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Dec 16, 2014 - to involve tandem Michael/aldol addition of the α and α' carbons of 1 to enone 2 ... condensation with 1,3-diarylprop-2-enones 4a-g under basic.
Accepted Manuscript Digest Paper Formal carbo [3+3] annulation and its application in organic synthesis Jing Feng, Bo Liu PII: DOI: Reference:

S0040-4039(15)00050-7 http://dx.doi.org/10.1016/j.tetlet.2015.01.035 TETL 45705

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Tetrahedron Letters

Received Date: Revised Date: Accepted Date:

30 October 2014 16 December 2014 2 January 2015

Please cite this article as: Feng, J., Liu, B., Formal carbo [3+3] annulation and its application in organic synthesis, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.01.035

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Formal Carbo [3+3] Annulation and Its Application in Leave this area blank for abstract info. Organic Synthesis Jing Fenga and Bo Liua,b,* a Key Laboratory of Green Chemistry & Technology of Ministry of Education,College of Chemistry, Sichuan University, Chengdu 610064, China b State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China [3+3]

1

Tetrahedron Letters journal homepage: www.elsevi er.com

Formal Carbo [3+3] Annulation and Its Application in Organic Synthesis Jing Feng,a Bo Liua,b,∗ a

Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China

b

State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China

ARTICLE INFO

ABSTRACT

Article history: Received Received in revised form Accepted Available online

This review describes a set of approaches to generate functionalized carbocycles via [3+3] annulation and their usefulness for synthesizing frameworks of natural products. This approach relies heavily on the 1,3-dianion/1,3-dielectrophile strategy for annulations of ketones, enamines, 1,3bis(silyl enol ethers) and other 1,3-dianionic synthons.

Keywords: cyclization cycloaddition annulation [3+3] carbocycles

1. Contents Introduction……………………………………..…………..…. Type I: 1,3-dianion/1,3-dielectrophile strategy………………... α,α'-annulation of ketones……………………...………..… α,α'-annulation of enamines………………………………... α,γ-annulation of enamines………………………………. annulation of 1,3-bis(silyl enol ethers)……………………... annulation of other 1,3-dianionic synthons…………...……. Type II: Allylation/radical cyclization strategy………. Other annulation strategies…………………………………….. Conclusion……………………………………………………... Acknowledgement…………………………………………….. References……………………………………………………... 2. Introduction Six-membered carbocycles, which include cyclohexane, benzene and their derivatives, occur as structural cores in a variety of biologically and pharmaceutically active products. Examples of such products include (+)-pancratistatin1, (-)-tetrodotoxin2 and other nitrogen-containing polyhydroxylated cyclohexane derivatives, which display a range of biological antitumor, anti-ulcer,

——— ∗

Corresponding author. Tel./fax:+86 28 8541 3712 E-mail address: [email protected]

2014 Elsevier Ltd. All rights reserved

and anti-infective properties. The benzene derivative hyrangenol shows cytotoxic activity against human gastric cancer cell lines3, while the benzene derivatives thunberginols C, D and E promote adipogenesis in murine 3T3-L1 cells4. The importance of six-membered carbocycles in synthetic chemistry makes them attractive synthetic targets. Particularly noteworthy synthetic strategies involve Diels-Alder reaction ([4+2] fashion)5, Robinson annulation reaction6, double Michael cyclization ([4+2]7a-b and [5+1]7c), and [2+2+2] cycloaddition8. Although [3+3] annulation is widely used to construct heteroatom-containing six-membered rings,9a-d the carbo [3+3]9e reaction has rarely been reported in the literature. In 1979, Chan and coworkers applied the [3+3] reaction to arene synthesis,10a and much later Langer achieved TiCl4-catalyzed annulation of 1,3bis(silyl enol ethers) with 1,3-dielectrophiles using a variety of substrates and reaction conditions.10b Cyclohexane derivatives can be obtained via , '-annulation of enamines with biselectrophiles such as ethyl -(bromomethyl) acrylate11 and the substrate scope and efficiency of this reaction has been promoted rapidly along with the prosperity of organocatalysis12. These classic approaches to the carbo [3+3] reaction are increasingly inadequate for meeting the needs of modern chemistry. As a result, a wide array of organocatalytic, metal-catalyzed, and even co-catalyzed asymmetric [3+3] annulations have been developed. These methodologies can be classified according to the electronic properties of the two, three-carbon synthons that participate in the reaction (Figure 1). Type I carbo [3+3] annula-

2

Tetrahedron Letters

tions involve the one-step or stepwise coupling of 1,3-dianions with 1,3-dielectrophiles. Type II reactions involve the addition of anions to electrophiles, followed by free radical cyclization. Type I 1,3-dianion/1,3-dielectrophile strategy

Type II Allylation/radical cyclization strategy

Scheme 2. Katritzky’s [3+3] annulations In 1997, Katritzky discovered that benzotriazole acts as an efficient neutral leaving group. This helped them generate heteroaromatized pyridine derivatives from 2-(benzotriazol-1yl)acetamide and 2-(benzotriazol-1-yl)acetonitrile.14 It also allowed them to synthesize 3,5-diaryl-substituted phenols (Scheme 2).15 In this procedure, 1-(benzotriazol-1-yl)propan-2-one 5 was first prepared from bromoacetone with benzaltriazol, and then it was subjected to tandem Michael addition/intramolecular aldol condensation with 1,3-diarylprop-2-enones 4a-g under basic conditions. Subsequent leaving of benzotriazole gave the intermediates 6a-g. After rearrangement, the 3,5-diaryl-substituted phenols 7a-g were obtained in moderate to good yield. Electrondeficient Ar1 or Ar2 facilitated this reaction (7c-7f), while 2substituted Ar2 hindered it (7g).

Figure 1. Type I and II carbo [3+3] annulations 3. Type I: 1,3-dianion/1,3-dielectrophile strategy R

O

9, NaH, two drops water,THF, 50 oC, 75% O

8

H

+ CO 2Et

O OEt

6 : 1.5 : 2.5

, '-annulation of ketones O

O +

1) KOH, EtOH, 2 oC, 8 days 2) CH 2N 2

OH

Ph O

1

OH COOMe O

Ph

2

10a/b

H

1) NaBH4 AcO CeCl3 .7H2 O 2) Ac2 O-Py AcO 3) OsO4 -NMO 4) Ac2 O-Py

R

H

AcO

OAc

OAc

11

12

13

O

MeO R=

O RO P RO

O

In 1959, Jung reported his discovery of [3+3] annulation of cyclohexanone 1 with enone 2 in KOH/EtOH (Scheme 1).13 Subsequently esterification with diazomethane generated the more complex bicyclo[3,3,1] 3. The mechanism was postulated to involve tandem Michael/aldol addition of the and ' carbons of 1 to enone 2.

R1

R1 Ar

R2

NaOH/EtOH

Bt

+ O

2 Ar 2 R

Ar 1

O 5

4a-g

O 6a-g R1 2 Ar 2 R

Ar 1

N Bt=

N N 7a-g

OH a:

Ar 1

= Ph,

R1

=

R2

1

=H

75%

1

2

b: Ar = 4-MeO-Ph, R = 4-Me, R = H c:

Ar 1

= Ph,

R1

= 4-Cl,

R2

=H

e: f:

Ar1

= 4-Cl-Ph,

R1

= 1-naphthyl,

1

1

= 4-Cl,

R1

R2

76%

=H

= 3-NO2 , 2

72% 91%

d: Ar 1 = Ph, R1 = 4-NO 2, R2 = H Ar 1

R CO2 Et

OAc

O

Ar 1

H

AcO + CO2 Et AcO R

+ CO2 Et AcO

3

Scheme 1. Jung’s [3+3] annulation

2

10c

10b

10a

CO2 Et O

O

9

3.1

R

R

+ CO2 Et

O

Ph3 P

H

H R

g: Ar = Ph, R = 2-Cl, R = 4-Cl

R2

94% =H

82% 52%

O

O OEt

9a

Scheme 3. Sharma’s [3+3] annulation

In 2000, Sharma and co-workers reported their progress towards synthesizing the C-C linked pseudo-saccharide precursors 11-13 (Scheme 3).16a These reactions serve their larger goal of transforming sugars into C-glycosides, C-C linked disaccharides, and C-linked spiro saccharides. In their [3+3] approach, those authors used the more delocalized ylide 9 instead of the more nucleophilic phosphonate 9a, ensuring that Michael addition would precede Wittig olefination.16b During 3-oxo-4-(triphenylphosphorylidene)-butanoate 9 undergwent the Michael addition/intramolecular Wittig sequence with sugar-derived enal 8, 2 equiv of NaH was added and most importantly two drops of water were added to promote annulation.16b Because of the chirality of substrate, the tandem reaction produced 10a, 10b and 10c as a 6:1.5:2.5 mixture.17 Four-step transformation converted the mixture of major compounds 10a/b into the respective isolable six-membered rings 11, 12 and 13. Diphenylprolinol silyl ethers have attracted the interest of many chemists after being independently developed by Hayashi’s group18 and Jørgensen’s group19. In 2009, Hayashi and coworkers reported using tert-butyldimethylsilyl ether of diphenylprolinol 18 in the [3+3] annulation of , -unsaturated aldehyde 14 with dimethyl 3-oxopentanedioate 15 (Scheme 4).20 In this reaction, 15 undergoes enantioselective Michael addition to eniminium salts, produced in situ from 14 and 18, followed by hydration of enamines to give the aldehyde. Subsequent

3

intramolecular Knoevenagel condensation produced , unsaturated ketones 16, and reduction by NaBH4 afforded 17 in up to 99% ee. These results demonstrate the excellent stereocontrol of Michael addition. Various aromatic aldehydes proved compatible with the reaction. Neither electron-deficient nor electron-rich aromatic substituents significantly influenced the reaction. Interestingly, when 1.5 equiv of dimethyl 3oxopentanedioate 15 was added, the product 16 did not form but instead a single isomer with a structure similar to that of 24 was obtained in 51% yield.

excess equiv of 15 with Hayashi’s adduct 16 in the presence of piperidine. This approach generated the bicyclic [3,3,1] 24 in up to 93% yield with good enantioselectivity and diastereoselectivity.

O R

H 14 + O

O

O

MeO

OMe

H 14 +

O

O

10 mol% 18 20 mol% PhCOOH R DCM, r.t.

O

O

R 2) piperidine (20 mol%) MeOOC OMe M eOH, 40o C

O COOMe

R MeO

N H Ph 22

17 OMe

OMe

O

O

O

O2 N

OH MeO

O

OH MeO

17b, 74% (99%, ee)

O

OH

O

MeO

17d, 71% (96%, ee)

R MeOOC

Ph

OHCOOMe 24

Entry

R

Yield(%)

Dr

1

p-MeOPh

93

92:8

ee (%) 91

2

2-Furyl

86

94:6

90

3

o-BrPh

86

> 99:1

96

Scheme 6. Jørgensen’s tandem [3+3]/[3+3] annulations

O MeO

One-Pot

COOMe

17c, 77% (99%, ee)

OMe

O OH

Br

O

OMe

Cl

COOMe OTMS

O

OMe

17a, 75% (95%, ee)

HO

OH

16

OH

23

O

NaBH 4

O

15

MeO

COOMe

OMe

O

MeO

OMe

MeO

MeO

HO MeOOC

15 (2.0 equiv)

O R

1)10 mol% 22 10 mol% PhCOOH toluene, r.t.

OTBS N H Ph

O

Ph

3.2

, '-annulation of enamines

18

17e, 65% (94%, ee)

Scheme 4. Hayashi’s [3+3] annulation

Subsequently 16a was transformed into 19-21, demonstrating the usefulness of this reaction pathway for natural product synthesis (Scheme 5).

The , '-annulation of enamines with 1,3-dielectrophiles plays an important role in the construction of bicyclo[n.3.1] frameworks. Many chemists like Lawton11a and Stetter11b devoted a lot of attention to this chemistry and made substantial progress. Scheme 7 shows the steps in Lawton’s , '-annulation of enamines.

COOEt N

OMe O

3 steps Ph

O 19

Ph MeO

Br

COOEt O

OMe H

2 steps

O

O Ph

O 16a

MeO

( )n

H ( )n

OH O 20

Scheme 7. Lawton’s , '-annulation of enamines

4 steps

OH

Ph MeO

OTBS

OH O 21

Scheme 5. Further transformations of 16a

Several months earlier than the Hayashi group, Jørgensen and co-workers reported a similar catalytic reaction in 2008 (Scheme 6). They found that when 2 equiv of 15 reacted with 14 in the presence of (S)-(-)- , -diphenyl-2-pyrrolidinemethanol trimethylsilyl ether 22 and piperidine, the bicyclic[3,3,1] 24 was obtained instead of Hayashi’s adduct 16.21 Jørgensen’s strategy was to achieve in one pot via a relay Michael/aldol reaction using 1.0

In 2010, Grainger and co-workers exploited this chemistry to construct the highly substituted cyclohexane framework of phyllaemblic acid and glochicoccins B and D (Scheme 8).22 They used protected dihydroxyacetone in this procedure as well as a cyclic acetal protecting group, which ensured the desired relative chirality for the two oxygen substituents. The procedure involved the reaction of 1,3-dioxan-5-ones 25 with pyrrolidine to form enamines, which underwent Michael addition to ethyl (bromomethyl)acrylate. The newly generated iminium tautomerized into enamine, which underwent a second Michael addition intramolecularly to the in-situ generated , -unsaturated ester, affording the bicyclo[3.3.1] framework 27. Ketal 27a and benzylidene acetal 27b were obtained in nearly identical yield around 40%, while the ortho acetal 27c was obtained in 61% yield. The chirality of the acetal can be explained in terms of the chair-boat transition state 26: the phenyl group thermodynamically prefers to be farther from the pyrrolidine ring, while the

4

Tetrahedron Letters

methoxy group prefers to be closer because it creates an additional anomeric stabilizing interaction. The relative chirality of the ester group reflects the kinetic protonation of the reaction.

COOMe O

O

1)

2)

N

N H

COOMe

Br

O

O H

O

R1 R2

O

H O

TEA

R1 R2

25

went conjugate addition to enone 29, followed by tautomerization from imine to enamine. Intramolecular trapping of enamine 30 generated imine 31a, which was reduced by NaBH4 to the tricyclic amino alcohol 32. This compound contains the same tricyclic amino alcohol framework as galbulimima alkaloid and himandrine, promoting the authors to propose that modifying the initial reagents slightly could lead to these natural products.

O

R 1 R2 27

OH

O N

1) L-proline, CHCl3, 45 oC, 50% 2) DBU, EtOH, 78oC, 80%

+ COOMe

COOMe

COOMe

O

O

O

H

H

H O

H

O

O

O

H

Ph

H

H O

MeO

O

(-)-31b

R2

O 26

27c, 61%

Scheme 10. Movassaghi’s asymmetric annulation

26b R1 = H, R2 = Ph 26c R 1 = OMe, R 2 = Me

The same research group also reported the catalytic asymmetric synthesis of 31. Imine 33, rather than iminium chloride 28, underwent asymmetric Michael addition with enone 29 in the presence of L-proline catalyst. Subsequent treatment with DBU afforded (-)-31b with 52% ee. After recrystallization, (-) -31b was obtained with 90% ee, meeting the significant requirements of total synthesis (Scheme 10).

R1

OH OH O

52% ee, recrystallization 90% ee, 51% yield

R1 O

O O

O O R OOC H R 1 = H, R 2 = H, Phyllaemblic acid R 1 = H, R 2 = Me, Phyllaemblic acid methyl ester R 1 = OH, R 2 = H, Glochicoccin D R 1 = OH, R 2 = Me, Glochicoccin B 2

16

t

BuO

O H N

O

N

O

H +

O

n-BuLi, Me2S CuBr

NHNS

O

COOtBu

COO tBu 6

HCl, THF/H 2O

Scheme 8. Grainger’s , '-annulation of enamines

Cl

H

N

29

N

O

MeO

27b, 41%

27a, 40%

33

Et3N H

H

13

OH

O

92%

NH

NH

NHNS

NHNS

34

35

36

NH O

28

29

N

30

4 steps

13

Me

HO

H

H

NaBH 4

H

HO H

N

4 10

(+)-Fastigiatine

H N

NH

Scheme 11. Shair’s total synthesis of (+)-fastigiatine

31a

32 HO H

H

HO H

H

H

H H

H

H N O

H OMe OBz OMe

himandrine

NH

H O

galbulimima alkaloid

Scheme 9. Movassaghi’s , '-annulation of enamines

Given that ethyl -(bromomethyl)acrylate works well as the 1,3-dielectrophile in these annulation reactions, researchers have also screened enones as possible alternative 1,3-dielectrophiles. In 2007, Movassaghi and co-workers reported the framework synthesis of galbulimima alkaloid and himandrine,23 in which formal [3+3] annulation of cyclic enamines with enones played a vital role (Scheme 9). Iminium chloride 28 was transformed into cuprate reagent24 using n-BuLi and CuBr•Me2S, and this under-

In addition to a polycyclic architecture similar to those of other lycopodium alkaloids, (+)-fastigiatine contains an unprecedented pentacyclic core with a C4-C10 bond. In 2010, Shair and co-workers reported the first synthesis of the lycopodium alkaloid (+)-fastigiatine, for which they used a similar [3+3] strategy (Scheme 11) to the one above (Scheme 9).25 Deprotecting 34 using hydrochloric acid generated the , -unsaturated ketone 35 in situ. The C6 of the enamine underwent 7-endo-trig Michael addition, and aldol addition of the enamine (generated in situ from imine) to C13 formed product 36. After a straightforward four-step transformation, (+)-fastigiatine was accomplished in 15 steps with nearly 30% overall yield. The Michael addition was highly diastereoselective, probably due to its axial addition anti to the C16 methyl group. Inspired by Jung’s work13 (Scheme 1), Tang and his coworkers changed the 1,3-dielectrophiles of Lawton’s work into enone esters, and invented the asymmetric version by using N-

5

(pyrrolidin-2-ylmethyl)-trifluoromethanesulfonamide 39 as the catalyst (Table 1).26 Various cyclic ketones 37 and enone esters 38 were examined. The ester group exerted little influence on yield or enantioselectivity (Table 1, entries 1-3), whereas the X group of cyclic ketones and the R1 group of enone esters substantially influenced the reaction.

NHTf O

O 2

COOR +

HO

37

NO2

R1

R 2OOC

O

O

H

+ X

38

40

entry

product

1

X=CH2, R1=Ph, R2=Me 1

yield(%)

ee(%)

80

90

2

2

X=CH2, R =Ph, R =Et

74

91

3

X=CH2, R1=Ph, R2=Bn

76

91

77

87

1

2

X=CH2, R =p-MeO-Ph, R =Me

4

R

X 37

5

X=CH2, R1=p-Me-Ph, R2=Me

80

90

6

X=CH2, R1=p-Br-Ph, R2=Me

77

90

7

X=CH2, R1=Me, R2=Et

56

94

8

X=O, R1=Ph, R2=Me

66

90

9

1

X=N(Me), R =Ph, R =Me

92

H

(20 mol%) neat / rt

OAc

O H 46

X

44

up to 98% ee Br O2 N O

O H

Br

NO2

Br

NO2

H

H

H O

46a 77% yield 96% ee

46b 94% yield 93% ee

46c 0 CF3

S

NH

2

R

45 (20 mol%) p-MeO-C 6 H4 -COOH

NO2

H

(20 mol%) neat / rt

R1

X

39

N (20 mol%) H p-MeO-C6H4-COOH

(Scheme 12), 46c were even not detected. These results suggest that these asymmetric [3+3] annulation are more likely to form bicyclo[3,3,1] (Table 1, entry 1-9 and Scheme 13, 46a) than bicycle[3,2,1] (Scheme 12, 42 and Scheme 13, 46b) or sixmembered ring (Scheme 12, 43 and Scheme 13, 46c), making this approach potentially powerful for constructing nitrogensubstituted six-membered rings.

N H

80

N H

CF3

45

Scheme 13. Tang’s organocatalytic [3+3] annulation involving pyrrolidine-thiourea

Table 1. Tang’s organocatalytic [3+3] annulation

Cyclopentanone and acyclic acetone were also tested with enone ester 41. Unfortunately, the ee value of 42 declined significantly, while acetone only give the 1,2-addition product (Scheme 12).

It may be possible to use metal−allenylidenes generated from propargyl alcohols or their derivatives as 1,3-dielectrophiles in this reaction. Theoretical and experimental studies indicate that these compounds have electrophilic centers on C and C .

NHTf HO O

O COOMe + Ph

41

N (20 mol%) H p-MeO-C6 H4 -COOH (20 mol%) neat / rt

MeOOC

Ph

NEt2

OAc

O

+ H

H

H

42 yield: 98%, ee: 64%

X

47

O Cu(OAc) 2. H 2O(5 mol%) L1 (5.5 mol%) DIPEA(1.2 equiv) MeOH, r.t., 12h

48

O COOMe + Ph

41

N (20 mol%) H p-MeO-C6 H4 -COOH (20 mol%) neat / rt

O HO

COOMe

Ph 43 yield: 99%, ee: 14%

X endo-adduct 49a

entry

X

yield (%)

endo/exo

1 2 3 4 5

X=O X=CH(CH3) X=CH(OMe) X=CH(tBu) X=-OCH2CH2O-

78 84 60 74 76

> 98:2 > 98:2 > 98:2 > 98:2 > 98:2

Scheme 12. Tang’s organocatalytic [3+3] annualation of cyclopentanone and acetone

N

Ph

+

NHTf

O

O

Ph

X exo-adduct 49b

ee of endo product (%) 93 89 95 81 98

N

PPh2

In 2009, Tang extended the scope of enone esters in this reaction to include (E)-2-nitroallylic acetates, which have properties similar to those of ethyl -(bromomethyl)acrylate (Scheme 13).27 Pyrrolidine-thiourea 45 proved to be more efficient than catalyst 39 (Table 1), giving the bicyclic[3,3,1] 46 in up to 98% ee. As in previous work (42 in Scheme 12 vs entry 1 in Table 1), the bicyclo[3,2,1] 46b was obtained in higher yield than 46a but with slightly lower enantioselectivity. Similar to the low levels of 43

Fe (Rc,Sp)-6 L1

Table 2. Hu’s metal-catalyzed [3+3] annulation In 2012, Hu and co-workers exploited this possibility to make substantial progress towards constructing the bicyclo[2,3,1],

6

Tetrahedron Letters

bicyclo[3,3,1] and bicyclo[4,3,1] skeleton via an asymmetric [3+3] strategy (Table 2, Scheme 14 and Scheme 15).28 This procedure involved , ’-annulation of enamines via a metalallenylidene intermediate generated from propargyl alcohol derivative 47. As the mechanism (Scheme 15) showed, nucleophilic attack of enamines 48 afford Cu-acetylide complex 50b, which underwent H shift to give Cu-vinylidene complex 50c. Further intramolecular nucleophilic attack finished the [3+3] annulation. And the combination of Cu(OAc)2•H2O and chiral tridentate ferrocenyl-P,N,N ligand L1 gave the endo-adduct 49a in moderate to good yield with good enantioselectivity and excellent endo-selectivity.

on gram scale from 56b and 57 in seven steps with 10% overall yield.

OAc

OH HO O NH

O

O

OEt

(+)-Pancratistatin

O

H

O

51

O OTBS

N O NH H

Ar

+

AcO

O

O

Et2 N

Et2N

Ph

X

CH C X CuL 50c

Et2N

X 50b

48

Ph

Et2N

O

PPTS, DMF

CuL X 50e

O

O

OH

58b 42% yield

O O

O

O

O

OH NO2

O OMe

Scheme 15. The mechanism of Hu’s metal-catalyzed [3+3] annulation

O

NO2

O

49a X CuL 50d

OH

O OH

O

O

NO 2 58

58a 38% yield

Ph

Ar

O

NO2 CuL

O

O

O

O

H shift

50a

Ph

Ph

+ H

H

Ph 47

N O NH H 6-epi-55

57

O

DIPEA

O O OTBS

N H

CHO

56

Scheme 14. Hu’s metal-catalyzed [3+3] annulation of 50

NEt2

O

Figure 2. Natural products containing highly oxygenated sixmembered rings.

NO 2

C C

(-)-Tetrodotoxin

O

endo 54, 48% yield, 98% ee, endo/exo > 98/2

CuL

AcO (MeO) 2HC BocHN

base free, r.t.

CuL

OH

Ph

52b

H

NH 2

OMe

O

55

NEt2

OH

N H N HO H

HO

OMe

Ph

endo 53, 50% yield, 98% ee, endo/exo > 98/2

Cu(OAc)2 .H2 O (5 mol%) L1 (5mol%) EtOH

OAc

O (+/-)-7-Deoxy-2-epiPancratistatin teraacetate

DIPEA, 0o C O

O O O OH

NH

O

O

BocHN

O 52a

O

OH

OH

OAc

H

H

HO (MeO) 2HC

NEt2

AcO

OH

58c 30% yield

O

OH NO2 58d 33% yield

Scheme 16. Alonso’s pyrrolidine-catalyzed [3+3] annulation These standard conditions need to be modified slightly when using enamines 52a and 52b in the reaction. More reactive 51 should be used instead of propargyl alcohol acetate 47, and the base, temperature and solvent need to be adjusted (Scheme 14). Nitro-enals also show promise as 1,3-dielectrophiles for this reaction. Alonso and co-workers reported a general method to synthesize -(hetero)aryl- -nitro- , -enals in 2008.29 In 2006, Alonso and co-workers used , ’-annulation of enamines to construct the polyhydroxylated cyclohexane ring of the potential antitumor agent (+)-pancratistatin (Figure 2).30 They utilized the -(hetero)aryl- -nitro- , -enal 56 as biselectrophile, while commercially available 2,2-dimethyl-1,3-dioxan-5-one 57 reacted with pyrrolidine to form the enamine. Fortunately, nitroenals 56 reacted with enamine in the presence of PPTS, creating five stereocenters in one step (Scheme 16). This method led to 58b in 42% yield. After further six-step transformations, (+/-)-7deoxy-2-epi-pancratistatin tetraacetate (Figure 2) was prepared

Alonso’s group later resorted to enantioselective [3+3] annulation.31 After screening various catalysts, such as proline and its derivatives, (R)-2-(methoxymethyl)-pyrrolidine was found to be the best, giving 58c in 75% ee and up to 99% ee after crystallization (Scheme 17). After further eight-step transformations, (+)pancratistatin was produced from 57 and 56c in nine steps. Since 58b was produced in up to 99% ee after crystallization under standard conditions, it is assumed that (+)-7-deoxypancratistatins can be synthesized in the same way. Using this methodology, Alonso and co-workers completed the total synthesis of (±)-tetrodotoxin (Figure 2) in 201032 and developed a concise pathway to the dioxaadamantane core (55 and 6-epi-55) (Figure 2) of (±)-tetrodotoxin in 2014.33

7

N H O

O

O

O

O

OMe O

O

OH

CHO

O 57

the (Z)-TS (Figure 3), forming the chiral methyl center in the (s)adduct. This mechanism may reflect high energy due to steric hindrance in (Z)-TS. Subsequent intramolecular aldol addition of enamine to carbonyl gave aldehyde 59/60 (50:44) along with little aromatic product 61 through dehydroxylation and aromatization. Aldehydes 59 and 60 are important intermediates in the total synthesis of (-)-isopulegol hydrate and (-)-cubebaol, respectively.

NO 2

O

O OMe

8 steps 58c OMe 38% yield, 75% ee, >99% ee, after crystallization

NO2 56c

(+)-Pancratistatin (+)- 7-deoxypancratistatins

O O

O

N H

CHO

O

OH NO 2

O

58b

NO2

O

O

O

OMe

O 57

O

In 2007, Hong and co-workers systematically studied [3+3] and [4+2] approaches to synthesizing aromatic aldehydes (Table 4).35 In that study, two catalyst systems were tested on various , -unsaturated aldehydes; the combination of pyrrolidine with acetic acid gave much higher yield and selectivity of the [3+3] annulation reaction than proline did. The results also showed that the R3 group exerts little influence on selectivity (Table 3, entries 1-3), whereas R1 and R2 groups play a decisive role (Table 4, entries 4-6).

39% yield, 51% ee, >99% ee, after crystallization

56b

1

R

Scheme 17. Alonso’s total synthesis of (+)-pancratistatin

2

1

7 CHO

+

3

R

1

6 5

62

63

Method

1

R1=R2=H, R3=CH3 R1=R2=H, R3=Ph R1=R2=H, R3=Ph R1=H, R2=CH3, R3=Et R1=H, R2=Pr, R3=Bu 1 R =CH3, R2=H, R3=Ph

Method A

CHO

N H

CHO

COOH

CHO OH

CHO

+

DMF, -10 oC

4

OH +

5

60

59 80% ee

61

6

95% ee 73% (50 : 44 : 6)

OH

OH

1

5

6 5

Method C Method C Method C Method B

3

R1 [4+2] 65

cat. I Yield (%) (64:65) 81% (96:4) 78% (100:0) 80% (100:0) 75% (82:18) 71% (10:90) 86% (0:100)

Method A

2

R2 4

64

aldehyde

6

3

R3 [3+3]

entry

3

R

7

3

R2 4

R3

R2 4

2

CHO

2

3.3 α,γ-annulation of enamines Since the enamines generated by ketones can undergo , ’annulation with 1,3-dielectrophiles, the enamines made from , unsaturated aldehydes should also act as 1,3-dianions at C and C .

7

CHO

1

CHO

cat. II Yield (%) (64:65) 20% (100:0) 23% (100:0) 40% ( 48:52) 80% (16:74) 75% (1:99) ND

Reagents and Conditions: Method A: catalyst, CH 3CN, 25 oC. Method B; catalyst, MnO2 , MeCN, reflux. Method C: (1) catalyst, CH3 CN, 25o C and (2) DDQ, C 6 H6 , reflux.

OH

OH and

O

+ (-)-Isopulegol hydrate

N H

(-)-Cubebaol

I

Scheme 18. Hong’s , -annulation of enamines

H O N

O H

O H

H O

O N

N

O

H

H

O H

vs

3.4 Annulations of 1,3-bis(silyl enol ethers)

O HOOC

N

N

O

H

(Z)-TS

II

Table 3. Hong’s comparison of [3+3] and [4+2] annulations

H (E)-TS

COOH

N H

OH

(s)- adduct

Langer and co-workers capitalized on Chan’s [3+3] annulation involving 1,3-bis(silyl enol ethers) 67 with 1,3-dielectrophile 66 to form arenes (Scheme 19).10 They used this approach to construct various highly functionalized arenes, which they reported in 2006.11

Figure 3. Mechanism of Hong’s [3+3] annulation OMe OMe MeO

In 2006, Hong and co-workers reported the first asymmetric [3+3] self-condensation of crotonaldehyde (Scheme 18).34 The enamine reacted with the iminium through the (E)-TS instead of

OMe 66

TMS

O

O TMS

+ OMe

TiCl4, CH2 Cl2 , -78o C to 20oC

OH COOMe

55%

67

Scheme 19. Chan’s [3+3] annulation

68

8

Tetrahedron Letters 3.5 Annulations of other 1,3-dianionic synthons OH

TMS

O

O

OH Ph

TMS

O

+

OMe

67 OH

R

(2) Na2 CO3,H 2O 52%

OMe

Ph

OH

OH

O

O

O

Cl2 Ti O

69

TMS

O

O

Cl

OMe TiCl2 O

71

Ph 72c

Utilizing this [3+3] strategy, Langer and his colleagues synthesized the framework of hyrangenol and thunberginol C and D in 2008. They used 1,3-bis(silyl enol ether) 67 with 1,3dielectrophile 69, which was obtained from acetylacetone and benzaldehe in two steps (Scheme 20).36 In the same year, the same research group synthesized the framework of the dye Alizarin Yellow R using diazene 73 as the 1,3-dielectrophile (Scheme 21).37 Diazene 73 was prepared from aniline in two steps. A possible mechanism for the formation of 71 is outlined in Scheme 20. The more reactive terminal carbon atom of 67 undergoes conjugate addition to 69, followed by cyclization to give intermediate 72c. The SN2 reaction of the chloride anion with the carbon atom which attached to the phenyl group generates the product 71. COOMe

TMS

O

TMS N

N

O

O TMS

Ph +

OMe 67

73

H

O CHO H

3

CHO O

R3

R2

OH

R1

H 78

77

product

yield(%)

de

OH H

50

4.9:1

OH H

52

9:1

60

9:1

HO H

HO H

HO

OH

Table 4. Molander’s [3+3] annulations

Scheme 20. Langer’s [3+3] annulation strategy to framework synthesis of hyrangenol and thunberginol

O

2

O

72b

O O

O H CHO

HO

3

H

Cl2 Ti O Ph

72a

substrate

H3C

Ph

Ph

OTMS

R

R2

SiMe3 THF 76

1

OMe

O

SnF2

H3C

71

OMe

O

entry O O

Hyrangenol (R1 = H, R 2 = H) Thunberginol C (R1 = OH, R 2 = H) Thunberginol D (R1 = OH, R 2 = OH)

R3 + CHO I

O

Me 3Si F

SiO2, wet THF, 14h, 69%

R2

R1

TiCl4 TMS

75

O O

+

70

O

R2

Cl

Sn

R1 1

69

67

O

(1) TiCl4,DCM, -78o C-20 oC

O TMS

(1) TiCl4,DCM, -78oC-20 oC (2) Na2CO3,H 2O 66%

HO N

N

Ph

74

COOH HO N

N COOH

Alizarin Yellow R

Scheme 21. Langer’s [3+3] annulation strategy to framework synthesis of alizarin yellow R

In 1987, Molander and co-workers reported a stereocontrolled [3+3] approach to six-membered carbocyles. They first prepared epoxy aldehyde 75 by Sharpless asymmetric epoxidation/Swern oxidation of allylic alcohol, then treated it with 3-iodo-2-[(trimethylsilyl)methyl]propene 76 in the presence of SnF238 (Table 4).39 The allytin trihalide generated from 76 and SnF2, which underwent an aldol reaction with the carbonyl in the Felkin-Ahn fashion with good diastereo-selectivity. Then the Sn4+ and F- co-catalyzed nucleophillic addition of allylsilane to the epoxide ring. The six-membered 78 was generated in moderate yield with moderate to good selectivity. Consistent with the the fact that the reaction proceeds through intermediate 77, stereo-controlling on the annulation reaction was easier using E epoxides (entries 2 and 3) than Z epoxides (entry 1), which displays lower diastero-selectivity due to steric hindrance. In 2001, Ila and Junjappa wrote a mini-review on the synthesis of naphthalenes and other condensed aromatic rings via treatment of -oxoketene dithioacetals 79 with allyl anions and Lewis acid (Scheme 22).40 In this approach, allyl metal anions (Grignard and lithium reagents) underwent 1,2-addition or sequential 1,4- and 1,2-addition to form carbinols 80a and 80b. After cycloaromatization in the presence of BF3•Et2O, carbinols 80a/b were transformed into the corresponding arenes.41 The regioselectivity of the allyl anions may be attributed to the hardsoft match principle as well as to steric effects. Organocuprate reagents promoted a one-pot addition-cycloaromatization reaction in the presence of TMSCl and TMEDA. In contrast, the stabilized benzyl carbanions derived from arylacetonitriles or benzyl phenyl sulphones underwent only 1,4-addition to give carbinols 80c, which cycloaromatized in the presence of H3PO4. In the case of -oxodithioacetals 81, obtained by reducing αoxoketene dithioacetals 80, only 1,2-addition occurred and the corresponding carbinol 80d was transformed into naphthalene via the same Lewis acid-catalyzed cycloaromatization.

9 SMe R2

MgBr 1,2-addition

R1

MgCl sequential 1,4- and 1,2-addition

SMe R2 R1

SMe

SMe

Ph

NO2

NO2

NH2 v

iii, iv

(dr = 90:10) (ee = 94%)

O

X

MeO

R1

OMe

MeO

86

OMe

MeO

87

OMe 88

O

SMe

NH

R2

N

R1

COOH

COOH

Trandolapril

MgCl

SMe R2

1,2-addition

R1

81

OH

Reagents and conditions: (i) NaOH, MeNO2 , 3h; (ii) 84, 85, CH 2 Cl2/EtOH, 64% (2 steps); (iii) Cs 2 CO3 , THF/DMF(3/1); (iv) DBU, CH 3 CN, -40o C, 60% (2 steps); (v) H2 , Pd/C, MeOH, 98%.

SMe

SMe BF .Et O/ 3 2 Ph C 6 H6 /

SMe R2

N Ar 85 H Ar Ar = 3,5-(CF3 )2C6 H3

80c

CuCl/TMSCl/ TMEDA 1,4-addition

R1

O

MgCl

NaBH4 /AcOH

R2

X H PO / 3 4

R1

PTO 2S

SMe

SMe

NaH/DMF 1,4-addition X=CN, SO2 Ph

OTMS

ii

83

CH2 Ph

R1

OMe

NO2

R2

80b

R2

PTO 2S

82

SMe BF .Et O/ 3 2 Ph C 6H 6/ OH

84

i

SO2PT

R1

CH2 Ph

R1

OMe

R2

80a

R2

X

O 79

O

SMe BF .Et O/ 3 2 C6 H 6/ OH

O

SMe

80d

R2 R1

Scheme 23. Cid’s synthesis of trandolapril MgCl

Li

1,2-addtion

Pre-bis(nucleophile) 83 was prepared from sulfone 82 in 90% yield, and it underwent asymmetric Michael addition with , unsaturated aldehyde 84 via iminium activation in the presence of diphenylprolinol silyl ether 85 (Scheme 23). Subsequent intramolecular Julia−Kocienski olefination in the presence of Cs2CO3 generated olefin 87. Using DBU and low temperature significantly increased the diastereoselectivity. Reduction by H2 afforded amine 88 in 98% ee and 90:10 de, demonstrating absolute stereocontrol of Michael addition and the importance of DBU. This stepwise Michael addition/intramolecular Julia−Kocienski olefination generated the cyclohexenylamine moieties 88 from 82 in five steps with perfect enantioselectivity, satisfying the requirements of the enantioselective synthesis of trandolapril (Scheme 23). This approach is more efficient than the low-yield Diels-Alder reaction and subsequent enzymatic resolution of the racemate.43b

Li

MgCl

MgCl

OMe MgCl

X

O OMe

OMe

O

X = H, OMe

sequential 1,4-and 1,2addition

MgCl

Li

Scheme 22. Ila and Junjappa’s [3+3] annulations Cyclohexenylamine moieties are important synthons in the preparation of various natural products. While [4+2] annulations of non-activated dienes with nitroalkenes require harsh conditions,42a introducing an electron-withdrawing group allows the reaction to proceed efficiently under mild conditions.42b,c However, this group must subsequently be removed, so identifying mild, efficient ways to do so should be a priority for future investigation. In 2013, Cid and co-workers reported their investigations into a new asymmetric [3+3] procedure to generate this moiety (Figure 4).43a

( )m

( )m O

SiMe3

O R

R

[3+2]

( )n

( )n

[3+3]

( )n I

R

OH R O

89

( )n

R ( )n

Scheme 24. Li’s [3+2] and [3+3] annulation strategy R

O2 N

[3+3] Michael addition

O

SO2PT

R = Aryl, allkyl

Intramolecular Julia-Kocienshi Olefination

[4+2] R NO 2

Diels-Alder reaction

R

NO2

PT = Phenyltetraazoa

Figure 4. Cid’s [3+3] annulation strategy to cyclohexenylamines

In 2013, Li and co-workers accomplished the total synthesis of (±)-hirsutene and (±)-capnellene via [3+2] annulations (Scheme 24).44 In this approach, the key intermediate 89 acted as both anion synthon and electrophile synthon at different stages. In the [3+3] approach, it can also serve as 1,3-dianionic synthon to react with methyl acrylate and construct the framework 94a of eudesmane sesquiterpene.

10

Tetrahedron Letters SiMe 3

SiMe3

O

i

2 steps

I

90

MeOOC

91

92

to this synthetic route: sulfide 101a was oxidized into sulphone 101b, increasing the yield to 60% (Scheme 27).47 They also systematically studied the unusual 6-endo-trig radical cyclization, and found that introducing R3Sn, PhSO2, or PhS may activate the olefin to generate the 6-endo-trig product.47

ii

OH

OH

iii-a or iii-b

+ H 94a

MeO

Br

SPh TMS

95

H

SPh

96

93

97

MeO

Reagents and conditions: (i) CH2 =CHCOOMe, NiCl2 .6H2 O, Zn, pyridine, 80%; (ii) Dibal-H, 90%; (iii-a) SnCl4, CH 2ClCH2 Cl, -20 oC, 61% (94a only); (iii-b) SnCl4, CH 2 Cl2 , -90o C,52% (94a/94b = 1:3).

(Bu3 Sn) 2, hv (Hg lamp), PhH, 10oC, 35% 98

Scheme 25. Li’s synthesis of intermediate 94a

Allysilane 91, which is easily prepared from readily available (+)-carvone derivative 90, underwent coupling with methyl acrylate in the presence of Ni(0)−pyridine catalyst to afford ester 92 in 80% yield. Subsequent reduction by Dibal-H generated aldehyde 93, which underwent SnCl4-catalyzed aldol reaction with allylsilane to form 94a/94b. Interestingly, solvent and temperature played a vital role in this transformation: 94a was produced in 61% yield only if 1,2-dichloroethane was used as the solvent and the temperature was -20oC; 94a/94b (1:3) was produced in 52% yield with dichloromethane solvent at -90oC (Scheme 25).

Scheme 26. Ward’s [3+3] annulation

O 96

O

O N

O

OR

O

TiCl4, 90%

OR

R = TBDMS SPh 100

99

Z 101a Z=SPh 101b Z=SO 2Ph hv (Me3Sn) 2 Ph2CO

HO

H

NH-(L)-Ala R1

OH

O

R2

O

4. Type II: Allylation/radical cyclization strategy

O

H

O

NHPMS O

O

O

H HN O

O

Actinobin R 1=Me, R2 =H Bactoblin R1 =CHCl2 , R 2=Me

OH

O 102 41% from 101a 60% from 101b

103

In 1994, Ward and co-workers applied this method to the synthesis of (+)-actinobolin and bactobolin (Scheme 27).46 Aldehyde 99 underwent the “two electron” process with 3-phenylthio-2(trimethyl-silylmethyl)-propene 96 to give alcohol 100 with chelation-controlled selectivity. Several subsequent transformations led to 101a. The “one electron” process under hv generated the cyclization product 102 in 40% yield with excellent diastereoselectivity. A further three-step transformation afforded 103, which is the key precursor of (+)-actinobolin and bactobolin. One year later, the group announced a modification

O

O

O

SPh TMS O

O

S

OBn RN HO

OBn RN

HO

While Type I approaches to [3+3] annulation involve 1,3dianions and 1,3-dielectrophiles, an alternative strategy is a sequence of Lewis acid-catalyzed allylation and free radial mediated annulation. In 1991, Ward and co-workers reported the application of the conjunction reagent 3-phenylthio-2(trimethylsilylmethyl)-propene 96. This compound underwent TiCl4-mediated allylation with acetal 95 in a so-called “two electron” process that formed 97. Subsequent free radical-mediated cyclization, as a so-called “one electron” process, ultimately afforded 98 (Scheme 26).45 These two steps generated a sixmembered ring. The regioselectivity (6-endo-dig vs 5-exo-trig) may reflect the importance of the phenylthiomethyl substituent on the olefin and the chairlike transition states. Attempts to alter the substituents on 95 and the reaction temperature gave disappointing results, particularly because of the low selectivity.

Br

TiCl4 , 95%

+

OHC

94b

MeO

OMe

SiMe 3

Scheme 27. Ward’s synthesis of (+)-actinobolin and bactobolin

5. Other annulation strategies O

O

O CH3 R 2

Me3 Si

+ 104

R1

SiMe 3 C

H

CH 3 105

TiCl4, CH2 Cl2

H 3C

SiMe3

R

2

2

R = Me, R = H

1

SiMe3 R2 107

R2 106

R = H, R = Me 1

CH 3

+ R1

R 1 = H, R2 = H 1

H3 C

CH3

56% 41% (70 : 30) 66% (57 : 43)

Scheme 28. Danheiser’s [3+3] annualtion

In 1995, Danheiser and co-workers discovered that TiCl4 catalyzes the [3+3] cyclization of 2-alkyl-substituted , -unsaturated acylsilanes 104 with allenylsilanes 105 (Scheme 28).48 One possible mechanism occurs as follows (Scheme 29): the Michael addition of allenylsilane 105 to , -unsaturated acylsilane 104 gives vinyl cation 108, and the subsequent 1,2-TMS shift and

11

intramolecular cyclization lead to intermediate 110. Ring expansion occurs via vinyl shift to the carbonyl, and the newly generated cation 111 undergoes the second TMS shift, followed by desilylation to give the [3+3] products 106 and 107.

120a/120b in the presence of TEA after standard [3+3] reaction conditions (Scheme 31). Even more complex and novel structures have been obtained in a similar manner. CHO

CHO H

OTiCl3 104 + 105

R1

R

SiMe3

108 Me3Si

O

R1

R1

R2

i, ii

nBu

SiMe3 109

+

Ph nBu

Ph 119 OAc TMS

OMe 118

120b (20%)

120a (56%)

Reagents and Conditions: i) 119 (1.0 equiv), PPh3 AuSbF 6 (5 mol%), CH2 Cl2 , 25o C, 30min. ii) Et3 N (10 mol%), 60oC, 2h.

1,2-TMS shift 106+ 107

SiMe3

Me3 Si

OTiCl3

2

H

H

Ph OMe

R1 R2

Cl3 Ti

C

OTiCl3 1,2-TMS Me Si 3 shift

Me3 Si

nBu

Scheme 31. Liu’s [3+3] annulation to aldehyde

SiMe3 R2

110

111

Scheme 29. Possible mechanism of Danheiser’s formal [3+3] annulation

Interestingly, the vinyl shift from 110 to 111 would be interrupted to give the [3+2] annulation products if changing 104 into t-butyldimethyl acylsilane, minimizing the reaction time (20:1

124 [Au]

iso 122c 80% yield, 42% ee

TMS 2.0 equiv

113

3% 1:1

R1

R2 R2

HO

Ar

H

OH MeO

PAr2

MeO

PAr2

i

Pr CHO

OMe 116

117

iso 122d 82% yield, 36% ee

82% d.r. >20:1

HO Ph

*

*

115

114 1.0 equiv

Ph

iso 122b 89% yield, 32% ee

H +

OMe 112

iso 122a 80% yield, 42%ee

Ph

122

L2 Ar 2 = 3,5-Me2 C6 H3

O

N2

O HO Isoprekinamycin

Dichroanal B

Scheme 30. Liu’s [3+3] annulation one more equiv of 113 is added, 117 can capture another molecule 113 to form 115. The innate chirality of 117 seems the most likely reason for the diastereoselectivity of 115. Using 2siloxymethylallylsilane 119 instead of 113 gave the aldehyde

Scheme 32. Aanz’s [3+3] annulation of o-alkynylstyrenes

Like benzo[α]fluorenes, carbazoles are also widespread in various biological natural products, such as tubingensin A, clausenine, clausenol and P7C3 (Figure 5).52 They also play an

12

Tetrahedron Letters

important role in photorefractive materials and organic dyes. In 2014, Wang and co-workers reported a novel Yb(OTf)3catalyzed [3+3] strategy to generate these structures.53

described above. Various propargylic alcohols were screened in the reaction with 125 or 133, and moderate to good yield was obtained. 6. Conclusions

Br OH

This review gives an overview of the formal carbo [3+3] strategy to form six-membered carbocyles. The , '-annulations of ketones or enamines illustrate the power of this tool in organic chemistry. Though this reaction has long been known, new progress on asymmetric annulations make it more attractive to synthetic chemists. The biological usefulness of the annulation products ensures the relevance of this family of reactions for a long time to come.

Br

MeO N N H

N H Tubingensin A

N H

OR OH

Clausenine, R=H Clausenol, R=Me

P7C3

Figure 5. Natural products containing carbazole

7. Acknowledgment

Propargylic alcohol 124 was transformed into allenic carbocation in situ by dehydroxylation in the presence of Yb(OTf)3, which underwent a Friedel-Crafts reaction to form intermediate 126. Subsequent 1,5-H shift, electrocyclic reaction, and 1,2-aryl shift generated intermediate 130, which underwent deprotonation to give product 131 (Scheme 33). Studies with deuteriumlabeling have corroborated this mechanism.

Ph Ph Ph

H OH

OH + N H 125

Ph 124

Ph

Yb(OTf) 3

N H

60% -H 2 O

131

Friedel-Craf ts reaction Ar 2

Ar 1

C H

N

H

Ar 1 Ar 2

Ar2

130 [1,2]-aryl shift

1,5-H shif t H

N

Ar 2

N

OH

126

Ar1

Ph

Ar 2

Ar 1

Ar 2 OH H

Ar 2 Ar 2

N 129

127

Ar 1 Ar N

electrocyclic reaction

2

Ar2 O Yb(OTf)2

H 128

Scheme 33. Wang’s [3+3] annulation of indole-2-methanols with propargylic alcohols Ph

Ph Ph

MeO

OH +

132

Yb(OTf) 3 OH

MeO Ph

MeO

H

133

74% -H 2 O

MeO

Ph Ph 134

Scheme 34. Wang’s [3+3] annulation of benzylic alcohols with propargylic alcohols When electron-rich benzylic alcohol 133 was used instead of indole-2-methanol 125 (Scheme 34), the [3+3] product 134 was generated in 74% yield. The mechanism may be similar to that

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