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Intramolecular Stoichiometric (Li Mg Zn) and Catalytic (Ni Pd Pt) Metallo-Ene Reactions in Organic Synthesis [New Synthetic Methods (75)].

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Intramolecular, Stoichiometric (Li, Mg, Zn) and
Catalytic (Ni, Pd, Pt) Metallo-Ene Reactions in Organic Synthesis
New Synthetic
Methods (75)
By Wolfgang Oppolzer"
Dedicated to Professor Elias J . Corey on the occasion of his 60th birthday
Metallo-ene reactions, hardly recognized until very recently, have experienced a breathtaking development when applied in an intramolecular sense. Efficient regio- and stereoselective magnesium-ene cyclizations have served as a cornerstone for numerous syntheses of
structurally diverse natural products (e.g., sesquiterpenes of marine o r plant origin, alkaloids, fragrances, insect defense compounds, and a fungitoxin). A brilliant example is the
synthesis of the elusive odorant (+)-khusimone which outshines 20 years of work in the
field of tricyclovetivane synthesis. Palladium-, platinum-, and nickel-catalyzed versions of
the metallo-ene reaction are in a comparatively early stage of exploration, but, nevertheless,
reveal intriguing potential. Hence an almost 100% stereospecific C-0-C-Pd-C-C
chirality transfer permits simple and selective, cis- o r trans-annelation processes. The mild cyclization conditions are compatible with various functional groups, such as nitrogen moieties,
which offer interesting perspectives for the preparation of heterocycles (e.g., alkaloids) difficult to obtain by other methods. Carbon monoxide insertion reactions of the cyclized ometal intermediates were shown to afford annelated cyclopentanones and cyclopentenones
with concomitant stereocontrolled formation of four carbon-carbon bonds. These and
other observations, highlighted in this article, provide a platform for further extensions and
applications of this powerful method in organic synthesis.
1. Introduction
The ene reaction, discovered 45 years ago by Alder et
al.,l'l usually involves the thermal reaction of an oleftn
containing an allylic hydrogen (ene) with an electron-deficient unsaturated compound (enophile) to form 1 : 1 adducts via a cyclic 6e transition state (e.g., A + B- C + D,
X = H, Scheme 1).
(CO,) with retenti~n,'~]
it follows that the ally1 unit and the
metal are transferred to the same face of the cyclopropene
2 to furnish intermediate 3.
'
I
EtzO O-20°C. 20 h
JI
R2
HOOC
A
B
Scheme i . X
=
H: ene reaction. X
D
C+
= M:
4
3
R1. R2, R3 = Me, H; X = CI,
metallo-ene reaction.
Br
Scheme 2.
Starting in 1970, Lehmkuhl et a1.I2]systematically studied
the analogous addition of allylic Grignard reagents A ,
X = MgCI, to alkenes or alkynes. Kinetic measurements
showed negative activation entropies of AS' = - 18 to
-24 cal K-' mol-'.[Zbl Further evidence for a concerted
suprafacial reaction via transition state C ', X = MgL,,
was provided by the addition of 2-alkenylmagnesium halides l to 3,3-dimethylcyclopropene 2 ; subsequent carboxylation with CO, yielded cis-2-allylcyclopropanecarboxylic
acids 412'] (Scheme 2). Given that the configuration of a
cyclopropyl-magnesium bond is stable and is carboxylated
[*I
38
Prof. Dr. W. Oppolzer
Dkpartement de Chimie Organique, Universite de Geneve
30, quai E. Ansermet, CH-1211 Geneve 4 (Switzerland)
0 VCH Verlagsgesellschaft mbH. 0-6940 Weinheim. 1989
This more than formal analogy with the classical ene
process has prompted us to classify transformations like
A B-+ D, X = metal, as metallo-ene reactions. Indeed,
closely related additions of a l l y l ~ i n c , -aluminum,[51
[~~
and
-boron reagents@]to (strained) alkenes, acetylenes, allenes,
and enol ethers have appeared in the literature since
1971.
Despite the extensive work of Lehmkuhl, the magnesium-ene reaction has received virtually no attention as a
strategic tool in organic synthesis. Problems of low regioand stereoselectivity and low overall efficiency may limit
the applicability of the bimolecular reactions, as exemplified by the addition of crotylmagnesium chloride to l-octene12".dl (Scheme 3).
+
0570-0833/89/0101-0038 $ 02.50/0
Angew. Chem. Int. Ed. Engl. 28 (1989) 38-52
Me
Et,O
100OC. 48 h
I
460to130"C
Anthracene (5Oh)
.,rg
X
I.
~
Me
~
tie
d
i0.1
rnrn
O=C=N-Ph
'
Scheme 5. The yield of 16, n
9, 10%
ultrasound
65 "C.THF 6 h
Mg powder
15, X = MgCl
J
16, X = C(0)NHPh
,
1'
14
=
2, was 69%based on 11
10, 1.2%
Schimc 3
In contrast, similar to intramolecular [4+ 21 cycloadditions"] and ene reactions,['] intramolecular versions of the
metallo-ene process may be regio- and stereoselective, entropically favored, and thus more efficient. This holds for
two different modes of cyclization (Scheme 4) in which the
enophile is linked by a suitable bridge, either to the terminal carbon atom (C-3, type I) or to the central carbon atom
(C-2, type 11) of the metallo-ene unit.
E
ther functionalizations and cyclizations involving the metalated and the two olefinic sites, offers a considerable potential in organic synthesis.
2. Intramolecular Magnesium- and Lithium-Ene
Reactions
2.1. Type-I Reactions
2.1.1. Initial Studies
The first encouraging example of an intramolecular
type-I magnesium-ene reaction dates back to 1972. As described by Felkin et al.,['zal2,7-octadienylmagnesium bromide 17 cyclized in boiling Et20 to give, after aqueous
21 in
workup, selectively cis-I-methyl-2-vinylcyclopentane
67% yield. Heating the solution of the transient Grignard
product 19 to 110°C (sealed tube, 24 h) furnished, after
hydrolysis, mainly the thermodynamically more stable
trans-cyclopentane 20 (20 :21 = 11 :l), indicating the re-
F
J
type-ll
H
G
Scheme 4. Type I : The bridge Y links the enophile to C-3 of the metallo-ene.
Type 11: The bridge Y links the enophile to C-2 of the metallo-ene.
Essential for the practicality of such processes was, furthermore, a convenient preparation of the 2-alkenylmetal
precursors E and G . In particular, the conventional treatment of allylic halides with Mg turnings in Et20 frequently
led to coupling products: e.g., 11 -+ 12 (Scheme 5).
Magnesium, activated by e ~ a p o r a t i o n or,
' ~ ~much more
conveniently, by sonication with anthracene (5%)/'o'
usually accomplished the metalation of 2-alkenyl chlorides
(e.g., 11) at -65°C in THF without significant coupling." The resulting, clean, alkali-metal- and alkali-halide-free solutions of Grignard reagents 13 are compatible
with the thermal
cyclization/trapping
sequence
13 + 15 16.'"' This easy preparation of the starting 2-alkenylmagnesium chlorides, as well as the propensity of the
cyclized alkylmagnesium intermediates F and H for fur-
P
-.
Angew. Chem. Int. Ed. Engl. 28 (1989) 38-52
CH3
20
Scheme 6.
39
versibility of the cyclization 1 7 s 1 9 at a higher temperature.1'2h1It is worth noting that 17 could be obtained in situ
from 1,3-butadiene, nPrMgBr and [(PPh3),NiCl2] (2 mol%)
and that 18 and 19 were also trapped by D20 or acetone.
The conversion 17-19-21
was also reported in a paTwo years later, the transformation of the isoprene
dimer 22 to 25 (mixture of stereoisomers) was observed
and interpreted as a conjugate addition of nBuLi to diene
22 followed by a (surprisingly smooth) intramolecular lithium-ene addition 23-24.'"]
2.1.2. Applications to Syntheses of Natural Products
After these more or less isolated reports it was the challenge of natural product synthesis which spurred the most
relevant exploration and extensions of the intramolecular
magnesium-ene reaction. Its strategic role in synthesis is
also illustrated by the following examples.
The synthesis of A9''2'-capnellene 33, published in
I 982,[l5]addressed the issue of rendering this process iterative to assemble polycyclopentanoid systems (Scheme 9).
nBu
n BuLi
TMEOA
I
1) Mg powder, Et,O
- 25 OC
57%
22
2) 6OOC. 23 h
3)o/-
-25toO"C
nBu,
nBu
20°C. 30min
S0CIF EGO
722
25
OH
11;
24
(42 : 58)
31
30
powder. Et20
70% 2) RT. 20h
Scheme 7. The yield of 25 was 58% based on 22 (two stereoisomers).
H
Me
A comparative study demonstrated the relative efficiency of a metalation/cyclization/hydrolysis reaction sequence to give 27 from enynyl bromides and phenyl ethers
26a and 26b.[14] These reactions obviously involve intramolecular zinc-, magnesium-, and lithium-ene additions to
a terminal acetylene unit (Scheme 8, Table 1).
26a
27
26b
Scheme 8.
Table I. Cyclizations of alkynes 26a and 26b to give 27 via intramolecular
metallo-ene reactions.
X
Br
Br
0 Ph
Metal
M
Solvent
Zn
Mg
Li
THF
Et20
THF
T
I"Cl
I
Ihl
Yield
27 [Yo]
20
la1
50
2
2
2-24
43
15
50
[a] Heated under reflux.
Also the cyclization of 1 :2 adducts of ally1 Grignard
derivatives to 1,3-butadiene o r isoprene giving divinylcyclohexylmethylmagnesium halides (mixtures of stereoisomers) has been ascribed to an intramolecular magnesium-ene process.'"]
40
\OH
32
33
Scheme 9.
Thus, in the first key step 29-30, the sterically congested bond between C-4 and C-11 was formed with high
stereochemical control. Trapping of the cyclized Grignard
intermediate with acrolein set the stage for the second
magnesium-ene cyclization which occurs at room temperature. Scavenging the bicyclic magnesium-ene product with
oxygen furnished alcohol 32 as a 3 :2 mixture of stereoisomers. This kinetically derived lack of diastereoselection
was of minor importance since the remaining closure of
ring C was accomplished by an intramolecular aldolization
with thermodynamic control over the configuration at C-6
and/or at C-10. Hence, the mixture 32 was channeled efficiently into the pure cis-anti-cis-triquinane 33.
Highly diastereocontrolled formation of a cis-1,2-disubstituted five-membered ring was again observed in the key
step 35 + 36 of the synthesis of (+)-6-protoilludene 41[I6l
(Scheme 10).
Copper-promoted trapping of the cyclized organomagnesium species 36 by 1,4 addition to methyl 2-butynoate
furnished the conjugated ester 37 in one synthetic operation from 34 (76%). The thus generated 1,2-cis-disposed
functionalities in 37 were ideally suited to form the remaining six- and four-membered rings simultaneously by
an intramolecular vinylketene/alkene cycloaddition
(38+ 39). The carbonyl group in 39 (chromatographically
Angew. Chem. Int.
Ed. Engl. 28 (1989) 38-52
Another approach to an unusual sesquiterpene, sinularene 51,["I involves the diastereocontrolled formation of a
six-membered ring by a magnesium-ene process (Scheme
11).
Thus, selective y-alkylation of the dianion 43 by the iodide 42 gave the (E)-carboxylic acid 44, which was converted into allylic chloride 45. Successive treatment of 45
with activated magnesium, heating to 5OoC, and C 0 2 trapping led to the formation of the bond between C-5 and C-6
and that between C-7 and C-15, giving the crystalline carboxylic acid 48 (47% overall yield) in a single operation. In
this case, however, the kinetically controlled cis relation of
36
U
magnesium-donor and -acceptor sites in 47 required an
epimerization at C-5 (KOH treatment of 49) to give, via a
final ester pyrolysis, the target molecule 51.
A related synthesis of 12-acetoxysinularene 58"81differs
in that the magnesium-ene unit is part of the norbornene
skeleton which carries the enophilic chain at C-2 (Scheme
12).
37
J
57% l l 0 O C
q;
U
+
-
Me
1 ) sBuLi. - 65%
2) DMF, O°C
3) NaBH4
40, x = 0
41, X = H,
39
A
Scheme 10.
86%
52
53,
54,
purified), furthermore, directed the olefin bond into the
6(7) position (instead of the otherwise favored 7(8) position). Although the [2+2] addition (38-39) did not show
the desired high stereoselectivity, this approach to the
protoilludene skeleton 39 in only two or three synthetic
operations from the readily available acyclic dienyl chloride 34 exemplifies the general potential of magnesiumene cyclizations when coupled with cycloaddition processes.
x
x
=
OH
= CI
-
NCS. DMS
384%
55, X = MgCl
J
act.
-650c
Mg*
I
1
80°C, 14h
58
42
R = 2,4,6-iPr3C6H,S0,
44
1) LiAIH,.
THF
Scheme
MoOPH
-ax
=
12. NCS = N-chlorosucctnimide, DMS = dimethyl
Moo,-pyridine-hexarnethylphosphoramidecomplex.
sulfide,
3) H20, HCI
@
50OCCi6h
H
47, X = MgCl
45,
x
= CI
I
Hence, by reversing the relative positions of the reaction
partners, the bond between C-5 and C-6 was closed in the
key step 55-56 with simultaneous formation of both the
methylene group and the C-12 Mg functionality. Accordingly, one synthetic operation provided alcohol 57 in 62%
yield from chloride 54. (Again, the initial cis relation of
C-12 and C-7 was altered thereafter by an epimerization at
c-5.)
The stereodirecting bias of a preexisting stereogenic center on the intramolecular magnesium-ene reaction is illustrated by the enantioselective syntheses of ( )-a-skytanthine 68 and (+)-&skytanthine 69, as well as of (+)-iridomyrmecine 70['91(Scheme 13).
Bromide 59, easily accessible in 94% enantiomeric purity via an asymmetric 1,4 addition of vinylcopper to a chiral 0-crotylenoate, was converted into the allylic chloride
61. Metalation of 61 with commercial Mg powder and
+
15
H
49, x = 0
50, X = CH,
Scheme I t
Angew. Chem. int. Ed. Engt. 28 (1989) 38-52
51
41
59
r
1#
Me
Mg. Et20
4OOC. 1 4 h
. fl:Me
CI
61
alcohol 64 to give diol 66 which was cyclized to give (+)skytanthine 68 ; alternatively, hydroboration(BBN)/oxidation of the benzoate 65 furnished predominantly the C4-epimer 67 which was transformed into either (+)-&skytanthine 69 or (+)-iridomyrmecine 70.
Whereas all foregoing applications rely on a kinetically
determined stereoselectivity of magnesium-ene cyclizations, it is apparently a thermodynamic control which governs the cyclization 72-73 at 138°C over 61 h to give,
after oxidative quenching with 02,an 83 :8 :9 mixture of
stereoisomers. The major all-trans alcohol 74 was converted into the dimethyl ester of truns,truns-boschnialic
acid 75120'(Scheme 14).
2.2. Type-I1 Magnesium-Ene Cyclizations
63, X = MgCl
64, X = OH, 49%
65, X = OC(0)Ph
//,
1)
2.2.1. Systematic Investigations
66, R1 =
R3 =
67, R' =
R3 =
cfl3
Me. R2 = H,
H
H. R2 = Me,
C(0)Ph
67:
1) TosCl/pyridine
NaOH
2) MeNH,
This version, in which the enophilic chain is attached to
the central atom C-2 of the magnesium-ene moiety was not
described until 1982 (see Scheme 15). A systematic investigation dealing with the efficiency as well as the regio- and
stereoselectivity of this reaction12" (Scheme 15, Table 2) involved heating 2-alkenylallylmagnesium chlorides 13 followed by quenching of the cyclized Grignard reagents with
phenyl isocyanate (Table 2, entries 1-5) or water (entry 6).
I
70
Me
CI
68, R' = Me, R2 = H
69, R1 = H, R2 = Me
R
11
Scheme 13. 9-BBN = 9-borabicyclo[3.3. Ilnonane.
heating of the resulting solution under reflux followed by
oxidative trapping of 63 with MoOPH at -78°C yielded
a n 88.4/5.9/3.0/ 1.4 stereoisomer mixture of cyclized alcohols (58%). The major isomer 64,isolated by flash chromatography (49% from 61), has the desired (4aS,7aR) configuration. This result is consistent with a favored transition
state 62 # (with the C-7 methyl group oriented toward the
convex face) assuming that 2,3-substituted 2-alkenylmagnesium halides react in their (Z)
form (cf. Section 2.2.1).
Stereoconvergent control over the remaining center C-4
was achieved by hydroboration(BH,)/oxidation of the free
fl
-
76
CIMg
'Me
71, X = CI
72, X = MgCl
d
Scheme 15
73, X
74, X
= MgCl
= OH
(83 : 8 : 9)
Table 2. Intramolecular type-I1 magnesium-ene reactions I1 +[13- 151- 16
or 77.
n
Entry
&L31%
l
2
3
1
42
13
1) act. Mg. THF
2) 138OC. 61 h
X
Scheme 14
d
15, X = MgCl
16, X = C(0)NHPh
77, X = H
"r,
Me
COOMe
COOMe
75
4
5
6
a
b
c
d
e
f
R
I
H
2
3
3
2
2
H
H
CH,
CH,
n-C6HI,
T
["Cl
f
130
80
130
130
80
80
23
17
17
23
17
17
Product
Yield
[04
[hl
16a
16b
16c
16d
16e
77f
71
72
71
40 la1
86
81
[a] 2Ooh of noncyclized dienylanilide isolated.
Angew. Chem. Int. Ed. Engl. 28 (1989) 38-52
It is worth noting that a six-membered ring (entries 2, 5,
6) was formed more readily than a five-membered (entry 1)
or a seven-membered ring (entries 3, 4), reflecting the
counterplay of entropic and angle-strain factors.
This study also revealed an astonishing regioselectivity
insofar as only products 16 or 77 (but no isomers derived
from 76 or 78) were observed, regardless of the distance
between the reactive units. Accordingly, the magnesium
was transferred to the distal site C-1‘ of the enophile and
the new C-C bond was formed at the proximal C-2’ site.
As to type-I1 cyclizations of nonsymmetrically substituted
magnesium-ene species (entries 4-6), a rapid 1,3-metal migration, 13s79,[221leaves two possibilities: C-C bond formation with either the more or less substituted ene terminal C-3 (13-15) or C-1 (79-80) of which only the
former regiochemistry was observed. Also the 3,3-dimethyl-substituted magnesium-ene component of 81 underwent C-C bond formation only to C-3 (generating a quaternary center) to give 84 (80%, Scheme 16).
r
I ) act. Mg. -78OC,
2) 130 OC. 6 h
n
n
1+
\
86. X = CI
85%
164% from
86
\L
K13. NaHCOJ
%
89%
i e Y
91,x=l
8 8 , X = H,, Y = MgCl
J;$SnH
89, X = H, Y = OH
Jones,
90, X = 0, Y = OH J75%
92. X = H
MeONa. MeOH
6
7
.
f
H 0 ‘‘‘
I1
Me
Me
0
93
94
Scheme 18
81,
x
=
CI
83, X = MgCl
84, X
82. X = MgCl
=
C(0)NHPh
Scheme 16.
Focusing on the stereochemistry it is interesting to note
that only cis isomers 16 and 77 were observed; this indicates highly selective olefin “insertion” into a ( a - e n e unit
13 (Scheme 17) which is in a rapid equilibrium with ( 0 - 1 3
(via the 1,3-Mg shift 13*79; see Scheme 15).
in 93. Basic methanolysis of lactone 92, accompanied by
C-3 epimerization, furnished the trans-related 3-methoxycarbonyl substituent, which was transformed into the pentenol side chain of 94.
By contrast, no diastereoselectivity was found in the
type-I1 magnesium-ene cyclization/oxidation 97 98
- ’-
\ /
0
1) Ti(OEt),.
EtOH
2) Mel, DBN
3) iBuZAIH
4) PBu3. CCI4
.T’
CH3
V
95
X*NH
96, 98%
97
1 ) Mgact.,-65”C,THF
2) 130 “C,23 h
1
‘
Me
15e
#
Scheme 17
2.2.2. Apprications to the Syntheses of Naturai Products
The above-mentioned type of stereocontrol is exploited
in a synthesis of the fungitoxin (f)-chokol-A 94[231
(Scheme 18).
Alcohol 85 (easily prepared from 1-hexen-5-one in two
steps) efficiently gave ally1 chloride 86 (CC14/PBu3; 85%
yield).
The
metalation/cyclization/oxidation
step
86 87 -+ 88 -+ 89 (described in detail) furnished cis-cyclopentylmethanol 89 (64Yo from 86 together with 2% of its
fruns epimer and 6% of a positional isomer derived from
80); 89 was then oxidized to cis-carboxylic acid 90.Iodolactonization/reduction, 90 -+ 91 92, assured the desired
cis disposition of the C-1-hydroxyl and C-2-methyl groups
L
98bf
i
-
-+
Angew. Chem. Int.
Ed. Engl. 28 (1989) 38-52
9 9 b . X = MgCl
100b. X = OH
Scheme 19. DBN
=
J
99a. X = MgCl
02
100a, X = OH
J
02
1,5-diazabicyclo[4.3.0]non-5-ene.
43
99- 100, which afforded the carrion beetle defense compound a-necrodol lOOa together with its C-1 epimer lOOb
(61%, 1 : 1
This is not surprising since transition states 98a ( + 100a) and 98b ( + 100b) suffer similar steric crowding due to the gem-dimethyl substitution
(Scheme 19).
Nevertheless, 95, obtained in enantiomerically pure
form via a methylcopper addition/Mannich reaction of a
chiral N-crotonoylsultam, provided (4R)-97, which
yielded, after separation from 100b, optically pure a-necrodol 100a, thus enabling an assignment of the absolute
configuration of the natural product.
A culmination of the type-I1 magnesium-ene cyclization
methodology is its ideal application to the regio-, diastereo-, and enantioselective synthesis of the otherwise elusive,
odoriferous norsesquiterpene ( )-khusimone 108'25'
(Scheme 20).
'
+
0"'
fluence of the preexisting centers C-5 and C-1 in 104 on
the generation of the stereogenic center C-8 conforms with
the sterically least congested transition state 105 # . Hence,
the magnesium-ene step provided the thermodynamically
unstable, sterically encumbered 7,7-dimethyl-6-methylene
moiety with perfect control over the chirality at C-8.
2.3. Type-I1 Zinc-Ene Cyclizations
The thermal type-I1 cyclizations of olefinic allylzinc
bromides 111 show interesting possibilities; the latter were
prepared in situ from chlorides 109 via transmetalation of
the Grignard intermediates 110 with ZnBrz (1.5 equiv.).
Quenching of the cyclized alkylzinc species with HZO
(-113) or CISnMe, (-114) provided oxygen and nitrogen heterocycles1261(Scheme 21, Table 3).
Br
\
I
X
R3
109, x = CI
110, X = MgCl
1 1 1 , X = ZnBr
112, X = ZnBr
113, X = H
114, X = SnMe3
I
102
101
n
1) OH OH/H@
103
J
Scheme 2 I
2 ) NaOEt. EtOH
3) LiAIHJEt20
Table 3 . Intramolecular type-iI zinc-ene reactions 111- 112-113 or 114 in
THF.
-
-#
Entry
Y
R'
R'
R2
M g powder
I
1) RT
I
2 ) 6OoC, 17h
2
3
4
5
6
7
l05#
104
a
b
0
O
c
d
e
o
O
OCHl
f
O
g
NCH,
H
H
H
H
H
CH,
ChHS H
H
H
-(CH&
H
H
H
CH3
H
H
H
H
H
7
f
I"C1
Ihl
80
80
130
80
80
130
80
23
45
22
48
24
22
24
Product
Yield
Ial
1'4
114a
113b
113c
113d
114e
113f
114g
57
80
50
76 [bl
62
0
64
[a1 Based o n 109. [b] 2 : I trons/cis mixture
H$
s ''1 H
1) LiAIH,. THF
2 ) MesCI. NEt3
3) HCI/H20. Et20
4) tBuOK
84%
106. X
=
MgCl
108
107,X = COOH
Analogous attempts to cyclize the allylmagnesium chlorides 110 failed, except for the transformation llOg- 114g
(76%). On the other hand, the less nucleophilic zinc derivatives 111 cyclized readily at 80°C, even with a terminally
methyl-substituted alkenyl unit (although at 13OoC, entry
3); however, the reaction failed with a cyclohexenyl enophile unit (entry 6).
Scheme 20.
2.4. Conclusions
Conjugate addition of a chiral dienolate 101 to cyclopentenone, coupled with an enolate trapping by ally1
bromide, chromatography, and crystallization, directly
gave enantiomerically pure 102 (37% from CyCkpxItenone), which was readily converted into allylic chloride
104. Slow addition of 104 to Mg powder (Merck) in THF,
heating the solution at 60°C for 17 h, and quenching with
COz gave, after crystallization, bicyclic carboxylic acid 107
(85% from 104). N o regio- o r stereoisomer of 107 was
found in the mother liquor. This particularly strong in44
The following trends can be seen from the available evidence.
Ring size: The ease of cyclization decreases in the following order relative to the size of the developing ring:
type I : 5 > 6 % 7
type 11: 6 > 5 = 7 % 8
Regioselectivity: Carbon-carbon bonds are preferentially formed between the proximal sites of ene and enoAngew. Chern. Inf. Ed. Engl. 28 (1989) 38-52
phile in the type-I process and between the more substituted ene terminal and the proximal enophile site in the
type-I I version.
Stereoselectivity: Type-I cyclizations usually furnish, under kinetic control, predominantly five- and six-membered
rings carrying cis-disposed magnesium-donor and -acceptor units even when a quaternary center is generated. 2,3Dialkyl-substituted allylmagnesium moieties react preferentially in their (Z)
form, inducing a cis relation of the C-3
substituent and the magnesium acceptor site in type-I1 cyclization products. However, the stereoselectivity of type-I
and type-I1 magnesium-ene cyclizations can be greatly
diminished by severe steric hindrance, for example, by critically placed gem-dimethyl groups (cf. 31, 98).
Limitations: The above examples involve only terminal
(or strained, cf. 46) olefinic enophile units since intramolecular insertions of 1,2-dialkyl, trialkyl, and cyclic alkenes
into allylmagnesium compounds could not be achieved.
Furthermore, attempts to apply these cyclizations to the
preparation of pyrrolidines have so far failed. Nevertheless, type-I1 cyclizations of allylzinc derivatives show potential in overcoming some of these limitations.
whereas simple olefins (e.g., styrene, cyclohexene, 1,4-cyclohexadiene, and 1,5-cyclooctadiene) did not undergo
this reaction.["]
3. I . 1. Type-I Cyclizations
However, we assumed that the intramolecular ene process L- M would be entropically favored and that a subsequent irreversible p-elimination M + N would withdraw
the ene product M from the equilibrium L=M.'30a1A further option is insertion/reductive elimination M + 0.'30b1
The thereby regenerated Pdo should continue the catalytic
cycle by oxidative addition to allyl derivatives I o r J (e.g.,
X = OR), thus providing in situ the olefinic allylpalladium
intermediates K (Scheme 23).
K
I
3. Palladium-, Nickel-, and Platinum-Catalyzed
Intramolecular Metallo-Ene Reactions
c
3.1. Palladium-Catalyzed Metallo-Ene Reactions
'-n
As a more interesting concept to circumvent these and
other constraints of magnesium-ene cyclizations, we envisaged the exploration of cataalytic intramolecular palladiumene reactions. Indeed, stoichiometric amounts of allylpalladium complexes 115 and norbornadiene have been
reported to undergo rapid, reversible formation of the 0allyl complexes 116, which at 37°C yielded the cis-insertion products 117[271
(Scheme 22).
L"
M
Pd"-H
N
-HO/ PdO
L
1
0
Scheme 23.
CF3
115
Pd"
L
116
117
L
118
Scheme 22. L
=
hexafluoroacetylacetonate.
Similar stoichiometric additions of allylpalladium species to norbornene'28' and 1,3-diene~['~]
are also known,
Angew. Chem. Int. Ed. Engl. 28 (1989) 38-52
Acetoxydienes 120 were readily obtained, predominantly as their ( E ) isomers, via Pd( PPh3),-catalyzed alkylationr3*]of disulfones 119a ( Y = S0,Aryl) or malonates
119b (Y = COOMe) with 4-acetoxy-2-butenyl methyl carbonate. Heating diene 120a (Y = Tos) with Pd(dba)* (0.07
equiv.)/PPh, (0.2 equiv.) in T H F at 70°C gave the expected cyclized 1,Cdiene 121a in 83% yield. Even more
conveniently, product 121a was obtained (76% yield) in
one operation from 119a via Pdo-catalyzed alkylation/cyc l i ~ a t i o n [(Scheme
~~]
24, Table 4, entry 2).
Solvent effects significantly influence this novel ene
process, as illustrated by the cyclization of the malonate
120b (- 121b). Whereas no reaction took place in toluene,
dichloromethane, o r N,N-dimethylformamide, the rate and
yield increased on proceeding from T H F (20%) to methanol (65%) to acetic acid (77%, entries 3-5).[301 Interestingly,
the presence of the phosphane turned out to be indispensable for the transformation 120b- 121b.
45
i
y
.+$.
A c O A O C O O M e or
1) NaH, 2) A c O A C l
5-7%Pd(PPh3),.
2OoC
>
AcO
119
I
120
i
7% Pd(dba),
82% 20% PPh3
THF. 7OoC, 2 h
AcOAOCOOMe
7% Pd(dba),
20% PPh3
adjacent vinyl group to give the transient 127, which undergoes retro-carbornetalation//3-elirnination 127 +. 125 +.
123.
In striking contrast to 8-alkyl-substituted 2,7-dienylmagnesium halides, which did not cyclize (cf. Section 2.1), the
allylpalladium unit of 129 inserted readily into a terminally mono- and even dimethyl-substituted olefinic bond
to give the transients 130 (Scheme 26, Table 5).
7% Pd(dba),
20% PPh,
76%
121
Scheme 24. dba
= dibenzylideneacetone
128
129
Pd
I
Table 4. Pd(dba),/PPh,-catalyzed cyclizations 120 + 121
Entry
I
2 [a]
3
4
5
Y
a
a
b
b
b
Tos
Tos
COOMe
COOMe
COOMe
Solvent
THF
TH F
THF
MeOH
AcOH
T
["CI
f
[hl
70
2
one-pot [a]
80
40
80
8
80
1.5
Yield
121 [%]
To s
L,Pd"H,
82
76
20
65
71
131
[a] One-pot reaction from 119a.
130
Scheme 26.
Intramolecular insertion of a 1,l-dialkylalkene into an
allylpalladium unit ( 124 +. 126) proceeded under the usual
conditions as illustrated by the cyclization 122 +. 12313']
(Scheme 25).
Table 5. Pd(dba)2/PPh,-catalyzed cyclizations 128- 131.
R
Entry
H$p>qTos
7%Pd(dba),
AcOHi;ioC,
20% PPhS 3 h
l
2
3
4
,
a
a
b
b
H
H
Me
Me
Solvent
TH F
AcOH
THF
AcOH
T
["CI
I
Yield
[hl
131 [%]
15
15
85
15
1.5
40
1.5
80
91
40
71
15
AcO'
122
123
1
?*
??
The efficient Pdo-catalyzed cyclizations (AcOH, 75 "C,
1.5 h) of acetoxydienes 128a and 128b furnished, in each
case, a single 1,5-diene product, 131a (91%) and 131b
(719/0), respectively. It follows that the cyclic alkylpalladium intermediates 130 eliminate the exocyclic Hb prefer-
LnPd"
E
Pd'IL,
124
125
1
T
retrocarbometalation
@ -A
E
132
133
carbometalation
Pd'lL,
126
i.i'
E
PdllL,
127
Scheme 25.
It appears that the cyclized alkylpalladium intermediate
126, unable to undergo p-elimination, carbometalates the
46
1
L
135
134
E = COOMe
Scheme 21.
Angew. Chem. In[. E d . Engl. 28 (1989) 38-52
Table
6.
Stereochemistry
132- 133 135.
+
Entry
1
2
3
4
of
Pd(PPh,),-catalyzed
132
E:Z
Equiv.
Pd(PPh,),
t
[h]
133
0 : 100
60 : 40
60 : 40
60 : 40
0.05
0.05
0.07
0.10
5
5
2
24
70
67
26(80)[a]
52
cyclizations
Yield [%]
133 :135
+ 135
\1
36 : 64
36 : 64
32 : 68
10 : 90
OMF
[a] Yield in parentheses based on recovered 132.
entially over Ha in agreement with the conformational constraints of a syn b-elimination process. Again, acetic acid
proved to be a better solvent than THF (cf. entries 1,2 and
3, 4).130'
The cyclization 132- 133 135 showed a kinetically
controlled 2 : 1 preference for the formation of the transdivinylcyclopentane (independent of the ene E / Z configuration (cf. Scheme 34); the ratio increased to 9 : l when
more catalyst and a longer reaction time were employed[321
(Scheme 27, Table 6).
This useful predominance of the thermodynamically
more stable trans product 135 (entry 4) presumably involves a palladium-catalyzed "Cope-type" equilibration
( 133% 134 135).
As expected, Pd(PPh3)4also proved to be a suitable catalyst for intramolecular palladium-ene reactions (Scheme
28).
I
144
145
cat. Pd(PPh3)4
AcOH
70-75"C
+
70-75OC
7
J
146
_1
147
\1.
\
b. c
*
"ii"'
P
Hf6
7% Pd(PPh3)4
AcOH. 85 OC. 2.5 h
63%
148
149
E = COOMe
a: m = 2,
n
=
1; b: m = 2, n = 2; c: m = 3, n = 1
Scheme 2Y.
AcO
136
137
70s
7% Pd(PPh3)4
AcOH. 80°C. 1 h
86%
4cO
H
138
139
S0,Ph
10% Pd(dba),
30
AcOH.
30%
rnin
PPhJ
100°C.
A
77%
140
Entry
Starting material
la1
1
2
3
4
5
6
145a
144a
145b
144b
145c
144e
t
m
n
[h]
2
2
2
2
3
1
1
2
2
1
1
1.1
4
3
3
4
1.8
3
Yield
149+ 148 [Yo]
84
55
60
69
73
80-92
149 : 148
298 : 5 2
298 : 5 2
>99: < I
5 :95
99 : I
2:98
[a] Entries 1-4: 7 mol% Pd(PPh&, 75°C. Entry 5 : 10 mol% Pd(PPh,)4, 70°C.
Entry 6: 5 mol% PdfPPh,),, 70°C.
QSOzPh
\ H
141
Scheme 28
Conversion 136- 137 illustrates the feasibility of this
method for six-membered ring formation. Acetoxydiene
138, containing a cyclic enophile unit, furnished stereoselectively the bicyclic product 139 in 86% yield.[301
The palladium-ene unit may also be part of a ring, as
shown by the stereoselective formation of a spiro system
(140- 141).[32".331
Stereochemically even more striking are the cyclizations
depicted in Scheme 29 and Table 7.
Angew. Chem. Int. Ed. Engl. 28 (1989) 38-52
Table 7. Stereocontrolled syntheses of bicyclo[4.3.0]-, L4.4.01-, and [5.3.0] ring
systems by Pd-catalyzed cyclizations of acetoxydienes 144 and 145 (in
AcOH).
Comparison of entries 1 and 2 shows that the trans- or
cis-olefinic cyclohexenyl acetates 145a or 144a, respectively, gave the same cis-annelated hexahydroindene 149a.1301
However, the conversion 144a- 149a is significantly slower, presumably due to the relatively slow trans/cis isomerization 146- 147. It appears that, in initially formed 146a,
coordination of the Pd atom with the trans-disposed enophile is highly unfavorable, which prevents its conversion
to 148a. However, a longer bridge or a larger preexisting
ring should permit allylpalladium/olefin coordination
even in the trans intermediates 146. Indeed, the trans-acetoxydiene 145b furnished exclusively the cis-fused octahydronaphthalene 149b, whereas the cis-acetoxydiene 144b
47
gave, with 95% stereospecificity, the trans-annelated product 148b (entries 3, 4).[33.341This interesting C-OC-Pd- C-C chirality transfer also provides selective
routes to cis- or trans-fused octahydroazulenes 149c or
148c, respectively (entries 5, 6).[32.341
These findings confirm that the olefin inserts predominantly into the o-(or
TI-)allylpalladium unit cis relative to the Pd atom (i.e., in a
suprafacial manner).
OH
NCS. PPh3. THF
20T. 4h
08%
150
151
100% ee
The gem-disulfone and malonate functionalities described above facilitate the preparation of the “palladiumene” precursors I (Scheme 23) and can be readily removed
or modified but they are nor essential for the cyclization
process. Thus, 3-acetoxy-substituted 1,7-octadienes J (e.g.,
155, 156) containing simple carbon bridges are very readily accessible and undergo smooth Pd-catalyzed cyclizati on^'^^] (Scheme 3 1).
Only products 157 and 158 containing an (E)-olefinic
bond were found, indicating the ene-type reaction of (E)allylpalladium intermediates.
Catalytic Pd-ene cyclizations may also open new perspectives in alkaloid synthesis, as shown by the smooth
formation of pyrrolidines and p i p e r i d i n e ~ . [ ~ ~ , ~ ’ ]
6 3 % [ t NaH.
E THF
8%Pd(PPh3)4
R‘
R‘
5% Pd(PPh3)4
AcOH. 7OoC, 2.5 h
E
67%
AcO“
159
152
153
R’
>96% ee
Scheme 30.
Scheme 30 exemplifies the analogous enantiospecific
preparation of a hexahydropentalene 153 from a readily
available, optically pure hydroxy acetate 150.132,341
162
161
Scheme 32.
Table 8. Synthesis of pyrrolidines and piperidines by Pd*-catalyzed cyclizations 159-160 and 162-160 (AcOH, S O T , 5 mol% Pd(PPh3)4).
Entry
1
2
3
4 [a1
5
6
Starting material
159a
159b
159c
159d
162e
162f
I
R‘
RZ
n
[h]
CH,Ph
-
-
1
1
1
2
C(0)Ph
H
1
3
1
0.5
4
0.5
3.5
COOCH2Ph
Tos
Tos
C(0)Ph
Tos
~
-
1
Yield
160 [Oh]
72
69
72
77
81
78
[a] 7 mol% of Pd(PPh3), used
M
R2
k’
e
O
P
Me0
155
156
i
i
5% Pd(PPh3)4
AcOH, 80°C
a : 1 h: b : 3.5h
5%Pd(PPh3)4
AcOH. 80 OC. 3.5 h
Me0
p
I
Me0
157a. R‘ = H, R2 = CF3 : 67%
157b. R’ = OMe, R2 = H : 94%
Scheme 3 I.
48
158: 83% (4:1)
Scheme 32 and Table 8 illustrate the cyclizations of
“palladium-ene” precursors I (159, entries 1-4) and J
(162, entries 5 , 6 ) containing a nitrogen atom as part of the
bridge. The leaving group in 162 can even be a simple hydroxyl group (entry 6).13’I
Stereospecific formation of the cis-fused octahydroquinoline 164 (85%) is depicted in Scheme 33, which also
shows the conversion of diallyl ether 165 to a 1 : 1 cis/trans
mixture of tetrahydrofurans 166 (75%).13’]
It is worth noting that the initiaI oxidative addition of
Pd’ to 165 proceeded with selective substitution of the allylic acetal group whereas the allylic ether moieties remained intact.
Pd’-catalyzed cyclizations of (E,Z)-, (Z,Z)-, (E,E)-, and
(2.E)-N-trifluoroacetamides 167 and 170 (Scheme 34, Table 9) again represent the insertion of terminally methylAngew. Chem. In[. E d . Engl. 28 (1989) 38-52
Tos
I
Tos
a ring, only cis-substituted insertion products are expected,
as confirmed by the annelation 171 -+ 174I3’](Scheme 35).
5% Pd(PPh3),
AcO
163
164, 85%
AcOH. 8OoC, 0.9 h
79%
AcO
5% Pd(PPh3)4
THp0J&n-C6HI
AcOH,
H
8oocv 2’’
165
Scheme 33. T H P
=
174
171
n-C6H1 3
‘r
1
166. 75%(1 : 1)
tetrdhydropyranyl.
substituted olefinic bonds into (@-allylpalladium components followed by B-elimination of a methyl hydrogen
atom[351(Scheme 34, Table 9).
172 #
173
Scheme 35.
3.1.2. Type-11 Cyclzations
Scheme 36 illustrates the feasibility of carrying out catalytic type-I1 palladium-ene cyclizations, for example, the
transformation 175- 176 (1 18”C, 8 h, 66% ~ i e l d ) . ~Cy~~.~~]
clization of 177 proceeded under milder conditions (SOOC,
6 h) to give piperidine 178 (63%).13”
169
170
Scheme 34.
Table 9. Pdo-catalyzed cyclizations 167- 168
+ 169 and 170-
168
-
+ 169.
7% Pd(dba)z
20% PPh,
~
Entry
1
2 [a]
3
4
5 [a]
6
Starting
material
E/Z
C-2-C-3
I
[h]
Yield
168 169 [%] 168 : 169
167
167
167
170
170
I70
E
E
Z
E
E
0.6
20
1.9
2
52
2.5
76
75
59
61
62
51
z
AcOH. 118OC. 8 h
+
88
88
91
28
30
30
66%
: 12
: 12
OAc
175
:9
:12
: 70
: 70
Tos
I
[a] 10 mol% of [polymer-C6HI-P(C,H,)*LPd (Fluka)
7% Pd(dba)z
25% PPh3
AcOH. 8OOC. 6 h
176
Tos
I
63%
OAc
Entries 2 and 5 exemplify the use of a polymer-supported palladium(0)-phosphane catalyst which may offer,
in general, practical advantages for carrying out palladium-catalyzed ene-type c y c l i ~ a t i o n s . As
‘ ~ ~to
~ the stereochemistry, dienes 167, containing a (3-enophile, gave, under kinetic control, predominantly the trans-divinylpyrrolidine 168 ( c 8 : 1 , entries 1-3), whereas dienes 170, containing an (@-enophile, afforded, less selectively (2.5 : I),
the cis product 169 (entries 4-6). This stereochemical outcome was independent of the E / Z configuration of the allyl acetates 167 and 170 in agreement with an (3-+(@allylpalladium isomerization prior to the insertion (indeed,
isomerizations (2)-167 4 Q - 1 6 7 and (2)-170-(@-170
were observed under the cyclization conditions).
By contrast, if the (2)
configuration of the allylpalladium unit (e.g., in 172 +) is enforced by incorporation into
Angew. Chem.
Inr. Ed. Engl. 28 (1989) 38-52
177
178
Scheme 36.
Also, dienyl acetate 179 (readily prepared from 6-hepten-2-one and lacking the disulfone moiety) was easily
transformed into (@-1,4-diene 182 (87%)[33*371
(Scheme
37).
This regiochemistry parallels that of stoichiometric additions of allylpalladium complexes to n~rbornadiene,[*~]
but
was subject to uncertainty in view of the relatively fast 1,3Pd
(formally analogous to the equilibrium
13=79; Scheme 15, Section 2.2.1). Accordingly, the conversion 179- 182 demonstrates a new stereocontrolled access to exocyclic trisubstituted alkenes involving C-C
bond formation at the less substituted allylpalladium ter49
7% Pd(dba),
20% PPh3
n
OAc
179
1a2
1'
The feasibility of Nio complexes as catalysts for intramolecular metallo-ene reactions was, despite the encouraging precedents, not straightforward and depended strongly
on their ligands. Systematic studies showed a 1 : 1 mixture
of N i ( ~ o d ) ~ / d p pto
b catalyze (10 mol Yo) the allylation/
elimination 183- 184 at 20°C in T H F with a synthetically
useful efficiency (76-92'0, entries 2-4).[33.411
The catalyst [Ni(cod)dppb], formed in situ, induced
smooth conversion of monocyclic trans-acetoxydiene 185
to the cis-fused 3-methylene-hexahydroindole 189 (88%),
which is also formed much more slowly (58%) from the cisprecursor 186l4I1(Scheme 39).
Scheme 37
AcO"'
of
1a5
minal and thus showing a regio- and stereochemistry opposite to the type-I1 magnesium-ene process (Scheme 15,
13 + 15).
1815
10% Ni(cod),
10% dppb
21
10% Ni(cod),
10% dppb
3.2. Platinum- and Nickel-Catalyzed Reactions
The above concept of catalytic metallo-ene cyclizations
(Scheme 23) may also be extended to platinum and nickel.
Norbornene has already been reported to undergo stoichiometric, bimolecular addition of a preformed allylnickel complex followed by carbomethoxylation of the adduct,[28a1as well as a nickel-catalyzed allylation/rearrangem e n t / e l i m i n a t i ~ n . [Allylnickel/olefin
~~~
insertions are apparently involved in Ni-catalyzed polymerizations and
oligomerizations of 1 , 3 - b ~ t a d i e n e such
I ~ ~ ~as the dimerization to l-methylene-2-vinylcyclopentane.~401
187
J
1a9
190
Scheme 39
3.5% R(PPh&. AcOH. 8OoC or
10% Ni(cod),. dppb. THF. 20 OC
AcO
1a3
1a4
Scheme 38. cod
nylphosphane).
=
1.5-cyclooctadiene; dppb = P,P-tetramethylenebis(diphe-
-
Table 10. Pt"- and NiD-catalyzedcyclizations 183- 184. €'to catalysis: 3.5
mol% Pt(PPh&, AcOH, 80°C. Nio catalysis: 10 mol% Ni(cod),, dppb, THF,
20°C.
Y
Entry
Cat.
Solvent
T
["CI
1
a
2
a
3
b
4
c
C(S02Ph)2
C(S02Ph)*
N-Tos
N-CPh,
Pto
Ni"
Ni"
Ni"
AcOH
THF
THF
THF
80
20
20
20
t
Ihl
5
3
12
0.7
Yield
["/.I
85
83
76
92
Heating dienyl acetate 183a with 3.5 mol% of F't(PPh,),
in acetic acid at 80°C furnished the expected cyclopentane
184a in 85% ~ i e l d ' ~ (Scheme
~ , ~ ' ] 38, Table 10, entry 1).
50
This indicates a preferred cis-allylnickel/olefn insertion
187- 189 analogous to the closely related palladium-catalyzed annelations 146a or 147a- 149a.
Coupling of an intramolecular nickel-ene process with a
methoxycarbonylation should regenerate a Ni' species to
continue the catalytic cycle analogous to the originally envisaged sequence I o r J + K L -+ M -+ 0 (Scheme 23).
Tricarbonyl(triphenylph~sphane)nickel[~~~
(25 mol%), a
stable, easy to handle solid (versus the highly volatile and
toxic Ni(CO),) readily catalyzed the conversion of dienyl
iodide 191 (THF/MeOH 4 : 1, 1 atm CO, room temperature) to the monocyclic cis-substituted pyrrolidine 193
(29%) and the bicyclic compound 194 (47%, 4 : I mixture of
isomers, Scheme 40).L4'1
It thus appears that the nickel-ene process 191 -+ 192 is
stereoselective and that 192 forms a C-acylnickel intermediate which inserts either methanol (-+193) or the internal
olefinic bond giving, after final methoxycarbonylation, ketoester 194. It is interesting to note that both insertion
pathways are preferred over a 6-elimination of 192.
Direct 0-elimination cannot interfere with allylnickel/alkyne insertion-carbonylation sequences. Very recently, the
Angew.
Chem. Int. Ed. Engt. 28 (1989) 38-S2
Tos
Tos
[Ni(CO)JPPh3]
THF/MeOH 4 : 1
A
Entry
CO (I atrn). RT
I
-
Table 11. [Ni(CO),PPh,]-catalyzed intramolecular allylation/carbonylation
of alkynes 197 199 ( + 200). 20-25 mol% catalyst, I atrn CO.
Ni"(C0)
L"
192
191
1
2
3
a
b
c
E/Z
of 197
Y
E
E
z
N-Tos
C(COOMe)2
C(COOMe)2
X
I
I
Br
T
["C]
f
RT
RT
[a]
20
20
[a]
[h]
Yield
199 [%I
Yield
200 I%]
69
-
41
36
62
14
[a] 48 h at RT then 12 h at 50°C.
6
299;
.Tos
Tos
COOMe
193
194 ( 4 : 1)
Scheme 40
bicyclization of (0and (3-195 to 196 (so%), promoted
by 200 mol% of Ni(CO), at 40°C, has been reported[431
(Scheme 41).
Br
/ I
..
200% Ni(C0)4
~
-
50%
OMe
196
195
3.3. Conclusions
Intramolecular metallo-ene reactions may be catalyzed
not only by complexes of Pdo but also by those of the other
d i n transition metals, Pto and Ni'. Nickel(o) requires an
inert atmosphere and a more subtle choice of ligands but
provides cis-diastereoselectivity in the cyclization step
(proceeding at room temperature in THF) and offers numerous possibilities in synthesis when combined with COinsertion reactions. The stereochemical evidence cited
above is not consistent with radical (cf. Scheme 29) or metallocyclic intermediates (cf. Scheme 34), but is in agreement with a suprafacial o-allylmetallo-ene type process or
a direct 71-allylmetal/alkene(alkyne) insertion pathway.
The compatibility of this reaction with nitrogen atoms as
part of the bridge offers interesting perspectives for alkaloid syntheses.
OMe
Scheme 41.
4. Summary and Outlook
Use of 25 mol% of the more practical [Ni(CO),PPh,] catalyst under CO (1 atm, THF/MeOH 4 : 1, room temperature) resulted in exclusive monocyclization of enynyl iodide 197a to 199a14'' (Scheme 42, Table 11, entry 1).
This unusual stereocontrolled approach to an exocyclic
trisubstituted olefinic bond is consistent with a suprafacial
allylnickel/acetylene insertion 197 198. Malonate 197b
yielded, under similar reaction conditions, the monocyclic
ester 199b (41%) and the bicyclic diester 200 (36%) in a
stereospecific manner (entry 2). Bicyclization (-, 200,62%)
was more prominent when starting with bromide 197c,
which required a higher reaction temperature (entry 3).14']
--f
p
1
8
X
[Ni(C0)3PPh3]
THF/MeOH 4 : 1
A
CO (1 a h )
198
f 97
COOMe
1
r-T'
COOMe
199
200
Scheme 42.
Angew. Chem. I n t .
Ed. Engl. 28 11989) 38-52
Stoichiometric, intramolecular metal-ene reactions
(M = Li, Mg, Zn) involving terminal or strained alkene
enophile units have served extensively as a cornerstone in
efficient syntheses of natural products. Most of this work
centers on allylmagnesium/alkene cyclizations because of
their diastereoselectivity, the accessibility of the starting
materials, and the propensity of the cyclized Grignard intermediates to be trapped by a vast array of electrophiles.
O n the other hand, the use of Mg is incompatible with several functionalities (e.g., certain heteroatoms) in the acyclic
precursor. Zinc-ene cyclizations seem to surmount some of
these limitations.
However, din-transition-metal-catalyzed versions promise, at the moment, an even wider range of possibilities.
The need to maintain the catalytic cycle by continuous regeneration of the zerovalent metal limits, however, the
functionalizability of the metalated center in the cyclized
intermediate. For the same reasons, the readily accessible
starting materials may contain various functional groups
which are compatible with the reaction conditions and
which may be of value for the syntheses of complex heterocycles such as alkaloids. The suprafacial nature of the
process permits a useful C-0-C-Pd-C-C
chirality
transfer.
The exploration of this field is still in its infancy and has
focused mainly o n the palladium-catalyzed process which
is easier to carry out and apparently more versatile (e.g.,
regarding the substitution pattern of the enophile unit)
than the less expensive nickel-catalyzed version. Already,
51
complementary regio- and stereoselectivities of intramolecular magnesium-, palladium-, and nickel-ene type processes have been recognized which may be put to advantage
in organic synthesis.
The future will supply more insight into the mechanisms; nevertheless, the depicted rationalizations have
proved to be of predictive value. The range of synthetically
useful insertion reactions which are to regenerate the catalytic species will certainly be expanded, as will the nature
of the metal, ligands, and starting materials. In particular,
the application and development of chiral ligands for
achieving asymmetric metallo-ene cyclizations is a considerable challenge. Finally, strategic use for the synthesis of
naturally occurring or new structures, difficult to obtain by
other methods, is expected to reveal the realistic and full
potential of the transition-metal-catalyzed versions.
I t is a privilege to acknowledge the crucial contributions of
my co-workers whose names are cited in the appropriate references. We thank the Swiss National Science Foundation,
Sandoz AG, Basel, and Givaudan SA, Vernier,for generous
support of this work.
Received: September 28, 1988 [A 706 IE]
German version: Angew. Chem. 101 (1989) 39
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Angew. Chem. Int. Ed. Engl. 28 (1989) 38-52
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