Selected Synthetic Strategies to Spirocyclics

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Selected Synthetic Strategies to Spirocyclics Sel ctedSyntheticStrategiestoSpirocy lics Sambasivarao Kotha,* Ashoke Chandra Deb, Kakali Lahiri, Ethirajan Manivannan Department of Chemistry, Indian Institute of Technology–Bombay, Mumbai 400076, India Fax +91(22)25723480; E-mail: [email protected] Received 19 September 2008; revised 21 October 2008

Abstract: The design and synthesis of spirocycles is a challenging task because it involves the creation of a quaternary center, which itself is considered to be one of the most difficult tasks among synthetic transformations. Some recent approaches based on metathesis, cycloaddition and transition-metal-mediated transformations to spirocycles are described here. 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Introduction Scope of the Review Alkylation Methods Transition-Metal-Based Approaches Rearrangement-Based Approaches Ring-Expansion Method Ring-Contraction Method Photochemical Approaches Ring Closure of Geminally Disubstituted Compounds Cycloaddition Tactics Other Cyclization Methods Metathesis Approaches Pauson–Khand Reaction Conclusions and Future Prospects

Key words: spiro compounds, metathesis, Diels–Alder reactions, domino reactions, Suzuki coupling, radical reactions, ring closure

tural element.4 Among the non-natural products (2, 15– 21), [5.5.5.5]fenestrane (2),5 spiranes,6coronanes, pagodane (18)7 and fenestrindanes 198 contain the spiro linkage as a fundamental unit (Figure 3). Spiro compounds having mutually perpendicular p-electron systems (‘spiro polyene’) which exhibit a new kind of homoconjugation known as ‘spiro conjugation’.9 In addition to various theoretical aspects, the spiro polyenes are also of industrial interest. For example, heterospirenes act as photochromic systems, which can undergo a reversible photochemical ring-opening reaction, and find their utility in silver-free imaging systems and as memories in data display devices.10 Some of the carbocyO O

acorenone B (5)

α-chamigrene (4)

β-vetivone (3) H

H

1

Introduction

H

Spirocyclic compounds have attracted the attention of organic chemists due to their unique structural challenges and their associated reactivity patterns. Many natural products,1,2 including fredericamycin (1) (Figure 1), spirovetivones, acorenones, chamigrenes and zizaene, angularly fused cyclopentanoids3 such as isocomene (7), crinipellin A (9), and laurenene (10), the ACAT inhibitor 11, aphidicolin (12), spirofornabuxine (13) and retigeranic acid (14) (Figure 2) possess a spiro linkage as a strucO O

OH

OH

O H

O

HO

H N

O crinipellin A (9) H

H

N

N

laurenene (10) OH

OH

O

HO O

H

H

O

fredericamycin (1)

H

H

MeO O

α-cedrene (8)

isocomene (7)

zizaene (6)

H

HO HO

SYNTHESIS 2009, No. 2, pp 0165–0193xx. 208 Advanced online publication: 09.01.2009 DOI: 10.1055/s-0028-1083300; Art ID: E22508SS © Georg Thieme Verlag Stuttgart · New York

H aphidicolin (12)

H H H

O

[5.5.5.5] fenestrane (2)

Figure 1

H

H

ACAT inhibitor (11)

H MeHN spirofornabuxine (13)

Figure 2

CO2H

retigeranic acid (14)

Natural products containing a spiro unit

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clic spiro compounds have also been used as building blocks in the thermotropic liquid crystals, which in turn are used in optical displays and screens.11 Most of the synthetic approaches to spirocyclic compounds involve alkylation methods, transition-metalbased processes, rearrangement-based approaches, cleavage of bridged ring systems, ring closure of geminally disubstituted compounds, cycloaddition tactics, and radical cyclization procedures as key steps (Figure 4).12 In gener-

al, these methods encounter problems associated with functional-group incompatibility at one or more stages and they are also restricted to a single substitution pattern; only in a few instances are the newly generated ring systems left with useful functionality for further synthetic manipulation. Therefore, there is a need to generate new methods to the spiro linkage under mild reaction conditions that allow for any additional functionality to be retained for further synthetic transformations.

Biographical Sketches

Synthesis 2009, No. 2, 165–193

Sambasivarao Kotha was born in Amarthalur, AP (India). He obtained his Ph.D. in 1985 under the supervision of Professor G. Mehta at the University of Hyderabad. After spending some time in the UK and in the USA, he joined the Indian Institute of Technology– Bombay (IIT-Bombay) in 1994 as an Assistant Professor and was promoted to

Professor in 2001. He was a recipient of the B. M. Birla prize in Chemical Sciences (1996), the Professor N. S. Narasimhan endowment award (2000), CRSI bronze medal (2004) and Bhagyatara National Award (2006). He is a member of the editorial board of the Indian Journal of Chemistry, Section B, and the Journal of Chemical Sciences of the Indian

Academy of Sciences. He has also been elected as a Fellow of National Academy of Sciences. During the last six consecutive years, several articles from his group have appeared on most accessed/most cited lists. His current research interests include organic syntheses and the development of new synthetic methods.

Ashoke Chandra Deb was born in Shillong, Meghalaya (India). He obtained his Ph.D. in synthetic organic chemistry from IIT-Bombay in 2004 under the guidance of Professor S. Kotha. His research area was the design and synthesis of the quaternary center within

molecular frames ranging from intricate natural products to theoretically interesting molecular entities using several methodologies, including ring-closing-metathesis and ring-opening cross-metathesis reactions. He placed within the first hundred rank in the National

Eligibility Test (NET) conducted by CSIR-UGC, New Delhi. Presently he is working as a scientist in Bhabha Atomic Research Centre, Mumbai. He was appointed as an Assistant Professor in Homi Bhabha National Institute (HBNI), Mumbai, India.

Kakali Lahiri (née Chakraborty) was born in Hooghly, West Bengal (India). She obtained her Ph.D. in 2002 under the guidance of Professor S. Kotha at IITBombay. Presently, she is

working as a research associate in the same department. Her research interests are related to synthetic methodology. She received the ADANI Award for the Best Teaching Assistantship

from the Department of Chemistry, IIT-Bombay, and was also the recipient of the IIT-Bombay best review paper award in 2005.

Manivannan Ethirajan was born in Chennai (India). He completed his M.S. in chemistry from Madras University and obtained his Ph.D. from IIT-Bombay under the mentorship of Professor S. Kotha. In 2001, he joined Professor G. R. Cook’s research group at North Dakota State Univer-

sity (USA) as a postdoctoral researcher, where he worked on small-molecule inhibitors for MMP enzymes, and then moved to Professor J. K. Cha’s research group at Wayne State University (USA), where he focused on synthesizing carbocycles using palladium as a catalyst. Currently, he is

working with Professor R. K. Pandey at Roswell Park Cancer Institute and his research interest focuses on the synthesis of porphyrinbased derivates and their applications as photodynamic therapy and tumor-imaging agents.

© Thieme Stuttgart · New York

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Selected Synthetic Strategies to Spirocyclics . . X

X

(i)

(vi)

M (v)

(ii)

spiro compound (iv)

(iii)

Y

X X

Figure 3

2

Non-natural products containing a spiro unit

Scope of the Review

Before describing the details of our review, we would like to mention that an important review by Sannigrahi, published in 1999, dealt with various synthetic aspects of spirocyclic compounds.12c In the present review, we discuss various general methods that involve the generation of spirocyclic centers. We try to cover the major advances that have been made since 1999, and as and when necessary, we include earlier references. Broadly, the methods that we review here can be divided into the following categories: (i) alkylation methods, (ii) transition-metal-based processes, (iii) rearrangement-based approaches, (iv) ring expansion method, (v) ring contraction method, (vi) photochemical approaches, (vii) ring closure of geminally disubstituted compounds, (viii) cyclization reactions, (ix) metathetic approaches, and (x) Pauson-Khand reaction methods.

3

Figure 4 Various approaches to spirocyclics: (i) alkylation methods; (ii) transition-metal-based processes; (iii) rearrangement-based approaches; (iv) ring closure of geminally disubstituted compounds; (v) cycloaddition tactics; (vi) radical cyclization method.

O O

+

20

21

Scheme 1 54%.

Br

O

steps

3

23

OK 22

Reagents and conditions: (i) KHDMS, THF, HMPA,

O Cl

Spiro compound 26 was prepared by treating dichloro compound 24 with indene (25) in the presence of sodium hydride and tetra(n-butyl)ammonium bromide (TBAB) as depicted in Scheme 2.14 Similarly, the spirobis(indane) 29

(i)

O

Alkylation Methods

Among the several available reports for the generation of spiro centers that use an alkylation reaction as a key step, selected examples are described here. Using an intramolecular alkylation reaction, Posner and Hamill13 synthesized b-vetivone (3) (Scheme 1). Lactone 20 was alkylated with an allylic/homoallylic dihalide such as 21 first in an intermolecular process and then intramolecularly, to give the spirolactone 23. The reaction proceeded through intermediate 22, and compound 23 was converted into the natural product b-vetivone (3) by a series of synthetic transformations.13

O

Br Br

(i)

+

O

Cl

O

O 24

25

Scheme 2 30%.

Reagents and conditions: (i) NaH, TBAB, benzene, r.t.,

OMe Br Br

Br

26

OMe

O

O

(i)

+

Br OMe 27

Scheme 3

28

OMe 29

Reagents and conditions: (i) NaH, THF, 17%.

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S. Kotha et al.

was prepared by reaction of tribromo compound 27 and 1-indanone derivative 28 in the presence of sodium hydride as depicted in Scheme 3.15 A useful method (Scheme 4) for the preparation of spirodiene 32 involved treatment of cyclopentadiene (31) with 1,2-bis(bromomethyl)benzene (30) and sodium hydride. Spirodiene 32 is a useful intermediate for the preparation of complex spirocyclic systems. Recently, Kotha and coworkers found that when a freshly cracked cyclopentadiene was treated with dibromide 30 in the presence of 18crown-6 and potassium hydride in tetrahydrofuran at room temperature, diene 32 was obtained in 55% yield.16

in this particular solvent, gave tetraol 43 as a mixture of stereoisomers. Dehydration of one of the isomers that crystallized out gave staurane-2,5,8,11-tetraene (44) in 80% yield. HO

OH

HO2C (i) O

(ii) O

O

O

O

O H

H

H

CO2H

41

40

39

(iii) Br

(i) or (ii) H

H

+

Br (v)

31

30

32

H

Scheme 4 Reagents and conditions: (i) NaH, 15%; (ii) KOH, 18crown-6, THF, r.t., 15 h, 55%.

The sesquiterpene (±)-erythrodiene (35), was synthesized using an intramolecular alkylation reaction, induced by mercuric chloride, and subsequent Wittig reaction, as depicted in Scheme 5.17 O OTMS

( )2

(i)–(iii)

(iv)

65%

74% 34

33

35

O O MgBr

MgBr (i)

+ 36

Scheme 6 65%.

37

Cl

[5.5.5.5]Fenestrane (2), a theoretically important non-natural spiro compound, was synthesized from key intermediate 39.19 Treatment of this diketone with osmium tetroxide to generate 40, followed by Jones oxidation, provided the di-acid 41, which upon acid-catalyzed cylization in the presence of naphthalenesulfonic acid (NSA) gave the tetraone 42 (Scheme 7). Diborane reduction of 42 in tetrahydrofuran, even though the compound is insoluble Synthesis 2009, No. 2, 165–193


(iv) O

H

HO

O H

OH

H

O

H 43

H 44

O H 42

Scheme 7 Reagents and conditions: (i) OsO 4 , NMO, 92%; (ii) Jones reagent (1.4 M), 70%; (iii) NSA, diglyme, cumene, heat, 70%; (iv) B2H6, THF, 0 °C, 2 d, 92%; (v) HMPA, reflux, 2 d, 80%.

Tin derivatives such as trimethylsilyltributyltin are excellent reagents for the generation of aryl anions which can be engaged easily in the intramolecular additions of carbonyl groups. For example, iodo derivative 45 undergoes cyclization in the presence of trimethylsilyltributyltin and tetraalkylammonium chloride to give spiro derivative 46 as shown in Scheme 8.20 CO2Me (i) I O 45

46

Scheme 8 Reagents and conditions: (i) n-Bu3SnSiMe3, BnEt3NCl, DMF, 60 °C, 53%.

Unactivated olefinic bonds have been shown to undergo tandem cyclization to give spirocyclic products. For example, activation of iodo derivative 47 with tert-butyllithium generated spirononane 48 as shown in Scheme 9.21 (i)–(iii)

38

Reagents and conditions: (i) CuBr·Me2S, THF, –30 °C,

OH H

H

Scheme 5 Reagents and conditions: (i) HgCl2, (Me3Si)2NH, CH2Cl2; (ii) HCl, NaI, THF; (iii) NaHCO3; (iv) Ph3P=CH2, THF, n-BuLi, reflux.

Bicyclic compound 38 containing a spiro[4.5] skeleton with a double bond a to the quaternary carbon center was assembled from the bis-Grignard reagent 36 (Scheme 6).18 The cuprate derived from 36 reacted with 1chlorocyclopent-1-en-3-one (37) to generate spiro compound 38 in good yield.

H

HO

I 47

84% 48

Scheme 9 Reagents and conditions: (i) t-BuLi, pentane, Et 2O, –78 °C; (ii) TMEDA, –78 °C to r.t.; (iii) MeOH.

Ionic carbocyclization of a-iodo cycloalkanones (e.g., 49) bearing an acetylenic side chain can be effected with a Lewis acid such as aluminum trichloride.22 Addition of iodine monochloride greatly enhances the yields of the spirocyclic ketone products (Scheme 10). In comparison with free-radical atom-transfer cyclization, the present

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Selected Synthetic Strategies to Spirocyclics

method allows annulation of both five- and six-membered rings. These spirocyclic ketones are core skeletons of several important natural products, such as gloiosiphone and ginkgolide. They also constitute the main frameworks of spirocyclic chiral auxiliaries with a C2 axis of symmetry. I O

O

H

O (i) H

H H

H 57

58

Scheme 13 Reagents and conditions: (i) RhCl(cod)(dppe), PhCN, 100 °C, 48 h, 93%.

O (i) I

49

50

Scheme 10 83%.

Reagents and conditions: (i) AlCl3, ICl, CH2Cl2, 0 °C,

Starting with adamantanone (51), the spiroadamantine derivative23 53 was prepared from the allyl vinyl ether intermediate 52 by treatment with a rhodium catalyst such as [RhCl(cod)(dppe)] at elevated temperature (Scheme 11). The key steps involved are Claisen rearrangement and rhodium-catalyzed intramolecular acylation of the corresponding enal intermediate.

O

O

O

(i)

steps

51

52

53

Scheme 11 Reagents and conditions: (i) RhCl(cod)(dppe), PhCN, reflux, 49%.

A similar strategy was used for the synthesis of spiro[4,5]decan-1-ones starting with compound 54, prepared from commercially available starting materials.24 The reaction proceeds via the formation of 2,2-disubstituted pentenals 55. This procedure allows the synthesis of spiroketone 56 (Scheme 12), a key intermediate in the total synthesis of acradienes and acorones.

skeleton 60 was prepared from the cyclohexanedicarbaldehyde 59 via a Robinson annulation and hydrogenation sequence (Scheme 14). The product’s linear molecular shape was confirmed by an X-ray structural analysis of the corresponding diketal derivative. O CHO (i), (ii) OHC O

59

60

Scheme 14 Reagents and conditions: (i) CH2=CHCOMe, H2SO4, toluene, 15%; (ii) H2 (3 bar), Pd/C, toluene, r.t., 86%.

Either of the enantiomers of cyclohex-2¢-enespirocyclohexane-2,4¢-dione (S or R) can be obtained from 2-formylcyclohexanone (61) using an asymmetric one-pot Robinson annulation as a key step (Scheme 15).26,27 In this regard, compound 61 was treated with methyl vinyl ketone (MVK), (S)-proline as the chiral auxiliary, and DMSO as the solvent. The S-isomer, 63, was obtained in 70% yield (after TLC purification) by carrying out the reactions in two steps, whereas the R-isomer, 62, was obtained in 49% yield (after column chromatographic separation) by conducting the reaction in a one-pot manner. This methodology has been extended to the annulation of a number of 2-formylcyclonones in order to obtain the corresponding optically active spiroenediones. O

O O

R

O R

O (i)

H

R

R = H, Me 54

56

CHO

(i)

55

Scheme 12 Reagents and conditions: (i) RhCl(cod)(dppe), PhCN, 160 °C, 50–55%.

O R-isomer 62

49%

(ii), (iii) 70%

O 61

O S-isomer 63

Scheme 15 Reagents and conditions: (i) (S)-proline, DMSO, MVK, 49%; (ii) MVK; (iii) (S)-proline, 70% (2 steps).

Recently, Bjørnstad and Undheim25 reported on rhodium(I)-effected spiroannulations. There, the reactions involved were tandem acylation–alkylations. For example, spiroketone 58 was prepared in 93% yield from pent-4enal 57 by intramolecular hydroacylation catalyzed by a rhodium(I)–diphosphino complex (Scheme 13).

Six- and seven-membered spirocycles (e.g., 67) can be obtained in one pot from allylsilane acetals like 4,4dimethoxy-2-trimethylsilylmethylbut-1-ene (65) and 5,5dimethoxy-2-trimethylsilylmethylpent-1-ene with O-silylated enolate 64 (Scheme 16).28 The reaction proceeded through the formation of the intermediate 66.

On another occasion, the synthesis of rod-like dispirohydrocarbon skeletons, suitable for liquid crystal applications, were described.11 The dispiro[5.2.5.2]hexadecane

A diastereoselective synthesis of C2-symmetric spiro compounds, in which chiral auxiliaries were employed, was reported.29 Racemic cis,cis-diol 70 was prepared by acid-catalyzed cyclization and reduction, and was reSynthesis 2009, No. 2, 165–193


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OTMS

CO2Et

CO2Et

(i)

TMS

H

OTBS

TMSO 64 +

OMe

OMe

TMS OMe

(ii)

(ii)

75%

MeO

74

73

CHO

(i), (ii)

75 (25%) + 76 (50%)

CO2Et

67

66

CO2Et

65

Scheme 16 Reagents and conditions: (i) TMSOTf, CH2Cl2, –78 °C; (ii) TMSOTMS, DMAP, Et3N. O

H

(i)

H 76 (45%)

OH OH

(ii)

68

+

75 (15%)

OO

HO2C

HO

O

Scheme 18 Reagents and conditions: (i) Et3N, TBSOTf, CH2Cl2, 15%; (ii) TBAF, THF, 30 min, 20 °C.

70

69 H

H OH OH

which, in combination with an oxidant counter-ion, provides SbCl5 as the true reactive species. The evidence for the direct involvement of SbCl5 as an oxidative species in the behavior of the aminium hexachloroantimonates, particularly tris(2,4-dibromophenyl)aminium hexachloroantimonate, came from the cyclization reaction of an adamantylidene-based olefin 77 induced by this salt (Scheme 19).

racemic cis,cis-diol

(iv) H

O

O

H (–)-(1R,5R,6R) 72a

H

71a (iii)

OH H

OH (iv) H

O O

(+)-(1S,5S,6S)

71b

72b

(i)

Scheme 17 Reagents and conditions: (i) PTSA, toluene, 72%; (ii) Li(t-Bu)(i-Bu)2AlH, THF, –78 °C, 85%; (iii) (+)-(R)-camphor, PTSA, benzene, 87%; (iv) PTSA, CH2Cl2/H2O (40:1), 90%.

solved by its conversion into the corresponding diastereomeric (+)-(1R)-camphor ketals (e.g. 71) (Scheme 17). Hydrolysis of the ketal produced (–)-(1R,5R,6R)-diol 72a and (+)-(1S,5S,6S)-diol 72b, respectively. Wendling and Miesch30 have studied the intramolecular reactivity of acetylenic w-keto ester derivatives (Scheme 18). The acetylenic w-keto ester 73 was converted into silyl enol ether 74 by conventional methods (TBSOTf, Et3N, CH2Cl2, 20 °C). Treatment of the silyl enol ether with tetra(n-butyl)ammonium fluoride led to a mixture of two easily separated products: the spiroketone 75 in 15% isolated yield and the corresponding allene derivative 76 in 45% isolated yield. According to the proposed mechanism, 75 was formed by deprotection of the silyl enol ether followed by intramolecular Michael addition. When compound 73 itself was treated directly with tetra(n-butyl)ammonium fluoride, the spiroketone and allene derivatives were obtained in 25% and 50% yield, respectively.

78

77

Scheme 19 Reagents and conditions: (i) tris(2,4-dibromophenyl)aminium hexachloroantimonate or SbCl5 (50 mol%), CH2Cl2, N2, 20 °C, 86%.

Samarium(II) iodide has been employed to promote a tandem intramolecular nucleophilic acyl substitution–intramolecular Barbier cyclization sequence, generating bicyclic and tricyclic ring systems in good yield and high diastereoselectivity. Additionally, a highly versatile ringexpansion–cyclization sequence allows a useful entry into several naturally occurring tricyclic ring systems containing seven- and eight-membered rings. This approach is well suited to the angular triquinane skeleton of sesquiterpenes such as silphinene. The broad applicability of this protocol for the formation of angularly fused tricyclic ring systems such as 80 is demonstrated in Scheme 20.32 Furthermore, these examples show the ability of samarium(II) iodide to promote reactions at sterically hindered carbonyl centers. Br

The cyclization of an adamantylidene-based olefin induced by the aminium hexachloroantimonate salts under a nitrogen atmosphere revealed that the oxidative activation by these salts may be due to the presence of SbCl6– Synthesis 2009, No. 2, 165–193


OH

TBSO

TBSO

(i)

31

CO2Et 79

Scheme 20

Br 80

Reagents and conditions: (i) SmI2, HMPA, 84%.

REVIEW


Spirocyclic systems 82 were obtained by way of a facile, palladium(II)-mediated synthesis (Scheme 21).33 A variety of cyclopentanones and cyclohexanones bearing unsaturated side chains a or g to the carbonyl group were converted into trimethylsilyl enol ethers (e.g., 81) and these were subjected to reaction with palladium(II) acetate under standard reaction conditions to obtain the spirocyclic targets (e.g., 82a,b).

(i)

O

171

titanocene-catalyzed hydrogenation of alkenes. Ligand 91 was obtained by thermolysis of the spiro derivative 90, which itself was prepared from trans-6-phenylcyclohex3-en-1-ol (88) by stereoselective oxacyclopropanation and subsequent phenylcuprate-induced ring opening, followed by complete resolution of the intermediate by (+)-camphorsulfonylation. Through an SN2 strategy, direct cyclopentadiene annulation of 89 furnished the spirodiene 90 (Scheme 24).

O

+

OTMS 81

82b (36%)

82a (58%)

Scheme 21 (1:1).

Ph

(i) oxacyclopropanation (ii) phenylcuprate ring opening

O O2SO

Reagents and conditions: (i) Pd(OAc)2, MeCN–CH2Cl2

Ph

OH (iii) camphorsulfonylation Ph

A one-step spiroannulation involving a cuprate reagent has been reported.34 This protocol involves the reaction of 3-halocycloalk-2-enones with a dicuprate, prepared from the organodilithium reagents and copper thiophenoxide. This methodology can provide an efficient access to spiro[4.4]nonanes, spiro[4.5]decanes, and spiro[5.5]undecanes. Under optimized reaction conditions, the chloroenone 83 reacted with 84 to provide the 9,9dimethylspiro[4.5]decan-7-one (85) in 96% yield (Scheme 22). O

O

CuSPhLi (i)

+ Cl CuSPhLi 83

84

Scheme 22

85

Reagents and conditions: (i) THF, –15 °C to r.t., 96%.

88

89

O

(i)

Ph thermolysis

91 Ph

90

Scheme 24 Reagents and conditions: (i) cyclopentadienylsodium– dimethoxyethane, NaH, oxacyclopentane, 0 °C, 2.5 h; heat, 4 h, 98%.

Based on a ring-opening radical-fragmentation strategy, medium-sized carbacycles have been prepared.37 Spirocyclobutanone 95 was prepared by way of a Kulinkovich reaction on cycloalkene carboxylate 92 and ensuing condensation of 1-cycloalkenylcyclopropan-1-ol 93 with bromoalkyl acetal 94 (Scheme 25). Subsequently, it was demonstrated that these spirocyclic compounds are useful precursors to eight-membered carbacycles, such as 96, which can be obtained by a facile radical fragmentation reaction sequence.

It was observed that the iodobenzene diacetate oxidation of a series of 4(2-alkenylaryl)phenols, such as 86, gave spirodienone products (Scheme 23).35 In most cases the yield of the products obtained were comparable with those obtained from the electrochemical oxidation. OH

O SO2

HO

OMe

CO2Me (i) MeO

+ 93

92

O

Br 94

(ii)

O H O (iii)

MeO MeO

(i) H MeO

OMe 86

Scheme 23

87

Br 96

MeO

95

Scheme 25 Reagents and conditions: (i) Ti(Oi-Pr)4, EtMgBr, 95%; (ii) TiCl4, 71%; (iii) n-Bu3SnH, AIBN, 99%.

Reagents and conditions: (i) PhI(OAc)2, MeOH, 74%.

Vollhardt and co-workers36 reported on the synthesis of the enantiomerically pure, chiral cyclopentadienyl ligand 91 that possesses C2 symmetry and a rigid structural arrangement which effectively shields one face of the attached metal. This ligand can be used in enantioselective

4

Transition-Metal-Based Approaches

A wide variety of spirocyclic compounds have been prepared via transition-metal-mediated processes. For example, the BCDE ring system of antitumor agent Synthesis 2009, No. 2, 165–193


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fredericamycin (1) was synthesized by Evans and Brandt38 who used a palladium-catalyzed cross-coupling reaction. Halogen–metal exchange of 2-bromobenzaldehyde ethylene ketal with n-butyllithium afforded the corresponding aryllithium derivative. Thus, the treatment of acyl chloride 97 with 2-lithiobenzaldehyde ethylene ketal in the presence of palladium(0) as catalyst and zinc chloride furnished aryl ketone 98.38 Deprotection of the cyclic ketal gave 99. Treatment of the latter with a catalytic amount of sodium methoxide in methanol afforded compound 100, which contains the BCDE ring system of 1 (Scheme 26).

H

p-Tol 104 (9%) + O

Br

(i)

OMe

+ Ts 101

CO2Me 103 (50%)

102

MeOH

O OMe

S

O

O

Ni

O

O

COCl

Ts 105

(i) 98

97

O

Scheme 27

MeO

Ts

106

CO2Me

Reagents and conditions: (i) Ni(CO)4, MeOH.

(ii) H

O CHO (i), (ii)

(iii), (iv) O MeO

Et

Et + H

49%

92% MeO

Spirocyclopentanone 103 was synthesized by Moretó and co-workers39 starting with tosylacetylene derivative 101. This strategy involved nickel-catalyzed addition of bromo compound 102 to one end of the triple bond followed by carbonylation at the other. The intermediate acylnickel species, 105, then underwent cyclization to deliver spirocyclopentanone 106 as depicted in Scheme 27. A minor product, 104, was also generated during the reaction. A titanium-catalyzed cascade reaction involving carboalumination of triene 107 was used to generate spirobicyclic compounds 110 (Scheme 28).40 Treatment of 107 with a catalytic amount of titanium(IV) isopropoxide and diethylaluminum chloride generated the quaternary carbon center (Scheme 28). Further cyclization of 109, obtained from 108, gave the spiro product 110 on treatment with oxygen. Spirocycles have also been prepared by metal-catalyzed cyclizations of enynes.41 For example, enyne 111, upon treatment with a palladium(0)-based catalyst system, gave spirocyclic diene 112 (Scheme 29). In another event, trienyne 113, under carbopalladation conditions, gave 114, a bis-spiro compound (Scheme 30).42 43

Pearson and Wang demonstrated the synthesis of spirocycles using Fe(CO)3 complexes, as depicted in Scheme 31. A new methodology for preparing stereodefined 2-azaspiro[5.5]undecan-1-one (d-lactam) derivaSynthesis 2009, No. 2, 165–193


H 110b

110a

99

Scheme 26 Reagents and conditions: (i) 2-bromobenzaldehyde ethylene ketal, n-BuLi, Et2O, ZnCl2, Pd(PPh3)4, 72%; (ii) PPTS, acetone–H2O, heat, 99%; (iii) NaOMe, MeOH, 0 °C to r.t.; (iv) PCC, CH2Cl2, 0 °C to r.t.

OH

OH

107

O

100

H

O2 H

O2

H

M Et

H M

Et

Et

109a

108

M = Al or Ti

M

109b

Scheme 28 Reagents and conditions: (i) Et2AlCl, Ti(Oi-Pr)4, hexane; (ii) O2.

(i)

HO

OMe

OMe

HO

111

112

Scheme 29 Reagents and conditions: (i) Pd2(dba)3·CHCl3, Ph3P, AcOH, benzene, 60 °C, 76%.

(i) PhO2S PhO2S

PhO2S 113

SO2Ph 114

Scheme 30 Reagents and conditions: (i) Pd2(dba)3·CHCl3, Ph3P, AcOH, benzene, r.t., 81%.

tives was developed, making use of an intramolecular coupling between the cyclohexadiene–Fe(CO)3 moiety and the pendant olefin. Heating amide complex 115 under a carbon monoxide atmosphere gave the spiro products 116 in 70% yield.

REVIEW (CO)3Fe

(CO)3Fe

Fe(CO)3

O O

(i)

CO2Me Ph

+

N O

O

N

O

116a

115

Scheme 31

173


N

116b

121 +

CO2Me (i)

CO2Me

+ CO2Me Ph

CO2Me

CO2Me Ph 124 (5%)

123 (86%, dr 79:21)

Reagents and conditions: (i) n-Bu2O, CO, 142 °C, 70%. 122

Indane-based spirocyclic compounds (e.g., 118) can be synthesized using a palladium-catalyzed intramolecular arylation reaction (Scheme 32).44 The reaction proceeded more readily with aryl bromides substituted with electronwithdrawing groups. For the less reactive 4-methoxyaryl derivatives, the use of lithium iodide as an additive gave the best results.

Br

L EWG

Pd (II) 1 2

125 CO2Me Ph

Scheme 34 Reagents and conditions: (i) PdCp(h3-C3H5), P(Oi-Pr)3, CH2Cl2, 40 °C, 24 h.

tion of the spiro ring can be favored over that of the [4+2]cycloaddition product.

(i)

Br

L

117

118

Scheme 32 Reagents and conditions: (i) K2CO3, Bu4NBr, Pd(OAc)2, DMF, 130 °C, 24 h, 68%.

Spirocycloalkane derivatives such as 120 have been prepared by intramolecular arylation of suitably functionalized substrates bearing electron-withdrawing groups like keto, formyl or nitro moieties. Arylation of substrate 119, containing a keto group, using a palladium-catalyzed intramolecular a-arylation reaction, gave spirocyclic compound 120 in 71% yield. The product was obtained as an inseparable mixture, isolated after acetylation, separation, and acid hydrolysis.45 The reactions were carried out in the presence of bis(triphenylphosphine)palladium(II) dichloride (10 mol%) and cesium carbonate (3 equiv) in tetrahydrofuran at 100 °C under an inert atmosphere (Scheme 33).

Similarly, spiro[4.4]nonane 129 was prepared by palladium-catalyzed domino cyclization of 7-methyleneundeca2,10-dienyl acetate 126 as shown in Scheme 35. The two five-membered rings were fused by way of insertion of the palladium catalyst to one of the olefin groups to form p-allyl–palladium intermediate 127 followed by intramolecular Heck reaction of the s-palladium intermediate 128. Finally, b-hydride elimination resulted in formation OH O

OH

OH O

OMe

gloiosiphone A (130)

steps OPMB

Br (i)

O

SO2Ph O

OPMB

PhO2S

PhO2S

(i) 119

126

120

PhO2S 129, dr = 60:40

Scheme 33 Reagents and conditions: (i) PdCl2(PPh3)2 (10 mol%), Cs2CO3 (3 equiv), THF, 100 °C, 14 h, 71%.

OAc PMBO

Spiro[2.4]heptane 123 was obtained via palladium(0)-catalyzed reaction between g-methylidine-d-valerolactone 121 and methyl acrylate (122).46 The p-allyl–palladium intermediate 125 formed during the reaction can undergo a ring closure either by nucleophilic attack at C2 or at C1 to generate the spiro derivative 123 and the six-membered [4+2]-cycloaddition product 124, respectively (Scheme 34). By changing the phosphine ligand, forma-

PMBO

PhO2S

PdLn

PhO2S

PhO2S

PdLn

PhO2S H 127

128

Scheme 35 Reagents and conditions: (i) Pd(OAc)2 (10 mol%), Ph3P, AcOH, 66%. Synthesis 2009, No. 2, 165–193


174

REVIEW

S. Kotha et al.

of the spirofused framework.47 The resulting spiro derivative was further extended to construct gloiosiphone A (130), a known antimicrobial agent.

I I

Spirofused heterocycles can be prepared from an enecarbamate tethered to an alkyne in a one-pot cyclization–reduction sequence.48 For instance, 3-substituted piperidine derivative 131 underwent a ring cyclization in the presence of platinum(II) chloride to form spiro system 133 (Scheme 36). Here, the platinum metal activates the alkyne moiety towards nucleophilic attack to give the azacarbenium ion intermediate which is quenched by alcohol to give rise to the hemiacetal 132. Removal of the hemiacetal functionality gave 133 in 80% yield.

Br (i), (ii)

I

140

ZnCl (iii) 139

138

141 Pd(0) 85%

M (i)

(ii) 142

N

N

Ts

Ts

131

OMe

80%

N

Scheme 38 Reagents and conditions: (i) Li wire, THF, r.t., 1 h; (ii) ZnCl2, THF, 0 °C to r.t., 1 h; (iii) (Ph3P)2Pd, THF, 66 °C, 10 h.

Ts

132

133

Scheme 36 Reagents and conditions: (i) PtCl2 (5 mol%), toluene, MeOH; (ii) BF3·OEt2, Et3SiH.

Methylenecyclobutane (134) can be converted, with suitable reagents,49 into spiro[3.3]heptane and spiro[3.4]octanes via a cyclic aluminum intermediate as shown in Scheme 37. Thus, when 134 was subjected to reaction with triethylaluminum and bis(cyclopentadienyl)zirconium(IV) dichloride, cycloaluminum intermediate 135 was generated. This 6-ethyl-6-aluminaspiro[3.4]octane (135), in the presence of allyl chloride and a palladium(0) catalyst, underwent a ring-contraction reaction to form spiro[3.3]heptane 136. Interestingly, in the presence of methylformate, copper(I) chloride, and base, the same intermediate 135 delivered spiro[3.4]octan-6-ol (137). (ii)

136 (88%)

(i) Al 134

(iii)

135 OH

137 (76%)

5

Rearrangement-Based Approaches

Extensive studies on optically active spirocyclics have led to the development of stereospecific methods for the preparation of spiro[4.4]nonanes.1d For example, Lewis acid catalyzed rearrangement of epoxide 143 gave rearranged spiro product 144 (Scheme 39).

O

(i)

N

O

N

OCp

OMe OMe OCp

143

144

OMe OMe

Scheme 39 94%.

Reagents and conditions: (i) BF3·OEt2, CH2Cl2, 0 °C,

Spiro compounds have been constructed by way of Nazarov cyclization of cross-conjugated ketones.51 For example, silicon-directed Nazarov cyclization of a-(trimethylsilylmethyl)divinyl ketone 145, in the presence of a mild Lewis acid such as iron(III) chloride, gave spiroketones 146 as depicted in Scheme 40.

Scheme 37 Reagents and conditions: (i) Et3Al, [Cp2ZrCl2], pentane, 0 °C to r.t.; (ii) Pd(acac)2, Ph3P, H2C=CHCH2Cl, Et2O, 0–20 °C; (iii) HCO2Me, CuCl, –15 °C to r.t., NaOH.

O

O

O

TMS (i)

50

Katz and co-workers reported the synthesis of spiro[cyclopent-2-ene-1,9¢-fluorene] (142) by palladium-catalyzed reaction of 2,2¢-diiodobiphenyl (140) with unsaturated organometallic 139 followed by a Heck coupling reaction of the resulting intermediate 141. The zinc derivative 139 was prepared from vinyl bromide derivative 138.

Synthesis 2009, No. 2, 165–193


145

+

146a

146b

Scheme 40 Reagents and conditions: (i) FeCl3, CH2Cl2, 61% (146a/ 146b = 5:1).

REVIEW


Later, another tactical variation of the above theme was reported.52 Silyl aldehyde 147 underwent cyclization in the presence of iron(III) chloride in dichloromethane to generate the spiroenone 149 as shown in Scheme 41. The reaction proceeded through the formation of silicon-stabilized carbocation 148 and the trimethylsilyl group had a role to play in the reaction. TMS

(i) 155

154

(ii)

156

Scheme 44

H

H

(i)

FeCl3

147

148

149

Reagents and conditions: (i) FeCl3, CH2Cl2, r.t., 78%.

Through a Michael–aldol approach, spiro derivative 151 was assembled (Scheme 42). Organocuprate addition to fulvene 150 gave lithium cyclopentadienide which then combined with the carbonyl functionality to produce the cyclohexanol.53 Interestingly, the reaction afforded a single spiro compound, 151, and its application was illustrated in the synthesis of b-vetivone (3). O

OH steps

(i)

150

3

151

Reagents and conditions: (i) Me2CuLi, Et2O, –20 °C,

In a novel approach to retigeranic acid (14),54 vinylcyclopropane 152 underwent thermal rearrangement to give pentacyclic intermediate 153, a useful precursor to the natural product as shown in Scheme 43. Retigeranic acid is the first isolated natural product found to contain the tricyclo[6.3.0.02,6]undecane skeleton. O

H H

CO2Et 152

Reagents and conditions: (i) H ; (ii) H+, H2O.

H

(i)

H H

Another interesting approach to a spirocyclic system58 involves the Claisen rearrangement of a dihydropyran. When the alkenyl bicyclic dihydropyran 166 was subjected to thermal rearrangement at 250 °C in a sealed tube, generation of the spiro derivative 167 took place in high yield (Scheme 47). The key feature of this reaction is the generation of a polyfunctionalized spiro derivative which can be further manipulated for assembling a variety of sesquiterpenes. A variety of spirocyclics were synthesized56 by way of a Nazarov cyclization and a Wagner–Meerwein rearrangement as key steps. For example, when compound 157 was treated with a stoichiometric amount of the copper bisoxazole complex 158, the spirocyclic derivative 162 was delivered in good yields (Scheme 45). It is believed that the spirocyclization occurred when oxyallyl cation intermediate 159 underwent a 4p-conrotatory electrocyclic cyclization followed by ring contraction to form spirocyclic cation 160, which in turn underwent an alkyl/aryl shift that led to 161, which itself was converted into spiro product 162. Padwa and co-workers57 have developed an elegant method for the synthesis of spirooxindole derivative 165 from 3-hydroxyindolin-2-one 163. The reaction proceeded via an ene-type reaction with the aid of the amide carbonyl moiety, leading to the formation of quasi-antiaromatic 2H-indol-2-one intermediate 164 as shown in Scheme 46.

6

O H

O +

O

O

FeCl3

Scheme 42 80–90%.

HO

TMS

O

Scheme 41

OH

175

CO2Et 153 steps 14

Scheme 43 Reagents and conditions: (i) PbCO3, 10–6 mmHg, 585 °C, 75–80%.

In another event, it has been reported55 that the symmetric diol 154, derived from cyclopentanone and acetylene, can be readily transformed into the spirocyclic ketone 156 through intermediate 155 as shown in Scheme 44.

Ring-Expansion Method

A useful spiroannulation method based on the conversion of a thioketal to a spiro compound was employed as the key step in the synthesis of various complex spirocycles. For example, treatment of 169 with silylated acyloin 168 in the presence of boron trifluoride–diethyl ether complex gave 170 as shown in Scheme 48.59 Pinacol-type rearrangement of 170 with mercury(II) chloride in refluxing benzene gave a 55% yield of spirodione 171. A useful synthesis of spirocyclic 1,3-diketone 173 was based on the rearrangement of b-keto epoxides such as 172 with boron trifluoride–diethyl ether complex at low temperature (Scheme 49).60 The epoxide is exo to the ring that bears the carbonyl functionality. Treatment of epoxide 172 in the presence of Lewis acid gave the ring-expanded spiroannulation product 173 in good yields. The Synthesis 2009, No. 2, 165–193


176

REVIEW

S. Kotha et al. O

O O

O

O OMe

O N

+

OMe

(i)

N

H 162

Cu F6Sb OMe

157

SbF6 158

LA

LA

LA O

O

O

O

O

OMe

H

H

OMe

OMe

161

MeO

160

159

Reagents and conditions: (i) CH2Cl2, r.t., 1 h, 76%.

Scheme 45

O

H

OR

O O

H

(i)

O

N

163 R = H, Me

Scheme 46

N H

164

O OTBS

(i)

> 95% dr OTBS 166

Scheme 47

167

Reagents and conditions: (i) toluene, 250 °C, 87%. O

OTMS (i) + EtS

SEt

TMSO EtS 170

169

O 173

172

165

Reagents and conditions: (i) BF3·OEt2, CH2Cl2, 80%.

O

(i)

O

O

N H

168

O

OMe

OMe H

OTMS

MeO

O

(ii)

Scheme 49 98%.

Reagents and conditions: (i) BF3·OEt2, CH2Cl2, –78 °C,

Another tactical variation of the above theme involves the construction of spirocyclic compounds using a siloxy-epoxide semipinacol ring-expansion process.61 Thus, the functionalized spirocyclic compound 175 was produced in high chemical yield and with complete diastereoselectivity using titanium tetrachloride as the Lewis acid promoter (Scheme 50). This method was also used to prepare 1-azaspirocyclic cyclohexanone and 1-azaspirocyclic cyclopentanone in high chemical yield but poor diastereoselectivity. The latter was improved by changing the Lewis acid and the nature of the silyl ether. Stereoselective 1,2rearrangement reactions of epoxides and their derivatives seems to be a useful protocol for the stereocontrolled formation of carbon atoms with four different substituents. OH O

O OTIPS

O 171

Scheme 48 Reagents and conditions: (i) BF3·OEt2, CH2Cl2, –40 °C, 44%; (ii) HgCl2, benzene, heat, 55%.

reaction is favored because the p-orbital of the carbonyl carbon is suitably placed to overlap with the developing empty p-orbital that is generated when the epoxide ring cleaves.

Synthesis 2009, No. 2, 165–193


(i) 93% 175 one diastereomer

174 O

(i) OTMS 62%

175 one diastereomer

176

Scheme 50 0.5 h.

Reagents and conditions: (i) TiCl 4, CH2Cl2, –78 °C,

REVIEW

7

177


Ring-Contraction Method

O

The first stereoselective synthesis of (–)-solavetivone (180) was achieved using a silicon-assisted ring-contraction reaction.62 Thus, treatment of decalin 177 with ferric bromide in dichloromethane at a low temperature resulted in the formation of spiro compound 179 via 178. Oxidation of 179 with chromyl chloride led to the required natural product (–)-solavetivone as shown in Scheme 51.

R (i) HO

HO 177

R = TMS

O

Bu

O 185

184

Bu CO2H O

186 (23% overall yield)

Scheme 53 Reagents and conditions: (i) hn, MeCN, 25 °C; (ii) RuO2, NaIO4, H2O, CCl4.

The photochemical rearrangement of 2-methoxy crossconjugated dienones 187 was used to generate spiro[4.5]decane system 188 as shown in Scheme 54.65 Compound 188 was further used in the synthesis of the key compound, spiro[4.5]dec-6-en-2-one 189, which was readily converted into (±)-a-vetispirene.

TMS TMS

(ii)

(i)

Bu

178 OH MeO

O

(i) (ii)

MeO O 187

O 188

179

(–)-solavetivone (180)

steps

Scheme 51 Reagents and conditions: (i) FeBr3, CH2Cl2, –60 °C, 25 min, 54%; (ii) CrO2Cl2, t-BuOH, DMP, CH2Cl2, 71%. (i) Grignard addition

8

Photochemical Approaches

(±)-Silphinenes 183 were synthesized in two steps by way of a strategy that used an arene–olefin meta photocycloaddition as the key step (Scheme 52).63 Photoirradiation of 181, obtained from commercially available starting materials, gave photoadducts 182a and 182b as a 1:1 mixture in 70% yield. Reductive cleavage of the cyclopropane ring in 182a with lithium in methylamine gave the natural product (±)-silphinene (183a) along with the regioisomer 183b in a ratio of 9:1 (74% combined yield).63

(i)

181

(ii)

182a

O

(ii) silica gel

+

183b

183a +

182b

Scheme 52 Reagents and conditions: (i) hn (vycor), pentane, 25 °C, 70%; (ii) Li, MeNH2, –78 °C, 74%.

189

(±)-α-vetispirene

Scheme 54

9

Reagents and conditions: (i) hn, AcOH–H2O, 28%.

Ring Closure of Geminally Disubstituted Compounds

Many syntheses of spiro structures are best accomplished with quaternary carbons carrying two functionalized chains that are then joined so as to generate the second ring of the spiro system. The Dieckmann condensation is the basis for Provencal and Leahy’s approach to spirocyclopentanones (Scheme 55). Diester 191, upon sequential Dieckmann condensation, hydrolysis and decarboxylation, furnished spiro compound 192.66 Compound 191 was prepared from ketone 190 by a sequence of reactions. The spiro system 196 was synthesized by use of Wittig reagent 194.67 The key step involved attack of enolate 193 on the cyclopropyl ring of phosphonium salt 194, resultO

64

To assemble spiroketone 186, Koft and Smith utilized a [2+2] photocycloaddition followed by cyclobutene cleavage as depicted in Scheme 53. Photoirradiation of enone 184 in acetonitrile furnished cycloadduct 185. The desired spiroketone 186 was then delivered through oxidative cleavage of 185.

steps

EtO2C

(i), (ii)

EtO2C

t-Bu 190

Scheme 55 HCl, THF.

O

78% 191

t-Bu

t-Bu 192

Reagents and conditions: (i) NaH, benzene, EtOH; (ii)

Synthesis 2009, No. 2, 165–193


178 OH

REVIEW

S. Kotha et al. O EtO2C

(i)

+ OEt

EtO2C OHC

F4BPh3P

193

condensation.69 Spirocyclic cyclopentenones 205 were synthesized from the aldehyde derivative 203 via Wacker oxidation of the terminal olefin followed by an intramolecular aldol condensation of the resulting keto aldehyde 204. Compound 203, a g,d-unsaturated aldehyde, was obtained by Claisen rearrangement from allyl alcohol 202, which itself was obtained from cyclohexanone 200 via compound 201 by Horner–Wadsworth–Emmons reaction and lithium aluminum hydride reduction (Scheme 58).

O

Ph3P

OEt 195

194

O EtO2C OEt 196

Scheme 56 38%.

Reagents and conditions: (i) 57% NaH, HMPT, r.t.,

The above strategy was extended to the spiroannulation of a cyclopentane ring onto the cyclic precursor 206 to obtain spirocyclic compound 207. Further, 207 was used for the formal total synthesis of acorone (208) and isoacorone (Scheme 59).70

(i)–(v) O

O CHO (i)

O

steps

O

O

O

(ii)

206

207

198 O

CHO

O acorone 208

Scheme 59 Reagents and conditions: (i) Wittig reaction, 77%; (ii) protection, 88%; (iii) reduction, 90%; (iv) Claisen rearrangement, 64%; (v) aldol condensation, 93%.

(i), (ii) 78% 199

197

Scheme 57 Reagents and conditions: (i) HgSO4, THF–H2O– H2SO4(concd), 60 min, 25 °C; (ii) NaOH, EtOH, 25 °C, 60 min.

ing in formation of ylide 195. The latter then underwent intramolecular Wittig olefination to generate spiro moiety 196 as shown in Scheme 56.67

For the first time, centrotetraindan 210 was prepared by subjecting ketol 209 to a cyclodehydration–reduction–cyclodehydration sequence (Scheme 60).71,72 This approach has been extended to prepare several complex benzoannulated fenestranes and centro-fused polyindane derivatives.

In another approach, an aldol condensation was used as a key step to construct a spiro system.68 For example, hydration of the acetylene functionality in compound 197 generated the required precursor 198. The crude keto aldehyde 198 then underwent aldol condensation to give spiroenone 199 in 78% overall yield (Scheme 57).68 Srikrishna and co-workers prepared spirocycles using a strategic combination of Claisen rearrangement and aldol

OH

O

(i)–(iii)

210

209

Scheme 60 Reagents and conditions: (i) H3PO4, toluene, 67%; (ii) LiAlH4, THF, 81%; (iii) H3PO4, toluene, 51%.

CHO

OH CO2Et

O

(ii)

(i)

t-Bu

55%

t-Bu

t-Bu 200

(iii)

201

202

t-Bu 203 (epimeric mixture 5:1) (iv) 68% CHO

O

t-Bu

t-Bu + 205a (17%)

(v) t-Bu

O 205b (48%)

O 204 (epimeric mixture 3:1)

Scheme 58 Reagents and conditions: (i) NaH, (EtO)2POCH2CO2Et, THF, r.t., 8 h; (ii) LiAlH4, Et2O, –70 °C, 3 h; (iii) CH2=CH(OEt), Hg(OAc)2, sealed tube, 36 h; (iv) PdCl2, CuCl2, O2, DMF, H2O, r.t., 24 h; (v) KOH (1 M), MeOH, THF, r.t., 8 h. Synthesis 2009, No. 2, 165–193


REVIEW


10

Cycloaddition Tactics

10.1

Diels-Alder [4+2] Approach

Various cycloaddition reactions have been used to generate spirocyclic compounds. For example, spiro compounds 212a–d were prepared in a ratio of 69:27:3:1 from enone 211 by a Lewis acid catalyzed Diels-Alder reaction (Scheme 61).73

O

211

(i)

+ isoprene

O

O H

H 212a

Scheme 61

212a–d

O

O H

H 212b

212c

212d

Reagents and conditions: (i) SnCl4·5H2O, r.t.

Bakkenolide A (217a), a sesquiterpene b-methylene spirolactone, was synthesized by a method that was based on an intramolecular Diels-Alder reaction (Scheme 62).74 In this context, the intramolecular Diels-Alder reaction of a functionalized triene led to a hydrindane bearing the required functional groups for a straightforward construction of the lactone moiety, thereby achieving the synthesis of bakkenolide A. Triene 214 was prepared from 4-benzyloxyacetoacetate (213) by sequential alkylations. The key intramolecular Diels-Alder reaction then furnished the unsaturated hydrindane 215 as a mixture of diastereomers. Treatment of this mixture with hydrogen in the presence of the palladium catalyst resulted in hydrogenation of the double bond. The hydrogenolysis of the benzyl group and

EtO

subsequent cyclization gave keto lactone 216. Finally, the exocyclic double bond was formed by a Wittig reaction, leading to bakkenolide A (217a). Four stereoisomers, 217a–d, were formed during the reaction in 62% yield in the ratio of 54:19:16:11. They were separated by reversephase preparative HPLC. A useful method75 has been reported for the synthesis of a spirocyclic lactam of required stereochemistry for the synthesis of gymnodimine, a member of a unique class of potent marine toxins. Gratifyingly, it was shown that the Diels-Alder reaction of tosylated dienophile 218 with diene 219 proceeded efficiently with diethylaluminum chloride at low temperature to give a single crystalline diastereomer of cycloadduct 220 (Scheme 63), which posseses the required framework for the gymnodimines. This reaction is, in fact, a formal Diels-Alder reaction proceeding through a stepwise process involving two sequential Michael reactions passing through highly stabilized carbocation intermediates. This overall sequence provides a concise entry into the spirocyclic gymnodimine building-block. O Ts

alkylation

(i)

N

Z or E 218

213

219

Scheme 63 67%.

220

Reagents and conditions: (i) Et2AlCl, CH2Cl2, –30 °C,

We reported a new method for the preparation of various 2,2¢-spirobiindane-1,3-dione derivatives with a [4+2]-cycloaddition reaction as a key step; these products may be useful precursors for the synthesis of unsymmetrical benO (i)

EtO BnO

O

OTBS

+

EtO

O

O N

BnO

BnO

Ts

OTBS

O

O

179

H

O 214

215 (ii) O (iii)

217a–d

O

O

H 216

O O

H

O

O

O

bakkenolide A (217a)

O

O

O

H 217b

H 217c

H 217d

Scheme 62 Reagents and conditions: (i) toluene, 2,6-di(tert-butyl)-4-hydroxytoluene (BHT), 190 °C, 93%; (ii) H2, Pd/C, EtOAc, HCl, dioxane, 54%; (iii) Ph3P=CH2, Et2O, 62%. Synthesis 2009, No. 2, 165–193


180

REVIEW

S. Kotha et al.

zoannulated fenestranes.76 We also demonstrated the utility of this [4+2]-cycloaddition methodology by preparing the key diene building block 223. In this regard, alkylation of indanedione 221 with highly sensitive 2,3-bis(iodomethyl)buta-1,3-diene (222) under phase-transfer-catalysis conditions gave diene 223 (Scheme 64). Reaction of the latter with various dienophiles was successful; for example, 223 reacted with dimethylacetylene dicarboxylate in anhydrous toluene under refluxing conditions for 24 hours to result directly in the aromatized product 224 (87% isolated yield). The same product can also be obtained by a [2+2+2]-cycloaddition strategy.76b O

O +

O

221

(i)

I I

O 223

222

+ O CO2Me

CO2Me

[4+2] (ii)

CO2Me O

CO2Me

224

diastereomer (Scheme 66).78 2-Methylenecycloalkane-1one derivative 229 is known to behave as a good Michael acceptor. TIPS

O

O

230

229

231

Scheme 66 Reagents and conditions: (i) TiCl 4, CH2Cl 2, –78 to –20 °C, 86%.

Moser and co-workers79 have developed a one-pot synthesis of spirocyclic ring systems starting with an arene– chromium tricarbonyl precursor. Their strategy can be applied to the stereoselective synthesis of fredericamycin A (1). The quaternary carbon center in spirocyclic compound 236 was generated through aldol addition of lithium ester enolate 233 to complex 232 (Scheme 67). This reaction was followed by a 1,4-silyl migration (234 → 235) and cyclization to afford the spiro product 236. The overall transformation is regarded as a [3+2]annulation reaction.

Scheme 64 Reagents and conditions: (i) MeCN, K2CO3, PTC, 71%; (ii) toluene, reflux, 24 h, 87%.

H

OLi

TMSO

OMe

O +

Tetracyclic ketones such as 226 and 228 can be synthesized from linear precursors by way of tandem intramolecular Diels–Alder reactions.77 The triple bond acts as a double dienophile, resulting in a two [4+2]-cycloaddition reactions in a single transformation from the corresponding dienes, 225 and 227 in this example (Scheme 65).

(i)

TIPS

+

(i)

steps

TMS Cr(CO)3 Cr(CO)3

232

236

233 cyclization Li

O

H

1,4-silyl migration

O

TMSO

H O

OMe O

O

(i)

(CO)3Cr

57%

Scheme 67

228

227

10.2

O

70%

Scheme 65

(CO)3Cr

TMS

Li 235

Reagents and conditions: (i) THF, –78 to 0 °C, 84%.

226

(i) O

OMe

234

225

1

O

Reagents and conditions: (i) BF3·OEt2, CH2Cl2, 0 °C.

[3+2]-Cycloaddition Approach

The Lewis acid promoted [3+2] cycloaddition of allylsilanes with an electron-deficient double bond has become a powerful tool for the synthesis of spirocyclic ring systems. Thus, the reaction of alkylidenecycloalkan-1-one 229 with allyltriisopropylsilane (230) in the presence of titanium(IV) chloride provided direct access to silylspirocyclopentanes such as 231, which was obtained as a single Synthesis 2009, No. 2, 165–193


Sequential annulation reactions of a dienone in the presence of allylsilane and titanium(IV) chloride resulted in the formation of a complex skeleton in a single experimental step.80 The initial dispiroketone intermediate 238 was formed by consecutive [3+2]-cycloaddition reactions between the allylsilanes and the two exocyclic double bonds of enone 237. The newly generated Lewis acid complex 238 underwent a Wagner–Meerwein rearrangement to form carbenium ion 239; this then underwent Friedel-Crafts alkylation to generate the pentacyclic framework 240, thereby creating five stereogenic centers in a single step (Scheme 68).

10.3

[2+2+2]-Cycloaddition Approach

The preparation of various 2,2¢-spirobiindane-1,3-dione derivatives like 243 was reported by our group to be pos-

REVIEW


sible from a key intermediate, namely bis-propargylated compound 242 (Scheme 69).76Indane-1,3-dione (221) was treated with 3-bromoprop-1-yne (241) under phasetransfer-catalysis conditions [K2CO3, anhyd MeCN, tetrabutylammonium hydrogen sulfate (TBAHS), r.t.] to obtain intermediate 242. Treatment of the compound 242 with h5-cyclopentadienylcobalt complex CpCo(CO)2 in the presence of various alkynes gave [2+2+2]-cycloaddition products 243.

TIPS O TIPS

H

Ph (i)

TIPS

237

240 H3O+ TiCl4

TIPS

TIPS

O

TIPS

Cl4Ti

TIPS

O

H

11

Other Cyclization Methods

11.1

Acid-Catalyzed or Cationic Cyclodimerization

H Ph 238

Scheme 68 47%.

239

O (i)

Br

+ 221

Recently, the synthesis of exocyclic cross-conjugated diferrocenyl trienes such as 244 was reported.81 These trienes were subjected to cyclodimerizations to generate spirocyclic dimers 246 (Scheme 70). Acid-catalyzed homoannular alkylation of one of the ferrocenyl substituents in the spirocyclic dimers resulted in the ‘three-petal’ carbocyclic system 247.

Reagents and conditions: (i) TiCl4, CH2Cl2, 40 °C,

O

O

241

In addition to the cyclodimerization of ferrocenyl-1,3dienes, cycloaddition and cyclodimerization reactions of 2,6-dibenzylidene- and 2,6-bis(4-methoxybenzylidene)1-methylcyclohexanol 248 was also studied.82 These compounds undergo in situ cyclodimerization involving [4+2] cycloaddition after dehydration of the tertiary alcohol by reaction with phosphorus oxychloride in pyridine or by treatment with alumina. In the presence of trifluoroacetic acid, acid-catalyzed cyclodimerization took place, leading to the methylidene-substituted spirocyclodimers 250, which themselves underwent intramolecular cyclization under prolonged contact with trifluoroacetic acid to form fused carbocyclic systems 251 (Scheme 71) which contain a central, ‘three petal’ fragment of six-membered rings.

O

242 +

O R

R

(ii)

R O

243

R

a R = CO2Me (22%) b R = Ph (26%) c R = TMS (26%)

Scheme 69 Reagents and conditions: (i) K2CO3, MeCN, TBAHS, 58%; (ii) CpCo(CO)2, n-octane, toluene, 140 °C.

H H H

Fc

Fc

H

Fc

H

H

Fc

(i) Fc

181

(ii)

Fc

246a

Al2O3

H

247a

Fc

245

Fc

H

Fe

Fc

OH H

Fc

Fc

H Fc

(iii) 244

Fe

H

Fc

Fc

(iv)

Fc

Fc = ferrocenyl

Fc

247b

246b Fc H

Fc H

Scheme 70 Reagents and conditions: (i) benzene, reflux, 2–7 h, 35%; (ii) TFA, benzene, reflux, 48 h, 63%; (iii) POCl3, pyridine, 5–10 °C → ∼20 °C, 42%; (iv) TFA, CH2Cl2, ~20 °C, 72 h, 42%. Synthesis 2009, No. 2, 165–193


182

REVIEW

S. Kotha et al. H HO

Ar

H

H

(i)

Ar

OH

O

O

H

H

OH

(i)

Ar

Ar

Ph

H

Ph H

248 Ar

a Ar = Ph b Ar = PMP

H

254

249

257

Ar

(ii)

Ar

C

H

Ar

H

H

R

O

Ar

Ni Ph Me N Me

(iii)

Ar

Ar CHAr

250

255 251

Scheme 71 Reagents and conditions: (i) POCl3, pyridine (249a = 67%, 249b = 72%) or Al2O3 (249a = 75%, 249b = 71%) or AcOH (quant.); (ii) AcOH–TFA (9:1) (250a = 68%, 250b = 67%); (iii) TFA (251a = 60%, 251b = 65%).

Oxidative Cyclization Method

An oxidative cyclization strategy with a catalytic amount of a hypervalent iodine(III) reagent can result in carbon– oxygen and even carbon–carbon bond formation.83 Along this vein, the oxidative spirocyclization reaction of phenol 252 with an environmentally friendly, recyclable hypervalent iodine(III) reagent, in combination with m-chloroperoxybenzoic acid as an effective chemical co-oxidant, was examined. This catalytic approach resulted in the conversion of phenol 252 into spirocyclic derivative 253 (Scheme 72). O

OH (i)

CO2H

O O

252

253

Scheme 72 Reagents and conditions: (i) 4-MeC6H4I(OCOCF3)2, MCPBA, TFA, CH2Cl2, r.t., 71%.

Spirocycle 257 can be synthesized from a simple acyclic precursor using nickel(0) as a catalyst.84 When dialdehyde 254 was treated in the presence of bis(1,5-cyclooctadiene)nickel(0) and N,N,N¢,N¢-tetramethylethylenediamine (TMEDA), 257 was delivered in 49% yield as a single diastereomer. The dialdehyde initially undergoes oxidative cyclization of the enal and alkyne groups to form the metallacycle intermediate 255. This intermediate is converted into the reactive bis-alkoxide species 256 by intramolecular aldol addition. Finally, aqueous workup protonates the alkoxides and delivers the target spirodiol (Scheme 73).

Synthesis 2009, No. 2, 165–193

Me N Me

O

N N

Ni O Me

Me

H Ph 256

CHAr

R = H, OMe

11.2

Me

Me

O


Scheme 73

Reagents and conditions: (i) Ni(cod)2, TMEDA, 49%.

The novel spiroquinone 264 was assembled by silver oxide oxidation of diethylstilbestrol.85 When stilbene derivative 258 was treated with six equivalents of silver oxide in dichloromethane at room temperature, the reactive orthoquinone intermediate 259 was formed. It then underwent a series of rearrangements (259 → 262), resulting in spirocatechol 263. Excess oxidizing agent present in the reaction mixture further oxidizes catechol 263 into spiroquinone 264 (Scheme 74). When the phenolic group of the starting stilbene is protected, such as methoxylated catechol 258b, then the reaction stops at the quinone stage (i.e., 259b) which further supports the rearrangement mechanism.

11.3

Asymmetric Carbocyclization

Mikami and co-workers86 demonstrated that a cationic rhodium(I) complex containing a skewphos ligand was useful as an enantioselective catalyst for asymmetric enetype carbocyclization of 1,6-enynes to generate quaternary stereogenic centers containing a spiro linkage. Cyclization of the six-membered-ring-containing ether derivative 265 at room temperature for 46 hours gave 266 (88% ee) along with olefin-migration product 267 in high enantiomeric excess (97% ee) (Scheme 75). Interestingly, the authors observed that the spirocyclization proceeded smoothly at room temperature in the case of amide pyran 268 to afford the desired spiro derivative 269 with extremely high enantioselectivity (94% ee) with no trace of olefin-migration product.

11.4

Domino Cyclization Method

Various alkaloids containing spiro linkage, such as erysodine 275, were constructed in an efficient manner by way of trimethylaluminum-mediated domino cyclization reactions (Scheme 76).87 When enol acetate 270 reacted with amine 271, the result was carboxamide intermediate 272, which on subsequent elimination of acetic acid provided

REVIEW


183

OR O 259b

O OR HO

or (i)

O

or (ii)

O

ascorbic acid

HO

Ag2O

HO

HO 263

264

258a R = H 258b R = OMe

O

O

OR O

HO

O

O

O

O

O

HO

259a R = H 259b R = OMe

Scheme 74

260 O

O H

O

Reagents and conditions: (i) Ag2O (6 equiv), CH2Cl2, r.t., 10 min, 99%; (ii) Ag2O (6 equiv), CH2Cl2, 0 °C, 30 min, 40%.

the N-acyliminium ion 273. This reactive species 273 then underwent electrophilic substitution on the aromatic ring to deliver the final tricyclic compound 274. In this methodology, three bonds were formed in a single step from cyclic enol acetate 270 and the aromatic amine derivative 271.

CO2Me (i)

+ CO2Me

O

O

CO2Me

O 267

266

265

(16%, 97% ee)

(53%, 88% ee) O

H 262

261

CO2Me

O (ii)

N Ts 268

TsN

CO2Me

269 (72%, 94% ee)

Scheme 75 Reagents and conditions: (i) [Rh(S,S)-skewphos)]2(SbF6)2 (5 mol%), CH2Cl2, r.t., 46 h. (ii) [Rh(S,S)-skewphos)]2(SbF6)2 (5 mol%), CH2Cl2, r.t., 36 h. OAc

An efficient protocol for the construction of spirocyclic lactams starting with primary amines, cycloalkenones, and acrylic acid methyl ester in the presence of trimethylaluminum was developed.88 Compound 278 was prepared in one step by phosphasilylation reaction from cyclopent2-en-1-one and acrylic acid methyl ester. The two-component domino reaction of 276 and 278 involved the generation of dimethylaluminum amide species 277, which reacted with the ester moiety of enone 278 to form an amide intermediate. The latter underwent Michael addition with its cyclic enone moiety to produce the spirolac-

CO2Me

HO

MeO 270

O

(i)

MeO

N

MeO

+ NH2

steps N

MeO

274 MeO erysodine (275)

MeO 271

MeO

N

O

AlMe2

O

MeO N MeO

MeO OAc 272

Scheme 76

273

Reagents and conditions: (i) Me3Al, benzene, reflux, 12 h, 79%. Synthesis 2009, No. 2, 165–193


184

BnNH2

REVIEW

S. Kotha et al. AlMe3 benzene

O BnNHAlMe2

+

MeO

277

276

CO2Et (ii)

CO2Et (i)

O

278

O (i)

N O

279

O

R

(i)

Reagents and conditions: (i) benzene, 80 °C, 79%. Ph

289

tam 279 in good yield (Scheme 77). Notably, bulky amines gave very poor yield of the spiro product 279, which clearly indicated that steric hindrance played a major role in this reaction.

290

Ph

R = SePh

Scheme 80 Reagents and conditions: (i) Ph3SnH, AIBN, benzene, reflux, 85%.

Roberti and co-workers89 developed a two-step reaction sequence involving the combination of a three-component domino Knoevenagel–Diels-Alder–epimerization reaction for the construction of natural-product-like structures that could be further derivatized by Suzuki coupling. One such synthesis of spirocyclic triones 285 is shown in Scheme 78.

11.5

O 288

MeO

MeO

Bn

Scheme 77

SnBu3

287

Scheme 79 Reagents and conditions: (i) n-Bu3SnH, AIBN, N2, 80– 85 °C, 10 mm, 60%; (ii) PPTS, CH2Cl2, r.t., 48 h, 100%.

O

O

O

286

CO2Et

quent treatment with pyridinium p-toluenesulfonate (PPTS) in dichloromethane gave the tin-free spirocyclic compound 288 in quantitative yield.90 A useful precursor for fredericamycin A (1) was assembled via radical cyclization of selenide 289 (Scheme 80). Phenylseleno ketone 289 generated the corresponding radical intermediate in the presence of triphenyltin hydride and 2,2¢-azobisisobutyronitrile. The a-keto radical thus formed underwent diagonal ring closure with the triple bond to generate spirocyclic product 290.91

Radical Cyclization Approach

Radical reactions have become an integral part of planned organic syntheses and in this regard spiro compounds are no exception. The most widely used procedure for the generation of spiro compounds is based on tin chemistry. Functionalized spiro system 287 was synthesized from propargyl compound 286, with a tin-mediated radical cyclization reaction as the key step (Scheme 79). Subse-

In connection with the synthesis of fredericamycin A (1), Rama Rao and co-workers1c employed the tin-mediated radical ring closure as a key step to generate spirocyclic system 292. In this respect, the radical cyclization of monobromo derivative 291 in refluxing benzene took

O

S N 280

+ O O

CO2H

Ph O

S

CO2H N H (i)

281

Br

O

+ O

Br 283

Ph 282

O

Ph HO

O

Ph

B(OH)2

O

O

O

CH2OH O

(ii)

285

284 Br

Scheme 78

Reagents and conditions: (i) MeOH, r.t., 72 h, 90%, dr >99:1; (ii) Pd(PPh3)4, Na2CO3 (aq), toluene–EtOH (3:1), 81%.

Synthesis 2009, No. 2, 165–193


REVIEW OMe OMe

O MeO Br

MeO

OMe OMe

O

O N

(i)

(H2C)n

(i)

MeO

(H2C)n

296

O MeO

291

297

N O

O

O (ii)

1,5-hydrogen transfer

1

MeO

SPh

PhSH OMe OMe

O

O

+

PhS

AIBN

292

Scheme 81 Reagents and conditions: (i) Ph3SnH, AIBN, benzene, reflux, 55%; (ii) BBr3, CH2Cl2, –78 °C, 30 min, 0 °C, 10 min.

O SPh

O SPh

place upon slow addition of triphenyltin hydride and 2,2¢azobisisobutyronitrile, and resulted in the desired spiro compound 292 (Scheme 81).1c Demethylation of 292 gave 1, which was found to be identical to a sample of the natural product. Tandem radical cyclization was found to be a useful tool for the construction of angular triquinanes. For example, a concise route to spiro system 294a and its C-9 epimer, 294b, was developed, and involved a tributyltin hydride mediated cyclization reaction of 293, as shown in Scheme 82.92 Wolff–Kishner reduction of the product mixture provided a second mixture, namely silphiperfolene (295a) and its C-9 epimer, 295b. H

H

O

silphiperfolene (295a) (triquinane natural product)

Br (i)

294a

O + H

SPh

n = 1, 92%, dr 60:40 n = 2, 73%, dr 62:38

MeO OMe OMe

Wolff–Kishner

+

reduction O

H

293

294b (C9-epi)-silphiperfolene

Scheme 82

185


Reagents and conditions: (i) Bu3SnH, 66%.

Thiophenol-mediated cyclizations for the synthesis of spirocyclic compounds from alkyne precursors were also demonstrated.93 The reaction cascade involved the intermolecular addition of a phenylthiyl radical to a terminal triple bond, generating an alkenyl radical. Subsequent 1,5hydrogen transfer and 5-exo-trig radical cyclization led to the spirocyclic compounds. During the cyclization process, a phenylthio moiety was incorporated into the final

5-exo-trig

PhSH SPh

Scheme 83 reflux.

Reagents and conditions: (i) PhSH, AIBN, t-BuOH,

cyclized product. As per Scheme 83, when the terminalalkyne-substituted cycloalkanone 296 was treated with thiophenol and 2,2¢-azobisisobutyronitrile under the standard reaction conditions of free-radical cyclization, spirocyclic ketone 297 was obtained with moderate stereoselectivity. Spiro[4.5]decanes are easily prepared in a stereoselective manner by sequential radical cyclizations. It was demonstrated that ω-alkynyl carbonyl compounds that bear an activated alkene, like 298, can be converted into spiro derivatives in the presence of samarium(II) iodide and an additive such as hexamethylphosphoramide or samarium metal.94 In the example shown, ketyl radical 299 generated during the reaction undergoes initial cyclization with the alkene moiety, resulting in the formation of a second radical intermediate, 300, which delivers the spirocyclic compound 301 upon cyclization with the alkyne group. The stereochemistry at C6 in the final product can be altered by changing the activator from hexamethylphosphoramide to samarium metal. The probable mechanism for the reaction sequence is shown in Scheme 84. Angularly fused tricyclic ketones can also be assembled by a tandem radical cyclization sequence.95 Treatment of the unstable iodo ketone 302 with tributyltin hydride and 2,2¢-azobisisobutyronitrile generated the key radical intermediate 303, which on further cyclizations delivered the tricyclic framework 305 in a smooth manner (Scheme 85). This methodology has been applied to the synthesis of tetracyclic alkaloids such as (+)-paniculatine (306). The synthesis of the tricyclic core of alkaloids like (±)-stemonamide (310a) and (±)-isostemonamide (310b) was reported by Ishibashi and co-workers.96 By utilizing a radical cascade cyclization, the monocyclic derivative 307 was converted into the tricyclic skeleton 309. Thus, Synthesis 2009, No. 2, 165–193


186

REVIEW

S. Kotha et al. R1 O Y X

5

6

OH

301a (5R,6S)

R1

R1

O

O Y

(i)

Y

X

X

1

O X Y

298 R1 = TMS, H Y = C, P X = OEt, (OEt)2

OR Sm

O

O

Sm

299a

300a R1

OSm

O

(ii) X

Y

X Y

O

O Sm

R1 299b

300b

R1 O Y X

5

6

OH

301b (5R,6R)

Scheme 84 Probable mechanism for tandem cyclization. Reagents and conditions: (i) SmI2, t-BuOH, Sm, THF, 0 °C to r.t.; (ii) SmI2, t-BuOH, HMPA, THF, 0 °C to r.t.

cursor was subjected to various intricate synthetic transformations to afford the alkaloids (±)-310a and (±)-310b.

Me SiMe2Ph

SiMe2Ph O

TMS

TMS

O

HO

(i)

I

N

H

steps

12

Metathesis Approaches

12.1

Ring-Closing-Metathesis (RCM) Approach

O H

302

SiMe2Ph

SiMe2Ph O

TMS

Scheme 85 82%.

TMS

O

H

303

H paniculatine (306)

305

304

Reagents and conditions: (i) Bu3SnH, AIBN, benzene,

treatment of enone 307 with tributyltin hydride and 1,1¢azobiscyclohexanecarbonitrile (ACN) in refluxing toluene delivered tricyclic dione 309 in a single step via the radical intermediate 308 (Scheme 86). This tricyclic preSynthesis 2009, No. 2, 165–193


Although there are numerous reports on the synthesis of five-membered spirocyclic systems, a strategically limited number of methods are at hand. The ring-closing-metathesis reaction, or RCM, is fairly common, can be induced by a variety of homogeneous catalysts, and has many and varied chemical applications. Recently, this methodology was applied in the preparation of several carbocyclic and heterocyclic systems. The two Grubbs catalysts that are generally useful for RCM are shown in Figure 5. These ruthenium complexes are less sensitive to moisture and air, can be handled without any special equipment, and they have remarkable functional group tolerance. The applications of RCM in the synthesis of spirocyclic compounds are discussed here. Even though the RCM strategy falls under the heading of ring closure of geminally disubstituted compounds, we have given this theme its own section because of its unique nature.

REVIEW

187


O

O

O

O

(i) (i) N

Br

RCM

N O

O

312

311

307

308 N

OMe

N

OMe

(ii) O

N

MeO O O

O

MeO

RCM

313

314

MeO O

N

O

H

N

(iii)

O

+

O O MeO

double RCM

309a

steps

stemonamide (310a) O

O N

O

H

N

316

315

Scheme 87 Reagents and conditions: (i) Grubbs I (5 mol%), DCE, r.t., 30 min., 94%; (ii) Grubbs I (2 mol%), benzene, 60 °C, 5 h, 95%; (iii) Grubbs I (5 mol%), CH2Cl2, r.t., 6 h, 98%.

309b

O

O (i)

isostemonamide (310b)

RCM

Scheme 86 Reagents and conditions: (i) Bu3SnH, ACN, toluene, reflux, 55% (ca. 1:1).

PCy3 Cl

Mes-N Ph

Cl

H

Cl

Ru Cl PCy3

N-Mes Ph

O

O 318

317

Scheme 88 Reagents and conditions: (i) Grubbs I (5–10 mol%), toluene, reflux, 77%.

Ru

Grubbs I

PCy3

H (i)

Grubbs II

O

O

Figure 5

N

HO

OH

+

OH

HO

First- and second-generation Grubbs catalysts

The Meyers research group reported the formation of spirocyclohexenone 312 by RCM of the diallyl intermediate 311.97 In connection with an unusual cyclic amino acid synthesis, the Undheim research group98 reported a useful spiroheterocycle, 314, obtained as an intermediate by way of an RCM as key step using the Grubbs I metathesis catalyst. Similarly, Harrity and co-workers99 reported the production of spiro[5.5]nonadiene 316 by RCM on tetraene derivative 315 under mild reaction conditions (Scheme 87). Our research group100 produced various spirocyclic systems from b-dicarbonyl compounds containing active methylene substrates. The reactions involved a palladiumcatalyzed allylation and an RCM as key steps, as shown in Scheme 88 with 317 → 318 as an example. In an extension of this methodology, tricyclic derivatives 321 and 322 were prepared from 318 as starting compound (Scheme 89).101 A double RCM was used in the formation of spirocyclic rings in a single step.102 To this end, the formation of spirocyclic compounds from tetraene 323 using double RCM was demonstrated. Further, NK-1 receptor antagonist 325 was prepared from spirocycle 324 in three steps. The key

320

319

318

(ii)

(ii)

HO

HO

HO

HO

321 (85%)

322 (40%)

Scheme 89 Reagents and conditions: (i) CH2=CHCH2MgCl, 66% (syn/anti = 5:1); (ii) Grubbs I (10 mol%), DCE, 60 °C.

steps involved in this strategy were the double RCM of tetraene 323 to prepare spirocycle 324 and the selective functionalization of one of the two double bonds in the spirocyclic compound. A reductive Heck reaction was used to discriminate between the two double bonds and the reaction delivered compound 325 in a highly regioand stereoselective manner. In a related report,103 a general method for the construction of an azaspiro system from cyclic ketones using imine alkylation and RCM as key steps was established (Scheme 91). It was observed that the formation of azaspi-

Synthesis 2009, No. 2, 165–193


188

REVIEW

S. Kotha et al. O HO O

O (i)

N

Ph

steps

Ts N Ph

Ts

324a + O

323 N

OCF3

Ph

N H

325

Ph

Ts 324b

Reagents and conditions: (i) Grubbs I, CHCl3, 86% (70% ds).

Scheme 90

rocyclic compounds can be executed under catalysis with the Grubbs I catalyst without nitrogen protection, although these transformations required high catalyst loading and longer reaction time (e.g., 326 to 327). Protection of the nitrogen group reduced the reaction time and catalyst loading (e.g., 326 to 330). Later, it was observed that cyclization of the unprotected dienes with the Grubbs II catalyst resulted in a rapid and efficient ring closure to the spirocyclic compounds in high yields (e.g., 326 → 328). This methodology can be extended towards the synthesis of complex natural products like halichlorine and pinnaic acid, both of which exhibit novel biological activities. BnO

H

H

BnO (ii)

HN

O

96% O Meldrum's acid (331) Me

332 Me

(iii)

N

81%

O

HN

328 (83%)

326

MeO2C

H

H

BnO (iii)

N

333 Me

O

O

O

O N

(iv)

O Me

O

O

N

O 88%

N Me

O

N Me

335

barbituric acid (334)

O 336

reaction conditions, as shown in Scheme 92.106 Since barbituric acid derivatives are well-known targets in medicinal chemistry and in materials and supramolecular sciences, it was anticipated that this methodology would find interesting applications in these areas. Schobert and Urbina-González107a reported the synthesis of butanolide derivative 337 (Figure 6), by RCM of diallyl tetronic acid derivatives. Several other groups have used the allylation and RCM strategy in the synthesis of various synthetic targets, including 338–340 (Figure 6).107b–d O

BnO

73%

O

O N

O O

(ii)

HN

327 (33%)

BnO

O O

(i)

Scheme 92 Reagents and conditions: (i) allyl bromide, KF, celite, MeCN; (ii) Grubbs I (5–10 mol%), CH2Cl2, r.t.; (iii) allyl bromide, K2CO3, BTEAC, CHCl3; (iv) Grubbs I (5–10 mol%), toluene, reflux.

H

(i)

O O

MeO2C

O

O O

O

N

O O

O O

329

330 (92%)

butanolide derivative 337

carbohydrate synthon 338

Scheme 91 Reagents and conditions: (i) Grubbs I (60 mol%), PTSA, CH2Cl2, 20 d; (ii) Grubbs II (10 mol%), PTSA, 56 h; (iii) Grubbs I (5 mol%), CH2Cl2, 2.5 h.

O

O

Kotha and co-workers prepared several biologically relevant b-dicarbonyl derivatives, such as Meldrum’s acid, barbituric acid, thiobarbituric acid, tetronic acid, and thiotetronic acid derivatives, by using allylation and RCM as key steps.104,105 Spiroannulation with these compounds was demonstrated to take place under two different sets of

Synthesis 2009, No. 2, 165–193


O spirolactone 339

O acorones 340

Figure 6 Selected examples of compounds prepared by using the allylation and RCM strategy

REVIEW

Selected Synthetic Strategies to Spirocyclics R

R

R

work of 11, an ACAT inhibitor (Figure 2), which is an important therapeutic agent.109a To this end, the readily available b-naphthol (344) was O-allylated to give derivative 345 (Scheme 94). Microwave-assisted Claisen rearrangement of 345 gave the C-allylated product 346. Along similar lines, the diallylated product 348 was prepared. It is interesting to note that the unexpected Claisen rearrangement product 348 was isolated. Even though the formation of this unusual Claisen rearrangement product involved the loss of aromatization in one ring, additional stabilization was gained because of the resonance energy of the enone, and this may be the driving force for its formation.109b When compound 348, dissolved in dichloromethane, was subjected to RCM in the presence of the Grubbs II catalyst at room temperature, 349 was the sole product. When the RCM of 348 was carried out with the Grubbs I catalyst instead, some double bond isomerization product was obtained along with the expected spiro derivative 349.

R

(ii)

(i)

R

341

aR=H b R = NO2

R

342

76% 70%

343

87% 85%

Scheme 93 Reagents and conditions: (i) allyl bromide, K2CO3, BTEAC, CHCl3; (ii) Grubbs I (5–10 mol%), toluene, reflux.

OH

O

(i)

OH (ii) 81%

95%

346

345

344

The spiroannulation protocol98,110 has also been used for the preparation of compounds that are structurally similar by adopting a different strategy (Scheme 95).111 For example, diallylation of tetralones 350 followed by RCM of 351 gave compounds 352. Application of the same strategy to indanones 353 gave a series of spiroindane derivatives 355.

(i) 90%

O

O

(iii) 83%

O

(ii) 68%

348

349

12.2

347

Scheme 94 Reagents and conditions: (i) allyl bromide, K2CO3, anhyd acetone, r.t., 4 h; (ii) MWI (power = 100%), 15 min; (iii) Grubbs II (5 mol%), CH2Cl2, r.t.

Ring-Opening Cross-Metathesis (ROCM) on Spirocyclics

Ring-opening cross-metathesis (ROCM) is similar to acyclic cross-metathesis, except that one of the acyclic olefins is generally replaced by a strained cycloalkane, such as norbornene.112 The driving force for such reactions is the release of strain energy. Olefin metathesis coupled with other reactions of alkenes, such as the Diels-Alder reaction or Claisen rearrangement, is less explored in the literature.

In a related study, 9,9-diallylfluorenes 342, obtained by the reaction of fluorenes 341 with allyl bromide in the presence of potassium carbonate and benzyltriethylammonium chloride (BTEAC) as a phase-transfer catalyst in chloroform, were subjected to RCM to deliver 343 (Scheme 93).108

Recently, a simple and general methodology to prepare spiroindane derivatives that contain six rings (e.g., 358)

The scope of the spiroannulation methodology was further extended through the preparation of the basic frame-

O

O

O (i)

(ii) R

R

R 350

351

aR=H b R = OMe

352

53% 49%

94% 90% O

O R2

(i)

R2

353 a R1 = R2 = H b R1 = OMe, R2 = H c R1 = Br, R2 = H d R1 = R2 = OMe

O (ii)

R1

R1

Scheme 95

189

R2 R1

354 49% 56% 65% 57%

355 81% 93% 86% 80%

Reagents and conditions: (i) NaH, allyl bromide, THF, r.t.; (ii) Grubbs I (5–10 mol%), toluene, reflux.

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was reported;16 the method used an ROCM strategy as a key step. In this strategy, the spiro Diels–Alder adduct 357 was prepared by a [4+2] cycloaddition of the spirodiene 32 with various dienophiles, such as 1,4-anthraquinone (356) as shown in Scheme 96. The adduct was then subjected to ROCM with a symmetrical acyclic alkene such as cis-1,4-diacetoxybut-2-ene to deliver the symmetrical spiroindane derivative product. To the best of our knowledge, this is the first example wherein complex spirocycles containing up to six rings were formed by using a sequential Diels–Alder and ROCM strategy.

32 O

+

O

(i)

O 356

O

(ii) AcO

H

O

O

AcO 358

Scheme 96 Reagents and conditions: (i) [4+2] cycloaddition, 65%; (ii) cis-1,4-diacetoxybut-2-ene, Grubbs II, 61%. OMe

OMe Co2(CO)6

O

O

(i) O

359

360

Scheme 97 Reagents and conditions: (i) Et2O–pentane, 60 °C, 9 h, 73%.

(i) O

O

13

Pauson–Khand Reaction

The intramolecular Pauson–Khand (IMPK) cyclization of dicobalt hexacarbonyl complexes of 1,6-enynes seems to be an extremely useful approach for the synthesis of various polycyclics containing a bicyclo[3.3.0]octanone fragment. For example, this IMPK approach was used to synthesize tetracyclic product 360 (Scheme 97), a precursor to the diterpene crinimpellin A (9; Figure 2).113 In this reaction, 360 was obtained in 73% yield when the cyclization took place upon thermolysis of 359 in a diethyl ether– pentane solution. In their work towards the formal synthesis of (±)-a and (±)-b-cedrene derivatives, Kerr and co-workers made use of an IMPK reaction. The tricyclic carbon skeleton 362 (Scheme 98) is a precursor in the synthesis of cedrone, which can be converted into a- and b-cedrene (8; Figure 2) by a known procedure.114 Enone 362 was obtained from 361 in high yield (91%) as a 2:1 mixture of stereoisomers when the IMPK reaction was carried out at room temperature using trimethylamine N-oxide (TMANO·2H2O) as a dehydrating agent (Scheme 98).

357

H

The novelty of this approach relies on the fact that during the ROCM, the stereochemical information is conserved throughout the synthetic sequence. This approach to functionalized spirocycles may open up new routes to unknown fenestranes5,8 and intricate natural products12c with spiro linkages.

The synthesis of a tricyclic enone such as angular triquinane 365 was reported to utilize an IMPK reaction as a key step (Scheme 99).115 Treatment of enyne 364 with dicobalt octacarbonyl in benzene gave enone 365 in 35% yield. This is a typical example of the generation of a quaternary carbon at a multiple ring fusion via IMPK; 365 ultimately leads to the natural product isocomene. The IMPK reaction was also used for the synthesis of spiro(cyclopropanebicyclo[n.3.0]alkenone) derivatives.116 The trimethylsilyl-protected enyne 368, with a carbonyl

O O

Co2(CO)6 361

steps

O

O H

362

cedrone (363) 2 steps

+ H α-cedrene

Scheme 98

Reagents and conditions: (i) TMANO·2H2O (9 equiv), 91%.

Synthesis 2009, No. 2, 165–193


H β-cedrene

REVIEW


191

O

i

EtO2C

CO2Et

(i)

O EtO2C 364

365

Scheme 99 35%.

CO2Et 372

375

EtO2C

Reagents and conditions: (i) Co2(CO)8, benzene, 80 °C,

CO2Et

(ii)

group adjacent to the acetylenic moiety, was synthesized from oxo-derivatives 366 and 367 by Wittig olefination followed by coupling with lithium (trimethylsilyl)acetylide. Pauson–Khand reactions of the methylene cyclopropane derivative 368 proceeded smoothly to give spirocyclopropanated bicyclic enone 369 (Scheme 100).

O

O +

(i) OEt

CO2Et

CO2Et

EtO2C

CO2Et

373 (36%)

OEt

CO2Et

CO2Et

EtO2C

CO2Et

374 (36%)

Scheme 102 Reagents and conditions: (i) Co/C, CO (30 atm), THF, 150 °C, 18 h, 87%; (ii) Co/C, CO (30 atm), THF, 130 °C, 18 h.

O O 366

367

O (ii)

TMS

TMS O

(iii)

369

O

368

Scheme 100 Reagents and conditions: (i) Br(CH2)3PPh3+Br–, NaH, DME, 70 °C, 11 h, 26%; (ii) lithium (trimethylsilyl)acetylide, BF3·OEt2, THF, –100 °C to –78 °C, 1.5 h, 70%; (iii) Co2(CO)8, MeCN, 80 °C, 16 h, 63%.

van der Waals and Keese117prepared [5.5.5.5]fenestrenedione 371 in 9.4% yield via tandem Pauson–Khand tetracyclization from the open-chain enediyne 370 shown in Scheme 101. In another study118 heterogeneous cobalton-charcoal (Co/C) was used as a catalyst in a tandem carbocycloaddition reaction of 1,6-diyne 372 and carbon monoxide (Scheme 102). A mixture of compounds 373 (36%) and 374 (36%) was obtained when the reaction was carried out at 130 °C. Further heating of 373 gave 374. When 372 was treated with cobalt-on-charcoal at 150 °C, the spiro compound 375 was obtained in 87% yield as the sole product. The above reacion was also attempted under dicobalt octacarbonyl catalysis. It is interesting to note that the heterogeneous cobalt-on-charcoal catalyst has advantages over the homogeneous dicobalt octacarbonyl system, including facile separation and reusability. O

H

H O

(i)

OTMS 370

371

OTMS

Scheme 101 Reagents and conditions: (i) Co2(CO)8, NMO, CH2Cl2, 9.4%.

14

Conclusions and Future Prospects

This review on recent synthetic approaches to spirocycles deals with various advances made up until 2007. Recently, Hudlicky pointed out that the generation of quarternary centers is a most difficult task.119 Here, we have described many successful solutions to this challenging task, including the design and synthesis of quaternary centers that reside within molecular frameworks ranging from intricate natural products to theoretically interesting molecular entities. We hope that this review will catalyze some of the future work dedicated to developing methodologies related to the creation of spiro centers.

Acknowlegment We thank DST and CSIR, New Delhi for their financial support of our research programmes over the past few years.

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