Gold-catalyzed cyclopenta- and cycloheptannulation cascades: A stereocontrolled approach to the scaffold of frondosins A and B

Article abstract of DOI:10.1002/anie.201006105

Golden cascades: Two diastereoselective gold-catalyzed cascade processes in which propargyl acetates react with alkenes or 1,4-dienes afford highly substituted five- and seven-membered rings, respectively (see scheme). The concerted nature of the gold-catalyzed Cope rearrangement has been used in the formal enantioselective synthesis of marine norsesquiterpenoids Frondosins A and B.

Full text of DOI:10.1002/anie.201006105

DOI: 10.1002/anie.201006105
Gold Catalysis
Gold-Catalyzed Cyclopenta- and Cycloheptannulation Cascades:
A Stereocontrolled Approach to the Scaffold of Frondosins A and B**
David Garayalde, Karolin Krꢀger, and Cristina Nevado*
Seven-membered ring carbocycles are ubiquitous motifs in a
wide variety of natural products including guanascaterpenes,
colchicines, phorbols, and frondosins among many others.[1]
Since direct cyclizations have proved to be inefficient to
construct this particular ring size, alternative strategies have
been devised and mainly focus on cycloaddition reactions.[2]
Both inter- and intramolecular rhodium-mediated [5+2]
cycloadditions between vinylcyclopropanes and unsaturated
moieties have been successfully developed.[3] Another wide-
Scheme 1. Design of a gold-catalyzed 1,2-acyloxy-rearrangement/cyclo-
propanation/cycloisomerization cascades.
spread method uses rhodium–vinyl carbenoids and dienes in
formal [4+3] cycloadditions.[4] However, this methodology
still presents several drawbacks: first, the metal carbenes are
generated from the corresponding diazo compounds, which
need to be pre-synthesized, thus adding extra steps to the
overall process, and secondly, only donor–acceptor carbe-
noids provide high levels of selectivity. The development of
versatile gold complexes in recent years has revealed gold
catalysis as a powerful tool to construct molecular complex-
cycloheptenylacetate 4aA in a 1:2 ratio (Table 1, entry 1). In
the presence of a more electrophilic phosphite ligand, five-
and seven-membered rings 3aA and 4aA could be detected
(Table 1, entry 2). The tris(2,4-di-tertbutylphenyl)phosphite–
gold complex afforded similar results upon heating to 808C
(Table 1, entry 3; Conditions I), whereas Ph3PAuSbF6, pro-
vided a mixture of cyclopropyl 2aA and the seven-membered
ring 4aA in a 1:2 ratio (Table 1, entry 4). A combination of
2.5 mol% [IPrAu]NTf2 and 2.5 mol% (PhO)3PAuSbF6 deliv-
ered 4aA in a 69% yield (Table 1, entry 5; Conditions II).
Finally, a [(2-biphenyl)di-tert-butylphosphine]–gold complex
selectively afforded 4aA in a 85% yield, thereby providing
ity.[5] As
a representative example, the gold-catalyzed
1,2-acyloxy migration of propargyl esters generates a gold
carbene, which can undergo a broad palette of transforma-
tions such as nucleophilic attack,[6] annulation,[7] subsequent
acyloxy rearrangement,[8] and olefin cyclopropanation.[9]
Recently, gold-catalyzed ring expansions of stabilized cyclo-
propyl rings were reported.[10] We envisioned that a reaction
sequence involving propargyl esters and dienes could be
orchestrated such that gold not only catalyzed the 1,2-acetoxy
migration and subsequent cyclopropanation, but could also
reactivate the in situ generated vinyl acetate, thereby trigger-
ing a formal homo-Cope rearrangement to give seven-
membered rings in a straightforward manner (Scheme 1;
path a).[11] Furthermore, if alkenes instead of dienes were
used, highly substituted cyclopentenyl acetates could be
obtained upon cyclopropyl ring opening (Scheme 1; path b).
Herein, we report the realization of these concepts and an
application in the formal enantioselective synthesis of marine
secondary metabolites frondosins A and B.
Table 1: Reaction optimization.[a]
Entry [Au], solvent, time[a]
Cond. 2aA/3aA/
4aA[b]
1
2
3
[IPrAu]NTf2, CH2Cl2, 30 min
–
–
I
1:0:2
0:1:5
0:1:3
The reaction of p-methoxyphenylpropargyl acetate (1a)
and (E)-(2-methylbuta-1,3-dienyl)benzene (A) in the pres-
ence of [IPrAu]NTf2 cleanly delivered cyclopropane 2aA and
(PhO)3PAuSbF6, CH2Cl2, 30 min
[(2,4-di-tBu-C6H3O)3P]AuSbF6, DCE, 808C,
30 min
4
5
Ph3PAuSbF6, CH2Cl2, 30 min
[IPrAu]NTf2 (2.5 mol%), CH2Cl2, 10 min
then (PhO)3PAuSbF6 (2.5 mol%), CH2Cl2,
30 min
–
II
1:0:2
1:1:10 (69)
[*] D. Garayalde, K. Krꢀger, Prof. Dr. C. Nevado
Organic Chemistry Institute
6
[{(2-biphenyl)di-tBu-phosphine}Au]SbF6,
CH2Cl2, 30 min
III
0:0:1 (85)
Universitꢁt Zꢀrich (Switzerland)
Fax: (+41)44-635-6888
E-mail: nevado@oci.uzh.ch
[a] Reaction conditions: 1a (1 equiv), A (1.1 equiv), [Au] (5 mol%),
258C, 0.1m. [b] Determined by H NMR analysis of the crude reaction
mixture. Numbers in brackets indicate the yields of the products isolated
after column chromatography. DCE=1,2-dichloroethane; IPr=1,3-
bis(2,6-diiso-propylphenyl)-imidazol-2-ylid.
1
[**] D.G. and K.K. thank the SNF and Givaudan AG, respectively, for
financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201006105.
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911

Communications
Table 2: Gold-catalyzed cycloheptannulation: Reaction scope.
benchmark substrate we evaluated
the influence of the diene in the
reaction.
Congested
alkenes
reacted efficiently providing access
to complex bicyclic scaffolds such as
4aB (Table 2, entry 2), whereas
more reactive monosubstituted
dienes such as C and D partially
polymerized under these condi-
tions. The bi-catalytic system (see
Conditions II in Table 1) proved to
be highly efficient for this type of
substrate, thus affording the corre-
Entry
1
Dienes
Product
Cond.[a] Yield [%][b]
1
1a (R1 =p-MeOC6H4)
A
4aA
III
85
sponding
cycloheptenylacetates
4aC,D in high yields (Table 2,
entries 3 and 4). Geranyl derivative
E reacted with 1a upon heating to
give 4aE in moderate yield
(Table 2, entry 5). Acetates bearing
2-naphthyl-, phenyl- and 3,5-di-
methoxyphenyl substituents in the
propargylic position (1b–d) reacted
smoothly under the Conditions II to
give the corresponding seven-mem-
bered rings (Table 2, entries 6–11).
2
1a
B
4aB
III
59
3
4
1a
1a
C
4aC (R2 =Ph, R3 =H)
II
II
92
77
1,1-Dialkylsubstituted
propargyl
acetates 1e and 1 f could also be
transformed into the corresponding
cycloheptenones 5eC and 5 fC upon
hydrolysis of the reaction mixture
under basic conditions (Table 2,
entries 12 and 13). This cyclohep-
tannulation process is highly stereo-
selective, affording only cis-cyclo-
heptenylacetates as major pro-
ducts.[12,13]
D
4aD (R2 =p-MeOC6H4,
R3 =H)
2
=
5
1a
E
4aE (R =-(CH2)2-CH
IV
37
C(Me)2, R3 =Me)
The chemoselectivity of the
reaction is also remarkable, as nei-
ther cyclopropane intermediates
(2)[14] nor products of a competitive
6
7
8
9
1b (R1 =2-napth)
C
D
C
D
C
4bC (R2 =Ph)
II
II
II
II
II
72
55
80
50
74
1b
4bD (R2 =p-OMeC6H4)
4cC (R2 =Ph)
1c (R1 =Ph)
1c
intramolecular
hydroarylation
4cD (R2 =p-MeOC6H4)
4dC (R2 =Ph)
could be detected under these reac-
10
1d (R1 =3,5-dime-
thoxyphenyl)
1d
tion conditions.[15]
11
D
4dD (R2 =p-MeOC6H4)
II
44
We hypothesized that alkenes
could also participate in this gold-
catalyzed cascade (Table 3). The
reaction of 1a with 4-methoxystyr-
ene (F; 1 equiv) in the presence of
the tris(2,4-di-tertbutylphenyl)phos-
phite–gold complex under the Con-
ditions I proved to be extremely
efficient, affording cyclopentenone
6aF in 90% yield. 6aF is formed
upon in situ hydrolysis of the corre-
12
13
1e (R1 =Me, Me)
1 f (R1 =-(CH2)5-)
C
C
5eC
5 fC
V
V
52
79
[a] Conditions II and III from Table 1; Conditions IV: same as Conditions III but with heating to 1208C in
DCE; Conditions V: same as Conditions IV with subsequent treatment with K2CO3/MeOH. [b] Yield of
isolated products.
sponding
cyclopentenylacetate
the optimal reaction conditions (Table 1, entry 6; Conditions
III).
We then set out to explore the scope of this gold-catalyzed
intermolecular cycloheptannulation (Table 2). Using 1a as a
under the reaction conditions (Table 3, entry 1).[16] Different
substitution patterns in the olefinic counterpart were then
examined. 1-Methoxy-4-(prop-1-en-2-yl)benzene (G), (Z)-1-
methoxy-4-(prop-1-enyl)benzene (H), and 5-vinylbenzo-[d]-
912
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[1,3]-dioxole (I) reacted with 1a
affording ketones 6aG–I in good
yields (Table 3, entries 2–4). Alkoxy
vinyl ethers (J–K) reacted smoothly
with 1a at room temperature fur-
nishing the corresponding cyclopen-
tenyl acetates 3aJ–K (Table 3,
entries 5 and 6). A bulkier pivaloyl
ester (1g) was also tolerated afford-
ing 3gJ in 82% yield (Table 3,
entry 7). Comparable results were
also obtained for 2-naphthyl- (1b),
3-methoxyphenyl- (1h), and benzo-
Table 3: Gold-catalyzed cyclopentannulation: Reaction scope.
Entry
Olefin
Product
Yield [%][a]
1
1a (X=Ac, R1 =p-
F
6aF (R2 =p-OMeC6H4, R3 =R4 =H) 90
MeOC6H4)
[d]-1,3-dioxole-substituted
(1i)
propargyl acetates as shown in
entries 8–14 in Table 3. The reac-
tion is also highly diastereoselective
since in most cases only trans-2,3-
disubstituted cyclopentenyl deriva-
tives were observed.[12]
2
3
1a
1a
G
H
6aG (R2 =p-MeOC6H4, R3 =Me,
R4 =H)
82[b]
6aH
78
63
(R2=p-MeOC6H4, R3 =H, R4 =Me)
A possible mechanism for these
transformations is shown in
Scheme 2. The gold-mediated iso-
merization of the propargyl ester
leads to an Au/carbene compound,
which reacts with the olefinic reac-
tant to form a cis-cyclopropane
intermediate.[9] Subsequent gold
reactivation of the vinyl acetate
moiety triggers the cyclopropyl
ring-opening, provided stabilization
of the in situ generated d+ is pres-
ent, thus forming a 1,5-dipole.[10] An
envelope conformation is proposed
for the transition state in which
4
5
1a
1a
I
J
6aI (R2 =[e], R3 =R4 =H)
3aJ (R2 =OBn)
83[c]
6
7
1a
K
J
3aK (R2 =OEt)
3gJ (R2 =OBn)
75[c,d]
82[c]
1g (X=Piv, R1 =p-
MeOC6H4)
substituents are disposed in
a
trans-pseudodiaxial fashion to min-
imize torsional/steric interactions,
and yields the trans-2,3-disubsti-
tuted cyclopentannulation products
3 (Scheme 2; path a).[17] In contrast,
when 1,4-dienes are used, the cyclo-
propyl system undergoes a gold-
catalyzed Cope rearrangement to
deliver the cis-2,3-disubstituted
8
9
1b (X=Ac, R1 =2-napth)
1b
J
K
3bJ (R2 =OBn)
3bK (R2 =OEt)
79[c]
73[c,d]
10
1h (X=Ac, R1 =m-
MeOC6H4)
K
3hK
60[c,d]
cycloheptenyl
acetates
4
(Scheme 2; path b).[11] A boatlike
transition state is proposed in this
case to account for the observed
cis relative stereochemistry.
11
12
1i (X=Ac, R1 =[e]
1i
)
J
K
3iJ (R2 =OBn)
3iK (R2 =OEt)
87[c]
87[c,d]
To capitalize on the structural
complexity developed in the formal
gold-catalyzed [4+3] cycloaddition,
we envisioned a synthetic applica-
tion towards the core of the fron-
dosins, marine norsesquiterpenoids
with promising biological activities,
with frondosin A as the most potent
member of the series.[18] Several
13
14
1i
1i
L
3iL (R2 =OBu)
59[c]
M
3iM (R2 =OtBu)
87[c,d]
[a] Yields of compounds isolated as single diastereoisomers unless otherwise stated. [b] After hydrolysis
of the crude mixture using K2CO3 (2 equiv), MeOH, RT, 30 min (d.r.=7:1). RT, 1 h. [c] Reaction at room
temperature. [d] Used 5 equiv olefin. [e] R1 =
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Communications
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frondosin A has been reported thus far.[19] Treatment of
pivaloate 1j and 6,6-dimethyl-1-vinyl cyclohexene (N) with
(S)-OMe-DTBM-BIPHEP–gold(I) complex afforded, quan-
titatively, the corresponding bicyclic cycloheptenyl pivaloate.
In situ hydrolysis and subsequent equilibration with NaOMe/
MeOH yielded the thermodynamically favored ketone 7 in
68% yield and more than 90% ee (Scheme 3).[12] Since this
bicyclic enone has been recently elaborated into Frondosins
A and B,[20] our approach represents a streamlined formal
enantioselective synthesis of both molecules.
In summary, we report herein two highly diastereoselec-
tive, gold-catalyzed, three-step cascade processes for the
synthesis of highly substituted five- and seven-membered
rings from propargyl acetates and alkenes or 1,4-dienes,
respectively. The reaction favors trans-2,3-disubstituted cyclo-
pentenylacetates through a tightly bound carbocationic
transition state whereas the gold-catalyzed Cope rearrange-
ment delivers cis-2,3-disubstituted cyclopheptenylacetates.
This formal [4+3] cycloaddition catalyzed by gold represents
an attractive alternative to previously reported rhodium-
catalyzed reactions both in terms of atom economy and
functional group tolerance. In addition, the concerted nature
of the process has allowed an alternative, formal enantiose-
lective synthesis of the frondosins A and B.
[12] See the Supporting Information for additional details.
[13] Treatment of the reaction mixtures listed in Table 2 with K2CO3/
MeOH afforded the thermodynamically favored trans-2,3-dis-
ubstituted cycloheptenones 5 quantitatively. The cycloheptenyl-
acetates 4 are thus formed under kinetic control. See the
Supporting Information.
Received: September 29, 2010
Published online: December 7, 2010
[14] The gold-free, thermal Cope rearrangement of several cyclo-
propyl intermediates (2aA-C) failed even at temperatures up to
808C. The cyclopropane 2aB is transformed into the corre-
sponding cycloheptenyl acetate 4aB upon treatment with the
Keywords: cascade reactions · cyclization · gold ·
homogeneous catalysis
.
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Angew. Chem. Int. Ed. 2011, 50, 911 –915

[(2-biphenyl)di-tertbutylphosphine]–gold complex. See the Sup-
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[16] Under the reaction conditions I (Table 1, entry 3), 2aA and 3aA
could be independently transformed into 6aA, meaning that
under these conditions, the cyclopropanes 2 are direct precursors
of the five-membered rings. See the Supporting Information.
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