C-C Bond Cleavage Approach to Complex Terpenoids: Development of a Unified Total Synthesis of the Phomactins

Article abstract of DOI:10.1021/jacs.0c07316

The rearrangement of carbon-carbon (C-C) single bonds in readily available carbocyclic scaffolds can yield uniquely substituted carbocycles that would be challenging to construct otherwise. This is a powerful and often non-intuitive approach for complex m

Full text of DOI:10.1021/jacs.0c07316

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Article
C–C Bond Cleavage Approach to Complex Terpenoids:
Development of a Unified Total Synthesis of the Phomactins
Paul R Leger, Yusuke Kuroda, Stanley Chang, Justin Jurczyk, and Richmond Sarpong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c07316 • Publication Date (Web): 16 Aug 2020
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C–C Bond Cleavage Approach to Complex Terpenoids: Development of
a Unified Total Synthesis of the Phomactins
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Paul R. Leger‡, Yusuke Kuroda§, Stanley Chang#, Justin Jurczyk, and Richmond Sarpong*
Department of Chemistry, University of California, Berkeley, California 94720, USA
ABSTRACT: The rearrangement of carbon-carbon (C–C) single bonds in readily available carbocyclic scaffolds can yield
uniquely-substituted carbocycles that would be challenging to construct otherwise. This is a powerful and often non-intuitive
approach for complex molecule synthesis. The transition metal-mediated cleavage of C–C bonds has the potential to broaden
the scope of this type of skeletal remodeling by providing orthogonal selectivities compared to more traditional pericyclic
and carbocation-based rearrangements. To highlight this emerging technology, a unified, asymmetric, total synthesis of the
phomactin terpenoids was developed, enabled by the selective C–C bond cleavage of hydroxylated pinene derivatives ob-
tained from carvone. In this full account, the challenges, solutions, and intricacies of Rh(I)-catalyzed cyclobutanol C–C cleav-
age in a complex molecule setting is described. In addition, details of the evolution of strategies that ultimately led to the total
synthesis of phomactins A, K, P, R, and T, as well as the synthesis and structural reassignment of Sch 49027, are detailed.
enlisted in this regard, the toolbox of rearrangement reac-
tions for carbocyclic skeletons remains relatively limited
INTRODUCTION
Terpenoids have long held the fascination of the chemical
community, in no small part due to their varied and intri-
guing molecular architectures and the challenge they pose
to de novo chemical synthesis.1 Terpenoid natural products
primarily consist of a hydrocarbon skeleton, punctuated by
varying degrees of oxidation/oxygenation. Because of their
inherent carbocyclic nature, the synthesis of terpenoids has
been dominated by methods for the precise construction of
carbon-carbon (C–C) bonds. In this context, C–C bond con-
struction can either begin from acyclic isoprene-derived
units which proceed through bioinspired polyene cycliza-
tions,2 or in a step-wise manner by substitution around the
periphery of a readily available carbocyclic starting mate-
rial to introduce target-relevant structural complexity (Fig-
ure 1A). The latter strategy can be effective, particularly
when readily available carbocycles with the requisite func-
tional handles are embedded within a larger natural prod-
uct framework.3 However, a large number of terpenoid nat-
ural products contain densely functionalized carbocycles
that do not directly correspond to an easily accessible pre-
cursor carbocycle.
and is often driven by the stereoelectronic effects inherent
to the substrate carbocycle.5 In contrast, transition metal-
mediated C–C bond cleavage processes provide promising
new avenues for remodeling carbon scaffolds that often
proceed with selectivities orthogonal to “classical” rear-
rangements (i.e., those catalyzed by Brønsted or Lewis ac-
ids, or thermally driven).6 When combined with or initiated
by a bond-forming process, transition metal-mediated C–C
bond cleavage has the potential to access novel carbocyclic
scaffolds and provide non-intuitive approaches to complex
molecule synthesis.7
Many significant advancements in terpenoid total synthe-
sis can be traced to the rearrangement of abundant carbo-
cyclic feedstocks. The skeletal or peripheral remodeling of
“chiral pool” compounds (e.g., Figure 1B) involving C–C
bond forming and cleavage is a particularly valuable ap-
proach to access new enantioenriched scaffolds that might
otherwise be difficult to build from classical C–C bond form-
ing processes that functionalize only the periphery of a ring
(as in Figure 1A).4 The possibility of C–C bond for-
mation/cleavage sequences often enables non-intuitive ret-
rosynthetic disconnections that can greatly simplify a syn-
thesis if used strategically. While various pericyclic and car-
bocation-based rearrangements have been successfully
Figure 1. (A) A sequential bond formation strategy. (B) A
strategy of bond formation followed by C–C bond cleavage
to access rearranged carbocycles.
In this Article, we report our studies on the underutilized
potential of metal-mediated C–C bond cleavage processes of
hydroxylated pinene derivatives derived from (+)-carvone
to form uniquely-substituted cyclohexenones. This skeletal
remodeling process has been applied in the asymmetric and
unified total synthesis of the phomactin terpenoids.
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Figure 2. (A) Representative members of the phomactin family of natural products. (B) Yamada’s synthesis of (+)-phomactin
D. (C) Pattenden’s synthesis of (±)-phomactin A. (D) Halcomb’s synthesis of (+)-phomactin A.
Structural Features of the Phomactins
furanochroman functional grouping that is unique to pho-
mactin A (1).13 The sheer number of studies toward the syn-
theses of these natural products highlights the synthetic
challenge associated with preparing these molecules. In
particular, formation of the densely functionalized cyclo-
hexyl core in enantioenriched form has proven surprisingly
difficult.
The phomactin natural products are a small class of ter-
penoids exemplified by phomactin A (1), the first of the sec-
ondary metabolites to be discovered in this class (Figure
2A).8 Phomactin A was first isolated from a Phoma species
of marine fungus in 1991 during a search for fungal metab-
olites that display platelet-activating-factor receptor
(PAFR) antagonism.9 Further investigation into this Phoma
species resulted in the isolation of additional phomactin
natural products including phomactin B2 (2), phomactin G
(3), and several other congeners.10 More recently in 2018,
Berlinck and coworkers disclosed six new phomactin terpe-
noids including phomactin R (4) and phomactin T (5),
which were isolated from the fungus Biatriospora sp. CBMAI
1333.11 To date, there have been 27 distinct phomactin nat-
ural products isolated and disclosed by various groups.12
The first completed total synthesis of a phomactin conge-
ner was of (+)-phomactin D (8), which was reported by
Yamada and coworkers in 1996 (Figure 2B).14 This synthe-
sis of the enantioenriched natural product set an important
precedent for future approaches by independently con-
structing the functionalized cyclohexyl system (13) and the
linear “strap” portion (14), then effecting a convergent cou-
pling to forge the macrocycle at a late-stage. As is described
within, our own strategy for a unified synthesis of the pho-
mactins benefitted immensely from many principles first
highlighted by Yamada. However, the Yamada synthesis
also revealed the difficulty in building the cyclohexane frag-
ment (see 13; highlighted in blue), requiring 25 steps and
many functional group interconversions to prepare this
complex piece.
The phomactin terpenoids are characterized by an unu-
sual bicyclo[9.3.1]pentadecane core that comprises their
carbocyclic framework (highlighted in green for phomactin
P (6), Figure 2A). As a result, each natural product contains
a densely functionalized cyclohexyl ring, bridged by a mac-
rocyclic “strap”. Phomactin A (1), the flagship molecule in
this terpenoid class, is arguably the most structurally com-
plex congener. It contains an oxadecalin framework embed-
ded in its core structure as well as a highly sensitive hydrox-
ylated dihydrofuran structural motif, which is also present
in phomactin G (3) and Sch 49027 (7).
In 2002, Pattenden and coworkers were the first to com-
plete a total synthesis of (±)-phomactin A (Figure 2C).15 Alt-
hough this was a racemic synthesis, the unique strategy em-
ployed by Pattenden et al. to introduce the “strap” motif
(16) early in the route led to a relatively short total synthe-
sis (19 steps longest linear sequence). Furthermore, deoxy-
genation of an intermediate compound prior to reaching 17
in the Pattenden route led to the racemic synthesis of (±)-
phomactin G (3).16 Shortly thereafter, in 2003, the first
asymmetric synthesis of (+)-phomactin A (1) was reported
by Halcomb and coworkers (Figure 2D).17 The Halcomb syn-
thesis utilized a convergent strategy that brought together
cyclohexyl core 20 and the linear “strap” 21, which had
been prepared separately. However, a sequential bond for-
mation strategy was employed, and elaboration of the initial
Previous Synthetic Studies
The phomacin natural products have garnered much at-
tention from the synthetic community over the past 30
years.8 In addition to the total syntheses of several members
(1, 2, 3 and 8) that had been completed prior to our studies,
there exists over 25 “progress toward” studies, featuring di-
verse strategies for the construction of either the common
bicyclo[9.3.1]pentadecane
core
or
the
reduced
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“chiral pool” compound (+)-pulegone (18) to cyclohexene functional handles for further late-stage diversification into
1
20 was remarkably challenging, requiring 18 steps.
a wide variety of natural products.
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In the intervening years before our own studies of the
phomactins, an inventive 22-step synthesis of (±)-phomac-
tin B2 (2) was accomplished by Wulff and coworkers,18 as
well as a 37-step synthesis of (±)-phomactin A (1) by Hsung
and coworkers that was highly illuminating in pointing out
many of the hidden challenges in approaching the syntheses
of these molecules.19 Recently, a formal synthesis of (+)-
phomactin A (1) was disclosed by Lee and coworkers that
intercepts a late-stage intermediate in the Halcomb route.20
While there have been many creative strategies developed
to synthesize phomactin-type terpenoids, we recognized
that there still existed an unmet synthetic challenge,
namely, an efficient strategy that could provide a unified
route to numerous phomactin congeners in enantioen-
riched form. Our solution to this problem was published in
2018, enabling the asymmetric total synthesis of six pho-
mactin congeners from a common late-stage synthetic in-
termediate and showcasing the power of a C–C bond for-
mation/cleavage strategy in terpenoid synthesis.11 Here, we
provide both a full account of the evolution of our synthetic
strategy as well as a demonstration of the intricacies of
metal-mediated C–C bond cleavage on complex substrates,
discovered over the course of our total synthesis endeavor.
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RESULTS AND DISCUSSION
Retrosynthetic Considerations
Our synthetic strategy was built on the recognition that
the central cyclohexyl ring of the phomactins could be ac-
cessed efficiently from abundant “chiral pool” compound
(+)-carvone (22, Figure 3A). While the intact carvone skel-
eton does not map directly onto the phomactin terpenoid
framework, we pictured a “rearranged” skeleton such as 24
as an ideal synthetic partner. In order to achieve the requi-
site carvone rearrangement, we sought to build on earlier
methodology studies from our research group on C–C bond
cleavage/functionalizations. Specifically, (+)-carvone can
be converted into dihydroxylated pinene derivative 23 us-
ing a previously reported two-step procedure involving
epoxidation of 22 with mCPBA followed by reductive cou-
pling of the epoxide and carbonyl moieties with in situ gen-
erated Cp2TiCl.21 Subjecting cyclobutanol 23 to substoichio-
metric amounts of [Rh(cod)OH]2 results in scission of the
C4–C5 bond of the cyclobutanol, thus effecting the skeletal
rearrangement of carvone into cyclohexenone 24.22 The
cleavage of the cyclobutanol C–C bonds occurs selectively
and results in the cleavage of the stronger C4–C5 bond over
the weaker C2–C5 bond.23
Figure 3. (A) Skeletal rearrangement of carvone into sub-
stituted cyclohexenone 24. (B) Generalized synthetic strat-
egy. (C) Initial retrosynthesis of common synthetic interme-
diate 25 involving delayed cyclobutanol fragmentation.
Key to the success of our carvone skeletal remodeling
strategy would be tactical manipulations of not just the
functional groups of cyclohexenone 24, but also those of in-
termediate cyclobutanol 23. In fact, we first envisioned sev-
eral potential benefits of delaying C–C bond cleavage until
after macrocyclization (Figure 3C). Here, the common syn-
thetic intermediate (25) could arise from enone 27 via
methylenation and selective oxidation at the bis-allylic C2
position. Enone 27 in turn could arise from cyclobutanol 28,
first through intramolecular sulfone alkylation to close the
macrocycle (in line with the precedent of ref. 14 and 13l),
followed by selective cleavage of the cyclobutanol to estab-
lish the syn disposed vicinal methyl groups of enone 27. We
hypothesized that by delaying the cyclobutanol opening, the
potentially challenging macrocyclization step24 would be fa-
cilitated by the rigid scaffold of the bicyclo[3.1.1] system.25
Indeed, examination of 3D models indicated that cyclobuta-
nol 28 was locked in a productive conformation for cycliza-
tion, placing the methylene sulfone moiety in an axial posi-
tion (see Figure 3C). Additionally, delaying cyclobutanol
fragmentation would provide a rigid template to exploit in
a hydroxy group-directed C–H functionalization of the al-
lylic methyl group of cyclobutanol 23.
Cyclohexenone 24 readily maps onto the congested cyclo-
hexene core structure of the phomactin natural products,
leading to the enantiospecific formation of this stereochem-
ically demanding portion of the phomactins in just three
steps from carvone. Furthermore, elaboration of cyclohex-
enone 24 into a late-stage common synthetic intermediate
(25) could be accomplished by the addition of a simple lin-
ear polyene such as 26 (Figure 3B), similar to the pioneer-
ing work showcased by Yamada and coworkers.14 This com-
mon synthetic intermediate bears functionality common to
all the phomactin congeners and contains key orthogonal
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Initial Strategy: π-allyl Stille Fragment Coupling
heptamolybdate and hydrogen peroxide proceeded
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smoothly. Interestingly, this sulfide to sulfone conversion
was found to be uniquely successful on this particular sub-
strate. Attempted sulfide oxidation on compound 33 re-
sulted in substantial rearrangement to [2.2.1]bicycle 36
caused by the nucleophilic alkene engaging the oxidant. It
appears that in 34, the acetate group effectively suppressed
this unwanted reactivity because of its electron-withdraw-
ing nature, leading to clean oxidation to sulfone 35.
Initial studies were undertaken to exploit the tertiary hy-
droxy group in cyclobutanol 23 as a directing group for
C(sp3)–H functionalization. After TBS protection of the pri-
mary hydroxy group of 23, the one-pot procedure devel-
oped by Hartwig and coworkers for silylation of alcohol
groups followed by dehydrogenative C–H silylation gave ox-
asilolane 29 in 80% yield (Scheme 1).26 Importantly, this re-
action is completely chemoselective toward functionaliza-
tion at the allylic methyl position over the alkyl methyl
group. This selectivity arises from both the slight activating
ability of the neighboring π-system as well as a favorable di-
hedral angle between the allylic methyl group and the si-
lyloxy group, which is close to 0°. In our envisioned ideal
scenario, the allyl silane functionality of 29 would be uti-
lized in a Hiyama-type coupling to achieve direct vinylation
at C2. However, with isobutenyl bromide as a model cross-
coupling partner, the desired skipped diene (30) was not
observed. Instead, cyclohexenone 31 was formed as the sole
product, presumably through an Uemura-type C–C cleav-
age/ cross-coupling sequence.27 Unfortunately, any type of
direct coupling at C2 from oxasilolane 29 or its derivatives
was unsuccessful, prompting us to investigate a polarity-re-
versal strategy. In preparation for these studies, Tamao-
Fleming oxidation of oxasilolane 29 yielded the corre-
sponding free diol, which was selectively acetylated to give
allylic acetate 32. Allylic acetate 32 proved competent as a
coupling partner with a range of vinyl nucleophiles.28
Allylic acetate 35 served as an excellent substrate for a π-
allyl Stille reaction29 with vinyl stannane 3830 to form cou-
pled product 39 in 55% yield along with 25% of the Grob
fragmentation product (40). This fragmentation could be
partially suppressed by converting the tertiary hydroxy
group of 35 to a TMS ether, thus forming desired adduct 41
in 61% yield. To complete the macrocycle, primary alcohol
41 was converted to allylic bromide 42 which upon treat-
ment with NaHMDS cleanly afforded macrocyclic product
43 with no trace of competing Grob fragmentation.31 The
TMS group was readily cleaved under the action of an acidic
Amberlyst® resin and methanol to give 44.
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Divergent Reactivity in the Rh(I)-Catalyzed C–C Bond Cleav-
age
Our access to 44 demonstrated that the rigid [3.1.1]bicy-
cle could be employed in the rapid construction of the car-
bocyclic framework of the phomactin natural products.
With the macrocycle in place, we next investigated the se-
lective scission of the embedded cyclobutanol. It is known
that Rh(I) catalysts are efficient at effecting the desired C–C
cleavage/protodemetalation on simpler substrates.32 How-
ever, the cyclobutanol ring opening of a complex substrate
such as 44 was unprecedented. We were uncertain as to
how (A) the additional strain resident in the macrocycle
would affect the selectivity of the C–C bond cleavage, (B)
whether Grob fragmentation would predominate, or (C)
whether the presence of several double bonds in the sub-
strate might bind the Rh complex in an unproductive man-
ner or participate in unwanted side reactions.
Scheme 1. Dehydrogenative C–H Silylation of Cyclobuta-
nol 23
We were pleased to find that heating cyclobutanol 44
with 10 mol % [Rh(cod)OH]2 to 40 °C in deuterated benzene
resulted in the desired C–C bond cleavage. However, it did
not result in formation of desired cyclohexenone 45, but in-
stead yielded the related -unsaturated ketone 46
(Scheme 3A). -Unsaturated ketone 46 presumably forms
via the intermediacy of alkyl rhodium species 47 which un-
dergoes a 1,3-Rh shift to give allylic rhodium species 48.22
Protodemetalation with protonation occurring at the α po-
sition then furnishes the observed product. To probe this
mechanistic hypothesis, small amounts of D2O were added
to the reaction mixture. A deuterium incorporation of 90%
was observed at the position α to the carbonyl (see d-46)
whereas no deuterium incorporation was observed on the
methyl group (i.e., at C19), supporting an intramolecular
rhodium shift that results in a protonation at C19.
For the purposes of the total synthesis, prior to exploring
vinyl cross-couplings of allylic acetates related to 32 en
route to the phomactins, primary alcohol 23 was converted
to phenyl sulfide 33 (Scheme 2) to provide a future handle
for macrocyclization and avoid the use of the TBS protecting
group that would be required otherwise. Iridium-catalyzed
dehydrogenative silylation was effected on 33 to function-
alize the allylic position, however, a subsequent Tamao-
Fleming oxidation proved challenging and led to non-spe-
cific decomposition. Fortunately, selenium dioxide proved
capable of directly effecting allylic oxidation of 33 to pro-
vide allylic acetate 34 after mono-acetylation. Oxidation of
phenyl sulfide 34 to sulfone 35 with ammonium
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Scheme 2. Synthesis of Macrocycle via π-Allyl Stille Cross-Coupling
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Interestingly, unconjugated enone 46 could not be read-
anticipated for a doubly allylic position. Furthermore, upon
the generation of a radical at C2, rapid olefin isomerization
occurred to form an undesired 1,3-diene system.36 Given
these challenges, which were not resolved even after ex-
haustive experimentation, we settled on examining syn-
thetic routes where oxygenation at C2 was pre-installed.
ily purified and isolated. Upon its exposure to air, rapid oxi-
dation occurred to give a 1:1 mixture of hydroxy enone 49
and enedione 50 in a combined yield of 50% (Scheme 3B).33
Although unexpected, we recognized that this facile oxida-
tion could be beneficial since several of the phomactin nat-
ural products bear oxygenation at C13 (e.g., phomactins B2
(2) and K (9), see Figure 2). One possible explanation for
this facile oxygenation is that the weakened α C–H bond of
46 allows for facile hydrogen atom abstraction to give al-
lylic radical 51.34 Radical combination with triplet oxygen
would form allylic peroxy species 52. This peroxy interme-
diate could either undergo in situ reduction to yield hydroxy
enone 49 or suffer the formal loss of a hydroxyl radical to
give enedione 50. Importantly, hydroxy enone 49 was
found to be stable and did not oxidize to enedione 50 over
prolonged exposure to air. Furthermore, hydroxy enone 49
could be selectively formed if dimethyl sulfide was added to
the reaction mixture immediately upon exposure of uncon-
jugated enone 46 to air (Scheme 3C), supporting the hy-
pothesis that both oxidation products arise from peroxy
species 52.
Scheme 3. (A) Proposed Pathway for the Formation of
Unconjugated Enone 46. (B) Mechanistic Hypothesis for
the Formation of Oxidation Products 49 and 50. (C) Di-
vergent Outcomes of the Rh(I)-Catalyzed C–C Cleavage
Optimization of the Rh(I)-catalyzed C–C cleavage for con-
jugated enone 45 required a subsequent olefin isomeriza-
tion. Although employing various bases was unsuccessful,
switching the solvent from benzene to methanol enabled
clean conversion to desired enone 45 in 89% yield (Scheme
3C). This ring cleavage/olefin isomerization transformation
seems to occur through a pathway analogous to that shown
in Scheme 3A by first forming -enone 46 followed by ole-
fin isomerization. Conducting the reaction in deuterated
methanol clearly shows the rapid formation of α-deutero
ketone d-46, which slowly converts to -deutero enone d-
45, consistent with this proposed mechanism.35
At this point, we were emboldened by the fact that the
Rh(I)-catalyzed C–C bond cleavage was achievable on this
late-stage, complex substrate (i.e., 44). Additionally, by sub-
tly altering the conditions for this C–C cleavage transfor-
mation, cyclobutanol 44 could be converted into either cy-
clohexenone 45 or its hydroxylated variant, 49. However, to
fully elaborate either of these compounds into phomactin
natural products, selective oxygenation at the doubly allylic
position (C2) was required. Unfortunately, oxygenation at
C2 proved to be an extremely challenging task. Due to the
constrained macrocycle, the two π systems flanking C2 are
not coplanar, resulting in less activation than would be
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Scheme 4. Synthesis of Macrocycle via 1,2-Addition to Aldehyde 53
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Revised Strategy: Fragment Coupling Using a 1,2-Addition
into an Aldehyde
product. Of note, diol 60 also participated in the Rh(I)-cata-
lyzed C–C bond cleavage process, producing the desired cy-
clohexanone (65) in 49% yield.
We recognized that instead of appending the linear
“strap” portion to allylic acetate 37, a coupling partner with
a higher oxidation state at C2 would maintain oxygenation
after the coupling reaction. To this end, 1,2-addition to alde-
hyde 53, accessed in 3 steps from cyclobutanol 33, was pur-
sued (Scheme 4).37 Treatment of vinyl iodide 5438 with t-bu-
tyl lithium at low temperatures followed by the addition of
aldehyde 53 readily gave bis-allylic alcohol 55 in 68% yield
as a 5:1 mixture of diastereomers. By advancing the major
diastereomer, formation of the macrocycle occurred in a
similar fashion as described for the previous route (see
Scheme 2). The newly formed hydroxy group at C2 in 55
was first protected as the TBS ether, then sulfide oxidation
was performed to give sulfone 56. Oxidative cleavage of the
PMB group followed by bromination yielded allylic bromide
57, which upon treatment with NaHMDS cleanly afforded
macrocycle 58 in 91% yield. Buffered conditions were then
employed for silyl group removal (TASF and acetic acid) be-
cause the previously employed acidic conditions resulted in
ionization of the bis-allylic TBS ether group whereas base-
promoted cleavage conditions resulted in Grob fragmenta-
tion of 58. Depending on the reaction temperature, cleavage
of primarily one or both silyl ethers could be achieved to
give cyclobutanol 59 or diol 60, respectively.
Scheme 5. Solvent Effects on the Rh(I)-Catalyzed C–C
Bond Cleavage and Mechanistic Insights
Next, we investigated the reductive removal of the sul-
fone moiety in macrocycle 65, fully aware that doing so in
the presence of an enone moiety could be problematic due
to its susceptibility to reduction (Scheme 6). Indeed, several
conditions (such as samarium iodide) only served to reduce
the enone, whereas milder reductants did not provide any
reactivity. Interestingly, Birch-type dissolving metal condi-
tions yielded fully reduced diol 66 as the minor product and
cyclopropanol 67 as the major product. Presumably, cyclo-
propanol 67 formed from the addition of an incipient car-
banion into the carbonyl group.40 While cyclopropanol 67
was somewhat unstable, it was amenable to selective C–C
cleavage by heating the mixture with sodium methoxide to
give enone 68.41 In a way, the fortuitously formed cyclopro-
panol likely served as an in situ “protecting group” for the
enone moiety, preventing further reduction under the harsh
dissolving metal conditions.
Regarding the Rh(I)-catalyzed C–C bond cleavage step for
cyclobutanol 59, the presence of a silyloxy group at C2
brought about a different reactivity profile as compared to
the previously employed cyclobutanol 44. Subjecting si-
lyloxy cyclobutanol 59 to 10 mol % [Rh(cod)OH]2 in ben-
zene resulted in the formation of triene 61, presumably
arising from β-silyloxy elimination of an intermediate allyl
rhodium species (62, Scheme 5). As in our previous studies
on cyclobutanol openings, switching the solvent from ben-
zene to methanol resulted in the formation of desired cyclo-
hexenone 63. Interestingly, and in direct contrast to the
conversion of 44 to 45, when the reaction was conducted in
deuterated methanol, deuterium incorporation was ob-
served at C19 (the newly unveiled methyl group) and not at
the γ position of enone 63.39 This observation strongly sup-
ports protodemetalation at C19 outcompeting the 1,3-Rh
shift on alkyl rhodium species 64 in the presence of metha-
nol. This outcome could be due to the additional steric bulk
of the TBS ether suppressing the 1,3-Rh shift and reducing
the formation of the competing β-silyloxy elimination
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Scheme 6. Reductive Sulfone Cleavage and Rearrange- Scheme 7. Revised Retrosynthetic Analysis with Early-
1
ment of the Resulting Cyclopropanol
Stage Cyclobutanol Fragmentation
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At this stage, a single carbon atom remained to be in-
stalled through methylenation of enone 68 to complete the
phomactin framework. Although seemingly trivial, this one
carbon addition proved to be another major challenge. The
majority of carbon-based nucleophiles that we investigated
did not react with enone 68 (e.g., phosphonium salts or al-
kyl zinc reagents42) whereas a few added in a 1,4-fashion
(e.g., methyl lithium). From an examination of the confor-
mation of 68, it is clear that the Bürgi-Dunitz approach to
the carbonyl group is extremely hindered. The macrocyclic
“strap” sits directly underneath the cyclohexenone ring sys-
tem, completely blocking this face. Moreover, the macrocy-
cle locks the cyclehexenone into a conformation that places
the C19 methyl group in a pseudo-axial position, severely
obstructing a Bürgi-Dunitz approach to the carbonyl group
from the top face.19 Given the challenges associated with a
direct 1,2-addition to encumbered enone 68, we took a few
steps back to again revise our synthetic strategy and incor-
porate the C20 group earlier in the sequence.
The synthesis sequence commenced with cyclobutanol
33, which upon exposure to 7.5 mol % of [Rh(cod)OH]2 re-
sulted in the desired C–C bond fragmentation (Scheme 8).
Again, the use of methanol as solvent was required to
achieve optimal yields. Sulfide to sulfone oxidation pro-
vided enone 72. Although direct methylenation of enone 72
was still troublesome, we were pleased to find that unlike
the more sterically congested 68, treatment with methyl
lithium added a methyl group in a 1,2-fashion to enone 72.
Subjecting the resulting 1,2-adduct to the Burgess reagent
provided a two-step methylenation. Allylic oxidation at that
stage with excess selenium dioxide provided aldehyde 71.
Following a similar aldehyde 1,2-addition protocol as be-
fore (i.e., 53 → 55), vinyl iodide 7043 was treated with t-bu-
tyl lithium and added to aldehyde 71 at low temperatures
to afford bis-allylic alcohol 73 as a 1:1 mixture of diastere-
omers. Protection of the resulting hydroxy group with a
SEM group followed by cleavage of the TBS group and bro-
mination of the primary alcohol group yielded allylic bro-
mide 74. Macrocyclization proceeded smoothly to give mac-
rocycle 75, even without the conformational bias imparted
by the rigid [3.1.1]bicyclic scaffold that had been previously
employed (i.e., 42 → 43 and 57 → 58). At this stage, reduc-
tive de-sulfonylation under Birch conditions afforded a
modest amount of desired product 76. However, by switch-
ing to sodium-mercury amalgam, 76 was formed in a satis-
factory 75% yield. Finally, cleavage of the SEM group with
TBAF in DMPU gave alcohol 25 as a 1:1 mixture of diastere-
omers.44 Although the stereochemistry at C2 is ultimately
inconsequential, we found that only one of the two alcohol
diastereomers was competent in subsequent chemistry.
Therefore, a one-pot oxidation/reduction sequence was
employed to give 25 as a single diastereomer. In this way,
the desired common intermediate to the phomactins (25) is
accessible in 16 steps from (+)-carvone, achieved through
the strategic application of C–C bond cleavage of carvone-
derived cyclobutanol 33. This system is readied for diversi-
fication into numerous phomactin congeners.
Successful Strategy to the Phomactins: Early-Stage Cyclobu-
tanol Fragmentation
In order to efficiently install the carbon unit at C20, we
recognized that cyclobutanol fragmentation and subse-
quent methylenation would be required prior to macrocy-
clization (Scheme 7). In our revised and ultimately success-
ful synthetic approach, unified access to the phomactin ter-
penoids would be accomplished through selective oxygena-
tion of common synthetic intermediate 25, which could be
formed through macrocyclization of sulfone 69. As shown
previously, addition of the “strap” portion (70) can be ac-
complished by 1,2-addition into aldehyde 71. We posited
that carbonyl methylenation would be viable on a less en-
cumbered substrate such as enone 72, which in turn can
arise from C–C bond cleavage of cyclobutanol 33.
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Scheme 8. Final Route to Common Intermediate 25
Page 8 of 14
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Synthesis of Phomactins R, P, and K
With the ultimate goal of synthesizing structurally com-
plex phomactins such as phomactins A and T, we initially set
our sights on advancing common intermediate 25 to the rel-
atively less functionalized phomactin R (4, Scheme 9). Ini-
tial directed epoxidation studies with VO(acac)2 and TBHP
resulted in a complex mixture of epoxides arising from con-
stitutional isomers as well as diastereomers. At low temper-
atures, switching the catalyst from VO(acac)2 to VO(OEt)3
resulted in improved selectivity, forming the desired epox-
ide (77) in 72% yield.45 Nuclear Overhauser effect (nOe)
correlations between the epoxide α-proton and the allylic
methyl group aided in confirming the relative configuration
of epoxide 77. Further confirmation was achieved upon al-
cohol oxidation with DMP to yield phomactin R (4), which
provided data fully consistent with those reported in the lit-
erature, completing the total synthesis in 18 steps from (+)-
carvone.
Structural Revision of Sch 49027 and Synthesis of Phomactins
A and T
During the course of our epoxidation studies on common
intermediate 25, we discovered that a second epoxidation
can occur to give bis-epoxide 78 if the reaction was allowed
to warm to 0 °C (Scheme 10). Again, the use of VO(OEt)3 was
critical for the successful formation of the bis-epoxide. We
recognized that further oxidation to bis-epoxyketone 79 af-
forded a compound at the appropriate oxidation state to
form phomactin A (1) following an epoxide-opening cas-
cade. In theory, a water molecule could serve to open both
epoxides and form tetrahydropyranone derivative 80. Fur-
thermore, water-mediated allylic transposition could give
phomactin A (1) following hemiketalization. Unfortunately,
this cascade cyclization reaction was not realized in our
hands. In fact, no reactivity was observed upon heating bis-
epoxyketone 79 with water, and the addition of Lewis acids
either failed to facilitate reactivity or led to a complex mix-
ture of non-specific decomposition products.
Scheme 9. Total Synthesis of Phomactins R, P, and K
A more controlled and step-wise epoxide opening was
next explored from bis-epoxyalcohol 78. After considerable
experimentation, we found that utilizing Me4NBH(OAc)3 as
a Lewis acid resulted in a mixture of compounds (81, 82,
and 83), all seemingly arising from the same allylic cation
(81 from a Meinwald rearrangement; 82 and 83 from ace-
tate trapping).48 The addition of CsOAc to the reaction mix-
ture resulted in a slight increase in the relative amount of
acetate 83 that was formed, whereas adding 18-crown-6 to
this mixture resulted in complete selectivity for this C20 ac-
etate (83). The free diol (84) was liberated from 83 by fil-
tration over a pad of silica gel.
Selective mono-oxidation of diol 84 with DMP was ac-
complished at 0 °C to yield ketone 85. Surprisingly, quench-
ing the reaction mixture with NaOMe (intended to cleave
the acetyl group) resulted in a compound that matched the
spectral data for Sch 49027. Although double bond isomer-
ization could not be ruled out, the more likely product of the
reaction is allylic alcohol 86, which led us to speculate that
86 is the true structure of Sch 49027 and not the originally
proposed enol-containing 7. The revised structure for Sch
49027 (86) was corroborated by careful analysis of several
2D NMR experiments – key HMBC correlations are indi-
cated in Scheme 10 and COSY correlations were observed
between all the protons in the cyclohexyl ring system.49
In line with the presumed biosynthetic pathway46 to these
natural products, sequential oxygenation of phomactin R
(4) should lead to the formation of phomactins P (6) and K
(9), respectively. Indeed, epoxidation of phomactin R (4)
with DMDO furnished phomactin P (6); however, the major
product was the diastereomeric compound resulting from
epoxidation of the other alkene face. Switching the oxidant
from DMDO to mCPBA reversed the diastereoselectivity and
produced phomactin P (6) in 66% yield. Phomactin P (6)
was further oxidized at C13 under Doyle oxidation condi-
tions47 using TBHP in the presence of Rh2(cap)4 to furnish
phomactin K (9) following DBU promoted loss of t-butanol.
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Scheme 10. Total Synthesis of Phomactin A and Sch 49027 (Revised Structure)
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Epimerization of the secondary allylic hydroxy group of
Sch 49027 (86) was expected to lead to spontaneous cy-
clization (see allylic alcohol 88) and formation of phomactin
A (1). In practice, oxidation of diol 84 with DMP at room
temperature led to the formation of ketone 87 after quench-
ing with NaOMe to cleave the acetyl group and achieve
spontaneous hemiketalization. Treatment of ketone 87
with NaBH4/CeCl3 or LiAlH4 did not lead to formation of
phomactin A (1) but instead led to the exclusive formation
of Sch 49027 (86). This alternative synthesis of 86 further
corroborates the revised structure of this natural product.
Switching to a sterically larger reductant such as DIBAL-H
resulted in a 1:2 mixture of phomactin A (1) and Sch 49027
(86), and utilizing Red-Al® gave a 2.2:1 mixture of the natu-
ral products, ultimately yielding phomactin A (1) in 51%
and completing its total synthesis in 20 steps from (+)-car-
vone.
Scheme 11. Total Synthesis of Phomactin T
CONCLUSION
The synthesis of the structurally unique phomactin T (5)
required additional oxidation at C20. To achieve this, allylic
epoxide 78 was subjected to Me4NBH(OAc)3 as before and
then quenched with NaOMe to give triol 89 (Scheme 11).
Global oxidation of triol 89 with DMP at 60 °C successfully
delivered aldehyde 90.50 Pinnick oxidation of aldehyde 90
was unsuccessful. However, we were excited to find that ox-
idation of 90 with mCPBA in wet DCM directly furnished
lactol 92. This process likely occurs first through diastere-
oselective epoxidation to give epoxy-aldehyde 91, then al-
dehyde hydration followed by a transannular epoxide open-
ing. Lactol 92 proved unstable to isolation, so a one-step
protocol was developed wherein manganese dioxide was
added along with mCPBA to directly furnish phomactin T
(5) from aldehyde 90, completing the total synthesis of this
topologically unique congener in 20 steps from (+)-carvone.
The phomactin terpenoids continue to provide fertile
ground for pushing the limits of modern synthetic chemis-
try. By leveraging a Rh(I)-catalyzed C–C bond cleavage re-
action, we were able to access “rearranged” carvone skele-
tons and address a key challenge in phomactin synthesis –
the enantiospecific construction of the congested cyclo-
hexyl core. This key recognition of the relationship between
carvone and the cyclohexyl core of the phomactins enabled
the development of efficient syntheses of diverse phomactin
congeners in enantioenriched form, culminating in the syn-
theses of phomactins A, K, P, R, T and Sch 49027, with the
latter structure reassigned as a result of this total synthesis
effort. Each of these terpenoids was synthesized in 18–20
steps from (+)-carvone. Additionally, each natural product
was produced in just 2–4 steps from a common late-stage
intermediate (25) through a series of carefully choreo-
graphed oxidation or rearrangement steps, underscoring
the unified approach that was developed.
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Page 10 of 14
fellowship. We are grateful to Professor Roberto G. S. Berlinck
As a result of this total synthesis endeavor, many intrica-
cies of transition metal-mediated C–C bond cleavage have
become apparent. Rh(I)-catalyzed fragmentation of cyclo-
butanols 44 and 59 revealed alternative processes that can
occur on complex substrates, for example, rhodium shift,
deconjugation, oxygenation, or silyloxy elimination. Addi-
tionally, slight differences in substrates or reaction condi-
tions were found to influence the protodemetalation step, a
phenomenon uniquely brought to light through the applica-
tion of C–C cleavage in a complex molecule setting.
1
2
3
4
5
6
7
8
(University of São Paulo, Brazil) for insightful discussions re-
garding the phomactins and an enjoyable collaboration on the
isolation and biological aspects of our joint research in this
area. We thank Dr. Hasan Celik and UC Berkeley’s NMR facility
in the College of Chemistry (CoC-NMR) for spectroscopic assis-
tance. Instruments in CoC-NMR are supported in part by NIH
S10OD024998.
REFERENCES
9
(1)
Maimone, T. J.; Baran, P. S. Modern synthetic efforts to-
More fundamentally, this work has demonstrated the
power of strategic C–C bond cleavage reactions in total syn-
thesis. While our strategy of cyclobutanol formation fol-
lowed by C–C cleavage might be non-intuitive, the overall
goal of remodeling carbocyclic skeletons warrants further
investigation and applications by the chemical community.
Furthermore, transition metal-mediated C–C cleavage pro-
cesses that concurrently forge one or more new bonds (via
cyclization or coupling) uniquely hold the power to decon-
struct and reconstruct carbocyclic frameworks in rapid
fashion. Future advancements in simultaneous C–C cleav-
age and reforming processes, as well as methodologies to
selectively cleave C–C bonds in unstrained rings, will fur-
ther advance the field of complex natural product synthe-
sis.51
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ward biologically active terpenes. Nat. Chem. Biol. 2007, 3, 396–
407.
(2)
Yoder, R. A.; Johnston, J. N. A Case Study in Biomimetic
Total Synthesis:ꢀPolyolefin Carbocyclizations to Terpenes and Ster-
oids. Chem. Rev. 2005, 105, 4730–4756.
(3)
(a) Money, T.; Wong, M. K. C. The Use of Cyclic Mono-
terpenoids as Enantiopure Starting Materials in Natural Product
Synthesis. Stud. Nat. Prod. Chem. 1995, 16, 123–288. (b) Gaich, T.;
Mulzer, J. Chiral Pool Synthesis: Starting from Terpenes. In: Com-
prehensive Chirality. Carreira, E. M.; Yamamoto, H., Eds.; Elsevier
Ltd, 2012; Vol. 2, pp 163–206.
(4)
For rearranged chiral pool compounds, see “level 2” and
“level 3” syntheses in: Brill, Z. G.; Condakes, M. L.; Ting, C. P.;
Maimone, T. J. Navigating the Chiral Pool in the Total Synthesis of
Complex Terpene Natural Products. Chem. Rev. 2017, 117, 11753–
11795.
(5)
(a) Ilardi, E. A.; Stivala, C. E.; Zakarian, A. [3,3]-Sigma-
tropic rearrangements: recent applications in the total synthesis of
natural products. Chem. Soc. Rev. 2009, 38, 3133–3148. (b) Molec-
ular Rearrangements in Organic Synthesis; Rojas, C. M.; Eds.; John
Wiley & Sons, Inc., 2015.
ASSOCIATED CONTENT
The following is available as Supporting Information:
Experimental details and spectroscopic data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(6)
For recent reviews in the field of transition metal-medi-
ated C–C cleavage, see: (a) Marek, I.; Masarwa, A.; Delaye, P.-O.;
Leibeling, M. Selective Carbon–Carbon Bond Cleavage for the Ste-
reoselective Synthesis of Acyclic Systems. Angew. Chem. Int. Ed.
2015, 54, 414–429. (b) Souillart, L.; Cramer, N. Catalytic C–C Bond
Activations via Oxidative Addition to Transition Metals. Chem. Rev.
2015, 115, 9410–9464. (c) Murakami, M.; Ishida, N. Potential of
Metal-Catalyzed C–C Single Bond Cleavage for Organic Synthesis. J.
Am. Chem. Soc. 2016, 138, 13759–13769. (d) Nairoukh, Z.; Cormier,
M.; Marek, I. Merging C–H and C–C bond cleavage in organic syn-
thesis. Nat. Rev. Chem. 2017, 1, 1–17. (e) Fumagalli, G.; Stanton, S.;
Bower, J. F. Recent Methodologies That Exploit C–C Single-Bond
Cleavage of Strained Ring Systems by Transition Metal Complexes.
Chem. Rev. 2017, 117, 9404–9432.
AUTHOR INFORMATION
Corresponding Author
*rsarpong@berkeley.edu
ORCID
Richmond Sarpong: 0000-0002-0028-6323
Present Addresses
(7)
For usage of C–C bond cleavage in complex molecule syn-
‡ RAPT Therapeutics, Inc., 561 Eccles Ave., South San Fran-
cisco, CA, 95080.
thesis, see: (a) Hoffmann, R. W. Overbred Intermediates. In Ele-
ments of Synthesis Planning; Springer-Verlag, 2009; pp 106–117.
(b) Murakami, M.; Ishida, N. Cleavage of Carbon-Carbon Single
Bonds by Transition Metals 2015, 253–272. (c) Wang, B.; Perea, M.
A.; Sarpong, R. Transition Metal-Mediated C–C Single Bond Cleav-
age: Making the Cut in Total Synthesis. Angew. Chem. Int. Ed. 2020,
Accepted Article. DOI: 10.1002/anie.201915657.
§ Research Foundation ITSUU Laboratory, C1232 Kanagawa
Science Park R&D Building, 3-2-1 Sakado, Takatsu-ku, Kawa-
saki, Kanagawa 213-0012, Japan.
# Gilead Alberta ULC, 1021 Hayter Road, Edmonton, Alberta,
T6S 1A1, Canada.
(8)
For a review of the phomactin natural products see: (a)
Funding Sources
Goldring, W. P. D.; Pattenden, G. The Phomactins: A Novel Group of
Terpenoid Platelet Activating Factor Antagonists Related Bioge-
netically to the Taxanes. Acc. Chem. Res. 2006, 39, 354–361. (b)
Ciesielski, J.; Frontier, A. The Phomactin Natural Products from Iso-
lation to Total Synthesis: A Review. Org. Prep. Proced. Int. 2014, 46,
214–251.
NIGMS R35 GM130345.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
(9)
Sugano, M.; Sato, A.; Iijima, Y.; Oshima, T.; Furuya, K.; Ku-
R.S. thanks the National Institutes of General Medical Sciences
for support (R35 GM130345). P. R. L. thanks the National Sci-
ence Foundation for a graduate fellowship. Y.K. thanks the Ja-
pan Society for the Promotion of Science (JSPS) for an Overseas
Research Fellowship and S. C. thanks the National Science and
wano, H.; Hata, T.; Hanzawa, H. Phomactin A; a novel PAF antago-
nist from a marine fungus Phoma sp. J. Am. Chem. Soc. 1991, 113,
5463–5464.
(10) (a) Sugano, M.; Sato, A.; Iijima, Y.; Furuya, K.; Haruyama,
H.; Yoda, K.; Hata, T. Phomactins, novel PAF antagonists from ma-
rine fungus Phoma sp. J. Org. Chem. 1994, 59, 564–569. (b) Sugano,
Engineering Council–Canada (NSERC) for
a postdoctoral
ACS Paragon Plus Environment

Page 11 of 14
Journal of the American Chemical Society
M.; Sato, A.; Iijima, Y.; Furuya, K.; Kuwano, H.; Hata, T. Phomactin E,
F, and G: New Phomactin-group PAF Antagonists from a Marine
Fungus Phoma sp. J. Antibiot. 1995, 48, 1188–1190.
(11) Kuroda, Y.; Nicacio, K. J.; Alves da Silva-Jr, I.; Leger, P. R.;
Chang, S.; Gubiani, J. R.; Deflon, V. M.; Nagashima, N.; Rode, A.;
Blackford, K.; Ferreira, A. G.; Sette, L. D.; Williams, D. E.; Andersen,
R. J.; Jancar, S.; Berlinck, R. G. S.; Sarpong, R. Isolation, synthesis and
bioactivity studies of phomactin terpenoids. Nature Chem. 2018,
10, 938–945.
Cyclohexadienone Annulations of Fischer Carbene Complexes:ꢀ
Model Studies for the Synthesis of Phomactins. Org. Lett. 2007, 9,
2799–2802. (q) Teng, D.; Wang, B.; Augatis, A. J.; Totah, N. I. Studies
toward the synthesis of phomactin A. An approach to the macrocy-
clic core. Tetrahedron Lett. 2007, 48, 4605–4607. (r) You, L.-F.;
Hsung, R. P.; Bedermann, A. A.; Kurdyumov, A. V.; Tang, Y.; Bu-
chanan, G. S.; Cole, K. P. An Enantioselective Synthesis of the ABD
Tricycle for (−)-Phomactin A Featuring Rawal’s Asymmetric Diels–
Alder Cycloaddition. Adv. Synth. Catal. 2008, 350, 2885–2891. (s)
Blackburn, T. J.; Helliwell, M.; Kilner, M. J.; Lee, A. T. L.; Thomas, E.
J. Further studies of an approach to a total synthesis of phomactins.
Tetrahedron Lett. 2009, 50, 3550–3554. (t) Shapland, P. D. P.;
Thomas, E. J. Synthesis of precursors of phomactins using [2,3]-
Wittig rearrangements. Tetrahedron 2009, 65, 4201–4211. (u)
Schwartz, K. D.; White, J. D. Synthesis of the Cyclohexane Core of
Phomactins and a New Route to the Bicyclo[9.3.1]pentadecane
Diterpenoid Skeleton. Org. Lett. 2011, 13, 248–251. (v) Huang, S.;
Du, G.; Lee, C.-S. Construction of the Tricyclic Furanochroman Skel-
eton of Phomactin A via the Prins/Conia-Ene Cascade Cyclization
Approach. J. Org. Chem. 2011, 76, 6534–6541. (w) Ciesielski, J.; Car-
iou, K.; Frontier, A. J. A Macrocyclic -Iodoallenolate Intermediate
Is Key: Synthesis of the ABD Core of Phomactin A. Org. Lett. 2012,
14, 4082–4085. (x) Ciesielski, J.; Gandon, V.; Frontier, A. J. Cascade
Cyclizations of Acyclic and Macrocyclic Alkynones: Studies toward
the Synthesis of Phomactin A. J. Org. Chem. 2013, 78, 9541–9552.
(y) Burnell, E. S.; Irshad, A.-R.; Raftery, J.; Thomas, E. J. Approaches
to phomactin A: unexpected late-stage observations. Tetrahedron
Lett. 2015, 56, 3255–3258. (z) Blackburn, T. J.; Kilner, M. J.;
Thomas, E. J. Synthetic approaches to phomactins: on the stereose-
lectivity of some [2,3]-Wittig rearrangements. Tetrahedron 2015,
71, 7293–7309. (aa) Du, G.; Bao, W.; Huang, J.; Huang, S.; Yue, H.;
Yang, W.; Zhu, L.; Liang, Z.; Lee, C.-S. Enantioselective Synthesis of
the ABC-Tricyclic Core of Phomactin A by a -Hydroxylation Strat-
egy. Org. Lett. 2015, 17, 2062–2065. (bb) Blackburn, T. J.; Thomas,
E. J. Synthetic approaches to phomactins: Novel oxidation of
homoallylic alcohols using tetra-n-propylammonium perruthe-
nate. Tetrahedron 2018, 74, 5399–5407. (cc) Burnell, E. S.; Irshad,
A.-R.; Lee, A. T. L.; Thomas, E. J. Synthetic approaches to phomac-
tins: Late stage stereochemical and reactivity issues. Tetrahedron
2018, 74, 6737–6748.
(14) Miyaoka, H.; Saka, Y.; Miura, S.; Yamada, Y. Total synthe-
sis of phomactin D. Tetrahedron Lett. 1996, 37, 7107–7110.
(15) (a) Goldring, W. P. D.; Pattenden, G. A total synthesis of
phomactin A. Chem Commun. 2002, 1736–1737. (b) Diaper, C. M.;
Goldring, W. P. D.; Pattenden, G. A total synthesis of (±)-phomactin
A. Org. Biomol. Chem. 2003, 1, 3949–3956.
(16) Goldring, W. P. D.; Pattenden, G. Total synthesis of (±)-
phomactin G, a platelet activating factor antagonist from the ma-
rine fungus Phoma sp. Org. Biomol. Chem. 2004, 2, 466–473.
(17) Mohr, P. J.; Halcomb, R. L. Total Synthesis of (+)-Phomac-
tin A Using a B-Alkyl Suzuki Macrocyclization. J. Am. Chem. Soc.
2003, 125, 1712–1713.
(18) Huang, J.; Wu, C.; Wulff, W. D. Total Synthesis of (±)-Pho-
mactin B2 via an Intramolecular Cyclohexadienone Annulation of a
Chromium Carbene Complex. J. Am. Chem. Soc. 2007, 129, 13366–
13367.
(19) (a) Tang, Y.; Cole, K. P.; Buchanan, G. S.; Li, G.; Hsung, R. P.
Total Synthesis of Phomactin A. Org. Lett. 2009, 11, 1591–1594. (b)
Buchanan, G. S.; Cole, K. P.; Li, G.; Tang, Y.; You, L.-F.; Hsung, R. P.
Constructing the architecturally distinctive ABD-tricycle of pho-
mactin A through an intramolecular oxa-[3+3] annulation strategy.
Tetrahedron 2011, 67, 10105–10118. (c) Buchanan, G. S.; Cole, K.
P.; Tang, Y.; Hsung, R. P. Total Synthesis of (±)-Phomactin A. Les-
sons Learned from Respecting a Challenging Structural Topology.
J. Org. Chem. 2011, 76, 7027–7039.
1
2
3
4
5
6
7
8
(12) (a) Chu, M.; Patel, M. G.; Gullo, V. P.; Truumees, I.; Puar, M.
S.; McPhail, A. T. Sch 47918: a novel PAF antagonist from the fungus
Phoma sp. J. Org. Chem., 1992, 57, 5817–5818. (b) Chu, M.; Tru-
umees, I.; Gunnarsson, I.; Bishop, W. R.; Kreutner, W.; Horan, A. C.;
Patel, M. G.; Gullo, V. P.; Puar, M. S. A Novel Class of Platelet Activat-
ing Factor Antagonists from Phoma sp. J. Antibiot. 1993, 46, 554–
563. (c) Koyama, K.; Ishino, M.; Takatori, K.; Sugita, T.; Kinoshita,
K.; Takahashi, K. Phomactin H, a novel diterpene from an unidenti-
fied marine-derived fungus. Tetrahedron Lett. 2004, 45, 6947–
6948. (d) Ishino, M.; Kiyomichi, N.; Takatori, K.; Sugita, T.; Shiro, M.;
Kinoshita, K.; Takahashi, K.; Koyama, K. Phomactin I, 13-epi-Pho-
mactin I, and Phomactin J, three novel diterpenes from a marine-
derived fungus. Tetrahedron 2010, 66, 2594–2597. (e) Ishino, M.;
Kinoshita, K.; Takahashi, K.; Sugita, T.; Shiro, M.; Hasegawa K.; Ko-
yama, K. Phomactins K–M, three novel phomactin-type diterpenes
from a marine-derived fungus. Tetrahedron 2012, 68, 8572–8576.
(f) Ishino, M.; Kamauchi, H.; Takatori, K.; Kinoshita, K.; Sugita, T.;
Koyama, K. Three novel phomactin-type diterpenes from a marine-
derived fungus. Tetrahedron 2016, 57, 4341–4344.
(13) (a) Foote, K. M.; Hayes, C. J.; Pattenden, G. Synthetic stud-
ies towards phomactin A. Concise synthesis of the novel tricyclic
furanochroman system. Tetrahedron Lett. 1996, 37, 275–278. (b)
Seth, P. P.; Totah, N. I. Studies toward the Tricyclic Core of Phomac-
tin A. Synthesis of the Reduced Furanochroman Subunit. Org. Lett.
2000, 2, 2507–2509. (c) Seth, P. P.; Chen, D.; Wang, J.; Gao, X.; To-
tah, N. I. The Dihydropyrone Diels–Alder Reaction: Development
and Application to the Synthesis of Highly Functionalized 1-Oxa-4-
decalones. Tetrahedron 2000, 56, 10185–10195. (d) Kallan, N. C.;
Halcomb, R. L. Synthesis of the Ring System of Phomactin D Using
a Suzuki Macrocyclization. Org. Lett. 2000, 2, 2687–2690. (e)
Chemler, S. R.; Danishefsky, S. J. Transannular Macrocyclization via
Intramolecular B-Alkyl Suzuki Reaction. Org. Lett. 2000, 2, 2695–
9
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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34
35
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2698. (f) Mi, B.; Maleczka, R. E.
A Nozaki−Hiyama−Kishi
Ni(II)/Cr(II) Coupling Approach to the Phomactins. Org. Lett. 2001,
3, 1491–1494. (g) Chemler, S. R.; Iserloh, U.; Danishefsky, S. J. En-
antioselective Synthesis of the Oxadecalin Core of Phomactin A via
a Highly Stereoselective Diels−Alder Reaction. Org. Lett. 2001, 3,
2949–2951. (h) Houghton, R. J.; Choi, S.; Rawal, V. H. Efficient As-
sembly of the Phomactin Core via Two Different Macrocyclization
Protocols. Org. Lett. 2001, 3, 3615–3617. (i) Foote, K. M.; John, M.;
Pattenden, G. Synthesis of the Oxygenated Bicyclo[9.3.1]pentade-
cane Ring System of Phomactin A using Chromium (II)-mediated
Macrocyclisation and Ring Closure Metathesis. Synlett 2001, 3,
365–368. (j) Mohr, P. J.; Halcomb, R. L. Convergent Enantioselective
Synthesis of the Tricyclic Core of Phomactin A. Org. Lett. 2002, 4,
2413–2416. (k) Foote, K. M.; Hayes, C. J.; John, M. P.; Pattenden, G.
Synthetic studies towards the phomactins. Concise syntheses of
the tricyclic furanochroman and the oxygenated bicyclo[9.3.1]pen-
tadecane ring systems in phomactin A. Org. Biomol. Chem. 2003, 1,
3917–3948. (l) Balnaves, A. S.; McGowan, G.; Shapland, P. D. P.;
Thomas, E. J. Approaches to the total synthesis of phomactins. Tet-
rahedron Lett. 2003, 44, 2713–2716. (m) Cole, K. P.; Hsung, R. P.
Intramolecular Formal oxa-[3 + 3] Cycloaddition Approach to the
ABD System of Phomactin A. Org. Lett. 2003, 5, 4843–4846. (n)
Cole, K. P.; Hsung, R. P. Unique structural topology and reactivities
of the ABD tricycle in phomactin A. Chem. Commun. 2005, 46,
5784–5786. (o) Ryu, K.; Cho, Y.-S.; Jung, S.-I.; Cho, C.-G. Regioselec-
tive Pd-Catalyzed Synthesis and Application of 3-Methyl-5-bromo-
2-pyrone toward Keto-phomactin A. Org. Lett. 2006, 8, 3343–3345.
(p) Huang, J.; Wang, H.; Wu, C.; Wulff, W. D. Intramolecular
(20) Huang, J.; Bao, W.; Huang, S.; Yang, W.; Lizhi, Z.; Du, G.;
Lee, C.-S. Formal Synthesis of (+)-Phomactin A. Org. Lett. 2018, 20,
7466–7469.
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(21) Bermejo, F. A.; Mateos, A. F.; Escribano, A. E.; Lago, R. M.;
(34) The α C–H bond is pseudo-axial, providing good overlap
between the C–H σ-bond and both the C–O π* orbital and C–C π*
orbital, thus weakening the C–H bond.
(35) See Supporting Figures 1 and 2 for details.
(36) See Supporting Table 1 for details.
Buron, L. M.; Lopez, M. R.; Gonzalez, R. R. Ti(III)-promoted cycliza-
tions. Application to the synthesis of (E)-endo-bergamoten-12-oic
acids. Moth oviposition stimulants isolated from Lycopersicon hir-
sutum. Tetrahedron 2006, 62, 8933–8942.
1
2
3
4
5
6
7
8
9
(22) Masarwa, A.; Weber, M.; Sarpong. R. Selective C–C and C–
H Bond Activation/Cleavage of Pinene Derivatives: Synthesis of En-
antiopure Cyclohexenone Scaffolds and Mechanistic Insights. J. Am.
Chem. Soc. 2015, 137, 6327–6334.
(23) As seen in a related X-ray structure, the C4–C5 bond is
the stronger, shorter bond (1.551 Å) compared to the weaker and
longer C2–C5 bond (1.567 Å), see ref. 22.
(24) Previous synthetic work to construct the phomactin
skeleton indicated that the macrocyclization step can be challeng-
ing and low yielding, particularly if the carbon at C1 is sp2 hybrid-
ized. Macrocyclization with substrates where C1 is sp3 hybridized
are often more facile, most likely due to better preorganization of
the pendant functional group. For example, see ref. 13f vs 15a. The
sulfone alkylation strategy employed in this work was previously
shown to be effective, but only if C1 was sp3 hybridized, see ref. 13l
and 13s. We initially hypothesized that the rigid [3.1.1]bicycle
would help facilitate cyclization while still maintaining sp2 hybrid-
ization at C1. However, as shown in the final synthetic route
(Scheme 8), this rigid bicycle was ultimately not required for suc-
cessful macrocyclization.
(25) For a review of preorganization in macrocyclization re-
actions, see: Martí-Centelles, V.; Pandey, M. D.; Burguete, M. I.; Luis,
S. V. Macrocyclization Reactions: The Importance of Conforma-
tional, Configurational, and Template-Induced Preorganization.
Chem. Rev. 2015, 115, 8736–8834.
(26) (a) Simmons, E. M.; Hartwig, J. F. Catalytic functionaliza-
tion of unactivated primary C–H bonds directed by an alcohol. Na-
ture 2012, 483, 70-73. (b) Li, B.; Driess, M.; Hartwig, J. F. Iridium-
Catalyzed Regioselective Silylation of Secondary Alkyl C–H Bonds
for the Synthesis of 1,3-Diols. J. Am. Chem. Soc. 2014, 136, 6586–
6589.
(27) (a) Nishimura, T.; Uemura, S. Palladium-Catalyzed Aryla-
tion of tert-Cyclobutanols with Aryl Bromide via C−C Bond Cleav-
age:ꢀ New Approach for the -Arylated Ketones. J. Am. Chem. Soc.
1999, 121, 11010–11011. (b) Weber, M.; Owens, K.; Masarwa, A.;
Sarpong, R. Construction of Enantiopure Taxoid and Natural Prod-
uct-like Scaffolds Using a C–C Bond Cleavage/Arylation Reaction.
Org. Lett. 2015, 17, 5432–5435.
(28) Allylic acetate 32 showed similar reactivity as allylic ac-
etate 35 toward coupling reactions.
(29) Del Valle, L.; Stille, J. K.; Hegedus, L. S. Palladium-cata-
lyzed coupling of allylic acetates with aryl- and vinylstannanes. J.
Org. Chem. 1990, 55, 3019–3023.
(30) Synthesized in 5 steps from 4-pentyn-1-ol. See Support-
ing Information for details.
(31) Without the TMS group on the cyclobutanol, subjecting
the macrocycle precursor to basic cyclization conditions only re-
sulted in Grob fragmentation.
(32) (a) Matsuda, T.; Makino, M.; Murakami, M. Rhodium-Cat-
alyzed Addition/Ring-Opening Reaction of Arylboronic Acids with
Cyclobutanones. Org. Lett. 2004, 6, 1257–1259. (b) Murakami, M.;
Makino, M.; Ashida, S.; Matsuda, T. Construction of Carbon Frame-
works through -Carbon Elimination Mediated by Transition Met-
als. Bull. Chem. Soc. Jpn. 2006, 79, 1315–1321. (c) Cramer, N.;
Seiser, T. -Carbon Elimination from Cyclobutanols: A Clean Access
to Alkylrhodium Intermediates Bearing a Quaternary Stereogenic
Center. Synlett 2011, 4, 449–460.
(33) (a) Seiser, T.; Cramer, N. Enantioselective C–C Bond Acti-
vation of Allenyl Cyclobutanes: Access to Cyclohexenones with
Quaternary Stereogenic Centers. Angew. Chem. Int. Ed. 2008, 47,
9294–9297. (b) Seiser, T.; Cramer, N. Rhodium(I)-Catalyzed Enan-
tioselective Activation of Cyclobutanols: Formation of Cyclohexane
Derivatives with Quaternary Stereogenic Centers. Chem. Eur. J.
2010, 16, 3383–3391.
(37) Other groups have utilized a similar aldehyde addition
strategy, see ref. 13z and 14.
(38) Synthesized in 5 steps from 4-pentyn-1-ol. See Support-
ing Information for details.
(39) See Supporting Figure 3 for details.
(40) Formation of the cyclopropane ring of 67 is likely facili-
tated by close proximity of the transient carbanion to the carbonyl
moiety. A related cyclopropane was observed in the reductive
desulfonylation of a phomactin intermediate, see ref. 13cc.
(41) For examples of cyclopropane rearrangements, see: (a)
Gibson, D. H.; DePuy, C. H. Cyclopropanol chemistry. Chem. Rev.
1974, 74, 605–623. (b) Kulinkovich, O. G. The Chemistry of Cyclo-
propanols. Chem. Rev. 2003, 103, 2597–2632.
(42) (a) Nysted, L. N. Methylenation reagent. 1975, US Patent
3865848, see Chem. Abstr., 1875, 83, 10406q. (b) Lombardo, L.
Methylenation of carbonyl compounds with ZnCH2Br2TiCl4. Appli-
cation to gibberellins. Tetrahedron Lett., 1982, 23, 4293–4296. (c)
Chand, H. R. Lombardo’s Reagent. Synlett 2009, 15, 2545-2546.
(43) Synthesized in 5 steps from 4-pentyn-1-ol. See Support-
ing Information and ref. 13z for details.
(44) Lipshutz, B. H.; Miller, T. A. Deprotection of 'sem' ethers:
A convenient, general procedure. Tetrahedron Lett. 1989, 30,
7149–7152.
(45) Nicolaou, K. C.; Harrison, S. T. Total Synthesis of Abysso-
micin C and atrop-Abyssomicin C. Angew. Chem. Int. Ed. 2006, 45,
3256–3260.
(46) For an overview of the proposed biosynthesis of the pho-
mactins, see ref. 8. For biosynthetic studies, see: (a) Tokiwano, T.;
Fukushi, E.; Endo, T.; Oikawa, H. Biosynthesis of phomactins: com-
mon intermediate phomactatriene and taxadiene. Chem. Commun.
2004, 1324–1325. (b) Tokiwano, T.; Endo, T.; Tsukagoshi, T.; Goto,
H.; Fukushi, E.; Oikawa, H. Proposed mechanism for diterpene syn-
thases in the formation of phomactatriene and taxadiene. Org. Bio-
mol. Chem. 2005, 3, 2713–2722. (c) Chow, S. Y.; Williams, H. J.; Pen-
nington, J. D.; Nanda, S.; Reibenspies, J. H.; Scott, A. I. Studies on
taxadiene synthase: interception of the cyclization cascade at the
verticillene stage and rearrangement to phomactatriene. Tetrahe-
dron 2007, 63, 6204–6209. (d) Palframan, M. J.; Pattenden, G. The
Verticillenes. Pivotal Intermediates in the Biosynthesis of the Tax-
anes and the Phomactins. Nat. Prod. Rep. 2019, 36, 108–121.
(47) Catino, A. J.; Forslund, R. E.; Doyle, M. P. Dirhodium(II)
Caprolactamate:ꢀ An Exceptional Catalyst for Allylic Oxidation. J.
Am. Chem. Soc. 2004, 126, 13622–13623.
(48) Honda, T.; Mizutani, H. Regioselective Ring-Opening of
2,3-Epoxy Alcohols with Tetramethylammonium Triacetoxyboro-
hydride. Heterocycles 1998, 48, 1753–1757.
(49) Compound 86 was also synthesized by the Pattenden
group, but was not identified as Sch 49027: Cheing, J. W.; Goldring,
W. P. D.; Pattenden, G. Synthetic studies towards congeners of pho-
mactin A. Re-examination of the structure of Sch 49028. Chem.
Commun. 2003, 22, 2788–2789.
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(50) At room temperature, the DMP oxidation of 89 primarily
produced Sch 49027 (86).
(51) For recent methodologies of C–C bond cleavage in un-
strained rings, see: (a) Xia, Y.; Lu, G.; Liu, P.; Dong, G. Catalytic acti-
vation of carbon–carbon bonds in cyclopentanones. Nature 2016,
539, 546–550. (b) Guo, J.-J.; Hu, A.; Chen, Y.; Sun, J.; Tang, H.; Zuo, Z.
Photocatalytic C−C Bond Cleavage and Amination of Cycloalkanols
by Cerium(III) Chloride Complex. Angew. Chem. Int. Ed. 2016, 55,
15319–15322. (c) Roque, J. B.; Kuroda, Y.; Göttemann, L. T.; Sar-
pong, R. Deconstructive fluorination of cyclic amines by carbon-
carbon cleavage. Science 2018, 361, 171–174. (d) Roque, J. B.; Ku-
roda, Y.; Göttemann, L. T.; Sarpong, R. Deconstructive diversifica-
tion of cyclic amines. Nature 2018, 564, 244–248. (e) Hu, A.; Chen,
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Y.; Guo, J.-J.; Yu, N.; An, Q.; Zuo, Z. Cerium-Catalyzed Formal Cy-
cloaddition of Cycloalkanols with Alkenes through Dual Photoexci-
tation. J. Am. Chem. Soc. 2018, 140, 13580–13585. (f) Zhao, K.; Yam-
ashita, K.; Carpenter, J. E.; Sherwood, T. C.; Ewing, W. R.; Cheng, P.
T. W.; Knowles, R. R. Catalytic Ring Expansions of Cyclic Alcohols
Enabled by Proton-Coupled Electron Transfer. J. Am. Chem. Soc.
2019, 141, 8752–8757.
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