Toward the synthesis of norzoanthamine: Building carbocyclic core by a transannular Michael reaction cascade

Article abstract of DOI:10.1021/ol2024554

A 12-step synthesis of the ABC carbocyclic core of norzoanthamine is described. It features an organocatalytic asymmetric intramolecular aldolization to set the stereochemistry of the entire molecule, a fragment coupling by selective alkylation of a bis-e

Full text of DOI:10.1021/ol2024554

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5696–5699
Toward the Synthesis of Norzoanthamine:
Building Carbocyclic Core by a
Transannular Michael Reaction Cascade
Haoran Xue, Jiong Yang,* and Peddabuddi Gopal
Department of Chemistry, Texas A&M University, College Station, Texas 77843-3255,
United States
yang@mail.chem.tamu.edu
Received September 9, 2011
ABSTRACT
A 12-step synthesis of the ABC carbocyclic core of norzoanthamine is described. It features an organocatalytic asymmetric intramolecular
aldolization to set the stereochemistry of the entire molecule, a fragment coupling by selective alkylation of a bis-enolate, and a transannular
Michael reaction cascade for rapid and stereoselective synthesis of the polycyclic core.
Zoanthamine (1), norzoanthamine (2), zoanthenol (3),
and 28-deoxyzoanthenamine (4) are representatives of a
small group of marine alkaloids originally isolated from
colonial zoanthids of the genus Zoanthus sp. (Figure 1).1
These compounds show a range of interesting biological
activities, such as cytotoxicity, inhibition of human platelet
aggregation, and antibacterial and anti-inflammatory
activities.2 Norzoanthamine is arguably the most notable
of this group due to its potent antiosteoporotic effect.3 This
property was characterized by suppression of the loss of
bone weight and bone strength of ovariectomized mice,
Figure 1. Examples of zoanthamines.
(1) For an excellent review, see: Behenna, D. C.; Stockdill, J. L.;
Stoltz, B. M. Angew. Chem., Int. Ed. 2008, 47, 2365–2386.
(2) For some references, see: (a) Rao, C. B.; Anjaneyulu, A. S. R.;
Sarma, N. S.; Venkatateswarlu, Y.; Rosser, R. M.; Faulkner, D. J.
J. Org. Chem. 1985, 50, 3757–3760. (b) Fukuzawa, S.; Hayashi, Y.;
Uemura, D.; Nagatsu, A.; Yamada, K.; Ijuin, Y. Heterocycl. Commun.
animal models that mimic postmenopausal osteoporosis.4
When orally administered in the form of its HCl salt,
norzoanthamine suppressed the loss of the trabecullar bone
and induced thickening of the cortical bone of ovariecto-
mized mice at a dosage of 2 mg/kg/day with no obvious side
effects over a period of four weeks. While norzoanthamine
appears to function through a mechanism that is different
from that of estrogen in inhibiting osteoporosis,3 its de-
tailed mode-of-action remains unknown.
Most of the zoanthamine alkaloids feature a topologi-
cally complex heptacyclic molecular skeleton that is densely
functionalizedand stereochemically complex. For example,
among the ten stereocenters of norzoanthamine (2), fiveare
1995, 1, 207–214. (c) Venkateswarlu, Y.; Reddy, N. S.; Ramesh, P.;
Reddy, P. S.; Jamil, K. Heterocycl. Commun. 1998, 4, 575–580. (d) Villar,
R. M.; Gil-Longo, J.; Daranas, A. H.; Souto, M. L.; Fernandez, J. J.;
Peixinho, S.; Barral, M. A.; Santafe, G.; Rodriguez, J.; Jimenez, C.
Bioorg. Med. Chem. Lett. 2003, 11, 2301–2306.
(3) (a) Fukuzawa, S.; Hayashi, Y.; Uemura, D.; Nagatsu, A.; Yama-
daK.; Ijuin, Y. Heterocycl. Commun. 1995, 1, 207–214. (b) Kuramoto,
M.; Hayashi, Y.; Fujitani, K.; Yamaguchi, K.; Tsuji, T.; Yamada, K.;
Ijuin, Y.; Uemura, D. Tetrahedron Lett. 1997, 38, 5683–5686. (c)
Kuramoto, M.; Hayashi, K.; Fujitani, Y.; Yada, M.; Tsuji, T.; Uemura,
D. Bull. Chem. Soc. Jpn. 1998, 71, 771–779. (d) Yamaguchi, K.; Yada,
M.; Tsuji, T.; Kuramoto, M.; Uemura, D. Biol. Pharm. Bull. 1999, 22,
920–924.
(4) Yamaguchi, K.; Hayama, T.; Makita, T.; Tsuji, T. J. Bone Miner.
Metab. 1997, 15, 138–144.
r
10.1021/ol2024554
Published on Web 09/30/2011
2011 American Chemical Society

concentrated on the six-membered C-ring and three of
them are all-carbon quaternary centers. The complex mo-
lecular structure and intriguing bioactivities make zoantha-
mines exciting but challenging synthetic targets. Twenty
years after isolation of the first zoanthamine alkaloid (i.e.,
1) by the research groups of Rau and Faulkner,5 Miyashita
and co-workers completed the first synthesis of nor-
zoanthamine in 2004 and subsequently converted it to
zoanthamine and zoanthenol.6 A second synthesis of nor-
zoanathamine was reported by Kobayashi and co-workers
in 2009.7 These successes were preluded by preliminary
studies from these two research groups and others.8 Early
investigations by the groups of Williams and Kobayashi
showed that the topologically complex bis-hemiaminal
DEFG ring system can be formed spontaneously from
acyclic amino alcohols under acidic reaction conditions.9
This polycyclization process (i.e., 5to 2, Scheme 1) was later
adapted by both Miyashita and Kobayashi in their synth-
eses of norzoanthamine. The relative ease of formation of
the DEFG ring system highlights the challenge associated
with synthesizing the highly functionalized and stereoche-
mically complex ABC carbocyclic core. Indeed, many of
these early synthetic routes assembled the ABC carbocycle
by intramolecular DielsꢀAlder reactions and subsequent
functional group manipulations.6,7 Development of effi-
cient synthetic approaches to the ABC carbocyclic core has
been and continues to be the focus of synthetic studies that
aim at zoanthamine alkaloids.10
Scheme 1. Synthetic Design
With the exception that its extra C250 has to be later
removed to complete the formation of Me-25, this tetra-
cyclic compound is a faithful representation of the ABC
carbocyclic core of norzoanthamine. It was envisioned to be
the product of a transannular Michael reaction cascade of
macrocyclic lactone 8,11 which could be synthesized from
cyclohexenone 9 and R-iodoketone 10. Herein we report a
12-step synthetic approach to the carbocyclic core of nor-
zoanthamine (i.e., 6) based on this synthetic design.
Our synthesis commenced with the enantioselective pre-
paration of cyclohexenone 9in 5 steps from ethyl acetoacetate
(Scheme 2). A modification of Snider’s original procedure
wasusedtopreparethebis-allylβ-ketoester 11 by the one-pot
double allylation reaction.12 The trisubstituted enoate 12 was
obtained in 87% yield by treatment of 11 with triflic anhy-
dride in a biphasic aq LiOH-hexanes system to form a (Z)-
enol triflate intermediate,13 followed by Fe(acac)3-catalyzed
methylation with MeMgBr.14 Only the (E)-enoate was
We embarked on developing an efficient synthetic route
to norzoanthamine and its simplified analogs that would
enable further biomedical investigation of this potent anti-
osteoporotic compound. Our convergent synthetic design
involved coupling of the tetracyclic β-ketoester 6 and the
C1ꢀC8 fragment 7(or its equivalent) to form 5(Scheme 1).7
The tetracyclic β-ketoester 6 contains five contiguous
stereocenters including two all-carbon quaternary ones.
(5) Rao, C. B.; Anjaneyula, A. S. R.; Sarma, N. S.; Venkatateswarlu,
Y.; Rosser, R. M.; Faulkner, D. J.; Chen, M. H. M.; Clardy, J. J. Am.
Chem. Soc. 1984, 106, 7983–7984.
(6) (a) Miyashita, M.; Sasaki, M.; Hattori, I.; Sakai, M.; Tanino, K.
Science 2004, 35, 495–499. (b) Miyashita, M. Pure Appl. Chem. 2007, 79,
651–665. (c) Yoshimura, F.; Sasaki, M.; Hattori, I.; Komatsu, K.; Sakai,
M.; Tanino, K.; Miyashita, M. Chem.;Eur. J. 2009, 15, 6626–6644.
This synthetic route was also applied by the same research group to
synthesize zoanthamine and zoanthenol. For zoantheol, see:(d) Taka-
hashi, Y.; Yoshimura, F.; Tanino, K.; Miyashita, M. Angew. Chem., Int.
Ed. 2009, 48, 8905–8908. (e) Yoshimura, F.; Takahashi, Y.; Tanino, K.;
Miyashita, M. Chem. Asian J. 2011, 6, 922–931. For zoanthamine, see ref
6b and 6c.
(7) (a) Murata, Y.; Yamashita, D.; Kitahara, K.; Minasako, Y.;
Nakazaki, A.; Kobayashi, S. Angew. Chem., Int. Ed. 2009, 48, 1400–
1403. (b) Yamashita, D.; Murata, Y.; Hikage, N.; Takao, K.-i.; Nakazaki,
A.; Kobayashi, S. Angew. Chem., Int. Ed. 2009, 48, 1404–1406.
(8) See references cited in ref 1 for previous synthetic studies toward
zoanthamines.
(9) (a) Williams, D. R.; Cortez, G. S. Tetrahedron Lett. 1998, 39,
2675–2678. (b) Hikage, N.; Furukawa, H.; Takao, K.-i.; Kobayashi, S.
Tetrahedron Lett. 1998, 39, 6237–6240. (c) Hikage, N.; Furukawa, H.;
Takao, K.; Kobayashi, S. Tetrahedron Lett. 1998, 39, 6241–6244.
(10) For some recent reports, see: (a) Behenna, D. C.; Stockdill, J. L.;
Stoltz, B. M. Angew. Chem., Int. Ed. 2007, 46, 4077–4080. (b) Stockdill,
J. L.; Behenna, D. C.; McClory, A.; Stoltz, B. M. Tetrahedron 2009, 65,
6571–6575. (c) Sugano, N.; Koizumi, Y.; Hirai, G.; Oguri, H.; Kobayashi,
S.; Yamashita, S.; Hirama, M. Chem. Asian J. 2008, 3, 1549–1557. (d)
Nguyen, T. X.; Dakanali, M.; Trzoss, L.; Theodorakis, E. A. Org. Lett.
2011, 13, 3308–3311.
(11) (a) Ho, T. In Tandem Organic Reactions; Wiley & Sons: New
York, 1992; Chapter 3, pp 33ꢀ56. For examples of synthetic methods
based on the Michael reaction cascade, see: (b) Lee, R. A. Tetrahedron
Lett. 1973, 14, 3333–3336. (c) Wu, L.-Y.; Bencivenni, G.; Mancinelli,
M.; Mazzanti, A.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed.
2009, 48, 7196–7199. (d) Bencivenni, G.; Wu, L.-Y.; Mazzanti, A.;
Giannichi, B.; Pesciaioli, F.; Song, M.-P.; Bartoli, G.; Melchiorre, P.
Angew. Chem., Int. Ed. 2009, 48, 7200–7203. (e) Wei, Q.; Gong, L.-Z.
Org. Lett. 2010, 12, 1008–1011. (f) Hoashi, Y.; Yabuta, T.; Takemoto,
Y. Tetrahedron Lett. 2004, 45, 9185–9188. (g) He, P.; Liu, X.; Shi, J.; Lin,
L.; Feng, X. Org. Lett. 2011, 13, 936–939. For examples of the Michael
reaction cascade in natural product synthesis, see:(h) Lavallee, J.-F.;
Deslongchamps, P. Tetrahedron Lett. 1988, 29, 6033–6036. (i) Zhang,
H.; Reddy, M. S.; Phoenix, S.; Deslongchamps, P. Angew. Chem., Int.
Ed. 2008, 47, 1272–1275. (j) Reddy, M. S.; Zhang, H.; Phoenix, S.;
Deslongchamps, P. Chem. Asian J. 2009, 4, 725–741. (k) Ihara, M.;
Toyota, M.; Fukumoto, K.; Kametani, T. Tetrahedron Lett. 1985, 26,
1537–1540. (l) Ihara, M.; Suzuki, M.; Fukumoto, K.; Kametani, T.;
Kabuto, C. J. Am. Chem. Soc. 1988, 110, 1963–1964. (m) Kanoh, N.;
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Org. Lett., Vol. 13, No. 20, 2011
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With both 9 and 10 in hand, efforts were made to unite
the two fragments and synthesize macrocyclic lactone 8.
Fragment coupling by enolization of 9 with LDA at
ꢀ78 °C and alkylation with R-iodoketone 10 in the pre-
senceof Me2Zn gave19in51% yield (Scheme4). However,
all attempts to convert 19 to macrocyclic lactone 8 were
either unsuccessful or occurred with low efficiency.
Scheme 2. Enantioselective Synthesis of Cyclohexenone 9
Scheme 4. Coupling of 9 and 10
To improve the overall efficiency, we sought to functiona-
lize 9 prior to its coupling with R-iodoketone 10 so that the
number of transformations necessary to arrive at macrocycle
8 would be minimized. The functionalization of 9 started
from reduction/oxidation to give aldehyde 20 in 58% yield
(Scheme 5). This was followed by the Roskamp reaction with
SnCl2 and ethyl diazoacetate to give β-ketoester 21.20 After
extensive experimentation, it was found that regioselective
alkylation of 21 could be achieved by deprotonation with
2.1 equiv of LDA at ꢀ78 °C in a solvent of THF-HMPA
followed by treatment with R-iodoketone 10 to give the
desired coupling product 23 in 53% yield. Presumably,
deprotonation of 21 with excess of LDA led to formation
of bis-enolate 22, which regioselectively reacted with 10 at the
more nucleophilic endocyclic enolate. This reaction repre-
sents a rare example of regioselective alkylation of bis-
enolates even though similar regioselective alkylations of
dianions of β-ketoesters have been well-known. Further
functionalization of 23 by desilylation and macrolactoniza-
tion led to macrocyclic lactone 8. A buffered condition (HF-
TBAF-Py) was necessary for optimal yield of desilylation of
23 while macrocyclization required refluxing a dilute solution
of 24 in toluene.21,22 A reactive acylketene (25) was presum-
ably formed under the reaction condition, and this transient
intermediate underwent an intramolecular acylation reaction
to give the macrocyclic lactone 8.
formed in this two-step procedure. Simultaneous oxidation
of both of the terminal alkenes of 12 by the Wacker oxidation
gave the symmetrical 2,6-heptanediketone 13 in 50% yield.15
A highly enantiomerically enriched cyclohexenone 9 (94%
ee, determined by HPLC using chiral stationary phase, see
Supporting Information) was obtained in 89% yield by the
asymmetric intramolecular aldolization of 13 catalyzed by
the quinidine-derived primary amine 14.16 The catalyst could
be recovered by column chromatography and reused without
affecting its activity and the enantioselectivity of the reaction.
Scheme 3. Synthesis of Iodoketone 10
(13) Babinski, D.; Soltani, O.; Frantz, D. E. Org. Lett. 2008, 10,
2901–2904.
The synthesis of R-iodoketone 10 started with the Wittig
olefination of dimethyl-1,3-acetonedicarboxylate (Scheme 3).17
Global reduction of the triester 15 followed by selective
allylic oxidation of the resulting triol with MnO2 generated
an R,β-unsaturated-γ-lactone intermediate, in which the
free hydroxyl group was protected with TBSCl to give 16.
(14) (a) Cahiez, G.; Avedissian, H. Synthesis 1998, 1199–1205. (b)
€
Scheiper, B.; Bonnekessel, M.; Krause, H.; Furstner, A. J. Org. Chem.
2004, 69, 3943–3049 and references cited therein.
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5, 369–384.
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Int. Ed. 2008, 47, 7656–7658. (b) Moyano, A.; Rios, R. Chem. Rev. 2011,
111, 4703–4832.
(17) Yamagiwa, Y.; Koreishi, Y.; Kiyozumi, S.; Kobayashi, M.;
Kamikawa, T.; Tsukino, M.; Goi, H.; Yamamoto, M.; Munakata, M.
Bull. Chem. Soc. Jpn. 1996, 69, 3317–3323.
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12, 989–993. (b) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron
Lett. 1977, 18, 4171–4174.
Aminolysis of 16 by MeNH(OMe) HClꢀMe3Al and pro-
3
tection of the resulting primary hydroxyl group as its PMB
ether gave 17 in high yield.18 The methyl ketone 18 was
obtained in 82% yield by reaction of the Weinreb amide 17
with MeMgBr. For R-halogenation, the methyl ketone was
enolized (TBSOTf, Et3N) to form a silyl enol ether inter-
mediate which was subjected to halogenation with NIS to
give the stereochemically defined R-iodoketone 10.19
(19) Reuss, R. H.; Hassner, A. J. Org. Chem. 1974, 39, 1785–1787.
(20) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54, 3258–
3260.
5698
Org. Lett., Vol. 13, No. 20, 2011

Scheme 5. Synthesis of Macrocyclic Lactone
Scheme 6. Transannular Michael Reaction Cascade of 8
Figure 2. X-ray based ORTEP drawing of 6. Spheres are drawn
at the 65% probability level.
The transannular Michael reaction cascade was effected
by treatment of 8 with TBAF in a solvent of DMF-THF at
4 °C for 2 h to give the tetracyclic 6 in 87% yield (Scheme 6).
Two bonds, two rings, and three consecutive stereocenters
(including two all-carbon quaternary ones) were simulta-
neously formed in this reaction. Only one diastereomeric
product was isolated, highlighting the stereoselective nature
of this transannular process. The stereochemistry of 6 was
determined by NMR spectroscopy and verified by X-ray
crystallography (Figure 2).23 Formation of 6 is consistent
with an all-chair-like transition state for the transannular
Michael reactions. However, this does not rule out the
possibility of a transannular DielsꢀAlder reaction path-
way.24 These two mechanistic possibilities cannot be dis-
tinguished because the highly informative stereochemical
information of one of the initially formed chiral centers
(C9) was lost to tautomerization.
quaternary ones. The synthesis proceeded in 12 linear steps
from ethyl acetoacetate and dimethyl-1,3-acetonedicarbox-
ylate. Most of the reactions were carried out at a gram or
multigram scale.25 Highlights include the organocata-
lytic asymmetric intramolecular aldolization to enantio-
selectively synthesize the cyclohexenone and set the stereo-
chemistry of the entire carbocyclic core, strategic inclusion
of a lactone (i.e., 16) to exploit the hidden symmetry of
fragment 10, regioselective alkylation through the interme-
diacy of a bis-enolate, and a highly stereoselective transan-
nular Michael reaction cascade. Completing the synthesis
of norzoanthamine and exploring the scope and stereoche-
mical outcome of the transannular Michael reaction cas-
cade are the focus of our current research.
In summary, we developed a short synthesis of the
densely functionalized and stereochemically complex car-
bocyclic core of norzoanthamine, which contained five con-
secutive stereocenters including two all-carbon substituted
Acknowledgment. We thank Dr. Joseph H. Reibenspies
of the X-ray Diffraction Laboratory in the Department
of Chemistry at Texas A&M University for X-ray
crystallography analysis, Dr. Howard J. Williams of
the same department for 2D NMR experiments, and
Prof. Daniel Romo of the same department for access
to analytical equipments. Financial support was pro-
vided by Texas A&M University and the Welch Foun-
dation (A-1700)
(21) (a) Gaffney, B. K.; Jones, R. A. Tetrahedron Lett. 1982, 23,
2257–2260. (b) Coleman, R. S.; Li, J.; Navarro, A. Angew. Chem., Int.
Ed. 2001, 40, 1736–1739. (c) Fang, L.; Yang, J.; Yang, F. Org. Lett. 2010,
12, 3124–3127.
(22) For an excellent review, see: Reber, K. P.; Tilley, S. D.; Sorensen,
E. J. Chem. Soc. Rev. 2009, 38, 3022–3034.
(23) Crystallographic data for 6 have been deposited with the
Cambridge Crystallographic Data Centre (CCDC 841829), and copies
of these data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif.
(24) See the discussion in ref 11n.
(25) Wernerova, M.; Hudlicky, T. Synlett 2010, 2701–2707.
Supporting Information Available. Experimental de-
tails and NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
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