Function-oriented synthesis: Studies aimed at the synthesis and mode of action of 1α-alkyldaphnane analogues

Article abstract of DOI:10.1021/ol0705649

An efficient synthetic route to the ABC tricyclic core of 1α-alkyldaphnanes has been developed. The conformational bias imparted by the C6-C9 oxo-bridge of BC-ring system 12 was used to elaborate the ABC-ring system precursor including the introduction of

Full text of DOI:10.1021/ol0705649

ORGANIC
LETTERS
2007
Vol. 9, No. 9
1829-1832
Function-Oriented Synthesis: Studies
Aimed at the Synthesis and Mode of
Action of 1r-Alkyldaphnane Analogues
Paul A. Wender,*,†,‡ Noel D’Angelo,† Vassil I. Elitzin,† Martin Ernst,†
Eileen E. Jackson-Ugueto,† John A. Kowalski,† Sharon McKendry,†
Markus Rehfeuter,† Robert Sun,† and David Voigtlaender†
Department of Chemistry and Department of Chemical and Systems Biology,
Stanford UniVersity, Stanford, California 94305-5080
wenderp@stanford.edu
Received March 6, 2007
ABSTRACT
An efficient synthetic route to the ABC tricyclic core of 1
C6 C9 oxo-bridge of BC-ring system 12 was used to elaborate the ABC-ring system precursor including the introduction of the
group. A completely diastereoselective palladium-catalyzed enyne cyclization was then employed to establish the A-ring with a C1 appendage.
r
-alkyldaphnanes has been developed. The conformational bias imparted by the
−
â
-C5 hydroxyl
The daphnanes, tiglianes, and ingenanes represent a remark-
able collection of synthetically challenging and biomedici-
nally important natural product leads.1 These compounds
incorporate a variety of ring sizes including, in the case of
gnidimacrin (1), a macrocycle of 13 members as well as a
highly varied array of functionalities punctuated by a rather
uncommon chiral ortho ester. All but one of the 14 carbons
that define the 5-7-6 core ring system of gnidimacrin are
stereogenic centers. Little is known about the biogenesis of
this natural product or its role in nature. However, it is
interesting that it has been isolated from three different plants
of three different continents,2 suggesting a primitive origin
to this compound class.
Of significance from a human health perspective, gnidi-
macrin and other 1R-alkyldaphnanes have been found to
exhibit potent and diverse biological activities such as
neurotrophic and antitumor activity.1b-e Gnidimacrin in
particular is active against a variety of cancer cell lines
(stomach, nonsmall cell lung, and leukemias) with IC50 values
as low as 0.35 nM.3 Significantly, however, it is not a general
toxin as many cell lines are insensitive to gnidimacrin
exposure.3,4 Of special therapeutic relevance, gnidimacrin’s
anticancer activity has also been shown in animal cancer
models in which significant life extensions and even cures
(2) (a) Kupchan, S. M.; Shizuri, Y.; Murae, T.; Sweeney, J. G.; Haynes,
H. R.; Shen, M. S.; Barrick, J. C.; Bryan, R. F.; Helm, D. V. D.; Wu, K.
K. J. Am Chem. Soc. 1976, 98, 5719-5720. (b) Tyler, M. I.; Howden, M.
E. H. J. Nat. Prod. 1985, 48, 440-445. (c) Feng, W. J. Med. Soc. Toho.
1992, 38, 896-909.
(3) Yoshida, M.; Feng, W. J.; Saijo, N.; Ikekawa, T. Int. J. Cancer 1996,
66, 268-273.
(4) Gnidimacrin has been screened against the NCI-60 panel showing a
difference of 2 to 3 orders of magnitude between some cell lines. These
data are available from the National Cancer Institute at the URL: http://
dtp.nci.nih.gov/dtpstandard/cancerscreeningdata/index.jsp.
† Department of Chemistry.
‡ Department of Chemical and Systems Biology.
(1) For reviews on this subject, see: (a) Evans, F. J., Ed. Naturally
Occurring Phorbol Esters; CRC Press: Boca Raton, FL, 1986; pp 217-
243. (b) Kowalski, J. A. Ph.D. Thesis, Stanford University, Stanford, CA
2005; pp 31-109. (c) He, W.; Cik, M.; Appendino, G.; Van Puyvelde, L.;
Leisen, J. E.; De Kimpe, N. Mini ReV. Med. Chem. 2002, 2, 185-200. (d)
Borris, R. P.; Blasko, G.; Cordell, G. A. J. Ethnopharmacol. 1988, 24, 41-
92. (e) Evans, F. J.; Soper, C. J. Lloydia 1978, 41, 193-233.
10.1021/ol0705649 CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/05/2007

have been reported.3 Yoshida et al. have provided compelling
evidence implicating protein kinase C (PKC) âII in the
activity of gnidimacrin, showing in one study that gnidima-
crin-insensitive cells can be rendered sensitive by PKCâII
transfection.5a-c Gnidimacrin is not alone in its fascinating
structure and therapeutic promise. Kirkinine B (2) (Figure
1), another 1R-alkyldaphnane, isolated from Synaptolepis
synthetic route to 1R-alkyldaphnanes and simplified deriva-
tives would introduce the macrocycle at the end of the
synthesis for maximum strategic flexibility. Because the role,
if any, of the macrocycle in biological activity is not known,
this approach was expected to allow access to both acyclic
and macrocyclic analogues as needed for comparative
evaluation. The ABC tricycle 3 was identified as a potentially
flexible precursor scaffold, as it incorporates differentiated
oxygen functionalities at C4, C5, C9, and C20 and latent
oxygen functionality at C3, C18, C13, and C14 in the form
of three selectively oxidizable alkenes (Scheme 1). Although
Scheme 1. Retrosynthetic Analysis of 1R-Alkyldaphnanes
Figure 1. Some representative 1R-alkyldaphnanes.
kirkii, has been shown to have nanomolar activity against
K562/C1000 human leukemia cells, as well as significant
neurotrophic activity.6
Studies on the therapeutic potential of 1R-alkyldaphnanes
have been hampered by low isolation yields and at least
initially by the absence of validated cellular targets. Prompted
by our interest in unaddressed synthetic problems and in new
modes of therapeutic action, we initiated studies some time
ago to access analogues of the 1R-alkyldaphnanes and to
elucidate the structural determinants for their activity as
needed to further investigate their mode of action and clinical
potential. The synthetic challenges presented by this class
of compounds are highlighted by the fact that no work on
their synthesis has appeared and only one member of the
daphnane family, resiniferatoxin (RTX), has been success-
fully synthesized.7 This communication describes our initial
studies directed at accessing 1R-alkyldaphnane analogues
using a strategy that allows for introduction of variable
functionalities at sites potentially critical for biological
potency and selectivity.
the synthesis of a related 5-7-6 tricyclic core found in
phorbol10 and RTX has been reported, the introduction of a
C1 alkyl group and oxidation at C5 and C18 pose entirely
new and significant challenges. In principle, tricycle 3 would
arise from a metal-catalyzed closure of enyne 4 which in
turn would be generated from the conjunction of allylic
bromide 6 and enone 7 followed by C5 oxygenation.
Controlling stereogenesis at C10, C4, and C5 would be the
bridged bicyclic subunit in 7 that conformationally fixes and
sterically biases the hydropyranyl subunit. Bicycle 7 would
emerge from the known oxidopyrylium-alkene [5+2] cy-
cloaddition of pyrone 8.11
Although ultimately our strategy incorporates a C1 side
chain functionalized with an appropriate handle for late-stage
modifications, it was decided to start with incorporation of
a methyl group at C1 to validate our synthetic plan and
provide a reference control for testing biological activity.
Our synthesis starts with the preparation of the substrate
for the key oxidopyrylium [5+2] cycloaddition12 that estab-
As exemplified by our bryostatin analogue program,8 our
studies on the 1R-alkyldaphnanes are directed at achieving
step-economical syntheses of structurally simplified ana-
logues that exhibit functional activity comparable or superior
to the natural product lead. Connectivity analysis9 guided
by analogue design considerations suggested that a preferred
(5) (a) Yoshida, M.; Yokokura, K.; Hidaka, H.; Ikekawa, T.; Saijo, N.
Int. J. Cancer 1998, 77, 243-250. (b) Yoshida, M.; Feng, W. J.; Nishio,
K.; Takahashi, M.; Heike, Y.; Saijo, N.; Wakasugi, H.; Ikekawa, T. Int. J.
Cancer 2001, 94, 348-352. (c) Yoshida, M.; Heike, Y.; Ohno, S.; Ikekawa,
T.; Wakasugi, H. Int. J. Cancer 2003, 105, 601-606.
(6) He, W.; Cik, M.; Van Puyvelde, L.; Van Dun, J.; Appendino, G.;
Lesage, A.; Van der Lindin, I.; Leysen, J. E.; Wouters, W.; Mathenge, S.
G.; Mudida, F. P.; De Kimpe, N. Bioorg. Med. Chem. 2002, 10, 3245-
3255.
(7) Wender, P. A.; Jesudason, C. D.; Nakahira, H.; Tamura, N.; Tebbe,
A. L.; Ueno, Y. J. Am. Chem. Soc. 1997, 119, 12976-12977.
(8) Wender, P. A.; Baryza, J. L.; Brenner, S. E.; Clarke, M. O.; Craske,
M. L.; Horan, J. C.; Meyer, T. Curr. Drug DiscoVery Technol. 2004, 1,
1-11.
(9) (a) Wender, P. A.; Miller, B. Org. Synth.: Theory Appl. 1993, 2, 27.
(b) Barone, R.; Chanon, M. Tetrahedron 2005, 61, 8916-8923.
(10) For the total synthesis of phorbol, see: (a) 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. (b) Wender, P. A.; McDonald, F. E. J.
Am. Chem. Soc. 1990, 112, 4956-4958. (c) Wender, P. A.; Rice, K. D.;
Schnute, M. E. J. Am. Chem. Soc. 1997, 119, 7897-7898. (d) Lee, K.;
Cha, J. K. J. Am. Chem. Soc. 2001, 123, 5590-5591.
(11) Wender, P. A.; Mascarenas, J. L. J. Org. Chem. 1991, 56, 6267-
6269.
(12) For reviews on oxidopyrylium [5+2] cycloadditions, 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.
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Org. Lett., Vol. 9, No. 9, 2007

lishes the BC core. The conversion of 9 to 8 through a
Claisen rearrangement sets the C11 stereocenter which in
turn is intended to control all other stereocenters in our plan
(Scheme 2). We have preliminarily investigated asymmetric
After debenzoylation of 12, the primary alcohol was
reprotected as TBS ether 7 (Scheme 3). Barbier-type cro-
Scheme 3. Synthesis of the Cyclization Precursor
Scheme 2. Synthesis of the BC-Ring System
catalysis of this transformation using different Lewis acids
in combination with Box,13 Pybox,14 and Arbox15 ligands.
The combination of Pybox and Zn(OTf)2 gave enantiomeric
excesses of up to 48%,16 an encouraging result given the
relative paucity of studies in this area.17 However, given the
immediate importance of addressing downstream strategic
issues, further studies in this series were conducted with
racemic compounds.
The original conditions employed in the [5+2] oxido-
pyrylium cycloaddition for the synthesis of 12 required
optimization for scale-up purposes. Previously, it was
reported that this reaction proceeds in 84% yield on a small
scale using 2.0 equiv of methyl triflate. However, on larger
scales, removing the excess methyl triflate became trouble-
some, increasing the possibility of overalkylation of oxi-
dopyrylium 11. It was found that complete conversion of 8
to 12 can be achieved using 1.0 equiv of MeOTf, provided
that the concentration of 8 was increased to 1.0 M. CDCl3
is used in the pyrone alkylation to allow NMR monitoring.
Additional modifications to the established procedure in-
cluded a slow addition of the pyrylium species 10 to a
solution of CsF in DMF and CH2Cl2 under further dilution
(0.02 M) to favor the intramolecular [5+2] cycloaddition
over intermolecular processes. Ultimately, these conditions
allowed for room-temperature oxidopyrylium generation and
[5+2] cycloaddition of 8 in 20-30 g batches and conversion
to cycloadduct 12 in 89% yield.
tylation of cycloadduct 7 afforded the desired alcohol 13 in
95% yield. In this step, the desired stereochemistry at C1 is
set with complete control of diastereoselectivity, presumably
through a Zimmerman-Traxler six-membered transition
state.18
Efforts to directly transpose the C10 alcohol in 13 to the
C5 position encountered complications. Thus, this alcohol
was first converted with complete stereoselectivity to the
â-C5 bromide which was cleanly inverted to the R-C5
alcohol. During this step, the C20 TBS ether was partially
cleaved, and upon workup, the crude mixture was treated
with acidic conditions to complete the cleavage of the C20
TBS group which was reprotected in a subsequent step. Initial
attempts to invert C5 either under Mitsunobu conditions or
by acid-catalyzed epimerization were unsuccessful. This
inversion was achieved, however, through a two-step se-
quence in which the C5 alcohol was first oxidized to the
corresponding enone 15 which was then reduced with
DIBAL-H from the less-encumbered R-face to provide the
desired â-C5 alcohol 16.
(13) Abraham, L.; Czerwonka, R.; Hiersemann, M. Angew. Chem., Int.
Ed. 2001, 40, 4700-4703.
(14) For a review on Box and Pybox catalysts, see: (a) Johnson, J. S.;
Evans, D. A. Acc. Chem. Res. 2000, 33, 325-335. (b) Evans, D. A.; Rovis,
T.; Johnson, J. S. Pure Appl. Chem. 1999, 71, 1407-1415.
(15) (a) Yoon, T. P.; Macmillan, D. W. C. J. Am. Chem. Soc. 2001,
123, 2911-2912. (b) Bolm, C.; Wieckhardt, K.; Zehnder, M.; Ranff, T.
Chem. Ber. 1991, 124, 1173-1180.
(16) In this case, the asymmetric induction was opposite to the desired
configuration; however, this can be easily reversed by changing the chiral
ligand.
(17) For reviews on asymmetric induction in Claisen rearrangements,
see: (a) Ito, H.; Taguchi, T. Chem Soc. ReV. 1999, 28, 43-50. (b) Enders,
D.; Knopp, M.; Schiffers, R. Tetrahedron: Asymmetry 1996, 7, 1847-
1882.
With the â-C5 alcohol installed, the C4 ketone was
revealed through hydrolysis of the C4 methyl enol ether. The
(18) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79,
1920-1923.
Org. Lett., Vol. 9, No. 9, 2007
1831

C10 stereochemistry was set during the process, consistent
with a stereoelectronically controlled axial protonation.
Subsequently, the C20 alcohol was reprotected as a TBS
ether.
CHCl3 in the presence of 2.5 equiv of acetic acid and 10
equiv of triethylsilane provided the desired product with
complete diastereoselectivity in 72% yield.
The relative stereochemistry of the ABC tricyclic core was
assigned through 1D NOE NMR experiments (Figure 2).
Addition of lithium phenyl acetylide to ketone 18 provided
the desired C4, C5 diol in excellent yield. This stereoselec-
tivity results from attack of the nucleophile from the less-
encumbered R-face. The relative stereochemistry at C4, C5,
and C10 was assigned on the basis of NOE experiments.
Subsequent protection of diol 19 as a cyclic carbonate
completed the synthesis of cyclization precursor 20.
Different conditions were screened for the key enyne
cyclization of 20 (Scheme 4). Initial attempts using di-n-
Scheme 4. Enyne Cyclization Studies
Figure 2. NOE data for the ABC-ring system 21.
Also the C1, C10 coupling constant of 12.2 Hz indicated a
trans-diaxial relationship between these two protons.
The completion of this ABC tricyclic daphnane core
represents the first example of a synthetic incorporation of
a C1 substituent into the A ring and a C5 hydroxyl group
into the B ring of a daphnane precursor/analogue compound.
This synthetic strategy allows step-economical access to the
complete daphnane core tricycle in only 22 steps and is
expected to allow access to the 1R-alkyldaphnanes and more
immediately to analogues incorporating the highly oxygen-
ated AB-ring functionality that putatively contacts the
receptor surface. Further studies incorporating a C1 side chain
with an appropriate functionalization handle and the rest of
the required functionality of the 1R-alkyldaphnanes are under
investigation in our laboratory.
butyl-zirconocene19 resulted in decomposition of 20. This
was attributed to instability of the carbonate moiety under
the reaction conditions.
Alternative conditions using palladium catalysis20 gave
better results. Treatment of carbonate 20 with 20 mol % of
Pd2dba3‚CHCl3, 40 mol % of tri-o-tolylphosphine, 1 equiv
of acetic acid, and 10 equiv of triethylsilane afforded a 45%
yield of 21. To improve the yield and reliability of this
reaction, different ligands were explored, and it was discov-
ered that the “ligandless” palladium conditions worked best.
Thus, treatment of carbonate 20 with 20 mol % of Pd2dba3‚
Acknowledgment. Support for this work was provided
by the National Institutes of Health (CA31841). Postdoctoral
fellowship support from Deutscher Akademischer Austausch-
dienst (DAAD) and the Ernst Schering Research Foundation
is also acknowledged.
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.
(19) (a) Negishi, E.; Holmes, S. J.; Tour, J. M.; Miller, J. A.; Cederbaum,
F. E.; Swanson, D. R.; Takahashi, T. J. Am. Chem. Soc. 1989, 111, 3336-
3346. (b) Rajanbabu, T. J.; Nugent, W. A.; Taber, D. F.; Fagan, P. J. J.
Am. Chem. Soc. 1988, 110, 7128-7135.
(20) (a) Trost, B. M.; Rise, F. J. Am. Chem. Soc. 1987, 109, 3161-
3163. (b) Trost, B. M.; Braslau, R. Tetrahedron Lett. 1988, 29, 1231-
1234.
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