Synthesis of the cyclopentane core of pepluanin A

Article abstract of DOI:10.1016/j.tet.2020.130981

The jatrophane class of natural products exhibit a wide range of biological activities with certain members of this family of complex sesquiterpenes being P-glycoprotein inhibitors. Considerable attention has been paid to the synthesis of biologically active jatrophanes although very few have succumbed to total synthesis. Herein we report a synthesis of the cyclopentane core of pepluanin A, a potent P-glycoprotein inhibitor, that features an iodocarbocyclization and an invertive acetal formation as key steps.

Full text of DOI:10.1016/j.tet.2020.130981

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Synthesis of the cyclopentane core of pepluanin A
Erin D. Shephed, Michal S. Hallside, Jack L. Sutro, Amber Thompson, Martin
Hutchings, Jonathan W. Burton
PII:
S0040-4020(20)30076-4
https://doi.org/10.1016/j.tet.2020.130981
TET 130981
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 November 2019
Revised Date: 16 January 2020
Accepted Date: 22 January 2020
Please cite this article as: Shephed ED, Hallside MS, Sutro JL, Thompson A, Hutchings M, Burton JW,
Synthesis of the cyclopentane core of pepluanin A, Tetrahedron (2020), doi: https://doi.org/10.1016/
j.tet.2020.130981.
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Synthesis of the cyclopentane core of
pepluanin A
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Erin D. Shepherd, Michal S. Hallside, Jack L. Sutro, Amber Thompson, Martin Hutchings and Jonathan W.
Burton
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1
3TA, UK
UCB Pharama, 208 Bath Road, Slough, Berkshire, SL1 3WE, UK.

1
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of the cyclopentane core of pepluanin A
Erin D. Shephed,a Michal S. Hallside,a Jack L. Sutro,a Amber Thompson,a Martin Hutchingsb and Jonathan
W. Burtona,*
aDepartment of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK.
bUCB Pharama, 208 Bath Road, Slough, Berkshire, SL1 3WE, UK.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The jatrophane class of natural products exhibit a wide range of biological activities with certain
members of this family of complex sesquiterpenes being P-glycoprotein inhibitors.
Considerable attention has been paid to the synthesis of biologically active jatrophanes although
very few have succumbed to total synthesis. Herein we report a synthesis of the cyclopentane
core of pepluanin A, a potent P-glycoprotein inhibitor, that features an iodocarbocyclization and
an invertive acetal formation as key steps.
Available online
Keywords:
pepluanin A
jatrophane
synthesis
2009 Elsevier Ltd. All rights reserved
.
cyclization
cyclopentane
and leads to the potential for design of more active analogues.6
For example, a large number of the jatrophanes that exhibit P-gp
inhibition lack oxygenation at C-2. It may therefore be the case
that an analogue of pepluanin A lacking a C-2 acetoxy group
would show increased potency with respect to the natural product
itself.
1. Introduction
Plants of the genus Euphorbia produce a large number of
structurally diverse terpenoid natural products that exhibit a vast
array of biological activities.1 Particularly interesting among
these natural products are the jatrophane diterpenes that are
characterised by a highly oxygenated trans-bicyclo-[10.3.0]-
pentadecane scaffold.2 These jatrophanes display a wide range of
important biological activities including cytotoxicity against
human cancer cell lines. However, what is most striking about
certain jatrophanes is their ability to inhibit the P-glycoprotein
(P-gp) and other efflux pumps that has implications for acquired
multidrug resistance (MDR).3 The selective inhibition of P-gp
resulting in reduced MDR, is currently an active area of research
for cancer chemotherapy given that the P-gp is overexpressed in
cancer cells. As noted above the jatrophanes display wide
structural variation and consequently wide variation in P-gp
inhibition. Pepluanin A 13a and euphodendroidin D 2,4 both
show inhibition of daunomycin efflux, with pepluanin A being
twice as active at inhibiting the P-gp efflux of daunomycin
compared with the current “gold-standard”, cyclosporin A.5
Similarly, epieuphoscopin B 33c is twice as potent as cyclosporin
A at inhibiting P-gp-mediated efflux of mitoxantrone. Pepluanin
A 1, euphodendroidin D 2 and epieuphoscopin B 3 are but three
of an ever-increasing number of biologically active jatrophane
diterpenes being isolated from Euphorbia spp.2 The structures of
jatrophane diterpenes differ in the extent of oxygenation, the
position of unsaturation, the type and extent of esterification and
in their relative configurations as exemplified by pepluanin A 1,
euphodendroidin D 2 and epieuphoscopin 3. The large number
of jatrophane diterpenes that have been isolated has, to a certain
extent, allowed a structure/activity relationship to be mapped out
Figure 1. Jatrophane diterpene skeleton and the structure of selected
jatrophane natural products.

2
Tetrahedron
As a result of the biological profile of these natural products
propionyl-17-norcharaciol12 (not shown) that was followed
shortly after by a report from the same group on the synthesis of
the natural product (-)-15-O-acetyl-4-O-propionyl-characiol 4
and a number of analogues using a carbonyl ene reaction as a key
step.6, 13 The Hiersemann syntheses represent a landmark in the
total synthesis of jatrophane diterpenes. Given the ever-
increasing number of biologically active jatrophanes being
isolated, particularly with efflux pump inhibition properties, it is
surprising that there have been so few total syntheses of these
natural products and indicates the challenge these targets present
to synthetic chemists.
and their intriguing structures, there has been significant interest
from the synthetic organic chemistry community; however, there
have been very few total syntheses of jatrophane natural products
although many groups have reported partial syntheses.7 The first
total synthesis of a jatrophane diterpene came from the group of
A. B. Smith, who prepared (±)-jatrophane and the non-natural
product (±)-epi-jatrophane8 as well as (+)-hydroxyjatrophanes A
and B (not shown).9 Racemic (±)-jatrophane was also prepared
by Stille and Hegedus10 with the synthesis of natural (+)-
jatrophane being reported by Wiemer.11 In 2006, Hiersemann
reported the synthesis of the non-natural (–)-15-O-acetyl-4-O-
Figure 2. Retrosynthesis of the cyclopentane core of pepluanin A. P = generic protecting group, R = alkyl group.
Beckwith-Houk transition state model for 5-hexenyl radical
2. Results and Discussion
cyclizations.14b, 21
For a number of years, we have been interested in the
oxidative radical cyclization of pentenyl malonates for the
formation of [3.3.0]-bicyclic γ-lactones and have used this
transformation for the synthesis of a number of natural
products.14 This oxidative radical cyclization was to be a key
step in the synthesis of the cyclopentane core of pepluanin A.
Our retrosynthesis of the cyclopentane core of pepluanin A is
shown in Figure 2. The poly-substituted cyclopentane 5 would
be derived from the bicyclic bromo-lactone 6 via reduction
followed by bromide substitution with inversion of configuration.
The bromo-lactone 6 should be readily prepared from the
carboxylic acid 7, which, in turn will be available from the
tricyclic bis-lactone 8, which itself might be synthetically
available via an oxidative C-H insertion reaction of the
carboxylic acid 9 (R = H).15 The corresponding ester 9 (R =
alkyl) was to be synthesized via oxidative radical cyclization
from the linear malonate 10. The malonate would be readily
prepared from the known ester 11 which is itself available from
the aldol product of t-butyl acetate and acrolein, the allylic
alcohol 12, which has been prepared in enantiopure form.16
Scheme 1. Synthesis of cyclization substrate. (i) LDA, THF, –78 °C, then
acrolein, quant. (ii) LDA, THF, HMPA, –78 °C, then MeI, 0 °C, 72%; (iii)
TBDMSCl, imidazole, CH2Cl2, 98%; (iv) DIBAL, THF, –20 °C, 88%; (v)
MsCl, Et3N, CH2Cl2; (vi) NaH, CH2(CO2Me)2, KI, THF, DMF, 80 °C, 89% (2
steps).
The synthesis began with the aldol reaction between t-butyl
acetate 13 and freshly distilled acrolein to give 12 (Scheme 1),17
followed by a Frater-Seebach alkylation18 to give the anti-aldol
11 (71%, > 20:1 dr); the relative configuration of 11 was
assigned by conversion into the known diol 14.19 Protection of
the allylic alcohol in 11 followed by ester reduction to give 15,
mesylation and reaction with sodio dimethyl malonate gave the
cyclization precursor 16. Exposure of the malonate 16 to our
standard oxidative radical cyclization conditions14b gave a 1:1
mixture of two diastereomers 17-cc and 17-cv20 in 41% yield
(Scheme 2). Lowering the reaction temperature to 40 °C gave
the products in 52% yield as a 1.5:1 mixture of diastereomers
favoring 17-cc where the methyl and silyloxy substituents are on
the concave face of the bicyclo[3.3.0]octane. The structures of
the bicyclic lactones were assigned through 1H NMR nOe
analysis (Scheme 2). We have previously rationalized the
outcome of related oxidative radical cyclizations using the
Scheme 2. Oxidative radical cyclization of malonate 16, along with
selected 1H-1H NMR nOe’s (dotted arrows) for 17-cc and 17-cv and proposed
cyclization transition structure 18. (i) Mn(OAc)3, Cu(OTf)2, MeCN, 40 °C,
52%, 17-cc:17-cv 1.5:1.
In this model it is more favorable for alkyl groups to occupy
pseudo-equatorial over pseudo-axial positions in the chair-like
transition state. The proposed transition state for the cyclization
of 16 would position the methyl group in a pseudo-equatorial
position with the alkoxy group occupying a pseudo-axial position
(18). Taguchi has shown,22 with iodine atom transfer reactions of

3
7
8
BnO, 21f
Me, 21g
Me
Me
20f
1:1.8
1:5
59%b
47%c
alkenyl-iodomalonates (Scheme 3), that allylic silyloxy groups
impart no stereocontrol giving the product γ-lactones 20a as a 1:1
mixtures of diastereomers.
20g
a21a,d,f and g, and 20a,d,f and g are known compounds;22 bdimethyl 3-
hydroxy-2-methylcyclopentane-1,1-dicarboxylate was also isolated (7%); c
22% starting material was also isolated.
O
O
O
EtO2C
H
MeO2C
H
MeO2C
H
O
O
O
TBDMSO
TBDMSO
TBDPSO
Scheme 3. Taguchi’s atom transfer cyclization of iodomalonates. (i)
benzene, 80 °C then heat, 50%, 1:1 mixture of 20a-cc and 20a-cv.
20b-cc
20a-cv
20c-cc
Surprisingly, formation of the same products 20a from malonate
21a under our standard oxidative radical cyclization conditions
using manganese(III) acetate and copper(II) triflate gives the
corresponding lactones as a mixture of diastereomers with 20a-cc
as the major product that carries the silyloxy substituent on the
concave face of the bicyclic lactone (Table 1 entries 1 and 2).
Indeed all of the oxidative radical cyclizations with substrates
bearing allylic alkoxy groups are mildly diastereoselective with
the major products formed having the alkoxy group on the inside
of the [3.3.0]-bicyclic γ-lactone (20cc), in keeping with axial
orientation in a Beckwith-Houk transition state (Table 1). The
best results were with an allylic t-butyldimethylsilyloxy (21a)
substituent with 0.2 M substrate concentration in acetonitrile at
40 °C to give the products 20a as a 4:1 mixture of diastereomers
in 78% yield favoring 20a-cc. The only exception is with the
benzyloxy substituted substrate 21f where the corresponding
product lactones 20f were formed as a 1.8:1 mixture of
diastereomers favoring the γ-lactone with the benzyloxy group on
the convex face of the [3.3.0]-bicyclic lactone 20f-cv.23
Although the lactones 20f were formed as a 1.8:1 mixture of
diastereomers, dimethyl 3-hydroxy-2-methylcyclopentane-1,1-
dicarboxylate (not shown) was also formed along with a number
of unidentified by products making accurate determination of the
diastereomeric ratio of the cyclization impossible. A control
experiment with an allylic methyl group (substrate 21g) gave the
product lactones 20g in 47% yield (22% recovered starting
material) as a 1:5 mixture of stereoisomers favoring 20g-cv in
Figure 3. Structures of 20a-cv, 20b-cc and 20c-cc from single crystal X-
ray diffraction.
The moderate selectivity of the cyclizations of the allylic
alkoxy-substituted malonates reported in Table 1 along with the
known preference for alkyl groups to adopt pseudo-equatorial
positions in the chair-like Beckwith-Houk transition state was
one of the guiding design principles for the synthesis of the core
of pepluanin A as we predicted that these two substituents would
exert their effects synergistically (transition state 18) and would
lead to the formation of 17-cc with high diastereocontrol
(Scheme 2). This however turned out not to be the case.
Taguchi has also shown that iodine-mediated ionic cyclizations
of substituted 5-hexenyl malonates can be highly
diastereoselective giving rise to the product [3.3.0]-bicyclic γ-
lactones in good yields and with high levels of diastereocontrol.22
In these iodine-mediated cyclizations substrates that bear an
allylic alkoxy substituent gave the corresponding [3.3.0]-bicyclic
γ-lactones with high levels of diastereocontrol favoring the
diastereomer with the alkoxy substituent on the concave face of
the bicyclic lactone. Use of a variety of Taguchi’s conditions
with substrate 16 resulted in only modest improvement in the
diastereoselectivity in the formation of the lactones 17 (Table 2,
entries 1-3). Use of a Grignard reagent as the base followed by
addition of iodine gave the product bicyclic lactones 17 as a 1:1
mixture of diastereomers in 45% yield (Table 2, entry 4).
keeping with the Beckwith-Houk model.
The relative
configurations of the bicyclic lactones 20 were assigned using 1H
NMR nOe experiments. A number of the bicyclic lactone
products were crystalline and single crystal X-ray structures of
20a-cv, 20b-cc and 20c-cc are shown in Figure 3 confirming the
1H NMR nOe assignments. Our results with allylic silyloxy
substrates 21a-c contrast with those of Taguchi.
These
contrasting results may potentially arise from the different
solvents used and the presence of Lewis acidic metal ions under
the manganese(III), copper(II) cyclization conditions.
Table 2. Iodine mediated cyclizations of substrate 16.
Table 1. Oxidative radical cyclizations of substrates 21.
Entry
additive
base
Crude d.r.
(cc:cv)
Yield
Entry
R’, substratea
tBuMe2SiO, 21a
tBuMe2SiO, 21a
tBuMe2SiO, 21b
tBuPh2SiO, 21c
BzO, 21d
R
Products
20a
d.r. cc:cv
2:1
Yield
78%
78%
75%
63%
63%
67%
1
2
3
4
5
6
Me
Me
Et
1
2
3
4
Ti(OiPr)4
Ti(OtBu)4
Ti(OtBu)4
none
CuO
CuO
1.5:1
2.5:1
2:1
41%
50%
38%
45%
20a
4:1
20b
2:1
2,6-dimethoxypyrdine
iPrMgCl
Me
Me
Me
20c
2:1
1:1
20d
2:1
AcO, 21e
20e
2:1
We reasoned that cyclization of the malonate 22 bearing a
methylene unit in place of the methyl group might provide better

4
Tetrahedron
stereocontrol in the key oxidative cyclization due to reduced
Scheme 5. Cyclization of dienyl malonate. (i) Mn(OAc)3, Cu(OTf)2,
MeCN, 40 °C, 29 46%, cc:cv 2.5:1 d.r.; (ii) Ti(Ot-Bu)4, CuO, I2, CH2Cl2, RT,
29 29%, 30 42%, cc:cv 20:1 dr.; (iii) EtMgBr, CuI, CH2Cl2, –78 °C, then I2,
RT, then 140 °C, 30 92%, cc:cv 16:1 d.r.
strain in the transition state (Figure 3). Furthermore, the product
methylene cyclopentane 23 would offer numerous options for
introduction of the C-3 tertiary alcohol in pepluanin A 1 as well
as allowing access to the C-2 methyl group present in other
members of the jatrophane family (e.g, 2 and 3).
O
O
O
MeO2C
O
MeO2C
O
MeO2C
(i)
+
O
O
O
H
H
H
TBDMSO
TBDMSO
TBDMSO
30cc
31a
31b
Figure 3. Proposed oxidative cyclization; P = protecting group
The cyclization substrate 28 was readily prepared using the
masked acrylate chemistry developed by Drewes24 that
commenced with an aldol reaction between the enolate derived
from amino-ester 24 and acrolein to give aldol 25 (Scheme 4).
Transformation of the amine in 25 into an amine oxide followed
by elimination on exposure to alumina gave the product alcohol
26 that was transformed into the corresponding silyl ether 27 and
thence to the malonate 28. Subjecting the malonate 28 to our
standard oxidative radical conditions gave multiple products
from which the deprotected lactones were isolated in 46% yield
as a 2.5:1 mixture of diastereomers favoring 29cc (Scheme 5).
Scheme 6. Epoxidation of 30cc along with the structure of 31a from
single crystal X-ray diffraction data. (i) m-CPBA, NaHCO3, CH2Cl2, RT, 31a
54%, 31b 17%. (ii) dimethyldioxirane, acetone, RT, 31a 14%, 31b 75%
The iodocyclization using ethylmagnesium bromide and
iodine is most likely ionic in nature. According to Chamberlain
and Hehre,25 the stereoselectivity of intramolecular electrophilic
addition to chiral allylic alcohols can be rationalized by placing
the hydroxy group on the ‘inside’ position resulting in a more
reactive ground-state. From here cyclization takes place via the
corresponding electrophile π-complex.26 In our system (Figure
4), this equates to the placing the silyloxy group in a pseudo-axial
orientation (as also proposed by Taguchi),22 with a corresponding
equatorial C–H bond (the inside alkoxy effect) followed by
cyclization via the corresponding olefin iodine π-complex
ultimately to give the major lactone diastereomer 30cc. If the
silyloxy group sits in a pseudo-equatorial orientation overlap
between the bonding π-orbital and the σ*C-O results in a less
nucleophilic π-bond and hence a disfavoured iodine π-complex,
as well as increased allylic strain with the exo-cyclic methylene
group. This results in a lower rate of formation for the minor
diastereomeric lactone 30cv.
Scheme 4. Synthesis of the cyclization precursor. (i) LDA, THF, –78 °C,
then acrolein, 97%; (ii) m-CPBA, CHCl3, 5 °C then alumina, 51%; (iii)
TBDMSCl, imidazole, CH2Cl2, 88%; (iv) DIBAL, THF, -20 °C, 86%; (v)
MsCl, Et3N, CH2Cl2; (v) CH2(CO2Me), NaH, KI, THF, DMF, 80 °C, 83% (2
steps).
Using Taguchi’s conditions (Ti(Ot-Bu)4, CuO, I2, CH2Cl2)
gave the protected lactones 30 in 42% yield along with the
desilylated products 29 in 42% yield with 20:1 diastereomeric
ratio favoring 30cc. Modification of Taguchi’s conditions using
EtMgBr as base and Cu(I)I at -78 °C followed by the addition of
I2 and then heating the crude reaction mixture to 140 °C,
conditions we had developed for
a conjugate addition,
carbocyclization, lactonization sequence that will be reported in
due course, gave the γ-lactones 30 in 92% yield as a 16:1 mixture
of diastereomers favoring 30cc. The relative configurations of
Figure 4. Proposed models for cyclization
1
Unfortunately, the TBDMS protecting group proved
incompatible with the basic reaction conditions required for
hydrolysis the methyl ester in 30cc so that the necessary angular
bromine atom could be introduced. We therefore changed the
allylic protecting group to a more base-stable triisopropylsilyl
group that also gave us the opportunity to synthesize the core in
enantioenriched form.
the lactones 30 were assigned by H NMR nOe analysis and
confirmed by single crystal X-ray analysis of the epoxide 31a
formed from 30cc on treatment with m-CPBA. Epoxidation of
the lactone with m-CPBA gave a 3:1 mixture of epoxides 31
favoring epoxide 31a the structures of which were assigned by
1H NMR nOe analysis and single crystal X-ray analysis of the
major diastereomer. Interestingly, use of DMDO resulted in
reversal of the selectivity of the epoxidation.
2.1. Synthesis of the core in enantiopure form.
The route towards the synthesis core of pepluanin A in
enantioenriched form began with the enzymatic resolution of the
butyl ester 34 with Candida Antarctica lipase B27 immobilized on
Immobead™ in the presence of vinyl acetate that allowed
isolation of the acetate 35 in 47% yield and 99% ee (Scheme 7);
the absolute configuration of the acetate was tentatively assigned

5
as R on the basis precedent for the esterification of other racemic
secondary alcohols with CAL-B27 and was confirmed by Mosher
ester analysis of a later intermediate (see below). The acetate in
35 could be hydrolyzed without loss of enantiomeric excess to
give (+)-34 on exposure to Amberlite IR-120 acidic resin in
methanol for 4 days at room temperature. The alcohol so formed
was readily converted into the silylether 36 which, in turn, was
converted into the cyclization substrate 37 using standard
procedures.
of the methyl ester in 38cc into the corresponding acid 41 was
readily achieved on exposure to lithium hydroxide and water
followed by acidification to pH 2 to give the corresponding
carboxylic acid in 41 in quantitative yield a transformation that
only proceeded in 20% yield with the TBDMS analogue 30cc
and in 42% yield with the TBDPS analogue (not shown).
Decarboxylative bromination of 41 was then readily achieved
using Barton chemistry.29 Here conversion of the carboxylic acid
41 into the corresponding acid chloride followed by addition of a
solution of the acid chloride in bromotrichloromethane to a
suspension
of
2-mercaptopyridine
N-oxide
in
bromotrichloromethane heated to 130 °C (bath temperature) gave
the desired bromide 42 in 79% yield as a low melting white solid.
Treatment of the α-bromolactone 42 with DIBAL at –78 °C
followed by the addition of MeOH and sodium methoxide gave
the α-hydroxy acetal 43 in 84%. This transformation most likely
proceeds via lactone reduction with DIBAL to give the lactol
anion 47 that is in equilibrium with the corresponding alkoxy
acetal 48.
Addition of methanol gives the deprotonated
hemiacetal 49 that undergoes intramolecular epoxide formation
with inversion of configuration. Opening of the epoxide 50 with
methoxide at the electronically favored acetal position provides
the acetal 43 with the tertiary hydroxyl group of pepluanin A
installed. This invertive acetal formation has precedent from the
groups of Shibatomi30 and Achmatowicz31 who showed that α-
flouroaldehydes and an α-tosyloxyaldehyde respectively form α-
hydroxy acetals with inversion of configuration on exposure to
basic methanol; a number of other groups have also shown that
α-halo acetals form α-hydroxy acetals on treatment with basic
methanol but the stereochemical course of these transformations
was not demonstrated.32 The diol acetal 43 was readily protected
as the bis-TBDMS ether giving 44 that on exposure to DMDO
gave the epoxide 45. The configuration of 45 was assigned on
the basis of 1H NMR nOe experiments. Selected nOes are shown
in Scheme 9 (box), additionally, both epoxide protons show
nOe’s to either or both of TBDMS groups that further supports
the structural assignment of the epoxide as 45. Reductive
opening of the epoxide 45 with SuperHydride™ gave the
differentially protected cyclopentane core of pepluanin A 46.
Scheme 7. Cyclization of dienyl malonate. (i) LDA, THF, –78 °C, then
acrolein, 94%; (ii) m-CPBA, CHCl3, RT, 63%; (iii) vinyl acetate, CAL-B on
Immobead™, hexane, 30 °C, 47%, 99% ee; (iv) MeOH, Amberlite™ IR-120,
RT, 89%, 99%ee; (v) TIPSOTf, 2,6-lutidine, CH2Cl2, 93%; (vi) DIBAL,
THF, -20 °C, 90%; (vi) MsCl, Et3N, CH2Cl2, (vii) CH2(CO2Me), NaH, KI,
THF, DMF, 80 °C, 84% (2 steps).
Exposure of the malonate 37 to our previously optimized
cyclization conditions gave the lactones 38 as a separable 5:1
mixture of diastereomers in 78% (38cc) and 15% (38cv) yields
respectively (Scheme 8); the relative configurations of 38cc and
38cv were assigned by analogy with the configurations of 30cc
and 30cv with the configuration of 38cc being further supported
1
by H NMR nOe analysis. The absolute configuration of 38cc
was assigned using Kakisawa’s extension of Mosher’s method28
with the secondary alcohol (29-cc) derived from treatment of the
major diastereomer 38cc with TBAF. Application of Kakisawa’s
method confirmed that the secondary alcohol had the expected
(R)-configuration (Scheme 8). Having assigned the absolute
configuration of the TIPS-protected lactone 38cc we moved to
convert it into the cyclopentane core of pepulanin A. Conversion
Scheme 8. Cyclization of diene 37 along determination of the relative and absolute configuration of 38. i) EtMgBr, CuI, CH2Cl2, –78 °C, then I2, RT, then
140 °C, 38cc 78%, 38cv 15%; (ii) TBAF, THF, 0 °C, 91%; (iii) (R) or (S)-α-methoxy-α-trifluoromethylphenylacetic, DCC, DMAP, CH2Cl2, (R)-MTPA ester (R)-
40 46%, (S)-MTPA ester (S)-40 53%.

6
Tetrahedron
Scheme 9. Synthesis of the core of prepluanin A along with proposed mechanism for the formation of 43 from 42. (i) LiOH, THF, water, RT, then HCl(aq)
to pH 2; (ii) (COCl)2, DMF, benzene, then concentrate, then CBrCl3, add solution to mercaptopyridine N-oxide sodium salt in CBrCl3 at 130 °C (bath
temperature), 79% (2 steps); (iii) DIBAL, THF –78 °C then MeOH, NaOMe, RT, 84%; (iv) TBDMSOTf, 2,6-lutidine, CH2Cl2, –78 to 0 °C, quant.; (v) DMDO,
acetone, RT, 88%; (vi) LiEt3BH, THF, 95%.
Melting points: Melting points were determined using a Griffin
heated metal block apparatus and are uncorrected.
3. Conclusions
Optical rotations: Optical rotations were measured using a
Perkin-Elmer 241 polarimeter in a cell of 1 dm path length (l).
Single Crystal X-ray Diffraction: Low temperature33 data were
collected using a Nonius Kappa-CCD diffractomter and reduced
using DENZO/SCALEPACK.34 The structures were solved
using SuperFlip35 and refined using CRYSTALS.36 Selected
refinement details for each structure are given below and full
details can be found in the ESI (CIF). Crystallographic data have
also been deposited with the Cambridge Crystallographic Data
Centre (CCDC 1963303-1963306) and copies of these data can
In conclusion, we have developed an enantioselective
synthesis of the differentially protected cyclopentane core of
pepluanin
A
46 that features
a
diastereoseletive
iodocarbocyclization and an invertive acetal formation as key
steps. Future work will aim to incorporate the cyclopentane 46 in
the total synthesis of pepluanin A.
4. Experimental section
be
obtained
free
of
charge
via
http://www.ccdc.cam.ac.uk/data_request/cif
Proton (1H) and carbon (13C) NMR spectra were recorded on
Bruker AVC 500 (500/125 MHz), Bruker AV 400 (400/100
MHz), AVN 400 (400/100 MHz) or AVIII 400 (400/100 MHz)
spectrometers. Proton and carbon chemical shifts (δH, δC) are
quoted in ppm and referenced to tetramethylsilane (δ = 0 ppm)
with residual protonated solvent as internal standard.
Assignments were made on the basis of chemical shifts, coupling
constants, COSY, HSQC data and comparison with previously
D
Specific rotations denoted as [ꢀ]T (T = temperature in °C, D
refers to the experimental D line of a sodium lamp, where the
wavelength of light = 589 nm. Compounds 21a,d,f and g, and
20a,d,f and g are known.22 Compound 21b was prepared by the
same method as Taguchi used for the preparation of compound
21a.22
4.1.1. tert-Butyl 3-hydroxypent-4-enoate 12
synthesized intermediates. Resonances are described as
s
(singlet), d (doublet), t (triplet), q (quartet), quin (quintet), m
(multiplet), br (broad), dd (double doublet). Coupling constants
(J) are given in Hz, and are rounded to the nearest 0.1 Hz and
averaged between corresponding coupling constants. H and H’
refer to diastereotopic protons attached to the same carbon and
imply no particular stereochemistry. Low resolution mass
spectra were recorded on a Fisons Platform spectrometer (ES).
High resolution mass spectra were recorded by the mass
spectrometry service at the Chemistry Research Laboratory,
University of Oxford, using a Bruker Daltronics microTOF
spectrometer (ES). m/z values are reported in Daltons with their
percentage abundances and, where known, the relevant fragment
ions in parentheses. High resolution values were calculated to
four decimal places from the molecular formula, all found values
To a stirred solution of diisopropylamine (10.8 mL, 77.0
mmol), in THF (250 mL), at –78 °C was added BuLi (48.4 mL,
1.6 M in hexanes, 77.5 mmol) dropwise. The reaction mixture
was stirred for 15 min before tert-butyl acetate 13 (8.90 mL, 66.4
mmol) was added and then stirred for 50 min at –78 °C. Freshly
distilled acrolein (4.44 g, 66.4 mmol), in THF (10 mL + 2 mL
rinse) was added rapidly and the reaction stirred for 5 min before
being quenched with sat. NH4Cl (aq) (20 mL) and extracted with
Et2O (130 mL). The separated organic layer was washed with
brine (2 × 60 mL), dried (MgSO4), filtered and concentrated in
vacuo to give the title compound 12 as a colorless oil (12.8 g,
>quant); Rf 0.42 (7:1 petrol:EtOAc); δH (400 MHz, CDCl3) 5.87
(1H, ddd, J = 5.9, 10.0, 17.0 Hz, CH=CH2), 5.30 (1H, dt, J =
17.0, 2.0 Hz, CH=CHH’), 5.14 (1H, dt, J = 10.0, 2.0 Hz,
CH=CHH’), 4.44–4.50 (1H, m, CHOH), 3.10 (1H, br s, OH),
2.50 (1H, dd, J = 16.0, 4.3 Hz, CHH’), 2.42 (1H, dd, J = 16.0, 8.1
Hz, CHH’), 1.47 (9H, s, CMe3); δC (100 MHz, CDCl3) 171.7
being
within
a
tolerance
of
5
ppm.
Infrared spectra were recorded on a Bruker Tensor 27 Fourier
Transform spectrometer, using diamond ATR. Absorption
maxima (νmax) are described as s (strong), m (medium), w (weak)
and br (broad) and quoted in wavenumbers (cm-1).

7
(C=O), 138.9 (CH=CH2), 115.1 (CH=CH2), 81.4 (CMe3), 69.0
(CHOH), 42.0 (CH2), 28.0 (CMe3); m/z LRMS (ESI+) 195
(M+Na+, 100%). Data in accordance with the literature values.17
4.1.4. (2S*,3R*)-2-methylpent-4-ene-1,3-diol 14
4.1.2. (2R*, 3R*)-tert-Butyl 3-hydroxy-2-
methylpent-4-enoate 11
To a stirred suspension of LiAlH4 (1.06 g, 27.9 mmol) in Et2O
(50 mL) at 0 °C was added a solution of (2R*,3R*)-tert-butyl 3-
((tert-butyldimethylsilyl)oxy)-2-methylpent-4-enoate (8.36 g,
27.9 mmol) in Et2O (50 mL) and the reaction stirred at RT for 1
h. The reaction was quenched with water (1.06 mL) and aq. 2 M
NaOH (1.06 mL). The mixture was stirred for 15 min then water
(2.1 mL) was added and the mixture stirred for 5 min. The
mixture was dried (MgSO4), filtered and concentrated in vacuo.
Purification by flash column chromatography (5:1→1:1
Petrol:EtOAc) gave the title compound 14 as a colorless oil
(2.25g, 19.4 mmol, 69%); δH (400 MHz, CDCl3) 5.85 (1H, ddd, J
= 17.0, 10.0, 7.0 Hz, CH2=CH), 5.24 (1H, d, J = 17.0 Hz,
CHH’=CH), 5.16 (1H, d, J = 10.0 Hz, CHH’=CH), 4.00 (1H, t, J
= 7.0 Hz, CHOH), 3.70–3.80 (1H, m, CHH’OH), 3.63 (1H, t, J =
8.0 Hz, CHH’OH), 3.35 (2H, br s, OH), 1.71–1.82 (1H, m,
CHMe), 0.84 (3H, d, J = 7.0 Hz, CHMe); δC (100 MHz CDCl3)
139.7 (CH2=CH), 116.3 (CH2=CH), 78.9 (CHOH), 67.3
(CH2OH), 39.9 (CHMe), 13.5 (CHMe). Data in accord with
literature values for enantiopure material.19
To a stirred solution of diisopropylamine (16.2 mL, 108
mmol), in THF (60 mL), at –78 °C was added BuLi (49.2 mL,
2.2 M in hexanes, 108 mmol) dropwise. The reaction mixture
was stirred for 15 min before tert-butyl 3-hydroxypent-4-enoate
12 (8.10 g, 47.0 mmol), was added dropwise as a solution in
HMPA (14 mL) and THF (30 mL). The reaction warmed to –40
°C and stirred for 20 min before cooling back to –78 °C and
adding MeI (6.00 mL, 133 mmol) dropwise. The reaction was
then warmed to 0 °C over 2 h quenched with sat. NH4Cl (aq)
(100 mL), followed by 1 M HCl until the aqueous layer reached
neutral pH. The aqueous layer was separated and extracted with
Et2O (3 × 100 mL). The combined organic layers were washed
with brine (100 mL), dried (MgSO4), filtered and concentrated in
vacuo. Purification by flash column chromatography (7:1
petrol:EtOAc) gave the title compound 11 as a colorless oil (6.30
g, 33.8 mmol, 72%); Rf 0.45 (7:1 petrol:EtOAc); νmax/cm-1 (thin
film) 3451br m, 2950m, 1730s; δH (400 MHz, CDCl3) 5.86 (1H,
ddd, J = 170, 10.0, 6.5 Hz, CH=CH2), 5.33 (1H, dt, J = 17.0, 2.0
Hz, CH=CHH’), 5.22 (1H, dt, J = 10.0, 2.0 Hz, CH=CHH’), 4.16
(1H, tt, J = 6.5, 2.0 Hz, CHOH), 2.48 (1H, qn, J = 6.5 Hz,
CHMe), 1.48 (9H, s, CMe3), 1.19 (3H, d, J = 6.5 Hz CHMe); δC
(100 MHz CDCl3) 175.0 (C=O), 139.3 (CH=CH2), 116.5
(CH=CH2), 81.2 (CMe3), 74.8 (CHOH), 45.8 (CHMe), 28.1
(CMe3), 14.1 (CHMe); m/z LRMS (ESI+) 209 (M+Na+, 100%);
HRMS (ESI+) found 209.1144, C10H18O3Na+ (M+Na+), requires
209.1148. In accordance with the lit. data reported for a 1:1
mixture of stereoisomers.37 Stereochemistry assigned by
conversion to known alcohol 14.
4.1.5. (2S*,3R*)-3-((tert-Butyldimethylsilyl)oxy)-
2-methylpent-4-en-1-ol 15
To a stirred solution of ester (2R*,3R*)-tert-butyl 3-((tert-
butyldimethylsilyl)oxy)-2-methylpent-4-enoate (800 mg, 2.67
mmol) in THF (5 mL) at –35 °C was added DIBAL (6.7 mL, 1 M
in hexane, 6.7 mmol) dropwise and the reaction was then stirred
at –20 °C for 90 min. The reaction was quenched with sat. aq.
Rochelle’s salt (10 mL) and diluted with EtOAc (10 mL) then
stirred vigorously at RT for 90 min. The aqueous layer was
separated and extracted with EtOAc (3 × 10mL). The combined
organic layers were dried (MgSO4), filtered and concentrated in
vacuo. Purification by flash column chromatography (4:1
petrol:EtOAc) gave the title compound 15 as a colorless oil (540
mg, 2.34 mmol, 88%); Rf 0.42 (4:1 petrol:EtOAc); νmax/cm-1 (thin
film) 3325br m, 2950s; δH (400 MHz, CDCl3) 5.83 (1H, ddd, J =
17.1, 10.3, 7.3 Hz, CH=CH2), 5.18 (1H, dt, J = 17.1, 1.5 Hz,
CH=CHH’), 5.15 (1H, dt, J = 10.3, 1.5 Hz, CH=CHH’), 4.07
(1H, ddt, J = 7.0, 6.3, 1.5 Hz, CHOTBDMS), 3.72 (1H, dd, J =
10.9, 3.6 Hz, CHH’OH), 3.57 (1H, dd, J = 10.9, 6.0 Hz,
CHHOH), 2.59 (1H, br s, OH), 1.72 (1H, qddd, J = 7.1, 7.0, 6.0,
3.6 Hz, CHMe), 0.95 (3H, d, J = 7.1 Hz, CHMe), 0.91 (9H, s,
CMe3), 0.10 (3H, s, SiMe), 0.05 (3H, s, SiMe); δC (100 MHz
CDCl3) 140.2 (CH=CH2), 115.5 (CH=CH2), 79.4 (CMe3), 65.9
(CHOTBDMS), 40.6 (CHMe), 25.8 (CMe3), 18.0 (SiCMe3), 14.1
(CHMe), -4.1 (SiMe), -5.0 (SiMe); m/z LRMS (ESI+) 253
(M+Na+, 16%); HRMS (ESI+): found 253.1602, C12H26O2SiNa+
(M+Na+), requires 253.1594.
4.1.3. (2R*,3R*)-tert-Butyl 3-((tert-
butyldimethylsilyl)oxy)-2-methylpent-4-enoate
To a stirred solution of alcohol 11 (500 mg, 2.7 mmol) in
CH2Cl2 (5 mL) was added imidazole (460 mg, 6.8 mmol), DMAP
(50 mg) and then TBDMSCl (471 mg, 3.1 mmol). The reaction
was stirred at RT for 20 h, then quenched with sat. NH4Cl (aq)
(10 mL). The aqueous layer was separated and extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were dried
(Na2SO4), filtered and concentrated in vacuo. Purification via
flash column chromatography (98:2 petrol:EtOAc) gave the title
compound as a colorless oil (800 mg, 2.67 mmol, 98%). Rf 0.45
(98:2 petrol:EtOAc); νmax/cm-1 (thin film) 2971w, 1739s; δH (400
MHz, CDCl3) 5.69 (1H, ddd, J = 6.7, 10.3, 17.3 Hz, CH=CH2),
5.12 (1H, dt, J = 17.3, 1.5 Hz, CH=CHH’), 5.08 (1H, dt, J = 10.3,
1.5 Hz, CH=CHH’), 4.24 (1H, tt, J = 6.7, 1.5 Hz, CHOSi), 2.39
(1H, qn, J = 6.7 Hz, CHMe), 1.39 (9H, s, CMe3), 0.94 (3H, d, J =
6.7 Hz, CHMe), 0.82 (9H, s, SiCMe3), 0.00 (3H, SiMe), -0.03
(3H, SiMe); δC (100 MHz, CDCl3) 173.9 (C=O), 138.6
(CH=CH2), 116.3 (CH=CH2), 80.1 (CMe3), 75.7 (CHOSi), 47.4
CHMe), 28.2 (CMe3), 25.8 (CMe3), 18.1 (SiCMe3), 12.6
(CHMe), -4.2 (SiMe), -5.0 (SiMe); m/z LRMS (ESI+) 323
(M+Na+, 100%); HRMS (ESI+): found 323.2018, C16H32O3SiNa+
(M+Na+), requires 323.2013.
4.1.6. (2S*,3R*)-3-((tert-Butyldimethylsilyl)oxy)-2-
methylpent-4-en-1-yl methanesulfonate

8
Tetrahedron
To a solution of alcohol 15 (1.66 g, 7.20 mmol) in CH2Cl2
(29 mL) at 0 °C was added Et3N (1.5 mL. 1.09 g, 10.8 mmol)
followed by MsCl (0.72 mL, 1.07 g, 9.4 mmol) and the reaction
mixture was stirred for 10 min and then quenched with sat. aq.
NH4Cl (30 mL). The organic layer was separated and the
aqueous layer extracted with CH2Cl2 (2 × 30 mL). The combined
organic layers were washed with brine (30 mL), dried (MgSO4)
to yield the title compound as a yellow oil; Rf 0.42 (4:1
petrol:EtOAc); νmax/cm-1 (thin film) 2930m, 1472m, 1357s; δH
(400 MHz, CDCl3) 5.76 (1H, ddd, J = 7.0, 10.3, 17.1 Hz,
CH=CH2), 5.19 (1H, dt, J = 17.1, 1.5 Hz, CH=CHH’), 5.15 (1H,
dt, J = 10.3, 1.5 Hz, CH=CHH’), 4.28 (1H, dd, J = 10.9, 4.8 Hz,
CHH’OMs), 4.14 (1H, J = dd, 10.9, 6.0 Hz, CHH’OMs), 4.04
(1H, ddt, J = 7.0, 6.3, 1.5 Hz, CHOTBDMS), 2.99 (3H, s, OMs),
1.90–2.04 (1H, m, CHMe), 0.98 (3H, d, J = 6.9 Hz, CHMe), 0.90
(9H, s, CMe3), 0.06 (3H, s, SiMe), 0.02 (3H, s, SiMe); δC (100
MHz, CDCl3) 139.0 (CH=CH2), 116.3 (CH=CH2), 75.0
(CHOTBDMS), 71.7 (CH2OMs), 39.5 (CHMe), 37.1 (SO2Me),
25.8 (CMe3), 18.1 (CMe3), 13.2 (CHMe), -4.1 (SiMe), -5.0
(SiMe); m/z LRMS (ESI+) 331 (M+Na+, 100%); HRMS (ESI+):
found 331.1374, C13H28O4SiSNa+ (M+Na+), requires 331.1370.
To copper(II) triflate (90 mg, 0.25 mmol) and mangaese(III)
acetate (201 mg, 0.75 mmol) was added malonate 16 (86 mg,
0.25 mmol) as a solution in degassed acetonitrile (1.25 mL) and
the reaction mixture was stirred at 80 °C for 4 h, then allowed to
coole to RT and diluted with water (2.5 mL) and EtOAc (5 mL).
The aqueous layer was separated, extracted with EtOAc (2 × 5
mL), dried (MgSO4) and the solvent removed in vacuo.
Purification
by flash
column
chromatography (4:1
petrol:EtOAc)gave the 2.177 as a colorless oil (35 mg, 0.11
mmol, 43%) followed by the 2.155 as a colorless oil (36 mg, 0.11
mmol, 44%); (Major 17-cc) Rf 0.22 (4:1 petrol:EtOAc); νmax/cm-1
(thin film) 2955m, 1772s, 1739s, 1255s; δH (400 MHz, CDCl3)
4.39 (1H, dd, J = 9.3, 1.9 Hz, CHHOR), 4.34 (1H, dd, J = 9.3,
7.1 Hz, CHHOR), 4.08 (1H, t, J = 3.9 Hz, CHOTBDMS), 3.77
(3H, s, OMe), 3.02 (1H, ddd, J = 6.9, 3.9, 1.9 Hz, CHCH2OR),
2.55 (1H, dd, J = 13.2, 7.3 Hz, CHH’CHMe), 2.08–2.16 (1H, m,
CHMe), 1.93 (1H, dd, J = 13.2, 11.5 Hz, CHH’CHMe), 0.97 (3H,
d, J = 6.9 Hz CHMe), 0.90 (9H, s, SiCMe3), 0.09 (3H, s, SiMe),
0.07 (3H, s, SiMe); δC (100 MHz CDCl3) 176.1 (C=O), 171.1
(C=O), 77.2 (CH2OR), 66.5 (CHOTBDMS), 59.3 (CCO2Me),
53.2 (CHCH2OR), 52.7 (OMe), 41.8 (CH2CHMe), 37.4
(CH2Me), 25.8 (CMe3), 18.0 (SiCMe3), 13.8 (CHMe), -4.1
(SiMe), -4.2 (SiMe); m/z LRMS (ESI+) 351 (M+Na+, 100%);
HRMS (ESI+): found 351.1604, C16H28O5SiNa+ (M+Na+),
requires 351.1598.
(Minor 17-cv) Rf 0.41 (4:1 petrol:EtOAc); νmax/cm-1 (thin film)
2956 m, 1778s, 1747s, 1254m; δH (400 MHz, CDCl3) 4.55 (1H, t,
J = 9.5 Hz, CHH’OR), 3.99 (1H, dd, J = 9.5, 3.7 Hz, CHH’OR),
3.84 (1H, dd, J = 3.7, 1.5 Hz, CHOTBDMS), 3.76 (3H, s,
CO2Me), 3.06 (1H, ddd, J = 9.5, 3.7, 1.5 Hz, CHCH2OR), 2.41
(1H, dd, J = 12.9, 12.3 Hz, CHH’CHMe), 2.20 (1H, dd, J = 12.9,
6.4 Hz, CHH’CHMe), 1.95–1.90 (1H, m, CHMe), 1.01 (3H, d, J
= 6.4 Hz, CHMe), 0.86 (9H, s, CMe3), 0.00 (3H, s, SiMe), 0.00
(3H, s, SiMe); δC (100 MHz CDCl3) 176.4 (C=O), 169.9 (C=O),
81.0 (CHOTBDMS), 69.6 (CH2OR), 59.8 (CHCH2OR), 54.1
(CCO2Me), 53.1 (OMe), 38.8 (CH2CHMe), 38.6 (CHMe), 25.6
(CMe3), 18.0 (SiCMe3), 12.9 (CHMe), -4.8 (SiMe), -4.9 (SiMe).
4.1.7. Dimethyl 2-((2S*,3R*)-3-((tert-
butyldimethylsilyl)oxy)-2-methylpent-4-en-1-
yl)malonate 16
To a stirred suspension of NaH (60% dispersion in mineral oil,
864 mg, 21.6 mmol) in DMF (30 mL) and THF (15 mL) at 0 °C
was added dimethyl malonate dropwise (2.5 mL, 2.85g, 21.6
mmol). The reaction mixture was warmed to RT and the crude
mesylate
(2S*,3R*)-3-((tert-butyldimethylsilyl)oxy)-2-
methylpent-4-en-1-yl methanesulfonate prepared above was
added as a solution in THF (14 mL) followed by the addition of
KI (358 mg, 2.16 mmol). The reaction mixture was warmed to
80 °C and stirred for 16 h, then allowed to cool to RT, quenched
with sat. aq. NH4Cl (30 mL) and petrol (30 mL) was added. The
aqueous layer was extracted with petrol (2 × 30 mL), the
combined organic layers were dried (MgSO4), filtered and the
solvent removed in vacuo. Purification by flash column
chromatography (9:1 petrol:EtOAc) gave the title compound 16
as a colorless oil (2.20 g, 6.40 mmol, 89%); Rf 0.62 (4:1
petrol:EtOAc); νmax/cm-1 (thin film) 2956m, 1758s, 1739s, 1253s;
δH (400 MHz, CDCl3) 5.73 (1H, ddd, J = 6.3, 10.2, 17.0 Hz,
CH=CH2), 5.15 (1H, dd, J = 17.0, 1.5 Hz, CH=CHH’), 5.10 (1H,
dd, J = 10.2, 1.5 Hz, CH=CHH’), 3.95 (1H, dd, J = 6.3, 4.9 Hz,
CHOTBDMS), 3.72 (6H, s, CO2Me), 3.48 (1H, dd, J = 9.3, 5.3
Hz, CH(CO2Me)2), 2.11 (1H, ddd, J = 13.7, 9.5, 5.3 Hz,
4.1.9. Dimethyl 2-(3-hydroxypent-4-en-1-
yl)malonate
A mixture of hydrochloric acid (2 M, 0.1 mL, 0.3 mmol) in
methanol (10 mL) was added to dimethyl 2-(3-(tert
-
CHH’CHMe), 1.62 (1H, ddd,
J = 13.7, 9.3, 6.1 Hz,
butyldimethylsilyloxy)pent-4-enyl)malonate 21a (2.00 g, 6.05
mmol). After 7 h of stirring at room temperature the reaction
mixture was concentrated under reduced pressure. The residual
oil was purified by flash column chromatography (petroleum
ether:ethyl acetate, 1:1) to give the title compound as a colorless
oil (1.15 g, 5.32 mmol, 88%); Rf = 0.13 (petroleum ether:ethyl
acetate, 3:1); νmax(neat)/cm−1 3419 (O-H), 3081, 3006, 2956,
2850, 1750 (C=O), 1733 (C=O), 1645 (C=C); δH(400 MHz;
CDCl3) 5.83 (ddd, J = 17.2, 10.4, 6.1 Hz, 1H, CH=CH2), 5.23 (d,
J = 17.2 Hz, 1H, CH=CHH), 5.11 (d, J = 10.4 Hz, 1H,
CH=CHH), 4.14-1.07 (m, 1H, CHOH), 3.72 (s, 6H, OMe), 3.40
CHH’CHMe), 1.47–1.57 (1H, m, CHMe), 0.88 (9H, s, CMe3),
0.87 (3H, d, J = 6.6 Hz, CHMe), 0.03 (3H, s, SiMe), 0.00 (3H, s,
SiMe); δC (100 MHz, CDCl3) 170.2 (C=O), 169.9 (C=O), 138.9
(CH=CH2), 115.6 (CH=CH2), 77.4 (COTBDMS) 52.5 (OMe),
52.4 (OMe), 50.0 (CH(CO2Me)2), 37.4 (CHMe), 31.3 (CH2), 25.9
(CMe3), 18.2c (SiCMe3), 15.0 (CHMe), -4.3 (SiMe), -5.0 (SiMe);
m/z LRMS (ESI+) 367 (M+Na+, 100%); HRMS (ESI+): found
367.1907, C17H32O5SiNa+ (M+Na+), requires 367.1911.
4.1.8. (3aR*,5S*,6S*,6aS*)-Methyl 6-((tert-
butyldimethylsilyl)oxy)-5-methyl-3-oxohexahydro-
1H- cyclopenta[c] furan-3a-carboxylate 17-cc and
(3aS*,5SR*,6S*,6aR*)-methyl 6-((tert-
butyldimethylsilyl)oxy)-5-methyl-3-oxohexahydro-
1H- cyclopenta[c] furan-3a-carboxylate 17-cv
(t,
J
=
7.5 Hz, 1H, CH(CO2Me)2), 2.07-1.88 (m, 3H,
OH), 1.58-1.50 (m, 2H,
CH2CH(CO2Me)2,
CH2CH2CH(CO2Me)); δC(100 MHz, CDCl3) 169.8 (CO), 169.7
(CO), 140.5 (CH=CH2) 115.1 (CH=CH2), 72.4 (CHOH), 52.5

9
(2×OMe), 51.3 (CH(CO2Me)2), 34.2 (CH2CH(CO2Me)2), 24.7
(CH2CH2CH(CO2Me)2); m/z LRMS (ESI+) 455.1 (2M+Na+,
100%), 239.0 (M+Na+, 92); HRMS (ESI+) found 239.0888,
C10H16NaO5+ (M+Na+), requires 239.0890.
requires 279.0662. Further elution of the column gave the
recovered starting material as a colorless oil (0.034 g, 34%)
4.1.12. 3-((tert-Butyldiphenylsilyl)oxy)pent-4-en-1-
yl 4-methylbenzenesulfonate
4.1.10. Dimethyl 2-(3-acetoxypent-4-en-1-
yl)malonate 21e
To
a
solution
of
3-hydroxypent-4-en-1-yl
4-
methylbenzenesulfonate (1.19 g, 4.64 mmol) in N,N-
dimethylformamide (10 mL), imidazole (0.948 g, 13.9 mmol)
was added followed by tert-butyl(chloro)diphenylsilane (1.53,
5.57 mmol). The clear reaction mixture was stirred at room
temperature for 5 h. sat. aq. NH4Cl (40 mL) was added followed
by Et2O (40 mL). The organic layer was washed with water (3 ×
40 mL), dried (MgSO4) and concentrated under reduced pressure.
Purification by flash column chromatography (petrol 30-
40:EtOAc, 9:1→6:1) gave a mixture of the title compound and 4-
methylbenzenesulfonic acid as a colorless oil (1.3:1, respectively,
1.91 g, approx. 65% yield of 324); Rf = 0.26 (petrol:Et2O, 8:1);
νmax(CDCl3)/cm−1 3564 (O-H, acid impurity), 1644 (C=C);
δH(400 MHz; CDCl3) 7.75-7.69 (3H, m, ArH), 7.64-7.56 (4H, m,
ArH), 7.47-7.26 (11H, m, ArH), 5.68 (1H, ddd, J = 17.0, 10.4,
6.5 Hz, CH=CH2), 4.92 (1H, d, J = 10.4 Hz, CH=CHH’), 4.88
Dimethyl 2-(3-hydroxypent-4-en-1-yl)malonate (0.500 g, 2.31
mmol) was dissolved in CH2Cl2 (7 mL). Triethylamine (1.00 mL,
7.17 mmol) was added followed by acetic anhydride (0.650 mL,
6.87 mmol) and 4-dimethylaminopyridine (0.030 g, 0.245
mmol). After stirring at room temperature for 3 h, the reaction
mixture was diluted with CH2Cl2 (20 mL). 50% sat. aq. NH4Cl
(30 mL) was added and the organic layer washed with 50% sat.
aq. sodium bicarbonate (30 mL). The two aqueous layers were
sequentially extracted with CH2Cl2 (3×30 mL) and the organic
layers combined, dried (Na2SO4) and concentrated under reduced
pressure. Purification by flash column chromatography (petrol
40-60:EtOAc, 9:1) gave the title compound 21e as a clear oil
(0.530 g, 2.05 mmol, 89%); found: C, 55.91%; H, 6.93%;
(1H, d,
J = 17.0 Hz, CH=CHH’), 4.26-4.21 (1H, m,
CHOTBDPS), 4.11-4.01 (2H, m, CH2OTs), 2.44 (3H s, Me), 1.86
(1H, dtd, J = 14.0, 7.1, 5.9 Hz, CHH’CH2OTs), 1.79-1.70 (1H,
m, CHH’CH2OTs), 1.01 (9H, s, SiCMe3); δC(125 MHz; CDCl3)
144.6 (Ar), 139.2 (CH=CH2), 135.8 (Ar), 135.8 (Ar), 135.2 (Ar),
134.8 (Ar), 133.6 (Ar), 133.6 (Ar), 133.0 (Ar), 129.8 (Ar), 129.7
(Ar), 129.6 (Ar), 129.6 (Ar), 127.9 (Ar), 127.7 (Ar), 127.6 (Ar),
127.4 (Ar), 115.6 (CH=CH2), 71.3 (CHOTBDPS), 67.1
(CH2OTs), 36.3 (CH2CH2OTs), 26.9 (SiCMe3), 19.2 (SiCMe3);
m/z LRMS (ESI+) 517.2 (M+Na+, 100%); HRMS found
517.1845, C28H34NaO4SSi+ (M+Na+) requires 517.1839.
C12H18O6 requires: C, 55.81%; H, 7.02%; Rf
= 0.45
(petrol:EtOAc, 3:1); νmax(CDCl3)/cm−1 3088, 2991, 2956, 2848,
1736 (C=O), 1647 (C=C), 1436, 1372, 1344, 1282, 1239, 1197,
1157, 1107, 1047, 1020, 962, 931, 855; δH(400 MHz; CDCl3)
5.74 (1H, dddd, J = 17.3, 10.4, 6.0, 0.7 Hz, CH=CH2), 5.23 (1H,
d, J = 17.3 Hz, CH=CHH’), 5.25-5.19 (1H, m, CHOAc), 5.18
(1H, d, J = 10.4 Hz, CH=CHH’), 3.72 (6H, s, 2×OMe), 3.36 (1H,
t, J = 7.5 Hz, CH(CO2Me)2), 2.05 (3H, d, J = 0.5 Hz, C(O)Me),
1.96-1.88 (2H, m, CH2CH(CO2Me)2), 1.68-1.60 (2H, m,
CH2CH2CH(CO2Me)2); δC(100 MHz; CDCl3) 170.2 (CO), 169.5
(2×CO), 135.7 (CH=CH2), 117.2 (CH=CH2), 73.8 (CHOAc),
52.5 (2×OMe), 51.1 (CH(CO2Me)2), 31.5 (CH2CH(CO2Me)2),
24.3 (CH2CH2CH(CO2Me)2), 21.1 (C(O)Me); m/z LRMS (ESI+)
281.1 (M+Na+, 100%); HRMS (ESI+) found 281.1002,
C12H18NaO6+ (M+Na+) requires 281.0996.
4.1.13. Dimethyl 2-(3-((tert-
butyldiphenylsilyl)oxy)pent-4-en-1-yl)malonate 21c
4.1.11. Hydroxypent-4-en-1-yl 4-
methylbenzenesulfonate
To a suspension of sodium hydride (60% suspension in
mineral oil, 0.072 g, 1.80 mmol) in tetrahydrofuran (2 mL),
dimethyl malonate (0.200 mL, 1.75 mmol) was slowly added via
syringe. 3- ((tert-butyldiphenylsilyl)oxy)pent-4-en-1-yl 4-
methylbenzenesulfonate (0.300 g, 0.600 mmol) was added via
syringe (2×0.5 mL, tetrahydrofuran rinse) followed by a small
amount of potassium iodide and N,N-dimethylformamide (2 mL).
The suspension was heated at 80 °C for 4 h and then cooled to
room temperature and poured into 50% sat. aq. NH4Cl (20 mL).
Et2O (40 mL) was added and the organic layer was washed with
water (3 × 30 mL), dried (MgSO4) and concentrated under
reduced pressure. Purification by flash column chromatography
(petrol 40-60:EtOAc, 6:1) gave the title compound 21c as a
Pent-4-ene-1,3-diol38 (0.100 g, 0.979 mmol) was dissolved in
CH2Cl2 (10 mL), triethylamine (0.15 mL, 1.07 mmol) was added
and the solution cooled to 0 °C. 4-Toluenesulfonyl chloride
(0.205 g, 1.07 mmol) was added and the reaction mixture
allowed to slowly warm to room temperature. After 25 h the
solution was concentrated under reduced pressure and the residue
purified by flash column chromatography (petroleum ether 40-
60:ethyl acetate, gradient, 1:1→1:8) to give the title compound as
a colorless oil (0.164 g, 0.640 mmol, 65%); Rf = 0.38 (petroleum
ether:ethyl acetate, 1:1); νmax(CDCl3)/cm−1 3534 (O-H), 3423 (O-
H); δH(400 MHz; CDCl3) 7.79 (2H, d, J = 8.0 Hz, ArH), 7.35
(2H, d, J = 8.0 Hz, ArH), 5.80 (1H, ddd, J = 17.1, 10.4, 6.0 Hz,
CH=CH2), 5.20 (1H, dd, J = 17.1, 1.1 Hz, 1H, CH=CHH’), 5.10
(1H, dd, J = 10.4, 1.1 Hz, 1H, CH=CHH’), 4.27-4.18 (2H, m,
CH2OTs), 4.10 (1H, dt, J = 10.5, 6.0 Hz, 1H, CHOH), 2.44 (3H,
s, Me), 2.21 (1H, br s, OH), 1.94-1.84 (1H, m, CHHCH2OTs),
1.79 (1H, ddt, J = 14.4, 8.5, 6.0 Hz, CHHCH2OTs); δC(100 MHz,
CDCl3) 144.8 (Ar), 139.8 (CH=CH2), 132.9 (Ar), 129.8 (Ar),
127.9 (Ar), 115.5 (CH=CH2), 69.0 (CH2OTs), 67.3 (CHOH),
35.8 (CH2CH2OTs), 21.6 (Me); m/z LRMS (ESI+) 279.1 (M+Na+,
100%); HRMS (ESI+) found 279.0662, C12H16NaO4S+ (M+Na+)
colorless oil (0.227 g, 0.499 mmol, 83%); Rf
= 0.24
(petrol:EtOAc, 6:1); νmax(neat)/cm−1 1754 (C=O), 1737 (C=O),
1644 (C=C); δH(400 MHz; CDCl3) 7.70-7.63 (4H, m, ArH), 7.43-
7.33 (6H, m, ArH), 5.77 (1H, ddd, J = 17.0, 10.5, 6.3 Hz,
CH=CH2), 5.01 (1H, d, J = 17.0 Hz, CH=CHH’), 5.00 (1H, d, J =
10.5 Hz, CH=CHH’), 4.19 (1H, q, J = 6.3 Hz, CHOTBDPS),
3.71 (3H, s, OMe), 3.69 (3H, s, OMe), 3.24 (1H, t, J = 7.5 Hz,
CH(CO2Me)2), 1.96-1.81 (2H, m, CH2CH(CO2Me)2), 1.56-1.41
(2H, m, CH2CH(CO2Me)2), 1.07 (9H, s, SiCMe3); δC(100 MHz;
CDCl3) 169.7 (2×CO), 139.9 (CH=CH2), 135.9 (Ar), 135.8 (Ar),
134.7 (Ar), 134.1 (Ar), 134.0 (Ar), 129.6 (Ar), 129.5 (Ar), 127.7
(Ar), 127.5 (Ar), 127.3 (Ar), 115.0 (CH=CH2), 73.8

10
Tetrahedron
(CHOTBDPS), 52.4 (2×OMe), 51.5 (CH(CO2Me)2), 34.8
4008/0/194, Rint=0.022, Final R1=0.0408, wR2=0.0986 (I>2s(I)).
(CH2CH2CH(CO2Me)2),
27.0
(SiCMe3),
23.7
Data in accord with literature.22
(CH2CH2CH(CO2Me)2), 19.3 (SiCMe3); m/z LRMS (ESI+) 477.2
(M+Na+, 72%); HRMS (ESI+) found 477.2068, C26H34NaO5Si+
(M+Na+) requires 477.2068.
Further elution of the column gave the title compound 20a-cc
as a colorless oil (3.9 g, 12.4 mmol, 58%); Rf = 0.40 (petrol 40-
60:EtOAc, 3:1); found: C, 57.28%; H, 8.29%; C15H26O5Si
requires: C, 57.29%; H, 8.33%; νmax(neat)/cm−1 2955, 2930,
2897, 2857, 1776 (C=O), 1741 (C=O), 1471, 1464, 1436, 1407,
1381, 1362, 1313, 1251, 1215, 1158, 1135, 1102, 1076, 1056,
1028, 1008, 992, 979, 939, 925, 890, 872, 837 (Si-C), 800, 777
(Si-C); δH (500 MHz; C6D6) 4.37 (ddd, J = 9.0, 2.0, 0.4 Hz, 1H,
CHHO), 4.08 (dd, J = 9.1, 7.7 Hz, 1H, CHHO), 3.90-3.85 (m,
1H, CHOTBDMS), 3.35 (s, 3H, OMe), 2.58 (ddd, J = 7.7, 6.2,
2.0 Hz, 1H, OCH2CH), 2.56-2.46 (m, 2H, CCH2), 1.59-1.44 (m,
2H, CCH2CH2), 0.98 (s, 9H, SiCMe3), -0.02 (s, 6H, SiMe2);
δC(125 MHz; C6D6) 175.5 (CO), 170.7 (CO), 74.7
(CHOTBDMS), 65.8 (CH2O), 59.9 (CCO2Me), 52.9 (OMe), 50.7
(OCH2C), 35.0 (CH2CHOTBDMS), 30.4 (CCH2), 25.7 (SiCMe3),
18.0 (SiCMe3), -4.6 (SiMe), -5.2 (SiMe); δH(500 MHz; CDCl3)
4.49 (dd, J = 9.1, 2.0 Hz, 1H, CHHO), 4.31 (dd, J = 9.1, 7.7 Hz,
1H, CHHO), 4.28 (ddd, J = 6.0, 5.3, 4.4 Hz, 1H, CHOTBDMS),
3.75 (s, 3H, OMe), 3.00 (ddd, J = 7.7, 6.0, 2.0 Hz, 1H,
OCH2CH), 2.39 (dt, J = 13.3, 7.3 Hz, 1H, CCHH), 2.25 (dt, J =
13.3, 7.3 Hz, 1H, CCHH), 1.84 (dtd, J = 12.8, 7.3, 4.4 Hz, 1H,
CCH2CHH), 1.66 (dtd, J = 12.8, 7.3, 5.3 Hz, 1H, CCH2CHH),
0.84 (s, 9H, SiCMe3), 0.03 (s, 6H, SiMe2); δC(125 MHz; CDCl3)
176.1 (CO), 170.6 (CO), 74.4 (CHOTBDMS), 66.2 (CH2O), 59.7
(CCO2Me), 53.1 (OMe), 50.5 (OCH2C), 35.0 (CCH2), 30.3
(CH2CHOTBDMS), 25.5 (SiCMe3), 17.8 (SiCMe3), -4.6 (Si
SiMe), -5.2 (Si SiMe); m/z LRMS (ESI+) 373.3
(M+NH4+MeCN+, 100%); HRMS (ESI+) found 332.1881,
4.1.14. (3aR*,6R*,6aS*)-Methyl 6-(tert-
butyldimethylsilyloxy)-3-oxohexahydro-1H-
cyclopenta-[c]furan-3a-carboxylate 20a-cv and
(3aR*,6S*,6aS*)-methyl 6-(tert-
butyldimethylsilyloxy)-3-oxohexahydro-1H-
cyclopenta-[c]furan-3a-carboxylate 20a-cc
Dimethyl
2-(3-(tert-butyldimethylsilyloxy)pent-4-
enyl)malonate 21a (7.0 g, 21.2 mmol) was dissolved in nitrogen
sparged acetonitrile (40 mL) and added via syringe (25 mL rinse)
to a mixture of manganese(III) acetate (12.0 g, 44.7 mmol) and
copper(II) triflate (7.7 g, 21.3 mmol). The reaction mixture was
diluted with nitrogen sparged acetonitrile (40 mL) and heated at
80 °C for 3 h 20 min under an atmosphere of nitrogen and then
cooled to room temperature. Water (600 mL), EtOAc (300 mL)
and brine (100 mL) were added and the aqueous layer extracted
with EtOAc (3 × 300 mL). The combined organic extracts were
dried (MgSO4) and con- centrated under reduced pressure to
yield the crude product (crude d.r. 2:1, 20a-cc: 20a-cv).
Purification by flash column chromatography (petrol 40-
60:EtOAc, gradient, 20:1→12:1→6:1→3:1 with 1% propane-2-
ol) gave the title compound 20a-cv as a white solid (1.34 g, 4.26
mmol, 20%); m.p. 38-40 °C; Rf = 0.51 (petrol 40-60:EtOAc,
3:1); found: C, 57.29%; H, 8.33%; C15H26O5Si requires: C,
57.35%; H, 8.24%; νmax(KBr)/cm−1 2955, 2929, 2893, 2858, 1772
(C=O), 1740 (C=O), 1464, 1438, 1386, 1235, 1155, 1060, 1021,
835 (Si-C), 777 (Si-C); δH(500 MHz; C6D6) 4.01 (dd, J = 9.6, 8.5
Hz, 1H, CHHO), 3.59 (dd, J = 7.5, 4.0 Hz, 1H, CHOTBDMS),
3.46 (dd, J = 9.6, 3.2 Hz, 1H, CHHO), 3.21 (s, 3H, OCH3), 2.82
(dddd, J = 13.4, 9.8, 7.4, 0.5 Hz, 1H, CCHH), 2.81-2.77 (m, 1H,
OCH2CH), 2.18 (ddd, J = 13.4, 7.3, 4.5 Hz, 1H, CCHH), 1.45
(ddddd, J = 13.2, 7.4, 4.5, 4.0, 1.3 Hz, 1H, CCH2CHH), 1.26
(dddd, J = 13.2, 9.8, 7.2, 4.6, Hz, 1H, CCH2CHH), 0.86 (s, 9H,
SiCMe3), -0.11 (s, 6H, SiMe2); δC(125 MHz; C6D6) 175.7 (CO),
170.0 (CO), 79.1 (CHOTBDMS), 69.2 (CH2O), 59.9 (CCO2Me),
55.2 (OCH2C), 52.5 (OMe), 34.5 (CH2CHOTBDMS), 31.3
(CCH2), 25.8 (SiCMe3), 18.0 (SiCMe3), -4.6 (SiMe), -4.9 (SiMe);
δH(500 MHz; CDCl3) 4.52 (dd, J = 9.6, 8.2 Hz, 1H, CHHO), 4.05
(dd, J = 9.6, 3.0 Hz, 1H, CHHO), 4.05-4.03 (m, 1H,
CHOTBDMS), 3.75 (s, 3H, OMe), 2.97 (dtdt, J = 8.2, 3.0, 1.7,
0.5 Hz, 1H, OCH2CH), 2.69 (ddd, J = 13.5, 9.7, 7.4 Hz, 1H,
CCHH), 2.14 (ddd, J = 13.5, 7.0, 4.6 Hz, 1H, CCHH), 1.81-1.74
(m, 1H, CCH2CHH), 1.69 (dddd, J = 13.2, 9.7, 7.0, 4.6 Hz, 1H,
CCH2CHH), 0.83 (s, 9H, SiCMe3), 0.03 (s, 6H, SiMe2); δC(125
MHz; CDCl3) 176.4 (CO), 170.0 (CO), 79.0 (CHOTBDMS),
70.0 (CH2O), 59.8 (CCO2Me), 54.8 (OCH2C), 53.3 (OMe), 34.6
(CH2CHOTBDMS), 31.2 (CCH2), 25.7 (SiCMe3), 18.0 (SiCMe3),
-4.5 (SiMe), -4.7 (SiMe); m/z LRMS (ESI+) 373.3
(M+NH4+MeCN+, 100%); HRMS (ESI+) found 337.1447,
C15H26NaO5Si+ (M+Na+) requires 337.1442. Single Crystal Data:
C15H30NO5Si+ (M+NH4 ) requires 332.1888. Data in accord with
+
literature.22
4.1.15. (3aR*,6R*,6aS*)-Methyl 6-(benzoyloxy)-3-
oxohexahydro-1H-cyclopenta[c] furan-3a-
carboxylate 20d-cv and (3aR *,6S*,6aS*)-methyl 6-
(benzoyloxy)-3-oxohexahydro-1H -
cyclopenta[c]furan-3a-carboxylate 20d-cc
Dimethyl 2-(3-(benzoyloxy)pent-4-en-1-yl)malonate 21d
(0.161 g, 0.500 mmol), manganese(III) acetate (0.269 g, 1.00
mmol) and copper(II) triflate (0.181 g, 0.50 mmol) were
dissolved in nitrogen sparged acetonitrile (2.5 mL). The reaction
mixture was heated at 40 °C for 5 h under an atmosphere of
nitrogen and then cooled to room temperature. sat. aq. sodium
bicarbonate (30 mL) was added followed by CH2Cl2 (30 mL).
The aqueous layer was extracted with CH2Cl2 (3 × 30 mL) and
the organic layers combined, dried (Na2SO4) and concentrated
under reduced pressure (crude product, d.r. 2:1, 20d-cc:20d-cv).
Purification by flash column chromatography (petrol 40-
60:EtOAc, 6:1) gave the title compound 20d-cv as a colorless oil
(0.033 g, 0.108 mmol, 21%); Rf = 0.51 (petrol:EtOAc, 1:1);
νmax(CDCl3)/cm−1 2978, 2957, 2919, 1778 (C=O), 1744 (C=O),
1718 (C=O), 1316, 1272, 1202, 1178, 1150, 1113, 1071, 1049,
1025, 977, 714; δH(500 MHz; CDCl3) 8.02-7.97 (m, 2H, ArH),
7.61-7.57 (m, 1H, ArH), 7.48-7.42 (m, 2H, ArH), 5.27 (ddd, J =
5.2, 2.4, 1.6 Hz, 1H, CHOBz), 4.67 (dd, J = 10.0, 8.6 Hz, 1H, H
CHHO), 4.38 (dd, J = 10.0, 2.9 Hz, 1H, CHHO), 3.79 (s, 3H,
OMe), 3.27 (ddt, J = 8.6, 2.9, 1.6 Hz, 1H, OCH2CH), 2.76 (ddd, J
= 13.5, 12.2, 7.0 Hz, 1H, CCHH), 2.43 (ddd, J = 13.5, 7.0, 2.4
Hz, 1H, CCHH), 2.20 (ddtd, J = 14.3, 7.0, 2.4, 1.6 Hz, 1H,
C15H26O5Si,
triclinic,
P¯1,
a=6.6840(2),
b=7.2294(2),
c=18.8432(6) Å,
α=99.3709(17)°,
β=90.3470(18)°,
γ=97.2494(14)°, V=890.87(5) Å3, Data/restraints/parameters

11
CCH2CHH), 1.95 (dddd, J = 14.3, 12.2, 7.0, 5.2 Hz, 1H,
CCH2CHH); δC(125 MHz; CDCl3) 175.3 (CO), 169.3 (CO),
166.0 (CO), 133.4 (Ar), 129.6 (Ar), 129.5 (Ar), 128.5 (Ar), 81.6
(CHOBz), 70.1 (CH2O), 60.5 (CCO2Me), 53.3 (OMe), 52.2
(OCH2C), 32.2 (CCH2), 31.5 (CH2CHOBz); m/z LRMS (ESI+)
327.1 ((M+Na+, 100%); HRMS (ESI+) found 327.0842,
C16H16NaO6+ (M+Na+), requires 327.0839.
31.8 (CH2), 31.4 (CH2), 30.3 (CH2), 21.0 (C(O)Me), 20.8
(C(O)Me); m/z LRMS (ESI+) 265.1 (M+Na+, 100%); HRMS
(ESI+) found 265.0689, C11H14NaO6 (M+Na+) requires
+
265.0683. The reaction was carried out with the same reagents
and quantities at room temperature for 24 h (crude product d.r.
2:1, 20e-cc:20e-cc).
4.1.17. (3aR*,6R*,6aS*)-Methyl 6-(benzyloxy)-3-
oxohexahydro-1H-cyclopenta[c] furan-3a-
carboxylate 20f-cv and (3aR*,6S*,6aS*)-methyl 6-
(benzyloxy)-3-oxohexahydro-1H-
Further elution of the column gave the title compound 20d-cc
as a colorless oil (0.079 g, 0.259 mmol, 52%); Rf = 0.37
(petrol:EtOAc, 1:1); νmax(CDCl3)/cm−1 2982, 2957, 1775 (C=O),
1735 (C=O), 1720 (C=O), 1270, 1251, 1160, 1112, 1070, 988,
713; δH(500 MHz; CDCl3) 8.02-7.98 (m, 2H, ArH), 7.62-7.57 (m,
1H, ArH), 7.49-7.43 (m, 2H, ArH), 5.55 (dt, J = 6.3, 4.7 Hz, 1H,
CHOBz), 4.48 (dd, J = 9.8, 7.2 Hz, 1H, CHHO), 4.43 (dd, J =
9.8, 2.0 Hz, 1H, CHHO), 3.83 (s, 3H, OMe), 3.43 (ddd, J = 7.2,
6.3, 2.0 Hz, 1H, OCH2CH), 2.61 (ddd, J = 14.0, 8.0, 6.0 Hz, 1H,
CCHH), 2.42 (ddd, J = 14.0, 7.4, 8.0 Hz, 1H, CCHH), 2.19 (dtd,
J = 13.5, 8.0, 4.7 Hz, 1H, CCH2CHH), 2.05 (dddd, J = 13.5, 7.4,
6.0, 4.7 Hz, 1H, CCH2CHH); δC(125 MHz; CDCl3) 175.6 (CO),
169.8 (CO), 165.7 (CO), 133.5 (Ar), 129.6 (Ar), 129.1 (Ar),
128.6 (Ar), 76.6 (CHOBz), 66.3 (CH2O), 60.2 (CCH2), 53.4
(OMe), 49.1 (OCH2C), 32.4 CH2CHOBz), 30.4 (CCH2); m/z
LRMS (ESI+) 327.1 (M+Na+, 100%); HRMS (ESI+) found
327.0839, C16H16NaO6+ (M+Na+), requires 327.0839.
cyclopenta[c]furan-3a-carboxylate 20f-cc and
dimethyl 3-hydroxy-2-methylcyclopentane-1,1-
dicarboxylate
A
mixture of dimethyl 2-(3-(benzyloxy)pent-4-en-1-
yl)malonate 21f (0.306 g, 1.00 mmol), manganese(III) acetate
dihydrate (0.537 g, 2.00 mmol) and copper(II) triflate (0.362 g,
1.00 mmol) was dissolved in nitrogen sparged acetonitrile (5
mL). The suspension was heated at 80 °C for 13 h 30 min under
an atmosphere of nitrogen and then cooled to room temperature.
Water (50 mL), EtOAc (50 mL) and brine (10 mL) were added
and the aqueous layer was ex- tracted with EtOAc (3 × 30 mL).
The combined organic extracts were dried (MgSO4), and
concentrated under reduced pressure (crude product relative
ratios 2:1.5:1, 20f-cv:20f-cc:cyclopentane, respectively).
Purification by flash column chromatography (petrol 30-
40:EtOAc, gradient, 12:1→6:1→3:1→1:1) gave the title
compound 20f-cv as a colorless oil (0.084 g, 0.289 mmol, 29%);
νmax(CDCl3)/cm−1 1775 (C=O), 1734 (C=O); δH(500 MHz;
CDCl3) 7.39-7.27 (m, 5H, ArH), 4.57 (dd, J = 9.6, 8.3 Hz, 1H,
CHHO), 4.55 (d, J = 11.9 Hz, 1H, CHHPh), 4.46 (d, J = 11.9 Hz,
1H, CHHPh), 4.11 (dd, J = 9.6, 2.7 Hz, 1H, CHHO), 3.87 (dt, J =
4.9, 2.7 Hz, 1H, CHOBn), 3.79 (m, 3H, OMe), 3.19 (dtd, J = 8.3,
2.7, 1.0 Hz, 1H, OCH2CH), 2.68 (ddd, J = 13.5, 10.6, 7.2 Hz, 1H,
CCHH), 2.28-2.22 (m, 1H, CCHH), 2.07-1.96 (m, 1H,
CCH2CHH), 1.73 (dddd, J = 13.6, 10.6, 7.0, 4.9 Hz, 1H,
CCH2CHH); δC(125 MHz; CDCl3) 175.9 (CO), 169.6 (CO),
137.6 (Ar), 128.5 (Ar), 127.8 (Ar), 127.5 (Ar), 85.5 CHOBn),
71.0 (CH2Ph), 70.3 (CH2O), 59.9 (CCO2Me), 53.2 (OMe), 51.6
(OCH2C), 31.4 (CCH2), 30.9 (CH2CHOBn); m/z LRMS (ESI+)
313.1 (M+Na+, 100%), 603.2 (2M+Na+, 80); HRMS (ESI+) found
4.1.16. (3aR*,6R*,6aS*)-Methyl 6-(acetoxyloxy)-3-
oxohexahydro-1H-cyclopenta[c] furan-3a-
carboxylate 20e-cv and (3aR *,6S*,6aS*)-methyl 6-
(acetoxyoxy)-3-oxohexahydro-1H-
cyclopenta[c]furan-3a-carboxylate 20e-cc
A mixture of dimethyl 2-(3-acetoxypent-4-en-1-yl)malonate
21e (0.130 g, 0.500 mmol), manganese(III) acetate dihydrate
(0.269 g, 1.00 mmol) and copper(II) triflate (0.181 g, 0.500
mmol) was dissolved in nitrogen sparged acetonitrile (2.5 mL).
The suspension was heated at 40 °C for 3 h 30 min under an
atmosphere of nitrogen and then cooled to room temperature.
Satu- rated aqueous sodium bicarbonate (30 mL) was added
followed by CH2Cl2 (30 mL). The aqueous layer was extracted
with CH2Cl2 (3 × 30 mL) and the organic layers combined, dried
(Na2SO4), and concentrated under reduced pressure (crude
product, d.r. 2:1, 20e-cc:20e-cv). Purification by flash column
chromatography (petrol 40-60:EtOAc, 6:1) gave a mixture of the
title compounds as a colorless oil (d.r. 2:1, 20e-cc:20e-cv, 0.081
g, 0.334 mmol, 67%); νmax(CDCl3)/cm−1 2979, 2959, 2919, 1777
(C=O), 1741 (C=O), 1436, 1377, 1268, 1240, 1156, 1131, 1090,
1048, 1020, 991, 732; δH(400 MHz; CDCl3) 5.24 (dt, J = 7.3, 5.5
Hz, 1H, CHOAc cc), 4.97 (dt, J = 5.3, 2.0 Hz, 1H, CHOAc cv),
4.58 (ddd, J = 9.9, 8.4, 0.8 Hz, 1H, CHHO cv), 4.38 (ddd, J =
9.7, 7.6, 0.7 Hz, 1H, CHHO cc), 4.30 (dd, J = 9.7, 2.0 Hz, 1H,
CHHO cc), 4.27 (dd, J = 9.9, 2.5 Hz, 1H, CHHO cv), 3.78 (s, 6H,
2×OMe), 3.33-3.28 (m, 1H, OCH2CH cc), 3.11-3.06 (m, 1H,
OCH2CH cv), 2.59 (dddd, J = 13.4, 12.1, 7.0, 0.6 Hz, 1H, CCHH
cv), 2.46 (dtd, J = 13.7, 7.6, 0.6 Hz, 1H, CCHH cc), 2.35-2.27
(m, 2H, CCHH cc, CCHH cv), 2.12-2.04 (m, 1H, CCH2CHH cc),
2.07 (s, 3H, OAc), 2.03 (s, 3H, OAc), 2.05-1.96 (m, 1H,
CCH2CHH cv), 1.87-1.70 (m, 2H, CCH2CHH cv, CCH2CH, cc);
δC(100 MHz; CDCl3) 175.5 (CO), 175.2 (CO), 170.5 (CO), 170.3
(CO), 169.7 (CO), 169.3 (CO), 81.2 (CHOAc cv), 75.8 (CHOAc
cc), 70.2 (CH2O b), 66.1 (CH2O cc), 60.4 (CCH2), 60.0 (CCH2),
53.3 (2×OMe), 52.0 (OCH2C cv), 48.2 (OCH2C cc), 32.0 (CH2),
313.1060, C16H18NaO5 (M+Na)+, requires 313.1046. Data in
+
accord with literature.22
Further elution of the column gave 20f-cc as a colorless oil
(0.063 g, 0.217 mmol, 22%); νmax(CDCl3)/cm−1,1773 (C=O),
1732 (C=O); δH(400 MHz; CDCl3) 7.40-7.24 (m, 5H, ArH), 4.64
(dd, J = 9.2, 2.5 Hz, 1H, CHHO), 4.59 (d, J = 12.0 Hz, 1H,
CHHPh), 4.24 (d, J = 12.0 Hz, 1H, CHHPh), 4.34 (dd, J = 9.2,
8.1 Hz, 1H, CHHO), 4.07 (td, J = 7.1, 5.0 Hz, 1H, CHOBn), 3.78
(s, 3H, OMe), 3.21-3.15 (m, 1H, OCH2CH), 2.37 (ddd, J = 13.7,
9.0, 7.3 Hz, 1H), 2.34-2.28 (m, 1H), 2.03-1.94 (m, 1H), 1.83-1.73
(m, 1H); m/z LRMS (ESI+) 313.1 (M+Na+, 100%), 603.2
+
(2M+Na+, 80); HRMS (ESI+) found 313.1046, C16H18NaO5
(M+Na+), requires 313.1046. Data in accord with literature.22
Further elution of the column gave dimethyl 3-hydroxy-2-
methylcyclopentane-1,1-dicarboxylate as a colorless oil (0.029 g,
0.134 mmol, 13%); νmax(CDCl3)/cm−1 3528 (O-H), 2954, 2915,
2884, 2849, 1731 (C=O); δH(500 MHz; CDCl3) 4.16-4.06 (m,
1H, CHOH), 2×3.75 (s, 3H, OMe), 2.64-2.54 (m, 2H, CHMe,
CCHH), 2.20 (ddd, J = 14.4, 9.8, 4.7 Hz, 1H, CCHH), 1.99

12
Tetrahedron
(dddd, J = 13.8, 9.8, 8.4, 5.4 Hz, 1H, HOCHCHH), 1.88
Hz, 1H, CHHO), 3.26 (s, 3H, OMe), 2.59-2.55 (m, 1H,
OCH2CH), 2.47 (ddd, J = 13.5, 7.0, 5.2 Hz, 1H, CCHH), 2.23
(ddd, J = 13.5, 9.0, 7.4 Hz, 1H, CCHH), 1.58-1.52 (m, 1H,
CCH2CHH), 1.48 (ddt, J = 13.0, 7.4, 5.2 Hz, 1H, CCH2CHH),
1.20 (s, 9H, SiCMe3); δC(125 MHz; C6D6) 175.6 (CO), 170.2
(CO), 136.0 (Ar), 136.0 (Ar), 133.8 (Ar), 133.6 (Ar), 130.3 (Ar),
75.5 (CHOTBDPS), 65.8 (CH2O), 60.0 (CCO2Me), 52.4 (OMe),
49.5 (OCH2C), 34.3 (CH2CHOTBDPS), 30.3 (CCH2), 27.0
(SiCMe3), 19.3 (SiCMe3); m/z LRMS (ESI+) 461.1 (M+Na+,
100%), 899.3 (2M+Na+, 100); HRMS (ESI+) found 461.1757,
C25H30NaO5Si+ (M+Na+), requires 461.1755. Single Crystal
Data: C25H30O5Si, orthorhombic, P212121, a=13.6562(5),
(dddd, J = 13.8, 8.9, 4.7, 2.2 Hz, 1H, HOCHCHH), 1.63 (br s,
1H, OH), 1.13 (d, J = 7.2 Hz, 3H, CHMe); δC (125 MHz; CDCl3)
174.5 (CO), 172.6 (CO), 76.6 (CHOH), 62.6 (C(CO2Me)2), 52.9
(OMe), 52.8 (OMe), 46.5 (CHMe), 34.1 (HOCHC2), 33.0
(CCH2), 10.6 (CHMe); m/z LRMS (ESI+) 239.1 (M+Na+, 100%);
HMRS (ESI+) found 239.0889, C10H16NaO5 (M+Na+), requires
+
239.0890.
The reaction was also carried out on the same scale, at 40 °C
for 12 h (crude product relative ratios 2:1.5:1, 20f-cv:20f-
cc:cyclopentane, respectively). Purification by flash column
chromatography (petrol 40-60:EtOAc, gradient, 6:1→3:1→1:1)
gave the title compound 20f-cv (0.110 g, 0.379 mmol, 38%), title
compound 20f-cc (0.062 g, 0.213 mmol, 21%) and dimethyl 3-
hydroxy-2-methylcyclopentane-1,1-dicarboxylate (0.015 g, 0.069
mmol, 7%).
b=9.7220(4),
c=16.9985(8) Å,
V=2256.82(16) Å3,
Data/restraints/parameters 3119/0/281, Rint=0.170, Flack
x=0.2(3), Final R1=0.0857, wR2=0.1700 (I>2s(I)).
4.1.19. (3aR*,6R*,6aS*)-Ethyl 6-(tert-
butyldimethylsilyloxy)-3-oxohexahydro-1H-
cyclopenta[c]furan-3a-carboxylate 20b-cv and
(3aR*,6S*,6aS*)-ethyl 6-(tert-
butyldimethylsilyloxy)-3-oxohexahydro-1H-
cyclopenta[c]furan-3a-carboxylate 20b-cc
4.1.18. (3aR*,6R*,6aS*)-Methyl 6-((tert-
butyldiphenylsilyl)oxy)-3-oxohexahydro-1H-
cyclopenta[c]furan-3a-carboxylate 20c-cv and
(3aR*,6S*,6aS*)-Methyl 6-((tert-
butyldiphenylsilyl)oxy)-3-oxohexahydro-1H-
cyclopenta[c]furan-3a-carboxylate 20c-cc
Diethyl
2-(3-((tert-butyldimethylsilyl)oxy)pent-4-en-1-
yl)malonate 21b (0.196 g, 0.546 mmol), manganese(III) acetate
(0.294 g, 1.09 mmol) and copper(II) triflate (0.198 g, 0.546
mmol) were dissolved in nitrogen sparged acetonitrile (2.7 mL).
The reaction mixture was heated at 40 °C for 3 h under an
atmosphere of nitrogen. Water (30 mL) was added followed by
EtOAc (30 mL). The organic layer was washed with brine (30
mL) and the combined aqueous layers extracted with EtOAc (3 ×
30 mL). The combined organic layers were dried (MgSO4) and
concetrated under reduced pressure to yield the crude product
(d.r. 2:1, 204A:204B). Purification by flash column
chromatography (petrol 30-40:EtOAc, gradient, 9:1→3:1→3:1)
gave recovered starting material 21c as a colorless oil (0.015 g,
0.042 mmol, 7%); Rf = 0.8 (petrol:EtOAc, 3:1).
Dimethyl
2-(3-((tert-butyldiphenylsilyl)oxy)pent-4-en-1-
yl)malonate 21c (0.197 g, 0.433 mmol), manganese(III) acetate
dihydrate (0.233 g, 0.869 mmol) and copper(II) triflate (0.157 g,
0.434 mmol) were dissolved in nitrogen sparged acetonitrile (2.1
mL). The reaction mixture was heated at 40 °C for 13 h under an
atmosphere of nitrogen and then cooled to room temperature.
Water (20 mL), EtOAc (30 mL) and sat. aq. NH4Cl (10 mL)
were added and the aqueous layer extracted with EtOAc (3 × 30
mL). The combined organic layers were dried (MgSO4) and
concentrated under reduced pressure to yield the crude product
(d.r. 2:1, 20c-cc:20c-cv). Purification by flash column
chromatography (dry loading, petrol 40-60:EtOAc, gradient, 6:1)
gave the title compound 20c-cv as a colorless oil (0.047 g, 0.107
mmol, 25%); Rf = 0.5 (petrol:EtOAc, 3:1); νmax(CDCl3)/cm−1
2956, 2931, 2894, 2858, 1779 (C=O), 1746 (C=O), 1472, 1461,
1428, 1266, 1243, 1150, 1111, 1040, 822, 741, 704; δH(500
MHz; CDCl3) 7.64-7.59 (m, 4H, ArH), 7.49-7.43 (m, 2H, ArH),
7.43-7.37 (m, 4H, ArH), 4.24 (dd, J = 9.8, 8.9 Hz, 1H, CHHO),
4.09-4.07 (m, 1H, CHOTBDPS), 3.80 (s, 3H, OMe), 3.63 (dd, J =
9.8, 3.3 Hz, 1H, CHHO), 3.03-2.98 (m, 1H, OCH2CH), 2.81
(ddd, J = 13.3, 11.0, 7.0 Hz, 1H, CCHH), 2.19 (ddd, J = 13.3,
7.0, 3.5 Hz, 1H, CCHH), 1.91 (ddtd, J = 13.4, 7.0, 3.5, 1.4 Hz,
1H, CCH2CHH), 1.59 (dddd, J = 13.4, 11.0, 7.0, 4.6 Hz, 1H,
CCH2CHH), 1.06 (s, 9H, SiCMe3); δC(125 MHz; CDCl3) 176.1
(CO), 169.8 (CO), 135.6 (Ar), 133.5 (Ar), 133.1 (Ar), 130.0 (Ar),
127.8 (Ar), 80.1 (CHOTBDPS), 69.6 (CH2O), 60.1 (CCO2Me),
54.6 (OCH2C), 53.1 (OMe), 34.3 (CH2CHOTBDPS), 31.7
(CCH2), 26.7 (SiCMe3), 19.0 (SiCMe3); m/z LRMS (ESI+) 461.2
(M+Na+, 100%), 899.3 (2M+Na+, 78); HRMS (ESI+) found
461.1748, C25H30NaO5Si+ (M+Na+), requires 461.1755.
Further elution of the column gave title compound 20b-cv as a
colorless oil (0.025 g, 0.076 mmol, 14%) Rf
= 0.62
(petrol:EtOAc, 3:1); νmax(KBr)/cm−1 2956, 2932, 2904, 2857,
2709, 1775 (C=O), 1736 (C=O), 1248, 1159, 1058, 1029, 838
(Si-C), 776 (Si-C); δH(500 MHz; CDCl3) 4.55 (ddd, J = 9.4, 8.3,
1.0 Hz, 1H, CHHO), 4.26-4.21 (m, 2H, OCH2Me), 4.08 (ddd, J =
9.4, 3.1, 0.8 Hz, 1H, CHHO), 4.08-4.05 (m, 1H, CHOTBDMS),
2.99 (dt, J = 8.3, 3.1 Hz, 1H, OCH2CH), 2.72 (ddd, J = 13.5, 9.5,
7.5 Hz, 1H, CCHH), 2.16 (ddd, J = 13.5, 7.0, 4.5 Hz, 1H,
CCHH), 1.81 (ddt, J = 13.9, 7.5, 4.5 Hz, 1H, CCH2CHH), 1.73
(dddd, J = 13.9, 9.5, 7.0, 4.8 Hz, 1H, CCH2CHH), 1.30-1.27 (m,
3H, OCH2Me), 0.87 (s, 9H, SiCMe3), 0.06 (s, 6H, SiMe2); δC(125
MHz; CDCl3) 176.4 (CO), 169.3 (CO), 78.8 (CHOTBDMS),
69.8 (CH2O), 62.1 (OCH2Me), 59.7 (CCO2Me), 54.8 (OCH2C),
34.5 (CH2CHOTBDMS), 30.8 (CCH2), 25.6 (SiCMe3), 17.8
(SiCMe3), 14.0 (CH2Me), -4.6 (SiMe), -4.9 (SiMe); m/z LRMS
(ESI+) 351.1 (M+Na+, 100%); HRMS (ESI+) found 351.1600,
C16H28NaO5Si+(M+Na+), requires 351.1598.
Further elution of the column gave 20c-cc as a white solid
(0.095 g, 0.216 mmol, 50%); m.p. 116-118 °C; Rf = 0.38
(petrol:EtOAc, 3:1); νmax(CDCl3)/cm−1 3463, 2961, 2935, 2860,
1775 (C=O), 1742 (C=O), 1720, 1429, 1247, 1155, 1102, 1049,
1022, 976, 746, 704; δH(500 MHz; C6D6) 7.74- 7.69 (m, 4H,
ArH), 7.34-7.26 (m, 6H, ArH), 4.69 (dd, J = 9.2, 2.3 Hz, 1H,
CHHO), 4.19-4.14 (m, 1H, CHOTBDPS), 4.09 (dd, J = 9.2, 8.0
Further elution of the column gave the title compound 20b-cc
as a white solid (0.088 g, 0.268 mmol, 49%) m.p. 44-46 °C; Rf =
0.48 (petrol:EtOAc, 3:1); νmax(CH2Cl2)/cm−1 2956, 2928, 2885,
2857, 1780 (C=O), 1774 (C=O), 1248, 1055, 835 (Si-C), 776 (Si-
C); δH(500 MHz; CDCl3) 4.51 (dd, J = 9.1, 2.1 Hz, 1H, CHHO),
4.33 (dd, J = 9.1, 7.7 Hz, 1H, CHHO), 4.30 (ddd, J = 6.2, 5.4, 4.4

13
Hz, 1H, CHOTBDMS), 4.24-4.19 (m, 2H, OCH2Me), 3.00 (ddd,
J = 7.7, 6.2, 2.1 Hz, 1H, OCH2CH), 2.41 (ddd, J = 13.5, 7.6, 6.8
Hz, 1H, CCHH), 2.26 (ddd, J = 13.5, 7.6, 6.8 Hz, 1H, CCHH),
1.86 (dtd, J = 12.7, 7.6, 4.4 Hz, 1H, CCH2CHH), 1.68 (dtd, J =
12.7, 6.8, 5.4 Hz, 1H, CCH2CHH), 1.29-1.25 (m, 3H, OCH2Me),
0.87 (s, 9H, SiCMe3), 0.06 (s, 6H, SiMe2); δC (125 MHz; CDCl3)
176.2 (CO), 170.1 (CO), 74.4 (CHOTBDMS), 66.3 (CH2O), 62.2
(ddd, J = 13.9, 8.2, 4.3 Hz, 1H, CCHH b), 2.55 (ddd, J = 7.4,
6.7, 1.6 Hz, 1H, OCH2CH b), 2.36 (ddd, J = 13.3, 11.8, 6.5 Hz,
1H, CCHH a), 2.36-2.25 (m, 1H, CHMe a), 2.29 (ddd, J = 13.3,
7.0, 2.1 Hz, 1H, CCHH a), 2.12 (ddd, J = 13.8, 8.7, 7.1 Hz, 1H,
CCHH b), 1.94-1.83 (m, 3H, 2HB & 1HA, CHMe b, CCH2CHH
a, CCH2CHH b), 1.51-1.39 (m, 1H, CCH2CHH b), 1.24 (qd, J =
11.8, 7.1 Hz, 1H, CCH2CHH a), 1.07 (d, J = 6.5 Hz, 3H, CHMe
b), 1.04 (d, J = 7.0 Hz, 3H, CHMe a); δC(100 MHz; CDCl3) 176.7
(CO b), 176.6 (CO a), 170.5 (CO a, b), 71.0 (CH2O b), 67.0
(CH2O a), 61.5 (CCO2Me a), 61.4 (CCO2Me b), 54.3 (OCH2C b),
53.1 (OMe a, b), 48.4 (OCH2C a), 41.7 (CHMe b), 37.4 (CHMe
a), 34.5 (CH2CHMe b), 33.8 (CCH2 a), 33.3 (CH2CHMe a), 32.7
(CCH2 b), 18.2 (CHMe b), 14.5 (CHMe a); m/z LRMS (ESI+)
419.2 (2M+Na+, 100%), 221.1 (M+Na+, 78); HRMS (ESI+) found
(CH2Me),
59.9
(CCO2Me),
50.6
(OCH2C),
35.0
(CH2CHOTBDMS), 30.1 (CCH2), 25.5 (SiCMe3), 17.8 (SiCMe3),
14.0 (CH2Me), -4.6 (SiMe), -5.1 (SiMe); m/z LRMS (ESI+) 679.3
(2M+Na+, 100%), 351.1 (M+Na+, 98); HRMS (ESI+) found
351.1600, C16H28O5SiNa+ (M+Na+), requires 351.1598. Single
Crystal Data: C16H28O5Si, monoclinic, P21, a=11.1296(2),
b=7.13140(10),
c=23.8950(5) Å,
Data/restraints/parameters
β=101.9519(7)°,
V=1855.42(6) Å3,
8106/1/398,
221.0786, C10H14NaO4 (M+Na+), requires 221.0784. The
+
Rint=0.055, Flack x=-0.15(9), Final R1=0.0406, wR2=0.0833
(I>2s(I)).
reaction was repeated with the same reagents on the same scale at
80 °C overnight to give a mixture of the title compounds 20g-cv
and 20g-cc (d.r. 5:1, 20g-cv:20g-cc) as a colorless oil (0.151 g,
0.762 mmol, 76%).
4.1.20. (3aR*,6R*,6aS*)-Methyl 6-methyl-3-
oxohexahydro-1H-cyclopenta[c] furan-3a-
carboxylate 20g-cv and (3aR*,6S*,6aS*)-methyl 6-
methyl-3-oxohexahydro-1H-cyclopenta[c] furan-3a-
carboxylate 20g-cc
4.1.21. Methyl 3-hydroxy-2-methylenepent-4-enoate
26
To a solution of amine 2524 (9.95 g, 54.7 mmol) in chloroform
(500 mL) at 0 °C was added dropwise a solution of purified
mCPBA (10 g, 60 mmol) in chloroform (150 mL). The reaction
was allowed to warm to RT over 16 h and then partially
concentrated in vacuo. The solution was then passed through a
column of basic alumina (deactivated with 6% w/w water)
eluting with chloroform. Concentration in vacuo then gave a
mixture of the title compound and starting amine that were
separated by flash column chromatography (4:1 petrol:Et2O) to
give the title compound 26 as a colorless oil (4.00 g, 28.2 mmol,
51%); Rf 0.62 (4:1 petrol:EtOAc); δH (400 MHz CDCl3) 6.28
(1H, br s, CHH’=C) 5.98 (1H, dddt, J = 17.1, 10.3, 5.4, 1.0 Hz,
CH2=CH), 5.88 (1H, br s, CHH’=C), 5.36 (1H, dt, J = 17.1, 1.0
Hz, CHH’=CH), 5.22 (1H, dt, J = 10.3, 1.0 Hz, CHH’=CH), 4.98
(1H, t, J = 5.4 Hz, CHOH), 3.80 (3H, s, OMe), 2.95 (1H, br m,
CHOH); δC (100 MHz CDCl3) 166.8 (CO), 141.1 (C=CH2),
138.1 (CH2=CH), 125.9 (C=CH2), 116.1 (CH2=CH), 72.2
(CHOH), 52.0 (OMe). In accordance with the literature values.24
HPLC data; column: Chiralpak OD, flow rate: 0.8 mL/min,
solvent: 5% IPA in hexane, retention time for (R) 13.20 min, (S)
15.20 min.
Dimethyl 2-(3-methylpent-4-en-1-yl)malonate 176 (0.215 g,
1.00 mmol), manganese(III) acetate (0.537 g, 2.00 mmol) and
copper(II) triflate (0.362 g, 1.00 mmol) were dissolved in
nitrogen sparged acetonitrile (5 mL). The reaction mixture was
heated at 40 °C for 3 h under an atmosphere of nitrogen and then
cooled to room temperature. Water (30 mL) was added followed
by EtOAc (30 mL) and sat. aq. sodium bicarbonate (10 mL). The
aqueous layer was extracted with EtOAc (3 × 30 mL) and the
organic layers combined, dried (MgSO4) and concentrated under
reduced pressure (crude d.r. 5:1 20g-cv:20g-cc). Purification by
flash column chromatography (petrol 40-60:EtOAc, 20:1) gave
recovered starting material 21g as a colorless oil (0.048 g, 0.224
mmol, 22%).
Further elution of the column gave the title compound 20g-cv
as a colorless oil (0.070 g, 0.353 mmol, 35%); νmax(CDCl3)/cm−1
2958, 2873, 1774 (C=O), 1742 (C=O), 1458, 1435, 1376, 1251,
1213, 1196, 1167, 1143, 1107, 1062, 1044, 1005, 984, 967;
δH(400 MHz; CDCl3) 4.50 (dd, J = 9.3, 6.7 Hz, 1H, CHHO), 4.14
(dd, J = 9.3, 1.6 Hz, 1H, CHHO), 3.76 (s, 3H, OMe), 2.61 (ddd, J
= 13.9, 8.2, 4.3 Hz, 1H, CCHH), 2.55 (ddd, J = 7.4, 6.7, 1.6 Hz,
1H, OCH2CH), 2.12 (ddd, J = 13.9, 8.7, 7.1 Hz, 1H, CCHH),
1.94-1.83 (m, 2H, CHMe, CCH2CHH), 1.51-1.39 (m, 1H,
CCH2CHH), 1.07 (d, J = 6.5 Hz, 3H, CHMe); δC(100 MHz;
CDCl3) 176.7 (CO), 170.5 (CO), 71.0 (CH2O), 61.4 (CCO2Me),
54.3 (OCH2C), 53.1 (OMe), 41.7 (CHMe), 34.5 (CH2CHMe),
32.7 (CCH2), 18.2 (CHMe); m/z LRMS (ESI+) 221.1 (M+Na+,
4.1.22. Methyl 3-((tert-butyldimethylsilyl)oxy)-2-
methylenepent-4-enoate 27
To a solution of alcohol 26 (3.88 g, 27.3 mmol) in CH2Cl2 (55
mL) was added sequentially imidazole (5.50 g, 72.6 mmol) and
TBDMSCl (5.00 g, 36.3 mmol). The reaction was stirred for 16 h
then quenched with sat. aq. NH4Cl (25 mL). The aqueous layer
was then separated and extracted with CH2Cl2 (2 × 50mL). The
combined organic layers were dried (Na2SO4), filtered and
concentrated in vacuo. Purification by flash column
chromatography (98:2 petrol:EtOAc) gave the title compound 27
as a colorless oil (6.17 g, 24.0 mmol, 88%); Rf 0.60 (petrol); δH
(400 MHz, CDCl3) 6.21 (1H, t, J = 1.5 Hz, CHH’=C), 5.96 (1H,
t, J = 1.5 Hz, CHH’=C), 5.83 (1H, ddd, J = 17.1, 10.1, 5.8 Hz,
CH2=CH), 5.27 (1H, dt, J = 17.1, 1.5 Hz, CHH’=CH), 5.05 (1H,
+
100%); HRMS (ESI+) found 221.0792, C10H14NaO4 (M+Na+),
requires 221.0784. Data in accord with literature.22
Further elution gave a mixture of compound 20g-cv and
compound 20g-cc as a colorless oil (0.023 g, 1.5:1, 20g-cv:20g-
cc, 0.116 mmol, 12%); νmax(CDCl3)/cm−1 2958, 2874, 1774
(C=O), 1742 (C=O), 1458, 1435, 1376, 1304, 1251, 1213, 1166,
1142, 1110, 1062, 1044, 1022, 1006, 984; δH(400 MHz; CDCl3)
4.50 (dd, J = 9.3, 6.7 Hz, 1H, CHHO b), 4.37 (dd, J = 9.7, 8.1
Hz, 1H, CHHO a), 4.29 (dd, J = 9.7, 3.4 Hz, 1H, CHHO a), 4.14
(dd, J = 9.3, 1.6 Hz, 1H, CHHO b), 3.77 (s, 3H, OMe a), 3.76 (s,
3H, OMe b), 3.09 (td, J = 8.1, 3.4 Hz, 1H, OCH2CH a), 2.61
dt,
J = 10.5, 1.5 Hz, CHH’=CH), 5.02–5.07 (1H, m,

14
Tetrahedron
CHOTBDMS), 3.75 (3H, s, OMe), 0.84 (9H, s, CMe3), 0.06
(3H, s, 205 SiMe), 0.04 (3H, s, SiMe); δC (100 MHz CDCl3)
166.5 (CO), 142.7 (CH2=C), 139.2 (CH2=CH), 124.2 (CH2=C),
114.5 (CH2=CH), 71.4 (CHOTBDMS), 51.7 (OMe), 25.8
(SiCMe3), 18.3 (SiCMe3), -4.8 (SiMe), -5.1 (SiMe). Data in
accordance with the literature values.39
To a stirred suspension of NaH (60% dispersion in mineral oil,
2.5 g, 62.4 mmol) in DMF (80 mL) and THF (40 mL) at 0 °C
was added dimethyl malonate dropwise (7.4 mL, 8.2 g, 62.4
mmol). The reaction mixture was warmed to RT and the crude
mesylate 3-((tert-butyldimethylsilyl)oxy)-2-methylenepent-4-en-
1-yl methanesulfonate prepared above was added as a solution in
THF (40 mL) followed by the addition of KI (1.04 g, 6.24
mmol). The reaction mixture was warmed to 80 °C and stirred
16 h, then allowed to cool to RT, quenched with sat. aq. NH4Cl
(80 mL) and petrol (80 mL) was added. The aqueous layer was
extracted with petrol (2 × 80 mL), the combined organic layers
were dried (MgSO4), filtered and the solvent removed in vacuo.
Purification by flash column chromatography gave the title
compound 28 as a colorless oil (5.88 g, 17.2 mmol, 83%); Rf 0.43
(10:1 petrol:EtOAc); νmax/cm-1 (thin film) 2955w, 1740s, 1230m;
δH (400 MHz CDCl3) 5.76 (1H, ddd, J = 17.0, 10.3, 5.5 Hz,
CH2=CH), 5.29 (1H, dt, J = 17.0, 1.5 Hz, CHH’=CH), 5.13 (1H,
dt, J = 10.3, 1.5 Hz, CHH’=CH), 5.12 (1H, br s, CHH’=C) 4.84
(1H, br s, CHH’=C), 4.57 (1H, d, J = 5.5 Hz, CHOTBDMS),
3.74 (1H, t, J = 7.8 Hz, CH(CO2Me)2), 3.73 (3H, s, OMe), 3.73
4.1.23. 3-((tert-Butyldimethylsilyl)oxy)-2-
methylenepent-4-en-1-ol
To a solution of ester 27 (6.17 g, 24.0 mmol) in THF (60 mL)
at -35 °C was added DIBAL (60 mL, 1 M in hexane, 60 mmol)
dropwise and the reaction stirred for 2 h at between -35 °C and -
20 °C. The reaction was then quenched by the slow addition of
MeOH (5 mL) followed by sat. aq. sat. aq. Rochelle’s salt (60
mL), sat. aq. NH4Cl (10 mL) and EtOAc (100 mL). The mixture
was vigorously stirred for 2 h. The aqueous layer was then
separated and extracted with EtOAc (2 × 150 mL). The combined
organic phases were dried (MgSO4), filtered and concentrated in
vacuo. Purification by flash column chromatography (6:1
petrol:EtOAc) gave the title compound as a colorless oil (4.76 g,
20.6 mmol, 86%); Rf 0.41 (6:1 petrol:EtOAc); νmax/cm-1 (thin
film) 3400br w, 2931m; δH (400 MHz CDCl3) 5.83 (1H, ddd, J =
17.0, 10.3, 5.5 Hz, CH2=CH), 5.29 (1H, dt, J = 17.0, 1.5 Hz,
CHH’=CH), 5.13 (1H, dt, J = 10.3, 1.5 Hz, CHH’=CH), 5.09
(2H, br s, CH2=C), 4.67 (1H, d J = 5.5 Hz, CHOTBDMS), 4.21
(1H, dd, J = 13.3, 5.5 Hz, CHH’OH), 4.08 (1H, dd, J = 13.3, 5.5
Hz, CHH’OH), 2.11 (1H, t, J = 5.5 Hz, OH), 0.90 (9H, s,
SiCMe3), 0.07 (3H, s, SiMe), 0.07 (3H, s, SiMe); δC (100 MHz
CDCl3) 149.1 (CH2=C), 139.7 (CH2=CH), 114.7 (CH2=CH),
111.9 (CH2=C), 76.6 (CHOTBDMS), 63.8 (CH2OH), 25.7
(SiCMe3), 18.3 (SiCMe3), -4.8 (SiMe), -5.1 (SiMe); m/z LRMS
(ESI+) 227 (M+Na+, 100); HRMS (ESI+): found 251.1441,
C12H24O2SiNa+ (M+Na+), requires 251.1438.
(3H, s, OMe), 2.69 (1H, dd,
CHH’CH(CO2Me)2), 2.61 (1H, dd,
J
=
15.5, 7.8 Hz,
J
= 15.5, 7.8 Hz,
CHH’CH(CO2Me)2), 0.91 (9H, s, SiCMe3), 0.06 (6H, s, SiMe2);
δC (100 MHz CDCl3) 169.6 (CO), 146.8 (CH2=C), 139.7
(CH2=CH), 114.9 (CH2=CH), 111.6 (CH2=C), 76.7
(CHOTBDMS), 52.5 (OMe), 52.5 (OMe), 50.6 (CH(CO2Me)2),
30.1 (CH2CH(CO2Me)2) 25.8 (SiCMe3), 18.3 (SiCMe3), -4.8
(SiMe), -5.0 (SiMe); m/z LRMS (ESI+) 365 (M+Na+, 100);
HRMS (ESI+): found 365.1754, C17H30O5SiNa+ (M+Na+),
requires 365.1755.
4.1.26. Methyl (3aR*,6R*,6aS*)-6-((tert-
butyldimethylsilyl)oxy)-5-methylene-3-
oxotetrahydro-1H-cyclopenta[c] furan-3a(3H)-
carboxylate 30cc and methyl (3aS*,6R*,6aR*)-6-
((tert-butyldimethylsilyl)oxy)-5-methylene-3-
oxotetrahydro-1H- cyclopenta[c] furan-3a(3H)-
carboxylate 30cv
4.1.24. 3-((tert-Butyldimethylsilyl)oxy)-2-
methylenepent-4-en-1-yl methanesulfonate
To a solution of alcohol 3-((tert-butyldimethylsilyl)oxy)-2-
methylenepent-4-en-1-ol (4.76 g, 20.8 mmol) in CH2Cl2 (80 mL)
at 0 °C was added Et3N (4.3 mL. 3.1 g, 31.2 mmol) followed by
MsCl (2.08 mL, 13.08 g, 27 mmol) and the reaction mixture was
stirred for 10 min and then quenched with sat. aq. NH4Cl (80
mL). The organic layer was separated, and the aqueous layer
extracted with CH2Cl2 (2 × 80 mL). The combined organic
layers were washed with brine (80 mL), dried (MgSO4) to yield
the title compound as a yellow oil; Rf 0.41 (6:1 petrol:EtOAc);
νmax/cm-1 (thin film) 2931m, 1359s, 1176s; δH (400 MHz CDCl3)
5.76 (1H, ddd, J = 17.1, 10.3, 5.9 Hz, CH2=CH), 5.36 (1H, s,
CHH’=C), 5.30 (1H, dt, J = 17.1, 1.5 Hz, CHH’=CH), 5.28 (1H,
s, CHH’=C), 5.15 (1H, dt, J = 10.3, 1.5 Hz, CHH’=CH), 4.68–
4.73 (3H, m, CHOTBDMS, CH2OMs), 3.00 (3H, s, SO2Me), 0.89
(9H, s, SiCMe3), 0.06 (6H, s, SiMe2); δC (100 MHz CDCl3) 143.4
(CH2=C), 138.9 (CH2=CH), 115.6 (CH2=C), 115.2 (CH2=CH),
74.8 (CHOTBDMS), 69.0 (CH2OMs), 37.8 (SO2Me), 25.7
(SiCMe3), 18.3 (SiCMe3), -4.8 (SiMe), -5.0 (SiMe); m/z LRMS
(ESI+) 329 (M+Na+, 100); HRMS (ESI+): found 329.1211,
C13H26O4SSiNa+ (M+Na+), requires 329.1213.
To a solution of malonate 28 (500 mg, 1.46 mmol) and CuI
(25 mg, 0.125 mmol) in CH2Cl2 (15 mL) cooled to –78 °C was
added ethylmagnesium bromide (0.70 mL, 3 M in Et2O, 2.1
mmol) and the mixture then stirred for 15 min. Iodine was added
(1.8 g, 5.8 mmol) and the reaction warmed to RT and stirred for
16 h. The reaction was quenched with sat. aq. Na2S2O3 (25 mL),
then diluted with H2O (100 mL) and CH2Cl2 (200 mL). The
aqueous layer was separated and extracted with CH2Cl2 (2 × 150
mL). The combined organic layers were washed with brine (100
mL), dried (Na2SO4), filtered and concentrated in vacuo. The
crude solid was then heated to 140 °C for 20 min before being
cooled to RT and purified by flash column chromatography (7:1
petrol:EtOAc) to give 30cv as a colorless oil (26.5 mg, 0.08
mmol, 6%) followed by 30cc as a colorless oil (412 mg, 1.26
mmol, 87%); (Major 30cc) Rf 0.52 (7:1 petrol:EtOAc); νmax/cm-1
(thin film) 2963m, 1775s, 1734s, 1249s; δH (400 MHz C6D6) 5.01
(1H, br m, CHH’=C), 4.80 (1H, br m, CHH’=C), 4.32 (1H, dd, J
= 9.3, 3.4 Hz, CHH’O), 4.25 (1H, dt, J = 7.2, 1.8 Hz,
CHOTBDMS), 4.04 (1H, dd, J = 9.3, 8.2 Hz, CHH’O), 3.33 (3H,
4.1.25. Dimethyl 2-(3-((tert-
butyldimethylsilyl)oxy)-2-methylenepent-4-en-1-
yl)malonate 28

15
spiro[cyclopenta[c] furan-5,2'-oxirane] -6a(6H)-
carboxylate 31b
s, OMe), 3.23 (1H, dt, J = 16.2, 2.3 Hz, CHH’C=CH2), 3.04 (1H,
dt, J = 16.2, 2.3 Hz, CHH’C=CH2), 2.86 (1H, td, J = 7.2, 3.4 Hz,
CHCHOTBDMS), 0.94 (9H, s SiCMe3), 0.00 (3H, s, SiMe), -
0.06 (3H, s, SiMe); δC (100 MHz CDCl3) 175.7 (C=O), 170.2
(C=O), 147.8 (CH2=C), 109.2 (CH2=C), 74.4 (CHOTBDMS),
66.0 (CH2OR), 57.4 (CCO2Me), 53.4 (OMe), 48.3 (CHCH2OR),
35.8 (CH2C=CH2), 25.8 (CMe3), 18.1 (SiCMe3), -4.8 (SiMe), -5.1
+
(SiMe); m/z LRMS (ESI+) 344 (M+NH4 , 100); HRMS (ESI+):
To a solution of alkene 30cc (40 mg, 0.125 mmol) in acetone
(0.5 mL) was added a solution of DMDO (3.0 mL, 0.08 M, 0.24
mmol) and the reaction was left to stand for 5 h. The reaction was
then concentrated in vacuo, followed by azeotropic drying with
isopropanol in vacuo. Purification by flash column
chromatography (6:1 petrol:EtOAc) gave the title compound 31b
as a colorless oil (32 mg, 94 ꢀmol, 75%) and epoxide 31a (6 mg,
18 ꢀmol, 14%); Rf 0.42 (6:1 petrol:EtOAc); νmax/cm-1 (thin film)
2955w, 1777s, 1744s, 1253m; δH (400 MHz CDCl3) 4.55 (1H,
dd, J = 9.3, 2.3 Hz, CHH’O), 4.41 (1H, dd, J = 9.3, 8.0 Hz,
CHH’O), 4.13 (1H, d, J = 8.0 Hz, CHOTBDMS), 3.81 (3H, s,
OMe), 3.26 (1H, td, J = 8.0, 2.3 Hz, CHCH2O), 2.97 (1H, d, J =
5.0 Hz, CCHH’OC), 2.73 (1H, d, J = 5.0 Hz, CCHH’OC), 2.63
(1H, d, J = 14.4 Hz, CHH’CCO2Me), 2.38 (1H, d, J = 14.4 Hz,
CHH’CCO2Me), 0.87 (9H, s, SiCMe3), 0.05 (6H, s, SiMe2); δC
(100 MHz CDCl3) 175.2 (CO), 169.4 (CO), 73.2 (CHOTBDMS),
65.8 (CH2O), 64.7 (CH2OC), 56.5 (CCO2Me), 53.6 (OMe), 49.2
(CH2OC), 46.9 (CHCH2O), 34.2 (CH2CCO2Me), 25.6 (SiCMe3),
18.0 (SiCMe3), -4.6 (SiMe), -5.1 (SiMe);
found 349.1434, C16H26O5SiNa+ (M+Na+), requires 349.1442.
(Minor 30cv) Rf 0.55 (7:1 petrol:EtOAc); νmax/cm-1 (thin film)
2956m, 1777s, 1733s, 1249s; δH (400 MHz CDCl3) 5.05 (1H, q, J
= 1.5 Hz, CHH’=C), 5.02 (1H, q, J = 1.5 Hz, CHH’=C), 4.53
(1H, dd, J = 9.5, 7.7 Hz, CHH’O), 4.18 (1H, dd, J = 3.8, 1.5 Hz,
CHOTBDMS), 4.06 (1H, dd, J = 9.5, 3.8 Hz, CHH’O), 3.76 (3H,
s, OMe), 3.38 (1H, dt, J = 16.8, 1.5 Hz, CHH’C=CH2), 3.02 (1H,
td, J = 7.7, 3.6 Hz, CHCHOTBDMS), 2.71 (1H, dt, J = 16.8, 1.5
Hz, CHH’C=CH2), 0.85 (9H, s, SiCMe3), 0.06 (3H, s, SiMe),
0.05 (3H, s, SiMe); δC (100 MHz CDCl3) 175.7 (CO), 169.4
(CO), 148.5 (CH2=C), 110.1 (CH2=C), 79.0 (CHOTBDMS), 69.5
(CH2O), 57.4 (CCO2Me), 53.76 (CHCH2O), 53.3 (OMe), 35.9
(CH2C=CH2), 25.6 (SiCMe3), 17.9 (SiCMe3), -4.5 (SiMe), -4.7
(SiMe);
4.1.27. Methyl (3aS*,4R*,5R*,6aR*)-4-((tert-
butyldimethylsilyl)oxy)-1-oxodihydro-1H,3H-
spiro[cyclopenta[c] furan-5,2'-oxirane] -6a(6H)-
carboxylate 31a
4.1.29. Butyl 3-(diethylamino)propanoate 32
To vigorously stirred water (500 mL) was added butyl acrylate
(82.0 mL, 570 mmol) and diethylamine (65.0 mL, 630 mmol).
The reaction was stirred for 1 h and then extracted with CH2Cl2
(3 × 500 mL). The combined organic layers were dried (Na2SO4),
filtered and then concentrated in vacuo to give the title compound
32as a yellow oil (102 g, 505 mmol, 89%); Rf 0.45 (9:1
CH2Cl2:MeOH); νmax/cm-1 (thin film) 2964m, 1735s, 1197m; δH
(400 MHz CDCl3) 4.08 (2H, t, J = 6.7 Hz, CH2Pr), 2.79 (2H, t, J
= 7.3 Hz, Et2NCH2), 2.51 (4H, q, J = 7.3 Hz, MeCH2), 2.44 (2H,
t, J = 7.3 Hz, CH2CO2Bu), 1.60 (2H, quin, J = 6.7 Hz, CH2Et),
1.31 (2H, sept, J = 6.7 Hz, CH2CH2Me), 1.02 (6H, t, J = 7.3 Hz,
NCH2Me), 0.92 (3H, t, J = 6.7 Hz, Me); δC (100 MHz CDCl3)
173.0 (CO), 64.3 (CH2Pr), 48.1 (Et2NCH2), 46.8 (NCH2Me), 32.3
(CH2CO2Bu), 30.7 (CH2Et), 19.2 (CH2CH2Me), 13.7
(CH2CH2Me), 11.9 (NCH2Me); m/z LRMS(ESI+) 202 (M+H+,
100); HRMS (ESI+): found 202.1799, C11H24O2N+ (M+H+),
requires 202.1802.
To a stirred solution of alkene 30cc (50 mg, 0.15 mmol) in
CH2Cl2 (1.5 mL) was added NaHCO3 (38 mg, 0.45 mmol) and
mCPBA (57 mg, 70% wt/wt, 0.23 mmol). The reaction was
stirred for 48 h before being quenched with sat. aq. Na2S2O3 (1
mL). The mixture was diluted with sat. aq. NaHCO3 (10 mL)
and CH2Cl2 (10 mL) and then the aqueous layer was separated
and extracted with CH2Cl2 (2 × 10 mL). The combined organic
layers were dried (Na2SO4), filtered and concentrated in vacuo.
Purification by flash column chromatography (4:1 petrol:EtOAc)
gave recovered starting material (7 mg, 21 ꢀmol, 14%), epoxide
31b (see below) (9 mg, 26 ꢀmol, 17%) and the title compound
31a (28 mg, 81 ꢀmol, 54%) as a white solid; m.p. 59–62 °C; Rf
0.35 (6:1 petrol:EtOAc); νmax/cm-1 (thin film) 2955w, 1777s,
1744s, 1253m; δH (400 MHz CDCl3) 4.55 (1H, dd, J = 9.2, 2.5
Hz, CHH’O), 4.40 (1H, dd, J = 9.2, 7.8 Hz, CHH’O), 3.94 (1H,
d, J = 5.5 Hz, CHOTBDMS), 3.80 (3H, s, OMe), 3.14 (1H, ddd, J
= 8.0, 5.6, 2.5 Hz, CHCH2O), 2.86 (1H, d, J = 4.9 Hz,
CCHH’OC), 2.77 (1H, d, J = 4.9 Hz, CCHH’OC), 2.57 (1H, d, J
= 14.3 Hz, CHH’CCO2Me), 2.47 (1H, d, J = 14.3 Hz,
CHH’CCO2Me), 0.88 (9H, s, SiCMe3), 0.10 (3H, s, SiMe), 0.04
(3H, s, SiMe); δC (100 MHz CDCl3) 175.2 (CO), 170.2 (CO),
74.5 (CHOTBDMS), 66.1 (CH2O), 64.8 (CH2OC), 56.7
(CCO2Me), 53.5 (OMe), 50.5 (CH2OC), 48.3 (CHCH2O), 33.7
(CH2CCO2Me), 25.7 (SiCMe3), 18.1 (SiCMe3), -4.5 (SiMe), -5.3
(SiMe); m/z LRMS (ESI+) 365 (M+Na+, 100); HRMS (ESI+):
found 365.1386, C16H26O6SiNa+ (M+Na+), requires 365.1391.
Single Crystal Data: C16H26O6Si, monoclinic, P21/c,
a=20.7306(4), b=7.96400(10), c=11.4367(2) Å, β=99.7675(6)°,
4.1.30. Butyl 2-((diethylamino)methyl)-3-
hydroxypent-4-enoate 33
To solution of diisopropylamine (21.9 mL, 156 mmol) in THF
(200 mL) at -78 °C was added BuLi (61.4mL, 2.5 M in hexane,
154mmol) and the reaction stirred for 15min. Butyl 3-
(dimethylamino)propionate 32 (26.5 g, 132 mmol) was then
added dropwise and the reaction stirred for 30 min at -78 °C then
warmed to RT for 30 min over which time a white precipitate
formed. The reaction was then cooled back to –78 °C and freshly
distilled acrolein (7.37 g, 132 mmol) was added dropwise as a
solution in THF (60 mL) and the reaction stirred for 1 h. The
reaction was quenched with NH4Cl (150 mL) and diluted with
V=1860.81(5) Å3,
Rint=0.017, Final R1=0. 0431, wR2=0.1157 (I>2s(I)).
Data/restraints/parameters
4222/26/221,
4.1.28. Methyl (3aS*,4R*,5S*,6aR*)-4-((tert-
butyldimethylsilyl)oxy)-1-oxodihydro-1H,3H-

16
Tetrahedron
4.1.32. Butyl (R)-3-acetoxy-2-methylenepent-4-
enoate 35
EtOAc (300 mL). The aqueous layer was separated was
separated and extracted with EtOAc (3 × 200 mL), and the
combined organic layers were dried (MgSO4), filtered and
concentrated in vacuo to give the crude title compound 33 as a
yellow oil (31.8 g, 124 mmol, 94%, d.r. 2:1); Rf 0.42 (10:1
EtOAc:MeOH); νmax/cm-1 (thin film) 3300br w, 2964m, 1730s,
1180s; data for major diastereomer: δH (400 MHz CDCl3) 5.78
(1H, ddd, J = 17.0 Hz, 10.3, 6.8 Hz, CH2=CH), 5.26 (1H, ddd, J
= 17.0, 1.6, 1.2 Hz, CHH’=CH), 5.09 (1H, ddd, J = 10.3, 1.7, 0.9
Hz, CHH’=CH), 4.35–4.41 (1H, m, CHOH), 3.96–4.08 (2H, m,
CH2Pr), 2.98–3.05 (1H, m, CHH’NEt2), 2.60–2.80 (4H, m,
CHCHH’NCH2Me), 2.35–2.45 (2H, m, NCH2Me), 1.52–1.63
(2H, m, CH2Et), 1.30–1.41 (2H, m, CH2CH2Me), 1.06 (6H, t, J =
7.1 Hz, NCH2Me), 0.91 (3H, t, J = 7.4 Hz, CH2CH2Me); δC (100
MHz CDCl3) 171.9 (CO), 138.3 (CH2=CH), 116.2 (CH2=CH),
76.6 (CHOH), 64.5 (CH2Pr), 55.9 (CHCO), 48.6 (CHCH2N),
46.7 (NCH2), 30.5 (CH2Et), 19.1 (CH2CH2Me), 13.7
(CH2CH2Me), 11.3 (NCH2Me);
To a stirred solution of alcohol 34 (13.9 g, 75.5 mmol) and
vinyl acetate (43 mL, 460 mmol) in hexane (400 mL) was added
Candida Antarctica lipase B immobilised on immobead™
recombinant from yeast (8.52 g, 7244 U/kg). The reaction was
warmed to 31 °C and stirred for 3 d. The reaction mixture was
then filtered and concentrated in vacuo. Purification by flash
column chromatography (12:1→6:1 petrol:Et2O) gave the acetate
35 as a colorless oil (8.03 g, 35.4 mmol, 47%, >99% e.e)
followed by alcohol (–)-34 (7.02 g, 38.1 mmol, 50%); Rf 0.42
(20:1 petrol:EtOAc); νmax/cm-1 (thin film) 2947w, 1744s, 1721s;
δH (400 MHz CDCl3) 6.34 (1H, s, C=CHH’), 6.10 (1H, br d, J =
6.4 Hz, CHOAc), 5.89 (1H, ddd, J = 17.0, 10.4, 6.4 Hz,
CH2=CH), 5.83 (1H, s, C=CHH’), 5.33 (1H, dt, J = 17.0, 1.0 Hz,
CHH’=CH), 5.24 (1H, dt, J = 10.4, 1.0 Hz, CHH’=CH), 4.17
(2H, t, J = 6.7 Hz, CH2Pr), 2.09 (3H, s, C(O)Me), 1.59 (2H, quin,
J = 6.7 Hz, CH2Et), 1.39 (2H, sept, J = 6.7 Hz, CH2Me), 0.93
(3H, t, J = 6.7 Hz, CH2Me); δC (100 MHz CDCl3) 169.5 (CO),
165.1 (CO), 139.0 (C=CH2), 134.3 (CH2=CH), 126.3 (C=CH2),
117.9 (CH2=CH), 71.9 (CHOAc), 64.9 (CH2Pr), 30.6 (CH2Et),
21.1 (C(O)Me), 19.2 (CH2Me), 13.7 (CH2Me); m/z LRMS (ESI+)
249 (M+Na+, 100); HRMS (ESI+): found 249.1091, C12H18O4Na+
data for the minor diastereomer: δH (400 MHz CDCl3) 5.87
(1H, ddd, J = 17.0, 10.5, 4.4 Hz, CH2=CH), 5.40 (1H, dd, J =
17.0, 1.8 Hz, CHH’=CH), 5.23 (1H, dt, J = 10.5, 1.9 Hz,
CHH’=CH), 4.60–4.65 (1H, m, CHOH), 3.96–4.08 (2H, m,
CH2Pr), 3.11 (1H, dt, J = 11.3, 4.2 Hz, CHCH2NEt2), 2.93 (1H,
dd, J = 13.0, 11.3 Hz, CHH’NEt2), 2.60–2.80 (3H, m,
CHCHH’NCH2Me), 2.35–2.45 (2H, m, NCH2Me), 1.52–1.63
(2H, m, CH2Et), 1.30–1.41 (2H, m, CH2CH2Me), 1.01 (6H, t, J =
7.1 Hz, NCH2Me), 0.91 (3H, t, J = 7.4 Hz, CH2CH2Me); δC (100
MHz CDCl3) 172.1 (CO), 137.8 (CH2=CH), 116.2 (CH2=CH),
73.5 (CHOH), 64.5 (CH2Pr), 51.7 (CHCO), 47.0 (NCH2), 45.8
(CHCH2N), 30.5 (CH2Et), 19.1 (CH2CH2Me), 13.7 (CH2CH2Me),
11.3 (NCH2Me); m/z LRMS (ESI+) 258 (M+H+, 100); HRMS
(ESI+): found 258.2058, C14H28O3N+ (M+H+), requires 258.2064.
(M+Na+), requires 249.1097; [α]D –31.7 (c = 1.0 in CHCl3).
25
HPLC data of racemate formed from the acetylation of (±)-34
using Ac2O and NEt3: column: Chiralpak OD, flow rate: 0.8
mL/min, solvent: 1% IPA in hexane, retention time for (S) 13.8
min, (R) 15.9 min.
4.1.33. Butyl (R)-3-hydroxy-2-methylenepent-4-
enoate (+)-34
4.1.31. Butyl 3-hydroxy-2-methylenepent-4-enoate
34
To a solution of acetate 35 (6.35 g, 23.1 mmol) in MeOH (100
mL) was added IR-120 Amberlite™ resin (50 g). The mixture
was stirred for 4 d and then filtered and concentrated in vacuo.
Purification by flash column chromatography (12:1→6:1
petrol:Et2O) gave recovered starting material 35 (440 mg, 1.9
mmol, 7%) and the title compound (+)-34 as a colorless oil (4.61
g, 25.1 mmol, 89%, >99% e.e.); physical data as above for
racemic alcohol 34; [α]D25 +13.5 (c = 1.0 in CHCl3).
To a stirred suspension of amine 33 (27.7 g, 108 mmol) and
NaHCO3 (24.1 g, 287 mmol) in CH2Cl2 (500 mL) cooled to 0 °C
was added a solution of mCPBA (43.5 g, 50% wt/wt, 126 mmol)
in CH2Cl2 (250 mL). The reaction was then warmed to RT and
stirred vigorously for 4 h. The mixture was concentrated in vacuo
to approximately 40 mL and diluted with pentane (300 mL), H2O
(150 mL) and sat. aq. NaHCO3 (150 mL). The aqueous layer
was separated and extracted with pentane (2 × 300 mL). The
combined organic layers were dried (MgSO4), filtered and
concentrated in vacuo. Purification by flash column
chromatography (6:1 petrol:Et2O) gave the title compound 34 as
a colorless oil (12.5 g, 67.8 mmol, 63%); Rf 0.56 (6:1
petrol:EtOAc); νmax/cm-1 (thin film) 3423br w, 2948w, 1712s; δH
(400 MHz CDCl3) 6.25 (1H, s, C=CHH’), 5.96 (1H, ddd, J =
17.3, 10.5, 5.6 Hz, CH2=CH), 5.83 (1H, t, J = 1.0 Hz, C=CHH’),
5.33 (1H, dt, J = 17.3, 1.0 Hz, CHH’=CH), 5.20 (1H, dt, J = 10.5,
1.0 Hz, CHH’=CH), 4.94 (1H, t, J = 5.6 Hz, CHOH), 4.18 (2H, t,
J = 6.8 Hz, CH2Pr), 2.95 (1H, d, J = 5.6 Hz, CHOH), 1.66 (2H,
quin, J = 6.8 Hz, CH2Et), 1.40 (2H, sept, J = 6.8 Hz, CH2Me),
0.94 (3H, t, J = 6.8 Hz, Me); δC (100 MHz CDCl3) 166.4 (CO),
141.3 (C=CH2), 138.2 (CH2=CH), 125.6 (C=CH2), 116.0
(CH2=CH), 72.3 (CHOH), 64.9 (CH2Pr), 30.6 (CH2Et), 19.2
(CH2Me), 13.7 (Me); m/z LRMS (ESI+) 207 (M+Na+, 100);
HRMS (ESI+): found 207.0990, C10H16O3Na+ (M+Na+), requires
207.0992. HPLC data: column: Chiralpak AD, flow rate: 0.8
mL/min, solvent: 1.5% IPA in hexane, retention time for (S) 19.7
min, (R) 21.3 min.
4.1.34. Butyl (R)-2-methylene-3-
((triisopropylsilyl)oxy)pent-4-enoate
To a solution of alcohol (+)-34 (4.61 g, 25.1 mmol) in CH2Cl2
(75 mL) at 0 °C was added sequentially 2,6-lutidine (4.40 mL,
37.6 mmol) and TIPSOTf (8.08 mL, 30.6 mmol). The reaction
was stirred for 30 min and then quenched with sat. aq. NaHCO3
(25 mL). The aqueous layer was then separated and extracted
with CH2Cl2 (2 × 50 mL). The combined organic layers were
dried (Na2SO4), filtered and concentrated in vacuo. Purification
by flash column chromatography (98:2 petrol:EtOAc) gave the
title
compound
butyl
(R)-2-methylene-3-
((triisopropylsilyl)oxy)pent-4-enoate as a colorless oil (7.91 g,
23.2 mmol, 93%); Rf 0.65 (petrol); νmax/cm-1 (thin film) 2959m,
1716s, 1463m; δH (400 MHz CDCl3) 6.24 (1H, dd, J = 1.8, 1.0
Hz, CHH’=C), 6.02 (1H, t, J = 1.2 Hz, CHH’=C), 5.82 (1H, ddd,
J = 17.1, 10.3, 5.9 Hz, CH2=CH), 5.28 (1H, dt, J = 17.1, 1.0 Hz,

17
CHH’=CH), 5.05 (1H, dt, J = 5.9, 1.0 Hz, CHOTIPS), 5.04 (1H,
dt, J = 10.3, 1.4 Hz, CHH’=CH), 4.16 (2H, dt, J = 6.7, 1.9 Hz,
OCH2), 1.61–1.69 (2H, m, OCH2CH2), 1.35–1.45 (2H, m,
CH2Me), 1.03–1.15 (21H, m, TIPS), 0.94 (3H, t, J = 7.4 Hz, Me);
δC (100 MHz CDCl3) 166.0 (CO), 143.5 (CH2=C), 139.8
(CH2=CH), 123.9 (CH2=C), 114.3 (CH2=CH), 71.6 (CHOTIPS),
64.5 (OCH2), 30.6 (OCH2CH2), 19.2 (CH2Me), 18.0 (CMe2),
12.2 (SiCHMe2). m/z LRMS (ESI+) 363 (M+Na+, 100); HRMS
(ESI+): found 363.2322, C19H36O3SiNa+ (M+Na+), requires
363.2326; [α]D25 -7.8 (c = 1.0 in CHCl3).
115.4 (CH2=C), 114.9 (CH2=CH), 75.2 (CHOTIPS), 68.7
(CH2OMs), 37.7 (SO2Me), 18.0 (SiCHMe2), 12.2 (SiCHMe2).
4.1.37. Dimethyl (R)-2-(2-methylene-3-
((triisopropylsilyl)oxy)pent-4-en-1-yl)malonate 37
To a stirred suspension of NaH (60% dispersion in mineral oil,
2.4 g, 60 mmol) in DMF (80 mL) and THF (40 mL) at 0 °C was
added dimethyl malonate dropwise (6.85 mL, 7.9 g, 60 mmol).
The reaction mixture was warmed to RT and the crude mesylate
36 prepared above was added as a solution in THF (40 mL)
followed by the addition of KI (1 g, 6.6 mmol). The reaction
mixture was warmed to 80 °C and stirred 16 h, then allowed to
cool to RT, quenched with sat. aq. NH4Cl (80 mL) and petrol (80
mL) was added. The aqueous layer was extracted with petrol (2
× 80mL), the combined organic layers were dried (MgSO4),
filtered and the solvent removed in vacuo. Purification by flash
column chromatography (15:1 petrol:EtOAc) gave the title
compound 37 as a colorless oil (6.40 g, 16.6 mmol, 84%); Rf 0.49
(10:1 petrol:EtOAc); νmax/cm-1 (thin film) 2955w, 1740s, 1230m;
δH (400 MHz CDCl3) 5.75 (1H, ddd, J = 17.1, 10.3, 5.7 Hz,
CH2=CH), 5.28 (1H, dt, J = 17.1, 1.5 Hz, CHH’=CH), 5.14 (1H,
t, J = 0.9 Hz, CHH’=C), 5.11 (1H, dt, J = 10.3, 1.5 Hz,
CHH’=CH), 4.84 (1H, t, J = 1.5 Hz, CHH’=C), 4.65 (1H, d, J =
5.8 Hz, CHOTIPS), 3.68–3.73 (1H, m, CH(CO2Me)2), 3.71 (3H,
s, OMe), 3.71 (3H, s, OMe), 2.58–2.72 (2H, m,
CH2CH(CO2Me)2), 1.01–1.11 (21H, m, TIPS); δC (100 MHz
CDCl3) 169.6 (CO), 147.0 (CH2=C), 140.2 (CH2=CH), 114.7
(CH2=CH), 111.2 (CH2=C), 74.5 (CHOTIPS), 52.5 (OMe), 50.5
(CH(CO2Me)2), 29.8 (CH2CH(CO2Me)2, 18.0 (SiCHMe2), 12.3
(SiCHMe2); m/z LRMS(ESI+) 407 (M+Na+, 100); HRMS (ESI+):
found 407.2223, C20H36OSiNa+ (M+Na+), requires 407.2224;
[α]D25 +11.6 (c = 1.0 in CHCl3).
4.1.35. (R)-2-Methylene-3-
((triisopropylsilyl)oxy)pent-4-en-1-ol
To
a
solution
of
(R)-2-methylene-3-
((triisopropylsilyl)oxy)pent-4-enoate (9.42 g, 25.6 mmol) in THF
(140 mL) at –78 °C was added DIBAL (71.6 mL, 1 M in hexane,
71.6 mmol) dropwise and the reaction was then warmed to
between - 35 °C and -20 °C for 2 h. The reaction was quenched
by the slow addition of MeOH (5 mL) followed by sat. aq. sat.
aq. Rochelle’s salt (60 mL), sat. aq. NH4Cl (10 mL) and EtOAc
(100 mL) and stirred vigorously until two clear phases formed on
standing. The aqueous layer was then separated and extracted
with EtOAc (2 × 150 mL). The combined organic phases were
dried (MgSO4), filtered and concentrated in vacuo. Purification
by flash column chromatography (6:1 petrol:EtOAc) gave the
title compound (R)-2-methylene-3-((triisopropylsilyl)oxy)pent-4-
en-1-ol as a colour oil (6.23 g, 23.1 mmol, 90%); Rf 0.45 (6:1
petrol:EtOAc); νmax/cm-1 (thin film) 3430br m, 2867s, 1464m; δH
(400 MHz CDCl3) 5.86 (1H, ddd, J = 17.2, 10.3, 5.5 Hz,
CH2=CH), 5.30 (1H, dt, J = 17.2, 1.5 Hz, CHH’=CH), 5.13 (1H,
dt, J = 10.3, 1.5 Hz, CHH’=CH), 5.09–5.13 (2H, br s, CH2=C),
4.84 (1H, d J = 5.9 Hz, CHOTIPS), 4.25 (1H, dd, J = 13.6, 4.0
Hz, CHH’OH), 4.12 (1H, dd, J = 13.6, 6.4 Hz, CHH’OH), 2.06
(1H, dd, J = 6.4, 4.0 Hz, OH), 1.03–1.15 (21H, m, TIPS); δC (100
MHz CDCl3) 149.3 (CH2=C), 140.2 (CH2=CH), 114.5
(CH2=CH), 111.6 (CH2=C), 77.0 (CHOTIPS), 63.3 (CH2OH),
18.0 (SiCHMe2), 12.2 (SiCHMe2); m/z LRMS (ESI+) 293
(M+Na+, 100); HRMS (ESI+): found 293.1909, C15H30O2SiNa+
(M+Na+), requires 293.1907; [α]D25 +11.3 (c = 1.0 in CHCl3).
4.1.38. Methyl (3aR,6R,6aS)-5-methylene-3-oxo-6-
((triisopropylsilyl)oxy)tetrahydro-1H-
cyclopenta[c]furan-3a(3H)-carboxylate 38cc and
methyl (3aS,6R,6aR)-5-methylene-3-oxo-6-
((triisopropylsilyl)oxy)tetrahydro-1H-
cyclopenta[c]furan-3a(3H)-carboxylate 38cv
4.1.36. (R)-2-Methylene-3-
((triisopropylsilyl)oxy)pent-4-en-1-yl
methanesulfonate 36
To a solution of malonate 37 (6.38 g, 16.6 mmol) and CuI
(158 mg, 0.83 mmol) in CH2Cl2 (150 mL) at -78 °C was added
ethylmagnesium bromide (8.30 mL, 3 M in Et2O, 24.9 mmol).
The reaction was stirred for 15 min, and then iodine (16.9 g, 66.4
mmol) was added. The reaction was warmed to RT and stirred
for 16 h and then quenched by the addition of sat. aq. NH4Cl (50
mL) and Na2S2O3 (25 mL), and then diluted with H2O (100 mL)
and CH2Cl2 (200 mL). The aqueous layer was separated and
extracted with CH2Cl2 (2 × 150 mL). The combined organic
layers were washed with brine (100 mL), dried (Na2SO4), filtered
and concentrated in vacuo. The crude mixture was then heated to
140 °C for 30 min before being cooled to RT and purified by
flash column chromatography (6:1 petrol:Et2O) to give 38cv as a
colorless oil (0.91 g, 2.5 mmol, 15%) followed by 38cc as a
colorless oil (4.81 g, 13.1 mmol, 78%); (Major 38cc) Rf 0.52 (7:1
petrol:EtOAc); νmax/cm-1 (thin film) 2945m, 1776s, 1743s, 1150s;
δH (400 MHz CDCl3) 5.18 (1H, s, CHH’=C), 5.05 (1H, s,
CHH’=C), 4.70 (1H, d, J = 7.7 Hz, CHOTIPS), 4.46 (1H, dd, J =
To
a
solution
of
(R)-2-methylene-3-
((triisopropylsilyl)oxy)pent-4-en-1-ol alcohol 26 (5.36 g, 19.8
mmol) in CH2Cl2 (80 mL) at 0 °C was added Et3N (4.3 mL. 3.1 g,
31.2 mmol) followed by MsCl (2.08 mL, 13.08 g, 27 mmol) and
the reaction mixture was stirred for 10 min and then quenched
with sat. aq. NH4Cl (80 mL). The organic layer was separated
and the aqueous layer extracted with CH2Cl2 (2 × 80 mL). The
combined organic layers were washed with brine (80 mL), dried
(MgSO4) to give the title compound 27 as a crude yellow oil; Rf
0.45 (6:1 petrol:EtOAc); νmax/cm-1 (thin film) 2931m, 1359s,
1176s; δH (400 MHz CDCl3) 5.77 (1H, ddd, J = 17.1, 10.3, 5.9
Hz, CH2=CH), 5.40 (1H, s, CHH’=C), 5.32 (1H, dt, J = 17.1, 1.4
Hz, CHH’=CH), 5.28 (1H, s, CHH’=C), 5.16 (1H, dt, J = 10.3,
1.4 Hz, CHH’=CH), 4.81 (1H, d, J = 5.9 Hz, CHOTIPS), 4.73
(2H, s, CH2OMs), 3.00 (3H, s, SO2Me), 1.02–1.06 (21H, m,
TIPS); δC (100 MHz CDCl3) 149.6 (CH2=C), 139.4 (CH2=CH),

18
Tetrahedron
9.4, 4.5 Hz, CHH’O), 4.31 (1H, dd, J = 9.4, 8.8 Hz, CHH’O),
trifluoromethylphenylacetic acid (0.048 g, 0.21 mmol), and the
reaction was stirred for 16 h. The mixture was filtered, and the
filtrate was concentrated in vacuo. Purification by flash column
chromatography (4:1 petrol:EtOAc) gave the title compound 39
as a colorless oil (0.014 g, 0.03 mmol, 46%); 0.12 (4:1
petrol:EtOAc); νmax/cm-1 (thin film) 1778s (CO) 1749(CO); δH
(400 MHz, CDCl3) δ 7.38 (5H, m, ArH), 5.74 (1H, d, J = 7.2 Hz,
CHOMPTA), 5.23 (1H, q, 1.9 Hz, HHC=C), 5.20 (1H, q, 1.9 Hz,
HHC=C), 4.22 (1H, dd, J = 9.8, 8.0 Hz, COOCHH’C), 3.93 (1H,
dd, J = 9.8, 3.5 Hz, COOCHH’C), 3.81 (3H, s, COOMe), 3.53
(3H, q, J = 1.3 Hz, ROOCCOMe), 3.51 (1H, dt, J = 7.7, 3.4 Hz,
COOCH2CH), 3.21 (1H, dt, J = 17.0, 2.3 Hz, H2C=CCHH’), 2.89
(1H, ddq, J = 17.0, 2.7, 1.5, Hz, H2C=CCHH’); δC (126 MHz,
CDCl3) 174.4 (CCOOCH2), 169.1 (CCOOMe), 166.0
(F3CCR2COOR), 142.8 (CH2=C), 131.6, 129.9, 128.6, 127.0,
123.1 (q, J = 288.8 Hz, CF3), 113.2 (CH2=C), 84.5 (q, J = 28.1
Hz, F3CC), 77.1 (COMPTA), 65.4 (COOCH2C), 58.0
(C(COOMe)COOCH2), 55.5 (ROOCCR2OMe), 53.6 (COOMe),
46.9 (C(OMPTA)CHCH2), 35.8 (CH2=CCH2); m/z HRMS (ESI+)
451.0973 found, C20H19F3O7Na+ (M+Na+), requires 451.0975.
3.79 (3H, s, OMe), 3.24 (1H, ddd, J = 8.8, 7.7, 4.5 Hz,
CHCH2O), 3.08 (1H, dtd, J = 16.0, 2.4, 0.9 Hz, CHH’C=CH2),
2.78 (1H, d, J = 16.0 Hz, CHH’C=CH2), 1.03–1.12 (21H, m,
TIPS); δC (100 MHz CDCl3) 175.7 (CO), 170.2 (CO), 147.0
(CH2=C), 109.2 (CH2=C), 74.2 (CHOTIPS), 65.9 (CH2O), 56.9
(CCO2Me), 53.4 (OMe), 47.7 (CHCH2OR), 35.9 (CH2C=CH2),
18.0 (CHMe2), 12.2 (SiCHMe2); m/z LRMS (ESI+) 391 (M+Na+,
100); HRMS (ESI+): found 391.1930, C19H32O5SiNa+ (M+Na+),
requires 391.1911; [α]D25 -69.6 (c = 1.0 in CHCl3).
(Minor 38cv) Rf 0.55 (7:1 petrol:EtOAc); νmax/cm-1 (thin film)
2956m, 1777s, 1747s, 1061s; δH (400 MHz CDCl3) 5.12 (1H, s,
CHH’=C), 5.07 (1H, s, CHH’=C), 4.56 (1H, dd, J = 9.4, 8.8 Hz,
CHH’O), 4.29 (1H, dd, J = 2.5, 0.8 Hz, CHOTIPS), 3.94 (1H, dd,
J = 9.4, 5.0 Hz, CHH’O), 3.78 (3H, s, OMe), 3.51 (1H, ddt, J =
16.4, 2.5, 0.8 Hz, CHH’C=CH2), 3.20 (1H, ddd, J = 8.8, 5.0, 2.5
Hz, CHCHOTIPS), 2.70 (1H, d, J = 16.4 Hz, CHH’C=CH2),
1.00–1.10 (21H, m, TIPS); δC (100 MHz CDCl3) 175.8 (CO),
169.5 (CO), 148.4 (CH2=C), 111.2 (CH2=C), 79.9 (CHOTIPS),
69.3 (CH2OR), 58.4 (CCO2Me), 54.2 (CHCH2O), 53.3 (OMe),
36.8 (CH2C=CH2), 17.9 (CHMe2), 12.2 (SiCHMe2); [α]D25 +11.3
(c = 1.0 in CHCl3).
4.1.41. Methyl (3aR,6R,6aS)-5-methylene-3-oxo-6-
(((S)-3,3,3-trifluoro-2-methoxy-2-
phenylpropanoyl)oxy)tetrahydro-1H-
4.1.39. Methyl (3aR,6R,6aS)-6-hydroxy-5-
methylene-3-oxotetrahydro-1H-cyclopenta[c]furan-
3a(3H)-carboxylate 29-cc
cyclopenta[c]furan-3a(3H)-carboxylate 40
To a stirred solution of the alcohol 39 (0.015 g, 0.07 mmol) in
CH2Cl2 (1 mL) was added DCC (0.043 g, 0.21 mmol), DMAP
To a stirred solution of 38cc (0.368 g, 1.00 mmol) in THF (5
mL) at 0 °C was added TBAF(1.30 mL, 1 M in THF, 1.30
mmol) and the reaction mixture was stirred for 5 min. sat. aq.
NH4Cl (2 mL) was added followed by EtOAc (10 mL) and the
mixture was allowed to warm to RT. The organic phase was
separated, and the aqueous phase extracted with ethyl acetate (3
× 10 mL). The combined organic extracts were washed with
brine, dried (MgSO4), filtered, and concentrated in vacuo.
Purification by flash column chromatography (3:1 petrol:EtOAc)
gave the title compound 29-cc as a colorless oil (0.193 g, 0.91
mmol, 91%);Rf 0.10 (3:1 petrol:EtOAc); νmax/cm-1 (thin film)
3478 (OH), 1766 (CO), 1737(CO); δH (500 MHz, CDCl3) 5.19
(1H, q, J = 1.9 Hz, HH’C=C), 5.12 (1H, q, J = 2.0 Hz, HH’C=C),
4.63 – 4.66 (1H, 1H, CHOH), 4.55 (1H, dd, J = 9.5, 3.1 Hz,
COOCHH’C), 4.41 (1H, dd, J = 9.5, 7.7 Hz, COOCHH’C), 3.80
(3H, s, OMe), 3.27 (1H, td, J = 7.6, 3.1 Hz, COOCHH’CCH),
3.13 (1H, dt, J = 16.7, 2.2 Hz, H2C=CCHH’), 2.95 (1H, dd, J =
16.6, 1.6 Hz, H2C=CCHH’); δC (126 MHz, CDCl3) 175.6
(CCOOCH2), 169.9 (CCOOMe), 148.7 (CH2=C), 109.8
(0.024
g,
0.21
mmol),
(S)-(+)-α-methoxy-α-
trifluoromethylphenylacetic acid (0.048 g, 0.21 mmol), and the
reaction was stirred for 16 h. The mixture was filtered, and the
filtrate was concentrated in vacuo. Purification by flash column
chromatography (4:1 petrol:EtOAc) to give the title compound
40 as a colorless oil (0.016 g, 0.04 mmol, 53%); 0.11 (4:1
petrol:EtOAc); νmax/cm-1 (thin film) 1779(CO), 1749(CO); δH
(400 MHz, CDCl3) δ 7.46 (5H, m, ArH), 5.76 (1H, d, J = 7.5 Hz,
CHOMPTA), 5.16 (2H, q, J = 1.9 Hz, H2C=C), 4.34 (1H, dd, J =
9.8, 8.0 Hz, COOCHH’C), 4.12 (1H, dd, J = 9.8, 3.4 Hz,
COOCHH’C), 3.81 (3H, s, COOMe), 3.52 (1H dt, J = 7.7, 3.9
Hz, COOCH2CH), 3.49 (3H, q, J = 1.3 Hz, ROOCCOMe), 3.17
(1H, dt, J = 17.1, 2.2 Hz, H2C=CCHH’), 2.82 (1H, m,
H2C=CCHH’); δC (126 MHz, CDCl3) 174.4 (CCOOCH2), 169.1
(CCOOMe), 166.0 (F3CCR2COOR), 142.8 (CH2=C), 131.2,
130.0 128.7, 127.35 (C-Ar), 123.19 (q, J = 288.6 Hz, CF3),
113.11 (CH2=C), 84.8 (q, J = 28.1 Hz, F3CC), 77.1 (COMPTA),
65.7
(COOCH2C),
58.0
(C(COOMe)COOCH2),
55.4
(ROOCCR2OMe), 53.7 (COOMe), 47.1 (C(OMPTA)CHCH2),
35.9 (CH2=CCH2); m/z HRMS (ESI+) 451.0972 found,
C20H19F3O7Na+ (M+Na+), requires 451.0975.
(CH2=C),
73.7
(COH),
66.1
(COOCH2C),
58.0
(C(COOMe)COOCH2), 53.5 (OMe), 48.4 (COHCHCH2), 36.2
(CH2=CCH2); m/z HRMS (ESI+) 235.0578 found, C10H12O5Na+
(M+Na+), requires 235.0577.
4.1.42. (3aR,6R,6aS)-5-Methylene-3-oxo-6-
((triisopropylsilyl)oxy)tetrahydro-1H-
cyclopenta[c]furan-3a(3H)-carboxylic acid 41
4.1.40. Methyl (3aR,6R,6aS)-5-methylene-3-oxo-6-
(((R)-3,3,3-trifluoro-2-methoxy-2-
phenylpropanoyl)oxy)tetrahydro-1H-
cyclopenta[c]furan-3a(3H)-carboxylate 39
To a rapidly stirred solution of ester 38cc (4.60 g, 12.5 mmol)
in THF:H2O (35 mL:35 mL) was added LiOH•H2O (2.61 g, 62.0
mmol). The reaction was stirred for 16 h and then carefully
acidified to pH 2 using 2 M aq. HCl (ca. 35 mL). The mixture
was then extracted with EtOAc (4 × 50 mL). The combined
To a stirred solution of the alcohol 39 (0.015 g, 0.07 mmol) in
CH2Cl2 (1 mL) was added DCC (0.043 g, 0.21 mmol), DMAP
(0.024
g,
0.21
mmol),
(R)-(+)-α-methoxy-α-

19
organic layers were dried (MgSO4), filtered and then
concentrated in vacuo to give the crude acid (4.43 g, 12.5 mmol,
quant.). The acid was used as the crude mixture for all further
reactions but an analytical sample can be obtained by purification
by flash column chromatography (2:1:0.01 petrol:EtOAc:AcOH)
to give the title compound 41 as a colorless oil; Rf 0.38 (2:1:0.01
petrol:EtOAc:AcOH); νmax/cm-1 (thin film) 3089br w, 2943m,
1774s, 1645s; δH (400 MHz CDCl3) 10.08 (1H, br s, CO2H), 5.21
(1H, s, CHH’=C), 5.08 (1H, s, CHH’=C), 4.76 (1H, d, J = 7.4
Hz, CHOTIPS), 4.47 (1H, dd, J = 9.5, 4.8 Hz, CHH’O), 4.36
(1H, dd, J = 9.5, 8.8 Hz, CHH’O), 3.36 (1H, ddd, J = 8.8, 7.4, 4.8
Hz, CHCH2O), 3.06 (1H, dt, J = 16.2, 2.0 Hz, CHH’CCO2H),
2.81 (1H, d, J = 16.2 Hz, CHH’CCO2H), 1.03–1.16 (21H, m,
TIPS); δC (100 MHz CDCl3) 176.2 (CO), 174.2 (CO), 146.7
(CH2=C), 109.6 (CH2=C), 74.3 (CHOTIPS), 66.4 (CH2O), 47.5
(CCO2H), 17.9 (CHMe2), 12.2 (SiCHMe2); m/z LRMS (ESI+)
377 (M+Na+, 100); HRMS (ESI+): found 377.1755,
C18H30O5SiNa+ (M+Na+), requires 377.1754; [α]D25 -20.8 (c = 1.0
in CHCl3).
mmol) dropwise. The reaction was stirred for 16 h at -78 °C
and then quenched by the addition of MeOH (95 mL). NaOMe
(16.9 mL, 25% wt/wt in MeOH, 74 mmol) was added and the
reaction was warmed to RT and stirred for 2 h. The reaction was
quenched by the addition of sat. aq. NH4Cl (50 mL) and sat. aq.
sat. aq. Rochelle’s salt (50 mL). The mixture was vigorously
stirred for 1 h and then diluted with H2O (100 mL) and EtOAc
(100 mL). The aqueous layer was separated and extracted with
EtOAc (2 × 150 mL). The combined organic layers were dried
(MgSO4), filtered and then concentrated in vacuo. Purification by
flash column chromatography (2:1 petrol:EtOAc) gave the title
compound 43 as a colorless oil (2.98 g, 7.96 mmol, 84%); Rf 0.34
(2:1 petrol:EtOAc); νmax/cm-1 (thin film) 3400br m, 2943w,
1079s; δH (400 MHz CDCl3) 5.06–5.08 (1H, m, CHH’=C), 4.88–
4.90 (1H, m, CHH’=C), 4.65 (1H, d, J = 5.7 Hz, CHOTIPS), 4.18
(1H, s, CH(OMe)2), 3.98 (1H, ddd, J = 11.5, 7.4, 3.0 Hz,
CHH’OH), 3.83 (1H, ddd, J = 11.5, 9.1, 4.1 Hz CHH’OH), 3.74
(1H, s, OH), 3.56 (3H, s, OMe), 3.49 (3H, s, OMe), 3.10 (1H, dd,
J = 9.1, 3.0 Hz, OH), 2.71 (1H, dt, J = 17.2, 2.2 Hz, CHH’COH),
2.43 (1H, ddt, J = 17.2, 2.0, 0.6 Hz, CHH’COH), 2.24 (1H, ddd,
J = 7.4, 5.7, 4.1 Hz, CHCH2OH), 1.02–1.06 (21H, m, TIPS); δC
(100 MHz CDCl3) 150.2 (CH2=C), 108.9 (CH(OMe)2), 108.2
(CH2=C), 82.5 (COH), 78.1 (CHOTIPS), 59.4 (CH2OH), 58.4
(OMe), 57.5 (OMe), 50.0 (CHCH2OH), 41.4 (CH2COH), 18.1 ×
(SiCHMe2), 12.4 (SiCHMe2); m/z LRMS(ESI+) 397 (M+Na+,
100); HRMS (ESI+): found 397.2378, C19H38O5SiNa+ (M+Na+),
requires 397.2381; [α]D25 -19.3 (c = 1.0 in CHCl3).
4.1.43. (3aS,4R,6aS)-6a-Bromo-5-methylene-4-
((triisopropylsilyl)oxy)hexahydro-1H-
cyclopenta[c]furan-1-one 42
4.1.45. tert-Butyl(((1S,2R,5R)-2-((tert-
butyldimethylsilyl)oxy)-2-(dimethoxymethyl)-4-
methylene-5-
((triisopropylsilyl)oxy)cyclopentyl)methoxy)dimethy
lsilane 44
To a solution of the crude acid 42 (4.43 g, 12.5 mmol) from
the previous step in benzene (40 mL) at 0 °C was added oxalyl
chloride (5.4 mL) followed by DMF (50 ꢀL). The reaction was
warmed to RT and stirred for 1 h by which point gas evolution
had ceased. The mixture was then concentrated in vacuo before
being redissolved in CBrCl3 (62 mL). The solution was then
added dropwise down the side of reflux condenser over a period
of approximately 1 h into a suspension of 2-mercaptopyridine N-
oxide sodium salt (2.28 g, 15.2 mmol) in CBrCl3 (62 mL) heated
to 130 °C (external oil bath temperature). The reaction was
stirred for a further 10 min and then cooled to RT and filtered,
washing with CH2Cl2. The solution was then concentrated in
vacuo. Purification by flash column chromatography (15:1
petrol:EtOAc) gave the title compound 42 as a white solid (3.74
g, 9.90 mmol, 79%); m.p. 38–40 °C; Rf 0.42 (15:1
petrol:EtOAc); νmax/cm-1 (thin film) 2944m, 1781s, 1464m; δH
(400 MHz CDCl3) 5.21 (1H, s, CHH’=C), 5.06 (1H, s, CHH’=C),
4.85 (1H, d, J = 7.7 Hz, CHOTIPS), 4.48 (1H, dd, J = 9.6, 3.3
Hz, CHH’O), 4.38 (1H, dd, J = 9.6, 8.0 Hz, CHH’O), 3.24 (1H,
d, J = 16.6 Hz, CHH’CBr), 3.21 (1H, td, J = 8.0, 3.3 Hz,
CHCH2O), 2.94 (1H, dd, J = 16.6, 2.0 Hz, CHH’O), 1.02–1.18
(21H, m, TIPS); δC (100 MHz CDCl3) 175.5 (CO), 146.7
(CH2=C), 110.0 (CH2=C), 74.2 (CHOTIPS), 65.1 (CH2OR), 53.7
(CBr), 53.6 (CHCH2O), 43.6 (CH2CBr), 18.0 (SiCHMe2), 12.3
(SiCHMe2); m/z LRMS (ESI+) 411 (M79+Na+, 50) 413
To a solution of diol 43 (2.89 g, 7.72 mmol) in CH2Cl2 (38
mL) at -78 °C was added 2,6-lutidine (4.04 mL, 35.0 mmol), and
TBSOTf (5.30 mL, 23 mmol). The reaction was then warmed to
0 °C and stirred for 1 h before being quenched with sat. aq.
NaHCO3 (50 mL) and diluted with petrol (70 mL). The aqueous
layer was separated and extracted with 10:1 petrol:EtOAc (2 × 50
mL). The combined organic layers were dried (MgSO4), filtered
and then concentrated in vacuo. Purification by flash column
chromatography (20:1 petrol:EtOAc) gave the title compound 44
as a colorless oil (4.65 g, 7.71 mmol, quant); Rf 0.67 (20:1
petrol:EtOAc); νmax/cm-1 (thin film) 2987m, 1463m; δH (400 MHz
CDCl3) 4.96–4.99 (1H, m, CHH’=C), 4.84–4.87 (1H, m,
CHH’=C), 4.63 (1H, d, J = 6.7 Hz, CHOTIPS), 4.19 (1H, s,
CH(OMe)2), 3.95 (1H, dd, J = 10.0, 7.2 Hz, CHH’OTBDMS),
3.86 (1H, dd, J = 10.0, 6.2 Hz, CHH’OTBDMS), 3.53 (3H, s,
OMe), 3.44 (3H, s, OMe), 2.52–2.54 (2H, m, CH2COTBDMS),
2.28 (1H, q, J = 6.7 Hz, CHCH2OTBS), 1.04–1.10 (21H, m,
TIPS), 0.89 (9H, s, SiCMe3), 0.85 (9H, s, SiCMe3), 0.10 (3H, s,
SiMe), 0.04 (6H, s, SiMe), 0.03 (3H, s, SiMe); δC (100 MHz
CDCl3) 152.5 (CH2=C), 110.1 (CH(OMe)2), 107.7 (CH2=C), 84.2
(COTBDMS), 75.6 (CHOTIPS), 60.0 (CH2OTBDMS), 58.9
(OMe), 56.9 (OMe), 52.2 (CHCH2OTBDMS), 41.0
(CH2COTBDMS), 26.2 (SiCMe3), 26.1 (SiCMe3), 18.8 (SiCMe3),
18.4 (SiCHMe2), 18.3 (SiCHMe2), 12.8 (SiCHMe2), -2.5 (SiMe),
-2.8 (SiMe), -5.2 (SiMe), -5.5 (SiMe); m/z LRMS (ESI+) 625
(M+Na+, 100); HRMS (ESI+): found 625.4108, C31H66O5Si3Na+
(M+Na+), requires 625.4110; [α]D25 -19.6 (c = 1.0 in CHCl3).
(M81+Na+, 50); HRMS (ESI+): found 411.0962, 413.0941,
25
C17H29O3BrSiNa+ (M+Na+), requires 411.0962, 413.0941; [α]D
-
36.8 (c = 1.0 in CHCl3).
4.1.44. (1R,2S,3R)-1-(Dimethoxymethyl)-2-
(hydroxymethyl)-4-methylene-3-
((triisopropylsilyl)oxy)cyclopentan-1-ol 43
To a stirred solution of lactone 42 (3.70 g, 9.50 mmol) in THF
(95 mL) at -78 °C was added DIBAL (37 mL, 1 M in hexane, 37

20
Tetrahedron
4.1.46. tert-Butyl(((3S,4R,5S,6R)-6-((tert-
SiMe), 0.03 (3H, s, SiMe), 0.02 (3H, s, SiMe); δC (100 MHz
butyldimethylsilyl)oxy)-6-(dimethoxymethyl)-4-
((triisopropylsilyl)oxy)-1-oxaspiro[2.4]heptan-5-
yl)methoxy)dimethylsilane 45
CDCl3) 110.7 (CH(OMe)2), 84.6 (quat), 83.0 (quat), 81.5
(CHOTIPS), 60.4 (CH2OTBS), 59.5 (OMe), 57.9 (OMe), 51.0
(CHCH2OTBS), 48.9 (CH2COTBS), 26.1 (SiCMe3), 22.2
(MeCOH), 18.6 (CMe3), 18.6 (CHMe2), 18.6 (CHMe2), 18.4
(CMe3), 13.5 (SiCHMe2), -2.0 (SiMe), -2.5 (SiMe), -5.1 (SiMe), -
5.4 (SiMe); m/z LRMS (ESI+) 643 (M+Na+, 100); HRMS (ESI+):
found 643.4213, C31H68O6Si3Na+ (M+Na+), requires 643.4216;
[α]D25 -8.7 (c = 1.0 in CHCl3).
DMDO (80 mL, 0.08 M in acetone, 6.4 mmol) cooled to -20
°C was added to alkene 44 (3.68 g, 6.10 mmol) at RT. The
reaction was stirred for 4 h at RT and then concentrated in vacuo
to approximately 10 mL and then diluted with petrol (90 mL),
dried (MgSO4), filtered and then concentrated in vacuo.
Purification by flash column chromatography (20:1
petrol:EtOAc) gave the title 45 compound as a colorless oil (3.34
g, 5.4 mmol, 88%); Rf 0.32 (20:1 petrol:EtOAc); νmax/cm-1 (thin
film) 2949m, 1471w; δH (400 MHz CDCl3) 4.29 (1H, s,
CH(OMe)2), 4.25 (1H, d, J = 7.9 Hz, CHOTIPS), 4.00 (1H, dd, J
= 10.1, 8.2 Hz, CHH’OTBDMS), 3.81 (1H, dd, J = 10.1, 5.8 Hz,
CHH’OTBDMS), 3.59 (3H, s, OMe), 3.42 (3H, s, OMe), 3.06
(1H, d, J = 5.0 Hz, CHH’OC), 2.72 (1H, d, J = 5.0 Hz,
Acknowledgments
This work was, in part, supported by Cancer Research (CR-
UK) grant number C38302/A12981, through an Oxford Cancer
Research Centre Prize DPhil Studentship to (EDS). We thank
the EPSRC and UCB Pharama for a CASE award to MSH. JS is
grateful to the EPSRC Centre for Doctoral Training in Synthesis
for Biology and Medicine (EP/L015838/1) for a studentship,
generously supported by AstraZeneca, Diamond Light
Source, Defence Science and Technology Laboratory, Evotec,
GlaxoSmithKline, Janssen, Novartis, Pfizer, Syngenta, Takeda,
UCB and Vertex.
CHH’OC), 2.42 (1H, ddd,
J
=
8.2, 7.9, 5.8 Hz,
CHCH2OTBDMS), 2.07 (1H, d, J = 14.3 Hz, CHH’COTBDMS),
1.97 (1H, d, J = 14.3 Hz, CHH’COTBS), 1.06 (21H, s, TIPS),
0.89 (9H, s, SiCMe3), 0.86 (9H, s, SiCMe3), 0.08 (3H, s, SiMe),
0.04 (3H, s, SiMe), 0.03 (6H, s, SiMe); δC (100 MHz CDCl3)
108.9 (CH(OMe)2), 84.1 (COTBDMS), 75.5 (CHOTIPS), 67.1
(CH2OC), 59.8 (CH2OTBDMS), 59.6 (OMe), 56.2 (OMe), 51.2
(CH2OC), 50.5 (CHCH2OTBDMS), 38.4 (CH2COTBDMS), 26.2
(SiCMe3), 26.1 (SiCMe3), 18.9 (SiCMe3), 18.4 (SiCMe3), 18.2
(SiCHMe2), 18.1 (SiCHMe2), 12.9 (SiCHMe2), -2.8 (SiMe), -2.9
(SiMe), -5.2 (SiMe), -5.4 (SiMe); m/z LRMS (ESI+) 641 (M+Na+,
100); HRMS (ESI+): found 641.4058, C31H66O6Si3Na+ (M+Na+),
requires 641.4059; [α]D25 -16.3 (c = 1.0 in CHCl3).
Dedication
Dedicated to Professor Steve Davies, an inspirational teacher
and researcher.
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Synthesis of the core of the P-glycoprotein inhibitor pepluanin A reported
Key methods involve selective iodocyclization and invertive acetal formation

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: