Domino double Michael-Claisen cyclizations: A powerful general tool for introducing quaternary stereocenters at C(4) of cyclohexane-1,3-diones and total synthesis of diverse families of sterically congested alkaloids

Article abstract of DOI:10.1021/jo801316s

(Chemical Equation Presented) Reactions of substituted acetone derivatives with acrylic acid esters (>200 mol %) in the presence of t-BuOK (200 mol %) in t-BuOH-THF (1:1 by volume) turned out to proceed as a cascade process consisting of the first Michael addition, the second Michael addition, and the last Claisen reaction to afford 4,4-disubstituted cyclohexane-1,3-diones. Only more substituted enolates play the role of a Michael donor in this cascade process, and therefore the ketone took up two alkoxycarbonylethyl groups on the same carbon bearing more substituents. Such intermediates were followed by intramolecular Claisen reactions leading to cyclohexane-1,3-diones bearing quaternary stereogenic centers at C(4), which bears an alkoxycarbonylethyl group and the substituent of the starting acetone derivatives. Thus-obtained 4,4-disubstituted cyclohexane-1,3-diones were successfully employed for total syntheses of intricate alkaloids of biological interest such as (+)-aspidospermidine, (±)-galanthamine, (±)-lycoramine, and (±)-mesembrine, all featuring quaternary stereogenic centers. DFT calculations provided us with clear-cut explanations for the observed chemoselectivity of the cascade process involving ketone-based enolates under thermodynamically controlled conditions.

Full text of DOI:10.1021/jo801316s

Domino Double Michael-Claisen Cyclizations: A Powerful General
Tool for Introducing Quaternary Stereocenters at C(4) of
Cyclohexane-1,3-diones and Total Synthesis of Diverse Families of
Sterically Congested Alkaloids
Teruhiko Ishikawa,* Kazuhiro Kudo, Ken Kuroyabu, Satoshi Uchida, Takayuki Kudoh, and
Seiki Saito*
Department of Medical and Bioengineering Science, Graduate School of Natural Science and Technology,
Okayama UniVersity, Tsushima, Okayama, Japan 700-8530
teruhiko@cc.okayama-u.ac.jp; saito-s@u-air.ac.jp
ReceiVed June 19, 2008
Reactions of substituted acetone derivatives with acrylic acid esters (>200 mol %) in the presence of
t-BuOK (200 mol %) in t-BuOH-THF (1:1 by volume) turned out to proceed as a cascade process consisting
of the first Michael addition, the second Michael addition, and the last Claisen reaction to afford 4,4-
disubstituted cyclohexane-1,3-diones. Only more substituted enolates play the role of a Michael donor in
this cascade process, and therefore the ketone took up two alkoxycarbonylethyl groups on the same
carbon bearing more substituents. Such intermediates were followed by intramolecular Claisen reactions
leading to cyclohexane-1,3-diones bearing quaternary stereogenic centers at C(4), which bears an
alkoxycarbonylethyl group and the substituent of the starting acetone derivatives. Thus-obtained 4,4-
disubstituted cyclohexane-1,3-diones were successfully employed for total syntheses of intricate alkaloids
of biological interest such as (+)-aspidospermidine, (()-galanthamine, (()-lycoramine, and (()-
mesembrine, all featuring quaternary stereogenic centers. DFT calculations provided us with clear-cut
explanations for the observed chemoselectivity of the cascade process involving ketone-based enolates
under thermodynamically controlled conditions.
Introduction
can be triggered by the Michael process involving more
substituted enolates as a Michael donor generated under
thermodynamically controlled conditions to provide diversified
cyclohexane-1,3-diones.2 Continuing studies of this process have
unveiled another hidden synthetic potential of the reaction that
one more Michael process can intervene after the initial Michael
process on the same site as for the initial event when the R,ꢀ-
unsaturated esters was employed in an excessive amount (2-4
equiv). Thus, we referred to this process as a double
Michael-Claisen reaction cascade (DMCRC) to provide an
extremely efficient way to functionalized cyclohexane-1,3-diones
bearing C(4)-quaternary stereogenic centers (3) (Scheme 1) in
Expeditious construction of main carbon frameworks that,
at the same time, leave behind key clues for further elaboration
of complex molecules should be crucial in modern organic
synthesis. This may play an important role in short syntheses
of natural products of biological interests. Cascade reactions
have received great attention in this context.1 We were
concerned with such reactions and previously found that
alkoxide-mediated domino Michael addition-Claisen reaction
of simple unsymmetrical ketones with R,ꢀ-unsaturated esters
(1) Tietze, L. F.; Haunert, F. In Stimulating Concepts in Chemistry; Shibasaki,
M., Stoddart, J. F., Vo¨gtle, F., Eds.; Wiley-VCE: Weinheim, Germany, 2000;
pp 39-64..
(2) Ishikawa, T.; Kadoya, R.; Arai, M.; Takahashi, H.; Kaisi, Y.; Mizuta,
T.; Yoshikai, K.; Saito, S. J. Org. Chem. 2001, 66, 8000–8009.
7498 J. Org. Chem. 2008, 73, 7498–7508
10.1021/jo801316s CCC: $40.75 2008 American Chemical Society
Published on Web 09/10/2008

Domino Double Michael-Claisen Cyclizations
TABLE 1. Summary of DMCRC and Enol Ether Formation
SCHEME 1. Double Michael-Claisen Reaction Cascade
(DMCRC)
SCHEME 2. Traditional Sequential Geminal Dialkylation of
3-Alkoxy-2-cyclohexen-1-one
a single pot. Furthermore two carbonyl groups of 3 were highly
selectively discriminated to give enol ethers (4) as indicated in
Scheme 1. It should be noted that 4f and 4g bear substituted
aromatic rings as one of the substituents at the C(4)-quaternary
stereogenic centers, which otherwise are difficult to access.
Access to 4,4-disubstituted-1-alkoxy-1-cyclohexen-3-one frame-
works such as 4 have usually relied upon traditional sequential
geminal dialkylation of 3-alkoxy-2-cyclohexen-1-one (5).3 For
example, alkylation of kinetically generated enolates from
4-methyl-1-ethoxy-1-cyclohexen-3-one (6)3c with LDA, which
can be provided through similar methylation of kinetic enolate
prepared from 3-ethoxy-2-cyclohexen-1-one (5),3a leads to
geminally alkylated product 7 as shown in Scheme 2. This
method, however, suffers from the severe limitation that it
cannot afford any aryl-substituted derivatives such as 4f or 4g
at all.
Besides the given synthetic efficacy and substituent diversi-
fication of the DMCRC process as just mentioned, we should
pay attention to the basic structural feature of 3 or 4, which
could be recognized as segments for several alkaloids of
biological interest such as Aspidosperma alkaloid aspidosper-
midine (8),4 Amarillydaseae alkaloids galanthamine (9)5 or
lycoramine (10),6 or Sceletium alkaloid mesembrine (11),7
depending on R. Indeed, concise total syntheses of all of these
alkaloids from 3b, 4g, and 4f have been achieved as delineating
the power of DMCRC, which will be presented.
We have also conducted DFT calculations in order to gain
more insight into the highly interesting chemoselectivity of this
reaction. This effort gave us rational theoretical understandings
why Michael reactions of ketone enolates having more substi-
tuted double bonds with R,ꢀ-unsaturated esters proceed more
rapidly than those having less substituted double bonds under
thermodynamically controlled conditions where such enolates
are interchangeable.
Results and Discussion
DMCRC Reactions Exemplified. In Table 1 are summarized
the results of DMCRC followed by discrimination of the two
carbonyl groups by enol etherification. Treating substituted
acetones (1a-g) with an excess amount of t-BuOK (2 equiv)
and tert-butyl acrylate (2, 2.5-4 equiv) in THF/t-BuOH mixed
solvent (1:1 by volume) led to 3a-g in acceptable yields
(3) (a) Gannon, W. F.; House, H. O. Org. Synth. 1960, 40, 41–42. (b) Kende,
A. S.; Fluzinsky, P. Org. Synth. 1986, 64, 68–69. (c) Hayashi, Y.; Gotoh, H.;
Tamura, T.; Yamaguchi, H.; Masui, Y.; Shoji, M. J. Am. Chem. Soc. 2005, 127,
16028–16029. See also: (d) Nicolaou, K. C.; Li, A.; Edmonds, D. J. Angew.
Chem., Int. Ed. 2006, 45, 7086–7090.
(4) For pioneering syntheses, see ref 18. For recent representative syntheses,
see: (a) Coldman, I.; Burrell, A. J. M.; White, L. E.; Adams, H.; Oram, N. Angew.
Chem., Int. Ed 2007, 46, 1–5. (b) Sharp, L. A.; Zard, S. Z. Org Lett 2006, 8,
831–834. (c) Pearson, W. H.; Aponick, A. Org. Lett. 2006, 8, 1661–1664. (d)
Iyengar, R.; Schildknegt, K.; Morton, M.; Aube´, J. J. Org. Chem. 2005, 70,
10645–10652. (e) Banwell, M. G.; Lupton, D. W.; Willis, A. C. Aust. J. Chem.
2005, 58, 722–737. (f) Tanino, H.; Fukunishi, K.; Ushiyama, M.; Okada, K.
Tetrahedron 2004, 60, 3273–3282. (g) Marino, J. P.; Rubio, M. B.; Cao, G.;
Dios, A. J. Am. Chem. Soc. 2002, 124, 13398–13399. (h) Kozmin, S. A.; Iwama,
T.; Huang, Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 4628–4641. (i)
Desmae¨le, D.; d′Angelo, J. J. Org. Chem. 1994, 59, 22922303. For beautiful
and systematic listing of literature for the total synthesis of 8 including its racemic
form, see ref 4g.
(5) For pioneering synthesis, see: (a) Barton, D. H. R.; Kirby, G. W. Proc.
Chem. Soc. London 1960, 392–393. For recent non-biomimetic syntheses: (b)
Hu, X.-D.; Tu, Y. Q.; Zhang, E.; Gao, S.; Wang, S.; Wang, A.; Fan, C.-A.;
Wang, M. Org. Lett. 2006, 8, 1823–1825. (c) Trost, B. M.; Tang, W. Angew.
Chem., Int. Ed. 2002, 41, 2795–2797. (d) Guillou, C.; Beunard, J.-L.; Gras, E.;
Thal, C. Angew. Chem., Int. Ed 2001, 40, 4745. For oxidative phenolic
coupling: (e) Kodama, S.; Hamashima, Y.; Nishide, K.; Node, M. Angew. Chem.,
Int. Ed. 2004, 43, 2659–2661. (f) Node, M.; Kodama, S.; Hamashima, Y.; Baba,
T.; Hamamichi, N.; Nishide, K. Angew. Chem., Int. Ed. 2001, 43, 3060–3062.
(6) For a recent synthesis, see: Fan, C.-A.; Tu, Y.-Q.; Song, Z.-L.; ZhangE.;
Shi, L.; Wang, M.; Wang, B.; Zhang, S.-Y Org. Lett. 2004, 6, 4691–4694, and
references therein.
(7) For pioneering synthesis, see: (a) Shamma, M.; Rodoriquez, H. R
Tetrahedron Lett. 1965, 6, 4847–4850. For recent representative synthesis, see:
(b) Taber, D. F.; He, Y. J. Org. Chem. 2005, 70, 7711–7714. (c) Taber, D. F.;
Neubert, T. D. J. Org. Chem. 2001, 66, 143–147. (d) Ogasawara, K.; Yamada,
O. Tetrahedron Lett. 1998, 39, 7747–7750. (e) Kamikubo, T.; Ogasawara, K.
Chem. Commun. 1998, 783–784. (f) Langlois, Y.; Dalko, P. I.; Brun, V.
Tetrahedron Lett. 1998, 39, 8979–8982. (g) Mori, M.; Kuroda, S.; Zhang, C.-
S.; Sato, Y. J. Org. Chem. 1997, 62, 3263–3270. (h) Denmark, S. E.; Marcin,
L. R. J. Org. Chem. 1997, 62, 1675–1686. (i) Meyers, A. I.; Hanreich, R.;
Wanner, K. T J. Am. Chem. Soc. 1985, 107, 7776–7778. For a beautiful and
systematic listing of literature for the total synthesis of 11, see ref 7h.
(8) Sodium tert-butoxide can also effect the desired DMCRC, but sodium
ethoxide gave unacceptable deteriorated product mixtures. We have also
attempted amine bases such as proline, which, however, resulted in no reaction.
Use of tert-butyl acrylate was the best choice in terms of chemical yields and
suppression of side reactions. When equimolar ketones and acrylic esters were
used, the DMCRC products was detected only in a trace amount in 1 for R )
alkyl, allyl, or benzyl groups. On the other hand, when R was aryl groups such
as 1f,g, the reactions led to only DMCRC products together with the unchanged
ketones recovered, and no Michael-Claisen product such as 4-arylcyclohexane-
1,3-dione was detected at all.
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Ishikawa et al.
SCHEME 3. DMCRC Mechanism
SCHEME 4. Control Experiment
(62-80%).8 For the following enol ether formation, almost
complete discrimination between the two carbonyl groups of 3
was realized for every entry under simple reaction conditions
using MeOH-TMSCl to obtain 4a-g in almost quantitative
yields from 3.
has led us to conclude that the other possible route to 3 from B
involving initial Claisen reaction to 22 followed by intramo-
lecular Michael reaction leading to 21 and the final intermo-
lecular Michael reaction with 2 can completely be ruled out as
indicated in brackets in Scheme 4.
As the DMCRC occurs under the thermodynamically con-
trolled conditions, we can draw the plausible mechanism as
shown in Scheme 3. We should pay attention to the significant
finding that the double Michael process rapidly took place at
the more substituted sites of both 1 and the initial Michael
products (12) before Claisen cyclization commenced as the final
step. Only type A enolate reacts with 29 to give 12, which
underwent the second Michael addition with 2 via type A′
enolate affording 13, an immediate precursor for 3 through the
final Claisen reaction. Hence, we can very quickly construct
quaternary centers bearing the desired substituents R even if
they are aryl groups. It should be mentioned that none of 16-20
was obtained at all, although there is a possibility that they could
be formed through routes indicated in Scheme 3.
In addition, although 12 obtained from a separate experiment
(1 equiv 2, t-BuOK, THF, rt) gave 21 (Scheme 4) as expected,2
21 did not lead to 3 by Michael reaction with 2 on treatment
with the same base. Accordingly, it can definitely be concluded
that 3 was furnished through an only route involving 1, A, 12,
A′, and 13 in this order. Such a control experiment (Scheme 4)
Since the type B enolate should exist as an equilibrium partner
of the type A enolate under the given reaction conditions,10
Michael reaction of B with 2 must have been very slow. The
same thing should be true for reaction between type B′ enolate
and 2. Since there has been a conflict of opinions with regard
to the equilibrium compositions for solutions of potassium
enolates derived from acyclic unsymmetrical ketones,11 we must
necessarily take kinetic aspects of Michael additions of equili-
brating enolates A and B or A′ and B′ with 2 into account in
order to rationalize the observed selectivity for the DMCRC
summarized in Table 1. As the evaluation of kinetic data of
this kind has not been available in the literature, we have
computed the transition state energies of the reaction.
DFT Calculations for Model Enolates and Reactions. In
order to diagnose enolate stability issues,11 DFT calculations
for 3-methyl-2-butanone based enolates 23 and 24 as a model
were conducted using the Gaussian 03 ab initio package12
employing B3LYP/6-31+G(d,p) as a basic function. Surpris-
ingly enough and contrary to the textbook statements,11a, the
more substituted enolate 24 was unequivocally less stable than
less substituted enolate 23 by 3.4 kcal/mol. This is also the case
for 2-butanone-based enolates 25-27.13 Although elucidation
of the main factors that control such incognizant relative stability
must await further studies, a stabilizing interaction between the
potassium atom and the enolate double bond14 may be more
(9) Michael reactions of acyclic or cyclic ketone enolates having a more
substituted double bond with nucleophiles (Nu). Nu ) ethyl or methyl
acrylate: (a) Miller, J. J.; de Benneville, P. L. J. Org. Chem. 1957, 22, 1268–
1269. (b) House, H. O.; Roelofs, W. L.; Trost, B. M. J. Org. Chem. 1966, 31,
646–655. Nu ) acrylonitrile: (c) Bruson; Hnt, A.; Riener, T. W. J. Am. Chem.
Soc. 1942, 64, 2850–2858 (double cyanoethylation). (d) Barkley, L. B.; Levine,
R. J. Am. Chem. Soc. 1950, 72, 3699–3701 (double cyanoethylation). (e)
Bachmann, W. E.; Wick, L. B. J. Am. Chem. Soc. 1950, 72, 3388–3392. (f)
Frank, R. L.; Pierle, R. C. J. Am. Chem. Soc. 1951, 73, 2341–2346. (h) Chapurlat,
R.; Huet, J.; Dreux, J. Bull. Soc. Chim. Fr. 1967, 2446–2450; 2450-2466.
(10) For discussion of this class, see: (a) Carey, F.; Sundberg, R. J. AdVanced
Organic Chemistry, 4th ed., Part B: Reaction and Synthesis; Kluwer Academic/
Plenum: New York, 2001; pp 5-8.
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Domino Double Michael-Claisen Cyclizations
SCHEME 5. Michael Reactions of Enolates 23 and 24 with Methyl Acrylate (MA)a
a Relative IRC energies for substrate-MA systems, activation energies (∆Eq) for each reaction, relative transition state energies for 31 and 32, and relative
energies for initial adducts (ester enolates 33 and 34). For DFT structures, atoms in blue represent the carbons of reaction centers and larger atom in green
designates potassium.
effectively involved in 23 than 24 or in 25 (25′) than 26 for
steric reasons. The more stable nature of 26 than 27 may be
attributed to a steric strain difference.
It turned out, however, that this is not a general trend. In the
phenyl acetone case (28, 29, and 30), the more substituted
enolates with Z or E geometry are more stable than less
substituted enolate 30 and (Z)-isomer 28 are much more stable
than the (E)-isomer by 8.2 kcal/mol, which is unexpectedly large
and can probably be ascribed to stabilizing interaction between
the potassium atom and the nearby phenyl ring (Figure 2).
Further DFT studies provided a similar stabilization by an
aromatic ring with conformational isomer 30 being more stable
than 30′ by 3.8 kcal/mol. Thus, in order to understand the
observed chemoselectivity of the DMCRC processes (Table 1),
we have conducted further DFT computations including Fukui′s
intrinsic reaction coordinate (IRC) protocol16 for a Michael
FIGURE 1. Correspondence between DMCRC products and some
alkaloids in terms of both carbon backbone and heteroatom location.
reaction of the above-mentioned model enolates.
The IRC energy for the 23-MA system was calculated to be
lower than that for the 24-MA system by 1.1 kcal/mol (Scheme
such as 31 or 32, respectively, relying on the Zimmerman-
Traxler concept (Scheme 5).15 Interestingly, 32 obtained from
more substituted enolate 24 is more stable than 31 from less
substituted enolate 23 by 3.75 kcal/mol, probably reflecting
much larger transannular interaction exerted by an isopropyl
group in 31 compared with that exerted by 1,2,2-trimethyl
substituents in 32. The following Claisen reaction leads to 35
via 34 as was clearly demonstrated previously.17 This result
provides a reason why the more substituted enolate reacts with
R,ꢀ-unsaturated esters more rapidly than the corresponding less
substituted enolates.
DFT calculations of the same level as that employed in the
case of 23 or 24 have been carried out for other model enolates
such as 25-30, and the results are shown in Scheme 6.
Interestingly, the IRC energy for the more substituted (Z)-enolate
(26) is lower than that for the less substituted enolate (25) by
1.15 kcal/mol, whereas the IRC energy for the more substituted
(E)-enolate (27) was higher than that for 25 by 1.92 kcal/mol.
From these data, we can expect that the more substituted (Z)-
enolate 26 would highly selectively give an adduct (39, thus
40) as a precursor for 4-methylcyclohexane-1,3-dione (41) under
thermodynamically controlled conditions including 26 as a
predominant component, by which we can explain why the
type-A enolate highly selectively led to 12 (Scheme 3). This is
5), reasonably reflecting the more stable nature of less-
substituted enolate 23 (Figure 2). Nevertheless 35 was obtained
exclusively from 24 as demonstrated previously.2 This fact is
given an answer by calculated transition state energies as
follows. The transition states of Michael reactions could
reasonably be formulated as a cyclic structure involving
coordination between the two oxygen atoms and the metal center
(11) (a) On page 8 of ref 10: “at equilibrium the more substituted enolate is
usually the dominant species. The stability of carbon-carbon double bonds
increases with increasing substitution, and this effect leads to the greater stability
of the more substituted enolate.” (b) On page 865 of Bruice, P. Y. Organic
Chemistry, 5th ed.; Pearson Prentice Hall: Upper Saddle River, NY, 2007: “The
enolate leading to 2,2-dimethylcyclohexanone is the thermodynamic enolate ion,
because it is the more stable enolate ion since it has the more substituted double
bond (alkyl substitution increases enolate ion stability for the same reason it
increases alkene stability).” (c) On the other hand, House and Kramar reported
that less substituted enolates should be a predominant partner of equilibrium
established between enolates generated from simple unsymmetrical acyclic
ketones by the action of triphenylmethylpotassium in 1,2-dimethoxyethane; they
analyzed deuterium distribution of recovered ketones after quenching the mixture
with CH3CO2D/D2O mixture. See: House, H. O.; Kramar, V. J. Org. Chem.
1963, 28, 3362–3379.
(12) For details of DFT calculations, see Supporting Information.
(13) For a recent ab initio study of thermodynamic stability of enolates
generated from 2-butanone with methoxide anion in MeOH, see: Ikeda, H.;
Yukawa, M.; Niiya, T. Chem. Pharm. Bull. 2006, 54, 731–734.
(14) Abbotto, A.; Streitwieser, A.; Schleyer, P. v. R. J. Am. Chem. Soc. 1997,
119, 11255–11268.
(15) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920–
1923.
(16) (a) Fukui, K. Acc. Chem. Res. 1981, 14, 363–368. (b) Gonzalez, C.;
Schlegel, H. B. J. Chem. Phys. 1989, 90, 2154–2161.
(17) See ref 2; 35 was obtained in 99% or 85% yield for tert-butyl or ethyl
acrylate, respectively.
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Ishikawa et al.
SCHEME 6. Michael Reactions of Enolates 25-30 with Methyl Acrylate (MA)a
a Relative IRC energies for substrate-MA systems, activation energies (∆Eq) for each reaction, relative transition state energies for 37-39 and 44-46,
and relative energies for initial adducts (ester enolates 39, 39′, 42, 47, 47′, and 48).
also consistent with the previous experiment demonstrating the
exclusive formation of 41 for consecutive Michael-Claisen
reaction of 2-butanone with tert-butyl acrylate in THF in the
presence of t-BuOK at room temperature where no formation
of 43 was observed.2 Results for DFT calculations carried out
with regard to Michael additions of phenyl acetone based
enolates (28-30) with methyl acrylate clearly indicates that there
would be no chance for 30 to give adduct 48 because of the
highly stable nature of (Z)-enolate 28, though an activation
energy for Michael addition of 28 was calculated to be the
highest among those obtained for these three enolates.
Curtin-Hammett principle may indicate that there would exist
small chance for (E)-enolate 29 to lead to 47′.
Finally, we carried out DFT calculations with regard to second
Michael reactions of ketone enolates 49, 50, and 51, which are
convertible from 47, 47′, and 48, respectively, with methyl
acrylate to examine whether such hypothetical reactions proceed
with very high chemoselectivity to give the expected adduct
such as 55. The results are shown in Scheme 7 and clearly
suggest that the reactions should pass through a transition state
such as 52 leading to 55 after the final Claisen reaction.18 This
model case can reasonably be related to the second Michael
processes for real cases listed in Table 1.
To the best our knowledge, the first example of double
Michael addition pertinent to the present kind was reported in
19429c and demonstrated that 2-butanone reacts with an exces-
sive amount of acrylonitrile to take up two cyanoethyl groups
on the methylene carbon, giving rise to 4-acetyl-4-methylhep-
tanedinitrile. Presumably the mechanism of this interesting
chemoselective reaction is the same.
Application to the Total Synthesis of Alkaloids. Three
carbon-carbon bonds can be formed in a single pot in the
DMCRC process to provide cyclohexane-1,3-diones 3 having
two substituents at C(4). The following enol ether formation
(18) Energy levels for the initial adducts (ester enolates) are not shown here.
Reflecting the corresponding transition state structure, the ester enolates produced
from 52 and 53 gave different DFT energy levels, although they lead to the
same adducts after protonation. See Supporting Information for detail.
7502 J. Org. Chem. Vol. 73, No. 19, 2008

Domino Double Michael-Claisen Cyclizations
SCHEME 7. DFT Results for Michael Reactions of Hypothetical Enolates 49-51 with Methyl Acrylate (MA)a
a Relative IRC energies for substrate-MA systems, activation energies (∆Eq) for each reaction, and relative transition state energies for 52-54.
takes place with almost complete regioselectivity leading to 4,
a 4,4-disubstituted-2-cyclohexen-1-one framework. As already
mentioned above, superimposing 3 or 4 upon some alkaloids
of biological interests such as 8-11 reveals a close cor-
respondence of the core scaffold.
realized via a newly developed protocol consisted of N-
methoxycarbonylation and subsequent acidic treatment in metha-
nol.23
Reduction of 57 with DIBALH and subsequent mesylation
of a thus-generated hydroxy group afforded chiral 4,4-disub-
stituted cyclohexenone (58), which on treatment with ethanol-
amine led to a bicyclic intermediate (59) in almost exclusive
diastereoselectivity. This process may commence by Michael
addition (58 f A or 58 f B) or SN2 reaction (58 f C), the
discrimination of which, however, was difficult because an
attempt to isolate any of these intermediates was in vain. This
result probably indicates that the following cyclization is fast,
and hence intramolecular Michael reaction might be appropriate:
the initial Michael addition of ethanolamine to 58 may be
sluggish because of a neopentyl-type structure of the Michael
acceptor. Although the mechanistic rationale of this process must
await future study, it is tentatively assumed that the process
involves the initial intermolecular SN2 reaction and subsequent
intramolecular Michael addition of thus-produced amine re-
sponsible for the observed very high % de as shown in Scheme
7 (58 f C f 59). Stork’s ketone 6020 was obtained via
chlorination of 59 followed by an intramolecular enolate
alkylation: the optical rotation and NMR spectra of 60 were
identical with those reported.24 Transformation of 60 to (+)-
aspidospermidine (8) was achieved after the reported proce-
dures.25 The present chirospecific route to 8 involves 9 steps
(+)-Aspidospermidine. Many Aspidosperma alkaloids have
received considerable attention as synthetic targets because of
their complex structures and potent biological activities.19
Aspidospermidine 8 is one of the families, and development of
methods for constructing its highly congested pentacyclic ring
system is still attractive for synthetic chemists. Since the first
synthesis of racemic aspidospermidine by Stork,20 many syn-
theses and formal syntheses have been reported.4 In Scheme 8
is illustrated the enantioselective total synthesis of (+)-aspi-
dospermidine 8 involving the optical resolution of dione 3b.
Since optical resolution of cyclohexane-1,3-diones having C(4)-
quaternary stereogenic centers has no precedent, we developed
such an experimental procedure. In the event, we have found a
series of practical protocol involving Lewis acid catalyzed
enamine formation with optically active primary amine, separa-
tion of diastereoisomers, and final transformation of the enamine
to enol ether, which should be an appropriate precursor for
enone. Specifically, zinc triflate catalyzed enamine formation
with (S)-1-phenylethylamine led to a mixture of 56a and 56b
in very high yield.21 The desired optically pure isomer 56a was
obtained by the combined use of recrystallization and MPLC
purification,22 and the conversion of 56a to the known 574i was
(22) Recrystallization afforded 56a-rich fraction in crystals and 56b-rich
fraction as a mother liquor, the respective fraction of which led to pure 56a and
56b via MPLC purification.
(23) We have succeeded in transforming vinylogous amide function in 56a
to ꢀ-methoxyenone function in 57 after extensive efforts: no previous report
has been found for the transformation of this kind. Optical rotation of 57 was
[R]29 +19.7 (c 1.40, EtOH), which is consistent with that {[R]22 +19.4 (c 8,
(19) Saxton, J. E. The Alkaloids; Cordell, G. A., Ed.; Academic Press: New
York, 1998; Vol. 51, Chapter1.
(20) Stork, G.; Dolfini, J. E. J. Am. Chem. Soc. 1963, 85, 2872–2873.
(21) An extensive survey of Lewis acid catalysts resulted in finding that
Zn(OTf)2 is extremely effective for this purpose. No formation of an isomer
stemmed from amine attack toward another carbonyl group at C(3) was detected
at all.
D
D
EtOH)} reported previously for 57; see ref 4i.
(24) Optical rotation of 60 was [R]29D-23.1 (c 0.71, CHCl3), which is
consistent with that {[R]29D-24.4 (c 0.88, CHCl3)} reported previously for 60;
see: Fukuda, Y.; Shindo, M.; Shishido, K. Org. Lett. 2003, 5, 749–751.
J. Org. Chem. Vol. 73, No. 19, 2008 7503

Ishikawa et al.
SCHEME 8. Total Synthesis of (+)-Aspidospermidine 8a
SCHEME 9. Total Synthesis of (()-Galanthamine and
(()-Lycoraminea
a Reagents and conditions: (a) DIBALH, toluene, -78 °C, 4 h; (b) TsOH,
THF, rt, 10 h; (c) Pd-C, MeOH, rt, 2 h, 65% for 3 steps; (d) MgCl2, THF,
50 °C, 2 d, 82%; (e) SO3 · Py, Et3N, DMSO, CH2Cl2, rt, 3 h, 74%; (f)
NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH, H2O, 80%; (g) DPPA,
Et3N, toluene-MeOH, reflux, 2 d, 80%; (h) (CH2O)n, TFA, DCE, 60 °C,
24 h, 75%; (i) TBDMSOTf, Et3N, CH2Cl2, rt, 12 h; (j) Pd(OAc)2,
p-benzoquinone, MeCN, rt, 2 d, 66% for 2 steps; (k) L-Selectride, THF
then LAH, THF, 50%.
under the subsequent debenzylation conditions. Thus, deben-
zylation was uneventfully carried out as usual to give a phenol
derivative (63) followed by MgCl2-mediated retro-Michael and
a phenolic hydroxy-Michael addition process leading to the
thermodynamically more stable dihydrobenzofuran 64 (82%
yield) and regenerating the 3-hydroxypropyl substituent on the
quaternary stereogenic center. The primary hydroxy group of
64 was oxidized to the corresponding carboxylic acid and
followed by a Curtius rearrangement using Shioiri′s condition27
to afford carbamate 65. Pictet-Spengler cyclization of 65 was
effected to give the key intermediate 66. The endgame total
synthesis of (()-galanthamine was carried out as follows: silyl
enol ether formation from 66 using TBDMSOTf followed by
Pd(II)-mediated oxidation28 regioselectively furnished an enone
function, which was subjected to stereoselective reduction using
L-Selectride followed by carbamate to N-methylamine conver-
sion with LAH. The overall yield from 1g was 6.5% in 13
steps.29 Stereoselective carbonyl reduction of 66 with L-
Selectride followed by carbamate reduction with LAH led to
(()-lycoramine as well in overall yield of 17% for 11 steps.
(()-Mesembrine. (-)-Mesembrine (11) is a member of the
Sceletium alkaloids with potent selective serotonin reuptake
inhibitory activity in the central nerves system.30 When one of
DMCRC products such as 4f was superimposed upon 11, we
recognized that the transformation of a 2-(alkoxycarbonyl)ethyl
substituent at C(4) to a 2-(N-methylamino)ethyl group would
be the only remaining synthetic task for the construction of
requisite atom framework of this natural product.
a Reagents and conditions: (a) 10 mol % Zn(OTf)2, (S)-1-phenylethy-
lamine, MeCN, 50 °C, 99%; (b) NaH, ClCO2Me, THF, then MeOH-HCl,
75%; (c) DIBALH, toluene, -78 °C, 4 h; (d) MsCl, Et3N, THF, rt, 10 h,
59% for 2 steps; (e) ethanolamine, MeOH, rt, 2 h; (f) MsCl, Et3N, THF, rt,
20 h (g); NaH, THF, rt, 3 h, 46% for 3 steps; (h) phenylhydrazine, AcOH;
(i) NaBH4/EtOH, 51% for 2 steps.
with 5.2% overall yield from readily available dione 3b, which
has unequivocally proven that cascade reactions such as
DMCRC process is highly profitable to short-cut synthesis of
8. Previous chirospecific total syntheses of 84g-i required 13-22
steps.26
(()-Galanthamine and (()-Lycoramine. Amaryllidaceae
alkaloids galanthamine (9) and lycoramine (10) have been
attracting much attention of synthetic and medicinal chemists
because of their biologically significant activities and their
potential diversity in pharmacology. Especially, 9 has been
known as a competitive and reversible inhibitor of acetyl-
colinesterase that enhances cognitive functions of Alzheimer′s
patients. Unique structural features of these alkaloids such as
the tetracyclic ring system and one spiro quaternary carbon
center are posing serious challenges to its practical total
synthesis. The main stream of synthetic endeavors for 9 has
recently shifted from venerable biomimetic oxidative phenolic
couplings5d to nonbiomimetic approaches.5a,c Total synthesis
of 9 or 10 presented here has been planned as a nonbiomimetic
strategy and was commenced with 4g supplied by DMCRC
utilizing commercially available ketone 1g, which is shown in
Scheme 9. DIBALH reduction of 4g afforded hydroxyenone
61, which was treated with TsOH to promote an intramolecular
oxy-Michael addition leading to the bicyclic intermediate 62.
This process played the important role of protecting the cyclic
CdC bond of the enone, which otherwise could be hydrogenated
Thus, as shown in Scheme 10, ester 4f was converted to
amide 67 by ammonolysis in MeOH and followed by a Hoffman
rearrangement using diacetoxyiodobenzene to afford the car-
(25) Spectroscopic data (1H and 13C NMR) of synthesized (+)-aspidosper-
midine were in agreement with those reported in the literature: see Supporting
Information of refs 4g or 4i. Also optical rotation observed ([R]24 +21.1 (c
D
0.1, EtOH) was in agreement with those reported for 8 (lit.4g [R]24 +20.5 (c
D
0.6, CHCl3); lit.4i [R]24 +20.8 (c 0.6, EtOH)).
D
(26) To the best of our knowledge, the shortest route to optically active
aspidospermidine so far was reported by Fuji et al.: 13 steps. Node, M.;
Nagasawa, H.; Fuji, K. J. Org. Chem. 1990, 55, 517–521.
(27) Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron 1974, 30, 2151–
2157.
(28) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011–1013.
(29) Spectroscopic data (1H and 13C NMR) of synthesized racemic galan-
thamine were in agreement with those reported in the literature; see ref 5b.
(30) Gericke, N. P.; Van Wyk, B. E. World Patent 9746234, 1997.
7504 J. Org. Chem. Vol. 73, No. 19, 2008

Domino Double Michael-Claisen Cyclizations
SCHEME 10. Total Synthesis of (()-Mesembrinea
molecular architectures, which at the same time gave us an
opportunity to reconsider not only important basic knowledge
with regard to the thermodynamic stability of ketone-based
enolates but also their reactivity in Michael addition toward R,ꢀ-
unsaturated esters.
4,4-Disubstituted cyclohexane-1,3-diones have significant
power in the total synthesis of complex alkaloids. The 2-cy-
clohexen-1-one derivatives bearing a quaternary C(4)-stereo-
genic center available from 4a-f have proven to be promising
intermediates for synthesizing diverse families of alkaloids of
biological interests. An optical resolution developed for the
enantioselective total synthesis of (+)-aspidpspermidine suggests
the potential wide applicability to other 4,4-disubstituted cy-
clohexane-1,3-dione derivatives. Ready availability of starting
ketones32 and operational simplicity of reactions command the
strategy to other synthesis.
a Reagents and conditions: (a) NH3/MeOH, rt, 5 h, 81%; (b) diacetoxy-
iodobenzene, aqueous KOH/MeOH, 84%; (c) DIBALH/toluene, -78 °C,
4 h; 72%; (d) ethyleneglycol, p-TsOH/THF, rt, 10 h; (e) LiAlH4/THF, rt,
3 h; (f) HCl/THF, rt, 3 h, 80% in 3 steps.
Experimental Section
General Procedure for the Synthesis of 3a-e and 4a-e. To
a solution of 1 (10 mmol) and tert-butyl acrylate (5.9 mL, 40 mmol)
in THF (5 mL) and t-BuOH (5 mL) was added potassium tert-
butoxide (2.2 g, 20 mmol) portionwise at 0 °C. The mixture was
stirred at 0 °C to room temperature for 2-3 h. The reaction was
quenched by the addition of 6 N HCl (3 mL) at 0 °C and extracted
with EtOAc. The combined organic extracts were dried over Na2SO4
and concentrated to give crude 3. To a solution of the crude 3 in
MeOH (15 mL) was added HCl/MeOH solution (30%, 1 mL) at
room temperature. The mixture was stirred at room temperature
for 1-2 h and concentrated to give an oil, which on column
chromatography afforded 4 as an oil.
The following descriptions for small-scale preparation of 4f are
representative.
Methyl 3-[1-(3,4-Dimethoxy)phenyl-4-methoxy-2-oxocyclo-
hex-3-en-1-yl]propanoate (4f). To a solution of 1f (338 mg, 1.74
mmol) in THF (2 mL) was added t-BuOH (2 mL) and tert-butyl
acrylate (0.57 mL, 3.0 equiv), followed by the addition of potassium
tert-butoxide (0.039 g, 1.3 equiv) at 0 °C. The mixture was stirred
at room temperature for 4 h. The reaction was quenched with 6 N
HCl at 0 °C, dried over Na2SO4, and concentrated to give a crude
mixture. To a solution of the crude mixture in MeOH (5 mL) was
added HCl/MeOH solution (30%, 0.5 mL) at 0 °C. The mixture
was stirred at room temperature for 12 h, quenched by the addition
of Et3N at 0 °C, and concentrated by a rotary evaporator to give an
oil, which on column chromatography afforded 4f (436 mg, 73%)
as a yellow oil: 1H NMR δ 2.45-2.02 (m, 8H), 3.59 (s, 3H), 3.61
(s, 3H), 3.84 (s, 3H), 3.85 (s, 3H), 5.37 (s, 1H), 6.81-6.75 (m,
3H); 13C NMR δ 200.4, 176.6, 173.8 148.8, 147.8, 131.7, 118.8,
111.0, 110.6, 102.1, 56.0, 55.9, 55.7, 51.4, 51.2, 34.8, 31.3, 30.1,
26.5; IR (film) 1736, 1612 cm-1; Rf ) 0.33 (hexane/EtOAc ) 1:1);
HRMS (EI), m/z 348.1560 (calcd for C19H24O6 m/z 348.1573). Anal.
Calcd for C19H24O6: C, 65.50; H, 6.94. Found: C, 65.32; H, 6.96.
Total Synthesis of (+)-Aspidospermidine (8). tert-Butyl
3-{(1S)-1-Ethyl-4-[(S)-1-phenylethyl]amino-2-oxocyclohex-3-en-
1-yl}propanoate (56a) and tert-Butyl 3-{(1R)-1-Ethyl-4-[(S)-1-
phenylethyl]amino-2-oxocyclohex-3-en-1-yl}propanoate (56b).
To a solution of 3b (3.11 g 11.5 mol) and (S)-(-)-1-phenylethy-
lamine (1.637 mL, 1.15 mmol, 1.1 equiv) in acetonitrile (50 mL)
was added Zn(OTf)2 (418 mg, 1.15 mmol, 10 mol %) at room
temperature. The mixture was stirred at 60 °C for 3 h and
concentrated to give a yellow oil, which on column chromatography
afforded a mixture of 56a and 56b (4.21 g, 99%) as a colorless
solid. Recrystallization of the mixture from EtOH/hexane (1:3)
mixed solvent (4 °C, 12 h) gave solids (56a rich, 6:1) and filtrates
(56b rich, 6:1). Subsequent preparative HPLC purification of thus-
FIGURE 2. Stability orders determined by DFT calculations for some
simple enolates 23-30 including their conformational isomers (25′ and
30′): total electronic energies together with Gibbs free energy indicated
in parenthesis.
bamate 68 (84% yield). Converting a 1-methoxy-1-cyclohexen-
3-one function in 68 to a cyclohexan-1-one function by
DIBALH reduction triggered intramolecular carbamate Michael
addition to afford the desired mesembrine backbone 69 in 72%
yield. The endgame of this total synthesis was carried out by a
series of synthetic steps involving acetalization (70), reduction
of a carbamate moiety with LiAlH4, and final acetal deprotec-
tion. The process requires 8 steps, giving a 29% overall yield
from commercially available (3,4-dimethoxy)phenylacetone 1f
without any tedious or complicated experimental operations.31
Concluding Remarks. The pivotal Michael-Michael-Claisen
cascade processes developed here provide concise, versatile, and
efficient routes to 4,4-disubstituted cyclohexane-1,3-diones.
Aliphatic or aromatic substituents can be introduced as one
substituent at the stereogenic C(4) center. Thus, the hidden
aspects of reactivity for equilibrated simple ketone-based
enolates have been given privilege for building up complex
(31) Spectroscopic data (1H and 13C NMR) of synthesized racemic mesem-
brine were in agreement with those reported in the literature; see refs 7c and 7h.
(32) Ketones 1a-f are commercial products.
J. Org. Chem. Vol. 73, No. 19, 2008 7505

Ishikawa et al.
obtained two parts was successful in complete separation between
56a and 56b; hexane/EtOAc ) 3/1, pressure ) 10 kg/cm2, 300
mm × 26 mm column packed with 40 g of SiO2 with a particle
size of 40 µm. The combined weight of pure 56a or 56b as a
colorless gum was 2.10 g for each. 56a: 1H NMR δ 0.82 (t, 3H, J
) 7.4 Hz), 1.41 (s, 9H), 1.48 (d, 3H, J ) 6.9 Hz), 1.48-1.90 (m,
6H), 2.10-2.20 (m, 2H), 2.40 (t, 2H, J ) 6.3 Hz), 4.44-4.51 (m,
1H), 4.92 (s, 1H), 5.02-5.20 (br, 1H), 7.20-7.38 (m, 5H); 13C
NMR δ 200.3, 173.5, 161.1, 142.8, 128.8, 127.4, 125.7, 97.9, 80.0,
52.7, 44.9, 30.5, 29.8, 29.4, 28.1, 27.8, 26.0, 23.2, 8.3; IR (film)
2978, 1720, 1581, 1539 cm-1; Rf ) 0.46 (hexane/EtOAc ) 1:1);
HRMS (EI), m/z 371.2444 (Calcd for C23H33NO3 m/z 371.2460).
56b: 1H NMR δ 0.79 (t, 3H, J ) 15.0 Hz), 1.41 (s, 9H), 1.39-1.60
(m, 2H), 1.47 (d, 3H, J ) 7.7 Hz), 1.70-1.90 (m, 4H), 2.14-2.50
(m, 4H), 4.41-4.54 (m, 1H), 4.96-5.00 (br, 2H), 7.20-7.38 (m,
6H); 13C NMR δ 200.2, 173.6, 161.3, 142.8, 128.8, 127.5, 125.7,
97.9, 80.0, 52.8, 44.9, 30.5, 29.7, 29.4, 28.1, 27.6, 26.0, 23.3, 8.3.
IR (film) 2978, 1720, 1581, 1539 cm-1; Rf ) 0.40 (hexane/EtOAc
) 1:1); HRMS (EI), m/z 371.2470 (Calcd for C23H33NO3 m/z
371.2460).
for 20 h, quenched with 2 N KOH (1 mL) at 0 °C, and extracted
with EtOAc. The combined extracts were dried over Na2SO4 and
concentrated to give 59 as a crude oil. To a solution of the crude
59 in THF (5 mL) was added Et3N (0.70 mL, 4.4 mmol, 4 equiv),
followed by the addition of methanesulfonyl chloride (0.23 mL,
3.3 mmol, 3 equiv) at 0 °C. The mixture was stirred at room
temperature for 20 h, quenched by the addition of water, and
extracted with EtOAc. The combined extracts were concentrated
to give an oil, which was dissolved in THF (5 mL), and to the
thus-obtained solution was added NaH (60% in oil, 132 mg, 3.3
mmol, 3 equiv) at 0 °C. The mixture was stirred at room temperature
for 3 h, quenched with NH4Cl at 0 °C, and concentrated to give an
oil, which on column chromatography afforded 60 as a colorless
oil (98 mg, 46%): [R]29D -23.1 (c 0.71, CHCl3) {lit.24 [R]29D -24.4
(c 0.88, CHCl3)}; 1H NMR δ 0.93 (t, 3H, J ) 7.6 Hz), 1.03-1.16
(m, 1H), 1.24-1.38 (m, 1H), 1.44-1.57 (m, 2H), 1.57-1.98 (m,
7H), 2.19-2.48 (m, 4H), 2.67 (ddd, 1H, J ) 2.1, 5.1, 8.7 Hz),
2.97-3.06 (m, 2H); 13C NMR δ 211.1, 73.4, 53.1, 52.8, 48.0, 36.7,
34.6, 32.7, 30.0, 26.0, 21.19, 21.15, 7.0 (NMR data are fully
consistent with those reported in the literature just mentioned above
for the optical rotation); IR (film) 2935, 2725, 1709 cm-1; Rf )
0.38 (hexane/EtOAc ) 3:1); HRMS (EI), m/z 207.1619 (calcd for
C13H21NO m/z 207.1623). Anal. Calcd for C13H21NO: C, 75.32;
H, 10.21; N, 6.76. Found: C, 75.18; H, 10.16; N, 6.80.
Methyl (+)-3-[(1S)-1-Ethyl-4-methoxy-2-oxocyclohex-3-en-
1-yl]propanoate (57). To a solution of 56a (1.55 g, 4.17 mmol) in
CH2Cl2 (10 mL) was added NaH (501 mg, 12.5 mmol, 3 equiv) at
0 °C, and the resulting mixture was stirred at 0 °C for 20 min. To
this mixture was added ethyl chloroformate (1.20 mL, 12.6 mmol,
3 equiv) at 0 °C, and the resulting mixture was stirred at room
temperature for 22 h. The reaction was quenched by the addition
of H2O and extracted with EtOAc. The combined extracts were
dried over Na2SO4 and concentrated to give a crude oil. To a
solution of the crude oil in MeOH (15 mL) was added HCl/MeOH
solution (30%, 1 mL) at room temperature. The mixture was stirred
at 60 °C for 16 h, quenched by the addition of saturated aqueous
solution of NaHCO3 (5 mL) at 0 °C, and extracted with EtOAc.
The combined extracts were dried over Na2SO4 and concentrated
to give a crude oil, which on column chromatography afforded 57
(+)-Aspidospermidine (8). To a solution of 60 (130 mg, 0.63
mmol) in AcOH (6 mL) was added phenylhydrazine (0.093 mL,
0.95 mmol, 1.5 equiv) at room temperature. The mixture was stirred
at 95 °C for 9 h, quenched by the addition of 15% aqueous NaOH
solution, and extracted with CH2Cl2. The combined extracts were
dried over Na2SO4, concentrated, and passed through a short column
of Al2O3 using AcOEt to give dehydroaspidospermidine as a yellow
oil (127 mg, 71%). To a solution of dehydroaspidospermidine (70
mg 0.25 mmol) in MeOH (3 mL) was added NaBH4 (47 mg 1.25
mmol, 5 equiv) at 0 °C, and the mixture was stirred at 0 °C to
room temperature for 2 h, quenched with water, and extracted with
EtOAc. The combined extracts were dried over Na2SO4 and
concentrated to obtain an oil, which was purified by column
as a pale yellow oil (753 mg, 75%): [R]21 +19.7 (c 1.4, EtOH)
D
[lit.4i [R]21D +19.4 (c 1.4, EtOH)]; 1H NMR δ 0.83 (t, 3H, J ) 7.5
Hz), 1.54 (dq, 2H, J ) 7.5, 12.1 Hz), 1.72-1.96 (m, 4H), 2.27 (dt,
2H, J ) 6.1, 9.8 Hz), 2.43 (t, 2H, J ) 7.6 Hz), 3.64 (s, 3H), 3.66
(s, 3H), 5.25 (s, 1H); 13C NMR δ 202.5, 176.3, 174.3, 101.4, 55.6,
51.6, 45.9, 29.1, 29.0, 28.9, 27.0, 25.4, 8.1 (NMR data are fully
consistent with those reported in the literature just mentioned
above); IR (film) 2943, 1736, 1651, 1612 cm-1; Rf ) 0.57 (hexane/
EtOAc ) 1:1); HRMS (EI), m/z 240.1368 (calcd for C13H20O4 m/z
240.1362). Anal. Calcd for C13H20O4: C, 64.98; H, 8.39. Found:
C, 65.11; H, 8.37.
chromatography to furnish (+)-8 (51 mg, 72%); [R]29 +21.1 (c
D
0.50, EtOH) {lit.4g [R]24D +20.5 (c 0.6, CHCl3); lit.4i [R]20D +20.8
1
(c 0.6, EtOH)}; H NMR δ 0.63 (t, 3H, J ) 7.7 Hz), 0.79-0.94
(m, 1H), 1.01-1.20 (m, 2H), 1.23-1.58 (m, 4H), 1.58-1.82 (m,
3H), 1.87-2.03 (m, 2H), 2.17-2.38 (m, 3H), 2.99-3.20 (m, 3H),
3.52 (dd, 1H, J ) 6.4, 11.2 Hz), 6.62 (d, 1H, J ) 7.7 Hz), 6.74 (t,
1H, J ) 7.3 Hz), 7.02 (dt, 1H, J ) 7.3, 7.7 Hz), 7.08 (d, 1H, J )
7.3 Hz); 13C NMR δ 149.4, 135.6, 127.0, 122.7, 118.9, 110.3, 71.2,
65.5, 53.8, 53.3, 52.9, 38.7, 35.6, 34.4, 29.9, 28.0, 23.0, 21.7, 6.7
(NMR data are also fully consistent with those reported in the
literature4g,i); IR (film) 3363, 2931, 2785, 1604 cm-1; Rf ) 0.23
(hexane/EtOAc ) 1:1); HRMS (EI), m/z 282.2093 (calcd for
C19H26N2 m/z 282.2096).
3-[(1R)-1-Ethyl-4-oxocyclohex-2-en-1-yl]propyl methane-
sulfonate (58). To a solution of 57 (447 mg, 1.86 mmol) in 22 mL
of toluene was added DIBALH in toluene (11.3 mL, 11.9 mmol,
6.0 equiv) at -78 °C. The mixture was stirred at -78 °C to room
temperature for 18 h. The reaction was quenched by the addition
of water at 0 °C, filtered through a celite pad, and concentrated to
give a crude oil. To a solution of the crude oil in THF (20 mL)
was added Et3N (0.59 mL, 3.7 mmol, 2.0 equiv), followed by the
addition of methanesulfonyl chloride (0.190 mL, 2.79 mmol, 1.5
equiv) at 0 °C. The mixture was stirred at 0 °C for 30 min and
concentrated to give an oil, which on column chromatography
afforded 58 as a brown oil (285 mg, 59%): 1H NMR δ 0.88 (t, 3H,
J ) 7.7 Hz), 1.42-1.60 (m, 4H), 1.68-1.80 (m, 2H), 1.81-1.90
(m, 2H), 2.39-2.44 (m, 1H), 2.99 (s, 3H), 4.21 (t, 2H, J ) 6.3
Hz), 5.92 (d, 1H, J ) 10.2 Hz), 6.65 (d, 1H, J ) 10.2); 13C NMR
δ 199.2, 157.5, 128.5, 69.9, 37.8, 37.3, 33.7, 32.9, 30.3, 30.1, 24.0,
8.2; IR (film) 2982, 1674, 1350 cm-1; Rf ) 0.40 (hexane/EtOAc
) 1:1); HRMS (EI), m/z 260.1079 (calcd for C12H20O4S m/z
260.1082).
Total Synthesis of (()-Galanthamine [(()-9]. 4a-(2-Benzy-
loxy-3-methoxy)phenyloctahydrochromen-7-one (62). To a solu-
tion of 4g (337 mg, 0.79 mmol) in toluene (5 mL) was added
DIBALH in toluene (4.0 mL, 4.0 mmol) at -78 °C. The mixture
was stirred at -78 °C for 4 h. The reaction was quenched by the
addition of water at 0 °C, filtered through a celite pad, and
concentrated to give an oil, which was briefly purified by passing
through a short silica gel column to afford crude 4,4-disubstituted
cyclohex-2-en-1-one (61). To a solution of 61 in THF (5 mL) was
added TsOH ·H2O (30 mg, 0.16 mmol) at 0 °C, and the mixture
was stirred at room temperature for 12 h, quenched with saturated
aqueous NaHCO3 at 0 °C, and extracted with EtOAc. The combined
organic extracts were dried over Na2SO4 and concentrated to give
an oil, which was purified by column chromatography to obtain
62 as a yellow oil (198 mg, 68%): 1H NMR δ 1.25-1.35 (m, 1H),
1.73-1.86 (m, 1H), 1.87-2.00 (m, 1H), 2.00-2.19 (m, 1H),
2.25-2.60 (m, 5H), 2.84 (td, 1H, J ) 14.0, 4.7 Hz) 3.19 (br t, 1H,
J ) 11.3 Hz), 3.90 (s, 3H), 3.92-3.99 (m, 1H), 4.92 (br s, 1H),
5.03 and 5.22 (ABq, 2H, J ) 11.3 Hz), 6.93 (dd, 1H, J ) 8.2, 2.2
(6aR,9aS,9bS)-6a-Ethyldecahydropropyrrolo[3,2,1-ij]quino-
lin-9-one (60). To a solution of 58 (267 mg, 1.02 mmol) in EtOH
(10 mL) was added 2-aminoethanol (0.12 mL, 2.1 mmol, 2 equiv)
at room temperature. The mixture was stirred at room temperature
7506 J. Org. Chem. Vol. 73, No. 19, 2008

Domino Double Michael-Claisen Cyclizations
Hz), 7.06 (dd, 1H, J ) 7.4, 2.2 Hz), 7.11 (t, 1H, J ) 8.2, 7.4 Hz),
7.32-7.53 (m, 5H); 13C NMR δ 209.9, 153.6, 147.2, 137.4, 137.0,
128.4 (2C), 127.9, 124.0, 119.5, 111.2, 79.2, 74.5, 68.4, 55.7, 44.9,
42.1, 38.2, 34.9, 26.8, 21.9; IR (film) 2956, 1720, 1577, 1462,
1263.1 cm-1; Rf ) 0.40 (hexane/EtOAc ) 2:1); HRMS (EI), m/z
366.1829 (calcd for C23H26O4 m/z 366.1831). Anal. Calcd for
C23H26O4: C, 75.38; H, 7.15. Found: C, 75.09; H, 7.17.
6.72 (d, 1H, J ) 7.4 Hz), 6.76 (d, 1H, J ) 7.1 Hz), 6.88 (dd, 1H,
J ) 7.4, 7.1 Hz); 13C NMR d 209.0, 178.7, 147.6, 144.4, 131.2,
122.2, 115.2, 111.8, 84.7, 55.8, 47.8, 41.6, 35.7, 33.9, 32.8, 29.5;
IR (KBr disk) 3580, 2870, 1720, 1619, 1492, 1282 cm-1; Rf ) 0.3
(EtOAc).
To a solution of the carboxylic acid (350 mg, 1.21 mmol) in
toluene (5 mL) were added diphenylphosphoryl azide (0.3 mL, 1.36
mmol) and Et3N (0.84 mL, 6.03 mmol) at room temperature, and
the resulting mixture was heated under reflux for 30 min, when
MeOH (5 mL) was added to the mixture. The mixture was stirred
at that temperature for 12 h, quenched with saturated aqueous
NaHCO3 at 0 °C, and extracted with EtOAc. The combined extracts
were dried over Na2SO4 and concentrated to give an oil, which
was purified by column chromatography to afford 65 as a yellow
oil (308 mg, 80%): 1H NMR δ 1.80-2.10 (m, 5H), 2.15-2.24 (m,
1H), 2.63 (dd, 1H, J ) 17.0, 3.6 Hz), 2.95 (dd, 1H, J ) 17.0, 3.3
Hz), 2.93-3.10 (m, 1H), 3.10-3.35 (m, 1H), 3.56 (s, 3H), 3.78 (s,
3H), 4.90-5.05 (br, 2H), 6.74 (d, 1H, J ) 7.7 Hz), 6.76 (d, 1H, J
) 7.7 Hz), 6.85 (t, 1H, J ) 7.7 Hz); 13CNMR δ 208.8, 156.8,
147.2, 144.2, 131.5, 121.9, 115.2, 111.5, 84.9, 55.6, 51.8, 47.0,
41.5, 39.2, 36.9, 35.5, 32.5; IR (film) 3361, 1716, 1619, 1531, 1268
cm-1; Rf ) 0.5 (EtOAc); HRMS (EI), m/z 319.1427 (calcd for
C17H21NO5 m/z 319.1420).
1,2-Dihydro-(N-methoxycarbonyl)narwedine (66). To a solu-
tion of 65 (109 mg, 0.34 mmol) in 1,2-dichloroethane (10 mL)
were added p-formaldehyde (50 mg, 1.7 mmol) and TFA (0.27 mL,
3.5 mmol) at room temperature. The mixture was stirred at 50 °C
for 8 h, quenched with saturated aqueous NaHCO3 at 0 °C, and
extracted with EtOAc. The combined extracts was dried over
Na2SO4 and concentrated to give an oil, which on column
chromatography afforded 66 as a colorless oil (113 mg, 100%):
1H NMR δ 1.74-1.90 (m, 2H), 1.90-2.12 (m, 2H), 2.23-2.36
(m, 2H), 2.61 (dd, 1H, J ) 17.6, 2.8 Hz), 2.96 (dd, 1H, J ) 17.6,
3.3 Hz), 3.16-3.36 (br, 1H), 3.61 (s, 3H), 3.79 (s, 3H), 4.00-4.44
(m, 2H), 4.69 (t, 1H, J ) 3.3 Hz), 4.65-4.93 (br, 1H), 6.63-6.71
(m, 2H); 13C NMR δ 207.9, 155.9, 147.5, 144.0, 131.3, 129.2,
121.2, 111.6, 88.0, 56.0, 52.5, 50.7, 47.6, 45.8, 39.9, 39.0, 35.4,
30.0; IR (neat) 2959, 1722, 1699, 1625, 1263 cm-1; Rf ) 0.4
(EtOAc); HRMS (EI), m/z 331.1415 (calcd for C18H21NO5 m/z
331.1420). Anal. Calcd for C18H21NO5: C, 65.24; H, 6.39; N, 4.23.
Found: C, 65.19; H, 6.43; N, 4.20.
4a -(2 -Hydroxy -3-methoxy)phenyloctahydrochromen -7-
one (63). A suspension of Pd/carbon (5%, 41 mg) in MeOH (1.5
mL) was stirred at room temperature for 2 h under H2 atmosphere.
To this mixture was added a solution of 62 (110 mg, 0.30 mmol)
in MeOH (1.5 mL) at room temperature, and the resulting mixture
was stirred at room temperature for 4 h under H2, filtered through
a celite pad, and concentrated to obtain a crude solid, which was
purified by column chromatography to afford 63 as a colorless
1
amorphous solid (83 mg, 100%): H NMR δ 1.37-1.47 (m, 1H),
1.77-1.88 (m, 1H), 1.90-2.08 (m, 1H), 2.19 (dt, 1H, J ) 13.1,
4.7 Hz), 2.30-2.44 (m, 4H) 2.50 (dt, 1H, J ) 15.1, 3.3 Hz)
2.80-2.93 (m, 1H) 3.59 (ddd, 1H, J ) 11.3, 3.0, 2.7 Hz) 4.07
(ddt, 1H, J ) 11.3, 5.2, 1.4 Hz) 5.03 (brs, 1H), 6.34 (s, 1H), 6.82
(dd, 1H, J ) 1.7, 8.0 Hz), 6.87 (t, 1H, J ) 8.0 Hz), 7.00 (dd, 1H,
J ) 8.0, 1.7 Hz); 13C NMR δ 210.3, 147.1, 144.3, 129.1, 119.7
(2C), 108.9, 79.1, 68.8, 56.1, 45.0, 41.6, 38.2, 33.3, 26.5, 22.0; IR
(film) 3338, 2956, 1713, 1585, 1255 cm-1; Rf ) 0.40 (hexane/
EtOAc ) 2:1); HRMS (EI), m/z 276.1355 (calcd for C16H20O4 m/z
276.1362).
9b-(3-Hydroxypropyl)-6-methoxy-1,4,4a,9b-tetrahydro-2H-
dibenzofuran-3-one (64). To a solution of 63 (627 mg, 2.27 mmol)
in THF (10 mL) was added MgCl2 (1.03 g, 5.67 mmol) at room
temperature, and the resulting mixture was stirred at 50 °C for 2 d.
The reaction was quenched by the addition of H2O at 0 °C and
extracted with EtOAc. The combined extracts were dried over
Na2SO4 and concentrated to give an oil, which on column
chromatography afforded 64 as a colorless oil (535 mg, 85%): 1H
NMR δ 1.35-1.50 (m, 1H), 1.58-1.73 (m, 1H), 1.75-2.05 (m,
5H), 2.24-2.29 (m, 1H), 2.67 (dd, 1H, J ) 17.3, 3.6 Hz), 2.96
(dd, 1H, J ) 17.3, 3.0 Hz), 3.64 (t, 1H, J ) 6.3, 6.1 Hz), 3.85 (s,
3 H), 4.95 (t, 1H, J ) 3.3, 3.0 Hz), 6.72 (d, 1H, J ) 7.4 Hz), 6.76
(d, 1H, J ) 7.1 Hz), 6.88 (t, 1H, J ) 7.4, 7.1 Hz); 13C NMR δ
209.3, 147.7, 144.3, 132.7, 121.9, 115.4, 111.4, 85.2, 62.7, 55.8,
48.0, 41.8 (2C), 35.9, 32.8, 27.5; IR (KBr disk) 3423, 2941, 1716,
1619, 1459, 1284 cm-1; Rf ) 0.10 (hexane/EtOAc ) 1:1); HRMS
(EI), m/z 276.1366 (calcd for C16H20O4 m/z 276.1362). Anal. Calcd
for C16H20O4: C, 69.54; H, 7.30. Found: C, 69.34; H, 7.27.
1,2,4a,9b-Tetrahydro-6-methoxy-9b-[3-(N-methoxycarbonyl-
amino)ethyldibenzofuran-3-one (65). To a solution of 64 (351
mg, 1.27 mmol) in DMSO (3 mL) and CH2Cl2 (3 mL) were added
SO3 ·Py (810 mg, 5.09 mmol) and Et3N (1.30 mL, 9.33 mmol) at
0 °C. The mixture was stirred at room temperature for 5 h, quenched
by the addition of saturated aqueous NH4Cl at 0 °C, and extracted
with CH2Cl2. The combined extracts were dried over Na2SO4 and
concentrated to give an oil, which, on column chromatography,
(()-Galanthamine [(()-9]. To a solution of 66 (238 mg, 0.71
mmol) in CH2Cl2 (4 mL) were added Et3N (0.30 mL, 2.15 mmol)
and tert-butyldimethylsilyl triflate (0.33 mL, 1.44 mmol) at 0 °C,
and the resulting mixture was stirred at room temperature for 3 h,
quenched with saturated aqueous NH4Cl at 0 °C, and extracted with
EtOAc. The combined extracts were dried over Na2SO4 and
concentrated to give an oil, which on column chromatography
afforded an enol silyl ether as a yellow oil (288 mg, 100%). To a
solution of this enol silyl ether (288 mg, 0.71 mmol) in CH3CN (4
mL) were added Pd(OAc)2 (240 mg, 1.07 mmol) and p-benzo-
quinone (116 mg, 1.07 mmol) at 0 °C, and the resulting mixture
was stirred at 50 °C for 2 d and filtered through a celite pad to
give an oil, which was purified by column chromatography to afford
1
afforded an aldehyde as a yellow oil (279 mg, 80%): H NMR δ
1.90-2.05 (m, 4H), 2.05-2.42 (m, 2H), 2.4-2.59 (m, 1H), 2.67
(dd, 1H, J ) 17.0, 3.6 Hz), 2.94 (dd, 1H, J ) 17.0, 3.3 Hz), 3.86
(s, 3H), 4.88 (t, 1H, J ) 3.6 Hz), 6.68 (d, 1H, J ) 7.7 Hz), 6.78
(d, 1H, J ) 8.0 Hz), 6.90 (t, 1H, J ) 8.0, 7.7 Hz), 9.73 (s, 1H);
13C NMR δ 208.6, 200.8, 147.6, 144.4, 131.3, 122.2, 115.1, 111.7,
84.8, 55.8, 47.7, 41.6, 39.3, 35.7, 33.0, 30.8; IR (film) 2937, 1720,
1618, 1492.6, 1284 cm-1; Rf ) 0.4 (hexane/EtOAc ) 1:1).
To a solution of the aldehyde (285 mg, 1.03 mmol) in tert-butanol
(4 mL) and H2O (1 mL) were added 2-methyl-2-butene (1.05 mL,
2.10 mmol), NaClO2 (280 mg, 3.10 mmol), and NaH2PO4 (250
mg, 1.60 mmol) at 0 °C. The mixture was stirred at room
temperature for 5 h and concentrated to obtain a yellow oil, which
was purified by column chromatography to afford a carboxylic acid
1
an enone (155 mg, 66%) as a yellow oil: H NMR δ 1.98-2.20
(m, 2H), 2.61 (dd, 1H, J ) 17.6, 2.8 Hz), 2.96 (dd, 1H, J ) 17.6,
2.2 Hz), 3.26-3.48 (m, 1H), 3.67 (s, 3H), 3.82 (s, 3H), 4.10-4.53
(m, 2H), 4.66-4.71 (br, 1H), 4.75-5.02 (m, 1H), 6.03 (d, 1H, J )
10.4 Hz), 6.69-6.75 (m, 2H); 13CNMR δ 193.9, 155.8, 147.4,
144.1, 143.4, 129.0, 127.2, 121.4, 120.8, 111.5, 87.6, 56.2, 52.7,
51.9, 51.6, 49.2, 46.0, 37.2; Rf ) 0.5 (EtOAc).
To a solution of the enone (46 mg, 0.14 mmol) in THF (3 mL)
was added L-Selectride (1 M in THF, 0.16 mL, 0.16 mmol) at -78
°C, and the resulting mixture was stirred at -78 °C to room
temperature for 5 h and concentrated to give a solid, which was
purified by column chromatography to obtain a colorless solid (46
mg, 99%). To a solution of the solid (24 mg, 0.07 mmol) in THF
(1 mL) was added LiAlH4 (10 mg, 0.26 mmol) at 0 °C, and the
mixture was stirred at room temperature for 2 d and filtered through
1
(276 mg, 91%) as a colorless crystals: H NMR δ 1.92-2.09 (m,
3 H), 2.16-2.46 (m, 5 H), 2.66 (dd, 1H, J ) 17.0, 3.3 Hz), 2.94
(dd, 1H, J ) 17.0, 3.0 Hz), 3.84 (s, 3H), 4.90 (t, 1H, J ) 3.3 Hz),
J. Org. Chem. Vol. 73, No. 19, 2008 7507

Ishikawa et al.
a celite pad to give a colorless solid, which on column chroma-
tography afforded (()-9 as a colorless solid (10 mg, 48%). 1H NMR
δ 1.60 (dd, 1H, J ) 13.8, 1.7 Hz), 2.01 (ddd, 1H, J ) 15.7, 5.0,
2.5 Hz), 2.11 (dd, 1H, J ) 13.8, 3.3 Hz), 2.21-2.39 (br, 1H), 2.42
(s, 3H), 2.69 (ddd, 1H, J ) 15.7, 3.3, 1.7 Hz), 3.08 (brd, 1H, J )
14.0 Hz), 3.28 (d, J ) 14.0 Hz, 1H), 3.72 (d, J ) 15.4 Hz, 1H),
3.83 (s, 3H), 4.12 (brd, 1H, J ) 15.4 Hz), 4.12-4.18 (m, 1H),
4.60-4.62 (br, 1H), 6.00 (d, 1H, J ) 10.4 Hz), 6.01 (dd, J ) 10.4,
1.2 Hz), 6.63 (d, 1H, J ) 8.2 Hz), 6.67 (d, 1H, J ) 8.2 Hz); 13C
NMR δ 145.9, 144.3 133.0, 127.8, 126.9, 126.7, 122.2, 111.4, 88.7,
62.1, 60.5, 56.0, 53.8, 48.2, 41.9, 33.7, 30.0 (NMR data are
consistent with those reported in the literature5b); IR (film) 2978,
1610, 1271 cm-1; Rf ) 0.2 (EtOAc); HRMS (EI), m/z 287.1526
(calcd for C17H21NO3 m/z 287.1521).
Acknowledgment. This paper is dedicated to the late Mr.
Satoshi Uchida who made major contributions to the synthesis
of (()-mesembrine and also to the late Professor Yoshihiko
Ito. This work was supported by a Grant-in-Aid for Scientific
Research on Priority Areas “Advanced Molecular Transforma-
tion of Carbon Resources” from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
Supporting Information Available: Representative experi-
mental procedures, physical properties and copies of NMR
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
Total Synthesis of (()-Mesembrine [(()-11]. See Supporting
Information.
JO801316S
7508 J. Org. Chem. Vol. 73, No. 19, 2008