Studies on the synthesis of apoptolidin: Synthesis of a C 1-C27 fragment of apoptolidin D

Article abstract of DOI:10.1021/jo200934w

Synthesis of a C₁-C₂₇ fragment, a key intermediate in the synthesis of apoptolidin D, is reported. The synthesis involves a combination of Heck coupling and Horner - Wadsworth - Emmons reaction for the C₁-C₇ trienoate portion and an efficient Suzuki cross-coupling protocol for the C₁₀-C₁₃ diene portion. (Figure presented)

Full text of DOI:10.1021/jo200934w

ARTICLE
pubs.acs.org/joc
Studies on the Synthesis of Apoptolidin: Synthesis of a C1ꢀC27
Fragment of Apoptolidin D
Madduri Srinivasarao, Youngsoon Kim, Xiaojin Harry Li, Daniel W. Robbins, and Philip L. Fuchs*
Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States
S Supporting Information
b
ABSTRACT: Synthesis of a C1ꢀC27 fragment, a key inter-
mediate in the synthesis of apoptolidin D, is reported.
The synthesis involves a combination of Heck coupling and
HornerꢀWadsworthꢀEmmons reaction for the C1ꢀC7 trienoate
portion and an efficient Suzuki cross-coupling protocol for the
C10ꢀC13 diene portion.
’ INTRODUCTION
Allyl alcohol 12 was prepared in 79% yield over two steps from
14 via Heck reaction followed by reduction, as reported by Li and
Zeng.10 Functionalization of alcohol 12 by use of Ph3P/CBr4,
PBr3, or I2/PPh3/imidazole was unsuccessful due to lack of
reactivity, while Tf2O/Et3N led to extensive decomposition.
However, alcohol 12 was converted to the carbonate 13 in order
to probe Pd-catalyzed11 allylic sulfinylation, a well-known pro-
cess (Scheme 2).12
To minimize steric complications with 12, primary bromide
17 was initially employed for alkylation trials. Heck coupling of
vinyl iodide 14 with crotonaldehyde provided dienal 15, which
afforded alcohol 16 upon reduction with sodium borohydride.
Appel reaction13 gave bromide 17 in 67% over three steps from
14 (Scheme 3).
Alkylation of 17 with sulfinate generated from 6 led to a
complex mixture containing unwanted SN20 alkylation products.
The attempted reactions involved generation of sulfinate from 6
by use of tetrabutylammonium fluoride (TBAF) in tetrahydro-
furan (THF) at reflux or in N,N-dimethylformmamide (DMF) at
room temperature, in the presence of activated powdered
molecular sieves. The resulting sulfur-centered sulfinate was
reacted with bromide 17 at 0 °C and warmed to room tempera-
ture, when a complex mixture was observed. A milder reaction
condition of CsF/TiCl4 in acetonitrile also failed to provide a
clean reaction. Moreover, all attempts with palladium-catalyzed
sulfination of carbonate 13 resulted exclusively in substrate
decomposition.14
Apoptolidin A (1) is a complex natural product isolated from
Nocardiopsis sp. by Seto and co-workers in 1997.1,2 Since its
isolation, a number of structural congeners were isolated and
studied for antiproliferative activity by Wender et al.3 Three
total syntheses4 and several partial syntheses5 have been re-
ported. Apoptolidin A (1) consists of a 20-membered macro-
lactone containing an all-E-trienoic system and a conjugated
diene moiety. Apoptolidin D3c (2) is the only natural analogue
that has the desmethyl modification in its triene portion.
Retrosynthetic Analysis for 3. Apoptolidin D (2) shows
comparable activity to apoptolidin A (1) in bioassays. Current
efforts are being targeted toward the synthesis of apoptolidins A
and D, which differ in their substitution at C-6 of the macrocycle
(Figure 1). Apoptolidins were to be prepared from compound 3
via glycosylation of sugars 4 and 5. Sugar 4 is a synthon for the
6-deoxy-4-O-methyl-L-glucose moiety found at O-9, and glycosyl
fluoride 56 is a synthon for the disaccharide containing L-olivo-
mycose and D-oleandrose, found at O-27. The original retro-
synthesis for 3 envisaged formation of the C1ꢀC7 triene by
RambergꢀB€acklund olefination.7 Sulfinate generated from β-tri-
methylsilylethyl sulfone 6 was to provide the sulfone precursor
upon reaction with allylic substrates such as 7 (Figure 2).
’ RESULTS AND DISCUSSION
As an alternative strategy for C6ꢀC7 bond formation via
C6-centered nucleophiles to avoid potential unfavorable SN20
alkylation, we explored JuliaꢀKocienski olefination.15 Alkylation
of 17 with tetrazole thiolate 18, followed by oxidation with cata-
lytic ammonium molybdate with hydrogen peroxide, provided the
Deprotection of 8 (prepared previously)8 led to a concomitant
removal of silyl ether at C-16. A regioselective bromination pro-
vided bromide 9 in moderate yield. Alkylation of 9 with
β-trimethylsilylethanethiolate, afforded sulfide 10, which was
oxidized under Noyori conditions9 to provide sulfone 6 in 91%
over two steps (Scheme 1). To validate the deprotection process,
the sulfinate generated from 6 was quenched with MeI to provide
sulfone 11 in 71% yield.
Received: June 8, 2011
Published: August 09, 2011
r
2011 American Chemical Society
7834
dx.doi.org/10.1021/jo200934w J. Org. Chem. 2011, 76, 7834–7841
|

The Journal of Organic Chemistry
ARTICLE
Figure 1. Late-stage glycosylation approach for apoptolidins A and D.
Figure 2. RambergꢀB€acklund olefination strategy.
Scheme 1. Synthesis and Methylation of Sulfone 6
Scheme 2. Functionalization of 12
Scheme 3. Preparation of Bromide 17
desired sulfone 19 in 64% yield over two steps (Scheme 4).
However, attempted JuliaꢀKocienski reaction provided less than
10% conversion to the triene 20 upon testing with dihydrocin-
namaldehyde as a model aldehyde.
A HornerꢀWadsworthꢀEmmons (HWE) protocol16 was next
undertaken. Accordingly, bromide 17 was stirred with triethyl-
phosphite at reflux for 17 h to provide phosphonate 21 in
excellent yield. Attempts to methylate 21 were unsuccessful.
However, HWE reaction of 21 with dihydrocinnamaldehyde as the
model substrate provided 20 in 90% yield and exclusive E-selectivity
(Scheme 5). This prompted undertaking the synthesis of apop-
tolidin D, lacking the methyl functionality at C-6.
With an early-stage HWE protocol for apoptolidin D in place, diol
23 previously prepared by Li et al.8 was subjected to p-methoxylphenyl
7835
dx.doi.org/10.1021/jo200934w |J. Org. Chem. 2011, 76, 7834–7841

The Journal of Organic Chemistry
ARTICLE
protection followed by deprotection to afford primary alcohol 24
in 81% over two steps. Swern oxidation of 24 provided aldehyde
25, which upon HWE with phosphonate 21 gave triene 26
in 90% yield with exclusive E-selectivity (Scheme 6). Deprotec-
tion of 26 by use of TBAF or buffered TBAFꢀHOAc led to
partial β-elimination of the PMB ether, while HF-Py led to
partial deprotection of the PMB moiety. Near-neutral condi-
tions with warm ammonium fluoride in methanol17 gave the
alcohol 27 in 81% yield. Oxidation of alcohol 27 also proved to
be very demanding. Various oxidizing protocols such as Dessꢀ
Martin periodinane, pyridinium chlorochromate (PCC), and
SO3/pyridine led to decomposition of starting alcohol. Oxida-
tion under Swern conditions provided the aldehyde 28 in 80%
yield. Triethylamine resulted in 20% epimerization; however,
H€unig’s base at ꢀ60 °C proved effective in avoiding epimeriza-
tion. Aldehyde 28 was subjected to HWE olefination with phos-
phonate 298 to provide a 2.2:1 mixture of vinyl sulfones 30 in
90% yield.
Scheme 4. Synthesis and JuliaꢀKocienski Olefination of 19
When vinyl sulfone mixture 30 was subjected to regioselective
alkylation with iodide 31, the R-alkylated product 34 was isolated
in 64% yield as a 1:1 diastereomeric mixture as expected (Scheme 7).8
However, attempts at alkylation with advanced substrates 3218 and 33
provided no alkylation product. Prolonged reaction times or heating
the reaction mixture led to extensive decomposition. Activation of the
iodides by silver tetrafluoroborate or use of other crown ethers also
did not provide the desired alkylation.
Suzuki19 cross-coupling was also studied for the construction
of C10ꢀC13 diene. Accordingly, aldehyde 28 was converted to
vinyl iodide 35 by Takai olefination (Scheme 8).20 Triol 36 was
prepared via lactol-directed osmylation as previously reported
by Kim and Fuchs.21 Triol 36 was subjected to Grieco pro-
cedure,22 affording olefin 37 in 89% yield. Cross-metathesis of
vinyl boronates with terminal olefins was reported by Morrill
et al.23 In the event, 37 was reacted with commercially available
vinyl pinacol boronate 38 in the presence of 20 mol % Grubbs’
second-generation catalyst, and the thus-obtained vinyl bor-
onate was subjected to cross-coupling with vinyl iodide 35 under
modified SuzukiꢀMiyaura conditions developed by Roush and
co-workers24 to afford the desired product 3 in 64% yield over
two steps. The current late-stage SuzukiꢀMiyaura cross-coupling
provides key intermediate 3 potentially applicable for synthesis of
apoptolidin D.
Scheme 5. Synthesis and HWE Reaction of 21
Scheme 6. Preparation of Vinyl Sulfone 30
7836
dx.doi.org/10.1021/jo200934w |J. Org. Chem. 2011, 76, 7834–7841

The Journal of Organic Chemistry
ARTICLE
Scheme 7. Alkylation of Vinyl Sulfone 30
Scheme 8. Synthesis of Compound 3
’ EXPERIMENTAL SECTION
was added CBr4 (716 mg in 3.6 mL of dichloromethane) at 25 °C. The
reaction was stirred at 25 °C for 30 min, quenched with water (10 mL),
and acidified to pH 1ꢀ2 with 5% HCl (∼2.5 mL). The organic layer was
separated, and the aqueous layer was extracted with dichloromethane.
The combined organic layer was dried under Na2SO4, and the solvent
was removed. The residue was separated by column chromatography
(support, silica gel; solvent, 5ꢀ20% ethyl acetate in hexanes) to provide
trienyl bromide 9 (0.52 g, 62%). 1H NMR (300 MHz, CDCl3) δ 7.22 (d,
J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 6.23 (d, J = 15.9 Hz, 1H), 5.62
(m, 1H), 5.47 (m, 2H), 5.32 (m, 2H), 4.49 (d, J = 11.4 Hz, 1H), 4.22 (d,
J = 11.4 Hz, 1H), 3.82 (m, 1H), 3.78 (s, 3H), 3.50 (m, 2H), 3.28 (m, 2H),
3.30 (s, 3H); 2.71 (s, 1H), 2.30 (m, 2H), 1.97 (m, 1H), 1.76 (s, 3H), 1.50
(m, 2H), 1.07 (d, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 159.0,
Preparation of 9. To a solution of triene 8 (0.93 g, 1.8 mmol) in
toluene (36 mL) was dropwise added diisobutylaluminum hydride
(DIBAL) (5.8 mL, 9.0 mmol, 1.55 M in toluene) at 0 °C. The reaction
was gradually warmed up to 10 °C during 2.5 h with stirring and then
quenched carefully with MeOH (∼1.5 mL) at 0 °C, followed by addition
of NaOH (20 mL, 10%). The organic layer was separated, and the
aqueous layer was extracted with ethyl acetate. The combined organic
layer was dried under Na2SO4, passed through a silica gel pad (2 in. ꢁ 2in.),
and washed with ethyl acetate. The solvent was removed to yield 0.73 g
of crude oil. To a solution of the crude oil (0.73 g), PPh3 (567 mg, 2.16
mmol), and pyridine (145 μL, 2.16 mmol) in dichloromethane (18 mL)
7837
dx.doi.org/10.1021/jo200934w |J. Org. Chem. 2011, 76, 7834–7841

The Journal of Organic Chemistry
ARTICLE
138.6, 134.9, 133.3, 133.0, 130.9, 129.2, 124.6, 120.4, 113.7, 87.0, 81.5,
72.8, 70.0, 56.4, 55.2, 41.0, 38.2, 32.1, 24.3, 14.5, 12.5; HRMS (ESI)
calcd for C24H35BrO4Na [M + Na]+ 489.1616, found 489.1625.
Preparation of Sulfide 10. A solution of β-trimethylsilylethyl
thiol (618 mg, 3.95 mmol) and NaH (154 mg, 3.86 mmol, 60% in
mineral oil) in THF (4.4 mL) was stirred at 0 °C for 15 min, and trienyl
bromide 9 (887 mg in 2 mL of THF) was added. The mixture was stirred
at 0 °C for 1 h and at 25 °C for 2.5 h. The reaction was quenched with
water and extracted with ethyl acetate. The solvent was removed, and the
residue was separated by column chromatography (support, silica gel;
solvent, 5% ethyl acetate in hexanes) to provide 10 as a colorless oil (900 mg,
91%). 1H NMR (300 MHz, CDCl3) δ 7.22 (d, J = 8.1 Hz, 2H), 6.85 (d,
J = 8.1 Hz, 2H), 6.19 (d, J = 15.9 Hz, 1H), 5.62 (m, 1H), 5.45 (m, 2H),
5.32 (m, 2H), 4.49 (d, J = 11.7 Hz, 1H), 4.29 (J = 11.7 Hz, 1H), 3.78 (s,
3H), 3.76 (m, 1H), 3.49 (m, 1H), 3.34 (m, 1H), 3.30 (s, 3H), 2.72 (m,
2H), 2.48 (t, J = 8.6 Hz, 2H), 2.25 (m, 3H), 1.85 (m, 1H), 1.70 (s, 3H),
1.50 (m, 2H), 1.03 (d, J = 7.2 Hz, 3H), 0.82 (m, 2H), ꢀ0.010 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 158.9, 138.1, 134.9, 133.4, 132.5, 131.0,
129.0, 125.3, 120.2, 113.6, 86.9, 82.5, 72.8, 69.8, 56.3, 55.1, 38.8, 35.6,
32.1, 28.0, 24.3, 17.3, 15.1, 12.4, ꢀ1.8; HRMS (ESI) calcd for C29H48-
O4SSiNa [M + Na]+ 543.2940, found 543.2942.
Preparation of Sulfone 6. To a solution of Na2WO4 (63 μL,
0.0062 mmol, 0.1 M in water), PhPO(OH)2 (63 μL, 0.1 M in water),
phase-transfer catalyst (Oct3MeNHSO3)(PTC) (63 μL, 0.1 M in toluene),
and H2O2 (54 μL, 0.79 mmol, 50% in water) in toluene (0.3 mL) was
added 10 (164 mg, 0.32 mmol) in toluene (0.33 mL) at 25 °C. The
reaction was stirred at this temperature for 2.5 h and then diluted with
water (3 mL). The mixture was extracted with ethyl acetate, and the
combined organic layer was dried under Na2SO4. The product 6 was
collected after the solvent was removed (177 mg, 100%). 1H NMR (300
MHz, CDCl3) δ 7.20 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 6.21
(d, J = 15.3 Hz, 1H), 5.61 (m, 1H), 5.49 (t, J = 7.2 Hz, 1H), 5.32 (m, 2H),
5.31 (s, 1H), 4.49 (d, J = 11.7 Hz, 1H), 4.25 (d, J = 11.7 Hz, 1H), 3.81
(m, 1H), 3.72 (s, 3H), 3.48 (m, 1H), 3.31 (m, 2H), 3.30 (s, 3H), 2.83
(m, 2H), 2.66 (m, 2H), 2.41 (m, 1H), 2.28 (m, 2H), 1.74 (s, 3H), 1.68
(s, 1H), 1.50 (m, 1H), 1.12 (d, J = 7.2 Hz, 3H), 0.98 (m, 2H), 0.010 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 159.1, 139.4, 134.9, 133.6, 133.1,
130.6, 129.2, 122.9, 120.3, 113.7, 86.9, 82.0, 72.8, 69.8, 56.4, 55.2, 53.8,
49.9, 33.5, 32.1, 24.3, 16.0, 12.5, 8.37, ꢀ2.1; HRMS (ESI) calcd for
C29H48O6SiS [M]+ 552.2941, found 552.2941.
Preparation of Sulfone 11. A mixture of 6 (21.5 mg, 0.039
mmol), TBAF (78 μL, 0.078 mmol, 1 M in THF), and molecular sieves
4Å molecular sieves (6 mg) in THF (0.39 mL) was stirred at 25 °C for
10 min and at 80 °C for 1 h. After it was cooled down to 25 °C, to the
mixture was added iodomethane (24 μL, 0.39 mmol). The mixture was
stirred at 25 °C for 3.5 h, quenched with water, and extracted with ethyl
acetate. The combined organic layer was washed with brine, and dried
under Na2SO4. The solvent was removed, and the residue was separated
by column chromatography (support, silica gel; solvent, 30ꢀ50% ethyl
acetate in hexanes) to give methyl trienyl sulfone 11 as a colorless oil
(13 mg, 71%). 1H NMR (300 MHz, CDCl3) δ 7.2 (d, J = 8.6 Hz, 2H),
6.85 (d, J = 8.6 Hz, 2H), 6.21 (d, J = 15.9 Hz, 1H), 5.61 (m, 1H), 5.49 (t,
J = 7.2 Hz, 1H), 5.32 (m, 3H), 4.49 (d, J = 11.6 Hz, 1H), 4.25 (d, J = 11.6
Hz, 1H), 3.81 (m, 1H), 3.78 (s, 3H), 3.48 (m, 1H), 3.33 (m, 2H), 3.30 (s,
3H), 2.84 (s, 3H), 2.75 (d, J = 14.1 Hz, 1H), 2.72 (d, J = 14.1 Hz, 1H),
2.43 (m, 1H), 2.30 (m, 2H), 1.74 (s, 3H), 1.53 (m, 2H), 1.12 (d, J = 6.6 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 159.1, 139.4, 134.8, 133.6, 133.1,
130.5, 129.2, 122.8, 120.3, 113.7, 86.9, 81.8, 72.8, 69.8, 57.2, 56.4, 55.2,
41.6, 33.8, 32.1, 24.3, 15.9, 12.4; HRMS (ESI) calcd for C25H38O6S
[M]+ 466.2389, found 466.2397.
for 1 h and then at 25 °C for 12 h. The reaction was quenched with
saturated CuSO4 (18 mL), and the solids were removed by filtration.
The organic layer was separated, and the aqueous layer was extracted
with ether. The combined organic layer was washed with water and brine.
After the solvent was removed, the residue was separated by column
chromatography (support, silica gel; solvent, 3ꢀ7% ethyl acetate in
hexanes) to provide 13 as a yellow oil (2.61 g, 96%). 1H NMR (300 MHz,
CDCl3) δ 6.92 (1H), 5.47 (dq, J = 2.7, 6.0 Hz, 1H), 5.45 (d, J = 2.7 Hz,
1H), 3.72 (3H), 1.89 (3H), 1.86 (3H), 1.45 (9H), 1.34 (d, J = 6.0 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 167.4, 154.9, 140.1, 135.0, 131.7,
129.2, 80.0, 71.5, 54.2, 27.8, 20.17, 16.6, 13.7; HRMS (CI, NH3) calcd
for C15H24O5 [M + H]+ 285.1702; found 285.1701.
Preparation of Dienal 15. To a solution of vinyl iodide10 14 (10 g,
37 mmol) and crotonaldehyde (5.2 g, 74 mmol) in acetonitrile (37 mL),
stirring at 25 °C, were added palladium acetate monomer (415 mg,
1.84 mmol) and silver carbonate (25.5 g, 93.0 mmol). After being stirred
at 25 °C for 15 h, the reaction mixture was passed through a pad of Celite
and evaporated in vacuo. The crude mixture was purified by flash column
chromatography (support, silica gel; solvent, hexanes to 5% EA in
hexanes, Rf = 0.5; 2% EA/hexanes) to provide aldehyde 15 as a yellow oil
(7 g; 81%). 1H NMR (CDCl3, 300 MHz) δ 10.06ꢀ10.09 (d, J = 8.4 Hz,
1H), 7.02 (s, 1H), 5.94ꢀ5.97 (d, J = 8.4 Hz, 1H), 2.29 (s, 3H), 3.47 (s,
3H), 1.49 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 190.9, 166.8, 154.4,
138.4, 133.7, 130.6, 81.2, 28.0, 17.6, 14.6; HRMS (CI, NH3) calculated
for C12H19O3 [M + H]+ 211.2695; found 211.2695.
Preparation of Dienol 16. NaBH4 (1.8 g, 47.6 mmol) was added
to a solution of aldehyde 15 (5 g, 23.8 mmol) in methanol (50 mL) in
three portions at 0 °C. The solution was warmed to 25 °C and stirred for
20 min. The reaction was then quenched with water and extracted with
ether (3 ꢁ 50 mL). The combined organic extract was washed with
saturated brine solution (30 mL) twice, and the combined organic layer
was dried over anhydrous MgSO4 and concentrated in vacuo to provide
1
crude alcohol 16 (4.9 g, 96%). H NMR (300 MHz, CDCl3) δ 6.99
(1H), 5.69 (t, J = 6 Hz, 1H), 4.27 (d, J = 6 Hz, 2H), 2.88 (br s, 1H), 1.95
(3H), 1.83 (3H), 1.50 (9H); 13C NMR (75 MHz, CDCl3, no proton
decoupling) δ 168.3, 142.2, 1, 40.2, 134.5, 133.5, 132.5, 128.1, 80.4, 60.8,
58.9, 57.0,30.6, 28.9, 27.2, 25.5, 19.2, 17.5, 16.6, 15.8, 14.9, 14.8, 13.2;
HRMS (CI) calculated for C12H20O3 [M]+ 212.1412; found 212.1417.
Preparation of Bromide 17. To a solution of crude alcohol 16 (5
g, 23.5 mmol) in dichloromethane were added triphenylphosphine (6.17
g, 23.5 mmol) and carbon tetrabromide (11.7 g, 35.2 mmol) at 25 °C.
After the mixture was stirred at this temperature for 40 min, a saturated
solution of bicarbonate and hexanes was added and the aqueous layer
was extracted with ether. The combined organic layer was dried over
anhydrous MgSO4 and evaporated to dryness. The crude mixture was
purified by flash column chromatography (support, silica gel; solvent,
hexanes to 5% EA in hexanes, Rf = 0.5; 2% EA/hexanes) to provide
yellow oil 17 (5.24 g; 81%). 1H NMR (CDCl3, 300 MHz) δ 5.88 (t, J =
8.4 Hz, 1H), 4.13 (d, J = 8.4 Hz, 1H), 2.02 (s, 3H), 1.96 (s, 3H), 1.55 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 167.8, 139.9, 138.3, 130.1, 128.4,
80.6, 28.1, 28.0, 16.3, 14.2; MS (EI) 274 (M+); HRMS (EI) calculated
for C12H19BrO2 274.0568, found 274.0569.
Preparation of Sulfone 19. To a solution of bromide 17 (500 mg,
1.82 mmol) in THF (24 mL) was added tetrazole thiolate 18 (547 mg,
2.73 mmol) at 25 °C, and the mixture was stirred for 30 min. Water was
added, and the mixture was extracted with ethyl acetate. The resulting
crude mixture was dissolved in methanol. To this solution were added
sodium tungstate dihydrate (30 mg, 0.0909 mmol) and aqueous H2O2
(50 wt % solution, 32 μL, 0.470 mmol) at 25 °C The resulting mixture
was stirred overnight and then quenched with a saturated solution of
sodium sulfite solution. The aqueous layer was then extracted with ether
(3 ꢁ 50 mL), and the combined layer was dried over anhydrous MgSO4.
The solvent was evaporated and the crude material was purified by flash
column chromatography (support, silica gel; solvent, hexanes to 5% EA
Preparation of Carbonate 13. To a solution of 12 (1.61 g,
7.11 mmol), pyridine (2.90 mL, 35.6 mmol), and DMAP (87 mg,
0.710 mmol) in dichloromethane (18 mL) was dropwise added methyl
chloroformate at 0 °C. The reaction mixture was stirred at this temperature
7838
dx.doi.org/10.1021/jo200934w |J. Org. Chem. 2011, 76, 7834–7841

The Journal of Organic Chemistry
ARTICLE
in hexanes, to 25% EA, Rf = 0.33; 30% EA/hexanes) to provide sulfone
19 as a colorless oil (470 mg; 64% over two steps). 1H NMR (CDCl3,
300 MHz) δ 7.01 (s, 1H), 5.80 (t, J = 6 Hz, 1H), 4.21 (d, J = 6 Hz, 2H),
1.99 (s, 3H), 1.96 (s, 3H), 1.54 (s, 9H).
Preparation of Triene 26. To a solution of phosphonate 21 (1.7 g,
5.0 mmol) in THF (18 mL) was added n-BuLi (2 M in cyclohexane,
1.26 mL, 2.5 mmol) at ꢀ78 °C. After the resulting yellow solution was
stirred for 1 h, a solution of aldehyde 25 (2.0 g, 4.2 mmol) in THF (3 mL)
was added via cannula. The mixture was stirred for 1 h and then warmedto
25 °C. After being stirred for 2 h at this temperature, the mixture was
quenched with water and extracted with ethyl acetate. The combined
organic extract was dried over anhydrous MgSO4. After evaporation of the
solvent, the crude mixture was purified by flash column chromatography
(support, silica gel; solvent, hexanes to 5% EA in hexanes, Rf = 0.5; 2%
ethyl acetate/hexanes) to provide 26 as a yellow oil (2.6 g; 90% yield). 1H
NMR (CDCl3, 300 MHz) δ 7.72ꢀ7.77 (m, 2H), 7.27ꢀ7.52 (m, 3H),
7.27ꢀ7.33 (m, 2H), 7.14 (s, 1H), 6.90ꢀ6.94 (m, 2H), 6.38ꢀ6.47 (dd, J =
12, 15 Hz, 1H), 6.17 (d, J = 12 Hz, 1H), 5.74 (dd, J = 9, 15 Hz, 1H), 4.45
(dd, J = 38.7, 11.7 Hz, 2H), 3.87 (s, 3H), 3.82 (d, J = 5.7 Hz, 1H), 3.79 (d,
J = 6.3 Hz, 1H), 2.84 (m, 1H), 1.21(d, J = 7.2 Hz, 2H), 2.09 (s, 3H), 2.00
(s, 3H), 1.58 (s, 9H), 1.18 (s, 9H); 13C NMR (CDCl3, 75 MHz)
135.7,133.6, 133.4, 132.1, 130.9, 129.7, 129.4, 127.7, 127.2, 126.1, 83.1,
80.1, 72.4, 68.0, 64.3, 55.3,39.1, 28.2, 26.8, 25.6, 19.2, 16.7, 15.8, 14.4;
HRMS (EI) calculated for C41H54O5Si [M]+ 654.3741, found 654.3725.
Preparation of Alcohol 27. Toa stirred solution oftriene26(1.0 g,
1.5 mmol) in methanol (15 mL) was added NH4F (0.79 g, 21 mmol) in
one portion. The resulting mixture was stirred at 60 °C for 15 h. Silica was
added and the solvent was evaporated to dryness. The crude mixture was
purified by flash column chromatography (support, silica gel; solvent,
hexanes to 20% EA in hexanes, Rf = 0.3; 20% EA/hexanes) to provide 27
as a yellow oil (515 mg, 81%). 1H NMR (CDCl3, 300 MHz) δ 7.34 (m,
2H), 7.13 (s, 1H), 6.93 (m, 2H), 6.41 (dd, J = 12, 15 Hz, 1H), 6.21 (d, J =
12 Hz, 12H), 5.78 (dd, J = 9, 15 Hz, 1H), 4.61(d, J = 6 Hz, 2H), 3.87 (s,
3H), 3.82 (d, J = 5.7 Hz, 1H), 3.79 (d, J = 6.3 Hz, 1H), 3.38 (m, 1H), 2.66
(m, 1H), 2.09 (s, 3H), 2.00 (s, 3H), 1.58 (s, 9H), 1.21 (d, J = 7.2 Hz, 2H);
13C NMR (75 MHz, CDCl3) δ 168.4, 159.4, 141.8, 138.6, 134.6, 132.7,
130.4, 129.6, 127.6, 126.7, 113.9, 83.3, 80.2, 72.3, 62.3, 55.3, 38.8, 28.2,
16.8, 16.4, 14.4, 1.1; HRMS (ESI) calculated for C25H36O5Na [M + Na]
439.2460, found 439.2452.
Preparation of Aldehyde 28. To a solution of oxalyl chloride
(0.1 mL, 3.6 mmol) in dichloromethane (6 mL) was added dimethyl
sulfoxide (0.51 mL, 7.2 mmol) at ꢀ78 °C. After the mixture was stirred
at the same temperature for 30 min, a solution of alcohol 27 (500 mg,
1.2 mmol) in dichloromethane (1 mL) was added, and the mixture was
stirred at ꢀ60 °C for 1.5 h. The reaction was then quenched with
diisopropylethylamine (2.8 mL, 16 mmol) at ꢀ78 °C and stirred for 1 h.
The solution was warmed to 0 °C over 30 min and then quenched with
saturated bicarbonate solution (30 mL). The layers were separated, and
the aqueous layer was extracted with dichloromethane (3 ꢁ 30 mL).
The combined organic layer was washed with saturated brine solution
(30 mL). The combined organic solvent was dried over anhydrous
MgSO4 and evaporated to provide aldehyde 28 (400 mg, 80% yield).
Rf = 0.3; 10% EA/hexanes). 1H NMR (300 MHz, CDCl3) δ 9.67 (d, J =
2.5 Hz, 1H), 7.44 ꢀ 7.22 (m, 2H), 7.12 (s, 1H), 6.94 (d, J = 8.7 Hz, 2H),
6.44 (dd, J = 14.9, 11.1 Hz, 1H), 6.19 (d, J = 10.8 Hz, 1H), 5.81 (dd, J =
15.0, 7.9 Hz, 1H), 4.68 (d, J = 11.5 Hz, 1H), 4.53 (d, J = 11.5 Hz, 1H),
3.87 (s, 3H), 3.68 (dd, J = 5.6, 2.5 Hz, 1H), 3.21ꢀ1.96 (m, 1H),
1.96ꢀ1.93 (m, 1H), 1.55 (d, J = 9.8 Hz, 1H), 1.32 (s, 9H), 1.19 (d, J = 6.9
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 203.7, 168.3, 159.6, 141.6,
136.7, 134.1, 133.3, 129.8, 129.3, 127.9, 127.2, 113.9, 86.2, 80.3, 77.6,
77.1, 76.7, 72.7, 55.3, 39.2, 28.2, 16.8, 15.4, 14.4; HRMS (ESI) calculated
for C25H34O5 [M]+ 414.2406, found 414.2395.
Preparation of Phosphonate 21. A solution of bromide 17 (4 g,
14.5 mmol) and triethylphosphite (2.4 g, 14.5 mmol) in toluene
(14.5 mL) was refluxed for 17 h. The solvent was evaporated and the
crude mixture was purified by flash column chromatography (support,
silica gel; solvent, hexanes to 30% EA in hexanes to 100% EA, Rf = 0.3;
70% EA/hexanes) to provide phosphonate 21 as a colorless oil (4.4 g;
91%). 1H NMR (CDCl3, 300 MHz) δ 7.06 (s, 1H), 5.58 (m, 2H), 4.11
(m, 4H), 2.70 (dd, J = 10.5, 7.8 Hz), 2.00 (s, 3H), 1.90 (d, J = 4.2 Hz,
3H), 1.84 (s, 3H), 1.55 (s, 9H), 1.35 (m, 6H); 13C NMR (75 MHz,
CDCl3) δ 165.9, 133.2, 130.1, 129.8, 128.5, 107.8, 104.9, 101.1, 85.2,
78.5, 76.2, 74.8, 70.2, 68.7, 56.8, 44.4, 44.1, 36.1, 25.9, 22.8, 22.9, 18.4,
18.1, 17.8, 1.1, ꢀ1.7, ꢀ1.8; 31P NMR (121 MHz, CDCl3) δ 26.92. MS
(ESI) calculated for C16H29O5P 332.18, found 354.79 [M + Na]. HRMS
(EI) calculated for C16H29O5P 333.1831, found 333.1828.
Preparation of Alcohol 24. To a solution of diol 238 (3.9 g,
10.9 mmol) and p-anisaldehyde dimethyl acetal (1.9 mL, 10.9 mmol) in
dry acetonitrile (54 mL) was added camphorsulfonic acid (253 mg,
1.09 mmol). The resulting red reaction mixture was stirred at 25 °C for
12 h. The mixture was then quenched with triethylamine and evaporated
to dryness. The crude mixture is filtered through silica gel (Rf = 0.3; 5%
EA/hexanes) to provide a crude yellow oil, which was dissolved in
toluene, and the solution was cooled to ꢀ55 °C. To this solution was
added DIBAL-H (1 M solution in toluene, 43.6 mL, 43.6 mmol) slowly,
and the reaction mixture was stirred for 5 h at this temperature. The
mixture was quenched with methanol at ꢀ50 °C. The mixture was then
warmed to 25 °C. Potassium sodium tartrate (2 g) was added, and the
mixture was stirred until the layers became clear. The aqueous layer was
extracted with ethyl acetate. The combined organic layer was washed
with saturated brine solution. The crude mixture was purified by flash
column chromatography (support, silica gel; solvent, hexanes to 20% EA
in hexanes, Rf = 0.4; 20% EA/hexanes) to provide 24 as a yellow oil (4.17 g;
80%). 1H NMR (300 MHz, CDCl3) δ 7.76 (dd, J = 7.7, 1.4 Hz, 2H),
7.57ꢀ7.39 (m, 3H), 7.32 (s, 1H), 7.25 (m, 2H), 6.92 (d, J = 8.6 Hz, 2H),
5.36 (s, 1H), 4.62 (d, J = 11.3 Hz, 1H), 4.45 (d, J = 11.3 Hz, 1H), 4.19 (d,
J = 7.1 Hz, 1H), 3.98ꢀ3.73 (m, 5H), 3.71ꢀ3.62 (m, 2H), 2.45 (s, 1H),
2.27ꢀ2.21 (m, 1H), 2.15ꢀ2.00 (m, 1H), 1.33 (t, J = 7.1 Hz, 1H), 1.13 (s,
9H), 0.93 (d, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 168.4,
159.4, 141.8, 138.6, 134.6, 132.7, 130.4, 129.6, 127.6, 126.7, 114.0, 83.2,
80.2, 77.6, 77.1, 76.7, 72.3, 62.3, 55.3, 38.8, 28.2, 16.8, 16.4, 14.4. HRMS
(EI) calculated for C29H37O4Si [M+ ꢀ H] 477.2461, found 477.2466.
Preparation of Aldehyde 25. To a solution of oxalyl chloride
(0.46 mL, 5.30 mmol) in dichloromethane (50 mL) was added dimethyl
sulfoxide (0.76 mL, 10.7 mmol) at ꢀ78 °C. After the mixture was stirred
at the same temperature for 30 min, a solution of alcohol 24 (3 g, 6.30 mmol)
in dichloromethane (12.7 mL) was added, and the mixture was stirred
for 1.5 h. The reaction was then quenched with diisopropylethylamine
(2.8 mL, 16.0 mmol) at ꢀ78 °C, and stirred for 1 h. The solution
was warmed to 0 °C over 30 min and then quenched with saturated
bicarbonate solution(30 mL). The layers were separated, and theaqueous
layer was extracted with dichloromethane (3 ꢁ 30 mL). The combined
organic layer was washed with saturated brine solution (30 mL). The
combined organic solvent was dried over anhydrous MgSO4 and evapo-
rated to provide aldehyde 25 (2.42 g, 81% yield). Rf = 0.3; 10% EA/hexanes.
1H NMR (CDCl3, 300 MHz) δ 9.90 (s, 1H), 7.78 (m, 4H), 7.54 (m, 6H),
7.28 (d, J = 8.1 Hz, 2H), 6.95 (d, J= 8.1 Hz, 2H), 4.47 (dd, J= 38.7, 11.7 Hz,
2H), 4.40 (d, J = 5.2 Hz, 3H), 3.84 (s, 3H), 3.82 (d, J = 5.7 Hz, 1H), 3.79 (d,
J = 6.3 Hz, 1H), 2.84 (m, 1H), 1.21 (d, J = 7.2 Hz, 2H), 1.18 (s, 9H);
13CNMR(75MHz,CDCl3) δ204.2, 159.4, 135.8, 135.7, 133.2, 133.1, 130.3,
130.0, 129.4, 127.9, 113.9, 78.3, 72.0, 62.9, 55.3, 48.4, 26.9, 19.3, 8.5; HRMS
(EI) calculated for C29H36O4SiNa [M + Na] 499.2281, found 499.2281.
Preparation of Sulfone 30. To a solution of phosphonate 298 (96mg,
0.29 mmol) was added n-BuLi (2.5 M in hexanes, 0.12 mL, 0.30 mmol) at
ꢀ78 °C. After the resulting yellow solution was stirred for 1 h, a solution of
aldehyde 28 (100 mg, 0.24 mmol) in THF was added via cannulation. The
mixture was stirred for 1 h and then warmed to room temperature. After
being stirred for 2 h at room temperature, the mixture was quenched with
7839
dx.doi.org/10.1021/jo200934w |J. Org. Chem. 2011, 76, 7834–7841

The Journal of Organic Chemistry
ARTICLE
water and extracted with ethyl acetate. The combined organic layer was dried
over anhydrous MgSO4. After evaporation of the solvent, the crude mixture
was purified by flash column chromatography (support, silica gel; solvent,
hexanes to 20% ethyl acetate in hexanes, Rf = 0.4; 30% ethyl acetate/hexanes)
to provide 30 as a thick yellow oil [128 mg; 90%, diastereomeric ratio (dr) =
2.2:1]. 1H NMR (300 MHz, CDCl3) δ7.97(m, 2H),7.92(m,2H),7.71(m,
3H), 7.59 (m, 3H), 7.26 (m, 3H), 7.13 (s, 1H), 6.93 (m, 2H) 6.32 (m, 1H),
6.19 (t, J = 15 Hz, 1H), 5.74 (m, 1H), 5.60 (m, 1H), 5.38 (m, 1H), 4.53 (m,
1H), 4.31 (m, 1H), 3.88 (s, 3H), 3.81(s, 3H), 3.57 (m, 1H), 3.08 (m, 1H),
2.87 (m, 1H), 2.52 (m, 1H), 2.07 (s, 3H), 2.03 (s, 3H), 1.59 (s, 9H), 1.26 (d,
J= 6.6 Hz, 1H), 0.120 (d, J=4.2Hz, 1H) 1.14(d,J=2.4Hz, 1H), 1.12(d,J=
3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 168.6, 159.1, 142.0, 139.3, 136.7,
135.0, 133.7, 132.2, 130.9, 129.4, 127.9, 127.4, 126.4, 113.8, 82.9, 80.2, 69.9,
66.3, 62.2, 55.3, 42.2, 31.9, 28.2, 20.8, 16.8, 16.0, 14.4; MS (ESI) calculated for
C35H44O6S [M]+ 592.79, found 592.50.
initial exotherm, the reaction mixture was warmed to 40 °C and stirred
for 4 h. The reactions was then quenched with water and extracted with
ethyl acetate. The combined organic layer was dried over anhydrous
MgSO4. After evaporation of the solvent, the crude mixture was purified
by flash column chromatography (support, silica gel; solvent, hexanes to
5% ethyl acetate in hexanes, Rf = 0.4; 20% EA/hexanes) to provide 37
(433 mg, 89% yield). 1H NMR (300 MHz, benzene-d6) 5.90 (ddt, J =
16.5, 10.2, 6.4 Hz, 1H), 5.24ꢀ4.98 (m, 2H), 4.42ꢀ4.06 (m, 2H),
4.06ꢀ3.85 (m, 3H), 3.78 (dd, J = 9.4, 3.8 Hz, 1H), 3.44 (s, 3H) 3.38 (s,
3H), 3.34 (s, 3H), 3.07 (dd, J = 27.1, 7.8 Hz, 1H), 2.48 (ddd, J = 29.2,
22.1, 8.2 Hz, 3H), 2.32 (m, 2H), 1.83 (m, 6H), 1.20 (d, J = 6 Hz, 1H),
1.05 (s, 9H), 0.98 (s, 9H), 0.93 (d, J = 6 Hz, 1H), 0.24 (s, 3H), 0.15
(s, 3H), 0.06 (s, 3H), 0.02 (s, 3H); 13C NMR (75 MHz, benzene-d6)
δ 176.1, 143.9, 133.1, 132.8, 132.4, 119.3, 107.1, 85.6, 82.6, 78.3, 76.4,
73.9, 73.6, 63.1, 56.0, 55.1, 43.8, 42.6, 42.1, 37.6, 35.7, 35.4, 30.9, 30.8,
23.1, 23.0, 17.0, 10.6, 0.8, 0.6, 0.3, 0.0; HRMS (ESI) calculated for
C33H66O9Si2Na [M + Na] 685.4345, found 685.4321.
Preparation of 3. To a mixture of 37 (15 mg, 0.022 mmol) and
boronate 38 (38 mg, 0.22 mmol) in toluene (0.022 mL) was added
Grubbs II catalyst (3.7 mg, 0.0044 mmol) at 25 °C. The resulting mixture
was stirred at 50 °C for 36 h. The reaction mixture was filtered through
silica gel, and the crude product was taken to a new reaction flask
containing vinyl iodide 35 (12 mg, 0.022 mmol) in THF (0.042 mL)
and water (0.010 mL). Tetrakis(triphenylphosphine)palladium(0) (10 mg,
9 μmol) was added at 25 °C and the reaction mixture was degassed by
freezeꢀthaw process 4 times. After the reaction mixture was stirred for
5 min, TlOEt (7 μL, 90 μmol) was added and the reaction stirred for 1 h.
The crude product was purified by flash column chromatography
(support, silica gel; solvent, hexanes to 20% ethyl acetate in hexanes,
Rf = 0.4, 20% ethyl acetate/hexanes) to provide 3 (15.3 mg, 64% yield
over two steps). 1H NMR (300 MHz, CDCl3) δ 7.36 (m, 2H), 7.20 (s,
1H), 6.97 (m, 2H), 6.36 (m, 1H), 6.26 (m, 1H), 6.02 (m, 1H), 5.64 (m,
2H), 5.40 (m, 2H), 5.24 (m, 2H), 4.24 (dd, 2H), 3.92 (s, 3H), 3.60 (m,
2H), 3.50 (t, 1H), 3.36 (s, 6H), 2.61 (m, 1H), 2.20 (m, 2H), 2.04 (s,
3H), 2.02 (s, 3H), 2.00 (s, 3H), 1.65 (s, 9H), 1.60 (s, 9H), 1.51 (s, 9H),
131 (s, 9H), 0.96 (s, 6H); LRMS (ESI) calculated for C60H102O13Si2Na
[M + Na]+ 1109.68, found 1109.39.
Preparation of Sulfone 34. Vinyl sulfone 30 (50 mg, 0.084
mmol) and 18-crown-6 (22 mg, 0.12 mmol) were azeotroped with
toluene (1 mL) three times and dried at high vacuum for 1 h. THF
(0.84 mL) was added and the reaction flask was cooled to ꢀ78 °C. A
solution of sodium hexamethyldisilazane (NaHMDS; 2 M in THF,
0.05 mL, 0.1 mmol) was added when the reaction turns bright yellow.
After the reaction mixture was stirred for 1 h at this temperature, a
solution of iodide 31 (46 mg, 0.12 mmol) in THF (0.2 mL) was added
slowly, during which the reaction color changes from bright yellow to
faint yellow. The mixture was stirred at ꢀ78 °C for 2 h and then slowly
warmed to 25 °C. The reaction was then quenched with water and
extracted with ether. The combined organic layer was dried over
anhydrous MgSO4. After evaporation of the solvent, the crude mixture
is purified by flash column chromatography (support, silica gel; solvent,
hexanes to 20% ethyl acetate in hexanes, Rf = 0.3; 2% ethyl acetate/
hexanes) to provide the desired allyl sulfones 34 (45 mg, 64%) as a 2.2:1
1
diastereomeric mixture. H NMR (300 MHz, CDCl3) δ 7.83 (m, 2H),
7.50 (m, 3H), 7.30 (s, 1H), 7.21 (m, 2H), 7.10 (s, 1H), 6.93 (m, 2H), 6.32
(m, 1H), 6.20 (m, 1H), 6.15 (d, J = 15 Hz, 1H), 5.74 (m, 1H), 5.60 (m,
1H), 5.25 (m, 2H), 5.20 (m, 1H), 4.53 (m, 1H), 4.31 (m, 1H), 3.88 (s,
3H), 3.81 (s, 3H), 3.57 (m, 1H), 3.08 (m, 1H), 2.87 (m, 1H), 2.52 (m,
1H), 2.07(s,3H), 2.03(s,3H), 1.59(s,9H), 1.26(d, J= 6.6 Hz, 1H), 0.120
(d, J = 4.2 Hz, 1H), 1.14 (d, J = 2.4 Hz, 1H), 1.12 (d, J = 3 Hz, 1H); MS
(ESI) calculated for C48H69O8SSiK [M ꢀ H + K] 872.95, found 872.95.
Preparation of Iodide 35. To a solution of chromium(II)
chloride (97 mg, 0.79 mmol) in dry THF (0.8 mL) was added a mixture
of aldehyde 28 (32 mg, 0.079 mmol) and iodoform (31 mg, 0.24 mmol)
in THF at 0 °C under strictly controlled nitrogen atmosphere. The
reaction turns wine-red from the initial aqua-green. After the reaction
mixture was stirred at 0 °C for 12 h, water was added. The mixture was
extracted with ethyl acetate. The combined extract was dried over
anhydrous MgSO4. After evaporation of the solvent, the crude mixture
was purified by flash column chromatography (support, silica gel;
solvent, hexanes to 5% ethyl acetate in hexanes, Rf = 0.3; 5% EA/
hexanes) to provide vinyl iodide 35 (35 mg, 82%). 1H NMR (300 MHz,
CDCl3) δ 7.41 (m, 2H) 7.10 (s, 1H), 6.95 (dd, J = 8.5, 6.4 Hz, 2H), 6.45
(m, 2H), 6.21 (m, 3H), 6.03 (m, 1H), 4.34 (dd, J = 11.6, 3.7 Hz, 2H),
3.88 (s, 3H), 3.64 (m, 1H), 2.03 (s, 3H), 1.97 (s, 3H), 1.66 (s, 9H), 1.42
(d, 3H); 13C NMR (75 MHz, CDCl3) δ 168.4, 159.4, 141.8, 138.6,
134.6, 132.7, 130.4, 129.6, 127.6, 126.7, 114.0, 83.2, 80.2, 77.6, 77.1, 76.7,
72.3, 62.3, 55.3, 38.8, 28.2, 16.8, 16.4, 14.4; HRMS (ESI) calculated for
C26H35IO4Na [M + Na]. 561.1478, found 561.1474.
’ ASSOCIATED CONTENT
S
Supporting Information. NMR spectra for all new com-
b
pounds (3, 6, 9ꢀ11, 13, 15ꢀ17, 19, 21, 24ꢀ28, 30, 34, 35, and
37). This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*pfuchs@purdue.edu
’ ACKNOWLEDGMENT
We sincerely thank Dr. Douglas Lantrip for his laboratory
assistance during these studies. We thank Dr. Karl Wood of
Purdue University for MS.
Preparation of Olefin 37. To a mixture of triol 3625 (500 mg, 0.73
mmol) and 2-nitroselenocyanate (200 mg, 0.88 mmol) in THF (3.7 mL)
at 0 °C was added tri-n-butylphosphine (0.36 mL, 1.5 mmol) under an atmo-
sphere of nitrogen. The reaction turned dark instantly. After the reaction
mixture was stirred at 25 °C for 1.5 h, solid sodium bicarbonate (307 mg,
3.65 mmol) was added, followed by hydrogen peroxide (30 wt % solution
in water, 0.22 mL, 2.2 mmol) slowly at 0 °C in an open flask. After the
’ REFERENCES
(1) Kim, J. W.; Adachi, H.; Shin-ya, K.; Hayakawa, Y.; Seto, H.
J. Antibiot. (Tokyo) 1997, 50, 628.
(2) For a recent review, see Daniel, P. T.; Koert, U.; Schuppan, J.
Angew. Chem., Int. Ed. 2006, 45, 872.
(3) (a) Wender, P. A.; Sukopp, M.; Longcore, K. Org. Lett. 2005,
7, 3025. (b) Wender, P. A.; Longcore, K. E. Org. Lett. 2009, 11, 5474.
7840
dx.doi.org/10.1021/jo200934w |J. Org. Chem. 2011, 76, 7834–7841

The Journal of Organic Chemistry
ARTICLE
(c) Wender, P. A.; Longcore, K. E. Org. Lett. 2007, 9, 691. (d) Wender,
P. A.; Gulledge, A. V.; Jankowski, O. D.; Seto, H. Org. Lett. 2002, 4, 3819.
(4) (a) Wehlan, H.; Dauber, M.; Mujica Fernaud, M. T.; Schuppan,
J.; Mahrwald, R.; Ziemer, B.; Juarez Garcia, M. E.; Koert, U. Angew.
Chem., Int. Ed. 2004, 43, 4597. (b) Nicolaou, K. C.; Li, Y.; Sugita, K.;
Monenschein, H.; Guntupalli, P.; Mitchell, H. J.; Fylaktakidou, K. C.;
Vourloumis, D.; Giannakakou, P.; O’Brate, A. J. Am. Chem. Soc. 2003,
125, 15443. (c) Crimmins, M. T.; Christie, H. S.; Long, A.; Chaudhary,
K. Org. Lett. 2009, 11, 831.
(5) (a) Bouchez, L. C.; Vogel, P. Chem.—Eur. J. 2005, 11, 4609.
(b) Chen, Y.; Evarts, J. B., Jr.; Torres, E.; Fuchs, P. L. Org. Lett. 2002,
4, 3571. (c) Craita, C.; Didier, C.; Vogel, P. Chem. Commun. 2007, 2411.
(d) Crimmins, M. T.; Long, A. Org. Lett. 2005, 7, 4157. (e) Handa, M.;
Scheidt, K. A.; Bossart, M.; Zheng, N.; Roush, W. R. J. Org. Chem. 2008,
73, 1031. (f) Handa, M.; Smith, W. J., 3rd; Roush, W. R. J. Org. Chem.
2008, 73, 1036. (g) Kim, Y.; Fuchs, P. L. Org. Lett. 2007, 9, 2445.
(h) Paquette, W. D.; Taylor, R. E. Org. Lett. 2004, 6, 103. (i) Pennington,
J. D.; Williams, H. J.; Salomon, A. R.; Sulikowski, G. A. Org. Lett. 2002,
4, 3823. (j) Sulikowski, G. A.; Lee, W. M.; Jin, B.; Wu, B. Org. Lett. 2000,
2, 1439. (k) Vargo, T. R.; Hale, J. S.; Nelson, S. G. Angew. Chem., Int. Ed.
2010, 49, 8678. (l) Ghidu, V. P.; Wang, J.; Wu, B.; Liu, Q.; Jacobs, A.;
Marnett, L. J.; Sulikowski, G. A. J. Org. Chem. 2008, 73, 4949. (m) Ghidu,
V. P.; Ntai, I.; Wang, L.; Jacobs, A. T.; Marnett, L. J.; Bachmann, B. O.;
Sulikowski, G. A. Org. Lett. 2009, 11, 3032.
(6) Srinivasarao, M.; Park, T.; Chen, Y.; Fuchs, P. L. Chem. Commun.
2011, 47, 5858.
(7) Paquette, L. A. Org. React. 1977, 25.
(8) Li, X.; Lantrip, D.; Fuchs, P. L. J. Am. Chem. Soc. 2003, 125, 14262.
(9) Sato, K.; Hyodo, M.; Aoki, M.; Zheng, X.-Q.; Noyori, R. Tetra-
hedron 2001, 57, 2469.
(10) Li, X.; Zeng, X. Tetrahedron Lett. 2006, 47, 6839.
(11) Moreno-Ma~nas, M.; Pleixats, R. Handbook of Organopalladium
Chemistry for Organic Synthesis 2002, 2, 1707.
(12) (a) Gais, H.-J.; Jagusch, T.; Spalthoff, N.; Gerhards, F.; Frank,
M.; Raabe, G. Chem.—Eur. J. 2003, 9, 4202. (b) Kuwano, R.; Kondo, Y.;
Shirahama, T. Org. Lett. 2005, 7, 2973. (c) Kuwano, R. Yuki Gosei Kagaku
Kyokaishi 2009, 67, 219. (d) Cacchi, S.; Fabrizi, G.; Goggiamani, A.;
Parisi, L. M. Synlett 2003, 0361, 0364.
(13) Appel, R. Angew. Chem. 1975, 87, 863. Angew. Chem., Int. Ed.
Engl. 1975, 14, 801.
(14) A variety of Pd catalysts were tried, including Pd(OAc)2,
Pd(PPh3)4, Pd(dba)3, and PPh3
(15) (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron
Lett. 1991, 32, 1175. (b) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.;
Morley, A. Synlett 1998, No. 1, 26. (c) Kocienski, P. J.; Bell, A.;
Blakemore, P. R. Synlett 2000, No. 3, 365.
(16) Wadsworth, W. S.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83,
1733.
(17) Zhang, W. J.; Robins, M. J. Tetrahedron Lett. 1992, 33, 1177.
(18) Iodides 32 and 33 were prepared by former group member
Dr. Y. Kim.
(19) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(20) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408.
(21) Kim, Y.; Fuchs, P. L. Org. Lett. 2007, 9, 2445.
(22) (a) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976,
41, 1485. (b) Sharpless, K. B.; Young, M. W. J. Org. Chem. 1975, 40, 947.
(23) Morrill, C.; Funk, T. W.; Grubbs, R. H. Tetrahedron Lett. 2004,
45, 7733.
(24) Frank, S. A.; Chen, H.; Kunz, R. K.; Schnaderbeck, M. J.; Roush,
W. R. Org. Lett. 2000, 2, 2691.
(25) Prepared via lactol-directed osmylation reported in Kim, Y.;
Fuchs, P. L. Org. Lett. 2007, 9, 2445.
7841
dx.doi.org/10.1021/jo200934w |J. Org. Chem. 2011, 76, 7834–7841