total synthesis of natural 8- and 9-membered lactones: recent advancements in medium-sized ring...

Total Synthesis of Natural 8- and 9-Membered Lactones: RecentAdvancements in Medium-Sized Ring Formation

Isamu Shiina*

Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan

Received June 1, 2006

Contents1. Introduction 239

1.1. Natural Medium-Sized Lactones 2391.2. Lactonization Methods 240

2. Total Synthesis of Natural 8-Membered Lactones 2422.1. Total Synthesis of Cephalosporolide D (1) 242

2.1.1. Shiina Total Synthesis (1998) 2422.1.2. Buszek Total Synthesis (2001) 244

2.2. Total Synthesis of Octalactins A and B 2442.2.1. Buszek Total Synthesis (1994) 2442.2.2. Clardy Total Synthesis (1994) 2472.2.3. Holmes Total Synthesis (2004) 2472.2.4. Shiina Total Synthesis (2004) 2482.2.5. Andrus Formal Total Synthesis (1996) 2522.2.6. Hatakeyama Synthesis of the Lactone

Moiety (1998)254

2.2.7. Garcia Synthesis of the Lactone Moiety(1998)

255

2.2.8. Buszek Alternative Synthesis of OctalactinA (2002)

256

2.2.9. Cossy Synthesis of the Lactone Moiety(2005)

257

2.2.10. Kodama Formal Synthesis (1997) 2582.2.11. Hulme Partial Synthesis (1997) 2592.2.12. Campagne Synthesis of the Fragments

(2000)259

3. Total Synthesis of 9-Membered Lactones 2603.1. Total Synthesis of Halicholactone 260

3.1.1. Wills Total Synthesis (1995) 2613.1.2. Takemoto−Tanaka Total Synthesis (2000) 2623.1.3. Kitahara Total Synthesis (2002) 2623.1.4. Datta Formal Synthesis (1998) 264

3.2. Total Synthesis of the Proposed Structure of2-Epibotcinolide

265

3.2.1. Shiina Total Synthesis (2006) 2663.2.2. Chakraborty Synthesis of the Lactone

Moiety (2006)266

3.3. Total Synthesis of Griseoviridin 2683.3.1. Meyers Total Synthesis (2000) 268

4. Conclusions 2695. Abbreviations 2716. Acknowledgments 2717. References 271

1. Introduction

1.1. Natural Medium-Sized LactonesNaturally occurring medium-sized lactones are categorized

as rare species of organic molecules, and a few limitedcompounds have been isolated to date as shown in Figure1. For example, only the three structures of cephalosporolideD (1)1 and octalactins A (2)2 and B (3)2 were unambiguouslyconfirmed as 8-membered lactones generated from naturalsources. As additional examples, the structures of solan-delactones (4),3 isolated from the hydroidSolanderia secundain 1996, and astakolactin (5),4 isolated from the spongeCacospongia scalarisin 2003, were suggested to be 8-mem-bered compounds as described in the same figure. On theother hand, the structures of botcinolide (7a)5 and 2-epibot-cinolide (7b),6 postulated to be 9-membered lactones, wererecently revised via the total synthesis of the assumedstructure by Shiina’s group and reinvestigation of thestructure by Nakajima’s group (Vide infra, section 3.2).Therefore, a saturated 9-membered lactone does not exist atthe present time as far as we know, although the commonstructure of the unsaturated 9-membered ring part in hali-cholactone (6a)7 and neohalicholactone (6b)7 was determinedby X-ray analysis. There are some related compounds having9-membered rings, such as antimycin A3b (8),8 well-knownas one of the antimycin diolide antibiotics, and griseoviridin(9),9 a sulfur-containing bicyclic macrolactam antibiotic.

It is widely postulated that producing medium-sizedring compounds is difficult not only by biosynthesis innature, as described above, but also by artificial synthetictechnology in the field of recently advanced organic syn-thesis.10 The compounds listed in Figure 2, i.e., vermicu-line (10),11 ascidiatrienolide A (11),12 gonioheptolide A(12),13 almuheptolide A (13),14 and gloeosporone (14),15

whose structures had initially been proposed as medium-sized lactones or cyclic ethers but were later revised asother types of compounds by the elaboration of the structure,also show the scarcity and novelty of these kinds ofmolecules.

Because there exist some excellent reviews highlightingthe lactonization methods,16 including an elegant report quiterecently summarized by Campagne’s group,17 this paperprovides (i) a brief introduction of the latest progress inlactonization technology and (ii) some splendid examplesof the total synthesis of medium-sized ring compounds, suchas cephalosporolide D (1), octalactins A (2) and B (3),halicholactone (6a), griseoviridin (9), and the pseudo struc-ture of 2-epibotcinolide (7b). Some additional comments onthe synthesis of antimycin A3b (8), a diolide including a

* Phone: 81-3-3260-4271. Fax: 81-3-3260-5609. E-mail: [email protected].

239Chem. Rev. 2007, 107, 239−273

10.1021/cr050045o CCC: $65.00 © 2007 American Chemical SocietyPublished on Web 12/22/2006

9-membered ring, will be given as an exceptional instancefor this article.

1.2. Lactonization MethodsThe synthesis of the macrocyclic framework is one of the

important processes for producing natural and unnaturaluseful compounds in organic chemistry.18 Recently, severaleffective C-C bond-forming reactions, such as transitionmetal-promoted coupling and olefin metathesis, have beenwidely studied for producing cyclic compounds. However,macrolactonization is still the most popular method forproducing cyclic compounds involving carboxylic estermoieties since there are some effective methods for con-structing the ester linkage. Actually, the chemical synthesisof macrolactones has made great progress due to thedevelopment of efficient methods for ring closure fromω-hydroxycarboxylic acids (seco-acids) or their activatedderivatives.16-18 Though a variety of numerous methods havebeen reported for the synthesis of macrolactones, there areonly several reactions which are widely used in the totalsynthesis of natural compounds as follows (Schemes 1 and2): (i) the Corey-Nicolaou S-pyridyl ester lactonizationmethod (eq 1); (ii) the Masamune thiol ester activationmethod (eq 2); (iii) the Mukaiyama onium salt method (eq3); (iv) the Yamaguchi mixed-anhydride method (eq 4); (v)the Keck-Steglich DCC/DMAP‚HCl activation method (eq5); (vi) the Mitsunobu alcohol activation method (eqs 6 and7); and (vii) the Shiina benzoic anhydride method (eqs 8and 9). Corey and Nicolaou used theS-pyridyl ester,19 whichwas generated by Mukaiyama thiol ester formation,20 as anactivated precursor for the lactonization. They first ac-complished the total synthesis of some macrolide moleculesincluding recifeiolide (15) as shown in Scheme 1 (eq 1).21

Masamune employed theS-tert-butyl ester as an intermediatein their total synthesis of 6-deoxyerythronolide B (16), andactivation of the thiol ester by a heavy metal efficientlypromoted the cyclization to form the desired polyoxygenatedmacrolactone (eq 2).22 Mukaiyama developed 1-alkyl-2-halopyridinium salts which function as useful reagents forthe preparation of carboxylic esters and lactones in thepresence of tertiary amines.23 After generation of theactivated onium salts from the correspondingω-hydroxy-carboxylic acids, spontaneous lactonization smoothly pro-ceeds to produce a variety of macrolactones. Bartlett firstused this lactonization for the preparation of brefeldin A (17)as shown in eq 3,24 and other groups also succeeded in thetotal synthesis of complex molecules employing this usefulreagent.25 Yamaguchi investigated the utility of a mixedanhydride composed of the 2,4,6-trichlorobenzoate moietywhich was generated from 2,4,6-trichlorobenzoyl chloridewith Et3N.26 The thermodynamic activation of the bulkymixed anhydride in the presence of DMAP afforded thecorresponding lactones in good yields. Yamaguchi then usedthis methodology for the preparation of methynolide (18) asdepicted in eq 4,27 and over 200 examples of application ofthis procedure showed the usefulness of their protocol.17 Keckreinvestigated the ability of the DCC dehydration couplingreaction based on the Steglich’s procedure.28 In the presenceof DMAP and the DMAP‚HCl salt, the DCC-inducedintramolecular cyclization efficiently takes place to generatemacrocyclic molecules, and they succeeded in the totalsynthesis of colletodiol (19) in high yield (eq 5).29 On theother hand, the Mitsunobu reaction,30 an outstanding alcoholactivation protocol, was also used for the preparation of themacrocyclic molecules.31 Mitsunobu demonstrated the po-tential of the lactonization in the alternative total synthesisof 19 (eq 6).32 Among the many instances of this strategyfor the preparation of cyclic molecules, it is notable thatMeyers has recently accomplished the total synthesis ofgriseoviridin (9) utilizing this lactone linkage formation (eq7).33

After following the developments of the lactonizationmethodology, Shiina and co-workers proposed a novelmixed-anhydride method for the preparation of lactonesincluding medium-sized ring compounds, and they appliedthis new technology for the preparation of several macro-cyclic molecules (Scheme 2). This reaction could be pro-moted by an acidic or basic activator, such as Lewis acids,DMAP, or DMAPO, and the ricinoleic acid lactone (20) wasfirst synthesized by the combination of 4-trifluoromethyl-benzoic anhydride (TFBA) with Lewis acid catalysts (eq8),34,35while the aleuritic acid lactone (21) was alternativelysynthesized using 2-methyl-6-nitrobenzoic anhydride (MNBA)with basic additives (eq 9).36,37

For almost all of the listed carboxylic acid activationmethods for the synthesis of lactones in Scheme 1, theactivated intermediates were generated in advance before thecyclization steps. For instance, the Yamaguchi method wasconventionally carried out using an excess amount of basesand it requires a stepwise operation; namely, seco-acids arefirst treated with 2,4,6-trichlorobenzoyl chloride and triethyl-amine to generate the corresponding mixed anhydrides. Afterfiltration of the mixture under an inert gas to remove theformed triethylammonium chloride, the filtrate containingthe mixed anhydrides is next used for acylation of thehydroxyl groups with an excess amount of DMAP underrefluxing toluene conditions. However, in the Shiina protocol,

Isamu Shiina was born in Tokyo, Japan, in 1967. He completed his B.S.and M.S. degrees in the Department of Applied Chemistry, Faculty ofScience, Tokyo University of Science (TUS), and he joined the ResearchInstitute for Science and Technology of TUS as an Assistant Professor inthe research group of Professor T. Mukaiyama in 1992. After receivinghis Ph.D. from the University of Tokyo under the supervision of ProfessorK. Narasaka in 1997, he was promoted to Lecturer at the TUS. He startedhis independent laboratory in the Department of Applied Chemistry, Facultyof Science, TUS, as a Lecturer in 1999, and then he was promoted toAssociate Professor in 2003. He has received the Chemical Society ofJapan Award for Young Chemists (1997) and The Fujisawa FoundationAward (2002) and Kurata Memorial Foundation Award (2004) and BanyuYoung Chemist Award (2006). His research interests include thedevelopment of useful synthetic methods, especially for asymmetricsynthesis and cyclization methodologies, and the total synthesis of complexnatural products and biologically important molecules. Theoretical calcula-tion strategies for the application to the synthetic design and analysis ofthe reaction mechanism are also involved in his research topics.

240 Chemical Reviews, 2007, Vol. 107, No. 1 Shiina

the seco-acids are simply added tothe mixture of thesubstituted benzoic anhydride and catalystsat room tem-perature to produce the desired cyclized compounds inexcellent yields with high purity. In this reaction,thesubstituted benzoic anhydridewas used as a dehydrationreagent to temporarily generate the activated mixed anhydridespecies along with the equilibrium processing in order togradually form the heterogeneous mixed anhydride from thesymmetric aromatic anhydride (Scheme 3). The followingchemoselective alcoholysis of the initially formed mixedanhydride takes place in good accordance with the consump-tion of the mixed anhydride to produce the desired lactonesin high yields.

This one-pot operation procedure prevents an increase inthe concentration of the activated intermediary mixedanhydride, and therefore, the ratio of the monomeric lactoneto the dimeric or origomeric compound would be totallyimproved by easily controlling the concentration of the mixedanhydride.38 This phenomenon was especially detected forthe effective preparation of the strained cyclic moleculesinvolving the medium-sized lactones.

As shown in Figures 3 and 4, a variety of molecules weresuccessfully synthesized according to the substituted benzoic

anhydride method under acidic or basic conditions. Thecompounds in group A, including the medium-sized lactones,such as cephalosporolide D (1),39 were prepared by the acidicpromotion method. Other compounds, i.e., ricinelaidic acidlactone (22),34 ricinoleic acid lactone (20), dihydroambret-tolide (23),34,40 epimer of the 9-membered ring part ofgriseoviridin (24),33 triene macrolide (25),41 and aromatizedlactones (26),42 were also generated using Lewis acid-promoted lactonization in the presence of symmetricallysubstituted benzoic anhydrides. On the other hand, the othercompounds in group B, including medium-sized lactones,such as octalactin A (2)43 and B (3),44 were prepared by thebasic promotion protocol. The representative polyoxygenatedlactone erythronolide A (27),45 musk compound (9E)-isoambrettolide (28),46 antitumor antibiotic patulolide C(29),47 antitumor antibiotic C-1027 chromophore (30),48

homo-muscone derivative (31),49 histone inhibitor spirucho-statin (32),50 antibiotic tubelactomicin A (33),51 antitumorfloresolide B (34),52 anti-insect 2-hydroxy-24-oxooctacosano-lide (35),53 19F-labeled antibiotic amphotericin B methyl ester(36),54 and antibiotic antimycin A3b (8)55 were effectivelysynthesized under the influence of MNBA combined withthe DMAP or DMAPO catalyst.

Figure 1. Natural eight- and nine-membered lactones and related compounds.

Total Synthesis of 8- and 9-Membered Lactones Chemical Reviews, 2007, Vol. 107, No. 1 241

Especially, for the preparation of the 9-membered dilactone37 in the total synthesis of antimycin A3b (8) by Wu,55 theefficiency of the Shiina MNBA lactonization for the forma-tion of the medium-sized ring core was certainly evaluatedby a detailed comparison with other established lactonizationmethods as shown in Table 1.

In this paper, the syntheses of 8- or 9-membered ringcompounds are reviewed along with a focus on the develop-ment of protocols for the preparation of the lactone linkageincluding other formation methods of the backbone skeletons.

2. Total Synthesis of Natural 8-MemberedLactones

2.1. Total Synthesis of Cephalosporolide D (1)Cephalosporolide D (1), a metabolite of fungus, was

isolated in 1985 from the fungusCephalosporium aphidicolatogether with related compounds by Hansonet al.1 Thestructure containing two chiral centers and an unusualsaturated 8-membered lactone was suggested by MS spectral,IR absorption,1H and13C NMR spectral studies. A similarcharacteristic structure was also found in octalactins A (2)and B (3). Shiina employed the TFBA lactonization methodfor the preparation of the 8-membered ring, while Buszek

employed theS-pyridyl ester activation protocol for formingthe cyclized compound.

2.1.1. Shiina Total Synthesis (1998)

Shiina determined the relative and absolute stereochemistryof 1 by the first enantioselective synthesis of (-)-1 usingthe asymmetric aldol reaction and rapid lactonization pro-moted by benzoic anhydride with acidic catalysts (Scheme4).39 The optically activeS-ethyl (R)-3-hydroxybutanal (40)was synthesized with a high enantioselectivity by theasymmetric aldol reaction between the acetaldehyde (38) and1-ethylthio-1-(trimethylsiloxy)ethene (39) derived fromS-ethyl ethanethioate using the chiral diamine-Sn(II) complex(cat.-I ) combined withn-Bu3SnF.56,57 The aldol 40 wasconverted to the optically active 3-(tert-butyldimethylsiloxy)-butanal (41) in good yield after protection with a combinationof TBSOTf and 2,6-lutidine and subsequent reduction withDIBAL. The Horner-Wadsworth-Emmons reaction of thealdehyde with (EtO)2POCH2COOEt produced thetrans-unsaturated ester, which was transformed into the corre-sponding saturated siloxy aldehyde41 by successive hydro-genation and reduction with DIBAL. The reaction of thechiral aldehyde41 with lithium enolate derived from theS-ethyl ethanethioate produced an aldol42 and its diastere-omer with poor diastereoselectivity (dr) 47:53). However,the asymmetric aldol reaction between the aldehyde41and the enol silyl ether39 in the presence of an enantiomerof the chiral diamine-Sn(II) complex (ent-cat.-I ) withn-Bu3SnF produced the corresponding aldol42 in good yieldwith high stereoselectivity (dr) 97:3). The thiol ester moietyof 42 was then converted into the corresponding ester bytransesterification, and successive benzylation of the estersusing trichloromethyl benzylimidate afforded the desireddialkoxy ester in high yield. Deprotection of the TBS groupand saponification of the formed ester with aqueous KOHafforded the desired hydroxy carboxylic acid43 in goodyield.

The lactonization of the seco-acid43was then tried usingthe Shiina mixed-anhydride method with a catalytic amountof Lewis acids and a stoichiometric amount of TFBA.34,35

When the reaction was carried out in the presence of acatalytic amount of TiCl2(OTf)2, the desired 8-memberedlactone44was only obtained in 2% yield. On the other hand,the cyclization reaction catalyzed by Sc(OTf)3 gave the8-membered lactone44 in 44% yield, and 31% of the seco-acid was recovered. After screening several catalysts in thisreaction, it was found that Hf(OTf)4 was the best promoterand it effectively catalyzed the reaction to produce the desired8-membered lactone44 in 81% yield based on an 83%conversion. It is noteworthy that this cyclization exclusivelygave the monomeric lactone and the corresponding diolidewas not formed at all under relatively concentrated condi-tions, although a small amount of the 16-membered diolidewas obtained along with the desired 8-membered lactonewhen the Yamaguchi method was applied to the carboxylicacid 43 under similar conditions. Finally, debenzylation ofthe lactone44 smoothly took place to produce (-)-cepha-losporolide (1) in excellent yield. The synthetic lactone wasrecrystallized, and X-ray crystallography showed its exactrelative stereochemistry.

In summary, an efficient method for the synthesis ofnatural cephalosporolide D was establishedVia the successiveenantioselective aldol reaction and effective construction ofthe 8-membered ring moiety. The absolute and relative

Figure 2. Proposed and revised structures of the medium-sizedring natural compounds.


Scheme 1. Effective Methods for the Preparation of a Lactone Linkage


configurations of the natural product were definitely con-firmed by its enantioselective synthesis.

2.1.2. Buszek Total Synthesis (2001)

Buszeket al. alternatively prepared cephalosporolide D(1) through their original pathway, and they determined therelative and absolute stereochemistry by the total synthesis.58

The cyclization was successfully attained using theS-pyridylester method activated by a silver salt.

The optically active protected alcohol45 and epoxide46were employed for the preparation of the synthetic interme-diates, and a seco-acid49 was obtained via adducts47 and48 according to Scheme 5. Lactonization of the seco-acid49 was then carried out after temporary conversion to theS-pyridyl ester.59 In the presence of AgBF4, at refluxtemperature in toluene, the cyclization proceeded and thedesired 8-membered lactone moiety50was obtained in 81%yield after 12 h of stirring. The final deprotection of the PMBgroup afforded the desired compound, (+)-1.

Buszek systematically generated many kinds of 8-mem-bered lactones from the corresponding seco-acids based ona similar strategy for the total synthesis of natural products,such as (+)- and (-)-cephalosporolide D, and octalactins Aand B. As the conclusion of their synthetic studies, it wassuggested that the conformations of the acyclic precursorsfor high-yielding lactonizations in the syntheses of 8-mem-bered lactones are influenced by the stereochemical arrange-

ment and location of the substituent groups on the carbonbackbone (Vide infra, section 2.2.1).

2.2. Total Synthesis of Octalactins A and B

Octalactins A (2) and B (3) were isolated from the marinebacterium Streptomycessp. in 1991,2 and the formercompound exhibits a potent cytotoxic activity against sometumor cell lines. The octalactins consist of a highly oxidizedmedium-sized ring framework, and the synthesis of thispeculiar complex structure has been one of the mostinteresting topics in organic chemistry. The absolute con-figurations of2 and3 were independently determined in 1994through the total synthesis of the natural (-)-octalactinsstarting from the (S)- and (R)-3-hydroxy-2-methylpropionicacid esters by Buszeket al.,60 and those of theent-octalactins(antipodes) were determined through a synthesis starting from(+)-citronellic acid by McWilliams and Clardy.61 In 2000,Buszeket al. alternatively synthesized octalactinsVia theformation of the 8-membered lactone moiety using the olefinmetathesis.62 Also, Holmeset al. recently accomplished thetotal synthesis of2 and3 utilizing their original rearrange-ment reaction to form the medium-sized ring of the octa-lactins.63 In 2004, Shiinaet al. further reported anothersynthesis of octalactins A and B using the MNBA rapidcyclization for the preparation of the medium-sized lactonepart.43,44In this section, the total syntheses of the octalactinsand other formal syntheses with related synthetic studies ofthe octalactins will be presented.

2.2.1. Buszek Total Synthesis (1994)

Buszek used methyl (S)-3-hydroxy-2-methylpropionate(51) as a starting material for the preparation of the left-hand segment of the octalactins (Scheme 6).60 First, 51 wasconverted to the corresponding PMB ether53 via 52 usingan established method. The regioselective hydroboration of53 and protection of the resulting primary alcohol producedthe MMTr ether. Desilylation and successive oxidation ofthe primary alcohol54with DMP, followed by condensationwith Seyferth’s reagent afforded the acetylene in good yield.64

Scheme 2. Synthesis of Ricinoleic Acid Lactone and Aleuritic Acid Lactone Using Substituted Benzoic Anhydride by Shiina(1994, 2002)

Scheme 3. Substituted Benzoic Anhydride Method for theSynthesis of Carboxylic Esters and Lactones


Finally, iodination of the terminal methyne carbon wasreadily accomplished to give the desired left-hand segment55.

Alternatively, methyl (R)-3-hydroxy-2-methylpropionate(ent-51) was used as a right-hand three-carbon unit in theBuszek synthesis. Conventional protection and successivetreatment ofent-51 gave the corresponding aldehyde56,which reacted with the left-hand segment55 in the presenceof a Ni(II)/Cr(II) mixed catalyst to give an inseparablemixture of alcohols57. Sequential hydrogenation of thisproduct over Lindlar’s catalyst followed by acetylation anddeprotection of the MMTr ether furnished a chromatographi-cally separable mixture of58 and its diastereomer.

Next, the two-step oxidation of58, which has a config-uration suitable for the synthesis of the octalactins, gave thecarboxylic acid, and then deacetylation provided the unsatur-ated hydroxy carboxylic acid59. Although lactonization ofthis seco-acid was accomplished using theS-pyridyl estermethod and the desired unsaturated 8-membered lactone wasobtained in 63-75% yield, however, it was found that

reducing the double bond could not be carried out under anyconditions. Therefore, Buszek decided to use saturatedhydroxy carboxylic acid as the seco-acid for the directpreparation of a trisubstituted 8-membered ring. Hydrogena-tion of the unsaturated hydroxy carboxylic acid59 gave thecorresponding saturated acyclic precursor. Although itrequires a long reaction time, the key lactonization unpre-dictably proceeded to afford the desired 8-membered lactone60 in 73% yield after 96 h. Buszek pointed out that thestereochemical arrangement in the acyclic precursor incombination with the sterically demanding protecting groupsinduces a preferred conformation in the presumed transi-tion state that facilitates ring closure. Furthermore, thedesilylation of 60 and successive oxidation with DMPafforded the aldehyde61, a main skeleton of the octalactins,in good yield.

The side chain was synthesized as follows: (R)-isopro-pyloxirane (63), which could be prepared fromL-valine (62)by the traditional transformation, was coupled with lithiumTMS-acetylide, and the resulting alcohol was protected by

Figure 3. Some lactones prepared by the substituted benzoic anhydride method using acidic catalysts (group A).

Table 1. Yields of Several Lactonizations for the Formation of the Synthetic Intermediate of Antimycin A3b55

entry method reagents (equiv) conditions yield/%

1 Corey-Nicolaou PySSPy (1.1)/PPh3 (1.1)/Cu(OTf)2 (1.0) PhMe/reflux/5.5 h 152 Corey-Nicolaou PySSPy (2.0)/PPh3 (2.0)/(CuOTf)2‚PhH (1.0) PhMe/reflux/2.5 h 133 Corey-Nicolaou PySSPy (4.0)/PPh3 (4.0)/(CuOTf)2‚PhH (1.0) PhMe/reflux/4 h 184 Yamaguchi TCBC (1.0)/Et3N (1.1)/DMAP (6.0) PhMe/reflux/18 h 05 Yamaguchi TCBC (1.6)/Et3N (2.0)/DMAP (10) PhMe/reflux/20 h 76 Yamaguchi TCBC (1.1)/Et3N (1.2)/DMAP (6.0) PhMe/reflux/17 h 107 Keck DCC (2.0)/DMAP‚HCl (2.0)/DMAP (3.0) CHCl3/reflux/21 h 238 Shiina (basic) MNBA (1.3)/DMAP (6.0) PhMe/20°C/19 h 589 Shiina (basic) MNBA (1.5)/DMAP (6.0)/MA 4 Å PhMe/23°C/23 h 62


the TBS group to give the silyl ether64. Next,C-desilylationand successive lithiation followed by methylation affordedthe corresponding inner alkyne, which was regioselectivelyhydrozirconated and iodinated to give the desired side chain,65.

The Ni(II)/Cr(II)-mediated cross coupling of the aldehyde61 with the vinyl iodide 65 gave an approximately 1.5:1separable mixture of diastereomers66. DMP oxidation of

the mixture afforded an enone, followed by desilylation andoxidative removal of the PMB ether to produce the synthetic(-)-octalactin B (3) in good yield. Furthermore, the majorcomponent of the allylic alcohol66 was subjected toepoxidation to afford a single diastereomer. Oxidation withDMP and deprotection of the TBS and PMB groups finallyfurnished the synthetic (-)-octalactin A (2). Through thisfirst total synthesis, the absolute configurations of the

Figure 4. Some lactones prepared by the substituted benzoic anhydride method using basic catalysts (group B).


naturally occurring octalactins A and B had been establishedat the same time.

2.2.2. Clardy Total Synthesis (1994)

Clardy started the synthesis from (+)-citronellic acid (67)for the preparation of the 8-membered ring portion (Scheme7).61 First,67was protected as its methyl ester and oxidativecleavage of the double bond gave the corresponding alde-hyde. The Oshima procedure for forming the methylenemoiety gave the desired terminal alkene, and subsequentsaponification of the ester yielded alkenoic acid68.65

Preparation of the acid chloride, SnCl4-induced cyclizationto form a mixture ofâ-chlorocycloheptanones, and succes-sive treatment with DBU afforded69 via the three-stepsequence.

Kinetic deprotonation of69 followed by quenching withchlorotrimethylsilane produces the cross-conjugated enolether 70. The bicyclic compound71 is stereoselectivelyformed in good yield via a Mukaiyama double-Michaelreaction with methyl vinyl ketone.66 A double Baeyer-Villiger oxidation of 71 produced an 85:15 ratio of theregioisomeric lactones72and73. The former compound wastreated with potassium hydroxide followed by hydrochloricacid to produce a mixture of acyl-migrated hydroxy lactones.After the secondary alcohol is protected as the TBDPS ether,the desired bicyclic lactone74 is isolated as a pure form.Alkylation on the convex face of74proceeds with excellentselectivity and furnishes the methylated compound75.Reduction of75with LiBH4 followed by selective protectionof the primary alcohol and Swern oxidation produced theketone76.

Since the direct Baeyer-Villiger oxidation of76gave the8-membered lactone in low conversions and substantialdecomposition of the ketone, Clardy used the deprotectedalcohol generated from76 by desilylation. Fortunately, thehydroxy ketone can be smoothly converted to the lactone77using trifluoroperoxyacetic acid while keeping the reactiontemperature below-10 °C to prevent formation of anyundesired products. The hydroxyl group is protected again

as the silyl ether under acidic conditions, followed bydeprotection of the chloroacetate using ammonolysis. Oxida-tion with the DMP smoothly proceeds to complete thesynthesis of the lactone aldehyde78.

The synthesis of the side chain starts with the readilyavailable (S)-2-hydroxy-3-methylbutanoic acid (79). Reduc-tion to the diol with LiAlH4 followed by mesylation gavemono-mesylate and bis-mesylate in an 85:15 ratio, respec-tively. Cyclization of the mono-mesylate was carried out withK2CO3 in methanol to give the corresponding epoxideent-63, which was then alkynylated with lithium (trimethylsilyl)-acetylide and BF3‚OEt2. The propargylic alcohol was isolatedin 43% overall yield from the diol and protected as theTBDPS ether80. Successive hydroboration and alkylationaccording to the Nozaki method afforded thecis-alkene81in good yield.67 Finally, the conversion of81 to the vinylhalide82 was completed and the vinyl bromide was used asthe chiral side chain of the octalactins.

Next, coupling the 8-membered ring part78 and the sidechain 82 that generates the basic octalactin backbone wasexamined. After generating the vinyl lithium reagent by themetalation of82 using t-BuLi at a very low temperature, asolution of 78 was added to the vinyl lithium solution toyield a mixture of epimeric secondary alcohols. The mixturewas oxidized with DMP to afford the corresponding ketone,and deprotection produced (+)-octalactin B (ent-3), one ofthe target compounds. The treatment ofent-3 with VO(acac)2and TBHP gave a 2:1 mixture of (+)-octalactin A (ent-2)and its epimeric epoxide. The produced samples showed theopposite sense of the optical rotation to that of the naturaloctalactins; therefore, this synthesis proved that the absoluteconfigurations of the naturally occurring products must bethe reverse of those of the synthetic octalactins.

2.2.3. Holmes Total Synthesis (2004)

Holmes used their original rearrangements, which havebeen successfully applied for the generation of other medium-sized cyclic ethers,68 to form the medium-sized lactones.63

In order to construct the precursor of the rearrangement, they

Scheme 4. Total Synthesis of Cephalosporolide D by Shiina (1998)39


prepared two segments and coupled these pieces by anintermolecular aldol reaction.

First, the acid-catalyzed hydrolysis followed by addi-tion of potassium hydroxide of tetraethoxymethylpropane(85), generated from the vinyl ether84, afforded salt86(Scheme 8). The enol acetate87 involving the aldehydemoiety was synthesized by reaction of salt86 with acetylchloride.

The synthesis of the chiral ketone88was achieved startingfrom methyl (R)-3-hydroxy-2-methylpropionate (ent-51) byprotection of the TBS group and successive Weinreb ketonesynthesis. Next, the 1,4-syn-selective aldol reaction betweenthe (+)-Ipc boron enolate of the ketone88and the aldehyde87 proceeded to give the adduct89, which was treated withEvansanti-reduction to deliver the diol90 (94% de) in goodyield.69 Exposure of the diol90 to triphosgene under basicconditions provided the unstable cyclic carbonate91 in goodyield. Treatment of the carbonate91with dimethyltitanocenein toluene at reflux for 30 min resulted in methylenationand subsequent Claisen rearrangement of the intermediate92 via the transition state93 as depicted in the scheme toproduce the desired 8-membered lactone94 in reasonableyield (42%). The saturated lactones were formed in excellentyield and with good selectivity (8.2:1) in favor of the desireddiastereomer by the hydrogenation at low-temperatureusing a rhodium catalyst on alumina. Removal of theprotective group from a mixture of the lactones with HF‚pyprovided the desired alcohol95 and the correspondingC4 epimer, which were separated at this stage. Oxidationof the alcohol95 with freshly prepared DMP afforded theacid-sensitive unstable aldehyde96, which was roughlypurified.

The vinyl iodide65 was synthesized in a manner similarto the route developed by Andrus in 1996 (Vide infra, section2.2.5).70 Thus, the known boronic acid97 was synthesizedfrom propargyl bromide and trimethylborate according to theprocedure of Yamamoto.71 The addition of the (+)-diethyltartrate allowed the formation of the corresponding enan-tiomerically pure boronic ester derivative. The subsequentreaction with 2-methylpropionaldehyde (98) provided the

homopropargylic alcohol in 80% ee. The unstable alcoholwas stored as a solution in toluene and was converted tothe corresponding silyl ether99. Methylation of the ter-minal acetylene occurred in quantitative yield by treatmentwith n-BuLi and MeI to afford 100. Finally, followingthe route of Buszek, hydrozirconation of the internalacetylene100 using Schwartz’s reagent,72 followed by theaddition of a solution of iodine, yielded the desired vinyliodide 65.

The reaction of vinyl iodide65 with aldehyde96 underthe influence of the Ni(II)/Cr(II) catalyst gave the desiredproducts101R and101â in excellent yield (91%) as a 1.8:1mixture of separable diastereomers. Oxidation of the minordiastereomer101â with DMP provided the ketone, followedby deprotection of the silyl group with HF‚py, which affordedthe corresponding hydroxy ketone in good yield. Finally, theenzymatic deprotection of the Ac group using lipase typeVII from Candida cylindracearealized the chemoselectivedeacylation after 7 days to produce (-)-octalactin B (3).73

Furthermore, in a manner similar to that reported by Buszek(Vide supra, section 2.2.1), Holmes subjected the majorallylic alcohol 101R to the directed epoxidation usingVO(acac)2 with TBHP to predominantly give theR-isomer.Oxidation of the epoxy alcohol using DMP afforded thecorresponding ketone, which was desilylated upon exposureto HF‚py, giving 102. Finally, the enzymatic hydrolysis ofthe protective group provided (-)-octalactin A (2) inquantitative yield. From the total synthesis of the octalactinsby Holmes, the usefulness of the Claisen rearrangement forthe construction of the medium-ring natural products wasproved.

2.2.4. Shiina Total Synthesis (2004)

Shiina used the asymmetric aldol reaction of (Z)-1-methoxy-2-methylseleno-1-(trimethylsiloxy)propene (103), atetrasubstituted ketene silyl acetal having the alkyl selenogroup at theC2-position, prepared from methyl 2-methylse-lenopropionate, under the influence of the (S)-chiral di-amine-Sn(II) complex (cat.-I ), for producing the opticallyactive synthetic units for the octalactins.43,44

Scheme 5. Total Synthesis of Cephalosporolide D by Buszek (2001)58


As shown in Scheme 9, the reaction of103with the achiralâ-siloxy aldehyde104 smoothly proceeded to give thecorrespondingsyn-aldol adduct105with high diastereo- andenantioselectivities. Next, the conversion of105 to thecorrespondinganti-aldol was carefully examined by theGuindon method,74 and the desiredanti-unit 106 waspreferentially obtained in high yield by successive Bn-imidateprotection and transformation to the Wittig reagent. There-fore, it was shown that the synthesis of theanti-1,2-Vic-hydroxymethyl units involved in the octalactins basicskeleton is easily attained by the combination of theasymmetric aldol reaction of103 with the successive

Guindon radical hydrogen transfer reaction.Similarly, the aldol reaction of103 with the achiral

R-siloxy aldehyde107 was carried out using the (R)-typechiral diamine-Sn(II) complex (ent-cat.-I). The reaction gavethe four-carbon unit108 with a high enantioselectivity.Treatment of108 with n-Bu2BOTf and i-Pr2NEt followedby n-Bu3SnH and Et3B promoted the diastereoselectivedeselenization again to produce the aldolanti-aldol in goodyield. The ester function was reduced by DIBAL to givethe corresponding diol, which was then converted to PMPacetal, and successive deprotection and oxidation gave thedesired aldehyde109 in good yield.

Scheme 6. Total Synthesis of Octalactins A and B by Buszek (1994)60


Two segments106and109were coupled in the presenceof NaHMDS to produce a linear polyoxy compound110 ingood yield. Reductive cleavage of the acetal moiety followedby protection of the resulting primary alcohol afforded thedisilyl ether. Deprotection of the TIPS group and theconventional stepwise oxidation or single-step oxidation byTEMPO of the resulting primary alcohol gave the corre-sponding carboxylic acid. The desired chiral linear seco-acid111 was then obtained by deprotection of the PMB groupand hydrogenation of the double bond without removal ofthe benzyl group.

This seco-acid111 was eventually cyclized to form the8-membered ring using the MNBA lactonization methodpromoted by basic catalysts.36,37 First, excess DMAP wasemployed as a promoter for the cyclization of111 in thepresence of MNBA at room temperature to give the8-membered lactone112 in 84% yield. Next, the amountof the catalyst was gradually decreased, and it was con-firmed that the use of 10 mol % of DMAP with excesstriethylamine was sufficient to produce112 in over 89%yield at room temperature. Furthermore, the use of 10 mol% of DMAPO afforded the targeted lactone in 90% yield

Scheme 7. Total Synthesis of Octalactins A and B by Clardy (1994)61


under very mild reaction conditions (room temperature)within a short time (13 h). Finally, the formed112was thenconverted to the 8-membered lactone aldehyde113 throughdeprotection of the TBDPS group and successive oxida-tion.

Buszeket al. reported the successful lactonization of asimilar seco-acid (Vide supra, section 2.2.1), which has thePMB group instead of the Bn group in111, using theS-pyridyl ester method. It is reported that the cyclizationrequires a high reaction temperature and longer reaction time(96 h); nevertheless, the reaction is accelerated by AgBF4.Although the desired lactone112could actually be obtainedin 63% yield from111 by the S-pyridyl ester method, thereaction sluggishly proceeded even under very severe condi-tions (96 h in refluxing toluene with AgBF4). Furthermore,

it was revealed that this reaction did not take place at all atroom temperature.

The side chain65 was prepared from an optically activealdol 114, which was generated by the asymmetric aldolreaction of enol silyl ether39with 2-methylpropionaldehyde(98).56,57The protection of114and the successive Fukuyamareduction using Et3SiH with Pd/C afforded the chiralaldehyde.75 On the basis of the Buszek synthesis of the sidechain (Vide supra, section 2.2.1), the aldehyde was trans-formed into the desired vinyl iodide65 via the siloxyalkyne100. The side chain65was finally introduced to the aldehyde113 using the method reported by McWilliams and Clardy(Vide supra, section 2.2.2) to give the multioxygenated8-membered lactone115, a precursor of the octalactins. Amixture of diastereomers was oxidized to generate the

Scheme 8. Total Synthesis of Octalactins A and B by Holmes (2004)63


corresponding enone, and successive deprotections of theTBS and Bn groups afforded the (-)-octalactin B (3).Final conversion of3 using TBHP was attained accordingto the literature method to furnish the target compound,(-)-octalactin A (2).

An efficient method for the synthesis of octalactins A andB was established via the enantioselective aldol reactionsand a very effective lactonization using new technology.First, optically activesyn-aldol adducts having asymmetricquaternary centers at the C2-position were temporallygenerated by the asymmetric aldol reaction using the Sn(II)complex (cat.-I ), and then theanti-Vic-hydroxymethyl units

were produced by the successive direct deselenization of thealdol adducts. Furthermore, a new method for constructingthe 8-membered lactone moiety of the octalactins has beensuccessfully established by way of the rapid cyclizationpromoted by MNBA under the influence of a catalyticamount of DMAP or DMAPO.

2.2.5. Andrus Formal Total Synthesis (1996)Andrus reported the formal total synthesis of the octalac-

tins using the method for the preparation of two keyintermediatesent-78 and 65 as described in Scheme 10.70

The 8-membered ring moiety ofent-78 was constructed by

Scheme 9. Total Synthesis of Octalactins A and B by Shiina (2004)43,44


the direct lactonization of hydroxy carboxylic acid using theKeck-Steglich method, whereas the chiral side chain65wassynthesized by the asymmetric nucleophilic addition of ametallic species possessing the chiral auxiliary group.

First, 1,3-propanediol (116) was mono-silylated by theconventional method, and the intermediate was oxidized withPCC to give the aldehyde117 in 77% overall yield. Theprotected 3-hydroxypropanal117 was added to (E)-((+)-(Ipc))2crotylborane (118) to afford the (4R,3S)-anti-homo-allylic alcohol 119 (anti/syn) 20:1, 95% ee) according tothe procedure of Brown.76 TBS protection of119 afforded120, and its ozonolysis followed by treatment with Ph3PdCHCO2Me yielded theR,â-unsaturated ester121. The doublebond of 121 was then reduced using magnesium in drymethanol and the successive half reduction with 1 equiv ofDIBAL at low temperature to provide the aldehyde122. Thesecond reaction with the enantiomeric (E)-((-)-(Ipc))2-crotylborane (ent-118) gave the (4S,3R)-homoallylic alcohol123 in high yield with excellent de. The alcohol123 wasacetylated and the terminal silyl ether group was cleaved bytreatment with HF‚py. The PDC oxidation in DMF was thenfollowed by NaOH hydrolysis to furnish the seco-acid124.

Lactonization of the 7-hydroxyheptanoic acid124to formthe 8-membered ring system under a variety of conditionshas been found to be impossible or, at best, very low yielding.On the other hand, using a modification of the Keck-Steglich conditions,28 it was found that addition of the seco-acid124as a 0.1 M ethanol-free chloroform solution to DCC,DMAP, and DMAP‚HCl in refluxing chloroform (0.01 M,12 h addition time, 24 h total reaction time) produced thelactone125in 73% yield after workup. Substituting the watersoluble carbodiimide EDCI for DCC greatly simplified thereaction, giving the product125 in 81% isolated yield afterchromatography. Finally, ozonolysis of the lactone125gavethe desired aldehydeent-78, which is an enantiomer of theClardy intermediate for the total synthesis of the octalactins(Vide supra, section 2.2.2).

The synthesis of the vinyl iodide65 was independentlycarried out by the addition of allenyl(bis-2,4-dimethyl-3-pentyl-D-tartrate)boronate (97′) to 2-methylpropionaldehyde(98) according to the Yamamoto procedure.71 Protection asthe TBS ether gave99 in an 82% overall yield and 95% ee.The terminal alkyne99 was treated withn-BuLi and anexcess amount of methyl iodide to afford the methylalkyne

Scheme 10. Formal Synthesis of Octalactins A and B by Andrus (1996)70


100 in good yield. Hydrozirconation with zirconacenehydride chloride at 40°C in benzene followed by trappingwith iodine generated65 according to Buszek’s procedure(Vide supra, section 2.2.1).

The Andrus synthesis provides an alternative synthesis ofthe anti,anti-substituted seco-acid124, the precursor to theoctalactin lactone partent-78, using sequential asymmetric(E)-crotylborane additions and successive cyclization of theprecursor via the Keck-Steglich method. Furthermore, theeffective allenylboronate addition was also established toproduce the side chain65 to complete the formal synthesis.Actually, this synthesis of the side chain of the octalactinswas successfully applied to the Holmes total synthesis (Videsupra, section 2.2.3).

2.2.6. Hatakeyama Synthesis of the Lactone Moiety(1998)

Hatakeyama employed the intramolecular Reformatskytype reaction promoted by SmI2 to form the 8-memberedlactone of the octalactins.77 The linear precursor132 wasprepared starting from the natural chiral pool via asymmetricepoxidation of the intermediate allylic alcohol (Scheme 11).

First, (R)-3-hydroxy-2-methylpropionate (ent-51) was pro-tected with THP and reduced by LiAlH4 to give thecorresponding alcohol126. Successive oxidation, conven-tional two-carbon elongation, and hydrogenation of the

double bond afforded the linear five-carbon unit (127). Asimilar repetition was carried out for the two-carbon enlarge-ment of 127 to provide the (E)-allylic alcohol 128, whichinvolves a linear seven-carbon unit. The Katsuki-Sharplesscatalytic asymmetric epoxidation of128was carried out, andthe desired epoxide129 was stereoselectively produced.78

In the presence of a catalytic amount of CuCN, theregioselective opening of the epoxide function by the reactionwith methyllithium afforded the desired 1,3-diol130, fol-lowed by oxidation with NaIO4 to remove the mixed 1,2-diol which was simultaneously produced as a byproductduring the epoxy-opening reaction. Selective mono-benzy-lation of130and successive bromoacetylation of the resultingsecondary alcohol afforded the bromoacetate131 in goodyield. By the sequential acidic methanolysis of131 andSwern oxidation, the desiredR-bromoacetoxy aldehydeintermediate132, a precursor for the SmI2-induced Refor-matsky reaction, was provided.

The key intramolecular cyclization via the Sm-enolateformation of132was carried out according to the literaturereported by Inanaga to produce the 1:2 epimeric mixture ofthe (3R)-hydroxy lactone133R and the (3S)-hydroxy lactone133â in 63% yield.79 Although the diastereoselectivity is notsatisfactory and the undesired isomer133â was obtained asa major product,133â could fortunately be converted to theneeded compound133R in high yield by sequential DMP

Scheme 11. Formal Synthesis of Octalactins A and B by Hatakeyama (1998)77


oxidation and NaBH4 reduction. Finally, protection of133Ras its TBS ether followed by hydrogenelytic removal of thebenzyl group afforded the alcohol134, which is the enan-tiomer of the Clardy intermediate (Vide supra, section 2.2.2).Further conversion of134 to the aldehydeent-78, which isalso the enantiomer of the key intermediate for the totalsynthesis of the octalactins, is also carried out by DMPoxidation. Therefore, the present work formally provided thenew route to the synthesis of the natural octalactins.

2.2.7. Garcia Synthesis of the Lactone Moiety (1998)Garcia reported a new route for the synthesis of the

octalactin 8-membered lactone part via the stereoselectivepreparation of theanti-1,2-Vic-hydroxymethyl units141and144 using the asymmetric BH3‚SMe2 reduction in thepresence of the (R)- or (S)-oxazaborolidines, followed bydiastereoselective hydroboration (Scheme 12).80 The Michaeladdition of the titanium enolate derived from the EvansN-acyloxazolidinone135to acrylonitrile was first carried outto stereoselectively afford the corresponding alkylated com-pound136.81 After reductive removal of the chiral auxiliaryfrom 136 and in situ protection of the primary alcohol, thenitrile 137 was cleanly converted into the aldehyde by

DIBAL reduction. Oxidation of the aldehyde with NaClO2/H2O2 afforded the carboxylic acid138. Transformation of138 into the ketone139 was successfully achieved by thesequential addition ofn-BuLi and of CH2dCMeLi. Next,139was treated with BH3‚SMe2 in the presence of the (R)-oxazaborolidine (cat.-II ),82 which gave the allylic alcohol140 in 95% yield with 91% de. Furthermore, hydroborationof a pivalated derivative of140 with an excess amount of9-BBN in THF followed by oxidation mainly led to theanti-2,3-Vic-hydroxymethyl unit 141, corresponding to theC3-C9 fragment of the octalactins.

The intermediate141 was transformed into the aldehyde142 by successive benzyl protection, deprotection of theTBDPS group, and Swern oxidation. The addition of lith-ium trimethylsilylacetylide to142provided a roughly equi-molar, inseparable mixture of ynols, and then oxidation ofsuch a mixture produced the acetylenic ketone143. Theborane-mediated reduction of143 in the presence of the (S)-oxazaborolidines (ent-cat.-II ) gave144 in good yield with asatisfactory selectivity (94% de). The successive hydrobo-ration of 144 with an excess of amount of (c-Hex)2BH inTHF, followed by treatment with H2O2 in aqueous NaHCO3afforded theâ-hydroxy acid145 in excellent yield. Trans-

Scheme 12. Partial Synthesis of Octalactins A and B by Garcia (1998)80


formation of 145 into the seco-acid146 required threeadditional steps: that is, the protection of the C3-hydroxylgroup, cleavage of the simultaneously generated silyl esterlinkage using aqueous NaHCO3, and subsequent deprotectionof the pivaloyl group using DIBAL without affecting thecarboxyl group or the TBDPS protecting group at-78 °C.Finally, the ring closure was carried out by the Corey-Nicolaou-Gerlach procedure under high-dilution conditionsaccording to the Buszek synthesis to produce the targetedlactone147 in 41% yield. In this partial synthesis, Bach andGarcia have demonstrated the tandem stereoselective reduc-tion/hydroboration methodology for producing a vinyl ketoneand an acetylenic ketone, which are applicable to thesynthesis of the chiral synthons in the octalactin lactonemoiety, with a high degree of stereocontrol.

2.2.8. Buszek Alternative Synthesis of Octalactin A (2002)Buszek alternatively synthesized the octalactin 8-mem-

bered ring part154 via a ring-closing olefin metathesis(RCM).62 The synthesis of the carboxylic acid152 and thealcohol componentsent-149of the diene ester precursor153

started from methyl (S)- and (R)-3-hydroxy-2-methylpropi-onates, respectively (Scheme 13). For the first generation oftheir total synthesis of the octalactins, it was found that theunsaturated lactone ring resisted any hydrogenation of thedouble bond. However, during their continuous effort totransform the key intermediate into the final target products,an effective hydrogenation method of a derivative of theunsaturated lactones was developed to complete the secondgeneration total synthesis.

Protection of methyl (S)-3-hydroxy-2-methylpropionate(51) as its TBDPS ether followed by DIBAL reduction indiethyl ether at-78 °C provided the alcohol148 in goodyield in two steps. The oxidation of148 with DMP wasimmediately followed by condensation with vinyl magnesiumbromide in THF at-78 °C to afford a 1:1 mixture of thediastereomers149and its epimer, which were separated byflash chromatography. The alcohol149 was first protectedas its PMB ether under the influence of a Lewis acidcatalysis, and the olefin was regioselectively hydroboratedwith 9-BBN and oxidized to give the desired primary alcohol150. Protection of the alcohol150 as its MMTr ether

Scheme 13. Alternative Synthesis of Octalactin A by Buszek (2002)62


followed by desilylation with TBAF gave the intermediatealcohol54, which was oxidized with DMP, and the resultingcrude aldehyde was immediately subjected to the Wittigolefination to afford the alkene151in good yield. Hydrolysisof the MMTr ether followed by Jones oxidation gave thedesired carboxylic acid152.

The synthesis of the other alcohol part was similarly startedfrom methyl (R)-3-hydroxy-2-methylpropionate (ent-51),which is the antipode of the Roche ester51. The secondaryallylic alcoholsent-149and its epimer were prepared in thesame manner described above through the intermediateprimary ent-148. The components152 and ent-149 werecoupled with DCC and DMAP to yield the diene ester153in good yield, and the precursor153 was used for the keyring closure. Fortunately, the diene cleanly underwent RCMin refluxing dichloromethane in the presence of the Grubbs’Ru complex (cat.-III )83 to afford the desired 8-memberedlactone154 in 86% yield after 24 h. It is a very remarkableresult that the medium-sized ring was effectively generatedfrom the acyclic simple precursor, which does not containadditional cyclic rings, via RCM.

As described in the previous report by the Buszek group,reduction of the double bond in154 could not be ac-complished due to the lack of reactivity resulting from thesevere steric interactions around the olefin moiety. However,by installing the side chain into the 8-membered ring part154 to transform the structure into one similar to theoctalactins, it was found that the hydrogenation of the alkene157 smoothly proceeded in the presence of Pearlman’scatalyst [although there is no detailed information oftransforming 155 to 157 through 156 in the literature].Finally, oxidative hydrolysis of the PMB ether with DDQgave the (-)-octalactin A (2).

Buszek developed the new method for the alternativesynthesis of octalactin A involving the construction of thekey 8-membered lactone core via the facile RCM meth-odology.

2.2.9. Cossy Synthesis of the Lactone Moiety (2005)Cossy reported the elegant synthesis of the octalactin

lactone part using enantioselective crotyltitanations to controlthe stereogenic centers at C3, C4, C7, and C8 in the linearprecursor starting from the achiral methyl 3-butenoate,followed by the rapid lactonization to form the medium-sized ring (Scheme 14).84 The anti-stereochemistry of the1,2-Vic-hydroxymethyl units in160and124was effectivelycontrolled by the allylation of the aldehyde with an opticallyactive crotyltitanium complex.

At first, the commercially available methyl 3-butenoate(158) was ozonolyzed and the unstable aldehyde159 wasdirectly treated with the highly diastereo- and enantioselectivecrotyltitanium (R,R)-complex (cat.-IV )85 to produce thehydroxy ester160 in 78% yield with a diastereoselectivitybetter than 96:4 and an enantioselectivity better than 97:3.The hydroxy ester160 was then transformed into thealdehyde163 in three steps; that is,160was subjected to across-metathesis reaction utilizing acrolein (161) and theHoveyda complex (cat.-V)86 at room temperature for 20 hto afford the unsaturated aldehyde162, followed by pro-tection of the hydroxyl group and hydrogenation of thedouble bond. The control of the two stereogenic centers atC7 and C8 in the intermediate homoallylic alcohol wasrealized again by a second enantioselective crotyltitanationusing the (S,S)-complex (ent-cat.-IV ). The coupling productwas treated with LiOH‚H2O to furnish the carboxylic acid124, which served as a precursor for the lactonization. The

Scheme 14. Formal Synthesis of Octalactins A and B by Cossy (2005)84


obtained seco-acid124was eventually cyclized to form the8-membered ring125 in 90% yield using the MNBAlactonization method promoted by DMAP in toluene at roomtemperature. After oxidative cleavage of the double bond in125, the aldehydeent-78 was quantitatively obtained, andent-78 was identified as an enantiomer of the intermediateduring the Clardy synthesis of octalactins (Vide supra, section2.2.2).

One of the most important steps is the enantioselectivecrotyltitanation of aldehydes159 and 163 to form thestereogenic centers. Other effective transformations of themolecules using a cross-metathesis reaction and rapid lac-tonization were also successfully applied to the synthesisof the octalactin lactone part. By comparison to theAntrus synthesis of the 8-membered lactone moiety usingthe Keck-Steglich method (Vide supra, section 2.2.5), theyield and efficiency for the formation of the medium-sized ring backbone were apparently improved by em-ploying the MNBA lactonization method in the Cossysynthesis.

2.2.10. Kodama Formal Synthesis (1997)

Kodama reported the original stereoselective synthesis ofthe linear C1-C9 fragment of octalactin A starting from(-)-citronellol (164) as shown in Scheme 15.87 Two stero-generic centers derived from the carbinol carbons wereconstructed by the Baker’s yeast asymmetric reduction andthe Sharpless asymmetric dihydroxylation.

The primary hydroxyl group in (-)-citronellol (164) wasfirst acetylated, and then, successive epoxidation withm-CPBA, acidic ring opening, and Swern oxidation gave theintermediateR-hydroxy ketone165. Baker’s yeast reduction

of the carbonyl group afforded the corresponding diol166,which has the (R)-configuration at the C6-position.88 Thediol 166 was then converted into the benzyl ether167 inthree steps: that is, acetonide protection, saponification ofthe acetate group, and benzylation of the resulting primarilyalcohol. According to the procedure developed by Kodamaet al.,89 167 was treated withn-BuLi to give the terminalolefin which was subjected to the asymmetric hydroxylationwith AD-mix-R to yield a diastereomeric mixture of the diol(anti/syn) 9:1), which was separated after converting it toMosher’s ester168. Protection of the secondary hydroxylgroup of168 as the PMB ether and removal of the MTPAester afforded the primary alcohol169. Transformation of169 to the bromide followed by reaction with 2-lithio-1,3-dithiane afforded170 in a good yield. Hydrolysis of theacetonide group in170 provided the corresponding (7R)-diol, which was further converted to the (7S)-epoxide171through the mesylate. The Lewis acid-catalyzed epoxideopening reaction afforded an allylic alcohol, and the suc-cessive protection of the hydroxyl group produced thepivalate ester172.

Next, the ester172 was subjected to hydroboration with9-BBN to yield the 1,3-diol173 via reduction of the estermoiety, and it was shown that the selectivity was 9:1.Stepwise protection of the 1,3-diol part in173 as TBDPSand then acetyl groups, hydrolysis of the dithiane function,and reduction of the resulting aldehyde gave the targetprimary alcohol174. The formed174 was identical to theintermediate in the Buszek total synthesis of the octalactins(Vide supra, section 2.2.1); therefore, this partial synthesisof the chiral synthons could be considered as a formalsynthesis of the octalactins.

Scheme 15. Formal Synthesis of Octalactins A and B by Kodama (1997)87


2.2.11. Hulme Partial Synthesis (1997)

Hulme accomplished the model synthesis of the octa-lactin 8-membered ring system possessing a side chainby way of the Evans-Tishchenko intramolecular cycliza-tion using the Sm(III) reagent (Scheme 16).90 The uniquestrategy for access to the construction of the medium-sizedring and for generation of theanti-aldol units is importantto describe.

First, enolization of thetert-butyl thioester 177 andreaction of the resulting (E)-enolate 178 with the 1,7-difunctionalized aldehyde176, which was prepared from the1,7-heptanendiol (175), produced the racemicanti-aldoladduct179 in a 79% yield with excellent diastereoselectivity(>20:1). Silyl protection of theâ-hydroxy thioester gave thecorresponding TBS ether in high yield. Generation of thephosphonate substrate180, for the Horner-Wadsworth-Emmons reaction with the aldehyde, was achieved byreaction of then-BuLi derived anion of diethylethanephos-phonate with the protectedâ-hydroxy thioester. The couplingof a â-ketophosphonate180and 3-methylbutyraldehydeViathe Horner-Wadsworth-Emmons reaction was carried outto produce the (E)-trisubstituted alkene181. Subsequentdeprotection and chemoselective TEMPO oxidation of theprimary hydroxyl group gave the cyclization precursor182in good yield.

The intramolecular Evans-Tishchenko reaction was thenattempted with182 through the intermediate183 using thefreshly prepared Sm(III) catalyst,91 generated from SmI2 and

benzaldehydein situ, to form a mixture of two inseparablediastereomers184in 30% combined yield (dr) 1:1). Finally,the mixture was treated with IBX, and a mixture of ketones185, which are the desired oxidized compounds, wasproduced. This synthetic approach showed the possibility offorming the octalactin 8-membered ring using a novelsamarium-mediated cyclization strategy.

2.2.12. Campagne Synthesis of the Fragments (2000)Campagne reported an original route for the synthesis of

the octalactins:92 that is, (i) preparation of the left-handsegment122using asymmetric Shi epoxidation, (ii) prepara-tion of the right-hand segment195 using the asymmetricvinylogous Mukaiyama aldol reaction, and (iii) joining thesesegments followed by lactonization to form the 8-memberedring core (Scheme 17). Although the synthesis is in progress,the strategy should be demonstrated in this section.

The left-hand segment (C1-C7 fragment) was firstsynthesized using a catalytic asymmetric Shi epoxidation toset up the configurations at C3 and C4. The commercialhexynol (186) was protected as the TBS ether and convertedinto the corresponding ynoate187by reaction withn-BuLiand methyl chloroformate. Trost isomerization of the ynoateled to the formation of the dienoate188in good yield.93 Next,the Shi epoxidation protocol in the presence of the chiralketone (cat.-VI )94 led to the formation of the expectedepoxide189 with a high enantioselectivity (91% ee). TheMiyashita AlMe3-mediated ring opening reaction of theepoxide189,95 and protection of the resulting alcohol as the

Scheme 16. Partial Synthesis of Octalactins A and B by Hulme (1997)90


TBS ether, led to the formation of the desiredanti-product121, which corresponds to the synthetic intermediate for theAndrus formal synthesis of the octalactins (Vide supra,section 2.2.5). Conversion of compound121 into the desiredleft-hand segment122 has also been previously describedin the literature.

Furthermore, the catalytic asymmetric vinylogousMukaiyama aldol reaction of the dienoate192 with 2-methylpropionaldehyde (98) in the presence of CuF com-bined with (S)-tol-BINAP (cat.-VII )96 was planned to formthe optically active vinylogous Mukaiyama adduct193. Thedienoate192 was prepared from the ethyl crotonate (190)via the corresponding intermediary tiglate191 using twosequential enolization steps trapped by MeI and TMSCl,respectively. Actually, the vinylogous Mukaiyama aldolreaction smoothly proceeded to form the desiredδ-hydroxyR,â-unsaturated ester193 in high yield with good selectivity(80% ee). The formed alcohol was protected as the TBSether, which was transformed into the corresponding Weinrebamide194. The reaction of194 with EtMgBr afforded theright-hand segment195 (C8-C15 fragment).

Although it is an ideal stage for the conjugation of the(C1-C7) and (C8-C15) subunits122 and 195 for thesynthesis of the octalactins, this synthetic study showed the

extensive utility of the asymmetric Shi epoxidation and thevinylogous Mukaiyama aldol reaction.

3. Total Synthesis of 9-Membered Lactones

3.1. Total Synthesis of Halicholactone

The marine metabolite halicholactone (6a) was isolatedfrom the marine spongeHalichondria okadai and firstreported in 1989 with the unsaturated derivative neohali-cholactone (6b).7 These compounds, both weak lipoxy-genase inhibitors, contain 20 carbon atoms and have beenproposed to be biosynthesized from arachidonic acid andeicosapentaenenoic acid, respectively. As well as havingimportant physiological properties, these compounds alsocontain a number of unusual structural features, involving a9-membered lactone and a cyclopropane ring. The relativestereochemistry between all the chiral centers in neohali-cholactone (6b) was established by an X-ray crystallographicstudy while the absolute configuration at the C15 carbinolof 6a and 6b was confirmed by degradation to a deriv-ative having the known stereochemistry.97 In this section,the total synthesis of halicholactone (6a) accomplished bythree groups will be presented, followed by showing one

Scheme 17. Partial Synthesis of Octalactins A and B by Campagne (2000)92


example of the formal synthesis for the preparation of theintermediate of6a.

3.1.1. Wills Total Synthesis (1995)Wills first accomplished the total synthesis of halicholac-

tone (6a) using (S)-malic acid (196) as the starting chiralpool (Scheme 18).98 The cyclopropane part was installed bythe reaction of theR,â-unsaturated ester with the trimeth-lysulfoxonium ylide, and the lactonization was attained usingYamaguchi’s mixed anhydride method to give the corre-sponding main skeleton. The coupling reaction with the sidechain afforded the peculiar 9-membered ring compoundshalicholactone (6a) and neohalicholactone (6b).

The transformation of (S)-malic acid (196) into theâ-hydroxy-γ-lactone197 was achieved by an establishedmethod. The PMB group was then attached to give thecorresponding protected lactone using the trichloroacetimi-

date protocol. Reduction of the lactone to the lactol198, amixture of diastereomers, was carried out using DIBAL atlow temperature in toluene. Although the reaction of198with the Wittig reagent derived from (4-carboxybutyl)-triphenylphosphonium bromide (199) was troublesome, ap-plication of a modified version of the Holmes conditions forthe synthesis of ascidiatrienolide A,12b a 10-memberedlactone, to this coupling afforded the adduct200 in goodyield after methylation using methanolic HCl.

Conversion of200 to theR,â-unsaturated ester202 wasaccomplished using a Swern oxidation followed by reactionwith the appropriate phosphonate ester201 under theconditions described by Masamune and Roush.99 The keycyclopropanation step of202was carried out using 2 equivof the trimethylsulfoxonium ylide,100 generated by thereaction of the sulfoxonium salt with sodium hydride. Amixture of the produced two diastereomers203and its isomer

Scheme 18. Total Synthesis of Halicholactone by Wills (1995)98


(5:2 ratio) was treated with DDQ to produce the correspond-ing alcohols, and the formed two isomers were separated byflash chromatography. The completion of the synthesis of205was achieved by ester hydrolysis using lithium hydroxidefollowed by lactonization of204 using the Yamaguchiprotocol.26 Thetert-butyl protecting group of the intermediatelactone205 was removed by TFA to give the carboxylicacid 206. The aldehyde207 was prepared from206 byNaBH4 reduction of the mixed anhydride from the reactionof the carboxylic acid206with ethyl chloroformate followedby oxidation with TPAP/NMO.

The side chain209 was prepared from the commerciallyavailable208via successive protection of the TBDPS groupand hydrozylconation followed by adding iodide. Next, a2:1 mixture of the adducts210was formed in good yield bythe coupling reaction of207and209using the Cr(II)/Ni(II)catalyst. After resolution of the diastereoisomeric mixtureby flash chromatography followed by desilylation of themajor component using TBAF, (-)-halicholactone (6a), thedesired 9-membered lactone, was successfully synthesized.

The above Wills results represent the first total synthesisof halicholactone (6a). One of the key steps is the Yamaguchilactonization to form the medium-sized lactone part of6a.Although it might be difficult to prepare the 9-memberedlactone moiety, smooth lactonization was attained becausethe cis-double bond provides both enthalpic and entropicassistance to this process, in contrast with the cyclization ofa saturated ring.

3.1.2. Takemoto−Tanaka Total Synthesis (2000)

Takemoto and Tanaka used the (diene)Fe(CO)3 complex212, generated from the dienedialdehyde with Fe(CO)3, asthe starting material for the synthesis of halicholactone(6a).101 Furthermore, they introduced the chirality of6a bythe asymmetric alkylation of the symmetrical dialdehyde212with Et2Zn under the influence of a chiral catalyst (Scheme19). The prepared optically active linear precursor was finallycyclized by RCM to afford the unsaturated 9-membered ringof the targeted molecule.

First, the meso complex212 was synthesized from 2,4-hexadien-1,6-diol (211) with Fe2(CO)9, followed by Swernoxidation. The catalytic asymmetric alkylation of the alde-hyde212with Et2Zn was regioselectively carried out usingthe Soai chiral amino alcohol to afford the correspondingmono-hydroxy aldehyde213with a high ee.102 The alcohol213was functionalized as a TBS ether, and then successivesubjection of the product to the Horner-Wadsworth-Emmons reaction produced anR,â-unsaturated ester214.Reduction of214 with DIBAL proceeded to generate theallylic alcohol, which was treated with OsO4 for thestereoselective dihydroxylation to afford the triol215 withan inseparable diastereoisomer in a 9:1 ratio. The regiose-lective protection of three hydroxyl groups of215with PivClgave a mono-pivalated diol, and the formed diol wasconverted into the bis-chloroacetoxy compound216. At thisstage, the diastereomer contaminant in216 was separatedout by silica gel column chromatography. Next, theyexamined the stereoselective introduction of a phenylsulfanylgroup by nucleophilic substitution. Treatment of the bis-chloroacetoxy compound216, bearing a reactive leavinggroup, with Me2AlSPh gave the desired phenyl sulfide217with high regio- and stereoselectivities.103

Next, to establish the regio- and stereoselective Simmons-Smith reaction,217was transformed into the allylic alcohol

220. After decomplexation of217 with CAN, successivetreatment of the resulting sulfide218 with m-CPBA andP(OMe)3 in refluxing MeOH furnished the bis-allylic alco-hol 219 in good yield. After219 was converted into therequisite product220 by the usual protection, reduction,and deprotection protocol, the reaction of220 with Et2Znand CH2I2 provided the desired mono-cyclopropanatedproduct221 as a single product. The homoallylic alcohol222 was synthesized from221 by the following sequence:removal of the pivaloyl group with MeLi, cleavage of a 1,2-diol with Pb(OAc)4, and introduction of an allyl group byKobayashi’s procedure.104 Although this manipulation gavethe undesiredâ-alcohol222â along with222R, the diaste-reomer222â was easily converted into222R via the usualMitsunobu protocol.

Finally, the formation of a 9-membered lactone possessinga (Z)-olefin was attempted. The homoallylic alcohol222Rwas protected with an EE group, and desilylation afforded adiol 223, which was then reprotected as a diacetate. The EEgroup was successfully removed, and the esterification of224with 5-hexenoic acid (225) and the RCM of the resultingproduct226 with the Ru complex (cat.-III )83 were investi-gated. Although the standard conditions of the RCM afford-ing the desired closure compound were unsatisfactory, theRCM conditions in the presence of Ti(Oi-Pr)4 produced thedesired (Z)-isomer in 72% yield along with the correspondingdimer (11%). The total synthesis of (-)-halicholactone (6a)was completed by methanolysis of two acetyl groups in theformed 9-membered lactone skeleton.

In summary, the asymmetric total synthesis of halicholac-tone from the (diene)Fe(CO)3 complex 212 had beenachieved. The key steps of the synthesis involve catalyticasymmetric alkylation, regio- and stereoselective phenyl-sulfenylation, regio- and stereoselective cyclopropanation,and formation of a 9-membered lactone by the RCM strategy.

3.1.3. Kitahara Total Synthesis (2002)

Kitahara employed their original chiral building blockcontaining a cyclopropyl part233, derived by the baker’syeast reduction of229, as an intermediate for the synthesisof halicholactone (6a), as shown in Scheme 20.105 Two chiralfragments were coupled by the Nozaki-Hiyama-Kishicoupling reaction, and the final formation of the 9-mem-bered ring was attained by way of RCM using Grubbs’catalyst.

The substrate, 4,4-ethylenedioxy-2-(ethoxycarbonyl)cyclo-hexanone (229), was prepared fromâ-2-furylacrylic acid(227) via the acidic ring opening reaction of the furan partand following protections of the ketone and ester function-alities to form an intermediate228, which was then convertedinto the ketone229 by cyclization via the intramolecularDieckman condensation.106 Asymmetric reduction of229with baker’s yeast gave a single product230 in 74% yieldbased on the unrecovered229 (67% efficiency); therefore,the chiral cyclohexanol derivative230 was easily preparedwith an extremely high optical purity (98% ee).107 Thehydroxy ester230was converted in nearly quantitative yieldto the THP ether, which was successively reduced withLiAlH 4 to form the primary alcohol231. After tosylation ofthe hydroxyl group, stepwise hydrolysis with PPTS andHClO4 was accomplished to give the hydroxy ketone232in good yield. Treatment of232 with t-BuOK in t-BuOHsmoothly afforded the key cyclopropyl ketone intermediate233.


The hydroxy ketone233 was directly converted into theprotected silyl enol ether234 by treatment with TIPSOTfand Et3N. Ozonolysis of 234, followed by the Wittigolefination, gave the carboxylic acid235 in good yield. Inorder to obtain the requisitetrans-cyclopropyl aldehyde239,isomerization of thecis-cyclopropyl carboxylic acid235 tothe correspondingtrans-compound238was carried out underbasic conditions. Although this attempt failed and a complexmixture was obtained when the carboxylic acid235was used,epimerization of thetert-butyl ester236generated from235usingtert-butyl trichloroacetoimidate successfully proceededunder the influence oft-BuOK to give 49% of thetrans-fusedtert-butyl ester237along with 28% of thetrans-fusedcarboxylic acid238. The carboxylic acid238was convertedinto the tert-butyl ester237 using the same conditions as

above. Reduction of237 with LiAlH 4 followed by TPAPoxidation gave the desired aldehyde239 in high yield.

Next, the synthesis of the vinyl iodide240 from com-mercially available (R)-1-octyn-3-ol (208) was examined foruse in the Nozaki-Hiyama-Kishi coupling reaction. Protec-tion of 208with TBSCl and successive hydrozylconation-iodination according to Schwartz’s method afforded a vinyliodide 209′, which is a similar segment to that utilized inthe Wills total synthesis of6a (Vide supra, section 3.1.1).The requisite vinyl iodide240was then prepared from209by successive deprotection of the TBS group and acetylation.The aldehyde239and the vinyl iodide240were treated withNiCl2/CrCl2 in a mixed solvent of DMSO and DMF at roomtemperature to give the desired allylic alcohol as a 2.5:1mixture of diastereomers in 90% yield. The mixture was

Scheme 19. Total Synthesis of Halicholactone by Takemoto/Tanaka (2000)101


cleanly separated, and the stereochemistry of the majorproduct241 was confirmed to be the desired (R)-isomer.Initial protection of the secondary hydroxyl group of241asthe acetate and subsequent removal of the TIPS group usingTBAF-HF gave 224, which was converted to226 byesterification with 5-hexenoic acid (225) according to theformer synthesis of the Takemoto-Tanaka group (Videsupra, section 3.1.2). The RCM reaction of226with Grubbs’reagent in the presence of a catalytic amount of Ti(Oi-Pr)4,reported by Takemoto, gave the (Z)-olefin, a 9-memberedlactone derivative, in 93% yield along with 3% of a dimer.Finally, methanolysis of the two acetates afforded the targeted(-)-halicholactone (6a).

In conclusion, the convergent total synthesis of hali-cholactone was attained using the optically active cyclopro-

pane compound233 as a useful chiral building block byKitahara’s group. The (Z)-selective RCM reaction was alsothe key step to construct the 9-membered unsaturated lactonelinkage.

3.1.4. Datta Formal Synthesis (1998)Datta reported the formal synthesis of halicholactone (6a)

by the preparation of the 9-membered lactone possessing acyclopropane part as one component of the functionalities(Scheme 21).108 Their strategy involved the stereoselectivesynthesis of a pivotaltrans-substituted bifunctional cyclo-propane ring which was generated by Charrete’s asymmetriccyclopropanation using a chiral dioxaborolane catalyst.

Cyclopropanation of thetrans-cinnamyl alcohol (242)according to Charette’s protocol,109 in the presence of the

Scheme 20. Total Synthesis of Halicholactone by Kitahara (2002)105


dioxaborolane chiral ligand (cat.-VIII ), cleanly afforded the(1R,2R)-cyclopropyl alcohol243 in high yield with a goodenantioselectivity (88% ee). Acetylation of the hydroxylgroup followed by oxidative degradation of the phenylmoiety to a carboxylic acid under standard conditionsprovided the key cyclopropane intermediate244 in a highoverall yield. Conversion of the carboxylic acid244 to thecorresponding Weinreb amide245 and its reaction withallylmagnesium bromide yielded the desired allyl ketone.Protection of the free hydroxyl group as its TBS ether andstereoselective reduction of the ketone246using K-Selectrideafforded a 1:9 ratio of the diastereomeric alcohols247R and247â, which were easily separated by column chromatog-raphy. The minor isomer247R was converted into therequired247â isomer via the Mitsunobu inversion of thehydroxyl group, and the major diastereoisomer247â wassuccessively treated with OsO4 and NaIO4 to give theexpected hydroxy aldehyde248.

The (Z)-selective Wittig reaction of this aldehyde248withthe reagent derived from (4-carboxybutyl)triphenylphospho-nium bromide (199) in the presence of NaHMDS yieldedthe lactone precursor249. Cyclization of the seco-acid249under Yamaguchi conditions cleanly afforded the expected9-membered lactone250 in 66% yield.26 The smoothformation of the lactone part has been attributed to thepresence of thecis-double bond, which provides favorableassistance to the above cyclization, as expected in the Willssynthesis. Finally, deprotection of the TBS linkage andoxidation of the resulting alcohol furnished the aldehyde207,a known precursor of halicholactone (6a), as described inthe Wills’ paper (Vide supra, section 3.1.1); therefore, theformal synthesis of6a has been achieved.

In summary, Datta accomplished the efficient synthesisof a known precursor of halicholactone using the bis-functionalized key cyclopropane intermediate243, which wassynthesized from thetrans-cinnamyl alcohol via stereose-lective cyclopropanation catalyzed by the chiral dioxaboro-lane ligand (cat.-VIII ). The medium-sized lactone moietyincluding thecis-double bond in the target intermediate wassuccessfully constructed using the Yamaguchi lactonizationmethod.

3.2. Total Synthesis of the Proposed Structure of2-Epibotcinolide

Botcinolide was first isolated from a strain of the fungusBotrytic cinerea(UK185RRC) by Cutleret al. in 1993,5 andthe pseudo 2-epimeric isomer, 2-epibotcinolide, was alsoextracted from the plant pathogenBotrytic cinerea(UCA992)by Colladoet al. in 1996.6 Other isomeric and homologouscompounds were also prepared from a similar fungus,110 andit was revealed that botcinolide and its relatives have asignificant biological activity that inhibits the growth ofseveral plants at low concentrations.

The structures of botcinolide (7a) and 2-epibotcinolide (7b)had been theorized to possess peculiar saturated 9-memberedrings based on an NMR analysis including enhanced NOEtechniques (Figure 1), however, the revised forms of botci-nolide and 2-epibotcinolide were recently proposed on thebasis of a reinvestigation of the structure by Nakajima’sgroup.111 Independently, Shiinaet al. have quite recentlyreported the method for the preparation of the target molecule7b and questioned the structure of the proposed 2-epibotci-nolide through its total synthesis.112

In this section, the total synthesis of the proposed structureof 2-epibotcinolide (pseudo-2-epibotcinolide) is presented

Scheme 21. Formal Synthesis of Halicholactone by Datta (1998)108


using the asymmetric aldol reaction for the generationof the chiral segments to build the linear polyoxygenatedsynthetic intermediates followed by the rapid MNBA lac-tonization to form the key 9-membered ring.

3.2.1. Shiina Total Synthesis (2006)For the Shiina synthesis,112 methyl (R)-lactate251 was

used as the starting material for the preparation of the chirallinear seco-acid259, as shown in Scheme 22. Successiveprotection of251 and reduction with DIBAL afforded thechiral siloxy aldehyde252, which in turn was treated withthe enol silyl ether253derived fromS-ethyl propanethioateusing the chiral diamine-Sn(II) complex (cat.-I ) combinedwith n-Bu2Sn(OAc)2.56,57 The asymmetric aldol reactionsmoothly proceeded, and the correspondingγ-siloxy-â-hydroxy-R-methyl thioester254, which has the requestedstereochemistry, was exclusively obtained. The secondaryhydroxyl group was protected as its TBS ether, and thereduction of the thioester moiety by the Fukuyama methodgave the aldehyde255.75 Conventional three-carbon elonga-tion using the successive Wittig reaction, reduction withL-Selectride, and oxidation with TPAP/NMO yielded theseven-carbon unit aldehyde256. The second aldol reactionof 256with lithium enolate derived fromS-ethyl propaneth-ioate took place with moderate diastereoselectivity, and thelinear nine-carbon polyoxygenated intermediate257 wasproduced. Next, the addition of two extra functionalities forthe linear compounds was attained by dihydroxylation of thedouble bond using OsO4 in pyridine solvent after threesteps: that is, protection of the secondary hydroxyl groupwith the BOM group, reduction of the ester function, andprotection of the resulting primary hydroxyl group. Theproduced diol258 was converted to the correspondingacetonide by treatment with 1-methoxycyclohexene andCSA, and the successive deacetylation of the protective groupfollowed by gradual oxidation of the primary alcohol intothe carboxylic acid proceeded in high yield. The TBSprotecting group on the C8 position was cleaved, and thenthe desired seco-acid259 for the formation of the 9-mem-bered lactone was produced at last.

Eventually, the lactonization of seco-acid259was carriedout in the presence of MNBA and DMAP, and the desiredmonomeric lactone260 was obtained in 71% yield alongwith the dimeric lactide261 (7%).36,37 Following the suc-cessful results of forming the novel saturated 9-memberedlactone, which corresponds to the main skeleton of thetargeted structure, further studies focused on the derivationof this key compound260 into one of the assumed naturallyoccurring botcinolides.

Before attaching the side chain on the backbone of the9-membered ring core, the stereochemistry of260 wasarranged by some transformation to the fragment couplingacceptor263. First, the BOM group of260was deprotectedby hydrogenation using Pd(OH)2, and the producedâ-hy-droxy lactone was oxidized by the TPAP/NMO conditions.Epimerization of theR-position of the formedâ-ketolactonesmoothly took place on silica gel, and the 2-epimericâ-ketolactone262was obtained in good yield. Stereoselectivereduction of the carbonyl group in262 was also ac-complished using NaBH4 in MeOH to afford the correspond-ing 2-epimerizedâ-hydroxy lactone, which was then con-verted into the THP ether, and the TBS protective group wasremoved by TBAF to afford the key intermediate263.

The side chain268 was synthesized starting from theachiral pentanal (264) by the asymmetric aldol reaction with

enol silyl ether39 derived from theS-ethyl ethanethioateusing the chiral diamine-Sn(II) complex (cat.-I ). Theresulting alcohol265 was protected as its TBS ether, andthe successive reduction formed an aldehyde, which wasfurther treated with KCN for the one-carbon homologation.Mesylation of a mixture of cyanohydrin266, and successivesubstitution with phenylselenol in the presence of Cs2CO3,afforded a mixture of diastereomers267. Oxidative elimina-tion of the phenylseleno group, followed by reduction withDIBAL and oxidation of the resulting alcohol, yielded thecorrespondingR,â-unsaturated carboxylic acid268.

Finally, the coupling reaction between the main 9-mem-bered ring263 and the chiral side chain268 was alsoinvestigated using MNBA esterification to form the desiredlactone, which involves all functionalities for producing theideal structure of 2-epibotcinolide (7b). The coupling productwas temporarily converted into the deprotected compound269, and the spectral data of the coupling product werecompared with those of the natural 2-epibotcinolide and otherbotcinolide derivatives reported by several groups; however,the chemical shift of the methyne proton (4.9 ppm inCD3OD) at C8 of the synthetic sample is significantlydifferent from the those of natural 2-epibotcinolide (3.7 ppmin CD3OD), botcinolide (3.6 ppm), 4-O-methylbotcinolide(3.6 ppm), and 3-O-acetyl-2-epibotcinolide (3.7 ppm). Fur-thermore, deprotection of269 afforded the intramoleculartransacylated compound270, which is facilely formed fromthe assumed 9-membered lactone7b.

Therefore, the proposed 9-membered ring structures of2-epibotcinolide (7b) and other related compounds areextremely doubtful, and reassigned structures should be givenfor the exact determination of these true forms.112 Inaccordance with Shiina’s representation of these results,Nakajima’s group has just shown the alternative structureof 2-epibotcinolide as depicted in Scheme 23.111 It issuggested again that the total synthesis of the complex naturalmolecules through the established and certain stereoselectivereactions is the most reliable way to determine the definitivestructure of the natural products.

In summary, Shiina accomplished the total synthesis ofpseudo-2-epibotcinolide through several featured syntheticapproaches: that is, (i) the chiral linear precursor of the9-membered ring compound was stereoselectively con-structed by the combination of the asymmetric aldol strategyfor producing â-hydroxy ester units, and (ii) the keycyclization reaction to form the 9-membered ring wasefficiently achieved by their original mixed-anhydride methodpromoted by MNBA with basic promoters.

3.2.2. Chakraborty Synthesis of the Lactone Moiety(2006)

Chakraborty reported an alternative method for the syn-thesis of the assumed structure of the 9-membered ring ofbotcinolides as shown in Scheme 24.113 The successivebenzylation of methyl (S)-3-hydroxy-2-methylpropionate (51)with Bn-imidate and the reduction of the resulting ester withLiAlH 4 provided the chiral alcohol272. The Swern oxida-tion of 272gave an aldehyde, which was treated with Ph3PdC(Me)CO2Et to exclusively give the correspondingE-olefin.The produced ester was next transformed into the aldehyde273 in two steps via a sequential reduction and oxidation.The aldol reaction of273 with the titanium enolate275derived from the chiral ketone274 gave the desiredsyn-isomer276as the major product in a 6:1 ratio. Silylation of


the hydroxyl group in276was then carried out to form thedesired TIPS ether, and successive cleavage of the TBS groupand protection using TESOTf with 2,6-lutidine furnished theintermediate ketone. The diastereoselective 1,3-syn-hydride

reduction of the ketone with DIBAL produced the allsyn-product277 as the major isomer.

Compound277was next treated with CSA to selectivelyremove the TES group, and the resulting 1,2-diol was

Scheme 22. Total Synthesis of Pseudo-2-epibotcinolide by Shiina (2006)112


protected as itsp-methoxybenzylidene acetal. Next, depro-tection of the TIPS group with TBAF furnished278, anddiastereoselective dihydroxylation of278 was carried outwith a catalytic amount of OsO4 to afford the allsyn-triol279. The selective silylation of the two secondary hydroxylgroups of279 gave the corresponding TBS ether, and thefollowing debenzylation produced the diol280. Reductivecleavage of thep-methoxybenzylidene acetal group of280gave a mixture of positioning isomers in a 3:2 ratio, andacylation of the former compound afforded the requisitealcohol 281. The tertiary hydroxyl group of281 was nextprotected as its TES ether, and hydride reduction was carriedout to deprotect the acetates to furnish282. A two-stepoxidation of282with TPAP followed by NaClO2 producedthe ketoacid283, and the carbonyl group of283 wasselectively reduced with DIBAL to give thesyn-product284.Finally, the Yamaguchi lactonization of the seco-acid284was performed by the following reverse-addition protocol:that is, the mixed anhydride from284dissolved in toluene,after evaporation of THF under reduced pressure, was slowlyadded using a syringe pump over ca. 5 h to asolution ofDMAP in toluene at 100°C to furnish the desired 9-mem-bered lactone285 in 62% yield.

Thus, the synthesis of the polyoxygenated nonalactone partcorresponding to the basic skeleton of the proposed structureof botcinolides was achieved using the highly stereoselectivealdol reaction of the titanium enolate from the lactate-derivedchiral ketone, the stereoselective dihydroxylation, and theYamaguchi lactonization. Although this method producedan 8-epimer of the precursor of 2-epibotcinolide, the chal-lenge of synthesizing the peculiar medium-sized ring struc-ture is very attractive. The synthetic studies on the polyoxy-genated 9-membered lactone part of the assumed structureof the botcinolides have produced fruitful results regardingthe properties of these rare molecules.

3.3. Total Synthesis of GriseoviridinGriseoviridin (9), consisting of an unsaturated 9-membered

lactone moiety, was isolated from a variety of soil organismsbelonging to the genusStreptomyces. The streptograminantibiotics in group A, such as griseoviridin, exhibit a strongsynergism when combined with those in group B, such asetamycin, with respect to their activity toward Gram-positivebacteria. The structure of griseoviridin was determined in1976 by X-ray studies9 but was reported in error with regardto the relative C18/C20 configuration. The correct config-uration of the 1,3-diol system in9 is syn, as shown in Figure1.33a The presence of the properly substituted 9-memberedring containing an ene-thio linkage adds considerably to thecomplexity of the synthetic problem for obtaining griseoviri-din (9).

3.3.1. Meyers Total Synthesis (2000)

After a number of attempts to accomplish the total synthe-sis of griseoviridin (9) over the past 20 years, Meyers finallysucceeded in showing the practical pathway producing thecomplicated natural molecule including the peculiar 9-mem-bered ring moiety.33 The synthesis of9 was started from thepreparation of the 9-membered lactone fragment291. Theother main part301 was also generated in a high enantio-meric purity, and then these compounds were coupled to pro-vide302, the proper precursor to9, as shown in Scheme 25.

An optically active aldehyde286 was first treated withthe lithium enolate of the allyl acetate, giving a diastereo-meric mixture ofâ-hydroxy esters, which were directly oxi-dized with DMP to produce theâ-ketoester287. Thecarbon-sulfur bond in289was then constructed by treatmentof 287 with sodium hydride andS-phthalimide288, whichwas prepared from commercially availableD-cystine by aprocedure adapted from a former study of Miller.114The vinylsulfide linkage in290was then installed by reduction of theâ-ketoester289 with NaBH4 followed by treatment withMsCl. The elimination of thein situ formed mesylate pro-ceeded to afford the required vinyl sulfide as a 20:1 (Z/E)mixture of olefin isomers. Removal of the TBS protectivegroup and hydrolysis of thetert-butyl ester were simulta-neously attained to give the desired hydroxy acid290. Thekey lactonization was then carried out under Mitsunobuconditions with inversion at the secondary hydroxyl groupto give the appropriately substituted ene-thiol lactone291in a 50-70% yield. The primary amine291, which corre-sponds to the key intermediate 9-membered ring to becoupled with the diene oxazole moiety301, was preparedby reductive removal of the Troc group using Cd/Pb.

To synthesize the oxazole-containing subunit301, anoptically active aldehyde299 was prepared from (S)-malicacid (196).115 The chelation-controlled borane reduction ofthe R-carboxyl of a methyl ester derived from196 wasperformed, and the resulting diol was transformed into itsacetonide derivative292. The ester was converted to theWeinreb amide293, and then it was treated with allylmag-nesium bromide to furnish theâ,γ-unsaturated ketone. Theketone was reduced with a high stereoselectivity (>99%)under chelation control to the single diastereomeric alcoholpossessing the 1,3-syn-configuration,116 and the resultingallylic alcohol was then masked as the TBS ether294. Theolefin part in294was subjected to ozonolysis to afford thecorresponding aldehyde, and oxidation of the formed alde-hyde with NaClO2/H2O2 gave the carboxylic acid, which wasimmediately transformed into the hydroxyamide296 bycoupling with (S)-serine methyl ester295 via the mixedanhydride. Cyclization to produce the oxazoline297 wasaccomplished in a 65-70% overall yield from the acid usingBurgess’ reagent.

Next, the oxazoline297 was transformed into the cor-responding oxazole in good yield by oxidation using theCu(I)/Cu(II) peroxide reagent originally developed by theauthors,117 and the TBS group in the oxazole was cleavedwith TBAF to generate the desired hydroxy dioxolane298.Trans-acetalization of the resulting dimethylacetal298 into1,3,5-mesitylideneacetal was then performed under equili-brating exchange conditions using CSA, followed by oxida-tion of the resulting alcohol to give the key aldehyde299.Wittig olefination of the aldehyde299 with allyl triphen-ylphosphorane produced the corresponding diene300 as a5:1 (Z/E) mixture of stereoisomers. Although the olefination

Scheme 23. Structure Revision of 2-Epibotcinolide byNakajima and Cutler (2006)111


reaction wasZ-selective, the mixture could be smoothlyphotoisomerized to the requiredE-diene in the presence ofiodine. Saponification of the methyl ester using lithiumhydroxide gave the requisite carboxylic acid301to be reactedwith lactone291.

The fragment coupling between the oxazole acid301andlactone amine291was eventually examined using EDCI withHOBt, and the desired amide302 was successfully synthe-sized in good yield. Next, transformation of the allyl ester302 into the allyl amide303 was carried out using a two-step sequence; that is, the allyl group in302 was removedin the presence of Pd(Ph3P)4 to produce the crude carboxylicacid, which was thereafter coupled with an allylamine usingEDCI with HOBt to afford the cyclization precursor303 ina high overall yield. The ring-closing metathesis of303using30% Grubbs’ catalyst furnished a single product in 37-42%

yield. The1H NMR spectra showed no sign of olefin isomersduring the RCM. Finally, acidic removal of the diol protect-ing group gave (-)-griseoviridin (9) as a single diastereomer.

In summary, griseoviridin was first synthesized by Meyersemploying the Mitsunobu lactonization and RCM whichinvolved a highly diastereoselective triene to provide thediene macrocyclic ring formation. Although some 9-mem-bered ring parts related to the substituted ene-thiol lactone291had already been synthesized by Meyers and some othergroups using the Mitsunobu cyclization over 20 years ago,33b

the only total synthesis of griseoviridin has now beenestablished by the authors.

4. ConclusionsRecent trends in the synthesis of naturally occurring 8-

and 9-membered lactones are summarized in the present

Scheme 24. Synthesis of the Lactone Part of 2-Epi-8-epibotcinolide by Chakraborty (2006)113


review article. During the past three decades of syntheticstudies of medium-sized ring compounds, many cycliza-tion methodologies have been investigated and applied tothe preparation of the peculiar structure of organic mole-cules. The three rare 8-membered lactones cephalosporolideD (1) and octalactins A (2) and B (3) were successfullysynthesized through several approaches to the formation ofthe medium-sized rings. On the other hand, the syntheticapproach to the pseudo structure of 2-epibotcinolide (7b)proved that there is currently no known naturally occurring

saturated-type 9-membered lactone. Some related com-pounds, such as halicholactone (6a) [unsaturated 9-mem-bered lactone], griseoviridin (9) [sulfur-containing bicyclicmolecule], and the antimycin families [9-membered dilac-tones], were isolated from nature and have been elegantlysynthesized by some research groups. Progress in syntheticstudies of medium-sized ring compounds will certainlycontribute to the distinguished and fruitful achievements ofthe chemical approach for producing natural compounds inthe future.

Scheme 25. Total Synthesis of Griseoviridin by Meyers (2000)33a


5. AbbreviationsAc acetylacac acetylacetonylAE asymmetric epoxidationaq aqueous9-BBN 9-borabicyclic[3.3.1]nonaneBn benzylBoc tert-butoxycarbonylBOM benzyloxymethylBurgess’ reagent (methoxycarbonylsulfamoyl)triethylammon-

ium hydroxide, inner saltca. circa (approximately)CAN cerium ammonium nitratecat. catalystc-Hex cyclohexylCp cyclopentadienylCSA 10-camphorsulfonic acidCy cyclohexyld daysDBU 1,8-diazabicyclo[5.4.0]undec-7-eneDCC dicyclohexylcarbodiimideDDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinoneDEAD diethyl azodicarboxylateDHP dihydropyranDIAD diisopropyl azodicarboxylateDIBAL diisobutylaluminum hydrideDMAP 4-N,N-(dimethylamino)pyridineDMAPO 4-N,N-(dimethylamino)pyridineN-oxideDMF N,N-dimethylformamideDMP Dess-Martin periodinane (1,1,1-tris(acetyloxy)-

1,1-dihydro-1,2-benziodoxol-3-(1H)-one)DMPU N,N′-dimethylpropyleneureaDMSO dimethyl sulfoxidedr diastereomeric ratioEDCI 1-ethyl-3-[3-(dimethylamino)propyl]carbodi-

imideEE 1-ethoxyethylee enantiomeric excessHMPA hexamethylphosphoramideHOBt 1-hydroxybenzotriazolei isoIBX o-iodoxybenzoic acidIpc isopenocampheylJones oxid CrO3/H2SO4

K-Selectride potassium tri-s-butylborohydrideLDA lithium diisopropylamideLHMDS lithium hexamethyldisilazideLindlar Pd/CaCO3liq liquidL-Selectride lithium tri-s-butylborohydridem-CPBA m-chloroperbenzoic acidMEM (2-methoxyethoxy)methylMes mesityl (2,4,6-trimethylphenyl)MMTr p-methoxyphenyldiphenylmethylMNBA 2-methyl-6-nitrobenzoic anhydrideMOM methoxymethylMS molecular sievesMs mesyl (methanesulfonyl)MTPA R-methoxy-R-(trifluoromethyl)phenylacetyln normalNaHMDS sodium hexamethyldisilazideNMO N-methylmorpholineN-oxideoxone potassium peroxymonosulfatep paraPCC pyridinium chlorochromatePDC pyridinium dichromatePiv pivaloyl (trimethylacetyl)PMB p-methoxybenzylPMP p-methoxyphenylPPTS pyridiniump-toluenesulfonate

Py pyridylpy pyridinePyBOP benzotriazolyloxy-tris[pyrrolidino]-phosphon-

ium hexafluorophosphateRCM ring-closing metathesisRed-Al sodium bis(2-methoxyethoxy)aluminum hydridert room temperatureSEM 2-(trimethylsilyl)ethoxymethylSwern oxid DMSO/(COCl)2 then Et3Ntert tertiaryTBAF tetra-n-butylammonium fluorideTBAI tetra-n-butylammonium iodideTBDPS tert-butyldiphenylsilylTBHP tert-butyl hydroperoxideTBS tert-butyldimethylsilylTCBC 2,4,6-trichlorobenzoyl chlorideTEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy radicalTES triethylsilylTf trifluoromethanesulfonylTFA trifluoroacetic acidTFBA 4-trifluoromethylbenzoic anhydrideTHF tetrahydrofuranTHP 2-tetrahydropyranylTIPS triisopropylsilylTMS trimethylsilylTPAP tetra-n-propylammonium perruthenateTroc 2,2,2-trichloroethoxycarbonylTs p-toluenesulfonylTsOH p-toluenesulfonic acid

6. Acknowledgments

The author expresses his hearty thanks to former andcurrent colleagues, who contributed to the total synthesis ofthe medium-sized ring compounds at Tokyo University ofScience. I also thank Professor Teruaki Mukaiyama for hishelpful discussions and encouragements concerning our ownresearch. Our own investigations in this area were partiallysupported by a Research Grant of the Center for Green Photo-Science and Technology and Grants-in-Aid for ScientificResearch from the Ministry of Education, Science, Sportsand Culture, Japan.

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