A synthesis of cyanolide a by intramolecular oxa-Michael addition

Article abstract of DOI:10.1055/s-0033-1341153

A synthesis of cyanolide A, a diolide natural product, has been achieved using a diastereoselective Barbier reaction, early-stage glycosylation, and intramolecular oxa-Michael addition to form the THP ring. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1341153

PAPER
▌1731
paper
A Synthesis of Cyanolide A by Intramolecular Oxa-Michael Addition
Synthesis of Cyanolide A
Roderick W. Bates,* Tee Guan Lek
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371
Fax +65(6791)1961; E-mail: roderick@ntu.edu.sg
Received: 08.02.2014; Accepted after revision: 14.03.2014
MeO
Abstract: A synthesis of cyanolide A, a diolide natural product, has
O
been achieved using a diastereoselective Barbier reaction, early-
stage glycosylation, and intramolecular oxa-Michael addition to
form the THP ring.
MeO
MeO
O
O
O
O
H
H
H
H
H
O
O
O
O
OMe
OMe
OMe
Key words: Michael addition, Barbier reaction, cyclisation, glyco-
sylation, natural products
H
O
1
The synthesis of several tetrahydropyran natural products
using intramolecular oxa-Michael addition is now well es-
tablished (Scheme 1).1 Several reports are from this labo-
ratory.2 This cyclisation can be carried out under very
mild conditions and with excellent stereochemical con-
trol. The Michael acceptor may be installed by either a
cross-metathesis reaction or by the more conventional
Horner–Wadsworth–Emmons or Wittig reaction. The ef-
ficiency of both the reactions used to install the Michael
acceptor and the oxa-Michael addition itself may be af-
fected by substituents in the allylic position (R1, R2).
While the oxa-Michael addition appears to proceed
smoothly when a single allylic substituent is present, this
significantly slows, but does not prohibit, the cross me-
tathesis.2b
H
OH
OH
HO
O
HO
OH
H
CO2R
Scheme 2 Cyanolide A and its retrosynthesis
dium-catalysed cyclocarbonylation for the formation of
the THP ether,4c Rychnovsky used a remarkable Sakurai
dimerisation,4e and Jennings employed oxonium ion
chemistry.4f Hong,4a Reddy,4b Pabbaraj,4d and Krische4h
each employed oxa-Michael additions, the latter two in
the opposite direction to that intended by us.
To begin the synthesis (Scheme 3), 1,2-epoxybutane was
resolved using Jacobsen’s catalyst.5 Ring opening of the
R-enantiomer 2 of the epoxide with lithium acetylide eth-
ylenediamine complex gave the homopropargylic alcohol
3 (79%).6 Lindlar reduction then gave the homoallylic al-
cohol 4 (80%).7 This procedure proved higher yielding
and more scaleable than straightforward epoxide opening
with a vinyl Grignard reagent. Cross metathesis of alkene
4 with methyl acrylate proceeded efficiently (70% yield)
at a quite modest catalyst loading (≤1 mol%). The result-
ing hydroxy ester 5 was subjected to Evans’ conditions8 to
give the 1,3-dioxane 6 as a single isomer (68%), as in the
Jennings synthesis.4f This compound proved labile and it
was found to be more efficient to directly reduce the crude
mixture with lithium aluminum hydride to the alcohol 7,
which could be purified. IBX oxidation then gave the la-
bile aldehyde 8 in 70% yield. This two-step conversion of
ester 6 to the aldehyde 8 proved to be superior, in our
hands, to direct reduction with DIBAL-H. We intended to
introduce the reverse-prenyl moiety by a Barbier reaction
with prenyl bromide. There is surprisingly little precedent
for the stereochemical outcome of such additions to β-
substituted aldehydes.9 In the case of indium-mediated re-
actions, the vast majority of studies involve α-substitu-
tion. Aldehyde 8 was immediately subjected to Barbier
R1
R1
R2
R2
HO
R3
O
R3
Z
Z
Scheme 1 Oxa-Michael addition for THP synthesis; Z = electron-
withdrawing group
Recently, the isolation and structure of cyanolide A (1), a
symmetrical diolide with activity against Biomphalaria
glabrata, the vector of schistosomiasis, has been report-
ed.3 Following the cross metathesis and intramolecular
oxa-Michael addition strategy (Scheme 2), this molecule
would have two allylic substituents and would be ideal to
challenge this strategy at this extreme, with the option of
ozonolysis-Horner–Wadsworth–Emmons in reserve, if
metathesis failed.
Cyanolide A (1) has been the subject of several synthe-
ses,4 including a short and elegant contribution by Krische
et al.4h While She employed a Liotta–Semmelhack palla-
SYNTHESIS 2014, 46, 1731–1738
Advanced online publication: 22.04.2014
DOI: 10.1055/s-0033-1341153; Art ID: SS-2014-T0094-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

1732
R. W. Bates, T. G. Lek
PAPER
addition using prenyl bromide. Three metals were em-
ployed, Sn(II), In(0), and Zn(0) (Table 1). In each case,
the same diastereoisomer 9 was found to be the major
product. The Mukaiyama conditions10 (Table 1, entry 2)
using tin(II) gave modest diastereoselectivity and the low-
est yield. The use of indium11 in DMF gave a higher yield,
but a similar diastereoselectivity at room temperature (en-
try 3). Both the yield and the diastereoselectivity could be
improved by employing lower temperatures (entries 4 and
5). Addition of lanthanum triflate12 also provided some
enhancement of the reaction, as did the addition of other
(cheaper) Lewis acids (entries 7 to 10). The use of zinc un-
der Luche conditions13 gave the optimum result (entry 1)
with the formation of a mixture of two diastereoisomers in
a 4:1 ratio, and in 87% yield. This is in contrast to the re-
sults of She4c who obtained a 1:1 ratio for a substrate with
a free alcohol group under similar conditions. The minor
isomer of 9 proved to be crystalline and X-ray
crystallography14 showed that it possessed the all syn ox-
ygenation pattern, indicating that the major isomer pos-
sessed the desired anti-syn pattern. This is consistent with
axial addition of an in situ generated prenyl nucleophile to
the aldehyde group of the substrate in the form of chelate
complex 10. The diastereoselectivity varies from approx-
imately 2:1 (entries 2–4) to 4:1 (entries 1 and 8). In each
case, metal ions capable of effective coordination are
present. It may be noted that diastereoselectivity is lower
in DMF, a strongly coordinating solvent, although this can
be largely ameliorated by the use of lower temperatures
(entries 5 and 6). In general, however, zinc proved to be
both an effective and economical choice.
1.
Li.en
2. H2, Lindlar's catalyst
O
OH
2
63%
4
MeO2C
Grubbs II
PhCHO
KOt-Bu
MeO2C
OH
68%
70%
5
6 R = CO2Me
7 R = CH2OH
8 R = CHO
LiAlH4
R
O
O
IBX
70%
Ph
Et
O
O
O
Ph
Br
see Table 1
OH
O
O
Mn+
Ph
10
9
Nu
Scheme 3 Cyanolide A synthesis: the first part
the reaction of the alcohol 9 with thiogylcoside 11, acti-
vated by methyl triflate and buffered with a bulky pyri-
dine,4a a very slow reaction was observed (120 h) in
diethyl ether giving a 45% yield of the desired β-glycoside
12, but as a single diastereoisomer (Table 2, entry 1),
while use of a greater excess of reagents for an even lon-
ger time, raised the yield, but eroded the diastereoselectiv-
ity (entry 2). Use of other solvents gave much lower yields
(entries 3 to 6). This stands in contrast to the reports of
glycosylation after THP formation in which the reaction is
more facile, but the stereoselectivity is much lower. It ap-
pears that the greater bulk of the acyclic system slows the
reaction but enhances the selectivity. Use of N-iodosuc-
cinimide (NIS) and triflic acid (entries 6 and 7), or NIS
and TMS triflate15 (entries 8–10), or the benzenesulfinyl
morpholine (BSM)-triflic anhydride combination16 (entry
11) as the activating agents did not give results that were
At this point, we wished to protect the free alcohol group
of Barbier adduct 9. Rather than using a standard protect-
ing group, we decided to take the opportunity of installing
the trimethylxylose moiety (Table 2, Scheme 4). Most
other syntheses leave this operation to a late or even final
stage. Interestingly, under the conditions often employed,
Table 1 Barbier Reactions: Aldehyde 8 and Prenyl Bromide
Entry
Reagent(s)
Solvent
Time (h)
Temp ( °C)
Yield (%)a
anti/syn
1
2
Zn
aq NH4Cl–THF (5:1)
DMF–H2O (8:1)
DMF–AcOH (2:1)
DMF–AcOH (2:1)
DMF–AcOH (2:1)
aq NH4Cl–THF (5:1)
aq NH4Cl–THF
18
42
18
18
18
18
18
3
0
87
55b
75
89
90
90
93
85b
91
92
80:20
69:31
67:33
68:32
74:26
78:22
77:23
80:20
75:25
76:24
SnCl2, NaI
In
r.t
3
r.t.
–10
–40
–40
r.t
4
In
5
In
6
In
7
In, La(OTf)3
In, La(OTf)3
In, ZnCl2
In, CeCl3
8
aq NH4Cl, )))
r.t
9
aq NH4Cl–THF
18
18
r.t
10
aq NH4Cl–THF
r.t
a Combined yield of anti- and syn-isomers.
b Incomplete reaction.
Synthesis 2014, 46, 1731–1738
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Cyanolide A
1733
Table 2 Glycosylation of Alcohol 9
Entry
Reagent(s)a
Solvent
Time (h)b
Temp ( °C)
Yield (%)c
α/β
1
2
MeOTf
Et2O
120
144
o.n.
96
r.t.
45
β only
20:80
–
MeOTf
Et2O
r.t.
61
3
MeOTf
THF
r.t.
0 (dec.)
28
4
MeOTf
MeCN
r.t.
1:1
5
MeOTf
CH2Cl2
48
r.t.
55
50:50
67:33
72:28
31:69
99 β
6
NIS, TfOH
NIS, TfOH
NIS, TMSOTf
NIS, TMSOTf
NIS, TMSOTf (× 2)
BSM, Tf2O
CH2Cl2
20
–15 to r.t.
–15 to r.t.
–55
60
7
MeCN
20
20d
50d
30
8
CH2Cl2–MeCN (1:3)
CH2Cl2–MeCN–EtCN (1:1:2)
CH2Cl2–MeCN–EtCN (1:1:2)
CH2Cl2
o.n.
o.n.
o.n.
0.5
9
–80
10
11
–80
50d
50
30:70
74:26
–75 to r.t.
a All reactions were run in the presence of activated 4 Å molecular sieves and DTBMP, except entry 9 (4 Å MS only).
b o.n.: overnight.
c Yield of isolated β-anomer.
d Incomplete reaction.
an overall improvement. Indeed, to obtain good β-selec- sodium hydride in refluxing THF to give the desired al-
tivity with NIS activation required the use of very low kene 15 in 60% yield. Use of the Sinisterra conditions19
temperatures (entries 8–10).
[Ba(OH)2] with this hindered aldehyde resulted in a mere
25% yield. Alkene 15 incorporates the α-silyloxyketone
acceptor moiety that we employed previously to ensure
stereoselective cyclisation under very mild conditions in
tandem with deprotection.2b The benzylidene acetal was
then cleaved using methanolic camphorsulfonic acid to
give tetrahydropyran 16 directly in 65% yield with ac-
companying cleavage of the TBS ether. As expected using
a ketonic acceptor, the THP ring was obtained as a single,
2,6-cis-diastereoisomer. The synthesis was then complet-
ed by cleavage of the α-hydroxy ketone moiety to carbox-
ylic acid 17 with sodium periodate on silica gel,20
followed by macrodimerisation in 60% yield by the meth-
Attempts to carry out the cross metathesis17 of alkene 12
with methyl vinyl ketone (as a model Michael acceptor)
using the Grubbs II catalyst, the Hoveyda–Grubbs II cat-
alyst, and the Stewart–Grubbs catalyst,18 developed for
hindered alkenes, were all fruitless, giving none of the de-
sired product. Instead, ozonolysis of the double bond gave
aldehyde 13 in 80% yield. This required reductive workup
with triphenylphosphine as the ozonide was stable to di-
methyl sulfide. Phosphonate 14 was prepared by the reac-
tion of the TBS ether of methyl glycolate with the lithium
anion of methyl diethylphosphonate. The Horner–
Wadsworth–Emmons reaction was then carried out using
Sp-Tol
O
1. O3; Ph3P
(EtO)2(O)P
MeO
OMe
2.
OTBS
OMe
11
OH
O
O
O
O
O
O
NaH
O
14
Ph
Ph
seeTable 2
48%
MeO
OMe
9
OMe
12
O
H
OH
O
O
O
O
O
O
O
MBNA, DMAP
60%
CSA, MeOH
65%
TBSO
1
H
Ph
X
MeO
OMe
MeO
OMe
OMe
OMe
15
16 X = COCH2OH
17 X = CO2H
NaIO4•SiO2
93%
Scheme 4 Completion of the cyanolide A synthesis
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1731–1738

1734
R. W. Bates, T. G. Lek
PAPER
1H NMR (400 MHz, CDCl3): δ = 5.90–5.73 (m, 1 H), 5.19–5.08 (m,
2 H), 3.57 (m, 1 H), 2.36–2.26 (m, 1 H), 2.18–2.08 (m, 1 H), 1.55–
1.43 (m, 2 H), 1.02–0.89 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 135.1, 118.2, 72.2, 41.6, 29.7,
10.1.
od of Shiina using 2-methyl-6-nitrobenzoic anhydride
(MNBA).4h,21 The sample of cyanolide A (1) obtained was
spectroscopically and chiroptically identical to those re-
21
ported {[α]D21 –51.3 (c 0.15, CHCl3); Lit.3,4h [α]D –59
(c 0.6, CHCl3), –41.92 (c 0.33, CHCl3)} and was obtained
in 1.2% overall yield in 13 steps from epoxide 2. This syn-
thesis shows that disubstitution in the allylic position of
the oxa-Michael addition precursor prevents the use of
cross metathesis using the current catalysts, but the Horn-
er–Wadsworth–Emmons reaction is still viable. On the
other hand, the oxa-Michael addition itself appears to be
unaffected by the disubstitution. Presumably, any delete-
rious effect on the reaction due to steric hindrance is com-
pensated by the benefits of the Thorpe–Ingold effect. In
addition, this synthesis of cyanolide A illustrates that, giv-
en an appropriate protecting group, Barbier additions to β-
Methyl (R,E)-5-Hydroxyhept-2-enoate (5)
A solution of Grubbs II catalyst (143 mg, 0.168 mmol) in CH2Cl2 (5
mL) was added in 4 portions over 4 h to a solution of 4 (2.40 g, 24.0
mmol) and methyl acrylate (6.20 g, 47.6 mmol) in CH2Cl2 (20 mL)
under N2. The mixture was heated at reflux overnight, then concen-
trated in vacuo. The residue was distilled (75 °C/0.5 Torr) and puri-
fied by flash chromatography on silica gel (5–20% EtOAc–hexane)
22
to give 5 as a colourless oil; yield: 2.65 g (70%); [α]D –11.5 (c
1.03, CHCl3); Rf = 0.24 (1: 3 EtOAc–hexane).
IR (neat): 3428, 1730, 1715, 1659, 1651 cm–1.
1H NMR (396 MHz, CDCl3): δ = 6.99 (dt, J = 15.0, 7.4 Hz, 1 H),
5.90 (dd, J = 15.5, 0.7 Hz, 1 H), 3.76–3.65 (m, 1 H), 3.73 (s, 3 H),
substituted aldehydes can proceed with synthetically use- 2.46–2.28 (m, 2 H), 1.68–1.41 (m, 3 H), 0.96 (dd, J = 7.7, 7.2 Hz, 3
H).
ful diastereoselectivity.
13C NMR (100 MHz, CDCl3): δ = 166.8, 145.6, 123.5, 72.0, 51.6,
39.8, 30.1, 10.0.
MS (ESI): m/z = 181.1 [M + Na]+.
All reactions requiring anhydrous conditions were carried out under
a N2 atmosphere using oven-dried glassware (120 °C), which was
HRMS (EI): m/z calcd for C8H15O3 [M + H]+: 159.1021; found:
159.1029.
cooled under vacuum. Anhydrous THF was obtained by distillation
from sodium metal and benzophenone under N2. CH2Cl2 and MeCN
were dried by distillation from CaH2 immediately prior to use under
N2. MeOH was dried by distillation from activated Mg under N2.
All other solvents and reagents were used as received. Flash chro-
matography was carried out on silica gel 230–400 mesh.
1H NMR spectra were recorded at 300, 400, or 500 MHz in CDCl3
solutions. 13C NMR spectra were recorded at the corresponding fre-
quency on the same instruments at 75, 100, or 125 MHz. Chemical
shifts are recorded in ppm and coupling constants are recorded in
Hz. Optical rotations are given with units of 10–1deg·cm2·g–1. Rota-
tions were measured at a wavelength of 589 nm. Melting points are
uncorrected.
Methyl 2-[(4R,6R)-6-Ethyl-2-phenyl-1,3-dioxan-4-yl]acetate (6)
Freshly distilled benzaldehyde (2.36 g, 2.3 mL, 22.2 mmol) fol-
lowed by t-BuOK solution (1 M in THF, 4 mL, 4 mmol) were added
to a solution of 5 (3.2 g, 20.2 mmol) in THF (30 mL) at 0 °C under
N2. The addition of benzaldehyde (2.36 g, 2.3 mL, 22.2 mmol) and
t-BuOK solution (4 mL, 4 mmol) was repeated twice at 15 min in-
tervals at 0 °C. The mixture was quenched with excess pH 7 phos-
phate buffer (100 mL) and extracted with Et2O (3 × 30 mL). The
combined organic layers were washed with brine (40 mL), dried
(MgSO4), and concentrated in vacuo. The residue was purified by
flash chromatography on silica gel (1–5% EtOAc–hexane) to give
6 as a colourless oil; yield: 3.6 g (68%); [α]D22 + 2.7 (c 1.03, CHCl3);
Rf = 0.66 (1:3 EtOAc–hexane).
(R)-Hex-5-yn-3-ol (3)
A solution of (R)-(+)-1,2-epoxybutane (2; 8.35 g, 115 mmol) in an-
hydrous DMSO (5 mL) was added dropwise to a suspension of lith-
ium acetylide ethylenediamine complex (16 g, 174 mmol) in
anhydrous DMSO (50 mL) at 5 °C under N2. The mixture was
stirred at 5 °C for 45 min, then at r.t. overnight. The mixture was
poured into ice water (150 mL) and stirred until effervescence
ceased. The mixture was neutralised with aq 20% HCl and the solu-
tion was extracted with Et2O (3 × 60 mL). The combined organic
layers were washed with dilute NaHCO3 (30 mL) and brine (50
mL), dried (MgSO4), and concentrated. The residue was purified by
short-path distillation (155 °C/1 atm) to give 3 as a colourless oil;
yield: 8.96 g (91.3 mmol, 79%); [α]D23 –5.0 (c 1.04, CHCl3) {Lit.6
S-enantiomer [α]D20 +5.4 (c 1.16, CHCl3)}.
IR (neat): 2963, 1738, 1437, 1348, 1217, 1171, 1138, 1099, 1028
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.54–7.46 (m, 2 H), 7.41–7.29 (m,
3 H), 5.56 (s, 1H ), 4.31 (dtd, J = 11.3, 6.7, 2.4 Hz, 1 H), 3.82–3.73
(m, 1 H), 3.71 (s, 3 H), 2.75 (dd, J = 15.7, 7.0 Hz, 1 H), 2.53 (dd,
J = 15.7, 6.2 Hz, 1 H), 1.76–1.74 (m, 1 H), 1.72–1.54 (m, 2 H), 1.41
(dt, J = 12.9, 11.2 Hz, 1 H), 1.00 (t, J = 7.5 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 171.2, 138.6, 128.6, 128.1, 126.1,
100.6, 77.9, 73.2, 51.7, 40.8, 36.1, 28.8, 9.5.
MS (ESI): m/z = 287.2 [M + Na]+.
HRMS (EI): m/z calcd for C15H21O4 [M + H]+: 265.1440; found:
1H NMR (396 MHz, CDCl3): δ = 3.67–3.72 (m, 1 H), 2.44 (ddd, J =
16.7, 4.7, 2.6 Hz, 1 H), 2.32 (ddd, J = 16.7, 6.8, 2.7 Hz, 1 H), 2.05
(dd, J = 3.5, 1.7 Hz, 1 H), 1.85 (s, 1 H), 1.73–1.48 (m, 2 H), 0.97 (t,
J = 7.5 Hz, 3 H).
265.1440.
2-[(2R,4S,6R)-6-Ethyl-2-phenyl-1,3-dioxan-4-yl]ethanol (7)
LiAlH4 (0.392 g, 10.3 mmol) was added portionwise to a solution
of 6 (1.82 g, 6.89 mmol) in Et2O (30 mL) cooled in an ice water bath
under N2. The mixture was stirred for 2 h at r.t., then quenched cau-
tiously with H2O in an ice bath until no further effervescence was
observed and a white precipitate had formed. The mixture was fil-
tered through a pad of Celite, dried (MgSO4), and concentrated in
vacuo to give 7 as a colourless solid, which was used without further
13C NMR (100 MHz, CDCl3): δ = 81.0, 71.3, 70.8, 29.2, 27.0, 10.0.
(R)-Hex-5-en-3-ol (4)
A solution of 3 (1.5 g, 15.3 mmol) in Et2O (30 mL) containing
Lindlar’s catalyst (0.15 g) was stirred under H2 at r.t. for 2 h. The
mixture was flushed with N2, filtered through a pad of Celite, and
the solvent was evaporated carefully by distillation to give 4 as a co-
lourless oil (1.226 g, 80%), which was used without further purifi-
22
purification (1.62 g, quant); mp 69–72 °C; [α]D –8.9 (c 0.55,
CHCl3).
23
23
cation; [α]D +4.1 (c 1.01, CHCl3) {Lit.22 [α]D +5.3 (c 10.76,
IR (mull): 3393, 2951, 2723, 1641, 1346, 1153, 1053, 1020 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.49 (dd, J = 3.9, 1.8 Hz, 2 H),
benzene)}.
7.39–7.31 (m, 3 H), 5.55 (s, 1 H), 4.12–4.06 (m, 1 H), 3.88–3.82 (m,
Synthesis 2014, 46, 1731–1738
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Cyanolide A
1735
2 H), 3.79–3.72 (m, 1 H), 2.15 (t, J = 5.2 Hz, 1 H), 2.00–1.77 (m, 2
H), 1.77–1.43 (m, 5 H), 1.00 (t, J = 7.5 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 138.9, 128.9, 128.4, 126.2, 100.9,
Minor Isomer
Mp 45–48 °C; [α]D21 +3.2 (c 0.48, CHCl3); Rf = 0.57 (1:3 EtOAc–
hexane).
IR (neat): 3516, 2961, 2872, 1638, 1454, 1410, 1346, 1215, 1099,
1016 cm–1.
78.3, 76.3, 60.7, 38.3, 36.6, 29.0, 9.7.
MS (ESI): m/z = 259.2 [M + Na]+.
HRMS (EI): m/z calcd for C14H21O3 [M + H]+: 237.1491; found:
237.1505.
1H NMR (396 MHz, CDCl3): δ = 7.47 (dd, J = 7.6, 1.9 Hz, 2 H),
7.36–7.29 (m, 3 H), 5.86 (dd, J = 17.3, 11.0 Hz, 1 H), 5.56 (s, 1 H),
5.03 (ddd, J = 10.8, 6.1, 1.4 Hz, 2 H), 4.14–4.03 (m, 1 H), 3.81–3.70
(m, 1 H), 3.63–3.56 (m, 1 H), 3.17 (d, J = 1.8 Hz, 1 H), 1.77–1.38
(m, 6 H), 1.02 (s, 3 H), 1.01 (s, 3 H), 0.98 (t, J = 7.5 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 145.6, 138.4, 128.8, 128.4, 126.1,
112.58, 100.9, 78.3, 78.2, 78.0, 41.3, 37.6, 36.7, 28.8, 23.2, 22.2,
9.5.
2-[(4R,6R)-6-Ethyl-2-phenyl-1,3-dioxan-4-yl]acetaldehyde (8)
Compound 7 (0.953 g, 4.03 mmol) was added to a solution of 2-io-
doxybenzoic acid (IBX, 1.69 g, 6.05 mmol) in DMSO (40 mL). The
mixture was stirred overnight at r.t. H2O (40 mL) and Et2O (40 mL)
were added and the mixture was filtered through a pad of Celite.
The organic layers were separated and the aqueous layer was ex-
tracted with Et2O (3 × 30 mL). The combined organic layers were
dried (MgSO4), and concentrated in vacuo. The residue was purified
by flash chromatography on silica gel (15% EtOAc–hexane) to give
MS (ESI): m/z = 327.3 [M + Na]+.
HRMS (ESI): m/z calcd for C14H19O3 + Na [M + Na]+: 327.1936;
found: 327.1932.
22
8 as a colourless viscous oil; yield: 0.83 g (88%); [α]D +2.3 (c
0.58, CHCl3) {Lit.15 [α]D23 +1.2 (c 0.049, C2H2Cl2)}; Rf = 0.33 (1:3
Thioglycoside 11
NaH (7.96 g of a 60% w/w suspension in mineral oil, 200 mmol)
was added slowly, portionwise to a solution of p-tolyl-1-thio-β-D-
xylopyranoside24 (6.50 g, 25.8 mmol) in anhydrous DMSO (60 mL)
under N2 and cooled in an ice water bath. Additional anhydrous
DMSO (20 mL) was added to the slurry and MeI (9.5 mL, 152
mmol) in anhydrous DMSO (10 mL) was added slowly to the reac-
tion mixture over a period of 1 h. The mixture was stirred for anoth-
er hour in an ice water bath and then allowed to warm to r.t.
overnight. The reaction was quenched with MeOH (1 mL) and
stirred for a further 20 min. The mixture was diluted with EtOAc
(50 mL) and H2O (100 mL). The aqueous layer was extracted with
EtOAc (2 × 40 mL) and the combined organic layers were dried
(MgSO4), filtered, and concentrated in vacuo. The residue was pu-
rified by chromatography on silica gel (10–15% EtOAc–hexane) to
EtOAc–hexane).
IR (neat): 3034, 2964, 2874, 2729, 1727, 1452, 1400, 1344, 1158,
1136, 1107, 1063, 1026 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.86 (t, J = 1.8 Hz, 1 H), 7.49 (dd,
J = 7.7, 1.5 Hz, 2 H), 7.39–7.29 (m, 3 H), 5.58 (s, 1 H), 4.47–4.37
(m, 1 H), 3.83–3.75 (m, 1 H), 2.82 (ddd, J = 16.8, 7.3, 2.1 Hz, 1 H),
2.62 (ddd, J = 16.8, 5.2, 1.6 Hz, 1 H), 1.77–1.68 (m, 2 H), 1.64–1.53
(m, 1 H), 1.52–1.40 (m, 1 H), 1.00 (t, J = 7.5 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 200.5, 138.5, 128.8, 128.3, 126.1,
100.8, 78.1, 72.0, 49.6, 36.3, 28.8, 9.5.
MS (ESI): m/z = 257.2 [M + Na]+.
HRMS (ESI): calcd for C14H19O3 [M + H]+: 235.1334; found:
235.1330.
21
give 11 as a colourless low melting solid; yield: 5.6 g (73%); [α]D
–8.5 (c 5.4, CHCl3); Rf = 0.45 (1:3 EtOAc–hexane).
Barbier Adduct 9
IR (neat): 2976, 2932, 2901, 2832, 1633, 1597, 1492, 1445, 1180,
1159, 1130, 1098 cm–1.
1H NMR (396 MHz, CDCl3): δ = 7.44–7.40 (m, 2 H), 7.13–7.09 (m,
2 H), 4.50 (d, J = 8.9 Hz, 1 H), 4.10 (dd, J = 11.3, 4.6 Hz, 1 H), 4.03–
3.95 (m, 1 H), 3.62 (s, 3 H), 3.60 (s, 3 H), 3.46 (s, 3 H), 3.23–3.11
(m, 2 H), 3.03 (dd, J = 8.8, 8.1 Hz, 1 H), 2.33 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 137.8, 132.7, 132.2, 129.8, 129.8,
88.2, 86.6, 82.0, 79.2, 66.5, 60.7, 58.7, 21.2.
MS (ESI): m/z = 321.16 [M + Na]+.
HRMS (ESI): m/z calcd for C15H22O4S + Na [M + Na]+: 321.1137;
Aldehyde 8 (1.0 g, 4.31 mmol, 1 equiv) and prenyl bromide23 (1.4
g, 9.45 mmol) was dissolved in a mixture of sat. aq NH4Cl and THF
(5:1, 30 mL). The mixture was cooled in an ice bath. Activated Zn
powder (0.62 g, 9.45 mmol) was added portionwise over 15 min.
The mixture was stirred for 1 h in the ice bath and at r.t. overnight.
Et2O (15 mL) was added and the mixture was filtered through a pad
of Celite. The layers were separated and the aqueous layer was ex-
tracted with Et2O (3 × 15 mL). The combined organic layers were
dried (MgSO4) and concentrated in vacuo. The residue was purified
by flash chromatography on silica gel (10% EtOAc–hexane) to give
the major isomer anti-9 (0.692 g, 69%) as a colourless viscous oil
and the minor isomer syn-9 (0.171 g, 17%) as a colourless crystal-
line solid.
found: 321.1134.
Glycoside 12
A solution of alcohol anti-9 (0.457 g, 1.50 mmol), thioglycoside 11
(1.12 g, 3.75 mmol), and 2,6-di-tert-butyl-4-methylpyridine (DT-
BMP, 0.923 g, 4.5 mmol) in Et2O (35 mL) containing 4Å MS (~80
mg) under N2 was stirred at r.t. for 15 min. MeOTf (0.863 g, 0.6 mL,
5.25 mmol) was added and the mixture was stirred for 5 days at r.t.
The reaction was quenched with sat. aq NaHCO3 (30 mL), diluted
with Et2O (20 mL), and filtered through a pad of Celite. The layers
were separated and the aqueous layer was extracted with Et2O (2 ×
20 mL). The combined organic layers were dried (MgSO4) and con-
centrated in vacuo. The residue was purified by flash chromatogra-
phy on silica gel (5–10% EtOAc–hexane) to give 12 as a colourless
viscous oil; yield: 0.442 g (61%).
Major Isomer
[α]D22 –32.0 (c 0.49, CHCl3); Rf = 0.53 (1:3 EtOAc–hexane).
IR (neat): 3499, 2963, 1738, 1638, 1454, 1344, 1138, 1101, 1067,
1028, 1015 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.50 (dd, J = 7.8, 1.5 Hz, 2 H),
7.39–7.29 (m, 3 H), 5.85 (dd, J = 17.5, 10.8 Hz, 1 H), 5.53 (s, 1 H),
5.07 (ddd, J = 16.8, 12.0, 1.4 Hz, 2 H), 4.12 (ddt, J = 10.9, 8.0, 2.9
Hz, 1 H), 3.81–3.67 (m, 2 H), 2.09 (d, J = 3.9 Hz, 1 H), 1.82–1.64
(m, 2 H), 1.62–1.45 (m, 4 H), 1.02 (s, 3 H), 1.01 (s, 3 H), 0.99 (t, J =
7.5 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 145.5, 139.1, 128.7, 128.3, 126.2,
113.4, 100.8, 78.4, 74.6, 73.9, 41.4, 37.5, 36.6, 29.0, 23.1, 22.3, 9.7.
MS (ESI): m/z = 327.3 [M + Na]+.
β-Anomer
[α]D21 –69.3 (c 0.26, CHCl3); Rf = 0.50 (1:3 EtOAc–hexane).
HRMS (ESI): m/z calcd for C14H19O3 + Na [M + Na]+: 327.1936;
found: 327.1932.
IR (neat): 3489, 2964, 2245, 1740, 1638, 1454, 1406, 1346, 1215,
1161, 1136, 1103 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1731–1738

1736
R. W. Bates, T. G. Lek
PAPER
1H NMR (396 MHz, CDCl3): δ = 7.54–7.47 (m, 2 H), 7.39–7.29 (m,
3 H), 5.92 (dd, J = 17.9, 10.4 Hz, 1 H), 5.47 (s, 1 H), 5.04–4.96 (m,
2 H), 4.30 (d, J = 7.7 Hz, 1 H), 4.20 (t, J = 10.9 Hz, 1 H), 3.85 (dd,
J = 11.5, 5.2 Hz, 1 H), 3.80–3.70 (m, 2 H), 3.63 (s, 3 H), 3.62 (s, 3
H), 3.44 (s, 3 H), 3.28–3.18 (m, 1 H), 3.13–2.92 (m, 3 H), 1.79–1.63
(m, 2 H), 1.60–1.42 (m, 3 H), 1.38–1.26 (dd, J = 23.8, 11.2 Hz, 1
H), 1.09 (s, 3 H), 1.08 (s, 3 H), 0.99 (t, J = 7.5 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 145.5, 139.7, 128.4, 128.2, 126.1,
112.2, 105.0, 100.2, 86.2, 84.6, 82.9, 79.9, 78.4, 72.9, 63.5, 61.0,
59.0, 42.2, 38.2, 37.30, 29.1, 24.7, 22.3, 9.7.
IR (neat): 2981, 2955, 2857, 2359, 1734, 1630, 1472, 1393, 1152,
1024 cm–1.
1H NMR (396 MHz, CDCl3): δ = 4.29 (s, 2 H), 4.18–4.09 (m, 4 H),
3.16 (d, J = 22.6 Hz, 2 H), 1.33 (td, J = 7.1, 0.5 Hz, 6 H), 0.91 (s, 9
H), 0.10–0.08 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 201.8 (d, J = 6.7 Hz), 69.7, 62.7
(d, J = 7.0 Hz), 37.5 (d, J = 128.8 Hz), 25.9, 18.5, 16.5 (d, J = 6.7
Hz), –5.3.
MS (ESI): m/z = 325.08 [M + H]+.
HRMS (ESI): m/z calcd for C13H29O5PSi + Na [M + Na]+:
MS (ESI): m/z = 501.5 [M + Na]+.
HRMS (ESI): m/z calcd for C27H42O7 + Na [M + Na]+: 501.2828;
347.1420; found: 347.1389.
found: 501.2827.
Alkene 15
A solution of phosphonate 14 (0.22 g, 0.66 mmol) in anhydrous
THF (2 mL) and added slowly to a stirred mineral oil suspension of
NaH (0.026 g (60% w/w), 0.66 mmol) in anhydrous THF (2 mL)
under N2. The mixture was stirred at r.t. for 10 min. A solution of
aldehyde 13 (0.080 g, 0.17 mmol) in anhydrous THF (2 mL) was
added and the mixture was heated at reflux for 24 h. The mixture
was quenched with sat. aq NH4Cl (10 mL) and extracted with EtO-
Ac (3 × 15 mL). The combined organic layers were dried (MgSO4),
and concentrated in vacuo. The residue was purified by flash chro-
matography on silica gel (20% EtOAc–hexane) to give 15 as a co-
lourless oil; yield: 0.066 g (60%); [α]D22 –90.6 (c 0.47, CHCl3); Rf =
0.32 (1:3 EtOAc–hexane).
α-Anomer
[α]D20 +27.6 (c 0.42, CHCl3); Rf = 0.45 (1:3 EtOAc–hexane).
1H NMR (400 MHz, CDCl3): δ = 7.50 (d, J = 6.8 Hz, 2 H), 7.41–
7.30 (m, 3 H), 5.98–5.87 (m, 1 H), 5.51 (s, 1 H), 5.04–4.94 (m, 3 H),
4.31 (t, J = 10.7 Hz, 1 H), 3.77–3.67 (m, 2 H), 3.63 (s, 3 H), 3.66–
3.60 (m, 2 H), 3.53 (s, 3 H), 3.48 (s, 3 H), 3.49–3.41 (m, 1 H), 3.23
(dt, J = 15.9, 8.1 Hz, 1 H), 3.13 (dd, J = 9.6, 3.7 Hz, 1 H), 1.88–1.79
(m, 1 H), 1.74–1.50 (m, 3 H), 1.40–1.29 (m, 2 H), 1.07 (s, 3 H), 1.05
(s, 3 H), 0.99 (t, J = 7.5 Hz, 3 H).
MS (ESI): m/z = 501.5 [M + Na]+.
HRMS (ESI): m/z calcd for C27H42O7 + Na [M + Na]+: 501.2828;
IR (neat): 2957, 2931, 2857, 2247, 1715, 1694, 1622, 1454, 1344,
1257, 1161, 1103, 1076 cm–1.
found: 501.2837.
1H NMR (396 MHz, CDCl3): δ = 7.49 (d, J = 6.9 Hz, 2 H), 7.42–
7.23 (m, 3 H), 7.06 (d, J = 16.3 Hz, 1 H), 6.36 (d, J = 16.3 Hz, 1 H),
5.46 (s, 1 H), 4.33 (s, 2 H), 4.25 (d, J = 7.6 Hz, 1 H), 4.19 (t, J = 10.7
Hz, 1 H), 3.86 (dd, J = 11.5, 5.3 Hz, 1 H), 3.81 (d, J = 9.4 Hz, 1 H),
3.78–3.71 (m, 1 H), 3.62 (s, 6 H), 3.44 (s, 3 H), 3.35–3.15 (m, 1 H),
3.13–2.89 (m, 3 H), 1.75–1.62 (m, 2 H), 1.60–1.41 (m, 3 H), 1.40–
1.29 (m, 1 H), 1.16 (s, 3 H), 1.12 (s, 3 H), 0.99 (t, J = 7.4 Hz, 3 H),
0.92 (s, 9 H), 0.09 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 198.8, 153.8, 139.5, 128.4, 128.2,
126.0, 123.2, 104.8, 100.2, 86.1, 84.4, 82.4, 79.7, 78.2, 72.5, 68.6,
63.5, 61.0, 60.9, 58.9, 42.5, 38.2, 37.1, 29.0, 25.9, 23.6, 23.0, 18.4,
9.7, –5.3.
Aldehyde 13
Ozone in oxygen was passed through a solution of glycoside 12
(0.27 g, 0.57 mmol) in CH2Cl2 (20 mL) at –78 °C until the solution
became blue. Ozone was passed through the solution for another 10
min. The excess ozone was flushed out with oxygen for 15 min. A
solution of Ph3P (0.44 g, 1.7 mmol) in CH2Cl2 (5 mL) was added at
–78 °C. The mixture was allowed to warm to r.t. and stirred over-
night. The mixture was concentrated in vacuo and purified by flash
chromatography on silica gel (20% EtOAc–hexane) to give 13 as a
colourless crystalline solid: yield: 0.22 g (80%); mp 93–95 °C;
[α]D20 –122.0 (c 0.73, CHCl3); Rf = 0.24 (1:3 EtOAc–hexane).
IR (neat): 2962, 2934, 2833, 1726, 1458, 1404, 1344, 1215, 1161,
1101, 1078 cm–1.
MS (ESI): m/z = 673.6 [M + Na]+.
HRMS (ESI): m/z calcd for C35H58O9Si + Na [M + Na]+: 673.3748;
1H NMR (396 MHz, CDCl3): δ = 9.63 (s, 1 H), 7.49 (d, J = 7.4 Hz,
2 H), 7.39–7.31 (m, 3 H), 5.47 (s, 1 H), 4.26 (d, J = 7.8 Hz, 1 H), 4.
24–4.19 (m, 1 H), 4.15 (dd, J = 9.0, 2.0 Hz, 1 H), 3.89 (dd, J = 11.5,
5.3 Hz, 1 H), 3.81–3.72 (m, 1 H), 3.61 (s, 3 H), 3.55 (s, 3 H), 3.45
(s, 3 H), 3.26–3.18 (m, 1 H), 3.13–2.99 (m, 2 H), 2.91 (dd, J = 8.9,
7.8 Hz, 1 H), 1.73–1.51 (m, 5 H), 1.43–1.30 (m, 1 H), 1.15 (s, 3 H),
1.08 (s, 3 H), 0.99 (t, J = 7.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 205.6, 139.4, 128.6, 128.3, 126.2,
126.1, 105.0, 100.3, 86.1, 84.2, 80.6, 79.7, 78.3, 72.5, 63.5, 61.0,
59.0, 51.3, 38.0, 37.1, 29.0, 19.1, 17.9, 9.7.
found: 673.3725.
Tetrahydropyran 16
A solution of 15 (0.12 g, 0.18 mmol) and CSA (0.017 g, 72 μmol)
in MeOH (3 mL) was stirred overnight at r.t. The mixture was con-
centrated in vacuo and the residue was purified by flash chromatog-
raphy on silica gel (80% EtOAc–hexane) to give 16 as a colourless
viscous oil; yield: 0.052 g (65%); [α]D21 –47.7 (c 0.22, CHCl3); Rf =
0.18 (7:3 EtOAc–hexane).
MS (ESI): m/z = 504.2 [M + Na]+.
HRMS (ESI): m/z calcd for C26H40O8 + Na [M + Na]+: 503.2621;
IR (neat): 3584, 3418, 2965, 2936, 2878, 1726, 1715, 1622, 1470,
1454, 1391, 1163, 1093 cm–1.
found: 501.2614.
1H NMR (396 MHz, CD2Cl2): δ = 4.32–4.13 (m, 3 H), 3.91 (dd, J =
11.6, 5.2 Hz, 1 H), 3.68–3.53 (m, 3 H), 3.56 (s, 3 H), 3.56 (s, 3 H),
3.42 (s, 3 H), 3.32 (dd, J = 11.6, 4.8 Hz, 1 H), 3.19 (ddd, J = 9.8, 8.6,
5.2 Hz, 1 H), 3.05 (td, J = 10.1, 2.0 Hz, 2 H), 2.90 (dd, J = 8.9, 7.6
Hz, 1 H), 2.74–2.49 (m, 3 H), 2.44 (dd, J = 15.8, 2.3 Hz, 1 H), 1.87
(ddd, J = 13.0, 4.7, 2.3 Hz, 1 H), 1.60–1.43 (m, 3 H), 1.43–1.29 (m,
2 H), 0.96 (s, 3 H), 0.90 (s, 3 H), 0.87 (t, J = 7.4 Hz, 3 H).
13C NMR (100 MHz, CD2Cl2): δ = 208.9, 105.9, 85.5, 84.5, 84.0,
79.9, 79.5, 77.1, 72.6, 69.0, 63.2, 60.7, 60.4, 58.5, 42.1, 38.7, 38.4,
36.8, 30.2, 21.9, 13.3, 9.6.
Phosphonate 14
n-BuLi (8.25 mL of a 1.6 M solution in hexanes, 13.2 mmol) was
added dropwise to a solution of methyl diethylphosphonate (2.15 g,
14.1 mmol) in anhydrous THF (30 mL) at –78 °C. The mixture was
stirred for 15 min. A solution of methyl glycolate TBS ether25 (1.93
g, 9.43 mmol) in THF (5 mL) was added to the mixture, which
stirred for 1 h at –78 °C and at r.t. for 2 h. The mixture was
quenched with H2O (20 mL) and extracted with EtOAc (2 × 20 mL).
The combined organic layers were dried (MgSO4) and concentrated
in vacuo. The residue was purified by flash chromatography on sil-
ica gel (50–85% EtOAc–hexane with 0.05% MeOH) to give 14 as
a colourless oil; yield: 2.14 g (70%); Rf = 0.05 (1:3 EtOAc–hexane).
MS (ESI): m/z = 471.5 [M + Na]+.
Synthesis 2014, 46, 1731–1738
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Cyanolide A
1737
HRMS (ESI): m/z calcd for C22H40O9 + Na [M + Na]+: 471.2570;
found: 471.2575.
References
(1) (a) Fuwa, H. Heterocycles 2012, 86, 1255. (b) Nising, C. F.;
Bräse, S. Chem. Soc. Rev. 2012, 41, 988. (c) Larossa, I.;
Romea, P.; Urpí, F. Tetrahedron 2008, 64, 2683. (d) Clarke,
P. A.; Santos, S. Eur. J. Org. Chem. 2006, 2045. (e) Boivin,
T. L. B. Tetrahedron 1987, 43, 3309.
(2) (a) Bates, R. W.; Song, P. Tetrahedron 2007, 63, 4497.
(b) Bates, R. W.; Song, P. Synthesis 2010, 2935. (c) Bates,
R. W.; Palani, K. Tetrahedron Lett. 2008, 49, 2832.
(3) Pereira, A. R.; McCue, C. F.; Gerwick, W. H. J. Nat. Prod.
2010, 73, 217.
Carboxylic Acid 17
NaIO4 adsorbed on silica gel (0.070 g, 0.20 mmol) was added to a
solution of tetrahydropyran 16 (0.015 g, 35 μmol) in CH2Cl2 (2 mL).
The mixture was stirred for 45 min at r.t., filtered through a pad of
Celite, and washed thoroughly with CHCl3 (3 × 10 mL) followed by
EtOAc (3 × 10 mL). The filtrate was concentrated in vacuo to give
17 as a colourless crystalline solid; yield: 0.014 g (93%); mp 170 °C
21
23
(dec.); [α]D –36.7 (c 0.30, CHCl3) {Lit.4h [α]D +50.34 (c 0.99,
benzene)}; Rf = 0.18 (7:3 EtOAc–hexane).
(4) (a) Hong, J.; Kim, H. Org. Lett. 2010, 12, 2880. (b) Hajare,
A. K.; Ravikumar, V.; Khaleel, S.; Bhuniya, D.; Reddy, D.
S. J. Org. Chem. 2011, 76, 963. (c) Yang, Z.; Xie, X.; Jing,
P.; Zhao, G.; Zheng, J.; Zhao, C.; She, X. Org. Biomol.
Chem. 2011, 9, 984. (d) Pabbaraja, S.; Satyanarayana, K.;
Ganganna, B.; Yadav, J. S. J. Org. Chem. 2011, 76, 1922.
(e) Gesinski, M. R.; Rychnovsky, S. D. J. Am. Chem. Soc.
2011, 133, 9727. (f) Sharpe, R. J.; Jennings, M. P. J. Org.
Chem. 2011, 76, 8027. (g) Tay, G. C.; Gesinski, M. R.;
Rychnovsky, S. D. Org. Lett. 2013, 15, 4536. (h) Waldeck,
A. R.; Krische, M. J. Angew. Chem. Int. Ed. 2013, 52, 4470.
(5) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.;
Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N.
J. Am. Chem. Soc. 2002, 124, 1307.
IR (neat): 3584, 3472, 2965, 2936, 2880, 1726, 1464, 1396, 1163,
1093 cm–1.
1H NMR (396 MHz, CDCl3): δ = 4.24 (d, J = 7.6 Hz, 1 H), 3.94 (dd,
J = 11.5, 5.1 Hz, 1 H), 3.81–3.73 (m, 1 H), 3.71–3.63 (m, 1 H), 3.62
(s, 3 H), 3.61 (s, 3 H), 3.54 (dd, J = 10.4, 1.4 Hz, 1 H), 3.47 (s, 3 H),
3.30 (dd, J = 11.4, 4.9 Hz, 1 H), 3.23 (ddd, J = 9.8, 8.6, 5.1 Hz, 1
H), 3.13–3.04 (m, 2 H), 2.97 (dd, J = 9.0, 7.7 Hz, 1 H), 2.51–2.33
(m, 3 H), 1.91–1.84 (m, 1 H), 1.66–1.38 (m, 5 H), 0.99 (s, 3 H), 0.90
(s, 3 H), 0.87 (t, J = 7.5 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 174.8, 106.2, 85.7, 84.9, 84.1,
81.2, 79.5, 77.9, 74.1, 63.4, 61.1, 61.0, 59.0, 40.9, 38.8, 37.1, 35.1,
29.8, 22.3, 13.6, 9.6.
MS (ESI): m/z = 457.5 [M + Na]+.
(6) For the S-enantiomer, see: Hernández-Torres, G.; Mateo, J.;
Urbano, A.; Carreño, M. C. Eur. J. Org. Chem. 2013, 6259.
(7) We found that making the catalyst following the procedure
of Lindlar gave a more reliable reaction: Lindlar, H.; Dubuis,
R. Org. Synth. Coll. Vol. 5; Wiley: New York, 1973, 880.
(8) Evans, D. A.; Gauchet-Prunet, J. A. J. Org. Chem. 1993, 58,
2446.
(9) For exceptions, in the case of indium, see: (a) Pacquette, L.
A.; Mitzel, T. M. J. Am. Chem. Soc. 1996, 118, 1931.
(b) Huang, J.-M.; Xu, K.-C.; Loh, T.-P. Synthesis 2003, 755.
(c) See also ref. 4c.
(10) Mukaiyama, T.; Harada, T. Chem. Lett. 1981, 621.
(11) (a) Shen, Z.-L.; Wang, S.-Y.; Chok, Y.-K.; Xu, Y.-H.; Loh,
T.-P. Chem. Rev. 2013, 113, 271. (b) Augé, J.; Lubin-
Germain, N.; Uziel, J. Synthesis 2007, 1739. (c) Kargbo, R.
B.; Cook, G. R. Curr. Org. Chem. 2007, 11, 1287.
(d) Podlech, J.; Maier, T. C. Synthesis 2003, 633. (e) Li, C.
J.; Chan, T.-H. Tetrahedron 1999, 55, 11149.
HRMS (ESI): m/z calcd for C22H40O9 + Na [M + Na]+: 457.2414;
found: 457.2425.
Cyanolide A (1)
A solution of carboxylic acid 17 (0.042 g, 96.7 μmol) in toluene (15
mL) was added over 5 h via a syringe pump to a solution of DMAP
(0.236 g, 1.93 mmol) and MNBA (0.100 g, 290 μmol) in anhydrous
toluene (45 mL) at 90 °C. The mixture was stirred overnight at
90 °C, then concentrated in vacuo, and purified by flash chromatog-
raphy on silica gel (60% EtOAc–hexane) to give cyanolide A (1) as
a colourless oil; yield: 0.025 g (60%); [α]D21 –51.3 (c 0.15, CHCl3);
Rf = 0.16 (2:3 EtOAc–hexane).
IR (neat): 2967, 2934, 1738, 1096 cm–1.
1H NMR (396 MHz, CDCl3): δ = 4.90 (dd, J = 14.1, 6.7 Hz, 2 H),
4.24 (d, J = 7.6 Hz, 2 H), 3.97 (dd, J = 11.6, 5.1 Hz, 2 H), 3.61 (s, 6
H), 3.60 (s, 6 H), 3.46 (s, 6 H), 3.51–3.41 (m, 4 H), 3.30 (dd, J =
11.5, 4.8 Hz, 2 H), 3.27–3.19 (m, 2 H), 3.13–3.04 (m, 4 H), 2.99–
2.92 (m, 2 H), 2.38 (dd, J = 16.2, 1.3 Hz, 2 H), 2.32–2.17 (m, 2 H),
2.00–1.93 (m, 2 H), 1.82 (dt, J = 16.3, 8.4 Hz, 2 H), 1.70–1.23 (m,
8 H), 0.95 (s, 6 H), 0.87 (s, 6 H), 0.85 (t, J = 7.6 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 171.9, 106.2, 85.9, 85.6, 84.3,
80.6, 79.6, 75.5, 74.1, 63.5, 61.2, 61.1, 59.0, 40.8, 38.9, 37.2, 35.3,
28.5, 22.3, 13.8, 9.7.
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(14) Details have been deposited with the Cambridge
Crystallographic Data Centre under deposition number
CCDC 977273, and may be obtained at
MS (ESI): m/z = 855.6 [M + Na]+.
http://www.ccdc.cam.ac.uk.
(15) Chao, C.-S.; Li, C.-W.; Chen, M.-C.; Chang, S.-S.; Mong,
K.-K. T. Chem. Eur. J. 2009, 15, 10972.
(16) Wang, C.; Wang, H.; Huang, X.; Zhang, L.-H.; Ye, X.-S.
Synlett 2006, 2846.
HRMS (ESI): m/z calcd for C42H72O16 + Na [M + Na]+: 855.4718;
found: 855.4703.
(17) (a) Connon, S. J.; Blechert, S. Angew. Chem. Int. Ed. 2003,
42, 1900. (b) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.;
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Acknowledgment
Financial support from Nanyang Technological University is grate-
fully acknowledged. We thank Professor Karol Grela (Polish Aca-
demy of Sciences and University of Warsaw) for helpful
discussions.
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Chem. 2004, 69, 1822.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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R. W. Bates, T. G. Lek
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Synthesis 2014, 46, 1731–1738
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