Studies towards the Synthesis of Leiodolide A

Article abstract of DOI:10.1055/s-0036-1588301

Two dienes comprising the complete heavy-atom framework of the macrocyclic core of the marine macrolide leiodolide A were prepared by esterification of an appropriate carboxylic acid and two alcohol building blocks. The latter were obtained in a stereosel

Full text of DOI:10.1055/s-0036-1588301

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–E
letter
A
C. W. Wullschleger et al.
Letter
Synlett
Studies towards the Synthesis of Leiodolide A
Christoph W. Wullschleger
TBSO
OTBS
Jun Li1
O
OTBS
R
R
O
OMe
O
11–13
steps
Adriana Edenharter
HO
OH OMe
O
N
O
Karl-Heinz Altmann*
N
H
O
ETH Zürich, Department of Chemistry and Applied
Biosciences, Institute of Pharmaceutical Sciences,
HCI 405, Vladimir-Prelog-Weg 4, 8093 Zürich,
Switzerland
(R)-(+)-Citronellal
TBSO
RCM ?
R = H, Me
R = H, Me
karl-heinz.altmann@pharma.ethz.ch
R =
O
OH
Leiodolide A
HO
Received: 24.06.2016
Accepted: 05.08.2016
Published online: 29.08.2016
DOI: 10.1055/s-0036-1588301; Art ID: st-2016-d0408-l
HO
17
13
O
O
N
O
O
O
HO
Abstract Two dienes comprising the complete heavy-atom framework
of the macrocyclic core of the marine macrolide leiodolide A were pre-
pared by esterification of an appropriate carboxylic acid and two alco-
hol building blocks. The latter were obtained in a stereoselective fash-
ion from (R)-citronellal via a Crimmins-type aldol reaction, oxidative
double bond cleavage, and efficient oxazole formation as the key trans-
formations. The possible ring-closing metathesis (RCM) based macro-
cyclization of the dienes was investigated under different conditions.
None of the cyclized product was obtained in any of these experiments,
thus indicating that RCM between C6 and C7 may not be a viable strat-
egy for the total synthesis of leiodolide A.
6
1
7
OH
OH
Leiodolide A (1)
13
O
O
17
O
O
Br
O
HO
N
OH
O
6
1
7
Key words leiodolide, natural product, oxazole, ring-closing metathe-
OH
sis, total synthesis
Leiodolide B (2)
Figure 1 Molecular structures of leiodolides A (1) and B (2)
Leiodolide A (1) is a 19-membered marine macrolide
that was isolated in 2006 by Fenical and co-workers from
the deep-water marine sponge Leiodermatium, together
with the related macrolactone leiodolide B (2, Figure 1).2
Leiodolides A/B exhibit several unique structural features,
including a conjugated oxazole ring), a carboxylic acid side
chain that also incorporates a tertiary alcohol moiety, and
in the case of leiodolide B (2), a bromine substituent.
the C13 stereocenter remained unassigned), a successful to-
tal synthesis would also yield the complete stereochemical
assignment of these natural products. The initial focus of
our synthetic work was on leiodolide A (1) with its some-
what less complex structural framework, which would fa-
cilitate analogue synthesis and SAR studies.
Leiodolide A (1) has shown significant cytotoxicity in
the NCI 60 cell-line panel, with an average GI50 of 2.0 μM
and sub-μM GI50 values against a number of noninterrelated
cancer cell lines, including HL-60 (leukemia, 0.26 μM), NCI-
H522 (non-small cell lung cancer, 0.26 μM), and OVCAR-3
(ovarian cancer, 0.25 μM).2 Based on these findings and giv-
en our longstanding interest in the chemistry and biology
of bioactive natural products,3 we were attracted to leiodo-
lides as targets for total synthesis and subsequent SAR eval-
uation. As the configuration of leiodolides had not been ful-
ly elucidated by the isolation group (the configuration of
Unfortunately, however, synthetic studies by Fürstner
and co-workers directed at the total synthesis of leiodolide
B (2) have shown that its structure had not been assigned
correctly by the isolation group (irrespective of the configu-
ration at C13).4 As none of the possible diastereoisomers of
nominal leiodolide B (2) prepared in the course of Fürst-
ner’s work exhibited spectral properties that were identical
with those reported for the natural product, the true struc-
ture of leiodolide B (2) is currently unknown. These find-
ings also cast doubt on the validity of the structure that has
been assigned to leiodolide A (1).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

B
C. W. Wullschleger et al.
Letter
Synlett
In contrast to nominal leiodolide B (2), no total synthe-
sis has been disclosed so far for (nominal) leiodolide A (1),
although a number of reports have described the synthesis
of building blocks and advanced intermediates.5 While all
of these efforts were based on the projected construction of
the macrocycle by macrolactonization, our own approach
towards leiodolide A (1) was to entail macrocycle formation
by ring-closing olefin metathesis (RCM) between C6 and C7
(Scheme 1).6
esterification
aldol coupling
OTBS
O
OTBS
TBSO
O
HO
8
7
R
O
OMe
O
O
N
+
O
O
OTBS
OBn
7
O
N
12
TBSO
OH OMe
Ph
O
6
+
N
R = H:
R = Me:
5
6
9
TBSO
O
HO
13
H
R
O
OMe
13
17
O
OMe
O
N
O
O
O
N
or
via 9
O
HO
6
1
7
OH
OTBS
OTBS
TBSO
H
OH
1
OH OMe
O
OMe
R = CH2OPG: 3
R = CH=C(CH3)CH2OPG: 4
PG = H or protecting group
11
N
10
N
O
O
Scheme 1 RCM-based retrosynthesis of leiodolide A (1)
Scheme 2 Retrosynthesis of model dienes 5 and 6
As the total synthesis was also meant to set the scene
for the subsequent preparation of side-chain-modified vari-
ants of 1, our diene substrate would not incorporate the
complete leiodolide A side chain, but rather a less complex,
functionalized moiety (as, for example, in dienes 3 or 4,
Scheme 1) that would allow further elaboration into both
the natural product as well as side-chain-modified ana-
logues.
We were, however, cognizant of the fact that only a lim-
ited number of examples have been described in the litera-
ture of RCM-based macrocyclizations involving the forma-
tion of a trisubstituted double bond for ring sizes >14.7
Likewise, we are aware of only one example of an RCM of a
diene substrate with one of the reacting double bonds be-
ing part of a vinyl oxazole moiety,8 although in contrast to
our case, this double bond was not further substituted (i.e.,
ring closure led to a disubstituted double bond). Given the
scarcity of literature data on related ring-closure reactions,
we decided to investigate the inherent feasibility of the pro-
jected RCM-based formation of the leiodolide A macrocycle
on two model dienes with C17 either unsubstituted (5;
Scheme 2) or bearing a simple methyl group in place of a
functionalized side chain precursor (6; Scheme 2). The re-
sults of these model studies are summarized in this com-
munication.
time, this strategy could be readily adapted to the synthesis
of dienes 3 or 4, which would be en route to the natural
product.
In the forward direction, the aldol reaction of acyl oxaz-
olidinone 12 and (R)-citronellal (13) under Crimmins con-
ditions (TiCl4, NMP)9 gave the desired aldol product 16 as a
single isomer in 66% yield after chromatographic purifica-
tion (the reaction produced four diastereoisomers in a
128:12:3:1 ratio)10 (Scheme 3). In contrast, conducting the
reaction under standard Evans aldol conditions with
Bu2BOTf as the Lewis acid gave only incomplete conversion
(ca. 55% based on 12) and a 27% yield of the aldol product.
Methylation of 16 with Meerwein salt gave the correspond-
ing methyl ether, which was elaborated into amide 17 by
oxidative cleavage of the double bond with NaIO4 in the
11
presence of catalytic amounts of KMnO4 and subsequent
DCC-mediated coupling of the ensuing carboxylic acid with
L-serine methyl ester in high overall yield (43% for the
three-step sequence from 16). It should be noted here that
initial attempts at osmium tetroxide promoted catalytic ox-
idative cleavage of 16 with Oxone® as the stoichiometric ox-
idant12 did not yield any of the desired product. In contrast,
the use of NaIO4 in combination with catalytic KMnO4 gave
the desired carboxylic acid reproducibly in yields of 66–
76%. Employing methodology that was developed by Wipf
and Williams,13 amide 17 was then transformed into oxaz-
ole 18 by treatment with DAST and subsequent oxidation of
the resulting oxazoline with BrCCl3 in 67% overall yield.
As depicted in Scheme 2, dienes 5 and 6 were to be ob-
tained from acid 7 by esterification with alcohols 9 and 10,
respectively. The latter would in turn be accessed from ox-
azolidinone 12 and (R)-citronellal (13) via a Crimmins-
type9 aldol reaction, while acid 7 was to be prepared from
aldehyde 8 by Wittig-type chemistry. Importantly at the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

C
C. W. Wullschleger et al.
Letter
Synlett
O
O
O
O
OH
b–d
OBn
a
O
N
O
N
OBn
12
16
Ph
Ph
O
O
O
OMe
O
O
OMe
H
N
O
O
N
OMe
e, f
O
N
OBn
O
OBn
N
OH
Ph
Ph
17
18
OMe
O
O
OMe
OMe
O
HO
TBSO
j, k
g–i
OTBS
N
OTBS
N
19
OMe
9
O
OMe
O
HO
l, m
OTBS
N
10
Scheme 3 Reagents and conditions: (a) i. 12, TiCl4, i-Pr2NEt, CH2Cl2, NMP, –78 °C, 80 min; ii. (R)-(+)-citronellal (13), –78 °C, 3.5 h, 66%; (b) Me3OBF4,
Proton Sponge®, CH2Cl2, 0 °C, 3 h, 85%; (c) NaIO4, KMnO4 (cat.), K2CO3, H2O–t-BuOH–EtOH (4:1:1), r.t., 2.5 h, 66–76%; (d) HCl·H-L-Ser-OMe, DCC, Et3N,
r.t., 75%; e) DAST, CH2Cl2, –78 °C, 80 min, 92%; (f) BrCCl3, DBU, CH2Cl2, r.t., 19 h, 74%; (g) NaBH4, THF–H2O (4:1), r.t., 5 h, 71%; (h) Pd/C, H2, EtOH, r.t.,
7.5 h, 72%; (i) TBSOTf, 2,6-lutidine, CH2Cl2, –78 °C, 45 min, 98%; (j) Ph3PCH3Br, NaHMDS, Et2O, r.t., 45 min; then 19 at –78 °C, r.t., 90 min, 78%; (k)
NaIO4, THF–H2O (4:1), r.t., 7 h, 57%; (l) DMP, CH2Cl2, 0 °C, 90 min, 58%; (m) MeMgI, THF, –78 °C, 90 min, 50%.
O
O
Reductive removal of the oxazolidinone moiety in 18
with NaBH4 in THF–H2O (4:1)14 gave the corresponding pri-
mary alcohol in good yield (71%); protecting group ex-
change (Bn → TBS) via catalytic hydrogenation and reaction
of the resulting free diol with TBSOTf then furnished bis-
TBS ether 19 (70% for two steps). Treatment of 19 with an
excess of Ph3PCH3Br and NaHMDS resulted in the direct
smooth conversion of the methyl ester moiety into an iso-
propenyl group.15 Subsequent selective cleavage of the pri-
O
O
OH
O
21
a
OTBS
b, c
O
N
O
N
HO
Bn
Bn
20
22
23
OTBS
OTBS
d
e, f
HOOC
O
24
7
16
Scheme 4 Reagents and conditions: (a) n-Bu2BOTf, i-Pr2NEt, CH2Cl2, –78 °C
to 0 °C, 4 h, 51%; (b) TBSCl, ImH, DMAP, CH2Cl2, r.t., 2h, 97%; (c) NaBH4,
THF–H2O, r.t., 22 h, 75%; (d) DMP, NaHCO3, CH2Cl2, 0 °C, 30 min, r.t., 30
min, 81%; (e) (MeO)2P(O)CH2COOMe, LiCl, DBU, MeCN, r.t., 1 h, 83%;
(f) LiOH·H2O, H2O2, THF–H2O–MeOH (4:1:1), r.t., 10 h, 87%.
mary TBS ether with NaIO4 then gave the free alcohol 9;
oxidation of 9 with DMP followed by reaction of the result-
ing aldehyde with MeMgBr furnished secondary alcohol 10
as a 6:4 mixture of diastereoisomers at C17 (leiodolide
numbering) in 29% yield (based on 9).
It had been our original plan to retain both the chiral
auxiliary as well as the benzyl ether protecting group until
after the installment of the isopropenyl moiety on the ox-
azole ring, but this approach was thwarted by the fact that
imide 18, in contrast to TBS ether 19 could not be converted
into the corresponding isopropenyl derivative. While no
conversion was observed with eight equivalents of
Ph3PCH3Br/NaHMDS (the stoichiometry used with 19), de-
composition was induced by increasing the excess of the
Wittig reagent, presumably due to opening of the oxazolid-
inone ring.
The synthesis of acid 7 is summarized in Scheme 4 and
commenced with the aldol reaction of the propionyl-oxazo-
lidinone 20 and acrolein (21), which produced the desired
syn-aldol product 22 in a moderate yield of 51% (single iso-
mer).17
Protection of the hydroxy group as a TBS ether followed
by reductive removal of the chiral auxiliary with NaBH4
gave monoprotected diol 23, which was elaborated into
acid 7 via aldehyde 24. The latter underwent a highly stereo-
selective Horner–Wadsworth–Emmons reaction with
methyl dimethylphosphonoacetate under Masamune–
Roush conditions;18 subsequent ester cleavage with LiOOH
then gave 7. Acid 7 was obtained in 43% overall yield for the
five-step sequence from aldol product 22.19
The esterification of acid 7 with alcohols 9 or 10 was
conducted under Yamaguchi conditions20 and gave the re-
spective dienes 5 and 6 in moderate yields (42% and 40%,
respectively; Scheme 5); no attempts were made to opti-
mize these transformations.21
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

D
C. W. Wullschleger et al.
Letter
Synlett
R
OMe
(3) For selected recent examples, see: (a) Brütsch, T. M.; Bucher, P.;
Altmann, K.-H. Chem. Eur. J. 2016, 22, 1292. (b) Chen, T.;
Altmann, K.-H. Chem. Eur. J. 2015, 21, 8403. (c) Gaugaz, F. Z.;
Redondo-Horcajo, M.; Barasoain, I.; Díaz, J. F.; Cobos-Correa, A.;
Kaufmann, M.; Altmann, K.-H. ChemMedChem 2014, 9, 2227.
(d) Wullschleger, C. W.; Gertsch, J.; Altmann, K.-H. Chem. Eur. J.
2013, 19, 13105. (e) Neuhaus, C.; Liniger, M.; Stieger, M.;
Altmann, K.-H. Angew. Chem. Int. Ed. 2013, 52, 5866.
(f) Zurwerra, D.; Glaus, F.; Betschart, L.; Schuster, J.; Gertsch, J.;
Ganci, W.; Altmann, K.-H. Chem. Eur. J. 2012, 18, 16868.
(4) Larivée, A.; Unger, J. B.; Thomas, M.; Wirtz, C.; Dubost, C.;
Handa, S.; Fürstner, A. Angew. Chem. Int. Ed. 2011, 50, 304.
(5) (a) Chellat, M. F.; Proust, N.; Lauer, M. G.; Stambuli, J. P. Org. Lett.
2011, 13, 3246. (b) Zhang, X.; Liu, J.; Sun, X.; Du, Y. Tetrahedron
2013, 69, 1553. (c) Ren, R.-G.; Li, M.; Si, C.-M.; Mao, Z.-Y.; Wei,
B.-G. Tetrahedron Lett. 2014, 55, 6903. (d) Lee, J.; Panek, J. S. Tet-
rahedron Lett. 2015, 56, 6868. (e) Ren, R.; Mao, Z.; Wei, B.; Lin, G.
Chin. J. Org. Chem. 2015, 35, 2313.
(6) For recent reviews on ring-closing olefin metathesis see, e.g.:
(a) Schmidt, B.; Hauke, S.; Krehl, S.; Kunz, O. In Comprehensive
Organic Synthesis; Elsevier: Amsterdam, 2014, 2nd ed., Vol. 5
1400. (b) van Lierop, N.; Bianca, J.; Lummiss, J. A. M.; Fogg, D. E.
In Olefin Metathesis; Grela, K., Ed.; John Wiley and Sons: Hobo-
ken, 2014, 85.
(7) Examples: (a) Sinha, S. C.; Sun, J.; Miller, G. P.; Wartmann, M.;
Lerner, R. A. Chem. Eur. J. 2001, 7, 1691. (b) Park, P. K.; O’Malley,
S. J.; Schmidt, D. R.; Leighton, J. L. J. Am. Chem. Soc. 2006, 128,
2796. (c) Trost, B. M.; Dong, G.; Vance, J. A. J. Am. Chem. Soc.
2007, 129, 4540. (d) Jin, J.; Chen, Y.; Li, Y.; Wu, J.; Dai, W.-M. Org.
Lett. 2007, 9, 2585. (e) Tannert, R.; Milroy, L.-G.; Ellinger, B.; Hu,
T.-S.; Arndt, H.-D.; Waldmann, H. J. Am. Chem. Soc. 2010, 132,
3063. (f) Yun, S. Y.; Hansen, E. C.; Volchkov, I.; Cho, E. J.; Lo, W.
Y.; Lee, D. Angew. Chem. Int. Ed. 2010, 49, 4261.
O
TBSO
HO
OTBS
N
R
O
OMe
O
9 or 10
O
N
a
+
OH
TBSO
OTBS
O
R = H:
R = Me:
5
6
7
Scheme 5 Reagents and conditions: (a) 2,4,6-trichlorobenzoyl chloride,
Et3N, THF, r.t., 50 min; then DMAP, toluene, r.t., 24 h, 5: 42%; 6: 40%.
In a series of preliminary small-scale experiments,
dienes 5 and 6 were subjected to different RCM conditions,
employing either the Grubbs,22 Hoveyda–Grubbs,23 or
Piers–Grubbs24 second-generation catalysts.25 Unfortunate-
ly, none of the desired cyclized product could be detected
(TLC, MS) under any of the conditions investigated, mostly
due to a lack of conversion.
Obviously, our screening has not been exhaustive and it
is conceivable that cyclization might be achievable under
conditions other than the ones investigated in this study.
Likewise, it cannot be ruled out that the 13S isomers of 5 or
6 (leiodolide numbering) could have a higher propensity to
undergo the reaction than 5 or 6. However, notwithstand-
ing these uncertainties, our data indicate that the formation
of the leiodolide A macrocycle by means of RCM between
C6 and C7 will at least be difficult to achieve.26 As a conse-
quence, we have redirected our own efforts towards the to-
tal synthesis of leiodolide A to a different cyclization ap-
proach, but still building on the chemistry that we have de-
veloped as part of this study for the synthesis of the C7–C17
segment. This work is currently ongoing and will be report-
ed in due course.
(8) Kita, M.; Oka, H.; Usui, A.; Ishitsuka, T.; Mogi, Y.; Watanabe, H.;
Tsunoda, M.; Kigoshi, H. Angew. Chem. Int. Ed. 2015, 54, 14174.
(9) (a) Crimmins, M. T.; She, J. Synlett 2004, 1371. (b) Crimmins, M.
T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem. 2001, 66,
894.
(10) Preparation of Aldol Product 16
To a cooled (–78 °C) solution of (4R,5S)-3-(2-(benzyloxy)ace-
tyl)-4-methyl-5-phenyloxazolidin-2-one (3.33 g, 10.2 mmol,
1.00 equiv) in CH2Cl2 (100 mL) was added TiCl4 (1.17 mL, 10.7
mmol, 1.05 equiv) dropwise (immediate very intense yellow
coloration), and the mixture was stirred for 15 min. Then
Hünig’s base (99.5%, 1.97 mL, 11.3 mmol, 1.10 equiv) was added
dropwise, and the dark-colored solution was stirred for 80 min
at –78 °C. After addition of N-methyl-2-pyrrolidinone (0.98 mL,
10.2 mmol, 1.00 equiv) at –78 °C, the mixture was stirred for
additional 10 min followed by the addition of (R)-(+)-citronellal
(13, 3.70 mL, 20.4 mmol, 2.0 equiv). The dark-colored reaction
mixture was stirred for 3.5 h at –78 °C and then allowed to
warm to 0 °C over a period of 20 min. The reaction was
quenched at 0 °C with 100 mL half-saturated aq NH4Cl. The
organic layer was separated, and the aqueous layer was
extracted with CH2Cl2 (3 × 75 mL). The combined organic
extracts were washed with sat. aq NaCl (100 mL), then dried
over Na2SO4, and concentrated to yield a yellow oil. Purification
of this material by flash chromatography (hexane–EtOAc, 5:1 →
3:1 → 2:1) afforded the desired aldol product as a viscous, color-
less oil (3.24 g, 66%) and a mixture of undesired diastereomers
(489 mg, 10%, dr = 12:3:1; ratio of all diastereoisomers formed
in the reaction = 128:12:3:1).
Acknowledgment
This work was supported by the ETH Zürich and by the Swiss Federal
Department of Economic Affairs, Education and Research, State Secre-
tariat for Education, Research and Innovation (SERI), as part of COST
Action CM0804 (‘Chemical Biology with Natural Products’) (SERI proj-
ect C11.0143). We are indebted to Dr. Bernhard Pfeiffer and Leo Bet-
schart for NMR support, and to Dr. Xiangyang Zhang, Louis Bertschi,
Rolf Häfliger, and Oswald Greter for HRMS spectra.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588301.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
References and Notes
(1) Sandoz GmbH, Biochemiestraße10, 6336 Langkampfen, Austria.
(2) Sandler, J. S.; Colin, P. L.; Kelly, M.; Fenical, W. J. Org. Chem.
2006, 71, 7245.
Rf = 0.44 (hexane–EtOAc 2:1); Rf = 0.13 (hexane–EtOAc, 5:1);
23
[α]D +45.8° (c 0.919, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

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C. W. Wullschleger et al.
Letter
Synlett
7.45–7.28 (m, 10 H), 5.72 (d, J = 7.1 Hz, 1 H), 5.14–5.09 (m, 1 H),
5.11 (d, J = 2.3 Hz, 1 H), 4.77 (quint, J = 6.8 Hz, 1 H), 4.72 (d, J =
11.4 Hz, 1 H), 4.50 (d, J = 11.4 Hz, 1 H), 4.09–4.01 (br m, 1 H),
2.16 (br d, J = 9.0 Hz, 1 H), 2.06–1.92 (m, 2 H), 1.78 (ddd, J = 13.6,
9.9, 4.3 Hz, 1 H), 1.73–1.66 (m, 1 H), 1.68 (s, 3 H), 1.60 (s, 3 H),
1.41–1.16 (m, 3 H), 0.92 (d, J = 6.7 Hz, 3 H), 0.90 (d, J = 6.7 Hz, 3
H). 13C NMR (100 MHz, CDCl3): δ = 170.7, 153.2, 137.2, 133.1,
131.3, 129.0, 128.9 (2 C), 128.6 (2 C), 128.6 (2 C), 128.3, 125.7 (2
C), 124.9, 80.6, 79.9, 73.2, 70.7, 55.5, 41.4, 37.9, 28.9, 25.8, 25.6,
19.1, 17.8, 14.5. IR (film): 3475 (w, br, 3600–3250), 2962 (w),
2925 (w), 1778 (s), 1709 (m), 1455 (m), 1342 (s), 1198 (s), 1147
(m), 1121 (s), 1030 (m). ESI-HRMS: m/z calcd for C29H37NNaO5
[M + Na]+: 502.2564; found: 502.2558.
(Aldrich 99%, 8.00 mg, 0.0650 mmol, 4.04 equiv) were added; a
suspension formed immediately after the addition of DMAP.
The resultant white/grey suspension was stirred at r.t. for 24 h,
when the reaction was quenched with sat. aq NaHCO3 (3 mL),
which was followed by the addition of EtOAc (4 mL). The
organic layer was separated and the aqueous solution was
extracted with EtOAc (2 × 4 mL). The combined organic extracts
were dried over Na2SO4 and concentrated under reduced pres-
sure. The residue was purified by flash chromatography
(EtOAc–hexane, 1:10) to afford ester 5 as an oil (4.4 mg, 42%).
1
Rf = 0.31 (hexane–EtOAc, 10:1). H NMR (400 MHz, CDCl3): δ =
7.43 (s, 1 H), 5.78–5.73 (m, 1 H), 5.71 (br t, J = 2.7 Hz, 1 H), 5.63
(t, J = 7.0, 1 H), 5.25 (dt, J = 17.1, 1.8 Hz, 1 H), 5.07 (dt, J = 10.4,
1.8 Hz, 1 H), 5.03 (br t, J = 1.5 Hz, 1 H), 4.51 (br d, J = 4.7 Hz, 1 H),
4.23 (dd, J = 10.1, 1.6 Hz, 1 H), 4.09–3.97 (m, 2 H), 3.40 (s, 3 H),
3.26–3.22 (m, 1 H), 3.08 (d, J = 7.0 Hz, 1 H), 2.84–2.70 (m, 2 H),
1.99 (br t, J = 1.1 Hz, 3 H), 1.84–1.75 (m, 1 H), 1.73–1.60 (m, 2
H), 1.56 (d, J = 2.8 Hz, 3 H), 1.44–1.39 (m, 2 H), 1.32–1.26 (m, 1
H), 0.94 (d, J = 6.3 Hz, 3 H), 0.893 (s, 9 H), 0.886 (s, 9 H), 0.08 (s,
6 H), 0.04 (s, 3 H), 0.02 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ =
172.0, 165.2, 160.6, 141.7, 140.0, 133.6, 133.6, 116.9, 114.2,
112.8, 80.7, 78.5, 70.2, 66.1, 58.5, 36.3, 35.1, 33.6, 29.5, 26.1,
26.0 (3 C), 25.9 (3 C), 19.9, 18.9, 18.5, 18.2, 12.0, –4.4, –4.6, –4.7,
–4.8.
(11) (a) Lemieux, R. U.; von Rudloff, E. Can. J. Chem. 1955, 33, 1701.
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(25) Reactions were carried out with 0.5 mg or 1 mg of dienes 5 or 6
at concentrations <0.004 M in DCE or toluene at reflux tempera-
ture for several hours. No conversion was observed at r.t. Con-
version was assessed by TLC and MS (ESI+). Diene 5 was only
investigated with the Grubbs II and the Hoveyda–Grubbs II cat-
alysts.
(19) The TES-protected variant of acid 7 has been prepared by an
analogous strategy: Crimmins, M. T.; O’Bryan, E. A. Org. Lett.
2010, 12, 4416.
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(21) Preparation of Ester 5
(26) While we were primarily interested in the behavior of the O-
protected dienes 5 and 6 (in light of the strategy depicted in
Scheme 1), we have also prepared small quantities of the free
parent compounds by treatment of 5 and 6 with HF-pyridine. In
orienting experiments with these materials on an analytical
scale we could not detect any cyclized product; in fact, the free
alcohols seemed to be highly prone to decomposition under
RCM conditions, although definitive conclusions are not possi-
ble, due to the small scale of the reactions.
To a solution of carboxylic acid 7 (9.30 mg, 0.0344 mmol, 2.14
equiv) and Et3N (0.011 mL, 0.0764 mmol, 4.75 equiv) in THF (0.5
mL) was added 2,4,6-trichlorobenzoyl chloride (9.0 μL, 0.0573
mmol, 3.56 equiv) dropwise. The reaction mixture was stirred
for 50 min, then a solution of alcohol 9 (6.40 mg, 0.0161 mmol,
1.00 equiv) in toluene (0.5 mL) and 4-dimethylaminopyridine
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E