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DOI: 10.1055/s-2008-1078270
Total Synthesis of Largazole
Publikationsverlauf
Publikationsdatum:
21. August 2008 (online)
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Abstract
The stereocontrolled total synthesis of largazole was accomplished, unambiguously confirming its structure. Key steps included the use of the Nagao thiazolidinethione auxiliary for a diastereoselective acetate aldol reaction, thiazoline-thiazole formation, and macrolactamization by use of the Mukaiyama reagent.
Key words
largazole - cyclodepsipeptide - total synthesis - antitumor - macrolactamization
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- Supporting Information
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References and Notes
Procedure for
the Preparation of Intermediate 13
(R)-3-Acetyl-4-isopropyl-1,3-thiazolidine-2-thione
(12, 821 mg, 4.0 mmol) was dissolved in
CH2Cl2 (10 mL), TiCl4 (751 mg,
4.0 mol) was added at 0 ˚C. After 5 min, the reaction was
brought to -78 ˚C, DIPEA (516 mg, 4.0
mmol) was added via a syringe over 10 min. The reaction was kept
at -78 ˚C for 2 h before aldehyde 11 (428.3
mg, 2.0 mmol) in CH2Cl2 (3 mL) was added dropwise.
Saturated NH4Cl (20 mL) was added to the reaction mixture
and CH2Cl2 (3 × 30 mL) was used for
extraction. The combined organic phases were dried over anhyd MgSO4 and
concentrated in vacuo to give the crude product, which was purified
by chromatogra-phy on SiO2, eluting with EtOAc-hexane
(1:8), to afford the desired compound 13 (692.1
mg, 83%) along with the minor isomer (53.2 mg, 6%).
Cyclodepsipeptide
20
[α]D
²0 17.5
(c 0.2, MeOH). ¹H
NMR (500 MHz, CDCl3): δ = 7.75 (s,
1 H), 7.18 (d, 1 H, J = 9.3
Hz), 6.50 (dd, 1 H, J = 2.7, 9.0
Hz), 5.88 (dd, 1 H, J = 6.9,
14.6 Hz), 5.65-5.71 (m, 1 H), 5.54 (dd, 1 H, J = 6.7, 15.5
Hz), 5.26 (dd, 1 H, J = 9.4,
17.6 Hz), 4.60 (dd, 1 H, J = 3.6,
9.4 Hz), 4.27 (dd, 1 H, J = 3.1, 17.6
Hz), 4.03 (d, 1 H, J = 11.3
Hz), 3.28 (t, 1 H, J = 10.5 Hz),
2.85 (dd, 1 H, J = 9.9,
16.3 Hz), 2.67-2.75 (m, 3 H), 2.37-2.46 (m, 2
H), 2.06-2.14 (m, 1 H), 1.86 (s, 3 H), 1.32 (s, 9 H), 0.68
(d, 3 H, J = 6.9
Hz), 0.53 (d, 3 H, J = 6.9
Hz). ¹³C NMR (125 MHz, CDCl3): δ = 173.5,
169.3, 168.8, 167.9, 164.5, 147.4, 132.8, 128.1, 124.1, 84.3, 71.9,
57.7, 47.8, 43.2, 41.0, 40.4, 39.4, 34.0, 31.8, 29.9, 24.1, 18.8,
16.6. ESI-MS: m/z (%) = 585.17
(100.0), 607.15 (88.8). ESI-HRMS: m/z calcd
for C25H37N4O4S4 [M + H]+:
585.1698; found [M + H]+:
585.1689.
Procedure for
the Synthesis of Largazole (1)
Compound 20 (9.9 mg, 0.02 mmol) was dissolved in degassed
THF-H2O (v/v = 4:1,
2 mL) and treated with n-Bu3P
(6.1 mg, 0.03 mmol) at r.t. for 6 h. The reaction solution was made
up to 50 mL with EtOAc and dried over anhyd Na2SO4.
The free thiol intermediate was obtained after removal of solvent
in vacuo. The thiol intermediate was then dissolved in CH2Cl2 (5
mL), DIPEA (21.9 mg, 0.17 mmol), and octanoyl chloride (22 mg, 0.136
mmol) was added at 0 ˚C followed by a catalytic quantity
of DMAP. The reaction mixture was stirred at r.t. for 10 min and
then quenched by sat. NaHCO3 (5 mL). CH2Cl2 (3 × 30
mL) was used for extraction. The combined organic phases were dried over
anhyd Na2SO4 and concentrated in vacuo to
give the crude product. Purification with chromatography on SiO2, using
EtOAc-hexane (2:1), provided the target molecule 1 (8.2 mg, 0.0132 mmol, 78%).
[α]D
²0 18.5
(c 0.2, MeOH). ¹H
NMR (500 MHz, CDCl3): δ = 7.76 (s,
1 H), 7.15 (d, 1 H, J = 9.3
Hz), 6.46 (dd, 1 H, J = 2.6, 9.5
Hz), 5.80-5.84 (m, 1 H), 5.65-5.68 (m, 1 H), 5.51
(dd, 1 H, J = 7.1,
15.5 Hz), 5.29 (dd, 1 H, J = 9.4,
17.6 Hz), 4.61 (dd, 1 H, J = 3.3,
9.2 Hz), 4.27 (dd, 1 H, J = 2.8,
17.6 Hz), 4.05 (d, 1 H, J = 11.3Hz),
3.28 (d, 1 H, J = 11.3
Hz), 2.90 (t, 2 H, J = 7.2
Hz), 2.86 (dd, 1 H, J = 10.5,
16.5 Hz), 2.68 (dd, 1 H, J = 2.0,
16.3 Hz), 2.53 (t, 2 H, J = 7.4
Hz), 2.29-2.33 (m, 2 H), 2.07-2.13 (m, 1 H), 1.87
(s, 3 H), 1.62-1.66 (m, 2 H), 1.25-1.30 (m, 8
H), 0.87 (t, 3 H, J = 6.8
Hz), 0.69 (d, 3 H, J = 7.0
Hz), 0.51 (d, 3 H, J = 7.1
Hz). ¹³C NMR (75 MHz, CDCl3): δ = 199.4,
173.5, 169.4, 168.9, 167.9, 164.6, 147.4, 132.7, 128.4, 124.2, 84.4,
72.1, 57.7, 44.1, 43.3, 41.1, 40.4, 34.2, 32.2, 31.6, 29.0, 28.9,
27.9, 25.6, 24.2, 22.6, 18.9, 16.6, 14.0. ESI-MS: m/z (%) = 623.23
(44.5) [M + H]+,
645.21 (100.0) [M + Na]+.
ESI-HRMS: m/z calcd for C29H43N4O5S3 [M + H]+:
623.2396; found: 623.2371 [M + H]+.