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Intramolecular [4+2] and [3+2] Cycloadditions in Organic Synthesis.

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Intramolecular [4 2) and [3 2) Cycloadditions
in Organic Synthesis
New synthetic
methods (18)
By Wolfgang Oppolzer[*I
Dedicated to Professor Madimir Prelog on the occasion of his 70th Birthday
Numerous examples of intramolecular cycloaddition of 1,3-dienes, nitrones, and azomethine
imines attest the preparative value of this variant for regioselective and stereoselective synthesis
of annelated and bridged ring systems. The common features, differences, and limitations
of these types of reaction are systematically reviewed.
1. Introduction
Thermally induced additions of 1,3-dienes and of 1,3-dipoles
to multiple bonds clearly lead to six- or five-membered rings
with the simultaneous formation of two o-bonds, via a highly
ordered aromatic transition state" -31. The stereochemical
consequences of a reaction course of this type are paralleled
by reactivity and orientation phenomena ascribed to frontier
orbital interaction^[^]. The great preparative importance of
these features of the mechanistically related reactions is shown,
inter alia, by a multitude of fascinating applications of the
bimolecular Diels-Alder reaction to the synthesis of complex
From investigations carried out in recent years it follows
that the synthetic potential of such cycloadditions is decisively
increased by the principle of intramolecularity. Intramolecular
additions of this type result not only in the simultaneous
formation of two rings, but also in certain consequences which
are superimposed on those of the classical bimolecular variants.
The aim of the present review is to collect the common
characteristics of intramolecular additions of 1,3-dienes,
nitrones, and azomethine imines and to indieate the possibilities and limitations of these processes. Entropy factors and
problems of kinetically controlled regio- and stereoselectivity
deserve special attention which justifies their detailed discussion. An attempt is made, with the aid of selected examples,
to demonstrate the scope and utility of these reactions in
the synthesis and biogenesis of structurally complex natural
already indicated the possibility of intramolecular [4 + 21 additions (type 11) as early as 195316], and other authors later
found occasional example^"^, it was not until the last decade
that the general utility of this reaction became apparentL8].
2.1. Acyclic Dienes
2.1 .I. Construction of 5,6- and 6,6-Ring Systems
The first systematic investigation of this type of reaction,
described by H . 0. House in 196519', suffices to bring certain
characteristic features to light. When heated to 130°C, the
trans-diene unit in the triene ( 1 ) adds smoothly to the double
bond of the acrylic ester linked to the diene by a bridge
of three carbon atoms leading to the trans-annelated hydrindane derivative (2). Surprisingly, under the same conditions the cis-substituted diene (3) reacts in a similar manner,
but with exclusive formation of the cis-annelated product
( 4 ) . In view of the fact that cis-substituted open-chain 1,3dienes usually undergo bimolecular Diels-Alder reactions only
with difficulty, we are forced to the conclusion that the reaction
(3)- ( 4 ) profits from entropy factors due to the spatial proximity of the reaction partners. (Examples given below show
that nonactivated dienophiles smoothly undergo intramolecular cycloaddition for the same reason.)
2. Intramolecular Diels-Alder Reactions
Bimolecular [4 21 cycloadditions (type I), whose general
applicability was recognized by Diels and Alder nearly 50
Type 1
Type I1
Scheme I . [4+ Z]-cycloaddition of dienes.
years agoc5],are today one of the most important types of
reaction used in organic synthesisl2I. Although Alder had
[*] Prof. Dr. W. Oppolzer
Dtpartment de Chimie Organique, Universitk de Genkve
CH-1211, Geneva 4 (Swnzerland)
f 31
Anyew. Chem. l n t . Ed. Engl. 16,10-23 (1977)
A further notable feature of intramolecular [4 + 21 additions
is the influence of orienting factors promoting the formation
of annelated products. For example, the reaction of the cisdiene (3) gave no trace of the bridged positional isomer
( 5 ) ; in this connection it should be remembered that the
addition in the intramolecular reactions (1) + (2) and
(3) -+ ( 4 ) takes place in the opposite direction to that strongly
favored in the bimolecular reaction ( 6 ) + (7) + (??)[Io1.
Consideration of models (see Section 2.6.2) shows that the
formation of a bridged adduct from ( I ) is blocked by strain,
whereas the formation of the transition state ( 3 ) + from (3)
does not require any deformation of the bond angles; thus,
the absence of ( 5 ) after thermolysis of (3) is due to other
causes, presumably the (entropically favored) easier closure
of a five-membered ring than that of a six-membered ring.
The pronounced stereoselectivity of the conversion ( 3 ) --t ( 4 ) ,
on the other hand, appears to be due to a strongly strained
transition state, which would have to be overcome in the
alternative reaction (3) + ( 2 ) (see Section 2.6.3). The endoposition of the ester group appears to be decisive for favoring
the reaction ( I ) + ( 2 ) over the reaction ( I ) (4).
states. Incidentally, this investigation provided the impetus
for the development of a productive general synthesis of the
then unknown N-butadienylamide~['~].
Using this process the readily available amine (15) could
be converted in two stages into the dienamide (16). When
The results of kinetic and stereochemical studies["] of the
thermal reaction ( 9 ) + (10) + ( 1 2 ) are in accord with the
above conclusions. For example, an activation entropy of
AS* = - 14.4 cal K - ' mol-' is found for the intramolecular
addition ofthe acrylamides ( 9 ) , R = tert-butyl, R'= H, whereas
bimolecular Diels-Alder reactions have considerably more
negative&* values (between -30 and -40 cal K-' mol-I).
Furthermore, the reaction ( 9 ) + (10) + ( 1 I ) becomes increasingly slower as the size of the nitrogen substituent R decreases
(probably for conformational reasons). The stereochemistry
of these kinetically controlled additions reflects again the preferential endo-orientation of terminal n-substituents R', i. e.
the trans-fused adducts (10) are formed selectively from the
amides (9), R = C O O E t or C6H5.This opens a simple route
to polysubstituted perhydroisoindoles with stereochemical
control of up to five chiral centers.
A close connection between systematic study and direct
application of intramolecular Diels-Alder reactions to the synthesis of natural products is shown in the following example.
Attempts to synthesize the physiologically active (but almost
inaccessible)alkaloid pumiliotoxin C (18) in a stereoselective
manner led to a study of the intramolecular additions of
dienamides (12), X or Y =O['21.It transpired that the amide
(12), X=Hz, Y = O , R=CH3, is converted at 200°C into
the very nearly pure cis-fused octahydroquinoline (13),
whereas the amide (121, X = O , Y=Hz, R=CzH5, affords,
with lower but reversed selectivity, the trans-lactam ( 1 4 ) and
its cis-isomer (23) in the ratio of 3 :2. The different courses
of the reaction can be due to a preferred coplanar arrangement
of the amide and diene units in the corresponding transition
A n g e w Chem. Int. E d . Engl. 16,lO-23 ( 1 9 7 7 )
heated in toluene for 24h at 215°C in a sealed, silylated
glass tube, (16) undergoes efficient intramolecular cycloaddition[I4".14bJ; the adducts ( I 7) (isolated in 60 to 90 % yield),
when hydrogenated and hydrolyzed, finally afforded the racemic alkaloid (18) in 60% yield together with three stereoisomers (in yields of 17, 15, and 2 %). The remarkable feature
of this synthesis is the simultaneous control over all four
chiral centers in the key step (16) + ( I 7), dictated by the
trans-configuration of the dienophile and, presumably, by the
double-bond character of the amide group.
Another route to pumiliotoxin C(14c1
is also based on an
intramolecular [4+2] addition [ ( 2 0 ) --t (21)], which favors
an endo-orientation of the three-carbon bridge; hydrogenation
and oxidation of the adduct (21) lead thus to an easily separable 2 : 1 mixture of the cis-hydrindanone ( 2 2 ) and its transannelated isomer. After Beckmann rearrangement of the main
product the carbonyl group of the perhydroquinolone (23)
H OSiMe,
serves for simple and stereoselective introduction of the propyl
group. For the preparation of cis-2,3,3a,6,7,7a-hexahydro-7amethyl-1 -indenone by thermolysis of truns-2-methyl-l,6,8nonatrien-3-one, see Ref." 51.
In the synthesis of carbocyclic systems by intramolecular
Diels-Alder reactions there occasionally arose the problem of
how to prepare the necessary polyene substrates by a rational
route. In this connection the (triethylsi1yloxy)pentadienylanion ( 2 5 ) recently became available as a convenient building
block for the construction and attachment of functionalized
diene and dienophile units because of its reactivity toward
electrophiles['61. Thus, y-alkylation of ( 2 5 ) led stereoselectively to (2)-silyloxydienes, for example ( 2 6 ) or (29). The
triene ( 2 6 ) underwent an intramolecular cycloaddition at
160°C and after ether cleavage afforded the hydrindanone
(28) in an overall yield of 55 %. When, however, the tetraene
( 2 9 ) was treated at 0°C with potassium fluoride, the transoctalone ( 3 2 ) was produced directly (in 62% yield) in an
astonishingly smooth (kinetically controlled) exo-addition of
the unisolable vinyl ketone (30).
isomer (central double bond) prior to its conversion into
(33). In subsequent steps the newly formed double bond
of the adduct ( 3 3 ) served as a bifunctional site to close the
pyrrolidine and the lactone rings of (35).
An elegant solution of stereochemical problems is also
encountered in the thermal conversion of ( 3 6 ) into ( 3 7 ) ,
which was conceived as the key step for construction of the
microbial metabolic product proxiphomine (39)[l8].The sole
adduct obtained, (37), apparently (concluded from the NMR
coupling JAB=7 Hz) contains the correct relative configuration
of the natural product ( 3 9 ) with respect to all four chiral
centers. Treatment of ( 3 7 ) with ammonia led to the isoindole
system (38).
160 "C
2.1.2. Construction of 6,7-and 6,12-Ring Systems
It can be assumed that bicyclic systems containing sevenor more-membered rings may be constructed by intramolecular addition if the distance between the diene and dienophile
units is increased.
(40 I
70 %
(41), X = 0
(42), X = CH,
A recent attempt to synthesize the alkaloid dendrobine
yielded its 8-epi-isomer (35)" 71. The endo-oriented addition
( 3 2 ) + ( 3 3 ) occurred with stereochemical control of all chiral
centersexcept the center next to the nitrile group. It is assumed
that ( 3 2 ) is formed by thermal isomerization from its (Z)NC Me
The validity of this assumption is demonstrated by the
Lewis acid-catalyzed conversion of the triene (40) into the
annelated cycloheptanone (41) (70 %), which was transformed
by methylenation into the sesquiterpene a-himachalene
(42)" 'I.
49 74
.. :
Angew. Chrm. Int. E d . Engl. 1 6 , l O - 2 3 (1977)
The fact that 12- and 13-membered rings can also be closed
by intramolecular cycloaddition to activated dienophiles is
exemplified by the thermolysis of (43)[201.When low steady
state concentrations are used (to suppress the undesired bimolecular addition), a 7: 3:4: 1 mixture of the stereo- and positionisomeric products ( 4 4 a ) , ( 4 4 b ) , ( 4 5 ) , and ( 4 6 ) is obtained
in 80 %, yield. This (kinetically and/or partially thermodynamically controlled) product ratio reflects the loss of the control
over regio- and stereochemistry that characterizes the previously discussed construction of 5,6- and 6,6-ring systems.
2.2. Endocyclic Dienes
Intramolecular cycloadditions of 1,3-dienes which are partly
or wholly incorporated in a ring may provide complicated
ring systems which are accessible by other routes only with
Similar considerations apply for the reaction (54)+(55)'231.
An interesting sequence of thermal inter- and intramolecular
cycloadditions that leads in one synthetic operation to the
formation of four C-C bonds (see also [7b1) is provided by
the reaction of ( 5 6 ) with dimethyl acetylenedicarbo~ylate[~~~.
At low temperature (to avoid hydrogen shifts) a 3 : 2 mixture
of ( 5 8 a ) and ( 5 8 b ) is immediately obtained via the intermediate bimolecular adducts ( 5 7 a ) and (576). The product
(58a) was converted in several steps into (59).
2.2.1. I-Vinylcycloalkenes
14 7)
This is illustrated, inter a h , by a model study on the synthesis of gibberellic acid in which the cycloaddition
( 4 7 ) + ( 4 8 ) is the key stepf2']. Stereoselective methylation
of the cyclohexadiene component in the adduct (48), followed
by modification of the lactone ring, leads to the indane derivative (49). This compound has the correct spatial arrangement
of functional groups for the construction of rings A and €3
of gibberellic acid.
2.2.2. Cyclopentadienes
Earlier work, whose objective was also the synthesis
of a natural product, examined the thermal behavior of
the mixture of cyclopentadienes ( 5 0 ) and (51)[221.When
2.2.3. Cyclohexadienes
Another sequence of thermal (cycloaddition-cycloreversion
and hydrogen-shift) reactions, involving participation of the
intermediate compounds (61 a ) and (62a), occurs when a-pyrone is heated with the dienone ( 6 0 ) at 230°C[251;the isomeric
products (63a), (65a), and (&a), are obtained directly in
yields of 37, 43, and 11 %, respectively. Thermolysis of the
pentenylcyclohexadiene (61 b ) is appreciably more selective, as it yields the adduct (636) in 73% yield with
small amounts of ( 6 5 b ) and ( 6 6 b ) ; clearly the hydrogen
shift (61 b ) -+ ( 6 2 b ) is slower than the addition
(61 b ) + (63b). Particularly noteworthy here is the fact that
- CO2
this mixture was heated at 176°C for 48 h the norbornene
(52) was the sole product, with no trace of the desired adduct
( 5 3 ) which could have served as a direct precursor of the
sesquiterpene longifolene. Hence it can be concluded that
( 5 0 ) and ( 5 1 ) equilibrate (by a 1,Shydrogen shift) and that
the irreversible addition (51) --t (52) proceeds faster than the
expected reaction ( 5 0 ) + (53), although here thermodynamic
control cannot be completely ruled out.
Aiigrw. Chem. I n f . Ed. Engl. 16, 10-23 (1977)
/ 5 8 a ) , R' = COOMe, R2 = H
( 5 8 6 1 , R' = H, R2 = COOMe
230 "C
( 5 7 a ) , R' = COOMe, R2 = H
(576), R' = H, R2 = COOMe
164) (not formed)
( a ) , X = 0 ; ( b ) , X = H~
the thermal reactions of ( 6 1 0 ) and (61b) yield no trace
of the position-isomeric adduct (64), although (owing to the
&-configuration of the diene with respect to the dienophilic
chain) no strain opposes that reaction.
The same regioselectivity that we encountered earlier in
the reaction ( 3 ) + ( 4 ) also characterizes the intramolecular
cycloaddition (68)- ( 6 Y ) r ] ,which provides the complex skeleton of the sesquiterpene patchoulol (70) in a single step[261;
the racemic natural product (70) is obtained by simple hydrogenation of the adduct (69). In comparison with several
multistage syntheses of p a t c h o u l ~ l [ ~the
~ ] ,reaction sequence
( 6 7 ) + (68) + (69) + (70) demonstrates the effectiveness of
intramolecular cycloadditions.
280 TI24 h
5 7'0 KOC(CH31,
requires bond formation between the terminal dienophile
center and the nearer end of the endocyclic diene system
in (71). This orientation, opposite to that in the examples
mentioned above, is probably due to an overlap of the dienophile with the double bond conjugated thereto. In the formation of (72) such an overlap is impossible on the grounds
of strain[z8c'.
A further application of intramolecular additions of cyclohexadienones exploits the easy preparation of (77) by Wessely
oxidation of the phenol (76) in the presence of acrylic acid.
On heating (77) in boiling benzene the lactone (78)[291 is
formed, the ring system of which is a component of the natural
products morellin and gambogic acid.
C- *- e p i m e r
h e
b H
No less impressive is a route to the structurally related
sesquiterpene seychellene (75), in which a smooth intramolecular addition of the easily accessible cyclohexadienone (71)
Already at 80°C a kinetically controlled reaction
gives, as with the analogous alkenylcyclohexadienones[28b1,
the regioisomeric adducts (72) and (73) in a ratio of 1 :3.
The main product (73) was converted into the alcohol (74),
which on acid catalysis rearranged to the desired terpene
(75). Remarkably, the formation of (73) as the main product
2.2.4. Endocyclic Heterodienes
The efficient intramolecular Diels-Alder addition of an isolated double bond to a 4,6-dihydroxypyrimidine has been
demonstrated recently by the thermolysis (79) + (80)[301.
2.3. Styrenes as Diene Components
An extremely simple synthetic route to Podophyllum
l i g n a n ~ ' ~described
by L. H . Kfernrn, may be taken as the
first application of an intramolecular [4+ 21 cycloaddition
to the synthesis of natural products. Thus, the natural lactone
(83) is obtained by merely heating the arylpropargyl ester
[*] Addition of a strong base appears to be decisive for this addition to
proceed successfully.
M eO
A n p n . Chem. Int. Ed. Etryl. 16, 10-23 ( I 977)
( 8 1 ) in boiling acetic anhydride. In this reaction the styrene
unit of (81 ,) clearly reacts as the diene and the triple bond
as the dienophile with the formation of an intermediate adduct
(82) which aromatizes to (83) by a 1,3-hydrogen shift.
Furthermore, at higher temperatures (180 to 235 "C) olefinic
double bonds that are relatively unreactive add intramolecularly to styrenes132a1.For example, the cis-fused isoindoline
derivative ( 8 5 ) is obtained exclusively by thermolysis of the
N,N'-bis(cinnamy1)amide (84), while the trans-system (87)
is obtained selectively from the isomeric amide (86). Steric
the multiple bond in the chain (with concomitant formation
of the arene system). This addition occurs smoothly even
with unreactive dienophiles, e. g. with isolated C-C and C-N
double or triple b o n d ~ I ~ ~presumably
because of the entropic
assistance resulting from the proximity of the reaction partner.
(For intramolecular cycloadditions of nitriles to 1,3-dienes
see [341.)
78 B
( a ) , n = 1; (b), n
interactions of the phenyl substituents are probably responsible for this mutually exclusive steric control which disfavors
on the one hand the exo-orientation of the chain in (84)
and on the other the endo-addition of (86). It is worth noting
the exclusive formation of 1:1 adducts in the above
cases, whereas bimolecular Diels-Alder reactions of styrenes
often yield the (undesirable) 2 :1 addition
difference underlines once more the preparatively advantageous influence of entropy factors on the reaction rate of
intramolecular cycloadditions, as also shown by the smooth
thermal transformation (88)+ (89)[32b1.
2; (c). n = 3
The limits of this influence are revealed when one compares
the efficient reactions (90a) --t ( 9 2 a ) and (906) + ( 9 2 b ) (both
give an 80% yield) with the thermal behavior of the higher
homolog ( 9 0 ~ ) ~even
~ ~at~high-dilution
' ;
the adduct (92c)
is formed in drastically reduced yield (20%), together with
the dimerization product (93) (6% yield).
56 %
2.4. o-Quinodimethanes
Another reaction sequence that is interesting from the
preparative point of view and whose course involves participation of an aromatic system was developed in the
laboratories of Sandoz Ltd.[331. Accordingly, tricyclic
systems of the type (iii) are obtained in excellent yield by
heating the readily accessible benzocyclobutenes (i) that carry
on C-I a chain of five o r six atoms with a terminal multiple
bond. Here, according to stereochemical and kinetic findi n g ~ we
[ ~have
~ ~a primary
reversible opening of the fourmembered ring to a nonaromatic intermediate (E)-quinodimethane ( i i ) , which undergoes irreversible cycloaddition to
Of the numerous possible variations offered by the inclusion
of heteroatoms and rings in the benzocyclobutene ( i ) , the
198a1, X = H,, R = COOMe
( 9 8 h j , X = 0, R = H
A q e w . Chem. Ifit. Ed. Engl. 16, 10-23 (1977)
90 7;
(100hl, X = 0
( 9 9 h ) , trans
1100a). X = H,
thermal reaction of (94) may be selected as an example;
already at 120°C it provides ( 6 9 ) in 73% yield and forms
the key step in the synthesis of the alkaloid chelidonine
The steric course of the related thermal transformations
of(98a), (98b), (lOOa), and (IOOb) may be cited as examples
to illustrate how intramolecular cycloadditions can be directed
toward endo- or exo-products merely by changing the conformation of the bridger33d,351.
High stereoselectivity was similarly observed in the key
steps (103)- (104) and (105)+(106) of two independent
steroid syntheses[361.
lanchnanthocarpone (1 13) also involves an intramolecular
Diels-Alder reaction : ( I 11 ) (I 12). In fact, the natural product (113) could be obtained in one synthetic operation by
oxidation of the catechol (110) with NaI04; the ensuing
12) proceeds readily at 25"C[38b1.
cycloaddition (11 1)-(I
A similar concept is encountered in the elegant biomimetic
synthesis of the lignan carpanone (109)[37a1.This route, which
is characterized by remarkable control over five chiral centers,
leads via phenol coupling of (107) to an intermediate bis(quinodimethide) (108); spontaneous intramolecular DielsAlder reaction of this gives the lignan (109) in 46%
Similar facts apply to the racemic natural product cyclopiperstachine ( I 15)r3']; this was isolated under mild conditions
from Piper trichostachyon and to all appearances arises in
nature by intramolecular cycloaddition of piperstachine (1 14),
which occurs in the same plant. This process was carried
out in the laboratory, but required temperatures above 110°C
to give stereochemically pure (115) in 33 % yield.
It is considerably more difficult to prove the key role postulated for the dihydropyridineacrylic ester ( 1 16n) (dehydrosecodine, not yet either isolated or synthesized)in the biosynthesis of iboga and aspidoderma alkaloids[401.
2.5. Biogenesis of Natural Products
The striking utility of intramolecular [4 21-cycloadditions
for the synthesis of complicated natural products leads inevitably to the question whether this reaction principle is also
used in nature. In answer to this, it may be recalled that
the synthesis of carpanone was patterned along the lines of
biogenetic ideas[37b1.The intermediacy of (108) in the biogenesis of (1 0 9 ) appears convincing in view of the mild conditions of the laboratory synthesis, the absence of optical activity
in the natural alkaloid (109), and the occurrence of the methyl
ether of the precursor (107) in the same plant.
Considering an earlier hypothesis[38a1it was very recently
suggested that the biogenetic pathway to the plant pigment
Nevertheless, it seems reasonable to regard intramolecular
Diels-Alder reactions of ( 1 1 6 ~ responsible
for the natural
occurrence of catharanthine ( I 17) and tabersonine (1 18).
In favor ofthis assumption, for example, is the in uiuo incorporation of secodine ( I 16b) into the aspidosperma skeleton'411,
whereas some in uitro experiments on indirect detection of
the bio-intermediate ( 1 16a) are subject to debater4'! However, this hypothesis provided the stimulus for a biomimetic
total synthesis of the aspidosperma alkaloid minovine based
Anyew. Chem. Int Ed. Engl. 16, 10-23 ( 1 9 7 7 )
on a bimolecular [4 21-addition (of a tetrahydropyridine
to a 2-(2-indolyl)acrylic ester)[431.
Nature seems to follow similar principles in the synthesis
of the alkaloid andraginine (120)[441;both its racemic char-
rrcms- Di enes
D (strained)
cis - D i m e s
acter and its partial synthesis by thermolysis of precondylocarpine acetate find a reasonable interpretation in the intramolecular cycloaddition of the postulated secodine derivative
2.6. Discussion
It is anticipated that the above features relating to intramolecularity are in general limited to [4+2]-additions in which
the diene and dienophile partners are linked by a bridge
of three or four atoms. The longer and more flexible this
bridge, the more the conditions resemble those for bimolecular
addition, as is shown by the reactions of ( 4 3 ) and (90c).
It must also be stated that the regio- and stereoselectivity
of intramolecular Diels-Alder reactions as discussed below
rely on a kinetically-controlled reaction course. To avoid loss
of this selectivity by the formation of thermodynamically controlled products it is recommended that such reactions be
carried out at the lowest possible temperatures even if longer
reaction times are necessary. These limitations apply equally
to the [3 + 21-additions discussed in Section 3.
2.6.1. Entropic Assistance
Intramolecular Diels-Alder reactions (type I1 in Scheme
1) take place under considerably milder conditions than are
required for the analogous bimolecular reactions (type I in
Scheme I ) [see, inter alia, the reactions of (9), R=CH3,
R'=COOEt, (301, (57), (108), and (Ill)]. The influence
of entropy is illustrated by the AS* values for the reactions
of ( 9 ) , which are less negative than -20 cal K - ' mol-';
their free activation energies (AG*) are thus lower by 5 to
7 kcal/mol than those for intermolecular 14 + 21-additions.
For the same reason, not only unactivated dienophiles, e:g.
isolated olefins, oxime ethers, and nitriles but also unreactive
(e. g. cis-substituted) 1,3-dienes undergo smooth intramolecular additions. [Catalysis of Diels-Alder reactions by Lewis
acids has been used only to a limited extent in the intramolecular variants, e. g. in the reaction ( 4 0 ) + (41 ).I
2.6.2. Direction of Addition
As follows from model considerations, intramolecular
14 21-additions to trans-dienes are necessarily oriented in
the direction A or B, since the orientation C is too strained
(Scheme 2). Furthermore, from cis-dienes, e. g. ( 3 ) , ( 2 4 ) , (61),
(68), and ( 7 9 ) , annelated rather than bridged adducts are
generally obtained; the observed preference for direction E
could here be ascribed to the fact that bond formation between
the nearer ends of the diene and the dienophile is entropically
more favorable than the orientation F. However, this influence
can be overridden by other factors, as shown by the reaction
Anqrw. Chrm. Inr. E d . Enyl. 16.10-23 ( 1 9 7 7 )
C (strained)
Scheme 2. Transition states ol intramolecular [4
length is three or four atoms.
+ 21-additions.
T h e bridge
2.6.3. Stereochemistry
[4+ 21-Additions I and I1 are synchronous multicenter
processes with characteristic stereospecificity. Intramolecular
additions 11, however, exhibit supplementary features which
differentiate between the endo- and exo-mode of addition
(Scheme 2). O n models it can be seen that in intramolecular
addition of cis-dienes the dienophile chain is forced into the
exo-position E, the transition state D being too strained.
The cis-adducts thus arising with high stereoselectivity, e. g.
( 4 ) , ( 2 1 ) [from ( 2 4 ) ] , and (631, can nevertheless be accompanied, or even outweighed, by products of competing sigmatropic or cisltrans-isomerization processes, e. g. in the formation of (33).
In the thermally more stable trans-dienes the orientations
A and B are both strain-free; as a result, the energy difference
between these two transition states depends on the bonding
and nonbonding interactions of the substituents and on other
conformational influences that are less clearly predictable.
For example, trans-dienophiles with terminal carbonyl or
phenyl groups lead selectively to trans-fused adducts, e. g.
(2) and ( l o ) , which, as in the bimolecular Diels-Alder reaction, reflects the favored endo-position of sp2 substituents.
However, this is not so for dienophiles as soon as the sp2
substituent forms an integral part of the bridge, as follows
from the reactions (9), R = H , ---t ( l O ) + ( l l ) , ( 3 0 ) - ( 3 1 ) ,
( 3 6 ) - (37), and ( 9 8 b ) - ( 9 9 b ) . The repulsive forces due
to the phenyl substituents appear to influence the spatial
characteristics of the reactions of ( 8 4 ) and (86). Other
examples, such as the thermolyses of (12), (98b), and (100b),
show the stereochemical influence of amide groups built into
the bridge. Quite generally, it should be possible, by conformational modification of the bridge, to direct intramolecular
cycloadditions more or less completely in the direction of
trans- or cis-anellated products.
Finally, it is of preparative importance to note the steric
induction of chiral centers by centers already present in the
bridge; here the conformational requirements of a highly
ordered transition state come into play. For example, in the
thermolyses of (16), (47), (68), (103), (IOS), and (108)
up to five chiral centers can be controlled simultaneously.
3. Intramolecular Cycloadditions of Nitrones and Azomethine Imines
It is due mainly to Huisgen and his school that the concept
of [3 2]-cycloaddition and its general application to the
synthesis of five-membered heterocycles has been visualized[3!
These reactions are closely related to the Diels-Alder reaction.
Examples are, inter alia, the bimolecular additions of nitrones
and azomethine imines to multiple bonds (Type IIIa and
111 b, respectively, in Scheme 3).
TypeIIIa, X = 0
TypeIVa, X = 0
TypeIIIb, X = NCOR
bim olecular
TypeIVb, X = NCOR
intram ol ecula r
.:pi; X
TypeVa, X = 0
TypeVb, X = NCOR
int r a m 01 e cular
Type VI
Scheme 3. [4+2]-Additions ofnitrones (Types IIla, IVa, V a ) and azomethine
imines (Types IIIb, IVb. Vb, VI).
Although intramolecular variants have recently been the
subject of a re~iew'~'',it seems justifiable to consider their
special features systematically in this article. However, the
discussion will be limited to a small selection of reactions
in which C-C double bonds are concerned (Types IV to
VI in Scheme 3).
( a ) , n = 1; ( b ) , n = 2
and/or activation of the olefinic componentr4];this difference,
which is useful for syntheses, again reflects the entropic
influence in intramolecular reactions. It is also worth noting
the regioselectivity of the addition of (122), which leads
mainly, if not exclusively, to annelated adducts (see Section
3.3.2). An exception is provided by the formation of bridged
isoxazolidines such as ( 1 2 5 ) from C-alkenylketonitrones,
probably owing to nonbonding interaction of the substituents.
Concerning the stereochemical aspects (see Section 3.3.3)
it appears that the C-(3-alkenyl)nitrones ( 1 2 2 ~ react
selectively to give cis-condensed isoxazolidines (123 a ) . The
kinetically controlled reaction of the homologous C-(5alkeny1)nitrones ( 122b)r5"1occurs less selectively; the transadducts (124b) are the main products, along with varying amounts of the cis-isomers (223b). However, at higher
temperatures (180-300'C)
equilibration of the trans- and
cis-adducts ( 1 24 b ) and (123 b ) occurs, presumably by 1,3dipolar cycloreversion, to afford finally the thermodynamically
more stable isomer (223b).
Isoxazolidines that are cis-fused to a six-membered ring
are, on the other hand, formed regio- and stereoselectively
from &,<-unsaturatedaldehydes under kinetic control, provided that carbons CI and p[51a,51b1
(or y and S[51c1) are part
of an aromatic ring. This is illustrated by the efficient reactions
( 1 2 6 ~ ) + ( 2 2 7 a ) , ( R 1 = R 2 = R 3 = H , 80% yield), which
3.1. Nitrones
Nitrones occupy a special place among the 1 , 3 - d i p o l e ~ [ ~ ~ ~ ,
not least because of their easy accessibility and the facility
with which their adducts can be modified. Thus, Beckrnann
described cycloaddition of the nitrone N-benzylidenebenzylamine N-oxide to phenyl isocyanate as early as 1890[471,but
the addition of nitrones to C-C double bonds was first
reported-simultaneously by several groups of workers-only
about 70 years later'481. It seems remarkable that bimolecular
and intramolecular nitrone-olefin additions were discovered
at the same time.
3.1 .I. C-Alkenylnitrones (Additions of Type IVa)
' , ~ intramolecular
Le Be1 et al. ~ h o w e d ' ~ ~that
of intermediate C-alkenylnitrones (Type IVa) can be easily
effected if olefinic aldehydes (121) are condensed with N-alkylhydroxylamines; annelated isoxazolidines (123) and/or (224)
are obtained in this way.
It is interesting that many of these additions to unactivated
C-C double bonds take place smoothly at 25"C, whereas
the bimolecular variant IIIa requires a higher temperature
( a ) , n = 1; ( b ) , n = 2
nevertheless become less efficient with increasing distance
C(126b) --t (227b),
R' = R 2= R 3 = H , 26 % yield]. It was also not unexpected
to find that ethoxycarbonyl or ether substituents (on the nearer
end of the alkene unit) can direct the intramolecular addition
partially towards bridged products, e.g. ( I 28), or (229); this
was also observed during model studies on the synthesis of
.Idy. The fact that the formation of annelated isoxaAngew. Chem. Int. Ed. Enyl. J6,J0-23 (19771
zolidines is generally dominant in additions of type IVa to
nonpolarized C-C double bonds is shown particularly clearly
in a model study for the synthesis of the alkaloid histrionicot~xin[~’’.
Namely, at 110°C the endocyclic ketonitrone (131 ),
=$J 19 %.
The same direction of addition is followed by the reaction
(138), R = H , C H 3 - + ( 1 3 9 )which
leads to the tropane skele(after cleavage of the N-0 bond).
In contrast, in the recently investigated intramolecular addition of N-(4-alkenyl)nitrones (141 )[551, it is mainly the nearer
alkene carbon that becomes linked to the nitrone-carbon.
The nitrones (141) are formed in situ by condensation of
formaldehyde with olefinic hydroxylamines ( 1 4 0 ) , which are
readily accessible by reduction of oximes with sodium cyanoborohydride. On heating the non-isolated nitrones (141 a )
i 130)
prepared by oxidation of the hydroxylamine (130), gave
mainly the annelated adduct (132), and only a trace of the
desired bridge isomer (133) which after cleavage of the N-0
bond affords the histrionicotoxin skeleton. It should be noted
that the conversion (132) + (133) could be accomplished
at higher temperatures, apparently zlia 1,3-dipolar cycloreversion. It follows that the bridged adduct (133) is thermodynamically more stable than the annelated isomer (132), whose
formation is kinetically controlled.
3.1.2. N-Alkenylnitrones (Additions of Type Va)
Intramolecular additions of Type Va, which necessarily
lead to bridged isoxazolidines, attracted little attention until
very recently. The first example was the thermolysis of the
N-(3-butenyl)nitrone (135), which was obtained by alkylation
of benzaldehyde oxime (134jrS3’;(136) was formed as the
sole adduct, with no trace of the position isomer (137). This
result corresponds to a regiospecific formation of the C-C
bond to the less substituted (terminal) alkene-carbon, as in
most bimolecular additions of nitrones (Type IIIa) to monosubstituted olefins. The high stereochemical control of the
intramolecular process indicates an endo-addition of the ( Z ) nitrone (135 ), the alternative exo-transition state being
excluded by angular strain (see Section 3.3.3).
at 1 I O T , a 2 : 1 mixture of the two positional isomers ( 2 4 2 a )
and ( I 43) was obtained in 75 %yield in a kinetically controlled
reaction. Much higher directional selectivity was observed
in thecorresponding reaction of (140b) which gave exclusively
the adduct (142b) in 90% yield. Similarly the hydroxylamine
(144), which also contains a 1,2-disubstituted double bond,
afforded (245) as the sole adduct.
The ready accessibility of N-(4-alkenyl)nitrones (from Nalkenylhydroxylamines) and the unequivocal direction of their
intramolecular additions to nonconjugated “symmetric“ C-C
bonds recently allowed a simpler56a’and e n a n t i o s e l e ~ t i v e ~ ~ ~ ~ l
synthesis of the lycopodium alkaloid luciduline (14 9 ) .
I 136)
Heating of the easily available hydroxylamine (146) with
an excess of paraformaldehyde and molecular sieves in toluene
furnished directly an 87 % yield of the isoxazolidine (148),
which on methylation, reduction and oxidation gave the alkaAngew. Chem. I n t . Ed. Engl. 16,10-23 ( 1 9 7 7 )
loid (149) in high yield. Comparison with another, multistage,
preparation of racemic (149)L56'1demonstrated for the first
time in the synthesis of natural products a superiority of
intramolecular nitrone additions over other types of reaction.
3.2. Azornethine Irnines
The history of these dipoles is more recent than that of
nitrones; the cycloadditions [type IIIb] of a few endocyclic
azomethine imines to multiple bonds were described by
Huisgen et al. in 1960[3a,57!
Surprisingly, it was only a few
years ago that convenient methods for the preparation of
open-chain (unstable) azomethine imines, analogous to those
for the preparation of nitrones, were found in the laboratories
of Sandoz Ltd.
Azomethine imines (151) were then obtained in situ from
N-acyl-N',N'-dimethylhydrazines via mercury compounds[581
or preferably by condensation of aldehydes with N-acyl-N'alkylhydrazines ( I 50)[591;subsequent trapping by bimolecular
addition (Type 111b) to dipolarophiles such as styrene,
furnished pyrazolidines in high yields. The simple reaction
(150) + (151) now allows olefinic substituents R', R2, and
R3 to be introduced specifically into the three positions of
the dipole; thus the intramolecular cycloadditions IV b, V b,
and VI may be easily realized.
3.2.1. C-Alkenylazomethine Imines (Additions of Type IV b)
(a), n = I; ( b ) , n = 2
For example, the adduct ( I 56a), R = H, was formed regioselectively on treatment of ( 2 5 4 ~ with
formaldehyde. Similarly
to the analogous additions of nitrones of Type Va, the direction
of the addition is reversed with the higher homologs (154b),
R = H ; one obtains only the regioisomer (157b), R = H . The
same direction of addition is preferred on heating the hydrazide
(154 b ) with benzaldehyde; the positional isomers (1 56b),
R=Ph, and ( 1 5 7 b ) , R = P h are formed in the ratio of 1 :7,
in a total yield of 54%, together with smaller amounts of
two stereoisomeric products. The stereochemistry observed
in these reactions is consistent with predominant addition
of the (Z)-dipole ( I 55 b ) , R = Ph.
3.2.3. N-Alkenoylazomethine Imines (Additions of Type VI)
Finally, the third reaction type, VI, requires that the dipolarophile chain is attached to the terminal nitrogen of the dipole.
C-Alkenylazomethine imines are conveniently accessible in
situ by condensing olefinic aldehydes with N-acyl-N'-alkylhydrazines (150) and undergo a spontaneous, regioselective
addition of Type IVb[601.
As shown by the example (152)+(153), cis-annelated pyrazolidines are formed directly and preferentially (although the
stereoselectivity is here less marked than for the analogous
additions of nitrones). Remarkably, the reaction of N,N'-bis(pmethoxybenzy1)hydrazine does not produce isolable pyrazolidine derivatives on reaction under similar conditions with
( 1 5 2 ) or with paraformaldehyde in ~ t y r e n e [ ~ ~ this
* ~ ' ]is; not
in agreement with the postulate[3a,6 1 1 that intermediate azomethine imines are formed when the last-mentioned hydrazine
reacts with aldehydes in the presence of carbon disulfide (or
3.2.2. N-Alkenylazomethine Imines (Additions of Type Vb)
As expected, the condensation of N-acyl-A"-alkenylhydrazines with aldehydes leads to azomethine imines (with an
alkenyl group on the central nitrogen of the dipole), which
can undergo intramolecular additions of type V bC6''.
A reaction of this type can be smoothly effected by heating
N-alkenoyl-N'-alkylhydrazines together with aldehydes[621,as
shown by the regio- and stereoselective conversion
(158) ---t (159) (160). The sole product is the sterically
homogeneously annelated adduct (1 60) (whose configuration
has not yet been clarified) with no trace of the bridged isomer
3.3. Discussion
The mechanistic relationship between 1,3-dipolar addition
and the Diels-Alder reaction makes it possible to discuss
the features of their intramolecular variants on a common
basis. However, nitrones and azomethine imines can add also
intramolecularly to C-C double bonds that are linked by
a short chain to the central atom of the dipole. In contrast,
Chem. Int. Ed. Engl. 16,lO-23 ( 1 9 7 7 )
the analogous Diels-Alder reaction would be blocked by the
formation of a developing bridgehead double bond. A further
difference concerns the rotation barriers of C-N and C-C
double bonds (Scheme 4). It seems reasonable to assume that
products. Bridged products, e. g. (I 28) and ( I 29), cannot
arise by way of the strongly strained orientation I but only
from (Z)-dipoles via the strain-free transition state L. However,
in additions of Type IV to nonpolarized double bonds, the
orientation L is disfavored compared with J and K, as is
manifested by the predominant formation of annelated products. This kinetically controlled regioselectivity, which is illustrated by the reaction sequence ( 1 3 1 ) (132) (1331, may
be due to the fact that bond formation between the nearer
ends of the dipole and dipolarophile is entropically favored.
This may also apply for the regioselectivity of the addition
(159) + (160); in this case the dipolarophile is attached to
the terminal nitrogen of the dipole.
X = 0, NC O R
Scheme 4. Rotation or acyclic nitrones and azomethine imines.
(Z)/(E)-isomerizations of acyclic nitrones and azomethine
imines are comparable in rate with the cycloaddition proc ~ s s6 3 ~f , which
~ ~ has
~ .been taken into account in the discussion
of the orientation rules (Section 3.3.2). Furthermore, it must
be remembered that, with the exception of strain, the proposed
orienting forces may be overridden by other factors. As in
the Diels-Alder reaction, cycloreversion can occur at higher
temperatures with the formation of thermodynamically controlled products; this is occasionally of preparative use, as
in the reaction ( 1 3 2 ) (133).
VI: X = C ; Y = 0, N C O R
N: X = 0, N CO R; Y = C
0: X
+ Y = C; 0, NCOH
Scheme 6. Transition states of additions V (see Scheme 3)
3.3.1. Entropic Assistance
In view of the strongly negative activation entropies of
bimolecular additions of Type II113b1,there can be no doubt
(despite the lack of data) that intramolecular reactions
of Types IV, V, and VI are entropically favored. This is indicated by the smooth intramolecular addition of sensitive, unisolable dipoles to unreactive double bonds, which becomes
less effective with increasing distance between the dipole and
the isolated alkene unit [see the reaction ( 1 2 6 b ) - (127b)l.
3.3.2. Direction of Addition
( E )- D i p o l e s
I< ( s t r a i n e d )
I (strained)
Scheme 5. Transitlon states of the additions IV (see Scheme 3)
Examination of models shows that in intramolecular additions of C-alkenyl-nitrones and -azomethine imines (Scheme
5 ) both ( Z ) -and (E)-dipoles are capable of forming annelated
It is more difficult to predict the direction of the additions
of type V. In these compounds the alkenyl chain is attached
to the central nitrogen of the dipole (Scheme 6). Thus, the
length of the chain as well as alkyl substituents on the alkene
component may influence the preference between the orientations M and N. For example, transition state M predominates
in intramolecular additions of N-(4-alkenyl)-nitrones and -azomethine imines.
3.3.3. Stereochemistry
For the kinetically controlled formation of cis- and/or transannelated adducts from C-alkenyl-nitrones and -azomethine
imines the transition states G, H, J, and K may be considered
(Scheme 5); however, a model of the (Z)-endo-transition state
K proves to be strained. This strain clearly becomes more
pronounced when the two reactants are separated from each
other either by only three atoms or by a chain of four atoms
two of which belong to one double bond. If (for reasons
given below) we assume predominant addition of (Z)-dipoles,
then this explains the selective formation of cis-annelated
adducts in the reactions of (121 a ) , (126), and (152) (also
in the reaction of citral with N-methylhydroxylamine) by way
of the strain-free (Z)-exo-transition state J. On the other hand,
the observed formation of trans-fused addition products from
the nitrones (122b) is consistent with the (E)-exo-transition
state G, provided we assume that cycloaddition is now slower
than the (Z/E)-isomerization. However, this does not preclude
the participation of a (Z)-endo-transition state K, where angle
deformation is diminished by the longer bridge.
I n the intramolecular addition of N-alkenyl-nitrones and
-azomethine imines we meet unequivocal steric relationships
(Scheme 6). These reactions (Type V) can occur only through
the endo-transition states M and/or N, since the alternative
em-orientations 0 require an inadmissible deformation of
the bond angles. As a result, the stereochemistry of the additions of type V depend only on the configuration of the
dipolarophile and the dipole; that the latter reacts preferably
in the (Z)-form is probable in view of the observed conversions
( 1 3 5 ) 4 ( 1 3 6 ) and (155b), R=Ph,
(156b), R=Ph.
The stereochemistry of the additions of Type VI has not
yet been investigated, although, as previously mentioned, the
reaction ( f 5 9 ) - + ( f61) is known to take place stereoselectively.
4. Final Considerations
Intramolecular concerted cycloaddition reactions of 1,3dienes, nitrones and azomethine imines have provided the
organic chemist with the opportunity of synthesizing in one
operation complex polycyclic molecules both in a regio- and
stereoselective manner. The large number of the classical bimolecular variants indicates that the preparative wealth conferred
by intramolecularity on these types of reaction is by no means
exhausted. As a further possibility we may mention as an
example the formation of more than two bonds by a controlled
combination of successive pericyclic reactions. In the future
it is to be hoped that new efficient routes to appropriately
functionalized precursors, together with a better understanding
of the theoretical implications will significantly increase the
scope of these reactions.
Some of our own work mentioned in this article was carried
out at Sandoz AG, Basle, and some at the University ofGeneva.
The latter investigations were kindly supported b y the Fonds
National Suisse de la Recherche Scientijlque, Sundoz AG, Basle,
and Gicaudait S A , Vernier. I am indebted to Frau Kathrin
Keller and to Roland Aclzini, Bartholomeus Bakker, Charles
Fehr, Wolfgang Frostl, Emil Pfenninger, Martin Petrzilka,
Samuel Siles, Roger L. Snowden and Jochen Warneke for their
caluable collaboration, and to m y colleagues Prof. Charles K
JeJord and Dr. Roger L. Snowden for helpful suggestions during
the writing of this manuscript.
Received: 30th August, 1976 [A 143 IE]
German version: Angew. Chem. 89, 10 (1977)
Translated by Express Translation Service, London
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Structural Rules for Globular Proteins
By Georg E. Schulz[*]
Is it possible to reach a detailed understanding of the complex three-dimensional structures
of native polypeptide chains? In view of the wealth of common physicochemical and phylogenetic
features discovered among proteins this question has become reasonable. The current state of
discussion is presented in this report
1. Introduction
The structure of a globular protein was first elucidated
16 years ago"]. Meanwhile about 40 proteins have been analyzed at atomic resolution, and the polypeptide chain
fold is known in about ten more cases. Thus the pioneering
era has undoubtedly come to an end. Protein structure models
have become everyday tools of the biochemist; with their
aid he can design and interpret his experiments much more
soundly than ever before.
The wealth of structural data available not only favors
biochemical aspects, but also challenges us to understand
the architecture of the observed structures and thus to trace
biology back to its physical roots on a much more fundamental
scale than was previously possible. Given an intimate knowledge of their architecture, a substantial increase in the number
of analyzable proteins can be predicted because those proteins
also become accessible which do not crystallize. Furthermore,
the study of historical relationships, and especially very early
stages of evolution, can be put on a firmer basis. Therefore,
efforts invested in this field may be expected to yield considerable rewards.
2. Energy Balance
Globular proteins consist of linear polypeptide chains (Fig.
I), which are synthesized from 20 different amino acids[41.
During or after synthesis these chains fold spontaneously
to an exact three-dimensional structure. The spontaneity of
folding is regarded as a generally valid principle, because it
could be demonstrated in renaturing experiments with several
proteins[5 'I. Thus all information pertaining to three-dimensional structure is already implicit in the chemical structure
of the chain, i. e. in the amino acid sequence. Folding is merely
a transition to an energetically more favorable state of the
[*] Dr. G. E. Schulz
Max-Planck-Institut fur medizinische Forschung
Jahnstrasse 29, D-6900 Heidelberg (Germany)
Angwe. Cliem. lnr. Ed. Engl. 16,23-32 (1977)
Fig. 1. Part of a peptide chain. Because of resonance the peptide bonds
are planar [2]. Therefore the dihedral angles 4 and li, at the CZ atoms
determine the chain fold. Steric hindrance permits adoption of only 15 %,
of all possible 9, li, orientations [3]. The relatively low mobility of the
side chains should be noted.
The principal types of interactions involved in folding are:
van der Waals forces between nonpolar groups, dipole forces
between polar groups, in particular hydrogen bonds, and "hydrophobic forces" (a synonym for water entropy) which describe the tendency of the apolar side chains to form a separate
hydrophobic phase-i. e. a kind of oil droplet"! In the free
energy balance
the binding enthalpies and the water entropy together oppose
the chain entropy term. Only when their contribution is SUEcient can the chain entropy be overcome and the chain "immobilized, i.e. constrained to a definite structure. For chains
containing about 100 residues a rough estimate yields values
of several hundred kcal/mol for the opposing contributions.
However, the resulting AG is of the order 10 k~al/mol['~.
Thus we are dealing with a delicately balanced system, which
renders detailed understanding more difficult.
Hydrophobic nuclei are found in all structurally known
proteins, confirming the importance of the water entropy term
in eq. (1). The packing density of these nuclei is as high as in
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synthesis, intramolecular, cycloadditions, organiz
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