nitrogen substituted donor-acceptor cyclopropanes in the total synthesis of natural products

Accepted Manuscript Digest paper Application of Oxygen/Nitrogen Substituted Donor-Acceptor Cyclopropanes in the Total Synthesis of Natural Products Santosh J. Gharpure, Laxmi Narayan Nanda PII: DOI: Reference:

S0040-4039(17)30055-2 http://dx.doi.org/10.1016/j.tetlet.2017.01.033 TETL 48536

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Tetrahedron Letters

Received Date: Revised Date: Accepted Date:

2 November 2016 5 December 2016 11 January 2017

Please cite this article as: Gharpure, S.J., Nanda, L.N., Application of Oxygen/Nitrogen Substituted Donor-Acceptor Cyclopropanes in the Total Synthesis of Natural Products, Tetrahedron Letters (2017), doi: http://dx.doi.org/ 10.1016/j.tetlet.2017.01.033

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Application of Oxygen/Nitrogen Substituted Donor-Acceptor Cyclopropanes in the Total Synthesis of Natural Products Santosh J. Gharpure, Laxmi Narayan Nanda indole alkaloids

carbocycle natural products

D

A

oxygen/nitrogen substituted D-A cyclopropanes

butanolide natural prducts

cyclic ether natural product

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Digest Paper

Application of Oxygen/Nitrogen Substituted Donor-Acceptor Cyclopropanes in the Total Synthesis of Natural Products Santosh J. Gharpure,* Laxmi Narayan Nanda Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai – 400076, India A RT I C L E I N F O

A BS T RA C T

Article history: Received Received in revised form Accepted Available online

Donor-acceptor (D-A) cyclopropanes show interesting reactivity and high selectivity in the cleavage of one of the cyclopropane bonds. This particular reactivity has been extensively explored in various transformations like cycloaddition, rearrangement and cascade reactions. This rich reactivity profile, particularly of oxygen/nitrogen substituted D-A cyclopropanes has led to their emergence as versatile building blocks in organic chemistry. This review summarises the applications of heteroatom substituted D-A cyclopropanes in the total synthesis of natural products. 2009 Elsevier Ltd. All rights reserved.

Keywords: Keyword_1 D-A cyclopropane Keyword_2 diazoketone Keyword_3 lactone Keyword_4 natural products Keyword_5 butanolide/butenolide/alkaloid

1. Introduction Cyclopropanes are an important class of compounds not only because of the structural curiosity associated with their strained structure but also owing to their occurrence in numerous bioactive natural products and drugs. Moreover, for quite some time they have proved to be valuable synthetic building blocks in organic synthesis. However, for better selectivity of cyclopropane bond cleavage, it is necessary to have appropriate activating groups – either an electron donating or an electron accepting group – on this strained three-membered ring in order to make polar reactions more facile. R

A

A

R D D

A Donor-Acceptor Cyclopropanes

D R D

R A

A

R D

D

A R

D

A A

D

A = Electron acceptor: COOEt, COR, CN, etc. D = Electron Donor: OR, OSiR3, NR1R 2, etc.

Figure 1.1: Donor-acceptor substituted cyclopropanes Cyclopropanes bearing electron-withdrawing groups typically react with nucleophiles acting as homo-Michael acceptors similar to electron-deficient alkenes. Cyclopropanes having electron donating group as substituents are prone to reactions with electrophilic reagents. D-A cyclopropanes substituted with both donor and acceptor groups are particularly useful since the electronic effects of these substituents ensure selective activation of the cyclopropane bond sandwiched between donor and acceptor substituent (Fig. 1.1).1 Due to the

ability of the D-A cyclopropanes to generate stabilised dipoles, in addition to typical reactions with nucleophiles and electrophiles, they can also participate as dipoles in a variety of cycloaddition reactions. They have also been shown to participate in reactions typical of cyclopropanes, like rapid ring opening under appropriate radical conditions. Over the years D-A cyclopropanes have emerged as important synthons in organic chemistry. The reactions employing D-A cyclopropanes involving cleavage of one of the cyclopropane bonds and resulting in ring opening are not only explored in the synthesis of natural products but they have also found use in the synthesis of unnatural products. 2 However, this review focuses only on the utilization of the oxygen/nitrogen substituted D-A cyclopropanes in the total synthesis of natural products. 2.1 Application of oxygen substituted D-A cyclopropanes in the synthesis of natural products Due to the remarkable reactivity and broad scope, the hetero atom substituted D-A cyclopropanes have been extensively utilized in the synthesis of various classes of natural products ranging from terpenes to alkaloids to cyclic ethers.1 This section discusses some interesting, representative cases where oxygen substituted D-A cyclopropanes were used in the key steps in the total synthesis of natural products. 2.1.1 Synthesis of Carbocyclic Natural Products D-A cyclopropanes bearing oxygen as a donor substituent have been used in the total synthesis of carbocyclic natural products such as prostaglandin (±)-PGF2 (1), -chamigrene (2) and (±)-nemorosone (3).

2 Scheme 1: Total synthesis of (±)-PGF2(1) Et 3SiO

N 2CHCO 2Et cat. CuSO 4

R1

CO 2Et

CO 2Et Et 3SiO

C6H 6, heat, OCH 2OMe 70% 5 d.r. 4:1

NEt 3.HF

H R1 4 OCH 2OMe

O R1

THF 95%

OCH 2OMe 6 PBPH THF

R1 = OTBS

-78 oC, 80% O

yields. Regiospecific cleavage of the D-A cyclopropane 8 under acid-catalysed solvolysis using camphorsulphonic acid in MeOH gave a mixture of acetals 14 (dr 1:1). Reduction of the ketone 14 with NaBH4 followed by hydrolysis of the acetal moiety furnished the diol 15, which was further elaborated to -chamigrene (2). Scheme 3: Total synthesis of (±)-nemorosone (3) OMe

OTIPS

HO O

CO 2H

R1 HO (±)-PGF 2

HO (1)

7

OCH 2OMe

Synthesis of prostaglandin (±)-PGF2(1) involved fluoride assisted cleavage of the siloxy substituted D-A cyclopropane 4, which was prepared by diastereoselective cyclopropanation of the silyl enol ether 5 with ethyl diazoacetate (Scheme 1). The key feature of this strategy was that the D-A cyclopropane 4 underwent a smooth ring cleavage under reaction conditions employed with retention of the newly generated stereocentre at the cyclopentene ring of the keto ester 6. Chemo- and stereoselective reduction of the ketone 6 using lithium cis, cis-trans-perhydro-9b-boraphenalyl hydride (PBPH) resulted in concomitant lactonisation to furnish the lactone 7. Lactone 7 was subsequently converted into (±)PGF2(1) in few steps.3 Scheme 2: Total synthesis of -chamigrene (2) O

CO 2Me

HO

O

OTs

1. H 2CrO 4 2. DBU quant. 2 step

9

11

10

44%

MeO 2C COCHN 2

O O

Rh 2(OAc) 4

O

CO 2Me O

quant. 8

13

12

MeOH/CSA 91% HO O O MeO

1. NaBH 4 2. HCl O

OH 2-3 steps

82% 14

15

[CuOTf] 2 PhMe toluene, r.t.

chamigrene (2)

Adams et al. accomplished the total synthesis of chamigrene (2) using ring opening reaction of D-A cyclopropane 8 (Scheme 2).4 The keto ester 9 was converted into the alcohol 10 by a series of reactions, which upon oxidation followed by elimination produced the required enone 11. The key reaction in their strategy involved a DielsAlder reaction of enone 11 with methyl methacrylate giving the dihydropyran 12, which was further transformed into corresponding diazoketone derivative 13. The D-A cyclopropane 8 was synthesized using intramolecular cyclopropanation of the dihydropyran moiety of the bicyclic diazoketone 13 using Rh2(OAc)4 as the catalyst in excellent

MeI, tBuOK THF, -78 0C-r.t.

O

O

O

OMe OTIPS

O

O

N2

then 2N HCl THF, r.t. 58% 2 steps

OMe 17

N

N

16

O OTIPS O

19

O

18 O OTIPS

O

22

O OTIPS

TBHP Pd(OH) 2-C

O

OAc

O

Cs 2CO3 70%

O

1.

LiTMP THF, HMPA 96%

O OTIPS

23 H

2.

LiTMP (2-Th)Cu(CN)Li 99%

R=

CO 2Me H

OO HO

O

Ph

R

Br O

20

H

Br O OTIPS

O OTIPS O

82% OAc 3 steps

21

H

1. DIBAL-H 2. Ac2O 3. DMP

O 24

H

O R R H (+) - nemorosone (3)

Nakada and co-workers completed the total synthesis of (±)nemorosone (3) using intramolecular cyclopropanation of an α-diazoketone 16 and regioselective ring opening of cyclopropane 17 as the key reactions. First, intramolecular cyclopropanation of diazoketone 16 was carried out in the presence of [CuOTf]2.PhMe and bis-oxazoline ligand 18 to produce the D-A cyclopropane 17 (Scheme 3). The resultant crude product was then treated with methyl iodide and potassium tert-butoxide to afford a dimethylated compound, which was then converted into di-ketone 19 via acid catalysed ring opening of D-A cyclopropane 17. The di-ketone 19 was further converted to corresponding keto-ester derivative 20. Reduction of the ester and ketone groups of 20 using DIBALH, chemoselective acylation of primary alcohol and oxidation of the secondary alcohol using Dess-Martin periodinane (DMP) gave the acetate derivative 21. The allylic oxidation on the acetate 21 installed the carbonyl group to yield the diketone 22, which was a key precursor for introduction of all allyl groups. Thus, the diketone 22 was transformed to the corresponding allylic compound 23, which on subsequent bisallylation furnished the triallyl substituted diketone 24, which was further utilized for the synthesis of (±)-nemorosone (3).5a Subsequently, they also described enantioselective formal synthesis of some other polycyclic polyprenylated acylphloroglucinol (PPAP) natural products.5b 2.1.2 Synthesis of Indole Alkaloids The [3+2] cycloaddition reaction of D-A cyclopropane was explored by Pagenkopf et al. in the synthesis of alkaloids like quebrachamine (25) and goniomitine (26). The cycloaddition reaction between the functionalized nitrile 27 and the D-A cyclopropane 28 in the presence of TMSOTf furnished the cycloadduct 29 (Scheme 4). Oxidation of the tetrasubstituted pyrrole 29 with catalytic palladium on carbon in refluxing

3 mesitylene provided the indole 30. Decarboxylation and deprotection of the indole 30 led to the lactam derivative 31, which upon N-acylation furnished the chloro imide derivative 32. An effective photocyclisation of indole 32 and reduction of the resultant product gave the quebrachamine (25).6 Scheme 4: Total synthesis of quebrachamine (25) Et

NC

CO 2Et

O NBn

MeO +

NBn

EtNO 2 74%

28

27

O

O

29

Et

CO 2Et Et

dioxane

H

N H

N H 40

30 N

THF 96%

Cl SnCl 4

O

Et

O

N H

N

1. hv (254 nm) Cl EtOH, H 2O, 85%

N

2. LiAlH 4 THF, 93%

32

quebrachamine (25)

N H quebrachamine (25)

Et

N H

CN Et

1. [Me 2N=CH 2]Cl 2. MeI, MeOH NBn 3. NaCN, DMF 70% 3 steps

30

N H

33

Na, NH 3 98% THF CN CN Et POCl 3, PhMe N H HN 35

Et

then NaBH 4 MeOH, 84%

O NH

N H

34

1. DIBAL-H 2. NaBH 4 44% 2 steps OH

OH cat. TsOH

N H HN 36

Et

MeOH Et 3N, 79%

N H HN

(tBu)

O 2Si

O O

N2 O 44 O

O

H

5 mol% O O C toluene (tBu) Si 2 O 92% H O 43 tBu N O Cu O N tBu C O

O

O

O NBn

Et

goniomitine (26)

The D-A cyclopropane 37 bearing tetrahydropyran moiety was also shown to be a useful precursor in the total synthesis of quebrachamine (25).7 Brønsted acid catalyzed ring opening of D-A cyclopropane 37 gave the lactone 38, which upon partial reduction using DIBAL-H yielded the corresponding lactol 39 (Scheme 6). Acid-catalyzed condensation with

N

2. LiAlH 4 NMM 37% over 6 steps

OH

N H H 41

Et

2.1.3 Synthesis of -Butyrolactone based Natural Products Butyrolactone based natural products are ubiquitous in nature and possess immense biological activities. The reactivity of D-A cyclopropanes has been extensively exploited in the synthesis of butyrolactone based natural products. Following section describes some of the important examples. Scheme 7: Formal synthesis of xylobovide (42)

O

O

1. 10% acetic acid 40 2. 10% acetic acid, NaBH 3CN

1. MsCl, Et 3N CHCl3

Et

N H

Et

In a divergent way, the same indole intermediate 30 was utilized in the synthesis of goniomitine (26). The cyanomethyl group was introduced on the indole ring of 30 to obtain homologated indole 33. The N-benzyl group was removed using Na/NH3/THF to give the free lactam unit 34. The tetracyclic core 35 was constructed by the reaction of amide 34 with POCl3 followed by the reduction of the imine intermediate with NaBH4. The cyanomethyl group was transformed to corresponding alcohol 36 and finally epimerization of the trans ring fusion of 36 was performed in presence of catalytic p-TsOH to obtain goniomitine (26) (Scheme 5). Scheme 5: Total synthesis of goniomitine (26) O

39 NH 3Cl

O

O Cl

OH O

O

38

NBn

31

O

O

Et

DIBAL-H O -78 oC, Et O 2

10% H 2SO 4

37

98%

NH N H

Et CO 2Et

N H Pd/C mesitylene

Et

O

CO 2Et Et TMSOTf

tryptamine salt 40 and subsequent reduction with sodium cyanoborohydride gave the diastereomeric mixture of tetracyclic indole 41. The free hydroxy group of indole 41 was converted into its mesylate, which underwent a cyclisation, fragmentation and reduction sequence to give natural product quebrachamine (25). Scheme 6: Total synthesis of quebrachamine (25)

Et H xylobovide (42)

F( tBu) 2Si

O

47

O

O

HO

H BF 3.OEt 2

H

O H O F( tBu) 2Si 45

toluene 95%

O

1. TsCl, py 2. NaI, acetone 95% over 2 steps O Zn/Cu, THF

I

O

O H O F( tBu) 2Si 46

H

O

Formal synthesis of xylobovide (42) was reported by Pagenkopf and co-workers using D-A cyclopropane 43, which was obtained from the diazoester 44 by copper catalyzed intramolecular cyclopropanation. Reaction of the D-A cyclopropane 43 with BF3·OEt2 in toluene furnished the alcohol 45. The alcohol 45 was converted into the iodide 46 via its tosylate using Finkelstein reaction (Scheme 7). Addition of the D-A cyclopropane bearing iodide 46 to a suspension of zinc-copper couple in dry THF resulted in rapid reduction and cleavage of the pyran ether to zinc alkoxide, which spontaneously underwent further ring opening to the aldehyde 47. Deprotection of the silyl group of the aldehyde 47 followed by hydrogenation led to a bicyclic furofuran, which was an advanced intermediate in the total synthesis of xylobovide (42).8 Snapper and Granger designed a route to the tetrahydrofurofuranone side chain of (+)-norrisolide (48) involving an enantioselective cyclopropanation followed by its thermal rearrangement as key steps (Scheme 8).9 Cyclopropanation of lactone 49 with dimethyl 2-

4 diazomalonate in the presence of Müller’s catalyst 50 furnished the D-A cyclopropane 51. The D-A cyclopropane 51 upon heating in refluxing benzene underwent ring opening of cyclopropane followed by rearrangement to corresponding the bicyclic furan derivative 52. The ester 52 was transformed into Weinreb amide 53, which was coupled with the hydrindane fragment 54 to form the lactone 55; the core skeleton of norrisolide natural product 48. The fragment 55 was further elaborated to (+)-norrisolide (48). Scheme 8: Total synthesis of (+)-norrisolide (48) CO 2Me N2 CO 2Me MeO 2C catalyst 50

O O

PhF, 70% 60-70% ee

49

H

O

O O

MeO 2C

oC

185 82%

H 51

H O

MeO

C6H 6

OTBS

cyclopropane 65. Chemoselective hydrolysis followed by catalytic hydrogenation of D-A cyclopropane 65 gave acid 66. The lactone 67 was obtained from the cyclopropane 65 by Brønsted acid catalyzed cyclopropane ring opening followed by lactonization reaction. Treatment of lactone 67 with pyridine resulted in an interesting ring opening-ring closing isomerisation reaction to provide the desired bicyclic lactone 68. Jones’ oxidation of lactone 68 led to acid 69, which upon allyl Grignard addition gave the allylated bicyclic lactone 70. The allylic group was transformed into corresponding ketone functionality containing lactone 71, which was elaborated into (–)-paeonilide (62) in three steps (Scheme 10).11 Scheme 10: Total synthesis of (–)-paeonilide (62)

H 52

MeO 2C

CuOTf, 64 N2 CO 2t-Bu MeO 2C

O t-Bu

O

O

Rh

O N

O O

4

MeO O H

Rh

O

H 54

O

H

50

O H

Shapiro reaction 92%

O H 55 AcO H

63

O

MeO

PhNHNH 2, 38% 83% ee

MeO 2C

H OTBS

N

O

H

Jones' reagent

HO 2C 69

O

O H 68

O

O O O

O

N 2CHCO 2Et Rh 2(OAc) 4 CH 2Cl 2 45%

BnO

O

H

78%

BnO H

CO 2Et

57

58

O

EtOH, H + HO

OEt

O

O

O

Me BnO

O 56

69% O

O

MeSO 3H O

61

O

CH 2Cl 2 67%

O

67

O

44%

H

O

1. BH 3. THF 2. BzCl, Et 3N 3. DMP

O O H O OBz paeonilide (62)

O

71

O

EtO2C

N2 CO 2Et PhNHNH 2, 63% 91% ee

H

H 1. O3 O 77

CO 2Me

O(CO)CO 2Me OHC CO 2Et H 78

2. DMS 94%

. SiMe3 BF 3 OEt 2 72%

O

O L

N

HO

O(CO)CO 2Me

CHO

O

O

BnO

Hg(OAc) 2 HO C 2 79%

CuOTf, L

N

urea H 2O 2 (CF 3CO)O Me

H

Total synthesis of paraconic acid natural products (72-75) was described employing a retro-aldol/lactonization sequence as key steps (Scheme 11).12 Enantioselective cyclopropanation of methyl ester of furan-2-carboxylic acid (76) gave the D-A cyclopropane 77, which upon furan ring cleavage by ozonolysis furnished the cyclopropane 78. The key intermediate 78 was subjected to allylation in the presence of BF3.OEt2 followed by treatment with base to furnish the lactone 79 via a retro-aldol/lactonization sequence. The lactone 79 was utilized in a divergent fashion to synthesise paraconic acid natural products (72-75). Scheme 11: Total synthesis of paraconic acids (72-75)

76

BnO EtO 2C 59

O

O

70

CO 2Me

HO

O

H

O

Jones' reagent

O HO 2C

O HO 2C

75% 2 steps

MgBr

O

Theodorakis et al. also utilized the intermolecular cyclopropanation of dihydrofuran derivative for the synthesis of furofuran ring 56; part structure of norrisolide (48). The DA cyclopropane 57 was prepared by intermolecular cyclopropanation of the dihydropyran derivative 58 with ethyl diazoacetate in moderate yield and good diastereoselectivity. Ring cleavage of the D-A cyclopropane 57 with acid furnished the acetal 59, which was subsequently converted into furan intermediate 60. The furofuranone derivative 61 was obtained from the ketone 60 by its reaction with methane sulphonic acid and it was further transformed into the lactone derivative 56 employing a Bayer-Villiger oxidation (Scheme 9).10 This compound constitutes the part structure of marine natural products belonging to the norrisane family. Scheme 9: Part structure synthesis of (+)-norrisolide (48)

CO 2t-Bu

py, H 2O

H norrisolide (48)

66

O H

O H HO 2C

88%

CO 2H

73%

O

H H

HCl

O

H

2. Pd-C, H 2 CO 2t-Bu 85% 2 steps

N

64

O O

65

O

HO 2C

1. LiOH H

H

O

O

H N MeO 53

O

O Me

OH

OEt O

BnO 60 EtO 2C

Reiser and Harrar explored another application of cyclopropane ring opening and lactonization chemistry for the synthesis of (–)-paeonilide (62). The synthesis commenced with asymmetric intermolecular cyclopropanation of furan-3methyl ester 63 with tert-butyl diazoacetate in the presence of CuOTf and bis-oxazoline ligand 64 to furnish the D-A

CO 2H

O 79

H

CO 2Et

64-72% 95:5 (trans:cis) CO 2H

R R O O O O R = n-C13H 24CO 2H: (+)R = n-C13H 27: (+)-roccellaric acid (72) protopraesorediosic acid (74) R = n-C11H 23: (+)-nephrosteranic acid (73) R = n-C H : (+)-methylenolacticin (75) 5 11

Similar approach was used in an elegant synthesis of (+)arglabin (80).13 The cyclopropane ent-78 underwent a

5 stereoselective Sakurai reaction with the chiral allylsilane 81 in the presence of BF3.OEt2 to furnish the desired adduct 82. The adduct 82, without further isolation was subjected to retro-aldol/lactonization cascade sequence in the presence of Ba(OH2).8H2O to obtain the key lactone fragment 83, which was manipulated to (+)-arglabin (80) in few more steps (Scheme 12). Scheme 12: Total synthesis of (+)-arglabin (80) CO 2Me O

CuOTf ent-64

EtO2C

N2 CO 2Et PhNHNH 2, 38% > 91% ee

76

H

O(CO)CO 2Me

1. O3

H O ent-77

2. DMS CO 2Me 94%

OHC CO 2Et H ent-78

reduction.15 Cyclopropanation of the silylenol ether with tert-butyl diazoacetate and opening of the D-A cyclopropane 91 with fluoride produced the -alkylated cyclopentanone 94. The cyclopentanone 94 was again transformed into the D-A cyclopropane 92 by following the same enol ethercyclopropanation strategy. The cyclopentannulated product 95 was obtained from the D-A cyclopropane 92 by reaction with the phosphonium salt 96 in presence of potassium fluoride, which was further used for the total synthesis of pentalenolactone E (90) (Scheme 14). Scheme 14: Total synthesis of pentalenolactone E (90)

SiMe3

1. Et 3SiH RhCl(PPh 3) 3 benzene

BF 3.OEt 2 81 OPMB

O

O

-EtOH

H

62%

H

OPMB H OH

OH

H

OPMB

H H

CO 2Et OH

H

83

2. Et 3SiCl Et 3N, DMF 3. N 2CHCO 2Et CuSO 4, benzene

93

OPMB H

H CHO H

H

SPh

O

Perali and Kalapati utilized the cyclopropane ring opening and lactonization strategy for the total synthesis of spirolactone (–)-longianone (84). The D-A cyclopropane 85 was obtained by stereoselective cyclopropanation of enantiomerically pure glycal 86 using methyl diazoacetate in the presence of [Rh2(OAc)4] as the catalyst. Bromonium ion initiated electrophilic ring opening of D-A cyclopropane 85 with N-bromosuccinimide gave bromide 87. Reaction of bromide 87 with potassium carbonate produced the bicyclic lactol 88 through ‘one-pot’ sequence of dehydrohalogenation, intramolecular hetero-Michael addition, ester hydrolysis and nucleophilic cyclization (Scheme 13). Treatment of lactol 88 with triethylsilane and trifluoroacetic acid effected the dehydroxylation and afforded the enantiomerically pure spirolactone 89, which was transformed into (–)-longianone (84) in three additional steps.14 Scheme 13: Total synthesis of (-)-longianone (84) Rh 2(OAc) 4 N2

O

O dioxane-H2O 66%

OBn

CO2Me OBn Br

85

86

87 K 2CO3 MeOH

O O

O (-)-longianone (84)

1. H 2, Pd-C 2. Swern oxidation 3. IBX 41% 3 steps

OH

NBS

CO 2Me

CO2Me

CH 2Cl 2, 60%

O

O 94

1. Et 3SiCl Et 3N, DMF 2. N 2CHCO 2Et CuSO 4, benzene 65% 2 steps

94, KF 18-crown-6

OTMS

CH3CN 95%

2C

CO 2Et 95

CO 2tBu

CO 2Et CO 2tBu 92

Scheme 15: Enantioselective total synthesis of Hagen’s gland lactones (98a-b)

(+)-arglabin (80)

OBn

tBuO

CO 2Me pentalenolactone E (90)

OH

O

SPh PPh 3BF 4 96

O

H H

91

Et 3NHF THF

70% from 93 CO 2tBu

OH H CO 2Et O(CO)CO2Me 82 O

O

OTMS

O

O

O O OBn 89

94% O

O TFA, Et 3SiH CH 2Cl 2, 92%

O OBn OH 88

An efficient total synthesis of the methyl ester of pentalenolactone E (90) was accomplished via a [3 + 2] annulation followed by ring opening of the donor acceptor cyclopropanes 91 and 92. The cyclopentenone 93 was converted into corresponding silylenol ether via conjugate

O

N2

Cu(acac) 2

CO 2Et R O R = n-C 4H 9 99a R = n-C6H13 99b

CH 2Cl 2 reflux

H O

nBu

3SnH,

1. LiAlH 4 THF, -78 oC

Br

CO 2Et

2. PPh 3, CBr 4 O R Py, CH 2Cl 2 R = n-C 4H 9 100a 74% R = n-C 4H 9 97a 80% 0 oC-r.t. R = n-C6H13 100b 65% R = n-C6H13 97b 60% (over 2 steps) R

O

O

O H H R = n-C 4H 9 98a 88% R = n-C 6H13 98b 92% R

CO 2Et

O

AIBN

C6H 6, reflux

I

H O

O

1. nBu 3SnH AIBN, C6H 6 reflux NaHCO 3, I 2

2. LiOH EtOH-H 2O (1:1) CO 2H

O H THF-H2O R O H H H R = n-C 4H 9 101a 70% R = n-C 4H 9 102a 75% R = n-C6H13 101b 64% R = n-C 6H13 102b 92% (over 2 steps) R

Gharpure et al. exploited the reactivity of D-A cyclopropanes 97a-b in the enantioselective total synthesis of Hagen’s gland lactones (98a-b).16a The requisite chiral D-A cyclopropanes 97a (>99% ee) and 97b (97% ee) were prepared by intramolecular, stereo- and regio-selective cyclopropanation of vinylogous carbonate moiety of diazoketones 99a and 99b, respectively. This was found to be a robust, high yielding method for the synthesis of cyclopropafuranones. The D-A cyclopropanes 97a-b upon chemoselective reduction of the ketone gave the corresponding alcohols, which were converted into the bromides 100a-b by their reaction with CBr4 and PPh3 in the presence of pyridine. The bromides 100a-b on reaction with n-Bu3SnH and AIBN in refluxing benzene followed by saponification furnished corresponding dihydrofuran acids 101a-b. The regioselectivity of D-A cyclopropane ring opening here was rather unusual as unlike typical cases, the bond that is not sandwiched between donor and acceptor was cleaved as radical initiators were used. Iodolactonization of acids 101a-b using iodine and NaHCO3 in THF-H2O yielded the lactones 102a-b in good yield. Finally, reductive removal of the iodine under radical

6 conditions using n-Bu3SnH and AIBN in refluxing benzene furnished the Hagen’s gland lactones (98a, 97% ee), (98b, 96% ee) (Scheme 15). Scheme 16: Synthesis of common intermediate lactol 105

103

OH DIBAL-H

O H

H 2. con. H 2SO 4 MeOH Me 69%

H

O

Me

O

1. LiAlH 4 CO 2Et THF, -78 oC 95%

H O

OMe

O 104

O

H toluene, -78 oC 99% Me

H O 105

OMe

Recently, a divergent/collective enantiospecific approach for the synthesis of butanolide and butenolide natural products by utilizing the regioselective ring opening reaction of a single D-A cyclopropane 103 was also demonstrated.16b The D-A cyclopropane 103, prepared from (S)-ethyl lactate,16c was converted into differentially oxidised lactone 104 using two step protocol involving chemoselective reduction using LiAlH4 followed by reaction of the resultant alcohol with catalytic conc. H2SO4 in MeOH. The lactone 104 was partially reduced to lactol 105 using DIBAL-H (Scheme 16). Scheme 17: Synthesis of butanolides 107a-f R

O Me

1. H 2, Pd-C MeOH

PPh 3

nBuLi,

THF o OMe -78 C-r.t. Me 62-86%

O

105 O

R

H

HO H

H

( )5 OH

Me

Me

(+)-juruenolide C (107a)

O

( )7

H Me

H

nBuLi,

OMe

O

( )7

Ph G-I

(Cy) 3P

O Me OH

OH Me Me (+)-2-epi(3S,4R,5S)-4-hydroxy-5-methyl-3blastmycinolactol (9-phenylnonyl)dihydrofuran-2(3H)-one (107e) (107d)

O Me

( )3

Me

OH (+)-2-epi-NFX (107f)

The lactol 105 was subjected to Wittig reaction with appropriate ylide partners to obtain olefin 106a-f, which upon hydrogenation followed by chemoselective oxidation completed the total synthesis of butanolide natural products 107a-f. Incidentally, these were the enantiospecific first total syntheses of (+)-juruenolide D (107b), (+)-butanolide (107c) and (+)-butanolide (107d) (Scheme 17). Both epi-blastmycinolactol (107e) and epi-NFX (107f) were further used in the the total syntheses of (+)-blastmycinone (108a) and (+)-antimycinone (108b) and their C2-epimers (108a'-b'). This was accomplished in two steps involving epimerisation at C2 using catalytic amount of NaOMe followed by acylation with isovaleryl chloride (Scheme 18). On the other hand, total synthesis of (+)-(S)-3-hexadecyl-5methyl-butenolide (109) also was achieved by converting the free hydroxy group of butanolide (107c) into mesylate followed by TBAF mediated elimination reaction.

HO H

H

Me O

116 OH

1. H 2, Pd-C MeOH

( )13 Me

O

OH 115 40 oC G-I 86% CH 2Cl 2

H

MeO

O

O

OH Me (3S,4R,5S)-3-hexadecyl-4(+)-juruenolide D hydroxy(107b) 5-methyldihydrofuran-2(3H)-one (107c)

O

Me

THF, 92%

O

OH

O

THF

-78 oC-0 oC

Cl

Ru

H

MeO

( ) 2 PPh 3Br 114

Me

O

O

O

OH O

O

O O

Scheme 19: Synthesis of bis-lactone intermediate 113

Cl

2. m-CPBA OMe TMSOTf Me O O O CH 2Cl 2 106a-f 107a-f 70-80% 2 steps R = aklyl, aryl groups

O

O

( )n Me ( )n Me O O ( )n Me 1. MeONa O MeOH + O O Me Me 2. isovaleryl Me Me OH O Me chloride O Me Me DMAP 107e n = 1 108a' (+)-2-epi-blastmycinone, CH 2Cl 2 108a (+)-blastmycinone, 107f n = 3 n=1 n=1 108b (+)-antimycinone, 108b' (+)-2-epi-antimycinone, n=3 n=3 O O 1. Et 3N, MsCl CH 2Cl 2, 0 oC ( )13 Me ( )13 Me O O 2. TBAF, acetone OH 0 oC, 90% Me Me over two steps (+)-(3S,4R,5S)-3(+)-(S)-3-hexadecyl-5hexadecyl-4-hydroxy methyl-butenolide -5-methyl-butanolide 109 107c

(Cy) 3P

HO

O

O

O O

105

R

OH

Scheme 18: Total Synthesis of blastmycinone (108a), antimycinone (108b) and (+)-(S)-3-hexadecyl-5- methylbutenolide (109)

OMe

2. m-CPBA TMSOTf CH 2Cl 2 77% 2 steps HO

Me O

O

113

OH

Me

O

The marine natural products (+)-ancepsenolide (110) and (+)hydroxyancepsenolide (111) were synthesized from a common intermediate 113, which was prepared from the same lactol 105. The synthesis of common intermediate 113 started with Wittig reaction of the ylide derived from pentenylphosphonium bromide salt 114 with lactol 105 to obtain the corresponding diene 115, which upon regioselective homodimerisation cross methathesis in the presence of Grubbs’ first generation (G-I) catalyst furnished a diastereomeric mixture of triene 116. All the diastereomers of the triene 116 were subjected to hydrogenation followed by chemoselective oxidation of acetal moieties produced the required bis-lactone 113 (Scheme 19). Scheme 20: Total synthesis of (+)-ancepsenolide (110), (+)hydroxyancepsenolide (111), and (+)-hydroxyancepsenolide acetate (117) O

O O

( )10

O

MsCl, Et 3N DMAP

CH 2Cl 2 0 oC-r.t. Me Me 76% MsCl (1 eq.) CH 2Cl 2, 0 oC-r.t. Et 3N, DMAP 55% (brsm 79%)

OH HO 113

O

O O Me

( )10 OH 111

O Me

(+)-hydroxyancepsenolide

Ac2O pyridine DMAP, r.t. 73%

O

O O Me

( )10

Me 110 (+)-ancepsenolide

O

O O

O

( )10 OAc 117

O

Me Me (+)-hydroxyancepsenolide acetate

7 The bis-lactone 113 was a divergently converted into the ancepsenolide (110) and (+)-hydroxyancepsenolide (111). Thus, treatment of bis-lactone 113 with excess of MsCl in the presence of DMAP and Et3N resulted in double elimination of the hydroxy groups to afford (+)-ancepsenolide (110) (Scheme 20). On the other hand, enantiospecific first total synthesis of (+)-hydroxyancepsenolide (111) was accomplished by mono-elimination of one the hydroxy group of C2-symmetrical bis-lactone 113 by reacting with one equivalent of MsCl, DMAP and Et3N. It was also converted to its acetate by treatment with Ac2O to get (+)hydroxyancepsenolide acetate (117). Scheme 21: Total synthesis of (±)-diospongin B (119) O

nBu

H CO 2Et

Ph

O

H

O

O

118

120

CH 2Cl 2 96% OH O

o Ph 0 C-r.t. Ph 68% (+)-diospongin B (119)

Ph

O

1. (MeO)NHMe.HCl Al3Me, C6H 6, reflux 75%

OTBS TBAF THF

O O 123

Ph

2. PhMgBr, THF Ph 0 oC, 79%

O

O

Br

O

CO 2Et

CH 2Cl 2, rt 88%

N3

N 126 Me

O

Br

O

PBu 3

CuOTf N2

L-selectride CO 2Et THF, -78 oC Ph 70%

O

O

Br

OH

3SnH

AIBN C6H 6, reflux Ph 60%

The lactone 127 possessing four rings was converted into the penatcyclic framework 128 having the allyl unit near to the lactone framework. Lemieux-Johnson reaction on the allylated pentacyclic framework 128 gave the aldeyde 129. The aldehyde unit was effectively transformed into the corresponding pentacyclic skeleton 130 containing the lactam unit through a series of reactions. This intermediate 130 upon Heck reaction with 2-methyl-3-butyen-2-ol and followed by cyclization furnished the hexacyclic core 131, which was elaborated to communesin F (125) through a series of reactions.18 Scheme 22: Total synthesis of communesin F (125)

aq. THF, 0 oC 83%

N N3 124 Me 1.6:1

N 127 Me

N H

121 HN O R1

TBSCl imidazole

Br

OTBS

N 130 Me

O

CO 2Et

122

Gharpure et al. also explored the reactivity of cyclopropapyranone 118 for the total synthesis of (±)diospongin B (119).16d The keto ester 118 underwent a regioselective ring opening of cyclopropane under radical conditions to give pyranone 120. The pyranone 120 upon stereoselective reduction of carbonyl group using L-selectride furnished the alcohol 121. The alcohol 121 upon silyl protection gave the ester 122, which was converted into corresponding Weinreb amide and its reaction with phenylmagensium bromide gave the ketone 123. Desilylation of 123 furnished the tetrahydropyran natural product (±)diospongin B (119) (Scheme 21). 2.2 Application of nitrogen substituted D-A cyclopropanes in the synthesis of indole alkaloid natural products In recent years, nitrogen substituted D-A cyclopropanes have emerged as important synthons for gaining access to nitrogen heterocycles. Computational investigations have revealed that these cyclopropanes undergo even more easily rearrangement reactions.17 Their versatility is demonstrated in their use in the total synthesis of complex indole alkaloid natural products. Some important examples in this domain are described in the following section. The D-A cyclopropane 124 was used as an important intermediate in the synthesis of communesin F (125). The DA cyclopropane 124 was synthesized using CuOTf catalysed intramolecular cyclopropanation of the indole moiety of 126 bearing diazoketone tethered to the indole ring. Reduction of the azide group in the nitrogen substituted D-A cyclopropane 124 with PBu3 in aqueous THF resulted in a two-step cascade reaction of cyclopropane ring opening followed by trapping of the iminium intermediate in-situ by the amino nucleophile to give the lactone 127 as a single diastereoisomer (Scheme 22).

OH 1.

O

Br

N 129 Me

N CO 2Me

O

LemiexCHO Johnson reaction 95%

N CO 2Me

O R

N 128 Me

N CO 2Me

R = allyl

R = allyl

R1 = (CH 2) 2NHBoc

O

Br

Pd(OAc) 2 2. PPTS P(o-Tol) 3 CHCl 3, 66% Et 3N, 68% O

Me

Boc N

HN

Me

N

N

O Me N 131 Me

N CO 2Me

N N H Me communesin F (125)

R1 = (CH 2) 2NHBoc

Scheme 23: CRI approach to ardeemins (132a-c) O N H

CO 2Et O

CuOTf N 2CHCO 2Et Intermolecular cascade CRI reaction dr = 17:1 88%

N Me 135

O

N N Me

O

136

3. DMP 4. Ph 3P=CH 2 38% from 136

N N Me 137

O

CHO

H O N

O

1. tBuOK 85% 2. (Boc) 2O from 137 3. DMP

N

N

1. LDA, MeI 2. LiBH 4

O N N CHO O

Me

N O R ardeemin R = H (132a) N-formalardeemin R = CHO (132b) N-acetylardeemin R = Ac (132c)

N Boc

NH

N Me rotamers 1:2 138

Me

139

Scheme 24: CRI approach to minfiensine (133) and vincorine (134) O

NHTs

R1

O

Intramolecular N cascade N2 Boc CRI reaction R2 140a R1 = R 2 = H 140b R1 = H, R 2 = CO 2Et CuOTf

Intramolecular cascade CRI reaction

OH

CuOTf

N N H

N N Boc Ts 141a

Me minfiensine (133) MeO

MeO 2C MeO

CO 2Et

O N

N N BocTs 141b

N Me vincorine (134) Me

Cascade or stepwise reaction of cyclopropanation/ringopening/iminium cyclization (CRI reaction) on tryptamine derivatives served as an important strategy for construction of

8 highly complex indole alkaloids like ardeemins (132a-c), minfiensine (133) and vincorine (134).19 The tryptophan derivative 135 was subjected to intermolecular cyclopropanation reaction with ethyl diazoacetate to obtain tetracyclic intermediate 136 via CRI approach, which was converted to the olefin 137 by a sequence of reactions involving alkylation, reduction, oxidation and Wittig olefination (Scheme 23). The olefin 137 was transformed to the tricyclic aldehyde 138 by treatment with tBuOK followed by Boc protection and subsequent oxidation. The tetracyclic advanced intermediate 139 was obtained from the aldehyde 138 in several steps, which was further transformed into ardeemin alkaloid natural products (132a-c). On the other hand, CRI on the indole diazo derivative 140a-b gave the tetracyclic intermediate 141a-b that was efficiently converted into minfiensine (133) and vincorine (134) alkaloids via a series of reactions (Scheme 24). Scheme 25: Total synthesis of aspidofractinine (142) O Br

O

O

N2

N

(TsNH) 2 Cl

DBU, THF 92%

N SO 2Ph 145

CuOTf Cl

O N

THF:py reflux, 61%

N

C6H 6 90 oC

N

anthracene Na

N

PhSe(O)OH

148

Cl

CH 2Cl 2 76%

N 143 SO Ph 2 2. AIBN, C6H 6 nBu SnH 1. NaI 3 acetone reflux 92% 2 steps O

N 144 SO 2Ph

O

N

N

N

DME, -70 96%

D

oC

N 146 SO 2Ph

147

SO 2Ph 55% O O

N

RaNi i-PrOH

N

LiAlH 4

149

N H 150

SO 2Ph

E

N

D

C B THF N reflux, 70% H aspidofractinine (142)

67%

N H

A

anthracene radical anion resulted in concomitant ringopening of the cyclopropane leading to the required imine 147 in good yield. Oxidation of intermediate 147 with phenylseleninic acid furnished the enimine 148. Heating the product 148 in benzene, produced its tautomer dienamine, which reacted with phenyl vinyl sulfone to give the DielsAlder adduct 149. Removal of sulphone gave lactam 150 and reduction of the lactam delivered the aspidofractinine (142) (Scheme 25).20 Waser et al. reported catalytic stereoselective cyclization of nitrogen substituted D-A cyclopropane resulting in either homo-Nazarov cyclization or trapping of iminium ion intermediate with nitrogen of indole moiety. The method was applied in the formal synthesis of aspidospermidine (151) and total synthesis of goniomitine (26).21a The synthesis involved coupling of the Weinreb amide possessing the nitrogen substituted D-A cyclopropane moiety 152 with the bislithiated dianion of N-carboxy indole 153 to furnish the ketone 154. The aminocyclopropane derivative 154 upon homo-Nazarov cyclization employing Cu(OTf)2, followed by deprotection resulted in the amine 155, concluding the successful formal synthesis of aspidospermidine (151) (Scheme 26). Similar approach was also used in the synthesis of jerantinine E.21b Interestingly, when the D-A cyclopropane 156 was treated with a Brønsted acid like TsOH, the iminium ion generated after ring opening of D-A cyclopropane was trapped by nitrogen of the indole moiety generating the ketone 157, which was converted to goniomitine (26) in four steps (Scheme 27).21a Scheme 27: Total synthesis of goniomitine (26)

H

MeO

tBuLi,

+

N Me

Cbz N

152 Et

153

N CO 2H

LiCl

H N

O

H

Cbz N

Et

H N

aspidospermidine (151)

OTIPS

O

Et N

3. Pd/C, H 2, EtOH 4. TBAF, THF 77% goniomitine (26) OH OTIPS

157

Et

Cu(OTf) 2

Et

N

HN H

1. NaBH 4, MeOH 2. Ac2O, py

Scheme 28: Total synthesis of eburnamonine (158) 154

N

Et

Cbz N H

CH 2Cl 2 93%

Et 156

THF

H H N

Cbz N TsOH

Scheme 26: Formal synthesis of aspidopermidine (151) O

H

O

H N

CHO O

MeCN

-20 oC N H 162 TEOC

O

OR

CHO

N O

TEOC Ph 3P=CH 2 N THF, -78 oC

In the synthesis of aspidofractinine (142), D-A cyclopropane 143 was involved as crucial intermediate for solving a problematic dearomatization of the indole moiety. The advanced intermediate 143 containing D-A cyclopropane was prepared by copper catalyzed intramolecular cyclopropanation of the diazoketone 144. The diazoketone 144 in turn was prepared from the bromide 145 by reaction with ditosyl hydrazide in the presence of DBU. Radical cyclization on the D-A cyclopropane 143 installed the D ring of aspidofractinine (142). Reductive detosylation of the indole 146 with sodium

H N

N

O Et eburnamonine (158)

H

TEOC N

O 159

Et

Et

TBAF 4Å MS

Et

155

N

163

R = p-NO2C6H 4 N 161 Li

H Cbz N

H

EtOHH 2SO 4

H N

reflux O

164

N

CF3CO 2H

Et

N

N

C6H 6, reflux

H

O 160

Et

Synthesis of the pentacyclic framework of eburnamonine (158) was achieved using an intramolecular imino Diels-Alder reaction.22 The TEOC-protected D-A cyclopropane 159 was the key intermediate for the generation of the imino dienophile 160 required for the Diels-Alder reaction. The lithiated indole 161 was reacted with TEOC-protected cyclopropane 163 to get the amide 163, which upon Wittig reaction with methyl phosphonium ylide gave the

9 cyclopropane 159. Reaction of the exo D-A cyclopropane 159 with TBAF generated the imine 160 via regioselective cleavage of the cyclopropane bond sandwiched between the donor and acceptor moiety. Trapping of the imine intermediate of 160 by the diene moiety in the presence of trifluroacetic acid generated the pentacyclic framework 164, which upon isomerisation gave eburnamonine (158) (Scheme 28). Scheme 29: Total synthesis of eburnamonine (165) 168 Rh 2(esp) 2

O N

Br

CO 2Me

CH 2Cl 2 49%

167 N 2

O CO 2Me

N

Br

166 BocN In(OTf) 3 CH 2Cl 2 71%

N Boc 168

O H N O

N

1. TFA 87%

H

deethyleburnamonine (165)

N

Br

2. NaCl DMSO 85%

159

dr = 3:1

Scheme 30: Total synthesis of

(170)

DMB N

DMB N

O O

171

O

Rh 2(OAc) 4

172 N 2 +

N H

CO 2Me H

H BocN

O

pinacolone 120 oC, 62%

N H

N H

N H DMB N HO H N H

DMB N O

O

HO N H

N H

DMB N

N H

DMB N

O HO N

O

H

1.

+ N N H 173 H

corresponding pentacyclic compound, which on Krapcho decarboxylation produced the eburnamonine (165). Stoltz, Wood and coworkers accomplished the total synthesis of the bis-indole based natural product K252A (170) using intermolecular cyclopropanation of indole moiety and late stage glycosylation of an indolocarbazole unit.24 Their synthesis started with the cyclopropanation of 2,2’-bis-indole (171) with diazolactam 172 in the presence of rhodium(II) acetate in pinacolone to obtain the desired indolocarbazole 173 via sequential cyclopropanation, ring opening, 6π electrocyclic ring closure followed by dehydrative aromatization (Scheme 30). In this sequence some amount of hemiaminal 174 was also observed, which was again converted to 173 by reaction with camphor-sulphonic acid (CSA). Coupling of the indolocarbazole 173 with furanose fragment 175 using CSA followed by deprotection provided the K252a (170). 3. Conclusion This review has summarized application of oxygen and nitrogen substituted D-A cyclopropanes in the synthesis of various carbocycle, lactone and indole alkaloid based natural products. Heteroatom substituted D-A cyclopropanes served as important precursor in the synthesis of various architecturally complex natural products. Specifically, the regioselective ring opening strategies under suitable reaction conditions facilitate the cascade reactions to construct polycyclic skeletons. The reactivity of hetero atom substituted D-A cyclopropanes proved to be a valuable tool in current scenario for the synthesis of natural products. Acknowledgments We are grateful to the CSIR, New Delhi, MoES, New Delhi and IRCC, IIT Bombay for the award of a research fellowship to LNN. We thank SERB, New Delhi for funding. We thank Drs. Manoj K. Shukla and U. Vijayasree and Mr. Sumit P. Mane for their contribution in the D-A cyclopropane work. References and notes

174 N H CSA or xylene, heating

1. 175, CSA MeO 84 oC O 2. TFA Me OMe thioanisole MeO 2C r.t. OH 175 46% 2 steps

H N

N

O

N O

K252A (170)

Me MeO 2C

OH

2.

eburnamonine (165).23 The required precursor 166 was constructed by an intermolecular cyclopropanation of diazoester 167 and enamine 168 using Rh2(esp)2 as the catalyst. In(OTf)3 catalysed D-A cyclopropane ring opening followed by Friedel-Craft alkylation gave the tetracyclic framework 169 (Scheme 29). Removal of Boc and ring closure was effected using trifluoroacetic acid to furnish the

(a) Reissig, H. U.; Zimmer, R. Chem. Rev. 2003, 103, 1151. (b) Yu, M.; Pagenkopf, B. L. Tetrahedron 2005, 61, 321. (c) Carson, C. A.; Kerr, M. A. Chem. Soc. Rev. 2009, 38, 3051. (d) Lebold, T. P.; Kerr, M. A. Pure Appl. Chem. 2010, 82, 1797. (e) Mel’nikov, M. Y.; Budynina, E. M.; Ivanova, O. A.; Trushkov, I. V. Mendeleev Commun. 2011, 21, 293. (f) Wang, Z. W. Synlett 2012, 2311. (g) Tang, P.; Qin, Y. Synthesis 2012, 44, 2969. (h) Cavitt, M. A.; Phun, L. H.; France, S. Chem. Soc. Rev. 2014, 43, 804. (i) Schneider, T. F.; Kaschel, J.; Werz, D. B. Angew. Chem. Int. Ed. 2014, 53, 5504. (j) Grover, H. K.; Emmett, M, R.; Kerr, M. A. Org. Biomol. Chem. 2015, 13, 655. (k) O-Connor, N. R.; Wood, J. L.; Stoltz, B. M. Isr. J. Chem. 2016, 56, 431. (l) Rassadin, V. A.; Six, Y. Tetrahedron 2016, 72, 4701. (a) Schneider, T. F.; Dittrich, B.; Werz, D. B. Org. Lett. 2009, 11, 2317. (b) Brand, C.; Rauch, G.; Zanoni, M.; Dittrich, B.; Werz, D. B. J. Org. Chem. 2009, 74, 8779. (c) Schneider, T. F.; Kaschel, J.; Awan, S. I.; Dittrich, B.; Werz, D. B. Chem. Eur. J. 2010, 16, 11276. (d) Kaschel, J.; Schneider, T. F.; Kratzert, D.; Stalke, D.; Werz, D. B. Angew. Chem. Int. Ed. 2012, 51, 11153. (e) Kaschel, J.; Schmidt, C. D.; Mumby, M.; Kratzert, D.; Stalke, D. Werz, D. B. Chem. Commun. 2013, 49, 4403. (f) Kaschel, J.; Schneider, T. F.; Kratzert, K.; Stalke, D.; Werz, D. B. Org. Biomol. Chem. 2013, 11, 3494. (g) Grave, L. K. B.; Barkawitz, P.; Jones, P. G.; Werz, D. B. Org. Lett. 2014, 16, 5804. (h) Racine, S.; Nanteuil, F De.; Serrano, E.; Waser, J. Angew. Chem. Int. Ed. 2014, 53, 8484. (i) Grave, L. K. B.; Pawliczek, M.; Wallbaum, J.; Jones, P. G.; Werz, D. B. Chem. Eur. J. 2016, 22, 521.

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11 Highlights   

A review of O/N substituted D-A cyclopropanes in natural product total synthesis. Overview of different ring opening reactions of D-A cyclopropanes. D-A cyclopropanes in carbocycle, lactone, cyclic ether and alkaloid synthesis.