Synthesis of Bioactive Side-Chain Analogues of TAN-2483B

Article abstract of DOI:10.1002/asia.201801767

The fungal metabolite TAN-2483B has a 2,6-trans-relationship across the pyran ring of its furo[3,4-b]pyran-5-one core, which has thwarted previous attempts at its synthesis. We have now developed a chiral pool approach to this core and prepared side-chain

Full text of DOI:10.1002/asia.201801767

CHEMISTRY
AN ASIAN JOURNAL
www.chemasianj.org
Accepted Article
Title: Synthesis of Bioactive Side-Chain Analogues of TAN-2483B
Authors: Joanne Harvey, Kalpani K. Somarathne, Jordan A. J.
McCone, Amira Brackovic, José Luis Pinedo Rivera, J. Robin
Fulton, Euan Russell, Jessica J. Field, Christopher L. Orme,
Hedley L. Stirrat, Jasmin Riesterer, Paul H. Teesdale-Spittle,
and John H. Miller
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To be cited as: Chem. Asian J. 10.1002/asia.201801767
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A Journal of
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Chemistry - An Asian Journal
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Synthesis of Bioactive Side-Chain Analogues of TAN-2483B
[
a]
[a,b]
[a]
[a]
Kalpani K. Somarathne, Jordan A. J. McCone,
Amira Brackovic, José Luis Pinedo Rivera, J.
[
a]
[c]
[c]
[a]
[a]
Robin Fulton, Euan Russell, Jessica J. Field, Christopher L. Orme, Hedley L. Stirrat, Jasmin
[
a]
[b,c]
[c]
[a,b]
Riesterer, Paul H. Teesdale-Spittle, John H. Miller, and Joanne E. Harvey*
Abstract: The fungal metabolite TAN-2483B has
a
2,6-trans-
metabolites including members of the waols, massarilactones,
fusidilactones, scirpyranes and thiessenolactones (Figure 1b).3–7
relationship across the pyran ring of its furo[3,4-b]pyran-5-one core,
which has thwarted previous attempts at its synthesis. We have now
developed a chiral pool approach to this core and prepared side-chain
analogues of TAN-2483B. The synthesis relies on ring expansion of
a reactive furan ring-fused dibromocyclopropane and alkynylation of
the resulting pyran. The furan ring is constructed by palladium-
catalysed carbonylative lactonisation.
Various side-chains are
appended through Wittig-type chemistry. The prepared analogues
showed micromolar activity towards cancer cell lines HL-60, 1A9 and
MCF-7 and certain human disease-relevant kinases, including
Bruton’s tyrosine kinase (Btk).
Introduction
The epimeric natural products (–)-TAN-2483A and B (1 and 2)
were discovered in a filamentous fungus culture, NF 2329 (FERM
BP-5905), by workers at Takeda Chemical Industries Ltd (Figure
1
=
a).1 The former compound was found to inhibit c-Src kinase (IC50
4 μM) and PTH-induced bone resorption (76% inhibition at 10
μM concentration). More recently, isolation of a mixture of TAN-
483A and B from a fungal Seimatosporium species (CF-097474)
2
led to determination of immunomodulatory activity, with inhibition
of NO production (IC50 = 2.26 μM) and IL-8 production (100% at
29.1 μM) in RAW264.7 mouse macrophage cancer cells, and
some antimicrobial activity (100% inhibition of gram-negative
bacteria A. baumannii CL5973 and E. coli MB5746 at 114 μM).2
Structurally, TAN-2483A and B contain a furo[3,4-b]pyran-5-one
core, which is common to a small family of bioactive fungal
[
a]
Dr K. K. Somarathne, Mr J. A. J. McCone, Dr A. Brackovic, Mr J. L.
Pinedo Rivera, Dr J. R. Fulton, Mr C. L. Orme, Mr. H. L. Stirrat, Ms
J. Riesterer, Dr J. E. Harvey*
School of Chemical and Physical Sciences
Centre for Biodiscovery
Victoria University of Wellington
Wellington, NEW ZEALAND
E-mail: joanne.harvey@vuw.ac.nz
Figure 1. a) TAN-2483A and B. b) Representative furo[3,4-b]pyran-5-one
[
[
b]
c]
Maurice Wilkins Centre for Molecular Biodiscovery
NEW ZEALAND
Mr E. Russell, Dr J. J. Field, Dr P. H. Teesdale-Spittle, Dr J. H. Miller
School of Biological Sciences
natural products.
An aldol-based synthetic approach to several of these
compounds has been developed by Snider and co-workers.8
The furo[3,4-b]pyran-5-one ring system has also been made by
multicomponent coupling methods, albeit with substituents
differing from those in the natural products.9 A related class of
Centre for Biodiscovery
Victoria University of Wellington
Wellington, NEW ZEALAND
Supporting information for this article includes full synthetic
methods, characterisation data and spectra, and is given via a link
at the end of the document
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fungal natural products containing a pyrano[4,3-b]pyran-5-one Results and Discussion
scaffold, the dinemasones,10 has also been prepared.11
The known glycal 413 was previously employed in our synthesis of
the core of TAN-2483B.12 According to the established four-step
synthesis from D-mannose (6),13 initial iodine-catalysed bis-
acetonide formation is followed by conversion of the hemiacetal 7
into a furanosyl chloride 8 (Scheme 2). In the published method,
TsCl is employed for the conversion of 7 into 8, which proceeds
via an intermediate tosylate.13 However, in our hands, purification
of the chloride 8 was challenging due to the significant quantities
of tosyl by-products contaminating the product. Instead, we found
that addition of hemiacetal 7 to a mixture of trichlorocyanuric acid
TAN-2483B (2) is stereochemically unique among these
molecules in its 2,6-trans-relationship between the furan linkage
and the E-propenyl group, and its total synthesis has remained
elusive.8 Several years ago, we reported12 the synthesis of the
bicyclic core of TAN-2483B (3, Scheme 1). Key transformations
included subjection of the known glycal 413 to
a
1
4
dichlorocyclopropanation–ring-expansion sequence to form the
pyran ring and carbonylative lactonisation to construct the
furanone component. While this strategy afforded the furo[3,4-
b]pyranone bicyclic system 315 with the desired 2,6-trans-
substitution pattern, the synthesis was low yielding. The causes
of the low yield were primarily a lack of stereoselectivity in
preparation of the C-glycoside 5 and the poor reactivity of the
chloroalkene 5 in the carbonylation step.
(TCCA,
1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione)
and
triphenylphosphine rapidly produces chloride 8 in high yield (80%).
Furthermore, due to the need for only 0.37 molar equivalents of
TCCA, purification of 8 is greatly facilitated. This subsequently
undergoes elimination in a dissolving metal reaction and benzyl
protection of the revealed hydroxyl group to deliver glycal 4. This
reaction sequence generally worked well, at scales up to 30 g.
Overall, using this method, we are able to obtain good yields of
glycal 4 from D-mannose (6) over the four-step sequence.
Scheme 1. Published synthesis of the bicyclic core of TAN-2483B.12
To address these issues and introduce the methyl substituent on
the furanone ring, we adopted an alternative strategy (Figure 2).
Key improvements included use of a brominated cyclopropane,
which would produce a more reactive bromoalkene upon ring
expansion, and alkynylation to introduce the required two-carbon
segment of the lactone.
Scheme 2. Optimised synthesis of D-mannose-derived glycal 4.
We previously reported cyclopropanation of glycal
dichlorocarbene under Makozsca’s conditions (CHCl
aqueous NaOH),16 isolation of the resulting dichlorocyclopropane
4
with
Figure 2. Strategic considerations in improved synthesis of TAN-2483B
analogues.
3
, 50%
and its subsequent ring expansion in the presence of silver
acetate.12 However, extension to the brominated equivalent
proved difficult due the very high reactivity of the
In exploring this chemistry, difficulties were encountered when
preparing the E-propenyl side chain present in the natural product
dibromocyclopropyl intermediate
9
(Scheme 3).
The
(
vide infra). Consequently, analogues of TAN-2483B with
dibromocyclopropane 9 could not be isolated, so it was essential
to find suitable conditions for the in situ ring-expansion step that
alternative side chains were initially sought as a testing ground for
the synthetic endeavours and in order to explore the structure-
activity relationships of this unique furo[3,4-b]pyran scaffold for
future drug discovery applications.
were compatible with carbene generation and provided
a
functional handle for alkynylation. This was eventually realised by
adaption of the anhydrous, heterogeneous cyclopropanation
conditions of Kasradze et al.17 When glycal 4 was treated with
bromoform, potassium carbonate, tetra-n-butylammonium
bromide and sodium acetate, the acetate 10 was obtained as a
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mixture of anomers in a 4:1 α:β ratio. The structure and the
stereochemical configuration of the anomers were confirmed by
an X-ray diffraction study of the minor isomer, 10β.
product by Julia-Kocienski reaction (ethyl 1-phenyl-1H-tetrazol-5-
yl sulfone,19 KHMDS or LiHMDS, THF) were unsuccessful,
leading to degradation that prevented isolation of any product or
starting material. Similar degradation was also observed in a
Wittig
reaction
with
the
ylide
derived
from
ethyltriphenylphosphonium iodide. It was supposed that the
observed degradation might be due to the sensitivity of the
aldehyde towards the basic sulfone anion and the ylide or, indeed,
the strong bases used to form the Julia-Kocienski and Wittig
reagents. This was borne out by the subsequent success of
reactions with stabilised ylides and phosphonate anions that are
less basic. Thus, a separable mixture of (Z)- and (E)-ethyl esters
Z-13a and E-13a was prepared (4:1 ratio, 71% overall yield) by
desilylation, diol cleavage and reaction of the aldehyde with ethyl
(
triphenylphosphoranylidene)acetate (14). Alternatively, the (Z)-
isomer Z-13a could be stereoselectively prepared by diol
cleavage and Still–Gennari reaction with the corresponding 2,2,2-
trifluoroethylphosphonate (17) (67% yield, 95:5 Z/E ratio),
followed by desilylation. Desilylation, diol cleavage and Horner-
Wadsworth-Emmons
reaction
with
methyl
diethylphosphonoacetate (15) provided the unsaturated methyl
ester as a separable mixture of the (Z)- and (E)-isomers (2:1 ratio
of Z-13b and E-13b, 37% yield over the three-step sequence).
Scheme 3. Cyclopropanation and ring expansion sequence, affording the pyran
10, and ORTEP diagram of the minor isomer of 10. The ellipsoid probability is
shown at 30%.
Reaction
of
the
aldehyde
with
(
triphenylphosphoranylidene)acetaldehyde
(16)
selectively
delivered the (E)-isomer E-13c (42% yield over the three-step
sequence, E-alkene only).
Stereoselective alkyne substitution of the acetate 10 (as either a
mixture of anomers or the individual separated anomers) with
bis(trimethylsilyl)acetylene under Lewis acidic conditions (tin
tetrachloride) produced a mixture of the acetonide 11 and diol 12
(
84% combined yield, Scheme 4). Each compound was formed
as a single stereoisomer and the X-ray diffraction study of the
acetonide 11 confirmed the α-configuration, as predicted based
on previous studies in related systems.18 After separation,
acetonide 11 was converted into diol 12 by refluxing in aqueous
THF in the presence of p-toluenesulfonic acid (the yield of diol 12
over the two steps was 79%).
Scheme 4. Alkynylation of glycosyl acetate 10 and ORTEP diagram of 11. The
ellipsoid probability is shown at 30%.
Scheme 5. Alkyne deprotection and side chain attachment.
Various unsaturated side chains were then attached (Scheme 5).
Desilylation of the alkyne could be achieved by treatment with
basic methanol or potassium fluoride, either before or after side-
chain attachment. The diol was cleaved with sodium periodate
and olefination reactions conducted on the resulting aldehyde
with a view to producing various unsaturated side chains.
Attempts to attach the E-propenyl side chain present in the natural
These side-chain variants were then individually subjected to
oxymercuration to afford the methyl ketones E/Z-20a–c (Scheme
6). Sodium borohydride reduction of the ketones proceeded
stereoselectively, with complete substrate control, to produce a
single isomer of each alcohol E/Z-21a,b and d. In the case of
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aldehyde E-20c, ceric chloride was added to promote 1,2-
reduction of the unsaturated side-chain, thus affording the diol E-
2
1d. The (S)-configuration at the new chiral centre was proposed
2
0
on the basis of the polar Felkin–Anh model and subsequently
confirmed for the (Z)-ethyl ester series (see crystal structure of 25
in Scheme 8, and associated discussion). We concluded that the
borohydride reduction afforded the same carbinol configuration
across the whole series based on comparison of the NMR spectra
of the series of side-chain analogues with those of the (Z)-ethyl
ester alcohol Z-21a and more advanced products, particularly
with regards to the near-identical chemical shifts and coupling
constants close to the methyl substituent.
Scheme 7. Hydrogenation of benzylated analogue Z-22a.
When the methyl ester Z-22b was debenzylated with titanium
tetrachloride, the desired product Z-23b was observed to form.
However, it was contaminated with the tricyclic dilactone 25 and
attempts to separate the mixture led to 25 as the sole isolated
product (Scheme 8). Presumably, this forms through attack of the
intermediate titanium alkoxide on the methyl ester. Small
quantities of 25 were also observed upon debenzylation of the Z-
ethyl ester Z-22a. Tricyclic 25 was a solid and the X-ray diffraction
study confirmed the proposed stereochemical configuration at all
positions, most crucially at C2.
Scheme 6. Preparation of TAN-2483B side-chain analogues.
The alcohols 21 were subjected to palladium-catalysed
carbonylative lactonisation to provide the furo[3,4-b]pyranones
E/Z-22a,b and d. This reaction with the bromoalkene was
significantly more efficient than the carbonylation of the related
chloroalkene in our earlier work, and yields were generally high.12
Attempts to debenzylate these penultimate products by
hydrogenolysis were not successful, instead causing
hydrogenation of the alkenes, as exemplified by the production of
Scheme 8. Formation and ORTEP diagram of tricyclic dilactone 25. The
ellipsoid probability is shown at 30%.
2
4 from Z-22a (Scheme 7). Oxidative cleavage using 1,2-
In a preliminary effort to gain further structure-activity information,
the diol E-23d was treated with acetic anhydride to form diacetate
dichloro-4,5-dicyanobenzoquinone (DDQ) gave the deprotected
product, but was too slow for practical use.
debenzylation of benzyl ethers 22a and
Pleasingly,
26 (Scheme 9).
d
with titanium
tetrachloride in dichloromethane led to the final compounds, E/Z-
3a and E-23d. The NMR data for these compounds correspond
2
closely to those reported previously for TAN-2483B and related
natural products, aside from the expected variations at the
different side chains.1
Scheme 9. Acetylation of 10-hydroxy-TAN-2483B (E-23d).
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A subset of the analogues was next studied in preliminary cell-
based and biochemical assays. Growth inhibition of cancer cell
lines by the Z- and E-ethyl esters Z-23a and E-23a and 10-
414 kinases. The kinases listed are those for which Z-23a caused inhibition
>
70% at 10 μM concentration, plus Src. Analogues E-23a, E-23d and 26
were tested against only the kinases inhibited by >70% by Z-23a. [d]
Analogues were dissolved in DMSO and assays conducted at 10 μM
concentration in duplicate. [e] Inhibition of kinase phosphorylation activity by
hydroxy-TAN-2483B (E-23d) was measured.
A standard
TM
colorimetric MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-
analogues was measured by the Z’-LYTE Fluorescent Kinase Assay. [f]
The binding of analogues to NUAK2 was measured by the LanthaScreen®
Eu Kinase Binding Assay protocol, conducted by Life Technologies.
tetrazolium bromide) cell proliferation assay was used as
previously described21 to evaluate cytotoxic activity against three
human cancer cell lines: HL-60 promyelocytic leukemia, MCF-7
breast cancer and 1A9 ovarian carcinoma. Low micromolar
activity was seen with the isomeric ethyl esters Z-23a and E-23a
Conclusions
(
1
IC50 = 3.6 and 2.4 μM, respectively, with HL-60 cells) (Table 1).
0-Hydroxy-TAN-2483B (E-23d) was somewhat less potent.
A
In summary, we have developed a synthetic strategy that delivers
the bicyclic core of TAN-2483B incorporating the full contingent of
functional and structural decorations. Key steps include the ring-
expansion of a ring-fused cyclopropane, α-selective anomeric
kinome-wide screen (against 414 human disease-relevant
kinases) was undertaken with ethyl ester Z-23a, which was found
to inhibit Bruton’s tyrosine kinase (Btk),22 a key drug target for
treating B-cell malignancies,23 and other non-receptor TEC-family
tyrosine kinases, including Bmx (bone marrow tyrosine kinase)24
and Txk (tyrosine kinase protein)25 (Table 1). Activity against the
oncogenic kinases PLK1 (polo-like kinase 1),26 NUAK227 (NUAK
family SNF1-like kinase 2) and MAPK14 (mitogen-activated
protein kinase 14 (p38alpha))28 was observed. The activity of
metabolic kinase AMPK A2/B1/G129 was also inhibited by Z-23a.
The inhibitory activity of the other analogues E-23a, E-23d and 26
for these kinases was markedly lower, although the E-isomer E-
alkynylation and Pd-catalysed carbonylative lactonisation.
A
range of side-chain analogues of the natural product were
prepared using Wittig-type methodology and studied
spectroscopically and biologically. The Z-ethyl ester analogue Z-
2
3a inhibits cancer cell growth and cancer-relevant kinases with
micromolar activity, thus presenting a lead for future optimisation.
The analogues E-23a and E-23d show some bioactivity in the
same systems.
23a retained reasonable activity against Btk and Bmx. None of
the analogues measured showed any significant inhibition of Src,
the kinase target inhibited by the natural product TAN-2483A.1
Experimental Section
Synthetic methods and product data for the series leading to compound Z-
2
3a are provided in this section. Full methods and data are given in the
Table 1. Cell and kinase activity of analogues Z-23a, E-23a, E-23d and 26.
Supporting Information file.
Analogue:
Cell line
HL-60
Z-23a
E-23a]
E-23d]
26
(
4
(
2R,5R,6S)-5-(Benzyloxy)-3-bromo-6-((R)-2,2-dimethyl-1,3-dioxolan-
-yl)-5,6-dihydro-2H-pyran-2-yl acetate (10α) and (2S,5R,6S)-5-
benzyloxy)-3-bromo-6-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-5,6-
dihydro-2H-pyran-2-yl acetate (10β). A suspension of glycal 4 (4.03 g,
4.6 mmol), potassium carbonate (10.7 g, 72.9 mmol, 5 equiv), tetra-n-
IC50 (μM)[a]
3.6
83
2.4
5.8
42
76
n.t.
n.t.
n.t.
1
1A9
butyl ammonium bromide (2.35 g, 7.30 mmol, 0.5 equiv), 18-crown-6 (1.90
g, 7.30 mmol, 0.5 equiv), and sodium acetate (5.00 g, 51.1 mmol, 3.5
equiv) in dry bromoform (26 mL) was vigorously stirred under an
atmosphere of argon at room temperature for 16 hours. The reaction flask
was then fitted with a reflux condenser and heated at 85 C for three days.
Small portions of bromoform were added over the three days (approx. 5
mL per day). The resulting dark brown mixture was then cooled to room
temperature and filtered over Celite , and the resulting solid was further
washed with ethyl acetate. The mixture was concentrated in vacuo and
initially purified by flash column chromatography (gradient elution 10:1 to
MCF-7
13.9
23.5
117
Kinase[b]
Percent inhibition at 10 μM[d]
Btk[e]
83%
80%
71%
81%
73%
75%
51%
48%
55%
67%
16%
25%
45%
50%
17%
31%
®
Bmx[e]
Txk[e]
5
:1 petroleum ether:ethyl acete) to afford a 4:1 mixture of α- and β-
anomers of acetate 10 (3.94 g, 9.21 mmol, 63%) as a sticky white solid.
3
= 0.18 (10:1 petroleum ether: ethyl acetate); IR (film from CHCl ) νmax
AMPK
A2/B1/G1
[
e]
R
f
-
1
1
812, 1644, 1604, 1496, 1454, 1328, 1308, 1288, 786, 761, 648 cm ;
PLK1[e]
81%
76%
74%
18%
12%
40%
12%
3%
21%
16%
28%
2779BrO
N [M+NH
+
]+ calcd 444.1016, found 444.1023. A
HRMS: m/z C19
H
6
4
NUAK2[f]
portion of the α-anomer 10α was purified from the mixture by recrystallizing
from a 5:1 petroleum ether:ethyl acetate solution to provide colourless
needles. H NMR (500 MHz, CDCl
6.49 – 6.47 (m, 1H, H-3), 6.25 (s, 1H, H-1), 4.70 (s, 2H, PhCH
2
1
MAPK14
24%
3
): δ
H
7.39–7.26 (complex m, 5H, Ar-H),
), 4.41 –
.36 (complex m, 1H, H-6), 4.10 (dd, J = 8.9, J = 6.3 Hz, 1H, H-7a), 4.03
[
e]
(p38 α)
4
Src[e]
˗38
13
10%
˗7%
(dd, J = 8.8 Hz, J = 4.6 Hz, 1H, H-7b), 3.94 (dd, J = 5.8 Hz, J = 1.6 Hz, 1H,
H-4), 3.69 (dd, J = 8.5 Hz, J = 2.1 Hz, 1H, H-5), 2.15 (s, 3H, OAc), 1.40 (s,
C); 13C NMR (125 MHz, CDCl
Ar), 128.2 (CH, Ar),
[
a] Cell growth inhibition was measured by MTT assays carried out in
3H, (CH
3
)
2
C), 1.37 (s, 3H, (CH
3
)
2
3
C
): δ 169.3
triplicate; n.t. = not tested. [b] A full kinome screen on Z-23a was performed
(C, OAc), 138.1 (C, Ar), 131.7 (CH, C-3), 128.5 (CH
,
with the Life Technologies SelectScreen® Kinase Profiling service against
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1
(
28.0 (CH, Ar), 124.6 (C, C-2), 109.6 (C, (CH
CH, C-5), 73.2 (CH, C-6), 72.1 (CH , PhCH ), 69.6 (CH, C-4), 67.2 (CH
, (CH C), 21.0 (CH , OAc). A portion
3
)C), 90.8 (CH, C-1), 77.0
1.4 Hz, 1H, H-5), 4.96 (d, J = 1.5 Hz, 1H, H-3), 4.74 (d, J = 11.7 Hz, 1H,
2
2
2
,
PhCH
3H, H-6, H-7, H-8), 3.84 (dd, J = 11.6 Hz, 3.1 Hz, 1H, H-9a), 3.79 (dd, J =
11.6 Hz, 5 Hz, 1H, H-9b), 0.18 (s, 9H, (CH
Si); 13C NMR (125 MHz,
CDCl ): δ 138.2 (C, Ar), 129.0 (CH, Ar), 128.6 (CH, Ar), 128.2 (CH, Ar),
126.7 (CH, C-5), 125.7 (CH, C-4), 99.2 (C, C-2), 92.2 (C, C-1), 72.6 (CH,
C-7), 71.5 (CH , PhCH ), 70.3 (CH, C-3), 70.0 (CH, C-8), 69.8 (CH, C-6),
64.5 (CH , C-9), -0.3 (CH , (CH Si); IR (film from CH Cl ) νmax 3486, 2985,
2873, 1644, 1454, 1297, 1106, 1079, 912, 843, 732, 698 cm ; HRMS: m/z
19 4
C H
2581BrO SiNa+ [M+Na]+ calcd 449.0580, found 449.0575 (Δ = 1.11
2 2
-a), 4.60 (d, J = 11.7 Hz, 1H, PhCH -b), 4.04 – 3.95 (complex m,
C-7), 27.1 (CH
3 3
, (CH )
2
C), 25.5 (CH
3
3
)
2
3
of the β-anomer 10β was obtained by crystallisation from the mixture by
vapour diffusion of dichloromethane into a solution of acetate anomers in
ethyl acetate (20:1 v/v). In this way, white solid needles were obtained.
3 3
)
3
C
22
m.p. 114.2–116.7 ˚C; R
f
0.18 (10:1 petroleum ether: ethyl acetate); [α]
D
2
2
1
=
-41 (c 0.56, CH
m, 5H, Bn), 6.49 (d, J = 5.8 Hz, 1H, H-3), 6.34 (s, 1H, H-1), 4.69 (s, 2H,
PhCH ), 4.40 (m, 1H, H-6), 4.11 (dd, J = 8.6, 6.4 Hz, 1H, H-7a), 3.92 (dd,
J = 5.6, 2.4 Hz, 1H, H-4), 3.89-3.84 (complex m, 2H, H-5 and H-7b), 2.13
s, 3H, Ac), 1.41 (s, 3H, (CH C), 1.38 (s, 3H, (CH
C); 13C NMR (500
MHz, CDCl ) δ 169.5 (C, CH CO), 137.7 (C, Bn), 130.4 (CH, C-3), 128.7
CH, Bn), 128.3 (CH, Bn), 127.4 (CH, Bn), 122.7 (CH, C-2), 109.5 (C,
2
Cl
2
); H NMR (500 MHz, CDCl
3
) δ
H
7.36–7.34 (complex
2
3
3
)
3
2
2
-
1
2
ppm).
(
3
)
2
3 2
)
3
C
3
(
R)-1-((2R,3R,6R)-3-(Benzyloxy)-5-bromo-6-((trimethylsilyl)ethynyl)-
(
(
3,6-dihydro-2H-pyran-2-yl)ethane-1,2-diol (12). Acetonide 11 (0.10 g,
CH
3
)
2
C), 90.0 (CH, C-1), 77.2 (CH, C-5), 72.9 (CH, C-6), 72.0 (CH
), 69.1 (CH, C-4), 66.9 (CH , C-7), 26.9 (CH , (CH C), 25.2 (CH
C), 20.9 (CH , Ac); IR (film from CHCl
2
,
0
.22 mmol) was dissolved in THF:H O (1:1, 4.3 mL) and treated with p-
2
PhCH
2
2
3
3
)
2
3
,
toluenesulfonic acid (0.05 g, 0.58 mmol, 1.2 equiv) and heated at reflux for
6 h. The mixture was quenched with the addition of saturated aqueous
NaHCO solution until the mixture was neutral. The crude material was
(CH
3
)
2
3
3
) νmax 2984, 2877, 1648, 1496,
1
-
1
1454, 1341, 1286 cm ; X-Ray Crystallography CCDC 1881960; (M
3
=
427.28 g/mol), orthorhombic, space group P212121 (no. 19), unit cell
purified using flash column chromatography (2:1 petroleum ether:ethyl
acetate) to give diol 12 (0.78 g, 0.184 mmol, 85%) as a colourless oil.
parameters a = 8.76484(14) Å, b = 10.33897(18) Å, c = 20.4180(3) Å, V =
1
850.27(5) Å3, Z = 4, T = 120.00(10) K, μ(Cu Kα) = 1.54184, Dcalc = 1.534
3
g/cm , 9604 reflections measured (8.66° ≤ 2Θ ≤ 143.48°), 3605 unique (R1
Ethyl (Z)-3-((2R,3R,6R)-3-benzyloxy-5-bromo-6-ethynyl-3,6-dihydro-
=
0.0205).
2
H-pyran-2-yl)acrylate (Z-13a) and ethyl (E)-3-((2R,3R,6R)-3-
benzyloxy-5-bromo-6-ethynyl-3,6-dihydro-2H-pyran-2-yl)acrylate (E-
3a). Diol 12 (279 mg, 0.645 mmol) was dissolved in dichloromethane (5.6
mL) and treated with methanol (1.4 mL) and potassium carbonate (446 mg,
.22 mmol, 5 equiv). The reaction mixture became a white suspension and
was stirred until the reaction was deemed complete based on TLC analysis
2 hours). This mixture was diluted with dichloromethane and filtered into
a brine solution. The aqueous layer was extracted with dichloromethane
2x10 mL) and the combined organic layers were dried over magnesium
(
((2R,5R,6S)-5-(Benzyloxy)-3-bromo-6-((R)-2,2-dimethyl-1,3-dioxolan-
1
4
1
-yl)-5,6-dihydro-2H-pyran-2-yl)ethynyl)trimethylsilane (11) and (R)-
-((2R,3R,6R)-3-(benzyloxy)-5-bromo-6-((trimethylsilyl)ethynyl)-3,6-
3
dihydro-2H-pyran-2-yl)ethane-1,2-diol (12). A solution of the acetate 10
4:1 α:β, 0.705 g, 1.65 mmol) and bis(trimethylsilyl)acetylene (1.13 g, 6.60
mmol, 4.0 equiv) in dry CH Cl (14.1 mL) under an atmosphere of argon
was cooled to -78 C. Tin tetrachloride (2.04 mL, 1M in CH Cl , 2.04 mmol,
.2 equiv) was added to the mixture over a period of 30 minutes. The
(
(
2
2
2
2
(
1
sulfate, filtrated and evaporated at room temperature under reduced
pressure to obtain the desilylated diol product as white solid (199 mg,
mixture was stirred at the same temperature for 2 hours, and then allowed
to warm to room temperature over 1 hour. The resulting brown mixture was
quenched by the slow addition of saturated aq. NaHCO solution at 0 C.
The layers were separated, and the organic layer was extracted with ethyl
acetate (3 x 10 mL). The combined organic layers were dried over
0
.563 mmol, 83%). The product was used in the next reaction without
further purification. A solution of the diol (120 mg, 0.34 mmol) in THF (10
mL) and pH 7 phosphate buffer (3 mL) was treated with NaIO (508 mg,
.38 mmol, 7 equiv.) in one portion. The resulting mixture was stirred for 1
3
4
2
2 4
anhydrous Na SO and concentrated in vacuo to give viscous brown oil.
hour, diluted with brine (50 mL), and extracted with Et
2
O (3×50 mL). The
The crude material was purified by flash column chromatography (gradient
elution 20:1 to 3:1 petroleum ether:ethyl acetate) to give acetonide-
protected alkyne 11 (0.244 g, 0.524 mmol, 32%) as a crystalline solid, and
the diol 12 (0.362 g, 0.851 mmol, 52%) as a colourless oil. Data for
acetonide 11: Compound 11 was recrystallised from diethyl ether at 2–
combined organic layers were washed with brine, dried over MgSO
4
and
evaporated under reduced pressure to give the aldehyde a white solid,
which was used without further purification. (Note: the evaporation should
be done at ambient temperature to avoid degradation). The crude
aldehyde thus obtained was dissolved in THF (10 mL) and treated with
ethyl (triphenylphosphoranylidene)acetate (236 mg, 0.68 mmol, 2 equiv.).
The solution was stirred overnight before concentrating under reduced
pressure and purifying with column chromatography (14:1 petroleum
ether: ethyl acetate) to yield (Z)-isomer Z-13a (94 mg, 68%) and (E)-isomer
E-13a (25 mg, 18%) as colourless oils (combined yield: 86% over two
22
8
°C. m.p. 87.6–89.8 ˚C; [α]
petroleum ether: ethyl acetate); 0.2 (20:1 petroleum ether: ethyl acetate);
1H NMR (500 MHz, CDCl
): δ 7.38–7.29 (complex m, 5H, Ar-H), 6.27 (dd,
J = 5.5 Hz, 1.3 Hz, 1H, H-5), 4.92 (d, J = 1.2 Hz, 1H, H-3), 4.69 (s, 2H,
PhCH ), 4.39 (m, 1H, H-8), 4.16 (dd, J = 8.5 Hz, 6.3 Hz, 1H, H-9a), 3.97
dd, J = 8.6 Hz, 5.3 Hz, 1H, H-9b), 3.91 (complex m, 2H, H-6 & H-7), 1.42
s, 3H, CH ), 1.40 (s, 3H, CH ), 0.19 (s, 9H, (CH
Si); 13C NMR (125 MHz,
): δ 138.2 (C, Ar), 128.5 (CH, Ar), 128.2 (CH, Ar), 128.0 (CH, Ar),
27.1 (CH, C-5), 125.1 (CH, C-4), 109.6 (C, (CH C), 99.6 (C, C-2), 92.4
C, C-1), 74.4 (CH, C-6), 73.1 (CH, C-8), 72.3 (CH , PhCH ), 70.06 (CH,
C-3), 70.05 (CH, C-7), 67.8 (CH , C-9), 27.0 (CH , (CH C), 25.7 (CH C),
) νmax 2986, 2959, 2873, 1643,
D
2 2 f
= -45 (c 0.32, CH Cl ); R 0.45 (5:1
3
H
2
(
(
steps). Data for (Z)-13a: R
f
0.33 (14:1 petroleum ether/ethyl acetate);
3
3
3
)
3
20
1
[α]
D
= -188 (c 0.26, CH
2
Cl
2
); H NMR (500 MHz, CDCl
3
): δ
H
7.33 – 7.26
CDCl
1
(
3
C
(complex m, 5H, Ar-H), 6.35 (dd, J = 11.8 Hz, 6.7 Hz, 1H, H-8), 6.33 (dd,
3 2
)
J = 5.6 Hz, 1.5 Hz, 1H, H-5), 5.94 (dd, J = 11.8 Hz, 1.6 Hz, 1H, H-9), 5.56
ddd, J = 6.7 Hz, 2.6 Hz, J = 1.7 Hz, 1H, H-7), 5.03 (apparent t, J = 1.9 Hz,
H, H-3), 4.58 (d, J = 11.8 Hz, 1H, PhCH -a), 4.51 (d, J = 11.8 Hz, 1H,
PhCH -b), 4.21 (dd, J = 5.6 Hz, 2.7 Hz, 1H, H-6), 4.15 (q, J = 7.1 Hz, 2H,
H-11), 2.51 (d, J = 2.3 Hz, 1H, H-1), 1.28 (t, J = 7.1 Hz, 3H, H-12); 13C
NMR (125 MHz, CDCl ): δ 165.6 (C, C-10), 145.8 (CH, C-8), 137.6 (C,
Bn), 128.4 (CH, Bn), 128.0 (CH, Bn), 127.9 (CH, Bn), 127.1 (CH, C-5),
24.4 (C, C-4), 120.5 (CH, C-9), 78.1 (C, C-2), 75.1 (CH, C-1), 71.9 (CH
PhCH ), 71.3 (CH, C-6), 71.0, (CH, C-7), 68.8 (CH, C-3), 60.4 (CH , C-11),
2
2
(
2
3
3
)
2
3 2
)
1
2
-
0.17 (CH
3
, (CH
3
)
3
2 2
Si). IR (film from CH Cl
2
-
1
1455, 1297, 1106, 1079, 1212, 906, 841, 731, 697 cm ; HRMS: m/z
+
+
C
22
H
3081BrO
4
Si [M+H] calcd 467.1074, found 467.1056 (Δ = 3.85 ppm);
3
C
X-Ray Crystallography CCDC 1881961; M = 465.45 g/mol, orthorhombic,
space group P212121 (no. 19), a = 8.35940(12) Å, b = 12.5766(2) Å, c =
1
2
,
3
2
1.9027(4) Å, V = 2302.69(6) Å , Z = 4, T = 119.99(10) K, μ(Cu Kα) =
2
2
1
≤
.54184, Dcalc = 1.3425 g/cm3, 13055 reflections measured (10.71° ≤ 2Θ
1
4.2 (CH
3
, C-12); IR (film from CH
2
Cl
2
) νmax 3031, 2931, 2872, 2116, 1648,
143.56°), 4375 unique (R1 0.0283). Data for diol 12: R
f
0.38 (2:1
-1
1539, 1454, 1497, 1388, 1366, 1334, 1031, 911, 846, 735, 698 cm ;
21
1
petroleum ether: ethyl acetate); [α]
D
= -100 (c 0.2, CH
2
Cl
2
); H NMR (500
2081BrO +
[M+H]+ calcd 393.0519, found 393.0533 (Δ =
HRMS: m/z C19
H
4
3
H
MHz, CDCl ): δ 7.37–7.32 (complex m, 5H, Ar-H), 6.38 (dd, J = 5.6 Hz,
3
.56 ppm). Data for (E)-13a: R 0.45 (2:1 petroleum ether/ethyl acetate);
f
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Chemistry - An Asian Journal
10.1002/asia.201801767
FULL PAPER
20
); 1H NMR (500 MHz, CDCl
[α]
D
= -112 (c 0.34, CH
2
Cl
2
3
): δ 7.35–7.28
C-6), 71.5 (CH
2
, PhCH
2
), 69.9 (CH, C-7), 68.1 (CH, C-2), 60.6 (CH
2
, C-11),
(
complex m, 5H, Bn), 7.02 (dd, J = 15.8, 4.2 Hz, 1H, H-8), 6.34 (d, J = 5.5
19.6 (CH , C-1), 14.2 (CH
3
3
, C-12); IR (film from CH Cl ) νmax 3467, 3031,
2
2
-
1
Hz, 1H, H-5), 6.22 (dd, J =15.8, 1.5 Hz, 1H, H-9), 5.09 (m, 1H, H-3), 4.73
m, 1H, H-7), 4.61 (d, J =11.8 Hz, 1H, PhCH a), 4.53 (d, J =11.8 Hz, 1H,
PhCH b), 4.23 (q, J = 7.1 Hz, 2H, H-11), 3.92 (dd, J = 5.3, 2.8 Hz, 1H, H-
), 2.53 (d, J = 2.1 Hz, 1H, H-1), 1.31 (t, J = 7.1 Hz, 3H, H-12); 13C NMR
125 MHz, CDCl ): δ 166.0 (C, C-10), 142.4 (CH, C-8), 137.4 (C, Bn),
28.5 (CH, Bn), 128.02 (CH, Bn), 127.98 (CH, Bn), 126.6 (CH, C-5), 124.9
2980, 2930, 1650, 1454, 1232, 1147, 856, 827, 697 cm ; HRMS: m/z
2779BrO
N [M+NH
+
]+ calcd 428.1067, found 428.1049 (Δ = 4.2 ppm).
(
2
19
C H
5
4
2
6
(
1
Ethyl
(Z)-3-((2R,3R,7S,7aS)-3-(benzyloxy)-7-methyl-5-oxo-3,5,7,7a-
3
tetrahydro-2H-furo[3,4-b]pyran-2-yl)acrylate (Z-22a). An oven dried
Schlenk tube fitted with a Youngs tap was charged with alcohol Z-21a
(
7
(
1
C, C-4), 122.7 (CH, C-9), 77.9 (C, C-2), 75.3 (CH, C-1), 72.2 (CH, C-7),
1.1 (CH , PhCH ), 71.0 (CH, C-6), 69.0 (CH, C-3), 60.5 (CH , C-11), 14.3
CH , C-12); IR (film from CH Cl ) νmax 2360, 2115, 1664, 1496, 1454, 1392,
368, 898, 847, 798, 645, 631, 603 cm ; HRMS: m/z C19
]+ calcd 408.0805, found 408.0819 (Δ = 3.43 ppm).
(
0.120 g, 0.291 mmol), Pd(OAc)
XantPhos (0.042 g, 0.073 mmol, 0.25 equiv), tetra-n-butylammonium
iodide (0.062 g, 0.052 mmol, 0.2 equiv), and Na CO (0.022 g, 0.581 mmol,
equiv) under an argon atmosphere. Dry 1,4-dioxane (3.4 mL) was then
added to the tube, and the solvent was degassed by the freeze-pump-thaw
method (3 cycles). The tube was then backfilled with CO gas and dry NEt
2
(0.013 g, 0.052 mmol, 0.2 equiv),
2
2
2
3
2
2
2
3
-
1
H
4
2379BrO N+
2
[M+NH
4
3
Ethyl (Z)-3-[(2R,3R,6R)-6-acetyl-3-(benzyloxy)-5-bromo-3,6-dihydro-
H-pyran-2-yl]acrylate (Z-20a). Alkyne Z-13a (1.43 g, 1.05 mmol) was
dissolved in tetrahydrofuran (4.2 mL) and treated with 10% aq. H SO (4.2
mL) and HgSO (0.065 g, 0.263 mmol, 0.25 equiv). The mixture was stirred
for 24 h, and quenched with saturated aq. NaHCO solution until neutrality
(0.081 mL, 0.581 mmol, 2 eq) was added to the mixture. Then, whilst
stirring vigorously, the tube was evacuated and back filled with CO gas
three times, turning the mixture deep purple. The tube was then sealed
and heated to 95 C whilst stirring vigorously for 19 h. After cooling to room
temperature, the mixture was filtered through a short pad of silica (eluted
2
2
4
4
3
was reached (pH monitored with universal indicator paper). The layers
were separated and the aqueous layer was extracted with ethyl acetate.
The combined organic layers were washed with saturated brine solution,
2 2
with CH Cl ) and concentrated under reduced pressure. The crude residue
was purified by flash column chromatography (3:1 petroleum ether:ethyl
acetate) to give lactone Z-22a (0.085 g, 0.237 mmol, 82%) as a light yellow
2
0
dried over Na
The resulting pale-yellow oil was purified by flash column chromatography
5:1 petroleum ether:ethyl acetate) to give ketone Z-20a (0.25 g, 0.63
mmol, 59%) as a colourless oil. R 0.31 (9:1 petroleum ether : ethyl
); 1H NMR (500 MHz, CDCl
): δ
2 4
SO , filtered, and concentrated under reduced pressure.
oil. R
f
0.37 (5:1 petroleum ether : ethyl acetate); [α]
D
= -178 (c 0.18,
1
CH Cl
2
2
); H NMR (500 MHz, CDCl
3
): δ
H
7.34 – 7.27 (m, 5H, Bn), 7.21 (dd,
(
J = 5.5 Hz, J = 3.4 Hz, 1H, H-5), 6.49 (dd, J = 11.7 Hz, 7.8 Hz, 1H, H-8),
5.99 (dd, J = 11.7 Hz, 1.5 Hz, 1H, H-9), 5.31 (ddd, J = 7.8 Hz, 3.4 Hz, 1.5
Hz, 1H, H-7), 5.14 (dd, J = 7.8 Hz, 1.5 Hz, 1H, H-3), 4.85 (apparent quintet,
f
21
acetate); [α]
D
= -133 (c 0.14, CH
2
Cl
2
3
H
7
=
.34 – 7.27 (m, 5H, Bn), 6.48 (dd, J = 5.3 Hz, 1.4 Hz, 1H, H-5), 6.35 (dd, J
11.6 Hz, 7.1 Hz, 1H, H-8), 5.49 (dd, J = 11.9 Hz, 1.5 Hz, 1H, H-9), 5.31
J = 6.8 Hz, 1H, H-2), 4.60 (d, J = 11.8 Hz, 1H, PhCH
Hz, 1H, PhCH -b), 4.42 (m, 1H, H-6), 4.14 (q, J = 7.1 Hz, 2H, H-11), 1.28
(m, 6H, H-1 & H-12); 13C NMR (125 MHz, CDCl
): δ 166.5 (C, C-13),
165.6 (C, C-10), 145.5 (CH, C-8), 137.4 (C, Ar), 135.0 (CH, C-5), 132.4 (C,
C-4), 128.5 (CH, Ar), 128.1 (CH, Ar), 127.8 (CH, Ar), 122.3 (CH, C-9), 78.4
2
-a), 4.50 (d, J = 11.8
2
(
4
(
ddd, J = 7.1 Hz, 3.0 Hz, 1.5 Hz, 1H, H-7), 4.74 (d, J = 1.5 Hz, 1H, H-3),
.59 (d, J = 11.9 Hz, 1H, PhCH -a), 4.52 (d, J = 11.8 Hz, PhCH -b), 4.17
dd, J = 5.3 Hz, 3.0 Hz, 1H, H-6), 4.13 (q, J = 7.2 Hz, 2H, H-11), 2.31 (s,
3
C
2
2
3
2
H, H-1), 1.26 (t, J = 7.1 Hz, 3H, H-12); 13C NMR (125 MHz, CDCl
02.8 (C, C-2), 165.3 (C, C-10), 144.6 (CH, C-8), 137.6 (C, Bn), 128.7 (CH,
3
): δ
(CH, C-2), 71.8 (CH
C-6), 60.5 (CH , C-11), 15.4 (CH
CH Cl ) νmax 2983, 1650, 1454, 1413, 1386, 1298, 1096, 920, 829, 736,
2
, PhCH
2
), 71.6 (CH, C-7), 71.2 (CH, C-3), 69.5 (CH,
2
3
, C-1), 14.2 (CH , C-12); IR (film from
3
C-5), 128.4 (CH, Bn), 128.0 (CH, Bn), 127.9 (CH, Bn), 121.5 (C, C-9),
21.3 (C-4), 81.2 (CH, C-3), 71.8 (CH , PhCH ), 71.4 (CH, C-6), 71.2 (CH,
C-7), 60.5 (CH , OCH CH ), 28.1 (CH , C-1), 14.1 (CH , OCH CH ); IR
Cl ) νmax 3063, 2872, 1649, 1496, 1454, 1388, 1302, 979,
2
2
-
1
+
[M+H]+ calcd 359.1489, found
1
2
2
689, 632 cm ; HRMS: m/z C20
H O
23 6
2
2
3
3
3
2
3
359.1477 (Δ = 3.3 ppm).
(film from CH
2
2
-
1
H
5 4
2579BrO N+ [M+NH ]+ calcd 426.0911, found
6
4
97 cm ; HRMS: m/z C19
26.0902 (Δ = 2.11 ppm).
Ethyl
tetrahydro-2H-furo[3,4-b]pyran-2-yl)acrylate (Z-23a). Benzyl-protected
lactone Z-22a (0.085 g, 0.236 mmol) was dissolved in CH Cl (3 mL) under
a nitrogen atmosphere and cooled to 0 C. TiCl (0.71 mL, 1M in CH Cl
(Z)-3-((2R,3R,7S,7aS)-3-hydroxy-7-methyl-5-oxo-3,5,7,7a-
2
2
Ethyl
(Z)-3-((2R,3R,6R)-3-(benzyloxy)-5-bromo-6-((S)-1-hydroxy-
4
2
2
ethyl)-3,6-dihydro-2H-pyran-2-yl)acrylate (Z-21a). Ketone Z-20a (0.098
0.71 mmol) was added to the solution dropwise, which was stirred for 10
g, 0.240 mmol) was dissolved in dry methanol (2.4 mL) under argon and
minutes and then allowed to warm to room temperature. After stirring for
cooled to -78 C. NaBH
4
(0.010 g, 0.263 mmol, 1.1 equiv) was added to
1.5 hours, the reaction was quenched with saturated aqueous NaHCO
3
the solution in one portion, and the reaction was stirred for 1.5 h. The
reaction was quenched with acetone (5 mL) and concentrated under
reduced pressure. The resulting brown residue was dissolved in distilled
solution (5mL), the layers were separated, and the aqueous layer was
extracted with EtOAc (3 x 5 mL). The combined organic layers were
washed with saturated brine solution, dried over anhydrous Na SO ,
2 4
water (3 mL) and CH
aqueous layer was extracted with CH
layers were washed with saturated brine solution, dried over anhydrous
Na SO , filtered, and concentrated under reduced pressure. The residue
2
Cl
2
(5 mL), and the layers were separated. The
filtered and concentrated under reduced pressure to give a yellow oil. The
crude material was purified by flash column chromatography (gradient
elution 5:1 to 2:1 petroleum ether:ethyl acetate) to give lactone Z-23a
(0.039 g, 58%) as a colourless oil, together with unreacted starting material
(0.010 g, 12%), and tricyclic compound 25 (0.082 g, 16%). Data for Z-
2
Cl (3 x 5 mL), the combined organic
2
2
4
was purified by flash column chromatography (5:1 petroleum ether:ethyl
acetate) to give alcohol Z-21a (0.092 g, 0.224 mmol, 93%) as a colourless
23a: R
f
0.17 (2:1 petroleum ether : ethyl acetate); 1H NMR (500 MHz,
7.16 (dd, J = 5.4 Hz, 3.3 Hz, 1H, H-5), 6.44 (dd, J = 11.7 Hz,
20
oil. R
f
0.24 (5:1 petroleum ether: ethyl acetate); [α]
D
= -65 (c 0.2, CH
2
Cl
2
);
CDCl ): δ
3
H
1
H NMR (500 MHz, CDCl
3
): δ 7.34 – 7.27 (m, 5H, Bn), 6.48 (dd, J = 4.8
H
8.1 Hz, 1H, H-8), 6.07 (dd, J = 11.9 Hz, 1.4 Hz, 1H, H-9), 5.31 (ddd, J =
7.7 Hz, 3.4 Hz, 1.5 Hz, 1H, H-7), 5.12 (dd, J = 7.7 Hz, 3.3 Hz, 1H, H-3),
4.84 (apparent quintet, J = 6.8 Hz, 2H, H-2), 4.70 (m, 1H, H-6), 4.18 (q, J
= 7.2 Hz, 2H, H-11), 2.52 (broad s, 1H, OH), 1.28 (overlapping signals, 6H,
H-1 and H-12); 13C NMR (125 MHz, CDCl
C=O), 143.9 (CH, C-8), 135.6 (CH, C-5), 131.1 (C, C-4), 123.4 (CH, C-9),
78.2 (CH, C-2), 73.0 (CH, C-7), 70.5 (CH, C-3), 64.1 (CH, C-6), 61.0 (CH
C-11), 15.4 (CH , C-1), 14.3 (CH , C-12); IR (film from CH Cl ) νmax 3572,
3458, 1650, 1447, 1414, 1386, 1331, 1301, 1121, 1042, 968, 917, 852,
Hz, 1.8 Hz, 1H, H-5), 6.44 (dd, J = 11.8 Hz, 7.7 Hz, 1H, H-8), 5.99 (dd, J =
1
4
4
4
1.7 Hz, 1.5 Hz, 1H, H-9), 5.80 (ddd, J = 7.7 Hz, 3.4 Hz, 1.4 Hz, 1H, H-7),
.62 (d, J = 11.9 Hz, 1H, PhCH -a), 4.55 (d, J = 11.9 Hz, 1H, PhCH -b),
2
2
.35 (qd, J = 6.5 Hz, J = 2.7 Hz, 1H, H-2), 4.16 (q, J = 7.1 Hz, 2H, H-11),
.12 (m, 1H, H-6), 4.05 (m, 1H, H-3), 1.34 (d, J = 6.5 Hz, 3H, H-1), 1.28 (t,
3
): δ 166.4 (C, C=O), 166.3 (C,
J = 7.2 Hz, 3H, H-12); 13C NMR (125 MHz, CDCl
) δ 166.1 (C, C=O), 144.3
CH, C-8), 137.6 (C, Bn), 129.2 (CH, C-5), 128.4 (CH, Bn), 128.0 (CH, Bn),
3
2
,
(
3
3
2
2
127.7 (CH, Bn), 125.4 (C, C-4), 122.7 (CH,C-9), 79.6 (CH, C-3), 72.0 (CH,
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-
1
+
+
8
2
22, 764, 731 cm ; HRMS: m/z C13
H
17
O
6
[M+H] calcd 269.1020, found
0.10 (2:1 petroleum ether:ethyl
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69.1012 (Δ = 3.0 ppm). Data for 25: R
acetate); H NMR (600 MHz, CDCl
f
1
3
): δ
H
6.92 (overlapping signals, 2H, H-
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8
(
4
(
& H-5), 6.13 (dd, J = 10.2 Hz, 2.2 Hz, 1H, H-8), 5.31 (m, 1H, H-6), 5.07
dt, J = 6.5 Hz, 2.3 Hz, 1H, H-7), 4.90 (dq, J = 7.8 Hz, 6.5 Hz, 1H, H-2),
.83 (dt, J = 7.8 Hz, 3.0 Hz, 1H, H-3), 1.27 (d, J = 6.51, 3H, H-1); 13C NMR
150 MHz, CDCl ): δ 163.8 (C, C-11), 159.3 (C, C-10), 143.2 (CH, C-8),
32.0 (C, C-4), 129.8 (CH, C-5), 122.7 (CH, C-9), 75.9 (CH, C-2), 69.3 (CH,
, C-1); IR (Neat)νmax 3010,
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900, 2800, 1780, 1764, 1724, 1696, 1370, 1318, 1187, 1008, 710 cm ;
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9 5
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orthorhombic, unit cell parameters: a = 7.42050(10), b = 9.29650(10), c =
-
-
1
1
1
4.39010(10), space group P212121, Z=4, T=120.00 (10) K, μ(Cu Kα) =
.54184, Dcalc = 1.487 g/cm , 9364 reflections measured (11.33° ≤ 2Θ ≤
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Acknowledgements
8119–9124.
We are grateful to the Maurice Wilkins Centre for a PhD
scholarship (JAJM) and flexible funding (JEH, PTS), Victoria
University of Wellington for a VUW Doctoral Scholarship (KKS)
and a URF grant (JEH, AB), and to the Wellington Medical
Research Foundation for financial support (JHM). We are
endebted to Russell Hewitt and Robert Keyzers for helpful
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Keywords: α-selective alkynylation • cyclopropane ring
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Entry for the Table of Contents
FULL PAPER
Kalpani K. Somarathne, Jordan A. J.
McCone, Amira Brackovic, José Luis
Pinedo Rivera, J. Robin Fulton, Euan
Russell, Jessica J. Field, Christopher L.
Orme, Hedley L. Stirrat, Jasmin
Riesterer, Paul H. Teesdale-Spittle,
John H. Miller, and Joanne E. Harvey*
Analogues of the fungal metabolite (–)-TAN-2483B were synthesised from D-
mannose via a cyclopropane ring expansion, α-selective alkynylation, Wittig-type
side-chain attachment and carbonylative lactonisation.
Page No. – Page No.
Synthesis of Bioactive Side-Chain
Analogues of TAN-2483B
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