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3 [2 + 2]-Photocycloaddition of Vinylogous Amides and Esters (Substrate Classes A2 and A3)

3 [2 + 2]-Photocycloaddition of Vinylogous Amides and Esters (Substrate Classes A2 and A3)

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6.3 [2 ỵ 2] Photocycloaddition of Vinylogous Amides and Esters



O



O

, h



R

R



R



OPG



R



R

R



A3



O



O



R



OPG



E



R



O



O



F



G



Scheme 6.18



Upon [2 ỵ 2] photocycloaddition to product E and protecting group removal, the

retro aldol fragmentation can be initiated by base or acid treatment (Scheme 6.18).

Under basic conditions, alkoxide F generates an enolate which is subsequently

protonated to the 1,5 diketone G.

With Q ¼ N, a similar fragmentation reaction is possible (retro Mannich reaction),

which leads to an imine or an iminium ion [57]. Fragmentations of this type have been

frequently used for substrates of type A3 but can also be found for substrate class A2,

A5, and A6 (vide infra).

6.3.1

Endocyclic Heteroatom Q in b-Position (Substrate Class A2)



Substrates of this compound class are classified as 4 oxa (Q ¼ O), 4 aza (Q ¼ N),

and 4 thia 2 cycloalkenones (Q ¼ S). They undergo both intra and intermolecular

[2 ỵ 2] photocycloaddition reactions smoothly. The regioselectivity of an intermo

lecular reaction is in favor of the HT product if an alkene is employed which is

substituted by a donor substituent. The regioselectivity is often higher than the

regioselectivity achieved in the reaction of the same alkene and a cycloalkenone.

4 Aza 2 cycloalkenones can only be used in [2 þ 2] photocycloaddition reactions

if the nitrogen atom is appropriately substituted by an electron withdrawing

substituent. Otherwise, a single electron transfer reaction precludes the photo

cycloaddition pathway [58].

6.3.1.1 4-Hetero-2-Cyclopentenones

3(2H) Furanones (4 oxa 2 cyclopentenones) have been extensively explored as

[2 ỵ 2] photocycloaddition substrates [59, 60]. A recent intermolecular example

(Scheme 6.19) illustrates the application of their photocycloaddition chemistry to



O



hν (λ > 320 nm)

[2'-acetonaphtone]

5 °C (CH 2Cl2)



H

+



O



O



46%



Ph

47



O



48



H H



O

O



O



Scheme 6.19



O



Ph H

49



H



j183



j 6 Formation of a Four Membered Ring



184



n=1

hν (λ = 350 nm)

r.t. (PhH)



O

O



O



n



62%

51



O



n=2

hν (λ = 350 nm)

r.t. (PhH)

90%



O



O

52



50



Scheme 6.20



natural product synthesis. The natural product biyouyanagin A (49) was obtained

from enone 47 and terpene fragment 48 in a stereoselective fashion [61]. The spatial

approach of the reaction partners is in line with a cyclic stereocontrol exerted by

the ring substituents, leading to the depicted cis anti cis product. The regioselectivity

and position selectivity may be understood based on the stability of the intermediate

1,4 biradical, but they are still remarkable given that four double bonds are available

for attack with two different modes of addition each.

The 3(2H) furanones are as the other 4 hetero 2 cyclopentenones normally

2,2 disubstituted to avoid enolization to the respective 3 hydroxyfuran. If one of the

substituents is an alkenyl side chain, then intramolecular [2 ỵ 2] photocycloaddition

reactions are possible with the regioselectivity being dependent on the chain length

(Scheme 6.20). The allyl substituted substrate 50 (n ¼ 1) gave predominantly the

formal straight product 51 [62], while the butenyl substituted substrate 50 (n ¼ 2)

resulted in formation of the crossed product 52 [63].

The 4 aza and 4 thia 2 cyclopentenone exhibit similar reactivity as their oxana

logues. As an example, the reaction with 2,3 dimethyl 2 butene is compared in

Scheme 6.21. All three compounds 53a 53c react in equally high yields, delivering

the products 54 as single diastereoisomers [58, 64, 65]. By comparison of the reaction

rates under identical conditions it was found that the azacompound 53b reacts most

rapidly, followed by the thiacompound 53c. The observed relative rate constants in

the reaction with 2,3 dimethyl 2 butene were 0.06: 0.11: 1.0 for 53a:53c:53b [65].

The utility of dioxopyrrolines in [2 ỵ 2] photocycloaddition reactions was compre

hensively demonstrated by Sano et al. [66]. Substrate 55, for instance, underwent

a clean reaction with 2 trimethylsilyloxy butadiene to provide bicyclic HT product 56

as a single diastereoisomer (Scheme 6.22). In line with previous observations [67], the

vinyl group was positioned exo relative to the five membered ring, and the silyloxy



O



hν (λ > 340 nm)

r.t. (PhH)



O



X



X

53

Scheme 6.21



54



54a X = O

54b X = NCOOEt

54c X = S



99%

90%

90%



6.3 [2 ỵ 2] Photocycloaddition of Vinylogous Amides and Esters



OTMS



O

COOMe



O



O



hν (λ > 290 nm)

0 °C (DME)

O



N

OMe

PhS



O

O



OTMS



N

79%



COOMe



COOMe



N



Ar



OMe



OMe

OMe



PhS

55



Ar



56



57



Scheme 6.22



group endo. A 1,3 anionic rearrangement was used for ring enlargement of the four

to a six membered ring. Further elaboration resulted in the cycloerythrinan 57, which

is a versatile precursor for many erythrinan alkaloids, for example, (Ỉ) erysotrine.

6.3.1.2 4-Hetero-2-Cyclohexenones

The photochemistry of 4 oxa 2 cyclohexenones is not significantly different from

the corresponding oxacyclopentenones. The reaction outcome of intermolecular

reactions is complicated by the fact that as with the corresponding carbocyclic

cyclohexenones a trans fusion of the cyclobutane to the six membered ring is

partially observed, depending on the nature of the alkene and the enone [59, 68]. The

reaction of enone 58 with cyclopentene yielded exclusively the cis anti cis products

59 with low facial diastereocontrol exerted by the existing stereogenic center

(Scheme 6.23). In an interesting consecutive reaction, both diastereoisomers 59

were converted into a single product 60 by an acid catalyzed retro Michael/retro

Aldol/Michael reaction sequence [69].

Benzannelated 4 oxa 2 cyclohexenones (chromones) react in a similar fashion to

deliver the respective cyclobutanes in a syn selective addition. The reaction has been

recently applied to the formal synthesis of (Ỉ) heliannuol D [70].

The utility of the [2 ỵ 2] photocycloaddition to 4 aza 2 cyclohexenones has been

explored by Comins et al. in synthetic approaches to different alkaloids [71, 72]. As

originally reported by Neier et al. the corresponding acyl and alkoxycarbonyl

substituted 2,3 dihydropyridin 4(1H) ones are particularly useful substrates [73]. In

a recent study, the intramolecular reaction of dihydropyridone 61 was found to lead

to the tricyclic product 62, which was further converted into the quinolizidine 63



O



O



hν (λ = 300 nm)

r.t. (EtOAc)

Ph



j185



O

58



Scheme 6.23



70%



Ph



H



O



H

59



[TsOH]

80 °C (PhH)

63%



H



O



Ph



CHO



60



j 6 Formation of a Four Membered Ring



186



O



N



90%



O



reductive

cleavage



O



hν (Hg lamp)

r.t. (ac)



OH



N



N



62



63



O

61



Scheme 6.24



(Scheme 6.24) [74]. The facial diastereoselectivity was controlled by the stereogenic

center in the starting material. An adjustment of the relative configuration was

performed by an oxidation/reduction sequence, and ring opening at the indicated

bond was achieved by a SmI2 induced reduction. It turned out that product 63 was

not identical to the lupin alkaloid ( ỵ ) plumerinine, to which structure 63 was

originally assigned.

The low triplet energy of 4 thia 2 cyclohexenones allows for [2 ỵ 2] photocycload

dition reactions of these substrates, even with electron deficient enenitriles and with

conjugated dienes, which serve commonly as triplet quenchers [75].

6.3.2

Exocyclic Heteroatom Q in b-Position (Substrate Class A3)



Substrates of class A3 are formally derived from cyclic 1,3 diketones or the respective

enols. The most commonly used substrates in [2 ỵ 2] photocycloaddition chemistry

are the corresponding oxygen derivatives (Q ¼ O), which are vinylogous esters or

anhydrides. In general, intermolecular reactions of substrates A3 are as compared

to the reactions of substrates A2 less efficient and lower yielding. The required

excitation wavelength is similar to A2, and the reactions are commonly initiated by

direct excitation but not by sensitization. As depicted in Scheme 6.18, the products of

a [2 ỵ 2] photocycloaddition invite fragmentation reactions, which have been used

extensively in synthesis. In a recent approach to the tricyclic skeleton of fusoxyspor

one (66), substrate 64 was converted into the tetracyclic product 65 (Scheme 6.25)

which, upon saponification, underwent the desired retro aldol reaction [76]. The

facial diastereoselectivity of the reaction as induced by the stereogenic center in

the chain can be understood based on 1,3 allylic strain arguments [77]. The relative

configuration in the ring is dictated by the cis fusion of the rings annelated to the

central cyclobutane.



O



hν (λ > 290 nm)

0 C (MeCN)

69%



OAc

64

Scheme 6.25



O



O



H

AcO H

65



66



6.3 [2 ỵ 2] Photocycloaddition of Vinylogous Amides and Esters



j187



Pd2(dba)3,

O

Ph2P



O



O



69



hν (Hg lamp)

−55 °C (MeCN)

O

O



50-70%



N

t Bu



O



10 °C (dioxane/THF)

O



O



O



89% (90% ee)

O



O



67



68



70



Scheme 6.26



A very useful extension of the de Mayo reaction has been recently introduced by

Blechert et al. (Scheme 6.26) [78]. The retro aldol fragmentation was combined with

an intramolecular enantioselective allylation (asymmetric ring expanding allylation)

catalyzed by a chiral Pd complex. Bicycloheptane 68, for example, was accessible by

intermolecular [2 ỵ 2] photocycloaddition of cyclopentenone 67 with allene. Further

transformation in the presence of Pd2(dba)3 (dba ¼ dibenzylideneacetone) and the

chiral oxazoline ligand 69 (tBu phox) resulted in the enantioselective formation of

cycloheptadione 70.

Substrates A3 (Q ¼ O) have been employed not only as starting materials for

fragmentation reactions but also to probe novel stereoselectivity concepts. The

photochemical transformation of axial chirality into central chirality was achieved

by Carreira et al., who employed chiral, enantiomerically pure allenes in intramo

lecular [2 ỵ 2] photocycloaddition reactions (Scheme 6.27) [79]. The reaction of

enantiomerically pure (99% ee) cyclohexenone 71, for example, yielded the two

diastereomeric products 72a and 72b, which differed only in the double bond

configuration. Apparently, the chiral control element directs the attack at the allene

to its re face. The double bond isomerization is due to the known configurational

liability of the vinyl radical formed as intermediate after the first C C bond formation

step (see Scheme 6.2, intermediate C).

In another approach to control the absolute configuration of enone photocycload

dition products, an intermediate iminium ion with a chiral secondary amine was

employed by Mariano et al. (Scheme 6.28) [80]. Irradiation of substrate 73 at relatively

short wavelength (direct ppà excitation) led, via intermediate 74, to the chiral

H SiMe3

hν (λ > 290 nm)

r.t. (C6H12)



O



O



H



SiMe3



O



H

SiMe3



+

O

71

Scheme 6.27



86%

d.r. = 56/44



O

72a (92% ee)



O

72b (86% ee)



j 6 Formation of a Four Membered Ring



188



O



hν (λ > 250 nm)

r.t. (MeCN)



O



N



O



O



N



H



O



Na2CO3

(H2O)



H

H



H

O



O



ClO4



51%

63% ee



O



ClO4



73



74



75



Scheme 6.28



cyclobutane 75. The enantioselectivity was dependent on the conversion and on the

reaction temperature. At 4  C, 78% ee was achieved at a conversion of 60%, while at

room temperature 82% ee was achieved after 40% conversion. The example depicted

in Scheme 6.28 relates to a reaction, which was run until conversion was almost

complete (90%).

In analogy to the vinylogous esters the corresponding amides of general structure

A3 (Q ¼ N) can be employed in intramolecular [2 ỵ 2] photocycloaddition reactions.

A recent study was concerned with the reactions of cyclic N alkenoyl b enaminones,

which underwent a regio and diastereoselective intramolecular [2 ỵ 2] photocyclo

addition [81]. The total synthesis of the alkaloid ( ) perhydrohistrionicotoxin (78)

by Winkler et al. includes a classic application of enaminone photochemistry

(Scheme 6.29) [82]. The vinylogous amide 76 was converted in a highly diastereo

selective fashion into the tetracylic product 77. Since the reaction was performed by

direct irradiation in a Pyrex vessel, it is likely that the enaminone chromophore is

responsible for the reaction but not the dioxenone, which requires short wavelength

excitation or sensitization (vide infra). The facial diastereoselectivity originates from

a pseudoequatorial orientation of the pentyl group in a chairlike transition state,

leading to 77. Cyclobutane ring opening was achieved by a retro aldol reaction

after transesterification of the dioxenone. Further elaboration eventually led to

the target 78.

Vinylogous thioesters (A3, Q ¼ S) have been used less frequently in [2 ỵ 2]

photocycloaddition as compared to their oxygen and nitrogen analogues [83]. More

recent applications can be found in the above mentioned study with chiral

allenes [79].



O

O

N

H



O



hν (λ > 290 nm)

0 C (MeCN)



76



H H



O



OH

O



O

95%

d.r. = 94/6



Scheme 6.29



O



HN



77



O



HN



78



6.4 [2 ỵ 2] Photocycloadditon of a,b Unsaturated Carboxylic Acid Derivatives



6.4

[2 ỵ 2]-Photocycloadditon of a,b-Unsaturated Carboxylic Acid Derivatives

(Substrate Classes A4, A5, and A6)

6.4.1

No Further Heteroatom Q in b-Position (Substrate Class A4)



The introduction of a heteroatom in a position to the carbonyl group leads to a

hypsochromic shift of the npà transition. Esters show only a weak absorption at

l ¼ 200 nm. Conjugation in a,b unsaturated carboxylic acid derivatives leads to

stronger absorption bands at l ¼ 200 250 nm, ascribed to the intense ppà and the

weak npà transition. In a,b unsaturated lactams, absorptions in the near ultraviolet

(200 220 nm) occur with high intensity (e 10 000). An additional weaker band

can be detected at lmax ffi 250 nm. Most substrates belonging to the classes A4 A6 are

transparent at l ! 280 nm. As a consequence, the irradiation set up needs some

adjustment in comparison to enones, and for this there are two options. First, direct

excitation can be achieved by the use of mercury lamps employing quartz vessels,

which are transparent above 200 nm. Second, one can rely on the irradiation

equipment used for enone photocycloaddition attempting a sensitized excitation.

Indeed, most a,b unsaturated carboxylic acid derivatives exhibit a relatively low

triplet energy (ET 330 kJ molÀ1), so that appropriate ketones can be used for

sensitization. Most conveniently, acetone (ET ¼ 330 kJ molÀ1) is used as a solvent.

It is also possible, however, to use a more sophisticated sensitizer, for example, an

acetophenone or benzophenone, in a transparent solvent. Sensitization results in a

direct promotion of the substrate into the ppà triplet state, from which photocy

cloaddition chemistry can occur according to Scheme 6.2.

6.4.1.1 a,b-Unsaturated Lactones

The [2 ỵ 2] photocycloaddition chemistry of a,b unsaturated lactones has been

widely explored. The factors governing regio and simple diastereoselectivity are

similar to what has been discussed in enone photochemistry (substrate class A1,

Section 6.2). The HT product is the predominant product in the reaction with

electron rich alkenes [84]. A stereogenic center in the g position of a,b unsaturated

g lactones (butenolides) can serve as a valuable control element to achieve facial

diastereoselectivity [85, 86]. The selectivity is most pronounced if the lactone is

substituted in the a and/or b position. The readily available chiral 2(5H) furanones

79 and 82 have been successfully employed in natural product total syntheses

(Scheme 6.30). In both cases, the intermediate photocycloaddition product

with 1,2 dichloroethylene was reductively converted into a cyclobutene. In the first

reaction sequence, the two step procedure resulted diastereoselectively (d.r. ¼ 88/12)

in product 80, which was separated from the minor diastereoisomer (9%). Direct

excitation (Hg lamp, quartz) in acetonitrile solution was superior to sensitized

irradiation (Hg lamp, Pyrex) in acetone, the former providing the photocycloaddition

products in 89% yield, the latter in only 45%. Cyclobutene 80 was further converted

into the monoterpenoid pheromone (ỵ) lineatin (81) [87]. In the second reaction



j189



j 6 Formation of a Four Membered Ring



190



1. Cl



Cl



hν (Hg lamp)

−15 °C (MeCN)

2. Zn, μw (EtOH)



O

O



64%



PivO



O H



H

O



O

PivO



79



80

1. Cl



O



81



Cl



hν (Hg lamp)

−20 °C (MeCN)

2. Zn, Ac2O (PhMe)



O



O



O



O



O



O



O



75%

PivO



O



PivO



O



82



83



OH



84



Scheme 6.30



sequence, the photocycloaddition proved under similar conditions to be equally

diastereoselective (d.r. ¼ 91/9), yielding after reduction the major diastereoisomer

83. The two quaternary stereogenic centers established in the photochemical

reactions were retained in the further synthetic route, which eventually led to the

sesquiterpene ( ) merrilactone A (84) [88].

The crossed intramolecular [2 ỵ 2] photocycloaddition of allenes to a,b unsat

urated g lactones has been extensively studied by Hiemstra et al. in an approach to

racemic solanoeclepin A (87). The sensitized irradiation of butenolide 85 in a 9 : 1

mixture of benzene and acetone, for example, led selectively to the strained photo

cycloadduct 86 (Scheme 6.31) [89]. The facial diastereoselectivity is determined

by the stereogenic center, to which the allene is attached. The carbon atom in a

position to the carbonyl carbon atom is attacked from its re face, forming a bond to

the tertiary allene carbon atom, while the b carbon atom is being connected to the

internal allene carbon atom by a si face attack. The method allows facial diaster

eocontrol over three contiguous stereogenic centers in the bicyclo[2.1.1]heptane

part of the natural product.

COOH

O

O



O

O



hν (λ = 300nm)

r.t (PhH/ac)



OBn

OH

O



60%



O



O



O



HO



O



O



MeO



BnO

85

Scheme 6.31



86



87



O



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3 [2 + 2]-Photocycloaddition of Vinylogous Amides and Esters (Substrate Classes A2 and A3)

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