reactiontook place, furnishing bis(isochroman-5-yl)methanes inhigh yield.

    These condensing agents have been previously employedfor the synthesis of 5,6-,66 5,7-67 and 6,7-dimethoxyisoch-romans;68 thus, this is a result of the characteristics of thestarting material. Interestingly, NMR studies were unableto detect rotation restrictions along the CAr–C axes ofthese rare compounds.69

    Exceptionally, however, Cutler and co-workers70 wereable to synthesize the plant growth regulator 3a, through6,8-dimethoxyisochroman intermediate 123 withoutdimerization (Scheme 14). In their approach, starting phe-nolic acid 124 was methylated to 125 and converted intobromide 126 by way of alcohol 127.

    Scheme 11

    OR1

    R

    105 R = Br, R1 = H106 R = Br, R1 = THP107 R = CH2CH(OH)Me, R1 = THP

    OH

    OH

    Me

    OH

    OH

    Me

    Cl

    Cl

    OH

    OH

    Me

    Cl

    +

    OMe

    O

    Me

    Cl

    Cl

    109 R = H111 R = Me

    110 R = H112 R = Me

    OMe

    O

    Me

    Cl

    OMe

    O

    Me

    Cl

    RH2C

    103 R = Cl104 R = OH

    ClCH2OMe, ZnCl2, r.t.

    (100%)ClCH2OMe, ZnCl2, reflux

    (100%)

    OMe

    O

    Me

    HOH2C

    CrO3, AcOH

    OMe

    O

    Me

    HO2C

    O

    Raney nickel,KOH–MeOH, H2, 72 h

    OH

    O

    Me

    HO2C

    O OH

    O

    Me

    O

    N

    H

    OHO2C

    DHP, TsOHPyridine

    1. Mg, THF,2. Propyleneoxide (92%)

    1 N HCl–MeOH(1:1), overnight

    (78%)

    Cl2, MeNO20 °C, 30 min

    (10%) (70%)

    Me2SO4, K2CO3,Me2CO, reflux (95%)

    Me2SO4, K2CO3,Me2CO, reflux (90%)

    ClCH2OMe, ZnCl2, r.t.

    (100%)

    H2O, K2CO3, reflux, 2 h (88%)

    (71%)

    (84%)

    HCl, reflux, 20 h

    (41%, overall)

    H+

    1. SOCl22. NaN3, DMF3. L-β-Phenylalanine

    (26%)114 115 100

    108

    113 102 101

    Scheme 12

    OH

    R

    Cl

    Ph

    O

    Alkyl

    Cl

    Cl

    HCl, H2CO

    (87%)

    HCl, H2CO

    HCl, H2CO

    HCl, H2CO

    (21%)(62%)

    118117

    116

    120119

    +

    Scheme 13

    OH

    OMe

    MeO R

    122a R = H (A, 84%)122b R = Me (A, 87%)122c R = C11H23 (B, 77%)

    O

    OMe

    MeO R

    O

    OMe

    MeO R

    Method A: BF3⋅Et2O, MeNO2, CH2(OEt)2,

    22 °C, 3 h

    Method B: HCl, HCHO, 1 h, r.t.

    121a R = H 121b R = Me 121c R = C11H23

  • REVIEW The Oxa-Pictet–Spengler Cyclization 197

    Synthesis 2006, No. 2, 187–220 © Thieme Stuttgart · New York

    Next, vinyl Grignard addition produced compound 128,which, once submitted to an oxymercuration–demercura-tion, afforded secondary alcohol 129. Upon treatmentwith methoxymethyl chloride (MOMCl), the alcohol fur-nished isochroman 123, presumably by in situ acid-cata-lyzed (from excess MOMCl) oxa-Pictet–Spenglercyclization of intermediate 130, which was not isolated.

    Because the 8-methoxy group could not be selectively re-moved, the synthesis took advantage of the comparativelyeasy selective demethylation of the 6-methoxy moiety of123. Therefore, the resulting 131 was protected as thebenzylthiomethyl ether derivative and the so-obtained132 was submitted to demethylation to furnish 133. Final-ly, reductive desulfurization afforded the target structure3a.

    Compounds 3 and 131, as well as some of their esters andethers, were active in the wheat coleoptile assay. In addi-tion, 3a and 131 were demonstrated to inhibit the enzymealdose reductase.71

    2.5 Synthesis of C-4-Substituted Isochroman Derivatives

    For the synthesis of 5-spirobenzodiazepinones, Gatta andSettimij72 prepared cyclopentyl b-phenethyl alcohol 134aand N-methylamino derivative 134b73 from ethyl phenyl-acetate 135, by intermediacy of 136.

    As shown in Scheme 15, alcohols 134 were condensedwith benzaldehyde under hydrochloric acid catalysis tofurnish 1-phenylisochromans 137. Chromium trioxide ox-idation of the latter74 followed by reaction of the resultingd-ketoacids 138 with substituted hydrazines afforded therequired benzodiazepine derivatives 139. The isochro-man-3-ones 140 seemed to be reaction intermediates, be-cause once heated under vacuum they were smoothlyconverted into the products 139.

    Interestingly, a different oxa-Pictet–Spengler reactionstrategy (Scheme 16) had to be employed for the synthesisof the related spirocyclic 1-phenylisochroman derivative

    Scheme 14

    Me

    OR

    RO CO2R

    Me

    OMe

    MeO R

    124 R = H125 R = Me

    127 R = CH2OH126 R = CH2Br

    Me

    OMe

    MeO

    Me

    OMe

    MeO

    OR

    Me

    Me

    OMe

    MeO

    O

    Me

    Me

    OMe

    RO

    O

    Me

    Me

    OH

    O

    O

    Me

    Me

    OH

    MeO

    O

    Me

    Me2SO4, K2CO3, Me2CO, reflux,

    18 h (95%)

    (96%)

    LiAlH4, Et2O, 0 °C, 2 h

    PBr3, Et2O, 0 °C, 2 h (95%)

    H2C=CHMgBr, THF, –25 °C, 2.5 h

    (68%)

    1. Hg(OAc)2, THF-H2O,

    r.t., 20 min

    2. NaBH4, 0 °C, 20 min (86%)

    128 NaH, MOMCl, THF, 65 °C, 2 h

    (91%)

    123

    EtSH, NaH, DMF, 130 °C, 6 h

    (72%)

    PhSCH2Cl, NaH, HMPA, NaI, r.t., 2 h (76%)

    131 R = H132 R = PhSCH2

    EtSH, NaH, DMF, 120 °C, 18 h

    3a 133

    (80%)

    W-6 Raney Nickel, EtOH,

    reflux, 3 h

    (92%)

    129 R = H130 R = CH2OMe

    "HCl"

    SPh

    Scheme 15

    OH

    R

    MeO

    MeOO

    R

    MeO

    MeO

    Ph

    O

    CO2H

    R

    MeO

    MeO

    Ph

    136a R = CH2CH2136b R = CH2(NMe)CH2

    R

    MeO

    MeO

    Ph

    N

    N

    PhCHO, dioxane, HCl, reflux

    CrO3 AcOH, 30 °C

    R1O

    R

    MeO

    MeO

    Ph

    O

    NHNHR1

    CO2EtMeO

    MeO

    CO2EtMeO

    MeO

    RNaH, DMF,

    BrCH2RCH2Br,6 h, 30 °C

    LiAlH4, Et2O, reflux

    (55–60%) (64–81%)

    135 134a R = CH2CH2134b R = CH2(NMe)CH2

    (83–89%)

    137a R = CH2CH2137b R = CH2(NMe)CH2

    (20%)

    (21–33%)

    138a R = CH2CH2138b R = CH2(NMe)CH2

    140a R = CH2CH2, R1 = H, Me140b R = CH2(NMe)CH2, R1 = H, Me

    139a R = CH2CH2, R1 = H (61%), R1 = Me (77%)139b R = CH2(NMe)CH2, R1 = H, Me

    R1-NHNH2, glyme, reflux, 3 h

    150 °C, 0.3 mmHg, 30 min (100%)

    R1-NHNH2, glyme, reflux, 3 h

    O

  • 198 E. L. Larghi, T. S. Kaufman REVIEW

    Synthesis 2006, No. 2, 187–220 © Thieme Stuttgart · New York

    141. This entailed the cyclization of 142, analogous to134a, with formaldehyde in acetic acid to furnish 143,which, once halogenated with chlorine to a-haloether 144,was reacted with phenylmagnesium bromide to furnishthe desired 1-phenylisochroman 141.75

    Scheme 16

    The 4,4-disubstituted isochroman 145 was prepared in45% yield by the team of Yamato,76 who employed 146 asstarting alcohol component (Scheme 17). Upon oxidationof 145 to the corresponding tetrahydroisocoumarin 147,the ability of both heterocycles to inhibit the release ofhistamine was tested; however they were determined to beinactive.

    Scheme 17

    Analogously, the same Japanese group prepared open-ring analogue 148 from g-chloronitrile 149 (Scheme 18),which was aminated and then subjected to a Pinner-typeacid-catalyzed methanolysis to furnish ester 150.

    The latter was reduced to b-phenethyl alcohol 151, whichwas then submitted in situ to an oxa-Pictet–Spengler cy-clization with paraformaldehyde and hydrochloric acid.Unfortunately, compound 148 was found to be inactive asa histamine release inhibitor.

    It is also worth mentioning that during the work on hy-potensive agents with peripheral and central action, Mc-Call and co-workers77 synthesized a series of 1,1,4,4-

    (152) and 1,1,3,3-tetrasubstituted isochromans (153) inmoderate to good yields (Scheme 19).

    This was carried out by the oxa-Pictet–Spengler reactionof the corresponding b-phenethyl alcohols 154 and 155with ethyl acetoacetate. In turn, alcohols 155 and 154were accessed in high yields from ester 135 by methylGrignard addition or LDA-mediated a-carbonyl alkyla-tion (to 156) and borane reduction, respectively.

    Scheme 19

    Catechin (157) is a phenolic pigment of vegetal originwhich acts as a natural antioxidant by the mechanism ofoxygen-radical scavenging. Its activity is rather poor com-pared to that exhibited by the flavonoid quercetin (158),which due to its planar geometry, is able to delocalize theradical through the entire molecule.

    Taking into account that the A and B rings of catechin areperpendicular,78 the group of Fukuhara synthesized theplanar analogue of catechin, 159, by reaction of the natu-ral product with acetone under BF3·Et2O catalysis(Scheme 20).79

    OH O

    O

    Cl

    O

    Ph

    HCHO, AcOH, 100 °C, 1 h

    Cl2, –5 °CPhMgBr,

    Et2O

    (89%)

    (64% overall)

    142 143

    144141

    O

    N

    Me

    147

    O

    N

    Me 145

    O

    (H2CO)n, HCl, dioxane, reflux, 10 h

    OH

    N

    Me

    146

    (45%)

    CrO3, AcOH, 30–35 °C, 2.5 h

    (32%)

    Scheme 18

    (25%)

    148

    O

    Me

    MeN

    Bn

    151

    OH

    Me

    MeN

    Bn

    150

    CO2Et

    Me

    MeN

    Bn

    149

    CN

    Me

    Cl

    1. BnNHMe, 140 °C, 2 h2. MeOH, H2SO4, 140 °C, 25 h

    LiAlH4, Et2O

    (38%)

    (H2CO)n, HCl, dioxane,

    reflux, 10 h

    MeO

    MeO

    CO2EtMeO

    MeO

    MeMe

    MeO

    MeO

    MeMe

    OH

    MeO

    MeOOH

    Me

    Me

    MeO

    MeOO

    Me

    Me

    135 156

    154155

    153 152

    MeO

    MeO

    MeMe

    O

    R1 R2 R1 R2

    1. LDA, MeI2. LDA, MeI

    BH3⋅SMe2MeMgBr

    MeC(O)CH2CO2Et, BF3⋅Et2O

    MeC(O)CH2CO2Et, BF3⋅Et2O

    CO2Et

  • REVIEW The Oxa-Pictet–Spengler Cyclization 199

    Synthesis 2006, No. 2, 187–220 © Thieme Stuttgart · New York

    Scheme 20

    This compound protected DNA from Fenton-reaction-mediated damage, and exhibited marked hydroxyl-radicalscavenging ability, exceeding that of catechin.80

    3 Intramolecular Oxa-Pictet–Spengler Cyclizations

    The intramolecular versions of the oxa-Pictet–Spenglercyclization comprise reactions in which the carbonylcomponent is attached to the b-aryl-ethanol in the form ofa mixed acetal, a vinyl ether, an a-acetoxy ether or a ha-lomethyl ether.

    Other versions include 1,3-dioxolanes as masked carbon-yls, in which case 4-hydroxyisochromans are the resultingproducts, unless a reducing agent is employed during thecyclization process. In the latter situation, isochromansare produced.

    The presence of substituents on the carbinolic or the ben-zylic positions of the alcohol moiety allows the prepara-tion of compounds with different substitution patterns onthe heterocyclic ring. There are no recorded examples of1,1-disubstituted isochromans prepared by this intramo-lecular cyclization protocol; however, the diastereoselec-tive synthesis of 1,3- and 1,4-disubstituted compounds ispossible, especially in the case of the former substitutionmotif.

    3.1 Synthesis of 1-Substituted Isochromans

    The synthesis of 6-methoxyisochroman from the meth-oxymethyl ether of 3-methoxyphenethyl alcohol was re-ported by Meyer and Turner.81a U-54537 (160;Scheme 21) is an antihypertensive agent, workingthrough the a-adrenergic receptors.81b,c Removal of the two methoxy groups of 160 gave 161a,which exhibited an increased preference for the D4 overthe D2 receptor, while retaining significant binding to oth-er CNS receptors.

    The synthesis of analogues 161a and 161b started with b-phenethyl alcohol (162), which was reacted with chloro-acetal 163 to give mixed acetal 164; this was isolated andsubjected to an oxa-Pictet–Spengler cyclization to iso-chroman 165 with aluminum chloride as the Lewis acidpromoter (Scheme 21).

    Scheme 21

    Displacement of the halogen with different aryl pipera-zines (166a and 166b) gave final products 161a and 161b.Compound 161b was found to have a 400-fold preferencefor D4 versus D2 receptors. Other piperazine and relatedderivatives were later prepared by Combourieu and co-workers, by way of the same general strategy.82

    3.2 Synthesis of 1,3- and 1,4-Disubstituted Isochromans

    The reaction of b-phenethyl alcohols with paraldehyde orparaformaldehyde in the presence of acids to form iso-chroman derivatives has been reported by severalgroups.83 These reactions most likely proceed through a-chloroethers or hemiacetals. A related transformation, oc-curring via an iodoacetal, was also reported by Jung.40a

    Mohler and Thompson84 disclosed an approach to iso-chromans under mild conditions that involved the priorpreparation of acetals or enolethers derived from b-phen-ethyl alcohols employing MEM chloride and ethyl vinylether, respectively, and their cyclization with titanium tet-rachloride as Lewis acid promoter. Before their break-through, only two reports mentioned the synthesis ofmixed acetals towards isochromans.60,85

    This group proposed a boat-like transition state for thering-closure process. In this reaction (Scheme 22), cy-clization of the acetals presumably starts by alkoxide ab-straction by the Lewis acid from 167a, leaving a stabilized

    O

    OH

    HO

    OH

    OH

    OH

    O

    O

    HO

    OH

    OH

    OH

    Me

    Me

    BF3⋅Et2O,Me2CO

    157

    159

    O

    OH

    HO

    OH

    OH

    OH

    158

    O

    OH

    O

    OEt

    Cl

    O

    Cl

    O

    N

    N

    R

    O

    N

    N

    FMeO

    MeO

    MsOH, CH2Cl2

    EtO

    OEt

    AlCl3, CH2Cl2

    NH N R

    166a R = F 166b R = OMe

    i-Pr2NEt, HOCH2CH2OH

    165 164

    162

    160

    161a R = F161b R = OMe

    Cl

    163

  • 200 E. L. Larghi, T. S. Kaufman REVIEW

    Synthesis 2006, No. 2, 187–220 © Thieme Stuttgart · New York

    oxocarbocation (167b) which undergoes electrophilic at-tack on the aromatic ring to afford species 167c. Finalelimination of a proton produces the isochroman nucleus168.

    Scheme 22

    Cyclization of a 52:48 mixture of acetals 167a derivedfrom 1-phenyl-2-propanol and ethyl vinyl ether gave a 4:1mixture of cis- and trans-1,3-dimethylisochroman. Theproduct distribution may be attributable to the fact that thecis isomer 168 has both of its methyl groups adopting apseudoequatorial orientation, which minimizes the 1,3-di-axial interaction across the oxygen – a feature already ob-served in other pyran derivatives.86

    Analogously, the outcome of the cyclizations reported byDeNinno, preferentially or exclusively leading to the 1,3-cis-isomers 169a, has been explained on the basis of anal-ysis of the reaction intermediates.87

    Assuming that the reaction takes place through a chair-like transition state, 1,3-trans-isochromans 169b are gen-erated when the bulky pro-C-3 substituent is locatedpseudoaxially in the E-oxonium ion intermediate (170b).On the other hand, the corresponding cis isomers arisefrom intermediates bearing the pro-C-3 substituent locat-ed in the more favorable pseudoequatorial position(170a). Interestingly, transition states involving Z-oxoni-um ions are disfavored due to severe 1,3-diaxial interac-tions.

    Some intramolecular oxa-Pictet–Spengler cyclizationsleading to 1,3- and 1,4-disubstituted isochroman deriva-tives have been described as particular cases of the Prinscyclization. This transformation is one of the most power-ful methods for accessing tetrahydropyran derivatives88

    and involves the coupling of homoallylic alcohols with

    several equivalents of simple aldehydes, under acid catal-ysis.89 Acetals can be used in place of aldehydes90 and al-lylsilane analogues of homoallylic alcohols facilitate thecyclizations.

    In addition, a-acetoxy ethers, readily available from thecorresponding esters by partial reduction and acetylationof the corresponding hemiacetal intermediates,91 are alsouseful cyclization substrates for this reaction as demon-strated by Dahanukar and Rychnovsky. These authorsused b-phenethyl alcohols in place of the homoallylic al-cohol component in their modified Prins sequence, andobtained good yields of isochromans.92

    In Rychnovsky’s cyclization protocol (Scheme 23), thechloroacetate 171b, derived from a b-substituted b-phen-ethyl alcohol, furnished exclusively 1,3-cis-isochroman172b in 90% yield through the intermediacy of 173b.However, in the example involving the a-substituted con-gener 171a, the same transformation from mixed acetal173a furnished 97% of 172a as a 3:1 diastereomeric mix-ture.

    Scheme 23

    Other examples of this kind of 1,3-induction during the in-tramolecular oxa-Pictet–Spengler reaction have been ob-served by the group of Kaufman93 in similar systems, inwhich the isochroman ring is formed under different con-ditions.

    3.3 Synthesis of 1,3,4-Trisubstituted Isochro-mans

    The group of Giles reported the titanium tetrachloride pro-moted diastereoselective isomerization of 2,5-dimethyl-4-naphthyldioxolanes into benzoisochromans and examinedthis transformation in relation to natural product synthe-sis.94

    The rearrangement, which has been regarded as an in-tramolecular version of the Mukaiyama reaction,95 provedto be highly versatile. Subsequent studies by this Austra-lian group explored the rearrangement’s scope and limita-tions by converting the corresponding 2,5-dimethyl-4-phenyl-dioxolanes into isochromans in high yield.96

    O+

    H R1

    RBrO

    Br

    R

    O

    Br

    R

    cis-isochroman, 169a trans-isochroman, 169b

    O

    H

    Me

    H

    MeOEt

    O

    H

    Me

    H

    Me+

    O

    H

    Me

    H

    Me

    +

    O

    H

    Me

    H

    MeH

    167a 167b

    167c168

    TiCl4

    170a R ≠ H, R1 = H170b R = H, R1 ≠ H

    O

    R2R1

    O

    ClO

    R2R1

    OAc

    Cl

    O

    R2R1

    Cl

    DIBAL-H, –78 °C, DMAP, Ac2O, –78 °C → r.t.

    (91–96%)

    TiCl4, CH2Cl2, –78 °C

    (173a, 97% 3:1; 173b, 90%)

    171a R1 = Me, R2 = H171b R1 = H, R2 = C6H13

    173a R1 = Me, R2 = H173b R1 = H, R2 = C6H13

    172a R1 = Me, R2 = H172b R1 = H, R2 = C6H13

  • REVIEW The Oxa-Pictet–Spengler Cyclization 201

    Synthesis 2006, No. 2, 187–220 © Thieme Stuttgart · New York

    These studies demonstrated that the 4,5-stereochemistryof the parent dioxolanes was transferred intact to the cor-responding 4,3-positions of the resulting isochromans, sothat 4,5-trans dioxolanes afford 3,4-cis isochromans. TheC-1 of the isochromans is derived from C-2 of the diox-olanes with a diastereoselectivity that seems to dependupon the aryl substitution and 4,5-stereochemistry of thesubstrate, and also upon the reaction temperature, whenthe C-1 substituent in the final compound is methyl.

    In a further extension of this process, the authors alsodemonstrated the conversion of methyl 4,5-trans-4-aryl-dioxolan-5-yl acetates into methylisochroman-3-yl ace-tates and the corresponding isochroman-g-lactones, astructural feature of the pyranonaphthoquinone antibiot-ics.97

    In a systematic exploration, Kaufman’s group more re-cently demonstrated that the oxa-Pictet–Spengler isomer-ization of acetals 174, derived from threo-diols 175,stereoselectively gives 1,3-cis-disubstituted isochromans176 when the substituents are bulkier or more complexthan simple methyl groups (Table 3).93

    The rearrangement occurs under the promotion of TiCl4,with other Lewis acids such as BF3·Et2O being ineffec-tive; however, in some isolated cases, this transformationwas demonstrated to take place under p-toluenesulfonicacid assistance.

    The proposed reaction mechanism (Scheme 24) involvesthe initial protonation (when TsOH is employed) or coor-dination of titanium tetrachloride with O-3 of the starting

    Table 3 An Intramolecular Oxa-Pictet–Spengler Cyclization

    Entry R1 R2 Conditions Yield (%)

    1 (CH2)3CO2Et CH2Br TiCl4, CH2Cl2, –30 °C → r.t., 2 h

    47

    2 (CH2)2CH2OBn CH2SPh TiCl4, CH2Cl2, –60 °C → –30 °C, 2 h

    26

    3 (CH2)2CN CH2SPh TiCl4, CH2Cl2, –30 °C, 2 h

    87

    4 (CH2)2CN (CH2)3SO2Ph TiCl4, CH2Cl2, –78 °C, 1.5 h

    59

    5 (CH2)2CN (CH2)3OTBDPS TiCl4, CH2Cl2, –45 °C, 4 h

    60

    (R)(R)

    Br

    MeO

    (R)(R)R1 OH

    OH (R)(R)

    Br

    MeO

    (R)(R)R1 O

    OR2

    (R)(R)

    Br

    MeO

    (R)(R)(S)(S) O R1

    OH

    R2

    R2CHO/R2C(OEt)2, TsOH, PhH, reflux TiCl4, CH2Cl2,

    175 174176

    see Table

    Scheme 24

    R1

    MeO

    R

    O

    OR2

    R1

    MeO

    R

    O

    O+

    R2

    Ti

    ClCl

    Cl

    R1

    MeO

    R

    O+

    OR2

    Ti

    ClCl

    Cl

    ..

    R1

    MeO

    R

    O

    Ti

    ClCl

    Cl

    O+

    R2

    ..

    R1

    MeO

    R

    O

    Ti

    Cl

    Cl

    Cl

    OR2

    +

    HCl–

    R1

    MeO

    R

    OR2

    OH

    TiCl4, CH2Cl2

    177 178

    179179

    181 180

    R = Cl, Br, OMeR1 = Me, CH2CO2MeR2 = Me

    Cl

    – TiCl4

    ClCl

    Cl

  • 202 E. L. Larghi, T. S. Kaufman REVIEW

    Synthesis 2006, No. 2, 187–220 © Thieme Stuttgart · New York

    acetal 177, leading to 178, where ring opening of the di-oxolane ring C-2–O-3 bond, to afford the correspondingintermediate oxocarbenium ions 179, takes place underassistance of O-1.

    In turn, this intermediate undergoes an allowed 6-enolen-do-endo-trig type electrophilic cyclization to furnish theisochroman 180 by way of 181. Alternatively, O-1 can beattacked; however, this leads to cleavage of the C-2–O-1bond and furnishes an alternative oxocarbenium ion thatcannot achieve the disallowed 5-enolendo-endo-trig typecyclization to dihydroisobenzofurans; therefore, thesespecies usually revert to the parent dioxolanes.

    The presence of an electron donor on the aromatic ringortho to the dioxolanyl side chain blocks this otherwisefavored cyclization position and offers a coordination sitefor the Lewis acid catalyst. In the absence of such a groupin this position, low yields of isochromans are achieved.As shown in Scheme 25,98 this kind of transformation wasalso employed by Cintrat and co-workers for the synthesisof 4-phenyl 3-substituted isochromans.

    This French team98 employed ortho esters such as 182 asacetal precursors; their reduction with tributyltin hydridegave the required acetals,99 while use of tributyltin deu-teride as reducing agent furnished deuterium-labeled for-mals (183-d), the rearrangement of which provided 1-deuteroisochromans 184-d. Unfortunately, reportedyields of isochromans were in the range of 5–30%.

    Scheme 25

    Unlike Giles’ protocol, the reaction does not take place inthe absence of triethylsilane, which acts as a reducingagent, according to the proposed reaction mechanismshown in Scheme 26. There, the silane agent may act pref-erentially before the cyclization of the common interme-diate 185, formed by reaction of 183 with TiCl4 accordingto the mechanism outlined in Scheme 26 (Path b, 185 →186). An alternative route (Path a), in which the reductionwould occur after the cyclization of 185 to 187, is alsopossible, but less likely to be operative.

    The use of deuterated triethylsilane provides a C-4-la-beled isochroman; in every case the 3,4-trans diphenylderivative 184 was isolated through the intermediacy of188, presumably due to steric reasons.

    Scheme 26

    4 The Oxa-Pictet–Spengler Condensation in the Absence of Acid Catalysts

    The oxa-Pictet–Spengler condensation may proceed inthe absence of an added acid catalyst in the case of highlyactivated substrates, like phenols.

    Working with phenethylamines, Kametani demonstratedthat 3-hydroxyphenethylamine (189) condensed with sev-eral aldehydes and ketones, without acid catalysis, to givethe corresponding 6-hydroxy-1,2,3,4-tetrahydroisoquino-lines 190, carrying one or two substituents on C-1(Scheme 27).100 This transformation was designated as‘phenolic cyclization’ because the phenolic moiety playsa key role in the cyclization process. The reaction was em-ployed for the synthesis of 2-benzazepines,101

    phthalazines102 and tetrahydroisoquinolines.103

    Scheme 27

    D

    Ph O

    OOMe

    Ph

    Ph O

    OD

    Ph

    O Ph

    Ph

    182 183-d

    184-d

    Bu3SnD, BF3⋅Et2O, CH2CH2, –78 °C, 7 h

    Et3SiH, TiCl4, CH2Cl2, –78 °C, 7 h

    (>95%)

    (30%)

    O

    OPh

    Ph Ph

    Cl4Ti

    O+

    O Ph

    Ph

    H

    O-TiCl4

    O

    O Ph

    Ph

    TiCl4

    Ph O+

    183 185

    187

    184

    186

    O Ph

    Ph

    H

    188

    Et3SiH

    Et3SiH

    Oxa-Pictet–Spengler

    Oxa-Pictet–Spengler

    Path a (unlikely)

    Path b (most probable)

    NH2

    RO

    O

    MeO

    Me CO2R

    N

    HO

    R1 R2

    OH

    MeONaNO2, HCl, H2O–AcOH, 80 °C, 1 h

    TsOH, 100 °C, 10 h (80%)

    NaOH, 100 °C, 1 h (75%)

    (85%)

    191

    190

    R1

    R2

    OR1 = H, R, ArR2 = R, Ar

    H

    193 R = Me194 R = H

    CO2Me

    MeO

    189 R = H192 R = Me

  • REVIEW The Oxa-Pictet–Spengler Cyclization 203

    Synthesis 2006, No. 2, 187–220 © Thieme Stuttgart · New York

    Kametani also reported that mixing 2-(3-methoxyphen-yl)ethanol (191), prepared from 192, with methyl pyru-vate without an acid catalyst gave no reaction and allowedrecovery of the starting material,104 but isochroman 193could be obtained in 80% yield by condensation of theformer reagents in the presence of catalytic amounts of p-toluenesulfonic acid. Saponification of 193 gave 75%yield of 194 (Scheme 27).

    The group of this Japanese scientist generalized and ex-tended this reaction, studying the cyclization of trans-2-(3-hydroxyphenyl)cyclohexanol (195), easily availablefrom the related ketone 196105 with several carbonyl com-pounds, accessing in this way hexahydro-6H-dibenzopy-rans (Scheme 28). Yields, however, were less than 30%.

    Scheme 28

    Heating of 195 with acetophenone (197) in ethanol for 24hours resulted in a poor yield of 1,2,3,4,4a,10b-hexa-hydro-6-methyl-6-phenyl-9-hydroxy-6H-dibenzo[b,d]py-ran 198; this increased to 75% upon addition of HCl.Analogously, reaction with cyclohexanone (199) gave thecyclohexyl derivative 200 (28%) which could be preparedin 85% yield when HCl was added as catalyst.

    5 Naturally Occurring Oxa-Pictet–Spengler Cyclizations

    Softwood lignins are produced principally from coniferylalcohol via radical coupling reactions of 201 and 202.Arylisochromans 203 were recently identified by NMR106

    in the trimer fraction of pine wood (from Pinus taeda) de-graded by the DFRC (degradation followed by reductiveprocedure) protocol.107a,b This implies a new pathwayfrom 204 following the initial b-1 coupling between theconiferyl alcohol radical 201 and the lignin oligomer rad-ical 202, which traditionally is known to give 205 and206.107c

    Whether arylisochromans are present as such in nativelignins is not clear, but even if not, the internal trapping ofa b-1 quinone methide intermediate 204 to give 207 sug-gests that it is presumably operating in vivo. The rationalefor the formation of such arylisochromans through an oxa-Pictet–Spengler intramolecular condensation is given inScheme 29.

    Presumably, 207 undergoes ring opening to oxocarbeni-um ion 208 through the intermediacy of 209; the mecha-nism furnishing 210 by way of 203 is analogous to otheroxa-Pictet–Spengler cyclizations. Although the identifi-cation of the arylisochroman structure in isolated milled

    O

    HO

    OH

    HO

    O

    HO

    Me Ph

    O

    HO

    1. EtOH, Na, reflux2. Crystallization3. Prep TLC

    (68%)

    OO

    Me

    EtOH, 200 °C, 48 h (28%), or

    EtOH, 0.25 M HCl,reflux, 15 h (85%)

    EtOH, reflux, 24 hlow yield, orEtOH, 0.5 N HCl, reflux, 15 h (75%)

    196 195

    198 200

    199197

    Scheme 29

    O

    MeO

    HO

    MeO

    OAr

    O

    HO

    HO

    O

    MeO

    HO

    OH OH

    MeO

    O

    OAr

    H+HO

    MeO

    HO

    O OH

    MeO

    O

    OAr

    HO

    MeO

    HO

    O OH

    MeO

    OH

    OAr

    +

    OH

    MeO

    O+

    OH

    OH

    OArMeO

    OH

    OH

    MeO

    O

    OH

    OH

    OArMeO

    OH

    H+

    OH

    MeO

    O

    OH

    OH

    OArMeO

    OH

    H+

    H+

    HO

    MeO

    HO

    OH

    OMe

    OHO OH

    H

    OAr

    Traditional β-1 mechanism

    HO

    MeO

    HO

    O+

    HO

    OMe

    OH

    OAr

    201

    202 204 206205

    208 209

    207

    208210203

    β-1 coupling

    . .

  • 204 E. L. Larghi, T. S. Kaufman REVIEW

    Synthesis 2006, No. 2, 187–220 © Thieme Stuttgart · New York

    wood lignins can be made firmly, the quantity visible inthe NMR spectra is low. The possibility remains that 203is a product of isolation and that its precursor 207, for ex-ample, may be the true in situ natural product.

    Either way, however, structure 203 provides compellingevidence for the occurrence of an internal cyclizationpathway from b-1 intermediate 204.In addition, it is interesting to note that the presence of 1-(3-methoxy-4-hydroxy)phenyl-6,7-dihydroxyisochro-man (L116, 211) and 1-phenyl-6,7-dihydroxyisochroman(L117, 212) in olive oil has been confirmed by chromato-graphic and spectroscopic means.

    These may be formed by an oxa-Pictet–Spengler cycliza-tion of hydroxytyrosol (24) known to occur in olive oil,and the corresponding aldehydes, under catalysis of fattyacids always present there in small amounts108

    (Scheme 30). The antioxidant and platelet aggregation in-hibiting properties of these isochromans have also beenreported.109

    Scheme 30

    6 Oxa-Pictet–Spengler Reactions towards Optically Active Compounds

    Few examples are available of optically active oxygen-bearing heterocycles accessed by way of the oxa-Pictet–Spengler condensation.

    These can be either intermolecular or intramolecular pro-cesses which entail (a) the use of chiral carbonyl compo-nents, (b) condensation of chiral substrates with carbonylsor masked carbonyls with formation of a new asymmetriccenter, in a process involving 1,3-chirality transfer, (c) cy-clization of chiral substrates with formaldehyde or itsequivalents without formation of a new chiral center, and(d) the resolution of diastereomeric compounds formedthrough an oxa-Pictet–Spengler reaction.

    In one of the rare examples described of chiral oxa-Pictet–Spengler cyclizations, Costa and co-workers disclosedtheir strategy to synthesize chiral analogues of etodolac(214). Based on the original synthesis, which relies on theoxa-Pictet–Spengler condensation of 7-ethyltryptophol(215b) with methyl b-ketobutyrate, these scientists pre-

    pared chiral b-ketoesters 216a–h by reaction of acetoace-tates 217a–h with 215a. The esters were synthesized byacetoacetylation of the chiral secondary alcohols 213a–hshown in Figure 6, which are derived from (–)-(1S)-b-pinene.110

    Regardless of the Lewis acid employed (Table 4), estersprepared with 213c and 213f gave racemic products (216cand 216f), while chiral auxiliaries 213e, 213g and 213hfurnished either racemic or chiral esters 216e, 216g and216h, respectively, depending on the Lewis acid em-ployed. This effect was dramatically noticeable in the caseof 213h. It was also observed that SnCl4 seemed to alwaysoutperform BF3·Et2O.

    Excellent yields of the final acids 214 were obtained bysaponification of the thus-obtained esters. In addition, bymeans of the oxa-Pictet–Spengler cyclization, Brenna andco-workers111 synthesized several esters and alcohols re-lated to etodolac, that were found to be difficult to resolveenzymatically. However, classical resolution with (+)-(R)-a-methylbenzylamine afforded a poorly soluble saltfrom which the pharmacologically active S enantiomercould be made free.

    The same Italian researchers demonstrated that the un-wanted enantiomer remaining in the mother liquors couldbe recycled, since it completely racemized by a ‘retro’oxa-Pictet–Spengler after refluxing two hours in toluenewith a catalytic amount of p-toluenesulfonic acid.111

    An oxa-Pictet–Spengler cyclization was employed by thegroup of Lesma during their synthesis of (+)-(20R)-15,20-dihydrocleavamine (218).112 This tetracyclic alkaloid isstructurally related to 16-b-carbomethoxyvelbanamine,the indole ‘upper half’ of the antitumoral bisindole alka-loids occurring in Catharantus roseus, such as vinblastineand vincristine.

    To this end, this Italian group enzymatically desymme-trized meso-piperidine-3,5-dimethanol and transformedthe R,R enantiomer into enol ether 219. Chiral enol ether219 was protected as its benzoate 220, and then was sub-

    HO

    HOOH

    HO

    HOO

    OH

    HO

    HOO

    211

    212

    24

    CHO

    MeO

    HO

    R-CO2H

    R-CO2H

    PhCHOMeO

    Figure 6

    OH OH

    OH

    213a

    213b

    213c

    OH

    213d

    OH

    213e

    OH

    OMe

    213f

    OH OMe

    OH OMe

    213g 213h

  • REVIEW The Oxa-Pictet–Spengler Cyclization 205

    Synthesis 2006, No. 2, 187–220 © Thieme Stuttgart · New York

    jected to oxa-Pictet–Spengler condensation with tryp-tophol (215a), yielding 74% of 221 as a mixture ofdiastereomers (Scheme 31).

    Reductive opening of the pyran ring of 221 provided 44%of 222, which was transformed into mesylate 223. This setthe stage for the intramolecular alkylation of the piperi-dine ring, which afforded 224 after hydrogenolytic depro-tection of the piperidine moiety. Benzoate 224 was finallyhomologated to 218 in 62% yield from 223, through theuse of organocopper chemistry.

    In search of potent and selective D1 agonists, DeNinnoand co-workers113 prepared 3-arylisochroman derivativeA68930 (225) by employing the oxa-Pictet–Spengler con-densation of a polysubstituted b-phenethyl alcohol withbromoacetal (82b).

    In one of the same group’s published sequences(Scheme 32), cyclohexylidene-protected catechol 226was ortho-metallated and the resulting organolithium spe-cies was employed to nucleophilically open styrene oxide(227) and furnish alcohol 228.

    This was stereospecifically cyclized with bromoacetal un-der BF3·Et2O promotion, and the resulting 1,3-cis disub-

    stituted isochroman 229 was transformed into the primaryamine 230 by nucleophilic displacement of the primarybromide by azide anion and subsequent reduction of theazide.

    Finally, mild acidic deprotection gave the target molecule225. Interestingly, these compounds are prone to epimer-ization upon prolonged exposure to organic acids such asTFA, such that this process results in a prevalence of thecorresponding trans isomers, which are thermodynami-cally more stable. In vitro, compound 225 exhibited D1/D2selectivity greater than 1500:1 and was more potent thanthe reference compound SKF38393 (231).

    Since the stereochemistry of the chiral center formed at C-1 is controlled by the center at C-3, in order to prepare thistarget compound in optically active form, ketone 232, eas-ily available from 228 by oxidation with PCC, was em-ployed as starting material.

    Once subjected to reduction with Brown’s chiral (–)- and(+)-diisopinocampheyl chloroboranes 233,114 compound232 gave chiral alcohols (R)-228 and (S)-228 in highenantiomeric excess (Scheme 33).

    Table 4 Oxa-Pictet–Spengler Mediated Synthesis of Optically Active Analogues of Etodolac: Condensation of 215a with Chiral Esters 217

    Entry R* of 217 from Lewis Acid Product Yield (%) de (%) [a]D

    1 213a BF3·Et2O 216a 87 10

    2 213b BF3·Et2O 216b 81 40 –8.54

    3 213b SnCl4 216b 70 36

    4 213c BF3·Et2O 216c 68 0

    5 213c SnCl4 216c 61 0

    6 213d BF3·Et2O 216d 58 73

    7 213d SnCl4 216d 57 84 –18.0

    8 213e BF3·Et2O 216e 85 10

    9 213e SnCl4 216e 73 0

    10 213f BF3·Et2O 216f 61 0

    11 213f SnCl4 216f 59 0

    12 213g BF3·Et2O 216g 80 0

    13 213g SnCl4 216g 78 24

    14 213h BF3·Et2O 216h 65 0

    15 213h SnCl4 216h 59 >95 –20.2

    NOH

    NO

    Me*

    Me OR*

    O O

    Lewis acid, THF, r.t.

    KOH, MeOH–H2O,reflux (90–96%)

    217

    216 R = R*214 R = H

    CO2R215a R = H215b R = Et

    R H H

  • 206 E. L. Larghi, T. S. Kaufman REVIEW

    Synthesis 2006, No. 2, 187–220 © Thieme Stuttgart · New York

    Interestingly, this led to the demontration that the activityof this isochroman resided mainly in one single enanti-omer; thus, the (1S,3R)-225 analogue exhibited a Ki of7200 nM and EC50 of 8580 nM, while the (1R,3S)-225enantiomer displayed a D1 binding Ki of 1.6 nM and anEC50 of 1.95 nM. Furthermore, the bulky phenyl ring wasvery important for achieving good activity, since thedesphenyl analogue 19a28c,30c was 200–400-fold less po-tent.

    The compounds were also orally active in vivo. A relatedcompound, 225a, known as A-77636, was prepared by thesame strategy.

    In addition, other cis-1,3-disubstituted isochroman deriv-atives were elaborated by the same group; the requiredchiral b-phenethyl alcohols were obtained by Corey’s ox-azaborolidine-mediated reduction of a ketone115 preparedwith the aid of chiral oxazaborolidines,116 or by the nu-cleophilic opening of chiral epoxides (for a similar strate-gy, see Scheme 37).

    Wünsch and Zott117 (Scheme 34) reported the regioselec-tive preparation of enantiopure 1,5-epoxy-3-benzazocinesand 1,6-epoxy-4-benzazocines, structurally related tobenzomorphans active as analgesics. They used an in-

    Scheme 31

    N

    OR

    Cbz

    N

    Cbz

    NO

    H

    HH

    N

    Cbz

    NOR

    H

    NOH

    H

    N

    NH

    H

    219 R = H220 R = Bz

    BzCN, i-Pr2NEt, CH2Cl2, r.t. (98%)

    F3CCO2H (0.13 mol equiv), 4Å MS, CH2Cl2, r.t., 45 h

    (74%)

    221

    Et3SiH, F3CSO3H, CH2Cl2, –50 °C, 6 h

    MsCl, i-Pr2NEt, CH2Cl2, r.t., 3 h

    (98%)

    222 R = H223 R = Ms

    1. NaOH, MeOH-H2O, r.t.2. TsCl, i-Pr2NEt, CH2Cl2, r.t., 6 h

    3. CuI, MeLi, Et2O, –40 °C (62% overall)

    224 R = OBz218 R = Me

    (44%)

    2. PhCl, i-Pr2NEt, reflux, 4 h

    MeO

    215a

    OBz

    OBz

    R

    1. H2, 5% Pd/C, EtOAc, r.t., 17 h

    OO

    OH(S)(S)

    OO

    OH(R)(R)

    O(S)(S)

    (R)(R)

    NH2

    OH

    HO

    O(R)(R)

    (S)(S)

    NH2

    OH

    HO

    OO

    O

    Me

    BCl

    2

    Me

    BCl

    2(S)-228 232 (R)-228

    (1R,3S)-225

    PCC, CH2Cl2, r.t., 4 h

    THF, –15 °C, 12 h (75%, ee = 98%)

    (–)-233 (+)-233

    (1S,3R)-225

    (90%)

    THF, –15 °C, 12 h (75%, ee = 98%)

    OH

    HO

    O

    (S)(S)

    (R)(R)

    NH2

    225a

    OO

    OH

    228

    Scheme 32

    OO

    OO

    OH

    OO

    O

    Ph

    Br

    OO

    O

    Ph

    NH2

    O

    NH2

    OH

    HO

    HO

    N H

    HO

    231

    225 230

    226

    228

    229

    O

    1. BuLi, THF, 0 °C

    2.(50%)

    BrCH2CH(OMe)2(82b), BF3⋅Et2O,Et2O, 0 °C, 24 h

    1. LiN3, DMF, 70 °C, 3 h2. LiAlH4, Et2O, 0 °C, 1 h

    (70%)

    HCl, EtOH, reflux, 3 h

    HCl

    12

    3456

    78

    227

    (77%)

    (87%)

  • REVIEW The Oxa-Pictet–Spengler Cyclization 207

    Synthesis 2006, No. 2, 187–220 © Thieme Stuttgart · New York

    tramolecular oxa-Pictet–Spengler condensation, with anacetal tether as the carbonyl moiety.

    The starting acetal was prepared from tyrosine (234)22 byits conversion to the corresponding (S)-3-(3,4-dihydrox-yphenyl)lactate 74a, methylation of the phenolic hydrox-yls to give 74b. p-Toluenesulfonic acid catalyzedaminolysis of the latter with aminoacetal provided the tar-get 235.

    Scheme 34

    Upon reaction with dioxane saturated with HCl, 60%yield of tricyclic lactam 236 was obtained, presumablythrough the intermediacy of acetal 237. Final deoxygen-ation of the lactam with lithium aluminum hydride to 238,followed by reductive methylation furnished the desiredanalogue 239.

    Similarly, the seven-membered heterocycle was preparedemploying aminopropanal diethyl acetal in place of ami-noacetal.

    Wünsch23 also reported that the oxa-Pictet–Spengler con-densation of 74a and methyl levulinate (240) gave mix-tures of cis and trans 1,1,3-trisubstituted isochromans 241(Scheme 35).

    After Williamson etherification to 242 and chromato-graphic separation of the isomers, the levorotatory cis-diastereomer (1S,3S)-242 was submitted to a Dieckmanncondensation, while the dextrorotatory diastereomer wasfirst epimerized at C-3 to (1R,3R)-242 and then subjectedto a Dieckmann condensation, leading to (R,R)-243.Enantiomeric ketones 244 were then prepared by saponi-fication and decarboxylation of their corresponding b-ke-toesters 243.

    Among the fragrances, Galaxolide (6), prepared and pat-ented in 1967 by Heeringa and Beets,118 is the ultimate re-sult of the chemical evolution of the benzenoid musks(Figure 7) which began over 110 years ago with musk ke-tone (245)118d and passed through phantolide (246).

    Figure 7

    The current annual production of Galaxolide is around3800 metric tons, and it has recently been detected in riv-ers and surface waters at mg/L levels.119 Interestingly, onlytwo of the four possible isomers of 6 are responsible forthe valuable musk scent; this information is of high valuein view of the low degradability of this product and in-creasing environmental concerns.

    The group of Fráter was able to prepare and separate thediastereomers (4RS,7SR)-6 and (4RS,7RS)-6 through theformation of chromium carbonyl complexes 247, asshown in Scheme 36.120

    NH2

    (S)(S)

    HO

    CO2H

    OH(S)(S)

    RO

    CO2MeRO

    OH(S)(S)

    MeO

    MeONH

    O

    O(S)(S)

    MeO

    MeONH

    O

    OMe

    74a R = H74b R = Me

    O

    (S)(S)

    MeO

    MeO

    (R)(R)N

    H

    O

    O

    (S)(S)

    MeO

    MeO

    (R)(R)N

    R

    238 R= H239 R= Me

    MeI, DMF, K2CO3, 12 h, 40 °C (67%)

    (99%)

    Dioxane, HCl (sat)48 h, r.t.

    (99%)

    LiAlH4, THF, 19 h, r.t.

    (83%)

    CH2=O, NaBH3CN,MeOH, 4 h, r.t. (98%)

    234

    235

    236

    237OMe

    MeO

    H2NCH2CH(OMe)2,TsOH, 1.5 h, 140 °C

    Scheme 35

    OH(S)(S)

    HO

    CO2MeHO

    O

    (S)(S)

    MeO

    MeO

    (S)(S)

    O

    (1S,3S)-242

    241

    O(S)(S)

    HO

    CO2MeHO

    Me

    MeO2C

    O(S)(S)

    MeO

    CO2MeMeO

    (S)(S)

    Me CO2Me

    (S,S)-244

    O

    (S)(S)

    MeO

    MeO

    (S)(S)

    Me CO2Me

    O

    Me

    (R,R)-243

    OMeO

    RMeO

    (R)(R)

    Me

    O

    (R)(R)

    MeO

    MeO

    (R)(R)

    Me CO2Me

    O

    O

    (R)(R)

    MeO

    MeO

    (R)(R)

    O

    Me

    74a

    CO2Me

    (R,R)-244

    (S,S)-243

    Me

    OMeO2C

    H+

    240

    Diastereomer separationDiastereomer separation

    CO2MeCO2Me

    (1R,3S)-242 R =(1R,3R)-242 R =

    O

    Me

    Me Me

    Me

    O2N

    NO2MeMe

    O

    Me

    Me

    MeMe

    MeMe

    Me

    O

    MeMe

    MeMe

    Me

    Me

    6

    245 246

  • 208 E. L. Larghi, T. S. Kaufman REVIEW

    Synthesis 2006, No. 2, 187–220 © Thieme Stuttgart · New York

    Scheme 36

    These authors120 also synthesized all four of its isomers(Scheme 37) through a strategy that consisted of reacting1,1,2,3,3-pentamethyl indane (248)121 with chiral propyl-ene oxides (R)-249 and (S)-249 under Friedel–Crafts-typeconditions122 promoted by titanium tetrachloride.

    Scheme 37

    This gave 54–57% yields of 1:1 diastereomeric mixturesof phenethyl alcohols (R)-250 and (S)-250, respectively.Interestingly, complete configurational inversion of theoxiranyl chiral centers was observed.

    Once submitted to the oxa-Pictet–Spengler cyclizationwith paraformaldehyde under sulfuric acid catalysis, theb-phenethyl alcohols 250 furnished two separate mixturesof galaxolide isomers in 84–87% yield. For these prod-ucts, the stereochemistry of the C-4 methyl group wasunequivocally established by correlation with the config-uration of the starting oxiranes.

    Each pair of diastereomers was separated through the useof the chromium complexes 247; Scheme 38 shows thepreferential formation of trans-247 from (4S,7R)-6, whichproved to be the most powerful compound, closely fol-lowed by (4S,7S)-6. The 4R isomers were demonstrated tobe much weaker and to not contribute to the odor profileof galaxolide.

    Scheme 38

    A more recent synthesis of diastereomers of galaxolide onC-7 was described by the group of Scrivanti.123 These Ital-ian scientists prepared compound (4S)-250, also from248, by employing palladium chemistry coupled to a cat-alytic hydrocarbonylation and an enantioselective catalyt-ic hydrogenation to build the 2-substituted hydroxypropylside chain with the proper configuration on the methylgroup. However, optical purities of the target compoundwere between 62% and 89%.

    Racemic etodolac (7), prepared according to the originaloxa-Pictet–Spengler synthesis of Humber,42 was convert-ed into its diastereomeric esters with (–)-borneol and theesters were separated by preparative HPLC. The enan-tiomers of the drug were then individually recovered(ee > 99.9%) after saponification.124

    Bornyl esters also allowed the unequivocal establishmentof the absolute configuration of etodolac (7). Thus, the Sabsolute configuration was assigned to the pharmacologi-cally active (+)-etodolac (anti-inflammatory and analge-sic), which is 2.6 times more potent than its enantiomer,on the basis of the crystallographic analysis of the S-(–)-bornyl ester of R-(–)-etodolac.125 Interestingly, however,the R enantiomer of the drug has been proposed as a drugfor treating hepatitis C.126

    O

    MeMe

    MeMe

    Me

    Me

    O

    (R)(R)

    (R)(R)

    MeMe

    MeMe

    Me

    Me

    O

    (R)(R)(R)(R)

    MeMe

    MeMe

    Me

    Me

    O

    (R)(R)(S)(S)

    MeMe

    MeMe

    Me

    Me

    O

    (R)(R)

    (S)(S)

    MeMe

    MeMe

    Me

    Me

    H2SO4, hνPhH–MeCN

    (71%)

    Cr(CO)3Cr(CO)3

    Cr(CO)6,Bu2O–THF

    (41%)(57%)

    (±)-6

    (4R,7R)-6(and enantiomer)

    (4R,7S)-6(and enantiomer)

    (7R)-247(7S)-247

    H2SO4, hνPhH–MeCN

    (51%)

    Cr(CO)6,Bu2O–THF

    MeMe

    MeMe

    Me

    MeMe

    MeMe

    MeOH

    (S)(S)

    Me

    MeMe

    MeMe

    MeOH

    (R)(R)

    Me

    (R)(R)

    MeMe

    MeMe

    MeO

    (S)(S)

    Me

    (S)(S)

    MeMe

    MeMe

    MeO

    (S)(S)

    Me

    (S)(S)

    MeMe

    MeMe

    MeO

    (R)(R)

    Me

    (R)(R)

    MeMe

    MeMe

    MeO

    (R)(R)

    Me

    248

    (S)(S)

    OMe

    H

    (R)(R)

    OMe

    H(54%)

    (57%)

    (CH2O)x,H2SO4 (cat.)

    (CH2O)x,H2SO4 (cat.)

    (87%)

    (84%)

    (R)-250

    (S)-250

    (S)-249

    (R)-249

    (4S,7R)-6

    (4S,7S)-6

    (4R,7S)-6

    (4R,7R)-6

    TiCl4

    O

    (S)(S)

    (R)(R)

    MeMe

    MeMe

    Me

    Me

    O

    CrOC

    COCO

    O

    CrCO

    CO

    OC

    (84%)(7%)

    [O][O]

    trans-247cis-247

    (4S,7R)-6

    Cr(CO)6,Bu2O–THF

    Cr(CO)6,Bu2O–THF

  • REVIEW The Oxa-Pictet–Spengler Cyclization 209

    Synthesis 2006, No. 2, 187–220 © Thieme Stuttgart · New York

    In a short communication of their results on the synthesisof selective dopamine D4 antagonists, useful for treatingschizophrenia and psychotic diseases, TenBrink and co-workers described the preparation of ester 251 by oxa-Pic-tet–Spengler condensation of b-phenethyl alcohol (162)and malonic acetal 252 (Scheme 39).127 After hydrolysisto 253, this was resolved enzymatically or by diastereo-meric salt formation with the enantiomeric a-phenethylamines 254.

    The resolved acids (R)-253 and (S)-253 were individuallyreduced to the corresponding alcohols 255 with borane,and these were coupled with different aryl piperazines166b and 256 through their mesylates. This allowed forthe synthesis of chiral compounds (R)-161b and 257, andtheir corresponding enantiomers. Isochroman derivative(S)-257 (U-101387) is known as sonepiprazole.

    An similar approach was followed by the same group intheir synthesis of isochroman-6-carboxamides such asPNU-109291 (258a) and PNU-142633 (258b)(Figure 8).128 These are both highly selective 5-HT1D ago-nists, useful for treatment of migraine, without cardiovas-cular side effects. The required chiral precursor wasobtained by enzymatic resolution of a carboxylic acidanalogous to 253.

    Figure 8

    7 Synthesis of Heterocycles other than Isochro-man Derivatives

    In addition to being used in the synthesis of isochromansand naphthopyrans, the oxa-Pictet–Spengler cyclizationwas extensively employed for the synthesis of pyranoin-doles, largely driven by the powerful pharmacologicalproperties of etodolac. Other heterocycles have also beenprepared following this strategy, thus extending the scopeof the reaction.

    There are few precedents on the oxa-Pictet–Spengler re-action being applied to the synthesis of furan deriva-tives;129 however, recently the group of Miles reported theoxa-Pictet–Spengler reaction of 1-(3-furyl)alkan-2-ols.130

    Scheme 40

    In their protocol, the heterocyclic alkan-2-ols 259, easilyavailable through the carbonyl-ene reaction of 3-methyl-ene-2,3-dihydrofuran 260 with different aldehydes(Scheme 40),131 were cyclocondensed with various alde-hydes 261 and acetone. Good yields were obtained of thehighly acid-sensitive 5,7-disubstituted 4,5-dihydro-7H-furano[2,3-c]pyrans (262), potentially useful starting ma-terials for the preparation of complex pyran-type naturalproducts.132

    Scheme 39

    OHOH

    OH

    O

    N

    (R)(R)N

    R

    O

    N

    (S)(S)N

    R

    NH N R

    (S)-255

    162

    O

    CO2R

    OEtCO2Et

    EtOTiCl4, CH2Cl2(90%)

    O(S)(S)

    CO2H

    251 R = Et253 R = H

    1. NaOHaq.2. HClaq.

    NH2

    (R)(R) Me

    (S)-253

    O(R)(R)

    CO2H(R)-253

    NH2

    (S)(S) Me

    O

    (R)-255

    O

    BH3⋅SMe2

    MsClMsCl

    (R)-161b R = OMe(R)-257 R = SO2NH2

    (S)-254 (R)-254

    252

    166b R = OMe256 R = SO2NH2

    NH N R166b R = OMe256 R = SO2NH2

    (S)-161b R = OMe(S)-257 R = SO2NH2

    BH3⋅SMe2

    O

    N

    (S)(S)N

    RH2NOC

    258a R = OMe258b R = CONH2

    R

    OHO

    Me(R)(R)O

    Me

    O

    Me H

    Me O

    (R)(R)

    Me Me

    O+O

    HH

    259 2