Dynamic kinetic resolution of α,β-unsaturated lactones through asymmetric copper-catalyzed conjugate reduction: Application to the total synthesis of eupomatilone-3

Article abstract of DOI:10.1002/anie.200501890

(Chemical Equation Presented) Only six steps were needed for the total synthesis of eupomatilone-3 in 48 % overall yield thanks to the development of a dynamic kinetic resolution that allowed the reductive conversion of a racemic α,β-unsaturated butenolid

Full text of DOI:10.1002/anie.200501890

Angewandte
Chemie
Stereoselective Butenolide Reduction
DOI: 10.1002/anie.200501890
Dynamic Kinetic Resolution of a,b-Unsaturated
Lactones through Asymmetric Copper-Catalyzed
Conjugate Reduction: Application to the Total
Synthesis of Eupomatilone-3**
Matthew P. Rainka, Jacqueline E. Milne, and
Stephen L. Buchwald*
Eupomatilones 1–7 are a family of lignans[1] isolated from the
Australian shrub Eupomatia bennettii, found in the tropical
and subtropical forests of New South Wales and Queens-
land.[2] All seven members of this family contain a highly
oxygenated biaryl motif, as well as a cis orientation of the
substituents at C4 and C5 of the butyrolactone ring. Of all the
members of the eupomatilone family, there have only been
three for which a total synthesis has been reported: eupoma-
tilone-6, eupomatilone-4, and 3-epi-eupomatilone-6.[3]
Despite this work, the total synthesis of enantiomerically
enriched members of the eupomatilone family has remained
an unsolved problem. Herein, we report the first asymmetric
[*] M. P. Rainka, J. E. Milne, Prof. S. L. Buchwald
Department of Chemistry, Room 18-490
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
Fax: (+1)617-253-3297
E-mail: sbuchwal@mit.edu
[**] We thank the National Institutes of Health (GM 46059) for support
of this work. We are grateful to Merck for additional support. We
thank Englehard for the generous supply of palladium compounds
and Dr. Rudy Schmid of Roche Basel for the donation of MeO-
BIPHEP. We also thank Dr. Lei Jiang for helpful discussions.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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total synthesis of one member of the family, eupomatilone-3.
The success of the synthesis was based on a highly efficient
Suzuki–Miyaura cross-coupling,[4] along with a dynamic
kinetic resolution[5] of an unsaturated lactone.
Our interest in the synthesis of eupomatilone-3 emanated
from the compoundꢀs interesting structural features, in
particular the biaryl motif, along with the cis orientation of
the substituents at C4 and C5 of the lactone portion of the
molecule. Our retrosynthetic analysis of eupomatilone-3 is
shown in Scheme 1. On the basis of our recent work in the
area of palladium-catalyzed cross-coupling reactions,[6] it was
believed we could assemble the highly oxygenated biaryl
portion of the molecule III by utilizing either a Negishi or
Suzuki–Miyaura coupling. Furthermore, we envisioned gen-
erating the desired lactone stereochemistry in I through either
a diastereoselective or an enantioselective copper-catalyzed
conjugate reduction reaction.[7]
loading
was
lowered
to
0.005 mol%
palladium
(0.00025 mol% [Pd2(dba)3]; dba = dibenzylideneacetone).
With a means to rapidly construct the biaryl portion of
eupomatilone-3, investigation began into the preparation of
the butenolide 6. When examining this motif, we turned to
Knochelꢀs method for the synthesis of butenolides by the
reaction of stabilized vinyl Grignard reagents with alde-
hydes.[9] To apply this method to this synthesis, the methyl
ester 2 first needed to be transformed to the corresponding
aryl aldehyde 4. Conversion of 2 into the benzyl alcohol 3 was
accomplished by borane reduction in THF. Intermediate 3
was oxidized with MnO2 to give the desired benzaldehyde
derivative 4 in essentially quantitative yield. Treatment of this
The synthesis was begun by investigating the cross-
coupling of known aryl bromide 1[8] with organometallic
reagents derived from bromo-3,4,5-trimethoxybenzene. By
employing reaction conditions found to be optimal with
palladium catalysts derived from the bulky phosphanylbiaryl
ligands RuPhos L1 (Negishi)[6b] or SPhos L2 (Suzuki–Miy-
aura)[6a,c] allowed for efficient production of biaryl
2
(Scheme 2). The Negishi coupling produced 2 in 93% yield
at a catalyst loading of 1 mol% palladium. With the
corresponding Suzuki–Miyaura reaction, it was found that 2
could be obtained in 93% yield even when the catalyst
Scheme 1. Retrosynthetic analysis of eupomatilone-3.
Scheme 2. Synthesis of eupomatilone-3 (yields are the average of two runs determined to be >95% pure by 1H NMR or GC). a) [Pd2(dba)3]
(0.0025 mol%), SPhos L2 (0.02 mol%), K3PO4 (2 equiv), THF, 808C. b) BH3·THF, THF, 608C. c) MnO2, CH2Cl2, RT. d) THF, À408C.
e) CuCl2·2H2O (5 mol%), MeO-BIPHEP L4 (5 mol%), NaOtBu (1.2 equiv), PMHS (6 equiv), tBuOH, THF, CH2Cl2, RT. f) NaHMDS, THF, 08C,
then MeI. PMHS: polymethylhydrosiloxane; NaHMDS: sodium hexamethyldisilazide.
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aldehyde with the vinyl Grignard reagent 5 (formed in situ
from the corresponding vinyl iodide[10]) according to Kno-
chelꢀs procedure provided the desired unsaturated lactone in
76% yield.
vided the highest enantioselectivities (except in the case of
the natural product, in which L4 gave the best result).[14] The
scope of the reaction was examined and the results are shown
in Table 1. Aside from 8, all products were formed with
enantioselectivities ranging from 77 to 87%. Thus, no clear
The next hurdle in the synthesis was the conversion of
butenolide 6 into cis-4,5-disubstituted lactone 7. The installa-
tion of this stereochemistry was explored by using an
asymmetric conjugate reduction reaction.[11,12] We have
previously demonstrated the asymmetric reduction of unsa-
turated lactones using a chiral copper–hydride catalyst.[12b]
Furthermore, we have succeeded in carrying out both kinetic
as well as dynamic kinetic resolutions of 3,5-disubstituted
cyclopentenones by employing similar catalysts.[12d] Despite
unsatisfactory results when reducing 3,4-disubstituted cyclo-
pentenones,[12d] we decided to attempt the kinetic resolution
of 6 under our standard conjugate reduction conditions[12] at
À308C in a 1:1 mixture of THF/CH2Cl2 (dichloromethane was
necessary due to the poor solubility of the lactone in THF).
After 50% conversion of 6, the desired cis compound 7 was
isolated in 46% yield and with 87% ee. Interestingly, the
process was completely diastereoselective: none of the
trans isomer was ever detected.
With this promising result, we sought to extend the
method to the dynamic kinetic resolution of unsaturated
lactones. We felt that performing the reaction in the presence
of excess base (NaOtBu) should allow for racemization of the
starting material such that complete conversion may be
effected. Unfortunately, no racemization occurred when
1.2 equivalents of NaOtBu was used at À308C, even after
prolonged reaction times. When the same experiment, how-
ever, was conducted at room temperature, complete con-
version of the starting material into the desired product was
observed. As in the case of the simple kinetic resolution, the
product was obtained as a single diastereomer and with
83% ee. This represents the first copper-catalyzed dynamic
kinetic resolution of an unsaturated lactone.
Table 1: Dynamic kinetic resolution of unsaturated lactones.
Product
ee [%]
Yield [%][a]
95
67
81
87
77
78
92
85
91
94
[a] Yields are the average of two runs determined to be greater than 95%
pure by 1H NMR spectroscopy or GC.
In an attempt to improve the enantioselectivity of the
reaction, other chiral bisphosphine ligands were used. It was
found that replacing p-tol-BINAP L3 with MeO-BIPHEP L4
while still performing the reaction at room temperature
provided the desired compound, again as a single diaster-
eomer, but now with 93% ee (when the kinetic resolution was
carried out at À308C with L4, the product was obtained with
95% ee). With the cis lactone prepared, all that remained to
complete the synthesis was to install the final methyl group in
the a position on the lactone ring. This was accomplished by
enolization of lactone 7 with NaHMDS followed by alkylation
with iodomethane to give synthetic eupomatilone-3 in 85%
yield; its spectra were in agreement with those published for
material obtained from the natural source.[2,13]
On the basis of the success of the dynamic kinetic
resolution reaction described above, we briefly examined
the scope of this process by using other g-aryl-containing
unsaturated lactones. Initial results employing L4 as the
supporting ligand provided poor enantioselectivity for sub-
strates other than the natural product, however the diaster-
eoselectivity remained high. A brief survey of the efficiency of
ligands for this process was undertaken and it was observed
that the commercially available SYNPHOS ligand L5 pro-
dependence on steric or electronic factors could be ascer-
tained.
Unfortunately, use of the same reaction conditions for the
dynamic kinetic resolution of lactones that contain simple
alkyl substituents in the g position failed to give more than
50% conversion of the starting material. This is presumably
due to poor racemization of the starting lactone. Additionally,
the reaction provided both the cis and trans isomers of the
product, and the enantiomeric enrichment of the cis product
was found to be low (< 25% ee).
In conclusion, the total synthesis of eupomatilone-3 was
achieved in six steps and in 48% overall yield. The key to the
success of the synthesis was the development of a dynamic
kinetic resolution that allowed the a,b-unsaturated buteno-
lide 6 to be reduced in high yield and with both high
enantiomeric and diastereomeric excess. This is the first
example of a copper-catalyzed dynamic kinetic resolution of
an unsaturated lactone. The method was then applied to
several g-aryl containing a,b-unsaturated butenolides. While
a number of catalysts based on chiral bisphosphines were
found to successfully promote this transformation, optimal
Angew. Chem. Int. Ed. 2005, 44, 6177 –6180
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Communications
[13] While the absolute configuration of the natural material is
unknown, the optical rotation measurements on the synthetic
material were in agreement with those on material from the
natural source.
enantioselectivity was obtained when employing the com-
mercially available SYNPHOS ligand L5.
Received: May 31, 2005
[14] a) C.-C. Pai, Y.-M. Li, Z.-Y. Zhou, A. S. C. Chan, Tetrahedron
Lett. 2002, 43, 2789; b) S. D. de Paule, S. Jeulin, V. Ratoveloma-
nana-Vidal, J.-P. GenÞt, N. Champion, P. Dellis, Tetrahedron
Lett. 2003, 44, 823; c) SYNPHOS was purchased from Strem
Chemicals, Inc.; d) While SEGPhos (another common ligand
employed in conjugate reduction chemistry with copper) is not
commercially available, in the near future we hope to test this
ligand in the dynamic kinetic resolution process.
Published online: August 30, 2005
Keywords: cross-coupling · eupomatilones · kinetic resolution ·
.
reduction · total synthesis
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