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2 [2 + 2]-Photocycloaddition of Enones (Substrate Type A1)

2 [2 + 2]-Photocycloaddition of Enones (Substrate Type A1)

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j 6 Formation of a Four Membered Ring



174



hν (Hg lamp)

r.t. (C6H12)



O



O



O



+



55%

4a/4b/4c =

44/30/26



3



O



H



+



H



H



4a



O



4b



H

H

O



H



43%

5a/5b = 90/10



4c

O



H



hν (Hg lamp)

r.t. (C6H12)



H



H



5a



+



5b



Scheme 6.3



rings are exclusively cis fused; that is, the reaction proceeds stereospecifically relative

to the cyclopentenone double bond without isomerization. Alkene double bond

isomerization is possible depending on the lifetime of intermediate C or C0 . Four and

five membered cyclic alkenes as reaction partners react stereospecifically for steric

reasons, whereas larger cyclic alkenes can produce diastereomeric mixtures. As an

example, the reaction of 3 methylcyclopenten 2 enone (3) with cyclohexene resulted

not only in the expected exo cycloaddition product 4a but also in the diastereomeric

products 4b and 4c (Scheme 6.3) [20]. Reaction with cyclopentene gave the single

exo product 5a, albeit in a relatively low yield. The endo product 5b was formed as

byproduct. The preferential formation of exo products is frequently observed, if a

cyclic enone reacts intermolecularly with a cyclic alkene.

The formation of exo products is also the predominant pathway if acyclic alkenes

are employed as reaction partners. The reaction of cyclopentenone and ethyl vinyl

ether serves as an instructive example (Scheme 6.4) for two reasons. First, it

exemplifies the regiochemical outcome (r.r. ẳ regioisomeric ratio) of the [2 ỵ 2]

photocycloaddition with HT products 7 being predominantly formed (versus

HH products 8). Second, it illustrates the exo preference with compound 7a pre

vailing over 7b (d.r. ¼ diastereomeric ratio) [21]. However, it is also clear from this



OEt

hν (λ = 366 nm)

r.t. (C5H12)



O



O



O

R2

R1



60%



R2



+



6

r.r. = 7/8 = 80/20

d.r. = 7a/7b = 64/36

Scheme 6.4



7a

7b



R1 = OEt, R2 = H

R1 = H, R2 = OEt



8a

8b



R1



6.2 [2 ỵ 2] Photocycloaddition of Enones



O



hν (λ > 290 nm)

−78 °C (CH2Cl2)



H



O

H



H



90%



H

9



j175



H



H



10



11



Scheme 6.5



example, that perfect regioselectivity in intermolecular [2 ỵ 2] photocycloaddition

reactions is difcult to achieve.

With regard to the simple diastereoselectivity, one can generalize that large

substituents normally adopt opposite (trans) positions in the cyclobutane product

whenever feasible.

The facial diastereoselectivity of intermolecular cyclopentenone [2 ỵ 2] photocy

cloaddition reactions is predictable if the cyclopentenone or a cyclic alkene reaction

partner is chiral. Addition occurs from the more accessible side, and good stereo

control can be expected if the stereogenic center is located at the a position to the

double bond. In their total synthesis of (Ỉ) kelsoene (11), Piers et al. [22] utilized

cyclopentenone 9 in the [2 ỵ 2] photocycloaddition to ethylene (Scheme 6.5). The

cyclobutane 10 was obtained as a single diastereoisomer. In a similar fashion, Mehta

et al. have frequently employed the fact that an approach to diquinane type cis bicyclo

[3.3.0]octenones occurs from the more accessible convex face. Applications can

be found in the syntheses of (ỵ) kelsoene [23], ( ) sulcatine G [24], and (Ỉ) merri

lactone A [25].

The single stereogenic center of g silylsubstituted cyclopentenone 12 allowed for

an excellent stereocontrol in the [2 ỵ 2] photocycloaddition to the strained cyclobu

tene 13, which in turn had been obtained by a [2 þ 2] photocycloaddition ring

contraction sequence (Scheme 6.6) [26]. Alkene 13 dictates the exo approach of the

cyclopentenone, but as a meso compound is of course not capable of controlling

the absolute configuration. Further elaboration of product 14 led to (ỵ) pentacyclo

anammoxic acid (15).

In a pioneering study, Zandomeneghi and Cavazza showed that the [2 ỵ 2]

photocycloaddition of racemic 4 acetyloxy 2 cyclopentenone can lead to a small, but

detectable, enantiomeric excess (ee) of the product if circularly polarized light (CPL)

is used as an irradiation source. By preferential excitation of the ( ) antipode of

the cyclopentenone with l CPL (351 363 nm laser) in the presence of acetylene, an

O



hν (Hg lamp)

−5 °C (MeCN)



H



O H H H H



+

50%

H



PhMe2Si

12

Scheme 6.6



PhMe2Si

13



H H H H



HOOC



7



H

14



15



j 6 Formation of a Four Membered Ring



176



O



O H



hν (λ > 290 nm)

r.t. (ac)



HO

H



4



53%

N

Ts

16



H

N



N



Ts

17



18



Scheme 6.7



enantiomerically enriched product (1% ee) was obtained. The unreacted starting

material was optically enriched in the (ỵ) enantiomer [27].

The regioselectivity of intramolecular [2 ỵ 2] photocycloaddition reactions is

predictable if ve membered ring formation is possible in the formation of biradicals

of type C or C0 (rule of five, vide supra). If five membered ring formation is not

feasible, then six membered rings are most readily formed. The facial diastereo

selectivity is efficiently controlled by a stereogenic center in the cyclopentenone if

the intramolecular alkene is attached via a tether to this stereogenic center. The key

step 16 ! 17 in the stereoselective synthesis of ( ) incarvilline (18) illustrates the

point (Scheme 6.7) [28]. The side chain attached to C 4 in the cyclopentenone 16

carries the terminal alkene, which reacts intramolecularly with perfect regio and

diastereoselectivity to cyclobutane 17.

If a stereogenic center is present in the chain, which connects the two olefin

partners, then conformational aspects must be taken into account. In the typical

scenario of a five membered ring formation, the larger substituent at the stereogenic

center resides frequently in the pseudoequatorial position of a chairlike conforma

tion. Enone 19 underwent intramolecular [2 ỵ 2] photocycloaddition to a furan ring

via conformation 190 in which both groups Et3SiO and CMe3 at the stereogenic center

can adopt a pseudoequatorial position (Scheme 6.8) [29]. The other chairlike



O

COOEt



H



O



COOEt

H



Et3SiO

Et3SiO



Me3C OSiEt

vs.



19



H

19'



O COOEt

O



19''

O

HO

O

O



O



O



CMe3

20



Scheme 6.8



O

O



quant.

Et3SiO



3 COOEt



O O



H



Me3C



CMe3



hν (λ > 350 nm)

r.t. (C6H12)



O

O



OH

CMe3



HO

21



6.2 [2 ỵ 2] Photocycloaddition of Enones



h ( > 290 nm)

r.t. (CH2Cl2)



O



80%

O



H



H

O

H



H O



d.r. = 86/14



HO

O



O

H



22''



22'



HO



j177



23a



hν (λ > 290 nm)

r.t. (MeOH)

65%



O



O



H



22



HO

O



H



HO



d.r. = >95/5



H



HO

22'''



22''''



23b



Scheme 6.9



conformation 1900 with two pseudoaxial substituents is not populated in the transition

state of the photocycloaddition, and neither are boatlike conformations. Product 20

was formed exclusively and further converted into the structurally complex natural

product (Ỉ) ginkgolide B (21).

While the steric bulk of a given substituent is normally invariable, hydrogen

bonding interactions can alter the size of a polar group, for example, of a hydroxyl

group [30]. A study by Snapper et al. showed that intramolecular [2 ỵ 2] photocy

cloaddition of hydroxyenone 22 occurred in nonpolar solvents (e.g., CH2Cl2) with

a preference for product 23a, whereas product 23b was formed as a single diaste

reoisomer in protic solvents (e.g., MeOH) (Scheme 6.9) [31]. An explanation for this

preference is based on the intramolecular hydrogen bonding favoring the boatlike

conformation 220 (and/or chairlike conformation 2200 ) in nonpolar solvents, and on

the intermolecular hydrogen bonding favoring boatlike conformation 22000 (and/or

chairlike conformation 220000 with a pseudoaxial hydroxyl group) [31].

In general, the stereoelectronic inuence of substituents in [2 ỵ 2] photocycload

dition reactions is minor, and the preferred ground state conformation often

accounts for the formation of the major diastereoisomer. Inspection of molecular

models and force field calculations provide a good picture of possible transition

states leading via 1,4 biradicals to cyclobutane products. The total synthesis of

(ỵ) guanacastepene represents another recent example for the use of stereoselective

intramolecular cyclopentenone olefin photocycloadditions in natural products

synthesis [32].

6.2.2

Cyclohexenones



Cyclohexenones require essentially identical irradiation conditions as cyclopente

nones (vide supra). The outcome of the intermolecular [2 ỵ 2] photocycloaddition to

alkenes is somewhat more complex as compared to cyclopentenones, because the



j 6 Formation of a Four Membered Ring



178



O



hν (λ > 290 nm)

r.t. (MeCN)



O



O



H

+



24



quant.

25a/25b/25c =

68/25/7



O



H



H H



+



H

25a



H

25b



25c



Scheme 6.10



twisted nature of the intermediate T1 state leads in the cyclobutane product not only

to a cis configuration along the former cyclohexenone a,b bond but also to a trans

configuration. This behavior is illustrated by the reaction of cyclohexenone (24) to

cyclopentene, which was one of the first reactions of this type ever studied [33] and

which has been reinvestigated in recent years (Scheme 6.10) [34, 35]. The exo product

25a with a cis anti cis arrangement of hydrogen atoms was the preferred product,

but the trans products 25b (trans anti cis) and 25c (trans syn cis) were formed in

significant amounts. The cis syn cis product was detected in low (<1%) quantities.

Isomerization into the thermodynamically more stable cis products was possible

upon base treatment generating two diastereoisomers, cis anti cis product 25a

(from 25a and 25c) and the cis syn cis product (from 25b) in a ratio of 75 : 25.

Cyclopentene reacted stereospecifically, that is, the former C C double bond

retained its cis configuration.

The formation of trans products is observed to a lesser extent in the reaction of

3 alkoxycarbonyl substituted cyclohexenones, in the reaction with electron deficient

alkenes and in the reaction with olefinic reaction partners, such as alkynes and

allenes, in which the four membered ring is highly strained (Scheme 6.11). The ester

26 reacted with cyclopentene upon irradiation in toluene to only two diastereomeric

products 27 [36]. The exo product 27a (cis anti cis) prevailed over the endo product

27b (cis syn cis); the formation of trans products was not observed. The well known

[2 ỵ 2] photocycloaddition of cyclohexenone (24) to acrylonitrile was recently re

investigated in connection with a comprehensive study [37]. The product distribu

tion, with the two major products 28a and 28b being isolated in 90% purity, nicely

illustrates the preferential formation of HH (head to head) cyclobutanes with elec

tron acceptor substituted olefins. The low simple diastereoselectivity can be inter

preted by the fact that the cyano group is relatively small and does not exhibit a

significant preference for being positioned in an exo fashion.

The last example depicted in Scheme 6.11 illustrates the exclusive cis product

formation observed with cyclohexenones and allenes in conjunction with a high

HH preference [38]. In addition, substrate 29 is chiral, and perfect facial diastereo

selectivity was observed due to cyclic stereocontrol. Product 30 served as intermediate

in a formal total synthesis of the triquinane (Ỉ) pentalenene (31).

Chiral cyclohexenones have been frequently employed in intermolecular [2 ỵ 2]

photocycloaddition reactions directed towards natural product synthesis. A further

case in point is the reaction of cyclohexenone 32 with trans 1,2 dichloroethylene



6.2 [2 ỵ 2] Photocycloaddition of Enones



O



O



hν (λ = 350 nm)

r.t. (PhCH3)



O



H

+



COOMe



91%

27a/27b = 87/13



MeOOC H



MeOOC



27a



26



CN

hν (λ = 350 nm)

r.t. (PhH)



O



O



H



27b



O



NC



CN



H



+

51%

28a/28b = 67/33



24

O



28a



28b



O

hν (λ > 290 nm)

−78 °C (CH2Cl2)

86%



29



30



31



Scheme 6.11



(Scheme 6.12) [39]. Cyclobutane 33 was formed with perfect stereocontrol over the

two stereogenic centers in a and b position to the carbonyl group. The concave shape

of the substrate forces a highly selective approach of the olefin. The relative and

absolute configuration at the chlorine bearing carbon atoms was not relevant, as

chlorine was subsequently eliminated under reductive conditions. Compound 33

was further elaborated into (Ỉ) sterpurene (34).

Intramolecular reactions of cyclohexenones follow pathways similar to those of

cyclopentenones, both with regard to regio and stereocontrol. The initially men

tioned intramolecular [2 þ 2] photocycloaddition of carvone (1) is a typical example

for five membered ring formation with high diastereofacial control (Scheme 6.1). In

this case, the rule of five requires the terminal carbon atom of the intermolecular



O



Cl



O



Cl

hν (C6H12)



H



Cl



MeOOC



Cl



H



95%

COOMe

32

Scheme 6.12



33



34



j179



j 6 Formation of a Four Membered Ring



180



O



O



O



hν (Hg lamp)

r.t. (MeOH)

80%



36



35



37



Scheme 6.13



olefin to be attached to the b carbon atom of the enone (crossed photocycloaddition).

The more common addition mode is the straight photocycloaddition (e.g.,

Schemes 6.7 to 6.9), as is also employed in the biomimetic [2 þ 2] photocycloaddition

of enone 35 to cyclobutane 36 (Scheme 6.13) [40]. Intermediate 36 was further

transformed into (ỵ) solanascone (37), a natural product, which is presumably

formed in nature by intramolecular [2 þ 2] photocycloaddition from the correspond

ing methyl bearing precursor solavetivone [41].

Control over the absolute configuration in cyclohexenone photocycloadditions has

been achieved by auxiliary induced diastereoselectivity. In particular, esters related

to compound 26, which are derived from a chiral alcohol but not from methanol,

lend themselves as potential precursors, from which the chiral auxiliary can be

effectively cleaved [42, 43]. In a recent study, the use of additives was advertised to

increase the diastereomeric excess in these reactions [44]. An intriguing auxiliary

induced approach was presented by Piva et al., who employed chiral b hydroxy

carboxylic acids as tethers to control both the regioselectivity and the diastereoselect

ivity of intramolecular [2 ỵ 2] photocycloaddition reactions [45]. In Scheme 6.14

the reaction of the (S) mandelic acid derived substrate 38 is depicted, which led

with very good stereocontrol almost exclusively to product 39a, with the other

diastereoisomer 39b being formed only in minor quantities (39a/39b ¼ 96/4). Other

acids, such as (S) lactic acid, performed equally well. The chiral tether could be

cleaved under basic conditions to afford enantiomerically pure cyclobutane lactones

in good yields.

Attempts to achieve absolute stereocontrol by means of chiral sensitizers or

chiral complexing agents [46] have seen little success with cyclohexenones and

other unfunctionalized enone substrates. Ester 26, for example, underwent an

O

O



hν (λ > 290 nm)

r.t. (CH2Cl2)



O

O

O

38

Scheme 6.14



62%

92% de



H



+

O



O

Ph



O



H



O

O



O

O



Ph

O



O



Ph

39a



O



39b



6.2 [2 ỵ 2] Photocycloaddition of Enones



intermolecular [2 ỵ 2] photocycloaddition to ethylene in the presence of g cyclodex

trin (g CD) with low but detectable enantiomeric excess (2.2%) [47].

6.2.3

para-Quinones and Related Substrates



Depending on the nature of the lowest lying triplet state (npà versus ppà ), para

quinones undergo either typical carbonyl photochemistry (Paternò B€

uchi reaction,

hydrogen abstraction) or typical alkene photochemistry ([2 ỵ 2] photocycloaddi

tion) [48]. The parent 1,4 benzoquinone (npà triplet ca. 76 kJ molÀ1 below ppà triplet)

undergoes mainly spirooxetane formation, while the parent 1,4 naphthoquinone

delivers products of both carbonyl and alkene photochemistry depending on

the nature of the olefin. Olefins, which are donor substituted, favor oxetane forma

tion. Electron donating substituents at the quinone destabilize the npà triplet,

leading to an increased preference for [2 ỵ 2] photocycloaddition. The relatively long

wavelength absorption of para quinones, many of which are colored, enables

photochemistry even with visible light. The parent compound, 1,4 benzoquinone,

exhibits a longest wavelength absorption at lmax ¼ 458 nm in hexane [49]. The

synthetically undesired intermolecular [2 ỵ 2] photocycloaddition of substrate 40,

which was meant to and eventually did undergo an intramolecular Diels Alder

reaction, illustrates the ease with which para quinone photocycloadditions can occur

(Scheme 6.15) [50]. Cyclobutane 41 was formed as a single diastereoisomer in 80%

yield upon heating substrate 40 in toluene (120  C) at ordinary room light. The

photochemical reaction course was proven upon irradiation with a visible light source

at room temperature.

An intramolecular naphthoquinone [2 ỵ 2] photocycloaddition (Scheme 6.16) led

directly to the formation of the natural product ( ) elecanacin (43a) [51]. Here,

hν (room light)

120 °C (PhMe)



O

O



O

O



H

OH



80%



OH

O H



O

40



41



Scheme 6.15



O



hν (λ = 350 nm)

r.t. (CH2Cl2)



O



O

42

Scheme 6.16



O



O



O



H



O



H



+



24% 43a

40% 43b



O



O



O



O

43a



43b



O



j181



j 6 Formation of a Four Membered Ring



182



O



TMSO



HO

hν (λ > 290 nm)

−50 °C (THF)

66%



TMSO



TMSO



H

O

HO



H



TMSO



O

44



O



O

45



46



Scheme 6.17



enantiomerically pure substrate 42 was irradiated in CH2Cl2 solution yielding the

desired natural product 43a as the minor diastereoisomer, and its isomer 43b as

the major isomer. The excess for the latter product is presumably due to a slight

preference of the methyl group to reside in the pseudoequatorial position of one

of the chairlike transition states en route to the respective products.

The intermolecular [2 ỵ 2] photocycloaddition of para tetrahydronaphthoqui

nones has been applied by Ward et al. to the synthesis of cyathin diterpenes [52].

An example is represented by the total synthesis of (Ỉ) allocyathin B3 (46), during the

course of which the diastereoselective [2 ỵ 2] photocycloaddition of allene to sub

strate 44 served as one of the pivotal steps (Scheme 6.17) [53]. The addition delivered

a mixture of regioisomers (r.r. ¼ 80/20), from which compound 45 was separated.

The facial diastereoselectivity was perfect due to the concave shape of the quinone.

Similarly, homobenzoquinones, in which one benzoquinone double bond

is replaced by a cyclopropane, react with very high facial diastereoselectivity. An

attack to the double bond occurred exclusively from the face opposite to the

cyclopropane [54].



6.3

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

(Substrate Classes A2 and A3)



Heteroatoms in b position lead to a slight bathochromic shift of the longest

wavelength absorption (lmax) as compared to cycloalkenones. This absorption band,

to which an npà character is assigned, is often difficult to detect by UV/visible

spectroscopy due to its low extinction coefficient (e 100). In addition, the intense

ppà absorption is shifted significantly to higher wavelengths for substrates A2 and A3

overlapping for strong donor heteroatoms with the weak npà band. The batho

chromic shift generally does not require a change in the irradiation set up as

compared to enones. An adjustment to longer wavelengths can be made if light

sources, which emit at a specific wavelength, are used.

From a preparative point of view the heteroatom in b position has an influence

because important latent cyclobutane cleavage pathways exist in the product. The

prototypical reaction of this type is the [2 ỵ 2] photocycloaddition/retro aldol reaction

sequence (de Mayo reaction) [55 57], the course of which is illustrated for substrate

A3 (Q ¼ O, PG ¼ protecting group) in the reaction with ethylene as a generic olen.



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 ẳ 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 ỵ 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 þ 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



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2 [2 + 2]-Photocycloaddition of Enones (Substrate Type A1)

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