Total synthesis of (±)-aspidophylline A

Article abstract of DOI:10.1021/ja203227q

We report the total synthesis of (±)-aspidophylline A, one of many complex furoindoline-containing alkaloids that has not been synthesized previously. Our route features a number of key transformations, including a Heck cyclization to assemble the [3.3.1]-bicyclic scaffold as well as a late-stage interrupted Fischer indolization to install the furoindoline and construct the natural product's pentacyclic framework.

Full text of DOI:10.1021/ja203227q

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Total Synthesis of (()-Aspidophylline A
Liansuo Zu, Ben W. Boal, and Neil K. Garg*
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
S Supporting Information
b
ABSTRACT: We report the total synthesis of (()-aspido-
phylline A, one of many complex furoindoline-containing
alkaloids that has not been synthesized previously. Our
route features a number of key transformations, including
a Heck cyclization to assemble the [3.3.1]-bicyclic scaffold
as well as a late-stage interrupted Fischer indolization to
Figure 1. Furoindoline alkaloids 1À3 from the Apocynaceae plants.
install the furoindoline and construct the natural product’s
pentacyclic framework.
or decades, indole alkaloids isolated from natural sources
F
have captivated the attention of synthetic chemists, leading to
innovations in synthetic methodology and stunning achieve-
ments in total synthesis.1 One particularly rich source of indole
alkaloids is the Apocynaceae family of plants, found predomi-
nantly in Southeast Asia.2 Natural products isolated from these
plants are characterized by intricate polycyclic structures and a
range of biological activity.2,3 Alkaloids 1À3 (Figure 1) are
representatives of more than 20 molecules in this family that
possess a furoindoline motif, none of which have been synthe-
sized previously.
With the ultimate goal of preparing alkaloids 1À3 and other
family members, we selected aspidophylline A (1) as our initial
synthetic target. 1 was isolated by Kam and co-workers in 2007
and was found to reverse drug resistance in resistant KB cells.3a
The intricate pentacyclic framework of 1 presents many synthetic
challenges, including the tricyclic furoindoline motif, a densely
substituted cyclohexyl ring containing five contiguous stereogenic
centers, and a bridged [3.3.1] bicycle. In this communication, we
report the first total synthesis of (()-aspidophylline A (1).
Our approach to 1 was inspired in part by our laboratory’s
previously described approach to fused indoline ring systems.4
Specifically, we demonstrated that reactions between aryl hy-
drazines 4 and latent aldehydes 5 under acidic conditions provide
basic furoindoline and pyrrolidinoindoline scaffolds 8 (Figure 2).
The transformation, termed the “interrupted Fischer indoliza-
tion”, proceeds via a charge-accelerated rearrangement/cycliza-
tion cascade (see transition structures 6 and 7).4a We envisioned
that such a process could be used to access the pentacyclic
framework of aspidophylline A if a late-stage diastereoselective
variant5 employing phenylhydrazine (9) and hemiketal 10 were
to be deemed feasible. The implementation of this endgame
strategy would not only serve to assemble the aspidophylline A
scaffold but also validate our interrupted Fischer indolization
methodology in a complex setting. It was anticipated that
hemiketal 10 could be prepared from bicycle 11, the product
of Heck cyclization of cyclohexylamine 12.6,7 Finally, 12 would
Figure 2. Interrupted Fischer indolization cascade and retrosynthetic
analysis of aspidophylline A (1).
be derived from [2.2.2]-bicyclic lactam 13, an intermediate
believed to be accessible from readily available known com-
pounds.8
Our synthesis commenced with the assembly of the [3.3.1]-
bicyclic motif of aspidophylline A (Scheme 1). The thermal
DielsÀAlder reaction between pyridinone 14 and maleic anhy-
dride furnished known bicycle 15,8 which was available in
multigram quantities. Microwave irradiation of 15 with Cu2O
and bipyridyl in a quinoline/water mixture delivered alkene 17.
The transformation of 15 to 17 likely proceeds by enol ether and
anhydride hydrolysis to furnish intermediate 16 followed by
Cu(I)-promoted oxidative bis(decarboxylation).9 Ketal protec-
tion and removal of the Bn protecting group provided lactam 18,
which in turn underwent N-tosylation and methanolysis to
Received: April 8, 2011
Published: May 09, 2011
r
2011 American Chemical Society
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Scheme 1
Figure 3. Interrupted Fischer indolization attempts employing sub-
strates 25 and 26.
Scheme 2
provide R,β-unsaturated ester 19. Subsequent alkylation with
allylic bromide 2010 provided vinyl iodide 21, the necessary
substrate for Heck cyclization. Upon treatment of substrate 21
with Pd(0) under Vanderwal’s conditions,7c bicycle 22 was
obtained in quantitative yield. Ketal deprotection and olefin
reduction furnished ketoester 23 as a mixture of C16 diastere-
omers (8:1 dr).
Having assembled the desired [3.3.1] bicycle, we turned our
attention to introducing a C7 substituent en route to the desired
interrupted Fischer indolization substrate. Although the lithium
enolate of 23 was found to be unreactive toward various
electrophiles, enolate alkylation proceeded smoothly with allyl
iodide at À50 °C. The resulting product 24 was isolated as a
single diastereomer and served as a versatile intermediate en
route to the desired hemiketal 2511 and an alternate substrate,
ketone 26.12 Unfortunately, the critical interrupted Fischer
indolization proved challenging. In fact, both direct and stepwise
variants of this key step (using substrates 25 and 26, respectively)
failed to deliver either of the desired products, pentacycle 27 or
tetracycle 28 (Figure 3).13,14
Hypothesizing that the [3,3]-sigmatropic rearrangement of
substrate 26 was sluggish,14,15 we sought to prepare a more rigid
substrate for use in the key step. The targeted substrate, lactone
31, was prepared following the sequence shown in Scheme 2.
Diastereoselective reduction of allyl ketone 24 provided alcohol
29,16 which underwent oxidative cleavage17 and reduction to
furnish diol 30. Acid-promoted lactonization followed by
DessÀMartin oxidation delivered ketoester 31. Much to our
delight, ketoester 31 proved to be an excellent substrate for
Fischer indolization. Reaction with phenylhydrazine in the
presence of trifluoroacetic acid (TFA) in dichloroethane at
40 °C generated intermediate 33, presumably via transition
structure 32. Removal of solvent followed by addition of
K2CO3 in MeOH with heating led to lactone methanolysis and
cyclization (see transition structure 34), affording pentacycle 27.
This one-pot sequence led to the introduction of three rings by
assembly of one CÀC bond and two CÀheteroatom bonds,
all with complete diastereoselectivity. Removal of the tosyl
protecting group of 27 followed by formylation furnished
aspidophylline A (1). Synthetic 1 was found to be indistinguish-
able from an authentic sample of the natural product by NMR,
mass spectrometric, and chromatographic comparisons.3a,18
In summary, we have achieved the first total synthesis of (()-
aspidophylline A (1), one of many complex furoindoline-con-
taining alkaloids that has not been synthesized previously. Our
route to 1 proceeds in 18 steps from known DielsÀAlder adduct
15 and features a number of key transformations, including (a)
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COMMUNICATION
an oxidative bis(decarboxylation) to furnish [2.2.2]-bicyclic
lactam 17, (b) a Heck cyclization to assemble the natural
product’s [3.3.1]-bicyclic scaffold, and (c) a late-stage inter-
rupted Fischer indolization to install the furoindoline and con-
struct the full pentacyclic framework of 1. Our synthesis of 1
validates the interrupted Fischer indolization approach to in-
tricate indoline-containing natural products and sets the stage for
future synthetic endeavors.
(9) (a) Fessner, W. D.; Sedelmeier, G.; Spurr, P. R.; Rihs, G.;
Prinzbach, H. J. Am. Chem. Soc. 1987, 109, 4626–4642. (b) Snow,
R. A.; Degenhardt, C. R.; Paquette, L. A. Tetrahedron Lett. 1976,
17, 4447–4450.
(10) (a) Ensley, H. E.; Buescher, R. R.; Lee, K. J. Org. Chem. 1982,
47, 404–408. (b) Sole, D.; Diaba, F.; Bonjoch, J. J. Org. Chem. 2003,
68, 5746–5749.
(11) The conversion of 24 to 25 was achieved through a sequence
involving (a) ketone protection as the cyclic ketal, (b) oxidative cleavage
of the terminal olefin, (c) reduction of the corresponding aldehyde, and
(d) acid-mediated ketal deprotection.
’ ASSOCIATED CONTENT
(12) The conversion of 24 to 26 was achieved through a sequence
involving (a) ketone protection as the cyclic ketal, (b) oxidative cleavage
of the terminal olefin, (c) reduction of the corresponding aldehyde,
(d) Piv protection of the resulting alcohol, and (e) acid-mediated ketal
deprotection.
S
Supporting Information. Detailed experimental proce-
b
dures and compound characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(13) Under a variety of interrupted Fischer indolization conditions,
substrate 25 underwent facile dehydration to the corresponding
dihydrofuran.
’ AUTHOR INFORMATION
Corresponding Author
neilgarg@chem.ucla.edu
(14) Although ketone 26 underwent condensation with phenylhy-
drazine under several interrupted Fischer indolization conditions, no
evidence of [3,3]-sigmatropic rearrangement was detected.
(15) Ketone 23, a substrate without the C7 side chain, readily
underwent Fischer indolization upon treatment with phenylhydrazine
and various acids. The factors that influence the likelihood of [3,3]-
sigmatropic rearrangement in this series of compounds are currently
under investigation.
(16) A more concise approach involving oxidative cleavage of the
terminal olefin in 24 led to substantial decomposition.
(17) Sabahi, A.; Novikov, A.; Rainier, J. D. Angew. Chem., Int. Ed.
2006, 45, 4317–4320.
’ ACKNOWLEDGMENT
The authors are grateful to the National Science Foundation
(CHE-0955864), Boehringer Ingelheim, DuPont, Eli Lilly, and
the University of California, Los Angeles, for financial support.
We thank the Garcia-Garibay laboratory (UCLA) for access to
instrumentation, Dr. John Greaves (UC Irvine) for mass spectra,
and Ryan Hollibaugh (UCLA) and Jose Alonso (UCLA) for
experimental assistance. We are grateful to Professor Kam
(University of Malaya, Malaysia) for providing an authentic
sample of aspidophylline A.
(18) Aspidophylline A was isolated as a 17:1 mixture of formamide
rotamers.
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