Macrocyclic lactam synthesis via a ring expansion reaction: Construction of the cripowellin skeleton

Article abstract of DOI:10.1021/ol047520+

(Chemical Equation Presented) The cripowellin ring skeleton, a macrocyclic [2.3.5]-bicyclic ketolactam, was smoothly generated via construction of a spiro(benzazepin-cyclohexane-1,3-dione) employing oxidative cyclization as a key step and a subsequent ring expansion reaction.

Full text of DOI:10.1021/ol047520+

ORGANIC
LETTERS
2005
Vol. 7, No. 6
1031-1034
Macrocyclic Lactam Synthesis via a
Ring Expansion Reaction: Construction
of the Cripowellin Skeleton
Bongjin Moon,*,†,‡ Sangbae Han,† Yeojin Yoon,† and Hyejin Kwon†
Department of Chemistry, Sogang UniVersity, Seoul 121-742, Korea, and Center for
BioactiVe Molecular Hybrids, Yonsei UniVersity, Seoul 120-749, Korea
bjmoon@ccs.sogang.ac.kr
Received December 3, 2004
ABSTRACT
The cripowellin ring skeleton, a macrocyclic [2.3.5]-bicyclic ketolactam, was smoothly generated via construction of a spiro(benzazepin-
cyclohexane-1,3-dione) employing oxidative cyclization as a key step and a subsequent ring expansion reaction.
Cripowellins A (1) and B (2) (Figure 1) are members of the
Amaryllidaceae alkaloids and were isolated from the bulbs
of Crinum powellii by Velten and colleagues in 1997.1,2 Their
structures were determined unambiguously by extensive
spectroscopic methods including X-ray crystallographic
analysis of cripowellin A diacetate (C14 and C6′ acetates).
activity, the 10-membered fused lactam skeleton of the
cripowellins appears to be unique to the Amaryllidaceae
alkaloid series.
Careful structural examination shows that the main
skeleton of cripowellin is closely related to other Amaryl-
lidaceae alkaloids such as mesembrine (3), crinane (4,
unnatural product), and crinine (5) (Figure 2). Oxidative
cleavage of the C2-C3 bond of the tetrahydroisoquinoline
moiety in the crinane skeleton reveals a structure that is
equivalent to the cripowellin skeleton. From this point of
view, it would also be interesting to determine if cripowellin
is biosynthetically derived from other Amaryllidaceae alka-
loids such as those of the crinane family.
Our interest in a total synthesis of cripowellin led us to
envision that the skeleton could be constructed via a ring
expansion reaction of spiro(benzazepine-cyclohexane-1,3-
dione) intermediate 6, as shown in Figure 3. Intramolecular
attack of the benzazepinylamine to the more electron-
deficient ketone (the R-hydroxy ketone) in 6 should promote
Figure 1. Structures of cripowellins A (1) and B (2).
The absolute stereochemistry was postulated on the assump-
tion that the carbohydrate moiety is biogenetically derived
from â-D-glucose.1 In addition to their interesting insecticidal
(1) Velten, R.; Erdelen, C.; Gehling, M.; Go¨hrt, A.; Gondol, D.; Lenz,
J.; Lockhoff, O.; Wachendorff, U.; Wendisch, D. Tetrahedron Lett. 1998,
39, 1737.
(2) Gehling, M.; Goehrt, A.; Gondol, D.; Lenz, J.; Lockhoff, O.;
Moeschler, H.; Velten, R.; Wendisch, D.; Andersch, W.; Erdelen, C.; Harder,
A.; Mencke, N.; Turberg, A.; Wachendorff-Neumann, U. German Patent
19610279, 1997.
† Sogang University.
‡ Yonsei University.
10.1021/ol047520+ CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/16/2005

Figure 4. Ban’s macrolactam syntheses via ring expansion.3
Because, to our knowledge, no similar reaction employing
a cyclic amino group and a cyclohexane-1,3-dione system
has been explored so far, we thought it would be interesting
to see whether the key reaction shown in Figure 3 could be
achieved.
To prepare key substrate 8, we planned to use an
intramolecular oxidative coupling reaction between an aryl
moiety and a cyclohexane-1,3-dione, a reaction that has been
extensively studied by the Kita group.5 Kita reported that
five- and six-membered spirobenzannulated compounds
could be obtained in reasonable yields using phenyl iodide
bis(trifluoroacetate) (PIFA) as an oxidant. Although seven-
membered ring formation was not reported in their study,
we hoped that such a cyclization would occur under similar
conditions.
Figure 2. Comparison of the cripowellin skeleton with other
Amaryllidaceae alkaloids.
a concomitant ring expansion to the keto-macrolactam ring
7. We hoped that the formation of the thermodynamically
more stable amide functionality would provide a driving
force for the formation of the fairly strained macrolactam
skeleton of 7.
Synthesis of the desired substrate 10 is illustrated in
Scheme 1. Alkylation of N-piperonyl-N-tosyl amide (15) with
excess 1,2-dibromoethane in the presence of K2CO3 in
DMSO yielded N-bromoethyl-N-piperonyl-N-tosylamide (16)
in 91% yield. Because it is known that direct C2-alkylation
of cyclohexane-1,3-dione with an alkyl halide is sluggish
due to strong competition with O-alkylation, we chose Piers’
protocol,6 which employs alkylation of 1,5-dimethoxy-1,4-
cyclohexadiene (17) and acid-catalyzed hydrolysis of the
resulting product 18 to afford the desired substrate 10.
Scheme 1. Synthesis of 10
Figure 3. Synthetic plan for the cripowellin skeleton.
In this paper, we describe synthetic efforts toward spiro-
(benzazepine-cyclohexane-1,3-dione) intermediate 8 from
N-piperonyl-N-[2-(2,6-dioxocyclohexyl)ethyl]-toluenesulfo-
nyl amide (10) or N-piperonyl-N-[2-(6-hydroxy-2-methoxy-
phenyl)-ethyl]toluenesulfonyl amide (11) and a model study
of the ring expansion reaction with an N-toluenesulfonyl-
protected version of dideoxy derivative 8 (compound 19).
A literature search led to our discovery of various ring
expansion reactions of 2-aminoethyl-substituted cyclopen-
tane-1,3-diones that were studied by Ban and colleagues.3
As shown in Figure 4, medium-sized ketolactams 12-14
could be obtained through controlled crisscross annulation,
involving an acyclic amino alkyl group in the substrates.4
With compound 10 in hand, oxidative cyclization using
various oxidants was attempted (Scheme 2). Unfortunately,
(4) Ohnuma, T.; Tabe, M.; Shiiya, K.; Ban, Y. Tetrahedron Lett. 1983,
24, 4249.
(5) Arisawa, M.; Ramesh, N. G.; Nakajima, M.; Tohma, H.; Kita, Y. J.
Org. Chem. 2001, 66, 59.
(6) Piers, E.; Grierson, J. R. J. Org. Chem. 1977, 42, 3755.
(3) Ohnuma, T.; Nagasaki, M.; Tabe, M.; Ban, Y. Tetrahedron Lett. 1983,
24, 4253.
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Org. Lett., Vol. 7, No. 6, 2005

Scheme 2. Various Cyclization Attempts of 10
Scheme 3. Synthesis of 11
no desired cyclized product 19 was observed under the
typical reaction conditions (PIFA in CF3CH2OH) developed
by Kita and colleagues,5 and only unidentifiable, complex
mixtures were obtained. Trials at highly dilute conditions
(∼0.001 M) did not result in any improvement. Changing
the N-protecting group from p-toluenesulfonyl to trifluoro-
acetate also did not provide any cyclization product under
the same conditions. Changing the oxidant to PIDA (phenyl
iodide diacetate) in methylene chloride showed no improve-
ment. When the substrate was subjected to a one-electron
oxidant, Mn(OAc)3, the reaction also yielded a complex
mixture where piperonal was identified as the major com-
ponent. In this case, it seems that the generated cyclohexane-
1,3-dione radical abstracted the benzylic hydrogen via 1,5-
hydrogen abstraction followed by further oxidation of the
resulting benzylic radical by Mn(OAc)3 to the corresponding
tosyl iminium ion, which was transformed to piperonal upon
hydrolytic workup. A similar 1,5-hydrogen abstraction under
Mn(OAc)3 conditions has been described in the literature.7
Because the oxidative cyclization approach using the
cyclohexane-1,3-dione substrate was problematic, we shifted
our strategy toward using 2-alkyl-3-methoxy phenol 11. Kita
and colleagues have reported an intramolecular phenolic
coupling reaction using a hypervalent iodine(III) reagent and
showed that the reaction is a powerful tool in the syntheses
of many Amaryllidaceae alkaloids.8 Compound 11 was
prepared in a straightforward manner as shown in Scheme
3. Methoxymethyl (MOM)-directed lithiation of 20 followed
by alkylation with allyl bromide and subsequent ozonolysis
provided aldehyde 21 in 63% yield over two steps.9 Reduc-
tive amination of aldehyde 21 with piperonylamine provided
the corresponding secondary amine 22 in 73% yield. After
protecting the amine with a p-toluenesulfonyl group (TsCl,
TEA, 67%), the MOM group of the resulting tosyl amide
23 was removed by treatment with a catalytic amount of
p-toluenesulfonic acid in refluxing 2-propanol10 to give the
desired phenol substrate 11.
In contrast to the use of cyclohexane-1,3-dione 10, when
phenol substrate 11 was treated with PIFA in CF3CH2OH at
room temperature, the oxidatively cyclized spirobenzazepin
product 24 was obtained in a moderate yield (58%) (Scheme
4). Having key intermediate 24 in our hands, we next
Scheme 4. Cyclization of 24
investigated the functionalization of the 5-methoxycyclo-
hexadienone moiety to install the C-14 and C-15 oxidation
state of cripowellin at this early stage. Unfortunately, various
conditions, including hydrolysis (HCl/H2O), epoxidation
(tBuOOH/Triton B11 or dimethyldioxirane12), and reduction
(H2, PtO2), failed to give any identifiable products. In most
cases, the dienone decomposed under these conditions. After
(7) Citterio, A.; Fancelli, D.; Finzi, C.; Pesce, L. J. Org. Chem. 1989,
54, 2713.
(8) (a) Kita, Y.; Takada, T.; Gyoten, M.; Tohma, H.; Zenk, M. H.;
Eichhorn, J. J. Org. Chem. 1996, 61, 5857. (b) Kita, Y.; Arisawa, M.;
Gyoten, M.; Nakajima, M.; Hamada, R.; Tohma, H.; Takada, T. J. Org.
Chem. 1998, 63, 6625.
(9) (a) Simas, A. B. C.; Coelho, A.; Costa, P. R. R. Synthesis 1999,
1017. (b) Pocci, M.; Bertini, V.; Lucchesini, F.; De Munno, A.; Picci, N.;
Iemma, F.; Alfei, S. Tetrahedron Lett. 2001, 42, 1351.
(10) Miyashita, N.; Yoshikoshi, A.; Grieco, P. A. J. Org. Chem. 1977,
42, 3772.
(11) (a) Yang, N. C.; Finnegan, R. A. J. Am. Chem. Soc. 1958, 80, 5845.
(b) Payne, G. C. J. Org. Chem. 1960, 25, 275.
(12) (a) Adam, W.; Bialas, J.; Hadjiarapoglou, L. Chem. Ber. 1991, 124,
2377. (b) Murray, R. W.; Singh, M. Org. Synth. 1997, 74, 91.
Org. Lett., Vol. 7, No. 6, 2005
1033

extensive screening of various reagents, only Stryker’s
reagent [(Ph3PCuH)6]13 was found to successfully mediate a
clean reaction to provide the reduced product 25 in good
yield (81%). Fortunately, 1,4-conjugate reduction was fa-
vored over 1,6-conjugate reduction in this case. In contrast
to cyclohexadienone 24, hydrolysis of methyl enol ether 25
proceeded cleanly to give cyclohexanedione 19 in 72% yield.
Finally, we treated spiro(benzazepin-cyclohexanedione)
N-tosyl amide 19 with sodium naphthalenide solution14 to
remove the toluenesulfonyl group, expecting either the amine
form of 26 or hemiaminal form of 27 as the product. The
starting material disappeared in 10 min and formed a single
new product, as judged by TLC analysis. In contrast to the
plane-symmetric dione 19, the resulting product lost signifi-
cant symmetry, according to 1H NMR spectroscopic analysis.
Surprisingly, additional spectroscopic analyses, including IR,
13C NMR, COSY, HMBC, and HR-MS (ESI), of the product
revealed that the product was not the predicted intermediate
hemiaminal 27 but the desired ketoamide 9. The IR spectrum
of the product showed the characteristic bands for the C17
ketone stretch at 1696 cm-1 and the C13 amide CdO stretch
at 1635 cm-1, which closely correlate with the values
observed for cripowellin A (1692 and 1653 cm-1, respec-
tively1). The presence of the ketone and amide functionality
was also confirmed by 13C NMR and HMBC (δ 213.8 and
173.5, respectively).
In summary, we have demonstrated that the cripowellin
skeleton can be efficiently constructed by ring expansion of
spiro(benzazepine-cyclohexane-1,3-dione) 19, which was
obtained by intramolecular oxidative cyclization of phenolic
compound 11 followed by a reduction/hydrolysis sequence.
We are currently pursuing functionalization of compound 9
to achieve the total synthesis of cripowellin and development
of an asymmetric version of this synthetic strategy.
Acknowledgment. This work was supported by the Korea
Research Foundation (KRF-2002-003-C00079). The authors
thank Professor Hanbin Oh for ESI-FTMS analysis of
compounds 25 and 9 and Dr. Michael Haukaas for his
editorial contributions to the manuscript.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) (a) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem.
Soc. 1988, 110, 291. (b) Chiu, P.; Li, Z.; Fung, K. C. M. Tetrahedron Lett.
2003, 44, 455.
(14) (a) McIntosh, J. M.; Matassa, L. C. J. Org. Chem. 1988, 53, 4452.
(b) Heathcock, C. H.; Blumenkopf, T. A.; Smith, K. M. J. Org. Chem.
1989, 54, 1548.
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