Oxidative Semisynthesis of Natural Products with DMDO

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Keywords: Natural products, DMDO, oxygen atom introduction, oxidation, dimethyldioxirane, ... matic methods, IBX) such as, starting material is directly treated.
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REVIEW ARTICLE

Oxidative Semisynthesis of Natural Products with DMDO Muhammad Faisala, Fayaz Ali Larika*, Aamer Saeeda*, Azhar Hussain Shaha, Pervaiz Ali Channara, Dost Muhammad Khana, Musrat Alib and Raj Kumarc a

Department of Chemistry, Quaid-i-Azam University-45320, Islamabad, Pakistan; bDepartment of Biological Sciences, Quaid-i-Azam University-45320, Islamabad, Pakistan; cDepartment of Chemistry, Faculty of Selcuk, University of Konya, Turkey

ARTICLE HISTORY Received: February 28, 2018 Revised: August 04, 2018 Accepted: August 06, 2018 DOI: 10.2174/1385272822666180827142304

Abstract: This review depicts in a concise way the oxidation reactions (C-H, double bond and oxidative cleavage) in natural products. The introduction of oxygen atom in natural products is an improved strategy to achieve pharmacologically active molecules or their synthetic analogues. Natural products are considered most intriguing skeletons to be synthesized in the laboratory mainly because they are blessed with multifunctional groups in one entity. The presence of more than one functional group in the molecules provokes the daunting tasks such as functional group tolerance and regio- or chemo-selectivity. Oxidation reaction is one of the widely exercised reactions in natural products chemistry as it renders the formation of new derivatives or analogues just by insertion of oxygen atom. Over the past decades, several oxidants have been reported but among all, the oxidant dimethyldioxirane (DMDO) holds great promise as it is attributed with mild reactivity, high functional group tolerance, excellent chemo- and regio-selectivity, ecofriendly and is easy to use and prepare, so these fascinating features provide immense incentive to natural product chemist to insert oxygen atom with great ease in natural products.

Keywords: Natural products, DMDO, oxygen atom introduction, oxidation, dimethyldioxirane, oxidant. 1. INTRODUCTION The synthesis of natural products poses the ultimate challenge to test the synthetic approaches and it also paves the way for the comprehension of medicinal chemistry and biochemistry of natural products. Recently, numerous concise and innovative approaches have been exercised in the synthesis of natural products; however, these modern methods heavily rely on the efficient reagents to carry out the designed steps in apt way. Increasing demand for efficient and scalable syntheses has been the hot topic for organic chemists and oxidation of carbon skeleton has been one of the most dynamic areas which have garnered a maximum interest of the chemists. Several organic and inorganic oxidants have been employed over the years in the synthesis of natural products and have achieved a considerable success. Moreover, oxidation chemistry being dynamic in its own way has evolved and has been seen a recent resurgence in the last decade as new small organic molecules have been designed to overcome the problems like economic and environmental challenges which are associated with inorganic oxidants. DMDO is metal-free organic oxidant, which bears a distinct ability to transfer oxygen atom to almost all functional groups and elements as well as atoms like iodine, selenium, and platinum [1-3]. It has several advantages over other oxidation methods (mCPBA, urea hydrogen peroxide UHP, iron catalyzed epoxidation, enzymatic methods, IBX) such as, starting material is directly treated

*Address correspondence to these authors at the Department of Chemistry, Quaid-iAzam University-45320, Islamabad, Pakistan; Tel +92-51-9064-2128; Fax: +92-519064-2241; E-mails: [email protected], [email protected] 1385-2728/18 $58.00+.00

with DMDO, solvent recycling (which is good for large-scale synthesis), offers high yield, cheap, environment friendly, reaction occurs at ambient or low temperature, no need of time-consuming steps (e.g. solvent extraction or chromatography), short reaction time and solvent is just evaporated to obtain pure products [4-7]. No toxic byproducts from the DMDO formulation have been reported to date, and acetone is no longer listed by the U. S. Environmental Protection Agency (EPA) as a hazardous air pollutant. DMDO is easy to handle and can be used for the oxidation of acidor base-sensitive substrates as well as for the preparation of hydrolytically labile products. In the past several years dimethyldioxiranes have rapidly grown into one of the more useful oxidation processes in the arsenal of synthetic chemists [8]. These oxidations can be carried out with ‘isolated’ dimethyldioxirane in acetone or by generating the dioxirane “in situ”, under mild conditions [9, 10]. The use of isolated dioxirane solutions offers the additional advantage of yielding essentially pure oxidation products in acetone since the dioxirane undergoes conversion to the solvent during the reaction [11]. Experiments using 18O-labeled reagents have shown that acetone is recycled in the system after DMDO oxidizes a target substrate [12]. The utility (reactivity and selectivity) of dimethyldioxirane oxidations has been extensively investigated. Oxidations performed by dimethyldioxirane have been found to be generally electrophilic in character and show retention of configuration. These fascinating features can furnish the incentive to pursue in situ generated DMDO mediated oxidation, we hope our review will take you on © 2018 Bentham Science Publishers

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3. THE VERSATILE ROLE OF DMDO IN C-H FUNCTIONALIZATION PROCESSES

tour where you will explore and learn recent and exciting reactions, which can successfully be employed in the practical organic synthesis of natural products.

3.1. DMDO-based Intermolecular C-H Functionalization of Bryostatin

2. PREPARATION OF DMDO

Nowadays non enzymatic approaches to C-H functionalization are widely employed in synthesis [13-17]. The prevalence of DMDO as the choice of majority for C-H oxidation can be attributed to its high functional group tolerance and high regioselectivity. It has the ability not to provoke epoxidation while the double bond is found in the molecule and instead of that, it affords C-H oxidation selectively. Wender et al. described DMDO-mediated intermolecular C-H functionalization of bryostatin, in which 2 was converted into 3 (70% yield) by using DMDO in excess at ambient temperature for 2 days (Scheme 2) [18]. Very good selectivity was achieved with DMDO, only C-9 was functionalized. After this, they tried to elaborate this selectivity to different analogues of 2, interestingly they found different products with DMDO when 4 was subjected to oxidation (Scheme 2). The formation of different products is due to competitive oxidation between C-9 and C-26 the later being thermodynamically not favored. The subtle variation in the chemical reactivity of 2 and 4 is due to difference in reactivity of primary and secondary alcohols and secondary alcohols being more reactive towards dioxiranes. Moreover, a DMDO rate for secondary alcohols is higher than ethers. They have successfully achieved oxy-functionalization of highly populated FGs (functional groups) and sensitively oriented bryostatin analogues via late-stage diversification in single step that otherwise would require multistep synthesis (scheme 2).

Dimethyldioxirane (1), a member of the family of smallest cyclic peroxides, is formed from buffered (pH 7–8) acetone–caroate (peroxymonosulfate) in water (Scheme 1). Due to its ease of preparation from commercially available and inexpensive reagents, dimethyldioxirane has been used as a versatile oxidizing reagent during the past 35 years. In 1979, Curci et al. studied the decomposition of the biphasic mixtures of caroate and acetone with 18crown-6-ether acting as a phase transfer catalyst for the in situ generation of dimethyldioxirane oxirane/acetone solutions via vacuum distillation. Baumstark et al. prepared DMDO in situ from acetone and used it in synthetic organic chemistry more than three decades ago, and now it has become a popular oxidizing reagent of unusual synthetic utility. Recently, Mikula and co-workers have resolved the big issue related with dimethyldioxirane that is in storage. Previously, it was known that 1 can neither be stored for a long time and nor can be purchased. But these workers reported a practical and efficient large-scale preparation of 1 in liter quantities and they found that 1 can be stored for 11 months without loss of reactivity [13-15]. O

Acetone

O

KHSO5 (oxone)

O

water, NaHCO3

1

DMDO

pH=7-8

Scheme 1. Preparation of dimethyldioxirane.

OH O

O

O

O O

OH

HO

O C7H15

O

O OH

OH O

O

1 acetone rt, 48h

O

O

O

O

HO O

O

O

CO2Me

C7H15

OH O

2

CO2Me 3 OH

OH

O

O

O

O O OH

O

O

CO2Me

O

O

O

O

O OH

acetone rt, 48h

HO O

O

O

OH O

O

DMDO

HO

O C7H15

O

C7H15

4

Scheme 2. High level of tolerance observed with DMDO.

CO2Me 5

O

O +

OH O

O

O

OH

O C7H15

HO O

O

CO2Me 6

O

O

O

O O

OH

+

HO

C7H15

O O

CO2Me 7

Oxidative Semisynthesis of Natural Products with DMDO

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OH OBn BnO

OBn

O

BnO

HO

O

O

DMDO, acetone DCM, p-TSOH

H OBn

O OH

OH

O

OBn

O

AcO 78%

O

AcO OH

9

8

SLO101 Scheme 3. Hydroxylation at 3 position with DMDO.

O

O

O

NH

NH

N

HO O

O

O

DMDO, acetone

OH

OH

O O

N

HO

O

O

O

O

O

O

O

O

11

10 Scheme 4. Epoxidation of olefin bond surrounded with various functionalities.

NH2 Cl

CF3

Cl

CF3

dimethyldioxirane, acetone, rt, 24 h, 64.2%

NH2

NH2

NH2 Cl

Cl

CF3

CF3

+ H N 12

O

13

HO O

OH Trantinterol 14

Mabuterol

15

Scheme 5. Synthetic route toward trantinterol.

3.2. Application of DMDO in the Synthesis of Kaempferol Glycoside SLO101 Maloney and co-workers reported the synthesis of kaempferol glycoside SLO101, they introduced OH group at 3 position by using DMDO as an oxidant and subsequent ring cleavage of 3membered heterocycles with small amount of p-TSOH (paratoluene sulfonic acid), the products obtained was in better yield [19, 20] (scheme 3). 4. EPOXIDATION OF DOUBLE BOND BY USING DMDO 4.1. Synthesis of 14-membered Ring Ketolides with Assistance of DMDO The synthesis of ketolides based on a 15-membered ring has posed challenges for the synthetic community [21]. Pavlovic et al. synthesized a series of novel homoerythromycin A ketolides [22]. Two different oxidants were tried for epoxidation that are mCPBA and DMDO. 10 was subjected to m-CPBA to obtain syn-epoxy Noxide and anti-epoxy N-oxide isomers in 1:1. The epoxidation of 10 was then done using dimethyldioxirane, as it is more sterically sen-

sitive oxidant and would favor the formation of the sterically less hindered syn-epoxide. Thus, treatment of 10 with a solution of dimethyldioxirane for 24 h in acetone afforded epoxides 11 in good yield (scheme 4). 4.2. DMDO-based Synthesis of Trantinterol Trantinterol 14 is a positional isomer of mabuterol and has been previously reported as a potent and long-acting selective alpha 2adrenoceptor agonist [23]. In anticipation of the requirement of large quantities of trantinterol for clinical studies, extensive research has been focused on developing more efficient processes for obtaining trantinterol with inexpensive starting materials. Wen et al. described an improved new method for trantinterol synthesis from readily available and inexpensive starting materials using DMDO as an oxidant (scheme 5). 4.3. Quinopimaric Acid Derivatives by Oxidation with DMDO Alienate diterpenoids (e.g., abietic, dehydroabietic and levopimaric acids) belong to naturally occurring terpenoids and they can be used for the synthesis of drugs and polymers [24-27].

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H O

H

O

H

H

O H H

H

H COOCH3

O

H

H COOCH3

O H

O

H

H

O H COOCH3

17

16

O H

OH

H+

DMDO

O

H

H COOCH3

18

OH 19

Scheme 6. Plausible reaction mechanism for DMDO oxidation. O O

O

O

H

H

H

H

DMDO

OH

DMDO

OH

H H

H

H O

H

H

O

H COOCH3

H COOCH3 20

H

O

H COOCH3

H COOCH3 22

21

H

O

23

Scheme 7. Oxidation of cyclic ethers with DMDO. OMe

H

O

80%

25 OH

OMe

a

e

H

OH

d OH

O OH

H

H

24

OH

26

f

27

OH

OH

+ H

O OH 28

O OH 29

Scheme 8. Reagents and conditions: (a) DMDO/acetone (0.08 M, 2 equiv), CH2Cl2, 25 oC, 1 h, 80%;(d) (I). DMDO/acetone (0.08 M, 3 equiv), CH2Cl2 , 25 C 2 h, I(II). NaSEt, DMF, 90oC, 8 h, 70%; (e) DMDO/acetone (0.08 M, 8.5 equiv), CH 2Cl2 , 2 oC, 20 min; II. NaSEt, DMF, 90 oC, 8 h, 70%; (f) I. DMDO/acetone (0.08 M, 8.5 equiv), CH 2Cl2 , 25oC, 1 h, (II). NaSEt, DMF, 90 oC, 8 h, 60% for 4, 20% for 2.

Kazakova et al. reported the novel synthesis of quinopimaric acid derivatives by oxidation with an excess of DMDO, resulted in high yield and excellent selectivity. The remarkable tolerance level of DMDO was observed, when it was treated in excess with 1 it does not oxidize double bond at C13 in 16 (scheme 6). The path of reaction shows epoxidation of the double C13 bond followed by subsequent ring rupturing to afford OH group at C14 and a double bond at C13. The hydroxy group promoted the cyclization at C4 (scheme 6). Cyclic ethers 20 and 22 were successfully oxidized with DMDO by C-H oxygen insertion route to form hemiacetals 21 and 23 in excellent yield (scheme 7).

4.4. DMDO Role in the Synthesis of Variously Oxidized Abietene Diterpenes A different approach was used for the divergent synthesis of oxidized abietane diterpenes (similar to which holds great importance in pharmacology) through oxygen insertion of 6,7-dehydroferuginol methyl ether with DMDO. DMDO is an ideal reagent for oxygen atom induction because it has ability to transfer oxygen via chemo and stereoselectivity [29-31]. Abietane diterpenes having sp 2 carbon at C6 and C7 was selectively oxidized by 1 [32, 33]. In all different reaction conditions, oxidation of C6 and C7 position was observed (scheme 8).

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O O

DMDO

DMDO S

S

O

R

O

30

R

O

31

32

O

33

Scheme 9. Selective epoxidation of squalene. O H

O

H

H 1.1 equiv DMDO

O n H

H BnO

H

acetone,-20oC 30 min

34

O

H

H OH

O H

O O

H

n H BnO

H 81%

35

H 36

Scheme 10. Synthesis of epoxide by DMDO.

4.5. Regioselective Oxidation of Squalene Through DMDO

4.7. Epoxidation of 5,7-dioxygenated Flavones with DMDO

Previously, Accotli et al. extensively studied the dioxirane based oxidations, recently they examined the direct regio and stereoselective epoxidation in acyclic terpenes, squalene with DMDO [34]. Chiral squalene 30 and 32 were transformed into 31 and 33, respectively (scheme 9).

DMDO is considered as the excellent oxidant for protected (methoxy or benzyloxy) flavones and anthocyanins [37]. Compton et al. used acyl substituted flavones to obtain 2,3-epoxidation products, they found major products in low yields initially and many byproducts [38]. When they increased the amount of DMDO they found oxidation at C-5 and different products but major product obtained was in low yield (Table 1). By induction of deactivating group, acyl substituents in ring A, the complicated situation was successfully resolved and 2,3-epoxidation products were obtained as shown in scheme 11.

These conversions were observed to occur with appropriate diastereo- and regio-selectivity, offering easy access to the important dioxides-based metabolites. 4.6. DMDO Application in the Total Synthesis of (+)-vigulariol

R2O

(+)-Vigulariol 36 was first extracted from sea pen Virgularia juncea, it possesses a core of four cycles and exhibit cytotoxicity. Becker et al. developed a short synthetic route for 36, by modifying earlier reported synthetic and mechanistic investigations [36]. Where cycloalkene 34 was treated with 1 it afforded oxirane 35 (Scheme 10). The less crowded face was found to be more reactive. Table 1.

O

R2O

Ph

O

DMDO

Ph O

acetone OR1

OR1 O 37

O 38

Scheme 11. 2,3-Epoxidation of flavone with DMDO.

Scope of epoxidation of flavone with DMDO. Entry

R1

R2

A

Me

Me

B

Ac

Ac

C

Bz

Bz

D

Ac

Me

E

Me

Bz

F

Me

Ac

G

H

Ac

H

H

Me

I

Bz

Me

J

Bz

Bn

K

Bn

Bn

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Br Br HO N3

N3

HO

N TFA NH2 N

Cl

H

N3

N3

NH N

N TFA NH2 N H

H N H

N Br

NH

TFA-

HO Cl

O

NH

40

NH

TFA-

H N

Br

H HO

39

HN N TFA NH2 N OH

Cl

N H

HO

O

NH N

41 TFA-

NH

Reagents and conditions: DMDO (1.4 equiv), H2O, 8 oC, 5 h; then TFA/DCM (2/1), 238 oC, 13 h

Scheme 12. Oxidation of double bond in the presence of several functional moieties.

R3SiO

R3SiO

H N

H N dimethyldioxirane, acetone

OSiR'3

CH2Cl, -20

OSiR3

oC,

24 h, 53%, racemic

OSiR'3 OSiR3 O 43

42 R3=Alkyl R

R Scheme 13. Epoxidation of carbazole based alkaloids with DMDO.

O

Br

O

OH

OH S

Br O OTPs 44

O

O then H3O 45

O

94%

O Cepanolide

Scheme 14. Regiospecific synthesis of cepanolide using DMDO to construct key part.

4.8. Role of DMDO in the Synthesis of Axinellamines A and B The axinellamines are marine natural products, having eight contiguous chiral centers and four cycles along with bis-guanidine core was first isolated in 1999 by Yamaguchi and co-workers [39]. Recently, the concise synthesis was reported by another group, where DMDO was used to convert the double bond 39 into epoxide, followed by ring opening with triflic acid (trifluoromethanesulfonic acid) to get the 1,2-diol product 40 (Scheme 12) [39]. 4.9. Epoxidation Reaction in the Carbazole Based Alkaloids Nature is a great reservoir for carbazole alkaloids, having useful pharmacological activities [40, 41]. The synthesis of carbazoles has been previously carried out in many laboratories [42]. Knöll and coauthors published the first total synthesis of titled compounds by using DMDO as an oxidant. Silyl groups are tolerated when carbazomadurins A and B were subjected to DMDO oxidation, which afforded 43 non-stereochemically [43] (scheme 13). 4.10. Regiospecific Synthesis of Cepanolide Using DMDO Organosulfur compounds (OCSs) reduce the risk of cancer disease [44, 45]. The protective effects of Allium (onions and garlic)

are associated with OCSs [46]. Cepanolide is also organo sulfur compound found in green onions and garlic. John and co-workers published a region-specific synthesis of cepanolide in 4 steps (66% yield). Treatment of 44 with an acetone solution of dimethyldioxirane provided the desired hydroxybutenolide 45 in excellent yield and showing the ability of DMDO to deprotect the protected (scheme 14). 4.11. Epoxidation of Camphene with DMDO Camphene belongs to the class of terpene and is an important constituent of many natural oils. The selective epoxidation of camphene double bond was reported by Grabowski et al. [48]. When it was subjected to DMDO, it was epoxidized to Z/E mixture. Gas chromatography (GC) analysis revealed that the obtained Z/E ratio was 1:8 (scheme 15). 4.12. Stereoselective Epoxidations of Carbohydrates-Based Oxepines Oxepines bearing carbohydrates have proven to be important starting materials for the synthesis of 1,2-anhydroseptanose, with the oxepines serving as ring-expanded glycals [49]. Based on the

Oxidative Semisynthesis of Natural Products with DMDO

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+

O

DMDO

O

acetone

+

O

O

1

46

7

Z-48

E-47 8:1

minor

major Scheme 15. Epoxidation of camphene by DMDO. OBn

O

OBn O

OBn

BnO

O

O O

DCM

BnO

BnO

OBn OBn O

BnO

49

O O

BnO

O

DCM 51

50

OBn OBn O 52

Scheme 16. Epoxidation of oxepines derived from galactose and mannose.

stereochemistry of the cyclic enol ether, high selectivity in the formation of one anhydrosugar in preference to another is common [50, 51]. Peczuh et al. determined the facial selectivity in the DMDO based epoxidations of carbohydrates (glucose, galactose and mannose) bearing oxepines [52]. Oxepines 49 and 51 derived from D-galactose and D-Mannose favour  epxoidation over epoxidation (Scheme 16). Selectivity in epoxidation of D-xylose based oxepines and Dglucose based oxepines support a model, “stereochemistry of oxygen present on oxepines largely determines the stereoselectivity of epoxidation” (Scheme 17). OBn O

BnO BnO

OBn

O O

53

DCM

54 OBn

O O

O

BnO

OBn BnO

O

O

BnO

O

DCM

55

4.13. DMDO-based Epoxidation of Glycals

O

BnO

electronegative substituents (ii) repulsive interaction between oxygen of DMDO and oxepines (ii) overall synchronicity in epoxide bond formation (iv) steric bulk. Dondoni and co-workers published an improved methodology for the epoxidation of D-glucal and D-galactal derivatives. They used biphasic solvent system (DCM/NaHCO3) with in situ generated DMDO (scheme 18). Benzyl and acetyl substituted D-glucal and D-galactal derivatives were subjected to epoxidation and they resulted in the formation of the corresponding 1,2-anhydrosugars in a 99% yield and 100% selectivity. The synthesized derivatives can serve as precursors in the synthesis of carbohydrate chemistry [53] (Scheme 19).

56

Halcomb et al. in particular have extensively developed the use of 1,2-anhydrosugars in oligosaccharide synthesis since 1989, by epoxidation of glycals [54]. In 2006, Dondoni and co-workers described a practical, multi-gram epoxidation of 3,4,6-tri-O-benzyl-Dglucal and D-galactal with dimethyldioxirane generated in situ from oxone/acetone under biphasic conditions, five years later Lafont et al. published an efficient biphasic phase transfer catalyst mediate epoxidation of glycals with DMDO [55] (scheme 20).

O O

BnO BnO BnO

O

OO

BnO BnO BnO

DCM

58

57

Scheme 17. Epoxidation of oxepines derived from D-xyloses and Dglucose.

Earlier Wei suggested “majority rule” and Rainier developed “asynchronicity rule” combining these two models and studies of Peczuh et al. the following conclusions can be drawn regarding the stereoselectivity of carbohydrates based oxepines. (i) orientation of

O O

O

4.14. Application of DMDO in the Synthesis of Maculalactone A The utility of small, strained heterocyclic rings has been extended to spiroheterocyclic systems by many researchers in recent past [56]. Duffy et al. synthesized novel class of spirocyclic heterocycles (spiroxy--lactones) by epoxidation of ketene dimers using DMDO as an oxidant and they explored the synthetic utility of spirocyclic heterocycles by synthesizing enantioselectively antifouling agent maculalactone A by way of tetronic acid intermediate [57] (scheme 21). There work provides an area for synthetic chemists towards the synthesis of spiroheterocycles found in natural products. 5. THE VERSATILE ROLE OF DMDO IN OXIDATION OF

i) DMDO, DCM, 0oC

O

O

ii) NaHOCH3, MeOH 59

Scheme 18. Epoxidation of protected oxepines with DMDO.

HO HO HO

O

O

60

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OAc AcO AcO

O

DMDO

AcO AcO

acetone 6.5 h

61

R2

OAc O O 62

OAc

R1 BnO

O

R2 DMDO

O

BnO

acetone 6.5 h

63

OAc

R1

O

64

99%

87%

Scheme 19. Formation of anhydrosugars with DMDO.

Ra

Ra OBn

Re BnO

DMDO, Bu4NHSO4

OBn

Re

NaHCO3, DCM, H2O

BnO

65

O

66

Re= OBn, Ra=H Re=H, Ra=OBn Re=(BnO)4-beta-D-Gal, Ra=H Scheme 20. Synthetic route to glycosides using epoxide as an intermediate.

O

O

O

O

O O

O

Ph

O R

R

DCM

R 67

O

R 68

Ph

dr=10-24:1

Ph

(+)-Maculalactone A

R=Ph Scheme 21. Synthesis of spiroheterocycles using DMDO.

O H N

N CbzHN

CO2Me

CbzHN

CO2Me

OH

DMDO, acetone

69

3 NH2

O

R

O

O

O N

N H

O

OH

O brasilibactin A

-78oC, 15 min

3 N O

HO

N

CHO

70 Scheme 22. Oxidation of amine to nitrone a key step towards the synthesis of brasilibactin A.

AMINE MOIETY 5.1. DMDO-based Synthesis of Brasilibactin A Brasilibactin A (despeptide) was isolated by Tsuda et al. from actinomycete [58]. Ying and co-authors accomplished the synthesis of brasilibactin A, by convergent strategy [59]. They used DMDO as it is potent tolerant for the many functional groups, to synthesize nitrone from amine moiety a key intermediate in their synthesis as shown in scheme 22.

and proposed multi-centered transition state after analyzing PKIE (primary kinetic isotopic effect and KIE) [60]. 6.2. DMDO-mediated Chemoselective Oxyfunctionalization

6. APPLICATION OF DMDO IN OXIDATION OF ALCOHOL

The brassinosteroids (BR) belong to group of phytohormones and they show inhibiting cancer cell lines activity [61]. Previous published methods for the synthesis of BR lacked either the generality or were lengthy [62]. Marek et al. designed better route for synthesis of BR, where DMDO was used for selective oxidation of secondary alcohol [63]. Oxyfunctionalization of 75 with 1 yielded chemoselectively the hydroxyl group containing ketone 76 (scheme 24).

6.1. Transformation of Secondary Alcohols into Ketones Using DMDO

7. OXIDATION OF ALLENES BY USING DMDO

DMDO 1 can successfully be employed for the conversion of secondary alcohols 71 (Scheme 23) into ketones in high yields. Two mechanistic approaches have been proposed for oxidation of secondary alcohols. Mello et al. suggested concerted insertion, whereas Angelis et al. proposed radical-cage process. Recently Baumstark et al. re-examined the earlier proposed kinetic effects

7.1 Synthesis of epi-cintreodiol with Assistance of DMDO Spirodiepoxide provides access to gabosine A, hypothemycin, picromycin, incednine, and epi-citreodiol 79 [64, 65]. William et al. reported the stereoselective formation and regioselective opening of silyl-substituted allenes (stereoelectronic effects of silyl substituted allenes were previously documented) by using DMDO [66-68]. The

Oxidative Semisynthesis of Natural Products with DMDO

O

Y

O + 1

OZ

O

k2

R2

R1

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O +

R

OH H

O

R2

R1

dried acetone 23 oC

71

R R

R

OH



H

O

 O

Me

O O

H

O

H

O

Me Me

R R

Me

Me

2 R1=R2=Me, Y=Z=H 3 R1=R2=Me, Y=D, Z=H 4 R1=R2=CD3, Y=Z=H 5 R1=R2=Me, Y=H, Z=D 6 R1=Ph, R2=Me, Y=Z=H 7 R1=Ph, R2=CD3, Y=Z=H

9

Me multi-centred

radical-cage

concerted

74

73

72

Scheme 23. Oxidation of secondary alcohols by DMDO with proposed transition states.

O

O

O

O H

H HO

Dimethyldioxirane Acetone

HO

H

O

HO

O

H

75

76

O

Scheme 24. Selective oxidation of secondary alcohol into ketone with DMDO. OH H H3C

TMS

(i) DMDO, CHCl3, -40 oC to rt

CH3

(ii) CH3Li, Et2O, -40 oC (iii) TBAF, CH3CN

77

HO

OH

O OCH3

CH3

HO

78

79

epi-citreodiol

Scheme 25. Synthesis of epi-citreodiol (fungal metabolite).

O H

OTBS

i-Pr 80

(i) DMDO (ii) N3

N3

H3C OH Me N

i-Pr

81

Et

O

O

OTBS

CH3

H N O H3C

H3C

OH

N H Et

O H N

O

CH3 i-Bu

O

epoxomicin Scheme 26. Synthesis of epoxomicin via spirodiepoxides derived from allenes.

key transformation for fungal metabolite was carried out, 77 was treated with DMDO followed by proteodesilation and single isomer 78 was achieved (scheme 25). 7.2. Synthesis of Spirodiepoxide with DMDO-comprehensive Solvent Effect Spirodiepoxide-based transformations offer new routes to highly enantio-enriched and densely functionalized motifs (i.e. epoxomicin) as shown in scheme 26. 8. DMDO-MEDIATED OXIDATIVE CLEAVAGE REACTIONS 8.1. Concise and Regiocontrolled Synthesis of Yangjinhualine A Datura metel L. (Solanaceae) is a shrubby herb, its dried leaves are known as yangjinhua, and yangjinhua is commonly used in clinics of china for the treatment of various diseases like insanity [69, 70]. Feng et al. [71] published the isolation of a novel compo-

nent of this fraction, named yangjinhualine A, it proves striking as these molecules have garnered considerable attention by the synthetic community [72-75]. The initial preparation of yangjinhualine A has been completed precisely, and entirely through regioncontrolled way by McCann and co-worker. Treatment of 82 with an acetone solution of dimethyldioxirane (DMDO) gave the silyl ester 83, which was not purified, but subjected to the action of aq. HCl in THF, to afford after flash chromatography racemic yangjinhualine A (yield 92%) [76, 77] (scheme 27). CONCLUSION AND FUTURE DIRECTIONS Oxidation chemistry is one of the rapidly evolving areas in the organic synthesis and numerous oxidants have been disclosed in the past decade to insert oxygen atom in the molecules. Dimethyldioxirane furnishes all the characters to be called versatile as it is blessed with mild reactivity, negligible toxicity, high functional group tolerance and exhibit high levels of stereo-control. DMDO has achieved great attention of natural product synthetic chemists

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Faisal et al.

TBSO

HO

TBSO O

HO

O

O

O

DMDO

82

H

OTIPS O

83

O

HO

O

O

84

Scheme 27. Oxidative cleavage of lactone with DMDO.

and its recent resurgence has been summarized herein compact review by highlighting the key step involved in the synthesis of natural products either by C-H functionalization, double bond epoxidation or by oxidative cleavage and in some cases via oxidation of amine moiety. The key step involved in the synthesis of natural products is highlighted and brief utility of each natural product is also discussed. Synthetic community has always evolved, and recently triflourodioxirane (TFDO), a more reactive analogue of DMDO, has found great utility in organic synthesis. In future, to achieve compatibility in organic synthesis, particularly in C-H activation, TFDO being more reactive may bring brighter results comparative to DMDO.

[13]

[14]

[15]

[16]

[17]

CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The author declares no conflict of interest, financial or otherwise. ACKNOWLEDGEMENTS Declared none.

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