B. M. Trost et al.
3H), 1.37 (s, 3H), 1.36 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=
154.9, 143.7, 134.5, 125.5, 113.2, 109.6, 108.7, 81.7, 77.7, 75.0, 73.6, 69.7,
60.3, 54.8, 39.1, 39.0, 38.6, 27.6, 27.3, 26.9, 26.6, 25.6 ppm; HRMS: m/z
calcd for C20H31O8: 399.2020 [MÀCH3]+; found: 399.2023.
(S)-2-[(E)-2-((4S,5S)-5-{[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methyl}-2,2-
dimethyl-1,3-dioxolan-4-yl)vinyl]-4-methylenetetrahydro-2H-pyran (18):
went a highly diastereoselective Ferrier addition of a Mar-
shall-type[56] with allenylstannane 83 at low temperature to
furnish exclusively the trans-disubstituted dihydropyran 84
in 85% yield, as confirmed by the absence of a nOe be-
tween the C5 and C9 hydrogen atoms (Scheme 15). This
A mixture of [Pd2ACTHNUTRGNENUG(dba)3]·CHCl3 (0.175 g, 0.169 mmol) and dppf (0.187 g,
0.338 mmol) in dry, degassed dichloroethane (10 mL) was stirred under a
N2 atmosphere at RT for 15 min, during which time it formed a clear
deep-red solution. This solution was transferred into a flask that con-
tained a solution of 17 (2.800 g, 6.755 mmol) in dry, degassed dichloro-
ethane (120 mL), rinsing with dichloroethane (5 mL) to ensure complete
transfer. The resulting mixture was placed in an oil bath, which was pre-
heated to 708C, and stirred for 12 h. After cooling to room temperature,
the mixture was concentrated in vacuo, and the residue was purified by
column chromatography (petroleum ether/EtOAc=15:1 to 10:1) to give
18 (1.999 g, 5.907 mmol, 87%) as a pale yellow oil. [a]2D3 = +15.9 (c=1.01
in CH2Cl2); IR (neat): n˜ =2986, 1380, 1370, 1244, 1090, 1059, 890 cmÀ1
;
Scheme 15. Completion of the southern fragment. i) 83, BF3·OEt3,
CH2Cl2, À78 to À408C; ii) LiOH, THF/H2O.
1H NMR (500 MHz, CDCl3): d=5.84 (ddd, J=15.5, 5.5, 0.6 Hz, 1H), 5.70
(ddd, J=15.5, 7.4, 1.3 Hz, 1H), 4.77–4.74 (m, 2H), 4.22 (ddd, J=13.0,
7.1, 6.0 Hz, 1H), 4.00 (t, J=7.9 Hz, 1H), 3.83–3.79 (m, 2H), 3.58 (dd, J=
8.2, 7.2 Hz, 1H), 3.42 (ddd, J=12.1, 11.0, 2.8 Hz, 1H), 2.34–2.27 (m, 2H),
2.17–2.14 (m, 1H), 2.10–2.05 (m, 1H), 1.92 (ddd, J=13.8, 7.1, 2.6 Hz,
1H), 1.65 (ddd, J=13.8, 9.9, 5.8 Hz, 1H), 1.40 (s, 9H), 1.35 ppm (s, 3H);
13C NMR (125 MHz, CDCl3): d=143.7, 135.5, 127.2, 109.0, 108.9, 108.6,
82.1, 78.0, 77.7, 73.7, 69.8, 68.4, 41.0, 36.2, 34.8, 27.2, 27.0, 25.7 ppm;
HRMS: m/z calcd for C19H30O5: 338.2093; found: 333.2087.
transformation allowed for the installation of the desired
propargylic ester in one step from glycal 12. The groups of
Williams[7h] and Nelson[7i] both successfully employed similar
allenyl stannanes in their syntheses of laulimalide. Finally,
saponification of the propargylic methyl ester 84 with lithi-
um hydroxide (2 equiv) resulted in the formation of the de-
sired acid 8 in 81% yield, completing the synthesis of the
southern fragment.
AHCTUNGTERG(NNUN 2R,3S,5R)-2,3-Dihydroxy-5-(4-methoxybenzylhydroxy)(2-methoxyphe-
nyl)oct-7-en-1-one (48): (R,R)-32 (4.0 mg, 0.00625 mmol) was placed
under a nitrogen atmosphere and THF (320 mL) was added. Diethylzinc
(13 mL, 0.0125 mmol, 1.0m in THF) was added dropwise and stirred for
15 min. Separately, powdered molecular sieves (4 ꢂ, 50 mg) and 2-hy-
droxy-2’-methoxyacetophenone (33; 54.0 mg, 0.325 mmol) were placed
into a vial and placed under a nitrogen atmosphere. (R)-3-((4-methoxy-
benzyl)oxy)hex-5-enal (57.0 mg, 0.250 mmol) in THF (320 mL) was added
in one portion. The mixture was cooled to 08C and the catalyst solution
was added through a syringe. The reaction mixture was then stirred at
room temperature for 12 h. HCl (1m) was added, and the mixture was ex-
tracted twice with CH2Cl2. The combined organic extracts were washed
with brine, dried (MgSO4), and evaporated. Column chromatography
(petroleum ether/EtOAc=4:1 to 2:1) provided 32 (53 mg, 52%) as a
white solid. M.p. 70–718C; [a]D23 =7.0 (c=1.0 CHCl3); IR (neat): n˜ =3452,
3075, 3008, 2936, 2915, 2839, 1667, 1599, 1533, 1514, 1487, 1465, 1438,
Conclusion
We have developed a novel synthesis of two similarly sized
fragments of laulimalide. The northern fragment was com-
pleted by using a diastereoselective dinuclear zinc aldol re-
action of a novel acylpyrrole aldol donor, followed by a
´
Julia–Kocienski olefination reaction. The southern fragment
was assembled through a key RhI-catalyzed cycloisomeriza-
tion reaction applied to a challenging diyne substrate. In the
following paper, we detail the union of the two fragments
and the completion of the total synthesis of laulimalide.
1
1395, 1293, 1246, 1179, 1076, 1035 cmÀ1; H NMR (400 MHz, CDCl3): d=
7.88 (dd, J=1.8, 5.9 Hz, 1H), 7.53–7.58 (m, 1H), 7.06–7.10 (m, 3H), 6.91
(d, J=7.9 Hz, 1H), 5.79–5.89 (m, 2H), 5.07–5.14 (m, 2H), 4.96 (d, J=
1.8 Hz, 1H), 4.53 (d, J=10.8 Hz, 1H), 4.31 (d, J=10.8 Hz, 1H), 4.20 (m,
1H), 4.09–4.13 (m, 1H), 3.89 (d, J=8.7 Hz, 1H), 3.78 (s, 3H), 3.73 (s,
3H), 2.29–2.45 (m, 2H), 2.06 (d, J=9.8 Hz, 1H), 1.73 (dddd, J=1.7, 2.5,
2.5, 7.2 Hz, 1H), 1.25 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=
200.9, 158.7, 134.5, 131.5, 130.7, 129.4, 123.8, 121.2, 117.4, 113.6, 111.6,
79.9, 75.5, 71.3, 68.4, 55.6, 55.2, 40.3, 38.7 ppm; HRMS (EI): m/z calcd
for C23H28O6: 423.1784 [M+Na]+; found: 423.1780; elemental analysis
calcd (%) for C23H28O6: C 68.98, H 7.05; found: C 68.90, H 7.08.
Experimental Section
ACHTUNGTRENNUNG(S,E)-1-((4R,5S)-5-[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methyl}-2,2-di-
methyl-1,3-dioxolan-4-yl)-7-hydroxy-5-methylenehept-2-enyl methyl car-
bonate (17): A solution of 3-butyn-1-ol (10; 291 mL, 3.85 mmol) and
alkene 9 (3.978 g, 11.55 mmol) in dry, degassed acetone (15 mL) was
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
cooled to 08C, and [CpRuACHTUNGTRENNG(U CH3CN)3]ACHTUNGTREN[NUNG PF6] (139 mg, 0.39 mmol) was
an argon atmosphere and THF (500 mL) was added. Diethylzinc (1.0m in
hexanes, 95 mL, 0.095 mmol) was added dropwise at RT and the reaction
mixture was stirred for 20 min to give the dinuclear zinc catalyst as a
yellow solution. Powdered molecular sieves (4 ꢂ, 50 mg) were placed
into a flame-dried flask, followed by acyl pyrrole 55 (63 mg, 0.411 mmol)
and the flask was placed under an argon atmosphere. Aldehyde 65
(50 mg, 0.316 mmol) in THF (500 mL) was then added to the acyl pyrrole/
molecular sieves mixture in one portion. The resulting mixture was
stirred vigorously and the catalyst was added dropwise through a syringe.
After stirring at RT for 12 h, the reaction mixture was hydrolyzed by
adding aqueous HCl (1m, 2 mL) and the mixture was extracted three
times with CH2Cl2. The combined organic layers were washed with brine,
added in one portion. The resulting orange mixture was stirred at 08C
for 10 min, and at RT for 18 h. The mixture was then concentrated in
vacuo, and the residue was purified by column chromatography (petrole-
um ether/EtOAc=4:1 to 2:1) to give the compound 17 (1.165 g,
2.811 mmol, 73%) as a pale yellow oil. [a]2D3 =À1.9 (c=1.06 in CH2Cl2);
IR (neat): n˜ =3496, 2987, 1752, 1443, 1380, 1269, 1069 cmÀ1 1H NMR
;
(500 MHz, CDCl3): d=5.86 (ddd, J=15.5, 7.1, 6.2 Hz, 1H), 5.59 (dd, J=
15.5, 7.4 Hz, 1H), 5.20 (dd, J=7.0, 4.9 Hz, 1H), 4.90 (s, 1H), 4.89 (s,
1H), 4.26–4.21 (m, 1H), 4.11–4.08 (m, 1H), 4.06–4.02 (m, 1H), 3.81 (dd,
J=8.1, 4.5 Hz, 1H), 3.78 (s, 3H), 3.70 (t, J=6.5 Hz, 2H), 3.60–3.57 (m,
1H), 2.83 (d, J=6.8 Hz, 2H), 2.29 (t, J=6.5 Hz, 2H), 1.94 (ddd, J=13.8,
7.7, 1.7 Hz, 1H), 1.72 (ddd, J=13.8, 9.9, 5.4 Hz, 1H), 1.40 (s, 3H), 1.39 (s,
2958
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 2948 – 2960