Asymmetric synthesis of: Trans -4,5-disubstituted γ-butyrolactones involving a key allylboration step. First access to (-)-nicotlactone B and (-)-galbacin

Article abstract of DOI:10.1039/c8ob00101d

An efficient asymmetric synthesis of trans-4,5-disubstituted γ-butyrolactones from aldehydes and enantioenriched γ-carbamate alkenylboronates is reported. The cornerstone of this strategy is the implementation of sequential [3,3]-allyl cyanate rearrangement/allylboration/nucleophilic addition/cyclisation reactions. Diverse γ-butyrolactones such as the flavouring compounds, (+)-trans-whiskey lactone and (+)-trans-cognac lactone, as well as an advanced intermediate towards the first synthesis of natural products, (-)-nicotlactone B and (-)-galbacin, have thus been obtained.

Full text of DOI:10.1039/c8ob00101d

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: S. Henrion, A.
Macé, M. M. Vallejos, T. Roisnel, B. Carboni, J. Villalgordo and F. Carreaux, Org. Biomol. Chem., 2018,
DOI: 10.1039/C8OB00101D.
This is an Accepted Manuscript, which has been through the
Volume 14 Number
1 7 January 2016 Pages 1–372
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

Please do not adjust margins
Page 1 of 7
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C8OB00101D
Journal Name
ARTICLE
Asymmetric synthesis of trans-4,5-disubstituted γ-butyrolactones
involving a key allylboration step. First access to (-)-nicotlactone B
and (-)-galbacin
Received 00th January 20xx,
Accepted 00th January 20xx
S. Henrion,a A. Macé,a M. M. Vallejos,b T. Roisnel, a B. Carboni,a J. M. Villalgordoc and F. Carreaux a*
DOI: 10.1039/x0xx00000x
An efficient asymmetric synthesis of trans-4,5-disubstituted γ-butyrolactones from aldehydes and enantioenriched γ-
carbamate alkenylboronates is reported. The cornerstone of this strategy is the implementation of sequential [3,3]-allyl
cyanate rearrangement/allylboration/nucleophilic addition/cyclisation reactions. Diverse γ-butyrolactones have thus been
obtained such as the flavouring compounds, (+)-trans-whiskey lactone and (+)-trans-cognac lactone, as well as an
www.rsc.org/
advanced intermediate towards the first synthesis of natural products, (-)-nicotlactone
B and (-)-galbacin.
Introduction
Trans-4,5-disubstituted-γ-butyrolactones represent a class of
compounds whose the structural unit can be encountered in
widespread naturally occurring substances as sex-attractant
pheromones
(Figure 1).1 That structural motif can also be used as a
construction platform to access biologically significant
alkylidene y-butyrolactones,2 such as the
-methylene
derivative which inhibits in vitro the growth of HL-60 myeloid
1 as well as the flavouring components 2 and 3
α
-
α
4
leukemia cells by activating apoptosis with no obvious toxic
side effects in T-lymphocytes or in murine splenocytes.3 In
addition, the 4,5-disubstituted five-membered ring lactones
was also considered as useful synthetic intermediates to
Fig.1 Structure of some biologically active substituted γ-butyrolactones and 2,5-diaryl-
3,4-disubstituted tetrahydrofuran lignans.
prepare lignans having
a
2,5-diaryl-3,4-disubstituted
Several strategies have been hitherto developed for the
tetrahydrofuran scaffold by alkylation and subsequent
introduction of an aromatic group, respectively at the C3 and
C2 positions.4 As an example, the biologically active natural
product (+)-galbacin has been obtained by this approach.5 To
the best of our knowledge, the synthesis of its optical antipod,
stereoselective synthesis of γ-lactones, only a few allow access
to a broad structural and stereochemical diversity.6 Taking into
account that functionalized homoallylic alcohols can be
considered as potential building blocks for the preparation of
lactone skeleton, the stereoselective allylboration of carbonyl
compounds has been successfully incorporated in various
synthetic approaches.7 Regarding the preparation of trans-4,5-
(-)-galbacin 5, was not reported to date. For all these reasons,
the development of new asymmetric syntheses of such
compounds is always of interest and more specially when
sequential one-pot procedure is implemented in order to
reduce purification steps, and minimize time and efforts.
disubstituted-γ-butyrolactones, chiral unfunctionalized (E)-
substituted allylboron reagents were used to give the final
products with excellent enantioselectivities.8 However, it
requires several steps since the resulting homoallylic alcohols
must be converted into diols via a hydroboration-oxidation
sequence followed by a selective oxidation of primary alcohols
before obtaining the expected five membered-rings. The
a Univ Rennes, CNRS, ISCR [(Institut des Sciences Chimiques de Rennes)] - UMR
6226, F-35000 Rennes, France. E-mail : francois.carreaux@univ-rennes1.fr.
bLaboratorio de QuÍmÍca Organica. Universidad Nacional del Nordeste. CONICET,
FACENA, Avenida Libertad 5460. Corrientes, 3400, Argentina.
reaction of chiral (E)-
aldehydes provides a more straightforward access to the
disubstituted -lactones via the formation of -sulfonamido
α-sulfonamidocrotylboronate with
γ
γ
cVillaPharma Research, Parque Tecnológico de Fuente Alamo, Ctra El Estrecho-
Lobosillo, Av. Azul, 30320 Murcia, Spain.
homoallyl alcohols which can be further easily cyclized into
Electronic Supplementary Information (ESI) available: Characterization and NMR lactol ethers.9 Nevertheless, the reactivity of this boronic ester
spectra of all compounds. DFT and computational data. Crystallographic data in CIF
. See DOI: 10.1039/x0xx00000x
with aldehydes is lower than usual, which implies, either
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 7
ARTICLE
Journal Name
heating at elevated temperature, or the use of high pressure at A large variety of compounds have thus been obtVaieinweAdrticalesOwnleinlel
room temperature for several days to obtain good yields. In all as
-butyrolactone natural products likeDtOhIe: 10(+.1)0-3tr9a/Cn8sO-wB0h0is1k0e1Dy
γ
cases, the purification of the key starting allylboronates can be lactone and (+)-trans-cognac lactone. As evidence of the
tedious depending upon the nature of chiral auxiliary located efficiency of this strategy, the first total syntheses of (-)-
on the boron atom and (or) the presence of a functional group nicotlactone B and (-)-galbacin were also described.
at alpha position to the boronate ester.
Keeping this in mind, one-pot procedures in situ generating
Results and discussion
the formation of allylboron reagents, before the subsequent
addition to carbonyl compounds, have emerged as efficient
The enantioenriched carbamate (S,E)-6a (98% ee) was first
synthetic tools to achieve such transformation. In this respect,
chosen as starting material for the optimization of the
the Miyaura’s group described an elegant and short synthesis
strategy. This last one can be prepared in multigram-scale
quantities from (S)-but-3-yn-2-ol.12 Dehydration reaction of
carbamate into cyanate group can be performed mainly under
two conditions.14 In our case, we favoured the use of the
trifluoroacetic anhydride (TFAA) as reagent in place of
triphenylphosphine in order to avoid the formation of the
corresponding oxide which can be difficult to remove. After 1h
at room temperature in the presence of triethylamine, the
of trans-4,5-disubstituted-γ-butyrolactones starting from (R,R)-
tartrate allyl boronate.10 The reaction with methyl 3-butenoate
under cross-metathesis conditions led to the stereoselective
formation of the linear (E)-allylboronate, which is directly
trapped with aldehydes before carrying out the last
lactonization step. Unfortunately, this process suffers from low
enantioselectivity.
As part of our efforts to develop sequential reactions
involving an allylboration step,11 we recently reported a [3,3]-
sigmatropic rearrangement/allylboration/cyclisation sequence
allowing to obtain optically pure functionalized seven-
membered ring carbamates from enantioenriched compounds
formation of the α-isocyanato allylboronate 7a resulting from
the domino dehydration/rearrangement sequence was
evaluated as complete by NMR-spectroscopic analysis of the
crude mixture (Scheme 3).15 The allyl boronate 7a was directly
treated without purification with aromatic aldehydes, and
then followed by addition of methanol. Using the 4-
nitrophenyl benzaldehyde, the acyclic enecarbamate 8aa was
6
(Figure 2).12 From a similar approach and taking advantage of
the fact that the homoallylic alcohols resulting from the
addition of -isocyanato allylboronic esters to aldehydes are
1
α
7
formed as single diastereomer (determined by H NMR) and
obtained as their protected O-Bpin form, we envisaged that
such intermediates could be subjected to an intermolecular
obtained with 89% overall yield from 6a after chromatographic
purification. In the case of the 4-fluorophenyl benzaldehyde,
an 1H NMR study of the crude product showed that the
formation of the desired enecarbamate 8ab was accompanied
by an important quantity of the five-membered ring 9ab (ratio
of 16/84 respectively), which probably comes from 8ab via an
intramolecular addition of the secondary alcohol to an iminium
species. These two structurally isomeric compounds cannot be
separated easily by purification on silica gel. Fortunately,
treatment under acidic conditions allowed the complete
trapping by addition of
corresponding acyclic enecarbamates
cyclization should lead to (tetrahydrofuran-2-yl)ethers
precursors to the
-lactone framework.13 In this paper, we
report our efforts regarding the implementation of this new
a
nucleophile to afford the
. An acid-catalyzed
as
8
9
γ
approach for
disubstituted
a
stereocontrolled synthesis of trans-4,5-
γ-butyrolactones 11 Asymmetric one-pot
sequential transformations were employed permitting the
.
synthesis of desired
of intermediates.
γ-butyrolactones without any purification
conversion of enecarbamates
8
into substituted 3-
aminotetrahydrobenzofurans, 9.
TFAA, Et3N,
pinB
pinB
CH2Cl2
0 °C, 1h
O
O
N
O
(S,E)-6a,
NH2
98% ee
OBPin
pinB
RCHO
MeOH
R
r.t., 12h
r.t., 12h
NCO
NCO
7a
OH
O
Ar = 4-NO2-C6H4, 89%,
+
MeO
R
ratio 8aa/9aa,100/0
Ar = 4-F-C6H4, 56%,
ratio 8ab/9ab, 16/84
R
N
H
O
O
NH
8
9
OMe
HCl 4N aq.,
CH2Cl2, r.t., 1h
Fig. 2 Strategy for the asymmetric synthesis of trans-4,5-disubstituted
butyrolactones from -carbamate alkenylboronates 6.
γ-
γ
Scheme 3 Synthesis of carbamates
8
and
9
from (S,E)-6a
.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Page 3 of 7
Organic & Biomolecular Chemistry
Journal Name
ARTICLE
1) TFAA, Et3N,
View Article Online
pinB
R1
DOI: 10.1m0-3C9P/BCA8,OCBH00C1l20,1D
CH2Cl2, 0 °C, 1h
2
10
11
2) R2CHO, r.t., 12h
3) MeOH, r.t., 12h
4) HCl 4N dioxane
MeOH, r.t., 2h
BF3.OEt2, 0 °C, 1h
O
O
(not isolated)
NH2
(S,E)-6a, R1 = Me
(R,E)-6a, R1 = Me
(S,E)-6b, R1 = C5H11
One-pot procedure
O
O
Scheme 4 Transformation of 9 into γ-butyrolactones 11.
F
O
O
O
O
NO2
11ab, 58%, >95% de
These latter can be considered as suitable intermediates to
11aa, 87%, >95% de
11ac 46%, >95% de
access
γ-butyrolactones. Indeed, the N,O-acetals 9aa and 9ab
can be efficiently transformed into the corresponding
γ-lactol
O
O
Br
methyl ethers 10 with methanol using a 4N hydrogen chloride
solution in dioxane.16 Subsequent oxidation by m-CPBA in the
presence of boron trifluoride etherate led to the expected
lactones 11aa and 11ab (Scheme 4). At this point of the work,
the enantiomeric excess was measured by chiral HPLC as being
of 98% (see supporting information). Compared to the starting
material (S,E)-6a, we can conclude that during all these
transformations, no loss of chirality occurred.17
11ae, 64%, >95% de
O
O
O
O
CF3
11ad, 81%, >95% de
11af, 40%, >95% de
O
O
OMe
O
11ah, 30%, >95% de
O
OMe
O
O
O
O
OMe
On the basis of these experimental results, we assumed
that there was still room for improvement of the procedure. In
fact, using appropriate acidic conditions in the presence of
11ai, 42%, >95% de
11ag, 47%, >95% de
C5H11
O
O
methanol, the enecarbamate intermediates
transformed into the corresponding -lactol methyl ethers 10
After some adjustments, we selected the optimized protocol,
shown in Scheme 5. Starting from (S,E)-6a, the -lactol methyl
8 could be directly
11ak, 40%, >95% de
γ
.
C4H9
O
O
O
((+)-Cognac lactone)
O
NO2
11aj, 40%, >95% de
11ba, 73%, >95% de
γ
((+)-Whiskey lactone)
ethers 10 were easily obtained according to a one-pot
sequence. After evaporation of volatile components, the crude
mixture was directly engaged in an oxidation reaction during
1h at 0°C. The single purification stage of this multistep
sequence was further carried out. Using this simplified
protocol, a large variety of hithertho unknown trans-4,5-
C5H11
O
O
O
O
OMe
NO2
11bb, 32%, >95% de
11ca, 66%, >95% de
OMe
disubstituted-γ-butyrolactones 11 have been thus obtained
Scheme 5 Selected process for the asymmetric synthesis of trans-4,5-disubstituted γ-
lactones 11.
from various aldehydes with modest to good overall yields (5
steps from (S,E)-6a) and in a highly diastereoselective manner
(> 95%, evaluated by 1H NMR before purification). It is
interesting to note that this excellent diastereoselectivity was
maintained even with aromatic aldehydes possessing strongly
electron donating groups on the ring (+M effect).18 In order to
highlight the versatility of this approach, other
enantioenriched carbamates (R,E)-6a and 6b have been
prepared and used as starting materials.12,19 In all cases, the
(-)-Galbacin is a natural product isolated, inter alia, from
Talauma hodgsonii Hook, F & Thoms,22 inhibits in particular
the growth of several human tumor cell lines.23,24 Among all
the
compound 11ai could be
asymmetric synthesis of (-)-galbacin,
γ
-butyrolactones previously prepared, we speculated that
key intermediate for the
via several
a
transformations on the scaffold such as a stereoselective
alkylation step and an electrophilic aromatic substitution
reaction (EArS) as reported in Figure 6.
corresponding
obtained in
γ
a
-butyrolactones 11ba
, 11bb and 11ca were
highly stereoselective way as previously
observed, showing the good level of reliability and
generalization of this approach.
This multi-stage procedure was also applied to the
synthesis of
trans-whiskey lactone 11aj20 and (+)-trans-cognac lactone
11ak 21
giving compounds which showed NMR and optical
γ-butyrolactone natural products, such as (+)-
,
properties in full agreement with those reported in the
literature.
Fig.6 Strategy for the synthesis of (-)-galbacin from the advanced intermediate 11ai.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 7
ARTICLE
Journal Name
View Article Online
DOI: 10.1039/C8OB00101D
Scheme 7 Diastereoselectivity of the Alkylation reaction of 11ai using diverse bases.
For the purpose of developing the first asymmetric
synthesis of that tetrahydrofuran lignan, the methylation
reaction of 11ai was tried under several basic conditions using
MeI as alkylating agent (Scheme 7). When the enolate was
generated using LiHMDS as base, the major product of
alkylation was the stereoisomer 12 having a cis-configuration
between C3 and C4. The origin of this π-facial stereoselectivity
could be mainly attributed to the presence of the substituent
at C5 favouring the anti-selectivity with respect to aromatic
group by a combination of different effects in the transition
state already reported in the literature.25 A computational
study on the alkylation of lithium enolate showed that the
anti-transition structure is 0.6 kcal/mol more favourable than
the syn-transition structure in Gibbs free energy, difference
which corresponds quite exactly to the ratio observed
Scheme 8 Asymmetric syntheses of (-)-nicotlactone B and (-)-galbacin with an X-ray
crystallographic structure of 5.
experimentally
(see
supporting
information).
The
Conclusion
stereoselectivity was inversed when the alkylation reaction
was performed employing KHDMS as base under the same We described in this paper a new asymmetric synthesis of
conditions of temperature, solvent and time. Unfortunately, trans-4,5-disubstituted-
-butyrolactones through an approach
the stereoisomer 13 with the required stereochemistry to based on sequential one-pot transformations including a [3,3]
access (-)-galbacin was obtained with a low yield and cannot allyl
cyanate rearrangement/allylboration/nucleophilic
be separated from 12 by purification.26
addition followed by a cyclization reaction and an oxidation
γ
To overcome this drawback, an epimerization of 12 under step. The value and the efficiency of this method was clearly
basic conditions was planned. Treatment of 12 (ratio 89/11) demonstrated by the synthesis of various lactone natural
with MeONa in MeOH for 18h at room temperature resulted in products, including (-)-nicotlactone B, as well as a bioactive
the inversion of configuration at chiral center C3 (ratio of 8/92 tetrahydrofuran lignan, (-)-galbacin whose the synthesis had
in favour of 13) (Scheme 8). It is interesting to note that 13
,
never been reported to date.
also named (-)-nicotlactone B,27 is a natural product present in
the Australian endemic plant Austrobaileya scandens whose
no asymmetric synthesis had yet been reported so far. The
reduction of 13 with DIBAL-H, followed by an acidic treatment
in the presence of methylorthoformate and para-
Experimental section
General information
Tetrahydrofuran
(THF)
was
distilled
over
toluenesulfonic acid (APTS) in methanol led to γ-lactol methyl
sodium/benzophenone, dichloromethane (DCM) was distilled
over P2O5.Amines were distilled over potassium hydroxide.
Trifluoroacetic anhydride was distilled over P2O5. Alcohols
were distilled over calcium hydride (CaH2). Triethylamine was
distilled over KOH and stored under argon atmosphere. All
aldehydes used were distilled under vacuum. NMR spectra
were recorded on Bruker apparatus at 300, 400 or 500 MHz for
ether 14 in 67% yield as an anomeric mixture. The final step of
our synthesis is the crucial building of remaining chiral center
C2 by introduction of a 1,2-methylenedioxybenzene moiety. To
this end, a Friedel-Craft type arylation was carried out in the
presence of a stoechiometric quantity of SnCl4 in CH2Cl2 at -78
°C for 2h. Under these conditions, the desired natural product
5
was obtained in good yield (85%) as a single stereoisomer. All
1
1H and 75, 101 or 126 MHz for 13C. Chemical shifts of H and
the spectroscopic data of this synthetic compound are
identical with those of natural (-)-galbacin.24 The relative
configurations of all chiral centers of (-)-galbacin were
afterwards confirmed by analysis of its X-ray crystallographic
structure.28
13C NMR were referenced to Me4Si as internal reference. Data
are represented as follows: chemical shift (ppm), multiplicity (s
= singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br
= broad), coupling constant J (Hz) and integration. All high-
resolution mass spectra (HRMS) were recorded on a Bruker
Micro-Tof-Q II or on a Waters Q-Tof 2 at the CRMPO (Centre
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Page 5 of 7
Organic & Biomolecular Chemistry
Journal Name
ARTICLE
Régional de Mesures de Physiques de l’Ouest – Rennes- Hz), 87.7, 40.6, 37.5, 16.0; HRMS (ESI) m/VziewcAarltcicdle.Onflioner
DOI: 10.1039/C8OB00101D
+
France) using positive ion electrospray. Purifications on a silica C11H11FO2Na [M+Na] 217.0635; found 217.0636.
gel were carried out on Acros silica gel 0.006-0.200 mm, 60 A.
Analytical thin layer chromatography was performed on Merck (4S,5S)-4-methyl-5-phenyldihydrofuran-2(3H)-one (11ac)19c
20
1
Silica gel 60 F254 plates. X-ray crystallographic data were
collected on an APEXII crystal diffractometer. The optical
rotations were measured on a Perkin Elmer Model 341
polarimeter (sodium D-line: 589 nm and mercury I-line: 365
nm). Melting points were measured on a melting point
apparatus Stuart SMP10. All analytical high-performance liquid
chromatography (HPLC) were performed on an Agilent
Technologies equipped with diode array UV detectors, using
Yield: 46%, colourless oil; [α]D = - 9 (c 0.75, CHCl3); H NMR
(300 MHz, CDCl3, δ ppm) 7.45 – 7.34 (m, 5H), 5.01 (d, J = 8.5
Hz, 1H), 2.74 (dd, J = 16.0, 7.2 Hz, 1H), 2.60 – 2.46 (m, 1H), 2.40
(dd, J = 16.0, 10.6 Hz, 1H), 1.16 (d, J = 6.4 Hz, 3H); 13C NMR (75
MHz, Acetone-d6, δ ppm) 176.1, 139.7, 129.4, 129.3, 127.2,
88.4, 40.6, 37.6, 16.1; HRMS (EI) m/z calcd. for C11H12O2Na
[M+Na]+ 199.0729; found 199.0729.
Chiralcel OD-H column. Enantioenriched compounds
prepared according to a literature procedure.12
6 were
(4S,5S)-4-methyl-5-(4-(trifluoromethyl)phenyl)dihydrofuran-2(3H)-
one (11ad)
Yield: 81%, orange oil; [α]I20 = + 15 (c 0.40, CH2Cl2); H NMR
1
A general experimental procedure for γ-butyrolactones synthesis
(300 MHz, Acetone-d6, δ ppm) 7.78 (d, J = 8.0 Hz, 2H), 7.68 (d,
J = 8.0 Hz, 2H), 5.15 (d, J = 8.3 Hz, 1H), 2.77 (dd, J = 15.9, 7.0
Hz, 1H), 2.64 – 2.50 (m, 1H), 2.45 (dd, J = 15.9, 10.4 Hz, 1H),
1.21 (d, J = 6.3 Hz, 3H); 19F NMR (282 MHz, Acetone-d6, δ ppm)
-63.1; 13C NMR (75 MHz, Acetone-d6, δ ppm) 175.9, 144.5 (q, J
= 1.3 Hz), 130.9 (q, J = 32.2 Hz), 127.8, 126.4 (q, J = 3.9 Hz),
125.2 (q, J = 271.3 Hz), 123.4, 87.3, 40.7, 37.3, 16.2; HRMS (ESI)
m/z calcd. for C12H11F3O2Na [M+Na]+ 267.0603; found
267.0604.
To a solution of carbamate 6a-c (1 eq.) in dry dichloromethane
(0.10M), under argon atmosphere were added trifluoroacetic
anhydride (3 eq.) and triethylamine (4.5 eq.). The solution was
stirred at 0 °C for one hour and then, aldehyde was added. The
resulting solution was stirred at 25 °C for 12 hours. Methanol
was added and the solution was stirred at 25 °C for additional
12 hours. Methanol (20 eq.) and HCl 4N in dioxane (10 eq.)
were added and the solution was stirred at room temperature
for additionally 2 hours. The reaction medium was diluted with
dichloromethane and neutralized with NaOH 2M. The aqueous
layer was extracted with dichloromethane. The combined
organic layers were dried over MgSO4, filtered, and
concentrated under vacuo. To the crude reaction in dry
dichloromethane (0.15M), cooled at 0 °C, were added Et2O·BF3
(4S,5S)-5-(4-bromophenyl)-4-methyldihydrofuran-2(3H)-one
(11ae)
1
Yield: 64%, slight yellow oil; [α]I20 = + 41 (c 1.45, CH2Cl2); H
NMR (300 MHz, Acetone-d6, δ ppm) 7.60 (d, J = 8.5 Hz, 2H),
7.40 (d, J = 8.5 Hz, 2H), 5.02 (d, J = 8.4 Hz, 1H), 2.74 (dd, J =
15.7, 6.9 Hz, 1H), 2.58 – 2.46 (m, 1H), 2.41 (dd, J = 15.7, 10.7
Hz, 1H), 1.16 (d, J = 6.3 Hz, 3H); 13C NMR (75 MHz, Acetone-d6,
δ ppm) 175.9, 139.1, 132.5, 129.3, 122.8, 87.5, 40.6, 37.4,
16.0; HRMS (ESI) m/z calcd. for C11H11BrO2Na [M+Na]+
276.9835; found 276.9837.
(3 eq.) and
a solution of m-CPBA (3 eq.) in dry
dichloromethane (0.50M). The mixture was stirred at 0 °C for 1
hour and quenched with a saturated solution of NaHCO3. The
aqueous phase was extracted with Et2O. The combined organic
layers were dried over MgSO4, filtered, and concentrated
under vacuo. The crude product was purified by silica gel
chromatography to give the desired lactone 11
.
(4S,5S)-4-methyl-5-(p-tolyl)dihydrofuran-2(3H)-one (11af)
1
Yield: 40%, orange oil; [α]I20 = + 30 (c 0.35, CH2Cl2); H NMR
(4S,5S)-4-methyl-5-(4-nitrophenyl)dihydrofuran-2(3H)-one (11aa)
20
1
(400 MHz, CDCl3, δ ppm) 7.25 – 7.14 (m, 4H), 4.91 (d, J = 8.3
Hz, 1H), 2.78 (dd, J = 16.9, 7.6 Hz, 1H), 2.56 – 2.39 (m, 1H), 2.36
(s, 3H), 2.33 (dd, J = 16.9, 10.5 Hz, 1H), 1.18 (d, J = 6.6 Hz, 3H);
13C NMR (101 MHz, CDCl3, δ ppm) 176.3, 138.8, 135.0, 129.5,
126.1, 88.4, 39.9, 37.5, 21.3, 16.6; HRMS (ESI) m/z calcd. for
C12H14O2Na [M+Na]+ 213.0886; found 213.0887.
Yield: 87%, orange oil; [α]D = + 13 (c 1.60, CH2Cl2); H NMR
(400 MHz, Acetone-d6, δ ppm) 8.29 (d, J = 8.7 Hz, 2H), 7.73 (d,
J = 8.7 Hz 2H), 5.21 (d, J = 8.5 Hz, 1H), 2.78 (dd, J = 16.3, 7.2 Hz,
1H), 2.61 – 2.52 (m, 1H), 2.47 (dd, J = 16.3, 10.5 Hz, 1H), 1.23
(d, J = 6.5 Hz, 3H); 13C NMR (101 MHz, Acetone-d6, δ ppm)
175.8, 148.9, 147.2, 128.1, 124.5, 86.8, 40.7, 37.2, 16.1; HRMS
(ESI) m/z calcd. for C11H11NO4Na [M+Na]+ 244.0580; found
244.0579.
(4S,5S)-5-(4-methoxyphenyl)-4-methyldihydrofuran-2(3H)-one
(11ag)29
20
Yield: 47%, orange oil; [α]D20 = + 13 (c 0.75, CHCl3); litt: [α]D
=
(4S,5S)-5-(4-fluorophenyl)-4-methyldihydrofuran-2(3H)-one (11ab)
+ 12 (c 1.00, CHCl3) 1H NMR (400 MHz, CDCl3, δ ppm) 7.26 (d, J
= 8.4 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 4.88 (d, J = 8.5 Hz, 1H),
3.82 (s, 3H), 2.78 (dd, J = 16.9, 7.7 Hz, 1H), 2.54 – 2.43 (m, 1H),
2.33 (dd, J = 16.9, 10.7 Hz, 1H), 1.16 (d, J = 6.5 Hz, 3H); 13C
NMR (101 MHz, CDCl3, δ ppm) 176.2, 160.1, 129.8, 127.7,
114.2, 88.3, 55.5, 39.8, 37.6, 16.4. HRMS (ESI) m/z calcd. for
C12H14O3Na [M+Na]+ 229.0835; found 229.0836.
1
Yield: 58%, yellow oil; [α]I20 = + 30 (c 1.05, CH2Cl2); H NMR
(300 MHz, Acetone-d6, δ ppm) 7.56-7.44 (m, 2H), 7.23-7.14
(m, 2H), 5.02 (d, J = 8.6 Hz, 1H), 2.74 (dd, J = 16.0, 7.2 Hz, 1H),
2.55-2.53 (m, 1H), 2.41 (dd, J = 16.0, 10.7 Hz, 1H), 1.15 (d, J =
6.4 Hz, 3H); 19F NMR (282 MHz, Acetone-d6, δ ppm) -115.2; 13
C
NMR (75 MHz, Acetone-d6, δ ppm) 176.0, 163.6 (d, J = 245.0
Hz), 135.8 (d, J = 3.1 Hz), 129.4 (d, J = 8.5 Hz), 116.2 (d, J = 21.8
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 6 of 7
ARTICLE
Journal Name
Yield: 32%, green oil; [α]D20 = - 35 (c 0.33, CH2Cl2);V1iHewNArMticRle O(4nl0in0e
MHz, CDCl3, δ ppm) 6.90-6.81 (m, 3H), 4D.8O8I: (1d0.,10J3=9/8C.86OHBz0,0110H1D),
3.90 (s, 3H), 3.89 (s, 3H), 2.80 (dd, J = 16.9, 7.6 Hz, 1H), 2.53 –
2.43 (m, 1H), 2.34 (dd, J = 16.9, 10.8 Hz, 1H), 1.18 (d, J = 6.6 Hz,
3H); 13C NMR (101 MHz, CDCl3, δ ppm) 176.3, 149.6, 149.5,
130.3, 119.0, 111.1, 109.1, 88.5, 56.2, 56.1, 39.9, 37.6, 16.5.
HRMS (ESI) m/z calcd. for C13H16O4Na [M+Na]+ 259.0940;
found 259.0941.
(4S,5S)-5-(3,4-dimethoxyphenyl)-4-methyldihydrofuran-2(3H)-one
(11ah)
Yield: 30%, green oil; [α]I20 = + 37 (c 0.33, CH2Cl2); 1H NMR (400
MHz, CDCl3, δ ppm) 6.90 – 6.81 (m, 3H), 4.88 (d, J = 8.6 Hz, 1H),
3.90 (s, 3H), 3.89 (s, 3H), 2.80 (dd, J = 16.9, 7.6 Hz, 1H), 2.53 –
2.43 (m, 1H), 2.34 (dd, J = 16.9, 10.8 Hz, 1H), 1.18 (d, J = 6.6 Hz,
3H); 13C NMR (101 MHz, CDCl3, δ ppm) 176.3, 149.6, 149.5,
130.3, 119.0, 111.1, 109.1, 88.5, 56.2, 56.1, 39.9, 37.6, 16.5;
HRMS (ESI) m/z calcd. for C13H16O4Na [M+Na]+ 259.0940;
found 259.0940.
(4S,5S)-5-(4-nitrophenyl)-4-pentyldihydrofuran-2(3H)-one
(11ca)
20
1
Yield: 66%, orange oil; [α]D = + 15 (c 0.50, CH2Cl2); H NMR
(300 MHz, CDCl3, δ ppm) 8.26 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.8
Hz, 2H), 5.10 (d, J = 7.3 Hz, 1H), 2.89 – 2.71 (m, 1H), 2.48 – 2.28
(m, 2H), 1.71 – 1.55 (m, 1H), 1.55 – 1.42 (m, 1H), 1.39 – 1.17
(m, 6H), 0.92 – 0.80 (m, 3H); 13C NMR (101 MHz, CDCl3, δ ppm)
175.3, 148.1, 145.7, 126.7, 124.1, 85.2, 53.4, 45.1, 34.9, 32.1,
31.6, 30.9, 22.4, 14.2, 13.9; HRMS (ESI) m/z calcd. for
C13H19NO4Na [M+Na]+ 300.1206; found 300.1207.
(4S,5S)-5-(benzo[d][1,3]dioxolo-5-yl)-4-methyldihydrofuran-2(3H)-
one (11ai)
Yield: 42%, colourless oil; [α]I20 = + 94 (c 0.35, CH2Cl2); 1H NMR
(400 MHz, CDCl3, δ ppm) 6.86 – 6.77 (m, 3H), 5.98 (s, 2H), 4.84
(d, J = 8.5 Hz, 1H), 2.78 (dd, J = 16.8, 7.6 Hz, 1H), 2.51 – 2.40
(m, 1H), 2.32 (dd, J = 16.8, 10.8 Hz, 1H), 1.16 (d, J = 6.5 Hz, 3H);
13C NMR (101 MHz, CDCl3, δ ppm) 176.0, 148.3, 148.2, 131.7,
120.2, 108.4, 106.5, 101.5, 88.4, 39.9, 37.5, 16.5; HRMS (ESI)
m/z calcd. for C12H12O4Na [M+Na]+ 243.0628; found 243.0628.
5,5'-((2S,3S,4S,5S)-3,4-dimethyltetrahydrofuran-2,5-
diyl)bis(benzo[d][1,3]dioxole), (-)-galbacin (5)24a
Yield from 14: 85%, colourless oil; [α]D20 = - 103 (c 0.88, CHCl3);
25
1
(4S,5R)-5-butyl-4-methyldihydrofuran-2(3H)-one (11aj) [(+)-
trans-whiskey lactone](2)19c
litt : [α]D = - 119 (c 0.02, CHCl3); H NMR (300 MHz, CDCl3, δ
ppm) 6.91 (d, J = 1.6 Hz, 2H), 6.83 (dd, J = 8.0, 1.6 Hz, 2H), 6.77
(d, J = 7.9 Hz, 2H), 5.94 (s, 4H), 4.59 (d, J = 9.2 Hz, 2H), 1.83 –
1.67 (m, 2H), 1.02 (d, J = 6.1 Hz, 6H); 13C NMR (101 MHz, CDCl3,
δ ppm) 147.9, 147.1, 136.5, 119.9, 108.1, 106.7, 101.1, 88.4,
51.2, 13.9. HRMS (ESI) m/z calcd. for C20H20NaO5 [M+Na]+
363.1202; found 363.1203.
25
Yield: 40%, colourless oil; [α]D20 = + 50 (c 0.6, CHCl3); litt : [α]D
= + 59.6 (c 0.71, CHCl3); 1H NMR (400 MHz, CDCl3, δ ppm) 4.00
(ddd, J = 8.2, 7.3, 4.1 Hz, 1H), 2.71 – 2.61 (m, 1H), 2.25 – 2.12
(m, 2H), 1.73 – 1.54 (m, 3H), 1.41– 1.31 (m, 3H), 1.13 (d, J = 6.4
Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3, δ
ppm) 176.7, 87.6, 37.3, 36.2, 33.8, 28.0, 22.6, 17.6, 14.0. HRMS
(ESI) m/z calcd. for C9H16O2Na [M+Na]+ 179.1042; found
179.1043.
Conflicts of interest
(4S,5R)-4-methyl-5-pentyldihydrofuran-2(3H)-one (11ak) [(+)-
trans-cognac lactone](3)20b
20
There are no conflicts to declare.
Yield: 40%, colourless oil; [α]D = + 70 (c 0.27, CHCl3); litt :
25
1
[α]D = + 72 (c 1.00, CHCl3); H NMR (300 MHz, CDCl3, δ ppm)
4.05-3.96 (m, 1H), 2.75 – 2.61 (m, 1H), 2.31 – 2.13 (m, 2H),
1.73 – 1.60 (m, 4H), 1.38 – 1.28 (m, 4H), 1.15 (d, J = 6.4 Hz, 3H),
0.92 (t, J = 5.8 Hz, 3H); 13C NMR (75 MHz, CDCl3, δ ppm) 176.6,
87.5, 37.2, 36.1, 34.0, 31.6, 25.4, 22.5, 17.5, 14.0. HRMS (ESI)
m/z calcd. for C10H18O2Na [M+Na]+ 193.1198; found 193.1199.
Acknowledgements
This work was supported by the University of Rennes 1 and the
Centre National de la Recherche Scientifique (CNRS). S. H.
thanks the Region Bretagne and VillaPharma Research for a
research fellowship. We also thank the CONICET y ANPCyT for
funding a postdoctoral fellowship to M. M. V.
(4R,5R)-5-methyl-5-(4-nitrophenyl)dihydrofuran-2(3H)-one
(11ba)
Notes and references
20
1
Yield: 73%, orange oil; [α]D = - 12 (c 1.60, CH2Cl2); H NMR
(400 MHz, Acetone-d6, δ ppm) 8.29 (d, J = 8.8 Hz, 2H), 7.73 (d,
J = 8.8 Hz, 2H), 5.21 (d, J = 8.5 Hz, 1H), 2.78 (dd, J = 16.3, 7.2
Hz, 1H), 2.61 – 2.52 (m, 1H), 2.47 (dd, J = 16.3, 10.5 Hz, 1H),
1.23 (d, J = 6.5 Hz, 3H); 13C NMR (101 MHz, Acetone-d6, δ
ppm) 175.8, 148.9, 147.2, 128.1, 124.5, 86.8, 40.7, 37.2, 16.1.
HRMS (ESI) m/z calcd. for C11H11NO4Na [M+Na]+ 244.0580;
found 244.0581.
1
(a) S. S. C. Koch and A. R. Chamberlin, In Studies in Natural
Products Chemistry, vol. 16, Edited by Atta-ur-Rahman.
Elsevier Science, 1995, 687-725. (b) M. Seitz and O. Reiser,
Curr. Opin. Chem. Biol., 2005, 9, 285.
R. R. A. Kitson, A. Millemaggi and R. J. K. Taylor, Angew.
Chem. Int. Ed., 2009, 48, 9426.
A. G. González, M. H. Silva, J. I. Padrón, F. León, E. Reyes, M.
Álvarez-Mon, J. P. Pivel, J. Quintana, F. Estévez and J.
Bermejo, J. Med. Chem., 2002, 45, 2358.
2
3
4
For some examples, see: (a) T. Esumi, D. Hojyo, H. Zhai and Y.
Fukuyama, Tetrahedron Lett., 2006, 47, 3979. (b) P. Xue, L.-P.
Wang, X.-Z. Jiao, Y.-J. Jiang, Q. Xiao, Z.-G. Luo, P. Xie and X.-T.
(4R,5R)-5-(3,4-dimethoxyphenyl)-4-methyldihydrofuran-
2(3H)-one (11bb)
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Page 7 of 7
Organic & Biomolecular Chemistry
Journal Name
ARTICLE
Liang, J. Asian Prod. Nat. Res., 2009, 11, 281. (c) H. Kim, A. C. 19 For the compound 6b, the enantiomeric exceVsisew(9Ar7ti%cle)Ownlianes
Kasper, E. J. Moon, Y. Park, C. M. Wooten, M. W. Dewhirst determined by GC for the starting (R)-but-3-yn-2-ol.
and J. Hong, Org. Lett., 2009, 11, 89. (d) T. S. Kaoud, H. Park, 20 For synthesis of (+)-trans-whiskey lactone described in the
DOI: 10.1039/C8OB00101D
S. Mitra, C. Yan, C.-C. Tseng, Y. Shi, J. Jose, J. M. Taliaferro, K.
Lee, P. Ren, J. Hong and K. N. Dalby, ACS Chem. Biol., 2012,
1873. (e) A. Theodorou and C. G. Kokotos, Green Chem.,
2017, 19, 670.
S. Hazra and S. Hajra, RSC. Adv., 2013, 3, 22834.
last two decade, see: (a) X. Jiang, C. Fu and S. Ma, Eur. J. Org.
Chem., 2010, 687. (b) J. S. Yadav, C. V. Rao, A. R. Prasad and
A.. A. K. Al Ghamdi, Synthesis, 2011, 3894. (c) T. Liang, W.
Zhang, T.-Y. Chen, K. D. Nguyen and M. J. Krische, J. Am.
Chem. Soc., 2015, 137, 13066.
7
,
5
6
(a) B. Mao, M. Fañanas-Mastral and B. L. Feringa, Chem. 21 For some recent synthesis of (+)-trans-cognac lactone, see:
Rev., 2017, 117, 10502. (b) N. Kaplaneris, A. Bisticha, G. N.
Papadopoulos, D. Limnios and C. G. Kokotos, Green Chem.,
2017, 19, 4451. (c) I. Triandafillidi, M. Raftopoulou, A.
(a) F. Schleth, T. Vogler, K. Harms and A. Studer, Chem. Eur.
J., 2004, 10, 4171. (b) D. A. Devalankar, P. V. Chouthaiwale
and A. Sudalai, Tetrahedron: Asymmetry, 2012, 23, 240.
22 L. M. Vieira, A. Kijjoa, A. M. S. Silva, I.-O. Mondranondra and
W. Herz, Phytochemistry 1998, 48, 1079.
Savvidou and C. G. Kokotos, ChemCatChem., 2017,
For some selected examples, see: (a) E. Moret and M.
9, 4120.
7
Schlosser, Tetrahedron Lett., 1984, 25, 4491. (b) P. V. 23 M. S. J Nascimento, M. Pedro, F. Cerqueira, M. Bastos, L. M.
Ramachandran, M. P. Krzeminski, M. V. R. Reddy and H. C. Vieira, A. Kijjoa and M. M. M. Pinto, Pharm. Biol., 2004, 42,
Brown, Tetrahedron: Asymmetry, 1999, 10, 11. (b) S. H. Yu, 449.
M. J. Ferguson, R. McDonald and D. G. Hall, J. Am. Chem. 24 For other biological activities in which (-)-galbacin was
Soc., 2005, 127, 12808. (c) V. Mamane, A. B. Garcia, J. D.
Umarye, T. Lessmann, S. Sommer and H. Waldmann,
Tetrahedron, 2007, 63, 5754. (d) S. Mitra, S. R. Gurrala and R.
S. Coleman, J. Org. Chem., 2007, 72, 8724. (e) T. G. Elford, A.
Ulaczyk-Lesandro, G. De Pascale, G. D. Wright and D. G. Hall,
tested, see: (a) G. Li, C.-S. Lee, M.-H. Woo, S.-H. Lee, H.-W.
Chang, and J.-K. Son, Biol. Pharm. Bull. 2004, 27, 1147. (b) P.
H. Nguyen, T. V. T. Le, H. W. Kang, J. Chae, S. K. Kim, K.-I.
Kwon, D. B. Seo, S. J. Lee and W. K. Oh, Bioorg. Med. Chem.
Lett., 2010, 20, 4128.
J. Comb. Chem. 2009, 11, 155. (f) F. Hessler, A. Korotvička, D. 25 K. Ando, J. Am. Chem. Soc., 2005, 127, 3964.
Nečas, I. Valterová and M. Kotora, Eur. J. Org. Chem. 2014, 26 This observation was also reported in the following paper,
2543.
(a) H. C. Brown, S. V. Kulkarni and U. S. Racherla, J. Org. 27 T. D. Tran, N. B. Pham, R. Booth, P. L. Forster and R. J. Quinn,
Chem., 1994, 59, 365. (b) P. V. Ramachandran, K. J. Padiya, V. J. Nat. Prod., 2015, 79, 1514.
Rauniyar, M. V. R. Reddy and H. C. Brown, Tetrahedron Lett., 28 CCDC 1578065 contains the supplementary crystallographic
see: ref.5.
8
9
2004, 45, 1015.
A. Schlapbach and R. W. Hoffmann, Eur. J. Org. Chem. 2001,
323.
10 Y. Yamamoto, M. Takahashi and N. Miyaura, Synlett, 2002, 29 G. Mandville, M. Ahmar and R. Bloch J. Org. Chem. 1996, 61
data for compound 5. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
www.ccdc.com.ac.uk/data_request/cif.
,
128.
1122.
11 (a) F. Carreaux, F. Possémé, B. Carboni, A. Arrieta, B. Lecea
and F. P. Cossio, J. Org. chem., 2002, 67, 9153. (b) X. Gao, D.
G. Hall, M. Deligny, A. Favre, F. Carreaux and B. Carboni,
Chem. Eur. J., 2006, 12, 3132. (c) F. Possémé, M. Deligny, F.
Carreaux and B. Carboni, J. Org. Chem., 2007, 72, 984. (d) R.
Hemelaere, F. Carreaux and B. Carboni, Chem. Eur. J., 2014,
20, 14518. (e) S. Touchet, A. Macé, T. Roisnel, F. Carreaux, A.
Bouillon and B. Carboni, Org. Lett., 2013, 15, 2712.
12 A. Macé, S. Touchet, P. Andres, F. Cossio, V. Dorcel, F.
Carreaux and B. Carboni, Angew. Chem. Int. Ed., 2016, 55
1025.
,
13 For a recent review about the enecarbamate chemistry, see:
G. Kovura and H. Kagan, Chem. Rev., 2011, 111, 4599.
14 For a review, see: P.-A. Nocquet, S. Henrion, A. Macé, B.
Carboni, J. M. Villalgordo and F. Carreaux, Eur. J. Org. Chem.,
2017, 1295.
15 At no moment, the transient allyl cyanate was detected by
1H NMR.
16 This transformation was also described using H2SO4 in
MeOH, see: C. Gaul and D. Seebach, Helv. Chim. Acta, 2002,
85, 772.
17 This outcome is in complete agreement with those observed
in the synthesis of seven-membered ring using a similar
strategy, see: ref. 12.
18 Under acidic conditions, the presence of
a π-electron
donating group at the 4-position of the aromatic ring could
favored the elimination of the hydroxyl functional group in
the acyclic enecarbamate intermediate 8, thus forming a
potential
benzylic
carbocation
with
loss
of
diastereoselectivity. For an example described in the
literature, see: S. Chaimanee, M. Pohmakotr, C. Kuhakarm,
V. Reutrakul and D. Soorukram, Org. Biomol. Chem., 2017,
15, 3985.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins