Dyotropic rearrangements of fused tricyclic β-lactones: Application to the synthesis of (-)-curcumanolide A and (-)-curcumalactone

Article abstract of DOI:10.1021/ja303414a

Dyotropic rearrangements of fused, tricyclic β-lactones are described that proceed via unprecedented stereospecific, 1,2-acyl migrations delivering bridged, spiro-γ-butyrolactones. A unique example of this dyotropic process involves a fused bis-lactone possessing both β- and δ-lactone moieties which enabled rapid access to the core structures of curcumanolide A and curcumalactone. Our current mechanistic understanding of the latter dyotropic process, based on computational studies, is also described. Other key transformations in the described divergent syntheses of (-)-curcumanolide A and (-)-curcumalactone from a common intermediate (11 and 12 steps from 2-methyl-1,3-cyclopentanedione, respectively), include a catalytic, asymmetric nucleophile (Lewis base)-catalyzed aldol-lactonization (NCAL) leading to a tricyclic β-lactone, a Baeyer-Villiger oxidation in the presence of a β-lactone, and highly facial-selective and stereocomplementary reductions of an intermediate spirocyclic enoate. The described dyotropic rearrangements significantly alter the topology of the starting tricyclic β-lactone, providing access to complex spirocyclic cyclopentyl-γ-lactones and bis-γ-lactones in a single synthetic operation.

Full text of DOI:10.1021/ja303414a

Article
pubs.acs.org/JACS
Dyotropic Rearrangements of Fused Tricyclic β‑Lactones: Application
to the Synthesis of (−)-Curcumanolide A and (−)-Curcumalactone
Carolyn A. Leverett,†,¶ Vikram C. Purohit,†,§ Alex G. Johnson,†,⊥ Rebecca L. Davis,‡ Dean J. Tantillo,‡
and Daniel Romo*,†
†Department of Chemistry, Texas A&M University, P.O. Box 30012, College Station, Texas 77842-3012, United States
‡Department of Chemistry, University of California-Davis, One Shields Avenue, Davis, California 95616, United States
S
* Supporting Information
ABSTRACT: Dyotropic rearrangements of fused, tricyclic β-
lactones are described that proceed via unprecedented
stereospecific, 1,2-acyl migrations delivering bridged, spiro-γ-
butyrolactones. A unique example of this dyotropic process
involves a fused bis-lactone possessing both β- and δ-lactone
moieties which enabled rapid access to the core structures of
curcumanolide A and curcumalactone. Our current mecha-
nistic understanding of the latter dyotropic process, based on
computational studies, is also described. Other key trans-
formations in the described divergent syntheses of (−)-curcu-
manolide A and (−)-curcumalactone from a common intermediate (11 and 12 steps from 2-methyl-1,3-cyclopentanedione,
respectively), include a catalytic, asymmetric nucleophile (Lewis base)-catalyzed aldol-lactonization (NCAL) leading to a tricyclic
β-lactone, a Baeyer−Villiger oxidation in the presence of a β-lactone, and highly facial-selective and stereocomplementary
reductions of an intermediate spirocyclic enoate. The described dyotropic rearrangements significantly alter the topology of the
starting tricyclic β-lactone, providing access to complex spirocyclic cyclopentyl-γ-lactones and bis-γ-lactones in a single synthetic
operation.
INTRODUCTION
■
Curcumanolides A (1) and B (2) are sesquiterpenoid natural
products previously isolated from Curcuma zedoara and related
species (Figure 1).1 Both of these spirolactones are present in
the crude drug Zedoary, the ground rhizome of C. zedoaria
Roscoe, which has been used medicinally in China for a variety
of indications.2 Curcumalactone (3), a dihydro derivative of
curcumanolide A, was isolated from C. aromatica Silisb3 and C.
Figure 1. Spirolactone natural products isolated from extracts of
wenyujin4 which have long been used as a remedies for cervical
Curcuma species.
cancer in China5 and were reported to exhibit anti-
inflammatory activity.3 While no information regarding the
biological activity of curcumanolides A and B is available, the
structural similarity with curcumalactone elevates their interest
as targets for further biological studies. In particular, the enoate
and spirocylic γ-lactone moieties attracted our interest since
these constitute potential electrophilic sites, which could render
these natural products as covalent modifiers of their putative
cellular targets.
selective synthesis of curcumanolide A from (−)-carvone
establishing the absolute configuration,7 and Fujita utilized an
enzymatic transesterification process to access (−)-curcu-
manolide A.8 However, the reported syntheses have led to
little additional biological information, and there is no
information regarding possible cellular targets.
Dyotropic rearrangements were originally defined as
reactions in which “two σ-bonds simultaneously migrate
intramolecularly” (Figure 2a),9 but a variety of examples have
since been reported in which the simultaneity of the two σ-
bond migrations varies from synchronous (and concerted) to
asynchronous (and concerted) to stepwise (separated by a
discrete intermediate).10 Several types of dyotropic rearrange-
ments have been employed in various synthetic contexts,
In addition to their potential bioactivity, the unique,
functionalized cyclopentane bearing a spirolactone found in
these natural products has attracted significant interest from the
synthetic community, leading to diverse strategies to access this
common core. The first total synthesis of curcumanolide A and
the only reported synthesis of curcumalactone to date, both in
racemic form, were accomplished by Kato employing a
bromonium-induced cyclization/ring contraction route from
geraniol.6 Subsequently, Honda reported the first enantio-
Received: April 17, 2012
© XXXX American Chemical Society
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Scheme 1. Retrosynthetic Analysis of Curcumalactone and
Curcumanolide A
(3) was envisioned employing our recently described
nucleophile-catalyzed aldol-lactonization (NCAL) process
involving desymmetrization of dione 7 with homobenzo-
tetramisole (HBTM) as the Lewis base promoter.21 This
process would deliver tricylic β-lactone 6 and subsequent
Baeyer−Villiger oxidation and dyotropic rearrangement would
provide bis-lactone 4 bearing the common spirocyclic core of
the targeted natural products. Completion of the synthesis of
(−)-curcumalactone and (−)-curcumanolide A would require
further transformations of the tricycle 4 including two
stereochemistry setting steps that would be dictated by the
topologically rich spirocyclic core. In particular, a facially
selective hydrogenation of an intermediate cyclopentene would
set the C4-methyl-bearing stereocenter of the two targets and a
diastereoselective reduction of an enoate would introduce the
C7-isopropyl-bearing stereocenter of curcumalactone.
Figure 2. (a) Prototypical dyotropic rearrangement wherein two σ-
bonds simultaneously migrate intramolecularly (b) Dyotropic
rearrangements of β-lactones involving hydrogen, electron-rich groups,
and amino migrations. (c) β-Lactone dyotropic rearrangements
involving acyl and carboxylate migrations.
ranging from the early report of a dyotropic interchange of
vicinal Br atoms on a steroid skeleton,11 to more recent
applications in the synthesis of N-cis-propenyl amides,12
trisubstituted olefins,13 and tetraazanaphthalenes.14 A widely
studied dyotropic process, of particular interest to us, is the
Lewis acid-mediated rearrangement of β-lactones leading to
various γ-butyrolactones (Figure 2b). This area of dyotropic
rearrangement chemistry commenced with seminal reports by
Mulzer on the ring expansion of β-lactones through a dyotropic
process in which the β-lactone oxygen and electron-rich
migrating groups exchanged positions.15 Related reports
include Reetz’s demonstration that acyclic amino migrating
groups allow for the generation of 3-amino-γ-lactones,16
RESULTS AND DISCUSSION
■
The synthesis of the core structure of both curcumanolide A
(1) and (−)-curcumalactone (3) began with the multigram-
scale synthesis of dione acid 7 from commercially available 2-
methyl-1,3-cyclopentanedione 8 (Scheme 2). We previously
Scheme 2. Multigram Synthesis of Dione Ketoacid 7 from
́
Cossıo’s study of the dyotropic rearrangement of propio-
a
lactones to γ-butyrolactones under similar conditions,17 and
Black’s examination of the dyotropic rearrangement of
spirobicyclic β-lactones to a variety of fused γ-butyrolactone
systems.18
1,3-Cyclopentanedione
While β-lactone dyotropic reactions with electron-rich
migrating groups have been studied extensively, we recently
reported the first example of a 1,2-acyl migration in a β-lactone
dyotropic process (Figure 2c).19 This Lewis-acid mediated,
stereospecific, dyotropic rearrangement of fused tricyclic β-
lactones enables the synthesis of spirocyclic, bridged γ-
butyrolactones. Subsequent studies revealed plausible mecha-
nistic pathways for this rearrangement, formulated on the basis
of both experimental and theoretical results.20 We projected
that a related dyotropic process involving a bis-lactone bearing
both a δ- and a β-lactone moiety would enable efficient access
to the spirocyclic core structure of members of the Curcuma
family of natural products. Herein, we describe concise
synthetic routes to (−)-curcumanolide A (1) and (−)-curcuma-
lactone (3) that demonstrate the utility of these dyotropic
processes for complex natural product synthesis with the latter
being the first reported asymmetric synthesis.
a
TBAI, tetrabutylammonium iodide.
utilized a four-step sequence to access this substrate;19 however,
scale-up of this sequence proved problematic and inefficient.
After extensive optimization, a streamlined synthesis of this key
substrate was developed involving a one-pot alkylation/
hydrolysis sequence to directly deliver dione acid 9 employing
commercially available methyl 4-bromocrotonate in 1 M NaOH
as solvent under phase transfer conditions. This method
enabled production of >20 g of dione acid 9 in a single run and
is useful for the large-scale synthesis of a number of related
dione acids following hydrogenation of the alkene.22
With a scaleable route to dione 7 in hand, extensive
optimization was required to develop a practical, catalytic,
asymmetric NCAL process to access tricyclic β-lactone (+)-6.
Initial studies of this transformation employed 1.5 equiv of
(−)-tetramisole·HCl (10)23 as a promoter in this desymmet-
Retrosynthetic Analysis of Curcumanolides and
Curcumalactone. Access to the spirocyclic cores (e.g., 4,
Scheme 1) of the curcumanolides (1, 2) and curcumalactone
B
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rization process and the modified Mukaiyama reagent 14,
which led to the desired product with high optical purity but
only in moderate yields (Table 1, entry 1). Several other
studied the use of alternative chiral isothiourea catalysts (11−
13, Table 1) developed by Birman and related to tetramisole
(10), as Lewis base promoters for the NCAL process.24 The
use of 20 mol % (S)-HBTM (11)24a provided good yields and
excellent enantioselectivities (58%, 96% ee) of tricyclic β-
lactone (+)-6 in conjunction with p-toluenesulfonyl chloride
(p-TsCl) as activating agent. A further significant increase in
yield was realized with use of the mild Lewis acid, LiCl (1.0
equiv), with no sacrifice in enantioselectivity (77%, 96% ee),
and this process was utilized to access a number of bicyclic and
tricyclic β-lactones with good to excellent yields and
enantioselectivities.21
Table 1. Optimization of the NCAL Process with Dione Acid
7 Leading to Tricyclic β-Lactone (+)-6
Toward the synthesis of curcumalactone and congeners,
conducting the NCAL process on gram scale with (R)-HBTM
provided a 65% yield of the desired tricyclic β-lactone (−)-6 in
high optical purity (98% ee, Scheme 3). The absolute
stereochemistry of (−)-6 was confirmed indirectly by
conversion of the enantiomeric tricyclic β-lactone (+)-6 derived
from (S)-HBTM to the corresponding oxazolidinone via a
Curtius rearrangement (Scheme 3, inset). Following conversion
to the N-p-bromobenzoate (+)-15, assignment of absolute
configuration of tricyclic β-lactone (+)-6 was made possible by
X-ray analysis using heavy atom anomalous dispersion.21 Thus,
the relative and absolute configuration of (−)-6 was secured by
comparison of NMR and optical rotations with the
enantiomeric series. A subsequent Baeyer−Villiger oxidation
of tricyclic β-lactone (−)-6 under buffered conditions led to
slow conversion to the ring-expanded δ-lactone (−)-5 in
moderate yield, setting the stage for the key dyotropic
rearrangement. It is worth noting that this oxidative rearrange-
ment is possible, notwithstanding the presence of the
potentially reactive β-lactone.
a
b
Single diastereomer observed by 1H NMR. Refers to isolated,
c
d
purified products. Determined by chiral GC analysis. (−)-
e
Tetramisole·HCl (10) and (S)-BTM (11) provide (−)-6. With 1.0
Dyotropic Rearrangements of Tricyclic Acyl-β-lac-
tones and Bis-lactones. We began our studies of the
dyotropic rearrangement of acyl-β-lactones with tricyclic β-
lactone 16a (Table 2), available by the NCAL reaction of a
cyclohexanedione precursor. We surmised that Lewis acid
activation of the β-lactone would promote a dyotropic
rearrangement via 1,2-acyl migration leading to simultaneous
and stereospecific ring expansion of the β-lactone to a γ-lactone
equiv LiCl added. CDI, carbonyldiimidazole; Ts, tosyl; Bz, benzoyl;
Napth, naphthyl.
carboxylic acid activating agents were explored but led to
inferior yields and generally significantly decreased enantio-
selectivities, especially when catalytic amounts of (−)-tetra-
misole·HCl were employed (Table 1, entries 2−5). We next
a
25
,
Scheme 3. Gram-Scale Synthesis of Optically Active Bis-lactone (−)-6 and Confirmation of Absolute Stereochemistry
a
HBTM, homobenzotetramisole; TsCl, p-toluenesulfonyl chloride; m-CPBA, m-chloroperoxybenzoic acid; NCAL, nucleophile-catalyzed aldol
lactonization; DPPA, diphenylphosphoryl azide. Inset: ORTEP representation of the X-ray crystal structure of tricyclic carbamate (+)-15; hydrogens
removed for clarity; thermal ellipsoids shown at 50% probability.
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supported computationally, as detailed below. Interestingly,
while Zn(II) salts led to good yields of dyotropic products in
most cases, subjecting β-lactone 16a to catalytic TMSOTf
provided only ring-opened diacid 17f (73%, entry 6), suggestive
of an intervening Grob-type fragmentation, which was
subsequently confirmed to occur due to adventitious TfOH
and not TMSOTf under these conditions.20 The first dyotropic
rearrangement of an optically active tricyclic β-lactone was also
performed with lactone (−)-16a (97% ee) using Zn(OTf)2 and
this provided γ-lactone (−)-17a in excellent yield (91%) with
high stereochemical fidelity (99% ee, chiral GC).
Table 2. Dyotropic 1,2-Acyl Migration of Tricyclic β-
Lactones
Toward application of the dyotropic process to the targeted
natural products, we studied the rearrangement of tricyclic bis-
lactone (−)-5 bearing both a δ- and β-lactone (Scheme 4).
Scheme 4. Enantioselective Synthesis of Spirolactone (+)-4
a
via a Bis-lactone Dyotropic Rearrangement
a
TMSOTf, trimethylsilyl trifluoromethanesulfonate.
While use of Zn(OTf)2 gave only recovered bis-lactone (−)-5,
a brief survey of Lewis acids led to use of substoichiometric
TMSOTf (15 mol %), which slowly produced the desired
spiro-γ-lactone (+)-4 in good yield (73%) and with complete
stereochemical fidelity (98% ee).
Mechanistic Studies of the Dyotropic Rearrangement
of Tricyclic β-Lactones Involving 1,2-Acyl Migrations.
The described dyotropic rearrangements of β-lactones
involving 1,2-acyl migrations were unprecedented in type I
dyotropic processes.10a Our initial hypotheses for this
rearrangement invoked a 2-electron-3-centered acylium inter-
mediate or a carboxylate-stabilized, four-membered transition
state. Both pathways would benefit from a homoconjugated,
carbonyl-assisted migration. However, subsequent theoretical
(B3LYP/6-31+G(d,p)) and experimental studies of this
dyotropic process (e.g., 16 → 17, Table 2) revealed that the
concertedness of this rearrangement was dependent on the
nature of the Lewis acid employed.20 Theoretical calculations
on both the Zn(OTf)2- and ZnCl2-promoted rearrangements of
16a to 17a revealed that these reactions occur in a stepwise
manner, involving an intermediate with a Zn(II)-complexed
carboxylate and a tertiary carbocation center (cf. 19, Figure 3).
However, attempts to trap this carbocation intermediate by
both inter- and intramolecular nucleophiles were unsuccessful.
These observations are consistent with the computational
results, which suggested that the 1,2-acyl shift/carbocation
capture process is extremely facile for [6-5] bicyclic
a
b
Refers to isolated yields. Reaction performed using 0.2 equiv
TMSOTf at 23 °C for 12 h instead of Zn(OTf)2. Isolated yield of
diacid 17f accompanied by only trace amounts of dyotropic product.
with concomitant ring contraction of the cyclohexanone. It
should be noted that in these rigid tricyclic systems,
stereospecificity is enforced due not solely to synchronicity of
migration but also to ring constraints. Importantly, β-lactone
substrate 16 possesses the required antiperiplanar relationship
between the migrating C4−O1 bond of the β-lactone and the
C5−CO bond of the cyclohexanone. After screening a variety
of Lewis acids, including AlBr3, Et2AlCl, LaCl3, PrCl3, YCl3,
MgBr2, Yb(OTf)3, In(OTf)3, and Mg(OTf)2, the best yields for
this transformation were realized using Zn(II) salts, providing
up to 94% yield of 17a when employing 1.1 equiv of Zn(OTf)2
(Table 2, entry 1). Substoichiometric amounts of Zn(OTf)2 led
to significant amounts of recovered starting material. Other
tricyclic β-lactones 16b−d were also studied under these
conditions and gave excellent yields of bridged γ-lactones 17b−
d (Table 2, entries 2−4) with high stereospecificity (dr >19:1).
It is important to note that in the case of tricyclic β-lactone 16e
(entry 5), which lacks the antiperiplanar relationship between
the β-lactone C4−O bond and the C5−acyl carbon, only olefin
acid 17e was isolated (55%), likely generated from β-lactone
opening and subsequent elimination. By a presumed similar
pathway, the tricyclic β-lactone 16b produced trace amounts
(3%) of β,γ-unsaturated acid 18 in addition to the expected
dyotropic product 17b in high yield. These two examples
provided our initial evidence for carbocation formation in the
Zn(II)-promoted dyotropic rearrangement, which was later
Figure 3. (a) Intermediate for Zn(II)-based Lewis acid-mediated and
(b) transition state structure for TMSOTf-mediated, dyotropic
rearrangement of tricyclic β-lactone 16a.
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Figure 4. Computed geometries (B3LYP/6-31+G(d,p))27 of species involved in the rearrangement of TMS-ent-5 to TMS-ent-4. Energies shown are
in kcal/mol and are relative to that of the reactant complex (ZPE-corrected energies in normal text; free energies at 25 °C in italics). Selected bond
lengths are given in Å.
carbocations, making this intermediate difficult to intercept.
Overall, the ΔG⧧ for the reaction with Zn(OTf)2 was calculated
to be 16 kcal/mol in the gas phase (<10 kcal/mol in CH2Cl2),
and the product was calculated to be favored by 12 kcal/mol
relative to the β-lactone− Zn(OTf)2 reactant.
In contrast, examination of the TMSOTf-mediated rear-
rangement of the tricyclic β-lactone 16a indicated that, unlike
the Zn(II)-bound species, this species can undergo a low-
barrier concerted dyotropic rearrangement (cf. 20, Figure 3).20
This reaction is predicted to have a barrier of only 6−7 kcal/
mol in the gas phase (5 kcal/mol in CH2Cl2). These results
indicate that the reaction can proceed readily at room
temperature to produce the desired γ-lactone, despite the fact
that only trace amounts of the γ-lactone product were observed
experimentally using TMSOTf.
Figure 5. Electrostatic potential surfaces for the stationary points
shown in Figure 4 (blue is most positive; charge range: 6.0 × 10−2 to
14.5 × 10−2; isovalue: 0.0200).
Dyotropic Rearrangements of Bis-lactones. We also
examined the mechanism of the bis-lactone dyotropic
rearrangement, which delivers the curcumalactone core (cf.
Scheme 4). Related dyotropic rearrangements have been used
in total synthesis efforts, with the most closely related being
that by Fuchs in his strategy to cephalostatin analogues.26 The
TMSOTf-promoted rearrangement of (−)-5 to (+)-4 is
predicted to be a concerted dyotropic rearrangement (Figure
4).27 The barrier for this rearrangement is approximately 7
kcal/mol higher than that predicted previously for the
analogous rearrangement of 16a,20 reflecting the different
propensities of ester and acyl groups for migration. In addition,
the transition state structure shown in Figure 4 also has shorter
partial bonds to the migrating groups and a longer central C−C
bond (1.48 vs 1.39 Å) than found for 16a.20 Thus, in contrast
to the rearrangement of 16a, in which substantial charge
separation occurs (the transition state structure for this process
resembles an acyl cation and a TMS-complexed carboxylate
migrating across a partial double bond, cf. Figure 3, 20), the
rearrangement shown in Figure 4 more closely resembles a
“double SN2” process, in which a lone pair on each migrating
oxygen attacks the backside of the other C−O bond. This
picture is borne out by computed electrostatic potential maps
for the structures in Figure 4. As shown in Figure 5, charge
separation actually appears to decrease slightly as the transition
state structure is reached. Silylation of the δ-lactone carbonyl is
also possible and is actually favored by approximately 8 kcal/
mol. Silylation is associated with an increase in double bond
character for the O−C bond within the δ-lactone ring and is
accompanied by greater angle strain for the smaller β-lactone
ring. However, the transition state structure for rearrangement
of the resulting species is predicted to be approximately 5 kcal/
mol higher in energy than that shown in Figure 4, and there
appears to be greater strain associated with the former
transition state structure, in contrast to the situation for the
corresponding reactants.28 If the β-lactone-complexed and δ-
lactone-complexed reactants can interconvert under the
reaction conditions, which seems plausible, then the Curtin−
Hammett principle29 is expected to apply, and the transition
state structure in Figure 3 is expected to correspond to the
predominant route to product.
Final Stages of the Synthesis of (−)-Curcumanolide A
(1) and (−)-Curcumalactone (3). We recognized that the
reactivity of the two γ-lactones present in the bis-lactone (+)-4
would require further differentiation to enable selective ring
cleavage of the bridged γ-lactone. We thus chose to introduce
the required β,β′-dimethyl enoate at an early stage to further
differentiate the reactivity of these two γ-lactones. Thus, aldol
condensation with acetone in a two stage, one-pot reaction
provided the desired enoate (+)-25 in 65% yield (Scheme 5).
In efforts to directly form the isopropylidene precursor 27 by
nucleophilic addition to the more strained, bridged, γ-lactone
over the less electrophilic α,β-unsaturated lactone, we first
tested a variety of conditions to generate tertiary alcohol 27 via
methyllithium or methyl Grignard addition. In early studies
with racemic bis-lactone ( )-25, treatment with 1.1 equiv MeLi
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Scheme 5. Aldol Addition/Elimination and Selective Ring-
Opening of Bis-lactone (+)-25
Table 3. Conditions Tested for the Diastereoselective,
Substrate-Directed Reduction of Enoate (−)-31 to (−)-33
a
entry
conditions
% yield (dr, 33:33′)
a
b
1
2
3
5 mol % PtO2, EtOH, 35 bar H2, 48 h
55 (<1:19)
c
CuBr, Red-Al, THF, 0 °C, 2 h
L-Selectride, THF, −78 °C → 0 °C, 1.5 h
ND (3:1)
b
83 (>19:1)
a
b
Use of EtOAc as solvent gave similar results. Isolated yield after
c
1
column chromatography. Ratio determined by H NMR analysis of
crude reaction mixture. Yield not determined (ND).
a
LHMDS, lithium bis(trimethylsilyl)amide; MsCl, methanesulfonyl
chloride.
Scheme 7. Dehydration of Tertiary Alcohol 33 Leading to
(−)-Curcumalactone (3)
Scheme 6. Conversion of Methyl Ester (−)-28 to the
Common Core (−)-31 and Synthesis of (−)-Curcumanolide
a
A (1)
however, these reagents were inferior, leading to low
conversion on scale-up. Ultimately, Burgess’ reagent (29)31 in
refluxing benzene was found to give high yields (84%) of an
inseparable exo/endo mixture (2.4:1) of olefinic products.
Several conditions were screened for the required olefin
reduction, including diimide reduction, and hydrogenation
with Pd/C and Wilkinson’s catalyst (Rh(PPh3)3Cl); however,
these conditions gave low conversion. Ultimately, hydro-
genation with 5 mol % PtO2 led to complete reduction at 1
atm H2 after 12 h with good facial selectivity (83% yield, ∼9:1
dr). The stereochemistry of the major diastereomer (−)-30 was
confirmed by X-ray analysis supporting the anticipated facial
selectivity providing the desired C4 stereochemistry. The minor
diastereomer obtained during this hydrogenation possesses the
relative stereochemistry found in curcumanolide B.
We next turned our attention to conversion of the methyl
ester to an isopropylidene group (Scheme 6). Selective addition
of Grignard reagents to the methyl ester over the spirolactone
was initially studied with MeMgI and MeMgBr under a variety
of conditions but all led to complex mixtures of products that
included monoaddition to the ester, and both 1,4- and 1,2-
addition to the spirolactone. The use of CeCl3 as an additive33
and subsequently CeCl3/LiCl34 had profoundly beneficial
effects, and ultimately the use of MeLi rather than MeMgI or
MeMgBr35 led to efficient conversion to the desired tertiary
alcohol (−)-31 in 79% yield. The final dehydration toward
(−)-curcumanolide A was accomplished by employing Burgess’
reagent (29) once again under conditions similar to those
previously reported by Kato,6b providing a 93% yield of a ∼3:1
mixture of curcumanolide A (1, major product) and the
corresponding exocyclic olefin regioisomer 32 (not shown).
Partial separation of this mixture could be achieved by column
chromatography providing pure (−)-curcumanolide A, and
characterization data including optical rotation correlated well
with previously reported data.1
a
Inset: ORTEP representation of the X-ray crystal structure of
spirolactone (−)-30; hydrogens removed for clarity; thermal ellipsoids
shown at 50% probability.32
did not deliver tertiary alcohol 27 but rather yielded dienyl
tetrahydrofuran 26, presumably formed by 1,2-addition and
subsequent alcohol elimination during the mild acid work-up.
Reaction with Grignard reagents (MeMgI or MeMgBr) gave a
mixture of recovered starting material and both mono- and bis-
1
addition products as judged by analysis of crude H NMR. As
an alternative, we next considered ring cleavage to a methyl
ester for subsequent conversion to the tertiary alcohol.
Employment of standard methanolysis conditions (NaOMe,
MeOH) provided some desired ester, but also the diester from
cleavage of both γ-lactones. However, use of Et3N in MeOH
under reflux conditions gave the desired hydroxy ester (−)-28
in modest yield with only trace amounts of the diester, and
finally a decrease in reaction temperature to 50 °C provided
exclusively the desired product in serviceable yield (51%) and
good recovery of starting material (34%).30 Longer reaction
times and increased amounts of Et3N led to similar results,
suggestive of reversible ring-opening of the two γ-lactones
under these conditions.
To install the C4-methyl-bearing stereocenter, we envisioned
dehydration of the secondary alcohol of (−)-28 at C4 followed
by a facially selective hydrogenation of the more sterically
accessible face syn to the C−O bond of the spirolactone
(Scheme 6). A number of standard alcohol elimination
products were screened at various temperatures including
SOCl2/Et3N, SOCl2/pyridine, MsCl/Et3N, MsCl/Et3N/DBU,
or MsCl/DMAP/pyridine and performed well on small scale;
In strategies toward curcumalactone, a key challenge posed is
setting the stereochemistry at C7 (cf. 33 in Table 3). Previous
synthetic studies typically led to the incorrect diastereomer at
F
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Scheme 8. 1H NMR Data (300 MHz) Supporting Intramolecular Protonation during Reduction with L-Selectride: (a) 1H NMR
Expansion (δ 1.7−3.15) of Saturated Lactone 33 for Comparison and Same Expansion Following Initial Deuterium Exchange of
a
Tertiary Alcohol with CD3OD for (b) 17 h and (c) 4 h, Leading to Deuterated 33 (D-33) in Different Ratios
a
Ratio of D incorporation based on integration: (b) ∼50% and (c) ∼30% D. Diastereotopic C6-protons going from two doublet of doublets to two
doublets due to deuteration at C7 are marked by asterisks.
C7 through reduction of related enoate intermediates or direct
alkylation leading primarily to C7-epi-curcumalactone. Thus, a
subsequent epimerization was required to achieve, at best, a
mixture of diastereomers.6b Given the presence of the tertiary
alcohol in intermediate 31, we considered two approaches to
set the C7-stereochemistry. The first involved a possible
hydroxyl-directed hydrogenation36 of the tetra-substituted
olefin, a process not without precedent.37 However, the
tetrasubstituted and electron-poor olefin in 31 was recalcitrant
to hydrogenation with multiple catalysts under various
conditions (Pd/C, Pd(OH)2/C, Pd/BaSO4,37a and Crabtree’s
catalyst) including high pressure (up to 35 bar H2). Only when
employing PtO2 at 35 bar H2 was reduction possible, providing
55% yield with 41% recovered starting material (Table 3, entry
1). This led to high diastereoselectivity for 33′ based on
comparison with previously described C7-epi-curcumalactone,6b
obtained following alcohol elimination of 33′, indicating that
the hydroxyl group was not directing the hydrogenation. A
second strategy would make use of the tertiary alcohol in a
different capacity. We considered the possibility of a 1,4-
conjugate reduction followed by intramolecular protonation of
the intermediate enolate by the tertiary alcohol in a facially
selective fashion to deliver curcumalactone (cf. 34 in Table 3).
Initially, reaction with the copper-hydride species generated in
situ from CuBr and Red-Al38 led to an ∼3:1 mixture of 33/33′,
indicating that some intramolecular protonation had likely
occurred, but also some possible coordination of the tertiary
alcohol with the cuprate species as described previously in the
literature.39 Ultimately, we discovered that 1,4-reduction with
L-selectride in THF at −78 °C followed by warming to 0 °C
and quenching at that temperature indeed led to the desired
diastereomer 33 in high diastereoselectivity and yield (dr >19:1,
83%).
The synthesis of (−)-curcumalactone was completed by
dehydration employing SOCl2 following the method of Kato6b
to deliver an ∼6.2:1 mixture of endo/exo olefin regioisomers in
57% yield (Scheme 7). This elimination could also be
performed with Burgess’ reagent in higher yields with slightly
decreased ratios of curcumalactone and the corresponding endo
regioisomer (92%, ∼5.5:1 3/35).6b Purification by column
chromatography delivered pure (−)-curcumalactone and both
spectral and optical rotation data correlated well with reported
values.6
The high diastereoselectivity observed from conjugate
reduction of enoate 31 with L-Selectride is noteworthy and
points to the likelihood of an intramolecular protonation of an
intermediate boron enolate since the diastereomeric product
33′ would be expected from an intermolecular protonation of
the enolate 34 (Table 3). We designed an experiment to probe
the hypothesis that intramolecular protonation by the adjacent
tertiary alcohol (i.e. via enolate 34, Table 3) was indeed
occurring following conjugate reduction. Intramolecular proto-
nation of enolates by alcohols has been described in the
literature,40 and the preferred conformation of the spirocyclic
G
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Present Addresses
system (i.e., 31) appeared conducive for such an intramolecular
protonation (see 34, Table 3). We reasoned that alcohol OH
→ OD exchange with excess CD3OD, followed by azeotropic
drying with xylenes and reduction with L-selectride, would lead
to deuterated species D-33 (Scheme 8). This process gave
varying amounts of D-33 depending on the time allowed for H
→ D exchange (4 vs 17 h, Scheme 8b,c); however, high
diastereoselectivity was consistently observed, suggestive of an
intramolecular protonation/deuteration. Incorporation of
deuterium at C7 is evidenced by simplification of the
diastereotopic C6-protons (indicated by *) from two sets of
doublet of doublets (dd, J = 10.5, 13.2) to a doublet (d, J =
13.2) centered at δ 2.47, due to exchange of a vicinal proton at
C7 for deuterium. Similar simplification is also observed with
the diastereotopic C6′ proton centered at δ 1.77 but is
obscured by other protons. Further confirmation of deuterium
incorporation came from HRMS analysis of the mixture of 33/
D-33.28 The inability to achieve complete deuterium
incorporation is not easily explained, given the high facial
selectivity that excludes intermolecular processes, but the
simplest explanation is incomplete deuterium exchange of the
tertiary alcohol. Importantly, this sequence provides a highly
stereocontrolled introduction of the C7 stereocenter, a
challenge encountered in the previous synthesis of curcuma-
lactone.6b
§Teva North America, 1090 Horsham Rd., North Wales, PA
19454
⊥Department of Molecular Microbiology and Immunity,
Oregon Health and Science University, 3181 S.W. Sam Jackson
Park Rd., Portland, OR 97239
¶Pfizer, Inc., 558 Eastern Point Rd., Groton, CT 06340
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for generous support from the National Science
Foundation (CHE-0809747 to D.R., CHE-0755207 REU
supporting A.G.J., CHE-0449845 and CHE-030089 (Pittsburgh
Supercomputer Center) to D.J.T., and the Welch Foundation
(A-1280 to D.R.). We thank Dr. Joe Reibenspies for the X-ray
analyses and Dr. Arjun Raghuraman for technical assistance.
REFERENCES
■
(1) Shiobara, Y.; Asakawa, Y.; Kodama, M.; Yasuda, K.; Takemoto, T.
Phytochemistry 1985, 24, 2629.
(2) Matthes, H. W. D.; Luu, B.; Ourisson, G. Phytochemistry 1980,
19, 2643.
(3) Jiehan, H.; Xiuwen, H.; Tao, J.; Zhenyun, Y.; Xiuying, W.; Jihong,
X.; Yongtian, G. Kexue Tongbao 1987, 32, 816.
(4) (a) Inayama, S.; Gao, J.-F.; Hariyama, K.; Hikichi, M.; Iitaka, Y.;
Guo, Y.-T.; Kawamata, T. Chem. Pharm. Bull. 1985, 33, 2179. (b) Gao,
J.-F.; Ohkura, T.; Harimaya, K.; Hikichi, M.; Kawamata, T.; Ying, W.-
X.; Iitaka, Y.; Inayama, S. Chem. Pharm. Bull. 1986, 34, 5122.
(5) See ref 3 and references cited therein.
(6) (a) Hirukawa, T.; Oguchi, M.; Yoshikawa, N.; Kato, T. Chem.
Lett. 1992, 2343. (b) Kato, T.; Mutoh, M.; Oguchi, M.; Yasuoka, H.
Sci. Iran. 1997, 4, 94.
(7) Honda, T.; Ishige, H. J. Chem. Soc., Perkin Trans. 1 1994, 3567.
(8) Fujita, T.; Tanaka, M.; Norimine, Y.; Suemune, H. J. Org. Chem.
1997, 62, 3824.
(9) (a) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1972, 11, 129.
(b) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1972, 11, 130. (c) Reetz,
M. T. Tetrahedron 1973, 29, 2189. (d) Reetz, M. T. Adv. Organomet.
Chem. 1977, 16, 33. (e) Hoffmann, R.; Williams, J. E., Jr. Helv. Chim.
Acta 1972, 55, 67.
CONCLUSIONS
■
In summary, we provided a full account of our recently
disclosed stereospecific dyotropic process to spirocyclic,
bridged γ-butyrolactones via Lewis-acid-mediated 1,2-acyl and
δ-lactone migrations. By employing these methods, concise
asymmetric routes to the spirocyclic sesquiterpene natural
products (−)-curcumanolide A and (−)-curcumalactone have
been accomplished through a key dyotropic process of a
tricyclic β,δ-bis-lactone, which establishes the spirocyclic
stereocenter. DFT calculations on this dyotropic rearrangement
suggest a double ‘SN2-like’ process of the two migrating
carboxylates with a diminution in charge separation as the
transition state structure is reached. The synthesis demonstrates
the utility of our catalytic, asymmetric NCAL process and the
ability to perform a Baeyer−Villiger oxidation in the presence
of a β-lactone. A highly diastereoselective 1,4-reduction
involving intramolecular protonation by a resident tertiary
alcohol established the final stereocenter found in curcuma-
lactone. The described enantioselective synthesis of curcuma-
nolide A and curcumalactone was accomplished in 11 and 12
steps, respectively, from 2-methyl-1,3-cyclopentanedione and
did not require the use of protecting groups. The synthetic
strategy described herein provides efficient routes to both
natural products, enabling further biological studies of these
potentially bioactive spirolactones.
́
(10) For a review and leading references, see: (a) Fernandez, I.;
Cossío, F. P.; Sierra, M. A. Chem. Rev. 2009, 109, 6687−6711.
(b) Davis, R. L.; Tantillo, D. J. J. Org. Chem. 2010, 75, 1693−1700.
(11) (a) Grob, C. A.; Winstein, S. Helv. Chim. Acta 1952, 35, 782−
802. (b) Barton, D. H. R.; Head, A. J. J. Chem. Soc. 1956, 932.
(12) (a) Lin, S.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2002, 41,
512. (b) Zhang, X.; Houk, K. N.; Lin, S.; Danishefsky, S. J. J. Am.
Chem. Soc. 2003, 125, 5111.
(13) Kocienski, P.; Barber, C. Pure Appl. Chem. 1990, 62, 1933.
(14) Stockner, F.; Kapplinger, C.; Beckert, R.; Gorls, H. Synlett 2005,
̈
̈
̈
643.
(15) Mulzer, J.; Bruntrup, G. Angew. Chem., Int. Ed. Engl. 1979, 18,
793.
̈
(16) Reetz, M. T.; Schmitz, A.; Holdgrun, X. Tetrahedron Lett. 1989,
̈
30, 5421.
ASSOCIATED CONTENT
■
(17) Arrastia, I.; Lecea, B.; Cossío, F. P. Tetrahedron Lett. 1996, 37,
245−248.
(18) (a) Black, T. H.; DuBay, W. J., III Tetrahedron Lett. 1988, 29,
1747. (b) Black, T. H; McDermott, T. S. J. Chem. Soc., Chem Commun.
1991, 184.
S
* Supporting Information
Complete ref 27d. Complete experimental and characterization
details for all new compounds reported, along with additional
details on calculations. Crystallographic files. This material is
available free of charge via the Internet at http://pubs.acs.org.
(19) Purohit, V. C.; Matla, A. S.; Romo, D. J. Am. Chem. Soc. 2008,
130, 10478.
(20) Davis, R. L.; Leverett, C. A.; Romo, D.; Tantillo, D. J. J. Org.
Chem. 2011, 76, 7167.
(21) Leverett, C. A.; Purohit, V. C.; Romo, D. Angew. Chem., Int. Ed.
AUTHOR INFORMATION
■
Corresponding Author
romo@tamu.edu
2010, 49, 9479.
H
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Journal of the American Chemical Society
Article
(22) The scope of this concise approach to dione acids will be
disclosed in a separate report.
(23) Birman, V. B.; Li, X. Org. Lett. 2006, 8, 1351.
(24) (a) Birman, V. B.; Li, X. Org. Lett. 2008, 6, 1115. (b) Padakanti,
P. K. Ph.D. Thesis, Washington University: St. Louis, MO, USA, 2010.
(25) CCDC 875167 (15) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
(26) (a) Li, W.; LaCour, T. G.; Fuchs, P. L. J. Am. Chem. Soc. 2002,
124, 4548. For selected dyotropic rearrangements in total synthesis
efforts, see: (b) Zhang, X.; Houk, K. N.; Lin, S.; Danishefsky, S. J. J.
Am. Chem. Soc. 2003, 125, 5111. (c) Denmark, S. E.; Montgomery, J. I.
Angew. Chem., Int. Ed. 2005, 44, 3732. For additional examples, see ref
10a.
(27) Calculations were performed at the B3LYP/6-31+G(d,p) level
of theory: (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Becke, A.
D. J. Chem. Phys. 1993, 98, 1372. (c) Lee, C.; Yang, W.; Parr, R. G.
Phys. Rev. B 1988, 37, 785. (d) Stephens, P.; Devlin, F. J.;
Chabalowski, C. F.; Frisch, M. J. J. Phys. Chem. 1994, 98, 11623
using GAUSSIAN03 (complete reference in Supporting Information).
(e) All structures were characterized by frequency analysis, and
reported energies from B3LYP/6-31G+(d,p) calculations include zero-
point energy (ZPE) corrections. Free energies at 25 °C are also
reported. Intrinsic reaction coordinate (IRC) calculations were also
used to characterize the transition state structure shown (see
Supporting Information for plot). (f) Gonzalez, C.; Schlegel, H. B. J.
Phys. Chem. 1990, 94, 5523. (g) Fukui, K. Acc. Chem. Res. 1981, 14,
363.
(28) See Supporting Information for further details.
(29) For leading references, see: Seeman, J. I. J. Chem. Educ. 1986,
63, 42.
(30) Henry-Riyad, H.; Lee, C.; Purohit, V. C.; Romo, D. Org. Lett.
2006, 8, 4363.
(31) Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A. J. Org. Chem.
1973, 38, 26.
(32) CCDC 842815 (30) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
(33) (a) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.;
Kamiya, Y. J. Am. Chem. Soc. 1989, 111, 4392. (b) Conlon, D. A.;
Kumke, D.; Moeder, C.; Hardiman, M.; Hutson, G.; Sailer. Adv. Synth.
Catal. 2004, 346, 1307.
(34) Krasovsky, A.; Kopp, F.; Knochel, P. Angew Chem. Int. Ed. 2006,
45, 497.
(35) (a) Dunn, T. B.; Ellis, J. M.; Kofink, C. C.; Manning, J. R.;
Overman, L. E. Org. Lett. 2009, 11, 5658. (b) Martin, C. L.; Overman,
L. E.; Rohde, J. M. J. Am. Chem. Soc. 2010, 132, 4894.
(36) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93,
1307.
(37) (a) Nishi, T.; Kataoka, M.; Moriswa, Y. Chem. Lett. 1989, 1993.
(b) Hanessian, S.; Abad-Grillo, T.; McNaughton-Smith, G. Tetrahe-
dron 1997, 53, 6281. (c) Lee, N.; Kim, Y.-W.; Chang, K.; Kim, K. H.;
Jew, S.-S.; Kim, D.-K. Tetrahedron Lett. 1996, 37, 2429.
(38) Semmelhack, M. F.; Stauffer, R. D.; Yamashita, A. J. Org. Chem.
1977, 42, 3180.
(39) Yang, J.; Long, Y. O.; Paquette, L. A. J. Am. Chem. Soc. 2003,
125, 1567.
(40) For representative examples, see: (a) Diba, A. K.; Noll, C.;
Richter, M.; Gieseler, M. T.; Kalesse, M. Angew Chem. Int. Ed. 2010,
49, 8367. (b) Jousseaume, T.; Wurz, N. E.; Glorius, F. Angew Chem.
Int. Ed. 2011, 50, 1410. (c) Kanoh, N.; Sakanishi, K.; Limori, E.;
Nishimura, K.; Iwabuchi, Y. Org. Lett. 2011, 13, 2864.
I
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