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Asymmetric Diels-Alder and Ene Reactions in Organic Synthesis. New Synthetic Methods (48)

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[I391 R. W. Denny, A. Nickon, Org. React. 20 (1973) 133; K. Nakanishi in K.
Nakanishi, T. Goto, S . Ito, S . Natori, S. Nozoe: Natural Products
Chemistry, Academic Press, New York 1975, Vol. 2, Chapter 12.
[I401 D. J. Coughlin, R. S. Brown, R. G . Salomon, J. Am. Chem. Suc. I01
(1979) 1533.
[I411 M. Suzuki, R. Noyori, N. Hamanaka, J . Am. Chem. SOC. 103 (1981)
5606.
[I421 H. Matsumoto, T. Nakano, K. Takasu, Y. Nagai, J. Org. Chem. 43
(1978) 1734, and references cited therein.
[I431 M. Suzuki, R. Noyori, N. Hamanaka, J . Am. Chem. Suc. 104 (1982)
2024.
[I441 M. Suzuki, H. Ohtake, R. Noyori, unpublished results.
11451 Review: N. A. Porter in W. A. Pryor: Free Radical in Biology, Vol. 4,
Academic Press, New York 1980, Chapter 8, p. 261.
[I461 J. A. Turner, W. Herz, Experientia 33 (1977) 1133; H. Graf, H. H. Ruf,
V. Ullrich, Angew. Chem. 95 (1983) 497; Angew. Chem. Int. Ed. Engl. 22
(1983) 487.
[I471 U. Diczfdlusy, P. Falardeau. S . Hammarstrom, FEBS Lett. 84 (1977)
271.
[I481 W. Lands, R. Lee, W. Smith, Ann. N . Y. Acad. Sci. 180 (1971) 107.
[I491 K. V. Honn, B. Cicone, A. Skoff, Science 212 (1981) 1270.
[ISO] R. Ueno, K. Honda, S . Inoue, 0. Hayashi, Pruc. Natl. Acad. Sci. USA
80 (1983) 1735.
[I511 1. Ganjian, W. Loher, I . Kubo, J. Chromatogr. 216 (1981) 380; W. Loher, 1. Ganjian, 1. Kubo, D. Stanley-Samuelson, S . S . Tobe, Proc. Natl.
Acad. Sci. USA 78 (1981) 7835; D. W. Stanley-Samuelson, J. A. Klocke,
1. Kubo, W. Loher, Entumol. Exp. Appl. 34 (1983) 35.
11521 D. E. Morse, H. Duncan, N. Hooker, A. Morse, Science lY6 (1977) 298;
K. Ono, M. Osada, T. Matsutani, K. Mori, T. Nomurd, Mar. B i d . Lett.
3 (1982) 223.
Asymmetric Diels-Alder and Ene Reactions in Organic Synthesis
New Synthetic
Methods
(48)
By Wolfgang Oppolzer*
I
I
Rapidly accumulating evidence shows the value of asymmetric Diels-Alder and ene reactions for the syntheses of enantiomerically pure molecules. This article presents a systematic and critical treatment of various stereoface-differentiating principles, including very
recent spectacular advances. The chiral information is mainly provided by covalently
bound auxiliaries, some of which are crystalline, inexpensive, and readily available from
naturally occurring monoterpenes, hydroxy acids, amino acids, steroids, and sugars. Nondestructive transfer of chirality leads to the efficient creation of u p to four chiral centers
with predictable relative and absolute configurations. Regenerative cleavage of the auxiliary group from the diastereomerically pure adducts furnishes a range of polyfunctional,
optically pure building blocks. Their synthetic potential is illustrated by strategic applications to the syntheses of physiologically interesting, chiral natural products such as prostaglandins, antibiotics, terpenoids, shikimic acid, alkaloids, and kainoids.
1. Introduction
2. Asymmetric Diels-Alder Reactions-General
The efficient construction of enantiomerically pure,
structurally complex molecules is a fundamental challenge
in organic synthesis. Only recently have extensive efforts
been made to induce asymmetry in carbon-carbon bond
forming reactions"]. Among these the Diels-Alder reaction
merits particular attention. Accordingly, this review focuses on the achievement of absolute configurational control in Diels-Alder reactions, underscoring various principles and illustrating their strategic applications to natural
product syntheses. Furthermore, the employment of analogous concepts in asymmetric ene reactions is outlined. Pertinent examples are selected based on the criteria of high
stereodifferentiation and removability of the chiral control
group from the product. Mechanistic discussions provide
insight into the three-dimensional nature of the corresponding transition states, assuming the operation of kinetic control.
[*] Prof. Dr. W. Oppolzer
Departement d e Chimie Organique, Universite de Genkve
30, quai Ernest-Ansermet, CH-I21 I Geneve 4 (Switzerland)
876
0 Verlag Chemie GmbH. 0-6940 Weinheim. 1984
Since its discovery in 1928 the Diels-Alder reaction has
been refined to become one of the most powerful tools in
organic synthesis[*]. A most attractive feature is the simultaneous, regioselective formation of two bonds leading to
the creation of up to four chiral centers at the binding sites
with largely predictable relative stereochemistry. Studies of
the control of the absolute topicity started in 1961, but substantial progress has only been achieved in recent years. At
present, this field is expanding rapidly, which justifies a selective rather than exhaustive review.
To illustrate the overall stereochemical features, we
mention the first reported example of a strategic application in synthesis.
Addition of 5-(methoxymethyl)cyclopentadiene l a to
acrylic acid 2a proceeded endo-selectively and anti with
respect to the diene sub~tituent[~l.
Consequently, the relative configuration of the four new chiral centers in 3a is
determined and, of four possible diastereoisomers, one is
formed selectively. As expected, the diene added at the
same rate to the two enantiotopic dienophile n-faces affording a 1 :1-mixture of the enantiomers (1R)-3a and
0570-0833/84/1111-0876 $ 02.50/0
Angew Chem. Inr. Ed. Engl. 23 (1984) 876-889
2) Both enantiomers or alternative topological counterparts should be readily available.
3) Be capable of efficient attachment and nondestructive
removal from the adduct with complete retention of the
induced configuration,
4) Permit facile purification of the major cycloadduct to
almost 100% d.e.
5) Impose crystallinity on intermediates and products.
Consequently, success in this research area relies on logical design and imagination, but also on numerous empirical parameters.
a, R'=
R2
3. Chiral Dienophiles
=H
3.1. Acrylates
The vast majority of work on asymmetric Diels-Alder
reactions deals with additions of 1,3-dienes to chiral, conjugated carboxylic esters. In this context, the relevant conformers of acrylates derived from secondary alcohols are
discussed briefly.
4
(1S)-3a. Since only the (1s)-enantiomer is suitable for the
synthesis of prostaglandins, exclusive diene addition from
the C,-re-face was required. Indeed, attachment of an appropriate chiral ester group R2 to the dienophile 2 caused
steric shielding of the now diastereotopic C,-si-face
thereby directing the AlCI,-promoted diene addition to the
C,-re-face. As a result of this n-face differentiation, the desired (1S)-3b was obtained from 2b in significant excess
over the undesired (1R)-isomer. Degradation of this mixture involving cleavage of the chiral control element R2
furnished ketone 4 in high enantiomeric purity[41.This example also serves to illustrate the definition of diastereomeric excess (d.e.) used throughout this review. For instance,
a hypothetical ratio (1S)-3b/(lR)-3b = 95 :5 amounts to
90% diastereomeric excess (d.e.) of (1S)-3b over (1R)-3b
and leads to the (1s)-ketone 4 in 90% enantiomeric excess
(e.e.). Accordingly, the n-face differentiation-related diastereomeric excess (e.g. 90% d.e. of (S)-3b) translates in
general into enantiomeric excess (e.g. 90% e.e. of 4) after
removal of the chiral auxiliary.
The above example demonstrates the addition of a prochiral diene to a chiral dienophile which carries a removable chiral auxiliary. Further options for n-topological differentiation in Diels-Alder reactions include the temporary
attachment of a chiral control group to the diene or, more
elegantly, the employment of a chiral catalyst. So far the
stoichiometric use of covalently bound chiral control
groups has proved to be more efficient and predictable. In
practical terms, the ideal prosthetic group should meet the
following criteria:
1) Provide a wide range of Diels-Alder adducts in high
chemical yield with virtually quantitative and predictable n-face stereodifferentiation.
Angew. Chem. Int. Ed. Engl. 23 (1984) 876-889
B
C
D
E
Conformation A, postulated by Prelog et aI.l5], implies
an anti-orientation of the large substituent RL and the
C=O group which is antiplanar to the olefinic bond. This
model differs slightly from conformer B, which, according
to X-ray data[61,exhibits a synperiplanar C-H,/C=O-relationship in the crystal. In solution, however, spectroscopic
evidence[71indicates an equilibrium between conformers B
and C, where the synplanar C=O/C=C-disposition of the
latter is disfavored by only AH=0.32 kcal/mol. If the
diene adds exclusively to the n-face opposite the larger
substituent, conformers B and C display reversed topicity.
Consistent with this element of unpredictability, no thermal Diels-Alder reactions of acrylates have ever surpassed
the threshold of 65% d.e. However, the situation changes
dramatically when the acrylate coordinates to a Lewis
acid. Supported by the results of X-ray['] and spectroscopic
studies['], we assume predominant coordination of various
Lewis acids (notably TiCI, and SnCI,) with the carbonyl
oxygen anti to the ester oxygen. This precludes conforma877
tion E on steric grounds and secures the C=O/C=C anticonformation D. Moreover, Lewis-acid coordination to
acrylates increases the regio- and endo-selectivity as well
as the rate of their [4 21-addition to 1,3-dienes. As a result
of this advantageous coincidence of effects, successful
asymmetric Diels-Alder reactions are generally carried out
at low temperatures in the presence of a Lewis acid. This
dichotomous influence of coordination on the activation
energies for conformer interconversion and cycloaddition
is also of predictive value for the rational design of chiral
control groups. One limitation, nevertheless, should be
mentioned. If the diene adds to the complex D from the
side opposite to the large group RL,tetragonalization of
the enoate centers may be sterically hindered. In fact,
enoates which carry a bulky ester substituent generally
show a decreased dienophile reactivity which restricts their
application to asymmetric Diels-Alder additions of mutually reactive diene and dienophile partners.
+
3.1.1. Addition of Bis(menthy1) Fumarate to 1,3-Butadiene
In 1963 Walborsky published his pioneering work on the
addition of bis(menthy1) fumarate 5 to 1,3-butadiene promoted by Lewis acids, affording the cyclohexene derivative 6"OI. Optimal results (80% yield, 78% d.e.) were obtained using TiC1, (1 mol per mol 5 ) in toluene at +25"C.
The reported rationalization refers to the Prelog model A
involving conformation F. Regardless of the validity of
this model, it should be considered that the high level of
diastereodifferentiation relies on the cooperative influence
of two chiral prosthetic groups (R* = ( - ) -menthy]).
(:).,
TlClL
RO
'
*
0
5
10
Table 1. Examples of reaction 8 - 9 in the presence of MX, at -20°C in
CHzCIz.
Entry
R
8 : MX,,
MX,
Yield
[%I
endo
[%I
d.e.
[Oh]
1 [a]
2[bl
3
4
5
6
7
H
H
H
Ph
Ph
Ph
Ph
1 : 1.0
1 : 0.43
SnCI4
BF,.0Et2
TiCI4
SnC14
SnCI4
Tic&
AICll
76
74-81
65
Icl
95
83
89
89
95
92
Icl
84
89
91
41
74
62
(99)
89
90
65
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 0.7
[a] At 4-8°C in toluene. [b] At 0°C. [c] Not reported [4].
induction of 99% d.e. based on the optical rotation of lor4].
This value was subsequently corrected to 89% (entries 4,
5)["] as a result of a study which also showed how significantly the extent of si-face selection depends (entries 5-7)
on the nature of the Lewis acid. The topological bias of the
8-phenylmenthyl group reported by Corey et al.I4l represents without doubt a landmark in asymmetric synthesis. It
COOR'
Q C O O R '
6
Si
n
h
is readily rationalize1 by postulating a conformationally
rigid cyclohexane G featuring an acrylate conformation D
and re-face shielding by the a-trans l-methyl-l-phenylethyl group[141.The enhanced diastereoselection may be a
consequence of complementary steric and aryl-acrylate nstacking effects. Nevertheless, limitations include the oily
nature of ( -)-8-phenylmenthol, the need for careful purification by medium pressure chromatography during its
preparation from ( +)-pulegone, and the difficult accessibility of its re-face directing (+)-enantiomer["].
3.1.2. Additions of Acrylates Derived from (-)-Menthol
to Cyclopentadiene
Employment of only one menthyl auxiliary, as in the addition of menthyl acrylate to (the even more reactive) cyclopentadiene at lower temperatures (8 +9 , R = H), does
not show the same degree of stereoselection as indicated in
Table 1 (entry 3["]). Early studies (entries 1, 2)[12,131
relied
entirely on chiroptic comparisons, which are insufficient to
assess the extent of an induction""]. The significantly
higher diastereotopic face differentiation exerted by the 8phenylmenthyl auxiliary was first reported to result in an
878
3.1.3. Addition of (S)-(+)-1,2,2-TrimethylpropylAcrylate
to Cyclopentadiene
A comparatively efficient C,-re-face directing auxiliary
had been reported previously. Thus, BF3 OEt,-induced
addition of the ester 12 to cyclopentadiene furnished the
(5s)-adduct 13 with high endo- and n-face stereoselectivity[l3I.The initially reported modest yield (Table 2, entry 1)
has been improved to 75% more recently (Table 2, entry
2)['61.It is worth noting that the absolute topicity is consistent with diene attack at the side opposite to the bulky tert+
Angew. Chem. Inf. Ed. Engl. 23 (1984) 876-889
H
11
O
H
12
I
RY
CIS I
oslendo
COOR'
13
Table 2. Examples of the reaction 12-13
(1 mol per mol 12) at -70°C in CH2C12.
Entry
1
2
Yield
endo
[W
[W
44
> 95
97
75
exo
in the presence of BF3.0Et2
3.2.1. Acrylates of the Types H to M
d. e.
Ref.
88
80-85
~131
[I61
Using the guidelines in Section 2, a number of alcohols I
were prepared and converted into the acrylates 11. To
compare the sign and extent of the topological bias provided by each auxiliary, the Lewis-acid promoted addition
to cyclopentadiene (11- 111) served as a test reaction.
butyl group of acrylate conformers B or D but not A. The
practical applicability suffers from the necessary separation of the oily auxiliary alcohol 11 from its enantiomer.
I
I1
I11
IV
3.1.4. Additions of Fumarates Derived from
3-Hydroxyisoborneol to Anthracene
In the course of a model experiment, fumarates 14 and
16 were added efficiently to anthracene at -30°C in
CH,CI, in the presence of AlC& (1 mol per mol educt)[I7l.
COOMe
c.'.':::R'=CH2Ph
COOMe
CONHPh
Acrylates from Various Auxiliary Alcohols: Alcohols 18
to 24 represent a cross-section of various, chiral auxiliary
compounds which emerged initially from this work. TiC1,mediated additions of their acrylates I1 to cyclopentadiene
afforded, predictably, either the (5R)-or the (SS)-2-norbornene adducts 111 with up to 88% diastereo~election~'~'.
14
Ph
COOMe
R'=CONHPh*
eM;&
0
16
92'10 R.R
17
The shielding of the fumarate 71-faces by the benzyloxy- or
N-phenylcarbamoyl substituents led to the (11S,12s)-adduct 15 (from 14) in up to 99% d.e. or to the (llR,12R)isomer 17 (from 16) in up to 92% d.e.
23
OH
81,5%R
OH
24 82,1%s
3.2. Working Concept for the Development of
x-Face Differentiating Acrylates
The properties of phenylmenthol stimulated a search for
more practical auxiliary alcohols: cyclohexanols locked in
a chair conformation (cf. H and K ) and conformationally
rigid cyclopentanols"4"l. Accordingly, a number of studies
focused on the si-face directing acrylates H , I, and J and
their re-face directing counterparts K , L, and M .
Angew. Chem. I n t . Ed. Engl. 23 (1984) 876-889
Acrylates from cis-3-Hydroxyisobornyl Ethers: Pursuing
the hypothetical role assigned to aryl/acrylate 71-stacking
and exploiting the ready availability of (+)- and (-)-camphor, the acrylates of the diphenylmethyl, a-naphthylmethyl, and b-naphthylmethyl ethers 25a-c were added to
cyclopentadiene. Whereas attempted catalysis by TiCL
failed because of rapid ether cleavage, high chemical
879
yields and up to 92% d.e. (Table 3) were conveniently obtained using the mild Lewis acid TiCl,(OiPr), [TiC14/
Ti(OiPr),, 1 : 11.
25
29 and 30 carry a tert-butyl shielding group attached to
the bornanol skeleton by a chain of two carbon atoms["].
In the TiCl,(OiPr),-induced addition of the acrylates of 29
(cis-exo) and 30 (cis-endo) to cyclopentadiene the topological bias provided by 30 is significantly higher than that of
29 (Table 4).
x
26
Table 3. Examples of the reaction of acrylates 11 derived from alcohols I
(cis-3-hydroxyisonorbornylethers 25 and 26) with cyclopentadiene to give
adducts I l l (for conditions, see text).
Entry
R
I
25a
25b
25c
25d
26
I
2
3
4
5
CHzPh
2-Naphthylmethyl
1-Naphthylmethyl
Neopentyl
Neopentyl
Yield
Adduct 111
endo
C-5
d.e.
[Oh]
[Oh]
"1
74
98
97
94
98
95
95
93
96
95
R
R
R
R
s
91
92
88
99.3
99.3
On testing the effect of steric bulk on acrylate n-face
shielding, it was found that the neopentyl ether 25d displayed a dramatically superior chirality directing ability"']
which is considerably greater than that of 8-phenylmenthol. Inspection of models having a staggered conformation of the neopentyl ether chain (consistent with X-raydata"']) indeed revealed that the tert-butyl group sterically
blocks the C,-re-face in the acrylate 27.
Table 4. Examples of the reaction of acrylates I1 derived from alcohols I (3alkylisoborneols 29 and 3-alkylborneols 30) with cyclopentadiene to give adducts 111 (for conditions, see text to Table 3).
Entry
1
2
I
29
30
Yield [%]
Adduct 111
endo [%I
C-5
75
89
89
92
d.e. [Yo]
S
66
94
R
3.2.2. Acrylates Derived from Camphor-10-sulfonic Acid
A new class of practical auxiliaries exploits the accessibility and crystalline nature of camphor- 10-sulfonic acid
derivatives.
c:::::
92 - 95%
____t
&OHS0,N:E
32
Me
31
83X
1
0
27
Me
34
33
a, R=CH(CH,)2; b, R=cyclohexyl
27
28
From the practical standpoint, it is worthwhile mentioning that the low melting, but crystalline auxiliaries 25d and
26 are readily accessible from either (+)- or (-)-camphor
in 60% overall yields. Their acrylates provide either the
(5R)- or the (%)-adducts 111 in 94 to 98% chemical yield
with 93 to 96% endo-selectivity and with over 99% diastereofacial differentiation (Table 3). Moreover, the auxiliaries
are nondestructively removed from the cycloadducts by
reduction with LiAlH, and can be readily separated from
the virtually enantiomerically pure alcohols IV by chromatography. The analogous Diels-Alder reaction of acrylate
27 with 1,3-butadiene in the presence of TiC1, (molar ratio
1 :4 : 1.4, 112 h at - 8 "C in CH,Cl,) gave the (R)-3-cyclohexenyl carboxylate 28 in 98% yield with 295.6% diastereofacial selection[201.
Acrylates Derived from 3-Alkylborneols and -isoborneols:
Further readily crystallizable auxiliary alcohols I such as
880
Starting from (+)-camphor-10-sulfonyl chloride, successive amidation and reduction with L-Selectride"] furnished
the crystalline sulfonamides 31 in 57 to 68% overall yield.
Their crystalline acrylates 32 undergo highly endo-selective TiCl,(OiPr),-promoted additions to cyclopentadiene at
-20°C to give adducts 33 (97 to 98% yield) in 88 to 93%
d.e.[223231.Intermediates and products were conveniently
purified by crystallization which, for example, increased
the diastereoisomeric purity of adduct 33a from 88% to
99% d.e. The auxiliaries 31 were regenerated straightforwardly by reducing the adducts 33 with LiAlH, and subsequent separation from alcohol 34 by direct crystallization.
Similarly, a series of aryl sulfones 35 were readily prepared in three steps from camphor-10-sulfonic acid. Their
usefulness as control groups in acrylate/cyclopentadiene
[*] L-Selectride= lithium tri-sec-butyl hydridoborate.
Angew. Chem. Inr. Ed. Engl. 23 (1984) 876-889
x
Me
Aryl=
a
B
+OH SO2 A r y l
35
J%
COOMe
b$J
dM4?Me
0
cycloadditions suffers from inferior n-face stereodifferentiation (64 to 69% d.e.) which outweighs other practical advantages[22,241.
v
kOAc
(OAc
40
t
39
I
I
L-Ara b 1nose
I
V
(2)Na104
CH=O
42
41
ee
32b
(1)NaOMe
100% ?
36
The superior topological differentiation of the sulfonamide-shielded acrylate 32b is consistent with the results
of an X-ray diffraction
In the crystal the uncomplexed acrylate adopts a strictly antiplanar arrangement of
the C,=C, and C=O bonds, the latter of which lies ca. 30"
out of the C-Ha plane. As a result of sulfonamide conjugation, the nitrogen is planar, projecting the surface of one
cyclohexane ring firmly on top of the olefinic bond. X-ray
crystal structure analysis of the phenyl sulfone 36 indicates an almost identical acrylate conformation but less
distinct shielding of its C,-re-face, which is perpendicular
to the sulfone-conjugated aryl
with a value published for enantiomerically impure 42
(e.e. -25%) ([a]E- 10.2", 95% EtOH, c = 1.812']) together
with the lack of reliable HPLC or GC data suggests that
this work should be evaluated with caution.
3.3. a$-Unsaturated Ketones
A series of interesting features distinguishes conjugated
a-hydroxy ketones 44 (X = H) and their enantiomers as
chiral d i e n o p h i l e ~ [ ~Their
~ . ~ ~preparation
].
involves separation of acid 43 from its enantiomer followed by successive
R'
3.2.3. (S)-Ethyl-0-acryloyl Lactate
Interestingly, addition of the acrylate of (+ethyl lactate
37 to cyclopentadiene was reported to proceed with 86%
C,-re-face selection in the presence of TiCI4, whereas the
topicity was inverted (although to the extent of only 32%
d.e.) by using BF3.0Et21251.
The (5s)-adduct 38 was purified by medium-pressure chromatography and saponified
with retention of configuration.
6
Et
3''
0R*
37
43
& - - hR
I
COOH
46
Table 5. Examples for the reaction of a,P-unsaturated ketones 44 with cyclopentadiene to give adducts 45 ; "endo" refers to the C=O group.
38
45
Entry
R'
R2
"Catalyst"
3.2.4. a,i?-Enoates with Chiral D-Substituents
High diastereotopic face differentiation has been
claimed for the thermal (1 10°C!) addition of the enoate 39
derived from L-arabinose to cyclopentadiene, which after
crystallization gave adduct 40 in 65% yield[261.However,
the composition of the mother liquor was not reported.
Destructive cleavage of the sugar template gave aldehyde
41, which was converted into ester 42. The confusing chiroptic comparison of the rotation of 42 ([a],- lo", CHC13)
Angew. Chem. Int. Ed. Engl. 23 (1984) 876-889
l a
2 a
H
H
3 b
4 b
5 c
H
H
Me
H
H
Me
Me
H
~
ZnCl,
-
ZnCI,
ZnCl,
T
["C]
[h]
-20
-43
+20
-20
0
24
1
12
16
24
f
Yield
[%I
endo
[%]
d.e.
[%I
90
89
9s
84
94
99
>99
83
97
90
-100
94
?
99
92
treatment with nBuLi and the appropriate vinyllithium reagent (molar ratio l :2 : 1.5). Addition of cyclopentadiene
occurs readily at -20°C even in the absence of a Lewis
88 1
acid (Table 5, entry 1) to give adduct 45a with 99% diastereotopic n-face differentiation. This high selectivity
undoubtedly derives from hydrogen bonding which locates
the chiral center within a rigid five-membered ring. The
bulky tert-butyl group enforces the C=O/C=C syn-conformation and directs the diene to the opposite enone face.
The unusually high reaction rate can also be assigned to
the hydrogen bond. In the presence of ZnCl,, BF3.0Et,, or
Ti(OiPr)4, Diels-Alder additions to 44 proceed at even
lower temperatures with improved endo- and 71-face selectivities (entries 3, 4). Apparently, the dienophile system becomes more conformationally rigid and “activated” by
chelation (44,X = metal), permitting efficient asymmetric
Diels-Alder additions of less reactive dienophiles (entries
4, 5) and of various acyclic dienes (see Sections 7.6 and
7.7). However, the inevitable destruction of the valuable
chiral auxiliary on oxidative removal (45 + 46) (successive
reaction with iBuZAIH, NaIO,, Jones reagent) is an obvious shortcoming.
3.4. N-Acryloyl and N-Crotonyl Compounds
3.4.1. N-Acyloxazolidones
As an extension of elegant applications of chiral N-acryloyloxazolidones to asymmetric aldolizations and enolate
a l k y l a t i ~ n s [ ~Diels-Alder
~],
reactions of the unsaturated
secondary amides 47 and 49 were examined[311.
played with similar efficacy by the norephedrine-derived
dienophiles 49. After recrystallization or chromatography,
the resulting cycloadducts 48 and 50 were obtained in 81
to 88% yield and 298% d.e. Nondestructive cleavage of
the oxazolidine auxiliaries from the adducts 48 and 50 by
“transesterification” with lithium benzyloxide furnished
the benzyl esters 51 or their enantiomers. The influence
52
51
exerted by Et2AlC1on the Diels-Alder additions of dienophiles 47 is most plausibly ascribed to the intermediacy of
the bidentate complex 52 which exhibits C=C/C=O-synplanarity. The electron deficiency and rigid structure of 52
account for the high reactivity and good n-face differentiation. Even less reactive acyclic dienes add smoothly to
such chelated dienophiles at temperatures < -30°C (6 h);
interestingly, in this case the (S)-benzyl derivatives 53
(Table 7) displayed much higher diastereoselectivity than
the isopropyl derivatives 47.
R’
Ph
54
53
Table 7. Examples for the reaction of the N-acryloyloxazolidones 53 with
butadienes in the presence of Et2A1C‘I(1.4 mol per mol 53, - 100 to -30°C)
to give the adducts 54.
Entry
Table 6. Examples for the reaction of N-acyloxazolidones 47 and 49 with cyclopentadiene to give adducts 48 and 50, respectively, in the presence of
Et,AICI (1.4 mol per mol educt, - lOO”C, 2 min). “endo” refers to the C=O
group.
~
1
2
3
4
Educt
47
47
49
49
R
H
Me
H
Me
Adduct
48
48
50
50
Yield
[%I [a1
endo
d.e.
R’
1
2
3
4
H
H
Me
Me
H
Me
H
Me
Me
H
Me
H
Yield
d. e.
(“4
la1
W.1 Ibl
d. e.
1’4 [al
90
> 98
> 99
> 98
> 98
85
84
83
77
88
90
> 98
[%I
[%I PI
81
82
82
88
>99
98
99
98
86
90
90
96
d.e.
[%I [a1
> 98
> 98
> 98
198
[a] Purified. [b] Crude.
Comparative studies of several Lewis acids revealed the
essential advantage of using more than 1 equivalent of
Et,AlCI. Thus, Et,AlCl-induced (1.4 equivalent) additions
of the valinol derivatives 47 to cyclopentadiene were complete within 2 min at -100°C and gave norbornenes 48
with 98 to 99% endo-selection and with 86 to 90% diastereofacial differentiati~n’~’].
Inverse n-face topicity was dis882
R’
[a] Purified. [b] Crude.
~~
Entry
R
50
49
3.4.2. N-Acylsultams Derived from Camphor
Exceptional dienophile “activation” coupled with the
practical advantages of camphor-10-sulfonamides distinguish the sultam auxiliary 55L”1.The highly crystalline sultam is available in two to three convenient synthetic operations from camphor- 10-sulfonyl chloride in 76% overall
yield. Efficient N-acylation furnished the crystalline, stable
N-acryloyl and N-crotonyl derivatives 56 and 57. EtAlC1,promoted Diels-Alder addition of butadiene to 56 proceeded readily at - 78°C to give the (5s)-adduct 58 in 93%
yield with 97% n-face selection (Table 8, entry 1). In the
presence of EtAlCl, or TiC14, cyclopentadiene added
Angew. Chem. lnt. Ed. Engl. 23 (1984) 876-889
I\
56, R
57, R
=
=
H
Me
y/N+~
59. R = H
60, R = M e
SO2
Table 8. Examples for the reaction of N-acryloylsultams 56, 57 and 61 to
give the adducts 58-60 and 62; “endo” refers to the C=O group.
Entry
1
2
3
4
5
Educt
56
56
57
57
61
Conditions [a]
A
B
c
A
A
Adduct Yield
[%I [bl
endo
[Oh1
d.e.
[%I [cl
d.e.
58
59
60
60
62
-
99.5
99
96
98
97
95
93
98
94
99
99
99
81
84
83
-
locked into conformation N ( 0 then being excluded),
which directs the diene to the less hindered bottom face
(Ca-re).
[%I [dl
~
-
[a] A: EtAICI2(1.5 rnol per mol educt), CH2Cl2,-78”C, 18 h. B: EtAICI2(1.5
mol per mol educt), EtCI, - 13OoC, 6 h. C : TiCI4 (0.5 mol per rnol educt),
CH2C12,-78”C, I h. [b] Recrystallized adducts, yields relative to dienophile.
[cl Crude. [dl Recrystallized adducts, ~ i100%
:
endo.
...
...M
Xn
X”
0
N
smoothly to 56 even at - 130°C and to the less reactive 57
at -78°C (entries 2, 3, 4). Under these conditions, 9699.5% endo and 93-98% x-face selectivities were achieved.
Moreover, each of the butadiene and cyclopentadiene adducts (58, 59, 6 0 ) was obtained virtually pure in 82 to 84%
yield after simple recrystallization. The sense of asymmetric induction could be easily reversed (61 -+ 62, entry 5 ) by
exploiting the ready availability of (-)-camphor.
3.5. a-Chloronitroso Dienophiles
An original approach to the enantiomerically pure oxazine derivatives 72 ( > 95% e.e.) involves hetero Diels-
x =c
,
R’
R
‘2
0
II
tBuOCl
CI/
‘R’
70
I
63.x =H,
67, X = O
64,u=n
65, R = Me
66
Reduction of the cycloadducts 58 - 60 with LiAlH, refurnished the sultam 55 (or its enantiomer from 6 2 ) in
89-95% yield after crystallization and gave the pure alcohols 63 to 66 in 89-95% yield on subsequent kugelrohr
distillation. Alternatively, saponification of adduct 58 with
LiOH gave the acid 67 without epimerization. It appears
that the remarkable Diels-Alder reactivity of the otherwise
stable N-acylsultams 56 and 57 is based on chelation of
the SO2 and C=O groups. The postulated chelate would be
Angew. Chem. Int. Ed. Engl. 23 (1984) 876-889
CI
72
70a
70b
883
Alder additions of 1,3-cyclohexadiene to chloronitroso
compounds 70, readily prepared from oximes 68. Methanolysis of the non-isolated adducts 71 in situ furnished
acetals 69 and oxazines 72. Thus, (1R,4S)-72 was obtained from the steroid derivative 70a (with 72% regeneration of the C-17 ketone)[331;the chloronitroso ether 70b derived from mannonolactone reacted considerably faster
with cyclohexadiene to give (after removal of the inexpensive auxiliary reagent) ( ~ ~ , 4 R ) - 7 2 [ ~ ~ 1 .
4. Chiral Dienes
Asymmetric Diels-Alder reactions of dienes substituted
with a removable chiral moiety to prochiral dienophiles
have been less extensively studied. Thermal additions of
1,3-dienol ethers derived from sugars suffer from low endoselectivity[351.So far, disappointing inductions have been
achieved in Diels-Alder reactions accelerated by high pressure, as exemplified by the additions of chiral 2,4-pentadienoates to p-benzoquinone; at 15 kbar the expected adducts were obtained in 58-98% yield, but in humble (250% d.e.) stereofacial selectivity[361.The general advantage
of Lewis-acid coordination is again illustrated by the
[4+2]-addition of the dienes 74 derived from (S)-@methylmandelic acid (readily accessible from 73) to acrolein
in the presence of BF3.0Et2(0.15 mol per mol 74, toluene,
- 20°C, 48 h) which gave adducts 75 in 98% yield with 60
to 64% diastereofacial differentiati~n[~'I.
Virtually complete asymmetric induction was observed
on addition of 74a to juglone [B(OAc), 1.6 mol per mol
74a, CHCI3, 0+20"C], giving 76 in 98% yield and >97%
d.e. These findings have been rationalized in terms of a
binding dienelaryl n-orbital overlap. In this n-stacking
model, methoxy/diene repulsion disfavors conformer P
over conformer Q , which undergoes preferential dienophile addition opposite to the phenyl-shielded diene-face.
The destruction of the chiral auxiliary on hydrogenolysis
constitutes a practical disadvantage.
The cooperative effect of chiral auxiliaries at the diene
and dienophile units is exemplified by the double diastereoface selective addition 74a 44a -.+ 77 (99% d.e.). On
analogous addition of the enantiomer of 74a to 44a, the
dienophile face-directing efficiency exceeds that of the
diene, leading to the adduct 77 (R* = (R)-0-methylmandeloyl) in 94% d.e.[291.
+
5. Chiral Catalysts
At first sight, the use of a chiral catalyst appears to be
the potentially most attractive method to achieve asymmetric Diels-Alder reactions of prochiral dienes and dienophiles. Compared to the stoichiometric use of a covalently
attached prosthetic group, two synthetic steps would b e
avoided.
5.1. Chiral Alkyloxy-Substituted Lewis Acids
The addition of cyclopentadiene to methacrolein
78 +80 catalyzed by ( -)-menthyloxyaluminum dichloride
79 is so far the only reported example that affords greater
than 60% asymmetric induction["]. Although when we attempted to reproduce this work, we obtained no more than
55% enantiomerically pure adduct 80, other [4 + 21-cycloadditions of cyclopentadiene to diverse dienophiles using various chiral Lewis acids were far less n-face selecti~e[,~].
0
o*
Ph
c
98
73q
78
79
80
5.2. Interaction between Chiral Catalyst and Chiral Diene
Auxiliary Reagent
CH=O
R
MeF
\"
0
0
P
884
U
Q
Traces (0.5 to 5 mol%) of soluble europium complexes
catalyze hetero Diels-Alder reactions of silyloxydienes to
arylaldehydes. Thus, dienes 81 reacted smoothly with benzaldehyde at room temperature in a highly endo-selective
manner to give exclusively cis-substituted dihydropyrans
82, which on acid-promoted elimination furnished dihydropyrones 83 in good overall yield. Using Eu(hfch as a
chiral catalyst (Table 9), (R)-83 was obtained from the prochiral diene 81a in only moderate e.e. (42%),but in an impressive 86% e.e. from the chiral diene 81b[401.Interestingly, the interactivity of diene auxiliary reagent and catalyst
Angew. Chem. Int. Ed. Engl. 23 (1984) 876-889
Table 10. Examples for the intramolecular reaction of polyenes 84 to give the
bicyclic adducts 85 and 86.
Aco2R AcoA
- Aconph
EuL,
Entry
MesSiO
Me,SiO
82
I
2
3
4
5
6
T FA
83
Table 9. Examples for the reaction of siloxydienes 81 with benzaldehyde to
give adducts 83 in the presence of europium compounds.
Entry
I
2
3
4
a
b
c
b
R
EuL, [a]
C-2
e.e.
[%I
tBu
(3R)menthyl
(3S)menthyl
(3R)menthyl
Eu(hfc),
Eu(hfc),
Eu(hfc),
Eu(fod),
R
R
R
42
86
S
10
18
is maximal when the individual 7c-facial biases are of opposite sense (entries 1-4).
6. Intramolecular Diels-Alder Reactions
a
b
c
d
e
f
~~
R
Conditions
[a1
Yield
[Oh1
85 :86
l
1
l
2
l
2
H
iPr
H
H
H
H
A
72 [b]
61 [b]
73 [c]
88 [c]
70 [c]
70 [CI
8 6 : 14
67 :33
95 : 5
97 : 3
15 : 85
6 : 94
Ph
81
~
n
B
C
C
C
c
[a] A: [( -)-bornyloxy]AICI, (1.6 mol per mol 84), 8"C, 336 h; B: [( -)-bornyloxylAICI, (1.8 mol per mol 84), 2 3 T , 92 h: C: Me2AICI (1.4 mol per mol
84), -3O"C, 5 h. [b] Overall yield 85 86. [c] Yield of >99% diastereomerically pure major product.
+
6.2. Chiral Auxiliary Reagents as Part of the Bridge
An interesting example is the thermal cycloaddition of
magnesium salt 88 to give adduct 89 in 76% d.e.f441.In contrast, analogous addition of free 87 proceeded slower and
without 7c-face selectivity. It thus appears that chelation of
the dienophile carbonyl group with the bridge-residing
control moiety accelerates the rate of addition and provides the essential conformational rigidity of 88. Repulsion between the a-fury1 methylene group and the phenyl
ring is minimized in the transition state which leads to 89.
Because of their high regio- and diastereo~electivity~~'~,
intramolecular cycloadditions have been widely used for
the efficient synthesis of numerous cyclic molecules. Absolute configurational control by means of removable chiral
auxiliaries is, however, at a comparatively early stage.
6.1. Chiral Dienophile Auxiliary Groups
Br
.OH
I
91
84
Me
Angew. Chem. Int. Ed. Engl. 23 (1984) 876-889
I
11
a7
Not surprisingly, concepts developed successfully for bimolecular asymmetric Diels-Alder reactions have been applied to intramolecular versions such as the transformations 84 + 85 and 84 + 86. Dienophile n-face shielding by
the 8-phenylmenthyl moiety proved to be less efficient (Table 10, entries 1, 2)[421than that by the N-oxazolidone
groups (entries 3 -6)[431.Moreover, the secondary amides
84c to 84f cyclized with superior endo-selectivity, and
products 85 or 86 were obtained in good yields and > 99%
d.e. after chromatography.
(1) NaN02/HOAc
89
(2) KOH/EtOH
(3) Ho
92
ou
After hydrogenation of the olefinic bond in 89, the chiral
auxiliary reagent was destructively cleaved by reduction to
give lactam 90, which was converted into 92, the enantiomer of naturally occurring farnesiferol-C.
885
7. Applications in Organic Synthesis
Natural product synthesis has often led to important
methodological advances by provoking either the discovery of new methods or the rigorous testing and refining of
existing ones. This holds also for the asymmetric DielsAlder reaction as outlined below.
&
7.1. Prostaglandins
In the course of attempts to synthesize the enantiomerically pure prostaglandin 97 the 8-phenylmenthyl auxiliary
reagent has been developed. Thus, the addition
l b 2b-+(lS)-3bE 93 (Section 2) simultaneously generated three enantiomerically enriched centers which correspond to the carbon atoms C-8, C-11, and C-12 of the
prostaglandin target molecule. The correct oxidation state
of C-11 was then established by Baeyer-Villiger oxidation
9 4 4 9 5 , and the center C-9 was induced by center C-8
during the transformation 95 -P 96. Crystallization provided enantiomerically pure 9614], which was converted
into 97 by established procedures.
98'99.='R
98, R=H
HoTcoo"Bu
f B u 4
Me
I
'I
99. R-OH
+
102
7.3. Loganin
The synthetic potential of enantiomerically pure cyclopentadiene-Diels-Alder adducts is further exemplified by
the synthesis of (*)-loganin 104 from ( k)-66[461.
Accordingly, the asymmetric 14 21-additions 47 +48I3'I and
61 -+ 6213'] generate the correct relative and absolute configuration of the centers C-5, C-7, C-8, and C-9 of the loganin precursor 66.
+
93
94
I
H
HO
d
66
95
103
-
4
OGlu
104
7.4. (-)-p-Santalene
A synthesis of the sandalwood constituent ( -)-D-santalene 108 (ca. 100% e.e.)[471relies on the TiC12(OiPr),-pro-
96
97
7.2. (+)-Brefeldin-A
One synthesis of (+)-brefeldin-A 102 started from the
diastereomerically enriched cycloadduct 13[l6]. Degradation of this furnished norbornenone 100 (80-85% e.e.),
which was transformed into crude 102. The final product
was purified by HPLC and crystallization to afford ca.
100% e.e. Alternatively, the cycloadduct 98 gave on hydroxylation and crystallization diastereomerically pure 99,
which on degradation refurnished the auxiliary reagent
(88%) and afforded 100 in >99% e.e.I4'!.
886
105
106
99%de
I
U'OH
108
107
Angew. Chem. I n r . Ed. Engl. 23 (1984) 876-889
moted cycloaddition of the chiral allenic ester 105 to cyclopentadiene (-20°C, 6 h) which gave adduct 106 in 98%
yield with 98% endo-selectively and 99% d.e. Subsequently,
106 was transformed into 108 following a protocol previously reported for the synthesis of racemic B-santalene[481. Notably, approximately 100% diastereomerically
pure intermediate 107 was obtained after crystallization in
82% yield (from crude 106).
7.7. ( +)-Pumiliotoxin-C
Addition of diene 118 to the enantiomer of 44b,
= Me, (BF3.0EtZ, toluene, - 78”C, 0.5 h)
afforded adduct 119 ( > 98% d.e.), which was transformed
into the pure enantiomer 120 of naturally occurring (-)pumili~toxin-C[*~I.
X = R ’ = H, R’
npr
7.5. (-)-Sarkomycin
For a possible synthesis of (R)-(
-)-sarkomycin 113[491
the butadiene cycloadducts 109[491,28[’01, and 110[291furnish the (R)-precursor 111 in high e.e.
> 98% d e
119
118
120
7.8. (+)-Ibogamine
The goal of synthesizing (+)-ibogamine 123 has initiated the study of asymmetric Diels-Alder additions of
chiral dienesI5’]. Adduct 75b (60% d.e.) gave on reductive
I
\/
PCOR‘
\
121
75b 60% d e
113
Pd ( PPhd,
112
7.6. (-)-Shikimic Acid
The (R)-carboxylic acid 114, accessible from adduct 28
in 83% yield by reduction with LiAlH4 and subsequent oxidation of 111 with Jones reagent’”], is a potential precursor of (-)-shikimic acid 115[”’].Another route to (-)-115
123 6 0 % e e
122
amination with tryptophan the secondary amine 121. Subsequent Pdo-catalyzed allylic displacement of the O-methylmandeloyl auxiliary yielded quinuclidine 122, which
was cyclized to give enantiomerically enriched 123.
8. Asymmetric Ene-Reactions
bH
115
114 9 5 . 6 % d e
A
The mechanistic similarity between the Diels-Alder cycloaddition and the ene-processLsZ1
leads one to expect the
applicability of analogous n-face differentiation concepts.
6 steps
8.1. Synthesis of (+)-a-Allokainic Acid
72%
OAc
OAc
116
117 > 9 8 % d e
+
involves BF3. OEt,-promoted [4 21-addition of diene 116
to 44a, X = R ’ = R2= H (-43”C, 5 h) giving 117 in 98%
d.e.Iz9I.
Angew. Chem. In!. Ed. Engl. 23 (1984) 876-889
In accord with this postulate, the total synthesis of (+)a-allokainic acid 126 features an MezAICI-mediated, intramolecular ene-reaction 124 + 125 which controls the relative (100%) and the absolute (90% d.e.) configuration of
the developing centers at C-3 and C-4[531.Subsequent saponification, decarboxylation, and crystallization yielded
the pure natural product 126 (ca. 100% e.e.) and refurnished the auxiliary reagent ( -)-8-phenylmenthol. The
strong enophile face-directing influence of the control
group has been explained by an antiplanar C,=C,/C=O
887
8.3. Additions of Allylboronates to Aldehydes
124
F
Another asymmetric ene-type process, the addition of
allylboronates to aldehydes (131 -+ 132)[551involves the
transfer of boron from carbon to oxygen and thus represents a version of the “metallo-ene reaction”[201.The chiral
auxiliary is attached to the boron atom and regenerated
from the adduct 132 by B/O-cleavage with nitrilotriethanol, which also affords the free homoallylic alcohols 133.
125
A
Al Et,CI
131
cp--si
127
d-1
128
,o-...
132. x = B y ) - . . .
133,x=ti
This first use of a camphor glycol as a chirality directing
group provides ene-face differentiations (C-1) of between
52 and 89% d.e. The preferred “exo”-mode of addition
controls the relative topicity C-l/C-2 (86-94%).
and a synperiplanar C=O/C-Ha enoate conformation
where the phenyl ring shields the CB-si-face.Evidence provided by ‘H-NMR spectroscopy indicates that this shielding occurs even in the absence of the Lewis acid. Coordination with R,AICl, however, was found to be essential for
the high reaction rate as well as for the diastereofacial- and
em-selectivity. As expected, the sense of asymmetric induction could be reversed (78% d.e.) by using the same
control group but changing the enoate geometry
(127- 128) which led to pure (-)-a-allokainic acid. The
topological considerations and practical problems encountered here prompted the careful reinvestigation of the phenylmenthyl-directed Diels-Alder reaction[’’], which has
stimulated the discovery of more practical and efficient
chiral au~iliaries~’~.
22,
321.
A crystal structure analysis of the 1 : 1 complex of ethyl
(3)-acryloyllactate 37 with TiCl, indicates chelation of
both ester carbonyl oxygen atoms by titanium and a synplanar C=O/C,=C, conformation. The selective blocking
of the C,-re-face is consistent with the results observed for
the TiCI,-assisted addition 37 d(5Q-38 (Section 3.2.3). In
the presence of BF3.0Et2 or EtAICI2 the addition
37 -+ (53)-38 (I56% d.e.) proceeds with the opposite topology and is in accord with a reactive conformation D
(Section 3.
8.2. Chiral Glyoxalates
9. Conclusions and Outlook
Similar enophile facial selection occurs in the SnC1,promoted addition of trans-2-butene to phenylmenthyl
glyoxalate 129 -+ 130[541.The excellent control over the
(23)-configuration in 130 was attributed to a selective reface shielding of the aldehyde C=O bond which is syn to
that of the ester carbonyl. This syn-relation might result
from chelation as depicted in transition state R. The preferred exo-mode of addition governs the relative configuration C-2/C-3 in 130.
The asymmetric Diels-Alder reaction is a powerful tool
for the synthesis of enantiomerically pure, complex molecules. Regenerable chiral dienophile auxiliaries in combination with a Lewis acid provide a number of advantages
such as conformational rigidity, acceleration in rate, improved endo-selectivity, and ease of purification by chromatography or crystallization. The capacity of chiral auxiliaries to override the influence of pre-existing chiral centers in the substrate(s) simplifies stereorational design in
synthesis. The relatively unexplored areas of diene auxiliaries and intramolecular versions are certain to receive
more attention. Progress in the development of chiral catalysts may be spurred on either by new structural information on coordinated dienophiles and dienes or by purely
empirical discoveries. The still modest performance of the
high-pressure methodology might benefit from technological advances. The potential of the same n-face differentiating principles in absolute acyclic stereoselection, as exemplified here by the ene process, applies also to other
classes of reaction.
239
130
888
8.4. Addendum
Angew. Chem. Int. Ed. Engl. 23 (1984) 876-889
It is clear that the field covered by this review has entered the stage of practical use in organic synthesis which
will put its scope and limits to the test in the near future.
It is a privilege to acknowledge the contributions of my
very able collaborators. Their names are cited in the appropriate references. Our own work mentioned in this article was
supported financially by the Swiss National Science Foundation, Sandoz AG, Basel, and Givaudan SA, Vernier. We
thank Professors D . A . Evans, G. Kresze, A . Vasella, P. A .
Bartlett, and G. Helmchen for kindly providing copies of
their unpublished manuscripts.
Received: August 8, 1984 [A 513 IE]
German version: Angew. Chem. 96 (1984) 840
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