Phosphorylated cyclopropanes in the synthesis of α-alkylidene-γ-butyrolactones: Total synthesis of (±)-savinin, (±)-gadain and (±)-peperomin e

Article abstract of DOI:10.1039/c6ob01527a

Phosphorylated cyclopropanes, generated via the Rh(ii)-catalysed intramolecular cyclopropanation of α-(diethoxyphosphoryl)acetates, have been found to be useful precursors in the synthesis of α-alkylidene-γ-butyrolactones. These cyclopropyl intermediates undergo regioselective reductive ring-opening and subsequent Horner-Wadsworth-Emmons olefination to complete the synthesis. Total syntheses of (±)-savinin and (±)-gadain, as well as the first total synthesis of (±)-peperomin E, are all described using this method.

Full text of DOI:10.1039/c6ob01527a

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: M. G. Lloyd, R. J.
Taylor and W. P. Unsworth, Org. Biomol. Chem., 2016, DOI: 10.1039/C6OB01527A.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
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
Information for Authors.
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 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.
www.rsc.org/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 18
View Article Online
DOI: 10.1039/C6OB01527A
Journal Name
ARTICLE
Phosphorylated cyclopropanes in the synthesis of α-alkylidene-γ-
butyrolactones: total synthesis of (±)-savinin, (±)-gadain and (±)-
peperomin E.
Received 00th January 20xx,
Accepted 00th January 20xx
Matthew G. Lloyd, Richard J. K. Taylor* and William P. Unsworth*
DOI: 10.1039/x0xx00000x
Phophorylated cyclopropanes, generated via the Rh(II)-catalysed intramolecular cyclopropanation of α-
(diethoxyphosphoryl)acetates, have been found to be useful precursors in the synthesis of α-alkylidene-γ-butyrolactones.
These cyclopropyl intermediates undergo regioselective reductive ring-opening and subsequent Horner–Wadsworth–
Emmons olefination to complete the synthesis. Total syntheses of (±)-savinin and (±)-gadain, as well as the first total
synthesis of (±)-peperomin E, are all described using this method.
www.rsc.org/
O
A) Previous work
: C–H Insertion/olefination
O
Introduction
PO(OEt)2
O
O
The high natural abundance and varied biological activities of
α-alkylidene-γ-butyrolactones has propagated much effort to
develop efficient methods for their synthesis.1 With this in
mind, we recently introduced a new catalytic approach to
PO(OEt)2
PO(OEt)2
O
O
R2
3
R1
N2
RhLN
C–H
Rh(II)
3
insertion
HWE
4
R CHO
R1 R2
R1 R2
base
R3
1
2
convert α-diazo-α-(diethoxyphosphoryl)acetates
alkylidene-γ-butyrolactones via telescoped C–H
insertion/olefination sequence, using an electrophilic
rhodium(II) carbenoid intermediate to perform the key C–H
1 into α-
O
O
5
a
PO(OEt)2
B) This work
:
O
O
cyclopropanation
/ringꢀopening
/olefination
2
N2
R1 R2
insertion step (Scheme 1A).2a The procedure has since been
applied to a range of functionalised compounds (generally
with high regioselectivity and diastereoselectivity) and it has
also been used in natural product synthesis,2b-d with one of the
main advantages of this method being the relative simplicity of
the requisite α-diazo-α-(diethoxyphosphoryl)acetate starting
materials, which are easily prepared in two steps from simple
alcohols.
R2
R1
5
6
Rh(II)
3
4
R CHO
base
HWE
O
O
Reductive
ringꢀopening
PO(OEt)2
R2
PO(OEt)2
O
O
R2
R1
7
H
O
3
R1
Herein, we describe an extension of this method, focusing
on the reactions of α-diazo-α-(diethoxyphosphoryl)acetates
derived from allylic alcohols (Scheme 1B). These starting
O
O
O
O
O
materials (6) are prepared just as easily as those in our earlier
work,2a-c but the C–H insertion step is replaced by
O
a
O
rhodium(II)-catalysed cyclopropanation reaction. This results in
the formation of phosphorylated cyclopropanes (α-
OMe
O
O
(±)ꢀpeperomin E
8
(±)ꢀsavinin, (E),
(±)ꢀgadain, (Z), 9
10
phosphoryl-3-oxabicyclo[3.1.0]hexanones of the form
may then undergo reductive ring-opening (
subsequent Horner–Wadsworth–Emmons olefination to
furnish α-alkylidene-γ-butyrolactones
7) which
OMe
O
O
7
→ 3) and
Scheme 1. Previous C–H insertion/olefination sequence to α-alkylidene-γ-
butyrolactones (A) compared with our new approach (B) based on the reaction
of phosphorylated cyclopropanes.
5.
This alternative route to α-alkylidene-γ-butyrolactones is
particularly useful in the case of substrates which do not react
well under our original C–H insertion conditions, and is
exemplified in this paper by the total syntheses of three
natural products, (±)-savinin 8, (±)-gadain 9 and (±)-peperomin
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 18
View Article Online
DOI: 10.1039/C6OB01527A
ARTICLE
Journal Name
E
10 (Scheme 1, box).3-4 Notably, none these natural products While no reaction products were isolated in the reaction of
could be formed using the reported C–H insertion compound 15, there was a noticeable and immediate colour
procedure,2a-c but all were successfully synthesised using the change upon addition of the rhodium(II) catalyst (green to dark
cyclopropanation methodology described herein.
orange/brown), which is indicative of a change in the
rhodium(II) complex, either as a result of ligand coordination
to one of the vacant axial coordination sites on the rhodium
catalyst or oxidation of Rh(II) to Rh(III).5 No such colour change
was observed in the related reactions shown in Scheme 2 (or
indeed in any of our previous successful C–H insertion
reaction), and it is likely that this outcome is caused by an
unwanted intramolecular interaction that is particular to this
system. We propose that following diazo decomposition, a
complex of the form 18 is produced via intramolecular
coordination of one of the oxygen atoms of the
methylenedioxy motif to rhodium carbenoid 17, and that this
non-productive pathway prevents catalyst turnover (Scheme
3).6
Results and discussion
This work was initiated during unsuccessful attempts to
synthesise isomeric natural products (±)-savinin 8 and (±)-
. (–)-Savinin was isolated in 1953 by Hartwell3a and
gadain
9
subsequent studies revealed that it possesses cytotoxic,
insecticidal and antiviral properties.3b-d (+)-Gadain was isolated
later in 1984 and was found to isomerise to (+)-savinin in acidic
solution.4 It was originally planned to use our published C–H
insertion/olefination method to synthesise each of these
compounds. Precedent from our earlier work, as well as
additional test reactions performed for this study, both
augured well for the success of this approach; unsubstituted
homobenzylic substrate 11a and benzylic methylenedioxy
substrate 13 had both already been shown to react well using
the original procedure, affording lactones 12a and 14
respectively, while homobenzylic substrates 11b
meta- and para-methoxy substituents 11a were also
compatible, furnishing lactones 12b . It therefore appeared
logical that the same procedure would be suitable for the
synthesis of (±)-savinin and (±)-gadain from closely related
diazo precursor 15, however, to our surprise, no reaction took
place when this compound was treated with mol%
–d bearing
–
d
8
9
2
rhodium(II) octanoate in CH2Cl2 at reflux (our standard C–H
insertion conditions), with starting material 15 being the only
material recovered from this reaction (Scheme 2).
Scheme 3. Proposed formation of complex 18 to account for the failure of
compound 15 to undergo C–H insertion.
Returning to the synthesis of (±)-savinin
8 and (±)-gadain 9, it
was at this stage that the use of α-diazo-α-
(diethoxyphosphoryl)acetates derived from allyic alcohols
were first considered to be viable precursors. Rhodium
carbenoids are well known to react with alkenes to form
cyclopropanes,7 and it was proposed that the resulting
cyclopropanes could undergo reductive ring-opening and
subsequent olefination to generate α-methylene-γ-
butyrolactones via an alternative pathway. It was also thought
that the rigidity imparted by the E-alkene moiety would
minimise unwanted coordination to the intermediate
carbenoid, hence the problems associated with the C–H
insertion of saturated α-diazo-α-(diethoxyphosphoryl)acetate
15 may be alleviated. As a model system, styrene derivative
19a was synthesised from cinnamyl alcohol and treated with 2
mol% rhodium(II) octanoate in CH2Cl2 at reflux, mirroring the
C–H insertion conditions, and pleasingly this led to the efficient
formation of cyclopropane 20a (Scheme 4). This compound
was isolated in 79% yield as a single diastereoisomer, with its
structure and relative configuration confirmed by X-ray
crystallography (Figure 1).8 Then, following a brief screen of
Scheme 2. Telescoped C–H insertion/olefination in the synthesis of compounds
12a–d and 14; the same procedure was unsuccessful for the synthesis of 16.
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
Organic & Biomolecular Chemistry
Page 3 of 18
Journal Name
View Article Online
DOI: 10.1039/C6OB01527A
ARTICLE
conditions capable of promoting reductive opening of the compound 19j reacted well, delivering cyclopropane 20j in
cyclopropane,9 it was found that the reaction of compound 73% yield under identical conditions to those that had failed to
24a with samarium(II) iodide10 in THF at
−78 °C led to the promote C–H insertion in its saturated analogue 15.
formation of lactone 21 in moderate unoptimised yield.11
O
PO(OEt)2
b) pꢀABSA
O
O
OH
O
a)
HO2C
PO(OEt)2
PO(OEt)2
PO(OEt)2
O
a) Rh2(oct)4 (2 mol%)
CH2Cl2, 45 °C, 20 h
O
LHMDS, THF
or
T3P, EtN(i-Pr)2, toluene
N2
Ph
Ph
R1 R2
22a–j
R1 R2
23a–j
DBSA, DBU
CH2Cl2
H
(76–100%)
O
19a
20a, 79%
O
b) SmI2, THF
–78 °C
PO(OEt)2
O
PO(OEt)2
R2
c) Rh2(oct)4
O
N2
O
O
CH2Cl2, 45 °C, 20 h
19a–j
R1
20a–j
H
(42–87%)
R1 R2
O
PO(OEt)2
O
O
PO(OEt)2
Ph
PO(OEt)2
PO(OEt)2
O
O
O
Ph
O
21, 48%
H
Scheme 4. Cyclopropanation and reductive ring-opening of styrene derivative
19a
H
H
.
20b, 78%
O
20c, 66%
20a
O
, 79%
O
PO(OEt)2
PO(OEt)2
PO(OEt)2
O
O
H
, 58%
H
H
20d
20e
20f
, 64%
, 48%
O
O
O
PO(OEt)2
PO(OEt)2
PO(OEt)2
O
O
O
O
Ph
Ph
H
X
H
O
H
20h
, X = Br, 74%
20g
20j
, 73%
, 51%
20i, X = OCH3, 53%
Figure 2. Synthesis of α-phosphoryl-3-oxabicyclo[3.1.0]hexanones 19
= H, R2 = Ph; R1 = R2 = H; R1 -Pr, R2 = H; R1 = H, R2 = CH=CHCH3;
CH3;
R1 = CH3, R2 = CH2CH2CH=C(CH3)2; R1 = Ph, R2 = Ph; R1 = H, R2 = 4-Br-
C6H4;
R1 = H, R2 = 4-CH3O-C6H4; R1 = H, R2 = 3,4-OCH2O-C6H3. T3P = propyl
phosphonic anhydride.
–
23a
–
j: a R1
b
c
=
n
d
e
R1 = R2
=
f
g
h
i
j
p
-ABSA = 4-acetamidobenzenesulfonyl azide. DBSA = 4-
n-dodecylbenzenesulfonyl azide. DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene.
Figure 1. X-ray crystal structure of compound 20a (CCDC 1465173).
With cyclopropane 20j in hand, the syntheses of (±)-savinin
8
To the best of our knowledge, the synthesis of compound 20a
represents the first reported example of an intramolecular
rhodium(II) catalysed cyclopropanation of an α-diazo-α-
(dialkoxyphosphoryl)acetate12 and pleasingly, the reaction is
also applicable to other allylic alcohol derivatives (Figure 2).
and (±)-gadain
9 was then completed in an additional two
steps. First, the treatment of compound 20j with samarium(II)
iodide delivered lactone 16 in 38% (unoptimised) yield, as a
single diastereoisomer, which was then heated at reflux in THF
with KOBu-t and piperonal,13 furnishing a 1.9:1 mixture of α-
The requisite starting materials 19a
yields via our reported two-step sequence2a-c from known
allylic alcohols 22a , before each was treated with 2 mol%
rhodium(II) octanoate in CH2Cl2 at reflux. variety of
substituted precursors were converted into phosphorylated
cyclopropanes 20a in moderate to good yields, including
substrates derived from unsubstituted allyl alcohol (19b), E-
disubstituted alkenes (19a 19d 19h-j), Z-disubstituted alkene
19c and trisubstituted alkenes (19e ). It is noteworthy that in
all cases a single diastereoisomer of the cyclopropane (20a
was observable in the unpurified 1H NMR spectra of the
product mixture, with the stereochemical outcome being
consistent with a concerted cyclopropanation reaction and the
geometry of the alkene precursor being translated into the
product. Of particular relevance to the synthesis of natural
–j were synthesised in high
methylene-γ-butyrolactones (±)-savinin 8, (±)-gadain 9 in 53%
overall yield (Scheme 5). These isomers were partially
separable by column chromatography, and the spectral data
for both compounds were in full agreement with those
published.3-4 Although it was not attempted in this work, the
–
j
A
–j
isomerisation of (±)-gadain
9
to (±)-savinin
8
has been
described and can be performed if required.4
,
,
O
O
O
P
–g
O
O
O
O
OEt
–j)
KOBuꢀt
piperonal
O
O
OEt
SmI2
THF
20j
THF, ꢀ
O
O
53%
(1.9:1, 8:9)
16
, 38%
product targets (±)-savinin
8 and (±)-gadain 9 is the fact that
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 18
View Article Online
DOI: 10.1039/C6OB01527A
ARTICLE
Journal Name
Scheme 5. Syntheses of (±)-savinin 8 and (±)-gadain 9.
O
O2N
a) HNO3
b) Pd/C,
O
O
X
O
O
O
ꢀ
NH4+ HCO2
Following the completion of this route, attention switched to a
more challenging target, lignan natural product (±)-peperomin
MeOH
O
OMe
E
10. (+)-Peperomin E was isolated in 1998 by Govindachari
OMe
, X = NH2, 93%
27, 59%
OMe
26
and co-workers from peperomia dindigulensis,14 a succulent
c) HBF4
28
herb, and has been shown to possess a range of biological
tBuONO, EtOH
e) Ph3PCHCO2Et
THF
properties;
these
include
anti-feedant
activity,14
29, X = N2—BF4, 91%
30, X = I, 61%
O
d) KI
acetone/water
cytotoxicity,15a inhibition of malignant lung tumour cells,15b
anti-angiogenic activity,15c inhibition of cancer cell lines15d and
anti-inflammatory activity.15e To the best of our knowledge,
there have been no reported syntheses prior to this
publication. It was considered that (+)-peperomin E might be
accessible either via our previously reported C–H
insertion/olefination method or the new cyclopropanation
route, and given the similarity of the requisite precursors 24
and 25, both of these methods were examined (Figure 3).
30
f)
O
Pd(OAc)2,
nBu4NBr,
NaHCO3
EtO
EtO
O
O
O
O
O
DMF
O
OMe
OMe
OMe
32
31, 95%
, 87%
g) DIBAL
THF
O
PO(OEt)2
h)
OH
O
HO2C
PO(OEt)2
O
O
O
O
O
T3P, DIPEA
toluene
O
O
O
OMe
OMe
OMe
OMe
, 99%
34
33
, 91%
i) DBSA
LHMDS, THF
j) Pd/C, H2
MeOH
k) DBSA
O
O
O
PO(OEt)2
O
PO(OEt)2
O
LHMDS, THF
O
N2
N2
O
O
O
O
Figure 3. Retrosynthesis of (±)-peperomin E 10
.
O
O
The synthesis began with the conversion of commercially
available aldehyde 26 into nitrobenzene 27 using concentrated
nitric acid, before sequential reduction, diazotisation and
iodination afforded iodobenzene derivative 30 in good overall
yield. Meanwhile, the same aldehyde precursor 26 was also
used in a Wittig olefination, furnishing cinnamate 31 in high
yield. This alkene was then reacted with iodide 30 in a Heck
OMe
OMe
OMe
OMe
25, 63%
24, 31% (over 2 steps)
Scheme 6. Synthesis of α-diazo-α-(diethoxyphosphoryl)acetates 40 and 41
.
To investigate the C–H insertion reaction pathway towards
peperomin E, α-diazo-α-(diethoxyphosphoryl)acetate 24 was
treated with 2 mol% rhodium(II) octanoate in CH2Cl2 at reflux
(Scheme 7). Perhaps unsurprisingly, no reaction was observed
under these conditions; this outcome is similar to that
observed when the analogous reaction was attempted on
related compound 15 as described earlier, and we propose
that the coordination of one of the oxygen atoms of the
methylenedioxy motif of 24 to the rhodium carbenoid (similar
to complex 18 in Scheme 3) also takes place in this system,
preventing effective catalyst turnover.
cross-coupling reaction using
a procedure reported by
Moreno-Mañas and co-workers16a (based on classical Jeffrey
conditions)16b to form diaryl compound 32 in good yield, and
subsequent reduction with DIBAL followed by acylation
proceeded well, furnishing phosphonate 34
.
Finally,
diazotisation with DBSA (4-n-dodecylbenzenesulfonyl azide)
and LHMDS in the usual way afforded the key
cyclopropanation precursor 25, while performing a standard
palladium on carbon hydrogenation prior to diazotisation, also
delivered its saturated analogue 24 (Scheme 6).
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
Organic & Biomolecular Chemistry
Page 5 of 18
Journal Name
View Article Online
DOI: 10.1039/C6OB01527A
ARTICLE
intermediates en route to α-alkylidene-γ-butyrolactone natural
products. Of particular note, the method has been found to
proceed well on systems in which the analogous C–H insertion
process fails, culminating in the total synthesis of three natural
products, (±)-savinin 8, (±)-gadain 9 and (±)-peperomin E 10. In
this work, we have focused on reductive ring-opening
reactions of the key phosphorylated cyclopropane
intermediates, but we anticipate that the same compounds
will also be amenable to a broader range of transformations;
nucleophilic ring-openings, cycloaddition reactions and
rearrangement reactions have all been demonstrated on
related donor-acceptor cyclopropanes17 and variants of these
will be investigated in due course.
Scheme
7.
(diethoxyphosphoryl)acetate 41
Failed
C–H
.
insertion
reaction
of
α-diazo-α-
Pleasingly, as was the case for the syntheses of (±)-savinin
8
and (±)-gadain 9, the cyclopropanation reaction of unsaturated
analogue 25 was successful. The cyclopropanation of α-diazo-
α-(diethoxyphosphoryl)acetate 25 with rhodium(II) octanoate
proceeded moderately well, although the isolated yield (35%)
was lower than is typical for this transformation. The use of a
bulkier rhodium catalyst (rhodium(II) triphenylacetate) led to a
modest improvement in the yield for this step. Next, the ring-
opening was performed by treating compound 36 with
samarium(II) iodide, affording lactone 37 in 55% yield and
finally, a facile, high-yielding Horner–Wadsworth–Emmons
olefination reaction completed the first reported total
synthesis of peperomin E 10. With the exception of the melting
point, all characterisation data recorded for our synthetic
material were in accord with those reported in the isolation
paper (Scheme 8).14
Experimental
Except where stated, all reagents were purchased from
commercial sources and used without further purification.
Except where stated, all experimental procedures were carried
out under an atmosphere of argon. Anhydrous CH2Cl2, toluene
and DMF were obtained from an Innovative Technology Inc.
PureSolv® solvent purification system. Anhydrous THF was
obtained by distillation over sodium benzophenone ketyl
immediately before use. 1H NMR, 13C NMR and 31P NMR
spectra were recorded on a JEOL ECX400 or JEOL ECS400
spectrometer, operating at 400 MHz, 100 MHz and 162 MHz
respectively. All spectral data were acquired at 295 K.
Chemical shifts (δ) are quoted in parts per million (ppm). The
residual solvent peak, δH 7.26 and δC 77.0 for CDCl3 and δH 2.50
and δC 39.5 for DMSO-d6. Coupling constants (J) are reported in
Hertz (Hz) to the nearest 0.1 Hz. The multiplicity abbreviations
used are: s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), br (broad). Signal assignment was achieved by
analysis of DEPT, COSY, NOESY, HMBC and HSQC experiments
where required. Spectra were processed using ‘iNMR’
software which can be obtained free of charge online. Infrared
(IR) spectra were recorded on either a ThermoNicolet IR-100
spectrometer with NaCl plates as a thin film dispersed from
either CH2Cl2 or CDCl3, or
a PerkinElmer UATR Two
spectrometer and are reported in wavenumbers (cm−1). Mass-
spectra were obtained by the University of York Mass
Spectrometry Service, using electrospray ionisation (ESI) on a
Bruker Daltonics, Micro-tof spectrometer. Melting points were
determined using Gallenkamp apparatus and are uncorrected.
Reactions were monitored using thin layer chromatography
(TLC), which was carried out on Merck silica gel 60F254 pre-
coated aluminium foil sheets and were visualised using UV
light (254 nm) and stained with basic aqueous potassium
permanganate. Flash column chromatography was carried out
using slurry packed Fluka silica gel (SiO2), 35–70 µm, 60 Å,
under a light positive pressure, eluting with the specified
solvent system. No issues associated with instability or
decomposition of the azide reagents or diazo products were
observed, with no special handling precautions required.
Scheme 8. Total synthesis of peperomin E 10
.
Conclusions
Phosphorylated cyclopropanes formed via the rhodium(II)
mediated cyclopropanation of allylic α-diazo-α-
General experimental
(diethoxyphosphoryl)acetates have been shown to be useful
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 18
View Article Online
DOI: 10.1039/C6OB01527A
ARTICLE
Journal Name
General procedure A: T3P-mediated esterifications
concentrated in vacuo. The residue was dissolved in THF (4.0
mL) and cooled to 0 C prior to the addition of KOBu-t (1.2
To a stirred solution of alcohol (8.00 mmol) in toluene (40 mL) equiv.) which was stirred at 0 C for 1 h and then cooled to 78
under an atmosphere of argon, was added sequentially C. Paraformaldehyde (2.0 equiv.) was added to the solution
diethylphosphonoacetic acid (DEPAA) (8.40 mmol, 1.05 eq.), and stirred for 15 mins at 78 C and a further 2 h at RT. The
°
°
−
°
−
°
N,N-diisopropylethylamine (DIPEA) (20.8 mmol, 2.6 eq.) and solution was quenched with sat. aq. NH4Cl (10 mL) and then
propylphosphonic anhydride (T3P) (10.4 mmol, 1.3 eq., 50% diluted with CH2Cl2 (20 mL). The organic layer was separated
w/w solution in EtOAc/THF). The solution was stirred at RT for and the aqueous extracted with EtOAc (2 × 20 mL). The
1–4 h (with progress monitored by TLC analysis), after which organic extracts were dried over Na2SO4, concentrated in
time it was diluted with water (50 mL) and extracted with vacuo and purified by column chromatography affording the
EtOAc (3
×
combined organic extracts with 10% aq. HCl (50 mL), sat. aq.
100 mL) followed by sequential washing of the
α-methylene-γ-butyrolactone product.
NaHCO3 (50 mL) and brine (50 mL). The organic extract was General procedure E: Rh(II)-catalysed cyclopropanation
then dried over MgSO4 and concentrated in vacuo, affording
the α-(diethoxyphosphoryl)acetate product, which was used To an oven dried sealable tube containing α-diazo-α-
without further purification.
(dialkoxyphosphoryl)acetate (0.200 mmol) flushed with argon
was added CH2Cl2 (4.0 mL) followed by Rh2(oct)4 (2 mol%). The
General procedure B: Base-mediated diazo transfer (LHMDS solution was stirred at 45
or NaH) vacuo. The residue was purified by column chromatography
affording the α-phosphoryl-3-oxabicyclo[3.1.0]hexanone
To a stirred solution of α-(diethoxyphosphoryl)acetate (5.0 product.
mmol) in THF (25 mL, 5 mL/mmol), cooled to 78 C under an
atmosphere of argon, was added lithium Compound Synthesis
bis(trimethylsilyl)amide (LHMDS) (6.0 mmol, 1.2 eq., 1.0 M
solution in THF) or NaH (6.0 mmol, 1.2 eq., 60% dispersion in 3-(4-Methoxyphenyl)propyl 2-(diethoxyphosphoryl)acetate
mineral oil). The solution was allowed to warm to RT and Synthesised using general procedure with 3-(4-
°C for 20 h and then concentrated in
−
°
.
A
stirred
for
10
mins,
after
azide
which
time
or
4- methoxyphenyl)propan-1-ol (831 mg, 5.00 mmol), toluene
acetamidobenzenesulfonyl
(p-ABSA)
4-n- (25.0 mL), DEPAA (1.03 g, 5.25 mmol), DIPEA (2.26 mL, 13.0
dodecylbenzenesulfonyl azide (DBSA) (6.0 mmol, 1.2 eq.) was mmol) and T3P (4.14 g, 6.50 mmol, 50% w/w solution in
added to the solution. After stirring for 1 h at RT the mixture EtOAc) affording the title compound as a yellow oil (1.66 g,
was diluted with diethyl ether (100 mL) and water (25 mL) 96%); Rf 0.09 (1:1 hexane:EtOAc); νmax (thin film)/cm-1 2982,
prior to extraction with diethyl ether (3
combined organic extracts were washed with sat. aq. NaHCO3 δH (400 MHz, CDCl3) 1.32 (6 H, t, J = 7.1), 1.88–1.95 (2 H, m),
(2 25 mL), dried over MgSO4, concentrated in vacuo and 2.62 (2 H, t, J = 7.6), 2.95 (2 H, d, J = 21.6), 3.75 (3 H, s), 4.10–
× 50 mL). The 1733, 1612, 1513, 1243, 1177, 1114, 1019, 964, 834, 813, 783;
×
purified by column chromatography affording the
α-
4.19 (6 H, m), 6.80 (2 H, d, J = 8.7), 7.07 (2 H, d, J = 8.7); δC (100
MHz, CDCl3) 16.2 (d, J = 6.4), 30.2, 30.9, 34.2 (d, J = 134.1),
55.1, 62.5 (d, J = 6.3), 64.7, 113.7, 129.2, 132.9, 157.8, 165.7
(d, J = 6.1); δP (162 MHz, CDCl3) 20.4; HRMS (ESI+): Found:
diazo(diethoxyphosphoryl)acetate product.
General procedure C: Base-mediated diazo transfer (DBU)
367.1286; C16H25NaO6P (MNa+) Requires 367.1281 (
−1.4 ppm
To a stirred solution of α-(diethoxyphosphoryl)acetate (5.0 error).
mmol) and p-ABSA or DBSA (7.5 mmol, 1.5 eq.) in CH2Cl2 (50
mL, 10 mL/mmol) cooled to 0
argon, was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (diethoxyphosphoryl)acetate (11b). Synthesised using general
(7.5 mmol, 1.5 eq.) dropwise. The solution was stirred procedure with 3-(4-methoxyphenyl)propyl 2-
°C under an atmosphere of 3-(4-Methoxyphenyl)propyl
2-diazo-2-
C
overnight with warming at RT, after which time the mixture (diethoxyphosphoryl)acetate (1.66 g, 4.82 mmol), DBSA (2.42
was filtered through a pad of Celite and silica. The filtrate was mL, 7.23 mmol), DBU (1.08 mL, 7.23 mmol) and CH2Cl2 (48.0
concentrated in vacuo then purified by column mL). Purification by column chromatography (1:1
chromatography
affording
the
α-
hexane:EtOAc) afforded the title compound 11b as a pale
yellow oil (1.70 g, 95%); Rf 0.57 (1:4 hexane:EtOAc); νmax (thin
film)/cm-1 2985, 2128, 1702, 1613, 1513, 1389, 1276, 1246,
diazo(diethoxyphosphoryl)acetate product.
General procedure D: One-pot Rh(II)-catalysed C–H 1018, 978, 813, 746, 591, 560; δH (400 MHz, CDCl3) 1.36 (6 H,
insertion/olefination sequence
td, J = 7.1, J = 0.8), 1.91–1.98 (2 H, m), 2.63 (2 H, t, J = 7.6),
3.78 (3 H, s), 4.11–4.27 (6 H, m), 6.82 (2 H, d, J = 8.7), 7.08 (2 H,
d, J = 8.7); δC (100 MHz, CDCl3) 16.1 (d, J = 7.3), 30.4, 30.9, 54.0
To an oven dried sealable tube containing
α-
diazo(diethoxyphosphoryl)acetate (0.200 mmol) flushed with (d, J = 226.6), 55.1, 63.5 (d, J = 5.9), 64.8, 113.8, 129.2, 132.7,
argon was added CH2Cl2 (4.0 mL) followed by Rh2(oct)4 (2 157.9, 163.3 (d, J = 12.3); δP (162 MHz, CDCl3) 10.8; HRMS
mol%). The solution was stirred at 45 °C for 20 h and then
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
Organic & Biomolecular Chemistry
Page 7 of 18
Journal Name
(ESI+): Found: 393.1196; C16H23N2NaO6P (MNa+) Requires 3-(3,4-Dimethoxyphenyl)propyl
View Article Online
DOI: 10.1039/C6OB01527A
ARTICLE
2-diazo-2-
393.1186 (−2.6 ppm error).
(diethoxyphosphoryl)acetate (11d). Synthesised using general
procedure with 3-(3,4-dimethoxyphenyl)propyl 2-
(diethoxyphosphoryl)acetate 152a (1.87 g, 5.00 mmol), DBSA
C
3-(3-Methoxyphenyl)propyl 2-(diethoxyphosphoryl)acetate
.
Starting with known alcohol 3-(3-methoxyphenyl)propan-1-ol (2.42 mL, 7.25 mmol), DBU (1.08 mL, 7.25 mmol) and CH2Cl2
(831 mg, 5.00 mmol),18 general procedure A was performed (50.0 mL). Purification by column chromatography (1:1
with toluene (25.0 mL), DEPAA (1.03 g, 5.25 mmol), DIPEA hexane:EtOAc) afforded the title compound 152b as a pale
(2.26 mL, 13.0 mmol) and T3P (4.14 g, 6.50 mmol, 50% w/w yellow oil (1.97 g, 98%); Rf 0.53 (1:4 hexane:EtOAc); νmax (thin
solution in EtOAc) affording the title compound as a yellow oil film)/cm-1 2936, 2127, 1701, 1515, 1465, 1274, 1260, 1156,
(1.66 g, 96%); Rf 0.09 (1:1 hexane:EtOAc); νmax (thin film)/cm-1 1015, 976, 799, 731, 589, 558; δH (400 MHz, CDCl3) 1.36 (6 H,
2982, 1736, 1601, 1585, 1489, 1392, 1262, 1154, 1117, 1025, td, J = 7.1, J = 0.8), 1.93–2.00 (2 H, m), 2.64 (2 H, t, J = 7.6),
970; δH (400 MHz, CDCl3) 1.33 (6 H, t, J = 7.1), 1.92–2.00 (2 H, 3.85 (3 H, s), 3.87 (3 H, s), 4.12–4.28 (6 H, m), 6.69–6.80 (3 H,
m), 2.67 (2 H, t, J = 7.7), 2.96 (2 H, d, J = 21.6), 3.78 (3 H, s), m); δC (100 MHz, CDCl3) 16.0 (d, J = 7.2), 30.3, 31.3, 53.7 (d, J =
4.13–4.20 (6 H, m), 6.72–6.77 (3 H, m), 7.16–7.21 (1 H, m); δC 229.3), 55.6, 55.7, 63.5 (d, J = 6.1), 64.7, 111.1, 111.5, 120.0,
(100 MHz, CDCl3) 16.3 (d, J = 6.5), 29.9, 31.9, 34.2 (d, J = 133.2, 147.2, 148.7, 163.2 (d, J = 12.5); δP (162 MHz, CDCl3)
133.8), 55.0, 62.6 (d, J = 6.6), 64.7, 111.2, 114.2, 120.7, 129.3, 10.7; HRMS (ESI+): Found: 423.1275; C17H25N2NaO7P (MNa+)
142.6, 159.6, 165.8 (d, J = 6.1); δP (162 MHz, CDCl3) 20.4; Requires 423.1292 (3.9 ppm error).
HRMS (ESI+): Found: 367.1272; C16H25NaO6P (MNa+) Requires
367.1281 (2.5 ppm error).
4-(4-Methoxybenzyl)-3-methylenedihydrofuran-2(3H)-one
(12b). Synthesised using general procedure D with 3-(4-
3-(3-Methoxyphenyl)propyl
2-diazo-2- methoxyphenyl)propyl 2-diazo-2-(diethoxyphosphoryl)acetate
(diethoxyphosphoryl)acetate (11c). Synthesised using general 11b (78 mg, 0.211 mmol), CH2Cl2 (4.2 mL), Rh2(oct)4 (3.3 mg,
procedure with 3-(3-methoxyphenyl)propyl 2- 4.2 mol), THF (4.2 mL), KOBu-t (28.4 mg, 0.253 mmol) and
C
ꢁ
(diethoxyphosphoryl)acetate (1.66 g, 4.82 mmol), DBSA (2.42 paraformaldehyde (12.7 mg, 0.422 mmol). Purification by
mL, 7.23 mmol), DBU (1.08 mL, 7.23 mmol) and CH2Cl2 (48.0 column chromatography (2:1 hexane:EtOAc) afforded the title
mL). Purification by column chromatography (1:1 compound 12b as a colourless oil (20 mg, 43%); Rf 0.53 (2:1
hexane:EtOAc) afforded the title compound 11c as a pale hexane:EtOAc); νmax (thin film)/cm-1 2912, 1760, 1611, 1513,
yellow oil (1.61 g, 90%); Rf 0.57 (1:4 hexane:EtOAc); νmax (thin 1301, 1248, 1179, 1114, 1033, 815; δH (400 MHz, CDCl3) 2.75
film)/cm-1 2983, 2127, 1701, 1602, 1584, 1489, 1455, 1389, (1 H, dd, J = 13.9, J = 8.8), 2.90 (1 H, dd, J = 13.9, J = 7.0), 3.28–
1273, 1015, 976, 780, 745, 590, 559; δH (400 MHz, CDCl3) 1.36 3.36 (1 H, m), 3.80 (3 H, s), 4.05 (1 H, dd, J = 9.2, J = 5.1), 4.33
(6 H, td, J = 7.1, J = 0.7), 1.94–2.01 (2 H, m), 2.67 (2 H, t, J = (1 H, dd, J = 9.2, J = 8.1), 5.42 (1 H, d, J = 2.3), 6.26 (1 H, d, J =
7.6), 3.78 (3 H, s), 4.11–4.27 (6 H, m), 6.71–6.77 (3 H, m), 7.20 2.6), 6.85 (2 H, d, J = 8.6), 7.09 (2 H, d, J = 8.6); δC (100 MHz,
(1 H, app. t, J = 7.8); δC (100 MHz, CDCl3) 16.1 (d, J = 6.9), 30.0, CDCl3) 39.0, 40.3, 55.2, 70.6, 114.1, 122.7, 129.4, 129.9, 137.6,
31.8, 53.9 (d, J = 226.6), 55.0, 63.5 (d, J = 6.2), 64.8, 111.1, 158.5, 170.7; HRMS (ESI+): Found: 241.0827; C13H14NaO3
114.2, 120.6, 129.3, 142.3, 159.6, 163.3 (d, J = 12.1); δP (162 (MNa+) Requires 241.0835 (3.5 ppm error).
MHz, CDCl3) 10.8; HRMS (ESI+): Found: 393.1177;
C16H23N2NaO6P (MNa+) Requires 393.1186 (2.2 ppm error).
4-(3-Methoxybenzyl)-3-methylenedihydrofuran-2(3H)-one
(12c). Synthesised using general procedure D with 3-(3-
2- methoxyphenyl)propyl 2-diazo-2-(diethoxyphosphoryl)acetate
3-(3,4-Dimethoxyphenyl)propyl
(diethoxyphosphoryl)acetate. Synthesised using general 11c (77 mg, 0.208 mmol), CH2Cl2 (4.2 mL), Rh2(oct)4 (3.2 mg,
procedure A with 3-(3,4-dimethoxyphenyl)propan-1-ol (981 4.2 mol), THF (4.2 mL), KOBu-t (28.0 mg, 0.250 mmol) and
ꢁ
mg, 5.00 mmol), toluene (25.0 mL), DEPAA (1.03 g, 5.25 paraformaldehyde (12.5 mg, 0.416 mmol). Purification by
mmol), DIPEA (2.26 mL, 13.0 mmol) and T3P (4.14 g, 6.50 column chromatography (2:1 hexane:EtOAc) afforded the title
mmol, 50% w/w solution in EtOAc) affording the title compound 12c as a colourless oil (20 mg, 44%); Rf 0.52 (2:1
compound as a yellow oil (1.87 g, 100%); Rf 0.09 (1:1 hexane:EtOAc); νmax (thin film)/cm-1 2915, 1762, 1601, 1490,
hexane:EtOAc); νmax (thin film)/cm-1 2936, 1732, 1515, 1465, 1262, 1154, 1116, 1040; δH (400 MHz, CDCl3) 2.77 (1 H, dd, J =
1257, 1236, 1157, 1140, 1116, 1019, 965; δH (400 MHz, CDCl3) 13.8, J = 9.0), 2.96 (1 H, dd, J = 13.8, J = 6.8), 3.33–3.42 (1 H,
1.31 (6 H, td, J = 7.1, J = 0.4), 1.89–1.96 (2 H, m), 2.62 (2 H, t, J m), 3.80 (3 H, s), 4.06 (1 H, dd, J = 9.2, J = 5.2), 4.35 (1 H, dd, J =
= 7.6), 2.95 (2 H, d, J = 21.6), 3.82 (3 H, s), 3.84 (3 H, s), 4.11– 9.2, J = 8.0), 5.47 (1 H, d, J = 2.4), 6.28 (1 H, d, J = 2.7), 6.71–
4.18 (6 H, m), 6.68–6.77 (3 H, m); δC (100 MHz, CDCl3) 16.2 (d, J 6.72 (1 H, m), 6.77 (1 H, br. d, J = 7.5), 6.79 (1 H, dd, J = 8.3, J =
= 6.4), 30.2, 31.4, 34.2 (d, J = 134.0), 55.7, 55.8, 62.5 (d, J = 2.5), 7.23 (1 H, app. t, J = 7.9); δC (100 MHz, CDCl3) 40.0, 40.1,
6.7), 64.7, 111.1, 111.5, 120.1, 133.5, 147.2, 148.7, 165.7 (d, J 55.3, 70.7, 112.1, 114.9, 121.3, 122.8, 129.9, 137.7, 139.1,
= 6.4); δP (162 MHz, CDCl3) 20.4; HRMS (ESI+): Found: 159.9, 170.8; HRMS (ESI+): Found: 241.0846; C13H14NaO3
397.1392; C17H27NaO7P (MNa+) Requires 397.1387 (
error).
− −4.5 ppm error).
1.4 ppm (MNa+) Requires 241.0835 (
4-(3,4-Dimethoxybenzyl)-3-methylenedihydrofuran-2(3H)-
one (12d). Synthesised using general procedure D with 3-(3,4-
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 8 of 18
View Article Online
DOI: 10.1039/C6OB01527A
ARTICLE
Journal Name
dimethoxyphenyl)propyl
2-diazo-2- 3-(1,3-Benzodioxol-5-yl)propyl
2-diazo-2-
(diethoxyphosphoryl)acetate 11d (86 mg, 0.215 mmol), CH2Cl2 (diethoxyphosphoryl)acetate (15). Synthesised using general
(4.3 mL), Rh2(oct)4 (3.4 mg, 4.3 mol), THF (4.3 mL), KOBu-t procedure with 3-(1,3-benzodioxol-5-yl)propyl 2-
ꢁ
B
(29.0 mg, 0.258 mmol) and paraformaldehyde (12.9 mg, 0.430 (diethoxyphosphoryl)acetate (2.09 g, 5.83 mmol), THF (29 mL),
mmol). Purification by column chromatography (2:1 LHMDS (7.00 mL, 7.00 mmol, 1.0 M solution in THF) and p-
hexane:EtOAc) afforded the title compound 12d as a colourless ABSA (1.68 g, 7.00 mmol). Purification by column
oil (20 mg, 37%); Rf 0.26 (2:1 hexane:EtOAc); νmax (thin chromatography (2:1 petrol:EtOAc) afforded the title
film)/cm-1 2911, 2836, 1759, 1590, 1515, 1465, 1260, 1157, compound 15 as a pale yellow oil (1.35 g, 60%); Rf 0.66 (1:1
1141, 1115, 1026; δH (400 MHz, CDCl3) 2.75 (1 H, dd, J = 13.9, J petrol:EtOAc); νmax (thin film)/cm-1 2984, 2130, 1704, 1504,
= 8.8), 2.90 (1 H, dd, J = 13.9, J = 7.0), 3.29–3.38 (1 H, m), 3.86 1490, 1390, 1280, 1246, 1099, 1020, 978; δH (400 MHz, CDCl3)
(3 H, s), 3.86 (3 H, s), 4.06 (1 H, dd, J = 9.2, J = 5.0), 4.34 (1 H, 1.35 (6 H, td, J = 7.1, J = 0.7), 1.88–1.95 (2 H, m), 2.60 (2 H, t, J
dd, J = 9.2, J = 8.0), 5.43 (1 H, d, J = 2.3), 6.26 (1 H, d, J = 2.6), = 7.5), 4.10–4.26 (6 H, m), 5.90 (2 H, s), 6.59 (1 H, dd, J = 7.9, J
6.68 (1 H, d, J = 2.0), 6.71 (1 H, dd, J = 8.1, J = 2.0), 6.81 (1 H, d, = 1.7), 6.64 (1 H, d, J = 1.7), 6.70 (1 H, d, J = 7.9); δC (100 MHz,
J = 8.1); δC (100 MHz, CDCl3) 39.6, 40.3, 55.8 (2C), 70.5, 111.2, CDCl3) 16.1 (d, J = 6.9), 30.4, 31.5, 53.8 (d, J = 228.5), 63.5 (d, J
111.9, 120.9, 122.7, 129.9, 137.5, 147.9, 149.0, 170.7; HRMS = 5.6), 64.6, 100.7, 108.1, 108.7, 121.0, 134.5, 145.8, 147.6,
(ESI+): Found: 271.0950; C14H16NaO4 (MNa+) Requires 271.0941 163.3 (d, J = 12.0); δP (162 MHz, CDCl3) 10.8; HRMS (ESI+):
(−
3.3 ppm error).
Found: 407.0967; C16H21N2NaO7P (MNa+) Requires 407.0979
(2.9 ppm error), Found: 385.1147; C16H22N2O7P (MH+) Requires
3-(1,3-Benzodioxol-5-yl) 2-(diethoxyphosphoryl)acetate. To 385.1159 (3.1 ppm error).
powdered LiAlH4 (1.516 g, 30.5 mmol) under argon was added
diethyl ether (120 mL) via cannula whilst being cooled to 0 °C. Cinnamyl 2-(diethoxyphosphoryl)acetate (23a). Synthesised
A solution of (E)-ethyl 3-(1,3-benzodioxol-5-yl)acrylate (1.68 g, using general procedure A with cinnamyl alcohol (4.03 g, 30.0
7.63 mmol) in diethyl ether (20 mL) was added dropwise via mmol), toluene (150 mL), DEPAA (5.06 mL, 31.5 mmol), DIPEA
cannula to the suspension over 5 mins and stirred at 0
°C for 1 (13.6 mL, 78.0 mmol) and T3P (24.8 g, 39.0 mmol, 50% w/w
h then at RT for 30 mins. The suspension was quenched at 0
°
C
solution in EtOAc) affording the title compound 23a as a yellow
dropwise with water (1.5 mL) followed by 15% aq. NaOH (1.5 oil (7.14 g, 76%). No further purification was required; Rf 0.23
mL) and again with water (4.5 mL) then stirred for 30 mins at (1:1 hexane:EtOAc); νmax (thin film)/cm-1 2984, 1737, 1449,
RT. The solution was filtered through a pad of Celite and 1393, 1264, 1163, 1114, 1050, 1023, 968; δH (400 MHz, CDCl3)
washed with diethyl ether (50 mL). The filtrate was 1.33 (6 H, t, J = 7.0), 3.01 (2 H, d, J = 21.6), 4.13–4.21 (4 H, m),
concentrated in vacuo affording the allylic alcohol, which was 4.80 (2 H, dd, J = 6.5, J = 1.2), 6.27 (1 H, dt, J = 15.9, J = 6.5),
used without further purification.
6.68 (1 H, d, J = 15.9), 7.24–7.28 (1 H, m), 7.30–7.34 (2 H, m),
To a solution of the allylic alcohol in methanol (30 mL) was 7.36–7.39 (2 H, m); δC (100 MHz, CDCl3) 16.3 (d, J = 6.2), 34.3
added palladium on carbon (10% wt. % loading, 100 mg). The (d, J = 134.2), 62.7 (d, J = 6.5), 66.0, 122.4, 126.6, 128.1, 128.6,
flask was evacuated and backfilled 4 times with argon then 4 134.7, 136.0, 165.6 (d, J = 6.1); δP (162 MHz, CDCl3) 20.2;
times with hydrogen. The mixture was stirred at RT for 16 h, HRMS (ESI+): Found: 335.1027; C15H21NaO5P (MNa+) Requires
after which the mixture was filtered through a pad of Celite 335.1019 (−
2.4 ppm error), Found: 313.1197; C15H22O5P (MH+)
and washed with methanol (50 mL). The filtrate was Requires 313.1199 (0.7 ppm error).
concentrated in vacuo to afford the saturated alcohol, which
was used without further purification.
Cinnamyl
2-diazo-2-(diethoxyphosphoryl)acetate
(19a).
Using general procedure A with the saturated alcohol, Synthesised using general procedure B with cinnamyl 2-
toluene (40 mL), DEPAA (1.29 mL, 8.01 mmol), DIPEA (3.46 mL, (diethoxyphosphoryl)acetate 23a (3.12 g, 10.0 mmol), THF (50
19.8 mmol) and T3P (6.31 g, 9.92 mmol, 50% w/w solution in mL), LHMDS (12.0 mL, 12.0 mmol, 1.0 M solution in THF) and
EtOAc) afforded the title compound as a colourless oil (2.21 g, p-ABSA (2.88 g, 12.0 mmol). Purification by column
81% over 3 steps); Rf 0.28 (1:1 petrol:EtOAc); νmax (thin chromatography (2:1 petrol:EtOAc) afforded the title
film)/cm-1 2988, 1735, 1511, 1493, 1450, 1246, 1116, 1024, compound 19a as a yellow oil (1.41 g, 42%); Rf 0.50 (1:1
970; δH (400 MHz, CDCl3) 1.34 (6 H, td, J = 7.1, J = 0.5), 1.88– petrol:EtOAc); νmax (thin film)/cm-1 2985, 2128, 1707, 1496,
1.96 (2 H, m), 2.62 (2 H, t, J = 7.6), 2.97 (2 H, d, J = 21.6), 4.11– 1449, 1380, 1275, 1214, 1164, 1120, 1020, 975; δH (400 MHz,
4.21 (6 H, m), 5.91 (2 H, s), 6.61–6.63 (1 H, m), 6.66–6.67 (1 H, CDCl3) 1.36 (6 H, t, J = 7.1, J = 0.8), 4.11–4.29 (4 H, m), 4.86 (2
m), 6.72 (1 H, d, J = 7.8); δC (100 MHz, CDCl3) 16.3 (d, J = 6.2), H, dd, J = 6.5, J = 1.3), 6.28 (1 H, dt, J = 15.9, J = 6.5), 6.68 (1 H,
30.3, 31.6, 34.3 (d, J = 134.2), 62.7 (d, J = 6.3), 64.6, 100.8, d, J = 15.9), 7.25–7.40 (5 H, m); δC (100 MHz, CDCl3) 16.1 (d, J =
108.2, 108.8, 121.2, 134.8, 145.8, 147.6, 165.8 (d, J = 6.2); δP 6.9), 53.9 (d, J = 227.3), 63.7 (d, J = 5.6), 66.0, 122.4, 126.6,
(162 MHz, CDCl3) 20.5; HRMS (ESI+): Found: 381.1061; 128.2, 128.6, 134.9, 135.9, 163.2 (d, J = 11.8); δP (162 MHz,
C16H23NaO7P (MNa+) Requires 381.1074 (3.3 ppm error), CDCl3) 10.5; HRMS (ESI+): Found: 361.0928; C15H19N2NaO5P
Found: 359.1245; C16H24O7P (MH+) Requires 359.1254 (2.6 (MNa+) Requires 361.0924 (
−
1.0 ppm error).
ppm error).
Diethyl
((1RS,5SR,6SR)-2-oxo-6-phenyl-3-
oxabicyclo[3.1.0]hexan-1-yl)phosphonate (20a). To an oven
8 | 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
Organic & Biomolecular Chemistry
Page 9 of 18
Journal Name
View Article Online
DOI: 10.1039/C6OB01527A
ARTICLE
dried 50 mL rbf containing cinnamyl 2-diazo-2- 7.1, J = 0.5), 2.98 (2 H, d, J = 21.6), 4.12–4.19 (4 H, m), 4.61–
(diethoxyphosphoryl)acetate 19a (676 mg, 2.00 mmol) flushed 4.64 (1 H, m), 5.24 (1 H, app. dq, J = 10.4, J = 1.3), 5.35 (1 H,
with argon was added CH2Cl2 (20 mL) followed by Rh2(oct)4 app. dq, J = 17.2, J = 1.5), 5.90 (2 H, ddt, J = 17.2, J = 10.4, J =
(31.1 mg, 0.04 mmol). The solution was stirred at 45 °C for 18 5.7); δC (100 MHz, CDCl3) 16.3 (d, J = 6.2), 34.2 (d, J = 134.3),
h. Concentration in vacuo and purification by column 62.7 (d, J = 6.2), 66.1, 118.7, 131.5, 165.5 (d, J = 6.1); δP (162
chromatography (1:10 hexane:EtOAc) afforded the title MHz, CDCl3) 20.1; HRMS (ESI+): Found: 259.0708; C9H17NaO5P
compound 20a as a pale yellow solid (490 mg, 79%); Rf 0.15 (MNa+) Requires 259.0706 (
−0.8 ppm error), Found: 237.0890;
(1:2 hexane:EtOAc); m.p. 79–81 °C; νmax (thin film)/cm-1 2989, C9H18O5P (MH+) Requires 237.0886 (
−1.6 ppm error).
2909, 1762, 1369, 1251, 1200, 1163, 1098, 1049, 1013, 971; δH
(400 MHz, CDCl3) 1.07 (3 H, td, J = 7.1, J = 0.5), 1.21 (3 H, t, J = (Z)-Hex-2-en-1-yl
2-(diethoxyphosphoryl)acetate
(23c).
7.1), 2.81 (1 H, app. t, J = 6.1), 3.30 (1 H, app. dt, J = 10.6, J = Synthesised using general procedure A with (Z)-hex-2-en-1-ol
5.2), 3.80 (2 H, dq, J = 8.2, J = 7.1), 3.88–4.08 (2 H, m), 4.41 (1 (2.16 g, 21.6 mmol), toluene (110 mL), DEPAA (3.65 mL, 22.7
H, dd, J = 9.3, J = 2.8), 4.51 (1 H, dd, J = 9.3, J = 4.7), 7.26–7.39 mmol), DIPEA (9.78 mL, 56.2 mmol) and T3P (17.8 g, 28.0
(5 H, m); δC (100 MHz, CDCl3) 16.0 (d, J = 6.3), 16.2 (d, J = 5.9 mmol, 50% w/w solution in THF) affording the title compound
28.1, 31.5 (d, J = 206.1), 34.9 (d, J = 3.0), 62.5 (d, J = 6.1), 62.8 23c as a yellow oil (1.87 g, 79%). No further purification was
(d, J = 6.6), 68.0 (d, J = 2.4), 128.0, 128.1, 129.4, 131.7 (d, J = required; Rf 0.70 (1:1 hexane:EtOAc); νmax (thin film)/cm-1
4.8), 171.9 (d, J = 10.1); δP (162 MHz, CDCl3) 15.3; HRMS (ESI+): 2963, 2933, 2874, 1738, 1460, 1394, 1267, 1115, 1056, 1026,
Found: 333.0861; C15H19NaO5P (MNa+) Requires 333.0862 (0.4 971, 842, 782; δH (400 MHz, CDCl3) 0.90 (3 H, t, J = 7.4), 1.32–
ppm error), Found: 311.1035; C15H20O5P (MH+) Requires 1.44 (8 H, m), 2.05–2.11 (2 H, m), 2.97 (2 H, d, J = 21.5), 4.13–
311.1043 (2.5 ppm error).
4.21 (4 H, m), 4.69 (2 H, dd, J = 6.9), 5.54 (1 H, dtt, J = 10.9, J =
6.9, J = 1.4), 5.66 (1 H, dtt, J = 10.9, J = 7.5, J = 1.2); δC (100
((4SR)-4-benzyl-2-oxotetrahydrofuran-3- MHz, CDCl3) 13.6, 16.3 (d, J = 6.2), 22.5, 29.5, 34.3 (d, J =
Diethyl
yl)phosphonate (21). To a solution of freshly prepared SmI2 134.3), 61.4, 62.7 (d, J = 6.2), 122.8, 135.6, 165.7 (d, J = 6.2); δP
(2.00 mL, 0.200 mmol, ~0.1 M in THF) in an oven dried sealable (162 MHz, CDCl3) 20.3; HRMS (ESI+): Found: 301.1181;
tube at
solution
−
78
°
of
C under an atmosphere of argon, was added a C12H23NaO5P (MNa+) Requires 301.1175 (
−
1.8 ppm error),
diethyl
((1RS,5SR,6SR)-2-oxo-6-phenyl-3- Found: 279.1361; C12H24O5P (MH+) Requires 279.1356 (
−
2.0
oxabicyclo[3.1.0]hexan-1-yl)phosphonate 20a (31 mg, 0.100 ppm error).
mmol) in THF (0.5 mL). The solution was stirred at 78 C for 5
mins then quenched with sat. aq. NH4Cl (5 mL) and then (2E,4E)-Hexa-2,4-dien-1-yl
−
°
2-(diethoxyphosphoryl)acetate
allowed to warm at RT. The mixture was diluted with water (5 (23d). Synthesised using general procedure A with (2E,4E)-
mL) and extrated with diethyl ether (3 × 10 mL). The combined hexa-2,4-dien-1-ol (491 mg, 5.00 mmol), toluene (25.0 mL),
organic extracts were dried over MgSO4, filtered and DEPAA (1.03 mL, 5.25 mmol), DIPEA (2.26 mL, 13.0 mmol) and
concentrated in vacuo. Purification by column chromatography T3P (4.14 g, 6.50 mmol, 50% w/w solution in EtOAc) affording
(1:2 hexane:EtOAc) afforded the title compound 21 as a pale the title compound 23d as an orange oil (1.36 g, 98%). No
yellow oil (15 mg, 48%); Rf 0.52 (1:4 hexane:EtOAc); νmax (thin further purification was required; Rf 0.26 (1:1 hexane:EtOAc);
film)/cm-1 2983, 2915, 1771, 1497, 1479, 1455, 1381, 1252,
ν
max (thin film)/cm-1 2984, 2934, 1735, 1444, 1393, 1258, 1112,
1206, 1160, 1047, 1020, 972, 753, 703; δH (400 MHz, CDCl3) 1020, 965; δH (400 MHz, CDCl3) 1.31 (6 H, t, J = 7.1), 1.73 (3 H,
1.29–1.33 (6 H, m), 2.81 (1 H, dd, J = 13.8, J = 8.6), 2.83 (1 H, d, J = 6.7), 2.95 (2 H, d, J = 21.5), 4.14 (4 H, app. quin., J = 7.5),
dd, J = 23.9, J = 4.5), 2.93 (1 H, dd, J = 13.8, J = 7.1), 3.11–3.24 4.61 (2 H, d, J = 6.7), 5.58 (1 H, dt, J = 15.2, J = 6.7), 5.73 (1 H,
(1 H, m), 3.99–4.29 (5 H, m), 4.45 (1 H, dd, J = 9.1, J = 6.9), dq, J = 15.2, J = 6.7), 6.01 (1 H, ddd, J = 15.2, J = 10.5, J = 1.2),
7.15–7.18 (2 H, m), 7.23–7.27 (1 H, m), 7.29–7.34 (2 H, m); δC 6.24 (1 H, dd, J = 15.2, J = 10.5); δC (100 MHz, CDCl3) 16.2 (d, J =
(100 MHz, CDCl3) 16.3 (d, J = 6.1), 16.3 (d, J = 6.1), 39.3 (d, J = 6.6), 18.1, 34.3 (d, J = 134.2), 62.6 (d, J = 6.6), 65.9, 122.8,
2.6), 39.3 (d, J = 10.1), 44.5 (d, J = 139.5), 62.9 (d, J = 6.8), 63.6 130.2, 131.6, 135.4, 165.5 (d, J = 6.1); δP (162 MHz, CDCl3)
(d, J = 6.8), 71.8 (d, J = 5.0), 127.0, 128.8, 129.0, 137.2, 171.7 20.2; HRMS (ESI+): Found: 299.1026; C12H21NaO5P (MNa+)
(d, J = 3.6); δP (162 MHz, CDCl3) 20.0; HRMS (ESI+): Found: Requires 299.1019 (
335.1030; C15H21NaO5P (MNa+) Requires 335.1019 (
3.4 ppm
error), Found: 313.1205; C15H22O5P (MH+) Requires 313.1199 3-Methyl-but-2-en-1-yl 2-(diethoxyphosphoryl)acetate (23e).
−2.4 ppm error).
−
(−
1.7 ppm error).
Synthesised using general procedure A with 3-methyl-but-2-
en-1-ol (431 mg, 5.00 mmol), toluene (25.0 mL), DEPAA (1.03
Allyl 2-(diethoxyphosphoryl)acetate (23b). Synthesised using mL, 5.25 mmol), DIPEA (2.26 mL, 13.0 mmol) and T3P (4.14 g,
general procedure A with allyl alcohol (1.16 g, 20.0 mmol), 6.50 mmol, 50% w/w solution in EtOAc) affording the title
toluene (100 mL), DEPAA (3.38 mL, 21.0 mmol), DIPEA (9.06 compound 23e as a yellow oil (1.25 g, 95%). No further
mL, 52.0 mmol) and T3P (16.5 g, 26.0 mmol, 50% w/w solution purification was required; Rf 0.24 (1:1 hexane:EtOAc); νmax
in EtOAc) affording the title compound 23b as an orange oil (thin film)/cm-1 2982, 2933, 1734, 1445, 1392, 1264, 1113,
(4.63 g, 98%). No further purification was required; Rf 0.26 (1:1 1051, 1029, 968; δH (400 MHz, CDCl3) 1.33 (6 H, t, J = 7.1), 1.70
petrol:EtOAc); νmax (thin film)/cm-1 2985, 1738, 1394, 1261, (3 H, s), 1.74 (3 H, s), 2.95 (2 H, d, J = 21.5), 4.12–4.19 (4 H, m),
1117, 1050, 1023, 971; δH (400 MHz, CDCl3) 1.32 (6 H, td, J = 4.62 (2 H, d, J = 7.3), 5.31–5.36 (1 H, m); δC (100 MHz, CDCl3)
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 10 of 18
View Article Online
DOI: 10.1039/C6OB01527A
ARTICLE
Journal Name
16.3 (d, J = 6.7), 18.0, 25.7, 34.3 (d, J = 134.5), 62.4, 62.6 (d, J = 141.8, 144.2; MS (ESI+): 249.07 (MK+), 233.09 (MNa+).
6.6), 118.0, 139.7, 165.8 (d, J = 6.5); δP (162 MHz, CDCl3) 20.4; Obtained data in accord with reported literature.20,21
HRMS (ESI+): Found: 287.1021; C11H21NaO5P (MNa+) Requires
287.1019 ( 0.9 ppm error).
The synthesis continued using general procedure A with
3,3-diphenylprop-2-en-1-ol (862 mg, 4.10 mmol), toluene (20.5
mL), DEPAA (0.69 mL, 4.30 mmol), DIPEA (1.86 mL, 10.7 mmol)
2- and T3P (3.40 g, 5.33 mmol, 50% w/w solution in EtOAc)
−
(E)-3,7-Dimethylocta-2,6-dien-1-yl
(diethoxyphosphoryl)acetate (23f). Synthesised using general affording the title compound 23g as an orange oil (1.59 g,
procedure A with geraniol (771 mg, 5.00 mmol), toluene (25.0 100%). No further purification was required; Rf 0.26 (1:1
mL), DEPAA (1.03 mL, 5.25 mmol), DIPEA (2.26 mL, 13.0 mmol) hexane:EtOAc); νmax (thin film)/cm-1 2983, 1736, 1445, 1265,
and T3P (4.14 g, 6.50 mmol, 50% w/w solution in EtOAc) 1113, 1025, 969, 774, 702; δH (400 MHz, CDCl3) 1.33 (6 H, t, J =
affording the title compound 23f as an orange oil (1.65 g, 99%). 7.1, J = 0.5), 3.00 (2 H, d, J = 21.5), 4.13–4.21 (4 H, m), 4.71 (2
No further purification was required; Rf 0.27 (1:1 H, d, J = 7.1), 6.18 (1 H, t, J = 7.1), 7.16–7.19 (2 H, m), 7.23–
hexane:EtOAc); νmax (thin film)/cm-1 2980, 2928, 1735, 1444, 7.40 (8 H, m); δC (100 MHz, CDCl3) 16.3 (d, J = 6.3), 34.5 (d, J =
1391, 1263, 1112, 1051, 1025, 966; δH (400 MHz, CDCl3) 1.32 134.2), 62.7 (d, J = 6.2), 63.7, 121.5, 127.7, 127.9, 127.9, 128.2,
(6 H, t, J = 7.1), 1.58 (3 H, s), 1.67 (3 H, d, J = 0.9), 1.69 (3 H, d, J 128.3, 129.7, 138.4, 141.4, 147.0, 165.7 (d, J = 6.3); δP (162
= 0.9), 2.00–2.09 (4 H, m), 2.96 (2 H, d, J = 21.5), 4.16 (4 H, app. MHz, CDCl3) 20.2; HRMS (ESI+): Found: 411.1325; C21H25NaO5P
quin., J = 7.4), 4.64 (2 H, d, J = 7.2), 5.04–5.08 (1 H, m), 5.31– (MNa+) Requires 411.1332 (1.8 ppm error).
5.36 (1 H, m); δC (100 MHz, CDCl3) 16.3 (d, J = 6.6), 16.4, 17.6,
25.6, 26.2, 34.3 (d, J = 134.2), 39.5, 62.4, 62.6 (d, J = 6.2), (E)-3-(4-Bromophenyl)allyl
2-(diethoxyphosphoryl)acetate
117.7, 123.6, 131.9, 142.9, 165.8 (d, J = 6.1); δP (162 MHz, (23h). Starting with known alcohol (E)-3-(4-bromophenyl)prop-
CDCl3) 20.4; HRMS (ESI+): Found: 355.1644; C16H29NaO5P 2-en-1-ol (1.58 g, 7.43 mmol),22 general procedure A was
(MNa+) Requires 355.1645 (0.3 ppm error).
performed with toluene (37.2 mL), DEPAA (1.53 g, 7.80 mmol),
DIPEA (3.36 mL, 19.3 mmol) and T3P (6.15 g, 9.66 mmol, 50%
3,3-Diphenylallyl 2-(diethoxyphosphoryl)acetate (23g). To a w/w solution in EtOAc) affording the title compound 23h as an
suspension of AgOAc (2.59 g, 15.5 mmol) and Pd(OAc)2 (11.2 orange oil (2.90 g, 100%). No further purification was required;
mg, 0.05 mmol) in AcOH (15 mL) was added iodobenzene (1.73 Rf 0.20 (1:1 hexane:EtOAc); νmax (thin film)/cm-1 2982, 1736,
mL, 15.5 mmol) and ethyl acrylate (0.54 mL, 5.00 mmol). The 1488, 1402, 1258, 1114, 1049, 1022, 967, 840, 785; δH (400
mixture was stirred under an atmosphere of argon, at 110 °C MHz, CDCl3) 1.32 (6 H, t, J = 7.1), 3.01 (2 H, d, J = 21.5), 4.13–
for 6 h then allowed cool at RT and diluted with EtOAc (20 mL). 4.20 (4 H, m), 4.78 (2 H, d, J = 6.3), 6.26 (1 H, dt, J = 15.9, J =
The mixture was filtered through a pad of Celite, washed with 6.3), 6.62 (1 H, d, J = 15.9), 7.24 (2 H, d, J = 8.5), 7.43 (2 H, d, J =
EtOAc (200 mL) and the filtrate concentrated in vacuo. 8.5); δC (100 MHz, CDCl3) 16.3 (d, J = 6.6), 34.3 (d, J = 134.2),
Purification by column chromatography (15:1 hexane:EtOAc) 62.7 (d, J = 6.7), 65.7, 122.0, 123.3, 128.1, 131.7, 133.2, 135.0,
afforded ethyl 3,3-diphenylacrylate as a yellow oil (1.26 g, 165.6 (d, J = 6.5); δP (162 MHz, CDCl3) 20.1; HRMS (ESI+):
100%); Rf 0.26 (15:1 hexane:EtOAc); ν
max (thin film)/cm-1 2980, Found: 413.0130; C15H2079BrNaO5P (MNa+) Requires 413.0124
1722, 1618, 1446, 1369, 1264, 1164, 1038, 771, 697; δH (400
(−1.4 ppm error).
MHz, CDCl3) 1.12 (3 H, t, J = 7.1), 4.06 (2 H, q, J = 7.1), 6.37 (1
H, s), 7.20–7.24 (2 H, m), 7.29–7.40 (8 H, m); δC (100 MHz, (E)-3-(4-Methoxyphenyl)allyl 2-(diethoxyphosphoryl)acetate
CDCl3) 14.0, 60.0, 117.5, 127.8, 128.1, 128.3, 128.3, 129.1, (23i).
Starting
with
known
alcohol
(E)-3-(4-
129.4, 139.0, 140.8, 156.5, 166.1; MS (ESI+): 275.10 (MNa+), methoxyphenyl)prop-2-en-1-ol (1.72 g, 8.34 mmol),23 general
253.12 (MH+). Obtained data in accord with reported procedure A was performed with toluene (41.7 mL), DEPAA
literature.19
(1.72 g, 8.76 mmol), DIPEA (3.78 mL, 21.7 mmol) and T3P (6.90
To a solution of ethyl 3,3-diphenylacrylate (1.33 g, 5.27 g, 10.8 mmol, 50% w/w solution in EtOAc) affording the title
mmol) in THF (19 mL) cooled to 78 °C was added dropwise compound 23i as an orange oil (2.79 g, 98%). No further
−
diisobutylaluminium hydride (DIBAL) (21.1 mL, 21.1 mmol, 1.0 purification was required; Rf 0.20 (1:1 hexane:EtOAc); νmax
M in hexane) and stirred for 2 h. The solution was quenched (thin film)/cm-1 2983, 1733, 1607, 1512, 1247, 1176, 1114,
with water (15 mL) dropwise and stirred for 30 mins at RT 1023, 966, 841; δH (400 MHz, CDCl3) 1.32 (6 H, t, J = 7.1), 3.00
before being filtered through a pad of Celite and silica and (2 H, d, J = 21.5), 3.80 (3 H, s), 4.13–4.20 (4 H, m), 4.77 (2 H, d,
washed with diethyl ether (500 mL). The filtrate was J = 6.7), 6.14 (1 H, dt, J = 15.8, J = 6.7), 6.62 (1 H, d, J = 15.8),
concentrated in vacuo. Purification by column chromatography 6.85 (2 H, d, J = 8.3), 7.31 (2 H, d, J = 8.3); δC (100 MHz, CDCl3)
(4:1 hexane:EtOAc) afforded 3,3-diphenylprop-2-en-1-ol (886 16.3 (d, J = 6.6), 34.3 (d, J = 134.2), 55.2, 62.7 (d, J = 6.7), 66.3,
mg, 80 %) as a white solid; Rf 0.33 (4:1 hexane:EtOAc); m.p. 114.0, 120.0, 127.8, 128.7, 134.5, 160.0, 165.7 (d, J = 6.5); δP
60–62 °C (lit.20 61–63 °C); νmax (thin film)/cm-1 3325, 3056, (162 MHz, CDCl3) 20.2; HRMS (ESI+): Found: 365.1129;
3024, 1598, 1494, 1444, 1074, 1013, 758, 692; δH (400 MHz, C16H23NaO6P (MNa+) Requires 365.1124 (
CDCl3) 1.50 (1 H, br s), 4.23 (2 H, d, J = 6.9), 6.26 (1 H, t, J = 6.9),
−1.2 ppm error).
7.16–7.19 (2 H, m), 7.24–7.40 (8 H, m); δC (100 MHz, CDCl3) (E)-3-(1,3-Benzodioxol-5-yl)allyl
2-
60.7, 127.4, 127.5, 127.6, 127.6, 128.2, 128.2, 129.7, 139.0, (diethoxyphosphoryl)acetate (23j). Synthesised using general
procedure A with (E)-3-(1,3-benzodioxol-5-yl)prop-2-en-1-ol
10 | 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
Organic & Biomolecular Chemistry
Page 11 of 18
Journal Name
View Article Online
DOI: 10.1039/C6OB01527A
ARTICLE
(1.95 g, 10.9 mmol), toluene (55 mL), DEPAA (1.85 mL, 11.5 (diethoxyphosphoryl)acetate 23d (1.36 g, 4.92 mmol), DBSA
mmol), DIPEA (4.95 mL, 28.4 mmol) and T3P (9.05 g, 14.2 (2.47 g, 7.38 mmol), DBU (1.10 mL, 7.38 mmol) and CH2Cl2
mmol, 50% w/w solution in EtOAc) affording the title (49.0 mL). Purification by column chromatography (2:1
compound 23j as a yellow oil (3.89 g, 100%). No further hexane:EtOAc) afforded the title compound 19d as a yellow oil
purification was required; Rf 0.17 (1:1 hexane:EtOAc); νmax (1.54 g, 75%); Rf 0.43 (1:1 hexane:EtOAc); νmax (thin film)/cm-1
(thin film)/cm-1 2986, 2908, 1733, 1654, 1607, 1504, 1491, 2985, 2127, 1705, 1445, 1375, 1274, 1113, 1020, 797, 745,
1446, 1398, 1354, 1248, 1195, 1164, 1021, 965; δH (400 MHz, 590, 561; δH (400 MHz, CDCl3) 1.34 (6 H, td, J = 7.1, J = 0.7),
CDCl3) 1.32 (6 H, t, J = 7.1, J = 0.4), 2.99 (2 H, d, J = 21.5), 4.12– 1.75 (3 H, dd, J = 6.7, J = 1.0), 4.09–4.25 (4 H, m), 4.68 (2 H, d, J
4.20 (4 H, m), 4.75 (2 H, dd, J = 6.6, J = 1.0), 5.95 (2 H, s), 6.09 = 6.7), 5.60 (1 H, dt, J = 15.2, J = 6.7), 5.75 (1 H, dq, J = 15.2, J =
(1 H, dt, J = 15.8, J = 6.6), 6.58 (1 H, d, J = 15.8), 6.74 (1 H, d, J = 6.7), 6.00–6.07 (1 H, m), 6.26 (1 H, dd, J = 15.2, J = 10.5); δC
8.0), 6.81 (1 H, dd, J = 8.0, J = 1.6), 6.91 (1 H, d, J = 1.6); δC (100 (100 MHz, CDCl3) 16.1 (d, J = 7.1), 18.1, 63.6 (d, J = 5.9), 66.0,
MHz, CDCl3) 16.3 (d, J = 6.2), 34.3 (d, J = 134.2), 62.7 (d, J = 122.8, 130.2, 131.8, 135.6, 163.2 (d, J = 12.6); δP (162 MHz,
6.2), 66.1, 101.1, 105.7, 108.3, 120.5, 121.5, 130.4, 134.5, CDCl3) 10.6; HRMS (ESI+): Found: 325.0930; C12H19N2NaO5P
147.7, 148.0, 165.6 (d, J = 6.1); δP (162 MHz, CDCl3) 20.2; (MNa+) Requires 325.0924 (
−1.9 ppm error).
HRMS (ESI+): Found: 379.0920; C16H21NaO7P (MNa+) Requires
379.0917 (
−
0.8 ppm error).
3-Methyl-but-2-en-1-yl
(diethoxyphosphoryl)acetate (19e). Synthesised using general
(19b). procedure with 3-methyl-but-2-en-1-yl 2-
with 3-(4- (diethoxyphosphoryl)acetate 23e (1.24 g, 4.69 mmol), DBSA
2-diazo-2-
Allyl
2-diazo-2-(diethoxyphosphoryl)acetate
C
Synthesised using general procedure
C
methoxyphenyl)propyl 2-(diethoxyphosphoryl)acetate 23b (2.35 g, 7.04 mmol), DBU (1.05 mL, 7.04 mmol) and CH2Cl2
(2.19 g, 9.27 mmol), DBSA (4.89 g, 13.9 mmol), DBU (2.08 mL, (47.0 mL). Purification by column chromatography (2:1
13.9 mmol) and CH2Cl2 (93.0 mL). Purification by column hexane:EtOAc) afforded the title compound 19e as a pale
chromatography (2:1 petrol:EtOAc) affording the title yellow oil (1.15 g, 85%); Rf 0.39 (1:1 hexane:EtOAc); νmax (thin
compound 19b as a pale yellow oil (2.02 g, 83%); Rf 0.43 (1:1 film)/cm-1 2983, 2933, 2124, 1700, 1445, 1374, 1271, 1110,
petrol:EtOAc); νmax (thin film)/cm-1 2992, 2932, 2129, 1707, 1016, 976, 746, 588, 556; δH (400 MHz, CDCl3) 1.34 (6 H, t, J =
1368, 1276, 1020, 983; δH (400 MHz, CDCl3) 1.33 (6 H, td, J = 7.1), 1.70 (3 H, s), 1.74 (3 H, s), 4.09–4.25 (4 H, m), 4.68 (2 H, d,
7.1, J = 0.8), 4.09–4.25 (4 H, m), 4.67 (1 H, app. dt, J = 5.6, J = J = 7.3), 5.29–5.35 (1 H, m); δC (100 MHz, CDCl3) 16.1 (d, J =
1.4), 5.24 (1 H, app. dq, J = 10.5, J = 1.3), 5.32 (1 H, app. dq, J = 7.3), 18.0, 25.7, 62.4, 63.6 (d, J = 5.9), 118.0, 139.9, 163.4 (d, J
17.2, J = 1.5), 5.89 (2 H, ddt, J = 17.2, J = 10.5, J = 5.6); δC (100 = 12.7); δP (162 MHz, CDCl3) 10.7; HRMS (ESI+): Found:
MHz, CDCl3) 16.1 (d, J = 6.9), 53.9 (d, J = 226.1), 63.6 (d, J = 313.0928; C11H19N2NaO5P (MNa+) Requires 313.0924 (
5.6), 65.9, 118.7, 131.4, 163.1 (d, J = 12.0); δP (162 MHz, CDCl3) ppm error).
10.4; HRMS (ESI+): Found: 285.0603; C9H15N2NaO5P (MNa+)
−1.4
Requires 285.0611 (2.9 ppm error), Found: 263.0792; (E)-3,7-Dimethylocta-2,6-dien-1-yl
C9H16N2O5P (MH+) Requires 263.0791 (
0.2 ppm error). (diethoxyphosphoryl)acetate (19f). Synthesised using general
procedure with (E)-3,7-dimethylocta-2,6-dien-1-yl 2-
2-diazo-2-(diethoxyphosphoryl)acetate (diethoxyphosphoryl)acetate 23f (1.65 g, 4.96 mmol), p-ABSA
2-diazo-2-
−
C
(Z)-Hex-2-en-1-yl
(19c). Synthesised using general procedure B with (Z)-hex-2- (1.79 g, 7.45 mmol), DBU (1.11 mL, 7.45 mmol) and CH2Cl2
en-1-yl 2-(diethoxyphosphoryl)acetate 23c (385 mg, 1.38 (50.0 mL). Purification by column chromatography (2:1
mmol), THF (50 mL), NaH (66.4 mg, 1.66 mmol, 60% dispersion hexane:EtOAc) afforded the title compound 19f as a yellow oil
in mineral oil) and p-ABSA (399 mg, 1.66 mmol). Purification by (1.12 g, 63%); Rf 0.56 (1:1 hexane:EtOAc); νmax (thin film)/cm-1
column chromatography (3:1 petrol:EtOAc) afforded the title 2981, 2915, 2124, 1701, 1444, 1378, 1273, 1021, 975, 797,
compound 19c as a yellow oil (315 mg, 75%); Rf 0.52 (1:1 744, 588, 559; δH (400 MHz, CDCl3) 1.32 (6 H, td, J = 7.1, J =
hexane:EtOAc); νmax (thin film)/cm-1 2962, 2128, 1709, 1445, 0.8), 1.56 (3 H, s), 1.64 (3 H, d, J = 1.0), 1.68 (3 H, d, J = 1.1),
1361, 1279, 1164, 1023, 978; δH (400 MHz, CDCl3) 0.88 (3 H, t, J 1.98–2.08 (4 H, m), 4.08–4.23 (4 H, m), 4.68 (2 H, d, J = 7.2),
= 7.4), 1.30–1.43 (8 H, m), 2.07 (2 H, qd, J = 7.4, J = 1.3), 4.09– 5.01–5.05 (1 H, m), 5.28–5.32 (1 H, m); δC (100 MHz, CDCl3)
4.25 (4 H, m), 4.72–4.74 (2 H, m), 5.52 (1 H, dtt, J = 10.9, J = 16.0 (d, J = 6.9), 16.4, 17.5, 25.5, 26.1, 39.4, 53.5 (d, J = 227.1),
6.9, J = 1.5), 5.65 (1 H, dtt, J = 10.9, J = 7.6, J = 1.3); δC (100 62.3, 63.5 (d, J = 5.9), 117.6, 123.5, 131.8, 143.0, 163.3 (d, J =
MHz, CDCl3) 13.5, 16.1 (d, J = 6.9), 22.4, 29.4, 53.8 (d, J = 12.6); δP (162 MHz, CDCl3) 10.7; HRMS (ESI+): Found: 381.1549;
227.5), 61.3, 63.6 (d, J = 6.0), 122.8, 136.0, 163.3 (d, J = 12.3); C16H27N2NaO5P (MNa+) Requires 381.1550 (0.3 ppm error).
δP (162 MHz, CDCl3) 10.6; HRMS (ESI+): Found: 327.1087;
C12H21N2NaO5P (MNa+) Requires 327.1080 (
−
2.1 ppm error), 3,3-Diphenylallyl
2-diazo-2-(diethoxyphosphoryl)acetate
Found: 305.1262; C12H22N2O5P (MH+) Requires 305.1261 (
ppm error).
−
0.5 (19g). Synthesised using general procedure B with 3,3-
diphenylallyl 2-(diethoxyphosphoryl)acetate 23g (1.59 g, 4.10
mmol), THF (20.5 mL), LHMDS (4.92 mL, 4.92 mmol, 1.0 M
(2E,4E)-Hexa-2,4-dien-1-yl
2-diazo-2- solution in THF) and p-ABSA (1.18 g, 4.92 mmol). Purification
(diethoxyphosphoryl)acetate (19d). Synthesised using general by column chromatography (2:1 hexane:EtOAc) afforded the
procedure
C
with
(2E,4E)-hexa-2,4-dien-1-yl
2- title compound 19g as a yellow oil (823 g, 48%); Rf 0.52 (1:1
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 11
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 12 of 18
View Article Online
DOI: 10.1039/C6OB01527A
ARTICLE
Journal Name
hexane:EtOAc); νmax (thin film)/cm-1 2984, 2126, 1703, 1494, 4.20 (4 H, m), 4.75 (2 H, dd, J = 6.6, J = 1.0), 5.95 (2 H, s), 6.09
1444, 1377, 1348, 1271, 1214, 1163, 1117, 1099, 1017, 976, (1 H, dt, J = 15.8, J = 6.6), 6.58 (1 H, d, J = 15.8), 6.74 (1 H, d, J =
796, 729, 699, 585, 558; δH (400 MHz, CDCl3) 1.35 (6 H, t, J = 8.0), 6.81 (1 H, dd, J = 8.0, J = 1.6), 6.91 (1 H, d, J = 1.6); δC (100
7.1, J = 0.8), 4.12–4.28 (4 H, m), 4.77 (2 H, d, J = 7.2), 6.19 (1 H, MHz, CDCl3) 16.3 (d, J = 6.2), 34.3 (d, J = 134.2), 62.7 (d, J =
t, J = 7.2), 7.16–7.19 (2 H, m), 7.22–7.39 (8 H, m); δC (100 MHz, 6.2), 66.1, 101.1, 105.7, 108.3, 120.5, 121.5, 130.4, 134.5,
CDCl3) 15.9 (d, J = 6.9), 53.5 (d, J = 227.1), 63.3, 63.4 (d, J = 5.7), 147.7, 148.0, 165.6 (d, J = 6.1); δP (162 MHz, CDCl3) 20.2;
121.1, 127.4, 127.7, 127.8, 128.0, 128.1, 129.3, 138.1, 141.0, HRMS (ESI+): Found: 379.0920; C16H21NaO7P (MNa+) Requires
147.1, 162.9 (d, J = 12.2); δP (162 MHz, CDCl3) 10.5; HRMS 379.0917 (
(ESI+): Found: 437.1242; C21H23N2NaO5P (MNa+) Requires
−
0.8 ppm error).
437.1237 (
−
1.1 ppm error).
Diethyl
((1RS,5SR)-2-oxo-3-oxabicyclo[3.1.0]hexan-1-
yl)phosphonate (20b). Synthesised using General procedure E
(E)-3-(4-Bromophenyl)allyl
2-diazo-2- with allyl 2-diazo-2-(diethoxyphosphoryl)acetate 19b (600 mg,
(diethoxyphosphoryl)acetate (19h). Synthesised using general 2.29 mmol), CH2Cl2 (17 mL) and Rh2(oct)4 (35.6 mg, 0.046
procedure with (E)-3-(4-bromophenyl)allyl 2- mmol). Purification by column chromatography (1:20
C
(diethoxyphosphoryl)acetate 23h (2.90 g, 7.41 mmol), DBSA hexane:EtOAc) afforded the title compound 20b as a dark
(3.72 mL, 11.1 mmol), DBU (1.66 mL, 11.1 mmol) and CH2Cl2 yellow oil (417 mg, 78%); Rf 0.30 (1:8 hexane:EtOAc); νmax (thin
(74.1 mL). Purification by column chromatography (2:1 film)/cm-1 2986, 2920, 2838, 1764, 1376, 1271, 1243, 1015; δH
hexane:EtOAc) afforded the title compound 19h as a yellow oil (400 MHz, CDCl3) 1.18–1.22 (1 H, m), 1.27 (3 H, td, J = 7.1, J =
(2.69 g, 87%); Rf 0.42 (1:1 hexane:EtOAc); νmax (thin film)/cm-1 0.5), 1.29 (3 H, td, J = 7.1, J = 0.5), 1.76 (1 H, ddd, J = 15.2, J =
2984, 2127, 1705, 1488, 1275, 1020, 975, 798, 744, 590, 560; 7.8, J = 4.7), 2.58–2.65 (1 H, m), 4.07–4.18 (5 H, m), 4.28 (1 H,
δH (400 MHz, CDCl3) 1.33–1.37 (6 H, m), 4.12–4.28 (4 H, m), dd, J = 9.5, J = 4.7); δC (100 MHz, CDCl3) 16.1 (d, J = 6.0), 17.3
4.83 (2 H, dd, J = 6.4, J = 1.3), 6.26 (1 H, dt, J = 15.9, J = 6.4), (d, J = 3.0), 22.5 (d, J = 207.0), 24.3 (d, J = 1.4), 63.0 (d, J = 6.2),
6.61 (1 H, d, J = 15.9), 7.24 (2 H, d, J = 8.5), 7.44 (2 H, d, J = 8.5); 63.0 (d, J = 6.2), 67.5 (d, J = 2.5), 171.5 (d, J = 10.6); δP (162
δC (100 MHz, CDCl3) 16.3 (d, J = 7.2), 63.8 (d, J = 6.1), 65.9, MHz, CDCl3) 17.9; HRMS (ESI+): Found: 257.0552; C9H15NaO5P
122.2, 123.3, 128.2, 131.9, 133.6, 135.0, 163.3 (d, J = 12.6); δP (MNa+) Requires 257.0549 (
−
1.2 ppm error), Found: 235.0737;
3.0 ppm error).
(162 MHz, CDCl3) 10.5; HRMS (ESI+): Found: 439.0019; C9H16O5P (MH+) Requires 235.0730 (
C15H1879BrN2NaO5P (MNa+) Requires 439.0029 (2.3 ppm error).
−
Diethyl
2-diazo-2- oxabicyclo[3.1.0]hexan-1-yl)phosphonate (20c). Synthesised
(diethoxyphosphoryl)acetate (19i). Synthesised using general using General procedure E with (Z)-hex-2-en-1-yl 2-diazo-2-
procedure with (E)-3-(4-methoxyphenyl)allyl 2- (diethoxyphosphoryl)acetate 19c (212 mg, 0.697 mmol), CH2Cl2
(diethoxyphosphoryl)acetate 23i (2.79 g, 8.15 mmol), DBSA (7.0 mL) and Rh2(oct)4 (10.8 mg, 13.9 mol). Purification by
((1RS,5SR,6SR)-2-oxo-6-propyl-3-
(E)-3-(4-Methoxyphenyl)allyl
C
ꢁ
(4.09 mL, 12.2 mmol), DBU (1.82 mL, 12.2 mmol) and CH2Cl2 column chromatography (1:10 hexane:EtOAc) afforded the
(81.5 mL). Purification by column chromatography (2:1 title compound 20c as a pale yellow oil (128 mg, 66%); Rf 0.15
hexane:EtOAc) afforded the title compound 19i as a yellow oil (1:2 hexane:EtOAc); νmax (thin film)/cm-1 2963, 2934, 2874,
(2.26 g, 75%); Rf 0.37 (1:1 hexane:EtOAc); νmax (thin film)/cm-1 1764, 1468, 1371, 1254, 1197, 1164, 1130, 1022, 976; δH (400
2985, 2127, 1704, 1607, 1512, 1273, 1250, 1176, 1020, 975; δH MHz, CDCl3) 0.97 (3 H, t, J = 7.1), 1.29–1.56 (10 H, m), 2.02–
(400 MHz, CDCl3) 1.35 (6 H, td, J = 7.1, J = 0.8), 3.80 (3 H, s), 2.11 (1 H, m), 2.70 (1 H, dddd, J = 11.2, J = 8.0, J = 5.4, J = 0.9),
4.11–4.27 (4 H, m), 4.82 (2 H, dd, J = 6.7, J = 1.2), 6.14 (1 H, dt, 4.13–4.29 (5 H, m), 4.42 (1 H, dd, J = 10.0, J = 5.4); δC (100
J = 15.8, J = 6.7), 6.62 (1 H, d, J = 15.8), 6.85 (2 H, d, J = 8.7), MHz, CDCl3) 13.7, 16.3 (d, J = 6.1), 16.3 (d, J = 6.1), 21.9, 24.9,
7.32 (2 H, d, J = 8.7); δC (100 MHz, CDCl3) 16.1 (d, J = 6.9), 55.2, 28.1 (d, J = 2.3), 28.1 (d, J = 203.3), 29.5 (d, J = 2.5), 63.1 (d, J =
63.7 (d, J = 6.1), 66.3, 114.0, 120.0, 127.9, 128.6, 134.7, 159.7, 6.3), 63.2 (d, J = 6.2), 64.6 (d, J = 3.0), 170.5 (d, J = 10.0); δP
163.2 (d, J = 12.8); δP (162 MHz, CDCl3) 10.6; HRMS (ESI+): (162 MHz, CDCl3) 18.8; HRMS (ESI+): Found: 299.1026;
Found: 391.1032; C16H21N2NaO6P (MNa+) Requires 391.1029 C12H21NaO5P (MNa+) Requires 299.1019 (
0.6 ppm error).
Found: 277.1212; C12H22O5P (MH+) Requires 277.1199 (
ppm error).
−
2.5 ppm error),
4.5
(−
−
(E)-3-(1,3-Benzodioxol-5-yl)allyl
2-
(diethoxyphosphoryl)acetate (19j). Synthesised using general Diethyl
((1RS,5SR,6RS)-2-oxo-6-((E)-prop-1-en-1-yl)-3-
procedure A with (E)-3-(1,3-benzodioxol-5-yl)prop-2-en-1-ol oxabicyclo[3.1.0]hexan-1-yl)phosphonate (20d). Synthesised
23j (1.95 g, 10.9 mmol), toluene (55 mL), DEPAA (1.85 mL, 11.5 using General procedure E with (2E,4E)-hexa-2,4-dien-1-yl 2-
mmol), DIPEA (4.95 mL, 28.4 mmol) and T3P (9.05 g, 14.2 diazo-2-(diethoxyphosphoryl)acetate 19d (68.6 mg, 0.250
mmol, 50% w/w solution in EtOAc) affording the title mmol), CH2Cl2 (5.0 mL) and Rh2(oct)4 (4.0 mg, 5.0
ꢁmol).
compound 19j as a yellow oil (3.89 g, 100%). No further Purification by column chromatography (1:10 hexane:EtOAc)
purification was required; Rf 0.17 (1:1 hexane:EtOAc); νmax afforded the title compound 20d as a pale yellow oil (33 mg,
(thin film)/cm-1 2986, 2908, 1733, 1654, 1607, 1504, 1491, 48%); Rf 0.34 (EtOAc); νmax (thin film)/cm-1 2983, 1767, 1370,
1446, 1398, 1354, 1248, 1195, 1164, 1021, 965; δH (400 MHz, 1276, 1246, 1157, 1025, 971, 590; δH (400 MHz, CDCl3) 1.32 (3
CDCl3) 1.32 (6 H, t, J = 7.1, J = 0.4), 2.99 (2 H, d, J = 21.5), 4.12– H, t, J = 7.1), 1.33 (3 H, t, J = 7.1), 1.72 (3 H, dd, J = 6.5, J = 1.6),
12 | 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
Organic & Biomolecular Chemistry
Page 13 of 18
Journal Name
2.17 (1 H, ddd, J = 9.4, J = 6.0, J = 5.3), 2.73 (1 H, app. dt, J = (3.8 mL) and Rh2(oct)4 (2.9 mg, 3.8
View Article Online
DOI: 10.1039/C6OB01527A
ARTICLE
ꢁ
mol). Purification by
10.3, J = 5.0), 4.14–4.22 (4 H, m), 4.27 (1 H, dd, J = 9.4, J = 3.0), column chromatography (1:10 hexane:EtOAc) afforded the
4.34 (1 H, dd, J = 9.4, J = 4.6), 5.60 (1 H, ddq, J = 15.3, J = 9.4, J title compound 20g as a pale yellow oil (38 mg, 51%); Rf 0.18
= 1.6), 5.80 (1 H, dq, J = 15.3, J = 6.5); δC (100 MHz, CDCl3) 16.2, (1:2 hexane:EtOAc); νmax (thin film)/cm-1 2982, 2908, 1761,
16.3, 17.9, 29.5 (d, J = 202.7), 30.3, 34.6 (d, J = 2.8), 62.8 (d, J = 1600, 1495, 1474, 1449, 1388, 1365, 1252, 1221, 1195, 1162,
6.5), 63.1 (d, J = 6.4), 67.7 (d, J = 2.9), 124.3 (d, J = 4.8), 130.8, 1071, 1054, 1019, 973, 710; δH (400 MHz, CDCl3) 1.11 (3 H, t, J
171.7 (d, J = 9.1); δP (162 MHz, CDCl3) 16.5; HRMS (ESI+): = 7.1), 1.22 (3 H, t, J = 7.1), 3.53 (1 H, dd, J = 12.3, J = 5.3), 3.68
Found: 297.0866; C12H19NaO5P (MNa+) Requires 297.0862 (1 H, ddq, J = 10.2, J = 9.5, J = 7.1), 3.89–3.99 (1 H, m), 4.04–
(−
1.1 ppm error), Found: 275.1044; C12H20O5P (MH+) Requires 4.13 (2 H, m), 4.27 (1 H, ddd, J = 9.9, J = 2.8, J = 0.7), 4.54 (1 H,
275.1043 (
−
0.3 ppm error).
dd, J = 9.9, J = 5.3), 7.16–7.34 (6 H, m), 7.42–7.50 (4 H, m); δC
(100 MHz, CDCl3) 16.2 (d, J = 6.1), 16.2 (d, J = 6.3), 33.7 (d, J =
Diethyl
((1SR,5SR)-6,6-dimethyl-2-oxo-3- 3.2), 37.3 (d, J = 203.9), 46.5 (d, J = 2.5), 62.4 (d, J = 6.2), 63.4
oxabicyclo[3.1.0]hexan-1-yl)phosphonate (20e). Synthesised (d, J = 6.5), 65.4 (d, J = 2.5), 127.6, 128.0, 128.4, 128.6, 129.1,
using General procedure E with 3-methyl-but-2-en-1-yl 2- 129.3, 136.5, 138.7 (d, J = 4.6), 171.3 (d, J = 10.4); δP (162 MHz,
diazo-2-(diethoxyphosphoryl)acetate 19e (74.0 mg, 0.255 CDCl3) 16.1; HRMS (ESI+): Found: 409.1172; C21H23NaO5P
mmol), CH2Cl2 (5.1 mL) and Rh2(oct)4 (4.0 mg, 5.1
Purification by column chromatography (1:10 hexane:EtOAc) C21H24O5P (MH+) Requires 387.1356 (0.9 ppm error).
ꢁ
mol). (MNa+) Requires 409.1175 (0.9 ppm error), Found: 387.1352;
afforded the title compound 20e as a pale yellow oil (39 mg,
58%); Rf 0.27 (EtOAc); νmax (thin film)/cm-1 2985, 1764, 1389, Diethyl
((1RS,5SR,6SR)-6-(4-bromophenyl)-2-oxo-3-
1364, 1260, 1181, 1052, 1025, 995, 971, 591; δH (400 MHz, oxabicyclo[3.1.0]hexan-1-yl)phosphonate (20h). Synthesised
CDCl3) 1.24 (3 H, s), 1.32 (3 H, t, J = 7.1), 1.35 (3 H, t, J = 7.1), using General procedure E with (E)-3-(4-bromophenyl)allyl 2-
1.50 (3 H, s), 2.58 (1 H, dd, J = 12.2, J = 5.3), 4.12–4.27 (5 H, m), diazo-2-(diethoxyphosphoryl)acetate 19h (97 mg, 0.250
4.38 (1 H, dd, J = 10.0, J = 5.3); δC (100 MHz, CDCl3) 16.3 (d, J = mmol), CH2Cl2 (5.0 mL) and Rh2(oct)4 (4.0 mg, 5.0
ꢁmol).
6.2), 16.3 (d, J = 6.8), 16.5, 21.6 (d, J = 4.8), 30.0 (d, J = 2.8), Purification by column chromatography (EtOAc) afforded the
33.9 (d, J = 197.6), 36.3 (d, J = 3.8), 62.6 (d, J = 6.5), 62.9 (d, J = title compound 20h as a pale yellow oil (72 mg, 74%); Rf 0.32
6.8), 65.2 (d, J = 2.9), 171.4 (d, J = 9.8); δP (162 MHz, CDCl3) (EtOAc); νmax (thin film)/cm-1 2982, 1768, 1492, 1369, 1252,
18.6; HRMS (ESI+): Found: 285.0865; C11H19NaO5P (MNa+) 1053, 1019, 974, 810, 590; δH (400 MHz, CDCl3) 1.09 (3 H, t, J =
Requires 285.0862
C11H20O5P (MH+) Requires 263.1043 (
(−1.1 ppm error), Found: 263.1043; 7.1), 1.21 (3 H, t, J = 7.1), 2.71 (1 H, app. t, J = 6.0), 3.24 (1 H,
−
0.2 ppm error).
app. dt, J = 10.7, J = 5.2), 3.81–4.08 (4 H, m), 4.38 (1 H, dd, J =
9.4, J = 2.8), 4.48 (1 H, dd, J = 9.4, J = 4.8), 7.22 (2 H, d, J = 8.5),
Diethyl ((1SR,5SR,6RS)-6-methyl-6-(4-methylpent-3-en-1-yl)- 7.43 (2 H, d, J = 8.5); δC (100 MHz, CDCl3) 16.0 (d, J = 6.6), 16.1
2-oxo-3-oxabicyclo[3.1.0]hexan-1-yl)phosphonate
(20f). (d, J = 6.0), 28.1, 31.4 (d, J = 205.8), 34.0 (d, J = 3.7), 62.6 (d, J =
with (E)-3,7- 6.6), 62.9 (d, J = 6.8), 67.8 (d, J = 3.1), 122.0, 130.9 (d, J = 5.7),
2-diazo-2- 131.0, 131.1, 171.5 (d, J = 10.2); δP (162 MHz, CDCl3) 15.0;
Synthesised using General procedure
dimethylocta-2,6-dien-1-yl
E
(diethoxyphosphoryl)acetate 19f (71.7 mg, 0.200 mmol), HRMS (ESI+): Found: 410.9970; C15H1879BrNaO5P (MNa+)
CH2Cl2 (4.0 mL) and Rh2(oct)4 (3.1 mg, 4.0 ꢁmol). Purification Requires 410.9967 (−0.6 ppm error), Found: 389.0154;
by column chromatography (2:1 → 1:1 hexane:EtOAc) afforded C15H1979BrO5P (MH+) Requires 389.0148 (
−1.5 ppm error).
the title compound 20f as a pale yellow oil (42 mg, 64%); Rf
0.20 (1:1 hexane:EtOAc); νmax (thin film)/cm-1 2977, 2912, Diethyl
((1RS,5SR,6SR)-6-(4-methoxyphenyl)-2-oxo-3-
1764, 1445, 1391, 1366, 1255, 1172, 1051, 1023, 993, 970, oxabicyclo[3.1.0]hexan-1-yl)phosphonate (20i). Synthesised
597; δH (400 MHz, CDCl3) 1.24 (3 H, d, J = 0.6), 1.33 (3 H, t, J = using General procedure E with (E)-3-(4-methoxyphenyl)allyl 2-
7.1), 1.36 (3 H, t, J = 7.1), 1.60 (3 H, s), 1.65 (3 H, d, J = 0.5), diazo-2-(diethoxyphosphoryl)acetate 19i (85 mg, 0.250 mmol),
1.76–1.93 (2 H, m), 2.03–2.12 (1 H, m), 2.17–2.26 (1 H, m), CH2Cl2 (5.0 mL) and Rh2(oct)4 (4.0 mg, 5.0 ꢁmol). Purification
2.59 (1 H, ddd, J = 12.5, J = 5.3, J = 0.5), 4.11–4.29 (5 H, m), by column chromatography (EtOAc) afforded the title
4.40 (1 H, dd, J = 10.0, J = 5.3), 5.05–5.10 (1 H, m); δC (100 compound 20i as a pale yellow oil (45 mg, 53%); Rf 0.23
MHz, CDCl3) 13.4, 16.3, 16.3, 17.6, 25.3, 25.6, 33.8 (d, J = 1.9), (EtOAc); νmax (thin film)/cm-1 2982, 1764, 1613, 1518, 1370,
34.2 (d, J = 198.2), 34.4 (d, J = 4.2), 35.7 (d, J = 3.6), 62.6 (d, J = 1294, 1249, 1182, 1052, 1020, 983, 820; δH (400 MHz, CDCl3)
6.6), 63.0 (d, J = 6.6), 65.2 (d, J = 2.1), 123.2, 132.2, 171.4 (d, J = 1.09 (3 H, td, J = 7.1, J = 0.4), 1.20 (3 H, t, J = 7.1), 2.73 (1 H,
9.6); δP (162 MHz, CDCl3) 18.8; HRMS (ESI+): Found: 353.1493; app. t, J = 6.1), 3.24 (1 H, app. dt, J = 10.6, J = 5.2), 3.76 (3 H, s),
C16H27NaO5P (MNa+) Requires 353.1488 (
Found: 331.1668; C16H28O5P (MH+) Requires 331.1669 (0.1 J = 9.3, J = 4.7), 6.83 (2 H, d, J = 8.8), 7.26 (2 H, d, J = 8.8); δC
−1.2 ppm error), 3.77–4.06 (4 H, m), 4.36 (1 H, dd, J = 9.3, J = 2.8), 4.46 (1 H, dd,
ppm error).
(100 MHz, CDCl3) 16.1 (d, J = 6.6), 16.2 (d, J = 6.0), 28.3, 31.6
(d, J = 206.2), 34.6 (d, J = 3.2), 55.2, 62.5 (d, J = 6.6), 62.8 (d, J =
Diethyl
((1SR,5SR)-2-oxo-6,6-diphenyl-3- 6.8), 68.0 (d, J = 3.0), 113.4, 123.5 (d, J = 5.6), 130.5, 159.3,
oxabicyclo[3.1.0]hexan-1-yl)phosphonate (20g). Synthesised 171.9 (d, J = 10.2); δP (162 MHz, CDCl3) 15.5; HRMS (ESI+):
using General procedure E with 3,3-diphenylallyl 2-diazo-2- Found: 363.0960; C16H21NaO6P (MNa+) Requires 363.0968 (2.1
(diethoxyphosphoryl)acetate 19g (78 mg, 0.188 mmol), CH2Cl2
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 13
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 14 of 18
View Article Online
DOI: 10.1039/C6OB01527A
ARTICLE
Journal Name
ppm error), Found: 341.1140; C16H22O6P (MH+) Requires solution of diethyl ((3RS,4SR)-4-(benzo[d][1,3]dioxol-5-
341.1149 (2.6 ppm error). ylmethyl)-2-oxotetrahydrofuran-3-yl)phosphonate 16 (59 mg,
0.166 mmol) in THF (3.3 mL) at 0 C was added KOBu-t (27.9
((1RS,5SR,6SR)-6-(1,3-benzodioxol-5-yl)-2-oxo-3- mg, 0.248 mmol). The solution was stirred at 0 C for 60 mins,
oxabicyclo[3.1.0]hexan-1-yl)phosphonate (20j). Synthesised after which, piperonal (49.8 mg, 0.332 mmol) was added to
using General procedure with (E)-3-(1,3-benzodioxol-5- the solution, which was refluxed for 2 h. After cooling at RT,
yl)allyl 2-diazo-2-(diethoxyphosphoryl)acetate 19j (68 mg, the solution was quenched with sat. aq. NH4Cl (10 mL). The
0.178 mmol), CH2Cl2 (3.6 mL) and Rh2(oct)4 (2.8 mg, 3.6 mol). organic layer was separated and the aqueous extracted with
Purification by column chromatography (1:10 hexane:EtOAc) EtOAc (2 10 mL). The organic extracts were dried over
afforded the title compound 29j as a pale yellow solid (46 mg, MgSO4, filtered and concentrated in vacuo. Purification by
73%); Rf 0.17 (1:2 hexane:EtOAc); m.p. 96–99 °C; νmax (thin column chromatography (5:1 hexane:EtOAc
3:1
film)/cm-1 2980, 2910, 1754, 1500, 1489, 1447, 1395, 1371, hexane:EtOAc) afforded the title compounds as mixture (
°
Diethyl
°
E
ꢁ
×
→
8:9
1311, 1233, 1214, 1180, 1098, 1014, 832, 807, 585; δH (400 1.9:1) (31 mg, 53%). Small quantities of each compound were
MHz, CDCl3) 1.15 (3 H, t, J = 7.1), 1.24 (3 H, t, J = 7.1), 2.74 (1 H, isolated separately for characterisation purposes.
app. t, J = 6.1), 3.21 (1 H, app. dt, J = 10.7, J = 5.2), 3.89–4.12 (4
Data for savinin, 8; White solid; Rf 0.20 (4:1 hexane:EtOAc);
H, m), 4.38 (1 H, dd, J = 9.3, J = 2.8), 4.48 (1 H, dd, J = 9.3, J = m.p. 127–129 °C (lit.3a 146.4–148.4 °C); νmax (thin film)/cm-1
4.7), 5.94 (2 H, s), 6.75 (1 H, d, J = 7.9), 6.81–6.84 (2 H, m); δC 2908, 1744, 1646, 1503, 1490, 1447, 1341, 1250, 1214, 1180,
(100 MHz, CDCl3) 16.1 (d, J = 6.5), 16.3 (d, J = 6.0), 28.4, 31.5 1037, 927, 810; δH (400 MHz, CDCl3) 2.59 (1 H, dd, J = 14.2, J =
(d, J = 205.7), 34.9 (d, J = 3.0), 62.6 (d, J = 6.1), 62.9 (d, J = 6.6), 10.1), 2.99 (1 H, dd, J = 14.2, J = 4.5), 3.71–3.77 (1 H, m), 4.22–
68.0 (d, J = 2.4), 101.2, 107.9, 109.8, 123.0, 125.3 (d, J = 5.1), 4.29 (2 H, m), 5.93 (1 H, d, J = 1.4), 5.94 (1 H, d, J = 1.4), 6.05 (2
147.4, 147.4, 171.8 (d, J = 10.2); δP (162 MHz, CDCl3) 15.4; H, s), 6.64 (1 H, dd, J = 7.8, J = 1.6), 6.67 (1 H, d, J = 1.6), 6.74 (1
HRMS (ESI+): Found: 377.0750; C16H19NaO7P (MNa+) Requires H, d, J = 7.8), 6.88 (1 H, d, J = 8.1), 7.05 (1 H, d, J = 1.7), 7.08 (1
377.0761 (2.8 ppm error), Found: 355.0925; C16H20O7P (MH+) H, dd, J = 8.1, J = 1.7), 7.50 (1 H, d, J = 1.9); δC (100 MHz, CDCl3)
Requires 355.0941 (4.4 ppm error).
37.5, 39.9, 69.5, 101.0, 101.7, 108.5, 108.6, 108.8, 109.2,
122.2, 125.8, 126.1, 128.2, 131.5, 137.5, 146.5, 147.9, 148.3,
Diethyl
((3RS,4SR)-4-(benzo[d][1,3]dioxol-5-ylmethyl)-2- 149.2, 172.6; HRMS (ESI+): Found: 375.0833; C20H16NaO6
oxotetrahydrofuran-3-yl)phosphonate (16). To a solution of (MNa+) Requires 375.0839 (1.5 ppm error), Found: 353.1019;
freshly prepared SmI2 (4.00 mL, 0.400 mmol, ~0.1 M in THF) in C20H17O6 (MH+) Requires 353.1020 (0.3 ppm error). Obtained
an oven dried sealable tube at −78 °
C under an atmosphere of data in accord with reported literature.3a,3b
argon, was added a solution of diethyl ((1RS,5SR,6SR)-6-(1,3-
Data for gadain,
9
; White solid; Rf 0.26 (4:1 hexane:EtOAc);
max (thin film)/cm-1 2906, 1741,
benzodioxol-5-yl)-2-oxo-3-oxabicyclo[3.1.0]hexan-1-
m.p. 136–139 °C (lit.4b 145 °C);
ν
yl)phosphonate 20j (70.9 mg, 0.200 mmol) in THF (1.0 mL). The 1634, 1600, 1503, 1488, 1446, 1246, 1171, 1083, 1037, 928,
solution was stirred at 78 C for 30 mins then quenched with 810; δH (400 MHz, CDCl3) 2.78 (1 H, dd, J = 13.8, J = 8.9), 2.91 (1
−
°
sat. aq. NH4Cl (1.70 mL) and then allowed to warm at RT. The H, dd, J = 13.8, J = 6.9), 3.29 (1 H, app. dtdd, J = 8.9, J = 7.1, J =
mixture was diluted with water (10 mL) and extracted with 3.8, J = 1.7), 4.10 (1 H, dd, J = 9.1, J = 3.8), 4.32 (1 H, dd, J = 9.1,
diethyl ether (3 × 20 mL). The combined organic extracts were J = 7.3), 5.95 (1 H, d, J = 1.4), 5.96 (1 H, d, J = 1.4), 6.00 (2 H, s),
dried over MgSO4, filtered and concentrated in vacuo. 6.59 (1 H, d, J = 1.7), 6.62 (1 H, dd, J = 7.9, J = 1.7), 6.69 (1 H, d,
Purification by column chromatography (1:4 hexane:EtOAc) J = 1.7), 6.76 (1 H, d, J = 7.9), 6.79 (1 H, d, J = 8.1), 7.15 (1 H, dd,
afforded the title compound 16 as a yellow oil (27 mg, 38%); Rf J = 8.1, J = 1.7), 7.74 (1 H, d, J = 1.7); δC (100 MHz, CDCl3) 40.7,
0.55 (EtOAc); νmax (thin film)/cm-1 2983, 2910, 1768, 1503, 44.2, 69.8, 101.0, 101.4, 107.9, 108.4, 109.3, 110.7, 122.3,
1490, 1443, 1245, 1196, 1149, 1018, 971, 809, 549; δH (400 125.2, 126.9, 127.9, 131.4, 140.4, 146.5, 147.6, 147.9, 149.0,
MHz, CDCl3) 1.33 (6 H, t, J = 7.1), 2.69–2.87 (3 H, m), 3.04–3.16 169.3; HRMS (ESI+): Found: 375.0843; C20H16NaO6 (MNa+)
(1 H, m), 4.04–4.22 (5 H, m), 4.44 (1 H, dd, J = 9.1, J = 6.9), 5.94 Requires 375.0839
(
−
1.2 ppm error), Found: 353.1027;
2.0 ppm error). Obtained
(2 H, s), 6.60 (1 H, dd, J = 7.9, J = 1.4), 6.65 (1 H, d, J = 1.4), 6.74 C20H17O6 (MH+) Requires 353.1020 (
−
(1 H, d, J = 7.9); δC (100 MHz, CDCl3) 16.3 (app. t, J = 6.4), 39.0 data in accord with reported literature.3c
(d, J = 10.0), 39.3 (d, J = 3.0), 44.5 (d, J = 139.9), 62.9 (d, J =
7.3), 63.7 (d, J = 7.0), 71.7 (d, J = 5.3), 101.1, 108.4, 109.1, 4-Methoxy-6-nitrobenzo[d][1,3]dioxole
(27).
Prepared
122.2, 130.8, 146.6, 148.0, 171.7 (d, J = 3.8); δP (162 MHz, according to a modified literature procedure:5 To a flask
CDCl3) 20.1; HRMS (ESI+): Found: 379.0923; C16H21NaO7P containing stirred concentrated nitric acid (70% solution, 100
(MNa+) Requires 379.0917 (
C16H22O7P (MH+) Requires 357.1098 (
−
1.6 ppm error), Found: 357.1100; mL) cooled to 0
0.8 ppm error).
°C was added 5-methoxypiperonal 26 (10.81 g,
−
60.0 mmol) portionwise over 2 h. After a further 1 h the yellow
mixture was poured onto ice water (1 L) to precipitate a pale
yellow solid, which was collected by suction filitration and
washed with water (3 × 100 mL). Purification by column
(RS,E)-4-(benzo[d][1,3]dioxol-5-ylmethyl)-3-
(benzo[d][1,3]dioxol-5-ylmethylene)dihydrofuran-2(3H)-one
((±)-savinin)
ylmethyl)-3-(benzo[d][1,3]dioxol-5-
ylmethylene)dihydrofuran-2(3H)-one ((±)-gadain) (9). To a hexane:EtOAc); m.p. 130–132 °C (lit.24 145–146 °C); νmax (thin
(8)
and
(RS,Z)-4-(benzo[d][1,3]dioxol-5- chromatography (7:1 hexane:EtOAc) afforded the title
compound 27 as a pale yellow solid (6.92 g, 59%); Rf 0.45 (4:1
14 | 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
Organic & Biomolecular Chemistry
Page 15 of 18
Journal Name
View Article Online
DOI: 10.1039/C6OB01527A
ARTICLE
film)/cm-1 3109, 1645, 1521, 1491, 1451, 1435, 1347, 1316, The residue was extracted with diethyl ether (3 × 250 mL). The
1218, 1198, 1112, 1090, 970, 918, 861, 770, 742; δH (400 MHz, combined organic extracts were washed with sat. aq. Na2S2O3
DMSO-d6) 3.93 (3 H, s), 6.24 (2 H, s), 7.53 (1 H, d, J = 2.2), 7.62 (250 mL) then water (250 mL) then dried over MgSO4, filtered
(1 H, d, J = 2.2); δH (400 MHz, CDCl3) 3.96 (3 H, s), 6.14 (2 H, s), and concentrated in vacuo. Purification by column
7.42 (1 H, d, J = 2.1), 7.56 (1 H, d, J = 2.1); δC (100 MHz, CDCl3) chromatography (8:1 hexane:EtOAc) afforded the title
56.8, 99.0, 103.3, 104.9, 141.1, 142.8, 142.9, 148.7; HRMS compound 30 as white crystals (4.78 g, 61%); Rf 0.63 (4:1
(ESI+): Found: 220.0218; C8H7NNaO5 (MNa+) Requires 220.0216 hexane:EtOAc); m.p. 55–58 °C (lit.28 71–72 °C); νmax (thin
(–0.6 ppm error). NMR data in accord with reported film)/cm-1 3098, 2939, 2893, 2775, 1623, 1483, 1443, 1414,
literature.25
1288, 1230, 1175, 1097, 1031, 966, 928, 811, 764, 709, 564; δH
(400 MHz, CDCl3) 3.85 (3 H, s), 5.94 (2 H, s), 6.81–6.82 (2 H, m);
7-Methoxybenzo[d][1,3]dioxol-5-amine (28). To a suspension δC (100 MHz, CDCl3) 56.6, 82.0, 101.7, 111.6, 116.8, 135.7,
of 4-methoxy-6-nitrobenzo[d][1,3]dioxole 27 (6.86 g, 34.8 144.4, 149.4; HRMS (ESI+): Found: 277.9441; C8H7IO3 (MNa+)
mmol) in MeOH (174 mL) under an atmosphere of argon, was Requires 277.9434 (
added ammonium formate (11.0 g, 174.0 mmol) and palladium
−2.3 ppm error).
on carbon (10% wt. % loading, 1.74 g). The solution was stirred (E)-Ethyl 3-(7-methoxybenzo[d][1,3]dioxol-5-yl)acrylate (31).
for 16 h then filtered through a pad of Celite and washed with To a solution of 5-methoxypiperonal 26 (5.17 g, 28.7 mmol) in
MeOH (100 mL). The filtrate was concentrated in vacuo. The THF
(86
mL)
was
added
residue was diluted with brine (250 mL) and extracted with (carbethoxymethylene)triphenylphosphorane (12.0 g, 34.4
EtOAc (2 × 250 mL). The combined organic extracts were dried mmol) and refluxed for 16 h. Concentration in vacuo and
over MgSO4, filtered and concentrated in vacuo. Purification by purification by column chromatography (4:1 hexane:EtOAc)
column chromatography (1:1 hexane:EtOAc) afforded the title afforded the title compound 31 as a crystalline white solid
compound 28 as an off-white solid (5.41 g, 93%); Rf 0.45 (1:1 (6.78 g, 95%); Rf 0.46 (4:1 hexane:EtOAc); m.p. 65–68 °C (lit.29
hexane:EtOAc); m.p. 75–76 °C (lit.26 85–86 °C); νmax (thin 76 °C); νmax (thin film)/cm-1 2996, 2975, 2908, 1702, 1622,
film)/cm-1 3397, 3312, 3210, 2886, 1640, 1508, 1459, 1183, 1593, 1511, 1431, 1324, 1281, 1171, 1137, 1093, 1038, 996,
1144, 1087, 1037, 958, 924, 802, 703, 618; δH (400 MHz, 925, 846, 819, 594, 477; δH (400 MHz, CDCl3) 1.31 (3 H, t, J =
DMSO-d6) 3.71 (3 H, s), 4.83 (2 H, br. s), 5.75 (2 H, s), 5.82 (1 H, 7.1), 3.90 (3 H, s), 4.23 (2 H, q, J = 7.1), 5.99 (2 H, s), 6.25 (1 H,
d, J = 2.0), 5.86 (1 H, d, J = 2.0); δH (400 MHz, CDCl3) 3.49 (2 H, d, J = 15.9), 6.68 (1 H, d, J = 1.4), 6.72 (1 H, d, J = 1.4), 7.54 (1 H,
br. s), 3.84 (3 H, s), 5.85 (2 H, s), 5.86 (1 H, d, J = 2.0), 5.96 (1 H, d, J = 15.9); δC (100 MHz, CDCl3) 14.3, 56.5, 60.4, 101.2, 101.9,
d, J = 2.0); δC (100 MHz, CDCl3) 56.4, 91.0, 94.3, 100.8, 128.0, 109.0, 116.6, 129.2, 137.2, 143.6, 144.2, 149.2, 167.0; HRMS
142.1, 143.9, 149.3; HRMS (ESI+): Found: 169.0657; C8H10NO3 (ESI+): Found: 273.0731; C13H14NaO5 (MNa+) Requires 273.0733
(MNa+) Requires 168.0655 (
−
0.8 ppm error).
(0.8 ppm error).
7-Methoxybenzo[d][1,3]dioxole-5-diazonium
Ethyl 3,3-bis(7-methoxybenzo[d][1,3]dioxol-5-yl)acrylate (32).
tetrafluoroborate (29). Procedure developed from literature Procedure developed from literature precedent:16 To an oven
precedent:26 To a solution of 7-methoxybenzo[d][1,3]dioxol-5- dried sealable tube was added (E)-ethyl 3-(7-
amine 28 (5.22 g, 31.2 mmol) in ethanol (10.3 mL), cooled to 0 methoxybenzo[d][1,3]dioxol-5-yl)acrylate 31 (500 mg, 2.00
°C was added an aqueous solution of HBF4 (50% w/, 11.0 g, mmol), 6-iodo-4-methoxybenzo[d][1,3]dioxole 30 (834 mg,
62.5 mmol) followed by tert-butyl nitrite (7.43 mL, 62.5 mmol) 3.00 mmol), tetra-n-butylammonium bromide (709 mg, 2.20
dropwise. The solution was stirred for 1 h after which diethyl mmol), NaHCO3 (420 mg, 5.00 mmol), Pd(OAc)2 (44.9 mg, 0.20
ether (50 mL) was added, forming a precipitate. The solution mmol) and DMF (5 mL). The tube was sealed and flushed with
was filtered and the solid washed with diethyl ether (3 × 100 argon then heated at 120 °C for 16 h. The mixture was cooled
mL). The solid was dried in vacuo, affording the title compound at RT, diluted with water (50 mL) and extracted with diethyl
29 as a yellow solid (7.57 g, 91%). No further purification was ether (3 × 50 mL). The combined organic extracts were washed
required. Rf 0.00 (1:1 hexane:EtOAc); m.p. decomposes at 126 with brine (50 mL), dried over MgSO4, filtered and
°C; νmax (thin film)/cm-1 3119, 2257, 1624, 1587, 1495, 1454, concentrated in vacuo. The residue was purified by column
1442, 1308, 1240, 1223, 1114, 1072, 1023, 962, 854, 522; δH chromatography (4:1 hexane:EtOAc) affording the title
(400 MHz, DMSO-d6) 3.94 (3 H, s), 6.45 (2 H, s), 7.95 (1 H, d, J = compound 32 as an orange oil that later crystallised (695 mg,
2.0), 8.29 (1 H, d, J = 2.0); δC (100 MHz, DMSO-d6) 57.5, 104.1, 87%); Rf 0.22 (4:1 hexane:EtOAc); m.p. 72–76 °C; νmax (thin
105.9, 106.5, 116.2, 143.2, 148.0, 148.9; HRMS (ESI+): Found: film)/cm-1 2976, 2939, 2900, 1715, 1627, 1600, 1506, 1426,
179.0447; C8H7N2O3 (MNa+) Requires 179.0451 (2.1 ppm 1377, 1290, 1222, 1171, 1112, 1083, 1044, 968, 929, 844, 730;
error).
δH (400 MHz, CDCl3) 1.16 (3 H, t, J = 7.1), 3.84 (6 H, app. s),
4.07 (2 H, q, J = 7.1), 5.97 (2 H, s), 5.99 (2 H, s), 6.18 (1 H, s),
6-Iodo-4-methoxybenzo[d][1,3]dioxole (30). To a solution of 6.36 (1 H, d, J = 1.3), 6.38 (1 H, d, J = 1.3), 6.48 (1 H, d, J = 1.5),
KI (10.4 g, 62.5 mmol) in water (187 mL) and acetone (125 mL) 6.51 (1 H, d, J = 1.5); δC (100 MHz, CDCl3) 14.0, 56.5, 56.7, 59.9,
was
added
7-methoxybenzo[d][1,3]dioxole-5-diazonium 101.5, 101.8, 102.2, 103.8, 108.7, 109.0, 116.2, 132.9, 132.9,
tetrafluoroborate 29 (7.57 g, 28.3 mmol) over 15 mins. The 135.3, 135.4, 136.5, 143.1, 143.1, 148.3, 148.8, 155.5, 165.9;
mixture was stirred for 1 h and the acetone removed in vacuo. HRMS (ESI+): Found: 423.1048; C21H20NaO8 (MNa+) Requires
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 15
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 16 of 18
View Article Online
DOI: 10.1039/C6OB01527A
ARTICLE
Journal Name
423.1050 (0.5 ppm error), Found: 401.1220; C21H21O8 (MH+) mg, 61%); Rf 0.21 (1:2 hexane:EtOAc); νmax (thin film)/cm-1
Requires 401.1231 (2.8 ppm error).
2982, 2940, 2905, 1733, 1632, 1507, 1449, 1430, 1266, 1193,
1128, 1091, 1019, 964, 929, 834; δH (400 MHz, CDCl3) 1.30 (6
H, t, J = 7.1), 2.24 (2 H, app. q, J = 7.2), 2.94 (2 H, d, J = 21.6),
3,3-Bis(7-methoxybenzo[d][1,3]dioxol-5-yl)prop-2-en-1-ol
(33).
methoxybenzo[d][1,3]dioxol-5-yl)acrylate 32 (1.32 g, 3.30 H, dq, J = 8.3, J = 7.1), 5.88 (4 H, s), 6.37 (2 H, d, J = 1.4), 6.38 (2
mmol) in THF (16 mL) cooled to 78 °C was added dropwise H, d, J = 1.4); δC (100 MHz, CDCl3) 16.2 (d, J = 6.1), 34.2 (d, J =
To
a
solution
of
ethyl
3,3-bis(7- 3.85 (6 H, s), 3.87 (1 H, t, J = 7.9), 4.05 (2 H, t, J = 6.5), 4.14 (4
−
DIBAL (6.60 mL, 6.60 mmol, 1.0 M in hexane) and stirred for 2 133.6), 34.2, 46.9, 56.6, 62.6 (d, J = 6.4), 63.6, 101.2, 101.4,
h. The solution was quenched with water (15 mL) dropwise 107.3, 133.6, 138.3, 143.3, 148.9, 165.5 (d, J = 5.9); δP (162
and stirred for 30 mins at RT before being filtered through a MHz, CDCl3) 20.4; HRMS (ESI+): Found: 561.1503; C25H31NaO11P
pad of Celite and washed with diethyl ether (500 mL). The (MNa+) Requires 561.1496 (
filtrate was concentrated in vacuo. Purification by column The synthesis continued using general procedure B with
chromatography (4:1 hexane:EtOAc) afforded the title 3,3-bis(7-methoxybenzo[d][1,3]dioxol-5-yl)propyl 2-
−1.1 ppm error).
compound 33 as a yellow gum (1.08 g, 91%); Rf 0.31 (4:1 (diethoxyphosphoryl)acetate (278 mg, 0.516 mmol), THF (2.58
hexane:EtOAc); νmax (thin film)/cm-1 3360br, 2889, 1626, 1505, mL), LHMDS (0.620 mL, 0.620 mmol, 1.0 M solution in THF)
1447, 1424, 1376, 1191, 1153, 1085, 1042, 967, 928, 844, 728; and DBSA (0.21 mL, 0.620 mmol). Purification by column
δH (400 MHz, CDCl3) 2.15 (1 H, br. s), 3.80 (3 H, s), 3.82 (3 H, s), chromatography (1:2 hexane:EtOAc) afforded the title
4.16 (2 H, d, J = 6.8), 5.91 (2 H, s), 5.95 (2 H, s), 6.04 (1 H, t, J = compound 24 as a yellow oil (147 mg, 51%); Rf 0.70 (1:4
6.8), 6.31 (1 H, d, J = 1.4), 6.31 (1 H, d, J = 1.4), 6.41 (1 H, d, J = hexane:EtOAc); νmax (thin film)/cm-1 2982, 2941, 2906, 2129,
1.5), 6.42 (1 H, d, J = 1.5); δC (100 MHz, CDCl3) 56.4, 56.5, 60.4, 1704, 1633, 1508, 1451, 1431, 1369, 1279, 1194, 1131, 1092,
101.4 (2C), 101.8, 103.8, 107.5, 109.1, 126.5, 133.1, 134.5, 1041, 1019, 977; δH (400 MHz, CDCl3) 1.36 (6 H, td, J = 7.1, J =
134.8, 136.5, 142.9, 143.1, 143.2, 148.4, 148.5; HRMS (ESI+): 0.7), 2.27 (2 H, app. q, J = 7.2), 3.85 (1 H, t, J = 7.8), 3.87 (6 H,
Found: 381.0938; C19H18NaO7 (MNa+) Requires 381.0945 (1.7 s), 4.11–4.27 (6 H, m), 5.92 (4 H, s), 6.37 (2 H, d, J = 1.4), 6.39
ppm error).
(2 H, d, J = 1.4); δC (100 MHz, CDCl3) 16.2 (d, J = 6.8), 34.5, 47.2,
53.7 (d, J = 231.7), 56.8, 63.6 (d, J = 5.7), 63.9, 101.5, 101.5,
2- 107.4, 133.8, 138.3, 143.4, 149.1, 163.2 (d, J = 11.8); δP (162
3,3-Bis(7-methoxybenzo[d][1,3]dioxol-5-yl)allyl
(diethoxyphosphoryl)acetate (34). Synthesised using general MHz, CDCl3) 10.7; HRMS (ESI+): Found: 587.1406;
procedure
yl)prop-2-en-1-ol 33 (973 mg, 2.72 mmol), toluene (13.6 mL),
DEPAA (559 mg, 2.85 mmol), DIPEA (1.23 mL, 7.07 mmol) and 3,3-Bis(7-methoxybenzo[d][1,3]dioxol-5-yl)allyl
T3P (2.25 g, 3.54 mmol, 50% w/w solution in THF) affording (diethoxyphosphoryl)acetate (25). Synthesised using general
the title compound 34 as a yellow oil (1.45 g, 99%); Rf 0.26 (1:2 procedure with 3,3-bis(7-methoxybenzo[d][1,3]dioxol-5-
A −0.8 ppm error).
with 3,3-bis(7-methoxybenzo[d][1,3]dioxol-5- C25H29N2NaO11P (MNa+) Requires 587.1401 (
2-diazo-2-
B
hexane:EtOAc); νmax (thin film)/cm-1 2984, 2936, 2902, 1733, yl)allyl 2-(diethoxyphosphoryl)acetate 34 (996 mg, 1.86 mmol),
1626, 1507, 1426, 1262, 1160, 1107, 1042, 1020, 965, 929, THF (9.30 mL), LHMDS (2.23 mL, 2.23 mmol, 1.0 M solution in
839, 728; δH (400 MHz, CDCl3) 1.29 (6 H, td, J = 7.1, J = 0.4), THF) and DBSA (0.75 mL, 2.23 mmol). Purification by column
2.95 (2 H, d, J = 21.5), 3.81 (3 H, s), 3.83 (3 H, s), 4.09–4.17 (4 chromatography (1:1 hexane:EtOAc) afforded the title
H, m), 4.65 (2 H, d, J = 7.2), 5.91 (2 H, s), 5.96 (2 H, s), 5.98 (1 H, compound 25 as a yellow oil (665 mg, 63%); Rf 0.27 (1:2
t, J = 7.2), 6.31 (1 H, d, J = 1.4), 6.33 (1 H, d, J = 1.4), 6.39 (1 H, hexane:EtOAc); νmax (thin film)/cm-1 2984, 2943, 2905, 2129,
d, J = 1.6), 6.41 (1 H, d, J = 1.6); δC (100 MHz, CDCl3) 16.2 (d, J = 1703, 1627, 1507, 1427, 1275, 1162, 1108, 1094, 1044, 1020,
6.6), 34.2 (d, J = 134.2), 56.5, 56.5, 62.6 (d, J = 6.5), 63.6, 101.4 970, 932; δH (400 MHz, CDCl3) 1.34 (6 H, td, J = 7.1, J = 0.6),
(2C), 101.9, 103.8, 107.7, 109.2, 120.5, 132.5, 134.8, 135.2, 3.84 (3 H, s), 3.86 (3 H, s), 4.08–4.27 (4 H, m), 4.74 (2 H, d, J =
136.0, 143.0, 143.2, 146.2, 148.6, 148.6, 165.5 (d, J = 6.5); δP 7.2), 5.95 (2 H, s), 5.99 (2 H, s), 6.01 (1 H, t, J = 7.2), 6.34–6.35
(162 MHz, CDCl3) 20.2; HRMS (ESI+): Found: 559.1348; (2 H, m), 6.42 (1 H, d, J = 1.6), 6.43 (1 H, d, J = 1.6); δC (100
C25H29NaO11P (MNa+) Requires 559.1340 (
−
1.5 ppm error).
MHz, CDCl3) 16.1 (2 C, d, J = 6.9), 53.6 (d, J = 228.1), 56.6, 56.7,
63.6–63.7 (3C, m), 101.6 (2 C), 102.1, 103.9, 107.9, 109.2,
3,3-Bis(7-methoxybenzo[d][1,3]dioxol-5-yl)propyl 2-diazo-2- 120.3, 132.5, 135.0, 135.4, 136.0, 143.1, 143.4, 146.9, 148.7,
(diethoxyphosphoryl)acetate (24). To a solution of 3,3-bis(7- 148.8, 163.3 (d, J = 12.7); δP (162 MHz, CDCl3) 10.6; HRMS
methoxybenzo[d][1,3]dioxol-5-yl)allyl
2- (ESI+): Found: 585.1240; C25H27N2NaO11P (MNa+) Requires
(diethoxyphosphoryl)acetate 34 (457 mg, 0.852 mmol) in 585.1245 (0.7 ppm error).
methanol (4.26 mL) was added palladium on carbon (10% wt.
% loading, 17 mg). The flask was purged 4 times with argon Diethyl ((1SR,5SR)-6,6-bis(7-methoxybenzo[d][1,3]dioxol-5-
then 4 times with hydrogen. The mixture was stirred at RT for yl)-2-oxo-3-oxabicyclo[3.1.0]hexan-1-yl)phosphonate
(36).
16 h. The mixture was filtered through a pad of Celite and
S
ynthesised using General procedure
E
with 3,3-bis(7-
2-diazo-2-
washed with methanol (50 mL) and the filtrate concentrated in methoxybenzo[d][1,3]dioxol-5-yl)allyl
vacuo. Purification by column chromatography (1:2 (diethoxyphosphoryl)acetate 25 (368 mg, 0.654 mmol), CH2Cl2
hexane:EtOAc) afforded 3,3-bis(7-methoxybenzo[d][1,3]dioxol- (13.1 mL) and rhodium(II) triphenylacetate dimer as complex
5-yl)propyl 2-(diethoxyphosphoryl)acetate as a yellow oil (280 with DCM (Rh2(tpa)4) (18.8 mg, 13.1
ꢁmol). Purification by
16 | 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
Organic & Biomolecular Chemistry
Page 17 of 18
Journal Name
column chromatography (1:4 hexane:EtOAc → EtOAc) afforded 30 mins at 0
View Article Online
DOI: 10.1039/C6OB01527A
ARTICLE
°
C then 1 h at RT then quenched by addition of
the title compound 36 as an off-white solid (153 mg, 44%); Rf sat. aq. NH4Cl (5 mL). The mixture was extracted with EtOAc (3
0.24 (1:4 hexane:EtOAc); m.p. 81–84 °C; νmax (thin film)/cm-1 × 25 mL) and the combined organic extracts dried over MgSO4,
2926, 1758, 1632, 1507, 1429, 1364, 1240, 1192, 1155, 1093, filtered and concentrated in vacuo. Purification by column
1042, 1015, 968, 929, 728; δH (400 MHz, CDCl3) 1.14 (3 H, t, J = chromatography (2:1 hexane:EtOAc) afforded the title
7.1), 1.27 (3 H, t, J = 7.1), 3.36 (1 H, dd, J = 12.5, J = 4.8), 3.69– compound 10 as a white crystalline solid (44 mg, 87%); Rf 0.68
3.81 (1 H, m), 3.88 (3 H, s), 3.89 (3 H, s), 3.91–4.01 (1 H, m), (1:1 hexane:EtOAc); m.p. 56–59 °C (lit.14 140 °C); νmax (thin
4.06–4.23 (2 H, m), 4.28 (1 H, dd, J = 9.9, J = 2.2), 4.50 (1 H, dd, film)/cm-1 2903, 1760, 1633, 1508, 1451, 1432, 1363, 1315,
J = 9.9, J = 5.3), 5.89–5.93 (4 H, m), 6.51 (1 H, br. s), 6.60–6.61 1195, 1130, 1092, 1042, 927, 730; δH (400 MHz, CDCl3) 3.66 (1
(2 H, m), 6.72 (1 H, d, J = 1.6); δC (100 MHz, CDCl3) 16.2 (d, J = H, d, J = 11.6), 3.75 (1 H, app. dddt, J = 11.6, J = 7.7, J = 4.4, J =
6.1), 16.3 (d, J = 6.5), 34.5 (d, J = 4.0), 37.8 (d, J = 203.9), 46.4 2.2), 3.88 (3 H, s), 3.89 (3 H, s), 3.98 (1 H, dd, J = 9.5, J = 4.4),
(d, J = 2.8), 56.7, 56.7, 62.3 (d, J = 6.5), 63.5 (d, J = 6.9), 65.5 (d, 4.32 (1 H, dd, J = 9.5, J = 7.7), 4.93 (1 H, d, J = 2.0), 5.93–5.95 (4
J = 3.5), 101.5, 101.6, 102.4, 102.9, 108.1, 109.3, 130.6 (d, J = H, m), 6.14 (1 H, d, J = 2.3), 6.36 (1 H, d, J = 1.5), 6.38 (1 H, d, J
1.8), 133.2 (d, J = 5.5), 134.6, 135.0, 143.1, 143.9, 148.7, 149.2, = 1.5), 6.45 (1 H, d, J = 1.5), 6.46 (1 H, d, J = 1.5); δC (100 MHz,
171.2 (d, J = 10.5); δP (162 MHz, CDCl3) 16.2; HRMS (ESI+): CDCl3) 42.4, 55.3, 56.8, 56.9, 69.7, 101.1, 101.5 (2C), 101.5,
Found: 557.1169; C25H27NaO11P (MNa+) Requires 557.1183 (2.5 107.9, 108.3, 124.9, 134.2, 134.3, 135.8, 136.0, 136.1, 143.4,
ppm error), Found: 535.1362; C25H28O11P (MH+) Requires 143.6, 149.2, 149.5, 170.7; HRMS (ESI+): Found: 435.1050;
535.1364 (0.2 ppm error).
C22H20NaO8 (MNa+) Requires 435.1050 (0.1 ppm error).
Obtained data in accord with reported literature, with the
Diethyl
((3RS,4SR)-4-(bis(7-methoxybenzo[d][1,3]dioxol-5- exception of the melting point.14
yl)methyl)-2-oxotetrahydrofuran-3-yl)phosphonate (37). To
an oven dried sealable tube containing SmI2 (10.6 mL, 1.06
mmol, ~0.1 M solution in THF) under an atmosphere of argon,
Acknowledgements
atmosphere and cooled to
−
solution of diethyl
78
°
C was added dropwise a
The authors wish to thank the Elsevier Foundation (M. G. L.),
the University of York and the Leverhulme Trust (for an Early
Career Fellowship, ECF-2015-013, W. P. U.) for funding, Dr.
Adrian C. Whitwood (University of York) for X-ray
crystallography and Euticals for kindly providing T3P.
((1SR,5SR)-6,6-bis(7-
methoxybenzo[d][1,3]dioxol-5-yl)-2-oxo-3-
oxabicyclo[3.1.0]hexan-1-yl)phosphonate 36 (142 mg, 0.266
mmol) in THF (2.66 mL). The mixture was stirred at −78 °C for
10 mins then quenched by addition of sat. aq. NH4Cl (5 mL)
and allowed to warm at RT. The biphasic mixture was
extracted with EtOAc (3 × 25 mL) and the combined organic
extracts dried over MgSO4, filtered and concentrated in vacuo.
Purification by column chromatography (1:2 hexane:EtOAc)
afforded the title compound 37 as a white solid (78 mg, 55%);
Notes and references
1
(a) R. R. A. Kitson, A. Millemaggi and R. J. K. Taylor, Angew.
Chem. Int. Ed., 2009, 48, 9426; (b) A. S.-Y. Lee, Y.-T. Chang,
S.-H. Wang and S.-F. Chu, Tetrahedron Lett., 2002, 43, 8489;
(c) P. V. Ramachandran, D. Pratihar and D. Biswas, Org. Lett.,
Rf 0.44 (1:2 hexane:EtOAc); m.p. 59–62 °C; ν
max (thin film)/cm-1
2006,
Lett., 2007,
8
, 3877; (d) P. V. Ramachandran and D. Pratihar, Org.
, 2087; (e) D. M. Hodgson, E. P. A. Talbot and B.
2981, 2909, 1770, 1633, 1508, 1451, 1433, 1370, 1316, 1248,
1197, 1156, 1132, 1091, 1042, 1021, 968, 731; δH (400 MHz,
CDCl3) 1.31 (3 H, t, J = 7.1), 1.31 (3 H, t, J = 7.1), 2.84 (1 H, d, J =
24.5), 3.44–3.53 (1 H, m), 3.61 (1 H, d, J = 12.4), 3.88 (3 H, s),
3.90 (3 H, s), 3.99–4.21 (5 H, m), 4.49 (1 H, dd, J = 9.4, J = 6.0),
5.90–5.92 (4 H, m), 6.37 (1 H, d, J = 1.4), 6.41 (1 H, d, J = 1.4),
6.45 (1 H, d, J = 1.3), 6.46 (1 H, d, J = 1.3); δC (100 MHz, CDCl3)
16.1 (d, J = 6.5), 16.2 (d, J = 6.2), 42.1 (d, J = 2.6), 44.8 (d, J =
133.0), 54.2 (d, J = 13.9), 56.7, 56.8, 63.1 (d, J = 7.0), 63.7 (d, J =
7.1), 70.6, 101.2, 101.4, 101.5, 101.9, 107.6, 107.9, 134.2,
134.3, 135.3, 136.2 (d, J = 1.8), 143.6, 143.6, 149.2, 149.4,
171.7 (d, J = 5.4); δP (162 MHz, CDCl3) 19.7; HRMS (ESI+):
Found: 559.1329; C25H29NaO11P (MNa+) Requires 559.1340 (1.8
ppm error).
9
P. Clark, Org. Lett., 2011, 13, 2594; (f) X. Su, W. Zhou, Y. Y. Li
and J. L. Zhang, Angew. Chem. Int. Ed., 2015, 54, 6874; (g) M.
G. Edwards, M. N. Kenworthy, R. R. A. Kitson, A. Perry, M. S.
Scott, A. C. Whitwood and R. J. K. Taylor, Eur. J. Org. Chem.,
2008, 4769; (h) M. G. Edwards, M. N. Kenworthy, R. R. A.
Kitson, M. S. Scott and R. J. K. Taylor, Angew. Chem. Int. Ed.,
2008, 47, 1935; (i) R. R. A. Kitson, R. J. K. Taylor and J. L.
Wood, Org. Lett., 2009, 11, 533; (j) R. R. A. Kitson, G. D.
McAllister and R. J. K. Taylor, Tetrahedron Lett., 2011, 52
561.
,
2
3
For reports from our group, see: (a) M. G. Lloyd, R. J. K.
Taylor and W. P. Unsworth, Org. Lett., 2014, 16, 2772; (b) M.
G. Lloyd, M. D'Acunto, R. J. K. Taylor and W. P. Unsworth,
Tetrahedron, 2015, 71, 7107; (c) M. G. Lloyd, M. D'Acunto, R.
J. K. Taylor and W. P. Unsworth, Org. Biomol. Chem., 2016,
14, 1641. For interesting examples of this transformation on
bicyclic systems reported by another group, see: (d) J.-Y. Shie
and J.-L. Zhu, Tetrahedron, 2016, 72, 1590.
(±)-Peperomin E (10). To a solution of diethyl ((3RS,4SR)-4-
(bis(7-methoxybenzo[d][1,3]dioxol-5-yl)methyl)-2-
(a) J. L. Hartwell, J. M. Johnson, D. B. Fitzgerald and M.
Belkin, J. Am. Chem. Soc., 1953, 75, 235; (b) H. L. Shieh, G. A.
oxotetrahydrofuran-3-yl)phosphonate 37 (66 mg, 0.123 mmol)
Cordell, D. C. Lankin and H. Lotter, J. Org. Chem., 1990, 55
,
in THF (2.5 mL) cooled to 0 °C under an argon atmosphere was
5139; (c) T. Honda, N. Kimura, S. Sato, D. Kato and H.
Tominaga, J. Chem. Soc., Perkin Trans. 1, 1994, 1043; (d) C.-C.
Wen, Y.-H. Kuo, J.-T. Jan, P.-H. Liang, S.-Y. Wang, H.-G. Liu, C.-
K. Lee, S.-T. Chang, C.-J. Kuo, S.-S. Lee, C.-C. Hou, P.-W. Hsiao,
added KOBu-t (16.6 mg, 0.148 mmol). The solution was stirred
for 30 mins after which paraformaldehyde (18.5 mg, 0.615
mmol) was added in one portion. The mixture was stirred for
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 17
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 18 of 18
View Article Online
DOI: 10.1039/C6OB01527A
ARTICLE
S.-C. Chien, L.-F. Shyur and N.-S. Yang, J. Med. Chem., 2007,
50, 4087.
Journal Name
Tang and M. Ando, J. Nat. Prod., 2006, 69, 790; (c) M.-G. Lin,
D.-H. Yu, Q.-W. Wang, Q. Lu, W.-J. Zhu, F. Bai, G.-X. Li, X.-W.
Wang, Y.-F. Yang, X.-M. Qin, C. Fang, H.-Z. Chen and G.-H.
4
5
J. Banerji, B. Das, A. Chatterjee and J. N. Shoolery,
Phytochemistry, 1984, 23, 2323.
Y. B. Koh and G. G. Christoph, Inorg. Chem., 1978, 17, 2590;
E. B. Boyar and S. D. Robinson, Platinum Metals Rev., 1982,
26, 65.
Yang, Chem. Biodiversity, 2011, 8, 862; (d) S. Xu, N. Li, M.-M.
Ning, C.-H. Zhou, Q.-R. Yang and M.-W. Wang, J. Nat. Prod.,
2006, 69, 247; (e) C. Tsutsui, Y. Yamada, M. Ando, D.
Toyama, J.-l. Wu, L. Wang, S. Taketani and T. Kataoka,
Bioorg. Med. Chem. Lett., 2009, 19, 4084.
6
The coordination of ether oxygen atoms to rhodium
carbenoids has been noted previously in related systems, see 16 (a) M. Moreno-Mañas, M. Pérez and R. Pleixats, Tetrahedron
(a) P. A. Evans, Modern Rhodium-Catalyzed Organic
Reactions, Wiley: New York, 2005; (b) A. Padwa and S. F.
Lett., 1996, 37, 7449; (b) T. Jeffrey, Tetrahedron 1996, 52,
10113.
Hornbuckle, Chem. Rev., 1991, 91, 263-309. The difference in 17 T. F. Schneider, J. Kaschel and D. B. Werz, Angew. Chem. Int.
reactivity between meta-methoxy substrates 11c and 11d Ed. 2014, 53, 5504.
and methylenedioxy system 15 may be a consequence of the 18 T. Horaguchi, E. Hasegawa, T. Shimizu, K. Tanemura and T.
lower nucleophilicity of anisole oxygen atoms, due to them Suzuki, J. Heterocyclic Chem., 1989, 26, 365.
being better able to overlap with the aromatic π-system as 19 D. Xu, C. Lu and W. Chen, Tetrahedron, 2012, 68, 1466.
result of their greater conformational freedom. 20 M. D. Turnbull, J. Chem. Soc., Perkin Trans. 1, 1997, 1241.
7
For selected examples, see: (a) A. Padwa and K. E. Krumpe, 21 Z.-X. Wang and Y. Shi, J. Org. Chem., 1998, 63, 3099.
Tetrahedron, 1992, 53, 5385; (b) M. P. Doyle, Chem. Rev., 22 N. K. Jobson, R. Spike, A. R. Crawford, D. Dewar, S. L. Pimlott
1986, 86, 919; (c) T. Ye and M. A. McKervey, Chem. Rev.,
and A. Sutherland, Org. Biomol. Chem., 2008, 6, 2369.
1994, 94, 1091; (d) M. P. Doyle and D. C. Forbes, Chem. Rev., 23 B. R. Ambler and R. A. Altman, Org. Lett., 2013, 15, 5578.
1998, 98, 911; (e) M. P. Doyle, M. A. McKervey and T. Ye, 24 M. E. Jung, P. Y. S. Lam, M. M. Mansuri and L. M. Speltz, J.
Modern Catalytic Methods for Organic Synthesis with Diazo
Compounds: From Cyclopropanes to Ylides, Wiley: New York, 25 A. F. Wagner, E. Walton, A. N. Wilson, J. O. Rodin, F. W.
Org. Chem., 1985, 50, 1087.
1998; (f) H. M. L. Davies and E. G. Antoulinakis Org. React.,
2001, 57, 1; (g) Z. Zhang and J. Wang, Tetrahedron, 2008, 64
6577; (h) H. Wang, D. M. Guptill, A. Varela-Alvarez, D. G. 26 D. V. Demchuk, A. V. Samet, N. B. Chernysheva, V. I.
Holly, N. G. Brink and K. Folkers, J. Am. Chem. Soc., 1959, 81,
,
4983.
Musaev and H. M. L. Davies, Chem. Sci. 2013,
4
, 2844; (i) S.
Ushkarov, G. A. Stashina, L. D. Konyushkin, M. M. Raihstat, S.
I. Firgang, A. A. Philchenkov, M. P. Zavelevich, L. M. Kuiava,
V. F. Chekhun, D. Y. Blokhin, A. S. Kiselyov, M. N. Semenova
and V. V. Semenov, Bioorg. Med. Chem., 2014, 22, 738.
Negretti, C. M. Cohen, J. J. Chang, D. M. Guptill and H. M. L.
Davies, Tetrahedron, 2015, 71, 7415.
CCDC 1465173 contains the supplementary crystallographic
8
9
data for compound 20a. These data can be obtained free of 27 C. Matheis, K. Jouvin and L. J. Goossen, Org. Lett., 2014, 16
,
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(a) T. E. Janini and P. Sampson, J. Org. Chem., 1997, 62, 5069;
5984.
28 H. Ishiwata, S. Sato, M. Kabeya, S. Oda, M. Suda, M.
Shibasaki, US2003027814 (A1); US6706703 (B2), 2003-02-06.
(b) A. Srikrishna and G. Nagaraju, Tetrahedron: Asymmetry, 29 M. Tanoguchi, T. Kashima, H. Saika, T. Inoue, M. Arimoto and
2012, 23, 170; (c) T. Norin, Acta Chem. Scand., 1963, 17, 738;
(d) A. Srikrishna, K. Krishnan and C. V. Yelamaggad,
Tetrahedron, 1992, 48, 9725; (e) D. L. J. Clive and D. Liu,
Angew. Chem. Int. Ed., 2007, 46, 3738; (f) T. Imamoto, T.
H. Yamaguchi, Chem. Pharm. Bull., 1989, 37, 68.
Hatajima and T. Yoshizawa, Tetrahedron Lett., 1994, 35
,
7805; (g) R. A. Batey and W. B. Motherwell, Tetrahedron
Lett., 1991, 32, 6649.
10 For SmI2 preparation, see: M. Szostak, M. Spain, D. J. Procter,
J. Org. Chem. 2012, 77, 3049.
11 For conceptually related processes involving Rh(II)-catalysed
aziridination followed by ring-opening of the newly formed
strained ring, see: (a) K. Guthikonda, P. M. Wehn, B. J.
Caliando, J. Du Bois, Tetrahedron 2006, 62, 11331; (b) W. P.
Unsworth, S. G. Lamont and J. Robertson, Tetrahedron 2014,
70, 7388; (c) W. P. Unsworth, T. Ronson, N. Clark, K. Stevens,
A. L. Thompson, S. Lamont and J. Robertson, Chem.
Commun. 2014, 50, 11393.
12 To the best of our knowledge there are
examples of intramolecular cyclopropanation reactions of α-
diazophosphonoacetates, all contained within single
3 published
a
publication. These reactions were performed using copper
metal to generate the intermediate carbenoid, with
Rh2(OAc)4 stated to be ineffective as a catalyst for the same
transformation, see: P. Callant, L. D'Haenens and M.
Vandewalle, Synth. Commun., 1984, 14, 155.
13 For related olefination reaction conditions see reference 1h.
14 T. R. Govindachari, G. N. Krishna Kumari and P. D. Partho,
Phytochemistry, 1998, 49, 2129;
15 (a) M.-J. Cheng, S.-J. Lee, Y.-Y. Chang, S.-H. Wu, I.-L. Tsai, B.
Jayaprakasam and I.-S. Chen, Phytochemistry, 2003, 63, 603;
(b) J.-l. Wu, N. Li, T. Hasegawa, J.-i. Sakai, T. Mitsui, H. Ogura,
T. Kataoka, S. Oka, M. Kiuchi, A. Tomida, T. Turuo, M. Li, W.
18 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins