Palladium(II)-catalyzed stereocontrolled cyclization via hemiacetal intermediates: Total synthesis of 5-epi-prelactone C

Article abstract of DOI:10.3987/COM-04-10034

Palladium(II)-catalyzed cyclization of 3,7-dihydroxy-4-methyl-5-octenal derivative was carried out to give 2,3,4,6-tetrasubstituted tetrahydropyran with stereoselective 1,3-chirality transfer in net retention of stereochemistry. The cyclized product was c

Full text of DOI:10.3987/COM-04-10034

HETEROCYCLES, Vol. 63, No. 5, 2004, pp. 1017 - 1021
Received, 12th February, 2004, Accepted, 2nd March, 2004, Published online, 8th March, 2004
PALLADIUM(II)-CATALYZED STEREOCONTROLLED CYCLIZATION
VIA HEMIACETAL INTERMEDIATES: TOTAL SYNTHESIS OF
5-EPI-PRELACTONE C
Masahiro Miyazawa, Magsarjav Narantsetseg, Hajime Yokoyama, Seiji
Yamaguchi, and Yoshiro Hirai*
Department of Chemistry, Toyama University, 3190 Gofuku, Toyama 930-8555,
Japan; e-mail: miyazawa@sci.toyama-u.ac.jp
Abstract – Palladium(II)-catalyzed cyclization of 3,7-dihydroxy-4-methyl-5-
octenal derivative was carried out to give 2,3,4,6-tetrasubstituted tetrahydropyran
with stereoselective 1,3-chirality transfer in net retention of stereochemistry. The
cyclized product was converted into 5-epi-prelactone C.
The polysubstituted δ-lactone structure can be found in many natural products, particularly polyketide
macrolide producing microorganisms. It is a very important to develop synthetic methodology for the
stereoselective construction of the δ-lactone structure, so many synthetic methods have been reported.1
We have reported an intramolecular substitution of an allylic alcohol by a heteroatom using a palladium
catalyst without activation of the allylic alcohol.2 And we recently developed a cyclization via a
hemiacetal intermediate using a palladium catalyst and found a stereoselective method for construction of
trisubstituted tetrahydropyran (Scheme 1).3 In connection with the palladium-catalyzed heterocyclization,
we applied the method to synthesis of a natural product having a δ-lactone structure.
OiPr
CHO
PdCl2(PhCN)2
O
i-PrOH, THF
Ph
OTHP
Ph
rt
1
2
Scheme 1
We planned the synthesis of (+)-prelactone C,4 which comprises an important class of highly
functionalized chiral δ-lactones and was isolated from the concanamycin-producing Streptomyces sp.5

Our retrosynthetic analysis of (+)-prelactone C (3) is shown in Scheme 2. Prelactone C would be
synthesized via oxidation of the hemiacetal (4a) (R = H) which might be prepared from the acetal (4b) (R
= Me) through an acidic treatment. The construction of 4b could be achieved by the palladium-catalyzed
heterocyclization of the aldehyde (5) derived from ketone (6) (X = Me) through an asymmetric reduction
of the carbonyl group. The syn silyl ether (6) having the C3 and C4 stereogenic centers was readily
obtainable by using the stereospecific methylation reaction of the γ,δ-epoxyacrylate (7) with
trimethylaluminum in the presence of water.6 The chiral epoxyacrylate (7) was readily accessible from the
cis-5-t-butyldimethylsilyloxy-2-penten-1-ol via the Katsuki-Sharpless asymmetric epoxidation7 followed
by a Wittig reaction.
OH
ODPS
OH
ODPS
CHO
*
1
5
8
O
O
O
OR
5
4a : R = H
4b : R = Me
3
O
ODPS
O
4
3
X
OTBS
EtO2C
OTBS
Scheme 2
7
6
First, the syn alcohol (6) (X = OEt) was prepared (Scheme 3). Protection of propargyl alcohol (NaH,
BnBr, 83% yield) furnished the benzyl ether (9). Treatment of 9 with n-BuLi and ethylene oxide and
protection of the resulting alcohol (TBSCl) afforded the TBS ether (10) (61% yield, two steps). Catalytic
hydrogenation of the triple bond with Lindlar catalyst followed by removal of the benzyl group gave the
Z-allylic alcohol (11) (79% yield, two steps). The allylic alcohol (11) was subjected to Katsuki-Sharpless
asymmetric epoxidation with (+)-DET resulting in formation of the α-epoxide (12) in 84% yield and 97%
ee.8
d,e
b,c
a
BnO
HO
HO
BnO
OTBS
79%
61%
OTBS
O
83%
8
9
10
11
OH
O
g,h
f
i
7
HO
EtO
OTBS
84%
92%
78%
OTBS
12
13
Scheme 3. Reagents and conditions: (a) BnBr, NaH, THF; (b) BuLi, ethylene oxide, THF; (c) TBSCl,
imidazole, DMF; (d) H2, 5% Pd/CaCO3, EtOH; (e) Na / NH3, THF; (f) (+)-DET, Ti(Oi-Pr)4, TBHP,
CH2Cl2, -20 oC; (g) (COCl)2, DMSO, CH2Cl2 then Et3N; (h) (EtO)2POCH2CO2Et, NaH, THF; (i) Me3Al,
H2O, CH2Cl2, -30 oC.
The Swern oxidation of the epoxy alcohol (12) ((COCl)2, DMSO then Et3N) followed by the
Horner-Emmons reaction of the resulting aldehyde furnished the trans-γ,δ-epoxyacrylate (7) (78% yield,

two steps). Methylation of 7 with Me3Al (10 equiv.) cleanly proceeded in the presence of water (6 equiv.)
giving the syn compound (13) as the sole product in 92% yield.
Protection of the hydroxy group (13) (TBDPSCl), reduction of the ester (DIBAL-H), and the Swern
oxidation of the resulting alcohol afforded the enal (14) (62% yield, three steps). 1,2-Addition of the enal
(14) with MeMgI furnished the alcohol (15) (95% yield). The diastereoselectivity of the addition was 1 :
1.
OH
ODPS
O
ODPS
a,b,c
62%
d
13
OTBS
H
OTBS
95%
14
15
Scheme 4. Reagents and conditions: (a) TBDPSCl, Et3N, DMAP; (b) DIBAL-H, THF; (c) (COCl)2,
DMSO, CH2Cl2 then Et3N; (d) MeMgI, THF
The absolute configuration of the C-7 position is crucial to induce the desired stereochemistry on the
newly formed C-O bond in the cyclized product (4), so stereoselective construction at the C-7 position is
indispensable. We planned oxidation of the alcohols (15) to the ketone (16), and then the ketone (16) was
stereoselectively reduced to give a diastereometically pure alcohol (17). Oxidation of the alcohols (15)
gave the ketone (16) in a quantitative yield. Asymmetric reduction of the enone (16) was initially
performed with (S)-BINAL-H9 but, somewhat surprisingly, the reduction afforded a mixture of
diastereomeric alcohols (17a) and (17b) (3:2, by 1H NMR). This problem could be overcome by changing
the reducing reagent. When 16 was submitted to reduction with (R)-Me-CBS / BMS in CH2Cl2, 17a was
obtained in good yield (96%) and good diastereoselectivity (17a:17b = 10:1).10
O
ODPS
OH
ODPS
OH
ODPS
[H-]
+
OTBS
OTBS
OTBS
16
17a
17b
Scheme 5
The cyclized precursor (20) was prepared from the alcohol (17a). Protection of the hydroxy group (17a)
(DHP, p-TsOH) afforded the THP ether (18) (88% yield). Selective deprotection of the TBS group (HF･
Py in THF) gave the alcohol (19) (62% yield). Finally, IBX oxidation of 19 furnished the aldehyde (20).11
OTHP
ODPS
OTHP
ODPS
CHO
OTHP
ODPS
c
b
a
17a
OTBS
OH
62%
88%
87%
20
19
18
Scheme 6. Reagents and conditions: (a) DHP, p-TsOH, CH2Cl2; (b) HF•Py, THF; (c) IBX, DMSO, THF
Treatment of the aldehyde (20) with 10 mol% of PdCl2(PhCN)2 catalyst and 2.2 equiv. of MeOH in THF
furnished the cyclized products (21) in 80% yield as a mixture of acetals.
ODPS
OTHP
ODPS
CHO
PdCl2(PhCN)2
MeOH, THF
80%
Scheme 7
O
21
OMe
20

We proposed the stereochemistry of 21 to lead it to the lactone (23). Treatment of 21 under acidic
o
condition (55% AcOH, 70 C) followed by IBX oxidation of the resulting hemiacetals afforded the
lactone (22) (61% yield, two steps). Removal of the DPS group with TBAF gave only 25% to 23 and
70% to β-eliminated product (24). Treatment of 22 with HF･Py furnished the alcohol (23) in good yield
(78%).
OH
ODPS
c
a,b
+
21
61%
O
O
O
O
O
O
22
23
24
Scheme 8. Reagents and conditions: (a) 55% AcOH, 70 oC; (b) IBX, DMSO, THF; (c) HF•Py, THF
1
The relative stereochemistry of 23 was established by the coupling constant of its H NMR spectrum.
Surprisingly, the spectra of the obtained compound (23)12 were not found to be identical to those of
natural (+)-prelactone C (Figure 1).
H
5.9
H
5.8
CH
O
10.4
3
H
O
H
O
8
H
CH
H
CH
3
3
O
OH
4.4
H
OH
H
H
H
7
5.5
3.3
5-epi-prelactone C (23)
prelactone C (3)
Figure 1 H-H Couping constants (Hz) of 23 and 3.
This was not entirely unexpected, as 23 was an epimer at the C-5 position of prelactone C. Our previous
results demonstrated that palladium(II)-catalyzed cyclization reaction proceeded stereoselectively with
net inversion of configuration.2 Extension of this methodology to the asymmetric synthesis of
(+)-prelactone C is currently being carried out in our laboratories.
In summary, we have demonstrated that intramolecular cyclization via a hemiacetal intermediate by using
a palladium(II)-catalyst proceeds stereoselectively with net retention of configuration, and we have
completed the synthesis of 5-epi-prelactone C.
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1
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1
12. 5-epi-Prelactone C (23): [α]25 –86.6o (c 0.5, MeOH); H-NMR (CDCl3, 600 MHz) δ : 5.83 (1H,
D
ddq, J = 15.4, 1.1, 6.6 Hz), 5.50 (1H, ddq, J = 15.4, 7.0, 1.7 Hz), 5.10 (1H, dd, J = 7.0, 3.3 Hz), 4.03
(1H, q, J = 5.3 Hz), 2.89 (1H, dd, J = 18.3, 5.9 Hz), 2.53 (1H, ddd, J = 18.3, 4.4, 0.7 Hz), 1.99 (1H,
ddq, J = 5.5, 3.3, 7.3 Hz), 1.75 (3H, dd, J = 6.6, 1.7 Hz), 0.99 (3H, d, J = 7.3 Hz); 13C-NMR (CDCl3,
150 MHz) δ : 170.48, 130.42, 126.00, 79.42, 67.82, 38.77, 36.50, 17.80, 11.00; IR (neat) : 3421,
2968, 2921, 1716, 1455, 1367, 1244, 1059, 968, 707 cm-1; EIMS m/z (%): 170 (2) M+, 152 (11);
FABMS m/z (%): 171 (12, M++H).