Total synthesis of (+)-fawcettidine

Article abstract of DOI:10.1002/anie.200800522

(Chemical Equation Presented) Alkaloids alchemy: A synthesis of the Lycopodium alkaloid (+)-fawcettidine (see structure) has been developed which requires 16 steps from (R)-(+)-pulegone as the chiral starting material. Key steps include a platinum(II)-cat

Full text of DOI:10.1002/anie.200800522

Angewandte
Chemie
DOI: 10.1002/anie.200800522
Alkaloid Synthesis
Total Synthesis of (+)-Fawcettidine**
Jennifer A. Kozak and Gregory R. Dake*
The structures of the Lycopodium family of alkaloids have
inspired several examples of landmark total syntheses
(Scheme 1).[1] Prominent examples include the constructions
Scheme 1. Lycopodium alkaloids.
of lycopodine by the research groups of Stork,[2] Heathcock,[3]
and Wenkert,[4] together with the investigation of annotinine
Scheme 2. Retrosynthetic analysis of 1. PG=protecting group, FGI=
functional group interconversions.
by Wiesner and Poon,[5] as well as the synthesis of fawcetti-
mine (2) by Inubushi and co-workers,[6] and by Heathcock
et al.[7] A synthesis of (+)-2 by using a gold(I)-catalyzed
annulation was disclosed by the Toste research group last
year.[8] Despite its near structural identity with 2,a total
synthesis of fawcettidine (1) has not yet been reported.
Fawcettidine (1) was isolated by Burnell et al. in the late
1950s from a Jamaican Lycopodium plant, Lycopodium
fawcetti.[9] The structure of fawcettidine was established
based on its semisynthesis from other members of the
Lycopodium family.[10] In addition to their interesting tetra-
cyclic structures,many Lycopodium alkaloids exhibit acetyl-
choline esterase (AChE) inhibition.[1b]
[6–8]
À
left the formation of the C13 N bond until the last step.
Our strategy differs markedly from this path,where a critical
disconnection leaves the formation of the seven-membered
ring within 1 until a late stage of the synthetic sequence. A
Ramberg–Bäcklund reaction emerged as a potential solu-
tion.[12] Functional group conversions of the hypothetical
intermediate a generated tricycle b,that could undergo the
key retro-annulation disconnection. We envisioned that
alkyne c could be converted directly into b by using
platinum(II) catalysis. If successful,this transformation
would accomplish the formation of a critical tricyclic inter-
mediate that would also install the quaternary center at C12
Our recent studies of platinum(II)-catalyzed annulations
using enamides as nucleophiles indicated a direct approach
towards the synthesis of 1.[11] The retrosynthetic analysis of 1
is presented in Scheme 2. Previous syntheses of 2 essentially
À
and the enamine functionality (C13 C14) within 1. As noted,
the exocyclic alkene that would be formed provides function-
alization necessary to facilitate formation of the final ring of 1.
A major question at the outset was the identity of an effective
thiol protecting group that would be compatible with the
platinum(II)-catalyzed procedure. (R)-(+)-Pulegone was
identified to be an appropriate chiral nonracemic starting
material.
[*] J. A. Kozak, Prof. Dr. G. R. Dake
Department of Chemistry
University of British Columbia
2036 Main Mall, Vancouver, BC, V6T 1Z1 (Canada)
Fax: (+1)604-822-2847
E-mail: gdake@chem.ubc.ca
(R)-(+)-Pulegone was elaborated to give sulfoxide 3 in
three steps as reported (Scheme 3).[13] Sulfoxide 3 was
converted into d keto ester 4 through a one-pot procedure.
Sequential treatment of 3 with DBU followed by methyl
acrylate at À408C then warming to 408C smoothly generated
4 in approximately 60% yield on a multigram scale. The
sulfinyl group proved very useful as it enabled high site
selectivity (for enolate generation) and provided a means for
[**] We thank the University of British Columbia and the Natural Science
and Engineering Research Council (NSERC) of Canada for the
financial support of our programs. J.A.K. thanks the NSERC for
PGSM and D fellowship awards. We acknowledge Dr. Brian O.
Patrick for X-ray crystallographic analysis, and thank Prof. Raymond
Andersen for access to his polarimeter.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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scale. When lower catalyst loadings (5 mol%) were used
these reactions were much slower,although the overall yields
were similar. Somewhat surprisingly,the platinum-catalyzed
procedure appeared to be unaffected by the thiocarbamate
functionality,thus highlighting the robust nature of this
reaction.[16] A chemoselective allylic oxidation was then
required. Much experimentation established that essentially
classical conditions (SeO2,14,-dioxane,85 8C) achieved this
transformation in adequate yield.[17] Given our difficulties in
achieving this conversion in high yield,effective methods for
the allylic oxidation of complex organic structures are still
required.
Scheme 3. Reagents and conditions: a) H2O2, LiOH (96%); b) NaH,
HSPh; c) NaBO3·4H2O, AcOH (88%, over 2 steps); d) 1. DBU, DMF,
À408C; 2. methyl methacrylate; 3. warming to 408C (63%, over 3
steps); e) BrMgCH2CH2CCSi(CH3)3, CuBr·DMS, THF, À78 to À408C
(83%); f) (C4H9)4NF, THF (96%). Ac=acetyl, DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene, DMF=N,N-dimethylformamide, DMS=dimethyl
sulfide.
Treatment of 9 with 1m sodium hydroxide cleanly
removed the carbamate group from the sulfur atom
(Scheme 5). As expected,the thiolate thus generated sponta-
installation of the double bond. Formation of 4 by this
procedure was more efficient than vinylogous Baylis–Hilman-
type reactions. A cuprate addition followed by desilylation
was used to produce 5 as an (ultimately inconsequential)
mixture of epimers. Importantly,the conjugate addition was
highly diastereoselective at C7 (fawcettidine numbering).[7,14]
At this point the substrate required elaboration to install
both the enamide functional group and the protected sulfide
moiety prior to annulation. To this end,amine salt 6[15] was
condensed with the epimeric mixture 5 to produce enamide 7
in 70% yield as a 10:1 mixture of enamide isomers
(Scheme 4). This mixture was carried forward without further
separation as these isomers interconvert in the next reaction.
Enamide 7 could be considered a potentially disastrous
substrate for a reaction involving platinum catalysis,consid-
ering the affinity of sulfur atoms towards platinum. Even
though the sulfur atom was protected as a thiocarbamate,this
step was approached with some trepidation. These fears
Scheme 5. Completion of the synthesis of 1. Reagents and conditions:
a) 1m NaOH (76%); b) 1. ethylene glycol, PPTS, benzene (87%);
2. mCPBA, CH2Cl2 (98%); c) CBr2F2, KOH·alumina, tBuOH, CH2Cl2
(46%); d) 1. H2, Pd/C, EtOH/THF (57%); 2. LiAlH4, THF (71%);
3. 1m HCl, THF (60%). mCPBA=meta-chloroperbenzoic acid,
PPTS=pyridinium para-toluenesulfonate.
neously added to the enone functionality in a conjugate
fashion to produce sulfide 10 in 76% yield. The protection of
the carbonyl group of 10 followed by sulfide oxidation with
mCPBA to give sulfone 11 proceeded uneventfully.
proved to be unfounded,however,as subjecting
7 to
platinum(II) chloride (10 mol%) led to smooth annulation
and formation of tricycle 8 in good yields,even on a gram
Our attempts to carry out the Ramberg–Bäcklund process
by using two-step procedure failed. The “one-step” procedure
disclosed by Chan et al. turned out to be successful.[18]
Treatment of 11 with dibromodifluoromethane in a tert-
butanol/dichloromethane solvent mixture and in the presence
of potassium hydroxide adsorbed onto alumina enabled the
isolation of alkene 12 in 46% yield. Interestingly,crystals of
12 were amenable to X-ray diffraction analysis,and a solid-
state molecular structure was obtained (Figure 1).[19] The
conversion of 12 into 1 was subsequently carried out by
hydrogenation over palladium on carbon,reduction of the
enamide to the enamine with lithium aluminum hydride,and
conversion of the ketal into its corresponding ketone with
aqueous hydrochloric acid.
As the original structural elucidation of 1 was defined by
conversion from other members of the Lycopodium family,
high-field NMR spectroscopic data are not available for
comparison. We note that 1 has spectroscopic features in
common with recently isolated hydroxylated derivatives of
1.[20] Specifically,key spectroscopic data include the 1H NMR
Scheme 4. Reagents and conditions: a) 6, AcOH, toluene, 1108C
(70%); b) PtCl2 (10 mol%), toluene, 908C (87%); c) SeO2, 1,4-diox-
ane, 858C (54%).
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[16] a) A. Fürstner,P. W. Davies, Angew. Chem. 2007, 119,3478 –
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[18] T.-L. Chan,S. Fong,Y. Li,T.-O. Man,C.-D. Poon, J. Chem. Soc.
Chem. Commun. 1994,1771 – 1772.
Figure 1. Solid-state molecular structure of compound 12 shown with
ellipsoids at 50% probability.
signal attributable to the enamine vinyl proton of 1 (d =
5.69 ppm,d, J = 5.2 Hz),and the corresponding IR stretches
(1741,1663 cm À1),both sets of which are consistent with data
from the original isolation report and with those of recently
reported fawcettidine relatives. Unfortunately,the optical
rotation data (in ethanol) for synthetic (+)-1 is at odds with
that reported in the original article.[9b,21] Our data (in chloro-
form) compares well with the reported optical rotation data
for synthetic and natural (+)-2.[8]
The first total synthesis of (+)-fawcettidine (1) has been
carried out in 16 steps by using (R)-(+)-pulegone as the chiral
starting material. Key features of this synthesis include a
platinum(II)-catalyzed annulation reaction of a highly func-
tionalized enamide,and a one-pot Ramberg–Bäcklund reac-
tion to form a seven-membered ring. The tolerance of
platinum(II) chloride catalysis to the functional groups
present in this study bodes well for the use of the annulation
strategy in the synthesis of other complex natural products.
Received: January 31,2008
Published online: April 22,2008
[19] CCDC 676469 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
Keywords: alkaloids · homogeneous catalysis · platinum ·
total synthesis
.
[20] K. Katakawa,A. Nozoe,N. Kogure,M. Kitajima,M. Hosokawa,
H. Takayama, J. Nat. Prod. 2007, 70,1024 – 1028.
[1] a) T. A. Blumenkopf,C. H. Heathcock, Alkaloids: Chemical and
Biological Perspectives, Vol. 3 (Ed.: S. W. Pelletier),Wiley,New
York, 1985,pp. 185 – 240; b) X. Ma,D. R. Gang, Nat. Prod. Rep.
2004, 21,752 – 772.
[21] Synthetic (+)-1: [a]1D9 = + 61 degcm3 gÀ1 dmÀ1 (c = 0.41 gcmÀ3
,
EtOH); [a]2D1 = + 92 degcm3 gÀ1 dmÀ1 (c = 0.41 gcmÀ3,CHCl 3);
reported data for natural (+)-1: [a]D = + 161 degcm3 gÀ1 dmÀ1
(c = 0.6 gcmÀ3,EtOH).
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