Total syntheses of cyanthiwigins B, F, and G

Article abstract of DOI:10.1002/chem.201100425

A concise and versatile approach toward the preparation of the cyanthiwigin family of cyathane natural products is described. By leveraging a unique double asymmetric catalytic alkylation procedure it is possible to quickly establish two of the most critical stereocenters of the cyanthiwigin framework with high levels of selectivity and expediency. The synthetic route additionally employs both a tandem ring-closing cross-metathesis reaction, and an aldehyde-olefin radical cyclization process, in order to rapidly arrive at the tricyclic cyathane core of the cyanthiwigin molecules. From this unifying intermediate, the preparations of cyanthiwigins B, F, and G are attained swiftly and without the need for protecting groups. Copyright

Full text of DOI:10.1002/chem.201100425

FULL PAPER
DOI: 10.1002/chem.201100425
Total Syntheses of Cyanthiwigins B, F, and G
John A. Enquist, Jr., Scott C. Virgil, and Brian M. Stoltz*[a]
Abstract: A concise and versatile ap-
ty and expediency. The synthetic route
additionally employs both a tandem
ring-closing cross-metathesis reaction,
and an aldehyde-olefin radical cycliza-
tion process, in order to rapidly arrive
proach toward the preparation of the
cyanthiwigin family of cyathane natural
products is described. By leveraging a
unique double asymmetric catalytic al-
kylation procedure it is possible to
quickly establish two of the most criti-
cal stereocenters of the cyanthiwigin
framework with high levels of selectivi-
at the tricyclic cyathane core of the cy-
anthiwigin molecules. From this unify-
ing intermediate, the preparations of
cyanthiwigins B, F, and G are attained
swiftly and without the need for pro-
tecting groups.
Keywords: asymmetric catalysis
·
diterpene · natural product · palla-
dium · total synthesis
Introduction
ral products, due to the steric crowding surrounding and
nested location of these critical stereocenters.
Structural features and synthetic challenges: The cyanthiwi-
gin diterpenoid natural products were originally isolated
from the marine sponge Epipolasis reiswigi.[1] Ten years
after initial characterization, additional, novel cyanthiwigin
molecules were found in extracts of the Jamaican sea
sponge Mermekioderma styx.[2] To date, over 30 different ex-
amples of cyanthiwigin diterpenoids have been isolated and
characterized from these two sources. The vast majority of
these compounds are structurally similar, and are unified
through the presence of a highly conserved tricyclic carbon
scaffold (Figure 1). The cyanthiwigin molecules belong to a
larger class of diterpene natural products known as the cya-
thanes. In keeping with the vast majority of other cyathane
compounds, the 20 carbon atoms of the cyanthiwigins are ar-
ranged into a fused [5-6-7] tricyclic core skeleton (1–30).[3]
However, in contrast to the remainder of the cyathanes, the
dual all-carbon quaternary stereocenters found in the cyan-
thiwigin molecules at C(6) and C(9) are arranged with a syn
relative stereochemical relationship, rather than an anti con-
figuration. Furthermore, these diterpene natural products
boast two additional points of stereogenicity at ring fusion
carbons C(4) and C(5). These structural features establish a
total of four contiguous stereocenters across the innermost
bonds of the carbon scaffold. Indeed, the central ring of the
cyanthiwigin [5-6-7] carbocyclic core imparts formidable
challenge to the synthetic preparation of any of these natu-
Structural differentiation among the members of the cyan-
thiwigin family is primarily manifest in variable oxidation of
the peripheral carbocyclic skeleton. Oxidative diversity in
the cyanthiwigins provides sparingly oxidized structures
such as cyanthiwigin G (7), as well as more heavily oxidized
examples as can be found in cyanthiwigin O (15). For many
of the less-oxidized cyanthiwigin compounds (e.g., cyanthi-
wigin F (6)) preparative approaches toward these molecules
can prove difficult owing to their sparse functionality. These
minimally elaborated structures possess very few reactive
handles upon which to leverage retrosynthetic planning. Be-
cause of this, synthetic routes toward the construction of
less-oxygenated cyathanes typically involve the installation
and subsequent removal of superfluous moieties, an often
cumbersome and inefficient method.
Biological activity: The cyanthiwigin natural products boast
a wide range of biological activities. The larger class of cya-
thanes in general possess a diverse set of bioactive proper-
ties, including antimicrobial and antineoplastic activity, as
well as k-opioid receptor agonism.[4] Most notably, some
members of the cyathane natural products possess the ca-
pacity to stimulate the synthesis of nerve growth factor
(NGF), a quality that implicates their potential application
as therapeutic agents for neurodegenerative diseases and
spinal injuries.[5] In addition, cyanthiwigin C has shown cyto-
toxic activity against both A549 human lung cancer cells
(IC50 =4.0 mgmLꢀ1) and P-388 human leukemia cells (IC50 =
11.2 mgmLꢀ1).[6] Cyanthiwigin F (6) has displayed cytotoxic
activity against human primary tumor cells (IC50 =
3.1 mgmLꢀ1).[2] Unfortunately, exhaustive investigation of
the entire family of cyanthiwigin molecules has been imped-
ed by a lack of sufficient material with which to perform the
required biological assays. As such, synthetic preparation of
these natural products has become an appealing goal.
[a] J. A. Enquist, Jr., Dr. S. C. Virgil, Prof. B. M. Stoltz
The Arnold and Mable Beckman Laboratories
of Chemical Synthesis Department of Chemistry
and Chemical Engineering, California Institute of Technology
1200 East California Blvd., MC 101-20, Pasadena, CA 91125 (USA)
Fax : (+1)626-395-8436
E-mail: stoltz@caltech.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100425.
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Figure 1. The cyanthiwigin diterpenoid molecules.
Previous synthetic efforts: Though the larger class of cya-
thane diterpenoid natural products has inspired numerous
total syntheses to date,[3] the cyanthiwigin molecules have
remained comparatively less explored. The first preparation
of any cyanthiwigin natural product was the total synthesis
of cyanthiwigin U (21) reported by Phillips and co-workers
in 2005.[7] This elegant synthetic work boasted a ring open-
ing, ring closing cross-metathesis reaction to efficiently con-
struct the completed tricyclic cyathane core. After the com-
pletion of cyanthiwigin U (21), Phillips was able to extend
his preparative route in order to arrive at cyanthiwigin W
(23) and cyanthiwigin Z (26).[8] In 2006, Reddy and co-work-
ers were the first to disclose the preparation of the natural
product cyanthiwigin AC (29), wherein they employed a
unique deconjugative spiro-bis-alkylation strategy.[9]
Retrosynthetic analysis: Because the members of the cyan-
thiwigin family of molecules differ from one another primar-
ily in terms of oxygenation, we hypothesized that a synthetic
route capable of rapidly preparing the carbocyclic core
would provide simultaneous access to many of these marine
natural products. Thus, our approach to the cyathane mole-
cule cyanthiwigin F (6) was developed with a specific focus
upon quickly constructing the tricyclic cyathane skeleton. In
keeping with this goal, our initial retrosynthetic maneuver
envisioned disconnection of either the five-membered A-
ring or the seven-membered C-ring to lead back to either bi-
cycle 31 or diketone 32, respectively (Scheme 1). In either
case, further simplification was anticipated via retrosynthetic
opening of the remaining peripheral ring, an operation that
would be addressed in the forward sense via ring-closing
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Total Syntheses of Cyanthiwigins B, F, and G
FULL PAPER
metathesis. If the seven-membered C-ring were to be closed
first, this strategy would lead to tetraolefin 33. Initial closure
of the five-membered A-ring would invoke triolefin precur-
sor 34. Regardless of the route employed, we expected that
either intermediate 33 or 34 would be accessible via enan-
tioenriched diketone 35.
Results and Discussion
Forward synthetic efforts: The following sections describe
the various reactions, routes, and experiments explored in
order to synthetically prepare the cyanthiwigin marine diter-
pene compounds.[12]
In order to target diketone 35, we envisioned the use of
enantioselective alkylation technology that had been previ-
ously developed in our lab.[10] At the outset of our synthetic
efforts toward the cyanthiwigin natural products, this stereo-
selective methodology had already proven quite reliable for
the formation of a-quaternary cyclohexanone products. We
predicted that by implementing this reaction on an appropri-
ately designed substrate, that it would be possible to forge
Double asymmetric catalytic alkylation: Studies toward the
total synthesis of cyanthiwigin F commenced with the Fisch-
er esterification of succinic acid (38) with allyl alcohol to
afford diallylsucciniate (37, Scheme 2A). Exposure of diallyl
succinate to a solution of allyl alkoxide in refluxing toluene
initiated the desired Claisen condensation, a transformation
immediately followed by subsequent Dieckmann cyclization
to generate cyclohexadione product 39 exclusively as its bis-
enol tautomer.[11] Thereafter, double methylation of bis-
ester 39 under standard conditions provided access to bis(b-
ketoester) 36 as a 1:1 mixture of racemic and meso diaste-
reomers. Combination and optimization of the steps in this
reaction sequence eventually facilitated the direct prepara-
tion of bis(b-ketoester) 36 from diallyl succinate (37). In the
event, addition of diallyl succinate (37) to a suspension of
sodium hydride in THF at room temperature, followed by
subsequent quenching with methyl iodide, allowed for the
generation of bis(b-ketoester) 36 under lower temperature
conditions in a single step (Scheme 2B).[13] While the yield
of the one-step procedure is nominally lower than that of
the two-step process, the ease of operation and facile scala-
bility of the more direct route outweigh these minimal
ꢀ
two carbon carbon bonds with enantiocontrol, thus provid-
ing rapid access to the critical diketone 35 in a single syn-
thetic procedure. This double stereoselective decarboxyla-
tive alkylation reaction was anticipated to employ bis(b-ke-
toester) 36 as the substrate, and in a forward sense, was ex-
pected to set both of the necessary all-carbon quaternary
stereocenters of the natural product. Fortuitously, com-
pounds similar to bis(b-ketoester) 36 have been known in
the literature for nearly a century. As such we were confi-
dent that this material could be prepared from diallyl succi-
nate (37) via an initial Claisen condensation and a subse-
quent Dieckmann cyclization.[11]
Scheme 1. Retrosynthetic analysis of cyanthiwigin F.
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B. M. Stoltz et al.
losses. Interestingly, the diastereomers of bis(b-ketoester) 36
were found to be separable, with each possessing distinct
physical properties. While the more polar of the two diaste-
reomers of bis(b-ketoester) 36 was always observed to be a
viscous oil, the less polar diastereomer was isolated as a
fluffy white solid. With cyclohexadione 36 in hand, we were
poised to address the double stereoselective decarboxylative
alkylation reaction.
Despite the potential benefits of double asymmetric trans-
formations, it should be emphasized that the starting materi-
al (36) for our envisioned reaction was attained as a 1:1
blend of racemic and meso diastereomers. Exposing such a
stereoisomeric mixture to an enantiopure catalyst is typical-
ly ill-advised, as the presence of pre-existing stereocenters
in the substrate could interfere with inherent catalyst selec-
tivity and afford reduced quantities of the desired prod-
uct.[15] Indeed, the potential development of mismatched
catalyst–substrate interactions, which would deleteriously
impact yield and selectivity of the reaction, was a major con-
cern. We were additionally mindful of the possibility for the
reaction to proceed via an undesired kinetic resolution.[16]
Subjecting a diastereomeric mixture of bis(b-ketoesters)
to the conditions of the stereoselective decarboxylative alky-
lation was a maneuver with many prospective outcomes. In
the event of diastereomeric interference between the sub-
strate and catalyst, the potential existed for incomplete ally-
lation or impeded decarboxylation. Even in the case of com-
plete transformation of bis(b-ketoester) 36 into the desired
diketone (35), the stereochemical course of the reaction was
difficult to predict. The diastereomeric mixture containing
three stereoisomers of starting material could possibly tra-
verse any of 16 distinct stereodefined pathways to give any
of three potential product stereoisomers (Scheme 3).
In order for the reaction to afford the desired diketone
product with acceptable yield and selectivity, the catalyst
employed had to meet several stringent requirements. First,
initial decarboxylation of each stereoisomer of starting ma-
terial ((R,R)-, meso-(R,S)-, or (S,S)-36) to give either inter-
mediate ketone enolate ((R)- or (S)-40) would need to pro-
ceed at roughly equivalent rates regardless of configuration.
If a large disparity in the rate of decarboxylation existed be-
tween different stereoisomers of starting bis(b-ketoester) 36,
undesired kinetic resolution would influence the down-
stream stereoselective bond formation. The same require-
ment would be necessary for the subsequent decarboxyla-
tion of intermediates 41 to yield the transient enolates (R)-
and (S)-42, and as such, all stereoisomers of 41 would need
to react at equal rates. The second requirement envisioned
was that all bond-forming reactions would occur under com-
plete catalyst stereocontrol. This would dictate that any pre-
existing or intermediately formed stereocenters present in
any isomer of bis(b-ketoester) 36 or intermediate 41 should
have no impact upon the selectivity of the allylation event.
Third, the catalyst control in these situations would be re-
quired to be highly selective, so as to preferentially guide all
of the possible ketone enolate stereoisomers ((S)- and (R)-
40, (S)- and (R)-42) toward the single desired, enantioen-
riched product (35).
Scheme 2. Preparation of the bis(b-ketoester) substrate for double allyla-
tion.
Previous to these efforts, our group had developed a suite
of enantioselective decarboxylative catalytic alkylation reac-
tions. Using this technology, it is possible to access enan-
tioenriched cyclohexanone products bearing all-carbon qua-
ternary stereocenters at the ketone a-position, starting from
substrates containing an allyl enol carbonate, silyl enol
ether, or b-ketoester moiety.[10] Having attained bis(b-ke-
toester) 36, we anticipated that exposure of this material to
the conditions of our palladium-catalyzed alkylation would
ꢀ
result in the formation of two independent C C bonds, thus
forging the all-carbon quaternary stereocenters correspond-
ing to positions C(6) and C(9) of the cyanthiwigin core.
While stereoselective transformations to set more than
one stereocenter have been reported in the literature prior
to our efforts, the implementation of a double catalytic, ste-
ꢀ
reoselective, C C bond-forming reaction in the context of
complex total synthesis has gone relatively unexplored.[14]
Nevertheless, these types of transformations are both effi-
cient and direct, as they set multiple stereocenters with a
single catalytic species, and are therefore increasingly desira-
ble for the rapid synthetic preparation of complex natural
products.
Despite initial uncertainty concerning the course of this
reaction, we reasoned that the stereoablative nature of the
stereoselective decarboxylative alkylation methodology
would minimize any undesired mismatched interactions.[17]
This fact, combined with the relatively distant relationship
between the two reactive centers in 36, gave us confidence
in the success of our double alkylation approach. Therefore,
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Total Syntheses of Cyanthiwigins B, F, and G
FULL PAPER
Scheme 3. Pathways of the double asymmetric catalytic alkylation.
we subjected a 1:1 diastereomeric mixture of racemic and
meso-36 to a solution of [PdACTHNUTRGNE(UNG dmdba)2] palladium(0) and (S)-
tert-butyl phosphinooxazoline (tBuPHOX, 43) in diethyl
ether (Scheme 4).[18] To our delight, this reaction proceeded
smoothly at 258C to give the desired, enantioenriched dike-
tone (R,R)-35 in 64% yield and 99% ee, along with 14% of
the meso diastereomer (4.4:1 diastereomeric ratio). This
critical reaction established both of the all-carbon quaterna-
ry stereocenters necessary for completion of the cyanthiwi-
gin molecules at an early stage of the synthesis. Creating
these nested and difficult points of chirality well in advance
was important to the versatility and flexibility of our route.
When considering the excellent enantioselectivity ob-
served in the double alkylation reaction, the modest diaste-
reoselectivity attained from this transformation was initially
perplexing. Investigation of literature pertinent to double
stereoselective transformations eventually revealed that the
Scheme 4. Double asymmetric catalytic alkylation of 36.
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B. M. Stoltz et al.
high levels of ee observed in diketone product (R,R)-35
come at the expense of a reduced diastereomeric ratio.[19,20]
When only a single undesired allylation event occurs while
traversing the possible mechanistic pathways detailed in
Scheme 3, an additional molecule of the undesired meso dia-
stereomer is produced (meso-(R,S)-35) regardless of which
alkylation occurs against preference. While this unwanted
material negatively impacts the diastereomeric ratio of the
isolated diketone, it nevertheless has no influence upon the
ee of the desired product. In order to adversely affect the ee
of cyclohexadione (R,R)-35, an individual molecule of bis(b-
ketoester) (R,R)-36, meso-(R,S)-36, or (S,S)-36 must under-
go two disfavored allylation events in sequence to afford
product (S,S)-35. Because the likelihood of two allylation
errors impacting a single substrate is very low in the pres-
ence of reasonable catalyst control, the total yield of the un-
wanted (S,S)-35 stereoisomer is negligible, and thus the
product ee is excellent. However, due to the much higher
likelihood of a single alkylation event yielding the undesired
configuration, the amount of diketone meso-(R,S)-35 afford-
ed through this reaction is larger than anticipated. In effect,
generation of the meso diastereomer serves as a buffer
against accumulation of undesired stereoisomer (S,S)-35, al-
lowing this reaction to sacrifice some small measure of dia-
stereomeric ratio in favor of exceptionally high levels of
enantioselectivity. This phenomenon (sometimes referred to
as the “Horeau Principle”), was first observed and rational-
ized by Langenbeck in 1936, and was later elaborated into
more thorough mathematical representations by Horeau,
Kagan, and Rautenstrauch.[19,20]
Scheme 5. Attempts toward diketone functionalization.
triflate formation (Scheme 6A). Slow addition of diketone
35 to a solution of potassium bis(trimethylsilyl)amide in tet-
rahydrofuran allowed generation of a monoanionic ketone
enolate. This intermediate was thereafter trapped via expo-
sure to a solution of phenyl bis(trifluoromethane)sulfoni-
mide to afford cyclohexanone 44 in reasonable yield. With
this newly desymmetrized material in hand, we attempted to
leverage the installed triflate to introduce functionality that
would enable construction of a bicyclic structure.
By submitting enol triflate 44 to the conditions of a palla-
dium-catalyzed carboxylation reaction in the presence of
methanol, conjugated ester 45 was obtained as the major
product. Unfortunately, purification of this material proved
difficult, and isolates of enoate 45 were regularly contami-
Diketone desymmetrization and elaboration: With the suc-
cessful generation of enantioenriched diketone (R,R)-35 at-
tained, our efforts were thereafter focused on elaboration of
this material via construction of the peripheral A- and C-
rings of the cyathane tricycle.
At this juncture of the synthesis, advancement of diketone
35 required differentiation between the functional groups of
this C2 symmetric substrate.[21] Initial desymmetrizing efforts
were attempted via careful addition of various Grignard re-
agents to cyclohexadione 35 in the hopes of executing a
single nucleophilic addition to either ketone moiety. Disap-
pointingly, these experiments ultimately proved unsuccessful
(Scheme 5). The steric encumbrance imposed by the a-qua-
ternary stereocenters of diketone 35 very likely impede ap-
proach of any incoming nucleophile toward either of the
carbonyl carbons, and thus renders this cyclohexadione in-
transigent to 1,2-addition conditions. An alternative desym-
metrization strategy investigated involved the attempted
mono-functionalization of the pendent allyl side chains of
substrate 35. Regrettably, this approach also proved ineffec-
tive. In cases where dihydroxylation or epoxidation condi-
tions were employed, only low yields were ever obtained,
and in every case the sparing material isolated was a mix-
ture of mono- and di-functionalized products.
Greater selectivity and reactivity was ultimately achieved
when diketone 35 was subjected to the conditions of enol
Scheme 6. A) Triflate formation and carboxylative attempts toward dike-
tone elaboration. B) An unanticipated carbonylative Heck reaction.
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Total Syntheses of Cyanthiwigins B, F, and G
FULL PAPER
nated with trace amounts of a strongly UV-active impurity.
Thorough and careful investigation of this contaminant
eventually revealed its identity as dienone 46, an unexpected
yet intriguing byproduct of this carbonylative methodology.
We suspected bicycle 46 to be the result of an intramolecu-
lar Heck-type reaction, wherein initial oxidative addition of
palladium into the enol triflate bond was followed by subse-
quent carbon monoxide insertion and eventual olefin inser-
tion into the pendant arm of 44. This hypothesis was later
strengthened when the methoxycarbonylation reaction was
repeated in the absence of the nucleophilic cosolvent
(Scheme 6B). Without methanol, these conditions afforded
exclusively the carbonylative Heck product 46.[22]
Interestingly, the structure of dienone product 46 suggests
that oxidative addition and carbon monoxide incorporation
occur before olefin complexation and insertion. While this
phenomenon is known, typically in these reactions carbony-
lation occurs as the final step of the transformation, taking
place only after olefin insertion.[22] This observed reversal in
expected reactivity is likely due to the difficulty of olefin in-
sertion directly following oxidative addition, a process that
would require cyclobutane formation. The relatively greater
ease of cyclopentanone formation provides a reasonable ex-
planation for pre-emptive carbon monoxide incorporation.
Regrettably, further elaboration of either enoate 45 or dien-
one 46 proved unproductive in our hands, and so alternative
methods of functionalizing triflate 44 were sought.
complicated enol stannane 50 in place of coupling partner
48 (Scheme 8).[25] This transformation progressed easily to
generate cyclohexanone 51. However, purification and ma-
nipulation of this material was difficult, due to the rapid de-
composition of the enol ether upon contact with silica gel or
prolonged exposure to atmospheric conditions, both of
which resulted in hydrolysis to reveal the latent ketone
moiety. In order to circumvent issues of instability experi-
enced with this intermediate, enol ether 51 was immediately
exposed to the Grubbs–Hoveyda generation II catalyst (52)
in order to execute ring-closing metathesis, and this process
was subsequently followed by acidic workup. This synthetic
procedure successfully closed the seven-membered C-ring of
the cyathane tricycle, ultimately generating bicyclic ketone
53. While our efforts were bolstered by the successful for-
mation of a [6,7]-bicyclic intermediate, this material never-
theless provided us with unanticipated difficulty. Formation
of bicycle 53 was always accompanied by an undesired shift
ꢀ
of the anticipated C(12) C(13) olefin into conjugation with
the newly revealed C(10) ketone.[26] If enone 53 were to be
used to pursue the synthesis of the cyanthiwigin molecules,
this new development would necessitate isomerization of
ꢀ
ꢀ
the C(11) C(12) olefin back into the C(12) C(13) position,
a task we regarded to be nontrivial. Furthermore, while the
oxygenation present at C(10) was the result of functionality
necessary for the stability of stannane 50, this newly formed
ketone was superfluous to the structure of the completed
natural product. Thus, removal of this moiety would be re-
quired at some later stage if enone 53 were to serve as a
viable synthetic intermediate. Because of these difficulties,
we opted not to pursue the further elaboration of dienone
53. Instead, we chose to investigate alternative cross cou-
pling-conditions for triflate 44.
In order to better gauge the reactivity of enol triflate 44,
we executed a number of cross-coupling reactions to test the
2
2
2
2
3
ꢀ
viability of sp –sp, sp –sp , and sp –sp hybridized carbon
carbon bond construction. Attempts at Sonogashira coupling
of ketone 44 and trimethylsilyl acetylene smoothly provided
access to enyne 47 in high yield (Scheme 7).[23] Similarly,
copper-accelerated Stille reaction of triflate 44 with enol
stannane 48 proved to be very effective.[24] After acidic
workup of this sp2–sp2 coupling reaction, enone 49 was ob-
tained in reasonable yield.
A reinvestigation of triflate 44 revealed the viability of a
direct sp2–sp3 bond formation via a Negishi cross-coupling
procedure. Zinc dust was first treated with 1,2-dibromo-
ethane and trimethylsilyl chloride, and to this activated
metal was added alkyl iodide 54. After generation of the
alkyl zinc species, a THF solution containing a palladium(0)
Encouraged by the successes of the preliminary Stille cou-
pling, we repeated this reaction while employing the more
Scheme 8. Formation, ring-closing metathesis, and acidic hydrolysis of the
Scheme 7. Palladium-catalyzed cross-coupling reactions of triflate 44.
enol ether species 51.
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B. M. Stoltz et al.
catalyst and triflate 44 was introduced to the mixture, thus
initiating Negishi cross-coupling of the two fragments
(Scheme 9).[27] After appropriate workup and purification,
tetraolefin 33 was isolated as the sole product of this reac-
tion. We were excited to find that ring-closing metathesis of
cyclohexanone 33 to form the seven-membered C-ring fur-
nished bicyclic product 31, a structure containing two of the
three rings of the cyathane skeleton. Notably, we found that
this ring-forming process was both faster and higher-yielding
when modified Grubbs–Hoveyda catalyst 55 was employed
in place of the Grubbs–Hoveyda second-generation catalyst
52.[28]
ꢀ
Scheme 10. Functionalization of the C(2) C(3) olefin via cross-metathe-
sis.
considerably in our synthetic efforts. By subjecting tetraole-
fin 33 to the conditions of concurrent ring-closing and cross-
metathesis in the presence of vinyl boronate 56, and execut-
ing a subsequent oxidative workup with sodium perborate, it
was possible to rapidly prepare bicyclic aldehyde 57
(Scheme 11).
2
3
ꢀ
Scheme 9. Negishi cross-coupling for the formation of an sp –sp carbon
carbon bond.
We anticipated that further advancement of this material
toward the cyanthiwigin natural products would undoubted-
ly require selective functionalization of the remaining allyl
ꢀ
side chain in the presence of the C(12) C(13) olefin. For
Scheme 11. Ring-closing and cross-metathesis reaction to generate the bi-
cyclic aldehyde speices 57.
this reason, we turned our attention toward the possibility
of using metathesis reactivity for the elaboration of the re-
maining terminal olefin. Cross-metathesis of vinyl boronate
species 56 with newly attained bicycle 31 proved fruitful,
and upon exposure to an oxidative workup involving aque-
ous sodium perborate, this process generated aldehyde 57 as
the major product (Scheme 10A).[29] With the success of the
ring-closing and cross-metathesis processes confirmed as in-
dependent reactions, we hypothesized that both transforma-
tions might be accomplished concurrently via the use of the
same catalyst.
Tricycle formation via radical cyclization: At this stage in
the synthesis, the synthetic challenges remaining to be ad-
dressed included the finalization of the tricyclic cyathane
core via installation of the five-membered A-ring, as well as
the establishment of both the C(4) and C(5) stereocenters.
We hypothesized that all of these pending goals might be ac-
complished in tandem through the use of a radical cycliza-
tion reaction. It was envisioned that the formation of a high-
energy acyl radical species via hydrogen atom abstraction
from aldehyde 57 would encourage thermodynamically-con-
In the event, the addition of methyl acrylate to the condi-
tions used for the ring-closing metathesis of tetraolefin 33
executed both formation of the seven-membered cyathane
C-ring and functionalization of the terminal allyl moiety
(Scheme 10B). By employing this reaction, monocyclic start-
ing material 33 was smoothly transformed into bicyclic
enoate 58 in a single synthetic operation. Though ester 58
was not amenable to further desired transformation, the
technique elucidated by its formation nevertheless aided
ꢀ
ꢀ
trolled carbon carbon bond formation with the C(4) C(5)
olefin. To test this hypothesis, we turned our attention
toward methods for the reliable production of acyl radical
intermediates from aldehydes.[30]
Preliminary attempts to generate an acyl radical for the
purpose of intramolecular cyclization were unfortunately
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Total Syntheses of Cyanthiwigins B, F, and G
FULL PAPER
unsuccessful. Subjecting bicyclic aldehyde 57 to tributylstan-
nane or triphenylstannane did not yield the desired product.
Both radical propagators were employed in combination
with either azobisisobutyronitrile (AIBN) or 2,2’-azobis(4-
methoxy-2,4-dimethyl valeronitrile) (V-70) initiators, yet in
each case only unreacted substrate 57 or nonspecific decom-
position were observed (Scheme 12).[31,32]
cal cyclization of 57 forged the desired cyclopentanone and
provided access to fully formed cyathane tricycle 63
(Scheme 14A). Minor optimization of this reaction was pos-
sible under lower temperature conditions, wherein using
tert-butylthiol as propagator and AIBN as initiator afforded
slightly increased yield of the desired product
(Scheme 14B). Regardless of the exact reagents used, both
reactions afforded 63 as a single diastereomer.
Scheme 12. Initial attempts at radical cyclization for A-ring formation.
In light of the failure of stannane reagents to furnish the
targeted tricyclic product, we sought alternative conditions
for the reliable formation of acyl radical species. After a
thorough investigation of the literature, we became familiar-
ized with aldehyde–olefin cyclization methodology devel-
oped by Tomioka et al. in 2005.[33] By implementing a bulky
thiol radical propagator and an appropriate initiator, Tomio-
ka was able to achieve the cyclization of aldehyde functional
groups onto olefins to form cyclic ketone products. By em-
ploying this reaction, it was demonstrated that in the pres-
ence of tert-dodecanethiol and AIBN, linear aldehyde 59
could be cyclized onto an isolated olefin moiety to be
smoothly converted into cyclopentanone 60 (Scheme 13).
Scheme 14. Application of Tomiokaꢁs methodology to A-ring formation.
It is possible that the diastereoselectivity observed in this
cyclopentanone-forming reaction is a consequence of ther-
modynamic control. After initial hydrogen-atom abstraction
from aldehyde 57, acyl radical species 64 is formed
(Scheme 15). Due to steric and conformational constraints,
ꢀ
this radical species has limited access to the C(4) C(5)
ꢀ
olefin. Indeed, acyl radical approach and carbon carbon
bond formation may only occur from the bottom face of the
bicyclic system as drawn in Scheme 15. Construction of this
bond in line with such a trajectory establishes the desired
stereochemistry at C(4), and additionally generates a rapidly
equilibrating tertiary radical at C(5) (65). Further hydrogen
atom abstraction from tert-butyl thiol to quench the radical
found in intermediate 65 proceeds under thermodynamic
control, and this affords the more stable trans-oriented[6,7]
ring fusion in preference to the cis-fused alternative. Ulti-
mately, these factors ensure that tricycle 63 is furnished as
the sole stereoisomeric product of the reaction. The forma-
tion of the five-membered A-ring to construct tricyclic dike-
tone 63 marked the completion of the cyathane core skele-
ton.
Attaining this material was of considerable significance to
our synthetic efforts, not only because of its proximity to cy-
anthiwigin F (6), but also because we envisioned that this
tricyclic diketone 63 could serve as a platform from which
to access other cyanthiwigin natural products. Fortunately,
solid crystals of this critical intermediate were amenable to
X-ray analysis (Figure 2).[34] The data collected from X-ray
Scheme 13. Radical cyclization conditions developed by Tomioka and co-
workers.[33]
Similarly, tert-dodecanethiol and 1,1’-azobis(cyclohexane-1-
carbonitrile) (V-40 initiator) enabled the conversion of alde-
hyde 61 into cyclohexanone 62.
Because our work required the cyclization of an aldehyde
onto an unconjugated olefin, we attempted to subject bicy-
clic aldehyde 57 to Tomiokaꢁs methodology with the inten-
tion of forming the required cyathane A-ring. Fortunately,
employing tert-dodecanethiol and V-40 initiator in the radi-
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9965

B. M. Stoltz et al.
Figure 2. X-ray crystal structure of tricycle 63 (shown with 50% probabil-
ity ellipsoids).[34]
employed with triflate 66 and 2-iodopropane, the only isolat-
ed material was reductive deoxygenation product 67
(Table 1, entry 1).
Because palladium-catalyzed cross-coupling of 66 and 2-
iodopropane was met with difficulty, alternative copper-cata-
lyzed methods to install the required three-carbon fragment
were investigated. Preliminary experiments involved direct
addition of isopropyl magnesium chloride to suspensions of
triflate 66 and catalytic amounts of either copper iodide or
Scheme 15. Mechanistic hypothesis and stereochemical rationale for the
radical cyclization of bicyclic aldehyde 57.
crystallography on diketone 63 revealed not only the stereo-
chemistry set by the radical cyclization reaction, but also
confirmed the relative stereochemistry established by the in-
itial double alkylation reaction
Table 1. Transition metal cross-coupling reactions toward preparation of cyanthiwigin F.
as well.
Completion of the cyanthiwigin
natural products: With tricyclic
diketone 63 in hand, the final
challenges remaining in the
total synthesis of cyanthiwigin
F were the installation of the
C(3) isopropyl group and intro-
ꢀ
duction of the C(2) C(3)
olefin. In order to address these
requirements, we envisioned
harnessing the reactivity of the
newly installed C(3) ketone to
establish a vinyl triflate suitable
for transition metal-catalyzed
cross-coupling reactions. In the
event, selective deprotonation
of diketone 63 with KHMDS
and trapping with N-phenyl
bis(trifluoromethane)sulfoni-
mide produced vinyl triflate 66
in reasonable yield (Table 1).
Having achieved the synthesis
of tricycle 66, we predicted that
isopropyl group installation
could be accomplished via a
Negishi cross-coupling process
similar to the one used previ-
ously.[27] Regrettably, when
Entry iPrX
Metal catalyst T [8C]
Yield 6 [%] Yield 67 [%] Yield 66 [%]
1
iPrZnI[b]
iPrMgCl
iPrLi
iPrMgCl
[Pd
G
65
0
0
0
ND[a]
65
0
0
0
2[c]
CuI
CuCN
CuBr·DMS
–
–
–
–
ꢀ10
ꢀ20
ꢀ20
ꢀ78!0
3[c]
73
57
99
0
27
99
99
19[i]
0
4[c]
17[i]
0
7[i]
0
5[d,e]
6[d]
7[d,f]
8[d,f,g]
9[h]
10
iPrMgCl + CuCN
iPrMgCl + CuBr·DMS
iPrLi + CuCN
iPrLi + CuCN
iPrMgCl
ꢀ78!ꢀ20 11[i]
10[i]
3[i]
0
ꢀ78!ꢀ20 8[i]
ꢀ20
0
0
0
0
[Ni
A
35
0
iPrMgCl
[Pd
[Pd
[Pd
N
ꢀ78!23
37[i]
ND
23
11
iPrMgCl
iPrMgCl + CuCN
35
12[d,f]
ꢀ78!0
41
0
[a] All reactions with yields listed as “ND” gave predominantly 67 as product, with no observed quantity of 6.
These reactions were analyzed via crude 1H NMR. [b] Reagent was formed via the addition of iPrI to activated
Zn0 metal. [c] Reaction performed via direct addition of iPrX to the metal catalyst. [d] Reaction involved the
use of a pre-formed cuprate species. [e] A lower-order cyanocuprate was employed (1:1 ratio of I-PrX to Cu).
[f] A higher-order cyanocuprate was employed (2:1 ratio of iPrX to CuCN). [g] BF3·Et2O was employed as an
these coupling conditions were additive. [h] Et2O was employed as solvent. [i] Yield based on NMR analysis.
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Total Syntheses of Cyanthiwigins B, F, and G
FULL PAPER
copper cyanide. Disappointingly, these reactions were simi-
larly ineffective, affording either the reduced tricycle 67, or
recovered triflate 66.[35] Use of copper bromide dimethyl sul-
fide complex for this direct-addition technique did yield
small quantities of the natural product, but these sparing
amounts of the desired compound were contaminated with
larger amounts of the reduction product 67. To rectify this
issue, we endeavored to approach the coupling via the use
of stoichiometric quantities of pre-generated isopropyl-cup-
rate reagents, using a variety of different copper sources
(entries 5–8). In all cases, we observed either low reactivity
or a preference for reductive deoxygenation.
Additional experiments into isopropyl cross-coupling in-
volved employing a number of nickel and palladium cata-
lysts in a series of Kumada-type reactions (entries 9–11),[36]
but the results overwhelmingly favored reduced product 67
in those instances where reactivity was observed. Finally, we
discovered that introduction of a pre-generated, higher-
order isopropyl cyanocuprate to a solution of triflate 66 and
Scheme 16. Advancement of tricycle 63 toward additional members of
the cyanthiwigin nautral products.
dichloro
(1,1’-bis(diphenylphosphino)ferrocene)palladium(II)
natural product. Nevertheless, 8-epi-cyanthiwigin E (71)
served as an invaluable intermediate in the preparation of
another cyanthiwigin compound. Treatment of enone 71
with Martinꢁs sulfurane in deuterated chloroform successful-
gave a combined 65% yield of the natural product (6) and
tricycle 67, in a 1.8:1 mixture favoring cyanthiwigin F
(entry 12).[37,38]
ꢀ
In addition to being instrumental in the total synthesis of
cyanthiwigin F, it was our hope that the completed cyathane
core represented by tricycle 63 would prove useful in the
synthesis of other diterpenes of this natural product family.
Starting from diketone 63, deprotonation at the a-position
of the C(3) ketone and trapping of the incipient enolate
with allyl chloroformate provided access to enol carbonate
68. Thereafter, treatment of this material with catalytic pal-
ladium(0) in acetonitrile provided enone 69 in high yield
(Scheme 16).[39] Unsaturated ketone 69 afforded an excellent
opportunity for direct introduction of the C(3) isopropyl
group via 1,2-addition, and so was exposed to isopropyl lithi-
um under Luche-type activation conditions. Cerium-mediat-
ed alkyl lithium reactivity proceeded with exclusive addition
to C(3), generating tertiary alcohol 70 as a mixture of incon-
sequential diastereomers.
ly eliminated the C(8) secondary alcohol to install the C(7)
C(8) olefin, thus finalizing the total synthesis of cyanthiwigin
G (7).[42,43]
The mixture of alcohols, 70, was then subjected to PCC in
dichloromethane, conditions anticipated to execute allylic
oxidation with concomitant oxygen transposition. In the
event, 70 was smoothly transformed into natural product 2,
Scheme 17. Completion of cyanthiwigings B and G.
thus completing the total synthesis of cyanthiwigin
B
(Scheme 17).[40] We further envisioned that cyanthiwigin B
(2) might be advanced toward other members of this natural
product family via selective carbonyl reduction at C(8).[41]
Conditions reported to selectively reduce ketones in the
presence of enones unfortunately provided exclusively over-
reduction of both carbonyl moieties, but this difficulty was
mitigated by immediate and selective reoxidation of the re-
sulting material with manganese(IV) dioxide. This allylic ox-
idation process generated enone 71 as the sole product of
reaction. Notably, tricycle 71 was found to be structurally
identical to cyanthiwigin E, with the single exception of the
configuration of the stereogenic alcohol present at C(8),
which was determined to be epimeric to that found in the
Conclusion
In summary, we have developed an efficient, versatile, and
enantioselective route to the cyanthiwigin natural products.
Our approach toward these molecules involves a rapid syn-
thesis of the central six-membered B-ring, with a specific
focus on early installation of both the C(6) and C(9) all-
carbon quaternary stereocenters. The use of a double asym-
metric decarboxylative catalytic alkylation reaction not only
enables access to the critical enantioenriched cyclohexa-
dione 35, but this methodology has additionally proven tol-
Chem. Eur. J. 2011, 17, 9957 – 9969
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9967

B. M. Stoltz et al.
(KAUST). The authors wish to thank NIH-NIGMS (R01M080269-01),
Amgen, Abbott, Boehringer Ingelheim, Merck, and Bristol-Myers
Squibbs, GlaxoSmithKline, Johnson and Johnson, Amgen, Merck Re-
search Laboratories, Pfizer, Novartis, Roche, Abbott Laboratories, Boeh-
ringer-Ingelheim, AstraZeneca, and Caltech for financial support. We
also wish to thank Dr. M. W. Day and Mr. L. M. Henling for X-ray crys-
tallographic expertise, Dr. Andrew Harned, Dr. David White, Daniel
Caspi, and J. T. Mohr for helpful discussions, and Professor Mark T.
Hamann for authentic samples and spectra of cyanthiwigins B, F, and G.
Ruthenium olefin metathesis catalysts were generously donated by Mate-
ria.
erant of a diastereomeric mixture of racemic and meso start-
ing materials in the same catalytic transformation. Because
of the ease with which stereoisomeric mixtures of precursor
bis(b-ketoester) 36 can be prepared, this stereoablative ap-
proach expedites the early phases of our synthesis consider-
ably. Our strategy also involves an efficient, single operation
ring-closing and cross-metathesis reaction to generate a bi-
cyclic aldehyde from a monocyclic tetraolefin. Combined
with a radical cyclization reaction, these techniques furnish
ready and rapid access to a versatile tricyclic intermediate
representing the completed cyathane core (63). By leverag-
ing this core compound as a branching point toward marine
natural products, our group was able to expediently prepare
multiple cyanthiwigin molecules. In particular, the total syn-
thesis of cyanthiwigin F (6) was accomplished in nine total
[1] D. Green, I. Goldberg, Z. Stein, M. Ilan, Y. Kashman, Nat. Prod.
Lett. 1992, 4, 193–199.
[2] a) J. Peng, K. Walsh, V. Weedman, J. D. Bergthold, J. Lynch, K. L.
Lieu, I. A. Braude, M. Kelly, M. T. Hamann, Tetrahedron 2002, 58,
7809–7819; b) J. Peng, M. A. Avery, M. T. Hamann, Org. Lett. 2003,
5, 4575–4578; c) J. Peng, N. Kasanah, C. E. Stanley, J. Chadwick, M.
Fronczek, M. T. Hamann, J. Nat. Prod. 2006, 69, 727–730.
[3] a) D. L. Wright, C. R. Whitehead, Org. Prep. Proced. Int. 2000, 32,
309–330; b) J. A. Enquist, Jr., Nat. Prod. Rep. 2009, 26, 661–680.
[4] T. Saito, F. Aoki, H. Hirai, T. Inagaki, Y. Matsunaga, T. Sakakibara,
S. Sakemi, Y. Suzuki, S. Watanabe, O. Suga, T. Sujaku, A. A. Smogo-
wicz, S. J. Truesdell, J. W. Wong, A. Nagahisa, Y. Kojima, N. Kojima,
J. Antibiot. 2003, 51, 983–990.
[5] a) Y. Obara, N. Nakahata, T. Kita, Y. Takaya, H. Kobayashi, S.
Hosoi, S. Kiuchi, T. Ohta, Y. Oshima, Y. Ohizumi, Eur. J. Pharma-
col. 1999, 370, 79–84; b) Y. Obara, H. Kobayashi, T. Ohta, Y. Ohi-
zumi, N. Nakahata, Mol. Pharmacol. 2001, 59, 1287–1297.
[6] S. H. Sennett, S. A. Pomponi, A. E. Wright, J. Nat. Prod. 1992, 55,
1421–1429.
ꢀ
steps, seven of which form carbon carbon bonds. Addition-
ally, the synthesis is highly efficient in terms of its use of
redox reactions, as only minimal oxidative or reductive pro-
cesses are employed. The flexibility and modularity of our
synthetic route later accommodated further extrapolation of
tricyclic intermediate 63 toward additional members of the
cyanthiwigin family, thus facilitating the preparation of cyan-
thiwigins B (2) and G (7).
Experimental Section
[7] M. W. B. Pfeiffer, A. J. Phillips, J. Am. Chem. Soc. 2005, 127, 5334–
5335.
[8] M. W. B. Pfeiffer, A. J. Phillips, Tetrahedron Lett. 2008, 49, 6860–
6861.
[9] T. J. Reddy, G. Bordeau, L. Trimble, Org. Lett. 2006, 8, 5585–5588.
[10] a) D. C. Behenna, B. M. Stoltz, J. Am. Chem. Soc. 2004, 126, 15044–
15045; b) J. T. Mohr, D. C. Behenna, A. M. Harned, B. M. Stoltz,
Angew. Chem. 2005, 117, 7084–7087; Angew. Chem. Int. Ed. 2005,
44, 6924–6927.
For general methods and complete Experimental Section, please see Sup-
porting Information.
Synthesis of diketone 35: A flame dried round bottom flask cooled under
argon was charged with bis(3,5-dimethoxydibenzylideneacetone)palladi-
um(0) ([PdACHTUNGTRENNUNG(dmdba)2], 0.268 g, 0.330 mmol, 0.05 equiv) and (S)-tBuPHOX
(43) (0.140 g, 0.362 mmol, 0.055 equiv). The flask was purged under
vacuum briefly, and then backfilled with argon. The solids were dissolved
in Et2O (500 mL), and the resulting solution was stirred at 258C for
30 min. After precomplexation, neat 36 (2.00 g, 6.59 mmol, 1.00 equiv)
was added to the reaction. The solution was stirred vigorously at 258C
for 10 h (Note: continual stirring is necessary due to the apparent low
[11] H. Ebert, Justus Liebigs Ann. Chem. 1885, 229, 45–88.
[12] J. A. Enquist, Jr., B. M. Stoltz, Nature 2008, 453, 1228–1230.
[13] Conditions for this optimized procedure were adapted from
a
solubility of [PdACHTUNGTRENNUNG(dmdba)2] in Et2O.), after which time the solvent was re-
Dieckmann reaction previously published by our group in Organic
Syntheses. See: J. T. Mohr, M. R. Krout, B. M. Stoltz, Org. Synth.
2009, 86, 194–211.
moved in vacuo. The crude oil was purified over silica gel using 3% ethyl
acetate in hexanes as eluent to afford 35 as a colorless oil (1.07 g, 78%,
4.4:1 d.r., 99% ee): Rf =0.7 (15:85 ethyl acetate/hexane); 1H NMR
(300 MHz, CDCl3): d = 5.68 (dddd, J=18.3, 10.2, 6.9, 6.9 Hz, 2H), 5.17–
5.09 (comp. m, 3H), 5.07–5.04 (m, 1H), 2.82 (d, J=14.7 Hz, 2H), 2.38 (d,
J=15 Hz, 2H), 2.34 (app ddt, J=13.2, 6.9, 1.0 Hz, 2H), 2.09 (app ddt,
J=13.5, 7.8, 0.9 Hz, 2H), 1.10 ppm (s, 6H); 13C NMR (125 MHz, CDCl3):
d = 212.8, 132.4, 120.0, 49.4, 48.4, 43.8, 24.3 ppm; IR (neat film, NaCl): n˜
[14] a) S. Masamune, W. Choy, J. Peterson, L. Sita, Angew. Chem. 1985,
97, 1–31; Angew. Chem. Int. Ed. Engl. 1985, 24, 1–30; b) H. Rieck,
G. Helmchen, Angew. Chem. 1995, 107, 2881–2883; Angew. Chem.
Int. Ed. Engl. 1996, 34, 2687–2689; c) A. D. Lebsack, J. T. Link,
L. E. Overman, B. A. Stearns, J. Am. Chem. Soc. 2002, 124, 9008–
9009; d) O. I. Kolodiazhnyi, Tetrahedron 2003, 59, 5953–6018; e) C.
Welter, A. Dahnz, B. Brunner, S. Streiff, P. Dꢂbon, G. Helmchen,
Org. Lett. 2005, 7, 1239–1242.
[15] H. Kagan, Tetrahedron 2001, 57, 2449–2468.
[16] E. L. Eliel, S. H. Wilen, Stereochemistry of Organic Compounds,
Wiley, New York, 1994, pp. 965–971.
[17] J. T. Mohr, D. C. Ebner, B. M. Stoltz, Org. Biomol. Chem. 2007, 5,
3571–3576.
[18] a) G. Helmchen, A. Pfaltz, Acc. Chem. Res. 2000, 33, 336–345; b) K.
Tani, D. C. Behenna, R. M. McFadden, B. M. Stoltz, Org. Lett. 2007,
9, 2529–2531.
= 3078, 2978, 1712, 1640, 1458, 1378, 1252, 1129, 1101, 998, 921 cmꢀ1
;
HRMS (EI): m/z: calcd for C14H20O2 [M]+: 220.1463, found 220.1466;
[a]2D5 = ꢀ163.1 (c = 0.52, CH2Cl2); chiral GC assay (GTA column):
1008C isothermal method over 90 min. tR = 67.7 min (Major enantiomer,
C2 diastereomer, 81.7%), 74.1 min (minor enantiomer, C2 diastereomer,
0.6%), 77.4 min (meso diastereomer, 17.6%). Achiral GC assay (DB-
Wax column): 1008C isotherm over 2.0 min, ramp 58Cminꢀ1 to 1908C,
then 1908C isotherm for 10.0 min; tR
= 18.5 min (C2 diastereomer,
81.0%), 18.7 min (meso diastereomer, 19.0%).
[19] W. Langenbeck, G. Triem, Z. Phys. Chem. Abt. A 1936, 117, 401–
409.
Acknowledgements
[20] a) J. P. Vigneron, M. Dhaenens, A. Horeau, Tetrahedron 1973, 29,
1055–1059; b) V. Rautentrauch, Bull. Soc. Chim. Fr. 1994, 131, 515–
524; c) S. E. Baba, K. Sartor, J. Poulin, H. Kagan, Bull. Soc. Chim.
Fr. 1994, 131, 525–533.
This publication is based on work supported by Award No. KUS-11-006-
02, made by King Abdullah University of Science and Technology
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Total Syntheses of Cyanthiwigins B, F, and G
FULL PAPER
[21] C. S. Poss, S. L. Schreiber, Acc. Chem. Res. 1994, 27, 9–17.
[22] a) E. I. Negishi, S. Ma, J. Amanfu, C. Copꢃret, J. A. Miller, J. M.
Tour, J. Am. Chem. Soc. 1996, 118, 5919–5931; b) T. Satoh, T. Itaya,
K. Okuro, M. Miura, M. Nomura, J. Org. Chem. 1995, 60, 7267–
7271; c) T. Matsuura, L. E. Overmann, D. J. Poon, J. Am. Chem.
Soc. 1998, 120, 6500–6503; d) N. Iwasawa, H. Satoh, J. Am. Chem.
Soc. 1999, 121, 7951–7952; e) T. Hayashi, J. Tang, K. Kato, Org.
Lett. 1999, 1, 1487–1489; f) G. D. Artman, III, S. M. Weinreb, Org.
Lett. 2003, 5, 1523–1526; g) X. Wu, P. Nilsson, M. Larhed, J. Org.
Chem. 2005, 70, 346–349; h) X. F. Wu, H. Neumann, M. Beller,
Angew. Chem. 2010, 122, 5412–5416; Angew. Chem. Int. Ed. 2010,
49, 5284–5288; i) K. S. Bloome, E. J. Alexanian, J. Am. Chem. Soc.
2010, 132, 12823–12825.
[23] a) K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett. 1975,
16, 4467–4470; b) M. Eckhardt, R. Brꢂckner, J. Suffert, Tetrahedron
Lett. 1995, 36, 5167–5170.
[24] X. Han, B. M. Stoltz, E. J. Corey, J. Am. Chem. Soc. 1999, 121,
7600–7605.
[25] P. B. Tivola, A. Deagostino, C. Prandi, P. Venturello, J. Chem. Soc.
Perkin Trans. 1 2001, 437–441.
[26] All attempts to directly isolate the bicyclic enol ether resulting from
ring-closing metathesis of 51 only provided enone 53, presumably as
the result of decomposition.
[27] a) A. O. King, N. Okukado, E. I. Negishi, J. Chem. Soc. Chem.
Commun. 1977, 683–684; b) T. Taishi, S. Takechi, S. Mori, Tetrahe-
dron Lett. 1998, 39, 4347–4350.
[28] I. C. Stewart, T. Ung, A. A. Pletnev, J. Berlin, R. H. Grubbs, Y.
Schrodi, Org. Lett. 2007, 9, 1589–1592.
[29] For development and synthetic application of the vinyl boronate
cross-metathesis, See: a) C. Morrill, T. W. Funk, R. H. Grubbs, Tetra-
hedron Lett. 2004, 45, 7733–7736; b) C. Morrill, R. H. Grubbs, J.
Org. Chem. 2003, 68, 6031–6034; c) J. T. Njardarson, K. Biswas, S. J.
Danishefsky, Chem. Commun. 2002, 2759–2761.
[30] a) W. H. Kharasch, W. H. Urry, B. M. Kuderna, J. Org. Chem. 1949,
14, 248–253; b) L. N. Starker, D. B. Cosulich, J. M. Smith, Jr., J. Am.
Chem. Soc. 1955, 77, 2534–2536; c) H. Stetter, H. Kuhlmann, Tetra-
hedron Lett. 1974, 15, 4505–4508.
[31] Faced with the difficulty of generating an appropriate acyl radical
species, we postulated that formation of a ketyl radical would be
more facile, as well as more reactive, see: a) M. C. P. Yeh, F. C.
Wang, J. J. Tu, S. C. Chang, C. C. Chou, J. W. Liao, Organometallics
1998, 17, 5656–5662; b) G. A. Molander, J. A. McKie, J. Org. Chem.
1992, 57, 3132–3139; c) G. A. Molander, C. Kenny, J. Org. Chem.
1991, 56, 1439–1445. Toward this end, bicyclic aldehyde 57 was
treated with a solution of samarium(II) iodide in the presence of
hexamethylphosphoramide (HMPA), with the expectation that
these conditions would afford an appropriate ketyl radical. Unfortu-
nately, rather than undergo the radical-olefin cyclization process we
envisaged, the ketyl radical instead engaged in an undesired intra-
molecular Pinacol-type coupling to yield [5-6-7] tricyclic system 72.
was added HMPA (25 mL), and the vial was cooled to ꢀ788C. Once
this temperature had been reached, SmI2 (921 mL, 0.1m in THF,
0.092 mmol, 1.2 equiv) was added dropwise to the reaction. After
complete addition of a single portion of SmI2, the reaction had not
reached completion. A second portion of SmI2 (921 mL, 0.1m in
THF, 0.092 mmol, 1.2 equiv) was added, and the reaction was al-
lowed to reach 08C over 30 min. After this time had elapsed, the re-
action was poured into a solution of brine (20 mL) that contained
citric acid (770 mg). The phases were separated, and the aqueous
layer was extracted with ethyl acetate (4ꢄ30 mL). Combined organ-
ic layers were washed with brine (40 mL), dried over MgSO4, fil-
tered, and concentrated in vacuo. The resulting crude material was
purified over silica using 10 ! 12 ! 15% ethyl acetate in hexanes
as eluent. This afforded diol 72 as a colorless oil (11 mg, 55%). Se-
lected characterization data is as follows: 1H NMR (500 MHz,
CDCl3): d = 5.33 (app t, J=6.8 Hz, 1H), 5.13 (s, 1H), 3.83 (app dt,
J=6.8, 4.3 Hz, 1H), 2.38 (d, J=4.4 Hz, 1H), 2.35–2.33 (m, 1H),
2.31 (s, 1H), 2.24–2.16 (m, 1H), 2.12 (ddd, J=14.5, 6.8, 0.8 Hz,
1H), 2.03 (app dt, J=14.7, 5.2 Hz, 2H), 1.95 (dddd, J=14.0, 8.9, 6.8,
5.3 Hz, 1H), 1.88 (dd, J=14.5, 6.8 Hz, 1H), 1.74 (ddd, J=12.7, 9.1,
5.3 Hz, 1H), 1.66 (s, 3H), 1.65–1.58 (m, 1H), 1.62 (d, J=4.8 Hz,
1H), 1.47 (d, J=14.1 Hz, 1H), 1.44 (ddd, J=12.7, 8.9, 7.2 Hz, 1H),
1.15 (s, 3H), 1.06 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d =
142.9, 139.3, 131.5, 121.3, 79.5, 79.0, 46.4, 44.6, 40.1, 39.7, 38.4, 35.9,
30.5, 29.8, 27.7, 25.7, 23.7 ppm.
[32] J. L. Namy, J. Souppe, H. B. Kagan, Tetrahedron Lett. 1983, 24, 765–
766.
[33] 664430 (63) contains the supplementary crystallographic 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.
[34] K. Yoshikai, T. Hayama, K. Nishimura, K. Yamada, K. Tomioka, J.
Org. Chem. 2005, 70, 681–683.
[35] D. S. Rawat, R. A. Gibbs, Org. Lett. 2002, 4, 3027–3030.
[36] K. Tamao, K. Sumitani, Y. Kiso, M. Zembayashi, H. Fujioka, S. I.
Kodama, I. Nakajima, A. Minato, M. Kumada, Bull. Chem. Soc.
Jpn. 1976, 49, 1958–1969.
[37] Although, to our knowledge, there have been no reports of cuprate-
mediated palladium cross-coupling reactions, there nevertheless do
exist reports of copper-accelerated Negishi reactions, see: A. Wei-
chert, M. Bauer, P. Wirsig, Synlett 1996, 473–474.
[38] Products 6 and 67 were ultimately separated via reverse phase
HPLC purification.
[39] a) I. Shimizu, J. Tsuji, J. Am. Chem. Soc. 1982, 104, 5844–5846; b) I.
Shimizu, I. Minami, J. Tsuji, Tetrahedron Lett. 1983, 24, 1797–1800;
c) I. Minami, K. Takahashi, I. Shimizu, T. Kimura, J. Tsuji, Tetrahe-
dron 1986, 42, 2971–2977.
[40] The final two steps of our synthetic route toward cyanthiwigin B
were adapted from Phillipsꢁ synthesis of cyanthiwigin U, see: ref. [7]
above.
[41] D. E. Ward, C. K. Rhee, Can. J. Chem. 1989, 67, 1206–1211.
[42] a) R. J. Arhart, J. C. Martin, J. Am. Chem. Soc. 1972, 94, 5003–5010;
b) J. C. Martin, J. A. Franz, R. J. Arhart, J. Am. Chem. Soc. 1974, 96,
4604–4611.
[43] An alternative approach toward cyanthiwigin G involving formation
of an enol triflate species from cyanthiwigin B (2) via deprotonation
at C(7) and trapping with N-phenyl bis(trifluoromethane)sulfoni-
mide, failed to achieve the desired product. Under these conditions,
only g-deprotonation at C(18) was observed.
To a flame dried vial was added a THF solution of aldehyde 57
(20 mg, 0.077 mmol, 1.0 equiv, in 500 mL solvent). To this solution
Received: February 8, 2011
Published online: July 18, 2011
Chem. Eur. J. 2011, 17, 9957 – 9969
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9969