Synthesis of the C1-C13 fragment of biselyngbyaside

Article abstract of DOI:10.1055/s-0031-1289898

An advanced intermediate vinyl iodide corresponding to the C1-C13 fragment of the macrolide biselyngbyaside was prepared by a cross-metathesis reaction between vinyl alcohol and -alkene building blocks. The latter fragment, containing two stereocenters, w

Full text of DOI:10.1055/s-0031-1289898

3002
LETTER
Synthesis of the C1–C13 Fragment of Biselyngbyaside
C
1–C13 Fragm
r
ent of
B
a
iselyngbya
m
side od Sawant, Martin E. Maier*
Institut für Organische Chemie, Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany
Fax +49(7071)295137; E-mail: martin.e.maier@uni-tuebingen.de
Received 16 September 2011
23
Abstract: An advanced intermediate vinyl iodide corresponding to
the C1–C13 fragment of the macrolide biselyngbyaside was pre-
14
17
13
pared by a cross-metathesis reaction between vinyl alcohol and
alkene building blocks. The latter fragment, containing two stereo-
centers, was obtained by employing an asymmetric alkylation, a
Wittig reaction, a hydrozirconation, and a Brown allylation as key
steps.
10
O
O
1
HO
HO
7
O
O
OMe
MeO
OH
Key words: natural products, Brown allylation, cross-metathesis,
1,5-diols, hydrozirconation
biselyngbyaside (1)
14
1
Biselyngbyaside (1) is a new macrolactone that was iso-
lated from a marine cyanobacterium Lyngbya sp. collect-
ed in the Okinawa prefecture (Figure 1).1 The compound
was found in the polar methanol extract. The high polarity
is likely due to the sugar part, which itself is somewhat un-
usual because it contains a 3-methoxy group. In prelimi-
nary assays, biselyngbyaside (1) displayed cytotoxicity
against HeLa S3 cells with an IC50 of 0.1 mg mL–1. Fur-
thermore, in a panel of 39 cell lines, the average growth
inhibition (GI) was 0.6 mM. Cells from the central nervous
systems turned out to be particularly sensitive. This assay
also led to the conclusion that biselyngbyaside most likely
inhibits cell proliferation through a novel mechanism. Ac-
cordingly, the total synthesis of this natural product and
the synthesis of analogues is very important. Other recent-
ly isolated 18-membered macrolides include FD-8912,3
and the tulearins.4
17
7
10
CO2H
13
OH
OMe
OR
2
cross-coupling
1 CO2H
7
I
14
+
17
10
SnBu3
13
OMe
OR
4
OH
3
cross-metathesis
Figure 1 Structure and retrosynthetic analysis of the macrolide
biselyngbyaside (1)
synthesis of the highly unsaturated fragment 24, corre-
sponding to acid 4, using cross-metathesis as the key step.
Fragment 24 (the protected form of 4) is characterized by
three double bonds and three stereocenters. The 1,5-diol
subunit with a double bond between is quite common in
polyketide-type natural products. One general route to this
functional group pattern relies on extension of homoallyl-
ic alcohols by cross-metathesis with acrolein followed by
asymmetric allylation.5 Another recent method developed
by Friestad et al.6 extends an a-silyloxy aldehyde in a
Julia–Kocienski reaction. In this approach, the sulfone-
containing fragment also contains a cyanohydrin function
at the g-position of the sulfone.7
From a structural point of view, the double bonds and the
sensitive allylic alcohols (at C3, C7, and C17) make the
synthesis very challenging. For example, elimination of
the sugar would generate a dienoate subunit. In order to
form the macrocycle a ring-closing metathesis approach
seems possible. However, the many double bonds in the
molecule could complicate the synthesis. Therefore, a
classical macrolactonization, either through Yamaguchi
or Mitsunobu cyclization, appears a viable option. The
lactonization approach generates seco acid 2 as an ad-
vanced precursor, however, it was not certain whether the
side chain would complicate the lactonization. Alterna-
tively, the side chain could be introduced after macrolac-
tone formation. Disconnection at the C13–C14 bond
simplifies the seco acid, resulting in two fragments, vinyl
With the vinyl iodide present, we realized that it should be
possible to use a cross-metathesis reaction to form the C4/
C5 double bond since vinyl iodides are essentially inert to
cross-metathesis conditions. This has been exploited by
Oishi, Murata, and co-workers in the context of the syn-
thesis of the polyol fragment of amphidinol 3.8
stannane 3 and vinyl iodide 4. In this paper, we detail the Thus, we first prepared the allylic alcohol 10 starting from
the racemic 3-hydroxy-4-pentenoate9 5 (Scheme 1). A ki-
netic resolution of racemic 5 with Amano lipase PS in the
presence of vinyl acetate in pentane (30 °C, 16 h) led to
SYNLETT 2011, No. 20, pp 3002–3004
Advanced online publication: 23.11.2011
DOI: 10.1055/s-0031-1289898; Art ID: B17911ST
x
x
.x
x
.2
0
1
1
1
approximately 50% conversion (assessed by H NMR
analysis).10 After chromatographic separation of the two
© Georg Thieme Verlag Stuttgart · New York

LETTER
C1–C13 Fragment of Biselyngbyaside
3003
compounds, (S)-6 and (R)-5, the acetate of (S)-6 was was generated by combining 19 and DIBAL-H (1.0
cleaved by stirring in methanol containing K2CO3. The equiv).16,17 The intermediate vinylmetal species was final-
enantiomeric excess for the optically pure (S)-5 according ly quenched with iodine (1.925 equiv), resulting in the
to chiral GC was 98.5%. After protection of the hydroxyl formation of vinyl iodide 20 (79% yield). At this point, the
group as its silyl ether, the carboxylic function of 7 was re- alcohol was oxidized to aldehyde 21, which then was sub-
duced with diisobutylaluminum hydride (DIBAL-H) to jected to a Brown allylation reaction.18 In this way, allyl
furnish alcohol 8 in good overall yield. Prior to using this alcohol 22 was obtained in 66% yield as mixture of dia-
fragment in the cross-metathesis, the primary alcohol was stereoisomers in a ratio of approximately 18:1 as deter-
1
converted into the corresponding pivaloate 9. Finally, mined by H NMR analysis (integration of 7-CH3). This
cleavage of the silyl ether by acid-catalyzed transetherifi- result indicates that very little racemization occurred on
cation resulted in the release of the C1–C4-fragment 10.
aldehyde 15 during the Wittig extension to 17. Continuing
with the synthesis, alcohol 22 was converted into the cor-
responding methyl ether 23 using Meerwein’s salt
Amano lipase PS
vinyl acetate
OH
OAc
OH
+
pentane, 30 °C, 16 h
CO2t-Bu
O
O
O
O
CO2t-Bu
CO2t-Bu
(R)-5 (53%)
NaHMDS, THF, –78 °C, 2 h
–15 °C, 20 h
O
N
O
N
5
(S)-6 (44%)
Ph
Ph
Br
OR
(95%)
K2CO3, MeOH
DIBAL-H, CH2Cl2
–78 °C, 2 h (84%)
Ph
Ph
(S)-6
CO2t-Bu
r.t., 45 min (82%)
11
12
(S)-5 R = H
7 R = TBS
R
NaBH4, THF–H2O
12 h (92%)
TBSCl, imidazole
DMF, 50 °C
(93%)
Swern oxidation
OH
CH2Cl2, –78 °C (96%)
13 R = H
n-BuLi, THF, –78 °C
TMSCl, 2 h (79%)
TBSO
OR
OH OPiv
p-TSA, MeOH
14 R = SiMe3
Me3Si
1
3
r.t., 1 h (94%)
4
Me3Si
8 R = H
10
PivCl, Et3N
H
16, toluene
DMAP, CH2Cl2
1 h (97%)
80 °C, 18 h (86%)
9 R = Piv
O
CO2Et
17
15
Scheme 1 Synthesis of the C1–C4 fragment 10 via kinetic resoluti-
on of hydroxy ester 5
R
i) Cp2ZrCl2, DIBAL-H
THF, 0 °C
DIBAL-H, CH2Cl2
–40 °C, 2 h (87%)
Besides the point of chirality at C3, the C1–C13 fragment
24 has two additional stereocenters at C7 and C10. It was
planned to introduce one (C10) by asymmetric alkylation
and the second (at C7) by Brown allylation. A further fea-
ture of the synthetic plan was to use a vinyl iodide at the
C12/C13 terminus for later chain extension by cross-
coupling reaction.
ii) I2, THF, –78 °C (79%)
OH
18 R = SiMe3
K2CO3, MeOH
r.t., 3 h (95%)
19 R = H
I
Dess–Martin oxidation
CH2Cl2, 0 °C (83%)
I
Accordingly, we started the synthesis with an asymmetric
propargylation11 of the chiral propionyl oxazolidinone 11,
derived from the Seebach auxiliary,12 which yielded pen-
tynoic acid derivative 12 in high yield and selectivity
(Scheme 2). Reductive removal of the auxiliary using
NaBH4 in aqueous tetrahydrofuran (THF) furnished pen-
tynol 13.13 Silylation of the acetylide function via the cor-
responding lithium acetylide was followed by Swern
oxidation of alcohol14 14 to generate aldehyde 15. One
reason for the silylation was to reduce the volatility of the
low molecular weight compounds of the synthetic se-
quence. With aldehyde 15 in hand, chain extension by a
Wittig reaction with the stabilized ylide15 16 was per-
formed to provide enoate 17 in 86% yield after chroma-
tography. In the next step, the trimethylsilyl group was
removed from the alkyne prior to the hydrozirconation,
which was performed with Cp2ZrCl2 (1.125 equiv) and
DIBAL-H (1.125 equiv). The hydrozirconation was per-
formed on the diisobutylalkoxy derivative of 19, which
H
OH
O
20
21
I
(–)-Ipc2Ballyl, Et2O
–90 °C, 5 h (66%)
10, Grubbs II cat.
toluene, 80 °C, 24 h
(44%)
OR
22 R = H
Me3OBF4, proton sponge
CH2Cl2, r.t. (91%)
23 R = Me
Ph3P
CO2Et
I
10
16
OH OPiv
13
7
1
OMe
24
OH OPiv
10
Scheme 2 Synthesis of the C1–C13 fragment 24 via alkylation,
allylation, and cross-metathesis as key steps
Synlett 2011, No. 20, 3002–3004 © Thieme Stuttgart · New York

3004
P. Sawant, M. E. Maier
LETTER
(7) For another useful strategy (double allylboration), see:
(Me3OBF4)19 in the presence of proton sponge.20,21 The
stage was then set for the crucial cross-metathesis reac-
tion.22 Initially, we attempted the metathesis reaction be-
tween homoallylic ether 23 and the silylated vinyl alcohol
9. However, neither the Hoveyda–Grubbs second-genera-
tion, nor the Grubbs second-generation catalyst, nor the
Grela catalyst led to formation of the desired product. In
contrast, the metathesis reaction with the vinyl alcohol 10
was successfully achieved.23 Among the various catalysts,
the Grubbs second-generation catalyst gave the best re-
sults, furnishing the advanced biselyngbyaside fragment
24 in 44% yield.
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In summary, a practical pathway to the C1–C13 section of
the novel macrolide biselyngbyaside has been outlined.
Key features of the strategy include a kinetic resolution to
furnish allylic alcohol 10 (C1–C4 fragment). The overall
yield for allylic alcohol 10 from the racemic aldol product
5 was 26% (six steps). A second fragment was synthe-
sized by asymmetric propargylation, a Wittig reaction,
and a Brown allylation reaction. The triple bond of enynol
19 was converted into the vinyl iodide function, which
subsequently allowed for a chemoselective cross-
metathesis reaction between the homoallylic ether 23 and
the vinyl alcohol 10. In all, the C1–C13 fragment 24 was
prepared in a longest linear sequence of 12 steps, with an
overall yield of 8.2%.
(12) For the preparation, see: Brenner, M.; La Vecchia, L.;
Leutert, T.; Seebach, D. Org. Synth., Coll. Vol. XI 2009, 896;
Org. Synth. 2003, 80, 57.
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Pettigrew, J. D.; Wilson, P. D. Org. Lett. 2006, 8, 1427.
(14) For the preparation of ent-14 by Evans alkylation, see:
Forsyth, C. J.; Xu, J.; Nguyen, S. T.; Samdal, I. A.; Briggs,
L. R.; Rundberget, T.; Sandvik, M.; Miles, C. O. J. Am.
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(b) Denmark, S. E.; Kobayashi, T.; Regens, C. S.
Tetrahedron 2010, 66, 4745.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
Financial support by the Deutsche Forschungsgemeinschaft and the
Fonds der Chemischen Industrie is gratefully acknowledged. This
work was carried out within the framework of COST action
CM0804 – Chemical Biology with Natural Products.
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References and Notes
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Org. Lett. 2002, 4, 3383.
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2008, 10, 3907.
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