Studies towards the synthesis of neopeltolide: Synthesis of a ring-closing metathesis macrocyclization precursor

Article abstract of DOI:10.1016/j.tetlet.2010.08.118

An advanced ring-closing metathesis precursor for the synthesis of the marine macrolide neopeltolide is prepared in a stereocontrolled manner by the coupling of the C2-C10 and C11-C16 subunits. The metathesis reaction of 4 with Grubbs' II or Nolan's indenylidene catalyst led to the unexpected formation of cycloheptene 18.

Full text of DOI:10.1016/j.tetlet.2010.08.118

Tetrahedron Letters 51 (2010) 5761–5763
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Studies towards the synthesis of neopeltolide: synthesis of a ring-closing
metathesis macrocyclization precursor
⇑
Gordon J. Florence , Romain F. Cadou
EaStChem and Centre for Biomolecular Sciences, School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
An advanced ring-closing metathesis precursor for the synthesis of the marine macrolide neopeltolide is
prepared in a stereocontrolled manner by the coupling of the C2–C10 and C11–C16 subunits. The metath-
esis reaction of 4 with Grubbs’ II or Nolan’s indenylidene catalyst led to the unexpected formation of
cycloheptene 18.
Received 12 July 2010
Revised 5 August 2010
Accepted 31 August 2010
Available online 7 September 2010
Ó 2010 Elsevier Ltd. All rights reserved.
In 2007, Wright and co-workers reported the isolation of neo-
peltolide (1, Scheme 1) from a deep-water sponge of the family
Neopeltidae off the north coast of Jamaica.1 The structure of the
marine natural product contains a 14-membered macrolide and a
trisubstituted cis-THP ring bearing an unsaturated oxazole-con-
taining side chain at C5. This side chain is identical to that found
in the marine macrolide leucascandrolide A, and it has been
hypothesized that this appendage is responsible for the biological
activity of both natural products.2 Initial biological testing by
Wright and co-workers revealed that neopeltolide displays anti-
fungal activity against the pathogen Candida albicans at a concen-
In contrast to the majority of previous syntheses of the neo-
peltolide aglycon that established all the stereocenters prior to for-
mation of the macrolactone, we envisaged the ambitious use of
macrocyclic conformations of suitable precursors to control the
introduction of the C3, C9 and C11 stereocenters (Scheme 1). A
similar tactic was employed by Floreancig3g and Sasaki,3k to intro-
duce the C9 stereocenter by hydrogenation of a macrocyclic alkene.
This would require the preparation of the key macrolide interme-
diate 3 via ring-closing metathesis (RCM) of precursor 4, which
in turn could be derived from the coupling of C2–C10 alkyne 5
and C11–C16 aldehyde 6. Herein, we detail an efficient and stereo-
controlled synthesis of 4 and studies of the subsequent RCM mac-
rocyclization reaction.
tration of 0.63 lg/mL. Neopeltolide also displays anticancer
activity against several cell lines including the P388 murine leu-
kaemia, the A549 human lung adenocarcinoma and the NCI/ADR-
RES ovarian sarcoma with IC50 values of 0.56, 1.2 and 5.1 nM,
respectively. The potent biological activity and challenging struc-
ture have attracted the attention of the synthetic community and
several total syntheses of the macrolide have been reported.3 Nota-
bly, the first two syntheses of neopeltolide by Panek3a and
Scheidt3b resulted in the reassignment of the C11 and C13 stereo-
centers. Following these reports, Kozmin and co-workers reported
the synthesis of neopeltolide and of a simplified analogue of leu-
cascandrolide A.2 On the basis of biological testing using those
two compounds, Kozmin proposed the cytochrome bc1 complex
as the molecular target of the two macrolides.
As part of our interest in the synthesis of the cyclic ether con-
taining bioactive natural products, we became interested in the
synthesis of neopeltolide.4 Our retrosynthetic strategy is outlined
in Scheme 1. The oxazole-containing side chain would be ap-
pended directly on aglycon 2 via Mitsunobu esterification, a tactic
adopted in many of the previous syntheses of both leucascandro-
lide A5 and neopeltolide.3
The synthesis of the C2–C10 alkyne 5 started from D-malic acid
(7), which was transformed into the known aldehyde 8 in five steps
(Scheme 2).6 Brown allylation7 using (+)-Ipc2BOMe and allylmag-
nesium bromide, followed by protection using TIPSOTf and 2,6-lu-
tidine provided silyl ether 9 in excellent yield and dr.8 Treatment of
silyl ether 9 with a 50% aqueous solution of trifluoroacetic acid
effectively cleaved the acetonide group and, reaction of the inter-
mediate diol with sodium hydride and trisyl imidazole afforded
epoxide 10 in 98% yield.9 Epoxide 10 was then opened with the
lithium anion of TMS–acetylene in the presence of BF3ꢀEt2O to pro-
vide alkyne 11. Deprotection of the TMS group using potassium
carbonate followed by protection of the C7 hydroxy group using
TBSOTf and 2,6-lutidine provided the C2–C10 fragment 5.
As outlined in Scheme 3, the synthesis of the C11–C16 aldehyde
6 started with vinyl Grignard addition to enantiopure (S)-1,2-
epoxypentane (12, prepared by Jacobsen hydrolytic kinetic resolu-
tion of racemic 1,2-epoxypentane).10,11 Subsequent protection of
the intermediate alcohol (TESOTf, 2,6-lutidine) and ozonolysis with
PPh3 work-up provided the C11–C16 aldehyde 6 in excellent yield
over three steps.
With alkyne 5 and aldehyde 6 in hand, our attention was
focussed on their union and elaboration to the ring-closing metath-
⇑
Corresponding author. Tel.: +44 1334 463834; fax: +44 1334 463808.
E-mail address: gjf1@st-andrews.ac.uk (G.J. Florence).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.118

5762
G. J. Florence, R. F. Cadou / Tetrahedron Letters 51 (2010) 5761–5763
TIPSO
OTBS
O
OTES
1,2-reduction
13
O
a - c
OMe
Me
OMe
Me
13
H
11
11
6
12
5
O
O
O
O
9
1
9
1
O
O
d
Mitsunobu
5
5
H
N
OH OTES
TESO
OH
OMe
OH
2
O
O
TIPSO
OTBS
O
O
N
1: neopeltolide
13
14
O
O
13
11
13
e
11
O
O
O
O
Me
TBS
O
9
1
1
OH OH
O
TIPSO
OTBS
1,4-addition
RCM
5
5
1,4-addition
OTIPS
3
OTIPS
15
f
alkyne
addition
TESO
O
OH
O
13
O
11
10
11
H
O
OH
OR
TBSO
6
O
g
1TBSO
TBSO
+
3
TIPSO
OTBS
5
3
10
OTIPS
16
OTIPS
17: R = H
4: R = C(O)CH=CH2
OTIPS
4
5
h
Scheme 1. Retrosynthetic strategy for neopeltolide (1).
Scheme 3. Synthesis of RCM precursor 4. Reagents and conditions: (a) vinylMgBr,
CuI, THF, ꢁ78 °C to rt, 3 h, 85%; (b) TESOTf, 2,6-lutidine, CH2Cl2, ꢁ20 °C, 1 h, 97%; (c)
O3 then Ph3P, CH2Cl2, ꢁ78 °C to rt, 2 h, 96%; (d) 5, n-BuLi 1.6 M in hexane, TMEDA,
THF, ꢁ78 °C, 0.5 h; then 6, ꢁ78 °C to ꢁ20 °C, 2 h, 81%; (e) CSA, MeOH/CH2Cl2 (1:1),
0 °C, 30 min, 77%; (f) Red-Al™, Et2O, rt, 1.5 h, 94%, E:Z = 6:1; (g), MnO2, Et2O, rt, 5 h,
64%; (h) acrylic acid, 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP, PhCH3, rt, 1 h,
51%.
esis precursor 4 (Scheme 3). Thus, treatment of alkyne 5 with
n-butyllithium and TMEDA, followed by addition of aldehyde 6
provided the desired addition product 13 as a 1:1 mixture of dia-
stereomers at C11, co-isolated with the [1,5] Brook rearrangement
product 14, in a combined 81% yield. This mixture of addition prod-
ucts was treated with CSA in MeOH/CH2Cl2 to remove cleanly the
TES ether to provide diol 15 in 77% yield. Reduction of the C9–
C10 alkyne 15 with Red-Al™ provided the corresponding E-allylic
alcohols 16 (E:Z = 6:1), which could be selectively oxidized with
manganese dioxide to afford hydroxy-enone 17 in 64% yield.12
Yamaguchi esterification of the C13-hydroxy group with acrylic
acid using trichlorobenzoyl chloride, triethylamine and DMAP
completed the synthesis of the ring-closing metathesis precursor
4 in 51% yield.13,14
With access to alkene 4 established, the stage was set to at-
tempt the ring-closing metathesis reaction to form the 14-mem-
bered macrolide (Scheme 4). This proved to be an
insurmountable obstacle and unfortunately, refluxing alkene 4 un-
der high dilution conditions with 5 mol % of Grubbs’ second gener-
ation catalyst15 was not successful and only led to the unexpected,
but efficient, formation of cylcoheptene 18 in 70% yield.16 Likewise
a similar result was obtained by reacting 4 with 20 mol % of No-
lan’s indenylidene complex 19 to provide 18 in a comparable
65% yield at room temperature.17 In the light of this unexpected
outcome, inspection of the low energy conformations of the simpli-
fied model 20,18 suggest that upon loading of the ruthenium com-
plex on the terminal C3-olefin, the intermediate carbene can
undergo addition to either of the Type II olefins, with the acrylate
at C13 appearing more readily accessible than the C9–C11-enone
in 20. However, the exclusive formation of the cycloheptene sug-
gests that either conformational flexibility of 20 and the interme-
diate carbene complex leads to preferential of C3–C7 metathesis
directly, or that the transient formation of a 14-membered macro-
lide 21 is followed by a transannular metathesis reaction due to the
conformational restraint imposed by the macrocycle.15 Further
experimental and computational studies are currently looking to
establish the precise metathesis pathway using simplified model
diene and triene systems.
OH
CO2H
O
O
5 steps
HO2C
O
H
7
8
a, b
O
c, d
TIPSO
TIPSO
O
O
10
9
e
TIPSO
OH
TMS
f, g
TIPSO
OTBS
11
5
Scheme 2. Synthesis of the C2–C10 fragment 5. Reagents and conditions: (a)
allylMgBr, (+)-Ipc2BOMe, PhCH3, ꢁ78 °C, 1 h; then 2 M NaOH, H2O2, 3 h, 90%, 97:3
dr; (b) TIPSOTf, 2,6-lutidine, CH2Cl2, ꢁ20 °C, 2 h, 97%; (c) TFA 50% aq, CH2Cl2, rt,
30 min, 71%; (d) NaH, TrisIm, THF, 0 °C to rt, 1.5 h, 98%; (e) TMS-C„C–H, n-BuLi
1.6 M solution in hexane, BF3ꢀEt2O, THF, ꢁ78 °C to ꢁ20 °C, 1.5 h, 95%; (f) K2CO3,
MeOH, rt, 16 h, 88%; (g) TBSOTf, 2,6-lutidine, CH2Cl2, ꢁ20 °C, 1 h, 97%.

G. J. Florence, R. F. Cadou / Tetrahedron Letters 51 (2010) 5761–5763
5763
References and notes
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Lawson, J. P.; Walker, D. G.; Linderman, R. J. J. Org. Chem. 1986, 51, 5111–5123.
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Prabhakar, K. J.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org. Chem. 1986, 51,
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8. All new compounds gave spectroscopic data in agreement with assigned
structures.
9. (a) Dounay, A. B.; Florence, G. J.; Saito, A.; Forsyth, C. J. Tetrahedron 2002, 58,
1865–1874; (b) Hicks, D. R.; Fraser-Reid, B. Synthesis 1974, 203; (c) Corey, E. J.;
Weigel, L. O.; Chamberlin, A. R.; Lipshutz, B. J. Am. Chem. Soc. 1980, 102, 1439–
1441.
10. (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science 1997, 277,
936–938; (b) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen,
K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124,
1307–1315.
11. Mori, K.; Takaishi, H. Tetrahedron 1989, 45, 1639–1646.
12. Denmark, S. E.; Jones, T. K. J. Org. Chem. 1982, 47, 4595–4597.
13. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
1979, 52, 1989–1993.
14. Spectroscopic data for RCM precursor 4: ½a D20
ꢁ17.7 (c 1.7, CHCl3); IR (KBr,
ꢂ
Scheme 4. Ring-closing metathesis of precursor 4. Reagents and conditions: (a)
Grubbs II (5 mol %), CH2Cl2, reflux, 16 h, 70%; (b) 19 (20 mol %), CH2Cl2, rt, 4 h, 65%.
neat) 2946, 2865, 1727, 1674, 1463, 1406, 1258, 1192, 1085 cmꢁ1; 1H NMR
(300 MHz, CDCl3) d 6.88 (1H, dt, J = 15.9, 7.2 Hz), 6.39 (1H, dd, J = 17.4, 1.8 Hz),
6.16–6.05 (2H, m), 5.91–5.79 (2H, m), 5.38 (1H, quin, J = 6.3 Hz), 5.11–5.05 (2H,
m), 3.96–3.91 (2H, m), 2.94 (1H, dd, J = 15.9, 6.6 Hz), 2.73 (1H, dd, J = 15.9,
6.3 Hz), 2.44–2.26 (4H, m), 1.79–1.38 (6H, m), 1.07 (21H, m), 0.94 (3H, t,
J = 7.2 Hz), 0.89 (9H, s), 0.07 (3H, s), 0.06 (3H, s); 13C NMR (75 MHz, CDCl3) d
196.7, 165.5, 144.6, 134.4, 132.5, 130.5, 128.6, 117.3, 70.6, 69.6, 69.1, 44.8,
44.1, 41.9, 40.7, 36.2, 25.8, 18.5, 18.2, 18.0, 13.8, 12.7, ꢁ4.2, ꢁ4.3; LRMS (ES+)
m/z 617 (100, [M+Na]+); HRMS (ES+) calcd for C33H62O5NaSi2 [M+Na]+
617.4034; found 617.4015.
In summary, we have prepared an advanced RCM macrocycliza-
tion precursor for the synthesis of neopeltolide in an expedient and
stereocontrolled manner from C2–C10 (5) and C11–C16 (6) sub-
units. However, the RCM of 4 led to the unexpected formation of
cycloheptene 18 under a range of conditions. Alternative strategies
for the synthesis of the key macrolide 3 for the synthesis of neo-
peltolide aglycon are currently underway and will be reported in
due course.
15. (a) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc.
2003, 125, 11360–11370; (b) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org.
Lett. 1999, 1, 953–956; For a review on RCM macrocyclization in natural
product synthesis, see: (c) Gradillas, A.; Pérez-Castells, J. Angew. Chem., Int. Ed.
2006, 45, 6086–6101.
16. Spectroscopic data for cycloheptane 18: ½a D20
ꢂ
ꢁ119.2 (c 1.8, CHCl3); IR (KBr,
neat) 2957, 2927, 2856, 1462, 1377, 1256, 1199 cmꢁ1
;
1H NMR (500 MHz,
CDCl3) d 5.69–5.67 (2H, m), 4.16–4.03 (2H, m), 2.41–2.26 (4H, m), 2.03 (2H, t,
J = 5.6 Hz), 1.07 (21H, s), 0.89 (9H, s), 0.06 (3H, s), 0.05 (3H, s); 13C NMR
(125 MHz, CDCl3) d 128.0, 127.9, 66.9, 66.8, 37.2, 37.1, 25.8, 18.15, 18.12, 12.3,
ꢁ4.8, ꢁ4.9; LRMS (ES+) m/z 397 (65, [MꢁH]+); HRMS (ES+) calcd for C22H45O2Si2
[MꢁH]+ 397.2953; found 397.2946.
Acknowledgements
This work was supported by the Royal Society (University Re-
search Fellowship to G.J.F.), the EPSRC/EaStChem (PhD studentship
to R.F.C.) and AstraZeneca. We thank Professor Steven P. Nolan (St.
Andrews) for the kind donation of ruthenium indenylidene cata-
lyst. We also thank the EPSRC National Mass Spectrometry Service
Centre, Swansea for mass spectral analysis.
17. Clavier, H.; Urbina-Blanco, C. A.; Nolan, S. P. Organometallics 2009, 28, 2848–
2854.
18. Macromodel (Version 8.0) was used in a 10000-step Monte-Carlo search with
model RCM precursor 20 (R = TMS) and macrolide 21 (R = TMS) using the
*
MM2 force field.