Total Synthesis of Laingolide A Diastereomers

Article abstract of DOI:10.1055/s-0034-1380133

The first total syntheses of two (±)-laingolide A diastereomers were achieved in 11 and 12 steps, respectively. The key steps include a tandem cross-dimerization/oxonia-Cope reaction and an intramolecular dehydrative cyclization for the formation of either the trans- or cis-enamide moieties.

Full text of DOI:10.1055/s-0034-1380133

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 1016–1023
paper
1016
G. Pomey, P. Phansavath
Paper
Synthesis
Total Synthesis of Laingolide A Diastereomers
Gaétan Pomey
O
O
Phannarath Phansavath*
O
O
N
N
O
or
Me
O
Me
PSL Research University, Chimie ParisTech-CNRS, Institut de
Recherche de Chimie Paris, 75005 Paris, France
phannarath.phansavath@chimie-paristech.fr
O
O
O
Received: 03.12.2014
Accepted 08.01.2015
Published online: 11.02.2015
DOI: 10.1055/s-0034-1380133; Art ID: ss-2014-z0732-op
H
O
1
O
N
2
N
O
O
Me
O
4
R
9
7
Abstract The first total syntheses of two (±)-laingolide A diastereo-
mers were achieved in 11 and 12 steps, respectively. The key steps in-
clude a tandem cross-dimerization/oxonia-Cope reaction and an intra-
molecular dehydrative cyclization for the formation of either the trans-
or cis-enamide moieties.
madangolide (3)
laingolide (1, R = Me)
laingolide A (2, R = H)
O
Key words natural products, total synthesis, macrocycles, ring expan-
sion, oxonia-Cope reactions
O
1
N
O
N
10
Me
O
Me
Laingolide (1),1 an unprecedented 15-membered mac-
rolide structure containing a trans-N-methyl enamide moi-
ety, was isolated in 1996 from the blue-green alga Lyngbya
bouillonii (Cyanophyceae) collected in Papua New Guinea
(Figure 1). This marine cyanobacterium proved to be an ex-
ceptionally rich source of secondary metabolites, because
two other macrolides, laingolide A (2) and madangolide (3),
were also isolated from the same organism a few years lat-
er.2 More recently, investigation of several collections of L.
bouillonii from shallow patch reefs in Apra Harbor, Guam,
gave laingolide B (4), a chlorinated analogue of laingolide
A.3
All members of the laingolide family decomposed
during characterization studies, preventing the testing of
the compounds for bioactivity and impeding the assign-
ment of their relative and absolute stereochemistries. Inter-
estingly, however, (–)-palmyrolide A (5), a structurally re-
lated neuroactive macrolide isolated from a marine cyano-
bacterial assemblage composed of Leptolyngba cf. species
and Oscillatoria species showed promising biological prop-
erties, significantly inhibiting calcium(2+) ion oscillations
in murine cerebrocortical neurons with an IC50 value of 3.70
μM.4 Several total syntheses of this compound have recently
O
5
O
7
Cl
laingolide B (4)
(−)-palmyrolide A (5)
Figure 1 Structures of laingolide (1), laingolide A (2), madangolide (3),
laingolide B (4), and palmyrolide A (5)
appeared in the literature.5 The first of those, reported by
Maio and co-workers,5a,b permitted the determination of
the absolute stereochemistry of palmyrolide A and a revi-
sion of the initially suggested relative stereochemistry be-
tween the C(5) methyl and the C(7) tert-butyl stereocen-
ters. The interaction of synthetic (–)-palmyrolide A diaste-
reomers and nonnatural analogues with voltage-gated
sodium channels was also examined.6 Because of their
structural similarity to palmyrolide A, laingolide deriva-
tives are potentially interesting secondary metabolites and,
as part of our work on the total synthesis of relevant bio-
molecules,7 we decided to study a route to laingolide A iso-
mers. Here, we report the first total synthesis of two lain-
golide A diastereomers, involving a tandem cross-dimeriza-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1016–1023

1017
G. Pomey, P. Phansavath
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Synthesis
tion/oxonia-Cope reaction and an intramolecular
dehydrative cyclization to install either the trans- or cis-
enamide moieties.
The relative configuration of the three stereogenic cen-
ters at C(2), C(7), and C(9) of the target isomer 6 of lain-
golide A was chosen on the basis of the stereochemistry of
the parent compound (–)-palmyrolide A, and our first ap-
proach relied on a Yamaguchi esterification for the final
macrocyclization step (Scheme 1).
Our synthesis began with the copper-catalyzed epoxide
opening of cyclohexene oxide (7) with isopropenylmagne-
sium bromide to give trans-2-isopropenylcyclohexanol (8;
Scheme 3).9 Oxidation of the alcohol 8 with pyridinium
chlorochromate then gave the corresponding cyclohexa-
none 9 in 81% yield.9b Subsequent oxonia-Cope [6+4] ring
enlargement8 of ketone 9 was carried out by treatment
with pivalaldehyde in the presence of 20 mol% of boron tri-
fluoride etherate to give a good yield of lactone 10 as a
82:18 mixture of the E- and Z-isomers. We expected that
hydrogenation of this mixture would produce both the cis-
and trans-products with respect to the C(7) and C(9) ste-
reocenters.
O
O
O
macro-
lactonization
N
1
N
CO2H
OH
2
Me
Me
7
O
9
H2C=C(Me)MgBr
CuBr•SMe2
THF, r.t., 3 h
PCC, CH2Cl2
r.t., 15 h
O
OH
O
6
81%
78%
Scheme 1 First macrocyclization approach
7
8
9
However, despite considerable experimentation, we
were unable to prepare the required cyclization precursor.
Therefore, we planned an alternative route involving, as the
key macrocyclization step, a dehydrative cyclization of
compound 18 to install the trans-enamide moiety (Scheme
2), an approach successfully adopted by Sudhakar et al.5d in
their total synthesis of (–)-palmyrolide A. The primary am-
ide-containing macrocyclization precursor 18 might be ob-
tained from the ten-membered lactone 12 by ring opening
with ammonia followed by introduction of a masked alde-
hyde segment. Compound 12 might, in turn, be obtained
from lactone 10 after diastereoselective hydrogenation of
the alkene function and stereoselective α-methylation. Fi-
nally, compound 10 might be obtained from the α–substi-
tuted cyclohexanone 9 and pivalaldehyde through a tandem
cross-dimerization/oxonia-Cope rearrangement, an elegant
method reported by Wang and Goeke8 for the efficient and
straightforward preparation of macrolactones.
R
t-BuCHO
BF3•OEt2, DCE
–20 °C, 6 h
H2 (1 atm)
10% Pd/C
EtOH, r.t., 48 h
O
O
O
O
91%
91%
H
10 (E/Z = 82:18)
11 R = H
12 R = Me
LDA, HMPA, MeI, THF
–78 °C to r.t., 2.5 h, 94%
Scheme 3 Preparation of lactone 12
To our surprise, however, reduction of the E/Z mixture
of the trisubstituted alkene 10 with palladium/carbon un-
der a hydrogen atmosphere proceeded in a highly stereo-
convergent manner, giving lactone 11 as a single trans-dia-
stereomer.10,11 Subsequent methylation of the ten-mem-
bered lactone with lithium diisopropylamide and
iodomethane in the presence of hexamethylphosphora-
mide gave the corresponding C(2)-methylated product as a
single diastereomer with a cis-relationship between the
stereocenters at C(2) and C(9).12 Having obtained the dia-
stereomerically pure lactone 12, we needed to introduce
the primary amide moiety required for the macrocycliza-
tion step. To achieve this, we initially planned to prepare
hydroxy amide 15 by direct ring opening of the lactone 12
with ammonia (Scheme 4).
O
O
O
H
O
N
Me
NH2
O
O
O
6
18
However, in our hands, the addition of ammonia to 12
under a variety of conditions failed to give the desired am-
ide 15, probably because of the steric hindrance provided
by the contiguous tert-butyl substituent at C(9), as ob-
served by Gerwick et al.4 in their attempts to hydrolyze the
lactone of (–)-palmyrolide A. We therefore prepared amide
O
O
O
O
O
12
10
9
Scheme 2 Retrosynthetic strategy for the laingolide A diastereomer 6
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1016–1023

1018
G. Pomey, P. Phansavath
Paper
Synthesis
in tetrahydrofuran allowed us to complete the first total
synthesis of a member of the laingolide family. Thus, the
cis-isomer (Z)-6 of laingolide A was obtained in 12 steps
from commercially available cyclohexene oxide (7).
To synthesize our initially target, the trans-laingolide A
isomer (E)-6, we decided to perform the macrocyclization
step with a precursor bearing a secondary N-methyl amide
to prevent intramolecular N–H–O hydrogen bonding in the
resulting enamide. To this end, we prepared amide 20 from
carboxylic acid 14 by treatment with HOBt, EDCI, and me-
thylamine. After a Yamaguchi esterification with 3-(1,3-di-
oxolan-2-yl)propanoic acid (16), acidic hydrolysis of ketal
21 gave the required cyclization precursor 22 (Scheme 6).
Heating the amido aldehyde 22 in refluxing toluene in
the presence of trifluoroacetic acid this time gave the trans-
laingolide A isomer (E)-6 as the major product, the struc-
ture and relative configuration of which were unambigu-
ously confirmed by X-ray analysis.
Scheme 4 Synthesis of hydroxy amide 15; HOBt = 1H-1,2,3-benzotri-
azol-1-ol
15 in three steps: reduction of lactone 12 with lithium alu-
minum hydride to give the corresponding diol 13, chemo-
selective oxidation of the primary alcohol group of 13 with
a
combination of 2,2,6,6-tetramethylpiperidinyl-1-oxyl
(TEMPO) and [bis(acetyloxy)iodo]benzene (BAIB),13 and
coupling of the resulting carboxylic acid 14 with aqueous
ammonia in the presence of N-ethyl-N′-(3-dimethylamino-
propyl)carbodiimide (EDCI) and 1H-1,2,3-benzotriazol-1-ol
(HOBt).14 An X-ray crystallographic analysis of amide 15
unambiguously confirmed its relative configuration
(Scheme 4). Subsequent esterification of 15 with 3-(1,3-di-
oxolan-2-yl)propanoic acid (16)15 in the presence of 2,4,6-
trichlorobenzoyl chloride, diisopropylethylamine, and 4-
(N,N-dimethylamino)pyridine under Yamaguchi condi-
tions5b,16 gave ketal 17 in 87% yield (Scheme 5).
Hydrolysis of ketal 17 with 10% hydrochloric acid gave
the macrocyclization precursor 18, which underwent dehy-
drative cyclization in refluxing toluene containing trifluo-
roacetic acid to give a 36% yield of the macrolactone 19,
bearing a cis-enamide moiety instead of the desired trans-
isomer. The structure of 19 was confirmed by an X-ray crys-
tal analysis. The possibility of internal hydrogen bonding
between the hydrogen on the nitrogen atom and the lac-
tone carbonyl group, which is prevented in the trans-iso-
mer, might account for the preferential formation of the cis-
enamide, as suggested by Reddy and co-workers5e for the
parent compound (–)-palmyrolide A. Finally, N-methylation
of macrolactone 19 using sodium hydride and iodomethane
Scheme 5 Total synthesis of the cis-isomer of laingolide A [(Z)-6]
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1016–1023

1019
G. Pomey, P. Phansavath
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Synthesis
from CaH2. Reactions were monitored by TLC using precoated silica
gel plates (Merck, ref. 5554 60 F254). The TLC plates were visualized
by means of UV radiation (λ = 254 nm) or a p-anisaldehyde staining
solution (Kagi–Mosher). NMR spectra were recorded on a Bruker AC
300 (1H: 300 MHz, 13C: 75 MHz) or an Avance 400 (1H: 400 MHz, 13C:
100 MHz) instrument. The chemical shifts are expressed in ppm ref-
erenced to residual CHCl3 (7.26 ppm for 1H and 77.16 for 13C). IR spec-
tra were recorded on a JACSO FTIR 4100 spectrometer. Melting points
were determined on a Stuart Scientific SMP1 apparatus and are un-
corrected. High-resolution mass spectra were obtained by using an
LTQ-Orbitrap (Thermo Fisher Scientific) at Pierre et Marie Curie Uni-
versity.
Crystallographic data for compounds 15, 19, and 6 have been deposit-
ed with the accession numbers CCDC 1032052, 1032053, and
1032054, respectively, and can be obtained free of charge from the
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB2
1EZ,
UK;
Fax:
+44(1223)336033;
E-mail:
depos-
it@ccdc.cam.ac.uk; Web site: www.ccdc.cam.ac.uk/conts/retriev-
ing.html.
trans-2-Isopropenylcyclohexanol (8)9b
A 0.5 M solution of CH2=C(Me)MgBr in THF (300 mL, 150 mmol, 1.1
equiv) was added to a slurry of CuBr·Me2S (1.40 g, 6.82 mmol, 0.05
equiv) in THF (100 mL) at –50 °C, and the mixture was stirred for 10
min at –50 °C. Cyclohexene oxide (13.4 g, 136.4 mmol, 1 equiv) was
added and the mixture was stirred for 3 h at r.t., poured into sat. aq
NH4Cl (100 mL), and extracted with Et2O (4 × 50 mL). The organic lay-
ers were combined, dried (MgSO4), filtered, and concentrated in vac-
uo. The residue was purified by flash chromatography [silica gel, PE–
EtOAc (9:1)] to give a yellow oil; yield: 14.97 g (78%); Rf = 0.38 (cyclo-
hexane–EtOAc, 7:3).
1H NMR (300 MHz, CDCl3): δ = 4.89 (br s, 1 H), 4.85 (br s, 1 H), 3.42
(td, J = 10.1, 4.4 Hz, 1 H), 2.10–2.01 (m, 1 H), 1.99–1.84 (m, 2 H), 1.81–
1.62 (m, 6 H), 1.38–1.11 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 146.8, 112.9, 70.8, 54.7, 34.2, 30.3, 25.8,
25.0, 19.3.
2-Isopropenylcyclohexanone (9)
PCC (39.7 g, 184.0 mmol, 2 equiv) was added to a solution of alcohol 8
(12.9 g, 92.0 mmol, 1 equiv) in CH2Cl2 (200 mL), and the mixture was
stirred overnight at r.t. Silica gel (100 g) was then added slowly, fol-
lowed by Et2O (600 mL). The solids were removed by filtration and
the filtrate was concentrated under vacuum. The residue was purified
by flash chromatography [silica gel, PE–CH2Cl2 (1:1)] to give a yellow
oil; yield: 10.25 g (81%); Rf = 0.21 (cyclohexane–CH2Cl2, 1:1).
Scheme 6 Total synthesis of the trans-isomer of laingolide A [(E)-6]
1H NMR (300 MHz, CDCl3): δ = 4.90 (d, J = 1.4 Hz, 1 H), 4.70 (s, 1 H),
2.98 (dd, J = 11.0, 4.7 Hz, 1 H), 2.46–2.21 (m, 2 H), 2.10–1.97 (m, 2 H),
1.97–1.80 (m, 2 H), 1.80–1.58 (m, 5 H).
13C NMR (75 MHz, CDCl3): δ = 211.0, 143.5, 112.8, 58.5, 42.2, 32.2,
27.7, 24.9, 21.4.
In conclusion, we have completed the first total synthe-
sis of two diastereomers of laingolide A. This short synthe-
sis relies on a tandem cross-dimerization/oxonia-Cope re-
action and an intramolecular dehydrative cyclization, and
proceeds in 11 or 12 steps and 6.72 and 3.2% overall yields,
respectively. To establish the relative configuration of natu-
ral laingolide A, syntheses of the three remaining trans-
diastereomers are currently in progress in our laboratories
and will be reported in due course.
(7E)- and (7Z)-10-tert-Butyl-8-methyl-3,4,5,6,9,10-hexahydro-2H-
oxecin-2-one [(E)-10, and (Z)-10]8
BF3·OEt2 (660 μL, 5.3 mmol, 0.2 equiv) was added dropwise to a solu-
tion of ketone 9 (3.7 g, 26.8 mmol, 1 equiv) and t-BuCHO (3.49 mL,
32.1 mmol, 1.2 equiv) in DCE (50 mL) at –20 °C. The mixture was
stirred for 2.5 h at –20 °C, the reaction was quenched with sat. aq
NaHCO3 (30 mL), and the mixture was extracted with EtOAc (3 × 15
mL). The organic layers were combined, dried (MgSO4), filtered, and
concentrated in vacuo. The residue was purified by flash chromatog-
All air- and/or water-sensitive reactions were carried out under an at-
mosphere of argon. Reaction solvents were purified before use. THF
and Et2O were distilled from Na–benzophenone; CH2Cl2 was distilled
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1016–1023

1020
G. Pomey, P. Phansavath
Paper
Synthesis
raphy [silica gel, PE–CH2Cl2 (6:4)] to give a mixture of two diastereo-
mers as a pale-yellow oil; yield: 5.46 g (91%; E/Z = 82:18). For analyti-
cal purposes, a sample of this mixture was separated by flash chro-
matography [silica gel, PE–CH2Cl2 (6:4)] to give pure (E)-10 and (Z)-
10.
1H NMR (300 MHz, CDCl3): δ = 4.73 (dd, J = 6.7, 3.3 Hz, 1 H), 2.49–2.38
(m, 1 H), 1.98–1.31 (m, 10 H), 1.16 (d, J = 7.1 Hz, 3 H), 1.09–0.70 (m, 1
H), 0.91 (s, 9 H), 0.85 (d, J = 6.8 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 177.0, 78.4, 41.9, 35.0, 31.9, 31.5, 31.4,
29.2, 26.6, 25.4, 22.1, 21.2, 17.8.
HRMS (ESI): m/z [M + Na]+ calcd for C15H28O2 + Na: 263.1981; found:
263.1985.
(E)-10
Rf = 0.47 (cyclohexane–CH2Cl2, 1:1).
1H NMR (300 MHz, CDCl3): δ = 5.02–4.98 (m, 1 H), 4.78 (dd, J = 10.9,
3.2 Hz, 1 H), 2.47 (ddd, J = 10.9, 9.1, 1.8 Hz, 1 H), 2.17–1.91 (m, 5 H),
1.92–1.78 (m, 2 H), 1.78–1.61 (m, 1 H), 1.57 (s, 3 H), 1.46–1.27 (m, 1
H), 0.94 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 174.2, 133.5, 130.1, 81.2, 41.2, 36.1,
33.5, 30.2, 28.7, 26.4, 25.6, 17.2.
2,7,10,10-Tetramethylundecane-1,9-diol (13)
LiAlH4 (496 mg, 13.1 mmol, 2 equiv) was added in portions to solu-
tion of lactone 12 (1.57 g, 6.5 mmol, 1 equiv) in Et2O (80 mL) at 0 °C.
The mixture was stirred at r.t. for 2 h and then H2O (30 mL) was care-
fully added. The mixture was filtered and the filtrate was extracted
with Et2O (3 × 15 mL). The organic layers were combined, dried
(MgSO4), filtered, and concentrated under vacuum. The residue was
purified by flash chromatography [silica gel, PE–EtOAc (7:3)] to give a
colorless oil; yield: 1.59 g (99%); Rf = 0.48 (cyclohexane–EtOAc 1:1).
(Z)-10
Rf = 0.34 (cyclohexane–CH2Cl2, 1:1).
IR (neat): 3293, 2927, 2865, 1464, 1362, 1076, 1029, 989, 902, 644
1H NMR (300 MHz, CDCl3): δ = 5.12 (d, J = 11.6 Hz, 1 H), 4.76 (dd, J =
11.7, 2.0 Hz, 1 H), 2.54 (t, J = 12.6 Hz, 1 H), 2.43–2.17 (m, 3 H), 2.08–
1.95 (m, 1 H), 1.91–1.57 (m, 7 H), 1.57–1.37 (m, 1 H), 0.96 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 173.8, 132.4, 129.1, 79.4, 35.5, 33.8,
32.2, 29.0, 27.3, 26.2, 24.8, 24.6.
cm–1
.
1H NMR (300 MHz, CDCl3): δ = 3.44 (dd, J = 10.5, 6.0 Hz, 1 H), 3.35 (dd,
J = 10.5, 6.5 Hz, 1 H), 3.24 (d, J = 10.0 Hz, 1 H), 2.21 (br s, 1 H), 1.72 (br
s, 1 H), 1.66–1.49 (m, 2 H), 1.49–0.94 (m, 10 H), 0.94–0.68 (m, 6 H),
0.84 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 77.6, 68.2, 39.4, 35.8, 35.5, 35.0, 33.1,
29.9, 27.2, 27.1, 25.8, 21.1, 16.6.
10-(tert-Butyl)-8-methyloxecan-2-one (11)
A solution of the 82:18 E/Z mixture of lactone 10 (10.8 g, 48.1 mmol,
1 equiv) in EtOH (1 L) was treated with 10% Pd/C (2.0 g, 1.9 mmol,
0.04 equiv). The argon atmosphere was replaced with H2 and the mix-
ture was stirred at r.t. under H2 (balloon) for 48 h. The suspension was
then filtered through a Celite pad that was washed with CH2Cl2 (200
mL). The filtrate was concentrated under reduced pressure, and the
residue was purified by flash chromatography [silica gel, PE–CH2Cl2
(7:3)] to give a yellow oil; yield: 9.89 g (91%); Rf = 0.42 (cyclohexane–
CH2Cl2, 1:1).
HRMS (ESI): m/z [M + Na]+ calcd for C15H32O2 + Na: 267.2294; found:
267.2299.
9-Hydroxy-2,7,10,10-tetramethylundecanoic Acid (14)
TEMPO (1.18 g, 7.59 mmol, 0.2 equiv) and PhI(OAc)2 (30.5 g, 94.8
mmol, 2.5 equiv) were added to a solution of diol 13 (9.27 g, 37.9
mmol, 1 equiv) in 2:1 CH2Cl2/H2O (180 mL). The mixture was stirred
at r.t. for 22 h then poured into sat. aq Na2S2O3 (60 mL) and extracted
with EtOAc (3 × 40 mL). The organic layers were combined, dried (Mg-
SO4), filtered, and concentrated under vacuum. The residue was puri-
fied by flash chromatography [silica gel, PE–EtOAc (7:3)] to give a yel-
low oil; yield: 9.57 g (98%); Rf = 0.22 (cyclohexane–EtOAc, 1:1).
IR (neat): 2954, 2870, 1726, 1468, 1366, 1263, 1082, 969, 640 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 4.71 (dd, J = 7.6, 2.5 Hz, 1 H), 2.33–2.23
(m, 2 H), 2.01–1.60 (m, 5 H), 1.60–1.39 (m, 3 H), 1.39–1.18 (m, 2 H),
1.18–0.70 (m, 1 H), 0.91 (s, 9 H), 0.89 (d, J = 7.0 Hz, 3 H).
IR (neat): 3438, 2933, 2867, 1707, 1464, 1366, 1223, 1072, 982, 642
13C NMR (75 MHz, CDCl3): δ = 175.9, 78.6, 35.1, 34.8, 32.0, 31.3, 29.4,
27.3, 26.3, 23.3, 22.6, 21.5.
HRMS (ESI): m/z [M + Na]+ calcd for C14H26O2 + Na: 249.1825; found:
249.1827.
cm–1
.
1H NMR (300 MHz, CDCl3): δ = 3.28 (dd, J = 10.2, 1.7 Hz, 1 H), 2.45
(sextet, J = 6.9 Hz, 1 H), 1.75–0.69 (m, 12 H), 1.16 (d, J = 6.9 Hz, 3 H),
0.91 (d, J = 6.7 Hz, 3 H), 0.88 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 182.9, 77.9, 39.5, 39.3, 35.4, 35.0, 33.7,
30.0, 27.6, 26.8, 25.8, 21.1, 16.9.
10-(tert-Butyl)-3,8-dimethyloxecan-2-one (12)
A 2.4 M solution of BuLi in hexanes (40.0 mL, 96.0 mmol, 2 equiv) and
HMPA (20.1 mL, 109.7 mmol, 2.3 equiv) were successively added to a
solution of i-Pr2NH (14.8 mL, 105.0 mmol, 2.2 equiv) in THF (30 mL) at
–50 °C. The mixture was stirred for 20 min at –50 °C and then a solu-
tion of lactone 11 (10.8 g, 47.7 mmol, 1 equiv) in THF (40 mL) was
added. The mixture was stirred for 30 min at –20 °C then added
through a cannula to a solution of MeI (8.9 mL, 143.1 mmol, 3 equiv)
in THF (30 mL) at r.t. The resulting solution was stirred for 2.5 h,
mixed with sat. aq NH4Cl (100 mL), and extracted with Et2O (3 × 30
mL). The organic layers were combined, dried (MgSO4), filtered, and
concentrated under vacuum. The residue was purified by flash chro-
matography [silica gel, PE–CH2Cl2 (7:3)] to give a single diastereomer
as a colorless oil; yield: 10.8 g (94%); Rf = 0.42 (cyclohexane–CH2Cl2,
1:1).
HRMS (ESI): m/z [M + Na]+ calcd for C15H30O3 + Na: 281.2087; found:
281.2089.
9-Hydroxy-2,7,10,10-tetramethylundecanamide (15)
EDCI (18.8 mg, 0.098 mmol, 1.2 equiv) and 1H-1,2,3-benzotriazol-1-
ol hydrate (13.3 mg, 0.098 mmol, 1.2 equiv) were added to a solution
of acid 14 (21 mg, 0.081 mmol, 1 equiv) in MeCN (1 mL). The mixture
was stirred overnight at r.t., and then 20% aq NH3 (400 μL, 4.35 mmol)
was added. The mixture was stirred for 40 min at r.t., poured into H2O
(10 mL), and extracted with EtOAc (3 × 5 mL). The organic layers were
combined, dried (MgSO4), filtered, and concentrated under vacuum.
The residue was purified by flash chromatography [silica gel, EtOAc–
PE (8:2)] to give a white solid; yield: 20 mg (96%); mp 95–96 °C; Rf =
0.23 (EtOAc–cyclohexane, 9:1).
IR (neat): 2956, 2871, 1725, 1466, 1365, 1267, 1074, 964 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1016–1023

1021
G. Pomey, P. Phansavath
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Synthesis
IR (neat): 3458, 2964, 2947, 2932, 2858, 1665, 1614, 1464, 1289,
1172, 1073, 1006, 975, 731, 651 cm–1
HRMS (ESI): m/z [M + Na]+ calcd for C19H33NO3 + Na: 346.2352; found:
346.2347.
.
1H NMR (300 MHz, CDCl3): δ = 5.92 (br s, 1 H), 5.61 (br s, 1 H), 3.25 (d,
J = 10.0 Hz, 1 H), 2.24 (sextet, J = 6.7 Hz, 1 H), 1.71–1.48 (m, 3 H),
1.47–0.90 (m, 9 H), 1.12 (d, J = 6.9 Hz, 3 H), 0.89 (d, J = 6.7 Hz, 3 H),
0.86 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 179.6, 77.6, 41.0, 39.4, 35.4, 35.0, 34.3,
29.9, 27.8, 26.9, 25.8, 21.1, 17.9.
(4Z)-15-tert-Butyl-6,8,13-trimethyl-1-oxa-6-azacyclopentadec-4-
ene-2,7-dione [(Z)-6]
A 60% dispersion of NaH in mineral oil (3.4 mg, 0.085 mmol, 1.1
equiv) and MeI (7 μL, 0.105 mmol, 1.5 equiv) were added successively
to a solution of dione 19 (25 mg, 0.077 mmol, 1 equiv) in THF (1 mL)
at 0 °C. The mixture was stirred at r.t. for 2 h, the reaction was
quenched with H2O (5 mL), and the mixture was extracted with EtOAc
(3 × 5 mL). The organic layers were combined, dried (MgSO4), filtered,
and concentrated under vacuum. The residue was purified by flash
chromatography [silica gel, cyclohexane–EtOAc (8:2)] to give an oil;
yield: 8 mg (31%); Rf = 0.18 (cyclohexane–EtOAc, 8:2).
HRMS (ESI): m/z [M + Na]+ calcd for C15H31NO2 + Na: 280.2247; found:
280.2247.
9-Amino-1-tert-butyl-3,8-dimethyl-9-oxononyl 3-(1,3-Dioxolan-
2-yl)propanoate (17)
DIPEA (145 μL, 0.83 mmol, 1.7 equiv) and 2,4,6-trichlorobenzoyl chlo-
ride (153 μL, 0.98 mmol, 2 equiv) were added to a mixture of amide
15 (126 mg, 0.49 mmol, 1 equiv), DMAP (150 mg, 1.23 mmol, 2.5
equiv), and carboxylic acid 16 (100 mg, 0.68 mmol, 1.4 equiv) in tolu-
ene (2.7 mL). The mixture was stirred overnight at r.t., the reaction
was quenched with H2O (10 mL), and the mixture was extracted with
EtOAc (3 × 5 mL). The organic layers were combined, dried (MgSO4),
filtered, and concentrated under vacuum. The residue was purified by
flash chromatography [silica gel, EtOAc–PE (7:3)] to give a colorless
oil; yield: 165 mg (87%); Rf = 0.25 (EtOAc–cyclohexane, 9:1).
1H NMR (300 MHz, CDCl3): δ = 6.46 (dd, J = 7.7, 1.8 Hz, 1 H), 5.67 (ddd,
J = 7.7, 3.4, 0.6 Hz, 1 H), 4.96 (dd, J = 12.3, 3.1 Hz, 1 H), 3.30 (dd, J =
12.2, 6.7 Hz, 1 H), 3.06 (s, 3 H), 2.97 (ddd, J = 18.6, 3.4, 2.2 Hz, 1 H),
2.80 (ddd, J = 18.6, 5.6, 3.4 Hz, 1 H), 1.73–1.11 (m, 11 H), 1.06 (d, J =
6.7 Hz, 3 H), 0.88 (s, 9 H), 0.83 (d, J = 6.6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 177.5, 170.5, 132.6, 122.6, 78.1, 38.3,
36.7, 36.5, 36.3, 34.8, 33.5, 31.3 29.8, 27.2, 26.3, 26.2, 20.9, 18.2.
HRMS (ESI): m/z [M + Na]+ calcd for C20H35NO3 + Na: 360.2509; found:
360.2503.
IR (neat): 3360, 2964, 2361, 1727, 1666, 1466, 1368, 1262, 1170,
1137, 1070, 980, 905 cm–1
.
9-Hydroxy-N,2,7,10,10-pentamethylundecanamide (20)
1H NMR (300 MHz, CDCl3): δ = 5.79 (br s, 2 H), 4.90 (t, J = 4.3 Hz, 1 H),
4.80 (m, 1 H), 3.96–3.80 (m, 4 H), 2.42 (t, J = 7.4 Hz, 2 H), 2.21 (sextet,
J = 6.8 Hz, 1 H), 2.03–1.89 (m, 2 H), 1.63–0.88 (m, 11 H), 1.11 (d, J = 6.9
Hz, 3 H), 0.83 (s, 9 H), 0.82 (d, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 179.7, 173.2, 103.3, 78.9, 65.1, 40.8,
37.2, 35.0, 34.7, 34.1, 29.2, 29.1, 28.7, 27.4, 26.4, 26.0, 20.9, 17.8.
A solution of 14 (4.15 g, 16.1 mmol, 1 equiv) in MeCN (40 mL) was
treated with EDCI (3.70 g, 19.3 mmol, 1.2 equiv) and 1H-1,2,3-ben-
zotriazol-1-ol (2.6 g, 19.3 mmol, 1.2 equiv). The mixture was stirred
for 3 h at r.t., and then a solution of 2 M solution of MeNH2 in MeOH
(40 mL, 80 mmol, 5 equiv) was added. The mixture was stirred for a
further 40 min at r.t., then poured into H2O (40 mL) and extracted
with EtOAc (3 × 20 mL). The organic layers were combined, dried
(MgSO4), filtered, and concentrated under vacuum. The residue was
purified by flash chromatography [silica gel, EtOAc–PE (8:2)] to give a
pale-yellow amorphous solid; yield: 3.70 g (85%); mp 80–81 °C; Rf =
0.30 (EtOAc–cyclohexane, 9:1).
(4Z)-15-tert-Butyl-8,13-dimethyl-1-oxa-6-azacyclopentadec-4-
ene-2,7-dione (19)
A solution of amino ester 17 (525 mg, 1.36 mmol, 1 equiv) in THF (20
mL) was treated with 10% aq HCl (20 mL, 57 mmol), and the mixture
was stirred for 21 h at r.t. Sat. aq NaHCO3 (100 mL) was slowly added
and then the mixture was extracted with Et2O (3 × 30 mL). The organ-
ic layers were combined, dried (MgSO4), filtered, and concentrated
under vacuum to give aldehyde 18 as a yellow oil; yield: 340 mg
(73%).
IR (neat): 3299, 2931, 2868, 1650, 1555, 1462, 1410, 1366, 1246, 1074
cm–1
.
1H NMR (300 MHz, CDCl3): δ = 5.65 (br s, 1 H), 3.25 (dd, J = 10.2, 1.7
Hz, 1 H), 2.78 (d, J = 4.8 Hz, 3 H), 2.14 (sextet, J = 6.9 Hz, 1 H), 1.72–
1.49 (m, 3 H), 1.49–1.05 (m, 8 H), 1.10 (d, J = 6.9 Hz, 3 H), 1.05–0.68
(m, 1 H), 0.89 (d, J = 6.7 Hz, 3 H), 0.86 (s, 9 H).
A solution of the crude aldehyde 18 (200 mg, 0.59 mmol, 1 equiv) in
toluene (80 mL) containing 4 Å MS (1.2 g) was treated with TFA (227
μL, 2.95 mmol, 5 equiv), and the mixture was stirred at the reflux for
1 h. It was then cooled to r.t., filtered, and poured into sat. aq NaHCO3
(30 mL) and extracted with EtOAc (3 × 15 mL). The organic layers
were combined, dried (MgSO4), filtered, and concentrated under vac-
uum. The residue was purified by flash chromatography [silica gel,
PE–EtOAc (9:1)] to give white solid 19; yield: 70 mg (36%); mp 85–
86 °C; Rf = 0.38 (cyclohexane–EtOAc, 8:2).
13C NMR (75 MHz, CDCl3): δ = 177.4, 77.6, 41.7, 39.4, 35.4, 35.0, 34.5,
29.9 27.9, 26.9, 26.3, 25.8, 21.1, 18.0.
HRMS (ESI): m/z [M + Na]+ calcd for C16H33NO2 + Na: 294.2403; found:
294.2402.
1-tert-Butyl-3,8-dimethyl-9-(methylamino)-9-oxononyl 3-(1,3-Di-
oxolan-2-yl)propanoate (21)
A mixture of amide 20 (3.23 g, 11.9 mmol, 1 equiv), DMAP (3.63 g,
29.7 mmol, 2.5 equiv), and carboxylic acid 16 (2.44 g, 16.7 mmol, 1.4
equiv) in toluene (60 mL) was treated with DIPEA (3.52 mL, 20.2
mmol, 1.7 equiv) and 2,4,6-trichlorobenzoyl chloride (3.72 mL, 23.8
mmol, 2 equiv). The mixture was stirred for 4 h at r.t., the reaction
was quenched with H2O (40 mL), and the mixture was extracted with
EtOAc (3 × 20 mL). The organic layers were combined, dried (MgSO4),
filtered, and concentrated under vacuum. The residue was purified by
flash chromatography [silica gel, EtOAc–PE (8:2)] to give a colorless
oil; yield: 3.47 g (73%); Rf = 0.32 (EtOAc–cyclohexane, 9:1).
IR (neat): 3371, 2963, 2931, 2357, 1690, 1660, 1501, 1460, 1371,
1298, 1279, 1252, 1196, 1075, 1041, 975, 957, 937, 815, 791, 762 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.36 (br d, J = 10.8 Hz, 1 H), 6.92 (ddd,
J = 8.9, 2.4, 2.3 Hz, 1 H), 4.93 (dd, J = 10.4, 0.8 Hz, 1 H), 4.75 (td, J = 9.2,
5.0 Hz, 1 H), 3.08 (ddd, J = 13.7, 5.0, 2.5 Hz, 1 H), 2.99 (dd, J = 13.7, 9.5
Hz, 1 H), 2.55 (sextet, J = 6.5 Hz, 1 H), 1.91–1.71 (m, 2 H), 1.40–0.98
(m, 9 H), 1.12 (d, J = 6.9 Hz, 3 H), 0.87 (s, 9 H), 0.77 (d, J = 6.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 174.0, 173.2, 126.3, 98.1, 79.5, 39.9,
38.8, 34.4, 33.1, 32.7, 32.2, 26.3, 26.0, 25.2, 22.3, 20.9, 15.4.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1016–1023

1022
G. Pomey, P. Phansavath
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Synthesis
IR (neat): 3301, 2959, 2933, 2875, 1730, 1648, 1550, 1367, 1251,
1169, 1137, 1071, 1039 cm–1
13C NMR (75 MHz, CDCl3): δ = 175.9, 171.6, 133.2, 103.1, 78.0, 38.0,
36.8, 35.1, 34.8, 34.7, 33.5, 30.9, 26.2, 26.1, 26.0, 25.5, 20.3, 17.4.
.
1H NMR (300 MHz, CDCl3): δ = 5.79 (br s, 1 H), 4.92 (t, J = 4.3 Hz, 1 H),
4.85–4.75 (m, 1 H), 4.00–3.76 (m, 4 H), 2.77 (d, J = 4.8 Hz, 3 H), 2.49–
2.35 (m, 2 H), 2.15 (sextet, J = 6.8 Hz, 1 H), 2.06–1.91 (m, 2 H), 1.69–
1.49 (m, 1 H), 1.49–1.05 (m, 9 H), 1.09 (d, J = 6.9 Hz, 3 H), 1.05–0.90
(m, 1 H), 0.84 (s, 9 H), 0.90–0.75 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 177.5, 173.2, 103.3, 78.9, 65.1, 41.5,
37.2, 35.0, 34.8, 34.2, 29.3, 29.1, 28.7, 27.5, 26.28, 26.27, 26.0, 20.9,
17.9.
HRMS (ESI): m/z [M + Na]+ calcd for C20H35NO3 + Na: 360.2509; found:
360.2512.
Acknowledgment
We thank the Ministère de l’Enseignement Supérieur et de la Recher-
che for a grant (G.P.). We are grateful to C. Férard for technical assis-
tance and to Dr. M.-N. Rager for carrying additional NMR
experiments.
HRMS (ESI): m/z [M + Na]+ calcd for C22H41NO5 + Na: 422.2877; found:
422.2879.
1-tert-Butyl-3,8-dimethyl-9-(methylamino)-9-oxononyl 4-Oxobu-
tanoate (22)
Supporting Information
Supporting information for this article is available online at
A solution of ester 21 (1.89 g, 4.75 mmol, 1 equiv) in THF (50 mL) was
treated with 20% aq HCl (50 mL), and the mixture was stirred for 5 h
at r.t. Sat. aq NaHCO3 (400 mL) was added slowly and the mixture was
extracted with Et2O (3 × 100 mL). The organic layers were combined,
dried (MgSO4), filtered, and concentrated under vacuum. The residue
was purified by flash chromatography [silica gel, EtOAc–PE (8:2)] to
give a colorless oil; yield: 1.58 g (94%); Rf = 0.32 (EtOAc–cyclohexane,
9:1).
http://dx.doi.org/10.1055/s-0034-1380133.
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References
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IR (neat): 3314, 2961, 2932, 2872, 1728, 1648, 1549, 1463, 1370,
1235, 1174, 1073, 963, 648 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 9.82 (s, 1 H), 5.69 (br s, 1 H), 4.86–4.75
(m, 1 H), 2.79 (d, J = 4.8 Hz, 3 H), 2.82–2.73 (m, 2 H), 2.67–2.57 (m, 2
H), 2.15 (sextet, J = 6.8 Hz, 1 H), 1.67–1.50 (m, 1 H), 1.50–1.04 (m, 9
H), 1.11 (d, J = 6.8 Hz, 3 H), 1.04–0.75 (m, 4 H), 0.86 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 200.4, 177.5, 172.3, 79.5, 41.6, 38.7,
37.2, 35.0, 34.8, 34.3, 29.4, 27.6, 26.9, 26.4, 26.3, 26.0, 20.9, 18.0.
HRMS (ESI): m/z [M + Na]+ calcd for C20H37NO4 + Na: 378.2615; found:
378.2616.
(4E)-15-tert-Butyl-6,8,13-trimethyl-1-oxa-6-azacyclopentadec-4-
ene-2,7-dione [(E)-6]
(6) Mehrotra, S.; Duggan, B. M.; Tello-Aburto, R.; Newar, T. D.;
Gerwick, W. H.; Murray, T. F.; Maio, W. A. J. Nat. Prod. 2014, 77,
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A solution of amino ester 22 (200 mg, 0.562 mmol, 1 equiv) in toluene
(120 mL) containing 4 Å MS (1.2 g) was treated with TFA (217 μL, 2.81
mmol, 5 equiv), and the mixture was stirred at the reflux with a
Dean–Stark apparatus for 3 d. The mixture was then cooled to r.t., fil-
tered, poured into sat. aq NaHCO3 (50 mL), and extracted with EtOAc
(3 × 20 mL). The organic layers were combined, dried (MgSO4), fil-
tered, and concentrated under vacuum. The residue was purified by
flash chromatography [silica gel, PE–EtOAc (9:1)] to give (E)-6 as a
white solid [yield: 45 mg (24%)], together with (Z)-6 as an oil [yield:
21 mg (11%)].
(8) Zou, Y.; Ding, C.; Zhou, L.; Li, Z.; Wang, Q.; Schoenebeck, F.;
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(E)-6
Mp 94–95 °C; Rf = 0.39 (cyclohexane–EtOAc, 7:3).
IR (neat): 2956, 2930, 2857, 1713, 1674, 1640, 1462, 1259, 1154,
(10) The relative configuration between the C(7) and C(9) stereocen-
ters in compound 11 was assigned on the basis of NOESY exper-
iments, and the trans relationship was later confirmed by an X-
ray crystal structure analysis of the parent compound 15.
(11) To ascertain that no enrichment in trans-11 at the expense of
the cis-isomer occurred during the purification process, a
sample of pure (Z)-10 was subjected to the hydrogenation reac-
tion and the trans-isomer was obtained exclusively.
1095, 959, 804, 649, 641 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.08 (d, J = 14.0 Hz, 1 H), 5.09 (dt, J =
14.1, 7.2 Hz, 1 H), 4.90 (dd, J = 12.0, 1.6 Hz, 1 H), 3.07 (s, 3 H), 3.04–
2.96 (m, 2 H), 2.91 (sextet, J = 6.5 Hz, 1 H), 1.68–0.91 (m, 11 H), 1.13
(d, J = 6.6 Hz, 3 H), 0.86 (s, 9 H), 0.76 (d, J = 6.2 Hz, 3 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1016–1023

1023
G. Pomey, P. Phansavath
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Synthesis
(12) Formation of the cis-isomer can be rationalized by considering
the most stable conformation of the 10-membered lactone
enolate (boat–chair–boat conformation), see: Still, W. C.;
Galynker, I. Tetrahedron 1981, 37, 3981.
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Hashimoto, Y. Chem. Pharm. Bull. 2006, 54, 1709.
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Chem. Soc. Jpn. 1979, 52, 1989.
(13) Epp, J. B.; Widlanski, T. S. J. Org. Chem. 1999, 64, 293.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1016–1023