A stereocontrolled synthesis of methyl (-)-nonactate

Article abstract of DOI:10.1055/s-2003-37129

A stereoselective synthesis of methyl (-)-nonactate is described. (E)-γ-Triethylsilyloxyalkene 13 generated from sulfone 10 and (S)-2-benzyloxypropanal underwent intramolecular iodoetherification in the presence of silver carbonate to provide cis-2,5-disubstituted tetrahydrofuran 8 as a key intermediate.

Full text of DOI:10.1055/s-2003-37129

LETTER
393
A Stereocontrolled Synthesis of Methyl (–)-Nonactate
S
tereocon
o
trolledSynth
o
e
sis of Methy
n
l
(–)-Nonactate Won Jeong,*a Byoung Young Woo,a Deok-Chan Ha,b Zaesung No*a
a
Medicinal Science Division, Korea Research Institute of Chemical Technology, Daejeon 305-343, Korea
Fax +82(42)8607160; E-mail: jeongjw@krict.re.kr
b
Department of Chemistry, Korea University, Seoul 136-701, Korea
Received 9 December 2002
O
Abstract: A stereoselective synthesis of methyl (–)-nonactate is
described. (E)-γ-Triethylsilyloxyalkene 13 generated from sulfone
10 and (S)-2-benzyloxypropanal underwent intramolecular iodo-
etherification in the presence of silver carbonate to provide cis-2,5-
disubstituted tetrahydrofuran 8 as a key intermediate.
O
O
O
O
O
O
Key words: asymmetric synthesis, cyclizations, sulfones, nonactic
acid, iodoetherifications
O
O
O
O
Nonactin 1 is a macrotetrolide ionophore antibiotic which
has been isolated from a variety of Streptomyces cultures.1
Nonactin is tightly bound to NH4 and currently used in
O
1
+
commercial ion selective electrodes (ISEs) for detecting
the cation down to micromolar levels.2 It consists of two
molecules of (–)-nonactic acid (–)-2 and two molecules of
(+)-nonactic acid (+)-2 arranged in an alternating order
(Figure 1). The important structural feature of nonactic
acid is the cis-2,5-disubstituted tetrahydrofuran, and in
view of construction of that many syntheses of nonactic
acids and its 8-epi-isomers in both optically active and
racemic form have been reported.3 But any completely
sterocontrolled asymmetric cyclization using an electro-
phile has not been shown. Iodoetherification of g-hy-
droxy-alkene4 has been a useful method for the
preparation of 2,5-disubstituted tetrahydrofuran and the
Ag2CO3-mediated intramolecular iodoetherification of g-
triethylsilyloxyalkene was newly developed to accom-
plish the total synthesis of pamamycin-607.5 In order to
widen the scope of this method to another synthesis of nat-
ural product, we have investigated a stereocontrolled syn-
thesis of methyl (–)-nonactate 15. Herein we report our
results.
OH
OH
1
1
CO2H
CO2H
O
O
8
8
6
3
6
3
(-)-2
(+)-2
Figure 1 Nonactin and nonactic acids
appointingly, only a 4:1 separable mixture of cis- and
trans-tetrahydrofuran was gained at –20 °C and when tol-
uene was used as a solvent the cis:trans ratio increased to
6.5:1. As a matter of course, to check the utility of this
method, basic studies using bases such as sodium bicar-
bonate and potassium carbonate instead of silver carbon-
ate were executed in various solvents and these induced
decrease of reaction rate and stereoselectivity.
As the stereochemical outcome of the cyclization of cis-
olefin 7 fell short of our expectation, we now focused on
the considerable influence of the olefin geometry on the
cyclization stereochemistry.4,8 So, isomerization of cis-
olefin 7 was carried out using thiophenol and AIBN in tol-
uene at 80 °C to give a 4:1 inseparable mixture of trans-
and cis-olefins. Iodoetherification of this mixture was per-
formed in the presence of silver carbonate and the
cis:trans ratio increased up to 10:1.
For the synthesis of methyl (–)-nonactate 15, the known
alcohol 3 (62% de)6 was silylated with chlorotriethylsi-
lane to afford 4 which was separable from its diastereomer
(Scheme 1). Olefin 4 was subjected to hydroboration and
the resulting alcohol 5 was transformed into phosphonium
salt 6 via the routine iodide formation. Wittig olefination
of phosphonium salt 6 and (S)-2-benzyloxypropanal7 was
performed with n-BuLi in THF and HMPA to give (Z)-g-
triethylsilyloxyalkene 7. For the preparation of cis-2,5-
disubstituted tetrahydrofuran 8, iodocyclization of 7 was
carried out with iodine in the presence of silver carbonate
in diethyl ether using the same method as reported.5a Dis-
Therefore, it was necessary that cyclization of pure trans-
olefin 13 should be attempted, and sulfone olefination was
executed (Scheme 2). Alcohol 5 was transformed into
benzothiazole sulfone and 1-phenyl-1H-tetrazole sulfone
via Mitsunobu reaction and oxidation, and the coupling
reactions of each sulfone and (S)-2-benzyloxypropanal
were performed.9 But only 1:1 mixture of trans- and cis-
olefins was gained. Accordingly, olefination using phenyl
sulfone was carried out. The hydroxyl group of 5 was con-
verted into sulfide using phenyl disulfide and tribu-
tylphosphine, and the subsequent oxidation with m-CPBA
Synlett 2003, No. 3, Print: 19 02 2003.
Art Id.1437-2096,E;2002,0,02,0393,0395,ftx,en;U13002ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

394
J. W. Jeong et al.
LETTER
OH
OTES
OTES
a
b
HO
OTBS
OTBS
OTBS
3
4
5
TESO
OTBS
OTES
c,d
e
-I +Ph3P
OTBS
OBn
7
6
OBn
OBn
f,g
OTBS
OTBS
O
O
+
8
9
Scheme 1 Reagents and conditions: (a) TESCl, imidazole, CH2Cl2, r.t., 79% of desired diastereomer; (b) H3B·SMe2, THF, r.t., then aq NaOH,
H2O2, r.t., 81%; (c) PPh3, I2, imidazole, THF, r.t.; (d) PPh3, K2CO3, CH3CN, 90 °C, 92% (2 steps); (e) n-BuLi, THF, HMPA, –10 °C, then (S)-
2-benzyloxypropanal, –78 °C to 0 °C, 68%; (f) I2, Ag2CO3, PhMe, –20 °C; (g) Bu3SnH, Et3B, THF, r.t., 91% (2 steps).
gave sulfone 10 as the coupling partner of (S)-2- product without any detectable trans-tetrahydrofuran. In
benzyloxypropanal. The coupling reaction was carried out case the reaction was carried out in toluene, only the de-
using LDA and successive acetylation furnished b-ace- sired cis-2,5-disubstituted tetrahydrofuran was obtained
toxysulfones 11. Olefination of 11 using 5% sodium in 91% yield. Reductive deiodination of the cyclized
amalgam provided a 4.5:1 inseparable mixture of trans- product furnished 8,10 the stereochemistry of which was
and cis-alkenes 12. Because the isomerization of cis-al- confirmed by the NOE experiments between H-3 and H-6
kene 7 was not good on large scale, we selected this strat- (4.0% enhancement from the cis relationship).
egy for the preparation of the trans-alkene 13. After
detriethylsilylation of a mixture 12, trans- and cis-g-hy-
droxyalkene were separated and silylated to afford g-tri-
ethylsilyloxyalkene. Iodoetherification of trans-alkene 13
was performed with iodine in the presence of silver car-
bonate in ether at –20 °C to give a mixture of cis-2,5-
disubstituted tetrahydrofuran and its TBS deprotected
Then the reason why the olefin geometry affects the
stereoselectivity can be explained as follows. The olefin
can be attacked by I+ on either face to give p complexes,
which form reversibly. So, the diastereofacial selectivity
of the process is dependent upon the relative abundances
and reactivities of the complexes. It is thought that the
conformational preference of both 16 and 17 to position
OAc
OTES
OTES
OTES
c,d
a,b
HO
PhO2S
OTBS
OTBS
OTBS
TESO
OBn SO2Ph
5
10
11
OBn
OBn
e
f,g
TESO
OTBS
OTBS
H
12
13
OBn
OBn
OH
1
h,i
j
k,l
OTBS
CO2H
CO2Me
O
O
O
8
6
3
8
14
15
Scheme 2 Reagents and conditions: (a) (PhS)2, Bu3P, CH2Cl2, r.t., 92%; (b) m-CPBA, NaHCO3, CH2Cl2, r.t., 83%; (c) LDA, THF, 0 °C, then
(S)-2-benzyloxypropanal, 0 °C, 82%; (d) Ac2O, DMAP, Et3N, r.t., 88%; (e) 5% Na/Hg, NaH2PO4, MeOH, –20 °C, 82%; (f) PPTS, MeOH, 0
°C, 75% for trans-olefin; (g) TESCl, imidazole, CH2Cl2, r.t., 96%; (h) I2, Ag2CO3, PhMe, –20 °C, 4 h, 91%; (i) Bu3SnH, Et3B, THF, r.t., 96%;
(j) KF, Jones reagent, acetone, 0 °C, 91%; (k) ClCO2CH3, DMAP, Et3N, CH2Cl2, 0 °C, 90%; (l) H2, 10% Pd/C, MeOH, r.t., 94%.
Synlett 2003, No. 3, 393–395 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Stereocontrolled Synthesis of Methyl (–)-Nonactate
395
Me
H
Acknowledgement
R
H
O
H
This work was supported by the Center for Biological Modulators
(21C Frontier R & D Program).
H
BnO
SiEt3
..
I+
References
16 trans, H in plane
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I+
R
H
BnO
Me
O
H
H
H
SiEt3
17 cis, H in plane
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Figure 2
the benzyloxy group as a directing group syn to I+ arises
because of stabilizing interaction between the positive
charge and the oxygen lone pair electrons (Figure 2). On
the basis of the Bartlett’s theory, the steric bulk of the O-
protecting group and its electrofugal properties are the
main factors which induce the desired cis-1,3 stereorela-
tionship via two transient trans-1,2 relationships.4a In the
case of cis-olefin 17 the direction of attack by I+ cause the
formation of trans-tetrahydrofuran and this result does not
correspond with the Bartlett’s theory and the mixture was
produced by equilibration. Next, TBS protected hydroxyl
group of 8 was oxidized11 using Jones reagent in the pres-
ence of potassium fluoride to give acid 14 which will be a
key intermediate for a synthesis of nonactin via coupling
with (+)-nonactic acid subunit. For the identification of
14, it was esterified using methyl chloroformate and the
resulting methyl ester was debenzylated with 10% palla-
dium on charcoal under hydrogen atmosphere to furnish
methyl (–)-nonactate 15 ([a]D23 = –14.0, c = 1.20, CHCl3).
Its spectral data were identical with those of the report-
ed.12
(9) (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O.
Tetrahedron Lett. 1991, 32, 1175. (b) Blakemore, P. R.;
Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998, 26.
(10) Spectral data for 8: 1H NMR (300 MHz, CDCl3): d = 7.34–
7.22 (5 H, m), 4.59 (1 H, d, J = 11.6 Hz), 4.47 (1 H, d, J =
11.6 Hz), 4.05–3.95 (1 H, m), 3.78–3.72 (2 H, m), 3.70–3.63
(1 H, m), 3.48 (1 H, dd, J = 9.8 Hz, 6.9 Hz), 1.99–1.82 (2 H,
m), 1.78–1.42 (5 H, m), 1.24 (3 H, d, J = 6.2 Hz), 0.89 (9 H,
s), 0.88 (3 H, d, J = 6.8 Hz), 0.04 (6 H, s); 13C NMR (75
MHz, CDCl3) δ 139.1, 128.3, 127.7, 127.3, 80.5, 76.0, 73.1,
70.7, 65.7, 44.0, 41.3, 31.6, 28.6, 25.9, 20.4, 18.3, 13.1, –5.4;
In conclusion, a stereocontrolled synthesis of methyl (–)-
nonactate 15 has been established using intramolecular
iodoetherification of (E)-g-triethylsilyloxyalkene in the
presence of silver carbonate and it was shown that the
geometry of olefin affected the stereoselectivity of iodo-
etherification greatly. Based on this result, further studies
for a total synthesis of nonactin are now in progress in our
laboratory.
IR (neat) 1251, 1070, 1028, 1006, 834 cm–1; HRMS (EI)
23
calcd for C23H40O5Si: 392.2747, found: 392.2748; [a]D
+23.0, c = 1.00, CHCl3.
=
(11) Liu, H.-J.; Han, I.-S. Synth. Commun. 1985, 15, 759.
(12) Takatori, K.; Tanaka, N.; Tanaka, K.; Kajiwara, M.
Heterocycles 1993, 36, 1489.
Synlett 2003, No. 3, 393–395 ISSN 0936-5214 © Thieme Stuttgart · New York