Studies on oxidopyrylium [5 + 2] cycloadditions: Toward a general synthetic route to the C12-hydroxy daphnetoxins

Article abstract of DOI:10.1021/ol062234e

12-Hydroxydaphnetoxins, members of the structurally fascinating daphnane diterpene family, exhibit a wide range of significant biological activities. A general route to the BC-ring system of 12-hydroxy daphnetoxins is reported based on D-ribose. Depending on the choice of protecting groups and solvent, the oxidopyrylium-alkene [5 + 2] cycloaddition originating from A provides cycloadduct diastereomer B or C with good to excellent selectivity.

Full text of DOI:10.1021/ol062234e

ORGANIC
LETTERS
2006
Vol. 8, No. 23
5373-5376
Studies on Oxidopyrylium [5
+ 2]
Cycloadditions: Toward a General
Synthetic Route to the C12-Hydroxy
Daphnetoxins
Paul A. Wender,*,†,‡ F. Christopher Bi,† Nicole Buschmann,† Francis Gosselin,†
Cindy Kan,† Jung-Min Kee,† and Hirofumi Ohmura†
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080, and
Department of Molecular Pharmacology, Stanford UniVersity School of Medicine,
Stanford UniVersity, Stanford, California 94305
wenderp@stanford.edu
Received September 8, 2006
ABSTRACT
12-Hydroxydaphnetoxins, members of the structurally fascinating daphnane diterpene family, exhibit a wide range of significant biological
activities. A general route to the BC-ring system of 12-hydroxy daphnetoxins is reported based on -ribose. Depending on the choice of
2] cycloaddition originating from A provides cycloadduct diastereomer B or C
D
protecting groups and solvent, the oxidopyrylium
with good to excellent selectivity.
−alkene [5 +
The daphnane diterpenes represent a large family of structur-
ally complex and densely functionalized natural products that
collectively exhibit remarkably diverse biological activities,
including neurotrophic, cytoprotective, antileukemic, anti-
hyperglycemic, antitumor, inflammatory, piscicidal, insec-
ticidal, nematocidal, and tumor-promoting.1 Within the
daphnane diterpene family are the C12-hydroxy daphnetox-
ins, which have additional oxygenation in the C-ring. The
12-hydroxy daphnetoxins gnididin, gniditrin, and gnidicin
(Figure 1), all of which possess C12-acyl groups, have
antileukemic activity, whereas the parent 12-hydroxydaph-
netoxin is devoid of similar activity.2 The additional oxy-
genation could have significant biological implications, as a
variety of acyl groups are tolerated in this position.
To date, there is only one total synthesis of a daphnane
(resiniferatoxin).3 Relatively few synthetic approaches to such
compounds have been described,4 and no reports on synthetic
routes to C12-hydroxydaphnetoxins have appeared. Several
years ago, we started to investigate strategies for the synthesis
of the C12-hydroxydaphnetoxins and describe herein our first
report on this project in the form of a stereocontrolled
synthesis of a potentially general 12-hydroxydaphnane
(2) (a) Kupchan, S. M.; Sweeny, J. G.; Baxter, R. L.; Murae, T.;
Zimmerly, V. A.; Sickles, B. R. J. Am. Chem. Soc. 1975, 97, 672-673.
(3) Wender, P. A.; Jesudason, C. D.; Nakahira, H.; Tamura, N.; Tebbe,
A. L.; Ueno, Y. J. Am. Chem. Soc. 1997, 119, 12976-12977.
(4) For noteworthy synthetic approaches to daphnane diterpenes, see:
(a) Jackson, S. R.; Johnson, M. G.; Mikami, M.; Shiokawa, S.; Carreira, E.
M. Angew. Chem., Int. Ed. 2001, 40, 2694-2697. (b) Ritter, T.; Zarotti,
P.; Carreira, E. M. Org. Lett. 2004, 6, 4371-4374. (c) Page, P. C. B.;
Hayman, C. M.; McFarland, H. L.; Willock, D. J.; Galea, N. M. Synlett
2002, 583-587.
† Department of Chemistry.
‡ Department of Molecular Pharmacology.
(1) For reviews on daphnane diterpenes, see: (a) Kowalski, J. A. Ph.D.
Thesis, Stanford University, Stanford, CA, 2005, pp 31-109. (b) He, W.;
Cik, M.; Appendino, G.; Puyvelde, L. C.; Leysen, J. E.; De Kimpe, N.
Mini-ReV. Med. Chem. 2002, 2, 185-200. (c) Borris, R. P.; Blasko, G.;
Cordell, G. A. J. Ethnopharmacol. 1988, 24, 41-92. (d) Evans, F. J.; Soper,
C. J. Lloydia 1978, 41, 193-233.
10.1021/ol062234e CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/17/2006

shown that substitution at C11 and C12 of the tether in
cycloaddition precursor 5 (Figure 2) allows for predictable
Figure 1. Retrosynthetic analysis.
precursor incorporating a highly elaborated and functionally
differentiated BC bicyclic core.
Our synthetic plan (Figure 1) was designed to access
various 12-hydroxydaphnetoxin derivatives through late-stage
variation of the C12-ester and orthoester precursor groups
in advanced intermediate 1. This tricycle would arise from
Pd-catalyzed cyclization of enyne 2, which in turn would
come from the BC-bicyclic system 3. This intermediate
represents a potentially general daphnane precursor, incor-
porating several target stereocenters and differentiated,
conformationally biased functionality suitable for introduc-
tion of the A-ring and other groups. This bicycle would
emerge from the D-ribose-derived pyranone 4 by an oxi-
dopyrylium [5 + 2] cycloaddition.5
The oxidopyrylium-alkene [5 + 2] cycloaddition, a highly
effective strategy level reaction,6 has been successfully
utilized by our group7 as well as others5,8 in synthesis.
Asymmetric versions have also been reported in the litera-
ture.9 Of relevance to the current study, we have previously
Figure 2. Previous examples of stereoselective intramolecular
oxidopyrylium-alkene [5 + 2] cycloaddition.
control over the formation of the C6, C8, and C9 stereo-
centers in cycloadduct 6, an intermediate in the synthesis of
phorbol.7a,e This selectivity was also observed in the cy-
cloaddition of 7 to give the C11-, C13-, and C14-substituted
precursor 8 to resiniferatoxin.3 More recently, Trivedi and
co-workers reported an elegant enantiodivergent approach
toward simpler systems (10) incorporating C11, C12, and
C13 substituents derived from D-ribose.9e,f We herein report
our progress on the first stereoselective intramolecular
cycloaddition using fully substituted tethers, which provides
access to the fully functionalized C-ring of 12-hydroxydaph-
netoxins. The effect of protecting groups and solvent on the
diastereoselectivity of the cycloaddition are also described.
Our synthesis starts with conversion of the commercially
available chiral building block D-ribose to the known
aldehyde 12 (Scheme 1).10 Following the literature procedure,
selective protection of D-ribose and primary iodide formation
proceeded well (Scheme 1). However, subsequent zinc-
mediated Vasella fragmentation11 of 11 using the literature
protocol with methanol as the solvent gave a large amount
of the methyl hemiacetal side product as reported. We found
that the use of a catalytic amount of acetic acid in THF/
ethanol provides a more selective route to the desired
aldehyde 12. Treatment of 12 with EtMgBr followed by
TPAP oxidation afforded ethyl ketone 13. The C11 stereo-
center was then set selectively by using a boron-mediated
substrate-controlled aldol reaction12 between ketone 13 and
known furfuryl aldehyde 19,7e providing hydroxy ketone 14
(5) For reviews, see: (a) Elitzin, V. I. Ph.D. Thesis, Stanford University,
Stanford, CA, 2005, pp 50-96. (b) Sammes, P. G. Gazz. Chim. Ital. 1986,
116, 109-114. (c) Ohkata, K.; Akiba, K.-Y. AdV. Heterocycl. Chem. 1996,
65, 283-374. (d) Chiu, P.; Lautens, M. Top. Curr. Chem. 1997, 190, 1-85.
(e) Mascaren˜as, J. L. AdV. Cycloaddit. 1999, 6, 1-54.
(6) For a definition and example, see: Wender, P. A.; Ternansky, R. J.
Tetrahedron Lett. 1985, 22, 2625-2628.
(7) For synthetic applications of oxidopyrylium-alkene cycloadditions
from this laboratory, see: (a) Wender, P. A.; Lee, H. Y.; Wilhelm, R. S.;
Williams, P. D. J. Am. Chem. Soc. 1989, 111, 8954-8957. (b) Wender, P.
A.; Kogen, H.; Lee, H. Y.; Munger, J. D.; Wilhelm, R. S.; Williams, P. D.
J. Am. Chem. Soc. 1989, 111, 8957-8958. (c) Wender, P. A.; McDonald,
F. E. J. Am. Chem. Soc. 1990, 112, 4956-4958. (d) Wender, P. A.;
Mascaren˜as, J. L. J. Org. Chem. 1991, 56, 6267-6269. (e) Wender, P. A.;
Rice, K. D.; Schnute, M. E. J. Am. Chem. Soc. 1997, 119, 7897-7898.
(8) For recent examples, see: (a) Magnus, P.; Shen, L. Tetrahedron 1999,
55, 3553-3560. (b) Magnus, P.; Waring, M. J.; Ollivier, C.; Lynch, V.
Tetrahedron Lett. 2001, 42, 4947-4950. (c) Ohmori, N. Chem. Commun.
2001, 1552-1553. (d) Lopez, F.; Castedo, L.; Mascaren˜as, J. L. Chem.
Eur. J. 2002, 8, 884-899. (e) Baldwin, J. E.; Mayweg, A. V. W.; Pritchard,
G. J.; Adlington, R. M. Tetrahedron Lett. 2003, 44, 4543-4545. (f) Snider,
B. B.; Grabowski, J. F. Tetrahedron Lett. 2005, 46, 823-825.
(9) (a) Ohmori, N.; Yoshimura, M.; Ohkata, K. Heterocycles 1997, 45,
2097-2100. (b) Lo´pez, F.; Castedo, L.; Mascaren˜as, J. L. Org. Lett. 2001,
3, 623-625. (c) Lo´pez, F.; Castedo, L.; Mascaren˜as, J. L. Org. Lett. 2002,
4, 3683-3685. (d) Lo´pez, F.; Castedo, L.; Mascaren˜as, J. L. J. Org. Chem.
2003, 68, 9780-9786. (e) Krishna, U. M.; Srikanth, G. S. C.; Trivedi, G.
K.; Deodhar, K. D. Synlett 2003, 2383-2385. (f) Krishna, U. M.; Deodhar,
K. D.; Trivedi, G. K. Tetrahedron 2004, 60, 4829-4836.
(10) Paquette, L. A.; Bailey, S. J. Org. Chem. 1995, 60, 7849-7856.
(11) Bernet, B.; Vasella, A. HelV. Chim. Acta 1979, 62, 1990-2016.
5374
Org. Lett., Vol. 8, No. 23, 2006

Scheme 1. Synthesis of Acetonide-Protected Pyranone 18
Figure 3. Oxidopyrylium-alkene [5 + 2] cycloaddition of
acetonide 18 and ORTEP diagram of cycloadduct 20.
in a >95:5 diastereomeric ratio. Chelation-controlled reduc-
tion of ketone 14 with DIBAL13 and selective protection14
of the C12 alcohol gave alcohol 16. Oxidative ring expansion
using VO(acac)2/t-BuOOH15 followed by acetylation pro-
vided the cycloaddition precursor 18 as an inconsequential
mixture of C6 epimers.
The key intramolecular oxidopyrylium-alkene [5 + 2]
cycloaddition was conducted by treating 18 with DBU (2.0
equiv) in acetonitrile at 80 °C. This resulted in the exclusive
formation of the undesired cycloadduct 20 in 84% yield. The
structure of 20 was initially assigned through 1D NOE NMR
experiments and subsequently confirmed by a single-crystal
X-ray analysis (Figure 3).
Figure 4. Proposed transition states in the oxidopyrylium-alkene
[5 + 2] cycloaddition.
The stereochemical outcome of this cycloaddition differs
from prior work and is potentially a consequence of the
acetonide protecting group preventing the tether from adopt-
ing the necessary chairlike transition state that would lead
to the desired cycloadduct (Figure 4).7e We anticipated that
replacing the acetonide with more flexible protecting groups
would allow access to the chairlike transition structure and
thus reverse the diastereoselectivity.
Dibenzyl ether 26a was prepared to test this hypothesis
(Scheme 2). Methanolysis and tritylation of D-ribose, fol-
lowed by protection of the remaining diol as benzyl ethers,
yielded 21. The trityl group was removed and the resulting
alcohol converted to primary iodide 22. In contrast to the
heterogeneous Vasella fragmentation conditions, we found
conditions to effect a tandem zinc-mediated reductive
fragmentation-diethylzinc addition.16 This new procedure
not only saved one step but also improved the reproducibility
of the reaction. Subsequent TPAP oxidation gave ethyl
ketone 23. Following the sequence used for acetonide 13,
ketone 23 was converted to acetoxy pyranone 26a (Scheme
2).
Treatment of acetoxypyranone 26a with DBU in aceto-
nitrile produced cycloadducts 27a and 28a in 84% yield as
a 3.5:1 mixture, favoring 27a (Scheme 2). This is a reversal
of the diastereoselectivity observed for the cycloaddition of
acetonide 18. The stereochemical assignments of both
diastereomers were made by chemical correlation with
cycloadduct 20 (Scheme 3). Both cycloadducts 27a and 28a
were subjected to hydrogenation, hydrogenolysis, and ac-
etonide protection procedures to afford 29 and 30, respec-
tively. When cycloadduct 20 was hydrogenated, the product
was 30, indicating that the minor diastereomer 28a arising
from the cycloaddition of 26a has the same stereochemistry
as that of cycloadduct 20 produced from 18.17
(12) (a) Paterson, I.; Wallace, D .J.; Vela´zquez, S. M. Tetrahedron Lett.
1994, 35, 9083-9086. (b) Carda, M.; Falomir, E.; Murga, J.; Castillo, E.;
Gonza´lez, F.; Marco, J. A. Tetrahedron Lett. 1999, 40, 6845-6848.
(13) Kiyooka, S.; Kuroda, H.; Shimasaki, Y. Tetrahedron Lett. 1986,
27, 3009-3012.
(14) Paterson, I.; Lister, M. A.; Ryan, G. R. Tetrahedron Lett. 1991, 32,
1749-1752.
(15) Ho, T.-L.; Sapp, S. G. Synth. Commun. 1983, 13, 207-211.
(16) (a) Hyldtoft, L.; Madsen, R. J. Am. Chem. Soc. 2000, 122, 8444-
8452. (b) Stadmu¨ller, H.; Lentz, R.; Tucker, C. E.; Stu¨demann, T.; Do¨nner,
W.; Knochel, P. J. Am. Chem. Soc. 1993, 115, 7027-7028.
(17) Chemical derivatization followed of 27a followed by NOE analysis
confirmed its stereochemistry as indicated. See the Supporting Information
for details.
Org. Lett., Vol. 8, No. 23, 2006
5375

Scheme 2. Synthesis and Cycloaddition of Dibenzyl Ether 26
Table 1. Solvent Effects on Cycloaddition Diastereoselectivity
solvent (ꢀ)a
T (°C)
time (h)
yield (%)
dr (27a/28a)
PhCH3 (2)
CH2Cl2 (9)
acetone (21)
DMF (37)
CH3CN (38)
PhCH3 (2)
CH2Cl2 (9)
CH2Cl2 (9)b
rt
rt
rt
rt
rt
100
66
95
27
24
24
48
18
60
79
87
61
80
66
63
83
8:1
7:1
4.5:1
3:1
4:1
5:1
98 °C
38 °C
rt
5.5:1
7:1
a Reactions were run at 0.1 M. b Reaction was run at 0.4 M.
27a. The less polar the solvent, the better the selectivity and
the longer the reaction time. Reaction times for complete
conversion varied from 24 h (acetonitrile) to 100 h (toluene).
A similar trend was observed by Mascaren˜as and co-workers
in their sulfinyl-directed [5 + 2] cycloadditions.9c Heating
the reaction further increased the rate but decreased the
diastereoselectivity. We found, however, that the rate can
be improved while maintaining high selectivity by running
the cycloaddition at higher concentration.
Scheme 3. Chemical Correlation of the Cycloadducts
In summary, we describe the first stereoselective intramo-
lecular oxidopyrylium-alkene [5 + 2] cycloaddition using
fully substituted tethers. Through variation in protecting
groups and solvent, the diastereoselectivity of this process
can be varied to favor either cycloadduct isomer. The
resulting BC-ring system incorporates five of the daphnane
target stereocenters. In addition, it incorporates differentiated
and conformationally biased functionality needed for elabo-
ration of these targets and, significantly, analogs. This
versatile BC-bicyclic building blocksa central element in
our synthetic strategysis available in homochiral form in
14 steps from ribose. The process is readily conducted on a
preparative scale (>15 g). Further studies to advance the
cycloaddition products toward such natural products and
analogues are in progress.
The reversal in the diastereoselectivity of cycloadditions
for 18 and 26a is consistent with our hypothesis that the
more flexible dibenzyl ethers enable the tether to adopt a
chairlike transition state during the cycloaddition. Models
suggest that this selectivity could be further improved by
minimizing the unfavorable gauche interaction between the
substituents at C12 and C13 when the tether adopts a chair
conformation. To address this point, we replaced the C12-
silyl ether with a smaller acetate group. The required
substrate 26b featuring a C12-acetate was prepared from diol
24 in a similar manner to the previous substrates. When
pyranone 26b was treated with DBU in acetonitrile at 80
°C, cycloadducts 27b and 28b were formed in 79% yield
now in an improved 5:1 ratio favoring 27b.
Acknowledgment. Support of this work was provided
by the National Institutes of Health (CA31841-21). Graduate
fellowship support from Roche Biosciences (F.C.B.), Amgen
(C.K.), and Eli Lilly (J.-M.K.) and postdoctoral fellowship
support from the Humboldt Foundation (N.B.), the National
Science and Engineering Research Council of Canada (F.G.),
and the Yoshida Foundation for Science and Technology
(H.O.) are also acknowledged.
Given that the cycloaddition proceeds through a polar
(zwitterionic) intermediate, the effects of solvent on the [5
+ 2] cycloaddition of acetoxy pyranone 26a were investi-
gated. The rate and diastereoselectivity of the cycloaddition
were solvent dependent (Table 1). The diastereomeric ratios
varied from 3:1 to 8:1 in favor of the desired cycloadduct
Supporting Information Available: Spectroscopic data
and experimental procedures for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL062234E
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Org. Lett., Vol. 8, No. 23, 2006