PAPER
Synthesis of the Enantiomers of 4-epi-SS20846A
3691
[α]D22 –58.7 (c 0.84, CHCl3).
13C NMR (100.4 MHz, CDCl3): δ = 156.2 (s), 130.8 (d), 130.3 (d),
130.2 (d), 129.6 (d), 64.7 (d), 52.6 (q), 50.7 (d), 36.4 (t), 34.2 (t),
31.9 (t), 18.1 (q).
ESI-MS: m/z (%) = 225 (15) [M+], 224 (13), 206 (66), 191 (85), 148
(100).
1H NMR (400 MHz, CDCl3): δ = 7.01 (dd, J = 14.4, 7.6 Hz, 1 H),
6.16 (d, J = 14.4 Hz, 1 H), 4.75–4.68 (br m, 1 H), 4.24–4.21 (m, 1
H), 3.89 (br d, J = 12.7 Hz, 1 H), 3.69 (s, 3 H), 3.33 (td, J = 12.9,
2.9 Hz, 1 H), 1.88–1.78 (m, 2 H), 1.73–1.58 (m, 2 H), 1.08 (s, 21 H).
13C NMR (100.4 MHz, CDCl3): δ = 156.0 (s), 145.7 (d), 76.5 (d),
64.5 (d), 54.2 (q), 52.7 (d), 36.7 (t), 34.6 (t), 32.7 (t), 18.2 (q, 3 C),
18.1 (q, 3 C), 12.2 (d, 3 C).
ESI-MS: m/z (%) = 467 (5) [M+], 424 (55), 340 (32), 214 (41), 145
(100).
Anal. Calcd for C12H19NO3: C, 63.98; H, 8.50; N, 6.22. Found: C,
64.15; H, 8.31; N, 6.07.
(E,Z)-18
1H NMR (400 MHz, CDCl3): δ = 6.40 (ddt, J = 15.4, 10.9, 1.4 Hz,
1 H), 6.04–5.92 (m, 2 H), 5.53–5.44 (m, 1 H), 4.91–4.83 (m, 1 H),
4.20–4.15 (m, 1 H), 3.97–3.91 (m, 1 H), 3.71 (s, 3 H), 3.36–3.28 (m,
1 H), 1.99–1.87 (m, 2 H), 1.74 (dd, J = 7.2, 1.6 Hz, 3 H), 1.72–1.69
(m, 2 H).
Anal. Calcd for C18H34INO3Si: C, 46.25; H, 7.33; N, 3.00. Found:
C, 46.11; H, 7.24; N, 2.87.
Methyl (2S,4R)-2-(Penta-1,3-dienyl)-4-(triisopropylsilyloxy)pi-
peridine-1-carboxylate (17)
(2S,4R)-2-[(E,E)-Penta-1,3-dienyl]piperidin-4-ol (1)4a
A soln of the Pd/SPhos catalyst was prepared by mixing Pd(OAc)2
(5.90 mg, 0.026 mmol) and SPhos (21.6 mg, 0.052 mmol) in anhyd
toluene (1.5 mL). The resulting solution was stirred at r.t. for 45 min
and used in the Suzuki reaction, as follows. Vinyl iodide 16 (247
mg, 0.53 mmol) and trans-1-propenylboronic acid MIDA ester (197
mg, 1.0 mmol) were dissolved in anhyd THF (30 mL) and the cata-
lyst soln (1.5 mL, 0.026 mmol Pd, 5% mol Pd) was added dropwise,
followed by degassed 1 M NaOH (5 mL), under vigorous stirring.
The mixture was heated at 50 °C for 5.5 h, then cooled to r.t. EtOAc
(70 mL) was added and the organic phase was washed once with
H2O (30 mL), dried over Na2SO4 and filtered, and the solvent was
evaporated to obtain crude 17. Purification by flash chromatogra-
phy (n-hexane–EtOAc, 12:1; Rf = 0.15) gave compound 17 as a 4:1
mixture of the E,E- and E,Z-isomers as a colorless oil; yield: 198 mg
(98%).
1H NMR (400 MHz, CDCl3): δ = 6.33 (dd, J = 15.2, 10.9 Hz, 1 H,
E,Z), 6.13 (dd, J = 15.2, 7.4 Hz, 1 H, E,Z), 6.02–5.93 (m, 3 H, E,E
and 1 H, E,Z), 5.66–5.58 (m, 1 H, E,E), 5.45–5.40 (m, 1 H, E,Z),
4.83–4.76 (m, 1 H, E,Z), 4.76–4.69 (m, 1 H, E,E), 4.24–4.21 (m, 1
H), 3.93–3.82 (m, 1 H), 3.70 (s, 3 H, E,Z), 3.68 (s, 3 H, E,E), 3.42–
3.32 (m, 1 H), 1.88–1.81 (m, 2 H), 1.73 (d, J = 6.6 Hz, 3 H, E,E),
1.72 (d, J = 7.0 Hz, 3 H, E,Z), 1.69–1.66 (m, 2 H, E,E), 1.65–1.63
(m, 2 H, E,Z), 1.06 (s, 21 H, E,E), 1.05 (s, 21 H, E,Z).
Carbamate 18 (80 mg, 0.36 mmol) was dissolved in 20% aq MeOH
(6 mL) and finely ground KOH (202 mg, 3.6 mmol) was added. The
resulting yellowish solution was refluxed for 5 d (TLC monitoring),
with the addition of fresh powdered KOH (10 equiv) every 24 h.
The mixture was cooled and the solvent was removed under re-
duced pressure. H2O (5 mL) was added to the residue and the mix-
ture was extracted with CHCl3 (5 × 5 mL). The combined organic
phases were dried over Na2SO4, filtered and the solvent was evapo-
rated to obtain crude 1. Purification on a short silica gel pad
(MeOH–EtOAc, 3:2 + 1% NH4OH; Rf = 0.19) afforded pure, final
compound 1 as a white solid; mp 65.5–67.0 °C; yield: 58 mg (97%).
[α]D24 –36.7 (c 0.30, CHCl3) {Lit.4a [α]D25 –37.0 (c 1.0, CHCl3)}.
1H NMR (400 MHz, CDCl3): δ = 6.16 (dd, J = 15.0, 10.3 Hz, 1 H),
6.02 (ddd, J = 15.0, 10.3, 1.4 Hz, 1 H), 5.73–5.64 (m, 1 H), 5.55 (dd,
J = 15.0, 6.4 Hz, 1 H), 3.72–3.64 (m, 1 H), 3.21–3.11 (m, 2 H), 2.69
(td, J = 12.7, 2.5 Hz, 1 H), 2.05–1.93 (m, 2 H), 1.85–1.65 (br s, 2
H), 1.75 (d, J = 5.5 Hz, 3 H), 1.40 (qd, J = 13.1, 4.3 Hz, 1 H), 1.29–
1.20 (m, 1 H).
Acknowledgment
Dr. Maurizio Passaponti is acknowledged for technical assistance,
and Ente Cassa di Risparmio di Firenze for granting a 400-MHz
NMR spectrometer.
13C NMR (100.4 MHz, CDCl3): δ = 156.1 (s), 133.6 (d, E,Z), 131.2
(d, E,E), 131.1 (d, E,E), 129.6 (d, E,E), 129.1 (d, E,Z), 128.5 (d,
E,E), 125.5 (d, E,Z), 124.5 (d, E,Z), 64.9 (d), 52.5 (q), 52.0 (d, E,Z),
51.8 (d, E,E), 37.4 (t, E,Z), 37.3 (t, E,E), 34.6 (t, E,Z), 34.5 (t, E,E),
33.0 (t), 18.1 (q, 6 C), 18.0 (q), 12.2 (d, 3 C).
Supporting Information for this article is available online at
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ESI-MS: m/z (%) = 381 (7) [M+], 270 (78), 207 (85), 192 (100).
Methyl (2S,4R)-4-Hydroxy-2-[(E,E)-penta-1,3-dienyl]piperi-
dine-1-carboxylate (18)
References
A 1.0 M TBAF in THF soln (0.83 mL, 0.83 mmol) was added to a
soln of compound 17 (198 mg, 0.52 mmol) in anhyd THF (40 mL)
and the resulting mixture was stirred at r.t. for 8.5 h. The solvent
was evaporated and the residue was purified by flash chromatogra-
phy (n-hexane–EtOAc, 1.1; Rf = 0.21) to give compound 18 as a 4:1
mixture of the E,E- and E,Z-isomers as a colorless oil; yield: 114 mg
(97%). The isomers were separated by argentation (silver ion)
chromatography19 (CH2Cl2–MeOH, 75:1) to obtain pure (E,E)-18
(82 mg, 70%) and (E,Z)-18 (19 mg), the latter together with an un-
identified impurity.
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(E,E)-18
[α]D25 –36.2 (c 0.57, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 6.09–6.00 (m, 2 H), 5.82 (dd,
J = 14.1, 5.9 Hz, 1 H), 5.73–5.63 (m, 1 H), 4.85–4.78 (m, 1 H),
4.18–4.13 (m, 1 H), 3.93 (dt, J = 13.6, 3.6 Hz, 1 H), 3.70 (s, 3 H),
3.35–3.23 (m, 1 H), 1.96–1.84 (m, 2 H), 1.74 (d, J = 6.2 Hz, 3 H),
1.72–1.68 (m, 2 H).
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3688–3692