Intermolecular radical addition reactions of α-iodo cycloalkenones and a synthetic study of the formal synthesis of enantiopure fawcettimine

Article abstract of DOI:10.1039/b714078a

The generation of α-carbonyl vinyl radicals from α-iodo cycloalkenones, the scope of their participation in intermolecular addition reactions with electron-withdrawing olefins are studied and a synthetic study of the formal synthesis of enantiopure fawcet

Full text of DOI:10.1039/b714078a

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Intermolecular radical addition reactions of a-iodo cycloalkenones and
a synthetic study of the formal synthesis of enantiopure fawcettimine{
Kuan-Miao Liu,*a Chi-Min Chau*a and Chin-Kang Shab
Received (in Cambridge, UK) 12th September 2007, Accepted 1st October 2007
First published as an Advance Article on the web 21st November 2007
DOI: 10.1039/b714078a
the formal synthesis of enantiopure fawcettimine by an intramo-
lecular radical cyclization.
The generation of a-carbonyl vinyl radicals from a-iodo
cycloalkenones, the scope of their participation in intermole-
cular addition reactions with electron-withdrawing olefins are
studied and a synthetic study of the formal synthesis of
enantiopure fawcettimine using this reaction is described.
Our experiment began by treating a refluxing benzene solution
of 2-iodocyclohex-2-enone (2) and acrylonitrile (1 equiv.) with a
benzene solution of Bu3SnH (1.2 equiv.) and AIBN (0.12 equiv.);
however, the expected amount of adduct was not obtained. We
believe that one of the reasons leading to the failure of this reaction
was the low concentration of acrylonitrile. To solve this problem,
we examined the dependence of the amount of acrylonitrile on the
yield of the product by increasing its amount from 3 equiv. up to
10 equiv. The desired adduct 2a was then successfully obtained in
yields of 13 and 39%, respectively. The yield of the adduct did not
increase any further, even when the amount of acrylonitrile was
increased above 10 equiv. In addition to the concentration of
acrylonitrile, the concentration of the resulting a-carbonyl vinyl
radical may also be an important factor in the success of this
intermolecular radical addition reaction. If the concentration of the
a-carbonyl vinyl radical is very high, the self-coupling reaction
would be significant. Based on this consideration, we attempted to
maintain a low concentration of generated radical at any given
instant by using the slow addition method. We found that the yield
of the product increased slightly; however, the reaction became
more complicated, and some of the enone was recovered.
Therefore, we used the intermittent addition method, in which
the reaction was performed by adding a benzene solution (0.5 M
with respect to Bu3SnH) of AIBN (0.12 equiv.) and Bu3SnH
(1.2 equiv.) to a refluxing benzene solution (0.2 M with
respect to a-iodocyclohexenone) of 2-iodocyclohex-2-enone and
acrylonitrile (10 equiv.) eight times at 40 min intervals, after
which 2a was obtained in 60% yield. These were the most
optimized reaction conditions for the intermolecular a-carbonyl
vinyl radical addition reaction with olefins, and were applied in
many other cases later. Several other sets of modified
conditions were also examined; however, none were better than
the present set.
Inter- and intramolecular radical reactions have been some of the
most important and effective synthetic methods in organic
synthesis, and they have frequently been used as key steps in the
construction of natural products.1 Synthetic applications of vinyl
radicals are often limited to intramolecular reactions; this may be
due to the fact that vinyl radicals are more reactive than alkyl
radicals and can easily be trapped by hydrogen, electron-deficient
double or triple bonds in the same molecule, or radical mediators,
such as Bu3SnH, in a reaction. In our previous studies, we have
demonstrated that the intramolecular cyclization of an a-carbonyl
radical could be used as an efficient step in the total synthesis of
several natural products, including (¡)-modhephene, (2)-dendro-
bine, (2)-5-oxosilphiperfor-6-exe, (+)-paniculatine and (2)-bakke-
nolide III, and in the formal synthesis of (2)-pinguisenol and (2)-
a-pinguisene.2
To the best of our knowledge, no reports so far have described
the use of an a-carbonyl vinyl radical for intermolecular carbon–
carbon bond formation. Herein, we report the intermolecular
addition reactions of a-carbonyl vinyl radicals generated from
a-iodo cycloalkenones with electron-withdrawing olefins (schema-
tically shown in Scheme 1). This reaction has important synthetic
value in the preparation of chiral a-substituted cyclic enones that
are difficult to obtain by other methods. In order to demonstrate
the versatility of this reaction, we also report a synthetic study of
In this study, four a-iodocycloalkenones, including 2-iodocy-
clopent-2-enone (1), 2-iodocyclohex-2-enone (2), 2-iodocyclohept-
2-enone (3) and even (R)-2-iodo-5-methylcyclohex-2-enone (5) (in
the study of the formal synthesis of fawcettimine), were employed
as the radical donors and various electron-withdrawing olefins
were used as radical acceptors. The final results are summarized in
Table 1. In addition, vinyl acetate, which is an electron-rich olefin,
was employed in this reaction; however, none of the desired adduct
was obtained. Based on these experimental results, we suggest that
a-carbonyl vinyl radicals are ideal electron-rich radical donors
under radical reaction conditions. To demonstrate the synthetic
utility of the intermolecular radical addition reaction, it was treated
Scheme 1 Intermolecular addition reactions of a-carbonyl vinyl radicals
with electron-withdrawing olefins.
aSchool of Applied Chemistry, Chung Shan Medical University,
Taichung 402, Taiwan, ROC. E-mail: lkm@csmu.edu.tw;
cmchau@csmu.edu.tw
bDepartment of Chemistry, National Tsing Hua University, Hsinchu 300,
Taiwan, ROC
{ Electronic supplementary information (ESI) available: Detailed experi-
1
mental procedures, H and 13C NMR spectroscopic data, and analytical
data of all the compounds in Table 1, and Scheme 1, Scheme 2 and
Scheme 3. See DOI: 10.1039/b714078a
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Chem. Commun., 2008, 91–93 | 91

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Table 1 Alkylation of a-iodo cycloalkenones with electron-withdrawing acceptorsa
a
Intermittent addition (8 times at 40 min intervals) was performed. The detailed experimental procedure is described in the ESI.
as an important step in the formal synthesis of enantiopure
fawcettimine.
Inubushi et al. using a Diels–Alder reaction as the key step.5a To
date, there are only three total synthesis reports (Inubushi et al. in
1979,5a and Heathcock et al. in 19865c and 19895d) and one
publication of the core skeleton synthesis (Mehta in 19915e) of
fawcettimine; however, none of them deals an enantiopure
synthesis.
Fawcettimine was first isolated from extracts of the alkaloids of
Lycopodium fawcetti collected in the Blue Mountain range of
Jamaica by the Burnell group in 1959. Because of their potent
acetylcholine esterase inhibition activity,3 coupled with an
extremely complex structure,4 various different synthetic meth-
odologies leading to this Lycopodium alkaloid were proposed and
studied by many groups.5 Unfortunately, the total or formal
synthesis was a really difficult challenge. Until 1979, the first
racemic total synthesis of fawcettimine was accomplished by
Herein, we propose a unique methodology for the formal
synthesis of enantiopure fawcettimine by using chiral enone 46 as
the starting material, and inter- and intramolecular radical reaction
sequences as the key steps. The synthetic scheme for obtaining
compound 11, whose structure is almost the same as that of the
Scheme 2 Reagents and conditions: (a) I2, pyridine, CH2Cl2, 95%; (b) acrylonitrile, AIBN, Bu3SnH, PhH, 70%; (c) 12, Mg, CuI, TMSCl, HMPA, THF;
t
NaI, m-CPBA, THF, 78% (2 steps); (d) Bu3SnH, AIBN, PhH, slow addition, 60 uC, 64%; (e) TFA, CH2Cl2, 78%; (f) SeO2, BuOOH, CH2Cl2; Jones’
reagent, 52%; (g) 13, LiClO4, Et2O; AcOH, THF, H2O, 40%.
92 | Chem. Commun., 2008, 91–93
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lithium perchlorate-mediated conjugate addition of freshly pre-
pared ketene silyl acetal, 13, to enone 10 afforded compound 11,
which was almost identical to the key intermediate in Heathcock’s
synthesis of fawcettimine, except for the carbonyl functionality on
the five-membered ring.
In conclusion,
a useful intermolecular radical addition
reaction of a-iodo cycloalkenone has been described. The formal
synthesis of enantiopure fawcettimine has been accomplished
stereoselectively, during which inter- and intramolecular
radical reactions were employed as key steps to facilitate the
construction of the core skeleton of the product. Further
applications using this strategy are currently under development
in our laboratory.
Notes and references
{ Crystal data: For 18: C17H27NOSi, M = 289.49, T = 296(2) K,
monoclinic, space group P21/c, a = 7.5791(14), b = 12.075(2), c =
19.243(4) s, b = 91.904(3)u, V = 1760.1(6) s3, Z = 4, F(000) = 632,
reflections collected: 10942, independent reflections: 4155 (Rint = 0.0240).
Final R indices [I . 2s(I)]: R1 = 0.0499, wR2 = 0.1341; R indices (all data):
R1 = 0.0780, wR2 = 0.1503.
For 19: C17H27NOSi, M = 289.49, T= 296(2) K, monoclinic, space
group P21/c, a = 11.6687(8), b = 12.3423(9), c = 12.2850(9) s, b =
95.921(2)u, V = 1759.8(2) s3, Z = 4, F(000) = 632, reflections collected:
10218, independent reflections: 3920 (Rint = 0.0201). Final R indices [I .
2s(I)]: R1 = 0.0463, wR2 = 0.1348; R indices (all data): R1 = 0.0577, wR2 =
0.1435.
Scheme 3 Proposed formation pathway of desired product 8a, and by-
products 18 and 19.
key intermediate in Heathcock et al.’s synthesis of fawcettimine, is
illustrated in Scheme 2. We suggest that compound 11 could be
converted into fawcettimine via a procedure similar to Heathcock
et al.’s process developed in 1989.5d
CCDC 663530 and 663530. For crystallographic data in CIF or other
electronic format see DOI: 10.1039/b714078a
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Optically pure cyano-enone 6 could be obtained in 70% yield
from chiral a-iodoenone 5 via a intermolecular radical addition
reaction with acrylonitrile. The CuI-mediated conjugate addition
of 4-(trimethylsilyl)-3-butynylmagnesium chloride was followed by
the trapping of the resulting enolate with chlorotrimethylsilane
(TMSCl) to obtain the trimethylsilyl enol ether. Without
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mixture of NaI and m-CPBA to afford the unstable iodo ketone 7
in 78% yield. The intramolecular radical cyclization of 7 was then
carried out by using a benzene solution of AIBN and Bu3SnH,
which was introduced using a syringe pump at reflux, and the
desired cyclized product 8 was obtained in 64% yield. It is
noteworthy that in the model study of fawcettimine, wherein the
racemic 5-methylcyclohex-2-enone was used as the starting
material, trace amounts of compounds 18 and 19 were separately
isolated during the radical cyclization reaction and their structures
ascertained by single crystal X-ray analysis.{ This result may be
rationalized by the 1,5-hydrogen transposition of vinyl radical 15,
formed by the 5-exo-dig cyclization of radical 14, followed by the
intramolecular 5-endo-trig radical cyclization of the resulting
radical 17. The proposed mechanism is illustrated in Scheme 3.
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relative stereochemistry of compounds 18 and 19 could be the
indirect evidence that allows the relative stereochemistry of
optically pure compound 11 to be assigned.
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Chem. Commun., 2008, 91–93 | 93