Efficient synthesis of syringolides, secosyrins, and syributins through a common approach

Article abstract of DOI:10.1016/j.tet.2008.11.079

A new common synthetic approach toward the elicitors syringolides and their related natural products, secosyrins and syributins, is described here. This uses d-arabinose as starting material and efficiently delivers the targeted compounds through a sequen

Full text of DOI:10.1016/j.tet.2008.11.079

Tetrahedron 65 (2009) 1048–1058
Contents lists available at ScienceDirect
Tetrahedron
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Efficient synthesis of syringolides, secosyrins, and syributins through
a common approach
*
Anastasia-Aikaterini C. Varvogli, Ioannis N. Karagiannis, Alexandros E. Koumbis
Laboratory of Organic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 541 24, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 August 2008
Received in revised form 5 November 2008
Accepted 20 November 2008
Available online 28 November 2008
A new common synthetic approach toward the elicitors syringolides and their related natural products,
secosyrins and syributins, is described here. This uses D-arabinose as starting material and efficiently
delivers the targeted compounds through a sequential tandem HWE olefination–lactonization process
and an IHMA reaction.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
a spontaneous hypersensitive response (HR) occurs causing
a localized cell death. Accumulation of phytoalexins around the
Many plant pathogens produce signal molecules (elicitors),
which are specifically recognized by certain resistant plants, initi-
ating an acute defense response.1 Among them, Gram-negative
bacteria expressing the class I homology group of avirulence gene D
(avrD) alleles (genes cloned from Pseudomonas syringae pv. tomato)
produce two relatively low molecular weight compounds, syrin-
golides 1 and 2 (1a and 1b, Fig. 1). These metabolites are the first
known extracellular non-proteinaceous elicitors.2 Soybean plants
carrying the disease-resistance complementary gene Rgp4 detect
through their encoded membrane receptors the presence of
syringolides when attacked by these pathogens. As a result
infected site is consequently induced and, overall, this defending
mechanism leads to the inability of the pathogen to successfully
parasitize the plant.2
Syringolides were isolated by Sims et al.2,3 from cultivars of the
plant pathogen P. syringae pv. tomato. Elucidation of their structure
was accomplished by the same group using NMR experiments and
confirmed by X-ray crystallography whereas their absolute con-
figuration was initially postulated based on the assumption that
they biosynthetically derive from the naturally occurring D-xylu-
lose. Both metabolites were found to have the same main core, an
oxygen-rich tricyclic C-glycosidic framework, indicating the latter
as the critical recognition feature.
Bicyclic secosyrins 1 and 2 (2a and 2b) share with syringolides
the rather rare 1,7-dioxaspiro[4.4]nonane skeleton,4 whereas
monocyclic syributins 1 and 2 (3a and 3b) are butenolide de-
rivatives (Fig. 1). All these metabolites, obviously structurally and
stereochemically related to 1, were isolated from the same culture
filtrates.5 Although 2 and 3 have simpler structures and, in sharp
contrast to 1, are not active elicitors, they are of equal interest since
they are co-produced with the latter. A possible biogenetic pathway
connects 1 and 2 (through a reverse Claisen cleavage) and, in turn, 2
and 3 (through a tandem retro Michael reaction and 1,3-acyl mi-
gration process).
Investigation of the nature of avrD gene, the function of its
protein expression and the receptor protein could provide a deeper
understanding of the HR phenomenon. Moreover, syringolides are
of particular biological interest since they behave analogously to
the antigens recognized by the immune system of vertebrates. The
unique properties of 1 triggered extensive work regarding their
biochemical evaluation in plant research6 and, in combination with
their stimulating structures and low natural abundance, resulted in
efforts toward their total syntheses.7–13 Secosyrins14–17 and syri-
butins9,16–19 have also been the synthetic target of several research
O
O
H
O
HO
O
OH
Me(CH2)n
H
O
1a n = 4
1b n = 6
O
O
O
OCO(CH2)nMe
OH
O
OH
HO
Me(CH2)nCOO
2a n = 4
2b n = 6
3a n = 4
3b n = 6
Figure 1.
* Corresponding author. Tel.: þ30 2310 997839; fax: þ30 2310 997679.
E-mail address: akoumbis@chem.auth.gr (A.E. Koumbis).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.079

A.-A.C. Varvogli et al. / Tetrahedron 65 (2009) 1048–1058
1049
plan a
plan b
IHMA
reaction
P'O
O
O
O
(CH2)nMe
O
2
ROOC
1
O
acylation
lactone
olefination
PO
OP
formation
7
HO
OH
Syributins (3)
one-pot tandem
olefination - lactonization
IHMA
O
reaction
O
O
O
OP'
HO
O
O
O
OH
OH
O
OP
OP
OP
OP
O
OH
Me(CH2)n
HO
acylation
PO
PO
D-arabinose (6)
4
5
Secosyrins (2)
O
O
O
H
acylation
HO
Me(CH2)n
IHMA
reaction
O
OH
H
Syringolides (1)
Scheme 1. Retrosynthetic analysis (P, P0¼protecting groups).
O
O
i
groups. Chiral pool approaches were mainly adopted for the
preparation of enantiopure 1–3, with a preference to use various
tartrates7,15,16 or carbohydrate derivatives20 as starting materials.
Interestingly, Wong’s group11,15–18 is the only one to have presented
so far a successful common strategy for the synthesis of all six
natural products.
TBDPSO
D-arabinose
O
BnO
ii
8
OTBDPS
OH
O
HO
OH
OH
iii
TBDPSO
In the context of our continuous research work21 concerning the
synthesis of natural products with intriguing structures and prop-
erties, using arabinose derivatives as starting materials, we recently
published22 a new total synthesis of secosyrins 1 and 2. Herein, we
wish to present in detail those results and, in addition, exhibit the
application of the same flexible strategy in the preparation of
syributins and syringolides.23
BnO
BnO
OH
10
9
OTBDPS
OTBDPS
O
iv
HO
BnO
v
O
O
O
O
BnO
2. Results and discussion
11
12
Scheme 2. Synthesis of the key ketone 12. (i) TBDPSCl, DMAP, pyridine, 0–25 ꢀC then
2,2-dimethoxypropane, p-TsOH, Me2CO, 25 ꢀC then NaH, BnBr, TBAI, THF, 0–25 ꢀC, 67%;
(ii) aq TFA, CH2Cl2, 0 ꢀC, 87%; (iii) NaBH4, MeOH, 0–25 ꢀC, 99%; (iv) 2,2-dimethoxy-
propane, p-TsOH, Me2CO, 25 ꢀC, 92%; (v) CrO3, Ac2O, pyridine, CH2Cl2, 25 ꢀC, 98%.
We envisioned the synthesis of all six natural products (1–3),
using butenolide derivative 4 (Scheme 1, plan a) as the common
advanced precursor. Thus, with the acylation left for the end steps,
the tetrahydrofuran ring formation is the next obvious disconnec-
tion for secosyrins and syringolides, employing an intramolecular
hetero-Michael addition (IHMA) reaction for the rather difficult
construction of the quaternary center. The unsaturated lactone ring
could be built in a single step from ketose 5 (P0¼H) via a one pot
tandem olefination–lactonization process. Ketose 5 is actually
a protected form of our synthetic targets biosynthetic precursor
combined literature protocols.24,25 Hydrolysis of the acetonide
protecting group in 8 was carefully performed upon treatment with
aqueous trifluoroacetic acid and the resulting lactol 9 was reduced
with NaBH4 to yield almost quantitatively triol 10.26 Selective
protection of the 1,2-diol system in 10, through the formation of the
isopropylidene intermediate 11, unmasked the C-4 hydroxyl
group,27 which under mild oxidation conditions led to the desired
silyl-ketone 12, the equivalent of our designed intermediate 5.
Having a few grams of 12 in our hands we decided to initially
investigate the possibility of constructing the tetrahydrofuran ring
first (plan b). Thus, acidic hydrolysis of 12 was performed to obtain
a mixture of anomeric ketofuranoses 13 (Scheme 3). This trans-
formation was found to be rather problematic and either low
conversion or partial decomposition after extended reaction times
was observed. It was expected that 13 could directly give tetrahy-
drofuran derivative 14 (and/or its Cquat diastereoisomer) under
Wittig olefination conditions, presuming a subsequent IHMA
reaction28 of the intermediate conjugated ester. However, all at-
tempts, at heating 13 with a stable ylide in various solvents and for
(D
-xylulose). This could be easily reached from
D-arabinose (6)
applying standard functional group manipulations.
An alternative approach to the 1,7-dioxaspiro[4.4]nonane sys-
tem, involving formation of the tetrahydrofuran ring before the
construction of the lactone from the corresponding hydroxy-ester
7, could be also employed (plan b). Although it is not possible to
obtain syributins through plan b, the feasibility of this approach to
deliver 1 and 2 was examined too.
Preparation of ketone 12, the key compound for both routes
described above, was realized as outlined in Scheme 2. The
known24 fully protected
b-D-arabinofuranose derivative 8 was
easily reached on a multigram scale and without chromatographic
purification of the intermediates, applying modifications of the

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A.-A.C. Varvogli et al. / Tetrahedron 65 (2009) 1048–1058
H
While we were able to diastereoselectively synthesize the de-
H
sired derivative 14, the low yield and the difficulties we encoun-
tered during its purification prompted us to turn our attention to
the fabrication of the furan ring at a later stage (plan a). For this
purpose ketone 12 was initially desilylated under nearly neutral
conditions in order to avoid epimerization at C-3 (Scheme 4).
Olefination of the obtained hydroxyketone 18 was then examined
(Table 1). In contrast to the results observed with silyl-protected
ketones (12 and 13),34 this substrate gave the desired butenolide 20
and the Z-unsaturated ester 19 under the Wittig reaction condi-
tions (entry 1) but in moderate yields. Further experimentation
using the HWE protocol with different bases, concentrations, and
temperature ranges allowed us to optimize the yield of 20 (entries
2–5). Concentration of starting material in the reaction mixture was
found to be a crucial parameter and, unexpectedly, slightly higher
values gave higher yields (entry 5). Employment of lithium hexa-
fluoroisopropoxide35 had a negative result (entry 6).
TBDPSO
HO
BnO
MeOOC
O
O
i
ii
H
12
TBDPSO
OH
BnO
14
OH
13
iii
vi
TBDPSO
TBDPSO
iv
OH
OH
O
MeO2C
BnO
15
(Z/E = 4:1)
MeO2C
BnO
16
O
(Z/E = 4:1)
v
TBDPSO
OH
O
OH
O
MeO2C
O
O
i
ii
O
BnO
17
O
12
BnO
19
O
OH
BnO
+
18
O
Scheme 3. Exploring synthetic plan b, building first the tetrahydrofuran ring. (i) aq
TFA, CCl4, ꢁ10 ꢀC, 59%; (ii) see text; (iii) (MeO)2P(O)CH2COOMe, n-BuLi, THF, 0–25 ꢀC,
90%; (iv) p-TsOH, MeOH, 0 ꢀC, 79%; (v) Et3N, CHCl3, 0 ꢀC, 14% of 17; (vi) NaH, THF, 0 ꢀC,
16% of 14 and 10% of 17.
O
iii
15
O
O
BnO
20
long periods, failed to give even the olefination intermediate. No
such product was isolated when ketone 12 was subjected to the
same reaction conditions as well.
iv
Next, the olefination step was examined in the presence of
a phosphonate derived unstable ylide using the Horner–Wads-
worth–Emmons (HWE) reaction protocol.29 To our delight an in-
separable mixture of isomeric unsaturated esters 15 (Z/E ca. 4:1) was
obtained in a very good yield from 12, when n-BuLi was used as
base.30 It is noteworthy that at this stage it was practically impos-
sible to confidently determine the exact stereochemistry of the
newly formed double bond in 15. This was indirectly achieved in
later stages (vide infra). Removal of the isopropylidene protecting
group led to 16 but again it was impossible to separate the isomeric
products31 or to securely determine their stereochemistry. Treating
the mixture of diols 16 with excess Et3N at room temperature
resulted in the very slow formation of a new compound, which was
found to be the six-membered unsaturated lactone 17, and not an
IHMA product. Indeed, aftera period of aweek, this reaction mixture
was resolved by chromatography and only 17 (14%) and recovered
diols 16 (76%, in a ratio of ca. 3.2:1) were obtained. This result clearly
gave us the first indication that the partiallyconsumed major isomer
could only have the correct Z stereochemistry for the lactonization.
On the other hand when the mixture of diols 16 was exposed to
an equimolar quantity of NaH, a rather complicated reaction mix-
ture was obtained in a short time. From this mixture we were able
to isolate after tedious chromatographic separations pure furan
derivative 14 along with lactone 17. The stereochemistry of the
quaternary carbon center in 14 was found to be identical with the
one in the targeted secosyrins.32 Formation of the corresponding
diastereoisomer of 14 during this reaction cannot be excluded.
Nevertheless, the higher polarity of the unresolved products led to
the speculation that they represent solely decomposition products.
Analogously, the cyclization of 16 was also tested in the presence of
t-BuOK but neither 14 nor 17 was formed.33 The capability of the
cation employed to stabilize or not the transition state probably
explains the different results obtained for this IHMA reaction.
O
O
O
O
v
OCO(CH2)nMe
OH
OH
OH
RO
BnO
21
22a n = 4, R = Bn
3a n = 4, R = H
22b n = 6, R = Bn
3b n = 6, R = H
vi
vi
Scheme 4. Building first the lactone ring (plan a), synthesis of syributins. (i) TBAF,
AcOH, THF, 0 ꢀC, 85%; (ii) see Table 1; (iii) TBAF, AcOH, THF, 25 ꢀC, 73% of 19, 18% of 20;
(iv) aq AcOH, 25 ꢀC, 95%; (v) Me(CH2)4COCl (for 22a) or Me(CH2)6COCl (for 22b), Et3N,
CH2Cl2, ꢁ20 ꢀC, 81% for 22a, 80% for 22b; (vi) AlCl3, m-xylene, CH2Cl2, ꢁ10 ꢀC, 92% for
3a, 90% for 3b.
It is believed that in both cases (Wittig and HWE) the E-selec-
tivity is a consequence of the free a-hydroxyl group present in 18.
This hydroxyl group forms an intramolecular hydrogen bond with
the ylide carbonyl in the intermediate betaine/oxaphosphetane (or
Table 1
Olefination of ketone 18
Entry Methoda M of 18 (mmol/L) Temp (ꢀC)/time (h) Yields of 20/19 (%)b
1
2
3
4
5
6
A
B
C
C
C
D
65
65
65
65
100
100
110/48
33/11
15/17
27/11
53/8
77/4
dc
ꢁ50 to 25/24
0 to 25/20
ꢁ50 to 0/3
ꢁ50 to 0/3
ꢁ40 to 0/4
a
A: Ph3P¼CHCO2Me, toluene; B: (MeO)2P(O)CH2CO2Me, t-BuOK, 18-C-6, THF; C:
(MeO)2P(O)CH2CO2Me, n-BuLi, THF; D: (MeO)2P(O)CH2CO2Me, n-BuLi, (CF3)2CHOH,
DME.
b
Yields refer to isolated pure compounds.
Only decomposition of starting material was observed.
c

A.-A.C. Varvogli et al. / Tetrahedron 65 (2009) 1048–1058
1051
O
O
(TBS or Bn) plays no important role regarding the diaster-
eoselectivity of this reaction. The stereochemistry of the newly
formed quaternary center was assigned by comparing the spectra
data of easily separable 24 and 25 with those obtained for the
analogous cyclized intermediates17 and it was indisputably assured
when 25 was hydrogenolyzed to give 26. Finally, diol 26 was
regioselectively acylated16 with hexanoic or octanoic anhydride to
afford secosyrin 1 (2a) and secosyrin 2 (2b), respectively.39
(a)
MeO
(b) MeO
HO
O
O
RO
RO
RO
P
RO
P
OSi
O
O
trans substituted
intermediate
cis substituted
intermediate
E-isomer
Z-isomer
A straightforward pathway involving the direct formation of
both rings in spiro lactone 25 (or/and 24) from ketone 18 was also
examined. The highly polar lactol 23, the acidic hydrolysis product
of 18,42 was treated with a large excess of the required phosphonate
but none of the expected products were formed. Spiro lactone 25
was also reached with spontaneous lactonization of the in-
termediate hydroxy-ester formed by desilylation of furan derivative
14 (plan b), proving that the latter had indeed the correct stereo-
chemistry at the quaternary center.
Figure 2. Favored intermediates of the HWE olefination of 18 (a) and 12 (b).
the corresponding oxy-anion) favoring the formation of the
E-isomer of 19. Employing a phosphonate enhances this result
through a three-center interaction (Fig. 2a). Finally, the E-isomer
spontaneously cyclizes36 to give 20 under the specific reaction
conditions. In contrast, the Z-isomer normally dominates when the
a
-hydroxyl was masked (see olefination of 12) since this favorable
As was originally planned, butenolide 20 was also used as the
key compound in order to investigate the synthesis of both syrin-
golides. Thus, applying a boron triflate promoted aldol condensa-
tion43 of 20 with hexanal or octanal led to the corresponding
diastereomeric 3-hydroxyalkyl-butenolides 27a and 27b (Scheme
6). Subsequently, these were smoothly oxidized upon treatment
with Dess–Martin periodinane to give ketones 28a and 28b. At this
stage our fundamental concern was to determine, which is the
correct order of removal of the remaining protecting groups (e.g.,
acetonide and benzyl). An initial attempt to achieve in one step the
simultaneous removal of both groups and the subsequent rings
closure using TMSI in acetonitrile gave erratic results.44 Then,
treatment of ketone 28b with DOWEX Hþ in methanol45 led almost
exclusively to tricycloketal 29.46 Unfortunately, the latter slowly
decomposed when treated with p-toluenesulfonic acid in acetone/
water. This result suggested that the desired tetrahydrofuran ring-
closure is facilitated only when the lactol ring can be simulta-
neously formed. For this reason we attempted the debenzylation of
28b before the formation of the tetrahydrofuran ring. However, the
interaction was absent. Additionally, in this case the bulky silyl
group preferentially occupies a trans position relatively to the ester
group (Fig. 2b).37 The same products (19 and 20) were formed, al-
though in the reverse distribution (ca. 4:1), when the mixture of
esters 15 was desilylated, confirming once again that Z-isomer was
the major component of the mixture.
For the completion of the synthesis of syributins, acetonide 20
was smoothly deprotected with acetic acid to afford 21 (Scheme 4).
Acylation of diol 21 was performed adding hexanoyl or octanoyl
chloride very slowly at low temperature to regioselectively obtain
mono-esters 22a and 22b, respectively. Then, Lewis acid (AlCl3)
promoted debenzylation38 of 22a and 22b led to the preparation of
syributins 1 and 2 (3a and 3b) in very good yields39 without af-
fecting the sensitive butenolide ring.
With the issue of constructing the lactone ring in a single step
resolved, we then turned our attention to the formation of the
spiro-system of secosyrins applying an IHMA reaction on 21
(Scheme 5). This approach had been earlier used17 for the cycliza-
tion of an analogous intermediate40 and proved to be fruitful in our
case as well. Practically, a number of different conditions (bases,
solvents, and temperatures)41 were employed to check not only the
feasibility of this ring-closure but its stereochemical outcome too.
However, the best results were obtained using the conditions
previously reported,17 giving in preference the desired spiro-
tetrahydrofuran system 25 along with its diastereoisomer 24 (in
a ratio of ca. 4.5:1). It seems that the neighboring protective group
O
O
i
HO
20
O
Me(CH2)n
ii
O
BnO
27a n = 4
27b n = 6
O
O
O
HO
O
O
i
ii
Me(CH2)n
14
iv
18
HO
BnO
O
iv or v
BnO
OH
28a n = 4
28b n = 6
23
O
O
O
O
O
O
iii
O
iii (for 28b)
OH
OH
21
O
O
O
+
Me(CH2)n
BnO
24
OH
BnO
OH
OH
BnO
O
O
30a n = 4
30b n = 6
25
Me(CH2)6
v
O
OBn
O
vi
O
O
vi
29
2a
2b
1a
1b
HO
26
Scheme 6. Synthesis of syringolides. (i) Me(CH2)4CHO (for 27a) or Me(CH2)6CHO (for
27b), Bu2BOTf, DIPEA, CH2Cl2, THF, ꢁ78 to ꢁ20 ꢀC, 88% for 27a, 89% for 27b; (ii) Dess–
Martin periodinane, CH2Cl2, 25 ꢀC, 94% for 28a, 93% for 28b; (iii) DOWEX Hþ, MeOH,
25 ꢀC, 97%; (iv) TiCl4, CH2Cl2, ꢁ30 ꢀC, 55% for 30a, 56% for 30b; (v) aq AcOH, 25 ꢀC, 80%
for 30a, 82% for 30b; (vi) AlCl3, m-xylene, CH2Cl2, ꢁ20 ꢀC then p-TsOH, acetone, H2O,
55% for 1a, 53% for 1b.
Scheme 5. Synthesis of secosyrins. (i) aq TFA, CH2Cl2, 0 ꢀC, 80%; (ii) (MeO)2-
P(O)CH2COOMe, n-BuLi, THF, ꢁ50 to 0 ꢀC; (iii) Et3N, CHCl3, 25 ꢀC, 63% of 25 and 14% of
24; (iv) TBAF, THF, 87%; (v) Pd/C, HCl, MeOH, EtOAc, 25 ꢀC, 99%; (vi) [Me(CH2)4CO]2O
(for 2a) or [Me(CH2)6CO]2O (for 2b), Et3N, DMAP, THF, 0 ꢀC, 72% for 2a, 76% for 2b.

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A.-A.C. Varvogli et al. / Tetrahedron 65 (2009) 1048–1058
mild Pd catalyzed transfer hydrogenolysis protocol (1,4-cyclo-
hexadiene protocol)47 was unsuccessful. Aluminum chloride pro-
moted debenzylation38 was also investigated but gave a very
complicated mixture, which after a short work up showed only
traces of syringolide 2 (1b) in the 1H NMR spectra.
was re-dissolved in a mixture of toluene/EtOH (10 mL, 4:1 v/v) and
the solvents were again removed under reduced pressure. This was
repeated three times and the final residue was dissolved in CHCl3
(80 mL). This solution was washed with a 0.5 M HCl solution
(20 mL), water (20 mL) and brine (20 mL), and dried (Na2SO4).
Evaporation of the solvents under reduced pressure gave a thick oil,
which was dissolved in the minimum volume of a mixture of
hexane/EtOAc (2:1 v/v) and passed through a short pad of silica gel
Examining again the reverse order of deprotections, we then
treated 28b with p-toluenesulfonic acid in acetone/water. Surpris-
ingly, this experiment was similarly disappointing. However, more
encouraging was the removal of the acetonide with TiCl4 giving in
moderate yields the desired diols 30a and 30b from 28a and 28b,
respectively.48 Even better results were obtained when the depro-
tection was performed with aqueous acetic acid furnishing the same
diols in good yields. In these latter cases (reactions employing either
TiCl4 or AcOH) formation of a ketal-like product (e.g., 29) was not
observed. At the final steps, diols 30a and 30b were debenzylated
with AlCl3/m-xylene to give initially a very complicated mixture.49
This was resolved upon treatment with p-toluenesulfonic acid in
acetone/water to yield the targeted tricycles, syringolide 1 (1a) and
syringolide 2 (1b), as crystalline solids.39
to yield crude 5-O-tert-butyldiphenylsilyl-D-arabinofuranose as
a colorless syrup. A solution of this lactol, 2,2-dimethoxypropane
(60 mL) and p-toluenesulfonic acid monohydrate (560 mg, 3 mmol)
in acetone (60 mL) was stirred at 25 ꢀC for 3 h. MeOH (60 mL) was
then added and the resulting mixture was diluted with CHCl3
(100 mL), neutralized with saturated aqueous sodium bicarbonate
solution and dried (NaSO4). Removal of the solvents under reduced
pressure gave crude 5-O-tert-butyldiphenylsilyl-1,2-O-isopropy-
lidene-b-D-arabinofuranose as a colorless oil. A solution of this
acetonide in dry THF (50 mL) was added dropwise to a suspension
of NaH (80% in mineral oil, 1.88 g, 62 mmol) in dry THF (250 mL) at
0 ꢀC. After the resulting slurry was vigorously stirred for 1 h, BnBr
(4.4 mL, 38 mmol) was added dropwise at 0 ꢀC, followed by the
addition of TBAI (350 mg, 0.9 mmol). The mixture was stirred at
25 ꢀC overnight. Then, it was quenched by the addition of a satu-
rated aqueous solution of ammonium chloride (25 mL) and
extracted with CH2Cl2 (2ꢂ100 mL). The combined organic phases
were washed with brine (50 mL), dried (NaSO4) and the solvents
were removed under reduced pressure. The residue was purified by
flash column chromatography on silica gel with a mixture of hex-
ane/EtOAc (10:1 v/v) to give 11.6 g of benzyl ether 8 (67% overall
3. Conclusions
In summary, we have presented a detailed study of the prepa-
ration of syringolides (1a and 1b) and their natural related me-
tabolites secosyrins (2a and 2b) and syributins (3a and 3b). As
a result, a convenient alternative synthesis of enantiopure 1–3 was
realized using a common synthetic strategy. This starts from the
known and readily available D-arabinose derived chiron 8 and leads
to the targeted natural products in good overall yields. Briefly, it
employs the stepwise construction of the spiro-framework present
in the desired products, following a well defined sequential HWE
olefination/lactonizationdIHMA pathway. Additionally, useful in-
formation regarding the formation of the butenolide ring and the
correct assembly of the syringolide tricyclic could be deduced from
the present in depth investigation.
from D-arabinose), as a colorless oil. Rf (hexane/EtOAc 3:1 v/v) 0.45;
25
25
[a
]
þ1.3 (c 1.5, CHCl3) [lit.24
[a
]
þ1.0 (c 1.0, CHCl3)]; IR (neat):
D
D
3071, 2933, 2859 cmꢁ1 1H NMR spectra were identical with that
;
reported in the literature;24 13C NMR (CDCl3, 75 MHz):
d 137.5 (C-
iArBn), 135.6, 133.2 (C-iArTBDPS), 133.1 (C-iArTBDPS), 129.72, 129.66,
128.5, 127.8, 127.7, 112.4 (CMe2), 105.7 (C-1), 85.2 (C-4), 85.1 (C-2),
82.9 (C-3), 71.7 (CH2Ph), 63.4 (C-5), 27.0 (CMe2), 26.8 (CMe3), 26.1
(CMe2), 19.2 (CMe3). HRMS (MALDI-FTMS): m/e calcd for
C31H38O5SiNa [(MþNa)þ]: 541.2381. Found: 541.2384.
4. Experimental
4.1. General
4.2.2. 4-O-Benzyl-5-O-tert-butyldiphenylsilyl-D-arabino-
All commercially available grade quality reagents were used
without further purification. All solvents were purified by standard
procedures before use. Dry solvents were obtained by the literature
methods and stored over molecular sieves. All reactions were
conducted under nitrogen atmosphere. All reactions were moni-
tored on commercial available pre-coated TLC plates (layer thick-
ness 0.25 mm) of Kieselgel 60 F254. Compounds were visualized by
use of a UV lamp or/and p-anisaldehyde ethanolic solution and
warming. Column chromatography was performed in the usual
furanose (9)
A 90% aqueous solution of TFA (27.5 mL) was added dropwise to
a solution of acetonide 8 (3.73 g, 7.2 mmol) in CH2Cl2 (50 mL) at
0 ꢀC. After 1 h, the mixture was neutralized by the careful addition
of a saturated aqueous sodium bicarbonate solution (approximately
200 mL). The aqueous phase was extracted with CH2Cl2
(2ꢂ100 mL), the combined organic phases were washed with brine
(25 mL), dried (Na2SO4) and the solvents were evaporated under
reduced pressure. The residue was purified by flash column chro-
matography on silica gel with a mixture of hexane/EtOAc (2:1 v/v)
to give 3.0 g of lactol 9 (87%), as a colorless oil (mixture of anomers,
ca. 1:1). Rf (hexane/EtOAc 2:1 v/v) 0.37; IR (neat): 3419, 3071, 2932,
way using Merck 60 (40–60 mm) silica gel. NMR spectra were
recorded on a 300 or a 400 MHz spectrometer (1H: 300/400 MHz,
13C: 75/100 MHz) in CDCl3, unless otherwise stated. Chemical shifts
are given in parts per million and J in hertz using solvent or tet-
ramethylsilane as an internal reference. IR spectra were recorded
on an FTIR instrument as indicated. Mass spectra were obtained by
electro spray technique, positive mode (ES-MS) or MALDI-FTMS.
2858 cmꢁ1 1H NMR (CDCl3, 300 MHz):
; d 7.68–7.59 (m, 8H, H-
oArTBDPS), 7.48–7.31 (m, 22H, ArH), 5.35–5.29 (m, 2H, H-1), 4.69 and
4.57 (ABq, J¼11.6 Hz, 2H, CH2Ph), 4.68 and 4.54 (ABq, J¼11.6 Hz, 2H,
CH2Ph), 4.33 (br s, 1H, 1ꢂH-3), 4.21–4.03 (m, 6H, 2ꢂH-3 and 1ꢂH-3
and 2ꢂH-4 and 1ꢂH-5), 3.97 (br d, J¼9.8 Hz, 1H, 1ꢂH-5), 3.86–3.80
(m, 2H, 2ꢂH-50), 3.65 (d, J¼11.0 Hz, 1H, OH), 3.58 (d, J¼11.0 Hz, 2H,
OH), 3.43 (d, J¼9.2 Hz, 1H, OH), 1.05 (s, 9H, CMe3), 1.03 (s, 9H,
4.2. Procedures
4.2.1. 4-O-Benzyl-5-O-tert-butyldiphenylsilyl-1,2-O-isopopylidene
CMe3); 13C NMR (CDCl3, 75 MHz):
d 137.6 (C-iArBn), 136.8 (C-iArBn),
b
-
D
-arabinofuranose (8)
TBDPSCl (9.5 mL, 37 mmol) was added dropwise in a solution of
135.6, 135.5, 132.1 (C-iArTBDPS), 132.0 (C-iArTBDPS), 130.07, 130.02,
128.6, 128.4, 128.1, 127.9, 127.8, 127.7, 103.8 (C-1b), 97.4 (C-1a), 84.4
(C-4), 84.2 (C-4), 83.2 (C-3), 82.4 (C-3), 76.5 (C-2), 76.4 (C-2), 72.2
(CH2Ph), 71.8 (CH2Ph), 64.7 (C-5), 64.1 (C-5), 26.7 (CMe3), 26.6
(CMe3), 19.1 (CMe3), 18.9 (CMe3). HRMS (MALDI-FTMS): m/e calcd
for C28H34O5SiNa [(MþNa)þ]: 501.2068. Found: 501.2070.
D-arabinose (5 g, 33 mmol) and DMAP (410 mg, 3.3 mmol) in dry
pyridine (100 mL) at 0 ꢀC. The resulting mixture was stirred at 25 ꢀC
for 48 h. Then, MeOH (80 mL) was added and the solvents were
removed under reduced pressure at 40 ꢀC. The obtained residue

A.-A.C. Varvogli et al. / Tetrahedron 65 (2009) 1048–1058
1053
4.2.3. (2R,3S,4R)-3-(Benzyloxy)-5-tert-butyldiphenylsilyloxy-
pentane-1,2,4-triol (10)
at ꢁ10 ꢀC. The reaction mixture was stirred at the same tempera-
ture for 30 min. Then, H2O (0.5 mL) was added, the mixture was
neutralized by the addition of solid sodium carbonate and extracted
with CHCl3 (3ꢂ5 mL). The combined organic phases were dried
(Na2SO4), the solvents were removed under reduced pressure and
the residue was purified by flash column chromatography on silica
gel with a mixture of hexane/EtOAc (4:1 v/v) to give 42 mg of lactols
13 (59%, ratio of ca. 3:1), as a colorless thick oil. Rf (hexane/EtOAc
NaBH4 (475 mg, 12.6 mmol) was added to a solution of lactol 9
(3.0 g, 6.27 mmol) in MeOH (90 mL) at 0 ꢀC and the resulting sus-
pension was stirred at 25 ꢀC overnight. Then, a few drops of glacial
acetic acid and EtOAc (150 mL) were added and the mixture was
washed with saturated aqueous sodium bicarbonate solution
(2ꢂ25 mL) and brine (25 mL). The organic phase was dried
(Na2SO4) and the solvents were removed under reduced pressure.
The residue was purified by flash column chromatography on silica
2:1 v/v) 0.25; IR (neat): 3445, 3071, 2931, 2858 cmꢁ1
;
1H NMR
(CDCl3, 300 MHz, for the major isomer): 7.71–7.62 (m, 4H,
d
gel with a mixture of hexane/EtOAc (2:1 v/v) to give 2.98 g of triol
10 (99%), as a colorless syrup. Rf (hexane/EtOAc 2:1 v/v) 0.28; [a]
D
H-oArTBDPS), 7.46–7.27 (m, 11H, H-pArTBDPS and H-mArTBDPS and
H-ArBn), 4.77 and 4.66 (ABq, J¼11.6 Hz, 2H, CH2Ph), 4.45 (br s,1H, H-
4), 4.23 (br d, J¼8.5 Hz, 1H, H-3), 4.11 (dd, J¼9.8, 3.0 Hz, 1H, H-5a),
3.95 (s, 1H, OH), 3.88 (d, J¼9.8 Hz, 1H, H-5b), 3.81 and 3.57 (ABq,
J¼11.0 Hz, 2H, CH2OSi), 2.31 (br s, 1H, OH), 1.06 (s, 9H, CMe3); 13C
25
25
ꢁ5.2 (c 1.5, CHCl3) [lit.26
[a
]
ꢁ5.0 (c 1.16, CHCl3)]; IR (neat): 3419,
D
3071, 2931, 2858 cmꢁ1 1H NMR and 13C NMR spectra were iden-
;
tical with those reported in the literature.26 HRMS (MALDI-FTMS):
m/e calcd for C28H36O5SiNa [(MþNa)þ]: 503.2224. Found:
503.2225.
NMR (CDCl3, 75 MHz, for the major isomer):
d 135.70, 135.65 (C-
iArBn), 132.4 (C-iArTBDPS), 132.5 (C-iArTBDPS), 130.0, 128.7, 128.4,
128.0, 127.9, 127.8, 103.6 (C-2), 84.6 (C-3), 74.7 (C-4), 73.6 (C-5), 73.2
(CH2Ph), 67.2 (C-1), 26.8 (CMe3), 19.1 (CMe3). HRMS (MALDI-FTMS):
m/e calcd for C28H34O5SiNa [(MþNa)þ]: 501.2068. Found: 501.2070.
4.2.4. (2R,3R,4R)-3-Benzyloxy-1-tert-butyldiphenylsilyloxy-4,5-
isopropylidenedioxy-2-pentol (11)
A solution of triol 10 (2.23 g, 4.6 mmol), 2,2-dimethoxypropane
(9.1 mL), and p-toluenesulfonic acid monohydrate (70 mg,
0.4 mmol) in acetone (9.1 mL) was stirred at 25 ꢀC for 24 h. Meth-
anol (25 mL) was added and the mixture was diluted with CHCl3
(50 mL), neutralized with saturated aqueous sodium bicarbonate
solution and dried (NaSO4). After evaporation of the solvents under
reduced pressure, the residue was purified by flash column chro-
matography on silica gel with a mixture of hexane/EtOAc (10:1 v/v)
to give 2.20 g of acetonide 11 (92%), as an amorphous white solid. Rf
(hexane/EtOAc 3:1 v/v) 0.61; mp 115–117 ꢀC (lit.26 115–117 ꢀC);
4.2.7. Methyl 2-((2R,3S)-3-benzyloxy-2-tert-butyldiphenyl-
silyloxymethyl-4-hydroxy-tetrahydrofuran-2-yl)acetate (14)
A solution of diols 16a and 16b (64 mg, 0.12 mmol, ratio of ca.
4:1) in dry THF (5 mL) was added dropwise to a suspension of NaH
(80% in mineral oil, 4 mg, 0.13 mmol) in dry THF (5 mL) at 0 ꢀC.
After 4 h at 0 ꢀC, the mixture was neutralized by the addition of
a few drops of AcOH and extracted with Et2O (3ꢂ3 mL). The com-
bined organic phases were washed with saturated aqueous solu-
tion of sodium bicarbonate (3 mL), brine (3 mL), and dried
(Na2SO4). Evaporation of the solvents under reduced pressure
yielded a residue, which was purified by flash column chroma-
tography on silica gel with a mixture of hexane/EtOAc (2:1 v/v) to
give, in the order of elution, 10 mg of furan derivative 14 (16%) and
25
25
[
a
]
þ6.7 (c 1.0, CHCl3) [lit.26
[
a
]
þ6.86 (c 1.02, CHCl3)]; IR (neat):
D
D
3486, 3071, 2932, 2858 cmꢁ1 1H NMR and 13C NMR spectra were
;
identical with those reported in the literature.26 HRMS (MALDI-
FTMS): m/e calcd for C31H40O5SiNa [(MþNa)þ]: 543.2537. Found:
543.2540.
6 mg of lactone 17 (10%). Compound 14: oil; Rf (hexane/EtOAc 1:1 v/
25
v) 0.61; [
a]
þ30.6 (c 0.3, CHCl3); IR (neat): 3440, 3068, 2931, 2858,
D
4.2.5. (3S,4R)-3-Benzyloxy-1-tert-butyldiphenylsilyloxy-4,5-
isopropylidenedioxy-pentan-2-one (12)
1738 cmꢁ1
;
1H NMR (CDCl3, 300 MHz):
d
7.73–7.69 (m, 4H, H-
oArTBDPS), 7.46–7.42 (m, 6H, H-pArTBDPS and H-mArTBDPS), 7.38–7.26
(m, 5H, H-ArBn), 4.66 and 4.47 (ABq, J¼11.4 Hz, 2H, CH2Ph), 4.20 (d,
J¼10.6 Hz,1H, CHHOSi), 4.20 (br s,1H, H-30), 4.11 (d, J¼1.7 Hz,1H, H-
40), 3.99 (dd, J¼9.8, 2.4 Hz, 1H, H-50a), 3.90 (d, J¼9.8 Hz, 1H, H-50b),
3.72 (d, J¼10.6 Hz, 1H, CHHOSi), 3.38 (s, 3H, OCH3), 2.70 and 2.42
A solution of alcohol 11 (1.74 g, 3.34 mmol) in dry CH2Cl2
(20 mL) was added dropwise to a suspension of CrO3 (0.77 g,
7.7 mmol) and dry pyridine (1.25 mL, 15.4 mmol) in dry CH2Cl2
(40 mL). Then, Ac2O (0.7 mL, 7.3 mmol) was added. After stirring at
25 ꢀC for 3 h, the reaction mixture was directly charged on a short
pad of silica gel. Elution with EtOAc afforded the impure product.
Traces of pyridine were removed by co-evaporation with toluene
(2ꢂ10 mL) and the residue was purified by flash column chroma-
tography on silica gel with a mixture of hexane/EtOAc (10:1 v/v) to
(ABq, J¼16.5 Hz, 2H, H-2), 1.59 (br s, 1H, OH), 1.08 (s, 9H, CMe3); 13
C
NMR (CDCl3, 75 MHz): d 171.2 (C-1), 137.7 (C-iArBn), 135.7, 132.2 (C-
iArTBDPS), 130.02, 129.96, 128.3, 127.9, 127.8, 127.7, 127.4, 86.9 (C-20),
86.3 (C-30), 75.1 (C-40), 73.6 (C-50), 73.1 (CH2Ph), 68.5 (C-100), 51.1
(OCH3), 36.9 (C-2), 26.8 (CMe3), 19.2 (CMe3). HRMS (MALDI-FTMS):
m/e calcd for C31H38O6SiNa [(MþNa)þ]: 557.2330. Found: 557.2333.
give 1.70 g of ketone 12 (98%), as a colorless oil. Rf (hexane/EtOAc
25
5:1 v/v) 0.44; [
a
]
ꢁ34.4 (c 2.6, CHCl3); IR (neat): 3071, 2933, 2892,
D
2858, 1738 cmꢁ1; 1H NMR (CDCl3, 300 MHz):
d
7.66–7.63 (m 4H, H-
4.2.8. (Z)- and (E)-Methyl (4R,5R)-4-benzyloxy-3-tert-butyl-
diphenylsilyloxymethyl-5,6-isopropylidenedioxy-hex-2-
enoate (15a and 15b)
oArTBDPS), 7.47–7.35 (m, 6H, H-pArTBDPS and H-mArTBDPS), 7.28–7.26
(m, 3H, H-oArBn and H-pArBn), 7.18–7.15 (m, 2H, H-oArBn), 4.58 and
4.50 (ABq, J¼18.9 Hz, 2H, H-1), 4.49 and 4.34 (ABq, J¼12.2 Hz, 2H,
CH2Ph), 4.22 (dd, J¼11.6, 6.1 Hz,1H, H-3), 3.94–3.87 (m, 2H, H-4 and
H-5a), 3.76 (dd, J¼8.6, 6.7 Hz, 1H, H-5b), 1.33 (s, 3H, CMe2), 1.29 (s,
A 15% solution of n-BuLi in hexanes (0.15 mL, 0.35 mmol) was
added dropwise to a solution of (MeO)2P(O)CH2COOMe (0.06 mL,
0.37 mmol) in dry THF (1 mL) at 0 ꢀC. The mixture was kept for
30 min at the same temperature before the dropwise addition of
a solution of ketone 12 (78 mg, 0.15 mmol) in dry THF (1 mL). After
stirring at 25 ꢀC for 20 h, a saturated aqueous solution of ammo-
nium chloride (2 mL) was added and the resulting slurry was
extracted with EtOAc (3ꢂ5 mL). The combined organic phases were
washed with brine (5 mL) and dried (Na2SO4). The solvents were
evaporated under reduced pressure and the residue was purified by
flash column chromatography on silica gel with a mixture of hex-
ane/EtOAc (10:1 v/v) to give 78 mg of inseparable unsaturated es-
ters 15a and 15b (90%, ratio of ca. 4:1), as a colorless oil. Compound
15a: Rf (hexane/EtOAc 6:1 v/v) 0.38; IR (neat, for the mixture): 3071,
3H, CMe2), 1.08 (s, 9H, CMe3); 13C NMR (CDCl3, 75 MHz):
d 207.2 (C-
2), 136.9 (C-iArBn), 135.6, 132.9 (C-iArTBDPS), 132.8 (C-iArTBDPS),
129.9, 128.4, 128.0, 127.7, 109.6 (CMe2), 82.5 (C-3), 76.0 (C-4), 73.3
(CH2Ph), 68.9 (C-1), 65.5 (C-5), 26.7 (CMe3), 26.1 (CMe2), 25.3
(CMe2), 19.2, (CMe3). HRMS (MALDI-FTMS): m/e calcd for
C31H38O5SiNa [(MþNa)þ]: 541.2381. Found: 541.2383.
4.2.6. (3S,4R)-3-Benzyloxy-2-tert-butyldiphenylsilyloxymethyl-
tetrahydrofuran-2,4-diol (13)
A 90% aqueous solution of TFA (1.1 mL) was added dropwise
to a solution of acetonide 12 (78 mg, 0.15 mmol) in CCl4 (0.11 mL)

1054
A.-A.C. Varvogli et al. / Tetrahedron 65 (2009) 1048–1058
2932, 2858, 1717 cmꢁ1; 1H NMR (CDCl3, 300 MHz):
d
7.66–7.63 (m,
4.41 (ABq, J¼11.6 Hz, 2H, CH2Ph), 4.41–4.38 (m, 1H, H-5), 4.28 and
4.20 (ABq, J¼17.7, 1.8 Hz, 2H, H-40), 4.03 (dd, J¼11.6, 7.3 Hz, 1H, H-
60a), 3.97 (d, J¼2.5 Hz, 1H, H-6), 3.89 (dd, J¼11.6, 6.1 Hz, 1H, H-60b),
2.40 (br s, 1H, OH), 1.08 (s, 9H, CMe3); 13C NMR (CDCl3, 75 MHz):
4H, H-oArTBDPS), 7.44–7.32 (m, 6H, H-pArTBDPS and H-mArTBDPS),
7.25–7.23 (m, 3H, H-oArBn and H-pArBn), 7.15–7.12 (m, 2H, H-
mArBn), 6.47 (s, 1H, H-2), 5.29 (d, J¼5.3 Hz, 1H, H-4), 4.55 and 4.49
(ABq, J¼9.2 Hz, 2H, CH2OSi), 4.35 and 4.26 (ABq, J¼11.8 Hz, 2H,
CH2Ph), 4.18 (q, J¼5.5 Hz, 1H, H-5), 3.77 (dd, J¼7.0, 4.6 Hz, 2H, H-6),
3.71 (s, 3H, OCH3), 1.29 (s, 6H, CMe2), 1.09 (s, 9H, CMe3); 13C NMR
d
163.5 (C-4), 156.6 (C-2), 136.6 (C-iArTBDPS), 135.4, 132.4 (C-iArBn),
132.3, 130.0, 128.5, 128.3, 128.0, 127.9, 116.5 (C-3), 80.2 (C-5), 72.8
(CH2Ph), 67.2 (C-6), 63.4 (C-40), 60.8 (C-60), 26.7 (CMe3), 19.1 (CMe3).
HRMS (MALDI-FTMS): m/e calcd for C30H34O5SiNa [(MþNa)þ]:
525.2068. Found: 525.2070.
(CDCl3, 75 MHz):
d 166.8 (C-1), 158.4 (C-3), 137.6 (C-iArBn), 135.4,
132.9 (C-iArTBDPS), 129.8, 128.1, 127.8, 127.5, 116.7 (C-2), 109.8
(CMe2), 77.8 (C-4), 76.1 (C-5), 71.6 (CH2Ph), 65.5 (CH2OSi), 62.9 (C-
6), 51.3 (OCH3), 26.8 (CMe3), 26.1 (CMe2), 25.8 (CMe2), 19.2 (CMe3).
HRMS (MALDI-FTMS): m/e calcd for C34H42O6SiNa [(MþNa)þ]:
597.2643. Found: 597.2642. Compound 15b: 1H NMR (CDCl3,
4.2.11. (3S,4R)-3-Benzyloxy-1-hydroxy-4,5-isopropylidenedioxy-
pentan-2-one (18)
A solution of TBAF in THF (1 M, 1.1 mL, 1.1 mmol) was added to
300 MHz, selected peaks):
H-4), 3.61 (s, 3H, OCH3), 1.39 (s, 3H, CMe2), 1.33 (s, 3H, CMe2), 1.04
(s, 9H, CMe3); 13C NMR (CDCl3, 75 MHz, selected peaks):
166.0 (C-
1), 156.3 (C-3), 137.8, 135.5, 132.9, 117.9 (C-2), 110.0 (CMe2), 78.2 (C-
4), 76.0 (C-5), 71.2 (CH2Ph), 65.7 (CH2OSi), 61.1 (C-6), 51.2 (OCH3),
26.7 (CMe3), 26.3 (CMe2), 25.6 (CMe2), 19.1 (CMe3).
d
6.05 (s, 1H, C-2), 5.19 (d, J¼15.3 Hz, 1H,
a solution of AcOH (65 mL, 1.1 mmol) in THF (10 mL). The resulting
mixture was added dropwise to a solution of silyl ether 12 (518 mg,
1 mmol) in THF (25 mL) at 0 ꢀC. After 1 h, EtOAc (30 mL) was added
and the mixture was washed with brine (30 mL). The aqueous
phase was back-extracted with EtOAc (2ꢂ30 mL). The combined
organic phases were dried (Na2SO4) and the solvents were removed
under reduced pressure. The obtained residue was purified by flash
column chromatography on silica gel with a mixture of hexane/
d
4.2.9. (Z)- and (E)-Methyl (4R,5R)-4-benzyloxy-3-tert-butyl-
diphenylsilyloxymethyl-5,6-dihydroxy-hex-2-enoate
(16a and 16b)
EtOAc (3:1 v/v) to give 238 mg of alcohol 18 (85%), as a colorless oil.
25
Rf (hexane/EtOAc 3:1 v/v) 0.20; [
a
]
ꢁ53.6 (c 3.4, CHCl3); IR (neat):
D
p-Toluenesulfonic acid monohydrate (2 mg, 0.01 mmol) was
added to solution of a 4:1 mixture of acetonides 15a and 15b
(57 mg, 0.1 mmol) in MeOH (5 mL), at 0 ꢀC. After 24 h at the same
temperature solid sodium bicarbonate was added, followed by
brine (5 mL). The mixture was extracted with EtOAc (3ꢂ5 mL) and
dried (Na2SO4). The solvents were removed under reduced pressure
and the residue was purified by flash column chromatography on
silica gel with a mixture of hexane/EtOAc (2:1 v/v) to give 42 mg of
inseparable diols 16a and 16b (79%, ratio of ca. 4:1), as a colorless
oil. Compound 16a: Rf (hexane/EtOAc 1:1 v/v) 0.39; IR (neat, for the
3445, 2987, 2935, 2892, 1727 cmꢁ1 1H NMR (CDCl3, 300 MHz):
;
d
7.40–7.32 (m, 5H, ArH), 4.69 and 4.61 (ABq, J¼19.7 Hz, 2H, CH2Ph),
4.51 and 4.43 (ABq, J¼20.1 Hz, 2H, H-1), 4.34 (dd, J¼11.0, 6.1 Hz, 1H,
H-3), 4.06–4.00 (m, 2H, H-4 and H-5a), 3.90 (dd, J¼8.6, 6.7 Hz, 1H,
H-5b), 2.91 (br s, 1H, OH), 1.43 (s, 3H, CMe2), 1.33 (s, 3H, CMe2); 13
C
NMR (CDCl3, 75 MHz):
d 210.4 (C-2), 136.5 (C-iAr), 128.4 (C-oAr),
128.1 (C-pAr), 127.9 (C-mAr), 109.7 (CMe2), 82.5 (C-3), 76.1 (C-4),
73.8 (CH2Ph), 67.7 (C-1), 65.3 (C-5), 25.9 (CMe2), 25.1 (CMe2). HRMS
(MALDI-FTMS): m/e calcd for C15H20O5Na [(MþNa)þ]: 303.1203.
Found: 303.1201.
mixture): 3445, 3071, 2932, 2858, 1717 cmꢁ1
;
1H NMR (CDCl3,
300 MHz): 7.67–7.62 (m, 4H, H-oArTBDPS), 7.46–7.30 (m, 6H, H-
d
4.2.12. (Z)-Methyl (4R,5R)-4-benzyloxy-3-hydroxymethyl-5,6-
isopropylidenedioxy-hex-2-enoate (19) and 4-((10R,20R)-10-
benzyloxy-20,30-isopropylidenedioxy-propyl)-furan-2(5H)-one (20)
pArTBDPS and H-mArTBDPS), 7.27–7.25 (m, 3H, H-oArBn and H-pArBn),
7.08–7.04 (m, 2H, H-oArBn), 6.55 (s, 1H, H-2), 5.21 (d, J¼6.1 Hz, 1H,
H-4), 4.44 (br s, 2H, H-30), 4.28 and 4.21 (ABq, J¼11.0 Hz, 2H,
CH2Ph), 3.75 (s, 3H, OCH3), 3.65–3.58 (m, 1H, H-5), 3.53–3.51 (m,
2H, H-6), 2.72 (br s, 2H, OH), 1.10 (s, 9H, CMe3); 13C NMR (CDCl3,
4.2.12.1. HWE reaction of 18. A 15% solution of n-BuLi in hexanes
(0.33 mL, 0.76 mmol) was added dropwise to
a solution of
75 MHz):
d
167.5 (C-1), 158.2 (C-3), 136.9 (C-iArTBDPS), 135.41,
(MeO)2P(O)CH2COOMe (0.15 mL, 0.93 mmol) in dry THF (3 mL) at
ꢁ50 ꢀC. The mixture was stirred for 30 min while the temperature
was left to rise to ꢁ10 ꢀC. Then, it was re-cooled to ꢁ50 ꢀC and
a solution of hydroxyketone 18 (126 mg, 0.45 mmol) in dry THF
(3 mL) was added dropwise. The resulting slurry was stirred for 3 h
while the temperature was left to rise to ꢁ10 ꢀC. A saturated
aqueous solution of ammonium chloride (15 mL) was added and
the mixture was extracted with EtOAc (3ꢂ15 mL). The combined
organic phases were washed with brine (15 mL), dried (Na2SO4)
and the solvents were removed under reduced pressure. The
obtained residue was purified by column chromatography on silica
gel with a mixture of hexane/EtOAc (6:1 v/v) to give, in the order of
135.35, 132.6 (C-iArBn), 129.9, 128.3, 128.0, 127.9, 127.8, 117.7 (C-2),
77.1 (C-4), 73.2 (CH2Ph), 72.1 (C-5), 62.8 (C-30), 62.6 (C-6), 51.7
(OCH3), 26.8 (CMe3), 19.2 (CMe3). HRMS (MALDI-FTMS): m/e calcd
for C31H38O6SiNa [(MþNa)þ]: 557.2330. Found: 557.2327. Com-
pound 16b: 1H NMR (CDCl3, 300 MHz, selected peaks):
d 6.05 (s, 1H,
H-2), 3.62 (s, 3H, OCH3), 1.04 (s, 9H, CMe3); 13C NMR (CDCl3,
75 MHz, selected peaks): 165.9 (C-1), 155.8 (C-8), 137.1 (C-
d
iArTBDPS), 132.2 (C-iArBn), 129.8, 117.1 (C-2), 78.7 (C-4), 72.7 (CH2Ph),
71.6 (C-5), 64.2 (C-30), 61.4 (C-6), 51.2 (OCH3), 26.5 (CMe3), 19.1
(CMe3).
4.2.10. (5R,6S)-5-Benzyloxy-4-tert-butyldiphenylsilyloxymethyl-6-
hydroxymethyl-5,6-dihydro-2H-pyran-2-one (17)
elution, 6 mg of alcohol 19 (4%) and 105 mg of lactone 20 (77%).
25
Compound 19: oil; Rf (hexane/EtOAc 3:1 v/v) 0.21; [
CHCl3); IR (neat): 3468, 2987, 2935, 1715 cmꢁ1
300 MHz): 7.33–7.29 (m, 5H, ArH), 6.16 (br s, 1H, H-2), 5.34 (d,
a
]
D
ꢁ21.8 (c 0.7,
Et3N (0.44 mL, 3.2 mmol) was added to a solution of diols 16a
and 16b (53 mg, 0.1 mmol, ratio of ca. 4:1) in CHCl3 (7 mL) at 0 ꢀC.
After stirring at 0 ꢀC for 7 days, the solvents were removed under
reduced pressure and the residue was purified by flash column
chromatography on silica gel with a mixture of hexane/EtOAc (2:1
v/v) to give 40 mg of unreacted starting material (16a and 16b in
;
1H NMR (CDCl3,
d
J¼3.7 Hz, 1H, H-4), 4.56 and 4.45 (ABq, J¼12.1 Hz, 2H, CH2Ph), 4.47
and 4.17 (ABq, J¼14.6 Hz, 2H, CH2OH), 4.33 (td, J¼6.7, 3.7 Hz, 1H, H-
5), 4.02 (t, J¼7.6 Hz, 1H, H-6a), 3.92 (t, J¼7.6 Hz, 1H, H-6b), 3.70 (s,
3H, MeO), 2.37 (br s, 1H, OH), 1.45 (s, 3H, CMe2), 1.36 (s, 3H, CMe2);
a ratio of ca. 3.2:1, 76%) and 7 mg of lactone 17 (14%), as a colorless
13C NMR (CDCl3, 75 MHz):
d 166.4 (C-1), 158.8 (C-3), 137.5 (C-iAr),
25
oil. Compound 17: Rf (hexane/EtOAc 1:1 v/v) 0.47; [
a
]
D
ꢁ40.4 (c 0.7,
128.3 (C-oAr),127.8 (C-pAr),127.7 (C-mAr),118.8 (C-2),110.1 (CMe2),
78.1 (C-4), 75.7 (C-5), 72.4 (CH2Ph), 65.9 (CH2OH), 62.7 (C-6), 51.4
(MeO), 26.0 (CMe2), 25.8 (CMe2). HRMS (MALDI-FTMS): m/e calcd
CHCl3); IR (neat): 3425, 3071, 2931, 2858, 1716 cmꢁ1
;
1H NMR
(CDCl3, 300 MHz): 7.64–7.60 (m, 4H, H-oArTBDPS), 7.48–7.37 (m,
d
6H, H-pArTBDPS and H-mArTBDPS), 7.24–7.21 (m, 3H, H-oArBn and H-
pArBn), 7.13–7.10 (m, 2H, H-mArBn), 6.33 (br s, 1H, H-3), 4.46 and
for C18H24O6Na [(MþNa)þ]: 359.1465. Found: 359.1466. Compound
25
20: oil; Rf (hexane/EtOAc 3:1 v/v) 0.17; [
a]
ꢁ48.3 (c 1.6, CHCl3); IR
D

A.-A.C. Varvogli et al. / Tetrahedron 65 (2009) 1048–1058
1055
(neat): 2987, 2936, 2890, 1780 cmꢁ1
;
1H NMR (CDCl3, 300 MHz):
residue was purified by flash column chromatography on silica gel
d
7.39–7.30 (m, 5H, ArH), 6.07 (s, 1H, H-3), 4.93 and 4.85 (dABq,
with a mixture of hexane/EtOAc (4:1 v/v) to give 117 mg of ester
22a (81%), as a colorless oil. Rf (hexane/EtOAc 1:1 v/v) 0.48; [a]
D
25
J¼18.0, 1.8 Hz, 2H, CH2Ph), 4.67 and 4.51 (ABq, J¼12.2 Hz, 2H, H-5),
4.43 (d, J¼4.9 Hz, 1H, H-10), 4.33 (ddd, J¼7.0, 6.1, 4.9 Hz, 1H, H-20),
4.03 (dd, J¼8.6, 7.0 Hz, 1H, H-30a), 3.82 (dd, J¼8.6, 6.1 Hz, 1H, H-30b),
1.40 (s, 3H, CMe2), 1.34 (s, 3H, CMe2); 13C NMR (CDCl3, 75 MHz):
ꢁ27.0 (c 0.4, CHCl3); IR (neat): 3454, 2945, 2931, 2872, 1780,
1747 cmꢁ1 1H NMR (CDCl3, 300 MHz):
;
d
7.42–7.28 (m, 5H, ArH),
6.11 (s, 1H, H-40), 4.94 (s, 2H, CH2Ph), 4.67 and 4.47 (ABq, J¼11.6 Hz,
2H, H-20), 4.40 (d, J¼3.7 Hz, 1H, H-3), 4.19 and 4.13 (dABq, J¼11.6,
4.9 Hz, 2H, H-1), 3.98–3.91 (m, 1H, H-2), 2.67 (d, J¼6.4 Hz, 1H, OH),
2.28 (t, J¼7.7 Hz, 2H, H-200), 1.59 (p, J¼7.3 Hz, 2H, H-300), 1.30–1.22
(m, 4H, H-400 and H-500), 0.89 (t, J¼6.7 Hz, 3H, H-600); 13C NMR
d
172.9 (C-2), 166.6 (C-4), 136.7 (C-iAr), 128.7 (C-oAr), 128.3 (C-pAr),
127.9 (C-mAr), 118.6 (C-3), 110.1 (CMe2), 76.10 (C-10), 75.2 (CH2Ph),
72.5 (C-20), 72.1 (C-5), 65.2 (C-30), 26.0 (CMe2), 24.9 (CMe2). HRMS
(MALDI-FTMS): m/e calcd for C17H20O5Na [(MþNa)þ]: 327.1203.
Found: 327.1201.
(CDCl3, 75 MHz):
d
173.9 (C-100), 172.9 (C-50), 166.8 (C-30), 136.2 (C-
iAr), 128.7 (C-oAr), 128.6 (C-pAr), 128.1 (C-mAr), 118.6 (C-40), 74.9
(C-3), 72.5 (C-2), 71.8 (C-20), 71.3 (CH2Ph), 64.4 (C-1), 33.9 (C-200),
31.2 (C-400), 24.4 (C-300), 22.2 (C-500), 13.9 (C-600). HRMS (MALDI-
FTMS): m/e calcd for C20H26O6Na [(MþNa)þ]: 385.1622. Found:
385.1622.
4.2.12.2. Wittig reaction of 18. Methyl (triphenylphosphoranyli-
dene)acetate (60 mg, 0.18 mmol) was added to a solution of
hydroxyketone 18 (42 mg, 0.15 mmol) in dry toluene (20 mL). The
mixture was heated at reflux for 48 h. Then, the solvent was re-
moved under reduced pressure and the residue was purified by
flash column chromatography on silica gel with a mixture of hex-
ane/EtOAc (6:1 v/v) to give 5 mg of alcohol 19 (10%) and 15 mg of
lactone 20 (33%).
4.2.15. Syributin 1 (3a)
A solution of benzyl ether 22a (72 mg, 0.2 mmol) in a 2:1 mix-
ture of dry CH2Cl2 and m-xylene (6 mL) was added to a suspension
of AlCl3 (80 mg, 0.6 mmol) in CH2Cl2 (4 mL) at ꢁ20 ꢀC. The reaction
mixture was vigorously stirred at 0 ꢀC for 6 h. Then, iced water
(2 mL) was added and extracted with Et2O (2ꢂ25 mL). The com-
bined organic phases were washed with brine (10 mL) and dried
(Na2SO4). The solvents were evaporated under reduced pressure
and the resulting residue was purified by flash column chroma-
4.2.12.3. Desilylation of 15a and 15b. A solution of TBAF in THF
(1 M, 0.1 mL, 0.1 mmol) was added to a solution of AcOH (6 mL,
0.1 mmol) in THF (4 mL). The resulting mixture was added drop-
wise to a solution of silyl ethers 15a and 15b (52 mg, 0.09 mmol,
ratio of ca. 4:1) in THF (4 mL) at 0 ꢀC. After 24 h at 25 ꢀC the mixture
was neutralized with saturated aqueous sodium bicarbonate solu-
tion and extracted with EtOAc (3ꢂ5 mL). The combined organic
phases were washed with brine (5 mL), dried (Na2SO4) and the
solvents were removed under reduced pressure. The residue was
purified by flash column chromatography on silica gel with a mix-
ture of hexane/EtOAc (6:1 v/v) to give 22 mg of alcohol 19 (73%) and
5 mg of lactone 20 (18%).
tography on silica gel with a mixture of hexane/EtOAc (3:1 v/v) to
25
give 50 mg of syributin 1 (3a, 92%) as a colorless oil. [
a
]
D
þ6.1 (c
20
0.9, CHCl3) [lit.17
[
a]
þ6.09 (c 0.8, CHCl3)]; IR, 1H NMR and 13C
D
NMR spectra were identical with those reported in the literature.16
HRMS (MALDI-FTMS): m/e calcd for C13H20O6Na [(MþNa)þ]:
295.1152. Found: 295.1153.
4.2.16. (2R,3R)-3-Benzyloxy-2-hydroxy-3-(50-oxo-20,50-
dihydrofuran-30-yl)-propyl octanoate (22b)
4.2.13. 4-((10R,20R)-10-Benzyloxy-20,30-dihydroxy-
propyl)-furan-2(5H)-one (21)
Following the procedure described for 22a, diol 21 (106 mg,
A solution of acetonide 20 (152 mg, 0.5 mmol) in 80% aqueous
AcOH (1 mL) was stirred at room temperature for 2 days. Then, the
reaction mixture was diluted with EtOAc (20 mL) and washed with
a saturated aqueous solution of sodium bicarbonate (2ꢂ10 mL). The
combined aqueous phases were back-extracted with EtOAc (10 mL).
The combined organic phases were washed with brine (10 mL),
dried (Na2SO4) and evaporated under reduced pressure. The
obtained residue was purified by flash column chromatography on
0.4 mmol) gave using octanoyl chloride 120 mg of ester 22b (80%)
25
as a colorless oil. Rf (hexane/EtOAc 1:1 v/v) 0.47; [
a
]
D
ꢁ27.0 (c 0.9,
CHCl3); IR (neat): 3453, 2940, 2928, 2857, 1780, 1747 cmꢁ1; 1H NMR
(CDCl3, 300 MHz):
7.40–7.27 (m, 5H, ArH), 6.10 (s, 1H, H-40), 4.94
d
(s, 2H, CH2Ph), 4.67 and 4.47 (ABq, J¼11.6 Hz, 2H, H-20), 4.40 (d,
J¼3.7 Hz, 1H, H-3), 4.19 and 4.13 (dABq, J¼11.6, 4.9 Hz, 2H, H-1),
3.98–3.94 (m, 1H, H-2), 3.00 (br s, 1H, OH), 2.27 (t, J¼7.3 Hz, 2H, H-
200), 1.60–1.56 (m, 2H, H-300), 1.33–1.23 (m, 8H, H-400-H-700), 0.88 (t,
silica gel with a mixture of hexane/EtOAc (2:1 v/v) to give 126 mg of
J¼6.4 Hz, 3H, H-800); 13C NMR (CDCl3, 75 MHz):
d
173.8 (C-100), 173.0
25
diol 21 (95%), as a colorless oil. Rf (hexane/EtOAc 1:2 v/v) 0.18; [
a
]
1DH
(C-50), 166.9 (C-30), 136.2 (C-iAr), 128.7 (C-oAr), 128.5 (C-pAr), 128.1
(C-mAr),118.5 (C-40), 75.0 (C-3), 72.4 (CH2Ph), 71.9 (C-2), 71.2 (C-20),
64.4 (C-1), 33.9 (C-200), 31.5 (C-600), 29.0 (C-500), 28.8 (C-400), 24.7 (C-
300), 22.5 (C-700), 14.0 (C-800). HRMS (MALDI-FTMS): m/e calcd for
C22H30O6Na [(MþNa)þ]: 413.1935. Found: 413.1933.
þ64.7 (c 0.8, CHCl3); IR (neat): 3406, 2926, 2860, 1747 cmꢁ1
;
NMR (CDCl3, 300 MHz):
d 7.37–7.28 (m, 5H, ArH), 6.09 (s, 1H, H-3),
4.90 (s, 2H, CH2Ph), 4.62 and 4.50 (ABq, J¼11.6 Hz, 2H, H-5), 4.45 (d,
J¼4.3 Hz, 1H, H-10), 3.80–3.76 (m, 1H, H-20), 3.68 (dd, J¼11.6, 3.7 Hz,
1H, H-30a), 3.58 (dd, J¼11.6, 6.1 Hz, 1H, H-30b), 3.41 (br s, 1H, OH),
2.87 (br s, 1H, OH); 13C NMR (CDCl3, 75 MHz):
d
173.6 (C-2), 167.9
4.2.17. Syributin 2 (3b)
(C-4), 136.5 (C-iAr), 128.7 (C-oAr), 128.4 (C-pAr), 128.0 (C-mAr),
118.0 (C-3), 76.0 (C-10), 73.0 (CH2Ph), 72.6 (C-5), 72.1 (C-20), 62.7 (C-
30). HRMS (MALDI-FTMS): m/e calcd for C14H16O5Na [(MþNa)þ]:
287.0890. Found: 287.0891.
Following the procedure described for 3a, benzyl ether 22b
(78 mg, 0.2 mmol) gave 54 mg of syributin 2 (3b, 90%), as a color-
25
20
less oil. [
a]
þ7.1 (c 0.6, CHCl3) [lit.17
[
a
]
þ7.03 (c 0.6, CHCl3)]; IR,
D
D
1H NMR, and 13C NMR spectra were identical with those reported in
the literature.16 HRMS (MALDI-FTMS): m/e calcd for C15H24O6Na
[(MþNa)þ]: 323.1465. Found: 323.1464.
4.2.14. (2R,3R)-3-Benzyloxy-2-hydroxy-3-(50-oxo-20,50-
dihydrofuran-30-yl)-propyl hexanoate (22a)
Et3N (60
m
L, 0.43 mmol) was added to a solution of diol 21
4.2.18. (3S,4R)-3-Benzyloxy-2-hydroxymethyl-tetrahydrofuran-
2,4-diol (23)
(106 mg, 0.4 mmol) in dry CH2Cl2 (15 mL) at ꢁ20 ꢀC. Then, hex-
anoyl chloride (60
mL, 0.43 mmol) was added dropwise (1 h) and
A 90% aqueous solution of TFA (0.26 mL) was dropwise added at
0 ꢀC to a solution of hydroxyketone 18 (31 mg, 0.11 mmol) in CH2Cl2
(0.5 mL). After 90 min, the solution was neutralized by the addition
of saturated aqueous sodium bicarbonate. The aqueous phase was
extracted with CH2Cl2 (2ꢂ3 mL) and the combined organic layers
the mixture was stirred at the same temperature. After 2 h, brine
was added (5 mL) and the mixture was extracted with Et2O
(2ꢂ25 mL). The combined organic phases were dried (Na2SO4), the
solvents were removed under reduced pressure and the resulting

1056
A.-A.C. Varvogli et al. / Tetrahedron 65 (2009) 1048–1058
were washed with brine (3 mL), dried (Na2SO4), and concentrated.
The residue was purified by flash column chromatography on silica
gel with a mixture of hexanes/ethyl acetate (1:1 v/v) to give 21 mg
of lactols 23 (80%, ratio of ca. 3:1) as a colorless syrup. Rf (hexane/
EtOAc 1:3 v/v) 0.10; IR (neat for the mixture): 3391, 2927,
a catalytic amount of 5% Pd/C (10 mg). The reaction mixture was
vigorously stirred at room temperature for 90 min. Then, it was
filtered through CeliteÒ with the aid of EtOAc (10 mL). The solvents
were removed under reduced pressure and the resulting residue
was purified by flash column chromatography on silica gel with
1716 cmꢁ1; 1H NMR (CDCl3, 300 MHz, for the major isomer):
d
7.36–
a mixture of EtOAc/MeOH (50:1 v/v) to give 52 mg of diol 26 (99%)
25
7.32 (m, 5H, ArH), 4.75 and 4.67 (ABq, J¼11.6 Hz, 2H, CH2Ph), 4.34
(br s, 1H, OH), 4.29 (br d, J¼4.9 Hz, 1H, OH), 4.23 (d, J¼3.7 Hz, 1H, H-
3), 4.13–4.08 (m, 1H, H-4), 4.01 (br d, J¼9.0 Hz, 1H, OH), 3.91–3.74
(m, 2H, H-5), 3.72 and 3.59 (ABq, J¼11.9 Hz, 2H, H-20); 13C NMR
as colorless needles. Mp 108 ꢀC (lit.16 107–108 ꢀC); [
a
]
D
þ75.9 (c
25
0.3, MeOH) [lit.16
[
a]
þ75.3 (c 0.22, MeOH)]; IR, 1H NMR and 13C
D
NMR spectra were identical with those reported in the literature.16
HRMS (MALDI-FTMS): m/e calcd for C7H10O5Na [(MþNa)þ]:
197.0420. Found: 197.0420.
(CDCl3, 75 MHz, for the major isomer):
d 136.6 (C-iAr), 128.4 (C-
oAr), 128.0 (C-pAr), 127.7 (C-mAr), 103.9 (C-2), 84.2 (C-3), 74.7 (C-4),
73.5 (C-5), 72.9 (CH2Ph), 65.2 (C-20). HRMS (MALDI-FTMS): m/e
calcd for C12H16O5Na [(MþNa)þ]: 263.0890. Found: 263.0891.
4.2.21. Secosyrin 1 (2a)
Diol 26 (26 mg, 0.5 mmol) gave, following a known procedure,16
25
29 mg of secosyrin 1 (2a, 72%), as a colorless oil. [
a]
þ40.0 (c 1.0,
D
20
4.2.19. (3R,4S,5R)-4-Benzyloxy-3-hydroxy-1,7-dioxaspiro[4.4]-
nonan-8-one (25) and (3R,4S,5S)-4-benzyloxy-3-hydroxy-1,7-
dioxaspiro[4.4]nonan-8-one (24)
CHCl3) [lit.17
[
a
]
D
þ40.2 (c 1.1, CHCl3)]; IR, 1H NMR, and 13C NMR
spectra were identical with those reported in the literature.16 HRMS
(MALDI-FTMS): m/e calcd for C13H20O6Na [(MþNa)þ]: 295.1152.
Found: 295.1150.
4.2.19.1. IHMA reaction of 21. Et3N (1.4 mL, 1 mmol) was added to
a solution of diol 21 (90 mg, 0.34 mmol) in CHCl3 (1.5 mL). The
mixture was stirred at room temperature for 4 days. Then, EtOAc
(10 mL) was added and the mixture was washed with brine
(2ꢂ10 mL). The organic phase was dried (Na2SO4) and the solvents
were removed under reduced pressure. The obtained residue was
purified by flash column chromatography on silica gel with a mix-
ture of hexane/EtOAc (3:1 v/v) to give, in the order of elution, 44 mg
of spiro-derivative 25 (63%) and 10 mg of spiro-derivative 24 (14%)
and 20 mg of unreacted starting material 21. Compound 24: solid, Rf
4.2.22. Secosyrin 2 (2b)
Diol 26 (26 mg, 0.5 mmol) gave, following a known procedure,16
25
34 mg of secosyrin 2 (2b, 76%), as a colorless oil. [
a]
þ42.5 (c 0.5,
D
20
CHCl3) [lit.17
[
a
]
þ42.3 (c 0.5, CHCl3)]; IR, 1H NMR, and 13C NMR
D
spectra were identical with those reported in the literature.17 HRMS
(MALDI-FTMS): m/e calcd for C15H24O6Na [(MþNa)þ]: 323.1465.
Found: 323.1468.
4.2.23. 4-((10R,20R)-10-Benzyloxy-20,30-isopropylidenedioxy-
propyl)-3-(100-hydroxyhexyl)-furan-2(5H)-one (27a)
[hexane/EtOAc 1:1 v/v (three times development)] 0.44; mp 75–
25
77 ꢀC; [
a
]
D
ꢁ3.7 (c 0.7, CHCl3); IR (neat): 3418, 2928, 2890,
DIPEA (280 mL, 1.63 mmol) was added to a solution of lactone 20
1779 cmꢁ1; 1H NMR (CDCl3, 300 MHz):
d
7.41–7.30 (m, 5H, ArH), 4.72
(124 mg, 0.41 mmol) in dry THF (3 mL) at 0 ꢀC. This mixture was
cooled to ꢁ78 ꢀC and a 1 M solution in CH2Cl2 of Bu2BOTf (0.8 mL,
0.8 mmol) was added. The resulting mixture was stirred at ꢁ78 ꢀC
and 4.56 (ABq, J¼12.2 Hz, 2H, CH2Ph), 4.53 and 4.32 (ABq, J¼10.4 Hz,
2H, H-6), 4.42 (br s,1H, H-4), 4.17 (dd, J¼9.8, 4.3 Hz,1H, H-3), 3.90 (d,
J¼1.8 Hz, 1H, H-2a), 3.83 (dd, J¼9.8, 1.8 Hz, 1H, H-2b), 2.76 and 2.68
(ABq, J¼18.3 Hz, 2H, H-9), 2.05 (br s, 1H, OH); 13C NMR (CDCl3,
for 1 h, then hexanal (73 mL, 0.61 mmol) was added and it was left at
ꢁ20 ꢀC for 1 h. Iced water (20 mL) was used to quench the reaction.
The obtained slurry was extracted with EtOAc (3ꢂ15 mL) and the
combined organic phases were washed with brine (10 mL) and dried
(Na2SO4). Evaporation of the volatiles under reduced pressure yiel-
ded a residue, which was purified by flash column chromatography
on silica gel with a mixture of hexane/EtOAc (4:1 v/v) to give 146 mg
of alcohols 27a (88%, mixture of diastereoisomers in a ratio of ca. 9:1)
as a colorless oil. Rf (hexane/EtOAc 3:1 v/v) 0.25; IR (neat): 3473,
75 MHz):
d 175.8 (C-8), 137.0 (C-iAr), 128.7 (C-oAr), 128.3 (C-pAr),
127.7 (C-mAr), 87.4 (C-4), 86.9 (C-5), 74.5 (C-3), 73.9 (CH2Ph), 73.8 (C-
6), 72.4 (C-2), 40.0 (C-9). HRMS (MALDI-FTMS): m/e calcd for
C14H16O5Na [(MþNa)þ]: 287.0890. Found: 287.0892. Compound 25:
25
oil; Rf [hexane/EtOAc 1:1 v/v (three times development)] 0.50; [a]
D
ꢁ5.3 (c 0.8, MeOH); IR (neat): 3445, 2930, 2910,1779 cmꢁ1; 1H NMR
(CDCl3, 300 MHz):
d 7.40–7.31 (m, 5H, ArH), 4.76 and 4.60 (ABq,
J¼12.2 Hz, 2H, CH2Ph), 4.45–4.41 (m, 1H, H-4), 4.37 and 4.28 (ABq,
J¼10.4 Hz, 2H, H-6), 4.11 (dd, J¼10.4, 4.9 Hz, 1H, H-3), 3.83
(dd, J¼10.4, 2.5 Hz, 1H, H-2a), 3.82 (d, J¼1.8 Hz, 1H, H-2b), 2.98 and
2.56 (ABq, J¼18.3 Hz, 2H, H-9), 2.74 (br s, 1H, OH); 13C NMR (CDCl3,
2934, 2872, 1749 cmꢁ1
;
1H NMR (CDCl3, 300 MHz, for the major
diastereoisomer): 7.35–7.30 (m, 5H, ArH), 4.93 and 4.79 (ABq,
d
J¼18.0 Hz, 2H, H-5), 4.82 (d, J¼3.9 Hz, 1H, H-10), 4.64 and 4.48 (ABq,
J¼12.0 Hz, 2H, CH2Ph), 4.57–4.50 (m,1H, H-100), 4.33–4.27 (m,1H, H-
200), 4.05–4.00 (m,1H, H-30a), 3.93 (dd, J¼8.6, 6.1 Hz,1H, H-30b), 2.97
(br d, J¼8.9 Hz, 1H, OH), 1.72–1.67 (m, 2H, H-200), 1.41 (s, 3H, CMe2),
1.35–1.25 (m, 6H, H-300-H-500),1.34 (s, 3H, CMe2), 0.89 (t, J¼6.5 Hz, 3H,
H-600); 13C NMR (CDCl3, 75 MHz, for the major diasteroisomer):
75 MHz):
d 175.7 (C-8), 137.1 (C-iAr), 128.7 (C-oAr), 128.2 (C-pAr),
127.7 (C-mAr), 87.4 (C-5), 86.2 (C-4), 76.5 (C-3), 74.7 (CH2Ph), 73.3 (C-
6), 72.5 (C-2), 35.4 (C-9). HRMS (MALDI-FTMS): m/e calcd for
C14H16O5Na [(MþNa)þ]: 287.0890. Found: 287.0891.
d
173.2 (C-2), 158.3 (C-4), 136.9 (C-iAr), 131.4 (C-3), 128.5 (C-oAr),
4.2.19.2. Desilylation of 14. A solution of TBAF in THF (1 M, 0.11 mL,
0.11 mmol) was added dropwise to a solution of silyl ether 14
(54 mg, 0.1 mmol) in THF (4 mL) at 0 ꢀC. After 8 h at 25 ꢀC the mix-
ture was quenched with saturated aqueous ammonium chloride
solution (2 mL) and extracted with EtOAc (2ꢂ5 mL). The combined
organic phases were washed with brine (3 mL), dried (Na2SO4) and
the solvents wereremoved under reduced pressure. The residuewas
purified by flash column chromatography on silica gel with a mix-
ture of hexane/EtOAc (3:1 v/v) to give 23 mg of lactone 25 (87%).
128.1 (C-pAr), 127.6 (C-mAr), 110.1 (CMe2), 77.2 (C-20), 73.6 (C-10),
72.2 (C-5), 70.8 (CH2Ph), 67.5 (C-30), 65.3 (C-100), 36.5 (C-200), 31.4 (C-
400), 26.0 (CMe2), 25.3 (C-300), 25.2 (CMe2), 22.5 (C-500), 13.9 (C-600).
HRMS (MALDI-FTMS): m/e calcd for C23H32O6Na [(MþNa)þ]:
427.2091. Found: 427.2090.
4.2.24. 4-((10R,20R)-10-Benzyloxy-20,30-isopropylidenedioxy-
propyl)-3-hexanoylfuran-2(5H)-one (28a)
Dess–Martin periodinane (573 mg, 1.35 mmol) was added in
portions in a solution of diastereoisomeric alcohols 27a (121 mg,
0.3 mmol) in CH2Cl2 (6 mL) at 25 ꢀC. The mixture was stirred for 3 h
and then saturated aqueous solution of sodium bicarbonate
(20 mL) was added and it was extracted with ether (3ꢂ25 mL). The
combined organic phases were washed with brine (20 mL) and
4.2.20. (3R,4S,5R)-3,4-Dihydroxy-1,7-dioxaspiro[4.4]nonan-
8-one (26)
A 10% methanolic solution of HCl (60
mL) was added to a solution
of benzyl ether 25 (78 mg, 0.3 mmol) in EtOAc (6 mL) followed by

A.-A.C. Varvogli et al. / Tetrahedron 65 (2009) 1048–1058
1057
dried (Na2SO4). Evaporation of the volatiles under reduced pressure
yielded a residue, which was purified by flash column chroma-
tography on silica gel with a mixture of hexane/EtOAc (4:1 v/v) to
organic phases were washed with brine (5 mL) and dried (MgSO4).
The solvents were evaporated under reduced pressure and the
resulting residue was passed very fast through a small column
containing silica gel using neat EtOAc as eluant. The solvent was
evaporated under reduced pressure and the residue was re-dis-
solved in acetone/H2O (3 mL, 1:1 v/v), p-toluenesulfonic acid
monohydrate (95 mg, 0.5 mmol) was added and the mixture was
stirred at 25 ꢀC for 3 days. Solid sodium bicarbonate was used to
neutralize the reaction. The mixture was left to vigorously stir for
2 h and subsequently it was extracted with EtOAc (2ꢂ15 mL). The
combined organic phases were washed with brine (5 mL) and
the solvents were removed under reduced pressure at 25 ꢀC. The
obtained residue gave upon the addition of a mixture of CHCl3/
hexane syringolide 1 (1a,15 mg, 55%), as colorless needles. Mp 112–
give 113 mg of ketone 28a (94%) as a colorless oil. Rf (hexane/EtOAc
20
3:1 v/v) 0.48; [
a
]
ꢁ51.4 (c 1.8, CHCl3); IR (neat): 2933, 2890, 1766,
D
1688 cmꢁ1
;
1H NMR (CDCl3, 300 MHz,):
d 7.35–7.27 (m, 5H, ArH),
5.14 and 4.85 (ABq, J¼20.1, 2H, H-5), 5.12 (d, J¼2.4 Hz, 1H, H-10),
4.53 (s, 2H, CH2Ph), 4.38 (dt, J¼1.8, 6.4 Hz, 1H, H-20), 4.10–4.00 (m,
2H, H-30), 3.03 (dt, J¼18.0, 7.3 Hz, 1H, H-200a), 2.91 (dt, J¼18.0,
7.3 Hz, 1H, H-200b), 1.65–1.56 (m, 2H, H-300), 1.45 (s, 3H, CMe2), 1.36–
1.30 (m, 4H, H-400, H-500), 1.31 (s, 3H, CMe2), 0.91 (t, J¼6.7 Hz, 3H, H-
600); 13C NMR (CDCl3, 75 MHz):
d
197.4 (C-100), 177.5 (C-2), 170.3 (C-
4), 136.5 (C-iAr), 128.5 (C-oAr), 128.3 (C-pAr), 127.8 (C-mAr), 125.3
(C-3), 110.2 (CMe2), 77.0 (C-20), 74.8 (C-10), 73.5 (C-5), 71.1 (CH2Ph),
65.5 (C-30), 41.8 (C-200), 31.1 (C-300), 25.8 (CMe2), 25.3 (CMe2), 22.7
(C-400), 22.4 (C-500), 13.8 (C-600). HRMS (MALDI-FTMS): m/e calcd for
C23H30O6Na [(MþNa)þ]: 425.1935. Found: 425.1935.
25
20
113 ꢀC (lit.2 112.5–114.5 ꢀC); [
a]
ꢁ81.0 (c 0.4, CHCl3) [lit.11
[a]
D
D
ꢁ81.3 (c 0.38, CHCl3)]; IR, 1H NMR, and 13C NMR spectra were
identical with those reported in the literature.9 HRMS (MALDI-
FTMS): m/e calcd for C13H20O6Na [(MþNa)þ]: 295.1152. Found:
295.1154.
4.2.25. 4-((10R,20R)-10-Benzyloxy-20,30-dihydroxypropyl)-3-
hexanoylfuran-2(5H)-one (30a)
4.2.27. 4-((10R,20R)-10-Benzyloxy-20,30-isopropylidenedioxy-
propyl)-3-(100-hydroxyoctyl)-furan-2(5H)-one (27b)
Following the procedure described for 27a, lactone 20 (122 mg,
0.4 mmol) gave with octanal 154 mg of alcohols 27b (89%, mixture
of diastereoisomers in a ratio of ca. 8:1) as a colorless oil. Rf (hex-
ane/EtOAc 3:1 v/v) 0.23; IR (neat): 3473, 2928, 2857, 1748 cmꢁ1; 1H
4.2.25.1. TiCl4 promoted deprotection. Protected diol 28a (20 mg,
0.05 mmol) was dissolved in dry CH2Cl2 (2 mL) under an Ar at-
mosphere. This was cooled to ꢁ30 ꢀC and a 1 M solution of TiCl4 in
dichloromethane (150 mL, 0.15 mmol) was slowly added. The mix-
ture was left to stir for 5 h at the same temperature and then
quenched by the addition of a saturated aqueous solution of am-
monium chloride (1 mL). The resulting slurry was vigorously stirred
at 25 ꢀC for 15 min. Then, EtOAc (10 mL) was added, the organic
phase was dried (MgSO4) and the solvents were removed under
reduced pressure. The obtained residue was purified by flash col-
umn chromatography on silica gel with a mixture of heptane/EtOAc
NMR (CDCl3, 300 MHz, for the major diasteroisomer):
d 7.35–7.30
(m, 5H, ArH), 4.93 and 4.80 (ABq, J¼17.7 Hz, 2H, H-5), 4.79 (d,
J¼4.3 Hz,1H, H-10), 4.63 and 4.50 (ABq, J¼11.6 Hz, 2H, CH2Ph), 4.56–
4.50 (m, 1H, H-100), 4.32–4.27 (m, 1H, H-20), 4.05–4.00 (m, 1H, H-
30a), 3.94 (dd, J¼8.5, 6.1 Hz, 1H, H-30b), 2.81 (br s, 1H, OH), 1.73–1.67
(m, 2H, H-200), 1.42 (s, 3H, CMe2), 1.35–1.24 (m, 10H, H-300, H-400, H-
500, H-600, H-700), 1.34 (s, 3H, CMe2), 0.88 (t, J¼6.7 Hz, 3H, H-800); 13C
(1:1 v/v) to give diol 30a (10 mg, 55%) as a pale yellow oil. Rf
20
(hexane/EtOAc 1:1 v/v) 0.14; [
a
]
ꢁ40.6 (c 0.3, CHCl3); IR (neat):
NMR (CDCl3, 75 MHz, for the major diasteroisomer): d 173.2 (C-2),
D
3441, 2956, 2871, 1761, 1687 cmꢁ1
;
1H NMR (CDCl3, 400 MHz,):
158.1 (C-4), 136.8 (C-iAr), 131.4 (C-3), 128.5 (C-oAr), 128.1 (C-pAr),
127.6 (C-mAr), 110.2 (CMe2), 77.2 (C-20), 73.6 (C-10), 72.3 (C-5), 70.8
(CH2Ph), 67.6 (C-30), 65.3 (C-100), 36.6 (C-200), 31.7 (C-600), 29.3 (C-500),
26.1 (C-300), 25.7 (CMe2), 25.2 (CMe2), 22.5 (C-700), 14.0 (C-800). HRMS
(MALDI-FTMS): m/e calcd for C25H36O6Na [(MþNa)þ]: 455.2404.
Found: 455.2407.
d
7.38–7.31 (m, 3H, ArH), 7.28–7.24 (m, 2H, ArH), 5.21 (d, J¼3.5 Hz,
1H, H-10), 5.14 and 4.87 (ABq, J¼19.9 Hz, 2H, H-5), 4.53 (s, 2H,
CH2Ph), 3.89 (br s, 1H, H-20), 3.78–3.68 (m, 2H, H-30), 3.07–2.86 (m,
3H, H-200, 1ꢂOH), 2.35 (br s, 1H, 1ꢂOH), 1.60 (quintet, 2H, H-300),
1.37–1.28 (m, 4H, H-400, H-500), 0.90 (t, J¼7.0 Hz, 3H, H-600); 13C NMR
(CDCl3, 100 MHz):
d
198.1 (C-100), 177.0 (C-2), 170.2 (C-4), 136.1 (C-
iAr), 128.83 (C-oAr), 128.81 (C-pAr), 128.3 (C-mAr), 126.1 (C-3), 76.5
(C-20), 73.9 (C-10), 73.4 (C-5), 70.9 (CH2Bn), 63.4 (C-30), 42.0 (C-200),
31.2 (C-300), 22.9 (C-400), 22.5 (C-500), 13.9 (C-600). HRMS (MALDI-
FTMS): m/e calcd for C20H26O6Na [(MþNa)þ]: 385.1622. Found:
385.1620.
4.2.28. 4-((10R,20R)-10-Benzyloxy-20,30-isopropylidenedioxy-
propyl)-3-octanoylfuran-2(5H)-one (28b)
Following the procedure described for 28a a mixture of alcohols
27b (140 mg, 0.32 mmol) gave 128 mg of ketone 28b (93%) as
20
a colorless oil. Rf (hexane/EtOAc 3:1 v/v) 0.47; [
a
;
]
ꢁ115.7 (c 0.9,
D
CHCl3); IR (neat): 2930, 2858, 1767, 1688 cmꢁ1
1H NMR (CDCl3,
4.2.25.2. AcOH promoted deprotection. Protected diol 28a (100 mg,
0.25 mmol) was dissolved in 80% aqueous AcOH (3 mL). This mix-
ture was stirred at 20 ꢀC for 4 h. Then, EtOAc was added (10 mL) and
it was carefully quenched by the addition of saturated aqueous
solution of sodium hydrogencarbonate (until pH 7). The resulting
slurry was extracted with EtOAc (3ꢂ15 mL) and the combined or-
ganic phases were washed with brine (10 mL). Evaporation under
reduced pressure of the solvent left a residue, which was purified
by flash column chromatography on silica gel with a mixture of
heptane/EtOAc (1:1 v/v) to give diol 30a (72 mg, 80%) as a pale
yellow oil.
300 MHz,):
d
7.36–7.25 (m, 5H, ArH), 5.14 and 4.84 (ABq, J¼20.1, 2H,
H-5), 5.12 (d, J¼2.4 Hz, 1H, H-10), 4.53 (s, 2H, CH2Ph), 4.37 (dt, J¼2.4,
6.1 Hz,1H, H-20), 4.11–4.00 (m, 2H, H-30), 3.03 (dt, J¼18.0, 7.3 Hz,1H,
H-200a), 2.91 (dt, J¼18.0, 7.3 Hz, 1H, H-200b), 1.64–1.55 (m, 2H, H-400),
1.45 (s, 3H, CMe2), 1.35–1.27 (m, 8H, H-300, H-500, H-600, H-700), 1.31 (s,
3H, CMe2), 0.89 (t, J¼6.7 Hz, 3H, H-800); 13C NMR (CDCl3, 75 MHz):
d
197.5 (C-100), 177.5 (C-2), 170.4 (C-4), 136.6 (C-iAr), 128.9 (C-oAr),
128.3 (C-pAr), 127.8 (C-mAr), 125.4 (C-3), 110.3 (CMe2), 77.1 (C-20),
74.9 (C-10), 73.6 (C-5), 71.1 (CH2Ph), 65.6 (C-30), 42.0 (C-200), 31.7 (C-
600), 29.1 (C-400), 29.0 (C-500), 25.9 (CMe2), 25.3 (CMe2), 23.1 (C-300),
22.6 (C-700), 14.0 (C-800). HRMS (MALDI-FTMS): m/e calcd for
C25H34O6Na [(MþNa)þ]: 453.2248. Found: 425.2251.
4.2.26. Syringolide 1 (1a)
A solution of diol 30a (36 mg, 0.1 mmol) in a 2:1 mixture of dry
CH2Cl2 and m-xylene (3 mL) was added to a suspension of AlCl3
(67 mg, 0.5 mmol) in CH2Cl2 (2 mL) at ꢁ20 ꢀC. The reaction mixture
was vigorously stirred at 0 ꢀC for 4 h. Iced water (2 mL) was added
and the mixture was left to stir vigorously until it warmed up to
20 ꢀC. Then it was extracted with EtOAc (2ꢂ10 mL). The combined
4.2.29. (1R,7R,8R)-7-Benzyloxy-4,10,11-trioxa-1-heptyl-
tricyclo[6.2.1.02,6]undec-2(6)-en-3-one (29)
Protected diol 28b (21 mg, 0.05 mmol) was dissolved in MeOH
(2 mL) and DowexÒ 50 W-X8 (250 mg) was added. The mixture was
stirred at 25 ꢀC for 20 h. Then, it was filtered and the resin was
washed with MeOH (1 mL). The solvent was evaporated under

1058
A.-A.C. Varvogli et al. / Tetrahedron 65 (2009) 1048–1058
Kinney, A.; Keen, N. T. Mol. Plant-Microbe Interact. 2002, 15, 1213–1218; (f) Slay-
maker, D. H.; Keen, N. T. Plant Sci. 2004, 166, 387–396; (g) Hagihara, T.; Hashi, M.;
Takeuchi, Y.; Yamaoka, N. Planta 2004, 218, 606–614; (h) Slaymaker, D. H.; Hop-
pey, C. M. Plant Sci. 2006, 170, 54–60.
7. (a) Wood, J. L.; Jeong, S.; Salcedo, A.; Jenkins, J. J. Org. Chem. 1995, 60, 286–287;
(b) Kuwahara, S.; Moriguchi, M.; Miyagawa, K.; Konno, M.; Kodama, O. Tetra-
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K.; Konno, M.; Kodama, O. Tetrahedron 1995, 51, 8809–8814.
reduced pressure and the obtained residue was purified by flash
column chromatography on silica gel with a mixture of heptane/
EtOAc (4:1 v/v) to give 18 mg (97%) of tricycloketal 29 as a colorless
20
oil. Rf (hexane/EtOAc 7:3 v/v) 0.42; [
a
]
ꢁ20.7 (c 0.4, CHCl3); IR
D
(neat): 3028, 2956, 2852, 1740, 1658 cmꢁ1
;
1H NMR (CDCl3,
400 MHz,): 7.41–7.37 (m, 3H, ArH), 7.32–7.29 (m, 2H, ArH), 4.85
d
8. (a) Henschke, J. P.; Rickards, R. W. Tetrahedron Lett.1
996, 37, 3557–3560; (b) Zeng,
(dd, J¼17.8, 2.0 Hz, 1H, H-5a), 4.75 (br s, 1H, H-7), 4.66–4.58 (m, 3H,
H-8 and CH2Ph), 4.51 (dd, J¼17.8, 1.4 Hz, 1H, H-5b), 4.09–4.05 (m,
1H, H-9a), 3.99–3.95 (m, 1H, H-9b), 2.31–2.24 (m, 1H, H-10a), 2.06–
1.99 (m, 1H, H-10b), 1.62–1.54 (m, 2H, H-30), 1.43–1.25 (m, 8H, H-20,
H-40, H-50, H-60), 0.86 (t, J¼6.9 Hz, 3H, H-70); 13C NMR (CDCl3,
C.-M.; Midland, S. L.; Keen, N. T.; Sims, J. J. J. Org. Chem. 1997, 62, 4780–4784; (c)
Yoda, H.; Kawauchi, M.; Takabe, K.; Ken, H. Heterocycles 1997, 45, 1895–1898.
9. Honda, T.; Mizutani, H.; Kanai, K. J. Org. Chem. 1996, 61, 9374–9378.
10. (a) Ishihara, J.; Sugimoto, T.; Murai, A. Synlett 1996, 335–336; (b) Ishihara, J.;
Sugimoto, T.; Murai, A. Tetrahedron 1997, 53, 16029–16040.
11. Yu, P.; Wang, Q.-G.; Mak, T. C. W.; Wong, H. N. C. Tetrahedron 1998, 54,1783–1788.
12. Chenevert, R.; Dasser, M. Can. J. Chem. 2000, 78, 275–279.
100 MHz): d 169.0 (C-3), 161.0 (C-6), 136.9 (C-iAr), 129.3 (C-2), 128.9
ˆ
(C-oAr), 128.7 (C-pAr), 128.0 (C-mAr), 104.3 (C-1), 77.2 (C-8), 73.5
(C-5), 73.0 (C-7), 68.6 (CH2Ph), 64.1 (C-9), 31.7 (C-50), 31.1 (C-30),
29.6 (C-10), 29.1 (C-40), 22.9 (C-20), 22.6 (C-60), 14.1 (C-70). HRMS
(MALDI-FTMS): m/e calcd for C22H28O5Na [(MþNa)þ]: 395.1829.
Found: 395.1833.
13. Cheˆnevert, R.; Dasser, M. J. Org. Chem. 2000, 65, 4529–4531.
14. (a) Carda, M.; Castillo, E.; Rodriguez, S.; Falomir, E.; Alberto Marco, J. Tetrahe-
dron Lett. 1998, 39, 8895–8896; (b) Donohoe, T. J.; Fisher, J. W.; Edwards, P. J.
Org. Lett. 2004, 6, 465–467.
15. Mukai, C.; Moharram, S. M.; Hanaoka, M. Tetrahedron Lett. 1997, 38, 2511–2512.
16. Mukai, C.; Moharram, S. M.; Azukizawa, S.; Hanaoka, M. J. Org. Chem. 1997, 62,
8095–8103.
17. Yu,P.;Yang,Y.;Zhang,Z.Y.;Mak,T.C.W.;Wong,H.N.C.J. Org. Chem.1997,62, 6359–6366.
18. Wong, H. N. C. Pure Appl. Chem. 1996, 68, 335–344.
4.2.30. 4-((10R,20R)-10-Benzyloxy-20,30-dihydroxypropyl)-3-
19. (a) Yoda, H.; Kawauchi, M.; Takabe, K.; Hosoya, K. Heterocycles 1997, 45, 1903–
1906; (b) Di Florio, R.; Rizzacasa, M. A. Aust. J. Chem. 2000, 53, 327–331; (c)
Krishna, P. R.; Narsingam, M.; Kannan, V. Tetrahedron Lett. 2004, 45, 4773–4775.
20. Refs. 8, 12, 14a, 19a.
21. (a) Koumbis, A. E.; Dieti, K. M.; Vikentiou, M. G.; Gallos, J. K. Tetrahedron Lett.
2003, 44, 2513–2516; (b) Gallos, J. K.; Stathakis, C. I.; Kotoulas, S. S.; Koumbis,
A. E. J. Org. Chem. 2005, 70, 6884–6890; (c) Koumbis, A. E.; Chronopoulos, D.
Tetrahedron Lett. 2005, 46, 4353–4355; (d) Koumbis, A. E.; Kaitaidis, A. D.;
Kotoulas, S. S. Tetrahedron Lett. 2006, 47, 8479–8481; (e) Koumbis, A. E.;
Kotoulas, S. S.; Gallos, J. K. Tetrahedron 2007, 63, 2235–2243.
22. Koumbis, A. E.; Varvogli, A.-A. C. Synlett 2006, 3340–3342.
23. Preliminary results of this work were presented in: (a) 1st European Chemistry
Congress, Budapest, Hungary, August 2006, p 329 (N-PO-94); (b) 2nd Hellenic
Symposium on Organic Synthesis, Athens, Greece, April 2007, p 53 (L17).
24. Pakulski, Z.; Zamojksi, A. Tetrahedron 1995, 51, 871–908.
octanoylfuran-2(5H)-one (30b)
4.2.30.1. TiCl4 promoted deprotection. Following the procedure de-
scribed for 30a protected diol 28b (22 mg, 0.05 mmol) gave diol
30b (11 mg, 56%) as a pale yellow oil. Rf (hexane/EtOAc 1:3 v/v)
20
0.13; [
a]
ꢁ44.6 (c 0.3, CHCl3); IR (neat): 3418, 2954, 2927, 2857,
D
1763, 1686 cmꢁ1 1H NMR (CDCl3, 400 MHz,):
; d 7.38–7.31 (m, 3H,
ArH), 7.28–7.23 (m, 2H, ArH), 5.21 (d, J¼3.5 Hz, 1H, H-10), 5.14 and
4.87 (ABq, J¼19.9 Hz, 2H, H-5), 4.54 (s, 2H, CH2Ph), 3.89 (br s, 1H, H-
20), 3.78–3.68 (m, 2H, H-30), 3.07–2.86 (m, 3H, H-200,1ꢂOH), 2.33 (br
s, 1H, 1ꢂOH), 1.61–1.58 (m, 2H, H-400), 1.32–1.25 (m, 8H, H-300, H-500,
H-600, H-700), 0.88 (t, J¼7.0 Hz, 3H, H-800); 13C NMR (CDCl3, 100 MHz):
25. Dahlman, O.; Garegg, P. J.; Mayer, H.; Schramek, S. Acta Chem. Scand. Ser. B 1986,
40, 15–20.
d
198.2 (C-100), 176.9 (C-2), 170.1 (C-4), 136.1 (C-iAr), 128.83 (C-oAr),
128.81 (C-pAr), 128.3 (C-mAr), 126.1 (C-3), 76.5 (C-20), 73.9 (C-10),
73.4 (C-5), 70.9 (CH2Bn), 63.4 (C-30), 42.0 (C-200), 31.7 (C-600), 29.1 (C-
400), 29.0 (C-500), 23.1 (C-300), 22.6 (C-700), 14.1 (C-800). HRMS (MALDI-
FTMS): m/e calcd for C22H30O6Na [(MþNa)þ]: 413.1935. Found:
413.1938.
26. Intermediates 10 and 11 have been previously prepared from D-mannitol, fol-
lowing a different synthetic scheme: (a) Toyota, M.; Hirota, M.; Hirano, H.;
Ihara, M. Org. Lett. 2000, 2, 2031–2034; (b) Kagawa, N.; Ihara, M.; Toyota, M.
Org. Lett. 2006, 8, 875–878.
27. Sugar numbering.
28. Wang, E. S.; Choy, Y. M.; Wong, H. N. C. Tetrahedron 1996, 52, 12137–12158.
29. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863–927.
30. Using NaH and t-BuOK as bases resulted in the formation of these esters in
almost the same ratios but in much lower yields.
31. As expected the ratio of Z/E isomers remained the same (ca. 4:1).
32. Structural assignment was based on NOE studies, which revealed the indicated
crucial effects (see Scheme 3).
4.2.30.2. AcOH promoted deprotection. Following the procedure
described for 30a protected diol 28b (100 mg, 0.23 mmol) gave diol
30a (74 mg, 82%) as a pale yellow oil.
33. Only slow decomposition of starting material was observed.
34. Obviously, the bulkiness of the TBDPS group played a decisive role regarding
the inactivity of these substrates.
35. Blasdel, L. K.; Myers, A. G. Org. Lett. 2005, 7, 4281–4283.
36. Bonadies, F.; Cardilli, A.; Lattanzi, A.; Pesci, S.; Scettri, A. Tetrahedron Lett. 1995,
36, 2839–2840; (b) Marcos, I. S.; Pedrero, A. B.; Sexmero, M. J.; Diez, D.; Garcia,
N.; Escola, M. A.; Basabe, P.; Conde, A.; Moro, R. F.; Urones, J. G. Synthesis 2005,
3301–3310.
37. Analogous conclusions could be reached by examining the opened formed
intermediates (erythro and threo).
38. Ono, M.; Saotome, C.; Akita, H. Tetrahedron: Asymmetry 1996, 7, 2595–2602.
39. These compounds were found to have identical physical and spectra data with
those reported in the literature.
4.2.31. Syringolide 2 (1b)
Following the procedure described for 1a diol 30b (40 mg,
0.1 mmol)gavesyringolide2(2b,16 mg, 53%),ascolorlessneedles.Mp
25
20
122–123 ꢀC (lit.2 123–124 ꢀC); [
a]
ꢁ76.4 (c 0.35, CHCl3) [lit.11
[a]
D
D
ꢁ74.7 (c 0.1, CHCl3)]; IR, 1H NMR, and 13C NMR spectra were identical
with those reported in the literature.7a,9 HRMS (MALDI-FTMS): m/e
calcd for C15H24O6Na [(MþNa)þ]: 323.1465. Found: 323.1464.
References and notes
40. The 3-O-TBS derivative instead of 3-O-benzyl one (21).
41. Triethylamine, t-BuOK, NaH, DBU, DBN in THF, CHCl3, DME were used.
42. It was observed that ketone 18 slowly decomposes, even when stored
at ꢁ20 ꢀC, giving lactol 23.
1. Bent, A. F.; Kunkel, B. N.; Dahlbeck, D.;Brown, K. L.; Schmidt, R.; Giraudat, J.; Leung,
J.; Staskawicz, B. J. Science 1994, 265, 1856–1860 and references cited therein.
2. Midland, S. L.; Keen, N. T.; Sims, J. J.; Midland, M. M.; Stayton, M. M.; Burton, V.;
Smith, M. J.; Mazzola, E. P.; Graham, K. J.; Clardy, J. J. Org. Chem. 1993, 58, 2940–
2945 and references cited therein.
43. Jefford, C. W.; Jaggi, D.; Boukouvalas, J. J. Chem. Soc., Chem. Commun. 1988,
1595–1596.
44. This approach gave directly 1a and 1b in good overall yields (45–55%) only
when 4–5 mg scale experiments were employed. Using bigger quantities of
starting material resulted in an unexplained dramatic drop of the yields.
Commercially available TMSI or the in situ generated one (from TMSCl and NaI)
was employed.
45. Practically, we observed no reaction when THF/H2O or acetone/H2O was used
as solvent.
46. No tetrahydrofuran-type product was found after careful investigation of the
reaction mixture.
47. Jung, M. E.; Usui, Y.; Vu, C. T. Tetrahedron Lett. 1987, 28, 5977–5980.
48. A simultaneous debenzylation (see Ref. 8b) did not occur.
49. Free triol, lactol, ketal, and desired syringolide were the major components of
this mixture as it was judged by the 1H NMR spectra and LC-MS analysis.
3. Smith, M. J.; Mazzola, E. P.; Sims, J. J.; Midland, S. L.; Keen, N. T.; Burton, V.;
Stayton, M. M. Tetrahedron Lett. 1993, 34, 223–226.
4. Wong, H. N. C. Eur. J. Org. Chem. 1999, 1757–1765.
5. Midland, S. L.; Keen, N. T.; Sims, J. J. J. Org. Chem. 1995, 60, 1118–1119.
6. Selected recent publications: (a) Keith, L. W.; Boyd, C.; Keen, N. T.; Partridge, J. E.
Mol. Plant-Microbe Interact. 1997, 10, 416–422; (b) Ji, C.; Okinaka, Y.; Takeuchi, Y.;
Tsurushima, T.; Buzzell, R. I.; Sims, J. J.; Midland, S. L.; Slaymaker, D.; Yoshikawa,
M.; Yamaoka, N.; Keen, N. T. Plant Cell 1997, 9, 1425–1433; (c) Ji, C.; Boyd, C.;
Slaymaker, D.; Okinaka, Y.; Takeuchi, Y.; Midland, S. L.; Sims, J. J.; Herman, E.;
Keen, N. T. Proc. Natl. Acad. Sci. U.S.A.1998, 95, 3306–3311; (d) Tsurushima, T.; Ji, C.;
Okinaka, Y.; Takeuchi, Y.; Sims, J. J.; Midland, S. L.; Yoshikawa, M.; Yamaoka, N.;
Keen, N. T. In Developments in Plant Pathology; Kohmoto, K., Yoder, O. C., Eds.;
Springer: 1998; Vol. 13, pp 139–140; (e) Okinaka, Y.; Yang, C.-H.; Herman, E.;