Intramolecular cyclobutadiene cycloaddition/cyclopropanation/thermal rearrangement: An effective strategy for the asymmetric syntheses of pleocarpenene and pleocarpenone

Article abstract of DOI:10.1021/ja0674340

The first total synthesis of the guaiane sesquiterpene natural products pleocarpenone and pleocarpenene is described. An intramolecular cycloaddition of cyclobutadiene, followed by cyclopropanation and thermal fragmentation of the resulting highly strained intermediate, is the strategy used to achieve this synthesis. The asymmetric route allowed for confirmation of the absolute stereochemistry of these natural products. Copyright

Full text of DOI:10.1021/ja0674340

Published on Web 12/22/2006
Intramolecular Cyclobutadiene Cycloaddition/Cyclopropanation/Thermal
Rearrangement: An Effective Strategy for the Asymmetric Syntheses of
Pleocarpenene and Pleocarpenone
Michael J. Williams, Holly L. Deak, and Marc L. Snapper*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
Received October 17, 2006; E-mail: marc.snapper@bc.edu
Scheme 2. Preparation of the Cyclobutene 5a
The introduction of new methods for accessing functionalized
medium ring-containing compounds more efficiently remains a
valuable objective.1 We have developed an intramolecular cyclo-
addition of cyclobutadiene2 followed by cyclopropanation and
rearrangement as an effective approach for the stereospecific
preparation of bicyclo[5.3.0]decane ring systems.3 Herein, we
describe the first application of this strategy in the asymmetric
preparation of pleocarpenone (1) and pleocarpenene (2), two guaiane
natural products isolated in 1976 from Pleocarphus reVolutus.4
Our approach to these natural products is summarized in Scheme
1. Since pleocarpenone is accessible through the ozonolysis/
epimerization of pleocarpenene,4c both natural products could arise
a Reaction conditions: (a) hν, PhH; Fe2(CO)9, 64%; (b) DIBAL,
Et2O, 0 °C to rt, 95%; (c) MnO2, CH2Cl2, 4 Å MS, 83%; (d)
CH2dCHCH2CH2MgBr, Et2O, -78 °C, 96%; (e) CH2dCHCO2Me (10
equiv), Grubbs’ second cat. (10) (2.5 mol %), 60 °C, (94%, 13:1 E:Z); (f)
CAN, acetone, (91%, 3.3:1 â:R); (g) MnO2, CH2Cl2, 4 Å MS (90%); (h)
catechol borane, (3aS)-tetrahydro-1-methyl-3,3,-diphenyl-1H,3H-pyrrolo[1,2-
c][1,3,2]oxazaborole (11) (15 mol %), toluene, -78 °C (96%, 92% ee); (i)
CH2dCHCO2Me (10 equiv), 10 (2.5 mol %), 60 °C, (94%, 13:1 E:Z); (j)
CAN, acetone; separation on 10 wt % AgNO3 on silica gel (80%, 2.7:1
â:R).
from cycloheptadiene 3. Intermediate 3, with the appropriate relative
stereochemistry at C1, C4, and C7, should be available through a
thermal rearrangement of cyclopropane 4.3a The requisite, highly
strained precursor 4 would be generated through a diastereoselective
cyclopropanation of cyclobutene 5 followed by further function-
alization. An intramolecular Diels-Alder with either racemic or
enantiomerically enriched cyclobutadiene 6 would be used to
generate cyclobutene 5.2
asymmetric addition of 3-butenylzinc reagents to the corresponding
cyclobutadieneiron tricarbonyl carboxaldehyde proceeded with poor
conversion and low enantioselectivity.6 Instead, the oxidation of
compound 9, followed by an asymmetric reduction of the resulting
ketone with the (S)-B-Me-CBS-catalyst 11, provided the enan-
tioenriched alcohol (-)-9 in 96% yield and 92% ee.7 Again, cross-
metathesis of (-)-9 with methyl acrylate led to ester (-)-6, which
upon oxidative cyclization provided the separable, enantioenriched
cyclobutenyl diastereomers (-)-5â and (+)-5R in approximately
3:1 ratio. Each of these enantiomerically enriched diastereomers
leads to a unique antipode of the natural product. Simply switching
the CBS catalyst antipode then provides the enantiomer of these
diastereomers, which in turn leads to the enantiomerically enriched
final products in the opposite ratio.
As illustrated in Scheme 3, further functionalization was neces-
sary to prepare cyclobutene 5 for cyclopropanation. Reduction of
the methyl ester with LAH afforded diol 12. An orthogonal one-
pot, bishydroxyl protection was developed to yield the acylated
secondary and silylated primary alcohol 13 in 87-89% yield (two
steps). After screening a range of conditions, considerable stereo-
chemical control was observed in the ethyl diazoacetate (EDA)
cyclopropanation of cyclobutene 13 using Cu(acac)2 as a catalyst.
Additional optimization allowed for a one-pot cyclopropanation/
deacetylation, generating the highly strained, cyclopropanated
intermediate 14 as the sole observable diastereomer (i.e., >20/1)
in 93-95% yield.8
Scheme 1. Retrosynthesis of Pleocarpenone and Pleocarpenene
An improved preparation of racemic and enantiomerically
enriched cyclobutene 5 is described in Scheme 2. The synthesis
was initiated by a photochemical electrocyclization of commercially
available R-pyrone 7, followed by addition of Fe2(CO)9, to generate
the iron cyclobutadiene methyl ester 8 in a single operation.2c
Reduction of iron complex 8 with DIBAL, followed by oxidation
of the resulting alcohol, yielded an aldehyde that upon treatment
with 3-butenyl magnesium bromide provided alcohol (()-9. Cross-
metathesis of the terminal olefin of 9 with methyl acrylate (in the
presence of 2.5 mol % of Hoveyda-Grubbs second generation
catalyst 10)5e,f generated the desired iron enone (()-6 in 94% yield
with a 13:1 E:Z selectivity.5 In this racemic route, cyclobutadiene
was liberated by CAN oxidation to yield a 1:3.3 mixture of C4
alcohol diastereomers (()-5R and (()-5â in 91% yield.2d These
isomers, which converge later in the synthesis, can be carried on
as a mixture or as isolated intermediates.
The highly compact and rigid nature of cyclopropane 14 provided
an opportunity for the stereocontrolled tailoring of the molecule’s
peripheral features. We envisioned that oxidation of the C4-hydroxyl
group followed by addition of excess MeMgCl to the resulting keto
ester should lead to diol 4 with the desired C4 stereochemistry.
The enantioselective route to (+)- and (-)-pleocarpenene requires
the asymmetric preparation of compound 9. Unfortunately, the
9
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10.1021/ja0674340 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Cyclopropanation of Cyclobutene 5a
naturally occurring material. In addition, the route allowed for
confirmation of the absolute stereochemistry of these systems.
In summary, a new strategy for generating 5-7 ring systems
has been employed in the first asymmetric total synthesis of
pleocarpenene (2) and pleocarpenone (1). An intramolecular
cycloaddition of cyclobutadiene followed by cyclopropanation and
thermal rearrangement (6 f 5 f 4 f 3) are highlighted as the
key steps in the synthesis.
Acknowledgment. We thank the National Institutes of Health
(GM62824) for financial support. We also thank Prof. M. Silva
(Universidad de Concepcio´n, Chile) for a sample of pleocarpenone.
We are grateful to Schering-Plough for X-ray facility support and
for a Graduate Student Fellowship (M.J.W.). We thank Dr. Steve
Schmidt (W.R. Grace) for helpful discussions and samples of Raney
Nickel.
a Data shown for one enantiomeric series. Reaction conditions: (a) (i)
LAH, THF, 0 °C to rt; (ii) TIPSCl, DMAP, Et3N, THF, 4 Å MS; Ac2O
(87-89%); (b) EDA, Cu(acac)2 (5 mol %), CH2Cl2, reflux; EtOH, rt; then
NaOEt(s) (93-95%); (c) (COCl)2, DMSO, THF, -62 °C; Et3N, rt; MeMgCl,
-78 °C (79-82%).
Supporting Information Available: Experimental procedures and
data on new compounds are provided (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
Since we had shown that carbonyl functionality adjacent to this
strained ring system could lead to facile ring opening,3b a tandem
oxidation/alkylation strategy was employed using procedures by
Nubbemeyer and Ireland to generate compound 4 in 79-82% yield.9
We expected the thermal rearrangement of the highly function-
alized cycloadduct 4 to yield the desired bicyclo[5.3.0]decane 3
with inversion of the C1 stereochemistry.3a Unfortunately, initial
fragmentations led to significant levels of decomposition and low
yields of the desired 5-7 ring system. Apparently, the acid-sensitive
tertiary allylic alcohol (C4) in cycloheptadiene 3 was responsible
for the poor outcome since addition of DBU rectified the problem.10
As illustrated in Scheme 4, the optimized rearrangement provided
the desired product 3 with inversion at C1 in 76% yield.
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after recrystallization).13 Ozonolysis and epimerization of 2 yielded
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