Synthesis of enantiomerically pure model compounds of the glucose-6-phosphate-T1-translocase inhibitors kodaistatins A-D. Inferences with regard to the stereostructure of the natural products

Article abstract of DOI:10.1016/j.tet.2013.05.091

The kodaistatins A and C (5a,b) inhibit a step in glucose-metabolism at ～100 nM concentrations. This makes them potential 'leads' in the therapy of diabetes. We elucidated the (S)-configuration of the side-chain stereocenter of kodaistatin A by ozonolysis/reduction. The ¹³C NMR shifts of kodaistatin A model cis-11 suggest that the diol moiety in the dihydroxycyclopentanone core of kodaistatin is trans-configured. This model was prepared from the Feringa lactone (21) and (S)-2-methylbutanal (27) in 23 steps (14 steps in the longest linear sequence). We employed the same strategy for the simplified kodaistatin A model iso-cis-12, which resulted from the same substrates in 11 steps (6 steps in the longest linear sequence). The cyclopentenone cores of both targets stemmed from a C₄+C₁ approach. The C₄ components were masked 'tartaric ketones' (16a,b) and a masked 'tartaric aldehyde' (18), respectively. The C₁ components were the lithium-derivatives of the side-chain bearing phosphonates 19 and 22, respectively. The desired acylation/deprotonation/Horner-Wadsworth- Emmons tandem reaction succeeded in a single operation with the 'tartaric aldehyde' 18 but required partly or exclusively additional operations when we incorporated the 'tartaric ketones' 16a or 16b, respectively. The 'tartaric ketones' 16a,b contained an α-siloxyethyl substituent. It is noteworthy that it had to be introduced by adding the benzyltrimethylammonium enolate of lactone 18 to acetaldehyde because the lithium enolate of this lactone fragmented by an acetone-releasing β-elimination.

Full text of DOI:10.1016/j.tet.2013.05.091

Tetrahedron 69 (2013) 7785e7809
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of enantiomerically pure model compounds of the
glucose-6-phosphate-T1-translocase inhibitors kodaistatins AeD.
Inferences with regard to the stereostructure of the natural products
y
z
*
€
€
Thomas Wuster , Natasza Kaczybura , Reinhard Bruckner , Manfred Keller
€
€
Institut fur Organische Chemie, Albert-Ludwigs-Universitat, Albertstr. 21, 79104 Freiburg, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 April 2013
Received in revised form 18 May 2013
Accepted 20 May 2013
Available online 24 May 2013
The kodaistatins A and C (5a,b) inhibit a step in glucose-metabolism at w100 nM concentrations. This
makes them potential ‘leads’ in the therapy of diabetes. We elucidated the (S)-configuration of the side-
chain stereocenter of kodaistatin A by ozonolysis/reduction. The 13C NMR shifts of kodaistatin A model
cis-11 suggest that the diol moiety in the dihydroxycyclopentanone core of kodaistatin is trans-config-
ured. This model was prepared from the Feringa lactone (21) and (S)-2-methylbutanal (27) in 23 steps
(14 steps in the longest linear sequence). We employed the same strategy for the simplified kodaistatin A
model iso-cis-12, which resulted from the same substrates in 11 steps (6 steps in the longest linear se-
quence). The cyclopentenone cores of both targets stemmed from a C4þC1 approach. The C4 components
were masked ‘tartaric ketones’ (16a,b) and a masked ‘tartaric aldehyde’ (18), respectively. The C1 com-
ponents were the lithium-derivatives of the side-chain bearing phosphonates 19 and 22, respectively.
The desired acylation/deprotonation/HornereWadswortheEmmons tandem reaction succeeded in
a single operation with the ‘tartaric aldehyde’ 18 but required partly or exclusively additional operations
when we incorporated the ‘tartaric ketones’ 16a or 16b, respectively. The ‘tartaric ketones’ 16a,b con-
Keywords:
Aldol addition
Cyclopentenone
Diabetes
Dienone
HornereWadswortheEmmons reaction
Tetraalkylammonium enolate
tained an
zyltrimethylammonium enolate of lactone 18 to acetaldehyde because the lithium enolate of this lactone
fragmented by an acetone-releasing -elimination.
a-siloxyethyl substituent. It is noteworthy that it had to be introduced by adding the ben-
b
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
populace of 20e79-year olds who suffered from diabetes were in
China (92.3 million), India (63.0 million), and the United States
(24.1 million).3 The largest proportions of diabetes-sick in the same
populace were citizens of the Pacific Islands of Micronesia (37.2%),
Nauru (30.1%), and Marshall Islands (27.1%).3 Considering the om-
nipresence and the commonness of this affliction, natural products
with anti-diabetic activity have aroused great interest as conceiv-
able cures.4 Fig. 1 exemplifies compounds of that sort, such as
chlorogenic acid (1),5 ilicicolinic acid A (3),5 and mumbaistatin6 (4).
Each of those inhibits the glucose-6-phosphate translocase7 and is
therefore a potential lead in the quest for effective anti-diabetes
agents. An embellishment of the chlorogenic acid core structure
led to the synthetic compound 2 as a veritable drug candidate.8 To
the best of our knowledge mumbaistatin is the currently most
potent glucose-6-phosphate translocase inhibitor at all.6 Little
wonder that systematic studies of structure/activity relationships
with modified mumbaistatins are underway also in academic
environments.9
Natural products continue playing a major role in finding ther-
apeutics and leads for novel medicines.1 In recent years the cer-
tainty of this assessment has spurred many efforts at
supplementing nature’s stock of such materials by synthetic com-
pounds dubbed ‘natural product-like’.2 Diabetes has been a major
health disorder in virtually all societies. According to the 2012
numbers by the International Diabetes Federation more than 370
million people (¼8.3% of the world’s population) were affected by
diabetes, the worldwide costs for the treatment of diabetes
amounted to 470 billion US dollars, and nonetheless 4.8 million
people died of this disease.3 The largest numbers of patients in the
* Corresponding author. Tel.: þ49 7601 2036029; e-mail address: reinhard.-
€
brueckner@organik.chemie.uni-freiburg.de (R. Bruckner).
y
Current address: Glob. Dep. Process Development Chemicals, Boehringer In-
In 2000 a joint team of Aventis Pharma Deutschland and Indian
chemists described several new glucose-6-phosphate translocase
inhibitors. In a screening program of natural products they worked
gelheim Pharma GmbH & Co. KG, Binger Straße 173, 55216 Ingelheim am Rhein,
Germany.
z
Current address: GVX/P e C6, BASF SE, 67056 Ludwigshafen, Germany.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.05.091

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T. Wuster et al. / Tetrahedron 69 (2013) 7785e7809
7786
rayed10 to reveal a (Z)-configuration of the semicyclic C]C bond.
HO2C OH
O
Consequently the same (Z)-configuration was attributed to the
pulvinone moiety of the kodaistatins A and C.10
O
OH
OH
OH
pulvinone unit
chlorogenic acid (1)
HO
OH
R
N
N
HO2C O
O
R
kodaistatins 5
O
OH
N
O
Cl
O
H
A, B
C, D
a, a'
b, b'
O
OH
OH
*
*
OH
HO
HO
*
O
O
2 (synthetic)
cyclopentenone core dienone side-chain
CO2H
HO
with 5a: a)
OH
HO
ilicicolinic acid A (3)
(S)-6
OH
O
Fig. 2. Structurally novel glucose-6-phosphate translocase inhibitors from Aspergillus
terreus Thom DSM 11247:10 kodaistatins A (5a) and C (5b). The absolute and relative
configurations of the stereocenters were left open by the original investigators.10
We clarified the side-chain stereocenter by the oxidative degradation shown at
the bottom. Reagents and conditions: (a) MeOH, ꢀ78 ꢁC, O3, 30 min; NaBH4
(15.0 equiv), ꢀ78 ꢁC, 30 min; ꢀ78 ꢁC /room temperature, 4 h; scale too small for
determining the yield.18
HO
HO
O
*
O
OH
OH
O
O
OH
OH
OH
*
O
OH O
OH O
O
O
The original investigators did not determine the relative con-
figuration of the stereocenters in the cyclopentenone moiety of the
kodaistatins.10 This is because the abundance of oxygen atoms in
that zone made several NMR criteria inapplicable, which otherwise
might have helped distinguishing a cis- from a trans-configured 1,2-
diol moiety. Without derivatizing at least one of the OH groups
there was neither a possibility of determining the absolute config-
uration of the OH-bearing stereocenters. Moreover, assessing the
configuration of the stereocenter in the side-chain relative to the
stereocenters in the diol moiety was an impossibility, and of course
there is no NMR method for establishing its absolute configuration.
Having a small sample of kodaistatin A at our disposal16 we
determined the absolute configuration of its side-chain stereo-
center by cleaving the adjacent C]C bond at ꢀ78 ꢁC with ozone
dissolved in methanol. After 30 min we added excess NaBH4 and
after another 30 min we discontinued feeding the cooling bath with
dry ice. After the temperature had risen to ambient we injected an
aliquot on a GLC apparatus charged with a ‘chiral’ capillary col-
umn.17,18 Thereby we retrieved the alcohol 6 on a scale too small to
determine the yield. The constitution and the (S)-configuration of
the probe were inferred from coinjections with an authentic sam-
ple of (S)-(þ)-6 and an authentic sample of rac-6.19
OH
OH
O
O
4a
cyclo-mumbaistatin (4b)
mixture = mumbaistatin (4)
Fig. 1. Selected glucose-6-phosphate translocase inhibitors from natural product
screenings (1,5 3,5 4,6) or from natural product-inspired laboratory syntheses (25).
up 200 L of a culture solution of Aspergillus terreus Thom DSM 11247
and isolated two yellow solids: 120 mg of kodaistatin A and 11 mg
of kodaistatin C∙10 A concomitant US patent11 and a subsequent
European patent12 claimed protection for a total of four such
compounds, namely for the kodaistatins AeD. The isolators desig-
nated kodaistatin B as a ‘diastereomer’ of kodaistatin A and
kodaistatin D as a ‘stereoisomer’ of kodaistatin C∙11,13
The structures of kodaistatins A (C35H34O11) and C (C35H34O12
)
were elucidated by mass spectrometry and intensive NMR stud-
ies.10 Kodaistatin C turned out to be a hydroxy-kodaistatin A.
Kodaistatins A and C comprise a cyclopentenone core, a dienone
side-chain, and a pulvinone substituent (Fig. 2). HMBC spectra
allowed identifying long-range H,C couplings and INADEQUATE
spectra evidenced 1-bond C,C couplings. NOESY spectra revealed
the (E)-configuration of the trisubstituted C]C bond in the acyclic
1,3-diene moiety. The disubstituted C]C bond is also (E)-config-
ured because its protons shows a vicinal coupling of 16 Hz. The
(Z)-configuration of the semicyclic C]C bond in the pulvinone
moiety of kodaistatins A and C did not emerge directly from the
spectra. It was assigned because of an indirect clue: there were
conspicuous 1H- and 13C-NMR14 similarities with analogous nuclei
in a side-product from the same culture solution, which had been
identified as aspulvinone E.15 A crystal of this side-product was X-
Pondering synthetic pathways toward the kodaistatins their
heavily substituted cyclopentenone core represents both a striking
feature and a point of concern. This is because its substitution
pattern is unique. Even similarly substituted cyclopentenones are
scarce, and not just in natural products but in all of organic
chemistry (Fig. 3).
2. Strategic considerations
An inference from the analysis of the introductory paragraphs
was that we’d better attempt to synthesize not right away one of
the kodaistatins but rather simpler model pounds. One reason was

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T. Wuster et al. / Tetrahedron 69 (2013) 7785e7809
7787
tested. If it failed, the structural elucidation of kodaistatin A would
have to be completed either by syntheses of the two diastereomers
5a with the stereostructures of cis-11 and iso-cis-11 or by syntheses
of the two diastereomers 5a with the stereostructures of trans-11
and iso-trans-11.
In principle cis-11 and trans-11 appear interconvertible by an
oxidation/reduction sequence, and so do iso-cis-11 and iso-trans-11.
Hence, making one of a pair of the respective isomers available
might provide the other in the sequel. In the current study we went
for the model pair cis-11 and trans-11 when we recognized that cis-
11 (but not iso-cis-11) might result from the conveniently accessi-
ble20e Feringa20 lactone,21e23 i.e., from compound 21. This is spec-
ified in the retrosynthetic analysis of Scheme 1.
Scheme 1 traces back model trans-11 (classified as our ‘later
model compound’) to model cis-11 (considered as our ‘1st model
compound’) bya redox sequence. The cyclopentenone core of model
cis-11 should emerge from a C4þC1 approach envisaged as a phos-
phonate acylation/deprotonation/HornereWadswortheEmmons
tandem reaction.24,25 A viable C4 component of this approach would
be whatever diastereomer of the masked ketoacid 15. It would react
as a bis-electrophile. The C1 component of our cyclopentenone ap-
proach would be the phosphonate 19. Due to an initial deprotona-
O
C
O
C
H
O
C
O
C
H
O
C
O
O
C
O
C
C
O
O
O
O
O
O
O
O
O
H
H
10
0
7
8
9
0
3
same 3
as for 8
O
C
O
C
O
O
C
O
C
C
O
O
O
O
O
O
H
H
H
"dihydro"-8
"dihydro"-9
"dihydro"-10
0
30
0
Fig. 3. Absence of the cyclopentenone substitution pattern identical (7) to that in the
kodaistatins (5) and scarcity of several cyclopentenone substitution patterns related
(8e10, ‘dihydro’ 8e‘dihydro’ 10) to that in the kodaistatins (5), as evidenced by the
number of hits (in italics) for a search (February 28th, 2013) of the respective sub-
structures with ‘free substituents on all atoms’ in the REAXYS database.
tion at C-a and because of another deprotonation of C-a, which
would occur after the acylation product 13 would have formed,
phosphonate 19 would react as a bis-nucleophile. These serial
deprotonations of 19 should be realized by letting 19 react with the
masked ketoacid 15 in the presence of 2 equiv of a strong base.
The arbitrarily configured diastereomer of the masked ketoacid
15, which our approach required, was expected to stem from an
acid-catalyzed cyclocondensation of methanol with the ketoacid
16a or with its epimer 16b or with a mixture of the two compounds
(Scheme 1). The ketoacids 16a and b looked like resulting from the
acylation of phenyllithium or a phenyl Grignard reagent by the silyl
ethers of the aldol addition products 17a and b. We planned to
obtain them from the known lactone 1826 and acetaldehyde. This
lactone is two synthetic steps away26 from the Feringa lactone
the incertitude about the relative and absolute configuration in the
diol moiety of the natural products 5a,b. Another consideration was
the difficulty of attaching the sterically demanding ortho-
substituted aryl moiety to the heavily substituted cyclopentenone
core. Accordingly we selected our kodaistatin model(s) from the
four diastereomers of the basic structure 11 (Fig. 4). They combine
the (S)-configured side-chain stereocenter of kodaistatin A with the
four permutations of the (R)- and (S)-configurations at the hy-
droxylated stereocenters. Moreover, they contain a phenyl ring
stead of the pulvinone moiety of the kodaistatins.
(2120). The latter is accessible from furfural (20) and
L-menthol in
another two steps.20e If the enolate of lactone 18 added to acetal-
dehyde with perfect simple diastereoselectivity,27 a single adduct
17a and b would be obtained. If no simple diastereocontrol oc-
curred, the aldol adduct would be a diastereomeric mixture (17a
and b). The latter would be as well suited as each of its constituents
for synthesizing the kodaistatin models cis- and trans-11. Of course,
attributing structures by NMR spectroscopy to synthetic in-
termediates with a homogenous CeO bond configuration would be
easier.
Since many lactone enolates do not aldol-add with much simple
diastereoselectivity we also targeted compound iso-cis-12, a sim-
plified model compound of the kodaistatins (Scheme 1). In the
context of the present project iso-cis-12 offered a possibility of
testing the viability of our C4þC1 strategy without having to deal
with diastereomeric mixtures. Conveniently iso-cis-12 might result
from the metalated phosphonate 22 and the same lactone 18,26
which was meant to precede the more elaborate model com-
pound cis-12.
The earlier mentioned phosphonate 19 and the last-mentioned
phosphonate 22 display the acetal-protected side-chain of the
kodaistatins linked with the C1 constituent of our C4þC1 approach to
the cyclopentenone cores of models cis- and trans-11 and of model
iso-cis-12, respectively (Scheme 1). Phosphonates 19 and 22 differ
only with respect to their O-bound moieties. Nevertheless we sim-
plified 19 and 22 retrosynthetically in two profoundly different
manners. In our original thinking a crossed aldol condensation with
O
O
HO
HO
HO
HO
O
O
O
O
O
O
cis-11
iso-cis-11
O
O
HO
HO
HO
HO
O
O
trans-11
iso-trans-11
Fig. 4. Kodaistatin model compounds containing the correctly (cf. Fig. 2) configured
dienone side-chain and either a cis-dihydroxylated cyclopentenone moiety (cis-11, iso-
cis-11) or a trans-dihydroxylated cyclopentenone moiety (trans-11, iso-trans-11). A
simplified analog iso-cis-12 of the kodaistatin model iso-cis-11 is depicted in Scheme 1
(upper right corner).
We hypothesized that once we would have gained an access to
one of the 11-diastereomers, which contains a cis-configured diol
moiety (cis-11, iso-cis-11), and also an access to one of the 11-dia-
stereomers, which contains a trans-configured diol moiety (trans-
11, iso-trans-11), NMR comparisons with the kodaistatins might
allow to attribute a cis- or trans-configuration to the diol moiety of
the latter. Whether then CD spectroscopy would suffice to unravel
the absolute configuration of kodaistatin A (5a) would have to be
the saturated aldehyde (S)-27 should render the a,b-unsaturated
aldehyde (S)-26.28 The latter was supposed to undergo a trans-se-
lective HornereWadswortheEmmons reaction29 with the

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T. Wuster et al. / Tetrahedron 69 (2013) 7785e7809
"1st model compound"
Ph
"later model compound"
"simplified model compound"
Ph
O
O
HO
HO
iso-cis-12
HO
HO
HO
HO
O
O
O
O
O
O
cis-11
trans-11
Ph
σ
O
PO(OBu)2
O
PO(OMe)2
MeO OMe
O
O
O
MeO OMe
O
O
O
O
13 (4 diastereomers)
14
σ
O O
σ
O
HO
O-
L
-menthyl
OMe
Ph
O
O
Ph
OH
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
L
O
O
O
-menthyl
L-menthyl
15 (4 diastereomers)
16a + 16b
17a + 17b
18
e
0
2
.
f
e
r
)
+
s
p
e
t
s
+
2
(
O-L-menthyl
O
O
ref.26
O
O
(MeO)2P
(BuO)2P
(2 steps)
O
O
MeO OMe
MeO OMe
21 (Feringa
lactone)
20
19
22
O
P(OMe)2
O
(BuO)2P
O
Br
(MeO)2P
HO
O
+
+ Br
MeO OMe
23
O
25
24
26
(S)-6
ref.28
O
(S)-27
Scheme 1. Retrosynthetic analyses of kodaistatin models cis-11, trans-11, and iso-cis-12.
s¼t-BuMe2Si.
ketodiphosphonate 25.30 The resulting
phosphonate would be ketalized.
a,b,g,d-unsaturated keto-
2432,33 and (3) a stereo-retentive Negishi coupling of Me2Zn with
the resulting monobromodiene.34
The last-mentioned step should have furnished the dime-
thylketal 22 uneventfully. In reality it tended to jeopardize the
stereointegrity of the trisubstituted C]C bond. We circumvented
this problem in the retrosynthetic analysis of phosphonate 19 as
detailed in Scheme 1. In that access, the acetal moiety was imple-
mented in the phosphonate 23 before the trisubstituted C]C bond
was established. The latter was planned to originate from a three-
step sequence: (1) a trans-selective hydrostannylation of the C^C
bond31 of the precursor phosphonate 23; (2) a Z-selective Stille-
coupling between the resulting stannane and gem-dibromoolefin
3. Results and discussion
The synthesis of the C4 bis-electrophile 18 from the Feringa
lactone 2120 was straightforward following the description from
Ref. 26 (Scheme 2, top line). The conversion of compound 18 into
whatever suitable diastereomer of the other C4 bis-electrophile 15
came to a halt one step before the last one, i.e., after reaching its
g-ketoacid precursors 16a and b (Scheme 2). Fortunately, the latter
intermediates lent themselves to a variation of our C4þC1 approach

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T. Wuster et al. / Tetrahedron 69 (2013) 7785e7809
7789
to the cyclopentenone core of the kodaistatin model cis-11 alright
(cf. Scheme 6). Therefore we did not invest undue efforts for pro-
gressing to 15 in adherence to the original design.
Aldol additions of dioxolane mono- or diester enolates or the
corresponding silylketene acetals have been described.35 Hence we
were surprised that treatment of the dioxolane-fused lactone 18
with LDA followed by the addition of acetaldehyde did not provide
the aldols 17a or b at all. The problem was that the lithium enolate
of lactone 18 reacted prematurely. On the one hand it fragmented,36
on the other hand it was acylated by the C]O bond of its not yet
deprotonated progenitor 18.36,37
O
O
O
HO
HO
a)
b)
O
O
O
O
Analogous lactone dimerizations are known.38,39 For instance,
O
O
L
O
L
O
the mono(lithium enolate) of a g-substituted a,b-epoxy-g-lactone
-menthyl
-menthyl
L-menthyl
dimerized by an acylation through the not yet deprotonated lactone
in up to 65% yield.39 Even the presence of propionaldehyde in the
epoxylactone/LDA mixture from the beginning gave no opportunity
for the desired aldol addition to compete.39 Eventually, a di-
21
28
18
c)
cf. footnote 36
merization was avoided by deprotonating the mentioned
a,b-ep-
-lactone by LDA in the presence of Me3SiCl.39 This provided
O
oxy-g
= t-BuMe Si
σ
2
Me3Si
O
the Ca-trimethylsilylated40
a,b-epoxy-g-lactone. The latter,
d)
O
2 equiv of various aldehydes, and 10 mol % of Bu4N4 F. (dried in
innovative
bypass
ꢀ
O
situ by molecular sieves 4 A) gave the desired aldol adducts in up to
O
L
62% yield.39,41,42 The feasibility of such lactone enolate Ca-trime-
thylsilylations and reports on the advantageous use of benzyl-
trimethylammonium enolates43 led us to implement a Ca-silylation
18/29 (99% yield) as the inaugural step of an ammonium enolate
addition route to the desired aldol adducts 17a and b (Scheme 2).
Treatment of silyllactone 29 with acetaldehyde (8 equiv) and an-
hydrous BnNMe3F (1.1 equiv) at ꢀ78 ꢁC to ꢀ10 ꢁC provided a ca. 1:1
mixture of epimeric aldol adducts 17a and b. The latter were sep-
arated by flash chromatography on silica gel,44 17a (45% yield)
eluting earlier than 17b (42% yield).
The epimers 17a and b were carried on separately (Schemes 2 and
6) until their follow-up products converged in our ‘1st model com-
pound’ cis-11 (Scheme 6).45 That observation proved the stereo-
structure ofaldol adduct17a because the stereostructure ofits epimer
17b was elucidated by an X-ray structural analysis46 (Fig. 5). The first
-menthyl
29
RO
O
RO
O
O
O
+
O
O
O
O
O
L
O
-menthyl
L-menthyl
R = H: 17a
52 : 48 R = H: 17b
e)
e)
(separable)
σ
R =
σ
: 30a
R = : 30b
f)
f)
O
σ
O
σ
OH
Ph
OH
Ph
O
O
O
O
O
O
O
O
L
-menthyl
L-menthyl
31a + epi-31a
31b + epi-31b
(87:13)a
(85:15)b
g)
g)
Fig. 5. ORTEP plot of the unit cell of an X-ray structure analysis of a single crystal of aldol
17b (cf. Scheme 2) at 120 K.46 All C-bound H atoms were refined while assuming perfectly
staggered orientations with respect to the vicinal AeB bonds (BsH). Only the H-atom of
theOH group was localizedand refinedisotropically without a conformationalconstraint.
σ
O O
σ
O O
Ph
X
Ph
X
O
O
O
O
kodaistatin models iso-cis-12 and cis-11, respectively (cf. Scheme 1). Reagents and
conditions: (a) KMnO4 (1.1 equiv), acetone/H2O (10:1), ꢀ5 ꢁC, 2.5 h; /50 ꢁC, 10 min;
49% (Ref. 26: 62%). (b) acetone (1.2 equiv), BF3$OEt2 (1.0 equiv), ethyl acetate, 0 ꢁC, 6 h;
/room temperature, 2 h; 97% (Ref. 26: 89%). (c) LDA (1.3 equiv), Me3SiCl (1.5 equiv),
THF, ꢀ78 ꢁC, addition of 18 during 15 min, 1 h; 99%. (d) Acetaldehyde (8.0 equiv), THF,
ꢀ78 ꢁC, addition of BnMe3N42F. (1.1 equiv), /ꢀ10 ꢁC during 2 h; 45% 17a separated
from 42% 17b (X-ray structural analysis: Fig. 5). (e) t-BuMe2SiOTf (3.0 equiv), NEt3
(7.5 equiv), CH2Cl2, room temperature, 2 h; 87% (30a); 97% (30b). (f) PhLi (2.0 equiv),
LiCl (5.0 equiv), THF, ꢀ10 ꢁC, 10 min. (g) p-TsOH (5 mol %), CHCl3, room temperature,
1 h (induces liberation of menthol). (h) RuCl3$H2O (10 mol %), NaIO4 (1.5 equiv), CCl4/
MeCN/H2O (2:2:3), 0 ꢁC, 45 min, /room temperature, 60 min; 34% over 3 steps (16a);
49% over the 3 steps (16b). (i) HCl-saturated MeOH/MeOH (1:4), ꢀ20 ꢁC, 18 h; 0 ꢁC,
15 h; room temperature, 12 h; no conversion. aAt 300 MHz in CDCl3 solution the major
O
O
X = H: 32a
X = OH: 16a
X = H: 32b
X = OH: 16b
h)
h)
O
σ
OMe
Ph
i)
i)
O
O
O
O
15
epimer displayed
5.43 ppm. bAt 300 MHz in CDCl3 solution the major epimer displayed
5.44 ppm and the minor epimer
[HC(OR)2]¼5.35 ppm.
d
[HC(OR)2]¼5.50 ppm and the minor epimer
d
[HC(OR)2]¼
Scheme 2. Conversion of the Feringa lactone (21) into the furanone 18 and into the
-ketocarboxylic acid (16a,b) equivalents of the furanones 15, precursors of the
d
[HC(OR)2]¼
g
d

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T. Wuster et al. / Tetrahedron 69 (2013) 7785e7809
7790
set of transformations of aldol adduct 17 comprised four steps both in
the a and in the b series (Scheme 2). Protection of the OH groups gave
the tert-butyldimethylsilylethers 30a,b. Unable to acylate phenyl-
magnesium bromide even in refluxing THF either of the 30 epimers
picked up phenyllithium, albeit in a 1:2 ratio. Speculating that the
nucleophilicity of the latter might be modified by aggregate forma-
tion we attenuated the reactivity of 2 equiv of phenyllithium by
5 equiv of LiCl such that the 30 epimers accepted that phenyl donor in
the desired 1:1 ratio. The 1H NMR spectrum of the crude products
evidenced more aliphatic protons than the expected ketoaldehyde
structures 32a and b would have contained. These excess protons
indicated that in spite of the aqueous workup the initially formed
hemiketal/acetal structures 31a and b were still intact.47 They
decomposed whenpurified by flash chromatography on silica gel44 in
the presence of p-TsOH, though. The resulting ketoaldehydes 32a and
b exhibited minor signals, the slower the chromatography the more
Following our retrosynthetic analysis of Scheme 1, the ketal-
substituted phosphonate 22 was derived from the ketobis
(phosphonate) 25 and the (S)-configured a,b-unsaturated aldehyde
26. These compounds were prepared and combined as shown in
Scheme 3. The 1,4-addition of dimethyl phosphite (33) to the ac-
rylate 34 was induced by AlMe3.48 The resulting phosphorylated
ester 36 allowed to acylate the lithiated phosphonic ester 37. This
rendered 77% of the ketobis(phosphonate) 25. Condensation of N-
tert-butylamine with propionaldehyde gave imine 35 in accordance
with Ref. 49. Moreover, oxidation of alcohol (S)-6 by NaOCl (stoi-
chiom.), TEMPO (cat.), and KBr (cat.) gave aldehyde (S)-27 as re-
ported.28 After lithiation with n-BuLi, imine 35 was added to
aldehyde (S)-27. The crude product was treated with oxalic acid.
This gave the (S)-configured a,b-unsaturated aldehyde 26 in 71%
yield.50 No HornereWadswortheEmmons olefinations, which en-
gage the ketobis(phosphonate) 25 or analogs thereof, have been
described in the literature.30 Nonetheless 25 underwent such an
olefination with enal 26 without a problem (K2CO3 in dioxane and
a small amount of H2O at 70 ꢁC). The ketophosphonate 38 resulted
in 75% yield, the newly formed C]C bond being exclusively trans-
configured.51 The ensuing ketalization in MeOH with trimethyl
formiate and cat. p-TsOH occurred at 0 ꢁC within 3 h. It rendered the
ketal-substituted phosphonate 22 in 87% yield. However, this re-
action was hampered by a partial isomerization of the tri-
substituted C]C bond. Usually 22 could not be obtained purer than
as a 88:12 mixture of the trans,E- and the trans,Z isomer.51 Grati-
fyingly, though, the stereocenter had stayed intact all the way from
alcohol (S)-6 into phosphonate 22. This was proven by an ozonol-
ysis of 22 followed by reduction of the crude product by NaBH4
because the resulting alcohol 6 was ꢂ99% (S)-configured.
intensely. Concluding that epimerization
a to the aldehyde function
was a risk we chromatographed the ketoaldehydes 32a and b as fast
as possible and oxidized them immediately. This rendered the
ketoacids 16a (dC]O ¼ 199.10 ppm, dCO H ¼ 169:36 ppm) and b (dC]
2
¼ 201.39 ppm, dCO H ¼ 172:75 ppm), in 34% and 49% overall yield
O
2
from silyl ethers 30a and b, respectively.
O
OMe
O
HO
(BuO)2PH
O
34
(S)-6
c)
33
a)
b)
In the retrosynthetic analysis of Scheme 1 the isomerically pure
ketal-substituted decadienyl phosphonate 19 was traced back to the
ketal-substituted pentynyl phosphonate 23 and the gem-dibromi-
nated alkene 24. The latter materials were obtained and processed as
detailed in Scheme 4. The 1,4-addition of dimethyl phosphite (39) to
methyl acrylate (34) was made work like the addition of dibutyl
phosphite (33) to the same acrylate (Scheme 3), namely by adding
AlMe3 (/74% 40).48 AlMe3 also served for deprotonating the hy-
drochloride of N,O-dimethylhydroxylamine, the resulting amide
converting the phosphorylated ester 40 into the Weinreb amide 41
(89% yield). The latter allowed the acylation of lithiated (trime-
thylsilyl)acetylene. The resulting ketone 42 was so sensitive that it
was ketalized without prior purification. The ketalized and silyl-
substituted phosphonate 43 resulted in 40% yield over the two
steps. It was desilylated by a substoichiometric amount of borax in
aqueous methanol.52 This delivered the ketal-substituted pentynyl
phosphonate 23 in 98% yield. Compound 23 was hydrostannylated
with Bu3SnH under PdCl2(PPh3)2 catalysis.53 To the extent that this
provided the 1-(tributylstannyl)alkene 44 (66% yield) the reaction
was trans-selective.54 Inadditionweobtainedthe 2-(tributylstannyl)
alkene iso-44 (18% yield). These isomers could be separated by flash
chromatography on silica gel,44 iso-44 eluting faster than 44.55,56 The
counterpart of the terminally stannylated alkene 44 for the Stille
coupling was the dibromoolefin 24. It was prepared as described32
from aldehyde (S)-2728 (which was synthesized as shown in
Scheme 3), PPh3, and Zn. The Stille-coupling between 44 and (S)-27
worked best in the presence of 10 mol % Pd(dba)2 and 30 mol % P(2-
Fur)3 in toluene. It was chemoselectivedbecause mono-coupling
occurreddand stereoselective,57 both as anticipated.33 The trans,Z-
configured bromodecadienyl phosphonate 45 resulted in 66%
yield.54 It underwent a stereo-retentive Negishi coupling with
Me2Zn in refluxing THF when 10 mol % of Pd(PtBu3)2 were present.
These conditions were adopted from a literature precedent where
2mol% ofPd(PtBu3)2 hadsufficed.34 Usingsuchasmall amountof the
catalyst caused an incomplete conversion of the bromodecadienyl
phosphonate 45. This faced us with the problem of being unable to
O
t-BuN
O
(BuO)2P
OMe
O
35
(S)-27
O
d)
36
P(OMe)2
Me
37
O
e)
f)
26
O
O
O
P(OMe)2
trans
E
(BuO)2P
(BuO)2P
O
O
25
38 (only trans,E)
g)
O
(BuO)2P
h)
trans
E
HO
MeO OMe
(S)-6 (
≥
99% ee)
22 (88:12 trans,E: trans,Z)
Scheme 3. Synthesis of the side-chain bearing phosphonate 22, the other precursor
(cf. Scheme 2) of the kodaistatin model iso-cis-12 according to the retrosynthetic
analysis of Scheme 1. Reagents and conditions: (a) AlMe3 (1.0 equiv), CH2Cl2, 0 ꢁC;
addition of 34 (1.0 equiv), /room temperature, 12 h; 95%. (b) t-BuNH2 (1.1 equiv),
€
MgSO4 (1.7 equiv), CH2Cl2, Ruckfluss, 1 h; 91% (Ref. 49: 96%). (c) NaOCl (1.1 equiv),
TEMPO (1 mol %), KBr (10 mol %), CH2Cl2/H2O (5:1), 0 ꢁC, 8 min; 89% (Ref. 28:
59e88%). (d) 35 (1.5 equiv), n-BuLi (1.4 equiv), THF, ꢀ78 ꢁC; /0 ꢁC, 20 min, /ꢀ78 ꢁC;
addition of (S)-27; /0 ꢁC, 4 h; addition of aq oxalic acid, /room temperature, 14 h;
71%. (e) LDA (1.5 equiv), THF, ꢀ78 ꢁC; addition of 37 (1.5 equiv); addition of 36; /room
temperature, 12 h; 77%. (f) 25 (2.0 equiv), K2CO3 (8 equiv), dioxane, 70 ꢁC, 1 h; addition
of 26, H2O (8 equiv), 40 h; 75%. (g) Trimethyl orthoacetate (1.0 equiv), p-TsOH
(10 mol %), 2,6-di-tert-butyl-4-methylphenol (10 mol %), MeOH (degassed), 0 ꢁC, 3 h;
87% of the indicated isomeric mixture. (h) Stream of ozonated oxygen, MeOH, ꢀ78 ꢁC,
30 min; addition of NaBH4 (6 equiv), /room temperature, 4 h; GLC analysis.

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T. Wuster et al. / Tetrahedron 69 (2013) 7785e7809
7791
O
O-L-menthyl
O
OMe
O
trans
(MeO)2PH
E
O
O
(BuO)2P
O
34
MeO OMe
O
39
(S)-27
O
18
22 (80:20 trans,E: trans,Z)
a)
O
b)
O
Br
(MeO)2P
X
a)
Br
trans
trans
E
Z
O
O
+
X = OMe:
40
24
c)
d)
MeO OMe
MeO OMe
O
O
X = NMe(OMe): 41
X = C CSiMe3: 42
O
O
46 (81:19 trans,E: trans,Z)
b)
e)
O
SnBu3
MeO OMe
(MeO)2P
trans
trans
E
Z
O
R
HO
HO
HO
+
(MeO)2P
O
O
iso-44
O
HO
O
MeO OMe
+
iso-cis-12
dia-iso-cis-12
R = SiMe3: 43
f)
O
R = H:
23
(MeO)2P
SnBu3
g)
MeO OMe
44
separated by preparative HPLC
Scheme 5. Completion of the simplified kodaistatin model iso-cis-12. Reagents and
conditions: (a) 22, n-BuLi (1.0 equiv), THF, ꢀ78 ꢁC, 1 h; addition of LDA (1.0 equiv),
ꢀ78 ꢁC, 5 min; addition of 18 (1.0 equiv); /ꢀ45 ꢁC, 18 h; 43%, 81:19 mixture trans,E-
46:trans,Z-46. (e) p-TsOH (5 mol %), H2O (101 equiv), acetonitrile, room temperature,
16 h; /60 ꢁC, 3 h; additional H2O (51 equiv), 60 ꢁC, 1 h; 90%.
O
Br
h)
trans
Z
(MeO)2P
MeO OMe
≥
45 ( 97% trans, 97% Z)
≥
Consecutive additions of 1 equiv of n-BuLi and 1 equiv of LDA to
a THF solution of an 80:20 trans,E:trans,Z-mixture of the decadienyl
phosphonate 22 at ꢀ78 ꢁC provided a 1:1 mixture the lithiated
phosphonate and LDA, as we had hoped (Scheme 5). After adding
1 equiv of the C4 bis(electrophile) 18, we warmed to ꢀ45 ꢁC and
allowed the reaction to proceed for 18 h. This delivered the cyclo-
pentenone 46 in 43% yield as an inseparable 81:19 trans,E:trans,Z-
mixture.51 Obviously both phosphonate stereoisomers had been
equally reactive. The dimethylketal and acetonide moieties of
compound 46 were cleaved in aqueous acetonitrile in the presence
of a small amount of tosic acid. The dimethylketal seemed to dis-
appear at room temperature while removing the acetonide required
heating to 60 ꢁC. The simplified kodaistatin model iso-cis-1251 and
its C]C bond stereoisomer dia-iso-cis-12 resulted as an unchanged
81:19 trans,E:trans,Z-mixture in 90% combined yield.51 The two
isomers were separable by preparative HPLC, which allowed to
characterize the constituents unambiguously. The accessibility of
compoundiso-cis-12 suggested that the synthesis strategy, onwhich
we had relied would probably be also viable for the synthesis of the
more advanced kodaistatin models cis-11 and trans-11.
i)
trans
O
E
(MeO)2P
MeO OMe
19 (
≥
97% trans, 97% E)
≥
j)
HO
(S)-6 (
≥
99% ee)
Scheme 4. Synthesis of the side-chain bearing phosphonate 19, the other precursor
(cf. Scheme 2) of the kodaistatin model cis-11 according to the retrosynthetic analysis
of Scheme 1. Reagents and conditions: (a) AlMe3 (1.0 equiv), CH2Cl2, 0 ꢁC, 50 min;
addition of 34 (1.0 equiv); /room temperature, 21 h; 74%. (b) CBr4 (2.5 equiv), PPh3
(2.5 equiv), Zn (3.0 equiv), CH2Cl2, room temperature, 96 h; /0 ꢁC; addition of (S)-27,
30 min; /room temperature, 6 h; 81% (ref.32a: 81%). (c) HN(OMe)Me$HCl (4.0 equiv),
AlMe3 (4.0 equiv), CH2Cl2, ꢀ10 ꢁC, 20 h; 89%. (d) Me3Si-acetylene (1.25 equiv), n-BuLi
(1.25 equiv), THF, ꢀ78 ꢁC, 1 h; addition of 41, /ꢀ40 ꢁC, 4 h; the crude product was
carried on without purification. (e) HC(OMe)3/MeOH (1:1), p-TsOH (5 mol %), 80 ꢁC,
7 h; 40% over the 2 steps. (f) Na2B4O7 (15 mol %), MeOH/H2O (3:1), 40 ꢁC, 3 h; 98%. (g)
Bu3SnH (1.2 equiv), PdCl2(PPh3)2 (5 mol %), THF (degassed), room temperature, 20 min;
66% 44 separated from 18% of regioisomer iso-44. (h) 24 (1.25 equiv), Pd(dba)2
(30 mol %), Pd[P(2-furyl)3]3 (10 mol %), 2,6-di-tert-butyl-4-methylphenol (5 mol %),
toluene (degassed), 50 ꢁC, 44 h; 66%. (i) ZnMe2 (1.2 M in toluene, 2.0 equiv), Pd(PtBu3)2
(10 mol %), 2,6-di-tert-butyl-4-methylphenol (5 mol %), THF (degassed), 0 ꢁC/55 ꢁC,
22 h; 87%. (j) Stream of ozonated oxygen, MeOH, ꢀ78 ꢁC, 30 min; addition of NaBH4
(6 equiv), /room temperature, 4 h; GLC analysis.
Scheme 6 shows how we combined the decadienyl phosphonate
19, which was our second latent C1 bis(nucleophile), with the
g-ketoacid 16a or its epimer 16b, both of which were latent C4 bis-
(electrophiles). These ketoacids were converted into the corre-
sponding ketoacyl chlorides by treatment with ‘chloroenamine’ in
THF.59 Either of these ketoacyl chlorides was combined with an
equimolar amount of a 1:1 mixture of LDA and the lithiated deca-
dienyl phosphonate 19 at ꢀ78 ꢁC. This provided, as we presumed, the
diketophosphonates 13a/epi-13a60 and 13b/epi-13b,60 respectively,
in 49% yield each, i.e., no HornereWadswortheEmmons olefination
had occurred. The dimethylketal moieties of the diketophospho-
nates 13 were cleaved by tosic acid in aqueous acetonitrile. This
rendered what we surmised were the triketophosphonates 47a/epi-
47a60 and 47b/epi-47b,60 respectively.
separate the coupling product 19 from residual bromide 45 by flash
chromatography on silica gel.44 Employing 10 mol % of the catalyst
led to a complete conversion of 45 and an 87% yield of phosphonate
19.54,58 As in phosphonate 22 (Scheme 3) the stereocenter in 19
(Scheme 4) was ꢂ99% (S)-configured. This was proved by ozono-
lyzing 19, reducing the crude product by NaBH4, and analyzing the
resulting alcohol 6 by chiral GLC.

σ
O O
σO O
Ph
OH
Ph
OH
O
b)
a)
O
trans
O
E
(MeO)2P
O
O
MeO OMe
O
O
16a
16b
19 (≥ 97% trans, ≥ 97% E)
Ph
Ph
σ
O
σ
O
PO(OMe)2
MeO OMe
PO(OMe)2
MeO OMe
O
O
O
O
O
σ
σ
= t-BuMe2Si
O
O
O
13a + epi-13a
13b + epi-13b
c)
d)
Ph
Ph
σ
O
σO
PO(OMe)2
O
PO(OMe)2
O
O
O
O
O
O
Ph
σO
Ph
o
OH
OH
O
O
O
O
O
O
*
*
47a + epi-47a
47b + epi-47b
OPO(OMe)2
OPO(OMe)2
O
O
O
e)
f)
48b (1 diastereomer)
Ph
σO
48a
Ph
OH
OH
σ
O
Ph
Ph
O
O
σ
O
σO
PO(OMe)2
PO(OMe)2
O
O
O
O
contd.
contd.
O
O
O
O
O
O
O
O
O
OPO(OMe)2
OPO(OMe)2
O
49a + epi-49a (85:15)
50a + epi-50a
50b + epi-50b
49b + epi-49b (91:9)
g)
contd.
not contd.
h)
σ
O
HO
HO
σ
O
Ph
Ph
Ph
Ph
i)
O
O
O
O
O
O
O
O
O
52b
k)
O
O
O
O
O
O
O
51a
52a
51b
j)
O
Ph
Ph
O
trans
E
HO
O
HO
HO
O
O
O
O
O
l)
m)
53
(S)-6 (≥ 99% ee)
cis-11
Scheme 6. Completion of the kodaistatin model cis-11. Treatment of the triketophosphonates 47a and b with base did not induce the desired cyclopentenone-delivering HornereWadswortheEmmons reactions only (a) or at all (b) since we
observed competing (a) or exclusive (b) enol phosphate formations instead. Reagents and conditions: (a) (i) Activation of 16a: 1-chloro-N,N,2-trimethylprop-1-en-1-ylamine (‘chloroenamine’; 1.2 equiv), THF, room temperature, 1.5 h; (ii)
lithiation of 19 (1.0 equiv): n-BuLi (1.0 equiv), ꢀ78 ꢁC, 1 h; LDA (1.0 equiv); (iii) diketophosphonate formation: lithio-19/LDA added to activated 16a at ꢀ78 ꢁC, 25 min; 49% 13a/epi-13a separated from 14% recovered 19. (b) Same as (a) but
starting from 16b and admitting 30 min for step (iii); 49% 13b/epi-13b separated from 31% recovered 19. (c) p-TsOH (5 mol %), MeCN/H2O (5:1), room temperature,16 h; the resulting triketophosphonates 47a/epi-47a were not purified. (d) Same
as (c) but starting from 13b/epi-13b and allowing for 16.5 h reaction time; the resulting triketophosphonates 47b/epi-47b were not purified. (e) K2CO3 (2.0 equiv), 18-crown-6 (4.0 equiv), benzene, 60 ꢁC, 2.5 h; 26% 51aþ(separately) 26% 49a/
epi-49a (over the 2 steps). (f) K2CO3 (2.2 equiv), 18-crown-6 (3.0 equiv), benzene, 60 ꢁC, 3.5 h; 32% 48bþ(separately) 26% 49b/epi-49b (over the 2 steps). (g) HBF4 (3.0 equiv), H2O (15 equiv), CH2Cl2, 40 ꢁC, 100 min; 45% 52a. (h) Same as (g) but
starting from 49b/epi-49b; 48% 52b. (i) NH4F (5.0 equiv),1,4-dioxane/H2O 7:2, 40 ꢁC,14 h; 64%. (j) Pr4NRuO4 (10 mol %), N-methylmorpholine-N-oxide (2.5 equiv), CH2Cl2 (degassed), room temperature, 3 h; 80%. (k) Same as (j) but starting from
52b; 90%. (l) H2O (110 equiv) in trifluoroacetic acid, room temperature, 3 h; 55%. (m) Stream of ozonated oxygen, MeOH, ꢀ78 ꢁC, 10 min; addition of NaBH4 (6 equiv), /room temperature, 4.5 h; GLC analysis.

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T. Wuster et al. / Tetrahedron 69 (2013) 7785e7809
7793
Each of the latter pairs of compounds was heated in a mixture of
K2CO3 and 18-crown-6 in benzene. Workup after 2.5 and 3.5 h,
substituent effects are unlikely to reflect configurational issues in
the diol moiety. They might rather indicate that the unsubstituted
phenyl ring in compound cis-11 models the ortho-substituted phe-
nyl ring of kodaistatin A (5a) poorly. An ortho-substituted instead of
an unsubstituted phenylsubstituent might be twisted moreseverely
relative to the cyclopentenone ring. It is conceivable that differential
twists expose side-chain protons in a different manner to the
shielding/deshielding sections of the anisotropy tensor.
respectively, gave a surprising result. A cyclopentenone (51a54
)
resulted only in the a-configured series (26% yield over the two
steps from 13a/epi-13a). It arose together with a 85:15 mixture of
the cyclopentenyl phosphates 49a54 and epi-49a (again 26% yield
from 13a/epi-13a). Starting from the differently configured trike-
tophosphonates 47b/epi-47b none of the cyclopentenone 51b
formed. Instead, we isolated a 91:9 mixture of the cyclopentenyl
phosphate epimers 49b54 and epi-49b (34% yield over the two steps
from 13b/epi-13b) and separately the side-chain based alkenyl
phosphate 48b54 (32% yield from 13b/epi-13b). This preference for
alkenyl phosphate formation can be interpreted as follows (details:
footnote61): (1) HornereWadswortheEmmons ring-closures were
slowed down due to steric hindrance. (2) Ring-closures by an aldol
addition were kinetically competitive; they limited the role of the
P(]O)(OMe)2 group to that of a by-stander. (3) Enolate formation
in the side-chain allowed a C/O and subsequently an O/O mi-
gration of the P(]O)(OMe)2 moiety.
Table 1
Chemical shift comparisons between model compound cis-11 (1H NMR: 499.6 MHz;
13C NMR: 125.6 MHz) and kodaistatin A10 (5a; 1H NMR: 600 MHz; 13C NMR:
151 MHz) in DMSO-d6 solutions at 300 K. Gray backgrounds point out 1H NMR
chemical shift differences with absolute values >0.20 ppm and 13C NMR chemical
shift differences with absolute values >3.00 ppm.
OH
HO
OH
Only the side-chain based alkenyl phosphate 48b was a genuine
loss in our synthesis. In contrast, the cyclopentenyl phosphates 49a/
epi-49a and 49b/epi-49b could be re-routed toward the kodaistatin
model cis-11. This succeeded by exposure to HBF4 in a 2-phase sys-
temcomposed of CH2Cl2/H2O. Eitherof the mixtures underwent two
structural changes: loss of the tert-butyldimethylsilyl group and 1,4-
elimination of dimethyl phosphate. As a result, we obtained the
cyclopentenones 52a54 and 52b54 in 45% and 48% yield, respectively.
Cyclopentenone 52a was also obtained by an NH4F-mediated desi-
lylation of the HornereWadswortheEmmons product 51a (64%
yield). The hydroxydiketones 52a and 52b converged to the trike-
tone 5354 upon oxidationwith TPAP.62 The yields of 53 were 80% and
90%, respectively. When we cleaved the acetonide ring of triketone
53 in aqueous trifluoroacetic acid the kodaistatin model cis-1154 was
attained in 55% yield. Ozonolysis of cis-11 and an ensuing reduction
with NaBH4 furnished the alcohol (S)-6 once more as a stereo-
chemically integer compound. Accordingly none of the steps be-
tween the phosphonate 19 and the model cis-11 had scrambled the
side-chain stereocenter.
O
O
OH
O
O
1'
3'
5'
7'
8'
1'
3'
5'
7'
8'
3
3
2''
2''
2'
4'
6'
2'
4'
6'
2
2
1''
1''
4
4
5 1
5 1
HO
HO
HO
HO
9'
9'
O
O
O
O
5a
cis-11
Nucleus
d
(1H)/ppm
cis-11
[
d
d
(1H)5a
(1H)cis-11]/
ꢀ
d
(
13C)/ppm
[
d(
d
(
13C)5a
13C)cis-11]/
ppm
ꢀ
5a
cis-11 5a
ppm
1
2
3
4
Devoid of H Devoid of H
Devoid of H Devoid of H
Devoid of H Devoid of H
Devoid of H Devoid of H
d
204.43 200.01 ꢀ4.42
135.32 137.24 þ1.92
165.30 161.61 ꢀ3.69
85.49 89.66 þ4.17
75.50 84.45 þ8.95
d
d
d
5
4.20
4.26
þ0.06
10
20
30
40
50
60
70
80
3.46þ3.72
Devoid of H
6.15
3.06þ3.29
ꢀ0.40ꢀ0.43 36.03 36.91 þ0.88
d
195.48 194.09 ꢀ1.39
123.68 122.60 ꢀ0.78
148.49 147.21 ꢀ1.28
131.80 131.62 ꢀ0.18
149.64 148.67 ꢀ0.97
34.39 34.22 ꢀ0.17
5.93
6.92
ꢀ0.22
ꢀ0.36
d
7.28
Devoid of H Devoid of H
5.85
2.44ꢀ2.50
5.57
2.44
ꢀ0.28
ꢀ0.03
A Swern oxidationwith trifluoroacetic anhydride as the activating
agent left our kodaistatin model cis-11 unaffected whereas TPAP or
the DesseMartin periodinane attacked the model but provided
product mixtures. These exploratory experiments contrasted with
our hope that an oxidation/reduction sequence might allow for
converting at least some kodaistatin model cis-11 into the epimeric
model trans-11. No more efforts with that objective were undertaken
at that stage.
1.22ꢀ1.32þ 1.21þ1.34
ꢀ0.06ꢀ0.05 29.38 29.35 ꢀ0.03
1.34ꢀ1.43
90
0.81
1.76
0.96
0.78
1.70
0.97
ꢀ0.03
ꢀ0.06
þ0.01
d
11.74 11.63 ꢀ0.11
12.15 12.11 ꢀ0.04
19.95 19.94 ꢀ0.01
210.94 207.71 ꢀ3.23
27.27 27.69 þ0.42
50-Me
70-Me
100
Devoid of H Devoid of H
2.13 2.32
200
þ0.21
Table 1 juxtaposes the 1H- and 13C NMR shifts of kodaistatin
model cis-11 and those the natural product kodaistatin A (5a10). The
4. Conclusions
absolute values of the six largest 13C-shift differences d5a
dcis-11
ꢀ
We achieved the first synthesis of the cyclopentenone cis-11. It
exhibits the unprecedented substitution pattern of the cyclo-
pentenone core of the glucose-6-phosphate-T1-translocase in-
hibitor kodaistatin A (5a). A cornerstone of our synthesis is
a C4þC1 approach to the cyclopentenone moiety. This approach
worked without problems for reaching the simplified kodaistatin
model iso-cis-12. It was not so straightforward for reaching the
advanced kodaistatin model iso-cis-11. This is because the desired
HornereWadswortheEmmons ring-closures 47/52 were out-
competed by ring-closures based on aldol-additions. The latter
were followed by P(]O)(OMe)2 migrations. They provided
alkenyl phosphates 48 and 49. The latter of those were not lost on
our way to cis-11. Seizable 13C NMR shift differences between our
model compound cis-11 and kodaistatin A (5a) suggest that the
latterdother than the formerdcontains a trans-1,2-diol moiety.
Unfortunately, we could not corroborate this inference by trans-
forming our model compound cis-11 into the hitherto elusive model
range from 8.95 to 1.92 ppm. They are associated with the nuclei of
the cyclopentenone ring and with the carbonyl substituent of the
quaternary stereocenter. These shift differences and the locations of
their origin could mean that our kodaistatin model cis-11 and the
natural product (5a) contain diastereomeric cyclopentenone moie-
ties. Since our model cis-11 is a cis-1,2-diol, one would then conclude
1
that 5a is a trans-1,2-diol. The absolute values of the six largest H
NMR shift differences d5a dcis-11 range from 0.43 to 0.21 ppm. They
ꢀ
stem from protons other than the only proton (5-H), which is
cyclopentenone-bound. In fact 5-H is only marginally deshielded in
5a versus cis-11 [d5a
ꢀdcis-11¼0.06 ppm], which does not hint at the
occurrence of a differentlyconfigured diol moiety in 5a versus cis-11.
Surprisingly, the mentioned larger 1H NMR shift differences are
associated with several protons located off and away from the diol
moiety. For instance, the 60-H resonance is shifted downfield by
0.28 ppm in 5a versus cis-11. Indeed, this kind of observation is
surprising no matter what the diol configuration. These remote

€
T. Wuster et al. / Tetrahedron 69 (2013) 7785e7809
7794
compound trans-11 and by including 13C NMR data of the latter in our
comparisons. We believe that synthesizing the kodaistatin models
trans-11 or iso-trans-11 remains conceivable on variations of the
present route to cis-11. However, one would then protect the latent
1,2-diol moiety differently than as an acetonide: the ‘dioxydiquinane’
51a with the cis-annulated acetonide formed alreadyso reluctantly in
the present study that obtaining the diastereomeric ‘dioxydiquinane’
with a trans-annulated acetonide appears almost impossible.
A while ago, Trost and Toste described a catalytic enantiose-
lective synthesis of a compound, whose structure corresponds to
an analog of the Feringa lactone 21; therein the menthyloxy
substituent gives way to a 2-naphthyloxy substituent.63 The en-
antiomer of that analog should be equally readily accessible. It
might be a cheaper progenitor of the cyclopentenone core of
kodaistatin models like iso-cis-11, which exhibit the opposite diol
configurations than the current models cis-11 and iso-cis-12.
natural kodaistatin A (5a) (10 mg, 16 mmol) in MeOH (1.0 mL) at
ꢀ78 ꢁC. After 10 min the flow of ozone/oxygen was stopped and
NaBH4 (3.6 mg, 95 mmol, 5.9 equiv) was added in one portion. The
dry-ice bath was removed and the mixture stirred for 3.5 h at room
temperature. Aqueous, saturated solution of NaHCO3 (1 mL) and
Et2O (1 mL) was added. After phase separation the aqueous phase
was extracted with Et2O (2ꢃ1 mL) and CH2Cl2 (2ꢃ1 mL) and the
combined organic phases were dried over Na2SO4. The resulting
solution was concentrated under reduced pressure and analyzed by
‘chiral’ GLC without further purification. GLC [CP-Chirasil-Dex CB,
25 mꢃ0.25 mm (CP-7502), 35 ꢁC isotherm, 45 min; þ10 ꢁC/min to
170 ꢁC, 20 min; 50 kPa H2 pressuredno additional carrier gas]:
ꢂ99% ee for the detectable enantiomer of 6, which was (S)-6 and
had Rt¼18.39 min [Rt of (R)-6¼17.55 min as read from the chro-
matogram obtained by coinjecting the described specimen of (S)-6
and a reference specimen of rac-6].
5.1.2.1. Preparation by ozonolysis of cis-11 (Scheme 6). A mixture
of ozone and oxygen was bubbled through a solution of cis-11
5. Experimental section
5.1. General information
(3.0 mg, 7.6
m
mol) in MeOH (1.0 mL) at ꢀ78 ꢁC. After 10 min the
flow of ozone/oxygen was stopped and NaBH4 (1.7 mg, 46 mmol,
6.1 equiv) was added in one portion. The dry-ice bath was removed
and the mixture stirred for 4.5 h at room temperature. Proceeding
analogously as in the preceding paragraph we undertook an anal-
ogous analysis by ‘chiral GLC’ without prior purification [CP-
Chirasil-Dex CB, 25 mꢃ0.25 mm (CP-7502), 35 ꢁC isotherm,
45 min; þ10 ꢁC/min to 170 ꢁC, 20 min; 50 kPa H2 pressuredno
additional carrier gas]: ꢂ99% ee for the detectable enantiomer of 6,
which was (S)-6 and had Rt¼17.47 min [Rt of (R)-6¼17.07 min as
read from the chromatogram obtained by coinjecting the described
specimen of (S)-6 and a reference specimen of rac-6].
Reactions were performed and reagents/solutions transferred in
oven-dried (80 ꢁC) glassware and plastic syringes/stainless steel
cannulas, respectively, always under an atmosphere of N2. ‘Room
temperature’ refers to indoor temperatures in the absence of air-
conditioning, i.e., to the range between 20 and 35 ꢁC. THF was dis-
tilled over potassium prior to use, diethyl ether over Na/K-alloy, and
dichloromethane, DMF, and diisopropylamine over calcium hydride.
Most products were purified by flash chromatography44 (column
diameter, filling height, and eluents are given in parentheses) on
Macherey-Nagel silica gel 60 (0.040e0.063 mm, 230e400 mesh,
ASTM). Yields refer to analytically pure samples. 1H NMR [TMS
5.1.2.2. Preparation by ozonolysis of 19 (Scheme 4). A mixture of
ozone and oxygen was bubbled through a solution of 19 (20 mg,
(
d
¼0.00) as internal standard in CDCl3, C6HD5 as internal standard
60
m
mol) in MeOH (1.0 mL) at ꢀ78 ꢁC. After 10 min the flow of ozone/
(d
¼7.1664) in C6D6, DMSO-d5 as internal standard (
d
¼2.5064) in
oxygen was stopped and NaBH4 (13.7 mg, 360 mmol, 6.00 equiv) was
DMSO-d6]: Varian Mercury VX 300, Bruker Avance 400, and Bruker
added in one portion. The dry-ice bath was removedand the mixture
stirred for 3.5 h at room temperature. Proceeding analogously as in
the preceding paragraph we undertook an analogous analysis by
‘chiral GLC’ without prior purification [CP-Chirasil-Dex CB,
25 mꢃ0.25 mm (CP-7502), 35 ꢁC isotherm, 45 min; þ10 ꢁC/min to
170 ꢁC, 20 min; 50 kPa H2 pressuredno additional carrier gas]: ꢂ99%
ee for the detectable enantiomer of 6, which was (S)-6 and had
Rt¼17.84 min [Rt of (R)-6¼17.87 min as read from the chromatogram
obtained by coinjecting the described specimen of (S)-6 and a ref-
erence specimen of rac-6].
DRX 500. 13C NMR [CDCl3 as internal standard (
d
¼77.1664) in CDCl3,
C6D6 as internal standard (
standard (
d
¼128.0664) in C6D6, DMSO-d6 as internal
d
¼39.5264) in DMSO-d6]: Bruker Avance 400 and Bruker
DRX 500. Assignments of 1H- and 13C NMR resonances usually refer
to the IUPAC nomenclature except within substituents, for which
primed numbers may be used; exceptions from this rule are in-
dicated in the formulas in the Experimental Part. MS, GLC/MS and
€
€
HPLC/MS: Dr. J. Worth and C. Warth, both Institut fur Organische
€
Chemie, Universitat Freiburg. Chiral GLC: Carlo Erba gas chromato-
graph, with CP-7502 capillary (Chirasil-Dex) running on 50 kPa
€
€
hydrogen. Combustion analyses: E. Hickl and F. Tonnies, Institut fur
5.1.3. (4R,5R)-4-Acetyl-2-[(S,3E,5E)-5,7-dimethyl-2-oxonona-3,5-
dienyl]-4,5-dihydroxy-3-phenylcyclopent-2-en-1-one (cis-11).
€
Organische Chemie, Universitat Freiburg. NMR: M. Schonhardt and F.
€
€
Reinbold, Institut fur Organische Chemie, Universitat Freiburg. IR
spectra: PerkineElmer Paragon 1000 spectrometer. Optical rotations
aexp were measured at 25 ꢁC with a PerkineElmer polarimeter 341
MC at 589 with two exceptions, namely the kodaistatin model cis-11
p
m
o
q
O
and compound 48b, whose optical rotations were measured at
1''
2''
25
l
¼578 nm. The corresponding specific rotations [
a] a]578 were
calculated from the time-averaged value for aexp furnished by the
25 or [
D
4
1'
5'
7'
9'
O 3'
HO
HO
5 1
€
apparatus. X-ray crystal structure analyses: Dr. J. Geier, Institut fur
O
€
Organische Chemie, Universitat Freiburg.
A solution of acetonide 53 (6.0 mg, 14
(9:1, 500
temperature for 2.5 h. The solvent was removed at 30 ꢁC in vacuo.
Flash chromatography44 (B 0.5 cm, 20 cm, packed with c-C6H12
mmol) in CF3CO2H/H2O
mL; corresponds to 200 equiv of H2O) was stirred at room
5.1.1. (S)-2-Methylbutanol [(S)-6].
,
HO
then c-C6H12/AcOEt 2:1/1:1) gave the title compound (3.0 mg,
1
4
54%, ꢂ94% trans,E) as a yellow oil; Rf value (c-C6H12/AcOEt 1:1,
25
impregnated with formic acid): 0.35; [
a
]
578
¼þ794, C6D6, c¼0.24);
5.1.2. Preparation by ozonolysis of kodaistatin A (5a) (Fig. 2). A
mixture of ozone and oxygen was bubbled through a solution of
IR (film):
n
¼3415, 3060, 2955, 2925, 2865, 1720, 1690, 1675, 1665,
1640, 1620, 1590, 1490, 1480, 1460, 1445, 1410, 1390, 1355, 1305,

€
T. Wuster et al. / Tetrahedron 69 (2013) 7785e7809
7795
1255, 1205, 1185, 1150, 1125, 1080, 1020, 980, 930, 865 cmꢀ1
NMR (499.6 MHz, DMSO-d6, sample contained ca. 6% of the trans,Z
;
1H
JH(A),7 ¼7.6 Hz, B part additionally split by JH(B),9 ¼7.5 Hz and
0
0
0
0
0
0
0
JH(B),7 ¼5.8 Hz, 8 -H2), 1.61 (3H, d, J5 -CH3,6 ¼1.3 Hz, 5 -CH3), 2.37 (1H,
4-OH, assignment exchangeable with 5-OH), 2.47 (1H, mc, 70-H),
2.53 (1H, 5-OH, assignment exchangeable with 4-OH), AB signal
(2H, dA¼3.02, dB¼3.23, JAB¼17.0 Hz, additional splitting not re-
solved, 10-H2), 3.59 (1H, d, J5,4¼5.4 Hz, 5-H), 4.08 (1H, mc, 4-H), 5.32
0
0
0
isomer of the title compound):
d
¼0.81 (3H, t, J9 ,8 ¼7.4 Hz, 9 -H3),
0
0
0
0.96 (3H, d, J7 -CH3,7 ¼6.6 Hz, 7 -CH3), 1.22e1.032 and 1.34e1.43 (2H,
2ꢃ m, 80-H2), 1.76 (3H, d, J5 -CH3,6 ¼0.9 Hz, 5 -CH3), 2.13 (3H, s, 2 -
H3), 2.44e2.52 (1H, m, 70-H, superimposed by solvent signal), AB
signal (2H, dA¼3.46, dB¼3.72, JAB¼17.3 Hz, 10-H2), 4.20 (1H, d, J5,5-
00
0
0
(1H, d, J6 ,7 ¼10.1 Hz, 60-H), 6.07 (1H, dd, J3 ,4 ¼15.8 Hz,
0
0
0
0
0
¼7.3 Hz, 5-H), 5.85 (1H, br d, J6 ,7 ¼9.8 Hz, 6 -H), 6.09 (1H, s, 4-
Junassignable¼0.6 Hz, 30-H), 6.93 (1H, ddd, J3,4¼2.9 H0z, J3,1 -H(A)¼J3,1 -
0
0
0
0
OH
OH), 6.15 (1H, d, J3 ,4 ¼15.8 Hz, 3 -H), 6.19 (1H, d, J5-OH,5-H¼7.3 Hz,
¼1.3 Hz, 3-H), 7.81 (1H, d, J4 ,3 ¼15.5 Hz, 4 -H); 13C NMR
0
0
0
0
0
H(B)
5-OH), 7.28 (1H, d, J4 ,3 ¼16.1 Hz, 4 -H), 7.40e7.45 (5H, m, Ph); 13C
(125.7 MHz, C6D6):
d
¼12.02 (C-90), 20.01 (50-CH3), 20.96 (70-CH3),
0
0
0
NMR (125.6 MHz, DMSO-d6, sample contained traces of a contam-
30.36 (C-80), 34.09 (C-70), 36.96 (C-10), 67.77 (C-4), 71.03 (C-5),
125.73 (C-30), 130.15 (C-50), 139.85 (C-40), 139.91 (C-2), 147.47 (C-60),
156.74 (C-3), 194.35 (C-20), 205.76 (C-1); MS (CI): m/z¼279.1 (MHþ).
inant):
d
¼11.74 (C-90), 12.15 (50-CH3), 19.95 (70-CH3), 27.27 (C-200),
29.38 (C-80), 34.39 (C-70), 36.03 (C-10), 75.50 (C-5), 85.49 (C-4),
123.68 (C-30), 127.84 and 128.62 (o- and m-Ar),129.65 (p-Ar),131.80
(C-50), 133.49 (q-Ar), 135.32 (C-2), 148.49 (C-40), 149.64 (C-60),
165.30 (C-3), 195.48 (C-20), 204.43 (C-1), 210.94 (C-100); HRMS (CI):
5.1.5. Dimethyl {(1R*,8S,4E,6E)-1-[(2R,3S,4R)-3-benzoyl-4-(tert-bu-
tyldimethylsiloxy)-2,3-(isopropylidenedioxy)-1-oxopentyl]-3,3-
dimethoxy-6,8-dimethyldeca-4,6-dienyl}phosphonate (13a) and
{(1S*,8S,4E,6E)-1-[(2R,3S,4R)-3-benzoyl-4-(tert-butyldimethylsi-
loxy)-2,3-(isopropylidenedioxy)-1-oxopentyl]-3,3-dimethoxy-6,8-
dimethyldeca-4,6-dienyl}phosphonate (epi-13a; *these configura-
tional descriptors are interchangeable).
MHþ, found m/z¼397.20210, i.e.,
D
¼þ1.5 ppm versus what
C24H29O5 requires (397.20150).
5.1.4. (4S,5S)-2-[(7S,3E,5E)-5,7-Dimethyl-2-oxonona-3,5-dienyl]-
4,5-dihydroxycyclopent-2-en-1-one (iso-cis-12) and (4S,5S)-2-
[(7S, 3E, 5Z)-5, 7-dimethyl-2-oxonona-3, 5-dienyl]-4, 5-
dihydroxycyclopent-2-en-1-one (dia-iso-cis-12).
Ph
1''O
t-BuMe2SiO
PO(OMe)2
4'
3
3
3'
1
5'
3
5
7
1'
2'
HO
HO
HO
HO
O
10
4
4
5'
7'
9'
5'
1' O 3'
1' O 3'
5 1
5 1
MeO OMe
O
O
7'
9'
O
O
numbering in accordance with the IUPAC name
iso-cis-12
dia-iso-cis-12
p
m
A suspension of dimethylketal 46 (81:19 trans,E:trans,Z mixture;
48.0 mg, 132 mol), para-toluenesulfonic acid (1.2 mg, 7.0 mol,
5 mol %), and H2O (240 L, 240 mg, 13.3 mmol, 101 equiv) in ace-
tonitrile (1 mL) was stirred at room temperature for 16 h and at
60 ꢁC for 3 h. More H2O (120
L, 120 mg, 6.77 mmol, 51 equiv) was
o
m
m
q
t-BuMe2SiO
m
5
PO(OMe)2
O
2
1''
4
1
2''
2'
4'
6'
3
O
9'
m
MeO OMe
O
O
added and stirring continued for 60 min. At room temperature
AcOEt (5 mL) and satd aq NaHCO3 (3 mL) were added. After phase
separation the aq phase was extracted with AcOEt (3ꢃ2 mL). The
combined organic phases were dried over Na2SO4 and the solvent
was removed in vacuo. Flash chromatography44 (B 1.5 cm, 20 cm, c-
C6H12/AcOEt 1:5/1:10) gave the title compounds (33 mg, 90%) as
an orange oil and as an 80:20 trans,E:trans,Z mixture. 9 mg of this
mixture were separated by preparative HPLC [stationary phase:
Chiralpak AD-H; eluent: n-heptane/isopropanol (85:15); substrate
concentration: 1.5 mg/mL; eluent flow: 16 mL/min] giving iso-cis-
12 (4 mg) and dia-iso-cis-12 (1 mg).
numbering for NMR assignments
A solution of acid 16a (365 mg, 892
dimethylamino)-2-methylprop-1-ene (131 mg, 981
m
mol) and 1-chloro-1-(N,N-
mol,
m
1.10 equiv) in THF (6 mL) was stirred at room temperature for
140 min and then cooled to ꢀ78 ꢁC. In parallel, n-BuLi (2.4 M in
hexane; 390
mL, 937
m
mol, 1.05 equiv) was added at ꢀ78 ꢁC to
ꢀ
a solution of freshly dried (4 A molecular sieves) phosphonate 19
(298 mg, 892
was stirred for 30 min at, which time LDA (0.31 M in THF, 3.00 mL,
937 mol, 1.05 equiv) was added via cannula. The last-mentioned
mmol, 1.00 equiv) in THF (3 mL); the resulting solution
iso-cis-12: 1H NMR (499.7 MHz, C6D6; sample contained residual
0
0
0
m
AcOEt, isopropanol, and n-heptane):
d
¼0.71 (3H, t, J9 ,8 ¼7.6 Hz, 9 -
0
0
0
H3), 0.79 (3H, d, J7 -CH3,7 ¼6.6 Hz, 7 -CH3), AB signal (2H, dA¼1.08,
solution was added rapidly to the previously described solution
(which contained the carboxylic chloride). After stirring the
resulting mixture for 20 min at ꢀ78 ꢁC it was poured into an ice-
cold aq phosphate buffer (pH¼5, 50 mL). After adding AcOEt
(20 mL) the phases were separated, the aq phase was extracted
with AcOEt (6ꢃ20 mL), the combined organic phases were dried
over Na2SO4, and the solvent was removed in vacuo. The crude
product was separated by flash chromatography44 (B 4.0 cm,
20 cm, packed with c-C6H12/AcOEt 10:1þ0.1 vol % NEt3, eluted with
c-C6H12/AcOEt 6:1/4:1) to give title compounds 13a/epi-13a
(315 mg, 49%) as an unquantified mixture of epimers [the 1H NMR
spectrum (300 MHz, C6D6) did not allow a more specific charac-
terization due to signal overlap] and some reisolated phosphonate
19 (42 mg, 14%).
0
dB¼1.18, JAB¼13.3 Hz, A part additionally split by JH(A),7 ¼7.2 Hz and
0
0
JH(A),9 ¼7.1 Hz, B part additionally split by JH(B),9 ¼7.5 Hz and
0
0
0
0
0
JH(B),7 ¼5.8 Hz, 8 -H2), 1.46 (3H, d, J5 -CH3,6 ¼1.3 Hz, 5 -CH3), 2.14 (1H,
mc, 70-H), 2.80e3.24 (2H, 4- and 5-OH), AB signal (2H, dA¼3.09,
dB¼3.23, JAB¼17.0 Hz, 10-H2), 3.73 (1H, d, J5,4¼5.7 Hz, 5-H),04.21 (1H,
0
0
dd, J4,5¼5.7, J4,3¼2.8 Hz, 4-H), 5.39 (1H, d, J6 ,7 ¼9.8 Hz, 6 -H), 5.99
0
0
0
(1H, d, J3 ,4 ¼15.8 Hz, 3 -H), 7.00 (1H, mc, possibly interpretable as
0
0
ddd, J3,4¼3.2 Hz, J3,1 -H(A)¼J3,1 -H(B)¼1.3 Hz, 3-H), 7.21 (1H, d,
J4 ,3 ¼15.8 Hz, 4 -H); 13C NMR (125.7 MHz, C6D6):
d
¼12.05 (C-90),
0
0
0
12.24 (50-CH3), 20.12 (70-CH3), 30.08 (C-80), 35.12 (C-70), 36.47 (C-
10), 67.99 (C-4), 71.23 (C-5), 123.84 (C-30), 132.10 (C-50), 139.98 (C-2),
148.67 (C-40), 149.66 (C-60), 156.99 (C-3), 194.55 (C-20), 205.24 (C-
1); MS (CI): m/z¼279.1 (MHþ).
dia-iso-cis-12: 1H NMR (499.7 MHz, C6D6; sample contained
0
0
0
5.1.6. Dimethyl {(1R*,8S,4E,6E)-1-[(2R,3S,4S)-3-benzoyl-4-(tert-bu-
tyldimethylsiloxy)-2,3-(isopropylidenedioxy)-1-oxopentyl]-3,3-
dimethoxy-6,8-dimethyldeca-4,6-dienyl}phosphonate (13b) and
rests of isopropanol and n-heptane)0:
d
¼0.71 (3H, t, J9 ,8 ¼7.6 Hz, 9 -
0
0
H3), 0.79 (3H, d, J7 -CH3,7 ¼6.6 Hz, 7 -CH3), AB signal (2H, dA¼1.06,
0
dB¼1.17, JAB¼13.4 Hz, A part additionally split by JH(A),9 ¼7.7 Hz and

€
T. Wuster et al. / Tetrahedron 69 (2013) 7785e7809
7796
{(1S*,8S,4E,6E)-1-[(2R,3S,4S)-3-benzoyl-4-(tert-butyldimethylsiloxy)-
2,3-(isopropylidenedioxy)-1-oxopentyl]-3,3-dimethoxy-6,8-
dimethyldeca-4,6-dienyl}phosphonate (epi-13b; *these configura-
tional descriptors are interchangeable).
HCO2H) furnished the title compound (543 mg, 78%) as a colorless
resin; Rf value (c-C6H12/AcOEt 3:1, impregnated with HCO2H): 0.25;
25
[a]
¼þ52 (CHCl3, c¼2.70); IR (film): ¼3055, 3015, 2930, 2855,
n
D
2660, 2545, 2355, 2335, 1730, 1675, 1595, 1575, 1470, 1445, 1415,
1370, 1320, 1255, 1215, 1190, 1135, 1155, 1095, 1020, 980, 940, 885,
835, 815, 775, 755 cmꢀ1; 1H NMR (499.6 MHz, CDCl3; because of line-
Ph
1''O
t-BuMe2SiO
PO(OMe)2
broadening at 300 K the spectrum was registered at 280 K):
d
¼ꢀ0.17
4'
3'
1
5'
3
5
7
1'
and 0.00 [2ꢃ 3H, 2ꢃ s, Si(CH3)2], 0.82 [9H, SiC(CH3)3], 1.24[3H, s, 1ꢃ
2'
O
10
0
0
0
acetonide-C(CH3)2], 1.45 (3H, d, J2 ,1 ¼6.3 Hz, 2 -H3), 1.48[3H, s, 1ꢃ
MeO OMe
O
O
0
0
0
acetonide-C(CH3)2], 4.64 (1H, q, J1 ,2 ¼6.4 Hz, 1 -H), 4.78 (1H, s, 2-H),
7.43 (2H, mc, m-Ar), 7.55 (1H, t, Jp-Ar,m-Ar¼7.5 Hz, p-Ar), 8.12 (2H, d, Jo-
numbering in accordance with the IUPAC name
¼7.6 Hz, o-Ar); 13C NMR (125.6 MHz, CDCl3):
¼ꢀ5.24 and
d
Ar,m-Ar
ꢀ4.52 [Si(CH3)2], 18.03 [SiC(CH3)3], 19.24 (C-20), 25.66 [SiC(CH3)3],
26.52 and 27.37 [acetonide-C(CH3)2], 70.54 (C-10), ca. 77.0 (C-2,
superimposed by solvent signal), 92.79 (C-3), 111.63 [acetonide-
C(CH3)2], 128.33 (m-Ar), 130.49 (o-Ar), 133.44 (p-Ar), 134.70 (q-Ar),
169.36 (C-1), 199.10 (C-4); combustion analysis: found C 61.45%, H
7.52%; calculated for C21H32O6Si: C 61.73%, H 7.89%.
p
m
o
q
t-BuMe2SiO
5
PO(OMe)2
O
2
1''
4
1
2''
2'
4'
6'
3
O
9'
MeO OMe
O
O
5.1.8. (2R,3S,4S)-3-Benzoyl-4-(tert-butyldimethylsiloxy)-2,3-(iso-
propylidenedioxy)pentanoic acid (16b).
numbering for NMR assignments
The title compounds were prepared from acid 16b (445 mg,
1.09 mmol) and 1-chloro-1-(N,N-dimethylamino)-2-methylprop-1-
ene (160 mg, 1.20 mmol, 1.10 equiv) in THF (6 mL) on the one hand
t-BuMe2SiO O
4
5
Ph
3
and from n-BuLi (2.4 M in hexane; 480
mL, 1.14 mmol, 1.05 equiv),
O
2
1 OH
phosphonate 19 (364 mg, 1.09 mol, 1.00 equiv), and LDA (0.38 M in
m
O
THF, 3.00 mL, 1.14 mmol, 1.05 equiv) in THF (3 mL) on the other
hand after stirring at ꢀ78 ꢁC for 30 min as described for the
preparation of compounds 13a/epi-13a. The crude product was
separated by flash chromatography44 like in the aforementioned
case. It provided the title compounds 13b/epi-13b (391 mg, 49%) as
an unquantified mixture of epimers [the 1H NMR spectrum
(300 MHz, C6D6) did not allow a more specific characterization due
to signal overlap] and some reisolated phosphonate 19 (113 mg,
O
numbering in accordance with the IUPAC name
m
o
t-BuMe2SiO O
q
1'
p
2'
4
3
O
2
1 OH
O
31%); 31P NMR (121.5 MHz, C6D6):
d¼23.84 and 23.90 [2ꢃ PO(Me)2].
O
5.1.7. (2R,3S,4R)-3-Benzoyl-4-(tert-butyldimethylsiloxy)-2,3-(iso-
propylidenedioxy)pentanoic acid (16a).
numbering for NMR assignments
t-BuMe2SiO O
The title compound was prepared from NaIO4 (389 mg,
4
5
Ph
1.82 mmol; 1.50 equiv) and RuCl3$H2O (25.2 mg, 121
mmol;
3
O
0.10 equiv) were added to a vigorously stirred solution of ketoal-
dehyde 32b (477 mg, 1.21 mmol) in a biphasic mixture of CCl4
(5 mL), MeCN (5 mL), and H2O (7.5 mL) as described for the prep-
aration of compound 16a. Flash chromatography44 as in the pre-
2
1 OH
O
O
numbering in accordance with the IUPAC name
ceding procedure delivered the title compound (325 mg, 66%) as
25
a colorless resin; [
a]
¼þ51 (CHCl3, c¼0.60); IR (film): ¼3055,
n
D
3020, 2980, 2950, 2930, 2890, 2855, 2745, 2705, 2655, 2560, 2360,
2335, 1730, 1685, 1650, 1600, 1575, 1470, 1460, 1455, 1445, 1380,
1375, 1295, 1250, 1220, 1180, 1155, 1090, 1020, 975, 960, 935, 915,
880, 830, 810 cmꢀ1; 1H NMR (499.6 MHz, CDCl3; sample contained
a trace of t-BuOMe; because of line-broadening at 300 K the
m
o
t-BuMe2SiO O
q
1'
p
2'
4
3
O
2
1 OH
O
O
spectrum was registered at 270 K):
d
¼ꢀ0.14 and 0.04 [2ꢃ 3H, 2ꢃ s,
Si(CH3)2], 0.76 [9H, SiC(CH3)3], 1.11[3H, s, 1ꢃ acetonide-C(CH3)2],
numbering for NMR assignments
0
0
0
1.32 (3H, d, J2 ,1 ¼6.3 Hz, 2 -H3), 1.45[3H, s, 1ꢃ acetonide-C(CH3)2],
0
At 0 ꢁC NaIO4 (543 mg, 2.55 mmol; 1.50 equiv) and RuCl3$H2O
(35.3 mg, 170 mmol; 0.10 equiv) were added to a vigorously stirred
0
0
4.60 (1H, q, J1 ,2 ¼6.4 Hz, 1 -H), 4.62 (1H, s, 2-H), 7.38 (2H, mc, m-Ar),
7.50 (1H, t, Jp-Ar,m-Ar¼7.4 Hz, p-Ar), 8.10 (2H, d, Jo-Ar,m-Ar¼7.9 Hz, o-
Ar), 8.4e9.8 (1H, br s, CO2H); 13C NMR (125.6 MHz, CDCl3):
d¼ꢀ4.82
solution of ketoaldehyde 32a (670 mg, 1.70 mmol) in a biphasic
mixture of CCl4 (5 mL), MeCN (5 mL), and H2O (7.5 mL). After 15 min
the mixture was warmed to room temperature where stirring was
continued for 3 h. After adding brine (15 mL) and AcOEt (10 mL) the
phases were separated. The aq phase was extracted with AcOEt
(4ꢃ10 mL). The combined organic phases were dried over Na2SO4.
The solvent was removed in vacuo. Flash chromatography44 (B 4 cm,
20 cm, c-C6H12/AcOEt 5:1/4:1/3:1: all eluents contained 0.2 vol %
and ꢀ4.77 [Si(CH3)2], 18.01 [SiC(CH3]3, assignment exchangeable
with C-20), 18.36 [C-20, assignment exchangeable with SiC(CH3)3],
25.80 [SiC(CH3)3], 26.80 and 27.21 (2ꢃ acetonide-CH3), 69.68 (C-10),
77.65 (C-2), 95.95 (C-3), 111.39 [acetonide-C(CH3)2], 127.85 (m-Ar),
130.93 (o-Ar), 132.88 (p-Ar), 136.19 (q-Ar), 172.79 (C-1), 201.39 (C-
4); HRMS (CI): MHþ, found m/z¼409.20470, i.e.,
¼þ0.1 ppm ver-
D
sus what C21H33O6Si requires (409.20464).

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T. Wuster et al. / Tetrahedron 69 (2013) 7785e7809
7797
00
5.1.9. (3S,4R,5R)-3-[(R)-1-Hydroxyethyl]-5-{(1R,2S,5R)-[2-isopropyl-
5-methylcyclohexyl]oxy}-3,4-(isopropylidenedioxy)-4,5-dihydro-3H-
furan-2-one (17a) and (3S,4R,5R)-3-[(S)-1-hydroxyethyl]-5-
{(1R,2S,5R)-[2-isopropyl-5-methylcyclohexyl]oxy}-3,4-(iso-
propylidenedioxy)-4,5-dihydro-3H-furan-2-one (17b).
H); 13C NMR (100.6 MHz, CDCl3):
d
¼15.35 (menthyl-CH3), 16.74 (C-2 ),
21.12 (menthyl-CH3), 22.36 (menthyl-CH3), 22.83 (menthyl-CH2),
25.33 (menthyl-CH), 27.25 and 27.26 [acetonide-C(CH3)2], 31.60 (menthyl-CH),
00
34.31 (menthyl-CH2), 39.77 (menthyl-CH2), 47.74 (menthyl-CH), 66.59 (C-1 ),
0
78.74 (C-1 ), 81.21 (C-4), 88.37 (C-3), 102.74 (C-5), 114.05 [acetonide-C(CH3)2],
174.91 (C-2); X-ray structural analysis: Fig. 5.
HO
1'' O
HO
1'' O
2''
2''
5.1.10. Dimethyl (S,4E,6E-3,3)-dimethoxy-6,8-dimethyldeca-4,6-
dienylphosphonate (19).
25O
O
5O
2
O
O
O
O
O
1'
O
2'
5'
2'
5'
1'
1
3
5
7
9
(MeO)2P
MeO OMe
17a
17b
At room temperature Pd(dba)2 (163 mg, 283
mmol, 0.10 equiv)
was added under an atmosphere of Ar to a solution of P(tBu)3
(138 mg, 682 mol, 0.24 equiv; weighed in a ‘glovebox’) in degassed
A
mixture of benzyltrimethylammonium fluoride hydrate
ꢀ
m
(266 mg, 1.57 mmol, 1.10 equiv), molecular sieves (4 A), and THF
(5 mL) was stirred at room temperature for 13 h. The resulting
suspension was soaked up in a syringe and added at ꢀ78 ꢁC in the
course of 18 min to a solution of lactone 29 (550 mg, 1.43 mmol)
THF (6 mL). After stirring for 10 min the solution was cannulated to
a solution of bromoolefin 45 (1.13 g, 2.83 mmol) in degassed THF
(24 mL). After cooling to 0 ꢁC ZnMe2 (1.2 M in toluene, 4.70 mL,
5.65 mmol, 2 equiv) was added slowly. The resulting mixture was
stirred at 55 ꢁC for 22 h. After re-cooling to 0 ꢁC satd aq NH4Cl
(15 mL) was added slowly. Et2O (30 mL) was added, the phases were
separated, and the aq phase was extracted with AcOEt (4ꢃ10 mL).
The combined organic phases were dried over Na2SO4 and the
solvent was removed in vacuo. Flash chromatography44 (B 4 cm,
20 cm, c-C6H12/acetone 4:1/c-C6H12/acetone 3:1/c-C6H12/ace-
tone 2:1, /c-C6H12/acetone 1:1, 0.2 vol % NEt3) yielded the title
and acetaldehyde (645 mL, 502 mg, 2.15 mmol, 8.00 equiv) in THF
(10 mL). The mixture was allowed to warm to ꢀ10 ꢁC over the
course of 2 h. After stirring for 40 min the mixture was poured into
ice-cold stirred satd aq NH4Cl (50 mL). The phases were separated.
The aq phase was extracted with Et2O (5ꢃ10 mL). The combined
organic phases were dried over Na2SO4. The solvent was removed
in vacuo. Three successive purifications by flash chromatography44
(B
4 cm, 20 cm, c-C6H12/AcOEt 15:1/10:1/5:1) gave di-
compound (823 mg, 87%, ꢂ97% trans,E) as a yellowish oil;
astereomer 17a (229 mg, 45%) in the early fractions and di-
astereomer 17b (214 mg, 42%) in the late fractions. The combined
yield was 87% and the mass ratio of the isolated diastereomers
52:48. Rf value (c-C6H12/AcOEt 5:1): 0.25; combustion analysis:
25
[a
]
¼22.7ꢁ (CHCl3, c¼2.50); IR (film):
¼3470, 2955, 2870, 2855,
n
D
2825, 1640, 1455, 1410, 1390, 1375, 1340, 1305, 1255, 1210, 1185,
1125, 1035, 980, 960, 930, 895, 880, 850, 815, 770, 750 cmꢀ1
NMR (400.1 MHz, C6D6, sample contained 3% of the trans,Z isomer
and rests of c-C6H12 and AcOEt):
;
1H
found C 64.19%, H 9.34%; calculated for C19H32O6: C 64.02%, H 9.05%.
25
d¼0.77 (3H, t, J10,9¼7.4 Hz, 10-H3),
Compound 17a: Colorless oil; [
a
]
¼ꢀ122 (CHCl3, c¼1.08); IR
D
0.86 (3H, d, J8-CH3,8¼6.7 Hz, 8-CH3), 1.10e1.29 (2H, m, 9-H2), 1.61
(3H, d, J6-CH3,7¼1.3 Hz, 6-CH3), 1.76e1.89 (2H, m, 1-H2), 2.20e2.31
(1H, m, 8-H), superimposed by 2.24e2.31 (2H, m, 2-H2), 2ꢃ3.07 [2ꢃ
(film):
n
¼2990, 2955, 2930, 2870, 2360, 1790,1455,1385,1375,1345,
1290, 1250, 1240, 1215, 1190, 1150, 1135, 1120, 1095, 1065, 1045, 1035,
1010, 985, 975, 930, 895, 875, 845, 815 cmꢀ1; 1H NMR (400.1 MHz,
3
CDCl3):
d
¼0.74 (3H, d, 3J¼6.9 Hz, menthyl-CH3), 0.82e1.04 (3H, m,
3H, 2ꢃ s, 3-(OCH3)2], 2ꢃ3.35 [2ꢃ 3H, 2ꢃ d, JPO(OCH3)2,P¼10.7 Hz,
menthyl-H), superimposed by 0.87 (3H, d, 3J¼6.9 Hz, menthyl-CH3)
and by 0.94 (3H, d, 3J¼6.3 Hz, menthyl-CH3), 1.22e1.31 (1H, m,
menthyl-H), 1.34e1.4600(1H, m, menthyl-H), superimposed by 1.41
PO(OCH3)2], 5.27 (1H, d, J7,8¼9.6 Hz, 7-H), 5.34 (1H, dd, J4,5¼15.9 Hz,
5J4,7¼0.5 Hz, 4-H), 6.69 (1H, dd, J5,4¼15.9 Hz, 4J5,7¼0.8 Hz, 5-H); 13
C
NMR (100.6 MHz, C6D6):
d
¼12.11 (C-10), 12.75 (6-CH3), 20.40 (d,
2
00 00
1J1,P¼143.3 Hz, C-1), 20.67 (8-CH3), 29.32 (d, J2,P¼3.9 Hz, C-2),
30.56 (C-9), 34.64 (C-8), 48.46 and 48.49 [2ꢃ 3-(OCH3)2], 51.74 [d,
2J1,P¼6.5 Hz, PO(OCH3)2], 102.10 (d, 3J3,P¼20.0 Hz, C-3), 125.56 (C-4),
131.87 (C-6), 139.18 (C-5), 140.98 (C-7); combustion analysis: found
C 57.26%, H 9.52%; calculated for C16H31O5P: C 57.47%, H 9.34%.
(3H, d, J2 ,1 ¼6.6 Hz, 2 -H3) and 1.44 as well as 1.45 [2ꢃ 3H, 2ꢃ s,
acetonide-C(CH3)2],1.62e1.72 (2H, m, menthyl-H),1.94e2.08 (1H, m,
00
00
00
menthyl-H), superimposed by 2.05 (1H, d, J1 -OH,1 ¼9.2 Hz, 1 -OH),
2.11e2.18(1H, m, menthyl-H), 3.58(1H, ddd, 2ꢃ 3J¼0010.7 Hz, 3J¼4.2Hz,
10-H), 4.10 (1H, dq, J1 ,1 -OH¼9.0 Hz, J1 ,2 ¼6.6 Hz,1 -H), 4.49 (1H, s, 4-
00 00
00 00
H), 5.60 (1H, s, 5-H); 13C NMR (100.6 MHz, CDCl3):
d¼15.37 (menthyl-
CH3), 18.23 (C-200), 21.09 (menthyl-CH3), 22.34 (menthyl-CH3), 22.90
(menthyl-CH3), 25.49 (menthyl-CH), 26.98 and 27.28 [acetonide-
C(CH3)2], 31.56 (menthyl-CH), 34.34 (menthyl-CH2), 39.61 (menthyl-
CH2), 47.66 (menthyl-CH), 66.49 (C-100), 78.12 (C-10), 81.41 (C-4), 87.62
(C-3), 100.85 (C-5), 114.35 [acetonide-C(CH3)2], 174.93 (C-2).
5.1.11. Dibutyl (S,4E,6E-3,3)-dimethoxy-6,8-dimethyldeca-4,6-
dienylphosphonate [(E,E)-22] in an 88:12 mixture with dibutyl (S,4E,6Z-
3,3)-dimethoxy-6,8-dimethyldeca-4,6-dienylphosphonate [(E,Z)-22].
O
P
Compound$17b: Colorless crystals, mp 112e113 ꢁC; [a]D25¼ꢀ136 (CHCl3,
c¼1.00); IR (film):¼2995, 2955, 2925, 2865, 2850, 2360, 2340, 1780, 1740,
1650, 1645, 1635, 1455, 1445, 1405, 1385, 1365, 1360, 1340, 1315, 1295, 1275,
1240, 1220, 1200, 1180, 1155, 1130, 1080, 1060, 1035, 1010, 985, 940, 920, 895,
1
3
5
7
9
O
MeO OMe
2
in an 88:12-mixture with
O
870, 850, 810 cmꢀ1; 1H NMR (400.1 MHz, CDCl3):
d
¼0.74 (3H, d, 3J¼6.9 Hz,
menthyl-CH3), 0.80e0.88 (1H, m, menthyl-H), superimposed by 0.86 (3H,
3
1
3
5
7
d, J¼7.0 Hz, menthyl-CH3), 0.90e1.01 (2H, m, menthyl-H) superimposed
P
O
by 0.95 (3H, d, 3J¼6.6 Hz, menthyl-CH3), 1.23e1.31 (1H, m, menthyl-H),
9
MeO OMe
2
00
00 00
superimposed by 1.25 (3H, d, J2 ,1 ¼6.4 Hz, 2 -H3), 1.34e1.46 (1H, m,
menthyl-H), superimposed by 1.43 and 1.46 [2ꢃ 3H, 2ꢃ incompletely resolved
4
At 0 ꢁC para-toluenesulfonic acid (9.0 mg, 52
mmol, 0.1 equiv) was
q, J¼0.6 Hz, acetonide-C(CH3)2], 1.63e1.72 (2H, m, menthyl-H), 1.98e2.10
(1H, m, menthyl-H), 2.11e2.19 (1H, m, menthyl-H), 2.53 (1H, d,
added under an atmosphere of Ar to a solution of ketophosphonate
38 (181 mg, 486 mol), 2,6-di-tert-butyl-4-methylphenol (11 mg,
50 mol, 0.1 equiv), and trimethyl orthoacetate (62 L, 59 mg,
J1 -OH,1 ¼2.5 Hz, 1 -OH), 3.58(1H, ddd, 2ꢃ 3J¼10.7 Hz, J¼4.2 Hz, 1 -H),
3
00
0
00
00
m
00
00 00
00 00
4.21(1H, qd, J1 ,2 ¼6.6Hz, J1 ,1 -OH¼2.5Hz,1 -H),4.41(1H,s,4-H),5.62(1H,s,5-
m
m

€
T. Wuster et al. / Tetrahedron 69 (2013) 7785e7809
7798
0.5 mmol, 1.0 equiv) in degassed MeOH (2 mL) in a Schlenk tube,
which was protected from light. After stirring for 3 h triethylamine
(7.0 mL, 5.1 mg, 50 mmol, 0.1 equiv) was added. The solution was
allowed to reach room temperature Brine (2 mL) was added, the
phases were separated, the aq phase was extracted with Et2O
(3ꢃ2 mL), the combined organic phases were dried over Na2SO4, and
the solvent was removed in vacuo. Flash chromatography44 (B
2.5 cm, 20 cm, degassed c-C6H12/acetone) gave the title compounds
(177 mg, 87%) as an 88:12 mixture of (E,E)-22 and (E,Z)-22; IR (film):
45 min phosphonate 37 (6.41 mL, 7.44 g, 60.0 mmol, 1.50 equiv)
was added over the course of 2 h by a syringe pump and there-
after over the course of 1 h the phosphorylated propionate 36
(11.2 g, 40.0 mmol). The mixture was gradually warmed to room
temperature. It was stirred for 17 h, at which time HCl (2 M,
75 mL) was added. The phases were separated. The aq phase was
extracted with CH2Cl2(3ꢃ50 mL), the combined organic phases
were dried over MgSO4, and the solvent was removed in vacuo.
The title compound (68% wt % of 16.9 g of a mixture with 36 and
37, i.e., 11.5 g 25, 77%) as a colorless oil; Rf value (acetone): 0.45;
1H NMR (300.1 MHz, CDCl3/TMS; sample contained 32 wt % of 36
n
¼2960, 2875, 1745, 1675, 1645, 1625, 1600, 1460, 1415, 1380, 1300,
1250, 1215, 1190, 1130, 1060, 1030, 980 cmꢀ1
;
1H NMR (300.1 MHz,
C6D6):
d
¼0.76 (3H, t, J10,9¼7.4 Hz, 10-H3), coincides with 0.76 (6H, t,
and 37):
d
¼0.94 (6H, t, 3J¼7.4 Hz, 2ꢃ CH3CH2CH2CH2O), 1.39 (4H,
3J¼7.4 Hz, 2ꢃ CH3CH2CH2CH2O), 0.86 (3H, d, J
¼6.7 Hz, 8-CH3),
tq, 3J¼7.5 Hz, 2ꢃ CH3CH2CH2CH2O), 1.64 (4H, tt, 3J¼7.1 Hz, 2ꢃ
CH3CH2CH2CH2O), 2.02 (2H, dt, 1J4,P¼18.0 Hz, J4,3¼7.7, 4-H2), 2.90
8ꢀCH3;8
1.10e1.29 (6H, 2ꢃ m, 9-H2þ 2ꢃ CH3CH2CH2CH2O), 1.39e1.49 (4H, m,
2ꢃ CH3CH2CH2CH2O), 1.61 [3H, d, 4J
¼1.0 Hz, 6-CH3, (E,E)-22],
(2H, dt, J3,P¼11.1 Hz, J3,4¼7.8 Hz, 3-H2), 3.12 (2H, d, 1J1,P¼22.7 Hz,
2
6ꢀCH3;7
1.74 [3H, d, 4J6ꢀCH ;7¼0.9 Hz, 6-CH3, (E,Z)-22],1.93 (2H, mc,1-H2), 2.25
1-H2), 3.79 (6H, d, JCH O;P¼11.3 Hz, 2ꢃ CH3O), AB signal (4H,
3
3
3
(1H, mc, 8-H), 2.32e2.41 (2H, m, 2-H2), 3.11 [6H, s, 3-(OCH3)2],
3.88e4.03 (4H, m, 2ꢃ CH3CH2CH2CH2O), 5.14 [1H, d, J7,8¼9.8 Hz, 7-H,
(E,Z)-22], 5.27 [1H, d, J7,8¼9.5 Hz, 7-H, (E,E)-22], 5.40 [1H, d,
J4,5¼15.8 Hz, 4-H, (E,E)-22], 5.51 [1H, d, J4,5¼15.8 Hz, 4-H, (E,Z)-22],
6.72 [1H, d, J5,4¼15.8 Hz, 5-H, (E,E)-22]; 13C NMR [100.6 MHz, C6D6/
C6D6; this sample contained essentially sterically pure (E,E)-22]:
dA¼4.00, dB¼4.03, JAB¼10.1 Hz,
A part additionally split by
3JH(A),P¼10.1 Hz and J
¼6.7 Hz, B part additionally
HðAÞ;CH2CH2CH2
split by 3JH(B),P¼10.0 Hz and JHðBÞ;CH CH CH ¼6.7 Hz, 2ꢃ
2
2
2
CH3CH2CH2CH2O).
5.1.14. (3R,4R,5R)-5-{(1R,2S,5R)-[2-Isopropyl-5-methylcyclohexyl]
oxy}-3,4-(isopropylidenedioxy)-3-(trimethylsilyl)-4,5-dihydro-3H-fu-
ran-2-one (29).
d
¼12.15 (C-10), 12.79 (6-CH3),13.75 (2ꢃ CH3CH2CH2CH2O), 19.11 (2ꢃ
CH3CH2CH2CH2O), 20.71 (8-CH3), 21.38 (d, 1J1,P¼143.7 Hz, C-1), 29.59
2
3
0
(d, J2,P¼3.9 Hz, C-2), 30.60 (C-9), 33.04 (d, JC-2 ,P¼5.8 Hz, 2ꢃ
O
CH3CH2CH2CH2O), 34.68 (C-8), 48.52 and 48.55 (2ꢃ OCH3), 65.18 (d,
Me3Si
2
JC-1 ,P¼6.5 Hz, 2ꢃ CH3CH2CH2CH2O), 102.26 (3J3,P¼20.3 Hz, C-3),
2
0
O
3
4 5O
125.69 (C-4), 131.91 (C-6), 139.23 (C-5), 141.01 (C-7).
O
O
2'
5'
1'
5.1.12. Dimethyl (3,3-dimethoxypent-4-ynyl)phosphonate (23).
O
1
3
5
(MeO)2P
MeO OMe
At ꢀ78 ꢁC mit n-BuLi (2.08 M in hexane, 6.63 mL, 13.8 mmol,
1.30 equiv) was added to a solution of diisopropylamine (1.93 mL,
1.39 g, 13.8 mmol, 1.30 equiv) in THF (35 mL). After stirring for
30 min trimethylsilyl chloride (2.03 mL, 1.73 g, 15.9 mmol,
1.50 equiv) was added. After stirring for 5 min the solution was
cannulated within 10 min to a ꢀ78 ꢁC solution of lactone 18 (3.30 g,
10.6 mmol) in THF (15 mL). After 30 min the mixture was poured
into ice-cold satd aq NH4Cl (100 mL). The phases were separated
and the aq phase was extracted with TBME (5ꢃ25 mL). The com-
bined organic phases were dried over Na2SO4 and the solvent was
removed in vacuo. The crude product (4.04 g, 99%) was a highly
At 40 ꢁC a solution of Na2B4O7$10H2O (13.8 mg, 68.4
10 mol %) in H2O (0.5 mL) was added to a solution of silylalkyne 43
(211 mg, 684 mol) in MeOH (5 mL). After 3 h the solution was
cooled to room temperature aq phosphate buffer (pH¼7, 3 mL) was
added, the phases were separated, and the aq phase was extracted
with Et2O (4ꢃ3 mL). The combined organic phases were dried over
Na2SO4 and the solvent was removed in vacuo. Flash chromatog-
raphy44 (B 2.5 cm, 20 cm, c-C6H12/acetone 3:1/c-C6H12/acetone
2:1/c-C6H12/acetone 1:1, 0.2 vol % NEt3) gave the title compound
(158 mg, 98%) as a colorless oil; Rf value (c-C6H12/acetone 2:1): 0.10;
mmol,
m
viscous oil, which crystallized slowly; Rf value (c-C6H12/AcOEt 5:1):
IR (film):
1410,1345,1295,1245,1190,1140,1150, 965, 890, 845, 815, 755, 710,
665 cmꢀ1; 1H NMR (400.1 MHz, C6D6):
n
¼3460, 3275, 3205, 2950, 2850, 2830, 2110, 1465, 1435,
25
0.65; mp 93e95 ꢁC; [
a
]
¼ꢀ129 (CHCl3, c¼1.00); IR (film): ¼2960,
n
D
2920, 2865, 2340, 1780, 1455, 1385, 1375, 1345, 1250, 1160, 1150,
1120, 1085, 1055, 1005, 990, 935, 845 cmꢀ1 1H NMR (400.1 MHz,
CDCl3; sample contained a trace of c-C6H12):
¼0.22 [9H, s,
d
¼2.04 (1H, 5-H), 2.05e2.15
;
(2H, m, 1-H2), 2.26e2.33 (2H, m, 2-H2), 3.12 [6H, s, 3-(OCH3)2], 3.34
[6H, d, JPOðOCH Þ ;P¼10.7 Hz, PO(OCH3)2]; 13C NMR (100.6 MHz,
3
d
3
2
Si(CH3)3], 0.75 (3H, d, 3J¼6.9 Hz, menthyl-CH3), 0.81e0.90 (1H, m,
menthyl-H), superimposed by 0.86 (3H, d, 3J¼7.1 Hz, menthyl-CH3),
0.92e1.02 (2H, m, menthyl-H), superimposed by 0.94 (3H, d,
3J¼6.6 Hz, menthyl-CH3), 1.18e1.27 (1H, m, menthyl-H), 1.32e1.42
(1H, m, menthyl-H), superimposed by 1.36 and 1.39 [2ꢃ 3H, 2ꢃ d,
both 4J¼0.6 Hz, acetonide-C(CH3)2], 1.62e1.70 (2H, m, menthyl-H),
2.06e2.18 (2H, m, menthyl-H), 3.53(1H, ddd, 2ꢃ 3J¼10.7 Hz,
3J¼4.3 Hz, 10-H), 4.24 (1H, s, 4-H), 5.56 (1H, s, 5-H); 13C NMR
2
C6D6):
d
¼20.48 (d, 1J1,P¼143.6 Hz, C-1), 31.19 (d, J2,P¼3.4 Hz, C-2),
2
50.19 [3-(OCH3)2], 51.73 [d, J1,P¼6.5 Hz, PO(OCH3)2], 74.41 (C-5),
3
79.89 (C-4), 99.12 (d, J3,P¼21.7 Hz, C-3); combustion analysis:
found C 46.15%, H 7.54%; calculated for C9H17O5P: C 45.76%, H 7.25%.
5.1.13. Dimethyl [4-(dibutoxyphosphoryl)-2-oxobutyl]phosphonate (25).
O
O
(100.6 MHz, CDCl3; sample contained a trace of c-C6H12):
d¼ꢀ4.00
P(OMe)2
1
4
[Si(CH3)3], 15.47 (menthyl-CH3), 21.15 (menthyl-CH3), 22.34
(menthyl-CH3), 22.78 (menthyl-CH2), 25.09 (menthyl-CH), 27.02
and 27.23 [acetonide-C(CH3)2], 31.63 (menthyl-CH), 34.27
(menthyl-CH2), 40.67 (menthyl-CH2), 47.62 (menthyl-CH), 79.03 (C-
3), 79.98 (C-10), 83.42 (C-4), 103.33 (C-5), 113.21 [acetonide-
C(CH3)2], 177.73 (C-2); combustion analysis: found C 62.17%, H
9.72%; calculated for C20H36O5Si: C 62.46%, H 9.44%.
P
3
O
2
O
At ꢀ78 ꢁC n-BuLi (2.50 M in hexane, 24.0 mL, 60.0 mmol,
1.50 equiv) was added to a solution of diisopropylamine (8.46 mL,
6.06 g, 60.0 mmol, 1.50 equiv) in THF (40 mL) while stirring. After

€
T. Wuster et al. / Tetrahedron 69 (2013) 7785e7809
7799
5.1.15. (3R,4R,5R)-3-[(R)-1-(tert-Butyldimethylsiloxy)ethyl]-5-
{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy}-3,4-(iso-
propylidenedioxy)-4,5-dihydro-3H-furan-2-one (30a).
value1 (c-C6H12/AcOEt 5:1): 0.65; Rf value2 (c-C6H12/AcOEt 20:1):
25
0.25; mp 70e72 ꢁC; [
a
]
¼ꢀ90 (CHCl3, c¼0.90); IR (film):
n
¼2955,
D
2930, 2860, 1790, 1470, 1460, 1385, 1375, 1350, 1250, 1210, 1195,
1155, 1130, 1095, 1025, 1005, 950, 925, 870, 835, 815 cmꢀ1; 1H NMR
t-BuMe2SiO
(400.1 MHz, CDCl3; sample contained a trace of c-C6H12):
d
¼0.09
O
and 0.10 [2ꢃ 3H, 2ꢃ s, Si(CH3)2], 0.73 (3H, d, 3J¼6.9 Hz, menthyl-
CH3), 0.82e1.01 (3H, m, menthyl-H), superimposed by 0.85 (3H, d,
3J¼6.9 Hz, menthyl-CH3) and by 0.90 [9H, SiC(CH3)3], 0.94 (3H, d,
2
3
O
4 5O
O
O
2'
5'
3J¼6.6 Hz, menthyl-CH3), 1.17 (3H, d, J2 ,1 ¼6.6 Hz, 2 -H3), 1.23e1.32
(1H, m, menthyl-H), 1.33e1.45 (1H, m, menthyl-H), superimposed
by 1.39 and 1.44 [2ꢃ 3H, 2ꢃ s, acetonide-C(CH3)2],1.62e1.71 (2H, m,
menthyl-H), 2.03e2.12 (1H, m, menthyl-H), 2.12e2.19 (1H, m,
menthyl-H), 3.55(1H, ddd, 2ꢃ 3J¼10.7 Hz, 3J¼4.3 Hz,10-H), 4.22 (1H,
00
1'
00 00
At 0 ꢁC NEt3 (1.12 mL, 818 mg, 8.00 mmol, 1.91 equiv) was added
to a solution of alcohol 17a (1.49 g, 4.19 mmol) and tert-butyldi-
methylsilyl triflate (2.89 mL, 3.32 g, 12.8 mmol, 3.05 equiv) in
CH2Cl2 (8 mL). The solution was allowed to reach room temperature
and stirred for 2.5 h. It was poured into ice-cold satd aq NH4Cl
(50 mL). The phases were separated and the aq phase was extracted
with CH2Cl2 (4ꢃ15 mL). The combined organic phases were dried
over Na2SO4 and the solvent was removed in vacuo. Flash chro-
matography44 (B 4 cm, 20 cm, c-C6H12/AcOEt 50:1/20:1) yielded
q, J1 ,2 ¼6.6 Hz, 1 -H), 4.48 (1H, s, 4-H), 5.59 (1H, s, 5-H); 13C NMR
00
00 00
(100.6 MHz, CDCl3; sample contained a trace of c-C6H12):
d
¼ꢀ4.70
and ꢀ4.19 [Si(CH3)2], 15.27 (menthyl-CH3), 18.17 [SiC(CH3)3], 19.29
(C-200), 21.12 (menthyl-CH3), 22.33 (menthyl-CH3), 22.75 (menthyl-
CH2), 25.15 (menthyl-CH), 26.01 [SiC(CH3)3], 27.34 and 27.47 [ace-
tonide-C(CH3)2], 31.60 (menthyl-CH), 34.33 (menthyl-CH2), 39.92
(menthyl-CH2), 47.69 (menthyl-CH), 66.91 (C-100), 78.89 (C-10),
80.95 (C-4), 89.46 (C-3), 104.16 (C-5), 113.84 [acetonide-C(CH3)2],
175.57 (C-2).
the title compound (1.71 g, 87%) as a colorless oil; Rf value (c-C6H12
/
25
AcOEt 5:1): 0.65; (c-C6H12/AcOEt 20:1): 0.25; [
a
]
¼ꢀ68 (CHCl3,
D
c¼1.03); IR (film):
n
¼2990, 2960, 2930, 2860, 1795, 1470, 1460,
5.1.17. (2R,3S)-3-[(R)-1-(tert-Butyldimethylsiloxy)ethyl]-2,3-(iso-
propylidenedioxy)-4-oxo-4-phenylbutanal (32a).
1385, 1375, 1360, 1345, 1290, 1255, 1215, 1185, 1155, 1140, 1120,
1100, 1075, 1060, 1020, 1005, 975, 935, 880, 835, 815 cmꢀ1; 1H NMR
(400.1 MHz, CDCl3):
d
¼0.07 and 0.09 [2ꢃ 3H, 2ꢃ s, Si(CH3)2], 0.75
(3H, d, 3J¼6.9 Hz, menthyl-CH3), 0.82e0.91 (1H, m, menthyl-H),
superimposed by 0.87 (3H, d, 3J¼6.9 Hz, menthyl-CH3), 0.89 [9H,
s, SiC(CH3)3], 0.91e1.01 (2H, m, menthyl-H), superimposed by 0.94
(3H, d, 3J¼6.6 Hz, menthyl-CH3), 1.19e1.29 (1H, m, menthyl-H),
1.34e1.44 (1H0,0 m, menthyl-H), superimposed by 1.36 (3H, d,
t-BuMe2SiO O
4
5
Ph
3
O
2
1
O
O
00 00
J2 ,1 ¼6.2 Hz, 2 -H3) as well as by 1.42 and 1.43 [2ꢃ 3H, 2ꢃ s, ace-
numbering in accordance with the IUPAC name
tonide-C(CH3)2], 1.62e1.71 (2H, m, menthyl-H), 2.02e2.15 (2H, m,
menthyl-H), 3.54(1H, ddd, 2ꢃ 3J¼10.7 Hz, 3J¼4.3 Hz, 10-H), 4.10 (1H,
o
m
t-BuMe2SiO O
q, J1 ,2 ¼6.3 Hz, 1 -H), 4.55 (1H, s, 4-H), 5.54 (1H, s, 5-H); 13C NMR
00
00 00
q
1'
p
2'
4
(100.6 MHz, CDCl3; sample contained a trace of c-C6H12):
d
¼ꢀ4.78
3
O
and ꢀ4.47 [Si(CH3)2], 15.26 (menthyl-CH3), 18.09 (C-200), 18.16
[SiC(CH3)3], 21.15 (menthyl-CH3), 22.34 (menthyl-CH3), 22.75
(menthyl-CH2), 25.34 (menthyl-CH), 25.88 [SiC(CH3)3], 26.72 and
27.25 [acetonide-C(CH3)2], 31.56 (menthyl-CH), 34.31 (menthyl-
CH2), 40.16 (menthyl-CH2), 47.65 (menthyl-CH), 66.69 (C-100), 78.60
(C-10), 81.56 (C-4), 88.35 (C-3), 101.81 (C-5), 114.01 [acetonide-
C(CH3)2], 174.89 (C-2); combustion analysis: found C 64.01%, H
10.10%; calculated for C25H46O6Si; C 63.79% H 9.85%.
2
1
O
O
numbering for NMR assignments
LiCl (772 mg, 18.2 mmol, 5.01 equiv) was dried in vacuo while
heating, cooled to room temperature, and dissolved in a solution of
lactone 30a (1.71 g, 3.63 mmol) in THF (35 mL). At ꢀ10 ꢁC PhLi (2 M
in nBu2O; 3.63 mL, 7.26 mmol, 5.98 mmol; 2.00 equiv) was added.
After 10 min the resulting mixture was poured into an ice-cold
aq phosphate buffer (pH¼7; 125 mL). The phases were separated
and the aq phase was extracted with AcOEt (4ꢃ30 mL). The com-
bined organic phases were dried over Na2SO4. The solvent was
removed in vacuo. The residue, i.e., 31a and/or epi-31a, was dis-
solved in c-C6H12Cl3 (7 mL) at room temperature p-TsOH (16.0 mg,
5.1.16. (3R,4R,5R)-3-[(S)-1-(tert-Butyldimethylsiloxy)ethyl]-5-
{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy}-3,4-(iso-
propylidenedioxy)-4,5-dihydro-3H-furan-2-one (30b).
t-BuMe2SiO
O
O
3
425O
93.9 mmol, 2.59 mol %) was added. After stirring for 1.5 the solution
O
was poured directly on a flash chromatography44 column (B 6 cm,
20 cm, c-C6H12/AcOEt 25:1/10:1/5:1) and purified to give the
title compound (contaminated with 7 mol % M-menthol; 633 mg;
44% over the two steps from lactone 30a) as a yellowish oil; Rf
value (c-C6H12/AcOEt 5:1): 0.25; 1H NMR (300.1 MHz, CDCl3;
O
2'
5'
1'
sample contaminated with 7 mol %
L
-menthol):
d
¼ꢀ0.27 and
Alcohol 17b (1.10 g, 3.09 mmol) was derivatized similarly as
described for the silylation 17a/30a, employing tert-butyldime-
thylsilyl triflate (2.13 mL, 2.45 g, 9.27 mmol, 3.00 equiv) in CH2Cl2
(8 mL) and NEt3 (1.12 mL, 818 mg, 8.00 mmol, 2.59 equiv). Flash
chromatography44 (B 4 cm, 20 cm, c-C6H12/AcOEt 50:1/20:1)
yielded the title compound (1.42 g, 98%) as a colorless solid; Rf
ꢀ0.06 [2ꢃ 3H, 2ꢃ s, Si(CH3)2], 0.80 [9H, SiC(CH3)3], 1.25[3H, s, 1ꢃ
0
0
0
acetonide-C(CH3)2], 1.42 (3H, d, J2 ,1 ¼6.3 Hz, 2 0-H3), 1.50[3H, s, 1ꢃ
0
0
acetonide-C(CH3)2], 4.55 (1H, q, J1 ,2 ¼6.3 Hz, 1 -H), superimposed
by 4.56 (1H, s, 2-H), 7.43 (2H, mc, m-Ar), 7.57 (1H, t, Jp-Ar,m-
¼7.4 Hz, 1 H, p-Ar), 8.19 (2H, d, Jo-Ar,m-Ar¼8.2 Hz, 2 H, o-Ar), 9.79
Ar
(1H, s, 1-H).

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T. Wuster et al. / Tetrahedron 69 (2013) 7785e7809
7800
5.1.18. (2R,3S)-3-[(S)-1-(tert-Butyldimethylsiloxy)ethyl]-2,3-(iso-
propylidenedioxy)-4-oxo-4-phenylbutanal (32b).
(126 MHz, CDCl3/CDCl3):
d
¼11.94 (C-10), 12.44 (6-CH3), 13.67 (2ꢃ
1
C-40), 18.82 (2ꢃ C-30), 19.66 (d, JC-1,P¼144.4, C-1), 20.23 (8-CH3),
3
2
30.01 (C-9), 32.63 (d, JC-2 ,P¼6.1 Hz, 2ꢃ C-20), 33.15 (d, JC-
0
2
¼3.3 Hz, C-2), 35.13 (C-8), 65.50 (d, JC-1 ,P¼6.4 Hz, 2ꢃ C-10),
0
2,P
3
t-BuMe2SiO O
123.59 (C-4), 131.86 (C-6), 148.79 (C-5), 150.17 (C-7), 197.87 (d, JC-
4
5
¼15.7 Hz, C-3); HRMS (EI, 70 eV): Mþ, found m/z¼372.2434, i.e.,
Ph
3,P
3
O
2
D
¼þ1.2 ppm versus what C20H37O4P requires (372.2429).
1
O
O
5.1.20. Methyl 3-(dimethylphosphoryl)propionate (40).
numbering in accordance with the IUPAC name
O
2
o
m
3
1
(MeO)2P
OMe
t-BuMe2SiO O
q
1'
p
2'
4
O
3
O
2
1
O
O
At 0 ꢁC AlMe3 (2 M in CH2Cl2, 100 mL, 200 mmol, 2.00 equiv)
was cannulated to a solution of dimethylphospite (39, 18.3 mL,
22.0 g, 200 mmol) in dichloromethane (200 mL) such that the
evolution of CH4 was tolerable and such that the dichloromethane
never boiled. Subsequently, the mixture was stirred for 50 min. The
acrylate 34 (18.1 mL, 17.2 g, 200 mmol, 1.00 equiv) was added
dropwise during 10 min. The cooling bath was removed up to
15 min later, such that the solution never warmed above room
temperature. After stirring at room temperature for 21 h and re-
cooling to 0 ꢁC H2O (ca. 150 mL in total) and HCl (4 M, ca. 150 mL
in total) were added dropwise and in turns, until the phases sep-
arated and the aq phase had pH¼1. The phases were separated, the
aq phase was extracted with CH2Cl2(4ꢃ100 mL), the combined
organic phases were dried over Na2SO4, and the solvent was re-
moved in vacuo. Fractionating distillation (85e100 ꢁC) in high
vacuum yielded the title compound (29.0 g, 74%) as a colorless oil;
numbering for NMR assignments
This reaction was performed similarly as described for the
conversion 30a/31a and/or epi-31a/32a yet employing LiCl
(634 mg, 15.0 mmol, 5.02 equiv), lactone 30b (1.41 g, 2.99 mmol),
PhLi (2 M in nBu2O, 2.99 mL, 5.98 mmol; 2.00 equiv), and p-TsOH
(13.0 mg, 76.3
20 cm, c-C6H12/AcOEt 25:1/10:1/5:1) provided the title com-
pound (contaminated with 9 mol % -menthol; 865 mg, 74% over
m
mol, 2.55 mol %). Flash chromatography44 (B 6 cm,
L
the two steps from lactone 30b) as a yellowish oil; Rf value (c-
C6H12/AcOEt 5:1): 0.25; 1H NMR (300.1 MHz, CDCl3; sample con-
taminated with 9 mol %
L
-menthol):
d
¼0.04 and 0.08 [2ꢃ 3H, 2ꢃ s,
0
0
0
Si(CH3)2], 0.85 [9H, SiC(CH3)3], 1.18 (3H, d, J2 ,1 ¼6.6 Hz, 2 -H3), 1.22
[3H, s, 1ꢃ acetonide-C(CH3)2], 1.49[3H, s, 1ꢃ acetonide-C(CH3)2],
0
0
0
4.44 (1H, q, J1 ,2 ¼6.5 Hz, 1 -H), 4.52 (1H, d, J2,1¼1.6 Hz, 2-H),
7.40e7.48 (2H, m, m-Ar), 7.53e7.61 (1H, m, p-Ar), 8.15e8.20 (2H, m,
o-Ar), 9.85 (1H, d, J2,1¼1.5 Hz, 1-H).
1H NMR (300.1 MHz, CDCl3/TMS):
d
¼2.01e2.17 (2H, mc, 3-H2),
2.54e2.66 (2H, mc, 2-H2), 3.70 (3H, s, CO2CH3), 3.74 [6H, d,
3JPO(OCH3)2,P¼10.8 Hz, PO(OCH3)2].
5.1.19. Dibutyl [(8S,4E,6E)-6,8-dimethyl-3-oxodeca-4,6-dienyl]phos-
phonate (38).
5.1.21. 3-(Dimethylphosphoryl)-N-methoxy-N-methylpropionamide
(41).
O
P
1'
O
4'
1
3
5
7
9
2
3
1
O
(MeO)2P
NMe(OMe)
2
O
O
At 70 ꢁC phosphonate 25 (8.75 g of a mixture with 36 and 37,
which contained 68% wt % of 38, i.e., 5.95 g 25, 16.0 mmol,
2.00 equiv) was added to a stirred suspension of K2CO3 (8.96 g,
64.0 mmol, 8.00 equiv) in 1,4-dioxane (30 mL). The mixture was
stirred for 1 h, at which time enal 26 (1.01 g, 8.00 mmol) and H2O
(1.15 mL, 1.15 g, 64 mmol, 8.00 equiv) were added. Stirring was
continued for 40 h. The mixture was cooled to room temperature
H2O (15 mL) and Et2O (15 mL) added. The phases were separated,
the aq phase was extracted with Et2O (4ꢃ20 mL), the combined
organic phases were dried over NaSO4, and the solvent was re-
At ꢀ10 ꢁC AlMe3 (2 M in CH2Cl2, 38.3 mL, 76.6 mmol,
3.00 equiv) was added dropwise and slowly (!) to a suspension of
N,O-dimethylhydroxylamine hydrochloride (7.50 g, 76.5 mmol,
3.00 equiv) in CH2Cl2 (50 mL). When the addition was complete,
we warmed to room temperature and stirred for 30 min. After re-
cooling to ꢀ10 ꢁC ester 40 (5.00 g, 25.5 mmol) was added. Stirring
was continued for 20 h. The reaction was quenched by the slow (!)
addition of satd aq NH4Cl (100 mL). The phases were separated,
the aq phase was extracted with CH2Cl2(5ꢃ100 mL), and the
combined organic phases were dried over Na2SO4. Removal of the
solvent under reduced pressure furnished a crude product (5.10 g,
89%), which was used without further purification; IR (film):
moved in vacuo. Flash chromatography44 (B 6 cm, 20 cm, c-C6H12
acetone 3:1) yielded the title compound (2.23 g, 75%) as a yellowish
oil; Rf value (c-C6H12/acetone 3:1): 0.30; IR (film):
/
n
¼2960, 2875,
n
1745, 1675, 1645, 1625, 1600, 1460, 1415, 1380, 1300, 1250, 1215,
¼3525, 3470, 3310, 2950, 2850, 2820, 1665, 1460, 1385, 1320,
1190, 1130, 1060, 1030, 980 cmꢀ1; 1H NMR (500 MHz, CDCl3/TMS):
1245, 1175, 1095, 1025, 990, 950, 850, 815, 745, 710 cmꢀ1; 1H NMR
0
0
0
d
¼0.85 (3H, t, J10,9¼7.5 Hz, 10-H3), 0.94 (6H, t, J4 ,3 ¼7.4 Hz, 2ꢃ 4 -
(400.1 MHz, CDCl3; sample contained residual CH2Cl2):
(2H, mc, 3-H2), 2.74 (2H, mc, 2-H2), 3.19 (3H, s, NCH3), 3.71 (3H, s,
d
¼2.10
H3), 1.00 (3H, d, J8-CH3,8¼6.8 Hz, 8-CH3), 1.26e1.36 (2H, m, 9-H2),
3
1.40 (4H, qt, J3 ,4 ¼J3 ,2 ¼7.4 Hz, 2ꢃ 30-H2), 1.65 (4H, tt,
NeOCH3), 3.76 [6H, d, JPOðOCH Þ ;P¼10.7 Hz, PO(OCH3)2]; 13C NMR
0
0
0
0
3
2
1
0
0
0
0
0
J2 ,1 ¼J2 ,3 ¼7.3 Hz, 2ꢃ 2 -H2), 1.79 (3H, s, 6-CH3), 2.08 (2H, mc, in-
terpretable as dt, 2J,P¼17.7 Hz, J1,2¼8.0 Hz, 1-H2), 2.44e2.50 (1H, m,
8-H), 2.89 (2H, mc, interpretable as dt, 3J2,P¼10.5 Hz, J2,1¼8.0 Hz, 2-
H2), 3.99e4.06 (mc, 2ꢃ 10-H2), 5.74 (1H, d, J7,8¼9.8 Hz, 7-H), 6.10
(1H, d, J4,5¼15.8 Hz, 4-H), 7.23 (1H, d, J5,4¼15.8 Hz, 5-H); 13C NMR
(100.6 MHz, CDCl3):
d
¼19.25 (d, J3,P¼144.1 Hz, C-3), 25.19 (C-2),
2
32.41 (NCH3), 52.42 [d, JC,P¼6.3 Hz, PO(OCH3)2], 61.33 (NeOCH3),
3
172.64 (d, JC-1,P¼20.3 Hz, C-1); combustion analysis: found C
37.34%, H 7.29%, N 6.11%; calculated for C7H16NO5P: C 37.34%, H
7.16%, N 6.22%.

€
T. Wuster et al. / Tetrahedron 69 (2013) 7785e7809
7801
5.1.22. Dimethyl 3-oxo-5-(trimethylsilyl)pent-4-ynylphosphonate (42).
(500 mg, 2.12 mol) and PdCl2(PPh3)2 (74.4 mg,106
mmol, 5.00 mol %)
in degassed THF (10 mL). Stirring was continued for 20 min. The
solvent was removed under reduced pressure. Two passages through
flash chromatography44 columns [B 2.5 cm, 20 cm, pure c-C6H12 (for
O
SiMe3
1
3
5
(MeO)2P
the separation of tin-containing products like Bu3SnBr)/c-C6H12
/
O
acetone 5:1, 0.2 vol % NEt3] gave a 79:21 mixture (900 mg, 84%) of the
terminal stannane 44 (738 mg, 66%) and its regioisomer iso-44
(162 mg, 18%);65 Rf value (c-C6H12/acetone 2:1): 0.40; IR (film):
At ꢀ78 ꢁC n-BuLi (2.3 M in hexane, 19.3 mL, 44.4 mmol,
1.25 equiv) was added to a solution of (trimethylsilyl)acetylene
(4.36 g, 44.4 mmol,1.25 equiv) in THF (100 mL). After stirring for 1 h
a solution of Weinreb amide 41 (8.00 g, 35.5 mmol) in THF (100)
was added dropwise. The resulting mixture was allowed to warm to
ꢀ40 ꢁC in the course of 30 min and stirred for 4 h. It was poured into
ice-cold HCl (4 M, 500 mL). The phases were separated, the
aq phase was extracted with AcOEt (4ꢃ150 mL), the combined or-
ganic phases were dried over Na2SO4, and the solvent was removed
in vacuo. Due to the lability of title compound versus silica gel or
heat it was immediately used for preparing 43.
n
¼3540, 3480, 2945, 2925, 2870, 2850,1465,1415,1375, 1340, 1290,
1255, 1210, 1180, 1125, 1035, 1000, 960, 920, 895, 850, 810, 690,
665 cmꢀ1; 1H NMR (400.1 MHz, C6D6):
d
¼0.91 (9H, t, J4 ,3 ¼7.3 Hz, 3ꢃ
0
0
40-H3), 0.93 (6H, t, J1 ,2 ¼8.0 Hz, flanked by Sn isotope satellites, which
0
0
were incompletely resolved, 3ꢃ10-H2),1.33 (6H, tq, J3 ,2 ¼J3 ,4 ¼7.3Hz,
3ꢃ 30-H2), 1.50e1.60 (6H, m, flanked by Sn isotope satellites, which
were incompletely resolved, 3ꢃ 20-H2), 1.80e1.90 (2H, m, 1-H2),
2.20e2.28 (2H, m, 2-H2), 3.10 [6H, s, 3-(OCH3)2], 3.38 [6H, d,
3JPOðOCH Þ ;P¼10.6 Hz, PO(OCH3)2], 5.91 (1H, d, J4,5¼19.6 Hz, each peak
0
0
0
0
3
2
flanked by Sn isotope satellites as two interwoven doublets,
3J4-H,117 ¼63.5 Hz, 3J4-H,119 ¼66.4 Hz, 4-H), 6.69 (1H, d, J5,4¼19.6 Hz,
Sn
Sn
5.1.23. Dimethyl 3,3-dimethoxy-5-(trimethylsilyl)pent-4-
each peak flanked by Sn isotope satellites as two interwoven dou-
ynylphosphonate (43).
blets, J5-H,117 ¼72.0 Hz, J5-H,119 ¼75.4 Hz, 5-H); 13C NMR
2
2
Sn
Sn
(100.6 MHz, C6D6):
d
¼9.82 (flanked by Sn isotope satellites as two
O
SiMe3
0
0
1
3
5
interwoven doublets, 1JC-1 ,117 ¼327.9 Hz, 1JC-1 ,119 ¼343.3 Hz, 3ꢃ C-
Sn
Sn
(MeO)2P
10),13.93 (3ꢃ C-40), 20.47 (d,1J1,P¼143.9 Hz, C-1), 27.64 (flanked by Sn
MeO OMe
3
0
isotope satellites as two superimposing doublets, JC-3 ,117
¼
Sn
3
2
JC-3 ,119 ¼53.1 Hz, 3ꢃ C-30), 28.53 (d, J2,P¼3.6 Hz, C-2), 29.60
0
Sn
(flanked by Sn isotope satellites as two superimposing doublets,
At room temperature p-toluenesulfonic acid (305 mg, 1.78 mmol,
5.01 mol %) was added to a solution of the crude alkynone 42 in MeOH
(60 mL) and trimethyl orthoformiate (60 mL). The resulting mixture
was refluxed for 6 h and then cooled to room temperature. NEt3
2
2
JC-2 ,117 ¼ JC-2 ,119 ¼21.0 Hz, 3ꢃ C-20), 48.61 [3-(OCH3)2], 51.80 [d,
0
0
Sn
Sn
2J1,P¼6.5 Hz, PO(OCH3)2], 102.31 (d, J3,P¼20.5 Hz, C-3), 133.23
(flanked by Sn isotope satellites as two interwoven doublets,
1J5-C,117 ¼346.7 Hz,1J5-C,119 ¼362.1 Hz, C-5),147.13 (C-4); combustion
3
Sn
Sn
(740 mL, 5.33 mmol,15.0 mol %) was added and Et2O (100 mL) and H2O
analysis: found C 48.17%, H 9.21%; calculated for C21H45O5PSn: C
(200 mL) as well. The phases were separated and the aq phase was
extracted with Et2O (4ꢃ100 mL). The combined organic phases were
dried over Na2SO4 and the solvent was removed in vacuo. Flash
47.84%, H 8.60%; HRMS (Method): [MꢀBu]þ, found m/z¼471.13240,
i.e.,
D¼þ0.3 ppm versus what C17H36O5PSn requires (471.13224).
chromatography44 (B 5 cm, 20 cm, c-C6H12/acetone 4:1/c-C6H12
/
5.1.25. Dimethyl [(S,4E,6Z)-6-bromo-3,3-dimethoxy-8-methyldeca-
4,6-dienyl]phosphonate (45).
acetone 3:1/c-C6H12/acetone 2:1, 0.2 vol % NEt3) yielded the title
compound (4.39 g, 40% over the two steps from Weinreb amide 41) as
a colorless oil; Rf value (c-C6H12/acetone 2:1): 0.20; IR (film):
n
¼3470,
O
Br
2955, 2500, 2845, 2830, 2150, 2050,1635,1465,1435,1410,1345,1300,
1
3
5
7
9
(MeO)2P
1250,1180,1135,1050, 965, 900, 850, 830, 760, 700, 645 cmꢀ1; 1H NMR
MeO OMe
(400.1 MHz, C6D6):
d
¼0.07 [9H, s, Si(CH3)3], 2.14e2.24 (2H, m, 1-H2),
2.33e2.40 (2H, m, 2-H2), 3.19 [6H, s, 3-(OCH3)2], 3.35 [6H, d,
3JPOðOCH Þ ;P¼10.6 Hz, PO(OCH3)2]; 13C NMR (100.6 MHz, C6D6):
3
2
At room temperature Pd(dba)2 (232 mg, 404 mmol, 0.10 equiv)
d
¼ꢀ0.35 [Si(CH3)3], 20.59 (d,1J1,P¼143.4Hz, C-1), 31.25(d, 2J2,P¼3.6 Hz,
under an atmosphere of Ar to a solution of P(2-furyl)3 (280 mg,
1.21 mmol, 0.30 equiv) in degassed toluene (5 mL). After stirring for
10 min a green solution was obtained. We added successively the
freshly distilled dibromoolefin 24 (1.22 g, 5.05 mmol, 1.25 equiv),
a solution of pure stannane 4466 (2.13 g, 4.04 mmol), and a solution of
C-2), 50.27 [3-(OCH3)2], 51.71 [d, 2JC,P¼6.5 Hz, PO(OCH3)2], 91.12 and
3
101.95 (C-4, C-5), 99.33 (d, J3,P¼21.5 Hz, C-3); combustion analysis:
found C 47.12%, H 8.27%; calculated for C12H25O5PSi: C 46.74%, H 8.17%.
5.1.24. Dimethyl [trans-3,3-dimethoxy-5-(tributylstannyl)]pent-4-
enylphosphonate (44) in a separable 79:21 mixture with dimethyl
[3,3-dimethoxy-4-(tributylstannyl)]pent-4-enylphosphonate (iso-44).
2,6-di-tert-butyl-4-methylphenol (44.0 mg, 202 mmol, 5.00 mol %) in
degassed toluene (10 mL). The mixture was stirred at 50 ꢁC under
seclusion from light for 44 h. After cooling to room temperature the
solution was transferred directly onto a flash chromatography44 col-
umn (B 6 cm, 20 cm, c-C6H12/acetone 4:1/c-C6H12/acetone 3:1/c-
C6H12/acetone 2:1, 0.2 vol % NEt3). The title compound (1.07 g, 66%,
ꢂ97% trans,Z)elutedasanorange-redoil.Whenstoredinarefrigerator
O
1'
1
3
5
(MeO)2P
Sn
4'
3
MeO OMe
44
at 3 ꢁC it solidified rendering orange-red platelets, which melted be-
25
tween 3 and 20 ꢁC; Rf value (c-C6H12/acetone 2:1): 0.25; [
a]
D
¼þ19.2
1'
(CHCl3, c¼1.28); IR (film):
1460, 1410, 1380, 1340, 1305, 1250, 1180, 1125, 1105, 1050, 1035, 965,
935, 910, 890, 850, 815 cmꢀ1 1H NMR (400.1 MHz, C6D6, sample
contained 3% of the trans,Z isomer and NEt3):
n
¼3465, 2955,2870,2855,2825,1650,1610,
O
Sn
4'
3
1
3
5
(MeO)2P
;
MeO OMe
d
¼0.75 (3H, t,
J10,9¼7.4 Hz, 10-H3), 0.82 (3H, d, J8-CH ,8¼6.7 Hz, 8-CH3), 1.12e1.21 (2H,
iso-44
3
m, 9-H2), 1.71e1.82 (2H, m, 1-H2), 2.18e2.26 (2H, m, 2-H2), 2.67 (1H,
At room temperature Bu3SnH (680
mL, 734 mg, 2.54 mmol,
1.20 equiv) was added slowly to a stirred solution of phosphonate 23
dqdd, J8,7¼9.1 Hz, J8,8-CH ¼J8,9-H(A)¼J8,9-H(B)¼6.8 Hz, 8-H), 3.01 and 3.02
3
[2ꢃ 3H, 2ꢃ s, 3-(OCH3)2], 3.32[6H, d,3JPO(OCH ) ,P¼10.7 Hz, PO(OCH3)2],
3
2

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T. Wuster et al. / Tetrahedron 69 (2013) 7785e7809
7802
5.50 (1H, d, J7,8¼9.2 Hz, 7-H), 5.99 (1H, dd, J4,5¼14.9 Hz, 5J4,7¼0.6 Hz, 4-
H), 6.69 (1H, d, J5,4¼14.8 Hz, 4J4,7¼0.7 Hz, 5-H); 13C NMR (100.6 MHz,
(49a) and (3S*,4R,5R)-4-[(1R)-1-(tert-butyldimethylsiloxy)ethyl]-2-
[(S,3E,5E)-5,7-dimethyl-2-oxonona-3,5-dienyl]-3-hydroxy-4,5-(iso-
propylidenedioxy)-3-phenylcyclopent-1-enyl dimethyl phosphate
(epi-49a; *these configurational descriptors are interchangeable) and
of (4R,5R)-4-[(R)-1-(tert-butyldimethylsiloxy)ethyl]-2-[(S,3E,5E)-5,7-
dimethyl-2-oxonona-3,5-dienyl]-4,5-(isopropylidenedioxy)-3-
phenylcyclopent-2-en-1-one (51a).
C6D6; sample contained residual NEt3):
d
¼11.87 (C-10), 19.26 (8-CH3),
20.16 (d, 1J1,P¼143.4 Hz, C-1), 29.16 (d, 2J2,P¼3.9 Hz, C-2), 29.56 (C-9),
38.25 (C-8), 48.63 and 48.66 [2ꢃ 3-(OCH3)2], 51.79 [d,
2JPOðOCH Þ ;P¼6.5 Hz, PO(OCH3)2], 101.74 (d, 3J3,P¼20.0 Hz, C-3), 123.51
3
2
(C-6), 132.84 (C-4), 133.92 (C-5), 142.14 (C-7); combustion analysis:
found C 45.15%, H 7.10; calculated for C15H28BrO5P: C 45.12%, H 7.07%.
p
m
5.1.26. (4R,5R)-2-[(S,3E,5E)-5,7-Dimethyl-2-oxonona-3,5-dienyl]-
4,5-dihydroxycyclopent-2-en-1-one [(3E,5E)-46] in an 81:19 mixture
with (4R,5R)-2-[(S,3E,5Z)-5,7-dimethyl-2-oxonona-3,5-dienyl]-4,5-
dihydroxycyclopent-2-en-1-one [(3E,5Z)-46].
o
q OH
t-BuMe2SiO
1''
2''
3
5 1
4
O
1'
5'
7'
9'
O 3'
1´
3´
5´
9´
O
OPO(OMe)2
4
O
5 1
MeO OMe
(3E,5E)-46
(3E,5Z)-46
49a + epi-49a
O
O
p
1´
3´
5´
m
o
4
O
9´
5 1
t-BuMe2SiO
MeO OMe
q
1''
O
2''
O
4
O
1' O
3'
5'
7'
9'
5 1
At ꢀ78 ꢁC n-BuLi (2.25 M in hexane, 220
mL, 0.50 mmol,1.00 equiv)
O
O
was added to a solution of an 80:20 mixture of phosphonates (E,E)-22
and (E,Z)-22 (209 mg, 0.50 mmol) in THF (1 mL); the solution was
stirred for 1 h. In a parallel experiment n-BuLi (2.25 M in hexane,
51a
At room temperature a solution of p-TsOH (3.0 mg, 18
5.1 mol %) and a mixture of the dimethoxy phosphonate epimers 13a
and epi-13a (255 mg, 352 mol) in acetonitrile/H2O [5:1 (vol:vol),
mmol,
220
m
L, 0.50 mmol, 1.00 equiv) was added at ꢀ78 ꢁC to a solution of
m
diisopropylamine (70 mL, 50 mg, 0.5 mmol,1.0 equiv) in THF (1 mL); it
3.83 mL, tantamount to 100 equiv H2O] was stirred for 16 h. AcOEt
(4 mL) and satd aq NaHCO3 (2 mL) were added. The phases were
separated, the aq phase was extracted with AcOEt (5ꢃ5 mL), and the
combined organic phases were dried over Na2SO4. The solvent was
removed in vacuo and the residue (which must have contained the
phosphonate epimers 47a and epi-47a) dissolved in benzene
was also stirred for 1 h. The resulting solution of LDA was transferred
dropwise via cannula to the solution of the lithiated phosphonates
(E,E)-22 and (E,Z)-22. After stirring for 5 min a solution of lactone 18
(156 mg, 0.50 mmol, 1.00 equiv) in THF (1 mL) was added dropwise.
The mixture wasallowed towarm to ꢀ45ꢁC inthecourseof2 h. Itwas
stirred for 18 h. The reactionwas quenched by adding H2O (3 mL). The
mixture was gradually warmed to room temperature while continu-
ing to stir. It was diluted with Et2O (3 mL) and the phases were sep-
arated. The aq phase was extracted with Et2O (3ꢃ5 mL), the combined
organic phases were dried over Na2SO4, and the solvent was removed
in vacuo. Flash chromatography44 (B 1.5 cm, 20 cm, c-C6H12/AcOEt
10:1, 0.2 vol% NEt3) gave the title compounds(79 mg, 43%)asan81:19
mixture of isomers (3E,5E)-46 and (3E,5Z)-46; 1H NMR (400.1 MHz,
C6D6; an unassignable peak superimposes with the resonance dA
(3 mL). K2CO3 (106 mg, 774 mmol, 2.20 equiv) was dried in vacuo
under heating. Benzene (4 mL) and 18-crown-6 (280 mg, 1.06 mmol,
3.01 equiv) were added. The resulting suspensionwas heated to 60 ꢁC
andstirred for10 min. The solution containing the crudephosphonate
epimers 47a and epi-47a (vide supra) was added. After stirring at
60 ꢁC for 3.5 h we cooled to room temperature and added AcOEt
(7 mL) and aq phosphate buffer (pH 7, 10 mL). The phases were sep-
arated, the aq phase was extracted with AcOEt (5ꢃ7 mL), the com-
bined organic phases were dried over Na2SO4, and the solvent was
removed in vacuo. Flash chromatography44 (B 2.5 cm, 20 cm, packed
with c-C6H12/AcOEt 10:1þ0.2 vol % NEt3, eluted with c-C6H12/AcOEt
5:1/3:1) led separately (first) to 51a (50 mg, 26%) and (thereafter) to
what we hold for an 85:15 mixture of C-3-epimers 49a and epi-49a
(62 mg, 26%), both as yellowish oils; Rf value 51a (c-C6H12/AcOEt 5:1):
0.55; Rf value 49a/epi-49a (c-C6H122/5AcOEt 3:1): 0.25.
0
0
0
¼2.68):
d
¼0.76 [3H, t, J9 ,8 ¼7.4 Hz, 9 -H3, (3E,5E)-46], 0.77 [3H, t,
part
0
0
0
0
0
0
J9 ,8 ¼7.4 Hz, 9 -H3, (3E,5Z)-46], 0.84 [3H, d, J7 -CH ,7 ¼6.7 Hz, 7 -CH3,
3
0
0
0
(3E,5E)-46], 0.86 [3H, d, J7 -CH ,7 ¼6.7 Hz, 7 -CH3, (3E,5Z)-46],1.08e1.24
(2H, m, 80-H2), in part super3imposed by 1.21 and 1.29 [2ꢃ 2H, 2ꢃ s,
acetonide-C(CH3)2],1.64 [3H, s, 50-CH3, (3E,5E)-46],1.75 [3H, s, 50-CH3,
(3E,5Z)-46], 2.24 [1H, mc, 70-H, (3E,5E)-46], 2.51 [1H, mc, 70-H, (3E,5Z)-
46], AB signal (2H, dA¼2.68, dB¼2.78, JAB¼15.6 Hz, A part additionally
split by JH(A),3¼1.1 Hz, B part additionally split by JH(B),3¼1.1 Hz,10-H2),
3.05 [6H, s, 20-(OCH3)2], 4.06 [1H, d, J5,4¼5.4 Hz, 5-H, (3E,5E)-46], 4.09
[1H, d, J5,4¼5.4 Hz, 5-H, (3E,5Z)-46], 4.53e4.56 [1H, m, 4-H, (3E,5E)-
85:15 49a:epi-49a mixture: [
a
]
¼þ117 (C6D6, c¼3.10); IR (film):
D
n
¼3320, 2960, 2930, 2860, 1690, 1675, 1650, 1620, 1490, 1460, 1450,
1375,1325,1290,1245,1215,1205,1190,1150,1045,1020, 975, 945, 930,
0
0
0
900, 870, 845, 835 cmꢀ1; 1H NMR (499.6 MHz, C6D6; sample contained
46], 4.60e4.62 [1H, m, 4-H, (3E,5Z)-46], 5.11 [1H, d, J6 ,7 ¼10.6 Hz, 6 -H,
0
0
0
traces of c-C6H12 and tert-BuOMe):
d
¼0.13 and 0.26 [2ꢃ 3H, 2ꢃ s,
(3E,5Z)-46], 5.23 [1H, d, J6 ,7 ¼9.6 Hz, 6 -H, (3E,5E)-46], 5.36 [1H, d,
0
0
0
0
0
0
0
0
0
0
0
0
Si(CH3)2], 0.65 (3H, t, J9 ,8 ¼7.4 Hz, 9 -H3), 0.74 (3H, d, J7 -CH3,7 ¼6.6 Hz, 7 -
J3 ,4 ¼15.9 Hz, 3 -H, (3E,5E)-46], 5.46 [1H, d, J3 ,4 ¼15.9 Hz, 3 -H,
0
0
0
CH3), 1.05 [9H, s, SiC(CH3)3], 0.98e1.19 (2H, m, 080-H2), 1.29 (3H, d,
(3E,5Z)-46], 6.57 [1H, d, J4 ,3 ¼15.9 Hz, 4 -H, (3E,5E)-46], 7.00 [1H, d,
00
0
00 00
0
0
0
0
J2 ,1 ¼6.0 Hz, 2 -H3), 1.31 (3H, d, J5 -CH ,6 ¼1.1 Hz, 5 -CH3), 1.68 and 1.73
J4 ,3 ¼15.9 Hz, 4 -H, (3E,5Z)-46], 7.05e7.07 [1H, m, 3-H, (3E,5E)-46],
7.07e7.09 [1H, m, 3-H, (3E,5Z)-46]; combustion analysis: found C
69.08%, H 8.87%; calculated for C21H32O5: C 69.20%, H 8.85%.
[2ꢃ 3H, 2ꢃ s, 2ꢃ acetonide-(CH3)2], 23.08 (1H, mc, 70-H), AX signal (2H,
dA¼2.92, dX¼4.12, JAX¼18.1 Hz, 10-H2), 3.48 and 3.51 [2ꢃ 3H, 2ꢃ d,
3
0
0
0
JPOðOCH Þ ;P¼11.3 Hz, PO(OCH3)2], 5.26 (1H, br d, J6 ,7 ¼10.4 Hz, 6 -H),
3
2
00
00 00
superimposed 0 by 5.28 (1H, q, J1 ,2 ¼6.2 Hz, 1 -H), 5.77 (1H, d,
5.1.27. Deprotection of ketals 13a and epi-13a and subsequent Hor-
nereWadswortheEmmons reaction: synthesis of a 85:15 mixture of
(3R*,4R,5R)-4-[(1R)-1-(tert-butyldimethylsiloxy)ethyl]-2-[(S,3E,5E)-
5,7-dimethyl-2-oxonona-3,5-dienyl]-3-hydroxy-4,5-(iso-
propylidenedioxy)-3-phenylcyclopent-1-enyl dimethyl phosphate
0
0
J3 ,4 ¼15.8 Hz, 3 -H), superimposed by 5.79 (1H, s, 5-H), 6.69 (1H, br s, 3-
0
0
0
OH), 7.05 (1H, d, J4 ,3 ¼15.8 Hz, 4 -H), 7.08e7.12 (1H, m, p-Ar), 7.25e7.29
(2H, m, m-Ar), 7.86 (2H, br s, o-Ar); 13C NMR (125.6 MHz, C6D6; sample
contained trace of c-C6H12):
d¼ꢀ4.82 and ꢀ3.91 [Si(CH3)2], 12.00 and

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T. Wuster et al. / Tetrahedron 69 (2013) 7785e7809
7803
12.09 (C-90,50-CH3),18.42 [SiC(CH3)3],19.50 (C-200), 20.02 (70-CH3), 26.22
[SiC(CH3)3], 28.47 and 29.63 [acetonide-C(CH3)2], 30.04 (C-80), 35.19 (C-
487 mmol) in acetonitrile/H2O [5:1 (vol:vol), 5.28 mL, tantamount
to 100 equiv H2O] provided a crude product (which must have
contained the phosphonate epimers 47b and epi-47b) under anal-
ogous conditions as described for the conversion 13a/epi-
13a/47a/epi-47a. 47b/epi-47b was carried on jointly with K2CO3
70), 37.54 (C-10), 54.62 [d, 2JPOðOCH Þ ;P¼6.4 Hz, 1ꢃ PO(OCH3)], 54.75 [d,
3
2JPOðOCH Þ ;P¼5.4 Hz, 1ꢃ PO(OCH3)]2, 69.24 (C-100), 83.44 (C-3), 83.86 (C-
3
5), 96.08 2(C-4), 113.67 [acetonide-C(CH3)2], 123.08 (C-30), 124.91 (d,
3J2,P¼7.5 Hz, C-2), 127.42 (p-Ar), 127.60 (m-Ar), 129.50 (o-Ar), 132.11 (C-
50),141.60 (q-Ar),149.72(C-40),150.56 (C-60), 151.86 (d, 2J1,P¼8.6 Hz, C-1),
199.16 (C-20); HRMS (CI): MþHþ, found m/z¼679.34310, i.e.,
(134 mg, 974
mmol, 2.00 equiv) and 18-crown-6 (515 mg,
1.95 mmol, 4.00 equiv) in benzene (8.3 mL) at 60 ꢁC (2.5 h) as de-
scribed for the analogous reaction of 47a/epi-47a. Flash chroma-
tography44 (B 4.0 cm, 20 cm, packed with c-C6H12/AcOEt 10:1,
eluted with c-C6H12/AcOEt 5:1/3:1) led separately (first) to what
we hold for a 91:9 mixture of epimers 49b and epi-49b (114 mg,
34%) and (thereafter) to 48b (105 mg, 32%), each of which was
D
¼ꢄ0.0 ppm versus what C35H56O9PSi requires (679.34312).
25
Compound 51a: [
a
]
¼þ297 (C6D6, c¼0.70); IR (film):
n
¼3415,
D
3060, 2955, 2930, 2885, 2855, 1715, 1690,1675,1610, 1590, 1495,1472,
1465, 1445, 1405, 1375, 1350, 1300, 1250, 1210, 1185, 1150, 1105, 1085,
1075, 1030, 1005, 970, 935, 865, 835, 815 cmꢀ1; 1H NMR (499.6 MHz,
a yellowish oil.
25
C6D6; sample contained trace of c-C6H12):
d
¼ꢀ0.24 and ꢀ0.17 [2ꢃ 3H,
Compound 48b: Rf value (c-C6H12/AcOEt 2:1): 0.30; [
a
]
¼þ56
578
0
0
0
2ꢃ s, Si(CH3)2], 0 0.71 (3H, t, J9 ,8 ¼7.4 Hz, 9 -H3), 0.78 (3H, d,
(C6H6, c¼0.52); IR (film):
n
¼3375, 3055, 2955, 2930, 2860, 1760,
0
0
0
J7 -CH ,7 ¼6.9 Hz, 7 -CH3), 0.84 [9H, s, SiC(CH3)3], 1.04e1.22 (2H, m, 8 -
1720, 1690, 1680, 1645, 1625, 1460, 1450, 1410, 1375, 1340, 1260,
1235, 1185, 1140, 1120, 1075, 1040, 1005, 960, 945, 855, 840,
3
00
00 00
H2), 1.24 (3H, d, J2 ,1 ¼6.3 Hz, 2 -H3), 1.48 (3H, s, 1ꢃ acetonide-CH3),
1.49 (3H, d, J5 -CH ,6 ¼1.3 Hz, 5 -CH3),1.52(3H, s,1ꢃ acetonide-CH3), 2.15
830 cmꢀ1 1H NMR (499.6 MHz, C6D6; sample contained traces of
;
0
0
0
3
(1H, mc, 70-H), AB signal (2H, dA¼3.44, dB¼3.71, JAB¼15.6 Hz, 10-H2),
c-C6H12 and tert-BuOMe):
d
¼ꢀ0.13 and ꢀ0.09 [2ꢃ 3H, 2ꢃ s,
00
4.22 (1H, q, J1 ,2 ¼6.3 Hz, 1 -H), 4.82 (1H, 0s, 5-H), 5.34 (1H, br d,
Si(CH3)2], 0.71 (3H, t, J9 ,8 ¼7.4 Hz, 90-H3), 0.80 (3H, d, J7 -
00 00
0
0
0
0
J6 ,7 ¼9.8 Hz, 6 -H), 6.22 (1H, d, J3 ,4 ¼15.8 Hz, 3 -H), 7.07e7.12 (1H, m, p-
¼6.6 Hz, 70-CH3), 0.85 [9H, s, SiC(CH3)3], 0.98 (3H, d,
0
0
0
0
0
CH3,7
0
00
0
0
0
00 00
Ar), 7.17e7.21 (2H, m, m-Ar), 7.27 (1H, d, J4 ,3 ¼15.1 Hz, 4 -H), 7.96e7.99
J2 ,1 ¼6.6 Hz, 2 -H3), 1.02e1.12 and 1.14e1.22 (2H, 2ꢃ m, 8 -H2),
(2H, m, o-Ar); 13C NMR (125.6 MHz, C6D6; sample contained trace of c-
1.31 (3H, s, 1ꢃ acetonide-CH3), 1.43 (3H, d, J5 -CH ,6 ¼1.3 Hz, 5 -CH3),
0
0
0
3
C6H12):
d
¼ꢀ4.99 and ꢀ3.81 [Si(CH3)2], 12.00 (C-90), 12.24 (50-CH3),
1.91 (3H, s, 1ꢃ acetonide-CH3), 2.18 (1H, mc, 70-H), 3.40 and 3.53
18.00 [SiC(CH3)3], 19.22 (C-200), 20.14 (70-CH3), 26.04 [SiC(CH3)3], 28.32
and 28.49 [acetonide-C(CH3)2], 30.13 (C-80), 35.07 (C-70), 37.27 (C-10),
68.87 (C-100), 78.95 (C-5), 92.57 (C-4), 115.39 [acetonide-C(CH3)2],
124.13 (C-30),128.58 (m-Ar), 129.41 (o-Ar),129.83 (p-Ar), 132.31 (C-50),
134.04 (q-Ar), 137.55 (C-2), 148.36 (C-40), 149.13 (C-60), 167.60 (C-3),
194.40 (C-20), 203.07 (C-1); HRMS (CI): MþHþ, found m/z¼553.33420,
[2ꢃ 3H, 2ꢃ d, JPOðOCH Þ ;P¼11.3 Hz, PO(OCH3)2], 4.34 (1H, q,
3
2
J1 ,2 ¼6.7 Hz, 0 100-H), 4.96 (1H, br s, 5-H), 5.23 (1H, br d,
00 00
0
0
J6 ,7 ¼9.5 Hz, 6 -H), AB signal [2H, dA¼5.54, dB¼5.66, JAB¼9.1 Hz, B
part additionally split by J1 ,P¼2.2 Hz (splitting vanishes upon031P-
0
decoupling), HA¼2-H, HB¼10-H], 5.83 (1H, d, J3 ,4 ¼15.8 Hz, 3 -H),
6.58 [1H, d, J3-OH,P¼1.3 Hz (splittingdthrough spacedvanishes
upon 31P-decoupling), 3-OH (vanishes upon treatment with D2O)],
0
0
i.e.,
D
¼ꢀ1.3 ppm versus what C33H49O5Si requires (553.33493).
0
0
0
6.70 (1H, d, J4 ,3 ¼15.4 Hz, 4 -H), 7.06e7.10 (1H, m, 1H, p-Ar),
7.24e7.28 (2H, m, m-Ar), 8.17e8.22 (2H, m, o-Ar); 13C NMR
(125.6 MHz, C6D6; sample contained traces of c-C6H12 and tert-
5.1.28. Deprotection of ketals 13b and epi-13b and (attempted) sub-
sequent HornereWadswortheEmmons reaction: synthesis of
(2R,3R,4R,5R)- or (2S,3S,4R,5R)-4-[(1S)-1-(tert-butyldimethylsiloxy)
ethyl]-2-[(S,1Z,3E,5E)-5,7-dimethyl-2-(dimethylphosphatyl)nona-
1,3,5-trienyl]-4,5-(isopropylidenedioxy)-3-phenylcyclopentane (48b)
and a 91:9 mixture of (3R*,4R,5R)-4-[(1S)-1-(tert-butyldimethylsiloxy)
ethyl]-2-[(S,3E,5E)-5,7-dimethyl-2-oxonona-3,5-dienyl]-3-hydroxy-
4,5-(isopropylidenedioxy)-3-phenylcyclopent-1-enyl dimethyl phos-
phate (49b) and (3S*,4R,5R)-4-[(1S)-1-(tert-butyldimethylsiloxy)ethyl]-
2-[(S,3E,5E)-5,7-dimethyl-2-oxonona-3,5-dienyl]-3-hydroxy-4,5-(iso-
propylidenedioxy)-3-phenylcyclopent-1-enyl dimethyl phosphate (epi-
49b; *these configurational descriptors are interchangeable).
BuOMe):
d
¼ꢀ5.64 and ꢀ4.43 [Si(CH3)2], 12.15 (C-90), 12.51 (50-
CH3), 17.86 [SiC(CH3)3], 18.79 (C-200), 20.67 (70-CH3), 25.68
[SiC(CH3)3], 28.82 and 29.89 [acetonide-C(CH3)2], 30.57 (C-80),
34.81 (C-70), 54.66 [d, 2JPOðOCH Þ ;P¼6.4 Hz, 1ꢃ PO(OCH3)], 55.10 [d,
3
2
2JPOðOCH Þ ;P¼5.4 Hz, 1ꢃ PO(OCH3)], 59.42 (C-2), 73.78 (C-100), 82.45
3
2
(C-3), 83.74 (C-5), 89.01 (C-4), 110.73 (d, 3J1 ,P¼5.4 Hz, C-10), 115.05
0
3
[acetonide-C(CH3)2], 121.24 (d, J3 ,P¼2.1 Hz, C-30), 127.61 (p-Ar),
0
127.69 (o-Ar), between 127.70 and 127.90 (superimposed by sol-
vent signal; m-Ar), 132.46 (C-50), 135.54 (C-40), 141.73 (C-60), 142.02
(q-Ar), 150.68 (d, J2 ,P¼8.6 Hz, C-20), 209.85 (C-1); 31P NMR
0
(202.3 MHz, C6D6):
d
¼ꢀ3.38 [OP(OMe)2]; 29Si NMR (99.3 MHz,
p
þ
C6D6):
d
¼23.63 (OSiMe2tBu); HRMS (EI): Mꢅ
,
found m/
m
z¼678.33480, i.e.,
D¼ꢀ0.7 ppm versus what C35H55O9PSi requires
o
q
(678.33530).
t-BuMe2SiO
OH
Compound 49b/epi-49b: Rf value (c-C6H12/AcOEt 2:1): 0.35;
1''
2''
25
[
a
]
¼þ5.2 (C6D6, c¼0.50); IR (film):
n
¼3445, 2985, 2950, 2935,
3
D
4
O
1'
3'
5'
9'
OPO(OMe)72'
5 1
2860, 3355, 2100, 1670, 1625, 1595, 1490, 1460, 1450, 1370, 1345,
1300, 1250, 1185, 1110, 1080, 1040, 1005, 955, 920, 890, 835,
O
O
810 cmꢀ1; 1H NMR (499.6 MHz, C6D6):
d
¼0.08 and 0.27 [2ꢃ 3H, 2ꢃ
48b (1 diastereomer)
p
s, Si(CH3)2], 0.608 (3H, t, J9 ,8 ¼7.4 Hz, 90-H3), 0.76 (3H, d,
0
0
0
0
0
J7 -CH ,7 ¼6.9 Hz, 7 -CH3), 1.05 [9H, s, SiC(CH3)3], 1.09e1.19 (2H, m, 8 -
3
m
0
0
0
H2), 1.24 (3H, s, 1ꢃ acetonide-CH3), 1.41 (3H, d, J5 -CH ,6 ¼1.0 Hz, 5 -
3
o
00
00 00
CH3), 1.57 (3H, s, 1ꢃ acetonide-CH3), 1.64 (3H, d, J2 ,1 ¼6.6 Hz, 2 -
H3), 2.12 (1H, mc, 70-H), AB signal (2H, dA¼3.29, dB¼3.65,
JAB¼17.0 Hz, 10-H2), 3.57 and 3.58 [2ꢃ 3H, 2ꢃ d,
q
OH
t-BuMe2SiO
1''
2''
3
4
3
O
00
1'
5'
7'
9'
O 3'
00 00
JPOðOCH Þ ;P¼11.4 Hz, PO(OCH3)2], 4.28 (1H, q, J1 ,2 ¼6.5 Hz, 1 -H),
5 1
3
5.21 (1H,2br d, J6 ,7 ¼9.8 Hz, 60-H), 5.38 (1H, s, 3-OH), 5.89 (1H, br 0s,
0
0
O
OPO(OMe)2
0
0
0
0
0
5-H), 5.97 (1H, d, J3 ,4 ¼15.8 Hz, 3 -H), 7.09 (1H, d, J4 ,3 ¼15.8 Hz, 4 -
H), 7.12e7.16 (1H, m, superimposed by solvent resonance p-Ar),
7.30e7.34 (2H, m, m-Ar), 7.92e8.00 (2H, br d, o-Ar); 13C NMR
49b + epi-49b
(125.6 MHz, C6D6):
d
¼ꢀ5.04 and ꢀ4.26 [Si(CH3)2], 12.05 (C-90, as-
p-TsOH (4.2 mg, 24
mmol, 4.9 mol %) and a mixture of the
signment exchangeable with 50-CH3), 12.30 (50-CH3, assignment
dimethoxy phosphonate epimers 13b and epi-13b (353 mg,

€
T. Wuster et al. / Tetrahedron 69 (2013) 7785e7809
7804
exchangeable with C-90), 18.16 [SiC(CH3)3], 18.89 (C-200), 20.19 (70-
CH3), 26.14 [SiC(CH3)3], 28.20 and 29.31 [acetonide-C(CH3)2], 30.17
(2H, m, o-Ar); 13C NMR (125.6 MHz, C6D6; sample contained traces
of c-C6H12):
d
¼12.04 (C-90), 12.25 (50-CH3), 18.13 (C-200), 20.17 (70-
2
(C-80), 35.08 (C-70), 37.56 (C-10), 54.57 [d, JPOðOCH Þ ;P¼6.4 Hz, 1ꢃ
CH3), 28.36 and 28.49 [acetonide-C(CH3)2], 30.18 (C-80), 35.15 (C-70),
36.45 (C-10), 67.41 (C-100), 78.35 (C-5), 92.57 (C-4), 115.37 [aceto-
nide-C(CH3)2],124.07 (C-30),128.62 (o-Ar),128.77 (m-Ar),129.57 (p-
Ar), 132.30 (C-50), 134.41 (q-Ar), 138.23 (C-2), 148.65 (C-40), 149.39
(C-60), 166.11 (C-3), 195.06 (C-20), 202.59 (C-1); HRMS (CI): MþHþ,
3
PO(OCH3)], 54.72 [d, JPOðOCH Þ ;P¼6.4 Hz, 1ꢃ PO(OC2H3)], 74.98 (C-
2
3
100), 85.03 (C-5), 88.03 (C-32), 91.54 (C-4), 113.84 [acetonide-
3
C(CH3)2], 124.40 (C-30), 127.40 (d, J2,P¼7.5 Hz, C-2), 127.40 (p-Ar),
127.60 (m-Ar), 129.62 (o-Ar), 132.26 (C-50), 141.73 (q-Ar), 147.48 (C-
40), 148.16 (d, 2J1,P¼6.4 Hz, C-1), 148.45 (C-60), 194.87 (C-20); HRMS
found m/z¼439.24870, i.e.,
D¼þ0.6 ppm versus what C27H35O5
(EI): [M-tBu]þ, found m/z¼621.26540, i.e.,
D
¼þ0.8 ppm versus
requires (439.24845).
what C31H46O9PSi requires (621.26487).
5.1.30. (4R,5R)-2-[(S,3E,5E)-5,7-Dimethyl-2-oxonona-3,5-dienyl]-4-
[(S)-1-hydroxyethyl]-4,5-(isopropylidenedioxy)-3-phenylcyclopent-
2-en-1-one (52b).
5.1.29. (4R,5R)-2-[(S,3E,5E)-5,7-Dimethyl-2-oxonona-3,5-dienyl]-4-
[(R)-1-hydroxyethyl]-4,5-(isopropylidenedioxy)-3-phenylcyclopent-
2-en-1-one (52a).
p
m
p
o
m
HO
q
o
O 1''
2''
HO
q
4
1'
5'
7'
9'
O 3'
1''
2''
5 1
4
O
1'
5'
7'
9'
O 3'
5 1
O
O
O
O
This compound was prepared analogously as described for
epimer 52a from HBF4 (50% in H2O, 22.0 L, 30.8 mg, 172 mol,
3.02 equiv, tantamount to 15.0 equiv H2O) and the surmised 91:9
m
m
5.1.29.1. Preparation of 52a from the surmised 85:15 mixture of
49a and epi-49a. At room temperature HBF4 (50% in H2O, 17.0 L,
23.8 mg, 138 mol, 3.00 equiv, tantamount to 14.4 equiv H2O)
was added to a solution of the surmised 85:15 mixture of 49a and
epi-49a (27 mg, 46 mol) in CH2Cl2 (2 mL). The mixture was
m
mixture of 49b and epi-49b (39 mg, 57 mmol). Flash chromatog-
raphy44 (B 1.5 cm, 20 cm, c-C6H12/AcOEt 6:1/4:1) yielded the
m
title compound (12 mg, 48%) as a slightly yellow oil; Rf value (c-
25
m
C6H12/AcOEt 3:1): 0.30; [
n
a
]
¼þ496 (C6D6, c¼1.17); IR (film):
D
stirred at 40 ꢁC for 100 min. Addition of CH2Cl2 (3 mL) and
aq phosphate buffer (pH¼7, 5 mL) was followed by phase sepa-
ration. The aq phase was extracted with CH2Cl2 (5ꢃ3 mL), the
combined organic phases were dried over Na2SO4, and the sol-
vent was removed in vacuo. Flash chromatography44 (B 1.5 cm,
20 cm, c-C6H12/AcOEt 6:1/4:1) yielded the title compound
(9 mg, 45%) as a slightly yellow oil; Rf value (c-C6H12/AcOEt 3:1):
0.30.
¼3575, 3480, 3035, 2960, 2925, 2870, 2355, 2280, 1720, 1690,
1665, 1620, 1590, 1495, 1480, 1460, 1455, 1445, 1400, 1370, 1350,
1310, 1250, 1210, 1185, 1160, 1125, 1080, 1045, 985, 900, 860 cmꢀ1
1H NMR (400.1 MHz, C6D6; sample contained ca. 5% of the trans,Z
;
isomer and traces of c-C6H12 and tert-BuOMe):0
d
¼0.71 (3H, t,
0
0
0
0
0
J9 ,8 ¼7.4 Hz, 9 -H3), 0.80 (3H, d, J7 -CH ,7 ¼6.6 Hz, 7 -CH3), 1.02 (3H,
3
00
0
00 00
d, J2 ,1 ¼6.6 Hz, 2 -H3), 1.04e1.24 (2H, m, 8 -H2), 1.36 (3H, s, 1ꢃ
0
0
0
acetonide-CH3), 1.45 (3H, d, J5 -CH ,6 ¼1.1 Hz, 5 -CH3), 1.48 (3H, s,
1ꢃ acetonide-CH3), 2.16 (1H, mc,3 70-H), AB signal (2H, dA¼3.19,
dB¼3.66, JAB¼16.3 Hz, 10-H2), 3.94 (1H, q, J1 ,2 ¼6.6 Hz, 1 -H), 4.79
00
5.1.29.2. Preparation of 52a from 51a. A solution of 51a
00 00
(20.0 mg, 36.2
(ice-bath) and diluted with water (100
mmol) in 1,4-dioxane (500 m
L) was cooled to 0 ꢁC
0
0
0
(1H, s, 5-H), 5.38 (1H, br d, J6 ,7 ¼9.6 Hz, 6 -H), 6.09 (1H, d,
0
m
L). Ammonium fluoride
0
0
J3 ,4 ¼15.8 Hz, 3 -H), 7.05e7.16 (3H, m, superimposed by solvent
0
(3.4 mg, 92 mmol, 2.5 equiv) was added in one portion. The resulting
0
0
signal, p-Arþm-Ar), 7.20 (1H, d, J4 ,3 ¼15.9 Hz, 4 -H), 7.74e7.79
mixture was stirred at 0 ꢁC for 90 min. No conversion was observed
(2H, m, o-Ar); 13C NMR (100.6 MHz, C6D6; sample contained
by TLC. Accordingly, the mixture was warmed to 40 ꢁC. After stir-
traces of c-C6H12):
d
¼12.02 (C-90), 12.25 (50-CH3), 17.09 (C-200),
20.15 (70-CH3), 28.34 and 28.39 [acetonide-C(CH3)2], 30.17 (C-80),
35.16 (C-70), 36.31 (C-10), 67.57 (C-100), 77.48 (C-5), 92.74 (C-4),
114.85 [acetonide-C(CH3)2], 124.17 (C-30), 128.61 (o-Ar), 128.92
(m-Ar), 129.94 (p-Ar), 132.30 (C-50), 134.23 (q-Ar), 137.84 (C-2),
148.68 (C-40), 149.48 (C-60), 166.22 (C-3), 195.04 (C-20), 201.73 (C-
ring for 1 h more ammonium fluoride (3.3 mg, 89
was added in one portion. The resulting suspension was diluted
with water (100 L) and 1,4-dioxane (200
L) and stirred at 40 ꢁC
mmol, 2.5 equiv)
m
m
for 13 h. The mixture was diluted with aq phosphate buffer (pH 7,
1 mL) and ethyl acetate (1 mL). After phase separation the aqueous
phase was extracted with ethyl acetate (5ꢃ1 mL). The combined
organic phases were dried over Na2SO4. The solvent was removed
under reduced pressure. Flash chromatography44 (B 1.5 cm, 20 cm,
c-C6H12/AcOEt 6:1/4:1/2:1) furnished the title compound
1); HRMS (CI): MþHþ, found m/z¼439.24770, i.e.,
D
¼ꢀ1.7 ppm
versus what C27H35O5 requires (439.24845).
5.1.31. (4R,5R)-4-Acetyl-2-[(S,3E,5E)-5,7-dimethyl-2-oxonona-3,5-
dienyl]-4,5(-isopropylidenedioxy)-3-phenylcyclopent-2-en-1-one
(53).
(9.9 mg, 64%).
25
Compound 52a: [
a
]
¼þ437 (C6D6, c¼0.90); IR (film):
n
¼3450,
D
3050, 2960, 2925, 2870, 1715, 1670, 1620, 1590, 1495, 1455, 1445,
1375, 1355, 1305, 1245, 1210, 1185, 1155, 1095, 1080, 1030, 985, 955,
925, 890, 855 cmꢀ1; 1H NMR (499.6 MHz, C6D6; sample contained
ca. 6% of the trans,Z isomer and traces of c-C6H12 and tert-BuOMe):
p
m
o
O
q
1''
2''
0
0
0
0
0
0
d
¼0.71 (3H, t, J9 ,8 ¼7.4 Hz, 9 -H3), 0.79 (3H, d, J7 -CH ,7 ¼6.6 Hz, 7 -
3
4
O
1'
5'
7'
9'
O 3'
00
CH3), 1.04e1.22 (2H, m, 80-H2), 1.11 (3H, d, J2 ,1 ¼6.3 Hz, 2 -H3), 1.40
00 00
5 1
0
(3H, s, superimposed by c-C6H12, 1ꢃ acetonide-CH3), 1.43 (3H, d, J5 -
O
O
0
0
¼0.9 Hz, 5 -CH3), 1.55 (3H, s, 1ꢃ acetonide-CH3), 2.15 (1H, mc,
CH3,6
70-H), AB signal (2H, dA¼3.31, dB¼3.60, JAB¼16.4 Hz,10-H2), 3.88 (1H,
00
00 00
0
0
q, J1 ,2 ¼6.3 Hz, 1 -H), 4.70 (1H, s, 5-H), 5.35 (1H, br d, J6 ,7 ¼9.8 Hz,
5.1.31.1. Preparation of 53 from 52a. At room temperature a so-
lution of alcohol 52a (10 mg, 23 mol) in degassed CH2Cl2 (500 L)
was added under an atmosphere of argon to a stirred mixture of N-
0
60-H), 6.06 (1H, d, J3 ,4 ¼15.8 Hz, 3 -H), 7.07e7.11 (1H, m, p-Ar),
m
m
0
0
7.14e7.19 (3H, m, superimposed by c-C6H12, m-Arþ40-H), 7.72e7.77

€
T. Wuster et al. / Tetrahedron 69 (2013) 7785e7809
7805
methylmorpholin-N-oxide monohydrate (7.8 mg, 58
m
mol,
L). After
15 min tetrapropylammonium perruthenate (0.8 mg, 2.3 mol,
drop of H2O. Et2O (2 mL) and brine (2 mL) were added. After phase
separation the aq phase was extracted with Et2O (3ꢃ1 mL). The
combined organic phases were dried over NaSO4, the solvent was
removed under reduced pressure, and the crude product separated
ꢀ
2.5 equiv) and molecular sieves (4 A) in CH2Cl2 (250
m
m
10 mol %) was added. After stirring at room temperature for 3 h
CH2Cl2 (2 mL) and aq phosphate buffer (pH¼7, 3 mL) were added.
The aq phase was extracted with CH2Cl2 (4ꢃ2 mL), the combined
organic phases were dried over Na2SO4, and the solvent was re-
moved at 30 ꢁC in vacuo. Flash chromatography44 (B 0.5 cm, 20 cm,
c-C6H12/AcOEt 5:1/3:1) gave the title compound (8.0 mg, 80%,
ꢂ97% trans,E) as a yellow oil.
by flash chromatography44 (B
2
cm, 20 cm, c-C6H12/AcOEt
50:1/25:1/15:1/5:1) into dimer 64 (7.0 mg, 11 mol, 15%; X-ray
crystal structure: footnote,37 Fig. 6) and a mixture (12 mg) of 62 and
-menthol. The latter was removed from that mixture in oil-pump
vacuum. What remained was 62 (8.0 mg, 22 mol, 15%).
m
L
m
5.1.31.2. Preparation of 53 from 52b. A solution of alcohol 52b
(20 mg, 46
morpholin-N-oxide monohydrate (15.5 mg, 115
and tetrapropylammonium perruthenate (1.6 mg, 4.6
m
mol) in degassed CH2Cl2 (750
m
L), N-methyl-
mol, 2.50 equiv),
mol,
m
m
10 mol %) was processed as described for the oxidation of alcohol
52a. Flash chromatography44 (B 1.5 cm, 20 cm, c-C6H12/AcOEt
5:1/3:1) gave the title compound (18 mg, 90%, ꢂ97% trans,E) as
a yellow oil.
25
Rf value (c-C6H12/AcOEt 3:1): 0.35; [
(film):
1645, 1620, 1595, 1460, 1440, 1415, 1375, 1355, 1305, 1250, 1210,
1185, 1110, 1080, 1025, 985, 850 cmꢀ1 1H NMR (499.6 MHz, C6D6;
a
]
¼þ96 (C6D6, c¼0.20); IR
D
n
¼2960, 2925, 2870, 2360, 2335, 2720, 1690, 1675, 1665,
;
sample contained ca. 3% of the trans,Z isomer and contam0inant
0
0
signals at
d
¼1.02 and 4.88 ppm):
d
¼0.71 (3H, t, J9 ,8 ¼7.4 Hz, 9 -H3),
0.78 (3H, d, 4J7 -CH ,7 ¼6.6 Hz, 7 -CH3), 1.04e1.13 and 1.13e1.20 (2H,
0
0
0
3
2ꢃ m, 80-H2), 1.036 (3H, s, 1ꢃ acetonide-CH3), 1.44 (3H, d,
4
0
0
J5 -CH ,6 ¼0.9 Hz, 5 -CH3), 1.57 (3H, s, 1ꢃ acetonide-CH3), 1.91 (3H, s,
3
200-H3), 2.10e2.19 (1H, mc, 70-H), AB signal (2H, dA¼3.42, dB¼3.46,
JAB¼16.6 Hz, 10-H2), 4.50 (1H, s, 5-H), 5.35 (1H, br d, J6 ,7 ¼10.1 Hz,
0
0
60-H), 6.04 (1H, d, J3 ,4 ¼15.4 Hz, 3 -H), 6.97e7.01 (1H, m, p-Ar),
0
0
0
0
0
0
7.04e7.08 (2H, m, m-Ar), 7.16 (1H, d, J4 ,3 ¼15.8 Hz, 4 -H, super-
imposed by solvent signal), 7.66e7.69 (2H, m, o-Ar); 13C NMR
(125.6 MHz, C6D6; sample contained contaminant signals at
Fig. 6. ORTEP plot of the unit cell of an X-ray structure analysis of a single crystal of
dimer 64 at 298 K.46 Hydrogen atoms were restrained to idealized positions and re-
fined isotropically based on a riding model.
d¼27.24, 28.53, and 94.24 ppm):
d
¼12.04 (C-90), 12.24 (50-CH3),
20.14 (70-CH3), 26.91 (C-200), 27.91 and 28.04 [acetonide-C(CH3)2],
30.16 (C-80), 35.14 (C-70), 36.51 (C-10), 82.09 (C-5), 95.03 (C-4),
117.39 [acetonide-C(CH3)2], 123.95 (C-30), 128.55 (o-Ar), 128.94 (m-
Ar), 130.07 (p-Ar), 132.26 (C-50), 133.93 (q-Ar), 138.38 (C-2), 148.61
(C-40), 149.43 (C-60), 166.36 (C-3),194.34 (C-20), 201.25 (C-1), 206.30
5.1.32.2. Preparation B. At ꢀ40 ꢁC n-BuLi (2.31 M in hexane,
130
mL, 300 mmol, 1.00 equiv) was added to a solution of diisopro-
(C-100); HRMS (CI): MþHþ, found m/z¼437.23210, i.e.,
¼ꢀ1.6 ppm
D
pylamine (44.0
mL, 31.7 mg, 314 mmol, 1.05 equiv) in THF (1 mL). The
versus what C27H33O5 requires (437.23280).
resulting mixture was stirred for 30 min. A solution of lactone 18
(94.0 mg, 300
m
mol) in THF (500
m
L) was pre-cooled to ꢀ40 ꢁC and
5.1.32. (3R,4R,5R)-3-(1-Hydroxy-1-methylethyl)-5-{[(1R,2S,5R)-2-
isopropyl-5-methylcyclohexyl]oxy}-3,4-(isopropylidenedioxy)-4,5-
dihydro-3H-furan-2-one (62) and hexacyclic dimer 64 of lactone 18.
added to the previously mentioned mixture via cannula. The
resulting mixture was stirred for 50 min. A solution of pre-cooled
acetaldehyde (17.0
mL, 13.3 mg, 301 mmol, 1.00 equiv) in THF
(255
m
L) was added via cannula. The mixture was stirred at ꢀ40 ꢁC
for 25 h until it was poured into satd aq NH4Cl (2 mL). Et2O (2 mL)
was added. After phase separation the aq phase was extracted with
Et2O (4ꢃ1 mL). The combined organic phases were dried over
NaSO4 and the solvent was removed under reduced pressure. Pu-
O
O
O
HO
OH
O
1''O
25O
O
O
2''
rification by flash chromatography44 (B 2.5 cm, 20 cm, c-C6H12
/
O
O
AcOEt 15:1/10:1/5:1) provided dimer 64 (30 mg, 48
mmol, 32%)
O
O
O
O
2'
5'
1'
and a mixture (33 mg) of 62 and -menthol. The latter was removed
L
under oil-pump vacuum leaving 62 (20 mg, 54 mmol, 18%).
62
64
Acknowledgements
5.1.32.1. Preparation A. At ꢀ50 ꢁC n-BuLi (2.31 M in hexane,
We thank Stefan Malsch for skillful technical assistance, Patrick
Kasper, Christian Schubert, and Charles Tchoubun for their contri-
butions in the course of their diploma or bachelor laboratory works,
65.0
propylamine (22.0
(500
18 (47.0 mg, 150
mL, 150 mmol, 1.00 equiv) was added to a solution of diiso-
mL, 15.8 mg, 157 mmol, 1.05 equiv) in THF
€
m
L). The mixture was stirred for 30 min. A solution of lactone
Dr. Jens Geier (Universitat Freiburg) for performing the X-ray anal-
mmol) in THF (500
m
L) was pre-cooled to ꢀ50 ꢁC
yses,46 Dr. Horst Hemmerle (at the time Aventis Pharma Deutsch-
land) for a sample of kodaistatin A,16 and Prof. Dr. Klaus Ditrich (BASF
SE, Ludwigshafen) for a donation of (S)-2-methylbutanol.
and added to the previously mentioned mixture via cannula. The
resulting mixture was stirred for 45 min. It was quenched by one

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T. Wuster et al. / Tetrahedron 69 (2013) 7785e7809
7806
18. The enantiomeric composition of alcohol 6 was determined by GLC analysis
Supplementary data
[CP-Chirasil-Dex CB 25 mꢃ0.25 mm (CP-7502; coating: Ref. 17) capillary; 35 ꢁ
C
isothermal; 45 min; þ10 ꢁC/min to 170 ꢁC; 20 min; 50 kPa H2 pressuredno
additional carrier gas]: Several compounds eluted from the column, one of
them being (S)-6. The latter eluted with Rt¼20.9 min. When we injected the
same ozonolysis products and co-injected rac-6, the peak attributed to (S)-6
(Rt¼20.9 min) was reinforced and an additional peak e which we attributed to
(R)-6dshowed up after Rt¼19.6 min.
Reproductions of 1H and 13C NMR data of compounds
prepared in this study and high-resolution representations of the
X-ray structures of compounds 17b (CCDC 932028) and 18 (CCDC
932027) can be found. Supplementary data related to this article
can be found at http://dx.doi.org/10.1016/j.tet.2013.05.091.
19. Reproductions of the GLCs of this analysis are included in the Supplementary
Data file.
20. (a) Feringa, B. L.; de Lange, B. Tetrahedron Lett. 1988, 29, 1303e1306; (b) Feringa,
B. L.; De Bene, B. Tetrahedron 1988, 44, 7213e7222; (c) Jansen, J. F. G. A.; Feringa,
B. L. Tetrahedron Lett. 1989, 30, 5841e5844; (d) de Jong, J. C.; van Bolhuis, F.;
Feringa, B. L. Tetrahedron: Asymmetry 1991, 2, 1247e1262; (e) Detailed exper-
imental procedure: Moradei, O. M.; Paquette, L. A.; Peschko, C.; Danheiser, R. L.
Org. Synth. 2003, 80, 66e73.
21. Other early preparations and uses of the Feringa lactone were described by (a)
Martel, J., Demoute, J.-P., Tessier, J., U.S. Patent 4769478 A1 (Roussel-Uclaf),
September 6, 1988; (b) Hoffmann, N.; Scharf, H.-D.; Runsink, J. Tetrahedron Lett.
1989, 30, 2637e2638; (c) Pelter, A.; Ward, R. S.; Jones, D. M.; Maddocks, P.
Tetrahedron: Asymmetry 1990, 1, 857e860.
References and notes
1. Selected reviews on natural product-based pharmaceuticals: (a) Butler, M. S. J.
Nat. Prod. 2004, 67, 2141e2153; (b) Koehn, F. E.; Carter, G. F. Nat. Rev. Drug
Discov. 2005, 4, 206e220; (c) Combinatorial Synthesis of Natural Product-based
Libraries; Kingston, D. G. I., Cragg, G. M., Newman, D. J., Eds.; Taylor & Francis
Group: Boca Raton, FL, 2005; (d) Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2007,
70, 461e477; (e) Molinari, G. Adv. Exp. Med. Biol. 2009, 655, 13e27; (f) Nicolaou,
K. C.; Chen, J. S.; Dalby, S. M. Bioorg. Med. Chem. 2009, 17, 2290e2303; (g)
Danishefsky, S. Nat. Prod. Rep. 2010, 27, 1114e1116; (h) Gray, A. I.; Igoli, J. O.;
Edrada-Ebel, R. Methods Mol. Biol. 2012, 864, 515e534.
22. Review on early uses of the Feringa lactone: Feringa, B. L.; de Jong, J. C. Bull. Soc.
2. Selected reviews on natural product-like libraries: (a) Abel, U.; Koch, C.; Spei-
tling, M.; Hansske, F. G. Curr. Opin. Chem. Biol. 2002, 6, 453e458; (b) Shang, S.;
Tan, D. S. Curr. Opin. Chem. Biol. 2005, 9, 248e258; (c) Nicolaou, K. C.; Pfeffer-
korn, J. A. Solid-phase synthesis of natural products and natural product-like
libraries In Handbook of Combinatorial Chemistry: Drugs, Catalysts, Materials;
Nicolaou, K. C., Hanko, R., Hartwig, W., Eds.; Wiley-VCH: Weinheim, Germany,
2005; pp 611e642; (d) Combinatorial Synthesis of Natural Product-based Li-
braries; Boldi, A. M., Ed.; Taylor & Francis Group: Boca Raton, FL, 2006; (e)
Nandy, J. P.; Prakesch, M.; Khadem, S.; Reddy, P. T.; Sharma, U.; Arya, P. Chem.
Rev. 2009, 109, 1999e2060; (f) Johnson, T. A.; Sohn, J.; Inman, W. D.; Estee, S. A.;
Loveridge, S. T.; Vervoort, H. C.; Tenney, K.; Liu, J.; Ang, K. K.-H.; Ratnam, J.; Bray,
W. M.; Gassner, N. C.; Shen, Y. Y.; Lokey, R. S.; McKerrow, J. H.; Boundy-Mills, K.;
Nukanto, A.; Kanti, A.; Julistiono, H.; Kardono, L. B. S.; Bjeldanes, L. F.; Crews, P.
J. Nat. Prod. 2011, 74, 2545e2555.
Chim. Belg 1992, 101, 627e640.
23. Recent synthesis applications of the Feringa lactone: (a) Yavorskyy, A.;
€
Shvydkiv, O.; Hoffmann, N.; Nolan, K.; Oelgemoller, M. Org. Lett. 2012, 14,
4342e4345; (b) Huang, Y.; Minnaard, A. J.; Feringa, B. L. Org. Biomol. Chem.
2012, 10, 29e31; (c) Cheng, P.; Clive, D. L. J. J. Org. Chem. 2012, 77,
3348e3364; (d) Ogura, A.; Yamada, K.; Yokoshima, S.; Fukuyama, T. Org.
Lett. 2012, 14, 1632e1635; (e) Feng, Z.; Yin, C. Synth. Commun. 2011, 41,
€
507e515; (f) Hickmann, V.; Kondoh, A.; Gabor, B.; Alcarazo, M.; Furstner, A.
J. Am. Chem. Soc. 2011, 133, 13471e13480; (g) Jahjah, R.; Gassama, A.; Du-
mur, F.; Marinkovic, S.; Hoffmann, N.; Lebrun, A.; Cadiou, C.; Richert, S.;
Landgraf, S.; Selles, P. J. Org. Chem. 2011, 76, 7104e7118; (h) Dalencon, S.;
Youcef, R. A.; Huet, F.; Legoupy, S.; Pipelier, M.; Dubreuil, D.; Maisonneuve,
V. J. Org. Chem. 2011, 76, 8059e8063.
24. Established C4þC1 approaches to cyclopentenones 54a,b following such a syn-
thetic strategy comprise the following variations when the C4 component
(56e60) is a 3-formyl-(a) or a 3-acylcarboxylic acid equivalent (b) and the C1
component a deprotonated phosphonate 58:
3. .http://www.idf.org/diabetesatlas/5e/Update2012March 6, 2013.
4. (a) Madsen, P.; Westergaard, N. Expert Opin. Ther. Pat. 2001, 11, 1429e1441; (b)
Harvey, A. L. Curr. Org. Chem. 2010, 14, 1670e1677; (c) Hung, H.-Y.; Qian, K.;
Morris-Natschke, S. L.; Hsu, C.-S.; Lee, K.-H. Nat. Prod. Rep. 2012, 29, 580e606.
5. Quoted after Ref. 4a.
R1
R1
PO(OR3)2
R2
R2
O
ꢁ
6. Vertesy, L., Kurz, M., Paulus, E. U.S. Patent 6,380,257, 2002.
7. Review on glucose-6-phosphate translocase and inhibitors thereof: (a) Ref. 4a;
(b) Van Schaftingen, E.; Gerin, I. Biochem. J. 2002, 362, 513e532; (c) Parker, J. C.
Drugs Fut. 2004, 29, 1025e1033; (d) Charkoudian, L. K.; Farrell, B. P.; Khosla, C.
Med. Chem. Commun. 2012, 3, 926e931.
8. Schwab, D.; Herling, A.; Hemmerle, H.; Schubert, G.; Hagenbuch, B.; Burger, H.-
J. J. Pharmacol. Exp. Ther. 2001, 296, 91e98.
Rx
Rx
O
54a,b
O
55a,b
R1
O
X
Rx
9. (a) Lee, T. S.; Das, A.; Koshla, C. Bioorg. Med. Chem. 2007, 15, 5207e5218; (b)
O
€
€
€
Neufeind, S.; Hulsken, N.; Neudorfl, J.-M.; Schlorer, N.; Schmalz, H.-G. Chem.
dEur. J. 2011, 17, 2633e2641.
56a,b
R1
ꢁ
OR4
O
10. Vertesy, L.; Burger, H.-J.; Kenja, J.; Knauf, M.; Kogler, H.; Paulus, E. F.; Ramakrishna, N.
V. S.; Swamy, K. H. S.; Vijayakumar, E. K. S.; Hammann, P. J. Antibiot. 2000,53,677e686.
11. Ramakrishna, N. V. S., Swamy, K. H. S., Vijayakumar, E. K. S., Nadkarni, S. R.,
Rx
ꢁ
PO(OR3)2
R2
Jayvanti, K., Herling, A., Kogler, H., Vertesy, L., Panshikar, R. M., Sridevi, K.,
O
Raman, M., Dalal, R. M. U.S. Patent 6,166,070, 2000.
57a,b
58
+
12. Dalal, R. M., Herling, W. A., Jayvanti, K., Kogler, H., Nadkarni, S. R., Panshikar, R.
M., Ramakrishna, N. V. S., Raman, M., Murthy, K. S. R., Sridevi, K., Hosamane, K.,
Swamy, S., Vertesy, L., Vijayakumar, E. K. S., EP Patent 0973760 B1, 2002.
13. Ref. 10 mentions the occurrence of kodaistatins B and D, too, yet more vaguely:
‘The strain Aspergillus terreus Thom DSM 11247 produces kodaistatin A as the
main component, with smaller quantities of kodaistatin C. The components B and
D, which occur only in traces, are isomers of compounds A and C, respectively.’
14. Aspulvinone E was isolated in the course of the kodaistatin study of Ref. 10. It
resembles the pulvinone moiety of the kodaistatins but was not considered
in terms of a biosynthetic relationship but appreciated as a ‘pulvinone sample
for free’ for an unambiguous structural analysis, which one would have pref-
erably executed with one of the kodaistatins. However, they eluded structure
R1
O
Rx
O
59a,b
R1'
O
a: R1 = H
b: R1 = H
Rx
O
60a,b
HO
OH
a) 56D58 strategy (for X ¼ OMe): Lin, C. -H.; Aristoff, P. A.; Johnson, P. D.;
McGrath, J. P.; Timko, J. M.; Robert, A., J. Org, Chem 1987, 52, 5594e5601; b)
57D58 strategy: ref. 26; c) 59D58 strategy: Canevet, J. C.; Sharrard, F.; Tetra-
hedron Lett 1982, 23, 181e184; a) 60D58 strategy: Aristoff, P. A.; Johnson, P. D.;
Harrison, A. W.; J. Am. Chem. Soc 1985, 107, 7967e7974.
elucidation by X-ray analysis:
O
O
OH
Z-aspulvinone E
15. (a) Sugiyama, H.; Ojima, N.; Kobayashi, M.; Senda, Y.; Ishiyama, J.-i.; Seto, S.
Agric. Biol. Chem. 1979, 43, 403e404; (b) A crystal structure analysis for as-
pulvinon D was reported by Begley, M. J.; Gedge, D. R.; Knight, D. W.; Pattenden,
G. J. Chem. Soc., Perkin Trans. 11979, 77e83 too. The two findings together show
that two of the earliest described naturally occurring pulvinones contain an (E)-
configured semicyclic C]C bond. This lends some plausibility to the ocurrence of
a (Z)-configured semicyclic C]C bond in the kodaistatins as well.
25. Variations of the C4þC1 approach to substituted cyclopentenones 54a,b
delineated in footnote 24 include uses of a protected 3-acylcarboxylic acids as
the C4 component (e.g. Lard, R. D., Kozar, L. G., Heathcock, C. H. Synth. Commun.
1975, 5, 1e5) or of a 3-(a-hydroxyalkyl)carboxylic acid derivative, which gives
a ketophosphonate intermediate, which must be oxidized before the Hor-
nereWadswortheEmmons cyclization takes place (e.g. Altenbach, H.-J., Hol-
zapfel, W., Smerat, G., Finkler, S. H. Tetrahedron Lett. 1985, 26, 6329e6332).
26. Sundermann, B.; Scharf, H.-D. Tetrahedron: Asymmetry 1996, 7, 1995e1998.
27. We were confident that the bicyclic core of lactone 18 (cf. Scheme 2) would
exert induced diastereoselectivity in the desired sense, i.e., without allowing
aldolization products iso-17a and iso-17b to form. This expectation was based
16. We are grateful to Dr. Horst Hemmerle, who at the time was a member of the
Hoechst Marion Roussel’s kodaistatin team for a donation of kodaistatin A
(thereafter Hoechst Marion Roussel developed into Aventis Pharma).
17. A CP-Chirasil-Dex CB column was employed.18 Its stationary phase consists of
poly(dimethylsiloxane)-bound b-cyclodextrin.

€
T. Wuster et al. / Tetrahedron 69 (2013) 7785e7809
7807
on the effectiveness of product development control in favoring a continued
cis- vs a trans-fusion of the five-membered rings.
HO
HO
O
O
O
O
O
O
O
O
and/or
-menthyl
O
O
O
O
L
O
O
O
L-menthyl
17b
O
O
L
17a
-menthyl
O
HO
HO
O
not attempted:
+
O
18
O
O
O
O
O
O
Li
O
O
O
O
a)
L
-menthyl
L
-menthyl
O
O
O
O
O
O
17a + 17b
iso-17a + iso-17b
O
L
O
-menthyl
L-menthyl
18
60
28. (a) Anelli, P. L.; Montanari, F.; Quici, S. Org. Synth. 1990, 69, 212e219 and; Org.
Synth.Collect Vol. 8; 1993; Collect Vol. 8367e371 (82e84% yield); (b) Jauch,
J.; Szesla, H.; Schurig, V. Tetrahedron 1999, 55, 9787e9792 (59% yield); (c)
Davies, J. R.; Kane, P. D.; Moody, C. J.; Slawin, A. M. Z. J. Org. Chem. 2005, 70,
5480e5481 (72% yield); (d) Pouysegu, L.; Margguerit, M.; Gagnepain, J.; Ly-
vinec, G.; Quideau, S.; Eatherton, A. J. Org. Lett. 2008, 10, 5211e5214 (88%
yield).
29. Cf., e g.: (a) Jessen, H. J.; Gademann, K.; Barbaras, D.; Hamburger, M. Org. Lett.
2009, 11, 3446e3449; (b) Raffier, L.; Piva, O. Beilstein J. Org. Chem. 2011, 7,
151e155; (c) Jessen, H. J.; Schumacher, A.; Shaw, T.; Pfaltz, A.; Gademann, K.
Angew. Chem 2011, 123, 4308e4312; Angew. Chem., Int. Ed. 2011, 50,
4222e4226.
O
O
O
O
O
O
L
-menthyl
Li
HO
O
61
O
O
30. The only 2-oxobutane-1,4-bisphosphonates described prior to 25 were tetrai-
sopropyl 2-oxobutane-1,4-bisphosphonate and tetraisopropyl 1,1-difluoro-2-
oxobutane-1,4-bisphosphonate: Jakeman, D. L.; Ivory, A. J.; Andrew;
Williamson, M. P.; Blackburn, G. M. J. Med. Chem. 1998, 41, 4439e4452.
31. Such hydrostannylations can be brought about via a radical chain reaction, using
Pd catalysis or introducing the Bu3Sn group by mixed cyanocuprates: Barbero, A.;
Pulido, F. J. Chem. Soc. Rev. 2005, 34, 913e920 and references cited therein.
32. Compound 24 had been prepared from (S)-27, PPh3, and Zn by (a) Rossi, R.;
Carpita, A.; Cossi, P. Tetrahedron 1992, 48, 8801e8824 (81% yield); (b) Tietze, L.-
O
O
O
O
O
L
-menthyl
Li
62 (isolated)
O
L
-menthyl
63
O
O
L-menthyl
O
OH
O
O
O
O
€
F.; Singidi, R. R.; Gericke, K. M.; Bockemeier, H.; Laatsch, H. Eur. J. Org. Chem.
O
€
€
2007, 5875e5878 (79% yield); (c) Knott, K. E.; Auschill, S.; Jager, A.; Knolker, H.-
J. Chem. Commun. 2009, 1467e1469 (77% yield).
O
O
L
O
O
+
L
-menthol
-menthyl
(isolated)
33. Selected examples for Z-selective Stille-coupling reactions between trans-alkenyl
stannanes and gem-dibromoolefins: (a) Xu, C.; Negishi, E.-i. Tetrahedron Lett.1999,
431e434; (b) Wong, L.; Shepburn, S. Org. Lett. 2003, 5, 3603e3606; (c) Langille, N.
F.; Panek, J. S. Org. Lett. 2004, 6, 3203e3206; (d) Marjanovic, J.; Kozmin, S. A. Angew.
Chem. 2007, 119, 9010e9013; Angew. Chem., Int. Ed. 2007, 46, 8854e8857.
34. The following precedence encouraged relying on this methodology
(Zeng, X., Qian, M., Hu, Q., Negishi, E.-i. Angew. Chem. 2004, 116,
2309e2313; Angew. Chem., Int. Ed. 2004, 43, 2259e2263):
64 (isolated)
65 (not isolated)
Reagents and conditions: a) LDA (1.0 equiv.), THF, ꢀ50 ꢁC, 45 min; 15% 62
separated from 15% 64 and from an unquantified amount of L-menthol.
37. This was proven by an X-ray diffraction analysis of a single crystal of the re-
spective compound 64 (Fig. 6).
38. Related lactone dimerizations were described by Csuk, R.; Schaade, M.;
Schmidt, A. Tetrahedron 1994, 50, 11885e11892.
39. (a) Kuramochi, K.; Itaya, H.; Nagata, S.; Takao, K.-i.; Kobayashi, S. Tetrahedron Lett.
1999, 40, 7367e7370;(b)Kuramochi, K.;Nagata,S.;Itaya,H.;Matsubara,Y.;Sunoki,
T.; Uchiro, H.; Takao, K.-i.; Kobayashi, S. Tetrahedron 2003, 59, 9743e9758.
40. The C2- and Ca silylation, respectively, of ester enolates including butyrolactone
enolate was first described by Larson, G. L.; Fuentes, L. M. J. Am. Chem. Soc. 1981, 103,
2418e2419.
Pd[P(t-Bu)3]2
(2.0 mol-%),
ZnMe2 (1.0 eq.)
trans
E
+
Bu
Br
THF, room
temp., 30 min
OSiMe2t-Bu
93% ( 98% trans,E)
41. The C2-trimethylsilylation of diethyl trans-2,3-epoxysuccinate and subsequent
ammonium enolate formations therefrom were first described by Eisch, J. J.;
Galle, J. E. J. Org. Chem. 1990, 55, 4835e4840.
Bu
≥
OSiMe2t-Bu
The essential for achieving stereoretention rather than stereoinversion (which
had previously been observed!) was using (t-Bu)3P or NHCs as ligands.
35. Aldol additions of the mono(lithium enolate) from 1,3-dioxolane-4,5-diesters:
(a) Naef, R.; Seebach, D. Angew. Chem 1981, 93 1113e1113; Angew. Chem., Int. Ed.
Engl 1981, 20, 1030e1031; (b) Evans, D. A.; Trotter, B. W.; Barrow, J. C. Tetra-
hedron 1997, 53, 8779e8794; aldol additions of the mono (lithium thioenolate)
from 1,3-dioxolane-4,5-dithioesters: (c) Barros, M. T.; Maycock, C. D. :; Ventura,
M. R. Org. Lett. 2003, 5, 4097e4099; (d) Nakamura, S.; Sato, H.; Hirata, Y.;
Watanabe, N.; Hashimoto, S. Tetrahedron 2005, 61, 11078e11106; aldol addi-
tions of lithium enolates from 1,3-dioxolane-4-monoesters: (e) Ladner, W.
Angew. Chem 1982, 94, 459e460; Angew. Chem., Int. Ed. Engl 1982, 21, 449e450;
(f) Timmer, M. S. M.; Stocker, B. L.; Seeberger, P. H. J. Org. Chem. 2006, 71,
8294e8297; (g) Mukaiyama aldol additions of the mono(silylketene-O, O-ac-
etal) from a 1,3-dioxolane-4,5-diester: Ref. b; (h) Mukaiyama aldol additions of
silylketene-O, S-acetal from a 5-substituted 1,3-dioxolane-4-thioester: Ref. d.
36. On the one hand the lithium enolate 60 of lactone 18 fragmented by an E1cb
elimination, which released acetone. This was evidenced by isolating the aldol
addition product 62 (pure diastereomer, configurational assignment tentative)
42. Similarly, the dimerization the mono(lithium enolate) of a
g-substituted a,b-
[N-(3,4-dimethoxylbenzyl)aziridino]- -lactone by acylation through its not yet
g
deprotonated precursor was observed in 35% yield (Valle, M. S., Tarrade-Matha,
A., Dauban, P., Dodd, R. H. Tetrahedron 2008, 64, 419e432). Nevertheless car-
bonyl compounds could be aldol-added in 15e66% yield. Alternatively, the
identical aldol adducts were obtained e yet in slightly lower yields e after (1)
the respective
a,b-[N-(3,4-dimethoxylbenzyl)aziridino]-g-lactone was C-, i.e.,
a
-trimethylsilylated with a mixture of LDA and Me3SiCl and after (2) the re-
sulting lactones were combined with carbonyl compounds in the presence of
Bu4N4 SiPh3F.2
43. (a) First description of the generation of ammonium enolates from silyl enol
ethers and ammonium fluorides: Kuwajima, I.; Nakamura, E.; Shimizu, M. J. Am.
Chem. Soc. 1982, 104, 1025e1030. This publication emphasized the advantage of
employing benzyltrimethylammonium fluoride rather than, e. g., tetrabutyl-
ammonium fluoride (b) First description of aldol additions of ammonium
enolates generated from silyl enol ethers and ammonium fluorides: Nakamura,
E.; Shimizu, M.; Kuwajima, I.; Sakata, J.; Yokoyama, K.; Noyori, R. J. Org. Chem.
1983, 48, 932e945; (c) First description of aldol additions of ammonium
of residual lithium enolate 60 to this acetone (and by isolating L-menthol,
enolates generated from [a-(trimethylsilyl)cyclopropyl]ketones or -esters and
a plausible follow-up product of the acetone-releasing fragmentation; (lower
right corner). Moreover we isolated the acylation (¼dimerization) product 64
of lithium enolate 60 and lactone 18, which served as its progenitor; 64 was
identified by an X-ray monocrystal structural analysis.37,46 The formation of
aldol adduct 62 meant that we should have scavenged the enolate 60 as aldol
addition products 17a,b by adding acetaldehyde earlier. However, the formation
of acylation product 64 implied that we should have continued waiting before
adding acetaldehyde because the deprotonation of the substrate had not yet
gone to completion. These requirements were irreconcilable.
ammonium fluorides: Paquette, L. A.; Blankenship, C.; Wells, G. J. J. Am. Chem.
Soc. 1984, 106, 6442e6443.
44. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923e2925.
45. This would have allowed to carry on the preceding aldol addition product as
a mixture of diastereomers 17a/b. We did not check this possibility in the
present investigation, though.
46. CCDC 932028 (17b) and CCDC 932027(64) contain the crystallographic data
for this paper. These data can be obtained free of charge from the

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T. Wuster et al. / Tetrahedron 69 (2013) 7785e7809
7808
Cambridge Crystallographic Data Centre via the link www.ccdc.cam.ac.uk/
data_request/cif.
Ph
47. Related hemiketal/acetals were reported inter alia by: (a) Mulzer, J.; Riether, D.
Tetrahedron Lett. 1999, 40, 6197e6200; (b) Tanaka, K.; Pimentel, M.; Berova, N.;
Nakanishi, K. Bull. Chem. Soc. Jpn. 2005, 78, 1843e1850.
σO
PO(OMe)2
O
*
and/or epimer
O
*
O
O
O
O
48. This reagent had been described for effecting the 1,4-addition of phosphite 39
to (phthalimidoylmethyl)vinylketone: Perumal, S. K.; Pratt, R. F. J. Org. Chem.
2006, 71, 4778e4785.
49. The preparation of imine 35 from propionaldehyde was described by De Kimpe,
N.; De Smaele, D.; Hofkens, A.; Dejaegher, Y.; Kesteleyn, B. Tetrahedron 1997, 53,
10803e10816 in 96% yield.
50. Condensation of imine 35 with rac-27 under the same conditions allowed
Moore, M. C.; Cox, R. J.; Duffin, G. R.; O’Hagan, D. Tetrahedron 1998, 54,
9195e9206 to isolate enal rac-26 “crude” in 95% yield.
51. The trans-configuration of the disubstituted C]C bond of the kodaistatin
models iso-cis-12 and dia-iso-cis-12 and their precursors trans,E- and
trans,Z-22, 38, and trans,E- and trans,Z-46 followed from the magnitude of
the respective JHeC]CeH values. The latter were 15.8 Hz, 15.7 Hz, 15.8 Hz
(both isomers), 15.8 Hz, and 15.9 Hz (both isomers), respectively. The
configuration of the respective methylated C]C bond was proved in the
kodaistatin models iso-cis-12 and dia-iso-cis-12 by the following ROESY
crosspeaks:
47b *
K2CO3 in benzene
O
Ph
σ
O
σ
O
Ph
P(OMe)2
O
O
O
O
O
O
O
O
(E)- and/or (Z)-66b
51b
standard = direct
aldol
addition
Horner-Wadsworth-
Emmons reaction
an oxaphosphetane
formation/ fragmen-
tation pathway to the
Horner-Wadswoth-
Emmons product
HO
HO
HO
HO
O
O
O
O
Ph
O
O
σ
iso-cis-12
dia-iso-cis-12
PO(OMe)2
O
52. Method: Watson, D. R. M.; Waugh, F. J. Organomet. Chem. 1972, 37, 45e56.
53. Conditions: Zhang, H. X.; Guibe, F.; Balavoine, G. J. Org. Chem. 1990, 55,
O
should be reserved
to cis-configured
substrate
O
ꢁ
O
1857e1867.
50b *
54. The trans-configuration of the disubstituted C]C bond of the kodaistatin
model cis-11 and its precursors 44, 45, 19, 48b (lies off-route), 49a, 49b, 51a,
52a, 52b, and 53 followed from the magnitude of the respective JHeC]CeH
values. The latter were 16.0 Hz, 19.6 Hz, 14.9 Hz, 15.9 Hz, 15.6 Hz, 15.8 Hz, 15.
8 Hz, 15.5 Hz, 15.8 Hz, 15.9 Hz, and 15.4 Hz, respectively. The (E)-configuration
of the methylated C]C bond was proved in the kodaistatin model cis-11 and in
48b (lies off-route), 51a, and 53 by the following NOESY or ROESY correlations:
Ph OH
O
σ
proton
migration
O
OPO(OMe)2
O
O
Ph
σO
OH
48b
PO(OMe)2
Ph
σ
O
OH
Ph
O
O
protonation
O
O
O
O
HO
HO
O
Ph
O
σ
O
O
67b *
O
O
OPO(OMe)2
48b
cis-11
O
σ
OPO(OMe)2
= t-BuMe2Si
O
oxaphos-
pholane
formation
O
68b *
O
σ
O
Ph
Ph
proton
migration
O
O
O
O
O
O
O
O
Ph
O
OH
Ph
OH
O
σ
σ
O
51a
53
ring
O
O
O
opening
P(OMe)2
OPO(OMe)2
70b *
O
O
55. The attempted stannylcupration of pentynyl phosphonate 23 adopting a pro-
cedure from Betzer, J.-F.; Delaloge, F.; Muller, B.; Pancrazi, A.; Prunet, J. J. Org.
Chem. 1997, 62, 7768e7780 failed; an unidentified mixture instead of the
1-(tributylstannyl)alkene 44 was obtained.
56. Effecting this separation could be avoided since it turned out that using the
mixture of 44/iso-44 in the Stille coupling with dibromoalkene 24 a kinetic
resolution took place: 44 coupled while iso-44 proved inert. The latter was easily
separable from the resulting 45/iso-44 mixture by flash chromatography.44
57. The isomeric purity of bromodecadienyl phosphonate 45 with respect to the
newly formed C]C bond was assessed as the integral ratio of the singlets of 4-
O
O
69b *
dioxaphos-
phinane
formation
Ph
σO
OH
Ph
OH
O
σ
O
ring
opening
O
O
O
O
O
O
Htrans,E-45
(
d
¼5.99 ppm) and 4-Htrans,Z-45
(d
¼6.14 ppm; this resonance was
OPO(OMe)2
P
OMe
barely visible) in the 1H NMR spectrum (400.1 MHz, C6D6).
MeO
O
58. In going from 45 to 19 the CahneIngoldePrelog descriptor for the configura-
tion of the trisubstituted C]C bond changes from Z to E although the stereo-
structure does not change.
59. Method: Devos, A.; Remion, J.; Frisque-Hesbain, A.-M.; Colens, A.; Ghosez, L. J.
Chem. Soc., Chem. Commun. 1979, 1180e1181.
72b *
71b *
proton
migration
60. The formation of these compounds was inferred from the synthetic context but
not corroborated spectroscopically.
Ph
Ph
OH
O
σO
σO
61. Pathways from the deprotonated HornereWadswortheEmmons reagent 47 not
just to the desired olefination product, i.e., to the cyclopentenone 51 (if at all) but
competitively (if not exclusively) to the enol phosphates 48 and 49 are ratio-
nalized in the ensuing Scheme. Side-chain configurations are exemplified for the
b series but the transformations of the epimeric HornereWadswortheEmmons
reagent 47a abide to an analogous mechanistic analysis. While plausible in
principle, the steps as shown do not allow to understand why we did not find 48a
but 48b or obtained 51a as opposed to not obtaining 51b. A 1,4 C/O migration of
a dimethylphosphoryl groupdi.e., a step akin to 67b/68bdwas involved in an
enol phosphate formation described by Moradei, O. M., du Mortier, C. M.,
proto-
nation
O
O
O
O
O
O
OPO(OMe)2
OPO(OMe)2
73b *
49b *
62. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639e666.
63. Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 3543e3544.
64. This calibration is listed by Gottlieb, H. E., Nudelman, A. J. Org. Chem. 1997, 62,
7512e7515 as ‘solvent residual peak’ [for
d
(1H)] or as ‘solvent signal’
ꢂ
Fernandez Cirelli, A. Tetrahedron 1997, 53, 7397e7402 and by Moradei, O. M., du
[for
d
(
13C)], respectively.
ꢂ
Mortier, C. M., Fernandez Cirelli, A. J. Carbohydr. Chem. 1999, 18, 709e719.

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7809
65. If the polarity of the eluent was increased incrementally (pure c-C6H12/c-
C6H12/acetone 15:1/10:1/5:1) the terminal stannane 44 could be enriched in
the later fractions until pure; iso-44 preceded 44 but was not isolated as a pure
compound.
66. Exceptionally, this experiment started from the pure stannane 44. Normally we
employed 44/iso-44 mixtures. This particular experiment is described in the
Experimental Section because it was run at a larger scale than the Stille cou-
plings performed with the mixtures.