Total synthesis of (+)-fawcettimine

Article abstract of DOI:10.1002/anie.200702695

An effective combination: With the first asymmetric total synthesis of fawcettimine (1) it has been shown that the use of organocatalytic annulation and gold(I)-catalyzed cyclization reactions provides an effective combination for the synthesis of complex molecules. The absolute configuration of 1 was established through an X-ray structure analysis of its hydrobromide. (Figure Presented).

Full text of DOI:10.1002/anie.200702695

Angewandte
Chemie
DOI: 10.1002/anie.200702695
Lycopodium Alkaloids
Total Synthesis of (+)-Fawcettimine**
Xin Linghu, Joshua J. Kennedy-Smith, and F. Dean Toste*
The fawcettimine class of Lycopodium alkaloids consists of
over 60 natural products.[1] Typically, these tetracyclic com-
pounds contain a single quaternary carbon center and are
derived biosynthetically from the lycopodane core through an
oxidative rearrangement reaction. In 1959, the first member
of this class, fawcettimine (1), was isolated by Burnell in the
Blue Mountain Range of Jamaica.[2] Inubushi and co-workers
later confirmed the structure by chemical correlation through
X-ray crystallography.[3] Heathcock and co-workers subse-
available 5-methyl-1,3-cyclohexanedione.[9,10] Later, the
Heathcock group reported a more efficient synthetic route
from the same commercially available compound, obtaining
(Æ )-fawcettimine in 16 steps and 10% overall yield.[4,11]
Our synthetic plan is shown in antithetic format in
Scheme 1. On the basis of Heathcockꢀs finding that fawcetti-
Scheme 1. Retrosynthetic analysis of 1. TBS=tert-butyldimethylsilyl.
mine is predominantly the thermodynamic isomer, we
rationalized that the C-4 configuration could be established
by equilibration to the correct isomer in the deprotection and
carbinolamine-forming step (6 to 1). We envisioned that the
quently demonstrated that the carbinolamine 1 was in
equilibrium with the corresponding ketone and therefore
underwent facile epimerization at C-4.[4] Since the discovery
of fawcettimine, a number of related compounds have also
been isolated. For example, the C4-functionalized derivatives
lycoflexin[5] (2) and alopecuridine[6] (3) were reported in 1973
and 1974, respectively. More recently, lycoposerramine-A[7]
(4) with a 1,2,4-oxadiazolidin-5-one structure and lycoposerr-
amine-B[8] (5) with a mono oxime functionality were discov-
ered and proposed to be biosynthetically derived from
fawcettimine (1).
À
C-5 ketone could be prepared from the C4 C5 olefin.
Disconnection to this olefin allows for formation of the
hydrindanone core, containing a quaternary carbon atom,
through
a transition-metal-catalyzed 5-endo-dig cycliza-
tion.[12] We envisioned cyclization onto an alkynyl iodide
leading to a vinyl iodide, which could then be functionalized
through cross-coupling. This route allows for flexibility in the
functional groups (X and Y) that could be employed for
construction of the azepine ring (7 to 6). Therefore, dis-
À
Prior to the work presented herein, two syntheses of
racemic (Æ )-fawcettimine have been reported. Inubushi and
co-workers accomplished its total synthesis in 27 steps,
proceeding in a 0.1% overall yield from commercially
connection of the C3 C4 bond provides bicyclic vinyliodide 8
that in turn could be prepared by the gold(I)-catalyzed
cyclization of silyl enol ethers developed by our laboratory (9
to 8).[12b,13] As previously described, this approach allows for
the diasteroselective construction of cis-fused 5,6-bicyclic
ketones. Finally, construction of the acetylenic cyclization
precursor could be completed by a Michael addition to a 2-
functionalized cyclohexen-3-one (10), presumably forming
the trans diastereomer.
[*] Dr. X. Linghu, Dr. J. J. Kennedy-Smith, Prof. F. D. Toste
Department of Chemistry
University of California, Berkeley
Berkeley, CA 94720-1460 (USA)
Fax: (+1)510-643-9480
To achieve an asymmetric synthesis of (+)-fawcettimine,
we first pursued a robust method for the formation of
E-mail: fdtoste@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.
enantioenriched
2-functionalized
cyclohexen-3-ones
(Scheme 2). To this end, iodide 11[14] was smoothly trans-
formed through a Suzuki–Miyaura cross-coupling reaction
into enones 10a,b with pendant oxygen or nitrogen function-
alities (X in Scheme 1) that could ultimately be employed to
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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reaction performed well on a
multigram scale, providing
nearly 10 g of dienone 10c in a
single run. This dienone was
converted into 15c in 69%
yield as a single diastereomer
using a sequence of conjugate
propargylation, acetylene iodi-
nation and gold(I)-catalyzed
cyclization analogous to that de-
scribed in Scheme 2.
We were pleased to find that
allyl-substituted vinyl iodide 15c
underwent smooth palladium-
catalyzed cross-coupling reac-
tions with
a
variety of sp3-
carbon–zinc and –boron spe-
cies.[18,19] As shown in Scheme 4,
protection of the carbonyl group
as the cyclic ketal and cross-
Scheme 2. Cross-coupling route to the hydridanone core of 1. phth=phthaloyl; dppf=1,1’-bis(diphenyl-
phosphino)ferrocene, 9-BBN-H=9-borabicyclononane, DMF=dimethylformamide.
construct the azepine ring. Utilizing the modified method of
the Haruta group,[15] tert-butyldimethylsilyltriflate (TBSOTf)
promoted 1,4-addition of allenyltributylstannane 12 to cyclo-
hexenones 10a,b gave trans silyl enol ethers 13a,b with
excellent diastereoselectivity (d.r. > 95:5). Iodination of the
ꢀ
terminal C C bond with N-iodosuccinimide (NIS) and silver
nitrate afforded iodoacetylenes 14a,b.[16] 5-Endo-dig carbo-
cyclization of 14a,b proceeded smoothly, catalyzed by (tri-
phenylphosphine)gold(I) tetrafluoroborate, to furnish the
hydrindanone core (15a,b) of fawcettimine (Scheme 2).
Notably, both the [4.3.0] bicyclic structure and carbon
quaternary center were installed in a single step.
With vinyl iodides 15a,b in hand, we attempted to employ
Scheme 3. Organocatalytic/gold-catalyzed cyclization approach to the
hydridanone core of 1. a) 12, TBSOTf, CH2Cl2, À788C; b) NIS, AgNO3,
DMF, 08C; c) 10% [Ph3PAu]Cl, 10% AgBF4, CH2Cl2/MeOH 10:1. 408C.
Ts =p-toluenesulfonyl.
transition-metal-catalyzed cross-coupling reactions to intro-
duce the C1–C3 carbon atoms with an appropriate functional
group (Y in Scheme 1) at C1. Unfortunately, Suzuki–Miyaura
and Negishi coupling methods, under various reaction con-
ditions, produced dehalogenated
compounds (16a,b) as the major
product without significant amounts
of the desired cross-coupling prod-
ucts (Scheme 2).
Given the failure of heteroatom-
substituted hydridanones to partici-
pate in the cross-coupling reaction,
we considered an approach wherein
the C9 functionality would be intro-
À
duced by hydroboration of a C C
double bond. While this compound
could be prepared by the cross-cou-
pling route described in Scheme 2, a
direct catalytic enantioselective
approach was developed using an
organocatalytic Robinson annulation
Scheme 4. Completion of the synthesis of (+)-fawcettimine (1); reagents and conditions: a) ethyl-
reaction between ketoester 17 and
crotonaldehyde (18), which gave 2-
allylcyclohexenone 10c in 88% ee
=
ene glycol, TsOH, benzene, reflux; b) 1) H2C CHCH2NHBoc, 9-BBN-H; 2) [PdCl2(dppf)], AsPh3,
Cs2CO3, DMF, RT; d) acetone/H2O, pyridinium p-toluenesulfonate (PPTS), reflux; e) BH3·THF, THF,
508C, then NaOH, H2O2, RT; f) Dess–Martin periodinane, CH2Cl2, 84% from 22 over 3 steps,
and 72% yield (Scheme 3).[17] This d.r.ꢁ10:1.
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Angewandte
Chemie
coupling under Trostꢀs conditions[20] provided the tert-butyl-
oxycarbonyl (Boc) protected amine. The double bond was
then converted into primary alcohol 21 using a hydrobora-
tion/oxidation sequence. We envisioned that the nine-mem-
bered ring could be constructed by an intramolecular SN2
reaction. However, attempts to effect this intramolecular
displacement with the mesylate or tosylate derivative of
alcohol 21 and the Boc-protected amine group under basic
conditions produced a complex mixture. On the other hand,
transformation of alcohol 21 to iodide 22 allowed for intra-
molecular alkylation of the amine to furnish the desired nine-
membered ring (23) in 62% yield.
Keywords: (+)-fawcettimine · alkaloids · cyclization · gold ·
total synthesis
.
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With the entire fawcettimine skeleton installed, all that
remained was to introduce the final oxygen atom and remove
the protecting groups. After deprotection of the carbonyl
group, the resulting enone was subjected to hydroboration
and reduction to afford a diastereomeric mixture of diols.
Their Dess–Martin oxidation provided diketone 24. A 10:1
mixture of two diastereomers was observed in favor of the
thermodynamic trans epimer, which is consistent with the
studies of Heathcockꢀs group.[4] Finally, removal of the Boc
group with trifluoroacetic acid (TFA) followed by basic work-
up gave (+)-fawcettimine (1) along with a small amount of
the C4 epimer that slowly isomerized to the natural product
over time. Treatment of the resulting amine with hydrogen
bromide afforded fawcettimine hydrobromide in good yield.
The spectral data (1H and 13C) for both fawcettime and its
hydrobromide salt were consistent with those reported by
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In conclusion, the first asymmetric total synthesis of (+)-
fawcettimine has been achieved in 13 steps from crotonalde-
hyde. Additionally, the absolute configuration of (+)-fawcet-
timine, which showed the same optical rotation as the natural
product,[21] was established by a crystal-structure analysis of
its hydrobromide (Figure 1). Ultimately this work demon-
[14] Iodide 11 was prepared by iodination of 5-methylcyclohexen-3-
one using the method reported in R. Benhida, P. Blanchard, J.-L.
Fourrey, Tetrahedron Lett. 1998, 39, 6849.
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[18] We propose that the reactivity of 15c might derive from
intramolecular coordination of the alkene to palladium. This
interaction results in occupation of the vacant site on the metal
center, which is required for the b-hydride elimination that
ulitmately leads to reduction of the vinyliodide.
Figure 1. Structure of (+)-fawcettimine·HBr in the crystal.
[19] For additional examples of cross-coupling with 15c, see Table 1
in the Supporting Information.
[20] B. M. Trost, C. B. Lee, J. Am. Chem. Soc. 1998, 120, 6818.
strates that organocatalytic annulation and gold(I)-catalyzed
cyclization reactions are an effective combination for the
synthesis of complex molecules.[22] A diverse synthesis of
other members of the fawcettimine-type Lycopodium alka-
loids using the strategies highlighted herein is a current focus
of our research and will be reported in due course.
[21] Synthetic 1: [a]RDT = + 89 degcm3 gÀ1 dmÀ1 (c = 0.55 gcmÀ3
,
MeOH); natural 1: [a]RDT = + 91 degcm3 gÀ1 dmÀ1 (c =
0.66 gcmÀ3, MeOH). We thank Prof. Da-Yuan Zhu (Shanghai
Institute of Materia Medica, Chinese Academy of Science) for
providing us with the optical rotation of natural fawcettimine.
[22] For a review on organocatalysis in the synthesis of natural
products, see: R. Marcia de Figueiredo, M. Christmann, Eur. J.
Org. Chem. 2007, 2575.
Received: June 19, 2007
Published online: August 29, 2007
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