α-Alkylidene-γ-butyrolactone synthesis via one-pot C-H insertion/olefination: substrate scope and the total synthesis of (±)-cedarmycins A and B

Article abstract of DOI:10.1016/j.tet.2014.09.054

Abstract A system for the synthesis of α-alkylidene-γ-butyrolactones via a one-pot C-H insertion/olefination sequence is described. The process is based on the rhodium catalysed C-H insertion reaction of α-diazo-α-(diethoxyphosphoryl)acetates. The mild reaction conditions, operational simplicity and ready availability of starting materials are all key features. A wide range of successful reaction systems are reported (41 examples) highlighting the generality of the method. The application of this method in the total synthesis of the natural products (±)-cedarmycins A and B is also described.

Full text of DOI:10.1016/j.tet.2014.09.054

Tetrahedron xxx (2014) 1e17
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
a
-Alkylidene-
g
-butyrolactone synthesis via one-pot CeH
insertion/olefination: substrate scope and the total synthesis
of (ꢀ)-cedarmycins A and B
,
Matthew G. Lloyd a, Mariantonietta D’Acunto b, Richard J.K. Taylor a
,
*
,
William P. Unsworth a
*
a Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK
b University of Salerno, Department of Chemistry and Biology, Via Giovanni Paolo II, 132, 84084 Fisciano, Salerno, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2014
Received in revised form 8 September 2014
Accepted 17 September 2014
Available online xxx
A system for the synthesis of
sequence is described. The process is based on the rhodium catalysed CeH insertion reaction of
a
ability of starting materials are all key features. A wide range of successful reaction systems are reported
(41 examples) highlighting the generality of the method. The application of this method in the total
synthesis of the natural products (ꢀ)-cedarmycins A and B is also described.
Ó 2014 Elsevier Ltd. All rights reserved.
a
-alkylidene-
g
-butyrolactones via a one-pot CeH insertion/olefination
-diazo-
-(diethoxyphosphoryl)acetates. The mild reaction conditions, operational simplicity and ready avail-
a
Dedicated to the memory of Alan Katritzky:
inspirational giant of heterocyclic chemistry,
collaborator and friend
Keywords:
CeH insertion
Rhodium carbenoids
a
-Methylene-g-butyrolactones
Tandem reactions
Cedarmycins A and B
1. Introduction
develop improved synthetic procedures using tandem/telescoped
reaction sequences.5 In particular a method for
a-alkylidene-g-
The synthesis of
a
-alkylidene-
g
-butyrolactones has captured
butyrolactone synthesis based on an intramolecular Michael addi-
tion of a phosphonate6 followed by olefination, either via a Hor-
nereWadswortheEmmons (HWE)6a,b or Wittig-type olefination.6c,d
These telescoped intramolecular Michael/olefination protocols
(TIMO) enable functionalised hydroxy-enone derivatives to be con-
the interest of synthetic chemists for many years1 and remains an
extremely important endeavour today.2 One reason for the sus-
tained high level of interest in this field is that a vast number of
natural products have been isolated containing this structural motif
(a
-methylene-
g
-butyrolactones are particularly prominent) and
verted into alkylidene-g-butyrolactones in one-pot, in good overall
this area has been well reviewed.3 Much of the reported synthetic
methodology was developed with such targets in mind, and has
facilitated many completed total syntheses. In addition, there is
yield (e.g., 1/3, Scheme 1).6 More recently, we reported a modified
version of this protocol in which the key CeC bond is installed via
a
rhodium(II) catalysed CeH insertion reaction of a diazo-
significant interest in the biological activity of
a
-alkylidene-
g
-
phosphonate, before performing the olefination via HWE olefination
butyrolactones: this stems from the fact that they are typically very
good Michael acceptors, in particular for cysteine residues, thus
imparting broad therapeutic potential and the capability to mod-
ulate a range of biological processes.4
in the same way (4/6, Scheme 1).7
A key advantage of the new CeH insertion methodology is the
comparative simplicity of the requisite starting materials. Unfunc-
tionalised alcohol derivatives can be used in place of the hydroxyl-
enone derivatives required for the TIMO reaction, which greatly
increases the generality and synthetic potential of this method. The
key CeH insertion step utilises a small amount of a relatively be-
nign, air-stable rhodium(II) carboxylate and furthermore, by using
a transition metal catalyst to effect this transformation, the
Our research group became interested in the synthesis of
a-alkylidene-g-butyrolactones as part of a research program to
* Corresponding authors. E-mail addresses: richard.taylor@york.ac.uk (R.J.K.
Taylor), william.unsworth@york.ac.uk (W.P. Unsworth).
http://dx.doi.org/10.1016/j.tet.2014.09.054
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.
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2
M.G. Lloyd et al. / Tetrahedron xxx (2014) 1e17
of the diazo product than more common procedures, in which ei-
ther sodium hydride, KOBu-t or triethylamine are typically used.13
Initial efforts focused on the reactions of homobenzyl alcohol
derivatives, along with their heteroaromatic analogues. This was
because related rhodium carbenoids are reported to undergo CeH
insertion preferentially into electron-rich positions (e.g., benzylic
CeH bonds).14 The formation of unwanted four-membered ring side
products was considered to be a genuine concern during this pro-
cess, based on literature precedent for similar transformations,13a,15
and hence these substrates, which were expected to be biased to-
wards the formation of the desired five-membered ring g-lactones,
were chosen in order to probe the key reaction. Optimisation ex-
periments were first performed using diazophosphonate 11a
(Scheme 3). It was found that the CeH insertion reaction worked
best when performed at 45 ꢁC for 20 h using 2 mol % of Rh2(oct)4 in
DCM.7 Conditions for the HWE olefination were based on those
developed as part of the TIMO reaction sequence described above;6
minor modifications made were to increase the number of equiv-
alents of KOBu-t (from 0.9 up to 1.2e1.5 equiv) and to reduce the
excess of paraformaldehyde used (from typically 5 equiv down to
2). The use of more than 1 equiv of base is noteworthy as related
HWE reactions are known to proceed better with sub-
stoichiometric amounts of base.6,17 Given that nitrogen gas is the
only byproduct formed during the CeH insertion step, it was pre-
dicted that these two steps could be performed in the one-pot
without work-up or purification. Indeed, this proved to be the
case; the most straightforward procedure is performed by con-
ducting the CeH insertion step in DCM as described above, before
cooling the crude reaction mixture and directly adding KOBu-t
(1.2e1.5 equiv), followed by paraformaldehyde (2 equiv). When
applied to diazophosphonate 11a, this telescoped one-pot sequence
Scheme 1. Telescoped approaches to a-alkylidene-g-butyrolactones.
possibility of developing an asymmetric variant is introduced.8 In
a recent preliminary communication7 in this area we described the
optimisation of the key procedure, initial scoping studies and the
application of the methodology towards the synthesis of a Staphy-
lococcus aureus (MRSA) virulence inhibitor (7, Fig. 1).2g,7 Herein we
report significantly expanded substrate scope results and discuss
the strengths and limitations of the methodology along with some
stereochemical, regiochemical and stereoelectronic aspects. The
successful application of this methodology towards the first total
synthesis of the natural product (ꢀ)-cedarmycin A (8a), as well as
the synthesis of closely related (ꢀ)-cedarmycin B (8b), is also
described.9
resulted in the formation of a-methylene-g-butyrolactone 12a in
65% overall yield (Scheme 3). It was later found that performing
a solvent switch (DCM toTHF) between the CeH insertion and HWE
steps, led to a small increase in yield to 71%. HWE reactions are most
commonly performed in ethereal solvents rather than chlorinated,
and this most likely accounts for the observed improvement.16 Note
that no further manipulation was performed during this solvent
switch; the DCM was simply removed under vacuum and THF was
added back into the same reaction vessel, before the HWE reaction
was completed as described above.
Fig. 1. MSRA inhibitor 7 and (ꢀ)-cedarmycins A and B.
2. Results and discussion
The requisite diazophosphonate substrates 11aeaf were made
in two steps from alcohols 9aeaf. The alcohols were first coupled
with diethyl phosphonoacetic acid (DEPAA) using propyl phos-
phonic anhydride (T3P)10 and N,N-diisopropylethylamine (DIPEA);
we have found T3P to be an excellent coupling reagent for a variety
of applications5c,e,11 and in the majority of cases the esters 10aeaf
were formed in excellent yields (usually >95%) and required no
purification other than aqueous work-up (Scheme 2). This was
followed by a Regitz diazo-transfer reaction to furnish the required
diazophosphonates, typically in good unoptimised yield
(23e89%).12 Note that LHMDS was used as the base for these
transformations as, in our hands, it generally afforded higher yields
Scheme 3. Formation of
THF) was performed following step (i).
a
-methylene-
g
-butyrolactone 12a. A solvent switch (DCM to
*
These conditions were then applied to a range of homobenzyl
alcohol derivatives, as well as some heteroaromatic variants
(Table 1). Electron-rich/neutral benzene derivatives generally react
well in the two-step telescoped procedure, furnishing
a-methylene-
g-butyrolactones 12aee in moderate to good yields (45e74%). As
already discussed, related rhodium carbenoids are reported to insert
preferentially into electron-rich CeH bonds, hence electron-
deficient benzene derivatives were expected to be poorer sub-
strates in comparison. Pleasingly, substitution with a para-bromo
group appears not to significantly impair the reaction as product 12f
was formed in reasonable yield (55%) under the standard conditions;
Scheme 2. Formation of diazophosphonates.
the incorporation of a bromo-substituent in this example is
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M.G. Lloyd et al. / Tetrahedron xxx (2014) 1e17
3
Table 1
not at all that surprising, given that Lewis basic residues capable of
coordinating to the vacant axial sites of the dirhodium(II) carboxyl-
ates are known to deactivate the catalyst.18,19 Pyridine nitrogen
atoms also appear to be incompatible (0% conversion for 11j/12j),
presumably for the same reason. Sulfur heteroatoms are better tol-
erated as evidenced by the formation of thiophene derivative 12k,
albeit in modest yield.
One-pot CeH insertion/olefination sequence for the formation of a-methylene-g-
butyrolactones: aromatic substratesa
Substrates with additional substitution were next examined
(Table 1, 12leo). Compound 12l was generated in good yield under
the standard conditions, demonstrating that insertion into steri-
cally hindered tertiary CeH bonds can take place (for other ex-
amples, see Table 2, 12abeaf). The conversion of dibenzyl substrate
Table 2
One-pot CeH insertion/olefination sequence for the formation of a-methylene-g-
butyrolactones: aliphatic substratesa
a Conditions (A) i) 2 mol % Rh2(oct)4, DCM (0.1 M), 45 °C, 20 h; ii) Remove
DCM in vacuo then add THF; iii) 1.5 equiv KOBu-t, 0 °C to –78 °C; iv) 2
equiv (CH2O)n, –78 °C to RT. (B) i) 2 mol % Rh2(oct)4, DCM (0.1 M), 45 °C,
20 h; ii) 1.2 equiv KOBu-t, 0 °C to –78 °C; iii) 2 equiv (CH2O)n, –78 °C to 0
°C. (C) i) 5 mol % Rh2(oct)4, DCM (0.1 M), 45 °C, 20 h; ii) 0.9 equiv KOBu-
t, 0 °C to –78 °C; iii) 10 equiv (CH2O)n, –78 °C to 0 °C.
b Rh2(esp)2 used in place of Rh2(oct)4.
important as it should facilitate the installation of additional func-
tionality (e.g., in cross-coupling reactions). The yield does drop when
a more strongly electron withdrawing trifluoromethyl group is
present (12g, 29%) and decreases further in the case of para-nitro-
substituted product (12h). In these two examples the yield was in-
creased marginally by using a higher catalyst loading and a greater
excess paraformaldehyde, but the overall yields remained relatively
low. Thus, a trend is revealed, whereby the isolated yields of products
12feh decrease as the electron withdrawing ability of the para-
substituent increases. Nonetheless, the fact that some product was
isolated in all of these electronically diverse systems is positive. In-
deed, the only homobenzylic substrate that failed to react at all was
the para-dimethylamine-substituted system (11i/12i); this result is
a Conditions i) 2 mol % Rh2(oct)4, DCM (0.1 M), 45 °C, 20 h; ii) Remove
DCM in vacuo then add THF; iii) 1.5 equiv KOBu-t, 0 °C to –78 °C; iv) 2
equiv (CH2O)n, –78 °C to RT.
b HWE performed at 0 °C
c 1.2 equiv KOBu-t used.
d The comparatively low yield is this case may result from the high volatility
of the product
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4
M.G. Lloyd et al. / Tetrahedron xxx (2014) 1e17
11m into lactone 12m is noteworthy as it proceeds with excellent
diasterocontrol, furnishing compound 12m as single trans-
diastereoisomer in excellent overall yield. Excellent regiocontrol
was also observed during the formation of the related product 12n;
in this example, the CeH insertion reaction of unsymmetrical
starting material 11n took place exclusively a-to the 4-MeO-C6H4
group,20 further highlighting the preference for insertion into
electron-rich CeH bonds. The reaction of dimethylated substrate
11o also proceeded in excellent overall yield, but gave a 1.45:1
mixture of the desired product 12o and its regioisomer 13, in which
insertion into one of the methyl CeH bonds has taken place. The
partial formation of lactone 13 highlights the importance of steric
factors on the key CeH insertion step. On electronic grounds, the
formation of product 12o is expected, but it appears likely that an
interplay between electronic factors and steric hindrance in the
CeH insertion step results in the partial formation of isomer 13 in
this case. Indeed, the CeH insertion step was found to be sensitive
to steric effects in a number of other examples (see later, Table 2),
which is reasonable, considering the combined bulk of phospho-
nate group and the intermediate rhodium carbenoid.
Fig. 2. X-ray crystal structure of cycloheptatriene 15b.
Attention then turned to the synthesis of
a-methylene-g-
butyrolactones from non-aromatic precursors (Table 2). For the
reasons described above,13a,15 it was considered that attempting to
direct the rhodium catalysed CeH insertion into less reactive, non-
benzylic CeH bonds may lead to competing side reactions (e.g., the
formation of
b
- and/or
d-lactones). However, we are pleased to
The reaction of the triphenyl substrate 14a, which did not pro-
ceed as planned, is an interesting example (Scheme 4). In this case,
treating diazo compound 14a under our standard CeH insertion
conditions resulted in almost complete recovery of the starting
material and the formation of a trace amount of an unknown side
product, which was not the expected lactone 14b. To generate
a larger amount of this product, in order to confirm its structure,
compound 14a was heated to 100 ꢁC using the more stable catalyst
Rh2(esp)2 in place of Rh2(oct)4; this led to the complete con-
sumption of the starting material and the isolation of the same
product (15) in 50% yield, which was assigned as a rapidly equili-
brating mixture of two tautomers, norcaradiene 15a and cyclo-
heptatriene 15b. This reaction pathway (known as the Buchner
reaction) proceeds via cyclopropanation of one of the phenyl rings,
followed by reversible electrocyclic ring opening/closing. Rhodium
carbenoid mediated variants of this reaction are well-known,21 and
the ratio of the two components in any mixture is dependent on the
substituents present.21c In this case the equilibrium is biased to-
wards the cycloheptatriene tautomer, as evidenced by the high
NMR chemical shifts (dH 5.31, dC 119.0 in CDCl3) of the position la-
belled (*) in Scheme 4.21c In the solid phase, the product appears to
exist exclusively in the cycloheptatriene form 15b, as the single
diastereoisomer shown: this assignment is supported by X-ray
crystallographic data (Fig. 2).22
report that in most cases, efficient
synthesis can be achieved. For example, lactones 12per were all
generated using the standard two-step sequence, with no evidence
for the formation of competing b- or d-lactone products in any of
these reactions. The sensitivity of the CeH insertion step to steric
factors was highlighted above and further evidence for this can be
a
-methylene- -butyrolactone
g
found in the syntheses of lactones 12s and 12t; the desired
methylene- -butyrolactone products were isolated in both cases,
but the yields were lower than those of substrate 12per, seemingly
decreasing in line with the steric bulk of the substituent -to the
a-
g
a
CeH insertion site. A similar trend was observed during the syn-
theses of homologues 12u and 12v. The lower homologue 12u was
formed in low yield, along with a significant amount of b-lactone
side product 16a. However, the higher homologue 12v, in which the
bulky OTBS group is more remote from the CeH insertion site, was
formed in a much more respectable yield (49%), with no evidence of
b-lactone formation. The formation of lactone 12w, via insertion
into an allylic CeH bond, is noteworthy as cyclopropanation may
have been expected to compete with CeH insertion in this case.
Pleasingly, no evidence for the formation of the alternative cyclo-
propane product was observed, although a small amount of known
butenolide 17,23 which presumably forms via isomerisation of the
methylene alkene of 12w, was also isolated.
Next, attention turned to the synthesis of bicyclic ring scaffolds
(12xeaa). Unfortunately the cyclopentane-fused bicyclic product
12x was not formed under the standard reaction conditions, which
instead furnished a complex mixture of unidentified products. The
analogous cyclohexane-fused product proceeded better, although
the CeH insertion was not as regioselective as most other exam-
ples, generating a mixture of
(12y/16b 1.8:1). More positively, the
g
-lactone and
b
-lactone products
-butyrolactone
a-methylene-
g
12y was formed with very good diasterocontrol; a 10:1 trans/cis
ratio of the two possible fused ring systems was observed, with
CeH insertion taking place predominantly into the equatorial CeH
bond. The process worked extremely well for the formation of
adamantanol-derived lactone 12z, which was formed in very good
yield over the two-step sequence (79%). Lactone 12aa, which is
derived from cycloheptanol, was also formed in good yield, with
reasonable diastereoselectivity (trans/cis 3.5:1), with no evidence
of
b-lactone formation. This example is likely to be important in
target synthesis, given that
a
-methylene- -butyrolactone scaffolds
g
based on fused five- and seven-membered rings of this type are
particularly prevalent in nature.3
g
-Lactone products formed via insertion into tertiary CeH
bonds typically proceed well. First, known lactone 12ab24 was
formed via insertion into an iso-butyl CeH bond. Note that the
Scheme 4. Buchner cyclisation of diazo compound 14a.
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M.G. Lloyd et al. / Tetrahedron xxx (2014) 1e17
5
Table 4
isolated yield in this case was low (23%) but that no side products or
starting material were detected in the crude 1H NMR spectra for
this reaction; the poor yield is likely to be a result of the high
volatility of the product. We then went on to examine the forma-
tion of spirocyclic products 12aceaf. Attempts to form the spi-
rocyclic cyclopropane adduct 12ac failed under the standard
conditions, but pleasingly the analogous four-, five- and six-
membered ring variants all furnished the desired products 12adeaf
in good overall yields (50e79%).
One-pot CeH insertion/olefination sequence for the formation of a-alkylidene-g-
butyrolactonesa
As described in our previous communication,7
a-alkylidene-g-
butyrolactones may also accessed using the same procedure
(Table 3). Diazophosphonate 11a can treated under the standard
conditions for CeH insertion, before performing the HWE step
using a range of aromatic and aliphatic aldehydes in place of
paraformaldehyde, affording products 18aeg as mixtures of E- and
Z-isomers in fair to excellent overall yield (36e91%).
Table 3
One-pot CeH insertion/olefination sequence for the formation of
a-alkylidene-g-
butyrolactones from 11aa
a Conditions (A) i) 2 mol % Rh2(oct)4, DCM (0.1 M), 45 °C, 20 h; ii) Remove
DCM in vacuo then add THF; iii) 1.5 equiv KOBu-t, 0 °C to –78 °C; iv) 2
equiv (CH2O)n, –78 °C to RT.
b HWE was performed at reflux
Entry
R
Product
E/Z
1:1
1:1.3
1:1.5
1:1
1:1.2
1.2:1
1:3.7
Yield (%)
1
2
3
4
5
6
7
Ph
18a
18bb
18c
18d
18ec
18f
65
69
91
61
56
39
67
4-NO2eC6H4
2-FeC6H4
4-PheC6H4
3,4-OCH2OeC6H3
CH3
n-Butyl
18g
a
Conditions: (i) 2 mol % Rh2(oct)4, DCM (0.1 M), 45 ꢁC, 20 h; (ii) remove DCM in
vacuo then add THF; (iii) 1.5 equiv KOBu-t, 0 ꢁC to ꢂ78 ꢁC; (iv) 2 equiv RCHO, ꢂ78 ꢁ
C
to rt.
Scheme 5. The total syntheses of (ꢀ)-cedarmycins A and B.
b
HWE was performed at 0 ꢁC.
HWE was performed at reflux.
c
agreement with those published9 and in the case of (ꢀ)-cedarmycin
A, this is its first reported total synthesis and thus confirms the
proposed structure.25 Of course, both of these syntheses are very
simple, but they do serve to highlight the relative ease with which
natural product targets can be accessed from simple precursors
using CeH activation chemistry.
We have since gone on to show that three other diazo-
phosphonates (11d, 11p, 11ae) can also be used to furnish alkyli-
dene-g-butyrolactones (Table 4). The substrates chosen include one
benzylic, one aliphatic and one spirocyclic system and each was
reacted with an aromatic and aliphatic aldehyde, to demonstrate
the generality of the methodology. As above, the products 18hem
were formed as mixtures of E- and Z-isomers, with partial dia-
stereoselectivity for the Z-isomer in some cases, typically in good
overall yields (32e77%). Note that all of these examples are unop-
timised and were performed using the standard reaction condi-
tions, with the exception of lactone 18m. In this case, the HWE
reaction did not proceed at room temperature (as indicated by TLC
analysis) hence this step was performed at reflux.
3. Conclusion
The telescoped CeH insertion/olefination sequence described
has been used to convert simple alcohol derivatives into a wide
range of
a
-alkylidene-
g
-butyrolactones, typically in good overall
-alkylidene- -butyr-
yield (in total, the formation of 41 distinct
a
g
olactone products are described). The reaction conditions are mild,
straightforward to perform and applicable to a wide range of sub-
strates. Furthermore, the products themselves are biologically im-
portant, hence the methods developed are expected to be widely
used by academic and industrial research groups. The application of
these methods in natural product synthesis has also been demon-
strated during the synthesis of (ꢀ)-cedarmycins A and B. The
methodology appears to be very well suited to natural product
synthesis and more complex biologically important targets are
currently under investigation, the results of which will be reported
in due course.
As described above, there is an abundance of biologically im-
portant compounds containing the
a-alkylidene-g-butyrolactone
motif found in nature.1e4 Future applications of this methodology
in the synthesis of such natural product targets are anticipated, as
demonstrated by the successful total syntheses of (ꢀ)-cedarmycins
A and B (8a and 8b, Scheme 5).9 Thus, lactone 12u (for its synthesis,
see Table 2 above) was first treated with TBAF to cleave the silyl
protecting group to furnish alcohol 19, before coupling it with each
of the acid chlorides 20a and 20b under standard conditions to
complete both syntheses. Both sets of spectral data were in full
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6
M.G. Lloyd et al. / Tetrahedron xxx (2014) 1e17
4. Experimental
the solution forming a suspension. After stirring for 1 h at rt the
mixture was diluted with ether (100 mL) and water (25 mL) prior to
extraction with ether (3ꢃ50 mL). The combined organic extracts
were washed with satd aq NaHCO3 (2ꢃ25 mL), dried over MgSO4,
concentrated in vacuo and purified by column chromatography
affording the a-diazo-a-(diethoxyphosphoryl)acetate product 11.
General procedure C: one-pot Rh(II)-catalysed CeH insertion/HWE
(11/12, DCM)
4.1. General aspects
Except where stated, all reagents were purchased from com-
mercial sources and used without further purification and all ex-
perimental procedures were carried out under an atmosphere of
argon. Anhydrous CH2Cl2, toluene and diethyl ether were obtained
from an Innovative Technology Inc. PureSolvÒ solvent purification
system. Anhydrous THF was obtained by distillation over sodium
benzophenone ketyl immediately before use. 1H NMR and 13C NMR
spectra were recorded on a JEOL ECX400 or JEOL ECS400 spec-
trometer, operating at 400 MHz and 100 MHz, respectively. All
To an oven dried sealable tube containing a-diazo-a-(dialkox-
yphosphoryl)acetate 11 (0.200 mmol) flushed with argon was
added DCM (4.0 mL) followed by Rh2(oct)4 or Rh2(esp)2 (2 or
5 mol %). The solution was stirred at 45 ꢁC for 20 h. The solution was
cooled to 0 ꢁC prior to the addition of KOBu-t (0.9, 1.2 or 1.5 equiv),
which was stirred at 0 ꢁC for 60 min and then cooled to ꢂ78 ꢁC.
Aldehyde (2.0, 5.0 or 10.0 equiv) was added to the solution and
stirred for 15 min at ꢂ78 ꢁC and a further 2 h at either 0 ꢁC, rt or
reflux. The solution was quenched with satd aq NH4Cl (10 mL) and
then diluted with DCM (20 mL). The organic layer was separated
and the aqueous extracted with EtOAc (2ꢃ20 mL). The combined
organic extracts were dried over Na2SO4, concentrated in vacuo and
spectral data was acquired at 295 K. Chemical shifts (d) are quoted
in parts per million (ppm). The residual solvent peak, dH 7.26 and dC
77.0 for CDCl3 was used as a reference. Coupling constants (J) are
reported in hertz (Hz) to the nearest 0.1 Hz. The multiplicity ab-
breviations used are: s singlet, d doublet, t triplet, q quartet, m
multiplet. Signal assignment was achieved by analysis of DEPT,
COSY, HMBC and HSQC experiments where required. Infrared (IR)
spectra were recorded on either a ThermoNicolet IR-100 spec-
trometer with NaCl plates as a thin film dispersed from either
CH2Cl2 or CDCl3, or a PerkinElmer UATR II spectrometer and the
data are assigned as being strong (s), medium (m), weak (w) or
broad (br) signals. Mass spectra (low- and high-resolution) 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. Thin layer chromatography 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 chro-
purified by column chromatography affording the
alkylidene- -butyrolactone product 12.
a-methylene/
g
General procedure D: one-pot Rh(II)-catalysed CeH insertion/HWE
(11/12, DCM with THF switch)
To an oven dried sealable tube containing a-diazo-a-(dialkox-
yphosphoryl)acetate 11 (0.200 mmol) flushed with argon was
added DCM (4.0 mL) followed by Rh2(oct)4 or Rh2(esp)2 (2 or
5 mol %). The solution was stirred at 45 ꢁC for 20 h and then con-
centrated in vacuo. The residue was diluted with THF (4.0 mL) and
cooled to 0 ꢁC prior to the addition of KOBu-t (0.9, 1.2 or 1.5 equiv),
which was stirred at 0 ꢁC for 60 min and then cooled to ꢂ78 ꢁC.
Aldehyde (2.0, 5.0 or 10.0 equiv) was added to the solution and
stirred for 15 min at ꢂ78 ꢁC and a further 2 h at either 0 ꢁC, rt or
reflux. The solution was quenched with satd aq NH4Cl (10 mL) and
then diluted with DCM (20 mL). The organic layer was separated
and the aqueous extracted with EtOAc (2ꢃ20 mL). The organic
extracts were dried over Na2SO4, concentrated in vacuo and puri-
matography was carried out using slurry packed Fluka silica gel
ꢀ
(SiO2), 35e70
m
m, 60 A, under a light positive pressure, eluting with
the specified solvent system. Petrol refers to petroleum ether
boiling point 40e60 ꢁC. Ether refers to diethyl ether. Experimental
procedures and characterisation data for compounds 7, 9m, 9n,
10a,b, 10d, 10leo, 10per, 10ae, 11a,b, 11d, 11leo, 11per, 11ae, 12a,b,
12d,121eo,12per,12ae,13 and 18aeg can be found in our previous
communication.7
fied by column chromatography affording the
dene- -butyrolactone product 12.
a-methylene/alkyli-
g
4.3. 3,4,5-Trimethoxyphenethyl 2-(diethoxyphosphoryl)ace-
tate (10c)
4.2. General experimental procedures
The majority of alcohols were commercially available. Alcohols
9c,26 9i,27 9j28 and 9k29 were prepared by LiAlH4 reduction of the
corresponding carboxylic acids and gave spectral data consistent
with those in the literature.
Synthesised using general procedure A affording the title com-
pound as a yellow oil (360 mg, 95%); Rf 0.10 (1:1 hexane/ethyl ac-
etate); nmax (thin film)/cmꢂ1 2939w, 2841w, 1733s, 1590s, 1508m,
1459m, 1422m, 1852w, 1238s, 1154w, 1123s, 1047w, 1018s, 967s,
827m, 778m; dH (400 MHz, CDCl3) 1.28e1.31 (6H, m), 2.88 (2H, t, J
7.2), 2.94 (2H, d, J 21.5), 3.79 (3H, s), 3.82 (6H, s), 4.07e4.15 (4H, m),
4.32 (2H, t, J 7.2), 6.41 (2H, s); dC (100 MHz, CDCl3) 16.2 (d, J 6.2),
34.2 (d, J 134.3), 35.2, 56.0, 60.7, 62.6 (d, J 6.3), 65.9, 105.7, 132.9,
136.6, 153.1, 165.7 (d, J 6.0); dP (162 MHz, CDCl3) 20.2; HRMS (ESIþ):
found: 413.1351; C17H27NaO8P (MNaþ) requires 413.1336.
General procedure A: esterifications using T3P (9/10)
To a stirred solution of alcohol 9 (8.00 mmol) in toluene (40 mL)
under argon were added sequentially diethyl phosphonoacetic acid
(1.35 mL, 8.40 mmol), DIPEA (3.62 mL, 20.8 mmol) and propyl
phosphonic anhydride (6.62 g, 10.4 mmol, 50% w/w solution in
ethyl acetate/THF). The solution was stirred at rt for 4 h after which
time it was diluted with water (50 mL) and extracted with ethyl
acetate (3ꢃ100 mL) followed by sequential washing of the com-
bined organic extracts with 10% aq HCl (50 mL), satd aq NaHCO3
(50 mL) and brine (50 mL). The organic extracts were dried over
4.4. 2-(Naphthalen-1-yl)ethyl 2-(diethoxyphosphoryl)acetate
(10e)
MgSO4 and concentrated in vacuo, affording the
yphosphoryl)acetate product 10, which was used without further
purification.
a
-(diethox-
Synthesised using general procedure A affording the title com-
pound as a yellow oil (1.74 g, 99%); Rf 0.20 (1:1 hexane/ethyl ace-
tate); nmax (thin film)/cmꢂ1 2982w, 1735s, 1598w, 1510w, 1496w,
1445w, 1395w, 1257s, 1163w, 1113m, 1048w, 1019s, 965s, 838w,
798w, 777s, 731s, 696m; dH (400 MHz, CDCl3) 1.31 (6H, t, J 7.1), 2.97
(2H, d, J 21.6), 3.44 (2H, t, J 7.5), 4.10e4.17 (4H, m), 4.48 (2H, t, J 7.5),
7.36e7.43 (2H, m), 7.47e7.56 (2H, m), 7.75e7.77 (1H, m), 7.85e7.87
(1H, m), 8.07e8.09 (1H, m); dC (100 MHz, CDCl3) 16.3 (d, J 6.2), 32.0,
34.3 (d, J 134.2), 62.6 (d, J 6.2), 65.4, 123.4, 125.4, 125.6, 126.2, 127.0,
General procedure B: diazotisation reactions (10/11)
To
a stirred solution of a-(diethoxyphosphoryl)acetate 10
(5.0 mmol) in THF (25 mL), cooled to ꢂ78 ꢁC under argon was added
LHMDS (6.0 mL, 6.0 mmol, 1.0 M solution in THF). The solution was
allowed to warm to rt and stirred for 10 min. 4-
Acetamidobenzenesulfonylazide (1.44 g, 6.0 mmol) was added to
Please cite this article in press as: Lloyd, M. G.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.054

M.G. Lloyd et al. / Tetrahedron xxx (2014) 1e17
7
127.5, 128.8, 131.9, 133.2, 133.8, 165.8 (d, J 6.1); dP (162 MHz, CDCl3)
20.3; HRMS (ESIþ): found: 373.1171; C18H23NaO5P (MNaþ) requires
373.1175.
(2H, m); dC (100 MHz, CDCl3) 16.3 (d, J 6.1), 32.1, 34.3 (d, J 134.3),
62.7 (d, J 6.5), 65.2, 123.5, 133.1, 136.5, 148.0, 150.1, 165.7 (d, J 6.1); dP
(162 MHz, CDCl3) 20.0; HRMS (ESIþ): found: 324.0976;
C
13H20NNaO5P (MNaþ) requires 324.0971.
4.5. 4-Bromophenethyl 2-(diethoxyphosphoryl)acetate (10f)
4.10. 2-(Thiophen-3-yl)ethyl 2-(diethoxyphosphoryl)acetate
(10k)
Synthesised using general procedure A affording the title com-
pound as a yellow oil (1.80 g, 96%); Rf 0.23 (1:1 hexane/ethyl ace-
tate); nmax (thin film)/cmꢂ1 2982w, 1735s, 1489m, 1443w, 1393w,
1256s, 1163w, 1114m, 1049w, 1020s, 964s, 804m; dH (400 MHz,
CDCl3) 1.29 (6H, td, J 7.1, 0.5), 2.89 (2H, t, J 6.9), 2.92 (2H, d, J 21.6),
4.06e4.13 (4H, m), 4.30 (2H, t, J 6.9), 7.08 (2H, d, J 8.5), 7.39 (2H, d, J
8.5); dC (100 MHz, CDCl3) 16.2 (d, J 6.2), 34.2 (d, J 134.3), 34.2, 62.6
Synthesised using general procedure A affording the title com-
pound as a yellow oil (2.41 g, 99%); Rf 0.33 (1:1 petrol/ethyl acetate);
nmax (thin film)/cmꢂ1 2983w, 1734s, 1393w, 1258s, 1115w, 1049w,
1020s, 968s; dH (400 MHz, CDCl3) 1.32 (6H, td, J 7.1, 0.5), 2.97 (2H, d,
J 21.6), 3.00 (2H, t, J 6.9), 4.14 (4H, dq, J 8.3, 7.1), 4.35 (2H, td, J 6.9,
0.5), 6.98 (1H, dd, J 4.9,1.3), 7.06 (1H, ddt, J 3.0,1.3, 0.9), 7.27 (1H, dd,
J 4.9, 3.0); dC (100 MHz, CDCl3) 16.3 (d, J 6.4), 29.4, 34.3 (d, J 134.4),
62.7 (d, J 6.5), 65.4, 121.7, 125.6, 128.2, 137.6, 165.8 (d, J 6.2); dP
(162 MHz, CDCl3) 20.2; HRMS (ESIþ): found: 329.0582;
(d, J 6.2), 65.5, 120.4, 130.6, 131.5, 136.4, 165.6 (d, J 6.1); dP (162 MHz,
79
CDCl3) 20.1; HRMS (ESIþ): found: 401.0124; C14
requires 401.0124.
H
BrNaO5P (MNaþ)
20
12H19NaO5PS (MNaþ) requires 329.0583.
4.6. 4-Trifluoromethylphenethyl 2-(diethoxyphosphoryl)ace-
tate (10g)
C
4.11. 3-Methylbutyl 2-(diethoxyphosphoryl)acetate (10s)
Synthesised using general procedure A affording the title com-
pound as a yellow oil (963 mg, 100%); Rf 0.19 (1:1 petrol/ethyl ac-
etate); nmax (thin film)/cmꢂ1 2940s, 2890w, 1712s, 1307m, 1251m,
1146w,1099m,1007m, 956w; dH (400 MHz, CDCl3) 1.30 (6H, td, J 7.1,
0.5), 2.94 (2H, d, J 21.6), 3.02 (2H, t, J 6.8), 4.11 (4H, dq, J 8.8, 7.1), 4.37
(2H, t, J 6.8), 7.35 (2H, d, J 8.0), 8.17 (2H, d, J 8.0); dC (100 MHz, CDCl3)
16.3 (d, J 6.2), 34.3 (d, J 134.4), 34.7, 62.7 (d, J 6.2), 65.3, 125.4 (q, J
3.7), 126.9 (q, J 271.1), 129.2, 129.7 (q, J 32.5), 141.7, 165.7 (d, J 6.1); dF
(376 MHz, CDCl3) ꢂ62.4; dP (162 MHz, CDCl3) 20.1; HRMS (ESIþ):
found: 391.0878; C15H20F3NaO5P (MNaþ) requires 391.0893.
Synthesised using general procedure A affording the title com-
pound as an orange oil (2.67 g, 100%); Rf 0.28 (1:1 hexane/ethyl
acetate); nmax (thin film)/cmꢂ1 2960w, 1735s, 1466w, 1392w, 1261s,
1116m, 1021s, 969m; dH (400 MHz, CDCl3) 0.90 (6H, d, J 6.6), 1.33
(6H, td, J 7.1, 0.4), 1.52 (2H, app. q, J 6.9), 1.63e1.76 (1H, m), 2.94 (2H,
d, J 21.6), 4.12e4.19 (6H, m); dC (100 MHz, CDCl3) 16.3 (d, J 6.2), 22.3,
24.8, 34.3 (d, J 134.2), 37.1, 62.6 (d, J 6.2), 64.2, 165.9 (d, J 6.2); dP
(162 MHz, CDCl3) 20.5; HRMS (ESIþ): found: 289.1356;
C
11H23NaO5P (MNaþ) requires 289.1175.
4.7. 4-Nitrophenethyl 2-(diethoxyphosphoryl)acetate (10h)
4.12. 3,3-Dimethylbutyl 2-(diethoxyphosphoryl)acetate (10t)
Synthesised using general procedure A affording the title com-
pound as an orange oil (4.72 g, 91%); Rf 0.12 (1:1 petrol/ethyl ace-
tate); nmax (thin film)/cmꢂ1 2936s, 1712s, 1577m, 1495s, 1371m,
1325m, 1249m, 1145w, 1095m, 1009m, 955w, 842w; dH (400 MHz,
CDCl3) 1.31 (6H, t, J 7.1), 2.94 (2H, d, J 21.6), 3.08 (2H, t, J 6.7), 4.13
(4H, dq, J 8.3, 7.1), 4.39 (2H, t, J 6.7), 7.41 (2H, d, J 8.8), 8.17 (2H, d, J
8.8); dC (100 MHz, CDCl3) 16.3 (d, J 6.2), 34.3 (d, J 134.6), 34.7, 62.7
(d, J 6.2), 64.9, 123.7, 129.8,145.3, 146.9, 165.6 (d, J 6.0); dP (162 MHz,
CDCl3) 20.0; HRMS (ESIþ): found: 368.0875; C14H20NNaO7P (MNaþ)
requires 368.0870 (ꢂ1.3 ppm error).
Synthesised using general procedure A affording the title com-
pound as an orange oil (2.70 g, 97%); Rf 0.41 (1:2 hexane/ethyl ac-
etate); nmax (thin film)/cmꢂ1 2958w, 2870w, 1736s, 1478w, 1396w,
1261s, 1116m, 1023s, 971m; dH (400 MHz, CDCl3) 0.92 (9H, s), 1.33
(6H, td, J 7.1, 0.5), 1.57 (2H, t, J 7.7), 2.94 (2H, d, J 21.6), 4.12e4.19 (6H,
m); dC (100 MHz, CDCl3) 16.3 (d, J 6.3), 29.5, 29.6, 34.3 (d, J 134.3),
41.5, 62.6 (d, J 6.3), 63.4, 165.9 (d, J 6.0); dP (162 MHz, CDCl3) 20.5;
HRMS (ESIþ): found: 303.1323; C12H25NaO5P (MNaþ) requires
303.1332.
4.8. 4-(Dimethylamino)phenethyl 2-(diethoxyphosphoryl)ac-
etate (10i)
4.13. 3-((tert-Butyldimethylsilyl)oxy)propyl 2-(diethox-
yphosphoryl)acetate (10u)
Synthesised using general procedure A affording the title com-
pound as an orange oil (1.77 g, 100%); Rf 0.44 (1:2 petrol/ethyl ac-
etate); nmax (thin film)/cmꢂ1 2988w, 1733s, 1522s, 1258s, 1114w,
1019s; dH (400 MHz, CDCl3) 1.32 (6H, td, J 7.1, J 0.5), 2.86 (2H, t, J 7.3),
2.91 (6H, s), 2.96 (2H, d, J 21.5), 4.14 (4H, dq, J 8.2, 7.1), 4.29 (2H, t, J
7.3), 6.69 (2H, d, J 8.7), 7.10 (2H, d, J 8.7); dC (100 MHz, CDCl3) 16.3 (d,
J 6.4), 33.9, 34.3 (d, J 134.2), 40.7, 62.6 (d, J 6.2), 66.5, 112.8, 125.1,
129.5, 149.5, 165.8 (d, J 6.1); dP (162 MHz, CDCl3) 20.4; HRMS (ESIþ):
found: 366.1444; C16H26NNaO5P (MNaþ) requires 366.1441.
To a solution of NaH (480 mg, 12.0 mmol, 60% dispersion in
mineral oil) in THF (20 mL) cooled to 0 ꢁC was added 1,3-
propanediol (0.80 mL, 11.0 mmol) dropwise over 5 min. The solu-
tion was allowed to warm to rt and stirred for 30 min after which
TBSCl (1.51 g, 10.0 mmol) was added then stirred at rt for 1 h. The
solution was diluted with water (25 mL), extracted with ether
(2ꢃ25 mL), washed with brine (25 mL), dried over MgSO4 and
concentrated in vacuo. The crude alcohol (1.96 g) was then treated
under the conditions of general procedure A affording the title
compound as a yellow oil (3.32 g, 90% over two steps); Rf 0.22 (1:1
hexane/ethyl acetate); nmax (thin film)/cmꢂ1 2956w, 2930m,
2857w, 1738s, 1473w, 1392w, 1258s, 1100m, 1054w, 1025s, 970m,
836s, 777m; dH (400 MHz, CDCl3) 0.04 (6H, s), 0.88 (9H, s), 1.34 (6H,
t, J 7.1), 1.85 (2H, tt, J 6.5, 6.0), 2.96 (2H, d, J 21.6), 3.69 (2H, t, J 6.0),
4.13e4.20 (4H, m), 4.24 (2H, t, J 6.5); dC (100 MHz, CDCl3) ꢂ5.4, 16.3
(d, J 6.2), 18.2, 25.8, 31.7, 34.3 (d, J 134.3), 59.2, 62.6 (d, J 6.3), 62.6,
165.8 (d, J 6.1); dP (162 MHz, CDCl3) 20.4; HRMS (ESIþ): found:
391.1691; C15H33NaO6PSi (MNaþ) requires 391.1676.
4.9. 2-(Pyridin-3-yl)ethyl 2-(diethoxyphosphoryl)acetate (10j)
Synthesised using general procedure A affording the title com-
pound as a yellow oil (4.49 g, 92%); Rf 0.44 (10:1 DCM/MeOH); nmax
(thin film)/cmꢂ1 2938s, 2887w, 1711s, 1468m, 1249s, 1100w, 1034w,
1010m, 957w; dH (400 MHz, CDCl3) 1.31 (6H, td, J 7.1, 0.5), 2.95 (2H,
d, J 21.6), 2.97 (2H, t, J 6.8), 4.13 (4H, dq, J 8.3, 7.1), 4.36 (2H, t, J 6.8),
7.25 (1H, ddd, J 7.8, 4.8, 0.8), 7.60 (1H, ddd, J 7.8, 2.3, 1.7), 8.48e8.51
Please cite this article in press as: Lloyd, M. G.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.054

8
M.G. Lloyd et al. / Tetrahedron xxx (2014) 1e17
4.14. 4-((tert-Butyldimethylsilyl)oxy)butyl 2-(diethox-
yphosphoryl)acetate (10v)
1020s, 967s, 890m, 836w, 814w; dH (400 MHz, CDCl3) 1.32 (6H, td, J
7.1, 0.5), 1.57e1.69 (6H, m), 2.09e2.14 (9H, m), 2.85 (2H, d, J 21.4),
4.10e4.18 (4H, m); dC (100 MHz, CDCl3) 16.3 (d, J 6.2), 30.7, 35.7 (d, J
132.8), 36.0, 41.1, 62.4 (d, J 6.2), 82.0, 164.5 (d, J 6.3); dP (162 MHz,
CDCl3) 21.2; HRMS (ESIþ): found: 353.1489; C16H27NaO5P (MNaþ)
requires 353.1488.
To a solution of NaH (240 mg, 6.00 mmol, 60% dispersion in
mineral oil) in THF (10 mL) cooled to 0 ꢁC was added 1,4-butanediol
(0.44 mL, 5.50 mmol) dropwise over 5 min. The solution was
allowed to warm to rt and stirred for 30 min after which TBSCl
(754 mg, 5.00 mmol) was added then stirred at rt for 1 h. The so-
lution was diluted with water (25 mL), extracted with ether
(2ꢃ25 mL), washed with brine (25 mL), dried over MgSO4 and
concentrated in vacuo. The crude alcohol (1.20 g) was then treated
under the conditions of general procedure A affording the title
compound as a yellow oil (1.76 g, 92% over two steps); Rf 0.43 (1:1
hexane/ethyl acetate); nmax (thin film)/cmꢂ1 2955w, 2929w, 2857w,
1737s, 1472w, 1391w, 1255s, 1164w, 1097s, 1052w, 1023s, 968s,
892w, 834s, 774s; dH (400 MHz, CDCl3) 0.01 (6H, s), 0.85 (9H, s), 1.31
(6H, td, J 7.1, 0.5), 1.51e1.58 (2H, m), 1.65e1.72 (2H, m), 2.93 (2H, d, J
21.6), 3.60 (2H, t, J 6.2), 4.10e4.17 (6H, m); dC (100 MHz, CDCl3) ꢂ5.4,
16.3 (d, J 6.2), 18.2, 25.1, 25.8, 28.9, 34.2 (d, J 134.2), 62.4, 62.6 (d, J
6.4), 65.5, 165.8 (d, J 6.2); dP (162 MHz, CDCl3) 20.4; HRMS (ESIþ):
found: 405.1833; C16H35NaO6PSi (MNaþ) requires 405.1833.
4.19. Cycloheptyl 2-(diethoxyphosphoryl)acetate (10aa)
Synthesised using general procedure A affording the title com-
pound as a colourless oil (1.45 g, 99%); Rf 0.31 (1:1 hexane/ethyl
acetate); nmax (thin film)/cmꢂ1 2982w, 2929m, 2861w, 1728s,
1446w, 1394w, 1266s, 1113m, 1051w, 1021s, 969s; dH (400 MHz,
CDCl3) 1.32 (6H, td, J 7.1, 0.5), 1.35e1.69 (10H, m), 1.85e1.92 (2H, m),
2.91 (2H, d, J 21.5), 4.10e4.18 (4H, m), 4.95 (1H, tt, J 8.3, 4.3); dC
(100 MHz, CDCl3) 16.3 (d, J 6.5), 22.7, 28.2, 33.5, 34.6 (d, J 133.5),
62.5 (d, J 6.2), 76.5, 165.1 (d, J 6.2); dP (162 MHz, CDCl3) 20.7; HRMS
(ESIþ): found: 293.1502; C13H26O5P (MHþ) requires 293.1512.
4.20. 2-Methylpropyl 2-(diethoxyphosphoryl)acetate
(10ab)15a
4.15. But-3-en-1-yl 2-(diethoxyphosphoryl)acetate (10w)
Synthesised using general procedure A affording the title com-
pound as a yellow oil (2.02 g, 100%); Rf 0.24 (1:1 petrol/ethyl ace-
tate); nmax (thin film)/cmꢂ1 2965m, 1735s, 1394w, 1265s, 1117w,
1052w, 1024s; dH (400 MHz, CDCl3) 0.94 (6H, d, J 6.7), 1.32 (6H, t, J
7.1), 1.95 (1H, app. nonet, J 6.7), 2.97 (2H, d, J 21.6), 3.92 (2H, d, J 6.7),
4.17 (4H, dq, J 8.3, 7.1); dC (100 MHz, CDCl3) 16.3 (d, J 6.5), 19.0, 27.6,
34.3 (d, J 134.0), 62.6 (d, J 6.2), 71.6, 165.9 (d, J 6.4); dP (162 MHz,
CDCl3) 20.5; HRMS (ESIþ): found: 275.1018; C10H21NaO5P (MNaþ)
requires 275.1019.
Synthesised using general procedure A affording the title com-
pound as a pale yellow oil (1.24 g, 99%); Rf 0.20 (1:1 hexane/ethyl
acetate); nmax (thin film)/cmꢂ1 2983w,1735s,1643w,1445w,1393w,
1257s, 1163w, 1115m, 1049w, 1019s, 964s, 839w, 782w, 733w; dH
(400 MHz, CDCl3) 1.33 (6H, td, J 7.1, 0.4), 2.40 (2H, app. qt, J 6.8, 1.4),
2.96 (2H, d, J 21.6), 4.12e4.20 (6H, m), 5.05e5.14 (2H, m), 5.78 (1H,
ddt, J 17.1, 10.3, 6.8); dC (100 MHz, CDCl3) 16.3 (d, J 6.2), 32.8, 34.2 (d,
J 134.3), 62.6 (d, J 6.3), 64.6, 117.4, 133.6, 165.8 (d, J 6.1); dP (162 MHz,
CDCl3) 20.3; HRMS (ESIþ): found: 273.0868; C10H19NaO5P (MNaþ)
requires 273.0862.
4.21. Cyclopropylmethyl 2-(diethoxyphosphoryl)acetate
(10ac)
4.16. Cyclopentyl 2-(diethoxyphosphoryl)acetate (10x)
Synthesised using general procedure A affording the title com-
pound as a yellow oil (1.23 g, 98%); Rf 0.23 (1:1 hexane/ethyl ace-
tate); nmax (thin film)/cmꢂ1 2984w, 1731s, 1446w, 1394w, 1369w,
1346w, 1257s, 1164w, 1115m, 1049w, 1018s, 966s, 943w, 889w,
839m; dH (400 MHz, CDCl3) 0.27e0.31 (2H, m), 0.55e0.59 (2H, m),
1.09e1.20 (1H, m), 1.34 (6H, t, J 7.1), 2.98 (2H, d, J 21.5), 3.97 (2H, d, J
7.3), 4.14e4.21 (4H, m); dC (100 MHz, CDCl3) 3.3, 9.6, 16.3 (d, J 6.4),
34.4 (d, J 134.2), 62.7 (d, J 6.3), 70.3, 165.9 (d, J 6.1); dP (162 MHz,
CDCl3) 20.4; HRMS (ESIþ): found: 273.0862; C10H19NaO5P (MNaþ)
requires 273.0862.
Synthesised using general procedure A affording the title com-
pound as a yellow oil (1.12 g, 85%); Rf 0.24 (1:1 hexane/ethyl ace-
tate); nmax (thin film)/cmꢂ1 2974m, 2874w, 1730s, 1443w, 1393w,
1368w, 1259s, 1165m, 1114m, 1050w, 1019s, 966s, 839m, 780m; dH
(400 MHz, CDCl3) 1.34 (6H, td, J 7.1, 0.4),1.54e1.90 (8H, m), 2.92 (2H,
d, J 21.6), 4.16 (4H, dq, J 8.1, 7.1), 5.20 (1H, tt, J 5.6, 2.7); dC (100 MHz,
CDCl3) 16.2 (d, J 6.2), 23.6, 32.4, 34.5 (d, J 133.5), 62.5 (d, J 6.2), 78.4,
165.5 (d, J 6.2); dP (162 MHz, CDCl3) 20.7; HRMS (ESIþ): found:
287.1020; C11H21NaO5P (MNaþ) requires 287.1019.
4.22. Cyclobutylmethyl 2-(diethoxyphosphoryl)acetate (10ad)
4.17. Cyclohexyl 2-(diethoxyphosphoryl)acetate (10y)
Synthesised using general procedure A affording the title com-
pound as a yellow oil (1.31 g, 99%); Rf 0.22 (1:1 hexane/ethyl ace-
tate); nmax (thin film)/cmꢂ1 2980w, 2941w, 1733s, 1445w, 1393w,
1334w, 1259s, 1163w, 1115m, 1049w, 1019s, 964s, 838m, 783m,
609m; dH (400 MHz, CDCl3) 1.32 (6H, td, J 7.1, 0.5), 1.71e1.96 (4H,
m), 2.00e2.08 (2H, m), 2.61 (1H, app. heptet, J 7.4), 2.95 (2H, d, J
21.6), 4.08e4.19 (6H, m); dC (100 MHz, CDCl3) 16.3 (d, J 6.2), 18.3,
24.6, 33.9, 34.3 (d, J 133.8), 62.6 (d, J 6.2), 69.2, 165.9 (d, J 6.2); dP
(162 MHz, CDCl3) 20.4; HRMS (ESIþ): found: 287.1033;
Synthesised using general procedure A affording the title com-
pound as a dark orange oil (4.43 g, 100%); Rf 0.33 (1:1 petrol/ethyl
acetate); nmax (thin film)/cmꢂ1 2985w, 2937s, 2862m, 1729s, 1258s,
1114w, 1016s, 964s; dH (400 MHz, CDCl3) 1.16e1.52 (6H, m), 1.30
(6H, td, J 7.1, 0.5), 1.65e1.73 (2H, m), 1.77e1.84 (2H, m), 2.90 (2H, d, J
21.6), 4.12 (4H, dq, J 8.4, 7.1), 4.76 (1H, tt, J 8.7, 4.2); dC (100 MHz,
CDCl3) 16.2 (d, J 6.2), 23.5, 25.2, 31.3, 34.5 (d, J 133.4), 62.4 (d, J 6.3),
73.9, 165.1 (d, J 6.4); dP (162 MHz, CDCl3) 20.6; HRMS (ESIþ): found:
301.1162; C12H23NaO5P (MNaþ) requires 301.1175.
C
11H21NaO5P (MNaþ) requires 287.1019.
4.18. Adamantan-1-yl 2-(diethoxyphosphoryl)acetate (10z)
4.23. Cyclohexylmethyl 2-(diethoxyphosphoryl)acetate (10af)
Synthesised using general procedure A affording the title com-
pound as a colourless oil (1.53 g, 93%); Rf 0.30 (1:1 hexane/ethyl
acetate); nmax (thin film)/cmꢂ1 2981w, 2910s, 2853w, 1728s, 1584w,
1457w, 1393w, 1369w, 1355w, 1321w, 1259s, 1164w, 1103m, 1049w,
Synthesised using general procedure A affording the title com-
pound as a yellow oil (1.44 g, 99%); Rf 0.53 (ethyl acetate); nmax (thin
film)/cmꢂ1 2927s, 2854m,1737s,1269s,1053w,1026s; dH (400 MHz,
CDCl3) 0.86e0.96 (2H, m), 1.04e1.24 (3H, m), 1.28 (6H, t, J 7.1),
Please cite this article in press as: Lloyd, M. G.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.054

M.G. Lloyd et al. / Tetrahedron xxx (2014) 1e17
9
1.54e1.70 (6H, m), 2.91 (2H, d, J 21.6), 3.89 (2H, d, J 6.6), 4.07e4.14
4.28. 4-Nitrophenethyl 2-diazo-2-(diethoxyphosphoryl)ace-
tate (11h)
(4H, m); dC (100 MHz, CDCl3) 16.2 (d, J 6.2), 25.5, 26.1, 29.3, 34.1 (d, J
134.2), 36.8, 62.5 (d, J 6.2), 70.5, 165.7 (d, J 6.2); dP (162 MHz, CDCl3)
20.5; HRMS (ESIþ): found: 315.1338; C13H25NaO5P (MNaþ) requires
315.1332.
Synthesised using general procedure B affording the title com-
pound as a colourless oil (111 mg, 49%); Rf 0.53 (1:2 petrol/ethyl
acetate); nmax (thin film)/cmꢂ1 2099s, 1681s, 1497s, 1326s, 1261s,
1006m; dH (400 MHz, CDCl3) 1.32 (6H, td, J 7.1, 0.8), 3.09 (2H, t, J
6.6), 4.05e4.23 (4H, m), 4.45 (2H, t, J 6.6), 7.40 (2H, d, J 8.8), 8.18 (2H,
d, J 8.8); dC (100 MHz, CDCl3) 16.1 (d, J 6.8), 34.9, 53.8 (d, J 228.4),
63.6 (d, J 5.7), 64.9, 123.7, 129.8, 145.1, 146.9, 163.2 (d, J 12.2); dP
(162 MHz, CDCl3) 10.3; HRMS (ESIþ): found: 394.0762;
4.24. 3,4,5-Trimethoxyphenethyl 2-diazo-2-(diethox-
yphosphoryl)acetate (11c)
Synthesised using general procedure B affording the title com-
pound as a yellow oil (202 mg, 54%); Rf 0.21 (1:1 hexane/ethyl ac-
etate); nmax (thin film)/cmꢂ1 2983w, 2940w, 2841w, 2125s, 1704s,
1590s, 1508m, 1459s, 1422m, 1389m, 1352w, 1274s, 1238s, 1155w,
1124s, 1012s, 977s, 815m, 745m, 589m, 559m; dH (400 MHz, CDCl3)
1.29 (6H, td, J 7.1, 0.7), 2.87 (2H, t, J 6.9), 3.77 (3H, s), 3.80 (6H, s),
4.02e4.19 (4H, m), 4.36 (2H, t, J 6.9), 6.38 (2H, s); dC (100 MHz,
CDCl3) 16.0 (d, J 6.9), 35.4, 53.5 (d, J 227.1), 55.9, 60.6, 63.5 (d, J 5.6),
65.9, 105.6, 132.8, 136.6, 153.1, 163.1 (d, J 12.5); dP (162 MHz, CDCl3)
10.4; HRMS (ESIþ): found: 439.1234; C17H25N2NaO8P (MNaþ) re-
quires 439.1241.
C
14H18N3NaO7P (MNaþ) requires 394.9775.
4.29. 4-(Dimethylamino)phenethyl 2-diazo-2-(diethox-
yphosphoryl)acetate (11i)
Synthesised using general procedure B affording the title com-
pound as a yellow oil (327 mg, 30%); Rf 0.48 (1:1 petrol/ethyl ace-
tate); nmax (thin film)/cmꢂ1 2985w, 2128s, 1704s, 1616w, 1523m,
1277s,1020s; dH (400 MHz, CDCl3) 1.32 (6H, td, J 7.1, 0.6), 2.85 (2H, t,
J 7.0), 2.90 (6H, s), 4.04e4.21 (4H, m), 4.33 (2H, t, J 7.0), 6.67 (2H, d, J
8.7), 7.06 (2H, d, J 8.7); dC (100 MHz, CDCl3) 15.9 (d, J 6.9), 34.0, 40.5,
53.4 (d, J 226.5), 63.4 (d, J 5.8), 66.3, 112.6, 124.8, 129.4, 149.3, 163.1
(d, J 12.3); dP (162 MHz, CDCl3) 10.6; HRMS (ESIþ): found: 392.1338;
4.25. 2-(Naphthalen-1-yl)ethyl 2-diazo-2-(diethox-
yphosphoryl)acetate (11e)
C
16H24N3NaO5P (MNaþ) requires 392.1346.
Synthesised using general procedure B affording the title com-
pound as a yellow oil (859 mg, 47%); nmax (thin film)/cmꢂ1 2984w,
2127s, 1708s, 1597w, 1511w, 1445w, 1388w, 1279s, 1215s, 1164w,
1095w, 1020s, 978m, 799m, 778m, 745w; dH (400 MHz, CDCl3) 1.32
(6H, td, J 7.1, 0.8), 3.45 (2H, t, J 7.2), 4.04e4.22 (4H, m), 4.55 (2H, t, J
7.2), 7.35e7.43 (2H, m), 7.47e7.57 (2H, m), 7.76e7.78 (1H, m),
7.85e7.88 (1H, m), 8.06e8.08 (1H, m); dC (100 MHz, CDCl3) 16.1 (d, J
6.9), 32.2, 53.5 (d, J 226.9), 63.6 (d, J 5.9), 65.5, 123.4, 125.4, 125.7,
126.3, 127.1, 127.6, 128.8, 131.9, 133.1, 133.8, 163.2 (d, J 12.2); dP
(162 MHz, CDCl3) 10.5; HRMS (ESIþ): found: 399.1075;
C18H21N2NaO5P (MNaþ) requires 399.1080.
4.30. 2-(Pyridin-3-yl)ethyl 2-diazo-2-(diethoxyphosphoryl)
acetate (11j)
Synthesised using general procedure B affording the title com-
pound as a yellow oil (497 mg, 23%); Rf 0.44 (7% MeOH in DCM);
nmax (thin film)/cmꢂ1 2939s, 2098s, 1684s, 1262s, 1104w, 1078w,
1008s, 964w; dH (400 MHz, CDCl3) 1.32 (6H, td, J 7.1, 0.8), 2.98 (2H, t,
J 6.7), 4.05e4.22 (4H, m), 4.41 (2H, t, J 6.7), 7.24 (1H, ddd, J 7.8, 4.8,
0.7), 7.56 (1H, ddd, J 7.8, 2.3, 1.7), 8.47e8.51 (2H, m); dC (100 MHz,
CDCl3) 15.8 (d, J 6.9), 32.0, 53.5 (d, J 226.1), 63.3 (d, J 5.8), 65.0, 123.1,
132.7, 136.1, 147.9, 149.9, 162.9 (d, J 12.1); dP (162 MHz, CDCl3) 10.4;
HRMS (ESIþ): found: 350.0876; C13H18N3NaO5P (MNaþ) requires
350.0876.
4.26. 4-Bromophenethyl 2-diazo-2-(diethoxyphosphoryl)ace-
tate (11f)
Synthesised using general procedure B affording the title com-
pound as a yellow oil (969 mg, 51%); Rf 0.48 (1:1 hexane/ethyl ac-
etate); nmax (thin film)/cmꢂ1 2983w, 2129s, 1708s, 1489w, 1384w,
1279s, 1216w, 1164w, 1094w, 1022s, 979m, 815w, 596w, 560w; dH
(400 MHz, CDCl3) 1.30 (6H, td, J 7.1, 0.8), 2.90 (2H, t, J 6.7), 4.02e4.19
(4H, m), 4.36 (2H, t, J 6.7), 7.07 (2H, d, J 8.5), 7.40 (2H, d, J 8.5); dC
(100 MHz, CDCl3) 16.0 (d, J 6.8), 34.5, 53.8 (d, J 228.5), 63.5 (d, J 5.8),
4.31. 2-(Thiophen-3-yl)ethyl 2-diazo-2-(diethoxyphosphoryl)
acetate (11k)
Synthesised using general procedure B affording the title com-
pound as a yellow oil (871 mg, 52%); Rf 0.43 (1:1 petrol/ethyl ace-
tate); nmax (thin film)/cmꢂ1 2989w, 2126s, 1703s, 1274s, 1017s,
977m; dH (400 MHz, CDCl3) 1.32 (6H, td, J 7.1, 0.8), 2.99 (2H, t, J 6.8),
4.05e4.22 (4H, m), 4.39 (2H, t, J 6.8), 6.95 (1H, dd, J 4.9, 1.3), 7.03
(1H, ddt, J 2.9, 1.3, 0.7), 7.25 (1H, dd, J 4.9, 2.9); dC (100 MHz, CDCl3)
16.0 (d, J 6.9), 29.5, 53.8 (d, J 228.2), 63.5 (d, J 5.6), 65.3, 121.7, 125.6,
128.1,137.4,163.3 (d, J 12.2); dP (162 MHz, CDCl3) 10.5; HRMS (ESIþ):
found: 355.0488; C12H17N2NaO5PS (MNaþ) requires 355.0488.
65.4, 120.5, 130.6, 131.5, 136.2, 163.1 (d, J 12.3); dP (162 MHz, CDCl3)
79
10.4; HRMS (ESIþ): found: 427.0038; C14
requires 427.0029.
H
BrN2NaO5P (MNaþ)
18
4.27. 4-Trifluoromethylphenethyl 2-diazo-2-(diethox-
yphosphoryl)acetate (11g)
Synthesised using general procedure B affording the title com-
pound as a pale yellow oil (386 mg, 36%); Rf 0.44 (1:1 petrol/ethyl
acetate); nmax (thin film)/cmꢂ1 2941s, 2099s, 1686s, 1308m, 1262m,
1147w, 1106w, 1051w, 1006w; dH (400 MHz, CDCl3) 1.31 (6H, td, J 7.1,
0.8), 3.03 (2H, t, J 6.7), 4.03e4.21 (4H, m), 4.43 (2H, t, J 6.7), 7.34 (2H,
d, J 8.0), 7.56 (2H, d, J 8.0); dC (100 MHz, CDCl3) 16.1 (d, J 6.8), 34.9,
53.9 (d, J 228.8), 63.6 (d, J 5.6), 65.3, 125.4 (q, J 3.8), 124.1 (q, J 271.9),
129.1 (q, J 32.3), 129.3, 141.5, 163.3 (d, J 11.6); dF (376 MHz, CDCl3)
ꢂ62.4; dP (162 MHz, CDCl3) 10.4; HRMS (ESIþ): found: 417.0779;
4.32. 3-Methylbutyl 2-diazo-2-(diethoxyphosphoryl)acetate
(11s)
Synthesised using general procedure B affording the title com-
pound as a pale yellow oil (1.18 g, 67%); Rf 0.65 (1:1 hexane/ethyl
acetate); nmax (thin film)/cmꢂ1 2960w, 2125s, 1701s, 1389w, 1272s,
1215w, 1164w, 1116w, 1091w, 1016s, 977m; dH (400 MHz, CDCl3)
0.91 (6H, d, J 6.6), 1.35 (6H, td, J 7.1, 0.8), 1.54 (2H, app. q, J 6.8),
1.62e1.75 (1H, m), 4.10e4.26 (4H, m), 4.22 (2H, t, J 6.8); dC
(100 MHz, CDCl3) 16.0 (d, J 6.9), 22.2, 24.8, 37.2, 53.5 (d, J 228.2),
C
15H18F3N2NaO5P (MNaþ) requires 417.0798.
Please cite this article in press as: Lloyd, M. G.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.054

10
M.G. Lloyd et al. / Tetrahedron xxx (2014) 1e17
63.4 (d, J 5.7), 64.1, 163.3 (d, J 12.0); dP (162 MHz, CDCl3) 10.8; HRMS
977m, 959m, 796m, 749m; dH (400 MHz, CDCl3) 1.29 (6H, td, J 7.1,
0.8), 1.49e1.86 (8H, m), 4.04e4.19 (4H, m), 5.21 (1H, tt, J 5.6, 2.7); dC
(100 MHz, CDCl3) 16.0 (d, J 7.0), 23.4, 32.6, 53.8 (d, J 227.0), 63.3 (d, J
5.6), 78.6, 163.0 (d, J 11.7); dP (162 MHz, CDCl3) 10.9; HRMS (ESIþ):
found: 313.0930; C11H19N2NaO5P (MNaþ) requires 313.0924.
(ESIþ): found: 315.1084; C11H21N2NaO5P (MNaþ) requires 315.1080.
4.33. 3,3-Dimethylbutyl 2-diazo-2-(diethoxyphosphoryl)ace-
tate (11t)
Synthesised using general procedure B affording the title com-
pound as a pale yellow oil (1.22 g, 66%); Rf 0.49 (1:1 hexane/ethyl
acetate); nmax (thin film)/cmꢂ1 2959m, 2880w, 2125s, 1702s, 1276s,
1216w, 1164w, 1119w, 1095w, 1016s, 976m; dH (400 MHz, CDCl3)
0.89 (9H, s), 1.31 (6H, td, J 7.1, 0.8), 1.54 (2H, t, J 7.4), 4.06e4.22 (4H,
m), 4.21 (2H, t, J 7.4); dC (100 MHz, CDCl3) 16.0 (d, J 6.9), 29.4, 29.6,
41.6, 53.5 (d, J 228.5), 63.3, 63.4 (d, J 5.6), 163.3 (d, J 12.3); dP
(162 MHz, CDCl3) 10.7; HRMS (ESIþ): found: 329.1223;
4.38. Cyclohexyl 2-diazo-2-(diethoxyphosphoryl)acetate (11y)
Synthesised using general procedure B affording the title com-
pound as a pale yellow oil (2.68 g, 88%); Rf 0.50 (1:1 petrol/ethyl
acetate); nmax (thin film)/cmꢂ1 2990w, 2937s, 2864m, 2124s, 1694s,
1279s, 1260s, 1115w, 1013s, 976s; dH (400 MHz, CDCl3) 1.18e1.50
(6H, m), 1.31 (6H, td, J 7.1, 0.8), 1.64e1.71 (2H, m), 1.77e1.82 (2H, m),
4.06e4.22 (4H, m), 4.84 (1H, tt, J 8.4, 4.1); dC (100 MHz, CDCl3) 16.0
(d, J 7.2), 23.2, 25.1, 31.4, 53.8 (d, J 228.0), 63.4 (d, J 5.7), 74.0, 162.8
(d, J 11.8); dP (162 MHz, CDCl3) 10.9; HRMS (ESIþ): found: 327.1082;
C
12H23N2NaO5P (MNaþ) requires 329.1237.
4.34. 3-((tert-Butyldimethylsilyl)oxy)propyl 2-diazo-2-(dieth-
C
12H21N2NaO5P (MNaþ) requires 327.1010.
oxyphosphoryl) acetate (11u)
4.39. Adamantan-1-yl 2-diazo-2-(diethoxyphosphoryl)acetate
(11z)
Synthesised using general procedure B affording the title com-
pound as a yellow oil (1.42 g, 60%); Rf 0.30 (2:1 petrol/ethyl acetate);
nmax (thin film)/cmꢂ1 2964w, 2931w, 2866w, 2128s, 1707s, 1474w,
1395w, 1281s, 1097m, 1024s, 838m, 777w; dH (400 MHz, CDCl3)
ꢂ0.05 (6H, s), 0.79 (9H, s), 1.26 (6H, td, J 7.1, 0.8), 1.77 (2H, tt, J 6.4,
6.0), 3.69 (2H, t, J 6.0), 4.02e4.17 (4H, m), 4.24 (2H, t, J 6.4); dC
(100 MHz, CDCl3) ꢂ5.7, 15.9 (d, J 6.9), 18.0, 25.6, 31.6, 53.5 (d, J
230.0), 58.8, 62.4, 63.3 (d, J 5.9),163.1 (d, J 11.6); dP (162 MHz, CDCl3)
10.6; HRMS (ESIþ): found: 417.1590; C15H31N2NaO6PSi (MNaþ) re-
quires 417.1581.
Synthesised using general procedure B affording the title com-
pound as a white solid (1.21 g, 74%); Rf 0.63 (1:1 hexane/ethyl ac-
etate); mp 51e54 ꢁC; nmax (thin film)/cmꢂ1 2912s, 2855w, 2125s,
1697s, 1457w, 1321m, 1269s, 1219w, 1164w, 1122w, 1023s, 966m; dH
(400 MHz, CDCl3) 1.30 (6H, td, J 7.1, 0.8), 1.60e1.61 (6H, m),
2.07e2.15 (9H, m), 4.05e4.20 (4H, m); dC (100 MHz, CDCl3) 16.0 (d, J
6.8), 30.7, 35.9, 41.4, 53.9 (d, J 228.4), 63.3 (d, J 5.6), 82.9, 162.0 (d, J
12.0); dP (162 MHz, CDCl3) 11.3; HRMS (ESIþ): found: 379.1384;
C
16H25N2NaO5P (MNaþ) requires 379.1393.
4.35. 4-((tert-Butyldimethylsilyl)oxy)butyl 2-diazo-2-(dieth-
oxyphosphoryl)acetate (11v)
4.40. Cycloheptyl 2-diazo-2-(diethoxyphosphoryl)acetate
(11aa)
Synthesised using general procedure B affording the title com-
pound as a yellow oil (1.05 g, 58%); Rf 0.74 (1:1 hexane/ethyl ace-
tate); nmax (thin film)/cmꢂ1 2954w, 2930w, 2857w, 2126s, 1703s,
1473w, 1389w, 1275s, 1257w, 1164w, 1095s, 1019s, 977s, 892w,
834s, 813w, 774s, 746w, 662w, 589m, 560m; dH (400 MHz, CDCl3)
ꢂ0.05 (6H, s), 0.79 (9H, s), 1.26 (6H, td, J 7.1, 0.8), 1.45e1.52 (2H, m),
1.61e1.68 (2H, m), 3.54 (2H, t, J 6.2), 4.02e4.18 (6H, m); dC
(100 MHz, CDCl3) ꢂ5.6, 15.9 (d, J 6.9), 18.0, 25.2, 25.7, 28.7, 53.5 (d, J
227.3), 62.2, 63.3 (d, J 6.0), 65.4,163.2 (d, J 11.9); dP (162 MHz, CDCl3)
10.6; HRMS (ESIþ): found: 431.1748; C16H33N2NaO6PSi (MNaþ) re-
quires 431.1738.
Synthesised using general procedure B affording the title com-
pound as a yellow oil (1.35 g, 89%); Rf 0.52 (1:1 hexane/ethyl ace-
tate); nmax (thin film)/cmꢂ1 2987w, 2930m, 2861w, 2125s, 1694s,
1446w, 1369w, 1322w, 1270s, 1215w, 1164w, 1120m, 1015s, 961s,
885w, 974m, 746s, 590s, 555s; dH (400 MHz, CDCl3) 1.26 (6H, td, J
7.1, 0.8), 1.31e1.66 (10H, m), 1.77e1.85 (2H, m), 4.01e4.17 (4H, m),
4.96 (1H, tt, J 8.1, 4.2); dC (100 MHz, CDCl3) 15.8 (d, J 7.0), 22.4, 27.9,
33.5, 53.7 (d, J 227.0), 63.2 (d, J 6.0), 76.5, 162.7 (d, J 11.9); dP
(162 MHz, CDCl3) 10.9; HRMS (ESIþ): found: 341.1226;
C
13H23N2NaO5P (MNaþ) requires 341.1237.
4.36. But-3-en-1-yl 2-diazo-2-(diethoxyphosphoryl)acetate
(11w)
4.41. 2-Methylpropyl 2-diazo-2-(diethoxyphosphoryl)acetate
(11ab)15a
Synthesised using general procedure B affording the title com-
pound as a yellow oil (790 mg, 60%); Rf 0.43 (1:1 hexane/ethyl ac-
etate); nmax (thin film)/cmꢂ1 2984w, 2126s, 1702s, 1643w, 1445w,
1384w, 1276s, 1164w, 1117w, 1092w, 1019s, 978s, 797m, 746m; dH
(400 MHz, CDCl3) 1.32 (6H, td, J 7.1, 0.8), 2.38 (2H, app. qt, J 6.7, 1.3),
4.07e4.23 (6H, m), 5.03e5.11 (2H, m), 5.74 (1H, ddt, J 17.1, 10.3, 6.7);
dC (100 MHz, CDCl3) 16.0 (d, J 6.9), 33.0, 53.7 (d, J 226.3), 63.5 (d, J
5.9), 64.5, 117.5, 133.4, 163.3 (d, J 12.1); dP (162 MHz, CDCl3) 10.6;
HRMS (ESIþ): found: 299.0768; C10H17N2NaO5P (MNaþ) requires
299.0767.
Synthesised using general procedure B affording the title com-
pound as a pale yellow oil (1.62 g, 73%); Rf 0.50 (1:1 petrol/ethyl
acetate); nmax (thin film)/cmꢂ1 2966m, 2127s, 1702s, 1276s, 1115w,
1019s, 978m; dH (400 MHz, CDCl3) 0.89 (6H, d, J 6.7), 1.31 (6H, td, J
7.1, 0.8), 1.91 (1H, app. nonet, J 6.7), 3.93 (2H, d, J 6.6), 4.06e4.22
(4H, m); dC (100 MHz, CDCl3) 16.0 (d, J 6.9), 18.7, 27.7, 53.7 (d, J
227.9), 63.4 (d, J 5.7), 71.5, 163.4 (d, J 11.9); dP (162 MHz, CDCl3) 10.8;
HRMS (ESIþ): found: 301.0913; C10H19N2NaO5P (MNaþ) requires
301.0924.
4.42. Cyclopropylmethyl 2-diazo-2-(diethoxyphosphoryl)ace-
tate (11ac)
4.37. Cyclopentyl 2-diazo-2-(diethoxyphosphoryl)acetate
(11x)
Synthesised using general procedure B affording the title com-
pound as a yellow oil (850 mg, 64%); Rf 0.43 (1:1 hexane/ethyl ac-
etate); nmax (thin film)/cmꢂ1 2986w, 2908w, 2125s, 1700s, 1446w,
1394w, 1348m, 1275s, 1216w, 1164w, 1115w, 1082w, 1018s, 977w,
958s, 796m, 746m, 590m, 560m; dH (400 MHz, CDCl3) 0.25e0.29
Synthesised using general procedure B affording the title com-
pound as a yellow oil (1.00 g, 83%); Rf 0.54 (1:1 hexane/ethyl ace-
tate); nmax (thin film)/cmꢂ1 2972m, 2875w, 2125s, 1696s, 1478w,
1443w, 1393w, 1321w, 1274s, 1218w, 1165m, 1121m, 1089w, 1018s,
Please cite this article in press as: Lloyd, M. G.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.054

M.G. Lloyd et al. / Tetrahedron xxx (2014) 1e17
11
(2H, m), 0.52e0.57 (2H, m), 1.07e1.17 (1H, m), 1.33 (6H, t, J 7.1), 4.01
(2H, d, J 7.3), 4.10e4.25 (4H, m); dC (100 MHz, CDCl3) 3.2, 9.8,16.1 (d,
J 6.9), 53.9 (d, J 226.8), 63.6 (d, J 5.6), 70.3, 163.5 (d, J 12.2); dP
(162 MHz, CDCl3) 10.6; HRMS (ESIþ): found: 299.0771;
72.0, 124.5, 122.6, 125.0, 125.5, 126.1, 126.7, 128.5, 129.3, 131.0, 134.2,
135.6, 137.6, 170.4; HRMS (ESIþ): found: 247.0728; C15H12NaO2
(MNaþ) requires 247.0730.
C
10H17N2NaO5P (MNaþ) requires 299.0767.
4.47. (SR)-4-(4-Bromophenyl)-3-methylenedihydrofuran-
2(3H)-one (12f)
4.43. Cyclobutylmethyl 2-diazo-2-(diethoxyphosphoryl)ace-
tate (11ad)
Synthesised using general procedure D with 4-bromophenethyl
2-diazo-2-(diethoxyphosphoryl)acetate 11f (90 mg, 0.222 mmol),
Synthesised using general procedure B affording the title com-
pound as a brown oil (949 mg, 68%); Rf 0.50 (1:1 hexane/ethyl ac-
etate); nmax (thin film)/cmꢂ1 2981w, 2942w, 2869w, 2125s, 1700s,
1445w, 1391w, 1335w, 1276s, 1216w, 1164w, 1117w, 1095w, 1019w,
977m, 797m, 747m, 590m, 560m; dH (400 MHz, CDCl3) 1.34 (6H, td,
J 7.1, 0.8), 1.72e1.97 (4H, m), 1.99e2.08 (2H, m), 2.57e2.68 (1H, m),
4.09e4.25 (6H, m); dC (100 MHz, CDCl3) 16.1 (d, J 7.0), 18.3, 24.5,
34.0, 53.8 (d, J 228.6), 63.5 (d, J 5.9), 69.2, 163.6 (d, J 12.0); dP
(162 MHz, CDCl3) 10.8; HRMS (ESIþ): found: 313.0917;
DCM (4.4 mL), Rh2(oct)4 (3.5 mg, 4.4 mmol), THF (4.4 mL), KOBu-t
(37.4 mg, 0.333 mmol) and paraformaldehyde (13.3 mg,
0.444 mmol). The HWE was performed at rt. Purification by column
chromatography (8:1 hexane/ethyl acetate) afforded the title com-
pound as a pale yellow oil (31 mg, 55%); Rf 0.40 (4:1 hexane/ethyl
acetate); nmax (thin film)/cmꢂ1 2972w, 2913w, 1761s,1666w, 1590w,
1489m, 1412m, 1274w, 1231m, 1107s, 1010s, 947w, 825s; dH
(400 MHz, CDCl3) 4.17e4.27 (2H, m), 4.71 (1H, app. t, J 8.4), 5.48
(1H, d, J 2.7), 6.39 (1H, d, J 3.0), 7.11 (2H, d, J 8.5), 7.50 (2H, d, J 8.5); dC
(100 MHz, CDCl3) 45.1, 72.3, 121.8, 124.3, 129.5, 132.3, 138.3, 138.5,
169.8; HRMS (ESIþ): found: 274.9679; C11H799BrNaO2 (MNaþ) re-
quires 274.9678.
C
11H19N2NaO5P (MNaþ) requires 313.0924.
4.44. Cyclohexylmethyl 2-diazo-2-(diethoxyphosphoryl)ace-
tate (11af)
4.48. (SR)-3-Methylene-4-(4-(trifluoromethyl)phenyl)dihy-
drofuran-2(3H)-one (12g)
Synthesised using general procedure B with NaH (1.2 equiv, 60%
dispersion in mineral oil) in place of LHMDS affording the title
compound as a yellow oil (410 mg, 68%); Rf 0.85 (ethyl acetate); nmax
(thin film)/cmꢂ1 2930s, 2131s, 1705s, 1280s, 1024s; dH (400 MHz,
CDCl3) 0.93e1.04 (2H, m), 1.11e1.30 (3H, m), 1.36 (6H, td, J 7.1, 0.8),
1.55e1.77 (6H, m), 4.01 (2H, d, J 6.5), 4.11e4.27 (4H, m); dC
(100 MHz, CDCl3) 16.0 (d, J 7.1), 25.5, 26.2, 29.3, 37.1, 53.7 (d, J 227.4),
63.5 (d, J 5.6), 70.6, 163.5 (d, J 12.0); dP (162 MHz, CDCl3) 10.9; HRMS
(ESIþ): found: 341.1228; C13H23N2NaO5P (MNaþ) requires 341.1237.
Synthesised
using
general
procedure
D
with
4-
trifluoromethylphenethyl 2-diazo-2-(diethoxyphosphoryl)acetate
11g (83 mg, 0.162 mmol), DCM (4.2 mL), Rh2(oct)4 (3.3 mg,
4.2 mmol), KOBu-t (28.4 mg, 0.253 mmol) and paraformaldehyde
(12.7 mg, 0.422 mmol). The HWE was performed at 0 ꢁC. Purifica-
tion by column chromatography (4:1 hexane/ethyl acetate) affor-
ded the title compound as a colourless oil (15 mg, 29%); Rf 0.59 (2:1
petrol/ethyl acetate); nmax (thin film)/cmꢂ1 2875w, 1741s, 1307s,
1097m, 1053w; dH (400 MHz, CDCl3) 4.24 (1H, dd, J 9.0, 7.1),
4.33e4.38 (1H, m), 4.75 (1H, app. t, J 9.0), 5.50 (1H, d, J 2.9), 6.44
(1H, d, J 2.9), 7.37 (2H, d, J 8.0), 7.65 (2H, d, J 8.0); dC (100 MHz,
CDCl3) 45.3, 72.2,123.8 (q, J 272.2),124.7,126.2 (q, J 3.8),128.3,130.2
(q, J 32.1), 138.1, 143.7, 169.6; dF (376 MHz, CDCl3) ꢂ62.6; HRMS
(ESIþ): found: 265.0447; C12H9F3NaO2 (MNaþ) requires 265.0447.
4.45. (SR)-3-Methylene-4-(3,4,5-trimethoxyphenyl)dihy-
drofuran-2(3H)-one (12c)
Synthesised using general procedure
trimethoxyphenethyl 2-diazo-2-(diethoxyphosphoryl)acetate 11c
(77 mg, 0.185 mmol), DCM (3.7 mL), Rh2(oct)4 (2.9 mg, 3.7 mol),
D
with 3,4,5-
m
THF (3.7 mL), KOBu-t (31.1 mg, 0.278 mmol) and paraformaldehyde
(11.1 mg, 0.370 mmol). The HWE was performed at rt. Purification
by column chromatography (2:1 hexane/ethyl acetate) afforded the
title compound as a colourless oil (22 mg, 45%); Rf 0.26 (2:1 hexane/
ethyl acetate); nmax (thin film)/cmꢂ1 2937w, 1763s, 1660w, 1591m,
1509m, 1461m, 1425m, 1347w, 1242m, 1124s, 1013m; dH (400 MHz,
CDCl3) 3.83 (3H, s), 3.84 (6H, s), 4.17e4.24 (2H, m), 4.68e4.75 (1H,
m), 5.56 (1H, d, J 2.6), 6.40e6.41 (3H, m); dC (100 MHz, CDCl3) 45.9,
56.2, 60.8, 72.7, 104.7, 124.3, 135.2, 137.4, 138.5, 153.7, 170.1; HRMS
(ESIþ): found: 287.0892; C14H16NaO5 (MNaþ) requires 287.0890.
4.49. (SR)-3-Methylene-4-(4-nitrophenyl)dihydrofuran-
2(3H)-one (12h)
Synthesised using general procedure C with 4-nitrophenethyl 2-
diazo-2-(diethoxyphosphoryl)acetate 11h (37 mg, 0.100 mmol),
DCM (2.0 mL), Rh2(esp)2 (3.8 mg, 5.0
mmol), KOBu-t (10.1 mg,
0.090 mmol) and paraformaldehyde (30.0 mg, 0.997 mmol). The
HWE was performed at 0 ꢁC. Purification by column chromatog-
raphy (2:1 petrol/ethyl acetate) afforded the title compound as
a colourless oil (4 mg, 18%); Rf 0.58 (1:1 petrol/ethyl acetate); nmax
(thin film)/cmꢂ1 2878s, 2809s,1737s,1575w,1496m,1327m,1092w,
1004w, 843w; dH (400 MHz, CDCl3) 4.27 (1H, dd, J 9.1, 6.8),
4.39e4.45 (1H, m), 4.78 (1H, app. t, J 9.1), 5.53 (1H, d, J 2.7), 6.48
(1H, d, J 3.1), 7.44 (2H, d, J 8.8), 8.26 (2H, d, J 8.8); dC (100 MHz,
CDCl3) 45.2, 71.9, 124.5, 125.1, 128.8, 137.7, 147.0, 147.6, 169.2; HRMS
(ESIþ): found: 242.0427; C11H9NNaO4 (MNaþ) requires 242.0424.
4.46. (SR)-3-Methylene-4-(naphthalen-1-yl)dihydrofuran-
2(3H)-one (12e)
Synthesised using general procedure D with 2-(naphthalen-1-
yl)ethyl 2-diazo-2-(diethoxyphosphoryl)acetate 11e (82 mg,
0.218 mmol), DCM (4.4 mL), Rh2(oct)4 (3.4 mg, 4.4
mmol), THF
(4.4 mL), KOBu-t (36.7 mg, 0.327 mmol) and paraformaldehyde
(13.1 mg, 0.436 mmol). The HWE was performed at rt. Purification
by column chromatography (4:1 hexane/ethyl acetate) afforded the
title compound as a colourless oil (28 mg, 57%); Rf 0.45 (4:1 hexane/
ethyl acetate); nmax (thin film)/cmꢂ1 3050w, 2918w, 1759s, 1662w,
1598w, 1511w, 1398m, 1261w, 1230w, 1111s, 1022m, 948w, 802m,
780s; dH (400 MHz, CDCl3) 4.36 (1H, dd, J 9.0, 6.3), 4.89 (1H, app. t, J
9.0), 5.03e5.08 (1H, m), 5.60 (1H, d, J 2.7), 6.51 (1H, d, J 3.0),
7.38e7.40 (1H, m), 7.47 (1H, app. t, J 7.7), 7.53e7.60 (2H, m),
7.81e7.88 (2H, m), 7.91e7.95 (1H, m); dC (100 MHz, CDCl3) 41.6,
4.50. (SR)-3-Methylene-4-(thiophen-3-yl)dihydrofuran-
2(3H)-one (12k)
Synthesised using general procedure C with 2-(thiophen-3-yl)
ethyl 2-diazo-2-(diethoxyphosphoryl)acetate 11k (69 mg,
0.208 mmol), DCM (4.2 mL), Rh2(oct)4 (3.2 mg, 4.2 mmol), KOBu-t
(28.0 mg, 0.250 mmol) and paraformaldehyde (12.5 mg,
0.416 mmol). The HWE was performed at 0 ꢁC. Purification by
column chromatography (5:1 petrol/ethyl acetate) afforded the title
Please cite this article in press as: Lloyd, M. G.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.054

12
M.G. Lloyd et al. / Tetrahedron xxx (2014) 1e17
compound as a colourless oil (12 mg, 32%); Rf 0.59 (2:1 petrol/ethyl
acetate); nmax (thin film)/cmꢂ1 3110w, 2910w, 1761s, 1404w, 1250m,
1109m, 1018m; dH (400 MHz, CDCl3) 4.23 (1H, dd, J 8.9, 7.3),
4.38e4.44 (1H, m), 4.68 (1H, app. t, J 8.9), 5.56 (1H, d, J 2.8), 6.38
(1H, d, J 3.1), 6.95 (1H, dd, J 5.0, 1.4), 7.15 (1H, ddd, J 3.0, 1.4, 0.5), 7.38
(1H, dd, J 5.0, 3.0); dC (100 MHz, CDCl3) 41.0, 71.9, 122.6, 123.8, 126.1,
127.4, 138.1, 139.4, 170.0; HRMS (ESIþ): found: 203.0134;
C9H8NaO2S (MNaþ) requires 203.0137.
123.2, 135.6, 170.6; HRMS (ESIþ): found: 265.1223; C12H22NaO3Si
(MNaþ) requires 265.1230.
4.53.2. Data for 16a. Rf 0.60 (4:1 hexane/ethyl acetate); nmax (thin
film)/cmꢂ1 2955m, 2930m, 2858m, 1826s, 1472w, 1408w, 1362w,
1257m, 1208w, 1099s, 1049m, 946w, 834s, 778m; dH (400 MHz,
CDCl3) 0.07 (3H, s), 0.07 (3H, s), 0.90 (9H, s), 2.00e2.09 (2H, m), 3.80
(2H, app. dd, J 6.6, 5.2), 5.16 (1H, app. ddt, J 7.5, 5.7, 1.8), 5.47 (1H,
app. t, J 1.7), 5.93 (1H, app. t, J 1.9); dC (100 MHz, CDCl3) ꢂ5.5, ꢂ5.4,
18.3, 25.9, 36.5, 58.6, 77.1, 115.3, 146.4, 163.6; HRMS (ESIþ): found:
265.1227; C12H22NaO3Si (MNaþ) requires 265.1230.
4.51. (SR)-4-Isopropyl-3-methylenedihydrofuran-2(3H)-one
(12s)
Synthesised using general procedure D with 3-methylbutyl 2-
diazo-2-(diethoxyphosphoryl)acetate 11s (56 mg, 0.191 mmol),
4.54. (SR)-4-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-3-
methylenedihydrofuran-2(3H)-one (12v)
DCM (3.8 mL), Rh2(oct)4 (3.0 mg, 3.8 mmol), THF (3.8 mL), KOBu-t
(25.7 mg, 0.229 mmol) and paraformaldehyde (11.5 mg,
0.382 mmol). The HWE was performed at 0 ꢁC. Purification by
column chromatography (8:1 pentane/ether) afforded the title
compound as a colourless oil (15 mg, 56%); Rf 0.30 (8:1 pentane/
ether); nmax (thin film)/cmꢂ1 2963m, 1762s, 1409w, 1267w, 1117m,
1039w, 979w; dH (400 MHz, CDCl3) 0.92 (3H, d, J 6.8), 0.95 (3H, d, J
6.8), 1.87e1.99 (1H, m), 2.93e2.99 (1H, m), 4.16 (1H, dd, J 9.3, 4.0),
4.35 (1H, dd, J 9.3, 8.1), 5.62 (1H, d, J 2.2), 6.34 (1H, d, J 2.5); dC
(100 MHz, CDCl3) 17.7, 19.1, 31.4, 44.6, 68.3, 123.1, 136.9, 171.2;
HRMS (ESIþ): found: 163.0722; C8H12NaO2 (MNaþ) requires
163.0730.
Synthesised using general procedure D with 4-((tert-butyldi-
methylsilyl)oxy)butyl 2-diazo-2-(diethoxyphosphoryl)acetate 11v
(87 mg, 0.213 mmol), DCM (4.2 mL), Rh2(oct)4 (3.3 mg, 4.2 mol),
THF (4.2 mL), KOBu-t (35.9 mg, 0.320 mmol) and paraformaldehyde
(12.8 mg, 0.426 mmol). The HWE was performed at rt. Purification
by column chromatography (4:1 hexane/ethyl acetate) afforded the
title compound as a colourless oil (27 mg, 49%); Rf 0.50 (4:1 hexane/
ethyl acetate); nmax (thin film)/cmꢂ1 2954m, 2929m, 2857m, 1767s,
1472w, 1257s, 1103s, 1020m, 940w, 836s, 777m; dH (400 MHz,
CDCl3) 0.05 (3H, s), 0.05 (3H, s), 0.89 (9H, s), 1.72 (1H, dddd, J 14.0,
9.1, 7.5, 5.1), 1.91 (1H, app. ddt, J 14.0, 5.7, 4.9), 3.17e3.26 (1H, m),
3.65e3.76 (2H, m), 4.07 (1H, dd, J 9.1, 6.1), 4.51 (1H, dd, J 9.1, 8.4),
5.60 (1H, d, J 2.6), 6.27 (1H, d, J 2.9); dC (100 MHz, CDCl3) ꢂ5.5, ꢂ5.5,
18.2, 25.8, 36.3, 36.8, 60.5, 71.7, 121.7, 138.4, 170.8; HRMS (ESIþ):
found: 279.1393; C13H24NaO3Si (MNaþ) requires 279.1387.
4.52. (SR)-4-(tert-Butyl)-3-methylenedihydrofuran-2(3H)-one
(12t)
Synthesised using general procedure D with 3,3-dimethylbutyl
2-diazo-2-(diethoxyphosphoryl)acetate 11t (58 mg, 0.189 mmol),
DCM (3.8 mL), Rh2(oct)4 (3.0 mg, 3.8 mmol), THF (3.8 mL), KOBu-t
4.55. (SR)-3-Methylene-4-vinyldihydrofuran-2(3H)-one
(12w)30 and 3-methyl-4-vinylfuran-2(5H)-one (17)23
(25.5 mg, 0.227 mmol) and paraformaldehyde (11.4 mg,
0.378 mmol). The HWE was performed at 0 ꢁC. Purification by
column chromatography (8:1 pentane/ether) afforded the title
compound as a colourless oil (10 mg, 34%); Rf 0.24 (8:1 pentane/
ether); nmax (thin film)/cmꢂ1 2962m, 1765s, 1492w, 1401w, 1364w,
1274m, 1250w, 1119m, 1041w, 969w, 822w; dH (400 MHz, CDCl3)
0.94 (9H, s), 2.74e2.78 (1H, m), 4.26e4.34 (2H, m), 5.66 (1H, dd, J
1.9, 0.7), 6.38 (1H, d, J 2.1); dC (100 MHz, CDCl3) 26.3, 33.5, 49.1, 67.8,
124.5, 136.2, 171.3; HRMS (ESIþ): found: 177.0878; C9H14NaO2
(MNaþ) requires 177.0886.
Synthesised using general procedure D with but-3-en-1-yl 2-
diazo-2-(diethoxyphosphoryl)acetate 11w (58 mg, 0.210 mmol),
DCM (4.2 mL), Rh2(oct)4 (3.3 mg, 4.2 mmol), THF (4.2 mL), KOBu-t
(35.3 mg, 0.315 mmol) and paraformaldehyde (12.6 mg,
0.420 mmol). The HWE was performed at rt. Purification by column
chromatography (8:1 pentane/ether) afforded the title compounds
3-methylene-4-vinyldihydrofuran-2(3H)-one 12w as a colourless
oil (10 mg, 38%) and 3-methyl-4-vinylfuran-2(5H)-one 17 as a col-
ourless oil (2.3 mg, 9%).
4.53. (SR)-4-(((tert-Butyldimethylsilyl)oxy)methyl)-3-
methylenedihydrofuran-2(3H)-one (12u) and (SR)-4-(2-((tert-
butyldimethylsilyl)oxy)ethyl)-3-methyleneoxetan-2-one (16a)
4.55.1. Data for 12w.31 Rf 0.54 (4:1 pentane/ether); nmax (thin film)/
cmꢂ1 2965, 2919, 2851, 1766, 1238, 1112; dH (400 MHz, CDCl3)
3.68e3.76 (1H, m), 4.02 (1H, dd, J 9.1, 7.4), 4.53 (1H, app. t, J 9.0),
5.23e5.28 (2H, m), 5.62 (1H, d, J 2.8), 5.71 (1H, ddd, J 16.6, 10.4, 8.2),
6.33 (1H, d, J 3.2); dC (100 MHz, CDCl3) 44.0, 70.0,119.2, 123.4, 135.0,
137.0, 170.1; HRMS (ESIþ): found: 147.0411; C7H8NaO2 (MNaþ) re-
quires 147.0417.
Synthesised using general procedure D with 3-((tert-butyldi-
methylsilyl)oxy)propyl
11u (83 mg, 0.210 mmol), DCM (4.2 mL), Rh2(oct)4 (3.3 mg,
4.2 mol), THF (4.2 mL), KOBu-t (35.3 mg, 0.315 mmol) and para-
2-diazo-2-(diethoxyphosphoryl)acetate
m
formaldehyde (12.6 mg, 0.420 mmol). The HWE was performed at
rt. Purification by column chromatography (8:1 hexane/ethyl ace-
tate) afforded the title compounds 4-(((tert-butyldimethylsilyl)oxy)
methyl)-3-methylenedihydrofuran-2(3H)-one 12u (9 mg, 18%) and
4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-methyleneoxetan-2-
one 16a (8 mg, 16%) as colourless oils.
4.55.2. Data for 17.23 Rf 0.29 (4:1 pentane/ether); nmax (thin film)/
cmꢂ1 2925, 2855, 1752, 1663, 1432, 1337, 1208, 1077, 1045; dH
(400 MHz, CDCl3) 1.94 (3H, s), 4.88e4.89 (2H, m), 5.49e5.56 (2H,
m), 6.72 (1H, dd, J 17.8, 11.0); dC (100 MHz, CDCl3) 8.8, 69.2, 121.0,
124.3, 126.9, 152.0, 178.1; HRMS (ESIþ): found: 147.0417; C7H8NaO2
(MNaþ) requires 147.0417.
4.53.1. Data for 12u. Rf 0.49 (4:1 hexane/ethyl acetate); nmax (thin
film)/cmꢂ1 2955m, 2930m, 2857m, 1766s, 1663w, 1472m, 1408w,
1362w, 1258m, 1115s, 1039m, 1004m, 940w, 837s, 815w, 778m; dH
(400 MHz, CDCl3) 0.05 (3H, s), 0.05 (3H, s), 0.88 (9H, s), 3.20e3.27
(1H, m), 3.65 (1H, dd, J 9.9, 7.2), 3.72 (1H, dd, J 9.9, 5.9), 4.21 (1H, dd,
J 9.3, 4.3), 4.42 (1H, dd, J 9.3, 8.2), 5.69 (1H, d, J 2.2), 6.31 (1H, d, J
2.5); dC (100 MHz, CDCl3) ꢂ5.6, ꢂ5.5, 18.2, 25.7, 41.2, 64.8, 68.4,
4.56. 3-Methylene-1-oxaspiro[3.5]nonan-2-one (16b),31 (3aS-
R,7aRS)-3-methylenehexahydrobenzofuran-2(3H)-one (trans-
12y)32 and (3aRS,7aRS)-3-methylenehexahydrobenzofuran-
2(3H)-one (cis-12y)32
Synthesised using general procedure C with cyclohexyl 2-diazo-
2-(diethoxyphosphoryl)acetate 11y (84 mg, 0.276 mmol), DCM
Please cite this article in press as: Lloyd, M. G.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.054

M.G. Lloyd et al. / Tetrahedron xxx (2014) 1e17
13
(5.4 mL), Rh2(oct)4 (4.3 mg, 0.006 mmol), KOBu-t (37.2 mg,
0.331 mmol) and paraformaldehyde (16.6 mg, 0.552 mmol). The
HWE was performed at 0 ꢁC. Purification by column chromatog-
raphy (20:1 hexane/ethyl acetate) afforded the title compounds
(18 mg, 43%) (16b/trans-12y/cis-12y 6:10:1); HRMS (ESIþ): found:
175.0726; C9H12NaO2 (MNaþ) requires 175.0730. Small quantities of
each compound were isolated separately for characterisation
purposes.
2.12e2.20 (1H, m), 2.33e2.42 (1H, m), 2.73e2.81 (1H, m), 4.15 (1H,
ddd, J 10.6, 9.3, 4.4), 5.46 (1H, d, J 3.2), 6.18 (1H, d, J 3.5); dC
(100 MHz, CDCl3) 25.1, 25.3, 27.3, 28.0, 33.0, 45.6, 83.3, 119.6, 141.0,
170.5; HRMS (ESIþ): found: 189.0889; C10H14NaO2 (MNaþ) requires
189.0886.
4.58.2. Data for cis-12aa.35 Rf 0.43 (4:1 hexane/ethyl acetate); dH
(400 MHz, CDCl3) 1.17e1.97 (9H, m), 2.03e2.09 (1H, m), 3.19e3.27
(1H, m), 4.71 (1H, ddd, J 10.6, 8.6, 3.6), 5.55 (1H, d, J 2.7), 6.27 (1H, d,
J 3.1); dC (100 MHz, CDCl3) 24.2, 27.4, 30.6, 31.2, 31.8, 43.1, 82.3,
122.0, 140.3, 170.4.
4.56.1. Data for 16b.32 Rf 0.70 (4:1 hexane/ethyl acetate); nmax (thin
film)/cmꢂ1 2937, 2861, 1814, 1450, 1177, 1107, 1011; dH (400 MHz,
CDCl3) 1.41e1.96 (10H, m), 5.41 (1H, d, J 1.9), 5.80 (1H, d, J 1.9); dC
(100 MHz, CDCl3) 23.0, 24.6, 34.5, 87.2, 113.0, 150.1, 163.8.
4.59. 4,4-Dimethyl-3-methylenedihydrofuran-2(3H)-one
(12ab)24
4.56.2. Data for trans-12y.33 Rf 0.65 (4:1 hexane/ethyl acetate);
nmax (thin film)/cmꢂ1 2940, 2864, 1770, 1251, 1132, 1026, 996; dH
(400 MHz, CDCl3) 1.32e1.44 (3H, m), 1.57e1.67 (1H, m), 1.83e1.87
(1H, m), 1.95e1.98 (1H, m), 2.11e2.15 (1H, m), 2.24e2.29 (1H, m),
2.37e2.44 (1H, m), 3.71 (1H, ddd, J 11.5, 10.8, 3.7), 5.38 (1H, d, J 3.1),
6.06 (1H, d, J 3.3); dC (100 MHz, CDCl3) 24.0, 24.8, 25.8, 30.4, 48.9,
83.1, 117.1, 139.6, 170.7.
Synthesised using general procedure D with 2-methylpropyl 2-
diazo-2-(diethoxyphosphoryl)acetate 11ab (85 mg, 0.305 mmol),
DCM (6.1 mL), Rh2(oct)4 (3.4 mg, 6.1
mmol), KOBu-t (41.1 mg,
0.366 mmol) and paraformaldehyde (18.3 mg, 0.610 mmol). The
HWE was performed at 0 ꢁC. Purification by column chromatog-
raphy (8:1 hexane/ethyl acetate) afforded the title compound as
a colourless oil (9 mg, 23%); Rf 0.39 (4:1 hexane/ethyl acetate); nmax
(thin film)/cmꢂ1 2966w, 2929w, 1760s, 1668w, 1464w, 1410w,
1371w, 1294m, 1169w, 1107m, 1014m; dH (400 MHz, CDCl3) 1.26
(6H, s), 4.03 (2H, s), 5.54 (1H, s), 6.20 (1H, s); dC (100 MHz, CDCl3)
26.9, 38.9, 78.3, 119.9, 144.7, 170.8; HRMS (ESIþ): found: 127.0758;
C7H11O2 (MHþ) requires 127.0754.
4.56.3. Data for cis-12y.33 Rf 0.57 (4:1 hexane/ethyl acetate); nmax
(thin film)/cmꢂ1 2936, 2864, 1763, 1263, 1127, 965; dH (400 MHz,
CDCl3) 1.31e1.94 (8H, m), 2.99e3.05 (1H, m), 4.52e4.56 (1H, m),
5.51 (1H, d, J 2.3), 6.20 (1H, d, J 2.5); dC (100 MHz, CDCl3) 20.5, 21.1,
26.3, 28.9, 39.6, 76.9, 119.8, 139.9, 171.0.
4.57. 6-Methylene-4-oxatetracyclo[6.3.1.13,10.03,7]tridecan-5-
one (12z)
4.60. 8-Methylene-6-oxaspiro[3.4]octan-7-one (12ad)
Synthesised using general procedure D with cyclobutylmethyl
2-diazo-2-(diethoxyphosphoryl)acetate 11ad (59 mg, 0.203 mmol),
DCM (4.0 mL), Rh2(oct)4 (3.2 mg, 4.1 mmol), THF (4.0 mL), KOBu-t
Synthesised using general procedure D with adamantan-1-yl 2-
diazo-2-(diethoxyphosphoryl)acetate 11z (75 mg, 0.210 mmol),
DCM (4.2 mL), Rh2(oct)4 (3.3 mg, 4.2 mmol), THF (4.2 mL), KOBu-t
(34.2 mg, 0.305 mmol) and paraformaldehyde (12.2 mg,
0.406 mmol). The HWE was performed at rt. Purification by column
chromatography (4:1 hexane/ethyl acetate) afforded the title com-
pound as a colourless oil (22 mg, 78%); Rf 0.42 (4:1 hexane/ethyl
acetate); nmax (thin film)/cmꢂ1 2935w, 1760s, 1662w, 1408w,
1296m,1117m,1005m, 942w, 814w; dH (400 MHz, CDCl3) 1.95e2.04
(2H, m), 2.18e2.30 (4H, m), 4.32 (2H, s), 5.80 (1H, s), 6.26 (1H, s); dC
(100 MHz, CDCl3) 15.3, 34.5, 44.5, 78.1, 119.9, 143.1, 169.8; HRMS
(ESIþ): found: 161.0571; C8H10NaO2 (MNaþ) requires 161.0573.
(35.3 mg, 0.315 mmol) and paraformaldehyde (12.6 mg,
0.420 mmol). The HWE was performed at rt. Purification by column
chromatography (4:1 hexane/ethyl acetate) afforded the title com-
pound as a white solid (34 mg, 79%); Rf 0.47 (4:1 hexane/ethyl ac-
etate); mp 88e90 ꢁC; nmax (thin film)/cmꢂ1 2921s, 2856m, 1967w,
1764s, 1675w, 1451w, 1279w, 1262m, 1242w, 1211m, 1151m, 1042s,
949s; dH (400 MHz, CDCl3) 1.57e1.89 (8H, m), 1.99e2.15 (3H, m),
2.30e2.35 (1H, m), 2.44e2.48 (1H, m), 2.81e2.84 (1H, m), 5.36 (1H,
d, J 3.2), 6.14 (1H, d, J 3.4); dC (100 MHz, CDCl3) 29.2, 29.2, 29.6, 30.9,
35.8, 37.6, 39.8, 41.1, 53.5, 80.4, 117.4, 138.6, 170.8; HRMS (ESIþ):
found: 227.1050; C13H16NaO2 (MNaþ) requires 227.1043.
4.61. 4-Methylene-2-oxaspiro[4.5]decan-3-one (12af)
Synthesised using general procedure D with cyclohexylmethyl
2-diazo-2-(diethoxyphosphoryl)acetate 11af (57 mg, 0.179 mmol),
DCM (3.6 mL), Rh2(oct)4 (2.8 mg, 3.6 mmol), THF (3.6 mL), KOBu-t
4.58. (3aSR,8aRS)-3-Methyleneoctahydro-2H-cyclohepta[b]fu-
ran-2-one (trans-12aa)33 and (3aRS,8aRS)-3-
methyleneoctahydro-2H-cyclohepta[b]furan-2-one (cis-
12aa)34
(30.2 mg, 0.269 mmol) and paraformaldehyde (10.8 mg,
0.358 mmol). The HWE was performed at rt. Purification by column
chromatography (4:1 hexane/ethyl acetate) afforded the title com-
pound as a colourless oil (15 mg, 50%); Rf 0.63 (4:1 hexane/ethyl
acetate); nmax (thin film)/cmꢂ1 2926m, 2854w, 1759s, 1661w,
1451m, 1407w, 1305m, 1254m, 1113s, 1013s, 943m, 815m; dH
(400 MHz, CDCl3) 1.24e1.75 (10H, m), 4.15 (2H, s), 5.54 (1H, s), 6.22
(1H, s); dC (100 MHz, CDCl3) 22.5, 25.0, 36.2, 42.4, 75.3, 120.7, 144.4,
171.3; HRMS (ESIþ): found: 189.0891; C10H14NaO2 (MNaþ) requires
189.0886.
Synthesised using general procedure D with cycloheptyl 2-
diazo-2-(diethoxyphosphoryl)acetate 11aa (72 mg, 0.226 mmol),
DCM (4.5 mL), Rh2(oct)4 (3.5 mg, 4.5 mmol), THF (4.5 mL), KOBu-t
(38.0 mg, 0.339 mmol) and paraformaldehyde (13.6 mg,
0.452 mmol). The HWE was performed at rt. Purification by column
chromatography (4:1 hexane/ethyl acetate) afforded the title com-
pounds as mixture of trans and cis isomers (trans-12aa/cis-12aa
3.5:1) (19 mg, 51%). A small quantity of the major (trans) compound
was separated for characterisation. The minor (cis) compound was
characterised from a mixture.
4.62. 1,1,2-Triphenylethyl 2-diazo-2-(diethoxyphosphoryl)ac-
etate (14a)
4.58.1. Data for trans-12aa.34 Colourless oil; Rf 0.50 (4:1 hexane/
ethyl acetate); nmax (thin film)/cmꢂ1 2929, 2861, 1761, 1667, 1454,
1400, 1313, 1262, 1246, 998; dH (400 MHz, CDCl3) 1.40e1.82 (8H, m),
Procedure for Grignard addition followed according to the lit-
erature procedure.35 To benzylmagnesium chloride solution
Please cite this article in press as: Lloyd, M. G.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.054

14
M.G. Lloyd et al. / Tetrahedron xxx (2014) 1e17
(20 mL, 40 mmol, 2 M in THF) cooled to 0 ꢁC under argon was added
benzophenone (5.47 g, 30 mmol). After 2 h stirring at rt a further
addition of benzylmagnesium chloride (10 mL, 20 mmol) was
made. The suspension was stirred overnight at rt. The suspension
was quenched with satd aq NH4Cl. The organic layer was removed
and the aqueous extracted with ethyl acetate (3ꢃ25 mL). The
combined organic extracts were dried over MgSO4 and concen-
trated in vacuo to afford the crude product as a white powder
(9.03 g). A portion of the crude material (3.35 g) was taken forward
to the following step without further purification. To a solution of
the crude material in toluene (60 mL) under argon was added se-
quentially diethyl phosphonoacetic acid (2.06 mL, 12.8 mmol),
DIPEA (5.52 mL, 31.7 mmol) and propyl phosphonic anhydride
(10.1 g, 15.8 mmol, 50% w/w solution in ethyl acetate). The solution
was stirred at 50 ꢁC for 1.5 h. The solution was diluted with water
(50 mL) and extracted with ethyl acetate (3ꢃ25 mL) followed by
sequential washing of the combined organic extracts with 10%
aq HCl (10 mL), satd aq NaHCO3 (10 mL) and brine (10 mL), dried
over MgSO4 and concentrated in vacuo to afford and dark orange oil
(4.60 g) as crude. Purification by column chromatography (1:2
petrol/ethyl acetate) afforded 1,1,2-triphenylethyl 2-(diethox-
yphosphoryl)acetate as a colourless oil (389 mg, 8% over two steps);
Rf 0.25 (1:2 petrol/ethyl acetate); nmax (thin film)/cmꢂ1 2937s,
1711s, 1251s, 1218w, 1012s; dH (400 MHz, CDCl3) 1.25 (6H, td, J 7.1,
0.3), 2.94 (2H, d, J 21.5), 4.02e4.13 (6H, m), 6.60e6.65 (2H, m),
7.06e7.18 (3H, m), 7.20e7.35 (10H, m); dC (100 MHz, CDCl3) 16.2 (d,
J 6.3), 35.2 (d, J 134.4), 42.7, 62.4 (d, J 6.2), 87.6, 126.3, 126.4, 127.1,
127.5, 127.8, 130.4, 135.3, 143.9, 163.8 (d, J 6.4); dP (162 MHz, CDCl3)
20.3; HRMS (ESIþ): found: 475.1636; C26H29NaO5P (MNaþ) requires
475.1645. 1,1,2-Triphenylethyl 2-(diethoxyphosphoryl)acetate
(308 mg, 0.681 mmol) was then treated under the conditions of
4.64. (SR,Z)-3-(4-Nitrobenzylidene)-4-phenyldihydrofuran-
2(3H)-one (Z-18h) and (SR,E)-3-(4-nitrobenzylidene)-4-
phenyldihydrofuran-2(3H)-one (E-18h)
Synthesised using general procedure D with phenethyl 2-diazo-
2-(diethoxyphosphoryl)acetate 11d (75 mg, 0.230 mmol), DCM
(4.6 mL), Rh2(oct)4 (3.6 mg, 4.6
mmol), THF (4.6 mL), KOBu-t
(38.7 mg, 0.345 mmol) and 4-nitrobenzaldehyde (69.5 mg,
0.460 mmol). The HWE was performed at 0 ꢁC. Purification by
column chromatography (10:1 hexane/ethyl acetate) afforded the
title compounds as mixture of (Z) and (E) isomers (Z-18h/E-18h 1:1)
(44 mg, 65%). Small quantities of each compound were isolated
separately for characterisation purposes.
4.64.1. Data for Z-18h. Pale yellow oil; Rf 0.40 (4:1 hexane/ethyl
acetate); nmax (thin film)/cmꢂ1 2920w, 1754s, 1597w, 1518s, 1345s,
1161s, 1074w, 1023w; dH (400 MHz, CDCl3) 4.39 (1H, app. t, J 8.0),
4.45 (1H, app. td, J 7.8, 2.7), 4.78 (1H, app. t, J 8.4), 6.72 (1H, d, J 2.7),
7.30e7.32 (2H, m), 7.35e7.39 (1H, m), 7.41e7.46 (2H, m), 7.88 (2H, d,
J 8.9), 8.19 (2H, d, J 8.9); dC (100 MHz, CDCl3) 48.8, 72.4, 123.2, 128.2,
128.2, 129.5, 131.3, 133.2, 138.5, 139.2, 139.3, 147.8, 168.0; HRMS
(ESIþ): found: 318.0749; C17H13NNaO4 (MNaþ) requires 318.0737.
4.64.2. Data for E-18h. Pale yellow oil; Rf 0.32 (4:1 hexane/ethyl
acetate); nmax (thin film)/cmꢂ1 2923w, 2854w, 1755s, 1691w,
1653w, 1598m, 1518s, 1343s, 1300w, 1226m, 1173s, 1021w; dH
(400 MHz, CDCl3) 4.33 (1H, dd, J 8.9, 3.5), 4.61 (1H, app. dt, J 8.1, 3.0),
4.78 (1H, app. t, J 8.5), 7.17e7.19 (2H, m), 7.24e7.34 (3H, m), 7.45
(2H, d, J 8.8), 7.84 (1H, d, J 2.4), 8.08 (2H, d, J 8.8); dC (100 MHz,
CDCl3) 44.5, 73.8, 123.6, 127.0, 128.0, 129.5, 130.8, 131.4, 136.3, 139.6,
139.6, 147.9, 171.4; HRMS (ESIþ): found: 318.0746; C17H13NNaO4
(MNaþ) requires 318.0737.
general procedure
B
with THF (3.4 mL), LHMDS (0.82 mL,
solution in THF) and 4-
0.82 mmol, 1.0
M
acetamidobenzenesulfonylazide (196 mg, 0.82 mmol). Purification
by column chromatography (2:1 petrol/ethyl acetate) afforded the
title compound as a white crystalline solid (171 mg, 53%); Rf 0.77
(1:2 petrol/ethyl acetate); nmax (thin film)/cmꢂ1 2938w, 2884w,
2100s, 1675s, 1264s, 1219w, 1005m; mp 68e72 ꢁC; dH (400 MHz,
CDCl3) 1.19 (6H, td, J 7.1, 0.7), 3.81e3.93 (2H, m), 4.03e4.13 (2H, m),
4.14 (2H, s), 6.61e6.65 (2H, m), 7.06e7.18 (3H, m), 7.22e7.34 (10H,
m); dC (100 MHz, CDCl3) 15.9 (d, J 7.6), 43.3, 55.2 (d, J 227.8), 63.1 (d,
J 5.4), 88.3, 126.1, 126.5, 127.2, 127.5, 128.0, 130.3, 135.3, 144.1, 162.2
(d, J 10.2); dP (162 MHz, CDCl3) 11.0; HRMS (ESIþ): found: 501.1527;
4.65. (SR,Z)-3-Pentylidene-4-phenyldihydrofuran-2(3H)-one
(Z-18i) and (SR,E)-3-pentylidene-4-phenyldihydrofuran-
2(3H)-one (E-18i)
Synthesised using general procedure D with phenethyl 2-diazo-
2-(diethoxyphosphoryl)acetate 11d (73 mg, 0.224 mmol), DCM
(4.5 mL), Rh2(oct)4 (3.5 mg, 4.5
mmol), THF (4.5 mL), KOBu-t
(37.7 mg, 0.336 mmol) and valeraldehyde (44.8
mL, 0.448 mmol).
The HWE was performed at reflux. Purification by column chro-
matography (8:1 hexane/ethyl acetate) afforded the title com-
pounds as mixture of (Z) and (E) isomers (Z-18i/E-18i 3.3:1) (29 mg,
56%). Small quantities of each compound were isolated separately
for characterisation purposes.
C
26H27N2NaO5P (MNaþ) requires 501.1550.
4.63. Diethyl ((1SR,3aSR)-1-benzyl-3-oxo-1-phenyl-3,3a-dihy-
dro-1H-cyclohepta[c]furan-3a-yl)phosphonate (15b)
To
yphosphoryl)acetate 14a (47 mg, 0.098 mmol) in toluene (5 mL)
flushed with argon was added Rh2(esp)2 (3.7 mg, 4.9 mol). The
a
solution of 1,1,2-triphenylethyl 2-diazo-2-(diethox-
4.65.1. Data for Z-18i. Pale yellow oil; Rf 0.53 (4:1 hexane/ethyl
acetate); nmax (thin film)/cmꢂ1 2957m, 2928m, 2871w, 1755s,
1667w, 1455w, 1373w, 1175m, 1127m, 1025s; dH (400 MHz, CDCl3)
0.88 (3H, t, J 7.1), 1.25e1.43 (4H, m), 2.66e2.82 (2H, m), 4.18e4.24
(2H, m), 4.61e4.67 (1H, m), 5.99 (1H, td, J 7.8, 2.2), 7.20e7.23 (2H,
m), 7.28e7.32 (1H, m), 7.34e7.39 (2H, m); dC (100 MHz, CDCl3) 13.8,
22.3, 27.2, 31.1, 46.9, 72.5, 127.6, 128.0, 128.8, 129.1, 140.7, 146.9,
169.8; HRMS (ESIþ): found: 253.1188; C15H18NaO2 (MNaþ) requires
253.1199.
m
mixture was stirred at 100 ꢁC for 4 h. Concentration in vacuo and
purification by column chromatography (1:1 petrol/ethyl acetate)
afforded the title compound as an off-white solid (22 mg, 50%); Rf
0.22 (1:1 petrol/ethyl acetate); mp 92e95 ꢁC; nmax (thin film)/cmꢂ1
2936w,1744s,1230m,1034w,1009m; dH (400 MHz, CDCl3) 1.35 (3H,
td, J 7.1, 0.4), 1.38 (3H, td, J 7.1, 0.4), 3.65 (1H, d, J 14.6), 4.10e4.28
(4H, m), 4.11 (1H, d, J 14.6), 5.31 (1H, dd, J 10.0, 6.3), 6.15e6.22 (2H,
m), 6.27e6.36 (2H, m), 7.09e7.16 (5H, m), 7.19e7.30 (3H, m),
7.32e7.36 (2H, m); dC (100 MHz, CDCl3) 16.4 (d, J 5.6), 16.7 (d, J 5.3),
45.6, 56.0 (d, J 145.2), 63.8 (d, J 7.5), 64.4 (d, J 7.3), 90.0 (d, J 3.8),
119.1, 124.2 (d, J 7.2), 125.6, 126.6, 127.7, 127.8, 128.4, 128.5 (d, J 7.4),
129.0, 129.9, 130.7, 134.4, 135.0, 141.3, 172.7 (d, J 3.6); dP (162 MHz,
CDCl3) 17.3; HRMS (ESIþ): found: 473.1477; C26H27NaO5P (MNaþ)
requires 473.1488.
4.65.2. Data for E-18i. Pale yellow oil; Rf 0.44 (4:1 hexane/ethyl
acetate); nmax (thin film)/cmꢂ1 2957m, 2928s, 2858m, 1759s,
1672w, 1456w, 1378w, 1184m, 1026m; dH (400 MHz, CDCl3) 0.76
(3H, t, J 7.2), 1.10e1.33 (4H, m), 1.88e2.01 (2H, m), 4.20e4.29 (2H,
m), 4.70 (1H, app. t, J 8.2), 6.92 (1H, td, J 7.7, 2.3), 7.19e7.21 (2H, m),
7.26e7.29 (1H, m), 7.31e7.36 (2H, m); dC (100 MHz, CDCl3) 13.6,
22.2, 29.2, 29.9, 43.4, 73.5, 127.2, 127.4, 129.0, 129.1, 141.7, 144.3,
Please cite this article in press as: Lloyd, M. G.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.054

M.G. Lloyd et al. / Tetrahedron xxx (2014) 1e17
15
171.2; HRMS (ESIþ): found: 253.1187; C15H18NaO2 (MNaþ) requires
253.1199.
37.1, 70.8, 129.8, 141.5, 171.7; HRMS (ESIþ): found: 247.1666;
14H24NaO2 (MNaþ) requires 247.1669.
C
4.66. (SR,Z)-3-(4-Nitrobenzylidene)-4-pentyldihydrofuran-
2(3H)-one (Z-18j) and (SR,E)-3-(4-nitrobenzylidene)-4-
pentyldihydrofuran-2(3H)-one (E-18j)
4.68. (SR,Z)-4-(4-Nitrobenzylidene)-2-oxaspiro[4.4]nonan-3-
one (Z-18l) and (SR,E)-4-(4-nitrobenzylidene)-2-oxaspiro[4.4]
nonan-3-one (E-18l)
Synthesised using general procedure D with heptyl 2-diazo-2-
Synthesised using general procedure D with cyclopentylmethyl
(diethoxyphosphoryl)acetate 11p (68 mg, 0.212 mmol), DCM
2-diazo-2-(diethoxyphosphoryl)acetate 11ae (61 mg, 0.200 mmol),
(4.2 mL), Rh2(oct)4 (3.3 mg, 4.2
mmol), THF (4.2 mL), KOBu-t
DCM (4.0 mL), Rh2(oct)4 (3.1 mg, 4.0 mmol), THF (4.0 mL), KOBu-t
(35.7 mg, 0.318 mmol) and 4-nitrobenzaldehyde (62.6 mg,
0.424 mmol). The HWE was performed at 0 ꢁC. Purification by
column chromatography (8:1 hexane/ethyl acetate) afforded the
title compounds as mixture of (Z) and (E) isomers (Z-18j/E-18j 1:1)
(42 mg, 68%). Small quantities of each compound were isolated
separately for characterisation purposes.
(33.7 mg, 0.300 mmol) and 4-nitrobenzaldehyde (60.5 mg,
0.400 mmol). The HWE was performed at 0 ꢁC. Purification by
column chromatography (8:1 hexane/ethyl acetate) afforded the
title compounds as an inseparable mixture of (Z) and (E) isomers (Z-
18l/E-18l 1:1.4), as a white solid (30 mg, 55%); Rf 0.32 (4:1 hexane/
ethyl acetate); nmax (thin film)/cmꢂ1 2959w, 2874w, 1755s, 1646w,
1597m, 1518s, 1492w, 1453w, 1344s, 1257w, 1227w, 1201w, 1160m,
1096m, 1023m, 910w, 851m; dH (400 MHz, CDCl3) 1.61e1.96 (16H,
m, E,Z), 4.04 (3H, s, E), 4.16 (3H, s, Z), 6.87 (1H, s, Z), 7.52 (2H, dd, J
8.9, 0.6, E), 7.65 (1H, s, E), 7.86 (2H, dd, J 8.9, 0.5, Z), 8.19 (2H, d, J 8.9,
Z), 8.25 (2H, d, J 8.9, E); dC (100 MHz, CDCl3) 24.6 (E/Z), 25.3 (E/Z),
37.1 (E), 39.3 (Z), 50.3 (E), 52.5 (Z), 77.5 (Z), 79.4 (E), 123.1 (Z), 123.5
(E), 130.0 (E), 131.1 (Z), 134.0 (Z), 134.3 (E), 136.6 (E), 137.3 (Z), 139.8
(Z), 140.9 (E), 147.5 (E/Z), 147.6 (E/Z), 168.9 (Z), 171.9 (E); HRMS
(ESIþ): found: 296.0899; C15H15NNaO4 (MNaþ) requires 296.0893.
4.66.1. Data for Z-18j. Yellow oil; Rf 0.46 (4:1 hexane/ethyl ace-
tate); nmax (thin film)/cmꢂ1 2928m, 2857m, 1752s, 1651w, 1597m,
1518s,1466w, 1378w,1344s,1175s, 1112w; dH (400 MHz, CDCl3) 0.91
(3H, t, J 7.0), 1.25e1.45 (6H, m), 1.57e1.68 (1H, m), 1.73e1.82 (1H,
m), 3.15e3.22 (1H, m), 4.09 (1H, dd, J 8.9, 5.1), 4.52 (1H, dd, J 8.9,
7.7), 6.93 (1H, d, J 2.2), 7.89 (2H, d, J 8.8), 8.21 (2H, d, J 8.8); dC
(100 MHz, CDCl3) 14.0, 22.5, 26.0, 31.7, 34.1, 42.0, 70.8, 123.2, 131.1,
133.0, 136.1, 139.7, 147.6, 168.6; HRMS (ESIþ): found: 312.1210;
C
16H19NNaO4 (MNaþ) requires 312.1206.
4.69. (SR,Z)-4-Pentylidene-2-oxaspiro[4.4]nonan-3-one (Z-
18m) and (SR,E)-4-pentylidene-2-oxaspiro[4.4]nonan-3-one
(E-18m)
4.66.2. Data for E-18j. Pale yellow solid; Rf 0.41 (4:1 hexane/ethyl
acetate); mp 114e117 ꢁC; nmax (thin film)/cmꢂ1 2929m, 2858m,
1754s, 1598m, 1520s, 1344s, 1225m, 1183s, 1112w; dH (400 MHz,
CDCl3) 0.86 (3H, t, J 7.0), 1.18e1.42 (6H, m), 1.50e1.67 (2H, m),
3.53e3.60 (1H, m), 4.28 (1H, dd, J 9.1, 2.0), 4.45 (1H, ddd, J 9.1, 7.0,
0.7), 7.56 (1H, d, J 2.1), 7.67 (2H, d, J 8.8), 8.29 (2H, d, J 8.8); dC
(100 MHz, CDCl3) 13.0, 22.4, 26.4, 31.4, 32.4, 38.1, 70.7, 124.1, 130.3,
133.4, 133.8, 140.3, 147.8, 171.6; HRMS (ESIþ): found: 312.1205;
Synthesised using general procedure D with cyclopentylmethyl
2-diazo-2-(diethoxyphosphoryl)acetate 11ae (63 mg, 0.207 mmol),
DCM (4.2 mL), Rh2(oct)4 (3.2 mg, 4.1
mmol), THF (4.2 mL), KOBu-t
(34.8 mg, 0.311 mmol) and valeraldehyde (44.0
mL, 0.414 mmol).
The HWE was performed at reflux. Purification by column chro-
matography (8:1 hexane/ethyl acetate) afforded the title com-
pounds as mixture of (Z) and (E) isomers (Z-18m/E-18m 2.4:1)
(14 mg, 32%). Small quantities of each compound were isolated
separately for characterisation purposes.
C
16H19NNaO4 (MNaþ) requires 312.1206.
4.67. (SR,Z)-4-Pentyl-3-pentylidenedihydrofuran-2(3H)-one
(Z-18k) and (SR,E)-4-pentyl-3-pentylidenedihydrofuran-
2(3H)-one (E-18k)
4.69.1. Data for Z-18m. Colourless oil; Rf 0.67 (4:1 hexane/ethyl
acetate); nmax (thin film)/cmꢂ1 2956m, 2929w, 2871m, 1752s,
1665m, 1453m, 1370m, 1164w, 1128w, 1105m, 1025s; dH (400 MHz,
CDCl3) 0.91 (3H, t, J 7.2), 1.24e1.46 (4H, m), 1.62e1.81 (8H, m), 2.72
(2H, app. q, J 7.4), 4.02 (2H, s), 6.08 (1H, t, J 7.7); dC (100 MHz, CDCl3)
13.9, 22.3, 24.5, 26.9, 31.4, 39.2, 50.8, 77.7, 132.8, 141.9, 170.1; HRMS
(ESIþ): found: 231.1354; C13H20NaO2 (MNaþ) requires 231.1356.
Synthesised using general procedure D with heptyl 2-diazo-2-
(diethoxyphosphoryl)acetate 11p (67 mg, 0.209 mmol), DCM
(4.2 mL), Rh2(oct)4 (3.3 mg, 4.2
mmol), THF (4.2 mL), KOBu-t
(35.2 mg, 0.314 mmol) and valeraldehyde (45.0
mL, 0.418 mmol).
The HWE was performed at rt. Purification by column chroma-
tography (8:1 hexane/ethyl acetate) afforded the title compounds as
mixture of (Z) and (E) isomers (Z-18k/E-18k 2.7:1) (36 mg, 77%).
Small quantities of each compound were isolated separately for
characterisation purposes.
4.69.2. Data for E-18m. Colourless oil; Rf 0.54 (4:1 hexane/ethyl
acetate); nmax (thin film)/cmꢂ1 2956s, 2934s, 2872s, 1758s, 1668m,
1455m, 1383w, 1362w, 1164w, 1028s; dH (400 MHz, CDCl3) 0.93 (3H,
t, J 7.1), 1.20e2.00 (12H, m), 2.29 (2H, app. q, J 7.5), 4.00 (2H, s), 6.70
(1H, t, J 8.0); dC (100 MHz, CDCl3) 13.8, 22.5, 25.5, 27.7, 31.0, 38.6,
48.8, 79.8, 132.5, 141.6, 171.4; HRMS (ESIþ): found: 231.1352;
4.67.1. Data for Z-18k. Colourless oil; Rf 0.75 (4:1 hexane/ethyl ac-
etate); nmax (thin film)/cmꢂ1 2957s, 2928s, 2858s, 1754s, 1668m,
1466m, 1378m, 1185m, 1127s, 1027s; dH (400 MHz, CDCl3) 0.87e0.92
(6H, m), 1.24e1.49 (11H, m), 1.56e1.65 (1H, m), 2.69e2.75 (2H, m),
2.88e2.97 (1H, m), 3.92 (1H, dd, J 8.8, 5.3), 4.37 (1H, dd, J 8.8, 7.9),
6.12 (1H, td, J 7.7, 1.6); dC (100 MHz, CDCl3) 13.9, 14.0, 22.3, 22.5, 25.9,
27.1, 31.3, 31.7, 34.2, 40.1, 70.8, 128.3, 144.1, 170.5; HRMS (ESIþ):
found: 247.1670; C14H24NaO2 (MNaþ) requires 247.1669.
C
13H20NaO2 (MNaþ) requires 231.1356.
4.70. (SR)-4-(Hydroxymethyl)-3-methylenedihydrofuran-
2(3H)-one (19)9b
To
methylenedihydrofuran-2(3H)-one 12u (29 mg, 0.120 mmol) in
THF (0.6 mL) cooled to 0 ꢁC under argon was added TBAF (144
L,
a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-3-
4.67.2. Data for E-18k. Colourless oil; Rf 0.66 (4:1 hexane/ethyl
acetate); nmax (thin film)/cmꢂ1 2961s, 2930s, 2859m, 1760s, 1676m,
1466m, 1380w, 1193m, 1021m; dH (400 MHz, CDCl3) 0.87e0.94 (6H,
m), 1.22e1.57 (12H, m), 2.15e2.28 (2H, m), 3.04e3.10 (1H, m), 4.12
(1H, dd, J 9.1, 2.2), 4.31 (1H, dd, J 9.1, 7.3), 6.73 (1H, td, J 7.7, 2.0); dC
(100 MHz, CDCl3) 13.8, 14.0, 22.4, 22.5, 26.1, 29.4, 30.7, 31.7, 34.2,
m
0.144, 1.0 M in THF) dropwise. The solution was stirred at 0 ꢁC for
1 h then quenched with satd aq NH4Cl (10 mL) and extracted with
ether (2ꢃ25 mL). The combined organic extracts were dried over
Na2SO4 and concentrated in vacuo. Purification by column
Please cite this article in press as: Lloyd, M. G.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.054

16
M.G. Lloyd et al. / Tetrahedron xxx (2014) 1e17
€
T. Angew. Chem., Int. Ed. 2002, 41, 1584; (d) Muller, S.; Murillo, R.; Castro, V.;
Brecht, V.; Merfort, I. J. Nat. Prod. 2004, 67, 62; (e) Ramachandran, P. V.; Pratihar,
D. Org. Lett. 2007, 9, 2087.
chromatography (1:2 hexane/ethyl acetate) afforded the title com-
pound as a pale yellow oil (12 mg, 78%); Rf 0.29 (1:2 hexane/ethyl
acetate); nmax (thin film)/cmꢂ1 3417br, 2924m, 1756s, 1407w,
1268m, 1120m, 1017m, 816m; dH (400 MHz, CDCl3) 3.26e3.34 (1H,
m), 3.76e3.78 (2H, m), 4.27 (1H, dd, J 9.4, 4.5), 4.47 (1H, dd, J 9.4,
8.2), 5.75 (1H, d, J 2.3), 6.36 (1H, d, J 2.6); dC (100 MHz, CDCl3) 40.9,
64.1, 68.2, 123.6, 135.2, 170.4; HRMS (ESIþ): found: 151.0360;
C6H8NaO3 (MNaþ) requires 151.0366.
2. For more recent examples see: (a) Kim, J. N.; Kim, K. H.; Park, B. R. Tetrahedron
Lett. 2010, 51, 6568; (b) Zhou, J.; Schmidt, A. M.; Ritter, H. Macromolecules 2010,
43, 939; (c) Hodgson, D. M.; Talbot, E. P. A.; Clark, B. P. Org. Lett. 2011, 13, 2594;
(d) Xie, L.; Xu, X.; Yang, Y.; Zhang, F. Chem. Commun. 2013, 49, 4697; (e) Yamada,
K.; Masaki, K.; Hagimoto, Y.; Kamiya, S.; Kunishima, M. Tetrahedron Lett. 2013,
54, 1758; (f) Nicponski, D. R. Tetrahedron Lett. 2014, 55, 2075; (g) En, D.; Liao,
W.-W.; Yan, Y.; Zhuang, Z.; En, D.; Guo, Y.; Yan, Y. Tetrahedron Lett. 2014, 55, 47;
(h) Chowdhury, A. K.; Fernandes, R. A.; Patil, P. H. Eur. J. Org. Chem. 2014, 237; (i)
Kunzmann, M. H.; Bach, N. C.; Bauer, B.; Sieber, S. A. Chem. Sci. 2014, 5, 1158.
3. For a recent review see: Kitson, R. R. A.; Millemaggi, A.; Taylor, R. J. K. Angew.
Chem., Int. Ed. 2009, 48, 9426 and references therein.
4.71. ( )-Cedarmycin A (8a)9a
4. (a) Picman, A. K. Biochem. Syst. Ecol. 1986, 14, 25; (b) Patel, B. B.; Waddell, T. G.;
Pagni, R. M. Fitoterapia 2001, 72, 511; (c) Pati, H. N.; Das, U.; Sharma, R. K.;
Dimmock, J. R. Mini-Rev. Med. Chem. 2007, 7, 131; (d) Higuchi, Y.; Shimoma, F.;
Ando, M. J. Nat. Prod. 2003, 66, 810.
5. For recent examples of tandem/telescoped processes developed in our research
group see: (a) Lubkoll, J.; Millemaggi, A.; Perry, A.; Taylor, R. J. K. Tetrahedron
2010, 66, 6606; (b) Burns, A. R.; McAllister, G. D.; Shanahan, S. E.; Taylor, R. J. K.
Angew. Chem., Int. Ed. 2010, 49, 5574; (c) Unsworth, W. P.; Kitsiou, C.; Taylor, R. J.
K. Org. Lett. 2013, 15, 258; (d) Osler, J. D.; Unsworth, W. P.; Taylor, R. J. K. Org.
Biomol. Chem. 2013, 11, 7587; (e) Unsworth, W. P.; Coulthard, G.; Kitsiou, C.;
Taylor, R. J. K. J. Org. Chem. 2014, 79, 1368.
6. (a) Edwards, M. G.; Kenworthy, M. N.; Kitson, R. R. A.; Perry, A.; Scott, M. S.;
Whitwood, A. C.; Taylor, R. J. K. Eur. J. Org. Chem. 2008, 4769; (b) Edwards, M. G.;
Kenworthy, M. N.; Kitson, R. R. A.; Scott, M. S.; Taylor, R. J. K. Angew. Chem., Int.
Ed. 2008, 47, 1935; (c) Kitson, R. R. A.; Taylor, R. J. K.; Wood, J. L. Org. Lett. 2009,
11, 5338; (d) Kitson, R. R. A.; McAllister, G. D.; Taylor, R. J. K. Tetrahedron Lett.
2011, 52, 561.
7. Lloyd, M. G.; Taylor, R. J. K.; Unsworth, W. P. Org. Lett. 2014, 16, 2772.
8. Efforts to develop an asymmetric variant of this reaction using chiral rhodiu-
m(II) catalysts are ongoing. For examples of asymmetric synthesis using chiral
dirhodium(II) catalysts see: (a) Doyle, M. P.; Winchester, W. R.; Hoorn, J. A. A.;
Lynch, V.; Simonsen, S. H.; Ghosh, R. J. Am. Chem. Soc. 1993, 115, 9968; (b) Doyle,
M. P.; Kalinin, A. V. J. Org. Chem. 1996, 61, 2179; (c) Davies, H. M. L.; Bruzinski, P.
R.; Lake, D. H.; Kong, N.; Fall, M. J. J. Am. Chem. Soc. 1996, 118, 6897; (d) Davies,
H. M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem. Soc. 2000, 122, 3063.
9. (a) Sasaki, T.; Igarashi, Y.; Saito, N.; Furumai, T. J. Antibiot. 2001, 54, 567; (b)
Yang, H. S.; Qiao, X. X.; Cui, Q.; Xu, X. H. Chin. Chem. Lett. 2009, 20, 1023.
10. Wissmann, H.; Kleiner, H. J. Angew. Chem., Int. Ed. Engl. 1980, 19, 133.
11. (a) Schmidt, J. P.; Beltran-Rodil, S.; Cox, R. J.; McAllister, G. D.; Reid, M.; Taylor,
R. J. K. Org. Lett. 2007, 20, 4041; (b) Unsworth, W. P.; Gallagher, K. A.; Jean, M.;
Schmidt, J. P.; Diorazio, L. J.; Taylor, R. J. K. Org. Lett. 2013, 15, 262; (c) Unsworth,
W. P.; Taylor, R. J. K. Org. Biomol. Chem. 2013, 11, 7250.
Preparation of 5-methylhexanoyl chloride 20a: to a solution of 5-
methylhexanoic acid (130.2 mg, 1.00 mmol) in DCM (2.5 mL) at 0 ꢁC
was added oxalyl chloride (253 mL, 3.00 mmol) dropwise. Stirred for
30 min at 0 ꢁC followed by 2 h at rt then concentrated in vacuo to
afford a colourless oil. To a solution of 4-(hydroxymethyl)-3-
methylenedihydrofuran-2(3H)-one 19 (5 mg, 0.039 mmol) and
triethylamine (8.2
methylhexanoyl chloride (10
methylhexanoyl chloride (10
m
L, 0.059 mmol) in DCM (0.20 mL) was added 5-
L). After additional 5-
L) was added and stirred for 16 h.
m
2 h
m
The solution was quenched with satd aq NH4Cl (1 mL) and
extracted with DCM (3ꢃ10 mL). The combined organic extracts
were dried over Na2SO4 and concentrated in vacuo. Purification by
column chromatography (4:1 hexane/ethyl acetate) afforded the
title compound as a colourless oil (6 mg, 85%); Rf 0.75 (1:1 hexane/
ethyl acetate); nmax (thin film)/cmꢂ1 2956m, 2871w, 1768s, 1739s,
1468w, 1252w, 1170m, 1115m, 1019w; dH (400 MHz, CDCl3) 0.88
(6H, t, J 6.6), 1.15e1.21 (2H, m), 1.51e1.65 (3H, m), 2.31 (2H, t, J 7.6),
3.39e3.47 (1H, m), 4.16 (1H, dd, J 11.2, 7.3), 4.18 (1H, dd, J 9.4, 4.9),
4.25 (1H, dd, J 11.2, 5.6), 4.48 (1H, dd, J 9.4, 8.4), 5.76 (1H, d, J 2.3),
6.39 (1H, d, J 2.7); dC (100 MHz, CDCl3) 22.4, 22.7, 27.7, 34.3, 38.0,
38.3, 64.7, 68.1, 124.2, 134.5, 169.8, 173.5; HRMS (ESIþ): found:
263.1251; C13H20NaO4 (MNaþ) requires 263.1254.
4.72. ( )-Cedarmycin B (8b)9
12. Regitz, M. Angew. Chem., Int. Ed. Engl. 1967, 6, 733.
13. (a) Callant, P.; D’Haenens, L.; Vandewalle, M. Synth. Commun. 1984, 14, 155; (b)
Hanson, P. R.; Sprott, K. T.; Wrobleski, A. D. Tetrahedron Lett. 1999, 40, 1455; (c)
Hiersemann, M.; Jaschinski, T. Org. Lett. 2012, 14, 4114.
14. (a) Evans, P. A. Modern Rhodium-catalyzed Organic Reactions; Wiley: New York,
NY, 2005; (b) Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861; (c)
Doyle, M. P. Chem. Rev. 1986, 86, 919; (d) Doyle, M. P.; Forbes, D. C. Chem. Rev.
1998, 98, 911.
15. (a) Gois, P. M. P.; Afonso, C. A. M. Eur. J. Org. Chem. 2003, 19, 3798; (b) Afonso, C.
A. M.; Gomes, L. F. R.; Trindade, A. F.; Candeias, N. R.; Gois, P. M. P.; Veiros, L. F.
Synthesis 2009, 3519; (c) Candeias, N. R.; Gois, P. M. P.; Afonso, C. A. M. Chem.
Commun. 2005, 391; (d) Afonso, C. A. M.; Candeias, N. R.; Gois, P. M. P.; Veiros,
L. F.; Gois, P. M. P. J. Org. Chem. 2008, 73, 5926.
16. For key reviews of the HWE reaction see: (a) Boutargy, J.; Thomas, R. Chem. Rev.
1974, 74, 87; (b) Nicolaou, K. C.; Harter, M. W.; Gunzner, J. L.; Nadin, A. Liebigs
Ann. 1997, 1283.
To a solution of 4-(hydroxymethyl)-3-methylenedihydrofuran-
2(3H)-one 19 (3 mg, 0.023 mmol) and triethylamine (4.8
0.035 mmol) in DCM (0.12 mL) was added hexanoyl chloride
(3.9 L, 0.035 mmol). The solution was stirred at rt for 10 min then
mL,
m
quenched with satd aq NH4Cl (1 mL) and extracted with DCM
(3ꢃ10 mL). The combined organic extracts were dried over Na2SO4
and concentrated in vacuo. Purification by column chromatography
(4:1 hexane/ethyl acetate) afforded the title compound as a colour-
less oil (3 mg, 57%); Rf 0.76 (1:1 hexane/ethyl acetate); nmax (thin
film)/cmꢂ1 2959m, 2936m, 2864w, 1768s, 1738s, 1270w, 1246w,
1168m, 1115m, 1018w; dH (400 MHz, CDCl3) 0.90 (3H, t, J 7.0),
1.25e1.36 (4H, m), 1.62 (2H, app. quin, J 7.5), 2.32 (2H, t, J 7.5),
3.39e3.47 (1H, m), 4.16 (1H, dd, J 11.2, 7.3), 4.18 (1H, dd, J 9.4, 4.9),
4.25 (1H, dd, J 11.2, 5.6), 4.48 (1H, dd, J 9.4, 8.4), 5.76 (1H, d, J 2.4),
6.38 (1H, d, J 2.7); dC (100 MHz, CDCl3) 13.9, 22.3, 24.5, 31.2, 34.0,
38.1, 64.7, 68.1, 124.1, 134.5, 169.8, 173.5; HRMS (ESIþ): found:
249.1099; C12H18NaO4 (MNaþ) requires 249.1097.
17. This has been attributed to the instability of
a-methylene-g-butyrolactones
with respect to base but, in this study, the use of 0.9 equiv of KOBu-t led to
a lower overall yield in all cases tested except for substrate 12g.
18. (a) Boyar, E. B.; Robinson, S. D. Platinum Met. Rev. 1982, 26, 65; (b) Davies, H. M.
L.; Walji, A. M.; Nagashima, T. J. Am. Chem. Soc. 2004, 126, 4271.
19. A rapid colour change (green to red) is observed upon the addition of sub-
strates 12i and 12j to a solution of Rh2(oct)4 in DCM, which is indicative of the
coordination of axial ligands to the catalyst.
20. The regiochemical assignment of 12n is supported by HMBC correlation data
(see Ref. 7x for details).
21. (a) Maguire, A. R.; Buckley, N. R.; O’Leary, P.; Ferguson, G. Chem. Commun. 1996,
2595; (b) Moody, C. J.; Miah, S.; Slawin, A. M. Z.; Mansfield, D. J.; Richards, I. C. J.
Chem. Soc., Perkin Trans. 1 1998, 4067; (c) McNamara, O. A.; Maguire, A. R.
Tetrahedron 2011, 67, 9.
Acknowledgements
The authors wish to thank Elsevier Foundation (M.G.L.), the
University of Salerno (M.D.) and the University of York (W.P.U.) for
funding and Dr. A.C. Whitwood (University of York) for X-ray
crystallography.
22. CCDC 1013524 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
23. Kido, F.; Noda, Y.; Maruyama, T.; Kabuto, C.; Yoshikoshi, A. J. Org. Chem. 1981, 46,
4264.
24. Brown, R. F. C.; Coulston, K. J.; Eastwood, F. W.; Irvine, M. J. Aust. J. Chem. 1991,
44, 87.
References and notes
25. The absolute configuration of both cedarmycin natural products was not de-
termined during their isolation (see Ref. 9a) and to the best of our knowledge
remains unknown.
1. For representative examples of a-alkylidene-g-butyrolactone syntheses see: (a)
Holy, N. L.; Wang, Y. F. J. Am. Chem. Soc. 1977, 99, 944; (b) Amos, R. A.; Katze-
nellenbogen, J. A. J. Org. Chem. 1978, 43, 560; (c) Kang, S.-K.; Kim, K.-J.; Hong, Y.-
Please cite this article in press as: Lloyd, M. G.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.054

M.G. Lloyd et al. / Tetrahedron xxx (2014) 1e17
17
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34. Dulcere, J. P.; Mihoubi, M. N.; Rodriguez, J. J. Chem. Soc., Chem. Commun. 1988, 237.
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Please cite this article in press as: Lloyd, M. G.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.054