Toward the synthesis of norzoanthamine: Complete fragment assembly

Article abstract of DOI:10.1021/jo070165r

(Chemical Equation Presented) The complex marine alkaloid norzoanthamine (2) was envisioned to be assembled from three key building blocks: the C ₁-C₅ fragment A, the C₆-C₁₀ fragment B, and the C₁₁-C<

Full text of DOI:10.1021/jo070165r

Toward the Synthesis of Norzoanthamine: Complete Fragment
Assembly
Martin Juhl, Rune Monrad, Inger Søtofte, and David Tanner*
Department of Chemistry, Technical UniVersity of Denmark, Building 201, KemitorVet,
DK-2800 Kgs.Lyngby, Denmark
dt@kemi.dtu.dk
ReceiVed January 27, 2007
The complex marine alkaloid norzoanthamine (2) was envisioned to be assembled from three key building
blocks: the C1-C5 fragment A, the C6-C10 fragment B, and the C11-C24 fragment C. The synthesis of
fragment A was achieved in 14 steps and 33% overall yield from (R)-γ-hydroxymethyl-γ-butyrolactone.
Fragment B was made in two steps from PMB-protected 4-pentynol in 76% yield. The C11-C24 fragment
C was made from (S)-carvone via (R)-isocarvone in 18 steps (6% overall yield). The convergent
stereoselective synthesis of the entire carbon framework (C1-C24) of the target molecule was achieved
via the following assemblage. Alkenyl iodide 20 derived from the C11-C24 fragment C was coupled to
fragment B (C6-C10) through a high-yielding Stille coupling reaction of these two sterically very
demanding coupling partners, affording the key Diels-Alder precursor 24. The intramolecular Diels-
Alder reaction proceeded smoothly in excellent yield and diastereoselectivity, generating the tricyclic
trans-anti-trans perhydrophenanthrene motif of norzoanthamine (C6-C24). The final fragment coupling
between lithiated fragment A (C1-C5) and aldehyde 40 (C6-C24) has also been successfully accomplished
affording the entire carbon framework of the natural product.
Introduction
densely functionalized heptacyclic alkaloids3 which exhibit an
impressive range of biological activity. For example, norzoan-
thamine, as well as other family members, that is, oxyzoan-
thamine 3, norzoanthaminone 4, and epinorzoanthamine 7, have
been reported to exhibit anticancer activity by inhibition of the
growth of P388 murine leukemia cells, with IC50 values of 24,
1.0, 2.6, and 7.0 µg/mL, respectively.4 Furthermore, 11-
hydroxyzoanthamine 5 and a synthetic derivative of norzoan-
thamine have shown strong inhibition against thrombin-,
collagen-, and arachidonic acid-induced aggregation, while
zoanthenol 6 has displayed a selective inhibitory activity induced
As part of a program to study toxic marine organisms in the
early 1980s, the species Zoanthus sp. was found off the coast
of Visakhapatnam, India. A novel marine alkaloid, zoanthamine
1, was isolated, and its structure and relative configuration were
established by means of X-ray crystallography and NMR
spectroscopy in 1984 (Figure 1).1 The absolute configuration
remained elusive until 1997, when Uemura and co-workers
published a report specifying the absolute stereostructure, based
on Mosher’s ester analysis of a derivative of norzoanthamine
2.2 The zoanthamine family is a structurally unique class of
(3) (a) Rahman, A. U.; Alvi, K. A.; Abbas, S. A.; Choudhary, M. I.;
Clardy, J. Tetrahedron Lett. 1989, 30, 6825-6828. (b) Kuramoto, M.;
Hayashi, K.; Yamaguchi, K.; Yada, M.; Tsuji, T.; Uemura, D. Bull. Chem.
Soc. Jpn. 1998, 71, 771-779. (c) Daranas, A. H.; Fernandez, J. J.; Gavin,
J. A.; Norte, M. Tetrahedron 1998, 54, 7891-7896. (d) Daranas, A. H.;
Fernandez, J. J.; Gavin, J. A.; Norte, M. Tetrahedron 1999, 55, 5539-
5546. (e) Nakamura, H.; Kawase, Y.; Maruyama, K.; Murai, A. Bull. Chem.
Soc. Jpn. 1998, 71, 781-787.
(1) 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.
(2) Kuramoto, M.; Hayashi, K.; Fujitani, Y.; Yamaguchi, K.; Tsuji, T.;
Yamada, K.; Ijuin, Y.; Uemura, D. Tetrahedron Lett. 1997, 38, 5683-
5686.
(4) Fukuzawa, S.; Hayashi, K.; Uemura, D.; Nagatu, A.; Yamada, K.;
Ijuin, Y. Heterocycl. Commun. 1995, 1, 207-214.
10.1021/jo070165r CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/25/2007
4644
J. Org. Chem. 2007, 72, 4644-4654

Norzoanthamine Synthesis
FIGURE 1. Family members of the zoanthamine alkaloids.
FIGURE 2. Retrosynthetic illustration of the key intramolecular Diels-Alder reaction.
by collagen, thereby rendering them viable leads as antiplatelet
drugs.5 Platelet aggregation plays a crucial role in physiological
hemostasis and pathological thrombosis. A significant disease
area of the latter is arterial thrombosis, which includes myo-
cardial infarction, stroke, and other cardiovascular diseases.5
With their enticing structure and intriguing biological profile,
the zoanthamine alkaloids have sparked considerable interest
from the synthetic community. To date, as far as we are aware,
six research groups other than our own have reported efforts
toward the total synthesis of zoanthamine and/or congeners:
Kobayashi,6 Williams,7 Hirama,8 Theodorakis,9 Irifune,10 and
Miyashita.11 The Miyashita group is currently alone in having
completed this formidable task, with the total synthesis of
norzoanthamine 2.
Results and Discussion
As shown in Figure 2, a key step in our proposed total
synthesis of the zoanthamine alkaloids is an intramolecular
Diels-Alder reaction. From previous synthetic efforts, which
included elaborate model studies, important intelligence was
gathered.12 To ensure the success of the Diels-Alder reaction,
the following are required: (1) no electron-donating (oxygen)
substituent at C10, but rather an electron-withdrawing group (2)
alcohol and not ketone functionality at C20, (3) (R)-configured
alcohol at C20, and (4) equatorial and not axial oriented MOM
ether at C17 (Figure 3). Therefore, inspired by a model study
based on carvone as a surrogate for the zoanthamine A-ring,
and the other major clues collected in our previous campaign,
a modified route to the zoanthamine alkaloids was designed
with norzoanthamine (2) as the prime target. Based on the
biological activity data published for the zoanthamine family
in recent years, norzoanthamine seems the most promising drug
lead in many disease areas.4,5
(5) Villar, R. M.; Gil-Longo, J.; Daranas, A. H.; Souto, M. L.; Ferna´ndez,
J. J.; Peixinho, S.; Barral, M. A.; Santafe´, G.; Rodriguez, J.; Jime´nez, C.
Bioorg. Med. Chem. 2003, 11, 2301-2306.
(6) (a) Hikage, N.; Furukawa, H.; Takao, K.; Kobayashi, S. Tetrahedron
Lett. 1998, 39, 6237-6240. (b) Hikage, N.; Furukawa, H.; Takao, K.;
Kobayashi, S. Tetrahedron Lett. 1998, 39, 6241-6244.
(7) (a) Williams, D. R.; Cortez, G. S. Tetrahedron Lett. 1998, 39, 2675-
2678. (b) Williams, D. R.; Brugel, T. A. Org. Lett. 2000, 2, 1023-1026.
(8) (a) Hirai, G.; Oguri, H.; Hirama, M. Chem. Lett. 1999, 141-142.
(b) Moharram, S. M.; Hirai, G.; Koyama, K.; Oguri, H.; Hirama, M.
Tetrahedron Lett. 2000, 41, 6669-6673. (c) Hirai, G.; Oguri, H.; Moharram,
S. M.; Koyama, K.; Hirama, M. Tetrahedron Lett. 2001, 42, 5783-5787.
(d) Hirai, G.; Koizumi, Y.; Moharram, S. M.; Oguri, H.; Hirama, M. Org.
Lett. 2002, 4, 1627-1630. (e) Hirai, G.; Oguri, H.; Hayashi, M.; Koyama,
K.; Koizumi, Y.; Moharram, S. M.; Hirama, M. Bioorg. Med. Chem. Lett.
2004, 14, 2647-2651.
(-)-Isocarvone 8 was synthesized following the procedure
of Theodorakis13 and incorporating minor changes recently
reported by Deslongchamps.14 The stereoselective alkylation of
the lithium enolate of (-)-isocarvone 8 with ethyl bromoacetate
proceeded smoothly, providing a 9:1 diastereomeric mixture of
ketoesters of which the desired trans ketoester 9 could be
(12) (a) Tanner, D.; Andersson, P. G.; Tedenborg, L.; Somfai, P.
Tetrahedron 1994, 50, 9135-9144. (b) Tanner, D.; Tedenborg, L.; Somfai,
P. Acta Chem. Scand. 1997, 51, 1217-1223. (c) Nielsen, T. E.; Tanner, D.
J. Org. Chem. 2002, 67, 6366-6371. (d) Nielsen, T. E.; Le Quement, S.;
Juhl, M.; Tanner, D. Tetrahedron 2005, 61, 8013-8024. (e) Juhl, M.;
Nielsen, T. E.; Le Quement, S.; Tanner, D. J. Org. Chem. 2006, 71, 265-
280.
(9) (a) Ghosh, S.; Rivas, F.; Fischer, D.; Gonzalez, M. A.; Theodorakis,
E. A. Org. Lett. 2004, 6, 941-944. (b) Rivas, F.; Ghosh, S.; Theodorakis,
E. A. Tetrahedron Lett. 2005, 46, 5281-5284.
(10) Irifune, T.; Ohashi, T.; Ichino, T.; Sakai, E.; Suenaga, K.; Uemura,
D. Chem. Lett. 2005, 34, 1058-1059.
(11) (a) Sakai, M.; Sasaki, M.; Tanino, K.; Miyashita, M. Tetrahedron
Lett. 2002, 43, 1705-1708. (b) Miyashita, M.; Sasaki, M.; Hattori, I.; Sakai,
M.; Tanino, K. Science 2004, 305, 495-499. (c) Miyashita, M. Method
for producing zoanthamine alkaloid and intermediate used in same. U.S.
Patent 2,006,036,094, 2006. (d) Miyashita, M. Fudan Xuebao, Ziran
Kexueban 2005, 44, 781-782. (e) Miyashita, M. Kagaku to Seibutsu 2005,
43, 636-638.
(13) (a) Gonzalez, M. A.; Ghosh, S.; Rivas, F.; Fischer, D.; Theodorakis,
E. A. Tetrahedron Lett. 2004, 45, 5039-5041. Other relevant references
with regards to the synthesis of isocarvone: (b) Mori, K.; Fukamatsu, K.
Liebigs Ann. Chem. 1992, 489-493. (c) Lavallee, J. F.; Spino, C.; Ruel,
R.; Hogan, K. T.; Deslongchamps, P. Can. J. Chem. 1992, 70, 1406-1426.
(d) Chen, J.; Marx, J. N. Tetrahedron Lett. 1997, 38, 1889-1892.
(14) Chen, L.; Deslongchamps, P. Can. J. Chem. 2005, 83, 728-740.
J. Org. Chem, Vol. 72, No. 13, 2007 4645

Juhl et al.
FIGURE 3. Overview of the retrosynthetic analysis of norzoanthamine.
SCHEME 1
SCHEME 2
isolated in 85% yield (Scheme 1). Diastereoselective lithium
aluminum hydride reduction of ketoester 9 in diethyl ether
afforded diol 10 as a crystalline solid in 72% yield. The
configuration at the two new stereocenters (C17 and C18,
norzoanthamine numbering) was confirmed by X-ray crystal-
lography, which showed the desired and expected equatorial
arrangement at both sites.15 Subsequent selective pivaloyl
protection of the primary C20 hydroxyl group of diol 10 afforded
78% of the desired 11. The moderate yield was due to formation
of significant amounts of byproduct containing a pivaloyl group
at the secondary C17 hydroxyl group (3% 12 and 13% 13).
Pivalate 11 was converted to the corresponding MOM ether 14
in excellent yield (96%) followed by reductive removal of the
pivaloyl ester using diisobutyl aluminum hydride affording
alcohol 15 in 97% yield. Oxidation of the C20 hydroxyl group
to the corresponding aldehyde 16 was accomplished via the
Parikh-Doering procedure16 in 98% yield.
and co-workers (Scheme 2).17 In our hands, the ensuing
hydrostannylation with similar substrates had previously suffered
from a lack of reproducibility (running the reaction at 0.1 M
concentration and syringe pump addition of the tributyltin
hydride at room temperature). By increasing the concentration
to 1 M and adding the tributyltin hydride at 0 °C the
hydrostannylation reaction became highly reliable and vinyl
stannane 19 could be obtained in an excellent 95% yield
(Scheme 2).
The iodo-destannylation reaction of vinyl stannane 19 proved
to be exceedingly prone to side reactions. The addition of a
solution of iodine in dichloromethane to a solution of vinyl
(15) See the Supporting Information.
(16) Parikh, J. R.; Doering, W. V. E. J. Am. Chem. Soc. 1967, 89, 5505.
(17) (a) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc.
1999, 121, 11245-11246. (b) Frantz, D. E.; Fassler, R.; Carreira, E. M. J.
Am. Chem. Soc. 2000, 122, 1806-1807. (c) Frantz, D. E.; Fassler, R.;
Tomooka, C. S.; Carreira, E. M. Acc. Chem. Res. 2000, 33, 373-381. (d)
Frantz, D. E.; Fassler, R.; Tomooka, C. S.; Carreira, E. M. Acc. Chem.
Res. 2000, 33, 373-381. (e) Boyall, D.; Lopez, F.; Sasaki, H.; Frantz, D.;
Carreira, E. M. Org. Lett. 2000, 2, 4233-4236. (f) Boyall, D.; Frantz, D.
E.; Carreira, E. M. Org. Lett. 2002, 4, 2605-2606.
The stereoselective formation (78% yield, dr ) 10:1) of
propargylic alcohol 18 from aldehyde 16 and alkyne 17
proceeded smoothly using the conditions developed by Carreira
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Norzoanthamine Synthesis
SCHEME 3
SCHEME 4
TABLE 1
stannane 19 in dichloromethane precooled to -78 °C, resulted
predominantly in formation of bicyclic ether 21 (75%) and only
13% yield of the desired vinyl iodide 20 (Scheme 3). A
remarkable solvent effect was observed when switching from
dichloromethane to diethyl ether. No reaction was observed
between stannane 19 and iodine at -78 °C in diethyl ether, but
running the reaction at 0 °C for 15 min resulted in quantitative
formation of the desired iodide 20.
The stage was now set for the first fragment coupling process
(Scheme 4) which called for a Stille reaction between two
sterically congested partners. On earlier occasions with similar
systems, only the Corey-modified Stille reaction18 provided the
desired cross-coupling products, albeit in disappointingly low
yields.12d,e In our initial attempts to improve the yield, the
sterically less-hindered trimethyltin species 22 was used instead
of the tributylstannane 23 (Scheme 4). Unfortunately, the
coupling reaction provided only 38% of the desired 24 over
the two-step sequence.
The fact that no byproducts derived from the C11-C24
fragment were observed and that the mass balance was off by
62% after the Stille coupling, led us to surmise that a water
soluble byproduct was formed, which was removed during
alkaline aqueous workup. One possibility could be that the Corey
conditions (excess lithium chloride and copper chloride in
DMSO) used in the Stille reaction were not only promoting
the coupling reaction, but also inducing cleavage of the methyl
ester in 22 and 24, similar to the first step in the Krapcho
reaction.19 The carboxylic acid thus formed would then be
removed during aqueous alkaline (aq. ammonia) workup,
explaining the poor mass balance of the reaction. Another point
of concern was the homocoupling of stannane 22, which
complicated chromatographic purification owing to coelution
with coupling product 24. On the basis of the hypothesis that
lithium chloride in DMSO was hydrolyzing the ester moiety,
the reaction was performed in DMSO omitting lithium chloride
equiv
Pd(PPh3)4
equiv
CuCl
entry
solvent
DMSO
DMSO/THF (1:1) 0.1
time [h] yield [%]
1
2
3
4
5
6
7
8
9
0.1
1
1
1
1
1
1
1
1
6
61
66
48
51
70
71
74
62
82a
12
50
49
6
THF
0.1
0.1
0.1
0.1
MeCN
DMA
NMP
5
NMP/THF (1:1) 0.1
NMP/THF (1:9) 0.1
10
48
10
NMP/THF (1:1) 0.1 + 0.045 1 + 0.25
a Additional Pd(PPh3)4 (0.045 equiv) was added in three portions during
the reaction, and additional CuCl (0.25 equiv) was added once during the
reaction.
entirely, while only 1 equiv of copper chloride was used.
Furthermore, tributylstannane 23 was used instead of trimethyl
stannane 22. A marked improvement was observed, affording
coupling product 24 in 61% yield, (Table 1, entry 1). Subse-
quently, different solvents and combinations of solvents were
screened. A general observation was that the presence of THF
as cosolvent decreased the amount of stannane homocoupling
product, but on the other hand resulted in longer reaction times
(Table 1, entries 2, 7, 8, and 9). Running the reaction in only
THF or MeCN resulted in reaction times above 2 days,
providing only modest yields of 48% and 51%, respectively
(Table 1, entry 3 and 4). Using DMA or NMP gave comparably
good results with yields around 70%, although the reaction in
(18) Han, X. J.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999,
121, 7600-7605.
(19) Krapcho, A. B. Synthesis 1982, 805-822.
J. Org. Chem, Vol. 72, No. 13, 2007 4647

Juhl et al.
SCHEME 5
SCHEME 6
NMP was somewhat faster (Table 1, entry 5 and 6). Combining
NMP with THF in a 1:1 ratio provided the best isolated yield
of coupling product 24 (74% yield, Table 1, entry 7). Using a
NMP/THF solvent ratio of 1:9 did not provide any improvement
to the reaction. Inspired by a report from Tadano and co-
workers,20 we added several portions of tetrakistriphenylphos-
phine palladium(0) and copper chloride during the reaction and
pleasingly 82% yield of the desired coupling product could then
be isolated (Table 1, entry 9).
The key intramolecular Diels-Alder (IMDA) reaction was
now at hand and worked admirably, providing cycloadduct 25
in 85% yield, after heating 24 in toluene for 27 h at 205 °C in
a sealed Carius tube (Scheme 5). A crucial observation here
was that precursor 24 should be completely free of even trace
amounts of residual Bu3SnI from the Stille coupling to obtain
reliable results in the IMDA reaction. The free hydroxyl group
at C20 in cycloadduct 25 was converted into the corresponding
MOM ether 26 under standard conditions in 92% yield (Scheme
5).
found to be the most favorable; R-hydroxylation, reduction, and
diol cleavage. R-Hydroxylation of the potassium enolate of ester
26 using molecular oxygen provided the corresponding R-hy-
droxy ester in 86% yield as a 4:1 mixture of diastereomers.
Subsequent reduction of the R-hydroxy ester failed using either
lithium borohydride or diisobutyl aluminum hydride which
resulted only in decomposition. Lithium aluminum hydride
provided the desired diol, but the product was unstable,
presumably because of diene formation by elimination of the
allylic alcohol at C10. A one-pot strategy to afford enone 27
was therefore developed, in which the R-hydroxy ester dissolved
in THF was exposed to lithium aluminum hydride at -78 °C
and warmed to room temperature over a period of 1 h, then
cooled to 0 °C, followed by the addition of a phosphate buffer
(pH ) 7.00) and sodium periodate. This technique afforded
enone 27 in 85% yield. Further optimization of the oxidative
decarboxylation sequence was achieved by use of the crude
mixture from the R-hydroxylation reaction of ester 26 in the
subsequent reduction/oxidative cleavage reaction, thus providing
enone 27 in 79% overall yield from ester 26.
The next task involved finding conditions to successfully
perform the crucial oxidative decarboxylation at C10, to access
enone 27 (Scheme 5) which in turn would allow introduction
of the two vicinal methyl groups at C9 and C22 via an initial
Michael addition. Several different procedures for oxidative
decarboxylation have been reported in the literature.21 After
extensive experimentation the following three-step sequence was
Simultaneously, a different strategy utilizing a Baeyer-
Villiger reaction to obtain the desired oxidation state at C10 was
explored, with a methyl ketone appendage as a precursor. In
this strategy a methyl ketone was positioned at C10 instead of
a methyl ester. The synthesis of the modified C6-C10 coupling
partner 31 was achieved in three steps from alkyne 28 (Scheme
6).
(20) Munakata, R.; Katakai, H.; Ueki, T.; Kurosaka, J.; Takao, K.;
Tadano, K. J. Am. Chem. Soc. 2004, 126, 11254-11267.
The subsequent three-step sequence, that is, Stille coupling,
IMDA reaction, and MOM ether formation to achieve the
desired Baeyer-Villiger precursor 33, proceeded under condi-
tions similar to those developed for the methyl ester series (Table
1 and Scheme 5). Unfortunately, the projected Baeyer-Villiger
reaction performed under alkaline conditions afforded only a
complex mixture of products, all of which still contained a
ketone functionality based on 13C NMR analysis (Scheme 7).
(21) For rearrangement of acyl peroxides see: (a) Kienzle, F.; Holland,
G. W.; Jernow, J. L.; Kwoh, S.; Rosen, P. J. Org. Chem. 1973, 38, 3440-
3442. (b) Field, S. J.; Young, D. W. J. Chem. Soc., Perkin Trans. 1 1982,
591-593. (c) Akhtar, M.; Gani, D. Tetrahedron 1987, 43, 5341-5349. (d)
Shiozaki, M.; Ishida, N.; Sato, S. Bull. Chem. Soc. Jpn. 1989, 62, 3950-
3958. (e) Hatanaka, M.; Ueda, I. Chem. Lett. 1991, 61-64. For Borodin-
Hunsdiecker type oxidations see: (f) Sternbach, D. D.; Hughes, J. W.; Burdi,
D. F.; Banks, B. A. J. Am. Chem. Soc. 1985, 107, 2149-2153. (g) Patel,
D. V.; Vanmiddlesworth, F.; Donaubauer, J.; Gannett, P.; Sih, C. J. J. Am.
Chem. Soc. 1986, 108, 4603-4614. For R-hydroxylation, reduction, and
diol cleavage see: (h) Corey, E. J.; Ensley, H. E. J. Am. Chem. Soc. 1975,
97, 6908. (i) Snyder, S. A.; Corey, E. J. J. Am. Chem. Soc. 2006, 128,
740-742.
A di-p-nitrobenzoyl ester derivative achieved in two steps
from the cycloadduct of 32 was prepared (35),22 and a single-
crystal X-ray analysis was performed, confirming the stereo-
4648 J. Org. Chem., Vol. 72, No. 13, 2007

Norzoanthamine Synthesis
SCHEME 7
chemical outcome of the IMDA reaction to be a result of an
exo transition state (Figure 4).23 The Baeyer-Villiger strategy
was not further pursued, and we now concentrated solely on
the route via ester 26.
iodide 38 to tert-butyl lithium at -78 °C for 4 min, followed
by the addition of aldehyde 40 to provide a diastereomeric
mixture of alcohols. The mixture of alcohols was immediately
oxidized using the Parikh-Doering protocol to the correspond-
ing diketone 41 in an as yet unoptimized overall yield of 25%
for the two-step sequence.
With a high-yielding and reproducible synthesis of the C6-
C24 fragment at hand focus was then directed toward the
synthesis of the C1-C5 fragment (Scheme 8) as well as the final
fragment assembly. The C1-C5 fragment was obtained from
azide 36 which was available from a previously described
route.24 Cleavage of the MOM ether in azide 36 was achieved
using a combination of zinc bromide and n-butyl thiol following
a protocol developed recently by Rawal and co-workers.25
Subsequent hydrogenation of the azide moiety using Pd/C under
a hydrogen atmosphere in the presence of Boc2O provided the
corresponding carbamate. This was followed by installation of
an acetonide and reductive removal of the pivaloyl ester
affording alcohol 37 in 81% yield for the four-step sequence.
Iodide 38 was obtained in 95% yield by subjecting alcohol 37
to a mixture of iodine, imidazole, and triphenylphosphine, thus
setting the stage for the final fragment coupling process.
The C6-C24 aldehyde coupling partner 40 was prepared from
enone 27 starting with cleavage of the C6 PMB ether using DDQ
to afford alcohol 39 in 72% yield as a colorless oil, which
solidified upon standing and could be recrystallized to provide
crystals suitable for X-ray crystallographic analysis.26 The crystal
structure confirmed the (R)-configuration at C20 installed through
the diastereoselective Carreira addition and the (S)-configuration
at both C12 and C21 set by an exo selective IMDA reaction.
The desired aldehyde 40 was obtained in excellent yield (90%)
by oxidation of alcohol 39 via the Parikh-Doering reaction
(Scheme 9).
In conclusion, a stereoselective synthesis of the C1-C24
carbon framework of norzoanthamine 2 has been achieved. In
this route, alkenyl iodide 20, corresponding to the C11-C24
fragment of norzoanthamine, was obtained in nine steps from
the known (-)-isocarvone. Coupling of 20 to the C6-C10
fragment 23 through a high-yielding Stille reaction involving
two sterically demanding coupling partners afforded the key
Diels-Alder precursor 24. The intramolecular Diels-Alder
reaction proceeded smoothly in excellent yield and diastereo-
selectivity, generating the trans-anti-trans perhydrophenanthrene
motif (C6-C24) of norzoanthamine, the desired stereochemistry
being verified by several X-ray crystal structures. The final
fragment coupling between lithiated 38 (C1-C5) and aldehyde
40 (C6-C24) was also accomplished, affording diketone 41
containing 27 out the 29 carbon atoms present in norzoan-
thamine. Current efforts are focused on the nontrivial issue of
installation of the vicinal C9 and C22 quartenary centers of
norzoanthamine and the final advance to the target.
Experimental Section
The coupling of fragment A (C1-C5) with freshly prepared
aldehyde 40 was achieved by subjecting an ethereal solution of
Ethyl 2-((1S,6R)-4-Methyl-2-oxo-6-(prop-1-en-2-yl)cyclo-
hex-3-enyl)acetate (9). (-)-Isocarvone 8 (4.24 g, 28.2 mmol)
(22) Prepared from the Diels-Alder adduct of 32 through a two-step
procedure: TBAF mediated cleavage of the TIPS ether and subsequent bis-
p-nitrobenzoyl ester formation using p-nitrobenzoyl chloride, pyridine, and
DMAP provided ketoester 35 in 53% yield from 32 as a white solid.
Recrystallization was performed in diethyl ether.
(23) See also the Supporting Information.
(24) Azide 36 was obtained in 9 steps from (R)-γ-hydroxymethyl-γ-
butyrolactone analogously to previously prepared azide
(25) Sohn, J. H.; Waizumi, N.; Zhong, H. M.; Rawal, V. H. J. Am. Chem.
Soc. 2005, 127, 7290-7291.
(26) See the Supporting Information.
FIGURE 4. The stereochemical outcome of the IMDA reaction was
verified by a X-ray crystal structure of di-p-nitrobenzoyl ester 35.
J. Org. Chem, Vol. 72, No. 13, 2007 4649

Juhl et al.
SCHEME 8
SCHEME 9
was dissolved in anhydrous THF (110 mL) and cooled to -78
°C under argon followed by the addition of LiHMDS (33.9 mL,
33.9 mmol, 1 M in hexanes) to the reaction mixture which was
stirred for 1 h. Ethyl bromoacetate (4.95 mL, 42.3 mmol) was
added to the reaction mixture and stirred for 4 h then warmed
to rt and stirred for 45 min. The reaction mixture was quenched
by the addition of sat. aqueous NaHCO3 (100 mL). The aqueous
phase was extracted with Et2O (2 × 100 mL), and the combined
organic phases were washed with brine (150 mL), then dried
(MgSO4), filtered, and evaporated to dryness in vacuo. The
residue was purified using flash column chromatography (20-
50:80-50, Et2O/pentane) providing 9 (5.66 g, 85%) as a
colorless oil. 9: Rf, 0.25 (AcOEt/hexane, 1:4); [R]23D +12.3 (c
1.2, CH2Cl2); IR (film) 2977, 1735, 1670, 1439, 1339, 1310,
1215, 1180, 1094, 1032, 902, 867; 1H NMR (300 MHz, CDCl3)
δ 5.89 (bs, 1H), 4.85 (app. quint, J ) 1.6 Hz, 1H), 4.83 (s,
1H), 4.17 (dq, J ) 0.9, 7.1 Hz, 2H), 2.79-2.74 (m, 2H), 2.47-
2.45 (m, 3H), 2.20 (dd, J ) 3.7, 18.0 Hz, 1H), 1.95 (s, 3H),
1.71 (s, 3H), 1.25 (t, J ) 7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 199.1, 172.7, 160.7, 144.7, 125.6, 114.4, 60.3, 47.6,
45.3, 36.5, 31.9, 24.1, 18.0, 14.1. Anal. Calcd for C14H20O3:
C, 71.16; H, 8.53. Found: C, 70.92; H, 8.53.
mixture was then warmed to 0 °C and stirred for 1 h followed
by removal of the ice bath, and the reaction was then allowed
to reach ambient temperature and stirred for 20 min. The
reaction was quenched by slow addition of H2O (2 mL), 15%
NaOH(aq) (2 mL), and H2O (6 mL). The precipitates were
filtered off and washed thoroughly with Et2O (3 × 30 mL) and
MeOH (3 × 30 mL). The combined organic phases were
evaporated to dryness in vacuo. The residue was purified by
flash column chromatography (AcOEt/pentane, 2:3) affording
10 (3.65 g, 72%) as a colorless oil, which crystallized upon
standing. 10: mp 61-62 °C; Rf, 0.20 (AcOEt/pentane, 1:1);
[R]23D +22.2 (c 1.5, CH2Cl2); IR (film) 3350, 2893, 1644, 1442,
1377, 1162, 1074, 1016, 1006, 894; 1H NMR (300 MHz, CDCl3)
δ 5.35 (bs, 1H), 4.80-4.76 (m, 2H), 4.02-3.96 (m, 1H), 3.83
(ddd, J ) 3.6, 5.7, 10.9 Hz, 1H), 3.82-3.71 (m, 1H), 3.61 (ddd,
J ) 3.1, 9.3, 11.1 Hz, 1H), 2.23 (ddd, J ) 4.9, 11.1, 11.1 Hz,
1H), 2.17-2.04 (m, 1H), 1.88-1.75 (m, 3H), 1.68 (s, 3H), 1.63
(s, 3H), 1.48 (dddd, J ) 2.2, 8.7, 8.7, 11.1 Hz, 1H), 1.35 (dddd,
J ) 3.4, 9.0, 9.0, 14.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
146.8, 136.1, 124.2, 113.2, 73.5, 62.3, 47.3, 43.4, 35.7, 35.4,
22.9, 17.9; EI-MS [M] 196 m/z. Anal. Calcd for C12H20O2: C,
73.43; H, 10.27. Found: C, 73.22; H, 10.22.
(1R,5R,6S)-6-(2-Hydroxyethyl)-3-methyl-5-(prop-1-en-2-
yl)cyclohex-2-enol (10). Ketoester 9 (6.1 g, 25.8 mmol) was
dissolved in anhydrous Et2O (30 mL) and added to a precooled
(-78 °C) suspension of LiAlH4 (1.96 g, 51.6 mmol) in Et2O
(90 mL) under argon and stirred for 10 min. The reaction
(R)-6-(Tri-isopropyl-silyloxy)-1-((1S,2R,6R)-2-(meth-
oxymethoxy)-4-methyl-6-(prop-1-en-2-yl)cyclohex-3-enyl)-
hex-3-yne-2-ol (18). A 25 mL round bottomed flask was
charged with Zn(OTf)2 (26.4 g, 72.6 mmol), and heated to 120
°C under vacuum for 3 h. After cooling to rt (+)-N-methyl-
4650 J. Org. Chem., Vol. 72, No. 13, 2007

Norzoanthamine Synthesis
ephedrine (13.2 g, 73.9 mmol) was added under argon, and the
flask was purged with argon two times and kept under vacuum
for 15 min. Anhydrous toluene (12 mL) followed by triethyl-
amine (10.2 mL) was added and after 2 h (but-3-ynyloxy)-
triisopropylsilane (17) (15.6 g, 68.9 mmol) was added in one
portion. After 1 h aldehyde 16 (5.03 g, 21.1 mmol) was added
in one portion at rt and stirred under argon. The reaction mixture
was stirred for 15 h upon which the reaction mixture had turned
yellowish. The mixture was diluted with AcOEt (100 mL) and
washed with sat. aqueous NH4Cl (2 × 50 mL). The combined
aqueous phases were back-extracted with AcOEt (3 × 50 mL),
and the combined organic phases were dried (Na2SO4), filtered,
and evaporated to dryness in vacuo. The residue was purified
by flash column chromatography (Et2O/pentane, 1:4-1:2)
providing propargylic alcohol 18 (7.6 g, 78%) as a colorless
oil and as a single diastereomer. (But-3-ynyloxy)triisopropyl-
silane 17 (8.0 g, 51%) was recovered. 18: Rf, 0.21 (Et2O/
((3E)-4-((2R,3aS,4R,7aS)-2,3,3a,4,5,7a-Hexahydro-6-meth-
yl-4-(prop-1-en-2-yl)benzofuran-2-yl)-3-iodobut-3-enyloxy)-
triisopropylsilane (21). A solution of the â-stannylated allylic
alcohol 19 (664 mg, 0.88 mmol) in CH2Cl2 (30 mL) was cooled
to -78 °C and a solution of iodine (178 mg, 0.97 mmol, CH2-
Cl2 (20 mL)) was added at once, stirred under argon for 15
min, and then poured into a sat. aqueous sodium thiosulfate
solution (10 mL). The aqueous phase was back-extracted with
CH2Cl2 (10 mL), and the combined organic phases were
evaporated to dryness and subjected to flash column chroma-
tography on demetalated silica gel (Et2O/pentane, 1:5) affording
21 (350 mg, 75%, contaminated with ISnBu3) and iodide 20
(67 mg, 13%) both as colorless oils. 21: Rf, 0.82 (Et2O/pentane,
1:2); [R]23D +14.1 (c 1.5, CHCl3); IR (film) 2956, 1642, 1457,
1378, 1248, 1105, 883, 743, 682; 1H NMR (300 MHz, CDCl3)
δ 6.33 (d, J ) 8.0 Hz, 1H), 5.61 (bs, 1H), 4.82 (m, 1H), 4.76
(s, 1H), 4.55 (ddd, J ) 7.8, 7.8, 8.0 Hz, 1H), 4.06 (bs, 1H),
3.79 (app. t, J ) 7.0 Hz, 2H), 2.82 (ddd, J ) 7.0, 7.0, 14.1 Hz,
1H), 2.61 (dddd, J ) 0.9, 7.0, 7.0, 14.1 Hz, 1H) 2.26-2.16 (m,
1H), 2.12-2.07 (m, 2H), 1.96-1.91 (m, 2H), 1.75 (s, 3H), 1.67
(s, 3H), 1.67-1.59 (m, 1H); 13C NMR (75 MHz, CDCl3) δ
146.4, 144.1, 140.5, 118.7, 112.4, 102.1, 76.1, 75.4, 62.2, 45.1,
42.9, 39.1, 36.6, 35.8, 29.1, 26.6, 23.6, 19.4, 18.0, 16.4, 13.6,
11.9; HRMS (ESI) calcd for [M + H+], 531.215; found,
531.2153.
pentane, 1:2); [R]23 +46.1 (c 2.0, CH2Cl2); IR (film) 3420,
D
3072, 2985, 2874, 2725, 1711, 1680, 1643, 1463, 1382, 1333,
1
1215, 1093, 1041, 892, 812, 737, 681; H NMR (300 MHz,
CDCl3) δ 5.46 (bs, 1H), 4.84-4.79 (m, 3H), 4.70 (d, J ) 7.0
Hz, 1H), 4.47-4.41 (m, 1H), 4.00-3.94 (m, 1H), 3.76 (t, J )
7.4 Hz, 2H), 3.43 (s, 3H), 3.38 (bs, 1H), 2.44 (ddd, J ) 1.9,
7.6, 7.6, 2H), 2.28 (ddd, J ) 5.1, 11.2, 11.2 Hz, 1H), 2.17-
2.05 (m, 1H), 1.95 (ddd, J ) 1.9, 5.3, 13.6 Hz, 1H), 1.84 (dd,
J ) 5.1, 17.6 Hz, 1H), 1.76-1.59 (m, 8H), 1.05 (s, 18H), 1.03
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 146.4, 136.8, 121.7,
113.7, 95.7, 82.9, 81.3, 80.9, 62.2, 62.1, 56.2, 47.4, 40.6, 39.0,
35.9, 23.2, 23.0, 18.2, 17.9, 11.9. Anal. Calcd for C27H48O4Si:
C, 69.78; H, 10.41. Found: C, 69.57; H, 10.63.
(2R,3E)-4-(Tributylstannyl)-6-(tri-isopropyl-silyloxy)-1-
((1S,2R,6R)-2-(methoxymethoxy)-4-methyl-6-(prop-1-en-2-yl-
)cyclohex-3-enyl)hex-3-en-2-ol (19). To propargylic alcohol 18
(7.7 g, 16.7 mmol) and dichlorobis(tris(o-toloyl)phosphine)-
palladium(II) (132 mg, 0.01 mmol) in THF (17 mL) at 0 °C
was added dropwise tributyltin hydride (8 mL, 29.7 mmol) over
a period of 0.45 h followed by removal of the ice bath allowing
the reaction mixture to reach rt. The reaction mixture was
purified directly by flash column chromatography (Et2O/pentane,
1:9-1:2) affording 19 (11.96 g, 95%) as a colorless oil. 19: Rf
0.56 (Et2O/pentane, 1:2); [R]23D +31.1 (c 2.0, CDCl3); IR (film)
3456, 2924, 1645, 1464, 1377, 1292, 1248, 1214, 1150, 1096,
1036, 919, 883, 782, 687; 1H NMR (300 MHz, CDCl3) δ 5.60
(d, J ) 7.7 Hz, 1H), 5.47 (s, 1H), 4.85 (s, 1H), 4.84 (d, J ) 7.0
Hz, 1H), 4.80 (s, 1H), 4.71 (d, J ) 7.0 Hz, 1H), 4.57 (bs, 1H),
3.94 (d, J ) 7.8 Hz, 1H), 3.69-3.53 (m, 2H), 3.45 (s, 3H),
3.42 (d, J ) 2.3 Hz, 1H), 2.70 (ddd, J ) 7.9, 7.9, 12.6 Hz,
1H), 2.42 (ddd, J ) 5.0, 8.4, 13.5 Hz, 1H), 2.26 (ddd, J ) 4.9,
10.9, 10.9 Hz, 1H), 2.18-2.05 (m, 1H), 1.85 (dd, J ) 4.6, 17.2
Hz, 1H), 1.71 (m, 10H), 1.64-1.40 (m, 8H), 1.30 (sextet, J )
7.2 Hz, 6H), 1.07 (s, 18H), 1.05 (s, 3H), 0.88 (m, 12H); 13C
NMR (75 MHz, CDCl3) δ 146.7, 140.9, 136.7, 121.8, 113.5,
95.6, 80.9, 67.0, 63.2, 56.1, 47.7, 39.8, 39.1, 37.3, 35.8, 29.1,
27.4, 23.0, 18.5, 18.0, 13.7, 11.9, 9.6. Anal. calcd for C39H76O4-
SiSn: C, 61.98; H, 10.14. Found: C, 62.05; H, 10.11.
(6R,2E,4E)-Methyl 3-(3-(4-Methoxybenzyloxy)propyl)-6-
hydroxy-4-(2-(tri-isopropyl-silyloxy)-ethyl)-7-((1S,2R,6R)-2-
(methoxymethoxy)-4-methyl-6-(prop-1-en-2-yl)cyclohex-3-
enyl)hepta-2,4-dienoate (24). A solution of the â-stannylated
allylic alcohol 19 (1.97 g 2.6 mmol) in Et2O (160 mL) was
cooled to 0 °C, and a solution of iodine (1.0 g, 4.0 mmol, in
55 mL of Et2O) was added at once and stirred under argon for
15 min. The reaction mixture was quenched by the addition of
sat. sodium thiosulfate solution (100 mL), the aqueous phase
was back-extracted with Et2O (50 mL), and the combined
organic phases were evaporated to dryness and purified by flash
column chromatography on silica gel (Et2O/pentane, 2:3) to give
iodide 20, which was used immediately for the next reaction.
A 50 mL Schlenk tube was charged with tetrakis(triphenylphos-
phine)palladium(0) (300 mg, 0.26 mmol) and copper(I)chloride
(257 mg, 2.6 mmol), and the mixture was degassed under high
vacuum with an argon purge. Iodide 20 and stannane 23
(2.88 g, 5.2 mmol) were dissolved in THF/NMP (1:1, 24 mL)
degassed by bubbling argon through the solution for 5 min and
then added to the Schlenk flask containing the salts, which was
precooled to -78 °C. The mixture was subjected to high vacuum
for 1 min and the flask was back-filled with argon. The reaction
J. Org. Chem, Vol. 72, No. 13, 2007 4651

Juhl et al.
mixture was stirred at rt for 2 h, and then more tetrakis-
(triphenylphosphine)palladium(0) (70 mg, 0.061 mmol, dis-
solved in 0.5 mL THF) was added. The mixture was stirred for
1 h, then more tetrakis(triphenylphosphine)palladium(0) (30 mg,
0.026 mmol) was added as a solid, and the mixture was stirred
for an additional 1 h. More tetrakis(triphenylphosphine)-
palladium(0) (30 mg, 0.026 mmol) and CuCl (25 mg, 0.25
mmol) was added, and the reaction mixture was stirred for an
additional 1.5 h, then the reaction mixture was diluted with
diethyl ether (150 mL) and washed with H2O (2 × 100 mL).
The aqueous layer was further extracted with diethyl ether (2
× 150 mL), and the combined organic layers were dried (Na2-
SO4) and evaporated in vacuo. The residue was purified by flash
column chromatography on silica gel (Et2O/pentane (1:2-2:1)
and AcOEt/CH2Cl2, (1:9-3:7)) affording coupling product 24
(1.56 g, 82%, two steps) as a colorless oil. 24: Rf, 0.22 (AcOEt/
1.05-1.02 (m, 21H), 0.70 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 175.5, 159.0, 136.3, 134.7, 131.7, 130.6, 129.1, 122.1, 113.6,
96.6, 81.5, 72.4, 69.7, 66.7, 65.0, 55.6, 55.4, 55.2, 51.7, 46.0,
43.0, 41.0, 38.5, 37.9, 31.3, 30.2, 28.5, 27.6, 23.5, 17.91, 17.86,
16.4, 11.8. HRMS (ESI) calcd for C42H68O8SiNa [M + Na],
751.4576; found, 751.4581.
(3R,4aS,4bR,8R,8aS,10R,10aS)-Methyl 2-(3-(4-Methoxy-
benzyloxy)propyl)-3,4,4a,4b,5,8,8a,9,10,10a-decahydro-1-(2-
(tri-isopropyl-silyloxy)-ethyl)-8,10-bis(methoxymethoxy)-
4a,6-dimethylphenanthrene-3-carboxylate (26). To a solution
of 25 (350 mg, 0.48 mmol) in CH2Cl2 (3.5 mL) under argon
was added N,N-diisopropylethylamine (2 mL, 11.5 mmol) and
methoxymethyl chloride (0.73 mL, 9.6 mmol), and the reaction
mixture was stirred for 2 h resulting in a slightly yellow
coloration. The reaction mixture was purified directly by flash
column chromatography on silica gel (Et2O/pentane, 2:3)
providing the title compound 26 (341 mg, 92%) as a colorless
CH2Cl2, 1:9); [R]23 +33.7 (c 4.0, CH2Cl2); IR (film) 3441,
D
2942, 1717, 1616, 1516, 1456, 1378, 1247, 1167, 1097, 887,
1
820, 681; H NMR (300 MHz, CDCl3) δ 7.26 (d, J ) 8.7 Hz,
2H), 6.86 (d, J ) 8.7 Hz, 2H), 5.85 (s, 1H), 5.78 (d, J ) 8.1
Hz, 1H), 5.47 (bs, 1H), 4.86-4.79 (m, 3H), 4.70 (d, J ) 7.0
Hz, 1H), 4.53-4.45 (m, 1H), 4.42 (s, 2H), 3.93 (d, J ) 8.5 Hz,
1H), 3.80 (s, 3H), 3.68 (s, 3H), 3.67-3.53 (m, 3H), 3.47 (t, J
) 6.5 Hz, 2H), 3.43 (s, 1H), 2.97-2.74 (m, 2H), 2.62 (ddd, J
) 7.6, 7.6, 14.4 Hz, 1H), 2.47 (ddd, J ) 5.4, 7.1, 14.0 Hz,
1H), 2.26 (ddd, J ) 4.9, 10.9, 10.9 Hz, 1H), 2.18-2.05 (m,
1H), 1.86 (dd, J ) 4.9, 17.2 Hz, 1H) 1.77-1.62 (m, 12H), 1.52
(ddd, J ) 6.4, 9.8, 15.9 Hz, 1H), 1.08 (m, 21H); 13C NMR (75
MHz, CDCl3) δ 167.0, 161.4, 159.0, 146.6, 138.1, 137.0, 136.8,
130.7, 129.2, 121.7, 115.7, 113.7, 112.8, 95.6, 80.7, 72.4, 69.9,
67.8, 62.1, 56.2, 55.2, 51.0, 47.7, 39.6, 39.1, 35.8, 30.8, 29.3,
25.7, 23.0, 18.6, 18.0, 11.9; HRMS calcd for [M + Na],
751.4581; found, 751.4582. Anal. Calcd for C42H68O8Si: C,
69.19; H, 9.40. Found: C, 69.37; H, 9.39.
oil. 26: Rf, 0.76 (Et2O/pentane, 3:2); [R]23 -3.2 (c 5.2, CH2-
D
Cl2); IR (film) 2942, 1739, 1613, 1513, 1465, 1378, 1363, 1302,
1
1248, 1151, 1101, 1041, 922, 883, 819, 681; H NMR (500
MHz, CDCl3) δ 7.25 (d, J ) 8.6 Hz, 2H), 6.87 (d, J ) 8.6 Hz,
2H), 5.41 (bs, 1H), 4.82-4.78 (m, 3H), 4.65 (d, J ) 7.0 Hz,
1H), 4.40 (s, 2H), 3.82-3.72 (m, 6H), 3.68-3.63 (m, 4H), 3.44
(s, 3H), 3.39-3.32 (m, 4H), 3.12 (app. t, J ) 8.1 Hz, 1H), 2.90
(ddd, J ) 4.3, 4.3, 12.8 Hz, 1H), 2.70-2.63 (m, 1H), 2.32-
2.16 (m, 3H), 1.90-1.82 (m, 3H), 1.78 (dd, J ) 7.4, 13.5 Hz,
1H), 1.68 (s, 3H), 1.65-1.52 (m, 4H), 1.31 (ddd, J ) 6.1, 10.2,
12.0 Hz, 1H), 1.14-1.02 (m, 23H), 0.70 (s, 3H); 13C NMR (75
MHz, C6D6) δ 175.0, 159.6, 135.7, 133.7, 133.6, 131.3, 129.4,
122.6, 114.0, 97.3, 95.7, 80.6, 76.6, 72.8, 70.2, 63.7, 59.8, 55.7,
55.4, 54.7, 52.8, 51.3, 44.9, 44.2, 40.2, 39.0, 37.9, 34.0, 30.7,
30.3, 27.9, 23.5, 18.40, 18.38, 12.4; HRMS (ESI) calcd for
C44H72O9SiNa [M + Na], 795.4843; found, 795.4825.
(3R,4aS,4bR,8R,8aS,10R,10aS)-Methyl 2-(3-(4-Methoxy-
benzyloxy)propyl)-3,4,4a,4b,5,8,8a,9,10,10a-decahydro-10-
hydroxy-1-(2-(tri-isopropyl-silyloxy)-ethyl)-8-(methoxymeth-
oxy)-4a,6-dimethylphenanthrene-3-carboxylate (25). A solution
of IMDA precursor 24 (245 mg, 0.336 mmol) in toluene (20
mL) was degassed by bubbling argon through the solution for
2 min then heated to 205 °C for 28 h in a sealed Carius tube.
The reaction mixture was evaporated to dryness and purified
using silica gel column chromatography (AcOEt/CH2Cl2, 1:7-
1:4) providing IMDA adduct 25 (209 mg, 85%) as a colorless
oil. 25: Rf, 0.41 (Et2O/pentane, 3:2); [R]23D -24.7 (c 3.5, CH2-
Cl2); IR (film) 3426, 2945, 1734, 1613, 1513, 1465, 1363, 1302,
(4aS,4bR,8R,8aS,10R,10aS)-2-(3-(4-Methoxybenzyloxy)-
propyl)-4,4a,4b,5,8a,9,10,10a-octahydro-1-(2-(tri-isopropyl-
silyloxy)-ethyl)-8,10-bis(methoxymethoxy)-4a,6-dimethyl-
phenanthren-3(8H)-one (27). To a yellow solution of KHMDS
(1.7 mmol, in 3.4 mL toluene, 0.5 M) at -78 °C under argon
was added ester 26 (658 mg, 0.85 mmol) in toluene (2 mL +
1.4 mL rinse). The reaction mixture was stirred for 2 min and
then triethylphosphite (0.3 mL, 1.7 mmol) was added. The
mixture was stirred for 2 min, and then the argon was exchanged
for an O2 atmosphere. The reaction mixture was stirred at -78
°C for 1.25 h, then quenched by the addition of sat. aqueous
NaHCO3 (10 mL). The mixture was transferred to a separation
funnel containing Et2O (50 mL) and H2O (30 mL). The aqueous
phase was extracted with Et2O (3 × 10 mL), and the combined
1
1248, 1151, 1094, 1040, 918, 883, 821, 735, 686; H NMR
(500 MHz, CDCl3) δ 7.23 (d, J ) 8.0 Hz, 2H), 6.86 (d, J )
8.0 Hz, 2H), 5.42 (bs, 1H), 4.77 (d, J ) 6.9 Hz, 1H), 4.69 (d,
J ) 6.9 Hz, 1H), 4.40 (bs, 3H), 3.94-3.83 (m, 3H), 3.80 (s,
3H), 3.76 (d, J ) 8.0 Hz, 1H), 3.66 (s, 3H), 3.42 (s, 3H), 3.39
(t, J ) 6.1 Hz, 2H), 3.12 (app. t, J ) 6.8 Hz, 1H), 2.81-2.75
(m, 1H), 2.70-2.63 (m, 1H), 2.55 (app. dt, J ) 3.9, 3.9, 13.1
Hz, 1H) 2.30-2.15 (m, 2H), 1.90-1.77 (m, 4H), 1.67 (s, 3H),
1.66-1.56 (m, 3H), 1.30-1.23 (m, 1H), 1.14-1.08 (m, 2H),
4652 J. Org. Chem., Vol. 72, No. 13, 2007

Norzoanthamine Synthesis
organic phases were washed with sat. aqueous NH4Cl (20 mL)
and brine (20 mL), then dried (MgSO4), filtered, and evaporated
in vacuo. A small portion of R-hydroxy ester 27a was subjected
to silica gel column chromatography (pentane/Et2O; 3:2-2:3),
and the major diastereomer was eluted free of its epimer and
characterized, but in practice the crude mixture was taken to
the next step. 27a: Rf, 0.34 (Et2O/pentane, 3:2); 1H NMR (300
MHz, CDCl3) δ 7.24 (d, J ) 8.7 Hz, 2H), 6.86 (d, J ) 8.7 Hz,
2H), 5.41 (bs, 1H), 4.84-4.77 (m, 5H), 4.64 (d, J ) 7.0 Hz,
1H), 4.39 (s, 2H), 3.88-3.82 (m, 2H), 3.80 (s, 3H), 3.73 (s,
3H), 3.71-3.65 (m, 2H), 3.44 (s, 3H), 3.42-3.36 (m, 7H), 2.91
(ddd, J ) 4.0, 4.0, 8.1 Hz, 1H), 2.78-2.67 (m, 1H), 2.52 (d, J
) 11.0 Hz, 1H), 2.41-2.26 (m, 2H), 2.06 (d, J ) 14.4 Hz,
1H), 2.03-1.93 (m, 1H), 1.83-1.74 (m, 3H), 1.66 (s, 3H), 1.59
(s, 3H),1.54-1.45 (m, 1H), 1.14 (app. q, J ) 11.8 Hz, 1H),
1.08-0.98 (m, 23H), 0.79 (s, 3H); 13C NMR (50 MHz, C6D6)
δ 177.3, 159.2, 138.2, 136.2, 134.0, 132.8, 129.3, 129.2, 126.4,
121.5, 113.7, 96.9, 95.7, 80.3, 75.5, 72.5, 70. 2, 62.7, 55.9, 55.6,
55.2, 52.7, 50.1, 47.1, 40.5, 38.7, 36.8, 33.6, 29.8, 29.7, 26.9,
23.4, 18.1, 16.1, 12.0; HRMS (ESI) calcd for C44H72O10SiNa
[M + Na], 811.4787; found, 811.4777. The R-hydroxy ester
27a (crude product) was dissolved in THF (3.4 mL) and cooled
to -78 °C followed by dropwise addition of lithium aluminum
hydride (3.4 mL, 3.4 mmol, 1 M in THF) and stirred for 2 min,
then warmed to rt and stirred for 1.25 h. The reaction was cooled
to 0 °C and phosphate buffer (pH ) 7.000 ( 0.010, Radiometer
analytical, Na2HPO4 27.5 mmol/L and KH2PO4 20.0 mmol/L,
Germicides, 4 mL) was added dropwise (violent gas evolution),
and the mixture was stirred for 2 min. Then THF (2 mL) and
NaIO4 (960 mg, 4.5 mmol) were added, and the reaction was
stirred for 1.75 h. Then more NaIO4 (330 mg, 1.5 mmol) was
added, and the reaction was stirred for 0.5 h.The temperature
was then raised to 28 °C, and the mixture was stirred for 0.5 h.
More NaIO4 (170 mg, 0.80 mmol) was then added. The reaction
mixture was stirred for 55 min then more NaIO4 (170 mg, 0.80
mmol) was added and stirred for 50 min after which full
conversion based on TLC analysis was achieved. The reaction
mixture was partitioned between Et2O (50 mL) and H2O (50
mL). The aqueous phase was extracted with Et2O (4 × 20 mL),
then brine was added to the aqueous phase and further extracted
with AcOEt (2 × 20 mL). The combined organic phases were
dried (MgSO4), filtered, and evaporated to dryness in vacuo.
The residue was purified by silica gel column chromatography
(AcOEt/hexane, 1:2) providing enone 27 (489 mg, 79% from
(4aS,4bR,8R,8aS,10R,10aS)-4,4a,4b,5,8a,9,10,10a-Octahy-
dro-1-(2-(tri-isopropyl-silyloxy)-ethyl)-2-(3-hydroxypropyl)-
8,10-bis(methoxymethoxy)-4a,6-dimethylphenanthren-3(8H)-
one (39). Enone 27 (29.6 mg, 0.041 mmol) was dissolved in a
mixture of CH2Cl2 (1 mL) and H2O (0.08 mL). DDQ (14.0 mg,
0.062 mmol) was added to the reaction mixture in one portion
and stirred vigorously for 30 min. Aqueous sat. NaHCO3 (10
mL) was added, and the reaction mixture was stirred for 5 min.
The mixture was partitioned between Et2O (30 mL) and H2O
(20 mL). The organic phase was washed with H2O (20 mL),
and the combined aqueous phases were back-extracted with Et2O
(2 × 10 mL). The combined organic phases were washed with
brine (20 mL) and dried (Na2SO4), filtered, and evaporated to
dryness in vacuo. The residue was purified by flash column
chromatography (Et2O/pentane, 1:1-0-1) affording 39 (17.9 mg,
72%) as a colorless oil. 39: mp 82-83 °C; Rf, 0.38 (AcOEt/
heptane, 3:2); [R]23 -21.6 (c 7.0, CH2Cl2); IR (film) 3459,
D
2941, 1653, 1595, 1559, 1465, 1379, 1211, 1150, 1101, 1041,
1
923, 883, 786, 728, 681, 658; H NMR (300 MHz, CDCl3) δ
5.51 (bs, 1H), 4.81 (d, J ) 7.0 Hz, 1H), 4.75 (d, J ) 7.0 Hz,
1H), 4.64 (d, J ) 7.0 Hz, 1H), 4.59 (d, J ) 7.0 Hz, 1H), 4.06
(ddd, J ) 4.7, 9.2, 9.2 Hz, 1H), 3.83-3.72 (m, 2H), 3.68-3.50
(m, 2H), 3.42 (ddd, J ) 5.1, 10.6, 10.6 Hz, 1H), 3.34 (s, 3H),
3.28 (s, 3H), 3.05 (ddd, J ) 4.6, 4.6, 13.1 Hz, 1H), 2.97-2.83
(m, 2H), 2.78 (app. t, J ) 5.6 Hz, 1H), 2.60-2.44 (m, 2H),
2.39 (d, J ) 16.9 Hz, 1H), 2.20 (d, J ) 10.5 Hz, 1H), 1.77 (d,
J ) 16.9 Hz, 1H), 1.76-1.61 (m, 2H), 1.57-1.47 (m, 4H), 1.41
(d, J ) 7.8 Hz, 2H), 1.15-0.97 (m, 23H), 0.53 (s, 3H); 13C
NMR (75 MHz, C6D6) δ 197.5, 156.2, 138.3, 135.0, 122.6, 97.2,
95.7, 80.1, 76.5, 62.8, 61.6, 55.9, 55.4, 52.8, 51.6, 45.7, 41.0,
39.2, 36.2, 33.0, 29.2, 23.5, 21.6, 18.3, 13.8, 12.3; HRMS (ESI)
calcd for C34H60O7SiNa [M + Na+], 631.4001; found, 631.4005.
26) as a colorless oil. 27: Rf, 0.43 (Et2O/pentane, 3:2); [R]23
D
-18.7 (c 1.7, CH2Cl2); IR (film) 2942, 1662, 1616, 1516, 1464,
1380, 1248, 1096, 922, 884, 821, 737, 685; 1H NMR (300 MHz,
CDCl3) δ 7.25 (d, J ) 8.8 Hz, 2H), 6.85 (d, J ) 8.8 Hz, 2H),
5.43 (bs, 1H), 4.84-4.75 (m, 3H), 4.64 (d, J ) 7.1 Hz, 1H),
4.41 (s, 2H), 3.91 (ddd, J ) 4.7, 9.2, 9.2 Hz, 1H), 3.79 (s, 3H),
3.78-3.75 (m, 1H), 3.72-3.63 (m, 2H), 3.45-3.37 (m, 8H),
2.97 (ddd, J ) 4.0, 4.0, 13.0 Hz, 1H), 2.92-2.82 (m, 1H), 2.56-
2.45 (m, 3H), 2.42 (d, J ) 10.6 Hz, 1H), 2.33 (ddd, J ) 6.5,
9.4, 13.4 Hz, 1H), 2.07 (d, J ) 17.1 Hz, 1H), 1.83-1.74 (m,
2H), 1.67 (s, 3H), 1.66-1.38 (m, 3H), 1.19 (app. q, J ) 12.0,
1H), 1.10-0.99 (m, 22H), 0.80 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 197.2, 159.0, 155.8, 138.1, 135.8, 130.6, 129.3, 121.5,
113.6, 96.9, 95.6, 80.6, 79.8, 76.1, 72.3, 69.8, 62.2, 56.1, 55.6,
55.2, 52.5, 51.6, 45.8, 41.0, 36.0, 35.6, 29.3, 29.0, 23.4, 22.2,
18.0, 13.8, 11.8; HRMS (ESI) calcd for C42H68O8SiNa [M +
Na], 751.4601; found, 751.4581.
(4aS,4bR,8R,8aS,10R,10aS)-4,4a,4b,5,8a,9,10,10a-Octahy-
dro-1-(2-(tri-isopropyl-silyloxy)-8,10-bis(methoxymethoxy)-
4a,6-dimethyl-2-((S)-5-methyl-6-((R)-2,2-dimethyloxazolidin-
5-yl)-3-oxohexyl)phenanthren-3(8H)-one (41). Alcohol 39
(48.7 mg, 0.080 mmol) was dissolved in CH2Cl2 (0.5 mL), and
the reaction was cooled to -30 °C and DIPEA (54 µL, 0.32
mmol) and DMSO (60 µL) were added. Sulfurtrioxide pyridine
complex (SO3‚pyr) (38 mg, 0.24 mmol) was dissolved in DMSO
(150 µL) and added dropwise to the reaction mixture and stirred
for 20 min while warming to -20 °C. The reaction was purified
directly by flash column chromatography (AcOEt/pentane, 1:4)
providing 40 (43.9 mg, 90%) as a colorless oil. 40: Rf, 0.59
1
(AcOEt/heptane, 3:2); H NMR (300 MHz, CDCl3) δ 9.48 (s,
1H), 5.53 (bs, 1H), 4.80-4.76 (m, 2H), 4.61 (d, J ) 7.0 Hz,
J. Org. Chem, Vol. 72, No. 13, 2007 4653

Juhl et al.
1H), 4.60 (d, J ) 7.0 Hz, 1H), 4.04 (ddd, J ) 4.7, 9.1, 9.1 Hz,
1H), 3.82-3.73 (m, 2H), 3.42 (ddd, J ) 4.9, 11.4, 11.4 Hz,
1H), 3.35 (s, 3H), 3.28 (s, 3H), 3.07 (ddd, J ) 5.1, 5.1, 13.3
Hz, 1H), 3.00-2.71 (m, 3H), 2.50-2.43 (m, 1H), 2.39 (d, J )
16.9 Hz, 1H), 2.30-2.23 (m, 2H), 2.18 (d, J ) 10.7 Hz, 1H),
1.75 (d, J ) 16.9 Hz, 1H), 1.58-1.47 (m, 4H), 1.42-1.36 (m,
2H), 1.15-0.91 (m, 23H), 0.53 (s, 3H); 13C NMR (75 MHz,
C6D6) δ 200.1, 196.0, 155.7, 137.2, 135.0, 122.6, 97.1, 95.7,
80,1, 76.3, 62.8, 55.9, 55.4, 52.8, 51.6, 45.7, 43.6, 41.0, 39.2,
36.2, 36.1, 29.1, 23.4, 19.3, 18.3, 13.7, 12.3. Iodide 38 (43.3
mg, 0.11 mmol) was dissolved in Et2O (0.2 mL) and cooled to
-78 °C, then t-BuLi (146 µL, 0.25 mmol) was added, and the
resulting mixture was stirred for 4 min at -78 °C under an
argon atmosphere. Then aldehyde 40 (43.9 mg, 0.072 mmol)
was dissolved in Et2O (0.2 mL) and added to lithiated 38 and
stirred for 2 h from -78 to -46 °C. The reaction mixture was
quenched by the addition of sat. aqueous NH4Cl (0.1 mL) and
warmed to rt. The mixture was purified directly by flash column
chromatography (AcOEt/hexane, 1:2) providing a diastereomeric
and rotameric mixture of alcohols (32.3 mg, 52%). The
diastereomeric mixture of alcohols (32.3 mg, 0.037 mmol) was
dissolved in CH2Cl2 (0.25 mL), the solution was cooled to -15
°C, and N,N-diisopropylethylamine (27 µL, 0.16 mmol) and
DMSO (30 µL) was added. SO3‚pyr (19 mg, 0.12 mmol) was
dissolved in DMSO (75 µL) and added dropwise to the reaction
mixture, and the mixture was stirred for 1 h while the
temperature reached 8 °C. The reaction was purified directly
by flash column chromatography (AcOEt/pentane, 1:4) affording
diketone 41 (15.4 mg, 25% from 40) as a colorless oil. 41: Rf,
0.51 (AcOEt/heptane, 1:1); [R]23D 1.8 (c 0.4, CH2Cl2); IR (film)
2939, 1700, 1653, 1465, 1395, 1151, 1101, 1042, 922, 882; 1H
NMR (300 MHz, CDCl3) δ 5.44 (bs, 1H), 5.82 (d, J ) 7.0 Hz,
1H) 4.81 (d, J ) 7.1 Hz, 1H), 4.76 (d, J ) 7.0 Hz, 1H), 4.65
(d, J ) 7.1 Hz, 1H), 4.10-3.87 (m, 2H), 3.78 (d, J ) 9.0 Hz,
1H), 3.75-3.60 (m, 3H), 3.44 (s, 3H), 3.38 (s, 3H), 3.03-2.95
(m, 2H), 2.89-2.79 (m, 1H), 2.75-2.53 (m, 3H), 2.50-2.38
(m, 4H), 2.09 (dd, J ) 2.5, 17.0 Hz, 1H), 1.83-1.75 (m, 1H),
1.68 (m, 5H), 1.56-1.44 (m, 16H), 1.19 (app. q, J ) 12.0 Hz,
1H), 1.07-1.01 (m, 27H), 0.94 (d, J ) 6.5 Hz, 3H), 0.83 (s,
3H); 13C NMR (75 MHz, C6D6) δ 201.7, 197.2, 157.4, 156.9,
137.0, 136.6, 135.7, 121.6, 96.8, 95.7, 79.9, 75.9, 62.2, 56.1,
55.7, 52.7, 51.7, 51.2, 45.8, 43.3, 41.2, 41.1, 39.8, 38.8, 38.7,
36.1, 35.8, 29.0, 28.4, 27.3, 26.4, 25.2, 24.3, 23.4, 20.4, 20.0,
18.8, 18.0, 13.9, 11.9; HRMS (ESI) calcd for C49H84NO12Si
[M + HCOO-], 906.5768; found, 906.5750.
Acknowledgment. We thank the Technical University of
Denmark, The Lundbeck Foundation, and the Augustinus
Foundation for financial support. We are indebted to Dr. Thomas
E. Nielsen for initial synthetic studies on fragment A.
Supporting Information Available: Experimental details for
the synthesis of 11, 14-16, 22, 23, 29-32, 33a, 33, 37, and 38;
copies of 1H NMR and/or 13C NMR spectra of all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO070165R
4654 J. Org. Chem., Vol. 72, No. 13, 2007