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3078 Current Organic Chemistry, 2014, 18, 3078-3119

Applications of Morita-Baylis-Hillman Reaction to the Synthesis of Natural Products and Drug Molecules

Subhendu Bhowmika and Sanjay Batraa,b,*

aMedicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, Uttar Pradesh, India; bAcademy of Scientific and Innovative Research, New Delhi

Abstract: The synthesis of complex natural products from simple and common intermediates has been one of the major goals in synthetic organic chemistry. Toward this objective, if such simple scaffolds are suitably decorated with diverse functional groups they present opportunities not only to synthesize the target compounds but also construct the close ana-logues to investigate the biological properties. The Morita-Baylis-Hillman (MBH) reaction is an organocatalyzed C-C bond forming reaction that leads to multifunctional products thereby offering viable alternatives for employing them for other complexity generating reactions. This property has been extensively utilized for the synthesis of natural products of microbial, ani-mal, terrestrial, and marine origins. Simultaneously, MBH adducts are precursors to several drug molecules or their intermediates. This comprehensive review assimilates applications of the Morita-Baylis-Hillman reaction for the synthesis of different natural products and drug molecules.

Keywords: Alkaloid, Drugs, Marine, Morita-Baylis-Hillman, Natural Product, Terpenoid.

1. INTRODUCTION

The Morita-Baylis-Hillman (MBH) reaction is considered to be a unique complexity generating organocatalytic reaction between an activated alkene and carbonyl electrophiles under the influence of a nucleophilic species providing a simple and convenient method for the synthesis of densely functionalized products (Fig. 1). First re-ported in 1968 by Morita [1] as carbinol addition reaction followed by patents from Baylis and Hillman in 1972 [2], this reaction has grown exponentially especially during the last two decades and has now become a standard method in the toolbox of the synthetic or-ganic chemists. Some of the hallmarks of this C-C bond forming reaction, which is generally performed using cheap and commer-cially available starting reagents, include atom-economy, ease of execution and chemospecific groups in the product for further syn-thetic diversifications. At least four different chemical groups (D-1 to D-4, Fig. 1) in the MBH adduct allow construction of diverse units in the realms of heterocyclic and natural product chemistry.

*Address correspondence to this author at the Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, Uttar Pradesh, India and Academy of Scientific and Innovative Research, New Delhi, India; Tel: +91-522-2772450/2772550, Xtn: 4705/4727; Fax: +91-522-2771941; E-mails: [email protected], [email protected]

The growth of the reaction gained momentum after a review of the literature encompassing the scope of the reaction and its appli-cation by Basavaiah et al. published in 1996 [3]. Another compre-hensive review from Basavaiah’s group in 2003 further catalyzed the progress of this reaction [4]. Subsequently, several groups joined into exploring the utility of adduct for many objectives and the progress made was assimilated in the form of reviews or mini-reviews [5]. During the course of our studies related to exploration of the MBH chemistry, we realized that despite several reviews on the development of this reaction, there is no dedicated review on applications of the MBH reaction in synthesis of natural products and drugs or drug intermediates. Although the 5th chapter of the book edited by Shi includes the information related to the impact of MBH chemistry in the natural product chemistry, it has limited availability [6]. In 2012, Lima and Vasconcellos reviewed the sev-eral derivatives generated employing the MBH chemistry which were demonstrated to show different pharmacological activities but

the impact of this reaction on obtaining drug or drug intermediates was not covered in this review [7]. This prompted us to write a comprehensive review concerning the use of the MBH reaction for the syntheses of natural products and drugs or drug intermediates. The search of literature for this review was performed using Sci-Finder. This review covers all citations describing the use of MBH

R R'

X EWG

REWG

XHR'catalyst

+

R = aryl, alkyl, heteroaryl, R' = H, CO2R, alkylX = O, NR; EWG = electron-withdrawing group

Activated alkeneAldehyde/ KetoneMorita-Baylis-Hillman adduct

D-1D-2

D-4

D-3

D = Diversity point

Fig. (1). MBH reaction displaying the 4-chemospecific groups in the adduct.

1875-5348/14 $58.00+.00 © 2014 Bentham Science Publishers

Applications of Morita-Baylis-Hillman Reaction Current Organic Chemistry, 2014, Vol. 18, No. 24 3079

reaction at any of the step during the synthesis of the target natural product or drug intermediate till February 2014. However the syn-thesis of natural product mimics using MBH chemistry is beyond the scope of this article. The schemes included in this review neces-sarily delineate the MBH reaction step but may not essentially out-line each step before or after the MBH reaction employed in the series to reach to the target molecule. Since the mechanistic details of the MBH reaction are discussed extensively in the published reviews and there is no significant development on this aspect in recent past, we are excluding it from the scope of this article. The contents of the review are arranged on the basis of the source of the natural products from where it was isolated followed by the synthe-sis of drug molecules.

2. SYNTHESIS OF NATURAL PRODUCTS OF MICROBIAL ORIGIN

Microorganisms such as bacteria and fungi are considered as precious sources for discovering natural compounds with diverse bioactivities. The screening of compounds of microbial origin has resulted into the discovery of an arsenal of antibiotics including penicillin, chloramphenicol, cephalosporin etc. and has also served as viable alternative for obtaining lead molecules for many other diseases. In the first section citations pertaining to the synthesis of bioactive natural products of microbial origin involving MBH reac-tion as the key step are presented.

2.1. Natural Products of Bacterial Origin

2.1.1. Phosphonothrixin Fields used the MBH adduct of acetaldehyde for the synthesis

of phosphonothrixin (7) [8], a phosphorous containing herbicidal natural product, isolated from Saccharothrix sp. ST-888 [9]. The phosphorylation of the MBH adduct (2) [10] of acetaldehyde with diethyl chlorophosphite led to a product which upon heating at 80 oC underwent Arbuzov reaction to afford E-allyl phosphoate 3 in 60 % yield (Scheme 1). Reduction of the ester in 3 gave the primary alcohol 4. Silyl ether protection followed by vicinal dihydroxylation with OsO4 gave 5 which upon selective oxidation of the secondary hydroxyl group furnished the protected phosphonothrixin 7. De-protecting all the functional groups afforded the salt free protonated phosphonothrixin 1.

2.1.2. Pentenomycin (–)-Pentenomycin I (16), a cyclopentenoid natural product with

antibacterial activity against both Gram-positive and Gram-negative

bacterial strains was isolated from the culture filtrate of Streptomy- ces eurythermus [11]. Sugahara and Ogasawara developed a novel route for the synthesis of this natural antibiotic by carrying out MBH reaction of formaldehyde with a chiral ketodicyclopentadiene (8) to prepare the adduct 9 [12]. Reducing the keto group in 9 with DIBAL-H afforded the endo-allyl alcohol 10 which was then ex- posed to NBS to dibrominate the double bond and subsequently dehydrobrominated to block one of the olefins regioselectively leading to 11. A series of reactions on 11 led to 14 from which the enone double bond of pentenomycin was regenerated via thermoly- sis in diphenyl ether at 280 oC to obtain 15. The acid-mediated de- protection of acetonide and MOM group in 15 afforded (-)-pente-nomycin I (16) in enantiomerically pure form (Scheme 2).

2.1.3. Epopromycin B

Epopromycin B (25), a novel plant cell wall synthesis inhibitor was isolated from the culture broth of Streptomyces sp. NK0400 [13]. Hatakeyama and co-workers developed an enantio- and diastereo-controlled route to the synthesis of epopromycin B and 2-epi-epopromycin B (28) using !-ICD-catalyzed MBH reaction as one of the key steps [14]. The synthesis was initiated with the MBH reaction of (S)-N-Fmoc-leucinal with HFIPA to afford a mixture of 18 and 19 which upon methanolysis by NaOMe afforded methyl esters 20 and 21, respectively (Scheme 3). However, performing an identical MBH reaction with (R)-N-Fmoc leucinal failed to afford the product. Subsequently the adduct 20 was subjected to epoxida-tion under two different conditions to afford the precursor 24 and 27 for epopromycin B and 2-epi-epopromycin B [15], respectively.

2.1.4. Acaterin

(-)-Acaterin (31), a secondary metabolite having 2-penten-4-olide structure, was isolated from Pseudomonus sp. [16]. It is an acetyl-CoA-cholesterol acyltransferase inhibitor and is projected to be effective in the treatment of diseases like atherosclerosis and hypercholesterolemia. The MBH adduct 31, generated from a reac-tion between ",!-unsaturated #-lactone (29) and octanal (30), was used by Frank and Figadère to accomplish the synthesis of racemic acaterin (31) (Scheme 4) [17]. During optimization studies for the MBH reaction, they discovered that the best yields of 31 was ob-tained when the reaction was performed in dioxane:water in the presence of Mg(ClO4)2 as additive. They discovered that irrespec-tive of use of chiral or achiral lactone only the racemic products were isolated.

Me

OH

CO2Me

1. (EtO)2P-Cl, Et3N2. 80 oC, 2 h Me

CO2Me

P

O

OEt

OEt

Me

P

O

OEt

OEt

OHDIBAL-H, Et2O, 0 oC

79%60%

1. TBSCl, Imidazole, DMF, 94%2. OsO4, NMO, CH2Cl2,rt, 80%

94%

Me

P

O

OEt

OEt

OTBS

OHOH

Me

P

O

OH

OH

OH

OOH

(±)-phosphonothrixin(7)(5)

(2) (3) (4)

1. TMSI, CH2Cl22. aq. HF, MeCNMe

P

O

OEt

OEt

OTBS

OOHPDC/Celite,

CH2Cl2

80%(6)

MeCHO

(1)

methyl acrylate, DABCO, dioxane

ref. 10

Scheme 1.

3080 Current Organic Chemistry, 2014, Vol. 18, No. 24 Bhowmik and Batra

O O

OH

OH

OH

O

BrOH

O

Br

OO

OMOM Br

OO

OMOMOH

Br

OO

OMOMOO

O

OOMOM

O

OH

OHOH

(-)-Pentenomycin I

HCHO, DMAP, THF, rt, 3.5 d

67%

(+)-KDP2

DIBAL-H, PhMe, -78 oC

97%

NBS, CH2Cl2,0 oC-rt, 1 h

3 stepsZn, MeOH/AcOH (10:1), 45 oC, 18 h

97%

PDC, CH2Cl2, rt, 24 h

91%

Ph2O, reflux, 20 min

93%

90% TFA, 0 oC, 24 h

62%

(16)

(8)(9) (10)

(11) (12) (13)

(14) (15)

Scheme 2.

HN

OH

CO2Me

Fmoc OH

OH

HN

OH

Fmoc OH

OHOTBS

HN

OH

Fmoc

OOTBS N

H

OHO

HN

O

O

O

OH

Epopromycin B

OsO4, NMO, acetone/H2O 0 oC

quant.

1. TBSOTf, 2,6- lutidine, CH2Cl2, -50 oC

2. LiBH4, THF, 0 oC70 % over 2 steps

DEAD, Ph3P, THF

60%

CHO

HNFmoc

HN

OH

Fmoc

O

O

CF3

CF3

HN

O

Fmoc

O

O

FmocHN

HN

OH

Fmoc

OMe

O

HN

OH

Fmoc

OMe

O

NaOMe, MeOH!-ICD, HFIPA, DMF, -55 oC, 48 h

HN

OH

CO2Me

Fmoc

O HN

OH

Fmoc

OOTBS N

H

OHO

HN

O

O

O

OH

2-epi-Epopromycin B

VO(OiPr)3, TBHP, CH2Cl2, -20 oC

77%

1. NaBH4, MeOH, 0 oC2. TBSOTf, 2,6-lutidine, CH2Cl2, -50 oC

95%

(25)

(28)

(17)

(18)

(19)

(20) (70%)

(21) (2%)

(22)

(23)(24)

(26) (27)

(20)

ref. 15

ref. 15

Scheme 3.

O

O

DABCO, Dioxane:H2O(1:1), 17 h

CHO

O

O OH

O

OH

O

O

O OH

C7H15

HO

rac-acaterin

O

O OH

(-)-Acaterin (31)

(29)

(30)

(31) (47%) (32) (11%)

(33) (10%)

Mg(ClO4)2 (additive)

Scheme 4.


CHOOH

CO2Me

OMEM

CO2MeOMEM

CO2H

O

OMEMO

MEMO

O

O(-)-acaterin (31)

Diastereomer of (-)-acaterin (41)

72% 83% 98%

73% 54%

93%

92%

methyl acrylate, quinuclidine, 48 h

MEMCl, DIPEA, CH2Cl2, 6 h

1 N aq. LiOH, THF:H2O (2:1), 24 h

(R)-(-)-3-butene-2-ol, DCC, DMAP, CH2Cl2, 24 h Grubbs cat., CH2Cl2,

reflux, 48 h

TiCl4, CH2Cl2, 8 h

TiCl4, CH2Cl2, 8 h

(34) (35)

MEMO

O

O

HO

O

O

HO

O

O

(36)(37)

(38)

(39)

(40)

( )4

( )4 ( )4 ( )4 ( )4

( )4( )4

( )4 ( )4

Scheme 5.

O

O

OH

CO2Me O

O

OTIPS

CO2Me O

O

OTIPS

OH

O

O

OTIPS

CO2H

O

O

OTIPS

NCO

OTBDPS

O

O

NHO

O

OTBDPS

O

O

OH

R

OH

R = NH2 (49)R = NHCOCHCl2 (50)

Chloramphenicol derivatives

TIPSOTf, 2,6-lutidine, CH2Cl2, rt, 30 min

95%

SnCl4, CH2Cl2, rt, 16 h

O2N

OH

HN

O

Cl

Cl

OH

chloramphenicol (51)

(43) (44) (45)

(46) (47)

(48)

5 steps OTBDPS

OTBDPS

1. TPAP, NMO, CH2Cl2, MS 4 Å, 15 min, rt, 96%2. NaClO2, NaH2PO4, t-BuOH, H2O, 2-methyl-but-2-ene, rt, 14 h, 90%

1. ClCO2Et, Et3N,0°C, 40 min2. NaN3, H2O, 0°C, 2 h, 3. reflux in PhMe

ref. 19

O

O

CHOref. 21

(42)

Scheme 6.

Nevertheless, later Singh et al. developed an asymmetric route to (-)-acaterin (31) and its diastereomer (41) starting from MBH adduct 35 (Scheme 5) [18]. A quinuclidine-mediated MBH reaction of caprylic aldehyde 34 with methyl acrylate gave the adduct 35.Protecting the hydroxyl group in 35 as methoxyethoxymethyl ether, followed by saponification and coupling with R-(-)-3-butene-2-ol gave the diallyl derivatives 39 and 40 as mixture of diastereomers. Ring closing metathesis and separation of the product gave the protected acaterin (39). A TiCl4-mediated de-protection of 39 gave the natural (-)-acaterin (31) whereas 40 afforded the other di-astereomer 41.

2.1.5. Chloramphenicol Chloramphenicol (51) is the first example of an antibiotic dis-

covered through screening of soil microorganisms and is also the only example of this class of compounds which was commercial-ized for therapeutics [19]. Coelho and Rossi developed a straight-forward and diastereoselective route to functionalized oxazolidines starting from the MBH adduct (43) of piperonal (Scheme 6) [20]. The protocol involved initial transformation of the MBH adducts into diol which was further extended to obtain the oxazolidine 48.Such oxazolidines were earlier reported to cleave to afford the chlo-ramphenicol [21].

Subsequently Mateus and Coelho developed an alternate route for the synthesis of amine diols starting from the MBH adducts which allowed them to access chloramphenicol (51), fluorampheni-col (58) and thiamphenicol (59) stereoselectively [22]. Their strat-egy involved the preparation of ene carbamate from the MBH ad-duct (54, 55) via a Curtius rearrangement followed by stereoselec-tive hydroboration to obtain the intermediate 2-amino-1,3-diols 56 or 57, respectively (Scheme 7). These intermediates were directly transformed into the title antibiotics.

2.1.6. Furaquinocine The furaquinocins class of antibiotics, isolated from the fermen-

tation broth of Streptomyces sp. [23] show a wide range of biological activities which include in vitro cytotoxicity against HeLa S3 and B16 melamona cells, antihypertensive activity, and inhibition of platelet aggregation and coagulation. All members of the furaquinocins possess a densely functionalized naphthoquinone core. Based on DYKAT process, Trost et al. developed the total synthesis of furaquinocin E (67) from the MBH derivative 62(Scheme 8) which was prepared from the MBH adduct 60 [24, 25]. They elegantly extended the scope of their strategy by developing the synthesis of furaquinocin A (68) and B (69) and three more


R

CHO

R

OH

CO2Me

DABCO, methyl acrylate, ultrasound

R

OH

NH2

OH

R

OH

NHCOCHCl2

OH

R

OH

NHCOCHF2

OH

R = NO2,(±)-chloramphenicol (51)R = SO2Me, (±)-thiamphenicol (59)

R = NO2, SO2Me

R = NO2,(±)-fluoramphenicol (58)

methyl dichloroacetate, reflux

methyldifluoroacetate, reflux 85%

65-79%95-97%

(52,53)(54,55)

(56,57)

4 steps

Scheme 7.

CNOCO2Me O

I

OCN

CN

O CN

OTIPS

BrO

OTIPS

Br CO2Me

(MeO)2OP CO2Me

3 steps

O

OH

O

MeOO

Furaquinocin E

LHMDS, THF, 0 oC

89%

(62)

2-iodoresorcinol, Pd2(dba)3, ligand, CH2Cl2, rt, 4 h

(64)

(61)

(65)

(67)

O CN

OAc(63)

1. PdCl2(MeCN)2(10 mol %), HCO2H, PMP, DMF, 50 oC, 6 h2. Ac2O, Et3N, DMAP, CH2Cl2, rt, 1 h

81%, 99% ee

O

OH

Me

HOH2C

O

MeOO

OH

Furaquinocin A

O

OH

CH2OH

Me

O

MeOO

OH

Furaquinocin B(68) (69)

1. DIBAL, CH2Cl2,-78 °C, 1 h

97%MeCHO CN

OH

(60)(1)

acrylonitrile, DABCO ref 25

O

OTIPS

MeOO

HO

1. nBuLi, THF, -78 oC2. MeO NPh

O

(66)

3. oxalic acid. THF/H2O

THF, -78 oC

1. toluene, 110 oC2. air, rt, 64%

54%

3. TBAF, THF, 0 oC 65%

OHOTBDMS

2.

NH HNO

Ph2P

O

PPh2

(R,R)

Scheme 8.


RhamO

TBSO

MeO2C

COMe

Br COMeH

CO2Me

HHRhamO

TBSO

BrH88%

(72)(70)

HHRhamO

TBSO

BrH

COMe

CO2Me

HHRhamO

TBSO

BrH CO2Me

COMePMe3,t-AmOH, 23 oC, 5 h

(71) (73)96:4

MeAlCl2, CH2Cl2,-78- 0 oC

93%

Scheme 9.

MeOPMB

Br

RhamO

TBSOH O

O

O

O

Me

OPMB

OO

RhamO

TBSO HBr

H

PMe3, t-AmOH, 23 oCO

Me

OPMB

OO

O

TBSO HBr

H

OO

Me MeO

Me

OMe

(-)-Spinosyn A pseudoaglycon

4 steps

MeOPMB

PMBO

H O

O

O

1. PMe3, t-AmOH,

23 oC2. TFA, CH2Cl2, 0 oC

O

Me

OH

OO

HO

H H

(-)-Spinosyn A aglycon

40%

(78)

(76)(74)(75)

(77)

Scheme 10.

TBSO

TBSO

H

O

CO2Me

H

H

TBSO

TBSO

H

O

MeO2C

H

H

H

HPMe3 , solvent, rt, 12 h

OO

OH

HH

HO

HO

H

H

FR182877 (82)(80)(79)

TBSO

TBSO

H

O

MeO2C

H

H

H

H+

(81)

solvent from t-AmOH, THF:H2O or 2,2,2-trifluoroethanol

Scheme 11.

analogues of furaquinocin E [26], thereby demonstrating the modu-lar property of the strategy. Dialkylation of 2-iodoresorcinol with the allylic carbamate (62) prepared from the MBH adduct gave 63in excellent yield and high stereoselectivity. Heck reaction in the presence of a sterically hindered base pentamethyl piperidine (PMP) followed by acetalization gave the acetate 64. Saponification of the acetate 64, TIPS protection of the free phenol followed by regioselective bromination of the phenyl ring afforded compound 65. Reduction of the nitrile group to the formyl group in 65 fol-lowed by HWE reaction gave the diene 66 which was transformed into the required furaquinocine E in 4 steps. A squaric acid-based methodology for generating napthaquinone was utilized for the process. 2.1.7. Spinosyn A

Spinosyn A (78), a polyketide natural product is the main com-ponent of a biosynthetic mixture produced by the soil microbe Sac-charopolyspora spinosa [27]. Because of its low toxicity to benefi-cial insects and quick degradation in the environment Dow Agro-Sciences marketed it as an agricultural insecticide against a variety of insects. Roush et al. developed a PMe3-catalyzed tandem in-tramolecular Diels-Alder reaction and vinylogous MBH reaction

(also known as Rauhut-Currier reaction) to obtain the tricyclic core of (-)-spinosyn A with five defined stereocentres (Scheme 9) [28]. They showed that the olefin geometry in 71 had a critical effect on the product distribution in the phosphine-catalyzed cyclization of enone-enoate. The (Z)-enoate 71 afforded the desired product 72 in excellent chemoselectivity (96:4) while with the (E)-enoate the selectivity is less (2:1). It was presumed that the (Z)-enoate re-stricted orbital alignment and therefore suppressed !-deprotonation, required for the formation of olefin migration by-product 73.

Subsequently they extended this protocol to achieve the total synthesis of both (-)-spinosyn A aglycon (78) and (-)-spinosyn A pseudoaglycon (76) (Scheme 10) [29].

2.1.8. FR182877 FR182877, an antimitotic agent which was isolated by Fujisawa

Pharmaceutical Co. from a strain of Streptomyces was found to also possess potent antitumor activities against a broad range of cancer cells, promoting microtubule assembly in vitro and inducing G2/M phase arrest in the cell cycle [30]. Methot and Roush reported a solvent dependent vinylogous MBH reaction route to the synthesis of the tricyclic core (80) of FR182877 (82) (Scheme 11) [31]. Theyshowed that although using tert-amylalcohol as medium gave a


diastereomeric mixture of the desired product (80) and a regioiso-meric product (81), in the presence of THF:H2O (3:1) 80 was formed as the sole product.

2.1.9. Syributins Krishna and co-workers accomplished the total synthesis of

syributins 1 (88) and 2 (89) from a diastereomeric mixture of the MBH adduct (84) of 2,3-O-isopropylidene-R-glyceraldehyde and ethylacrylate (Scheme 12) [32]. Interestingly they found that per-forming the MBH reaction in dioxane-water not only afforded the product at normal temperature and pressure but also enhanced the stereoselctivity in favour of S-isomer. The reduction of the ester group in 84 gave the primary alcohol 85 that upon reaction with acryloyl chloride furnished a diene 86. Ring closing metathesis in the presence of Grubbs 1st generation catalyst gave an advanced intermediate 87. This was then transformed into the syributins 1 and 2.

2.1.10. (+)-Tubelactomicin A Tubelactomicin A (94), a 16-member macrolide antibiotic, was

first isolated from the culture broth of Nocardiasp.MK703-102F1 [33]. Tadano and co-workers achieved the total synthesis of natural (+)-tubelactomicin A in 54 steps from methyl (R)-lactate (90) in 6.2% overall yield using the MBH reaction between 91 and methyl acrylate as one of the key steps (Scheme 13) [34].

2.1.11. Dihydroeponemycin Dihydroeponemycin (100), an active derivative of eponemycin

targets the subunits of both constitutive proteasome and immuno-proteasome. Kim et al. developed an improved route to the synthe-sis of hydroxymethyl substituted enone 97 and transformed it to the natural dihydroeponemycin via combination of Wittig–Horner and Baylis–Hillman type two-step “one-pot” reaction [35]. Initial reac-tion of Boc–Leu–OMe (95) with dimethyl methylphosphonate gave the precursor 96 which served as the substrate for the one-pot reac-tion to afford 97 in good yields. Subsequent protection and epoxida-tion gave the epoxy derivative 98 which upon amide coupling yielded the dihydroeponemycin 100 (Scheme 14).

2.1.12. (S)-4,5-dihydroxy-2,3-pentanedione (DPD) Autoinducers are extremely important for many bacterial spe-

cies to increase their population. Among various autoinducers, identified so far, a borate, known as autoinducer-2 (AI-2), formed from the metabolic product (S)-4,5-dihydroxy-2,3-pentanedione (DPD) is produced by a large number of both Gram-negative and Gram-positive bacteria [36]. Doutheau et al. developed a DABCO-catalyzed MBH reaction between 2-(tert-butyldimethylsilyloxy) ethanal (101) and 3-buten-2-one in THF to obtain the adduct 102which after reductive ozonolysis of the double bond resulted into racemic DPD. They also applied the same sequence to other sub-

OO

CHO

OO

OH

OEt

O

OO

OH

OH

OO

OH

O

O

OO

HOO

O

O

O

OH

HOO (CH2)nCH3

O

Syributin 1 (n = 4) (88)Syributin 2 (n = 6) (89)

ethyl acrylate, DABCO, dioxane:H2O (1:1), rt, 24 h

72%

LiAlH4, AlCl3,ether, 0 oC, 2 h

65%

acrolyl chloride, DIPEA, CH2Cl2,0 oC-rt, 10 h

75%

Grubbs I, CH2Cl2,reflux, 48 h

62%

(83) (84) (85)

(86) (87)

Scheme 12.

MeMeO2C

OH

OHC

OTBDPS

Me

OTBDPS

MeOH

MeO2C

MOMO

Me

SnBu3

CO2Me

OH

Me

HO2C

MOMO

Me

O

O

Me

H

HMe

Me

Me

(+)-tubelactomicin A

methyl acrylate, DABCO, MeOH

86%

5 steps

6.2% overall yield

(90) (91) (92)

(93)(94)

17 steps

8 steps

Scheme 13.


strates for preparing the chain elongated analogues of DPD (Scheme 15) [37]. They found that along with the acyclic form 103the two cyclic anomers 104 and 105 remain in equilibrium.

In an extension of their work, subsequently they reported an asymmetric synthesis of trifluoromethyl analogue of DPD [38]. The CF3-group was introduced by reacting TMSCF3 with the "-methylene ester 109, which was prepared from the MBH reaction between (tert-butyldimethylsilyloxy) acetaldehyde (101) and HFIPA (Scheme 16).

2.1.13. Luminacin D Jogireddy and Maier disclosed a novel route to the synthesis of

Luminacin D (123), an angiogenesis inhibitor isolated from the soil bacteria Streptomyces sp. Mer-VD1207 [39]. Several Luminacin derivatives showed antitumor activity with IC50 values of less than 0.1 mg/mL in a rat aorta matrix culture model [40]. The starting material for the synthesis was prepared by a simple MBH reaction between propanaldehyde (120) and methyl acrylate. Then by OH transposition and two highly stereoselective asymmetric aldol reac-

BocHN

O

OCH3BocHN

O

P

O

OCH3

OCH3BocHN

O OHTFA.H2N

O OTBDPS

O

O OH

OO

HN

OHO

Dihydroeponemycin

CH2O, K2CO3,H2O, rt, 4 h

HN

O

CO2H

OTBDPS

1. HBTU, HOBt, DIPEA, CH2Cl2,rt, 12 h; 2. TBAF, THF, rt, 10 min.

3 steps

(100)

(95) (96) (97) (98)

(99)

55.6%

( )3

Scheme 14.

R1

OTBDMSR2

OR1

ORR2

OH O

MeR1

OHR2

OH

O

O

Me

R = TBDMS

3-butene-2-one, DABCO, THF, 0 oC O3, MeOH

O

CH3

OH

OOHH4

H5

H6O

OH

Me

OOHH7H8

H9

Two cyclic anomeric form of DPD

103104 105101

102

R1, R2 = H

Scheme 15.

HFIPA, DABCO, THF, 0 oC, 2 h

TBDMSO

O

TBDMSO

OH O

OCH(CF3)2

TBDMSO

O O

O

TBDMSO

OH

CO2Me OO

CO2Me

OO

OMe

F3COSiMe3

O

HO

OH

CF3O

OHO

OH

CF3

Et3N, MeOH, rt, 2 h

CSA, MeOH then 2,2-DMP, rt, 1.35 h

TMSCF3, CsF, rt, 26 h

aq. HCl, THF, rt, 18 h

1. O3, CD3OD, -78 oC2. Me2S, -78 oC-rt, 24 h

O

HOHO CF3

HO

HO

H2O

O

HO

OBO

OHHO

CF3

HOB(OH)4

-

-2 H2OO O

BO

OH

OH

OH

CH3

HO

OOH

OH

CH3

OHHO

OOH

CH3

HO O

cyclic DPD

(115) (116) (104,105)

(101)

(106)

(107)

(108) (109)

(110) (111)(112) (113)

(114)

45% 78%

78% over two steps

OTBDMS

Scheme 16.


tions the total synthesis of luminacin D was achieved over several steps (Scheme 17).

2.1.14. (+)-Fostriecin and (+)-Phoslactomycin B Phoslactomycins A–F and I produced by the soil bacteria spe-

cies Streptomyces belongs to the phoslactomycin family of antifun-gal and antitumor antibiotics together with fostriecin [41]. In addi-tion, these compounds are selective inhibitors of serine/threonine phosphatase 2A and presumed to be responsible for their antitumor activity. Hatakeyama et al. reported the formal asymmetric synthe-sis of (+)-fostriecin and (+)-phoslactomycin B from a common intermediate 128 resulting into a general route to phoslactomycin family [42]. Initially a !-ICD-catalyzed MBH reaction between 3-(4-methoxybenzyloxy)propanal (124) and HFIPA gave the adduct 125 in 58% yield and 99% ee. Thereafter, methanolysis of 125 gave the methyl ester 126 which was transformed to the epoxide 128 via a seven step sequence involving silylation, DIBAL-H reduction, DMP oxidation, HWE reaction, desilylation and epoxidation. A vanadium-mediated epoxidation afforded the epoxide 128 stereose-

lectively (Scheme 18). This epoxide was the common precursor to the two natural products.

2.1.15. Gabosine

Gabosines, the naturally occurring cyclitol, were isolated from Streptomyces strains and were found to display biological activities like antibiotic, anticancer, and DNA binding properties [43]. Shaw and co-workers used DMAP-catalyzed MBH reaction as one of the key steps to accomplish the syntheses of (-)-gabosine E (139)and (+)-4-epi-gabosine E (140) starting from methyl ",D-gluco-pyranoside and methyl ",D-mannopyranoside, respectively (Scheme 19) [44]. They demonstrated that the presence of an acetyl group at C-6 position of sugar-derived cyclic enone (137) prevented the aromatization of the MBH adduct 138 formed via the reaction between the enone and formaldehyde.

Later in an alternate approach, Krishna and Kadiyala reported a combination of diastereoselective MBH reaction and RCM reaction as a flexible route to readily access the cyclohexenoid skeletons.

CHOHO

MeO2CO

H

O O OPMB

HO

O OH O

OO

OHOH

methyl acrylate, DABCO, rt, 5 d

Luminacin D

(120)(121)

(122) (123)

13 steps 14 steps

Scheme 17.

O OPMB OH OPMBO

OF3C

CF3OH OPMBO

MeO

MOMO OPMB

EtO2C

O

6 steps

MOMO OPMB

OH

OH

OOOTES

SETO O10 steps

MOMO OPMB

O

OH12 steps

OOOTES

SETO O

AllocHN

!-ICD, HFIPA, DMF, -55 oC

Et3N, MeOH, 0 oC-rt

LiEt3BH, THF, -78-0 oC

DIBAL-H, THF, -78 oC

OO

R1

R2 OH

O OH R3P

O

HO

HO

Fostriecin: R1 = H, R2 = Me, R3 =PD113,271: R1 = OH, R2 = Me, R3 =Phoslactomycin B: R1 = Et, R2 = CH2CH2NH2, R3 =

OHOH

98%58%

98%

85%

(133-135)

(124) (125) (126)

(128)(129) (130)

(131) (132)

MOMO OPMB

EtO2C

VO(acac)2,t-BuO2H, CH2Cl2,-20 oC-rt

87%

(127)

c-C6H11

Scheme 18.

HOBnO

I

R2

R1OMe

O

R2BnO

AcO

R1

O

R2BnO

AcO

R1

OHO

HHO

HO

HO

OH

4 stepsHCHO, DMAP, THF, -10 oC, 2 d

O

OHHO

HO

H

OH

1. PTSA, CH2Cl2/MeOH (9:1)

2.BCl3, CH2Cl2, 0 oC, 4 h

46%49%

(+)-4-epi-Gabosine E(-)-4-Gabosine E

(136) (137) (138)(140)(139)

Scheme 19.


The cyclohexenoids were synthetically manipulated further to ob-tain gabosine I, gabosine G and epi-gabosine I (Scheme 20) [45].

Very recently Chanti Babu et al. reported the synthesis of ga-bosine C and other related analogues by applying RCM reaction followed by MBH reaction strategy (Scheme 21) [46].

2.2. Natural Products of Fungus Origin 2.2.1. Mycestericine E

(-)-Mycestericin E (167) is a potent immunosuppressive agent, isolated from the culture broth of the fungus Mycelia sterilia ATCC 20349 [47]. Hatakeyama and co-workers reported an enantio- and

diastereo-controlled synthesis of this natural compound [48]. The key step of the sequence was a !-ICD-catalyzed asymmetric MBH reaction between aldehyde 161 and HFIPA to obtain the enanti-omerically pure adduct 162 in 47% yield. Transforming 162 to its methyl ester followed by Sharpless epoxidation gave the epoxy derivative 163, which was converted to the epoxytrichloroacetimi-date 164 that upon BF3.OEt2-mediated cyclization resulted into the formation of an oxazolidine 165 stereoselectively (Scheme 22). A sequential Moffatt oxidation, NaClO2 oxidation and esterification of 165 furnished the methyl ester 166 which after de-protection and saponification afforded (-)-mycestericin in 4.7 % overall yield.

O

O

OH

OH

O

O

OH

OTBDPSO

O

TBDPSO HOCO2Et

OO

HO OO

OO

OOOH

O

O

O

HO O

OH

OH

OH

O OH

Gabosine I

OAc

OH

OH

O OH

Gabosine G

TBDPSCl, imidazole, CH2Cl2, 12 h

79%

1. Swern oxid.2. ethyl acrylate, DABCO, DMSO, 24 h

1.Swern oxid.2. vinylMgBr, THF, -20 oC, 0.33 h

87% from II

Grubbs II, PhMe, reflux, 5 h

83%

(148)(147)

(141) (142) (143) (144)

(145)(146)

85%

3 steps

Scheme 20.

OO

OO

HOHO

OO

BzOHO

OO HO

MOMO

OO

MOMO

OO

MOMO

OO

OH OO

O

PPTS, MeOH, 0 oC, 6 h

70%

pyridine, benzoyl chloride, CH2Cl2, 7 h

92%

1. DIPEA, MOM-Cl, CH2Cl2, 12 h2. K2CO3, MeOH, 0 oC, 3 h

83%

1. Swern Oxid.2. vinyl magnesium bromide, THF, 0 oC, 3 h

84%

O

MOMO

OO

O

MOMO

OH

HO

OH

O

HO

OH

HO

OH

O

HO

O

O

IBX, DMSO, 3 h, 0 oC

91%

Hoveyda-Grubbs catalyst (5 mol%), CH2Cl2, reflux, 8 h

60%

aq. HCHO (37–40%), DMAP, 100 oC, 3 d

38%

TFA, MeOH, 0 oC, 4 h

70%

ref.

HO

OH

HO CO2MeR2R1

5 steps

R1 = OMe, R2 = H, 70% ; (+)-Pericosine B (159)R2 = H, R2 = OMe, 67%; (+)-Pericosine C (160)

(149) (150) (151) (152)

(155)(154)(153)

(156) (157) (158)

(+)-Gabosine C (+)-COTC

Scheme 21.


2.2.2. Mniopetals Mniopetals A-F are drimen type sesquiterpenes isolated from

Mniopetalum sp. 87256 and demonstrated to be inhibitors of HIV reverse transcriptase [49]. Jauch in 2001 reported the total synthesis of mniopetal F (173) from the MBH adduct prepared via lithium phenyl selenide promoted reaction between an aldehyde 169 and Feringa’s butenolide 170. Subsequently an endo-selective in-tramolecular Diels-Alder reaction (IMDA) gave 172 which upon inversion of the hindered secondary alcohol and a new variant of Perkin-Doering oxidation gave the title compound. The total syn-thesis was 14 steps long with an overall yield of 10% (Scheme 23)[50].

By employing the same methodology, the total synthesis of mniopetal E (174) was achieved (Scheme 24) [50b].

OOHO O(+)Menthyl

OTBDPSH

H

OOHO OH

CHOH

H

HO6 steps

Mniopetal E(172) (174)

Scheme 24.

In another approach, a solid phase MBH reaction was applied to the resin bound aldehyde 175 to accomplish the synthesis of the tricyclic core (177) of the mniopetals which is delineated in Scheme 25 [50c].

2.2.3. (+)-Harziphilone Harziphilone (182) is a novel fungal metabolite isolated from

the extract of the fermentation broth of Trichloderma harzianum[51]. It has the inhibitory activity against the binding of REV pro-tein to PRE-RNA with IC50 values of 2.0 !M. Besides it shows cytotoxicity at 38 !M against the murine cell line M-109. Sorensen and co-workers applied a vinylogous MBH reaction for the success-ful synthesis of (+)-harziphilone (Scheme 26) [52]. An intramolecu-lar 1,4-addition reaction results into an allenoate ion 179 which upon proton transfer transforms into zwitterion 180. Thereafter the nucleophilic catalyst is eliminated via a !-elimination to yield 181which undergo a 6$-electrocyclization to furnish (+)-harziphilone (182).

2.2.4. Phaseolinic Acid Paraconic acids, a group of highly substituted #-butyrolactones

isolated from moss, lichens, fungi and cultures of Penicillium sp. were reported to display a broad spectrum of biological activities like antitumor, antifungal and antibacterial [53]. Selvakumar and

O O3 5

CHOR

OH O

O CF3

CF3R

OH

OTBDPS3 stepsO

ON

CCl3

ROTBDPS

OH

3 5O

OH

CO2H

H2N OH

(-)-Mycestericin E

!-ICD, HFIPA, DMF–CH2Cl2 (1:1), -55 oC, 24 h

47%

BF3·OEt2CH2Cl2, -23 oC

71%(167)

(161)(162)

(163)

(165)

R

O

OTBDPSO

HN

CCl3R

OH

CO2Me

OTBDPS

HNCOCl3

O O3 5R =

3 steps

(164)(166)

DBU, CCl3CN, CH2Cl2, 0 °C

81%

Scheme 22.

P

O

MeOMeO

O

OMe H

O

OTBDPS O OTBDPS

O(+)Menthyl

O

HO

OOHO O(+)Menthyl

OTBDPSH

H

OOHO OH

CHOH

H

Mniopetal F

5 steps

OO

O(+)Menthyl

Feringa's butenolide

Li(SePh), THF, 170,-60 °C, 6 h

88%

xylene, silylated flask,140 °C, 60 h

68%

7 steps

(170)

(168) (169) (171)

(172) (173)

Scheme 23.

H

O

O

W

Li(SePh)170, -60 °C, 6 h O O

O(+)Menthyl

O

HO

W

OOOO

H

H

(175) (176) (177)

9 steps

Scheme 25.


co-workers developed an approach for the synthesis of butenolides, the core unit of the class of natural products [54]. The protocol involved an initial MBH reaction to obtain the adduct 184 which was acrolylated to 185, followed by RCM reaction between two electron deficient dienes to produce 186. It was then employed for the synthesis of (±)-phaseolinic acid 188 (Scheme 27).

2.2.5. Methyl-7-dihydro-trioxacarcinoside B Koert et al. achieved the synthesis of methyl-7-dihydro-

trioxacarcinoside B (192), a branched octose from the quino-cyclines utilizing the MBH adduct 189 [55]. The enzymatic resolu-tion of the MBH adduct with Pseudomonas AK20 (Amano) af-

forded the product in >99% ee. A highly anti-selective reduction of the ketone and a RCM reaction were the key steps employed for transforming MBH adduct to the cyclic intermediate 191. Further substrate-controlled stereoselective epoxidation and a regio- and stereo-selective epoxide ring opening by allyl alcohol were used to introduce the C(3)-OH group as required in methyl-7-dihydro-trioxacarcinoside B 192 (Scheme 28).

2.2.6. Sphingofungins Sphingofungins E and F, two highly oxygenated "-quaternary

amino acids were isolated from the fermentation broth of Paecilo-myces variotii in 1992 [56]. Wang and Lin developed a flexible

O

O Me

Me

HO

HO

O

O Me

Me

HO

HO

NN

O

O

Me

Me

HO

HO

DABCO, CHCl3, rt, 24 h

intramolecular 1,4-addition

(+)-Harziphilone

(182)

(178) (179)

O

O

Me

Me

HO

HO

(180)

O

O

Me

Me

HO

HO

(181)

N!-elimination

6" -electrocyclization

Scheme 26.

CHOOH

CO2EtO

CO2EtO

OO

CO2Et

OO

CO2Et

C5H11 OO

CO2H

C5H11

(±)-Phaseolinic acid

DABCO, ethyl acrylate, sulpholane, rt

acrolyl chloride, Et3N, CH2Cl2, 0 oC-rt

95%

Grubbs II, Ti(OiPr)4, CH2Cl2,50 oC

87%

Pd/C, HCO2NH4,MeOH, reflux

83%(188)

(183) (184) (185)

(186) (187)

Scheme 27.

H

O

Me Me

O OHO

HO

O

O

HO

OO

HO

OMe

OHOH

methyl vinyl ketone, DABCO, rt, 15 h Grubbs cat II

74%

Methyl-7-dihydro-trioxacarcinoside B(192)

(1)(189)

(190)

(191)

6 steps

8 steps

81%

Scheme 28.


approach for the asymmetric syntheses of sphingofungins E (199)and F (202), with efficient use of the MBH adduct [57]. The syn-thesis was initiated with the MBH reaction of L-(+)-tartaric acid derived aldehyde 193 with methyl acrylate under neat condition. Sharpless dihydroxylation followed by mesylation and base medi-ated epoxidation gave the epoxy derivative which was then reduced to afford 196, a common substrate for the synthesis of both the natural compounds (Schemes 29 and 30).

2.2.7. Oidiodendrolides Tetranorditerpene dilactones oidiolactones A-D (210-213) are

produced by the filamentous fungi represented by Oidiodendron truncatum and Oidiodendron griseum whereas the podolactones such as nagilactone F (214) are produced by different species of the Podocarpus plant [58, 59]. The podolactones are associated with

very good biological activities like antifungal, antitumoral, antifeedant, etc. Hanessian and co-workers developed an efficient and high-yielding strategy for the synthesis of these biologically active dilactones by using MBH reaction, the stereocontrolled con-struction of !-lactone via bromolactonization, and catalytic Refor-matsky type reaction as the key steps [60]. By employing these reactions, a common intermediate 207 was prepared which was then successfully converted to CJ-14,445, LL-Z1271!, oidiolac-tones A, B, C, and D, and nagilactone F in good yields via several steps (Scheme 31).

2.2.8. Cyclitol MK7607 (221), an unsaturated carbapyranose, was isolated

from Curvularia eragrostidis D2452 [61]. Another compound (+)-streptol (222), a C-4 epimer of MK7607, isolated from the cul-

OO

CHO

BnOmethyl acrylate, DABCO, rt, 2-7 d

OO

BnO OH

CO2Me

OO

BnO

NHO

OTBS

O

OMOM

4 steps

1. H2, Pd(OH)2, EtOAc-MeOH2. Swern oxidation3. Wittig reaction

OO

NHO

OTBS

O

OMOMC6H13

OO

145 steps

Sphingofungin E

O OH

OH

OHCO2H

NH2

OH

4 6

OO

BnO

OH

OTBSO 5 steps

(193) (194)

(197)

(198) (199)

(196)

79% OO

BnO OH

CO2Me

(195)major minor

Scheme 29.

O OH

OH

OHCO2H

NH24 6

Sphingofungin F

I2, PPh3, Et2O-MeCN, rt, 3 h

97%O

O

BnO

I

OTBS

O O

O

BnO

H3C OTBS

OLiBHEt3, THF, rt, 15 minO

O

BnO

OH

OTBSO

(196)(202)

(200) (201)

ref. 57b

Scheme 30.

O

CO2HH

O

CO2HH

OHHCHO, Me2PhP, CHCl3/MeOH, rt, 40 h

1. Br2, CHCl3,rt, 30 min2.K2CO3, DMF, 18-crown-6, rt, 12 h

OO

O

H

OHTESCl, Imidazole, CH2Cl2, 0 °C-rt, 3 h

OO

O

H

OTES

OO

H

HO CO2Et

OTES

IOEt

O

NiCl2(PPh3)2, ZnEt2,CH2Cl2, 0 °C-rt, 3 h

95% 57% 89%

72%

CJ-14,445 (208)LL-Z1271! (209)Oidiolactones A-D (210-213)Nagilactone F (214)

(203) (204) (205)

(206) (207)

71%

Scheme 31.


ture filtrate of an unidentified Streptomyces sp., inhibited the ger-mination of lettuce seedlings [62]. Krishna and Kadiyala reported the synthesis of these cyclitol analogues from (R,R)-tartaric acid by using MBH and RCM reactions as the two key steps to construct the diastereomeric cyclohexenoids which were independently trans-formed into the target compounds (Scheme 32) [63]. The substrate 216 was prepared from (R,R)-tartaric acid by following the litera-ture method [64].

2.2.9. Trichodermone A Trichodermone A (229) was isolated from the strain Tricho-

derma sp. YLF-3 and was reported to possess potent antibacterial properties [65]. Krishna and Kadiyala applied their MBH/RCM strategy for obtaining this natural compound too [66]. The synthesis was initiated by performing MBH reaction between acetaldehyde and ethyl acrylate to obtain the adduct 224. A Sharpless kinetic

resolution of 224 gave the MBH adduct as (S)-isomer. After a series of reaction, the homologation of this adduct was accomplished to obtain the bis-olefin 227. RCM reaction in Hoveyda-Grubbs II catalyst (10 mol%) successfully afforded the MOM protected cy-clopentenol 228 which was de-protected to obtain 229 in good yields (Scheme 33).

2.2.10. Isoaspinonene Krishna and co-workers extended the application of MBH reac-

tion for the total synthesis of isoaspinonene (235), a secondary me-tabolite isolated from the cultures of Aspergillus ochraceus [67]. In this case the synthesis was initiated from a chiral aldehyde 230 that could be readily generated from racemic propyleneoxide. The MBH adduct of this aldehyde and ethyl acrylate was isolated in excellent yield (85%). This MBH adduct was first transformed to a cyclic ether 232 from 231 in five steps. A sequential chelation-controlled

(R,R)-Tartaric acidO O

MOMO

HO

OO

MOMOOH

EtO2C

CO2Et

MOMO

OO

OHCO2Et

MOMO

OO

OH

MOMO

OO

OH

OH

HO

OH

OH

OH

OH

(+)-MK7607

HO

OH

OH

OH

OH

1. Swern oxid.2. DABCO, ethyl acrylate, DMF, 24 h

80%

Hoveyda Grubbs II

DIBAL-H, THF, -10 oC, 3 h

99%

DOWEX, MeOH, 70 oC, 2 h

90%

(+)-Streptol

(221)

(222)

(215)(216) (217) (218) major (219) minor

(220)

ref 64

Scheme 32.

H

O OH

CO2EtOH

CO2Et

OMOM

OH

OMOMO

OH

OH

MOMO OMOM OH

MOMOMOMO

HO

HO

HO

O

Trichodermone A

ethyl acrylate, DABCO, DMF, rt, 12 h

85%

(-)-DIPT, Ti(OiPr)4,CHP, -20 oC, 4 d 6 steps

45%

Red Al, CH2Cl2,0 oC, 3 h

79%

5 stepsHoveyda-Grubbs II, PhMe, reflux, 5 h

94%

1. DMP, CH2Cl2, 0 oC2. TFA, CH2Cl2, 0 oC, 2 h

98%

(229)

(1) (223) (224) (225) (226)

(227)(228)

Scheme 33.

CHO

OPMB PMBO

OH

CO2Et

O

OAc

O

O

OAc

OH O

OAc

OH

OTBDPS

O

OAc

OH

OH

5 steps

ethyl acrylate, DABCO, DMSO, rt, 24 h

85%

vinylMgBr, THF, -78 oC, 1 h

93%

Hoveyda-Grubbs II, PhMe, 110 oC, 1 h

TBAF, THF, 0 oC-rt, 12 h

80%

Isoaspinonene(235)

(230) (231) (232)

(233) (234)

60%

Scheme 34.


Grignard reaction, Wittig olefination and cross-metathesis reaction afforded isoaspinonene (Scheme 34).

2.2.11. (+)-Lysergic Acid (+)-Lysergic acid (241), a member of pharmacologically impor-

tant Ergot alkaloids, was isolated from the fungus Claviceps pur-purea. Very recently, Jia and co-workers reported two different enantioselective strategies featuring metal-catalyzed reactions to achieve the total synthesis of (+)-lysergic acid [68]. In one of their approaches they used the allyl bromide 238, prepared from the MBH adduct of formaldehyde, to generate the precursor 239 for RCM reaction (Scheme 35).

3. NATURAL PRODUCTS OF MOSS ORIGIN 3.1. (±)-Ricciocarpine A

(±)-Ricciocarpine A (244), the furanosesquiterpene which was isolated from the liverwort Ricciocarpos natans exhibits very good molluscicidal activity against the water snail Biomphalaria glabrata[69]. Krische and Agapiou reported a vinylogous MBH reaction with 242 to prepare this sesquiterpene lactone [70]. They found that the enone-enoate was not reactive in the PBu3-catalyzed reaction while the analogous enone-thioenoate 242 reacts smoothly to afford the cyclic product 243 chemoselectively (Scheme 36).

3.2. Palhinine Core Isopalhinine A (256), a lycopodium alkaloid was isolated from

the nodding club moss Palhinhaea cernua [71]. It is characterized with a complex pentacyclic framework. Very recently Sizemore and Rychnovsky reported a MBH/IMDA strategy to construct the isot-wistane core of palhinine natural products [72]. The MBH/IMDA reaction sets the vicinal all carbon stereocenters of the natural prod-ucts. The MBH reaction was used to generate the dienophile frag-ment 247 of the siloxydiene. The MBH precursor 246 in turn was synthesized in 5 steps from cyclohexenone by using Mukaiyama-Michael approach as the key step. The IMDA reaction of 248 under mild condition (TMSOTf/Et3N) followed by thermal heating af-

forded the regioisomeric mixture of products which contains the isotwistane core 251 of delphinium alkaloid cardionine 257. But the IMDA reaction of 248 using TMSCl/Et3N and heating at 90 oC in DMF afforded the isotwistane core 255 of isopalhinine (Scheme 37).

4. NATURAL PRODUCTS OF TERRESTRIAL ORIGIN 4.1. Alkaloids

4.1.1. Quinine Webber and Krische accomplished the stereoselective formal

synthesis of (±)-quinine in 16 steps and 4 % overall yield from aminoacetaldehye dimethylacetal [73]. The hallmark of the synthe-sis was a catalytic enone cycloallylation that combines the nucleo-philic feature of MBH reaction and electrophilic feature of Tsuji-Trost reaction. Using these reactions they transformed the interme-diate 258 to the tetrahydropyridine 259 in 68% yields. Reducing 259 in the presence CuI/DIBAL-H gave the piperidine 260 which was transformed to (±)-7-hydroxyquinine in highly stereoselective manner. Indeed they could obtain the (±)-7-hydroxyquinine in 13 steps and 11% overall yield (Scheme 38). However their attempt to deoxygenate the C-7 hydroxyl group was unsuccessful. This led them to perform C-7 deoxygenation before the amine epoxide cy-clization. Hence the piperidine 259 was initially transformed to enone 263 which after reduction to alcohol, acetylation and for-mate-mediated reduction gave the advance intermediate 265 which was reported [74] to afford quinine in 4 steps (Scheme 39).

4.1.2. Grandisines Grandisine alkaloids which were isolated from the leaves of the

Australian rainforest tree Elaeocarpus grandis exhibit affinity for the human !-opioid receptor [75]. Tamura and co-workers com-pleted the synthesis of grandisine D (269) by using an aldol reaction of 8-formylindolizidine 268 with (S)-5-methylcyclohexenone [76]. The key intermediate 8-formylindolizidine (268) was synthesized by a Brønsted acid mediated stereoselective MBH ring-closure reaction of 267 via acyl iminium ion (Scheme 40).

NBoc

I

NMeBocOHC

NBoc

I

NMeBoc

BrCO2Me

NBoc

I

NMe

CO2Me

NBoc

I

N Me

MeO2C

H

NH

NHO2C

H

Me

(+)-Lysergic acid

Ph3PCH3Br, t-BuOK, THF

92%

1. TMSOTf, 2,6-lutidine, CH2Cl2, 0 oC2. K2CO3, MeCN, 60 oC

Grubbs II, PTSA, PhMe, 50 oC

88%

(241)(236) (237) (239) (240)(238)

3 steps

Scheme 35.

O

SEtO

O

Me Me

O

SEtO

O

Me Me

PBu3 (20 mol%), t-BuOH, 135 oC

81%

O

O

O

H

HMeMe

3 steps

(±)-Ricciocarpin A(244)(242) (243)

Scheme 36.


OSETO

O

SETO

OH

CO2Me

O

OTBS

CO2Me

methyl acrylate, MeOH (cat), quinuclidine (cat)

77%

TMSO

TBSOCO2Me

TMSO

OTBS

CO2Me

HOO

CO2MeCO2Me

OTBS OTBS

TMSO

OTBS

CO2Me

O

CO2Me

OTBS

O

CO2Me

OTBS

TMSOTf, Et3N, CH2Cl2, 0 oC-rt

o-DCB, 180 oC

TMSCl, Et3N, DMF, 90 oC

43% 36%

2:1 dr40%

1:1 dr28%

4 steps5 steps

NO

OOH

OH

Isopalhinine A

HO

N

Me

OH

OCOiPrHO

cardionine

(256) (257)

(248)

(253)

(249) (250) (251) (252)

(255)(254)

(245) (246) (247)

Scheme 37.

NTrs

O

Me

OCO2Me

NTrs

Me

OPd(PPh3)4, PMe3,t-AmOH, rt, 30 min

68% NTrs

Me

O

NBoc

OH

N

OMe

N

OMe

NOH

OH

7-Hydroxyquinine

3 steps

CuI, MeLi, DIBAL-H, THF-HMPA, -78 oC, 1.5 h

4 steps

(262)

(258) (259) (260)

(261)

O

77%

Scheme 38.


NTrs

Me

O

4 stepsNCbz

O

N

OMe

N

OMe

N

OH

Quinine(266)

(259) (263)

NCbz

OAc

N

OMe

NCbz

N

OMe

1. L-selectride, THF, -78 oC2. Ac2O, Et3N, DMAP, CH2Cl2, 0 oC

Pd(PPh3)4, PBu3,HCO2H, Et3N, THF, 25 oC, 4 h

78%

(264)

(265)

ref 74

Scheme 39.

N O

OHC

EtO

AcO

NO

AcO

OHCH

N

HO

O

HTfOH, Me2S, MeCN, -35 oC-rt, 2 h

67%

dr = 96:4

9 steps

Grandisine D(267) (268) (269)

Scheme 40.

N OEtO

AcO

NOHC

AcO

OH

NOHC O

H

O

nBu2BOTf, DIPEA, CH2Cl2 N

OH

OH

O

H

NO

HO

O

H

Grandisine D

28% aq. NH3,MeOH N

OH

NO

Grandisine B

NO

HOH

O

H

NOHC O

H

O

nBu2BOTf,DIPEA, CH2Cl2 N

HO

O

H

9-epi-ent-Grandisine D

28% aq. NH3,MeOH

NO

HNO

9-epi-ent-Grandisine B

TfOH, Me2S, MeCN, -35 oC to rt

67%

5 steps 5 steps

5 steps

quant

78%

quant 40%

(271) (272)

(274) (275)

(268) (269) (270)

(269) (273)

OHC

(267)

Scheme 41.

The same group extended this protocol to the synthesis of gran-disine B (272), 9-epi-ent-grandisine B (275) and 9-epi-ent-grandisine D (274). Grandisine B was synthesized by using grandis-ine D as the biogenetic precursor (Scheme 41) [77]. The isoquinu-clidinone of grandisine B was formed from grandisine D by an intramolecular imine formation.

4.1.3. (+)-Heliotridine and (-)-Retronecine Aggarwal et al. reported a novel methodology in which a broad

range of Michael acceptors were allowed to couple with the readily available iminium ion in inter- and intramolecular MBH type reac-tion to afford densely functionalized heterocycles [78]. The imin-ium ions, generally present as masked N,O-acetals, were generated


by TMSOTf, while BF3.Et2O in the presence of Me2S was used to achieve the target. More importantly, the process was highly enan-tioselective for cyclic enones. As an application of the protocol, they formulated a short synthesis of (+)-heliotridine (279) and (-)-retronecine (280), as shown in Scheme 42.

4.1.4. (-)-Trachelanthamidine

Synthesis of pyrrolizidine nucleus was also demonstrated by Kamimura via an aza-Baylis-Hillman equivalent reaction followed by RCM reaction [79]. They showed that the optically active MBH adduct 283 underwent a two-step conversion to N-allyl-!-amino-R-methylene ester 285 in high yield, which gave chiral 2,5-dihydro-pyrrole 286 through RCM reaction catalyzed by Grubbs II catalyst. The 2,5-dihydropyrrole was further transformed to the pyrrolozidi-none (287) framework which was the precursor for the total synthe-sis of (-)-trachelanthamidine (Scheme 43) [80].

4.1.5. Vibsanin E Vibsanin E (294) was first isolated from Viburnum awabuki by

Kawazu [81]. Later Fukuyama et al. determined the absolute stereochemistry of this natural compound [82]. Williams et al.reported a protecting group-free approach for constructing the

a protecting group-free approach for constructing the tricyclic core of vibsanin E [83]. The tricyclic system was prepared via an acid-catalyzed reaction of 291 which was obtained via the Gaiëd-modified Baylis-Hillman reaction of the cyclic enone 290. Subse-quently by a retro-Claisen/Claisen reaction, the CO2Et group was incorporated and by Zercher reaction the ring was expanded to achieve the synthesis of tricyclic core 293 of vibsanin E (Scheme 44).

4.1.6. Tacamonine

Tacamonine (300) is one of the few tacamane type indole alka-loids and was first isolated in 1984 from Tabernaemontana eglan-dulosa [84]. Tacamonine is known for its vasodilator and hypoten-sive activities. Chang et al. developed a one-pot synthesis of N-alkyl 3-(E)-alkylidene-5-substituted sulfonylpiperidine-2,6-diones via a [3+3] annulation between N-alkyl "-substituted sul-fonyl acetamides and ",!-unsaturated esters obtained via the MBH reaction [85]. In their attempt to highlight the application of the protocol for the synthesis of natural product, they demonstrated that the sulphonyl acetamide 296, derived from tryptamine, undergoes similar transformation to afford piperidine-2,6-dione 297 that was

NO

OAc

OEt NO

OAc

OEt

CHO

NO

OAc

CHO

HN

O

OAc

H

NO

OAc

H

OHOH

acrolein, Hoveyda-Grubbs, CH2Cl2, rt, 12 h

74%

TMSOTf, BF3.OEt2,Me2S, MeCN, rt, 3 h

65%

3:1 trans:cis

LiALH4, THF, reflux, 1 h

38% 12%

(+)-Heliotridine (-)-Retronecine(279) (280)

(276) (277) (278)

Scheme 42.

m-CPBA, CH2Cl2,rt, 30 min

R

NHTs

CO2tBu

R

N

CO2tBu

Ts

Br

K2CO3, DMF,rt, 21 h

N

CO2tBu

Ts

Grubbs II CH2Cl2,reflux, 3 h

S

O

NOTBS TBSO

NH

CO2tBu

S

O

p-Tol

OTBS

t-butylacrylate, PhSMgBr, CH2Cl2, -50 oC, 37 h

SPh

R

NH

CO2tBu

S

O

p-Tol1. m-CPBA2. PhMe, 110 oC, 8 h

90%78% over two steps

N

H

O

HO

5 steps

(-)-Trachelanthamidine

N

H

HO

(288)

(281) (282) (283)

(284) (285) (286)(287)

85% 76%

OTBSR =

ref 80

Scheme 43.

O

O

O

OO

Vibsanin E

OO O

OHCH2O, DMAP, 60 oC, 5 d

43%

O

O1. HCl2. LDA3. NCCO2Et

EtO2C O

O

EtO2CZnEt2, CH2I2

50%

(294)

(289) (290) (291)(292) (293)

Scheme 44.


transformed to an advance intermediate 299 for the synthesis of tacamonine (Scheme 45) [86].

4.1.7. Strychnos Alkaloids Andrade and Sirasani developed a sequential one-pot bis-

cyclization route to the synthesis of tetracyclic framework of Strychnos alkaloids [87]. Their protocol involved a AgOTf-mediated spirocyclization of appropriately functionalized indole 3-carbinamide 301 to afford the intermediate 302 which in the pres-ence of DBU underwent an intramolecular aza-MBH reaction to afford the tetracyclic core 303 of Strycnos alkaloid (Scheme 46).

Later they extended the cascade protocol involving spirocycli-zation/ aza-Baylis-Hillman reaction for the synthesis of (±)-akuam-

micine (308) and (±)-strychnine (310) from appropriately substi-tuted intermediate 307 and 309, respectively (Schemes 47 and 48)[87b].

Extending the scope of their protocol, this group also developed the total synthesis of another indole alkaloid (-)-leuconicine A and B (Scheme 49) [87c].

4.1.8. Neocryptolepine Neocryptolepine, an indoloquinoline alkaloid isolated from

Cryptolepis sanguinolenta exhibit potent antimalarial activity against chloroquine-resistant strains of P. falciparum. Basavaiah and Reddy developed a one-pot strategy for the synthesis of "-carbolines from MBH acetates [88]. Their synthesis involved

NHO

Tryp

S

O

O

Tol

OMeO

AcO

NH

NNaH, THF, 67 oC

72%O

O

TolO2S

NH

N

O

TolO2S

NaH, then LiAlH4

76%

NH

N

O

Na(Hg), MeOH

90%

N

H

HO

Tacamonine(300)

(296)(295) (297) (298)

(299)

ref 86

Scheme 45.

NH

NBn

CO2Me

O

Br

NCO2Me

NBnO

H

NH

CO2Me

NBn

O

H

AgOTf, DTBMP, PhMe, rt, 1.5 h

DBU, rt, 12 h

70% overall yield

(301) (302) (303)

Scheme 46.

NBoc

CHO

HN

N

O

Br

I

Me

CO2Me

N

ON

I

Me

CO2Me

NH

N

Me

CO2Me

HNH

N

CO2Me

OI

Me

H

AgOTf, DTBMP, PhMe, rt, 1.5 h

DBU, rt, 12 h3 steps

63%

(±)-Akuammicine

3 steps

(308)

(304) (305)(306)

(307)

Scheme 47.


three key reaction steps- mono alkylation of 2-nitroarylacetonitriles with MBH acetates [89], chemoselective reduction of nitro group into amino group using Fe/AcOH and formation of two rings. They employed this strategy to the synthesis of indoloquinoline alkaloid neocryptolepine 318 in 22% overall yield (Scheme 50).

4.1.9. Grandiamide Grandiamide D (324), gigantamide A (328) and dasyclamide

(327) were isolated by Duong et al. from the leaves of Aglaia gi-gantean [90]. Very recently Ilangovan and Saravanakumar reported the synthesis of these natural products by using MBH adduct 320 as the common intermediate [91]. They showed that the MBH reaction of ethyl acrylate with aldehyde 318 afforded the racemic adduct 320 which was then converted to the intermediate 323 and dasy-clamide 327 via EDCI coupling reaction. Dasyclamide was then converted to gigantamide A by PCC oxidation method (Scheme 51).

4.2. Terpenoids

4.2.1. Mikanecic Acid

Mikanecic acid (332), a terpenoid dicarboxylic acid was iso-lated from the products of alkaline hydrolysis of the alkaloid mika-noidine obtained from Senecio mikakioides otto [92]. Basavaiah et al. reported a simple two-step route involving sequential Diels-Alder reaction and saponification to prepare this terpenoid. Initially the MBH adduct 329 was converted in situ to the diene 330 which underwent a stereoselective Diels-Alder reaction to produce 331which upon hydrolysis in the presence of KOH gave mikanecic acid in good yield (Scheme 52) [93].

4.2.2. (+)-Arnicenone

(+)- Arnicenone (342), an isocomene-type angular triquinane sesquiterpene isolated from the essential oil of rhizomes and roots of Arnica plants, was synthesized by Ogasawara and co-workers by using MBH adduct 9 as the starting material [94]. A DIBAL-H reduction of 9 gave 10 which upon NBS-mediated regioselective olefin protection furnished 333 in excellent yields. The Eschen-moser rearrangement reaction with 333 was used for the diastereo-selective formation of the exo-acetamide 334 which was trans-formed to the propargyl derivative 335. The Pauson-Khand reaction with 335 afforded the polycyclic enone 336 as an epimeric mixture. The tricyclic core 337 was prepared in 10 steps from 336 using retro-Diels-Alder reaction and Wolf-Kishner reduction as one of the key steps. The tricyclic compound 337 was subsequently converted to (+)-arnicenone by methylation and exo-methylketone formation (Scheme 53).

NBoc

CHO7 steps

NH

N

CO2Me

I

H

OTBS

5 stepsN

N

OO

H

H

(±)-Strychnine

(304) (309) (310)

Scheme 48.

NH

N

CO2Me

OI

Me

H

N

N

O

O R

Et

H

H

H

(-)-Leuconicine A: OMe (311)(-)-Leuconicine B: NH2 (312)

(307)

6 steps

Scheme 49.

O

OAc

NH

N

NH

N

NH

N

NN

Me

1. K2CO3, THF, rt, 48 h2. Fe/AcOH, reflux, 1 h

DDQ, dioxane, reflux, 8 h

THF, MeI, reflux, 12 h

40 %

82%68%

CN

NO2

Neocryptolepine(318)

(313) (314) (315)(316)

(317)

+

Scheme 50.


4.2.3. Clerodane Decalin Core The clerodane class of natural products is diterpenes that ex-

hibit potent antiproliferative activity against several types of hu-man-cancer-cell lines. Schaus et al. formulated an asymmetric syn-thetic protocol toward the synthesis of clerodane decalin core of asmarine via a two-step ring-annulation procedure [95]. The first step of the synthesis to construct the core of clerodane was the asymmetric MBH reaction of cyclohexenone 245 with aldehydes 343 promoted by Et3P and binapthol-derived Brønsted acids whereas the second step involved BF3.OEt2-catalyzed intramolecu-lar Hosomi–Sakauri reaction as outlined in Scheme 54.

4.2.4. ABC Core of Neovibsanins Neovibsanins A and B, members of vibsane class of diterpe-

noids exhibit unique activity of promoting neurite outgrowth of NGF-mediated PC-12 cells. Mehta and Bhat demonstrated the util-ity of MBH adduct to achieve the synthesis of the tricyclic core furo-furanone 351 of neovibsanin alkaloids [96]. An initial MBH reaction of suitably decorated cyclohexenone 290 with formalde-

hyde gave the adduct 291 (Scheme 55). Protecting the hydroxyl group gave 349 which upon addition of propargyl alcohol afforded 350. A series of reactions with 350 resulted into the tricyclic core of neovibsanins in good yields.

4.2.5. ABC and FGH Segments of Rubrifloradilactone C

Rubrifloradilactone (361), isolated from Chinese medicinal plants is a Schisandra nortriterpenoid bearing an eight-ring frame-work and is ascribed with potent anti-HIV and cytotoxic activity [97]. Mehta and co-workers also reported the synthesis of ABC and FGH segments of rubrifloradilactone C using the MBH adduct 355prepared from cycloheptenone. Similar to the synthesis of neovib-sanin core 351, here too adding propargyl alcohol to the OH-protected MBH adduct 356 resulted into 357 which was then con-verted to the allyl alcohol 358 (Scheme 56). It was disclosed that oxidation of the primary alcohol (359) to aldehyde via MnO2 re-sulted into the tricyclic ABC core 360 via oxa-Michael reaction followed by lactonization cascade.

PMBOO

PMBO

OH

OEt

O

PMBO

OH

OH

O

NH

OHN

O

OPMB

OH

NH

OHN

O

OH

OH

(±)-Grandiamide D

ethyl acrylate, DABCO, dioxane/H2O, rt, 40 h

65%

LiOH, THF/H2O, rt, 6 h

95%

1. 322,EDCI.HCl, Et3N, CHCl3/THF, rt, 19 h

67%

TFA, CH2Cl2, 5 h, rt

75%

PMBO

OH

OEt

O

PMBOOEt

O

PMBOOH

O

NH

OHN

O

OH

Dasyclamide

1. AcCl, Py, CH2Cl2,0 oC-rt, 30 min, 95%

2. NaBH4, t-BuOH, rt, 19 h, 91%

KOH, MeOH/H2O, rt, 3h

85%

1. 322,EDCI.HCl, Et3N, CHCl3/THF, rt 19 h, 70%

2. TFA, CH2Cl2, rt, 4h, 60%

NH

O

N

O

OH

Gigantamide A

PCC, CHCl3/DMSO (3:1), rt

25%

NH

O

NH2

(322)

(324)

(327) (328)

(319) (320) (321)

(323)

(320) (325) (326)

Scheme 51.

OH

CO2R CO2RCO2R

CO2R

CO2H

CO2H**

MsCl, Et3N KOH/MeOH

R = chiral group Mikanecic acid(332)(329) (330) (331)

[4+2]

Scheme 52.


OH

HO

OH

O

OHO

O

CONMe2

Br

Br

O

BrCONMe2

O

BrCONMe2

O

Co2(CO)8, CH2Cl2then DMSO, CH2Cl2, reflux

LDA, propargyl bromide, THF, -78 oC

75% 66%

MeC(OMe)2NMe2,Ph2O, reflux

87%

NBS, CH2Cl2,0 oC

99%

DIBAL-H

H

BnO

O

BnO

O

BnO

O

PhS

O

O

O O

10 steps

t-BuOK, MeI, HMPA, THF, -25 oC

67%

MeMgI, CuBr.Me2S

89%

3 steps CaCO3, Ph2O, reflux

87%

PTSA, CH2Cl2,reflux

70%

(+)-Arnicenone(342)

(9) (MBH adduct) (10)(333)

(334) (335)

(336) (337) (338)(339)

(340)

(341)

O

HCHO, DMAP, THF, rt, 3.5 d

67%

(8)

Scheme 53.

H

O

PhMe2Si

O OH

PhMe2Si

OO OH

H

H

PEt3, (R)-7, THF, -10 oC, 48 h

BF3.OEt2, CH2Cl2,-78 to -10 oC

81%

98% de

(343) (245) (344)(345)

86%

99% de

N

NN

N

NHO

H

Asmarine A(346)

Ar

OH

OH

Ar

Ar = 3,5-(Me)2C6H3

(R)-7

N

NN

N

NHO

H

Asmarine A(347)

Scheme 54.


O

O

O O OH O OTBS

OTBSHO

HO

OO

OH

3 steps

CH2O, DMAP, sodium dodecyl sulfonate, THF:H2O (1:1), rt, 16 h

56%

TBSCl, imidazole, DMAP, CH2Cl2,rt, 1 h

98%

propargyl alcohol, nBuLi, THF, 0 oC,8 h

52%

(348) (290) (291) (349)

(350) (351)

OOH

R2

R1

RO

Neovibsanin A: R1 = Me, OMe (352)Neovibsanin B: R1 = OMe, Me (353)

Scheme 55.

O O

HO

O

TBSO TBSO

HO

THPO

HOHO

HO O

O

O

H A

B C

CH2O, DMAP, THF, rt, 6 h

TBSCl, imidazole, DMAP, CH2Cl2,rt, 1 h

46% over two steps

tetrahydro-2-(proynloxy)-2H-pyran, nBuLi,-70 to -20 oC, 8 h

86%

MnO2,CH2Cl2, rt, 2 h

92%

(354) (355) (356) (357)

(359) (360) O

O

O

H

H

O

O

O

OH

H

HO

OOH

H

H

A

BC

D

E

F GH

Rubrifloradilactone C

(361)

THPO

3 stepsHO

O

(358)

Scheme 56.

O O OTBS OHOTBS

H

OHO

H

OH

H HOH

OH

O

OO

HH

H

FG H

1. CH2O, DMAP, THF, rt, 6 h2. TBSCl, imidazole, DMAP, CH2Cl2, rt, 1 h

1. Pd/C, H2, EtOAc, rt, 3 h, 89%2.MeMgI, Et2O, 0 oC, 1h, 76 %

1. TBAF, THF, rt, 1 h, 80 %2. DMP, CH2Cl2, rt, 1 h, 55%

propargyl alcohol,nBuLi, THF,-78 to -60 oC, 6 h

(364) (365)

(366) (367)

(362) (363)

3 steps

60%

Scheme 57.

The FGH core 367 of rubrifloradilactone C was achieved by almost similar route using OH-protected MBH adduct 363 and us-

ing the propargylic alcohol 366 instead of allyl alcohol in oxidation followed by lactonization reaction (Scheme 57) [98].


4.3. Lignans

4.3.1. Eupomatilones Eupomatilones (374,375) are structurally novel lignans which

were isolated in 1991 by Carrol and Taylor from the shrub Eupoma-tia bennettii [99]. They are characterized by a biaryl system with a substituted !-lactone ring system attached to one of the aryl rings. Kabalka and Venkataiah reported the synthesis of these natural products by constructing the !-lactone from the homoallylic alco-hols which in turn were prepared from the intermediates afforded

from the MBH adduct [100]. Whereas, treating the boronate 368with the biphenyl aldehyde in the presence of Lewis acid afforded the alcohol 372 and 373 in low yields, the Barbier allylation of identical substrate with allyl bromide 369 furnished the same alco-hols in good yields (Scheme 58). Intramolecular cyclization of the alcohol under mild acidic condition using PTSA gave the lactone leading to completion of synthesis of eupomatilone 2 (374) and 5 (375). Further, isomerisation and reduction of the double bond of the lactone provided access to epi-eupomatilone 6 (376).

MeO

MeO

OMe

CHO

R

OR1

OR2

OAc

CO2MeCO2Me

B

O

O

MeO

MeO

OMe

R

OR1

OR2

OH

CO2Me

MeO

MeO

OMe

R

OR1

OR2

O

O

MeO

MeO

OMe

MeO

OMe

OMe

O

O

OH

CO2Me CO2Me

Br

Bis(pinacolato)-diborone, Pd2(dba)3,PhMe, 50 oC, 5 h

1. Sc(OTf)3, rt,3 d, 12%2. BF3.OEt2, rt, 3 d, 15% or 3. 90 oC, 3 d, 19%

NBS, PPh3, rt, 12 h In, THF:H2O (1:1), 2 h

78%68-70%

PTSA, CH2Cl2, rt, 12 h

93-94%

370 or 371

R = R1 = R2 = OMe, (370)R = H, R1 = R2 = -CH2-, (371)

R = R1 = R2 = OMe, Eupomatilone 2 (374)R = H, R1 = R2 = -CH2-, Eupomatilone 5 (375)

epi-Eupomatilone 6

(376)

(295) (368)

(2) (369)(372, 373)

370 or 371

Scheme 58.

O

O

OH

CO2Me O

O

OH

CO2Me

CN

O

O

O

O

O

O

O

O

OMeMeO

OMe

Yatein

O

O

O

O

OMeMeO

OMe

R

R1

Podorhizol: R = OH, R1 = H, (380)epi-Podorhizol: R = H, R1 = OH, (381)

NaCN, NH4Cl, DMF:H2O (3:1), 12 h

87%

CrO3-H2SO4,acetone, 0 oC

trimethoxy benzyl bromide, LDA, THF,-78 oC, 6 h

trimethoxy benzaldehyde, LDA, THF, -78 oC, 1 h

80%

80%

(382)

(43) (377)

(379)

O

O

O

CO2Me

CN94%

(378)

3 steps

O

O

CHOref 21

(42)

Scheme 59.


4.3.2. (±)-Yatein, (±)-Podorhizol and (±)-epi-Podorhizol Coelho and co-workers demonstrated a simple and efficient

method for the diastereoselective preparation of hydroxylated !-piperonyl-#-butyrolactones and extended this protocol to the syn-thesis of the biologically active lignans (±)-yatein (382), (±)-podorhizol (380) and (±)-epi-podorhizol (381) (Scheme 59) [101]. These lignans are endowed with interesting biological properties such as insect feeding deterrent and anti-viral activity (yatein), moderate anti-tumor activity (podorhizol) and antibacterial activity (epi-podorhizol). The butyrolactones were prepared by direct oxida-tion of lactol, which was synthesized in one step from the cyanide-ester 380 using reductive conditions. They prepared the cyanide ester 378 by a diastereoselective Michael addition reaction of NaCN with the MBH adduct 43 to furnish 377 followed by its oxi-dation with CrO3-H2SO4. Interestingly, they showed that the use of MBH adduct as Michael acceptor afforded the syn-isomer while !-ketoester of the corresponding adduct afforded the anti-isomer stereoselectively.

4.4. Others

4.4.1. Methyl Jasmonate Methyl jasmonate (385) was first isolated from Jasmanirus

grandiflorum and later from Rosmarinus officinalis. It is of para-mount importance to the fragrance industry because of its elegant and radiant jasmine scent. This molecule was commercialized by Firmenich SA under the trade name of Hedione®. Chapius and co-workers accomplished the synthesis of the jasmanoid skeleton with versatile stereocontrol and modification to the C(2) side chain

(Scheme 60) [102]. The three key steps of the process were MBH reaction of a suitable aldehyde with cyclopentene-1-one in the pres-ence of Bu3P to obtain the adduct 383 followed by MeC(OMe)3,PivOH-mediated orthoester Claisen rearrangement affording 384. A Pd/Al2CO3-mediated reduction of the double bond in 384 gave the corresponding analogues of methyl jasmonate 385. However in terms of fragrance none of the synthetic analogues was found to be better than the natural compound.

4.4.2. Umbelactone Umbelactone-1 is one of the examples of naturally occurring

#-(hydroxymethyl)-",!-butenolide isolated from Memycelon umbe-latum Brum and the crude extracts of this plant elicit a broad spec-trum of bio-activities including antiviral (against Ranikhet disease virus), antiamphetory and spasmolytic [103]. Kamal et al. devel-oped a lipase-mediated chemoenzymetic resolution protocol to prepare both isomers of umbelactone-1 [104]. The synthesis was initiated with the MBH reaction of aldehyde 387 with methyl acry-late in MeOH as medium to obtain the adduct 388 which was trans-formed to the allylic alcohol 389 by following a series of known reactions (Scheme 61). Resolution of this allylic alcohol with lipase PS-C (Pseudomonas cepacia immobilized on modified ceramic particles) in vinyl acetate gave the (R)-isomer 391 as acetate and as (S)-isomer 390 as alocohol. A sequential acryloylation, RCM reac-tion and debenzylation furnished 390 and 391, the respective enan-tiomers of umbelactone-1.

4.4.3. 6-Tuliposide B (+)-6-Tuliposide B (399), a phytoanticipius produced by tulip

tissues is ascribed with potent antimicrobial activity against Gram-

OO

R

OHO

R

O

O

OR

O

O

O

O

O

RR O

Bu3P, BINOL, THF, 20 oC,3-15 h

MeC(OMe)3,PivOH, 110 oC, 3 h

Pd/Al2O3,135 oC

[Ph3PPr]Br, NaN(SiMe3)2,-20 to 20 oC

Methyl jasmonate: R = CH2OH cis-Hedione: R = Et(385) (386)(383) (384)(362)

Scheme 60.

BnOH

OBnO

OH

CO2Me 3 steps BnO

OH

BnO

O

O

O

O

BnO

BnO

OHO

O

HO

(S)-(-)-Umbelactone-1

(R)-(+)-Umbelactone-1

methyl acrylate, quinuclidine, MeOH, rt

90%

acryloyl chloride, Et3N, DMAP, CH2Cl2, 0 oC-rt

Grubbs II, CH2Cl2, 35 oC

O

O

HO85% 65%

K2CO3, MeOH, 0 oC-rt

90%

TiCl4, CH2Cl2,0 oC-rt

90%

BnO

OH

BnO

OAc

Lipase PS-C,vinyl acetate, hexane, 6 h

46%

45%

(394)

(396)

(387) (388) (389)

(390)

(391)

(392) (393)

(395)

3 steps

Scheme 61.


positive and Gram-negative strains of bacteria and certain fungi tolerant strains of bacteria. Ubukata and co-workers disclosed the synthesis of (+)-6-tuliposide B from D-glucose in nine steps using MBH reaction as the key step [105]. The MBH reaction of 2-(tert-butyldimethylsilyloxy)-acetaldehyde (101) with 6-O-ac-ryloyl-1-O-(2-trimethylsilylethyl)-!-D-glucopyranoside (397) fol-lowed by a mild de-protection procedure using TFA in CH2Cl2 gave the natural compound 399 (Scheme 62). The interesting feature of their protocol was that both isomers of the MBH adduct were used to synthesize the (+) and (-) isomers of tuliposide-B. In order to confirm the structure of the prepared compound, these workers

transformed each of them to (-)-tulipalin B (400) and (+)-tulipalin-B (402).

Subsequently this group developed an alternate protocol for the synthesis of (+)-tuliposide B where the sugar part was introduced at the later stage of the reaction sequence [106]. A stereoselective MBH reaction of 318 with N-acryloyl camphor sultam 403 was the key step in this approach (Scheme 63).

4.4.4. Onychine Onychine (414), a 4-azafluorenone natural product was isolated

from the trunkwood of the Brazilian tree Onychopetalum amazoni-

TBDMSOH

OO

HOHO

O

OTMSET

OH

O

HOHO

O

O

OTMSET

OH

OH

TBDMSO

3-HQD, rt, 40 h

R:S = 92:8

O

TFA:CH2Cl2(2:1), 1.5 h

96%(S-398) O

HOHO

O

O

OH

OH

OH

TBDMSOTFA:CH2Cl2(2:1), 1 d

O

O

OH

quantitative

(+)-6-Tuliposide B(-)-Tulipalin B

TFA:CH2Cl2(2:1), 1.5 h

93%(R-398) O

HOHO

O

O

OH

OH

OH

TBDMSOTFA:CH2Cl2(2:1), 1 d

O

O

OH

quantitative

(+)-Tulipalin B

40%

(400)

(402)

(101) (397)(398)

(399)

(401)

Scheme 62.

SO2

N

O

PMBOH

OO O

O

PMBO

PMBO

DABCO, DMF, 0 oC, 5 d

90%

OH

CO2MePMBOEt3N, MeOH

90%

1. TBDMSOTf, Et3N, CH2Cl2, quantitative2. LiOH, MeCN:H2O,60 oC, 92%

OTBDMS

CO2HPMBO

OTMSOTMSO

O

O

OTMSETOTMS

OHTBDMSO

407,DIC, DMAP, CH2Cl2, 0 oC

61%

(+)-6-Tuliposide B (399) (-)-Tulipalin B (400)

TFA:CH2Cl2(2:1)

(318) (403)(404) (ee>99%) (405)

(406)

(408)

O

OTMSTMSO

TMSO

OH

OTMSET

(407)

Scheme 63.


cum. It shows potential antimitotic activity against C. albicans.Clary and Back initiated the total synthesis of onychine by prepar-ing tetrahydropyridine intermediate (411) via a vinylogous aza-MBH reaction of N-(benzylidine)benzenesulfonamide 409 with methyl 2,4-pentadienoate 410 (Scheme 64) [107]. A sequential saponification, acid chloride formation and intramolecular Friedel Craft’s reaction on 411 resulted into the 4-azafluorenone core 412.

4.4.5. (±)-Leiocarpin A Leiocarpin A (423) and Goniodol (422) are two pyranopyrone

containing natural compounds, isolated from the Goniothalamus Sp.and have been reported to display anticancer activity. Paioti and Coelho disclosed a diastereoselective approach for the total synthe-sis of (±)-leiocarpin A and (±)-goniodiol starting from the MBH adduct of benzaldehyde [108]. These biologically active styryl lac-tones were synthesized from a common ",!-unsaturated lactone intermediate 421, prepared in five steps and 40% overall yield, from the MBH adduct 416. They found that under basic condition the lactone 421 directly afford leiocarpin A (423), while under acidic condition it gave (±)-goniodiol (422) (Scheme 65).

4.4.6. Isoparvifuran Isoparvifuran (429) is an antifungal agent isolated from the

heartwood of Dalbergia parviflora [109]. Namboothiri et al. ac-complished the first total synthesis of isoparvifuran by using MBH reaction as the key step [110]. An initial MBH reaction between nitrostyrene 424 and ethyl-2-oxoacetate afforded 425, which upon base-mediated addition of phenol gave the benzofuran 426 in 76% yield (Scheme 66). Alkaline hydrolysis of the ester group in 426followed by CaO-NaOH-mediated decarboxylation gave benzylated Isoparvifuran 428 in 80% yield. De-protection of the benzyl group by Pd-catalyzed hydrogenolysis afforded the natural product isop-arvifuran 429 in an overall yield of 47% for six steps.

5. NATURAL PRODUCTS OF MARINE ORIGIN 5.1. epi-Epoxydon

Epoxydon (439) and epi-epoxydon (438) are two epoxycyclo-hexenone-based natural products isolated from the Aspiospora monagnei Saccardo, a fungal endophyte isolated from the inner

N

H

SO2PhCO2Me

+

N

CO2Me

PhO2S

NPhO2S

O

NPhO2S

OH

H N

O

HQD, DBU, DMF, hn

73%

1. NaOH, THF2. SOCl23. AlCl3, DCE

86%

Me2CuLi, THF, -78 oC-rt

86%

1. DBU, 240 oC2. DDQ, PhMe

84%

Onychine(414)

(409) (410) (411)(412) (413)

Scheme 64.

PhCHO Ph

OH

CO2MePh

OH

OH

CO2Me Ph

OTBS

OTBS

CHOPh

TBSO

OTBS

OH

Ph

TBSO

OTBS

O

O

Ph

TBSO

OTBS

O

O

O

OO

Ph

OH

(±)-Leiocarpin A

methyl acrylate, rt, 96 h

85%

1. O3, MeOH, -72 oC,then Me2S, 1 h2. NaBH4, CH2Cl2,-72 oC, 12 h

70 %

allylSn(nBu)3,TiCl4, CH2Cl2,-72 oC, 1 h

79%

acryloyl chloride, Et3N, CH2Cl2, 0 oC

83%

Grubbs I, CH2Cl2, reflux, 18 h

64%

TBAF, THF, 0 oC-rt, 12 h

50%

HF, Py, MeCN, rt, 24h

Ph

OH

O

O

OH

(±)-Goniodiol (423)(422)

(416) (417) (418) (419)

(420) (421)

(415)

74%

Scheme 65.

PhNO2

1. CHOCO2Et, DMAP, MeCN, 30 oC, 30 min2. AcCl, Py, CH2Cl2,0 oC, 20 min, 84% Ph

NO2

CO2EtAcO

O

Ph

BnO

MeOCO2Et

O

PhBnO

MeOCO2H

O

PhBnO

MeOO

PhHO

MeO

MeO

BnO

OH

76%

KOH, EtOH/H2O (9:1),30 oC, 3 h

93%

CaO/NaOH (9:1), DMA, reflux, 4 h

80%

Pd/C, H2, THF, 30oC, 1.5 h

99%

Isoparvifuran(429)

(424)(425) (426)

(427) (428)

K2CO3, PhMe, 30 oC, 30h

Scheme 66.


tissue of the North Sea algae Polysiphonia violacea. They possess interesting antifungal, antibacterial and phytotoxic activity. Taylor and Genski unveiled a Et3N/nBu3P-catalyzed MBH reaction be-tween an O-protected epoxidised hydroxyquinol (436) and para-formaldehyde to synthesize (±)-epi-epoxydon (438) (Scheme 67)[111]. The synthesis started with the Diels-Alder reaction between p-benzoquinone (431) and cyclopentadiene (430) to obtain 432which was then transformed to the epoxyquinol derivative 435.

5.2. N-Boc-dolaproine

Almeida and Coelho reported a stereoselective total synthesis of N-Boc-dolaproine (Dap), an amino acid residue of the antineoplas-

tic pentapeptide dolastatin 10 (445). The initial step of the synthesis involved MBH reaction between N-Boc-prolinal (440) and methyl acrylate under ultrasound condition to furnish the adduct 441(Scheme 68) [112]. A diastereoselective double bond hydrogena-tion in 441 yielded the intermediate 442 which upon hydrolysis of the ester group gave O-methyl-N-Boc-dolaproine 443. Simultane-ously, methyl group de-protection of the ester group in 442 afforded 444.

5.3. Salinosporamide Salinosporamide A (450) is a bioactive natural product of a ma-

rine organism that is widely distributed in ocean sediments. It is an effective proteosome inhibitor with in vitro cytotoxic activity

O

O

OR

CH2O, Et3Al, nBu3P, CH2Cl2,N2, 0 oC, 2-3 h

O

O

OR

HO

O

O

OH

HOHF.Py, MeOH, rt, 3-24 h

58-70%

R = SiEt2, TBS

42-44%

O

O O

O

H

H

MeOH, 0 oC, 48 h

74%

O

O

H

H

O

TBHP, TBD, MeCN, rt, 9 h

85%

nBu4NBH4, THF, -78 oC to -50 oC, 4 h

O

OH

H

H

O

Ph2O, heat, 30 min

O

O

OH

94%

Et2SiCl, imidazole, 86%

orTBSOTf, 2,6-lutidine, 43%

epi-Epoxydon(438)

(430) (431) (432) (433) (434)

(435) (436) (437)

O

O

OH

HO

Epoxydon(439)

Scheme 67.

NBoc

CHON

Boc

OMe

OOHHN

Boc

OMe

OOH

N

Boc

OH

OOMe

N

Boc

OH

OOH

N-Boc-Dolaproine

methyl acrylate, ultrasound, 5 d

75%

H2, Pd/C, EtOAc, rt

91%

83:17

1. Me3OBF4, CH2Cl2,proton sponge, rt, 18 h (70%)

LiOH, THF, rt, 16 h

87%

(440)

(444)

(441) (442)(443)

3:1

Me2NN

O

H

N

O

Me OMe

N

O OMe

N

O

H

Ph

N

S

Dolastatin 10 (445) Dap

2. LiOH, THF, rt, 16 h

Scheme 68.

MeO

HN

O

CO2Me

MeHO

MeOO

N CO2Me

Me

N

PMBCO2Me

OBn

MeO

O

NO

PMBCO2Me

OBn

OHMe

NH

OO

OH

O

ClMe

PTSA, PhMe, reflux, 12 h

80%

4 steps

quinuclidine, DME, 0 oC, 7 d

90%

Salinosporamide A

(450)

(446) (447) (448)

(449)

9 stepsH

Scheme 69.


against several tumor cell lines with IC50 values in nanomolar range. Corey et al. utilized an intramolecular MBH reaction be-tween keto group and acrylamide subunit for the cyclization to produce a highly substituted 4-methylene-5-oxo-pyrrolidine deriva-tive (449), which served as the starting material in the enantioselec-tive total synthesis of salinosporamide A (Scheme 69) [113].

5.4. Halichlorine Spiro Subunit Clive et al. reported the synthesis of bicyclic amines with nitro-

gen at a ring-fusion position via a sequential MBH reaction be-tween N-protected !-amino aldehydes 451 and acrylates followed by O-acetylation and N-deprotection, as shown in scheme 70. They extended this strategy to the synthesis of the halichlorine’s spiro subunit 455 [114].

5.5. (+)-Hippospongic Acid A (+)-Hippospongic acid A (463) which was isolated from the

marine sponge Hippospongia sp. bears a triterpenoid structure and is known to inhibit gastrulation in starfish embryos. In addition to this it is also found to exhibit modest inhibitor of both DNA polym-erase (IC50 = 5.9-17.5 !M), and DNA topoisomerase I/II (IC50 = 15-20 !M), the two enzymes responsible for DNA replication [115]. Further, this molecule is effective at inducing apoptosis in the human gastric cancer cell line NUGC-3 by arresting the cell

cycle at G1/G2. Trost et al. utilized a Pd-catalyzed DYKAT of MBH adducts 458 to achieve the total synthesis of (+)-hippo-spongic acid [116]. The DYKAT cyclization substrate was obtained via two MBH reactions and one Claisen rearrangement. Subse-quently by DYKAT cyclization strategy they could synthesize the pyran ring with required stereocenter which after a series of reac-tions afforded (+)-hippospongic acid in enantiomerically pure form (Scheme 71).

5.6. C1–C11 Fragment of Caribenolide I Franck et al. successfully synthesized the C1-C11 fragment

(467) of caribenolide I (468), a 26-membered macrolactone that possesses in vitro cytotoxicity against human colon tumor cells (T/C = 150% at a dose of 0.03 mg/kg), starting from the MBH reac-tion between 3-para-methoxybenzyloxypropanal (124) and methy-lacrylate in the presence of 3-HQD, as illustrated in Scheme 72[117]. The stereogenic centres at C2, C3 and C10 were controlled during the aldol reaction of the aldehyde 464 using thioxazolidi-none moiety as the chiral auxiliary.

5.7. Semiplenamide C and E Semiplenamide, the naturally occurring fatty acid derivatives,

isolated from the marine cyanobacterium Lyngia semiplena, possess potent toxicity towards the brine shrimp model system [118]. The

N

O

O

Cl OH

MeH

NO

Me

CHO

NO

Me

HO

MeO2CNO

Me

AcO

MeO2C

HN

Me

AcO

MeO2C

MeO2C

N

MeMeO2C

MeO2C

H

methyl acrylate, DABCO, Sc(OTf)3, 5 d

AcCl, Py, CH2Cl2,0 oC-rt, 2 h

Me3OBF4,CH2Cl2, 1.5 h

aq. Na2CO3,MeCN, 2 h

Halichlorine(456)

(451) (452) (453)

(454)(455)

37% over two steps

77% over two steps

Scheme 70.

RO R

OH

MeO2C R

TBDPSO

O R

TBDPSO

OH

MeO2C

R

HO

OAc

MeO2C

O

R

MeO2CO

R

HO2C

(Pd(!-allyl)Cl)2, L,N(Hex)4Cl, dioxane

LiOH, THF/H2O

98%50%

methyl propiolate, HMPA, DIBAL-H

1. AcCl2. TBAF, AcOHDABCO, methyl

acrylate

20%

5 steps

82% 75%

R =

(+)-Hippospongic acid

(457) (458) (459) (460)

(461) (462)(463)

NHO

Ph Ph

HNO

PPh2Ph2P

L

Scheme 71.


allyl bromide 470 obtained from the MBH adduct 469 was used for the synthesis of this natural compound by Das et al. [119]. The EDCI coupling between 472 and (S)-alaninol afforded the allyl amide 473 which was converted to the semiplenamide C and E by simply acetylating the hydroxyl group (Scheme 73).

5.8. (±)-Spisulosine (ES285) Coelho et al. developed a novel approach to diastereoselective

total synthesis of the anti-tumoral agent (±)-spisulosine (481) which was isolated from the extracts of Spisulapolynyma [120]. The syn-

thesis of the target natural compound involved the initial formation of an acyloin 479 from the MBH adduct of the aldehyde 476 which was subsequently used in a highly diastereoselective reductive ami-nation reaction to produce 480. The deprotection of 480 afforded (±)-spisulosine in 10% overall yield (Scheme 74).

5.9. Sporolide Precursor Gademann and co-workers utilized the MBH adduct (363) pre-

pared from cyclopentene-1-one (362) and formaldehyde for the synthesis of a precursor 485 of marine macrolide sporolides, iso-

PMBOCHO

62%PMBO

OH

CO2Me 6 stepsPMBO

TBSO O

N O

SO

BnPh

Ph

TiCl4, DIPEA, -78 oC, CH2Cl2

PMBO

TBSO OH

N

O

O

PhPh

S

Bn

PMBO

TBSO OH

OMe

O

K2CO3, MeOH

83%

OTBS

OTES

OMe

O

OO

H

O

C1-C11 fragment of Caribenolide I(467)

(126) (464) (465)

(466)

(124)

7 steps O

HO

HOHO

O

OHO OH

O

O

O

1

67

11

15 19 2124

25

29

Caribenolide I(468)

methyl acrylate, HQD

Scheme 72.

R

OH

CO2Et RCO2Et

Br

RCO2Et R

CO2H

R NH

O

OHR N

H

O

O CH3

OR = Me(CH2)11CH2- for Semiplenamide C (474)R = Me(CH2)13CH2- for Semiplenamide E (475)

PPh3/CBr4,CH2Cl2, rt, 1.5 h

98%

1. Zn, CH2Cl2, rt, 30 min2. AcOH,0 oC-rt, 30 min

87-89%

85% methanolic KOH, rt, 5 h

83-84%

(S)-alaninol, HOBt, DIPEA, EDCI, 0 oC,15 min, rt, 24 h

79-81%

Ac2O, DMAP, Py, rt, 4 h

92%

(469) (470) (471) (472)

(473)

Scheme 73.

H

O OTBS

CO2Me

OTBS

CO2H

OTBS

O

OTBS

NHBn

OH

NH2

(±)-Spisulosine

1. methyl acrylate, MeOH, DABCO, 50 oC, 96 h, 60%2. TBSOTf, Et3N, CH2Cl2, 6 h, 70%

NaOH, MeOH/H2O (1:1), 70 oC, 30 h

quantitative

1. ClCO2Et, acetone,5 oC, 5 min2. NaN3, rt, 2 h3. PhMe, reflux, 2 h4. H2O, reflux, 12 h,

40%

BnNH2, CH2Cl2,40 oC- rt, then NaBH3CN, rt, 20 h

70%

1. Pd/C, H2, AcOH, CH2Cl2,50 oC, 20 h, 90%2. HCl, MeOH/CH2Cl2, 50 oC, 20 h, 98%.

(481)

(476) (477) (478)

(479) (480)

( )13

( )13

( )13 ( )13

( )13 ( )13

Scheme 74.


lated from the marine bacterium Salinispora tropica (Scheme 75)[121].

5.10. Pericosine

Pericosines, a class of densely oxygenated cyclohexenoid natu-ral products, were isolated from the sea hare Aplysia kurodai and are found to be cytotoxic metabolites of the fungus periconia bys-soid OUPS-N133 [122]. Besides they have significant activity against the murine P 388 cell lines and human cancer cell lines [123]. Vankar and co-workers reported MBH reaction followed by RCM reaction mediated route for the total synthesis of pericosine B and pericosine C and their enantiomers from D-ribose (Scheme 76)[124]. Their synthesis started with substrate 489 derived from commercially available D-ribose 488 [125].

Simultaneously they also accomplished the synthesis of (-)-pericosine B and (-)-pericosine C following the identical syn-thetic sequence but starting from D-ribose derived hemiacetal 499(Scheme 77) [126].

6. NATURAL PRODUCTS OF ANIMAL ORIGIN 6.1. Tricyclic Core of Solanoeclepin A

Hiemstra et al. utilized intramolecular [2+2] photocycloaddition of an allene butenolide 506 for compact tricyclic core 507, 508 of solanoeclepin A (509), a hatching agent of potato cyst nematodes [127]. This key allene butenolide was prepared from the allyl bro-mide 504 which in turn was prepared in four steps from the MBH adduct 503 obtained via the MBH reaction between benzyl butadi-enolate 502 and paraformaldehyde (Scheme 78).

O

O

OO

MeO

OHH

OH

H

H

OH R2

R1O

Me

O

OH

H

Sporolide A: R1 = Cl, R2 = HSporolide B: R1 = H, R2 = Cl

O O OH OTf

O

O

OTBS

O

O

OTBS

TMS

O

OOH O

OHO

HOO O

O

O

H

HO

CH2O, PPhMe2

97%

TMSDIPEA, 2,6-utidine, CuI, Pd(PPh3)4

quantitative

6 steps

CeCl3.2LiCl, LiN(Me2Ph)2,-78 oC

H

precursor of Sporolide(486-487)

(363) (482) (483) (484)

(485)

(362)

H H

Scheme 75.

D-Ribose

O

O O

HO

O O

HO OH

O O

HO OMOM

O

OOMOM

OH

CO2Me

Grubb's II, PhMe, 110 oC

86%

NaBH4, MeOH, 0 oC

97%

3steps1. CrO3, Py, Ac2O, CH2Cl2, 0 oC

2. methyl acrylate, DABCO, DMF

OO

CO2Me

OMOM

HO

OO

CO2Me

OMOM

HO

OO

CO2Me

OMOM

MeO

OO

CO2Me

OMOM

MeO

HOHO

CO2Me

OH

MeO

HOHO

CO2Me

OH

MeO

Ag2O, MeI, THF.Me2S, rt, 3h 95%

Ag2O, MeI, THF.Me2S, rt, 3h

91%

TFA, MeOH, 0 oC-rt

81%

TFA, MeOH, 0 oC-rt

88%

(+)-Pericosine C

(+)-Pericosine B

ref 124

(498)

(496)

(488)

(489) (490) (491) (492)

(493) (494)

(497)

(495)

Scheme 76.


6.2. Himanimide A Basavaiah and co-workers developed a one-pot sulphonic acid-

mediated procedure for the synthesis of unsymmetrical 3,4-disubstituted maleimide and maleic anhydride derivatives from the MBH adducts 511 of "-keto esters 510 and acrylonitrile. They ex-tended this strategy for the synthesis of biologically active hi-manimide A (513) in 11.38% overall yield (Scheme 79) [128]. Sub-sequently, application of identical protocol on the MBH adducts of "-ketoesters and acrylate afforded a series of maleic anhydride. The 3-benzyl-4-phenyl maleic anhydride 515, prepared during the study is a natural compound isolated from Aspergillus nidulans (Scheme 80).

PhCO2Me

HO CO2Et

Ph

Bn

OO

OC6H6, CH3SO3H, reflux, 4 h

52%

(514) (515)

Scheme 80.

6.3. Leu- and Met-enkephalin Analogues Leu-enkephalin (522) and met-enkephalin (523) are two en-

dogeneous peptide ligands towards the "-opioid receptor isolated from brain tissue and are involved in a large number of physiologi-cal processes. Their roles in behaviour, neuroendocrinology and pain transmission are well documented. Negri et al. employed the MBH adduct 517 [129] of formaldehyde and tert-butyl acrylate to prepare two conformationally constrained analogues of leu-enkephalin and met-enkephalin to study their biological activities [130]. They first completed the synthesis of the N-terminus of the pepetide by carbamate formation and two subsequent SN# reactions. Following, the C-terminus was synthesized by EDCI coupling with appropriate amino acid as outlined in scheme 81.

6.4. Pheromones [2E]-Butyl-oct-2-enal (532) is an alarm pheromone component

of the African weaver ant Oecophylla longinoda [131] and [2E]-2-tridecylheptadec-2-enal (533) is an unusual metabolite from the red alga Laurencia species Laurencia undulataand Laurencia papillosa[132]. Basavaiah and Hyma reported the synthesis of these impor-tant pheromones by using MBH reaction between aldehyde 524 or

D-Ribose

O

O O

HO

ref 125

HO

CO2Me

OH

MeO

(-)-Pericosine B

HO

CO2Me

OH

MeO

(-)-Pericosine C

OHOH

(500)(496)

(488)

(499)

Scheme 77.

Ph3P CO2Bn

CO2Bn CO2Bn

OH OR

BrMeOCl, Et3N, CH2Cl2

82%

DABCO, CH2O, THF

60%

OO

OR

OO O

O

ORO

O

OTIPSO

OO

505, AgOCOCF3,CH2Cl2, -78 oC - rt

hv

60%

R = TIPS (507)R = Bn (508)

22-60%(501) (502) (503) (504)

(506) (505) (509)

4 steps

Me MeO

O

O

Me

HO

O

O

Me

HO

H CO2H

OH

Solanoeclepin A

Scheme 78.

TBDMSO

CO2Et

O

TBDMSO

CNHO CO2Et

HO

NHO

O

O

NHO

O

Himanimide A

acrylonitrile, DABCO, 4d, rt

CH3SO3H, C6H6,reflux, 4 h

48% 47%

Br

K2CO3, acetone, reflux, 6 h

50%

(513)(510) (511) (512)

Scheme 79.


525 and methyl acrylate [133]. The respective cinnamate 530 and 531 were prepared via SN2´ substitution reaction onto the acetates 528 and 529 with appropriate Grignard reagent. Subsequently, DI-BAL-H mediated reduction of the ester group reduction to alcohol followed by oxidation of hydroxyl group to formyl afforded the corresponding pheromones 532 and 533 (Scheme 82).

(±)-Sitophilate (536) is the aggregation pheromone produced by male of the granary weevil Sitophilus granaries [134]. Coelho’s and Almeida’s groups have accomplished the synthesis of this compound using pentan-3-yl acrylate (534) as the activated alkene in the MBH reaction with 1-propanal under ultrasound condition in the presence of DABCO (Scheme 83) [135]. The MBH adduct 535thus obtained was reduced with Pd/C to obtain racemic sitophilate 536 in 81% yield.

In a different study Sá et al. used 2-methylbut-1-al (537) as the electrophile in MBH reaction with methyl acrylate to obtain the MBH adduct 538 which was transformed to insect pheromone 541via bromination, zinc promoted reduction and saponification steps (Scheme 84) [136].

Besides Das et al. were also able to synthesize five important insect pheromones which included (2E,4S)-2,4-dimethylhex-2-enoic acid, a mandibular-gland secretion pheromone of the male carpenter ant in the genus Camponotus, (+)-(S)-manicone (544) and (+)-(S)-normanicone (545), two mandibular-gland constituents of Manica ants, (+)-dominicalure-I (546) and (+)-dominicalure-II (547), two aggregation pheromones of the lesser grain borer Rhyzoperthadominica (Scheme 85) [137]. Here too, the functionali-zation of the acid group of the MBH adduct 538 prepared from the

OtBu

O

HO

O

NC

OCl

CH2Cl2, rt O

NCl

H

O

O OtBu

O

O

NFmocHN

H

OH

O

4 steps

O

NFmocHN

H

N

O

H

HN

R

CO2Me

O

NHN

H

N

O

H

HN

R

CO2H

O

H2N

HO

CF3CO2 Leu-enkephalin: R = CH2CH(CH3)2, (522) Met-enkephalin: R = CH2CH2SCH3, (523)

1. Phe-Leu-OMe. HCl or2. Phe-Met-OMe. HClEDCI, Et3N, CH2Cl2, 0 oC-rt

3 steps

(517) (518) (519)

(520) (521)

quantitativeCH2O

t-Butyl acrylate, Me3N, H2O

(516)64%

Scheme 81.

RCHO R

OAc

CO2Me RCO2Me

R1

RCHO

R1

H

H

methyl acrylate, DABCO, rt, 6d

R1MgBr, THF, 0 oC-reflux, 6 h

1. DIBAL-H, dry Et2O, -78 oC, 3h, 71%2. PCC, NaOAc, CH2Cl2, rt, 3 h, 65%

61%

(528,529) (530) R = nC5H11, R1 = nC3H7(531) R = nC14H29, R1 = nC12H25

(524) R = nC5H11(525) R = nC14H29

(532) R = nC5H11, R1 = nC3H7(533) R = nC14H29, R1 = nC12H25

R

OH

CO2Me

AcCl, Py, benzene, 0 oC-rt, 3 h

86%85%(526,527)

Scheme 82.

CHOO

O OH

O

O OH

O

ODABCO, MeCN, ultrasound, 8 d

43%

H2, 5% Pd/C, EtOAc

81%1:1

(±)-Sitophilate

(534) (535) (536)(120)

Scheme 83.


chiral aldehyde 537 was the highlighting feature of their strategy for obtaining 544 and 545. Likewise, 548 and 549 were obtained via reaction of chiral pentan-2-ol with the alkenoic acids derived from the MBH adduct of ethyl and iso-propyl aldehyde.

7. SYNTHESIS OF DRUG MOLECULES 7.1. Pregabalin

The starting material 551 for pregabalin (555), an anticonvul-sant drug used for the treatment of neropathic pain is synthesized by Pfizer via MBH reaction between isobutyraldehyde 550 and acrylo-nitrile followed by treatment with ethyl chloroacetate. A Pd-catalyzed carbonylation afforded 552 which upon hydrolysis in the presence of KOH yielded the potassium salt 553. Asymmetric hy-

drogenation of 553 in the presence of a chiral Rh-catalyst ([(R,R)-(Me-DuPHOS)Rh(COD)]-BF4 gave the precursor 554 in 96.6% ee(Scheme 86) [138].

7.2. (+)-Efaroxan Precursor Coelho et al. elegantly utilized the MBH adduct 557 prepared

from 2-fluorobenzaldehyde and methyl acrylate for the straightfor-ward, enantioselective synthesis of R-(+)-2-ethyl-2,3-dihydrofuran-2-carboxylic acid (562) in 8 steps. A LiMe2Cu-mediated nucleo-philic substitution reaction, Sharpless epoxidation and intramolecu-lar cyclization for preparing the cyclic ether were some of the key steps in the synthesis (Scheme 87) [139]. Compound 562 is the direct precursor of R-(+)-efaroxan, used for the treatment of neu-

H

O OH

CO2MeCO2Me

Br

CO2Me CO2Hmethyl acrylate, DABCO

72%

HBr, H2SO4

75%

Zn, AcOH

88%

NaOH, MeOH/H2O

83%

(E)-2,4-Dimethyl-2-hexenoic acid,Pheromone

(537) (538) (539) (540) (541)

Scheme 84.

CHO

H

OH

OMe

O

HOH

O

H Cl

O

H

R2CuLi, Et2O, -78 oC R

O

H

R = Et, (+)-(S)-Manicone, (544)R = Me, (+)-(S)-Normanicone, (545)

methyl acrylate, DABCO, dioxane, 0 oC, 20 h

1. NaBH4,CuCl2.H2O, MeOH, rt

2. NaOH, MeOH/H2O

SOCl2,C6H6,reflux

R1CO2H

1. SOCl2, C6H6,reflux

2. (+)-(2S)-pentan-2-ol

R O

O

R1 = Et, (+)-(S)-Dominicalure-I, (548)R1 = iPr, (+)-(S)-Dominicalure-II, (549)

(537)(538) (542) (543)

(546,547)

71%

Scheme 85.

CHOMe

MeMe

Me

OCO2Et

CN

NC

Me

Me

OEt

O

NC

Me

Me

O-K+

O

2 steps

1. acrylonitrile, DBU, DBP, 50 oC, 97%2. ClCO2Et, Py, CH2Cl2, rt, 95%

Pd(OAc)2, PPh3,CO (300 psi), EtOH, 50 oC

KOH, MeOH, 45 oC

Pregabalin(555)

(550)(551) (552) (553)

83% 88%

Me

Me

CO2K

CN

[(R,R)-(Me-DuPHOS)Rh(COD)]-BF4

asymmetric hydrogenation

96.6% ee

Me

Me

CO2K

NH2

(554)

Scheme 86.

CHO

F

OH

F

CO2Me

OAc

F

CO2Me

F

CO2Me 4 steps

F

CO2HO

F

CO2H

OH O CO2H

methyl acrylate, DABCO, MeOH, ultrasound, 16 h

90%

AcCl, Et3N, DMAP, CH2Cl2, 12 h

90%

LiMe2Cu, Et2O, -30 oC, 20 min

68%

5% Pd/C, EtOH, rt, 12 h

80%

NaH, PhMe:DMF (8:2), 110 oC, 16 h

65%

(556) (557)(558)

(559)

(560) (561) (562)

ON

N

H

ON

N

H

(563) (564)

(R)-Efaroxan KU14R

Scheme 87.


rodegenerative diseases (Alzheimer’s or Parkinson disease), mi-graine and type II (non-insulin dependent) diabetes.

They extended the approach to develop an asymmetric synthe-sis of both enantiomers of DFP analogues 573 and 574 from the epoxide precursor 570 (Scheme 88) [140].

7.3. LK-903 Das and co-workers reported an efficient and stereoselective

synthesis of (E)-"-methylcinnamic acids in one-pot by reduction of the unmodified MBH adduct methyl-3-hydroxy-3-aryl-2-methyl-enepropanoate (576) with I2/NaBH4. The protocol was extrapolated for the total synthesis of 1-[p-(myristyloxy)-"-methylcinnamoyl] glycerol, LK-903 (580), a highly active hypolipidemic agent by functional group transformation of the acid moiety (Scheme 89)[141].

7.4. Sordarin Core Ciufolini et al. utilized the MBH adduct 583, prepared from the

reaction between a typical aldehyde 556 and acrylonitrile, to obtain the ketone 586, which served as the useful building block for the

preparation of analogues of the potent antifungal agent, sordarin 587. It was presumed that the exposure of the adduct 583 to TIP-SOTf induces the formation of the bis-trialkylsilyl derivative 584,which undergoes a spontaneous Diels-Alder reaction to furnish 585as mixture of diastereomers (Scheme 90) [142].

7.5. Bupropion

Bupropion or [(±)-"-t-butylamino 3-chloropropiophenone] is a potent inhibitor of dopamine reuptake with subtle noradrenergic reuptake. Bupropion is a typical antidepressant, which has been licensed by FDA to treat the smoker’s abstinence syndrome. Bupropion is administered in its racemic form, since it racemizes very quickly in the body when administered in its enantiomerically pure form. Coelho et al. used the MBH reaction to accomplish the total synthesis of (±)-bupropion in eight steps with an overall yield of 25%. In this approach they performed the MBH reaction of methyl acrylate with 3-chlorobenzaldehyde under sonication. Sub-sequently, the MBH adduct was transformed to the acyloin deriva-tive (591) which was utilized to prepare bupropion (Scheme 91)[143].

R

CHO

R

OR1

CO2Me

R

CO2Me

R

OHR

R1O

R

OHO

R

OO

O

O

S

O

OO

O

O

R = SCH3 R1 = H, Ac

R = SO2CH3, R1 = CH2OHR = SO2CH3, R1 = CH3

MeLi, CuI,-20 to -40 oC, 10 h

60%

DIBAL-H, CH2Cl2,-78 oC, 2 h

89%

Methyl acrylate, DABCO, ultrasound, 48 h

1. (-)-DIPT, Ti(OiPr)4,TBHP, CH2Cl2, -40 to -20 oC, 70%

2. (a) MsCl, Et3N, CH2Cl2,0 oC, 10 min(b) LiAlH4, THF, 0 oC, 30 min

Pd(OAc)2,bathocuproine, H2O, O2, 100 oC, 30 h

55%

CF3CO2iPr, DBU, MeCN, reflux, 10 h

85%

DFP analogue 1

S

O

OO

O

O

DFP analogue 2

(573) (574)

(565) (567) (568)

(569)(570) (571)

(572)

DPC, DMAP, 2-isopropoxyacetic acid, DCE

70%

R

OH

CO2MeAcCl, Et3N, DMAP, CH2Cl2, 0 oC, 12 h

88%79%

(566)

Scheme 88.

RO

CHO

RO

OH

CO2Me

RO

CO2Me

RO

CO2H

O

O

HO

RO

O

O

O

O

RO

O

OH

OH

methyl acrylate, DABCO, Dioxane:H2O (1:1), rt, 7 d

73%

I2, NaBH4, THF, rt, 3 h

1. 60% KOH, MeOH, rt, 2 h2. dil. HCl

75% over two steps

Boc2O, DMAP, THF, rt, 16 h

92%

Amberlyst-15, MeOH, rt, 2 h

LK-903, Hypolidpidemic agent

R= nC14H29

94% (580)

(575) (576) (577) (578)

(579)

Scheme 89.


7.6. (+)-L-733,060 and (+)-CP-99,994 Garrido and co-workers developed an asymmetric synthesis of

non-peptidic neurokinin NK1 receptor antagonists (+)-L-733,060 and (+)-CP-99,994, starting from the MBH adduct of benzaldehyde. Their synthesis included a domino Ireland-Claisen rearrangement, asymmetric Michael addition with the acetyl derivative 595 to ob-tain the !-amino acid 596 (Scheme 92) [144].

7.7. Alpidem and Zolpidem Alpidem and zolpidem are two anxiolytic and hypnotic drugs

with imidazo[1,2-a]pyridine core structures. Namboothiri and co-workers reported a cascade inter-intramolecular double aza-Michael addition reaction of 2-aminopyridines with MBH acetates 602 to synthesize imidazo[1,2-a]pyridines in one-pot. They further ex-tended the protocol for the synthesis of alpidem 606 and zolpidem 607 (Scheme 93) [145].

7.8. Tamiflu Oseltamivir phosphate (Tamiflu), an orally effective anti-

influenza drug is reported to inhibit the nuraminidase enzyme of several influenza viral strains. Sudalai et al. reported an enantiose-lective route for the synthesis of tamiflu and (-)-methyl 3-epi-shikimate using Sharpless asymmetric epoxidation to initially pre-pare the epoxy alcohol 608 which was oxidized to aldehyde 609(Scheme 94). A diastereoselective Barbier allylation reaction on

609 with the allyl bromide 238 prepared from the MBH adduct afforded the product 610 which was tailored further to arrive at a diene 611 [146]. A RCM reaction was performed on 611 to con-struct the cyclohexene core 612 of the molecule. The target com-pound was achieved via the aziridation route as reported earlier [147].

Recently, we also reported the synthesis of Corey’s tamiflu in-termediate from N-Boc-L-serine methyl ester using MBH reaction as one of the key steps [148]. The N-Boc-L-serine methyl ester (616) was synthetically manipulated to the acetonide protected aldehyde 617 which was subjected to MBH reaction with ethyl acrylate under neat condition to generate the adduct 618. Thereafter acetylation of 618 followed by reduction via SN2' displacement reaction afforded the diene 620. The RCM reaction and hydroxyl group elimination gave the Corey’s intermediate 622 in 22% overall yield (Scheme 95). Simultaneously, we utilized N-Boc-D-serine methyl ester to prepare the other isomer of the Corey’s tamiflu in-termediate via identical route.

In addition, the Corey’s intermediate was utilized to synthesize GABA reuptake receptor inhibitor natural neurotoxin gabaculine as HCl salt (625) by simple saponification and Boc-deprotection (Scheme 96).

In addition, during the preparation of the manuscript Taylor and co-workers reported a novel synthesis of natural neurite outgrowth inducer (±)-neuchromenin using MBH reaction as one of the key steps [149].

O

OMe

MeO2CO

OMe

CO2Me

CH3HO

O

OMeCO2Me

CN

HO

OTIPS

OMe

CO2Me

NC

TIPSO

CO2Me

TIPSONC OTIPS

OMe

CO2Me

ONC X

OR

Y

acrolein, DBU, MeCN, rt

acrylonitrile, DABCO

57%

TIPSOTf, Et3N, rt

72%

OHC CO2H

OO

HO

Me

Me

H

HOOH

H

sordarin

X = OR or CNY = H or alk

(581) (582) (583)

(584)

(585) (586)

(587)

Scheme 90.

Cl

OH

OH

Cl

O

OH

Cl

OHN

(±)-Bupropion

Cl

OTBS

CO2H

1. ClCO2Et, 5 oC, 5 min2. NaN3, rt, 2 h3. PhMe, reflux, 2 h4. H2O, reflux, 12 h

45%

1. NaBH4, MeOH, rt, >99%2. TBAF, THF, rt, 2 h, 97%

IBX, DMSO, rt, 30 h

85%

1. Tf2O, 2,6-lutidine, CH2Cl2, -40 oC, 30 min2. t-BuNH2, 12 h

75%

(594)

(590)

(592) (593)

Cl

OH

CO2Me

(589)Cl

CHO

(588) Cl

OTBS

O

(591)

methyl acrylate, DABCO, sonicator

89%

Scheme 91.


PhCHO Ph

OH

CO2Me PhCO2Me

OAc

Ph N

Ph

Ph

CO2Me

CO2H

NH

O

MeO2C

Ph NH

HO

Ph

NH

O

Ph

CF3

F3C

NH

HN

PhOMe

4 steps

(+)-CP-99,994

(+)-L-733,060

methyl acrylate, DBU Ac2O, Py

H2, Pd/C, AcOH(S)-2, n-BuLi

73%88%55%

Ph NH

Ph

(S)-2

(599)

(600)

(595)(596)

(597) (598)

(415) (416)

Scheme 92.

X

NO2

1. CHOCO2Et DMAP, CH3CN30 oC, 10-20 min2. Py, AcCl, CH2Cl2, 0 oC, 30 min

96-98%

N

N

EtO2C

X

XX

NO2

AcO CO2Et

N

N

EtO2C

X

X N

NX

X

R2N

O

N

X

NH2

MeOH, 30 oC 20 min

89-92%

KOH EtOH/H2O (9:1), 30 oC, 3-4 h

1.PCl5, CH2Cl2, 40 oC, 1 h2. NHR2, 0 oC, 30 min

93-95%

X = Cl, R = nPr, 86%, Alpidem (606)X = R = Me, 96%, Zolpidem (607)

(601) (602) (604)

(605)

(603)

Scheme 93.

OOH

TBSO

O

CHOTBSO

BrCO2Et

O

TBSOCO2Et

OH

O

CO2Me

OMOM

TEMPO, PhI(OAc)2

95%

Zn, aq. NH4Cl, THF, 10 h

64%

5 steps

O H

H

MOMO CO2Me

Grubbs II, CH2Cl2

90%

AcN

CO2Me

OMOM

H

H

CO2Et

OH

O

AcHN

CO2Et

NH2

O

AcHN

ref 147

1. 3-pentanol, BF3.OEt22. 2N HCl, EtOH

81%

(615)

(608) (609) (610)(611)

(612) (613)(614)

(218)

Scheme 94.


MeO2C NHBoc

OH

NBoc

CHO

O NBocO

HO CO2Et

NBocO

AcO CO2Et

NBocO

CO2Et

O NBoc

CO2Et

NHBoc

CO2Et

ethyl acrylate, DABCO, rt, 2d

82%

AcCl, Py, 0 oC-rt, 1.5h

93%

DABCO, NaBH4,dioxane:H2O (1:1), rt, 1h

Hoveyda-Grubbs II, PhMe, 60 oC, 8h 3 steps

ref 147

89%

71%

7 steps

NH2

CO2EtO

AcHN

(623)

(616)(617) (618) (619)

(620) (621) (622)

Scheme 95.

NHBoc

CO2Et

NHBoc

CO2H

NH3

CO2HLiOH,THF:H2O, rt, 4 h

4N HCl, EtOAc, rt, 4 h

94% 81% Cl

(622)(624) (625)

Scheme 96.

8. CONCLUSION

In summary, the chemistry related to MBH adducts or their de-rivatives has made tremendous impact in the realms of synthetic natural product chemistry for accomplishing synthesis of a variety of natural products. Besides, employing the MBH chemistry in the scheme of events also allows construction of close analogues of the required natural products which provides a platform to develop structure activity relationship if the original compound has bioactiv-ity. Moreover, the influence of MBH reaction on obtaining drugs/ drug intermediate is also growing which is demonstrated by formu-lating simple routes to popular drug like Tamiflu. Although there has been formidable development in the area, it is envisaged that as the MBH adducts and their derivatives offers limitless opportuni-ties, the synthetic chemists will be sufficiently motivated to keep on exploring new/alternate synthesis of natural products using this chemistry.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

One of the authors (S.B.) gratefully acknowledges the financial support from Council of Scientific and Industrial Research, New Delhi in the form of fellowship. S.B. ackwoledges the funding from Department of Science and Technoly, New Delhi vide grant num-ber SR/S1/OC-01/2010. This is CDRI Communication No. 8856.

ABBREVIATIONS

Ac = acetyl Am = amyl aq = aqueous

Boc = tert-butyloxycarbonyl Cbz = benzyloxycarbonyl conc = concentrated CSA = camphor sulphonic acid d = day(s) DABCO = diazabicyclo[2.2.2]octane DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene DBP = Di-n-butyl phthalate DCB = dichlorobenzene DDQ = 2,3-dichloro-5,6-dicyanobenzoquinone de = diastereomeric excess DEAD = diethyl azodicarboxylate DIBAL-H = diisobutylaluminium hydride DIC = diisopropyl carbodimide DIPEA = diisopropyl ethylamine DIPT = diisopropyl tryptamine DFP = diisofluorophosphate DMA = dimethoxyacetamide DMAP = 4-dimethyl aminopyridine DME = 1,2-dimethoxyethane DMF = N,N-dimethylformamide DMP = Dess-Martin periodinane DMSO = dimethylsulphoxide dr = diastereomeric ratio DTBMP = 2,6-Di-tert-butyl-4-methylpyridine DYKAT = Dynamic kinetic asymmetric transformation EDCI = N-ethyl-N'-(3-dimethylaminopropyl)-

carbodiimide ee = enantiomeric excess E = Entgegen


Et = Ethyl EtOAc = ethyl acetate Et2O = diethyl ether EWG = electron withdrawing group FDA = Food and Drug Administration Fmoc = Fluorenylmethyloxycarbonyl chloride h = hour(s) h" = ultraviolet irradiation HBTU = O-Benzotriazole-N,N,N',N'-tetramethyl-

uronium-hexafluoro-phosphate Hex = hexyl HFIPA = 1,1,1,3,3,3-Hexafluoroisopropylacrylate HIV = human immunodeficiency virus HMPA = hexamethylphosphoryl azide HOBt = 1-hydroxybenzotriazole HQD = hydroxyquinuclidine HWE = Horner-Wadsworth-Emmons IBX = 2-Iodoxybenzoic acid IC50 = inhibitory concentration required for 50%

inhibition ICD = isocupridine IMDA = intramolecular Diels-Alder i-Pr = isopropyl LDA = lithium diisopropylamide LHMDS = lithium hexamethyldisilazide MBH = Morita-Baylis-Hillman m-CPBA = meta-chloroperoxybenzoic acid Me = methyl MEM = methoxyethoxymethyl min = minute(s) MOM = methylmethylether Ms = mesyl (methanesulfonyl) MS = molecular sieves MW = microwave N = normality NBS = N-bromosuccinimide NMM = N-methyl morpholine NMO = N-methyl morpholine-N-oxide NMP = N-methyl pyrrolidin-2-one Tf = trifluoromethane sulphonate PCC = pyridinium chlorochromate PDC = pyridinium dichromate Pd/C = palladium on carbon Ph = phenyl PivOH = pivalic acid PMB = para-methoxybenzyl PPTS = pyridinium p-toluene sulphonate PTSA = para-toluenesulphonic acid Py = pyridine rt = room temperature RCM = ring closing metathesis sec = secondary SN = nucleophilic substitution

TBAB = tetrabutyl ammonium bromide TBAI = tetrabutyl ammonium iodide TBAF = tetrabutyl ammonium fluoride TBD = triazabicyclodecene TBDMS = tertiary-butyl dimethyl silyl TBDPS = tertiary-butyl diphenyl silyl TBHP = tertiary-butylhydroperoxide TBS = tertiary-butyl silyl TEMPO = 2,2,6,6-Tetramethylpiperidinyloxy tert = tertiary TES = triethylsilane TFA = trifluroacetic acid THF = tetrahydrofuran TIPS = triisopropylsilyl TMS = trimethylsilyl TMSET = 2-(trimethylsilyl)ethyl tol = tolyl TPAP = Tetrapropylammonium perruthenate Ts = para-toluenesulphonyl Z = Zussamen

REFERENCES[1] Morita, K.; Suzuki, Z.; Hirose, H. A tertiary phosphine-catalyzed reaction of

acrylic compounds with aldehydes. Bull. Chem. Soc. Jpn., 1968, 41, 2815. [2] Baylis, A.B.; Hillman, M.E.D. German Patent 2155113, 1972; Chem. Abstr.,

1972, 77, 34174q. [3] Basavaiah, D.; Dharma Rao, P.; Suguna Hyma, R. The Baylis-Hillman

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Received: September 27, 2014 Revised: November 17, 2014 Accepted: November 22, 2014

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