Total synthesis of (+)-fendleridine (aspidoalbidine) and (+)-1 -acetylaspidoalbidine

Article abstract of DOI:10.1021/ja908819q

A total synthesis of the Aspidosperma alkaloids (+)-fendleridine and (+)-1-acetylaspidoalbidine is detailed, providing access to both enantiomers of the natural products and establishing their absolute configuration. Central to the synthetic approach is a

Full text of DOI:10.1021/ja908819q

Published on Web 02/11/2010
Total Synthesis of (+)-Fendleridine (Aspidoalbidine) and
(+)-1-Acetylaspidoalbidine
Erica L. Campbell, Andrea M. Zuhl, Christopher M. Liu, and Dale L. Boger*
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research
Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
Received October 20, 2009; E-mail: boger@scripps.edu
Abstract: A total synthesis of the Aspidosperma alkaloids (+)-fendleridine and (+)-1-acetylaspidoalbidine
is detailed, providing access to both enantiomers of the natural products and establishing their absolute
configuration. Central to the synthetic approach is a powerful intramolecular [4+2]/[3+2] cycloaddition
cascade of a 1,3,4-oxadiazole in which the pentacyclic skeleton and all the stereochemistry of the natural
products are assembled in a reaction that forms three rings, four C-C bonds, and five stereogenic centers
including three contiguous quaternary centers, and introduces the correct oxidation state at C19 in a single
synthetic operation. The final tetrahydrofuran bridge is subsequently installed in one step, enlisting an
intramolecular alcohol addition to an iminium ion generated by nitrogen-assisted opening of the cycloadduct
oxido bridge, with a modification that permits release of useful functionality (a ketone) at the cleavage
termini.
Introduction
Fendleridine (1) and 1-acetylaspidoalbidine (2) are the parent
members of the aspidoalbine family of alkaloids.1 Fendleridine
(aspidoalbidine, 1) was first isolated in 1964 from the Venezu-
elan tree Aspidosperma fendleri WOODSON by Burnell (Figure
1),2 and later in 1979 from the bark of the Venezuelan tree
Aspidosperma rhombeosignatum MARKGRAF by Medina and
co-workers.3 In addition, fendleridine (1) represents the parent
compound to 1-acetylaspidoalbidine (2) that was first disclosed
in 1963 by Djerassi, having been isolated from Vallesia
dichotoma RUIZ et PAV in Peru,4 and that has been referred
to as dehydroxyhaplocidine5 in a more recent isolation. Unique
to the aspidoalbines is the oxidized C19 N,O-ketal embedded
in the characteristic Aspidosperma alkaloid pentacyclic ring
system typically linked to an oxidized C5 substituent. More
highly oxidized Aspidosperma alkaloids have been disclosed
bearing the hexacyclic core structure of 1 and 2 that incorporate
further hydroxylation of the aromatic ring, a five-membered
lactone versus tetrahydrofuran, or further unsaturation in the
six-membered rings.6
Figure 1. Natural product structures.
ketal (Hg(OAc)2 in 5% aqueous AcOH), forming the tetrahy-
drofuran ring bridging an alcohol on the two-carbon side chain
at C5 to C19,7 confirming the originally proposed structure. A
year earlier, Ban disclosed the first total synthesis of 1-acety-
laspidoalbidine (2) from a common intermediate8 and inferred
that it could not be readily deacetylated to provide fendleridine
(1). Ban subsequently reported an improved formal synthesis
of 2 in 1987,9 and an impressive formal synthesis of 1-acety-
laspidoalbidine (2) was disclosed in 1991 by Overman, where
entry into an advanced pentacyclic intermediate was ac-
complished using a signature aza-Cope-Mannich rearrange-
ment.10 In these efforts, fendleridine (1) and 1-acetylaspidoal-
bidine (2) were prepared in racemic form, and the assignment
of their absolute configuration remains to be unambiguously
established.11
The only total synthesis of fendleridine (1) disclosed to date
was reported in 1976 by Ban and co-workers and relied on a
C19 oxidation and subsequent cyclization to install the C19 N,O-
(1) (a) Hesse, M. Indolalkaloide in Tabellen-Erga¨nzungswerk; Springer-
Verlag: Berlin, 1968; p 77.
(2) Burnell, R. H.; Medina, J. D.; Ayer, W. A. Can. J. Chem. 1966, 44,
28.
(3) Medina, J. D.; Genova, L. D. Planta Med. 1979, 37, 165.
(4) (a) Brown, K. S.; Budzikiewicz, H.; Djerassi, C. Tetrahedron Lett.
1963, 4, 1731. (b) Walser, A.; Djerassi, C. HelV. Chim. Acta 1965,
48, 391.
(7) Honma, Y.; Ohnuma, T.; Ban, Y. Heterocycles 1976, 5, 47.
(8) Ban, Y.; Ohnuma, T.; Seki, K.; Oishi, T. Tetrahedron Lett. 1975, 16,
727.
(5) Mitaine, A. C.; Mesbah, K.; Richard, B.; Petermann, C.; Arrazola,
S.; Moretti, C.; Zeches-Hanrot, M.; Le Men Olivier, L. Planta Med.
1996, 62, 458.
(9) Yoshido, K.; Sakuma, Y.; Ban, Y. Heterocycles 1987, 25, 47.
(10) Overman, L. E.; Robertson, G. M.; Robichaud, A. J. J. Am. Chem.
Soc. 1991, 113, 2598.
(6) Saxton, J. E. In The Alkaloids; Cordell, A. G., Ed.; Academic: San
Diego, 1998; Vol. 51, p 2.
9
10.1021/ja908819q  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 3009–3012 3009

A R T I C L E S
Campbell et al.
Scheme 1
The key reaction cascade is initiated by an intramolecular
[4+2] cycloaddition reaction of a 1,3,4-oxadiazole with a
tethered dienophile,16,17 where the intrinsic regioselectivity is
dictated by the linking tether. Following the initiating [4+2]
cycloaddition, loss of N2 from the initial cycloadduct provides
an intermediate 1,3-dipole, which is stabilized by the substitution
at the dipole termini. The intrinsic dipole/dipolarophile regi-
oselectivity of the ensuing 1,3-dipolar cycloaddition is reinforced
by the linking tether, and the relative stereochemistry is dictated
by an exclusive endo indole [3+2] cycloaddition, where the
dipolarophile is sterically directed to the face opposite the newly
formed fused lactam.15,18 In total, four C-C bonds, three rings,
five relative stereogenic centers including a C19 N,O-ketal, and
the complete natural product skeleton are assembled in a single
step. Subsequent adjustment of the C3 substituent and acid-
catalyzed oxido bridge cleavage, with intermediate generation
and reaction of an iminium ion flanked by two quaternary
centers, leads to introduction of the sixth tetrahydrofuran ring,
with release of a stable cyanohydrin precursor to a C3 ketone.
Figure 2. Key cycloaddition cascade and retrosynthetic analysis.
In the course of the development of an approach to the total
synthesis of members of the Aspidosperma alkaloids including
vindoline12 anditsextensiontothetotalsynthesisofvinblastine13,14
and vincristine,14 we introduced a powerful tandem [4+2]/[3+2]
cycloaddition cascade reaction of 1,3,4-oxadiazoles that is
especially suited for the preparation of their pentacyclic ring
system.15 Herein, we report the extension of these studies in
the total synthesis of 1 and 2 that is even more ideally suited
for implementation of the cascade cycloaddition reaction, taking
advantage of the cycloadduct intrinsic oxidation state at C19
for closure of the tetrahydrofuran ring and with a modification
that permits introduction of useful functionality following
cleavage of the cycloadduct oxido bridge (Figure 2).
Results and Discussion
The required 1,3,4-oxadiazole 5 bearing the tethered indole
dipolarophile was prepared from 1-benzyltryptamine (7,19
Scheme 1) in a three-step sequence. Treatment of 7 with 1,1-
carbonyldiimidazole (CDI) afforded urea 8 (97%), which was
reacted with methyl oxalyl hydrazide 920 to provide 10.
Dehydration of 10 by treatment of TsCl and Et3N afforded the
oxadiazole 5 (81% for two steps).
The acyl chain carboxylic acid 6 containing the tethered
initiating dienophile was prepared in four steps from oxepane-
2,5-dione (11,21 Scheme 2), which was subjected to methanoly-
(11) For the total synthesis of the related alkaloid aspidophytine, see: (a)
He, F.; Bo, Y.; Altom, J. D.; Corey, E. J. J. Am. Chem. Soc. 1999,
121, 6771. (b) Sumi, S.; Matsumoto, K.; Tokuyama, H.; Fukuyama,
T. Tetrahedron 2003, 59, 8571. (c) Mejia-Oneto, J. M.; Padwa, A.
Org. Lett. 2006, 8, 3275. (d) Marino, J. P.; Cao, G. Tetrahedron Lett.
2006, 47, 7711. (e) Nicolaou, K. C.; Dalby, S. M.; Majumder, U. J. Am.
Chem. Soc. 2008, 130, 14942.
(16) (a) Boger, D. L. Tetrahedron 1983, 39, 2869. (b) Boger, D. L. Chem.
ReV. 1986, 86, 781.
(12) (a) Ishikawa, H.; Elliott, G. I.; Velcicky, J.; Choi, Y.; Boger, D. L.
J. Am. Chem. Soc. 2006, 128, 10596. (b) Choi, Y.; Ishikawa, H.;
Velcicky, J.; Elliott, G. I.; Miller, M. M.; Boger, D. L. Org. Lett.
2005, 7, 4539. (c) Ishikawa, H.; Boger, D. L. Heterocycles 2007, 72,
95. (d) Elliott, G. I.; Velcicky, J.; Ishikawa, H.; Li, Y.; Boger, D. L
Angew. Chem., Int. Ed. 2006, 45, 620. (e) Yuan, Z. Q.; Ishikawa, H.;
Boger, D. L. Org. Lett. 2005, 7, 741. (f) Wolkenberg, S. E.; Boger,
D. L. J. Org. Chem. 2002, 67, 7361.
(17) (a) Vasiliev, N. V.; Lyashenko, Y. E.; Kolomiets, A. F.; Sokolskii,
G. A. Khim. Geterostsikl. Soedin. 1987, 562. (b) Thalhammer, F.;
Wallfahrer, U.; Sauer, J. Tetrahedron Lett. 1988, 29, 3231. (c) Seitz,
G.; Wassmuth, H. Chem.-Ztg. 1988, 112, 80. (d) Warrener, R. N.;
Groundwater, P.; Pitt, I. G.; Butler, D. N.; Russell, R. A. Tetrahedron
Lett. 1991, 32, 1985.
(18) (a) Padwa, A.; Price, A. T. J. Org. Chem. 1998, 63, 556. (b) Padwa,
A.; Price, A. T. J. Org. Chem. 1995, 60, 6258. (c) Padwa, A.; Lynch,
S. M.; Mejia-Oneta, J. M.; Zhang, H. J. Org. Chem. 2005, 70, 2206.
(d) Mejia-Oneta, J. M.; Padwa, A. Org. Lett. 2004, 6, 3241. (e) Mejia-
Oneta, J. M.; Padwa, A. Tetrahedron Lett. 2004, 45, 9115.
(19) Luo, S.; Fu, X.; Fang, F.; Zhuang, Z.; Xiong, W.; Jia, X.; Zhai, H.
Org. Lett. 2006, 8, 115.
(13) Ishikawa, H.; Colby, D. A.; Boger, D. L. J. Am. Chem. Soc. 2008,
130, 420.
(14) Ishikawa, H.; Colby, D. A.; Seto, S.; Va, P.; Tam, A.; Kakei, H.;
Rayl, T. J.; Hwang, I.; Boger, D. L. J. Am. Chem. Soc. 2009, 131,
4904.
(15) (a) Wilkie, G. D.; Elliott, G. I.; Blagg, B. S. J.; Wolkenberg, S. E.;
Soenen, D. R.; Miller, M. M.; Pollack, S.; Boger, D. L. J. Am. Chem.
Soc. 2002, 124, 11292. (b) Elliott, G. I.; Fuchs, J. R.; Blagg, B. S. J.;
Ishikawa, H.; Tao, H.; Yuan, Z. Q.; Boger, D. L. J. Am. Chem. Soc.
2006, 128, 10589.
(20) Christl, M.; Lanzendoerfer, U.; Groetsch, M. M.; Ditterich, E.;
Hegmann, J. Chem. Ber. 1990, 123, 2031.
(21) Van der Ende, A. E.; Kravitz, E. J.; Harth, E. J. Am. Chem. Soc. 2008,
130, 8706.
9
3010 J. AM. CHEM. SOC. VOL. 132, NO. 9, 2010

Synthesis of (+)-Fendleridine and (+)-Acetylaspidoalbidine
A R T I C L E S
Scheme 2
Scheme 4
Scheme 3
cyanohydrin 18 (quantitative). The reversibly generated iminium
ion derived from oxido bridge protonation and opening is
flanked by two quaternary centers, facilitating direct trap by
the pendant alcohol. Diastereoselective ketone reduction con-
ducted directly on the cyanohydrin 18 was effected with Na-
Selectride to yield alcohol 19 (85%). Although of no conse-
quence since the alcohol is subsequently removed, the reduction
proceeds by hydride delivery from the more hindered concave
face of the ketone, which adopts a boat conformation,23a
producing the secondary alcohol occupying an equatorial
position in a six-membered ring also adopting a boat
conformation.23b Presumably, this preferential axial approach
of the large hydride reducing agent from the most hindered face
avoids an apparently more significant destabilizing electrostatic
interaction between the reagent and the adjacent axial indoline
nitrogen.
Consistent with challenges inherent in the reduction of the
ketone derived from 18, the use of NaBH4 in methanol required
longer reaction times and resulted in poorer conversion and
lower diastereoselectivity, and ketone often persisted in the
reaction. Additionally, the protecting group on the indoline
nitrogen proved important at this stage of the synthesis. Initially,
a carboxybenzyl (CBz) protecting group was utilized in our
efforts but afforded the transesterified oxazolidinone derived
from intramolecular displacement of benzyl alcohol when the
alcohol was exposed to basic conditions. These limitations were
addressed through the use of the N-benzyl group to protect the
indoline nitrogen.
sis to afford methyl ester 12 (91%) and subsequent silyl ether
protection of the resulting primary alcohol yielding 13 (88%).
Wittig olefination of 13 to provide 14 (88%) and hydrolysis of
the methyl ester afforded 6 (96%).
Coupling of 1,3,4-oxadiazole 5 with 6 was effected by
treatment with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (EDCI) and 4-dimethylaminopyridine (DMAP)
to provide 4 (74%), the precursor for the [4+2]/[3+2] cycload-
dition cascade (Scheme 3). The tandem cycloaddition reaction
occurred cleanly at 180 °C in o-dichlorobenzene to afford 3 in
yields as high as 71% (55-71%) as a single diastereomer.22
The relative stereochemistry of 3 was assigned on the basis of
NMR and was in accord with expectations, which was later
confirmed through X-ray analysis of 20.23 Treatment of 3 with
NH3 and MeOH effected clean conversion to the primary amide
that underwent subsequent dehydration to afford the nitrile 16
(90%, two steps).
Subsequent introduction of the tetrahydrofuran ring with
formation of the C19 N,O-ketal proved straightforward (Scheme
4). Cleavage of the tert-butyldimethylsilyl ether with Bu4NF in
acetic acid afforded the primary alcohol 17 that could be
converted to the cyanohydrin 18 by further treatment with formic
acid in methanol. More conveniently, treatment of 16 with HF/
pyridine provided a direct, single-step conversion to the stable
With the alcohol in hand, subsequent conversion of 19 to
the methyldithiocarbonate 20 (4.7 equiv of NaH, 4.0 equiv of
CS2, tetrahydrofuran (THF), 0 °C, 1 h followed by 3.0 equiv of
MeI, 25 °C, 2 h, 92%) was readily effected (Scheme 4).
Separation of the enantiomers of 20 (R ) 1.39) was carried out
on a semipreparative Daicel ChiralCel OD column (2 × 25 cm,
30% i-PrOH/hexane, 7 mL/min flow rate) to provide natural
(-)-20 (tR ) 19.2 min) and ent-(+)-20 (tR ) 26.5 min). The
natural enantiomer (shown), whose absolute configuration was
(22) The cycloaddition of the corresponding free alcohol was also
investigated but was unsuccessful, resulting in intramolecular trans-
esterification.
(23) (a) The boat conformation was established by X-ray and atomic
coordinates for the ketone derived from cyanohydrin 18 (CCDC751262)
have been deposited with the Cambridge Crystallographic Data
Center. (b) The boat conformation, structure, stereochemistry, and
absolute configuration were established by X-ray and atomic coordi-
nates for 20 (CCDC751263) have been deposited with the Cambridge
Crystallographic Data Center.
9
J. AM. CHEM. SOC. VOL. 132, NO. 9, 2010 3011

A R T I C L E S
Campbell et al.
Scheme 5
100%) and requiring no further purification. Treatment of each
enantiomer of fendleridine (2) with Ac2O in pyridine cleanly
afforded (+)- and ent-(-)-1-acetylaspidoalbidine (2, 81%),
respectively. Both (+)-1 ([R]2D5 +43 (c 1.1, CHCl3)) and (+)-2
([R]2D5 +38 (c 0.2, CHCl3) and +42 (c 0.2, MeOH)) were
identical in all respects with the properties reported for the
naturally derived materials,4,5 and the H NMR of synthetic 2
1
was in full agreement with a copy of the spectrum of authentic
2. The optical rotation for fendleridine (1) has not been reported,
and that of 1-acetylaspidoalbidine (2) has been reported as +46
(CHCl3)4 and +1 (c 0.2, CHCl3).5 The origin of these differences
is not known, but our synthetic 2 matches closely that reported
in the original Djerassi work,4 and the consistent dextrorotatory
sign of the rotations recorded with naturally derived material
was used for the absolute configuration assignments.
Conclusion
established with a single-crystal X-ray structure determination
of (-)-20 bearing a heavy atom (S),23b was converted to and
matched the absolute configuration of (+)-1-acetylaspidoalbidine
(2), whose optical rotation was previously reported.4,5 Deoxy-
genation of 20 was accomplished under Barton-McCombie
conditions (Bu3SnH, cat. AIBN, toluene, 100 °C, 1 h, 77%) to
provide 21.
Full details of the development of the total synthesis of (+)-
and ent-(-)-fendleridine (1) and (+)- and ent-(-)-1-acetylaspi-
doalbidine (2) and the assignment of their absolute configuration
are disclosed by enlisting an intramolecular tandem [4+2]/[3+2]
cycloaddition cascade of a 1,3,4-oxadiazole that allowed the
assembly of the entire natural product skeleton and all necessary
stereochemistry in a single step, while also directly providing
the desired oxidation state at C19 and facilitating ring closure
of the tetrahydrofuran.
Treatment of amide 21 with Lawesson’s reagent24 cleanly
afforded the thiolactam 22 (85%, Scheme 5). Although initial
efforts focused on a single-step desulfurization and cleavage of
the N-benzyl protecting group through extended treatment with
Raney-Ni, its removal from the final product proved difficult.
Consequently, the desulfurization and debenzylation were
accomplished in a two-step sequence. The thioamide was
removed first by reductive desulfurization of 22 upon treatment
with Raney-Ni to yield 23 (80%). The N-benzyl group on 23
was then removed by the reaction with Na and t-BuOH in THF/
NH3,25 cleanly affording (+)- and ent-(-)-fendleridine (1,
Acknowledgment. We thank Prof. Ze`ches-Hanrot for providing
1
the H NMR spectrum of authentic natural 1-acetylaspidoalbidine
and Dr. R. Chadha for the X-ray structure determination of 20.
We gratefully acknowledge the financial support of the National
Institutes of Health (CA042056) and the Skaggs Institute for
Chemical Biology. A.Z. is a NSF and Skaggs Fellow.
Supporting Information Available: Full experimental details
and characterization (PDF, CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
(24) Yde, B.; Yousif, N. M.; Pederson, U.; Thomsen, I.; Lawesson, S. O.
Tetrahedron 1984, 40, 2047.
(25) Overman, L. E.; Shin, Y. Org. Lett. 2007, 9, 339.
JA908819Q
9
3012 J. AM. CHEM. SOC. VOL. 132, NO. 9, 2010