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DOI: 10.1055/s-0029-1219839
Stereoselective Synthesis of (-)-PF1163A via Prins Cyclization
Publication History
Publication Date:
16 April 2010 (online)
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Abstract
A highly stereoselective and convergent total synthesis of PF1163 A is described while proving the versatility of Prins cyclization in natural product synthesis. The Prins cyclization, Yamaguchi esterification, and ring-closing metathesis reactions are the key steps utilized in the synthesis of macrolactone.
Keywords
(-)-PF1163A - 13-membered macrolactone - Prins cyclization - ring-closing metathesis
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1a
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References
Aldehyde 9 was prepared from (R)-citronellol in two steps in 76% overall yield as shown in Scheme [4] .
![](https://www.thieme-connect.de/media/synlett/201008/d361_s4.gif)
Scheme 4
{(2
S
,4
R
)-6-[(
R
)-5-(Benzyloxy)-3-methylpentyl]-tetrahydro-4-(methoxymethoxy)-2
H
-pyran-2-yl} Methyl 4-Methylbenzenesulfonate (10)
To a stirred solution of
alcohol 9 (1.8 g, 3.78 mmol) in anhyd CH2Cl2 (20
mL) at 0 ˚C were added DIPEA (1.31 mL, 7.56 mmol),
DMAP (cat.) and MOMCl (0.91 g, 11.34 mmol) successively, the resulting
mixture was stirred for 3 h at r.t. and then quenched by adding
H2O (10 mL) and extracted with CH2Cl2 (3 Ž 20
mL). The organic extracts were washed with brine (10 mL), dried
over anhyd Na2SO4, and concentrated under
reduced pressure to remove the solvent, and the crude residue was
purified by column chromatography to afford the pure product 10 as a liquid (1.80 g, 92%). R
f
= 0.7
(SiO2, 10% EtOAc in hexane); clear oil; R
f
= 0.5
(EtOAc-hexane, 3:7). [α]D
²0 -2.6
(c 1.15, CHCl3). ¹H
NMR (300 MHz, CDCl3): δ = 7.82-7.76
(m, 2 H), 7.38-7.22 (m, 7 H), 4.66 (s, 2 H), 4.49 (s, 2
H), 4.14-3.92 (m, 2 H), 3.73-3.61 (m, 1 H), 3.59-3.43
(m, 3 H), 3.35 (s, 3 H), 3.25-3.14 (m, 1 H), 2.43 (s, 3
H), 1.98-1.88 (dd, 2 H, J = 9.4,
2.8 Hz), 1.78-1.01 (m, 10 H), 0.87 (d, 3 H, J = 6.4 Hz). ¹³C
NMR (75 MHz, CDCl3): δ = 144.6,
138.6, 132.9, 129.7, 128.3, 127.9, 127.5, 127.4, 94.3, 76.1, 72.8,
72.5, 72.4, 72.0, 68.5, 55.2, 38.0, 36.6, 34.4, 33.1, 32.5, 29.8,
21.5, 19.5. IR (KBr): νmax = 2922,
2852, 1456, 1362, 1037, 979 cm-¹. ESI-MS: m/z = 521 [M+ + H],
543 [M+ + Na].
(4
S
,6
S
,9
R
)-4-(Methoxymethoxy)-9-methyldodec-11-en-6-ol (16)
To a stirred soln of 15 (0.8 g, 2.15 mmol) in anhyd THF (8 mL),
TBAF (4.3 mL, 4.3 mmol) was added, and the mixture was stirred at
0 ˚C for 2 h. The reaction mixture was quenched
with H2O (5 mL) and extracted with EtOAc (2 × 5 mL),
and the combined organic layers washed with brine (10 mL), dried
over anhyd Na2SO4, and concentrated under reduced
pressure to remove the solvent. The crude residue was then purified
by column chromatography on silica gel (EtOAc-hexane, 1:9)
to afford 16 as a white solid; yield 0.46 g
(83%); clear oil; R
f
= 0.4
(EtOAc-hexane, 2:8); [α]D
²0 +12.1
(c 0.9, CHCl3). ¹H
NMR (300 MHz, CDCl3): δ = 5.85-5.70
(m, 1 H), 5.05-4.94 (m, 2 H), 4.76-4.62 (m, 2 H),
3.90-3.76 (m, 2 H), 3.40 (s, 2 H), 2.13-2.02 (m,
1 H), 1.96-1.84 (m, 1 H), 1.68-1.08 (m, 10 H),
0.99-0.84 (m, 6 H). ¹³C NMR
(75 MHz, CDCl3): δ = 137.5,
115.5, 96.2, 75.9, 68.2, 55.8, 41.2, 41.1, 37.0, 34.9, 32.9, 32.4,
19.4, 18.7, 14.1. IR (KBr): νmax = 3453,
2930, 1459, 1376, 1038, 911 cm-¹. ESI-MS: m/z = 281 [M+ + Na].
(2
S
)-(4
S
,6
S
,9
R
)-4-(Methoxymethoxy)-9-methyldodec-11-en-6-yl
3-{4-[2-(benzyloxy)ethoxy]phenyl}-2-(
N
-Methylbut-3-enamido)
Propanoate (19)
To a stirred
solution of N-Boc-deprotected amine (200
mg, 0.35 mmol) in anhyd CH2Cl2 (12 mL) was
added carboxylic acid fragment B (33 mg,
0.38 mmol) and then HOBt (4 mg, 0.035 mmol) followed by EDCI (201
mg, 1.05 mmol). The reaction was stirred for 6 h at r.t., quenched
with HCl (1 N, 15 mL), and diluted with Et2O (20 mL).
The aqueous layer was extracted with Et2O (20 mL), and
the resulting solution washed with brine (10 mL), dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was purified
by silica gel chromatography (EtOAc-hexane, 3:7) to afford
diene 2 as a colorless oil (160 mg, 75%). R
f
= 0.4 (EtOAc-hexane,
3:7); [α]D
²0 -9.3
(c 0.5,CHCl3). ¹H
NMR (300 MHz, CDCl3): δ = 7.36-7.23
(m, 5 H), 7.11-7.01 (m, 2 H), 6.86-6.77 (m, 2
H), 5.85-5.65 (m, 2 H), 5.35-5.27 (m, 1 H), 5.11-4.90
(m, 4 H), 4.64-4.44 (m, 4 H), 4.13-4.06 (m, 2 H),
3.82-3.76 (m, 2 H), 3.51-3.39 (m, 1 H), 3.36-3.18
(m, 4 H), 3.14-2.86 (m, 4 H), 2.82 (s, 3 H), 2.10-1.96
(m, 1 H), 1.94-1.80 (m, 1 H), 1.67-1.19 (m, 11
H), 0.95-0.82 (m, 6 H). ¹³C
NMR (75 MHz, CDCl3): δ = 171.1,
169.5, 157.6, 137.1, 131.0, 129.8, 129.1, 128.4, 127.7, 117.7, 115.9, 114.9,
114.6, 96.2, 74.5, 73.4, 72.8, 68.5, 67.3, 57.8, 55.8, 41.3, 39.2,
38.9, 37.4, 33.9, 32.7, 32.3, 31.6, 29.8, 19.4, 18.2, 14.3. IR (KBr): νmax = 2924,
2856, 1650, 1243, 1046 cm-¹. ESI-MS: m/z = 660 [M+ + Na].
(3
S
,10
R
,13
S
)-3-[4-(2-hydroxyethoxy)benzyl]-13-
S
-2-(methoxymethoxy)pentyl-4,10-dimethyl-1-oxa-4-azacyclotridecane-2,5-dione (21)
To solution of compound 20 (0.200 g, 0.328 mmol) in EtOAc (10 mL)
was added Pd/C 10% (50 mg) and the mixture stirred
under H2 atmosphere for 7 h. After completion, the reaction
mass was filtered through Celite, and the solvent was removed under
reduced pressure to give crude product 21.
Purification using column chromatog-raphy on silica gel (hexane-EtOAc,
4:1) gave pure product as a colorless solid (0.145 g, 85% yield); [α]D
²5 -48.5
(c 0.5, CHCl3). ¹H
NMR (300 MHz, CDCl3): δ = 7.22-7.07
(m, 2 H), 6.83 (d, 2 H, J = 8.5
Hz), 5.13-5.02 (m, 1 H), 4.66-4.39 (m, 2 H), 4.08-4.02
(m, 2 H), 3.97-3.90 (m, 2 H), 3.35 (s, 3 H), 3.23-3.11
(t, 1 H, J = 11.1
Hz), 3.07-2.91 (m, 3 H), 2.88-2.57 (m, 1 H), 2.26-2.07
(m, 1 H), 1.72-1.08 (m, 19 H), 0.92-0.89 (m, 2
H), 0.85 (t, 3 H, J = 6.8
Hz), 0.81 (d, 3 H, J = 6.2
Hz). ¹³C NMR (75 MHz, CDCl3): δ = 169.9, 130.2,
129.9, 114.8, 114.5, 75.4, 72.2, 69.0, 61.45, 55.7, 55.5, 39.0,
38.7, 37.3, 33.5, 33.3, 31.5, 30.1, 29.6, 25.1, 24.1, 20.5, 17.9,
14.2. IR (film): ν = 3437 (OH), 2926, 2869, 1728, 1636,
1512, 1247, 1038 cm-¹. ESI-MS: m/z = 544 [M + Na]+.
(3
S
,10
R
,13
S
)-3-[4-(2-hydroxyethoxy)benzyl]-13-[(
S
)-2-hydroxy
pentyl]-4,10-dimethyl-1-oxa-4-azacyclotridecane-2,5-dione [PF1163
A(1)]
To a stirred
solution of 21 (0.02 g, 0.03 mmol) in anhyd TFA-CH2Cl2 (1:5,
2 mL) was added at 0 ˚C, and the reaction mixture
was stirred for 2 h at r.t. The reaction mixture was quenched with
NaHCO3 (1 mL) and extracted with CH2Cl2 (2 × 2
mL), and the combined organic layers were washed with brine (2 mL),
dried (Na2SO4), and concentrated under reduced
pressure. The residue was purified by silica gel chromatography
(EtOAc-hexane, 3:7) to afford 1 as
a colorless oil (13 mg, 75%). R
f
= 0.4
(EtOAc-hexane, 7:3); [α]D
²0 -88.5
(c 1.0, MeOH). ¹H
NMR (200 MHz, CDCl3):
δ = 7.20-7.03
(m, 2 H), 6.84-6.75 (m, 2 H), 5.82-5.66 (m, 1 H),
5.14-4.91 (m, 1 H), 4.01 (s, 1 H), 3.90 (s, 1 H), 3.53-3.27 (m,
2 H), 3.01-2.80 (m, 3 H), 2.78-2.52 (m, 1 H),
2.38-2.24 (m, 1 H), 1.76-1.02 (m, 22 H), 0.91
(t, J = 7.8
Hz, 3 H), 0.82 (d, J = 7.8
Hz, 3 H). ¹³C NMR (75 MHz, CDCl3): δ = 173.9, 171.7,
157.4, 130.3, 128.8, 114.5, 73.2, 69.1, 66.6, 61.3, 56.0, 49.4,
42.1, 39.0, 33.9, 33.2, 29.7, 24.1, 20.7, 19.0, 14.0. IR (KBr): νmax = 3429,
2924, 2856, 1728, 1632, 1511, 1459, 1247 cm-¹.
ESI-HRMS: m/z [M + Na]+ calcd
for C27H43O6NNa: 500.2988; found:
500.2979.