Formal total synthesis of (+)-neopeltolide

Article abstract of DOI:10.1021/jo301425c

This paper describes the formal total synthesis of (+)-neopeltolide, a cytotoxic macrolide isolated from the marine sponge Neopeltidae. The key features of the synthesis include an asymmetric Evans alkylation to fix the C9-methyl center, Jacobsen hydrolyt

Full text of DOI:10.1021/jo301425c

Note
pubs.acs.org/joc
Formal Total Synthesis of (+)-Neopeltolide
Sudhakar Athe, Balla Chandrasekhar, Saumya Roy, Tapan Kumar Pradhan, and Subhash Ghosh*
CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
S
* Supporting Information
ABSTRACT: This paper describes the formal total synthesis of (+)-neo-
peltolide, a cytotoxic macrolide isolated from the marine sponge Neopeltidae.
The key features of the synthesis include an asymmetric Evans alkylation to fix
the C9-methyl center, Jacobsen hydrolytic kinetic resolution of terminal epoxides
followed by their regioselective opening to fix the stereocenters at the C11 and
C13 positions, respectively, a Pd-catalyzed oxa-Michael reaction to construct the
tetrahydropyran ring, and Yamaguchi macrolactonization to form the macro-
cyclic core of the molecule.
Scheme 1. Retrosynthetic Analysis of (+)-Neopeltolide (1)
econdary metabolites produced by marine sponges are the
Ssource of architecturally complex and pharmacologically
important compounds. In 2007, Wright and co-workers isolated
neopeltolide, a 14-membered macrolide containing a trisub-
stituted THP ring bearing an O-acylated unsaturated oxazole
having a side chain at C5 position from deep-water sponge of
the family Neopeltidae.1 They established the planar structure
and its relative stereochemistry with the help of detailed NMR
spectroscopic studies. However, in the same year, the
correction of the stereocenters and determination of the
absolute stereochemistry was reported independently by
Panek2a and Scheidt2b through its first total syntheses. Initial
biological studies carried out by Wright and co-workers
revealed that it exhibits potent cytotoxic activities against
various cell lines with nanomolar IC50 values. It also exhibits
antifungal activity against Candida albicans. Because of its
fascinating biological activity and appealing architecture, several
total syntheses,2 formal total syntheses,3 and syntheses of
analogues4 have been reported in the literature. In this paper,
we report the formal total synthesis of (+)-neopeltolide that
exploits a Pd-catalyzed oxa-Michael reaction for the con-
struction of a 2,4,6-trisubstituted tetrahydropyran ring in the
molecule. The retrosynthetic strategy is depicted in Scheme 1.
Retrosynthetically, (+)-neopeltolide could be obtained from the
known keto compound 2 via stereoselective reduction followed
by attachment of the known side chain. Compound 2 could be
obtained from the diol compound 3 through selective oxidation
of the primary alcohol followed by Yamaguchi macrolactoniza-
tion. Compound 4 is a precursor of compound 3, as the
transformation could be achieved through a Pd-catalyzed
intramolecular oxa-Michael reaction, a methodology developed
by Gouverneur et al.5 Again, combination of 5 and 6 by means
of a Horner−Wadsworth−Emmons (HWE) reaction might
provide the desired enone 4.
Accordingly, our synthesis commenced from the known
alcohol 7, which was prepared via an Evans alkylation
reaction.6a,b TBDPS protection of 7 with TBDPSCl and Et3N
in CH2Cl2 provided compound 86c in quantitative yield.
Epoxidation of the olefin 8 with mCPBA afforded a
Received: July 16, 2012
Published: October 5, 2012
© 2012 American Chemical Society
9840
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Note
diastereomeric mixture of terminal epoxides, which on Jacobsen
hydrolytic kinetic resolution with (S,S)-1a furnished diaster-
eomerically pure terminal epoxide 9A (de >98%, 44%) and the
diol compound 9B (de >95%, 45%).7 However, the diol 9B was
converted back to the required epoxide 9A by following a three-
step reaction sequence, as shown in Scheme 2.8 The terminal
epoxide was then opened with vinylmagnesium bromide to give
the homoallylic alcohol 10 in 90% yield. Methylation of the
secondary hydroxyl group furnished the O-methylated
compound 11,9 which on epoxidation followed by Jacobsen
hydrolytic kinetic resolution with (R,R)-1b afforded diaster-
eomerically pure terminal epoxide 12A (de >98%, 43%) and
the diol compound 12B (45%).7 Again the diol 12B was
converted back to the required epoxide following the same sort
of reactions as used earlier for the transformation of 9A from
9B.8 Opening of the terminal epoxide with ethylmagnesium
bromide10 at −40 °C led to the formation of the secondary
alcohol 13, which on benzylation provided the fully protected
compound 14.11 TBDPS deprotection of 14 with TBAF in
THF gave the primary alcohol 15,12a which on tosylation
followed by tosyl displacement with cyanide generated the
cyano compound 16 in 84% over three steps. Finally, partial
reduction of the cyano group with DIBAL-H, followed by
hydrolysis of the intermediate imine, afforded the aldehyde 6.12
The ketophosphonate 5 was synthesized from the known
compound 1713 in two steps. Addition of the anion generated
from CH3PO(OMe)2 to the aldehyde 17 afforded a secondary
alcohol, which on oxidation with DMP provided the
ketophosphonate 5 in 80% yield over two steps (Scheme 3).
a
Scheme 2. Synthesis of Aldehyde 6
a
Scheme 3. Synthesis of Ketophosphonate 5
a
Reagents and conditions: (i) n-BuLi, MePO(OMe)2, THF, −78 °C
to room temperature, 1 h; (ii) DMP, CH2Cl2, 0 °C to room
temperature, 1 h, 80%, over two steps.
After synthesizing the two key fragments, we turned our
attention to coupling them together. Accordingly, a Horner−
Wadsworth−Emmons (HWE) reaction between 5 and 6 was
performed with DIPEA and LiCl in CH3CN to furnish
compound 18 (Scheme 4) in 77% yield.14 TBS deprotection
of 18 with HF-Py in CH3CN provided the crucial intermediate
4 for an oxa-Michael reaction. To perform the oxa-Michael
reaction, compound 4 was subjected to different Pd catalysts
(Table 1); however, the best result was obtained with
Pd(CH3CN)4BF4 in CH2Cl2 and provided chromatographically
separated compound 19A in 48% yield along with the
unrequired isomer 19B in 12% yield.5 The required isomer
19A was subjected to benzyl deprotection to give diol
compound 3 in 95% yield. Selective oxidation of the primary
alcohol with TEMPO provided an aldehyde, which on further
oxidation under Pinnick conditions15 followed by Yamaguchi
macrolactonization16 of the resulting seco acid provided the
known macrocyclic ketone 2, whose analytical and spectral data
were in good agreement with the literature report.2c,d
In conclusion, a formal total synthesis of (+)-neopeltolide
has been achieved by using Evans asymmetric alkylation,
Jacobsen hydrolytic kinetic resolution, a Horner−Wadsworth−
Emmons (HWE) reaction, a Pd-catalyzed intramolecular oxa-
Michael reaction, and Yamaguchi macrolactonization as key
steps. The known keto compound 2 was synthesized in 27
steps (longest linear sequence) from compound 8 with an
overall yield of 3.49%.
a
Reagents and conditions: (i) TBDPS-Cl, Et3N, DMAP, CH2Cl2, 0 °C
to room temperature, 12 h, quantitative; (ii) (a) mCPBA, CH2Cl2,
0
°C to room temperature, 10 h, 96%, (b) (S,S)-1a, H2O, 24 h, 44%
(9A), 45% (9B); (iii) (a) AcCl, 2,4,6-collidine, CH2Cl2, −78 °C, 10 h,
(b) MsCl, Et3N, CH2Cl2, 0 °C, 2 h, (c) K2CO3, MeOH, 0 °C, 1 h, 66%
over three steps; (iv) vinylmagnesium bromide, CuI, THF, −40 to 0
°C, 1 h, 90%; (v) KH, MeI, THF; 0 °C to room temperature, 30 min,
91%; (vi) (R,R)-1b, H2O, 24 h, 43% (12A), 45% (12B); (vii) EtMgBr,
CuI, THF, −40 °C to room temperature, 1 h, 88%; (viii) benzyl
trichloroacetimidate, CF3SO3H, cyclohexane/CH2Cl2 (2/1), 0 °C to
room temperature, 2 h, 88%; (ix) TBAF, THF, 0 °C to room
temperature, 3 h, 99%; (x) (a) TsCl, Et3N, DMAP, CH2Cl2, 0 °C to
room temperature, 3 h, (b) NaCN, NaI, DMSO, 90 °C, 1 h, 84% over
two steps; (xi) DIBAL-H, CH2Cl2, −78 to 0 °C, 1 h, then 3 N NaOH,
0 °C, 89%.
EXPERIMENTAL SECTION
tert-Butyl((S)-2-methyl-3-((S)-oxiran-2-yl)propoxy)-
diphenylsilane (9A) and (2R,4S)-5-(tert-Butyldiphenylsilyloxy)-
4-methylpentane-1,2-diol (9B). To a stirred solution of olefin 8 (6
■
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Note
under vacuum. The epoxide prepared above (5.8 g, 16.3 mmol) was
added in one portion, and the stirred mixture was cooled in an ice−
water bath. Water (162 μL, 9 mmol) was added slowly to the reaction
mixture, and the reaction mixture was stirred for 24 h at room
temperature. The crude products were purified by column
chromatography (SiO2, 2% EtOAc in hexane for 9A and 40%
EtOAc in hexane for 9B) to give compound 9A as a colorless oil (2.52
g, 44%) and 9B (2.36 g, 45%).
Scheme 4. Coupling of Compounds 5 and 6 and Completion
of the Synthesis
a
Analytical data of compound 9A: Rf = 0.4 (SiO2, 10% EtOAc in
hexane); [α]D24 = −2.97° (c 5.35, CHCl3); IR νmax 3418, 1627, 1108,
701 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.66−7.59 (m, 4H), 7.42−
7.31 (m, 6H), 3.51 (dq, J = 10.0, 6.0 Hz, 2H), 2.86 (m, 1H), 2.69 (m,
1H), 2.38 (dd, J = 5.0, 2.0 Hz, 1H), 1.90 (m, 1H), 1.66 (m, 1H), 1.35
(m, 1H), 1.05 (s, 9H), 1.0 (d, J = 7.0 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 135.5, 133.7, 129.5, 127.6, 68.7, 50.9, 47.5, 36.2, 33.7, 26.8,
19.2, 16.6; MS (ESI) m/z 377 [M + Na]+; HRMS (ESI, TOF) calcd
for C22H30O2SiNa [M + Na]+ 377.1912, found 377.1897.
Analytical data of compound 9B: Rf = 0.4 (SiO2, 60% EtOAc in
hexane); [α]22 = −1.13° (c 4.05, CHCl3); IR νmax 3347, 2931, 1465,
D
1426, 1107, 1066, 821, 739, 701 cm−1; 1H NMR (300 MHz, CDCl3) δ
7.70−7.62 (m, 4H), 7.49−7.34 (m, 6H), 3.84 (m, 1H), 3.65−3.38 (m,
4H), 2.88 (br s, 1H), 2.03 (br s, 1H), 1.91 (m, 1H), 1.52−1.43 (m,
2H), 1.06 (s, 9H), 0.92 (d, J = 6.8 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 135.6, 135.5, 133.3, 129.7, 127.7, 69.9, 68.7, 66.9, 37.5, 32.2,
26.8, 19.2, 17.5; MS (ESI) m/z 395 [M + Na]+; HRMS (ESI, TOF)
calcd for C22H32O3SiNa [M + Na]+ 395.2018, found 395.2023.
Experimental Procedure for the Conversion of 9B to 9A. To
a solution of compound 9B (2 g, 5.36 mmol) in anhydrous CH2Cl2
(20 mL) at −78 °C was added 2,4,6-collidine (1.4 mL, 10.7 mmol).
After 10 min, acetyl chloride (0.4 mL, 5.9 mmol) was added to the
reaction mixture and stirring was continued for another 10 h at the
same temperature. The reaction mixture was quenched with saturated
aqueous NH4Cl solution and extracted with EtOAc. The combined
organic layers were washed with saturated CuSO4 solution, water, and
brine, dried (Na2SO4), and concentrated in vacuo. The monoacetyl
compound (Rf = 0.5, 40% EtOAc in hexane) thus obtained was used
for the next reaction.
To a solution of crude monoacetyl compound (1.96 g, 4.7 mmol) in
anhydrous CH2Cl2 (15 mL) at 0 °C was added Et3N (1.3 mL, 9.4
mmol). After 10 min of stirring, MsCl (0.5 mL, 7.1 mmol) and then
DMAP (58 mg, 0.47 mmol) were added to the reaction mixture, the
temperature was raised to room temperature, and stirring was
continued for another 2 h. The reaction mixture was then quenched
with saturated aqueous NH4Cl solution and diluted with EtOAc. The
organic layer was separated and washed successively with water and
brine, dried (Na2SO4), and concentrated in vacuo. The mesylate (Rf =
0.5, 20% EtOAc in hexane) thus obtained was used directly in the next
reaction.
a
Reagents and conditions: (i) LiCl, DIPEA, CH3CN, room temper-
ature, 30 min, then 6, 12 h, 77%; (ii) HF-Py, CH3CN, 0 °C to room
temperature, 12 h, 80%; (iii) Pd(CH3CN)4BF4, CH2Cl2, room
temperature, 12 h, 19A (48%) and 19B (12%); (iv) (a) separation,
(b) 19A, H2, Pd/C, EtOAc, rtoom temperature, 2 h, 95%; (v) (a)
TEMPO, BAIB, CH2Cl2, 0 °C to room temperature, 5 h; (b) NaClO2,
t
2-methyl-2-butene, NaH2PO4, BuOH/H2O (2/1), 0 °C to room
temperature, 1 h, 77% over two steps; (c) Cl3C6H2COCl, Et3N, THF,
room temperature, 1 h, then it was added to a solution of DMAP in
toluene at 80 °C, 16 h, 83%.
Table 1
combined
yield, %
entry
1
cat. (10 mol %)
PdCl2
conditions
19A:19B
CH2Cl2, room temp,
12 h
2
3
4
5
6
Pd(OAc)2
CH2Cl2, room temp,
12 h
Pd(PPh3)2Cl2
Pd(dppf)Cl2
Pd(CH3CN)2Cl2
CH2Cl2, room temp,
12 h
To a solution of mesylate (2.09 g, 4.2 mmol) in anhydrous
methanol (15 mL) at room temperature was added anhydrous K2CO3
(2.93 g, 21.2 mmol) under a nitrogen atmosphere, and stirring was
continued for 1 h. The reaction mixture was diluted with water, and
methanol was evaporated under reduced pressure. Then the reaction
mixture was extracted with EtOAc. The organic layer was washed with
water and brine and dried over Na2SO4. Purification by column
chromatography (SiO2, 2% EtOAc in hexane) gave pure compound
9A (1.38 g, 66%, over three steps) as a colorless oil.
CH2Cl2, room temp,
24 h
n.d.
3:2
4:1
10
45
60
CH2Cl2, room temp,
12 h
Pd(CH3CN)4BF4 CH2Cl2, room temp,
12 h
g, 17.7 mmol) in CH2Cl2 (53 mL) at 0 °C was added mCPBA (70%,
5.24 g, 21.2 mmol). The reaction mixture was stirred at room
temperature for 10 h and then quenched with saturated aqueous
NaHCO3 solution. The resulting mixture was extracted with EtOAc,
washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4),
and concentrated in vacuo. The residue was purified by column
chromatography (SiO2, 2% EtOAc in PE) to yield a diastereomeric
mixture of epoxides (6 g, 96%) as a colorless oil.
A mixture of Co(II) (S,S)-N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-
cyclohexanediamino precatalyst (49 mg, 0.08 mmol) in toluene (1
mL) and AcOH (9.4 μL, 0.08 mmol) was stirred while open to the air
for 1 h at room temperature. The solvent was removed by a rotary
evaporator under reduced pressure, and the brown residue was dried
(4R,6S)-7-(tert-Butyldiphenylsilyloxy)-6-methylhept-1-en-4-
ol (10). To a cold (−20 °C) suspension of CuI (268 mg, 1.4 mmol) in
THF (10 mL) was added a solution of vinylmagnesium bromide (1 M
in THF, 21 mL, 21 mmol) via a syringe under an argon atmosphere.
The resulting mixture was stirred for 5 min and then cooled to −40 °C
before adding a solution of epoxide 9A (2.5 g, 7.0 mmol) in THF (10
mL). The reaction mixture was warmed to −20 °C and stirred for 1 h
at this temperature. The reaction mixture was quenched with saturated
aqueous NH4Cl solution, and the aqueous layer was extracted with
EtOAc. The combined organic layers were washed with water and
brine, dried (Na2SO4), filtered, and concentrated in vacuo. The
product was purified by silica gel column chromatography (SiO2, 3%
EtOAc in hexane) to yield alcohol 10 (2.42 g (90%) as a clear liquid:
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Note
24
Rf = 0.4 (SiO2, 10% EtOAc in hexane); [α]D = −5.93° (c 4.30,
and brine, dried (Na2SO4), and concentrated in vacuo. The crude
benzyl ether was purified by column chromatography (SiO2, 2%
EtOAc in hexane) afforded compound 14 as a colorless oil (632 mg,
CHCl3); IR νmax 3396, 2363, 1641, 1107, 701 cm−1; H NMR (300
1
MHz, CDCl3) δ 7.72−7.62 (m, 4H), 7.47−7.33 (m, 6H), 5.83 (m,
1H), 5.16−5.06 (m, 2H), 3.75 (m, 1H), 3.50 (d, J = 6.0 Hz, 2H), 2.45
(bs, 1H), 2.31−2.12 (m, 2H), 1.89 (dd, J = 12.8, 6.8 Hz, 1H), 1.51 (m,
1H), 1.35 (m, 1H), 1.06 (s, 9H), 0.89 (d, J = 6.8 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 135.6, 135.0, 133.5, 129.6, 127.6, 117.6, 69.7,
69.0, 42.6, 41.6, 33.2, 26.8, 19.20, 17.2; MS (ESI) m/z 405 [M + Na]+;
HRMS (ESI, TOF) calcd for C24H34O2SiNa [M + Na]+ 405.2225,
found 405.2228.
24
88%): Rf = 0.5 (SiO2, 2.5% EtOAc in hexane); [α]D = +14.11° (c
1.76, CHCl3); IR νmax 3030, 2927, 2859, 1459, 1369, 1091, 836, 738
cm−1; 1H NMR (300 MHz, CDCl3) δ 7.70−7.63 (m, 4H), 7.45−7.29
(m, 11H), 4.51 (ABq, J = 11.3 Hz, 2H), 3.63−3.41 (m, 4H), 3.24 (s,
3H), 1.78 (m, 1H), 1.64−1.31 (m, 7H), 1.16 (m, 1H), 1.05 (s, 9H),
0.99−0.89 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 139.0, 135.6,
133.9, 129.5, 128.3, 127.8, 127.5, 127.4, 75.8, 75.7, 71.0, 69.0, 56.0,
40.2, 37.8, 36.6, 32.4, 26.9, 19.3, 18.3, 17.2, 14.3; MS (ESI) m/z 533
[M + H]+; HRMS (ESI, TOF) calcd for C34H48O3SiNa 555.3270 [M
+ Na]+, found 555.3254.
tert-Butyl((2S,4R)-4-methoxy-2-methylhept-6-enyloxy)-
diphenylsilane (11). Alcahol 10 was converted to O-methylated
compound 11 according to the reported procedure:9 Rf = 0.5 (SiO2,
24
10% EtOAc in hexane); [α]D = −12.02° (c 3.60, CHCl3); IR νmax
(2S,4S,6S)-6-(Benzyloxy)-4-methoxy-2-methylnonan-1-ol
(15). Compound 14 (600 mg, 1.1 mmol) was converted to alcohol 15
according to the procedure reported earlier.12a Purification by column
chromatography (SiO2, 15−20% EtOAc in hexane) afforded
compound 15 as a colorless liquid (328 mg, 99%): Rf = 0.2 (SiO2,
1638, 1104, 701 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.72−7.63 (m,
4H), 7.45−7.34 (m, 6H), 5.78 (m, 1H), 5.05 (t, J = 9.0 Hz, 2H), 3.53
(m, 1H), 3.43 (m, 1H), 3.34−3.27 (m, 4H), 2.33−2.16 (m, 2H), 1.88
(m, 1H), 1.60 (m, 1H), 1.21 (m, 1H), 1.05 (s, 9H), 0.96 (d, J = 6.0
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 135.9, 135.6, 134.7, 133.9,
129.4, 127.5, 116.9, 78.1, 69.2, 56.2, 38.0, 37.5, 32.3, 26.8, 19.3, 16.9;
MS (ESI) m/z 397 [M + H]+; HRMS (ESI, Orbitrap) calcd for
C25H37O2Si [M + H]+ 397.25573, found 397.25617.
29
20% EtOAc in hexane); [α]D = +12.57° (c 1.79, CHCl3); IR νmax
1
3424, 2927, 2870, 1457, 1373, 1200, 1085, 738 cm−1; H NMR (500
MHz, CDCl3) δ 7.36−7.26 (m, 5H), 4.58 and 4.46 (ABq, J = 11.3 Hz,
2H), 3.57 (m, 1H), 3.50−3.39 (m, 3H), 3.29 (s, 3H), 2.18 (br s, 1H),
1.78 (dq, J = 12.9, 6.5 Hz, 1H), 1.72−1.55 (m, 4H), 1.50 (m, 1H),
1.45−1.35 (m, 2H), 1.30 (m, 1H), 0.96−0.90 (m, 6H); 13C NMR (75
MHz, CDCl3) δ 138.8, 128.3, 127.8, 127.5, 76.0, 70.9, 68.4, 56.3, 39.8,
39.1, 36.4, 33.4, 18.2, 17.8, 14.3; MS (ESI) m/z 317 [M + Na]+;
HRMS (ESI, TOF) calcd for C18H30O3Na [M + Na]+ 317.2092, found
317.2088.
tert-Butyl((2S,4S)-4-methoxy-2-methyl-5-((R)-oxiran-2-yl)-
pentyloxy)diphenylsilane (12A) and (2S,4S,6S)-7-(tert-Butyldi-
phenylsilyloxy)-4-methoxy-6-methylheptane-1,2-diol (12B).
Epoxide 12A and the diol 12B were prepared by following the same
procedure as used above for the synthesis of 9A and 9B.
Analytical data for 12A: Rf = 0.6 (SiO2, 10% EtOAc in hexane);
24
[α]D = +2.54° (c 2.75, CHCl3); IR νmax 3047, 2931, 2859, 1736,
(3R,5S,7S)-7-(Benzyloxy)-5-methoxy-3-methyldecanenitrile
(16). Compound 15 (200 mg, 1.0 mmol) was converted to cyano
compound 16 by following the same procedure as described in earlier
published work.12a Purification by column chromatography (SiO2, 5%
EtOAc in hexane) afforded compound 16 as a colorless liquid (259
mg, 84%): Rf = 0.2 (SiO2, 10% EtOAc in hexane); [α]D24 = +38.02° (c
3.60, CHCl3); IR νmax 3031, 2927, 2362, 1516, 1367, 1089, 835, 776,
1
1465, 1427, 1189, 1103, 821, 741, 702 cm−1; H NMR (300 MHz,
CDCl3) δ 7.71−7.62 (m, 4H), 7.47−7.32 (m, 6H), 3.57−3.41 (m,
3H), 3.35 (s, 3H), 3.02 (m, 1H), 2.79 (m, 1H), 2.47 (m, 1H), 1.86 (m,
1H), 1.79−1.65 (m, 2H), 1.61 (m, 1H), 1.2 (m, 1H), 1.05 (s, 9H),
0.97 (d, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 136.1, 135.8,
134.1, 129.7, 127.7, 77.1, 69.3, 57.0, 49.8, 47.7, 38.4, 37.8, 32.5, 27.0,
19.5, 17.2; MS (ESI) m/z 413 [M + H]+; HRMS (ESI, TOF) calcd for
C25H36O3SiNa [M + Na]+ 435.2331, found 435.2335.
1
738, 698 cm−1; H NMR (300 MHz, CDCl3) δ 7.40−7.26 (m, 5H),
4.60 and 4.43 (ABq, J = 11.3 Hz, 2H), 3.58 (m, 1H), 3.42 (m, 1H),
3.26 (s, 3H), 2.39−2.19 (m, 2H), 2.02 (m, 1H), 1.70−1.30 (m, 8H),
1.09 (t, J = 6.8 Hz, 3H), 0.99−0.90 (m, 3H); 13C NMR (75 MHz,
CDCl3) δ 138.7, 128.3, 127.8, 127.5, 118.6, 75.8, 75.7, 71.0, 56.4, 40.5,
39.8, 36.3, 27.3, 24.8, 19.7, 18.1, 14.3; MS (ESI) m/z 326 [M + Na]+;
HRMS (ESI, TOF) calcd for C19H29NO2Na [M + Na]+ 326.2096,
found 326.2090.
Analytical data for compound 12B: Rf = 0.4 (SiO2, 60% EtOAc in
24
hexane); [α]D = +5.95° (c 4.45, CHCl3); IR νmax 3393, 2930, 2859,
2362, 1464, 1427, 1103, 1081, 819, 740, 701 cm−1; H NMR (300
1
MHz, CDCl3) δ 7.71−7.61 (m, 4H), 7.48−7.33 (m, 6H), 3.84 (m,
1H), 3.72 (br s, 1H), 3.65−3.52 (m, 2H), 3.51−3.38 (m, 3H), 3.33 (s,
3H), 2.20 (br s, 1H), 1.91−1.69 (m, 2H), 1.69−1.48 (m, 2H), 1.25
(m, 1H), 1.06 (s, 9H), 0.96 (d, J = 6.42 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 135.5, 133.8, 133.7, 129.6, 127.6, 79.6, 71.5, 68.7, 66.7, 55.7,
37.2, 37.1, 32.3, 26.8, 19.2, 17.6; MS (ESI) m/z 453 [M + Na]+;
HRMS (ESI, TOF) calcd for C25H38O4SiNa [M + Na]+ 453.243,
found 453.2444.
(4S,6S,8S)-9-(tert-Butyldiphenylsilyloxy)-6-methoxy-8-meth-
ylnonan-4-ol (13). Alcohol 13 was synthesized from the epoxide 12A
in 88% yield by following the same procedure as used above for the
synthesis of compound 10: Rf = 0.4 (SiO2, 10% EtOAc in hexane);
(S)-Dimethyl 6-(Benzyloxy)-4-(tert-butyldimethylsilyloxy)-2-
oxohexylphosphonate (5). To a solution of freshly distilled
dimethyl methylphosphonate (2 mL, 18 mmol) in anhydrous THF
(37 mL) was added n-BuLi (1.6 M solution in hexane, 9 mL, 15
mmol) in a dropwise manner at −78 °C and stirred at the same
temperature for 1 h. Compound 17 (2 g, 6.2 mmol) was added to the
reaction mixture as a THF solution (12 mL) slowly over a period of 10
min. The resulting mixture was stirred for 1 h at the same temperature
and then warmed to ambient temperature before quenching with
saturated aqueous NH4Cl solution at 0 °C. The product was extracted
with EtOAc, washed with water and brine, dried over Na2SO4, and
concentrated in vacuo. The hydroxyl compound (Rf = 0.4, 70% EtOAc
in hexane) thus obtained was directly used after silica gel column
chromatography for the next reaction.
24
[α]D = +4.75° (c 4.50, CHCl3); IR νmax 3449, 2954, 2930, 2861,
1463, 1427, 1384, 1104, 1085, 819, 704, 701 cm−1; H NMR (300
1
MHz, CDCl3) δ 7.72−7.62 (m, 4H), 7.48−7.33 (m, 6H), 3.88 (m,
1H), 3.62−3.41 (m, 3H), 3.32 (s, 3H), 2.97 (br s, 1H), 1.91−1.57 (m,
4H), 1.56−1.15 (m, 5H), 1.06 (s, 9H), 1.01−0.88 (m, 6H); 13C NMR
(75 MHz, CDCl3) δ 135.6, 133.8, 129.5, 127.9, 127.6, 77.6, 68.8, 68.4,
56.5, 39.8, 39.2, 36.9, 32.5, 26.8, 19.2, 18.8, 17.3, 14.1; MS (ESI) m/z
443 [M + H]+; HRMS (ESI, TOF) calcd for C27H42O3SiNa [M +
Na]+ 465.2800, found 465.2805.
((2S,4S,6S)-6-(Benzyloxy)-4-methoxy-2-methylnonyloxy)-
(tert-butyl)diphenylsilane (14). To a solution of compound 13
(600 mg, 1.45 mmol) in cyclohexane and CH2Cl2 (2/1, 6 mL) were
added benzyl trichloroacetimidate (30 mg, 2.9 mmol) and
trifluoromethanesulfonic acid (0.5 mL, 0.14 mmol) at 0 °C, and
stirring was continued at room temperature for 2 h. The reaction
mixture was then diluted with CH2Cl2 and passed through a short pad
of silica gel and washed with cyclohexane and DCM (2/1, 10 mL).
The combined filtrates were washed with saturated aqueous NaHCO3
To a solution of the alcohol prepared above (2.5 g, 5.5 mmol) in
CH2Cl2 (16 mL) was added NaHCO3 (1.4 g, 16.5 mmol) at room
temperature. Dess−Martin periodinane (DMP; 4.7g, 11 mmol) was
added to the reaction mixture and stirred for 1 h at room temperature
under a nitrogen atmosphere. Saturated Na2S2O3 and NaHCO3 were
then added, and the biphasic mixture was stirred for 15 min and
extracted with EtOAc. The combined organic layers were washed with
water and brine, dried (Na2SO4), and concentrated in vacuo.
Purification of the residue by column chromatography (SiO2, 20%
EtOAc in hexane) provided pure compound 5 as a colorless oil (2.2 g,
80%): Rf = 0.5 (SiO2, 60% EtOAc in hexane); [α]D24 = +9.61° (c 2.85,
CHCl3); IR νmax 3421, 2953, 2929, 2856, 1714, 1460, 1367, 1254,
1
1031, 836, 779 cm−1; H NMR (300 MHz, CDCl3) δ 7.37−7.26 (m,
9843
dx.doi.org/10.1021/jo301425c | J. Org. Chem. 2012, 77, 9840−9845

The Journal of Organic Chemistry
Note
5H), 4.47 (ABq, J = 11.3 Hz, 2H), 4.33 (dd, J = 11.3, 6.1 Hz, 1H), 3.76
(d, J = 1.5 Hz, 3H), 3.74 (d, J = 1.5 Hz, 3H), 3.53 (td, J = 6.1,1.5 Hz,
2H), 3.12 (s, 1H), 3.05 (s, 1H), 2.79 (d, J = 6.0 Hz, 2H), 1.84−1.66
(m, 2H), 0.85 (s, 9H), 0.04 (d, J = 6.5 Hz, 6H); 13C NMR (75 MHz,
CDCl3) δ 200.6, 138.2, 128.2, 127.5, 127.4, 72.8, 66.3, 66.2, 52.9, 52.8,
51.3, 43.2, 41.5, 37.0, 25.7, 17.8; MS (ESI) m/z 445 [M + H]+; HRMS
(ESI, TOF) calcd for C21H37O6PSiNa [M + Na]+ 467.1994, found
467.1974.
(3S,9R,11S,13S,E)-1,13-Bis(benzyloxy)-3-(tert-butyldimethyl-
silyloxy)-11-methoxy-9-methylhexadec-6-en-5-one (18). To a
solution of 16 (200 mg, 0.66 mmol) in CH2Cl2 (4 mL) was added
DIBAL-H (1 M, 1.4 mL, 1.4 mmol) at −78 °C, and the mixture was
stirred for 1 h at the same temperature. Then it was quenched with 3
N aqueous NaOH solution (1.45 mL) and stirred for an additional 1 h
at 0 °C. The reaction mixture was diluted with CH2Cl2 (6 mL),
washed with water and brine, dried (Na2SO4), and concentrated in
vacuo. The aldehyde 6 (Rf = 0.3; SiO2, 10% EtOAc in hexane) thus
obtained was directly used after flash chromatography for the next
reaction.
To compound 5 (340 mg, 0.76 mmol) in anhydrous CH3CN (6
mL) were added LiCl (33 mg, 0.76 mmol) and DIPEA (1.3 mL, 7.6
mmol) sequentially at room temperature, and the reaction mixture was
stirred for 30 min. Aldehyde 6 (179 mg, 0.58 mmol) was transferred to
the reaction mixture as a solution of CH3CN under a nitrogen
atmosphere, and the resulting mixture was stirred at the same
temperature for 12 h. CH3CN was evaporated on a rotary evaporator,
and the residue was dissolved in EtOAc, washed with a saturated
aqueous solution of NH4Cl, water, and brine, dried (Na2SO4), and
concentrated in vacuo. Purification by column chromatography (SiO2,
one (19B). To a stirred solution of compound 4 (66 mg, 0.12 mmol)
in anhydrous CH2Cl2 (3 mL) was added Pd(CH3CN)4BF4 (6 mg, 10
mol %) at room temperature under an argon atmosphere, and the
mixture was stirred at room temperature for 12 h. The reaction
mixture was then diluted with Et2O and filtered through a short pad of
silica gel. The solvent was removed in vacuo to give the crude
products, which were further purified by column chromatography
(SiO2, 8% EtOAc in hexane) to afford compound 19A as a colorless oil
(32 mg, 48%) and (SiO2, 9% EtOAc in hexane) 19B (8 mg, 12%).
Analytical data for compound 19A: Rf = 0.5 (SiO2, 20% EtOAc in
hexane); [α]D24 = +3.47° (c 0.835, CHCl3); IR νmax 2923, 2861, 1718,
1
1456, 1369, 1092, 738, 629 cm−1; H NMR (500 MHz, CDCl3) δ
7.35−7.17 (m, 10H), 4.56 and 4.42 (two d, J = 12.0 Hz, 2H), 4.44 (s,
2H), 3.74 (m, 1H), 3.65−3.48 (m, 4H), 3.40 (m, 1H), 3.21 (s, 3H),
2.36−2.23 (m, 2H), 2.21−2.09 (m, 2H), 1.92−1.74 (m, 2H), 1.70−
1.22 (m, 10H), 1.17 (m, 1H), 0.97−0.82 (m, 6H); 13C NMR (75
MHz, CDCl3) δ 207.4, 139.0, 138.3, 128.4, 128.3, 127.7, 127.6, 127.4,
75.8, 75.7, 74.6, 73.8, 70.9, 66.3, 56.4, 48.4, 47.9, 43.9, 42.4, 40.2, 36.6,
36.5, 25.9, 19.7, 18.3, 14.3; MS (ESI) m/z 353 [M + Na]+; HRMS
(ESI, TOF) calcd for C32H46O5Na [M + Na]+ 533.3242, found
533.3229.
Analytical data for compound 19B: Rf = 0.45 (20% EtOAc in
hexane); [α]D24 = −6.99° (c 0.30, CHCl3); IR νmax 2923, 2855, 2362,
1
1718, 1459, 1273, 1027, 709 cm−1; H NMR (500 MHz, CDCl3) δ
7.35−7.16 (m, 10H), 4.60−4.36 (m, 4H), 4.25 (m, 1H), 4.13 (m, 1H),
3.64−3.45 (m, 3H), 3.41 (m, 1H), 3.21 (s, 3H), 2.52−2.40 (m, 2H),
2.21(dd, J = 14.0, 7.0 Hz, 1H), 2.14 (dd, J = 14.0, 6.0 Hz, 1H), 1.84
(m, 1H), 1.78−1.68 (m, 2H), 1.66−1.22 (m, 9H), 1.08 (m, 1H),
0.98−0.82 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 207.6, 138.9,
138.3, 129.5, 128.3, 127.8, 127.6, 127.5, 75.9, 75.6, 73.0, 72.2, 70.9,
69.0, 66.2, 47.2, 46.9, 41.7, 40.2, 37.2, 34.6, 25.9, 22.6, 20.4, 18.5, 14.3;
MS (ESI) m/z 353 [M + Na]+; HRMS (ESI, Orbitrap) calcd for
C32H46O5Na [M + Na]+ 533.32375, found 533.32605.
5% EtOAc in hexane) afforded pure compound 18 as a colorless oil
24
(271.6 mg, 77%): Rf = 0.6 (SiO2, 10% EtOAc in hexane); [α]D
=
+21.20° (c 2.90, CHCl3); IR νmax 3030, 2953, 2927, 2859, 1669,1627,
1
1459, 1369, 1252, 1091, 836, 777, 738, 698 cm−1; H NMR (500
MHz, CDCl3) δ 7.38−7.26 (m, 10H), 6.76 (m, 1H), 6.08 (d, J = 15.9
Hz, 1H), 4.59 (d, J = 10.9 Hz, 1H), 4.52−4.43 (m, 2H), 4.38 (dt, J =
11.9, 5.9 Hz, 1H), 3.62−3.51 (m, 4H), 3.45 (m, 1H), 3.25 (s, 3H),
2.77 (dd, J = 6.9, 5.9 Hz, 1H), 2.62 (dd, J = 5.9, 4.9 Hz, 1H), 2.21 (m,
1H), 2.03 (m, 1H), 1.88−1.75 (m, 3H), 1.67−1.45 (m, 5H), 1.44−
1.35 (m, 2H), 1.20 (m, 1H), 0.98−0.90 (m, 6H), 0.85 (s, 9H), 0.03 (d,
J = 20.9 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 198.9, 146.1, 138.8,
138.4, 132.6, 128.3, 127.8, 127.5, 127.4, 75.7, 75.6, 72.8, 70.9, 66.8,
66.5, 56.4, 47.8, 41.6, 40.2, 40.1, 37.5, 36.4, 29.6, 29.1, 25.7, 19.7, 18.2,
17.9, 14.3; MS (ESI) m/z 648 [M + Na]+; HRMS (ESI, TOF) calcd
for C38H60O5SiNa [M + Na]+ 647.4107, found 647.4107.
(2R,6S)-2-((2S,4S,6S)-6-Hydroxy-4-methoxy-2-methylnonyl)-
6-(2-hydroxyethyl)dihydro-2H-pyran-4(3H)-one (3). To a sol-
ution of 19A (28 mg, 0.05 mmol) in EtOAc (8 mL) was added Pd−C
(10%), and the mixture was hydrogenated using a H2-filled balloon for
2 h. It was then filtered through a short pad of Celite, and the filter
cake was washed with EtOAc. The filtrate and washings were
combined and concentrated in vacuo. Purification by column
chromatography (SiO2, 60% EtOAc in hexane) afforded compound
3 as a colorless oil (17.1 mg, 95%): Rf = 0.5 (100% EtOAc); [α]24
=
D
+3.38° (c 1.95, CHCl3); IR νma1x 3406, 2924, 2286, 1713, 1459, 1373,
1329, 1239, 1136, 1083 cm−1; H NMR (500 MHz, CDCl3) δ 3.94−
3.76 (m, 4H), 3.71 (m, 1H), 3.54 (m, 1H), 3.37 (s, 3H), 2.41−2.21
(m, 4H), 1.92−1.66 (m, 6H), 1.53−1.32 (m, 4H), 1.31−1.18 (m, 3H),
0.94 (dd, J = 13.8, 6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 206.7,
77.5, 75.9, 75.5, 68.5, 60.0, 56.8, 48.3, 47.6, 43.8, 41.2, 40.1, 39.6, 38.2,
26.7, 20.0, 18.7, 14.0; MS (ESI) m/z 331 [M + H]+, 353 [M + Na]+;
HRMS (ESI, Orbitrap) calcd for C18H35O5 [M + H]+ 331.24790,
found 331.24827.
(1R,5S,7S,9S,11R)-7-Methoxy-9-methyl-5-propyl-4,15-
dioxabicyclo[9.3.1]pentadecane-3,13-dione (2). BAIB (12.8 mg,
0.04 mmol) was added to a solution of 3 (12 mg, 0.036 mmol) and
TEMPO (0.56 mg, 0.003 mmol) in CH2Cl2 (1 mL) at 0 °C. After the
reaction mixture was stirred at room temperature for 5 h, the mixture
was diluted with CH2Cl2 (2 mL), washed with saturated aqueous
Na2S2O3 solution, and extracted with CH2Cl2. The combined organic
layers were washed with aqueous NaHCO3 solution and brine, dried
(Na2SO4), and concentrated. The crude aldehyde was immediately
used for the next reaction.
The conversion of crude aldehyde to seco acid followed by its
macrolactonization, leading to the formation of compound 2 (7 mg,
64%) from 3, was carried out according to the reported
procedure.3a,2e,f
Analytical data for compound 2: Rf = 0.45 (20% EtOAc in
hexane); [α]D24 = +17.12° (c 0.80, CHCl3); IR νmax 2923, 1726, 1250,
1091 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.21 (m, 1H), 4.04 (tt, J =
10.8, 2.9 Hz, 1H), 3.58 (m, 1H), 3.50 (dt, J = 9.8, 2.9 Hz, 1H), 3.33 (s,
3H), 2.71 (dd, J = 14.8, 3.9 Hz, 1H), 2.51 (dd, J = 14.8, 9.8 Hz, 1H),
(3S,9R,11S,13S,E)-1,13-Bis(benzyloxy)-3-hydroxy-11-me-
thoxy-9-methylhexadec-6-en-5-one (4). To a solution of
compound 18 (150 mg, 0.24 mmol) in anhydrous CH3CN (1 mL)
was added HF-py complex (40%, 0.1 mL) at 0 °C. The mixture was
warmed to room temperature and stirred for 18 h. The reaction
mixture was cautiously poured into aqueous NaHCO3 solution and
extracted with EtOAc. The combined organic layers were washed with
water and brine, dried (Na2SO4), and concentrated in vacuo.
Purification by column chromatography (SiO2, 16% EtOAc in hexane)
afforded compound 4(104 mg, 80%) as a colorless oil: Rf = 0.4 (30%,
24
EtOAc in hexane); [α]D = +22.73° (c 4.35, CHCl3); IR νmax 3441,
1
2926, 2869, 2363, 1659, 1456, 1367, 1090, 739, 698 cm−1; H NMR
(500 MHz, CDCl3) δ 7.33−7.18 (m, 10H), 6.75 (m, 1H), 6.03 (d, J =
15.82 Hz, 1H), 4.56 and 4.40 (ABq, J = 11.86 Hz, 2H), 4.48 (s, 2H),
4.21 (m, 1H), 3.63 (m, 2H), 3.54 (m, 1H), 3.43−3.28 (m, 2H), 3.20
(s, 3H), 2.65 (d, J = 5.93 Hz, 2H), 2.20 (m, 1H), 2.03 (m, 1H), 1.84−
1.69 (m, 3H), 1.62−1.32 (m, 7H), 1.17 (m, 1H), 0.97−0.89 (m, 6H);
13C NMR (75 MHz, CDCl3) δ 200.2, 147.0, 139.0, 138.0, 132.0, 128.3,
128.2, 127.7, 127.6, 127.4, 75.7, 75.8, 73.1, 71.0, 67.8, 66.4, 56.4, 46.2,
41.6, 40.2, 40.1, 36.3, 36.1, 29.0, 19.8, 18.1, 14.2; MS (ESI) m/z 511
[M + H]+; HRMS (ESI, TOF) calcd for C32H46O5Na [M + Na]+
533.3242, found 533.3240.
(2R,6S)-2-((2S,4S,6S)-6-(Benzyloxy)-4-methoxy-2-methyl-
nonyl)-6-(2-(benzyloxy)ethyl)dihydro-2H-pyran-4(3H)-one
(19A) and (2S,6S)-2-((2S,4S,6S)-6-(Benzyloxy)-4-methoxy-2-
methylnonyl)-6-(2-(benzyloxy)ethyl)dihydro-2H-pyran-4(3H)-
9844
dx.doi.org/10.1021/jo301425c | J. Org. Chem. 2012, 77, 9840−9845

The Journal of Organic Chemistry
Note
2.43 (m, 1H), 2.36−2.28 (m, 2H), 2.24 (dd, J = 14.8, 11.8 Hz, 1H),
1.85 (m, 1H), 1.73−1.46 (m, 6H), 1.42 (m, 1H), 1.38−1.16 (m, 3H),
1.01 (d, J = 6.9 Hz, 3H), 0.92 (t, 7.9 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 205.8, 169.9, 79.7, 75.7, 73.4, 73.3, 56.2, 48.7, 46.9, 44.3,
42.5, 41.9, 39.9, 36.9, 31.0, 25.4, 18.9, 13.8; MS (ESI) m/z 349 [M +
Na]+; HRMS (ESI, Orbitrap) calcd for C18H30O5Na [M + Na]+
349.19885, found 349.19904.
Tokunaga, M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen,
E. N. J. Am. Chem. Soc. 2002, 124, 1307.
(8) Boger, D. L.; Panek, J. S. J. Org. Chem. 1981, 46, 1208.
(9) Canova, S.; Bellosta, V.; Bigot, A.; Mailliet, P.; Mignani, S.; Cossy,
J. Org. Lett. 2007, 9, 145.
(10) Cel
54, 10457.
́ ̀
imene, C.; Dhimane, H.; Lhommet, G. Tetrahedron 1998,
(11) Eckenberg, P.; Groth, U.; Huhn, T.; Richter, N.; Schmeck, C.
Tetrahedron 1993, 49, 1619.
ASSOCIATED CONTENT
■
(12) (a) Chakraborty, T. K.; Chattopadhyay, A. K. J. Org. Chem.
2008, 73, 3578. (b) Matsuo, G.; Kawamura, K.; Hori, N.; Matsukara,
H.; Nakata, T. J. Am. Chem. Soc. 2004, 126, 14374.
(13) (a) Kobayashi, Y.; Tan, C.-H.; Kishi, Y. Angew. Chem., Int. Ed.
2000, 39, 4279. (b) Meyers, A. I.; Lawson, J. P. Tetrahedron Lett. 1982,
23, 4883. (c) Liu, C.; Coward, J. K. J. Org. Chem. 1991, 56, 2262.
(d) Majewski, M.; Clive, D. L. J.; Anderson, P. C. Tetrahedron Lett.
1984, 25, 2101. (e) Sawant, P.; Maier, M. E. Tetrahedron 2010, 66,
9738.
(14) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
2183.
(15) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37,
2091.
S
* Supporting Information
1
Figures giving H and 13C NMR spectra for all of the new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: subhash@iict.res.in.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(16) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989.
We thank the CSIR (S.A. and S.R.) and UGC (B.C. and
T.K.P.), New Delhi, for research fellowships.
REFERENCES
■
(1) Wright, A. E; Botelho, J. C.; Guzman, E.; Harmody, D.; Linley,
P.; McCarthy, P. J.; Pitts, T. P.; Pomponi, S. A.; Reed, J. K. J. Nat. Prod.
2007, 70, 412.
(2) For the total synthesis of neopeltolide, see: (a) Youngsaye, W.;
Lowe, J. T.; Pohlki, F.; Ralifo, P.; Panek, J. S. Angew. Chem., Int. Ed.
2007, 46, 9211. (b) Custar, D. W.; Zabawa, T. P.; Scheidt, K. A. J. Am.
Chem. Soc. 2008, 130, 804. (c) Woo, S. K.; Kwon, M. S.; Lee, E. Angew.
Chem., Int. Ed. 2008, 47, 3242. (d) Paterson, I.; Miller, N. A. Chem.
Commun. 2008, 4708. (e) Fuwa, H.; Naito, S.; Goto, T.; Sasaki, M.
Angew. Chem., Int. Ed. 2008, 47, 4737. (f) Guinchard, X.; Roulland, E.
Org. Lett. 2009, 11, 4700.
(3) For the formal synthesis of neopeltolide, see: (a) Vintonyak, V.
V.; Maier, M. E. Org. Lett. 2008, 10, 1239. (b) Kartika, R.; Gruffi, T.
R.; Taylor, R. E. Org. Lett. 2008, 10, 5047. (c) Tu, W.; Floreancig, P. E.
Angew. Chem., Int. Ed. 2009, 48, 4567. (d) Kim, H.; Park, Y.; Hong, J.
Angew. Chem., Int. Ed. 2009, 48, 7577. (e) Yadav, J. S.; Krishana, G. G.;
Kumar, S. N. Tetrahedron 2010, 66, 480. (f) Fuwa, H.; Saito, A.; Sasaki,
M. Angew. Chem., Int. Ed. 2010, 49, 3041. (g) Martinez-Solorio, D.;
Jennings, M. P. J. Org. Chem. 2010, 75, 4095. (h) Yang, Z.; Zhang, B.;
Zhao, G.; Yang, J.; Xie, X.; She, X. Org. Lett. 2011, 13, 5916.
(i) Raghavan, S.; Samanta, P. K. Org. Lett. 2012, 14, 2346. (j) Sharma,
G. V. M.; Reddy, S. V.; Ramakrishna, K. V. S. Org. Biomol. Chem. 2012,
10, 3689.
(4) For structure−activity studies, see: (a) Ulanovskaya, O. A.; Janjic,
J.; Suzuki, M.; Sabharwal, S. S.; Schumacker, P. T.; Kron, S. J.; Kozmin,
S. A. Nat. Chem. Biol. 2008, 4, 418. (b) Vintonyak, V. V.; Kunze, B.;
Sasse, F.; Maier, M. E. Chem. Eur. J. 2008, 14, 11132. (c) Custar, D.
W.; Zabawa, T. P.; Hines, J.; Crews, C. M.; Scheidt, K. A. J. Am. Chem.
Soc. 2009, 131, 12406. (d) Fuwa, H.; Saito, A.; Naito, S.; Konoki, K.;
Yotsu-Yamashita, M.; Sasaki, M. Chem. Eur. J. 2009, 15, 12807.
(e) Cui, Y.; Tu, W.; Floreancig, P. E. Tetrahedron 2010, 66, 4867.
(f) Cui, Y.; Balachandran, R.; Day, B. W.; Floreancig, P. E. J. Org.
Chem. 2012, 77, 2225.
(5) Reiter, M.; Turner, H.; Gouverneur, V. Chem. Eur. J. 2006, 12,
7190.
(6) (a) Chakraborty, T. K.; Suresh, V. R. Chem. Lett. 1997, 6, 565.
(b) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737. (c) Tan, Z.; Negishi, E. Angew. Chem., Int. Ed. 2004, 43,
2911.
(7) (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N.
Science 1997, 277, 936. (b) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.;
9845
dx.doi.org/10.1021/jo301425c | J. Org. Chem. 2012, 77, 9840−9845