An efficient synthesis of the carbocyclic core of zoanthenol

Article abstract of DOI:10.1016/j.tet.2009.05.023

A concise strategy for the synthesis of the carbocyclic portion of zoanthenol is disclosed. The key step involves a 6-endo radical-mediated conjugate addition that constructs the quaternary stereocenter at C(12) and closes the B ring in a stereoselective

Full text of DOI:10.1016/j.tet.2009.05.023

Tetrahedron 65 (2009) 6571–6575
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An efficient synthesis of the carbocyclic core of zoanthenol
*
Jennifer L. Stockdill, Douglas C. Behenna, Andrew McClory, Brian M. Stoltz
The Arnold and Mabel Beckman Laboratories of Chemical Synthesis, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise strategy for the synthesis of the carbocyclic portion of zoanthenol is disclosed. The key step
involves a 6-endo radical-mediated conjugate addition that constructs the quaternary stereocenter at
C(12) and closes the B ring in a stereoselective manner. The synthesis of the C-ring fragment uses an
enantioselective desymmetrization to simultaneously establish the absolute stereochemistry of two
vicinal quaternary stereocenters. In only 17 steps from known compounds, the route affords an ABC ring
system containing all three quaternary stereocenters and appropriate functionality to complete the
synthesis of zoanthenol.
Received 18 March 2009
Received in revised form 1 May 2009
Accepted 8 May 2009
Available online 18 May 2009
Dedicated to Professor Larry E. Overman
on the occasion of his receipt of the
Tetrahedron Prize
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
envisioned to be accessible from tetracycle 5, which in turn could
be formed from aryl bromide 6 by radical-induced intramolecular
The zoanthamine family of natural products has provided
a challenging platform for synthetic innovation since the first
member of the family was isolated 25 years ago (Fig. 1).1,2 This
structurally complex and stereochemically dense family of natural
products exhibits a range of important biological activities in-
cluding anti-osteoporotic, anti-inflammatory, antibacterial, and
cytotoxic properties.2 A number of synthetic groups have made
important contributions2 in efforts to access these complex alka-
loids, including the total syntheses of norzoanthamine by Miyashita
et al. in 2004 and by Kobayashi et al. in 2008.3 To date no groups
have reported the synthesis of zoanthenol (1), but Hirama et al.
have disclosed an advanced strategy for its completion.4
Our synthetic efforts toward the zoanthamine alkaloids initially
focused on the assembly of the challenging carbocyclic core (ABC
rings) of zoanthenol (1). We were drawn to zoanthenol as our initial
target due to its oxidized A ring, which allowed for a greater di-
versity of synthetic approaches because of the range of chemistry
available to aromatic systems. The carbocyclic core was of special
concern due to the density of stereochemical elements arrayed in
the B and C rings. Our retrosynthetic analysis began by unraveling
the heterocyclic DEFG rings of zoanthenol, revealing a tricyclic core
with a functionalized side-chain (2, Scheme 1). The cyclization
events2 required to convert compound 2 to the natural product
were well-established as thermodynamically favorable by
Kobayashi et al.,5 Williams and Cortez,6 and Miyashita et al.3a Dis-
connection of the side-chain from intermediate 2 at the C(8)–C(9)
bond revealed tricyclic alkyne 3 and lactam 4. Tricycle 3 was
conjugate addition. This tethered A–C ring system would arise from
the addition of benzylic Grignard reagent 7 to enal 8. Enal 8 would
be derived from methyl ketone 9, which could be obtained from the
desymmetrization of meso anhydride 10.
2. Results and discussion
Zoanthenol’s C ring is arguably the most complex region of the
molecule because it is fused to three other rings and boasts five
consecutive stereocenters, of which three are all-carbon quaternary
centers. It was our expectation that the C ring would pose the
greatest challenges in stereochemical control, as well as in carbon–
carbon bond-construction. The vicinal all-carbon quaternary cen-
ters (at C(9) and C(22)) posed a particular challenge, thus our
strategy was to establish this functionality at an early stage. We
targeted the known Diels–Alder cycloadduct 117 (Scheme 2) as
a starting material that could be converted to a meso anhydride,
which could in turn be desymmetrized with a chiral reagent to
allow the enantioselective synthesis of zoanthenol. In fact, several
reports indicated that the selective methanolysis of a meso anhy-
dride was a viable approach.8 We anticipated that employing
a strong acid would induce desilylation of anhydride 11 followed by
in situ dehydration. Gratifyingly, the treatment of Diels–Alder ad-
duct 11 with 0.5 equivalents of sulfuric acid in 1,2-dichloroethane
produced anhydride 10 in 94% yield. At this point, we were poised
to attempt the key desymmetrization. To our delight, treatment of
anhydride 10 with quinine and methanol in toluene at 22 ꢀC
resulted in the formation of half-ester 12 in >99% yield and 50% ee.
Performing the reaction at À50 ꢀC increased the enantiomeric ex-
cess to 77% while maintaining a good yield.9 The enantiomer of
* Corresponding author.
E-mail address: stoltz@caltech.edu (B.M. Stoltz).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.023

6572
J.L. Stockdill et al. / Tetrahedron 65 (2009) 6571–6575
26
28
O
H
O
OH
O
H
20
18
O
O
16
25
18
A
B
21
22
13
27
29
10
12
11
14
C
24
D
9
O
6
O
O
O
O
O
E
N
O
N
N
O
1
F
O
G
3
30
Zoanthamine
Norzoanthamine
Zoanthenol
O
R
O
H
O
O
H
H
O
O
O
O
O
O
O
O
O
O
O
N
O
N
N
O
O
3
R
R'
30
R = H, Norzoanthaminone
R = Me, Zoanthaminone
Zoanthenamide
R = OH, 3-Hydroxyzoanthamine
R' = OH, 30-Hydroxyzoanthamine
Figure 1.
half-ester 12 could be obtained in similar yield and enantiopurity
by substituting quinine for quinidine. Finally, the enantioselectivity
could be further increased to 85% by employing O-(À)-(menthyl
acetate)quinidine in the reaction at À50 ꢀC for 10 days.10 To the best
of our knowledge, this work represents the first example of the
desymmetrization of a meso anhydride that simultaneously estab-
lishes the absolute stereochemistry of two vicinal all-carbon qua-
ternary stereocenters.11
newly established stereochemical information. We were pleased to
find that iodolactonization of half-ester 12 could be affected with
good positional selectivity and yield (87%) to provide 13 (Scheme 3).
Treatment of the iodolactone with silver acetate led to a syn-peri-
planar vinylogous attack by the acetate nucleophile to afford allylic
acetate 14. Recrystallization enhanced the enantiomeric excess of
this acetate to 98%. Methanolysis of iodolactone 14 produced allylic
alcohol 15, the connectivity and relative stereochemistry of which
were determined unambiguously by X-ray analysis. We sought to
convert the ester and lactone functionalities at C(8) and C(23) to the
With our desymmetrized C ring in hand, we sought to oxy-
genate C(10) and C(21) using the carboxylic acid as a relay for the
OMe
OMe
OH
O
O
O
OMe
OH
O
9
O
Boc
8
O
O
O
O
N
O
O
N
O
7
+
3
TBSO
BocHN
OTBS
4
Zoanthenol (1)
2
OMe
OMe
TBSO
O
TBSO
O
O
O
O
Br
O
OTBS
OTBS
5
6
H
O
O
O
OMe
O
O
TBSO
O
+
MgBr
O
O
O
OTBS
OTBS
7
8
9
10
Scheme 1.

J.L. Stockdill et al. / Tetrahedron 65 (2009) 6571–6575
6573
O
OTBS
O
O
quinine (1 equiv)
OMe
OH
H2SO4 (0.5 equiv)
DCE, reflux, 3 d
MeOH (3 equiv)
O
O
toluene, –50 ºC, 72 h
O
(85% yield, 77% ee)
(94% yield)
O
O
11
10
12
Scheme 2.
O
O
O
O
21
O
KI, I2, NaHCO3
ACN/H2O, dark
OMe
O
AgOAc
OMe
OH
I
OMe
Py, 32 °C
O
10
(87% yield)
(82% yield)
OAc
O
12
13
14
recrystallized
to 98% ee
O
OH
OH
O
O
O
23
K2CO3
MeOH
TBSOTf, Py
OMe
LAH, THF
OMe
O
O
8
CH2Cl2, 0 → 23 °C
OH
0 → 23 °C
(83% yield
2 steps)
(93% yield)
OH
TBSO
OTBS
15
confirmed by
16
17
X-ray
Scheme 3.
alcohol oxidation state. Thus, allylic alcohol 15 was smoothly sily-
lated upon treatment with TBSOTf and pyridine to provide 16,
which was reduced with lithium aluminum hydride to form triol 17
in 83% yield over the two steps. Triol 17 is a versatile intermediate
that has facilitated the exploration of a number of synthetic ap-
proaches to zoanthenol.12
We turned our attention to the conversion of triol 17 to the
proposed C-ring synthon 8. Thus, allylic alcohol 17 was selectively
oxidized,13 the primary alcohols were constrained with an acetal
functionality, and the resulting enone was hydrogenated to afford
ketone 18 in excellent yield over three steps (Scheme 4). The ketone
formation of enal 8 in 65% yield with complete recovery of the
unreacted enol triflate 19.
The A and C rings were smoothly coupled by treatment of enal 8
with benzylic Grignard 7,12,14 affording alcohol 20 in 87% yield as
a 10:1 mixture of diastereomers (Scheme 5). Subsequent oxidation
of this alcohol with Dess–Martin periodinane15 provided the cor-
responding enone (21) in 89% yield. To explore the possibility of
a radical-induced cyclization of the A ring into the C-ring enone, the
C(13) aryl bromide derivative of enone 21 was synthesized. N-
Bromosuccinimide is known to brominate positions para to elec-
tron releasing groups.16 While there was little precedent to suggest
the superior directing ability of silyl ethers relative to methyl ethers
in this reaction, there was significant evidence that hydroxyls were
superior to methyl ethers.17 As a result, we carried out a three-step
protocol to regioselectively produce aryl bromide 6. The yield for
the sequence was disappointingly low, owing to competitive desi-
lylation and general decomposition during the silylation and
was then
a-methylated under standard conditions to provide
methyl ketone 9 as a mixture of diastereomers. The mixture was
enolized with KHMDS and trapped by N-phenyl bis(trifluoro-
methanesulfonimide) to afford enol triflate 19 in 92% yield. Treat-
ment of enol triflate 19 under the reductive carbonylation
conditions developed during our earlier studies14 led to the
OH OH
O
1. (NH4)6Mo7O24●4H2O, aq H2O2
K2CO3, (n-Bu)4NCl, THF
LDA, –78 °C, 2h
O
then HMPA, 0 °C, 1h
OH
then MeI, –30 °C
O
2. CuSO4, acetone
3. Pd/C, H2, EtOAc
OTBS
OTBS
(72% yield, 10% yield 18)
(92% yield, 3 steps)
17
18
H
O
O
P(c-Hex)2
OTf
(c-Hex)2P
O
O
O
O
O
O
Pd(OAc)2, CO, DMA, LiCl
TEA, Et3SiH, 35 °C
KHMDS, THF
PhNTf2, –25 °C
(92% yield)
OTBS
OTBS
(65% yield, 35% recovered 19)
OTBS
9
19
8
Scheme 4.

6574
J.L. Stockdill et al. / Tetrahedron 65 (2009) 6571–6575
OMe
H
O
TBSO
OH
OMe
O
O
Et2O:CH2Cl2 1.2:1
–12 °C
TBSO
O
O
+
MgBr
(87% yield)
10:1 dr
OTBS
OTBS
7
8
20
OMe
OMe
TBSO
O
TBSO
O
1. TBAF, THF
DMP, CH2Cl2
2. NBS, ACN
O
O
O
13
14
3. TBSCl, DMAP, imidazole
CH2Cl2, 40 °C
0 °C
Br
O
(89% yield)
(29% yield, 3 steps)
OTBS
OTBS
6
21
NBS, ACN, CH2Cl2, 0 °C
(80% yield, 4:1 ratio of isomers)
Scheme 5.
bromination steps. We were pleased to find that direct bromination
of enone 21 afforded bromoarene 6 in 80% yield as a 4:1 mixture of
isomers resulting from bromination at C(13) and C(14), re-
spectively. Gratifyingly, the desired isomer was the major product,
and the mixture was adequate for the investigation of the radical
cyclization.
With aryl bromide 6 in hand, we began to explore radical cy-
clization reactions to close the B ring of zoanthenol. Although endo
radical conjugate addition cyclization reactions are much less
common than exo reactions,18 good precedent for arene radical
conjugate addition to make a quaternary center and a six-mem-
bered ring did exist.19 To our delight, we found that in the presence
of azo radical initiators (e.g., AIBN) and a hydrogen atom donor (e.g.,
Bu3SnH), significant amounts of ketone 5 were formed from 6
(Scheme 6). In addition to the desired product, debrominated
material (21) was obtained. Fortunately, the reduced material is
readily separated from tetracycle 5 and can be rebrominated to
allow for sufficient material throughput. The most effective con-
ditions for the cyclization employed the azo initiator V-70 with
slow addition of Ph3SnH at 32 ꢀC. The use of V-70, which de-
composes more readily (t1/2z10 h at 30 ꢀC) than AIBN (t1/2z10 h at
80 ꢀC), allows us to initiate the radical reaction at lower tempera-
tures and reduces the amount of debrominated enone recovered,
resulting in improved yields of 5. In the event, cyclization occurs to
provide tetracycle 5 in 40% yield as a single diastereomer pos-
sessing the desired stereochemistry at both the newly formed all-
carbon quaternary center and the tertiary center at the B–C ring
junction. The stereochemical outcome of the key radical cyclization
was unambiguously confirmed by X-ray structure analysis of alco-
hol 22, which was obtained by DIBAL reduction of ketone 5.20
OMe
OMe
OMe
CN
OMe
N
O
TBSO
O
TBSO
O
TBSO
N
MeO
NC
V-70
O
O
O
O
O
O
+
13
14
12
Br
Ph3SnH, PhH, 32 °C
OTBS
OTBS
OTBS
6
21
5
4 : 1 mixture of
(40% yield)
(6 : bromide positional isomer)
OMe
TBSO
OH
O
O
DIBAL
THF, 0 °C
(68% yield)
OTBS
22
(silyl groups removed for clarity)
Scheme 6.

J.L. Stockdill et al. / Tetrahedron 65 (2009) 6571–6575
6575
Importantly, this result completes the synthesis of the carbocyclic
References and notes
core of zoanthenol, requiring just 17 steps from known Diels–Alder
adduct 11.
1. (a) Roa, C. B.; Anjaneyulu, A. S. R.; Sarma, N. S.; Venkateswarlu, Y.; Rosser, R. M.;
Faulkner, D. J.; Chen, M. H. M.; Clardy, J. J. Am. Chem. Soc. 1984, 106, 7983–7984;
(b) Roa, C. B.; Anjaneyula, A. S. R.; Sarma, N. S.; Venkatateswarlu, Y. J. Org. Chem.
1985, 50, 3757–3760; (c) Fukuzawa, S.; Hayashi, Y.; Uemura, D.; Nagatsu, A.;
Yamada, K.; Ijuin, Y. Heterocycl. Commun. 1995, 1, 207–214; (d) Atta-ur-Rahman;
Alvi, K. A.; Abbas, S. A.; Choudhary, M. I.; Clardy, J. Tetrahedron Lett. 1989, 30,
3. Conclusions
´
´
6825–6828; (e) Daranas, A. H.; Fernandez, J. J.; Gavın, J. A.; Norte, M. Tetrahe-
dron 1998, 54, 7891–7896; (f) Daranas, A. H.; Ferna´ndez, J. J.; Gavı´n, J. A.; Norte,
M. Tetrahedron 1999, 55, 5539–5546.
In summary, we have described an efficient synthetic approach
to the carbocyclic core of zoanthenol that addresses the demanding
combination of a fused polycyclic framework and multiple contig-
uous stereocenters. The synthetic approach is highlighted by
a versatile desymmetrization of a bis-quaternary meso anhydride
that enables access to either enantiomer of zoanthenol by selecting
the appropriate cinchona alkaloid. The resulting stereochemical
information is then relayed around the C ring by a series of dia-
stereoselective reactions. Additionally, good selectivity is observed
during the Grignard addition to couple the A and C rings, and the
superior directing ability of a silyl ether in the presence of a methyl
ether was established in arene bromination reactions. Finally, the
key radical cyclization occurs with excellent diastereoselectivity to
construct the third all-carbon quaternary center within a single six-
membered ring and establishes the correct relative stereochemis-
try for the tertiary center at the B–C ring junction. Overall, the
approach allows access to the challenging carbocyclic core of
zoanthenol in 17 steps.
2. Behenna, D. C.; Stockdill, J. L.; Stoltz, B. M. Angew. Chem., Int. Ed. 2008, 47, 2365–
2386 and references therein.
3. (a) Miyashita, M.; Sasaki, M.; Hattori, I.; Sakai, M.; Tanino, K. Science 2004, 305,
495–499; (b) Murata, Y.; Yamashita, D.; Kitahara, K.; Minasako, Y.; Nakazaki, A.;
Kobayashi, S. Angew. Chem., Int. Ed. 2008, 47, 1400–1403; (c) Yamashita, D.;
Murata, Y.; Hikage, N.; Takao, K.; Nakazaki, A.; Kobayashi, S. Angew. Chem., Int.
Ed. 2008, 47, 1403–1406.
4. Sugano, N.; Koizumi, Y.; Hirai, G.; Oguri, H.; Kobayashi, S.; Yamashita, S.;
Hirama, M. Chem. Asian J. 2008, 3, 1549–1557.
5. (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; (c) Hikage, N.; Furukawa, H.; Takao, K.; Kobayashi, S.
Chem. Pharm. Bull. 2000, 48, 1370–1372.
6. Williams, D. R.; Cortez, G. A. Tetrahedron Lett. 1998, 39, 2675–2678.
7. Birman, V. B.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 2080–2081.
8. (a) For a review, see: Chen, Y.; McDaid, P.; Deng, L. Chem. Rev. 2003, 103, 2965–
2983; (b) For an application in synthesis, see: Starr, J. T.; Koch, G.; Carreira, E. M.
J. Am. Chem. Soc. 2000, 122, 8793–8794.
9. Treatment of 10 with catalytic quinine (10 mol %), pentamethylpiperidine
(1 equiv), and methanol for 18 days at À50 ꢀC provided half-ester 12 in 88%
yield and 70% ee.
10. In practice, high ee material was most readily accessible by advancing the 77%
ee material and recrystallizing at a later step. For the purpose of synthetic
explorations, racemic material was employed and could be accessed by use of
catalytic quinine (10 mol %) at ambient temperature with 1.1 equiv of DBU, 3–
5 equivalents MeOH, and 0.1 M toluene.
11. Petersen, E. A.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 11943–11948.
12. Stockdill, J. L.; Behenna, D. C.; Stoltz, B. M. Tetrahedron Lett. 2009, 50, 3182–
3184.
13. Trost, B. M.; Masuyama, Y. Tetrahedron Lett. 1984, 25, 173–176.
14. Behenna, D. C.; Stockdill, J. L.; Stoltz, B. M. Angew. Chem., Int. Ed. 2007, 46, 4077–
4079.
15. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7278.
16. (a) Carreno, M. C.; Ruano, J. L. G.; Sanz, G.; Toledo, M. A.; Urbano, A. J. Org. Chem.
1995, 60, 5328–5331; (b) Berthelot, J.; Guette, C.; Desbe`ne, P.-J.; Basselier, J.-J.
Can. J. Chem. 1989, 67, 2061–2066.
Acknowledgements
The authors wish to thank Novartis (graduate fellowship to
J.L.S.), the Philanthropic Education Organization (Scholar Award to
J.L.S.), the Fannie and John Hertz Foundation (graduate fellowship
to D.C.B.), Abbott, Amgen, Boehringer-Ingelheim, Bristol-Myers
Squibb, Merck, and Caltech for their generous financial support.
Additionally, we acknowledge Prof. Li Deng of Brandeis University
for the kind donation of O-(À)-(menthyl acetate)quinidine and for
helpful discussions.
17. Carreno, M. C.; Ruano, J. L. G.; Sanz, G.; Toledo, M. A.; Urbano, A. Synlett 1997,
1241–1242.
18. For an excellent review of intramolecular radical conjugate addition, see:
Zhang, W. Tetrahedron 2001, 57, 7237–7262.
Supplementary data
19. Rajamannar, T.; Balasubramanian, K. K. J. Chem. Soc., Chem. Commun. 1994,
25–26.
20. TBS groups removed from the figure for clarity.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.05.023.