Total synthesis of (-)-tuberostemonine

Article abstract of DOI:10.1021/ja028603t

The first total synthesis of the complex pentacyclic Stemona alkaloid tuberostemonine was accomplished in 24 steps and in 1.4% overall yield from a hydroindole intermediate which is readily obtained in three steps from Cbz-L-tyrosine. An innovative synthe

Full text of DOI:10.1021/ja028603t

Published on Web 11/21/2002
Total Synthesis of (-)-Tuberostemonine
Peter Wipf,* Stacey R. Rector, and Hidenori Takahashi
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
Received September 18, 2002
Since the first report on the isolation of a pure Stemona alkaloid
in 1936, >40 congeners have been isolated from genus Stemona
(family Stemonaceae, order Dioscoreales) and, to a lesser extent,
from genus Croomia plants.1 The structure of the complex
polycyclic tuberostemonine (1), the major Stemona alkaloid, was
elucidated in the 1960s by a combination of crystallographic,
spectroscopic, and degradative techniques.2 The biological activity
of Stemona alkaloids covers an unusually broad range, and
applications in Eastern folk medicine against pulmonary tuberculosis
and bronchitis as well as insecticides are well documented.3
Tuberostemonine was also found to function as a glutamate
antagonist at the crayfish neuromuscular junction.3b Several syn-
theses of other Stemona alkaloids have been completed,4 and we
now report the first total synthesis of tuberostemonine.
Figure 1. Retrosynthetic analysis.
Key steps of our retrosynthetic analysis are a ring-closing
metathesis reaction to form the azepane followed by the addition
of a lithiated ortho ester to introduce the right-side butyrolactone
(Figure 1). Bicycle 2, which is obtained in three steps from Cbz-
L-tyrosine and has already provided the lynchpin for our stenine
synthesis,4b,5 serves as a scaffold for installation of nine of the ten
stereogenic carbons of tuberostemonine, including the fused left-
side butyrolactone which is obtained by a Claisen rearrangement
and halolactonization.4a,b
Scheme 1. Reduction and Double Allylation of Hydroindole Core
2a
Our approach began with an improvement to the π-allyl
palladium reaction on compound 2 (Scheme 1).4b,5 Previously, we
had reported this reduction in the presence of triethylammonium
formate using PBu3 as the Pd ligand.4b Although excellent yields
(>90%) could be attained, the reaction required scrupulously
oxygen-free techniques and >99% pure PBu3. We were delighted
to discover that the crystalline and more air-stable PBn3 also works
well as a ligand for the π-allyl palladium complex. The reduction
can now be performed on scales as large as 47 g with yields
reproducibly exceeding 80%. Silylation of the secondary alcohol
was followed by carbamate deprotection and cinnamylation of the
resulting amine 5. Fluoride-induced deprotection of the silyl ether
gave alcohol 7 in 80% yield from 3. After oxidation to the enone,
a stereoselective (>95% dr) axial dienolate alkylation was ac-
complished with KHMDSA and allyl iodide.6
To effect the key metathesis reaction, a solution of 8 in CH2Cl2
was heated at reflux in the presence of 2-5 mol % of the ruthenium
catalyst 97 (Scheme 2). The resulting double bond in azepine 10
was removed via a high-yielding, three-step sequence to give tri-
cycle 11 after transient protection of the enone double bond by
conjugate addition-â-elimination of thiophenol. Ester 12 was
obtained as a single diastereomer after Luche reduction and TBDMS
protection.
a (a) Pd2(dba)3CHCl3, NEt3, HCOOH, PBn3, THF, 65 °C (93%); (b)
TBDMS-Cl, imidazole, DMAP, CH2Cl2 (97%); (c) Et3SiH, Pd(OAc)2, NEt3,
CH2Cl2, room temperature (90%); (d) cinnamyl bromide, K2CO3, toluene,
60 °C (96%); (e) TBAF, THF, room temperature (96%); (f) TPAP, NMO,
CH2Cl2 (88%); (g) KHMDSA, allyl iodide, -90 °C (66%).
in an excellent yield of ketone 15. The carbonyl group was
subsequently reduced with L-Selectride to give a 7:1 ratio of
diastereomeric alcohols favoring the Felkin-Anh product. Exposure
of this mixture of alcohols to TsOH in methanol removed both the
ortho ester and the silyl ether protecting groups and also catalyzed
the cyclization, affording the desired lactone 16 as a single
diastereomer in 70% yield.
The final transformations toward tuberostemonine began with a
Claisen rearrangement11,12 using N,N-dimethylacetamide dimethyl
acetal (Scheme 4). All attempts to subject 17 to halolactonization
failed or resulted in decomposition, but an alternative selenolac-
tonization13 followed by a Keck allylation4b,14 proceeded unevent-
fully to give tetracycle 20 after selective R-methylation of the fused
lactone.4a,b
In preparation for the introduction of the right-side butyrolactone,
we added Weinreb amide 13, obtained in 94% yield from ester
12,8 to a solution of the lithium anion formed from bromo ortho
ester 14 and LiDBB in THF (Scheme 3).9,10 This process resulted
Since previously successful oxidative conditions4b to convert the
allyl side chain to the desired ethyl group failed, we needed to
develop a new method for this chain contraction. Gratifyingly, we
* Corresponding author. E-mail:pwipf@pitt.edu.
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10.1021/ja028603t CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Azepine Annulation and Selective Alkene Reductiona
In conclusion, the pentacyclic Stemona alkaloid tuberostemonine
was prepared in 24 steps and 1.4% overall yield from bicycle 2,
which is readily obtained in three steps from Cbz-L-tyrosine and
has served as a key building block for other alkaloid syntheses.4b,19
Among the highlights of our approach are the 3-fold use of
ruthenium catalysts, first in an azepine ring-closing metathesis and
then in the alkene isomerization and cross-metathesis propenyl-
vinyl exchange, as well as the stereoselective attachment of the
γ-butyrolactone to the core tetracycle by use of the lithiated ortho
ester 14.
Acknowledgment. This work was supported by a grant from
the National Institutes of Health (AI-33506).
a (a) 9, CH2Cl2 reflux (92%); (b) PhSH, NEt3, CH2Cl2 (91%); (c)
(PPh3)3RhCl, H2, EtOH/CH2Cl2, room temperature; (d) DBU, CH2Cl2, room
temperature (89%); (e) CeCl3‚7H2O, NaBH4, THF/MeOH, 0 °C (71%); (f)
TBDMS-Cl, imidazole, DMAP, CH2Cl2, room temperature (79%).
Supporting Information Available: Experimental procedures and
characterization data for 3, 16, and 1 and 1D and 2D NMR spectra for
1. This material is available free of charge via the Internet at http://
pubs.acs.org.
Scheme 3. Butyrolactone Attachmenta
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Scheme 4. Completion of Total Synthesisa
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were able to accomplish a novel sequence by first isomerizing the
allyl group using a modification of a method developed by Roy et
al. for allyl ethers,15 followed by ethylene cross-metathesis on 21
in the presence of Ru catalyst 2316 and TsOH17 to access the desired
terminal vinyl group. Phosphine-free conditions were important to
avoid extensive chromatographic purification that led to decomposi-
tion. The first total synthesis of tuberostemonine was completed
by a catalytic hydrogenation over Pd on carbon.18
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