Synthesis of Scyphostatin Analogues through Hypervalent Iodine-Mediated Phenol Dearomatization

Article abstract of DOI:10.1021/acs.joc.7b02366

A concise synthesis of two scyphostatin analogues is achieved from readily available ortho-substituted phenols. Key features include an asymmetric and biomimetic hydroxylative phenol dearomatization (HPD) reaction promoted by a chiral salen-type bis(λ⁵-iodane) reagent, followed by an in situ regio- and diastereocontrolled epoxidation.

Full text of DOI:10.1021/acs.joc.7b02366

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Article
Synthesis of Scyphostatin Analogues through
Hypervalent Iodine-mediated Phenol Dearomatization
Mourad El Assal, Philippe A. Peixoto, Romain Coffinier, Tony Garnier, Denis Deffieux,
Karinne Miqueu, Jean-Marc Sotiropoulos, Laurent Pouységu, and Stephane Quideau
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02366 • Publication Date (Web): 09 Oct 2017
Downloaded from http://pubs.acs.org on October 9, 2017
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The Journal of Organic Chemistry
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Synthesis of Scyphostatin Analogues through Hypervalent Iodine-
mediated Phenol Dearomatization
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Mourad El Assal,† Philippe A. Peixoto,† Romain Coffinier,†,§ Tony Garnier,†,|| Denis Deffieux,† Karinne
Miqueu,‡ JeanꢀMarc Sotiropoulos,‡ Laurent Pouységu,*,† and Stéphane Quideau*,†
†
Univ. Bordeaux, ISM (CNRS–UMR 5255), 351 cours de la Libération, 33405 Talence Cedex, France
‡
CNRS/UNIV PAU & PAYS ADOUR, Institut des Sciences Analytiques et de PhysicoꢀChimie pour l’Environnement et les
Matériaux (IPREM, UMR 5254), Hélioparc, 2 avenue du Président Angot, 64053 Pau Cedex 09, France
Supporting Information Placeholder
ABSTRACT: A concise synthesis of two scyphostatin analogues is achieved from readily available orthoꢀsubstituted phenols. Key
features include an asymmetric and biomimetic hydroxylative phenol dearomatization (HPD) reaction promoted by a chiral Salenꢀ
type bis(λ5ꢀiodane) reagent, followed by an in situ regioꢀ and diastereocontrolled epoxidation.
INTRODUCTION
Scheme 1. (+)ꢀscyphostatin (1), (+)ꢀepoxysorbicillinol (2),
and proposed biosynthetic elaboration of their epoxyꢀ
cyclohexenone motif 5
(+)ꢀScyphostatin (1) was isolated in 1997 from a mycelial
extract of Trichopeziza mollissima (Lasch) Fuckel [syn.:
Dasyscyphus mollisimus (Lasch) Dennis] that belongs to the
Hyaloscyphaceae family.1 This fungal polyketide exhibits a
potent (IC50 = 1.0 ꢀM) and selective inhibitory activity
against neutral sphingomyelinase (NꢀSMase),2 a key enzyme
of the sphingomyelin metabolism and related ceramide proꢀ
duction, which is associated to inter alia inflammatory proꢀ
cesses, cell apoptosis and neurodegenerative disorders.3
Hence, (+)ꢀscyphostatin (1) has attracted attention as a total
synthesis target,4 and has fuelled numerous methodological
developments aiming at the elaboration of its lipophilic sideꢀ
chain5 and highly functionalized polar core.6,7 Such studies
gave access to some analogues of 1 as novel NꢀSMase inꢀ
hibitor candidates.6a,b,d,8
then be epoxidized in a regioꢀ and diastereoselective manner
to furnish typeꢀ5 epoxyꢀcyclohexenones (Scheme 1).
The highly oxygenated cyclohexane ring of the scyphosꢀ
So far, approximately half of the synthesis studies toꢀ
wards the polar head of 1 and analogues thereof4b,e,6,8b have
relied on oxygenative phenol dearomatization (OPD) proꢀ
cesses.10 Moreover, almost all these OPD reactions were
promoted by hypervalent organoiodine reagents (i.e.,
iodanes), and they were all based on substrateꢀcontrolled
approaches to reach the desired stereochemistry of the orthoꢀ
quinol intermediate and final epoxyꢀcyclohexenone
unit.4b,e,6,8b However, nonꢀracemic syntheses of orthoꢀ
quinols11,12 are also possible through reagentꢀcontrolled
tactics, notably using chiral iodanes.13 Herein we describe
our own synthesis efforts towards the polar head of scyphosꢀ
tatin
polar
head,
i.e.,
a
6ꢀalkylꢀ4,5ꢀepoxyꢀ6ꢀ
hydroxycyclohexꢀ2ꢀenꢀ1ꢀone moiety, is also found in (+)ꢀ
epoxysorbicillinol (2) (Scheme 1). These polyketides 1 and 2
are the only two natural products we are aware of that disꢀ
play such an epoxyꢀcyclohexenone motif 5, which can derive
from the hydroxylative phenol dearomatization (HPD) of an
orthoꢀsubstituted phenol 3 into the corresponding orthoꢀ
quinol 4 (Scheme 1). In fact, such a transformation has reꢀ
cently proven to be operational in the biosynthesis of 2 with
the dearomatization of sorbicillin into the orthoꢀquinol sorbꢀ
icillinol (not shown).9 Such orthoꢀquinols of type 4 would
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tatin (1), following two different iodaneꢀmediated OPD
approaches, which are based on i) substrateꢀ
furnished spiroketal 7 in a nearly quantitative yield with
1
2
3
4
5
6
7
8
a
excellent levels of both purity and diastereomeric ratio (dr) ≥
95:5 (1H NMR analysis) in favor of the (R,R)ꢀ7 spiroketal.12b
Unfortunately, this remarkable diastereocontrol was tarꢀ
nished by the rapid [4+2] dimerization of 7 into the known
cyclodimer 812b,14 (Scheme 3). The bromine atom thus did
not fulfill its role of blocking the cyclodimerization event,
which was clearly observed during the acquisition of 13C
NMR data. No improvement was obtained with the bulkier
iodine atom, as dimerization went even faster and was alꢀ
stereocontrolled access to chiral orthoꢀquinone monoketals
in a nonꢀracemic form using the achiral λ3ꢀiodane (diaceꢀ
toxy)iodosylbenzene PhI(OAc)2,12b and ii)
a reagentꢀ
stereocontrolled (and biomimetic) HPD reaction promoted
by a homeꢀmade chiral λ5ꢀiodane.12e
RESULTS AND DISCUSSION
9
1
Our retrosynthetic analysis of the polar head of (+)ꢀ
scyphostatin (1), i.e., the (4S,5S,6S)ꢀ4,5ꢀepoxyꢀ6ꢀhydroxyꢀ6ꢀ
[(2S)ꢀ2ꢀaminoꢀ3ꢀhydroxypropyl]cyclohexꢀ2ꢀenꢀ1ꢀone (6), is
outlined in Scheme 2. We first envisioned a substrateꢀ
controlled approach based on the utilization of our orthoꢀ
quinone spiroketal (R,R)ꢀ712b as the key chiral synthon on
which to perform the required functionalization steps (path
a).6c,12a,b The spiroketal 7 can be prepared by a PhI(OAc)2ꢀ
mediated oxidative dearomatization of phenol (R)ꢀ3a, which
bears a chiral proꢀspiroketal ethanol unit Oꢀtethered to the
ortho position.12a,b The presence of a bromine atom at the
para position is to prevent or at least retard the selfꢀ
dimerization of the dearomatized species through [4+2]
cycloaddition events.11 This choice of a bromine atom was
inspired by the work of Taylor, who successfully used the
orthoꢀquinone monoketal 4ꢀbromoꢀ6,6ꢀdimethoxycyclohexaꢀ
2,4ꢀdienone (not shown) for the synthesis of scyphostatin
analogues.6c Looking for a more straightforward access to 6,
we also considered the preparation of the orthoꢀquinol inꢀ
termediate (S,S)ꢀ4 through an enantioselective (and biomiꢀ
metic) HPD conversion of phenol (S)ꢀ3b using one of our
chiral λ5ꢀiodane reagents (path b).12e The added advantage of
the orthoꢀquinol (S,S)ꢀ4 is that its chiral allylic alcohol moieꢀ
ty would be ideally suited for directing the regioꢀ and stereoꢀ
chemistry of the final epoxidation step.
ready observed during the H NMR analysis. This analysis
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also indicated a slightly lower diastereocontrol (dr =
90:10).12a Therefore, spiroketal (R,R)ꢀ7 was systematically
freshly prepared and purified by silica gel column chromaꢀ
tography (easily reproducible 40ꢀ50% yields) to discard any
[4+2] cyclodimer contaminant.
Scheme 3. Synthesis of spiroketal (R,R)ꢀ7 and Xꢀray strucꢀ
ture of its [4+2]ꢀcyclodimer 8
The capacity of this 4ꢀbrominated spiroketal (R,R)ꢀ7 to inꢀ
duce asymmetry during nucleophilic 1,2ꢀaddition was then
first evaluated with commercially available Grignard reaꢀ
gents (Scheme 4). Methylmagnesium bromide (MeMgBr, 2
equiv) furnished the expected tertiary alcohol 9a in 74%
yield with an excellent stereoselectivity, as only one diaꢀ
Scheme 2. Retrosynthetic analysis of the polar head of (+)ꢀ
scyphostatin (1)
1
stereomer (dr ≥ 95:5) was observed by H NMR analysis.
The structure and stereochemistry of the (S,R,R)ꢀ9a was
established unambiguously by 2D NMR experiments, includꢀ
ing a diagnostic NOESY correlation between the newly
introduced methyl group and the H3a signal (see the Supportꢀ
ing Information). A high level of diastereocontrol was also
reached using phenylmagnesium bromide (PhMgBr), as the
1,2ꢀadduct (R,R,R)ꢀ9b was also isolated with a dr ≥ 95:5 (1H
NMR), albeit in a lower yield of 54%. A better yield (88%)
with a slightly lower selectivity (dr = 90:10) was obtained
for the major 1,2ꢀadduct (R,R,R)ꢀ9c in the case of the reacꢀ
tion of 7 with ethynylmagnesium bromide. In contrast, a
poor selectivity (dr = 58:42) and a moderate yield were noꢀ
ticed when using allylmagnesium bromide to get compound
9d. Such contrasting results may be due to the facts that i)
the allylic carbon nucleophile of the Grignard reagent is not
bonded tightly enough to the Mg chelating center, hence
weakening any stereodiscriminating interaction with the
spiroketalic tertꢀbutyl group (vide infra), and ii) the forꢀ
mation of 9d may compete with that of degradation products
possibly derived from anionic oxyꢀCope rearrangement
events. Surprisingly, the addition of vinylmagnesium broꢀ
mide to spiroketal 7 afforded the remarkably stable 1,6ꢀ
adduct 10 as the sole product, which was isolated in 71%
yield with a dr = 90:10 (1H NMR). The stereochemistry of
the major diastereomer (R,R,R)ꢀ10 was determined by the
Substrate-controlled OPD approach (path a). Phenol
(R)ꢀ3a was prepared in an overall yield of 88% through 5
steps encompassing a Williamson reaction between 5ꢀ
bromoꢀ2ꢀbenzyloxyphenol and the enantiomerically enriched
2ꢀtertꢀbutyloxirane generated by using the Jacobsen’s methꢀ
od.12b Next, the dearomative spirocyclization of (R)ꢀ3a was
achieved upon treatment with PhI(OAc)2 (1.0 equiv) in
2,2,2ꢀtrifluoroethanol (ca. 0.04 M) at –35 °C, followed by
quenching of the released acetic acid with powdered Naꢀ
HCO3 at the same low temperature, without addition of any
water (Scheme 3). A simple filtration–evaporation procedure
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observation of a correlation between the H10 signal and that Information). Indeed, the Lewis structure of isomer-3 shows
1
2
3
4
5
6
7
8
of the spiroketalic tBu group (see the Supporting Inforꢀ
mation). Addition of MgBr2 (2.0 equiv) to the reaction mixꢀ
ture enabled us to detect by 1H NMR analysis the formation
of the 1,2ꢀadduct, but in an unsatisfactory 1:3 mixture with
the 1,6ꢀadduct. The use of vinyl lithium, which was generatꢀ
ed through lithiumꢀbromine exchange on vinyl bromide by
reaction with tBuLi, at a temperature below –100 °C led to
the isolation of the 1,2ꢀadduct in a moderate yield (46%)
with a disappointing selectivity (dr = 65:35), together with
the surprising formation of some 9c (16%). A competing
vinylcarbene rearrangement into an acetylide anion may be
invoked to explain the formation of 9c. In summary, this
brief study demonstrated the potential of this twoꢀstep seꢀ
quence in which the chiral tether of phenol 3a showed its
efficacy in inducing asymmetry not only during the
PhI(OAc)2ꢀmediated spiroketalization, but also during the
1,2ꢀaddition of some Grignard reagents.
stabilizing interactions of the oxygen atoms O and O1 with
the Grignard moiety. This stabilization involves i) significant
donorꢀacceptor interactions between the oxygen lone pairs
and the vacant Mg orbital [i.e., 29.9 (O) and 16.9 (O1)
kcal.molꢀ1], and ii) a negative hyperconjugation of these
oxygen lone pairs with the σ*(Mg–Me) and/or σ*(Mg–Br)
antibonding orbitals [i.e., 11.3 and 10.4 kcal.molꢀ1, respecꢀ
tively] (see Figure S8 in the Supporting Information).
Me
9
Br
Me
Mg
Br
dMg–O = 2.25 Å
Mg
dMg–O = 2.23 Å
dMg–O2 = 2.20 Å
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O
O
O
O
dMg–O2 = 2.22 Å
O2
O2
O2
O2
tBu
O1
O1
O1
O1
tBu
isomer-1: +1.25 kcal.mol-1
(pro-S intermediate)
isomer-2: +2.08 kcal.mol-1
(pro-R intermediate)
tBu
tBu
Scheme 4. Grignard additions to spiroketal (R,R)ꢀ7
dMg–O = 2.16 Å
O2
O2
dMg–O = 2.21 Å
dMg–O1 = 2.20 Å
dMg–O1 = 2.28 Å
O1
O1
Br
O
O
Me
Mg
Me
Mg
Br
isomer-3: 0 kcal.mol-1
(pro-S intermediate)
isomer-4: +1.09 kcal.mol-1
(pro-R intermediate)
Figure 1. DFT structures and relative stability (Gibbs enerꢀ
gies in kcal.molꢀ1) of the isomers corresponding to the 1,2ꢀ
addition of MeMgBr onto (R,R)ꢀ7
Scheme 5. Conversion of 9a into 5a through an epoxidaꢀ
tion/debromination/ketal cleavage sequence
In these reactions, the Grignard reagent would attack the
ketone of 7 from its less hindered face, i.e., the face that is
not occupied by the tertꢀbutyl group on the spiroketal moieꢀ
ty. This facial discrimination might be amplified by chelation
of the Mg cation with the spiroketal oxygen farther away
from the bulky tertꢀbutyl group. This hypothesis was corrobꢀ
orated by DFT calculations (wB97xD/6ꢀ31G**,15 see the
Supporting Information), which were performed on the 1,2ꢀ
addition of MeMgBr onto (R,R)ꢀ7. The study of the potential
energy surface (PES) led to the localization of four isomers
as local minima. Two proꢀS (isomersꢀ1 and ꢀ3) and two proꢀ
R (isomersꢀ2 and ꢀ4) intermediates were identified according
to the oxygen atoms involved in the Mgꢀcentered chelating
system (i.e., O⋅⋅⋅Mg⋅⋅⋅O1 versus O⋅⋅⋅Mg⋅⋅⋅O2) and the resultꢀ
ing orientation of the MeMgBr reagent (Figure 1). These
theoretical results showed that isomers involving the spiroꢀ
cyclic O2 atom (i.e., isomersꢀ1 and ꢀ2) are slightly higher in
energy than those displaying a Mg chelation with the spiroꢀ
cyclic O1 atom (i.e., isomersꢀ3 and ꢀ4). Hence, the most
favored proꢀS structure shows that the Mg atom is in interacꢀ
Epoxidation of (S,R,R)ꢀ9a was next considered, and we
thus anticipated to draw benefit from its chiral (S) allylic
alcohol moiety to impose the desired regiochemistry and
diastereoselectivity.16 Indeed, upon treatment with mꢀCPBA
in CHCl3 at room temperature, and in the presence of K2CO3
to quench the released mꢀchlorobenzoic acid, 9a was sucꢀ
cessfully converted into the epoxyꢀalcohol 11, which was
isolated as the sole diastereomer in a quantitative yield
(Scheme 5). The expected cis relationship between the hyꢀ
droxyl group and the oxirane ring of 11 was confirmed
through a NOESY correlation between the H7 signal and that
of the methyl group (see the Supporting Information). Of
particular note is that direct epoxidation of spiroketal 7 carꢀ
ried out under conditions previously described either for the
tion with the sp2 oxygen atom of the carbonyl group (dMg–O
=
2.16 Å) and the spirocyclic oxygen atom O1 (dMg–O1 = 2.28
Å), which is in opposite position to the bulky tertꢀbutyl
group (Figure 1). These data are in accordance with our
experimental observation on (S,R,R)ꢀ9a as the sole isolated
product. This bonding situation was also highlighted by
natural bond orbital (NBO) analysis (see the Supporting
synthesis
of
scyphostatin
analogues6c
(i.e.,
tBuOOH/1,3,4,6,7,8ꢀhexahydroꢀ2Hꢀpyrimido[1,2ꢀ
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a]pyrimidine in CH2Cl2 at 0 °C) or for the epoxidation of
was here not fully assigned because of the detection in NMR
electronꢀdeficient olefins17 (i.e., (nBu4N)2S2O8/H2O2/NaOH
in CH3CN at rt), gave cyclodimer 8 and no epoxidized mateꢀ
rial.
spectra of diastereomeric mixtures due to the THP protective
group. In summary, the complete sequence, starting from the
dearomative spiroketalization of phenol 3a into 7, gave
access to the advanced intermediate 19 in an overall yield of
about 10% at best. Moreover, our inability to scaleꢀup the
preparation of 17 and to improve the epoxidation step effiꢀ
ciency prevented us from generating substantial amounts of
19. Nevertheless, the final deprotection step could be tested
by treating 19 under acidic conditions in the aim of concomiꢀ
tantly cleaving the THP group and the spiroketal unit. Unforꢀ
tunately, treatment of 19 with the MKꢀ10 clay (vide supra)
led to a complex and intractable mixture. Complex mixtures
were also obtained when 19 was treated with either Amberꢀ
lite® IR120ꢀH+ resin in THF/H2O (20:1), HꢀMordenite zeoꢀ
lite in toluene/H2O (15:1),20a or PdCl2(CH3CN)2 in aceꢀ
tone.20b Although the use of pꢀTsOH•H2O in acetone12b also
led to full degradation of 19, that of pꢀTsOH•H2O in the
presence of pyridinium pꢀtoluenesulfonate (PPTS)20c in
acetone/H2O (8:1) at room temperature for 2 days enabled
the conversion of 19 into a more polar compound. But
instead of 5b, we disappointingly identified a primary
alcohol resulting from the cleavage of the THP group, but
with the spiroketal moiety still in place. All attempts to
subject this compound to either MKꢀ10 clay, Amberlite®
IR120ꢀH+, or formic acid dried over anhydrous copper sulꢀ
fate20d were to no avail. In view of these additional
difficulties, we decided to move away from this subtrateꢀ
controlled approach and to focus our efforts on the
implementation of reagentꢀcontrolled asymmetric reactions
by taking advantage of our recently developed chiral
iodanes.12eꢀg
1
2
3
4
5
6
7
8
The next step was the reductive debromination of 11 upon
treatment with Bu3SnH and a catalytic amount of AIBN in
refluxing THF. These conditions6c furnished the desired
compound 12, but in a 1:1 mixture with the bromohydrin 13.
This undesired concomitant oxirane ringꢀopening was cirꢀ
cumvented by treating the 1:1 mixture with K2CO3 in MeOH
at room temperature to promote an intramolecular Williamꢀ
son reaction, which thus enabled the isolation of the adꢀ
vanced intermediate 12 in a 65% overall yield over the two
steps (Scheme 5). Finally, removal of the spiroketalic chiral
auxiliary was successfully achieved using Montmorillonite
Kꢀ10 (MKꢀ10)6c in CH2Cl2 at room temperature to afford the
epoxyꢀcyclohexenone 5a in a ca. 1:1 mixture with diol 14.
Unfortunately, we were unable to separate 5a and 14 effiꢀ
ciently. Nevertheless, a yield of 54% of 5a as the sole diaꢀ
9
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1
stereomer could be estimated by H NMR analysis (see the
Supporting Information). Interestingly, as previously obꢀ
served by Taylor and coꢀworkers using their dimethyl ketal
analogue of 11,6c reductive debromination prior to ketal
cleavage was crucial. Indeed, the spiroketal moiety of the
vinyl bromide 11 survived several acidic conditions, such as
MKꢀ10 in CH2Cl2, Amberlyst® in THF, pꢀTsOH•H2O in
acetone, and 40% aq. HF in CH3CN/CH2Cl2 (1:3), while the
use of stronger acidic media, such as 1M aq.
HCl/MeOH/THF (1:1:4) and 2M aq. HCl/THF (1:1) led in
nearly quantitative yields (95 and 90%, respectively) to a
1,2ꢀdiol that resulted from the oxirane opening, but with the
spiroketal moiety still intact (see the Supporting Inforꢀ
mation).
Scheme 6. Substrateꢀcontrolled synthesis of the polar head
of (+)ꢀscyphostatin (1)
Therefore, we were pleased to validate this short sequence
of stereoselective transformations from our spiroketal (R,R)ꢀ
7 to access an epoxyꢀcyclohexenone of type 5, and we were
then eager to try it with a more functionalized and scyphosꢀ
tatinꢀrelated 2ꢀaminoꢀ3ꢀhydroxypropylꢀtype nucleophile.
This synthon was prepared in gram scale, following a known
threeꢀstep procedure,18a,b starting from commercially availaꢀ
ble NꢀBoc Lꢀserine methyl ester (15). The resulting NꢀBoc
chlorotetrahydropyranyl (THP) ether 16 was isolated in an
overall yield of 70% (Scheme 6). Its acid sensitive THP
protective group was selected to be easily cleaved at a late
stage along with the spiroketal moiety of 7. Next, a combinaꢀ
tion of nꢀbutyllithium (nꢀBuLi, 1.0 equiv) and lithium naphꢀ
thalenide (LiNp, 2.0 equiv)18 at –78 °C in THF was used to
generate in situ the dianion 16’.18a,b The resulting mixture
was treated dropwise with freshly prepared spiroketal (R,R)ꢀ
7 at the same low temperature, and the desired 1,2ꢀadduct 17
was isolated as a sole product in 33% yield (Scheme 6). This
moderate yield was unlikely due to technical issues related to
the handling of 16’,19 but rather to numerous sideꢀreactions
and resulting (not isolated) byꢀproducts. This somewhat
cumbersome reaction could nevertheless be performed using
200ꢀ300 mg of 7 to give access to 20ꢀ30 mg of the spiroketal
17. This highly functionalized intermediate was then sucꢀ
cessfully epoxidized upon treatment with mꢀCPBA in the
presence of K2CO3 (vide supra) in CHCl3 at room temperaꢀ
ture for 7 days, and compound 18 was isolated in 41% yield.
Reductive debromination of 18 into 19 was cleanly achieved
in a quantitative yield, after removing tin salts by trituration
with Et2O. The stereochemistry of compounds 17, 18 and 19
Reagent-controlled OPD approach (path b). This invesꢀ
tigation began with the synthesis of phenols of type 3b (see
Scheme 2) featuring the requisite (2S)ꢀ2ꢀaminoꢀ3ꢀ
hydroxypropyl sideꢀchain at the ortho position. We relied on
the known preparation of the NꢀFmoc protected iodoꢀ
derivative of
accessible in 3 steps (40% overall yield) from commercially
available ꢀserine (20). A gramꢀscale Negishiꢀtype coupling
L
ꢀserine tertꢀbutyl ester 21,21 which was readily
L
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Scheme 8. λ3ꢀIodaneꢀmediated dearomative spirolactonizaꢀ
reaction between the in situ generated 21ꢀderived organozinc
1
2
3
4
5
6
7
8
species and the OꢀMOM protected 2ꢀiodophenol 22 gave
access to the orthoꢀsubstituted adduct 23 in a very good yield
of 83% (Scheme 7). Next, both MOM ether and tBu ester
functions of 23 were successfully deprotected in one step
using acidic conditions (i.e., 20 equiv of trifluoroacetic acid)
in the presence of triethylsilane (3 equiv), in CH2Cl2 at room
temperature, and the lactone 24 was isolated in an excellent
92% yield.22 Saponification of this lactone 24 using 0.1M aq.
NaOH in THF, followed by a mildly acidic treatment (i.e.,
5% aq. citric acid, which was crucial to avoid any undesired
relactonization back to 24), gave phenol 25 quantitatively
(Scheme 7). Another transformation of lactone 24 consisted
in its NaBH4ꢀmediated reduction into the phenolic primary
alcohol 26 (91% yield), which was then silylated to obtain
phenol 27a (79% yield).
tion/[4+2]ꢀcyclodimerization conversion of phenol 25
9
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
Scheme 7. Synthesis of phenolic substrates featuring a (S)ꢀ2ꢀ
aminoꢀ3ꢀhydroxypropyl–type unit at their ortho position
Therefore, we pursued our investigations with phenol 27a,
whose silylated primary alcohol function would prevent any
spirocyclization, and which should thus be better adapted to
an HPD reaction/epoxidation sequence. Our recent successes
in asymmetric HPD reactions promoted by chiral iodanes12e,f
led us to select our Salenꢀtype bis(λ5ꢀiodanes) 32 and 33,
which are readily accessible in hundreds of milligrams by
DMDOꢀmediated oxygenation of their bis(amidoiodoarene)
precursors, themselves easily prepared through coupling of
oꢀiodobenzoic acid with C2ꢀsymmetrical chiral diamines
(Figure 2).12e The simpler amideꢀcontaining and achiral λ5ꢀ
iodane 31 (Figure 2) was also prepared by DMDOꢀmediated
oxygenation of its oꢀiodobenzamide precursor (see the Supꢀ
porting Information).
With these two phenols in hands, we first envisaged a oneꢀ
pot dearomative spirolactonization/epoxidation reaction to
convert the phenol 25 into the epoxide 29 via the spirolacꢀ
tone (S,S)ꢀ28 (Scheme 8). In order to verify the reachability
of such spirolactone, phenol 25 was first dearomatized using
the achiral λ3ꢀiodane PhI(OAc)2 or its trifluoroacetoxy variꢀ
ant PhI(OCOCF3)2, in the presence of NaHCO3 in CH2Cl2 at
low temperature (i.e., 0 °C or –20 °C). Unfortunately, the
spirolactone 28 could not be detected, and a 1:1 mixture of
the [4+2]ꢀcyclodimers 30 and 30’ could instead be isolated
in a combined yield of 43%. Each cyclodimer was separated
by preparative thin layer chromatography (ca. 15% yield
each). Their structure could not be fully determined due to
the lack of Xꢀray quality crystals, but they were unambiguꢀ
ously characterized by NMR analysis, which confirmed that
30 and 30’ were derived from the homochiral [4+2]ꢀ
cyclodimerization of (S,S)ꢀ28 and (S,R)ꢀ28, respectively
(Scheme 8).11a,14 However, all attempts to trap these transient
spirolactones with epoxidizing agents, such as mꢀCPBA and
3,3ꢀdimethyldioxirane (DMDO), were to no avail.
Figure 2. (Chiral) λ5ꢀiodanes selected for the (asymmetric)
hydroxylative phenol dearomatization (HPD) reaction
Table 1 summarizes the main results we gathered using
these λ5ꢀiodanes to initiate the desired HPD reacꢀ
tion/epoxidation transformation of 27a. When this phenol
was treated with 1.1 equivalent of iodane 31 at –20 °C under
experimental conditions previously reported [i.e., a 10 mM
solution of starting phenol in CH2Cl2/CF3CH2OH (85:15) in
the presence of TFA (1.0 equiv)],12e followed by addition of
freshly prepared DMDO (ca. 0.07 M in acetone; 4 equiv), we
were pleased to observe the complete conversion of 27a into
two main products, which were separated by preparative
TLC. NMR analysis led to the identification of the expected
4,5ꢀepoxyꢀ6ꢀhydroxyꢀcyclohexꢀ2ꢀenꢀ1ꢀones 34a and 35a,
which were isolated in 49% yield as a 66:34 diastereomeric
mixture (Table 1, entry 1). It is worth noting that i) the orꢀ
thoꢀquinol intermediate(s) of type 4 (see Scheme 2) could
not be isolated, and ii) the use of mꢀCPBA as the epoxidizing
agent (instead of DMDO) led to degradation of the reaction
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Page 6 of 15
material. Furthermore, the isolation of 34a and 35a indicates
Scheme 9. Synthesis of the NꢀFmoc scyphostatin analogues
36a and 37a
1
2
3
4
5
6
7
8
that DMDO was able to epoxidize the orthoꢀquinol intermeꢀ
diate(s) of type 4 in the requested regioꢀ and diastereoselecꢀ
tive fashion (i.e., cis stereochemistry with respect to the
alcohol function). Similar diastereoselectivity was observed
when the reaction was run in pure CH2Cl2 at –20 °C, but the
dr value increased to 74:26 when the temperature was lowꢀ
ered to –50 °C during the HPD step (Table 1, entries 2 and
3). Most importantly, the contribution of our chiral Salenꢀ
type iodanes 32 and 33 toward our objective to control the
asymmetry of the reaction turned out to be significant, since
the oneꢀpot HPD/epoxidation conversion of 27a was
achieved at –50 °C with diastereomeric ratios of 82:18 and
87:13 by using (S,S)ꢀ32 and (S,S)ꢀ33, respectively (Table 1,
entries 5 and 8). In contrast, the conversion of 27a showed a
clear mismatch effect when using the (R,R) enantiomers of
these bis(λ5ꢀiodanes), since it led to the 34a/35a mixture
with a dr of 47:53 and 35:65 when using (R,R)ꢀ32 and (R,R)ꢀ
33 , respectively (Table 1, entries 6 and 9).
9
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
Phenol 27a was again selected as starting material, and we
first proceeded with its conversion into its Nꢀacetyl analogue
27b (Scheme 10). NꢀFmoc deprotection of 27a with triethylꢀ
amine, followed by inꢀsitu amidation with a large excess of
acetic anhydride (50 equiv), gave the N,Oꢀbis(acetylated)
derivative, which was smoothly Oꢀdeacetylated upon treatꢀ
ment with K2CO3 in methanol to furnish phenol 27b in 98%
yield. Under similar experimental conditions, this time using
commercial palmitic anhydride (4 equiv), phenol 27c was
isolated in 78% yield. These two highꢀyielding Nꢀ
transprotection reactions were conveniently performed on a
200 mg scale. With this facile access to 27c from 27a, we
were ready to engage this Nꢀpalmitoyl phenolic substrate in
our iodaneꢀmediated HPD/epoxidation/desilylation seꢀ
quence.
Table 1. λ5ꢀIodaneꢀmediated hydroxylative phenol dearomaꢀ
tization/epoxidation conversion of phenol 27aa
Scheme 10. Conversion of NꢀFmoc phenol 27a into its Nꢀ
acetyl and Nꢀpalmitoyl analogues 27b and 27c
Unfortunately, these reagentꢀcontrolled asymmetric
transformations of 27a into 34a/35a suffered from moderate
yields of ca. 30ꢀ40%. These disappointing yields can find
explanation in the observation of a concomitant formation of
some unstable (and thus not isolated) orthoꢀquinonoid byꢀ
product (ca. 30% as estimated by 1H NMR) that could result
from a competitive iodaneꢀmediated oxygenation at the
unsubstituted ortho position of the starting phenol. Nevertheꢀ
less, this straightforward and possibly biomimetic asymmetꢀ
ric HPD/epoxidation sequence gave access to NꢀFmoc anaꢀ
logues of scyphostatin 36a and 37a by simple Oꢀdesilylation
of 34a and 35a upon treatment with glacial acetic acid in
THF/H2O (1:1) (Scheme 9). However, unambiguous eviꢀ
dences of the stereochemistry of 34a/35a and thus 36a/37a
were still lacking, so we decided to apply our sequence to the
synthesis of the known scyphostatin Nꢀpalmitoyl analogue
36c,6f,8b,d so far one of the most potent irreversible inhibitor
of NꢀSMase.8b
Hence, phenol 27c was dearomatized/epoxidized under the
conditions that previously offered the best compromise beꢀ
tween yield and diastereoselectivity. Upon treatment with the
achiral λ5ꢀiodane 31 at –50 °C for 3 hours, followed by inꢀ
situ reaction with DMDO (4 equiv) at –20 °C for 12 hours
(see Table 1, entry 3), 27c was successfully transformed into
the expected 34c/35c diastereomeric mixture in 36% yield
with a dr of 70:30 (Scheme 11). The added control of asymꢀ
metry brought by our chiral λ5ꢀiodane reagent (S,S)ꢀ33 at –20
°C for 1 hour (see Table 1, entry 7) led to a higher value of
79:21 with a similar chemical yield of 34%. The epoxyꢀ
cyclohexenone products 34c and 35c could be separated for
characterization purpose or directly desilylated with acetic
acid in THF/H2O to furnish the desired Nꢀpalmitoyl scyphosꢀ
tatin analogues 36c and 37c. The (+)ꢀscyphostatin analogue
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was unambiguously identified as being the major diastereꢀ Tetrahydrofuran (THF) and dichloromethane (CH2Cl2) were
1
2
3
4
5
6
7
8
omer 36c by comparison with literature data, in particular
purified by filtration through alumina under N2. Synthesis
grade 2,2,2ꢀtrifluoroethanol (SigmaꢀAldrich), acetone, ethyl
acetate (EtOAc), and (diacetoxy)iodosylbenzene (Simafex)
were used as received. Reactions run at room temperature
were performed between 20 and 25 °C. Solvent evaporations
were conducted under reduced pressure at temperatures less
than 40 °C unless otherwise noted (e.g., volatile comꢀ
pounds). Column chromatography was carried out under
positive pressure using 40ꢀ63 ꢀm silica gel and the indicated
solvents [v/v; used without purification, including petroleum
ether (PET, boiling range 40ꢀ60 °C)]. Melting points of
either recrystallized solids or amorphous powders were
measured in open capillary tubes, using a digital Büchi Bꢀ
540 melting point apparatus, and are uncorrected. Optical
rotations were determined on a Krüss P3001 digital polarꢀ
27
optical rotation measurements {lit.8d
[
α]
= +15.0 (c =
D
1
0.04, MeOH)}, as well as H and 13C NMR spectra6f recordꢀ
ed in methanolꢀd4 (Scheme 11). Furthermore, the scyphosꢀ
tatin analogues 36c and 37c could also be obtained by desiꢀ
lylation of 34c/35c directly generated by Nꢀtransprotection of
the NꢀFmoc Oꢀsilylated epoxyꢀcyclohexenones 34a/35a (see
Schemes S3 and S4 in the Supporting Information). NMR
data and optical rotation measurement of the resulting
epoxyꢀcyclohexenone 36c were again consistent with those
previously reported.6f,8d Thus, this access to 36c enabled us to
confirm the stereochemical assignments of the NꢀFmoc
variants 36a/37a, and hence those of 34a/35a (see Scheme
9).
9
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
Scheme 11. Synthesis of the Nꢀpalmitoyl scyphostatin anaꢀ
logues 36c and 37c
imeter at λ = 589 nm (i.e., sodium D line), using a 1.0 mL
25
cell (l = 0.5 dm), and are given as [
α]
(concentration in
D
g/100 mL solvent). IR spectra were recorded between 4000
and 400 cmꢀ1 with a Bruker IFS55 (OPUS/IR 3.0.2) FTꢀIR
spectrometer, and samples were dissolved in dichloroꢀ
methane or acetone before analysis as a thin film on a zincꢀ
selenium pellet after solvent evaporation (neat), unless othꢀ
1
erwise noted (NaCl pellets). H NMR spectra of samples in
the indicated solvent were run at 300 or 400 MHz on Bruker
DPXꢀ300 or ꢀ400 spectrometers. Chemical shifts are given in
ppm (δ) comparatively to the residual solvent signal, which
was used as an internal reference (acetoneꢀd6: δ = 2.05 ppm;
CDCl3: δ = 7.26 ppm; DMSOꢀd6: δ = 2.50 ppm; methanolꢀ
d4: δ = 3.31 ppm; THFꢀd8: δ = 1.72, 3.58 ppm). Coupling
constants (J) are given in Hertz (Hz), and the following
abbreviations are used to describe the signal multiplicity: s
(singlet), bs (broad singlet), d (doublet), t (triplet), q (quadꢀ
ruplet), m (multiplet). 13C NMR spectra of samples in the
indicated solvent were run at 75.5 or 100 MHz on Bruker
DPXꢀ300 or ꢀ400 spectrometers. Chemical shifts are given in
ppm (δ) comparatively to the residual solvent signal, which
was used as an internal reference (acetoneꢀd6: δ = 29.84,
206.26 ppm; CDCl3: δ = 77.16 ppm; DMSOꢀd6: δ = 39.52
ppm; methanolꢀd4: δ = 49.00 ppm; THFꢀd8: δ = 25.31, 67.21
ppm). Carbon multiplicities were determined by either
DEPTꢀ135 or JꢀMod experiments. Stereochemical assignꢀ
ments were achieved by NOESY experiments. Low resoluꢀ
tion (LRMS) mass spectra were obtained by electrospray
ionization (ESIMS), and were recorded on a Thermo Finniꢀ
gan LCQ Deca XP spectrometer using an ion trap mass with
an electrospray source under atmospheric pressure, at the
mass spectrometry laboratory of the Institut Européen de
Chimie et Biologie (IECB, CNRS–UMS 3033). High resoluꢀ
tion (HRMS) mass spectrometric analyses were obtained
from the Centre d’Etude Structurale et d’Analyse des
Molécules Organiques (CESAMO, Université de Bordeaux),
France.
CONCLUSION
In summary, we have developed an efficient and concise
synthesis of two (+)ꢀscyphostatin analogues (36a and 36c)
and their corresponding diastereomers (37a and 37c) from
readily available phenols featuring
a (2S)ꢀ2ꢀaminoꢀ3ꢀ
hydroxypropyl sideꢀchain at their ortho position. Key feaꢀ
tures of the synthesis of the highly oxygenated polar head of
scyphostatin, and analogues thereof, include an asymmetric
and biomimetic hydroxylative phenol dearomatization
(HPD) promoted by chiral Salenꢀtype bis(λ5ꢀiodane) reaꢀ
gents, followed by an in situ DMDOꢀmediated regioꢀ and
diastereoselective epoxidation. This reagentꢀcontrolled oxiꢀ
dative phenol dearomatization (OPD) approach paves the
way for a straightforward access to other scyphostatin anaꢀ
logues as NꢀSMase inhibitor candidates.
General procedure for Grignard addition to spiroketal
7. To a stirred solution of freshly purified spiroketal 712b (1.0
equiv) in dry THF (ca. 30 mM) cooled at –78 °C was added
dropwise a commercially available solution of RMgBr (2.0
equiv). The resulting mixture was stirred at –78 °C for 1
hour, after which time it was allowed to warm to –50 °C, and
stirring was maintained until TLC monitoring, eluting with
PET/acetone (4:1), indicated complete consumption of the
starting material. Hydrolysis of the reaction mixture was then
performed at this temperature by dropwise addition of satuꢀ
EXPERIMENTAL SECTION
General Information. All moisture and oxygen sensitive
reactions were carried out in flameꢀdried glassware under N2.
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rated aqueous NH4Cl (1 mL). It was then allowed to warm to
9-Bromo-(2R)-tert-butyl-(6S)-(prop-2-enyl)-1,4-
Page 8 of 15
1
2
3
4
5
6
7
8
room temperature, and it was diluted with EtOAc and satuꢀ
rated aqueous NH4Cl. The layers were separated and the
aqueous layer was extracted twice with EtOAc. The comꢀ
bined organic layers were dried over MgSO4, filtered and
evaporated to give a crude product, which was purified by
column chromatography, to give the tertiary alcohol 9.
dioxaspiro[4.(5R)]deca-7,9-dien-6-ol (9d). Reaction was
performed using allylmagnesium bromide (1.0 M in Et2O).
Column chromatography, eluting with PET/acetone (from
99:1 to 97:3), furnished 9d as a yellow oil (60 mg, 58%, dr =
1
58:42): H NMR (CDCl3, 300 MHz): major diastereomer:
δ
= 0.90 (s, 9H, Hꢀ15, tBu), 2.53 (d, J = 7.2 Hz, 2H, Hꢀ11),
2.55 (bs, 1H, OH), 3.78 (t, J = 7.6 Hz, 1H, Hꢀ3), 3.83 (t, J =
6.7 Hz, 1H, Hꢀ2), 4.11 (dd, J = 7.3, 7.0 Hz, 1H, Hꢀ3), 5.08
(d, J = 12.8, 2H, Hꢀ13), 5.73 (d, J = 10.2 Hz, 1H, Hꢀ7), 5.77ꢀ
5.96 (m, 1H, Hꢀ12), 5.88 (dd, J = 1.2, 10.2 Hz, 1H, Hꢀ8)
(–)-9-Bromo-(2R)-tert-butyl-(6S)-methyl-1,4-
dioxaspiro[4.(5R)]deca-7,9-dien-6-ol (9a). Reaction was
performed using methylmagnesium bromide (3.0 M in THF).
Column chromatography, eluting with PET/acetone (95:5),
9
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
5.96 (d, J = 0.8 Hz, 1H, Hꢀ10), minor diastereomer:
δ = 0.95
furnished 9a as a pale yellow oil (45 mg, 74%, dr ≥ 95:5):
25
(s, 9H, Hꢀ15, tBu), 2.52 (d, J = 7.2 Hz, 2H, Hꢀ11), 2.62 (bs,
1H, OH), 3.59ꢀ3.70 (m, 1H, Hꢀ3), 3.97ꢀ4.06 (m, 2H, Hꢀ2),
5.08 (d, J = 12.3 Hz, 2H, Hꢀ13), 5.73 (d, J = 10.0 Hz, 1H, Hꢀ
7), 5.82ꢀ5.98 (m, 1H, Hꢀ12), 5.87 (dd, J = 1.6, 10.2 Hz, 1H,
Hꢀ8), 6.04 (d, J = 1.4 Hz, 1H, Hꢀ10).
[
α]
= –16.9 (c = 0.59, CHCl3); IR (neat): ν = 3476, 2957,
D
1
2933, 2873, 1145, 1020, 744 cmꢀ1; H NMR (CDCl3, 300
MHz): = 0.90 (s, 9H, Hꢀ13, tBu), 1.34 (s, 3H, Hꢀ11, Me),
δ
2.57 (bs, 1H, OH), 3.73ꢀ3.84 (m, 2H, Hꢀ2 + Hꢀ3b), 4.10 (dd,
J = 5.4, 7.3 Hz, 1H, Hꢀ3a), 5.76 (d, J = 10.0 Hz, 1H, Hꢀ7),
5.82 (dd, J = 1.4, 10.1 Hz, 1H, Hꢀ8), 5.97 (d, J = 1.0 Hz, 1H,
9-Bromo-(2R)-tert-butyl-(10R)-ethenyl-1,4-
Hꢀ10); 13C NMR (CDCl3, 75.5 MHz):
δ = 139.7 (Cꢀ7), 129.2
dioxaspiro[4.(5R)]dec-8-en-6-one (10). Reaction was perꢀ
formed using vinylmagnesium bromide (1.0 M in THF).
Column chromatography, eluting with PET/acetone (98:2),
(Cꢀ10), 125.5 (Cꢀ8), 119.4 (Cꢀ9), 110.1 (Cꢀ5), 85.9 (Cꢀ2),
74.2 (Cꢀ6), 66.2 (Cꢀ3), 32.7 (Cꢀ12), 25.5 (Cꢀ13), 20.5 (Cꢀ
11); LRMS (ESIMS): m/z (%) = 327 (42) [MNa+], 325 (42)
[MNa+], 301 (17), 299 (20); HRMS (ESI) calcd for
C13H1979BrNaO3 325.0415, found 325.0423.
afforded 10 as a pale yellow oil (55 mg, 71%, dr = 90:10):
1
IR (neat):
ν
= 2961, 2908, 2874, 1742, 1638, 1011 cmꢀ1; H
NMR (CDCl3, 300 MHz): major diastereomer:
δ
= 0.92 (s,
9H, Hꢀ14, tBu), 2.91 (dd, J = 3.6, 21.1 Hz, 1H, Hꢀ7), 3.16
(dd, J = 4.1, 21.1 Hz, 1H, Hꢀ7), 3.51 (d, J = 7.2 Hz, 1H, Hꢀ
10), 3.72 (t, J = 7.1 Hz 1H, Hꢀ2), 3.8 (t, J = 7.3 Hz 1H, Hꢀ3),
4.05 (t, J = 7.2 Hz, 1H, Hꢀ3), 5.25 (d, J = 18.3 Hz, 1H, Hꢀ
12a), 5.31 (d, J = 10.9 Hz, 1H, Hꢀ12b), 5.72 (ddd, J = 7.2,
10.2, 17.3 Hz, 1H, Hꢀ11), 6.14 (t, J = 3.8 Hz, 1H, Hꢀ8); 13C
(–)-9-Bromo-(2R)-tert-butyl-(6R)-phenyl-1,4-
dioxaspiro[4.(5R)]deca-7,9-dien-6-ol (9b). Reaction was
performed using phenylmagnesium bromide (1.0 M in THF).
Column chromatography, eluting with PET/acetone (95:5),
afforded 9b as a pale yellow oil (39 mg, 54%, dr ≥ 95:5):
25
[
α]
= –0.4 (c = 0.62, CHCl3); IR (neat):
ν
= 3534, 2960,
D
1152, 1114 cmꢀ1; H NMR (CDCl3, 300 MHz):
δ
= 0.90 (s,
1
NMR (CDCl3, 75.5 MHz): major diastereomer:
δ = 201.3
(Cꢀ6), 130.9 (Cꢀ11), 125.9 (Cꢀ8), 119.73 (Cꢀ9), 119.69 (Cꢀ
12), 106.5 (Cꢀ5), 84.1 (Cꢀ2), 67.2 (Cꢀ3), 58.9 (Cꢀ10), 39.7
(Cꢀ7), 32.7 (Cꢀ13), 25.3 (Cꢀ14); minor diastereomer:
200.5 (Cꢀ6), 130.8 (Cꢀ11), 125.7 (Cꢀ8), 119.9 (Cꢀ9), 119.5
(Cꢀ12), 106.8 (Cꢀ5), 84.8 (Cꢀ2), 67.9 (Cꢀ3), 60.2 (Cꢀ10), 40.2
(Cꢀ7), 31.9 (Cꢀ13), 25.6 (Cꢀ14); LRMS (ESIMS): m/z (%) =
339 (100) [MNa+], 337 (87) [MNa+]; HRMS (ESI) calcd for
C14H1979BrNaO3 337.0415, found 337.0427.
9H, Hꢀ13, tBu), 3.63 (t, J = 7.4 Hz, 1H, Hꢀ3), 3.74 (dd, J =
6.1, 7.3 Hz, 1H, Hꢀ2), 3.82 (dd, J = 6.0, 7.3 Hz, 1H, Hꢀ3),
5.86 (d, J = 9.8 Hz, 1H, Hꢀ7), 6.01 (d, J = 1.3 Hz, 1H, Hꢀ10),
6.09 (dd, J = 1.7, 10.0 Hz, 1H, Hꢀ8), 7.29ꢀ7.58 (m, 5H, Hꢀ14
δ =
+ Hꢀ15 + Hꢀ16); 13C NMR (CDCl3, 75.5 MHz):
δ = 138.2
(Cꢀ7), 137.7 (Cꢀ11), 129.4 (Cꢀ10), 127.9 (Cꢀ15), 127.8 (Cꢀ
16), 126.9 (Cꢀ8), 126.2 (Cꢀ14), 120.2 (Cꢀ9), 109.9 (Cꢀ5),
86.2 (Cꢀ2), 77.2 (Cꢀ6), 66.4 (Cꢀ3), 32.7 (Cꢀ12), 25.4 (Cꢀ13);
LRMS (ESIMS): m/z (%) = 389 (69) [MNa+], 387 (75)
[MNa+], 365 (100), 363 (81), 349 (9), 347 (12); HRMS (ESI)
calcd for C18H2179BrNaO3 387.0572, found 387.0561.
(–)-9-Bromo-(2R)-tert-butyl-(7S,8R)-epoxy-(6S)-methyl-
1,4-dioxaspiro[4.(5R)]dec-9-en-6-ol (11). To a stirred iceꢀ
cold solution of cyclohexaꢀ2,4ꢀdienol 9a (81 mg, 0.27 mmol)
in CHCl3 (3 mL, ca. 0.1 M) was added K2CO3 (48 mg, 0.35
mmol) and mꢀCPBA (70% purity, 72 mg, 0.29 mmol). The
reaction mixture was then stirred at room temperature for 3
hours, until total consumption of the starting material [TLC
monitoring, PET/Et2O (3:2)]. The solvent was removed
under reduced pressure and the resulting white solid was
subjected to column chromatography, eluting with PET/Et2O
(–)-9-Bromo-(2R)-tert-butyl-(6R)-ethynyl-1,4-
dioxaspiro[4.(5R)]deca-7,9-dien-6-ol (9c). Reaction was
performed using ethynylmagnesium bromide (0.5 M in
THF). Column chromatography, eluting with cyclohexꢀ
ane/acetone (4:1), gave 9c as a white amorphous powder
(133 mg, 88%, dr = 90:10), which was crystallized from PET
by slow evaporation, to give colorless crystals: mp 92ꢀ94 °C;
25
(4:1), to give 11 as a yellow oil (84 mg, quantitative yield, dr
[
α]
= –1.6 (c = 1.23, CHCl3); IR (neat): ν = 3466, 3297,
D
1
25
2964, 2904, 2877, 2115, 1011 cmꢀ1; H NMR (CDCl3, 300
MHz): = 0.94 (s, 9H, Hꢀ14, tBu), 2.49 (s, 1H, Hꢀ12), 2.91
> 95:5): [
α]
D = –4.7 (c = 0.85, CHCl3); IR (neat):
ν
= 3467,
1640, 1258, 1146, 800 cmꢀ1; H NMR (CDCl3, 300 MHz):
δ
1
δ
= 0.91 (s, 9H, Hꢀ13, tBu), 1.27 (s, 3H, Hꢀ11, Me), 2.90 (bs,
1H, OH), 3.35 (d, J = 4.0 Hz, 1H, Hꢀ7), 3.60 (dd, J = 2.6, 4.1
Hz, 1H, Hꢀ8), 3.65 (t, J = 8.3 Hz, 1H, Hꢀ3b), 3.82 (dd, J =
6.1, 8.1 Hz, 1H, Hꢀ2), 4.05 (dd, J = 6.1, 8.2 Hz, 1H, Hꢀ3a),
6.00 (d, J = 2.1 Hz, 1H, Hꢀ10); 13C NMR (CDCl3, 75.5
(bs, 1H, OH), 3.82 (t, J = 8.2 Hz, 1H, Hꢀ3), 4.12 (dd, J = 6.5,
8.4 Hz, 1H, Hꢀ2), 4.25 (dd, J = 6.4, 7.9 Hz, 1H, Hꢀ3), 5.90
(d, J = 9.8 Hz, 1H, Hꢀ7), 6.03 (dd, J = 1.5, 9.8 Hz, 1H, Hꢀ8),
6.08 (d, J = 1.1 Hz, 1 H, Hꢀ10); 13C NMR (CDCl3, 75.5
MHz):
δ = 132.7 (Cꢀ7), 129.6 (Cꢀ10), 128.1 (Cꢀ8), 119.7 (Cꢀ
MHz):
δ = 133.2 (Cꢀ10), 121.3 (Cꢀ9), 107.1 (Cꢀ5), 86.4 (Cꢀ
9), 108.7 (Cꢀ5), 86.6 (Cꢀ2), 82.0 (Cꢀ12), 73.0 (Cꢀ11), 70.2
(Cꢀ6), 67.2 (Cꢀ3), 32.7 (Cꢀ13), 25.4 (Cꢀ14); LRMS (ESIMS):
m/z (%) = 337 (90) [MNa+], 335 (100) [MNa+], 256 (19)
[MNa–Br]+; HRMS (ESI) calcd for C14H1779BrNaO3
335.0259, found 335.0253.
2), 73.1 (Cꢀ6), 65.7 (Cꢀ3), 59.9 (Cꢀ7), 55.5 (Cꢀ8), 32.6 (Cꢀ
12), 25.5 (Cꢀ13), 19.4 (Cꢀ11); LRMS (ESIMS): m/z (%) =
343 (100) [MNa+], 341 (98) [MNa+]; HRMS (ESI) calcd for
C13H1979BrNaO4 341.0364, found 341.0372.
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The Journal of Organic Chemistry
10 min, after which time freshly prepared LiNp18c (0.5 M in
(–)-(2R)-tert-butyl-(7S,8R)-epoxy-(6S)-methyl-1,4-
1
dioxaspiro[4.(5R)]dec-9-en-6-ol (12). To a stirred solution
of epoxyꢀalcohol 11 (66 mg, 0.21 mmol) in dry THF (30
mL) was added Bu3SnH (90 mg, 0.31 mmol) and AIBN (1.7
mg, 0.01 mmol). The reaction mixture was then heated under
reflux for 3 hours, after which time another portion of
Bu3SnH (90 mg, 0.31 mmol) was added. After 2 additional
hours under reflux, the reaction mixture was allowed to cool
to room temperature, SiO2 (ca. 200 mg) was then added, and
stirring at room temperature was maintained for 30 min. The
mixture was filtered, and the resulting solid residue was
washed with CH2Cl2. Evaporation of the combined filtrates
afforded a 1:1 mixture (1H NMR analysis) of the expected
product 12 and its corresponding bromohydrin 13. For charꢀ
acterization purpose, compound 13 could be purified by
column chromatography, eluting with cyclohexane/acetone
(95:5). Otherwise, the 12/13 mixture was diluted in dry
MeOH (3 mL) and treated with K2CO3 (86 mg, 0.62 mmol)
at room temperature. The resulting mixture was stirred until
disappearance of the bromohydrin [TLC monitoring,
PET/acetone (4:1)]. The reaction was made neutral upon
washing with saturated aqueous NH4Cl (5 mL), and extractꢀ
ed with EtOAc (3 × 5 mL). The combined organic layers
were washed with brine (10 mL), dried over MgSO4, filtered
and evaporated. The resulting oily residue was partitioned
between hexane (10 mL) and acetonitrile (10 mL). The polar
layer was then washed with hexane (2 × 10 mL) to remove
all the stannous salts, and evaporated. Purification of the
residue by column chromatography, eluting with cyclohexꢀ
THF, 3.3 mL, 1.66 mmol) was added dropwise over 5 min.
The resulting dark solution was stirred at −78 °C for 2 hours,
after which time freshly prepared orthoꢀquinone spiroketal
(R,R)ꢀ7 (159 mg, 0.55 mmol) was added dropwise. The
reaction mixture immediately became colorless. It was kept
at low temperature (i.e., between −78 °C and −40 °C) overꢀ
night (ca. 12 h), and then quenched with saturated aqueous
NH4Cl (1 mL), and allowed to warm to room temperature.
The reaction was diluted with EtOAc (20 mL) and saturated
aqueous NH4Cl (20 mL). After separation of the layers, the
aqueous phase was extracted with EtOAc (2 × 20 mL). The
combined organic layers were dried over MgSO4, filtered
and evaporated. Purification of the residue by column chroꢀ
matography, eluting with cyclohexane/acetone (95:5), afꢀ
forded the 1,2ꢀadduct 17 as a colorless oil (42 mg, 33%): IR
2
3
4
5
6
7
8
9
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
(neat):
1034, 987, 763 cmꢀ1; H NMR (CDCl3, 300 MHz): THPꢀ
based diastereomeric mixture: = 0.88 (s, 9H, Hꢀ13, tBu),
ν = 3508, 3388, 2956, 2871, 1714, 1505, 1366, 1174,
1
δ
1.44 (s, 9H, Boc tBu), 1.48ꢀ1.94 (m, 9H), 3.41 (dd, J = 4.0,
9.8 Hz, 1H), 3.46ꢀ3.51 (m, 1H), 3.65 (dd, J = 5.3, 10.0 Hz,
1H), 3.70ꢀ3.89 (m, 4H), 4.09 (dd, J = 6.2, 7.9 Hz, 1H), 4.55ꢀ
4.58 (m, 1H), 5.21 (bs, 1H, NH), 5.88 (dd, J = 1.7, 10.2 Hz,
1H), 5.95ꢀ6.04 (m, 2H); 13C NMR (CDCl3, 75.5 MHz): THPꢀ
based diastereomeric mixture:
δ = 155.8, 155.1, 138.0,
129.5, 126.5, 119.7, 110.6, 99.2, 98.7, 85.7, 79.3, 76.2, 70.7,
66.4, 62.4, 62.0, 47.9, 43.4, 32.8, 32.8, 30.5, 30.4, 30.1, 29.7,
28.5, 28.4, 28.3, 26.9, 25.7, 25.4, 25.3, 25.3, 25.2, 25.2, 19.5,
19.1; LRMS (ESIMS): m/z (%) = 1117 (60) [2M+Na+], 1115
(100) [2M+Na+], 1113 (40) [2M+Na+], 570 (75) [MNa+],
568 (70) [MNa+], 490 (15) [MNa+–Br+H]; HRMS (ESI)
calcd for C25H4079BrNNaO7 568.1886, found 568.1879.
ane/acetone (95:5), gave 12 as a colorless oil (46 mg, 65%,
25
dr > 95:5): [
α]
= –62.3 (c = 1.34, CHCl3); IR (neat):
ν
δ
=
=
D
3653, 1248, 1148 cmꢀ1; H NMR (CDCl3, 300 MHz):
1
0.90 (s, 9H, Hꢀ13, tBu), 1.24 (s, 3H, Hꢀ11, Me), 2.93 (bs,
1H, OH), 3.33 (d, J = 4.0 Hz, 1H, Hꢀ7), 3.36 (dt, J = 1.9, 4.2
Hz, 1H, Hꢀ8), 3.68 (t, J = 8.1 Hz, 1H, Hꢀ3), 3.83 (dd, J = 6.0,
7.9 Hz, 1H, Hꢀ2), 4.06 (dd, J = 6.1, 8.3 Hz, 1H, Hꢀ3), 5.70
(dd, J = 1.9, 10.0 Hz, 1H, Hꢀ10), 6.09 (dd, J = 3.8, 10.0, 1H,
9-Bromo-(2R)-tert-butyl-(7S,8R)-epoxy-(6S)-[(2S)-(N-
tert-butoxycarbonyl)-(O-tetrahydropyranyl)-2-amino-3-
hydroxypropyl]-1,4-dioxaspiro [4.(5R)]dec-9-en-6-ol (18).
To a stirred solution of cyclohexaꢀ2,4ꢀdienol 17 (26 mg, 48
µmol) in CHCl3 (1 mL) was added K2CO3 (9 mg, 62 µmol)
and mꢀCPBA (70% purity, 12 mg, 48 µmol). The reaction
mixture was stirred at room temperature overnight (ca. 12 h),
until total consumption of the starting material [TLC moniꢀ
toring, PET/acetone (4:1)]. The solvent was removed under
reduced pressure and the resulting white solid was subjected
to column chromatography, eluting with cyclohexꢀ
ane/acetone (95:5), to afford 18 as a yellow oil (11 mg,
Hꢀ9); 13C NMR (CDCl3, 75.5 MHz):
δ = 134.3 (Cꢀ10), 126.5
(Cꢀ9), 106.6 (Cꢀ5), 86.2 (Cꢀ2), 73.6 (Cꢀ6), 65.7 (Cꢀ3), 59.2
(Cꢀ7), 48.7 (Cꢀ8), 32.7 (Cꢀ12), 25.5 (Cꢀ13), 19.5 (Cꢀ11);
LRMS (ESIMS): m/z (%) = 263 (100) [MNa+]; HRMS (ESI)
calcd for C13H20NaO4 263.1253, found 263.1257.
25
Bromohydrin 13 was isolated as a colorless oil: [
72.1 (c = 0.85, CHCl3); IR (neat):
= 3467, 760 cmꢀ1; H
NMR (CDCl3, 300 MHz): = 0.94 (s, 9H, Hꢀ13, tBu), 1.40
α] D = –
1
ν
41%): IR (neat):
1502, 1467, 1366, 1251, 1172, 1061, 1033, 734 cmꢀ1; H
NMR (CDCl3, 300 MHz): = 0.90 (s, 9H, tBu), 1.44 (s, 9H,
ν = 3520, 3390, 2958, 2926, 2871, 1711,
δ
1
(s, 3H, Hꢀ11, Me), 3.78 (dd, J = 8.1, 8.9 Hz, 1H, Hꢀ3), 3.94
(dd, J = 6.1, 8.9 Hz, 1H, Hꢀ2), 3.98 (d, J = 6.4 Hz, 1H, Hꢀ7),
4.10 (dd, J = 6.1, 8.1 Hz, 1H, Hꢀ3), 4.75 (ddd, J = 1.9, 2.9,
6.4 Hz, 1H, Hꢀ8), 5.57 (dd, J = 1.7, 10.0 Hz, 1H, Hꢀ10), 5.97
δ
Boc tBu), 1.44ꢀ2.01 (m, 8H), 3.13 (bs, 1H, OH), 3.39 (dd, J
= 5.1, 9.8 Hz, 1H), 3.49ꢀ3.55 (m, 1H), 3.60ꢀ3.66 (m, 3H),
3.74 (dd, J = 4.1, 8.9 Hz, 1H), 3.79ꢀ3.86 (m, 2H), 4.00ꢀ4.05
(m, 2H), 4.06 (t, J = 3.0 Hz, 1H), 5.04 (bs, 1H, NH), 6.01 (s,
1H); 13C NMR (CDCl3, 75.5 MHz): major THPꢀbased diaꢀ
(dd, J = 2.8, 10.2, 1H, Hꢀ9); 13C NMR (CDCl3, 75.5 MHz):
δ
= 130.0 (Cꢀ9), 128.7 (Cꢀ10), 107.2 (Cꢀ5), 86.7 (Cꢀ2), 78.0
(Cꢀ7), 76.7 (Cꢀ6), 67.2 (Cꢀ3), 51.8 (Cꢀ8), 32.6 (Cꢀ12), 25.5
(Cꢀ13), 19.8 (Cꢀ11); LRMS (ESIMS): m/z (%) = 345 (100)
[MNa+], 343 (92) [MNa+], 241 (23) [MNa–Br]+; HRMS
(ESI) calcd for C13H2179BrNaO4 343.0515, found 343.0507.
stereomer:
δ = 155.5, 133.3, 121.9, 107.3, 98.9, 86.7, 86.5,
75.7, 70.6, 65.8, 62.1, 58.2, 55.7, 46.7, 32.6, 31.2, 30.4, 29.7,
28.4, 25.5, 19.3; LRMS (ESIMS): m/z (%) = 1149 (49)
[2M+Na+], 1147 (100) [2M+Na+], 1145 (47) [2M+Na+], 586
(51) [MNa+], 584 (48) [MNa+]; HRMS (ESI) calcd for
C25H4079BrNNaO8 584.1835, found 584.1817.
9-Bromo-(2R)-tert-butyl-(6S)-[(2S)-(N-tert-
butoxycarbonyl)-(O-tetrahydropyranyl)-2-amino-3-
hydroxypropyl]-1,4-dioxaspiro[4.(5R)]deca-7,9-dien-6-ol
(17). To a stirred solution of chloride (R)ꢀ16 (212 mg, 0.72
mmol) in dry THF (9 mL) at −78 °C, under an atmosphere of
argon, was added dropwise nꢀBuLi (1.3 M in hexanes, 0.6
mL, 0.8 mmol). The solution was then stirred at –78 °C for
(2R)-tert-Butyl-(7S,8S)-epoxy-(6S)-[(2S)-(N-tert-
butoxycarbonyl)-(O-tetrahydropyranyl)-2-amino-3-
hydroxy propyl]-1,4-dioxaspiro[4.(5R)]dec-9-en-6-ol (19).
To a stirred solution of epoxyꢀalcohol 18 (37 mg, 0.066
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 15
mmol) in dry THF (3 mL) was added Bu3SnH (29 mg, 0.099 The solution was stirred at room temperature overnight (ca.
1
2
3
4
5
6
7
8
mmol) and AIBN (1.1 mg, 0.006 mmol). The reaction mixꢀ
ture was then heated under reflux for 3 hours, after which
time it was allowed to cool to room temperature, and then
diluted with Et2O (4 mL). Powdered SiO2 (80 mg) was added
in one portion to the reaction mixture, which was kept under
stirring at room temperature for 30 min. The mixture was
filtered, and the resulting solid residue was washed with
Et2O. The combined filtrates were evaporated, and the resultꢀ
ing residue was purified by column chromatography, eluting
with PET/acetone (9:1), to furnish 19 as a colorless oil (39
12 h), after which time it was quenched with 1M aqueous
HCl (10 mL) and extracted with EtOAc (3 × 20 mL). The
combined organic layers were washed with brine (10 mL),
dried over Na2SO4, filtered and evaporated. Purification of
the residue by column chromatography, eluting with cycloꢀ
hexane/EtOAc (85:15), furnished lactone 24 (71 mg, 92%)
25
as a white solid: mp 164ꢀ165 °C; [
CHCl3); IR (neat):
1H NMR (CDCl3, 300 MHz):
α]
= +37.8 (c = 0.45,
D
ν
= 1777, 1721, 1536, 1313, 1226 cmꢀ1;
= 2.98 (t, J = 15.1 Hz, 1H),
δ
9
3.48 (dd, J = 6.7, 15.1 Hz, 1H), 4.25 (t, J = 6.7 Hz, 1H), 4.45
(d, J = 6.7 Hz, 2H), 4.51ꢀ4.69 (m, 1H), 5.81 (d, J = 4.0 Hz,
1H), 7.03ꢀ7.37 (m, 6H), 7.42 (t, J = 7.2 Hz, 2H), 7.62 (d, J =
7.2 Hz, 2H), 7.78 (d, J = 7.2 Hz, 2H); 13C NMR (CDCl3,
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
mg, quantitative yield): IR (neat):
ν
= 3515, 3400, 1707,
1
1174 cmꢀ1; H NMR (CDCl3, 300 MHz):
δ
= 0.91 (s, 9H,
tBu), 1.45 (s, 9H, Boc tBu), 1.45ꢀ2.02 (m, 8H), 2.52 (m, 1H),
2.97 (bs, 1H, OH), 3.27ꢀ3.50 (m, 1H), 3.42ꢀ3.56 (m, 2H),
3.69ꢀ3.92 (m, 3H), 3.99ꢀ4.20 (m, 3H), 4.49ꢀ4.66 (m, 2H),
5.70 (d, J = 9.3 Hz, 1H), 5.84ꢀ5.99 (m, 1H); 13C NMR
75.5 MHz):
δ = 168.2, 155.7, 150.8, 143.7, 143.6, 141.3
(2C), 128.9, 128.6, 127.8 (2C), 127.1 (2C), 125.0 (2C),
121.2, 120.0 (2C), 116.7 (2C), 67.3, 49.7, 47.1, 30.8; LRMS
(ESIMS): m/z (%) = 418 (55), 409 (25), 408 (100) [MNa+],
504 (47); HRMS (ESI) calcd for C24H19NNaO4 408.1206,
found 408.1218.
(CDCl3, 75.5 MHz): THPꢀbased diastereomeric mixture:
δ =
154.7, 154.6, 130.8, 130.7, 127.3 (2C) 107.1, 99.3, 98.6,
86.5, 80.4, 80.3, 73.9, 73.0, 70.6, 69.8, 66.0, 62.3, 62.1, 53.9
(2C), 50.8, 50.6, 34.3, 33.9, 32.6, 30.6, 30.5, 28.3, 25.5,
19.4; LRMS (ESIMS): m/z (%) = 990 (57) [2M+Na+], 988
(15), 986 (100); HRMS (ESI) calcd for C25H41NNaO8
506.2730, found 506.2746.
(+)-N-Fmoc-(2S)-2-amino-3-(2-
hydroxyphenyl)propanoic acid (25). To a stirred solution
of lactone 24 (23 mg, 0.060 mmol) in dry THF (2.6 mL) was
added 1M aqueous NaOH (0.7 mL, 0.066 mmol). The soluꢀ
tion was stirred at room temperature for 30 min, after which
time it was quenched by adding 5% aqueous citric acid (10
mL), and extracted with CH2Cl2 (3 × 10 mL). The combined
organic layers were washed with brine (10 mL), dried over
Na2SO4, filtered and evaporated to afford 25 as a white solid
(+)-tert-Butyl
N-Fmoc-(2S)-2-amino-3-(2-
methoxymethoxyphenyl)propanoate (23). To a stirred
suspension of Zn (736 mg, powder, 11.25 mmol) in dry
DMF (2 mL) was added, at room temperature, TMSCl (237
µL, 1.88 mmol). Stirring at room temperature was mainꢀ
tained for 30 min, after which time a solution of Lꢀserine
(24 mg, quantitative yield), which was used without further
25
derivative 21 (1.85 g, 3.75 mmol) in dry DMF (9 mL) was
added dropwise. The reaction mixture was stirred for 15 min
[i.e., until consumption of 21, as indicated by TLC monitorꢀ
ing, eluting twice with cyclohexane/EtOAc (85:15)], after
which time aryl iodide 22 (1,19 g, 4.88 mmol), P(oꢀtol)3
(1.49 g, 4.88 mmol) and Pd2(dba)3 (240 mg, 0.263 mmol)
were successively added. The resulting mixture was then
heated at 50°C for 2 hours, then cooled down to room temꢀ
perature, diluted with EtOAc (60 mL), and quenched with
saturated aqueous NaHCO3 (50 mL). After separation of the
two layers, the aqueous layer was extracted with EtOAc (3 ×
40 mL). The combined organic layers were washed with
brine (30 mL), dried over Na2SO4, filtered and evaporated.
Purification of the residue by column chromatography, elutꢀ
purification: mp 120ꢀ121 °C; [
IR (neat):
MHz): = 2.89 (dd, J = 9.6, 13.4 Hz, 1H), 3.21 (dd, J = 4.7,
α]
D = +52.4 (c = 0.85, THF);
ν
= 1720, 1450, 1111 cmꢀ1; 1H NMR (THFꢀd8, 300
δ
13.6 Hz, 1H), 4.03ꢀ4.25 (m, 3H), 4.44ꢀ4.63 (m, 1H), 6.61ꢀ
6.67 (m, 3H), 6.96 (t, J = 7.2 Hz, 1H), 7.08 (d, J = 7.0 Hz,
1H), 7.14ꢀ7.24 (m, 2H), 7.29 (t, J = 7.3 Hz, 2H), 7.49ꢀ7.62
(m, 2H), 7.71 (d, J = 7.4 Hz, 2H), 8.44 (s, 1H); 13C NMR
(THFꢀd8, 75.5 MHz):
δ = 173.8, 156.5, 156.4, 145.1, 142.0,
131.8, 128.2, 128.0 (2C), 127.5 (2C), 126.0 (2C), 125.9,
125.0, 120.3 (2C), 119.9, 115.4 (2C), 67.0, 54.8, 48.0, 33.2;
LRMS (ESIMS): m/z (%) = 427 (45), 426 (100) [MNa+];
HRMS (ESI) calcd for C24H21NNaO5 426.1317, found
426.1328.
(+)-N-Fmoc-(2S)-2-amino-3-(2-
ing with cyclohexane/EtOAc (85:15), gave 23 (1.57 g, 83%)
hydroxyphenyl)propanol (26). To a stirred iceꢀcold suspenꢀ
sion of NaBH4 (118 mg, 3.12 mmol) in absolute EtOH (10
mL) was added dropwise a solution of lactone 24 (240 mg,
0.623 mmol) in dry CH2Cl2 (10 mL). The reaction mixture
was stirred at 0 °C for 30 min, after which time it was diluted
with EtOAc (50 mL) and quenched with 1M aqueous HCl
(50 mL) at the same temperature. After separation of the two
layers, the aqueous phase was extracted with EtOAc (3 × 30
mL). The combined organic layers were washed with a 1:1
solution of brine and 1M aqueous HCl (20 mL), dried over
Na2SO4, filtered and evaporated. Purification of the residue
by column chromatography, eluting with cyclohexꢀ
ane/EtOAc (40:60), furnished the phenolic alcohol 26 as a
25
as an orange amorphous solid: mp 49ꢀ50 °C; [
(c = 0.40, CHCl3); IR (neat):
1; 1H NMR (CDCl3, 300 MHz):
α]
= +32.5
D
ν
= 2922, 1726, 1494, 1155 cmꢀ
= 1.42 (s, 9H), 3.12 (d, J =
δ
7.2 Hz, 2H), 3.50 (s, 3H), 4.19 (t, J = 7.0 Hz, 1H), 4.36 (d, J
= 7.2 Hz, 2H), 4.60 (q, J = 7.4 Hz, 1H), 5.15ꢀ5.30 (m, 2H),
5.68 (d, J = 8.0 Hz, 1H), 6.96 (t, J = 7.2 Hz, 1H), 7.19 (dt, J
= 7.9, 16.9 Hz, 3H), 7.27ꢀ7.36 (m, 2H), 7.41 (t, J = 7.3 Hz,
2H), 7.57 (t, J = 7.1 Hz, 2H), 7.77 (d, J = 7.5 Hz, 2H); 13C
NMR (CDCl3, 75.5 MHz):
δ = 171.2, 155.7, 155.5, 143.8
(2C), 141.2, 131.2 (2C), 128.4, 127.5 (2C), 126.9 (2C),
125.6, 125.0 (2C), 121.7, 119.8 (2C), 114.0, 94.6, 81.7, 66.7,
56.1, 54.9, 47.0, 33.4, 27.8 (3C); LRMS (ESIMS): m/z (%) =
528 (30), 526 (100) [MNa+], 504 (47) [MH+]; HRMS (ESI)
calcd for C30H34NO6 504.2381, found 504.2391.
white amorphous solid (220 mg, 91%): mp 159ꢀ160 °C;
25
[
α]
D = +26.7 (c = 0.45, acetone); IR (neat):
ν
= 3318, 1710,
1703, 1692, 1525 cmꢀ1; 1H NMR (acetoneꢀd6, 300 MHz):
2.81ꢀ2.97 (m, 2H), 3.61 (s, 2H), 3.82ꢀ3.98 (m, 1H), 4.07 (m,
δ =
(+)-N-Fmoc 3-amino-3,4-dihydrocoumarin (24). To a
stirred solution of 23 (100 mg, 0.199 mmol) was added
Et3SiH (95 µL, 0.596 mmol) and TFA (307 µL, 3.98 mmol).
1H), 4.13ꢀ4.43 (m, 3H), 6.44 (d, J = 7.2 Hz, 1H), 6.78 (td, J
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The Journal of Organic Chemistry
= 1.1, 7.5 Hz, 1H), 6.87 (dd, J = 1.2, 8.1 Hz, 1H), 7.03ꢀ7.10 2.66 (m, 2H), 2.72ꢀ2.83 (m, 1H), 3.28 (d, J = 8.4 Hz, 1H),
1
2
3
4
5
6
7
8
(m, 1H), 7.17 (d, J = 7.3 Hz, 1H), 7.31 (tdd, J = 1.2 , 3.4, 7.5
Hz, 2H), 7.40 (t, J = 7.5 Hz, 2H), 7.66 (d, J = 7.4 Hz, 2H),
7.84 (d, J = 7.5 Hz, 2H), 8.52 (s, 1H); 13C NMR (acetoneꢀd6,
3.51 (d, J = 5.8 Hz, 1H), 3.58 (d, J = 4.5 Hz, 1H), 3.66ꢀ3.78
(m, 1H), 4.16ꢀ4.28 (m, 2H), 4.29ꢀ4.44 (m, 5H), 4.64 (dd, J =
9.4, 19.4 Hz, 1H), 6.17 (t, J = 8.4 Hz, 2H), 6.46 (t, J = 7.4
Hz, 1H), 6.80 (dd, J = 3.7, 10.1 Hz, 1H), 7.04 (dd, J = 8.4,
17.8 Hz, 2H), 7.26ꢀ7.36 (m, 4H), 7.36ꢀ7.44 (m, 4H), 7.69 (d,
J = 7.4 Hz, 4H), 7.86 (d, J = 7.4 Hz, 4H); 13C NMR (aceꢀ
75.5 MHz):
δ = 157.2, 156.4, 145.1 (2C), 142.1 (2C), 132.2,
128.5 (2C), 128.4, 127.9 (2C), 126.2, 126.1, 125.8, 120.8
(2C), 120.5, 116.2, 67.0, 64.0, 55.0, 48.1, 32.4; LRMS
(ESIMS): m/z (%) = 412 (100) [MNa+], 391 (15), 390 (65)
[MH+]; HRMS (ESI) calcd for C24H24NO4 390.1700, found
390.1710.
toneꢀd6, 100 MHz):
δ = 207.1, 194.7, 174.2, 173.9, 156.7
(2C), 147.9, 144.9 (4C), 142.1 (4C), 132.4, 131.7, 129.2
(2C), 128.6 (4C), 128.0 (4C), 126.1 (3C), 120.8 (4C), 82.9,
80.9, 67.4, 52.3, 51.4, 51.3, 50.7, 50.6, 47.9, 45.7, 43.8, 42.8,
39.7, 37.4; LRMS (ESIMS): m/z (%) = 827 (4), 826 (32),
825 (100) [MNa+]; HRMS (ESI) calcd for C48H38N2NaO10
825.2424, found 825.2439.
9
(+)-N-Fmoc-O-(tert-butyldimethylsilyl)-(2S)-2-amino-3-
(2-hydroxyphenyl)propanol (27a). To a stirred iceꢀcold
solution of phenolic alcohol 26 (215 mg, 0.55 mmol) in dry
CH2Cl2 (25 mL) was added freshly distilled iPr2NEt (563 µL,
3.31 mmol). The resulting solution was stirred at 0 °C for 20
min, after which time TBSOTf (380 µL, 1.66 mmol) was
added dropwise at 0 °C. The reaction mixture was stirred an
additional 15 min, after which time it was quenched by addꢀ
ing saturated aqueous NaHCO3 (30 mL), and extracted with
CH2Cl2 (3 × 20 mL). The combined organic layers were then
shaken vigorously with 1M aqueous HCl for 5 min. The
layers were separated and the aqueous phase was further
extracted with CH2Cl2 (3 × 10 mL). The combined organic
layer was dried over Na2SO4, filtered and evaporated. Purifiꢀ
cation of the residue by column chromatography, eluting
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
2nd cyclodimer (30’ or 30), which corresponds to the lower
spot on preparative TLC, was isolated as a white amorphous
25
solid: [
α]
D = –16.2 (c = 0.40, acetone); IR (neat):
ν
= 2971,
2934, 1717, 1665, 1567, 1164 cmꢀ1; H NMR (acetoneꢀd6,
1
300 MHz): = 2.15 (d, J = 12.1 Hz, 1H), 2.28ꢀ2.52 (m, 2H),
δ
2.94 (dd, J = 9.9, 12.1 Hz, 1H), 3.42 (d, J = 8.3 Hz, 1H),
3.49ꢀ3.60 m, 1H), 3.66ꢀ3.82 (m, 2H), 4.15ꢀ4.43 (m, 6H),
4.74ꢀ4.98 (m, 2H), 6.06ꢀ6.21 (m, 2H), 6.50 (t, J = 7.3 Hz,
1H), 6.81 (dd, J = 4.3, 10.0 Hz, 1H), 7.03 (dd, J = 8.8, 18.0
Hz, 2H), 7.31 (t, J = 7.3 Hz, 4H), 7.40 (d, J = 7.3 Hz, 4H),
7.68 (dd, J = 3.9, 10.0 Hz, 4H), 7.85 (d, J = 7.4 Hz, 4H); 13
C
with cyclohexane/EtOAc (90:10), afforded the phenol 27a as
NMR (acetoneꢀd6, 75.5 MHz):
δ = 204.9, 193.3, 174.0,
25
a pale brown solid (220 mg, 79%): mp 38ꢀ39 °C; [
+40.0 (c = 0.30, CHCl3); IR (neat):
α]
=
D
173.7, 156.7 (2C), 147.5, 144.9 (4C), 142.1 (4C), 135.4,
131.1, 129.8 (2C), 128.6 (4C), 128.0 (4C), 126.1 (3C), 120.8
(4C), 83.1, 80.3, 67.5, 67.4, 52.4, 50.6, 49.8, 47.9, 43.3, 41.4,
40.3, 39.2, 37.6; LRMS (ESIMS): m/z (%) = 827 (11), 826
(55), 825 (100) [MNa+]; HRMS (ESI) calcd for
C48H38N2NaO10 825.2424, found 825.2435.
ν
= 2922, 1726, 1494,
1
1155 cmꢀ1; H NMR (CDCl3, 300 MHz):
δ
= 0.12 (s, 3H,
Me), 0.14 (s, 3H, Me), 0.97 (s, 9H, tBu), 2.78 (dd, J = 8.9,
13.9 Hz, 1H), 2.97 (d, J = 12.6 Hz, 1H), 3.61 (s, 2H), 3.78 (s,
1H), 4.25 (t, J = 6.9 Hz, 1H, Fmoc CH), 4.46 (d, J = 7.2 Hz,
2H, Fmoc CH2), 5.19 (bd, J = 6.9 Hz, 1H, OH), 6.84 (td, J =
1.2, 7.5 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 7.5
Hz, 1H), 7.12ꢀ7.20 (m, 1H), 7.32 (td, J = 1.2, 7.4 Hz, 2H),
7.42 (t, J = 7.2 Hz, 2H), 7.60 (dd, J = 6.0, 12.6 Hz, 3H), 7.78
N-Cyclohexyl-2-iodylbenzamide (31). To a stirred iceꢀ
cold solution of commercially available 2ꢀiodobenzoic acid
(1.0 g, 4.03 mmol, 1 eq.) in dry CH2Cl2 (40 mL) was added
dropwise Ghosez’s reagent (i.e., 1ꢀchloroꢀN,N,2ꢀtrimethylꢀ1ꢀ
propenylamine, 0.8 mL, 6.05 mmol). The resulting solution
was warmed up to room temperature, and stirred for 30 min,
after which time it was cooled again at 0 °C for the addition
of cyclohexylamine (0.5 mL, 4.23 mmol) and freshly disꢀ
tilled Et3N (1.1 mL, 8.06 mmol). After warming to room
temperature, the reaction mixture was stirred for 1.5 h, after
which time it was successively washed with saturated aqueꢀ
ous NaHCO3 (2 × 30 mL) and 1M aqueous HCl (2 × 30 mL).
The layers were separated, and the aqueous phase was exꢀ
tracted with CH2Cl2 (3 × 15 mL). The combined organic
layers were dried over Na2SO4, filtered and evaporated. The
resulting solid residue was purified by column chromatogꢀ
raphy, eluting with cyclohexane/EtOAc (70:30), to afford the
Nꢀcyclohexylꢀ2ꢀiodobenzamide as a white powder (1.20 g,
(d, J = 7.5 Hz, 2H); 13C NMR (CDCl3, 75.5 MHz):
δ =
156.7, 155.7, 143.8, 143.7, 141.3 (2C), 131.1, 128.5, 127.7
(2C), 127.0 (2C), 125.03, 124.97, 122.9, 120.2, 120.0 (2C),
116.8, 67.0, 62.3, 52.8, 47.2, 31.8, 25.8 (3C), 18.3, –5.40, –
5.43; LRMS (ESIMS): m/z (%) = 527 (13), 526 (35) [MNa+],
505 (40), 504 (100) [MH+]; HRMS (ESI) calcd for
C30H38NO4Si 504.2565, found 504.2575.
Spirolactone-based [4+2]-Cyclodimers 30 and 30’. To a
stirred solution of phenolꢀcarboxylic acid 25 (199 mg, 0.49
mmol) in dry CH2Cl2 (20 mL), cooled at 0 °C or –20 °C, was
added NaHCO3 (46 mg, 0.54 mmol). After 5 min stirring,
PhI(OAc)2 (174 mg, 0.54 mmol) or PhI(OCOCF3)2 (232 mg,
0.54 mmol) was added in one portion, and the reaction mixꢀ
ture was stirred at the same temperature for 3 hours, after
which time the solvent was evaporated. The resulting orange
oily residue was purified by column chromatography, eluting
with CH2Cl2/EtOAc (75:25), to afford a 1:1 mixture of cyꢀ
clodimer 30 and 30’ (85 mg, 43%). Further purification of 20
mg of this mixture was achieved by preparative TLC, eluting
four times with CH2Cl2/EtOAc (85:15), to give 7 and 8 mg
of each cyclodimer (i.e., 15% yield for each product).
90%): IR (neat):
(DMSOꢀd6, 300 MHz):
ν
= 3230, 1655, 504 cmꢀ1; 1H NMR
= 1.01ꢀ2.00 (m, 10H), 3.70 (s, 1H),
δ
7.14 (t, J = 7.2 Hz, 1H), 7.27 (d, J = 6.5 Hz, 1H), 7.42 (t, J =
7.2 Hz, 1H), 7.85 (d, J = 7.7 Hz, 1H), 8.23 (d, J = 7.5 Hz,
1H); 13C NMR (DMSOꢀd6, 75.5 MHz):
δ = 168.0, 143.5,
138.8, 130.4, 127.9, 127.8, 93.6, 48.1, 32.2 (2C), 25.2, 24.7
(2C); LRMS (ESIMS): m/z (%) = 681 (15) [2M+Na+], 352
(100) [MNa+]. This material (200 mg, 0.554 mmol) was next
oxidized at 0 °C with freshly prepared 3,3ꢀdimethyldioxirane
(DMDO, typically 0.07 M in acetone, 4 equiv).12e The resultꢀ
ing mixture was stirred at room temperature overnight (ca.
12 h), after which time the solvent was evaporated to give
1st cyclodimer (30 or 30’), which corresponds to the highꢀ
er spot on preparative TLC, was isolated as a white amorꢀ
25
phous solid: [
α]
D = +52.1 (c = 0.35, acetone); IR (neat):
ν
=
2950, 2927, 1721, 1650, 1548, 1245, 1119 cmꢀ1; H NMR
1
(acetoneꢀd6, 400 MHz): = 2.23 (t, J = 12.2 Hz, 1H), 2.46ꢀ
δ
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Page 12 of 15
the Nꢀcyclohexylꢀ2ꢀiodylbenzamide (31) as a white powder
(240 mg, quantitative yield), which was used without further
purification: mp 212 °C; IR (neat): = 3224, 1650, 725, 550
cmꢀ1; H NMR (DMSOꢀd6, 300 MHz):
= 1.03ꢀ1.50 (m,
560 (6), 559 (44), 558 (100) [MNa+]; HRMS (ESI) calcd for
C30H37NNaO6Si 558.2288, found 558.2284.
1
2
3
4
5
6
7
8
ν
(4S,5S,6S)-4,5-Epoxy-6-hydroxy-6-[(2S)-N-Fmoc-2-
amino-3-hydroxy)propyl]cyclohex-2-en-1-one (36a) and
(4R,5R,6R)-4,5-Epoxy-6-hydroxy-6-[(2S)-N-Fmoc-2-
1
δ
5H), 1.55ꢀ1.93 (m, 5H), 3.84 (s, 1H), 7.73 (t, J = 7.4 Hz,
1H), 7.93 (t, J = 7.4 Hz, 1H), 8.26 (dd, J = 7.6, 16.1 Hz, 2H),
amino-3-hydroxypropyl]cyclohex-2-en-1-one (37a).
A
9.04 (d, J = 7.6 Hz, 1H); 13C NMR (DMSOꢀd6, 75.5 MHz):
δ
stirred solution of 34a/35a (66:34 diastereomeric mixture, 20
mg, 0.037 mmol) in a 1:1 mixture of THF/H2O (2 mL) was
treated with glacial AcOH (3 mL) at room temperature, and
the resulting mixture was stirred overnight (ca. 12 h). Next,
the solution was diluted with EtOAc (40 mL), and was
poured dropwise onto vigorously stirred saturated aqueous
NaHCO3 (150 mL). Stirring was kept for 15 min, after which
time the layers were separated. The aqueous phase was exꢀ
tracted with EtOAc (3 × 20 mL). The combined organic
layers were washed with brine (20 mL), dried over Na2SO4,
filtered and evaporated to dryness. The resulting oily residue
(17 mg) was purified by preparative TLC, eluting three times
with EtOAc/acetone (20:1), to afford 36a as a pale yellow oil
(9 mg, 58%) and 37a as a colorless oil (4 mg, 28%).
25
= 164.9, 149.0, 132.7, 131.3, 128.7, 127.1, 123.1, 49.5, 32.0
(2C), 25.1, 24.8 (2C); LRMS (ESIMS): m/z (%) = 745 (38)
[2M+Na+], 384 (100) [MNa+]; HRMS (ESI) calcd for
C13H16INNaO3 384.0073, found 384.0084.
9
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
(4S,5S,6S)-4,5-Epoxy-6-hydroxy-6-[(2S)-N-Fmoc-2-
amino-3-(tert-butyldimethylsilyloxy)propyl]cyclohex-2-
en-1-one (34a) and (4R,5R,6R)-4,5-Epoxy-6-hydroxy-6-
[(2S)-N-Fmoc-2-amino-3-(tert-butyldimethylsilyloxy)-
propyl]cyclohex-2-en-1-one (35a). A stirred solution of
phenol 27a (52 mg, 0.103 mmol) in dry CH2Cl2 (10 mL, ca.
10 mM) was cooled at –50 °C (or at –20 °C, see Table 1).
The λ5ꢀiodane reagent (R,R)ꢀ32 (72 mg, 0.113 mmol) (or
another λ5ꢀiodane, 1.1 equiv, see Table 1 and the Supporting
Information) and TFA (8 ꢀL, 0.103 mmol) were added, and
the reaction mixture was stirred at the same low temperature
until complete consumption of the starting material as indiꢀ
cated by TLC monitoring (ca. 1ꢀ3 h). Next, a solution of
freshly prepared DMDO (ca. 0.07 M in acetone, 4 equiv; i.e.,
5.9 mL, 0.412 mmol) was added at –20 °C, and the resulting
mixture was stirred overnight (ca. 12 h) at this temperature,
after which time the solvent was evaporated. The resulting
yellow oily residue was subjected to column chromatogꢀ
raphy, eluting with CH2Cl2/cyclohexane/EtOAc (4:4:1) and
then with cyclohexane/EtOAc (7:3), to give a 1:1 diastereoꢀ
meric mixture of 34a/35a as a colorless oil (33% yield). This
material was further separated by preparative TLC, eluting
three times with cyclohexane/Et2O (3:7), to furnish pure 34a
and 35a as colorless oils (10 mg each; i.e.,15% each).
25
Compound 36a: [
(neat):
= 3349, 2928, 1745, 1637 cmꢀ1; H NMR (methaꢀ
nolꢀd4, 400 MHz): = 1.80 (dd, J = 9.9, 14.5 Hz, 1H), 2.00
α]
= +17.2 (c = 0.45, MeOH); IR
D
1
ν
δ
(dd, J = 2.8, 14.5 Hz, 1H), 3.36 (dd, J = 6.3, 11.0 Hz, 1H),
3.43 (dd, J = 6.3, 11.0 Hz, 1H), 3.47 (td, J = 1.4, 3.8 Hz,
1H), 3.61 (d, J = 3.8 Hz, 1H), 3.62ꢀ3.74 (m, 1H), 4.20 (t, J =
6.3 Hz, 1H), 4.34 (dd, J = 6.3, 10.4 Hz, 1H), 4.46 (dd, J =
6.3, 10.4 Hz, 1H), 5.94 (dd, J = 1.4, 9.9 Hz, 1H), 7.05 (dd, J
= 3.8, 9.9 Hz, 1H), 7.27ꢀ7.35 (m, 2H), 7.35ꢀ7.43 (m, 2H),
7.66 (t, J = 6.7 Hz, 2H), 7.79 (d, J = 7.4 Hz, 2H); 13C NMR
(methanolꢀd4, 100 MHz):
δ = 199.8, 158.0, 145.5 (2C),
145.4, 142.69, 142.66, 132.1, 128.8 (2C), 128.2 (2C), 126.2,
126.1, 120.9 (2C), 77.5, 67.5, 65.7, 58.2, 40.2, 30.7, 29.5;
LRMS (ESIMS): m/z (%) = 445 (45), 444 (100) [MNa+], 504
(47); HRMS (ESI) calcd for C24H23NNaO6 444.1418, found
444.1425.
Compound 34a: [
(neat):
= 3352, 2937, 1748, 1642, 1226 cmꢀ1; H NMR
(CDCl3, 400 MHz): = 0.05 (s, 6H), 0.89 (s, 9H), 1.87 (dd, J
α]
= +14.3 (c = 0.70, CHCl3); IR
D
1
25
ν
Compound 37a: [
(neat):
nolꢀd4, 300 MHz):
α]
= +7.4 (c = 0.20, MeOH); IR
D
1
ν
= 3362, 2911, 1742, 1645 cmꢀ1; H NMR (methaꢀ
δ
= 9.6, 14.1 Hz, 1H), 2.01 (dd, J = 3.4, 14.5 Hz, 1H), 3.47ꢀ
3.74 (m, 4H), 3.76ꢀ3.89 (m, 1H), 4.05 (s, 1H), 4.22 (t, J = 6.4
Hz, 1H), 4.32ꢀ4.46 (m, 2H), 4.97 (d, J = 8.2 Hz, 1H), 6.12
(dd, J = 1.4, 9.6 Hz, 1H), 7.06 (dd, J = 3.4, 9.6 Hz, 1H), 7.31
(d, J = 7.4 Hz, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.53ꢀ7.63 (m,
2H), 7.76 (d, J = 7.5 Hz, 2H); 13C NMR (CDCl3, 100 MHz):
δ
= 1.80ꢀ188 (m, 2H), 3.36 (dd, J = 5.5,
10.5 Hz, 1H), 3.44 (dd, J = 5.5, 10.5 Hz, 1H), 3.47ꢀ3.52 (m,
1H), 3.64 (d, J = 3.9 Hz, 1H), 3.79ꢀ3.89 (m, 1H), 4.19 (t, J =
6.5 Hz, 1H), 4.36 (dd, J = 6.5, 10.5 Hz, 1H), 4.48 (dd, J =
6.5, 10.5 Hz, 1H), 4.57 (s, 1H), 5.89 (dd, J = 1.2, 9.9 Hz,
1H), 7.11 (dd, J = 3.9, 9.9 Hz, 1H), 7.32 (t, J = 7.3 Hz, 2H),
7.39 (t, J = 7.2 Hz, 2H), 7.66 (d, J = 7.3 Hz, 2H), 7.80 (d, J =
7.3 Hz, 2H); LRMS (ESIMS): m/z (%) = 423 (15), 422 (60)
[MH+]; HRMS (ESI) calcd for C24H24NO6 422.1598, found
422.1606.
δ
= 197.8, 155.6, 144.1, 144.0, 143.8, 141.3 (2C), 130.4,
127.7 (2C), 127.0 (2C), 125.0, 124.9, 120.0 (2C), 66.7, 65.5,
56.1, 48.2, 47.9, 47.2, 38.8, 29.7, 25.9 (3C), 18.3, –5.4, –5.5;
LRMS (ESIMS): m/z (%) = 560 (15), 559 (51), 558 (100)
[MNa+]; HRMS (ESI) calcd for C30H37NNaO6Si 558.2288,
found 558.2289.
(+)-N-Acetyl-O-(tert-butyldimethylsilyl)-(2S)-2-amino-
3-(2-hydroxyphenyl)propanol (27b). To a stirred solution
of NꢀFmoc phenol 27a (100 mg, 0.199 mmol) in dry CH2Cl2
(2 mL) was added Ac2O (0.95 mL, 9.95 mmol) and freshly
distilled Et3N (2 mL). The reaction mixture was stirred at
room temperature for 2 days, after which time the solvent
was evaporated. The resulting residue was taken in MeOH (5
mL), and treated with powdered K2CO3 (4.13 g, 29.85
mmol). Stirring at room temperature was kept for 4 h, after
which time the reaction mixture was diluted with EtOAc (15
mL), and quenched with 5% aqueous citric acid (30 mL).
The layers were then separated, and the aqueous phase was
extracted with EtOAc (3 × 10 mL). The combined organic
layers were washed with brine (20 mL), dried over Na2SO4,
25
Compound 35a: [
(neat):
(CDCl3, 400 MHz):
α
]
= +10.0 (c = 0.50, CHCl3); IR
D
1
ν
= 3365, 2912, 1744, 1630, 1255 cmꢀ1; H NMR
δ
= 0.05 (s, 6H), 0.89 (s, 9H), 1.91ꢀ1.99
(m, 2H), 3.54ꢀ3.63 (m, 3H), 3.73ꢀ3.94 (m, 3H), 4.21 (t, J =
6.4 Hz, 1H), 4.41 (d, J = 6.4 Hz, 2H), 5.01 (d, J = 7.4 Hz,
1H), 6.08 (d, J = 6.7 Hz, 1H), 7.32 (t, J = 7.4 Hz, 2H), 7.40
(t, J = 7.4 Hz, 2H), 7.53ꢀ7.62 (m, 2H), 7.77 (d, J = 7.5 Hz,
2H); 13C NMR (CDCl3, 100 MHz):
δ = 198.1, 155.6, 145.0
(2C), 143.8, 141.3 (2C), 130.0, 127.7 (2C), 127.0 (2C), 125.0
(2C), 120.0 (2C), 66.6, 65.2, 56.3, 48.8, 48.0, 47.2, 39.3,
29.7, 25.8 (3C), 18.2, –5.4, –5.5; LRMS (ESIMS): m/z (%) =
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filtered and evaporated. The resulting residue was purified stirred overnight (ca. 12 h), after which time the solvent was
1
2
3
4
5
6
7
8
by column chromatography, eluting with cyclohexꢀ
ane/EtOAc (9:1), then with CH2Cl2, and finally with
evaporated. The resulting yellow oily residue was subjected
to column chromatography, eluting with CH2Cl2/EtOAc
(9:1), to afford a 65:35 diastereomeric mixture 34c/35c as a
pale yellow oil (57 mg, 55%). Part of this material (30 mg,
0.056 mmol) was next taken in 10 mL of AcOH/THF/H2O
(3:1:1), at room temperature, and the reaction mixture was
stirred overnight (ca. 12 h). The solution was then diluted
with EtOAc (40 mL) and was poured dropwise onto vigorꢀ
ously stirred saturated aqueous NaHCO3 (150 mL). Stirring
was kept for 15 min, after which time layers were separated.
The aqueous phase was extracted with EtOAc (3 × 20 mL).
The combined organic layers were washed with brine (20
mL), dried over Na2SO4, filtered and evaporated to dryness.
The resulting oily residue (19 mg) was purified by preparaꢀ
tive TLC, eluting twice with EtOAc/acetone (20:1), to furꢀ
nish 36c (9 mg, 39%) and 37c (5 mg, 22%) as white amorꢀ
phous solids.
CH2Cl2/EtOAc (4:1), to give Nꢀacetyl phenol 27b as a pale
25
yellow oil (63 mg, 98%): [
IR (neat):
NMR (CDCl3, 300 MHz):
α
]
= +28.2 (c = 0.50, CHCl3);
D
1
ν
= 3294, 2954, 2927, 1655, 1589, 837 cmꢀ1; H
δ
= 0.11 (s, 3H), 0.13 (s, 3H), 0.95
(s, 9H), 2.05 (s, 3H), 2.72 (dd, J = 8.4, 14.1 Hz, 1H), 2.96
(dd, J = 2.4, 14.1 Hz, 1H), 3.61 (qd, J = 3.7, 10.6 Hz, 2H),
3.75ꢀ3.91 (m, 1H), 6.17 (d, J = 6.4 Hz, 1H), 6.79 (td, J = 1.2,
7.8 Hz, 1H), 6.95 (ddd, J = 1.4, 7.8, 16.3 Hz, 2H), 7.09ꢀ7.20
9
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
(m, 1H); 13C NMR (CDCl3, 75 MHz):
δ = 171.3, 156.1
130.7, 128.5, 123.2, 119.7, 116.9, 61.8, 51.9, 32.1, 25.8 (3C),
23.1, 18.3, –5.4, –5.5; LRMS (ESIMS): m/z (%) = 326 (11),
325 (39), 324 (100) [MH+]; HRMS (ESI) calcd for
C17H30NO3Si 324.1995, found 324.2010.
(+)-N-Palmitoyl-O-(tert-butyldimethylsilyl)-(2S)-2-
amino-3-(2-hydroxyphenyl)propanol (27c). To a stirred
solution of NꢀFmoc phenol 27a (198 mg, 0.393 mmol) in dry
CH2Cl2 (2 mL) was added commercially available palmitic
anhydride (778 mg, 1.57 mmol) and freshly distilled Et3N (4
mL). The reaction mixture was stirred at room temperature
for 2 days, after which time the solvent was evaporated. The
25
Compound 36c: [
α
]
= +15.4 (c = 0.04, MeOH) [lit.8d
D
27
[
α]
D = +15.0 (c = 0.04, MeOH)]; IR (neat):
ν
= 3362, 2924,
= 0.90
1743, 1242 cmꢀ1; 1H NMR (methanolꢀd4, 300 MHz):
δ
(t, J = 6.6 Hz, 3H), 1.20ꢀ1.36 (m, 24H), 1.49ꢀ1.66 (m, 2H),
1.81 (dd, J = 9.3, 14.7 Hz, 1H), 2.03 (dd, J = 3.0, 14.7 Hz,
1H), 2.08ꢀ2.18 (m, 2H), 3.41 (dd, J = 5.2, 10.9 Hz, 1H), 3.48
(dd, J = 5.2, 10.9 Hz, 1H), 3.61 (td, J = 1.4, 3.8 Hz, 1H),
3.66 (d, J = 3.8 Hz, 1H), 3.95ꢀ4.06 (m, 1H), 6.10 (dd, J =
1.4, 9.9 Hz, 1H), 7.17 (dd, J = 3.8, 9.9 Hz, 1H); 13C NMR
resulting residue was taken in
a
1:1 mixture of
MeOH/CH2Cl2 (40 mL), and treated with powdered K2CO3
(4.07 g, 29.48 mmol). Stirring at room temperature was kept
for 4 hours, after which time the reaction mixture was diluted
with EtOAc (30 mL), and quenched with 5% aqueous citric
acid (45 mL). The layers were then separated, and the aqueꢀ
ous phase was extracted with EtOAc (3 × 15 mL). The comꢀ
bined organic layers were washed with brine (30 mL), dried
over Na2SO4, filtered and evaporated. The resulting residue
was purified by column chromatography, eluting with cycloꢀ
(methanolꢀd4, 75 MHz):
δ = 199.5, 176.0, 145.8, 132.0, 77.6,
65.6, 58.2, 47.7, 39.5, 37.1, 33.1, 30.8, 30.7, 30.6, 30.5, 30.4,
26.7, 23.7, 14.4; LRMS (ESIMS): m/z (%) = 440 (6), 439
(35), 438 (100) [MH+]; HRMS (ESI) calcd for C25H44NO5
438.3214, found 438.3221.
25
Compound 37c: [
(neat):
(methanolꢀd4, 300 MHz):
α
]
= +5.4 (c = 0.03, MeOH); IR
D
1
= 3318, 2923, 2852, 1732, 1466 cmꢀ1; H NMR
hexane/EtOAc/Et3N (70:30:3:1), to afford Nꢀacetyl phenol
ν
20
27c as a colorless oil (146 mg, 72%): [
0.60, CHCl3); IR (neat):
α]
= +16.7 (c =
D
δ
= 0.90 (t, J = 6.6 Hz, 3H), 1.23ꢀ
ν
= 3294, 2925, 2854, 1650, 1459
1.37 (m, 24H), 1.50ꢀ1.65 (m, 2H), 1.86ꢀ1.93 (m, 1H), 2.03ꢀ
2.20 (m, 3H), 3.39 (dd, J = 6.0, 10.9 Hz, 1H), 3.47 (dd, J =
5.2, 10.9 Hz, 1H), 3.61 (td, J = 1.5, 3.9 Hz, 1H), 3.70 (d, J =
3.9 Hz, 1H), 4.05ꢀ4.16 (m, 1H), 6.05 (dd, J = 1.5, 9.9 Hz,
1H), 7.21 (dd, J = 1.3, 9.8, 1H); 13C NMR (methanolꢀd4, 75
1
cmꢀ1; H NMR (CDCl3, 300 MHz):
δ
= 0.11(s, 3H), 0.13 (s,
3H), 0.88 (t, J = 6.5 Hz, 3H), 0.95 (s, 9H), 1.23ꢀ1.27 (m,
24H), 1.61ꢀ1.66 (m, 2H), 2.23 (t, J = 7.5 Hz, 2H), 2.71 (dd, J
= 9.3, 14.0 Hz, 1H), 2.96 (dd, J = 2.2, 14.0 Hz, 1H), 3.62
(qd, J = 3.6, 10.5 Hz, 2H), 3.78ꢀ3.94 (m, 1H), 6.21 (d, J =
6.7 Hz, 1H), 6.78 (t, J = 7.1 Hz, 1H), 6.95 (dd, J = 7.1, 18.2
Hz, 2H), 7.08ꢀ7.18 (m, 1H), 8.64 (s, 1H); 13C NMR (CDCl3,
MHz):
δ = 200.0, 175.9, 146.5, 131.6, 77.3, 65.4, 58.1, 49.4,
40.4, 37.2, 33.1, 30.8, 30.7, 30.6, 30.5, 30.4, 26.8, 23.7, 14.4;
LRMS (ESIMS): m/z (%) = 440 (2), 439 (40), 438 (100)
[MH+]; HRMS (ESI) calcd for C25H44NO5 438.3214, found
438.3223.
75 MHz):
δ = 174.3, 156.1, 130.6, 128.3, 123.3, 119.5,
116.7, 62.0, 51.7, 36.5, 32.2, 31.9, 29.7, 29.6 (3C), 29.5
(2C), 29.4, 29.3 (2C), 29.1, 25.8 (3C), 25.6, 22.6, 18.2, 14.1,
–5.4, –5.5; LRMS (ESIMS): m/z (%) = 522 (5), 521 (45),
520 (100) [MH+]; HRMS (ESI) calcd for C31H58NO3Si
520.4181, found 520.4192.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: xxxxx
(4S,5S,6S)-4,5-Epoxy-6-hydroxy-6-[(2S)-N-palmitoyl-2-
amino-3-hydroxy)propyl]cyclohex-2-en-1-one (36c) and
(4R,5R,6R)-4,5-Epoxy-6-hydroxy-6-[(2S)-N-palmitoyl-2-
1H and 13C NMR spectra for all new compounds;
HPLC traces of 27a; computational results (PDF)
amino-3-hydroxypropyl]cyclohex-2-en-1-one (37c).
A
stirred solution of phenol 27c (100 mg, 0.192 mmol) in dry
CH2Cl2 (20mL, ca. 10 mM) was cooled at –20 °C. The λ5ꢀ
iodane reagent 31 (76 mg, 0.211 mmol) (or chiral λ5ꢀiodane
(S,S)ꢀ33, 1.1 equiv) and TFA (15 µL, 0.192 mmol) were
added, and the reaction mixture was stirred at the same low
temperature until complete consumption of the starting mateꢀ
rial as indicated by TLC monitoring (ca. 1ꢀ3 h). Next, a
solution of DMDO (ca. 0.07 M in acetone, 4 equiv; i.e., 11
mL) was added at –20 °C, and the resulting mixture was
AUTHOR INFORMATION
Corresponding Authors
*Eꢀmail: laurent.pouysegu@uꢀbordeaux.fr
*Eꢀmail: stephane.quideau@uꢀbordeaux.f
Present Address
§ Normandie Univ., COBRA, CNRS–UMR 6014, Rouen Fꢀ
76000, France.
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Page 14 of 15
Claus, R. A.; Wüstholz, A.; Müller, S.; Bockmeyer, C. L.; Riedel,
|| Syntivia, Centre Pierre Potier, BP50624, Toulouse Fꢀ31106
Cedex 1, France.
N. H.; Kinscherf, R.; Deigner, H.ꢀP. ChemBioChem 2005, 6, 726–
737. (d) Watanabe, K.; Oguchi, T.; Takizawa, T.; Furuuchi, M.;
Abe, H.; Katoh, T. Heterocycles 2007, 73, 263–268.
1
2
Notes
3
4
5
6
7
8
9
(9) (a) al Fahad, A.; Abood, A.; Fisch, K. M.; Osipow, A.; Daꢀ
vison, J.; Avramovic, M.; Butts, C. P.; Piel, J.; Simpson, T. J.; Cox,
R. J. Chem. Sci. 2014, 5, 523–527. (b) Harned, A. M.; Volp, K. A.
Nat. Prod. Rep. 2011, 28, 1790–1810. (c) Sperry, S.; Samuels, G. J.;
Crews, P. J. Org. Chem. 1998, 63, 10011–10014.
(10) Selected reviews and articles on dearomatization in natural
product synthesis: (a) Quideau, S.; Pouységu, L.; Peixoto, P. A.;
Deffieux, D. Top. Curr. Chem. 2016, 373, 25–74. (b) Sun, W.; Li,
G.; Hong, L.; Wang, R. Org. Biomol. Chem. 2016, 14, 2164ꢀ2176.
(c) Wu, W.ꢀT.; Zhang, L.; You, S.ꢀL. Chem. Soc. Rev. 2016, 45,
1570–1580. (d) Ding, Q.; Ye, Y.; Fan, R. Synthesis 2013, 45, 1–16.
(e) Zhuo, C.ꢀX.; Zhang, W.; You, S.ꢀL. Angew. Chem. Int. Ed.
2012, 51, 12662–12686. (f) Roche, S. P.; Porco, J. A., Jr. Angew.
Chem. Int. Ed. 2011, 50, 4068–4093. (g) Pouységu, L.; Deffieux,
D.; Quideau, S. Tetrahedron 2010, 66, 2235–2261.
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support from the Ministère de la Recherche, the
CNRS, the Conseil Régional d’Aquitaine, and the Agence Naꢀ
tionale de la Recherche (ANRꢀ10ꢀBLANꢀ0721; IODINNOV),
including doctoral scholarships for M.E.A., R.C and T.G., is
gratefully acknowledged. UPPA, MCIA (Mésocentre de Calcul
Intensif Aquitain) and CINES under allocation 2017
(A002080045) made by Grand Equipement National de Calcul
Intensif (GENCI) are acknowledged for computational facilities.
We thank Simafex (France) for providing us with (diaceꢀ
toxy)iodosylbenzene, and S. Desjardins (Univ. Québec à Montꢀ
réal, Master student) for his contribution to the substrateꢀ
controlled approach.
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(11) (a) Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. Rev.
2004, 104, 1383–1429. (b) Liao, C.ꢀC.; Peddinti, R. K. Acc. Chem.
Res. 2002, 35, 856–866. (c) Quideau, S.; Pouységu, L. Org. Prep.
Proc. Int. 1999, 31, 617–680.
REFERENCES
(1) (a) Tanaka, M.; Nara, F.; SuzukiꢀKonagai, K.; Hosoya, T.;
Ogita, T. J. Am. Chem. Soc. 1997, 119, 7871–7872. (b) Saito, S.;
Tanaka, N.; Fujimoto, K.; Kogen, H. Org. Lett. 2000, 2, 505–506.
(2) (a) Nara, F.; Tanaka, M.; Hosoya, T.; SuzukiꢀKonagai, K.;
Ogita, T. J. Antibiot. 1999, 52, 525–530. (b) Nara, F.; Tanaka, M.;
MasudaꢀInoue, S.; Yamasato, Y.; DoiꢀYoshida, H.; Suzukiꢀ
Konagai, K.; Kumakura, S.; Ogita, T. J. Antibiot. 1999, 52, 531–
535.
(3) (a) Wascholowski, V.; Giannis, A. Drug News Perspect.
2001, 14, 581–590. (b) Bienias, K.; Fiedorowicz, A.; Sadowska, A.;
Prokopiuk, S.; Car, H. Pharmacol. Rep. 2016, 68, 570–581.
(4) (a) Inoue, M.; Yokota, W.; Murugesh, M. G.; Izuhara, T.;
Katoh, T. Angew. Chem. Int. Ed. 2004, 43, 4207–4209. (b) Takagi,
R.; Miyanaga, W.; Tojo, K.; Tsuyumine, S.; Ohkata, K. J. Org.
Chem. 2007, 72, 4117–4125. (c) Inoue, M.; Yokota, W.; Katoh, T.
Synthesis 2007, 622–637. (d) Fujioka, H.; Sawama, Y.; Kotoku, N.;
Ohnaka, T.; Okitsu, T.; Murata, N.; Kubo, O.; Li, R.; Kita, Y.
Chem. Eur. J. 2007, 13, 10225–10238. (e) Pitsinos, E.; Athinaios,
N.; Xu, Z.; Wang, G.; Negishi, E.ꢀi. Chem. Commun. 2010, 46,
2200–2202.
(5) (a) Hoye, T. R.; Tennakoon, M. A. Org. Lett. 2000, 2, 1481–
1483. (b) Tan, Z.; Negishi, E.ꢀi. Angew. Chem. Int. Ed. 2004, 43,
2911ꢀ2914. (c) McAllister, G. D.; Taylor, R. J. K. Tetrahedron Lett.
2004, 45, 2551ꢀ2554. (d) Takagi, R.; Tsuyumine, S.; Nishitani, H.;
Miyanaga, W.; Ohkata, K. Aust. J. Chem. 2004, 57, 439–447.
(6) (a) Arenz, C.; Giannis, A. Angew. Chem. Int. Ed. 2000, 39,
1440–1442. (b) Arenz, C.; Gartner, M.; Wascholowski, V.; Giannis,
A. Bioorg. Med. Chem. 2001, 9, 2901–2904. (c) Runcie, K. A.;
Taylor, R. J. K. Org. Lett. 2001, 3, 3237–3239. (d) Pitsinos, E. N.;
Wascholowski, V.; Karaliota, S.; Rigou, C.; Couladouros, E. A.;
Giannis, A. ChemBioChem 2003, 4, 1123–1125. (e) Tagaki, R.;
Tojo, K.; Iwata, M.; Ohkata, K. Org. Biomol. Chem. 2005, 3, 2031–
2036. (f) Pitsinos, E. N.; Cruz, A. Org. Lett. 2005, 7, 2245–2248.
(g) Cha, J. Y.; Burnett, L. G.; Huang, Y.; Davidson, J. B.; Pettus, T.
R. R. J. Org. Chem. 2011, 76, 1361–1371.
(7) (a) Fujioka, H.; Kotoku, N.; Sawama, Y.; Nagatomi, Y.; Kita,
Y. Tetrahedron Lett. 2002, 43, 4825–4828. (b) Murray, L. M.;
O’Brien, P.; Taylor, R. J. K. Org. Lett. 2003, 5, 1943ꢀ1946. (c)
Katoh, T.; Izuhara, T.; Yokota, W.; Inoue, M.; Watanabe, K.;
Nobeyama, A.; Suzuki, T. Tetrahedron 2006, 62, 1590–1608. (d)
Fraser, C. J.; Howell, G. P.; Harrity, J. P. A. Org. Biomol. Chem.
2012, 10, 9058–9066. (e) Mehta, G.; Modugu, N. R. J. Org. Chem.
2013, 78, 3367ꢀ3373. (f) Kuwata, K.; Suzuki, M.; Inami, Y.;
Hanaya, K.; Sugai, T.; Shoji, M. Tetrahedron Lett. 2014, 55, 2856–
2858.
(12) (a) Pouységu, L.; Sylla, T.; Garnier, T.; Rojas, L. B.; Charꢀ
ris, J.; Deffieux, D.; Quideau, S. Tetrahedron 2010, 66, 5908ꢀ5917.
(b) Pouységu, L.; Chassaing, S.; Dejugnac, D.; Lamidey, A.ꢀM.;
Miqueu, K.; Sotiropoulos, J.ꢀM.; Quideau, S. Angew. Chem. Int. Ed.
2008, 47, 3552–3555. (c) Quideau, S.; Fabre, I.; Deffieux, D. Org.
Lett. 2004, 6, 4571–4573. (d) Mejorado, L. H.; Hoarau, C.; Pettus,
T. R. R. Org. Lett. 2004, 6, 1535–1538. (e) Coffinier, R.; El Assal,
M.; Peixoto, P. A.; Bosset, C.; Miqueu, K.; Sotiropoulos, J.ꢀM.;
Pouységu, L.; Quideau, S. Org. Lett. 2016, 18, 1120–1123. (f)
Bosset, C.; Coffinier, R.; Peixoto, P. A.; El Assal, M.; Miqueu, K.;
Sotiropoulos, J.ꢀM.; Pouységu, L.; Quideau, S. Angew. Chem. Int.
Ed. 2014, 53, 9860–9864. (g) Quideau, S.; Lyvinec, G.; Marguerit,
M.; Bathany, K.; OzanneꢀBeaudenon, A.; Buffeteau, T.; Cavagnat,
D.; Chénedé, A. Angew. Chem. Int. Ed. 2009, 48, 4605–4609. (h)
Dohi, T.; Maruyama, A.; Takenaga, N.; Senami, K.; Minamitsuji,
Y.; Fujioka, H.; Caemmerer, S. B.; Kita, Y. Angew. Chem. Int. Ed.
2008, 47, 3787–3790.
(13) (a) Yoshimura, A.; Zhdankin, V. V. Chem. Rev. 2016, 116,
3328–3435. (b) Berthiol, F. Synthesis 2015, 47, 587–603. (c)
Romero, R. M.; Wöste, T. H.; Muñiz, K. Chem. Asian J. 2014, 9,
972–983. (d) Parra, A.; Reboredo, S. Chem. Eur. J. 2013, 19,
17244–17260.
(14) Gagnepain, J.; Méreau, R.; Dejugnac, D.; Léger, J.ꢀM.; Casꢀ
tet, F.; Deffieux, D.; Pouységu, L.; Quideau, S. Tetrahedron 2007,
63, 6493–6505.
(15) DFT calculations were also performed with B3LYP funcꢀ
tional, B3LYP taking into account the solvent (i.e., THF), and B97D
functional including dispersion. All of these calculations gave
similar results (see the Supporting Information).
(16) (a) Adam, W.; Wirth, T. Acc. Chem. Res. 1999, 32, 703–
710. (b) Henbest, H. B.; Wilson, R. A. L. J. Chem. Soc. 1957, 1958ꢀ
1965.
(17) Yang, S. G.; Hwang, J. P.; Park, M. Y.; Lee, K.; Kim, Y. H.
Tetrahedron 2007, 63, 5184–5188.
(18) (a) Barfoot, C. W.; Harvey, J. E.; Kenworthy, M. N.;
Kilburn, J. P.; Ahmed, M.; Taylor, R. J. K. Tetrahedron 2005, 61,
3403–3417. (b) Kenworthy, M. N.; Kilburn, J. P.; Taylor, R. J. K.
Org. Lett. 2004, 6, 19–22. (c) Foubelo, F.; Yus, M. Tetrahedron:
Asymmetry 1996, 7, 2911–2922, and references therein.
(19) When dianion 16’ reacted with cyclohexanone, the expected
1,2ꢀadduct18a,b was isolated as a 1:1 diastereomeric mixture in ca.
80% yield, thus confirming the correct handling of the dilithium
salt.
(20) (a) Rao, M. N.; Kumar, P.; Singh, A. P.; Reddy, R. S. Synth.
Commun. 1992, 22, 1299–1305. (b) Lipshutz, B. H.; Pollart, D.;
Monforte, J.; Kotsuki, H. Tetrahedron Lett. 1985, 26, 705–708. (c)
Wipf, P.; Kim, Y.; Jahn, H. Synthesis 1995, 1549–1561. (d) Aubert,
(8) (a) Kenworthy, M. N.; McAllister, G. D.; Taylor, R. J. K.
Tetrahedron Lett. 2004, 45, 6661–6664. (b) Wascholowski, V.;
Giannis, A.; Pitsinos, E. N. ChemMedChem 2006, 1, 718–721. (c)
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C.; Gotteland, J.ꢀP.; Malacria, M. J. Org. Chem. 1993, 58, 4298–
4305.
(21) Deboves, H. J. C.; Montalbetti, C. A. G. N.; Jackson, R. F.
W. J. Chem. Soc., Perkin Trans. 1 2001, 1876–1884.
(22) The absence of racemization during this acidꢀpromoted
lactonisation step was checked by comparison with the outcome of
the same synthesis sequence run using DLꢀserine. HPLC traces of
the resulting phenols (+)ꢀ27a and (±)ꢀ27a, respectively, are given in
the Supporting Information (see Figure S1).
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