Synthesis of the proposed structure of queenslandon

Article abstract of DOI:10.1016/j.tet.2009.11.024

The proposed structure of the benzolactone queenslandon (6) was synthesized utilizing a triol containing building block prepared from d-ribose. While a ring-closing metathesis approach did not lead to the macrocycle, alkylation of a benzyl(phenyl)selane, elimination to generate the styrene double bond, followed by Mitsunobu macrolactonization proved to be successful. Spectral data suggest that the structure of queenslandon should be revised, probably to the C11 epimer.

Full text of DOI:10.1016/j.tet.2009.11.024

Tetrahedron 66 (2010) 94–101
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of the proposed structure of queenslandon
*
Vaidotas Navickas, Martin E. Maier
Institut fu¨r Organische Chemie, Universita¨t Tu¨bingen, Auf der Morgenstelle 18, 72076 Tu¨bingen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 October 2009
Received in revised form 3 November 2009
Accepted 5 November 2009
Available online 10 November 2009
The proposed structure of the benzolactone queenslandon (6) was synthesized utilizing a triol containing
building block prepared from D-ribose. While a ring-closing metathesis approach did not lead to the
macrocycle, alkylation of a benzyl(phenyl)selane, elimination to generate the styrene double bond, fol-
lowed by Mitsunobu macrolactonization proved to be successful. Spectral data suggest that the structure
of queenslandon should be revised, probably to the C11 epimer.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Benzolactone
Cross metathesis
Mitsunobu macrolactonization
Chiron approach
1. Introduction
being used. Among the polyketides resorcylic acid lactones rep-
resent a unique family of privileged structures.1 These 14-mem-
Natural polyketides cover an enormous structural space, even
though simple building blocks like acetate and propionate are
bered lactones are mycotoxins and are produced by fungal
strains. Besides the resorcylic acid part, which results from an
intramolecular aldol condensation, typical structural features
include a double bond or ketomethylene function next to the aryl
ring. In addition, the aliphatic part can be functionalized with
keto or hydroxyl groups. The discovery, that radicicol (1) is a po-
tent and selective Hsp90 inhibitor renewed interest in the RALs
(Fig. 1). One of the most simple RAL, zearalenone (2) shows es-
trogenic activity. Its binding to Hsp90 and kinases is low.2 Then
there are several RALs, which are characterized by a cis-enone in
the macrocyclic ring. These macrolactones like LL-Z1640–2 (3),3
radicicol A (4) or L-783,277 (5)4,5 are potent kinase inhibitors.6
Among the RALs, queenslandon (6) is unique since it features
a dihydroxyacetone subunit and a highly oxidized benzoic acid.7
It was isolated from the strain Chrysosporium queenslandicum
IFM51121. According to the original report queenslandon showed
activity against several fungal strains but not bacteria. In order to
further delineate its biological properties a synthetic route to
queenslandon seemed highly desirable.
OH
O
Me
HO
O
O
O
O
HO
HO
Cl
O
O
radicicol (1)
zearalenone (2)
8'
7'
OH O 10'
OH
O
1
HO
HO
O
O
O
O
4
MeO
OH
MeO
OH
3'
5
1'
R
L-783277 (5)
R = H: LL-Z1640-2 (3)
R = OMe: radicicol A (4)
HO
O
17
We previously described a strategy toward the core structure 12
of queenslandon using a chiral glycolate for construction of the
dihydroxyacetone region (Fig. 2).8 Thus, an aldol reaction on one
side and a Tebbe olefination followed by a hydroboration and
a Suzuki cross-coupling stitched the glycolate between the vinyl-
benzoic acid and the aliphatic part. However, this strategy could not
be extended to the real system due to problems in the late stage
oxidative cleavage of the dioxane.
4
1
O
9
MeO
8
13
OH
12
MeO
HO
queenslandon (6)
O
Figure 1. Structures of some representatives resorcylic acid lactones (RALs).
Therefore, a different strategy was chosen where the di-
* Corresponding author. Tel.: þ49 7071 2975247; fax: þ49 7071 295137.
E-mail address: martin.e.maier@uni-tuebingen.de (M.E. Maier).
hydroxyacetone part was fashioned from
D-(þ)-ribose (Fig. 3). In
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.024

V. Navickas, M.E. Maier / Tetrahedron 66 (2010) 94–101
95
OTBDPS
OH
1. acetone, H+
CO2Me
CuCl2·2H2O
TBDPSO
D-ribose
O
CH3CN (73%)
2. MePPh3Br, KOtBu
THF
O
OR
13 R = H
14 R = Piv
X
1. 9-BBN
2. Pd(0)
O
OMOM
O
OMOM
PivCl, Py
CH2Cl2 (95%)
CO2Me
I
O
aldol
O
PMP
PMP
PMP
PMP
OH
7 X = O
18, Grubbs 2nd
9
10
PhCH(OMe)2
CSA, CH2Cl2
(67%)
RO
PivO
8 X = CH2
O
OH
toluene, 80 °C
(74%)
O
O
PivO
OH
O
Ph
steps
steps
16 R = H
15
O
O
PMBBr, NaH
DMF (57%)
(CAN)
(Mitsunobu)
17 R = PMB
11
12
OTBS
OTBS
OTBS
O
O
OH
HO
OH
O
O
H2, Pd/C
PMP
Me2C(OH)CN
PPh3, DEAD
PMP
EtOAc (98%)
(89%)
PMBO
PivO
PMBO
PMBO
O
O
Figure 2. Previous strategy toward the core structure 12 of queenslandon.
RO
O
Ph
O
Ph
O
Ph
CN
20 R = Piv
21 R = H
22
19
OP2
DIBAL-H, toluene
–80 °C (81%)
OTBS
OP1
OH
O
CO2R
+
OH
O
MeO
MeO
HF·Py, THF
–15 °C (100%)
DIBAL-H
toluene
P3O
D-ribose
OP3
MeO
MeO
HO
OH
OP4
metathesis
PMBO
PMBO
(96%)
O
O
O
O
Ph
23 X = O
O
25
Ph
X
Figure 3. Plan for the synthesis of queenslandon via a metathesis strategy.
MePPh3Br, KOtBu
THF, 0 °C (75%)
24 X = CH2
OTBS
addition, we planned to form the styrene double bond either by
intramolecular or intermolecular metathesis.
18
Scheme 1. Synthesis of alkenol 25 from D-ribose.
2. Results and discussion
0.002–0.004 M). With the Grubbs–Hoveyda catalyst (5 mol %,
CH2Cl2, room temperature, 0.002 M) substrate 30 dimerized (45%
yield). The fact that the nor-methoxy substrate 35 gave macro-
lactone 36 (26%) in presence of Grubbs second generation catalyst
(5 mol %, toluene, 80 ꢀC, 0.004 M) points to steric or electronic in-
terference by the 4-methoxy group (Scheme 2).
The synthesis of the aliphatic sector was started with
D
-(þ)-ri-
bose, which was converted via acetonide formation and Wittig
reaction to alkenol 13 (Scheme 1).9 A subsequent pivaoylation
followed by hydrolysis of the acetal, mediated by CuCl2$2H2O10 led
to triol 15 in good yield. A transacetalization reaction on benzal-
dehyde dimethylacetal produced 1,3-dioxane 16 thereby exposing
the central hydroxyl function. This group was then protected as
PMB ether. In the next step a cross-metathesis reaction11 between
alkene 17 and pent-4-en-2-ol derivative12 18 (1 equiv) using
Grubbs second generation catalyst (5 mol %) at 80 ꢀC in toluene
provided an excellent yield of alkene 19. A subsequent catalytic
hydrogenation of the double bond furnished the differently pro-
tected pentaol 20. Reductive cleavage of the pivalate group was
followed by chain extension of alcohol 21 to nitrile 22 using Mit-
sunobu conditions.13 Reduction of nitrile 22 to the corresponding
aldehyde and Wittig reaction furnished terminal alkene 24. Re-
moval of the silyl protecting group provided alkenol 25.
The aromatic fragment of the metathesis route toward the sty-
rene double bond was prepared from known hydroxyphthalide14 26
via Wittig olefination. Acid 27 and alkenol 25 were then combined
via Mitsunobu esterification to provide benzoic ester 28 in excellent
yield.15 Based on previous experience, a clean inversion could be
assumed.16 Ester 28 served as precursor for various substrates 28–
33 that were intended for RCM. Thus, oxidative cleavage of the PMB
ether followed by oxidation provided ketone 29. Treatment of acetal
29 with conc. HCl in MeOH removed the benzylidene acetal gen-
erating dihydroxy ketone 30. We also prepared the derivatives 31–
33. Unfortunately, none of the substrates 28–33 could be cyclized
with the Grubbs second generation catalyst (5 mol %, toluene, 80 ꢀC,
Therefore, we turned to a strategy pioneered by Winssinger
et al.6,5 for the synthesis of other resorcylic acid lactones. This is
characterized by alkylation of a 2-(phenylselanylmethyl)benzoate
with an alkyl iodide followed by elimination of the derived
phenylselenoxide. Accordingly, aldehyde 23 was reduced to primary
alcohol 37 (Scheme 3). Reaction of alcohol 37 with iodine and PPh3
gave iodide 38. Alkylation of the lithium anion of benzyl (phenyl)-
selane6,17–19 39 in THF/HMPA afforded crude selenoether. The crude
selenidewas oxidized leading afterelimination toE-alkene40 in 75%
yield. Simultaneous cleavage of the trimethylsilylethanyl (TMSE)
ester and the silyl ether furnished hydroxy acid 41. Somewhat to our
surprise the cyclization of hydroxy acid 41 under Mitsunobu con-
ditions went quite well and gave macrolactone 34a in 77% yield.20
MacroModel calculations on a model compound (PMB and Ph
replaced by methyl group) showed an all equatorial orientation of
the substituents in the dioxane ring (see Supplementary data). Thus,
the cyclic acetal seems to favor macrolactonization by imposing
conformational constraint on the aliphatic region. Selective removal
of the PMB protecting group with DDQ was followed by oxidation of
alcohol 42 to ketone 34b. Finally, the benzylidene acetal was cleaved
by acid-catalyzed transacetalization. Treatment of the crude dihy-
droxy ketone with BCl3 (4.0 equiv) at ꢁ50 ꢀC, gave rise to the pro-
posed structure 6 of queenslandon. The chemoselective ether

96
V. Navickas, M.E. Maier / Tetrahedron 66 (2010) 94–101
MeO
OTBS
O
MeO
MeO
O
CO2H
MePPh3Br, KOtBu
O
NaBH4
THF, 0 °C (76%)
MeO
MeO
23
I2, PPh3
imidazole
(93%)
37 X = OH
38 X = I
OH
THF/MeOH
(94%)
PMBO
MeO
26
27
MeO
O
X
O
Ph
alcohol 25, PPh3
O
PMBO
SiMe3
MeO
O
DEAD, toluene/Et2O
(95%)
MeO
O
1. a) LDA, THF/HMPA
–80 °C
b) add 38
O
MeO
O
Ph
28
MeO
MeO
O
O
2. H2O2, THF
(75%)
SiMe3
MeO
SePh
1. DDQ, CH2Cl2
2. DMP, CH2Cl2
39
O
MeO
O
MeO
O
MeO
O
O
Ph
OTBS
OH
O
Ph
TBAF
29
MeO
MeO
MeO
O
O
THF (84%)
conc. HCl, MeOH
O
MeO
40
(60%, from 28)
MeO
OR
OPMB
MeO
MeO
OR
OR
CO2H
TBSOTf
2,6-lutidine
CH2Cl2 (86%)
30 R = H
Ph
O
PPh3, DEAD
O
31 R = TBS
toluene (77%)
O
MeO
MeO
MeO
O
41
HCl (conc.)
OPMB
28
O
PMBO
MeOH (67%)
MeO
O
RO
DMP
MeO
OR
O
O
O
32 R = H
TBSOTf
2,6-lutidine
CH2Cl2 (100%)
CH2Cl2 (94%)
MeO
MeO
Ph
33 R = TBS
Grubbs 2nd
R
MeO
DDQ
CH2Cl2/H2O
(64%)
34a R = PMB
42 R = H
MeO
MeO
O
28 – 33
X
O
OR
OR
X
MeO
28, 34a H, OPMB CHPh
MeO
O
1. HCl, MeOH
34a-f
29, 34b
30, 34c
31, 34d
O
O
O
CHPh
H
TBS
H
O
2. BCl3, CH2Cl2
O
O
17
–50 °C
HO
O
(43%)
MeO
O
Ph
32, 34e H, OPMB
O
34b
MeO
4
1
O
OH
33, 34f H, OPMB TBS
12
10
MeO
O
MeO
O
OH
8
6
Grubbs 2nd
O
MeO
O
OH
OH
O
toluene, 80 °C
Scheme 3. Synthesis of the proposed structure of queenslandon via Mitsunobu
(26%)
MeO
MeO
OH
lactonization.
35
36
OH
comes from a comparison of the queenslandon structure 6 with the
related compounds 3d5. In these macrolides C11 (or C30) have op-
posite configuration. The measured optical rotations for 6 are
O
Scheme 2. Synthesis of various substrates for the RCM approach.
20
20
[
a
]
¼ꢁ41.0 (c 0.5, CH2Cl2), [
a
]
¼ꢁ51.0 (c 0.1, CH3OH). The liter-
D
D
20
ature value for the isolated queenslandon7 amounts to [
a]
D
¼þ24.4
cleavage next to a carboxylic group is well known.1,21 However, this
is also evident from the NOESY spectrum where the phenolic OH (3-
OH) showed correlations to 17-H and 17-CH3. In addition, the HMBC
spectrum displays the expected correlations (5-OCH3/C-5 and 6-
OCH3/C-6). Macrolactone 6 shows moderate cytostatic activity with
(c 0.028, CH3OH). Efforts are now underway to prepare the C11
epimer of 6.
3. Conclusion
an IC50 of 33
L929.
m mM) against the mouse fibroblast cell line
g mLꢁ1 (84
In conclusion, we accomplished the synthesis of the proposed
structure of the macrolactone queenslandon (6). The structural
challenges of this natural product include a highly substituted
electron-rich benzoic acid part and an aliphatic region featuring
The 1H NMR signatures of 6 matched nicely the ones published
for the simple model compound 12. In particular, a NOESY cross peak
between 11-H (4.60–4.67) and 13-H (4.36–4.41) suggests the cis-
orientation at these methine carbons. However, with regard to the
published data for queenslandon we observed some distinct dis-
crepancies. For example, there are big differences (
(keto function), C9 (alkene carbon), and C11 (
might conclude that something is wrong with C11 since both C9 and
C12 are in the vicinity to C11. Further support for this hypothesis
a dihydroxy ketone subunit. This subunit was fashioned from D-ri-
bose via triol 15. Via formation of a benzylidene acetal the hydroxyl
functions could be differentiated. Thereafter, this central fragment
was extended via cross-metathesis at the alkene and substitution of
the primary alcohol by cyanide. Several substrates that were
intended for a ring-closing metathesis reaction failed to cyclize to
d ppm>3) for C12
ppm¼6.4). Thus, one
d

V. Navickas, M.E. Maier / Tetrahedron 66 (2010) 94–101
97
the corresponding macrolactone. The only ester that cyclized with
moderate yield was the 6-nor-methoxy compound 35. Finally, io-
dide 38 was used to alkylate the trimethylsilylethyl 2-methyl-
benzoate derivative 39. This led after elimination of phenylselanol
to seco acid 41. This substrate underwent a clean Mitsunobu lac-
tonization, probably facilitated by conformational constraint im-
posed through the benzylidene acetal. The spectral data showed
that the prepared lactone 6 does not correspond to queenslandon.
Since the biggest differences are observed for the chemical shifts
around C11 it is likely that the configuration of C11 should be
inverted. This work highlights the role of organic synthesis in
detecting errors in structure elucidation of natural products.22
temp. After being stirred for 1 h the reaction mixture was washed
with satd. NaHCO3 (100 mL), satd. NaCl solution, dried over MgSO4,
filtered, and concentrated in vacuo. The crude product was purified
by flash chromatography (petroleum ether/EtOAc, 5:1) to give
hydroxydioxane 16 (8.3 g, 91%) as a colorless oil. Rf (petroleum
20
ether/EtOAc, 5:1) 0.17; [
a
]
ꢁ31.3 (c 0.9, CH2Cl2); dH (400 MHz,
D
CDCl3) 1.23 (s, 9H, C(CH3)3), 3.30 (t, J¼9.2 Hz, 1H, CHOH), 3.82–3.86
(m, 1H, PivOCH2CH), 4.07–4.11 (m, 1H, H2C]CHCHOH), 4.34 (dd,
J¼12.2, 4.1 Hz, 1H, PivOCH2), 4.56 (dd, J¼12.2, 4.1 Hz, 1H, PivOCH2),
5.32 (m, 2H, CH2]CH), 5.63 (s, 1H, CHPh), 6.00 (ddd, J¼17.0, 10.7,
6.4, 1H, CH2]CH), 7.34–7.37 (m, 3H, H aryl), 7.48–7.50 (m, 2H, H
aryl); dC (150 MHz, CDCl3) 27.2 (C(CH3)3), 39.0 (C(CH3)3), 63.5
(PivOCH2), 66.2 (CHOH), 79.4 (PivOCH2CH), 81.8 (CH2]CHCHOH),
100.6 (CHPh), 118.9 (CH2]CH), 126.2, 128.2, 129.0, 134.5 (C aryl),
137.4 (CH]CH2), 179.5 (C]O); HRMS (ESI): [MþNa]þ calcd for
C18H24O5Na 343.15159, found 343.15164.
4. Experimental section
4.1. (R)-2-((4R,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)-2-
hydroxyethyl pivalate (14)
4.4. ((2S,4R,5S,6S)-5-(4-Methoxybenzyloxy)-2-phenyl-6-vinyl-
1,3-dioxan-4-yl)methyl pivalate (17)
To an ice-cooled solution of diol9 13 (16.65 g, 88.6 mmol) and
DMAP (1.07 g, 8.8 mmol) in a CH2Cl2/pyridine mixture (120 mL,
5:1) was added PivCl (11.0 mL, 106.3 mmol) in a dropwise fashion.
After the addition, the reaction mixture was allowed to warm to
room temperature. Stirring was continued for 2 h before the re-
To a cooled (ꢁ5 ꢀC) suspension of NaH (0.54 g, 13.4 mmol, 60% in
mineral oil) in anhydrous DMF (40 mL) was added dropwise a so-
lution of alcohol 16 (1.23 g, 3.8 mmol) in DMF (5 mL) at the same
temperature. After complete addition, the reaction mixture was
stirred for 1 h at ꢁ5 ꢀC before a solution of freshly prepared PMBBr8
(1.28 g, 6.4 mmol) in DMF (5 mL) was added. After being stirred for
additional 2 h at ꢁ5 ꢀC the reaction was quenched with satd. NH4Cl
(10 mL) and the product extracted with EtOAc (3ꢂ100 mL). The
combined organic layers were washed with water, satd. NaCl solu-
tion, dried over MgSO4, filtered, and concentrated in vacuo. The
crude product was purified by flash chromatography (petroleum
action mixture was washed with 1
solution. The organic layer was dried over MgSO4, filtered, and
N
HCl (5ꢂ100 mL) and satd. NaCl
concentrated in vacuo. The crude pivaloate 14 (22.8 g, 95%) was
pure enough to be introduced to the next step without additional
20
purification. Rf (petroleum ether/EtOAc, 5:1): 0.25; [
a
]
þ9.7 (c
D
2.2, CH2Cl2); dH (400 MHz CDCl3) 1.21 (s, 9H, C(CH3)3), 1.34 (s, 3H,
CH3C), 1.46 (s, 3H, CH3C), 3.84 (dd, J¼7.9, 5.3 Hz, 1H, CH2CHOH),
4.04–4.17 (m, 2H, CH2OPiv), 4.36 (ddd, J¼7.9, 4.3, 3.8 Hz,1H, CHOH),
4.69 (t, J¼6.6 Hz, 1H, CH2]CHCHOR), 5.30–5.43 (m, 2H, CH2]CH),
5.98 (ddd, J¼17.3, 10.4, 6.9 Hz, 1H, CH2]CH); dC (150 MHz CDCl3)
25.3 (C(CH3)3), 27.2 (CH3), 27.7 (CH3), 38.9 (C(CH3)3), 66.6 (Piv-
OCH2), 68.8 (CH2CHOH), 77.5 (CHOH), 78.5 (CH2]CHCHOR), 109.0
(C(CH3)2), 118.3 (CH2]CH), 133.7 (CH]CH2), 179.1 (C]O); HRMS
(ESI): [MþNa]þ calcd for C14H24O5Na 295.15159, found 295.15162.
ether/EtOAc, 10:1) to give PMB ether 17 (0.97 g, 57%) as a colorless
20
oil. Rf (petroleum ether/EtOAc, 10:1) 0.26; [
a
]
¼þ5.5 (c 0.8,
D
CH2Cl2); dH (400 MHz, CDCl3) 1.26 (s, 9H, C(CH3)3), 3.40 (t, J¼9.4 Hz,
1H, CHOPMB), 3.83 (s, 3H, OCH3), 3.91–3.94 (m, 1H, PivOCH2CH),
4.19–4.23 (m, 1H, H2C]CHCHOH), 4.34 (m, 1H, CH2Ar), 4.44–4.52
(m, 2H, CH2Ar, PivOCH2), 4.63 (d, J¼10.2 Hz, 1H, PivOCH2), 5.39 (d,
J¼10.4 Hz, 1H, CH2]CH), 5.58 (d, J¼10.4 Hz, 1H, CH2]CH), 5.63 (s,
1H, CHPh), 6.09 (ddd, J¼17.3, 10.7, 6.6, 1H, CH2]CH), 6.90–6.92 (m,
2H, PMB), 7.25–7.29 (m, 2H, PMB), 7.35–7.39 (m, 3H, H aryl), 7.50–
7.52 (m, 2H, H aryl); dC (150 MHz, CDCl3) 27.2 (C(CH3)3), 38.9
(C(CH3)3), 55.3 (OCH3), 62.9 (ArCH2), 73.8 (CHOPMB), 74.4 (Piv-
OCH2), 78.4 (PivOCH2CH), 81.6 (CH2]CHCHOH), 100.3 (CHPh), 114.0
(C aryl), 118.8 (CH2]CH), 126.2, 128.2, 128.9, 129.4, 129.8 (C aryl),
135.1 (CH]CH2), 137.5 (C aryl), 159.6 (C aryl), 178.2 (C]O); HRMS
(ESI): [MþNa]þ calcd for C26H32O6Na 463.20911, found 463.20878.
4.2. (2R,3S,4S)-2,3,4-Trihydroxyhex-5-enyl pivalate (15)
To an ice-cooled solution of acetonide 14 (10.56 g, 38.8 mmol) in
acetonitrile (100 mL) was added CuCl2$2H2O (46.0 g, 271.6 mmol)
portionwise within 1 h and then the reaction mixture was allowed
to warm to room temperature. After being stirred for 12 h at room
temperature, inorganic solids were filtered off, and the filter cake
washed with acetonitrile (100 mL). The combined filtrates were
washed with satd. NH4Cl (3ꢂ100 mL), dried over Na2SO4, filtered,
and concentrated in vacuo. The crude product was purified by flash
chromatography (petroleum ether/EtOAc, 5:1) to give triol 3
4.5. ((2S,4R,5S,6S)-6-((R,E)-4-(tert-Butyldimethylsilyloxy)-
pent-1-enyl)-5-(4-methoxybenzyloxy)-2-phenyl-1,3-
dioxan-4-yl)methyl pivalate (19)
(6.59 g, 73%) as a white amorphous solid. Rf (petroleum ether/
20
EtOAc, 1:1) 0.26; [
a
]
ꢁ6.7 (c 1.0, CH2Cl2); dH (400 MHz, CDCl3)
D
1.22 (s, 9H, C(CH3)3), 2.54 (br s, 3H, 3ꢂOH), 3.55 (dd, J¼7.9, 5.3 Hz,
1H, CH2CHOH), 3.84 (ddd, J¼7.9, 4.3, 3.8 Hz, 1H, CHOH), 4.32–4.35
(m, 3H, PivOCH2 and H2C]CHCHOH), 5.98 (m, 2H, CH2]CH), 5.99
(ddd, J¼17.2, 10.5, 6.6 Hz, 1H, CH2]CH); dC (150 MHz, CDCl3): 27.2
(C(CH3)3), 39.0 (C(CH3)3), 66.3 (PivOCH2), 72.4 (CH2CHOH), 72.8
(CHOH), 74.7 (CH2]CHCHOH), 118.3 (CH2]CH), 136.3 (CH]CH2),
179.8 (C]O); HRMS (ESI): [MþNa]þ calcd for C11H20O5Na
255.12029, found 255.12023.
Alkene 17 (1.76 g, 4.0 mmol) was dissolved in degassed toluene
(17.6 mL) and then alkene12 18 (0.8 g, 4.0 mmol) was added. The
reaction mixture was slightly warmed (to around 40–50 ꢀC) and
Grubbs second catalyst (170 mg, 5 mol %) was added. The temper-
ature was brought to 80 ꢀC and maintained for 2 h. After that air was
bubbled through the reaction (for approx. 5 min) and the solvent
was evaporated in vacuo. The crude product was purified by flash
chromatography (petroleum ether/EtOAc, 10:1) to give metathesis
product 19 (1.80 g, 74%) as a colorless oil. Rf (petroleum ether/EtOAc,
20
4.3. ((2S,4R,5S,6S)-5-Hydroxy-2-phenyl-6-vinyl-1,3-dioxan-4-
yl)methyl pivalate (16)
5:1) 0.34; [
a
]
D
ꢁ9.8 (c 0.4, CH2Cl2); dH (400 MHz, CDCl3) 0.04 (s,
6H, Si(CH3)2), 0.88 (s, 9H, SiC(CH3)3), 1.14 (d, J¼6.1 Hz, 3H,
TBSOCHCH3), 1.23 (s, 9H, C(CH3)3), 2.04–2.27 (m, 2H, CH2), 3.34 (t,
J¼9.2 Hz, 1H, CHOPMB), 3.79 (s, 3H, OCH3), 3.84–3.89 (m, 2H, Piv-
OCH2CHOR, TBSOCH), 4.11–4.15 (m, 1H, CH]CHCHOR), 4.27–4.31
(m, 1H, PivOCH2), 4.41–4.47 (m, 3H, PivOCH2, CH2 of PMB), 4.58 (d,
To a solution of triol 15 (6.59 g, 28.0 mmol) in CH2Cl2 (80 mL)
was added CSA (1.29 g, 5.6 mmol) followed by the dropwise addi-
tion of benzaldehydedimethylacetal (5.1 mL, 33.6 mmol) at room

98
V. Navickas, M.E. Maier / Tetrahedron 66 (2010) 94–101
J¼10.3 Hz, 1H, PivOCH2), 5.58 (s, 1H, CHPh), 5.64–5.70 (m, 1H,
CH]CHCH2), 5.94–6.02 (m, 1H, CH]CHCH2), 6.86–6.88 (m, 2H,
PMB), 7.18–7.22 (m, 2H, PMB), 7.32–7.34 (m, 3H, H aryl), 7.46–7.48
(m, 2H, H aryl); dC (150 MHz, CDCl3) ꢁ4.7, ꢁ4.5 (Si(CH3)2), 18.1
(CH2), 23.6 (CHCH3), 25.9 (SiC(CH3)3), 27.2 (C(CH3)3), 38.9 (C(CH3)3),
42.9 (SiC(CH3)3), 55.3 (OCH3), 63.0 (CH2 of PMB), 68.4 (CHCH3), 73.9
(CHOPMB), 74.3 (PivOCH2), 78.4 (PivOCH2CHOR), 81.5 (CH2CHOR),
100.3 (CHPh), 114.0, 126.2, 128.2, 128.8, 128.9, 129.5 (C aryl), 129.7
(CH]CHCH2), 132.4 (CH]CHCH2), 137.6, 159.6 (C aryl), 178.2
(C]O); HRMS (ESI): [MþNa]þ calcd for C35H52O7SiNa 635.35310,
found 635.34213.
(HOCH2CHOR), 80.7 (CH2CHOR), 100.3 (CHPh), 114.0, 126.1, 128.2,
128.8, 129.8, 137.8, 159.5 (C aryl); HRMS (ESI): [MþNa]þ calcd for
C30H46O6SiNa 553.29559, found 553.29557.
4.8. 2-((2S,4R,5S,6S)-6-((R)-4-(tert-Butyldimethylsilyloxy)-
pentyl)-5-(4-methoxybenzyloxy)-2-phenyl-1,3-
dioxan-4-yl)acetonitrile (22)
To a stirred solution of alcohol 21 (0.54 g, 1.0 mmol) in diethyl
ether (3.4 mL) was added PPh3 (0.59 g, 2.2 mmol) at ꢁ5 ꢀC. The
mixture was stirred at the same temperature for 15 min before DEAD
(0.98 mL, 2.2 mmol) was added dropwise. The reaction mixture be-
came like a white paste. After 20 min acetone cyanohydrine
(0.21 mL, 2.2 mmol) was added dropwise and the solids dissolved.
The mixture was stirred at ꢁ5 ꢀC for 6 h and for additional 12 h at
room temperature. After that the solvent was evaporated and the
residue purified by flash chromatography (petroleum ether/EtOAc,
4.6. ((2S,4R,5S,6S)-6-((R)-4-(tert-butyldimethylsilyloxy)-
pentyl)-5-(4-methoxybenzyloxy)-2-phenyl-1,3-
dioxan-4-yl)methyl pivalate (20)
Metathesis product 19 (1.64 g, 2.67 mmol) was dissolved in
EtOAc (5 mL), Pd/C (10% wt) was added and a balloon filled with
hydrogen was attached through a rubber septum. The reaction
mixture was stirred for 5 h at room temperature and then the pal-
ladium catalyst was filtered off through a pad of CeliteÒ, washed
with EtOAc (2ꢂ10 mL). The filtrate was concentrated in vacuo and
the residue purified by flash chromatography (petroleum ether/
10:1) to give nitrile 22 (0.487 g, 89%) as a colorless oil. Rf (petroleum
20
ether/EtOAc, 5:1) 0.42; [
a
]
ꢁ1.0 (c 1.4, CH2Cl2); dH (400 MHz,
D
CDCl3) 0.03 (s, 3H, Si(CH3)2), 0.04 (s, 3H, Si(CH3)2), 0.87 (s, 9H,
SiC(CH3)3), 1.12 (d, J¼6.1 Hz, 3H, TBSOCHCH3), 1.37–1.65 (m, 4H,
2ꢂCH2), 1.86–1.88 (m, 2H, CH2), 2.54–2.75 (m, 2H, NCCH2), 3.23 (t,
J¼9.2 Hz, CHOPMB), 3.63–3.68 (m,1H, CH2CH2CH), 3.76–3.85 (m, 5H,
OCH3, NCCH2CH and TBSOCHCH3), 4.50–4.69 (dd, J¼17.9,10.9 Hz, 2H,
CH2 of PMB), 5.54 (s, 1H, CHPh), 6.89–6.92 (m, 2H, H of PMB), 7.25–
7.27 (m, 2H, H of PMB), 7.34–7.35 (m, 3H, H aryl), 7.47–7.49 (m, 2H, H
aryl); dC (150 MHz, CDCl3) ꢁ4.7, ꢁ4.4 (Si(CH3)2),18.1, 21.4 (CH2), 23.8
(CHCH3), 25.9 (SiC(CH3)3), 29.3 (NCCH2), 32.1 (CH2), 39.6 (SiC(CH3)3),
55.3 (OCH3), 68.4 (CHCH3), 75.0 (CH2 of PMB), 75.6 (CH2CH2CH), 76.8
(CHOPMB), 80.6 (HOCH2CHO), 100.4 (CHPh), 114.0 (C aryl), 116.9
(NC),126.1,128.2,128.9,129.2,129.9,137.1,159.8 (C aryl); HRMS (ESI):
[MþNa]þ calcd for C31H45NO5SiNa 562.29592, found 562.29624.
EtOAc,10:1) to give protected polyol 20 (1.60 g, 98%) as colorless oil.
20
Rf (petroleum ether/EtOAc, 5:1) 0.34; [
a]
ꢁ0.1 (c 4.4, CH2Cl2); dH
D
(400 MHz, CDCl3) 0.04 (s, 3H, Si(CH3)2), 0.05 (s, 3H, Si(CH3)2), 0.88 (s,
9H, SiC(CH3)3), 1.13 (d, J¼6.1 Hz, 3H, TBSOCHCH3), 1.25 (s, 9H,
(C(CH3)3), 1.39–1.62 (m, 4H, 2ꢂCH2), 1.85–1.90 (m, 2H, CH2), 3.32 (t,
J¼9.1 Hz,1H, HCOPMB), 3.64–3.68 (m, 1H, CH2CHOR), 3.77–3.80 (m,
4H, OCH3, HCOTBS), 3.84–3.87 (m,1H, PivOCH2CHOR), 4.28–4.32 (m,
1H, PivOCH2), 4.50–4.57 (m, 3H, PivOCH2, CH2 of PMB), 5.54 (s, 1H,
CHPh), 6.88–6.91 (m, 2H, PMB), 7.25–7.27 (m, 2H, PMB), 7.33–7.36
(m, 3H, H aryl), 7.46–7.48 (m, 2H, H aryl); dC (150 MHz, CDCl3) ꢁ4.7,
ꢁ4.4 (Si(CH3)2), 18.1, 21.3 (CH2), 23.8 (CHCH3), 25.9 (SiC(CH3)3), 27.2
(C(CH3)3), 32.1 (CH2), 38.9 (SiC(CH3)3), 39.6 (C(CH3)3), 55.3 (OCH3),
63.0 (CH2 of PMB), 68.5 (CHCH3), 74.1 (CHOPMB), 74.7 (PivOCH2),
78.5 (PivOCH2CHOR), 80.4 (CH2CHOR), 100.2 (CHPh), 114.0, 126.0,
128.1, 128.6, 129.5, 129.7, 137.8, 159.6 (C aryl), 178.2 (C]O); HRMS
(ESI): [MþNa]þ calcd for C35H54O7SiNa 637.35310, found 637.35287.
4.9. 2-((2S,4R,5S,6S)-6-((R)-4-(tert-Butyldimethylsilyloxy)-
pentyl)-5-(4-methoxybenzyloxy)-2-phenyl-1,3-
dioxan-4-yl)acetaldehyde (23)
A solution of nitrile 22 (0.49 g, 0.90 mmol) in CH2Cl2 (10 mL) was
cooled to ꢁ80 ꢀC followed by slow addition of DIBAL-H (5.4 mL, 1
M
in hexane, 5.4 mmol). After being stirred for 1 h at ꢁ80 ꢀC satd.
NH4Cl solutionwas added and the mixture allowed to warm to room
temperature. The organic layer was separated and the aqueous
phase extracted with CH2Cl2 (2ꢂ10 mL). The combined organic
layers were dried over MgSO4, filtered, and concentrated in vacuo.
The residue was purified by flash chromatography (petroleum
4.7. ((2S,4R,5S,6S)-6-((R)-4-(tert-Butyldimethylsilyloxy)-
pentyl)-5-(4-methoxybenzyloxy)-2-phenyl-1,3-
dioxan-4-yl)methanol (21)
A solution of pivaloate 20 (1.18 g, 1.92 mmol) in CH2Cl2 (15 mL)
was cooled to ꢁ80 ꢀC and then DIBAL-H (11.52 mL,11.5 mmol,1
M
in
ether/EtOAc, 10:1) to give aldehyde 23 (469 mg, 96%) as a colorless
20
hexane) was added over 1 h at the same temperature. The reaction
mixture was stirred for an additional 1 h before satd. NH4Cl (5 mL)
was added dropwise and the reaction mixture was allowed to
warm to room temperature. The layers were separated and the
aqueous layer extracted with CH2Cl2 (2ꢂ10 mL). The combined
organic extracts were washed with satd. NaCl solution (20 mL),
dried over MgSO4, filtered, and concentrated in vacuo. The residue
was purified by flash chromatography (petroleum ether/EtOAc, 5:1)
oil. Rf (petroleum ether/EtOAc, 5:1) 0.42; [
a]
ꢁ7.8 (c 1.7, CH2Cl2);
D
dH (400 MHz, CDCl3) 0.06 (s, 6H, Si(CH3)2), 0.90 (s, 9H, SiC(CH3)3),
1.16 (d, J¼6.1 Hz, 3H, TBSOCHCH3), 1.41–1.65 (m, 4H, 2ꢂCH2), 1.87–
1.91 (m, 2H, CH2), 2.65–2.83 (m, 2H, CHOCH2), 3.14 (t, J¼9.2 Hz, 1H,
CHOPMB), 3.68–3.73 (m, 1H, CH2CH2CH), 3.80–3.84 (m, 4H, OCH3,
TBSOCHCH3), 4.18–4.24 (m, 1H, CHOCH2CH), 4.49–4.62 (dd, J¼17.8,
10.9 Hz, 2H, CH2 of PMB), 5.59 (s,1H, CHPh), 6.90–6.92 (m, 2H, PMB),
7.25–7.27 (m, 2H, PMB), 7.34–7.36 (m, 3H, H aryl), 7.46–7.48 (m, 2H,
H aryl), 9.82 (t, J¼2.3 Hz, 1H, CHO); dC (150 MHz, CDCl3) ꢁ4.7, ꢁ4.4
(Si(CH3)2), 18.1, 21.3 (CH2), 23.8 (CHCH3), 25.9 (SiC(CH3)3), 32.1
(CH2), 39.6 (SiC(CH3)3), 46.3 (CHOCH2), 55.3 (OCH3), 68.5 (CHCH3),
74.7 (CH2 of PMB), 75.9 (CH2CH2CH), 77.4 (CHOPMB), 80.8
(O]CCH2CH), 100.3 (CHPh), 114.0, 126.0, 128.1, 128.8, 129.3, 129.8,
137.5, 159.7 (C aryl), 200.2 (CHO); HRMS (ESI): [MþCH3OHþNa]þ
calcd for C32H50O7SiNa 597.32180, found 597.32221.
to give alcohol 21 (0.82 g, 81%) as a colorless oil. Rf (petroleum
20
ether/EtOAc, 5:1) 0.17; [
a]
ꢁ22.4 (c 1.4, CH2Cl2); dH (400 MHz,
D
CDCl3) 0.04 (s, 6H, Si(CH3)2), 0.87 (s, 9H, Si(CH3)3), 1.12 (d, J¼6.1 Hz,
3H, CHCH3), 1.36–1.60 (m, 4H, 2ꢂCH2), 1.82–1.88 (m, 2H, CH2), 1.95
(br s, 1H, OH), 3.38 (t, J¼9.2 Hz, 1H, CHOPMB), 3.62–3.71 (m, 1H,
CH2CHOCHPh), 3.73–3.77 (m, 1H, TBSOCHCH3), 3.77–3.80 (m, 4H,
OCH3, HOCH2), 3.93–3.96 (m, 1H, HOCH2), 4.58 (s, CH2 of PMB), 5.56
(s, 1H, CHPh), 6.88–6.90 (m, 2H, PMB), 7.25–7.28 (m, 2H, PMB),
7.34–7.38 (m, 3H, H aryl), 7.47–7.49 (m, 2H, H aryl); dC (150 MHz,
CDCl3) ꢁ4.7, ꢁ4.4 (Si(CH3)2), 18.1, 21.3 (CH2), 23.8 (CHCH3), 25.9
(SiC(CH3)3), 32.0 (CH2), 39.7 (SiC(CH3)3), 55.3 (OCH3), 62.2 (CH2 of
PMB), 68.5 (CHCH3), 73.3 (HCOPMB), 74.7 (PivOCH2), 80.4
4.10. 3,4,6-Trimethoxy-2-vinyl-benzoic acid (27)
KOtBu (0.41 g, 3.34 mmol) was added in one portion to a stirred
suspension of PPh3MeBr (1.22 g, 3.34 mmol) in THF (12 mL) at 0 ꢀC.

V. Navickas, M.E. Maier / Tetrahedron 66 (2010) 94–101
99
After 0.5 h hydroxyphthalide14 26 (0.10 g, 0.42 mmol) was added in
one portion and the mixture was allowed to warm to rt. After 2 h,
water (2 mL) was added followed by addition of 1 N HCl until the
pH of a reaction mixture was approx. 2. The organic layer was
separated and the aqueous phase extracted with EtOAc (2ꢂ10 mL).
The combined organic extracts were washed with satd. NaCl solu-
tion (20 mL), dried over MgSO4, filtered and concentrated in vacuo.
The residue was purified by flash chromatography (petroleum
ether/EtOAc, 1:4) to give styrene 27 (76 mg, 76%) as a white crys-
talline solid. Rf (petroleum ether/EtOAc, 1:4) 0.56; dH (400 MHz,
CDCl3) 3.70 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 5.49
(dd, J¼11.7, 1.3 Hz, 1H, CH2]CH), 7.75 (dd, J¼17.8, 1.3 Hz, 1H,
CH2]CH), 6.46 (s, 1H, H aryl), 6.84 (dd, J¼17.8, 11.5 Hz, 1H,
CH2]CH); dC (150 MHz, CDCl3) 56.0, 56.7, 60.4 (OCH3), 96.3 (CH
aryl), 113.7 (CH2]CH), 120.4, 130.4 (C aryl), 132.0 (CH2]CH), 141.0,
153.6, 154.8 (C aryl), 171.1 (C]O); HRMS (ESI): [MþNa]þ calcd for
C12H14O5Na 261.07390, found 261.07378.
5.52 (s, 1H, CHPh), 6.89–6.91 (m, 2H, PMB), 7.25–7.27 (m, 2H, PMB),
7.25–7.27 (m, 3H, H aryl), 7.46–7.48 8 (m, 2H, H aryl); dC (150 MHz,
CDCl3) ꢁ4.7, ꢁ4.3, (Si(CH3)2), 1.6 (CH2I), 18.1, 21.5 (CH2), 23.8
(CHCH3), 25.9 (SiC(CH3)3), 32.2 (CH2), 36.3 (HOCH2CH2) 39.7
(SiC(CH3)3), 55.3 (OCH3), 68.5 (CHCH3), 74.8 (CH2 of PMB), 77.6
(CH2CH2CH), 80.0 (HCOPMB), 80.6 (ICH2CH2CH), 100.0 (CHPh),
114.0, 126.0, 128.1, 128.7, 129.6, 129.7, 137.9, 159.6 (C aryl); HRMS
(ESI): [MþNa]þ calcd for C31H47IO5SiNa 677.21297, found 677.21222.
4.13. 2-(Trimethylsilyl)ethyl 2-((E)-3-((2S,4R,5S,6S)-6-((R)-4-
(tert-butyldimethylsilyloxy)pentyl)-5-(4-methoxybenzyloxy)-
2-phenyl-1,3-dioxan-4-yl)prop-1-enyl)-3,4,6-
trimethoxybenzoate (40)
(a) Alkylation: To a solution of phenylbenzyl selenoether17 39
(65.4 mg, 0.14 mmol) in a THF/HMPA mixture (3.3 mL, 10:1) was
added dropwise a preformed solution of LDA (0.22 mmol) in THF
(0.54 mL) whereby the reaction mixture turned red. After 20 min,
a precooled (ꢁ40 ꢀC) solution of alkyl iodide 38 (89.2 mg, 0.1 mmol)
inTHF (0.5 mL) was added slowly and the resulting reaction mixture
was stirred for 2 h at ꢁ80 ꢀC before satd. NH4Cl solution (5 mL) was
added. The reaction mixture was allowed to warm to room tem-
perature, then the layers were separated and the aqueous phase
extracted with EtOAc (2ꢂ10 mL). The combined organic layers were
washed with satd. NaCl solution, dried over MgSO4, filtered, and
concentrated in vacuo to a volume of around 2 mL. This solution was
filtered through a short pad of CeliteÒ and the Celite washed with
EtOAc (2ꢂ10 mL). The combined organic washings were evaporated
to give crude alkylation product (118.9 mg), which was directly in-
troduced to the next step. Rf (petroleum ether/EtOAc, 3:1) 0.43.
(b) Elimination: Thecrude alkylationproduct (119 mg, 0.1 mmol)was
dissolved in THF (2 mL) and H2O2 (0.026 mL, 0.25 mmol, 30%) was
added at rt. After being stirred for 2 h, the reaction was quenched
with satd. Na2S2O8 solution (2 mL), and the mixture extracted with
EtOAc (2ꢂ10 mL). The combined organic layers were washed with
satd. NaCl solution, dried over MgSO4, filtered, and evaporated. The
crude product was purified by flash chromatography (petroleum
4.11. 2-((2S,4R,5S,6S)-6-((R)-4-(tert-Butyldimethylsilyloxy)-
pentyl)-5-(4-methoxybenzyloxy)-2-phenyl-1,3-
dioxan-4-yl)ethanol (37)
A solution of aldehyde 23 (107 mg, 0.20 mmol) in a THF/MeOH
mixture (3.3 mL, 10:1) was cooled in an ice/salt bath and NaBH4
(17.1 mg, 0.24 mmol) was added in one portion. The reaction mixture
was stirred in an ice bath for 1 h followed by the addition of satd.
NH4Cl solution (5 mL). The mixture was extracted with EtOAc
(3ꢂ10 mL). The combined organic layers were washed with satd.
NaCl solution, dried over MgSO4, filtered and concentrated in vacuo.
The crude product was purified by flash chromatography (petroleum
ether/EtOAc, 5:1) to give alcohol 37 (102 mg, 94%) as a colorless oil. Rf
20
(petroleum ether/EtOAc, 1:1) 0.77; [
a
]
ꢁ2.3 (c 1.3, CH2Cl2); dH
D
(400 MHz, CDCl3) 0.04 (s, 6H, SiC(CH3)2), 0.87 (s, 9H, SiC(CH3)3), 1.12
(d, J¼6.1 Hz, 3H, CHCH3), 1.37–1.47 (m, 2H, CH2), 1.58–1.73 (m, 2H,
CH2), 1.83–1.91 (m, 2H, CH2), 2.13–2.18 (m, 2H, HOCH2CH2CH), 3.12
(m, 1H, CHOPMB), 3.61–3.66 (m, 1H, CH2CH2CH), 3.77–3.88 (m, 7H,
OCH3, TBSOCH, HOCH2, HOCH2CH2CH), 4.56 (dd, J¼19.0, 10.4 Hz, 2H,
CH2 of PMB), 5.53 (s, 1H, CHPh), 6.88–6.90 (m, 2H, PMB), 7.24–7.26
(m, 2H, PMB), 7.33–7.36 (m, 3H, H aryl), 7.44–7.46 (m, 2H, H aryl); dC
(150 MHz, CDCl3) ꢁ4.7, ꢁ4.3 (Si(CH3)2),18.1, 21.5 (CH2), 23.8 (CHCH3),
25.9 (SiC(CH3)3), 32.2 (CH2), 34.3 (HOCH2CH2) 39.7 (SiC(CH3)3), 55.3
(OCH3), 60.7 (HOCH2), 68.5 (CHCH3), 74.9 (CH2 of PMB), 77.8
(CH2CH2CH2CH), 80.2 (HCOPMB), 80.7 (HOCH2CH2CH),100.2 (CHPh),
114.0, 125.9, 128.2, 128.7, 129.7, 137.8, 159.6 (C aryl); HRMS (ESI):
[MþNa]þ calcd for C31H48O6SiNa 567.31124, found 567.31077.
ether/EtOAc, 8:1) to give styrene 40 (85.5 mg, 75% over 2 steps) as
20
a colorless oil. Rf (petroleum ether/EtOAc, 3:1) 0.41; [
a
]
þ10.4 (c
D
0.5, CH2Cl2); dH (400 MHz, CDCl3) ꢁ0.04 (s, 9H, Si(CH3)3), 0.03 (s, 6H,
Si(CH3)2), 0.87 (s, 9H, SiC(CH3)3), 1.12 (d, J¼6.1 Hz, 3H, CHCH3), 1.40–
1.88 (m, 8H, 3ꢂCH2, CH2TMS), 2.53–2.63 (m, 1H, CH]CHCH2), 2.76–
2.79 (m, 1H, CH]CHCH2), 3.14 (t, J¼9.2 Hz, 1H, CHOPMB), 3.58–3.62
(m, 4H, OCH3, TBSOCH), 3.71–3.80 (m, 8H, 2ꢂOCH3, HC]CHCH2CH,
CH2CH2CH), 3.87 (s, 3H, OCH3), 4.20–4.35 (m, 2H, OCH2CH2TMS),
4.56–4.65 (m, 2H, CH2 of PMB), 5.49 (s, 1H, CHPh), 6.34–6.41 (m, 2H,
H2CCH]CH, H aryl), 6.55 (d, J¼16.3 Hz, 1H, H2CCH]CH), 6.87–6.89
(m, 2H, H aryl), 7.25–7.32 (m, 6H, H aryl), 7.47–7.49 (m, 2H, H aryl); dC
(150 MHz, CDCl3) ꢁ4.7, ꢁ4.4 (Si(CH3)2), ꢁ1.6 (Si(CH3)3), 17.3
(CH2TMS), 18.1 (SiC(CH3)3), 21.6 (CH2), 23.8 (CHCH3), 25.9
(SiC(CH3)3), 32.8 (CH2), 36.2 (CH]CHCH2), 39.7 (CH2), 55.3, 56.1,
56.5, 60.4 (OCH3), 63.5 (CH2CH2TMS), 68.6 (CHCH3), 74.8 (CH2 of
PMB), 77.5 (CH2CH2CH), 80.0 (CHOPMB), 80.7 (CH]CHCH2CH), 96.1
(CH aryl), 100.0 (CHPh), 113.9, 116.1, 125.6, 126.1, 128.0 (C aryl), 128.4
(CH]CHCH2), 129.5, 130.0 (C aryl), 130.5 (CH]CHCH2), 132.5, 138.3,
140.7,153.1,153.8,159.4 (C aryl),168.1 (C]O); HRMS (ESI): [MþNa]þ
calcd for C47H70O10Si2Na 873.43997, found 873.43955.
4.12. (2S,4R,5S,6S)-6-((R)-4-(tert-Butyldimethylsilyloxy)-
pentyl)-4-(2-iodoethyl)-5-(4-methoxybenzyloxy)-2-
phenyl-1,3-dioxane (38)
Iodine (407 mg, 1.60 mmol) was added to a cooled solution (ice
bath) of PPh3 (392 mg, 1.49 mmol) and imidazole (131 mg,
1.91 mmol) in CH2Cl2 (3 mL). The resulting yellow suspension was
stirred for 20 min at the same temperature before a solution of al-
cohol 37 (584 mg, 1.07 mmol) in CH2Cl2 (1 mL) was added. The
cooling bath was removed and the resulting yellowish suspension
was stirred for additional 12 h at ambient temperature. After that,
the CH2Cl2 was evaporated and the residue purified by flash chro-
matography (petroleum ether/EtOAc, 20:1) to give primary iodide
38 (655 mg, 93%) as a slightly yellow oil. Rf (petroleum ether/EtOAc,
4.14. 2-((E)-3-((2S,4R,5S,6S)-6-((R)-4-Hydroxypentyl)-5-(4-
methoxybenzyloxy)-2-phenyl-1,3-dioxan-4-yl)prop-1-enyl)-
3,4,6-trimethoxybenzoic acid (41)
20
10:1) 0.59; [
a
]
þ19.2 (c 0.9, CH2Cl2); dH (400 MHz, CDCl3) 0.04 (s,
D
6H, Si(CH3)2), 0.88 (s, 9H, SiC(CH3)3), 1.13 (d, J¼6.1 Hz, 3H, CHCH3),
1.37–1.47 (m, 2H, CH2), 1.57–1.43 (m, 2H, CH2), 1.86–2.04 (m, 2H,
CH2), 2.35–2.39 (m, 2H, ICH2CH2), 3.07 (t, J¼9.2 Hz, 1H, CHOPMB),
3.29–3.34 (m, 2H, ICH2CH2CH, CH2CH2CH), 3.62–3.74 (m, 2H, ICH2),
3.77–3.81 (m, 4H, OCH3, TBSOCH), 4.50–4.60 (m, 2H, CH2 of PMB),
To a cooled (ice bath) solution of ester 40 (85.5 mg, 0.1 mmol) in
THF (1.5 mL) was added TBAF (0.6 mL, 0.8 mmol, 1 M in THF) and
the mixture was allowed to warm to room temperature. After being

100
V. Navickas, M.E. Maier / Tetrahedron 66 (2010) 94–101
stirred overnight satd. NH4Cl solution (3 mL) was added to the
mixture. The layers were separated and the aqueous phase
extracted with EtOAc (3ꢂ5 mL). The combined organic layers were
dried over MgSO4, filtered, and concentrated in vacuo. The crude
residue was purified by flash chromatography (petroleum ether/
(m, 2H, CH2), 2.64–2.77 (m, 2H, HC]CHCH2), 3.71 (s, 3H, OCH3),
3.74–3.72 (m, 5H, OCH3, CHOH, CH2CHOCHPh), 3.86–3.91 (m, 4H,
OCH3, CH]CHCH2CH), 5.34–5.38 (m, 1H, CH3CH), 5.46 (s, 1H,
CHPh), 6.38–6.45 (m, 2H, H aryl, CH]CHCH2), 6.69 (d, J¼16.5 Hz,
1H, CH]CHCH2), 7.32–7.41 (m, 3H, H aryl), 7.65–7.67 (m, 2H, H
aryl); dC (150 MHz, CDCl3) 17.2 (CH2),19.0 (CH3CH), 29.4, 34.5 (CH2),
35.1 (CH]CHCH2), 56.1, 56.5, 60.7 (OCH3), 62.9 (CH3CH), 73.6
(CH2CH2CHOCHPh), 78.8 (CH]CHCH2CH), 79.1 (CHOH), 96.4 (C
aryl), 102.1 (CHPh), 116.8 (C aryl), 126.6 (CH]CHCH2), 127.0, 129.1,
129.7 (C aryl), 132.0 (CH]CHCH2), 138.2, 140.4, 153.1, 153.3 (C aryl),
167.8 (C]O); HRMS (ESI): [MþNa]þ calcd for C28H34O8Na
521.21459, found 521.21456.
EtOAc, 1:2) to give hydroxy acid 41 (53.5 mg, 84%) as a white
20
amorphous solid. Rf (petroleum ether/EtOAc, 1:5) 0.68; [
a
]
D
þ8.0
(c 0.2, CH2Cl2); dH (400 MHz, CDCl3) 1.13 (d, J¼6.1 Hz, 3H, CHCH3),
1.50–1.82 (m, 6H, 3ꢂCH2), 2.63–2.64 (m, 1H, CH]CHCH2), 2.78–
2.82 (m, 1H, CH]CHCH2), 3.23–3.27 (dd, J¼9.2, 9.2 Hz, 1H,
CHOPMB), 3.62–3.65 (m, 4H, OCH3, HOCHCH3), 3.75–3.81 (m, 8H,
2ꢂOCH3, CH]CHCH2CH, CH2CH2CH), 3.86 (s, 3H, OCH3), 4.55–4.66
(m, 2H, CH2 of PMB), 5.48 (s, 1H, CHPh), 6.37–6.42 (m, 2H, H aryl,
CH]CHCH2), 6.61–6.65 (d, J¼16.3 Hz, HC]CHCH2), 6.85–6.87 (m,
2H, PMB), 7.25–7.33 (m, 6H, H aryl), 7.46–7.48 (m, 2H, H aryl), 8.58
(br s, 1H, CO2H); dC (150 MHz, CDCl3) 20.8 (CH2), 23.2 (HOCHCH3),
31.5 (CH2), 35.8 (CH]CHCH2), 38.8 (CH2), 55.2, 56.0, 56.5 (OCH3),
68.1 (HOCHCH3), 74.6 (CH2 of PMB), 75.7 (CH2CH2CH), 79.8
(CH]CHCH2CH), 80.6 (CHOPMB), 96.0 (C aryl), 100.5 (CHPh), 113.9
(C aryl), 126.0 (CH]CHCH2), 126.2, 128.1, 128.6, 129.5, 130.1, 131.1 (C
aryl), 132.4 (CH]CHCH2), 138.0, 140.6, 153.2, 154.2, 159.3 (C aryl),
176.8 (C]O) (very small); HRMS (ESI): [MþNa]þ calcd for
C36H44O10Na 659.28267, found 659.28274.
4.17. Ketone 34b
Dess–Martin periodinane (0.063 mL, 0.03 mmol, sol 15wt % in
CH2Cl2) was added dropwise to a cooled (ice bath) solution of al-
cohol 42 (9.8 mg, 0.02 mmol) in CH2Cl2 (1 mL). Then the reaction
mixture was allowed to warm to room temperature and stirred for
additional 2 h. After that, the resulting suspension was loaded di-
rectly on a flash column. Elution (petroleum ether/EtOAc, 1:1) gave
ketone 34b (9.2 mg, 94%) as a white amorphous solid. Rf (petroleum
20
ether/EtOAc, 1:1) 0.34; [
a
]
þ25.4 (c 0.5, CH2Cl2); dH (400 MHz,
D
CDCl3) 1.28 (d, J¼6.4 Hz, 3H, CHCH3), 1.41–1.64 (m, 4H, 2ꢂCH2),
1.88–1.93 (m, 1H, CH2CH2CH), 2.10–2.14 (m, 1H, CH2CH2CH), 2.72–
2.80 (m, 1H, CH]CHCH2), 3.09–3.15 (m, 1H, CH]CHCH2), 3.68 (s,
3H, OCH3), 3.79 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 4.50–4.55 (m, 2H,
CH]CHCH2CH and CH2CH2CHOCHPh), 5.13–5.17 (m, 1H, CH3CH),
5.94 (s, 1H, CHPh), 6.30 (ddd, J¼16.3, 14.0, 6.9 Hz, 1H, CH]CHCH2),
6.41 (s, 1H, H aryl), 6.47 (d, J¼16.3 Hz, 1H, CH]CHCH2), 7.35–7.44
(m, 3H, H aryl), 7.62–7.64 (m, 2H, H aryl); dC (150 MHz, CDCl3) 19.9
(CH2), 20.4 (CH3CH), 30.1, 36.6 (CH2), 36.4 (CH]CHCH2), 56.1, 56.5,
60.3 (OCH3), 72.0 (CH3CH), 81.7 (CH2CH2CHOCHPh), 82.8
(CH]CHCH2CH), 96.5 (C aryl), 99.9 (CHPh), 116.2 (C aryl), 126.5,
126.8 (CH]CHCH2), 128.5 (C aryl), 129.1 (C aryl), 129.3
(CH]CHCH2), 129.5, 138.0 (C aryl), 140.8, 152.7, 153.8 (C aryl), 167.4
(C]O), 207.5 (C]O ketone); HRMS (ESI): [MþNa]þ calcd for
C28H32O8Na 519.19894, found 519.19936.
4.15. Macrolactone 34a
To a solution of acid 41 (60.2 mg, 0.095 mmol) in toluene
(9.5 mL) was added PPh3 (55.6 mg, 0.19 mmol) at 0 ꢀC. After being
stirred for 15 min at 0 ꢀC, DEAD (0.097 mL, 0.19 mmol) was added
dropwise and the resulting mixture allowed to warm to room
temperature. After 12 h the toluene was evaporated and the crude
material purified by flash chromatography (petroleum ether/
EtOAc, 3:1) to give macrolactone 34a (45.3 mg, 77%) as a colorless
oil. Rf (petroleum ether/EtOAc, 1:1) 0.41; [
20
a
]
þ52.4 (c 1.3,
D
CH2Cl2); dH (400 MHz, CDCl3) 1.31 (d, J¼6.3 Hz, 3H, CHCH3), 1.54–
1.81 (m, 2H, CH2), 1.98–2.00 (m, 2H, CH3CHCH2CH2), 2.24–2.30 (m,
2H, CH2CH2CHOCHPh), 2.67–2.74 (m, 1H, CH]CHCH2), 2.80–2.84
(m, 1H, CH]CHCH2), 3.69 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.80–
3.85 (m, 4H, OCH3, HCOPMB), 3.88–3.91 (m, 4H, OCH3,
CH2CH2CHOCHPh), 4.54–4.64 (m, 2H, CH2 of PMB), 5.35–5.39 (m,
1H, CH3CH), 5.50 (s, 1H, CHPh), 6.46 (s, 1H, H aryl), 6.53–6.60 (m,
1H, CH]CHCH2), 6.66–6.70 (d, J¼16.7 Hz, 1H, CH]CHCH2), 6.82–
6.84 (m, 2H, H aryl), 7.21–7.24 (m, 3H, H aryl), 7.34–7.41 (m, 3H, H
aryl), 7.64–7.66 (m, 2H, H aryl); dC (150 MHz, CDCl3) 17.9 (CH2),18.9
(CH3CH), 30.0, 34.1 (CH2), 36.4 (CH]CHCH2), 55.2, 56.1, 56.5, 60.5
(OCH3), 70.1 (CH2 of PMB), 73.0 (CH3CH), 73.2 (CH2CH2CHOCHPh),
77.8 (CH]CHCH2CH), 78.9 (CHOPMB), 96.3 (C aryl), 101.3 (CHPh),
113.9, 116.8 (C aryl), 126.8 (CH]CHCH2), 127.0, 128.4, 129.0, 129.1,
129.2, 130.3 (C aryl), 132.4 (CH]CHCH2), 138.5, 140.6, 153.0, 153.5,
159.3 (C aryl), 167.9 (C]O); HRMS (ESI): [MþNa]þ calcd for
C36H42O9Na 657.24604, found 657.24650.
4.18. (3S,7S,9R,E)-7,9,16-Trihydroxy-13,14-dimethoxy-3-
methyl-4,5,6,7,9,10-hexahydro-3H-benzo[c][1]oxacy-
clotetradecine-1,8-dione (6)
(a) Acetal cleavage: Ketone 34b (15.5 mg, 0.03 mmol) was dissolved
in MeOH (1 mL) and then a solution of MeOH/HCl conc. (1.05 mL,
20:1) was added dropwise at room temperature. After being stirred
for 0.5 h, the solution was neutralized with satd. NaHCO3 and the
mixture extracted with EtOAc (2ꢂ10 mL). The combined organic
layers were washed with satd. NaCl solution, dried with MgSO4,
filtered, and concentrated in vacuo to provide the dihydroxy ketone
(8.0 mg) as a yellow oil. The compound was directly introduced to
the next step.
4.16. Macrolactone 42
(b) OMe cleavage: To a solution of crude dihydroxy ketone (8.0 mg,
0.02 mmol) in CH2Cl2 (1 mL) was added BCl3 (0.08 mL, 0.08 mmol,
Macrolactone 34a (12.7 mg, 0.021 mmol) was dissolved in
CH2Cl2 (0.5 mL), then water was added (0.25 mL) followed by DDQ
(5.7 mg, 0.025 mmol). The resulting mixture was stirred for 1 h at
room temperature and then satd. NaHCO3 solution was added. The
layers were separated and the aqueous layer extracted with CH2Cl2
(3ꢂ5 mL). The combined organic extracts were washed with satd.
NaHCO3 solution (5 mL), satd. NaCl solution, dried over MgSO4, and
filtered. The solvent was evaporated and the residue purified by
flash chromatography (petroleum ether/EtOAc, 3:1) to give alcohol
1
M
sol in CH2Cl2) dropwise at ꢁ50 ꢀC. After 20 min the reaction was
quenched with satd. NaOAc (3 mL). The layers were separated and
aqueous phase extracted with CH2Cl2 (3ꢂ5 mL). The combined
organic extracts were washed with satd. NaCl solution, dried over
MgSO4 and the solvent was evaporated. The residue was purified
via flash chromatography (CH2Cl2/MeOH, 40:1) to give compound
22 (5.2 mg, 43% over 2 steps) as a colorless crystalline solid. Rf
20
(petroleum ether/EtOAc, 1:5) 0.47; [
a
]
D
ꢁ41.0 (c 0.5, CH2Cl2),
20
[a
]
ꢁ51.0 (c 0.1, CH3OH); dH (400 MHz, CDCl3) 1.18–1.33 (m, 2H,
D
42 (6.6 mg, 64%) as a white amorphous solid. Rf (petroleum ether/
CH2), 1.37 (d, J¼6.1 Hz, 3H, CH3CH), 1.45–1.75 (m, 3H, CH2), 2.12–
2.20 (m, 1H, CH2), 2.70–2.76 (m, 1H, CH]CHCH2), 3.03–3.09 (m, 2H,
CH]CHCH2, CH2CH2CHOH), 3.44–3.49 (m, 1H, CH]CHCH2CHOH),
20
EtOAc, 1:1) 0.28; [
a]
þ55.7 (c 0.6, CH2Cl2); dH (400 MHz, CDCl3)
D
1.30 (d, J¼6.4 Hz, 3H, CHCH3), 1.50–1.75 (m, 4H, 2ꢂCH2), 2.08–2.22

V. Navickas, M.E. Maier / Tetrahedron 66 (2010) 94–101
101
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ences therein.
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1189–1193.
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Cao, D.-R.; Sun, J.-B.; Li, G. Chem.dEur. J. 2002, 8, 3747–3756.
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3.58 (s, 3H, OCH3), 3.86 (s, 3H. OCH3), 4.36–4.41 (m, 1H,
CH2CH2CHOH), 4.60–4.67 (m,1H, CH]CHCH2CHOH), 5.00–5.06 (m,
1H, CH3CH), 5.84 (ddd, J¼15.3, 8.9, 3.3 Hz, 1H, CH]CHCH2), 6.40 (s,
1H, H aryl), 6.65 (d, J¼15.3 Hz, 1H, CH]CHCH2), 11.56 (br s, 1H, OH
aromatic); dC (150 MHz, CDCl3) 20.5 (CH2), 20.7 (CHCH3), 32.5
(CH2), 35.6 (CH2), 37.0 (CH]CHCH2), 55.9, 60.6 (OCH3), 73.2
(CH3CH), 73.4 (CH]CHCH2CH), 75.0 (CH2CH2CHOH), 99.7 (CH aryl),
103.7 (C aryl), 126.6 (CH]CHCH2), 127.3 (CH]CHCH2), 133.5, 140.3,
158.7, 160.9 (C aryl), 170.7 (C]O ester), 213.0 (C]O ketone); HRMS
(ESI): [MþNa]þ calcd for C20H26O8Na 417.15199, found 417.15197.
Acknowledgements
´
13. (a) Wilk, B. K. Synth. Commun. 1993, 23, 2481–2484; (b) Aesa, M. C.; Baan, G.;
´ntay, C. Synth. Commun. 1995, 25, 1545–1550.
Nova´k, L.; Sza
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16. In this paper the inversion could be shown by X-ray on the derived macro-
lactone Ugele, M.; Sasse, F.; Knapp, S.; Fedorov, O.; Zubriene, A.; Matulis, D.;
Maier, M. E. ChemBioChem. 2009, 10, 2203–2212.
Financial support by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie is gratefully acknowledged.
We also thank Dr. Florenz Sasse (HZI Braunschweig, Germany) for
the cytotoxicity assay.
Supplementary data
17. Barluenga, S.; Dakas, P.-Y.; Ferandin, Y.; Meijer, L.; Winssinger, N. Angew. Chem.
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18. Seleno ether 39 was prepared in eight steps from 5-bromovanillin: (a) Sa´nchez,
I. H.; Larraza, M. I.; Basurto, F.; Yafn˜ez, R.; Avila, S.; Tovar, R.; Joseph-Nathan, P.
Tetrahedron 1985, 41, 2355–2359; (b) Evans, G. E.; Staunton, J. J. Chem. Soc.,
Perkin Trans. 1 1988, 755–761; (c) Fu¨rstner, A.; Stelzer, F.; Rumbo, A.; Krause, H.
Chem.dEur. J. 2002, 8, 1856–1871; for an overall Scheme, see supporting
information.
19. For a recent application of this methodology, see: (a) Jogireddy, R.; Dakas, P.-Y.;
Valot, G.; Barluenga, S.; Winssinger, N. Chem.dEur. J. 2009, 15, 11498–11506;
(b) Dakas, P.-Y.; Jogireddy, R.; Valot, G.; Barluenga, S.; Winssinger, N. Chem.dEur. J.
2009,15,11490–11497.
Supplementary data associated with this article (remaining
procedures for Scheme 1 and 2, copies of NMR spectra) can be
found in the online version, at doi:10.1016/j.tet.2009.11.024.
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