The telescoped intramolecular Michael/olefination (TIMO) approach to α-alkylidene-γ-butyrolactones: Synthesis of (+)-paeonilactone B

Article abstract of DOI:10.1002/anie.200705329

(Chemical Equation Presented) Scoping out TIMO: A telescoped intramolecular Michael addition/proton transfer/ Horner-Wadsworth-Emmons olefination sequence was developed to provide rapid access to α-alkylidene-γ- butyrolactones (see scheme). The method was applied to prepare a range of tetrahydrobenzofuran-2,5-diones and related systems, and it was utilized in a short synthesis of enantiomerically pure (+)-paeonilactone B.

Full text of DOI:10.1002/anie.200705329

Angewandte
Chemie
DOI: 10.1002/anie.200705329
Tandem Reactions
The Telescoped Intramolecular Michael/Olefination (TIMO)
Approach to a-Alkylidene-g-butyrolactones: Synthesis of
(+)-Paeonilactone B**
Michael G. Edwards, Martin N. Kenworthy, Russell R. A. Kitson, Mark S. Scott, and
Richard J. K. Taylor*
a-Alkylidene-g-butyrolactones are widespread in nature and
have diverse and potentially useful biological properties.[1]
Representative examples range from the relatively simple
paeonilactone B,[2] to more complex compounds such as
helenalin isobutyrate[3a] and the recently isolated montahi-
bisciolide.[3b]
Scheme 1. Proposed TIMO approach to a-alkylidene-g-butyrolactones.
sequence would be cis selective in the formation of tetrahy-
drobenzofuran-2,5-dione 4 (n = 1).
Numerous procedures are available to prepare a-alkyli-
dene-g-butyrolactones; in particular,the initial construction
of the lactone with subsequent methylenation is popular,but
the majority of the routes are lengthy and low yielding.[1–3] As
part of our growing interest in tandem or telescoped
processes,[4] we designed a one-pot approach to a-alkyli-
dene-g-butyrolactones (Scheme 1). The key was the use of
diethyl phosphonoacetate 1,which,after deprotonation,was
expected to undergo an intramolecular Michael addition[5,6] to
give enolate 2. We anticipated subsequent proton transfer to
generate the more stable phosphonate anion 3 and then
addition of an aldehyde to initiate an intermolecular Horner–
Wadsworth–Emmons (HWE) olefination[7] to yield cyclic
dicarbonyl compound 4. In addition,we anticipated that the
Ketophosphonate 5 was used to assess the viability of the
approach shown in Scheme 1. Compound 5 was prepared
from readily available 4-hydroxy-2-cyclohexenone[8] and
commercially available diethyl phosphonoacetic acid by
using 2-propanephosphonic acid anhydride (T3P) as the
coupling agent. When ketophosphonate 5 was treated with
KOtBu in THF,the expected Michael adduct 6 was obtained
in 50% yield (Scheme 2). Phosphonate 6 was used to optimize
the key HWE methylenation in terms of base,solvent,
stoichiometry,and formaldehyde source. KO tBu in THF
proved to be the best base/solvent combination and para-
formaldehyde was the optimal formaldehyde source. The a-
methylene lactone product 7a was highly base-sensitive,and
the use of a substoichiometric quantity of base (0.95 equiv)
gave product 7a in 83% yield.
A more efficient transformation was achieved by per-
forming a sequential one-pot process. Thus,treatment of
ketophosphonate 5 with KOtBu (0.95 equiv) in THF,and the
addition of paraformaldehyde after 60 minutes,produced the
expected a-methylene lactone 7a in 77% overall yield. This
result emphasizes the advantages of a sequential one-pot
process—it avoids a complicated intermediate workup pro-
cess and the overall yield is improved (77%,compared to
43% over two steps). This variant was termed a telescoped
intramolecular Michael addition/HWE olefination (TIMO)
process. Lactone 7a is novel although the corresponding trans
isomer is known.[9] The cis arrangement of 7a was confirmed
by obtaining an X-ray crystallographic structure.[10]
[*] Dr. M. G. Edwards, Dr. M. N. Kenworthy, R. R. A. Kitson,
Dr. M. S. Scott, Prof. Dr. R. J. K. Taylor
Department of Chemistry
Universityof York
Heslington, York, YO10 5DD (U.K.)
Fax: (+44)1904-434-523
E-mail: rjkt1@york.ac.uk
[**] We thank Elsevier Science for postdoctoral funding (M.G.E.,
M.N.K., and M.S.S), the EPSRC for studentship support (R.R.A.K),
Archimica for a gift of T3P, and GlaxoSmithKline for additional
support. We are also grateful to Dr. A. C. Whitwood (Universityof
York, X-ray crystallography) and Dr. T. Dransfield (University of York,
mass spectrometry) for technical assistance.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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1935

Communications
Table 1: Scope of the TIMO reaction.[a]
EntryProduct
HWE Conditions
Yield [%]
1
[b]
[c]
60[e]
2[f]
55[g]
3[f]
[c]
60[g]
Scheme 2. a) The two-step approach to 7a. b) The TIMO approach to
7a.
4
[d]
[d]
[d]
[b]
84
Subsequent to our initial success,we investigated the
scope of the TIMO sequence in terms of both the aldehyde
and enone components (Table 1).
5[h]
52
Acetaldehyde was used as the HWE partner under the
optimized reaction conditions to generate ethylidene lactone
7b,as a 1:1 mixture of E/Z isomers,in a 60% yield (Table 1,
entry 1). Aromatic aldehydes were suitable coupling partners
when potassium bis(trimethylsilyl)amide (KHMDS) was used
as the base. In the two examples explored (Table 1,entries 2
and 3),reasonable yields of the expected adducts 7c and 7d
were obtained exclusively as the E isomers. Adduct 7d
provided crystals suitable for X-ray crystallographic analy-
sis[10] and confirmed the cis ring junction and the E configu-
ration of the alkene. Preliminary studies were also carried out
to evaluate the scope of the g-hydroxy enone substrate. Thus,
several analogues of 5 were prepared by using similar
chemistry (see the Supporting Information) and subjected
to the TIMO sequence. The cycloheptanone-annelated prod-
uct 8 was obtained in excellent yield,and the telescoped
process was more efficient than the corresponding two-step
sequence (84% versus 22%,Table 1,entry 4). In the cyclo-
pentenone series (Table 1,entry 5),the 5,5-dimethyl analogue
gave the expected g-butyrolactone 9 in 52% yield (unopti-
mized; the sequential process was inferior,giving the product
in 31% overall yield); compound 9 was crystalline and the
structure was confirmed by X-ray crystallography.[10] To
explore the effect of a substituent at the a-carbon atom of
the enone,the TIMO reaction of an a-allylated enone was run
under standard conditions and the expected bicyclo adduct 10
was obtained in good yield as a 3:1 diastereomeric mixture
(Table 1,entry 6). Finally,a ketophosphonate derived from a
tertiary alcohol underwent the TIMO sequence to give the
highly functionalized bicyclic adduct 11 in 71% yield (Table 1,
entry 7).
6
84[i]
71
7
[a] Unless otherwise stated, Michael addition was performed using
KOtBu (0.95 equiv) for 1 h at 08C. [b] Reaction mixture warmed from
À788C to 08C and stopped after 1 h. [c] Reaction mixture warmed from
À788C to 08C over 15 h and then heated to reflux for 1 h. [d] Reaction
mixture warmed from À788C to 08C and stopped after 1.5 h. [e] 1:1 E/Z
mixture. [f] KHMDS (0.95 equiv) was used. [g] E:Z ratio >95:<5.
[h] Michael addition performed overnight at room temperature. [i] The
ratio of anti:syn diastereomers was 3:1.
relief,and in 1985 paeonilactones A,B,and C were isolated
from the root of Paeonia Albiflora Pallas.[2] Paeonilactone B
(17)[2] was chosen as it has been prepared in racemic[12] and
optically pure (+ enantiomer)[13] forms,but the lengthy routes
attest to the problems associated with the preparation of such
a densely functionalized molecule. The Novozyme 435
resolution procedure described by Roberts and co-workers[14]
was employed to convert racemic alcohol 12 into (À)-13
(Scheme 3). Kinetic enolate generation and subsequent
methylation gave 14 as a mixture of diastereomers; the
55% yield of 14 is modest because of the ease with which
aromatization occurs in these systems. Silyl enol ether
formation,subsequent oxidation by using a modified Rubot-
tom oxidation with 2,2-dimethyldioxirane (DMDO),[15] and
deprotection gave trans-diol 15 in an efficient and highly
Our attention turned to a natural product target to
validate the utility of the TIMO sequence. Paeony root has a
long history of use in Chinese and Japanese medicine for pain
1936
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Chemie
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Scheme 3. Synthesis of (+)-paeonilactone B [(+-17] byusing TIMO
chemistry. LDA=lithium diisopropylamide, TESCl=chlorotriethylsi-
lane, DIAD=diisopropyl azodicarboxylate.
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stereoselective three-step process (d.r. = 33:1); the use of
DMDO proved to be crucial because m-CPBA gave a 3:1
ratio at best.
Mitsunobu coupling of alcohol 15 and diethyl phosphono-
acetic acid proceeded with the desired inversion of the
configuration to give the coupled product 16 in a respectable
yield (notably,in the presence of the unprotected tertiary
alcohol). Ketophosphonate 16 was then subjected to the
TIMO reaction using KOtBu in THF at 08C and subsequent
treatment with paraformaldehyde. We were delighted that
this procedure delivered (+)-paeonilactone B [(+)-17] in
70% yield. The authenticity of (+)-17 was confirmed by
HRMS methods,melting points (measured: 86–87 8C,liter-
ature:[2] 88–898C),and optical rotation values (measured:
[a]2D0 = +23.8 degcm3 gÀ1 dmÀ1 (c = 1.04 g/100cm3,MeOH),
literature:[2] [a]D20 = +23.2 degcm3 gÀ1 dmÀ1).
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[10] CCDC 658935 (7a),659261 ( 7d),and 658922 ( 9) contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre at www.ccdc.cam.ac.uk/data_request/cif.
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The value of the telescoped intramolecular Michael
addition/proton transfer/HWE olefination sequence can be
gauged by the brevity of the route; [6 steps and a 13% overall
yield from the known and readily accessible enantiopure
starting material (À)-13].
We are extending the scope of the TIMO methodology
described herein and investigating its utility for the prepara-
tion of more complex targets.
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Received: November 20,2007
Published online: January 28,2008
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Keywords: a-methylene lactones · Michael addition ·
olefination · phosphonates · tandem reactions
.
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1937