A highly stereoselective formal synthesis of hapalosin

Article abstract of DOI:10.1055/s-0033-1338952

A flexible and highly diastereoselective formal synthesis of hapalosin, a cyclodepsipeptide isolated from the blue green alga Hapalosiphon welwitschii and having multidrug-resistance-reversing activity is described. The synthetic route involves the addition of organometallic reagent to N-tert- butanesulfinylimine, Jung nonaldol aldol reaction, and Yamaguchi esterification as key steps. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1338952

LETTER
▌1415
lAetteHr ighly Stereoselective Formal Synthesis of Hapalosin
Synthesis of Hapalosin
Harish Kumar, A. Srinivas Reddy, J. S. Yadav, B. V. Subba Reddy*
Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad – 500 007, India
Fax +91(40)27160512; E-mail: basireddy@iict.res.in
Received: 07.02.2013; Accepted after revision: 24.04.2013
as an integral part of the starting material except the ap-
proach of Huang and Maier.2d,4a,b Structure–activity rela-
tionship studies clearly indicate that the modification of
the C-9 side chain of the β-hydroxyl-γ-amino acid moiety
Abstract: A flexible and highly diastereoselective formal synthesis
of hapalosin, a cyclodepsipeptide isolated from the blue green alga
Hapalosiphon welwitschii and having multidrug-resistance-revers-
ing activity is described. The synthetic route involves the addition
of organometallic reagent to N-tert-butanesulfinylimine, Jung non- may increase the MDR-reversing activity of hapalosin.
aldol aldol reaction, and Yamaguchi esterification as key steps.
Therefore, there is a scope for improving the MDR-re-
versing activity of hapalosin by making analogues with
different substitution at C-9.
Key words: Sharpless asymmetric epoxidation, Jung nonaldol
aldol reaction, Yamaguchi esterification, hapalosin
In continuation of our research program on the total syn-
thesis of natural products,5 we describe herein a conver-
gent strategy for the synthesis of hapalosin (1). The key
step of our approach is the addition of an organometallic
reagent to a chiral N-tert-butanesulfinylimine which pro-
vides direct access to analogues of hapalosin by merely
altering the organometallic reagent. The retrosynthetic
outline of our approach is depicted in Scheme 1.
Multidrug resistance (MDR) is one of the major obstacles
in the success of chemotherapy1a,b and MDR-reversing
agents can be applied to suppress unwanted phenotypes.
The phenomenon of MDR involves the overexpression of
P-glycoprotein which acts as an ATP-dependent drug ef-
flux pump.1a,b Enhanced efflux results in reduction of the
drug accumulation in cells with a concomitant reduction
in drug-mediated cytotoxicity.
L-valine
Ellmann's auxillary
The marine natural product, hapalosin (1) is a 12-mem-
bered depsipeptide isolated from Hapalosiphon wel-
witschii by Moore et al. found to exhibit MDR-reversing
activity; its structure was elucidated by spectroscopic
methods (Figure 1).1c
Jung reaction
1
O
OBn
Me
12
11
O
2
1N0
Me
O
O
O
3
O
4
9
HO
MOMO
N
Cbz
8
( )5
5 O
O
O
( )5
6
7
O
O
2
hapalosin (1)
Me
O
N
O
OMOM
HO
OTBS
O
O
HO2C
5
CO2H
+
+
( )5
HO
CO2Bn
N
Cbz
Me
hapalosin
5
4
3
Figure 1 Chemical structure of hapalosin (1)
L-valine
n-octanal
O
PMBO
However, a few approaches to the total synthesis of
hapalosin have been reported.2 Ghosh et al.2b reported
the first total synthesis of hapalosin (1), revised its struc-
ture, and also disclosed its structure–activity relationships.
Hapalosin exists in two conformers wherein the major s-cis
conformer attributes to MDR-reversing activity.
6
Scheme 1 Retrosynthetic analysis of hapalosin (1)
It was envisaged that a 12-membered cyclic depsipeptide
could be prepared through Yamaguchi esterification of
the alcohol 10 with acid 3. The fragment 4 (β-hydroxy ac-
id) was anticipated to be obtained by Jung’s protocol,6
while the fragment 5 (α-hydroxy ester) could be prepared
from a commercially available L-valine. The fragment 3
(α-amino-β-hydroxy acid) was proposed to be prepared
using sulfinylimine chemistry. The problem of epimeriza-
tion of the stereocenter adjacent to the carbonyl group
would be eliminated by following the Elman’s method.7
In addition, there have been some reports on the synthesis
of the β-hydroxy-γ-amino acid fragment of hapalosin.2–4
In most of the reported strategies for the synthesis of the
β-hydroxy-γ-amino acid, the benzyl group was introduced
SYNLETT 2013, 24, 1415–1419
Advanced online publication: 05.06.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338952; Art ID: ST-2013-D0124-L
© Georg Thieme Verlag Stuttgart · New York

1416
H. Kumar et al.
LETTER
Accordingly, we began the synthetic sequence from n-oc-
tanal which was converted into allylic alcohol 7 by Wittig
olefination with a stable ylide Ph3P=C(Me)CO2Et in ben-
zene under reflux for three hours and reduction of the re-
sulting ester. Epoxidation of allylic alcohol under
Sharpless conditions afforded the chiral epoxide 8 in 85%
yield. Treatment of epoxide 8 with TBSOTf and DIPEA
under Jung reaction conditions6 gave the aldehyde which
was then subjected to oxidation with NaClO2 to afford the
acid 4. The secondary alcohol 5 was prepared through di-
azotization and hydroxylation followed by protection of
the free acid group with benzyl chloride using Et3N and
DMAP.4e The condensation of the acid 4 with alcohol 5
gave the ester 9 which was then treated with HF·pyridine
to afford the fragment 10 (Scheme 2).
OR
OTBS
O
c–e
a, b
N
PMBO
PMBO
S
6
11
O
12
R = TBDMS
OR
OR
g–i
f
HN
HN
S
Cbz
14
R = MOM
O
13
de: 93%
R = TBDMS
OR
OR Cbz
N
k, l
j
HO2C
O
Me
c
a, b
( )5
OH
N
n-octanal
( )5
OH
Me
Cbz
7
8
15
R = MOM
3
R = MOM
OR
O
OR
O
d, e
f
OBn
Scheme 3 Reagents and conditions: (a) vinylmagnesium bromide,
CuCN, THF, –78 to –40 °C, 4 h, 95%; (b) TBSCl, DMAP, imidazole,
CH2Cl2, 0 °C to r.t., 3 h; (c) DDQ, CH2Cl2–H2O, r.t, 1 h; (d) (COCl)2,
DMSO, Et3N, CH2Cl2, –78 °C; (e) CuSO4, tert-butylsulfinamide,
CH2Cl2, r.t., 78% (over four steps); (f) BnMgCl, CH2Cl2, –40 °C,
85%; (g) 4 M HCl in dioxane, EtOH, 0 °C to r.t., 15 min; (h)
NaHCO3, CbzCl, THF–H2O, 0–25 °C, 3 h; (i) DIPEA, MOMCl,
CH2Cl2, 0 °C to r.t., 3 h, 83%, (over three steps); (j) NaH, MeI, DMF,
0 °C to r.t., 3 h, 92%; (k) OsO4, NaIO4, lutidine, 0 °C; (l) Na2HPO4,
NaClO2, 2-methylbut-2-ene, t-BuOH–H2O, r.t., 3 h, 82% (over two
( )5
O
( )5
OH
O
OBn
O
4
9
R = TBDMS
R = TBDMS
OH
5
OH
O
e
OBn
( )5
O
O
10
by deprotection of both TBS ether and N-tert-butylsulfi-
nyl groups of 13 followed by treatment with 1,1-carbon-
yldiimidazole in THF under reflux conditions (Scheme 4).
Scheme 2 Reagents and conditions: (a) Ph3C(Me)=CO2Et, toluene,
reflux; (b) DIBAL-H, CH2Cl2, 0 °C, 2 h, 86% (over two steps); (c)
(–)-DIPT, Ti(Oi-Pr)4, TBHP, CH2Cl2, –20 °C, 92%; (d) TBSOTf,
DIPEA, CH2Cl2, –40 °C, 5 h; (e) Na2HPO4, NaClO2, 2-methyl-2-bu-
tene, t-BuOH–H2O, 25 °C, 3 h, 90% (over two steps); (f) 2,4,6-tri-
chlorobenzoyl chloride, Et3N, DMAP, toluene, 0–25 °C, 8 h, 90%; (g)
HF·pyridine, THF, 25 °C, 30 min, 88%.
NH2
a
HN
O
OH
13a
O
The synthesis of pivotal intermediate, β-hydroxy-γ-amino
acid 3 is outlined in Scheme 3. Treatment of epichlorohy-
drin with PMB alcohol followed by Jacobsen’s kinetic
resolution of the epoxide gave the PMB-protected chiral
epoxide 6.8 Regioselective ring opening of the epoxide 6
with vinylmagnesium bromide in the presence of CuCN in
dry THF at 0 °C gave the allylic alcohol in 95% yield.
Protection of the secondary alcohol as its silyl ether fol-
lowed by deprotection of the PMB ether gave the primary
alcohol which was then oxidized to afford the correspond-
ing aldehyde. The direct condensation of the aldehyde
with (S)-N-tert-butanesulfinamide using CuSO4 in dichlo-
romethane at 0 °C gave the (S)-N-tert-butylsulfinylimine
2 in 78% yield. Subsequent addition of benzylmagnesium
chloride to (S)-N-tert-butanesulfinylimine7 in dichloro-
methane at 0 °C afforded the chiral sulfinamide 13 with
93% de (by HPLC).
16
Scheme 4 Reagents and conditions: (a) 1,1′-carbonyldiimidazole,
THF, reflux.
The structure of 16 was characterized by NMR experi-
ments including 2-D nuclear Overhauser effect spec-
troscopy (NOESY) and double-quantum-filtered
1
correlation spectroscopy (DQFCOSY). From H NMR
experiments, the couplings 3JH2–H3 = 7.5 Hz, 3JH2–H4(pro-R)
3
3
= 9.0 Hz, JH2–H4(pro-S) = 5.1 Hz, JH3–H5(pro-S) = 9.4 Hz,
and 3JH3–H5(pro-R) = 4.1 Hz, were determined for H2, H3,
H4, and H5. The configuration at C3 in the five-mem-
bered ring is supported by the NOESY cross peaks be-
tween H4(pro-R)/H5(pro-S), H4(pro-R)/H5(pro-R),
H4(pro-S)/H5(pro-S), and H4(pro-S)/H5(pro-R) and
also the presence of NOE cross peaks between H1/H4
(pro-R) and H3/H6. The assigned structure was further
supported by the energy-minimized structure (Figure
2).
The anti configuration of the 1,2-amino alcohol 13a was
confirmed by NOE studies. The substrate 16 was prepared
Synlett 2013, 24, 1415–1419
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Hapalosin
1417
OH
O
OBn
O
OBn
a
O
( )5
O
Me
O
MOMO
O
10
N
Cbz
+
( )5
O
OR Cbz
N
HO2C
O
Me
2
ref. 2b
3
R = MOM
O
O
N
O
Figure 2 Structure of substrate 16 confirmed by NOE
HO
( )5
O
O
The sequential deprotection of both TBS ether and N-tert-
butylsulfinyl group using 4 M HCl in dioxane–ethanol
mixture at 0 °C gave the 1,2-amino alcohol which was
then protected with CbzCl in THF–H2O (3:1) under
Schotten–Baumann conditions to afford the carbamate
whose secondary hydroxyl group was protected as a
MOM ether to give the compound 14 in 83% yield over
three steps. Methylation of compound 14 using MeI in the
presence of NaH in THF–DMF (8:2) followed by dihy-
droxylation of the olefin with a catalytic amount of OsO4
and stoichiometric N-methylmorpholine-N-oxide (NMO)
afforded the diol. Oxidative cleavage of the diol using
NaIO4 gave the aldehyde which was further transformed
into carboxylic acid 3 by Pinnick oxidation. However, the
presence of two rotamers was observed in the NMR spec-
trum of N-methyl derivative 3. After removal of the MOM
ether, a single rotamer was observed in the 1H NMR and
13C NMR spectra of 3. The compound 14 also shows a sin-
gle rotamer in the 1H NMR spectrum. The existence of ro-
tamers may be due to the presence of nonbonding
interactions between the MOM ether and the N-methyl
group (Scheme 3).
hapalosin
Scheme 5 Reagents and conditions: (a) 2,4,6-trichlorobenzoyl chlo-
ride, Et3N, DMAP, toluene, 0 °C to r.t., 9 h, 92%.
Acknowledgment
H.G and A.S.R. thank CSIR, New Delhi, India for the award of
fellowships.
References and Notes
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With a successful synthesis of fragments 10 and 3, the
next step was to assemble both fragments. Thus the cou-
pling of diester 10 with acid 3 under Yamaguchi condi-
tions gave the target ester 2 in 92% yield (Scheme 5).9 The
spectroscopic data for 210 were in good agreement with
the data reported in the literature.3d
In summary, we have accomplished a convergent synthe-
sis of hapalosin (1) in a highly diastereoselective manner.
The stereocenters of hapalosin were established by Jacob-
son kinetic resolution, Sharpless epoxidation, Jung’s non-
aldol aldol reaction, and stereoselective addition of
benzylmagnesium chloride to tert-butanesulfinyl ald-
imine. It is a modular approach which can produce a vari-
ety of hapalosin analogues with different substitutions at
C-9 in order to improve the MDR-reversing activity of
hapalosin.
(d) Wagner, B.; Gonzalez, G. I.; Dau, M. E. T. H.; Zhu, J.
Bioorg. Med. Chem. 1999, 7, 737. (e) Dinh, T. Q.;
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1415–1419

1418
H. Kumar et al.
LETTER
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Du, X.; Armstrong, R. W. J. Med. Chem. 1998, 41, 981.
cm–1. ESI-HRMS: m/z calcd for C23H36O5: 415.2460 [M +
Na]+; found: 415.2474.
(E)-N-[(R)-2-(tert-Butyldimethylsilyloxy)pent-4-
enylidene]-2-methylpropane-2-sulfinamide (12)
Rf = 0.60 (10% EtOAc–hexane); yellow viscous liquid;
[α]D25 +159.0 (c 0.5, CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 7.95 (d, J = 4.5 Hz, 1 H), 5.90–5.75 (m, 1 H), 5.17–5.08
(m, 2 H), 4.53–4.46 (m, 1 H), 2.48–2.41 (m, 2 H), 1.20 (s, 9
H), 0.90 (s, 9 H), 0.08 (s, 3 H), 0.06 (s, 3 H). 13C NMR (75
MHz, CDCl3): δ = 170.8, 133.1, 118.2, 74.0, 56.7, 40.2,
25.7, 22.4, 18.1, 4.9, 4.5. IR (neat): νmax = 2959, 2930, 2861,
1729, 1600, 1580, 1462, 1381, 1274, 1122, 1072, 801, 772,
743 cm–1. ESI-HRMS: m/z calcd for C15H31NO2SSi:
318.1923; found: 318.193 [M + H]+ 7.
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V. S. Tetrahedron Lett. 2012, 53, 5749. (b) Reddy, B. V. S.;
Reddy, B. P.; Pandurangam, T.; Yadav, J. S. Tetrahedron
Lett. 2011, 52, 2306. (c) Reddy, P. J.; Reddy, A. S.; Yadav,
J. S.; Reddy, B. V S. Tetrahedron Lett. 2012, 53, 4054.
(d) Reddy, P. J.; Reddy, A. S.; Yadav, J. S.; Reddy, B. V. S.
Tetrahedron Lett. 2012, 53, 4051. (e) Reddy, N. S.; Reddy,
A. S.; Yadav, J. S.; Reddy, B. V. S. Tetrahedron Lett. 2012,
53, 6916.
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J. A. J. Org. Chem. 1999, 64, 1278. (b) Harried, S. S.;
Croghan, M. D.; Kaller, M. R.; Lopez, P.; Zhong, W.;
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8883. (d) Robak, M. A.; Herbage, M. A.; Ellman, J. A.
Chem. Rev. 2010, 10, 3600.
N-[(2S,3R)-3-(tert-Butyldimethylsilyloxy)-1-phenylhex-
5-en-2-yl]-2-methylpropane-2-sulfinamide (13)
Rf = 0.60 (10% EtOAc–hexane); yellow viscous liquid;
[α]D25 +8.0 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ =
7.28–7.23 (m, 2 H), 7.19–7.12 (m, 3 H), 5.87–5.77 (m, 1 H),
5.18–5.10 (m, 2 H), 3.63–3.59 (m, 1 H), 3.58–3.53 (m, 1 H),
2.90–2.84 (m, 1 H), 2.76–2.70 m, 1 H), 2.45–2.38 (m, 1 H),
2.36–2.28 (m, 1 H), 0.99 (s, 9 H), 0.93 (s, 9 H), 0.14 (s, 3 H),
0.08 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 139.0, 134.2,
129.3, 128.2, 126.0, 117.6, 74.5, 61.6, 55.7, 38.6, 34.9, 29.6,
25.9, 22.3, –4.4, –4.3. IR (neat): νmax = 2958, 2929, 2860,
1729, 1600, 1580, 1462, 1381, 1276, 1123, 1072, 1040, 836,
774, 742 cm–1. ESI-HRMS: m/z calcd for C22H39NO2SSi:
410.2549; found: 410.2557 [M + H]+.
(8) Yadav, J. S.; Swamy, T.; Reddy, B. V. S. Synlett 2008, 2773.
(9) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi,
M. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
(10) [(2R,3R)-3-Heptyl-2-methyloxiran-2-yl]methanol (8)
25
Rf = 0.50 (20% EtOAc–hexane); light yellow liquid; [α]D
+10.5 (c 1, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 3.73–
3.52 (m, 2 H), 3.03 (t, J = 6.4 Hz, 1 H), 1.61–1.43 (m, 2 H),
1.40–1.23 (m, 13 H), 0.90–0.85 (m, 3 H). 13C NMR (75
MHz, CDCl3): δ = 65.4, 63.8, 60.3, 31.7, 29.3, 29.1, 28.1,
26.4, 22.5, 14.0. IR (neat): νmax = 3427, 2927, 2858, 1728,
1462, 1382, 1278, 1127, 1073, 1041, 872, 771, 744, 723, 704
cm–1. ESI-HRMS: m/z calcd for C11H22O2: 209.1517 [M +
Na]+; found: 209.1524.
(2S,3R)-[(S)-1-(Benzyloxy)-3-methyl-1-oxobutan-2-yl]-3-
(tert-butyldimethylsilyloxy)-2-methyldecanoate (9)
Rf = 0.70 (10% EtOAc–hexane); yellow viscous liquid;
[α]D25 –18.0 (c 0.5, CHCl3). 1H NMR (300 MHz, CDCl3): δ
= 7.37–7.30 (m, 5 H), 5.20–5.11 (dd, J = 12.8, 6.0 Hz, 2 H),
4.83 (d, J = 4.5 Hz, 1 H), 4.03–3.96 (dt, J = 6.0, 5.3 Hz, 1 H),
2.69–2.58 (dq, J = 6.8, 5.3 Hz, 1 H), 2.32–2.15 (d of sept, J
= 6.8, 4.5 Hz, 1 H), 1.55–1.22 (m, 12 H), 1.18 (d, J = 6.8 Hz,
3 H), 0.98 (d, J = 7.6 Hz, 3 H), 0.94 (d, J = 6.8 Hz, 3 H), 0.89
(t, J = 6.0 Hz, 3 H), 0.87 (s, 9 H), 0.05 (s, 3 H), 0.02 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 174.7, 169.5, 135.5, 128.5,
128.3, 128.1, 76.6, 73.0, 66.7, 44.6, 35.2, 31.8, 30.2, 29.7,
29.2, 25.8, 24.5, 22.6, 18.8, 18.1, 17.2, 14.1, 12.1, –4.6, –4.3.
IR (neat): νmax = 2959, 2929, 2861, 1730, 1600, 1581, 1463,
1381, 1277, 1072, 1040, 957, 772, 743 cm–1. ESI-HRMS:
m/z calcd for C29H50O5Si: 529.3314 [M + Na]+; found:
529.3322.
Benzyl-(2S,3R)-3-(methoxymethoxy)-1-phenylhex-5-en-
2-ylcarbamate (14)
Rf = 0.60 (10% EtOAc–hexane); yellow viscous liquid;
[α]D25 –19.0 (c 0.5, CHCl3). 1H NMR (300 MHz, CDCl3): δ
= 7.28–7.08 (m, 10 H), 5.87–5.68 (m, 1 H), 5.17–5.00 (m, 2
H), 4.90–4.86 (m, 2 H), 4.60 (s, 2 H), 4.00–3.90 (m, 1 H),
3.74–3.64 (m, 1 H), 3.33 (s, 3 H), 2.92 (dd, J = 4.5, 14.5 Hz,
1 H), 2.60–2.50 (m, 1 H), 2.40–2.30 (m, 1 H), 2.30–2.20 (m,
1 H). 13C NMR (75 MHz, CDCl3): δ = 155.8, 138.2, 136.7,
134.1, 129.2, 128.4, 127.9, 127.8, 126.3, 117.8, 97.0, 80.8,
66.4, 55.9, 54.4, 36.7, 35.1. IR (neat): νmax = 3376, 2960,
2930, 2864, 1729, 1600, 1581, 1461, 1381, 1278, 1124,
1072, 1040, 771, 743, 702 cm–1. ESI-HRMS: m/z calcd for
C22H27NO4: 370.2018; found: 370.2020 [M + H]+.
(3R,4R)-4-[(Benzyloxycarbonyl)(methyl) amino]-3-
(methoxymethoxy)-5-phenylpentanoic Acid (3)
Rf = 0.60 (10% EtOAc–hexane); yellow viscous liquid;
[α]D25 –31.4 (c 0.7, CHCl3). 1H NMR (300 MHz, CDCl3): δ
(both rotamers) = 7.43–7.03 (m, 10 H), 5.20–4.75 (m, 5 H),
4.20 (m, 1 H), 3.40 (major, s, 3 H), 3.38 (minor, s, 3 H),
3.27–3.17 (m, 1 H), 2.97–2.54 (m, 6 H). 13C NMR (75 MHz,
CDCl3): δ = 175.2 (175.7), 156.2 (156.4), 137.9 (138.0),
136.0 (136.5), 128.6, 128.2, 128.1, 127.8, 127.7, 127.6,
127.2, 126.1, 126.0, 96.8, 76.4 (76.5), 67.2, 66.7 (66.9), 55.8
(55.9), 36.9, 34.0 (34.2). IR (neat): νmax = 3064, 3030, 2958,
2930, 2847, 1706, 1455, 1402, 1280, 1212, 1142, 1074,
1031, 919, 743, 699 cm–1. ESI-HRMS: m/z calcd for
C22H27NO6: 402.1916; found: 402.1925 [M + H]+.
(2S,3R)-(R)-1-(Benzyloxy)-3-methyl-1-oxobutan-2-yl-3-
{[(3R,4S)-4-{[(benzyloxy)carbonyl](methyl)amino}-3-
(methoxymethoxy)-5-phenylpentanoyl]oxy}-2-
(2S,3R)-[(S)-1-(Benzyloxy)-3-methyl-1-oxobutan-2-yl]-3-
hydroxy-2-methyldecanoate (10)
Rf = 0.40 (10% EtOAc–hexane); yellow viscous liquid;
[α]D25 –10.5 (c 1.0, CHCl3). 1H NMR (300 MHz, CDC0l3): δ
= 7.40–7.30 (m, 5 H), 5.25–5.13 (dd, J = 17.9, 12.1 Hz, 2 H),
4.99 (d, J = 3.8 Hz, 1 H), 4.12–4.03 (m, 1 H), 2.92–2.84 (br
s, 1 H), 2.73–2.64 (dq, J = 6.9, 3.0 Hz, 1 H), 2.35–2.22 (d of
sept, J = 6.9, 3.8 Hz, 1 H), 1.56–1.22 (m, 12 H), 1.17 (d, J =
6.9 Hz, 3 H), 0.99 (d, J = 6.9 Hz, 3 H), 0.94 (d, J = 6.9 Hz, 3
H), 0.88 (t, J = 6.7 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ
= 175.2, 170.3, 135.0, 128.6, 128.5, 128.4, 76.4, 71.9, 67.3,
44.4, 33.4, 31.8, 29.9, 29.5, 29.2, 26.2, 22.6, 18.8, 16.9, 14.1,
9.4. IR (neat): νmax = 3064, 3017, 2921, 2853, 1609, 1577,
1525, 1456, 1346, 1305, 1142, 1071, 767, 741, 705, 567
methyldecanoate (2)
Rf = 0.60 (10% EtOAc–hexane); yellow viscous liquid;
[α]D25 –22.5 (c 0.9, CHCl3). 1H NMR (300 MHz, CDCl3): δ
(both rotamers) = 7.38–7.04 (m, 15 H), 5.30–4.61 (m, 7 H),
4.35–4.25 (m, 1 H), 3.40 (major, s, 3 H), 3.39 (minor, s, 3 H),
3.27–3.16 (m, 1 H), 2.99–2.40 (m, 9 H), 2.30–2.20 (m, 1 H),
1.60–1.17 (m, 15 H), 0.95 (dd, J = 3.7, 6.8 Hz, 6 H), 0.90–
0.84 (m, 3 H). 13C NMR (75 MHz, CDCl3): δ = 177.5, 170.6,
Synlett 2013, 24, 1415–1419
© Georg Thieme Verlag Stuttgart · New York

LETTER
166.5, 145.4, 138.5, 137.2, 128.8, 128.5, 128.4, 128.3,
Synthesis of Hapalosin
1419
= 2959, 2929, 2859, 1735, 1703, 1582, 1600, 1459, 1380,
1276, 1192, 1129, 1073, 1031, 963, 920, 743, 698 cm–1. ESI-
HRMS: m/z calcd for C45H61NO10: 798.4193; found:
798.4200 [M]+.
127.9, 127.7, 127.4, 126.7, 126.3, 126.2, 122.4, 97.4, 97.2,
76.8, 76.6, 74.5, 74.4, 67.2, 66.8, 66.6, 60.6, 57.4, 56.2, 43.0,
42.8, 37.9, 37.7, 37.4, 34.3, 31.9, 31.7, 30.1, 29.7, 29.3, 29.1,
25.3, 22.6, 18.7, 17.1, 14.2, 14.0, 12.6, 12.3. IR (neat): νmax
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1415–1419

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