Gold(I)-catalyzed cyclizations of silyl enol ethers: Application to the synthesis of (+)-lycopladine A

Article abstract of DOI:10.1002/anie.200602035

(Chemical Equation Presented) In control: Gold(I)-catalyzed intramolecular addition of silyl enol ethers to alkynes and allenes allows for the diastereoselective synthesis of cyclopentenes with control of the position of the double bond. The utility of th

Full text of DOI:10.1002/anie.200602035

Angewandte
Chemie
Carbocyclization
DOI: 10.1002/anie.200602035
Gold(I)-Catalyzed Cyclizations of Silyl Enol
Ethers: Application to the Synthesis of
(+)-Lycopladine A**
Steven T. Staben, Joshua J. Kennedy-Smith,
David Huang, Britton K. Corkey, Rebecca L. LaLonde,
and F. Dean Toste*
The construction of carbocycles containing quaternary ste-
reocenters continues to be an important synthetic challenge.[1]
We recently described the gold(I)-catalyzed cyclizations of
[*] S. T. Staben, J. J. Kennedy-Smith, D. Huang, B. K. Corkey,
R. L. LaLonde, Prof. Dr. F. D. Toste
Department of Chemistry
University of California
Berkeley, CA 94720 (USA)
Fax (+1)510-643-9480
E-mail: fdtoste@uclink.berkeley.edu
[**] We gratefully acknowledge the University of California, Berkeley,
NIHGMS (R01 GM073932-01), Merck Research Laboratories,
Bristol-Myers Squibb, Amgen Inc., DuPont, GlaxoSmithKline, Eli
Lilly & Co., Pfizer, AstraZeneca, and Roche for financial support.
J.J.K.-S. thanks Eli Lilly & Co. for a graduate fellowship. We thank
Lauren A. Young for the preparation of tributylallenylstannane.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Scope of AuI-catalyzed carbocyclizations of silyl enol ethers and alkynes[a].
enolizable b-keto esters and b-dike-
tones onto appended alkynes as a
method for cyclopentene forma-
tion.[2] Although broadly applicable
to the diastereoselective formation
of a variety of cyclic and bicyclic
systems, the method is limited to the
synthesis of quaternary carbon
atoms that bear two carbonyl func-
tionalities. Our proposed mecha-
nism for these transformations
involves the addition of the enol
tautomer of the keto ester to a
gold(I)-complexed alkyne and the
subsequent protonolysis of the
resulting vinyl–gold(I) species. On
the basis of this hypothesis, we
envisioned taking advantage of the
well-precedented nucleophilicity of
silyl enol ethers as “frozen enol
equivalents” in gold(I)-catalyzed
cyclization reactions.[3,4] Described
herein is the development of the
gold(I)-catalyzed cyclization of silyl
enol ethers onto alkynes and allenes
and the application of this carbon–
carbon bond-forming reaction to an
expedient total synthesis of (+)-
lycopladine A.[5]
Several issues must be con-
fronted in employing silyl enol
ethers in gold(I)-catalyzed reac-
tions. First, unlike enol nucleo-
philes, the silylated counterparts
lack the proton source necessary
for the protonolysis of the vinyl–
gold(I) intermediate. Thus, an
external proton source is required
to complete the catalytic cycle. The
competitive reaction of this proton
source[6,7] and the electrophilic cat-
ionic gold(I) species[8] with the
highly nucleophilic silyl enol ether
must be avoided. With this in mind,
we examined the feasibility of the
gold(I)-catalyzed 5-exo cyclization
Entry Substrate
Product
Yield [%]
1
2
3
5
R1 =Me
R1 =Ph
R2 =Me
R2 =H
4
6
90
83
3
4
5
7
9
8
83[b]
10 94
12 80
11
6
7
8
13
15
17
14 77[c]
16 91[c]
18 75[c]
9
19 R1 =allyl
R2 =H
20 77
22 85
10
21
R2 =Ph
11
12
23
25
24 73
26 75
13
27
28 91
[a] Reaction conditions: [AuClPPh3] (10 mol%), AgBF4 (10 mol%), silyl enol ether (0.4m) in CH2Cl2/H2O
(10:1), 408C. [b] Reaction carried out in toluene/MeOH(10:1, 0.4 m) at room temperature, and the
product was isolated as a 9:1 mixture with the corresponding enone. [c] Reaction conditions: [AuClPPh3]
(10 mol%) and AgOTf (10 mol%) in CH2Cl2/MeOH(10:1), 0 8C. TIPS=triisopropylsilyl, Ts=p-
toluenesulfonyl.
of silyl enol ether 1 with water as the external proton source.
A catalytic amount of [Ph3PAuCl]/AgBF4 in a 10:1 dichloro-
methane/water mixture at 408C for 30 minutes provided
bicyclic ketone 2 in 78% yield of the isolated product
[Eq. (1); OTf = trifluoromethanesulfonate]. The identity of
the counterion proved to be key as other complexes (namely,
ClO4, SbF6, and OTf salts) produced the desired cyclized
product with varying amounts of hydrolyzed enol ethers.
Additionally, we found that methanol could be substituted as
the proton source with only a slight deterioration in the yield
of the isolated product 2.
Under these conditions, the gold(I)-catalyzed exo-dig
cyclization proved to be general in scope (Table 1, entries 1–
8). Alkyl, aryl, and hydrogen substitution was tolerated at the
a-position in the completely diastereoselective formation of
bicyclic systems. For example, the gold(I)-catalyzed cycliza-
tion of enol ether 3 afforded bicyclic product 4, which
contains three consecutive all-carbon quaternary stereocen-
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Chemie
ters, in 90% yield (Table 1, entry 1). Fur-
thermore, the mildness of the reaction
conditions is highlighted by the fact that
non-quaternary a-stereocenters can be cre-
ated diastereoselectively with minimal iso-
merization of the exo-methylene unit into
conjugation with the ketone function
(Table 1, entry 3). Furthermore, exo-meth-
ylene cyclohexane 10 was prepared in 94%
yield through a gold(I)-catalyzed 6-exo-dig
cyclization (Table 1, entry 4). The gold(I)-
catalyzed reaction also operates effectively
with acyclic silyl enol ether 13, thus afford-
ing exo-methylene cyclopentane 14 in 77%
yield (Table 1, entry 6). Moreover, the
reaction can be employed to construct
spirocyclic ketone 16 and amide 18 in 91
and 75% yield, respectively (Table 1,
entries 7 and 8).
We envisioned that this catalyst system Scheme 1. Synthesis of (+)-lycopladine A. Reagents and conditions: a) I2 (0.6 equiv), PhI(OCOCF3)2
(0.6 equiv), pyridine, CH2Cl2, room temperature (85%); b) (BnOCH2CH2CH2)3B, [PdCl2(dppf)]
(5 mol%), AsPh3 (5 mol%), Cs2CO3, DMF, THF, H2O (72%); c) tributylallenylstannane, TBSOTf,
might be extended to allow the construc-
tion of cyclopentenes, with control of the
location of the double bond, simply by
varying the electrophilic component. Grat-
CH2Cl2, ꢀ78!ꢀ108C (93%); d) NIS, AgNO3, DMF, 08C!RT (82%); e) [AuClPPh3]/AgBF4 (10 mol%),
CH2Cl2/MeOH(10:1), 40 8C (95%); f) 39, [Pd(PPh3)4] (5 mol%), NaOMe, MeOH/PhH (83%);
g) PhCH3, 1908C, 4 h (60%); h) 10% Pd/C, 1,4-cyclohexadiene, EtOH(75%). Bn =benzyl, DMF=di-
methylformamide, dppf=1,1’-bis(diphenylphosphino)ferrocene, NIS=N-iodosuccinimide, Pin=pina-
ifyingly, silyl enol ethers also participated
as nucleophiles in gold(I)-catalyzed 5-
endo-dig additions to alkynes, which
allows for the production of a variety of
col.
systems
bearing
endocyclic
olefins
the construction of cyclopentenes with control of the position
of the unsaturation (compare 20 with 32).
(Table 1, entries 9–13). Notably an aryl iodide, a functional
group susceptible to oxidative addition by other d10-transi-
tion-metal catalysts, remains untouched in the AuI-catalyzed
process (Table 1, entry 10). Additionally, a variety of hetero-
aromatic groups were well tolerated at the acetylenic position
(Table 1, entries 11–13). Moreover, similar conditions can be
employed for the use of allenes as the electrophilic partner in
a 5-endo-trig cyclization [Eqs. (2) and (3); TBS = tert-butyl-
The utility of the gold(I)-catalyzed method for the
formation of non-ester-bearing all-carbon quaternary centers
was immediately realized in an expedient total synthesis of
the recently isolated fawcettimine alkaloid (+)-lycopladine A
(42). Isolated from Lycopodium complantum, lycopladine A
(42) shows modest but selective cytotoxicity against murine
lymphoma L1210 cells and possesses an unprecedented C16N-
type alkaloid skeleton, including a novel pyridyl-fused
hydrindanone core.[5] We envisioned that a gold(I)-catalyzed
5-endo-dig cyclization could be employed to construct the
hydrindanone core of lycopladine A. To this end, cyclohex-
enone 36 was obtained through iodination[10] and subsequent
B-alkyl Suzuki–Miyaura coupling[11] of readily obtainable
(R)-(+)-5-methyl-2-cyclohexen-1-one (35;[12] Scheme 1).
Conjugate propargylation of tributylallenylstannane pro-
moted by tert-butyldimethylsilyl trifluoromethanesulfonate
(TBSOTf)[13] followed by iodination of the resultant terminal
alkyne[14] diastereoselectively furnished iodoacetylene 37 and
set the stage for the key gold(I)-catalyzed 5-endo-dig cycliza-
tion. Reaction of silyl enol ether 37 under our optimized
conditions gave hydrindanone vinyl iodide 38 in 95% yield as
a single diastereomer. Vinyl iodide 38 underwent Suzuki
coupling with boronic ester 39[15] to afford N,N’-dimethylhy-
drazone 40 in 83% yield. Notable is the consecutive use of
two catalytic reactions mediated by d10 metals with orthog-
onal reactivity (AuI and Pd0), thus allowing rapid and
convergent access to all of the carbon atoms of lycopladine.
Thus, heating 40 promoted a cascade sequence involving
double-bond isomerization, 6p electrocyclization, and elimi-
dimethylsilyl].[9] For example, allene 31 smoothly underwent
a gold(I)-catalyzed cyclization to afford bicylic cyclopentenes
32 in 72% yield. Therefore, the combination of the gold(I)-
catalyzed alkyne and allene cyclization reactions allows for
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Communications
[7] Addition of alcohols to enol ethers is proposed in the gold(I)-
catalyzed formation of ketals from alkynes: a) J. H. Teles, S.
Brode, M. Chabanas, Angew. Chem. 1998, 110, 1475; Angew.
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K. I. Grandberg, V. P. Dyadchenko, Izv. Akad. Nauk SSSR Ser.
Khim. 1974, 2872; b) Y. Ito, M. Inouye, M. Suginome, M.
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in 60% yield.[16] The benzyl ether protecting group was
removed under conditions for transfer hydrogenation to
complete the asymmetric total synthesis of (+)-lycopladine A
(42) and thereby establish the absolute stereochemistry of this
alkaloid.
In summary a gold(I)-catalyzed addition of silyl enol
ethers to alkynes and allenes has been developed. The
reaction allows for the diastereoselective synthesis of a
variety of bicyclic frameworks containing all-carbon quater-
nary centers. Taken together, the gold(I)-catalyzed 5-exo-dig,
5-endo-dig, and 5-endo-trig pentannulation reactions provide
access to cyclopentenes with control of the position of the
double bond. The utility of these reactions was demonstrated
by an efficient total synthesis of (+)-lycopladine A (8 steps,
17% overall yield from enone 35) which takes advantage of
the orthogonal reactivity of the AuI and Pd0 centers towards
unsaturated iodides.[17] Further demonstration of the utility of
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Received: May 22, 2006
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Published online: August 4, 2006
Keywords: alkaloids · carbocyclization · gold ·
.
homogeneous catalysis · silyl enol ethers
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