Total Synthesis of -Mitrephorone A

Article abstract of DOI:10.1021/jacs.8b09685

The first synthesis of mitrephorone A is disclosed along with discussion and study of synthetic strategies. The natural product includes a highly congested hexacyclic ent-trachylobane diterpenoid framework featuring a rare, embedded oxetane. The synthetic analysis presented dissects a number of approaches for the synthesis of the central oxetane, including carbonyl-olefin photocycloadditions, Prins-type cyclizations, and oxidative ring closures. In the successful route, three [4 + 2] cycloadditions enable rapid construction of all carbocycles. A novel late-stage oxidative cyclization of a hydroxy diosphenol with Koser's reagent furnishes the pivotal oxetane moiety.

Full text of DOI:10.1021/jacs.8b09685

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Article
Total Synthesis of (–)-Mitrephorone A
Matthieu J. R. Richter, Michael Schneider, Marco Brandstaetter, Simon Krautwald, and Erick M Carreira
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b09685 • Publication Date (Web): 09 Nov 2018
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Total Synthesis of (–)-Mitrephorone A
Matthieu J. R. Richter, Michael Schneider, Marco Brandstätter, Simon Krautwald and Erick M.
Carreira*
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ETH Zꢀrich, Vladimir-Prelog-Weg 3, HCI, 8093 Zꢀrich, Switzerland
ABSTRACT: The first synthesis of (–)-mitrephorone A is disclosed along with discussion and study of synthetic strategies. The
natural product includes a highly congested hexacyclic ent-trachylobane diterpenoid framework featuring a rare, embedded oxetane.
The synthetic analysis presented dissects a number of approaches for the synthesis of the central oxetane, including carbonyl-olefin
photocycloadditions, Prins-type cyclizations, and oxidative ring closures. In the successful route, three [4+2] cycloadditions enable
rapid construction of all carbocycles. A novel late-stage oxidative cyclization of a hydroxy diosphenol with Koser’s reagent furnishes
the pivotal oxetane moiety.
oxetane. In this respect, (–)-mitrephorone B (2b) displays no
activity when examined in the same assay.8
Introduction
The anticancer agent taxol is the most notable example of
oxetane-containing natural products.1 Although in synthetic en-
deavors to taxol accessing the oxetane is tangential,2 there are
numerous other targets, wherein installation of the oxacycle is
central to the synthesis strategy. These include thromboxane
A2,3 oxetanocin A,4 oxetin,5 merrilactone A,6 and more recently
dictyoxetane.7 Isolated in 2005 by Oberlies and co-workers
from the Bornean shrub Mitrephora glabra, (–)-mitrephorone
A (1) contains a fully substituted oxetane embedded in a penta-
cyclic carbon skeleton (Scheme 1).8 The pentacyclic carbon
skeleton and tricyclo[3.2.1.02,7]octane scaffold render (–)-mi-
trephorone A a member of the family of ent-trachylobanes.9 In
addition to antimicrobial activity, this diterpene exerts potent
and broad cytotoxicity against various cancer cell lines (MCF-
7, NCI-H460, SF-268), which has been largely attributed to the
The highly congested structure features a tetrasubstituted
cyclopropane, four quaternary centers and five contiguous ste-
reocenters. Additionally, the presence of a rare 1,2-diketone
render this natural product a veritable challenge in synthetic
chemistry. Herein, we report the first and enantioselective total
synthesis of (–)-mitrephorone A along with accompanying syn-
thetic studies. The salient features of the strategy include cy-
cloaddition reactions to gain rapid entry to the carbocyclic
framework along with oxidative cyclization of a hydroxy enol
ketone to afford the central oxetane.
Results and Discussion
Retrosynthetic Analysis. The key challenge presented by
(–)-mitrephorone A is the unusual hexasubstituted oxetane, in-
cluding a stereogenic quaternary center, fully integrated in the
diterpene scaffold. Accordingly, at the heart of the retrosyn-
thetic analysis are the oxetane and the means for its introduc-
tion. The fully substituted oxacycle precludes consideration of
alkylative ring-closing strategies at tertiary C(sp3) centers,
which are expected to be challenging. A strategy involving in-
tramolecular, carbonyl-olefin [2+2] cycloaddition might over-
come this limitation as Paternò–Büchi reactions have proven
successful for highly substituted substrates.10 Concerted for-
mation of the apposite C–O and C–C bonds enables two discon-
nection strategies I and II (Scheme 2).
Scheme 1. Structure/Activity of (–)-Mitrephorone A and
Retrosynthetic Analysis
In strategy I (bond disconnection in blue) there are two op-
tions. In the first of these, the decalyl system is produced by
transannular cycloaddition reaction. Because the starting trans-
cyclodecene in 5 can exist in at least two atropodiastereomeric
forms, the system is considerably complicated, especially when
contrasted against the second alternative. In this regard, -ke-
toester 6 lacks a macrocycle, is easier to prepare, and the β-ste-
reocenter may provide a bias for stereocontrol in a Paternò–
Büchi reaction. In strategy II (bond disconnection in red), for-
mation of the oxetane would result from intramolecular [2+2]
cycloaddition of enone 7. An attractive feature of this approach
is that 7 may be retrosynthetically partitioned into two simi-
larly-sized fragments.
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Scheme 2. Strategic Disconnection of the Oxetane Core Em-
ploying a [2+2] Cycloaddition Approach
C(●)-C(●) and C(●)-C(●). First reported in 1968,14a this type of
Diels–Alder reaction that leads to a cyclopropane has been the
subject of methodological studies,14b-n but to the best of our
knowledge this powerful transformation has not been utilized in
the context of a total synthesis.
1
2
3
4
[2+2] Cycloaddition Studies. The synthesis of 1 com-
menced with TADDOL-catalyzed Diels–Alder reaction of
methacrolein (8) with Rawal’s diene (9),15 followed by Wittig
methenylation and acidic hydrolysis16 to afford cyclohexenone
4 in 70% overall yield and 88% ee (Scheme 4). Introduction of
a methyl ester using Mander’s reagent17 and TBS protection
gave triene 11 in 59% overall yield. This efficient sequence set
the stage for intramolecular cycloaddition to generate the cyclo-
propane. Thus, heating a solution of 11 in toluene at 190 °C
gave 12 as a single product. The addition of propylene oxide as
acid scavenger to the reaction mixture proved vital to prevent
hydrolysis of the starting material over the course of the reac-
tion.18 Subsequent in situ reduction of the ester with DIBAL-H
and quenching with aqueous HCl yielded hydroxyketone 3
(85%).
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In an altogether different analysis, the juxtaposition of the
oxetane and α-diketone in 1 suggests an approach involving an
enolonium C(sp2) synthon (Scheme 1). Two mechanistically
distinct approaches can be considered for oxetane construction
in (–)-mitrephorone A (Scheme 3). In one of these, the nucleo-
philic enol or enolate attacks an electrophilic oxygen, such as a
hydroperoxide (LG = OH, pathway A). In this context, Dussault
and co-workers had demonstrated that γ-peroxyketones are
readily transformed into ketooxetanes under basic conditions.11
Scheme 4. Construction of the Tricyclooctane Corea
Scheme 3. Complementary Modes of Oxidative Cyclization
aReagents and conditions: (a) Rawal's diene (9), (S,S)-1-Np-
TADDOL (10) (20 mol%), PhMe, –80 °C, then Ph3P=CH2, –78 °C
to RT, then 1 M aq HCl, RT, 70%, 88% ee; (b) LDA, THF, –78 °C,
then HMPA, MeO2CCN; (c) LiHMDS, t-BuMe2SiOTf, THF, –78
°C, 59% (2 steps); (d) propylene oxide, PhMe, 190 °C, then
DIBAL-H, –78 °C, then 1 M aq HCl, –78 °C to RT, 85%.
In another approach, the enone functions as an electrophile
that is engaged by the nucleophilic tertiary alcohol, forming the
oxetane as part of an oxidative cyclization (pathway B). Exper-
imentally, the latter is a more flexible approach given the vari-
ety of options available for the identity of the leaving group
(LG), which includes metals, halides and sulfonates, among
others.12 There are but four examples reported in the literature
in which ’-hydroxy methyl ketones are converted into oxeta-
nyl ketones by treatment with PhI(OAc)2;12b the reaction ap-
pears to only work in 70-75% yield for closely related 17β-ac-
etyl-17-hydroxysteroids. However, the reaction of the simpler
substrate1-acetyl-1-hydroxycyclohexane was reported to pro-
ceed in about 10% yield. To the best of our knowledge, there is
no precedence for hydroxy diosphenol substrates oxidatively
closing to the corresponding oxetanyl diketones. This second
approach with the enone as acceptor can be considered syntheti-
cally equivalent to the process invoking an enolonium synthon.
Having established a reliable and scalable route to 3, pre-
cursors to probe both [2+2] strategies (Scheme 2) were rapidly
accessed (see SI). However, extensive studies on either
Scheme 5. Investigation of [2+2] Cycloadditions
The ester attached to the decalyl fragment of 2a (Scheme 1)
alludes to the implementation of an intramolecular Diels–Alder
reaction to furnish both rings in a single step.13 This approach
prescribes the use of a tricyclo[3.2.1.02,7]octane (3) as a starting
point. Cursory examination of 3 would suggest cyclopropana-
tion approaches for its synthesis. However, closer inspection re-
vealed that 3 might be derived from intramolecular cycloaddi-
tion of a 5-vinyl-1,3-cyclohexadiene derivative of 4, joining
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system were not met with success (Scheme 5). For example, ir-
were undertaken to improve the diastereoselectivity in the ke-
tone addition reaction. An overview of the various approaches
is provided in Table 1 (see SI for detailed experimental studies).
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3
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7
8
radiation of a solution of ketoester 13 in deuterated benzene in
a quartz vessel with a 400 W mercury-vapor lamp at RT gave
Norrish type II products along with decomposed material. Irra-
diation of ketones 7, 15, and 16 in various solvents (PhH,
MeCN, CDCl3) resulted in recovery of the starting material or
gave complex mixtures. Isomerization of the 1,2-disubstituted
cis-olefin in 16 to the trans isomer was also observed.
In order to optimize facial selectivity in the ketone addition
reaction, three different approaches were investigated: 1) use of
chiral auxiliaries, 2) addition of chiral ligands for RLi/La or
RxZn and 3) variation of reaction conditions. We reasoned that
maximum effect of a chiral auxiliary would be observed by its
installation in close proximity to the ketone. In this respect, ox-
idation of the primary alcohol in 3 offers the opportunity to in-
troduce a chiral acetal22 or aminal.23 Dess–Martin oxidation of
hydroxyketone 3 to the corresponding aldehyde followed by
condensation with either (R,R)-hydrobenzoin (25) or (R,R)-
N,N′-dimethylcyclohexane-1,2-diamine (26) gave acetal 27 and
aminal 28, respectively (Scheme 7).
We proceeded to examine oxetane formation from carbonyl
olefins mediated by acids.19 Common reagents such as TiCl4,
BF3·OEt2, Me2AlCl and other aluminum based Lewis acids rou-
tinely afforded unreacted starting material or complex mixtures.
Neither oxetane products nor Prins-type intermediates were ob-
served. Presumably, the sterically demanding environment at
the carbonyl group hampered nucleophilic attack by the olefin.
We also examined Brønsted acids to promote cyclization. For
instance, treatment of 7 with anhydrous HCl in 1,4-dioxane re-
turned starting material, even at elevated temperatures (70 °C).
Addition of triflic acid at 0 °C to a solution of 7 in CH2Cl2 gave
a complex mixture. In light of these unsuccessful approaches,
we turned our attention to the oxidative cyclization strategy.
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Scheme 7. Synthesis of Acetal 27 and Aminal 28a
Towards the Diels–Alder Reaction. Construction of the
remaining two carbocycles was addressed. Conversion of the
primary alcohol in 3 to the homologated aldehyde provides a
handle for the introduction of various dienophiles. O-Mesyla-
tion followed by treatment with KCN in hot DMSO gave neo-
pentylic nitrile 20 in 84% yield (Scheme 6).20
aReagents and conditions: (a) Dess–Martin periodinane (DMP),
t-BuOH, CH2Cl2, RT; (b) (R,R)-hydrobenzoin (25), p-TsOH·H2O
(10 mol%), PhMe, 50 °C, 66% (from 3); (c) (R,R)-N,N′-dimethyl-
cyclohexane-1,2-diamine (26), PhH, 70 °C, 80% (from 3).
Scheme 6. Elaboration of the Tricyclooctane Corea
Table 1. Studies of Addition to Various Ketones
entry
substrate
conditions
dr
1
2
21, THF, 0 °C to RT
21, THF, –45 °C to RT
1:1.2a
27
aReagents and conditions: (a) MsCl, Et3N, CH2Cl2, 0 °C; (b)
KCN, DMSO, 80 °C, 84% (2 steps); (c) (E)-tributyl(penta-2,4-
dien-2-yl)stannane, n-BuLi (penta-2,4-dien-2-yllithium (21)),
THF, –78 °C, then 20, LaCl3·2LiCl, THF, –78 °C, 68% (dr =
1:1.2); (d) Et3SiCl, imidazole, DMF, 80 °C, 81%; (e) DIBAL-H,
PhMe, –78 to 0 °C, 89%.
b
–
28
3
6:1a,c
, THF,
0 °C to RT
b
We then examined introduction of the 1,3-diene for the tar-
geted Diels–Alder cycloaddition reaction. However, ketone 20
proved inert towards addition by dienyllithium 21, presumably
as a consequence of competitive enolization. Knochel and co-
workers have reported the use of soluble lanthanum salts to en-
able addition of Grignard reagents to sterically hindered ke-
tones.21 In our hands, ketone 20 reacted with dienyllithium 21
in the presence of LaCl3·2LiCl to furnish tertiary alcohol as a
separable mixture of diastereomers (68%, dr = 1:1.2), from
which 22 was isolated in 28% yield. Structural analysis of ke-
tonitrile 20 revealed that the methyl group, which breaks the
mirror symmetry of the carbon framework, is considerably dis-
tanced to the carbonyl group, and thus it imposes low stereoin-
duction on the nucleophilic addition. Extensive investigations
4
5
, ZnMe2,
(S,S)-salen, PhMe, RT
–
29
3
21, (+)-sparteine, THF,
–45 to –20 °C
1:1.2a
6
7
21, THF–Et3N (1:1)
1:1.2a
1:1.2a
21, THF–TMEDA (4:3)
aDetermined by 1H NMR analysis of the crude mixture. bNo con-
version of the starting material. cThe diastereomers were not as-
signed.
Addition of dienyllithium 21 to 27 (entry 1) resulted in the
same diastereoselectivity as observed for the addition to 20 (dr
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= 1:1.2). Under the same reaction conditions, aminal 28 (entry
Page 4 of 8
perature, we observed concomitant formation of the Diels–Al-
der adduct.33 Thus, a convenient one-pot procedure involving in
situ oxidation and cycloaddition was carried out. Substitution
of the sulfone using various methyl cuprates posed a challenge,
owing to competing 1,2-addition and allylic oxidation. The use
of Me2CuLi in thoroughly degassed Et2O was essential in a pro-
cedure that provides dienone 32 as a single diastereomer in 52%
overall yield from 31. No isomerization to the conjugated 1,3-
diene was observed under the reaction conditions. Subsequent
chemoselective reduction of the more electron-rich and acces-
sible carbon-carbon double bond was achieved with Adams’
catalyst under an atmosphere of hydrogen34 to give enone 33 in
90% yield.
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2
3
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5
6
7
8
2) did not furnish adduct. The use of other transmetalation
protocols or dienylmetal species (Mg, Ce) also led to full recov-
ery of the starting material. In contrast, isopropenylmagnesium
bromide added cleanly to ketone 28 (entry 3) and gave the cor-
responding tertiary alcohol as a mixture of diastereomers in a
ratio of 6:1 as determined by 1H NMR analysis of the unpurified
product. Despite the improved selectivity, conversion of the
1,1-disubstituted olefin to diene 24 would require multiple
steps, reducing the efficiency of the route.
9
A broader study on stereoselective additions to ketones 3
and 29 was undertaken that included examination of the influ-
ence of chiral ligands/additives. Cozzi has documented stere-
oselective alkynylation of hindered, enolizable ketones employ-
ing (S,S)-salen-Zn complexes to give tertiary alcohols in up to
81% ee.24 Unfortunately, under similar conditions, starting ma-
terial 29 was recovered unchanged (entry 4). Sparteine holds a
prominent position in stereoselective reactions of organolithium
reagents.25 Yet, the use of (–)-sparteine and diene 21 (1:1) in the
addition to 3 once again did not improve the diastereoselectivity
(entry 5). Solvents other than THF, such as Et2O and PhMe,
were not suitable because of the insolubility of the La(III) salts.
It has been noted that amine cosolvents can dramatically affect
the distereoselectivity of organolithium additions to ketones.26
However, addition of dienyllithium 21 to ketone 3 in mixtures
of THF and amine bases such as Et3N (entry 6) or TMEDA (en-
try 7) gave the same selectivity as observed before (dr = 1:1.2).
In summary, all attempts to improve facial selectivity for the
addition of dienyllithium 21 to 3 and its derivatives were un-
fruitful. As such, tertiary alcohol 22 was further elaborated.
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Scheme 8. [4+2] Cycloaddition Strategies and Dienophile
Analysis
The manipulation of the tertiary hydroxy group proved
tricky in a number of respects for 22 as well as closely related
structures. For example, attempts to acylate routinely resulted
in elimination to give a triene. We also observed that the tertiary
hydroxyl in 22 had a proclivity to form a cyclic imidate by ad-
dition to the nitrile, rendering introduction of a variety of pro-
tecting groups difficult. Finally, the reaction of 22 with
Et3SiCl/imidazole at 80 °C for 3.5 days furnished 23 in 81%
yield.27 Subsequent reduction of the nitrile group with DIBAL-
H afforded aldehyde 24 (89%).28
The next steps in the synthesis route were aimed at installa-
tion of the quaternary center that incorporates an ester. The in-
herent reactivity of α,β-unsaturated ketone 33 suggested conju-
gate addition of a methoxycarbonyl proxy. The neighboring si-
lyl ether and tetrasubstituted carbon center create a sterically
demanding periphery that complicated reactivity towards 1,4-
addition. For example, no reaction was observed when enone
33 was treated with higher-order vinyl cuprate
Access to the Pentacyclic Framework. In principle, intra-
molecular [4+2] cycloaddition reaction involving a trisubsti-
tuted, olefinic dienophile would provide direct access to the
completed decalyl subunit (Scheme 8). However, initial inves-
tigations deemed such a route untenable because of high tem-
peratures required for cycloaddition (240 °C), which resulted in
product mixtures. We reasoned that incorporation of an acety-
lenic dienophile could overcome the sluggish reactivity im-
posed by the 1,1-disubstitution of the unactivated diene.29,30 As
shown in Scheme 8, attempted cycloaddition of the correspond-
ing 1-propynyl ketone gave only unsatisfactory results. This led
us to consider alternative terminal groups at the ynone, which
would satisfy two key criteria: sufficient activation to render ef-
ficient cycloaddition and its function as a placeholder for a me-
thyl group. To this end, sulfonyl ynones are highly reactive in
cycloaddition reactions31 and the resulting sulfonyl enones
readily undergo addition-elimination with alkyl cuprates.32
((C2H3)2Cu(CN)Li2)35
or
an
aluminum
alkynylide
(Et2AlCCTMS).36 Nagata’s reagent (Et2AlCN) has been com-
monly used in the hydrocyanation of hindered enones.37 In our
hands, desired ketonitrile was obtained as a separable mixture
of diastereomers at the newly installed quaternary center (7.8:1
1
as determined by H NMR of the unpurified product) from
which 34 was isolated in 76% yield.
With nitrile 34 in hand, different pathways to access methyl
ester 38 were explored. Alkaline conditions (KOH) resulted in
loss of cyanide to return enone 33. Ghaffar and Parkins previ-
Addition of aldehyde 24 to lithiated alkyne 30 furnished
secondary alcohol 31 in 93% yield (Scheme 9). In the next step,
during the subsequent oxidation of 31 with DMP at room tem-
ously reported
the hydration of nitriles using
[PtH(PMe2OH)((PMe2O)2H)] (35),38 which exhibits high
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Scheme 9. Construction of the Pentacyclic Framework of (–)-Mitrephorone Aa
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aReagents and conditions: (a) ethynyl p-tolyl sulfone (30), LDA, THF, –78 °C, then 24, 93% (dr = 2:1, inconsequential); (b) DMP,
t-BuOH, RT; (c) Me2CuLi, Et2O, 0 °C, 52% (2 steps), dr > 20:1; (d) PtO2 (10 mol%), H2 (1 atm), EtOH, RT, 90%; (e) Et2AlCN,
PhMe, 0 °C, 76% 34, 10% Cquat-epi-34; (f) Ghaffar–Parkins catalyst (35, 50 mol%), EtOH–H2O (4:1), 80 °C, then KOH, 170 °C,
79%; (g) TMSCHN2, PhH–MeOH (4:1), 0 °C to RT, 92%; (h) SeO2, 1,4-dioxane, 100 °C, 87%. bThermal ellipsoids displayed at 50%
probability level. The triethylsilyl group on the tertiary alcohol was omitted for clarity.
functional group tolerance and was shown to hydrolyze even
hindered nitriles.39 To our satisfaction, subjecting ketonitrile 34
to substoichiometric quantities of the homogenous Platinum
catalyst in aqueous ethanol at 80 °C cleanly afforded the corre-
sponding primary amide 36 (>95% yield).
trephorone family. Our observation that 2a undergoes facile ox-
idative ring closure using iodine(III) suggests that biooxidation
of a hydroxy diosphenol may be operative.
Scheme 10. Completion of the Total Synthesisa
Unfortunately, all initial attempts to convert the amide into
the carboxylate failed. Although O-methylation using Meer-
wein’s salt afforded the intermediate methyl imidate, it was re-
luctant to undergo hydrolysis to the targeted methyl ester.40 In
addition, various nitrosation methods (NOBF4,41 t-BuONO42)
resulted only in decomposition of starting material. In contrast,
subjecting amide 36 to KOH at 170 °C cleanly furnished car-
boxylic acid 37.43 This observation led us to the development of
a one-pot hydration/hydrolysis procedure, affording 37 in 79%
yield from 34. Subsequent esterification with TMSCHN2 ulti-
mately provided methyl ester 38 in 92% yield.
Synthesis of (–)-Mitrephorone A. In setting the stage for
oxidative cyclization to access the oxetane, the 1,2-diketone
was installed next. Riley oxidation of ketone 38 using SeO2 ef-
ficiently furnished α-diketone 39 in 87% yield.44,45 Deprotection
of the hindered silyl ether in 39 with tris(dimethylamino)sul-
fonium difluorotrimethylsilicate (TASF) cleanly gave tertiary
alcohol 2a as the tautomeric enol ketone in 82%.46 Oxetane for-
mation was envisioned to involve conjugate addition of the hy-
droxy group to the enone followed by oxidation. In the context
of previously reported iodine(III)-mediated oxidative cycliza-
tions,47 we reasoned that ligand exchange at ArIX2 by enol in
2a could trigger the targeted 4-exo-trig cyclization.48 In prac-
tice, one-pot deprotection of silyl ether 39 (TASF) and subse-
quent reaction with Koser’s reagent (PhI(OH)OTs) proved suc-
cessful and completed the total synthesis of (–)-mitrephorone A
(Scheme 10). The spectroscopic data (1H NMR, 13C NMR, IR,
[α]D) and high-resolution mass collected for 1 were in full
agreement with that reported for the natural product.
aReagents and conditions: (a) TASF, H2O, DMF, 0 °C, then
PhI(OH)OTs, 65%.
Conclusion
In conclusion, we have reported the first and enantioselec-
tive synthesis of (–)-mitrephorone A. The intramolecular Diels–
Alder reaction of 5-vinyl-1,3-cyclohexadiene intermediate 11
enabled rapid construction of the characteristic tricy-
clo[3.2.1.02,7]octane core. The use of a highly reactive β-sul-
fonyl alkynone en route to dienone 32 efficiently furnished the
pentacyclic carbon framework of the natural product. A pivotal
feature of this synthesis is the oxidative cyclization with hyper-
valent iodine to generate an embedded oxetane. In a broader
sense, formation of four-membered oxacycles from the corre-
sponding hydroxy diosphenols has no precedence and thus ex-
Along with 1, Oberlies and coworkers isolated (–)-mi-
trephorone B (2b), which prominently features a diosphenol
and lacks the tertiary hydroxy group present in 2a. No biosyn-
thetic pathways have been proposed for any member of the mi-
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Sisido, K. Bull. Chem. Soc. Jpn. 1979, 52, 1506. (f) Loeliger, P.; Mayer, H.
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Supporting Information. The Supporting Information is available
free of charge on the ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
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* E-mail: erickm.carreira@org.chem.ethz.ch
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
ETH Zꢀrich and the Swiss National Science Foundation
(205320_169135/1) are gratefully acknowledged for financial sup-
port. Sven Papidocha is kindly acknowledged for synthetic studies
towards 3.
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(48) Recent commentary on the mechanism involving ketones and I(III)
56, 2599. As the tertiary alcohol in 2a is highly hindered, a mechanism pro-
ceeding via putative intermediate 40 is likely over an alternative involving
alcohol activation.
reagents invoke the formation of an O–I(III) adduct involving the enol tau-
tomer of ketones, see: Arava, S.; Kumar, J. N.; Maksymenko, S.; Iron, M.
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