Denmark et al.
JOCArticle
Conclusion
2.42 (s, 3 H, ArylCH3), 2.17 (dd, J=18.2, 11.4 Hz, 1 H, HC(6)),
1.79 (dd, J=18.5, 2.3 Hz, 1 H, HC(6)), 1.70 (s, 3 H, H3C(20)),
0.35 (s, 3 H, H3CSi), 0.35 (s, 3 H, H3CSi); 13C NMR (126 MHz,
CDCl3) δ 199.1 (C(7)), 170.8 (CO2), 147.4 (C(100)), 143.8 (C(4)),
138.4 (C(10)), 136.3 (C(400)), 134.0 (C(800), C(1200)), 129.76
(C(300), C(500)), 129.6 (C(1000)), 128.4 (C(700)), 128.3 (C(900),
C(1100)), 127.4 (C(200), C(600)), 64.8 (C(2)), 52.5 (C(5)), 49.8
(OCH3), 47.5 (C(6)), 42.0 (C(3)), 21.8 (ArylCH3), 19.7 (C(20)), -
1.5 (SiCH3), -2.3 (SiCH3); IR (neat) νmax 2484 (w), 2954 (m),
1746 (s), 1722 (m), 1349 (s), 1162 (s), 1109 (s), 818 (m), 667 (s),
596 (s) cm-1; LRMS (CI) m/z 135.1 (29.5), 210.1 (46.1), 270.1
(16.2), 330.2 (39.5), 408.1 (21.6), 426.2 (32.6), 470.2 (10.2), 486.2
(100.0, [M þ H]þ); HRMS (CI, [M þ H]þ) m/z calcd 486.1770,
found 486.1767; TLC Rf 0.30 (silica gel, hexanes/EtOAc, 3/1,
UV); [R]D -22.3 (c = 0.5, EtOH).
The total syntheses of isodomoic acids G (1) and H (2)
have been achieved via a common intermediate, alkenylsi-
lane 26, and through an efficient sequence (12-step longest
linear sequence) that addressed three important synthetic
challenges. Key intermediate 17, a sensitive vinylglycine
derivative, was prepared in excellent yield under mild condi-
tions and without loss of enantiomeric purity. The rhodium-
catalyzed carbonylative silylcarbocyclization reaction of 17
with dimethylphenylsilane afforded a densely substituted
pyrrolidine 25 in good yield. A setback was encountered when
the core silanes 21 and 22 failed to undergo cross-coupling
with side-chain iodide 3, prompting the reversal the polarity,
which led to the discovery of a stereochemically divergent
desilylative iodination. The ability to invert the double-bond
configuration allowed us to expand the initial objective and
include isodomoic acid H (2) as a target molecule. In the
process of the optimizing the cross-coupling of alkenyl
iodide 29, an important insight was garnered for the cross-
coupling of base-sensitive substrates. The hydration level
was found critical to moderate the basicity of fluoride, thus
avoiding the substrate decomposition as well as catalyst
deactivation. Notably, the completion of this exercise was
accompanied with deepened knowledge of two underutilized
catalytic synthetic transformations, silylcarbocyclization
and silicon-based cross-coupling, in complex molecule
syntheses.
Preparation of Methyl (2S,3S,4Z)-1-[(4-Methylphenyl)sulfonyl]-
2-methoxycarbonyl-4-[(iodo)ethylidene]-3-pyrrolidineacetate (29).
In a flame-dried, 50-mL, round-bottomed flask equipped with a
magnetic stir bar and a gas inlet adaptor was dissolved 793.3 mg
(1.54 mmol) of 28 in 10 mL of CH2Cl2. To this solution was
added 499.7 mg (3.08 mmol, 2.0 equiv) of ICl. An exotherm was
observed, and the reaction mixture, a dark-purple solution, was
stirred at rt for 1 h. Then the reaction was quenched by adding
10 mL of satd aq Na2S2O3 solution. The purple color quickly
faded, and this mixture became a yellow suspension. The
quenched reaction mixture was transferred to a 60 mL separa-
tory funnel. The aqueous layer was extracted with 3 ꢀ 10 mL of
CH2Cl2. The combined organic layers were washed with 30 mL
of satd aq Na2S2O3 solution and 30 mL of brine, dried over
anhydrous MgSO4, filtered, and were concentrated under
reduced pressure. The crude product was purified using flash
chromatography (silica gel (90 g), hexanes/EtOAc, 5/1 (1 L), 4/1
(1 L), 3/1 (1 L)) to afford 672.9 mg (86%) of 29 as an off-white
solid. Data for 29: mp 82-83 °C; 1H NMR (500 MHz, CDCl3) δ
7.73 (d, J=8.1 Hz, 2 H, HC(200), HC(600)), 7.33 (d, J=8.0 Hz, 2
H, HC(300), HC(500)), 4.67 (s, 1 H, HC(2)), 4.09 (ddd, J=14.5,
1.9, 1.9 Hz, 1 H, HC(5)), 3.95 (dd, J = 14.5, 1.9 Hz, 1 H, HC(5)),
3.72 (s, 3 H, C(8)O2CH3), 3.60 (s, 3 H, C(7)O2CH3), 3.41 (dd, J=
8.7, 6.1 Hz, 1 H, HC(3)), 2.45 (s, 3 H, ArylCH3), 2.44 (s, 3 H,
H3C(20)), 2.34 (d, J = 5.4 Hz, 1 H, HC(6)), 2.33 (dd, J=9.5 Hz, 1
H, HC(6)); 13C NMR (126 MHz, CDCl3) δ 171.2 (C(7)), 170.8
(C(8)), 144.0 (C(100)), 141.7 (C(4)), 136.0 (C(400)), 129.9 (C(300),
C(500)), 127.5 (C(200), C(600)), 91.9 (C(10)), 66.5 (C(2)), 57.8
(C(5)), 52.7 (C(7)O2CH3), 52.4 (C(8)O2CH3), 43.4 (C(3)), 36.9
(C(6)), 30.0 (ArylCH3), 21.8 (C(20)); IR (thin film) νmax 3447 (w),
2955 (m), 2255 (w), 1667 (w), 1560 (w), 1436 (m), 1351 (m),
1261 (m), 1209 (m), 1161 (s), 1096 (s), 913 (w), 816 (w), 730 (w),
666 (m) cm-1; LRMS (ESI) m/z 508.0 ([M þ H]þ), 530.0 ([M þ
Na]þ), 545.9 (100.0, ([M þ K]þ)); HRMS (ESI, [M þ H]þ) calcd
508.0291, found 508.0276; TLC Rf 0.24 (silica gel, hexanes/
EtOAc, 2:1, UV); [R]D -7.8 (c=0.5, EtOH). Anal. Calcd for
C18H22INO6S: C, 42.61; H, 4.37; N, 2.76. Found: C, 42.92; H,
4.24; N, 2.71.
Experimental Section
Preparation of (2S,3S,4E)-1-[(4-Methylphenyl)sulfonyl]-2-
methoxycarbonyl-4-[(phenyldimethylsilyl)ethylidene]-3-pyrroli-
dineacetaldehyde (25). To an oven-dried glass liner (L = 3 cm)
in a drybox was added 64.6 mg (0.25 mmol, 5 mol %) of
Rh(acac)(CO)2. The glass liner was sealed with a septum and
was taken out. Rh(acac)(CO)2 was then dissolved in 10 mL of
toluene, resulting in a light green solution. A solution of 1.607 g
(5.00 mmol) of 17 and 0.80 mL (5.25 mmol, 1.05 equiv) of
HSiMe2Ph in 40 mL of toluene was transferred via cannula to
the glass liner under Ar. The color of the mixture quickly
turned to light yellow. The glass tube was opened and was
quickly placed in a stainless steel bomb. The bomb was sealed
and then placed on a rocker. The bomb was purged with CO by
pressurizing to ∼500 psi followed by venting three times.
Finally, the bomb was then pressurized with 500 psi of CO.
The bomb was heated to 120 °C in the course of ∼1 h, and it was
rocked at this temperature for 12 h. At the end of the reaction
period, the autoclave was cooled to rt, and the pressure was
released. The glass liner was taken out, and the red-orange
reaction mixture was treated with a solution of 76.1 mg (1.00
mmol, 20 mol %) of thiourea in 4 mL of EtOH. Upon treatment,
this mixture quickly became a suspension, and the color gradu-
ally darkened from yellow to brown. It was stirred at rt under air
for 40 min before it was filtered through a layer of silica gel. The
silica gel was eluted with 100 mL of EtOAc, and the combined
filtrates were concentrated under reduced pressure. The crude
product was purified using flash chromatography (silica gel
(240 g),hexanes/EtOAc, 10/1 (2 L), 5/1 (2 L), 3/1 (3 L)) to afford
in total 1.860 g (77%) of trans-25 and cis-25 (trans-25/cis-25=
PreparationofMethyl (2S,3S,4Z)-1-(4-Methylphenylsulfonyl)-
2-methoxycarbonyl-4-[(2E,5R)-5-methoxycarbonyl-1-methyl-2-
hexen-1-ylidene]-3-pyrrolidineacetate (35). To a 50-mL Schlenk
flask equipped with a magnetic stir bar was added 59.5 mg
(0.057 mmol, 5 mol %) of Pd2(dba)3 CHCl3. The Schlenk flask
3
was evacuated and purged with Ar three times. In another 50 mL,
round-bottomed flask equipped with a magnetic stir bar and a
gas inlet adaptor, 578.2 mg (1.14 mmol) of 29 and 276.7 mg
(1.37 mmol, 1.2 equiv) of 34 were dissolved in 11 mL of THF. To
this solution were added 0.31 mL (17.10 mmol, 15.0 equiv) of
1
8:1) as a light yellow liquid. Data for trans-25: H NMR (500
MHz, CDCl3) δ 9.26 (s, 1 H, HC(7)), 7.71 (d, J=8.2 Hz, 2 H,
HC(200), HC(600)), 7.42 (dd, J = 7.7, 1.6 Hz, 2 H, HC(800),
HC(1200)), 7.39-7.25 (m, 5 H, HC(Aryl)), 4.23 (s, 1 H, HC(2)),
4.09 (d, J=14.3 Hz, 1 H, HC(5)), 4.03 (d, J=14.1 Hz, 1 H,
HC(5)), 3.57 (s, 3 H, OCH3), 3.19 (d, J=10.9 Hz, 1 H, HC(3)),
H2O and 3.4 mL (3.4 mmol, 3.0 equiv) of TBAF 3H2O solution
3
(1.0 M in THF) sequentially. The resulting orange-brown solu-
tion was transferred via cannula to the Schlenk flask under Ar.
The reaction mixture quickly turned from dark-purple to dark-
green, and it was stirred at rt under Ar for 1 h. Then the reaction
214 J. Org. Chem. Vol. 76, No. 1, 2011