Chapter 19 Compounds With Carbon Carbon Multiple Bonds II ...carborad.com/Volume II/Chapter 19/Cyclization Reactions.pdf · Compounds With Carbon–Carbon Multiple Bonds II: Cyclization

Chapter 19

Compounds With Carbon–Carbon Multiple

Bonds II: Cyclization Reactions

I. Introduction ........................................................................................................................415

II. Ease of Reaction between a Carbon-Centered Radical and a Multiple-Bond ....................415

III. Reaction Selectivity ............................................................................................................417

A. Chemoselectivity ......................................................................................................417

B. Regioselectivity ........................................................................................................418

1. Five-Membered Versus Six-Membered Ring Formation ...............................420

2. Six-Membered Versus Seven-Membered Ring Formation .............................425

3. Three- and Four-Membered Ring Formation ..................................................426

4. Seven-Membered and Larger Ring Formation ................................................427

C. Stereoselectivity ........................................................................................................428

1. Five-Membered Ring Formation.....................................................................428

2. Six-Membered Ring Formation ......................................................................435

3. Seven-Membered and Larger Ring Formation ................................................436

IV. Unsaturated Carbohydrates that Undergo Radical Cyclization ..........................................438

A. α,β-Unsatruated Carbonyl Compounds ....................................................................438

B. Silyl Ethers and Silaketals ........................................................................................440

C. Alkenyl and Alkynyl Ethers, Esters, Acetals, and Alcohols ....................................442

D. Compounds with Terminal Triple Bonds .................................................................445

E. Compounds in Which the Multiple Bond is not Electron-Deficient ........................446

V. An Organization for Carbohydrates That Undergo Radical Cyclization ...........................447

VI. Summary................................................................................... .........................................448

VII. References ..........................................................................................................................458

I. Introduction

The structural requirements for a molecule destined to undergo radical cyclization are that it

contain a substituent from which a radical (almost always a carbon-centered one) can be generated

and that it have a properly positioned multiple bond. Carbohydrates that meet these requirements

include unsaturated iodides, bromides, thionocarbonates, cyclic thionocarbonates, xanthates, and

phenyl selenides. Ring formation in the reactions of these compounds usually is regiospecific and

often highly stereoselective.

II. Ease of Reaction between a Carbon-Centered Radical and a Multiple Bond

Once structural requirements have been met, successful radical cyclization depends on re-

action rates. The basic question is “Will ring formation occur before competing reactions inter-

416 Chapter 19 vene?” The answer to this question depends upon the nature of the radical center and multiple bond

and on the separation between these two. The ability of a radical to add to a multiple bond to form

a new ring will be addressed first; then, the effect of the separation between the radical center and

the multiple bond will be considered.

O

CH2OAc

OAc

OAc

AcO Br

( 1 ) +Bu3SnH

O

CH2OAc

OAc

OAc

AcO CH2CH2CN

CH2=CHCN

V-70

Et2O25

oC

68%

V-70 = CH3OCCH2CN NCCH2COCH3

CN

CH3

CN

CH3

CH3

CH3CH3

CH3

( 2 )

AIBNO

CH2OAc

AcO Cl

OAc

HNAc

THF

O

CH2OAc

AcO CH2CH=CH2

OAc

HNAc

CH2=CHCH2SnBu3

66% (10/1)

A beginning point for discussing reactivity between a radical center and a multiple bond

during internal addition is to recall some of the findings in Chapter 18 about addition reactions that

are not internal. Such reactions take place rapidly when a radical is nucleophilic (as are most

carbon-centered radicals) and a multiple bond is electron-deficient. This description fits the reac-

tion shown in eq 1.1,2

If a multiple bond is not electron-deficient, radical addition normally is too

slow to compete with hydrogen-atom abstraction; however, minimizing or eliminating effective

hydrogen-atom donors from a reaction mixture can enable addition to occur even when the

multiple bond is not electron-deficient. An example of this type of reaction is shown in eq 2, where

Bu3SnH is not present in the reaction mixture even though Bu3Sn· is there and acts as the

chain-carrying radical.3,4

Addition of a radical to a multiple bond is potentially much faster when the reaction is

intramolecular. If a radical center and a multiple bond in a molecule are positioned so that they

frequently come within bonding distance, the rate of internal addition increases to the point that

even for a multiple bond that is not electron-deficient, cyclization competes effectively with

hydrogen-atom abstraction. In the reaction shown in eq 3, internal addition to a double bond that is

not electron-deficient takes place even in the presence of Bu3SnH.5

Compounds With Carbon–Carbon Multiple Bonds II: Cyclization Reactions 417

Bu3SnHO

O

CH2OAc

AcO

OAc I( 3 )

AIBN

C6H6

80 oC

O

O

CH2OAc

AcO

OAc

CH3

60%

III. Reaction Selectivity

Chemoselectivity, regioselectivity, and stereoselectivity are defining characteristics of radi-

cal reactions. Nowhere are they more important (particularly the latter two) than when a new ring

is being formed. Understandably then when regioselectivity and stereoselectivity were broached in

Chapters 10 and 11 of Volume I, discussion often turned to cyclization reactions. Some of the

ideas and topics from these chapters are revisited here but now with an exclusive focus on their

importance to new ring formation.

( 4 ) Bu3SnH

AIBNO

O

Si

BrCH2 OEt

CH2OR

1

R = SiMe2t-Bu

O

O

Si

OEt

CH2OR

notformed

O

O

Si

OEt

CH2OR

48%

+NaBH3CNt-BuOH

( 5 ) Bu3SnH

AIBNO

O

Si

BrCH2 OEt

CO2Et

2

O

O

Si

OEt

CH2CO2Et

not formed

O

O

Si

OEt

CO2Et

+

more electron-deficient

less electron-deficient

NaBH3CN

49%

t-BuOH

A. Chemoselectivity

Chemoselectivity enters into consideration at two places in radical cyclization reactions. The

first is during radical formation, where it determines which atom or group in a molecule will react

418 Chapter 19 to form the radical that adds to a multiple bond. Chemoselectivity next is of consequence when a

newly formed radical has the possibility of adding to more than one multiple bond. In the reaction

shown in eq 4, for example, halogen-atom abstraction from the bromide 1 produces a radical that

can add to either of two double bonds.6,7

Addition to one produces a five-membered ring while

reaction with the other forms a six-membered ring. Although these two bonds are comparable in

reactivity, the product with the five-membered ring forms more rapidly. (The reasons for usually

forming a product with a five-membered ring are discussed in the next section.) If, however, the

double bond for which reaction produces a six-membered ring, is decidedly more reactive (i.e.,

substantially more electron-deficient), as is the case in compound 2 (eq 5), the chemoselectivity of

the cyclization process changes, and only the product with the larger ring forms.6,7

O

O

OAc

CH2OAc

AcO

I Bu3Sn

Bu3SnH

Bu3Sn

Bu3SnI

O

O

OAc

CH2OAc

AcO

CH2

O

O

OAc

CH2OAc

AcO

O

O

OAc

CH2OAc

AcO

O

O

OAc

CH2OAc

AcO

CH3

88%

-

-

Scheme 1

B. Regioselectivity

Radical cyclization is nearly always a kinetically controlled process.8 Kinetic control often

leads to regiospecific formation of the less stable cyclic radical. In the reaction shown in Scheme

1,5,9

for example, even though cyclization to give a six-membered ring is possible and would

generate a more stable radical, the only reaction pathway followed leads to the smaller ring and the

less stable radical. The reaction shown in Scheme 2, where the primary radical 3 forms in pref-

erence to the tertiary radical 4, provides a particularly striking example of a kinetically controlled,

radical cyclization.10

There are cyclization reactions that take place under thermodynamic control when the proper

conditions are met. In the reaction shown in eq 6 the major product contains a six-membered ring,


Bu3Sn

NH

N

O

O

O

HOCH2 B

SeArHN

CH3

Ar = C6H5

- Bu3SnSeAr

O

HOCH2 B

HN

CH3

Bu3SnH

- Bu3Sn

O

HOCH2 B

HN

CH3

O

HOCH2 B

HNCH2

CH3

3

4

O

HOCH2 B

HNCH3

CH3

Scheme 2

73%

( 6 ) O

O

T

Si

TrO

O

O

T

Si

CH3

TrO

0.5 equiv of Bu3SnH 87% 6%

3.0 equiv of Bu3SnH 3% 75%

+

Si

O

O

C6H5Se T

TrO

Bu3SnH

T = NH

N

O

O

CH3

Tr = C(C6H5)3

when reaction is conducted in dilute Bu3SnH solution,11

but at high Bu3SnH concentration reaction

regioselectivity changes to give a product with a five-membered ring.11,12

This concentration

dependence can be explained by the more rapidly formed, but less stable, radical 5 having suf-

ficient time and energy, when the concentration of Bu3SnH is low, to be converted into the more

stable radical 6, either by a rearrangement that involves a cyclic transition state or by a fragmen-

tation-addition sequence (Scheme 3).13

At high Bu3SnH concentration hydrogen-atom abstraction

occurs before ring expansion can take place.

420 Chapter 19

Bu3SnH

5

O

SiO

SiO

Si

O

Si

Bu3SnH

6

OSi

kinetically controlledproduct

thermodynamicallycontrollled product

Scheme 3

O

Si

OSi

rearrangementpathway

elimination-additionpathway

- Bu3Sn

- Bu3Sn

high Bu3SnH

low Bu3SnH concentration

concentration

1. Five-Membered Versus Six-Membered Ring Formation

a. Five-Membered Rings

If a radical center and a multiple bond in a molecule are situated so that either a five- or

six-membered ring is possible, the smaller ring generally will form.14,15

The reason for producing

the smaller ring is that the strain engendered in reaching the transition state leading to a

six-membered ring is greater than that necessary for forming a ring with five members (Scheme

4)16–18

Both chair-like14,16

and boat-like16,19

transition-states are possible during five-mem-

bered-ring formation (Scheme 5). For the unsubstituted 5-hexenyl radical the chair-like transition

state is calculated to be lower in energy than its boat-like counterpart, but only slightly so.16

(The

“flagpole” and eclipsing interactions that contribute to making the boat conformation of cyclo-

hexane much less stable than the chair conformation are not as severe in the boat-like transition

state for radical cyclization.) Both transition states (boat-like and chair-like) leading to a


five-membered ring (Scheme 5) are calculated to be lower in energy than any transition states lead-

ing to a six-membered ring. These calculations match well the experimental observation that cycli-

zation of the 5-hexenyl radical gives a five-membered ring in a highly regioselective fashion (eq 7,

R = H).14,20

They also are consistent with the reactions shown in Schemes 1 and 2, where

five-membered rings form in preference to six-membered ones.

less strainedtransition state

more strainedtransition state

less stableradical

more stableradical

Scheme 4

R R R

+ ( 7 )

A B

A /B = 98/2 (experimental)

A /B = 91/9 (calculated)

A /B = 2/3 (experimental)

A /B = 2/2.4 (calculated)

R = H R = CH3

The greater ease of formation of five-membered rings when compared to six-membered ones

is illustrated in a quantitative fashion by the approximately fifty-fold difference in rate constants

for cyclization of the 5-hexenyl (eq 8) and 6-heptenyl (eq 9) radicals.20

A qualitative example of

this type of difference in reactivity involving a pair of carbohydrates is found in the reactions

shown in equations 10 and 11, where formation of a five-membered ring occurs in the normal

manner, but cyclization to give a six-membered ring does not take place rapidly enough to

compete with simple reduction.21

422 Chapter 19

chair-liketransition state

boat-liketransition state

Scheme 5

( 8 )

2%

15%85%

98%

k1

k2

~~k1

k2

50

+

+ ( 9 )

O

O

CH2OAc

AcO

BrCH2

O

O

CH2OAc

AcO

( 10 )

80 oC

C6H6

AIBNBu3SnH

76%


O

O

CH2OAc

AcO

BrCH2

O

O

CH2OAc

AcO

CH3

+

O

O

CH2OAc

AcO

notdetected

( 11 ) Bu3SnH

AIBN

C6H6

80 oC

b. Six-Membered Rings

Six-membered-ring formation takes place when structural features in a radical inhibit

forming a five-membered ring. Possible inhibiting factors include: a) greater ring strain at the

transition state for forming a five-membered ring as opposed to a six-membered one; b) steric

hindrance that is sufficient to make bonding difficult at the carbon atom of the multiple bond

needed to form a five-membered ring; c) structure and reactivity associated with the radical center

that favors six-membered-ring formation.22

( 12 ) O

OMe2C

CH3

O O

CMe2

7 8

O

O

Me2C

O O

CMe2

OCOC6H5

S AIBNBu3SnH

76%

cis-fusedrings

85 oC

C6H5CH3

Reactions of the phenyl thionocarbonates 7 and 9 illustrate the importance of ring strain in

determining the size of a ring being formed by radical cyclization. Compound 7 undergoes the

expected cyclization to give a product (8) with a five-membered ring (eq 12), but similar reaction

of 9 forms only a compound (10) with a six-membered ring (eq 13).22

Reaction producing the

larger ring does so because forming a five-membered ring would introduce the substantial strain at

the transition state inherent in a reaction leading to a product (11) with a pair of trans-fused,

five-membered rings.

Steric effects can have a powerful, modifying influence on the cyclization of simple organic

radicals; thus, the 5-hexenyl radical preferentially forms a five-member ring (eq 7, R = H), but the

5-methyl-5-hexenyl radical, more hindered at C-5, regioselectively generates a product with a

six-membered ring (eq 7, R = CH3).14,16

Steric effects do not exercise the control shown in eq 7 in

determining ring size in the cyclization reaction pictured in eq 12, where the C-5 substituents do

not force formation of any product with a new six-membered ring; in fact, study of 7 and similar

compounds shows that the steric effects associated with C-5 substitution are unable, by them-

selves, to promote any six-membered-ring formation.22

424 Chapter 19

( 13 )

O

OMe2C

O O

CMe2

CH39

10

O

O

Me2C

O OCMe2

OCOC6H5

S

AIBNBu3SnH

62%

O

O

Me2C

O OCMe2

C6H5CH3

85 o

C

trans-fusedrings

11

Clear examples of steric effects controlling radical cyclization in the reactions of carbohy-

drates are lacking, but the reactions shown in Scheme 6 suggest a steric component to regio-

selectivity. Formation of the spiro compound 15 takes place when R=CH3 or OBz, but when R is a

hydrogen atom, products 16 and 17 are formed (Scheme 6).23

One proposal is that larger substit-

uents favor formation of the spironucleoside 15 by sterically hindering reaction at C-2', but when

the C-2' substituent is a hydrogen atom, reaction takes place to form products 16 and 17, com-

pounds with new six-membered rings. Regioselectivity in this reaction also could be explained by

product-radical stability; that is, compound 15 forms only when the intermediate radical 12 has

stabilizing substituents at C-2'.

The nature of the radical center also can have an effect on the regioselectivity of ring for-

mation. The intermediate primary radical in the reaction shown in eq 12 forms a product with a

new, five-membered ring, but the analogous vinylic radical cyclizes to form products with new

six-membered rings (Scheme 7).22

The possibility exists that, as shown in Scheme 7, a

five-membered ring does form, but it then rearranges to a more stable six-membered-ring radical.

If such a transformation takes place, it would be reminiscent of the silyl-ether rearrangement

pictured in Scheme 3.

( 14 )

85%

Bu3SnH

Si

O

O

TrOCH2

RO

OR

SeC6H5

110 oC

C6H5CH3

AIBN

Si

O

O

TrOCH2

RO

OR

R = SiMe2t-Bu


Bu3Sn -Bu3SnBr

Scheme 6

ON

NHt-BuMe2SiO

t-BuMe2SiO R

O

O

Si

BrCH2

+

17

- Bu3Sn - Bu3SnBu3SnHBu3SnH

15

12

NSiO

R

14

OR

N

Si

OR

N

Si

NSiO

R

13

N

SiO

R

+

16

N

SiO

R

Bu3SnH

- Bu3Sn

0% R = H 32% 58%

41% R = CH3 0% 8%

75% R = OBz 0% 0%

2. Six-Membered Versus Seven-Membered Ring Formation

When constructed from carbon, nitrogen, and oxygen atoms, six-membered rings form more

rapidly than seven-membered ones, but sometimes ring formation is not fast enough to prevent

hydrogen-atom abstraction prior to cyclization. The reaction shown in eq 11 is one in which

internal radical addition to a multiple that is not electron-deficient is too slow for ring formation to

compete with simple reduction. In contrast, cyclization involving a similar double bond (i.e., one

that also is not electron-deficient) does take place in the reaction shown in eq 3 because the rate of

426 Chapter 19 competing hydrogen-atom abstraction is reduced to an insignificant level by maintaining a low

Bu3SnH concentration during the reaction.5

O

O

Me2C

O OCMe2

Bu3SnH

O OCMe2

SnBu3Bu3Sn

O OCMe2

SnBu3

O OCMe2

SnBu3

CH2

O

O

Me2C

O OCMe2

SnBu3

O

O

Me2C

O OCMe2

SnBu3

60% 4%

+

- Bu3Sn

Scheme 7

As long as the only atoms in the ring are second row elements, radical cyclization typically

produces a six-membered, rather than a seven-membered ring (eq 3). If an atom of the third-row

element silicon is present, a seven-membered ring can be produced (eq 14).24

This change in regio-

selectivity can be explained, at least in part, by longer bond lengths to silicon making approach of

the radical center to the terminal carbon atom in the double bond the lower energy pathway.25

Seven-membered ring formation depends upon the terminal carbon atom in the double bond being

unsubstituted; otherwise, steric effects raise the transition-state energy sufficiently to favor for-

mation of a six-membered ring.25

3. Three- and Four-Membered Ring Formation

Forming a three-membered ring is not a promising beginning for radical cyclization because

the strained, cyclic radical produced would open readily to its more stable, acyclic counterpart (eq

15).26

Although ring strain also hinders formation of products with four-membered rings, the lesser


magnitude of the strain increases the possibility for isolating a cyclic product;27,28

thus, the reaction

shown in Scheme 8 produces a compound with a four-membered ring.27

This reaction is kinetically

controlled; otherwise, it would lead to a less strained, five-membered ring, one that contains an

oxygen-stabilized radical.

( 15 )

O

ORO

OCMe2

O

CH2I

CO2Et

O

RO

O

CH2

CO2Et

Bu3Sn

- Bu3SnI

O

RO

O

CHCO2Et

Bu3SnH

- Bu3Sn

O

ORO

OCMe2

O

CH2CO2EtR =

O

Scheme 8

O

RO

O

CO2Et

Radical philicity, which often is a significant factor in determining regioselectivity in kine-

tically controlled reactions, rationalizes the direction of ring closure in the reaction shown in

Scheme 8. The nucleophilic, carbon-centered radical adds to the electron-deficient, β carbon atom

in the α,β-unsaturated ester portion of the molecule. Frontier-orbital interactions, also useful in

explaining kinetically controlled reactions, make the same prediction; that is, reaction should

occur at the β carbon atom in an α,β-unsaturated ester (see Section II.B.2 of Chapter 18).

4. Seven-Membered and Larger Ring Formation

Radical cyclization can be surprisingly effective in forming rings with seven,24,29,30

eight,31–37

nine,36,38–43

ten,44

or even eleven45

members. Generating these larger rings from carbohydrates

often is associated with the linking together of two monosaccharide units by a tether containing

silicon and oxygen atoms.31–36,37–42

An example of such a reaction is shown in Scheme 9, where

cyclization produces an eight-membered ring.35

Although the most common method for joining a

428 Chapter 19 radical forming group and a multiple bond is by a silicon–oxygen tether, other connecting linkages

are possible. These other tethers include phosphoramidic43

(nine-membered ring formed) and

ketal46

(nine-membered ring formed) connectors, as well as bridging units consisting of pyranoid45

(eleven-membered ring formed) and furanoid37

(eight-membered ring formed) rings.

O

BnOCH2OBn

SeC6H5BnO

O

Si

O

OSi

CH2OBn

O

O

O

Si

CH2OBn

O

O

BnOCH2OBn

BnO

OSi

O

CH2OBn

OMe

OBn

O

- Bu3SnBu3SnH

- Bu3SnSeC6H5

Bu3Sn

Scheme 9

OCH2OBn

OMeOBn

O

C. Stereoselectivity

1. Five-Membered Ring Formation

a. Chair-Like Transition States

Even though the complex substitution patterns present in many carbohydrates introduce a

variety of possibilities for steric and polar interactions, the chair-like, transition-state model

typically predicts the primary stereochemical outcome of a cyclization reaction forming a

five-membered ring (Scheme 10).14,47,48

The lowest energy transition state for such a reaction has

as many pseudoequatorial “ring substituents” as possible. An example is shown in Scheme 11,49


where if one assumes the reaction passes through a chair-like transition state that maximizes

pseudoequatorial substituents, it is possible to explain the stereochemistry in the final product.

R3

R4

R2

R1

R3

R4

R1

R2R3

R4

R1

R2

shadow chair

transition state structure

R3

R4

R1

R2

Scheme 10

OBz

CH2OR

OBz

CH2CO2Me

shadow chair

transition state structure

RO

I

OBz OBz

CH2CO2Me

OBz

CH2OR

OBz

CH2CO2Me

OBz

OBz

CH2OR

CH2CO2Me

ROCH2

MeCO2CH2

OBz

OBz

72%

Bu3SnH Bu3Sn

Bu3Sn

Bu3SnH

Scheme 11

-

-R = Si(C6H5)t-Bu

OBz

CH2OR

OBz

CH2CO2Me

=

CH2CO2Me

OBz

CH2OR

OBz

430 Chapter 19

shadow chair

Bu3Sn Bu3SnSeC6H5

OTrOB

SeC6H5

R

chair-liketransition state

boat-liketransition state

O

B

OTr

R

shadow boat

O

OTr

BR

O

R OTr

B

OBTrO

R

OBTrO

R

89% 3%

R = CO2MeNH

N

O

O

B =

Scheme 12

-

Bu3SnH, - Bu3Sn

R

O

OTr

B

b. Boat-Like Transition States

Although chair-like, transition-state structures can be used to rationalize the stereoselectivity

in most radical cyclization reactions, calculations indicate that boat-like structures should be in-

cluded as possibilities.16

In the reaction shown in Scheme 12,50

for example, the minor product can

be explained by invoking a boat-like transition state. With the structural complexity of carbo-

hydrates and the general similarity in energies between boat-like and chair-like transition states, it

is not surprising to find that the major stereoisomer in the cyclization reaction pictured in Scheme

13 appears to arise from a boat-like transition state.19,51

c. Factors Affecting Transition-State Stability

(1.) Pseudo-1,3-Diaxial Interactions

In the reaction shown in Scheme 13 it is possible to identify a psuedo-1,3-diaxial inter-

action52

in the intermediate radical 19 and the associated, chair-like transition state 21.19,51

In the

conformationally isomeric radical 18 and its associated, boat-like transition state 20 this desta-


bilizing interaction is absent. The stereochemistry of the product from ring formation indicates that

1,3-diaxial interaction is the primary factor causing reaction to occur by the pathway passing

through the boat-like transition state 20 (Scheme 13).19,51

Bu3SnH - Bu3Sn

BnO

BnO

OCImO

OC6H5

S

Bu3Sn

O

OC6H5

BnO

OBn

H

OBn

BnO

O

shadow boat

OBn

BnO

O

shadow chair

OBnO

OC6H5

BnOH

18

19

pseudo1,3-diaxialinteraction

OBnO

OC6H5

BnOH

20 21

OBnO

OC6H5

BnOH

- Bu3SnBu3SnH

OBn

O

OC6H5

BnO

CH3

H

OBn

O

OC6H5

BnOCH3

H

57% 0%

Scheme 13

- Bu3SnSC(=O)Im

pseudo1,3-diaxialinteraction

Im = N

N

432 Chapter 19

R2

H

R1 R3

R1

R2

H R3

22 23

( 16 )

R1, R2, R3 are groups sterically

larger than a hydrogen atom.

24

25allylicstrain

BnOBnO

BnO

CH2OH

5%

BnOBnO

BnO

BnOBnO

BnO CH2OH

64%

BnOBnO

BnO

I

Co(salen) complex

NaBH4, O2

Scheme 14

NaBH4, O2

BnOBnO

BnO

(2.) Allylic Strain

Another phenomenon that is credited with affecting transition-state stability is allylic strain,

which can be defined in terms of the partial structures shown in eq 16.53

Conformation 23 is

favored energetically over 22 because the destabilizing steric interaction between R1 and R3 in 22

is greater than the corresponding interaction between H and R3 in 23. Such interaction also affects

the transition-state energies for reactions from these two conformers; thus, reaction occurs pref-

erentially, sometimes exclusively, from 23. In the reaction shown in Scheme 14 allylic strain

destabilizes conformation 24, but bond rotation to give conformer 25 relieves this strain.54,55

In a

similar manner strain relief causes the reaction shown in Scheme 15 to occur primarily via a

boat-like transition state derived from 26.54,55


26

allylicstrain

BnO

BnO

CH2OH

OBn

40%

BnO

BnO CH2OH

OBn

10%

BnO

BnO

OBn

Co(salen) complex

NaBH4, O2

BnO

BnO

OBn I

BnO

BnO

OBn

Scheme 15

NaBH4, O2

O

O

CH2OBn

R2

R1

OBn

SeC6H5

Bu3SnHO

CH2OBn

R2

O

R1

Me

OBn( 17 ) +

AIBN

C6H6

80 oC

O

CH2OBn

R2

O

R1

Me

OBn

29a R1 = H, R2 = OBn

29b R1 = OBn, R2 = H

54%

86%

46%

14%

(3.) Hydrogen Bonding56,57

The energies of the transition states in the reactions shown in Scheme 16 depend upon

whether R is a hydrogen atom or a trimethylsilyl group. When the trimethylsilyl group is in place,

the chair-like transition state 28 is preferred because it places all substituents in pseudoequatorial

positions.56

If the trimethylsilyl groups are replaced by hydrogen atoms, a different, chair-like

transition state (27), one that has two pseudoaxial substituents but is stabilized by hydrogen

bonding, has lower energy. The reactions described in Scheme 16, therefore, illustrate the power

of hydrogen bonding in influencing reaction stereoselectivity.

434 Chapter 19

ORCO2Me

OR'

OR

OR'

CO2MeRO

RO

favoredwhen

R = SiMe3

favoredwhenR = H

ORCO2Me

OR'

OR

OR'

CO2MeRO

RO

2827

OR'

CO2MeRO

RO

ORCO2Me

OR'

OR

R = H

R = Me3Si

55%

9%

14%

75%

Scheme 16

R' = SiMe2t-Bu

isolated asa lactone

when R = H

Bu3SnH - Bu3SnBu3SnH - Bu3Sn

[Additional (minor) cyclic products are formed in these reactions.]

(4.) Conformation of an Existing Ring

The reactions shown in eq 17 illustrate the effect that the stereochemistry of a remote ring

substituent can have on reaction stereoselectivity.58

It is unlikely that the C-4 benzyloxy groups in

the radicals formed from the allyl ethers 29a and 29b are close enough to the radical center or the

multiple bond to influence reaction directly. A more likely possibility is that substituent stereo-

chemistry affects pyranoid-ring conformation in the intermediate radicals and that differences in

conformation (or in the mixture of accessible conformations) determine reaction stereoselectivity.

The idea that inversion of configuration at C-4 can change intermediate-radical conformation in

these reactions (eq 17) is supported by the observation that other pyranos-1-yl radicals that are

epimeric at C-4 adopt quite different radical conformations.59


Scheme 17

Bu3Sn - Bu3SnI

3031

32 33

pseudo 1,3-diaxial interaction

32/33 = 9/1

- Bu3SnBu3SnHBu3SnH - Bu3Sn

I

EtO2C

O O

O

CMe2

EtO2C

O OCO2Et

OCO2Et

CO2Et

O O

O

CMe2

O O

O

CMe2

CO2Et

EtO2C

O

2. Six-Membered Ring Formation

Chair-like transitions states also provide a basis for understanding stereoselectivity in

six-membered ring formation. In the cyclization reaction shown in Scheme 17, product formation

can be explained by assuming that two chair-like transition states (30 and 31) are accessible during

reaction.60

The difference in energy between these two depends primarily on steric interactions

involving the CH2CO2CH3 group. The transition state 31 with its pseudo-1,3-diaxial interaction

would be expected to be higher in energy than the transition state 30, which avoids such inter-

action. The highly stereoselective formation of 32 is consistent with this proposed difference in

transition-state energies (Scheme 17).

436 Chapter 19

Si

O

O

TBSO

OTBS

TrOCH2 SeC6H5

34

Bu3Sn

Si

O

O

TBSO

OTBSTrOCH2

35

Si

O

O

TBSO

OTBS

TrOCH2

36

O

HO

TrOCH2

HO

HO

OH

85%

H2O2, KF, THF

KHCO3, MeOH

Tr = C(C6H5)3

TBS = SiMe2t-Bu

Scheme 18

Bu3SnH

- Bu3Sn

Si

O

O

- Bu3SnSeC6H5

3. Seven-Membered and Larger Ring Formation

In the reaction shown in Scheme 18 the size of the t-butyldimethylsilyl groups causes the

pyranoid ring in the phenyl selenide 34 to adopt a 1C4 conformation. If this conformation is

maintained during cyclization, as appears to be the case, radical addition to the vinyl group will

occur exclusively from the α face of the pyranoid ring in the radical 35 to give, after hydro-

gen-atom abstraction, the cyclic silyl ether 36.24,29b

When protection is provided by the less ster-

ically demanding benzyl groups, more conformational flexibility exists in the pyranoid ring (4C1

and 1C4 interconvert more easily) and radical addition occurs from either face of the ring system

(Scheme 19).24,29b

Further indications exist of the importance of radical conformation in forming rings with

seven or more members. In the reaction shown in eq 18 the rigidity of the radical derived from the

iodide 37 reduces the number of conformations possible but includes one that holds the radical

center and the double bond in close enough proximity that cyclization gives the major product; in

contrast, in the reaction shown in eq 19 the greater flexibility of the radical generated from the

iodide 38 changes the opportunity for interaction between reactive centers to the point that a

complex mixture of products is formed.61


Bu3SnH

Scheme 19

O

Si

OBnOCH2

BnO

BnO SeC6H5

Si

O

O

BnO

OBnBnOCH2 SeC6H5

Bu3Sn - Bu3SnSeC6H5

- Bu3Sn

64% 16%

OH

OBnOCH2

BnO

BnO

OH

OH

OBnOCH2

BnO

BnO

OH

KF, KHCO3, H2O2,

MeOH, THF

Si

O

O

Si

O

O

Si

O

O

Si

O

O

Si

O

O

+

KF, KHCO3, H2O2,

MeOH, THF

Bu3SnH - Bu3Sn

Bu3Sn - Bu3SnSeC6H5

( 18 )

50%

Bu3SnH

80 oC

C6H5CH3

AIBN

O O

O

O

CMe2

Me2C

OH

O O

O

O

CMe2

Me2C

OH

I

37

438 Chapter 19

( 19 ) Bu3SnH

80 oC

C6H5CH3

AIBN

O O

BnO

BzO

CMe2

OBn

I

38

complex mixtureof products

IV. Unsaturated Carbohydrates That Undergo Radical Cyclization

The unsaturated carbohydrates that undergo radical cyclization are an eclectic mixture of

compounds in which the reactive multiple bond in each typically is electron-deficient. Reduced

electron density in the multiple bond can be caused either by conjugation of this bond with a

carbonyl group or by having an electronegative substituent attached to it. Ring formation still can

occur when a double or triple bond is not electron-deficient, but as described earlier in this Chapter

(Section II), in such a situation cyclization is slower and less able to compete with other radical

reactions.

( 20 )

AIBN

C6H5CH3

110 oC

Bu3SnH

NH

NO

CH2 I

OAc

O

O

ClNH

NO

OAc

O

O

H

Cl

75%

A. α,β-Unsaturated Carbonyl Compounds

The electron-deficient double bond in an α,β-unsaturated ester is an attractive target for in-

ternal addition of a carbon-centered radical.44,60–94

The majority of reactions of this type produce

five-membered rings;62–85,93

fewer, but still a significant number, form six-membered

rings.60,81,82,86–91

Formation of smaller27

and larger27,94

rings also takes place, but such reactions are

far less common. (Examples of internal radical addition in α,β-unsaturated esters are found in the

reactions shown in Schemes 8, 16, and 17.) The radicals that participate in this type of reaction

usually are generated from halogenated carbohydrates but also can be formed from reaction of

carbohydrates containing O-thionocarbonyl,79

cyclic O-thionocarbonyl,65

O-thionocarbamoyl,72-74

phenyl seleno,50

aryl telluro,77

O-acyl-N-hydroxy-2-thiopyridonyl,88

and vinyl75,76

groups.

Other α,β-unsaturated carbonyl compounds that undergo radical cyclization include nuc-

leosides that have a carbon-centered radical in the sugar portion of the molecule. In these reactions


cyclization occurs by internal radical addition to a carbon–carbon double bond in the nitrogenous

base.95–101

Since the substrate in most of these reactions is a derivative of uridine, cyclization is, in

effect, an internal addition to an α,β-unsaturated lactam (eq 20).96

Bu3Sn

Br

N

HN

O

AcOCH2

OAc

O

Br

O

OAc

- Bu3SnBr

N

HN

O

AcOCH2

OAc

O

O

OAc

Br

H

39

N

HN

O

O

O

AcOCH2

OAc OAc

O

AcOCH2

AcO AcO

N

NH

OO

- Br

Scheme 20

40%

7%

40

NO

OAc

H Br

40

N

O

Br

AcO

H

- Br

NO

OAc

HBr

39

N

O

Br

AcO

H

440 Chapter 19

Other cyclization reactions of carbonyl compounds include internal addition to α,β-un-

saturated aldehydes,109

ketones,110,111

and lactones,112

and to lactams that are α,β- and γ,δ-unsat-

urated.102–108

Reaction of the unsaturated lactam pictured in Scheme 20 begins with halogen-atom

abstraction that is followed by 1,5-transfer of a hydrogen atom to give the interconverting radicals

39α and 39β. New rings form when these radicals react to give the cyclic, stereoisomeric radicals

40α and 40β, respectively.102

The stereoselectivity of this reaction depends upon the stereochem-

istry of the C-2' substituent and changes when the configuration at C-2' is inverted.102

O

OEt

CH2OBn

O

Me2SiCH2Br

O

O OEt

Me2Si

CH2OBn

( 21 )

AIBN

C6H6

80 oC

Bu3SnH

73%

B. Silyl Ethers and Silaketals

One method for connecting a radical forming group and a multiple bond is with a silicon–

oxygen tether. In some compounds of this type (e.g., the substrate in the reaction pictured in eq 611

)

the multiple bond is located in a substituent group,11–13,113–123

while in others23,124–133

(eq 21),124

it

is part of a ring system. As mentioned earlier in the chapter (Section III.B.4), connecting the

reacting segments of a molecule through a silicon–oxygen bond is particularly useful in producing

larger (seven-,24,29

eight-,31–36

and nine-membered38–42

) rings. An example of a reaction that forms

a larger ring is shown in Scheme 18, where an allyl group is tethered to the 2-position in the phenyl

selenide 34.24,29b

A similar tether connects the two saccharide units in the radical 41, an

intermediate destined to form an eight-membered ring that then is converted into a partially

protected C-disaccharide (Scheme 21).32

The carbon-centered radicals in these reactions usually

are generated by treating phenyl selenides with tri-n-butyltin hydride.

Having a vinyl group tethered to a radical-forming substituent through a silyl ether linkage

can provide the structure needed to form either a five-membered or a six-membered ring.11-13,113-120

It is worth recalling (Section III.B) that in compounds of this type the size of a ring formed can

depend on the concentration of the hydrogen-atom donor; thus, in the reaction shown in eq 6,

higher Bu3SnH concentration causes formation of a five-membered ring, but lower concentration

favors a six-membered one.11

Scheme 3 contains a rationalization for this concentration depend-

ence.

In the radical reactions of the unsaturated silyl ethers pictured in Schemes 18, 19, and 21 and

eq 21, the final step is hydrogen-atom abstraction from Bu3SnH. When the substrate is an unsat-

urated iodide and no Bu3SnH is present in the reaction mixture, the cyclic product is a silyl ether

that contains an iodine atom (Scheme 22).119b

Reaction of this product with fluoride ion eliminates


both the silicon-containing group and an iodide ion and introduces additional unsaturation into the

final product.

Bu3SnSeAr

OCH3

OO

CMe2

SeAr

O

Si

OO

O

O

OMe

C6H5

Scheme 21

Bu3Sn

OO

OC6H5

O

OMeSi

O

CH3

O

OMe2C

O

41

Bu3SnH - Bu3Sn

OO

OC6H5

O

OMeSi

O

O

OMe2C

OCH3

OO

OC6H5

HO

OMe

OCH3

OO

CMe2

OH

Bu4NF

H2O

THF

I

O

O

O

O

OMe

Me2Si H

Ar

42 43

O

O

OMe

Me2Si H

O

O

OMe

Me2Si

H

- I

O

O

HO

O

OMe

Ar

H

O

O

OMe

Me2Si

H

I

Ar = C6H5

F

- Me2SiF2

- I

Scheme 22

42 - 43

442 Chapter 19

A process similar to that shown in Scheme 22 takes place in the reaction pictured in Scheme

23, where homolytic cleavage of the C–Se bond is followed by ring formation to generate the

cyclic radical 44. If diphenyl diselenide (C6H5SeSeC6H5) is added to the reaction mixture, the

yield of the unsaturated nucleoside 45 increases from 47% to 77%. Diphenyl diselenide reduces

competing radical reactions (e.g., hydrogen-atom abstraction) by rapidly reacting with 44 to form

an intermediate selenide from which the product 45 is produced by an elimination reaction.115b

i-Pr2Si

O

O

O

O

i-Pr2Si

SeC6H5

B

OMe2Si

Scheme 23

OB

O

Me2Si

h

- C6H5Se

OB

O SiMe2

44

- C6H5Se(C6H5Se)2

OB

O SiMe2

SeC6H5

O

HO

HO B

OH

Bu4NF

THF

45

C. Alkenyl and Alkynyl Ethers, Esters, Acetals, and Alcohols

A molecule with an O-allyl5,9,45,58,134–146

or an O-propargyl21,147–157

group and a properly

positioned, radical-forming substituent will react to form a new ring system. Equations 22136

and

23152

describe reactions of compounds of this type. These reactions take place even though ring

formation produces highly reactive radicals, a primary radical from an allyl ether (eq 24) and a

vinylic one from a propargyl ether (eq 25). Not surprisingly, ring formation takes place readily in

compounds where cyclization does not need to produce such reactive radicals; in fact; as long as

reactive centers can come within bonding distance, radical cyclization occurs in a wide variety of

unsaturated radicals.158–186

Some specific examples are shown in equations 26 and 27, where ring

formation takes place in molecules in which the multiple bond is located in an existing ring system

(eq 26)159

or is part of an acyclic structure (eq 27).185

( 22 ) AIBN

C6H6

80 oC

Bu3SnHO

BnO

BnOCH2

BnO

BnO

O

I O

BnO

BnOCH2

BnO

BnO

O

CH3

H


( 23 )

AIBN

C6H6

80 oC

Bu3SnHOAcOCH2

AcO

AcO

O

I

OAcOCH2

AcO

AcO

O64%

( 24 )

O O

CH2

( 25 )

O O

O

OEt

CH2OTr

O

EtOCHCH2I

O

O OEt

CH2OTr

EtO

( 26 )

AIBN

C6H6

80 o

C

Bu3SnH

85%

Cyclization takes a different course in its final stage when a radical is formed by electron

transfer from samarium(II) iodide.187

In such a reaction the cyclic radical reacts with additional

SmI2 to form an organosamarium intermediate that undergoes elimination to produce a carbon–

carbon double bond (Scheme 24).164

In the reaction shown in Scheme 24 an O-acetyl group is

eliminated, but even a hydroxyl group (presumably complexed with SmI2) can depart in forming

the double bond (eq 28).164

( 27 )

AIBN

C6H6

80 oC

(C6H5)3SnH

70%

OMe

MeO

HO

I

OMe

OMeHO

444 Chapter 19

Scheme 24

I

AcO

O O

CMe2

OAc

AcO

O O

CMe2

OAc

AcO

O O

CMe2

OAc

AcO

O O

CMe2

SmI2

OAc

AcO

O O

CMe2

AcO

O O

CMe2

6%76%

+

SmI2

- SmI3

SmI2

- AcOSmI2

( 28 )

51%

HMPA

SmI2

THFMeOH

HO

O O

CMe2

I

HO

O O

CMe2

OH

The course of radical cyclization in allyl ethers and related compounds sometimes is altered

by internal hydrogen-atom abstraction.58,88,134,138,171,172,185

Hydrogen-atom abstraction by a

carbon-centered radical from a C–H bond does not take place readily. The best possibility for this

type of reaction occurs when a radical is particularly reactive [e.g., the primary radical produced

from an allyl ether (eq 24) or the vinylic radical from a propargyl ether (eq 25)] and the abstraction

is internal. Such reaction happens following cyclization of the pyranos-1-yl radical 46 (Scheme

25).58,134,138

Although the radicals 47 and 48, produced in this reaction, are both primary, only 48

has the proper stereochemistry for internal hydrogen-atom abstraction. In a similar reaction the

vinylic radical 49, produced during ring formation, abstracts a hydrogen atom from the


neighboring O-benzyl group in route to formation of a mixture of cyclic compounds (Scheme

26).172

- Bu3Sn

OBnOCH2

BnO

BnOO

Scheme 25

O

BnOCH2

OH

CH2

46

47 48

H

O

BnOCH2

OCH2

H

O

BnOCH2

OCH3

H

O

BnOCH2

BnO

BnOO

HCH2D

55% 10% 35%

O

BnOCH2

BnO

BnOO

CH2DH

D

O

BnOCH2

BnO

BnOO

CH3

H

Bu3SnD - Bu3Sn- Bu3Sn

Bu3SnDBu3SnD

internalhydrogen

abstraction

+

D. Compounds with Terminal Triple Bonds

A triple bond in a molecule can have more than one role in a radical cyclization reaction. In

addition to being the multiple bond that combines with a radical centered on a carbon atom else-

where in the molecule, as occurs in the reaction shown in eq 27, a triple bond also can be the source

for a carbon-centered radical that adds to another multiple bond.188

When a radical (usually the

tri-n-butyltin radical) reacts with the triple bond in a compound such as the propargyl ether 50 to

form a vinylic radical, rapid internal reaction of this radical takes place if there is a second multiple

bond within bonding distance (Scheme 27190

).189–200

Although the tri-n-butyltin radical also can add to a double bond,75

triple bond addition is a

far more likely beginning step in a cyclization reaction.193,201

The difference in reactivity between

a double and a triple bond is apparent in the reaction shown in eq 29,193

where a triple bond reacts

in preference to a similarly positioned double bond. These differences in reactivity between double

and triple bonds are determined by the rate of radical cyclization rather than stannyl radical addi-

tion. The stannyl radical actually adds more rapidly to a double bond than to triple bond, but the

446 Chapter 19 adduct radical from addition to a double bond reverts more rapidly and cyclizes more slowly than

that from addition to a triple bond.201

OBn

BnO

HO

OCH2C6H5

OBnHO

H

OBn

BnO

HO

I

- Bu3SnI

Bu3Sn

49

- C6H5CHO

OBnHO

HH

Bu3SnH

- Bu3Sn

OBnHO

HHCH3

OBnHO

62% 18%

+

Scheme 26

OCHC6H5

OBnHO

H H

- Bu3Sn

O

CH3

O OR

SnBu3

Scheme 27

O

CH3

O OR

O

CH3

O OR

SnBu3

- AcOSnBu3

HOAcO

CH3

O OR

SnBu3

O

CH3

O OR

93%

50

SnBu3

Bu3SnH

E. Compounds in Which the Multiple Bond is not Electron-Deficient

If a carbon-centered radical and a multiple bond are in separate molecules, radical addition

only competes effectively with other radical reactions (e.g., hydrogen-atom abstraction) when the


multiple bond is electron-deficient. If this bond is not electron-deficient, successful addition is rare

and requires conditions that minimize competing reactions. When the two reactive centers are in

the same molecule and can come into close proximity, cyclization can be competitive when the

multiple bond is not electron-deficient (eq 35).

5,183,202–210 In fact, even if this bond is electron-rich,

ring formation can take place (eq 30211

).211–221

( 29 )

54%

O

O

CH2OR

O

(C6H5)3SnH

Et3B-O2

C6H5CH3

R = Si(C6H5)2t-Bu

O

O

CH2OR

OH

(C6H5)3Sn

+two minorproducts

( 30 )

AIBN

C6H6

80 oC

Bu3SnH

80%

BrO

O

O

O

C6H5

OEt

O

O

O

O

C6H5

OEt

CH2

Figure 1. Possible carbohydrate frameworks

pyranoid ring furanoid ring open-chain structure

C3 C2

C1

OC5

C4

C6

The framework in a typical sugar has one of the three structural typesshown above. (A hexose is used as an example.) A framework radicalis one centered on a numbered carbon atom, and a framework multiplebond is one involving at least one of these atoms.

C3 C2

C1

C5

C4

C6

C5

C6

C4

C3 C2

C1

O

V. An Organization for Carbohydrates That Undergo Radical Cyclization

It is useful in organizing radical cyclization reactions to divide them into groups that have

common features. One method for doing this places radicals of similar structure together. Where

carbohydrates are concerned, such a plan can be based on the location of the radical center and the

multiple bond. A radical center can exist on an atom that is part of the molecular framework

448 Chapter 19 (Figure 1) or part of a substituent group. The same possibilities exist for the multiple bond. Cyc-

lization reactions of carbohydrates then naturally divide into the four basic types shown in Figure

2. (A short-hand terminology describing these four types has been proposed45

and is included in

Figure 2.) This division provides the basis for constructing Tables 1-4. In addition to these four

tables, two smaller ones are included in recognition of the importance of radical cyclization reac-

tions in the synthesis of nucleosides (Table 5) and carbon-linked disaccharides (Table 6.)

Figure 2. Possible types of cyclization reaction for carbohydrate derivatives

O

O

O

O

O

O

Si

CH2

O

Si

O

a framework radical adding to a framework multiple bind

O

OO

O

O O

a framework radical adding to a substituent multiple bond

a substituent radical adding toa framework multiple bond

a substituent radical adding toa substituent multiple bond

S CC=C

C SC=C

C CC=C

S SC=C

VI. Summary

Forming a new ring by internal addition of a carbon-centered radical to a multiple bond is a

powerful tool in carbohydrate synthesis. Regioselectivity and stereoselectivity are vital aspects of


this type of reaction. Being able to predict regioselectivity is critical because a cyclization reaction

potentially can form rings of two sizes. Since the newly formed ring nearly always has an addi-

tional chiral center (sometimes two), understanding stereoselectivity is essential in predicting

stereochemistry in the cyclic product.

Compounds with five-membered rings are the ones most often produced by radical cycli-

zation. Reactions that form five-membered rings are capable of generating six-membered rings

also, but rarely do so because the transition state leading to the larger ring has greater ring strain.

Compounds with six-membered rings are the major products when cyclization is capable of

forming either six- or seven-membered rings consisting only of second row elements. Larger rings

(seven or more members) are created when a radical center and a distant multiple bond are linked

by a tether, usually one containing a silicon–oxygen bond.

The stereoselectivity of reactions that produce five- and six-membered rings usually can be

rationalized by assuming that the reaction passes through a chair-like transition state. The lowest

energy transition state for such a reaction has as many substituents as possible in pseudoequatorial

positions. A variety of factors (pseudo-1,3-diaxial interaction, allylic strain, hydrogen bonding,

conformation of an existing ring) affect transition-state energy and can, on occasion, cause a

boat-like transition state to be more stable than a chair-like one.

Various types of unsaturated carbohydrates, often α,β-unsaturated esters, undergo radical

cyclization. Also prominent among reactive compounds are those in which the radical-forming

part of the molecule and the portion containing the multiple bond are connected by a silicon–

oxygen tether. A third group of compounds that cyclize readily includes allyl and propargyl ethers

and related compounds.

450 Chapter 19

radical formingsubstituent

type ofmultiple bond

number of atomsin the new ring

references

Table 1. Framework Radical Reacting With a Framework Multiple Bond

CH CHCH2O

CH2 CHCH O

CH2 CHCH O

CH2 CHCH O

CH CHCH O

HC CCH O

CH CHCO2R

CH CHCO2Et

CH CHCO2Me

HC CCH O

HC CCH O

C6H5C CCH O

C6H5C CCH O

Me2SiC CC O

C CCO2Me

C CHCO2R

CH CHCO2Me

Br

Br

I

I

CH CH CO

N

Br

I

I

I

I

I

I

I

I

I

I

I

I

I

5

5

6

7

5

5

6

7

5

6

7

6

7

5

5

5

5

5

164, 182

54, 55

168

166

61, 168

49

87, 89

91, 92

172

172

61

61

171, 172, 185

186

61

171, 174

60, 64, 68, 69,85, 92, 164

62, 66, 67, 69,70, 84, 91, 93

210

207

22

208, 210

5

5

6

5

MeSC(=S)O

MeSC(=S)O

MeSC(=S)O

CH CH O

CH2 CHCH CH

CH2 CCH O

CH2 CHCH2MeSC(=S)O





references

Table 1. Framework Radical Reacting With a Framework Multiple Bond (Continued)

C6H5OC(=S)O

C6H5OC(=S)O

C6H5OC(=S)O

C6H5OC(=S)O

C6H5OC(=S)O

CH2 CCH O

CH2 CCH O

HC CCH O

HC CCH O

C6H5C CCH

ImC(=S)O

ImC(=S)O

ImC(=S)O CH2 CHCH O

OCH CH

HC CCH O

O

O

S CH CHCO2Me

S

C

S

NOC

O

S

NOC

O

S

CH CHCO2R

HC CCH2

CH CHCO2Me

O

C CH CCO2t-Bu

CH

O

CH CHCH CH2

5

6

5

6

6

5

5

5

5

5

6

5

6

5

22, 201

22, 201

178, 181

179, 180, 219

175, 176

51, 160, 213

51, 160, 213

181

57, 63, 65, 83

70, 89

88

202

86

207

158

158

6

5

C6H5S

C6H5S

CH2 CHCH2

CH2 CHCH O

CH CHCO2MeMeSC(=S)O 5 210

452 Chapter 19

C CCH O

CH CHCO2Et

CH CHCO2R

CH CHCH O

CH2 CHCO

CH2 CHCH O

CH CHCO2Me

C6H5S

MeOC6H4Te

H2C C

HC C

HC C

HC C

HC C

5

5

5

6

6

6

7

158

77

75, 76

166

22

196, 201

61

Table 1. Framework Radical Reacting With a Framework Multiple Bond (Continued)

references number of atomsin the new ring




CH2 CHCH O

CH2 CHCH2O

CH2 CHCH2

Me3SiCH CHCH O

(CH3)3CCH CHCH2O

CH CHCO2Et

HC CCH2O

Me3SiC CCH O

C CCH2O

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

5

6

6

6

5

5

5

5

4

5

6

5 + 6

6

5

5

6

5, 136, 144, 189

206

5, 152

204

189

152

9

107

96, 97, 99, 100

9, 144, 169, 170

112

27

91

60, 91

114

5, 152

CH2 CHCH O

CH2 CHSiO

C6H5CH CHCH2O

CH CHCO2Et

CH CHCO2Et

CH CHCO2Et

CH CHCO2

82

5

CH CHC(=O)NH

CH CHC CHC(=O)NH

I

I

I

C6H5C CCH2

5 177, 189

I 1525

Table 2. Framework Radical Reacting With a Substituent Multiple Bond

referencesnumber of atomsin the new ring



Br

Br

Br

Br CH2 CHCH2O

123

148

203, 206, 209

143, 144, 145, 149

5 + 6

5

6

5

CH2 CHSiO

CH2 CHC(Me)2O

CH2 CHCH2

454 Chapter 19

CH CHCO2

C CHCO2Me

5

5

6

7

5

5

6

5

6

143

27, 203

99

27

102-106, 108

84

143, 148, 151

143, 151

27CH CHCO2Et

CH CHCO2Et

HC CCH2

C CCHO 109

5

CH CC(=O)NH

Br

Br

Br

CH CHCO2R

Br

Br

Br

Br

Br

Br

Br

HC CCH2O

CH CHC CHC(=O)NH

Br 1435C CCH2O




references

Table 2. Framework Radical Reacting With a Substituent Multiple Bond (Continued)

CH2 CHCH2O

CH2 CHCH2O 6

CH2 CHCH O

CH2 CHSiO

CH2 CHSiO

CH2 CHSiO

9

7

8

6

5

C6H5Se

C6H5Se

C6H5Se

C6H5Se

C6H5Se

C6H5Se

C6H5Se

C6H5Se

C6H5Se

C6H5Se CH2 CHSiO

36

58, 134, 135,138, 139, 146, 157

139, 140

140, 157

161

24, 28, 29

36

13, 28, 118

115, 116, 119

11, 12, 113-116

5

5

5

5 + 6

C CHCH2O

CH2 CHCH2SiO

CH2 CHCH2SiO

C CHCH2NH 5C6H5Se 10


5

6 95

140

10, 167C6H5Se

C6H5Se

C6H5Se

C6H5Se

C6H5Se

C6H5Se

C6H5Se

5

5

5

7

6

CH2 CHCH2NH

CH CHCO2

CH CHC(=O)N

121

134

58, 134, 135,138, 139, 146, 157

HC CCH2O

Me3SiC CCH2O

Me3SiC CSi

RC CCH2O 173

Table 2. Framework Radical Reacting With a Substituent Multiple Bond (Continued)

references number of atomsin the new ring



8OCH CHCO2Et

7OCH CHCO2Et

6OCH CHCO2Et

RC CSiOArSO2

5

CH2 CHSiO

5CH CHCO2

6

5

5

CH2 CHC N

CH2 CHCH2O

HC CCH2O

CH2 CHCH O

CH2 CHCH2O

C(=O)H

NO2

C CH

C CH

C CH

C CH

C6H5SO2

ArSO2

ImC(=S)O

C6H5OC(=S)O

C6H5OC(=S)O

CH3SC(=O)O

CH3SC(=O)O

CH3SC(=O)O

HC CCH2O

101CH CC(=O)NH

OCH CHCO2Et

CH2 CHCH2O

5

5

199

72, 73, 74

199

199

117

199

137

153

117

220

157

149, 150, 154, 155

165

141, 142

6

5

5

5

5

456 Chapter 19

CH2 CCO2Me

CH2 CHCH O

CH CHCH O

CH CCH O

C C O

CH C O

N

Br

I

I

I

5

5

6

6 + 7

6

5

5

5

21, 6, 7,109, 159

6, 7

185

21, 81, 109,124-127,129,132, 159, 163

184

152, 162

130

94

94

124, 133, 183, 211,212, 214, 218

7

23, 216

71

37

109

CH CHCO2Et

HC CCH O

5Br

Br

Br

Br

Br

Br

Br

Br

Br

Br

Br

Br

Cl

8CH2 CHCH O

5

23

23, 215, 217

6

5

5 + 6C C O

N

C C O

N

CH CCO2Me

6

9

9

CH CHCO2Et

CH2 CCN

CH CCHO

O

CH CHCH O

CH CHCH O




references

Table 3. Substituent Radical Reacting With a Framework Multiple Bond

C C O

CH CHCH O

C6H5C(=S)O

CH2C CH

C CH

C CH

5

5

5

CH CHCO

CH CHCH O

5 21, 190-193, 195

192, 214

195

221


CH2 CHCH2O

CH CHCO2

HC CCH2O

I

I

I

5

5

11

110, 111

111

98

44

45

156

200

197

197, 198

194

111, 205

CH2 CH

10

Br

Br

Br

6CH2 CHC

5 + 6

CH2 CHCH

CH CC O

5

I

CH CC(=O)NH

HC C

5

CH2 CHCH2O

HC C CH CHC 5

HC C

5 + 6

HC C

(CH3)2C CHCH2O

CH CHC(=O)N 6

6 147HC O

HC C 194

5CH CHC

Table 4. Substituent Radical Reacting With a Substituent Multiple Bond

referencesnumber of atomsin the new ring






references

Table 5. Nucleoside Synthesis

Br 5

5

80

50

79

CH CHCO2Et

5C6H5Se

C6H5OC(=S)O

CH CHCO2Me

CH CHCO2Et

458 Chapter 19




references

Table 6. Carbon-Linked Saccharides

I

I

I

5 9

33

31

31, 32, 35, 38, 43

38-41, 43, 46

33, 34

117

42

38

5SiC CCH O

C6H5Se

C6H5Se

C6H5Se

C6H5Se

C6H5Se

C6H5SO2

C6H4NSO2

8

8

7

8

9

11

8

9

30

CH CHCH O

CH2 CO

CF2 CO

CH2 CCH O

CH2 CCH O

CH2 CCH O

CH2 CCH O

CH2 CO

CH2 CCH O

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