Synthesis of the C-8-C-24 Fragment of Maltepolide C by Using a Tandem Dihydroxylation/SN2 Cyclization Sequence

Article abstract of DOI:10.1002/ejoc.201500629

A highly stereoselective synthesis of the C-8-C-24 fragment of maltepolide C has been achieved in a convergent and efficient manner by utilizing a tandem Sharpless asymmetric dihydroxylation (SAD)/S_N2 cyclization reaction sequence as the key st

Full text of DOI:10.1002/ejoc.201500629

FULL PAPER
DOI: 10.1002/ejoc.201500629
Synthesis of the C-8–C-24 Fragment of Maltepolide C by Using a Tandem
Dihydroxylation/SN2 Cyclization Sequence
Debendra K. Mohapatra,*[a] D. Sai Reddy,[a] G. Sudhakar Reddy,[a] and Jhillu S. Yadav[a]
Keywords: Asymmetric synthesis / Natural products / Dihydroxylation / Cyclization / Lactones / Macrocycles
A highly stereoselective synthesis of the C-8–C-24 fragment
the key step. Other important steps include a Crimmins-
of maltepolide C has been achieved in a convergent and ef- modified Evans aldol reaction, a Brown asymmetric allyl-
ficient manner by utilizing a tandem Sharpless asymmetric
dihydroxylation (SAD)/SN2 cyclization reaction sequence as
ation, a Horner–Wadsworth–Emmons olefination, and a
Corey–Bakshi–Shibata (CBS) reduction.
Introduction
For more than a century, natural products, which are iso-
lated from plants and microbes, have played a key role in
drug discovery.[1–3] In recent years, myxobacteria, a group
of proteobacteria that reside mostly in soil, were found to
be a rich source of new secondary metabolites. Several re-
search groups across the globe have successfully isolated
medicinally important secondary metabolites from myxo-
bacteria, such as epothilone, chondramide, tubulysin A, and
rhizopodin.[4] Very recently Prusov et al.[5] isolated a family
of structurally related unique secondary metabolites from
the fermentation broth of the myxobacterium Sorangium
cellulosum So ce1485, and their structures have been deter-
mined by extensive 2D NMR analysis and chemical corre-
lations as well as molecular modeling (Figure 1). The as-
signed structures were further confirmed by X-ray crystallo-
graphic studies. The maltepolides have been tested against
a panel of transformed cell lines and show moderate cyto-
static activity. Among them maltepolide C has the best cy-
tostatic activity with an IC50 value = 2.5 μgmL–1 (4.6 μm).
Significant structural features of the maltepolides include
the 20-membered macrolactone ring that contains either a
tetrahydrofuran (THF) or a vinylic epoxide moiety and a
disubstituted (E)-configured double bond. In continuation
of our research efforts on the development of practical syn-
thetic routes of biologically important tetrahydrofuran-con-
taining natural products,[6] we have chosen maltepolide C
as our target molecule (Figure 1).
Figure 1. Structures of maltepolides A–E (1–5).
and aldehyde 9 under Horner–Wadsworth–Emmons ole-
fination conditions. The advanced β-keto phosphonate 8 is
synthesized from 3-benzyloxypropionaldehyde (10), which
involves a Brown asymmetric allylation, a tandem Sharpless
asymmetric dihydroxylation (SAD)/SN2 cyclization, and a
Crimmins-modified Evans aldol reaction as the key steps.
Fragment 9 is accessed from d-mannitol (11).
The retrosynthetic analysis of maltepolide C (3) is de-
picted in Scheme 1. From this perspective, the C-8–C-24
fragment 7 is obtained by coupling β-keto phosphonate 8
Results and Discussion
The synthesis of fragment 8 began with the coupling of
3-benzyloxypropionaldehyde (10) and chiral imide 12[7] by
employing Crimmins-modified Evans aldol conditions[8] to
obtain syn-aldol product 13 in 86% yield with excellent dia-
stereoselectivity (96:4 by HPLC analysis; Scheme 2). Next,
compound 13 was treated with NaBH4 in MeOH to obtain
[a] Natural Products Chemistry Division, CSIR – Indian Institute
of Chemical Technology,
Hyderabad 500007, India
E-mail: mohapatra@iict.res.in
www.iictindia.org
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500629.
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Synthesis of the C-8–C-24 Fragment of Maltepolide C
Scheme 1. Retrosynthetic analysis of maltepolide C (3).
a 1,3-diol in 89% yield, and the resulting primary hydroxyl followed by a two-carbon homologation with (ethoxycar-
group was regioselectively protected as its silyl ether by bonylmethylene)triphenylphosphorane[9] in benzene to af-
using tert-butyldiphenylsilyl chloride (TBDPSCl) and imid- ford α,β-unsaturated ethyl ester 16 in 87% yield over two
azole to give compound 14 in 95% yield. The benzyl ether steps. The secondary hydroxyl group of 16 was converted
linkage of 14 was smoothly removed with Pd-C under into mesylate ester 17 in 95% yield by employing MeSO2Cl,
hydrogen to obtain diol 15 in 89% yield. The resulting pri- Et3N, and a catalytic amount of 4-(N,N-dimethylamino)-
mary alcohol functionality was selectively converted into an pyridine (DMAP). With the key intermediate in hand, the
aldehyde by using 2,2,6,6-tetramethyl-1-piperidinyloxy next task was the dihydroxylation step followed by the SN2-
(TEMPO) and bis(acetoxy)iodobenzene (BAIB) conditions type cyclization to prepare the tetrahydrofuran moiety, as
Scheme 2. Synthesis of aldehyde 22 (DIPEA = N,N-diisopropylethylamine, NMP = N-methyl-2-pyrrolidone, Ms = methylsulfonyl).
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D. K. Mohapatra, D. S. Reddy, G. S. Reddy, J. S. Yadav
FULL PAPER
developed by Marshall et al.[10] For this purpose, mesylate
The synthesis of the other chiral subunit 9 began from
derivative 17 was subjected to a Sharpless asymmetric dihy- 27 (Scheme 4), which was prepared from commercially
droxylation[11] with AD-mix-α (AD = asymmetric dihy- available d-mannitol according to a reported procedure.[17]
droxylation), MeSO2NH2, and OsO4 in tBuOH/H2O (1:1) The resulting secondary alcohol functionality was protected
to afford trans,anti-tetrahydrofuran 18 in 89% yield (no as a benzyl ether by using benzyl bromide and NaH to give
other isomer was detected by NMR analysis). The stereo- the product in 94% yield, which upon treatment with a
chemistry of trans,anti-tetrahydrofuran 18 was confirmed catalytic amount of camphorsulfonic acid (CSA) in MeOH
by NOESY spectral analysis. No interaction was observed afforded diol 28 in 87% yield. The primary alcohol func-
between the C-2 and C-5 protons, whereas a strong interac- tionality of 28 was regioselectively protected as its tert-bu-
tion was observed for the C-2 and C-3 protons. The newly tyldimethysilyl (TBS) ether by employing TBSCl and imid-
generated alcohol functionality was protected as its methyl azole in CH2Cl2 to give compound 29 in 91% yield. The
ether by using Ag2O and MeI in N,N-dimethylformamide secondary alcohol was then protected as its methyl ether
(DMF) to furnish 19 in 93% yield (Scheme 2). The ester with MeI and NaH to obtain compound 30 in 95% yield.
of compound 19 was then treated with diisobutylaluminum The removal of TBS protecting group in 30 followed by
hydride (DIBAL-H) to obtain the aldehyde in 88% yield, oxidation of the resulting primary alcohol using Dess–
which was treated with phosphonate ester 20 under Ando’s Martin periodinane[18] afforded aldehyde 9 in 89% yield
conditions[12] to give (Z)-α,β-unsaturated ester 21 (Z/E, over two steps.
96:4) in 89% yield. The ester group of 21 was reduced with
DIBAL-H to give aldehyde 22 in 89% yield.
A Brown asymmetric allylation[13] of aldehyde 22 gave
allyl alcohol 23 in 87% yield (dr 95:5 by HPLC analysis),
and the stereochemistry of the newly generated asymmetric
center was confirmed by Mosher ester[14] analysis
(Scheme 3). Allyl alcohol 23 was then protected as its meth-
oxymethyl (MOM) ether by using MOMCl and DIPEA to
afford compound 24 in 96% yield. Next, the TBDPS group
was smoothly removed by employing tetra-n-butylammo-
nium fluoride (TBAF) in THF to give primary alcohol 25
in 93% yield. The treatment of 25 with TEMPO and
BAIB[15] in CH3CN/H2O (9:1) as the solvent gave the corre-
sponding carboxylic acid in 87% yield, which was immedi-
ately converted into methyl ester 26 in 97% yield by using
freshly generated CH2N2. Ester 26 was then subjected to a
nucleophilic addition with the lithiated derivative of di-
methyl methylphosphonate to furnish β-keto phos-
phonate[16] 8 in 92% yield.
Scheme 4. Synthesis of aldehyde 9 (TBAI = tetra-n-butylammo-
nium iodide, DMP = Dess–Martin periodinane).
With the requisite fragments in hand, the coupling reac-
tion between 8 and 9 was carried out under Horner–
Wadsworth–Emmons olefination conditions[19] to obtain
trans-α,β-unsaturated ketone 32 exclusively in 95% yield
(Scheme 5). Compound 32 was selectively reduced with
Scheme 3. Synthesis of the phosphonate intermediate 8 (Ipc = iso-
pinocampheyl).
Scheme 5. Synthesis of C-8–C-24 fragment of maltepolide C.
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Synthesis of the C-8–C-24 Fragment of Maltepolide C
Corey–Bakshi–Shibata [(R)-CBS] reagent[20] to give the C-
8–C-24 fragment of maltepolide C in 89% yield (95:5 by
HPLC analysis).
1 H), 1.96–1.87 (m, 1 H), 1.70 (m, 1 H), 1.27 (d, J = 6.8 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 201.5, 177.6, 137.9,
136.5, 129.4, 128.9, 128.4, 127.7, 127.2, 126.9, 73.3, 71.6, 69.0, 68.5,
43.8, 36.7, 33.9, 32.1, 11.0 ppm. MS (ESI): m/z = 452 [M + Na].
(2S,3S)-5-(Benzyloxy)-1-[(tert-butyldiphenylsilyl)oxy]-2-methyl-
pentan-3-ol (14): To a stirred solution of 13 (16.2 g, 37.71 mmol) in
MeOH (120 mL) was added NaBH4 (2.1 g, 56.6 mmol) at 0 °C. The
reaction mixture was stirred at room temperature for 3 h. Upon
Conclusions
In summary, a stereoselective synthesis of the C-8–C-24
fragment of maltepolide C has been achieved in a conver- completion (monitored by TLC), the reaction was quenched with a
saturated solution of NH4Cl (70 mL), and the MeOH was removed
under reduced pressure. The residue was extracted with ethyl acet-
ate (3 ϫ 100 mL), and the combined organic layers were washed
with brine (200 mL) and dried with anhydrous Na2SO4. The sol-
vent was removed under reduced pressure, and purification of the
crude product by silica gel column chromatography (ethyl acetate/
hexane, 1:4) furnished the diol (7.5 g, 89%) as a colorless liquid,
which was used immediately in the next step. To a stirred solution
of the diol (6.5 g, 29.01 mmol) in CH2Cl2 (50 mL) were added imid-
azole (2.95 g, 43.5 mmol) and TBDPCl (8.7 g, 31.1 mmol) at 0 °C,
and the reaction mixture was stirred at the same temperature for
30 min. Upon completion (monitored by TLC), the reaction mix-
ture was quenched with water (40 mL). The organic layer was sepa-
rated, and the aqueous layer was extracted with CH2Cl2 (3 ϫ
50 mL). The combined organic layers were dried with anhydrous
Na2SO4, and the solvent was removed under reduced pressure. The
crude residue was purified by silica gel column chromatography
(ethyl acetate/hexane, 2:5) to afford 14 (12.7 g, 95%) as a colorless
gent and efficient manner by utilizing the Crimmins-modi-
fied Evans aldol reaction, a tandem SAD/SN2 cyclization,
a Brown asymmetric allylation, a Horner–Wadsworth–Em-
mons olefination, and a CBS reduction as the key transfor-
mations. Further studies toward the total synthesis of mal-
tepolide C are currently underway in our laboratory and
will be reported in due course.
Experimental Section
General Methods: Air and moisture-sensitive reactions were carried
out in anhydrous solvents under argon in oven- or flame-dried
glassware. All anhydrous solvents were distilled prior to use. THF,
benzene, toluene, and diethyl ether were distilled from Na and
benzophenone. CH2Cl2, dimethyl sulfoxide (DMSO), DMF, and
hexane were distilled from CaH2, and MeOH and EtOH were dis-
tilled from Mg. Commercial reagents were used without purifica-
tion. Column chromatography was carried out by using silica gel
(60–120 mesh). Specific rotations [α]D are reported in units of
10–1 degcm2 g–1. Infrared spectra were recorded in CHCl3 solutions
or as neat samples, and the data are reported as wave numbers
(cm–1). A TOF analyzer was used for HRMS measurements. The
chemical shifts of the 1H and 13C NMR spectroscopic data are
reported in ppm downfield from tetramethylsilane, and the cou-
pling constants (J) are reported in Hertz [Hz]. The following ab-
breviations are used to designate the multiplicity of the NMR sig-
nals: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet),
br. (broad).
liquid; [α]2D5 = –3.6 (c = 3.4, CHCl ). IR (neat): ν
= 3454, 2959,
˜
3
max
2857, 1717, 1655, 1468 cm–1. 1H NMR (300 MHz, CDCl3): δ =
7.71–7.63 (m, 4 H), 7.47–7.23 (m, 11 H), 4.53 (s, 2 H), 4.02 (m, 1
H), 3.74–3.62 (m, 4 H), 3.17 (d, J = 3.3 Hz, 1 H), 1.99–1.59 (m, 3
H), 1.06 (s, 9 H), 0.93 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 138.2, 135.6, 135.5, 133.3, 133.2, 129.7,
128.3, 127.7, 127.6, 73.2, 71.9, 68.8, 67.8, 40.1, 34.1, 26.8, 19.2,
10.8 ppm. HRMS (ESI): calcd. for C29H38O3NaSi [M + Na]+
485.2487; found 485.2493.
(3S,4S)-5-[(tert-Butyldiphenylsilyl)oxy]-4-methylpentane-1,3-diol
(15): To a stirred solution of 14 (10.0 g, 21.6 mmol) in MeOH
(70 mL) was added commercial Pd/C (10% w/w, 1.0 g) in one por-
tion. The resulting suspension was stirred under an H2 balloon for
12 h until the starting materials were completely consumed (moni-
tored by TLC). The suspension was filtered through Celite, and the
filter cake was washed with ethyl acetate (100 mL). The combined
filtrates were dried with anhydrous Na2SO4 and concentrated under
reduced pressure. The crude residue was purified by silica gel col-
umn chromatography (ethyl acetate/hexane, 7:1) to afford 15
(7.17 g, 89%) as a colorless liquid; [α]2D5 = –7.5 (c = 2.5, CHCl3).
(2R,3S)-1-[(R)-4-Benzyl-2-thioxothiazolidin-3-yl]-5-(benzyloxy)-3-
hydroxy-2-methylpentan-1-one (13): To a stirred solution of (R)-1-
(4-benzyl-2-thioxothiazolidin-3-yl)propan-1-one (12, 17.7 g,
67.1 mmol) in CH2Cl2 (150 mL) was added TiCl4 (7.2 mL,
67.1 mmol) dropwise at 0 °C to form an orange slurry. After stir-
ring for 10 min, DIPEA (11.1 mL, 67.1 mmol) was added dropwise.
The resultant dark red solution was stirred for 40 min at 0 °C, and
then NMP (13.2 mL, 134.16 mmol) was added. The reaction mix-
ture was stirred for an additional 20 min and was then cooled to
–78 °C. 3-Benzyloxypropionaldehyde (10, 10.0 g, 60.9 mmol) in
CH2Cl2 (50 mL) was added, and the resultant mixture was stirred
at –78 °C for 2 h and at 0 °C for 1 h. Upon completion (monitored
by TLC), the reaction was quenched with a saturated NH4Cl
(100 mL) solution. The organic phase was separated, and the re-
maining aqueous phase was washed with CH2Cl2 (2ϫ 200 mL).
The combined organic portions were dried with anhydrous Na2SO4
and concentrated under reduced pressure. The crude residue was
purified by silica gel column chromatography (ethyl acetate/hexane,
1:12) to obtain aldol adduct 13 (22.4 g, 86%, dr Ͼ20:1) as a pale
IR (neat): ν
= 3518, 3070, 2957, 1718, 1656, 1427, 1218 cm–1.
˜
max
1H NMR (500 MHz, CDCl3): δ = 7.67 (ddd, J = 8.1, 5.2, 1.5 Hz,
4 H), 7.48–7.36 (m, 6 H), 4.12–4.06 (m, 1 H), 3.90–3.83 (m, 2 H),
3.76 (dd, J = 10.2, 4.1 Hz, 1 H), 3.71–3.65 (m, 1 H), 1.88–1.77 (m,
2 H), 1.59–1.50 (m, 1 H), 1.06 (s, 9 H), 0.92 (d, J = 7.1 Hz, 3
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 135.6, 135.5, 132.8,
132.7, 129.9, 129.9, 127.8, 75.3, 68.4, 62.3, 39.6, 35.3, 26.8, 19.1,
10.9 ppm. HRMS (ESI): calcd. for C22H32O3NaSi [M + Na]+
395.2013; found 395.2202.
(5S,6S,E)-Ethyl 7-[(tert-Butyldiphenylsilyl)oxy]-5-hydroxy-6-meth-
ylhept-2-enoate (16): To a solution of 15 (7.0 g, 18.78 mmol) in
yellow liquid; [α]2D5 = –58.4 (c = 1.8, CHCl ). IR (neat): ν
=
˜
3
max
2925, 1567, 1467, 1218, 1037 cm–1. 1H NMR (300 MHz, CDCl3): CH2Cl2 (70 mL), were added TEMPO (0.293 g, 1.88 mmol) and
δ = 7.40–7.23 (m, 10 H), 5.30 (m, 1 H), 4.60–4.47 (m, 3 H), 4.17 BAIB (6.67 g, 20.7 mmol) at 0 °C, and the reaction mixture was
(dd, J = 5.8, 3.4 Hz, 1 H), 3.72–3.59 (m, 2 H), 3.42–3.31 (m, 2 H),
stirred at room temperature for 2 h. Upon completion (monitored
3.24 (dd, J = 13.1, 3.6 Hz, 1 H), 3.04 (m, 1 H), 2.87 (d, J = 11.5 Hz, by TLC), the reaction mixture was diluted with CH2Cl2 (50 mL),
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and the solution was washed with saturated aqueous Na2S2O3
(70 mL) and saturated NaHCO3 solution (70 mL). The aqueous
layer was extracted with CH2Cl2 (2ϫ 100 mL). The combined or-
ganic layers were dried with Na2SO4 and concentrated under re-
duced pressure. The crude residue was passed through a small bed
of silica gel (ethyl acetate/hexane, 1:12) to afford the aldehyde
(6.4 g) as a colorless liquid, which was used for the next step with-
out any further characterization. To a stirred solution of the alde-
hyde (6.0 g, 16.2 mmol) in benzene (60 mL) was added ethyl 2-(tri-
phenylphosphoranylidene)acetate (8.47 g, 24.3 mmol) at room tem-
perature. The reaction mixture was stirred at 60 °C for 10 h. Upon
completion of the reaction (monitored by TLC), the solvent was
removed under reduced pressure. The crude residue was purified
by silica gel column chromatography (ethyl acetate/hexane, 1:19) to
umn chromatography (ethyl acetate/hexane, 1:6) to give tetra-
hydrofuran derivative 18 (3.9 g, 89%) as a viscous liquid; [α]2D5
=
+8.3 (c = 1.6, CHCl ). IR (neat): ν
= 3455, 2959, 2856, 1710,
˜
3
max
1514, 1218 cm–1. H NMR (500 MHz, CDCl3): δ = 7.71–7.65 (m,
4 H), 7.44–7.36 (m, 6 H), 4.63 (d, J = 3.4 Hz, 1 H), 4.48 (d, J =
4.4 Hz, 1 H), 4.44 (m, 1 H), 4.3–4.19 (m, 2 H), 3.72–3.63 (m, 2 H),
2.43 (br. s, 1 H), 2.03 (m, 1 H), 1.95 (m, 1 H), 1.85 (m, 1 H), 1.29
(t, J = 7.1 Hz, 3 H), 1.05 (s, 9 H), 0.94 (d, J = 6.9 Hz, 3 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 170.5, 135.6, 133.8, 133.7, 129.5,
127.6, 81.8, 80.6, 73.6, 65.9, 61.1, 40.2, 37.9, 29.6, 26.8, 19.3 ppm.
HRMS (ESI): calcd. for C26H36O5NaSi [M + Na]+ 479.2224; found
479.2222.
1
Ethyl (2R,3S,5R)-5-{(S)-1-[(tert-Butyldiphenylsilyl)oxy]propan-2-
yl}-3-methoxytetrahydrofuran-2-carboxylate (19): To a stirred solu-
tion of compound 18 (3.3 g, 7.22 mmol) in DMF (25 mL) were
added Ag2O (3.35 g, 14.4 mmol) and methyl iodide (3.5 mL,
57.9 mmol) at 0 °C. The resultant mixture was stirred at room tem-
perature for 24 h. Upon completion (monitored by TLC), the reac-
tion mixture was filtered through a bed of Celite, and the filtrate
was diluted with water. The aqueous layer was extracted with ethyl
acetate (3ϫ 50 mL), and the combined organic layers were dried
with anhydrous Na2SO4 and concentrated under reduced pressure.
The crude residue was purified by silica gel column chromatog-
raphy (ethyl acetate/hexane, 1:19) to afford compound 19 (3.16 g,
93%) as a colorless liquid; [α]2D5 = –9.1 (c = 1.8, CHCl3). IR (neat):
afford 16 (6.7 g, 93%) as a colorless liquid; [α]2D5 = –3.2 (c = 1.1,
1
CHCl ). IR (neat): ν
= 3017, 2961, 1749, 1469, 1216 cm–1. H
˜
3
max
NMR (300 MHz, CDCl3): δ = 7.71–7.62 (m, 4 H), 7.48–7.34 (m, 6
H), 7.00 (m, 1 H), 5.91 (d, J = 15.7 Hz, 1 H), 4.19 (q, J = 7.1 Hz,
2 H), 4.03 (m, 1 H), 3.77 (dd, J = 10.2, 3.9 Hz, 1 H), 3.66 (m, 1
H), 2.99 (d, J = 3.6 Hz, 1 H), 2.50–2.26 (m, 2 H), 1.77 (m, 1 H),
1.29 (t, J = 7.1 Hz, 3 H), 1.06 (s, 9 H), 0.94 (d, J = 7.0 Hz, 3
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 166.4, 145.7, 135.6,
135.5, 132.8, 132.7, 129.9, 129.8, 127.8, 123.3, 73.0, 68.4, 60.2, 38.8,
37.2, 26.8, 19.1, 14.2, 10.2 ppm. HRMS (ESI): calcd. for
C26H36O4NaSi [M + Na]+ 463.2275; found 463.2274.
Ethyl (5S,6S,E)-7-[(tert-Butyldiphenylsilyl)oxy]-6-methyl-5-[(meth-
ylsulfonyl)oxy]hept-2-enoate (17): Et3N (2.7 mL, 20.1 mmol) and
mesyl chloride (1.6 mL, 20.1 mmol) were added to a stirred solu-
tion of 16 (5.9 g, 13.4 mmol) in CH2Cl2 (60 mL) at 0 °C, and the
resultant mixture was stirred at room temperature for 2 h. Upon
completion (monitored by TLC), the reaction was quenched with
saturated NH4Cl (40 mL). The organic layer was separated, and
the aqueous layer was extracted with CH2Cl2 (3ϫ 100 mL). The
combined organic layers were dried with anhydrous Na2SO4, and
the solvent was removed under reduced pressure. The crude residue
was purified by silica gel column chromatography to afford 17
(6.5 g, 95%) as pale yellow liquid; [α]2D5 = +10.1 (c = 2.2, CHCl3).
ν
˜
= 2929, 2850, 1709, 1567, 1219 cm–1. 1H NMR (300 MHz,
max
CDCl3): δ = 7.72–7.61 (m, 4 H), 7.46–7.32 (m, 6 H), 4.55 (d, J =
5.1 Hz, 1 H), 4.40 (m, 1 H), 4.28–4.12 (m, 3 H), 3.77–3.56 (m, 2
H), 3.32 (s, 3 H), 2.10 (m, 2 H), 1.97 (m, 1 H), 1.70 (m, 1 H), 1.28
(t, J = 7.1 Hz, 3 H), 1.05 (s, 9 H), 0.93 (d, J = 6.8 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 170.1, 135.6, 133.8, 133.7, 129.5,
127.6, 82.7, 80.8, 65.9, 60.6, 57.8, 40.1, 33.8, 26.9, 19.3, 14.3,
12.3 ppm. HRMS (ESI): calcd. for C27H38O5NaSi [M + Na]+
493.2381; found 493.2378.
Ethyl (Z)-3-[(2S,3S,5R)-5-{(S)-1-[(tert-Butyldiphenylsilyl)oxy]prop-
an-2-yl}-3-methoxytetrahydrofuran-2-yl]-2-methylacrylate (21): To a
stirred solution of compound 19 (3.0 g, 6.37 mmol) in CH2Cl2
(50 mL), was added DIBAL-H (1.4 m in toluene, 5.0 mL,
7.01 mmol) at –78 °C, and the reaction mixture was stirred at the
same temperature for 2 h. Upon completion (monitored by TLC),
the reaction mixture was quenched with a saturated solution of
sodium potassium tartrate, and the resultant mixture was stirred at
room temperature for 2 h. The organic layer was separated, and
the aqueous layer was extracted with CH2Cl2 (3ϫ 50 mL). The
combined organic layers were dried with anhydrous Na2SO4, and
the solvent was removed under reduced pressure. Purification of the
IR (neat): ν
= 3070, 2958, 1469, 1427, 1219 cm–1. 1H NMR
˜
max
(500 MHz, CDCl3): δ = 7.69–7.61 (m, 4 H), 7.47–7.37 (m, 6 H),
6.87 (dt, J = 15.1, 7.4 Hz, 1 H), 5.90 (m, 1 H), 5.07 (m, 1 H), 4.21
(q, J = 7.2 Hz, 2 H), 3.60–3.56 (m, 2 H), 2.97 (s, 3 H), 2.79–2.63
(m, 2 H), 1.91 (m, 1 H), 1.29 (t, J = 7.2 Hz, 2 H), 1.07 (s, 9 H),
0.90 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 165.8, 142.2,
135.5, 133.0, 129.7, 127.7, 124.8, 81.1, 64.6, 60.3, 38.4, 38.2, 35.3,
26.8, 19.1, 14.2, 10.8 ppm. HRMS (ESI): calcd. for C27H38O6NaSSi
[M + Na]+ 541.2051; found 541.2050.
Ethyl (2R,3S,5R)-5-{(S)-1-[(tert-Butyldiphenylsilyl)oxy]propan-2- crude product by silica gel column chromatography (ethyl acetate/
yl}-3-hydroxytetrahydrofuran-2-carboxylate (18): To a stirred solu-
tion of K2CO3 (4.0 g, 128.9 mmol), K3[Fe(CN)6] (9.5 g, 9.9 mmol),
and hydroquinine 1,4-phthalazinediyl diether [(DHQ)2PHAL,
77 mg, 0.96 mmol] in tBuOH/H2O (40 mL, 1:1) were added meth-
hexane, 1:13) afforded the corresponding aldehyde (2.3 g, 88%) as
a colorless liquid, which was immediately used in next step. To a
stirred suspension of NaH (60% in mineral oil, 0.296 g, 7.4 mmol)
in THF (30 mL) was added ester phosphonate 20 (2.67 g,
ane sulfonamide (0.916 g, 9.6 mmol) and OsO4 (3 mg, 0.096 mmol) 7.4 mmol) at 0 °C. After stirring at 0 °C for 30 min, the reaction
at room temperature, and the solution was stirred for 15 min. The
reaction mixture was cooled to 0 °C, and a solution of mesylate
17 (5.0 g, 9.6 mmol) in tBuOH/H2O (20 mL, 1:1) was added. The
resultant mixture was stirred at the same temperature for 12 h. The
reaction mixture was then warmed to room temperature and stirred
for 12 h. Upon completion (monitored by TLC), the reaction mix-
ture was quenched with a saturated solution of Na2SO3 (20 mL).
The aqueous layer was separated and then extracted with ethyl
acetate (4ϫ 50 mL). The combined organic extracts were washed
with brine, dried with anhydrous Na2SO4, and concentrated under
reduced pressure. The crude residue was purified by silica gel col-
mixture was cooled to –78 °C, and a solution of the aldehyde (2.1 g,
4.93 mmol) in THF (10.0 mL) was added. The resulting mixture
was stirred at –78 °C for 1 h, and the mixture was quenched with
a saturated NH4Cl solution (50 mL). The reaction mixture was ex-
tracted with ethyl acetate (3ϫ 50 mL). The combined extracts were
washed with brine (100 mL), dried with anhydrous Na2SO4, and
concentrated under vacuum. The residue was purified by silica gel
column chromatography (ethyl acetate/hexane, 1:19) to obtain com-
pound 21 (2.17 g, 89%); [α]2D5 = –20.3 (c = 0.9, CHCl3). IR (neat):
ν
= 3012, 2945, 1678, 1550, 1219 cm–1. 1H NMR (300 MHz,
˜
max
CDCl3): δ = 7.72–7.73 (m, 4 H), 7.46–7.32 (m, 6 H), 6.08 (d, J =
5270
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 5266–5274

Synthesis of the C-8–C-24 Fragment of Maltepolide C
7.6 Hz, 1 H), 5.13 (dd, J = 7.5, 4.0 Hz, 1 H), 4.26–4.13 (m, 3 H), NMR (500 MHz, CDCl3): δ = 7.68–7.64 (m, 4 H), 7.50–7.46 (m, 2
4.09 (m, 1 H), 3.75–3.61 (m, 2 H), 3.28 (s, 3 H), 2.12 (dd, J = 12.8,
H), 7.42–7.33 (m, 9 H), 5.90 (m, 1 H), 5.68 (dd, J = 8.4, 1.2 Hz, 1
5.3 Hz, 1 H), 1.96 (s, 3 H), 1.86 (m, 1 H), 1.68 (m, 1 H), 1.29 (t, J H), 5.62 (m, 1 H), 5.06–4.96 (m, 2 H), 4.80 (d, J = 8.2, 3.6 Hz, 1
= 7.1 Hz, 3 H), 1.04 (s, 9 H), 0.93 (d, J = 6.8 Hz, 3 H) ppm. 13C H), 4.11 (m, 1 H), 3.96 (m, 1 H), 3.75 (m, 1 H), 3.59 (m, 1 H), 3.55
NMR (75 MHz, CDCl3): δ = 167.4, 140.9, 135.6, 133.9, 133.8, (s, 3 H), 3.32 (s, 3 H), 2.51 (m, 1 H), 2.35 (m, 1 H), 2.15 (m, 1 H),
129.4, 128.5, 127.5, 83.9, 79.5, 79.1, 66.0, 60.4, 57.4, 40.7, 35.2,
26.8, 20.3, 19.3, 14.2, 12.5 ppm. HRMS (ESI): calcd. for
C30H42O5NaSi [M + Na]+ 533.2699; found 533.2715.
1.90 (m, 1 H), 1.51 (s, 3 H), 1.04 (s, 9 H), 0.94 (d, J = 6.7 Hz, 3
H) ppm.
tert-Butyl[(S)-2-{(2R,4S,5S)-4-methoxy-5-[(R,Z)-3-(methoxymeth-
(R,Z)-1-[(2S,3S,5R)-5-{(S)-1-[(tert-Butyldiphenylsilyl)oxy]propan-2-
oxy)-2-methylhexa-1,5-dien-1-yl]tetrahydrofuran-2-yl}propoxy]-
yl}-3-methoxytetrahydrofuran-2-yl]-2-methylhexa-1,5-dien-3-ol (23): diphenylsilane (24): To a stirred solution of compound 23 (0.75 g,
To a stirred solution of compound 21 (1.7 g, 3.4 mmol) in CH2Cl2 1.45 mmol) in CH2Cl2 (20 mL) was added diisopropyl ethylamine
(50 mL) was added DIBAL-H (1.4 m in toluene, 2.6 mL, 3.7 mmol) (0.65 mL, 3.7 mmol), and the resultant mixture was stirred at 0 °C
at –78 °C, and the reaction mixture was stirred at the same tem-
perature for 2 h. Upon completion (monitored by TLC), the reac-
tion mixture was quenched with a saturated solution of sodium
potassium tartrate (50 mL) and stirred at room temperature for 2 h.
The organic layer was separated, and the aqueous layer was ex-
tracted with CH2Cl2 (3 ϫ 50 mL). The combined organic layers
were dried with anhydrous Na2SO4, and the solvent was removed
under reduced pressure. Purification of the crude residue by silica
gel column chromatography (ethyl acetate/hexane, 1:9) afforded the
corresponding aldehyde 22 (1.3 g, 89%) as a colorless liquid, which
was immediately used in the next step. Allymagnesium bromide
(1 m in Et2O, 2.8 mL, 2.8 mmol) was added to a stirred solution of
(+)-(Icp)2BOMe (0.84 g, 2.6 mmol) in Et2O (20 mL) at 0 °C. The
solution was warmed to room temperature and then stirred for an
additional 1 h to obtain a white suspension. The suspension was
then cooled to 0 °C and allowed to settle for 30 min. The superna-
tant was added to a stirred solution of aldehyde 22 (0.95 g,
2.04 mmol) in Et2O (10 mL) at –78 °C, and the resulting mixture
was stirred for 3 h at –78 °C and then quenched with NaOH (2 m
solution, 26 mL) and 30% H2O2 (3 mL). The resulting mixture was
stirred at room temperature overnight and then extracted with ethyl
acetate (3 ϫ 40 mL). The combined organic layers were washed
with H2O (75 mL) and brine (75 mL), dried with Na2SO4, and con-
centrated under reduced pressure. The residue was purified by silica
gel column chromatography (ethyl acetate/hexane, 1:12) to afford
alcohol 23 (0.901 g, 87%) as a colorless liquid; [α]2D5 = +5.8 (c =
for 30 min. Methoxymethyl chloride (0.24 mL, 2.9 mmol) in
CH2Cl2 (10 mL) was added to the reaction at the same temperature,
and the resultant mixture was then stirred at room temperature
for an additional 10 h. Upon completion (monitored by TLC), the
reaction was quenched with water (20 mL), and the solution was
extracted with CH2Cl2 (3ϫ 30 mL). The combined organic layers
were dried with anhydrous Na2SO4, and the solvent was removed
under reduced pressure. The crude residue was purified by silica
gel column chromatography (ethyl acetate/hexane, 1:24) to afford
compound 24 (0.781 g, 96%) as a colorless liquid; [α]2D5 = +14.6 (c
= 1.3, CHCl ). IR (neat): ν
= 3058, 2918, 1693, 1596, 1464,
˜
3
max
1
1217 cm–1. H NMR (500 MHz, CDCl3): δ = 7.69–7.64 (m, 4 H),
7.437–7.34 (m, 6 H), 5.75 (m, 1 H), 5.68 (dd, J = 8.6, 1.1 Hz, 1 H),
5.04 (m, 1 H), 4.96 (m, 1 H), 4.60 (dd, J = 8.5, 3.8 Hz, 1 H), 4.56
(m, 1 H), 4.50 (dd, J = 8.4, 5.6 Hz, 1 H), 4.44 (m, 1 H), 4.10 (m,
1 H), 3.81 (t, J = 3.7 Hz, 1 H), 3.74 (dd, J = 9.9, 4.9 Hz, 1 H), 3.59
(dd, J = 9.9, 6.6 Hz, 1 H), 3.33 (s, 3 H), 3.31 (s, 3 H), 2.41 (m, 1
H), 2.26 (m, 1 H), 2.13 (m, 1 H), 1.93–1.86 (m, 1 H), 1.73–1.65 (m,
4 H), 1.05 (s, 9 H), 0.93 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 138.1, 135.6, 135.6, 134.8, 133.9, 133.9,
129.4, 129.4, 127.5, 126.2, 116.7, 93.1, 83.1, 78.6, 76.6, 72.8, 66.2,
57.1, 55.3, 40.9, 37.9, 34.6, 26.8, 19.3, 17.9, 12.5 ppm. HRMS
(ESI): calcd. for C33H48O5NaSi [M + Na]+ 575.3163; found
575.3165.
(S)-2-{(2R,4S,5S)-4-Methoxy-5-[(R,Z)-3-(methoxymethoxy)-2-meth-
ylhexa-1,5-dien-1-yl]tetrahydrofuran-2-yl}propan-1-ol (25): To a
stirred solution of 24 (0.5 g, 0.9 mmol) in THF (10.0 mL) was
added TBAF (1 m in THF, 1.3 mL, 1.3 mmol) at 0 °C. The resulting
mixture was stirred at room temperature for an additional 10 h.
Upon completion (monitored by TLC), the reaction was quenched
with water (20 mL), and the solution was extracted with ethyl acet-
ate (3 ϫ 30 mL). The combined organic layers were dried with an-
hydrous Na2SO4, and the solvent was removed under reduced pres-
sure. The crude residue was purified by silica gel column
chromatography (ethyl acetate/hexane, 1:18) to give alcohol 25
(0.265 g, 93%) as a colorless liquid; [α]2D5 = –65 (c = 1.1, CHCl3).
1.5, CHCl ). IR (neat): ν
= 3386, 3014, 2930, 1468, 1428,
˜
3
1
max
1217 cm–1. H NMR (500 MHz, CDCl3): δ = 7.70–7.65 (m, 4 H),
7.44–7.33 (m, 6 H), 5.74 (m, 1 H), 5.55 (dd, J = 8.0, 1.1 Hz, 1 H),
5.13–5.01 (m, 2 H), 4.68 (dd, J = 7.9, 4.2 Hz, 1 H), 4.47 (t, J =
6.6 Hz, 1 H), 4.13 (m, 1 H), 3.82 (m, 1 H), 3.74 (dd, J = 10.0,
4.8 Hz, 1 H), 3.59 (dd, J = 10.0, 6.4 Hz, 1 H), 3.34 (s, 3 H), 2.35–
2.36 (m, 2 H), 2.11 (ddd, J = 13.2, 6.5, 2.2 Hz, 1 H), 1.87 (m, 1
H), 1.80–1.72 (m, 4 H), 1.05 (s, 9 H), 0.94 (d, J = 6.9 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 141.9, 135.6, 134.7, 133.9, 133.8,
129.5, 127.5, 123.3, 117.7, 82.6, 78.4, 76.4, 69.8, 66.1, 57.2, 40.8,
39.7, 34.3, 26.8, 19.3, 18.5, 12.6 ppm. HRMS (ESI): calcd. for
C31H44O4NaSi [M + Na]+ 531.2901; found 531.2898.
IR (neat): ν
= 3319, 3062, 2987, 2934, 2831, 1653, 1496,
˜
max
1214 cm–1. H NMR (500 MHz, CDCl3): δ = 5.76 (m, 1 H), 5.67
1
(R)-[(R,Z)-1-{(2S,3S,5R)-5-[(S)-1-(tert-Butyldiphenylsilyloxy)- (d, J = 8.7 Hz, 1 H), 5.14–5.03 (m, 2 H), 4.69 (dd, J = 8.7, 3.6 Hz,
propan-2-yl]-3-methoxytetrahydrofuran-2-yl}-2-methylhexa-1,5- 1 H), 4.54 (d, J = 6.8 Hz, 1 H), 4.49 (dd, J = 13.3, 5.6 Hz, 1 H),
1
dien-3-yl] 3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate (23a): H
4.44 (d, J = 6.8 Hz, 1 H), 3.96 (td, J = 9.5, 5.9 Hz, 1 H), 3.79 (t, J
NMR (500 MHz, CDCl3): δ = 7.78–7.64 (m, 4 H), 7.50–7.46 (m, 2 = 3.8 Hz, 1 H), 3.60 (m, 1 H), 3.54 (m, 1 H), 3.39 (br. s, 1 H), 3.32
H), 7.42–7.33 (m, 9 H), 5.95 (m, 1 H), 5.69 (dd, J = 8.3, 1.2 Hz, 1 (s, 3 H), 3.31 (s, 3 H), 2.43 (dt, J = 15.0, 7.6 Hz, 1 H), 2.31–2.22
H), 5.99–588 (m, 2 H), 4.79 (m, 1 H), 4.15–4.09 (m, 2 H), 3.89 (m, (m, 2 H), 1.78–1.62 (m, 5 H), 0.77 (d, J = 6.9 Hz, 3 H) ppm. 13C
1 H), 3.73 (m, 1 H), 3.59 (m, 1 H), 3.50 (s, 3 H), 3.25 (s, 3 H), 2.46
NMR (125 MHz, CDCl3): δ = 138.6, 134.3, 125.5, 117.1, 92.9, 83.4,
(m, 1 H), 2.33 (m, 1 H), 2.11 (dd, J = 13.1, 5.0, Hz, 1 H), 1.90 (m, 82.2, 76.9, 72.4, 68.3, 57.2, 55.2, 41.2, 37.8, 37.1, 17.8, 13.1 ppm.
1 H), 1.74 (s, 3 H), 1.05 (s, 9 H), 0.93 (d, J = 6.8 Hz, 3 H) ppm.
HRMS (ESI): calcd. for C17H30O5Na [M + Na]+ 337.1985; found
337.1985.
(S)-[(R,Z)-1-{(2S,3S,5R)-5-[(S)-1-(tert-Butyldiphenylsilyloxy)-
propan-2-yl]-3-methoxytetrahydrofuran-2-yl}-2-methylhexa-1,5- Methyl (R)-2-{(2R,4S,5S)-4-Methoxy-5-[(R,Z)-3-(methoxymeth-
1
dien-3-yl] 3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate (23b): H
oxy)-2-methylhexa-1,5-dien-1-yl]tetrahydrofuran-2-yl}propanoate
Eur. J. Org. Chem. 2015, 5266–5274
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5271

D. K. Mohapatra, D. S. Reddy, G. S. Reddy, J. S. Yadav
FULL PAPER
(26): Bis(acetoxy)iodobenzene (0.309 g, 0.96 mmol) and TEMPO
1.62 (m, 2 H), 1.03 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR (125 MHz,
(7 mg, 0.046 mmol) were added sequentially to a stirred solution of CDCl3): δ = 205.2, 174.9, 137.4, 134.5, 126.2, 117.1, 93.2, 83.1,
alcohol 25 (0.146 g, 0.46 mmol) in CH3CN (9 mL) and water
(1 mL) at 0 °C, and the resultant mixture was warmed to room
temperature. Upon completion (monitored by TLC), the reaction
was quenched with saturated aqueous Na2S2O3 (20 mL) and then
diluted with ethyl acetate (30 mL). The organic layer was separated,
and the aqueous layer was extracted with ethyl acetate (2ϫ 30 mL).
The combined organic phases were washed with saturated aqueous
NaHCO3 (50 mL) and brine (50 mL), dried with anhydrous
Na2SO4, and concentrated under reduced pressure. The crude resi-
due was purified by silica gel column chromatography (ethyl acet-
ate/hexanes, 1:1) to furnish the pure acid (136 mg, 87% yield) as a
colorless liquid, which was immediately used in the next step. To a
stirred solution of the acid (0.1 g, 0.3 mmol) in diethyl ether
(10 mL) at 0 °C was added a freshly prepared diazomethane solu-
tion in diethyl ether (5 mL), and the resultant mixture was stirred
at the same temperature for 10 min. Upon completion (monitored
by TLC), the reaction mixture was quenched with a saturated solu-
tion of Na2S2O3 (10 mL) at 0 °C and then stirred at room tempera-
ture for 1 h to evaporate the excess amount of diazomethane. The
organic layer was separated, and the aqueous layer was extracted
with diethyl ether (2ϫ 10 mL). The combined organic layers were
washed with brine (2ϫ 20 mL), dried with anhydrous Na2SO4, and
concentrated under reduced pressure to give the crude residue,
which was purified by silica gel column chromatography (ethyl
acetate/hexane, 1:19) to give methyl ester 26 (105 mg, 97%) as a
79.9, 72.2, 57.3, 55.4, 52.3, 52.2, 42.5, 41.5, 37.9, 36.4, 20.7, 17.8,
12.4 ppm. HRMS (ESI): calcd. for C20H35O8NaP [M + Na]+
457.1962; found 457.1956.
(2R,3S)-3-(Benzyloxy)butane-1,2-diol (28): To a suspension of NaH
(60% in mineral oil, 8.6 g, 20.16 mmol) in dry THF (40 mL) was
added alcohol 27 (2.5 g, 13.44 mmol) in THF (20 mL) at 0 °C, and
the suspension was stirred at room temperature for 1 h. To the
stirred solution was added benzyl bromide (2.3 mL, 20.16 mmol)
followed by TBAI (0.4 g, 1.3 mmol) slowly at 0 °C. The reaction
mixture was stirred at room temperature for an additional 4 h and
then quenched with water (50 mL) at 0 °C. The resultant mixture
was extracted with ethyl acetate (3ϫ 70 mL). The combined or-
ganic layers were washed with brine solution (100 mL) and dried
with anhydrous Na2SO4, and the solvent was then removed under
reduced pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane, 1:19) to give 2-[1-(benz-
yloxy)ethyl]-1,4-dioxaspiro[4.5]decane (3.4 g, 94%) as a pale yellow
liquid, which was immediately used for the next step. To a stirred
solution of the compound (3.0 g, 10.8 mmol) in MeOH (30 mL)
was added camphorsulfonic acid (252 mg, 1.08 mmol) at 0 °C, and
the resulting solution was stirred at ambient temperature for 5 h.
Upon completion (monitored by TLC), the reaction was quenched
with an aqueous NaHCO3 solution (30 mL), and the MeOH was
removed under reduced pressure. The residue was extracted with
ethyl acetate (3ϫ 50 mL), and the combined organic layers were
washed with brine (75 mL) and dried with anhydrous Na2SO4. The
solvent was removed under reduced pressure, and purification of
the crude product by silica gel column chromatography (ethyl acet-
ate/hexane, 1:4) furnished alcohol 28 (1.9 g, 87%) as a colorless
light yellow liquid; [α]2D5 = +27.4 (c = 0.4, CHCl ). IR (neat): ν
˜
3
max
= 2921, 2851, 1725, 169, 1514, 1219 cm–1. 1H NMR (500 MHz,
CDCl3): δ = 5.83 (m, 1 H), 5.68 (d, J = 8.1 Hz, 1 H), 5.15–5.03 (m,
2 H), 4.65 (dd, J = 8.2, 3.4 Hz, 1 H), 4.58–4.49 (m, 2 H), 4.46 (d,
J = 6.7 Hz, 1 H), 4.34 (q, J = 7.6 Hz, 1 H), 3.84 (m, 1 H), 3.68 (s,
3 H), 3.35 (s, 3 H), 3.23 (s, 3 H), 2.61 (m, 1 H), 2.54 (m, 1 H), 2.29
(m, 1 H), 2.21 (dd, J = 13.2, 4.5 Hz, 1 H), 1.78–1.69 (m, 4 H), 1.12
(d, J = 7.0 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 174.8,
139.1, 134.9, 125.3, 116.7, 93.1, 82.6, 78.4, 76.8, 72.8, 57.1, 55.3,
51.6, 45.0, 38.0, 34.7, 17.9, 12.8 ppm. HRMS (ESI): calcd. for
C18H30O6Na [M + Na]+ 365.1940; found 365.1966.
liquid; [α]2D5 = +37.8 (c = 2.0, CHCl ). IR (neat): νmax = 3239, 3110,
˜
3
2979, 1694, 1643, 1530, 1318, 1219 cm–1 1H NMR (500 MHz,
.
CDCl3): δ = 7.37–7.24 (m, 5 H), 4.62 (d, J = 11.6 Hz, 1 H), 4.46
(d, J = 11.6 Hz, 1 H), 3.72–3.61 (m, 4 H), 1.21 (d, J = 6.3 Hz, 3
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 138.0, 128.4, 127.7,
127.7, 76.6, 73.9, 71.1, 63.2, 15.3 ppm. HRMS (ESI): calcd. for
C11H16O3Na [M + Na]+ 219.0997; found 219.1010.
Dimethyl [(R)-3-{(2R,4S,5S)-4-Methoxy-5-[(R,Z)-3-(methoxymeth-
oxy)-2-methylhexa-1,5-dien-1-yl]tetrahydrofuran-2-yl}-2-oxobutyl]-
phosphonate (8): To a stirred solution of dimethyl methyl phos-
phonate (163 mg, 1.3 mmol) in THF (5 mL) was slowly added
nBuLi (2.5 m in hexane, 0.4 mL, 1 mmol) at –78 °C under nitrogen,
and the resultant mixture was slowly warmed to 0 °C. After 1 h, the
reaction mixture was again cooled to –78 °C, and ester 26 (75 mg,
0.22 mmol) in THF (10 mL) was slowly added. The reaction mix-
ture was then stirred at the same temperature for 1 h. Upon com-
plete consumption of the starting material (monitored by TLC),
the reaction was quenched with saturated NH4Cl (10 mL), and the
mixture was extracted with ethyl acetate (3ϫ 10 mL). The com-
bined organic layers were washed with brine (20 mL), dried with
Na2SO4, and concentrated under reduced pressure to obtain the
crude residue, which was purified by silica gel column chromatog-
raphy (ethyl acetate/hexane, 1:1) to afford the desired keto phos-
phonate 8 (87 mg, 92%) as a colorless liquid; [α]2D5 = –65.4 (c = 0.5,
(2R,3S)-3-(Benzyloxy)-1-[(tert-butyldimethylsilyl)oxy]butan-2-ol
(29): To a stirred solution of alcohol 28 (1.0 g, 5.1 mmol) in CH2Cl2
(30 mL) were added imidazole (0.52, 7.6 mmol) and TBSCl
(0.844 g, 5.6 mmol) at 0 °C, and the reaction mixture was stirred at
the same temperature for 30 min. Upon completion (monitored by
TLC), the reaction was quenched with water (25 mL), and the or-
ganic layer was separated. The aqueous layer was extracted with
CH2Cl2 (3ϫ 30 mL). The combined organic layers were dried with
anhydrous Na2SO4 and concentrated under reduced pressure. The
crude residue was purified by silica gel column chromatography
(ethyl acetate/hexane, 2:5) to afford TBS-protected compound 29
(1.39 g, 91%) as a colorless liquid; [α]2D5 = +11.7 (c = 2.3, CHCl3).
1
IR (neat): ν
= 3388, 3029, 2928, 1599, 1540, 1241 cm–1. H
˜
max
NMR (300 MHz, CDCl3): δ = 7.40–7.23 (m, 5 H), 4.63 (d, J =
11.7 Hz, 1 H), 4.48 (d, J = 11.7 Hz, 1 H), 3.79–3.48 (m, 4 H), 1.27
(d, J = 6.1 Hz, 3 H), 0.9 (s, 9 H), 0.08 (s, 6 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 138.5, 128.3, 127.6, 127.5, 81.9, 75.2, 74.1,
70.9, 63.7, 25.8, 18.2, 15.4, –5.4 ppm. HRMS (ESI): calcd. for
C17H30O3Si [M + H]+ 311.2042; found 311.2054.
CHCl ). IR (neat): νmax = 3019, 2922, 2852, 1551, 1449, 1214 cm–1.
˜
3
1H NMR (700 MHz, CDCl3): δ = 5.74 (m, 1 H), 5.57 (d, J =
8.8 Hz, 1 H), 5.13 (d, J = 17.2 Hz, 1 H), 5. 05 (d, J = 9.9 Hz, 1 H),
4.73 (dd, J = 8.8, 3.5 Hz, 1 H), 4.60 (d, J = 6.7 Hz, 1 H), 4.47 (t,
J = 7.2 Hz, 1 H), 4.44 (d, J = 6.7 Hz, 1 H), 4.16 (m, 1 H), 3.77 (d,
J = 2.0 Hz, 3 H), 3.76 (d, J = 2.1 Hz, 3 H), 3.70 (t, J = 3.9 Hz, 1
H), 3.51 (m, 1 H), 3.36 (s, 3 H), 3.30 (s, 3 H), 3.12 (m, 1 H), 2.96
[(2R,3S)-3-(Benzyloxy)-2-methoxybutoxy](tert-butyl)dimethyl-
silane (30): To a suspension of NaH (60% in mineral oil, 0.252 g,
6.2 mmol) in dry THF (10 mL) was added alcohol 29 (1.3 g,
4.18 mmol) in THF (5 mL) at 0 °C, and the suspension was stirred
(m, 1 H), 2.48 (m, 1 H), 2.29–2.23 (m, 2 H), 1.72 (s, 3 H), 1.69– at room temperature for 1 h. Methyl iodide (0.38 mL, 6.2 mmol)
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Synthesis of the C-8–C-24 Fragment of Maltepolide C
was then added slowly at 0 °C. The resultant mixture was stirred
at room temperature for an additional 4 h and then quenched with
water (20 mL) at 0 °C. The mixture was extracted with ethyl acetate
(2ϫ 20 mL), and the combined organic layers were washed with
brine solution (50 mL), dried with anhydrous Na2SO4, and concen-
trated under reduced pressure. The residue was purified by silica
gel column chromatography (ethyl acetate/hexane, 1:19) to give 30
(1.3 g, 95%) as a pale yellow liquid; [α]2D5 = +5.8 (c = 0.9, CHCl3).
chromatography (ethyl acetate/hexane, 1:19) to afford 32 (62 mg,
95%) as a colorless oil; [α]2D5 = +18.4 (c = 1.9, CHCl3). IR (neat):
ν
˜
= 2922, 2852, 1712, 1516, 1464, 1378, 1215 cm–1. 1H NMR
max
(500 MHz, CDCl3): δ = 7.36–7.25 (m, 5 H), 6.78 (dt, J = 15.9,
5.6 Hz, 1 H), 6.41 (d, J = 15.9 Hz, 1 H), 5.84–5.70 (m, 1 H), 5.56
(d, J = 8.6 Hz, 1 H), 5.20–4.98 (m, 2 H), 4.69 (dt, J = 12.1, 6.0 Hz,
1 H), 4.65–4.54 (m, 3 H), 4.47–4.39 (m, 3 H), 3.83 (t, J = 5.5 Hz,
1 H), 3.71 (d, J = 3.8 Hz, 1 H), 3.69–3.62 (m, 1 H), 3.38–3.32 (m,
6 H), 3.29 (s, 3 H), 3.09–2.95 (m, 1 H), 2.53–2.40 (m, 1 H), 2.33–
2.21 (m, 1 H), 2.15 (dt, J = 34.2, 17.2 Hz, 1 H), 1.79–1.64 (m, 6
H), 1.14 (t, J = 6.9 Hz, 3 H), 1.06 (d, J = 6.9 Hz, 3 H) ppm. 13C
IR (neat): ν
= 3030, 2986, 1724, 1549, 1215 cm–1. 1H NMR
˜
max
(500 MHz, CDCl3): δ = 7.38–7.25 (m, 5 H), 4.61 (d, J = 11.9 Hz,
1 H), 4.52 (d, J = 4.9 Hz, 1 H), 3.70 (d, J = 5.2 Hz, 2 H), 3.68–
3.62 (m, 1 H), 3.51–3.47 (m, 3 H), 3.29 (dd, J = 9.8, 5.2 Hz, 1 H), NMR (125 MHz, CDCl3): δ = 200.3, 141.9, 137.5, 135.9, 133.7,
1.21 (d, J = 6.9 Hz, 3 H), 0.89 (s, 9 H), 0.06 (s, 3 H), 0.05 129.4, 127.3, 126.6, 126.5, 125.7, 115.9, 92.5, 82.7, 82.5, 77.2, 76.6,
(0.05) ppm. 13C NMR (125 MHz, CDCl3): δ = 138.8, 128.3, 127.6, 75.1, 71.6, 70.6, 56.8, 56.3, 54.4, 48.1, 47.9, 37.0, 33.7, 16.9, 14.7,
127.4, 84.6, 74.6, 70.0, 62.4, 59.0, 25.9, 18.2, 15.2, –5.4, –5.4 ppm.
HRMS (ESI): calcd. for C18H32O3Si [M + H]+ 325.2198; found
325.2211.
10.8 ppm. HRMS (ESI): calcd. for C30H44O7Na [M + 23]+
539.2976; found 539.2976.
(2S,3R,6R,7S,E)-7-(Benzyloxy)-6-methoxy-2-{(2R,4S,5S)-4-meth-
oxy-5-[(R,Z)-3-(methoxymethoxy)-2-methylhexa-1,5-dien-1-yl]-
tetrahydrofuran-2-yl}oct-4-en-3-ol (7): To a 10 mL round-bottomed
flask charged with a magnetic stir bar was added the (R)-CBS cata-
lyst (49 mg, 0.18 mmol) in THF (3 mL) under argon. The reaction
mixture was cooled to –40 °C, and BH3·Me2S (2 m in THF,
0.18 mL, 0.36 mmol) was added. To this was added dropwise a
solution of ketone 32 (45 mg, 0.09 mmol) dissolved in THF (2 mL),
and the resultant mixture was stirred at –40 °C for 8 h. Upon com-
pletion (monitored by TLC), the reaction was quenched with
MeOH (1 mL) and diluted with saturated aqueous NH4Cl (5 mL).
The mixture was extracted with ethyl acetate (3ϫ 10 mL), and the
combined organic extracts were washed with brine (2ϫ 15 mL),
dried with anhydrous Na2SO4, and concentrated under reduced
pressure. The crude oil was purified by silica gel column
chromatography (ethyl acetate/hexane, 1:6) to furnish the desired
alcohol 7 (40 mg, 89%) as a colorless liquid; [α]2D5 = –48.1 (c = 1.2,
(2R,3S)-3-(Benzyloxy)-2-methoxybutan-1-ol (31): To a stirred solu-
tion of compound 30 (1.0 g, 3.09 mmol) in MeOH (25 mL) was
added camphorsulfonic acid (71 mg, 0.31 mmol) at 0 °C, and the
resulting mixture was stirred at ambient temperature for 0.5 h.
Upon completion (monitored by TLC), the reaction was quenched
with aqueous NaHCO3 (20 mL), and the MeOH was removed un-
der reduced pressure. The residue was extracted with ethyl acetate
(3ϫ 30 mL), and the combined organic layers were washed with
brine (75 mL) and dried with anhydrous Na2SO4. The solvent was
removed under reduced pressure, and purification of the crude
product by silica gel column chromatography (ethyl acetate/hexane,
1:5) furnished alcohol 31 (0.582 g, 90 %) as a colorless liquid;
[α]2D5 = +15.2 (c = 0.5, CHCl ). IR (neat): νmax = 3493, 3031, 2985,
˜
3
2857, 1620, 1458, 1377, 1213 cm–1. 1H NMR (500 MHz, CDCl3):
δ = 7.36–7.32 (m, 4 H), 7.32–7.26 (m, 1 H), 4.63 (d, J = 11.6 Hz,
1 H), 4.52 (d, J = 11.7 Hz, 1 H), 3.75 (t, J = 4.2 Hz, 2 H), 3.68 (m,
1 H), 3.46 (s, 3 H), 3.18 (m, 1 H), 1.26 (d, J = 6.3 Hz, 3 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 138.3, 128.4, 127.6, 84.2, 75.2,
71.2, 70.7, 61.2, 58.2, 16.4 ppm. HRMS (ESI): calcd. for
C10H18O3Na [M + Na]+ 233.1153; found 233.1160.
CHCl ). IR (neat): νmax = 3408, 3030, 2986, 2865, 1724, 1549, 1375,
˜
3
1215 cm–1. H NMR (500 MHz, CDCl3): δ = 7.37–7.30 (m, 5 H),
1
5.81–5.56 (m, 4 H), 5.16–5.03 (m, 2 H), 4.77 (m, 1 H), 4.62 (s, 2
H), 4.57 (d, J = 6.7 Hz, 1 H), 4.49–4.42 (m, 2 H), 4.13–4.04 (m, 2
H), 3.69 (t, J = 3.9 Hz, 1 H), 3.64 (m, 1 H), 3.58 (m, 1 H), 3.35 (s,
3 H), 3.33 (s, 3 H), 3.31 (s, 3 H), 2.47 (m, 1 H), 2.37–2.22 (m, 2
H), 1.74 (s, 3 H), 1.73–1.60 (m, 2 H), 1.15 (d, J = 6.2 Hz, 3 H),
0.74 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
138.9, 137.4, 134.8, 134.5, 129.1, 128.2, 127.6, 127.3, 126.0, 117.1,
93.5, 85.0, 82.8, 77.6, 77.1, 76.8, 72.5, 71.6, 57.3, 56.9, 55.5, 55.4,
44.4, 31.9, 22.6, 18.1, 16.5, 14.1, 13.0 ppm. HRMS (ESI): calcd. for
C28H40O4NaSi [M + Na]+ 541.3136; found 541.3138.
(2R,6R,7S,E)-7-(Benzyloxy)-6-methoxy-2-{(2R,4S,5S)-4-methoxy-
5-[(R,Z)-3-(methoxymethoxy)-2-methylhexa-1,5-dien-1-yl]tetra-
hydrofuran-2-yl}oct-4-en-3-one (32): To a solution of primary
alcohol 31 (0.1 g, 0.48 mmol) in CH2Cl2 (30 mL) was added Dess–
Martin periodinane (0.3 g, 0.72 mmol) at 0 °C. The resulting mix-
ture was stirred at room temperature for 3 h. Upon completion
(monitored by TLC), the reaction mixture was filtered through a
small bed of Celite, and the filtrate was washed with saturated
NaHCO3 (2 ϫ 20 mL). The combined aqueous layers were ex-
tracted with CH2Cl2 (2ϫ 20 mL), and the combined organic layers
were dried with anhydrous Na2SO4 and concentrated under re-
duced pressure. Purification of the crude product by silica gel col-
umn chromatography (ethyl acetate/hexane, 1:12) afforded the cor-
responding aldehyde 9 (0.87 g, 89%) as a pale yellow liquid, which
was immediately used in next step. To a stirred solution of keto
phosphonate 8 (0.05 g, 0.12 mmol) in THF (10 mL) was added an-
hydrous Ba(OH)2 (30 mg, 0.18 mmol) at 0 °C under nitrogen. The
light yellow suspension was stirred at the same temperature for
30 min. A solution of aldehyde 9 (25 mg, 0.12 mmol) in wet THF
(THF/H2O, 40:1; 41 mL) was then added at 0 °C, and the reaction
mixture was stirred at room temperature for 12 h. Upon comple-
tion (monitored by TLC), the reaction was quenched with a satu-
rated NH4Cl solution (10 mL). The mixture was extracted with
ethyl acetate (3ϫ 20 mL), and the combined organic layers were
dried with anhydrous Na2SO4 and concentrated under reduced
pressure. The crude residue was purified by silica gel column
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra for all new compounds.
Acknowledgments
The authors thank the Council of Scientific and Industrial Re-
search (CSIR), New Delhi for financial support as part of the XII
Five Year plan programme under title ORIGIN (CSC-0108).
D. S. R. and S. R. G. thank the CSIR and the University Grants
Commission (UGC), New Delhi for financial assistance in the form
of fellowships.
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Received: May 14, 2015
Published Online: July 2, 2015
5274
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 5266–5274